bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-alcoholic steatohepatitis patients exhibit reduced CD47, and increased sphingosine, cholesterol and MCP1 levels in the erythrocyte membranes
Authors: Papadopoulos Charalampos , Spourita Eleftheria , Mimidis Konstantinos , Kolios George , Tentes Ioannis , Anagnostopoulos Konstantinos 
Published: January 2022

ABSTRACTNon-alcoholic steatohepatitis (NASH) constitutes a significant cause of deaths, liver transplantations and economic costs worldwide. Despite extended research, investigations on the role of erythrocytes are scarce. Red blood cells from experimental animals and human patients with NASH, present phosphatidylserine exposure which is then recognized by Kupffer cells. This event leads to erythrophagocytosis, and amplification of inflammation through iron disposition. In addition, it has been shown that erythrocytes from NASH patients release the chemokine MCP1, leading to increased TNF-α release from macrophages RAW 264.7. However, erythrophagocytosis can also be caused by reduced CD47 levels. In addition, increased MCP1 release could be either signal-induced, or caused by higher MCP1 levels on the erythrocyte membrane. Finally, erythrocyte efferocytosis could provide additional inflammatory metabolites. In this study, we measured the erythrocyte membrane levels of CD47 and MCP1 by ELISA, and cholesterol and sphingosine with thin-layer chromatography. 18 patients (8 men, 10 women aged 56.7±11.5 years) and 14 healthy controls (7 men, 7 women aged 39.3±15.5 years) participated in our study. The erythrocyte CD47 levels were decreased in the erythrocyte membranes of NASH patients (844±409 pg/ml) compared to healthy controls (2969±1936 pg/ml) with P(Healthy>NAFLD)=99.1%, while the levels of MCP1 were increased in NASH patients (389±255 pg/ml), compared to healthy controls (230±117 pg/ml) with P(Healthy<NAFLD)=88.9%. Moreover, in erythrocyte membranes there was a statistically significant accumulation of sphingosine and cholesterol in NASH patients, compared to healthy controls. Our results imply that erythrocytes release chemotactic “find me” signals (MCP1), while containing reduced “do not eat me” signals (CD47). These molecules can lead to erythrophagocytosis. Next, increased “goodbye” signals (sphingosine and cholesterol) could augment inflammation by metabolic reprogramming.
Development of a clinical model to predict vagus nerve stimulation response in pediatric patients with drug-resistant epilepsy
Authors: Muthiah Nallammai , Mallela Arka N. , Vodovotz Lena , Sharma Nikhil , Akwayena Emefa , Welch William , Ibrahim George M. , Abel Taylor J. 
Published: January 2022

AbstractIntroductionEpilepsy impacts 470,000 children in the United States, and children with epilepsy are estimated to expend 6 times more on healthcare than those without epilepsy. For patients with antiseizure medication (ASM)-resistant epilepsy and unresectable seizure foci, vagus nerve stimulation (VNS) is a treatment option. Predicting response to VNS has been historically challenging. We aimed to create a clinical prediction score which could be utilized in a routine outpatient clinical setting.MethodsWe performed an 11-year, single-center retrospective analysis of patients <21 years old with ASM-resistant epilepsy who underwent VNS. The primary outcome was ≥50% seizure frequency reduction after one year. Univariate and multivariate logistic regressions were performed to assess clinical factors associated with VNS response; 70% and 30% of the sample were used to train and validate the multivariate model, respectively. A prediction score was developed based on the multivariate regression. Sensitivity, specificity, and area under the receiver operating curve (AUC) were calculated.ResultsThis analysis included 365 patients. Multivariate logistic regression revealed that variables associated with VNS response were: <4 years of epilepsy duration before VNS (p=0.008) and focal motor seizures (p=0.037). The variables included in the clinical prediction score were: epilepsy duration before VNS, age at seizure onset, number of pre-VNS ASMs, if VNS was the patient’s first therapeutic epilepsy surgery, and predominant seizure semiology. The final AUC was 0.7013 for the “fitted” sample and 0.6159 for the “validation” sample.ConclusionsWe developed a clinical model to predict VNS response in one of the largest samples of pediatric VNS patients to date. While the presented clinical prediction model demonstrated an acceptable AUC in the training cohort, clinical variables alone likely do not accurately predict VNS response. This score may be useful upon further validation, though its predictive ability underscores the need for more robust biomarkers of treatment response.
Cell lineage specification during development of the anterior lateral plate mesoderm and forelimb field
Authors: Newton Axel H , Williams Sarah M , Major Andrew T , Smith Craig A 
Published: January 2022

AbstractThe lateral plate mesoderm (LPM) is a transient embryonic tissue that gives rise to a diverse range of mature cell types, including the cardiovascular system, the urogenital system, endoskeleton of the limbs, and mesenchyme of the gut. While the genetic processes that drive development of these tissues are well defined, the early cell fate choices underlying LPM development and specification are poorly understood. In this study, we utilize single-cell transcriptomics to define cell lineage specification during development of the anterior LPM and the forelimb field in the chicken embryo. We identify the molecular pathways directing differentiation of the aLPM towards a somatic or splanchnic cell fate, and subsequent emergence of the forelimb mesenchyme. We establish the first transcriptional atlas of progenitor, transitional and mature cell types throughout the early forelimb field and uncover the global signalling pathways which are active during LPM differentiation and forelimb initiation. Specification of the somatic and splanchnic LPM from undifferentiated mesoderm utilizes distinct signalling pathways and involves shared repression of early mesodermal markers, followed by activation of lineage-specific gene modules. We identify rapid activation of the transcription factor TWIST1 in the somatic LPM preceding activation of known limb initiation genes, such as TBX5, which plays a likely role in epithelial-to-mesenchyme transition of the limb bud mesenchyme. Furthermore, development of the somatic LPM and limb is dependent on ectodermal BMP signalling, where BMP antagonism reduces expression of key somatic LPM and limb genes to inhibit formation of the limb bud mesenchyme. Together, these findings provide new insights into molecular mechanisms that drive fate cell choices during specification of the aLPM and forelimb initiation.
Functional resilience of mutually repressing motifs embedded in larger networks
Authors: Harlapur Pradyumna , Duddu Atchuta Srinivas , Hari Kishore , Jolly Mohit Kumar 
Published: January 2022

AbstractElucidating the design principles of regulatory networks driving cellular decision-making has important implications in understanding cell differentiation and guiding the design of synthetic circuits. Mutually repressing feedback loops between ‘master regulators’ of cell-fates can exhibit multistable dynamics, thus enabling multiple “single-positive” phenotypes: (high A, low B) and (low A, high B) for a toggle switch, and (high A, low B, low C), (low A, high B, low C) and (low A, low B, high C) for a toggle triad. However, the dynamics of these two network motifs has been interrogated in isolation in silico, but in vitro and in vivo, they often operate while embedded in larger regulatory networks. Here, we embed these network motifs in complex larger networks of varying sizes and connectivity and identify conditions under which these motifs maintain their canonical dynamical behavior, thus identifying hallmarks of their functional resilience. We show that an increased number of incoming edges onto a motif leads to a decay in their canonical stand-alone behaviors, as measured by multiple metrics based on pairwise correlation among nodes, bimodality of individual nodes, and the fraction of “single-positive” states. We also show that this decay can be exacerbated by adding self-inhibition, but not self-activation, loops on the ‘master regulators’. These observations offer insights into the design principles of biological networks containing these motifs, and can help devise optimal strategies for integration of these motifs into larger synthetic networks.
A preliminary description of the ecological characteristics of wild waterbird Japanese encephalitis virus hosts in high risk landscapes in India
Authors: Walsh Michael G. , Pattanaik Amrita , Vyas Navya , Saxena Deepak , Webb Cameron , Sawleshwarkar Shailendra , Mukhopadhyay Chiranjay 
Published: January 2022

AbstractWild reservoirs of Japanese encephalitis virus are under-studied globally, which presents critical knowledge gaps for JEV infection ecology despite decades of received wisdom regarding this high-impact mosquito-borne virus. As a result, ardeid birds, generally understood to be the primary reservoirs for JEV, as well as other waterbirds occupying landscapes at high risk for spillover to humans, are frequently ignored by current surveillance mechanisms and infrastructure. This is particularly true in India, which experiences a high annual burden of human outbreaks. Incorporating wild reservoirs into surveillance of human and livestock populations is therefore essential but will first require a data-driven approach to target individual host species. The current study sought to define a preliminary ecological profile of JEV hosts based on 1) species ecological traits, and 2) species presence and abundance adjusted for the biotic constraints of sympatry. Optimal host species tended to be generalists and demonstrate regionally-increasing populations. While ardeid bird species richness, abundance, and relative abundance did demonstrate the strongest and most consistent associations with the distribution of human JEV outbreaks, this study also identified several individual species among two other bird families in these landscapes, the Anatidae and the Rallidae, which also exhibited an optimal host profile and were strongly associated with the distribution of outbreaks. The findings from this work provide the first data-driven evidence base to inform wildlife sampling for the monitoring of JEV circulation in outbreak hotspots in India and thus identify good preliminary targets for the development of One Health wildlife JEV surveillance.
Fiber-parenchyma trade-off underlies changes in tropical forest structure and xylem architecture across a soil water gradient
Authors: Lourenço Jehová , Bittencourt Paulo Roberto de Lima , Enquist Brian J. , Milanez Camilla Rozindo Dias , Arx Georg von , Morino Kiyomi , Thomaz Luciana Dias , Rowland Lucy 
Published: January 2022

AbstractWood anatomical traits can underpin tropical forest structural and functional changes across soil water gradients and therefore could improve our mechanistic understanding of how plants adapt to environmental change.We assessed how the variation in the forest maximum height (Hmax), stem diameter, and wood density (WD) is associated with variation in xylem traits (area of fibers and parenchyma, conductive area [CondA, sum of all vessels lumens], vessel lumen area [VLA], vessel density [VD], and vessel wall reinforcement [VWR]) across 42 plots of a Brazilian Atlantic Forest habitat that span strong soil water gradients.We found that in wetter communities, greater height and lower WD were associated with greater parenchyma area (capacitance), and lower fibers, VD, VWR. Contrastingly, in drier communities, lower height was associated with higher fiber area (xylem reinforcement), WD, VD, and VWR, while parenchyma area and vessels are reduced.Tree communities vary from conservative resource-use and structurally dependent hydraulic safety (Fibers) to acquisitive resource-use and capacitance dependent hydraulic safety (parenchyma). Such a fiber-parenchyma trade-off (FPT) underlies the variation in tree height across a soil water gradient. Wood anatomy is fundamental to understanding and predicting the impacts of environmental change on forest structure.
Forebrain glucocorticoid receptor overexpression alters behavioral encoding of hippocampal CA1 pyramidal cells in mice
Authors: Gavade Swapnil , Wei Qiang , Johnston Colin , Kounelis Savannah , Laborc Klaudia , Akil Huda , Spencer-Segal Joanna L. 
Published: January 2022

AbstractStress hormone signaling via the glucocorticoid receptor (GR) modulates vulnerability to stress-related disorders, but whether GR influences how the brain encodes contextual experience is unknown. Mice with lifelong GR overexpression in forebrain glutamatergic neurons (GRov) show increased sensitivity to environmental stimuli. This phenotype is developmentally programmed and associated with profound changes in hippocampal gene expression. We hypothesized that GR overexpression influences hippocampal encoding of experiences. To test our hypothesis, we performed in vivo microendoscopic calcium imaging of 1359 dorsal CA1 pyramidal cells in freely behaving male and female WT and GRov mice during exploration of a novel open field. We compared calcium amplitude and event rate as well as sensitivity to center location and mobility between genotypes. GRov neurons exhibited higher average calcium activity than WT neurons in the novel open field. While most neurons showed sensitivity to center location and/or mobility, GRov neurons were more likely to be sensitive to center location and less likely to be sensitive to mobility, as compared to WT neurons. More than one-third of behavior-selective GRov neurons were uniquely sensitive to location without mobility sensitivity; these uniquely center-sensitive neurons were rare in WT. We conclude that dorsal CA1 pyramidal cells in GRov mice show increased activity in a novel environment and preferentially encode emotionally salient behavior. This heightened sensitivity to a novel environment and preferential encoding of emotionally salient elements of experience could underlie differential stress vulnerability in humans with increased glucocorticoid sensitivity.Significance Statement (120 words maximum)Endogenous stress hormones, glucocorticoids, are known to alter vulnerability to stress-related disorders. Here, we find that increased sensitivity to glucocorticoid via lifelong overexpression of glucocorticoid receptor in forebrain neurons (GRov) alters the encoding of environmental experiences in the hippocampus. GRov mice showed increased activity of dorsal CA1 hippocampal pyramidal cells during exploration of a novel environment and more sensitivity to emotionally relevant behaviors. These changes in how hippocampal neurons encode environmental experiences could underlie the differences in stress vulnerability in humans with genetic and epigenetic differences in glucocorticoid receptor signaling.
BitterMatch: Recommendation systems for matching molecules with bitter taste receptors
Authors: Margulis Eitan , Slavutsky Yuli , Lang Tatjana , Behrens Maik , Benjamini Yuval , Niv Masha Y. 
Published: January 2022

AbstractBitterness is an aversive cue elicited by thousands of chemically diverse compounds. Bitter taste may prevent consumption of foods and jeopardize drug compliance. The G protein-coupled receptors for bitter taste, TAS2Rs, have species-dependent number of subtypes and varying expression levels in extraoral tissues. Molecular recognition by TAS2R subtypes is physiologically important, and presents a challenging case study for ligand-receptor matchmaking. Inspired by hybrid recommendation systems, we developed a new set of similarity features, and created the BitterMatch algorithm that predicts associations of ligands to receptors with ~80% precision at ~50% recall. Associations for several compounds were tested in-vitro, resulting in 80% precision and 42% recall. The encouraging performance was achieved by including receptor properties and integrating experimentally determined ligand-receptor associations with chemical ligand-to-ligand similarities. BitterMatch can predict off-targets for bitter drugs, identify novel ligands and guide flavor design. Inclusion of neighbor-informed similarities improves as experimental data mounts, and provides a generalizable framework for molecule-biotarget matching.
Critical assessment of pan-genomics of metagenome-assembled genomes
Authors: Li Tang , Yin Yanbin 
Published: January 2022

AbstractBackgroundLarge scale metagenome assembly and binning to generate metagenome-assembled genomes (MAGs) has become possible in the past five years. As a result, millions of MAGs have been produced and increasingly included in pan-genomics workflow. However, pan-genome analyses of MAGs may suffer from the known issues with MAGs: fragmentation, incompleteness, and contamination, due to mis-assembly and mis-binning. Here, we conducted a critical assessment of including MAGs in pan-genome analysis, by comparing pan-genome analysis results of complete bacterial genomes and simulated MAGs.ResultsWe found that incompleteness led to more significant core gene loss than fragmentation. Contamination had little effect on core genome size but had major influence on accessory genomes. The core gene loss remained when using different pan-genome analysis tools and when using a mixture of MAGs and complete genomes. Importantly, the core gene loss was partially alleviated by lowering the core gene threshold and using gene prediction algorithms that consider fragmented genes, but to a less degree when incompleteness was higher than 5%. The core gene loss also led to incorrect pan-genome functional predictions and inaccurate phylogenetic trees.ConclusionsWe conclude that lowering core gene threshold and predicting genes in metagenome mode (as Anvi’o does with Prodigal) are necessary in pan-genome analysis of MAGs to alleviate the accuracy loss. Better quality control of MAGs and development of new pan-genome analysis tools specifically designed for MAGs are needed in future studies.
Bicarbonate Activation of Monomeric Photosystem II-PsbS/Psb27 Complex
Authors: Fantuzzi Andrea , Haniewicz Patrycja , Farci Domenica , Loi M. Cecilia , Park Keunha , Büchel Claudia , Bochtler Matthias , Rutherford A. William , Piano Dario 
Published: January 2022

AbstractIn thylakoid membranes, Photosystem II monomers from the stromal lamellae contain the subunits PsbS and Psb27 (PSIIm-S/27), while Photosystem II monomers from granal regions (PSIIm) lack these subunits. Here, we have isolated and characterised these two types of Photosystem II complexes. The PSIIm-S/27 showed enhanced fluorescence, the near-absence of oxygen evolution, as well as limited and slow electron transfer from QA to QB compared to the near-normal activities in the granal PSIIm. However, when bicarbonate was added to the PSIIm-S/27, water splitting and QA to QB electron transfer rates were comparable to those in granal PSIIm. The findings suggest that the binding of PsbS and/or Psb27 inhibits forward electron transfer and lowers the binding affinity for the bicarbonate. This can be rationalized in terms of the recently discovered photoprotection role played by bicarbonate binding via the redox tuning of the QA/QA•− couple, which controls the charge recombination route, and this limits chlorophyll triplet mediated 1O2 formation (Brinkert K et al. (2016) Proc Natl Acad Sci U S A. 113(43):12144-12149). These findings suggest that PSIIm-S/27 is an intermediate in the assembly of PSII in which PsbS and/or Psb27 restrict PSII activity while in transit, by using a bicarbonate-mediated switch and protective mechanism.One sentence summaryA photosystem II monomer with PsbS and Psb27 as additional subunits, is inactive as isolated but activated by bicarbonate, and is attributed to be a late-stage intermediate in photoassembly.
Mixing genome annotation methods in a comparative analysis inflates the apparent number of lineage-specific genes
Authors: Weisman Caroline M. , Murray Andrew W. , Eddy Sean R. 
Published: January 2022

SummaryComparisons of genomes of different species are used to identify lineage-specific genes, those genes that appear unique to one species or clade. Lineage-specific genes are often thought to represent genetic novelty that underlies unique adaptations. Identification of these genes depends not only on genome sequences, but also on inferred gene annotations. Comparative analyses typically use available genomes that have been annotated using different methods, increasing the risk that orthologous DNA sequences may be erroneously annotated as a gene in one species but not another, appearing lineage-specific as a result. To evaluate the impact of such “annotation heterogeneity,” we identified four clades of species with sequenced genomes with more than one publicly available gene annotation, allowing us to compare the number of lineage-specific genes inferred when differing annotation methods are used to those resulting when annotation method is uniform across the clade. In these case studies, annotation heterogeneity increases the apparent number of lineage-specific genes by up to 15-fold, suggesting that annotation heterogeneity is a substantial source of potential artifact.
Ovariectomy increases paclitaxel-induced mechanical hypersensitivity and reduces anti-inflammatory CD4+ T cells in the dorsal root ganglion of female mice
Authors: Goode Diana J. , Mecum Neal E. 
Published: January 2022

AbstractChemotherapy is often dose limiting due to the emergence of a debilitating neuropathy. IL-10 and IL-4 are protective against peripheral neuropathy, yet the cell source is unknown. Using flow cytometry, we found that naïve females had a greater frequency of anti-inflammatory CD4+ T cells in the dorsal root ganglion (DRG) than males. In response to paclitaxel, females had reduced hypersensitivity and a greater frequency of anti-inflammatory CD4+ T cells (FoxP3, IL-10, IL-4) in the DRG than ovariectomized and male mice. These findings support a model in which estrogen promotes antiinflammatory CD4+ T cells in female DRG to suppress peripheral neuropathy.HighlightsCD4+ T cells are present in the dorsal root ganglion of naïve and paclitaxel-treated male and female mice.Naïve female mice have a higher frequency of CD4+ T cells in the dorsal root ganglion compared to ovariectomized female and male mice.Paclitaxel induces more severe mechanical hypersensitivity in ovariectomized female and male mice compared to estrogen-competent female mice.Paclitaxel increases pro- and anti-inflammatory CD4+ T cells in the dorsal root ganglion of both male and female mice, but the increase in anti-inflammatory T cells is more robust in female mice.Ovariectomy reduces cytokine-producing CD4+ T cells in the dorsal root ganglion and prevents the PTX-induced increase in cytokine-producing CD4+ T cells in the dorsal root ganglion.Graphical AbstractImage created withBiorender.com