bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcomes and gut microbiota analysis of severe alcohol-associated hepatitis patients undergoing healthy donor fecal transplant or pentoxifylline therapy: single-center experience from Kerala
Authors: Philips Cyriac Abby , Ahamed Rizwan , Rajesh Sasidharan , Singh Shobhit , Tharakan Ajit , Abduljaleel Jinsha K , Augustine Philip
Published: December 2022

Background

Severe alcohol-associated hepatitis (SAH) patients with infections have a high short-term mortality rate. Gut microbiota dysbiosis plays an important role in the pathogenesis of SAH. Preliminary studies have demonstrated long-term benefits with healthy donor fecal microbiota transplantation (FMT). Data on FMT compared with pentoxifylline for SAH and relevant gut microbial changes are lacking in literature.

Methods

From January 2019 to February 2021, retrospective analysis of a single hospital’s records revealed 47 SAH patients undergoing FMT (100 mL/day via nasoduodenal tube for 7 days) and 25 matched patients receiving pentoxifylline (400 mg/8 h for 28 days). The primary end point was a 6-month survival rate. Secondary end points included incidence of ascites, hepatic encephalopathy, infections, acute kidney injury, and gut microbiota changes between post-therapy groups. Biomarker discovery and network analysis were also performed to identify significant taxa of gut microbiota in post-treatment groups in retrospectively stored stool samples.

Results

All were males. The 6-month survival rate was higher in the patients undergoing FMT than in patients receiving pentoxifylline (83.0% vs 56.0%, P = 0.012). At the end of 6-month follow-up, the incidences of clinically significant ascites (56.0% vs 25.5%, P = 0.011), hepatic encephalopathy (40.0% vs 10.6%, P = 0.003), and critical infections (52.0% vs 14.9%, P < 0.001) in patients administered pentoxifylline were significantly higher than those in patients treated with FMT. At 3 months, biomarker analysis revealed a significant abundance of Bifidobacterium and Eggerthella in the FMT group and the pentoxifylline group, respectively. At 6 months, Bifidobacterium in the FMT group and pathogenic Aerococcaceae in the pentoxifylline group were notable. Network analysis showed beneficial taxa (Bifidobacterium) as a central influencer in those undergoing FMT at 6 months.

Conclusions

Healthy donor FMT improved survival rate and reduced liver-related complications compared with pentoxifylline. These clinical benefits were associated with favorable modulation of intestinal bacterial communities. Difficult-to-treat SAH patients may be safely bridged to transplantation using FMT. Controlled trials evaluating long-term outcomes are an unmet need.
Novel compound heterozygous mutations in UHRF1 are associated with atypical immunodeficiency, centromeric instability and facial anomalies syndrome with distinctive genome-wide DNA hypomethylation
Authors: Unoki Motoko , Velasco Guillaume , Kori Satomi , Arita Kyohei , Daigaku Yasukazu , Yeung Wan Kin Au , Fujimoto Akihiro , Ohashi Hirofumi , Kubota Takeo , Miyake Kunio , Sasaki Hiroyuki
Published: December 2022

Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is in most cases caused by mutations in either DNA methyltransferase (DNMT)3B, zinc finger and BTB domain containing 24, cell division cycle associated 7 or helicase lymphoid-specific. However, the causative genes of a few ICF patients remain unknown. We, herein, identified ubiquitin-like with plant homeodomain and really interesting new gene finger domains 1 (UHRF1) as a novel causative gene of one such patient with atypical symptoms. This patient is a compound heterozygote for two previously unreported mutations in UHRF1: c.886C > T (p.R296W) and c.1852C > T (p.R618X). The R618X mutation plausibly caused nonsense-mediated decay, while the R296W mutation changed the higher order structure of UHRF1, which is indispensable for the maintenance of CG methylation along with DNMT1. Genome-wide methylation analysis revealed that the patient had a centromeric/pericentromeric hypomethylation, which is the main ICF signature, but also had a distinctive hypomethylation pattern compared to patients with the other ICF syndrome subtypes. Structural and biochemical analyses revealed that the R296W mutation disrupted the protein conformation and strengthened the binding affinity of UHRF1 with its partner LIG1 and reduced ubiquitylation activity of UHRF1 towards its ubiquitylation substrates, histone H3 and proliferating cell nuclear antigen -associated factor 15 (PAF15). We confirmed that the R296W mutation causes hypomethylation at pericentromeric repeats by generating the HEK293 cell lines that mimic the patient’s UHRF1 molecular context. Since proper interactions of the UHRF1 with LIG1, PAF15 and histone H3 are essential for the maintenance of CG methylation, the mutation could disturb the maintenance process. Evidence for the importance of the UHRF1 conformation for CG methylation in humans is, herein, provided for the first time and deepens our understanding of its role in regulation of CG methylation.
Intransigent vs. volatile opinions in a kinetic epidemic model with imitation game dynamics
Authors: Della Marca Rossella , Loy Nadia , Menale Marco
Published: December 2022

In the mathematical epidemiology community, there is an increasing interest in shaping the complex interplay between human behaviour and disease spreading. We give a contribution in this direction by illustrating a method to derive behavioural change epidemic models from a stochastic particle description by the means of kinetic equations. We consider a susceptible–infected–removed-like model where contact rates depend on the behavioural patterns adopted across the population. The selection of the social behaviour happens during the interactions between individuals adopting alternative strategies and it is driven by an imitation game dynamics. Agents have a double microscopic state: a discrete label, which denotes the epidemiological compartment to which they belong, and the degree of flexibility of opinion, i.e. a measure of the personal attitude to change opinion and, hence, to switch between the alternative social contact patterns. We derive kinetic evolution equations for the distribution functions of the degree of flexibility of opinion of the individuals for each compartment, whence we obtain macroscopic equations for the densities and average flexibilities of opinion. After providing the basic properties of the macroscopic model, we numerically investigate it by focusing on the impact of the flexibility of opinion on the epidemic course and on the consequent behavioural responses.
Scoping review of health information technology usability methods leveraged in Africa
Authors: Dougherty Kylie , Hobensack Mollie , Bakken Suzanne
Published: December 2022

Objective

The aim of this study was to explore the state of health information technology (HIT) usability evaluation in Africa.

Materials and Methods

We searched three electronic databases: PubMed, Embase, and Association for Computing Machinery. We categorized the stage of evaluations, the type of interactions assessed, and methods applied using Stead’s System Development Life Cycle (SDLC) and Bennett and Shackel’s usability models.

Results

Analysis of 73 of 1002 articles that met inclusion criteria reveals that HIT usability evaluations in Africa have increased in recent years and mainly focused on later SDLC stage (stages 4 and 5) evaluations in sub-Saharan Africa. Forty percent of the articles examined system-user-task-environment (type 4) interactions. Most articles used mixed methods to measure usability. Interviews and surveys were often used at each development stage, while other methods, such as quality-adjusted life year analysis, were only found at stage 5. Sixty percent of articles did not include a theoretical model or framework.

Discussion

The use of multistage evaluation and mixed methods approaches to obtain a comprehensive understanding HIT usability is critical to ensure that HIT meets user needs.

Conclusions

Developing and enhancing usable HIT is critical to promoting equitable health service delivery and high-quality care in Africa. Early-stage evaluations (stages 1 and 2) and interactions (types 0 and 1) should receive special attention to ensure HIT usability prior to implementing HIT in the field.
Thoracic chordoma in a 36-year-old female
Authors: Kassels Austin C , Melamed Joshua , Rogers Austin , Johnstone David
Published: December 2022

Chordomas are rare tumors that occur in the bones of the skull base and spine, affecting 1 in 1 000 000 people per year. Thoracic chordomas comprise just 1% of chordomas. A 36-year-old female underwent a right video-assisted thoracoscopic surgical resection for a cystic mass at the level of T2-3 which was well-circumscribed. Despite efforts to achieve an intact resection, there was tumor spillage due to friability, and it was taken off the bony vertebral body with no margin. The final pathologic diagnosis was chordoma. Thoracic chordomas are rare, slow-growing, recurring neoplasms that require proper preoperative diagnostic imaging and ideally preoperative trocar computed tomography-guided biopsy from a posterior approach if anatomic access is possible. They are prone to dissemination and sarcomatous differentiation. The surgical approaches for reported thoracic chordoma tumors vary due to their rarity and the variation in tumor location and presentation.
Proton exudation mediated by GmVP2 has widespread effects on plant growth, remobilization of soil phosphorus, and the structure of the rhizosphere microbial community
Authors: Xie Baoxing , Chen Qianqian , Lu Xing , Chen Kang , Yang Yuesheng , Tian Jiang , Liang Cuiyue
Published: December 2022

Increased root secretion of H+ is a known strategy in plant adaption to low phosphorus (P) stress as it enhances mobilization of sparingly soluble P sources in the soil. However, our knowledge of the full effects induced by this enhanced acidification of the rhizosphere remains incomplete. In this study we found that P deficiency increased the net H+ flux rate from soybean (Glycine max) roots. Among the eight H+-pyrophosphatase (GmVP) genes in the soybean genome, GmVP2 showed the highest expression level under low P conditions. Transient expression of a GmVP2-GFP construct in tobacco (Nicotiana tabacum) leaves, together with functional characterization of GmVP2 in transgenic soybean hairy roots demonstrated that it encodes a plasma-membrane transporter that mediates H+ exudation. Overexpression of GmVP2 in Arabidopsis resulted in enhanced root H+ exudation, promoted root growth, and improved the utilization of sparingly soluble Ca-P. The improved root growth caused by GmVP2-overexpression might be due to the differential expression of genes related to hormone and flavonoid metabolism, and to root development. Overexpression of GmVP2 also changed the structure of the rhizospheric microbial community, as reflected by a preferential accumulation of Acidobacteria. Overall, our results suggest that GmVP2 mediates H+ exudation in the root response to Pi starvation, and that this influences plant growth, the mobilization sparingly soluble P-sources, and the structure of the microbial community in a coordinated manner.
On the detection of the electromagnetic counterparts from lensed gravitational wave events by binary neutron star mergers
Authors: Ma Hao , Lu Youjun , Guo Xiao , Zhang Siqi , Chu Qingbo
Published: December 2022

Future ground-based gravitational wave (GW) detectors, i.e. Einstein telescope (ET) and Cosmic Explorer (CE), are expected to detect a significant number of lensed binary neutron star (BNS) mergers, which may provide a unique tool to probe cosmology. In this paper, we investigate the detectability of the optical/infrared electromagnetic (EM) counterparts (kilonovae/afterglows) from these lensed BNS mergers by future GW detectors and EM telescopes using simple kilonova, afterglow, and lens models. ET and CE are expected to detect ${\sim}5.32^{+26.1}_{-5.10}$ and $67.3^{+332}_{-64.7}$ lensed BNS mergers per year. We find that the EM counterparts associated with all these mergers will be detectable by an all sky-survey in the H band with the limiting magnitude mlim ≳ 27, while the detectable fraction is ${\lesssim}0.4{{\ \rm per\ cent}}$ in the g/z band if with mlim ≲ 24. Generally, it is more efficient to search the lensed EM counterparts by adopting the infrared bands than the optical/UV bands with the same mlim. Future telescopes like Vera C. Rubin Observatory, China Space Station Telescope, and Euclid can hardly detect the EM counterparts of even one lensed BNS merger. Roman Space Telescope (RST) and James Webb Space Telescope (JWST) have the capability to detect about a few or more such events per year. Moreover, the time delays and separations between the lensed image pairs are typically in the ranges from minutes to months and from 0.1 to 1 arcsec, suggesting that both the GW and EM images of most lensed BNS mergers can be well resolved by not only CE/ET in the time domain but also RST/JWST spatially.
The evolution of circumstellar discs in the galactic centre: an application to the G-clouds
Authors: Owen James E , Lin Douglas N C
Published: December 2022

The Galactic Centre is known to have undergone a recent star formation episode a few Myr ago, which likely produced many T Tauri stars hosting circumstellar discs. It has been suggested that these discs may be the compact and dusty ionized sources identified as ‘G-clouds’. Given the Galactic Centre’s hostile environment, we study the possible evolutionary pathways these discs experience. We compute new external photoevaporation models applicable to discs in the Galactic Centre that account for the subsonic launching of the wind and absorption of UV photons by dust. Using evolutionary disc calculations, we find that photoevaporation’s rapid truncation of the disc causes them to accrete onto the central star rapidly. Ultimately, an accreting circumstellar disc has a lifetime ≲ 1 Myr, which would fail to live long enough to explain the G-clouds. However, we identify a new evolutionary pathway for circumstellar discs in the Galactic Centre. Removal of disc material by photoevaporation prevents the young star from spinning down due to magnetic braking, ultimately causing the rapidly spinning young star to torque the disc into a ‘decretion disc’ state which prevents accretion. At the same time, any planetary companion in the disc will trap dust outside its orbit, shutting down photoevaporation. The disc can survive for up to ∼10 Myr in this state. Encounters with other stars are likely to remove the planet on Myr time-scales, causing photoevaporation to restart, giving rise to a G-cloud signature. A giant planet fraction of $\sim 10{{\ \rm per\ cent}}$ can explain the number of observed G-clouds.
Direct emission of strong radio pulses during magnetar flares
Authors: Thompson Christopher
Published: December 2022

The emission of intense radio pulses by flaring magnetars is investigated. Small-scale current gradients can be imprinted into a strongly magnetized outflow by the same processes that source fireball radiation in the closed magnetosphere. This structure arises from a combination of crustal yielding, internal tearing, and turbulent cascade. We consider the quasi-linear development of weak, small-scale currents as (i) they are stretched out and frozen by relativistic expansion, and then (ii) pass through a shock. In particular, we derive the amplitudes of the ordinary and fast waves that emerge downstream of a relativistically magnetized shock in response to a mode that is frozen into the upstream flow (a frozen Alfvén wave or entropy wave). An upstream mode with comoving wavelength exceeding the skin depth can linearly convert to a secondary mode propagating above the plasma frequency. A simple and accurate treatment of shocks with extreme magnetization is developed, and the formation of internal shocks in the outflow from a bursting, rotating magnetar is outlined. The emission process described here does not require a strong shock or cool e± pairs (in contrast with the electromagnetic maser shock instability). In some cases, a high-frequency wave is reflected back to the observer, but with a minuscule amplitude that makes it subdominant to other emission channels. The dominant secondary electromagnetic mode is superluminal at emission, is subject to weak induced scattering within the outflow, and can reach the observer in the radio band.
Framing School Integration: A Computational Analysis of Newspaper Discourse, 1990–2020
Authors: Diehl David K
Published: December 2022

Research on public opinion finds that most Americans support the racial integration of schools in theory. At the same time, however, they tend to oppose specific policies for achieving it. How is it that the American public comes to conceive of school integration as both an abstract idea and a set of concrete policies? Research has shown that one major source of the public’s understanding of complex social issues like school integration are news media organizations and the choices they make in how they cover them—that is, how they frame social issues. This article examines how school integration was framed in the news between 1990 and 2020. It does so with a dataset of over 13,000 articles from 25 newspapers. The article also examines determinants of those frames, asking what contextual factors shape the production of the news. The results reveal three overarching trends in how school integration was covered in the media over time: depoliticization, historicization, and neoliberalization. These trends varied by the political slant of the newspaper, by location (whether it is in a former Jim Crow state), and by whether the newspaper has a national readership. The author discusses implications for research and policy.
Cellular and molecular responses to ethyl-parathion in undifferentiated SH-SY5Y cells provide neurotoxicity pathway indicators for organophosphorus impacts
Authors: Amar Saroj K , Donohue Keri B , Gust Kurt A
Published: December 2022

High-fidelity nonanimal screening methods are needed that can rapidly and accurately characterize organophosphorus compound (OP)-induced neurotoxicity. Herein, the efficacy of human neuroblastoma cell line (SH-SY5Y) to provide molecular and cellular responses characteristic of the OP neurotoxicity pathway was investigated in response to the OP-model compound, ethyl-parathion. Undifferentiated SH-SY5Y cells were exposed to ethyl-parathion for 30 min at 0 (control), 0.5, 2.5, 5, 10, and 25 µg/ml. Dose-responsive reductions in cell viability were observed with significant reductions at ≥10 µg/ml. From these results, ethyl-parathion exposures of 0 (control), 5, and 10 µg/ml were selected to examine bioindicators underlying the OP neurotoxicity pathway including: reactive oxygen species (ROS), cell membrane peroxidation, mitochondrial membrane potential (MMP), and apoptosis. Ethyl-parathion elicited highly significant increases in ROS relative to controls (p < .01) at both exposure concentrations, confirmed using N-acetyl cysteine (NAC) as a ROS quencher which alleviated ROS increases. A response characteristic of increased ROS exposure, cell membrane-lipid peroxidation, significantly increased (p < .05) at the highest ethyl-parathion exposure (10 µg/ml). As a likely consequence of membrane-lipid peroxidation, ethyl-parathion-induced reductions in MMP were observed with significant effects at 10 µg/ml, reducing MMP by 58.2%. As a culmination of these cellular-damage indicators, apoptosis progression was investigated by phosphatidylserine translocation where ethyl-parathion-induced dose-responsive, highly significant (p < .01) increases at both 5 and 10 µg/ml. Overall, the mechanistic responses observed in undifferentiated SH-SY5Y cells corresponded with in vivo mammalian results demonstrating potential for this nonanimal model to provide accurate OP neurotoxicology screening.
The evolution of the HIV-1 protease folding stability
Authors: Ferreiro David , Khalil Ruqaiya , Gallego María J , Osorio Nuno S , Arenas Miguel
Published: December 2022

The evolution of structural proteins is generally constrained by the folding stability. However, little is known about the particular capacity of viral proteins to accommodate mutations that can potentially affect the protein stability and, in general, the evolution of the protein stability over time. As an illustrative model case, here, we investigated the evolution of the stability of the human immunodeficiency virus (HIV-1) protease (PR), which is a common HIV-1 drug target, under diverse evolutionary scenarios that include (1) intra-host virus evolution in a cohort of seventy-five patients sampled over time, (2) intra-host virus evolution sampled before and after specific PR-based treatments, and (3) inter-host evolution considering extant and ancestral (reconstructed) PR sequences from diverse HIV-1 subtypes. We also investigated the specific influence of currently known HIV-1 PR resistance mutations on the PR folding stability. We found that the HIV-1 PR stability fluctuated over time within a constant and wide range in any studied evolutionary scenario, accommodating multiple mutations that partially affected the stability while maintaining activity. We did not identify relationships between change of PR stability and diverse clinical parameters such as viral load, CD4+ T-cell counts, and a surrogate of time from infection. Counterintuitively, we predicted that nearly half of the studied HIV-1 PR resistance mutations do not significantly decrease stability, which, together with compensatory mutations, would allow the protein to adapt without requiring dramatic stability changes. We conclude that the HIV-1 PR presents a wide structural plasticity to acquire molecular adaptations without affecting the overall evolution of stability.
Characterizing Variation in the Bacterial and Fungal Tare Soil Microbiome of Seed Potato
Authors: Delventhal Kayla , Skillman Victoria , Li Xiaoping , Busby Posy E. , Frost Kenneth
Published: December 2022

For tuberizing crops such as potato ( Solanum tuberosum), the geocaulosphere, or the thin zone of soil in contact with and influenced by the tuber, is a distinct habitat that exists between the potato and the soil environment. Geocaulosphere soil that remains associated with the tuber after harvest is called tare soil. However, beyond potato pathogens, the microbes present in tare soil are understudied. We used internal transcribed spacer and 16S metabarcoding to characterize the microbial communities present in 130 tare soils of commercially produced seed potato plantlets used for potato production in Oregon. In 2018 and 2019, tare soils were opportunistically sampled from seed potato plantlets that were collected from farmers in the Columbia Basin of Oregon. This sampling effort included seed tubers of 23 cultivars that had originated from 40 commercial seed farms in 11 states. We identified a core microbiome consisting of 61 bacterial and 26 fungal taxa, some of which are not common to the potato microbiome, and others which have been reported to either possess biocontrol activities, promote plant growth, or cause disease in potato. Seed grower farm accounted for the greatest amount of compositional variation among tare soil microbiome samples, with more similar communities found on seed tubers grown on farms near to each other. Learning which factors shape tare soil microbial community composition and whether those communities influence plant health are essential steps towards potato microbiome management.
Improved Genome Assembly Resource of the Plant Pathogen Fusarium avenaceum
Authors: Gottschalk Christopher , Evans Breyn , Collum Tamara D.
Published: December 2022

Fusarium avenaceum is a generalist plant pathogen of concern due to its potential to produce mycotoxins on plant products. Previous research efforts have sequenced and assembled genomes of F. avenaceum. However, those works relied on limited next-generation sequencing technologies that resulted in fragmented and incomplete genome assemblies. To address this, we utilized high-depth third-generation long-read sequencing and several different genome assembly software to generate a new, highly contiguous genome of F. avenaceum. Moreover, we conducted a thorough annotation of the genome using a mix of long-read cDNA and short-read RNAseq data. Our genome was more contiguous than the current reference genome Fustri1, matched the estimated genome size and chromosome number, and contained a similar number of annotated genes to other F. avenaceum genome assemblies. Lastly, we conducted a secondary metabolite (SM) cluster analysis that identified 60 gene clusters associated with SM biosynthesis, five more than the reference F. avenaceum genome. In conclusion, our genome and associated annotation information will help advance research on plant-fungal interactions, food safety, and Fusarium spp. diversity.

[Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Draft Genomes of Five Fusarium oxysporum f. sp. niveum Strains Isolated from Infected Watermelon from Texas with Temporal and Spatial Differences
Authors: Thomas Vanessa E. , Isakeit Thomas , Antony-Babu Sanjay
Published: December 2022

Fusarium oxysporum f. sp. niveum (FON) is a soilborne fungal pathogen of watermelon that has significantly impacted production worldwide. In the United States, watermelon growers can experience 30 to 100% yield loss from this soil pathogen. In this study, we present five draft genome sequences of FON-race 2 isolates collected from four different counties within Texas, spanning more than 23 years. The estimated genome sizes of the de novo assembled genomes were W2 = 49 Mb, COM = 48 Mb, HAR = 49 Mb, STORM = 49 Mb, and PRU = 48 Mb. These sizes were on par with the previously sequenced FON races 0 and 2 from Texas, which ranged from 49 to 54 Mb. Gene prediction program AUGUSTUS predicted 13,554 genes in W2, 13,658 genes in COM, 13,678 genes in HAR, 13,821 genes in STORM, and 13,347 genes in PRU. The information from our five genome drafts contributes to the southeast genomic dataset of FON for comparative genomic analysis. Furthermore, the sequences are beneficial in the understanding of changes within the FON genome over time.

[Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2023.
Differentiating and Managing Rare Thrombotic Microangiopathies During Pregnancy and Postpartum
Authors: Lim Ming Y. , Abou-Ismail Mouhamed Yazan , Branch D. Ware
Published: December 2022

The most common thrombotic microangiopathy (TMA) of pregnancy is the well-recognized syndrome of preeclampsia with hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. However, rare TMAs, including thrombotic thrombocytopenic purpura, complement-mediated hemolytic-uremic syndrome, and catastrophic antiphospholipid syndrome, may occur during pregnancy or postpartum and present with features similar to those of preeclampsia with severe features. Early recognition and treatment of these infrequently encountered conditions are key for avoiding serious maternal morbidities with long-term sequelae and possible maternal or fetal death. Differentiating between preeclampsia with severe features and these rare TMAs is diagnostically challenging as there is significant overlap in their clinical and laboratory presentation. Given the rarity of these TMAs, high-quality evidence-based recommendations on diagnosis and management during pregnancy are lacking. Using current objective information and recommendations from working groups, this report provides practical clinical approaches to diagnose and manage these rare TMAs. This report also discusses how to manage individuals with a history of these rare TMAs who are planning to conceive. To optimize favorable outcomes, a multidisciplinary approach including obstetricians, maternal-fetal medicine specialists, hematologists, and nephrologists alongside close clinical and laboratory monitoring is vital.
LncRNA NEAT1 regulates HCV-induced Hepatocellular carcinoma by modulating the miR-9-BGH3 axis
Authors: Tripathi Sachin Kumar , Pal Apala , Ghosh Suchandrima , Goel Amit , Aggarwal Rakesh , Banerjee Soma , Das Saumitra
Published: December 2022

Chronic hepatitis C virus (HCV) infection is a leading cause of end-stage liver diseases, such as fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Several cellular entities, including paraspeckles and their related components, are involved in viral pathogenesis and cancer progression. NEAT1 lncRNA is a major component of paraspeckles that has been linked to several malignancies. In this study, analysis of the Cancer Genome Atlas (TCGA) database and validation in HCV-induced HCC tissue and serum samples showed significantly high expression of NEAT1 in patients with liver cancer. Moreover, we found that NEAT1 levels increased upon HCV infection. To further understand the mechanism of NEAT1-induced HCC progression, we selected one of its targets, miR-9–5 p, which regulates BGH3 mRNA levels. Interestingly, miR-9–5 p levels were downregulated upon HCV infection, whereas BGH3 levels were upregulated. Additionally, partial NEAT1 knockdown increased miR-9–5 p levels and decreased BGH3 levels, corroborating our initial results. BGH3 levels were also upregulated in HCV-induced HCC and TCGA tissue samples, which could be directly correlated with NEAT1 levels. As a known oncogene, BGH3 is directly linked to HCC progression mediated by NEAT1. We also found that NEAT1 levels remained upregulated in serum samples from patients treated with direct-acting antivirals (DAA), indicating that NEAT1 might be a molecular trigger that promotes HCC development. Collectively, these findings provide molecular insights into HCV-induced HCC progression via the NEAT1-miR-9-BGH3 axis.
In-depth Temporal Transcriptome Profiling of Monkeypox and Host Cells using Nanopore Sequencing
Authors: Kakuk Balázs , Dörmő Ákos , Csabai Zsolt , Kemenesi Gábor , Holoubek Jiří , Růžek Daniel , Prazsák István , Dani Virág Éva , Dénes Béla , Torma Gábor , Jakab Ferenc , Tóth Gábor E. , Földes Fanni V. , Zana Brigitta , Lanszki Zsófia , Harangozó Ákos , Fülöp Ádám , Gulyás Gábor , Mizik Máté , Kiss András Attila , Tombácz Dóra , Boldogkői Zsolt
Published: December 2022

The recent Monkeypox outbreak showed the importance of studying the basic biology of orthopoxviruses. However, the transcriptome of its causative agent has not been investigated before neither with short-, nor with long-read sequencing approaches. This Oxford Nanopore long-read RNA-Sequencing dataset fills this gap. Our direct cDNA and native RNA sequencing data enable the in-depth characterization of the transcriptomic architecture and dynamics of the gene expressions of monkeypox virus; and also the deeper understanding of the changes it causes in the host cells on a transcriptome level.
Hypotrochoidal scaffolds for cartilage regeneration
Authors: van Kampen Kenny A. , Olaret Elena , Stancu Izabela-Cristina , Duarte Campos Daniela F. , Fischer Horst , Mota Carlos , Moroni Lorenzo
Published: December 2022

The main function of articular cartilage is to provide a low friction surface and protect the underlying subchondral bone. The extracellular matrix composition of articular cartilage mainly consists of glycosaminoglycans and collagen type II. Specifically the collagen type II organization has a characteristic organization in three distinct zones; (1) the superficial zone which has collagen fibers oriented parallel to the surface, (2) the intermediate zone where there is no predominant orientation, and (3) the deep zone which shows a high orientation with fibers perpendicular to the underlying bone. Collagen type II fibers in these 3 zones take an arch-like organization that can be mimicked with segments of a hypotrochoidal curve. In this study, a script was developed that allowed the fabrication of scaffolds with a hypotrochoidal design. This design was investigated and compared to a regular 0-90 woodpile design. The results showed that the hypotrochoidal design was successfully fabricated. Micro-CT analyses divided the areas of the scaffold in their distinct zones. In addition, the mechanical analyses revealed that the hypotrochoidal design had a lower component Young’s modulus while the toughness and strain at yield were higher compared to the woodpile design. Fatigue tests showed that the hypotrochoidal design lost more energy per cycle due to the damping effect of the unique microarchitecture. Finite element analyses revealed that the hypotrochoidal design had an improved stress distribution compared to the 0-90 woodpile design due to the lower component stiffness. In addition, data from cell culture under dynamic stimulation demonstrated that the collagen type II deposition was improved in the hypotrochoidal design. Finally, Alcian blue staining revealed that the areas where the stress was higher during the stimulation produced more glycosaminoglycans. Our results highlight a new and simple scaffold design based on hypotrochoidal curves that could be used for cartilage tissue engineering.
Histone H1.0 Couples Cellular Mechanical Behaviors to Chromatin Structure
Authors: Hu Shuaishuai , Chapski Douglas J. , Gehred Natalie , Kimball Todd H. , Gromova Tatiana , Flores Angelina , Rowat Amy C. , Chen Junjie , Packard René R. Sevag , Olszewski Emily , Davis Jennifer , Rau Christoph D. , McKinsey Timothy A. , Garrido Manuel Rosa , Vondriska Thomas M.
Published: December 2022

Tuning of genome structure and function is accomplished by chromatin binding proteins, which determine the transcriptome and phenotype of the cell. We sought to investigate how communication between extracellular stress and chromatin structure may regulate cellular mechanical behaviors. We demonstrate that the linker histone H1.0, which compacts nucleosomes into higher order chromatin fibers, controls genome organization and cellular stress response. Histone H1.0 has privileged expression in fibroblasts across tissue types in mice and humans, and modulation of its expression is necessary and sufficient to mount a myofibroblast phenotype in these cells. Depletion of histone H1.0 prevents transforming growth factor beta (TGF-β)-induced fibroblast contraction, proliferation and migration in a histone H1 isoform-specific manner via inhibition of a transcriptome comprised of extracellular matrix, cytoskeletal and contractile genes. Histone H1.0 is associated with local regulation of gene expression via mechanisms involving chromatin fiber compaction and reprogramming of histone acetylation, rendering the cell stiffer in response to cytokine stimulation. Knockdown of histone H1.0 prevented locus-specific histone H3 lysine 27 acetylation by TGF-βand decreased levels of both HDAC1 and the chromatin reader BRD4, thereby preventing transcription of a fibrotic gene program. Transient depletion of histone H1.0in vivodecompacts chromatin and prevents fibrosis in cardiac muscle, thereby linking chromatin structure with fibroblast phenotype in response to extracellular stress. Our work identifies an unexpected role of linker histones to orchestrate cellular mechanical behaviors, directly coupling cellular force generation, nuclear organization and gene transcription.

Graphical Abstract
A selectivity filter in the EMC limits protein mislocalization to the ER
Authors: Pleiner Tino , Hazu Masami , Tomaleri Giovani Pinton , Nguyen Vy , Januszyk Kurt , Voorhees Rebecca M.
Published: December 2022

Tail anchored proteins (TAs) play essential roles at both the ER and mitochondria, and their accurate localization is critical to proteostasis. Biophysical similarities lead to mistargeting of mitochondrial TAs to the ER, where they are delivered to the ER membrane protein complex (EMC). We showed that the EMC directly contributes to sorting fidelity of mitochondrial TAs and multipass substrates that contain positively charged soluble domains. Leveraging an improved structural model of the human EMC, we used mutagenesis and site-specific crosslinking to map the path of a TA from its cytosolic capture by methionine-rich loops to its membrane insertion through a hydrophilic vestibule. Positively charged residues at the entrance to the vestibule function as a selectivity filter that uses charge-repulsion to reject mitochondrial TAs. Substrate discrimination by the EMC provides a biochemical explanation for one role of charge in TA sorting and protects compartment identity by limiting protein misinsertion.
Acute adenoviral infection elicits an arrhythmogenic substrate prior to myocarditis
Authors: Padget Rachel L. , Zeitz Michael J. , Blair Grace A. , Wu Xiaobo , North Michael D. , Tanenbaum Mira T. , Stanley Kari E. , Phillips Chelsea M. , King D. Ryan , Lamouille Samy , Gourdie Robert G. , Hoeker Gregory S. , Swanger Sharon A. , Poelzing Steven , Smyth James W.
Published: December 2022

Background

Viral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and a resulting lack of mechanistic understanding. Myocarditis is a major cause of sudden cardiac death in young adults, where current knowledge in the field is dominated by later disease phases, and pathological immune responses. However, little is known regarding how infection can acutely induce an arrhythmogenic substrate prior to significant immune responses. Adenovirus is a leading cause of myocarditis, but due to species-specificity, models of infection are lacking and it is not understood how adenoviral infection may underlie sudden cardiac arrest. Mouse Adenovirus Type-3 (MAdV-3) was previously reported as cardiotropic, yet has not been utilized to understand mechanisms of cardiac infection and pathology.

Methods

We have developed MAdV-3 infection as a model to investigate acute cardiac infection and molecular alterations to the infected heart prior to an appreciable immune response or gross cardiomyopathy.

Results

Optical mapping of infected hearts exposes decreases in conduction velocity concomitant with increased Cx43Ser368 phosphorylation, a residue known to regulate gap junction function. Hearts from animals harboring a phospho-null mutation at Cx43Ser368 are protected against MAdV-3 induced conduction velocity slowing. Additional to gap junction alterations, patch clamping of MAdV-3-infected adult mouse ventricular cardiomyocytes reveals prolonged action potential duration as a result of decreasedIK1andIKscurrent density. Turning to human systems, we find human adenovirus type-5 (HAdV-5) increases phosphorylation of Cx43Ser368 and disrupts synchrony in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), indicating common mechanisms with our mouse whole heart and adult cardiomyocyte data.

Conclusions

Together, these findings demonstrate that adenoviral infection creates an arrhythmogenic substrate through direct targeting of gap junction and ion channel function in the heart. Such alterations are known to precipitate arrhythmias and likely contribute to sudden cardiac death in acutely infected patients.
No association between thePlasmodium vivax crt-oMS334 or In9pvcrtpolymorphisms and chloroquine failure in a clinical cohort from Malaysia
Authors: Rumaseb Angela , Moraes Barros Roberto R. , Sá Juliana M. , Juliano Jonathan J. , William Timothy , Braima Kamil A. , Barber Bridget E. , Anstey Nicholas M , Price Ric N. , Grigg Matthew J. , Auburn Sarah , Marfurt Jutta
Published: December 2022

Increasing reports of resistance to a frontline malaria blood-stage treatment, chloroquine (CQ), raise concerns for the elimination ofPlasmodium vivax. The absence of an effective molecular marker of CQ resistance inP. vivaxgreatly constrains surveillance of this emerging threat. A recent genetic cross between CQ sensitive (CQS) and CQ resistant (CQR) NIH-1993 strains ofP. vivaxlinked a moderate CQR phenotype with two candidate markers inP. vivaxCQ resistance transporter gene (pvcrt-o): MS334 and In9pvcrt. Longer TGAAGH motifs at MS334 were associated with CQ resistance, as were shorter motifs at the In9pvcrtlocus. In this study, high-grade CQR clinical isolates ofP. vivaxfrom Malaysia were used to investigate the association between the MS334 and In9pvcrtvariants and treatment efficacy. Amongst a total of 49 independent monoclonalP. vivaxisolates assessed, high-quality MS334 and In9pvcrtsequences could be derived from 30 (61%) and 23 (47%), respectively. Five MS334 and six In9pvcrtalleles were observed, with allele frequencies ranging from 2 to 76% and 3 to 71%, respectively. None of the clinical isolates had the same variant as the NIH-1993 CQR strain, and none were associated with CQ treatment failure (allp>0.05). Our findings suggest that thepvcrt-oMS334 and In9pvcrtmarkers cannot be used universally as markers of CQ treatment efficacy in an area of high-grade CQ resistance. Further studies applying hypothesis-free genome-wide approaches are warranted to identify more effective CQR markers forP. vivax.
Genome-wide meta-analysis identifies novel maternal risk variants and enables polygenic prediction of preeclampsia and gestational hypertension
Authors: Honigberg Michael C. , Truong Buu , Khan Raiyan R. , Xiao Brenda , Bhatta Laxmi , Vy Thi Ha , Guerrero Rafael F. , Schuermans Art , Selvaraj Margaret Sunitha , Patel Aniruddh P. , Koyama Satoshi , Cho So Mi Jemma , Vellarikkal Shamsudheen Karuthedath , Trinder Mark , Urbut Sarah M. , Gray Kathryn J. , Brumpton Ben M. , Patil Snehal , Zöllner Sebastian , Antopia Mariah C. ,   Genes & Health Research Team,   Estonian Biobank Research Team,   nuMoM2b Research Team, Saxena Richa , Nadkarni Girish N. , Do Ron , Yan Qi , Pe’er Itsik , Verma Shefali Setia , Gupta Rajat M. , Haas David M. , Martin Hilary C. , van Heel David A. , Laisk Triin , Natarajan Pradeep
Published: December 2022

Preeclampsia and gestational hypertension are common pregnancy complications associated with adverse maternal and offspring outcomes. Current tools for prediction, prevention, and treatment are limited. We tested the association of maternal DNA sequence variants with preeclampsia in 20,064 cases and 703,117 controls and with gestational hypertension in 11,027 cases and 412,788 controls across discovery and follow-up cohorts using multi-ancestry meta-analysis. Altogether, we identified 18 independent loci associated with preeclampsia/eclampsia and/or gestational hypertension, 12 of which are novel (e.g.,MTHFR-CLCN6,WNT3A,NPR3,PGR, andRGL3), including two loci (PLCE1,FURIN) identified in multi-trait analysis. Identified loci highlight the role of natriuretic peptide signaling, angiogenesis, renal glomerular function, trophoblast development, and immune dysregulation. We derived genome-wide polygenic risk scores that predicted preeclampsia/eclampsia and gestational hypertension in external datasets, independent of first trimester risk markers. Collectively, these findings provide mechanistic insights into the hypertensive disorders of pregnancy and advance pregnancy risk stratification.
Altered lipid homeostasis underlies selective neurodegeneration in SNX14 deficiency
Authors: Zhou Yijing , Sanchez Vanessa B. , Xu Peining , Flores-Mendez Marco , Ciesielski Brianna , Yoo Donna , Teshome Hiab , Henne Mike , O’Brien Tim , Mesaros Clementina , Akizu Naiara
Published: December 2022

Dysregulated lipid homeostasis is emerging as a potential cause of neurodegenerative disorders. However, evidence of errors in lipid homeostasis as a pathogenic mechanism of neurodegeneration remains limited. Here, we show that the cerebellar neurodegeneration caused by SNX14 deficiency is associated with lipid metabolism defects. Recentin vitroandin silicostudies indicate that SNX14 is an inter-organelle lipid transfer protein that regulates lipid droplet biogenesis and fatty acid desaturation, suggesting that human SNX14 deficiency belongs to an expanding class of cerebellar neurodegenerative disorders caused by altered cellular lipid homeostasis. To test this hypothesis, we generated a mouse model that recapitulates the human SNX14 deficiency at genetic and phenotypic level. Through histological and transcriptomic analyses, we demonstrate that cerebellar Purkinje cells are selectively vulnerable to SNX14 deficiency, while forebrain regions preserve their neuronal content. Ultrastructure and lipidomic studies reveal widespread lipid storage and metabolism defects in SNX14 deficient mice. Furthermore, we identify a unique lipid metabolite profile that links the accumulation of acylcarnitines with the selective cerebellar neurodegeneration in SNX14 deficiency. These findings highlight the importance of lipid homeostasis for neuronal function and survival and suggest a mechanism for selective cerebellar vulnerability to altered lipid homeostasis.
New gene evolution with subcellular expression patterns detected in PacBio-sequenced genomes ofDrosophilagenus
Authors: Dong Chuan , Zhang Li , Xia Shengqian , Sosa Dylan , Arsala Deanna , Long Manyuan
Published: December 2022

Previous studies described gene age distributions in the focal species ofDrosophila melanogaster. Using third-generation PacBio technology to sequenceDrosophilaspecies we investigated gene age distribution in the two subgenera ofDrosophila. Our work resulted in several discoveries. First, our data detected abundant new genes in entireDrosophilagenus. Second, in analysis of subcellular expression, we found that new genes tend to secret into extracellular matrix and are involved in regulation, environmental adaption, and reproductive functions. We also found that extracellular localization for new genes provides a possible environment to promote their fast evolution. Third, old genes tend to be enriched in mitochondrion and the plasma membrane compared with young genes which may support the endosymbiotic theory that mitochondria originate from bacteria that once lived in primitive eukaryotic cells. Fourth, as gene age becomes older the subcellular compartments in which their products reside broadens suggesting that the evolution of new genes in subcellular location drives functional evolution and diversity inDrosophilaspecies. Additionally, based on the analysis of RNA-Seq of twoD. melanogasterpopulations, we determined a universal paradigm of “from specific to constitutive” expression pattern during the evolutionary process of new genes.
Intercellular Mitochondrial Transfer as a Rescue Mechanism in Response to Protein Import Failure
Authors: Needs Hope I , Pereira Gonçalo C. , Glover Emily , Witt Alina , Hübner Wolfgang , Dodding Mark P. , Henley Jeremy M , Collinson Ian
Published: December 2022

Mitochondria are the powerhouses of eukaryotic cells, composed mostly of nuclear-encoded proteins imported from the cytosol. Thus, problems with the import machinery will disrupt their regenerative capacity and the cell’s energy (ATP) supplies–particularly troublesome for energy demanding cells like neurons and myocytes. Unsurprisingly then, dysfunctional import is implicated in disease. This study explores the consequences of import failure in mammalian cells; wherein, blocking the import machinery has profound effects on mitochondrial ultra-structure and dynamics, but, surprisingly, does not impact import. The explanation is an astonishing response involving intercellular mitochondrial transferviatunnelling nanotubes: for the import of healthy mitochondria and jettisoning of those with jammed import sites. These observations support the existence of a widespread mechanism for the rescue of mitochondrial protein import failure.

One-Sentence Summary

A mitochondrial import rescue mechanism involving intercellular mitochondrial transport through tunneling nanotubes (TNTs).