bluuebunny/crossref_metadata_2025_split huggingface dataset:
NOP16 is a histone mimetic that regulates Histone H3K27 methylation and gene repression
Authors: Takashima Ken , Lee Dian-Jang , Trovero María Fernanda , Rothi M. Hafiz , Mistry Meeta , Zhang Ying , Li Zhouyihan , Davis Christopher P. , Li Zilan , Natale Julia , Schmid Ernst , Al Haddad Joseph , Hoffmann Gabriela Brunsting , Dietmann Sabine , Sui Shannan Ho , Oshiumi Hiroyuki , Lieberman Judy , Greer Eric Lieberman 
Published: June 2023

AbstractPost-translational modifications of histone tails alter chromatin accessibility to regulate gene expression. Some viruses exploit the importance of histone modifications by expressing histone mimetic proteins that contain histone-like sequences to sequester complexes that recognize modified histones. Here we identify an evolutionarily conserved and ubiquitously expressed, endogenous mammalian protein Nucleolar protein 16 (NOP16) that functions as a H3K27 mimic. NOP16 binds to EED in the H3K27 trimethylation PRC2 complex and to the H3K27 demethylase JMJD3. NOP16 knockout selectively globally increases H3K27me3, a heterochromatin mark, without altering methylation of H3K4, H3K9, or H3K36 or acetylation of H3K27. NOP16 is overexpressed and linked to poor prognosis in breast cancer. Depletion of NOP16 in breast cancer cell lines causes cell cycle arrest, decreases cell proliferation and selectively decreases expression of E2F target genes and of genes involved in cell cycle, growth and apoptosis. Conversely, ectopic NOP16 expression in triple negative breast cancer cell lines increases cell proliferation, cell migration and invasivityin vitroand tumor growthin vivo, while NOP16 knockout or knockdown has the opposite effect. Thus, NOP16 is a histone mimic that competes with Histone H3 for H3K27 methylation and demethylation. When it is overexpressed in cancer, it derepresses genes that promote cell cycle progression to augment breast cancer growth.
Processing and Storage Methods Affect Oral and Gut Microbiome Composition
Authors: Superdock Dorothy K. , Zhang Wei , Poole Angela C. 
Published: June 2023

ABSTRACTAcross microbiome studies, fecal and oral samples are stored and processed in different ways, which could affect the observed microbiome composition. Here, we compared treatment methods, which included both storage conditions and processing methods, applied to samples prior to DNA extraction to determine how each affects microbial community diversity as assessed by 16S rRNA gene sequencing. We collected dental swab, saliva, and fecal samples from 10 individuals, with three technical replicates per treatment method. We assessed four methods of processing fecal samples prior to DNA extraction. We also compared different fractions of frozen saliva and dental samples to fresh samples. We found that lyophilized fecal samples, fresh whole saliva samples, and the supernatant fraction of thawed dental samples retained the highest levels of alpha diversity in samples. The supernatant fraction of thawed saliva samples had the second highest alpha diversity compared to fresh. Then we investigated the differences in microbes between different treatments at the domain and phylum levels as well as identified the amplicon sequence variants (ASVs) that were significantly different between the methods producing the highest alpha diversity and the other treatment methods. Lyophilized fecal samples had a greater prevalence of Archaea as well as a greater ratio of Firmicutes to Bacteroidetes compared to the other treatment methods. Our results provide practical considerations, not only for selection of processing method, but also for comparing results across studies that use these methods. Our findings also indicate differences in treatment method could be a confounding factor influencing the presence, absence, or differential abundance of microbes reported in conflicting studies.
Agent Orange exposure and prostate cancer risk in the Million Veteran Program
Authors: Lui Asona J. , Pagadala Meghana S. , Zhong Allison Y. , Lynch Julie , Karunamuni Roshan , Lee Kyung Min , Plym Anna , Rose Brent S. , Carter Hannah , Kibel Adam S. , DuVall Scott L. , Gaziano J. Michael , Panizzon Matthew S. , Hauger Richard L. , Seibert Tyler M. 
Published: June 2023

AbstractPurposeExposure to Agent Orange, a known carcinogen, might increase risk of prostate cancer (PCa). We sought to investigate the association of Agent Orange exposure and PCa risk when accounting for race/ethnicity, family history, and genetic risk in a diverse population of US Vietnam War veterans.Methods & MaterialsThis study utilized the Million Veteran Program (MVP), a national, population-based cohort study of United States military veterans conducted 2011-2021 with 590,750 male participants available for analysis. Agent Orange exposure was obtained using records from the Department of Veterans Affairs (VA) using the US government definition of Agent Orange exposure: active service in Vietnam while Agent Orange was in use. Only veterans who were on active duty (anywhere in the world) during the Vietnam War were included in this analysis (211,180 participants). Genetic risk was assessed via a previously validated polygenic hazard score calculated from genotype data. Age at diagnosis of any PCa, diagnosis of metastatic PCa, and death from PCa were assessed via Cox proportional hazards models.ResultsExposure to Agent Orange was associated with increased PCa diagnosis (HR 1.04, 95% CI 1.01–1.06, p=0.003), primarily among Non-Hispanic White men (HR 1.09, 95% CI 1.06– 1.12, p<0.001). When accounting for race/ethnicity and family history, Agent Orange exposure remained an independent risk factor for PCa diagnosis (HR 1.06, 95% CI 1.04–1.09, p<0.05). Univariable associations of Agent Orange exposure with PCa metastasis (HR 1.08, 95% CI 0.99–1.17) and PCa death (HR 1.02, 95% CI 0.84–1.22) did not reach significance on multivariable analysis. Similar results were found when accounting for polygenic hazard score.ConclusionsAmong US Vietnam War veterans, Agent Orange exposure is an independent risk factor for PCa diagnosis, though associations with PCa metastasis or death are unclear when accounting for race/ethnicity, family history, and/or polygenic risk.
Reliable, standardized measurements for cell mechanical properties
Authors: Pérez-Domínguez Sandra , Kulkarni Shruti G. , Pabijan Joanna , Gnanachandran Kajangi , Holuigue Hatice , Eroles Mar , Lorenc Ewelina , Berardi Massimiliano , Antonovaite Nelda , Marini Maria Luisa , Alonso Javier Lopez , Redonto-Morata Lorena , Dupres Vincent , Janel Sebastien , Acharya Sovon , Otero Jorge , Navajas Daniel , Bielawski Kevin , Schillers Hermann , Lafont Frank , Rico Felix , Podestà Alessandro , Radmacher Manfred , Lekka Małgorzata 
Published: June 2023

AbstractAtomic force microscopy (AFM) has become indispensable for studying biological and medical samples. More than two decades of experiments have revealed that cancer cells are softer than healthy cells (for measured cells cultured on stiff substrates). The softness or, more precisely, the larger deformability of cancer cells, primarily independent of cancer types, could be used as a sensitive marker of pathological changes. The wide application of biomechanics in clinics would require designing instruments with specific calibration, data collection, and analysis procedures. For these reasons, such development is, at present, still very limited, hampering the clinical exploitation of mechanical measurements. Here, we propose a standardized operational protocol (SOP), developed within the EU ITN network Phys2BioMed, which allows the detection of the biomechanical properties of living cancer cells regardless of the nanoindentation instruments used (AFMs and other indenters) and the laboratory involved in the research. We standardized the cell cultures, AFM calibration, measurements, and data analysis. This effort resulted in a step-by-step SOP for cell cultures, instrument calibration, measurements, and data analysis, leading to the concordance of the results (Young’s modulus) measured among the six EU laboratories involved. Our results highlight the importance of the SOP in obtaining a reproducible mechanical characterization of cancer cells and paving the way toward exploiting biomechanics for diagnostic purposes in clinics.
Immunogenicity of COVID-19 vaccines and their effect on the HIV reservoir in older people with HIV
Authors: Matveev Vitaliy A. , Mihelic Erik Z. , Benko Erika , Budylowski Patrick , Grocott Sebastian , Lee Terry , Korosec Chapin S. , Colwill Karen , Stephenson Henry , Law Ryan , Ward Lesley A. , Sheikh-Mohamed Salma , Mailhot Geneviève , Delgado-Brand Melanie , Pasculescu Adrian , Wang Jenny H. , Qi Freda , Tursun Tulunay , Kardava Lela , Chau Serena , Samaan Philip , Imran Annam , Copertino Dennis C. , Chao Gary , Choi Yoojin , Reinhard Robert J. , Kaul Rupert , Heffernan Jane M. , Jones R. Brad , Chun Tae-Wook , Moir Susan , Singer Joel , Gommerman Jennifer , Gingras Anne-Claude , Kovacs Colin , Ostrowski Mario 
Published: June 2023

ABSTRACTOlder individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity of these vaccines and their effects on HIV reservoirs are not available. We followed 68 PWH aged 55 and older and 23 age-matched HIV-negative individuals for 48 weeks from the first vaccine dose, after the total of three doses. All PWH were on antiretroviral therapy (cART) and had different immune status, including immune responders (IR), immune non-responders (INR), and PWH with low-level viremia (LLV). We measured total and neutralizing Ab responses to SARS-CoV-2 spike and RBD in sera, total anti-spike Abs in saliva, frequency of anti-RBD/NTD B cells, changes in frequency of anti-spike, HIV gag/nef-specific T cells, and HIV reservoirs in peripheral CD4+T cells. The resulting datasets were used to create a mathematical model for within-host immunization. Various regimens of BNT162b2, mRNA-1273, and ChAdOx1 vaccines elicited equally strong anti-spike IgG responses in PWH and HIV-participants in serum and saliva at all timepoints. These responses had similar kinetics in both cohorts and peaked at 4 weeks post-booster (third dose), while half-lives of plasma IgG also dramatically increased post-booster in both groups. Salivary spike IgA responses were low, especially in INRs. PWH had diminished live virus neutralizing titers after two vaccine doses which were ‘rescued’ after a booster. Anti-spike T cell immunity was enhanced in IRs even in comparison to HIV-participants, suggesting Th1 imprinting from HIV, while in INRs it was the lowest. Increased frequency of viral ‘blips’ in PWH were seen post-vaccination, but vaccines did not affect the size of the intact HIV reservoir in CD4+T cells in most PWH, except in LLVs. Thus, older PWH require three doses of COVID-19 vaccine to maximize neutralizing responses against SARS-CoV-2, although vaccines may increase HIV reservoirs in PWH with persistent viremia.
Acute stress reshapes third-party punishment and help decisions: Behavioral evidence and neurocomputational mechanisms
Authors: Wang Huagen , Wu Xiaoyan , Xu Jiahua , Zhu Ruida , Zhang Sihui , Xu Zhenhua , Mai Xiaoqin , Liu Chao , Qin Shaozheng 
Published: June 2023

AbstractPeople tend to intervene in others’ injustices by either punishing the transgressor or helping the victim. Injustice events often occur under stressful circumstances. However, how acute stress affects a third party’s intervention in injustice events remains open. Here, we show a stress-induced shift in third parties’ willingness to engage in help instead of punishment by acting on emotional salience and central-executive and theory-of-mind networks. Acute stress decreased the third party’s willingness to punish the violator and the severity of the punishment and increased their willingness to help the victim. Computational modeling revealed a shift in intervention severity bias from punishment toward help under stress. This finding is consistent with the increased dorsolateral prefrontal engagement observed with higher amygdala activity and greater connectivity with the ventromedial prefrontal cortex. A brain connectivity theory-of-mind network predicted stress-induced severity bias in punishment. Our findings suggest a neurocomputational mechanism of how acute stress reshapes third parties’ decisions by reallocating neural resources in emotional, executive and mentalizing networks to inhibit punishment bias and decrease punishment severity.
A transcriptomics-based drug repositioning approach to identify drugs with similar activities for the treatment of muscle pathologies in spinal muscular atrophy (SMA) models
Authors: Hoolachan Joseph M , McCallion Eve , Sutton Emma R , Çetin Özge , Pacheco-Torres Paloma , Dimitriadi Maria , Okoh Magnus , Walter Lisa M , Claus Peter , Wood Matthew JA , Tonge Daniel P , Bowerman Melissa 
Published: June 2023

ABSTRACTSpinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by the reduction of survival of motor neuron (SMN) protein levels. Although three SMN-augmentation therapies are clinically approved that significantly slow down disease progression, they are unfortunately not cures. Thus, complementary SMN-independent therapies that can target key SMA pathologies and that can support the clinically approved SMN-dependent drugs are the forefront of therapeutic development. We have previously demonstrated that prednisolone, a synthetic glucocorticoid (GC) improved muscle health and survival in severeSmn-/-;SMN2and intermediateSmn2B/-SMA mice. However, long-term administration of prednisolone can promote myopathy. We thus wanted to identify genes and pathways targeted by prednisolone in skeletal muscle to discover clinically approved drugs that are predicted to emulate prednisolone’s activities. Using an RNA-sequencing, bioinformatics and drug repositioning pipeline on skeletal muscle from symptomatic prednisolone- treated and untreatedSmn-/-;SMN2SMA andSmn+/-;SMN2healthy mice, we identified molecular targets linked to prednisolone’s ameliorative effects and a list of 580 drug candidates with similar predicted activities. Two of these candidates, metformin and oxandrolone, were further investigated in SMA cellular and animal models, which highlighted that these compounds do not have the same ameliorative effects on SMA phenotypes as prednisolone; however, a number of other important drug targets remain. Overall, our work further supports the usefulness of prednisolone’s potential as a second-generation therapy for SMA, identifies a list of potential SMA drug treatments and highlights improvements for future transcriptomic-based drug repositioning studies in SMA.
Visual mental imagery in typical imagers and in aphantasia: A millimeter-scale 7-T fMRI study
Authors: Liu Jianghao , Zhan Minye , Hajhajate Dounia , Spagna Alfredo , Dehaene Stanislas , Cohen Laurent , Bartolomeo Paolo 
Published: June 2023

AbstractMost of us effortlessly describe visual objects, whether seen or remembered. Yet, around 4% of people report congenital aphantasia: they struggle to visualize objects despite being able to describe their visual appearance. What neural mechanisms create this disparity between subjective experience and objective performance? Aphantasia can provide novel insights into conscious processing and awareness. We used ultra-high field 7T fMRI to establish the neural circuits involved in visual mental imagery and perception, and to elucidate the neural mechanisms associated with the processing of internally generated visual information in the absence of imagery experience in congenital aphantasia. Ten typical imagers and 10 aphantasic individuals performed imagery and perceptual tasks in five domains: object shape, object color, written words, faces, and spatial relationships. In typical imagers, imagery tasks activated left-hemisphere frontoparietal areas, the relevant domain-preferring areas in the ventral temporal cortex partly overlapping with the perceptual domain-preferring areas, and a domain-general area in the left fusiform gyrus (the Fusiform Imagery Node). The results were valid for each individual participant. In aphantasic individuals, imagery activated similar visual areas, but there was reduced functional connectivity between the Fusiform Imagery Node and frontoparietal areas. Our results unveil the domain-general and domain-specific circuits of visual mental imagery, their functional disorganization in aphantasia, and support the general hypothesis that conscious visual experience - whether perceived or imagined - depends on the integrated activity of high-level visual cortex and frontoparietal networks.
Inclusion of glycopeptides in hydrogen/deuterium exchange mass spectrometry analysis of SARS-CoV-2 spike ectodomain provides in-creased sequence coverage
Authors: Haynes Christopher A. , Keppel Theodore R. , Mekonnen Betlehem , Osman Sarah H. , Zhou Yu , Woolfitt Adrian R. , Baudys Jakub , Barr John R. , Wang Dongxia 
Published: June 2023

Hydrogen/deuterium exchange mass spectrometry (HDX-MS) can provide precise analysis of a protein’s conformational dynamics across varied states, such as heat-denatured vs. native protein structures, localizing regions that are specifically affected by such conditional changes. Maximizing protein sequence coverage provides high confidence that regions of interest were located by HDX-MS, but one challenge for complete sequence coverage is N-glycosylation sites. The deuteration of glycopeptides has not always been identified in previous reports of HDX-MS analyses, causing significant sequence coverage gaps in heavily glycosylated proteins and uncertainty in structural dynamics in many regions throughout a glycoprotein. We report HDX-MS analysis of the SARS-CoV-2 spike protein ectodomain in its trimeric pre-fusion form, which has 22 predicted N-glycosylation sites per monomer, with and without heat treatment. We identified glycopeptides and calculated their isotopic mass shifts from deuteration. Inclusion of the deu-terated glycopeptides increased sequence coverage of spike ectodomain from 76% to 84%, demonstrated that glycopeptides had been deuterated, and improved confidence in results localizing structural re-arrangements. Inclusion of deuterated glycopeptides improves the analysis of the conformational dynamics of glycoproteins such as viral surface antigens and cellular receptors.Abstract Figure
Mapping neurodevelopmental diversity in executive function
Authors: Mareva Silvana ,   The CALM Team, Holmes Joni 
Published: June 2023

AbstractExecutive functions can be conceptualised as either a set of higher-order cognitive skills that enable us to engage in flexible thinking and regulate our thoughts and behaviours, or as the ability to integrate knowledge, beliefs, and values when applying cognitive control in everyday situations. These two perspectives map onto the ways in which executive function is measured in childhood – using either structured laboratory tasks or ratings of everyday behaviours. Differences in executive functioning are associated with neurodevelopmental differences, but evidence for associations between specific profiles of executive function and specific neurodevelopmental conditions is mixed. In this study, we adopt a data-driven approach to identify common profiles of executive function in a transdiagnostic sample of 566 neurodivergent children, using both performance and rating-based measures of executive function. Three profiles of executive function were identified: one had consistent difficulties across both types of assessments, while the other two had inconsistent profiles of predominantly rating- or predominantly task-based difficulties. Children with these different profiles had differences in academic achievement and mental health outcomes and could further be differentiated from a comparison group of neurotypical children on both shared and profile-unique patterns of neural white matter organisation. Importantly, children’s executive function profiles were not directly related to diagnostic categories or to dimensions of neurodiversity associated with specific diagnoses (e.g., hyperactivity, inattention, social communication). These findings support the idea that there are separate domains of executive function and that the two types of assessment tapping these functions are dissociable and provide non-redundant information related to neurodevelopmental differences. These findings advance our understanding of executive function profiles in neurodivergent populations and their relationship to behavioural outcomes and neural variation.
Deep Learning in Automating Breast Cancer Diagnosis from Microscopy Images
Authors: Gu Qiangqiang , Prodduturi Naresh , Hart Steven N. 
Published: June 2023

AbstractContextBreast cancer is one of the most common cancers in women. With early diagnosis, some breast cancers are highly curable. However, the concordance rate of breast cancer diagnosis from histology slides by pathologists is unacceptably low. Classifying normal versus tumor breast tissues from microscopy images of breast histology is an ideal case to use for deep learning and could help to more reproducibly diagnose breast cancer. Since data preprocessing and hyperparameter configurations have impacts on breast cancer classification accuracies of deep learning models, training a deep learning classifier with appropriate data preprocessing approaches and optimized hyperparameter configurations could improve breast cancer classification accuracy.Methods and MaterialUsing 12 combinations of deep learning model architectures (i.e., including 5 non-specialized and 7 digital pathology-specialized model architectures), image data preprocessing, and hyperparameter configurations, the validation accuracy of tumor versus normal classification were calculated using theBreAstCancerHistology (BACH) dataset.ResultsThe DenseNet201, a non-specialized model architecture, with transfer learning approach achieved 98.61% validation accuracy compared to only 64.00% for the digital pathology-specialized model architecture.ConclusionsThe combination of image data preprocessing approaches and hyperparameter configurations have a profound impact on the performance of deep neural networks for image classification. To identify a well-performing deep neural network to classify tumor versus normal breast histology, researchers should not only focus on developing new models specifically for digital pathology, since hyperparameter tuning for existing deep neural networks in the computer vision field could also achieve a high (often better) prediction accuracy.