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How to Write a Research Paper | A Beginner's Guide

A research paper is a piece of academic writing that provides analysis, interpretation, and argument based on in-depth independent research.

Research papers are similar to academic essays , but they are usually longer and more detailed assignments, designed to assess not only your writing skills but also your skills in scholarly research. Writing a research paper requires you to demonstrate a strong knowledge of your topic, engage with a variety of sources, and make an original contribution to the debate.

This step-by-step guide takes you through the entire writing process, from understanding your assignment to proofreading your final draft.

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Table of contents

Understand the assignment, choose a research paper topic, conduct preliminary research, develop a thesis statement, create a research paper outline, write a first draft of the research paper, write the introduction, write a compelling body of text, write the conclusion, the second draft, the revision process, research paper checklist, free lecture slides.

Completing a research paper successfully means accomplishing the specific tasks set out for you. Before you start, make sure you thoroughly understanding the assignment task sheet:

• Read it carefully, looking for anything confusing you might need to clarify with your professor.
• Identify the assignment goal, deadline, length specifications, formatting, and submission method.
• Make a bulleted list of the key points, then go back and cross completed items off as you’re writing.

Carefully consider your timeframe and word limit: be realistic, and plan enough time to research, write, and edit.

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There are many ways to generate an idea for a research paper, from brainstorming with pen and paper to talking it through with a fellow student or professor.

You can try free writing, which involves taking a broad topic and writing continuously for two or three minutes to identify absolutely anything relevant that could be interesting.

You can also gain inspiration from other research. The discussion or recommendations sections of research papers often include ideas for other specific topics that require further examination.

Once you have a broad subject area, narrow it down to choose a topic that interests you, m eets the criteria of your assignment, and i s possible to research. Aim for ideas that are both original and specific:

• A paper following the chronology of World War II would not be original or specific enough.
• A paper on the experience of Danish citizens living close to the German border during World War II would be specific and could be original enough.

Note any discussions that seem important to the topic, and try to find an issue that you can focus your paper around. Use a variety of sources , including journals, books, and reliable websites, to ensure you do not miss anything glaring.

Do not only verify the ideas you have in mind, but look for sources that contradict your point of view.

• Is there anything people seem to overlook in the sources you research?
• Are there any heated debates you can address?
• Do you have a unique take on your topic?
• Have there been some recent developments that build on the extant research?

In this stage, you might find it helpful to formulate some research questions to help guide you. To write research questions, try to finish the following sentence: “I want to know how/what/why…”

A thesis statement is a statement of your central argument — it establishes the purpose and position of your paper. If you started with a research question, the thesis statement should answer it. It should also show what evidence and reasoning you’ll use to support that answer.

The thesis statement should be concise, contentious, and coherent. That means it should briefly summarize your argument in a sentence or two, make a claim that requires further evidence or analysis, and make a coherent point that relates to every part of the paper.

You will probably revise and refine the thesis statement as you do more research, but it can serve as a guide throughout the writing process. Every paragraph should aim to support and develop this central claim.

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A research paper outline is essentially a list of the key topics, arguments, and evidence you want to include, divided into sections with headings so that you know roughly what the paper will look like before you start writing.

A structure outline can help make the writing process much more efficient, so it’s worth dedicating some time to create one.

Your first draft won’t be perfect — you can polish later on. Your priorities at this stage are as follows:

• Maintaining forward momentum — write now, perfect later.
• Paying attention to clear organization and logical ordering of paragraphs and sentences, which will help when you come to the second draft.
• Expressing your ideas as clearly as possible, so you know what you were trying to say when you come back to the text.

You do not need to start by writing the introduction. Begin where it feels most natural for you — some prefer to finish the most difficult sections first, while others choose to start with the easiest part. If you created an outline, use it as a map while you work.

Do not delete large sections of text. If you begin to dislike something you have written or find it doesn’t quite fit, move it to a different document, but don’t lose it completely — you never know if it might come in useful later.

Paragraph structure

Paragraphs are the basic building blocks of research papers. Each one should focus on a single claim or idea that helps to establish the overall argument or purpose of the paper.

Example paragraph

George Orwell’s 1946 essay “Politics and the English Language” has had an enduring impact on thought about the relationship between politics and language. This impact is particularly obvious in light of the various critical review articles that have recently referenced the essay. For example, consider Mark Falcoff’s 2009 article in The National Review Online, “The Perversion of Language; or, Orwell Revisited,” in which he analyzes several common words (“activist,” “civil-rights leader,” “diversity,” and more). Falcoff’s close analysis of the ambiguity built into political language intentionally mirrors Orwell’s own point-by-point analysis of the political language of his day. Even 63 years after its publication, Orwell’s essay is emulated by contemporary thinkers.

Citing sources

It’s also important to keep track of citations at this stage to avoid accidental plagiarism . Each time you use a source, make sure to take note of where the information came from.

You can use our free citation generators to automatically create citations and save your reference list as you go.

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The research paper introduction should address three questions: What, why, and how? After finishing the introduction, the reader should know what the paper is about, why it is worth reading, and how you’ll build your arguments.

What? Be specific about the topic of the paper, introduce the background, and define key terms or concepts.

Why? This is the most important, but also the most difficult, part of the introduction. Try to provide brief answers to the following questions: What new material or insight are you offering? What important issues does your essay help define or answer?

How? To let the reader know what to expect from the rest of the paper, the introduction should include a “map” of what will be discussed, briefly presenting the key elements of the paper in chronological order.

The major struggle faced by most writers is how to organize the information presented in the paper, which is one reason an outline is so useful. However, remember that the outline is only a guide and, when writing, you can be flexible with the order in which the information and arguments are presented.

One way to stay on track is to use your thesis statement and topic sentences . Check:

• topic sentences against the thesis statement;
• topic sentences against each other, for similarities and logical ordering;
• and each sentence against the topic sentence of that paragraph.

Be aware of paragraphs that seem to cover the same things. If two paragraphs discuss something similar, they must approach that topic in different ways. Aim to create smooth transitions between sentences, paragraphs, and sections.

The research paper conclusion is designed to help your reader out of the paper’s argument, giving them a sense of finality.

Trace the course of the paper, emphasizing how it all comes together to prove your thesis statement. Give the paper a sense of finality by making sure the reader understands how you’ve settled the issues raised in the introduction.

You might also discuss the more general consequences of the argument, outline what the paper offers to future students of the topic, and suggest any questions the paper’s argument raises but cannot or does not try to answer.

You should not :

• Offer new arguments or essential information
• Take up any more space than necessary
• Begin with stock phrases that signal you are ending the paper (e.g. “In conclusion”)

There are four main considerations when it comes to the second draft.

• Check how your vision of the paper lines up with the first draft and, more importantly, that your paper still answers the assignment.
• Identify any assumptions that might require (more substantial) justification, keeping your reader’s perspective foremost in mind. Remove these points if you cannot substantiate them further.
• Be open to rearranging your ideas. Check whether any sections feel out of place and whether your ideas could be better organized.
• If you find that old ideas do not fit as well as you anticipated, you should cut them out or condense them. You might also find that new and well-suited ideas occurred to you during the writing of the first draft — now is the time to make them part of the paper.

The goal during the revision and proofreading process is to ensure you have completed all the necessary tasks and that the paper is as well-articulated as possible. You can speed up the proofreading process by using the AI proofreader .

Global concerns

• Confirm that your paper completes every task specified in your assignment sheet.
• Check for logical organization and flow of paragraphs.
• Check paragraphs against the introduction and thesis statement.

Fine-grained details

Check the content of each paragraph, making sure that:

• each sentence helps support the topic sentence.
• no unnecessary or irrelevant information is present.
• all technical terms your audience might not know are identified.

Next, think about sentence structure , grammatical errors, and formatting . Check that you have correctly used transition words and phrases to show the connections between your ideas. Look for typos, cut unnecessary words, and check for consistency in aspects such as heading formatting and spellings .

Finally, you need to make sure your paper is correctly formatted according to the rules of the citation style you are using. For example, you might need to include an MLA heading  or create an APA title page .

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Checklist: Research paper

I have followed all instructions in the assignment sheet.

My introduction presents my topic in an engaging way and provides necessary background information.

My introduction presents a clear, focused research problem and/or thesis statement .

My paper is logically organized using paragraphs and (if relevant) section headings .

Each paragraph is clearly focused on one central idea, expressed in a clear topic sentence .

Each paragraph is relevant to my research problem or thesis statement.

I have used appropriate transitions  to clarify the connections between sections, paragraphs, and sentences.

My conclusion provides a concise answer to the research question or emphasizes how the thesis has been supported.

My conclusion shows how my research has contributed to knowledge or understanding of my topic.

My conclusion does not present any new points or information essential to my argument.

I have provided an in-text citation every time I refer to ideas or information from a source.

I have included a reference list at the end of my paper, consistently formatted according to a specific citation style .

I have thoroughly revised my paper and addressed any feedback from my professor or supervisor.

I have followed all formatting guidelines (page numbers, headers, spacing, etc.).

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Comprehensive Review of Uterine Fibroids: Developmental Origin, Pathogenesis, and Treatment

Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA

Michal Ciebiera

Second Department of Obstetrics and Gynecology, Center of Postgraduate Medical Education, ul. Cegłowska 80, 01-809, Warsaw, Poland

Maria Victoria Bariani

Mohamed ali.

Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt

Hoda Elkafas

Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, USA

Department of Pharmacology and Toxicology, Egyptian Drug Authority, formerly National Organization for Drug Control and Research, Cairo 35521, Egypt

Thomas G Boyer

Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA

Ayman Al-Hendy

Associated data.

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing the most common tumors in women worldwide. To date, no long-term or noninvasive treatment option exists for hormone-dependent uterine fibroids, due to the limited knowledge about the molecular mechanisms underlying the initiation and development of uterine fibroids. This paper comprehensively summarizes the recent research advances on uterine fibroids, focusing on risk factors, development origin, pathogenetic mechanisms, and treatment options. Additionally, we describe the current treatment interventions for uterine fibroids. Finally, future perspectives on uterine fibroids studies are summarized. Deeper mechanistic insights into tumor etiology and the complexity of uterine fibroids can contribute to the progress of newer targeted therapies.

Graphical Abstract

ESSENTIAL POINTS

• Developmental exposure to EDCs in early life reprograms myometrial stem cells, thus increasing the risk of uterine fibroids development.
• Several risk factors such as age, race, obesity, parity, hypertension, vitamin D deficiency, and diet in late life can trigger uterine fibroids pathogenesis.
• Pathogenic exon 2 mutations in MED12 promote uterine fibroids formation and disrupt CDK8/19 kinase activity.
• Several vital pathways and mechanisms such as sex hormones, ECM, Wnt/β-catenin, TGF-β, growth factors, epigenetic and epitranscriptomic regulation, YAP/TAZ, Rho/ROCK, and DNA damage repair pathways contribute to the development of uterine fibroids.
• Fertility therapy is highly needed for the treatment of patients with uterine fibroids.

Uterine fibroid lesions were initially known as the “uterine stone.” In the second century AD, they were called scleromas. The term fibroid was first introduced in the 1860s. Uterine fibroids are the most common pelvic tumors among women of reproductive age, affecting more than 70% of women worldwide, particularly women of color ( 1-3 ). Uterine fibroids are heterogeneous in composition and size among women and within the same individual, and vary in number between individuals ( 4-14 ). In addition, the fibroid pseudocapsule presents as a fibro-neurovascular structure surrounding a uterine fibroid, separating it from normal peripheral myometrium ( 15-18 ). Although benign, uterine fibroids are associated with significant morbidity; they are the primary indication for hysterectomy, and a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor ( 19 , 20 ). Accordingly, the annual USA health care costs associated with uterine fibroids have been estimated at ~$34 billion ( 21 ). Uterine fibroids thus represent significant societal health and financial burden.

Epidemiology, Risk/Protective Factors, Driver Mutations, and Tumor-Initiating Stem Cells

Risk factors and epidemiology.

The prevalence of uterine fibroids is increasing in some populations, such as in African American women ( 22 ). However, its reported incidence is likely to be an underestimation, as many tumors are asymptomatic or slightly symptomatic and therefore remain undiagnosed ( 1 ). In addition, approximately only 25% to 30% of women report the clinical symptoms of uterine fibroids ( 5 ).

The most important and frequently reported risk factor for uterine fibroids is race, disproportionately impacting African American women ( Figs. 1 and ​ and2). 2 ). Other risk factors include older age, premenopausal state, nonparity, family history of uterine fibroids, hypertension, food additives, and frequent consumption of soybean milk. On the other hand, protective factors for uterine fibroids include combined oral contraception or injectable medroxyprogesterone acetate in the depot form, smoking in women of low mass, and parity ( 1 ). Other important risk factors include obesity ( 23-25 ), vitamin D deficiency ( 26-28 ), excessive vitamin E levels ( 29 ), altered reproductive tract microbiome ( 30 ), exposure to endocrine-disrupting chemicals (eg, organophosphate esters and plasticizers) ( 31 , 32 ), and various early-life adverse environmental exposures ( 33 ). Individual and environmental risk factors associated with tobacco smoking and alcohol abuse can also contribute to the formation of uterine fibroids ( 34 , 35 ). More risk factors are associated with a higher probability of uterine fibroid formation and development ( 1 , 23 ).

Developmental origin of fibroids from myometrial stem cells. Intrauterine and early-life adverse environmental exposure to endocrine-disrupting chemicals may act as the early hit to induce normal myometrial stem cells’ reprogramming by hijacking epigenomic plasticity. The plasticity of the developing epigenome is susceptible to epigenomic changes in myometrial stem cells following later-life adverse exposures, thereby leading to mutations and their transformation into tumor-initiating stem cells. The development and growth of fibroids are mainly characterized by abnormal cell proliferation, inhibited apoptosis, DNA instability, excessive deposition of ECM, and other critical biological pathways. Abbreviations: ECM, extracellular matrix; MED12, RNA polymerase II transcriptional mediator complex subunit 12; ncRNAs, non-coding RNA.

Risk factors for uterine fibroids that mainly affect inflammation, DNA damage pathways, and genetic instability. External and internal factors, such as EDC exposure, hyper-responsiveness to sex steroid hormones, obesity, vitamin D deficiency, and altered reproductive tract microbiome, contribute to chronic systemic inflammation. The inflammatory environment, EDC exposure, and vitamin D deficiency promote DNA damage and the accumulation of mutations. Consequently, these genetic events may activate the pathways involved in cell proliferation, the inhibition of apoptosis, and ECM remodeling, ultimately leading to the development and growth of fibroids. Abbreviations: E2, estrogen; EDCs, endocrine-disrupting chemicals; MED12 , RNA polymerase II transcriptional mediator complex subunit 12; P4, progesterone.

These points require some additional comments. Epidemiologists understand that they must study women from the community to eliminate bias and have a prospective study design with a large sample size and low loss to follow-up to enable the measurement of age-specific incidence and other risk factor-related pathogenesis of uterine fibroids ( 36 ). Improvement of awareness and education for uterine fibroids in the community will help to better understand the risk factors of this diseases. Notably, data from uterine fibroid research in underrepresented groups are lacking ( 37 ). On the other hand, epidemiological studies may reflect both the natural and false effects of a selected factor on the investigated outcome. Findings may be subject to different explanations because they may occur due to random errors, biases, or confounding, which may produce false results. These factors need to be considered at both the design and analysis stage of a study to minimize them. Notably, the same instruments for health outcomes evaluation in exposed and unexposed groups should be applied to avoid misclassification or bias. Studies without including confounding variables from the onset or without matching by age, race, and other factors should always be treated with caution ( 38 ).

Increasing age is a significant risk factor for uterine fibroids, especially among women at the premenopausal stage and those ≥ 40 years of age ( 24 , 39 , 40 ). For instance, 60% of African American women aged 35–49 years reported uterine fibroids, whereas 80% of those aged ≥ 50 have uterine fibroids. Among White women, 40% of those aged ≤ 35 years and 70% aged ≥ 50 years developed uterine fibroids ( 3 ). These tumors have not been detected in prepubertal girls, and only sporadic cases have been reported in adolescents. However, the factor(s) involved in their development at such an early age is unknown. Due to the slight difference in biochemical pathways, uterine fibroids in young women do not exhibit typical uterine fibroid biology. In several cases, adolescent patients had a translocation between chromosomes 12 and 14, which is a confirmed risk factor for uterine fibroids ( 41 , 42 ). Women at the menopausal stage have shrunk uterine fibroid lesions and decreased sex hormones. Notably, the use of hormonal replacement therapy may cause these lesions to regrow and may induce the first clinical symptoms of uterine fibroids ( 43 ).

Race and ethnicity

Populations of different races/ethnicities vary in the risk of developing uterine fibroids. The United States Census recognized 5 racial categories (White or European; Black or African American; Asian American; American Indian/Alaska Native; and Native Hawaiian/Pacific Islander) as well as people of 2 or more races ( https://www.census.gov/topics/population/race/about.html . Accessed July, 2021). In addition, the Census Bureau also classified Hispanic or Non-Hispanic as ethnicity. Medical records and self-report were used and demonstrated that Black women, the largest racial minority in the United States, are most likely out of any racial category to develop uterine fibroids ( 3 , 5 , 44-46 ). The severity of uterine fibroid–derived symptoms also tended to be greater among African American women ( 47 ). Uterine fibroids are 3 times more common in African American women and 2 times more common in Hispanic women compared with White women.( 3 , 46 ). The more common occurrence of uterine fibroids in African American women may be attributed to higher concentrations of steroid hormones in African American women and may also be due to gene polymorphism, including the catechol-Ο-methyltransferase (COMT) encoding gene ( 48 ). However, the etiology of the increased incidence of uterine fibroids in African American women has not been fully elucidated. Additionally, the relationship between the higher incidence of uterine fibroids and more severe manifestations of disease may be due to vitamin D deficiency in African American women ( 49 , 50 ). African American women are diagnosed with vitamin D deficiency at a rate of 5 to 10 times more than that of White women. It is thought that the limited absorption of ultraviolet (UV) radiation, which is essential for vitamin D metabolism, may be the reasoning for this discovery ( 50 ).

Furthermore, the African American population experiences higher levels of racial discrimination ( 51 , 52 ) and there are multiple ways by which perceived racism can affect health ( 53 ). A positive association between self-reported experiences of racial discrimination and the incidence of uterine fibroids was demonstrated in a large follow-up study of the cohort of the Black Women’s Health Study ( 54 ). In this sense, Vines et al have found an association with the presence of uterine fibroids among the African American women in the high-stress intensity group ( 55 ).

Discrimination is thought to negatively influence physical wellbeing through the stress response ( 56 , 57 ). The hypothesis that stress led to uterine fibroid pathogenesis could be explained by the fact that disturbance of the hypothalamic–pituitary–adrenal axis and the subsequent release of stress biomarkers such as cortisol and epinephrine ( 58 ) have been linked with increased uterine fibroid risk ( 59 ). In addition, stress also may provoke fluctuations in estrogen and progesterone hormone levels ( 60 , 61 ), both important in uterine fibroid development. Furthermore, it is also biologically plausible that the higher uterine fibroid risk observed in African American women is associated with the systemic inflammation provoked by stress-related factors ( Fig. 2 ) ( 62 ). To date, studies on the role of stress in uterine fibroid development among women of various race/ethnic groups are limited. In this sense, more studies that examine perceived racism as a chronic stressor linked to occurrence of uterine fibroids are needed to fully understand these dependencies.

Obesity is directly related to increased energy consumption and reduced physical activity ( 63 ). Currently, obesity is the fifth leading cause of death ( 64 ). Several studies have found obesity as a significant risk factor for uterine fibroids development ( 23 , 65 ), which has been attributed to the metabolic functions of adipose tissues. Adipose tissues produce and release various cytokines and growth factors involved in regulating diverse physiological and pathological processes, including immunity and inflammation ( 66 ). Adrenal androgens are mostly metabolized by aromatase in adipose tissues to estrogens ( 67-69 ). Obesity and particularly excess visceral fat may be complemented with the reduced production of the sex hormone–binding globulin (SHBG), which binds circulating hormones, disrupting the hormonal activity toward sensitive tissues, and thereby influencing the delicate hormonal balance in the body ( 70 ).

Each kilogram of excessive body weight is correlated with an increased risk of uterine fibroids development ( 71 , 72 ). A study conducted in the United States found that women diagnosed with uterine fibroids are heavier than those without uterine fibroids ( 72 ). Moreover, an increase in the body mass index (BMI) by one unit ( 23 ), higher waist-to-hip ratios, and body fat percentage exceeding 30% ( 73 ) increase the risk for uterine fibroids. Abdominal visceral fat also enhances this risk ( 65 ). A recent meta-analysis of 22 studies, including 325 899 participants, and 19 593 cases, found a positive association between obesity and the risk or prevalence of fibroids ( 74 ).

Obesity is most prevalent among African Americans compared with other racial and ethnic populations in the United States, contributing to the higher risk of developing uterine fibroids in the African American population ( 25 ). Uterine fibroids occur more frequently in obese postmenopausal women and those who have undergone hormonal replacement therapy ( 75 ). Furthermore, obese women diagnosed with type 2 diabetes are more likely to develop uterine fibroids ( 75 ), and this observation has been related to elevated concentrations of insulin-like growth factor (IGF-1) ( 76 ). Insulin resistance plays a role in the development of uterine fibroids in obese women.

Main epidemiological studies demonstrated an inverse association between parity and uterine fibroids, suggestive of a protective effect ( 77 ). Nulliparous women are more commonly affected by uterine fibroids than multiparous women ( 44 ). Each subsequent child may lower the risk of this pathology ( 74 ). These study analyses were based on USA data, which need further investigation related to the difference in race and ethnicity in other countries. Steroid hormone exposure during pregnancy and dramatic remodeling of the uterine tissues after each pregnancy may be attributable to a decrease in uterine fibroid formation ( 77 , 78 ).

Hypertension

There is a direct correlation between arterial hypertension and uterine fibroids ( 44 , 79 , 80 ). Increased diastolic blood pressure is associated with a higher risk of uterine fibroids, regardless of use of antihypertensive drugs ( 79 ). Women suffering from hypertension are 5 times more likely to develop uterine fibroids ( 81 ), and earlier diagnosis of hypertension is a significant factor. The formation of lesions is attributed to the chronic destruction of the myometrium due to increased blood flow and cytokines secreted by injured myometrial cells ( 79 ).

Vitamin D deficiency and diet

Vitamin D is a collective term for fat-soluble steroid compounds with pleiotropic solid influence in the human body ( 82 , 83 , 84 ) Vitamin D is synthesized in the human skin from 7-dehydrocholesterol upon exposure to sunlight. Then, it is transported by the vitamin D-binding protein to the liver and kidneys, where it is converted to 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)D] ( 83 ), respectively, and ultimately carried to the target tissues ( 85 ).

Age, race, health, and even clothing affect the rate at which vitamin D is produced in the skin ( 86 ). Endogenous vitamin D production from sun exposure is influenced by climate, namely, reduced and/or inefficient sunlight absorption may cause vitamin D deficiency ( 86 ). The synthesis of vitamin D decreases with age ( 82 , 86 ). Of note, individuals with darker skin pigmentation and complexion need longer sun exposure to produce adequate amounts of vitamin D ( 87 ). Approximately 80% of African American women have vitamin D deficiency, compared with only 20% of Caucasian women ( 88 ). The higher risk of vitamin D deficiency in African Americans has been attributed to due to darker skin pigmentation and decreased access to solar radiation, resulting in increased risk for uterine fibroids ( 89 ).

Adequate vitamin D can also be ensured through diet or supplementation ( 90 ). The most stable form in circulating blood, 25(OH)D, is used to assess vitamin D levels in individuals ( 91 ). However, different organizations have different classifications for 25(OH)D levels. According to the Endocrine Society, vitamin D deficiency is defined as 25(OH)D serum concentrations ≤20 ng/mL; insufficient , between 21 and 29 ng/mL; and sufficient , ≥30 ng/mL ( 92 ). Meanwhile, the United States Institute of Medicine (IOM) defines the sufficient 25(OH)D serum level as ≥20 ng/mL ( 93 ). ( 94 )

Some experts consider low 25(OH)D serum concentrations as a marker of poor health ( 90 ). Conversely, increased concentrations of vitamin D have been associated with reduced prolonged menstruation cycle ( 95 ), infertility, hyperandrogenism, insulin resistance, and polycystic ovary syndrome (PCOS) ( 96 ). Furthermore, abnormal vitamin D levels tend to change the maternal-fetal vascular system and may cause abnormal pregnancy development, dysregulated metabolism, and disrupted placental function ( 97 ).

The role of vitamin D in the pathogenesis of uterine fibroids has been investigated ( 26 ). Three main studies demonstrated that vitamin D levels are much lower in the sera of uterine fibroid patients, suggesting the vitamin D may be linked to the pathogenesis of uterine fibroids. ( 98-100 ).

Lifestyle factors, such as diet and level of physical activity influence the formation of uterine fibroids. Women consuming more green vegetables, fruit, and fish than red meat are less commonly diagnosed with uterine fibroids ( 27 , 49 , 101 ). Of note, African American women consume lesser amounts of fruits, vegetables, vitamins, and minerals compared with White women ( 102 , 103 ). Diets rich in citrus fruits markedly reduced the risk of uterine fibroids ( 104 ). ( 88 , 105 , 106 ).

Protective Factors

The use of oral and injectable contraceptives can reduce the risk of developing uterine fibroids ( 44 ). Hormonal contraception protected women from developing clinical symptoms of uterine fibroids ( 107 ). However, using oral contraceptives at adolescence may be considered a risk factor for developing symptomatic uterine fibroids later in life, whereas using them after adolescence reduces the risk ( 44 , 108-110 ). Contraceptives increase estrogen and progesterone concentrations in the body, indicating that mechanisms other than hormonal levels are involved in the development of uterine fibroids ( 5 ).

Some substances of plant origin can prevent cell division and formation of fibrosis while modulating hypercritical pathways involved in the development of uterine fibroids ( 111 ). The use of phytochemicals in the prevention and treatment of uterine fibroids has been investigated and showed promising options ( 111-113 ). However, some substances that had been considered potentially helpful have been associated with adverse effects. For example, elevated vitamin E concentration in the serum may be an risk factor for uterine fibroids in Caucasian women. Vitamin E can function as a ligand for estrogen receptors (ERs) due to its structural determinants ( 29 ).

In addition, the consumption of milk and other dairy products may influence the development of uterine fibroids. An increased risk of uterine fibroids was associated with consumption of milk or soybeans ( 114 ). Other prospective cohort studies have yielded controversial results. One study reported no clear association with overall dairy consumption, whereas another study found that yogurt consumption and calcium intake from foods reduced the risk of uterine fibroid development ( 115 ). Moreover, some of the risk factors are described in the environmental exposure section.

Uterine Fibroids Driver Mutations

Within the past decade, the application of rapidly advanced genomic technologies, including high-throughput sequencing methodologies, has led to the identification of recurrent and largely mutually exclusive genetic alterations (so-called drivers ) responsible for the formation of uterine fibroids. Among these, somatic mutations in the Xq13 gene encoding the RNA Polymerase II (Pol II) mediator subunit MED12 are the most prevalent, occurring in 45–90% cases of uterine fibroids depending upon patient ethnicity ( 8 , 116-128 ). A proportionally smaller fraction of uterine fibroids has been attributed to genetic alterations leading to the overexpression of HMGA2 , disruption of the COL4A5-COL4A6 locus, and biallelic loss of FH encoding the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase ( 117 , 129 ) . Additionally, recurrent deletions and rearrangements involving chromosomes 6p21, 7q22, 22q, and 1p have been observed in patients with uterine fibroids. However, these mutations generally co-occur with other genetic alterations, suggesting that they represent secondary driver events restricted to a subpopulation of tumor cells ( 121 , 130-133 ). Altogether, the identification of different fibroids driver mutations has permitted the genetic stratification of these tumors into at least 4 molecular subtypes ( 129 , 134 , 135 ). Interestingly, transcriptome-wide gene expression profiling studies of different uterine fibroid subtypes have revealed that distinct driver mutations are generally characterized by unique gene expression signatures, indicative of distinct pathways to tumorigenesis. This suggests that MED12 mutation–positive and MED12 mutation–negative uterine fibroids are likely unrelated by driver mutations occurring in a common MED12 -dependent pathway ( 129 , 134 ). There are 4 main driver mutations discovered in uterine fibroids.

High-frequency MED12 mutations have been observed in tumors from women of diverse racial and ethnic origins, including those of North American, European, African, Asian, and Middle Eastern descent, thus implicating MED12 as a dominant universal driver of uterine fibroids ( 8 , 118-128 ). Nonetheless, data from a recent meta-analysis indicates that MED12 mutations occur more frequently in women of African as opposed to non-African descent ( 136 ). Regarding uterine fibroid–linked mutations in MED12, are all located within exons 1 or 2, and most are missense mutations with a smaller proportion corresponding to small in-frame deletions and insertions ( 118 , 129 , 137 ). Exon 2 mutations are far more frequent than those in exon 1, with the latter accounting for ~1% to 2% of pathogenic alterations reported in uterine fibroids ( 10 , 129 ). Although missense mutations in exon 2 are distributed throughout the coding sequence, most are clustered in codons 36, 43, and 44, suggesting the importance of their corresponding and evolutionarily highly conserved amino acid residues ( 7 , 8 , 118 , 121 , 128 ). Notably, in addition to uterine fibroids, MED12 exon 2 mutations are also found at similarly high frequency (~80%) in breast fibroepithelial tumors, and to a lesser extent (~5%) of chronic lymphocytic leukemias ( 138-144 ).

In addition to their high frequency occurrence, several additional findings suggest that MED12 mutations are true drivers of fibrotic transformation. First, predominant monoallelic expression of mutant MED12 has been observed almost uniformly in MED12 mutation–positive uterine fibroids, indicating a pathogenic requirement for a functionally altered MED12 allele ( 7 , 129 , 137 ). Second, targeted expression of a MED12 mutant transgene ( c. 131G>A; p.G44D) in the uterine mesenchyme of mice was sufficient to induce uterine fibroid formation, providing direct genetic proof of disease causality ( 145 ).

Combined molecular and clinical analyses have been applied to identify relationships between MED12 mutation status and tumor characteristics as well as patient clinical variables. These analyses have consistently revealed that MED12 mutations are associated with smaller tumor size, conventional tumor histology, and increased tumor number within the uterus ( 7 , 123 , 146-152 ). While most of these studies have been underpowered to detect associations with additional clinical features, a comparatively larger analysis including 750 fibroid tumors from 244 hysterectomy patients confirmed these associations and additionally found MED12 mutations to be positively correlated with subserosal (compared to intramural) location and inversely correlated with parity ( 10 ). No associations were observed between MED12 mutations and patient infertility, smoke consumption, BMI, history of pelvic inflammatory disease and chlamydia, hypertension, thyroid disorder, diabetes, oral contraceptive use, or family history of uterine fibroids ( 10 ). The observation that MED12 mutation–positive uterine fibroids are associated with a subserous location was subsequently confirmed in another large retrospective study that included 361 tumors from 234 myomectomy patients whose median age of 34 years also revealed that the MED12 mutation frequency in uterine fibroids from fertile-age women is comparable to that found in perimenopausal women ( 153 ). Altogether, these analyses support the relevance of MED12 driver mutations in the pathogenesis and clinical presentation of uterine fibroids.

The noted association between MED12 mutations and smaller tumor size has been variously ascribed to underlying study bias (ie, early clinical intervention in response to the combinatorial burden of multiple co-existing MED12 -mutant tumors) or inherent biological differences in the growth properties of MED12 mutation–positive and MED12 mutation–negative tumors in situ . While the underlying basis for this association remains unknown, the notion that MED12 mutation–positive and MED12 mutation–negative tumors might exhibit unique growth features is supported by studies showing a clear distinction in the ability of primary cells from either tumor type to survive monolayer culture in vitro. Thus, while primary cells from MED12 mutation–negative uterine fibroids were shown capable of survival and maintenance for many passages under normal culture conditions, those derived from MED12 mutation–positive tumors were shown to be rapidly lost within the first several passages ( 154 ). Interestingly, while passaging of cells was noted to accelerate the loss of MED12–mutated cells from cultures, cell loss was nonetheless still observed in confluent cells absent passaging, revealing an apparent requirement for a niche-derived soluble factor(s) or matrix component(s) that is lacking in vitro ( 155 ). These novel findings reveal inherently unique growth requirements, and possible therapeutic vulnerabilities, for cells from MED12 mutation–positive uterine fibroids, and further suggest that alternative models will be required to overcome what currently constitutes a significant barrier to mechanistic studies concerning the molecular basis of MED12 in the pathogenesis of uterine fibroids.

An extenuating factor in rapid loss of MED12-mutant cells from culture may relate to the recent observation that MED12 mutation–positive uterine fibroids, compared with MED12 mutation–negative tumors, exhibit apparently greater cellular heterogeneity. In this regard, prior studies have revealed that uterine fibroids, while clonally derived, are nonetheless heterogeneous in their cellular composition, consisting predominantly of smooth muscle cells and fibroblasts, along with smaller numbers of vascular smooth muscle cells, vascular endothelial cells, and immune cells ( 156 , 157 ). Significantly, recent work has shown that MED12 -mutant tumors, compared with MED12 -WT (HMGA-overexpressing) tumors, harbor significantly more collagen-producing tumor-associated fibroblasts (TAFs) that also contribute significantly to excessive levels of extracellular matrix (ECM) observed in MED12 -mutant tumors ( 158 ). Notably, only smooth muscle cells, but not TAFs, carry MED12 mutations, suggesting antecedent divergence from a common progenitor before cell type–specific mutation acquisition or, alternatively, an extratumoral origin for TAFs. Interestingly, this work also showed that within MED12-mutant tumors, smooth muscle cells grow in response to progesterone, which has no effect on TAFs that instead grow in response to estrogen ( 158 ). The observation that MED12 mutation–positive uterine fibroids comprise similar ratios of smooth muscle cells and TAFs that respond differently to steroid hormones could explain the intriguing observation that estrogen alone can attenuate regression, but not promote growth, of progesterone-dependent MED12-mutant tumor xenografts ( 159 ). The high ratio of TAFs could also explain the rapid disappearance of MED12 -mutant smooth muscle cells from primary cultures of uterine fibroids. Thus, growth-deficient MED12-mutant cells could be overwhelmed by TAFs, for which standard culture conditions were originally optimized. Ultimately, the number of heterogenous cell types within MED12 mutation–positive uterine fibroids and the degree to which they are clonally related remains to be firmly established, and newer technologies, including single-cell RNA sequencing, could help to resolve these outstanding issues.

The molecular basis by which pathogenic mutations in MED12 drive uterine fibroid formation is presently unclear, but dysregulation of RNA Pol II-driven gene expression is implicated. Mediator is a conserved multiprotein interface found between gene-specific transcription factors and Pol II ( 137 ) and channels regulatory signals from activator and repressor proteins to affect changes in gene expression programs that control diverse physiological processes, including cell growth, homeostasis, development, and differentiation. Structurally, Mediator is comprised of a 26-subunit core that binds tightly to Pol II in the so-called holo-enzyme ( 137 ). MED12, MED13, CycC, and CDK8 (or its paralog CDK19) comprise a 4-subunit “kinase” module that variably associates with the core Mediator ( 137 ).( 137 ). Notably, the kinase module is a major ingress of signal transduction through the Mediator, and MED12-dependent CDK8 activation is required for the nuclear transduction of signals initiated by multiple oncogenic pathways, with which MED12 is biochemically and genetically linked ( Fig. 3 ) ( 137 ). Furthermore, MED12 is a target of oncogenic mutation in colon, prostate, and renal cell carcinomas ( 119 , 160 , 161 ). However, these mutations predominantly occur in the MED12 C-terminus and thus lie distant from fibroids-linked mutations that cluster in the N-terminus, suggesting distinct tumorigenic mechanisms ( 162 ).

Role of MED12 mutation in the pathogenesis of fibroids. Two mutually compatible models are demonstrating that fibroids driver mutations in MED12 trigger myometrial stem cell transformation and fibroids formation through altered signaling. In the first model (A), MED12 mutations in exon 2 disrupt the CDK8 T-loop conformation to affect Mediator kinase activity and the phosphorylation of downstream targets, including those that control myometrial stem cell fate and/or function. In the second model (B), MED12 mutations alter gene expression programs that control myometrial stem cell fate and/or function through kinase-independent mechanisms, such as MED12 interactions with transcriptional regulatory proteins ( 173 ). The 2 models are not mutually exclusive, and both scenarios could contribute to fibroids pathogenesis. Shown here is the 4-subunit Mediator kinase module comprising MED13, MED12, CycC, and CDK8/19 that variably associates with a core Mediator, which is collectively composed of 26 different subunits arranged into 3 structurally defined domains, ie, Head, Middle, and Tail. The structure of the core Mediator is from Clark et al ( 137 ), whereas that of the kinase module is from Li et al ( 167 ). Abbreviations: CDK8/19, cyclin-dependent kinase 8/19; CycC, cyclin C; MED12/13, RNA polymerase II transcriptional mediator complex subunit 12/13; MMSC, myometrial stem cell; UFs, uterine fibroids.

Uterine fibroid–linked mutations in MED12 are all located within exons 1 or 2, most of which are missense mutations, and a smaller proportion include in-frame deletions and insertions ( 118 , 129 , 137 ). Particularly, those occurring in exon 2 are far more frequent than those in exon 1, with the latter accounting for ~6% of pathogenic alterations reported in uterine fibroids ( 129 ). Although missense mutations in exon 2 are distributed throughout the coding sequence, most are clustered in codons 36, 43, and 44, suggesting the importance of their corresponding and evolutionary highly conserved amino acid residues ( 7 , 8 , 118 , 121 , 128 ).

Within the Mediator kinase module, MED12 is known to activate CycC-CDK8, and the mechanistic basis has recently been clarified ( 128 , 163-167 ). Thus, MED12 binds directly to CDK8, leading to structural reconfiguration and stabilization of the CDK8 activation (T)-loop in a manner critically dependent upon MED12 residues recurrently mutated in uterine fibroids ( 167 ). These observations suggest that uterine fibroid driver mutations in MED12 could alter T-loop conformation and disrupt CDK8 kinase activity ( Fig. 3 ) ( 167 ). Indeed, pathogenic exon 2 mutations in MED12 have been confirmed to disrupt CDK8/19 kinase activity both in vitro and in clinically relevant patients with uterine fibroids ( 128 , 129 , 165 , 166 ). Collectively, these studies reveal a common molecular defect associated with uterine fibroid–linked mutations in MED12 and implicate the aberrant Mediator-associated CDK8/19 kinase activity in the pathogenesis of uterine fibroids. Mechanistically, Mediator kinase activity has been implicated in diverse cellular processes ranging from controlling transcription factor half-life and RNA Pol II activity to regulating chromatin chemistry and functional status ( 137 , 168 , 169 ). Accordingly, its disruption as a direct consequence of uterine fibroid mutations in MED12 could have broad implications for the dysregulation of gene expression programs that collectively contribute to tumor formation. Nonetheless, MED12 has also been shown to regulate transcription in a CDK8-independent manner ( 170-173 ), although this function is largely mediated through the MED12 C-terminus that lies spatially distant from N-terminal residues mutated in uterine fibroids ( Fig. 3 ). Because MED12 mutations have been linked to pathways directly implicated in uterine fibroid pathology, including the Wnt/β-catenin, protein kinase B/mammalian target of rapamycin (AKT/mTOR), progesterone receptor, focal adhesion, extracellular matrix, angiogenic, and HIF1α pathways, among others ( 7 , 134 , 137 , 174-176 ), the relative contribution of CDK8 to MED12-dependent regulation of these pathways and the extent to which altered Mediator kinase activity contributes to their dysregulation will be an important area of future investigation.

Finally, the molecular basis for the high-frequency occurrence of MED12 exon 2 mutations in uterine fibroids is not presently understood. Either of 2 alternative scenarios can be posited. First, high-frequency MED12 exon 2 mutations might simply reflect the selection of clustered mutations among disparate others arising randomly throughout the MED12 gene through errors of replication, particularly if these mutations similarly impact an important biological function of MED12 in the myometrium. As described previously, all uterine fibroid driver mutations in MED12 disrupt Mediator-associated CDK8/19 kinase activity, and it is perhaps notable that Mediator kinase has been implicated in the control of stem cell plasticity and fate determination. For example, a developmentally programmed reduction in CDK8 expression is associated with naïve pluripotency during animal development in vivo, and chemical inhibition of CDK8/19 was recently shown sufficient to revert primed pluripotent stem cells to a naïve pluripotent state in vitro ( 177 , 178 ). Furthermore, CDK8 has been implicated in cancer stem cell self-renewal and tumorigenicity in colon and brain cancer ( 179 , 180 ). Finally, within the uterus, it was recently shown that Mediator kinase subunits are enriched in myometrial stem cells (MMSCs), and further, that chemical inhibition of CDK8/19 in MMSCs led to reduced phosphorylation of stem cell-enriched transcription factors and altered expression of myogenic genes. Thus, it seems possible that MED12 exon 2 mutations, through disruption of Mediator kinase activity, could provide a selective advantage to myometrial stem/progenitor cells by altering their growth and/or differentiative trajectory, leading to the formation of uterine fibroid stem cells that, in turn, seed and sustain monoclonal tumor growth.

An alternative hypothesis to explain the high-frequency occurrence of MED12 exon 2 mutations invokes a sequence- or structure-specific basis for clustered mutagenesis through error-prone repair of site-specific DNA damage. Replication fork arrest as occurs, for example, on repeat and satellite sequences or noncanonical B-DNA, is often processed through DNA double-strand break intermediates, which are prone to erroneous repair and punctual mutagenesis (or chromosomal rearrangements) ( 181 ). Accordingly, such error-prone sequences, should they reside in the vicinity of MED12 exon 2, might favor the occurrence of high-frequency somatic mutations found in uterine fibroids. However, the genomic sequence within and flanking MED12 exon 2 is characterized by neither particularly high GC content nor repeat motifs characteristic of replication-resistant DNA, perhaps arguing against replication-dependent site-specific mutagenesis as a basis for the high-frequency occurrence of MED12 mutations. Nonetheless, it was recently noted that this region does harbor a 16-bp sequence with significant homology to a putative terminator-based hairpin sequence within the tRNA gene cluster of Staphylococcus aureus , a common component of the uterine microbiota ( 182 ). On this basis, it was hypothesized that MED12 hot-spot mutations arise through site-specific mutagenesis brought on by replication-dependent processing of aberrant R-loops produced by insertion of S. aureus RNA with the homologous DNA sequence in MED12 ( 182 ). Although speculative, this intriguing hypothesis nonetheless does invoke a direct link between host and microbiome that together form a complex interrelationship prone to homeostatic disruption and the development of human disease ( 183 , 184 ). While the genic basis for high-frequency MED12 mutations in uterine fibroids thus remains obscure, it is nonetheless clear that once incurred, these mutations interact with additional environmental components including hormonal, angiogenic, and growth regulatory factors to drive tumor progression.

The high mobility group A (HMGA) family includes related HMGA1 and HMAG2 non-histone chromosomal proteins that regulate transcription by altering chromatin structure. The HMGA non-histone proteins bind to the AT-rich enhancers or promoters’ minor groove and introduce structural alterations in chromatin. One of the most commonly observed cytogenetic abnormalities (8%-10%) in uterine fibroids is a translocation involving chromosomes 12 and 14, which disrupts a putative regulatory sequence typically 5′ of the HMGA2 gene ( 185 , 186 ). In addition, the expression levels of HMGA2 are elevated in uterine fibroids compared to myometrium with 12q15 rearrangements ( 187 , 188 ). Uterine fibroids with HMGA2 aberrations displayed significant upregulation of proto-oncogene pleomorphic adenoma gene 1 ( PLAG1 ), suggesting that HMGA2 triggered the pathogenesis of uterine fibroids through PLAG1 activation ( 189 ).

Mutations in fumarate hydratase ( FH ) on chromosome 1 in band q42 were found in uterine fibroids ( 190 , 191 ). Heterozygous germline mutations in the FH gene caused a syndrome known as hereditary leiomyomatosis and renal cell carcinoma (HLRCC) ( 192 ). FH deficiency, accounting for up to 1.6% of uterine fibroids, alters the expression profiles of fibroids, most strikingly increasing the expression of genes involved in glycolysis ( 132 ) as well as activating nuclear factor erythroid 2 related factor 2 (NRF2) target genes ( 189 ).

COL4A5/COL4A6

Similar to the FH deficiency subtype, COL4A5/COL4A6 deletions are a rare subtype constituting about 2% of uterine fibroids ( 193 ). Integrated data analysis reveals insulin receptor substrate-4 ( IRS4 ), a gene located adjacent to COL4A5 , as the most uniquely expressed gene in this uterine fibroid subtype ( 189 ).

Additionally, a small number of mutually exclusive drive mutations were recently identified. Germline mutations in SRCAP members YEATS4 and ZNHIT1 predispose women to uterine fibroids. The fibroids bearing these mutations exhibited defective deposition of the histone variant H2A.Z ( 194 ). Moreover, an integrative computational approach (decomposition and classification of genomic tensors) can discriminate normal and uterine fibroid subtype ( 195 ), suggesting that the inclusion of epigenetic features can help better understand the state and complexity of uterine fibroids.

Conversion of Myometrial Stem Cells to Uterine Fibroid Stem Cells

The human myometrium is the muscular wall of the uterus that is formed by an intricate network of smooth muscle fibers dispersed throughout an extracellular matrix of connective tissue. This process contributes to the normal tonicity of the uterus. Increasing evidence supports the hypothesis that uterine fibroids originate from stem cells in the myometrium, although the specific cell of origin has not yet been identified ( 196 , 197 ). Stem cells derived from the myometrium and uterine fibroids have been isolated, and tumor-initiating cells in fibroids have been identified ( 198-201 ). Moreover, the markers used to enrich putative mesenchymal stem cells are similarly enriched for MMSCs from myometrium and uterine fibroids ( 202 ). Notably, MED12 mutations are only found in uterine fibroid stem cells and not in MMSCs ( 203 ). In addition, distinct MED12 mutations have been detected in different uterine fibroid tumors derived from the same uterus ( 7 ), indicating that the emergence of each mutation might be an independent event. The prevailing model for fibroid pathogenesis invokes the genetic transformation of a single MMSC into a tumor-initiating cell that seeds and sustains clonal tumor growth through endocrine, autocrine, and paracrine growth factors and hormone receptor signaling ( 204 ).

Several factors have been proposed as the origin of tumor-initiating cells, including genomic instability, inflammatory microenvironment, cell fusion, lateral gene transfer, and developmental environmental insult ( 205 , 206 ). The adverse effect of developmental environmental insult may cause the deregulation of multiple developmental processes, including the disruption of stem cell niche, developmental reprogramming, and altered stem cell characteristics. Somatic stem/progenitor cells from various hormone-supported tissues remained susceptible to endocrine-disrupting chemicals (EDCs) ( 206 , 207 ). In uterine fibroids, developmental exposure to EDCs impaired the biological characteristics of MMSCs in an Eker rat model with Tsc2 mutation. This model spontaneously develops uterine fibroids with 63% incidence. However, early-life exposure to EDCs, such as diethylstilbestrol (DES), increased the penetrance of the Tsc2 mutation, resulting in 100% incidence ( 208 ).

The impact of environmental exposure to MMSCs that increase susceptibility to uterine fibroid development have been investigated using the same model. The more MMSCs in the DES-exposed myometrium have been observed than those exposed to vehicle. In addition, MMSCs from 5-month-old DES rats exhibited increased proliferation rates compared to MMSCs from age-matched control rats ( 206 ). These results suggest that developmental exposure to EDCs targets MMSCs and alters their characteristics, which may underlie reprogramming of epigenome and initiation of hormone-dependent uterine fibroid pathogenesis ( Fig. 1 ).

Early and late epigenome and environment interactions can potentially impact uterine function and increase the risk of uterine fibroids ( Fig. 1 ) by shaping the developing epigenome of target genes ( 209 ). This epigenomic reprogramming may remain transcriptionally and phenotypically silent until triggered by a later life event, such as exposure to risk factors. For example, during a critical developmental window of the liver, exposure to BPA induced epigenomic reprogramming at specific genes and chromatin states in the neonatal liver to accelerate acquiring an adult epigenetic signature. Although it persists until adulthood, much of this reprogramming remained transcriptionally silent until a later-life challenge with a Western-style diet high in fat, fructose, and cholesterol, which disrupted metabolic function and significantly elevated serum cholesterol and lipid levels ( 209 ). Further studies on stem cells from reproductive organs may contribute to a better understanding of the genome-environment interaction leading to reproductive diseases, including uterine fibroids.

The occurrence of MED12 driver mutations and how they interact synergistically with other implicated pathways in uterine fibroids remain largely unknown. Therefore, the further investigation is highly needed to elucidate the mechanism of interplay between hormones, environments, DNA repair system, and other factors in the occurring of MED12 mutations.

Environmental Exposure and Pathogenesis of Uterine Fibroids

Direct, intensive, and adverse environmental exposure, air pollution.

Air pollution is one of the leading causes of death. Exposure to air pollutants affects vital cellular mechanisms and is intimately linked with the etiology of many chronic diseases such as chronic obstructive pulmonary disease and asthma ( 210-212 ). Particulate matter (PM) is a class of pollutants that comprises a complex combination of small-sized particles and gaseous components, such as organic chemicals, smoke, soot, sulfates, nitrates, acidic components, dust particles, and soil. The United States Environmental Protection Agency considers PM the pollutant category with the most significant impact factor on human health ( 213-215 ). Air pollution, including PM2.5, results in infertility, menstrual irregularity, and endometriosis ( 216 ). In addition, chronic exposure to PM2.5 is associated with the incidence of clinically symptomatic uterine fibroids ( 216 ). A 10-year cohort-based case-control study that included 11 028 Taiwanese women diagnosed with uterine fibroids suggested that exposure to PM2.5 and O 3 may increase the risk of developing uterine fibroids ( 217 ). However, only limited research has investigated the relationship between air pollution and uterine fibroid development; therefore, more studies are needed to confirm these findings in other populations.

Alcohol consumption

Heavy alcohol consumption is a risk factor for uterine fibroids ( 35 ). The Nurses’ Health Study II revealed the positive association between current alcohol consumption and risk of uterine fibroids ( 35 , 218 ). The Black Women Health Study concluded that uterine fibroids risk among African American women is positively correlated with past and current alcohol intake ( 219 ). In a study involving 133 000 female teachers and school administrators, drinking at least 20 g of alcohol per day was significantly associated with an increased risk for uterine fibroids ( 220 ). Another cross-section study on premenopausal Japanese women supported this causal risk factor for uterine fibroids and reported that mean alcohol intake is significantly higher among women with fibroids than those without ( 221 ). Moreover, a study of 1146 premenopausal African American and Caucasian women showed that current alcohol intake in Caucasian women is associated with an increased risk of uterine fibroids compared to African Americans and nondrinkers. Although no correlation between alcohol intake and uterine fibroid risk in African Americans was found, the relationship of current and past drinking history and uterine fibroid size was generally similar among African American and White women ( 35 ).

Although the underlying mechanism is largely unknown, several studies have proposed that alcohol intake increases the levels of steroid hormones in premenopausal women ( 222-224 ). Alcohol intake also altered the growth factors and cytokines, which play a critical role in uterine fibroid pathogenesis. Moreover, alcohol-induced DNA damage might be a contributor. Acetaldehyde, an endogenous and alcohol-derived metabolite, caused DNA damage, particularly double-stranded breaks, that, despite the activation of recombination repair, resulted in chromosomal rearrangements in stem cells ( 225 ). Other studies have reported alcohol-induced mitochondrial DNA damage in lung, brain, and breast cancers ( 226-228 ). More studies are needed to explore alcohol-induced DNA damage in uterine fibroids.

Cigarette smoking

The effect of smoking on uterine fibroids remains controversial ( 229 ). An inverse correlation between smoking and uterine fibroids risk was reported ( 220 , 230 , 231 ). However, this association was not found in other case-control and prospective cohort studies ( 2 , 232 , 233 ). Early studies found that estrone and estradiol levels were reduced in smokers relative to nonsmokers, and cigarette smoking altered the hepatic metabolism of estrogen, thus resulting in lower circulating levels of activated estrogen ( 2 ). However, the components of cigarette smoke may also exert estrogen-related effects on the uterus to promote cell proliferation ( 2 ).

Developmental Exposures

Epidemiological studies and endocrine-disrupting chemical effects.

Various niche factors act on stem cells during development to alter gene expression and induce their proliferation or differentiation for fetus development. During development and tissue maintenance, the highly plastic state of stem/progenitor cells permits the required flexibility for proper tissue formation and repair. Unfortunately, this plasticity also provides an opportunity for aberrant cellular reprogramming via epigenetic mechanisms due to inappropriate exposures to toxins ( 234 ). Developmental adverse exposure can lead to persistent, life-long effects and result in various diseases ( 235-237 ).

EDCs interfere with the body’s endocrine system to produce adverse developmental, reproductive, neurological, and immune effects ( 198 , 238 , 239 ). An increasing number of studies have shown that endocrine disruptors may pose a serious disease risk during development ( 240 ). According to epidemiological and experimental studies, EDCs increased the risk of tumorigenesis, especially in organs susceptible to endocrine regulation. For example, upon exposure to estrogen and progesterone, differentiated myometrial cells secreted wingless-type (WNT) ligands that induced the nuclear translocation of β-catenin in stem/progenitor cells from uterine fibroids. The activation of the β-catenin pathway ultimately enhanced the growth and proliferation of these stem/progenitor cells ( 241 ).

EDCs can exhibit nonmonotonic dose–response curves and produce a pathophysiologic effect even at low doses. Numerous EDCs can interact with nuclear receptors to exert their actions in target cells and tissues ( 242-244 ). For example, the binding of EDCs to nuclear receptors can alter hormonal functions by mimicking the naturally occurring hormones in the body, thereby blocking the binding of endogenous hormones, or by interfering with the production or regulation of hormones and/or their receptors. An EDC may interact with more than one receptor, and multiple EDCs can interact with the same receptor, highlighting the complexity of the response of animals and humans to environmental EDC exposures. Notably, EDCs exposure can increase the risk of uterine fibroids ( Figs. 2 and ​ and4). 4 ). Two extensive prospective studies reported a positive association between developmental exposure to DES, a synthetic and nonsteroid estrogen, and uterine fibroids risk. ( 245 , 246 ). In the Nurses’ Health Study II ( n = 11 831), prenatal exposure to DES increased the risk of uterine fibroids by 13% in women older than 35 years ( 246 ), and exposure during the first trimester of gestation increases the risk by 21%. Large fibroids were more commonly found in those exposed to prenatal DES in the second National Institute of Environmental Health Sciences (NIEHS) uterine fibroid study. In a subset of the NIEHS sister study, the main factors associated with increased risk of uterine fibroids included DES exposure, maternal or gestational diabetes, and monozygotic twins, having risk ratios of 2.02, 1.54, and 1.94, respectively. However, another prospective cohort study, which employed medical records to document exposure, reported no association between prenatal DES exposure and uterine fibroids. Many other EDCs, including parabens, environmental phenols, alternate plasticizers, organophosphate esters, tributyltin, and phthalates, have been associated with uterine fibroids outcomes and their related processes. Phthalates have received increasing attention as they are tightly linked to uterine fibroid prevalence and severity ( 31 , 247-249 ) ( Figs. 1 and ​ and2 2 ).

Estrogen receptor-mediated signaling pathways in the myometrium. The biosynthesis of natural E2 occurs in the ovary downstream the actions of the LH and the FSH, which are regulated by the GnRH. E2 mediates its biological response through several pathways, which can be classified as genomic and nongenomic. There are 3 main mechanisms of genomic regulation mediated by ER. Firstly, in the classical pathway, E2 ligands passively enter the cells by diffusion. ERα and ERβ are localized in the cytosol and are attached to the chaperon Hsp90, which is released after binding with estrogen. The estrogen-bound receptors form dimers that enter the nucleus and bind to the ERE, specific DNA sequences of the promoters of target genes affecting their transcription. Secondly, the nonclassical pathway involves binding the E2-bound ER to TFs that are already bound to the DNA. The third mechanism is hormone-independent. The ER can regulate E2 responses by activating the signaling of growth factors via the phosphorylation of different serine (118/167) residues on the receptor. In addition to upregulating gene expression, E2 exerts its nongenomic rapid biological actions by interaction with membrane receptors. GPER, a membrane-integrated 7-transmembrane receptor, activates heterotrimeric G-proteins after binding with estrogen to elicit various nongenomic responses, such as calcium signaling, PKC, and cAMP/PKA pathways. Bound-membrane ERs (ERα, ERβ, ER36, and ER46) also activate cytosolic signalings, such as PI3K/Akt and MAPK. In addition, the activation of kinases results in the phosphorylation of specific transcription factors that regulate gene expression. EDCs are exogenous, manufactured chemicals, such as genistein, bisphenol A, and phthalates that mimic natural estrogen molecular and cellular responses, thereby altering the functions of the endocrine system. These chemicals are associated with the developmental origin of fibroids and their pathogenesis. Abbreviations: AC, adenylyl cyclase; AKT, protein kinase B; cAMP, cyclic AMP; CoA, coactivator; E2, estrogen; EDCs, endocrine-disrupting chemicals; EGFR, epidermal growth factor receptor; ER, estrogen receptor; ERE, estrogen-responsive elements; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; GPER, G-protein coupled estrogen receptor 1; Hsp90, heat shock protein 90; IGFR, insulin-like growth factor 1 receptor; IP3, inositol trisphosphate; LH, luteinizing hormone; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; mER, membrane-bound estrogen receptor; mTOR, mammalian target of rapamycin; PI3K, phosphoinositol-3-kinase; PKA, protein kinase A; PKC, protein kinase; PLC, phospholipase C; Raf, Rapidly Accelerated Fibrosarcoma Kinase; Ras, Ras GTPase; TFs, transcription factors.

Experimental studies using animal models

Diverse animal species and techniques have been used for the in vivo investigation of uterine fibroid pathophysiology. These animal models include the xenotransplantation of human uterine fibroid tissues ( 250-252 ) or cells ( 253 , 254 ) in mice, the implementation of genetically modified mice ( Tsc2 knockout ( 255 ), GPR10 overexpression ( 256 ), β-catenin overexpression ( 257 )), and the utilization of species that spontaneously develop uterine fibroids, such as the guinea pig ( 258 ), the potbellied pig ( 257 ), and the Eker rat. The latter carries a germline mutation in the tuberous sclerosis complex-2 ( Tsc2 ) tumor suppressor gene and develop uterine fibroids with a frequency of about 65% by 16 months of age ( 259 ). Although the Eker rat model is the most widely used in vivo animal model to study uterine fibroids, this animal model has some limitations. For example, mutations in the Tsc gene have not been linked to the disease in humans. In addition, the developing uterine fibroids show relatively small amounts of collagenous connective tissue stroma ( 260 ), unlike the human uterine fibroids, which present a high amount of abnormally formed cross-linked collagen ( 261 ). Finally, Eker rats develop both benign and malignant smooth muscle tumors ( 260 ). However, studies in the Eker rat animal model provide a great opportunity to reveal links between early-life exposure to EDCs and the origin and development of uterine fibroids. Upon neonatal exposure to EDCs, Eker rats developed increased susceptibility to spontaneous uterine fibroids, multiplicity, and tumor size with age ( 208 , 262-264 ), whereas those without the Tsc2 mutation did not develop any tumors. These studies suggest that developmental exposure to EDCs increases the penetrance of the Tsc2 mutation ( 208 ). In addition, the window of susceptibility to environmental exposures coincided with critical periods of myometrial development ( 208 ). Exposure to DES during postnatal day (PND) 3–5 or 10–12 increased tumor incidence from 63% to 95% and 100%, respectively, in Eker rats carrying germline TSC2 mutation. During this time, estrogen protection of the developing uterus is disrupted ( 265 ) as DES and other xenoestrogens do not bind circulating steroid hormone–binding proteins, such as alpha-feto protein A. A later exposure at PND 17–19 did not result in increased uterine fibroid incidence. Overall, developmental exposure to EDCs during a critical time window of uterus development increases uterine fibroid risk later in life ( Figs 1 & 2).

Molecular mechanism underlying developmental EDC exposure–induced risks of uterine fibroids

During development, various niche factors act on stem cells to alter gene expression, therefore altering the signaling pathway and modulating its biological characteristics for the development of the fetus. The adverse developmental exposure can lead to persistent, life-long effects and result various diseases via pathological reprogramming ( 208 , 209 , 234 , 240 , 266 ).

Early-life exposures to 3 EDCs (ie, DES, genistein, and BPA) have been investigated to detect their effect on estrogen signaling, which plays a role in triggering fibroids formation in an animal model ( 267-269 ). All 3 EDCs act as ER ligands and induce ER-mediated gene transcription. However, only DES and genistein induced nongenomic ER signaling to activate phosphoinositide-3-kinase (PI3K)/AKT in the developing uterus. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is phosphorylated by activated PI3K/AKT signaling to repress EZH2 activity and reduce the levels of histone 3 lysine 27 trimethyl (H3K27me3). Significantly, decreased H3K27 methylation via developmental exposure correlated with the promoting effect of xenoestrogens on uterine fibroids.

In addition to EZH2, altered DNA methylation patterns due to environmental exposure have been reported in animal studies. Neonatal exposure induced the reprogramming of DNA methylation in animals exposed to DES during PND 1–5 compared with PND 17 (prepubertal), 21, and 30 (postpuberty) ( 270 ). Furthermore, neonatal DES exposure reprogrammed LTF, an estrogen-responsive gene. At PND 21 and 30, the promoter upstream of the estrogen response element was demethylated in animals exposed to DES during PND 1–5. Importantly, this postpubertal DES-induced demethylation was dependent on ovarian hormones, as evidenced by the absence of this demethylation in DES-exposed ovariectomized mice ( 270 ). Another animal study showed that neonatal DES exposure–induced metabolic changes last until adulthood, suggesting a permanent effect on energy metabolism in the uterus ( 271 ). Thus, developmental exposure to EDCs causes uterine diseases via epigenomic reprogramming. However, studies on the mechanism of epigenetic reprogramming by EDCs and its influence on fibroids development are limited. Additional mechanistic studies to elucidate the epigenetic biomarkers/signatures specific to EDCs can contribute to the development of precision medicine.

The reprograming of MMSCs, the cell origin of uterine fibroids, was recently identified following early-life exposure in the Eker rat (PND 10-12) to EDC. MMSCs isolated from prefibroid-stage tissue were analyzed using omics methods and showed altered biological pathways, including estrogen signaling ( 272 ) and inflammatory pathways ( 273 , 274 ). The reprogramming of estrogen pathways is driven by activated mixed-lineage leukemia protein-1 ( 275 ). In addition, DNA hypomethylation is involved in regulating estrogen and estrogen-responsive genes in MMSCs ( 274 , 276 ). In summary, EDC exposure epigenetically targeted MMSCs, imparting a hormonal imprint on key signaling pathways, thus resulting in an increased risk of uterine fibroids in a hormone-dependent manner ( 274 ) ( Figs. 1 , ​ ,2, 2 , and ​ and4 4 ).

Due to some limitations using animal models, the use of 3-dimensional (3D) models has attracted more attention in uterine fibroids research ( 277-279 ), particularly using myometrial stem cells instead of differentiated myometrial cells ( 280 ). The 3D model provides a more biomimetic cell culture environment than 2D substrates, with the advantage of more closely mimicking in vivo tissue architecture. MMSC-material interactions in 3D with topographical cues may provide an effective means to regulate many fibroid-related biological events, including differentiation, epigenetic state, or cell reprogramming, and rapidly advance our understanding of how the environment impacts risk for this disease as well as the tumor process via conversion of MMSCs to tumor-initiating cells.

Notably, so far, very few studies have attempted to disentangle the effects of early-life exposures concomitantly with late-life exposure on the pathogenesis of uterine fibroids. Thus, mechanistic insights into fibroid pathogenesis through the integration of risk exposures, genetic, epigenome, and MMSC biology will better understand the onset of fibroids.

Key Pathways Contributing to Uterine Fibroids Formation

Estrogen and progesterone.

Classically, uterine fibroids were considered estrogen-dependent tumors, based on their association with reproductive age ( 281 , 282 ). The estrogen signaling pathway as a major impactful pathway in uterine fibroids comprises genomic (direct and indirect effects of gene expression) and nongenomic factors, including the Ras-Raf-MEK (MAPK/ERK kinase)-mitogen-activated protein kinase (MAPK) and PI3K-phosphatidylinositol-3,4,5-trisphosphate (PIP3)-Akt-mTOR) pathways (the Ras-Raf-MEK-MAPK and PI3K-PIP3-Akt-mTOR pathways, respectively) ( Figs. 4 and ​ and5 5 ).

Critical pathways in uterine fibroids pathogenesis. The WNT/β-catenin, TGF-β, growth factor–regulated signaling, ECM, estrogen signaling, YAP/TAZ, Rho/ROCK, and DNA damage repair pathways play essential roles in fibroids formation and development. In addition, the crosstalk and interaction among these pathways may initiate and trigger uterine fibroids pathogenesis. Abbreviations: AKT, protein kinase B; APC, adenomatous polyposis coli; Bad, BCL2 associated agonist of cell death; CK1α, casein kinase 1 alpha; E2, Estrogen; ECM, extracellular matrix; ERE, estrogen-responsive elements; ERK, extracellular-signal-regulated kinase; ERα/β, estrogen receptor alpha/beta; FAK, focal adhesion kinase; GSK-3β, glycogen synthase kinase 3 beta; Hsp90, heat shock protein 90; LRP, lipoprotein receptor-related protein; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; mER, membrane-bound estrogen; MLC, Myosin regulatory light chain 2; MRN, Mre11-Rad50-Nbs1 complex; mTOR, mechanistic target of rapamycin; P, phosphorylated site; PDK1, 3-phosphoinositide-dependent protein kinase 1; PI3K, phosphatidylinositol 3-kinase; RAF, Rapidly Accelerated Fibrosarcoma kinase; RHO, Ras-homologous; RTK, receptor tyrosine kinases; SMAD, mothers against DPP (decapentaplegic); Src, proto-oncogene tyrosine-protein kinase; TF, transcription factor; TGFβ, transforming growth factor beta; TGFβR, transforming growth factor beta receptor; Wnt, Wingless-related integration site; YAP, Yes-associated protein; TAZ, transcriptional coactivator with PDZ-binding domain.

Several aberrations in ERs and signaling pathways are implicated in uterine fibroid pathobiology ( 283 ). Recently, another role for estrogen has been identified, ie, estrogen-induced, progesterone receptor expression and allowing progesterone receptor ligands to act on their target cells ( 284 ). Uterine fibroid cells have been shown to increase the expression of progesterone receptors in response to estradiol ( 285 ). Progesterone and progesterone receptors play a key role in uterine fibroid growth and development ( 286 , 287 ). Increased proliferation of uterine fibroid cells in vitro was observed upon exposure to both estradiol and progesterone ( 288 ). Finally, a uterine fibroid xenograft animal model showed that steroids, including estradiol and progesterone, are required for tumor growth ( 289 ), supported by selective progesterone receptor modulators (SPRMs) ( 290 ).

Extracellular Matrix and Growth Factors

Excessive ECM accumulation and aberrant remodeling are crucial for fibrotic diseases, including uterine fibroids ( Fig. 5 ). Uterine fibroid cells are characterized by abundant disorganized ECM deposition, which contributes to the formation of the bulk structure of the tumor. The large amounts of glycosaminoglycans and highly cross-linked interstitial collagens present in uterine fibroids ( 291 ) underlie the increased stiffness of the ECM. It is proposed that this ECM-rich rigid structure is the cause of the abnormal bleeding and pelvic pain ( 292 ). Moreover, ECM stiffness greatly impacts how cells sense physical forces and translate them into biochemical and biological responses, a molecular process collectively known as mechanotransduction. A clear example of proteins that respond to mechanical signals is β-catenin ( 293 , 294 ), a protein known to be involved in the pathobiology of uterine fibroids ( 294 ). It has been proposed that uterine fibroids can be divided into 4 stages based on the extracellular collagenous matrix content ( 295 , 296 ). Excessive collagen production by the transformed myocyte and its accumulation in the ECM results in decreased microvessel density, followed by myocyte death due to extreme deprivation of nutrients and oxygen ( 297 ). At the same time, changes in the ECM stiffness may activate mechanotransduction pathways that contribute to the myocyte phenotypic transformation. Interestingly, recent studies have linked mechanotransduction, nuclear rupture, and subsequent DNA damage in other diseases ( 298 , 299 ). Unraveling the interactions among different mechanobiology pathways in the uterine fibroid’s context would eventually help to comprehend better the origin and development of these tumors.

ECM accumulation is also affected by growth factors (transforming growth factor [TGF]-β, activin-A, and platelet-derived growth factor ), cytokines (tumor necrosis factor-α [TNF-α]), steroid hormones (estrogen and progesterone) ( 300 ), and microRNAs (particularly the miR-29 family, including miR-200c and miR-93/106b) ( 301-303 ). Interestingly, ECM acts as a reservoir of profibrotic growth factors and enhances their activity by increasing their stability and prolonging signaling duration. Therefore, a better understanding of ECM composition and metabolism in uterine fibroids is critical for developing new therapeutics for uterine fibroids. At present, several classes of drugs, including gonadotropin-releasing hormone (GnRH) agonist (leuprolide acetate), GnRH antagonists, SPRMs (eg, ulipristal acetate), and natural compounds (vitamin D), targeting the ECM have been studied as treatment options for uterine fibroids ( 303 , 304 ). In this sense, a local collagenase injection from Clostridium histolyticum , which specifically cleavage interstitial collagens, has been proposed as an alternative treatment for uterine fibroids. Notably, a phase I clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02889848","term_id":"NCT02889848"}} NCT02889848 ) has been completed, and it demonstrated the safety and tolerability of this treatment. Furthermore, direct injection of collagenase from C. histolyticum significantly reduced the stiffness of uterine fibroid tissue ( 305 ), which is fundamental to continued tumor growth throughout the activation of mechanotransduction pathways. Therefore, such mechanotransduction pathways may be disturbed after the reduction of fibroid stiffness, leading to ECM remodeling and finally to reduced fibroid size.

DNA Damage and Repair

Dna damage in the uterus.

Women are exposed to several exogenous (eg, EDCs) and endogenous factors that can impart pathophysiological alterations in internal organs, including the uterus. Endogenous factors include regular menses and hormonal changes that induce DNA damage through oxidative stress. Fluctuations in circulating estrogen and progesterone levels during the menstrual cycle can lead to increased tumor susceptibility in women, including breast cancer. Additionally, DNA damage and repair, and apoptosis occur cyclically in the normal myometrium during the follicular phase. Smooth muscle cells proliferate in the luteal phase, which may be a vulnerable period for DNA damage. These damages need to be properly repaired; otherwise, the hormonal imbalance can lead to diseases. For example, repeated incidents of damage to myometrial cells affect DNA repair activity, which could predispose the uterine environment to chronic inflammation, thereby creating an ideal environment for uterine fibroid development. However, the biological mechanisms involved in uterine fibroid progression remain unknown. This section will discuss studies on DNA lesions in uterine fibroids ( 306-308 ) ( Fig. 5 ).

Defective DNA damage response pathways

Although the mechanistic basis underlying genomic instability in uterine fibroids remains to be established, defects in DNA damage response and repair gene expression programs are heavily involved. Several DNA repair genes in uterine fibroid tumors are downregulated compared with adjacent matched myometrium from the same women, suggesting that impaired DNA repair capacity is linked to the genomic integrity and subsequent initiation/propagation of uterine fibroids. In addition, the expression of DNA repair-related genes RAD51 and BRCA1 , which are involved in double-stranded break (DSB) homologous recombination (HR), were deregulated in uterine fibroid tumors ( 309 , 310 ).

Interestingly, human uterine fibroid stem cells have accumulated DNA damage and reduced DNA repair gene expression and signaling, suggesting that human fibroid stem cells have impaired DNA repair capacity compared with normal myometrium stem cells. This compromised DNA repair system may contribute to promote mutagenesis, as well as the growth and propagation of uterine fibroids ( 311 ). In addition, DNA damage was significantly increased in uterine fibroids relative to MMSCs, as shown by increased mean percentage DNA in the tail of alkaline comet assay. Moreover, uterine fibroid stem cells had decreased expression of total DNA repair-related proteins belonging to DSB repair, specifically HR, and differential phosphorylation in comparison to adjacent MMSCs, indicating altered DNA damage response and increased DNA damage as evidenced by increased phosphorylation of histone H2A.X at serine 139 (ie, γ-H2AX) as a response to DNA DSB formation ( 311 ).

A germline mutation in Tsc2 predisposes to uterine fibroids in Eker rats, which is attributed to “second hits” in the normal allele of this gene. The risk for developing these tumors is significantly increased by early-life exposure to EDCs, suggesting that the early drivers for these tumors modulate increased uterine fibroid penetrance. Analyses of DNA repair capacity using gene and protein expression and DNA repair function in MMSCs derived from adult rats exposed to DES during uterine development were conducted. Adult MMSCs isolated from developmentally exposed rats showed decreased DNA end-joining ability, increased DNA damage, and impaired ability to repair DNA double-strand breaks compared with those from age-matched, vehicle-exposed rats, suggesting that early-life developmental EDC exposure alters the power of MMSCs to repair and reverse DNA damage, thereby providing a driver for the acquisition of mutations that may promote the development of these tumors in adulthood ( 312 ).

Other types of DNA repair, including nucleotide excision repair, which removes bulky DNA adducts caused by polycyclic aromatic hydrocarbons, and base-excision repair of oxidative DNA damage ( 313 ), should be explored in the context of uterine fibroids ( Fig. 5 ).

Wnt/β-Catenin Signaling Pathway

The Wnt/β-catenin signaling pathway is involved in various physiological events, including development, tissue renewal, cell proliferation and differentiation, and several types of tumorigenesis ( 314 , 315 ). This pathway has also been recently investigated in uterine fibroid formation ( 241 , 316 , 317 ) ( Fig. 5 ). However, contrasting results on the β-catenin expression in uterine fibroids have been reported: 1 study detected upregulated expression in uterine fibroids ( 318 ), whereas others detected no difference between uterine fibroids and myometrium ( 319 ). Recently, the mislocalization of β-catenin has been causally linked to uterine fibroids phenotype, wherein fibroids expressed higher levels of nuclear β-catenin than normal myometrium tissues. Moreover, estrogen activated β-catenin nuclear translocation and enhanced β-catenin responsive gene expression in human uterine fibroids cells via the ER ( 320 ). Thus, a paracrine role for the WNT/β-catenin pathway that enables mature myometrium or fibroid cells to send mitogenic signals to neighboring tissue stem cells in response to estrogen and progesterone has been proposed, thus leading to the growth of uterine fibroids ( 241 ).

The use of vitamin D3 has been associated with the inhibition of the Wnt/β-catenin pathway and decreased uterine fibroid cell proliferation ( 321 , 322 ). β-catenin inhibitors, such as ICG-001, cordycepin, and XAV939, and histone deacetylase (HDAC) inhibitors (HDACi), including apicidin and HDACi VIII, exhibited antiproliferative effects on uterine fibroid cells by suppressing the β-catenin signaling pathway. Additionally, HDACi exposure induced cell cycle arrest and apoptosis of uterine fibroid cells, thus representing a promising epigenetic-based therapy for uterine fibroids ( 320 ). Recently, the MED12 somatic mutation has been revealed to modulate oncogenic Wnt4/β-catenin and mTOR signaling pathways in uterine fibroids ( 174 ).

Compounds targeting Wnt/β-catenin signaling and other vital pathways are summarized in Table 2 .

Compounds targeting key pathways involved in uterine fibroids pathogenesis

Abbreviations: Akt, protein kinase B; COMT, Catechol-O-methyltransferase; ECM, extracellular matrix; EGCG, epigallocatechin gallate; GnRH, gonadotropin-releasing hormone; HDAC, histone deacetylase; miR, microRNA; mTOR, mechanistic target of rapamycin; PI3K, phosphoinositide 3-kinase; SPRM, selective progesterone receptor modulator; TGF-β, transforming growth factor beta; PGR, progesterone receptor; UF, uterine fibroids.

YAP/TAZ Pathway

ECM accumulation and aberrant cell proliferation are essential components in uterine fibroid pathogenesis. An important regulatory mechanism that connects mechanical stimuli to cellular proliferation is the Hippo pathway, including the effector proteins Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) as main mediators. YAP/TAZ has been involved in fibrotic diseases such as lung fibrosis ( 323 ) as well as in hormone-regulated organs such as ovary ( 324 ) with aberrant activation that resulted in tumorigenesis ( 325 ). A recent study has shown that YAP/TAZ nuclear localization in situ and confluent cells was higher in uterine fibroid cells compared with normal myometrium and associated tissue stiffness was higher in uterine fibroids compared with normal myometrium. Moreover, exposing fibroid cells to verteporfin (a YAP inhibitor) reduced cell survival and reduced fibronectin deposition ( 326 ). Furthermore, a recent study showed that the antifibrotic drug nintedanib inhibited YAP and produced antifibrotic effects ( 327 ). The same study showed that in vivo injection of collagenase into uterine fibroids led to a reduction in Hippo/YAP signaling and crucial genes and pathways involved in fibroid growth ( 327 ) ( Table 2 ). More studies are encouraged to further explore the role of the Hippo/YAP/TAZ pathway in fibroid pathogenesis with subsequent identification of novel targeted therapeutic strategies.

Rho/ROCK Signaling Pathway

Studies showed that mechanotransduction activates the Ras homolog family (Rho), which interacts with its downstream target Rho-kinase (ROCK) and activates the ERK/p38 MAPK-signaling cascade, and resulting in increased cell proliferation, decreased apoptosis, and upregulation of genes involved in ECM composition and remodeling ( 303 ). RhoA expression was found to be higher in uterine fibroid compared with myometrial cells ( 328 ). Interestingly, inhibition of integrin-β1 caused a decrease in active RhoA expression in uterine fibroid cells ( 301 ), while Fasudil, a ROCK inhibitor, relaxed the contraction of uterine fibroid cells in 3D collagen gels ( 278 ). It might be interesting to pursue potential antifibrotic effects of these pathway inhibitors in further studies.

Epigenetic Regulation

Tumorigenesis cannot be exclusively explained by genetic changes, as epigenetic processes are also involved ( 329 , 330 ). All epigenetics involved in regulation of gene activities, including DNA methylation, histone modification, non-coding RNA, and heterochromatinization, are disturbed in the pathogenomics of uterine fibroids ( 331 , 332 ).

Numerous data demonstrated aberrant alterations of genome methylation/demethylation in uterine fibroid cells ( 175 , 333 ). In addition, unsupervised clustering of results from DNA methylation analysis can segregate normal myometrium from uterine fibroids and classify uterine fibroids into subtypes according to MED12 mutation or the activation of HMGA2 or HMGA1 . Moreover, HOXA13 encoding the class of transcription factors called homeobox genes was identified to be hypomethylated and upregulated in fibroids compared to myometria. Abnormal HOXA13 expression was considered an essential factor contributing to the homeotic transformation into a more cervical phenotype which was linked to the development of uterine fibroids ( 135 ). MicroRNAs play a significant role in the epigenetic control of uterine fibroid development. Significant alteration in the synthesis profile of regulatory microRNAs of the families let7, miR-21, miR-93, miR-106b, miR-29, and miR-200 has been observed ( 334 , 335 ). More recently, studies on the role of long non-coding RNAs in the pathogenesis of uterine fibroids have been investigated, further demonstrating the critical role of RNA network in uterine fibroids ( 332 , 336-338 ). Epigenetic changes in the uterine fibroid genome can activate critical transduction signaling pathways, such as Wnt/β-catenin and Wnt/MAPK ( 320 , 339 ). More studies focusing on the epigenetic regulation of pathways involved in uterine fibroid pathogenesis can provide potential therapies against this disease.

Inflammation

Inflammation is a protective response from the immune system against foreign agents and involves immune cells and the release of molecular mediators. However, prolonged inflammatory status leaves the body in a constant state of alert and subsequently transforms into chronic inflammation. Chronic inflammation contributes to various conditions, including gynecologic diseases and cancer ( 340 , 341 ).

Tumor-extrinsic chronic systemic inflammation is caused by many factors, including obesity, tobacco smoking, autoimmune diseases, environmental chemical exposure, vitamin D deficiency, and excessive alcohol consumption ( 342 , 343 ). In addition, a normal cell can be transformed into a tumorous cell when repeatedly subjected to DNA damage during prolonged inflammatory status, thus triggering tumor-initiating mutations via impaired DNA repair pathways ( Fig. 2 ). Consequently, these genetic events may induce the proliferation, recruitment, and activation of inflammatory cells and increase the production of reactive oxygen species and cytokines, contributing to tumor-intrinsic inflammation ( 344 ).

Some epidemiological studies have explored the relationship between uterine fibroids and self-reported diagnosis of reproductive tract infection (RTIs) and inflammation ( 233 , 345 , 346 ). History of pelvic inflammatory disease and chlamydia infection, and intrauterine device use have been positive associated with uterine fibroid risk ( 233 ). In contrast, no association between uterine fibroids and self-reported diagnosis of pelvic inflammatory disease in African American and Caucasian women was found. However, a positive correlation with a self-reported history of chlamydia infection in Caucasian women and trichomonas, syphilis, and bacterial vaginosis in African American women has been reported ( 345 ). There is no significant association between self-reported RTIs and uterine fibroids. However, adverse associations of chlamydia infection and pelvic inflammatory disease with multiple fibroids have been reported ( 346 ). More studies using serology and biochemical characterization of past infections are needed to clarify the associations between RTIs and uterine fibroids. Interestingly, multiple associations between the higher occurrence of uterine fibroid inflammatory mediator gene polymorphisms, including interleukin (IL)-1β ( 347 , 348 ), IL-4 ( 349 ), TNF-α ( 349 , 350 ), IL-6 ( 351 ), IL-10 ( 348 ), and IL-12b receptor ( 352 ), have been reported.

A chronically active inflammatory immune system is suggested to be involved in uterine fibroid formation ( 341 , 353-355 ). It is hypothesized that in the uterus of a woman with a chronically inflammatory immune profile (due to chronic low-grade systemic inflammation) suffering a series of insults, including intrauterine infection, injury, and menses, the immune system response is exacerbated, thereby directly or indirectly inducing cell proliferation and fibrosis, which are implicated in the formation and growth of uterine fibroids ( 354 ). Numerous studies using molecular strategies and focusing on inflammatory mediators in the context of uterine fibroids have been conducted. They detected the expression of a significant number of cytokines and chemokines with proinflammatory and profibrotic features in uterine fibroids ( Table 1 ). Future research employing high-throughput methods and bioinformatic analysis should be conducted.

Inflammatory factors involved in uterine fibroids pathophysiology

Abbreviations: CCR5, C-C chemokine receptor type 5; CXCL12, C-X-C Motif Chemokine Ligand 12; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; INF-γ, interferon gamma; MCP-1, monocyte chemoattractant protein-1; MIP-1α/β, macrophage inflammatory protein 1 alpha/beta; NFkB, nuclear factor kappa B; PD-L1, programmed death-ligand 1; SCs, stem cells; TMA, tissue microarray; TNF-α, tumor necrosis factor alpha; TSLP, thymic stromal lymphopoietin; UF, uterine fibroid.

The characterization of infiltrating and circulating immune cells in women with uterine fibroids has received increasing attention. More tissue-CD68-positive macrophages inside the uterine fibroids and in the surrounding myometrium have been found than in distant myometrium tissues (at least 1.5 cm from the border of fibroids). However, no differences in the number of CD45-positive leukocytes and MCT-positive mast cells have been observed ( 355 ). A recent study in a Chinese population demonstrated that the numbers of circulating CD4+CD8+ T cells, regulatory T (Treg, CD4+) cells, and T follicular helper (Tfh) cells was notably increased in patients with uterine fibroids relative to the healthy controls, whereas the numbers of natural killer (NK) and delta gamma (γδ) T cells (CD4− CD8−) was reduced ( 356 ). Furthermore, the levels of immune check-point PD-L1 proteins were increased in uterine fibroids compared to adjacent myometrial tissues ( 357 ). Interestingly, uterine fibroids demonstrated decreased PD-L1 expression and cytotoxic T-cell infiltration compared with malignant leiomyosarcomas, indicating that the immune system behavior spectrum varies among different uterine smooth muscle tumors ( 358 ).

The expression of growth factors and cytokines is partly regulated by ovarian steroid hormones ( 359 ), critical in uterine fibroids formation and growth ( 197 ). The relationship between uterine fibroid development and early-life exposure to xenoestrogen in the context of inflammation was recently revealed in an Eker rat animal model ( 360 ). The immune cells and secreted cytokines and chemokines may influence uterine fibroid development and the tumor microenvironment. The myometrial and systemic immune profiles of women with fibroids should be investigated better to understand the role of inflammation linking to epigenome ( 33 ) in uterine fibroid pathogenesis.

Role of Vitamin D Pathway

Vitamin D forms a complex with a specific receptor called the vitamin D receptor (VDR) to mediate its pleiotropic functions via steroid transcriptional mechanisms ( 361 ). VDR modulates the expression of various genes in a tissue-specific manner. Vitamin D exhibits antiproliferative and pro-apoptotic activities and induces cell differentiation in different diseases ( 82 , 362 ), including musculoskeletal, infectious, cardiovascular, metabolic, autoimmune, neurocognitive diseases, and cancers. The role and mechanism of vitamin D action in uterine fibroids have been investigated in the past decade. In 2011, the antifibrotic effect of vitamin D was reported, showing that vitamin D is associated with reduced expression of TGF-β3-induced ECM proteins, including fibronectin and collagen type 1 in uterine fibroid cells, which were otherwise overexpressed ( 363 ). Vitamin D also inhibited the growth and proliferation of uterine fibroid cells by downregulating proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase 1 (CDK1), and B-cell lymphoma 2, and inhibiting the expression and activity of catechol-O-methyltransferase (COMT) ( 364 ). In addition, TGF-β3, a vital factor in the pathogenesis of uterine fibroids, was inhibited by increased concentrations of vitamin D ( 365 ). In the Eker rat uterine fibroid model, the administration of vitamin D decreased the size of uterine fibroids ( 366 ). In 2013, the regulatory role of vitamin D in the expression and activity of matrix metalloproteinases (MMPs), which are involved in ECM deposition, was revealed ( 99 ). Later, active vitamin D was reported to function as a potent anti-estrogen and antiprogesterone agent ( 367 ).

Furthermore, the administration of vitamin D reduced the levels of Wnt/β-catenin, leading to the downregulation of mTOR signaling expression in uterine fibroids with MED12 somatic mutations ( 321 ). The same study reported that vitamin D suppresses the expression of FEN1, an enzyme involved in DNA damage repair, in a concentration-dependent manner ( 321 ). In 2018, low serum vitamin D levels in animals were associated with increased expression of sex steroid receptors and proliferation-related genes, fibrosis, and enhanced inflammation. Vitamin D-deficient diet enhanced DNA damage in murine myometrium ( 368 ). Importantly, vitamin D also exhibits anti-inflammatory functions, and the inflammation-induced pathology of uterine fibroids has been described ( 369 ). Vitamin D suppressed the uterine fibroid phenotype by targeting different DNA repair networks ( 370 ). Recently it was reported that long-lasting and high-dose treatment with vitamin D induced significant lesion volume reduction through reduced cell proliferation via the inhibition of TGF-β3 expression and inducing apoptosis ( 371 ). Italian researchers found that vitamin D in women acted as an antiproliferative compound against small uterine fibroids ( 372 ) by arresting cell growth and inhibiting the Wnt/β-catenin pathway ( 322 ). Vitamin D effectively reduces proliferation and extracellular matrix formation in different molecular subtypes of uterine fibroids ( 371 ). In the first randomized study trial, the supplementation of 50 000 IU of vitamin D for 12 weeks inhibited lesion growth, whereas the volume of uterine fibroids in the placebo group increased ( 373 ).

Overall, the relationship between vitamin D and uterine fibroid metabolism has been characterized. Recently, our research team proposed a preliminary clinical instruction of 25(OH)D measurements and vitamin D supplementation that may be useful for clinicians involved in treating patients with uterine fibroids ( 374 ).

Role of the Microbiome

Foreign microorganisms colonizing our body include bacteria, yeasts, fungi, protozoa, archaea, and viruses; these are collectively referred to as the “microbiome” ( 375 ). The cells comprising the microbiome and the host are considered as a single ecological and biological unit, the so-called human halobiont .

Intestinal estrogen metabolism

Gut microbes shape the complex micro-ecological system of the human body ( 376 , 377 ). Many human intestinal microbes influence the physiological functions of the host and have profound effects on the synthesis and secretion of hormones, trace elements, growth factors, and immune system function. The intestinal flora and the host have a mutually beneficial relationship and are interdependent ( 377 ). The intestinal flora can be modified via hormone interaction both in vitro and in vivo, thus affecting the body’s biological equilibrium ( 378 ). Recently, whether the intestinal flora can control the levels of estrogen and its metabolites has been explored. The enzyme glucuronidase in the intestinal flora improved estrogen reabsorption ( 377 , 379 , 380 ). Several bacteria in the intestinal flora can metabolize estrogen, and they are referred to as the estrobolome . High bacterial enzyme activity of the estrobolome elevates the level of free estrogen in the enterohepatic circulation by promoting an endogenous hormonal environment, leading to an increase in hormone levels which may have a direct and indirect impact on the risk of uterine fibroids ( 381 ).

The abundance of the intestinal flora closely correlates to systemic estrogen. Many bacteria at the family and species levels control estrogen content, particularly Clostridium and Pneumococcus exhibit the most significant effect on estrogen metabolism ( 377 , 382 ). Reduced estrogen levels have been related to decreased intestinal flora diversity, including the phylum Bacteroidetes , and increased abundance of the phylum Firmicutes and species diversity of the phylum Proteobacteria ( 377 , 383 ). In addition, it has been shown that elevated levels of estrogen and its metabolites have related to the abundance of several taxa in the class Clostridia , including the order Clostridiales and the family Ruminococcaceae ( 384 ).

Wang et al have studied the effect of hysterectomy on the intestinal flora diversity, ie, the number of different species present, in patients with uterine fibroids ( 377 ). The top 3 dominant bacteria, Bacteroidetes, Proteobacteria , and Firmicutes , were the same in preoperative and postoperative patients at the phylum level. However, the enrichment of Bacteroidetes in postoperative patients was significantly lower than in preoperative patients, whereas the abundance of Proteobacteria was significantly higher. Although at the class level, Gammaproteobacteria, Bacteroidia , and Clostridia predominated in both groups, the author found a statistically higher abundance of Gammaproteobacteria (Proteobacteria) in patients after the surgery. Specifically, at the order level, the higher average abundance observed was in Enterobacteriales ( 377 ). Wang’s study reported that estrogen levels in the body could alter the intestinal flora; however, the underlying mechanism of this regulation remains unknown ( 377 ). Deeper analysis may help to understand whether gut microbiota could influence the risk of uterine fibroids through effects on endogenous estrogens.

Female reproductive tract sterility and uterine fibroid microbiome

For many years, the female reproductive tract was considered a sterile organ ( 30 , 385 , 386 ). Culture-based technologies were usually utilized to detect bacterial residence; however, they have limited applications as many microorganisms are difficult to culture in vitro. With the launch of the Human Microbiome Project in 2007, modern sequencing technologies using taxonomy-associated marker genes, such as the 16s rRNA gene or whole-genome sequences, have been used to distinguish bacteria at the species level ( 387 ). In addition, body sites that were historically supposed to be sterile are colonized by microorganisms ( 386 , 388 ). Specifically, the Human Microbiome Project reported that the uterine cavity harbors a unique microbiome ( 30 , 386 , 389 ). However, the specific function of the uterine microbiome remains unknown ( 385 , 389 ).

A pilot study evaluated the distribution of bacteria in African American women with uterine fibroids. The authors evaluated the bacterial diversity on the endometrium, adjacent myometrium, and uterine fibroids and compared them with samples from healthy controls. A greater diversity was found in the uterine fibroid patient samples compared with controls. In addition, uterine fibroid patients showed a significantly increased abundance of Bacteroidetes, Firmicutes , and Actinobacteria in the endometrium. At the general level, uterine fibroid tissues were significantly enriched in Clostridium, Allobaculum, Anaerostipes, Odoribacter, Turicibacter, Oscillospira, Ruminococcus, and Coprococcus , which are commonly associated with the gut environment. These results suggest that the systemic distribution of the gut bacteria extends to the uterus of patients with uterine fibroids, following dysbiosis or gut-barrier impairment ( 390 ). Further studies are needed to better understand whether the uterine microbiome play a role in the pathogenesis of uterine fibroids.

Conducting investigations using human tissue is critical for deciphering many normal and pathogenic processes and developing disease diagnosis techniques and future therapies. However, it could be a challenge to state the significance of the findings since uterine fibroid samples are obtained at a specific time point, at which limited information about biological samples is available. For example, whether the uterine fibroids are growing or shrinking at the time of sample collection is a relevant question. In addition, the heterogeneity of uterine fibroids also represent structural properties and collagen content changes ( 391 ), genetic ( 9 ), epigenetic ( 194 , 392 ), and cell type variations. Furthermore, due to the paracrine and mechanical effect of uterine fibroids, the manner of collecting the myometrium is a significant factor. Notably, the biology of myometrium from the uterus with fibroids or without fibroids differs ( 393 , 394 ). For these reasons and more, uterine fibroid studies need to be carefully designed and should take these factors into consideration. When working with samples, it is crucial to consider multiple factors, including race, age, BMI, menstrual cycle phase, driver mutations, to draw concise conclusions.

Integration of Multiple Pathways in Uterine Fibroids

It is important to emphasize that during the initiation and development of uterine fibroids, many biological events coincide, and multiple abnormal pathways interact, contributing to the pathogenesis of uterine fibroids. For instance, estrogen signaling activated the β-catenin pathway via the estrogen/receptor axis, therefore induced β-catenin nuclear translocation and enhanced β-catenin responsive gene expression in human uterine fibroids cells. Vitamin D3 has been associated with inhibiting the Wnt/ β-catenin, proinflammatory pathways, and ECM deposition in uterine fibroid cells ( 395 ) and restored the DNA repair capacity in both uterine fibroid cells and at-risk MMSCs ( 370 , 396 ). Diet-induced vitamin D deficiency triggered inflammation and DNA damage in murine myometrium ( 368 ). Moreover, VDR -knockdown in normal human myometrial cells increased DNA damage and inhibited DNA repair capacity ( 370 ). These studies suggested the interaction of the vitamin D3/receptor pathway with β-catenin and DNA repair pathway. Activator protein 1 (AP1) is a family of transcription factors consisting of FOS and JUN members that form homodimers or heterodimers involved in many biological processes, including differentiation, proliferation, apoptosis, and fibrotic diseases. Recent studies demonstrated that AP1 signaling promotes ECM deposition ( 397 ), and ECM activated β-catenin signaling in uterine fibroids ( 317 ). In addition, uterine fibroids expressed higher Class I HDAC enzyme levels than normal myometrial tissues, associated with activated β-catenin signaling. ( 320 ). Notably, MED12 mutations have been linked to multiple pathways directly implicated in uterine fibroid pathology as described ( 7 , 134 , 137 , 174 , 175 ). Considering that diverse pathways play a role in the pathogenesis of uterine fibroids ( Fig. 5 ), additional studies will be necessary to identify the molecular mechanism underlying the interaction network and signaling in uterine fibroids.

Malignant Transformation of Uterine Fibroids

Uterine leiomyosarcoma is a rare, aggressive, malignant tumor, which originates from the smooth muscle layer in the uterus and shares many common clinical grounds with uterine fibroids ( 398 ). Approximately 6 out of every 1 000 000 women are diagnosed with uterine leiomyosarcoma yearly. Unfortunately, its prognosis is poor, with the lowest survival rates among soft-tissue sarcomas. Uterine leiomyosarcoma represents ~1% of all uterine malignancies, and the average age of patients ranges from 40 to 50 years. Uterine leiomyosarcoma mainly metastasizes to the lungs, liver, brain, kidney, and bones ( 399 ).

Characteristics Common Between Uterine Fibroids and Leiomyosarcoma

Notably, uterine leiomyosarcomas and uterine fibroids share several common clinicopathological features that complicate their differential diagnosis. First, both tumors arise from the myometrium as focal masses within the uterine wall. Second, abnormal uterine bleeding, pelvic pain/pressure, and a pelvic mass are the primary presenting signs and symptoms for both uterine leiomyosarcoma and uterine fibroids, making it difficult to differentiate between them ( 400-403 ). Third, uterine leiomyosarcoma and fibroids share morphological and molecular characteristics that cannot be differentiated through current clinical diagnostic tests. Finally, it is said that the Black women are at higher risk for both uterine fibroids and leiomyosarcoma ( 404 , 405 ). Because suspected uterine fibroids are often conservatively managed or with minimally invasive treatments, the misdiagnosis of leiomyosarcoma for a benign uterine fibroid could potentially result in significant treatment delays, increasing patient morbidity and mortality ( 406 ).

Malignant Transformation of Uterine Fibroids to Leiomyosarcomas

It has been debated whether uterine fibroids and uterine leiomyosarcoma are part of a disease continuum. Genetic studies have demonstrated that uterine leiomyosarcomas arise de novo and may be unrelated to benign fibroids. Uterine leiomyosarcoma typically has complex karyotypes and aneuploids, while uterine fibroids have characteristic rearrangements, many of which are shared by other benign neoplasms. Intermediate forms between these 2 patterns had not been described. However, recent microarray data identified a rare subset of uterine fibroids with deletions of chromosome 1 that have transcriptional profiles that cluster with those of uterine leiomyosarcoma, suggesting that some rare leiomyosarcomas may arise from a specific subset of uterine fibroids ( 407 ). Moreover, the observation that up to 4% to 30% of uterine leiomyosarcomas harbor exon 2 mutations in the established fibroids driver gene MED12 suggests that a subset of malignant leiomyosarcomas may derive from benign uterine fibroids ( 119 , 408 , 409 ). The discrepancy in the frequency of uterine fibroids and uterine leiomyosarcoma lies in the fact that only rare histological and karyotypic variants of fibroids may be responsive to malignant progression ( 410 ). Notably, a large number of random chromosomal aberrations in uterine leiomyosarcoma suggests that genomic instability is involved in the pathogenesis of these tumors, and such instability hinders efforts to identify the primary change(s) that may now be discovered through studies of variant uterine fibroids ( 411 ).

Novel therapeutic advances for the aggressive type of uterine cancer leiomyosarcoma are hindered by the overall lack of knowledge about the functional consequences of the complex genomic and pathway alterations found in patients and limited characterization of tumor biology. The employment of new models together with advanced technologies such as single-cell sequencing, mass cytometry, and other high-throughput approaches will ultimately help to characterize the mechanisms of its pathogenesis, resistance to conventional treatments and develop novel options for treating the patients with this aggressive disease.

Future Perspectives

Despite substantial progress in our understanding of the pathobiology of uterine fibroids, several gaps need to be addressed ( Fig. 6 ).

Future research prospects. Studies elucidating the interplay among genes, epigenome, and epitranscriptome in the context of stem cell biology, microbiome, and the interaction between the endometrium and uterine fibroids can advance the knowledge on the pathogenesis of uterine fibroids and are expected to contribute to developing novel therapeutic approaches for the treatment of patients with uterine fibroids. Abbreviations: ALKBH5, ALKB homolog 5; FTO, fat mass and obesity-associated protein; HMB: heavy menstrual bleeding; IGFBPs, insulin-like growth factor binding protein-3; METTL3,14, methyltransferase like 3 and 14; UFs, uterine fibroids; YTHDF1/YTHDC1, YTH domain-containing protein.

Transcriptome and Epigenome Analysis

The early-life environment dramatically affects the functions of developing organs and increases disease susceptibility across the lifespan. In a rat model, early-life exposure to DES affected several signaling pathways, including estrogen signaling, and reprogrammed histone mark H3K4me3 and DNA methylation patterns in MMSCs derived from the developing myometrium, thus accelerating the acquisition of an adult epigenomic signature. Furthermore, this epigenomic reprogramming persisted long after the initial exposure. These findings demonstrate the importance of the epigenome, that is, early interactions between the gene and environment reprogram the epigenome, and interactions in adulthood accelerate or activate restricted epigenetic reprogramming to increase genome instability and initiate fibroids pathogenesis. Omics studies also demonstrated that uterine fibroids contain disrupted epigenome linked with genetic stability ( 135 , 412 ). Notably, the myometrium of uterine fibroids patients has a distinct transcriptomic pattern compared with non-diseased myometrium ( 394 ), and cells from diseased myometrium responded differently to progesterone ( 413 ). These studies suggest that adjacent myometrium from the uterus with uterine fibroids should not be considered as normal tissue.

To further elucidate the role of interaction among the genes, epigenome, and environment in process of uterine fibroid pathogenesis, the following issues should be addressed. First, the genetic landscapes of normal, at-risk, and uterine fibroids stem cells should be characterized using genome-wide omics methods to better understand the genome, epigenome, and epitranscriptome. Second, the other insults that cause the abnormal reprogramming of MMSCs should be identified. Lastly, the interaction between early hits in early life and late hits in adult life should be explored in the context of uterine fibroid development.

Recently, the rapid development of single-cell multi-omics approaches is transforming our understanding of disease initiation and progression. Therefore, they can be utilized to assess the transcriptome, epigenome, spatial profiling, and proteome of uterine fibroids, contributing to increased knowledge on the cell state, ontogeny, epigenome state, phenotype, and function of uterine fibroids ( Fig. 6 ).

Epitranscriptomics

The epitranscriptome refers to the complete ensemble of chemical modifications affecting the RNA transcripts (coding and non-coding RNAs), and epitranscriptomics is an emerging field in molecular medicine with vast potential. To date, more than 160 different chemical modifications in RNA have been identified in living organisms. N6-methyladenosine (m 6 A) is the most pervasive, abundant, and conserved in eukaryotic mRNAs, occurring in ~25% of transcripts genome-wide, and it is enriched near stop codons, 5′- and 3′-untranslated regions, and within long internal exons ( 414 , 415 ). m 6 A is co-transcriptionally incorporated by so-called writers , including the METTL3-METTL14 core methyltransferase complex and associated proteins, such as RBM15, WTPA, and VIRMA, that confer target mRNA specificity, eliminated by demethylases FTO and ALKBH5 ( erasers ), and recognized by readers , including the YTH protein family ( Fig. 6 ). m 6 A-bound readers ultimately determine the posttranscriptional fate of methylated mRNAs by modulating cellular activities that control RNA stability, processing, and translation. m 6 A is thus a pervasive regulator of gene expression and a key determinant of cell fate and function. Accordingly, the disruption of its homeostasis has been implicated in several pathological conditions, including cancer. Thus far, epitranscriptomic studies on uterine fibroids are mainly unknown. However, several key m 6 A regulators were recently revealed to be dysregulated in uterine fibroids, suggesting that epitranscriptomics play an important role in uterine fibroid pathogenesis ( 416 , 417 ). However, more studies are needed to explore the function of the RNA methylation machinery and m 6 A in uterine fibroid development. Recently, a potent and selective catalytic inhibitor of METTL3 was developed and can reduce acute myeloid leukemia growth and increase differentiation and apoptosis, suggesting that targeting METTL3 as a potential therapeutic strategy against diseases such as acute myeloid leukemia. Therefore, investigations on epitranscriptomic targeting uterine fibroids should be conducted.

Endometrium Receptivity and Heavy Menstrual Bleeding

Uterine fibroids cause female reproductive disorders, including heavy menstrual bleeding and poor receptivity and implantation, leading to infertility and affecting millions of women globally. These disorders indicate endometrial dysfunctions and are related to the presence of adjacent uterine fibroids. Remarkably, the degree of dysfunction is associated with the location and size of the uterine fibroids ( 418 ). However, how fibroids affect endometrial functions remains unclear.

Uterine fibroid-caused expansion in the endometrial surface area generally results in more significant menstrual bleeding and transformations in the shape of uterine cells, thus eventually affecting gene expression and function. Furthermore, recent studies demonstrated that uterine fibroids could actively influence the adjacent endometrium and the entire uterine cavity ( 419 ). Therefore, elucidating the mechanism underlying the effect of uterine fibroids on the endometrium is necessary. In addition, the impact of uterine fibroids on endometrium function via exosome is a promising area to be explored ( 266 , 420 ) ( Fig. 6 ).

The impact of alterations in the endometrial microbiome on uterine fibroid pathogenesis has not been investigated. The paradigm that the uterus is a sterile environment remains highly controversial. The vagina contains trillions of bacterial cells, whereas the uterus and the Fallopian tubes are generally considered sterile. As alterations in the gut microbiota can lead to several pathologies, such as inflammation, autoimmune diseases, and obesity, it is proposed that the uterine microbiota may be altered in patients with uterine fibroids. A diverse microbiota has been detected in fibroids relative to other uterine tissues and those from healthy controls. In addition, uterine fibroids may associate with local and systemic inflammation that may promote the translocation of the gut microbiota into the endometrium. Future studies should explore the composition and identify the role of the microbiome in uterine fibroids. How bioactive metabolites from the microbiome provide the constituents of the fibroids microenvironment and affect the surrounding tissues should also be investigated ( Fig. 6 ).

Leiomyosarcoma

Although the current standard practice has been used to differentiate aggressive leiomyosarcoma from benign uterine fibroids, further studies are needed to explore early diagnosis tools to distinguish these 2 uterine tumors. Currently, several approaches are employed in basic research, which may lead to future clinical practice options.

Promoter-based imaging system

Uterine leiomyosarcoma is most often discovered by chance when a woman has a hysterectomy performed for uterine fibroids. To differentiate uterine leiomyosarcomas from fibroids with imaging, a molecular bio-imaging probe for noninvasive differentiation approach was recently established in a preclinical animal model ( 398 ). The diagnostic strategy was to use the cancer-specific enhanced survivin expression in malignant vs normal/benign cells to test its promoter driving potential of a downstream reporter gene that will detect cancer cells once activated. Because of solid promoter activity, tumor specificity, and capacity for clinical translation, survivin promoter-driven biological signal may represent a practical, new system to facilitate early leiomyosarcomas diagnosis. One study reported that adenovirus (Ad-SUR-LUC) was injected into the animals and paired the imaging reporter gene with a complementary imaging agent in a system that can be used to measure bioluminescence driven by the surviving promoter. This approach could distinguish leiomyosarcoma lesions from normal uterine tissue or benign uterine fibroid lesions with good accuracy. In this regard, this system can impact the management of suspicious uterine masses, a current major challenge in clinical gynecology.

Genetic and transcriptome profiling

In recent years, high-throughput sequencing technologies have provided unprecedented opportunities to depict the development of diseases at multiple molecular levels. The integration and analysis of these multi-omics datasets allow us to yield a better understanding and a clearer picture of the under-studied systems ( 421 , 422 ). Through integrated comparative genomic and transcriptomic analysis, differential genetic targets between uterine leiomyosarcoma and fibroids have been identified ( 423 , 424 ). In leiomyosarcomas, genetic mutation burden exhibited higher copy number variations, single nucleotide variants, small insertions/deletions, and gene fusions compared with uterine fibroids. Comparative genomic hybridization (CGH) array analysis reveals a chromosomal and genomic complexity starting from uterine fibroids, with few chromosomal alterations, to uterine leiomyosarcoma, which harbors many intrachromosomal damages, and chromothripsis as evidence of their genomic complexity ( 116 , 424 , 425 ). In addition, a differential transcriptomic profile was observed for uterine leiomyosarcomas ( 423 ). These novel genetic and transcriptional targets may be potential diagnostic markers to differentiate uterine leiomyosarcoma from fibroids ( 423 , 426 ).

Aberrant specific pathways

The Hedgehog pathway is one of the key regulators involved in many biological events. Malfunction of this pathway is associated with various diseases, including several types of female cancers ( 427 ). An initial study demonstrated that elevated expression of SMO and GLI 1, the key members of the Hedgehog pathway, was observed in leiomyosarcoma relative to normal myometrium and uterine fibroid tumors. In addition, overexpression of Hedgehog proteins was correlated with poor prognosis in leiomyosarcomas patients ( 428 ). A subsequent study demonstrated that the expression profile of Hedgehog signaling pathway markers and the response to Hedgehog pharmacological inhibition differed between leiomyosarcoma cells and fibroids cells ( 429 ). The expression of crucial Hedgehog members SMO and GLIs 1, 2, and 3 was upregulated in leiomyosarcoma cells, increasing the nuclear levels of GLI proteins. Treatment with LDE225 (SMO inhibitor) and Gant61 (GLI inhibitor) resulted in a significant reduction in GLI protein levels in leiomyosarcoma concomitantly with a decrease in leiomyosarcoma cell proliferation, migration, and invasion ( 429 ).

Additionally, the expression of DNMT members (1, 3a, and 3b) was upregulated in leiomyosarcoma compared to normal uterine smooth muscle cells. Treatment of leiomyosarcoma cells with DNMT inhibitor (5-Aza-dC) decreased the expression of SMO and GLI1 as well as nuclear translocation of GL1 and 2 concomitantly with a decrease in leiomyosarcoma cell proliferation, migration, and increase in leiomyosarcoma cell apoptosis ( 429 ). These studies showed that the Hedgehog pathway and DNA methylation network and their interaction might play an essential role in uterine leiomyosarcoma development.

Targeted Therapeutics

Targeted therapy exclusively focuses on uterine fibroid cells to shrink tumor lesions with minimal insult to surrounding tissues, not interfering with systemic hormones or fertility. Targeted therapies have been proposed via the local injection of collagenase from Clostridium histolyticum and gene therapy to deliver designed viral vectors. Collagenase can dissolve disorganized extracellular collagen fibers in uterine fibroids, and proof-of-principle studies have significantly reduced uterine fibroid size ( 430 , 431 ). Moreover, a phase I clinical trial with 15 women demonstrated the safety and tolerability of collagenase derived from C. histolyticum ( {"type":"clinical-trial","attrs":{"text":"NCT02889848","term_id":"NCT02889848"}} NCT02889848 ). Localized targeted strategy via modified adenovirus vectors ( 432 , 433 ) resulted in reduced tumor size and showed the absence of adenovirus in surrounding tissues, uterine fibroid-targeting specificity, and good safety profile. Adenovirus expressing dominantly negative ERs has also been used, and inhibition of fibroid growth in nude mice was observed ( 434 ). Magnetic nanoparticles can enhance the effectiveness of gene therapy against both differentiated human fibroid cells and tumor-initiating stem cells ( 435 ). Using localized nonsurgical adenovirus-based alternative for the treatment of uterine fibroids, the combination of viral-based gene delivery and nanotechnology led to more efficient targeting of fibroid tumors, the lower viral dose required, and consequently, an overall safer profile ( 435 ). Novel targeted therapies against uterine fibroids with better efficacy profile are needed, especially for African American women.

In summary, considerable progress has been made in the past decade to study the interplay of steroid hormones, risk factors, stem cells, genetics, and epigenetics that contribute to the developmental origin and pathogenesis of uterine fibroids. Deeper mechanistic insights into uterine fibroids’ etiology and complexity will lead to long-term, fertility-friendly, and effective drugs for preventing patients with this common tumor.

Acknowledgments

We would like to thank Dr. Darlene Dixon for critically reviewing our manuscript and Ms. Jinda Sekhon for editing our manuscript. Figures were created using BioRender.

Financial Support: This work was supported in part by National Institutes of Health (grant numbers: RO1 ES028615, RO1 HD094378, U54 MD007602, RO1 087417, RO1 HD094380, and HD106285).

Author Contributions: Q.Y. and A.A. conceived the manuscript. M.V.B., T.B., and Q.Y. contributed to the figures. M.V.B., M.A., and Q.Y. contributed to the tables. All authors wrote sections of the manuscript.

Abbreviations

Contributor information.

Qiwei Yang, Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA.

Michal Ciebiera, Second Department of Obstetrics and Gynecology, Center of Postgraduate Medical Education, ul. Cegłowska 80, 01-809, Warsaw, Poland.

Maria Victoria Bariani, Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA.

Mohamed Ali, Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.

Hoda Elkafas, Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, USA. Department of Pharmacology and Toxicology, Egyptian Drug Authority, formerly National Organization for Drug Control and Research, Cairo 35521, Egypt.

Thomas G Boyer, Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA.

Ayman Al-Hendy, Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA.

Additional Information

Disclosures: Dr. Ayman Al-Hendy is a consultant for Abb-vie, Myovant, and OBS-EVA. No conflicts are declared for the remaining authors.

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Research Paper – Structure, Examples and Writing Guide

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Research Paper

Definition:

Research Paper is a written document that presents the author’s original research, analysis, and interpretation of a specific topic or issue.

It is typically based on Empirical Evidence, and may involve qualitative or quantitative research methods, or a combination of both. The purpose of a research paper is to contribute new knowledge or insights to a particular field of study, and to demonstrate the author’s understanding of the existing literature and theories related to the topic.

Structure of Research Paper

The structure of a research paper typically follows a standard format, consisting of several sections that convey specific information about the research study. The following is a detailed explanation of the structure of a research paper:

The title page contains the title of the paper, the name(s) of the author(s), and the affiliation(s) of the author(s). It also includes the date of submission and possibly, the name of the journal or conference where the paper is to be published.

The abstract is a brief summary of the research paper, typically ranging from 100 to 250 words. It should include the research question, the methods used, the key findings, and the implications of the results. The abstract should be written in a concise and clear manner to allow readers to quickly grasp the essence of the research.

Introduction

The introduction section of a research paper provides background information about the research problem, the research question, and the research objectives. It also outlines the significance of the research, the research gap that it aims to fill, and the approach taken to address the research question. Finally, the introduction section ends with a clear statement of the research hypothesis or research question.

Literature Review

The literature review section of a research paper provides an overview of the existing literature on the topic of study. It includes a critical analysis and synthesis of the literature, highlighting the key concepts, themes, and debates. The literature review should also demonstrate the research gap and how the current study seeks to address it.

The methods section of a research paper describes the research design, the sample selection, the data collection and analysis procedures, and the statistical methods used to analyze the data. This section should provide sufficient detail for other researchers to replicate the study.

The results section presents the findings of the research, using tables, graphs, and figures to illustrate the data. The findings should be presented in a clear and concise manner, with reference to the research question and hypothesis.

The discussion section of a research paper interprets the findings and discusses their implications for the research question, the literature review, and the field of study. It should also address the limitations of the study and suggest future research directions.

The conclusion section summarizes the main findings of the study, restates the research question and hypothesis, and provides a final reflection on the significance of the research.

The references section provides a list of all the sources cited in the paper, following a specific citation style such as APA, MLA or Chicago.

How to Write Research Paper

You can write Research Paper by the following guide:

• Choose a Topic: The first step is to select a topic that interests you and is relevant to your field of study. Brainstorm ideas and narrow down to a research question that is specific and researchable.
• Conduct a Literature Review: The literature review helps you identify the gap in the existing research and provides a basis for your research question. It also helps you to develop a theoretical framework and research hypothesis.
• Develop a Thesis Statement : The thesis statement is the main argument of your research paper. It should be clear, concise and specific to your research question.
• Plan your Research: Develop a research plan that outlines the methods, data sources, and data analysis procedures. This will help you to collect and analyze data effectively.
• Collect and Analyze Data: Collect data using various methods such as surveys, interviews, observations, or experiments. Analyze data using statistical tools or other qualitative methods.
• Organize your Paper : Organize your paper into sections such as Introduction, Literature Review, Methods, Results, Discussion, and Conclusion. Ensure that each section is coherent and follows a logical flow.
• Write your Paper : Start by writing the introduction, followed by the literature review, methods, results, discussion, and conclusion. Ensure that your writing is clear, concise, and follows the required formatting and citation styles.
• Edit and Proofread your Paper: Review your paper for grammar and spelling errors, and ensure that it is well-structured and easy to read. Ask someone else to review your paper to get feedback and suggestions for improvement.
• Cite your Sources: Ensure that you properly cite all sources used in your research paper. This is essential for giving credit to the original authors and avoiding plagiarism.

Research Paper Example

Note : The below example research paper is for illustrative purposes only and is not an actual research paper. Actual research papers may have different structures, contents, and formats depending on the field of study, research question, data collection and analysis methods, and other factors. Students should always consult with their professors or supervisors for specific guidelines and expectations for their research papers.

Research Paper Example sample for Students:

Title: The Impact of Social Media on Mental Health among Young Adults

Abstract: This study aims to investigate the impact of social media use on the mental health of young adults. A literature review was conducted to examine the existing research on the topic. A survey was then administered to 200 university students to collect data on their social media use, mental health status, and perceived impact of social media on their mental health. The results showed that social media use is positively associated with depression, anxiety, and stress. The study also found that social comparison, cyberbullying, and FOMO (Fear of Missing Out) are significant predictors of mental health problems among young adults.

Introduction: Social media has become an integral part of modern life, particularly among young adults. While social media has many benefits, including increased communication and social connectivity, it has also been associated with negative outcomes, such as addiction, cyberbullying, and mental health problems. This study aims to investigate the impact of social media use on the mental health of young adults.

Literature Review: The literature review highlights the existing research on the impact of social media use on mental health. The review shows that social media use is associated with depression, anxiety, stress, and other mental health problems. The review also identifies the factors that contribute to the negative impact of social media, including social comparison, cyberbullying, and FOMO.

Methods : A survey was administered to 200 university students to collect data on their social media use, mental health status, and perceived impact of social media on their mental health. The survey included questions on social media use, mental health status (measured using the DASS-21), and perceived impact of social media on their mental health. Data were analyzed using descriptive statistics and regression analysis.

Results : The results showed that social media use is positively associated with depression, anxiety, and stress. The study also found that social comparison, cyberbullying, and FOMO are significant predictors of mental health problems among young adults.

Discussion : The study’s findings suggest that social media use has a negative impact on the mental health of young adults. The study highlights the need for interventions that address the factors contributing to the negative impact of social media, such as social comparison, cyberbullying, and FOMO.

Conclusion : In conclusion, social media use has a significant impact on the mental health of young adults. The study’s findings underscore the need for interventions that promote healthy social media use and address the negative outcomes associated with social media use. Future research can explore the effectiveness of interventions aimed at reducing the negative impact of social media on mental health. Additionally, longitudinal studies can investigate the long-term effects of social media use on mental health.

Limitations : The study has some limitations, including the use of self-report measures and a cross-sectional design. The use of self-report measures may result in biased responses, and a cross-sectional design limits the ability to establish causality.

Implications: The study’s findings have implications for mental health professionals, educators, and policymakers. Mental health professionals can use the findings to develop interventions that address the negative impact of social media use on mental health. Educators can incorporate social media literacy into their curriculum to promote healthy social media use among young adults. Policymakers can use the findings to develop policies that protect young adults from the negative outcomes associated with social media use.

References :

• Twenge, J. M., & Campbell, W. K. (2019). Associations between screen time and lower psychological well-being among children and adolescents: Evidence from a population-based study. Preventive medicine reports, 15, 100918.
• Primack, B. A., Shensa, A., Escobar-Viera, C. G., Barrett, E. L., Sidani, J. E., Colditz, J. B., … & James, A. E. (2017). Use of multiple social media platforms and symptoms of depression and anxiety: A nationally-representative study among US young adults. Computers in Human Behavior, 69, 1-9.
• Van der Meer, T. G., & Verhoeven, J. W. (2017). Social media and its impact on academic performance of students. Journal of Information Technology Education: Research, 16, 383-398.

Appendix : The survey used in this study is provided below.

Social Media and Mental Health Survey

• How often do you use social media per day?
• Less than 30 minutes
• 30 minutes to 1 hour
• 1 to 2 hours
• 2 to 4 hours
• More than 4 hours
• Which social media platforms do you use?
• Others (Please specify)
• How often do you experience the following on social media?
• Social comparison (comparing yourself to others)
• Cyberbullying
• Fear of Missing Out (FOMO)
• Have you ever experienced any of the following mental health problems in the past month?
• Do you think social media use has a positive or negative impact on your mental health?
• Very positive
• Somewhat positive
• Somewhat negative
• Very negative
• In your opinion, which factors contribute to the negative impact of social media on mental health?
• Social comparison
• In your opinion, what interventions could be effective in reducing the negative impact of social media on mental health?
• Education on healthy social media use
• Counseling for mental health problems caused by social media
• Social media detox programs
• Regulation of social media use

Thank you for your participation!

Applications of Research Paper

Research papers have several applications in various fields, including:

• Advancing knowledge: Research papers contribute to the advancement of knowledge by generating new insights, theories, and findings that can inform future research and practice. They help to answer important questions, clarify existing knowledge, and identify areas that require further investigation.
• Informing policy: Research papers can inform policy decisions by providing evidence-based recommendations for policymakers. They can help to identify gaps in current policies, evaluate the effectiveness of interventions, and inform the development of new policies and regulations.
• Improving practice: Research papers can improve practice by providing evidence-based guidance for professionals in various fields, including medicine, education, business, and psychology. They can inform the development of best practices, guidelines, and standards of care that can improve outcomes for individuals and organizations.
• Educating students : Research papers are often used as teaching tools in universities and colleges to educate students about research methods, data analysis, and academic writing. They help students to develop critical thinking skills, research skills, and communication skills that are essential for success in many careers.
• Fostering collaboration: Research papers can foster collaboration among researchers, practitioners, and policymakers by providing a platform for sharing knowledge and ideas. They can facilitate interdisciplinary collaborations and partnerships that can lead to innovative solutions to complex problems.

When to Write Research Paper

Research papers are typically written when a person has completed a research project or when they have conducted a study and have obtained data or findings that they want to share with the academic or professional community. Research papers are usually written in academic settings, such as universities, but they can also be written in professional settings, such as research organizations, government agencies, or private companies.

Here are some common situations where a person might need to write a research paper:

• For academic purposes: Students in universities and colleges are often required to write research papers as part of their coursework, particularly in the social sciences, natural sciences, and humanities. Writing research papers helps students to develop research skills, critical thinking skills, and academic writing skills.
• For publication: Researchers often write research papers to publish their findings in academic journals or to present their work at academic conferences. Publishing research papers is an important way to disseminate research findings to the academic community and to establish oneself as an expert in a particular field.
• To inform policy or practice : Researchers may write research papers to inform policy decisions or to improve practice in various fields. Research findings can be used to inform the development of policies, guidelines, and best practices that can improve outcomes for individuals and organizations.
• To share new insights or ideas: Researchers may write research papers to share new insights or ideas with the academic or professional community. They may present new theories, propose new research methods, or challenge existing paradigms in their field.

Purpose of Research Paper

The purpose of a research paper is to present the results of a study or investigation in a clear, concise, and structured manner. Research papers are written to communicate new knowledge, ideas, or findings to a specific audience, such as researchers, scholars, practitioners, or policymakers. The primary purposes of a research paper are:

• To contribute to the body of knowledge : Research papers aim to add new knowledge or insights to a particular field or discipline. They do this by reporting the results of empirical studies, reviewing and synthesizing existing literature, proposing new theories, or providing new perspectives on a topic.
• To inform or persuade: Research papers are written to inform or persuade the reader about a particular issue, topic, or phenomenon. They present evidence and arguments to support their claims and seek to persuade the reader of the validity of their findings or recommendations.
• To advance the field: Research papers seek to advance the field or discipline by identifying gaps in knowledge, proposing new research questions or approaches, or challenging existing assumptions or paradigms. They aim to contribute to ongoing debates and discussions within a field and to stimulate further research and inquiry.
• To demonstrate research skills: Research papers demonstrate the author’s research skills, including their ability to design and conduct a study, collect and analyze data, and interpret and communicate findings. They also demonstrate the author’s ability to critically evaluate existing literature, synthesize information from multiple sources, and write in a clear and structured manner.

Characteristics of Research Paper

Research papers have several characteristics that distinguish them from other forms of academic or professional writing. Here are some common characteristics of research papers:

• Evidence-based: Research papers are based on empirical evidence, which is collected through rigorous research methods such as experiments, surveys, observations, or interviews. They rely on objective data and facts to support their claims and conclusions.
• Structured and organized: Research papers have a clear and logical structure, with sections such as introduction, literature review, methods, results, discussion, and conclusion. They are organized in a way that helps the reader to follow the argument and understand the findings.
• Formal and objective: Research papers are written in a formal and objective tone, with an emphasis on clarity, precision, and accuracy. They avoid subjective language or personal opinions and instead rely on objective data and analysis to support their arguments.
• Citations and references: Research papers include citations and references to acknowledge the sources of information and ideas used in the paper. They use a specific citation style, such as APA, MLA, or Chicago, to ensure consistency and accuracy.
• Peer-reviewed: Research papers are often peer-reviewed, which means they are evaluated by other experts in the field before they are published. Peer-review ensures that the research is of high quality, meets ethical standards, and contributes to the advancement of knowledge in the field.
• Objective and unbiased: Research papers strive to be objective and unbiased in their presentation of the findings. They avoid personal biases or preconceptions and instead rely on the data and analysis to draw conclusions.

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Research papers have many advantages, both for the individual researcher and for the broader academic and professional community. Here are some advantages of research papers:

• Contribution to knowledge: Research papers contribute to the body of knowledge in a particular field or discipline. They add new information, insights, and perspectives to existing literature and help advance the understanding of a particular phenomenon or issue.
• Opportunity for intellectual growth: Research papers provide an opportunity for intellectual growth for the researcher. They require critical thinking, problem-solving, and creativity, which can help develop the researcher’s skills and knowledge.
• Career advancement: Research papers can help advance the researcher’s career by demonstrating their expertise and contributions to the field. They can also lead to new research opportunities, collaborations, and funding.
• Academic recognition: Research papers can lead to academic recognition in the form of awards, grants, or invitations to speak at conferences or events. They can also contribute to the researcher’s reputation and standing in the field.
• Impact on policy and practice: Research papers can have a significant impact on policy and practice. They can inform policy decisions, guide practice, and lead to changes in laws, regulations, or procedures.
• Advancement of society: Research papers can contribute to the advancement of society by addressing important issues, identifying solutions to problems, and promoting social justice and equality.

Limitations of Research Paper

Research papers also have some limitations that should be considered when interpreting their findings or implications. Here are some common limitations of research papers:

• Limited generalizability: Research findings may not be generalizable to other populations, settings, or contexts. Studies often use specific samples or conditions that may not reflect the broader population or real-world situations.
• Potential for bias : Research papers may be biased due to factors such as sample selection, measurement errors, or researcher biases. It is important to evaluate the quality of the research design and methods used to ensure that the findings are valid and reliable.
• Ethical concerns: Research papers may raise ethical concerns, such as the use of vulnerable populations or invasive procedures. Researchers must adhere to ethical guidelines and obtain informed consent from participants to ensure that the research is conducted in a responsible and respectful manner.
• Limitations of methodology: Research papers may be limited by the methodology used to collect and analyze data. For example, certain research methods may not capture the complexity or nuance of a particular phenomenon, or may not be appropriate for certain research questions.
• Publication bias: Research papers may be subject to publication bias, where positive or significant findings are more likely to be published than negative or non-significant findings. This can skew the overall findings of a particular area of research.
• Time and resource constraints: Research papers may be limited by time and resource constraints, which can affect the quality and scope of the research. Researchers may not have access to certain data or resources, or may be unable to conduct long-term studies due to practical limitations.

About the author

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Researcher, Academic Writer, Web developer

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Comprehensive Review of Uterine Fibroids: Developmental Origin, Pathogenesis, and Treatment

Affiliations.

• 1 Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA.
• 2 Second Department of Obstetrics and Gynecology, Center of Postgraduate Medical Education, ul. Cegłowska 80, 01-809, Warsaw, Poland.
• 3 Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.
• 4 Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL 60612, USA.
• 5 Department of Pharmacology and Toxicology, Egyptian Drug Authority, formerly National Organization for Drug Control and Research, Cairo 35521, Egypt.
• 6 Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229-3900, USA.
• PMID: 34741454
• PMCID: PMC9277653
• DOI: 10.1210/endrev/bnab039

Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing the most common tumors in women worldwide. To date, no long-term or noninvasive treatment option exists for hormone-dependent uterine fibroids, due to the limited knowledge about the molecular mechanisms underlying the initiation and development of uterine fibroids. This paper comprehensively summarizes the recent research advances on uterine fibroids, focusing on risk factors, development origin, pathogenetic mechanisms, and treatment options. Additionally, we describe the current treatment interventions for uterine fibroids. Finally, future perspectives on uterine fibroids studies are summarized. Deeper mechanistic insights into tumor etiology and the complexity of uterine fibroids can contribute to the progress of newer targeted therapies.

Keywords: developmental origin; epigenetics pathways; future directions; genetic instability; novel treatment; reprogramming; uterine fibroids.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Publication types

• Research Support, N.I.H., Extramural
• Leiomyoma* / etiology
• Leiomyoma* / therapy
• Myometrium / pathology
• Risk Factors
• Uterine Neoplasms* / etiology
• Uterine Neoplasms* / pathology
• Uterine Neoplasms* / therapy

Grants and funding

• R01 ES028615/ES/NIEHS NIH HHS/United States
• R01 HD094380/HD/NICHD NIH HHS/United States
• U54 MD007602/MD/NIMHD NIH HHS/United States
• R01 HD087417/HD/NICHD NIH HHS/United States
• R01 HD106285/HD/NICHD NIH HHS/United States
• R01 HD094378/HD/NICHD NIH HHS/United States

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A bibliometric analysis of sustainable development goals (SDGs): a review of progress, challenges, and opportunities

• Published: 07 May 2023

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• Manoranjan Mishra   ORCID: orcid.org/0000-0003-4545-7218 1 , 11 ,
• Sudarsan Desul   ORCID: orcid.org/0000-0003-4867-236X 2 , 12 ,
• Celso Augusto Guimarães Santos   ORCID: orcid.org/0000-0001-7927-9718 3 ,
• Shailendra Kumar Mishra   ORCID: orcid.org/0000-0002-1840-0374 4 ,
• Abu Hena Mustafa Kamal   ORCID: orcid.org/0000-0002-2054-2398 5 ,
• Shreerup Goswami   ORCID: orcid.org/0000-0002-2558-3623 6 ,
• Ahmed Mukalazi Kalumba   ORCID: orcid.org/0000-0001-7593-9096 7 ,
• Ramakrishna Biswal   ORCID: orcid.org/0000-0003-3681-9790 8 ,
• Richarde Marques da Silva   ORCID: orcid.org/0000-0001-6601-5174 9 ,
• Carlos Antonio Costa dos Santos   ORCID: orcid.org/0000-0003-2414-2911 10 &
• Kabita Baral   ORCID: orcid.org/0000-0003-0241-738X 11  

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The Sustainable Development Goals (SDGs) are a global appeal to protect the environment, combat climate change, eradicate poverty, and ensure access to a high quality of life and prosperity for all. The next decade is crucial for determining the planet’s direction in ensuring that populations can adapt to climate change. This study aims to investigate the progress, challenges, opportunities, trends, and prospects of the SDGs through a bibliometric analysis from 2015 to 2022, providing insight into the evolution and maturity of scientific research in the field. The Web of Science core collection citation database was used for the bibliometric analysis, which was conducted using VOSviewer and RStudio. We analyzed 12,176 articles written in English to evaluate the present state of progress, as well as the challenges and opportunities surrounding the SDGs. This study utilized a variety of methods to identify research hotspots, including analysis of keywords, productive researchers, and journals. In addition, we conducted a comprehensive literature review by utilizing the Web of Science database. The results show that 31% of SDG-related research productivity originates from the USA, China, and the UK, with an average citation per article of 15.06. A total of 45,345 authors around the world have contributed to the field of SDGs, and collaboration among authors is also quite high. The core research topics include SDGs, climate change, Agenda 2030, the circular economy, poverty, global health, governance, food security, sub-Saharan Africa, the Millennium Development Goals, universal health coverage, indicators, gender, and inequality. The insights gained from this analysis will be valuable for young researchers, practitioners, policymakers, and public officials as they seek to identify patterns and high-quality articles related to SDGs. By advancing our understanding of the subject, this research has the potential to inform and guide future efforts to promote sustainable development. The findings indicate a concentration of research and development on SDGs in developed countries rather than in developing and underdeveloped countries.

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Sustainable development goals: a bibliometric analysis of literature reviews

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Bibliometric analysis of scientific publications on “sustainable development goals” with emphasis on “good health and well-being” goal (2015–2019)

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Avoid common mistakes on your manuscript.

1 Introduction

The Anthropocene era is marked by a range of significant global challenges, including climate change, environmental degradation, public health issues such as global pandemics, rising social inequality, and food and water scarcity in several countries (Huang & Chang, 2022 ; Khojasteh et al., 2022 ). The growing human population demands the speedy development of modern infrastructure, including housing, health care, quality roads, education, communication, and related services (Aravindaraj & Rajan Chinna, 2022 ). Traditional lifestyles and values are eroding fast and being replaced by technology-driven living standards (Chen & Wang, 2022 ; Wahab et al., 2012 ).

The rapid development of the global economy driven by excessive consumption of natural resources and unsustainable development policies has led to serious socioeconomic and environmental challenges in recent decades (Guo et al., 2022 ). Achieving benchmarks of economic growth at any cost has become a top priority for governments to withstand international competition and fulfill local aspirations. In this process, narratives on development often ignore and overlook the irreversible harm caused by developmental hazards to natural entities and the amount of entropy raised in the earth’s system (Alcántara-Ayala, 2002 ; Hemingway & Gunawan, 2018 ).

Sustainability has an important role in the world agenda, mainly after the advances of the Rio Declaration on Environment and Development in 1992 (Rio 92), the Declaration of Principles for the Sustainable Management of Forests, and the Agenda 21 of the United Nations Conference on Environment and Development (Guo et al., 2022 ). These advances discussed how to make sustainable development a reality in the world. Furthermore, in September 2001, the United Nations presented the Millennium Development Goals (MDGs) as a list of common goals for the world community to achieve by 2015. Since then, remarkable progress has been made toward achieving the MDGs (Fehling et al., 2013 ). The objectives of MDGs were to minimize deepening global mistrust toward international economic institutions and provide a unique platform for the member states to act collectively with individual accountability (McArthur, 2014 ). Thus, implementing the MDGs would improve health standards, reduce maternal and child mortality, minimize social disparities, promote gender justice and eradicate poverty among populations to make the earth system a better place to live (Chasse, 2016 ; Doyle & Stiglitz, 2014 ). Long-time concerted and consistent efforts of the UN ultimately succeeded in convincing member states to envisage the tenets of MGDs in their development policies and follow the proposed timelines (Lomazzi et al., 2014 ).

In 2015, the United Nations General Assembly adopted the Sustainable Development Goals (SDGs) in the 2030 Agenda for sustainable development, which included 17 goals and 169 targets. Since then, greater attention has been paid to sustainability at different levels of governance structures in financial institutions, companies in the public and private sectors, and in governments across the planet (Death and Gabay, 2015 ). Nevertheless, the ongoing deforestation of the Amazon (Silva et al., 2023 ) and rising levels of greenhouse gas emissions are posing severe threats to the health of our planet. This, in turn, is leading to a chain of climate phenomena that have an impact on the economies of nations and the quality of life of their populations (Espinoza et al., 2023 ), as well as an increase in the frequency of severe natural disasters (Mishra et al., 2022 ). Thus, what are the current progress, challenges, and opportunities for the SDGs? Understanding the level of discussion on the SDGs theme is crucial for us to know the available proposals and solutions and see the path forward. In this sense, SDGs have sparked significant interest among a wide range of stakeholders, including those involved in environmental decision-making, business, finance (Di Vaio et al., 2022 ), and water services, particularly governance, management, and technical solutions (Di Vaio et al., 2021 ). Currently, there is global consensus on the importance of implementing the SDGs, which can lead to development while preserving the environment and the population’s quality of life (Bebbington & Unerman, 2018 ). Water sustainability issues were included in the UN’s Agenda 2030 and 17 SDGs, providing a common framework for measuring sustainable development from a social, economic, and environmental perspective (Glass & Newig, 2019 ).

Before sustainable development, the major pitfall of approaches includes the absence of sectoral integration in making strategies and their implementation on the ground level (Garcia-Feijoo et al., 2020 ). The negative consequences of development policies included focusing on a specific sector over other development sectors, which resulted in diverging outputs and followed by trend-setting of broad objectives (Morley et al., 2017 ). The SDGs were considered to determine the international development agenda and the countries’ development policies and programs. Although the SDGs are universal, member states are free to adopt the goals of their choice based on available resources, socioeconomic priorities, and their decided pace of transformation (Eisenmenger et al., 2020 ). The inception of SDGs has triggered many systematic studies to understand, prioritize, and evaluate the progress of goals adopted by countries. The findings of these studies are expected to promote rigorous, evidence-based, reliable, and timely evaluation of achievements toward fulfilling the purposes of countries in their diverse socioeconomic settings (Kroll et al., 2019 ; Mensah, 2019 ; Weitz et al., 2018 ). Currently, decisions made regarding the SDGs are critical for the social, political, environmental, and economic sustainability of the planet. Understanding the global context based on a review of progress, challenges, and opportunities regarding the SDGs is crucial and must be studied.

Research, innovation, and sustainable education are essential mechanisms to achieve the SDGs. Over the years, the study of SDGs has experienced a consistent increase in research activity since its approval in 2015. The existing body of knowledge on SDGs provides researchers with the opportunity to explore the SDGs research domain from a variety of perspectives based on previous publications, which is essential for revealing the structure of the domain and helping researchers better understand the status quo and future trends of SDGs-related topics and to focus their studies more effectively. Some studies have attempted to assess the literature on SDGs by examining prior works. These studies can be classified into two types: qualitative and quantitative review studies. Among the qualitative SDGs review studies, Allen et al. ( 2018 ) conducted an assessment of national progress and approaches to implementing the SDGs in different countries based on existing literature. Caiado et al. ( 2018 ) discussed the roles and opportunities provided by ICTs and AI for achieving the SDGs. Lund et al. ( 2018 ) systematically reviewed how the SDGs can be used to address the social causes of mental disorders and how they could be improved to help prevent mental disorders. Leal Filho et al. ( 2020 ) explored the potential effects of the coronavirus pandemic on the SDGs. To analyze the inclusion, progress, and challenges of the implementation of SDGs, Persson et al. ( 2016 ) revised the SDGs based on alignment and internalization and concluded that increased attention and visibility of nationally defined and internalized targets are likely to enhance implementation effectiveness and should therefore be accommodated in the follow-up and review systems. Allen et al. ( 2016 ) revised and assessed 80 quantitative models that have the potential to support national development planning for the SDGs. Hak et al. ( 2016 ) highlighted the importance of indicators in analyzing the SDGs. Guo et al. ( 2022 ) measured and evaluated SDG indicators with big earth data for a more comprehensive analysis of SDGs.

In recent years, to supplement the existing qualitative reviews of SDGs research, scholars have also explored the SDGs domain through quantitative support such as meta-analysis and bibliometric analysis. Among these quantitative studies, Yamaguchi et al. ( 2023 ) performed a bibliometric analysis of the literature on SDGs to assess the evolution and consolidation of scientific research from 2015 to 2022 retrieved from the Web of Science core collection and descriptive bibliometric analysis. The results showed that the field of SDGs is fast-growing, with a trend toward diversification of research areas. Similarly, many bibliometric studies are being published on SDGs, mainly related to the business sector, education, and poverty (Pizzi et al., 2020 ; Prieto-Jiménez et al., 2021 ; Yu and Huang, 2021 ). However, there is little bibliometric research that covers the general aspects of the SDGs and their evolution. We believe that multi-disciplinary bibliometric research on the SDGs literature is still needed to enable researchers to capture more comprehensive, diverse, and detailed information in this area. To serve as a complement to previous bibliometric studies, this paper attempts to continue the bibliometric journey by exploring the SDGs research domain from a more holistic perspective. In simple words, this study investigates the bibliometric analysis of progress, challenges, opportunities, trends, and prospects of SDGs by the global community from 2015 to 2022, providing insight into the evolution and maturity of scientific research in this field.

The major factors that distinguish this study from previous bibliometric studies on SDGs are the use of a new bibliometric technique, the SciMat, which examines the intellectual structure of SDGs research from both static and dynamic perspectives. Additionally, we analyzed the contents of the most cited articles on each cluster generated by the SciMat tool. Diverse maps of science, including a word cloud of keywords, the most cited keywords, a conceptual structure map, a keyword co-occurrence network, and strategic diagrams, were constructed to depict the intellectual structure of the SDGs domain from different angles.

A bibliometric analysis of the SDGs can have a significant impact on understanding the evolution and consolidation of scientific research on the subject. It can provide an overview of scientific production, identify trends, gaps, and strengths in research, and establish relationships between different authors, institutions, and countries. In this way, bibliometric analysis can contribute to the planning of future research and improve the efficiency of efforts to achieve the SDGs. Furthermore, it can help assess the progress and impact of efforts already made to achieve the SDGs’ goals and targets, as well as identify areas where more effort and investment are needed. In short, a bibliometric analysis of the SDGs can provide a solid foundation for evidence-based decision-making and contribute to the success of global sustainable development efforts.

In order to analyze the published research on SDGs, we divided this work into several sections, such as this Introduction to the topic, containing a brief theoretical review and the objective of this study. Section two contains a literature review highlighting a brief evolutionary history of the development of MDGs and SDGs, the similarities/differences between MDGs and SDGs, and comparisons with other policies around the world. Section three describes the methodology used, database selection and search strategy, and bibliometric analysis. Section four presents the results and analysis, section five highlights the major discussions about SDGs, and section six shows the conclusions of this study. The study of SDGs has seen a steady rise in research since its approval in 2015. The exponential growth of publications has shown a slowing in recent years, suggesting a consolidation phase where literature reviews play a crucial role as high-evidence documents.

2 A brief history of the development of MDGs and SDGs

2.1 evolutionary history of mdgs and sdgs.

Toward the end of the twentieth century, defining development has increasingly become associated with ‘wellbeing,’ which is generally perceived as more than mere economic growth. There has been increasing consensus on rejecting the hegemony of Gross Domestic Product (GDP), a monetary measure to establish the market value of the finished or final goods and services produced or availed during a specified time period by any country, as an indicator of development. By 1980, emphasis is given to devising alternative indicators to measure and assess development (Allen et al., 2018 ). Some alternatives are the Genuine Progress Indicator, World Value Survey, Gross National Happiness Index, Happy Planet Index, Better Life Index, and many others (Costanza et al., 2009 ; Rajkarnikar, 2022 ). This is in the context of the broader realization that overemphasis on economic growth-centric development has led to massive environmental degradation, economic inequality, conflict, and socio-cultural unrest. The challenges are how to define development. Which indicators are to be monitored to assess development?

Most importantly, ensure that these indicators emphasize improving environmental conditions, quality of social life, reducing economic inequality, and establishing peace and harmony; however, it does not compromise economic development. None of these alternative indicators of development are entirely adequate. However, they become a building block for the foundation of alternative thinking that emphasizes inclusiveness, sustainability, eco-friendly, trans-disciplinary-and-cooperative effort, and global consensus.

The UN’s MDGs were one of the outcomes of these discourses adopted by the UN in 2000. The MDGs comprised eight primary targets, with the first objective being to eradicate extreme poverty and hunger (Chen et al., 2023 ). This objective had a fixed target to reduce the number of people living on less than a dollar per day by half. The second objective was to achieve universal primary education, while the third was to promote gender equity and empower women. The fourth was to reduce child mortality rates below the age of five by two-thirds, and the fifth target was to improve maternal health. The sixth was to combat diseases such as AIDS and Malaria, and the seventh objective was to ensure environmental sustainability by enhancing access to drinking water and other environmental amenities, especially for underprivileged populations. The eighth SDG aimed to promote global partnerships for development. While the MDGs focused on individual development rather than national development, all SDGs promote the idea of equitable development. National and international cooperation is focused on making development accessible to all, especially those who are underprivileged and underdeveloped (Kherbache & Oukaci, 2020 ). By 2020, progress toward achieving the MDGs had been mixed. However, the MDGs framework was widely recognized as a successful program by the end of its term in 2015. For example, the number of people living in extreme poverty declined from 1.9 billion in 1990 to 836 million in 2015, and the average primary education enrolments across the developing world increased from 83% in 2000 to 91% in 2015. However, the positive trend in reducing poverty was interrupted in 2020 due to the COVID-19 crisis, leading to a significant increase in poverty, with the number of people living in extreme poverty rising by 70 million to surpass 700 million. The global extreme poverty rate rose to 9.3%, up from 8.4% in 2020 (World Bank, 2023 ). Similarly, substantial improvements were made in gender equality. Klasen ( 2018 ) found a persistent gender gap in areas of opportunities, wage rate, political and economic empowerment, and other well-being parameters. Some goals were achieved at the global level, while many countries failed to meet the target. For example, child and maternal mortalities were reduced by approximately half by 2015, but children from poor households were still more likely to be affected by malnutrition, and infant mortality rates were twice as high in the poorest households compared to those in richer households (Awaworyi Churchill, 2020 ).

Similarly, the goal of access to safe drinking water was not successfully achieved in rural areas (United Nations, 2015 ). In a nutshell, the progress was uneven. Further, in other goals, though a significant level of success was achieved, the target was not met. MDG assessments suggest adding new goals and changes to existing goals. For example, Swain and Yang-Wallentin ( 2020 ) indicate that adding a ninth goal to the eight MDGs eliminates extreme inequality at the national level in every country. The MDGs were criticized for their lack of adequate focus on people with disabilities (Wolbring, 2011 ), conflict and peace (Hill et al., 2010 ), and human rights (Fehling et al., 2013 ). To summarize, as MDG Gap Task Force, founded by the UN, gives a comprehensive view of the status of the implementation of the MDGs (United Nations, 2015 ). No development program or initiative is ever cent percent successful. The impact assessment of a program is always along with a continuous range in which the present status stands somewhere. From several impact reports, one thing is evident MDGs certainly made visible impacts on the targeted aspects. For example, one of the noteworthy achievements is a decline in extreme poverty from 47 to 14% from 1990 to 2015 (United Nations, 2015b ). Similarly, the share of undernourished people was also reduced to half.

Further, the child mortality rate declined by 45% during this period (United Nations, 2015b ). However, infectious diseases, gender, and income inequality continued to prevail, and millions of people were still in extreme poverty. Around the globe, more than 60 million people were affected by the conflict from 1990 to 2015 (United Nations, 2015b ). While MDGs had considerable achievements, there were some lacunas as well. The distribution pattern of MDGs implementation varies from region to region and goal to goal. Many developing nations were seriously off-target in cases of undernourishment, infant mortality, maternal mortality, and sanitation. For infant and maternal mortality, around 53% and 61% of the developing nations were reported to be seriously off-target. Again, 40% of the nations were seriously off-target for sanitation. On the other hand, many countries had remarkable progress in eradicating extreme poverty, achieving education and gender parity, and providing clean drinking water. The implementation of MDGs had a differential impact on different sections of people. For example, the poorer sections of the developing nations were often left out of the benefits reaped by MDGs (World Bank, 2016 ). Thus, the accomplishments of the MDGs have neither been uniform across all the goals nor across different parts of the globe. Regional variation in the level of achievement in the case of goals like infant mortality rate, maternal mortality rate, and eradication of malnutrition were low, indicating the poor status of these goals across the world.

On the other hand, high regional variations were noticed in the achievements of the goals, such as eradication of poverty, sanitation, maternal mortality rate, and infant mortality rate. There are also differences in the degree of consistency in implementing MDGs. For example, a very low level of consistency in the status of goals is noticed in countries of the Middle East, North Africa, and South Africa. The MDGs were targeted to be achieved by 2015, but the target status at the end of 2015 sowed the seed of thought among the policymakers to chalk out another set of goals to substantiate the earlier existing MDGs. Therefore, the 17 SDGs were reinvented out of the earlier eight MDGs.

The first framework of SDGs was chalked out at the Rio + 20 conferences (the United Nations Conference on Sustainable Development) in Rio de Janeiro in June 2012 to carry forward the impetus sowed by the MDGs in the pursuit of holistic global development. In July 2014, a document containing 17 goals was proposed by the UN General Assembly Open Working Group (OWG) for the General Assembly’s approval in September 2015. This document served as the first official draft of the SDGs. The global community adopted the 2030 agenda for sustainable development goals, including 17 SDGs and 169 targets, and 232 indicators, in September 2015. Subsequently, global SDGs commenced in 2016 and offer an evidence-based policy framework for sustainable development and planning till 2030. SDGs represent the commitment of member countries to achieve sustainability in various sectors (Allen et al., 2018 ). SDGs became an important component of the international development agenda for all countries and significantly influenced national planning post-2015. While the SDGs are universal, the countries have the liberty to determine their priorities and target and scale, and pace of transformation.

Assessing the process of SDGs interventions and their progress over different goals by member countries continues to be challenging. As discussed by Allen et al. ( 2018 ), one of the overarching challenges is dealing with each goal in isolation. That means the integration of sustainable economic, social, and environmental development objectives is yet to be achieved. The interactive relationship between seventeen SDGs and 169 targets compels the planning practices to see it holistically. In 2016, in the first voluntary national review of SDGs was fairly presented, the implication of the knowledge gap of a detailed view of interactive relations among targets and goals and the ability to maintain a holistic perspective has an impairing impact on the planning and implementation of SDGs (Weitz et al., 2018 ).

2.2 Similarity and difference between MDGs and SDGs

Since there was a disparity in the achievement status of the MDGs, efforts were taken to build the SDGs in a way so that a sustainable world could be made with equal value for environmental sustainability, social inclusion, and economic development. It is essential to understand that SDGs are not formulated to replace MDGs; instead, they are intended to substantiate them. Some of the goals under SDGs are improvisations over the previous MDGs, while some new goals have been incorporated into this new framework. Compared to MDGs, SDGs are considered a broader and more complex, integrated, and stimulating agenda for all countries to implement.

Relative to the formulation of MDGs, the process of devising the SDGs was more participatory, involving consultation with civil societies, the private sectors, and the governments of a fair number of countries. The result is a far more comprehensive list of goals, far greater targets (169), and several indicators (232), including many of those goals left out by MDGs. For example, it emphasizes climate change, the environment, peace and conflict, work, and the ocean. However, like MDGs, SDGs are criticized for not emphasizing human rights (Sengupta, 2018 ).

Given the comprehensiveness of SDGs, their assessment requires immense human and financial capital that seems too enthusiastic for developing countries with limited resources (Fenny, 2018 ). The MDGs requirements were more modest (21 targets and 60 indicators) in nature and also complex. While 93 SDGs indicators out of 232 are classified as Tier 1. Again, these indicators are more conceptual clarity, and more than 50% of the countries regularly comply with these data. The left-out indicators are defined as Tier 2 (72 indicators) with conceptual clarity, but data are unavailable. However, the data related to Tier 3 (62 indicators) are not regularly collected by countries because of the non-availability of a well-established methodology or available format of data collection.

The challenge of ensuring environmental sustainability is more marked since the new SDGs try to integrate sustainability issues with multidimensional poverty and inequality. While MDGs considered four different types of environmental targets, the number has expressively increased in the SDGs, containing seven environmental goals (i.e., goals No. 7, 9, 11, 12, 13, 14, and 15), monitored through 77 indicators. The goals are as follows: Goal 7: ensure access to affordable, reliable, sustainable, and modern energy for all, Goal 9: build resilient infrastructure, promote sustainable industrialization, and foster innovation, Goal 11: make cities inclusive, safe, resilient, and sustainable, Goal 12: ensure sustainable consumption and production patterns, Goal 13: take urgent action to combat climate change and its impacts, Goal 14: conserve and sustainably use the oceans, seas, and marine resources, and Goal 15: sustainably manage forests, combat desertification, halt and reverse land degradation, halt biodiversity loss.

2.3 Comparing with other policies around the world

The MDGs of the United Nations have been one of the most talked-about policy interventions globally in the last couple of decades. These policy targets have been formulated, critically reviewed, implemented, and analyzed for the achievements and impacts they have made on the globe. As global needs have changed with changing socio-political equations and dynamics, a strong need has been felt to shift the MDGs framework paradigm. Therefore, the MDGs have been revisited and reinvented to give rise to a set of SDGs. MDGs went on to a certain extent to achieve these goals. They paved the way for higher-order growth needs as SDGs, which aim to address more profound and complex health issues, including mental well-being, nutritional security, quality education, innovation, peace and justice, cultural vitality, equality, and environmental and social resilience, etc.

3 Methodology

The study’s methodology is based on a qualitative method focused on the content of papers related to SDGs, as proposed by Di Vaio et al. ( 2020 ). The methodology applied in this study has two stages. In the first stage, the data extraction method, which includes database selection, and the search strategy, were illustrated, and then the bibliometric analysis was done using bibliometric techniques with the help of appropriate software. These databases have been chosen because they notoriously publish theoretical or empirical studies on topics related to SDGs (Alvino et al., 2021 ). The details of the workflow are presented in Figure 1 .

Research flow, methodology, and tools

3.1 Database selection and search strategy

To collect data for this review, we must select one of the citation databases that index all literature related to SDGs. The Scopus and Web of Science are commonly used databases by the research community for literature searches and bibliometric analyses (Mishra et al., 2020 , 2021 ; Sudarsana & Baba, 2019 ). In this study, the Web of Science (WoS) core collection citation database was used as the primary source of data collection for processing and analysis. This study used the year 2015 because SDGs were adopted on September 2015, and further, we have extended it till October 2022, which is the most recent data available. This database is considered the most well-known citation database, and bibliographical data are stored in a well-structured manner (D’Amore et al., 2022 ; Harzing & Alakangas, 2016 ; Vaio et al., 2021 ), which sufficiently validates the use of the WoS database in the existing study. The effectiveness of the analysis results mainly depends on the search strategy technique. Thus, an effective search strategy was constructed according to the database characteristics after selecting the database to be used.

The following advance query was used: TS = (“sustainable development goals” OR “SDGS” OR “millennium development goals”), [refined by]: DOCUMENT TYPES: (ARTICLE OR REVIEWS) AND [excluding] PUBLICATION YEARS: (2023), Timespan: 2015–2022. Indexes: SCI-EXPANDED, SSCI, CPCI-S, A&HCI, CPCI-SSH, BKCI-S, BKCI-SSH, ESCI, IC, CCR-EXPANDED. This query retrieved 12,176 publications (articles and reviews) from 2015 to 2022 on October 2 (2022). The above time period was fixed because SDGs were adopted on September 2015. The identified 12,176 literature records, the citation information, bibliographic information, abstract and keywords, and other information were exported to.txt format files. Then, the dataset in a Bibliometrix package file was transferred from Rstudio software for performing bibliometric analysis and thematic trend analysis (Aria & Cuccurullo, 2017 ). Next, it was transferred to SciMat software for extracting strategic diagrams and thematic evolution maps, after which a specific analysis was performed (Cobo et al., 2012 ).

3.2 Bibliometric analysis

Bibliometrics uses mathematical and statistical methods to analyze literature quantitatively regarding scientific publications’ production, growth, maturation, and consumption. As a result, it has been widely used as an essential tool for assessing and analyzing development status in the research field in terms of the researcher’s production (Ellegaard & Wallin, 2015 ), the collaboration between institutions (Skute et al., 2019 ), the impact of state scientific investment in national R&D productivity (Fabregat-Aibar et al., 2019 ), and the academic quality (van Raan, 1999 ), among other possibilities (Glänzel, 2012 ). The bibliometrics analysis consists of performance analysis and science mapping analysis. Performance analysis is based on bibliometric indicators that measure the production of individual actors (author, intuition, county, and journal) and the impact achieved through publications and citation data. Science mapping analysis provides the topological and temporal representation of a particular research field’s cognitive and social structure (Cobo et al., 2012 ).

A wide variety of bibliometrics tools are available for bibliometric analysis; the mainstream bibliometrics analysis tools include Biblioshiny (R Package), VOSviewer, BibExcel, SciMAT, and CiteSpace (Aria & Cuccurullo, 2017 ; Cobo et al., 2011 , 2012 ; Moral-Muñoz et al., 2020 ). Each tool has different mapping principles, algorithms, visual outputs, and strengths and weaknesses. However, a single tool is not suitable for all types of analysis (Cobo et al., 2011 ). Following Cobo’s review, CiteSpace, Biblioshiny (R Package), and SciMAT were finally selected for this study. The details of each tool as given below.

3.2.1 Biblioshiny (R-tool software)

Biblioshiny is an open-source application that has the potential to import data from different sources (Scopus, Web of Science, among others) and provides various types of bibliometrics analysis (Aria & Cuccurullo, 2017 ). In this study, we have utilized several modules offered by the Bibliometrix application. These modules are primary information, annual scientific production, citation, more relevant sources, more relevant author and affiliation, country, and word cloud.

3.2.2 VOSviewer

VOSviewer is another bibliometric tool widely used for creating bibliometric networks of different actors (e.g., authors and organizations) using various network analysis methods such as co-author, co-citation, term co-occurrence, and bibliographic coupling (Van Eck & Waltman, 2009 ). In this study, we used the term co-occurrence analysis to identify major themes of a research domain. The maps obtained from this software include nodes and edges, indicating the keywords (nodes) and their relationship (edges). Interested readers are referred to the VOSviewer manual for more details about these different analyses ( https://www.vosviewer.com/publications ).

3.2.3 CiteSpace

CiteSpace is also an open-source package based on the Java platform developed by Drexel University (Chen, 2006 ). Indeed, its prime aim is to facilitate the dynamic tracking of emerging trends in the knowledge domain, focusing on identifying key points and turning points in developing knowledge in a field. In the present study, this is mainly applied to the burst detection of analysis function to find hotspots in the research field.

3.2.4 SciMAT

SciMAT is an open-source software tool developed to perform a bibliometrics analysis under a longitudinal framework and provides support to different types of analysis. In this study, we utilized the term co-occurrence module to identify closely linked concepts and explore the thematic evolution of the nexus during the last six years. The information related to the procedure and implementation of this software is presented in (Cobo et al., 2012 ). This software offers two types of maps: strategic diagrams and thematic evolution maps.

3.3 Strategic diagrams

Strategic diagrams (Figure 2 ) reflect the research themes and research keywords based on two indicators of cluster centrality (indicating the strength of interdisciplinary links and the centrality of the theme in research development) and density (indicating the degree of strength)) (Cobo et al., 2012 ). The first diagram (a) is a two-dimensions map divided into four quadrants based on their relevance. The themes are represented as a circle, and their size is proportional to publications associated with the theme. The second is a diagram where the components and their relationship are represented. The four areas, according to their relevance, are Motor themes (Q1: Upper-right quadrant), Highly developed and isolated themes (Q2: Upper-left quadrant), Emerging or declining themes (Q3: Lower-left quadrant), and Basic and transversal themes (Q4: Lower-right quadrant). Motor themes are well-developed topics and the main field of research. Highly developed and isolated themes are topics at a reasonable level in terms of density but are not very central and considered marginal. Emerging or declining is an undeveloped and marginal issue. At the same time, basic and transverse are central issues with a lack of proper density.

Structure of the strategic diagram

4 Result and analysis

To conduct a bibliometric analysis of SDGs related to data retrieved from the WoS in terms of publication, citations, and impact, the following analysis types were considered: Information about data, trends, and characteristics of research publication, most preferred and productive journals, productive author, journal and country, most cited documents, keyword analysis, and thematic evaluation. The detailed results are as follows.

4.1 Information about data

Table 1 provides information on articles retrieved from the Web of Science published from 2015 to 2022. It was found that 12,176 publications published in 1956 journals use 14,120 keywords plus and 26,262 author’s keywords. The number of authors contributing to this domain is 45345, a very high number. There is a high collaboration in SDGs literature, as shown by the collaboration index. The average citation per article is 15.06, and the articles per author ratio are 0.269, which means, on average, almost four authors have written one document.

4.2 Literature trend analysis and characteristics of research publication

In 2015, the SDGs were set up by the United Nations General Assembly (UN-GA) to work toward a sustainable society in which economic prosperity is achieved, and social and environmental concerns are met. Those goals are intended to be completed by 2030 and are included in an UN-GA Resolution called the 2030 Agenda or Agenda 2030. Since then, the interest of the academic community and specialists in the issue of sustainable development, implementations of SDGs at national, regional, and global levels, and informality have materialized in papers, reports, and various other publications.

Table 2 provides the year-wise growth rate of publications and their citations concerning SDGs. A total of 12176 research articles related to SDGs were published from 2015 to 2022, cited 189960 times in total, with an average citation rate per article of 15.06 during the period. In 2015, only 298 articles were published, and these articles received 8725 citations. Since then, it can be seen from Table 2 that the number of published journal articles about SDGs has an obviously and continuously increased trend. This trend shows that progressively more attention has been paid to this domain in recent years. Among the 12176 articles, about 51% were published in the last two years, while nearly 26% were published in 2022. The annual distribution of citation count has shown a slight fluctuation trend. The year 2022 had the highest number of articles, at 3249, and these articles have received 6487 citations. The highest number of citations (34736) was acquired in 2018.

4.3 Most preferred and productive journals for publications

Academic journals are considered the prime medium for disseminating scientific output and are worth researching in any scientific domain (Wuni et al., 2019 ). The most preferred and prominent journals that publish articles in the SDGs domain have been explored. A total number of 3732 articles regarding SDGs were published in these top 15 journals between 2015 and 2022. Table 3 gives the leading journals, each with the number of publications, citations, and the Impact Factor (IF). The leading journals preferred by the researcher are sustainability, Switzerland, with 1730 (12%) publications, 13545 citations, and 3.88 impact factor, followed by Journal of Cleaner Production, UK, with 371 (2.9%) publications, 8574 citations, and 11.07 IF, and Science of the Total Environment, Netherlands with 191 (1.5%) publications, 5655 citations, and 10.75 IF. The table shows that the Journal of Cleaner Production has the highest h-index of 51, the Sustainability has an h-index of 43, and the journal Science of the Total Environment has an h-index of 34. The table also shows that although sustainability has 1359 more publications (total of 1730) than the Journal of Cleaner Production (total of 371 publications), the Journal of Cleaner Production’s impact factor is almost three times higher than Sustainability. A very interesting feature is that in SDGs, the International Journal of Environmental Research and Public Health is the 6 th most productive journal having a total number of productions of 153, but its h-index is too low. It is also observed that Switzerland produces a greater number of journals in this field than other countries.

4.4 Highly productive countries and their collaborations

All corresponding authors and their affiliations in each article were considered in the analysis of the most predominant ones. The articles originate from 137 countries/regions. Figure 3 shows the geographical distribution of production for the countries/regions. Table 4 presents the statistics of the top 10 countries/regions based on the total publications in this field. The USA is the most prolific country with 1313 publications (10.7%), followed by China and the UK with 1310 (10.7%) and 1171 (9.6%) publications each. The three countries account for 31% of the total publications, indicating their prominent position in the research field. Furthermore, the USA’s publications have received the highest number of citations (34013) compared to others, showing that it dominates the publication count and has a solid academic influence in the research field.

Geographical distribution of production in the WoS

Concerning collaboration, the UK and the USA again topped for both Single Country Publications (SCP) and Multiple Country Publication (MCP) (Table 4 ). The ratio of MCP to total publications for most of the Top 10 countries was 22–62%. Still, it was about 50% for the UK, reflecting that each country exhibited a strong preference for international cooperation regarding the SDGs study. Table 4 also includes the 2022 SDGs Index Rank of each country.

4.5 Highly productive institutions/organizations

Table 5 provides the top 10 most productive institutions/organizations in SDGs research in terms of publications. The first-ranked institution is the University of Oxford in the UK, which has published 307 articles in this research field, and most of the articles related to maternal mortality (Kassebaum et al., 2016 ; GBD 2017 DALYs and HALE Collaborators, 2018 ) and maternal health (Patel et al., 2018 ) (see Table 6 ). The second and third were the London School of Hygiene & Tropical Medicine and the Tehran University of Medical Sciences, which published 259 and 244 articles, respectively. The majority of these ten institutions are from the UK (30%) and Australia (20%), and the rest are from Iran (10%), South Africa (10%), the USA (10%), China (10%) and Brazil (10%). It is important to note that there is no single institution from India, even though it was placed in the top ten countries list.

Regarding collaborations, the University of Oxford has strong collaborations with other institutions, especially the University of Cape Town, the London School of Hygiene & Tropical Medicine, King’s College London, Johns Hopkins University, and Stanford University, as depicted in Fig.  4 .

Collaboration network of top 50 organizations/instructions. The node represents a country; the size of a node is proportional to the number of appearances in the dataset. The line represents relationships between two organizations; the thickness of the line reflects the strength of the relationships

4.6 Analysis of the highly productive authors

In this section, the main authors who structured the field of research on the SDGs were identified. Figure 5 presents Lotka’s law distribution map. The ordinate indicates the proportion of authors of different kinds of literature to all authors, and the abscissa indicates the number of documents. The dotted line in the figure is a general image description of Lotka’s law. As shown in Figure 3 , 35605 researchers published an article, accounting for 78.5% of the total. The number of scholars who published more than six papers was 921, accounting for 0.2% of the total. It can be seen that the researchers in the SDGs research area and the number of documents are similar to the dotted line in the figure, which basically obeys the general law of Lotka’s law. This reflects that the number of authors who have written only one or two articles in the field of SDGs is relatively large. Most scholars in this field have just started in this area, and perhaps this is why research has not yet been in-depth.

The frequency distribution of scientific productivity

Table 7 provides the top 10 most prolific authors by the number of articles from 2015 to 2022, which account for 2.3% of overall articles published from 2015 to 2022. The author with the largest number of papers published and the highest h-index is Zulfiqar Ahmad Bhutta. He has published papers in the field of SDGs since 2015. His main research direction is to evaluate health-related SDGs, as presented in Table 8 . One of Zulfiqar Ahmad Bhutta’s papers is ‘Global, regional, and national disability-adjusted life-years (DALYs) for 315 diseases and injuries and healthy life expectancy, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015’, published in Lancet in 2016, has the highest number of citations ( TC = 1196). Regarding citations, Christopher J. L. Murray has achieved the highest citations compared with other authors. Andrew Adewale Alola, Avik Sinha, and Festus Victor Bekun are published on the same topic, i.e., renewable energy. From the geographical perspective, the core authors from the USA account for 30% of the top 10 core authors, which means that the USA currently has stronger research strength in the SDGs research field than other countries.

4.7 Keyword analysis

Researchers are using keywords to provide a concise description of the research content. As a result, it is one way to identify hot topics and themes of a research domain based on keyword analysis (Zhang et al., 2016 ). The selected documents in the field of SDGs were further examined based on highly occurred keywords via bibliometric software. The Web of Science database offers two types of keywords- author’s keywords and keywords plus. Keywords plus are words or phrases that frequently appear in the titles of an article’s references but do not appear in the title of the article itself (Garfield, 1990 ). The results of this analysis are presented in the form of word clouds. Word cloud analyses of the 30 most frequent keywords in the publication collection are shown in Figure 6 , where a higher occurrence results in a larger font size. The published research trends focused on common terms such as management, impact, health, policy, framework, and governance

Word clouds of the 30 most frequent keywords plus

A deeper analysis was conducted on the co-occurrence of 3739 authors’ keywords which appeared at least ten times in the collection (Figure 7 ). Each node represents a keyword (or topic). The thickness of lines between two nodes represents the strength of the relationship between them, determined by the frequency they appeared together in published papers. Some core research areas were highlighted: sustainable development goals, climate change, agenda 2030, circular economy, Africa, poverty, global health, governance, food security, sub-Saharan Africa, millennium development goals, universal health coverage, indicators, gender, and inequality. The 288 most frequent authors’ keywords were classified into 11 different clusters coded in different colors. Figures 7 and 8 depict several keywords that frequently appeared with sustainable development goal keywords together in published papers.

The co-occurrence of 739 authors’ keywords (at least ten times). The thickness of lines represents the strength of the relationship between keywords, determined by the frequency they appeared together in published papers

The keywords that frequently appeared with the sustainable-development-goals keyword in published papers

4.8 Keyword burst analysis

We carried out keyword burst detection to identify research hotspots of the SDGs domain using CiteSpace (Bommer et al., 2018 ). Table 9 shows 39 keywords with bursts of at least one year. In chronological order, the burst keywords in the SDGs field have changed over the years from 2015 to 2022. The keywords with a burst period greater than four years include global burden (2015–2020), human rights (2015–2020), child mortality (2015–2019), disease (2015–2019), aid (2015–2019), and maternal mortality (2015–2019), which direct that these topics got more attention and are more influential than other keywords. Thus, they became research hotspots of the SDGs domain in corresponding periods. Besides, the perspective and future beginning to burst in 2019 continue to the present, which is currently research hotspots. In connection to burst strength, the millennium development goal (53.01) is the strongest burst, followed by care (24.26), morality (23.75), health (18.33), developing country (17.92), and intervention (16.23), which are research hotspots in their corresponding periods. We argue that the SDGs field’s research hotspots are currently the perspective and future of SDGs-related research.

4.9 Research topics and thematic evolution

SciMAT software offers two types of maps: strategic diagrams and thematic evolution maps. A strategic diagram has been widely used to analyze the trend of change in topics in terms of density and centrality. In contrast, a thematic evolution map has been used to analyze the evolution of topics. To trace the most highlighted themes of the SDGs domain, the study period was divided into two annual intervals (2015–2018 and 2019–2022). Thematic maps of authors’ keywords for each interval and the whole period were generated using SciMAT software from the co-word analysis. In the thematic map (strategic diagram), the circle size is proportional to the number of documents associated with each research theme. An analysis of the results obtained for each period is shown below.

4.9.1 First period (2015–2018)

According to the strategic diagram (Figure 9 ), four research themes can be observed in the 2434 papers selected in this period contributed by 11974 authors: Climate-Change, Millennium-Development-Goals, Middle-Income-Country, Model and Determinants. Of these, two were considered motor themes (Climate-Change and Millennium-Development-Goals), one a highly developed and isolated theme (Middle-Income-Country), one emerging or declining (Model), and finally, one other was considered basic (Determinants). The performance measures for each theme, as shown in Table 10 , complement the information provided by the diagram. According to Table 10 , the following two relevant themes are highlighted: Climate-Change and Millennium-Development-Goals. These themes attain a high impact rate in comparison with the remaining themes.

Strategic diagram for the 2015–2018 period

The motor theme Climate-Change obtained the highest citation count in this period and recorded the highest h-index score. It is related to general topics of SDGs (Climate Action). Mainly, it is focused on how it affects every country on every count due to the rise in average surface temperatures on Earth. It has become a hot research field today since it disrupts national economies and affects lives, costing people, communities, and countries dearly today and even more tomorrow. Figure 10 a depicts a cluster network of Climate-Change. Topics Such as progress on health and climate change (Watts et al., 2017 ), approaches to managing social and environmental issues in the tropics (Reed, 2016 ), soil health and carbon management (Lal, 2016 ), importance of soil and its awareness (Keesstra et al., 2016 ), land degradation Neutrality (Cowie et al., 2018 ), nature-based solutions in land management for enhancing ecosystem services (Keesstra et al., 2018 ), national land system sustainability emergency via sustainability programs (Bryan et al., 2018 ), Strengthening protected areas for biodiversity and ecosystem services (Xu et al., 2017 ), Smart Sustainable Cities (Bibri & Krogstie, 2017 ), future economic consequences of diabetes and Kidney Disease (Luyckx et al., 2018 ), maternal mortality (GBD 2017 DALYs and HALE Collaborators, 2018 ; Kassebaum et al., 2016 ), Sustainable Wellbeing (Costanza et al., 2016 ), social inclusiveness (Gupta & Vegelin, 2016 ), policy for managing the food, water, and energy (Rasul, 2016 ), approaches for Global Sustainable Development (Liu et al., 2018 ), implementation of SDGs (Stafford-Smith et al., 2017 ), sustainable development indicators (Hak et al., 2016 ), transformative innovation policy (Schot & Steinmueller, 2018 ), off-grid solar energy (Nerini et al., 2018 ), electricity access (Alstone et al., 2015 ) are disused in this cluster.

Thematic network of ( a ) climate-change and ( b ) millennium-development-goals

Millennium-Development-Goals is one of the motor themes and is the second most crucial theme of this period. This theme comprises research conducted on different aspects of Nations Millennium Development Goals (Figure 10 b), especially healthcare access and quality (Abbott et al., 2017 ; Fullman et al., 2018 ; Milat et al., 2015 ), health policy (Buse & Hawkes, 2015 ), Children mortality (Ebener et al., 2015 ; Wolf et al., 2018 ), global rules for the private sector (Scheyvens et al., 2016 ), drinking water (Adams, 2018 ; Martinez-Santos, 2017 ), poverty (Asadullah & Savoia, 2018 ), MDGs progress (Gaffey et al., 2015 ; Mohammadi et al., 2017 ; Moucheraud et al., 2016 ). It mainly focuses on the global development agenda transitions from the MDGs to the SDGs.

The basic and transversal theme determinants are composed of a few publications, but they received the best impact (h-index) in this period. It represents the research conducted (Figure 11 a) on different aspects of Determinants, such as women, infants, and inequality. It mainly focuses on delivery care services (Pulok et al., 2016 ), Intimate partner violence (Mohammed et al., 2017 ), maternal health care services (Ganle, 2016 ; Mehata et al., 2017 ), and mortality (Ahmed et al., 2016 ; Dendup et al., 2018 ). Middle-Income-Countries is a highly developed and isolated theme that represents research conducted on Middle-Income-Countries (Figure 11 b) with living conditions of poor rural households, Early Childhood Development (Black et al., 2015 , 2017 ; Richter et al., 2017 ), Equity in vaccination coverage nutrition (Arsenault et al., 2017 ), and child marriage (Kalamar et al., 2016 ).

Thematic networks of ( a ) determinants and ( b ) middle-income-countries

4.9.2 Second period (2019–2022)

In this period, a total of 9742 publications were contributed by 36816 authors, distributed in eight SDGs themes (Figure 12 ), with five major research themes (Motor themes plus basic theme): Sustainable-Development-Goals, CO 2 -Emissions, Areas, Emissions, and Strategies. Regarding the performance measures shown in Table 11 , five themes stand out due to the citations achieved and scored h-index over 8: Sustainable-Development-Goals, CO 2 -Emissions, Strategies, Children, and Areas. However, the motor themes Sustainable-Development-Goals and CO 2 -Emissions are the most inflectional for structuring the SDGs research field.

Strategic diagram for the 2019–2021 period

Sustainable-Development was consolidated as a motor theme in this period (Figure 12 ). Moreover, it is the theme with the highest number of documents and achieves the highest number of citations count and h-index score. It obtains the highest density score, which means that its research has great internal cohesion. SDGs rise from the evolution of the themes of Climate change, Model, and Millennium-Development-Goal of the previous period. The research (Figure 13 a) on this theme relates to 17 goals.

Thematic network of ( a ) SDGs, ( b ) CO 2 -Emissions, ( c ) strategies, and ( d ) children

To further show more information from this cluster, some most cited papers of this cluster are also investigated. To name a few, Salvia et al. ( 2019 ) examined the difficulties and potentials in pursuing and implementing the SDGs, especially among developing nations. Schroeder et al. ( 2019 ) studied the contribution of circular economy practices such as repair, remanufacturing, and recycling to SDGs. More efforts in skill training, technology development, and multistakeholder partnerships are required to make advanced Circular Economy practices. Hughes et al. ( 2019 ) discussed Blockchain research, practice, and its potential in the future in various fields and factors. Leal et al. ( 2019 ) noted that the implementation of the SDGs at universities is still in the initial stage. They provided an overview of the level of emphasis placed on the SDGs by Higher Education Institutions. Nerini et al. ( 2019 ) explored the connection of climate change action with other SDGs. They suggested that climate change action can strengthen all 17 SDGs while undermining efforts to achieve 12. Governance processes and structures must be better connected to maximize the legitimacy and effectiveness of action in both domains. Huovila et al. ( 2019 ) reported the standardized indicators for smart, sustainable cities that balance sustainability and smartness. Fonseca et al. ( 2020 ) mapped the relationship between SDGs. They found no significant correlation with other SDGs, epically Climate action and partnerships for the goals, which provides scope for future research.

The theme of CO 2 emissions emerged during this period and can be considered one of the main topics of SDGs, as evidenced by its high h-index score and the considerable number of citations. CO 2 emissions have evolved from the themes of Determinants and Millennium Development Goals in the previous period. Across the globe, countries are consistently facing one of the greatest challenges of the 21st century: saving and sustaining the environment. The most developed countries are often the largest emitters of carbon dioxide (CO 2 ), resulting in an urgent policy drive toward environmental sustainability.

The research on this theme relates to ecological footprint, greenhouse gas emissions, natural resources, pollution, technological innovation, and supply chain (Figure 13 b). To further show more information from this cluster, some most cited papers of this cluster are also investigated. To name a few, following the SDG 17 of improving global partnerships for sustainable development, Shahbaz et al. ( 2019 ) explored the association between foreign direct investment and carbon emissions in the Middle East and North African region in the 1990–2015 period. They found that there is a need to develop comprehensive trade and energy policies by targeting cleaner production practices for a sustainable environment and fulfilling the objectives of SDGs. Sarkodie and Strezov ( 2019 ) examined the effect of foreign direct investment inflows, economic development, and energy consumption on disaggregate greenhouse gas emissions. Alola et al. ( 2019 ) discussed the role of trade policy, energy consumption, economic growth, and fertility rate on environmental pollution in 16 European member countries. Saint Akadiri et al. ( 2019 ) reported that by using renewable energy, carbon emission mitigation is very much achievable in the EU-28 countries and should also be adopted by all countries as an effective global policy to achieve SDGs by the year 2030.

The basic theme of strategies appears in this period as one of the emerging research themes. It mainly focuses (Figure 13 c) on 17 SDGs strategies for promoting sustainable practices and solutions that address our society’s main issues. To further show more information from this cluster, some most cited papers of this cluster are also investigated. To name a few, Chen et al. ( 2020 ) proposed strategies for green chemistry principles implementation from the aspects of governance, industry, and education. Dantas et al. ( 2021 ) reviewed the contribution of the circular economy and industry 4.0 toward achieving SDGs.

The highly developed and isolated motor theme of children appears in this period as a bifurcation of the MDGs theme from the previous period. The research (Figure 13 d) is related to disease, risk, interventions, childhood development, and disability. To further present information from this cluster, we investigated some of the most cited papers. The bold new target of safely managed water, sanitation, and hygiene for all by 2030 warrants the attention of researchers, policymakers, and practitioners. Cumming et al. ( 2019 ) reported that major water, sanitation, and hygiene interventions did not affect childhood stunting, and mixed effects on childhood diarrhea resulted from five consensus points. Chen et al. ( 2019 ) studied how dietary changes can significantly contribute to achieving the 2030 national SDGs. Early childhood development is key to achieving SDGs and can be negatively influenced by many adversities, including home violence, neglect, abuse, and parallel health. There were consistent and strongly negative relationships between all measures of childhood adversity and all five childhood growth and development outcome measures at the age of 18 months (Bhopal et al., 2019 ). Bhutta et al. ( 2020 ) reported how countries could reduce child stunting, with or without closing geographical, economic, and other population inequalities. Josenhans et al. ( 2020 ) studied the sexual exploitation of boys. Hall et al. ( 2019 ) suggested that research should focus on interventions to alleviate poverty-related stress to achieve the United Nations SDGs. Toska et al. ( 2020 ) reported that children of an adolescent mother with AIDS show more health problems than others. This should be controlled in a country with a high number of adolescents.

4.9.3 The most cited publications

The contents of the most cited papers are considered to be of great importance in the academic world, as they reflect the impact of research in a particular field. By analyzing the most cited papers, it is possible to understand the current state of knowledge in a certain area and identify gaps that need to be filled in future research. In this context, it is also possible to understand the implications for future research based on the contents of the most cited papers (Gaffey et al., 2015 ). When it comes to the SDGs, the most cited papers are a reflection of the current state of research in the field and provide important insights into the areas that need further investigation. Table 12 displays the most frequently cited papers according to the total number of citations received. It is noteworthy that the papers authored by Liu et al. ( 2016 ), Pecl et al. ( 2017 ), Zhang et al. ( 2015 ), Black et al. ( 2017 ) Kruk et al. ( 2018 ), Patel et al. ( 2018 ), Black ( 2015 ), and GBD 2017 DALYs and HALE Collaborators ( 2018 ), Kassebaum et al. ( 2016 ) occupy the top 10 spots in the ranking. The majority of these papers focus on health, climate change, nitrogen, and agriculture.

The selected articles address various topics related to the SDGs established by the United Nations. The most cited papers on the SDGs reflect this need, as they often involve the analysis of inequalities and the identification of ways to ensure that everyone has access to the resources and opportunities they need to thrive (Zhu et al., 2021 ). Among the top 10 most cited articles, we have selected the six most highly cited ones for special attention. Liu et al. ( 2016 ) study investigated the causes of infant mortality at the global, regional, and national levels, offering important implications for achieving SDGs related to health. Meanwhile, Pecl et al. ( 2017 ) discussed the effects of climate change on biodiversity, highlighting the importance of preserving ecosystems for human well-being. Zhang et al. ( 2015 ) analyzed nitrogen management as a form of sustainable development, given its importance for agriculture and pollution reduction. On the other hand, Black et al. ( 2017 ) conducted a study on early childhood development, emphasizing the importance of this period for the formation of healthy and productive adults. Kruk et al. ( 2018 ) addressed the need for high-quality health systems to achieve SDGs related to health, highlighting the importance of innovation and political commitment. Finally, Patel et al. ( 2018 ) work explored the relationship between mental health and sustainable development, emphasizing the need for public policies that address this issue in an integrated manner. Together, these articles highlight the complexity and interdependence of the SDGs, as well as the need for an integrated approach to sustainable development. In addition, the studies emphasize the importance of research and innovation in addressing global challenges and achieving the goals established by the United Nations (Table 12 ).

In conclusion, the contents of the most cited papers on the SDGs provide important insights into the current state of research in the field and the implications for future research. The need for interdisciplinary approaches, practical solutions, a focus on equity and social justice, and innovation and technological solutions are some of the key implications that can be derived from the analysis of the most cited papers. By considering these implications, future research can contribute to the achievement of the SDGs and ensure that everyone has access to a high quality of life and prosperity.

5 Discussion

To assess the distribution of SDGs in literature review publications over the years, the articles were individually analyzed and classified. It should be noted that the publications could be included in multiple categories. As a result, the majority of documents were categorized under general aspects of sustainability, including environmental sciences, environmental studies, and green science and sustainable technology.

The results of the bibliometric analysis indicate that research and development on the SDGs are more concentrated in developed countries than in developing and underdeveloped nations. This trend highlights the need for greater investment and engagement from developing countries in addressing the global sustainability challenges posed by the SDGs. This study is the first to conduct a bibliometric analysis of the SDGs and examine the progress, challenges, and opportunities during the period from 2015 to 2022. The results of this study reveal differences in the utilization of the SDGs theme.

Based on the analysis and results obtained from this paper, we have observed a huge disparity in participation in the development process through scientific contributions. The current development trajectories also follow the same path, with countries and regions with more resources contributing more than those with fewer resources. According to Sweileh ( 2020 ), the highest volumes of research are found in SDGs 1, 3, 11, 12, and 15. Similar results were obtained by Sianes et al. ( 2022 ), who used bibliometric methodologies to evaluate the impacts of SDGs on the academic agenda, while Salvia et al. ( 2019 ) highlighted that SDGs 11, 12, 13, and 15 were high research themes, and SDGs 8 and 14 were least researched.

According to the results obtained, articles related to SDGs on hunger, energy, and peace were only published starting in 2017, while articles related to more applied and diverse SDGs research were found starting in 2018, as also reported by Yamaguchi et al. ( 2023 ). Regarding the studies published starting in 2018, those of an environmental nature, i.e., related to nature and technology areas such as water and sanitation, industry, innovation and infrastructure, food and agriculture, business and management, development studies, and urban studies, climate change, and ecosystems, can be highlighted. These results show progress and a trend in SDGs studies, pointing to a growth in environmental research. Similar findings have been reported in previous studies by Sweileh ( 2020 ), Londono-Pineda and Cano ( 2022 ), and Yamaguchi et al. ( 2023 ). However, Yamaguchi et al. ( 2023 ) focused on the most cited articles, and Sweileh ( 2020 ) only analyzed articles with the phrase “sustainable development goal”, while this study has a broader scope. In addition, Londono-Pineda and Cano ( 2022 ) analyzed the main methodologies used for evaluating SDGs through bibliometric analysis. Scopus and Web of Science were identified by El Mohadab et al. ( 2020 ) as the primary databases for bibliometric analysis.

This study demonstrates that countries with the most institutional affiliations from authors also have corresponding funding to support research in diverse universities and institutions. Most of the publications found were articles published in highly indexed journals. However, the concentration of cutting-edge knowledge in specific countries, institutions, and authors is a concern. According to Londono-Pineda and Cano ( 2022 ), co-authorship can be an efficient strategy for institutions in developing countries to generate high-impact publications on issues related to SDG assessments. Sweileh ( 2020 ) notes that collaboration related to SDGs in America and Europe is strong, but collaboration in African and Asian countries is poor. To promote a more comprehensive assessment of the SDGs, it is necessary to transcend independent SDG assessments and recognize the thresholds of each dimension, allowing for the consideration of trade-offs among the SDGs. Didegah and Thelwall ( 2013 ) suggest that inviting and collaborating with researchers from third-world countries would help publish high-impact factor journals and attract funds for research proposals related to SDGs.

It can be inferred that there is a regionalization of research interest related to various goals and targets of SDGs. The developed world (USA, Canada, Australia, and Europe) is more interested in SDG 4 (Quality Education), SDG 11 (Sustainable Cities and Communities), SDG 12 (Responsible Consumption and Production), and SDG 13 (Climate Action) but the African world more interested in SDG 13 (Climate Action), SDG 1 (No Poverty), SDG 2 (Zero Hunger), SDG 5 (Gender Equality), SDG 6 (Clean Water and Sanitation), SDG 15 (Life on Land) (Körfgen et al., 2018 ; Salvia et al., 2019 ). Thus, it is observed that most of the research on SDGs is related to social problems like poverty, hunger, education, conflict, gender, and peace. However, global warming and climate change are also global environmental threats to the life-supporting system on earth (Zhenmin & Espinosa, 2019 ). These results were expected, as environmental sciences are an interdisciplinary academic field that integrates physics, biology, and geography and studies the environment and the solution to environmental problems, covering a wide range of topics (Yamaguchi et al., 2023 ).

The top 10 countries, institutions, and authors publishing on SDGs represent the world’s developed economies. However, most research carried out was related to social problems (poverty, hunger, education, gender, and peace) in the underdeveloped world (Yamaguchi et al., 2023 ). The lack of participation or opportunity to contribute to the global goals research would make countries remain unaware of the happenings around the world, thus making SDGs 2030 unattainable. One of the primary goals of the SDGs is to demonstrate the world as a whole rather than just a few countries. However, the patterns of research and development highlight that research interest is regionalized according to the scale of the problem in their area (Sweileh, 2020 ).

Climate, ecosystems, health systems, and inequality have been major research areas in the past, contributing to SDGs 13, 14, 15, 3, and 10 (Yamaguchi et al., 2023 ). The highly productive countries contributing to SDGs research themes include the USA, UK, Australia, Germany, China, Switzerland, Spain, India, and South Africa. European countries, including Sweden, Austria, France, Finland, and Denmark, are top of the list of high research citations. The top 10 productive institutions/organizations in SDGs research are based on the UK, USA, Australia, Switzerland, and South Africa. The top 10 prolific authors in SDGs come from the USA, Switzerland, the UK, Canada, and Iran. The gap is evident in the goals covered, countries’ participation, institutions, and the share of authors from particular regions. Developed countries research more on SDGs than developing and underdeveloped countries, where most of the world population lives (Salvia et al., 2019 ; Sweileh, 2020 ). The voices of these people are silent in research publications. Their narratives fail to find a place in our research documents.

The study makes a valuable contribution to the literature as the first review to focus on the most frequently evaluated SDGs, and one of the few studies, along with Sweileh ( 2020 ), Londono-Pineda and Cano ( 2022 ), and Yamaguchi et al. ( 2023 ), to identify the recurrent types of assessments related to the 2030 Agenda for SDGs. The findings are in line with the need for research that promotes more comprehensive assessments of the agenda, as highlighted by Ahner-Mchaffie et al. ( 2018 ), El Mohadab et al. ( 2020 ), Meschede ( 2020 ) and Zhu et al. ( 2021 ). To achieve a more comprehensive assessment of the SDGs, it is essential to move beyond individual evaluations and instead recognize the interdependence and trade-offs among the various dimensions, which can be achieved by acknowledging the thresholds of each SDG.

6 Concluding remarks: the way forward

This study investigated the bibliometric analysis of trends, trajectories, and prospects of SDGs by the global community based on the Web of Science core database from 2015 to 2022. Even after seven years of implementation of SDGs, the agenda of 2030 are having still complex interlink age between goals and also overambitious targets. The result of the study revealed an increasing trend of publication during the studied period, but goals are not highlighted in a consolidated manner.

The top five countries with the highest number of publications and citations are from the developed world (USA, China, UK, Australia, and Spain), whereas the least contributing countries are from the developing world. Again, the top 5 productive authors are also from the developed world. It has been highlighted that good health and well-being are the thematic areas of research for the underdeveloped world, and climate action is a focus area of research for high-income countries. Thus, it shows that the goals of SDGs are not consolidated but divisive in nature, and the reason may be practical challenges surrounding implementing SDGs. Again, keyword analysis emphasized about core research areas: ‘sustainable development goals, climate change, agenda 2030, circular economy, Africa, poverty, global health, governance, food security, sub-Saharan Africa, millennium development goals, universal health coverage, indicators, gender, and inequality’; and these words are primary needs of human life.

The goals related to the basic needs of human being to just have human life should not treat as unrealistic aspirations and call for prioritizing SDGs. Therefore, education, funding, and innovation of green technology are critical elements to achieve the target of SDGs in 2030. Again, there is a need for a periodical investigation of SDGs-related published documents to get an insight into the gap in achieving the global 2030 agenda.

There is no specific theory regarding the SDGs. Instead, they represent a holistic approach to global development with 17 interconnected and interdependent goals. Achieving them requires collaboration from all sectors of society, emphasizing an integrated approach, technology, financial inclusion, and continuous monitoring. The importance of collaboration, an integrated approach, technology, financial inclusion, and continuous monitoring has been identified as the main theoretical findings of the SDGs. There are no specific practical discoveries related to the SDGs, as they represent a holistic approach to global development, with goals such as eradicating poverty, ensuring gender equality, protecting the environment, and promoting economic growth. Practical advancements related to the SDGs have been made in areas such as policy and decision-making, partnerships and collaboration, data and measurement, and financing. The implementation of SDGs has also demonstrated the importance of a multi-stakeholder approach, innovative financing mechanisms, and technology to achieve sustainable development.

Studies on the SDGs are highly complex due to the interdisciplinary nature and scope of the objectives and targets involved in this theme. Therefore, more research should be carried out to fill this gap by developing more effective and reliable methods to verify progress toward the SDGs. To achieve this, it is recommended to incorporate other bibliographic databases to further increase the reach of the bibliometric review of this topic, including non-Web of Science databases and the inclusion of grey literature such as reports from government and non-governmental agencies.

Data availability

The data that support the findings of this study are available upon reasonable request.

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Sudarsan Desul

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MM, DS, and CAGS designed the research; MM and DS wrote the original draft; DS, CAGS, and RMS worked on the visualization; MM, DS, CAGS, SKM, AHMK, SG, KAM, RKB, RMS, CACS, KB performed the manuscript review and editing; MM provided funding acquisition, project administration, and resources; and MM, DS, CAGS, SKM, AHMK, SG, KAM, RKB, RMS, CACS, and KB wrote the final paper.

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Mishra, M., Desul, S., Santos, C.A.G. et al. A bibliometric analysis of sustainable development goals (SDGs): a review of progress, challenges, and opportunities. Environ Dev Sustain (2023). https://doi.org/10.1007/s10668-023-03225-w

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• Published: 23 August 2023

Assembly of 43 human Y chromosomes reveals extensive complexity and variation

• Pille Hallast   ORCID: orcid.org/0000-0002-0588-3987 1   na1 ,
• Peter Ebert   ORCID: orcid.org/0000-0001-7441-532X 2 , 3 , 4   na1 ,
• Mark Loftus 5 , 6   na1 ,
• Feyza Yilmaz 1 ,
• Peter A. Audano   ORCID: orcid.org/0000-0002-5187-0415 1 ,
• Glennis A. Logsdon   ORCID: orcid.org/0000-0003-2396-0656 7 ,
• Marc Jan Bonder 8 , 9 ,
• Weichen Zhou   ORCID: orcid.org/0000-0003-4755-1072 10 ,
• Wolfram Höps 11 ,
• Kwondo Kim   ORCID: orcid.org/0000-0001-8254-528X 1 ,
• Chong Li 12 ,
• Savannah J. Hoyt   ORCID: orcid.org/0000-0001-7804-3236 13 ,
• Philip C. Dishuck   ORCID: orcid.org/0000-0003-2223-9787 7 ,
• David Porubsky   ORCID: orcid.org/0000-0001-8414-8966 7 ,
• Fotios Tsetsos 1 ,
• Jee Young Kwon 1 ,
• Qihui Zhu 1 ,
• Katherine M. Munson   ORCID: orcid.org/0000-0001-8413-6498 7 ,
• Patrick Hasenfeld   ORCID: orcid.org/0000-0003-2319-2482 11 ,
• William T. Harvey 7 ,
• Alexandra P. Lewis 7 ,
• Jennifer Kordosky 7 ,
• Kendra Hoekzema 7 ,
• Human Genome Structural Variation Consortium (HGSVC) ,
• Rachel J. O’Neill   ORCID: orcid.org/0000-0002-1525-6821 13 , 14 , 15 ,
• Jan O. Korbel 11 ,
• Chris Tyler-Smith 16 ,
• Evan E. Eichler   ORCID: orcid.org/0000-0002-8246-4014 7 , 17 ,
• Xinghua Shi 12 ,
• Christine R. Beck   ORCID: orcid.org/0000-0001-7821-8489 1 , 14 , 15 ,
• Tobias Marschall   ORCID: orcid.org/0000-0002-9376-1030 2 , 4 ,
• Miriam K. Konkel 5 , 6   na2 &
• Charles Lee   ORCID: orcid.org/0000-0001-7317-6662 1   na2  

Nature volume  621 ,  pages 355–364 ( 2023 ) Cite this article

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• DNA sequencing
• Genome evolution
• Genome informatics
• Molecular evolution
• Structural variation

The prevalence of highly repetitive sequences within the human Y chromosome has prevented its complete assembly to date 1 and led to its systematic omission from genomic analyses. Here we present de novo assemblies of 43 Y chromosomes spanning 182,900 years of human evolution and report considerable diversity in size and structure. Half of the male-specific euchromatic region is subject to large inversions with a greater than twofold higher recurrence rate compared with all other chromosomes 2 . Ampliconic sequences associated with these inversions show differing mutation rates that are sequence context dependent, and some ampliconic genes exhibit evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, Yq12, is composed of alternating repeat arrays that show extensive variation in the number, size and distribution, but retain a 1:1 copy-number ratio. Finally, our data suggest that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kb away from the currently established 1 boundary. The availability of fully sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of traits with specific Y-chromosomal variants and garnering insights into the evolution and function of complex regions of the human genome.

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The complete sequence of a human Y chromosome

Arang Rhie, Sergey Nurk, … Adam M. Phillippy

Eighty million years of rapid evolution of the primate Y chromosome

Yang Zhou, Xiaoyu Zhan, … Guojie Zhang

The structure, function and evolution of a complete human chromosome 8

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Data availability

All data generated and used in this study were derived from lymphoblast lines available from the Coriell Institute for Medical Research for research purposes ( https://www.coriell.org/ ). Further details are provided in Supplementary Table 1 . All data generated by the HGSVC (PacBio HiFi, ONT-UL, Hi-C, RNA-seq, Iso-seq and Bionano Genomics optical genome maps) are available at the International Nucleotide Sequence Database Collaboration (INSDC) under the following NCBI project IDs: PRJEB58376 , PRJNA988114 , PRJEB41077 , PRJEB39684 and PRJEB39750 . The HPRC ( https://humanpangenome.org/ ) year 1 PacBio HiFi, ONT long-read sequencing and Bionano Genomics optical mapping data files are available at INSDC ( PRJNA701308 ). Further details are provided in Supplementary Table 1 . Existing testis Iso-seq data from seven individuals are available from the European Nucleotide Archive (ENA) under accessions SRX9033926 and SRX9033927 . The GEUVADIS expression data are available through ArrayExpress under accession E-GEUV-3 . The Genome in a Bottle (GIAB) data can be downloaded from ENA ( PRJNA200694 ). Large supplementary data files such as the assembled genomes are available online ( ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/data_collections/HGSVC3/working/20230412_sigY_assembly_data ).

Code availability

Project code implemented to produce the assemblies and the basic quality control/evaluation statistics is available at GitHub ( https://github.com/marschall-lab/project-male-assembly ). All scripts written and used in the study of the Yq12 subregion are available at GitHub ( https://github.com/Markloftus/Yq12 ).

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Acknowledgements

Funding was provided by National Institutes of Health (NIH) grants U24HG007497 (to C. Lee, E.E.E., J.O.K. and T.M.), U01HG010973 (to T.M., E.E.E. and J.O.K.), R01HG002385 and R01HG010169 (to E.E.E.), and GM123312 (to S.J.H. and R.J.O.); the German Federal Ministry for Research and Education (BMBF 031L0184 to J.O.K. and T.M.); the German Research Foundation (DFG 391137747 to T.M.); the German Human Genome-Phenome Archive (DFG (NFDI 1/1) to J.O.K.); the European Research Council (ERC Consolidator grant 773026 to J.O.K.); the EMBL (to J.O.K. and P. Hasenfeld); the EMBL International PhD Programme (to W.H.); the Jackson Laboratory Postdoctoral Scholar Award (to K.K.); NIH National Institute of General Medical Sciences (NIGMS R35GM133600 to C.R.B.; 1P20GM139769 to M.K.K. and M.L.) and the National Cancer Institute (NCI) (P30CA034196 to C.R.B. and P.A.A.); U24HG007497 (P. Hallast, F.Y., Q.Z., F.T. and J.Y.K.); NIGMS K99GM147352 (to G.A.L.); and Wellcome grant 098051 (to C.T.-S.). This work was also supported, in part, by the P30 CA034196 grant from the NCI. E.E.E. is an investigator of the Howard Hughes Medical Institute. We thank A. Rhie and A. Phillippy for coordination and discussions; Y. Xue for discussions and advice throughout the project; J. Wood and the members of the Genome Reference Informatics Team at the Wellcome Sanger Institute for suggestions and feedback on assembly evaluation; L. Skov for advice and sharing his scripts for gene conversion detection; the members of the HPRC ( https://humanpangenome.org ) for making their data publicly available; the staff at Clemson University for their allotment of compute time on the Palmetto Cluster; staff at the Center for Information and Media Technology at Heinrich Heine University Düsseldorf and the Scientific Services at the Jackson Laboratory, including the Genome Technologies Service for their assistance with the work described herein and Research IT for providing computational infrastructure and support and the members of the Phillippy laboratory (NIH/NHGRI) for their Verkko support; and the people who contributed samples as part of the 1000 Genomes Project.

Author information

These authors contributed equally: Pille Hallast, Peter Ebert, Mark Loftus

These authors jointly supervised this work: Miriam K. Konkel, Charles Lee

A list of authors and their affiliations appear at the end of the paper

Authors and Affiliations

The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA

Pille Hallast, Feyza Yilmaz, Peter A. Audano, Kwondo Kim, Fotios Tsetsos, Jee Young Kwon, Qihui Zhu, Christine R. Beck & Charles Lee

Institute for Medical Biometry and Bioinformatics, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany

Peter Ebert & Tobias Marschall

Core Unit Bioinformatics, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany

Peter Ebert

Center for Digital Medicine, Heinrich Heine University, Düsseldorf, Germany

Department of Genetics & Biochemistry, Clemson University, Clemson, SC, USA

Mark Loftus & Miriam K. Konkel

Center for Human Genetics, Clemson University, Greenwood, SC, USA

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA

Glennis A. Logsdon, Philip C. Dishuck, David Porubsky, Katherine M. Munson, William T. Harvey, Alexandra P. Lewis, Jennifer Kordosky, Kendra Hoekzema & Evan E. Eichler

Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

Marc Jan Bonder

Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA

Weichen Zhou

Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany

Wolfram Höps, Patrick Hasenfeld & Jan O. Korbel

Department of Computer and Information Sciences, Temple University, Philadelphia, PA, USA

Chong Li & Xinghua Shi

Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA

Savannah J. Hoyt & Rachel J. O’Neill

Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA

Rachel J. O’Neill & Christine R. Beck

The University of Connecticut Health Center, Farmington, CT, USA

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK

Chris Tyler-Smith

Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA

Evan E. Eichler

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Human Genome Structural Variation Consortium (HGSVC)

• Pille Hallast
• , Peter Ebert
• , Mark Loftus
• , Feyza Yilmaz
• , Peter A. Audano
• , Glennis A. Logsdon
• , Marc Jan Bonder
• , Weichen Zhou
• , Wolfram Höps
• , Kwondo Kim
• , Philip C. Dishuck
• , David Porubsky
• , Fotios Tsetsos
• , Jee Young Kwon
• , Qihui Zhu
• , Katherine M. Munson
• , Patrick Hasenfeld
• , William T. Harvey
• , Alexandra P. Lewis
• , Jennifer Kordosky
• , Kendra Hoekzema
• , Jan O. Korbel
• , Evan E. Eichler
• , Xinghua Shi
• , Christine R. Beck
• , Tobias Marschall
• , Miriam K. Konkel
•  & Charles Lee

Contributions

PacBio production sequencing: Q.Z., K.M.M., A.P.L. and J.K. ONT production: Q.Z. and K.H. Strand-seq production: P. Hasenfeld. and J.O.K. ONT re-basecalling and methylation calling: P.A.A. and W.T.H. Genome assembly: P.E., F.Y. and T.M. Assembly analysis and evaluation: P.E., P. Hallast, F.Y., W.H. and F.T. Assembly-based variant calling: P.E., P.A.A., P. Hallast and C.R.B. Variant quality control, merging and annotation: P.A.A. and P. Hallast. Short-read calling, phylogeny construction and dating: P. Hallast. Analysis of Bionano Genomics optical maps: F.Y. Strand-seq inversion detection and genotyping: D.P. MEI discovery and integration: W.Z., M.L. and M.K.K. Inversion analysis: P. Hallast, D.P., K.K., M.L. and M.K.K. Gene conversion and evolutionary rate: K.K., P. Hallast and M.K.K. Gene families: M.L., F.Y. and M.K.K. Analyses on Y subregions: P.E., P. Hallast, M.L., F.Y., G.A.L., P.A.A., W.H., K.K., F.T., M.K.K., E.E.E. and C.Lee. RNA-seq analysis: M.J.B. Methylation and meQTL analysis: M.J.B. HiC analysis: C. Li. and X.S. Repeat annotation: S.J.H. and R.J.O. Iso-seq analysis: P.C.D. and E.E.E. Gene annotations F.Y. and P.C.D. Supplementary materials: P. Hallast, P.E., M.L., F.Y., P.A.A., G.A.L., M.J.B., W.Z., W.H., K.K., C. Li, S.J.H., P.C.D., F.T., J.Y.K., Q.Z., K.M.M., P. Hasenfeld, X.S. and M.K.K. Display items: P. Hallast, P.E., M.L., F.Y., G.A.L., W.H., K.K., F.T. and M.K.K. Manuscript writing: P. Hallast, P.E., M.L., P.A.A., G.A.L., M.J.B., W.Z., M.K.K., C.Lee with contributions from all of the other authors. All of the authors contributed to the final interpretation of data. HGSVC co-chairs: C. Lee, J.O.K., E.E.E. and T.M.

Corresponding author

Correspondence to Charles Lee .

Ethics declarations

Competing interests.

E.E.E. is a scientific advisory board member of Variant Bio, Inc. C. Lee is a scientific advisory board member of Nabsys and Genome Insight. The following authors have previously disclosed a patent application (no. EP19169090) relevant to Strand-seq: J.O.K., T.M. and D.P. The other authors declare no competing interests.

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Extended data figures and tables

Extended data fig. 1 variation in structure and composition across y-chromosomal subregions..

a . Overview of the Y chromosome. A three-way comparison of sequence identity between GRCh38 Y, NA19317 (E1b1a1a1a1c1a1a3a1-CTS8030) and the T2T Y (excluding Yq12 and PAR2 subregions), highlighting substantial differences in the size and orientation of some subregions. b . Focus on Yq12. Sequence identity heatmaps of the Yq12 subregion for six contiguously assembled samples (HG01890, HG02666, HG01106, HG02011, HG00358 and HG01952), two samples (NA19705 and HG01928) with a single gap in the Yq12 subregion (gap location marked with asterisk) and the T2T Y using 5kb window size. c . Focus on TSPY repeat array. Sequence identity heatmaps of ~20.3-kbp TSPY repeat units for three males highlighting putative expansion events harbouring both single and multiple repeat units. Red shades from lighter to darker indicate sequence identity from 99–100%, respectively, while white fill indicates sequence identity <99%. The last copy on the right is the single separate repeat unit containing the TSPY2 gene. See Fig. S22 for heatmaps of all samples. d . Dotplots of the TSPY repeat array for HG02666 with 5 kbp of flanking regions showing identical matches of 2, 5, and 10 kbp in size indicating regions with high sequence identity. See Fig. S25 for additional examples.

Extended Data Fig. 2 Distribution of genetic variants across the Y chromosome and repeat elements in PAR1, XDR1 and XTR1 subregions.

a . Distribution of variant sizes for SVs (≥ 50 bp, top), Indels (< 50 bp, middle), and SNVs (bottom) with the Y chromosome coloured by subregion. High peaks in heterochromatin are apparent for SVs, but are absent in SNVs and indels. b . Repeat element distribution across 10 samples with contiguously assembled PAR1 regions and the T2T Y. Repeat elements on sense (+) and antisense (−) strand are shown, coloured according to repeat class. Extensive differences in size can be seen between samples, especially in the satellite arrays located close to the telomere (in dark red), and substantial differences in repeat element composition in PAR1 vs. the male-specific XDR1 and XTR1 regions. The locations of PAR1, XDR1 and XTR1 subregions in each individual are shown in black, red and black, respectively. Please note that the maroon colour of the “Unknown” elements close to the telomere is caused by significant clustering of those elements. DNA: DNA repeat elements, snRNA: small nuclear RNA, tRNA: transfer RNA, rRNA: ribosomal RNA, srpRNA: signal recognition particle RNA, scRNA: small conditional RNA, RC: rolling circle.

Extended Data Fig. 3 Examples of structural variation identified in the assembled Y chromosomes.

a . Inversions identified in the AZFc /ampliconic 7 subregion. Top - comparison between the T2T Y and select de novo assemblies, bottom - GRCh38 Y and the de novo assemblies (see Fig. S34 for details on AZFc /ampliconic 7 subregion composition). Potential NAHR path is shown below the dotplot. b . Inverted duplication affecting roughly two thirds of the 161 kbp unique ‘spacer’ sequence in the P3 palindrome, spawning a second copy of the TTTY5 gene and elongating the LCRs in this region. A detailed sequence view reveals a high sequence similarity between the duplication and its template, and its placement in Y phylogeny supports emergence of this variant in the common ancestor of haplogroup E1a2 carried by NA19239, HG03248 and HG02572 (Fig. 3a ).

Extended Data Fig. 4 RBMY1 gene similarity and architecture.

a . A schematic distribution of individual RBMY1 gene copies (filled rectangles) within analysed Y chromosome assemblies (42 + T2T + GRCh38). The RBMY1 gene copies are located in four primary regions (NA19239 carries a partial duplication of gene region 2 and the composition of HG02666 suggests at least one inversion within the RBMY regions). Fill colours refer to the assigned network community (NC) and indicates a similar sequence ( Methods ). Assembly of this region was not contiguous in HG03065 (brown line) and was not included in the analysis. b . A secondary directed network showing connections between NCs with the most similar consensus sequences. An edge pointing from one node to a second node indicates that the second node was the first’s closest match (i.e., most similar sequence; ties are allowed and shown as multiple edges stemming from a node). The width of the edge represents the sequence similarity between two nodes (i.e., NC consensus sequence similarity; thicker means fewer SNVs). The node size is representative of the total edges pointing to the node. c . RBMY1 phylogenetic analysis of exonic nucleotide sequences. Shown is the unrooted phylogenetic tree of RBMY1 genes constructed using a maximum likelihood approach ( Methods ). This tree is rooted at the midpoint with the total count of RBMY1 copies shown on the right. The scale bar represents the average number of substitutions per site. RBMY1 copies located in regions 1 and 2 (primarily dark blue, orange, dark/light green, and pink) distinguish themselves from those located downstream in regions 3 and 4 (primarily light blue and purple copies).

Extended Data Fig. 5 TSPY gene similarity and architecture.

a . TSPY array visualization of each sample with contiguous assembly in this region. Individual TSPY gene copies are shown (rectangles), and their colour is based on the assigned network community (NC) ( Methods ). Sample names with black rectangles (NA19331, HG03732 and HG03492) carry the IR3/IR3 inversion and were re-oriented for visualization. Asterisks within individual gene copies indicate possible gene conversion (GC) or recombination (R) events unique to that gene copy. If a GC/R event is shared by an NC an asterisk is shown in the NC legend rectangle. The TSPY2 gene copy is shown as a red rectangle. b . A secondary directed network showing the sequence similarity between NC consensus sequences. An edge pointing from one node to a second node indicates that the second node was the first’s closest match (i.e., most similar sequence; ties are allowed and shown as multiple edges stemming from a node). The width of the edge represents the sequence similarity between two nodes (i.e., NC consensus sequence similarity; thicker means fewer SNVs). The node size is representative of the total edges pointing to the node. c . TSPY phylogenetic analysis of exonic nucleotide sequences. Shown is the unrooted phylogenetic tree of TSPY genes constructed using a maximum likelihood approach ( Methods ). This tree is rooted at the midpoint and the total count of TSPY copies is shown on the right. The scale bar represents the average number of substitutions per site. The early split/rise of NC1 within the tree, in conjunction with the secondary directed network and manual comparison of TSPY sequences (as well as their presence across all lineages) suggests that NC1 TSPY copies represent the ancestral TSPY gene sequence.

Extended Data Fig. 6 DNA methylation patterns as determined from the ONT data across the three contiguously assembled Y chromosomes.

Methylation patterns for samples: a . HG1890, b . HG02666 and c . HG00358. The three dot plots (in grey) show the smoothed DNAme levels, in 5 kbp windows for visualization, in beta-scale ranging from 0 (not methylated) to 1 (methylated). The locations of Yq12 repeat arrays ( DYZ18 , 2.7kb-repeat, 3.1kb-repeat, DYZ1 and DYZ2 ) and the Y-chromosomal subregions are shown below as bar plots.

Extended Data Fig. 7 Functional analyses on the Y chromosome with DNA-methylation, RNA expression and HiC information as anchored to GRCh38 Y.

a . The top three panels show DNA-methylation levels and variation over the studied chromosomes (n = 41). In black (top dot plot) the average methylation is shown, in green (middle dot plot) the variation in DNAme levels across the studied genomes. The bottom boxplot represents the DNA methylation segmentation using PycoMeth-seg ( Methods ). In grey shades 2,861 methylation segments, and in red shades the 340 significantly differentially methylated segments (DMS). The CpG sites that fall in a DMS are coloured in a lighter shade in the top two dot plots, the dot plots are in beta-scale, ranging from 0 (not methylated) to 1 (methylated). b . Average insulation scores (top) and variance of insulation scores between any two samples (bottom) across 40 samples with Hi-C data with 10 kbp resolution. Regions with lower insulation scores are more insulated and more likely to be topologically associating domain (TAD) boundaries, while regions with higher scores are more likely to stay inside TADs (the regions between the two adjacent TAD boundaries). The y-axis represents the average insulation scores ranging from −2 (most insulated) to 2 (least insulated) and the variance insulation scores ranging from 0 (no variance) to 8 (more variance). c . The Geuvadis-based gene-expression analysis, shown are the 205 genes on the Y chromosome (grey shades), the 64 genes expressed in the Geuvadis LCLs (blue shades), of which 22 are differentially expressed (red shades, Supplementary Results ‘Functional analysis’ for additional details).

Extended Data Fig. 8 Composition of the Y-chromosomal (peri-)centromeric regions.

a . Organization of the chromosome Y centromeric region from 21 genomes representing all major superpopulations. The structure (top), α-satellite HOR organization (middle), and sequence identity heat map (bottom) for each centromere is shown and reveals the presence of novel HORs in over half of the centromeres. Note - the sizes of the DYZ3 α-satellite array are shown on top as determined using RepeatMasker ( Methods ). b . Genetic landscape of the Y-chromosomal pericentromeric region for three select samples (see Figs. S47 – S48 for all samples). The top panel shows locations and composition of the pericentromeric region with repeat array sizes shown for each Y chromosome (the DYZ3 α-satellite array size as determined using RepeatMasker, Methods ). The middle panel shows (UL-)ONT read depth and bottom sequence identity head maps generated using the StainedGlass pipeline 74 (using a 5 kbp window size).

Extended Data Fig. 9 Divergence of DYZ18 , Yq11/Yq12 transition region and DYZ1 repeat units.

An overview of the Bray-Curtis distance/dissimilarity of k-mer abundance profiles for individual DYZ18 (grey), 3.1-kbp (red), 2.7-kbp (blue) and DYZ1 (black) repeats versus their consensus sequence. The Yq11/transition region/Yq12 are shown for each of the seven samples with a completely assembled Yq12 subregion. Lighter colours indicate less distance/dissimilarity (i.e., more similar) k-mer abundance profiles compared to their consensus sequence. Results indicate that arrays located on the proximal and distal boundaries of the Yq12 subregion contain repeats with k-mer abundance compositions less similar to their consensus sequence (i.e., more diverged). The size of individual lines is a function of the length of the repeat. The repeat unit orientation (above = sense, below = antisense) was determined based on RepeatMasker annotations of satellite sequences within repeats ( Methods ).

Extended Data Fig. 10 Divergence of Yq12 DYZ2 repeat units.

An overview of the divergence of individual DYZ2 subunits for a . samples with completely assembled Yq12 subregion (HG01890, HG02666, HG01106, HG02011, T2T Y, HG00358, HG01952), and b . the two most closely related genomes (NA19317 and NA19347) with incompletely assembled Yq12 subregions. The size of individual lines is a function of the length of the repeat. The repeat unit orientation (above = sense, below = antisense) was determined based on RepeatMasker annotations of satellite sequences within repeats ( Methods ). A higher divergence was observed within the subunits located in arrays at the proximal and distal ends of the Yq12 subregion. Additionally, DYZ2 subunits located near the boundaries of individual arrays tend to be more diverged than those located centrally. Between the closely related genomes, the divergence of DYZ2 repeats within the shared DYZ2 arrays are highly similar.

Supplementary information

Supplementary information.

Supplementary Results 1–9 providing more quality control and in-depth analyses of gene content, inversions, the Yq12 region and putatively functional consequences of the Y variation; Supplementary Figs. 1–74, complementing all analyses in the main text and in the Supplementary Results; and Supplementary References 1–46.

Reporting Summary

Supplementary tables.

Supplementary Tables 1–61, complementing all analyses in the main text and in the Supplementary Results. The file includes a short description of each table in the table of contents (the first table sheet in the document).

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Hallast, P., Ebert, P., Loftus, M. et al. Assembly of 43 human Y chromosomes reveals extensive complexity and variation. Nature 621 , 355–364 (2023). https://doi.org/10.1038/s41586-023-06425-6

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In the new study Miller, Brincat and Roy suggest another advantage consistent with cognitive control being based on an interplay of large-scale coordinated rhythmic activity: “Subspace coding.” This idea postulates that brain rhythms organize the otherwise massive number of possible outcomes that could result from, say, 1,000 neurons engaging in independent spiking activity. Instead of all the many combinatorial possibilities, many fewer “subspaces” of activity actually arise, because neurons are coordinated, rather than independent. It is as if the spiking of neurons is like a flock of birds coordinating their movements.  Different phases and frequencies of brain rhythms provide this coordination, aligned to amplify each other, or offset to prevent interference. For instance, if a piece of sensory information needs to be remembered, neural activity representing it can be protected from interference when new sensory information is perceived.

“Thus the organization of neural responses into subspaces can both segregate and integrate information,” the authors write.

The power of brain rhythms to coordinate and organize information processing in the brain is what enables functional cognition to emerge at that scale, the authors write. Understanding cognition in the brain, therefore, requires studying rhythms.

“Studying individual neural components in isolation—individual neurons and synapses—has made enormous contributions to our understanding of the brain and remains important,” the authors conclude. “However, it’s becoming increasingly clear that, to fully capture the brain’s complexity, those components must be analyzed in concert to identify, study, and relate their emergent properties.”

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Heterogeneity and Endogenous Compliance: Implications for Scaling Class Size Interventions

This paper examines the scalability of the results from the Tennessee Student-Teacher Achievement Ratio (STAR) Project, a prominent educational experiment. We explore how the misalignment between the experimental design and the econometric model affects researchers' ability to learn about the intervention's scalability. We document heterogeneity in compliance with class-size reduction that is more extensive than previously acknowledged and discuss its consequences for the evaluation of the experiment. Guided by this finding, we implement a new econometric framework incorporating heterogeneous treatment effects and endogenous class size determination. We find that the effect of class size on test scores differs considerably across schools, with only a small fraction of schools having significant benefits from reduced class sizes. We discuss the challenges this poses for the intervention's scalability and conclude by analyzing targeted class-size interventions.

We thank Michael Dinerstein for useful comments and suggestions. We also thank the participants of the workshops and seminars where we presented our work. The views expressed herein are those of the authors and do not necessarily reflect the views of the National Bureau of Economic Research.

MARC RIS BibTeΧ

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Biostatistics Graduate Program

Yeji ko is first author of annals of epidemiology paper.

Posted by duthip1 on Thursday, April 18, 2024 in News .

Congratulations to PhD student Yeji Ko on the publication of Adjustment for duration of employment in occupational epidemiology in the June 2024 issue of Annals of Epidemiology  (appearing online ahead of print this week). Professor Ben French , who was r ecently elected to the National Council for Radiation Protection and Measurements , is the paper’s corresponding author. Ko, French, and colleagues at Oak Ridge Associated Universities examined the healthy worker survivor effect in relation to radiation risk among nuclear workers, using simulation studies to arrive at reliable results and conclude that “it is crucial to flexibly adjust for duration of employment to account for confounding arising from the healthy worker survivor effect in occupational epidemiology.” The work was made possible by the Oak Ridge Associated Universities (ORAU) Directed Research and Development Grant, which promotes collaborations between universities and ORAU scientists for foundational research efforts.

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About 1 in 4 U.S. teachers say their school went into a gun-related lockdown in the last school year

Twenty-five years after the mass shooting at Columbine High School in Colorado , a majority of public K-12 teachers (59%) say they are at least somewhat worried about the possibility of a shooting ever happening at their school. This includes 18% who say they’re extremely or very worried, according to a new Pew Research Center survey.

Pew Research Center conducted this analysis to better understand public K-12 teachers’ views on school shootings, how prepared they feel for a potential active shooter, and how they feel about policies that could help prevent future shootings.

To do this, we surveyed 2,531 U.S. public K-12 teachers from Oct. 17 to Nov. 14, 2023. The teachers are members of RAND’s American Teacher Panel, a nationally representative panel of public school K-12 teachers recruited through MDR Education. Survey data is weighted to state and national teacher characteristics to account for differences in sampling and response to ensure they are representative of the target population.

We also used data from our 2022 survey of U.S. parents. For that project, we surveyed 3,757 U.S. parents with at least one child younger than 18 from Sept. 20 to Oct. 2, 2022. Find more details about the survey of parents here .

Here are the questions used for this analysis , along with responses, and the survey methodology .

Another 31% of teachers say they are not too worried about a shooting occurring at their school. Only 7% of teachers say they are not at all worried.

This survey comes at a time when school shootings are at a record high (82 in 2023) and gun safety continues to be a topic in 2024 election campaigns .

Teachers’ experiences with lockdowns

About a quarter of teachers (23%) say they experienced a lockdown in the 2022-23 school year because of a gun or suspicion of a gun at their school. Some 15% say this happened once during the year, and 8% say this happened more than once.

High school teachers are most likely to report experiencing these lockdowns: 34% say their school went on at least one gun-related lockdown in the last school year. This compares with 22% of middle school teachers and 16% of elementary school teachers.

Teachers in urban schools are also more likely to say that their school had a gun-related lockdown. About a third of these teachers (31%) say this, compared with 19% of teachers in suburban schools and 20% in rural schools.

Do teachers feel their school has prepared them for an active shooter?

About four-in-ten teachers (39%) say their school has done a fair or poor job providing them with the training and resources they need to deal with a potential active shooter.

A smaller share (30%) give their school an excellent or very good rating, and another 30% say their school has done a good job preparing them.

Teachers in urban schools are the least likely to say their school has done an excellent or very good job preparing them for a potential active shooter. About one-in-five (21%) say this, compared with 32% of teachers in suburban schools and 35% in rural schools.

Teachers who have police officers or armed security stationed in their school are more likely than those who don’t to say their school has done an excellent or very good job preparing them for a potential active shooter (36% vs. 22%).

Overall, 56% of teachers say they have police officers or armed security stationed at their school. Majorities in rural schools (64%) and suburban schools (56%) say this, compared with 48% in urban schools.

Only 3% of teachers say teachers and administrators at their school are allowed to carry guns in school. This is slightly more common in school districts where a majority of voters cast ballots for Donald Trump in 2020 than in school districts where a majority of voters cast ballots for Joe Biden (5% vs. 1%).

What strategies do teachers think could help prevent school shootings?

The survey also asked teachers how effective some measures would be at preventing school shootings.

Most teachers (69%) say improving mental health screening and treatment for children and adults would be extremely or very effective.

About half (49%) say having police officers or armed security in schools would be highly effective, while 33% say the same about metal detectors in schools.

Just 13% say allowing teachers and school administrators to carry guns in schools would be extremely or very effective at preventing school shootings. Seven-in-ten teachers say this would be not too or not at all effective.

How teachers’ views differ by party

Republican and Republican-leaning teachers are more likely than Democratic and Democratic-leaning teachers to say each of the following would be highly effective:

• Having police officers or armed security in schools (69% vs. 37%)
• Having metal detectors in schools (43% vs. 27%)
• Allowing teachers and school administrators to carry guns in schools (28% vs. 3%)

And while majorities in both parties say improving mental health screening and treatment would be highly effective at preventing school shootings, Democratic teachers are more likely than Republican teachers to say this (73% vs. 66%).

Parents’ views on school shootings and prevention strategies

In fall 2022, we asked parents a similar set of questions about school shootings.

Roughly a third of parents with K-12 students (32%) said they were extremely or very worried about a shooting ever happening at their child’s school. An additional 37% said they were somewhat worried.

As is the case among teachers, improving mental health screening and treatment was the only strategy most parents (63%) said would be extremely or very effective at preventing school shootings. And allowing teachers and school administrators to carry guns in schools was seen as the least effective – in fact, half of parents said this would be not too or not at all effective. This question was asked of all parents with a child younger than 18, regardless of whether they have a child in K-12 schools.

Like teachers, parents’ views on strategies for preventing school shootings differed by party. 

Note: Here are the questions used for this analysis , along with responses, and the survey methodology .

About half of Americans say public K-12 education is going in the wrong direction

What public k-12 teachers want americans to know about teaching, what’s it like to be a teacher in america today, race and lgbtq issues in k-12 schools, from businesses and banks to colleges and churches: americans’ views of u.s. institutions, most popular.

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