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Abstract Background SARS-CoV-2 infections usually cause immune dysregulation in the human body. Studies of immunological changes resulting from coinfections with Mycobacterium tuberculosis (Mtb) or HIV are limited. Methods We conducted a retrospective study focusing on patients with COVID-19. A total of 550 patients infected with SARS-CoV-2 were enrolled in our study and categorized into four groups based on the presence of coinfections; 166 Delta-infected patients, among whom 103 patients had no coinfections, 52 who were coinfected with Mtb, 11 who were coinfected with HIV, and 384 Omicron-infected patients. By collecting data on epidemiologic information, laboratory findings, treatments, and clinical outcomes, we analyzed and compared clinical and immunological characteristics. Results Compared with those in the Delta group, the median white blood cell, CD4 + T-cell and B-cell counts were lower in the Mtb group and the HIV group. Except for those in the Omicron group, more than half of the patients in the three groups had abnormal chest CT findings. Among the three groups, there were no significant differences in any of the cytokines. Compared with those in the Delta group, the disease duration and LOS were longer in the Mtb group and the HIV group. For unvaccinated Delta-infected patients, in the Mtb and HIV groups, the number of B cells and CD4 + T cells was lower than that in the Delta group, with no significant difference in the LOS or disease duration. In the Mtb group, three (6%) patients presented with a disease duration greater than four months and had decreased lymphocyte and IL17A counts, possibly due to double infections in the lungs caused by SARS-CoV-2 and M. tuberculosis. Conclusions We found that SARS-CoV-2 patients coinfected with Mtb or HIV exhibited a longer disease duration and longer LOS, with a decrease in B cells and CD4 + T cells, suggesting that these cells are related to immune function. Changes in cytokine levels suggest that coinfection with Mtb or HIV does not result in dysregulation of the immune response. Importantly, we discovered a chronic course of coinfection involving more than four months of Mtb and SARS-CoV-2 infection.

Abstract The modification and recognition of 5‐methylcytosine (m5C) are involved in the initiation and progression of various tumor types. However, the precise role and potential mechanism of Y‐box‐binding protein 1 (YBX1) in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, it is found that YBX1 is frequently upregulated in ESCC compared with matched nontumor tissues. Gain‐ and loss‐of‐function assays show that YBX1 promoted the proliferation and metastasis of ESCC cells both in vitro and in vivo. Functional studies revealed that NOP2/Sun RNA methyltransferase family member 2 (NSUN2) is a critical RNA methyltransferase that facilitates YBX1‐mediated ESCC progression. Mechanistically, integrated analysis based on RNA immunoprecipitation sequencing (RIP‐seq) and m5C methylated RNA immunoprecipitation and sequencing (MeRIP‐seq) assays identified spermine oxidase (SMOX) as a target gene containing an m5C site in its coding sequence (CDS) region, which coincided well with the binding site of YBX1. Overexpression of SMOX‐WT but not SMOX‐Mut partially restored the proliferation and invasion ability of ESCC cells curbed by YBX1 knockdown. Moreover, YBX1 activated the mTORC1 signaling pathway by stabilizing SMOX mRNA. The study reveals that YBX1 promotes ESCC development by stabilizing SMOX mRNA in an m5C‐dependent manner, thus providing a valuable therapeutic target for ESCC.

Oropharyngeal microbiomes play a significant role in the susceptibility and severity of COVID-19, yet the role of these microbiomes play for the development of COVID-19 Omicron variant have not been reported. A total of 791 pharyngeal swab samples were prospectively included in this study, including 297 confirmed cases of Omicron variant (CCO), 222 confirmed case of Omicron who recovered (CCOR), 73 confirmed cases of original strain (CCOS) and 199 healthy controls (HC). All samples completed MiSeq sequencing. The results showed that compared with HC, conditional pathogens increased in CCO, while acid-producing bacteria decreased. Based on six optimal oropharyngeal operational taxonomy units (OTUs), we constructed a marker microbial classifier to distinguish between patients with Omicron variant and healthy people, and achieved high diagnostic efficiency in both the discovery queue and the verification queue. At same time, we introduced a group of cross-age infection verification cohort and Omicron variant subtype XBB.1.5 branch, which can be accurately distinguished by this diagnostic model. We also analyzed the characteristics of oropharyngeal microbiomes in two subgroups of Omicron disease group-severity of infection and vaccination times, and found that the change of oropharyngeal microbiomes may affect the severity of the disease and the efficacy of the vaccine. In addition, we found that some genera with significant differences gradually increased or decreased with the recovery of Omicron variant infection. The results of Spearman analysis showed that 27 oropharyngeal OTUs were closely related to 6 clinical indexes in CCO and HC. Finally, we found that the Omicron variant had different characterization of oropharyngeal microbiomes from the original strain. Our research characterizes oropharyngeal microbiomes of Omicron variant cases and rehabilitation cases, successfully constructed and verified the non-invasive diagnostic model of Omicron variant, described the correlation between microbial OTUs and clinical indexes. It was found that the infection of Omicron variant and the infection of original strain have different characteristics of oropharyngeal microbiomes.

Abstract NSUN2 is a nuclear RNA methyltransferase which catalyzes 5-methylcytosine (m5C), a posttranscriptional RNA modification. Aberrant m5C modification has been implicated in the development of multiple malignancies. However, its function in pancreatic cancer (PC) needs to be elucidated. Herein, we determined that NSUN2 was overexpressed in PC tissues and related to aggressive clinical features. Silence of NSUN2 by lentivirus weakened the capability of proliferation, migration and invasion of PC cells in vitro and inhibited the growth and metastasis of xenograft tumors in vivo. Contrarily, overexpression of NSUN2 stimulated PC growth and metastasis. Mechanistically, m5C-sequencing (m5C-seq) and RNA-sequencing (RNA-seq) were carried out to identify downstream targets of NSUN2 and results showed that loss of NSUN2 led to decreased m5C modification level concomitant with reduced TIAM2 mRNA expression. Further validation experiments proved that NSUN2 silence accelerated the decay of TIAM2 mRNA in a YBX1-dependent manner. Additionally, NSUN2 exerted its oncogenic function partially through enhancing TIAM2 transcription. More importantly, disruption of the NSUN2/TIAM2 axis repressed the malignant phenotype of PC cells through blocking epithelial-mesenchymal transition (EMT). Collectively, our study highlighted the critical function of NSUN2 in PC and provided novel mechanistic insights into NSUN2/TIAM2 axis as promising therapeutic targets against PC.

Diabetic nephropathy (DN) represents a significant microvascular complication in diabetes, entailing intricate molecular pathways and mechanisms associated with cardiorenal vascular diseases. Prolonged hyperglycemia induces renal endothelial dysfunction and damage via metabolic abnormalities, inflammation, and oxidative stress, thereby compromising hemodynamics. Concurrently, fibrotic and sclerotic alterations exacerbate glomerular and tubular injuries. At a macro level, reciprocal communication between the renal microvasculature and systemic circulation establishes a pernicious cycle propelling disease progression. The current management approach emphasizes rigorous control of glycemic levels and blood pressure, with renin-angiotensin system blockade conferring renoprotection. Novel antidiabetic agents exhibit renoprotective effects, potentially mediated through endothelial modulation. Nonetheless, emerging therapies present novel avenues for enhancing patient outcomes and alleviating the disease burden. A precision-based approach, coupled with a comprehensive strategy addressing global vascular risk, will be pivotal in mitigating the cardiorenal burden associated with diabetes.

ABSTRACTThe length of stay (LOS) in hospital varied considerably in different patients with COVID-19 caused by SARS-CoV-2 Omicron variant. The study aimed to explore the clinical characteristics of Omicron patients, identify prognostic factors, and develop a prognostic model to predict the LOS of Omicron patients. This was a single center retrospective study in a secondary medical institution in China. A total of 384 Omicron patients in China were enrolled. According to the analyzed data, we employed LASSO to select the primitive predictors. The predictive model was constructed by fitting a linear regression model using the predictors selected by LASSO. Bootstrap validation was used to test performance and eventually we obtained the actual model. Among these patients, 222 (57.8%) were female, the median age of patients was 18 years and 349 (90.9%) completed two doses of vaccination. Patients on admission diagnosed as mild were 363 (94.5%). Five variables were selected by LASSO and a linear model, and those with P < 0.05 were integrated into the analysis. It shows that if Omicron patients receive immunotherapy or heparin, the LOS increases by 36% or 16.1%. If Omicron patients developed rhinorrhea or occur familial cluster, the LOS increased by 10.4% or 12.3%, respectively. Moreover, if Omicron patients’ APTT increased by one unit, the LOS increased by 0.38%. Five variables were identified, including immunotherapy, heparin, familial cluster, rhinorrhea, and APTT. A simple model was developed and evaluated to predict the LOS of Omicron patients. The formula is as follows: Predictive LOS = exp(1*2.66263 + 0.30778*Immunotherapy + 0.1158*Familiar cluster + 0.1496*Heparin + 0.0989*Rhinorrhea + 0.0036*APTT).

Type 2 diabetes (T2D) is the leading cause of diabetes worldwide and is increasing rapidly, especially in youth. It accounts for most diabetes deaths in adults ≥20 years old in the Americas, with type 2 diabetes responsible for most of the disease burden. The incidence and burden of type 2 diabetes in adolescents and young adults have risen in recent decades globally. Countries with lower socioeconomic status had the highest incidence and burden, and females generally had higher mortality and disease burden than males at ages

Lipids are main energy source for insects reproduction, which are becoming emerging target for pest management. Azadirachtin (AZA) is a multi-targeted and promising botanical insecticide, but its reproduction toxicity mechanism related to lipids metabolism is poorly understood. Here, we applied lipidomic and transcriptomic to provide a comprehensive resource for describing the effect of AZA on lipids remodeling in ovary of Spodoptera litura. The results showed that AZA exposure obviously altered the contents of 130 lipids subclasses (76 upregulated and 54 downregulated). In detail, AZA exposure changed the length and saturation degrees of fatty acyl chain of most glycerolipid, phospholipid and sphingolipid as well as the expression of genes related to biosynthesis of unsaturated fatty acids and fatty acids elongation. Besides, following the abnormal lipids metabolism, western blot analysis suggested that AZA induce insulin resistance-like phenotypes by inhibiting insulin receptor substrates (IRS) /PI3K/AKT pathway, which might be responsible for the ovary abnormalities of S. litura. Collectively, our study provided insights into the lipids metabolism event in S. litura underlying AZA exposure, these key metabolites and genes identified in this study would also provide important reference for pest control in future.

Summary: Lysosome motility is critical for the cellular function. However, Rab7-related transport elements showed genetic differences between vertebrates and invertebrates, making the mechanism of lysosomal motility mysterious. We suggested that Rab7 interacted with RILP as a feature of highly evolved organisms since they could interact with each other in Spodoptera frugiperda but not in Drosophila melanogaster. The N-terminus of Sf-RILP was identified to be necessary for their interaction, and Glu61 was supposed to be the key point for the stability of the interaction. A GC-rich domain on the C-terminal parts of Sf-RILP hampered the expression of Sf-RILP and its interaction with Sf-Rab7. Although the corresponding vital amino acids in the mammalian model at the C-terminus of Sf-RILP turned to be neutral, the C-terminus would also help with the homologous interactions between RILP fragments in insects. The significantly different interactions in invertebrates shed light on the biodiversity and complexity of lysosomal motility.

Background: Ubiquitin-proteasome system (UPS) is implicated in cancer occurrence and progression. Targeting UPS is emerging as a promising therapeutic target for cancer treatment. Nevertheless, the clinical significance of UPS in hepatocellular carcinoma (HCC) has not been entirely elucidated.Methods: Differentially expressed UPS genes (DEUPS) were screened from LIHC-TCGA datasets. The least absolute shrinkage and selection operator (LASSO) and stepwise multivariate regression analysis were conducted to establish a UPS-based prognostic risk model. The robustness of the risk model was further validated in HCCDB18, GSE14520, and GSE76427 cohorts. Subsequently, immune features, clinicopathologic characteristics, enrichment pathways, and anti-tumor drug sensitivity of the model were further evaluated. Moreover, a nomogram was established to improve the predictive ability of the risk model.Results: Seven UPS-based signatures (ATG10, FBXL7, IPP, MEX3A, SOCS2, TRIM54, and PSMD9) were developed for the prognostic risk model. Individuals with HCC with high-risk scores presented a more dismal prognosis than those with low-risk scores. Moreover, larger tumor size, advanced TNM stage, and tumor grade were observed in the high-risk group. Additionally, cell cycle, ubiquitin-mediated proteolysis, and DNA repair pathways were intimately linked to the risk score. In addition, obvious immune cell infiltration and sensitive drug response were identified in low-risk patients. Furthermore, both nomogram and risk score showed a significant prognosis-predictive ability.Conclusion: Overall, we established a novel UPS-based prognostic risk model in HCC. Our results will facilitate a deep understanding of the functional role of UPS-based signature in HCC and provide a reliable prediction of clinical outcomes and anti-tumor drug responses for patients with HCC.

Background: Recent studies highlighted the functional role of protein arginine methyltransferases (PRMTs) catalyzing the methylation of protein arginine in malignant progression of various tumors. Stratification the subtypes of hepatocellular carcinoma (HCC) is fundamental for exploring effective treatment strategies. Here, we aim to conduct a comprehensive analysis of PRMTs with bioinformatic tools to identify novel biomarkers for HCC subtypes classification and prognosis prediction, which may be potential ideal targets for therapeutic intervention.Methods: The expression profiling of PRMTs in HCC tissues was evaluated based on the data of TCGA-LIHC cohort, and further validated in HCC TMA cohort and HCC cell lines. HCC was systematically classified based on PRMT family related genes. Subsequently, the differentially expressed genes (DEGs) between molecular subtypes were identified, and prognostic risk model were constructed using least absolute shrinkage and selection operator (LASSO) and Cox regression analysis to evaluate the prognosis, gene mutation, clinical features, immunophenotype, immunotherapeutic effect and antineoplastic drug sensitivity of HCC.Results: PRMTs expression was markedly altered both in HCC tissues and HCC cell lines. Three molecular subtypes with distinct immunophenotype were generated. 11 PRMT-related genes were enrolled to establish prognostic model, which presented with high accuracy in predicting the prognosis of two risk groups in the training, validation, and immunotherapy cohort, respectively. Additionally, the two risk groups showed significant difference in immunotherapeutic efficacy. Further, the sensitivity of 72 anticancer drugs was identified using prognostic risk model.Conclusion: In summary, our findings stratified HCC into three subtypes based on the PRMT-related genes. The prognostic model established in this work provide novel insights into the exploration of related therapeutic approaches in treating HCC.

As we all known, estimating the proportion of passenger route choice is of great significance in almost every aspect of urban rail transit control system, including passenger allocation, fare clearing and flow control strategies. Existing researches only pay attention to the route choice through travel time, but usually ignore the influence in different periods of the day. Therefore, this paper proposes a novel estimation method for the proportion of passenger route choice in different periods. Firstly, by introducing the normalized value of passenger flow and the standard coefficient of peak passenger flow, the train operation time is divided into peak and flat periods. Secondly, the travel time distribution of each route can be obtained by estimating the expected value and standard deviation of passenger travel time in each different period. The Naïve Bayes algorithm is further employed to realize the identification of the proportion of passenger route choices. Finally, this proposed algorithm is applied to Hangzhou Metro. The result shows that by using the segmented estimation, the error can be reduced by more than 60% compared with the whole-day experiment, which indicates the superiority of the method.

BackgroundThe continued ‘evolution’ of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the emergence of the Omicron variant after the Delta variant, resulting in a significant increase in the number of people with COVID-19. This increase in the number of cases continues to have a significant impact on lives. Therefore, a more detailed understanding of the clinical characteristics of Omicron infection is essential.MethodsUsing medical charts, we extracted clinical information for 384 patients infected with the Omicron variant in Anyang City, Henan Province, China. Epidemiology and clinical characteristics were compared with a cohort of people infected with the Delta variant in Zhengzhou in 2021.FindingsCommon initial symptoms at onset of illness were cough [240 (63%)], expectoration [112 (29%)], fever [96 (25%)], nasal congestion [96 (25%)] and myalgia or fatigue [30 (6%)]. In patients with the Omicron variant, levels of total cholesterol, low-density lipoprotein and creatinine increased in 52 (14%), 36 (9%) and 58 (15%) patients, respectively, compared with patients with the Delta variant [one (1%), one (1%) and two (2%)]. Levels of triglyceride and high-density lipoprotein also increased. In patients with the Omicron variant, the levels of specific gravity and the erythrocyte sedimentation rate were increased in 115 (30%) and 81 (21%) patients, and serum levels of complement 3 decreased in 93 (41%).ResultsCompared with patients infected with Delta, no major differences in initial clinical symptoms were identified in patients infected with Omicron. However, dyslipidemia and kidney injury were much more severe in patients with the Omicron variant, and the erythrocyte sedimentation rate was increased. Due to decreased levels of complement 3, the immunity of patients with the Omicron variant was weak.

Ribosomal proteins (Rps) are indispensable in ribosome biogenesis and protein synthesis, which tightly correlate with cell growth and proliferation in different physiological processes across species. Up to now, genes coding for Rps have been identified and studied in many species, however, their information still remains elusive in many insect species, especially in Spodoptera litura. In this study, 81 Rp genes were identified from S. litura genome and were mapped to their positions on the chromosomes. In addition, their physical and chemical properties, gene structure, phylogenetic relationships, targeted microRNAs were also analyzed. Gene ontology analysis disclosed that Rp genes were closely associated with processes related to ribosome biosynthesis, proteins translation processing, molecular binding activities. The quantitative real-time PCR (qRT-PCR) revealed expression profiles of Rp genes varied in different stages of oogenesis, and found that most Rp genes accumulated in previtellogenesis stage. This study described the comprehensive genome-wide analysis of Rp gene family in agricultural pests, which provided foundation for further characterizing the roles of Rps in oogenesis of insects, and some Rp genes may further serve as targets for innovative pest control.

Azadirachtin is one of the most successful botanical pesticides in agricultural pest control. To build a repertoire of proteins and pathways in response to azadirachtin exposure during ovarian development, iTRAQ-based comparative proteomic was conducted. 1423 and 1686 proteins were identified as differentially accumulated proteins (DAPs) by comparing the protein abundance in adult ovary with that in pupal ovary under normal and azadirachtin exposure condition, respectively. Bioinformatics analysis indicated that pupae-to-adult transition requires proteins related to proteasome and branched chain amino acids (BCAAs) degradation for ovary development. Azadirachtin exposure strongly affected glycosylation-related pathway. And proteins related to vitamin B6 synthesis were necessary for ovary development under normal and AZA-exposure condition. RNAi assays confirmed the essential roles of DAPs related to glycosylation and vitamin B6 synthesis in moth growth and ovary development. The results enhance our understanding of the molecular regulatory network for ovary development and provide valuable resources for using AZA-responsive proteins to develop novel bio-rational insecticides.

Vulnerability analysis is the premise of operational risk management and control for the large-scale and complex urban rail transit network (URTN) under the operation interruption of important stations. The temporary operation interruption of one station in an emergency may lead to the cascading failure and the paralysis of the whole URTN due to the load of other stations exceeding the limited capacity. The priority of important stations is proposed by combining its location and function in URTN. In addition, focusing on the analysis of the travel behaviour of passengers and the synergy of public transport networks, a novel cascading failure evolution model is established to simulate the cascading failure process of URTN under different attack scenarios. The vulnerability indicators are constructed to dynamically evaluate the vulnerability of URTN considering cascading failure evolution, which are different from the traditional vulnerability indicators based on complex network theory. Taking the Beijing urban rail transit network as an example, the dynamic simulation results show that the cascading failure of URTN is closely related to the temporal-spatial distribution of passenger flows and malicious attacks are more destructive than random attacks. Compared with the important stations with the largest betweenness or degree, the interrupted stations with largest intensity have a greater impact on the operational stability of URTN. Moreover, increasing the capacity coefficient of the station can reduce the vulnerability of URTN.

Chemical pesticides and adjuvants have caused many negative effects. Botanical compounds provide solutions for the development of environment friendly pesticides and the management of increasing pest resistance. Curcumin, a natural polyphenol, showed synergistic effects on avermectin upon the destructive agricultural pest, Spodoptera litura. However, the botanical synergist and its relevant mechanisms remain unclear. In the article, curcumin significantly enhanced the growth inhibition and midgut structural damage of avermectin on the larvae of S. litura, and the synergistic effects were confirmed with pot experiments. There were only a few influences on the gene expression of avermectin targets, while apoptotic and autophagic related genes and proteins were accumulated in the avermectin/curcumin mixed regent (0.013/0.0013 μg/mL) treated group. Moreover, the potential mechanism was explored with an in vitro model, insect Spodoptera frugiperda Sf9 cell line. Morphology observation featured the damage on cells and Hoechst33258 staining revealed the fragments of DNA after treating with the avermectin/curcumin mixed regent (10/1 μg/mL). Dansylcadaverine and LysoTracker staining, as well as the gene expressions, supposed that curcumin exhibited autophagy inducing effects and the mixed regent possessed a higher ability to induce apoptosis and autophagy. All these results suggested that the synergistic effects of curcumin on the pest management of avermectin potentially mainly derived from the enhancement of programed cell death. It provides new sights for the application of natural compounds in integrated pest management and enriches examples of synergistic mechanisms.

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