bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elucidating the Epigenetic Landscape of Type 2 Diabetes: A Multi-Omics Analysis Revealing Novel CpG Sites and Their Association with Cardiometabolic Traits
Authors: Chung Ren-Hua , Wang Chun-Chao , Onthoni Djeane Debora , Liao Ben-Yang , Hsu Tzu-Sheng , Martin Eden R. , Hsiung Chao A. , Sheu Wayne Huey-Herng , Chiou Hung-Yi 
Published: May 2024

AbstractType 2 Diabetes (T2D) is a complex, multifactorial disease with a significant global health burden. Genome-Wide Association Studies (GWAS) have identified numerous genetic variants associated with T2D, yet understanding their functional mechanisms remains challenging due to the polygenic nature of the disease and the prevalence of non-coding region variants. This study leverages a multi-omics approach integrating methylome-wide association studies (MWAS), Mendelian Randomization (MR), and functional analyses in human pancreatic cells and mouse models to elucidate the functional consequences of genetic variants on T2D. Using summary statistics calculated from large-scale GWAS for T2D and a DNA methylation (DNAm) prediction model, our MWAS tested the association of DNAm at CpGs in whole blood with T2D across the genome. We identified 87 significant and independent CpG sites associated with T2D risk in Europeans, including 13 novel CpG sites located in or near genes not previously associated with T2D, with these results being replicated in an additional dataset. Our analyses also revealed a significant overlap of these CpGs with cardiometabolic traits, underscoring the interconnectedness of metabolic diseases. Additionally, we demonstrated trans-ethnic effects of significant CpGs in East Asians, highlighting their global relevance. Functional analyses in human pancreatic alpha and beta cells identified potential regulatory roles of these CpGs in gene expression, particularly in genes involved in glucose metabolism. Notably, differential expression of the PPP1R3B gene, regulated by a significant CpG, between T2D cases and normal controls was observed in both alpha and beta cells, with mouse models confirming its role in glucose homeostasis. Our findings provide new insights into the epigenetic architecture of T2D, revealing novel genetic susceptibilities and highlighting potential targets for therapeutic intervention.
Conserving steppe-land birds under climate change: a gap analysis for the Eurasian Stone-curlew (Burhinus oedicnemus) in the Western Palearctic
Authors: Simoncini Andrea , Ramellini Samuele , Falaschi Mattia , Brambilla Mattia , Martineau Alexis , Massolo Alessandro , Giunchi Dimitri 
Published: May 2024

ABSTRACTClimate change is having dramatic impacts on the distribution of animals. Birds, and especially steppe-land birds, are particularly sensitive to climate change and identifying areas that are critical for their conservation is pivotal, as well as estimating the expected impact on these areas under different climate and land use change scenarios. In-situ climate refugia (areas suitable under both current and future climates) are especially valuable for the conservation of climate-sensitive species, and is therefore important to identify them and evaluate their coverage by protected areas. Via species distribution modelling, we aimed to identify in-situ climate refugia in the Western Palearctic for the Eurasian Stone-curlewBurhinus oedicnemus, an umbrella steppic species of conservation concern. We used a comprehensive dataset of occurrences in the breeding period to fine-tune a Maxent species distribution model and project it under three carbon emission scenarios of increasing severity for the year 2050. We then identified in-situ climate refugia and performed a gap analysis estimating the percentage of refugia falling within the network of currently protected areas. In all modelled future scenarios a northward expansion of suitable breeding habitats was predicted, and suitable areas had similar extents, with a slight increase of the overall suitability under more severe scenarios. According to our results, the Eurasian Stone-curlew has the potential to maintain viable populations in the Western Palearctic, even though dispersal limitations might hinder the colonization of newly suitable breeding areas. In-situ climate refugia were mainly identified outside protected areas, particularly in Northern Africa and the Middle East. Therefore, we advocate targeted actions in climate refugia to promote the conservation of this and other steppe-land species under global environmental change.
Plasmacytoid dendritic cells are dispensable or detrimental in murine systemic or respiratory viral infections
Authors: Ngo Clemence , Rahmani Khalissa , Valente Michael , Collinet Nils , Bessou Gilles , Fabregue Manon , Sharkaoui Sarah , Mazzoli Sophie , Pierini-Malosse Camille , Sansoni Amandine , Fiore Frederic , Laprie Caroline , Gaya Mauro , Gregoire Claude , Broggi Achille , Milpied Pierre , Escalière Bertrand , Vu Manh Thien Phong , Fallet Mathieu , Chasson Lionel , Tran Hien , Le Bert Marc , Malissen Bernard , Zarubica Ana , Dalod Marc , Tomasello Elena 
Published: May 2024

AbstractPlasmacytoid dendritic cells (pDCs) are major producers of type I/III interferons. As these cytokines are crucial for antiviral defense, it is assumed to be also the case for pDCs. However, robust evidence supporting this dogma is scarce. Genetic mutations or pharmacological manipulations causing pDC loss or disrupting their interferon production affect other immune cells, which could confound interpretation. To overcome this bottleneck, we engineered pDC-less mice, specifically and constitutively devoid of pDCs as expressing diphtheria toxin under coordinated control of theSiglechandPacsin1genes co-expressed uniquely in pDCs. pDC-less mice mounted protective intrinsic and innate immune responses against systemic infection with mouse Cytomegalovirus, and were more resistant to intranasal infection with influenza virus and SARS-CoV2. Thus, contrary to dogma, pDCs and their interferon production proved dispensable or deleterious during systemic or respiratory viral infections, respectively. pDC-less mice will enable rigorously revisiting the roles of pDCs in health and disease.
Maternal behavior influences vocal practice and learning processes in the greater sac-winged bat
Authors: Fernandez Ahana A. , Serve Nora , Fabian Sarah-Cecil , Knörnschild Mirjam 
Published: May 2024

AbstractLearning, particularly vocal learning, is often a social process. In human infants, it is well-established that social interactions influence speech acquisition and are hypothesized to modulate attentiveness and sensory processes, thereby affecting the speech-learning process. However, our understanding of how social interactions shape vocal ontogenetic processes in non-human mammals, particularly those which vocally learn, remains limited. In the batSaccopteryx bilineata, pups acquire the adult vocal repertoire through a distinctive babbling behavior that shows interesting similarities to human infant babbling. While babbling encompasses many different syllable types, it is particularly noteworthy that pups learn song syllables by imitating adult singing males. The pups’ social environment involves frequent interactions with their mothers, whereas adult males mainly serve as the primary source of acoustic input. We monitored the vocal ontogeny of wild pups, investigating whether their social environment influenced three aspects of babbling: the amount of vocal practice, the pups’ final syllable repertoire size and the production of the syllable types acquired through vocal learning. The results demonstrate that maternal behavioral displays significantly influence the amount of vocal practice, the presence and versatility of song syllable types in babbling and the percentage of mature song syllables. Our findings show that maternal feedback plays a significant role in the vocal ontogeny and learning processes ofS. bilineata, thus enhancing our understanding of the relationship between social feedback and vocal development in mammalian vocal learners.
Benchmarking 13 tools for mutational signature attribution, including a new and improved algorithm
Authors: Jiang Nanhai , Wu Yang , Rozen Steven G. 
Published: May 2024

ABSTRACTMutational signatures are characteristic patterns of mutations caused by endogenous mutational processes or by exogenous mutational exposures. There has been little benchmarking of approaches for determining which signatures are present in a sample and estimating the number of mutations due to each signature. This problem is referred to as “signature attribution”. We show that there are often many combinations of signatures that can reconstruct the patterns of mutations in a sample reasonably well, even after encouraging sparse solutions. We benchmarked thirteen approaches to signature attribution, including a new approach called Presence Attribute Signature Activity (PASA), on large synthetic data sets (2,700 synthetic samples in total). These data sets recapitulated the single-base, insertion-deletion, and doublet-base mutational signature repertoires of 9 cancer types. For single-base substitution mutations, PASA and MuSiCal outperformed other approaches on all the cancer types combined. However, the ranking of approaches varied by cancer type. For doublet-base substitutions and small insertions and deletions, while PASA outperformed the other approaches in most of the nine cancer types, the ranking of approaches again varied by cancer type. We believe this variation reflects inherent difficulties in signature attribution. These difficulties stem from the fact that there are often many attributions that can reasonably explain the pattern of mutations in a sample and from the combinatorial search space due to the need to impose sparsity. Tables herein can provide guidance on the selection of mutational signature attribution approaches that are best suited to particular cancer types and study objectives.
Pleiotropy and Disease Interactors: The Dual Nature of Genes Linking Ageing and Ageing-related Diseases
Authors: Vega Magdaleno Gustavo Daniel , de Magalhaes Joao Pedro 
Published: May 2024

AbstractAgeing-related diseases (ARDs) exhibit a broad spectrum of phenotypes yet consistently increase in incidence with advancing age. This suggests that, despite their diversity, ARDs could potentially share common biological processes deeply rooted in the mechanisms of ageing, presenting opportunities for unified therapeutic strategies. Using a network approach, we analysed gene proximity to 52 ARDs from the UK Biobank, integrating with protein-protein interaction (PPI), gene coexpression, KEGG pathways, and ageing-related genes. Interestingly, while most ageing-related genes did not associate with ARDs, they were closer to multiple ARDs than random genes. This was mainly due to indirect connections to diverse Communities of ARDs (ARCs), what we calliARC-Interactors, implying indirect association to multiple ARDs through interaction with ARD-related genes, primarily via PPI and KEGG. Genes that are associated with multiple ARCs,i.e.,Pleiotropicgenes, were predominantly related to immunological disorders. We found a polarizing effect. When compared to multiple ageing- and disease-related genes, highPleiotropicgenes showed the highest tissue specificity and lowest coexpression with themselves and other diseases. In contrast, high iARC-interactivegenes (as those of ageing) significantly displayed the exact opposite effects, suggesting two mechanisms for genes to affect multiple ARDs, one operating through modulatory genes that simultaneously affect numerous tissues and processes; and another rather specialised, affecting single tissues that are widespread across the body, as potentially occurring in autoimmune diseases. Lastly, we used Machine Learning (ML) to predict potentially novel ageing-related genes based on each network’siARC-Interactionsand genes’ proximity to ARDs. PPI and KEGG showed the best performance with their top candidate genes enriched for regulation of protein metabolic process, protein stabilization, positive regulation of developmental process, and cellular response to chemical stimulus. This work paints a deeper picture of the multiple types of interactions between ageing-related processes and ARDs.
Pervasive ancestry bias in variant effect predictors
Authors: Pathak Ankit K. , Bora Nikita , Badonyi Mihaly , Livesey Benjamin J. ,   SG10K_Health Consortium, Ngeow Joanne , Marsh Joseph A. 
Published: May 2024

ABSTRACTComputational variant effect predictors (VEPs) are playing increasingly important roles in the interpretation of human genetic variants. We observe striking differences in the ways that many VEPs score variants from European compared to non-European populations. We advocate for the adoption of population-free VEPs, i.e. those not trained on human population or clinical variants, to improve health equity and enhance the accuracy of genetic diagnoses across diverse populations.
Impact of liver-specific survival motor neuron (SMN) depletion on central nervous system and peripheral tissue pathology
Authors: de Almeida Monique Marylin Alves , De Repentigny Yves , Gagnon Sabrina , Sutton Emma R. , Kothary Rashmi 
Published: May 2024

AbstractSpinal muscular atrophy (SMA) is an inherited neuromuscular disorder stemming from deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased levels of SMN protein, and subsequent motor neuron death and muscle atrophy. While traditionally viewed as a disorder predominantly affecting motor neurons, recent research suggests the involvement of various peripheral organs in SMA pathology. Notably, the liver has emerged as a significant focus due to the observed fatty liver phenotype and dysfunction in both SMA mouse models and SMA patients. Despite these findings, it remains unclear whether intrinsic depletion of SMN protein in the liver contributes to pathology in the peripheral or central nervous systems. To address this knowledge gap, we developed a mouse model with a liver-specific depletion of SMN by utilizing anAlb-Cretransgene together with oneSmn2Ballele and oneSmnexon 7 allele flanked by loxP sites. Initially, we evaluated phenotypic changes in these mice at postnatal day 19 (P19), a time when the severe model of SMA, theSmn2B/-mice, typically exhibit many symptoms of the disease. Our findings indicate that liver-specific SMN depletion does not induce motor neuron death, neuromuscular pathology or muscle atrophy, characteristics typically observed in theSmn2B/-mouse at P19. However, mild liver steatosis was observed at this time point, although no changes in liver function were detected. Notably, pancreatic alterations resembled that ofSmn2B/-mice, with a decrease in insulin-producing β-cells and an increase in glucagon-producing α-cells, accompanied by a reduction in blood glucose and an increase in plasma glucagon and glucagon-like peptide (GLP-1) levels. Moreover, these changes were transient, as P60 mice exhibited recovery of liver and pancreatic function. While the mosaic pattern of the Cre-mediated excision precludes definitive conclusions regarding the contribution of liver-specific SMN depletion to overall tissue pathology, our findings highlight an intricate connection between liver function and pancreatic abnormalities in SMA, adding a nuanced layer to our understanding of the disease’s complexities.
Characteristics of JN.1-derived SARS-CoV-2 subvariants SLip, FLiRT, and KP.2 in neutralization escape, infectivity and membrane fusion
Authors: Li Pei , Faraone Julia N. , Hsu Cheng Chih , Chamblee Michelle , Zheng Yi-Min , Carlin Claire , Bednash Joseph S. , Horowitz Jeffrey C. , Mallampalli Rama K. , Saif Linda J. , Oltz Eugene M. , Jones Daniel , Li Jianrong , Gumina Richard J. , Xu Kai , Liu Shan-Lu 
Published: May 2024

SUMMARYSARS-CoV-2 variants derived from the immune evasive JN.1 are on the rise worldwide. Here, we investigated JN.1-derived subvariants SLip, FLiRT, and KP.2 for their ability to be neutralized by antibodies in bivalent-vaccinated human sera, XBB.1.5 monovalent-vaccinated hamster sera, sera from people infected during the BA.2.86/JN.1 wave, and class III monoclonal antibody (Mab) S309. We found that compared to parental JN.1, SLip and KP.2, and especially FLiRT, exhibit increased resistance to COVID-19 bivalent-vaccinated human sera and BA.2.86/JN.1-wave convalescent sera. Interestingly, antibodies in XBB.1.5 monovalent vaccinated hamster sera robustly neutralized FLiRT and KP.2 but had reduced efficiency for SLip. These JN.1 subvariants were resistant to neutralization by Mab S309. In addition, we investigated aspects of spike protein biology including infectivity, cell-cell fusion and processing, and found that these subvariants, especially SLip, had a decreased infectivity and membrane fusion relative to JN.1, correlating with decreased spike processing. Homology modeling revealed that L455S and F456L mutations in SLip reduced local hydrophobicity in the spike and hence its binding to ACE2. In contrast, the additional R346T mutation in FLiRT and KP.2 strengthened conformational support of the receptor-binding motif, thus counteracting the effects of L455S and F456L. These three mutations, alongside D339H, which is present in all JN.1 sublineages, alter the epitopes targeted by therapeutic Mabs, including class I and class III S309, explaining their reduced sensitivity to neutralization by sera and S309. Together, our findings provide insight into neutralization resistance of newly emerged JN.1 subvariants and suggest that future vaccine formulations should consider JN.1 spike as immunogen, although the current XBB.1.5 monovalent vaccine could still offer adequate protection.
Systematic analysis of gut bacterial carcinogen metabolism and its functional consequences
Authors: Zhang Boyao , Maftei George-Eugen , Bartmanski Bartosz , Zimmermann Michael 
Published: May 2024

SummaryOrganic carcinogens, in particular DNA-reactive compounds, contribute to the irreversible initiation step of tumorigenesis through introduction of genomic instability. Although carcinogen bioactivation and detoxification by human enzymes has been extensively studied, carcinogen biotransformation by human-associated bacteria, the microbiota, has not yet been systematically investigated. We tested the biotransformation of 68 mutagenic carcinogens by 34 bacterial species representative for the upper and lower human gastrointestinal tract and found that the majority (41) of the tested carcinogens undergo bacterial biotransformation. To assess the functional consequences of microbial carcinogen metabolism, we developed a pipeline to couple gut bacterial carcinogen biotransformation assays with Ames mutagenicity testing and liver biotransformation experiments. This revealed a bidirectional crosstalk between gut microbiota and host carcinogen metabolism, which we validated in gnotobiotic mouse models. Overall, the systematic assessment of gut microbiota carcinogen biotransformation and its interplay with host metabolism highlights the gut microbiome as an important modulator of exposome-induced tumorigenesis.
The role of affect regulation and mentalizing in mediating the attachment-epistemic trust relationship. Differences between junior and senior students…Who is at risk?
Authors: Karagiannopoulou Evangelia , Lianos Panagiotis , Andriopoulou Panoraia , Rentzios Christos , Fonagy Peter 
Published: May 2024

AbstractResearch on emotional factors and mental health in higher education has gained traction. Much attention has focused on first-year students as a potentially at-risk group, though some studies suggest that all students might face similar risks. This study examines differences between junior and senior undergraduates in terms of mentalizing, emotion regulation (ER), and psychological mindedness. These constructs relate to understanding one’s own and others’ mental states, potentially mediating the relationship between attachment and epistemic trust (ET). The current study includes 460 undergraduate students, most of whom are female (96%). Results show that senior students score higher on reappraisal, certainty, and interest/curiosity compared to junior students. However, these factors did not mediate the relationship between anxious attachment orientation and ET. Certainty and interest/curiosity mediated the relationship between avoidant attachment orientation and ET, suggesting similar mediation patterns for junior and senior students. On the other hand, suppression and uncertainty/confusion were critical mediators in the relationship between insecure (anxious and avoidant) attachment orientations and epistemic trust. These findings are discussed within the framework of attachment and mentalizing literature, along with relevant connections to educational studies.
Victimization Status Among Persons with Disabilities and its Predictors: Evidence from Bangladesh National Survey on Persons with Disabilities
Authors: Rahman Mizanur , Rana Md Shohel , Khandaker Gulam , Rahman Md Mostafizur , Khan Md Nuruzzaman 
Published: May 2024

BackgroundPersons with disabilities often face various forms of victimization, yet there is limited research exploring this phenomenon in Bangladesh. This study aims to investigate the victimization status among persons with disabilities and identify its predictors.MethodsData of 4293 persons with disabilities analyzed in this study were extracted from the 2021 National Survey on Persons with Disabilities. Victimization status (yes, no) was considered as the outcome variables. Explanatory variables considered were factors at the individual, household, and community levels. A multilevel mixed-effect logistic regression model was used to explore the association of the outcome variable with explanatory variables by dividing the total sample into age groups of 0-17 years and ≥ 18 years.ResultsThe study found that 44% of persons with disabilities in Bangladesh experienced victimization, predominantly involving neighbours (90.64%), friends (28.41%), and family members (27.07%). Among persons aged 0-17 years, increasing age was associated with higher likelihood of being victimized, while residing in the richest households or certain divisions like Khulna and Rangpur was associated with lower likelihoods. Conversely, among respondents aged 18-95 years, increasing age was associated with lower likelihood of being victimized. Unmarried respondents had increased likelihood of victimization compared to married individuals. Furthermore, persons residing in the richest wealth quintile compared to the poorest, and residence in certain divisions such as Chattogram, Khulna, Mymensingh, Rangpur, and Sylhet reported higher likelihoods of victimization compared to those in the Barishal division.ConclusionThis study’s findings underscore that around 4 in 10 persons with disabilities are being victimized. Tailored programs and awareness-building initiatives covering neighbours, friends, and family members of persons with disabilities are important to ensure dignified lives for this population.