bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fecal biomarkers of environmental enteric dysfunction and the gut microbiota of rural Malawian children: an observational study
Authors: Chaima David , Pickering Harry , Hart John D. , Burr Sarah E. , Maleta Kenneth M. , Kalua Khumbo , Bailey Robin L. , Holland Martin J. 
Published: January 2021

SummaryEnvironmental enteric dysfunction (EED) is a subclinical condition of the gut characterized by changes in morphology and function with underlying chronic inflammatory responses. This study characterized composition and diversity of the gut microbiota in rural Malawian children with and without signs of EED. Fecal samples were collected from children aged 1-59 months. Neopterin, myeloperoxidase and alpha-1 antitrypsin concentrations were quantified by ELISA and combined to form a composite EED score using principal component analysis. DNA was extracted from fecal samples and V4-16S rRNA sequencing was used to characterize the gut microbiota. The concentrations of all three biomarkers decreased with increasing age, which is consistent with other studies of children living in similar low-income settings. Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria were the dominant phyla while Faecalibacterium and Bifidobacterium were the most prevalent genera. Increased alpha diversity was associated with a reduction in neopterin concentration. Microbiota composition was associated with the composite EED score. Increased abundance of Succinivibrio was associated with reduced composite EED scores.HighlightsIn Malawian children, fecal concentrations of myeloperoxidase, alpha-1 antitrypsin and neopterin decreased with ageA marginal negative association was found between alpha diversity of the gut microbiota and fecal neopterin concentrationA higher abundance of Succinivibrio was found in children with lower concentrations of biomarker of environmental enteric dysfunctionFatty acid biosynthesis, tetrapyrrole biosynthesis and pyrimidine nucleotide degradation pathways were associated with environmental enteric dysfunction biomarker score
Myocardial BDNF regulates cardiac bioenergetics through the transcription factor Yin Yang 1
Authors: Yang Xue , Zhang Manling , Xie Bingxian , Zimmerman Raymond , Wang Qin , Wei An-chi , Peng Zishan , Khalifa Moustafa , Reynolds Michael , Om Matthew , Zhu Guangshuo , Bedja Djahida , Jiang Hong , Jurczak Michael , Shiva Sruti , Scott Iain , O’Rourke Brian , Kass David A. , Paolocci Nazareno , Feng Ning 
Published: January 2021

AbstractCirculating Brain-derived Neurotrophic Factor (BDNF) is markedly decreased in heart failure patients. Both BDNF and its receptor, Tropomyosin Related Kinase Receptor (TrkB), are expressed in cardiomyocytes, however the role of myocardial BDNF signaling in cardiac pathophysiology is poorly understood. We found that cardiac-specific TrkB knockout (cTrkB KO) mice displayed a blunted adaptive cardiac response to exercise, with attenuated upregulation of transcription factor networks controlling mitochondrial biogenesis/metabolism, including Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). The cTrkB KO mice developed an exacerbated heart failure progression with transaortic constriction. The downregulation of PGC-1α in cTrkB KO mice exposed to exercise or TAC resulted in decreased cardiac energetics. We further unraveled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signaling pathway, the pleiotropic transcription factor Yin Yang 1 (YY1). Taken together, our findings suggest that myocardial BDNF plays a critical role in regulating cellular energetics in the cardiac stress response.
Shape analysis of gamma rhythm supports a superlinear inhibitory regime in an inhibition-stabilized network
Authors: Krishnakumaran R , Raees Mohammed , Ray Supratim 
Published: January 2021

AbstractVisual inspection of stimulus-induced gamma oscillations (30-70 Hz) often reveals a non-sinusoidal shape. Such distortions are a hallmark of non-linear systems and are also observed in mean-field models of gamma oscillations. A thorough characterization of the shape of the gamma cycle can therefore provide additional constraints on the operating regime of such models. However, the gamma waveform has not been quantitatively characterized, partially because the first harmonic of gamma, which arises because of the non-sinusoidal nature of the signal, is typically weak and gets masked due to a broadband increase in power related to spiking. To address this, we recorded local field potential (LFP) from the primary visual cortex (V1) of two awake female macaques while presenting full-field gratings or iso-luminant chromatic hues that produced huge gamma oscillations with prominent peaks at harmonic frequencies in the power spectra. We found that gamma and its first harmonic always maintained a specific phase relationship, resulting in a distinctive shape with a sharp trough and a shallow peak. Interestingly, a Wilson-Cowan (WC) model operating in an inhibition stabilized mode could replicate this shape, but only when the inhibitory population operated in the super-linear regime, as predicted recently. However, another recently developed model of gamma that operates in a linear regime driven by stochastic noise failed to produce salient harmonics or the observed shape. Our results impose additional constraints on models that generate gamma oscillations and their operating regimes.
Biochemical and Structural Characterization of Two Cif-Like Epoxide Hydrolases fromBurkholderia cenocepacia
Authors: Taher Noor M. , Hvorecny Kelli L. , Burke Cassandra M. , Gilman Morgan S.A. , Heussler Gary E. , Adolf-Bryfogle Jared , Bahl Christopher D. , O’Toole George A. , Madden Dean R. 
Published: January 2021

AbstractEpoxide hydrolases catalyze the conversion of epoxides to vicinal diols in a range of cellular processes such as signaling, detoxification, and virulence. These enzymes typically utilize a pair of tyrosine residues to orient the substrate epoxide ring in the active site and stabilize the hydrolysis intermediate. A new subclass of epoxide hydrolases that utilize a histidine in place of one of the tyrosines was established with the discovery of the CFTR Inhibitory Factor (Cif) fromPseudomonas aeruginosa. Although the presence of such Cif-like epoxide hydrolases was predicted in other opportunistic pathogens based on sequence analyses, only Cif and its homologue aCif fromAcinetobacter nosocomialishave been characterized. Here we report the biochemical and structural characteristics of Cfl1 and Cfl2, twoCif-like epoxide hydrolases fromBurkholderia cenocepacia. Cfl1 is able to hydrolyze xenobiotic as well as biological epoxides that might be encountered in the environment or during infection. In contrast, Cfl2 shows very low activity against a diverse set of epoxides. The crystal structures of the two proteins reveal quaternary structures that build on the well-known dimeric assembly of the α/β hydrolase domain, but broaden our understanding of the structural diversity encoded in novel oligomer interfaces. Analysis of the interfaces reveals both similarities and key differences in sequence conservation between the two assemblies, and between the canonical dimer and the novel oligomer interfaces of each assembly. Finally, we discuss the effects of these higher-order assemblies on the intra-monomer flexibility of Cfl1 and Cfl2 and their possible roles in regulating enzymatic activity.
Hyperoxia Inhibits the Growth of Mouse Forebrain Oligodendrocyte Progenitors
Authors: Moore Lisamarie , McLane Lauren E. , Wahl Stacey , Ornelas Isis M. , Wood Teresa L. , Canoll Peter , Levison Steven W. 
Published: January 2021

ABSTRACTNG2 chondroitin sulfate proteoglycan positive oligodendrocyte progenitor cells (OPCs) reside throughout the brain. They divide asymmetrically and differentiate into myelinating oligodendrocytes throughout adulthood. OPCs have been successfully isolated from rodents using several techniques including magnetic beads, immunopanning and exploiting differential centripetal adhesion. Whereas rat OPCs are relatively simple to propagatein vitro, it has been difficult to expand mouse OPCs. Therefore, we evaluated the effects of oxygen levels, growth factors and extracellular matrix components to produce a simple and reproducible method to prepare large numbers of nearly homogenous cultures of primary mouse OPCs from postnatal day 0-2 mouse telencephala. Using the McCarthy and de Vellis mechanical separation method OPCs were separated from mixed culture of glial cells. When the OPCs were plated onto fibronectin coated tissue culture plates in a biochemically defined medium that contained fibroblast growth factor-2 (FGF-2) and platelet derived growth factor AA (PDGFAA), and they were maintained in a standard tissue culture incubator, they proliferated very slowly. By contrast, mouse OPCs doubled approximately every 7 days when maintained in a 2% oxygen, nitrogen buffered environment. After 3 passages, greater than 99% of these OPCs were NG2+/PDGFRα+. In medium containing only FGF-2, mouse OPCs progressed to late stage OPCs whereupon A2B5 expression decreased and O4 expression increased. When these cells were differentiated between passages 1 and 3, the majority of the OPCs differentiated into MBP+ mature oligodendrocytes However, cells that were repeatedly passaged beyond 4 passages progressed to a late O4+ OPC (even with mitogens present) and when differentiated by mitogen removal a minority of the OPCs differentiated into MBP+ cells. These studies reveal significant differences between mouse and rat OPCs and an inhibitory role for oxygen in mouse OPC proliferation.
Targeted delivery of a phosphoinositide 3-kinase γ inhibitor to restore organ function in sepsis through dye-functionalized lipid nanocarriers
Authors: Press Adrian T. , Babic Petra , Hoffmann Bianca , Müller Tina , Foo Wanling , Hauswald Walter , Benecke Jovana , Beretta Martina , Cseresnyés Zoltán , Hoeppener Stephanie , Nischang Ivo , Coldewey Sina M. , Gräler Markus H. , Bauer Reinhard , Gonnert Falk , Gaßler Nikolaus , Wetzker Reinhard , Figge Marc Thilo , Schubert Ulrich S. , Bauer Michael 
Published: January 2021

AbstractJaundice, the clinical hallmark of infection-associated liver dysfunction, reflects altered membrane organization of the canalicular pole of hepatocytes and portends poor outcomes. Mice lacking phosphoinositide 3-kinase-γ (PI3Kγ) are protected against membrane disintegration and hepatic excretory dysfunction. However, they exhibit a severe immune defect that hinders neutrophil recruitment to sites of infection. To exploit the therapeutic potential of PI3Kγ inhibition in sepsis, a targeted approach to deliver drugs to hepatic parenchymal cells without compromising other cells, in particular immune cells, seems warranted. Here we demonstrate that nanocarriers functionalized through DY-635, a fluorescent polymethine dye and a ligand of organic anion transporters can selectively deliver therapeutics to hepatic parenchymal cells. Applying this strategy to a murine model of sepsis, we observed PI3Kγ-dependent restoration of biliary canalicular architecture, maintained excretory liver function, and improved survival without impairing host defense mechanisms. This strategy carries the potential to expand targeted nanomedicines to disease entities with systemic inflammation and concomitantly impaired barrier functionality.One-Sentence SummaryDye-functionalized liposomes allow delivery of a PI3Kγ inhibitor to hepatocytes to resolve sepsis-related liver failure without ‘off-target’ effects on immunity.Graphical AbstractTargeting PI3Kγ in hepatocytes by dye-functionalized liposomes to resolve sepsis-related liver failure without ‘off-target’ effects on immunity.
Molecular mechanism for kinesin-1 direct membrane recognition
Authors: Antón Zuriñe , Weijman Johannes F. , Williams Christopher , Moody Edmund R.R. , Mantell Judith , Yip Yan Y. , Cross Jessica A. , Williams Tom A. , Steiner Roberto A. , Crump Matthew , Woolfson Derek N. , Dodding Mark P. 
Published: January 2021

AbstractThe cargo-binding capabilities of cytoskeletal motor proteins have expanded during evolution through both gene duplication and alternative splicing. For the light chains of the kinesin-1 family of microtubule motors, this has resulted in an array of carboxy-terminal domain sequences of unknown molecular function. Here, combining phylogenetic analyses with biophysical, biochemical and cell biology approaches we identify a highly conserved membrane-induced curvature-sensitive amphipathic helix within this region of a newly defined subset of long kinesin light chain paralogues and splice isoforms. This helix mediates the direct binding of kinesin-1 to lipid membranes. Membrane binding requires specific anionic phospholipids and is important for kinesin-1 dependent lysosome positioning, a canonical activity that until now has been attributed exclusively the recognition of organelle-associated cargo adaptor proteins. This leads us to propose a new protein-lipid coincidence detection framework for kinesin-1 mediated organelle transport.
DevKidCC allows for robust classification and direct comparisons of kidney organoid datasets
Authors: Wilson Sean B. , Howden Sara E. , Vanslambrouck Jessica M. , Dorison Aude , Alquicira-Hernandez Jose , Powell Joseph E. , Little Melissa H. 
Published: January 2021

AbstractKidney organoids provide a valuable resource to understand kidney development and disease. Clustering algorithms and marker genes fail to accurately and robustly classify cellular identity between human pluripotent stem cell (hPSC)-derived organoid datasets. Here we present a new method able to accurately classify kidney cell subtypes, a hierarchical machine learning model trained using comprehensive reference data from single cell RNA-sequencing of human fetal kidney (HFK). We demonstrate the tool’s (DevKidCC) performance by application to all published kidney organoid datasets and a novel dataset.DevKidCCis available on Github and can be used on any kidney single cell RNA-sequence data.
Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection
Authors: Sohail Aaqib , Iqbal Azeem A. , Sahini Nishika , Tantawy Mohamed , Winterhoff Moritz , Ebensen Thomas , Geffers Robert , Schughart Klaus , Chen Fangfang , Preusse Matthias , Pils Marina C. , Guzman Carlos A. , Mostafa Ahmed , Pleschka Stephan , Falk Christine , Michelucci Alessandro , Pessler Frank 
Published: January 2021

AbstractItaconate has recently emerged as a metabolite with immunomodulatory properties. We evaluated effects of endogenous itaconate and exogenous itaconate, dimethyl-, and 4-octyl-itaconate on host responses to influenza A virus infection. Infection inducedACOD1(the enzyme catalyzing itaconate synthesis) mRNA in monocytes and macrophages, which correlated with viral replication and was abrogated by itaconate treatment. Pulmonary inflammation and weight loss were greater inAcod1-/-than wild-type mice, and ectopic synthesis of itaconate in human epithelial cells reduced infection-induced inflammation. The compounds induced different recruitment programs in infected human macrophages, and transcriptome profiling revealed that they reversed infection-triggered interferon responses and modulated inflammation in cell lines, PBMC, and lung tissue. Single-cell RNA sequencing of PBMC revealed that infection inducedACOD1exclusively in monocytes, whereas treatment silenced IFN-responses in monocytes, lymphocytes, and NK cells. Viral replication did not increase under treatment despite the dramatically repressed IFN responses, but 4-octyl itaconate inhibited viral transcription in PBMC. The results reveal dramatic reprogramming of host responses by itaconate and derivatives and their potential as adjunct treatments for hyperinflammation in viral infection.
Sex-specific differences in the function and differentiation of ABCs mark TLR7-driven immunopathogenesis
Authors: Ricker Edd , Manni Michela , Flores-Castro Danny , Jenkins Daniel , Gupta Sanjay , Rivera-Correa Juan , Meng Wenzhao , Rosenfeld Aaron M. , Pannellini Tania , Bachu Mahesh , Chinenov Yurii , Sculco Peter K. , Jessberger Rolf , Prak Eline T. Luning , Pernis Alessandra B. 
Published: January 2021

ABSTRACTSex differences characterize immune responses to viruses and autoimmune diseases like SLE. ABCs are an emerging population of CD11c+T-bet+B cells critical for antiviral responses and autoimmune disorders. DEF6 and SWAP70, are two homologous molecules whose combined absence in double-knock-out mice (DKOs) leads to a lupus syndrome in females marked by an accumulation of ABCs. Here we demonstrate that DKO ABCs exhibit sex-specific differences in their expansion, upregulation of an ISG signature, and further differentiation. BCR sequencing and fate mapping experiments reveal that DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+and CD11c-effector populations with pathogenic and proinflammatory potential.Tlr7duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function, and differentiation of ABCs contributing to the sex-bias that accompanies TLR7-driven immunopathogenesis.
The extinction and survival of sharks across the end-Cretaceous mass extinction
Authors: Bazzi Mohamad , Campione Nicolás E. , Ahlberg Per E. , Blom Henning , Kear Benjamin P. 
Published: January 2021

AbstractSharks (Selachimorpha) are iconic marine predators that have survived multiple mass extinctions over geologic time. Their fossil record is represented by an abundance of teeth, which traditionally formed the basis for reconstructing large-scale diversity changes among different selachimorph clades. By contrast, corresponding patterns in shark ecology, as measured through morphological disparity, have received comparatively limited analytical attention. Here, we use a geometric morphometric approach to comprehensively examine the dental morphology of multiple shark lineages traversing the catastrophic end-Cretaceous mass extinction — this event terminated the Mesozoic Era 66 million years ago. Our results show that selachimorphs maintained virtually static levels of dental disparity in most of their constituent clades during the Cretaceous/Paleogene transition. Nevertheless, selective extinctions did impact on apex predator lineages characterized by triangular blade-like teeth, and in particular, lamniforms including the dominant Cretaceous anacoracids. Other groups, such as, triakid carcharhiniforms, squalids, and hexanchids, were seemingly unaffected. Finally, while some lamniform lineages experienced morphological depletion, others underwent a post-extinction disparity increase, especially odontaspidids, which are typified by narrow-cusped teeth adapted for feeding on fishes. This disparity shift coincides with the early Paleogene radiation of teleosts, a possible prey source, as well as the geographic relocation of shark disparity ‘hotspots’, perhaps indicating a regionally disjunct pattern of extinction recovery. Ultimately, our study reveals a complex morphological response to the end-Cretaceous mass extinction event, the dynamics of which we are only just beginning to understand.
Multivariable Association Discovery in Population-scale Meta-omics Studies
Authors: Mallick Himel , Rahnavard Ali , McIver Lauren J. , Ma Siyuan , Zhang Yancong , Nguyen Long H. , Tickle Timothy L. , Weingart George , Ren Boyu , Schwager Emma H. , Chatterjee Suvo , Thompson Kelsey N. , Wilkinson Jeremy E. , Subramanian Ayshwarya , Lu Yiren , Waldron Levi , Paulson Joseph N. , Franzosa Eric A. , Bravo Hector Corrada , Huttenhower Curtis 
Published: January 2021

AbstractIt is challenging to associate features such as human health outcomes, diet, environmental conditions, or other metadata to microbial community measurements, due in part to their quantitative properties. Microbiome multi-omics are typically noisy, sparse (zero-inflated), high-dimensional, extremely non-normal, and often in the form of count or compositional measurements. Here we introduce an optimized combination of novel and established methodology to assess multivariable association of microbial community features with complex metadata in population-scale observational studies. Our approach, MaAsLin 2 (Microbiome Multivariable Associations with Linear Models), uses general linear models to accommodate a wide variety of modern epidemiological studies, including cross-sectional and longitudinal designs, as well as a variety of data types (e.g. counts and relative abundances) with or without covariates and repeated measurements. To construct this method, we conducted a large-scale evaluation of a broad range of scenarios under which straightforward identification of meta-omics associations can be challenging. These simulation studies reveal that MaAsLin 2’s linear model preserves statistical power in the presence of repeated measures and multiple covariates, while accounting for the nuances of meta-omics features and controlling false discovery. We also applied MaAsLin 2 to a microbial multi-omics dataset from the Integrative Human Microbiome (HMP2) project which, in addition to reproducing established results, revealed a unique, integrated landscape of inflammatory bowel disease (IBD) across multiple time points and omics profiles.
Modulations of local synchrony over time lead to resting-state functional connectivity in a parsimonious large-scale brain model
Authors: Portoles Oscar , Qin Yuzhen , Hadida Jonathan , Woolrich Mark , Cao Ming , van Vugt Marieke 
Published: January 2021

AbstractBiophysical models of large-scale brain activity are a fundamental tool for understanding the mechanisms underlying the patterns observed with neuroimaging. These models combine a macroscopic description of the within- and between-ensemble dynamics of neurons within a single architecture. A challenge for these models is accounting for modulations of within-ensemble synchrony over time. Such modulations in local synchrony are fundamental for modeling behavioral tasks and resting-state activity. Another challenge comes from the difficulty in parametrizing large scale brain models which hinders researching principles related with between-ensembles differences. Here we derive a parsimonious large scale brain model that can describe fluctuations of local synchrony. Crucially, we do not reduce within-ensemble dynamics to macroscopic variables first, instead we consider within and between-ensemble interactions similarly while preserving their physiological differences. The dynamics of within-ensemble synchrony can be tuned with a parameter which manipulates local connectivity strength. We simulated resting-state static and time-resolved functional connectivity of alpha band envelopes in models with identical and dissimilar local connectivities. We show that functional connectivity emerges when there are high fluctuations of local and global synchrony simultaneously (i.e. metastable dynamics). We also show that for most ensembles, leaning towards local asynchrony or synchrony correlates with the functional connectivity with other ensembles, with the exception of some regions belonging to the default-mode network.Author summaryHere we present and evaluate a parsimonious model of large-scale brain activity. The model represents the brain as a network-of-networks structure. The sub-networks describe the neural activity within a brain region, and the global network encodes interactions between brain regions. Unlike other models, it capture progressive changes of local synchrony and local dynamics can be tuned with one parameter. Therefore the model could be used not only to model resting-state, but also behavioural tasks. Furthermore, we describe a simple framework that can deal with the arduous task of identifying global and local parameters.