bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low mutation rate but high male-bias in the germline of a short-lived opossum
Authors: Peña-Garcia Yadira , Wang Richard J. , Raveendran Muthuswamy , Harris R. Alan , Samollow Paul B. , Rogers Jeffrey , Hahn Matthew W. 
Published: December 2024

AbstractAge and sex have been found to be important determinants of the mutation rate per generation in mammals, but the mechanisms underlying these factors are still unclear. One approach to distinguishing between alternative mechanisms is to study species that reproduce at very young ages, as competing hypotheses make different predictions about patterns of mutation in these organisms. Here, we study the germline mutation rate in the gray short-tailed opossum, Monodelphis domestica, a laboratory model species that becomes reproductively mature at less than six months of age. Whole-genome sequencing of 22 trios reveals the lowest mutation rate per generation found in mammals thus far (0.26 × 10-8 per base pair per generation at an average parental age of 313 days), which is expected given their early reproduction. We also examine the mutation spectrum and find fewer mutations at CpG sites in opossums than in humans, consistent with the lower CpG content in the opossum genome. We observe that two-thirds of mutations are inherited from the male parent in opossums, slightly lower than the degree of male bias observed in organisms that reproduce at much older ages. Nevertheless, the very young age at reproduction in opossums suggests that ongoing spermatogonial divisions in males after puberty are not the primary driver of the observed male mutation bias. These findings contribute to a growing body of evidence that the differences between male and female germline mutation may arise from mechanisms other than cell division post-puberty.Article SummaryThis study investigates the germline mutation rate in the gray short-tailed opossum, a marsupial with early reproductive maturity. By sequencing 22 families, we report the lowest mutation rate recorded in mammals but a typical male mutation bias. These findings add to growing evidence that challenges the traditional view that continuing cell division is the primary driver of male-biased mutations. Instead, the study suggests that alternative mechanisms, such as differences in DNA repair, may influence sex-specific mutation rates.
Linking multiple serological assays to infer dengue virus infections from paired samples using mixture models
Authors: Hamins-Puértolas Marco , Buddhari Darunee , Salje Henrik , Huang Angkana T. , Hunsawong Taweewun , Cummings Derek A.T. , Fernandez Stefan , Farmer Aaron , Kaewhiran Surachai , Khampaen Direk , Srikiatkhachorn Anon , Iamsirithaworn Sopon , Waickman Adam , Thomas Stephen J. , Endy Timothy , Rothman Alan L. , Anderson Kathryn B. , Rodriguez-Barraquer Isabel 
Published: December 2024

AbstractDengue virus (DENV) is an increasingly important human pathogen, with already half of the globe’s population living in environments with transmission potential. Since only a minority of cases are captured by direct detection methods (RT-PCR or antigen tests), serological assays play an important role in the diagnostic process. However, individual assays can suffer from low sensitivity and specificity and interpreting results from multiple assays remains challenging, particularly because interpretations from multiple assays may differ, creating uncertainty over how to generate finalized interpretations. We develop a Bayesian mixture model that can jointly model data from multiple paired serological assays, to infer infection events from paired serological data. We first test the performance of our model using simulated data. We then apply our model to 677 pairs of acute and convalescent serum collected as a part of illness and household investigations across two longitudinal cohort studies in Kamphaeng Phet, Thailand, including data from 232 RT-PCR confirmed infections (gold standard). We compare the classification of the new model to prior standard interpretations that independently utilize information from either the hemagglutination inhibition assay (HAI) or the enzyme-linked immunosorbent assay (EIA). We find that additional serological assays improve accuracy of infection detection for both simulated and real world data. Models incorporating paired IgG and IgM data as well as those incorporating IgG, IgM, and HAI data consistently have higher accuracy when using PCR confirmed infections as a gold standard (87-90% F1 scores, a combined metric of sensitivity and specificity) than currently implemented cut-point approaches (82-84% F1 scores). Our results provide a probabilistic framework through which multiple serological assays across different platforms can be leveraged across sequential serum samples to provide insight into whether individuals have recently experienced a DENV infection. These methods are applicable to other pathogen systems where multiple serological assays can be leveraged to quantify infection history.
Tumor break load quantitates structural variant-associated genomic instability with biological and clinical relevance across cancers
Authors: Lakbir Soufyan , de Wit Renske , de Bruijn Ino , Kundra Ritika , Madupuri Ramyasree , Gao Jianjiong , Schultz Nikolaus , Meijer Gerrit A. , Heringa Jaap , Fijneman Remond J. A. , Abeln Sanne 
Published: December 2024

AbstractWhile structural variants (SVs) are a clear sign of genomic instability, they have not been systematically quantified per patient. Therefore, the biological and clinical impact of high numbers of SVs in patients is unknown. We introduce tumor break load (TBL), defined as the sum of unbalanced SVs, as a measure for SV-associated genomic instability. Using pan-cancer data from TCGA, PCAWG, and CCLE, we show that a high TBL is associated with significant changes in gene expression in 26/31 cancer types that consistently involve upregulation of DNA damage repair and downregulation of immune response pathways. Patients with a high TBL show a higher risk of recurrence and shorter median survival times for 5/15 cancer types. Our data demonstrate that TBL is a biologically and clinically relevant feature of genomic instability that may aid patient prognostication and treatment stratification. For the datasets analyzed in this study, TBL has been made available in cBioPortal.
ROS1 immunohistochemistry as a potential predictive biomarker for ROS1-targeted therapy in breast cancer: impact of antibody clone selection
Authors: Sokolova Anna , Joshi Vaibhavi , Chittoory Haarika , Walsh Michael , Lim Malcolm , Kutasovic Jamie R. , Ferguson Kaltin , Simpson Peter T. , Lakhani Sunil R. , McCart Reed Amy E. 
Published: December 2024

AbstractAimsInvasive lobular carcinoma (ILC) may show targetable vulnerabilities secondary to the characteristic loss of the cell adhesion protein E-cadherin. Specifically, a synthetic lethal interaction was identified between E-cadherin loss and ROS1 inhibition. Several clinical trials are currently underway to assess the efficacy of ROS1 inhibitors in ILC, however, ROS1 expression has not been confirmed in ILC tumours and ROS1 has not been validated as a biomarker in the breast cancer setting. This study aimed to (i) examine ROS1 expression in a large cohort of breast cancer cases and (ii) investigate the biology and clinical significance of ROS1 positivity in breast cancer.MethodsROS1 immunohistochemistry was performed on a large cohort of ILC (n=274) and invasive carcinoma of no special type (NST; n=431) cases with extensive clinicopathological data. The staining performance of four ROS1 antibody clones was compared.ResultsThere was marked variation in ROS1 status according to antibody clone. D4D6 and SP384 were negative in almost all breast cancer cases, whereas EP282 and EPMGHR2 were positive in 37% and 47% of ILC cases, and 49% and 74% of NST cases, respectively. Only data from clones D4D6 and SP384 were highly concordant, while EP282 and EPMGHR2 were positive in distinct breast cancer subtypes.ConclusionsAssessment of ROS1 status in breast cancer appears to be highly antibody clone dependent. ROS1 antibody clone selection will be an important consideration in the design of clinical trials investigating the clinical validity of ROS1 as a predictive biomarker in breast cancer.
Early-life infectious disease exposure, the “hygiene hypothesis”, and lifespan: evidence from hookworm
Authors: Lawton Ralph I. 
Published: December 2024

AbstractExposure to infectious disease in early life may have long-term ramifications for health and lifespan. However, reducing pathogen exposure may not be uniformly beneficial. The rise of modern sanitation and reduction of infectious diseases has been implicated in increasing levels of allergy and immune dysregulation: termed, the “hygiene hypothesis.” This study leverages quasi-experimental variation from combining pre-campaign hookworm exposure with the Rockefeller Sanitary Commission’s de-worming campaign in the early 20th century to rigorously examine the impacts of childhood hookworm exposure on adult lifespan and morbidity. Findings show de-worming before age five leads to 2.5 additional months of life in a large sample of adult death records. Further, decreasing hookworm exposure is related to improvements in biomarkers for inflammation and skin-tested allergies, in contrast to predictions of the “hygiene hypothesis”. Placebo tests using health outcomes that should not be affected by de-worming do not show similar patterns. Overall, childhood de-worming leads to improvements in morbidity and lifespan decades later.
Genomic and proteomic characterization of sulfate-reducing symbionts of gutless marine annelids
Authors: D’Angelo Grace , Kleiner Manuel , Mankowski Anna , Cifuentes-Anticevic Jerónimo , Violette Marlene J. , Anda Valerie De , Kröber Eileen , Dubilier Nicole , Liebeke Manuel 
Published: December 2024

AbstractSulfate-reducing bacteria inhabit marine and terrestrial environments, forming syntrophic associations with other bacteria, archaea and eukaryotes. A notable example is the symbiosis between sulfate-reducing bacteria (SRB) and gutless oligochaete worms found in marine sediments worldwide. These endosymbionts participate in a syntrophic sulfur exchange with the primary endosymbiont of gutless oligochaetes, a sulfur-oxidizing bacterium, thus providing otherwise inaccessible metabolic capabilities to the animal host. Here, we used a combination of metagenomic and metaproteomic analysis to describe the metabolic functions of SRBs from gutless annelids. Identified as members of the Desulfobacteria class, closely related to theDesulfococcusandDesulfosarcinagenera, these SRB symbionts exhibit a range of common and unique metabolic capabilities. Our analyses revealed their core metabolism of complete oxidation of acetate to CO2 via the Wood-Ljungdahl pathway, glyoxylate bypass of the TCA cycle, degradation of glycine as a nitrogen source, and presence of transporters for essential nutrients. A large-scale genome comparison revealed that the sulfate-reducing endosymbionts, named here "CandidatusDesulfoconcordia", have metabolic distinctions with respect to their free-living counterparts that could indicate adaptation to the energy and nutrient requirements of their symbiotic niche. The enrichment of functions like peptidases and amino acid transporters together with their abundant expression in the proteomes and the reduction of sugar and sulfur scavenging functions in the symbiotic genomes indicate a symbiosis-driven ecological role distinct from free-living SRBs. Our study revealed the metabolic capabilities that have enabled "CandidatusDesulfoconcordia" to adapt to their multi-domain associations.
A skewed picture of functional diversity in global drylands
Authors: Tordoni Enrico , Puglielli Giacomo , Beccari Eleonora , Carmona Carlos P. 
Published: December 2024

SummaryRecently, Gross et al. (Nature 632, 808-814) found that plant phenotypic diversity dramatically increases with aridity globally, challenging conventional environmental filtering theories. However, some methodological choices by Gross et al. might overestimate the effect of aridity on phenotypic diversity: (i) We detected a skewed distribution of sampling sites towards the arid end of the analyzed gradient; (ii) We posited that fine-tuning of some statistical parameters might further challenge their estimates. We reanalyzed Gross et al. data accounting for these effects and found a substantially reduced change of phenotypic diversity with increasing aridity. Gross et al. surely represents a cornerstone for future research on trait diversity in a drier world, but their interpretations need to be considered alongside our findings. Importantly, the points raised by our reanalysis provide general guidelines for future research on plant phenotypic diversity changes along environmental gradients.
Current transcriptome database and biomarker discovery for immunotherapy by immune checkpoint blockade
Authors: Zhang Han , Lu Binfeng , Lu Xinghua , Saeed Anwaar , Chen Lujia 
Published: December 2024

AbstractImmune checkpoint blockade (ICB) has revolutionized the current immuno-oncology and significantly improved clinical outcome for cancer treatment. Despite the advancement in clinics, only a small subset of patients derives immune response to the ICB therapy. Therefore, a robust predictive biomarker that identifies potential candidate becomes increasingly crucial in delivering this technology to the public. In this review, we first discuss the biomarkers that focus on tumor genome, tumor microenvironment and tumor-host interaction. Then, we compare existing databases for biomarker discovery for ICB response. We also present IOhub - an interactive web portal that incorporates 36 bulk and 10 single-cell transcriptome datasets for benchmark analysis of the current biomarkers. Finally, we highlight the trending interest in antibody drug conjugate and combination treatment and their use in precision immuno-oncology.
Changes in urinary proteome of rats before and after noise exposure
Authors: Yang Minhui , Zhao Chenyang , Gao Youhe 
Published: December 2024

AbstractThis study established an acute noise exposure model in which 10 rats were exposed to a 119 dB noise environment for 9 hours daily over a period of 7 consecutive days. Proteomic analysis was performed on urine samples collected from the rats. A comparison of protein expression profiles before and after noise exposure identified 219 differentially expressed proteins, 30 of which are known to be associated with hearing loss. Notably, Gelsolin plays a critical role in regulating the growth and stability of the mechanosensory hair bundles in mammalian cochlear outer hair cells. Deficiency of Lysosome-associated membrane glycoprotein 1 has been reported to cause vacuolization and structural alterations in lysosomal membrane proteins in cochlear marginal cells, leading to hearing loss in mice. Similarly, SLIT and NTRK-like family member 6 deficiency is linked to delayed synaptogenesis and auditory dysfunction in mice. These findings indicate that high-decibel noise exposure induces significant changes in urinary protein expression, many of which are associated with auditory damage as previously reported.
Gender–specific Single Transcript Level Atlas of Vasopressin and its Receptor (AVPR1a) in the Mouse Brain
Authors: Gumerova Anisa , Pevnev Georgii , Korkmaz Funda , Cheliadinova Uliana , Burganova Guzel , Vasilyeva Darya , Cullen Liam , Barak Orly , Sultana Farhath , Zhou Weibin , Sims Steven , Laurencin Victoria , Frolinger Tal , Kim Se-Min , Goosens Ki A. , Yuen Tony , Zaidi Mone , Ryu Vitaly 
Published: December 2024

ABSTRACTVasopressin (AVP), a nonapeptide synthesized predominantly by magnocellular hypothalamic neurons, is conveyed to the posterior pituitaryviathe pituitary stalk, where AVP is secreted into the circulation. Known to regulate blood pressure and water homeostasis, it also modulates diverse social behaviors, such as pair–bonding, social recognition and cognition in mammals including humans. Importantly, AVP modulates social behaviors in a gender–specific manner, perhaps, due to gender differences in the distribution in the brain of AVP and its main receptor AVPR1a. There is acorpusof integrative studies for the expression of AVP and AVPR1a in various brain regions, and their functions in modulating central and peripheral actions. In order to purposefully address sexually dimorphic and novel roles of AVP on central and peripheral functions through its AVPR1a, we utilized RNAscope to mapAvpandAvpr1asingle transcript expression in the mouse brain. As the most comprehensive atlas of AVP and AVPR1a in the mouse brain, this compendium highlights the importance of newly identified AVP/AVPR1a neuronal nodes that may stimulate further functional studies.
High-Resolution Transcriptional Impact of AIRE: Effects of Pathogenic Variants p.Arg257Ter, p.Cys311Tyr, and Polygenic Risk Variant p.Arg471Cys
Authors: Berger Amund Holte , Oftedal Bergithe Eikeland , Wolff Anette Susanne Bøe , Husebye Eystein Sverre , Knappskog Per Morten , Bratland Eirik , Johansson Stefan 
Published: December 2024

AbstractThe Autoimmune Regulator, AIRE, acts as a transcriptional regulator in the thymus, facilitating ectopic expression of thousands of genes important for the process of negative T-cell selection and immunological tolerance to self. Pathogenic variants in the gene encoding AIRE are causing Autoimmune polyendocrine syndrome type 1 (APS-1), defined by multiorgan autoimmunity and chronic mucocutaneous candidiasis. More recently, Genome Wide Association Studies (GWAS) have also implicated AIRE in several common organ-specific autoimmune diseases including Autoimmune primary adrenal insufficiency, type 1 diabetes and pernicious anemia. We developed a highly sensitive cell-system approach based on HEK293FT cells transfected withAIREthat allowed us to characterise and functionally evaluate the transcriptional potential of genetic variants in theAIREgene. We confirm that our cell system recapitulates the expression of the vast majority of known AIRE induced genes including well-characterised tissue restricted antigens (TRAs), but also increases the total number of identified AIRE induced genes by an order of magnitude compared to previously published strategies. The approach differentiates between categories ofAIREvariants on the transcriptional level, including the nonsense variant p.R257* (near complete loss of function), the p.C311Y variant associated with dominantly inherited APS-1 (severely impaired function), and the polygenic risk variant p.R471C (slightly increased function) linked to common organ-specific autoimmunity. The increased activity of p.R471C compared to wildtype indicates different molecular mechanisms for monogenic and polygenic AIRE related autoimmunity.
Mapping and characterization of a novel powdery mildew resistance locus (PM2) inCannabis sativaL
Authors: Seifi Soren , Leckie Keegan M. , Giles Ingrid , O’Brien Taylor , MacKenzie John O. , Todesco Marco , Rieseberg Loren H. , Baute Gregory J. , Celedon Jose M. 
Published: December 2024

AbstractBreeding genetic resistance to economically important crop diseases is the most sustainable strategy for disease management and enhancing agricultural and horticultural productivity, particularly where the application of synthetic pesticides is prohibited. Powdery mildew disease, caused by the biotrophic fungal pathogenGolovinomyces ambrosiae, is one of the most prevalent threats to the cannabis and hemp industry worldwide. In this study, we used bulk-segregant analysis (BSA) combined with high-throughput sequencing to identify and map a novel single dominant resistance (R) locus (designatedPM2), that strongly suppresses powdery mildew infection and sporulation inCannabis sativa. Histochemical analysis revealed that PM2-induced resistance is mediated by a highly localized hypersensitive response mainly in the epidermal cells of the host. Importantly, genetic markers capable of tracking PM2 resistance in breeding populations were developed using associated SNPs identified in this study.
Factors hindering the implementation of PPP in Iraq
Authors: Al-Tameemi Khaldoon Shehab , Alfaiz Sundus Khaleel , Al-Sadoon Nidhal 
Published: December 2024

PurposeIt is a worldwide phenomenon that infrastructure development is considered a catalyst for a country’s economic growth, enhanced service delivery and improved quality of life. Iraq has a considerable lack of necessary infrastructure. Many developing and developed nations utilise public-private partnerships (PPPs) as a means to address their infrastructure investment requirements. This study, however, uniquely investigates the specific factors hindering the implementation of PPP in Iraq, focusing on Iraq’s distinct political, economic and legislative challenges.Design/methodology/approachA thorough literature review, guided by systematic principles similar to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), has been conducted to understand PPP and highlight the factors that can facilitate the effective implementation of PPP around the globe. Afterwards, a questionnaire survey was deployed to relevant stakeholders in Iraq to examine these factors in the specific context of Iraq. Subsequently, in-depth interviews with key Iraqi decision-makers were carried out to discuss the questionnaire results in more detail and pinpoint particular barriers impeding successful PPP implementation in Iraq. These data were then rigorously analysed to highlight Iraq’s unique challenges, and the results were discussed to provide a contextual understanding. Based on these insights, conclusions and recommendations are drawn accordingly.FindingsThe results revealed that one of the main factors hindering the implementation of PPP in Iraq is the absence of a legal and regulatory framework that can give PPP implementation its legitimacy in Iraq. Other factors include the overall reluctance of several Iraqi legislators towards the PPP system and the unavailability of an environment attractive to investors.Originality/valueThe findings and recommendations set forth in this research can aid champions of the PPP system within the government of Iraq in devising an effective plan. Unlike similar studies, this paper addresses barriers specific to Iraq, such as political reluctance and regulatory gaps, providing new insights to guide policy. This plan is intended to foster a PPP mindset among relevant lawmakers, ensuring the successful approval of PPP laws and regulatory frameworks.