bluuebunny/crossref_metadata_2025 huggingface dataset:
Can Universities be a Gleam of Hope During COVID-19? Entrepreneurial Intentions Approach for Academia in Pakistan
Authors: Li Guohao , Pervaiz Sabeeh , He Qi
Published: July 2021

The COVID-19 epidemic has wreaked havoc on the economics of several countries. Downsizing, job shortages, and unemployment are among the significant effects. The markets are supported by the need to train and educate our youth to be job producers rather than job seekers. This study sought to investigate the role of universities in the formation of students’ attitudes toward entrepreneurship by analyzing the influence of locus of control, extracurricular activities, and curriculum on entrepreneurial intention among Pakistani university students. This study collected data from 536 students across 15 universities in Pakistan through a weblink questionnaire. SPSS and AMOS were used to test the theoretical model. Results confirmed that locus of control positively affects entrepreneurial intentions and is the strongest predictor among the other two variables. Extracurricular activities positively affect entrepreneurial intentions, and curriculum is also positively affecting entrepreneurial intentions. This study concluded that entrepreneurial education and acquaintance are essential in bringing entrepreneurial intentions among students. Locus of control is found to be the most substantial element in developing entrepreneurial intentions among students. Educational institutions can play a critical role by proactively contributing through their efficient and proficient curricula, professional and experienced teachers, and locus of control by combining curricular and co-curricular activities.
Lateral Lymph Node Metastases in T1a Papillary Thyroid Carcinoma: Stratification by Tumor Location and Size
Authors: Zhang Xiaojun , Chen Wenkuan , Fang Qigen , Fan Jie , Feng Lu , Guo Lanwei , Liu Shanting , Ge Hong , Du Wei
Published: July 2021

Objective

To analyze the incidence and risk factors for lateral lymph node metastases (LNMs) in T1a papillary thyroid carcinoma (PTC) with a focus on tumor location and size.

Materials and Methods

The incidence of lateral LNM in 345 cases of T1a PTC was retrospectively analyzed. Univariate and multivariate analyses were performed to assess the relationships between lateral LNM and clinicopathological characteristics.

Results

The incidence of skip metastasis to lateral LNM in T1a PTC located in the upper lobe was 12.1% (8/66). Logistic regression analysis indicated tumor size >5 mm (OR = 5.04, 95% CI = 1.79 to 14.18, P = 0.002), upper lobe location (OR = 7.68, 95% CI = 3.05–19.34, P < 0.001) and the number of central neck LNM (<2: OR = 24.79, 95% CI = 8.23–74.60, P < 0.001; ≥2: OR = 4.99, 95% CI = 1.95–12.73, P < 0.001) were independently associated with lateral LNM. Comparing the lateral and central LNM stratification based on tumor location revealed that both the incidences of lateral (33.3%) and central (30.3%) LNM of T1a PTC located in the upper lobe were higher than those of T1a PTC located in the middle and lower lobes. Of T1a PTC located in the upper lobe, the incidence of lateral LNM was 33.3% (22/66), which was higher than that [30.3% (20/66)] of central LNM. This finding is reversed in all T1a PTC cases and T1a PTC cases with tumor located in the middle and lower lobes.

Conclusion

A particularly high likelihood of lateral LNM was observed in T1a PTC patients with tumor located in the upper lobe of the thyroid gland, especially the tumor >5 mm in size, which could be considered a risk factor for lateral LNM in the clinical management of T1a PTC.
22q11.2 Low Copy Repeats Expanded in the Human Lineage
Authors: Vervoort Lisanne , Dierckxsens Nicolas , Pereboom Zjef , Capozzi Oronzo , Rocchi Mariano , Shaikh Tamim H. , Vermeesch Joris R.
Published: July 2021

Segmental duplications or low copy repeats (LCRs) constitute duplicated regions interspersed in the human genome, currently neglected in standard analyses due to their extreme complexity. Recent functional studies have indicated the potential of genes within LCRs in synaptogenesis, neuronal migration, and neocortical expansion in the human lineage. One of the regions with the highest proportion of duplicated sequence is the 22q11.2 locus, carrying eight LCRs (LCR22-A until LCR22-H), and rearrangements between them cause the 22q11.2 deletion syndrome. The LCR22-A block was recently reported to be hypervariable in the human population. It remains unknown whether this variability also exists in non-human primates, since research is strongly hampered by the presence of sequence gaps in the human and non-human primate reference genomes. To chart the LCR22 haplotypes and the associated inter- and intra-species variability, we de novo assembled the region in non-human primates by a combination of optical mapping techniques. A minimal and likely ancient haplotype is present in the chimpanzee, bonobo, and rhesus monkey without intra-species variation. In addition, the optical maps identified assembly errors and closed gaps in the orthologous chromosome 22 reference sequences. These findings indicate the LCR22 expansion to be unique to the human population, which might indicate involvement of the region in human evolution and adaptation. Those maps will enable LCR22-specific functional studies and investigate potential associations with the phenotypic variability in the 22q11.2 deletion syndrome.
Prediction of Disease Genes Based on Stage-Specific Gene Regulatory Networks in Breast Cancer
Authors: Fan Linzhuo , Hou Jinhong , Qin Guimin
Published: July 2021

Breast cancer is one of the most common malignant tumors in women, which seriously endangers women’s health. Great advances have been made over the last decades, however, most studies predict driver genes of breast cancer using biological experiments and/or computational methods, regardless of stage information. In this study, we propose a computational framework to predict the disease genes of breast cancer based on stage-specific gene regulatory networks. Firstly, we screen out differentially expressed genes and hypomethylated/hypermethylated genes by comparing tumor samples with corresponding normal samples. Secondly, we construct three stage-specific gene regulatory networks by integrating RNA-seq profiles and TF-target pairs, and apply WGCNA to detect modules from these networks. Subsequently, we perform network topological analysis and gene set enrichment analysis. Finally, the key genes of specific modules for each stage are screened as candidate disease genes. We obtain seven stage-specific modules, and identify 20, 12, and 22 key genes for three stages, respectively. Furthermore, 55%, 83%, and 64% of the genes are associated with breast cancer, for example E2F2, E2F8, TPX2, BUB1, and CKAP2L. So it may be of great importance for further verification by cancer experts.
The Impact of Programmed Cell Death on the Formation of Tertiary Lymphoid Structures
Authors: Dieudé Mélanie , Kaci Imane , Hébert Marie-Josée
Published: July 2021

Tertiary lymphoid structures are clusters of lymphoid tissue that develop post-natally at sites of chronic inflammation. They have been described in association with infection, autoimmune disorders, cancer, and allograft rejection. In their mature stage, TLS function as ectopic germinal centers, favoring the local production of autoantibodies and cytokines. TLS formation tends to parallel the severity of tissue injury and they are usually indicative of locally active immune responses. The presence of TLS in patients with solid tumors is usually associated with a better prognosis whereas their presence predicts increased maladaptive immunologic activity in patients with autoimmune disorders or allograft transplantation. Recent data highlight a correlation between active cell death and TLS formation and maturation. Our group recently identified apoptotic exosome-like vesicles, released by apoptotic cells, as novel inducers of TLS formation. Here, we review mechanisms of TLS formation and maturation with a specific focus on the emerging importance of tissue injury, programmed cell death and extracellular vesicles in TLS biogenesis.
APRANK: Computational Prioritization of Antigenic Proteins and Peptides From Complete Pathogen Proteomes
Authors: Ricci Alejandro D. , Brunner Mauricio , Ramoa Diego , Carmona Santiago J. , Nielsen Morten , Agüero Fernán
Published: July 2021

Availability of highly parallelized immunoassays has renewed interest in the discovery of serology biomarkers for infectious diseases. Protein and peptide microarrays now provide a rapid, high-throughput platform for immunological testing and validation of potential antigens and B-cell epitopes. However, there is still a need for tools to prioritize and select relevant probes when designing these arrays. In this work we describe a computational method called APRANK (Antigenic Protein and Peptide Ranker) which integrates multiple molecular features to prioritize potentially antigenic proteins and peptides in a given pathogen proteome. These features include subcellular localization, presence of repetitive motifs, natively disordered regions, secondary structure, transmembrane spans and predicted interaction with the immune system. We trained and tested this method with a number of bacteria and protozoa causing human diseases: Borrelia burgdorferi (Lyme disease), Brucella melitensis (Brucellosis), Coxiella burnetii (Q fever), Escherichia coli (Gastroenteritis), Francisella tularensis (Tularemia), Leishmania braziliensis (Leishmaniasis), Leptospira interrogans (Leptospirosis), Mycobacterium leprae (Leprae), Mycobacterium tuberculosis (Tuberculosis), Plasmodium falciparum (Malaria), Porphyromonas gingivalis (Periodontal disease), Staphylococcus aureus (Bacteremia), Streptococcus pyogenes (Group A Streptococcal infections), Toxoplasma gondii (Toxoplasmosis) and Trypanosoma cruzi (Chagas Disease). We have evaluated this integrative method using non-parametric ROC-curves and made an unbiased validation using Onchocerca volvulus as an independent data set. We found that APRANK is successful in predicting antigenicity for all pathogen species tested, facilitating the production of antigen-enriched protein subsets. We make APRANK available to facilitate the identification of novel diagnostic antigens in infectious diseases.
Gout Augments the Risk of Cardiovascular Disease in Patients With Psoriasis: A Population-Based Cohort Study
Authors: Chen Zhiyong , Xu Yiwen , Chen Miao , Cui Ran , Wang Yu-Hsun , Dai Sheng-Ming , Wei James Cheng-Chung
Published: July 2021

Objective

Patients with psoriasis (PsO) have a high frequency of concomitant gout and increased risk of cardiovascular diseases (CVD). We aimed to estimate the synergistic impact of gout on the risk of CVD in patients with PsO.

Methods

A population-based cohort of patients registered in the National Health Insurance Research Database of Taiwan between 2000 and 2013 was stratified according to the presence of PsO and gout. Propensity score analysis was used to match age and gender at a ratio of 1:4. Cox proportional hazard models and subgroup analyses were used to estimate the hazard ratios (HRs) for CVD adjusted for traditional risk factors. The Kaplan–Meier method was used to plot the cumulative incidence curves.

Results

Patients with combined PsO and gout (n = 97), PsO alone (n = 388), gout alone (matched, n = 388) and matched controls (n = 388) were identified. Compared with the patients with PsO alone, the patients with combined PsO and gout had a significantly higher risk of CVD (relative risk 2.39, 95% CI 1.56 to 3.65). After adjustment for traditional risk factors, the risk of CVD was higher in patients with gout alone (HR 2.16, 95% CI 1.54 to 3.04) and in patients with combined PsO and gout (HR 2.72, 95% CI 1.73 to 4.28).

Conclusions

Gout augments the risk of CVD independently of traditional risk factors in patients with PsO.
Duck Tembusu Virus Infection Promotes the Expression of Duck Interferon-Induced Protein 35 to Counteract RIG-I Antiviral Signaling in Duck Embryo Fibroblasts
Authors: Zhou Peng , Ma Lei , Rao Zaixiao , Li Yaqian , Zheng Huijun , He Qigai , Luo Rui
Published: July 2021

Duck Tembusu virus (DTMUV) is an emerging pathogenic flavivirus that has caused a substantial drop in egg production and severe neurological disorders in domestic waterfowl. Several studies have revealed that viral proteins encoded by DTMUV antagonize host IFN-mediated antiviral responses to facilitate virus replication. However, the role of host gene expression regulated by DTMUV in innate immune evasion remains largely unknown. Here, we utilized a stable isotope labeling with amino acids in cell culture (SILAC)-based proteomics analysis of DTMUV-infected duck embryo fibroblasts (DEFs) to comprehensively investigate host proteins involved in DTMUV replication and innate immune response. A total of 250 differentially expressed proteins were identified from 2697 quantified cellular proteins, among which duck interferon-induced protein 35 (duIFI35) was dramatically up-regulated due to DTMUV infection in DEFs. Next, we demonstrated that duIFI35 expression promoted DTMUV replication and impaired Sendai virus-induced IFN-β production. Moreover, duIFI35 was able to impede duck RIG-I (duRIG-I)-induced IFN-β promoter activity, rather than IFN-β transcription mediated by MDA5, MAVS, TBK1, IKKϵ, and IRF7. Importantly, we found that because of the specific interaction with duIFI35, the capacity of duRIG-I to recognize double-stranded RNA was significantly impaired, resulting in the decline of duRIG-I-induced IFN-β production. Taken together, our data revealed that duIFI35 expression stimulated by DTMUV infection disrupted duRIG-I-mediated host antiviral response, elucidating a distinct function of duIFI35 from human IFI35, by which DTMUV escapes host innate immune response, and providing information for the design of antiviral drug.
CD4+CD25+CD127-Foxp3+ and CD8+CD28- Tregs in Renal Transplant Recipients: Phenotypic Patterns, Association With Immunosuppressive Drugs, and Interaction With Effector CD8+ T Cells and CD19+IL-10+ Bregs
Authors: Aly Mostafa G. , Ibrahim Eman H. , Karakizlis Hristos , Weimer Rolf , Opelz Gerhard , Morath Christian , Zeier Martin , Ekpoom Naruemol , Daniel Volker
Published: July 2021

Introduction

Gaps still exist regarding knowledge on regulatory cells in transplant recipients. We studied the phenotypic patterns of CD4+, CD8+CD28- Tregs, and CD19+IL-10+ Bregs in the blood of healthy controls (HC), end-stage kidney disease patients (ESKD), early and late stable renal transplant recipients (Tx), and transplant recipients with steroid-treated acute cellular rejection 1 week–3 months after successful treatment. We also investigated the relationship between immunosuppressive drugs and the aforementioned regulatory cells in transplant recipients.

Methods

We recruited 32 HC, 83 ESKD, 51 early Tx, 95 late Tx, and 9 transplant patients with a recent steroid-treated acute cellular rejection. Besides CD19+IL-10+ Bregs, we analyzed absolute and relative frequencies of CD4+CD25+CD127-Foxp3+ Tregs and CD8+CD28- Tregs and their expression of IL-10, TGF-ß, IFN-g, and Helios.

Results

We found a negative correlation between absolute CD4+CD25+CD127-Foxp3+ Treg and relative CD19+IL-10+ Breg frequencies in early Tx recipients (r=-0.433, p=0.015, n=31). In that group, absolute CD4+CD25+CD127-Foxp3+ Tregs were negatively associated with steroid dose and tacrolimus trough levels (r=-0.377, p = 0.021, n=37; r=-0.43, p=0.033, n=25, respectively), opposite to IL-10+ Bregs, whose frequency apparently was not negatively affected by potent immunosuppression early posttransplant. We found also lower CD4+CD25+CD127-Foxp3+ Tregs in patients treated with basiliximab or rATG as compared with ESKD patients (p=0.001 and p <0.001, respectively). No difference in absolute IL-10+ Bregs could be detected among these 3 patient groups. Early Tx recipients showed lower CD4+CD25+CD127-Foxp3+ Tregs within 3 months of antibody induction than after 3 months (p = 0.034), whereas IL-10+ Bregs showed higher relative counts during the first 3 months post antibody induction than after 3 months (p = 0.022). Our findings suggest that IL-10+ Bregs decrease with time posttransplantation independent of the effect of antibody induction and dose of other immunosuppressive drugs.

Conclusion

These findings suggest that CD19+IL-10+ Bregs and CD4+CD25+CD127-Foxp3+ Tregs behave in opposite ways during the early posttransplant period, possibly due to a predominant negative impact of high doses of immunosuppressants on Tregs. CD19+IL-10+Bregs do not seem to be suppressed by antibody induction and early potent immunosuppression with chemical drugs.
Suitability of Free-Living Marine Nematodes as Bioindicators: Status and Future Considerations
Authors: Ridall Aaron , Ingels Jeroen
Published: July 2021

Nematodes are among the most abundant organisms on Earth, and have important roles in terrestrial, freshwater, and marine ecosystems. Free-living marine nematodes have been used successfully as indicators of biological health and ocean pollution for at least the past 40 years, but their use as bioindicators is not ubiquitous. They have been most often used specifically as indicators of heavy metal and hydrocarbon pollution, with far fewer instances of their use as indicators of biological, environmental, or physical perturbations. Although free-living marine nematodes are among the best bioindicators owing to their worldwide distributions, abundances, and genus- and species-specific responses to environmental pollution, there are still some challenges that prevent their use globally. Here, we present a review of characteristics that make free-living marine nematodes excellent bioindicators, recent studies that have used them as bioindicators, and suggestions for future directions in the use of these fauna as indicators in the marine environment. Specifically, we consider the use of marine nematodes for microplastics (an understudied class of pollutants that are a future threat to global biodiversity), the value of current nematode indices as measures of ecosystem health, and the importance of improved and continued international collaboration in the field of marine nematology.
Genetics of Severe Cutaneous Adverse Reactions
Authors: Yang Shang-Chen , Chen Chun-Bing , Lin Mao-Ying , Zhang Zhi-Yang , Jia Xiao-Yan , Huang Ming , Zou Ya-Fen , Chung Wen-Hung
Published: July 2021

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) are T cells-mediated life-threatening immune reactions, most commonly induced by drug. The last decade has seen significant progress in SCARs research. Recent studies have unveiled the pathogenesis of SCARs involved in susceptible genes, including human leukocyte antigens (HLA) and drugs-T cell receptor (TCR) interaction that may trigger T cell activation with downstream immune signaling of cytokines/chemokines and specific cytotoxic proteins releases. Advances in identification of multiple genetic alleles associated with specific drugs related SCARS in different populations is an important breakthrough in recent years for prevention of SCARs. This article summarized the findings on genetic factors related to SJS/TEN, especially for HLA.
Geographic and Age Variations in Low Body Mass Index Among Community-Dwelling Older People in Xinjiang: A Cross-Sectional Study
Authors: Liu Jinling , Qu Qun , Xuekelati Saiyare , Bai Xue , Wang Li , Xiang Hong , Wang Hongmei
Published: July 2021

Background: Studies have shown an association between undernutrition and increased adverse outcome, as well as substantial geographic and age variations in undernutrition. Body mass index (BMI), a core indicator of undernutrition, is easy to measure and reflects the nutritional and health status of the human body. It is a simple and suitable tool for epidemiological investigations in large sample populations. Herein, we provide the first description of geographic and age variations in the prevalence of low BMI among community-dwelling older people in Xinjiang.

Methods: From January 2019 to December 2019, using a multi-stage random sampling method, we conducted a cross-sectional epidemiological survey of the community-dwelling older people in Xinjiang at different latitudes. Of the 87,000 participants, the statistical analyses included 86,514 participants with complete data.

Results: In Xinjiang, the prevalence of low BMI was 7.7% in the community-dwelling older people. The BMI gradually decreased with increasing age and gradually increased with latitude. The prevalence of low BMI in northern Xinjiang was 5.3%, which was significantly lower than that in eastern (7.7%) and southern (9.3%) Xinjiang. In the 60–69-, 70–79-, 80–89-, and ≥90-year age groups, the prevalence rates of low BMI were 5.8, 7.9, 10.0, and 13.9%, respectively. After adjusting for confounding factors (sex, ethnic group, hypertension, diabetes, hyperlipemia, smoking, and drinking), multivariate logistic regression analysis showed that the odds ratios (95% CI) for low BMI in eastern and southern Xinjiang were 1.165 (1.056–1.285) and 1.400 (1.274–1.538), respectively, compared to northern Xinjiang. The adjusted odds ratios (95% CI) for low BMI in the 70–79-, 80–89-, and ≥90-year age groups were 1.511 (1.39–1.635), 2.233 (2.030–2.456), and 3.003 (2.439–3.696), respectively, compared to the 60–69-year age group.

Conclusion: The results of this study revealed geographic and age variations in the prevalence of low BMI in the community-dwelling older people in Xinjiang. The prevalence of low BMI gradually increased as the latitude decreased and as age increased.
Soluble CD163 Is a Predictor of Mortality in Patients With Decompensated Cirrhosis
Authors: Zhang Yue , Huang Chenkai , Nie Yuan , Liu Qi , Xiao Nanxi , Liu Linxiang , Zhu Xuan
Published: July 2021

Background: Soluble CD163 (sCD163) is a scavenger receptor membrane protein expressed almost exclusively on Kupffer cells and other macrophages. It was found to be associated with the severity of liver cirrhosis. The aim of the present study was to determine whether the novel biomarker sCD163 predicts outcomes in patients with decompensated cirrhosis.

Materials and Methods: A single-center, observational, prospective study with 345 decompensated cirrhosis patients was conducted in the Gastroenterology Department between January 2017 and December 2020. Their plasma samples were tested by enzyme-linked immunosorbent assay (ELISA) for sCD163 within 24 hours of admission. These patients were followed up at 28 days, 3 months and 6 months. The independent risk factors were identified with uni- and multivariate logistic regression analyses. We evaluated the predictive performance of the new scoring system (including sCD163) and the original scoring system.

Results: The sCD163 level was significantly higher in non-surviving patients than in surviving patients. Positive associations were found between sCD163 levels and the Child-Turcotte-Pugh (CTP), Model for End-Stage Liver Disease (MELD) and albumin-bilirubin (ALBI) scores. Logistic regression confirmed that sCD163 was an independent risk factor for 28-day, 3-month, and 6-month mortality. The areas under the receiver operating characteristic curves (AUROCs) of the use of sCD163 for the prediction of 28-day, 3-month, and 6-month mortality were relatively higher (AUROCs: 0.856; 0.823 and 0.811, respectively). The AUROCs of the new scores obtained by adding sCD163 to the original scoring systems (CTP + sCD163, MELD + sCD163 and ALBI + sCD163) showed that the new scoring systems had better predictive performance than the original scoring systems at all time points (P < 0.001).

Conclusion: sCD163 is a prognostic predictor of short-term and long-term outcomes in decompensated cirrhosis patients. Accordingly, the addition of sCD163 to the original clinical scoring systems improved their prognostic performance.
Elevations in Liver Transaminases in COVID-19: (How) Are They Related?
Authors: Pott-Junior Henrique , Bittencourt Natália Queiroz Prado , Chacha Silvana F. G. , Luporini Rafael Luís , Cominetti Marcia Regina , Anibal Fernanda de Freitas
Published: July 2021

Liver involvement in COVID-19 is not yet well-understood, but elevations in liver transaminases have been described to occur in 14–53% of the cases and are more frequently seen in severe disease. This cross-sectional study explored the relationship between the elevations in liver transaminases and inflammatory parameters in 209 adults with COVID-19. Demographic and clinical data, serum levels of inflammatory cytokines and liver aminotransferases were analyzed. Three groups were formed according to the liver transaminase abnormalities: (I) Normal transaminases, (II) Borderline transaminases elevation, and (III) Mild to severe transaminases elevation. Altered liver transaminases were directly related to disease severity, showing association with the NEWS2 score at admission and greater need for ICU or death. Moreover, higher levels of IL-2 and CRP were associated with borderline transaminases elevations, whereas higher levels of IL-10 and Neutrophil to Lymphocyte ratio were associated with mild to severe transaminases elevation. These results reinforce the importance of liver transaminases in patients with COVID-19 as a complementary marker for disease severity and also point to them as a parameter reflecting the continuous dynamics between viral infection and the immune response.
Biological Therapy in Primary Sjögren's Syndrome: Effect on Salivary Gland Function and Inflammation
Authors: Chowdhury Farzana , Tappuni Anwar , Bombardieri Michele
Published: July 2021

Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease. It is the second most common rheumatic autoimmune disorder, affecting 0.7% of European Americans and up to 1% of people globally. pSS is characterized by the impaired secretory function of exocrine glands, including salivary and lachrymal glands. A lymphocytic infiltration of these organs leads to the common and debilitating symptoms of oral and ocular dryness, majorly affecting the quality of life of these patients. Currently, no disease-modifying drug has been approved for the treatment of pSS, with therapies largely aimed at relieving symptoms of dry mouth and dry eyes. In particular, management of oral dryness still represents a major unmet clinical need in pSS and a significant burden for patients with this condition. Recently, several randomized clinical trials in pSS with biological therapies targeting specific mechanistic pathways implicated in the disease pathogenesis, including B-cell hyperactivity, T-cell co-stimulation and the aberrant role of cytokines, have been completed with mixed results. In this review, we summarize evidence from recent clinical trials investigating biological therapy in pSS, specifically highlighting efficacy, or lack thereof, in modulating local inflammation and improving salivary gland function.
The Tetracycline Resistance Gene, tet(W) in Bifidobacterium animalis subsp. lactis Follows Phylogeny and Differs From tet(W) in Other Species
Authors: Nøhr-Meldgaard Katrine , Struve Carsten , Ingmer Hanne , Agersø Yvonne
Published: July 2021

The tetracycline resistance gene tet(W) encodes a ribosomal protection protein that confers a low level of tetracycline resistance in the probiotic bacterium Bifidobacterium animalis subsp. lactis. With the aim of assessing its phylogenetic origin and potential mobility, we have performed phylogenetic and in silico genome analysis of tet(W) and its flanking genes. tet(W) was found in 41 out of 44 examined B. animalis subsp. lactis strains. In 38 strains, tet(W) was flanked by an IS5-like element and an open reading frame encoding a hypothetical protein, which exhibited a similar GC content (51–53%). These genes were positioned in the same genomic context within the examined genomes. Phylogenetically, the B. animalis subsp. lactis tet(W) cluster in a clade separate from tet(W) of other species and genera. This is not the case for tet(W) encoded by other bifidobacteria and other species where tet(W) is often found in association with transferable elements or in different genomic regions. An IS5-like element identical to the one flanking the B. animalis subsp. lactis tet(W) has been found in a human gut related bacterium, but it was not associated with any tet(W) genes. This suggests that the IS5-like element is not associated with genetic mobility. tet(W) and the IS5 element have previously been shown to be co-transcribed, indicating that co-localization may be associated with tet(W) expression. Here, we present a method where phylogenetic and in silico genome analysis can be used to determine whether antibiotic resistance genes should be considered innate (intrinsic) or acquired. We find that B. animalis subsp. lactis encoded tet(W) is part of the ancient resistome and thereby possess a negligible risk of transfer.
Meta-Analysis and Structural Dynamics of the Emergence of Genetic Variants of SARS-CoV-2
Authors: Castonguay Nicolas , Zhang Wandong , Langlois Marc-André
Published: July 2021

Graphical Abstract

Errors are regularly made when SARS-CoV-2 replicates its RNA genome. The viral polymerase complex is error-prone with imperfect proofreading abilities. These errors or mutations often lead to deleterious or neutral effects on the virus. However, sometimes these mutations have a positive effect and create genetic variants of the virus with different features including increased transmissibility, pathogenicity, and immune escape capabilities. When mutations work collaboratively to create a new virus feature, this is called epistasis.
Development of Moore Swab and Ultrafiltration Concentration and Detection Methods for Salmonella Typhi and Salmonella Paratyphi A in Wastewater and Application in Kolkata, India and Dhaka, Bangladesh
Authors: Liu Pengbo , Ibaraki Makoto , Kapoor Renuka , Amin Nuhu , Das Abhishek , Miah Rana , Mukhopadhyay Asish K. , Rahman Mahbubur , Dutta Shanta , Moe Christine L.
Published: July 2021

Enteric fever is a severe systemic infection caused by Salmonella enterica serovar Typhi (ST) and Salmonella enterica serovar Paratyphi A (SPA). Detection of ST and SPA in wastewater can be used as a surveillance strategy to determine burden of infection and identify priority areas for water, sanitation, and hygiene interventions and vaccination campaigns. However, sensitive and specific detection of ST and SPA in environmental samples has been challenging. In this study, we developed and validated two methods for concentrating and detecting ST/SPA from wastewater: the Moore swab trap method for qualitative results, and ultrafiltration (UF) for sensitive quantitative detection, coupled with qPCR. We then applied these methods for ST and SPA wastewater surveillance in Kolkata, India and Dhaka, Bangladesh, two enteric fever endemic areas. The qPCR assays had a limit of detection of 17 equivalent genome copies (EGC) for ST and 25 EGC for SPA with good reproducibility. In seeded trials, the Moore swab method had a limit of detection of approximately 0.05–0.005 cfu/mL for both ST and SPA. In 53 Moore swab samples collected from three Kolkata pumping stations between September 2019 and March 2020, ST was detected in 69.8% and SPA was detected in 20.8%. Analysis of sewage samples seeded with known amount of ST and SPA and concentrated via the UF method, followed by polyethylene glycol precipitation and qPCR detection demonstrated that UF can effectively recover approximately 8, 5, and 3 log10 cfu of seeded ST and SPA in 5, 10, and 20 L of wastewater. Using the UF method in Dhaka, ST was detected in 26.7% (8/30) of 20 L drain samples with a range of 0.11–2.10 log10 EGC per 100 mL and 100% (4/4) of 20 L canal samples with a range of 1.02–2.02 log10 EGC per 100 mL. These results indicate that the Moore swab and UF methods provide sensitive presence/absence and quantitative detection of ST/SPA in wastewater samples.
Human Norovirus NTPase Antagonizes Interferon-β Production by Interacting With IkB Kinase ε
Authors: Zheng Zifeng , Li Yuncheng , Zhang Mudan , Liu Yalan , Fu Ming , Gong Sitang , Hu Qinxue
Published: July 2021

Human norovirus (HuNoV) is the leading cause of epidemic acute gastroenteritis worldwide. Type I interferons (IFN)-α/β are highly potent cytokines that are initially identified for their essential roles in antiviral defense. It was reported that HuNoV infection did not induce IFN-β expression but was controlled in the presence of IFN-β in human intestinal enteroids and a gnotobiotic pig model, suggesting that HuNoV has likely developed evasion countermeasures. In this study, we found that a cDNA clone of GII.4 HuNoV, the predominantly circulating genotype worldwide, inhibits the production of IFN-β and identified the viral NTPase as a key component responsible for such inhibition. HuNoV NTPase not only inhibits the activity of IFN-β promoter but also the mRNA and protein production of IFN-β. Additional studies indicate that NTPase inhibits the phosphorylation and nuclear translocation of interferon-regulatory factor-3 (IRF-3), leading to the suppression of IFN-β promoter activation. Mechanistically, NTPase interacts with IkB kinase ε (IKKε), an important factor for IRF-3 phosphorylation, and such interaction blocks the association of IKKε with unanchored K48-linked polyubiquitin chains, resulting in the inhibition of IKKε phosphorylation. Further studies demonstrated that the 1-179 aa domain of NTPase which interacts with IKKε is critical for the suppression of IFN-β production. Our findings highlight the role of HuNoV NTPase in the inhibition of IFN-β production, providing insights into a novel mechanism underlying how HuNoV evades the host innate immunity.
Combining Genome-Wide Gene Expression Analysis (RNA-seq) and a Gene Editing Platform (CRISPR-Cas9) to Uncover the Selectively Pro-oxidant Activity of Aurone Compounds Against Candida albicans
Authors: Alqahtani Fatmah M. , Handy Scott T. , Sutton Caleb L. , Farone Mary B.
Published: July 2021

Candida albicans is the major fungal cause of healthcare-associated bloodstream infections worldwide with a 40% mortality rate. The scarcity of antifungal treatments due to the eukaryotic origin of fungal cells has challenged the development of selectively antifungal drugs. In an attempt to identify novel antifungal agents, aurones SH1009 and SH9051, as synthetically bioactive compounds, have been recently documented as anti-Candida agents. Since the molecular mechanisms behind the inhibitory activities of these aurones in C. albicans are unclear, this study aimed to determine the comprehensive cellular processes affected by these aurones and their molecular targets. Genome-wide transcriptional analysis of SH1009- and SH9051-treated C. albicans revealed uniquely repressed expression in different metabolic pathways, particularly trehalose and sulfur amino acid metabolic processes for SH1009 and SH9051, respectively. In contrast, the most commonly enriched process for both aurones was the up-regulation of RNA processing and ribosomal cleavages as an indicator of high oxidative stress, suggesting that a common aspect in the chemical structure of both aurones led to pro-oxidative properties. Additionally, uniquely induced responses (iron ion homeostasis for SH1009 and arginine biosynthesis for SH9051) garnered attention on key roles for the aurone functional groups. Deletion of the transcription factor for the trehalose biosynthesis pathway, Tye7p, resulted in an SH1009-resistant mutant, which also exhibited low trehalose content, validating the primary molecular target of SH1009. Aurone SH9051 uniquely simulated an exogenous supply of methionine or cysteine, leading to sulfur amino acid catabolism as evidenced by quantifying an overproduction of sulfite. Phenyl aurone, the common structure of aurones, contributed proportionally in the pro-oxidative activity through ferric ion reduction effects leading to high ROS levels. Our results determined selective and novel molecular mechanisms for aurone SH1009 and also elucidated the diverse cellular effects of different aurones based on functional groups.
RNF213 p.R4810K (c.14429G > A) Variant Determines Anatomical Variations of the Circle of Willis in Cerebrovascular Disease
Authors: Eto Futoshi , Yoshimoto Takeshi , Okazaki Shuhei , Nishimura Kunihiro , Ogura Shiori , Yamaguchi Eriko , Fukuma Kazuki , Saito Satoshi , Washida Kazuo , Koga Masatoshi , Toyoda Kazunori , Morimoto Takaaki , Maruyama Hirofumi , Koizumi Akio , Ihara Masafumi
Published: July 2021

Introduction

Dysregulation of the RING finger protein 213 (RNF213) gene impairs vascular formation in experimental animal models. In addition, vascular abnormalities in the circle of Willis are associated with cerebrovascular disease. Here, we evaluated the relationship between the East Asian founder variant RNF213 p.R4810K and consequent anatomical variations in the circle of Willis in cerebrovascular disease.

Patients and Methods

The present study is an observational cross-sectional study. It included patients with acute anterior circulation non-cardioembolic stroke admitted to our institution within 7 days of symptom onset or last-known-well from 2011 to 2019, and those who participated in the National Cerebral and Cardiovascular Center Biobank. We compared anatomical variations of the vessels constituting the circle of Willis between RNF213 p.R4810K (c.14429G > A) variant carriers and non-carriers using magnetic resonance angiography and assessed the association between the variants and the presence of the vessels constituting the circle of Willis. Patients with moyamoya disease were excluded.

Results

Four hundred eighty-one patients [146 women (30%); median age 70 years; median baseline National Institutes of Health Stroke Scale score 5] were analyzed. The RNF213 p.R4810K variant carriers (n = 25) were more likely to have both posterior communicating arteries (PComAs) than the variant non-carriers (n = 456) (56% vs. 13%, P < 0.01). Furthermore, variant carriers were less likely to have an anterior communicating artery (AComA) than non-carriers (68% vs. 84%, P = 0.04). In a multivariate logistic regression analysis, the association of RNF213 p.R4810K variant carriers with the presence of both PComAs and the absence of AComA remained significant.

Conclusion

Our findings suggest that the RNF213 p.R4810K variant is an important factor in determining anatomical variations in the circle of Willis.
Research Progress on the Mechanism of Mitochondrial Autophagy in Cerebral Stroke
Authors: Lei Li , Yang Shuaifeng , Lu Xiaoyang , Zhang Yongfa , Li Tao
Published: July 2021

Mitochondrial autophagy is an early defense and protection process that selectively clears dysfunctional or excessive mitochondria through a distinctive mechanism to maintain intracellular homeostasis. Mitochondrial dysfunction during cerebral stroke involves metabolic disbalance, oxidative stress, apoptosis, endoplasmic reticulum stress, and abnormal mitochondrial autophagy. This article reviews the research progress on the mechanism of mitochondrial autophagy in ischemic stroke to provide a theoretical basis for further research on mitochondrial autophagy and the treatment of ischemic stroke.
Estrogen Deficiency Induces Mitochondrial Damage Prior to Emergence of Cognitive Deficits in a Postmenopausal Mouse Model
Authors: Zhao Wei , Hou Yue , Song Xinxin , Wang Lei , Zhang Fangfang , Zhang Hanting , Yu Haiyang , Zhou Yanmeng
Published: July 2021

Background: Estrogen deficiency contributes to the development of Alzheimer’s disease (AD) in menopausal women. In the current study, we examined the impact of estrogen deficiency on mitochondrial function and cognition using a postmenopausal mouse model.

Methods: Bilateral ovariectomy was conducted in adult females C57BL/6J. Cognitive function was examined using the Morris water maze (MWM) test at 2 weeks, 1, 2, and 3 months after ovariectomy. Neurodegeneration was assessed using an immunofluorescence assay of microtubule-associated protein 2 (MAP2) in the hippocampus and immunoblotting against postsynaptic density-95 (PSD95). Mitochondrial function in the hippocampus was assessed using immunoblotting for NDUFB8, SDHB, UQCRC2, MTCO1, and ATP5A1. Mitochondrial biogenesis was examined using immunoblotting for PGC-1α, NRF1, and mtTFA. Mitochondrion fission was assessed with immunoblotting for Drp1, whereas mitochondrion fusion was analyzed with immunoblotting for OPA1 and Mfn2. Mitophagy was examined with immunoblotting for PINK1 and LC3B. Mice receiving sham surgery were used as controls.

Results: Ovariectomy resulted in significant learning and memory deficits in the MWM test at 3 months, but not at any earlier time points. At 2 weeks after ovariectomy, levels of Drp1 phosphorylated at Ser637 decreased in the hippocampus. At 1 month after ovariectomy, hippocampal levels of NDUFB8, SDHB, PGC-1α, mtTFA, OPA1, and Mfn2 were significantly reduced. At 2 months after ovariectomy, hippocampal levels of MAP2, PSD95, MTCO1, NRF1, and Pink1 were also reduced. At 3 months, levels of LC3B-II were reduced.

Conclusions: The cognitive decline associated with estrogen deficiency is preceded by mitochondrial dysfunction, abnormal mitochondrial biogenesis, irregular mitochondrial dynamics, and decreased mitophagy. Thus, mitochondrial damage may contribute to cognitive impairment associated with estrogen deficiency.
A Data-Driven Investigation on Surface Electromyography Based Clinical Assessment in Chronic Stroke
Authors: Ye Fuqiang , Yang Bibo , Nam Chingyi , Xie Yunong , Chen Fei , Hu Xiaoling
Published: July 2021

Background:Surface electromyography (sEMG) based robot-assisted rehabilitation systems have been adopted for chronic stroke survivors to regain upper limb motor function. However, the evaluation of rehabilitation effects during robot-assisted intervention relies on traditional manual assessments. This study aimed to develop a novel sEMG data-driven model for automated assessment.

Method:A data-driven model based on a three-layer backpropagation neural network (BPNN) was constructed to map sEMG data to two widely used clinical scales, i.e., the Fugl–Meyer Assessment (FMA) and the Modified Ashworth Scale (MAS). Twenty-nine stroke participants were recruited in a 20-session sEMG-driven robot-assisted upper limb rehabilitation, which consisted of hand reaching and withdrawing tasks. The sEMG signals from four muscles in the paretic upper limbs, i.e., biceps brachii (BIC), triceps brachii (TRI), flexor digitorum (FD), and extensor digitorum (ED), were recorded before and after the intervention. Meanwhile, the corresponding clinical scales of FMA and MAS were measured manually by a blinded assessor. The sEMG features including Mean Absolute Value (MAV), Zero Crossing (ZC), Slope Sign Change (SSC), Root Mean Square (RMS), and Wavelength (WL) were adopted as the inputs to the data-driven model. The mapped clinical scores from the data-driven model were compared with the manual scores by Pearson correlation.

Results:The BPNN, with 15 nodes in the hidden layer and sEMG features, i.e., MAV, ZC, SSC, and RMS, as the inputs to the model, was established to achieve the best mapping performance with significant correlations (r> 0.9,P< 0.001), according to the FMA. Significant correlations were also obtained between the mapped and manual FMA subscores, i.e., FMA-wrist/hand and FMA-shoulder/elbow, before and after the intervention (r> 0.9,P< 0.001). Significant correlations (P< 0.001) between the mapped and manual scores of MASs were achieved, with the correlation coefficientsr= 0.91 at the fingers, 0.88 at the wrist, and 0.91 at the elbow after the intervention.

Conclusion:An sEMG data-driven BPNN model was successfully developed. It could evaluate upper limb motor functions in chronic stroke and have potential application in automated assessment in post-stroke rehabilitation, once validated with large sample sizes.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT02117089.
Ferroptosis and Its Role in Epilepsy
Authors: Cai Yuxiang , Yang Zhiquan
Published: July 2021

Epilepsy is one of the most common symptoms of many neurological disorders. The typical excessive, synchronous and aberrant firing of neurons originating from different cerebral areas cause spontaneous recurrent epileptic seizures. Prolonged epilepsy can lead to neuronal damage and cell death. The mechanisms underlying epileptic pathogenesis and neuronal death remain unclear. Ferroptosis is a newly defined form of regulated cell death that is characterized by the overload of intracellular iron ions, leading to the accumulation of lethal lipid-based reactive oxygen species (ROS). To date, studies have mainly focused on its role in tumors and various neurological disorders, including epilepsy. Current research shows that inhibition of ferroptosis is likely to be an effective therapeutic approach for epilepsy. In this review, we outline the pathogenesis of ferroptosis, regulatory mechanisms of ferroptosis, related regulatory molecules, and their effects on epilepsy, providing a new direction for discovering new therapeutic targets in epilepsy.
The Microbiota-Gut-Brain Axis in Health and Disease and Its Implications for Translational Research
Authors: Schächtle Melanie Anna , Rosshart Stephan Patrick
Published: July 2021

Over the past decades, microbiome research has evolved rapidly and became a hot topic in basic, preclinical and clinical research, for the pharmaceutical industry and for the general public. With the help of new high-throughput sequencing technologies tremendous progress has been made in the characterization of host-microbiota interactions identifying the microbiome as a major factor shaping mammalian physiology. This development also led to the discovery of the gut-brain axis as the crucial connection between gut microbiota and the nervous system. Consequently, a rapidly growing body of evidence emerged suggesting that the commensal gut microbiota plays a vital role in brain physiology. Moreover, it became evident that the communication along this microbiota-gut-brain axis is bidirectional and primarily mediated by biologically active microbial molecules and metabolites. Further, intestinal dysbiosis leading to changes in the bidirectional relationship between gut microbiota and the nervous system was linked to the pathogenesis of several psychiatric and neurological disorders. Here, we discuss the impact of the gut microbiota on the brain in health and disease, specifically as regards to neuronal homeostasis, development and normal aging as well as their role in neurological diseases of the highest socioeconomic burden such as Alzheimer’s disease and stroke. Subsequently, we utilize Alzheimer’s disease and stroke to examine the translational research value of current mouse models in the spotlight of microbiome research. Finally, we propose future strategies on how we could conduct translational microbiome research in the field of neuroscience that may lead to the identification of novel treatments for human diseases.