bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targets of sexual selection on theDrosophilawing
Authors: De Lisle Stephen P. , Branden Anneli , Paajarvi Vag Ellen 
Published: October 2024

AbstractIdentification of traits causally linked to fitness allows for direct tests of the adaptive value of traits. In the case ofDrosophilaand other insects, wing interference patterns – striking structural color variation generated by optical thin-film interference – have been implicated in mate choice and sexual selection. Yet, we expect wing interference patterns may covary with many aspects of wing morphology, such as size and shape. Here, we used a competitive mating assay inDrosophila melanogasterto assess the degree to which sexual selection acts on wing color independently of wing size and shape. We found that 16% of multivariate wing color, and 17% of corresponding estimated wing thickness, can be explained by wing size and shape. Projection pursuit regression identified three suites of traits – a linear combination of color variables, wing size, and a linear combination of wing shape variables – as the most important predictors of fitness. Analysis of the corresponding selection gradients revealed a combination of strong directional selection on wing size, combined with multivariate stabilizing selection on wing size and shape, with weak but significant directional selection on wing color. Our results suggest that sexual selection may act on a complex combination of wing color and morphology in flies.
Advanced lung cancer inflammation index as a predictor of all-cause and cardiovascular mortality among American hypertensive patients
Authors: Hu Nan , Feng Yin , He Liqun 
Published: October 2024

ABSTRACTBACKGROUNDThe predictive value of advanced lung cancer inflammation index (ALI) in all-cause mortality and cardiovascular mortality among hypertensive patients has not been thoroughly investigated.METHOD AND RESULTSA total of 2805 hypertensive patients from the National Health and Nutrition Examination Surveys from 2005-2006 to 2017-2018 were ultimately included in the analysis. Over the study period, participants were followed up for an average of 57.6 months, during which 311 deaths occurred, with 89 deaths attributed to cardiovascular causes. Survey-weighted restricted cubic spline (RCS) analysis revealed a nonlinear negative correlation between ALI and both all-cause and cardiovascular mortality among hypertensive patients. Survey-weighted Cox proportional hazards models revealed that in the highest ALI quartile experienced a 53.8% reduction in all-cause mortality and an 83.5% reduction in cardiovascular mortality compared with those in the lowest quartile. Survey-weighted Kaplan-Meier survival analysis also revealed that the all-cause mortality and cardiovascular mortality of hypertensive patients in the high ALI group were significantly lower than those in the low ALI group. Time-dependent ROC curves were used to assess the accuracy of survival outcomes and the area under the curve (AUC) values for the ability of ALI to predict all-cause mortality at 1, 3, and 5 years among hypertensive patients were 0.772, 0.672, and 0.634, respectively, whereas the AUC values for predicting cardiovascular mortality were 0.735, 0.760, and 0.723, respectively.CONCLUSIONSALI can be a valuable and effective tool for identifying high-risk hypertensive patients and guiding targeted interventions.
New therapeutic combination to enhance endocytosis of antibodies and nucleic-acid aptamers targeting EGFR in glioblastoma cells
Authors: Cruz Da Silva Elisabete , D’Ancona Charlène , Justiniano Hélène , Calco Valérie , Sensoy Dilara , Villa Pascal , Vauchelles Romain , Lehmann Maxime , Choulier Laurence 
Published: October 2024

ABSTRACTActive targeting is based on the binding of ligands to receptors present on the surface of targeted cells, in order to promote the internalization of the drugs conjugated to the ligands. Several conjugates are already in use or under development for active targeting of tumors, the most widely known being antibody-drug conjugates (ADC). They combine the specificity of monoclonal antibodies with the cytotoxicity of chemotherapeutic molecules. Other than antibodies, nucleic-acid aptamers, are promising ligands to deliver conjugated drugs by active targeting in tumor cells. The therapeutic efficacy of conjugates largely depends on their endocytosis and vesicular trafficking. However, so far, no therapeutic approach to enhance endocytosis of conjugates is available. In recent studies, we showed that gefitinib, a tyrosine kinase inhibitor directed against the epidermal growth factor receptor EGFR, induces a massive, non-physiological endocytosis of EGFR, known as gefitinib-mediated endocytosis (GME), in different glioblastoma cell lines. We thus hypothesized that besides promoting endocytosis of EGFR, gefitinib could also promote endocytosis of its ligands. In this study, we proved by quantitative fluorescence bioimaging, that gefitinib is indeed able to strengthen the endocytosis of fluorophore-conjugated EGFR-specific antibodies and aptamers. We also showed that the GME potentiates the toxicity of an antibody-drug conjugate, even at low concentrations. Our results suggest the development of a new therapeutic combination, of ADC and gefitinib, to potentiate the delivery of ADC and likely other conjugates targeting EGFR in glioblastoma, while limiting side effects on non-targeted cells.
3D-UHU-TU: A Three-Dimensional Bladder Cancer Model in a Healthy Urothelial Environment
Authors: Murray Benjamin O. , Gao Jinhui , Swarbrick Katherine , Freeman Alex , Rohn Jennifer L. 
Published: October 2024

AbstractBladder cancer cases and fatalities continue to rise worldwide with treatment outcomes not improving in the last four decades. Poor translation of potential new therapies from pre- clinical studies to the clinic could be one reason behind this. The patient-derived xenograft (PDX) mouse is the gold-standard for testing new bladder cancer therapies, but there are key physiological and molecular differences between mouse and human bladders. Thus, more human cell-based models may improve translation of treatments.Here, we introduce a bladder cancer microtissue model called3DUrine-tolerantHumanUrothelium-Tumour (3D-UHU-TU), which incorporates spheroids derived from human bladder cancer cell lines RT112 (low grade) and T24 (high grade) into the previously published 3D-UHU healthy urothelial model in a 100% urine environment. Both low- and high-grade 3D- UHU-TU models were characterised using immunofluorescence and immunohistochemistry staining with diagnostic markers (CK7, CK20 and GATA3), cadherin markers (E- and N-Cadherin), invasion and migration markers (MMP-2 and MMP-9) and a proliferation marker (Ki-67). Both models expressed the correct markers in the correct spatial areas. We also investigated the utility of both 3D-UHU-TU models as a platform to test treatments, using the conventional chemotherapeutic Mitomycin C as proof of principle. After 2 hours of treatment and 24 hours of recovery, cell lysis and nuclear damage were observed in both low- and high- grade cancer spheroids, with minimal damage to the surrounding healthy urothelium. At higher doses, cancer spheroids either disintegrated or were reduced in size, with the healthy urothelium still intact.Taken together, 3D-UHU-TU is a novel,in vitromodel for testing both the safety and efficacy of new treatments. Furthermore, our work lays the foundation for testing treatments on patient-derived tumour spheroids in a personalised medicine approach.
Designing minimalE. coligenomes using variational autoencoders
Authors: Shcherbakova Anastasiia , Buchan Daniel , Barnes Chris P. 
Published: October 2024

AbstractDesigning minimal bacterial genomes remains a key challenge in synthetic biology. There is currently a lack of efficient tools for the rapid generation of streamlined bacterial genomes, limiting research in this area. Here, using a pangenome dataset forEscherichia coli, we explore how generation of minimal genomes can be achieved using variational autoencoders. Our results show that variational autoencoders can successfully create minimised genomes retaining the essential genes identified in the literature. This study proposes a rapid, machine learning-based approach for bacterial sequence generation, that could accelerate the genomic design process.
Bioorthogonal cyclopropenones for investigating RNA structure
Authors: Chen Sharon , Sibley Christopher D. , Latifi Brandon , Balaratnam Sumirtha , Dorn Robert S. , Lupták Andrej , Schneekloth John S. , Prescher Jennifer A. 
Published: October 2024

AbstractRNA sequences encode secondary and tertiary structures that impact protein production and other cellular processes. Misfolded RNAs can also potentiate disease, but the complete picture is lacking. To establish more comprehensive and accurate RNA structure-function relationships, new methods are needed to interrogate RNA and trap native conformations in cellular environments. Existing tools primarily rely on electrophiles that are constitutively “on” or triggered by UV light, often resulting in high background reactivity. We developed an alternative, chemically triggered approach to crosslink RNAs using bioorthogonal cyclopropenones (CpOs). These reagents selectively react with phosphines to provide ketenes—electrophiles that can trap neighboring nucleophiles to forge covalent crosslinks. As proof-of-concept, we synthesized a panel of CpOs and appended them to thiazole orange (TO-1). The TO-1 conjugates bound selectively to a model RNA aptamer (Mango) with nanomolar affinity, confirmed by fluorescence turn-on. After phosphine administration, covalent crosslinks were formed between the CpO probes and RNA. The degree of crosslinking was both time and dose-dependent. We further applied the chemically triggered tools to model RNAs in biologically relevant conditions. Collectively, this work expands the toolkit of probes for studying RNA and its native conformations.
Endogenous neuronal DNA double-strand breaks are not sufficient to drive brain aging and neurodegeneration
Authors: Cohen Sarah , Cheradame Laura , Pratt Karishma J. B. , Collins Sarah , Barillas Ashlie , Carlson Annika , Ramani Vijay , Legube Gaëlle , Villeda Saul A. , Mullins R. Dyche , Schwer Bjoern 
Published: October 2024

ABSTRACTLoss of genomic information due to the accumulation of somatic DNA damage has been implicated in aging and neurodegeneration1–3. Somatic mutations in human neurons increase with age4, but it is unclear whether this is a cause or a consequence of brain aging. Here, we clarify the role of endogenous, neuronal DNA double-strand breaks (DSBs) in brain aging and neurodegeneration by generating mice with post-developmental inactivation of the classical non-homologous end-joining (C-NHEJ) core factor Xrcc4 in forebrain neurons. Xrcc4 is critical for the ligation step of C-NHEJ and has no known function outside of DSB repair5,6. We find that, unlike their wild-type counterparts, C-NHEJ-deficient neurons accumulate high levels of DSB foci with age, indicating that neurons undergo frequent DSBs that are typically efficiently repaired by C-NHEJ across their lifespan. Genome-wide mapping reveals that endogenous neuronal DSBs preferentially occur in promoter regions and other genic features. Analysis of 3-D genome organization shows intra-chromosomal clustering and loop extrusion of neuronal DSB regions. Strikingly, however, DSB accumulation caused by loss of C-NHEJ induces only minor epigenetic alterations and does not significantly affect gene expression, 3-D genome organization, or mutational outcomes at neuronal DSBs. Despite extensive aging-associated accumulation of neuronal DSBs, mice with neuronal Xrcc4 inactivation do not show neurodegeneration, neuroinflammation, reduced lifespan, or impaired memory and learning behavior. We conclude that the formation of spontaneous neuronal DSBs caused by normal cellular processes is insufficient to cause brain aging and neurodegeneration, even in the absence of C-NHEJ, the principal neuronal DSB repair pathway.
Low fidelity DNA polymerase IV accelerates genome evolution inPseudomonas aeruginosa
Authors: Castell Sofía D. , Fernandez Consuelo M. , Tumas Ignacio N. , Margara Lucía M. , Miserendino María C. , Ceschin Danilo G. , Pezza Roberto J. , Monti Mariela R. 
Published: October 2024

ABSTRACTSpecialized DNA polymerases are crucial for bypassing lesions and facilitating various cellular processes. Despite extensive research, the mutagenic effects of these error-prone enzymes on genomes are still not fully understood. In this study, we examined the genomic instability caused by Pol IV in the bacterial pathogenPseudomonas aeruginosa. Pol IV mutagenesis primarily involved the misincorporation of oxidized guanine nucleotides opposite template adenine. This activity led to a distinctive mutational signature, characterized by A to C transversions occurring preferentially at AT sites flanked by a 5’G and/or 3’C. Furthermore, Pol IV preferentially targeted specific chromosomal locations near the replication termination region and rRNA-encoding operons. Several genes associated with virulence, motility, antibiotic resistance and chemotaxis are located in these difficult-to-replicate regions, making them hotspots for Pol IV-mutagenesis. Notably, half of the mutation events catalyzed by Pol IV effectively impaired gene function. This can be attributed to the strong bias of Pol IV for mutating specific codons with its preferred sequence contexts, leading to substitutions primarily to the unreactive Ala and Gly residues. Remarkably, mutation signatures identified for Pol IV were also present in genomes from clinical isolates ofP. aeruginosa, providing compelling evidence for its role in genetic diversification during pathogen adaptation.
Splitting Schizophrenia: Divergent Cognitive and Educational Outcomes Revealed by Genomic Structural Equation Modelling
Authors: Watson Cameron James , Zvrskovec Johan , Merola Giuseppe Pierpaolo , Gilchrist Lachlan , Haussler Senta M , Schattner Miryam , Lo Chris Wai Hang , Breen Gerome , Murray Robin M , Lewis Cathryn M , Vassos Evangelos 
Published: October 2024

AbstractThe genetic relationship between schizophrenia, IQ, and educational attainment (EA) is complex. Schizophrenia polygenic scores (PGS) are linked to lower IQ, whilst higher IQ-PGS correlates with reduced schizophrenia risk. Paradoxically, genetic predisposition to higher EA has been associated with increased schizophrenia risk, a relationship potentially confounded by genetic overlap between schizophrenia and bipolar disorder. Through Genomic Structural Equation Modelling we dissected the genetic contribution to schizophrenia, identifying 63 SNPs uniquely associated with schizophrenia (SZspecific) and 78 shared with bipolar disorder (PSYshared). Both schizophrenia (rg = -0.22) and SZspecific (rg = -0.24) were genetically negatively correlated with IQ, the correlations between bipolar disorder and PSYshared with IQ were less pronounced (both rg = -0.07). Schizophrenia exhibited minimal correlation with EA (rg = 0.01), yet the latent variables demonstrated divergent relationships; PSYshared was positively correlated (rg = 0.11), whereas SZspecific was negatively correlated (rg = -0.06). PGS analyses in the UK Biobank (n=381,688), corroborated these divergent relationships, SZspecific-PGS was negatively associated with EA (β = -0.13, p < 2e-16), whereas the PSYshared-PGS was positively associated (β = 0.14, p < 2e-16). Mendelian Randomisation provided additional support, but also confirmed the presence of genetic pleiotropy. Our findings underscore the utility of genetic methods in dissecting neuropsychiatric disorders, supporting the existence of two possible pathways to schizophrenia: one shared with bipolar disorder and another with stronger neurodevelopmental underpinnings.
Accelerated epigenetic aging and prospective morbidity and mortality among U.S. veterans
Authors: Bourassa Kyle J. , Anderson Livia , Woolson Sandra , Dennis Paul A. , Garrett Melanie E. , Hair Lauren , Dennis Michelle , Sugden Karen , Williams Benjamin , Houts Renate ,   VA Mid Atlantic MIRECC Workgroup, Calhoun Patrick S. , Naylor Jennifer C. , Ashley-Koch Allison E. , Beckham Jean C. , Caspi Avshalom , Taylor Gregory A. , Hall Katherine S. , Moffitt Terrie E. , Kimbrel Nathan A. 
Published: October 2024

AbstractEpigenetic measures of aging derived from DNA methylation are promising biomarkers associated with prospective morbidity and mortality, but require validation in real-world medical settings. Using data from 2,216 post-9/11 veterans, we examined whether accelerated DunedinPACE aging scores were associated with chronic disease morbidity, predicted healthcare costs, and mortality assessed over an average of 13.1 years of follow up in VA electronic health records. Veterans with faster DunedinPACE aging scores developed more chronic disease and showed larger increases in predicted healthcare costs over the subsequent 5, 10, and 15 years. Faster aging was associated with incident myocardial infarction, stroke, diabetes, cancer, liver disease, and renal disease, as well greater risk of mortality due to all-causes and chronic disease. These findings provide evidence that accelerated epigenetic aging is associated with worsening prospective health across multiple chronic diseases and organ systems assessed using electronic health records from an integrated healthcare system.
Pathogenicity evaluation of coding germline variants identifies rare alleles enriched in hematological patients of a founder population
Authors: Koski Jessica R. , Langohr Laura , Räisänen Tuulia , Lahtinen Atte K. , Hakkarainen Marja , Heckman Caroline A. , Wartiovaara-Kautto Ulla , Pitkänen Esa , Kilpivaara Outi 
Published: October 2024

AbstractBackgroundThe clinical significance of most germline variants in hematological malignancies (HMs) remains unknown. This presents a challenge in the clinical setting, as the inability to accurately detect pathogenic variants can influence therapeutic decisions. Population isolates have been shown to be beneficial in pathogenic variant discovery due to presence of rare deleterious variants in relatively high frequencies.MethodsWe developed and applied PaVaDi, a computational pipeline that follows American College of Medical Genetics and Genomics (ACMG) guidelines, to evaluate the pathogenicity of germline variants in 511 HM patients from the Finnish founder population. We conducted an exome-wide burden analysis to assess the overall contribution of pathogenic variants to HMs and identified significant gene associations. We also examined genes previously associated with hematological diseases and DNA repair in more detail, and performed protein stability analyses to resolve variants of unknown significance (VUS).ResultsThe exome-wide burden analysis revealed potential pathogenic alleles inCUX2, RNPC3,andMFSD2Athat have not previously been linked to HM predisposition. We also identified the largest series ofCHEK2variant carriers reported in hematological diseases, including pathogenic/likely pathogenic (P/LP) variants (n=19), Ile200Thr (i.e., Ile157Thr) (n=49), and other variants of uncertain significance (n=3).CHEK2variants were 1.7-fold enriched in patients compared to controls (13.9% vs 8.3%,p=2×10−5). Strikingly, Ile200Thr was enriched over four-fold in acute lymphoblastic leukemia patients. Finally, protein structure stability analyses suggested novelMPOvariants to be potentially highly deleterious.ConclusionsThis study highlights the importance of germline testing in hematological malignancies and demonstrates the utility of population isolates for pathogenic variant discovery. Our findings identify a significant burden of deleterious variants in HM patients, particularly inCHEK2, and underscore the potential of multi-disease joint analyses in revealing germline contributions to hematological diseases.
PrEP Engagement and Youth Experiencing Homelessness in a sample of Youth Experiencing Homelessness in New York City: A Brief Report
Authors: Sisselman-Borgia Amanda , Ross Jonathan , Watnick Dana , Saint-Louis Nicole 
Published: October 2024

AbstractFew studies have examined pre-exposure prophylaxis (PrEP) engagement among youth experiencing homelessness (YEH), despite their high HIV risk. We assessed awareness of, willingness to use, and plans to take PrEP among YEH receiving services at nine organizations in New York City. Among 113 participants, 49 (43%) identified as LGBTQIA and 74 (65%) reported food insecurity. In total, 53 (47%) had heard of PrEP before the survey, 82 (73%) reported willingness to take PrEP, and 28 (25%) had a plan to take it. Interventions to improve awareness of PrEP and encourage use are critical to reducing HIV in YEH.
Explainable AI-based analysis of human pancreas sections identifies traits of type 2 diabetes
Authors: Klein L , Ziegler S , Gerst F , Morgenroth Y , Gotkowski K , Schöniger E , Heni M , Kipke N , Friedland D , Seiler A , Geibelt E , Yamazaki H , Häring HU , Wagner S , Nadalin S , Königsrainer A , Mihaljević A L , Hartmann D , Fend F , Aust D , Weitz J , Schwartzenberg R Jumpertz-von , Distler M , Maier-Hein K , Birkenfeld A L , Ullrich S , Jäger P , Isensee F , Solimena M , Wagner R 
Published: October 2024

AbstractType 2 diabetes (T2D) is a chronic disease currently affecting around 500 million people worldwide with often severe health consequences. Yet, histopathological analyses are still inadequate to infer the glycaemic state of a person based on morphological alterations linked to impaired insulin secretion and β-cell failure in T2D. Giga-pixel microscopy can capture subtle morphological changes, but data complexity exceeds human analysis capabilities. In response, we generated a dataset of pancreas whole-slide images with multiple chromogenic and multiplex fluorescent stainings and trained deep learning models to predict the T2D status. Using explainable AI, we made the learned relationships interpretable, quantified them as biomarkers, and assessed their association with T2D. Remarkably, the highest prediction performance was achieved by simultaneously focusing on islet α-and δ-cells and neuronal axons. Subtle alterations in the pancreatic tissue of T2D donors such as smaller islets, larger adipocyte clusters, altered islet-adipocyte proximity, and fibrotic patterns were also observed. Our innovative data-driven approach underpins key findings about pancreatic tissue alterations in T2D and provides novel targets for research.