bluuebunny/crossref_metadata_2025 huggingface dataset:
Abundant genetic variation is retained in many laboratory schistosome populations
Authors: Jutzeler Kathrin S. , Platt Roy N. , Diaz Robbie , Morales Madison , Clec’h Winka LE , Chevalier Frédéric D. , Anderson Timothy J.C.
Published: October 2024

Schistosomes are obligately sexual blood flukes that can be maintained in the laboratory using freshwater snails as intermediate and rodents as definitive hosts. The genetic composition of laboratory schistosome populations is poorly understood: whether genetic variation has been purged due to serial inbreeding or retained is unclear. We sequenced 19 – 24 parasites from each of five laboratorySchistosoma mansonipopulations and compared their genomes with published exome data from fourS. mansonifield populations. We found abundant genomic variation (0.897 – 1.22 million variants) within laboratory populations: these retained on average 49% (π = 3.27e-04 – 8.94e-04) of the nucleotide diversity observed in the four field parasite populations (π = 1.08e-03 – 2.2e-03). However, the pattern of variation was very different in laboratory and field populations. Tajima’s D was positive in all laboratory populations except SmBRE, indicative of recent population bottlenecks, but negative in all field populations. Current effective population size estimates of laboratory populations were lower (2 – 258) compared to field populations (3,174 – infinity). The distance between markers at which linkage disequilibrium (LD) decayed to 0.5 was longer in laboratory populations (59 bp – 180 kb) compared to field populations (9 bp – 9.5 kb). SmBRE was the least variable; this parasite also shows low fitness across the lifecycle, consistent with inbreeding depression. The abundant genetic variation present in most laboratory schistosome populations has several important implications: (i) measurement of parasite phenotypes, such as drug resistance, using laboratory parasite populations will determine average values and underestimate trait variation; (ii) genome-wide association studies (GWAS) can be conducted in laboratory schistosome populations by measuring phenotypes and genotypes of individual worms; (iii) genetic drift may lead to divergence in schistosome populations maintained in different laboratories. We conclude that the abundant genetic variation retained within many laboratory schistosome populations can provide valuable, untapped opportunities for schistosome research.
A TEMPORAL MODEL OF TUMOR-IMMUNE DYNAMICS IN HIGH GRADE SEROUS OVARIAN CANCER
Authors: Egan Donagh , Glennon Kate , Treacy Ann , Fabre Aurelie , McCormack Janet , Hill Salisha , Morrison Ryan , Liebler Daniel , Kolch Walter , Brennan Donal
Published: October 2024

Patients with high-grade serous ovarian cancer (HGSOC) typically present with widespread metastasis, obscuring a temporal understanding of tumor-immune dynamics. We performed multi-site global proteomics and matched immunohistochemistry (IHC) of CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) in patient samples. The protein expression profiles were ordered by pseudotime, recapitulating metastatic progression observed in the clinic, and providing a framework to explore tumor-immune dynamics from localized to metastatic disease. Metastatic progression correlated with immune cell infiltration and the recruitment of Tregs to counterbalance the effect of γδ and CD4+ T cells. Whilst later-stage metastases recruited Tregs via chemokines induced by SNX8, early-stage tumors relied more on antigen presentation. The exclusion of CD4+ TILs from the epithelium was correlated with metastatic progression, whereas CD8+ TILs were not, likely due to a predominance of exhausted CD8+ T cells. In early-stage tumors, keratin-expressing cancer cells recruited Tregs via MHC class II, resulting in an inflammatory phenotype characterized by limited IFNγ production and non-clonally expanded T cells. Additionally, IFI44L expression on macrophages caused immune exclusion by downregulating CD53 on T cells. Our findings reveal novel mechanisms of immune escape associated with localized disease and metastatic progression in HGSOC, highlighting potential targets to improve the efficacy of immunotherapy.
The dual trxG/PcG protein ULTRAPETALA1 modulates H3K27me3 and directly enhances POLYCOMB REPRESSIVE COMPLEX 2 activity for fine-tuned reproductive transitions
Authors: Geshkovski Vangeli , Engelhorn Julia , Izquierdo Jean-Baptiste , Laroussi Hamida , Thouly Caroline , Turchi Laura , Le Masson Marie , Thévenon Emmanuel , Petitalot Ambre , Simon Lauriane , Desset Sophie , Michl-Holzinger Philipp , Parrinello Hugues , Grasser Klaus D. , Probst Aline , Margueron Raphaël , Vachon Gilles , Kadlec Jan , Carles Cristel C.
Published: October 2024

The antagonistic POLYCOMB (PcG) REPRESSIVE COMPLEX 2 (PRC2) and trithorax (trxG) chromatin machineries play a major role in orchestrating gene expression during the development of multicellular eukaryotes. These complexes are well known for depositing and maintaining the repressive H3K27me3 and activating H3K4me3 marks, respectively. However, the mechanisms that govern the switch between these functions remains elusive, especially in plants, whose lifelong, flexible development relies heavily on this process. Here we demonstrate that the plant specific ULTRAPETALA1 (ULT1) protein, previously reported as a trxG factor that antagonizes the PRC2 enzymatic subunit CURLY LEAF (CLF), also exhibits a repressive function, increasing H3K27me3 levels at over a thousand genes. We discovered a physical interaction between ULT1 and PRC2 components, particularly the SWINGER (SWN) enzymatic subunit. We further show that ULT1 significantly enhances PRC2SWNenzymatic activityin vitro, corroborating our epigenomic and developmental genetic data that reveal different ULT1 activity depending on the catalytic subunit of the PRC2 complex. This study provides new insights into the relative activities of CLF and SWN and introduces a novel mechanistic framework for a chromatin switch mediated by a bivalent trxG/PcG factor.

Key message

ULTRAPETALA1 counteracts or promotes PRC2 activity at hundreds of developmental genes inArabidopsis thaliana, and activates the deposition of the repressive H3K27me3 chromatin mark via direct interaction with PRC2.

This is the first instance of a bivalent trxG / PcG factor which functions as a cofactor of PRC2 HMTs.
Insufficient evidence for a severe bottleneck in humans during the Early to Middle Pleistocene transition
Authors: Cousins Trevor , Durvasula Arun
Published: October 2024

A recently proposed model suggests a strong bottleneck in the panmictic ancestral population of modern humans during the Early to Middle Pleistocene transition. Here, we show this model provides a substantially worse fit to the data than a panmictic model without the bottleneck.
The cyclin-G associated kinase (GAK) is a novel mitotic kinase and therapeutic target in diffuse large B-cell lymphoma
Authors: Lightfuss Olivia B , Kumar Preet , Li Lingxiao , Shastri Toral , Newsam Austin D , Manara Paola , Alaoui Abdessamad Y , Parets Diego E Hernandez , Younes Pierre A , Chahar Dhanvantri , Arumov Artavazd , Coughlin Caroline A , Williams Indigo P , Fattakhov Nikolai , Martinez Alicia Bilbao , Landgren Ola , Schurer Stephan C , Lemmon Vance , Maura Francesco , Bilbao Daniel , Feng Yangbo , Al-Ali Hassan , Schatz Jonathan H
Published: October 2024

Diffuse large B cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma and the most frequently diagnosed hematologic malignancy in the United States. DLBCL exhibits significant molecular and clinical heterogeneity, and at least a third of patients are left uncured with standard frontline chemoimmunotherapy. As such, there is a critical need to identify novel targeted therapies to improve outcomes. We conducted a phenotypic screen of kinase inhibitors against DLBCL cell lines and non-malignant controls. We identified the cyclin G-associated kinase (GAK) as a tumor-selective, readily druggable target whose inhibition killed DLBCL cell lines, while sparing non-malignant blood cells. Upon investigation of GAK's cellular function, we discovered that inhibition results in G2/M-phase cell cycle arrest. Immunofluorescent confocal microscopy revealed significant chromosome misalignment and spindle distortion in DLBCL cells following GAK-inhibition, disrupting progression through mitosis. Analysis of RNA-seq data from clinical samples showed increased GAK expression associates strongly with RB1 deficiency in DLBCL cases, suggesting dependency on GAK for proper mitotic progression linked to retinoblastoma associated protein (RB) loss of function, a common DLBCL driver. In cell-cycle analyses and under microscopy, RB-deficient DLBCL cells treated with an exquisitely selective GAK inhibitor showed complete arrest at G2/M, pronounced distortion of mitotic spindles, and widespread chromosomal damage. Finally, in vivo studies of DLBCL xenograft-bearing NSG mice achieved a dramatic tumor-burden reduction in response to targeted GAK inhibition. These results reveal a novel cell cycle kinase suitable for therapeutic exploitation in DLBCL patients and linked to the common, undruggable biomarker of RB loss of function.
Vitamin E supplementation prevents ferroptosis in round spermatids of aged mice
Authors: Germeraad Jasper , Kikkawa Takako , Osumi Noriko
Published: October 2024

Germ cell depletion in the aged testes has traditionally been attributed to removal by apoptosis. This study aimed to determine whether ferroptosis, an alternative form of cell death driven by iron-dependent lipid peroxidation, also contributes to germ cell loss in the lipid-rich environment of the testis. Here, we demonstrate that pre-meiotic cells are eliminated via apoptosis, whereas post-meiotic round spermatids (RSs) are mainly removed through ferroptosis. Surprisingly, we detected a greater abundance of Y-chromosome-bearing RSs (Y-RSs) than X-carrying RSs (X-RSs) in the aged testis, implying that X-RSs might be more prone to ferroptosis. Young mice fed a vitamin E (VE) deficient diet recapitulated age-related phenotypes, while VE supplementation prevented ferroptosis and promoted the survival of X-RSs in aged mice. Overall, this study reveals that aging causes ferroptosis in RSs, specifically impacting X-RSs, which can be prevented by VE supplementation, effectively reversing age-induced deterioration and contributing to healthy testicular aging.
Targets of sexual selection on theDrosophilawing
Authors: De Lisle Stephen P. , Branden Anneli , Paajarvi Vag Ellen
Published: October 2024

Identification 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

BACKGROUND

The 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 RESULTS

A 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.

CONCLUSIONS

ALI 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

Active 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

Bladder 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

Designing 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

RNA 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.
Cell-Free Recombinase Integrated Boolean Output System (CRIBOS)
Authors: Chen Jingyao , Borison Aviva , Densmore Doug , Wong Wilson
Published: October 2024

Cell-free gene expression systems are increasingly important in fundamental research and biomanufacturing, offering a versatile platform for studying gene circuits and bio-computation. We present the Cell-Free Recombinase Integrated Boolean Output System (CRIBOS), a site-specific recombinase-based multiplex genetic circuit platform designed for cell-free environments. With CRIBOS, we build over 20 multi-input-multi-output circuits, including 2-input-1-output genetic circuits and a 2-input-4-output decoder. Combined with allosteric transcription factors (aTFs)-based sensors, the circuits demonstrate multiplex environmental sensing. Moreover, utilizing paper-based CRIBOS, which demonstrates remarkable portability and stability in a paper-based setting, we present a biological memory storage device that can preserve DNA-based biological information for over four months with minimal resources, energy costs, and maintenance requirements. Implementing CRIBOS not only expands the application of multiplex Boolean logic gates from cellular systems to the cell-free environment but also augments their overall versatility, opening new avenues for designing and applying sophisticated genetic circuits.
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

Loss 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

Specialized 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

The 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

Epigenetic 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

Background

The 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.

Methods

We 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).

Results

The 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.

Conclusions

This 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

Few 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

Type 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.
SCALING UP THE TASK-SHARING OF AN EVIDENCE-BASED PSYCHOLOGICAL TREATMENT FOR DEPRESSION IN RURAL INDIA
Authors: Agrawal Ravindra , Sood Mohit , Patel Anushka , Sharma Tanushri , Yadav Harshita , Kaur Jigyasa , Kumari Smita , Sharma Prashant , Shukla Vandana , Tripathi Balkrishan , Dongare Namdeo , Narasimhamurti Nityasri Sankha , Bhan Anant , Tiwari Sharad , Sakalle Shailesh , Patel Vikram
Published: October 2024

Background

Majority evidence on task-sharing of psychological treatments for depression is focused on randomized controlled trials with project staff delivered treatment. Ours is a scaling up of a brief evidence-based psychological treatment (the Healthy Activity Program, HAP) by community health workers (ASHA) in rural India. Our objective was to test the acceptability, feasibility and effectiveness of ASHA delivered HAP.

Method

ASHA were recruited in three rural districts in Madhya Pradesh, India. During the study duration, 1001 ASHA completed training using the EMPOWER approach (digital curricula and supervision protocols); 458 ASHA went on to deliver the HAP to adults with depression screened opportunistically. This paper describes the delivery of the HAP over a one-year period (24-07-2022 till 30-06-2023). The primary outcomes were treatment completion, patient and ASHA satisfaction, and change in depression symptom scores on treatment completion; we also explored if treatment effects were sustained at long-term (i.e., 9 month) among a consecutively recruited sub-sample of 10% of the total participants (n=246).

Results

94.3% of the NSPs completed the full training. 2208 patients (12.1% of the total screened) had depression and all 2208 (100%) agreed to receive the treatment. A total of 13,008 sessions were delivered with a 97.82% completion rate. We found substantial reduction in depressive symptom severity from baseline to immediate post-treatment [Cohen’s d=2.52; CI: 2.44 to 2.61], which was sustained at 9-month follow-up [Cohen’s d=.96, 95% CI: .81 to 1.11]. Lower baseline depression, male gender, longer treatment duration, and higher educational status of the ASHA predicted better treatment outcome at endline. Both ASHA and patients reported high levels of satisfaction.

Conclusion

The scaling up of a brief evidence based psychological treatment by existing frontline workers through digital platforms for training and supervision is associated with both high levels of satisfaction, treatment completion and remission rates.
An exposome-wide investigation of 2923 Olink proteins with non-genetic factors in Chinese adults
Authors: Iona Andri , Wang Baihan , Clarke Jonathan , Chan KaHung , Kakkoura Maria G. , Clarke Charlotte , Wright Neil , Yao Pang , Mazidi Mohsen , Im Pek Kei , Rahmati Maryam , Kartsonaki Christiana , Morris Sam , Fry Hannah , Millwood Iona Y , Walters Robin G , Chen Yiping , Du Huaidong , Yang Ling , Avery Daniel , Schmidt Dan Valle , Li Feifei , Yu Canqing , Sun Dianjianyi , Lv Jun , Hill Michael , Li Liming , Clarke Robert , Bennett Derrick A , Chen Zhengming
Published: October 2024

Background

Previous studies in European populations have identified a large number of genetic variants affecting plasma levels of Olink proteins, but little is known about the non-genetic factors influencing plasma levels of proteins, particularly in Chinese populations.

Methods

We measured plasma levels of 2,923 proteins, using Olink Explore platform, in 2,006 participants in the China Kadoorie Biobank. Linear regression analyses were used to assess the cross-sectional associations of individual proteins with 37 exposures across multiple domains (e.g. socio-demographic, lifestyle, environmental, sample processing, reproductive factors, clinical measurements, and health-related indices), adjusted for potential confounders and multiple testing. These were further replicated and compared with similar analyses in Europeans.

Results

Overall 31 exposures were associated with at least one protein, with age (n=1,154), sex (n=827), BMI (n=869) showing the highest number of associations, followed by frailty index (n=597), SBP (n=479), RPG (n=387), ambient temperature (n=292), and HBsAg-positivity (n=282), with diet and physical activity showing little associations. Likewise, of the 2,923 proteins examined, 65% were associated with at least one exposure, with three proteins (CDHR2, CKB, and PLAT) showing the largest number of associations with baseline characteristics (n=14). The patterns of associations differed by sex, chiefly due to differences in lifestyle and reproductive factors. Over 90% of proteomic associations with key exposures in the current study were replicated in the UK Biobank.

Conclusions

In Chinese adults, the exposome-wide assessment of Olink proteins identified a large number of associations with a wide range of exposures, which could inform future research priorities and analytic strategies.
The Differential Burden of Acute Rhinovirus Infections in Children with Underlying Conditions
Authors: Sánchez Códez María Isabel , Benavente Fernández Isabel , Moyer Katherine , Leber Amy L. , Ramilo Octavio , Mejias Asuncion
Published: October 2024

Introduction

Rhinoviruses (RVs) are well-known trigger of wheezing episodes in children with asthma. Their role in other pediatric chronic medical conditions is not fully know.

Methods

Patients ≤21 years hospitalized or evaluated as outpatients with symptomatic RV infection were identified from 2011-2013. Patients were categorized based on the type of underlying disease and differences in clinical parameters, RV loads (CTvalues), viral and bacterial coinfections and clinical outcomes compared between groups. Multivariable analyses were performed to identify the comorbidities associated with oxygen requirement, PICU admission, and prolonged hospitalization.

Results

Of 1,899 children analyzed, 77.7% (n=1477) had an underlying comorbidity including asthma (36.8%), prematurity (7.7%), chronic respiratory diseases (6.4%), congenital heart disease (CHD, 3.2%), immunocompromised hosts (ICH; 1.4%) and others (22.2%). Prevalence of comorbidities increased with age (70%, infantsvs84%-87%, children >1 year; p<0.0001). Median RV loads were intermediate-high (24-26 CTvalues), irrespective of the underlying disease. RV/ viral co-detections were identified in 11% of ICH vs 20%-30% in all other children while bacterial co-infections were identified in 2.9% of children. Multivariable models identified asthma, prematurity, CHD and bacterial coinfections consistently associated with all three clinical outcomes (p<0.0001). Older age and higher RV loads were also associated with increased odds of PICU admission.

Conclusions

The prevalence of comorbidities was high in children with RV infections. Of those, asthma, prematurity and CHD were consistently associated with severe disease. Bacterial co-infections and higher RV loads further predicted worse clinical outcomes, highlighting the importance of identifying clinical phenotypes for future targeted interventions.
The Incidence and Prevalence of SARS-CoV-2 in the UK Population from the UKHSA Winter COVID Infection Study
Authors: Fyles Martyn , Mellor Jonathon , Paton Robert , Overton Christopher E. , Phillips Alexander M. , Glaser Alex , Ward Thomas
Published: October 2024

The SARS-CoV-2 virus continues to cause substantial morbidity and mortality, particularly during the winter period. The Winter Covid Infection Study (WCIS) ran from the 14thof November 2023 to the 7thof March 2024, and enabled the UK Health Security Agency to publish fortnightly estimates of the incidence and prevalence of SARS-CoV-2. Testing was performed using Lateral Flow Devices (LFD), and a repeat testing design was used to estimate key epidemiological parameters of SARS-CoV-2. This facilitated the estimation of time-varying prevalence, incidence, and test sensitivity. A Bayesian multilevel regression and poststratification model was developed to produce representative and unbiased estimates. In England and Scotland, prevalence peaked at 4.54% (95% CI: 3.90 to 5.24), and incidence peaked at 498 (95% CrI: 429 to 585) new infections per 100,000 individuals per day. The average LFD test sensitivity in England and Scotland during the study was estimated to be 72.1% (95% CrI: 70.3, 74.0), though due to epidemic phase bias this varied from a minimum value of 68.6% (95% CrI: 66.4 to 70.7) to a maximum value of 77.2% (95% CrI: 75.3 to 79.2). The novel study design of WCIS addressed key survey design challenges faced by previous large-scale SARS-CoV-2 population prevalence studies. The study demonstrated the utility and cost-benefit of LFD tests in large community surveys of prevalence.
Racial and ethnic and sex differences in at-home estimates of sleep-disordered breathing parameters among Mexican American, Black, and Non-Hispanic White adults
Authors: Leng Yue , Cavaillès Clémence , Peltz Carrie , O’Bryant Sid E. , Redline Susan , Yaffe Kristine
Published: October 2024

Background

Racial and ethnic and sex differences in sleep may exist, but there are limited data directly comparing objective estimates of sleep-disordered breathing (SDB), particularly in rapid eye movement (REM) versus non-rapid eye movement (NREM) sleep, among Black, Mexican American (MA) and non-Hispanic White (NHW) men and women. Our goal is to investigate health disparities in SDB in a new, diverse cohort of older adults.

Research Question

Do SDB parameters during REM and NREM sleep differ by race and ethnicity or sex in community-dwelling older adults?.

Methods

The Dormir Study conducted a comprehensive sleep examination among eligible participants enrolled in the ongoing community-based Health and Aging Brain Study-Health Disparities (HABS-HD) cohort (2020-4), among Black, MA, and NHW adults aged 50 years and older. Here we characterize racial and ethnic and sex differences in SDB indices assessed by an FDA-approved Peripheral Arterial Tonometry (PAT)-based home sleep testing system.

Results

We examined 821 participants, including 543 (66.1%) women, and 284 (34.6%) MA and 174 (21.2%) Black individuals, with a mean age of 66.6±8.5 years. Around half (50.5%) of the participants had moderate to severe SDB as defined by the respiratory event index (REI based on 3% desaturations) of ≥15/ hour, 72.7% with moderate to severe REM SDB (REM-REI ≥ 15/hour) and 39.5% with moderate to severe NREM SDB (NREM-REI ≥15/hour). The prevalence of SDB did not differ by race or sex. However, significant racial and ethnic and sex differences were observed for REM-specific SDB metrics. Overall, Black women had the highest REM REI, and NHW men had the lowest REM REI and REM ODI. After controlling for age, sex, education, income, employment status, cognitive status, BMI, history of hypertension, diabetes, stroke, and coronary heart disease, and sleep medication use, Black participants had a REM-REI that was 3 events per hour higher than that of NHW adults, while NREM-REI were similar. MA individuals had similar REM or NREM SDB parameters compared to NHW adults but exhibited higher average blood oxygen levels.

Conclusions

In this community-based cohort of middle- to older-aged NHW, MA, and Black adults, PAT-based measures of in-home sleep indicate a higher prevalence of REM SDB in Black adults, particularly Black women, compared to their NHW counterparts; this contrasts with the similar NREM parameters observed across racial and ethnic groups. Given the close link between REM SDB and adverse health outcomes, clinicians should pay more attention to this sleep apnea phenotype, especially in minoritized populations.
Effect of comprehensive medication management on mortality in critically ill patients
Authors: Sikora Andrea , Min Wanyi , Hu Mengxuan , Devlin John W. , Murphy David J. , Murray Brian , Zhao Bokai , Shen Ye , Chen Xianyan , Smith Susan E. , Rowe Sandra , Liu Tianming , Li Sheng
Published: October 2024

Background

Medication management in the intensive care unit (ICU) is causally linked to both treatment success and potential adverse drug events (ADEs), often associated with deleterious consequences. Patients with higher severity of illness tend to require more management. The purpose of this evaluation was to explore the effect of comprehensive medication management (CMM) on mortality in critically ill patients.

Methods

In this retrospective cohort study of adult ICU patients, CMM was measured by critical care pharmacist (CCP) medication interventions. Propensity score matching was performed to generate a balanced 1:1 matched cohort, and logistic regression was applied for estimating propensity scores. The primary outcome was the odds of hospital mortality. Hospital and ICU length of stay were also assessed.

Results

In a cohort of 10,441 ICU patients, the unadjusted mortality rate was 11% with a mean APACHE II score of 9.54 ± 4.18 and Medication Regimen Complexity-Intensive Care Unit (MRC-ICU) score of 5.78 ± 4.09. Compared with CCP interventions less than 3, more CCP interventions was associated with a significantly reduced risk of mortality (estimate -0.04, 95% confidence interval -0.06 - -0.03, p < 0.01) and shorter length of ICU stay (estimate -2.77, 95% CI -2.98 - - 2.56, p < 0.01).

Conclusions

The degree by which CCPs deliver CMM in the ICU is directly associated with reduced hospital mortality independent of patient characteristics and medication regimen complexity.