bluuebunny/crossref_metadata_2025 huggingface dataset:
Requirements for the Interaction With Highly Automated Construction Site Delivery Trucks
Authors: Colley Mark , Mytilineos Stefanos , Walch Marcel , Gugenheimer Jan , Rukzio Enrico
Published: February 2022

Automated trucks for long-distance journeys seem within reach. With such automation, no human driver could be available. However, the last mile of the delivery is likely to involve humans. Therefore, either a human driver should still be present, or construction site workers must interact with the automated truck. While automated trucks capable of dealing with various construction sites could be feasible, the development could be costly and time-consuming. To define cooperative solutions for automated deliveries incorporating interaction between automated trucks and humans, a workshop with truck drivers (N= 7) was conducted. Based on this workshop, a model of the delivery process, including communication needs, is proposed. Requirements addressing the issues for highly automated delivery are derived from this process.
Computational Design of a Multi-Epitope Vaccine Against Porphyromonas gingivalis
Authors: Shaker Bilal , Ahmad Sajjad , Shen Junhao , Kim Hyung Wook , Na Dokyun
Published: February 2022

Porphyromonas gingivalisis a Gram-negative pathogenic bacterium associated with chronic periodontitis. The development of a chimeric peptide-based vaccine targeting this pathogen could be highly beneficial in preventing oral bone loss as well as other severe gum diseases. We applied a computational framework to design a multi-epitope-based vaccine candidate againstP. gingivalis. The vaccine comprises epitopes from subunit proteins prioritized from theP. gingivalisreference strain (P. gingivalisATCC 33277) using several reported vaccine properties. Protein-based subunit vaccines were prioritized through genomics techniques. Epitope prediction was performed using immunoinformatic servers and tools. Molecular modeling approaches were used to build a putative three-dimensional structure of the vaccine to understand its interactions with host immune cells through biophysical techniques such as molecular docking simulation studies and binding free energy methods. Genome subtraction identified 18 vaccine targets: six outer-membrane, nine cytoplasmic membrane-, one periplasmic, and two extracellular proteins. These proteins passed different vaccine checks required for the successful development of a vaccine candidate. The shortlisted proteins were subjected to immunoinformatic analysis to map B-cell derived T-cell epitopes, and antigenic, water-soluble, non-toxic, and good binders of DRB1*0101 were selected. The epitopes were then modeled into a multi-epitope peptide vaccine construct (linked epitopes plus adjuvant) to enhance immunogenicity and effectively engage both innate and adaptive immunity. Further, the molecular docking approach was used to determine the binding conformation of the vaccine to TLR2 innate immune receptor. Molecular dynamics simulations and binding free energy calculations of the vaccine–TLR2 complex were performed to highlight key intermolecular binding energies. Findings of this study will be useful for vaccine developers to design an effective vaccine for chronic periodontitis pathogens, specificallyP. gingivalis.
Biosynthetic Microcin J25 Exerts Strong Antibacterial, Anti-Inflammatory Activities, Low Cytotoxicity Without Increasing Drug-Resistance to Bacteria Target
Authors: Yu Haitao , Shang Lijun , Yang Guangxin , Dai Ziqi , Zeng Xiangfang , Qiao Shiyan
Published: February 2022

Multidrug resistant (MDR) bacterial infection has emerged, raising concerns about untreatable infections, and posing the highest health risks. Antimicrobial peptides (AMPs) are thought to be the best remedy for this problem. Here, we showed biosynthetic microcin J25 (MccJ25) exhibited excellent bactericidal activity against standard and clinically relevant veterinary MDR strains with high stability, no cytotoxicity, and no increase in drug resistance. Analysis of antimicrobial mechanism possessed by sensitive enterotoxigenic Escherichia coli (ETEC) based on electron microscopy and Sytox Green methods was carried out. Results showed excellent activity against ETEC was due to permeabilizing bacterial membranes and strong affinity. MccJ25 exhibited high endotoxin-neutralizing activity in both in vivo and in vitro environments, and mice exposed to lipopolysaccharide (LPS) showed decreased plasma LPS levels and improved survival after administration of MccJ25. In an LPS-treated mouse septicemia model, MccJ25 treatment significantly alleviated inflammatory responses by inhibiting proinflammatory factor secretion and expression. In a mouse E. coli infection model, administration of MccJ25 effectively improved host defense against clinically source cocktail of multidrug-resistant E. coli strains induced intestinal inflammation and bacteria dissemination. Results of studies on anti-inflammatory mechanisms showed that MccJ25 downregulated nuclear factor kappa B kinase and mitogen-activated protein kinase, thereby reducing the production of toll-like receptor 4, myeloid differentiation factor 88 and decreasing the key proinflammatory cytokines. These findings clarify MccJ25 may be an ideal antibacterial/antiendotoxic drug candidate that has the potential to further guide the development of anti-inflammatory and/or antimicrobial agents in the war against MDR bacterial infection.
Fatty Acid Metabolic Signaling Pathway Alternation Predict Prognosis of Immune Checkpoint Inhibitors in Glioblastoma
Authors: Liu Rongrong , Liang Weidong , Hua Qian , Wu Longqiu , Wang Xiangcai , Li Qiang , Zhong Fangjun , Li Bin , Qiu Zhengang
Published: February 2022

Introduction

Glioblastoma(GBM) is a highly malignant primary brain tumor. Even after undergoing surgery and chemotherapy, patients with this affliction still have little to no chance of survival. Current research on immunotherapy treatment for GBM shows that immune-checkpoint inhibitors (ICIs) may be a promising new treatment method. However, at present, the relationship between the fatty acid metabolic process and the prognosis of GBM patients who are receiving immunotherapy is not clear.

Methods

First, we downloaded a GBM cohort that had been treated with immunotherapy, which included the mutation and prognosis data, and the TCGA-GBM and Jonsson-GBM queues. CIBERSORT and single sample gene set enrichment analysis(ssGSEA) were used to evaluate immune cell scores. Gene set enrichment analysis (GSEA) was used to evaluate the patient’s accessment score. The pRRophetic algorithm was used to evaluate the drug sensitivity of each patient. Univariable and multivariate cox regression analyses, as well as the Kaplan-Meier (KM) method, were used to evaluate the relationship between the fatty acid metabolic process and the prognosis of GBM patients.

Results

The univariate and multivariate cox regression models showed that the fatty acid metabolic process mutant-type (MT) can be used as an independent predictor of the efficacy of immunotherapy for GBM patients. In addition, fatty acid metabolic process MT is related with significantly longer overall survival (OS) time than the wild-type(WT) variant. However, the mutation status of the fatty acid metabolic process has nothing to do with the prognosis of GBM patients who are receiving conventional treatment. Our analysis showed that fatty acid metabolic process MT correlated with significantly increased natural killer T (NKT) cells and significantly decreased CD8+T cells. At the same time, GSEA analysis revealed that fatty acid metabolic process MT was associated with significantly increased immune activation pathways and an enriched fraction of cytokine secretion compared with WT.

Conclusions

We found that fatty acid metabolic process MT may be used as an independent predictor of the efficacy of ICI treatment in GBM patients. Use of the fatty acid metabolic process MT will result in higher immunogenicity rates, a significant increase in the proportion of activated immune cells, and improvement of the immune microenvironment.
Simvastatin Downregulates the SARS-CoV-2-Induced Inflammatory Response and Impairs Viral Infection Through Disruption of Lipid Rafts
Authors: Teixeira Lívia , Temerozo Jairo R. , Pereira-Dutra Filipe S. , Ferreira André Costa , Mattos Mayara , Gonçalves Barbara Simonson , Sacramento Carolina Q. , Palhinha Lohanna , Cunha-Fernandes Tamires , Dias Suelen S. G. , Soares Vinicius Cardoso , Barreto Ester A. , Cesar-Silva Daniella , Fintelman-Rodrigues Natalia , Pão Camila R. R. , de Freitas Caroline S. , Reis Patrícia A. , Hottz Eugenio D. , Bozza Fernando A. , Bou-Habib Dumith C. , Saraiva Elvira M. , de Almeida Cecília J. G. , Viola João P. B. , Souza Thiago Moreno L. , Bozza Patricia T.
Published: February 2022

Coronavirus disease 2019 (COVID-19) is currently a worldwide emergency caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In observational clinical studies, statins have been identified as beneficial to hospitalized patients with COVID-19. However, experimental evidence of underlying statins protection against SARS-CoV-2 remains elusive. Here we reported for the first-time experimental evidence of the protective effects of simvastatin treatment both in vitro and in vivo. We found that treatment with simvastatin significantly reduced the viral replication and lung damage in vivo, delaying SARS-CoV-2-associated physiopathology and mortality in the K18-hACE2-transgenic mice model. Moreover, simvastatin also downregulated the inflammation triggered by SARS-CoV-2 infection in pulmonary tissue and in human neutrophils, peripheral blood monocytes, and lung epithelial Calu-3 cells in vitro, showing its potential to modulate the inflammatory response both at the site of infection and systemically. Additionally, we also observed that simvastatin affected the course of SARS-CoV-2 infection through displacing ACE2 on cell membrane lipid rafts. In conclusion, our results show that simvastatin exhibits early protective effects on SARS-CoV-2 infection by inhibiting virus cell entry and inflammatory cytokine production, through mechanisms at least in part dependent on lipid rafts disruption.
Role of Hypoxia in the Interferon Response
Authors: Arnaiz Esther , Harris Adrian L.
Published: February 2022

In solid tumors, as the tumor grows and the disease progresses, hypoxic regions are often generated, but in contrast to most normal cells which cannot survive under these conditions, tumour cells adapt to hypoxia by HIF-driven mechanisms. Hypoxia can further promote cancer development by generating an immunosuppressive environment within the tumour mass, which allows tumour cells to escape the immune system recognition. This is achieved by recruiting immunosuppressive cells and by upregulating molecules which block immune cell activation. Hypoxia can also confer resistance to antitumor therapies by inducing the expression of membrane proteins that increase drug efflux or by inhibiting the apoptosis of treated cells. In addition, tumor cells require an active interferon (IFN) signalling pathway for the success of many anticancer therapies, such as radiotherapy or chemotherapy. Therefore, hypoxic effects on this pathway needs to be addressed for a successful treatment.
Nicotine in Inflammatory Diseases: Anti-Inflammatory and Pro-Inflammatory Effects
Authors: Zhang Wenji , Lin Hui , Zou Mingmin , Yuan Qinghua , Huang Zhenrui , Pan Xiaoying , Zhang Wenjuan
Published: February 2022

As an anti-inflammatory alkaloid, nicotine plays dual roles in treating diseases. Here we reviewed the anti-inflammatory and pro-inflammatory effects of nicotine on inflammatory diseases, including inflammatory bowel disease, arthritis, multiple sclerosis, sepsis, endotoxemia, myocarditis, oral/skin/muscle inflammation, etc., mainly concerning the administration methods, different models, therapeutic concentration and duration, and relevant organs and tissues. According to the data analysis from recent studies in the past 20 years, nicotine exerts much more anti-inflammatory effects than pro-inflammatory ones, especially in ulcerative colitis, arthritis, sepsis, and endotoxemia. On the other hand, in oral inflammation, nicotine promotes and aggravates some diseases such as periodontitis and gingivitis, especially when there are harmful microorganisms in the oral cavity. We also carefully analyzed the nicotine dosage to determine its safe and effective range. Furthermore, we summarized the molecular mechanism of nicotine in these inflammatory diseases through regulating immune cells, immune factors, and the vagus and acetylcholinergic anti-inflammatory pathways. By balancing the “beneficial” and “harmful” effects of nicotine, it is meaningful to explore the effective medical value of nicotine and open up new horizons for remedying acute and chronic inflammation in humans.
Endothelium-Released Microvesicles Transport miR-126 That Induces Proangiogenic Reprogramming in Monocytes
Authors: Arderiu Gemma , Peña Esther , Civit-Urgell Anna , Badimon Lina
Published: February 2022

We have recently shown that in ischemic tissue, the hypoxic endothelial cells (EC) release extracellular microvesicles (EMVs) that are rich in tissue factor (TF). These TF-EMVs induce monocyte (Mo) homing to the ischemic zone, their differentiation into EC-like cells, and the formation of new blood vessels increasing tissue perfusion. In addition to membrane proteins, EMVs contain noncoding RNAs that can modulate cellular signaling pathways in the recipient cells. Here, we have investigated whether miRNA contained into secreted EMVs may be transferred into Mo where they could modulate EC-like cell differentiation and angiogenic responses. Our results indicated that EMVs released from activated ECs contain high levels of miR-126 and that the levels are directly proportional to TF expression in EMVs. Interestingly, miR-126 is transferred to Mo when they are incubated with TF-EMVs. Increased levels of miR-126 in Mo do not promote EC-like cell differentiation but regulate angiogenesis by targeting several components of the VEGF pathway, as SPRED1 and PI3KR2. Our findings reveal that activated ECs secrete EMVs carrying miR-126, which can modulate Mo reprogramming of angiogenic genes.
Cooperation of RNA-Binding Proteins – a Focus on Roquin Function in T Cells
Authors: Behrens Gesine , Heissmeyer Vigo
Published: February 2022

Post-transcriptional gene regulation by RNA-binding proteins (RBPs) is important in the prevention of inflammatory and autoimmune diseases. With respect to T cell activation and differentiation, the RBPs Roquin-1/2 and Regnase-1 play pivotal roles by inducing degradation and/or translational silencing of target mRNAs. These targets encode important proinflammatory mediators and thus Roquin and Regnase-1 functions dampen cellular programs that can lead to inflammation and autoimmune disease. Recent findings demonstrate direct physical interaction of both RBPs. Here, we propose that cooperativity of trans-acting factors may be more generally used to reinforce the regulatory impact on selected targets and promote specific cell fate decisions. We develop this concept for Roquin and Regnase-1 function in resting and activated T cells and discuss the involvement in autoimmunity as well as how the therapeutic potential can be used in anti-tumor therapies.
Houttuynia Essential Oil and its Self-Microemulsion Preparation Protect Against LPS-Induced Murine Mastitis by Restoring the Blood–Milk Barrier and Inhibiting Inflammation
Authors: Liu Yuanyuan , Jiang Yu , Yang Yanfang , Wang Hongliang , Ye Jun , Liu Dongdong , Chen Yanmin , Lian Chunfang , Wang Renyun , Gao Yue , Meng Yingying , Gao Lili , Liu Yuling
Published: February 2022

Mastitis is a common inflammatory disease caused by bacterial infection to the mammary gland that impacts human and animal health and causes economic losses. Houttuynia essential oil (HEO), extracted from Houttuynia cordata Thunb, exhibits excellent antibacterial and anti-inflammatory properties. The aim of the study was to investigate the effects of HEO and a self-microemulsion preparation of HEO (SME-HEO) on inflammation and the blood–milk barrier (BMB) in lipopolysaccharide-induced murine mastitis. HEO and SME-HEO significantly downregulated pro-inflammatory factors TNF-α and IL-1β, upregulated anti-inflammatory factor IL-10, inhibited MPO expression, and alleviated histopathological injury in murine mammary gland tissues. Additionally, HEO and SME-HEO protected the integrity of the BMB by upregulating the expression of junction proteins ZO-1, claudin-1, claudin-3, and occludin. The anti-inflammatory effect of HEO against murine mastitis was mediated by blocking the MAPK signaling pathway and expression of iNOS. By inhibiting the release of inflammatory factors and protecting the integrity of the BMB, HEO may provide a novel treatment for mastitis.
Steroid-Refractory Gut Graft-Versus-Host Disease: What We Have Learned From Basic Immunology and Experimental Mouse Model
Authors: Song Qingxiao , Nasri Ubaydah , Zeng Defu
Published: February 2022

Intestinal graft-versus-host disease (Gut-GVHD) is one of the major causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). While systemic glucocorticoids (GCs) comprise the first-line treatment option, the response rate for GCs varies from 30% to 50%. The prognosis for patients with steroid-refractory acute Gut-GVHD (SR-Gut-aGVHD) remains dismal. The mechanisms underlying steroid resistance are unclear, and apart from ruxolitinib, there are no approved treatments for SR-Gut-aGVHD. In this review, we provide an overview of the current biological understanding of experimental SR-Gut-aGVHD pathogenesis, the advanced technology that can be applied to the human SR-Gut-aGVHD studies, and the potential novel therapeutic options for patients with SR-Gut-aGVHD.
BmNPV p35 Reduces the Accumulation of Virus-Derived siRNAs and Hinders the Function of siRNAs to Facilitate Viral Infection
Authors: Zhao Shudi , Chen Guanping , Kong Xiangshuo , Chen Nan , Wu Xiaofeng
Published: February 2022

Antiviral immunity involves various mechanisms and responses, including the RNA interference (RNAi) pathway. During long-term coevolution, viruses have gained the ability to evade this defense by encoding viral suppressors of RNAi (VSRs). It was reported that p35 of baculovirus can inhibit cellular small interference RNA (siRNA) pathway; however, the molecular mechanisms underlying p35 as a VSR remain largely unclear. Here, we showed that p35 of Bombyx mori nucleopolyhedrovirus (BmNPV) reduces the accumulation of virus-derived siRNAs (vsiRNAs) mapped to a particular region in the viral genome, leading to an increased expression of the essential genes in this region, and revealed that p35 disrupts the function of siRNAs by preventing them from loading into Argonaute-2 (Ago2). This repressive effect on the cellular siRNA pathway enhances the replication of BmNPV. Thus, our findings illustrate for the first time the inhibitory mechanism of a baculovirus VSR and how this effect influences viral infection.
HDAC3-Regulated PGE2 Production by Microglia Induces Phobic Anxiety Susceptibility After Stroke and Pointedly Exploiting a Signal-Targeted Gamma Visual Stimulation New Therapy
Authors: Zhu Hongrui , Guo Yi , Huang Ailing , Shen Huidan , Chen Yang , Song Jingyi , Guan Ao , Wu Liang , Wang Huiting , Deng Bin
Published: February 2022

Background

Phobic anxiety present after stroke (called poststroke anxiety, PSA) can hamper the rehabilitation of patients and disrupt their usual activities. Besides, the symptoms and mechanisms of PSA are different from those in nonstroke populations that have generalized anxiety disorder. What’s more, the treatment approaches for phobic anxiety are confined to unitary or general methods with poor efficiency.

Methods

Behavioural test screen combined bioinformatics analysis explored molecular changes between generalized anxiety disorder in nonstroke mice (restraint stress, RS) and photothrombotic stroke mice exposed to environmental stress (PTS + RS, mimicking PSA). Multiple molecular biological and neurobiological methods were employed to explain mechanisms in vitro and in vivo. And exploiting gamma flicker stimulation device for therapy.

Results

Microglial (MG) overactivation is a prominent characteristic of PTS + RS. HDAC3 was mainly upregulated in activated-microglia from damaged cortex and that local prostaglandin E2 (PGE2) production increased in MG via HDAC3-mediated activation of NF-κB signalling by p65 deacetylation. A high content of PGE2 in damaged ischaemic cortex could diffuse freely to amygdala, eliciting anxiety susceptibility of PSA via EP2. Importantly, gamma flicker stimulation relieved anxious behaviour of PTS + RS by modulating the HDAC3/Cox1/EP2 network at some extent.

Conclusions

HDAC3-regulated PGE2 production by microglia constitutes phobic anxiety susceptibility after stroke and a protective approach of gamma visual stimulation can be a candidate new therapy.
Proactive In-Water Ship Hull Grooming as a Method to Reduce the Environmental Footprint of Ships
Authors: Swain Geoffrey , Erdogan Caglar , Foy Lauren , Gardner Harrison , Harper Michael , Hearin John , Hunsucker Kelli Z. , Hunsucker J. Travis , Lieberman K. , Nanney Mark , Ralston Emily , Stephens Abraham , Tribou Melissa , Walker Bruce , Wassick Ann
Published: February 2022

The application of a proactive grooming program to manage the fouling control coatings applied to ship hulls provides an opportunity to address the climate crisis, invasive species and the discharge of biocides into the marine environment. A large percentage of the total power required to propel a ship is to overcome the viscous drag created between the hull and the water. The powering penalty due to increases in coating roughness and the development of biofouling are well documented. In addition, poorly maintained fouling control coatings may lead to the transportation of invasive species. In-water hull cleaning is therefore an important part of ship operations; however, this is typically implemented as a reactive measure when fouling reaches a critical level and requires powerful machinery which damages the coatings, creates unwanted discharge and in many locations the discharge will require capture and disposal. Ship hull grooming is being developed as a proactive method to manage fouling control coatings that will ensure that they are maintained in a smooth and fouling free condition, there is no transport of invasive species or excessive discharge of material that occurs during cleaning. This manuscript will summarize the findings of many years of research and development.
Discerning the Putative U and V Chromosomes of Saccharina japonica (Phaeophyta) by Cytogenetic Mapping of Sex-Linked Molecular Markers
Authors: Du Yu , Liu Peng-Fei , Li Zhi , Zheng Qian , Bi Yan-Hui , Zhou Zhi-Gang
Published: February 2022

Saccharina japonica, an importantly industrial species in brown seaweeds, has a typical alternate life history of heteromorphic generations and UV sex determination system. But up to now, the sex chromosomes, U and V, in this kelp remain to be evidenced cytologically. In the present study, the female-linked (SJ-f_000170 and MSj68-58-2) and male-linked (SJ-13_001840 and MSj68-16-2) molecular markers developed on the basis of Ectocarpus sex-determining regions (SDRs) were selected after PCR amplification and Southern blotting analysis. Mono-color fluorescence in situ hybridization (FISH) to the kelp metaphase chromosomes with each of these confirmed sex-linked markers as a probe indicated that the hybridization signals were confined to either female or male gametophytes exclusively. The shape and size of hybridized chromosomes and the relative location of these sex-linked markers on them suggested that the marked chromosomes in a sex were the same, which was further confirmed by dual-color FISH observations. SJ-f_000170 and SJ-13_001840, corresponding to each sex, were therefore used to map the sporophyte metaphase chromosomes by dual-color FISH technique, and they were hybridized on different chromosomes as expected. The sporophyte metaphase chromosomes as hybridized by SJ-f_000170 and SJ-13_001840 resembled those in either female or male gametophytes, suggesting that they were the putative U and V, respectively, chromosomes in S. japonica. To further demonstrate the reliability of this inference, genomic information of the screened bacterial artificial chromosome (BAC) clones carrying two female-linked markers, for example, from the constructed BAC libraries of the kelp female gametophytes was provided. The insert sequencing of two selected BAC clones revealed that repetitive elements were rich whereas gene density was poor, which was characterized as non-recombining SDR sequences in brown seaweed Ectocarpus sp. and liverwort Marchantia polymorpha. The present study laid a solid foundation for unveiling the mystery of S. japonica sex chromosomes.
Antidepressants Usage and Risk of Pneumonia Among Elderly Patients With the Parkinson's Disease: A Population-Based Case-Control Study
Authors: Kuo Wei-Yin , Huang Kuang-Hua , Kuan Yu-Hsiang , Chang Yu-Chia , Tsai Tung-Han , Lee Chien-Ying
Published: February 2022

The patients with Parkinson's disease (PD) are associated with a higher risk of pneumonia. Antidepressants exert an anticholinergic effect in varying degrees and various classes of antidepressants also can produce a different effect on immune function. The relationship between the risk of pneumonia and the use of antidepressants among elderly patients with PD is unknown. The study investigated the risk of pneumonia associated with the use of antidepressants in elderly patients with PD. This case-control study was based on data from the longitudinal health insurance database in Taiwan. We analyzed the data of 551,975 elderly patients with PD between 2002 and 2018. To reduce the potential confounding caused by unbalanced covariates in non-experimental settings, we used propensity score matching to include older patients without pneumonia to serve as the comparison. The antidepressants in the study included tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin, and norepinephrine reuptake inhibitors (SNRIs). The conditional logistic regression was used to investigate the association between antidepressants and pneumonia. Control variables in the study included sex, age, income level, urbanization, Charlson comorbidity index score, and comorbidities related to pneumonia. In terms of TCAs users, compared with patients not receiving TCAs, current users had a lower risk of incident pneumonia (adjusted odds ratio [aOR] = 0.86, 95%CI= 0.82–0.90) and recent users (aOR= 0.83, 95%CI= 0.80–0.87). In terms of MAOIs users, current users had a lower risk of incident pneumonia (aOR= 0.88, 95%CI= 0.83–0.93), recent users (aOR= 0.89, 95%CI= 0.85–0.93). In terms of SSRIs users, current users had a higher risk of incident pneumonia (aOR= 1.13, 95%CI= 1.01–1.17), recent users (aOR= 1.01, 95%CI= 1.06–1.13), and past users (aOR= 1.19, 95%CI= 1.17–1.21). In terms of SNRIs users, past users had a higher risk of incident pneumonia (aOR= 1.07, 95%CI= 1.03–1.10). The incident pneumonia is associated with the use of individuals of different classes of antidepressants. The use of TCAs (such as, amitriptyline and imipramine) had a lower odds of incident pneumonia. The use of MAOIs (such as, selegiline and rasagiline) had a lower odds of pneumonia during recent use. The use of SSRIs (such as, fluoxetine, sertraline, escitalopram, paroxetine, and citalopram) and SNRIs (such as, milnacipran, and venlafaxine) had a higher odds of incident pneumonia.
Prediction Model of Immunosuppressive Medication Non-adherence for Renal Transplant Patients Based on Machine Learning Technology
Authors: Zhu Xiao , Peng Bo , Yi QiFeng , Liu Jia , Yan Jin
Published: February 2022

Objectives

Predicting adherence to immunosuppressive medication (IM) is important to improve and design future prospective, personalized interventions in Chinese renal transplant patients (RTPs).

Methods

A retrospective, multicenter, cross-sectional study was performed in 1,191 RTPs from October 2020 to February 2021 in China. The BAASIS was used as the standard to determine the adherence of the patients. Variables of the combined theory, including the general data, the HBM, the TPB, the BMQ, the PSSS and the GSES, were used to build the models. The machine learning (ML) models included LR, RF, MLP, SVM, and XG Boost. The SHAP method was used to evaluate the contribution of predictors to predicting the risk of IM non-adherence in RTPs.

Results

The IM non-adherence rate in the derivation cohort was 38.5%. Ten predictors were screened to build the model based on the database. The SVM model performed better among the five models, with sensitivity of 0.59, specificity of 0.73, and average AUC of 0.75. The SHAP analysis showed that age, marital status, HBM-perceived barriers, use pill box after transplantation, and PSSS-family support were the most important predictors in the prediction model. All of the models had good performance validated by external data.

Conclusions

The IM non-adherence rate of RTPs was high, and it is important to improve IM adherence. The model developed by ML technology could identify high-risk patients and provide a basis for the development of relevant improvement measures.
Establishing a Public Resource for Acceptable Surrogate Endpoints to Support FDA Marketing Applications
Authors: Agyeman Abena S. , Siegel Jeffrey N. , Leptak Christopher
Published: February 2022

Following a comprehensive and coordinated effort between CBER and CDER, FDA established a table of acceptable surrogate endpoints (SEs) to support drug marketing applications. The publicly accessible SE Table was first published in 2018 as a response to the 21st Century Cures Act legislation and is updated every 6 months to reflect current FDA thinking. The criteria for the table headings and content were chosen to foster succinctness and consistency, while reflecting the degree of scientific understanding for each listed SE. Prior to the publication of the SE table there was the misconception that FDA only approved drugs based on a limited number of SEs. Contrary to this viewpoint, the SE table demonstrates that FDA frequently uses SEs as they are used in over 100 disease/use and patient population combinations. This article describes the considerations and approach taken when establishing the SE table as well as a discussion of the benefits and limitations of the SE table when used by various stakeholders.
RNA Virus Diversity in Birds and Small Mammals From Qinghai–Tibet Plateau of China
Authors: Zhu Wentao , Yang Jing , Lu Shan , Jin Dong , Pu Ji , Wu Shusheng , Luo Xue-Lian , Liu Liyun , Li Zhenjun , Xu Jianguo
Published: February 2022

Most emerging and re-emerging viruses causing infectious diseases in humans and domestic animals have originated from wildlife. However, current knowledge of the spectrum of RNA viruses in the Qinghai-Tibet Plateau in China is still limited. Here, we performed metatranscriptomic sequencing on fecal samples from 56 birds and 91 small mammals in Tibet and Qinghai Provinces, China, to delineate their viromes and focused on vertebrate RNA viruses. A total of 184 nearly complete genome RNA viruses belonging to 28 families were identified. Among these, 173 new viruses shared <90% amino acid identity with previously known viral sequences. Several of these viruses, such as those belonging to genera Orthonairovirus and Hepatovirus, could be zoonotic viruses. In addition, host taxonomy and geographical location of these viruses showed new hosts and distribution of several previously discovered viruses. Moreover, 12 invertebrate RNA viruses were identified with <40% amino acid identity to known viruses, indicating that they belong to potentially new taxa. The detection and characterization of RNA viruses from wildlife will broaden our knowledge of virus biodiversity and possible viral diseases in the Qinghai–Tibet Plateau.
Anti-influenza Virus Activity of Methylthio-Formycin Distinct From That of T-705
Authors: Takizawa Naoki , Takada Hisashi , Umekita Maya , Igarashi Masayuki , Takahashi Yoshiaki
Published: February 2022

Seasonal influenza virus epidemics result in severe illness, and occasionally influenza pandemics cause significant morbidity and mortality, although vaccines and anti-influenza virus drugs are available. By screening an in-house library, we identified methylthio-formycin (SMeFM), an adenosine analog, as a potent inhibitor of influenza virus propagation. SMeFM inhibited the propagation of influenza A and B viruses (IC50: 34.1 and 37.9 nM, respectively) and viruses showing reduced susceptibility to baloxavir and neuraminidase inhibitors but not T-705 (Favipiravir). However, the combination of T-705 and SMeFM inhibited the propagation of the influenza virus not in an antagonistic but in a slightly synergistic manner, suggesting that SMeFM has targets distinct from that of T-705. SMeFM induced A-to-C transversion mutations in virus genome RNA, and SMeFM triphosphate did not inhibit in vitro viral RNA synthesis. Our results show that SMeFM inhibits the propagation of the influenza virus by a mechanism different from that of T-705 and is a potential drug candidate to develop for anti-influenza drug.
Thermophilic Composting of Human Feces: Development of Bacterial Community Composition and Antimicrobial Resistance Gene Pool
Authors: Werner Katharina A. , Poehlein Anja , Schneider Dominik , El-Said Khaliel , Wöhrmann Michael , Linkert Isabel , Hübner Tobias , Brüggemann Nicolas , Prost Katharina , Daniel Rolf , Grohmann Elisabeth
Published: February 2022

In times of climate change, practicing sustainable, climate-resilient, and productive agriculture is of primordial importance. Compost from different resources, now treated as wastes, could be one form of sustainable fertilizer creating a resilience of agriculture to the adverse effects of climate change. However, the safety of the produced compost regarding human pathogens, pharmaceuticals, and related resistance genes must be considered. We have assessed the effect of thermophilic composting of dry toilet contents, green cuttings, and straw, with and without biochar, on fecal indicators, the bacterial community, and antibiotic resistance genes (ARGs). Mature compost samples were analyzed regarding fecal indicator organisms, revealing low levels of Escherichia coli that are in line with German regulations for fertilizers. However, one finding of Salmonella spp. exceeded the threshold value. Cultivation of bacteria from the mature compost resulted in 200 isolates with 36.5% of biosafety level 2 (BSL-2) species. The majority is known as opportunistic pathogens that likewise occur in different environments. A quarter of the isolated BSL-2 strains exhibited multiresistance to different classes of antibiotics. Molecular analysis of total DNA before and after composting revealed changes in bacterial community composition and ARGs. 16S rRNA gene amplicon sequencing showed a decline of the two most abundant phyla Proteobacteria (start: 36–48%, end: 27–30%) and Firmicutes (start: 13–33%, end: 12–16%), whereas the abundance of Chloroflexi, Gemmatimonadetes, and Planctomycetes rose. Groups containing many human pathogens decreased during composting, like Pseudomonadales, Bacilli with Bacillus spp., or Staphylococcaceae and Enterococcaceae. Gene-specific PCR showed a decline in the number of detectable ARGs from 15 before to 8 after composting. The results reveal the importance of sufficiently high temperatures lasting for a sufficiently long period during the thermophilic phase of composting for reducing Salmonella to levels matching the criteria for fertilizers. However, most severe human pathogens that were targeted by isolation conditions were not detected. Cultivation-independent analyses also indicated a decline in bacterial orders comprising many pathogenic bacteria, as well as a decrease in ARGs. In summary, thermophilic composting could be a promising approach for producing hygienically safe organic fertilizer from ecological sanitation.
Genome Context Influences Evolutionary Flexibility of Nearly Identical Type III Effectors in Two Phytopathogenic Pseudomonads
Authors: Baltrus David A. , Feng Qian , Kvitko Brian H.
Published: February 2022

Integrative Conjugative Elements (ICEs) are replicons that can insert and excise from chromosomal locations in a site-specific manner, can conjugate across strains, and which often carry a variety of genes useful for bacterial growth and survival under specific conditions. Although ICEs have been identified and vetted within certain clades of the agricultural pathogen Pseudomonas syringae, the impact of ICE carriage and transfer across the entire P. syringae species complex remains underexplored. Here we identify and vet an ICE (PmaICE-DQ) from P. syringae pv. maculicola ES4326, a strain commonly used for laboratory virulence experiments, demonstrate that this element can excise and conjugate across strains, and highlight that this element contains loci encoding multiple type III effector proteins. Moreover, genome context suggests that another ICE (PmaICE-AOAB) is highly similar in comparison with and found immediately adjacent to PmaICE-DQ within the chromosome of strain ES4326, and also contains multiple type III effectors. Lastly, we present passage data from in planta experiments that suggests that genomic plasticity associated with ICEs may enable strains to more rapidly lose type III effectors that trigger R-gene mediated resistance in comparison to strains where nearly isogenic effectors are not present in active ICEs. Taken together, our study sheds light on a set of ICE elements from P. syringae pv. maculicola ES4326 and suggests how genomic context may lead to different evolutionary dynamics for shared virulence genes between strains.
Substantive Morphological Descriptions, Phylogenetic Analysis and Single Nucleotide Polymorphisms of Aspergillus Species From Foeniculum vulgare
Authors: Mahata Pranab Kumar , Dass Regina Sharmila , Pan Archana , Muthusamy Babylakshmi
Published: February 2022

Ascomycetous fungi are found associated with a wide variety of substrates which range from fresh water to marine ecosystems, tropical to temperate forest soils and deserts, throughout the world over. These demystifying fungi exist as endophytes, pathogens and saprobes. They have been studied due to their ability to contaminate foods and feedstuffs, causing an elaboration of mycotoxins. The objectives of the study included extensive analyses of the morphological features of fungi, especially Aspergilli, which have been presented while studying them on specific mycological media. It is also an elaborate compilation of substantive macro- and micro-morphological characterization of different Aspergilli isolated from the spice Foeniculum vulgare used in India and other countries in the world. Further, a first of its kind attempt has been made to study their relative abundance and frequency of occurrence, molecular phylogeny and genetic relatedness to characterize the Aspergilli into specific sections, groups and clades. Single nucleotide polymorphism (SNP) analysis was carried out to evaluate the functional consequences of nucleotide variations, synonymous and non-synonymous mutations in the protein structure. The study resulted in a total of 3,506 Aspergillus isolates, which were obtained from seventy (70) fennel samples, representing 14 Aspergillus species. The two most frequently found species were A. niger and A. flavus with a relative abundance of 32.24 and 11.63%, respectively. The taxonomy and current placements have been reappraised with suggestions and prospects for future research from six sections namely Terrei, Flavi, Fumigati, Nidulantes, Nigri, and Versicolores. In addition, a total number of 27 isolates were studied and deposited at the National Centre for Biotechnology Information (NCBI) and five Aspergillus species have been identified and are being reported for the first time from the fennel seeds, based on partial sequence analysis of the official fungal barcode namely, Internal Transcribed Spacer (ITS) and a functional gene, beta tubulin gene locus, coupled with phenotypic characterization. SNPs for specific DNA regions have been used to identify variants in Aspergilli obtained from Indian fennel seeds for the first time. The need for a polyphasic approach of morphological identification and genetic characterization of Aspergilli from Foeniculum vulgare is addressed and presented here in adequate detail. Our current work makes extensive use of partial beta-tubulin gene sequences analyses to evaluate the association between SNPs in five Aspergillus species sections.
Colorful Treasure From Agro-Industrial Wastes: A Sustainable Chassis for Microbial Pigment Production
Authors: Grewal Jasneet , Woła̧cewicz Mikołaj , Pyter Weronika , Joshi Namrata , Drewniak Lukasz , Pranaw Kumar
Published: February 2022

Graphical Abstract

An illustration exhibiting perusal of natural pigment production as a safe alternative to synthetic ones.
Inhibition of Arenavirus Entry and Replication by the Cell-Intrinsic Restriction Factor ZMPSTE24 Is Enhanced by IFITM Antiviral Activity
Authors: Stott-Marshall Robert J. , Foster Toshana L.
Published: February 2022

In the absence of effective vaccines and treatments, annual outbreaks of severe human haemorrhagic fever caused by arenaviruses, such as Lassa virus, continue to pose a significant human health threat. Understanding the balance of cellular factors that inhibit or promote arenavirus infection may have important implications for the development of effective antiviral strategies. Here, we identified the cell-intrinsic zinc transmembrane metalloprotease, ZMPSTE24, as a restriction factor against arenaviruses. Notably, CRISPR-Cas9-mediated knockout of ZMPSTE24 in human alveolar epithelial A549 cells increased arenavirus glycoprotein-mediated viral entry in pseudoparticle assays and live virus infection models. As a barrier to viral entry and replication, ZMPSTE24 may act as a downstream effector of interferon-induced transmembrane protein (IFITM) antiviral function; though through a yet poorly understood mechanism. Overexpression of IFITM1, IFITM2, and IFITM3 proteins did not restrict the entry of pseudoparticles carrying arenavirus envelope glycoproteins and live virus infection. Furthermore, gain-of-function studies revealed that IFITMs augment the antiviral activity of ZMPSTE24 against arenaviruses, suggesting a cooperative effect of viral restriction. We show that ZMPSTE24 and IFITMs affect the kinetics of cellular endocytosis, suggesting that perturbation of membrane structure and stability is likely the mechanism of ZMPSTE24-mediated restriction and cooperative ZMPSTE24-IFITM antiviral activity. Collectively, our findings define the role of ZMPSTE24 host restriction activity in the early stages of arenavirus infection. Moreover, we provide insight into the importance of cellular membrane integrity for productive fusion of arenaviruses and highlight a novel avenue for therapeutic development.
Roles of AaVeA on Mycotoxin Production via Light in Alternaria alternata
Authors: Wang Liuqing , Wang Meng , Jiao Jian , Liu Hongmei
Published: February 2022

Alternaria alternata is a principal plant pathogen responsible for the biosynthesis of mycotoxins, including tenuazonic acid (TeA), alternariol (AOH), and alternariol monomethyl ether (AME). The velvet gene VeA is involved in fungal growth, development, and secondary metabolism, including mycotoxin biosynthesis via light regulation. In this study, the detailed regulatory roles of AaVeA in A. alternata with various light sources were investigated from the comparative analyses between the wild type and the gene knockout strains. In fungal growth and conidiation, mycelial extension was independent of light regulation in A. alternata. Red light favored conidiation, but blue light repressed it. The absence of AaVeA caused the marked reduction of hyphae extension and conidiophore formation even though red light could not induce more spores in ΔAaVeA mutant. The differentially expressed genes (DEGs) enriched in hyphal growth and conidiation were drastically transcribed from the comparatively transcriptomic profile between the wild type and ΔAaVeA mutant strains with or without light. In mycotoxin production, TeA biosynthesis seems no obvious effect by light regulation, but AOH and AME formation was significantly stimulated by blue light. Nevertheless, the disruption of AaVeA resulted in a marked decrease in mycotoxin production and the action of the stimulation was lost via blue light for the abundant accumulation of AOH and AME in the ΔAaVeA strain. From DEG expression and further verification by RT-qPCR, the loss of AaVeA caused the discontinuous supply of the substrates for mycotoxin biosynthesis and the drastic decline of biosynthetic gene expression. In addition, pathogenicity depends on AaVeA regulation in tomato infected by A. alternata in vivo. These findings provide a distinct understanding of the roles of AaVeA in fungal growth, development, mycotoxin biosynthesis, and pathogenicity in response to various light sources.
Intracellular pH Control by Membrane Transport in Mammalian Cells. Insights Into the Selective Advantages of Functional Redundancy
Authors: Doyen Denis , Poët Mallorie , Jarretou Gisèle , Pisani Didier F. , Tauc Michel , Cougnon Marc , Argentina Mederic , Bouret Yann , Counillon Laurent
Published: February 2022

Intracellular pH is a vital parameter that is maintained close to neutrality in all mammalian cells and tissues and acidic in most intracellular compartments. After presenting the main techniques used for intracellular an vesicular pH measurements we will briefly recall the main molecular mechanisms that affect and regulate intracellular pH. Following this we will discuss the large functional redundancy found in the transporters of H+ or acid-base equivalents. For this purpose, we will use mathematical modeling to simulate cellular response to persistent and/or transient acidification, in the presence of different transporters, single or in combination. We will also test the presence or absence of intracellular buffering. This latter section will highlight how modeling can yield fundamental insight into deep biological questions such as the utility of functional redundancy in natural selection.