bluuebunny/crossref_metadata_2025 huggingface dataset:
Assembly and Activity of the WASH Molecular Machine: Distinctive Features at the Crossroads of the Actin and Microtubule Cytoskeletons
Authors: Fokin Artem I. , Gautreau Alexis M.
Published: April 2021

The Arp2/3 complex generates branched actin networks at different locations of the cell. The WASH and WAVE Nucleation Promoting Factors (NPFs) activate the Arp2/3 complex at the surface of endosomes or at the cell cortex, respectively. In this review, we will discuss how these two NPFs are controlled within distinct, yet related, multiprotein complexes. These complexes are not spontaneously assembled around WASH and WAVE, but require cellular assembly factors. The centrosome, which nucleates microtubules and branched actin, appears to be a privileged site for WASH complex assembly. The actin and microtubule cytoskeletons are both responsible for endosome shape and membrane remodeling. Motors, such as dynein, pull endosomes and extend membrane tubules along microtubule tracks, whereas branched actin pushes onto the endosomal membrane. It was recently uncovered that WASH assembles a super complex with dynactin, the major dynein activator, where the Capping Protein (CP) is exchanged from dynactin to the WASH complex. This CP swap initiates the first actin filament that primes the autocatalytic nucleation of branched actin at the surface of endosomes. Possible coordination between pushing and pulling forces in the remodeling of endosomal membranes is discussed.
Autophagy Inhibitors Do Not Restore Peroxisomal Functions in Cells With the Most Common Peroxisome Biogenesis Defect
Authors: Klouwer Femke C. C. , Falkenberg Kim D. , Ofman Rob , Koster Janet , van Gent Démi , Ferdinandusse Sacha , Wanders Ronald J. A. , Waterham Hans R.
Published: April 2021

Peroxisome biogenesis disorders within the Zellweger spectrum (PBD-ZSDs) are most frequently associated with the c.2528G>A (p.G843D) mutation in the PEX1 gene (PEX1-G843D), which results in impaired import of peroxisomal matrix proteins and, consequently, defective peroxisomal functions. A recent study suggested that treatment with autophagy inhibitors, in particular hydroxychloroquine, would be a potential therapeutic option for PBD-ZSD patients carrying the PEX1-G843D mutation. Here, we studied whether autophagy inhibition by chloroquine, hydroxychloroquine and 3-methyladenine indeed can improve peroxisomal functions in four different cell types with the PEX1-G843D mutation, including primary patient cells. Furthermore, we studied whether autophagy inhibition may be the mechanism underlying the previously reported improvement of peroxisomal functions by L-arginine in PEX1-G843D cells. In contrast to L-arginine, we observed no improvement but a worsening of peroxisomal metabolic functions and peroxisomal matrix protein import by the autophagy inhibitors, while genetic knock-down of ATG5 and NBR1 in primary patient cells resulted in only a minimal improvement. Our results do not support the use of autophagy inhibitors as potential treatment for PBD-ZSD patients, whereas L-arginine remains a therapeutically promising compound.
Differential Transcriptomes and Methylomes of Trophoblast Stem Cells From Naturally-Fertilized and Somatic Cell Nuclear-Transferred Embryos
Authors: Sun Jin , Zheng Weisheng , Liu Wenqiang , Kou Xiaochen , Zhao Yanhong , Liang Zehang , Wang Lu , Zhang Zihao , Xiao Jing , Gao Rui , Gao Shaorong , Jiang Cizhong
Published: April 2021

Trophoblast stem cells (TSCs) are critical to mammalian embryogenesis by providing the cell source of the placenta. TSCs can be derived from trophoblast cells. However, the efficiency of TSC derivation from somatic cell nuclear transfer (NT) blastocysts is low. The regulatory mechanisms underlying transcription dynamics and epigenetic landscape remodeling during TSC derivation remain elusive. Here, we derived TSCs from the blastocysts by natural fertilization (NF), NT, and a histone deacetylase inhibitor Scriptaid-treated NT (SNT). Profiling of the transcriptomes across the stages of TSC derivation revealed that fibroblast growth factor 4 (FGF4) treatment resulted in many differentially expressed genes (DEGs) at outgrowth and initiated transcription program for TSC formation. We identified 75 transcription factors (TFs) that are continuously upregulated during NF TSC derivation, whose transcription profiles can infer the time course of NF not NT TSC derivation. Most DEGs in NT outgrowth are rescued in SNT outgrowth. The correct time course of SNT TSC derivation is inferred accordingly. Moreover, these TFs comprise an interaction network important to TSC stemness. Profiling of DNA methylation dynamics showed an extremely low level before FGF4 treatment and gradual increases afterward. FGF4 treatment results in a distinct DNA methylation remodeling process committed to TSC formation. We further identified 1,293 CpG islands (CGIs) whose DNA methylation difference is more than 0.25 during NF TSC derivation. The majority of these CGIs become highly methylated upon FGF4 treatment and remain in high levels. This may create a barrier for lineage commitment to restrict embryonic development, and ensure TSC formation. There exist hundreds of aberrantly methylated CGIs during NT TSC derivation, most of which are corrected during SNT TSC derivation. More than half of the aberrantly methylated CGIs before NT TSC formation are inherited from the donor genome. In contrast, the aberrantly methylated CGIs upon TSC formation are mainly from the highly methylated CGIs induced by FGF4 treatment. Functional annotation indicates that the aberrantly highly methylated CGIs play a role in repressing placenta development genes, etc., related to post-implantation development and maintaining TSC pluripotency. Collectively, our findings provide novel insights into the transcription dynamics, DNA methylation remodeling, and the role of FGF4 during TSC derivation.
Deciphering Gut Microbiota Dysbiosis and Corresponding Genetic and Metabolic Dysregulation in Psoriasis Patients Using Metagenomics Sequencing
Authors: Xiao Shiju , Zhang Guangzhong , Jiang Chunyan , Liu Xin , Wang Xiaoxu , Li Yafan , Cheng Meijiao , Lv Hongpeng , Xian Fuyang , Guo Xinwei , Tan Yong
Published: April 2021

Background

Increasing evidence has shown that alterations in the intestinal microbiota play an important role in the pathogenesis of psoriasis. The existing relevant studies focus on 16S rRNA gene sequencing, but in-depth research on gene functions and comprehensive identification of microbiota is lacking.

Objectives

To comprehensively identify characteristic gut microbial compositions, genetic functions and relative metabolites of patients with psoriasis and to reveal the potential pathogenesis of psoriasis.

Methods

DNA was extracted from the faecal microbiota of 30 psoriatic patients and 15 healthy subjects, and metagenomics sequencing and bioinformatic analyses were performed. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database, cluster of orthologous groups (COG) annotations, and metabolic analyses were used to indicate relative target genes and pathways to reveal the pathogenesis of psoriasis.

Results

Compared with healthy individuals, the gut microbiota of psoriasis patients displayed an alteration in microbial taxa distribution, but no significant difference in microbial diversity. A distinct gut microbial composition in patients with psoriasis was observed, with an increased abundance of the phyla Firmicutes, Actinobacteria and Verrucomicrobia and genera Faecalibacterium, Bacteroides, Bifidobacterium, Megamonas and Roseburia and a decreased abundance of the phyla Bacteroidetes, Euryarchaeota and Proteobacteria and genera Prevotella, Alistipes, and Eubacterium. A total of 134 COGs were predicted with functional analysis, and 15 KEGG pathways, including lipopolysaccharide (LPS) biosynthesis, WNT signaling, apoptosis, bacterial secretion system, and phosphotransferase system, were significantly enriched in psoriasis patients. Five metabolites, hydrogen sulfide (H2S), isovalerate, isobutyrate, hyaluronan and hemicellulose, were significantly dysregulated in the psoriatic cohort. The dysbiosis of gut microbiota, enriched pathways and dysregulated metabolites are relevant to immune and inflammatory response, apoptosis, the vascular endothelial growth factor (VEGF) signaling pathway, gut-brain axis and brain-skin axis that play important roles in the pathogenesis of psoriasis.

Conclusions

A clear dysbiosis was displayed in the gut microbiota profile, genetic functions and relative metabolites of psoriasis patients. This study is beneficial for further understanding the inflammatory pathogenesis of psoriasis and could be used to develop microbiome-based predictions and therapeutic approaches.
Exercise Training Preserves Myocardial Strain and Improves Exercise Tolerance in Doxorubicin-Induced Cardiotoxicity
Authors: Gomes-Santos Igor L. , Jordão Camila P. , Passos Clevia S. , Brum Patricia C. , Oliveira Edilamar M. , Chammas Roger , Camargo Anamaria A. , Negrão Carlos E.
Published: April 2021

Doxorubicin causes cardiotoxicity and exercise intolerance. Pre-conditioning exercise training seems to prevent doxorubicin-induced cardiac damage. However, the effectiveness of the cardioprotective effects of exercise training concomitantly with doxorubicin treatment remains largely unknown. To determine whether low-to-moderate intensity aerobic exercise training during doxorubicin treatment would prevent cardiotoxicity and exercise intolerance, we performed exercise training concomitantly with chronic doxorubicin treatment in mice. Ventricular structure and function were accessed by echocardiography, exercise tolerance by maximal exercise test, and cardiac biology by histological and molecular techniques. Doxorubicin-induced cardiotoxicity, evidenced by impaired ventricular function, cardiac atrophy, and fibrosis. Exercise training did not preserve left ventricular ejection fraction or reduced fibrosis. However, exercise training preserved myocardial circumferential strain alleviated cardiac atrophy and restored cardiomyocyte cross-sectional area. On the other hand, exercise training exacerbated doxorubicin-induced body wasting without affecting survival. Finally, exercise training blunted doxorubicin-induced exercise intolerance. Exercise training performed during doxorubicin-based chemotherapy can be a valuable approach to attenuate cardiotoxicity.
Effect of Groundwater on Noise-Based Monitoring of Crustal Velocity Changes Near a Produced Water Injection Well in Val d'Agri (Italy)
Authors: Berbellini Andrea , Zaccarelli Lucia , Faenza Licia , Garcia Alexander , Improta Luigi , De Gori Pasquale , Morelli Andrea
Published: April 2021

We study the crustal velocity changes occurred at the restart of produced water injection at a well in the Val d'Agri oil field in January–February 2015 using seismic noise cross-correlation analysis. We observe that the relative velocity variations fit well with the hydrometric level of the nearby Agri river, which may be interpreted as a proxy of the total water storage in the shallow aquifers of the Val d'Agri valley. We then remove from the relative velocity trend the contribution of hydrological variations and observe a decrease in relative velocity of ≈ 0.08% starting seven days after the injection restart. In order to investigate if this decreasing could be due to the water injection restart, we compute the medium diffusivity from its delay time and average station-well distance. We found diffusivity values in the range 1–5 m2/s, compatible with the observed delay time of the small-magnitude (ML ≤ 1.8) induced seismicity occurrences, triggered by the first injection tests in June 2006 and with the hydraulic properties of the hydrocarbon reservoir. Our results show that water storage variations can not be neglected in noise-based monitoring, and they can hide the smaller effects due to produced water injection.
Bariatric Surgery: Consequences on Functional Capacities in Patients With Obesity
Authors: Reinmann Aline , Gafner Simone Chantal , Hilfiker Roger , Bruyneel Anne-Violette , Pataky Zoltan , Allet Lara
Published: April 2021

Introduction

Bariatric surgery leads to loss of fat and fat-free mass (FFM). To preserve FFM it is recommended that weight loss interventions are accompanied by physical activity. However, it remains unknown if functional capacities spontaneously improve after a substantial weight loss. Study’s aim was to assess the effect of bariatric surgery on strength, functional capacities and quality of life of participants with a body mass index (BMI) ≥ 35 kg/m2.

Method

Anthropometric parameters (weight, BMI, waist circumference), physical functions (quadriceps strength, walking capacity, spatio-temporal gait parameters, dynamic balance, lower limb power) and quality of life were assessed before and at three months after the bariatric surgery in 33 individuals who did not follow any physical activity program.

Results

The anthropometric parameters, quality of life and three functional abilities (walking capacity, normal gait speed and lower limb power) improved significantly three months post-surgery. In contrast, fast gait speed, absolute strength, normalized strength, and dynamic balance did not improve.

Discussion

A massive weight loss should be accompanied by an exercise program aiming to maintain FFM and to enhance muscle strength and balance. Such a program might also enhance functional capacities and help to sustain the weight loss over time.
Valorization of Wastewater Resources Into Biofuel and Value-Added Products Using Microalgal System
Authors: Arora Kanika , Kaur Parneet , Kumar Pradeep , Singh Archana , Patel Sanjay Kumar Singh , Li Xiangkai , Yang Yung-Hun , Bhatia Shashi Kant , Kulshrestha Saurabh
Published: April 2021

Wastewater is not a liability, instead considered as a resource for microbial fermentation and value-added products. Most of the wastewater contains various nutrients like nitrates and phosphates apart from the organic constituents that favor microbial growth. Microalgae are unicellular aquatic organisms and are widely used for wastewater treatment. Various cultivation methods such as open, closed, and integrated have been reported for microalgal cultivation to treat wastewater and resource recovery simultaneously. Microalgal growth is affected by various factors such as sunlight, temperature, pH, and nutrients that affect the growth rate of microalgae. Microalgae can consume urea, phosphates, and metals such as magnesium, zinc, lead, cadmium, arsenic, etc. for their growth and reduces the biochemical oxygen demand (BOD). The microalgal biomass produced during the wastewater treatment can be further used to produce carbon-neutral products such as biofuel, feed, bio-fertilizer, bioplastic, and exopolysaccharides. Integration of wastewater treatment with microalgal bio-refinery not only solves the wastewater treatment problem but also generates revenue and supports a sustainable and circular bio-economy. The present review will highlight the current and advanced methods used to integrate microalgae for the complete reclamation of nutrients from industrial wastewater sources and their utilization for value-added compound production. Furthermore, pertaining challenges are briefly discussed along with the techno-economic analysis of current pilot-scale projects worldwide.
Ingestion and Depuration of Microplastics by a Planktivorous Coral Reef Fish, Pomacentrus amboinensis
Authors: Santana Marina F. M. , Dawson Amanda L. , Motti Cherie A. , van Herwerden Lynne , Lefevre Carine , Kroon Frederieke J.
Published: April 2021

Microplastics are ubiquitous contaminants in marine environments and organisms. Concerns about potential impacts on marine organisms are usually associated with uptake of microplastics, especially via ingestion. This study used environmentally relevant exposure conditions to investigate microplastic ingestion and depuration kinetics of the planktivorous damselfish,Pomacentrus amboinensis. Irregular shaped blue polypropylene (PP) particles (longest length 125–250 μm), and regular shaped blue polyester (PET) fibers (length 600–700 μm) were selected based on physical and chemical characteristics of microplastics commonly reported in the marine environment, including in coral reef ecosystems. Individual adult damselfish were exposed to a single dose of PP particles and PET fibers at concentrations reported for waters of the Great Barrier Reef (i.e., environmentally relevant concentrations, ERC), or future projected higher concentrations (10x ERC, 100x ERC). Measured microplastic concentrations were similar to their nominal values, confirming that PP particles and PET fibers were present at the desired concentrations and available for ingestion by individual damselfish. Throughout the 128-h depuration period, the 88 experimental fish were sampled 2, 4, 8, 16, 32, 64, and 128-h post microplastic exposure and their gastrointestinal tracts (GIT) analyzed for ingested microplastics. While damselfish ingested both experimental microplastics at all concentrations, body burden, and depuration rates of PET fibers were significantly larger and longer, respectively, compared to PP particles. For both microplastic types, exposure to higher concentrations led to an increase in body burden and lower depuration rates. These findings confirm ingestion of PP particles and PET fibers byP. amboinensisand demonstrate for the first time the influence of microplastic characteristics and concentrations on body burden and depuration rates. Finally, despite measures put in place to prevent contamination, extraneous microplastics were recovered from experimental fish, highlighting the challenge to completely eliminate contamination in microplastic exposure studies. These results are critical to inform and continuously improve protocols for future microplastics research, and to elucidate patterns of microplastic contamination and associated risks in marine organisms.
A Glycolysis-Based Long Non-coding RNA Signature Accurately Predicts Prognosis in Renal Carcinoma Patients
Authors: Cao Honghao , Tong Hang , Zhu Junlong , Xie Chenchen , Qin Zijia , Li Tinghao , Liu Xudong , He Weiyang
Published: April 2021

Background

The prognosis of renal cell carcinoma (RCC) varies greatly among different risk groups, and the traditional indicators have limited effect in the identification of risk grade in patients with RCC. The purpose of our study is to explore a glycolysis-based long non-coding RNAs (lncRNAs) signature and verify its potential clinical significance in prognostic prediction of RCC patients.

Methods

In this study, RNA data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate cox regression displayed six significantly related lncRNAs (AC124854.1, AC078778.1, EMX2OS, DLGAP1-AS2, AC084876.1, and AC026401.3) which were utilized in construction of risk score by a formula. The accuracy of risk score was verified by a series of statistical methods such as receiver operating characteristic (ROC) curves, nomogram and Kaplan-Meier curves. Its potential clinical significance was excavated by gene enrichment analysis.

Results

Kaplan-Meier curves and ROC curves showed reliability of the risk score to predict the prognosis of RCC patients. Stratification analysis indicated that the risk score was independent predictor compare to other traditional clinical parameters. The clinical nomogram showed highly rigorous with index of 0.73 and precisely predicted 1-, 3-, and 5-year survival time of RCC patients. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set enrichment analysis (GSEA) depicted the top ten correlated pathways in both high-risk group and low-risk group. There are 6 lncRNAs and 25 related mRNAs including 36 lncRNA-mRNA links in lncRNA-mRNA co-expression network.

Conclusion

This research demonstrated that glycolysis-based lncRNAs possessed an important value in survival prediction of RCC patients, which would be a potential target for future treatment.
HMGB1 Promotes the Release of Sonic Hedgehog From Astrocytes
Authors: Xiao Yifan , Sun Yan , Liu Wei , Zeng FanFan , Shi Junyu , Li Jun , Chen Huoying , Tu Chang , Xu Yong , Tan Zheng , Gong Feili , Shu Xiji , Zheng Fang
Published: April 2021

High mobility group box 1 protein (HMGB1) is known to be a trigger of inflammation in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, it may play a different role in some way. Here we investigated the effect of HMGB1 on promoting sonic hedgehog (shh) release from astrocytes as well as the possible signal pathway involved in it. Firstly, shh increased in astrocytes after administration of recombinant HMGB1 or decreased after HMGB1 was blocked when stimulated by homogenate of the onset stage of EAE. Moreover, the expression of HMGB1 receptors, toll-like receptor (TLR) 2 and receptor for advanced glycation end products (RAGE) increased after HMGB1 administration in primary astrocytes. However, the enhancing effect of HMGB1 on shh release from astrocytes was suppressed only after RAGE was knocked out or blocked. Mechanistically, HMGB1 functioned by activating RAGE-mediated JNK, p38, stat3 phosphorylation. Moreover, HMGB1 could induce shh release in EAE. Additionally, intracerebroventricular injection of recombinant shh protein on the onset stage of EAE alleviated the progress of disease and decreased demylination, compared to the mice with normal saline treatment. Overall, HMGB1 promoted the release of shh from astrocytes through signal pathway JNK, p38 and stat3 mediated by receptor RAGE, which may provide new insights of HMGB1 function in EAE.
Single-Nucleotide Variants in the AIM2 – Absent in Melanoma 2 Gene (rs1103577) Associated With Protection for Tuberculosis
Authors: Figueira Mariana Brasil de Andrade , de Lima Dhêmerson Souza , Boechat Antonio Luiz , Filho Milton Gomes do Nascimento , Antunes Irineide Assumpção , Matsuda Joycenéa da Silva , Ribeiro Thaís Rodrigues de Albuquerque , Felix Luana Sousa , Gonçalves Ariane Senna Fonseca , da Costa Allyson Guimarães , Ramasawmy Rajendranath , Pontillo Alessandra , Ogusku Mauricio Morishi , Sadahiro Aya
Published: April 2021

Tuberculosis (TB) remains a serious public health burden worldwide. TB is an infectious disease caused by the Mycobacterium tuberculosis Complex. Innate immune response is critical for controlling mycobacterial infection. NOD-like receptor pyrin domain containing 3/ absent in melanoma 2 (NLRP3/AIM2) inflammasomes are suggested to play an important role in TB. NLRP3/AIM2 mediate the release of pro-inflammatory cytokines IL-1β and IL-18 to control M. tuberculosis infection. Variants of genes involved in inflammasomes may contribute to elucidation of host immune responses to TB infection. The present study evaluated single-nucleotide variants (SNVs) in inflammasome genes AIM2 (rs1103577), CARD8 (rs2009373), and CTSB (rs1692816) in 401 patients with pulmonary TB (PTB), 133 patients with extrapulmonary TB (EPTB), and 366 healthy control (HC) subjects with no history of TB residing in the Amazonas state. Quantitative Real Time PCR was performed for allelic discrimination. The SNV of AIM2 (rs1103577) is associated with protection for PTB (padj: 0.033, ORadj: 0.69, 95% CI: 0.49-0.97). CTSB (rs1692816) is associated with reduced risk for EPTB when compared with PTB (padj: 0.034, ORadj: 0.50, 95% CI: 0.27-0.94). Serum IL-1β concentrations were higher in patients with PTB than those in HCs (p = 0,0003). The SNV rs1103577 of AIM2 appeared to influence IL-1β release. In a dominant model, individuals with the CC genotype (mean 3.78 ± SD 0.81) appeared to have a higher level of IL-1β compared to carriers of the T allele (mean 3.45 ± SD 0.84) among the patients with PTB (p = 0,0040). We found that SNVs of AIM2 and CTSB were associated with TB, and the mechanisms involved in this process require further study.
PMMA-Based Continuous Hemofiltration Modulated Complement Activation and Renal Dysfunction in LPS-Induced Acute Kidney Injury
Authors: Stasi Alessandra , Franzin Rossana , Divella Chiara , Sallustio Fabio , Curci Claudia , Picerno Angela , Pontrelli Paola , Staffieri Francesco , Lacitignola Luca , Crovace Antonio , Cantaluppi Vincenzo , Medica Davide , Ronco Claudio , de Cal Massimo , Lorenzin Anna , Zanella Monica , Pertosa Giovanni B. , Stallone Giovanni , Gesualdo Loreto , Castellano Giuseppe
Published: April 2021

Sepsis-induced acute kidney injury (AKI) is a frequent complication in critically ill patients, refractory to conventional treatments. Aberrant activation of innate immune system may affect organ damage with poor prognosis for septic patients. Here, we investigated the efficacy of polymethyl methacrylate membrane (PMMA)-based continuous hemofiltration (CVVH) in modulating systemic and tissue immune activation in a swine model of LPS-induced AKI. After 3 h from LPS infusion, animals underwent to PMMA-CVVH or polysulfone (PS)-CVVH. Renal deposition of terminal complement mediator C5b-9 and of Pentraxin-3 (PTX3) deposits were evaluated on biopsies whereas systemic Complement activation was assessed by ELISA assay. Gene expression profile was performed from isolated peripheral blood mononuclear cells (PBMC) by microarrays and the results validated by Real-time PCR. Endotoxemic pigs presented oliguric AKI with increased tubulo-interstitial infiltrate, extensive collagen deposition, and glomerular thrombi; local PTX-3 and C5b-9 renal deposits and increased serum activation of classical and alternative Complement pathways were found in endotoxemic animals. PMMA-CVVH treatment significantly reduced tissue and systemic Complement activation limiting renal damage and fibrosis. By microarray analysis, we identified 711 and 913 differentially expressed genes with a fold change >2 and a false discovery rate <0.05 in endotoxemic pigs and PMMA-CVVH treated-animals, respectively. The most modulated genes were Granzyme B, Complement Factor B, Complement Component 4 Binding Protein Alpha, IL-12, and SERPINB-1 that were closely related to sepsis-induced immunological process. Our data suggest that PMMA-based CVVH can efficiently modulate immunological dysfunction in LPS-induced AKI.
Transcriptomic Profiling Identifies Neutrophil-Specific Upregulation of Cystatin F as a Marker of Acute Inflammation in Humans
Authors: Sawyer Andrew J. , Garand Mathieu , Chaussabel Damien , Feng Carl G.
Published: April 2021

Cystatin F encoded by CST7 is a cysteine peptidase inhibitor known to be expressed in natural killer (NK) and CD8+ T cells during steady-state conditions. However, little is known about its expression during inflammatory disease states in humans. We have developed an analytic approach capable of not only identifying previously poorly characterized disease-associated genes but also defining regulatory mechanisms controlling their expression. By exploring multiple cohorts of public transcriptome data comprising 43 individual datasets, we showed that CST7 is upregulated in the blood during a diverse set of infectious and non-infectious inflammatory conditions. Interestingly, this upregulation of CST7 was neutrophil-specific, as its expression was unchanged in NK and CD8+ T cells during sepsis. Further analysis demonstrated that known microbial products or cytokines commonly associated with inflammation failed to increase CST7 expression, suggesting that its expression in neutrophils is induced by an endogenous serum factor commonly present in human inflammatory conditions. Overall, through the identification of CST7 upregulation as a marker of acute inflammation in humans, our study demonstrates the value of publicly available transcriptome data in knowledge generation and potential biomarker discovery.
Effect of Inflammatory Cytokines/Chemokines on Pulmonary Tuberculosis Culture Conversion and Disease Severity in HIV-Infected and -Uninfected Individuals From South Africa
Authors: Rambaran Santhuri , Naidoo Kogieleum , Lewis Lara , Hassan-Moosa Razia , Govender Dhineshree , Samsunder Natasha , Scriba Thomas J. , Padayatchi Nesri , Sivro Aida
Published: April 2021

Novel tuberculosis (TB) prevention and control strategies are urgently required. Utilising specimens from the Improving Retreatment Success (NCT02114684) trial we assessed the associations between inflammatory markers, measured during active TB, with treatment response and disease severity in HIV-infected and uninfected individuals. Multiplex immunoassays and ELISA were used to measure plasma expression of 24 cytokines/chemokines. Cytokines were log transformed to adjust for skewness. We conducted a nested, un-matched, case (n= 31) - control (n=101) study with cases defined as those participants who failed to sputum culture convert within 8-weeks of TB treatment initiation. Additionally, we examined the association between the measured cytokines and time to culture conversion and presence of lung cavitation using cox proportional hazards and logistic regression models, respectively. Multivariable analyses adjusted for a wide range of baseline clinical and demographic variables. IP-10 expression during active TB was associated with increased odds of sputum culture conversion by 8-weeks overall (aOR 4.255, 95% CI 1.025 – 17.544, p=0.046)) and among HIV-infected individuals (OR 10.204, 95% CI 1.247 – 83.333, p=0.030). Increased MCP-3 (aHR 1.723, 95% CI 1.040 – 2.855, p=0.035) and IL-6 (aHR 1.409, 95% CI 1.045 – 1.899, p=0.024) expression was associated with a shorter time to culture conversion in the total cohort. Higher plasma expression of IL-6 (aHR 1.783, 95% CI 1.128 – 2.820, p=0.013), IL-1RA (aHR 2.595, 95% CI 1.136 – 5.926, p=0.024), IP-10 (aHR 2.068, 95% CI 1.034 – 4.137, p=0.040) and IL-1α (aHR 2.008, 95% CI 1.053 – 3.831, p=0.035) were significantly associated with shorter time to culture conversion among HIV-infected individuals. Increased IL-6 and IL-1RA expression was significantly associated with the presence of lung cavitation during active TB in the total cohort (OR 2.543, 95% CI 1.254 – 5.160, p=0.010), (OR 4.639, 95% CI 1.203 – 21.031, p=0.047) and in HIV-infected individuals (OR 2.644, 95% CI 1.062 – 6.585, p=0.037), (OR 7.795, 95% CI 1.177 – 51.611, p=0.033) respectively. Our results indicate that inflammatory cytokines/chemokines play an important role in TB disease outcome. Importantly, the observed associations were stronger in multivariable models highlighting the impact of behavioural and clinical variables on the expression of immune markers as well as their potential effects on TB outcome.
Using Domain Based Latent Personal Analysis of B Cell Clone Diversity Patterns to Identify Novel Relationships Between the B Cell Clone Populations in Different Tissues
Authors: Alon Uri , Mokryn Osnat , Hershberg Uri
Published: April 2021

The B cell population is highly diverse and very skewed. It is divided into clones (B cells with a common mother cell). It is thought that each clone represents an initial B cell receptor specificity. A few clones are very abundant, comprised of hundreds or thousands of B cells while the majority have only a few cells per clone. We suggest a novel method - domain-based latent personal analysis (LPA), a method for spectral exploration of entities in a domain, which can be used to find the spectral spread of sub repertoires within a person. LPA defines a domain-based spectral signature for each sub repertoire. LPA signatures consist of the elements, in our case - the clones, that most differentiate the sub repertoire from the person’s abundance of clones. They include both positive elements, which describe overabundant clones, and negative elements that describe missing clones. The signatures can also be used to compare the sub repertoires they represent to each other. Applying LPA to compare the repertoires found in different tissues, we reiterated previous findings that showed that gut and blood tissues have separate repertoires. We further identify a third branch of clonal patterns typical of the lymphatic organs (Spleen, MLN, and bone marrow) separated from the other two categories. We developed a python version of LPA analysis that can easily be applied to compare clonal distributions - https://github.com/ScanLab-ossi/LPA. It could also be easily adapted to study other skewed sequence populations used in the analysis of B cell receptor populations, for instance, k-mers and V gene usage. These analysis types should allow for inter and intra-repertoire comparisons of diversity, which could revolutionize the way we understand repertoire changes and diversity.
Three-Dimensional Molecular Cartography of the Caribbean Reef-Building Coral Orbicella faveolata
Authors: Little Mark , George Emma E. , Arts Milou G. I. , Shivak Jade , Benler Sean , Huckeba Joel , Quinlan Zachary A. , Boscaro Vittorio , Mueller Benjamin , Güemes Ana Georgina Cobián , Rojas Maria Isabel , White Brandie , Petras Daniel , Silveira Cynthia B. , Haas Andreas F. , Kelly Linda Wegley , Vermeij Mark J. A. , Quinn Robert A. , Keeling Patrick J. , Dorrestein Pieter C. , Rohwer Forest , Roach Ty N. F.
Published: April 2021

All organisms host a diversity of associated viruses, bacteria, and protists, collectively defined as the holobiont. While scientific advancements have enhanced the understanding of the functional roles played by various components of the holobiont, there is a growing need to integrate multiple types of molecular data into spatially and temporally resolved frameworks. To that end, we mapped 16S and 18S rDNA metabarcoding, metatranscriptomics, and metabolomic data onto three-dimensional reconstructions of coral colonies to examine microbial diversity, microbial gene expression, and biochemistry on two colonies of the ecologically important, reef-building coral,Orbicella faveolataand their competitors (i.e., adjacent organisms interacting with the corals: fleshy algae, turf algae, hydrozoans, and other corals). Overall, no statistically significant spatial patterns were observed among the samples for any of the data types; instead, strong signatures of the macroorganismal hosts (e.g., coral, algae, hydrozoa) were detected, in the microbiome, the transcriptome, and the metabolome. The 16S rDNA analysis demonstrated higher abundance of Firmicutes in the coral microbiome than in its competitors. A single bacterial amplicon sequence variant from the genusClostridiumwas found exclusively in allO. faveolatasamples. In contrast to microbial taxa, a portion of the functionally annotated bacterial RNA transcripts (6.86%) and metabolites (1.95%) were ubiquitous in all coral and competitor samples. Machine learning analysis of microbial transcripts revealed elevated T7-like cyanophage-encoded photosystem II transcripts inO. faveolatasamples, while sequences involved in bacterial cell division were elevated in turf algal and interface samples. Similar analysis of metabolites revealed that bacterial-produced antimicrobial and antifungal compounds were highly enriched in coral samples. This study provides insight into the spatial and biological patterning of the coral microbiome, transcriptome, and metabolome.
Impacts of Changed Ice-Ocean Stress on the North Atlantic Ocean: Role of Ocean Surface Currents
Authors: Wu Yang , Wang Zhaomin , Liu Chengyan
Published: April 2021

The importance of considering ocean surface currents in ice-ocean stress calculation in the North Atlantic Ocean and Arctic sea ice is investigated for the first time using a global coupled ocean-sea ice model. Considering ocean surface currents in ice-ocean stress calculation weakens the ocean surface stress and Ekman pumping by about 7.7 and 15% over the North Atlantic Ocean, respectively. It also significantly reduces the mechanical energy input to ageostrophic and geostrophic currents, and weakens the mean and eddy kinetic energy by reducing the energy conversion rates of baroclinic and barotropic pathways. Furthermore, the strength of the Atlantic Meridional Overturning Circulation (AMOC), the Nordic Seas MOC, and the North Atlantic subpolar gyre are found to be reduced considerably (by 14.3, 31.0, and 18.1%, respectively). The weakened AMOC leads to a 0.12 PW reduction in maximum northward ocean heat transport, resulting in a reduced surface heat loss and lower sea surface temperature over the North Atlantic Ocean. This reduction also leads to a shrink in sea ice extent and an attenuation of sea ice thickness. These findings highlight the importance of properly considering both the geostrophic and ageostrophic components of ocean surface currents in ice-ocean stress calculation on ocean circulation and climate studies.
The Restoration of Vitamin D Levels Slows the Progression of Renal Ischemic Injury in Rats Previously Deficient in Vitamin D
Authors: dos Santos Michele Santiago , Canale Daniele , Bernardo Desiree Rita Denelle , Shimizu Maria Heloisa Massola , Seguro Antonio Carlos , Volpini Rildo Aparecido , de Bragança Ana Carolina
Published: April 2021

Chronic kidney disease (CKD) remains a global public health problem. The initial damage after ischemia/reperfusion (I/R) injury plays an important role in the pathogenesis of acute kidney injury (AKI) and predisposition to CKD. Several studies have been showing that nontraditional risk factors such as AKI and hypovitaminosis D could also be involved in CKD progression. Vitamin D deficiency (VDD) is associated with hemodynamic changes, activation of inflammatory pathways and renal disease progression (RDP) following I/R-AKI. Strategies for prevention and/or slowing RDP have been determined and the sufficiency of vitamin D has been emerging as a renoprotective factor in many diseases. Therefore, we investigated the effect of the restoration of vitamin D levels in the progression of I/R injury (IRI) in rats previously deficient in vitamin D. On day 30, male Wistar rats were submitted to bilateral 45 min IRI and divided into three groups: IRI, standard diet for 120 days; VDD+IRI, vitamin D-free diet for 120 days; and VDD+IRI+R, vitamin D-free diet in the first 30 days and just after I/R, we reintroduced the standard diet in the last 90 days. After the 120-day protocol, VDD+IRI+R rats presented an improvement in the renal function and renal protein handling followed by a smaller fractional interstitial area. Furthermore, those animals exhibited a reestablishment regarding the hemodynamic parameters and plasma levels of aldosterone, urea and PTH. In addition, the restoration of vitamin D levels reestablished the amount of MCP1 and the renal expressions of CD68+ and CD3+ cells in the VDD+IRI+R rats. Also, VDD+IRI+R rats showed a restoration regarding the amount of collagen type III and renal expressions of fibronectin, vimentin and α-SMA. Such changes were also accompanied by a reestablishment on the renal expression of VDR, Klotho, JG12, and TGF-β1. Our findings indicate that the restoration of vitamin D levels not only improved the renal function and hemodynamics but also reduced the inflammation and fibrosis lesions observed in I/R-AKI associated with VDD. Thus, monitoring of vitamin D status as well as its replacement in the early stages of kidney injury may be a therapeutic alternative in the mitigation of renal disease progression.
The Diagnostic Yield of the Multidisciplinary Discussion in Patients With COVID-19 Pneumonia
Authors: Calabrese Fiorella , Pezzuto Federica , Giraudo Chiara , Vedovelli Luca , Fortarezza Francesco , Del Vecchio Claudia , Lunardi Francesca , Fraia Anna Sara , Cocconcelli Elisabetta , Vuljan Stefania Edith , Gregori Dario , Crisanti Andrea , Balestro Elisabetta , Spagnolo Paolo
Published: April 2021

Purpose: The hypothesis of the study was that a multidisciplinary approach involving experienced specialists in diffuse parenchymal lung disease might improve the diagnosis of patients with COVID-19 pneumonia.

Methods: Two pulmonologists, two radiologists, and two pathologists reviewed 27 patients affected by severe COVID-19 pneumonia as the main diagnosis made by non-pulmonologists. To evaluate whether the contribution of specialists, individually and/or in combination, might modify the original diagnosis, a three-step virtual process was planned. The whole lung examination was considered the gold standard for the final diagnosis. The probability of a correct diagnosis was calculated using a model based on generalized estimating equations. The effectiveness of a multidisciplinary diagnosis was obtained by comparing diagnoses made by experienced pulmonologists with those made by non-pulmonologists.

Results: In 19% of cases, the diagnosis of COVID-19-related death was mainly incorrect. The probability of a correct diagnosis increased strikingly from an undedicated clinician to an expert specialist. Every single specialist made significantly more correct diagnoses than any non-pulmonologist. The highest level of accuracy was achieved by the combination of 3 expert specialists (p = 0.0003).

Conclusion: The dynamic interaction between expert specialists may significantly improve the diagnostic confidence and management of patients with COVID-19 pneumonia.
Spectrum and Clinical Characteristics of Symptomatic and Asymptomatic Coronavirus Disease 2019 (COVID-19) With and Without Pneumonia
Authors: Zeng Huihui , Ma Yiming , Zhou Zhiguo , Liu Wenlong , Huang Peng , Jiang Mingyan , Liu Qimi , Chen Ping , Luo Hong , Chen Yan
Published: April 2021

Background: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has become a global pandemic. Based on symptoms, COVID-19 cases can be classified as symptomatic or asymptomatic. However, there is limited information about the differences between COVID-19 patients with and without pneumonia. Our study aimed to further discuss the spectrum and clinical characteristics of symptomatic and asymptomatic COVID-19 patients with and without pneumonia.

Methods: In China, all COVID-19 cases are hospitalized in designated hospitals until two continuous negative oropharyngeal swabs obtained, which allows the professional monitoring of symptoms and clinical characteristics. We stratified all COVID-19 cases in our database and evaluated clinical characteristics in different COVID-19 subgroups (symptomatic with pneumonia, symptomatic without pneumonia, asymptomatic with pneumonia, and asymptomatic without pneumonia).

Results: According to symptoms and laboratory and radiologic findings, COVID-19 cases were defined as symptomatic with pneumonia, symptomatic without pneumonia, asymptomatic with pneumonia, or asymptomatic without pneumonia. There were differences in the clinical characteristics and prognosis among the four groups. Both non-invasive mechanical ventilation (18, 4.2%) and invasive mechanical ventilation (11, 2.6%) were applied in only the symptomatic with pneumonia group. Likewise, extracorporeal membrane oxygenation and continuous renal replacement therapy were applied in only the symptomatic with pneumonia group. There were no differences in viral load, the durations of viral shedding, and hospitalization among the four groups.

Conclusion: We have defined a comprehensive spectrum of COVID-19 with and without pneumonia. The symptomatic with pneumonia group consumed more medical resources than the other groups, and extra caution and monitoring should be applied in this group. The asymptomatic COVID-19 group had a similar viral load and viral shedding duration as the symptomatic COVID-19 group.
Three Immune-Related Prognostic mRNAs as Therapeutic Targets for Pancreatic Cancer
Authors: Zhang Cangang , Zou Yueji , Zhu Yanan , Liu Yi , Feng Hui , Niu Fan , He Pengcheng , Liu Haibo
Published: April 2021

Objective: Pancreatic cancer is a highly lethal malignancy globally. This study aimed to probe and validate immune-related prognostic mRNAs as therapeutic targets for pancreatic cancer.

Methods: Gene transcriptome data of pancreatic cancer and normal pancreas were retrieved from TCGA-GTEx projects. Two thousand four hundred and ninety-eight immune-related genes were obtained from the IMMUPORT database. Abnormally expressed immune-related genes were then identified. Under univariate and multivariate cox models, a gene signature was constructed. Its predictive efficacy was assessed via ROCs. The interactions between the 21 genes were analyzed by Spearson analysis and PPI network. Using the GEPIA and The Human Protein Atlas databases, their expression and prognostic value were evaluated. The TIMER database was utilized to determine the relationships between MET, OAS1, and OASL mRNAs and immune infiltrates. Finally, their mRNA expression was externally verified in the GSE15471 and GSE62452 datasets.

Results: An immune-related 21-gene signature was developed for predicting patients' prognosis. Following verification, this signature exhibited the well predictive performance. There were physical and functional interactions between them. MET, OAS1, and OASL mRNAs were all up-regulated in pancreatic cancer and associated with unfavorable prognosis. They showed strong correlations with tumor progression. Furthermore, the three mRNAs were distinctly associated with immune infiltrates. Their up-regulation was confirmed in the two external datasets.

Conclusion: These findings identified three immune-related prognostic mRNAs MET, OAS1, and OASL, which may assist clinicians to choose targets for immunotherapy and make personalized treatment strategy for pancreatic cancer patients.
Review of Kyotorphin Research: A Mysterious Opioid Analgesic Dipeptide and Its Molecular, Physiological, and Pharmacological Characteristics
Authors: Ueda Hiroshi
Published: April 2021

Tyrosine-arginine (kyotorphin), an opioid analgesic dipeptide, was discovered more than 40 years ago in 1979. The evidence accumulated during this period has established the physiological significance of kyotorphin as a neuromodulating peptide, and pharmacological applications. Some of the following important findings have been discussed in this review: (1) kyotorphin is unevenly distributed in the brain; it is found in high concentrations in the pain pathway, which involves the regions associated with morphine analgesia; (2) kyotorphin is subcellularly localized in the synaptosome fraction or nerve-ending particles; (3) a specific synthetase generates kyotorphin from tyrosine and arginine; (4) kyotorphin may be also processed from calpastatin by a novel calcium-activated neutral protease or calpain; (5) kyotorphin preloaded into the synaptosome is released by high K+ depolarization in a Ca2+-dependent manner; (6) kyotorphin has a specific G protein coupled receptor, which mediates the activation of phospholipase C (PLC) and inhibition of adenylyl cyclase through Gi; (7) leucine-arginine works as a specific kyotorphin receptor antagonist; 8) membrane-bound aminopeptidase or excretion through a peptide transporter, PEPT2, may contribute to the inactivation of kyotorphin; and (9) kyotorphin causes increased Met-enkephalin release from brain and spinal slices. It is also known that the opening of plasma membrane Ca2+ channels through a conformational coupling of the InsP3 receptor with the transient receptor potential C1, which is downstream of the kyotorphin receptor-mediated activation of Gi and PLC, could be a potential underlying mechanism of Met-enkephalin release. Considering these findings, translational research is an exciting domain that can be explored in the future. As kyotorphin is a small molecule, we could design function-added kyotorphin derivatives. These studies would include not only the brain-permeable kyotorphin derivatives but also hybrid kyotorphin derivatives conjugated with small compounds that have additional pharmacological actions. Further, since there are reports of kyotorphin being involved in either the etiology or treatment of Alzheimer's disease, epilepsy, inflammation, and chronic pain, studies on the beneficial effects of kyotorphin derivatives should also be expected in the future.