bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA methylation profiling of immune cells from tuberculosis-exposed individuals overlaps with BCG-induced epigenetic changes and correlates with the emergence of anti-mycobacterial ‘corralling cells’
Authors: Pehrson Isabelle , Braian Clara , Karlsson Lovisa , Idh Nina , Danielsson Eva Kristin , Andersson Blanka , Paues Jakob , Das Jyotirmoy , Lerm Maria 
Published: September 2021

AbstractThe mechanism of protection of the only approved tuberculosis (TB) vaccine, Bacillus Calmette Guérin (BCG) is poorly understood. In recent years, epigenetic modifications induced by BCG have been demonstrated to reflect a state of trained immunity. The concept of trained immunity is now explored as a potential prevention strategy for a variety of infections. Studies on human TB immunity are dominated by those using peripheral blood as surrogate markers for immunity. Here, we instead studied the lung compartment by obtaining induced sputum from subjects included in a TB contact tracing. CD3- and HLA-DR-positive cells were isolated from the collected sputum and DNA methylome analyses performed. Unsupervised cluster analysis revealed that DNA methylomes of cells from TB-exposed individuals and controls appeared as separate clusters, and the numerous genes that were differentially methylated were functionally connected. The enriched pathways were strongly correlated to previously reported epigenetic changes and trained immunity in immune cells exposed to the BCG vaccine in human and animal studies. We further demonstrated that similar pathways were epigenetically modified in human macrophages trained with BCG in vitro. Finally, we found evidence of an M. tuberculosis-triggered emergence of a non-macrophage cell population from BCG-trained macrophage cultures. These cells did not phagocytose M. tuberculosis, but ‘corralled’ the bacteria into focal points, resulting in limitation of bacterial growth. Altogether, our study demonstrates that similar epigenetic changes are induced by M. tuberculosis and BCG and suggests that the modifications promote transformation of macrophages (or an unknown progenitor) to establish a yet undescribed cellular defense mechanism which we term ‘corralling’, based on the metaphorical resemblance to sheepdog herding.
Investigating Presence of Ethnoracial Bias in Clinical Data using Machine Learning
Authors: Velichkovska Bojana , Gjoreski Hristijan , Denkovski Daniel , Kalendar Marija , Celi Leo Anthnoy , Osmani Venet 
Published: September 2021

AbstractAn important target for machine learning research is obtaining unbiased results, which require addressing bias that might be present in the data as well as the methodology. This is of utmost importance in medical applications of machine learning, where trained models should be unbiased so as to result in systems that are widely applicable, reliable and fair. Since bias can sometimes be introduced through the data itself, in this paper we investigate the presence of ethnoracial bias in patients’ clinical data. We focus primarily on vital signs and demographic information and classify patient ethnoraces in subsets of two from the three ethnoracial groups (African Americans, Caucasians, and Hispanics). Our results show that ethnorace can be identified in two out of three patients, setting the initial base for further investigation of the complex issue of ehtnoracial bias.
Severe COVID-19 is characterised by inflammation and immature myeloid cells early in disease progression
Authors: Townsend Liam , Dyer Adam H , Naughton Aifric , Imangaliyev Sultan , Dunne Jean , Kiersey Rachel , Holden Dean , Mooney Aoife , Leavy Deirdre , Ridge Katie , Sugrue Jamie , Aldoseri Mubarak , Kelliher Jo Hannah , Hennessy Martina , Byrne Declan , Browne Paul , Bacon Christopher L , Doyle Catriona , O’Riordan Ruth , McLaughlin Anne-Marie , Bannan Ciaran , Martin-Loeches Ignacio , White Arthur , McLoughlin Rachel M , Bergin Colm , Bourke Nollaig M , O’Farrelly Cliona , Conlon Niall , Ní Cheallaigh Clíona 
Published: September 2021

SummarySARS-CoV-2 infection causes a wide spectrum of disease severity. Immune changes associated with severe disease include pro-inflammatory cytokine production and expansion of immature myeloid populations. The relative importance of the immunological changes in driving progression to severe disease remain poorly understood.We aimed to identify and rank clinical and immunological features associated with progression to severe COVID-19. We sought to use tests available in an on-site diagnostic hospital laboratory to identify an immunological signature for severe disease development which could be detected prior to peak severity thereby allowing initiation of therapeutic interventions. We used univariate and multivariate analysis, including unbiased machine learning, to investigate the relationships between clinical and demographic characteristics, inflammatory markers, and leukocyte immunophenotypes with progression to severe disease in 108 patients and to rank these in importance. A combination of four features (elevated levels of interleukin-6 and C-reactive protein, coupled with reduced monocyte HLA-DR expression and reduced neutrophil CD10 expression), were strongly predictive of severe disease with an average prediction score of 0.925.HighlightsSevere COVID-19 can be predicted by a combination of emergency myelopoiesis (CD10-neutrophils and HLA DR-monocytes) and inflammation (raised IL-6 and CRP)These changes can be identified from tests carried out prior to peak illness severity in a diagnostic laboratoryThis predictive model was derived from a cohort of patients with a wide range of ages, frailty and COVID-19 severityGraphical Abstract
Consequences of coupled barriers to gene flow for the build-up of genomic differentiation
Authors: Kunerth Henry D. , Bogdanowicz Steven M. , Searle Jeremy B. , Harrison Richard G. , Coates Brad S. , Kozak Genevieve M. , Dopman Erik B. 
Published: September 2021

ABSTRACTTheory predicts that when different barriers to gene flow become coincident, their joint effects enhance reproductive isolation and genomic divergence beyond their individual effects, but empirical tests of this ‘coupling’ hypothesis are rare. Here, we analyze patterns of gene exchange among populations of European corn borer moths that vary in the number of acting barriers, allowing for comparisons of genomic variation when barrier traits or loci are in coincident or independent states. We find that divergence is mainly restricted to barrier loci when populations differ by a single barrier, whereas the coincidence of temporal and behavioral barriers is associated with divergence of two chromosomes harboring barrier loci. Furthermore, differentiation at temporal barrier loci increases in the presence of behavioral divergence and differentiation at behavioral barrier loci increases in the presence of temporal divergence. Our results demonstrate how the joint action of coincident barrier effects leads to levels of genomic differentiation that far exceed those of single barriers acting alone, consistent with theory arguing that coupling allows indirect selection to combine with direct selection and thereby lead to a stronger overall barrier to gene flow. Thus, the state of barriers – independent or coupled – strongly influences the accumulation of genomic differentiation.
Viral Phrenology
Authors: Wilson David , Roof Danielle 
Published: September 2021

AbstractWe introduce Viral Phrenology, a new scheme for understanding the genomic composition of spherical viruses base on the locations of their structural protrusions. We used icosahedral point arrays to classify 135 distinct viral capsids collected from over 600 capsids available in the VIPERdb. Using gauge points of point arrays, we found 149 unique structural protrusions. We then show how to use the locations of these protrusions to determine the genetic composition of the virus. We then show that ssDNA, dsDNA, dsRNA and ssRNA viruses use different arrangements for distributing their protrusions. We also found that Triangulation number is also partially dependent on the structural protrusions. This analysis begins to tie together Baltimore classification and Triangulation number using point arrays.
Multi-landmark alignment of genomic signals reveals conserved expression patterns across transcription start sites
Authors: Vilar Jose M. G. , Saiz Leonor 
Published: September 2021

AbstractThe prevalent one-dimensional alignment of genomic signals to a reference landmark is a cornerstone of current methods to study transcription and its DNA-dependent processes but it is prone to mask potential relations among multiple DNA elements. We developed a systematic approach to align genomic signals to multiple locations simultaneously by expanding the dimensionality of the genomic-coordinate space. We analyzed transcription in human and uncovered a complex dependence on the relative position of neighboring transcription start sites (TSSs) that is consistently conserved among cell types. The dependence ranges from enhancement to suppression of transcription depending on the relative distances to the TSSs, their intragenic position, and the transcriptional activity of the gene. Our results reveal a conserved hierarchy of alternative TSS usage within a previously unrecognized level of genomic organization and provide a general methodology to analyze complex functional relationships among multiple types of DNA elements.
ProtView: A versatile tool for in silico protease evaluation and selection in a proteomic and proteogenomic context
Authors: Puliasis Sophia S. , Lewandowska Dominika , Hemsley Piers , Zhang Runxuan 
Published: September 2021

ABSTRACTTools have been created to generate in silico proteome digests with different protease enzymes and provide useful information for selecting optimal digest schemes for specific needs. This can save on time and resources and generate insights on the observable proteome. However, there remains a need for a tool that evaluates digest schemes beyond protein and amino acid coverages in the proteomic domain. Here, we present ProtView, a versatile in-silico protease/protease combination and digest evaluation workflow that maps in silico digested peptides to both protein and genome references, so that the potential observable sections of the proteome, transcriptome and genome can be identified. This supports the identification and quantification of the proteomic evidence of transcriptional, co-transcriptional, post-transcriptional and translational regulations. Benchmarking against biological data comparing multiple proteases shows that ProtView can correctly estimate the relative performances among the digest schemes. ProtView provides this information in a way that is easy to interpret, allowing for digest schemes to be evaluated before carrying out an analysis, in a broader context to optimize proteomic and proteogenomic experiments. ProtView is available at https://github.com/SSPuliasis/ProtView.
Modelling rheumatoid arthritis: A hybrid modelling framework to describe pannus formation in a small joint
Authors: Macfarlane Fiona R , Chaplain Mark AJ , Eftimie Raluca 
Published: September 2021

AbstractRheumatoid arthritis (RA) is a chronic inflammatory disorder that causes pain, swelling and stiffness in the joints, and negatively impacts the life of affected patients. The disease does not have a cure yet, as there are still many aspects of this complex disorder that are not fully understood. While mathematical models can shed light on some of these aspects, to date there are few such models that can be used to better understand the disease. As a first step in the mechanistic understanding of RA, in this study we introduce a new hybrid mathematical modelling framework that describes pannus formation in a small proximal interphalangeal (PIP) joint. We perform numerical simulations with this new model, to investigate the impact of different levels of immune cells (macrophages and fibroblasts) on the degradation of bone and cartilage. Since many model parameters are unknown and cannot be estimated due to a lack of experiments, we also perform a sensitivity analysis of model outputs to various model parameters (single parameters or combinations of parameters). Finally, we discuss how our model could be applied to investigate current treatments for RA, for example, methotrexate, TNF-inhibitors or tocilizumab, which can impact different model parameters.
Schema Playground: A tool for authoring, extending, and using metadata schemas to improve FAIRness of biomedical data
Authors: Cano Marco , Tsueng Ginger , Zhou Xinghua , Hughes Laura D. , Mullen Julia L. , Xin Jiwen , Su Andrew I. , Wu Chunlei 
Published: September 2021

AbstractBackgroundBiomedical researchers are strongly encouraged to make their research outputs more Findable, Accessible, Interoperable, and Reusable (FAIR). While many biomedical research outputs are more readily accessible through open data efforts, finding relevant outputs remains a significant challenge. Schema.org is a metadata vocabulary standardization project that enables web content creators to make their content more FAIR. Leveraging schema.org could benefit biomedical research resource providers, but it can be challenging to apply schema.org standards to biomedical research outputs. We created an online browser-based tool that empowers researchers and repository developers to utilize schema.org or other biomedical schema projects.ResultsOur browser-based tool includes features which can help address many of the barriers towards schema.org-compliance such as: The ability to easily browse for relevant schema.org classes, the ability to extend and customize a class to be more suitable for biomedical research outputs, the ability to create data validation to ensure adherence of a research output to a customized class, and the ability to register a custom class to our schema registry enabling others to search and re-use it. We demonstrate the use of our tool with the creation of the Outbreak.info schema—a large multi-class schema for harmonizing various COVID-19 related resources.ConclusionsWe have created a browser-based tool to empower biomedical research resource providers to leverage schema.org classes to make their research outputs more FAIR.
How to Extend the Capabilities of a Commercial Two-Photon Microscope to Perform Super-Resolution Imaging, Wavelength Mixing and Label-Free Microscopy
Authors: Peres Chiara , Nardin Chiara , Yang Guang , Mammano Fabio 
Published: September 2021

AbstractMultimodal microscopy combines multiple non-linear techniques that take advantage of different optical processes to generate contrast and increase the amount of information that can be obtained from biological samples. However, the most advanced optical architectures are typically custom-made and require complex alignment procedures, as well as daily maintenance by properly trained personnel for optimal performance. Here, we describe a hybrid system we constructed to overcome these disadvantages by modifying a commercial upright microscope. We show that our multimodal imaging platform can be used to seamlessly perform two-photon STED, wavelength mixing and label-free microscopy in both ex vivo and in vivo samples. The system is highly stable and endowed with remote alignment hardware that ensures simplified operability for non-expert users. This optical architecture is an important step forward towards a wider practical applicability of non-linear optics to bioimaging.
Activation of the Zinc-sensing receptor GPR39 promotes T cell reconstitution after hematopoietic stem cell transplant
Authors: Iovino Lorenzo , Cooper Kirsten , deRoos Paul , Kinsella Sinéad , Evandy Cindy , Ugrai Tamas , Mazziotta Francesco , Ensbey Kathleen S , Granadier David , Hopwo Kayla , Smith Colton , Gagnon Alex , Galimberti Sara , Petrini Mario , Hill Geoffrey R. , Dudakov Jarrod A. 
Published: September 2021

ABSTRACTProlonged lymphopenia represents a major clinical problem after cytoreductive therapies such as chemotherapy and the conditioning required for hematopoietic stem cell transplant (HCT), contributing toward the risk of infections and malignant relapse. Restoration of T cell immunity is dependent on tissue regeneration in the thymus, the primary site of T cell development; although the capacity of the thymus to repair itself diminishes over lifespan. However, although boosting thymic function and T cell reconstitution is of considerable clinical importance, there are currently no approved therapies for treating lymphopenia. Here we found that Zinc (Zn), is critically important for both normal T cell development as well as repair after acute damage. Accumulated Zn in thymocytes during development was released into the extracellular milieu after HCT conditioning, where it triggered regeneration by stimulating endothelial cell-production of BMP4 via the cell surface receptor GPR39. Dietary supplementation of Zn was sufficient to promote thymic function in a mouse model of allogeneic HCT, including enhancing the number of recent thymic emigrants in circulation; although direct targeting of GPR39 with a small molecule agonist enhanced thymic function without the need for prior Zn accumulation in thymocytes. Together, these findings not only define an important pathway underlying tissue regeneration, but also offer an innovative preclinical approach to treat lymphopenia in HCT recipients.KEY POINTSThymocytes release zinc after HCT conditioning is sensed by GPR39 and promotes epithelial repairPharmacologic stimulation of GPR39 promotes T cell reconstitution after HCT
A MYB transcription factor, PlMYB308, plays an essential role in flower senescence of herbaceous peony
Authors: Ji Xiaotong , Xu Zhuangzhuang , Wang Meiling , Zhong Xuyang , Zeng Lingling , Sun Daoyang , Niu Lixin 
Published: September 2021

AbstractHerbaceous peony is an important cut-flower plant cultivated across the world, but its short vase life substantially restricts the economic value of this crop. It is well established that endogenous hormones regulate the senescing process, but the molecular mechanism of them in flower senescence is still unclear. Here, we isolated a MYB transcription factor gene PlMYB308 from herbaceous peony flowers. Transcript abundance of PlMYB308 was strongly up-regulated in senescing petals. Silencing of PlMYB308 resulted in delayed peony flower senescence, and dramatically increased gibberellin (GA) but reduced ethylene and abscisic acid (ABA) levels in petals. Ectopic overexpression of PlMYB308 in tobacco accelerated flower senescence, and reduced GA but increased ethylene and ABA accumulation. Correspondingly, biosynthetic genes of ethylene, ABA, and GA showed variable expression levels in petals after silencing or overexpression of PlMYB308. A dual-luciferase assay showed that PlMYB308 specifically bound to the PlACO1 promoter. High expression levels of PlMYB308 were accompanied by low petal anthocyanin accumulation in senescing petals. A further bimolecular fluorescence complementation assay revealed an interaction between PlMYB308 and PlbHLH33, which was supposed to inhibit the anthocyanin biosynthesis. Taken together, our results suggest that the PlMYB308-PlACO1 and PlMYB308-PlbHLH33 regulatory checkpoints perhaps positively and negatively operate the production of ethylene and anthocyanin, respectively, and thus contribute to the senescence with impaired pigmentation in herbaceous peony flowers.
Neurodevelopmental processes in the prefrontal cortex derailed by chronic HIV-1 viral protein exposure
Authors: McLaurin Kristen A. , Li Hailong , Booze Rosemarie M. , Mactutus Charles F. 
Published: September 2021

AbstractDue to the widespread access to, and implementation of, combination antiretroviral therapy, individuals perinatally infected with human immunodeficiency virus type 1 (HIV-1) are living into adolescence and adulthood. Perinatally infected adolescents living with HIV-1 (pALHIV) are plagued by progressive, chronic neurocognitive impairments; the pathophysiological mechanisms underlying these deficits, however, remains understudied. A longitudinal experimental design from postnatal day (PD) 30 to PD 180 was utilized to establish the development of pyramidal neurons, and associated dendritic spines, from layers II-III of the medial prefrontal cortex (mPFC). Three putative neuroinflammatory markers (i.e., IL-1β, IL-6, and TNF-α) were evaluated early in development (i.e., PD 30) as a potential mechanism underlying synaptic dysfunction in the mPFC. Constitutive expression of HIV-1 viral proteins induced prominent neurodevelopmental alterations, independent of biological sex, in pyramidal neurons from layers II-III of the mPFC. Specifically, HIV-1 transgenic rats exhibited prominent deficits in dendritic and synaptic pruning, a developmental decrease in synaptic connectivity, and an age-related decline in synaptic efficacy. Examination of dendritic spine morphology revealed an age-related population shift towards a more immature dendritic spine phenotype in HIV-1 transgenic animals. There was no compelling evidence for neuroinflammation in the mPFC during early development. Understanding the neural mechanisms underlying chronic neurocognitive impairments in pALHIV may afford a key target for innovative therapeutics and cure strategies; an urgent need given the growing population of pALHIV.
Contiguously-hydrophobic sequences are functionally significant throughout the human exome
Authors: Lohia Ruchi , Hansen Matthew E.B. , Brannigan Grace 
Published: September 2021

AbstractHydrophobic interactions have long been established as essential to stabilizing structured proteins as well as drivers of aggregation, but the impact of hydrophobicity on the functional significance of sequence variants has rarely been considered in a genome-wide context. Here we test the role of hydrophobicity on functional impact using a set of 70,000 disease and non-disease associated single nucleotide polymorphisms (SNPs), using enrichment of disease-association as an indicator of functionality. We find that functional impact is uncorrelated with hydrophobicity of the SNP itself, and only weakly correlated with the average local hydrophobicity, but is strongly correlated with both the size and minimum hydrophobicity of the contiguous hydrophobic domain that contains the SNP. Disease-association is found to vary by more than 6-fold as a function of contiguous hydrophobicity parameters, suggesting utility as a prior for identifying causal variation. We further find signatures of differential selective constraint on domain hydrophobicity, and that SNPs splitting a long hydrophobic region or joining two short regions of contiguous hydrophobicity are particularly likely to be disease-associated. Trends are preserved for both aggregating and non-aggregating proteins, indicating that the role of contiguous hydrophobicity extends well beyond aggregation risk.Statement of SignificanceProteins rely on the hydrophobic effect to maintain structure and interactions with the environment. Surprisingly, no signs that amino acid hydrophobicity influences natural selection have been detected using modern genetic data. This may be because analyses that treat each amino acid separately do not reveal significant results, which we confirm here. However, because the hydrophobic effect becomes more powerful as more hydrophobic molecules are introduced, we tested whether unbroken stretches of hydrophobic amino acids are under selection. Using genetic variant data from across the human genome, we found evidence that selection pressure increases continually with the length of the unbroken hydrophobic sequence. These results could lead to improvements in a wide range of genomic tools as well as insights into disease and protein evolutionary history.