bluuebunny/crossref_metadata_2025_split huggingface dataset:
DeepAge: Harnessing Deep Neural Network for Epigenetic Age Estimation From DNA Methylation Data of human blood samples
Authors: Dip Sajib Acharjee , Ma Da , Zhang Liqing 
Published: August 2024

AbstractAccurate prediction of biological age from DNA methylation data is a critical endeavor in understanding the molecular mechanisms of aging and developing age-related disease interventions. Traditional epigenetic clocks rely on linear regression or basic machine learning models, which often fail to capture the complex, non-linear interactions within methylation data. This study introduces DeepAge, a novel deep learning framework utilizing Temporal Convolutional Networks (TCNs) to enhance the prediction of biological age from DNA methylation profiles using selected CpGs by a Dual-Correlation based apparoach. DeepAge leverages a sequence-based approach with dilated convolutions to effectively capture long-range dependencies between CpG sites, addressing the limitations of prior models by incorporating advanced network architectures including residual connections and dropout regularization. The dual correlation feature selection enhances our model’s predictive capabilities by identifying the most age-relevant CpG sites. Our model outperforms existing epigenetic clocks across multiple datasets, offering significant improvements in accuracy and providing deeper insights into the epigenetic determinants of aging. The proposed method not only sets a new standard in age estimation but also highlights the potential of deep learning in biologically relevant feature extraction and interpretation, contributing to the broader field of computational biology and precision medicine.
AAB-seq: An antigen-specific and affinity-readable high-throughput BCR sequencing method
Authors: Hu Mengzhu , Lian Qiuyu , Cui Xiaonan , Dong Xue , Xin Hongyi , Shi Weiyang 
Published: August 2024

AbstractB-cell receptor (BCR) sequencing is a powerful antibody discovery tool but current methodology is often inefficient, and lead generation often requires the production and testing of numerous antibody candidates, and it is difficult to provide affinity information for their antibodies at the same time. Here, we introduce AAB-seq (antigen affinity-readable High-throughput BCR sequencing), an efficient antibody screening tool to identify antigen binding affinity of thousands of paired BCRs. It employs fluorophore and DNA barcode-labeled antigen and secondary antibody targeting Ig light chain to label B cells and uses high throughput single cell BCR sequencing and surface protein profiling to obtain the ratio of surface bound antigen to surface BCR in thousands of B-cells. Using AAB-seq, we accurately identified valuable candidate antibodies 1743-3 and 1743-13 from SARS-CoV-2 RBD immunized mouse, providing a basis for further development of SARS-CoV-2 antibody drugs. Thus, AAB-seq allows high throughput identification of antibody sequences paired with antigen affinity, which improves the screening efficiency of functional antibodies and provides an effective solution for the rapid discovery and development of new therapeutic monoclonal antibodies.
Complete genome sequences of two new strains of the shipworm endosymbiont,Teredinibacter turnerae
Authors: Gasser Mark T. , Flatau Ron , Altamia Marvin , Filone Claire Marie , Distel Dan 
Published: August 2024

AbstractWe present the complete genome sequences of two strains ofTeredinibacter turnerae, SR01903 and SR02026, shipworm endosymbionts isolated from the gills ofLyrodus pedicellatusandTeredo bartschi, respectively, and derived from Oxford Nanopore sequencing. These sequences will aid in the comparative genomics of shipworm endosymbionts and understanding of host-symbiont selection.
Identification of biomarkers for COVID-19 associated secondary hemophagocytic lymphohistiocytosis
Authors: Canny Susan P. , Stanaway Ian B. , Holton Sarah E. , Mitchem Mallorie , O’Rourke Allison R. , Pribitzer Stephan , Baxter Sarah K. , Wurfel Mark M. , Malhotra Uma , Buckner Jane H. , Bhatraju Pavan K. , Morrell Eric D. , Speake Cate , Mikacenic Carmen , Hamerman Jessica A. 
Published: August 2024

AbstractOBJECTIVESWe aimed to define and validate novel biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system.DESIGNIn two cohorts of adult patients presenting with COVID-19 in 2020 and 2021, clinical lab values and serum proteomics were assessed. Subjects identified as having sHLH were compared to those with COVID-19 without sHLH. Eight deceased patients defined as COVID-sHLH underwent genomic sequencing in order to identify variants in immune-related genes.SETTINGTwo tertiary care hospitals in Seattle, Washington (Virginia Mason Medical Center and Harborview Medical Center).PATIENTS186 patients with COVID-19INTERVENTIONSNoneMEASUREMENTS AND MAIN RESULTSNine percent of enrolled COVID-19 subjects met our defined criteria for sHLH. Using broad serum proteomic approaches (O-link and SomaScan), we identified three biomarkers for COVID-19 associated sHLH (soluble PD-L1, TNF-R1, and IL-18BP), supporting a role for proteins previously associated with other forms of sHLH (IL-18BP and sTNF-R1). We also identified novel biomarkers and pathways of COVID-sHLH, including sPD-L1 and the syntaxin pathway. We detected variants in several genes involved in immune responses in individuals with COVID-sHLH, including inDOCK8and inTMPRSS15, suggesting that genetic alterations in immune-related genes may contribute to hyperinflammation and fatal outcomes in COVID-19.CONCLUSIONSBiomarkers of COVID-19 associated sHLH, such as soluble PD-L1, and pathways, such as the syntaxin pathway, and variants in immune genes in these individuals, suggest critical roles for the immune response in driving sHLH in the context of COVID-19.Key PointsQUESTIONTo define biomarkers that could identify individuals with COVID-19 associated secondary hemophagocytic lymphohistiocytosis (sHLH) and to test whether fatalities due to COVID-19 in the presence of sHLH were associated with specific defects in the immune system.FINDINGSIn two independent cohorts using two different platforms, we identified sPD-L1, IL-18BP, and sTNF-R1 as COVID-sHLH biomarkers. We identified the syntaxin pathway as important in COVID-sHLH and variants in immune-related genes in a subset of deceased COVID-sHLH subjects.MEANINGImmune related proteins and pathways are dysregulated in COVID-sHLH.
Differential EBV protein-specific antibody response between responders and non-responders to EBVSTs immunotherapy
Authors: Sarathkumara Yomani D. , Van Bibber Nathan W. , Liu Zhiwei , Heslop Helen E. , Rouce Rayne H , Coghill Anna E. , Rooney Cliona M , Proietti Carla , Doolan Denise L. 
Published: August 2024

AbstractEpstein–Barr virus (EBV) is associated with a diverse range of lymphomas. EBV-specific T-cell (EBVST) immunotherapies have shown promise in safety and clinical effectiveness in treating EBV-associated lymphomas, but not all patients respond to treatment.To identify the set of EBV-directed antibody responses associated with clinical response in patients with EBV-associated lymphomas, we comprehensively characterized the immune response to the complete EBV proteome using a custom protein microarray in 56 EBV-associated lymphoma patients who were treated with EBVST infusions enrolled in Phase I clinical trials.Significant differences in antibody profiles between responders and non-responders emerged at 3 months post-EBVST infusion. Twenty-five IgG antibodies were present at significantly higher levels in non-responders compared to responders at 3 months post-EBVST infusion, and 10 of these IgG antibody associations remained after adjustment for sex, age, and cancer diagnosis type. Random forest prediction analysis further confirmed that these 10 antibodies were important for predicting clinical response. Differential IgG antibody responses were directed against LMP2A (four fragments), BGRF1/BDRF1 (two fragments), LMP1, BKRF2, BKRF4, and BALF5.Paired analyses using blood samples collected at both pre-infusion and 3 months post-EBVST infusion indicated an increase in the mean antibody level for six other anti-EBV antibodies (IgG: BGLF2, LF1, BGLF3; IgA: BGLF3, BALF2, BBLF2/3) in non-responders. Overall, our results indicate that EBV-directed antibodies can be biomarkers for predicting the clinical response of individuals with EBV-associated lymphomas treated with EBVST infusions.
Randomized Clinical Trial of ICECaP (Individualized Coordination and Empowerment for Care Partners of Persons with Dementia): Primary Mental Health and Burden Outcomes
Authors: Gallagher Virginia T. , Arp Anna , Thompson Ryan , Rossetti Agustina , Patrie James , Reilly Shannon E , Manning Carol A. 
Published: August 2024

AbstractEfficacy of the Individualized Coordination and Empowerment for Care Partners of Persons with Dementia (ICECaP), an intervention that involves one-on-one individualized support from a dementia care coordinator for a dementia care partner, compared to an active control group. At least once monthly contact is made from a dementia care coordinator to the dementia care partner by telephone, video conferencing, email, or in-person support at clinical visits for the person with dementia. In this pilot randomized unblinded control trial of ICECaP, n=61 (n=90 randomized) care partners completed 12-months of the ICECaP intervention and n=69 (n=92 randomized) care partners received routine clinical support (controls) in an outpatient memory care clinic at an academic medical center, from which the participants were recruited (ClinicalTrials.gov:NCT04495686, funded by Department of Defense and Virginia Department for Aging and Rehabilitative Services). Early termination endpoints (death and higher level of care) and trial drop out were comparable across groups. Primary efficacy outcomes were evaluated by comparing changes in care partner mental health, burden, and quality of life from baseline to 12-months between ICECaP and controls. Linear-mixed ANCOVA revealed no significant group differences in longitudinal changes on measures of caregiving burden, care partner depression, anxiety, quality of life, or reactions to the behavioral symptoms of the person with dementia. Hypothesized reasons for lack of initial efficacy on primary 12-month outcomes are discussed.
“Characteristics and Predictors of Pediatric and Adult Patients with Inherited Retinal Degenerations at Time of Presentation: Tertiary Care Ophthalmology Clinic Data”
Authors: McLaughlin Matthew T. , Ganansky Caleb P. , Taher Ayman W. , Trudrung Melissa A. , Van De Car William , Le Jonathan , Peterson Kyle D. , Stepien Kimberly E. , Schmitt Melanie A. 
Published: August 2024

AbstractInherited Retinal Degenerations (IRDs) are a group of diseases where genetic variants lead to retinal photoreceptor dysfunction and subsequent visual impairment. We aimed to compare the characteristics of pediatric versus adult IRD patients at the time of presentation at a tertiary care IRD clinic. A retrospective chart review of 538 patients with IRDs was conducted. Information obtained included age, diagnosis, presenting characteristics, demographics, distance from the clinic, and referring physician. This study found that high hyperopia, congenital syndactyly, high refractive error, high astigmatism, and a history of developmental delay were most predictive of pediatric presentation. In adults, we found reduced central vision, peripheral vision loss, color vision deficits, nyctalopia, flashes/floaters, cataracts, diabetes mellitus, obesity, cardiac conditions, and a family history of cataract were most predictive of presentation. There was a greater proportion of pediatric patients presenting from 20 or more miles away. Additionally, there was no significant difference between the type of healthcare provider referring adult or pediatric patients. This study identifies characteristics predictive of pediatric and adult presentation in IRD patients thus addressing current knowledge gaps. A better understanding of these characteristics may provide for quicker recognition, education of clinicians likely to encounter IRDs, and allow for earlier treatment.
Daxx mediated histone H3.3 deposition on HSV-1 DNA restricts genome decompaction and the progression of immediate-early transcription
Authors: Roberts Ashley P.E. , Orr Anne , Iliev Victor , Orr Lauren , McFarlane Steven , Yang Zhousiyu , Epifano Ilaria , Loney Colin , Collados Rodriguez Milagros , Cliffe Anna R. , Conn Kristen L. , Boutell Chris 
Published: August 2024

AbstractHerpesviruses are ubiquitous pathogens that cause a wide range of disease. Upon nuclear entry, their genomes associate with histones and chromatin modifying enzymes that regulate the progression of viral transcription and outcome of infection. While the composition and modification of viral chromatin has been extensively studied on bulk populations of infected cells by chromatin immunoprecipitation, this key regulatory process remains poorly defined at single-genome resolution. Here we use high-resolution quantitative imaging to investigate the spatial proximity of canonical and variant histones at individual Herpes Simplex Virus 1 (HSV-1) genomes within the first 90 minutes of infection. We identify significant population heterogeneity in the stable enrichment and spatial proximity of canonical histones (H2A, H2B, H3.1) at viral DNA (vDNA) relative to established promyelocytic leukaemia nuclear body (PML-NB) host factors that are actively recruited to viral genomes upon nuclear entry. We show the replication-independent histone H3.3/H4 chaperone Daxx to cooperate with PML to mediate the enrichment and spatial localization of variant histone H3.3 at vDNA that limits the rate of HSV-1 genome decompaction to restrict the progress of immediate-early (IE) transcription. This host response is counteracted by the viral ubiquitin ligase ICP0, which degrades PML to disperse Daxx and variant histone H3.3 from vDNA to stimulate the progression of viral genome expansion, IE transcription, and onset of HSV-1 replication. Our data support a model of intermediate and sequential histone assembly initiated by Daxx that limits the rate of HSV-1 genome decompaction independently of the stable enrichment of histones H2A and H2B at vDNA required to facilitate canonical nucleosome assembly. We identify HSV-1 genome decompaction upon nuclear infection to play a key role in the initiation and functional outcome of HSV-1 lytic infection, findings pertinent to the transcriptional regulation of many nuclear replicating herpesvirus pathogens.
Methanogenesis inhibition remodels microbial fermentation and stimulates acetogenesis in ruminants
Authors: Ni Gaofeng , Walker Nicola , Fischer André , Stemmler René T. , Schmidt Oliver , Jain Surbhi , Jespersen Marion , Grinter Rhys , Wang Min , Pope Phillip B. , Müller Volker , Watson Mick , Ver Loren van Themaat Emiel , Kindermann Maik , Greening Chris 
Published: August 2024

AbstractRumen microbiota enable ruminants to grow on fibrous plant materials but also produce methane, driving 5% of global greenhouse gas emissions and leading to a loss of gross energy content. Methanogenesis inhibitors such as 3-nitrooxypropanol (3-NOP) decrease methane emissions in ruminants when supplemented in feed. Yet we lack a system-wide, species-resolved understanding of how the rumen microbiota remodels following inhibition and how this influences animal production. Here, we conducted a large-scale trial with 51 dairy calves to analyse microbiota responses to 3-NOP, pairing host performance, emissions, and nutritional profiles with genome-resolved metagenomic and metatranscriptomic data. 3-NOP supplementation decreased methane emissions by an average of 62%, modulated short-chain fatty acid and H2levels, and did not affect dietary intake or animal performance. We created a rumen microbial genome catalogue with an unprecedented mapping rate. We observed a strong reduction of methanogens and stimulation of reductive acetogens, primarily novel uncultivated lineages such asCandidatusFaecousia. However, there was a shift in major fermentative communities away from acetate production in response to hydrogen gas accumulation. Thus, the divergent responses of the fermentative and hydrogenotrophic communities limit potential productivity gains from methane reduction. Reporting one of the largest reductions in methane emissions in a field trial to date, this study links ruminant greenhouse gas emissions and productivity to specific microbial species. These findings also emphasise the importance of microbiota-wide analysis for optimising methane mitigation strategies and identify promising strategies to simultaneously reduce emissions while increasing animal production.Significance StatementOne strategy to increase the sustainability and productivity of livestock production is to modulate ruminant microbiota to produce absorbable nutrients rather than the potent greenhouse gas methane. Previous studies show supplementing feed with methanogenesis inhibitors such as 3-nitrooxypropanol reduces methane emissions, but also leads to inconsistent productivity gains. Here we report a definitive field trial, combining animal data, meta-omics, and structural modelling, to resolve the key microbes and pathways controlling nutrient and methane production in ruminants. We show that shifts in composition and gene expression of hydrogen-cycling microbes reduce emissions but limit productivity gains. These findings offer insights at unprecedented resolution, while the data and analytical framework provide valuable resources to develop solutions to enhance livestock productivity and sustainability.
Working memory processing boosts the neural representation of long-term memories
Authors: Sabo Melinda , Klatt Laura-Isabelle , Schneider Daniel 
Published: August 2024

AbstractUnderstanding the interaction between short-term and long-term memory systems is essential for advancing our knowledge of human memory. This study investigates whether working memory processes, specifically attentional prioritization (Experiments 1 and 2) and testing (Experiment 2), can enhance the neural activity associated with recently encoded long- term memories. A total of 86 participants completed a novel three-phase memory task that integrated a traditional long-term memory learning task with a working memory paradigm. In the first phase, participants encoded object-location associations. During the second phase, these associations were reintroduced in a working memory task that manipulated attentional prioritization; participants were required to report the location of the cued object. In the final phase, participants recalled the locations associated with each object. By analyzing both behavioral performance and electroencephalogram (EEG) data collected during this retrieval phase, we found that attentional prioritization in working memory significantly improved long- term memory retrieval, a finding supported by corresponding neural evidence. Additionally, Experiment 2 demonstrated that both prioritization and testing in working memory jointly enhance the neural representation of long-term memories. These findings indicate that working memory processes can dynamically alter the neural patterns underlying long-term memory representations, revealing a more integrated role for working memory in long-term memory consolidation.
Predicting rifampicin resistance inM. tuberculosisusing machine learning informed by protein structural and chemical features
Authors: Lynch Charlotte I , Adlard Dylan , Fowler Philip W 
Published: August 2024

AbstractBackgroundRifampicin remains a key antibiotic in the treatment of tuberculosis. Despite advances in cataloguing resistance-associated variants (RAVs), novel and rare mutations in the relevent gene,rpoB, will be encountered in clinical samples, complicating the task of using genetics to predict whether a sample is resistant or not to rifampicin. We have trained a series of machine learning models with the aim of complementing genetics-based drug susceptibility testing.MethodsWe built a Test+Train dataset comprising 219 susceptible mutations and 46 RAVs. Features derived from the structure of the RNA polymerase or the change in chemistry introduced by the mutation were considered, however, only a few, notably the distance from the rifampicin binding site, were found to be predictive on their own. Due to the paucity of RAVs we used Monte Carlo cross-validation with 50 repeats to train four different machine learning models.ResultsAll four models behaved similarly with sensitivities and specificities in the range 0.84-0.88 and 0.94-0.97 although we preferred the ensemble of Decision Tree models as they are easy to inspect and understand. We showed that measuring distances from molecular dynamics simulations did not improve performance.ConclusionsIt is possible to predict whether a mutation inrpoBconfers resistance to rifampicin using a machine learning model trained on a combination of structural, chemical and evolutionary features, however performance is moderate and training is complicated by the lack of data.
New imaging tools reveal live cellular collagen secretion, fibril dynamics and network organisation
Authors: Kent Olivia , Casey Ellie R. , Brown Max , Bell Steven , Ehrman Matt , Flagler Mike , Määttä Arto , Benham Adam M. , Hawkins Timothy J. 
Published: August 2024

AbstractAlthough light microscopy has been used to examine the early trafficking of collagen within the cell, much of our understanding of the detailed organisation of cell deposited collagen is from static electron microscopy studies. To understand the dynamics of live cell collagen deposition and fibril organisation, we generated a bright photostable mNGCol1α2 fusion protein and employed a range of microscopy techniques to follow its intracellular transport and elucidate extracellular fibril formation. Our findings reveal the dynamics of fibril growth and the dynamic nature of collagen network interactions at the cellular level. Notably we observed molecular events that build network organisation, including fibril bundling, bifurcation, directionality along existing fibrils, and looping/intertwining behaviours. Strikingly, mNGCol1α2 fluorescence intensity maxima can mark a fibril before another growing collagen fibril intersects at this location. Our study shows that N-terminal protease site is not an absolute requirement for collagen fibril incorporation and is, to our knowledge, the first time that cell-directed collagen fibrillogenesis has been visualised at high resolution in real time. The approach paves the way for assessing the dynamic organisation and assembly of collagen into the extracellular matrix in skin models and other tissues during health, ageing and disease.