bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large complex structural rearrangements in human genomes harbor cryptic structures
Authors: Audano Peter A. , Paisie Carolyn ,   The Human Genome Structural Variation Consortium (HGSVC), Beck Christine R. 
Published: December 2024

AbstractStructural variation is a major contributor to human diversity, adaptation, and disease. Simple structural variant (SV) types include deletions, insertions, duplications, inversions, and translocations, and SVs account for most of the variable bases between genomes. Complex structural variants (CSVs) that consist of one or more simple eventsin cisappear more frequently in diseases and cancers where DNA repair, apoptosis, and cell cycle checkpoints are compromised, although CSVs can also appear in germline genome sequences of healthy individuals. CSVs are often characterized by short tracts of homology or no homology, and while CSVs are more prevalent in complex regions that contain large repeats, smaller stretches of homology can also enable their formation across more unique loci. Long-read assemblies have increased the size of detectable SVs and expanded variant detection into more complex regions of the genome, and while they reconstruct CSVs, methods for identifying CSVs from assemblies is limited. Here, we have developed a new assembly-based approach to trace through complex loci rather than relying upon reference representations of alignments. We can now access CSVs in large complex segmental duplications, reveal structures that were previously unknown, and identify SV breakpoints with greater accuracy. We find 72 large CSVs per genome and 128 unique complex structures and CSVs in highly repetitive regions can now be detected including several distinct complex events in repetitiveNBPFgenes that was not previously callable with short-read or long-read CSV methods. This approach is implemented within a key assembly-based variant calling tool, PAV, and represents a substantial improvement identifying complex variants now ascertainable from contiguous genome assemblies.
A proteomic map of B cell activation and its shaping by mTORC1, MYC and iron
Authors: James Olivia , Sinclair Linda V. , Lefter Nadia , Salerno Fiamma , Brenes Alejandro , Howden Andrew J.M. 
Published: December 2024

SummaryUsing high resolution quantitative mass spectrometry, we have explored how immune activation and the metabolic checkpoint kinase mTORC1 (mammalian target of rapamycin complex 1) regulate the proteome of B lymphocytes. B cell activation via the B cell receptor, CD40 and the IL-4 receptor induced considerable re-modelling of the B cell protein landscape, with a 5-fold increase in total cellular protein mass within 24 hours of activation. Analysis of copy numbers per cell of >7,500 proteins revealed increases in the metabolic machinery that supports B cell activation and nutrient and amino acid transporters that fuel B cell biosynthetic capacity. We reveal that mTORC1 controls activation-induced cell growth and B cell proteome remodelling and inhibiting mTORC1 impairs the expression of amino acid transporters that fuel B cell protein production. We also show that mTORC1 activity regulates the expression of the transcription factor MYC and the transferrin receptor CD71. Blocking MYC activity phenocopied mTORC1 inhibition in many ways including impaired CD71 expression, while limiting iron availability during B cell activation impaired B cell growth and protein synthesis. This work provides a detailed map of naïve and immune activated B cell proteomes and a greater understanding of the cellular machinery that direct B cell phenotypes. This work also provides new insights into the role of mTORC1, MYC and iron in regulating activation-induced proteome remodelling and protein production in B cells.
MrHAMER2: high-accuracy long-read RNA sequencing to decode isoform-specific variation in viral transcripts during latency
Authors: Gallardo Christian M. , Albert Jessica L. , Qazi Andrew A. , Ventura Roni Lobato , Deshmukh Savitha , Beliakova-Bethell Nadejda , Torbett Bruce E. 
Published: December 2024

ABSTRACTAlternative splicing (AS) greatly expands the repertoire of proteins encoded by the human genome. Viruses have been shown to hijack AS to sustain replication or lead to latency. In HIV infection, the virus integrates into the host genome, becoming a transcriptional unit that directly engages in AS to regulate its gene expression. Sequencing advances have enabled insights into HIV gene expression dynamics during productive replication. However, viral isoform dynamics during latency remain largely uncharacterized due to the low abundance of both spliced viral transcripts and their originating cellular subsets, making their accurate detection and quantification challenging. To address current gaps, we developed MrHAMER2, a high-accuracy long-read RNA sequencing method that leverages dual Unique Molecular Identifier (UMI) tagging of cDNA to accurately capture and quantify full-length isoforms with high dynamic range and 99.968% single-nucleotide accuracy. We then use MrHAMER2 to decode the spliced HIV transcriptome in a primary cell model of latency and show substantial changes in viral isoforms bearing intron retentions accompanied by changes in their potential to generate translatable protein.
Provides Apparent Predictive Biomarker in a Phase I/II Study of Pembrolizumab With Gemcitabine in Patients with Previously-Treated Advanced Non-Small Cell Lung Cancer (NSCLC)
Authors: Sanborn Rachel E. , Jensen Shawn M. , Paustian Christopher , Chang Shu-Ching , Vetto Eloy , Vu Quyen , Rajamanickam Venkatesh , Bernard Brady , Koguchi Yoshinobu , Redmond William , Fox Bernard A. 
Published: December 2024

AbstractRetrospective characterization of cell-cell relationships in the tumor microenvironment provides significantly better predictive power than PD-L1 expression, tumor mutational burden (TMB), or gene expression profiles. In this small study assessing the safety and possible efficacy of gemcitabine and pembrolizumab in immunotherapy-naïve patients with NSCLC who have received prior treatment, we investigated both standard and novel immune parameters on 16 enrolled patients. The combination of gemcitabine and pembrolizumab could be administered safely but did not demonstrate synergism compared with historical controls. Novel findings of this study are that elevated frequencies of Tregulatory cells near CD3 T cells at baseline was associated with improved outcome to treatment (p<0.05). Integrating this Treg / T cell relationship metric together with overall T cell density yielded a tumor inflammation score which correlated (p<0.002) with disease response. We postulate this is indicative of ongoing anti-cancer immune response. Additionally, while prior studies documented that IgG Ab responses to TAA can identify targets of a coordinated T and B cell response and evidence of immune surveillance, this study found that high autoantibody responses, while not statistically significant, trended towards a worse outcome (p=0.06). This suggests to us that tumors may have developed mechanisms to escape the immune response to these TAAs.
Chlorhexidine Bathing for Candida auris Decolonization among Adult Patients in Healthcare Settings: Protocol for a Systematic Review and Meta-Analysis
Authors: Belfakir Messaouda , Sherif Moustafa , Adam Balazs 
Published: December 2024

AbstractBackgroundCandida auris (C. auris) poses a significant threat in healthcare settings, characterized by its high morbidity and mortality rates. While the use of chlorhexidine bathing has been suggested as a potential strategy for C. auris decolonization in adult patients within healthcare settings, a comprehensive and systematic evaluation of its effectiveness and associated outcomes is notably lacking.AimThis study seeks to systematically assess the effectiveness of daily chlorhexidine bathing for Candida auris decolonization in adult patients within healthcare settings. The study’s primary objectives are to evaluate the impact of this intervention on reducing colonization rates, infection occurrences, and outbreak incidences, while concurrently evaluating any associated adverse events. The study’s secondary objectives are to identify adverse events, and to explore and quantify the effect sizes of potential risk factors, if identified, that may influence the outcomes of chlorhexidine bathing for C. auris decolonization.Methods and AnalysisIn adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines, this protocol outlines the methodology for our systematic review and meta-analysis. The study commenced with an extensive presearch conducted from June to August 2023 on PubMed, followed by searches across other three key databases: Embase, Web of Science, and Scopus, in September 2023. The systematic search will encompass all available years of publication without applying any publication date filters. Records located in the literature search will be uploaded to the systematic review software Covidence to facilitate deduplication, blinded screening, and the selection of eligible studies. Two independent reviewers will rigorously screen records, extract data, and perform risk of bias assessments, with a third researcher resolving conflicts. The results will be synthesized narratively in summary tables, with the potential for meta-analysis contingent upon the findings, focusing on the effectiveness and adverse events of daily chlorhexidine bathing for C. auris decolonization in adult patients within healthcare settings. Additionally, we will investigate whether certain risk factors, if identified, have an impact on the outcomes by quantifying their effect sizes.Ethics and DisseminationThe ethical framework of this systematic review obviates the need for ethics approval, as it relies exclusively on published research. The outcomes of this study will be disseminated via publication in a peer-reviewed journal, shared with stakeholders, and made publicly accessible.PROSPERO RegistrationCRD42023459048.
Frailty in older patients with atrial fibrillation and its relationship with anticoagulant use: a multi-centred observational study in New South Wales
Authors: Nguyen Tu N , Fujita Kenji , Hilmer Sarah N 
Published: December 2024

AbstractBackground and aimsEvidence of the impact of frailty on oral anticoagulant (OAC) prescription in older people with atrial fibrillation (AF) is conflicting. This study aimed to examine the prevalence of frailty in hospitalised older patients with AF and its relationship with OAC prescription during admission. The secondary aim was to examine the association between frailty and rate/rhythm control medication prescriptions.MethodsThis retrospective observational study included adults aged ≥65 with AF admitted to six hospitals in Australia in 2022. Frailty was defined by a Frailty Index ≥0.25. Logistic regression models were applied to examine the association between frailty and the prescriptions of OAC, rate-control and rhythm-control drugs during hospitalisation. Results are presented as odds ratios and 95% confidence intervals (CI).ResultsThere were 685 patients, with a mean age of 82.6(SD 8.3), 49.8% female and 42.8% identified as frail. Overall, 75.6% were prescribed OAC (67.9% in the frail versus 81.4% in the non-frail, p<0.001), 37.7% received rate-control drugs (42.0% in the frail versus 34.4% in the non-frail, p=0.044), 27.3% received rhythm-control drugs (22.9% in the frail versus 30.6% in the non-frail, p=0.024). The adjusted odds ratios of frailty on prescriptions were 0.58 (95% CI 0.39-0.86) for OAC, 1.75 (95%CI 1.22-2.52) for rate-control drugs, and 0.83 (95%CI 0.55-1.24) for rhythm-control drugs.ConclusionsThe study revealed a high prevalence of frailty in older inpatients with AF. Frailty was associated with reduced likelihood of prescription of OAC during admission and increased likelihood of prescribing rate-control medications, with no independent impact on rhythm-control therapy. Further studies are needed to understand these prescribing patterns.
A hospital-based cluster-randomized controlled trial of free influenza vaccination before hospital discharge compared to routine care in patients with heart failure (PANDA II): Statistical Analysis Plan
Authors: Shan Sana , Billot Laurent , Du Xin , Dong Jianzeng , Anderson Craig 
Published: December 2024

AbstractThe PANDA II trial aims to evaluate whether a free influenza vaccination program for patients hospitalized in China with acute heart failure provides benefits compared to current routine practice of no influenza vaccination. It is designed as a two-arm, parallel, cluster-crossover randomized trial of 122 hospitals conducted over three influenza seasons. This statistical analysis plan pre-specifies the method of analysis for every outcome and key variable collected in the trial.The primary outcome is a composite of all-cause mortality and re-admission to hospital within a 12- month period after the initial 30-day post-discharge period. The primary analysis will include all recruited participants analysed according to the intervention allocated to the hospital during their enrolment period. It will consist in an individual-level hierarchical logistic regression adjusted for the effect of the period and for clustering by hospital using both a random hospital effect and a random hospital-period effect. The effect of the influenza vaccination program will be estimated as an odds ratio and 95% confidence interval.Sensitivity analyses will include covariate adjustments as well as a cluster-level analysis and subgroup analyses according to eight pre-specified subgroups.
Characterizing Population-level Changes in Human Behavior during the COVID-19 Pandemic in the United States
Authors: Urmi Tamanna , Pant Binod , Dewey George , Quintana-Mathé Alexi , Lang Iris , Druckman James N. , Ognyanova Katherine , Baum Matthew , Perlis Roy H. , Riedl Christoph , Lazer David , Santillana Mauricio 
Published: December 2024

AbstractThe transmission of communicable diseases in human populations is known to be modulated by behavioral patterns. However, detailed characterizations of how population-level behaviors change over time during multiple disease outbreaks and spatial resolutions are still not widely available. We used data from 431,211 survey responses collected in the United States, between April 2020 and June 2022, to provide a description of how human behaviors fluctuated during the first two years of the COVID-19 pandemic. Our analysis suggests that at the national and state levels, people’s adherence to recommendations to avoid contact with others (a preventive behavior) was highest early in the pandemic but gradually—and linearly—decreased over time. Importantly, during periods of intense COVID-19 mortality, adherence to preventive behaviors increased—despite the overall temporal decrease. These spatial-temporal characterizations help improve our understanding of the bidirectional feedback loop between outbreak severity and human behavior. Our findings should benefit both computational modeling teams developing methodologies to predict the dynamics of future epidemics and policymakers designing strategies to mitigate the effects of future disease outbreaks.
The genetic architecture of the β-globin chain in individuals with and without sickle cell disease in Nigeria: A case for beta thalassemia?
Authors: Babalola Oluwatoyin Aduke , Fasola Foluke Atinuke , Brown Biobele Jotham , Zhang Jing , Zheng Yonglan , Odetunde Abayomi , Falusi Adeyinka Gladys , Olopade Olufunmilayo 
Published: December 2024

ABSTRACTBackgroundReports on beta thalassemia in the Nigerian population are conflicting, and the prevalence and role of beta thalassemia in Nigerian sickle cell disease (SCD) patients remain unclear. There is a need to set the records straight to ascertain the prevalence and effect of beta thalassemia in these patients.Methods123 SCD patients and 117 age- and sex-matched controls were recruited. For the cases, the age range was 3 – 69 years, median(IQR) = 16(9 - 29). A separate cohort of 26 SCD patients were studied along. Full blood count was calculated, and the hemoglobin fractions were estimated by High Performance Liquid Chromatography. The 1.6kb beta-globin gene region was amplified from germline DNA and Sanger sequencing was performed. Single nucleotide polymorphisms (SNPs) were detected and annotated, and haplotypes were constructed.ResultsContrary to recent reports, the prevalence of beta thalassemia in this population is <1%. Aside the sickle, hemoglobin C and beta thalassemia mutations, eight other variants were identified. Only three of these variants were found in the SCD patients and are in linkage disequilibrium. The sickle and hemoglobin C mutations arose on the major ancestral haplotype, while the beta thalassemia intermedia mutation (rs33915217C>A) was found on the minor ancestral haplotype, atypical of Africa. Two rare variants (rs537944366T>C and rs33915217C>A) are reported for the first time in the Yoruba population.ConclusionThere is a need for a re-assessment of the diagnosis of beta thalassemia in this and other African populations for the proper management of SCD and other anemia-related cases.
Application of a GRF-GIF chimera enhances plant regeneration for genome editing in tomato
Authors: Swinnen Gwen , Lizé Eléonore , Sánchez Miguel Loera , Stolz Stéphanie , Soyk Sebastian 
Published: December 2024

AbstractGenome editing has become a routine tool for functionally characterizing plant and animal genomes. However, stable genome editing in plants remains limited by the time- and labor- intensive process of generating transgenic plants, as well as by the efficient isolation of desired heritable edits. In this study, we evaluated the impact of the morphogenic regulatorGRF-GIFon plant regeneration and genome editing outcomes in tomato. We demonstrate that expressing a tomatoGRF-GIFchimera reliably accelerates the onset of shoot regeneration from callus tissue culture by approximately one month and nearly doubles the number of recovered transgenic plants. Consequently, theGRF-GIFchimera enables the recovery of a broader range of edited haplotypes and simplifies the isolation of mutants harboring heritable edits, but without markedly interfering with plant growth and development. Based on these findings, we outline strategies that employ basic or advanced diagnostic pipelines for efficient isolation of single and higher-order mutants in tomato. Our work represents a technical advantage for tomato transformation and genome editing, with potential applications across other Solanaceae species.
Three-dimensional regulatory hubs support oncogenic programs in glioblastoma
Authors: Breves Sarah L. , Campigli Di Giammartino Dafne , Nicholson James , Cirigliano Stefano , Mahmood Syed Raza , Lee Uk Jin , Martinez-Fundichely Alexander , Jungverdorben Johannes , Singhania Richa , Rajkumar Sandy , Kirou Raphael , Studer Lorenz , Khurana Ekta , Polyzos Alexander , Fine Howard A. , Apostolou Effie 
Published: December 2024

SUMMARYDysregulation of enhancer-promoter communication in the context of the three-dimensional (3D) nucleus is increasingly recognized as a potential driver of oncogenic programs. Here, we profiled the 3D enhancer-promoter networks of primary patient-derived glioblastoma stem cells (GSCs) in comparison with neuronal stem cells (NSCs) to identify potential central nodes and vulnerabilities in the regulatory logic of this devastating cancer. Specifically, we focused on hyperconnected 3D regulatory hubs and demonstrated that hub-interacting genes exhibit high and coordinated expression at the single-cell level and strong association with oncogenic programs that distinguish IDH-wt glioblastoma patients from low-grade glioma. Epigenetic silencing of a recurrent 3D enhancer hub—with an uncharacterized role in glioblastoma—was sufficient to cause concordant downregulation of multiple hub-connected genes along with significant shifts in transcriptional states and reduced clonogenicity. By integrating published datasets from other cancer types, we also identified both universal and cancer type-specific 3D regulatory hubs which enrich for varying oncogenic programs and nominate specific factors associated with worse outcomes. Genetic alterations, such as focal duplications, could explain only a small fraction of the detected hyperconnected hubs and their increased activity. Overall, our study provides computational and experimental support for the potential central role of 3D regulatory hubs in controlling oncogenic programs and properties.HIGHLIGHTS- 3D regulatory “hubs” in glioblastoma enrich for highly coregulated genes at a single-cell level and expand oncogenic regulatory networks.- Targeted perturbation of a highly recurrent 3D regulatory hub in GSCs results in altered transcriptional states and cellular properties.- 3D regulatory hubs across cancer types associate with tumor-specific and universal oncogenic programs and worse outcomes.- The majority of hyperconnected hubs do not overlap with structural variants, suggesting epigenetic mechanisms.eTOCHere we profile the 3D enhancer connectomes of primary patient-derived human glioblastoma stem cells (GSCs), identify hyperconnected 3D regulatory “hubs”, and examine the impact of 3D hub perturbation on the transcriptional program and oncogenic properties.
The Diverse Phenotypic and Mutational Landscape Induced by Fluoroquinolone Treatment
Authors: Mohiuddin Sayed Golam , Kavousi Pouria , Figueroa Diego , Ghosh Sreyashi , Orman Mehmet A. 
Published: December 2024

AbstractDespite extensive research on antibiotic resistance, the potential effects of antibiotic treatments on bacterial tolerance and resistance remain a significant concern. Although bacterial cells adopt a variety of mutational strategies to resist unfavorable circumstances, it is still unclear how antibiotic tolerance and resistance mechanisms affect bacterial fitness characteristics and whether evolved mutants exhibit similar properties across different cell populations subjected to the same conditions. Here, we usedEscherichia coli, a fluoroquinolone antibiotic (ofloxacin), and adaptive laboratory evolutionary experiments to demonstrate that ofloxacin tolerance and resistance can evolve independently across different cell populations exposed to identical conditions. Fitness attributes, such as lag score, doubling time, competition score, and other metabolic features, were variably affected by antibiotic tolerance and resistance mechanisms. However, we did not observe strong and apparent correlations between fitness trade-offs and antibiotic tolerance and resistance. While our whole-genome sequencing identified some shared mutations, such as single nucleotide polymorphisms in theicdgene (a crucial citric acid cycle gene), evolved cell populations exhibited diverse genetic mutations without a clear pattern of a conserved evolutionary pathway. Our study also identifies unique phenotypes, such as those displaying significantly lower minimum inhibitory concentration levels compared to the parental strain yet showing remarkably high tolerance to the same antibiotic. Altogether, our study, examining the phenotypic and mutational landscapes of fluoroquinolone-induced strains, contributes to our understanding of complex bacterial adaptation mechanisms.