bluuebunny/crossref_metadata_2025 huggingface dataset:
Succinate Is a Natural Suppressor of Antiviral Immune Response by Targeting MAVS
Authors: Xiao Yue , Chen Xinyi , Wang Zhun , Quan Jiazheng , Zhao Xibao , Tang Haimei , Wu Han , Di Qianqian , Wu Zherui , Chen Weilin
Published: March 2022

Succinate is at the crossroads of multiple metabolic pathways and plays a role in several immune responses acting as an inflammation signal. However, whether succinate regulates antiviral immune response remains unclear. Here, we found that the production of succinate was reduced in RAW264.7 cells during vesicular stomatitis virus (VSV) infection. Using diethyl succinate to pretreat the mouse peritoneal macrophages and RAW264.7 cells before VSV infection, the production of interferon-β (IFN-β), chemokine (C–X–C motif) ligand 10 (CXCL-10), and IFN-stimulated genes 15 (ISG15) was significantly decreased, following which the VSV replication in diethyl succinate-pretreated cells was obviously increased. Moreover, succinate decreased the expression of IFN-β in serum, lung, and spleen derived from the VSV-infected mice. The overall survival rate in the VSV-infected mice with diethyl succinate pretreatment was also remarkably downregulated. Furthermore, we identified that succinate inhibited the activation of MAVS-TBK1-IRF3 signaling by suppressing the formation of MAVS aggregates. Our findings provide previously unrecognized roles of succinate in antiviral immune response and establish a novel link between metabolism and innate immune response.
Comprehensive Analysis of the Tumor Immune Microenvironment Landscape in Glioblastoma Reveals Tumor Heterogeneity and Implications for Prognosis and Immunotherapy
Authors: Zhao Rongrong , Pan Ziwen , Li Boyan , Zhao Shulin , Zhang Shouji , Qi Yanhua , Qiu Jiawei , Gao Zijie , Fan Yang , Guo Qindong , Qiu Wei , Wang Shaobo , Wang Qingtong , Zhang Ping , Guo Xing , Deng Lin , Xue Hao , Li Gang
Published: March 2022

Background

Glioblastoma (GBM) is a fatal brain tumor with no effective treatment. The specific GBM tumor immune microenvironment (TIME) may contribute to resistance to immunotherapy, a tumor therapy with great potential. Thus, an in-depth understanding of the characteristics of tumor-infiltrating immune cells is essential for exploring biomarkers in GBM pathogenesis and immunotherapy.

Methods

We estimated the relative abundances of 25 immune cell types in 796 GBM samples using single sample gene set enrichment analysis (ssGSEA). Unsupervised clustering was used to identify different GBM-associated TIME immune cell infiltration (GTMEI) patterns. The GTMEIscore system was constructed with principal component analysis (PCA) to determine the immune infiltration pattern of individual tumors.

Results

We revealed three distinct GTMEI patterns with different clinical outcomes and modulated biological pathways. We developed a scoring system (GTMEIscore) to determine the immune infiltration pattern of individual tumors. We comprehensively analyzed the genomic characteristics, molecular subtypes and clinicopathological features as well as proteomic, phosphoproteomic, acetylomic, lipidomic and metabolomic properties associated with the GTMEIscore and revealed many novel dysregulated pathways and precise targets in GBM. Moreover, the GTMEIscore accurately quantified the immune status of many other cancer types. Clinically, the GTMEIscore was found to have significant potential therapeutic value for chemotherapy/radiotherapy, immune checkpoint inhibitor (ICI) therapy and targeted therapy.

Conclusions

For the first time, we employed a multilevel and multiplatform strategy to construct a multidimensional molecular map of tumors with different immune infiltration patterns. These results may provide theoretical basises for identifying more effective predictive biomarkers and developing more effective drug combination strategies or novel immunotherapeutic agents for GBM.
PD-1 N58-Glycosylation-Dependent Binding of Monoclonal Antibody Cemiplimab for Immune Checkpoint Therapy
Authors: Lu Dan , Xu Zepeng , Zhang Ding , Jiang Min , Liu Kefang , He Juanhua , Ma Dongli , Ma Xiaopeng , Tan Shuguang , Gao George F. , Chai Yan
Published: March 2022

Immune checkpoint therapy (ICT) with a monoclonal antibody (MAb) against programmed cell death protein 1 (PD-1) is a powerful clinical treatment for tumors. Cemiplimab is a human IgG4 antibody approved in 2018 and is the first MAb proven to be effective for locally advanced basal cell carcinoma. Here, we report the crystal structure of cemiplimab bound to PD-1 and the effects of PD-1 N-glycosylation on the interactions with cemiplimab. The structure of the cemiplimab/PD-1 complex shows that cemiplimab mainly binds to PD-1 with its heavy chain, whereas the light chain serves as the predominant region to compete with the binding of PD-L1 to PD-1. The interaction network of cemiplimab to PD-1 resembles that of camrelizumab (another PD-1-binding MAb), and the N58 glycan on the BC loop of PD-1 may be involved in the interaction with cemiplimab. The binding affinity of cemiplimab with PD-1 was substantially decreased with N58-glycan-deficient PD-1, whereas the PD-1/PD-L1 blocking efficiency of cemiplimab was attenuated upon binding to the N58-glycosylation-deficient PD-1. These results indicate that both the binding and blocking efficacy of cemiplimab require the N58 glycosylation of PD-1. Taken together, these findings expand our understanding of the significance of PD-1 glycosylation in the interaction with cemiplimab.
NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond
Authors: Zhu Yuanfeng , Chen Xiaoli , Liu Xin
Published: March 2022

Infection with SARS-CoV-2, the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic, causes respiratory problems and multifaceted organ dysfunction. A crucial mechanism of COVID-19 immunopathy is the recruitment and activation of neutrophils at the infection site, which also predicts disease severity and poor outcomes. The release of neutrophil extracellular traps (NETs), occurring during a regulated form of neutrophil cell death known as NETosis, is a key effector function that mediates harmful effects caused by neutrophils. Abundant NETosis and NET generation have been observed in the neutrophils of many COVID-19 patients, leading to unfavorable coagulopathy and immunothrombosis. Moreover, excessive NETosis and NET generation are now more widely recognized as mediators of additional pathophysiological abnormalities following SARS-CoV-2 infection. In this minireview, we introduce subtypes of NET-producing neutrophils (e.g., low-density granulocytes) and explain the biological importance of NETs and the protein cargos of NETs in COVID-19. In addition, we discuss the mechanisms by which SARS-CoV-2 causes NETosis by upregulating viral processes (e.g., viral entry and replication) as well as host pro-NET mechanisms (e.g., proinflammatory mediator release, platelet activation, and autoantibody production). Furthermore, we provide an update of the main findings of NETosis and NETs in immunothrombosis and other COVID-19-related disorders, such as aberrant immunity, neurological disorders, and post COVID-19 syndromes including lung fibrosis, neurological disorder, tumor progression, and deteriorated chronic illness. Finally, we address potential prospective COVID-19 treatment strategies that target dysregulated NETosis and NET formation via inhibition of NETosis and promotion of NET degradation, respectively.
Decline of Humoral and Cellular Immune Responses Against SARS-CoV-2 6 Months After Full BNT162b2 Vaccination in Hospital Healthcare Workers
Authors: Bonnet Benjamin , Chabrolles Hélène , Archimbaud Christine , Brebion Amélie , Cosme Justine , Dutheil Frédéric , Lambert Céline , Junda Maud , Mirand Audrey , Ollier Amandine , Pereira Bruno , Regagnon Christel , Vidal Magali , Evrard Bertrand , Henquell Cécile
Published: March 2022

Clinical trials and real-world evidence on COVID-19 vaccines have shown their effectiveness against severe disease and death but the durability of protection remains unknown. We analysed the humoral and T-cell immune responses in 110 healthcare workers (HCWs) vaccinated according to the manufacturer’s recommended schedule of dose 2 three weeks after dose 1 from a prospective on-going cohort in early 2021, 3 and 6 months after full vaccination with the BNT162b2 mRNA vaccine. Anti-RBD IgG titres were lower in HCWs over 60 years old 3 months after the second dose (p=0.03) and declined in all the subjects between 3 and 6 months with a median percentage change of -58.5%, irrespective of age and baseline comorbidities. Specific T-cell response measured by IGRA declined over time by at least 42% (median) in 91 HCWs and increased by 33% (median) in 17 others. Six HCWs had a negative T-cell response at 6 months. Ongoing follow-up should provide correlates of long-term protection according to the different immune response profiles observed. COVIDIM study was registered under the number NCT04896788 on clinicaltrials.gov.
HIV-gp140-Specific Antibodies Generated From Indian Long-Term Non-Progressors Mediate Potent ADCC Activity and Effectively Lyse Reactivated HIV Reservoir
Authors: Dhande Jayshree R. , Bagul Rajani D. , Thakar Madhuri R.
Published: March 2022

Strategies to reduce the human immunodeficiency virus (HIV) reservoir are urgently required. The antibody-dependent cellular cytotoxicity (ADCC)-mediating anti-HIV antibodies have shown an association with HIV control. We assessed if such antibodies can be generated in vitro and whether the generated antibodies can facilitate the reduction of reactivated HIV reservoir. We isolated HIV-1-gp140-specific memory B cells from HIV-1-infected long-term non-progressors (LTNPs) with or without plasma ADCC and cultured them to generate anti-HIV antibodies. The ability of the generated antibodies to mediate ADCC and facilitate NK cell-mediated lysis of reactivated HIV reservoir was assessed by the rapid fluorometric antibody-dependent cellular cytotoxicity assay and a flow-based novel latency reduction assay, respectively. All LTNPs showed the presence of gp140-specific memory B cells [median: 0.79% (0.54%–1.225%)], which were successfully differentiated into plasma cells [median 72.0% (68.7–82.2%)] in an in-vitro culture and secreted antibodies [median OD: 0.253 (0.205–0.274)]. The HIV-gp140-specific antibodies were generated from 11/13 LTNPs irrespective of their plasma ADCC status. The generated antibodies from LTNPs with plasma ADCC showed higher ADCC potency (median: 37.6%, IQR: 32.95%–51%) and higher reduction in reactivated HIV reservoir (median: 62.5%, IQR: 58.71%–64.92%) as compared with the antibodies generated from LTNPs without plasma ADCC (ADCC: median: 8.85%, IQR: 8%–9.7%; and % p24 reduction median: 13.84, IQR: 9.863%–17.81%). The potency of these antibodies to reduce latent reservoir was two-fold higher than the respective plasma ADCC. The study showed that the potent ADCC-mediating antibodies could be generated from memory B cells of the LTNPs with plasma ADCC activity. These antibodies also showed potent ability to facilitate NK cell-mediated lysis of reactivated HIV reservoirs. It also indicated that memory B cells from individuals with plasma ADCC activity should be preferentially used for such antibody generation. The important role of these antibodies in the reduction of latent reservoirs needs to be further evaluated as a useful strategy to obtain a functional cure for HIV infection.
Helicobacter pylori Infection of Primary Human Monocytes Boosts Subsequent Immune Responses to LPS
Authors: Frauenlob Tobias , Neuper Theresa , Mehinagic Muamera , Dang Hieu-Hoa , Boraschi Diana , Horejs-Hoeck Jutta
Published: March 2022

Infection with Helicobacter pylori (H. pylori) affects almost half of the world’s population and is a major cause of stomach cancer. Although immune cells react strongly to this gastric bacterium, H. pylori is still one of the rare pathogens that can evade elimination by the host and cause chronic inflammation. In the present study, we characterized the inflammatory response of primary human monocytes to repeated H. pylori infection and their responsiveness to an ensuing bacterial stimulus. We show that, although repeated stimulations with H. pylori do not result in an enhanced response, H. pylori-primed monocytes are hyper-responsive to an Escherichia coli-lipopolysaccharide (LPS) stimulation that takes place shortly after infection. This hyper-responsiveness to bacterial stimuli is observed upon infection with viable H. pylori only, while heat-killed H. pylori fails to boost both cytokine secretion and STAT activation in response to LPS. When the secondary challenge occurs several days after the primary infection with live bacteria, H. pylori-infected monocytes lose their hyper-responsiveness. The observation that H. pylori makes primary human monocytes more susceptible to subsequent/overlapping stimuli provides an important basis to better understand how H. pylori can maintain chronic inflammation and thus contribute to gastric cancer progression.
Enhanced Thermal and Antibacterial Properties of Stereo-Complexed Polylactide Fibers Doped With Nano-Silver
Authors: Zhao Shiyou , Ke Huizhen , Yang Tingting , Peng Qiqi , Ge Jianlong , Yao Lirong , Xu Sijun , Zhirong Ding , Pan Gangwei
Published: March 2022

Stereo-complexed polylactide (sc-PLA) fibers with excellent heat resistance and antibacterial properties were prepared by electrospinning. Due to poor heat resistance, common poly(L-lactide) (PLLA) fibers have poor dimensional stability at high temperatures and cannot be sterilized and recycled as a medical filter material. In this research, PLLA/poly(D-lactide) (PDLA) blends doped with silver nanoparticles (AgNPs) were electrospun to obtain the sc-PLA fibers. The effect of thermal induction temperature on the crystalline structure and thermal properties of sc-PLA fibers was investigated. Moreover, the influence of the addition amount of AgNPs on the crystal structure of sc-PLA fibers was studied, and the antibacterial properties of the sc-PLA fibers with different addition amounts of AgNPs were analyzed. The thermal induction is beneficial to the formation of stereo-complexed crystals of sc-PLA fibers, and finally completely stereo-complexed PLA fibers were obtained. The melting temperature of the completely stereo-complexed PLA fibers was 50°C higher than that of the PLLA fibers; therefore, the sc-PLA fibers have better heat resistance. The addition of AgNPs was conducive to the formation of stereo-complexed crystals of sc-PLA fibers. In addition, the antibacterial rate of sc-PLA fibers against E. coli and S. aureus was 99.99 ± 0.01% when the addition amount of AgNPs was only 0.15 wt%. The fiber membrane obtained in this experiment can be used as a reusable filter material, and the sc-PLA fiber membrane has broad application prospects in the biomedical field.
Potential for Further Mismanagement of Fever During COVID-19 Pandemic: Possible Causes and Impacts
Authors: Singh Samer , Kishore Dhiraj , Singh Rakesh K.
Published: March 2022

Fever remains an integral part of acute infectious diseases management, especially for those without effective therapeutics, but the widespread myths about “fevers” and the presence of confusing guidelines from different agencies, which have heightened during the coronavirus disease 2019 (COVID-19) pandemic and are open to alternate interpretation, could deny whole populations the benefits of fever. Guidelines suggesting antipyresis for 37.8–39°C fever are concerning as 39°C boosts the protective heat-shock and immune response (humoral, cell-mediated, and nutritional) whereas ≥40°C initiates/enhances the antiviral responses and restricts high-temperature adapted pathogens, e.g., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), strains of influenza, and measles. Urgent attention is accordingly needed to address the situation because of the potential public health consequences of the existence of conflicting guidelines in the public domain. We have in this article attempted to restate the benefits of fever in disease resolution, dispel myths, and underline the need for alignment of national treatment guidelines with that of the WHO, to promote appropriate practices and reduce the morbidity and mortality from infectious diseases, such as COVID-19.
Surgery Treatment of Primary Tumors of the Inferior Vena Cava
Authors: Wang Shizhi , Li Yuqiu , Yang Qijun , Zhang Xue , Cheng Yunqi , Li Zimeng , Wang Jingyi , Zeng Qingfu
Published: March 2022

Background

Primary tumor of the inferior vena cava is a rare tumor, which arises from the smooth muscle of vascular walls. Surgery appears the only curative treatment. However, the optimal surgical methods and surgical management are not well-studied. In this article, we reviewed the successful treatment experience of patients in our center who had resection of primary tumor of the inferior vena cava and reviewed the relevant literature.

Methods

Four cases of patients who undergoing initial resection of primary tumors of the inferior vena cava from September 2017 to August 2021 in the Second Affiliated Hospital of Nanchang University were screened and followed up. They were discussed and cases reported in this field were reviewed.

Results

Among the four patients, three of them were female. The median age of the disease is 53.75 years (range 45–60 years). After surgical treatment, tumors were removed in all patients, and some patients had reconstruction of inferior vena cava. There were no disease-specific deaths, no serious complications, and no recurrence during follow-up in these cases.

Conclusions

Careful preoperative examination, correct surgical treatment methods, and multidisciplinary collaboration can lead to safe and successful operations, which improve the survival rate of patients.
An Infodemic of Misinformation on Stem Cell Therapy Among the Population of Saudi Arabia: A Cross-Sectional Study
Authors: Aboalola Doaa , Badraiq Heba , Alsiary Rawiah , Zakri Samer , Aboulola Neda , Haneef Loay , Malibari Dalal , Baadhaim Moayad , Alsayegh Khaled
Published: March 2022

In recent years, the industry of unproven stem cell-based therapies has been on the rise around the globe, putting patients at great risk of potential harm. In this cross-sectional study, we aimed to assess the level of knowledge and awareness of the general public, including patients and/or their relatives, in Saudi Arabia on stem cell therapy and to assess the degree of willingness to try stem cell-based treatment options, should it be offered to them.

Methods

A voluntary questionnaire of 16 questions was distributed randomly through social media outlets.

Results

In the survey of this study, 2,030 individuals participated. A total of 1,292 (63.6%) stated that they would accept stem cell therapy or would recommend it to their friends and relatives. Alarmingly, 72.1% of participants were unaware that using unapproved stem cell-based treatments may lead to serious health complications including cancer. More than 20% believed that stem cell therapy is already approved for organ/tissue regeneration. Worryingly, 60.6% of the physicians and 56.4% of the medical students stated that they would recommend stem cell treatment for their patients.

Conclusions

There is a concerning spread of misinformation among the Saudi population, including physicians, regarding stem cell therapy. This calls for a targeted effort to raise awareness about the current status of stem cell treatment in the general public and among health care practitioners.
N6-Methyladenosine Modification Participates in the Progression of Hepatitis B Virus-Related Liver Fibrosis by Regulating Immune Cell Infiltration
Authors: Zhao Tong , Qi Jianni , Liu Tiantian , Wu Hao , Zhu Qiang
Published: March 2022

Aim

N6-methyladenosine (m6A) modification has been demonstrated to play an important part in hepatitis B virus (HBV) infection and immune response. This study aims to further investigate whether m6A modification plays an important role in the progression of HBV-related liver fibrosis through the regulation of immune cell infiltration.

Methods

In this study, 124 chronically HBV infected cases were obtained from the Gene Expression Omnibus database. In total, 489 m6A-and-stage related genes were selected to be associated with the m6A modification and the stage of liver fibrosis. Based on these genes, we identified two distinct gene clusters, gene clusterA and gene clusterB. The immune characteristics of the two clusters were comprehensively compared. The m6A-S score was constructed as quantification of individual m6A status. The correlations between m6A regulators and infiltrating immune cells were examined and compared in different pairs of groups with various m6A traits.

Results

Biological functions, immune cell infiltration, and cytokines expression were compared between the two gene clusters proving that the gene clusterB was more immune active and had a more advanced liver fibrosis stage. The m6A-S score was associated with immune infiltration and the progression of liver fibrosis. Five different grouping conditions with different m6A traits were set up. According to the intersection of significant genes and cells, ALKBH5 interacting with macrophage and WTAP interacting with nature killer T cells may be key points in the progress of liver fibrosis.

Conclusions

N6-methyladenosine modification is closely related to the immune cell infiltration and the fibrosis stage of chronic HBV-infected liver tissue. It provides us a better understanding of the progression of liver cirrhosis via evaluating the m6A modification pattern and immune infiltration characteristics.
Oral and Gut Microbial Dysbiosis and Non-alcoholic Fatty Liver Disease: The Central Role of Porphyromonas gingivalis
Authors: Wang Ting , Ishikawa Taichi , Sasaki Minoru , Chiba Toshimi
Published: March 2022

Gut microbiota play many important roles, such as the regulation of immunity and barrier function in the intestine, and are crucial for maintaining homeostasis in living organisms. The disruption in microbiota is called dysbiosis, which has been associated with various chronic inflammatory conditions, food allergies, colorectal cancer, etc. The gut microbiota is also affected by several other factors such as diet, antibiotics and other medications, or bacterial and viral infections. Moreover, there are some reports on the oral-gut-liver axis indicating that the disruption of oral microbiota affects the intestinal biota. Non-alcoholic fatty liver disease (NAFLD) is one of the systemic diseases caused due to the dysregulation of the oral-gut-liver axis. NAFLD is the most common liver disease reported in the developed countries. It includes liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Recently, accumulating evidence supports an association between NAFLD and dysbiosis of oral and gut microbiota. Periodontopathic bacteria, especially Porphyromonas gingivalis, have been correlated with the pathogenesis and development of NAFLD based on the clinical and basic research, and immunology. P. gingivalis was detected in the liver, and lipopolysaccharide from this bacteria has been shown to be involved in the progression of NAFLD, thereby indicating a direct role of P. gingivalis in NAFLD. Moreover, P. gingivalis induces dysbiosis of gut microbiota, which promotes the progression of NAFLD, through disrupting both metabolic and immunologic pathways. Here, we review the roles of microbial dysbiosis in NAFLD. Focusing on P. gingivalis, we evaluate and summarize the most recent advances in our understanding of the relationship between oral-gut microbiome symbiosis and the pathogenesis and progression of non-alcoholic fatty liver disease, as well as discuss novel strategies targeting both P. gingivalis and microbial dysbiosis.
Incidence Trends of Five Common Sexually Transmitted Infections Excluding HIV From 1990 to 2019 at the Global, Regional, and National Levels: Results From the Global Burden of Disease Study 2019
Authors: Fu Leiwen , Sun Yinghui , Han Min , Wang Bingyi , Xiao Fei , Zhou Yiguo , Gao Yanxiao , Fitzpatrick Thomas , Yuan Tanwei , Li Peiyang , Zhan Yuewei , Lu Yong , Luo Ganfeng , Duan Junyi , Hong Zhongsi , Fairley Christopher K. , Zhang Tong , Zhao Jin , Zou Huachun
Published: March 2022

Objective

Sexually transmitted infections (STIs) are common worldwide and pose a challenge to public health. We conducted this study to assess the annual incidence of five common STIs, including syphilis, chlamydia, gonorrhea, trichomoniasis, and genital herpes at the global, regional, and national levels.

Materials and Methods

We obtained detailed data on STIs excluding HIV from 1990 to 2019 from the Global Burden of Disease (GBD) 2019 database. Estimated annual percentage change (EAPC) was calculated to quantify trends in age-standardized incidence rates (ASR) of STIs, stratified by gender, sociodemographic index (SDI) region, and pathogenic microorganism.

Results

Globally, incident cases of STIs increased by 58.15% from 486.77 million in 1990 to 769.85 million in 2019, but the annual change in ASR was only −0.04% (95% CI −0.09 to 0.01) per year. EAPC was 0.16 (0.06 to 0.26) for syphilis, 0.09 (0.05 to 0.13) for genital herpes, 0.06 (0.03 to 0.09) for trichomoniasis, −0.21 (−0.36 to −0.06) for chlamydia, and −0.14 (−0.19 to −0.08) for gonorrhea. High SDI regions reported significant increases in ASR of syphilis and chlamydia.

Conclusions

The burden of disease from STIs remains large, though control of STIs has contributed to the decreasing incidence in most regions, especially in the low-SDI regions. Globally, over the past 20 years, the ASR has remained stable for trichomoniasis and genital herpes decreased for chlamydia and gonorrhea, and increased for syphilis.
Optimization and Effect of Water Hardness for the Production of Slightly Acidic Electrolyzed Water on Sanitization Efficacy
Authors: Yan Pianpian , Jo Hyeon-yeong , Chelliah Ramachandran , Jo Kyoung hee , Woo Nam Chan , Wook Min Seung , Oh Deog Hwan
Published: March 2022

Slightly acidic electrolyzed water (SAEW) has been recently proposed as a novel promising sanitizer and cleaner in the agricultural and food industries. However, several factors, including water hardness, were considered to strongly affect the physical properties and sanitization efficacy of SAEW. To study the effect of water hardness on the SAEW production, we evaluated the production properties and sanitization effect of SAEW, which was generated from water sources in 16 representatively geographical locations of South Korea. The results showed that the hardness of water sources from Kangwon-do, Jeollanam-do, and Daegu was 22–41 ppm; that from Busan, Gyeongnam-do, Gwangju Bukgu was 80–443 ppm, and that from seven other locations was 41–79 ppm. SAEW is produced from water hardness less than 50 ppm and greater than 80 ppm was beyond the accepted pH range (5.0–6.5). Notably, high-hardness water (>80 ppm) containing 5% HCl could be used to produce SAEW with accepted pH. The SAEW generated from low-hardness water with additions of 2% HCl and 2 M NaCl at 7 A showed accepted pH and higher germicidal effect. Furthermore, SAEW with the available chlorine concentration of 27–41 mg/L for 1 min was sufficient to completely inactivate non–spore-forming foodborne pathogens. Sanitization efficacy was not markedly affected by storage conditions for SAEW at 40 ppm. Our results demonstrated that the degree of water hardness is an important factor in the production of SAEW, which would provide a foundation for commercial application of SAEW.
Rewiring the Metabolic Network to Increase Docosahexaenoic Acid Productivity in Crypthecodinium cohnii by Fermentation Supernatant-Based Adaptive Laboratory Evolution
Authors: Liu Liangsen , Diao Jinjin , Bi Yali , Zeng Lei , Wang Fangzhong , Chen Lei , Zhang Weiwen
Published: March 2022

Docosahexaenoic acid (DHA, 22:6n-3) plays significant roles in enhancing human health and preventing human diseases. The heterotrophic marine dinoflagellate Crypthecodinium cohnii is a good candidate to produce high-quality DHA. To overcome the inhibition caused by the fermentation supernatant in the late fermentation stage of DHA-producing C. cohnii, fermentation supernatant-based adaptive laboratory evolution (FS-ALE) was conducted. The cell growth and DHA productivity of the evolved strain (FS280) obtained after 280 adaptive cycles corresponding to 840 days of evolution were increased by 161.87 and 311.23%, respectively, at 72 h under stress conditions and increased by 19.87 and 51.79% without any stress compared with the starting strain, demonstrating the effectiveness of FS-ALE. In addition, a comparative proteomic analysis identified 11,106 proteins and 910 differentially expressed proteins, including six stress-responsive proteins, as well as the up- and downregulated pathways in FS280 that might contribute to its improved cell growth and DHA accumulation. Our study demonstrated that FS-ALE could be a valuable solution to relieve the inhibition of the fermentation supernatant at the late stage of normal fermentation of heterotrophic microalgae.
Metabolomic Insights Into Endophyte-Derived Bioactive Compounds
Authors: Mishra Sushma , Priyanka  , Sharma Shilpi
Published: March 2022

Among the various plant-associated microbiota, endophytes (the microbial communities inhabiting plant endosphere without causing disease symptoms) exhibit the most intimate and specific association with host plants. Endophytic microbes influence various aspects of plant responses (such as increasing availability of nutrients, tolerance against biotic and abiotic stresses, etc.) by modulating the primary and secondary metabolism of the host. Besides, endophytic microbes produce a diverse array of bioactive compounds, which have potential applications in the pharmaceutical, food, and cosmetic industries. Further, there is sufficient evidence for endophyte-derived plant metabolites, which could be pursued as alternative sources of commercially important plant metabolites. The field of bioprospecting, the discovery of novel chemistries, and endophyte-mediated production of plant metabolites have witnessed a boom with the advent of omics technologies (especially metabolomics) in endophyte research. The high throughput study of small metabolites at a particular timepoint or tissue forms the core of metabolomics. Being downstream to transcriptome and proteome, the metabolome provides the most direct reflection of the phenotype of an organism. The contribution of plant and microbial metabolomics for answering fundamental questions of plant-endophyte interaction, such as the effect of endophyte inoculation on plant metabolome, composition of metabolites on the impact of environmental stressors (biotic and abiotic), etc., have also been discussed.
Immobilization of Ochrobactrum sp. on Biochar/Clay Composite Particle: Optimization of Preparation and Performance for Nitrogen Removal
Authors: Sun Pengfei , Huang Xiao , Xing Yixiao , Dong Wenlong , Yu Jianghua , Bai Jie , Duan Weiyan
Published: March 2022

The objective of this study was to prepare biochar/clay composite particle (BCCP) as carrier to immobilize Ochrobactrum sp. to degrade ammonia nitrogen (NH4+-N), and the effects of calcined program and immobilizing material were investigated. Results reflected that the parameters were as follows: calcined temperature 400°C, heating rate 20°C min–1, and holding time 2 h, and the adsorption capacity could reach 0.492 mg g–1. Sodium alginate/polyvinyl alcohol, as embedding material, jointed with NH4+-N adsorption process and then degraded by Ochrobactrum sp. with 79.39% degradation efficiency at 168 h. Immobilizing Ochrobactrum sp. could protect strain from high salt concentration to achieve the exceeding degradation efficiency than free bacteria, but could not block the impact of low temperature.
Performance of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Identification of Scedosporium, Acremonium-Like, Scopulariopsis, and Microascus Species
Authors: Wei Linwei , Shao Jin , Song Yinggai , Wan Zhe , Yao Limin , Wang Hong , Yu Jin
Published: March 2022

Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has emerged as a powerful microorganism identification tool. Research on MALDI-TOF MS identification of rare filamentous fungi is still lacking. This study aimed to evaluate the performance of MALDI-TOF MS in the identification of Scedosporium, Acremonium-like, Scopulariopsis, and Microascus species. Sabouraud broth cultivation and formic acid/acetonitrile protein extraction were used for MALDI-TOF MS identification by a Bruker Biotyper system. An in-house database containing 29 isolates of Scedosporium, Acremonium-like, Scopulariopsis, and Microascus spp. was constructed. A total of 52 clinical isolates were identified using the Bruker Filamentous Fungi Library v1.0 (FFL v1.0) alone, and Filamentous Fungi Library v1.0 plus the in-house library, respectively. The mass spectrum profile (MSP) dendrograms of the 28 Scedosporium isolates, 26 Acremonium-like isolates, and 27 Scopulariopsis and Microascus isolates were constructed by MALDI Biotyper OC 4.0 software, respectively. The correct species identification rate significantly improved when using the combined databases compared with that when using FFL v1.0 alone (Scedosporium spp., 75% versus 0%; Acremonium-like spp., 100% versus 0%; Scopulariopsis and Microascus spp., 100% versus 62.5%). The MSP dendrograms differentiated Acremonium-like species, Scopulariopsis and Microascus species clearly, but cannot distinguish species in the Scedosporium apiospermum complex. In conclusion, with an expanded database, MALDI-TOF MS is an effective tool for the identification of Scedosporium, Acremonium-like, Scopulariopsis, and Microascus species.
A Practical Approach for Predicting Antimicrobial Phenotype Resistance in Staphylococcus aureus Through Machine Learning Analysis of Genome Data
Authors: Wang Shuyi , Zhao Chunjiang , Yin Yuyao , Chen Fengning , Chen Hongbin , Wang Hui
Published: March 2022

With the reduction in sequencing price and acceleration of sequencing speed, it is particularly important to directly link the genotype and phenotype of bacteria. Here, we firstly predicted the minimum inhibitory concentrations of ten antimicrobial agents for Staphylococcus aureus using 466 isolates by directly extracting k-mer from whole genome sequencing data combined with three machine learning algorithms: random forest, support vector machine, and XGBoost. Considering one two-fold dilution, the essential agreement and the category agreement could reach >85% and >90% for most antimicrobial agents. For clindamycin, cefoxitin and trimethoprim-sulfamethoxazole, the essential agreement and the category agreement could reach >91% and >93%, providing important information for clinical treatment. The successful prediction of cefoxitin resistance showed that the model could identify methicillin-resistant S. aureus. The results suggest that small datasets available in large hospitals could bypass the existing basic research and known antimicrobial resistance genes and accurately predict the bacterial phenotype.
The Construction and Immunogenicity Analyses of Recombinant Pseudorabies Virus With NADC30-Like Porcine Reproductive and Respiratory Syndrome Virus-Like Particles Co-expression
Authors: Zhao Jun , Zhu Ling , Xu Lei , Li Fengqing , Deng Huidan , Huang Yao , Gu Sirui , Sun Xianggang , Zhou Yuancheng , Xu Zhiwen
Published: March 2022

Porcine reproductive and respiratory syndrome (PRRS) and pseudorabies (PR) are highly infectious swine diseases and cause significant financial loss in China. The respiratory system and reproductive system are the main target systems. Previous studies showed that the existing PR virus (PRV) and PRRS virus (PRRSV) commercial vaccines could not provide complete protection against PRV variant strains and NADC30-like PRRSV strains in China. In this study, the PRV variant strain XJ and NADC30-like PRRSV strain CHSCDJY-2019 are used as the parent for constructing a recombinant pseudorabies virus (rPRV)-NC56 with gE/gI/TK gene deletion and co-expressing NADC30-like PRRSV GP5 and M protein. The rPRV-NC56 proliferated stably in BHK-21 cells, and it could stably express GP5 and M protein. Due to the introduction of the self-cleaving 2A peptide, GP5 and M protein were able to express independently and form virus-like particles (VLPs) of PRRSV in rPRV-NC56-infected BHK-21 cells. The rPRV-NC56 is safe for use in mice; it can colonize and express the target protein in mouse lungs for a long time. Vaccination with rPRV-NC56 induces PRV and NADC30-like PRRSV specific humoral and cellular immune responses in mice, and protects 100% of mice from virulent PRV XJ strain. Furthermore, the virus-neutralizing antibody (VNA) elicited by rPRV-NC56 showed significantly lower titer against SCNJ-2016 (HP-PRRSV) than that against CHSCDJY-2019 (NADC30-like PRRSV). Thus, rPRV-NC56 appears to be a promising candidate vaccine against NADC30-like PRRSV and PRV for the control and eradication of the variant PRV and NADC30-like PRRSV.
Coronavirus Usurps the Autophagy-Lysosome Pathway and Induces Membranes Rearrangement for Infection and Pathogenesis
Authors: Liang Haowei , Luo Dan , Liao Hai , Li Shun
Published: March 2022

Autophagy is a crucial and conserved homeostatic mechanism for early defense against viral infections. Recent studies indicate that coronaviruses (CoVs) have evolved various strategies to evade the autophagy–lysosome pathway. In this minireview, we describe the source of double-membrane vesicles during CoV infection, which creates a microenvironment that promotes viral RNA replication and virion synthesis and protects the viral genome from detection by the host. Firstly, CoVs hijack autophagy initiation through non-structural proteins and open-reading frames, leading to the use of non-nucleated phagophores and omegasomes for autophagy-derived double-membrane vesicles. Contrastingly, membrane rearrangement by hijacking ER-associated degradation machinery to form ER-derived double-membrane vesicles independent from the typical autophagy process is another important routine for the production of double-membrane vesicles. Furthermore, we summarize the molecular mechanisms by which CoV non-structural proteins and open-reading frames are used to intercept autophagic flux and thereby evade host clearance and innate immunity. A comprehensive understanding of the above mechanisms may contribute to developing novel therapies and clinical drugs against coronavirus disease 2019 (COVID-19) in the future.
Genotyping Based on CRISPR Loci Diversity and Pathogenic Potential of Diarrheagenic Escherichia coli
Authors: Bai Zhiye , Zhang Shiqin , Wang Xiang , Aslam Muhammad Zohaib , Wang Wen , Li Hongmei , Dong Qingli
Published: March 2022

Diarrheagenic Escherichia coli (DEC) can cause epidemic diarrhea worldwide. The pathogenic potential of different strains is diverse and the continuous emergence of pathogenic strains has brought serious harm to public health. Accurately distinguishing and identifying DEC with different virulence is necessary for epidemiological surveillance and investigation. Clustered regularly interspaced short palindromic repeats (CRISPR) typing is a new molecular method that can distinguish pathogenic bacteria excellently and has shown great promise in DEC typing. The purpose of this study was to investigate the discrimination of CRISPR typing method for DEC and explore the pathogenicity potential of DEC based on CRISPR types (CT). The whole genome sequences of 789 DEC strains downloaded from the database were applied CRISPR typing and serotyping. The D value (Simpson’s index) with 0.9709 determined that CRISPR typing had a higher discrimination. Moreover, the same H antigen strains with different O seemed to share more identical spacers. Further analyzing the strains CRISPR types and the number of virulence genes, it was found that there was a significant correlation between the CRISPR types and the number of virulence genes (p < 0.01). The strains with the largest number of virulence genes concentrated in CT25 and CT56 and the number of virulence genes in CT264 was the least, indicating that the pathway potential of different CRISPR types was variable. Combined with the Caco-2 cell assay of the laboratory strains, the invasion capacity of STEC strains of different CRISPR types was different and there was no significant difference in the invasion rate between different CRISPR type strains (p > 0.05). In the future, with the increase of the number of strains that can be studied experimentally, the relationship between CRISPR types and adhesion and invasion capacities will be further clarified.
Umbilical Cord Blood Mononuclear Cell Treatment for Neonatal Rats With Hypoxic Ischemia
Authors: Lyu Hao , Sun Dong Ming , Ng Chi Ping , Cheng Wendy S. , Chen Jun Fan , He Yu Zhong , Lam Sin Yu , Zheng Zhi Yuan , Huang Guo Dong , Wang Chi Chiu , Young Wise , Poon Wai Sang
Published: March 2022

Background

Hypoxic-ischemic encephalopathy (HIE) occurs when an infant’s brain has not received adequate oxygen and blood supply, resulting in ischemic and hypoxic damage. Currently, supportive care and hypothermia therapy have been the standard treatment for HIE. However, there are still over 20% of treated infants died and 19–30% survived with significant disability. HIE animal model was first established by Rice et al., involving the ligation of one common carotid artery followed by hypoxia. In this study, we investigated human umbilical cord blood (HUCB) and its two components mononuclear cell (MNC) and red cell fraction (RCF) in both short and long term study using a modified HIE rat model.

Methods

In this modified HIE model, both common carotid arteries were occluded, breathing 8% oxygen in a hypoxic chamber for 60-min, followed by the release of the common carotid arteries ligature, mimicking reperfusion injury. For cell therapeutic study, cells were intravenously injected to HIE rat pups, and both behavioral and histological changes were assessed at selected time points.

Result

Statistically significant behavioral improvements were demonstrated on Day 7 and 1 month between saline treated HIE rats and UCB/MNC treated rats. However, at 3 months, the therapeutic improvements were only showed between saline treated HIE animals and MNC treated HIE rats. For histological analysis 1 month after cell injection, the number of functional neurons were statistically increased between saline treated HIE and UCB/MNC/RCF treated HIE rats. At 3 months, the significant increase in functional neurons was only present in MNC treated HIE rats.

Conclusion

We have used a bilateral temporary occlusion of 60 min, a moderately brain damaged model, for cell therapeutic studies. HUCB mononuclear cell (MNC) therapy showed benefits in neonatal HIE rats in both short and long term behavioral and histological assessments.
Basic Surveillance Parameters Improve the Prediction of Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage
Authors: Csók István , Grauvogel Jürgen , Scheiwe Christian , Bardutzky Jürgen , Wehrum Thomas , Beck Jürgen , Reinacher Peter C. , Roelz Roland
Published: March 2022

Background

To establish a practical risk chart for prediction of delayed cerebral infarction (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) by using information that is available until day 5 after ictus.

Methods

We assessed all consecutive patients with aSAH admitted to our service between September 2008 and September 2015 (n = 417). The data set was randomly split into thirds. Two-thirds were used for model development and one-third was used for validation. Characteristics that were present between the bleeding event and day 5 (i.e., prior to >95% of DCI diagnoses) were assessed to predict DCI by using logistic regression models. A simple risk chart was established and validated.

Results

The amount of cisternal and ventricular blood on admission CT (Hijdra sum score), early sonographic vasospasm (i.e., mean flow velocity of either intracranial artery >160 cm/s until day 5), and a simplified binary level of consciousness score until day 5 were the strongest predictors of DCI. A model combining these predictors delivered a high predictive accuracy [the area under the receiver operating characteristic (AUC) curve of 0.82, Nagelkerke's R2 0.34 in the development cohort]. Validation of the model demonstrated a high discriminative capacity with the AUC of 0.82, Nagelkerke's R2 0.30 in the validation cohort.

Conclusion

Adding level of consciousness and sonographic vasospasm between admission and postbleed day 5 to the initial blood amount allows for simple and precise prediction of DCI. The suggested risk chart may prove useful for selection of appropriate candidates for interventions to prevent DCI.
Psychosis in Alzheimer's Disease Is Associated With Increased Excitatory Neuron Vulnerability and Post-transcriptional Mechanisms Altering Synaptic Protein Levels
Authors: DeChellis-Marks Michael R. , Wei Yue , Ding Ying , Wolfe Cody M. , Krivinko Joshua M. , MacDonald Matthew L. , Lopez Oscar L. , Sweet Robert A. , Kofler Julia
Published: March 2022

Alzheimer's disease with psychosis (AD+P) is a heritable phenotypic variant of the disease which is associated with more rapid cognitive deterioration compared to Alzheimer's disease without psychosis (AD–P). Cognitive decline in AD correlates with synapse loss, and our previous studies suggest that those with AD+P have a differentially affected synaptic proteome relative to those with AD–P. In this study, we utilized RNA-sequencing of dorsolateral prefrontal cortex (DLPFC) in a cohort of 80 AD cases to evaluate novel transcriptomic signatures that may confer risk of psychosis in AD. We found that AD+P was associated with a 9% reduction in excitatory neuron proportion compared to AD–P [Mean (SD) AD+P 0.295 (0.061); AD–P 0.324 (0.052), p = 0.026]. mRNA levels contributed only modestly to altered synaptic proteins in AD+P relative to AD–P. Instead, network analysis identified altered expression of gene modules from protein ubiquitination, unfolded protein response, eukaryotic initiation factor 2 (EIF2) signaling and endoplasmic reticulum stress pathways in AD+P. We previously found that neuropathologies account for ~18% of the variance in the occurrence of psychosis in AD. Further inclusion of cell type proportions and differentially expressed modules increased the percent of the variance in psychosis occurrence accounted for in our AD cohort to 67.5%.