bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling Reactive Ammonia Uptake by Secondary Organic Aerosol in a Changing Climate: A WRF-CMAQ Evaluation
Authors: Zhu Shupeng , Wu Kai , Nizkorodov Sergey A. , Dabdub Donald
Published: March 2022

In addition to the well-constrained inorganic acid-base chemistry of ammonia resulting in fine particulate matter (PM2.5) formation, ammonia also reacts with certain organic compounds in secondary organic aerosol (SOA) to produce less basic nitrogen-containing organic compounds. In this study, the potential meteorology and air quality impacts of the heterogeneous uptake of NH3 by SOA are investigated using the WRF-CMAQ two-way coupled model, which calculates the two-way radiative forcing feedback caused by aerosol between meteorology and chemistry in a single simulation. Simulations with and without the NH3-SOA uptake are performed over the contiguous US for July 2014 and July 2050 under the RCP 8.5 IPCC scenario to study the potential impact of climate change. A comparison with multiple observation network data shows that the NH3-SOA uptake improves the model performance for PM2.5 prediction (bias reduced from −22% to −17%), especially the underestimation of organic carbon over the Southeastern US (bias reduced from −17% to −7%). Secondly, the addition of the NH3-SOA chemistry significantly impacts the concentration of NH3 and NH4+, thus affecting the modeled particle acidity. Including the NH3-SOA uptake also impacts the meteorological conditions through the WRF-CMAQ two-way feedback. Moreover, the impact on meteorological conditions results in different windspeed or dispersion conditions, thus affecting air quality predictions. Finally, simulations including the NH3-SOA uptake under the warmer climate conditions of 2050 show a smaller impact on air quality predictions than it does under current climate conditions. This study confirms the importance and necessity of including NH3-SOA chemistry in air quality predictions.
A microRNA Transcriptome-wide Association Study of Prostate Cancer Risk
Authors: Larson Nicholas B. , McDonnell Shannon K. , Fogarty Zachary , Liu Yuanhang , French Amy J. , Tillmans Lori S. , Cheville John C. , Wang Liang , Schaid Daniel J. , Thibodeau Stephen N.
Published: March 2022

Large genome-wide association studies have identified hundreds of single-nucleotide polymorphisms associated with increased risk of prostate cancer (PrCa), and many of these risk loci is presumed to confer regulatory effects on gene expression. While eQTL studies of long RNAs has yielded many potential risk genes, the relationship between PrCa risk genetics and microRNA expression dysregulation is understudied. We performed an microRNA transcriptome-wide association study of PrCa risk using small RNA sequencing and genome-wide genotyping data from N = 441 normal prostate epithelium tissue samples along with N = 411 prostate adenocarcinoma tumor samples from the Cancer Genome Atlas (TCGA). Genetically regulated expression prediction models were trained for all expressed microRNAs using the FUSION TWAS software. TWAS for PrCa risk was performed with both sets of models using single-SNP summary statistics from the recent PRACTICAL consortium PrCa case-control OncoArray GWAS meta-analysis. A total of 613 and 571 distinct expressed microRNAs were identified in the normal and tumor tissue datasets, respectively (overlap: 480). Among these, 79 (13%) normal tissue microRNAs demonstrated significant cis-heritability (median cis-h2 = 0.15, range: 0.03–0.79) for model training. Similar results were obtained from TCGA tumor samples, with 48 (9%) microRNA expression models successfully trained (median cis-h2 = 0.14, range: 0.06–0.60). Using normal tissue models, we identified two significant TWAS microRNA associations with PrCa risk: over-expression of mir-941 family microRNAs (PTWAS = 2.9E-04) and reduced expression of miR-3617-5p (PTWAS = 1.0E-03). The TCGA tumor TWAS also identified a significant association with miR-941 overexpression (PTWAS = 9.7E-04). Subsequent finemapping of the TWAS results using a multi-tissue database indicated limited evidence of causal status for each microRNA with PrCa risk (posterior inclusion probabilities <0.05). Future work will examine downstream regulatory effects of microRNA dysregulation as well as microRNA-mediated risk mechanisms via competing endogenous RNA relationships.
Case Report: Identification of a Novel Heterozygous Missense Mutation in COL4A3 Gene Causing Variable Phenotypes in an Autosomal-Dominant Alport Syndrome Family
Authors: Hu Yanglin , Li Wei , Tian Lulu , Fu Shuai , Min Yonglong , Liu Jia , Xiong Fei
Published: March 2022

Alport syndrome (AS) is a genetic kidney disease of basement membrane collagen disorder accounting for approximately 2% of ESRD patients. Next-generation and whole-exome sequencing methods are increasingly frequently used as an efficient tool not only for the diagnosis of AS but also for the establishment of genotype–phenotype correlation. We herein report the identification of a novel heterozygous missense mutation in COL4A3 gene (c.G3566A: p.G1189E) causing variable phenotypes in an ADAS Family based on the combination of clinical, histologic, pedigree, and genetic sequencing information. The proband is a 48-year-old Chinese woman suffering from persistent subnephrotic proteinuria and intermittent hematuria without renal function impairment over a 10-year time-span. Renal biopsy showed diffuse thin basement membrane and focal interstitial foam cell infiltration. The proband’s mother progressed to end-stage renal failure and the proband’s sister presented with subnephrotic proteinuria and intermittent hematuria as well. AS was highly suspected and confirmed by exome sequencing which revealed a novel heterozygous missense mutation in COL4A3 gene (c.G3566A: p.G1189E) in all the affected family members, although their current medical conditions vary significantly. Our present finding emphasizes the significance of next-generation sequencing technology for genetic screening which gives us an accurate clinical diagnosis of ADAS patients. The identification of c.G3566A as a new ADAS-related mutation contributes to both genetic diagnosis of ADAS and further functional study of COL4A3. The variable phenotypes from the same genotype of our case also provide more information to genotype–phenotype correlation study.
Origin and Evolution of Enzymes with MIO Prosthetic Group: Microbial Coevolution After the Mass Extinction Event
Authors: Peng Fei , Engel Ulrike , Aliyu Habibu , Rudat Jens
Published: March 2022

After major mass extinction events, ancient plants and terrestrial vertebrates were faced with various challenges, especially ultraviolet (UV) light. These stresses probably resulted in changes in the biosynthetic pathways, which employed the MIO (3,5-dihydro-5-methylidene-4H-imidazole-4-one)-dependent enzymes (ammonia-lyase and aminomutase), leading to enhanced accumulation of metabolites for defense against UV radiation, pathogens, and microorganisms. Up to now, the origin and evolution of genes from this superfamily have not been extensively studied. In this report, we perform an analysis of the phylogenetic relations between the members of the aromatic amino acid MIO-dependent enzymes (AAM), which demonstrate that they most probably have a common evolutionary origin from ancient bacteria. In early soil environments, numerous bacterial species with tyrosine ammonia-lyase genes (TAL; EC 4.3.1.23) developed tyrosine aminomutase (TAM; EC 5.4.3.6) activity as a side reaction for competing with their neighbors in the community. These genes also evolved into other TAL-like enzymes, such as histidine ammonia-lyase (HAL, EC 4.3.1.3) and phenylalanine ammonia-lyase (PAL; EC 4.3.1.24), in different bacterial species for metabolite production and accumulation for adaptation to adverse terrestrial environmental conditions. On the other hand, the existence of phenylalanine aminomutase (PAM; EC 5.4.3.10) and phenylalanine/tyrosine ammonia-lyase (PTAL; EC 4.3.1.25) strongly indicates the horizontal gene transfer (HGT) between bacteria, fungi, and plants in symbiotic association after acquiring the PAL gene from their ancestor.
Genomic Resources for Salminus brasiliensis
Authors: Graciano Raissa Cristina Dias , Oliveira Rafael Sachetto , Santos Isllas Miguel , Yazbeck Gabriel M.
Published: March 2022

The Neotropical region bears the most diverse freshwater fish fauna on the planet and is the stage for dramatic conservation struggles. Initiatives aiming for conservation of a single emblematic fish, a flagship species, to which different onlookers relate on a cultural/personal level, holds promise towards engagement and conservation actions benefiting whole biological communities and ecosystems. Here, we present the first comprehensive genomic resources for Salminus brasiliensis, a potential flagship Neotropical species. This fish faces pressing conservation issues, as well as taxonomic uncertainty, being a main species relevant to angling and commercial fisheries. We make available 178 million Illumina paired-end reads, 90 bases long, comprising 16 Gb (≈15X coverage) of filtered data, obtained from a primary genomic library of 500-bp fragments. We present the first de novo genomic assembly for S. brasiliensis, with ∼1 Gb (N50 = 10,889), as well as the coding genome annotation of 12,962 putative genes from assembled genomic fragments over 10 kb, most of which could be identified from the Ostariophysi GenBank database. We also provide a genome-wide panel for more than 80,000 predicted microsatellite loci for low-cost, fast and abundant DNA marker development for this species. A total of 47, among 52 candidates, empirically assayed microsatellites were confirmed as polymorphic in this fish. All genomic data produced for S. brasiliensis is hereby made publicly accessible. With the disclosure of these results, we intend to foster general biology studies and to provide tools to be applied immediately in conservation and aquaculture in this candidate flagship Neotropical species.
Bruton’s Tyrosine Kinase Supports Gut Mucosal Immunity and Commensal Microbiome Recognition in Autoimmune Arthritis
Authors: Bonami Rachel H. , Thurman Christina E. , Verma Sonam , Westlake Camille S. , Nyhoff Lindsay E. , Barron Bridgette B. , Reboldi Andrea , Kendall Peggy L.
Published: March 2022

Bruton’s tyrosine kinase (Btk) deficiency preferentially eliminates autoreactive B cells while sparing normal humoral responses, but has not been studied in mucosal immunity. Commensal microbes and intact BTK signaling have been independently shown to be essential for arthritis development in K/BxN mice. Here, we examine how BTK-mediated signaling interfaces with the gut microbiome.Btk-deficient K/BxN mice were found to have small Peyer’s Patches with reduced germinal center and IgA class-switched B cells. IgA-switched plasma cells in small intestines were reduced, especially in villi ofBtk-deficient mice. IgH CDR3 sequencing showed similar V gene diversity and somatic hypermutation frequency despiteBtkdeficiency but showed reduced CDR3 amino acid polarity, suggesting potential qualitative differences in the gut plasma cell repertoire. Small intestinal IgA was low and IgA coating of commensal bacteria was reduced. IgA-seq showed a shift in small intestinal microbes that are normally IgA-coated into the uncoated fraction inBtk-deficient mice. Overall, this study shows that BTK supports normal intestinal IgA development in response to commensals.

This manuscript was previously published as a preprint at:https://www.biorxiv.org/content/10.1101/2021.03.10.434762v2.
mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum Disorder
Authors: Wang Baojiang , Qin Yueyuan , Wu Qunyan , Li Xi , Xie Dongying , Zhao Zhongying , Duan Shan
Published: March 2022

Autism spectrum disorder (ASD) is a complex pervasive neurodevelopmental disorder and neuroinflammation may contribute to the pathogenesis of ASD. However, the exact mechanisms of abnormal release of proinflammatory mediators in ASD remain poorly understood. This study reports elevated plasma levels of the proinflammatory chemokine (C-C motif) ligand 5 (CCL5) in children with ASD, suggesting an aberrant inflammatory response appearing in the development of ASD. Mining of the expression data of brain or blood tissue from individuals with ASD reveals that mTOR signaling is aberrantly activated in ASD patients. Our in vitro study shows that suppression of mTOR reduces the gene expression and release of CCL5 from human microglia, supporting that CCL5 expression is regulated by mTOR activity. Furthermore, bacterial lipopolysaccharide (LPS)-induced CCL5 expression can be counteracted by siRNA against NF-κB, suggests a determining role of NF-κB in upregulating CCL5 expression. However, a direct regulatory relationship between the NF-κB element and the mTOR signaling pathway was not observed in rapamycin-treated cells. Our results show that the phosphorylated CREB can be induced to suppress CCL5 expression by outcompeting NF-κB in binding to CREB-binding protein (CREBBP) once the mTOR signaling pathway is inhibited. We propose that the activation of mTOR signaling in ASD may induce the suppression of phosphorylation of CREB, which in turn results in the increased binding of CREBBP to NF-κB, a competitor of phosphorylated CREB to drive expression of CCL5. Our study sheds new light on the inflammatory mechanisms of ASD and paves the way for the development of therapeutic strategy for ASD.
Macrophage Subsets and Death Are Responsible for Atherosclerotic Plaque Formation
Authors: Li Hongxia , Cao Zhiqiang , Wang Lili , Liu Chang , Lin Hongkun , Tang Yuhan , Yao Ping
Published: March 2022

Cardiovascular diseases, the notorious killer, are mainly caused by atherosclerosis (AS) characterized by lipids, cholesterol, and iron overload in plaques. Macrophages are effector cells and accumulate to the damaged and inflamed sites of arteries to internalize native and chemically modified lipoproteins to transform them into cholesterol-loaded foam cells. Foam cell formation is determined by the capacity of phagocytosis, migration, scavenging, and the features of phenotypes. Macrophages are diverse, and the subsets and functions are controlled by their surrounding microenvironment. Generally, macrophages are divided into classically activated (M1) and alternatively activated (M2). Recently, intraplaque macrophage phenotypes are recognized by the stimulation of CXCL4 (M4), oxidized phospholipids (Mox), hemoglobin/haptoglobin complexes [HA-mac/M(Hb)], and heme (Mhem). The pro-atherogenic or anti-atherosclerotic phenotypes of macrophages decide the progression of AS. Besides, apoptosis, necrosis, ferroptosis, autophagy and pyrotopsis determine plaque formation and cardiovascular vulnerability, which may be associated with macrophage polarization phenotypes. In this review, we first summarize the three most popular hypotheses for AS and find the common key factors for further discussion. Secondly, we discuss the factors affecting macrophage polarization and five types of macrophage death in AS progression, especially ferroptosis. A comprehensive understanding of the cellular and molecular mechanisms of plaque formation is conducive to disentangling the candidate targets of macrophage-targeting therapies for clinical intervention at various stages of AS.
Influence of Combination Antiretroviral Therapy on HIV-1 Serological Responses and Their Implications: A Systematic Review and Meta-Analysis
Authors: Liang Yuanhao , Lin Hongqing , Dzakah Emmanuel Enoch , Tang Shixing
Published: March 2022

We aimed to analyze HIV-1 seroreversion caused by combination antiretroviral therapy (cART) and to explore antibody levels of anti-HIV-1 as an alternative biomarker of HIV-1 reservoir. We searched PubMed, Embase, the Cochrane Library, and Web of Science up to August 2021 for publications about the performance of HIV-1 serological assays or the association between antibody responses against HIV-1 and HIV-1 reservoirs. Potential sources of heterogeneity were explored by meta-regression analysis, including the year of publication, country, pretreatment viral load, sample size, the timing of treatment, time on cART, and principle or type of serological assay. Twenty-eight eligible studies with a total population of 1,883 were included in the meta-analysis. The pooled frequency of HIV-1 seronegativity is 38.0% (95% CI: 28.0%–49.0%) among children with vertical HIV-1 infection and cART initiation at the age of less than 6 months, while the percentage of HIV-1 seronegativity declined to 1.0% (95% CI: 0%–3.0%) when cART was initiated at the age of >6 months. For adult patients, 16.0% (95% CI: 9.0%–24.0%) of them were serologically negative when cART was initiated at acute/early infection of HIV-1, but the seronegative reaction was rarely detected when cART was started at chronic HIV-1 infection. Substantial heterogeneity was observed among the studies to estimate the frequency of HIV-1 seronegativity in the early-cART population (I2≥ 70%,p< 0.05 and all), while mild heterogeneity existed for the deferred-cART subjects. Moreover, anti-HIV-1 antibody response positively correlates with HIV-1 reservoir size with a pooled rho of 0.43 (95% CI: 0.28–0.55), suggesting that anti-HIV antibody level may be a feasible biomarker of HIV-1 reservoir size.
Role of Immune Cells in Biliary Repair
Authors: Lan Tian , Qian Shuaijie , Tang Chengwei , Gao Jinhang
Published: March 2022

The biliary system is comprised of cholangiocytes and plays an important role in maintaining liver function. Under normal conditions, cholangiocytes remain in the stationary phase and maintain a very low turnover rate. However, the robust biliary repair is initiated in disease conditions, and different repair mechanisms can be activated depending on the pathological changes. During biliary disease, immune cells including monocytes, lymphocytes, neutrophils, and mast cells are recruited to the liver. The cellular interactions between cholangiocytes and these recruited immune cells as well as hepatic resident immune cells, including Kupffer cells, determine disease outcomes. However, the role of immune cells in the initiation, regulation, and suspension of biliary repair remains elusive. The cellular processes of cholangiocyte proliferation, progenitor cell differentiation, and hepatocyte-cholangiocyte transdifferentiation during biliary diseases are reviewed to manifest the underlying mechanism of biliary repair. Furthermore, the potential role of immune cells in crucial biliary repair mechanisms is highlighted. The mechanisms of biliary repair in immune-mediated cholangiopathies, inherited cholangiopathies, obstructive cholangiopathies, and cholangiocarcinoma are also summarized. Additionally, novel techniques that could clarify the underlying mechanisms of biliary repair are displayed. Collectively, this review aims to deepen the understanding of the mechanisms of biliary repair and contributes potential novel therapeutic methods for treating biliary diseases.
A Novel Gene CDC27 Causes SLE and Is Associated With the Disease Activity
Authors: Shang Shunlai , Zhou Yena , Chen Keng , Chen Lang , Li Ping , Li Diangeng , Cui Shaoyuan , Zhang Mei-Jun , Chen Xiangmei , Li Qinggang
Published: March 2022

Background

As genetic genetic factors are important in SLE, so screening causative genes is of great significance for the prediction and early prevention in people who may develop SLE. At present, it is very difficult to screen causative genes through pedigrees. The analytical method described herein can be used to screen causative genes for SLE and other complex diseases through pedigrees.

Methods

For the first time, 24 lupus pedigrees were analyzed by combining whole exon sequencing and a variety of biological information tools including common-specific analysis, pVAAST (pedigree variant annotation, analysis and search tool), Exomiser (Combining phenotype and PPI associated analysis), and FARVAT (family based gene burden), and the causative genes of these families with lupus identified. Selected causative genes in peripheral-blood mononuclear cells (PBMCs) were evaluated by quantitative polymerase chain reaction (qPCR).

Results

Cell division cycle 27 (CDC27) was screened out by common-specific analysis and Exomiser causative gene screening. FARVAT analysis on these families detected only CDC27 at the extremely significant level (false discovery rate <0.05) by three family-based burden analyses (BURDEN, CALPHA, and SKATO). QPCR was performed to detect for CDC27 in the PBMCs of the SLE family patients, sporadic lupus patients, and healthy people. Compared with the healthy control group, CDC27 expression was low in lupus patients (familial and sporadic patients) (P<0.05) and correlated with lupus activity indicators: negatively with C-reactive protein (CRP) (P<0.05) and erythrocyte sedimentation rate (P<0.05) and positively with complement C3 and C4 (P<0.05). The CDC27 expression was upregulated in PBMCs from SLE patients with reduced lupus activity after immunotherapy (P<0.05). Based on Receiver operating characteristic (ROC) curve analysis, the sensitivity and specificity of CDC27 in diagnosing SLE were 82.30% and 94.40%.

Conclusion

The CDC27 gene, as found through WES combined with multiple analytical method may be a causative gene of lupus. CDC27 may serve as a marker for the diagnosis of SLE and is closely related to the lupus activity. We hope that the analytical method in this study will be used to screen causative genes for other diseases through small pedigrees, especially among non-close relatives.
Phase-Field Simulation of γ′-Co3 (Al, W) Evolution Kinetics with Antiphase Boundaries in Co-Based Monocrystal Superalloys
Authors: Ju Yinfei , Li Yongsheng , Shi Shujing , Sang Peng , Wang Huiyu , Long Hongli
Published: March 2022

Antiphase boundaries (APBs) of L12 ordered γ′-Co3 (Al, W) precipitates have an essential effect on the high-temperature strength of Co-based monocrystal superalloys. In this work, the antiphase boundaries and their effects on the evolution kinetics of γ′ phase are studied with the phase-field model. The formation of APBs between γ′ phases with different crystallographic variants induces a sharp increase in free energy; the width of APBs measured by the edge-to-edge distances of the γ′ phase is consistent with the experimental results of superalloys. Also, a coupling behavior of Ostwald ripening and APB’s migration in the coarsening of the γ′ phase is revealed. In addition, the volume fraction of the γ′ phase with four antiphase domains is lower than that of the single-domain γ′ phase, and the time exponent of the particles’ number density of the γ′ phase at the steady coarsening stage changes from –0.99 of single domain to –0.8 of APBs. The results show that the high-energy APBs can reduce the coarsening rate of γ′ phases, which are significant in the microstructure and composition designing of the ordered precipitates with APBs in Co-based superalloys.
Can Gene Expression Analysis in Zero-Time Biopsies Predict Kidney Transplant Rejection?
Authors: Vonbrunn Eva , Angeloni Miriam , Büttner-Herold Maike , Müller-Deile Janina , Heller Katharina , Bleich Erik , Söllner Stefan , Amann Kerstin , Ferrazzi Fulvia , Daniel Christoph
Published: March 2022

Zero-time biopsies are taken to determine the quality of the donor organ at the time of transplantation. Histological analyses alone have so far not been able to identify parameters that allow the prediction of subsequent rejection episodes or graft survival. This study investigated whether gene expression analyses of zero-time biopsies might support this prediction. Using a well-characterized cohort of 26 zero-time biopsies from renal transplant patients that include 4 living donor (LD) and 22 deceased donor (DD) biopsies that later developed no rejection (Ctrl, n = 7), delayed graft function (DGF, n = 4), cellular (T-cell mediated rejection; TCMR, n = 8), or antibody-mediated rejection (ABMR, n = 7), we analyzed gene expression profiles for different types of subsequent renal transplant complication. To this end, RNA was isolated from formalin-fixed, paraffin-embedded (FFPE) sections and gene expression profiles were quantified. Results were correlated with transplant data and B-cell, and plasma cell infiltration was assessed by immunofluorescence microscopy. Both principal component analysis and clustering analysis of gene expression data revealed marked separation between LDs and DDs. Differential expression analysis identified 185 significant differentially expressed genes (adjusted p < 0.05). The expression of 68% of these genes significantly correlated with cold ischemia time (CIT). Furthermore, immunoglobulins were differentially expressed in zero-time biopsies from transplants later developing rejection (TCMR + ABMR) compared to non-rejected (Ctrl + DGF) transplants. In addition, immunoglobulin expression did not correlate with CIT but was increased in transplants with previous acute renal failure (ARF). In conclusion, gene expression profiles in zero-time biopsies derived from LDs are markedly different from those of DDs. Pre-transplant ARF increased immunoglobulin expression, which might be involved in triggering later rejection events. However, these findings must be confirmed in larger cohorts and the role of early immunoglobulin upregulation in zero-biopsies needs further clarification.
The Efficacy and Safety of Adalimumab in Treating Pediatric Noninfectious Chronic Anterior Uveitis With Peripheral Retinal Vascular Leakage: A Pilot Study
Authors: Song Hang , Zhao Chan , Xiao Junyan , Gao Fei , Li Donghui , Zhang Meifen
Published: March 2022

Purpose

This study is aimed to assess the efficacy of adalimumab in alleviating peripheral vascular leakage in pediatric chronic anterior uveitis patients, along with its ability to improve best-corrected visual acuity (BCVA) and inflammation parameters, its efficacy in reducing topical glucocorticosteroids (GCs) and systemic immunomodulatory therapy (IMT), and its safety profile.

Methods

A self-controlled study of pediatric chronic anterior uveitis patients who presented with peripheral retinal vascular leakage on ultra-widefield fluorescein fundus angiography and underwent adalimumab treatment was conducted. The primary outcome was the extent of retinal vascular leakage at the 3- and 6-month follow-up visits. Secondary outcomes included BCVA, inflammation parameters (fresh keratic precipitates, anterior chamber cell, and vitreous cell grades), frequency of topical glucocorticosteroid eye drops, IMT load, and adverse effects at the 3- and 6-month follow-up visits.

Results

Twenty patients with a mean age of 9.30 ± 3.26 years old were included. The mean follow-up period was 9.0 ± 3.0 months, with all patients followed up for at least 6 months. At the 3- and 6-month follow-ups, the peripheral vascular leakage score decreased significantly (2.87, 95% CI (2.14, 3.60), p < 0.001 for 3 months, 2.75, 95% CI (1.76, 3.73), p < 0.001 for 6 months). Alongside BCVA (p = 0.013 for 3 months, p = 0.005 for 6 months) was improved significantly, inflammatory parameters represented by fresh keratic precipitates, anterior chamber cell, and vitreous cell grades were improved significantly (p < 0.001, p < 0.001, for all parameters) and topical GC usage was significantly reduced (p < 0.001, p < 0.001) at 3 and 6 months. There was also a statistically significant reduction in systemic IMT load at 6 months (p < 0.001). Adverse events in the observation period included local redness around the injection site and mild upper respiratory symptoms.

Conclusion

Adalimumab could effectively alleviate peripheral vascular leakage in pediatric patients with chronic anterior uveitis. It could also be helpful in improving BCVA and inflammation parameters and decreasing topical glucocorticosteroid eye drops and systemic IMT. Adalimumab is generally safe for pediatric uveitis.
A Retrospective and Multicenter Study on COVID-19 in Inner Mongolia: Evaluating the Influence of Sampling Locations on Nucleic Acid Test and the Dynamics of Clinical and Prognostic Indexes
Authors: Yu Lan , Wang Ailan , Li Tianbao , Jin Wen , Tian Geng , Yun Chunmei , Gao Fei , Fan Xiuzhen , Wang Huimin , Zhang Huajun , Sun Dejun
Published: March 2022

COVID-19 is spreading widely, and the pandemic is seriously threatening public health throughout the world. A comprehensive study on the optimal sampling types and timing for an efficient SARS-CoV-2 test has not been reported. We collected clinical information and the values of 55 biochemical indices for 237 COVID-19 patients, with 37 matched non-COVID-19 pneumonia patients and 131 healthy people in Inner Mongolia as control. In addition, the results of dynamic detection of SARS-CoV-2 using oropharynx swab, pharynx swab, and feces were collected from 197 COVID-19 patients. SARS-CoV-2 RNA positive in feces specimen was present in approximately one-third of COVID-19 patients. The positive detection rate of SARS-CoV-2 RNA in feces was significantly higher than both in the oropharynx and nasopharynx swab (P < 0.05) in the late period of the disease, which is not the case in the early period of the disease. There were statistically significant differences in the levels of blood LDH, CRP, platelet count, neutrophilic granulocyte count, white blood cell number, and lymphocyte count between COVID-19 and non-COVID-19 pneumonia patients. Finally, we developed and compared five machine-learning models to predict the prognosis of COVID-19 patients based on biochemical indices at disease onset and demographic characteristics. The best model achieved an area under the curve of 0.853 in the 10-fold cross-validation.
The Benefits, Challenges and Impacts of Telehealth Student Clinical Placements for Accredited Health Programs During the COVID-19 Pandemic
Authors: Bacon Rachel , Hopkins Sian , Kellett Jane , Millar CaraJane , Smillie Linda , Sutherland Rebecca
Published: March 2022

Introduction

Despite the advantages of telehealth, there has been a reluctance in its widespread adoption. During the COVID-19 pandemic, telehealth services and related placements increased internationally. Yet, there is currently limited research on the use of telehealth for student clinical placements.

Aim

To explore the perceived benefits, challenges, and impacts of telehealth placements for key stakeholders (clients, students, clinical educators, and placement co-ordinators) in allied health courses.

Methods

Stakeholder experiences with telehealth placements, undertaken within an Australian Allied Health University Clinic, were explored in virtual focus groups held between November 2020 and March 2021. These discussions used semi-structured interview questions, were audiotaped and transcribed verbatim. They were then thematically analyzed independently by two researchers, then cross-checked for consistency, using a qualitative descriptive approach, with reflexivity applied.

Results

Twenty-six stakeholders from six allied health disciplines participated in seven homogeneous focus groups. Three themes were identified: (1) telehealth placements support competency development and graduate employability; (2) telehealth placements enable students to provide person centered-care; and (3) telehealth placements enabled innovation.

Conclusion

Telehealth placements can make a valuable contribution as part of an overall placement program within accredited health courses and offer distinct advantages to student learning outcomes.
Increasing of Blood Brain Barrier Permeability and the Association With Depression and Anxiety in Systemic Lupus Erythematosus Patients
Authors: Wang Xiangyu , Ma Lihua , Luo Yuli , Yang Yifan , Upreti Bibhuti , Cheng Yuqi , Cui Ruomei , Liu Shuang , Xu Jian
Published: March 2022

Objective

To study changes in blood brain barrier (BBB) permeability in systemic lupus erythematosus (SLE) patients, and explore the association between the alterations in BBB permeability and depression/anxiety in SLE.

Methods

Brain dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) images were collected from 42 SLE patients and 23 healthy controls (HCs). Based on the Patlak pharmacokinetic model, the Ktrans value of each voxel in the whole brain of each subject was calculated. BBB permeability indicator (the Ktrans value) between SLE patients and healthy control group was compared. Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) were used to assess the mental health of SLE patients. The difference in BBB permeability was compared on SLE patients with depression/anxiety, SLE patients without depression/anxiety and HCs by ANOVA analysis.

Results

The Ktrans value of the right insular region of the SLE group was significantly higher than that of the healthy control group. And the Ktrans value of the right insular region in SLE patients with depression/anxiety was significantly increased compared with SLE patients without depression/anxiety and HCs.

Conclusions

SLE patients have increased BBB permeability, mainly in the right insular area. The increased BBB permeability in the right insular region is associated with the depression/anxiety in SLE patients.
The Small RNA CyaR Activates Translation of the Outer Membrane Haem Receptor chuA in Enterohemorrhagic Escherichia coli
Authors: Sy Brandon M. , Tree Jai J.
Published: March 2022

To sense the transition from environment to host, bacteria use a range of environmental cues to control expression of virulence genes. Iron is tightly sequestered in host tissues and in the human pathogen enterohemorrhagic Escherichia coli (EHEC) iron-limitation induces transcription of the outer membrane haem transporter encoded by chuAS. ChuA expression is post-transcriptionally activated at 37°C by a FourU RNA thermometer ensuring that the haem receptor is only expressed under low iron, high temperature conditions that indicate the host. Here we demonstrate that expression of chuA is also independently regulated by the cAMP-responsive small RNA (sRNA) CyaR and transcriptional terminator Rho. These results indicate that chuAS expression is regulated at the transcription initiation, transcript elongation, and translational level. We speculate that additional sensing of the gluconeogenic environment allows further precision in determining when EHEC is at the gastrointestinal epithelium of the host. With previous studies, it appears that the chuAS transcript is controlled by eight regulatory inputs that control expression through six different transcriptional and post-transcriptional mechanisms. The results highlight the ability of regulatory sRNAs to integrate multiple environmental signals into a layered hierarchy of signal input.
A Novel Lineage of Cile-Like Viruses Discloses the Phylogenetic Continuum Across the Family Kitaviridae
Authors: Ramos-González Pedro L. , Chabi-Jesus Camila , Tassi Aline D. , Calegario Renata Faier , Harakava Ricardo , Nome Claudia F. , Kitajima Elliot W. , Freitas-Astua Juliana
Published: March 2022

An increasing number of plant species have been recognized or considered likely reservoirs of viruses transmitted by Brevipalpus mites. A tiny fraction of these viruses, primarily those causing severe economic burden to prominent crops, have been fully characterized. In this study, based on high-throughput sequencing, transmission electron microscopy analyses of virions in plant-infected tissues, viral transmission experiments, and the morphoanatomical identification of the involved Brevipalpus mites, we describe molecular and biological features of viruses representing three new tentative species of the family Kitaviridae. The genomes of Solanum violifolium ringspot virus (SvRSV, previously partially characterized), Ligustrum chlorotic spot virus (LigCSV), and Ligustrum leprosis virus (LigLV) have five open reading frames (ORFs) > 500 nts, two distributed in RNA1 and three in RNA2. RNA1 of these three viruses display the same genomic organization found in RNA1 of typical cileviruses, while their RNA2 are shorter, possessing only orthologs of genes p61, p32, and p24. LigCSV and LigLV are more closely related to each other than to SvRSV, but the identities between their genomic RNAs were lower than 70%. In gene-by-gene comparisons, ORFs from LigCSV and LigLV had the highest sequence identity values (nt sequences: 70–76% and deduced amino acid sequences: 74–83%). The next higher identity values were with ORFs from typical cileviruses, with values below 66%. Virions of LigLV (≈ 40 nm × 55 nm) and LigCSV (≈ 54 nm × 66 nm) appear almost spherical, contrasting with the bacilliform shape of SvRSV virions (≈ 47 nm × 101 nm). Mites collected from the virus-infected plants were identified as Brevipalpus papayensis, B. tucuman, and B. obovatus. Viruliferous B. papayensis mites successfully transmitted LigCSV to Arabidopsis thaliana. SvRSV, LigCSV, and LigLV seem to represent novel sub-lineages of kitaviruses that descent on parallel evolutionary branches from a common ancestor shared with the tentative cile-like virus hibiscus yellow blotch virus and typical cileviruses. Biological and molecular data, notably, the phylogenetic reconstruction based on the RdRp proteins in which strong support for monophyly of the family Kitaviridae is observed, mark an advance in the understanding of kitavirids.
Approaches to Unmask Functioning of the Uncultured Microbial Majority From Extreme Habitats on the Seafloor
Authors: Böhnke Stefanie , Perner Mirjam
Published: March 2022

Researchers have recognized the potential of enzymes and metabolic pathways hidden among the unseen majority of Earth’s microorganisms for decades now. Most of the microbes expected to colonize the seafloor and its subsurface are currently uncultured. Thus, their ability and contribution to element cycling remain enigmatic. Given that the seafloor covers ∼70% of our planet, this amounts to an uncalled potential of unrecognized metabolic properties and interconnections catalyzed by this microbial dark matter. Consequently, a tremendous black box awaits discovery of novel enzymes, catalytic abilities, and metabolic properties in one of the largest habitats on Earth. This mini review summarizes the current knowledge of cultivation-dependent and -independent techniques applied to seafloor habitats to unravel the role of the microbial dark matter. It highlights the great potential that combining microbiological and biogeochemical data from in situ experiments with molecular tools has for providing a holistic understanding of bio-geo-coupling in seafloor habitats and uses hydrothermal vent systems as a case example.
Unraveling the Effects of Biochemical Drivers on the Bacterial Communities and Volatile Profiles in Refrigerated Sturgeon Filets at 4°C
Authors: Tan Chunming , Xiao Mengyuan , Wu Ruiyun , Li Pinglan , Shang Nan
Published: March 2022

Spoilage bacteria seriously influence the flavor and quality of fish meat. In this study, we investigated the quality characteristics, bacterial community, and volatile profiles of refrigerated (4°C) sturgeon filets during 10-day storage. On day 10, the refrigerated samples showed the lowest bacterial diversity and the largest difference in microbiota and biochemistry. The dominant genera in the fresh samples were Macrococcus, Acinetobacter, Moraxella, Brucella, and Pseudomonas, while the dominant bacteria changed into Acinetobacter, Carnobacterium, Macrococcus, Pseudomonas, and Psychrobacter at the end of storage. Our results suggest that these dominant taxa contribute to the spoilage of the refrigerated sturgeon filets. Meanwhile, during the storage, total viable counts, total volatile basic nitrogen, thiobarbituric acid-reactive substances, and trichloroacetic acid-soluble peptide significantly increased (P < 0.05), while the sensory score decreased steadily. Additionally, the ATP-related compounds and the K-value showed similarly increasing trends. The shelf-life of the refrigerated sturgeon filets was less than 8 days. The gas chromatography–ion mobility spectrometry results suggest that hexanal, ethyl acetate, ethanol, butanal, 1-propanol, isopentyl alcohol, 2-pentanone, 2-heptanone, ethyl propanoate, and propyl sulfide are potential chemical spoilage markers. The predicted metabolic pathways indicated an abundant carbohydrate metabolism and amino metabolism in the refrigerated sturgeon filets. This study provides insight into the determinants of sturgeon shelf-life and the spoilage process involved in refrigerated fish.
Nested Spatial and Temporal Modeling of Environmental Conditions Associated With Genetic Markers of Vibrio parahaemolyticus in Washington State Pacific Oysters
Authors: Fries Brendan , Davis Benjamin J. K. , Corrigan Anne E. , DePaola Angelo , Curriero Frank C.
Published: March 2022

The Pacific Northwest (PNW) is one of the largest commercial harvesting areas for Pacific oysters (Crassostrea gigas) in the United States. Vibrio parahaemolyticus, a bacterium naturally present in estuarine waters accumulates in shellfish and is a major cause of seafood-borne illness. Growers, consumers, and public-health officials have raised concerns about rising vibriosis cases in the region. Vibrio parahaemolyticus genetic markers (tlh, tdh, and trh) were estimated using an most-probable-number (MPN)-PCR technique in Washington State Pacific oysters regularly sampled between May and October from 2005 to 2019 (N = 2,836); environmental conditions were also measured at each sampling event. Multilevel mixed-effects regression models were used to assess relationships between environmental measures and genetic markers as well as genetic marker ratios (trh:tlh, tdh:tlh, and tdh:trh), accounting for variation across space and time. Spatial and temporal dependence were also accounted for in the model structure. Model fit improved when including environmental measures from previous weeks (1-week lag for air temperature, 3-week lag for salinity). Positive associations were found between tlh and surface water temp, specifically between 15 and 26°C, and between trh and surface water temperature up to 26°C. tlh and trh were negatively associated with 3-week lagged salinity in the most saline waters (> 27 ppt). There was also a positive relationship between tissue temperature and tdh, but only above 20°C. The tdh:tlh ratio displayed analogous inverted non-linear relationships as tlh. The non-linear associations found between the genetic targets and environmental measures demonstrate the complex habitat suitability of V. parahaemolyticus. Additional associations with both spatial and temporal variables also suggest there are influential unmeasured environmental conditions that could further explain bacterium variability. Overall, these findings confirm previous ecological risk factors for vibriosis in Washington State, while also identifying new associations between lagged temporal effects and pathogenic markers of V. parahaemolyticus.
Pathogenic Leptospira Evolved a Unique Gene Family Comprised of Ricin B-Like Lectin Domain-Containing Cytotoxins
Authors: Chaurasia Reetika , Marroquin Alan S. , Vinetz Joseph M. , Matthias Michael A.
Published: March 2022

Leptospirosis is a globally important neglected zoonotic disease. Previous data suggest that a family of virulence-modifying (VM) proteins (PF07598) is a distinctive feature of group I pathogenic Leptospira that evolved as important virulence determinants. Here, we show that one such VM protein, LA3490 (also known as Q8F0K3), is expressed by Leptospira interrogans serovar Lai, as a secreted genotoxin that is potently cytotoxic to human cells. Structural homology searches using Phyre2 suggested that VM proteins are novel R-type lectins containing tandem N-terminal ricin B-chain-like β-trefoil domains. Recombinant LA3490 (rLA3490) and an N-terminal fragment, t3490, containing only the predicted ricin B domain, bound to the terminal galactose and N-acetyl-galactosamine residues, asialofetuin, and directly competed for asialofetuin-binding sites with recombinant ricin B chain. t3490 alone was sufficient for binding, both to immobilized asialofetuin and to the HeLa cell surface but was neither internalized nor cytotoxic. Treatment of HeLa cells with rLA3490 led to cytoskeleton disassembly, caspase-3 activation, and nuclear fragmentation, and was rapidly cytolethal. rLA3490 had DNase activity on mammalian and bacterial plasmid DNA. The combination of cell surface binding, internalization, nuclear translocation, and DNase functions indicate that LA3490 and other VM proteins evolved as novel forms of the bacterial AB domain-containing toxin paradigm.
Exchange of a Single Amino Acid Residue in the HybG Chaperone Allows Maturation of All H2-Activating [NiFe]-Hydrogenases in Escherichia coli
Authors: Haase Alexander , Sawers R. Gary
Published: March 2022

The biosynthesis of the NiFe(CN)2CO organometallic cofactor of [NiFe]-hydrogenase (Hyd) involves several discreet steps, including the synthesis of the Fe(CN)2CO group on a HypD-HypC scaffold complex. HypC has an additional function in transferring the Fe(CN)2CO group to the apo-precursor of the Hyd catalytic subunit. Bacteria that synthesize more than one Hyd enzyme often have additional HypC-type chaperones specific for each precursor. The specificity determinants of this large chaperone family are not understood. Escherichia coli synthesizes two HypC paralogs, HypC and HybG. HypC delivers the Fe(CN)2CO group to pre-HycE, the precursor of the H2-evolving Hyd-3 enzyme, while HybG transfers the group to the pre-HybC of the H2-oxidizing Hyd-2 enzyme. We could show that a conserved histidine residue around the amino acid position 50 in both HypC and HybG, when exchanged for an alanine, resulted in a severe reduction in the activity of its cognate Hyd enzyme. This reduction in enzyme activity proved to be due to the impaired ability of the chaperones to interact with HypD. Surprisingly, and only in the case of the HybGH52A variant, its co-synthesis with HypD improved its interaction with pre-HycE, resulting in the maturation of Hyd-3. This study demonstrates that the conserved histidine residue helps enhance the interaction of the chaperone with HypD, but additionally, and in E. coli only for HybG, acts as a determinant to prevent the inadvertent maturation of the wrong large-subunit precursor. This study identifies a new level of control exerted by a bacterium synthesizing multiple [NiFe]-Hyd to ensure the correct enzyme is matured only under the appropriate physiological conditions.
A Cell Wall Hydrolase MepH Is Negatively Regulated by Proteolysis Involving Prc and NlpI in Escherichia coli
Authors: Jeon Wook-Jong , Cho Hongbaek
Published: March 2022

Cell wall assembly of Gram-negative bacteria requires DD-endopeptidase activity that cleaves peptidoglycan (PG) crosslinks in addition to PG synthetic activity, and the activity of DD-endopeptidases needs to be tightly regulated to maintain cell wall integrity during PG expansion. Among the major DD-endopeptidases functioning for PG assembly in Escherichia coli, MepS and MepM have been shown to be negatively controlled by the periplasmic protease Prc. In this study, we performed a genetic selection using the synthetic lethality between the mepS and mepM mutations in rich medium to uncover regulatory mechanisms controlling the activity of DD-endopeptidases other than MepS and MepM. This selection revealed mutations in prc and nlpI as suppressors. Gene deletion analyses revealed that MepH is required for suppression of the MepS— MepM— growth defect by the prc or nlpI mutation. We also discovered that MepH is directly degraded by Prc and that this degradation is further promoted by NlpI. Thus, our study showed that all three DD-endopeptidases which play major roles in PG assembly of E. coli under normal physiological conditions are controlled by a common periplasmic protease.