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Background Women facing increased energetic demands in childhood commonly have altered adult ovarian activity and shorter reproductive lifespan, possibly comprising a strategy to optimize reproductive success. Here, we sought to understand the mechanisms of early-life programming of reproductive function, by integrating analysis of reproductive tissues in an appropriate mouse model with methylation analysis of proxy tissue DNA in a well-characterized population of Bangladeshi migrants in the UK. Bangladeshi women whose childhood was in Bangladesh were found to have later pubertal onset and lower age-matched ovarian reserve than Bangladeshi women who grew-up in England. Subsequently, we aimed to explore the potential relevance to the altered reproductive phenotype of one of the genes that emerged from the screens. Results Of the genes associated with differential methylation in the Bangladeshi women whose childhood was in Bangladesh as compared to Bangladeshi women who grew up in the UK, 13 correlated with altered expression of the orthologous gene in the mouse model ovaries. These mice had delayed pubertal onset and a smaller ovarian reserve compared to controls. The most relevant of these genes for reproductive function appeared to be SRD5A1, which encodes the steroidogenic enzyme 5α reductase-1. SRD5A1 was more methylated at the same transcriptional enhancer in mice ovaries as in the women’s buccal DNA, and its expression was lower in the hypothalamus of the mice as well, suggesting a possible role in the central control of reproduction. The expression of Kiss1 and Gnrh was also lower in these mice compared to controls, and inhibition of 5α reductase-1 reduced Kiss1 and Gnrh mRNA levels and blocked GnRH release in GnRH neuronal cell cultures. Crucially, we show that inhibition of this enzyme in female mice in vivo delayed pubertal onset. Conclusions SRD5A1/5α reductase-1 responds epigenetically to the environment and its downregulation appears to alter the reproductive phenotype. These findings help to explain diversity in reproductive characteristics and how they are shaped by early-life environment and reveal novel pathways that might be targeted to mitigate health issues caused by life-history trade-offs.

Women facing increased energetic demands in childhood commonly have altered adult ovarian activity and shorter reproductive lifespan, possibly comprising a strategy to optimize reproductive success. Here, we sought to understand the mechanisms of early-life programming of reproductive function, by integrating analysis of reproductive tissues in an appropriate mouse model with methylation analysis of proxy tissue DNA in a well-characterized population of Bangladeshi migrants in the UK. Bangladeshi women whose childhood was in Bangladesh were found to have later pubertal onset and lower age-matched ovarian reserve than Bangladeshi women who grew-up in England. Subsequently, we aimed to explore the potential relevance to the altered reproductive phenotype of one of the genes that emerged from the screens. Of the genes associated with differential methylation in the Bangladeshi women whose childhood was in Bangladesh as compared to Bangladeshi women who grew up in the UK, 13 correlated with altered expression of the orthologous gene in the mouse model ovaries. These mice had delayed pubertal onset and a smaller ovarian reserve compared to controls. The most relevant of these genes for reproductive function appeared to be SRD5A1, which encodes the steroidogenic enzyme 5[alpha] reductase-1. SRD5A1 was more methylated at the same transcriptional enhancer in mice ovaries as in the women's buccal DNA, and its expression was lower in the hypothalamus of the mice as well, suggesting a possible role in the central control of reproduction. The expression of Kiss1 and Gnrh was also lower in these mice compared to controls, and inhibition of 5[alpha] reductase-1 reduced Kiss1 and Gnrh mRNA levels and blocked GnRH release in GnRH neuronal cell cultures. Crucially, we show that inhibition of this enzyme in female mice in vivo delayed pubertal onset. SRD5A1/5[alpha] reductase-1 responds epigenetically to the environment and its downregulation appears to alter the reproductive phenotype. These findings help to explain diversity in reproductive characteristics and how they are shaped by early-life environment and reveal novel pathways that might be targeted to mitigate health issues caused by life-history trade-offs.

Cancer progression involves the sequential accumulation of genetic alterations that cumulatively shape the tumour phenotype. In prostate cancer, tumours can follow divergent evolutionary trajectories that lead to distinct subtypes, but the causes of this divergence remain unclear. While causal inference could elucidate the factors involved, conventional methods are unsuitable due to the possibility of unobserved confounders and ambiguity in the direction of causality. Here, we propose a method that circumvents these issues and apply it to genomic data from 829 prostate cancer patients. We identify several genetic alterations that drive divergence as well as others that prevent this transition, locking tumours into one trajectory. Further analysis reveals that these genetic alterations may cause each other, implying a positive-feedback loop that accelerates divergence. Our findings provide insights into how cancer subtypes emerge and offer a foundation for genomic surveillance strategies aimed at monitoring the progression of prostate cancer.

Cancer progression involves the sequential accumulation of genetic alterations that cumulatively shape the tumour phenotype. In prostate cancer, tumours can follow divergent evolutionary trajectories that lead to distinct subtypes, but the causes of this divergence remain unclear. While causal inference could elucidate the factors involved, conventional methods are unsuitable due to the possibility of unobserved confounders and ambiguity in the direction of causality. Here, we propose a method that circumvents these issues and apply it to genomic data from 829 prostate cancer patients. We identify several genetic alterations that drive divergence as well as others that prevent this transition, locking tumours into one trajectory. Further analysis reveals that these genetic alterations may cause each other, implying a positive-feedback loop that accelerates divergence. Our findings provide insights into how cancer subtypes emerge and offer a foundation for genomic surveillance strategies aimed at monitoring the progression of prostate cancer.

Abstract Background Migration from one environment to another often causes marked changes in developmental conditions. Here we compare epigenetic ageing and stability of the epigenetic maintenance system among British-Bangladeshi women who grew up in Bangladesh (adult migrants), where there are higher pathogen loads and poorer health care, to second-generation Bangladeshis who grew up in the UK. In our previous studies of these migrants, those who spent their childhoods in Bangladesh also had lower levels of reproductive hormones and a shorter reproductive lifespan compared to those who grew up in the UK, suggesting life history trade-offs during development. In the present study, we hypothesised that women who grew up in Bangladesh would have i) an older epigenetic/biological age compared to the women with a childhood in the UK and ii) that differences in the pace of epigenetic ageing might also be reflected by altered stability of DNA methylation marks. Results Illumina EPIC array methylation data from buccal tissue was used to establish epigenetic age estimates from 15 adult migrants and 11 second-generation migrants, aged 18-35 years. Using residuals from linear regression of DNA methylation-based biological age (DNAm age) on the chronological age, the results showed significant differences (p=0.016) in epigenetic age estimates: women whose childhood was in Bangladesh are on average 6.02 (± 2.34) years older, than those who grew up in London. We further investigated the efficiency of the epigenetic maintenance system which purportedly is reflected by epigenetic clocks. Methylation states of CpGs at the LHCGR/LHR locus, which contributes to Horvath’s multi tissue epigenetic clock were evaluated. Based on the Ratio of Concordance Preference (RCP) approach that uses double-stranded methylation data, we find that maintenance of epigenetic information is more stable in women who grew up in Bangladesh. Conclusions The work supports earlier findings that adverse childhood environments lead to phenotypic life history trade-offs. The data indicate that childhood environments can induce subtle changes to the epigenetic maintenance system that are detectable long after exposure occurred. The implication of such a finding warrants further investigation as it implies that a less flexible epigenetic memory system established early in life could reduce the capacity to respond to different environmental conditions in adult life. Competing Interest Statement The authors have declared no competing interest. Footnotes * E-Mail addresses: RS: reinhard.stoger{at}nottingham.ac.uk; MS: minseung{at}stanford.edu; GL gregoryleeman{at}outlook.com; RDE: richard.emes{at}nottingham.ac.uk; KB: khurshida.begum{at}qmul.ac.uk; PM: philippa{at}tx.technion.ac.il; GRB: g.r.bentley{at}durham.ac.uk * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE133355 * https://github.com/gregoryleeman/fold * http://www.gregoryleeman.com/fold

Abstract Reproductive function and duration of the reproductive life span are phenotypically plastic and programmed in response to the early-life environment. Such adaptive responses are described and rationalized in life history theory in the context of resource availability, but the molecular mechanisms responsible have remained enigmatic. In this study, we hypothesized that epigenetic modifications underlie adaptive reproductive strategies, and found distinct methylation patterns in buccal DNA of Bangladeshi women who grew up in Bangladesh or the UK. The later pubertal onset and lower ovarian reserve associated with Bangladeshi childhood was seen to correlate with more numerous childhood infections, so we adopted a mouse model of pre-pubertal colitis to mimic these conditions. These mice have a similarly-altered reproductive phenotype, which enabled us to determine its mechanistic basis. Several genes encoding proteins with known functions in follicle recruitment were differentially expressed in the mice ovaries, and were also differentially methylated in the women’s buccal DNA. One of these, SRD5A1 which encodes the steroidogenic enzyme 5α reductase-1, was down-regulated in the mice ovaries and hyper methylated at the same putative transcriptional enhancer as in the women’s DNA; the levels of methylation correlating with gene expression levels. Srd5a1 expression was down-regulated also in the hypothalamus where 5α reductase-1 catalyzes production of neurosteroids that regulate gonadotropin releasing hormone (GnRH). Chemical inhibition of this enzyme affected both GnRH synthesis and release, and resulted in delayed pubertal onset in vivo. The activity of 5α reductase-1 in hypothalamus and ovary and the sensitivity of SRD5A1 to epigenetic regulation attest to its role in directing long-term physiological strategies in response to environmental conditions. In the reproductive axis, this includes timing of pubertal onset, adult reproductive function and duration of the reproductive lifespan. Competing Interest Statement The authors have declared no competing interest.

Background/Objectives: Despite the lifting of the COVID-19 public health emergency, SARS-CoV-2 infections continue to be recorded worldwide. The continued prevalence of infection has been attributed to the ability of the virus to evade host immune responses, including neutralizing antibody-derived immunity. The vast majority of antibody escape mutations has been associated with the S1 subunit of the spike protein. The other region of the spike, the S2 subunit, is the most conserved region amongst coronaviruses. We hypothesized that S2-specific antibody levels are modest in vaccinated and SARS-CoV-2-infected patients, resulting in suboptimal neutralization of distant coronaviruses. Methods: Here, we analyzed S1- and S2-specific antibody levels in SARS-CoV-2-infected individuals, including a mixed cohort of those with and without immunosuppression and prior vaccination. Results: We found that S2-specific antibody responses were generally lower than S1-specific antibody responses. Intriguingly, Omicron-S1-specific antibody levels were higher than Wuhan-S1-specific antibody levels despite all vaccinated participants having received Wuhan-spike-based immunogens. This emphasizes the importance of the infecting variant and vaccine immunogen in the production of spike-targeting antibodies and associated hybrid immunity. Although S1-specific antibody levels were generally higher than their S2-specific counterparts, the correlation between neutralization and binding antibody levels was mostly higher in S2- compared with S1-specific responses. Conclusions: We conclude that S2-based immunogens are suitable for the induction of antibody-based immunity against novel SARS-CoV-2 variants but also against more distant coronaviruses, which would support a better protection for the immunocompromised as well as other vulnerable populations.

BACKGROUNDSARS-CoV-2 has evolved subvariants since the emergence of the Omicron variant in 2021. Whether these changes impact viral shedding and transmissibility is not known.METHODSPOSITIVES is a prospective longitudinal cohort of individuals with mild SARS-CoV-2 infection. Ambulatory, immunocompetent participants who did not receive antivirals self-administered 6 anterior nasal swabs over 15 days. Samples were analyzed by qPCR to quantify viral RNA, semiquantitative viral culture to detect shedding of replication-competent virus, and whole-genome sequencing to classify subvariants. Our predictor of interest was Omicron subvariants: BA.1x, BA.2x, BA.4/5x, XBB.x, and JN.x. Outcomes included RNA levels and duration of shedding replication-competent virus. We additionally explored whether symptoms are a valid marker for ending isolation.RESULTSThe median peak nasal SARS-CoV-2 RNA (6.0-6.3 log10 RNA copies/mL), median days to peak RNA (4-5 days), median days to undetectable viral RNA (12-14 days), and median days to negative viral culture (4-8 days) were similar across Omicron subvariants. Number and duration of symptoms were also similar. For all subvariants, a sizeable percentage (range 27.5%-56.0%) shed replication-competent virus after fever resolution and improvement of symptoms.CONCLUSIONDespite ongoing viral evolution, key aspects of viral dynamics of SARS-CoV-2 infection, including the duration of shedding replication-competent virus, have not substantially changed across Omicron subvariants. Replication-competent shedding of these subvariants is detected for a large proportion of people who meet criteria for ending isolation.FUNDINGNIH (U19 AI110818, R01 AI176287, K24 HL166024), the Massachusetts Consortium on Pathogen Readiness, and the Massachusetts General Hospital Department of Medicine.

Long COVID is a heterogeneous condition characterized by a wide range of symptoms that persist for 90 days or more following SARS-CoV-2 infection. Now more than five years out from the onset of the SARS-CoV-2 pandemic, the mechanisms driving Long COVID are just beginning to be elucidated. Adipose tissue has been proposed as a potential reservoir for viral persistence and tissue dysfunction contributing to symptomology seen in Long COVID. To test this hypothesis, we analyzed subcutaneous adipose tissue (SAT) from two cohorts: participants with subacute COVID-19 (28-89 days post-infection) compared to pre-pandemic controls, and participants with Long COVID compared to those with those classified as \"indeterminate\" based on the RECOVER-Adult Long COVID Research Index (12-47 months post-infection). We found no evidence of persistent SARS-CoV-2 RNA in adipose tissue in any participant. SAT from participants with subacute COVID-19 displayed significant transcriptional remodeling, including depleted immune activation pathways and upregulated Hox genes and integrin interactions, suggesting resident immune cell exhaustion and perturbations in tissue function. However, no consistent changes in gene expression were observed between Long COVID samples and samples from indeterminant participants. Thus, SAT may contribute to inflammatory dysregulation following COVID-19, but does not appear to play a clear role in Long COVID pathophysiology. Further research is needed to clarify the role of adipose tissue in COVID-19 recovery.

Plagiarism is the representation of another author's language, thoughts, ideas, or expressions as one's own original work. In educational contexts, there are differing definitions of plagiarism depending on the institution. Prominent scholars of plagiarism include Rebecca Moore Howard, Susan Blum, Tracey Bretag, and Sarah Elaine Eaton, among others. Plagiarism is considered a violation of academic integrity and a breach of journalistic ethics. It is subject to sanctions such as penalties, suspension, expulsion from school or work, substantial fines and even incarceration. Recently, cases of \"extreme plagiarism\" have been identified in academia. The modern concept of plagiarism as immoral and originality as an ideal emerged in Europe in the 18th century, particularly with the Romantic movement. Generally, plagiarism is not in itself a crime, but like counterfeiting fraud can be punished in a court for prejudices caused by copyright infringement, violation of moral rights, or torts. In academia and industry, it is a serious ethical offense. Plagiarism and copyright infringement overlap to a considerable extent, but they are not equivalent concepts, and many types of plagiarism do not constitute copyright infringement, which is defined by copyright law and may be adjudicated by courts. Plagiarism might not be the same in all countries. Some countries, such as India and Poland, consider plagiarism to be a crime, and there have been cases of people being imprisoned for plagiarizing. In other instances plagiarism might be the complete opposite of \"academic dishonesty,\" in fact some countries find the act of plagiarizing a professional's work flattering. Students who move to the United States and other Western countries from countries where plagiarism is not frowned upon often find the transition difficult.