bluuebunny/crossref_metadata_2025 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

Non-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

Introduction

Epilepsy 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.

Methods

We 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.

Results

This 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.

Conclusions

We 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

The 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

Elucidating 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

Wild 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

Wood 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

Stress 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

Bitterness 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

Background

Large 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.

Results

We 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.

Conclusions

We 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

In 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 summary

A 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

Comparisons 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

Chemotherapy 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.

Highlights

CD4+ 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 Abstract

Image created withBiorender.com
Graphics processing unit-accelerated Monte Carlo simulation of polarized light in complex three-dimensional media
Authors: Yan Shijie , Jacques Steven L. , Ramella-Roman Jessica C. , Fang Qianqian
Published: January 2022

Significance

Monte Carlo (MC) methods have been applied for studying interactions between polarized light and biological tissues, but most existing MC codes supporting polarization modeling can only simulate homogeneous or multi-layered domains, resulting in approximations when handling realistic tissue structures.

Aim

Over the past decade, the speed of MC simulations has seen dramatic improvement with massively-parallel computing techniques. Developing hardware-accelerated MC simulation algorithms that can accurately model polarized light inside 3-D heterogeneous tissues can greatly expand the utility of polarization in biophotonics applications.

Approach

Here we report a highly efficient polarized MC algorithm capable of modeling arbitrarily complex media defined over a voxelated domain. Each voxel of the domain can be associated with spherical scatters of various radii and densities. The Stokes vector of each simulated photon packet is updated through photon propagation, creating spatially resolved polarization measurements over the detectors or domain surface.

Results

We have implemented this algorithm in our widely disseminated MC simulator, Monte Carlo eXtreme (MCX). It is validated by comparing with a reference CPU-based simulator in both homogeneous and layered domains, showing excellent agreement and a 931-fold speedup.

Conclusion

The polarization-enabled MCX (pMCX) offers biophotonics community an efficient tool to explore polarized light in bio-tissues, and is freely available at http://mcx.space/.
hAMRoaster: a tool for comparing performance of AMR gene detection software
Authors: Wissel Emily F. , Talbot Brooke M. , Toyosato Noriko A. B. , Petit Robert A , Hertzberg Vicki , Dunlop Anne , Read Timothy D.
Published: January 2022

Background

The use of shotgun metagenomics for AMR detection is appealing because data can be generated from clinical samples with minimal processing. Detecting antimicrobial resistance (AMR) in clinical genomic data is an important epidemiological task, yet a complex bioinformatic process. Many software tools exist to detect AMR genes, but they have mostly been tested in their detection of genotypic resistance in individual bacterial strains. Further, these tools use different databases, or even different versions of the same databases. Understanding the comparative performance of these bioinformatics tools for AMR gene detection in shotgun metagenomic data is important because this data type is increasingly used in public health and clinical settings.

Methods

We developed a software pipeline, hAMRoaster (Harmonized AMR Output compAriSon Tool ER;https://github.com/ewissel/hAMRoaster), for assessing accuracy of prediction of antibiotic resistance phenotypes. For evaluation purposes, we simulated a highly resistant mock community and several low resistance metagenomic short read (Illumina) samples based on sequenced strains with known phenotypes. We benchmarked nine open source bioinformatics tools for detecting AMR genes that 1) were conda or Docker installable, 2) had been actively maintained, 3) had an open source license, and 4) took FASTA or FASTQ files as input. hAMRoaster calculated sensitivity, specificity, precision, and accuracy for each tool, comparing detected AMR genes to susceptibility testing.

Conclusion

Overall, all tools were precise and accurate at all genome coverage levels tested (5x, 50x, 100x sequenced bases / genome length) in the highly resistant mock community with more variability in the low resistance community (1x coverage). This study demonstrated that different bioinformatic tools and pipelines yield differences in AMR gene identification across drug classes, and that these differences become important if researchers are interested in resistance to specific drug classes.

Significance

Software selection for metagenomic AMR prediction should be driven by the context of the clinical/research questions and tolerance for true and false negative results. The ability to assess which bioinformatics tool best fits a particular dataset prior to beginning a large-scale project allows for more efficient processing and analysis using optimal tools for a particular research question. As prediction software and databases are in a state of constant refinement, the approach used here—creating synthetic communities containing taxa and phenotypes of interest along with using hAMRoaster to assess performance of candidate software—offers a template to aid researchers in selecting the most appropriate strategy at the time of analysis.
The AAA+ ATPase RavA-ViaA complex sensitizes Escherichia coli to aminoglycosides under anaerobic low energy conservation conditions
Authors: Khoury Jessica Y. El , Zamarreño Beas Jordi , Huguenot Allison , Py Béatrice , Barras Frédéric
Published: January 2022

Aminoglycosides have been used against Gram-negative bacteria for decades. Yet, uncertainties remain about various aspects of their uptake mechanism. Moreover their killing efficiency is well known to vary as a function of growth conditions and types of metabolism used by the targeted bacterium. Here we show that RavA, an AAA+ ATPase from the MoxR subfamily, associated with its VWA-containing partner, ViaA sensitize E. coli to lethal concentrations of AG, including gentamycin (Gm) and tobramycin, but not of antibiotics of other classes. We show this sensitizing effect to be due to enhanced Gm uptake in a proton motive force dependent manner. We evaluated the influence of RavA ViaA throughout a series of growth conditions, including aerobiosis and anaerobiosis. This led us to observe that the sensitizing effect of RavA ViaA varies with the respiratory chain used, i.e. RavA ViaA influence was prominent in the absence of exogenous electron acceptor or with fumarate, i.e. in poor energy conservation conditions, and dispensable in the presence of nitrate or oxygen, i.e. in high level of energy conservation. We propose RavA ViaA to be able to sense energetic state of the cell and to be used under low energy conditions for facilitating uptake of chemicals across the membrane, including Gm.

Author Summary

Antibiotic resistance is a major public health, social and economic problem. Aminoglycosides are known for their high efficiency against Gram-negative bacteria but their use is restricted to life threatening infections because of their nephrotoxicity and ototoxicity at therapeutic dose. Elucidation of AG sensitization mechanisms in bacteria will allow the use of a decreased effective dose of AGs. Here we identified new molecular actors, RavA and ViaA, which sensitize E. coli to AG under anaerobiosis. RavA belongs to the AAA+ ATPase family while ViaA bears a VWA motif. Moreover we show here that the influence of RavA ViaA on AG sensitivity varies with growth conditions and respiratory metabolism used by E. coli. This is a significant step forward as anaerobiosis is well known to reduce antibacterial activity of AG. This study emphasizes the crucial importance of the relationships between culture conditions, metabolism and antibiotic resistance.
Genome-wide Analysis Reflects Novel 5-Hydroxymethylcytosines Implicated in Diabetic Nephropathy
Authors: Yang Ying , Zeng Chang , Yang Kun , Zhang Zhou , Cai Qinyun , He Chuan , Zhang Wei , Liu Song-Mei
Published: January 2022

Long-term complications of type 2 diabetes (T2D) are the major causes for T2D-related disability and mortality. Notably, diabetic nephropathy (DN) has become the most frequent cause of end-stage renal disease (ESRD) in most countries. Understanding epigenetic contributors to DN can provide novel insights into this complex disorder and lay the foundation for more effective monitoring tools and preventive interventions, critical for achieving the ultimate goal of improving patient care and reducing healthcare burden. We have used a selective chemical labeling technique (5hmC-Seal) to profile genome-wide distributions of 5-hydroxymethylcytosines (5hmC), a gene activation mark, in patient-derived circulating cell-free DNA (cfDNA). Differentially modified 5hmC genes were identified across T2D patients with DN (n = 12), T2D patients with non-DN vascular complications (non-DN) (n = 29), and T2D patients with no complications (controls) (n = 14). Specifically, differential 5hmC markers between DN and controls revealed relevant pathways such as NOD-like receptor signaling pathway and tyrosine metabolism. A ten-gene panel was shown to provide differential 5hmC patterns between controls and DN, as well as between controls and non-DN patients using a machine learning approach. The 5hmC profiles in cfDNA reflected novel DN-associated epigenetic modifications relevant to the disease pathogenesis of DN. Importantly, these findings in cfDNA, a convenient liquid biopsy, have the potential to be exploited as a clinically useful tool for predicting DN in high risk T2D patients.
Development of an effective immune response in adults with Down Syndrome after SARS-CoV-2 vaccination
Authors: Esparcia-Pinedo Laura , Yarci-Carrión Ayla , Mateo-Jiménez Gloria , Ropero Noelia , Gómez-Cabañas Laura , Lancho-Sánchez Ángel , Martín-Gayo Enrique , Sanchez-Madrid Francisco , Moldenhauer Fernando , Gutiérrez-Cobos Ainhoa , de Asúa Diego Real , Alfranca Arantzazu
Published: January 2022

Immune dysregulation in individuals with Down syndrome (DS) leads to an increased risk for hospitalization and death due to COVID-19 and may impair the generation of protective immunity after vaccine administration. The cellular and humoral responses of 55 DS patients who received a complete SARS-CoV-2 vaccination regime at one to three (V1) and six (V2) months were characterised. SARS-CoV-2-reactive CD4+ and CD8+ T lymphocytes with a predominant Th1 phenotype were observed at V1, and increased at V2. Likewise, a sustained increase of SARS-CoV-2-specific circulating Tfh (cTfh) cells was observed one to three months after vaccine administration. Specific IgG antibodies against SARS-CoV-2 S protein were detected in 96% and 98% of subjects at V1 and V2, respectively, though IgG titers decreased significantly between both timepoints.

The work shows the cellular and humoral responses to SARS-CoV-2 vaccination of individuals with Down syndrome (DS) after one to three (V1) and six (V2) months. An effective immune response after six months was observed in 98% of DS individuals.
Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from ‘phenocopy’ non-progressors
Authors: Eratne Dhamidhu , Keem Michael , Lewis Courtney , Kang Matthew , Walterfang Mark , Loi Samantha , Kelso Wendy , Cadwallader Claire , Berkovic Samuel F , Li Qiao-Xin , Masters Colin L , Collins Steven , Santillo Alexander , Velakoulis Dennis ,   The MiND Study Group
Published: January 2022

Background

Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative ‘non-progressor’, ‘phenocopy’ mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay.

Methods

Cerebrospinal fluid (CSF) NfL, amyloid beta 1-42 (AB42), total and phosphorylated tau (T-tau, P-tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow up information, patients were categorised as Progressors. Non-Progressors were subtyped in to Phenocopy Non-Progressors (non-neurological/neurodegenerative final diagnosis), and Static Non-Progressors (static deficits, not fully explained by non-neurological/neurodegenerative causes).

Results

Forty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Phenocopy, 8 Static), 20 controls. NfL concentrations were lower in Non-Progressors (Non-Progressors Mean, M=554pg/mL, 95%CI:[461, 675], Phenocopy Non-Progressors M=459pg/mL, 95%CI:[385, 539], Static Non-Progressors M=730pg/mL, 95%CI:[516, 940]), compared to bvFTD Progressors (M=2397pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non-Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Static Non-Progressors tended to have higher T-tau and P-tau levels compared to Phenocopy Non-Progressors.

Conclusion

This study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD from phenocopy non-progressor variants, at baseline, with high accuracy, in a real-world clinical setting. This has important clinical implications, to improve outcomes for patients and clinicians facing this challenging clinical dilemma, as well as for healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non-progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL
Improved prediction of new COVID-19 cases using a simple vector autoregressive model: Evidence from seven New York State counties
Authors: Kitaoka Takayoshi , Takahashi Harutaka
Published: January 2022

With the rapid spread of COVID-19, there is an urgent need for a framework to accurately predict COVID-19 transmission. Recent epidemiological studies have found that a prominent feature of COVID-19 is its ability to be transmitted before symptoms occur, which is generally not the case for seasonal influenza and SARS. Several COVID-19 predictive epidemiological models have been proposed; however, they share a common drawback—they are unable to capture the unique asymptomatic nature of COVID-19 transmission. Here, we propose vector autoregression (VAR) as an epidemiological county-level prediction model that captures this unique aspect of COVID-19 transmission by introducing newly infected cases in other counties as lagged explanatory variables. Using the number of new COVID-19 cases in seven New York State counties, we predicted new COVID-19 cases in the counties over the next 4 weeks. We then compared our prediction results with those of 11 other state-of-the-art prediction models proposed by leading research institutes and academic groups. The results showed that VAR prediction is superior to other epidemiological prediction models in terms of the root mean square error of prediction. Thus, we strongly recommend the simple VAR model as a framework to accurately predict COVID-19 transmission.
Estimating body fat distribution – a driver of cardiometabolic health – from silhouette images
Authors: Klarqvist Marcus D. R. , Agrawal Saaket , Diamant Nathaniel , Ellinor Patrick T. , Philippakis Anthony , Ng Kenney , Batra Puneet , Khera Amit V.
Published: January 2022

Background

Inter-individual variation in fat distribution is increasingly recognized as clinically important but is not routinely assessed in clinical practice because quantification requires medical imaging.

Objectives

We hypothesized that a deep learning model trained on an individual’s body shape outline – or “silhouette” – would enable accurate estimation of specific fat depots, including visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volumes, and VAT/ASAT ratio. We additionally set out to study whether silhouette-estimated VAT/ASAT ratio may stratify risk of cardiometabolic diseases independent of body mass index (BMI) and waist circumference.

Methods

Two-dimensional coronal and sagittal silhouettes were constructed from whole-body magnetic resonance images in 40,032 participants of the UK Biobank and used to train a convolutional neural network to predict VAT, ASAT, and GFAT volumes, and VAT/ASAT ratio. Logistic and Cox regressions were used to determine the independent association of silhouette-predicted VAT/ASAT ratio with type 2 diabetes and coronary artery disease.

Results

Mean age of the study participants was 65 years and 51% were female. A deep learning model trained on silhouettes enabled accurate estimation of VAT, ASAT, and GFAT volumes (R2: 0.88, 0.93, and 0.93, respectively), outperforming a comparator model combining anthropometric and bioimpedance measures (ΔR2 = 0.05-0.13). Next, we studied VAT/ASAT ratio, a nearly BMI- and waist circumference-independent marker of unhealthy fat distribution. While the comparator model poorly predicted VAT/ASAT ratio (R2: 0.17-0.26), a silhouette-based model enabled significant improvement (R2: 0.50-0.55). Silhouette-predicted VAT/ASAT ratio was associated with increased prevalence of type 2 diabetes and coronary artery disease.

Conclusions

Body silhouette images can estimate important measures of fat distribution, laying the scientific foundation for population-based assessment.
A deep learning model for breast ductal carcinoma in situ classification in whole slide images
Authors: Kanavati Fahdi , Ichihara Shin , Tsuneki Masayuki
Published: January 2022

The pathological differential diagnosis between breast ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) is of pivotal importance for determining optimum cancer treatment(s) and clinical outcomes. Since conventional diagnosis by pathologists using micro-scopes is limited in terms of human resources, it is necessary to develop new techniques that can rapidly and accurately diagnose large numbers of histopathological specimens. Computational pathology tools which can assist pathologists in detecting and classifying DCIS and IDC from whole slide images (WSIs) would be of great benefit for routine pathological diagnosis. In this paper, we trained deep learning models capable of classifying biopsy and surgical histopathological WSIs into DCIS, IDC, and benign. We evaluated the models on two independent test sets (n=1,382, n=548), achieving ROC areas under the curves (AUCs) up to 0.960 and 0.977 for DCIS and IDC, respectively.
Coupled abiotic-biotic cycling of nitrous oxide in tropical peatlands
Authors: Buessecker Steffen , Sarno Analissa F. , Reynolds Mark C. , Chavan Ramani , Park Jin , Ortiz Marc Fontánez , Pérez-Castillo Ana G. , Pisco Grober Panduro , Urquiza-Muñoz José David , Reis Leonardo P. , Ferreira-Ferreira Jefferson , Furtunato Maia Jair M. , Holbert Keith E. , Penton C. Ryan , Hall Sharon J. , Gandhi Hasand , Boëchat Iola G. , Gücker Björn , Ostrom Nathaniel E. , Cadillo-Quiroz Hinsby
Published: January 2022

Atmospheric nitrous oxide (N2O) is a potent greenhouse gas thought to be mainly derived from microbial metabolism as part of the denitrification pathway. Here, we report that in unexplored peat soils of Central and South America, N2O production can be driven by abiotic reactions (≤ 98 %) highly competitive to their enzymatic counterparts. Extracted soil iron positively correlated with in-situ abiotic N2O production determined by isotopic tracers. Moreover, we found that microbial N2O reduction accompanied abiotic production, essentially closing a coupled abiotic-biotic N2O cycle. Anaerobic N2O consumption occurred ubiquitously (pH 6.4-3.7), with proportions of diverse clade II N2O-reducers increasing with consumption rates. Our findings show denitrification in tropical peat soils is not a purely biological process, but rather a “mosaic” of abiotic and biotic reduction reactions. We predict hydrological and temperature fluctuations differentially affect abiotic and biotic drivers and further contribute to the high N2O flux variation in the region.
An ancient truncated duplication of the anti-Mullerian hormone receptor type 2 gene is a potential conserved master sex determinant in the Pangasiidae catfish family
Authors: Wen Ming , Pan Qiaowei , Jouanno Elodie , Montfort Jerome , Zahm Margot , Cabau Cédric , Klopp Christophe , Iampietro Carole , Roques Céline , Bouchez Olivier , Castinel Adrien , Donnadieu Cécile , Parrinello Hugues , Poncet Charles , Belmonte Elodie , Gautier Véronique , Avarre Jean-Christophe , Dugue Remi , Gustiano Rudhy , Hà Trần Thị Thúy , Campet Marc , Sriphairoj Kednapat , Ribolli Josiane , de Almeida Fernanda L. , Desvignes Thomas , Postlethwait John H. , Bucao Christabel Floi , Robinson-Rechavi Marc , Bobe Julien , Herpin Amaury , Guiguen Yann
Published: January 2022

The evolution of sex determination (SD) mechanisms in teleost fishes is amazingly dynamic, as reflected by the variety of different master sex-determining genes identified, even sometimes among closely related species. Pangasiids are a group of economically important catfishes in many South-Asian countries, but little is known about their sex determination system. Here, we generated novel genomic resources for 12 Pangasiid species and provided a first characterization of their SD system. Based on an Oxford Nanopore long-read chromosome-scale high quality genome assembly of the striped catfish Pangasianodon hypophthalmus, we identified a duplication of the anti-Müllerian hormone receptor type II gene (amhr2), which was further characterized as being sex-linked in males and expressed only in testicular samples. These first results point to a male-specific duplication on the Y chromosome (amhr2by) of the autosomal amhr2a. Sequence annotation revealed that the P. hypophthalmus Amhr2by is truncated in its N-terminal domain, lacking the cysteine-rich extracellular part of the receptor that is crucial for ligand binding, suggesting a potential route for its neofunctionalization. Short-read genome sequencing and reference-guided assembly of 11 additional Pangasiid species, along with sex-linkage studies, revealed that this truncated amhr2by duplication is also conserved as a male-specific gene in many Pangasiids. Reconstructions of the amhr2 phylogeny suggested that amhr2by arose from an ancient duplication / insertion event at the root of the Siluroidei radiation that is dated around 100 million years ago. Altogether these results bring multiple lines of evidence supporting that amhr2by is an ancient and conserved master sex-determining gene in Pangasiid catfishes, a finding that highlights the recurrent usage of the transforming growth factor β pathway in teleost sex determination and brings another empirical case towards the understanding of the dynamics or stability of sex determination systems.
Plasma cell maintenance and antibody secretion are under the control of Sec22b-mediated regulation of organelle dynamics
Authors: Bonaud Amélie , Gargowitsch Laetitia , Gilbert Simon M. , Rajan Elanchezhian , Herrerias Pablo Canales , Stockholm Daniel , Rahman Nabila F. , Collins Mark O. , Hill Danika L. , Alloatti Andres , Alouche Nagham , Balor Stéphanie , Soldan Vanessa , Gillet Daniel , Barbier Julien , Bachelerie Françoise , Smith Kenneth G.C. , Bruhns Pierre , Amigorena Sebastian , Balabanian Karl , Linterman Michelle A. , Peden Andrew A. , Espéli Marion
Published: January 2022

Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the SNARE Sec22b as a unique and critical regulator of plasma cell maintenance and function. In absence of Sec22b, plasma cells were barely detectable and serum antibody titres were dramatically reduced. Accordingly, Sec22b deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b is indispensable for efficient antibody secretion but also for plasma cell fitness through the regulation of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil a critical role for Sec22b-mediated regulation of plasma cell biology through the control of organelle dynamics.
The salmon louse genome may be much larger than sequencing suggests
Authors: Wyngaard Grace A. , Skern-Mauritzen Rasmus , Malde Ketil , Prendergast Rachel , Peruzzi Stefano
Published: January 2022

The genome size of organisms impacts their evolution and biology and is often assumed to be characteristic of a species. Here we present the first published estimates of genome size of the ecologically and economically important ectoparasite, Lepeophtheirus salmonis (Copepoda, Caligidae). Four independent L. salmonis genome assemblies of the North Atlantic subspecies Lepeophtheirus salmonis salmonis, including two chromosome level assemblies, yield assemblies ranging from 665 – 790 Mbps. These genome assemblies are congruent in their findings, and appear very complete with Benchmarking Universal Single-Copy Orthologs analyses finding >92% of expected genes and transcriptome datasets routinely mapping >90% of reads. However, two cytometric techniques, flow cytometry and Feulgen image analysis densitometry, yield measurements of 1.3-1.6 Gb in the haploid genome. Interestingly, earlier cytometric measurements reported genome sizes of 939 and 567 Mbps in L. salmonis salmonis samples from Bay of Fundy and Norway, respectively. Available data thus suggest that the genome sizes of salmon lice are variable. Current understanding of eukaryotic genome dynamics suggests that the most likely explanation for such variability involves repetitive DNA, which for L. salmonis makes up ≈60% of the genome assemblies.