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ABSTRACTHeartland virus (HRTV), an emerging tick-borne pathogenic bunyavirus, has been a concern since 2012, with an increasing incidence, expanding geographical distribution, and high pathogenicity in the United States. Infection from HRTV results in fever, thrombocytopenia, and leucopenia in humans, and in some cases, symptoms can progress to severe outcomes, including haemorrhagic disease, multi-organ failure, and even death. Currently, no vaccines or antiviral drugs are available for treatment of the HRTV disease. Moreover, little is known about HRTV-host interactions, viral replication mechanisms, pathogenesis and virulence, further hampering the development of vaccines and antiviral interventions. Here, we aimed to provide a brief review of HRTV epidemiology, molecular biology, pathogenesis and virulence on the basis of published article data to better understand this virus and provide clues for further study.

Abstract Crimean-Congo hemorrhagic fever virus (CCHFV) is a biosafety level-4 pathogen requiring urgent research and development efforts. The glycoproteins of CCHFV, Gn and Gc, are considered to play multiple roles in the viral life cycle by interactions with host cells; however, these interactions remain largely unclear to date. Here, we analyzed the cellular interactomes of CCHFV glycoproteins and identified 45 host proteins as high-confidence Gn/Gc interactors. These host molecules are involved in multiple cellular biological processes potentially associated with the physiological actions of the viral glycoproteins. Then, we elucidated the role of a representative cellular protein, HAX1. HAX1 interacts with Gn by its C-terminus, while its N-terminal region leads to mitochondrial localization. By the strong interaction, HAX1 sequestrates Gn to mitochondria, thus depriving Gn of its normal Golgi localization that is required for functional glycoprotein-mediated progeny virion packaging. Consistently, the inhibitory activity of HAX1 against viral packaging and hence propagation was further elucidated in the contexts of pseudotyped and authentic CCHFV infections in cellular and animal models. Together, the findings provide a systematic CCHFV Gn/Gc-cell protein-protein interaction map, but also unravel a HAX1/mitochondrion-associated host antiviral mechanism, which may facilitate further studies on CCHFV biology and therapeutic approaches.

Background. Intracerebral hemorrhage (ICH, IH) is a stroke syndrome characterized by high mortality and disability rates. However, the apoptotic mechanisms underlying ICH remain incompletely understood. We employed bioinformatics methods to identify key apoptotic genes associated with ICH, thereby offering potential therapeutic targets and contributing to a deeper understanding of the pathogenic mechanisms of apoptosis in ICH. Materials and Methods. We retrieved microarray data of ICH patients from the Gene Expression Omnibus database and intersected it with apoptotic genes, filtering out apoptosis-related differentially expressed genes (ARDEGs). Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted, and a logic regression-based diagnostic model for ICH was constructed. Key genes were identified through least absolute shrinkage and selection operator regression after model validation. Subsequently, mRNA-transcription factor (mRNA-TF), mRNA–microRNA (mRNA–miRNA), mRNA-RNA-binding protein (mRNA-RBP), and mRNA-drug regulatory networks were established, followed by immune infiltration analysis. Results. We identified 29 ARDEGs related to ICH, primarily participating in biological processes such as the extrinsic apoptotic signaling pathway and neuroinflammatory response. The ICH model confirmed PPP1R15A, IL1R1, and TYROBP as key genes with diagnostic and therapeutic value. Thirteen immune cell types showed a correlation with ICH; notably, activated dendritic cells and CD56dim natural killer cells exhibited significant correlations, and key genes were positively correlated with all 13 immune cell types. The regulatory networks (mRNA-TF, mRNA–miRNA, mRNA-RBP, and mRNA-drug) provided insights into the apoptotic gene regulation mechanisms and potential drugs in ICH. Conclusion. Through bioinformatics analysis, we identified PPP1R15A, IL1R1, and TYROBP as crucial genes in the occurrence and progression of ICH, with the potential involvement of Activated dendritic cells and CD56dim natural killer cells in these processes.

Abstract Background Next-generation sequencing (NGS) has revolutionized almost all fields of biology, agriculture and medicine, and is widely utilized to analyse genetic variation. Over the past decade, the NGS pipeline has been steadily improved, and the entire process is currently relatively straightforward. However, NGS instrumentation still requires upfront library preparation, which can be a laborious process, requiring significant hands-on time. Herein, we present a simple but robust approach to streamline library preparation by utilizing surface bound transposases to construct DNA libraries directly on a flowcell surface. Results The surface bound transposases directly fragment genomic DNA while simultaneously attaching the library molecules to the flowcell. We sequenced and analysed a Drosophila genome library generated by this surface tagmentation approach, and we showed that our surface bound library quality was comparable to the quality of the library from a commercial kit. In addition to the time and cost savings, our approach does not require PCR amplification of the library, which eliminates potential problems associated with PCR duplicates. Conclusions We described the first study to construct libraries directly on a flowcell. We believe our technique could be incorporated into the existing Illumina sequencing pipeline to simplify the workflow, reduce costs, and improve data quality.

Severe fever with thrombocytopenia syndrome (SFTS) is a life-threatening infectious disease caused by a novel phlebovirus, SFTS virus (SFTSV). Currently, there is no vaccine or antiviral available and the viral pathogenesis remains largely unknown. In this study, we demonstrated that SFTSV infection results in substantial production of serum interferon-γ (IFN-γ) in patients and then that IFN-γ in turn exhibits a robust anti-SFTSV activity in cultured cells, indicating the potential role of IFN-γ in anti-SFTSV immune responses. However, the IFN-γ anti-SFTSV efficacy was compromised once viral infection had been established. Consistently, we found that viral nonstructural protein (NSs) expression counteracts IFN-γ signaling. By protein interaction analyses combined with mass spectrometry, we identified the transcription factor of IFN-γ signaling pathway, STAT1, as the cellular target of SFTSV for IFN-γ antagonism. Mechanistically, SFTSV blocks IFN-γ-triggered STAT1 action through (1) NSs-STAT1 interaction-mediated sequestration of STAT1 into viral inclusion bodies and (2) viral infection-induced downregulation of STAT1 protein level. Finally, the efficacy of IFN-γ as an anti-SFTSV drug in vivo was evaluated in a mouse infection model: IFN-γ pretreatment but not posttreatment conferred significant protection to mice against lethal SFTSV infection, confirming IFN-γ's anti-SFTSV effect and viral antagonism against IFN-γ after the infection establishment. These findings present a picture of virus-host arm race and may promote not only the understanding of virus-host interactions and viral pathogenesis but also the development of antiviral therapeutics.

Background: During Enterovirus type 71 (EV71) infection, the structural viral protein 1 (VP1) activates endoplasmic reticulum (ER) stress associated with peripheral myelin protein 22 (PMP22) accumulation and induces autophagy. However, the specific mechanism behind this process remains elusive. Methods: In this research, we used the VP1-overexpressing mouse Schwann cells (SCs) models co-transfected with a PMP22 silencing or Autocrine motility factor receptor (AMFR/gp78) overexpressing vector to explore the regulation of gp78 on PMP22 and its relationship with autophagy and apoptosis. Results: The activity of gp78 could be influenced by EV71-VP1, leading to a decrease in the ubiquitination and degradation of PMP22, resulting in PMP22 accumulation in ER. In VP1-overexpressing mouse SCs, all three ER stress sensors, including pancreatic endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1) and the related downstream signals (C/EBP-homologous protein (CHOP) and Caspase 12) were activated, as well as the ER-resident chaperone Glucoseregulated protein 78 (GRP78). In addition, VP1 upregulated the autophagy marker Microtubule-associated protein 1 light chain 3 beta (LC3B), while PMP22 silencing or gp78 overexpression reversed the phenomenon. Meanwhile, PMP22 silencing or gp78 overexpression increased proliferation of EV71-VP1-transfected mouse SCs. Conclusion: Gp78 could regulate PMP22 accumulation through ubiquitination degradation and cause ER stress and autophagy in EV71-VP1-overexpressing mouse SCs. Therefore, the gp78/PMP22/ER stress axis might emerge as a promising therapeutic target for myelin and neuronal damage induced by EV71 infection. [ABSTRACT FROM AUTHOR]

Summary: To investigate the molecular mechanisms underlying islet dysfunction and insulin resistance in diet-induced diabetes, we conducted temporal RNA sequencing of tissues responsible for insulin secretion (islets) and action (liver) every 4 weeks in mice on high-fat (HFD) or chow diet for 24 weeks, linking to longitudinal profile of metabolic characteristics. The diverse responses of α, β, and δ cells to glucose and palmitate indicated HFD-induced dynamic deterioration of islet function from dysregulation to failure. Insulin resistance developed with variable time course in different tissues. Weighted gene co-expression network analysis and Ingenuity Pathway Analysis implicated islets and liver jointly programmed β-cell compensatory adaption via cell proliferation at early phase and irreversible islet dysfunction by inappropriate immune response at later stage, and identified interconnected molecules including growth differentiation factor 15. Frequencies of T cell subpopulation showed an early decrement in Tregs followed by increases in Th1 and Th17 cells during progression to diabetes.

Sensitivity analysis (SA) is an effective tool for studying crop models; it is an important link in model localization and plays an important role in crop model calibration and application. The objectives were to (i) determine influential and non-influential parameters with respect to above ground biomass (AGB), canopy cover (CC), and grain yield of winter wheat in the Beijing area based on the AquaCrop model under different water treatments (rainfall, normal irrigation, and over-irrigation); and (ii) generate an AquaCrop model that can be used in the Beijing area by setting non-influential parameters to fixed values and adjusting influential parameters according to the SA results. In this study, field experiments were conducted during the 2012–2013, 2013–2014, and 2014–2015 winter wheat growing seasons at the National Precision Agriculture Demonstration Research Base in Beijing, China. The extended Fourier amplitude sensitivity test (EFAST) method was used to perform SA of the AquaCrop model using 42 crop parameters, in order to verify the SA results, data from the 2013–2014 growing season were used to calibrate the AquaCrop model, and data from 2012–2013 and 2014–2015 growing seasons were validated. For AGB and yield of winter wheat, the total order sensitivity analysis had more sensitive parameters than the first order sensitivity analysis. For the AGB time-series, parameter sensitivity was changed under different water treatments; in comparison with the non-stressful conditions (normal irrigation and over-irrigation), there were more sensitive parameters under water stress (rainfall), while root development parameters were more sensitive. For CC with time-series and yield, there were more sensitive parameters under water stress than under no water stress. Two parameters sets were selected to calibrate the AquaCrop model, one group of parameters were under water stress, and the others were under no water stress, there were two more sensitive parameters (growing degree-days (GDD) from sowing to the maximum rooting depth (root) and the maximum effective rooting depth (rtx)) under water stress than under no water stress. The results showed that there was higher accuracy under water stress than under no water stress. This study provides guidelines for AquaCrop model calibration and application in Beijing, China, as well providing guidance to simplify the AquaCrop model and improve its precision, especially when many parameters are used.

Bladder cancer is becoming one of the most common malignancies across the world. Although treatment strategy has been continuously improved, which has led to cisplatin-based chemotherapy becoming the standard medication, cancer recurrence and metastasis still occur in a high proportion of patients because of drug resistance. The high efficacy of regorafenib, a broad-spectrum kinase inhibitor, has been evidenced in treating a variety of advanced cancers. Hence, this study investigated whether regorafenib could also effectively antagonize the survival of cisplatin-resistant bladder cancer and elucidate the underlying mechanism. Two types of cisplatin-resistant bladder cancer cells, T24R1 and T24R2, were isolated from T24 cisplatin-sensitive bladder cancer cells. These cells were characterized, and T24R1- and T24R2-xenografted tumor mice were created to examine the therapeutic efficacy of regorafenib. T24R1 and T24R2 cells exhibited higher expression levels of epithelial–mesenchymal transition (EMT) and stemness markers compared to the T24 cells, and regorafenib could simultaneously inhibit the viability and the expression of EMT/stemness markers of both T24R1 and T24R2 cells. Moreover, regorafenib could efficiently arrest the cell cycle, promote apoptosis, and block the transmigration/migration capabilities of both types of cells. Finally, regorafenib could significantly antagonize the growth of T24R1- and T24R2-xenografted tumors in mice. These results demonstrated the therapeutic efficacy of regorafenib in cisplatin-resistant bladder cancers. This study, thus, provides more insights into the mechanism of action of regorafenib and demonstrates its great potential in the future treatment of cisplatin-resistant advanced bladder cancer patients. [ABSTRACT FROM AUTHOR]

Objective: Recently, several cohort studies suggested a positive relationship between serum uric acid (SUA) and type 2 diabetes mellitus (T2DM), which is inconsistent with the results of functional research. Our aim was to further evaluate this correlation by conducting a systematic review. Methods: Computerized literature searches of the Medline database, EMBASE database, and PubMed were used to evaluate the relationship between SUA and T2DM in cohort studies. Cochran's Q and I2 statistics were used to evaluate heterogeneity among studies, and pooled relative risk (RR) and odds ratio (OR) with 95% confidence intervals (CIs) were calculated using random-effects and fixed-effects models. The summary RR and OR of per 1Â mg/ml-SUA increase were calculated separately because of their different epidemiological implications and calculation methods. Additionally, sensitivity analysis, stratified analysis, meta-regression, and multiple meta-regression were applied to investigate the heterogeneity among studies. Results: A total of 970 articles were retrieved from the searches. Sixteen publications of cohort studies containing 61,714 participants were included. The pooled RR was 1.131 (95% CI: 1.084â1.179) with significant heterogeneity among studies (I2Â =Â 51.9%, PÂ =Â 0.018). Adjusted RR to evaluate the stability of the relationship between SUA and T2DM in the sensitivity analysis was similar (RRÂ =Â 1.140, 95% CI:Â 1.087â1.197), with statistically significant heterogeneity (I2Â =Â 54.5%, PÂ =Â 0.015). Stratified analysis and meta-regression showed that the positive relationship remained irrespective of age, sex, region, and adjustment for confounding factors including body mass index, fasting blood glucose, systolic blood pressure, diastolic blood pressure, alcohol consumption, smoking, blood cholesterol, waist circumference, fatty liver, and drugs affecting SUA. Conclusion: Although SUA is independently associated with development of T2DM, insulin resistance increased as the baseline SUA concentration increased; thus, the correlation between SUA and T2DM requires further evaluation and the baseline insulin resistance status should also be considered. Keywords: Uric acid, Diabetes, Meta-analysis

This is a retrospective cohort study by analyzing a multi‐institutional electronic medical records database in Taiwan to compare long‐term effectiveness and risk of major adverse cardiac events (MACE) in chemotherapy‐naïve metastatic castration‐resistant prostate cancer (mCRPC) patients treated with enzalutamide (ENZ) or abiraterone (AA). Patients aged 20 years and older and newly receiving androgen receptor targeted therapies ENZ or AA from September 2016 to December 2019 were included. We followed patients from initiation of therapies to the occurrence of outcomes (prostate‐specific antigen (PSA) response rate, PSA progression free survival (PFS), overall survival (OS), and MACE), death, the last clinical visit, or December 31, 2020. We performed multivariable Cox proportional hazard models to compare ENZ and AA groups for the measured outcomes. A total of 363 patients treated with either ENZ (n = 157) or AA (n = 206) were identified. The analysis found a significantly higher proportion of patients with a PSA response rate higher than 50% among those receiving ENZ than among those receiving AA (ENZ vs AA: 75.80% vs 63.59%, P =.01). However, there was no significant difference in PSA PFS (adjusted hazard ratio: 0.86; 95% CI 0.63‐1.17) and OS (0.68: 0.41‐1.14) between the use of ENZ and AA in chemotherapy‐naïve mCRPC patients. Regarding the cardiovascular (CV) safety outcome, there was a significantly lower risk of MACE in patients receiving ENZ, compared to patients receiving AA (0.20: 0.07‐0.55). The findings suggest that enzalutamide may be more efficacious for PSA response and suitable for chemotherapy‐naïve mCRPC patients with high CV risk profile. [ABSTRACT FROM AUTHOR]