bluuebunny/crossref_metadata_2025 huggingface dataset:
Downregulation of long non-coding RNA AIRN promotes mitophagy in alcoholic fatty hepatocytes by promoting ubiquitination of mTOR
Authors: Shen Sujian , Wang Jianzhang , Lin Li miao
Published: May 2021

Long non-coding RNAs (lncRNAs) are crucial in chronic liver diseases, but the specific molecular mechanism of lncRNAs in alcoholic fatty liver (AFL) remains unclear. In this study, we investigated the in-depth regulatory mechanism of mTOR affected by AIRN non-protein coding RNA (lncRNA-AIRN) in the development of AFL. LncRNA-AIRN was highly expressed in the liver tissues of AFL C57BL/6 mice and oleic acid+alcohol (O+A) treated AML-12 cells by using quantitative real-time PCR. RNA pull-down and RNA immunoprecipitation experiments demonstrated that there was an interaction between lncRNA-AIRN and mTOR, and that interference with lncRNA-AIRN could promote the mTOR protein level. Results of cycloheximide-chase assay showed that the protein level of mTOR was decreased with the treatment time after the knockdown of lncRNA-AIRN. Furthermore, the knockdown of lncRNA-AIRN reduced mTOR protein level by promoting the E3 ubiquitin ligase FBXW7-mediated ubiquitination. The lncRNA-AIRN/mTOR axis was involved in the regulation of the mitophagy of O+A treated hepatocytes, which was confirmed by the cell transfection and the MTT assay. SPSS 16.0 was used for analyzing data. The difference between the two groups was analyzed by performing Student’s t-test, and ANOVA was used to analyze the difference when more than two groups. P values < 0.05 were considered to be significantly different. Our findings demonstrated that the knockdown of lncRNA-AIRN influenced mitophagy in AFL by promoting mTOR ubiquitination.
Issues of Increasing the Competitiveness of Industrial Enterprises in the Context of Modernization of the Economy
Authors: Turdiev A. , Matrizayeva D. , Mubashirov A.
Published: May 2021

This article examines the main priorities of developing construction industry and increase its export potential and competitiveness, management of economic growth efficiency of construction and assembly enterprises.
Social Workers and Their Legal Status
Authors: Kushbakova A.
Published: May 2021

The legal status of a social worker, as well as other persons interested in social work, is determined by the greed of the totality of their rights and obligations. Their content in many cases depends on whether such persons carry out their activities on the basis of a transaction with an organization or on their own initiative, on behalf of a state body, local government or commercial organization, within the framework of an employment or civil law agreement.
Principles of Legal Regulation of Medical Insurance
Authors: Boltaev M.
Published: May 2021

The introduction of health insurance is carried out within the legal framework and the legal regulation of relations with it is based on certain basic and basic principles and principles. Typically, the principles are the basic rules embedded in the content of the norms governing the legal regulation of health insurance, and also serve as a starting point on which to apply and rely when existing norms are insufficient in the regulation of relevant issues. The principles of health insurance also represent the basic rules for the establishment, implementation and regulation of this system from a social, economic, legal and organizational point of view. Their establishment at the legislative level serves to ensure the consistency of the implementation of health insurance activities, to ensure the balance of rights and obligations between the insurer, the insured, the insured and the medical institution.
Features of Insolvency (Bankruptcy) of Individual Entrepreneurs
Authors: Saifetdinova A. , Nesterova T.
Published: May 2021

The article analyzes some of the features of the legal regulation of recognition of individual entrepreneurs as insolvent (bankrupts) in the Russian Federation. Special attention is paid to the consequences of non-appeal of an individual entrepreneur within the period established by law with an application for recognition as a bankrupt; the impossibility of initiating two bankruptcy cases of a citizen who has the status of an individual entrepreneur; the debtor's property subject to sale within the framework of an insolvency (bankruptcy) case.
On the Linguodidactical Basis of Formation of Written Speech by Students in the Classes of the Russian Language in Non-language Facilities
Authors: Otorbaeva N.
Published: May 2021

In the era of globalization, when the whole world has the opportunity to communicate and conduct a dialogue from anywhere in the world, the role in the knowledge of languages used for international communication is increasing. Among these languages we can distinguish Russian, as it is spoken in more than one hundred countries. Russian studies are of great importance in the Kyrgyz Republic, for which training programs have been defined, textbooks have been published, and education in higher education institutions is conducted in Russian as well. In theory, teachers know this, but in practice, teachers face problems that are caused by a weak ability of students to express their thoughts not only in oral speech, but also in writing. The author of the article touched upon and outlined the issues of teaching and problems in the assimilation of written speech. Lingodidactic foundations should be used as the foundation for teaching students of non-linguistic faculties. This approach would allow for an outline that would show step-by-step the ways of effective teaching of the Russian language within the walls of the university.
Pensamiento visible en educación inicial: Transformaciones para el siglo XXI
Authors: López Portela Laura Ximena , De Pro Bueno Antonio
Published: May 2021

El artículo presenta resultados de uno de los objetivos de la investigación, “Caracterización y análisis de la implementación del enfoque Pensamiento Visible en instituciones de Educación Inicial en Bogotá D.C”; a través de la cual se buscó comprender las características del enfoque, así como su relación con los objetivos de la Educación Inicial en Colombia, teniendo en cuenta la mirada de agentes educativos expertos en el tema y analizando las condiciones que se requieren para implementarlo.

 

La metodología en la investigación es cualitativa, no pretende llegar a conclusiones universales sino específicas. También se caracteriza como investigación básica orientada,  según Colás, Buendía, Hernández (2009) se lleva a cabo con la idea de que producirá una amplia base de conocimientos susceptible de constituir una plataforma que permita resolver problemas ya planteados, como la discusión que actualmente se encuentra en auge en Colombia acerca del propósito de Educación Inicial.
rol del educador especial en la terapia asistida con animales
Authors: Aguilera Tovar Yojan Mauricio , Ardila Rodríguez Liceth Lorena
Published: May 2021

Las terapias alternativas son cada vez de uso más frecuente en la atención complementaria de las personas con discapacidad y se convierten en un nuevo campo de actuación del educador especial dentro de su rol profesional, quien busca el fortalecimiento de una calidad de vida óptima para estas personas desde una perspectiva integral en todo el ciclo vital. El propósito de este proyecto de investigación es fundamentar y analizar una propuesta reflexiva acerca del rol del licenciado en educación especial enfocado a la terapia asistida con animales. Desde un enfoque cualitativo se realizó una investigación de tipo fenomenológico-hermenéutico con base en la recolección de información en campo que se obtuvo durante las practicas pedagógicas y la revisión documental desarrollada durante el proceso, para así, lograr un producto científico que proporcione un análisis crítico reflexivo sobre el rol que tiene el educador especial en este ámbito, y más específicamente en un contexto donde se trabaja con animales. En este sentido, este documento fundamenta la manera cómo el educador especial puede reorientar su rol de acuerdo al contexto en el que está inmerso y a las características específicas de la población con la que logra trabajar, priorizando su intervención desde el ámbito pedagógico en la intervención asistida con animales. Los resultados demuestran que el educador especial puede fortalecer en el espacio terapéutico las competencias básicas para el aprendizaje, la confianza en el usuario o estudiante y las bases para la autonomía que les permita alcanzar su potencial, puede aportar además adaptaciones metodológicas para el diseño de estrategias didácticas orientadas al mejor aprovechamiento de la terapia dentro del equipo interdisciplinar. Al usar esta línea en su intervención, la educación asistida por animales se convierte en posibilidad de aporte y aprendizaje dentro del trabajo interdisciplinario en las instituciones, y genera situaciones que facilitan una atención integral.
Development of Clostridium saccharoperbutylacetonicum as a Whole Cell Biocatalyst for Production of Chirally Pure (R)-1,3-Butanediol
Authors: Grosse-Honebrink Alexander , Little Gareth T. , Bean Zak , Heldt Dana , Cornock Ruth H. M. , Winzer Klaus , Minton Nigel P. , Green Edward , Zhang Ying
Published: May 2021

Chirally pure (R)-1,3-butanediol ((R)-1,3-BDO) is a valuable intermediate for the production of fragrances, pheromones, insecticides and antibiotics. Biotechnological production results in superior enantiomeric excess over chemical production and is therefore the preferred production route. In this study (R)-1,3-BDO was produced in the industrially important whole cell biocatalyst Clostridium saccharoperbutylacetonicum through expression of the enantio-specific phaB gene from Cupriavidus necator. The heterologous pathway was optimised in three ways: at the transcriptional level choosing strongly expressed promoters and comparing plasmid borne with chromosomal gene expression, at the translational level by optimising the codon usage of the gene to fit the inherent codon adaptation index of C. saccharoperbutylacetonicum, and at the enzyme level by introducing point mutations which led to increased enzymatic activity. The resulting whole cell catalyst produced up to 20 mM (1.8 g/l) (R)-1,3-BDO in non-optimised batch fermentation which is a promising starting position for economical production of this chiral chemical.
Profiling of Diagnostic Information of and Latent Susceptibility to Bacterial Keratitis From the Perspective of Ocular Bacterial Microbiota
Authors: Ren Zhichao , Liu Qing , Li Wenfeng , Wu Xian , Dong Yanling , Huang Yusen
Published: May 2021

The ocular surface possesses its own bacterial microbiota. Once given a chance, opportunistic pathogens within ocular microbiota may lead to corneal infection like bacterial keratitis (BK). To reveal the possible factor that makes people vulnerable to BK from the perspective of ocular bacterial microbiota, as well as to compare diagnostic information provided by high-throughput 16S rDNA sequencing and bacterial culture, 20 patients with BK and 42 healthy volunteers were included. Conjunctival swabs and corneal scrapings collected from the diseased eyes of BK patients were subjected for both high-throughput 16S rDNA sequencing and bacterial culture. Conjunctival swabs collected from the normal eyes of BK patients and healthy volunteers were sent only for sequencing. For identifying the pathogens causing BK, high-throughput 16S rDNA sequencing presented a higher positive rate than bacterial culture (98.04% vs. 17.50%), with 92.11% reaching the genus level (including 10.53% down to the species level). However, none of the sequencing results was consistent with the cultural results. The sequencing technique appears to challenge culture, and could be a complement for pathogen identification. Moreover, compared to the eyes of healthy subjects, the ocular microbiota of three sample groups from BK patients contained significantly less Actinobacteria and Corynebacteria (determinate beneficial symbiotic bacteria), but significantly more Gammaproteobacteria, Pseudomonas, Bacteroides, and Escherichia-Shigella (common ocular pathogenic bacteria). Therefore, it is speculated that the imbalance of protective and aggressive bacteria in the ocular microbiota of healthy people may trigger susceptibility to BK. Based on this speculation, it seems promising to prevent and treat infectious oculopathy through regulating ocular microbiota.
Home Sweet Home: Plasmodium vivax-Infected Reticulocytes—The Younger the Better?
Authors: Thomson-Luque Richard , Bautista José M.
Published: May 2021

After a century of constant failure to produce an in vitro culture of the most widespread human malaria parasite Plasmodium vivax, recent advances have highlighted the difficulties to provide this parasite with a healthy host cell to invade, develop, and multiply under in vitro conditions. The actual level of understanding of the heterogeneous populations of cells—framed under the name ‘reticulocytes’—and, importantly, their adequate in vitro progression from very immature reticulocytes to normocytes (mature erythrocytes) is far from complete. The volatility of its individual stability may suggest the reticulocyte as a delusory cell, particularly to be used for stable culture purposes. Yet, the recent relevance gained by a specific subset of highly immature reticulocytes has brought some hope. Very immature reticulocytes are characterized by a peculiar membrane harboring a plethora of molecules potentially involved in P. vivax invasion and by an intracellular complexity dynamically changing upon its quick maturation into normocytes. We analyze the potentialities offered by this youngest reticulocyte subsets as an ideal in vitro host cell for P. vivax.
Integrated DNA Methylation and Gene Expression Analysis Identified S100A8 and S100A9 in the Pathogenesis of Obesity
Authors: Chen Ningyuan , Miao Liu , Lin Wei , Zou Donghua , Huang Ling , Huang Jia , Shi Wanxin , Li Lilin , Luo Yuxing , Liang Hao , Pan Shangling , Peng Junhua
Published: May 2021

Background: To explore the association of DNA methylation and gene expression in the pathology of obesity.

Methods: (1) Genomic DNA methylation and mRNA expression profile of visceral adipose tissue (VAT) were performed in a comprehensive database of gene expression in obese and normal subjects. (2) Functional enrichment analysis and construction of differential methylation gene regulatory networks were performed. (3) Validation of the two different methylation sites and corresponding gene expression was done in a separate microarray dataset. (4) Correlation analysis was performed on DNA methylation and mRNA expression data.

Results: A total of 77 differentially expressed mRNAs matched with differentially methylated genes. Analysis revealed two different methylation sites corresponding to two unique genes—s100a8-cg09174555 and s100a9-cg03165378. Through the verification test of two interesting different expression positions [differentially methylated positions (DMPs)] and their corresponding gene expression, we found that methylation in these genes was negatively correlated to gene expression in the obesity group. Higher S100A8 and S100A9 expressions in obese subjects were validated in a separate microarray dataset.

Conclusion: This study confirmed the relationship between DNA methylation and gene expression and emphasized the important role of S100A8 and S100A9 in the pathogenesis of obesity.
Visualizing Water Desaturation in Frozen Gas Diffusion Layers With Flow Field Segmentation via Synchrotron X-Ray Radiography
Authors: Zhang Yuzhou , Anderson Ryan , Zhu Ning , Zhang Lifeng
Published: May 2021

Synchrotron X-ray tomography images were used to study dynamic, regional water transfer behavior in the gas diffusion layer (GDL) during thawing and desaturation processes. Initially saturated, frozen GDLs were thawed and desaturated with air in a serpentine gas flow channel. On-the-fly (OTF) high speed CT scans via synchrotron X-ray allowed the capture of consecutive water transfer inside the GDL under the cold start-up gas purging condition. Desaturation data of Sigracet 35AA GDLs with three superficial gas velocities (2.88–5.98 m/s) were selected for analysis. Multiple spatial segmentation levels based on the flow field geometry, including channel vs. rib, individual channels and ribs, and smaller sections in each channel and rib, were applied to the in-plane direction to study the GDL regional thawing and desaturation behaviors. Each segmentation volume had a similar desaturation pattern in general; however, water distribution and desaturation show heterogeneity over the GDL domain, as well as relation with factors including the flow field geometry, air traveling distance, and initial saturation level. These data from the segmentation analysis expand the knowledge of localized water transfer behavior during the cold start thawing process. These data can also provide valuable information for future cold start modeling and help in optimizing the PEM fuel cell flow field design.
Genetic Landscape of Rare Autoinflammatory Disease Variants in Qatar and Middle Eastern Populations Through the Integration of Whole-Genome and Exome Datasets
Authors: Sharma Parul , Jain Abhinav , Scaria Vinod
Published: May 2021

Rare monogenic autoinflammatory diseases are a group of recurrent inflammatory genetic disorders caused due to genetic variants in over 37 genes. While a number of these disorders have been identified and reported in Middle Eastern populations, the carrier frequency of these genetic variants in the Middle Eastern population is not known. The availability of whole-genome and exome datasets of over 1,000 individuals from Qatar persuaded us to explore the genetic epidemiology of rare autoinflammatory genetic variants. We have systematically analyzed genetic variants in genome-scale datasets from Qatar with a compendium of variants associated with autoinflammatory diseases. The variants were systematically reclassified according to the American College of Medical Genetics and Genomics guidelines for interpretation of variant pathogenicity. Our analysis identified seven pathogenic and likely pathogenic variants with significant differences in their allele frequencies compared to the global population. The cumulative carrier frequency of these variants was found to be 2.58%. Furthermore, our analysis revealed that five genes, implicated in rare autoinflammatory diseases, were under natural selection. To the best of our knowledge, this is the first and most comprehensive study on the population-scale analysis and genetic epidemiology of genetic variants that cause rare autoinflammatory disease in Middle Eastern populations.
Signatures of Discriminative Copy Number Aberrations in 31 Cancer Subtypes
Authors: Gao Bo , Baudis Michael
Published: May 2021

Copy number aberrations (CNA) are one of the most important classes of genomic mutations related to oncogenetic effects. In the past three decades, a vast amount of CNA data has been generated by molecular-cytogenetic and genome sequencing based methods. While this data has been instrumental in the identification of cancer-related genes and promoted research into the relation between CNA and histo-pathologically defined cancer types, the heterogeneity of source data and derived CNV profiles pose great challenges for data integration and comparative analysis. Furthermore, a majority of existing studies have been focused on the association of CNA to pre-selected “driver” genes with limited application to rare drivers and other genomic elements. In this study, we developed a bioinformatics pipeline to integrate a collection of 44,988 high-quality CNA profiles of high diversity. Using a hybrid model of neural networks and attention algorithm, we generated the CNA signatures of 31 cancer subtypes, depicting the uniqueness of their respective CNA landscapes. Finally, we constructed a multi-label classifier to identify the cancer type and the organ of origin from copy number profiling data. The investigation of the signatures suggested common patterns, not only of physiologically related cancer types but also of clinico-pathologically distant cancer types such as different cancers originating from the neural crest. Further experiments of classification models confirmed the effectiveness of the signatures in distinguishing different cancer types and demonstrated their potential in tumor classification.
Screening and Mapping for Head Blast Resistance in a Panel of CIMMYT and South Asian Bread Wheat Germplasm
Authors: He Xinyao , Juliana Philomin , Kabir Muhammad R. , Roy Krishna K. , Islam Rabiul , Marza Felix , Peterson Gary , Singh Gyanendra P. , Chawade Aakash , Joshi Arun K. , Singh Ravi P. , Singh Pawan K.
Published: May 2021

Wheat blast (WB) is a destructive disease in South America and its first outbreak in Bangladesh in 2016 posed a great risk to food security of South Asian countries. A genome wide association study (GWAS) was conducted on a diverse panel of 184 wheat genotypes from South Asia and CIMMYT. Phenotyping was conducted in eight field experiments in Bolivia and Bangladesh and a greenhouse experiment in the United States. Genotypic data included 11,401 SNP markers of the Illumina Infinium 15K BeadChip and four additional STS markers on the 2NS/2AS translocation region. Accessions with stable WB resistance across experiments were identified, which were all 2NS carriers. Nevertheless, a dozen moderately resistant 2AS lines were identified, exhibiting big variation among experiments. Significant marker-trait associations (MTA) were detected on chromosomes 1BS, 2AS, 6BS, and 7BL; but only MTAs on 2AS at the 2NS/2AS translocation region were consistently significant across experiments. The resistant accessions identified in this study could be used in production in South Asian countries as a preemptive strategy to prevent WB outbreak.
Opinion Review of Socioeconomic Impact of COVID-2019 on Women's Health
Authors: Salami Victory U. , Okoduwa Stanley I. R. , Chris Aimee O. , Ayilara Susannah I. , Okoduwa Ugochi J.
Published: May 2021

The global battle to survive the onslaughts of the Coronavirus Disease 2019 (COVID-19) started in December 2019 and continues today. Women and girls have borne the brunt of the hardship resulting from the health crises. This paper examined the effects of COVID-19 on women. Socioeconomic factors resulting from the pandemic, especially in relation to women's health, were discussed after studying published articles. They include gender specificity and COVID-19, the economic toll of COVID-19 on women, pregnancy and COVID-19, gender-based violence due to COVID-19, and health-care impacts of COVID-19. Making up the majority in the healthcare workforce, women were at higher risk of infection with COVID-19 due to their exposure as caregivers to infected patients. The pandemic took its toll on them as part of the greater population in the informal sector of the economy due to the lockdown directive, as many experienced severe monetary shortages and job losses. Pregnant women infected with COVID-19 were prone to severe diseases, maternal complications, and death due to their weakened immunity and exposure during clinical procedures. Gender-based violence was observed to have increased across the globe for women. The results of this review strongly indicate that women are disproportionately affected by the ongoing COVID-19 health crisis. This review will help health-care professionals and policymakers arrive at properly-thought-through decisions to better manage health crises. Governments and all key players should address the challenge by devising effective policies with a gendered view.
Latent TGF-β Activation Is a Hallmark of the Tenascin Family
Authors: Aubert Alexandre , Mercier-Gouy Perrine , Aguero Stéphanie , Berthier Laurent , Liot Sophie , Prigent Laura , Alcaraz Lindsay B. , Verrier Bernard , Terreux Raphaël , Moali Catherine , Lambert Elise , Valcourt Ulrich
Published: May 2021

Transforming growth factor-β (TGF-β) isoforms are secreted as inactive complexes formed through non-covalent interactions between bioactive TGF-β entities and their N-terminal pro-domains called latency-associated peptides (LAP). Extracellular activation of latent TGF-β within this complex is a crucial step in the regulation of TGF-β activity for tissue homeostasis and immune cell function. We previously showed that the matrix glycoprotein Tenascin-X (TN-X) interacted with the small latent TGF-β complex and triggered the activation of the latent cytokine into a bioactive TGF-β. This activation most likely occurs through a conformational change within the latent TGF-β complex and requires the C-terminal fibrinogen-like (FBG) domain of the glycoprotein. As the FBG-like domain is highly conserved among the Tenascin family members, we hypothesized that Tenascin-C (TN-C), Tenascin-R (TN-R) and Tenascin-W (TN-W) might share with TN-X the ability to regulate TGF-β bioavailability through their C-terminal domain. Here, we demonstrate that purified recombinant full-length Tenascins associate with the small latent TGF-β complex through their FBG-like domains. This association promotes activation of the latent cytokine and subsequent TGF-β cell responses in mammary epithelial cells, such as cytostasis and epithelial-to-mesenchymal transition (EMT). Considering the pleiotropic role of TGF-β in numerous physiological and pathological contexts, our data indicate a novel common function for the Tenascin family in the regulation of tissue homeostasis under healthy and pathological conditions.
Differentially Expressed Genes in Hepatopancreas of Acute Hepatopancreatic Necrosis Disease Tolerant and Susceptible Shrimp (Penaeus vannamei)
Authors: Mai Hung N , Caro Luis Fernando Aranguren , Cruz-Flores Roberto , White Brenda Noble , Dhar Arun K.
Published: May 2021

Acute hepatopancreatic necrosis disease (AHPND) is a lethal disease in marine shrimp that has caused large-scale mortalities in shrimp aquaculture in Asia and the Americas. The etiologic agent is a pathogenic Vibrio sp. carrying binary toxin genes, pirA and pirB in plasmid DNA. Developing AHPND tolerant shrimp lines is one of the prophylactic approaches to combat this disease. A selected genetic line of Penaeus vannamei was found to be tolerant to AHPND during screening for disease resistance. The mRNA expression of twelve immune and metabolic genes known to be involved in bacterial pathogenesis were measured by quantitative RT-PCR in two populations of shrimp, namely P1 that showed susceptibility to AHPND, and P2 that showed tolerance to AHPND. Among these genes, the mRNA expression of chymotrypsin A (ChyA) and serine protease (SP), genes that are involved in metabolism, and crustin-P (CRSTP) and prophenol oxidase activation system 2 (PPAE2), genes involved in bacterial pathogenesis in shrimp, showed differential expression between the two populations. The differential expression of these genes shed light on the mechanism of tolerance against AHPND and these genes can potentially serve as candidate markers for tolerance/susceptibility to AHPND in P. vannamei. This is the first report of a comparison of the mRNA expression profiles of AHPND tolerant and susceptible lines of P. vannamei.
Immune Landscape of Gastric Carcinoma Tumor Microenvironment Identifies a Peritoneal Relapse Relevant Immune Signature
Authors: Zhang Chuang , Li Danni , Yu Ruoxi , Li Ce , Song Yujia , Chen Xi , Fan Yibo , Liu Yunpeng , Qu Xiujuan
Published: May 2021

Background

Gastric cancer (GC) still represents the third leading cause of cancer-related death worldwide. Peritoneal relapse (PR) is the most frequent metastasis occurring among patients with advanced gastric cancer. Increasingly more evidence have clarified the tumor immune microenvironment (TIME) may predict survival and have clinical significance in GC. However, tumor-transcriptomics based immune signatures derived from immune profiling have not been established for predicting the peritoneal recurrence of the advanced GC.

Methods

In this study, we depict the immune landscape of GC by using transcriptome profiling and clinical characteristics retrieved from GSE62254 of Gene Expression Omnibus (GEO). Immune cell infiltration score was evaluated via single-sample gene set enrichment (ssGSEA) analysis algorithm. The least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to select the valuable immune cells and construct the final model for the prediction of PR. The receiver operating characteristic (ROC) curve and the Kaplan-Meier curve were used to check the accuracy of PRIs. Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to explore the molecular pathways associated with PRIs.

Results

A peritoneal recurrence related immune score (PRIs) with 10 immune cells was constructed. Compared to the low-PRIs group, the high-PRIs group had a greater risk. The upregulation of the focal adhesion signaling was observed in the high-PRIs subtype by GSEA and KEGG. Multivariate analysis found that both in the internal training cohort and the internal validation cohort, PRIs was a stable and independent predictor for PR. A nomogram that integrated clinicopathological features and PRIs to predict peritoneal relapse was constructed. Subgroup analysis indicated that the PRIs could obviously distinguish peritoneal recurrence in different molecular subtypes, pathological stages and Lauren subtypes, in which PRIs of Epithelial-Mesenchymal Transitions (EMT) subtype, III-IV stage and diffuse subtype are higher respectively.

Conclusion

Overall, we performed a comprehensive evaluation of the immune landscape of GC and constructed a predictive PR model based on the immune cell infiltration. The PRIs represents novel promising feature of predicting peritoneal recurrence of GC and sheds light on the improvement of the personalized management of GC patients after surgery.
Current Perspectives on the Role of TNF in Hematopoiesis Using Mice With Humanization of TNF/LT System
Authors: Gogoleva Violetta S. , Atretkhany Kamar-Sulu N. , Dygay Arina P. , Yurakova Taisiya R. , Drutskaya Marina S. , Nedospasov Sergei A.
Published: May 2021

TNF is a multifunctional cytokine with its key functions attributed to inflammation, secondary lymphoid tissue organogenesis and immune regulation. However, it is also a physiological regulator of hematopoiesis and is involved in development and homeostatic maintenance of various organs and tissues. Somewhat unexpectedly, the most important practical application of TNF biology in medicine is anti-TNF therapy in several autoimmune diseases. With increased number of patients undergoing treatment with TNF inhibitors and concerns regarding possible adverse effects of systemic cytokine blockade, the interest in using humanized mouse models to study the efficacy and safety of TNF-targeting biologicsin vivois justified. This Perspective discusses the main functions of TNF and its two receptors, TNFR1 and TNFR2, in steady state, as well as in emergency hematopoiesis. It also provides a comparative overview of existing mouse lines with humanization of TNF/TNFR system. These genetically engineered mice allow us to study TNF signaling cascades in the hematopoietic compartment in the context of various experimental disease models and for evaluating the effects of various human TNF inhibitors on hematopoiesis and other physiological processes.
The Role of IL-36 in Infectious Diseases: Potential Target for COVID-19?
Authors: Wang Xiaofang , Yi Panpan , Liang Yuejin
Published: May 2021

IL-36 is a member of the interleukin 1 cytokine family, which is currently experiencing a renaissance due to the growing understanding of its context-dependent roles and advances in our understanding of the inflammatory response. The immunological role of IL-36 has revealed its profound and indispensable functional roles in psoriasis, as well as in several inflammatory diseases, including inflammatory bowel disease (IBD), systemic lupus erythematosus, rheumatoid arthritis (RA) and cancer. More recently, an increasing body of evidence suggests that IL-36 plays a crucial role in viral, bacterial and fungal infections. There is a growing interest as to whether IL-36 contributes to host protective immune responses against infection as well as the potential implications of IL-36 for the development of new therapeutic strategies. In this review, we summarize the recent progress in understanding cellular expression, regulatory mechanisms and biological roles of IL-36 in infectious diseases, which suggest more specific strategies to maneuver IL-36 as a diagnostic or therapeutic target, especially in COVID-19.
Interferon Gamma Induces the Increase of Cell-Surface Markers (CD80/86, CD83 and MHC-II) in Splenocytes From Atlantic Salmon
Authors: Morales-Lange Byron , Ramírez-Cepeda Felipe , Schmitt Paulina , Guzmán Fanny , Lagos Leidy , Øverland Margareth , Wong-Benito Valentina , Imarai Mónica , Fuentes Derie , Boltaña Sebastián , Alcaíno Javier , Soto Carlos , Mercado Luis
Published: May 2021

Type II interferon gamma (IFNγ) is a pleiotropic cytokine capable of modulating the innate and adaptive immune responses which has been widely characterized in several teleost families. In fish, IFNγ stimulates the expression of cytokines and chemokines associated with the pro-inflammatory response and enhances the production of nitrogen and oxygen reactive species in phagocytic cells. This work studied the effect of IFNγ on the expression of cell-surface markers on splenocytes of Atlantic salmon (Salmo salar). In vitro results showed that subpopulations of mononuclear splenocytes cultured for 15 days were capable of increasing gene expression and protein availability of cell-surface markers such as CD80/86, CD83 and MHC II, after being stimulated with recombinant IFNγ. These results were observed for subpopulations with characteristics associated with monocytes (51%), and features that could be related to lymphocytes (46.3%). In addition, a decrease in the expression of zbtb46 was detected in IFNγ-stimulated splenocytes. Finally, the expression of IFNγ and cell-surface markers was assessed in Atlantic salmon under field conditions. In vivo results showed that the expression of ifnγ increased simultaneously with the up-regulation of cd80/86, cd83 and mhcii during a natural outbreak of Piscirickettsia salmonis. Overall, the results obtained in this study allow us to propose IFNγ as a candidate molecule to stimulate the phenotypic progression of a small population of immune cells, which will increase antigen presenting cells markers. Thereby, modulatory strategies using IFNγ may generate a robust and coordinated immune response in fish against pathogens that affect aquaculture.
Healing of Ocular Herpetic Disease Following Treatment With an Engineered FGF-1 Is Associated With Increased Corneal Anti-Inflammatory M2 Macrophages
Authors: Dhanushkodi Nisha R. , Srivastava Ruchi , Coulon Pierre-Gregoire A. , Prakash Swayam , Roy Soumyabrata , Bagnol Didier , David Eveleth D. , BenMohamed Lbachir
Published: May 2021

Herpes simplex virus 1 (HSV-1) infects the cornea and caused blinding ocular disease. In the present study, we evaluated whether and how a novel engineered version of fibroblast growth factor-1 (FGF-1), designated as TTHX1114, would reduce the severity of HSV-1-induced and recurrent ocular herpes in the mouse model. The efficacy of TTHX1114 against corneal keratopathy was assessed in B6 mice following corneal infection with HSV-1, strain McKrae. Starting day one post infection (PI), mice received TTHX1114 for 14 days. The severity of primary stromal keratitis and blepharitis were monitored up to 28 days PI. Inflammatory cell infiltrating infected corneas were characterized up to day 21 PI. The severity of recurrent herpetic disease was quantified in latently infected B6 mice up to 30 days post-UVB corneal exposure. The effect of TTHX1114 on M1 and M2 macrophage polarization was determined in vivo in mice and in vitro on primary human monocytes-derived macrophages. Compared to HSV-1 infected non-treated mice, the infected and TTHX1114 treated mice exhibited significant reduction of primary and recurrent stromal keratitis and blepharitis, without affecting virus corneal replication. The therapeutic effect of TTHX1114 was associated with a significant decrease in the frequency of M1 macrophages infiltrating the cornea, which expressed significantly lower levels of pro-inflammatory cytokines and chemokines. This polarization toward M2 phenotype was confirmed in vitro on human primary macrophages. This pre-clinical finding suggests use of this engineered FGF-1 as a novel immunotherapeutic regimen to reduce primary and recurrent HSV-1-induced corneal disease in the clinic.
Therapeutic Liposomal Vaccines for Dendritic Cell Activation or Tolerance
Authors: Nagy Noémi Anna , de Haas Aram M. , Geijtenbeek Teunis B. H. , van Ree Ronald , Tas Sander W. , van Kooyk Yvette , de Jong Esther C.
Published: May 2021

Dendritic cells (DCs) are paramount in initiating and guiding immunity towards a state of activation or tolerance. This bidirectional capacity of DCs sets them at the center stage for treatment of cancer and autoimmune or allergic conditions. Accordingly, many clinical studies use ex vivo DC vaccination as a strategy to boost anti-tumor immunity or to suppress immunity by including vitamin D3, NF-κB inhibitors or retinoic acid to create tolerogenic DCs. As harvesting DCs from patients and differentiating these cells in vitro is a costly and cumbersome process, in vivo targeting of DCs has huge potential as nanoparticulate platforms equipped with activating or tolerogenic adjuvants can modulate DCs in their natural environment. There is a rapid expansion of the choices of nanoparticles and activation- or tolerance-promoting adjuvants for a therapeutic vaccine platform. In this review we highlight the most recent nanomedical approaches aimed at inducing immune activation or tolerance via targeting DCs, together with novel fundamental insights into the mechanisms inherent to fostering anti-tumor or tolerogenic immunity.
Antibodies Against Angiotensin II Receptor Type 1 and Endothelin A Receptor Are Associated With an Unfavorable COVID19 Disease Course
Authors: Miedema Jelle , Schreurs Marco , van der Sar – van der Brugge Simone , Paats Marthe , Baart Sara , Bakker Marleen , Hoek Rogier , Dik Willem Arnout , Endeman Henrik , Van Der Velden Vincent , van Gammeren Adriaan , Ermens Antonius , Aerts Joachim G. , Thüsen Jan Von Der
Published: May 2021

Background

Lung histopathology demonstrates vasculopathy in a subset of deceased COVID19 patients, which resembles histopathology observed in antibody-mediated lung transplant rejection. Autoantibodies against angiotensin II type 1 receptor (AT1R) and Endothelin receptor Type A (ETAR) have been demonstrated in antibody-mediated rejection and may also be associated with severe COVID19 infection. Objective To assess AT1R and ETAR auto-antibodies in COVID19 patients and controls, and explore their association with disease course.

Methods

65 hospitalized patients with COVID19 infection were included. Clinical and laboratory findings were retrospectively assessed. Patients with unfavorable disease course, admitted at the intensive care unit and/or deceased during hospital admission (n=33) were compared to admitted COVID19 patients with favorable disease course (n=32). The presence of antinuclear antibodies (ANA) and auto-antibodies against AT1R or ETAR in peripheral blood were compared between COVID19 with unfavorable and favorable disease course and age matched controls (n=20).

Results

The presence of ANA was not significantly different between COVID19 patients with unfavorable (n=7/33; 21%) and favorable disease course (n=6/32; 19%) (p= 0.804) and controls (n=3/20; 15%). Auto-antibodies against AT1R were significantly increased in unfavorable disease course (median 14.59 U/mL, IQR 11.28 – 19.89) compared to favorable disease course (median 10.67 U/mL, IQR 8.55 – 13.0, p< 0.01). ETAR antibody titers were also significantly increased in unfavorable disease course (median 7.21, IQR 5.0 – 10.45) as compared to favorable disease course (median 4.0, IQR 3.0 – 6.0, p <0.05).

Conclusion

Auto-antibodies against AT1R and ETAR are significantly increased in COVID19 patients with an unfavorable disease course.
Element-Selective Targeting of Nutrient Metabolites in Environmental Samples by Inductively Coupled Plasma Mass Spectrometry and Electrospray Ionization Mass Spectrometry
Authors: Li Jingxuan , Boiteau Rene M. , Babcock-Adams Lydia , Acker Marianne , Song Zhongchang , McIlvin Matthew R. , Repeta Daniel J.
Published: May 2021

Metabolites that incorporate elements other than carbon, nitrogen, hydrogen and oxygen can be selectively detected by inductively coupled mass spectrometry (ICPMS). When used in parallel with chromatographic separations and conventional electrospray ionization mass spectrometry (ESIMS), ICPMS allows the analyst to quickly find, characterize and identify target metabolites that carry nutrient elements (P, S, trace metals; “nutrient metabolites”), which are of particular interest to investigations of microbial biogeochemical cycles. This approach has been applied to the study of siderophores and other trace metal organic ligands in the ocean. The original method used mass search algorithms that relied on the ratio of stable isotopologues of iron, copper and nickel to assign mass spectra collected by ESIMS to metabolites carrying these elements detected by ICPMS. However, while isotopologue-based mass assignment algorithms were highly successful in characterizing metabolites that incorporate some trace metals, they do not realize the whole potential of the ICPMS/ESIMS approach as they cannot be used to assign the molecular ions of metabolites with monoisotopic elements or elements for which the ratio of stable isotopes is not known. Here we report a revised ICPMS/ESIMS method that incorporates a number of changes to the configuration of instrument hardware that improves sensitivity of the method by a factor of 4–5, and allows for more accurate quantitation of metabolites. We also describe a new suite of mass search algorithms that can find and characterize metabolites that carry monoisotopic elements. We used the new method to identify siderophores in a laboratory culture of Vibrio cyclitrophicus and a seawater sample collected in the North Pacific Ocean, and to assign molecular ions to monoisotopic cobalt and iodine nutrient metabolites in extracts of a laboratory culture of the marine cyanobacterium Prochorococcus MIT9215.
A Brief Review on the Evolution of Metallic Dental Implants: History, Design, and Application
Authors: Kandavalli Sumanth Ratna , Wang Qingge , Ebrahimi Mahmoud , Gode Ceren , Djavanroodi Faramarz , Attarilar Shokouh , Liu Shifeng
Published: May 2021

In recent years, significant advances in the field of medical materials have begun to emerge, especially in nanotechnology. The modern area of nanostructured implants possesses wide applications in various medical implants including their dental use. Nano-surface functions present substantial resolutions to medical obstacles through improved biomaterial proficiency, innovative dental-implant designs, and surface design procedures, such as nanoscale adhesive surfaces, bio-chemical anodization, and surface modification technique. This work covers dental implant history, nanotechnological advances, and its development that includes a description, basic properties, and the related results of composites and surface morphology, and the different types of nanomaterials used in dental implants. Significant attempts have been made over the last few decades to strengthen osteointegration and prevent bacterial attachment to the implant surfaces. The micro and nano-topography of the hierarchical surface orchestrate the biological reactions of implants and may solve the problems associated with implant-tissue issues. This research investigates the implant articles from 1964 to 2021, which offers a brief description of the nanostructured biomaterials to enhance dental implants’ performance and may open new frontiers in the advancement of implant technology.
Factors Associated With Working in Remote Indonesia: A National Cross-Sectional Study of Early-Career Doctors
Authors: Putri Likke Prawidya , Russell Deborah Jane , O'Sullivan Belinda Gabrielle , Kippen Rebecca
Published: May 2021

Background: Doctor shortages in remote areas of Indonesia are amongst challenges to provide equitable healthcare access. Understanding factors associated with doctors' work location is essential to overcome geographic maldistribution. Focused analyses of doctors' early-career years can provide evidence to strengthen home-grown remote workforce development.

Method: This is a cross-sectional study of early-career (post-internship years 1–5) Indonesian doctors, involving an online self-administered survey on demographic characteristics, and; locations of upbringing, medical clerkship (placement during medical school), internship, and current work. Multivariate logistic regression was used to test factors associated with current work in remote districts.

Results: Of 3,176 doctors actively working as clinicians, 8.9% were practicing in remote districts. Compared with their non-remote counterparts, doctors working in remote districts were more likely to be male (OR 1.5,CI 1.1–2.1) or unmarried (OR 1.9,CI 1.3–3.0), have spent more than half of their childhood in a remote district (OR 19.9,CI 12.3–32.3), have completed a remote clerkship (OR 2.2,CI 1.1–4.4) or internship (OR 2.0,CI 1.3–3.0), currently participate in rural incentive programs (OR 18.6,CI 12.8–26.8) or have previously participated in these (OR 2.0,CI 1.3–3.0), be a government employee (OR 3.2,CI 2.1–4.9), or have worked rurally or remotely post-internship but prior to current position (OR 1.9,CI 1.2–3.0).

Conclusion: Our results indicate that building the Indonesian medical workforce in remote regions could be facilitated by investing in strategies to select medical students with a remote background, delivering more remote clerkships during the medical course, deploying more doctors in remote internships and providing financial incentives. Additional considerations include expanding government employment opportunities in rural areas to achieve a more equitable geographic distribution of doctors in Indonesia.
Side Effects of Pesticides and Metabolites in Groundwater: Impact on Denitrification
Authors: Michel Caroline , Baran Nicole , André Laurent , Charron Mickael , Joulian Catherine
Published: May 2021

The impact of two pesticides (S-metolachlor and propiconazole) and their respective main metabolites (ESA-metolachlor and 1,2,4-triazole) on bacterial denitrification in groundwater was studied. For this, the denitrification activity and the bacterial diversity of a microbial community sampled from a nitrate-contaminated groundwater were monitored during 20 days in lab experiments in the presence or absence of pesticides or metabolites at 2 or 10 μg/L. The kinetics of nitrate reduction along with nitrite and N2O production all suggested that S-metolachlor had no or only little impact, whereas its metabolite ESA-metolachlor inhibited denitrification by 65% at 10 μg/L. Propiconazole and 1,2,4-triazole also inhibited denitrification at both concentrations, but to a lesser extent (29–38%) than ESA-metolachlor. When inhibition occurred, pesticides affected the reduction of nitrate into nitrite step. However, no significant differences were detected on the abundance of nitrate reductase narG and napA genes, suggesting an impact of pesticides/metabolites at the protein level rather than on denitrifying bacteria abundance. 16S rRNA gene Illumina sequencing indicated no major modification of bacterial diversity in the presence or absence of pesticides/metabolites, except for ESA-metolachlor and propiconazole at 10 μg/L that tended to increase or decrease Shannon and InvSimpson indices, respectively. General growth parameters suggested no impact of pesticides, except for propiconazole at 10 μg/L that partially inhibited acetate uptake and induced a decrease in microbial biomass. In conclusion, pesticides and metabolites can have side effects at environmental concentrations on microbial denitrification in groundwater and may thus affect ecosystem services based on microbial activities.