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Abstract Somatic mobilization of LINE-1 (L1) has been implicated in cancer etiology. We analyzed a recent TCGA data release comprised of nearly 5000 pan-cancer paired tumor-normal whole-genome sequencing (WGS) samples and ~9000 tumor RNA samples. We developed TotalReCall an improved algorithm and pipeline for detection of L1 retrotransposition (RT), finding high correlation between L1 expression and “RT burden” per sample. Furthermore, we mathematically model the dual regulatory roles of p53, where mutations in TP53 disrupt regulation of both L1 expression and retrotransposition. We found those with Li-Fraumeni Syndrome (LFS) heritable TP53 pathogenic and likely pathogenic variants bear similarly high L1 activity compared to matched cancers from patients without LFS, suggesting this population be considered in attempts to target L1 therapeutically. Due to improved sensitivity, we detect over 10 genes beyond TP53 whose mutations correlate with L1, including ATRX, suggesting other, potentially targetable, mechanisms underlying L1 regulation in cancer remain to be discovered.

In the summer of 1912, James Joyce spent several weeks in Galway, visiting Nora Barnacle’s family and writing essays for Il Piccolo della Sera. Two essays produced during his stay in the West of Ireland are directly concerned with the region and its inhabitants: one describes the past and present of Galway city and the other is an account of his trip to Aranmor, the biggest Aran Island off the west coast of Galway. Joyce’s selective focus on the past glories of those places and utopian vistas connected with the development of the Galway Harbour is interesting as a counterpoint to the notion of the West of Ireland, shared by representatives of the Anglo-Irish Revival who saw a relatively homogeneous repository of traditional Celtic values in the region. Joyce’s journalistic representation of Galway and Aran deserves attention also because it anticipates late twentieth-century emphasis on hybridity, miscegenation and transcultural mobility. Finally, Joyce’s two 1912 essays are a significant reflection of his own fluctuating attitudes to Ireland and its history, at a point when he was gradually abandoning his epideictic rhetoric of “Ireland, Island of Saints and Sages” to embrace a more cosmopolitan view of the West of Ireland as a milieu shaped by various European influences. ABSTRAKT Latem 1912 roku James Joyce spędził kilka tygodni w Galway, odwiedzając rodzinę Nory Barnacle, a także przygotowując artykuły dla triesteńskiego Il Piccolo della Sera. Dwa teksty, które wówczas powstały, dotyczą bezpośrednio zachodu Irlandii – regionu Galway i jego mieszkańców. Jeden z nich opisuje przeszłość i teraźniejszość samego miasta Galway, natomiast drugi stanowi relację z wycieczki Joyce’a do Aranmor, największej z Wysp Arańskich leżących na zachód od Galway. Joyce wybiera z przeszłości regionu elementy stanowiące powód do dumy dla jego mieszkańców, opisując także perspektywy rozwoju zachodniego wybrzeża Irlandii w związku z planem rozbudowy miejscowego portu (the Galway Harbour Scheme). Takie spojrzenie na zachód Irlandii stanowi istotny kontrapunkt w stosunku do wizji regionu przedstawianej w twórczości przedstawicieli Irlandzkiego Odrodzenia, którzy dostrzegali tam przede wszystkim skarbnicę tradycyjnych wartości „celtyckich” o stosunkowo jednorodnym charakterze. Dziennikarskie spojrzenie na Galway i Wyspy Arańskie zasługuje na uwagę współczesnego czytelnika tekstów Joyce’a, ponieważ antycypuje kluczowe znaczenie zyskujących popularność dopiero pod koniec XX wieku kategorii, takich jak hybrydowość czy mobilność transkulturowa. I wreszcie artykuły Joyce’a napisane dla Il Piccolo della Sera w 1912 roku dostarczają wartościowego materiału do refleksji nad zmieniającą się perspektywą pisarza na Irlandię i jej historię, powstały bowiem w okresie, kiedy Joyce stopniowo odchodził od retoryki charakteryzującej wykład z 1907 roku pt. „Irlandia – wyspa świętych i mędrców”, zmierzając w kierunku znacznie bardziej kosmopolitycznego postrzegania zachodu Irlandii jako przestrzeni w istotny sposób kształtowanej przez rozmaite wpływy europejskie.

Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10-8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.

Background: We investigated the association between prenatal GDM exposure and offspring DNA methylation (DNAm) age at 3–10 years of age in the Tianjin GDM Observational Study. Methods: This study included 578 GDM and 578 non-GDM mother-child pairs. Children underwent an exam with anthropometric measurements and blood draw for DNAm analysis (Illumina 850 K array) at a median age of 5.9 years (range 3.1–10.2). DNAm age was calculated using two epigenetic clock algorithms (Horvath and Hannum). The residual resulting from regressing DNAm age on chronological age was used as a metric for age acceleration. Results: Chronological age was positively correlated with Horvath DNAm age (r = 0.53, p < 0.0001) and Hannum DNAm age (r = 0.38, p < 0.0001). Offspring age acceleration was higher in the GDM group than non-GDM group after adjustment for potential confounders (Horvath: 4.96 months higher, adjusted for sex, pre-pregnancy BMI, cell-type proportions, and technical bias, p = 0.0002; Hannum: 11.2 months higher, adjusted for cell-type proportions and technical bias, p < 0.0001). Increased offspring DNAm age acceleration was associated with increased offspring weight-for-age Z-score, BMI-for-age-Z-score, waist circumference, body fat percentage, subscapular skinfold, suprailiac skinfold, upper-arm circumference, and blood pressure; findings were stronger in the GDM group. Conclusions: We found that offspring of women with GDM exhibit accelerated epigenetic age compared to control participants, independent of other maternal factors. Epigenetic age in offspring was associated with cardiometabolic risk factors, suggesting that GDM and GDM-associated factors may have long-term effects on offspring epigenetic age and contribute to health outcomes.

The key problem identified in this essay is connected with many Polish researchers’ ambivalent attitude to submitting their research to academic journals published in English. This is particularly true of humanities researchers but a similar ambivalence has also affected social sciences in Poland. Simultaneously, through recourse to its author’s own experience and empirical observations, this essay demonstrates a range of strategies that may be utilized to overcome reluctance to reach international readerships. Adopting a more relaxed style, structures and vocabulary, associated, in Polish universities, with lack of sophistication and pandering to non-academic audiences, is opposed, as a strategy, to translating Polish texts into English. In the context of academic writing, communication skills prove to be language and culture specific. Therefore, for those who do not speak English as their L1, the best way to acquire those skills is by extensive reading in English, including literary works and other academic writings, preferably by Anglophone researchers. Imitation of successful communication strategies (i.e. templates and logic unique to academic argumentation) is highly recommended. Furthermore, Polish researchers who want to be published in English must bear in mind that academic English is “writer-responsible” as opposed to academic Polish, which puts on the reader the onus of responsibility for the comprehension of each text.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P

Using a functional approach to investigate the epigenetics of type 2 diabetes (T2D), we combine three lines of evidence-diet-induced epigenetic dysregulation in mouse, epigenetic conservation in humans, and T2D clinical risk evidence-to identify genes implicated in T2D pathogenesis through epigenetic mechanisms related to obesity. Beginning with dietary manipulation of genetically homogeneous mice, we identify differentially DNA-methylated genomic regions. We then replicate these results in adipose samples from lean and obese patients pre- and post-Roux-en-Y gastric bypass, identifying regions where both the location and direction of methylation change are conserved. These regions overlap with 27 genetic T2D risk loci, only one of which was deemed significant by GWAS alone. Functional analysis of genes associated with these regions revealed four genes with roles in insulin resistance, demonstrating the potential general utility of this approach for complementing conventional human genetic studies by integrating cross-species epigenomics and clinical genetic risk.

This essay offers a comparative perspective on several narrative representations of two partitions that were established in Europe in the 1920s. Partitions of Ireland and of Upper Silesia had markedly different consequences and political vicissitudes but there are also significant parallels when it comes to selected bordering practices as well as patterns and modes of remembering partition that have been exploited in contemporary writings from either region/country. The principal focus of the essay is on how partition narratives and other representations of bordering have reflected and perpetuated tropes and images connected with social and political divisions in either society. Of particular significance is the persistence of geopolitical lines that may have disappeared from maps and territories and yet they have continued to inspire contemporary identity projects that are informed by stories and memories of the past in borderland areas. The two borders – and their narrative representations – are discussed with reference to Anna Bernard’s concept of ‘partition literature’, Tim Ingold’s ‘ghostly lines’ as well as Astrid Erll’s notion of ‘travelling memory’ and its effects on the nexus of territory and identity in recent writings from Northern Ireland and Upper Silesia. [ABSTRACT FROM AUTHOR]

Genome-wide association studies in the fields of reproductive medicine and endocrinology are yielding robust genetic variants associated with disease. Integrated genomic, transcriptomic, and epigenomic molecular profiling studies are common methodologies used to understand the biologic pathways perturbed by these variants. However, molecular profiling resources do not include the tissue most relevant to many female reproductive traits, the endometrium, while the parameters influencing variability of results from its molecular profiling are unclear. We investigated the sources of DNA methylation and RNA expression profile variability in endometrium (n = 135), endometriotic disease tissue (endometriosis), and subcutaneous abdominal fat samples from 24 women, quantifying between-individual, within-tissue (cellular heterogeneity), and technical variation. DNA samples (n = 96) were analyzed using Illumina HumanMethlylation450 BeadChip arrays; RNA samples (n = 39) were analyzed using H12-expression arrays. Variance-component analyses showed that, for the top 10–50% variable DNA methylation/RNA expression sites, between-individual variation far exceeded within-tissue and technical variation. Menstrual-phase accounted for most variability in methylation/expression patterns in endometrium (Pm = 7.8 × 10−3, Pe = 8.4 × 10−5) but not in fat and endometriotic tissue; age was significantly associated with DNA methylation profile of endometrium (Pm = 9 × 10−5) and endometriotic disease tissue (Pm = 2.4 × 10−5); and smoking was significantly associated with DNA methylation in adipose tissue (Pm = 1.8 × 10−3). Hierarchical cluster analysis showed significantly different methylation signatures between endometrium and endometriotic tissue enriched for WNT signaling, angiogenesis, cadherin signaling, and gonadotropin-releasing-hormone-receptor pathways. Differential DNA methylation/expression analyses suggested detection of a limited number of sites with large fold changes (FC > 4), but power calculations accounting for different sources of variability showed that for robust detection >500 tissue samples are required. These results enable appropriate study design for large-scale expression and methylation tissue-based profiling relevant to many reproductive and endocrine traits.

[This corrects the article DOI: 10.1371/journal.pgen.1007813.].

John Millington Synge’s contributions to the development of modern Irish drama and to the Gaelic Revival (and, thereby, to Irish memory culture at large) are undeniable. Little is known, however, of his relationship with Miss Molly Allgood, who was an actress at the Abbey Theatre and his fiancée. In this essay I read Joseph O’Connor’s 2010 novel, Ghost Light, as a specimen of posthumous ventriloquism – a work of fiction which seeks to give voice to an elderly, forgotten woman who, in 1952 and thenceforth, after her death, was shamefully deprived of her right to keep Synge company in the collective memory of her nation. O’Connor creates prosthetic memories (which I call mnemofictions) for Molly Allgood so that she may eventually claim her due place in Irish memory culture. Consequently, O’Connor’s work of fiction effectively redeems a past whose records were originally censored and tampered with.

This paper aims to describe the role of India, the biggest neighbor of Bangladesh, and the outmost support of the Soviet Union in the emergence of Bangladesh as an Independent State. The paper describes the background of the Bangladesh’s Liberation war in 1971. The political situation in East Pakistan just before the crisis is described in details, especially the results of general elections which were held in December 1970. A central part of the article is dedicated to the role of India and the contribution of Indian people, government and armed forces. Almost 10 million men and women were forced to leave Bangladesh and entered various states of India like West Bengal, Tripura, Assam, Meghalaya, Bihar and Uttar Pradesh where they were accommodated as refugees. The personal implication of Indira Gandhi was very high, she traveled around the world to gather support for the Bangladesh cause. India spent thousand of rupees for the liberation war of Bangladesh; but also sacrificed the lives of its officers and soldiers. Moreover, the paper touches upon the USSR’s involvement into the Liberation war of Bangladesh in context of Soviet-American rivalry during cold war.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.

This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.

A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

The article presents an overview of Bangladesh’s foreign policy. It analyzes the main directions of Bangladesh’s cooperation with its leading partners. The author studies the changing pattern of Bangladesh’s foreign policy since it gained its independence in 1971 till the present. He focuses on the changing pattern of foreign policy of Bangladesh regarding bilateral relation with Russia during different regimes under the leadership of Sheikh Mujibur Rahman (Sheikh Mujib), General Ziaur Rahman (Zia), General H.M. Ershad (Ershad), Khaleda Zia, Sheikh Hasina and the Caretaker Government. The author seeks to link the domestic changes in the country in 1970-2000-ies, namely the change of governments and regimes, with the adjustment of the foreign policy priorities, including relations with Russia. The article shows dependence of Bangladesh’s foreign policy priorities on interests of successive power political forces.