Tumor microenvironment reprogramming combined with immunogenic enhancement by nanoemulsions potentiates immunotherapy.

The combination of immune checkpoint inhibitors and immunogenic cell death (ICD) inducers has become a promising strategy for the treatment of various cancers. However, its efficacy remains unmet because of the dense stroma and defective vasculatures in the tumor microenvironment (TME) that restricts the intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Herein, cancer-associated fibroblasts (CAFs)-targeted nanoemulsions are tailored to combine the ICD induction and the TME reprogramming to sensitize checkpoint blockade immunotherapy. Melittin, as an ICD inducer and an antifibrotic agent, is efficiently encapsulated into the nanoemulsion accompanied by a nitric oxide donor to improve its bioavailability and tumor targeting. The nanoemulsions exhibited dual functionality by directly inducing direct cancer cell death and enhancing the tumoral immunogenicity, while also synergistically reprogramming the TME through reversing the activated CAFs, decreasing collagen deposition and restoring tumor vessels. Consequently, these nanemulsions successfully facilitated the CTLs infiltration and suppressing the recruitment of immunosuppressive cells. A combination of AE-MGNPs and anti-CTLA-4 antibody greatly elicited a striking level of antitumor T-cell response to suppress tumor growth in CAFs-rich colorectal tumor models. Our work emphasized the integration of the ICD induction with simultaneous modulation of the TME to enhance the sensitivity of patients to checkpoint blockade immunotherapy.

Associations of a proinflammatory diet, habitual salt intake, and the onset of type 2 diabetes: A prospective cohort study from the UK Biobank.

AIM: To explore the relationship between proinflammatory diet, habitual salt intake and the onset of type 2 diabetes. METHODS: This prospective study was conducted among 171 094 UK Biobank participants who completed at least one 24-h dietary questionnaire and were free of diabetes at baseline. Participants were followed up until 1 March 2023 for type 2 diabetes incidence, with diagnosis information obtained from linked medical records. An Energy-adjusted Diet Inflammatory Index (E-DII) was calculated based on 28 food parameters. Habitual salt intake was determined through the self-reported frequency of adding salt to foods. The associations between E-DII, habitual salt intake and type 2 diabetes incidence were tested by the Cox proportional hazard regression model. RESULTS: Over a median follow-up period of 13.5 years, 6216 cases of type 2 diabetes were documented. Compared with participants with a low E-DII (indicative of an anti-inflammatory diet), participants with a high E-DII (indicative of a proinflammatory diet) had an 18% heightened risk of developing type 2 diabetes. The association between E-DII and type 2 diabetes tends to be linear after adjustment for major confounders. Participants with a proinflammatory diet and always adding salt to foods had the highest risk of type 2 diabetes incidence (hazard ratio 1.60, 95% confidence interval 1.32-1.94). CONCLUSIONS: Our findings indicate that a proinflammatory diet and higher habitual salt intake were associated with an increased risk of type 2 diabetes. These results support the public health promotion of an anti-inflammatory diet and reducing salt intake to prevent the onset of type 2 diabetes.

Association between glycemia risk index and arterial stiffness in type 2 diabetes.

AIM: This study aims to investigate the association of glycemia risk index (GRI), a novel composite metric derived from continuous glucose monitoring (CGM), with arterial stiffness in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 342 adults with type 2 diabetes were enrolled between April and June 2023 from 11 communities in Shanghai, China. Medical examinations, including measurements of anthropometric parameters, blood pressure, and venous blood samples were conducted. Brachial-ankle pulse wave velocity (baPWV) was examined to evaluate arterial stiffness. All the participants underwent a 14 day CGM recording and GRI was calculated from the CGM data. RESULTS: The mean age was 70.3 ± 6.8 years, and 162 (47.4%) were male. Participants with a higher baPWV had significantly higher levels of GRI and hyperglycemia component (both P for trend < 0.05). Linear regression revealed the significant positive linear associations of the GRI with baPWV in unadjusted or adjusted models (All P < 0.05). In the multivariable logistic analysis, each increase in the GRI quartile was associated with a 1.30-fold (95% CI 1.01-1.68, P for trend < 0.05) higher prevalence of increased arterial stiffness after adjustment for age, sex, BMI, diabetes duration, current smoking status, blood pressure, and lipid profile. Subgroup analyses showed that the association between the GRI quartiles and increased arterial stiffness was stronger among participants with a diabetes duration ≥15 years (P for interaction = 0.014). CONCLUSION: Glycemia risk index assessed by continuous glucose monitoring is associated with increased arterial stiffness in type 2 diabetes.

Weak Ion-Exchange Based Magnetic Swarm for Targeted Drug Delivery and Chemotherapy.

Swimming microrobots that are actuated by multiple stimuli/fields display various intriguing collective behaviors, ranging from phase separation to clustering and giant number fluctuation; however, it is still chanllenging to achieve multiple responses and functionalities within one colloidal system to emulate high environmental adaptability and improved tasking capability of natural swarms. In this work, a weak ion-exchange based swarm is presented that can self-organize and reconfigure by chemical, light, and magnetic fields, showing living crystal, amorphous glass, liquid, chain, and wheel-like structures. By changing the frequency and strength of the rotating magnetic field, various well-controlled and fast transformations are obtained. Experiments show the high adaptability and functionality of the microrobot swarm in delivering drugs in confined spaces, such as narrow channels with turns or obstacles. The drug-carrying swarm exhibits excellent chemtherapy for Hela and CT26 cells due to the pH-enhanced drug release and locomotion. This reconfigurable microswarm provides a new platform for biomedical and environmental applications.

Annual incidence and fatality rates of notifiable infectious diseases in southeast China from 1950 to 2022 and relationship to socioeconomic development.

Background: Over the past 70 years, China has advanced significantly in the prevention and treatment of infectious diseases while simultaneously undergoing a socioeconomic transformation, making it a useful source of data for analysing relationships between public health policy and the control of infectious diseases. Methods: We collected data on the incidence of notifiable infectious diseases and associated fatalities in Jiangsu province in southeast China from the Provincial Center for Disease Control and Prevention, Provincial Institute of Parasitic Diseases, and the Nationwide Notifiable Infectious Diseases Reporting Information System. We compared data from different historical periods using descriptive statistical methods, joinpoint regression, and correlation analysis. Results: During 1950-2022, 75 754 008 cases of 46 notifiable infectious diseases were reported in Jiangsu, with an average annual incidence was 1679.49 per 100 000 population and a fatality rate of 1.82 per 1000 persons. The incidence of classes A-B decreased (average annual percent change (AAPC) = -2.1) during the entire study period, while the incidence of class C increased (AAPC = 10.8) after 2004. The incidence of intestinal diseases (AAPC = -4.4) and vector-borne and zoonotic diseases (AAPC = -8.1) decreased rapidly, while the incidence of sexually transmitted and blood-borne diseases (AAPC = 1.8) increased. The number of medical and health institutions and the per capita gross domestic product correlated negatively with the annual incidence of diseases in classes A-B, but not with fatality rates. Conclusions: Although the annual incidence of many severe infectious diseases has decreased in Jiangsu since 1950, the incidence of sexually transmitted and blood-borne diseases increased. Socioeconomic growth and sustainable investment in health systems are associated with better control of infectious diseases.

Associations of Relative Fat Mass, a Novel Adiposity Indicator, with Non-Alcoholic Fatty Liver Disease and Cardiovascular Disease: Data from SPECT-China.

Purpose: This study aimed to determine the associations of relative fat mass (RFM), a novel adiposity indicator, with the prevalence of non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) and compared the disease discriminative ability of RFM with other common adiposity indicators in the general Chinese population. Patients and Methods: This cross-sectional study consisted of 11,532 adult participants from the SPECT-China study (2014-2016). We included RFM and six other adiposity indicators, including body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), visceral adiposity index (VAI), and lipid accumulation product (LAP). Binary logistic regression analysis was used to assess the relationship between adiposity indicators and the prevalence of NAFLD and CVD. The receiver operating characteristic (ROC) curve was used to evaluate the ability to screen NAFLD and CVD. Results: After adjusting for confounding variables, RFM showed a strong association with the prevalence of NAFLD and CVD. In men, each 1-SD (standard deviation) increase in RFM was associated with more than 3-fold increased risk of NAFLD (OR: 4.33, 95% CI: 3.79-4.93) and 66% increased risk of CVD (OR: 1.66, 95% CI: 1.36-2.02); in women, per 1-SD increase in RFM was associated with about 4-fold increased risk of NAFLD (OR: 5.16, 95% CI: 4.62-5.77) and 26% increased risk of CVD (OR: 1.26, 95% CI: 1.08-1.47). ROC analysis showed that RFM and WHtR were the strongest predictors for CVD. Conclusion: RFM was significantly associated with prevalent NAFLD and CVD in Chinese adults and might be considered a simple tool for disease prediction. Further large longitudinal studies are needed to verify our findings.

Analysis of the spatial-temporal distribution characteristics of hepatitis E in Jiangsu province from 2005 to 2020.

Objective: This study attempts to analyze the spatial clustering and spatial-temporal distribution characteristics of hepatitis E (HE) at the county (city and district) level in Jiangsu province to provide a scientific basis for the prevention and control of HE. Method: The information on HE cases reported in the Chinese Center for Disease Control and Prevention Information System from 2005 to 2020 was collected for spatial autocorrelation analysis and spatial-temporal clustering analysis. Result: From 2005 to 2020, 48,456 HE cases were reported in Jiangsu province, with an average annual incidence rate of 3.87/100,000. Male cases outnumbered female cases (2.46:1), and the incidence was highest in the 30-70 years of age group (80.50%). Farmers accounted for more than half of all cases (59.86%), and in terms of the average annual incidence, the top three cities were all in Zhenjiang city. Spatial autocorrelation analysis showed that Global Moran's I of HE incidence varied from 0.232 to 0.513 for the years. From 2005 to 2020, 31 counties (cities and districts) had high and statistically significant HE incidence, and two clustering areas were detected by spatial-temporal scanning. Conclusion: HE incidence in Jiangsu province from 2005 to 2020 was stable, with age and gender differences, regional clustering, and spatial-temporal clustering. Further investigation of HE clustering areas is necessary to formulate corresponding targeted prevention and control measures.

Dengue determinants: Necessities and challenges for universal dengue vaccine development.

Dengue illness can range from mild illness to life-threatening haemorrhage. It is an Aedes-borne infectious disease caused by the dengue virus, which has four serotypes. Each serotype acts as an independent infectious agent. The antibodies against one serotype confer homotypic immunity but temporary protection against heterotypic infection. Dengue has become a growing health concern for up to one third of the world's population. Currently, there is no potent anti-dengue medicine, and treatment for severe dengue relies on intravenous fluid management and pain medications. The burden of dengue dramatically increases despite advances in vector control measures. These factors underscore the need for a vaccine. Various dengue vaccine strategies have been demonstrated, that is, live attenuated vaccine, inactivated vaccine, DNA vaccine, subunit vaccine, and viral-vector vaccines, some of which are at the stage of clinical testing. Unfortunately, the forefront candidate vaccine is less than satisfactory, and its performance depends on serostatus and age factors. The lessons from clinical studies depicted ambiguity concerning the efficacy of dengue vaccine. Our study highlighted that viral structural heterogeneity, epitope accessibility, autoimmune complications, genetic variants, genetic diversities, antigen competition, virulence variation, host-pathogen specific interaction, antibody-dependent enhancement, cross-reactive immunity among Flaviviruses, and host-susceptibility determinants not only influence infection outcomes but also hampered successful vaccine development. This review integrates dengue determinants allocated necessities and challenges, which would provide insight for universal dengue vaccine development.

Cancer-associated fibroblast-targeted nanodrugs reshape colorectal tumor microenvironments to suppress tumor proliferation, metastasis and improve drug penetration.

Cancer-associated fibroblasts (CAFs) produce a critical tumor-promoting effect by cellular crosstalk with cancer cells and remodel the extracellular matrix (ECM) to form a protective physical barrier. The simple elimination of CAFs is not sufficient to govern the CAF-shaped aggressive tumor microenvironment (TME) because of the complexity of tumors. Herein, a CAF-targeted poly (lactic-co-glycolic acid) (PLGA) nanoemulsion is tailored to simultaneously deliver doxorubicin (DOX) and small interfering RNA (siRNA) targeting hepatocyte growth factor (HGF) for the combination of chemotherapy and gene therapy. The nanoemulsion (apt-Si/DNPs) shows a high specificity towards CAFs due to the aptamer modification and efficiently induces the apoptosis of CAFs, thus decreasing ECM deposition in the TME. Importantly, the delivered siRNA reduces the expression of the HGF in the remaining CAFs, which overcomes chemotherapy-induced upregulation of HGF mRNA and prevents the reproduction of CAFs through the autocrine HGF closed-loop. Owing to these synergetic effects, tumor proliferation, migration and invasion are prominently inhibited and tumor permeability is improved significantly. Overall, these results emphasize the potential of CAF-targeted combination treatments to inhibit tumor progression and metastasis, as well as overcome therapeutic resistance.

Upregulation of Long Noncoding RNA MALAT1 in Colorectal Cancer Promotes Radioresistance and Aggressive Malignance.

Background: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a conserved transcript with 8000 nt, is highly associated with malignancy of numerous cancer types. However, the function of MALAT1 plays in regulating the response to radiotherapy in colorectal cancer (CRC) remains unclear. Thus, the object of this study is to investigate the functions of MALAT1 in CRC radioresistance. Methods: First, the expression of MALAT1 in colon adenocarcinoma (COAD) was analyzed through the Cancer Genome Atlas (TCGA) database. Then, we detected the expression level of MALAT1 in tumor tissues and CRC cell lines and analyzed the relevance of MALAT1 and clinicopathological parameters. In the end, the effect of silencing MALAT1 on the radiosensitivity of CRC cells was investigated, and its potential mechanism was preliminarily illustrated. Results: The analysis of TCGA data showed that MALAT1 was closely related to the type of tumor, and high expression of MALAT1 was remarkably relevant to poor outcome. MALAT1 was highly expressed in CRC tissues and cell lines and related to tumor stages. Knockdown of MALAT1 could significantly suppress colony survival, proliferation, and migration and increase apoptosis, G2/M phase arrest, and formation of gamma-H2AX foci in HCT116, whether in combination with X-rays or not. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis demonstrated that the regulated proteins were principally enriched in the glycosaminoglycan degradation pathway after silencing MALAT1. Conclusion: Our results implied that MALAT1 was highly expressed in CRC and associated with tumor stage and prognosis. Silencing MALAT1 can increase HCT116 cell radiosensitivity, which may be potentially influenced by glycosaminoglycan degradation pathway.

Disease burden in patients with severe hand, foot, and mouth disease in Jiangsu Province: a cross-sectional study.

This study aimed to estimate the disease burden and health-related quality of life (HRQOL) among patients with severe hand, foot, and mouth disease (HFMD) in Jiangsu Province, China. We analyzed the surveillance data of HFMD cases in Jiangsu Province from 2009 to 2020. Moreover, a cross-sectional study was conducted in Nanjing and Suzhou, China, between January 2017 and May 2018. Patients with severe HFMD and their parents were recruited from selected hospitals. Questionnaires and hospital management systems were used to collect data on direct economic burden. The HRQOL of children was assessed using the TNO-AZL Preschool Quality of Life (TAPQOL) scale. A total of 1,348,737 confirmed cases of HFMD were reported to the NNDRS in Jiangsu province during 2009-2020. Of these, 9,622 were severe cases, with 62 (.64%) of these being fatal. From January 2017 to May 2018, data was collected from 362 severe HFMD cases using a structured questionnaire. The median per capita direct economic burden was RMB 16142.88, and was associated with the region and length of hospital stay (P < .05). The direct economic burden for all cases of severe HFMD in Jiangsu province between 2017 and 2018 was approximately RMB 16.64 million. Finally, the median (IQR) of the TAPQOL scale for children with severe HFMD was 69.23 (56.20, 82.27). Severe HFMD infection is a relatively large burden for individuals, and the burden of EV-A71 infection was seen to be even greater for the population. Prevention of severe HFMD should strengthen hygiene habits and targeted measures for EV-A71 vaccination.

Abnormal vibration perception threshold alters the gait features in type 2 diabetes mellitus patients.

Objective: It is generally believed that gait characteristics of diabetic neuropathic patients differ from those of non-diabetic ones. However, it is still unclear how the abnormal foot sensation influences the gait during walking in type 2 diabetes mellitus (T2DM). For the purpose of gaining a better insight into the alterations of detailed gait parameters and figuring out important aspects in the gait indexes by peripheral neuropathy in elder T2DM patients, we compared the gait features in participants with normal glucose tolerance (NGT) controls and diabetic individuals complicated by peripheral neuropathy or not. Subjects and methods: Gait parameters were observed during the 10-m walk on flat land among different conditions of diabetes in 1,741 participants from three clinical centers. Subjects were divided into four groups: persons with NGT were taken as the control group; patients with T2DM included three subgroups: DM control (no chronic complications), DM-DPN (DM complicated by only peripheral neuropathy), and DM-DPN+LEAD (DM complicated by both neuropathy and artery disease). The clinical characteristics and gait parameters were assessed and compared among these four groups. Analyses of variance were employed to verify possible differences of gait parameters between groups and conditions. Stepwise multivariate regression analysis was performed to reveal possible predictors of gait deficits. Receiver operating characteristic (ROC) curve analysis was employed to find any discriminatory power of diabetic peripheral neuropathy (DPN) for the step time. Results: In participants burdened with DPN, whether complicated by lower extremity arterial disease (LEAD) or not, step time increased sharply (p < 0.05). Stepwise multivariate regression models showed that independent variables of gait abnormality were sex, age, leg length, vibration perception threshold (VPT), and ankle-brachial index (ABI) (p < 0.01). Meanwhile, VPT was a significant independent predictor of step time, spatiotemporal variability (SDA), and temporal variability (SDB) (p < 0.05). ROC curve analysis was explored to find the discriminatory power of DPN for the occurrence of increased step time. The area under the curve (AUC) value was 0.608 (95% CI: 0.562-0.654, p < 0.01), and the cutoff point was 538.41 ms accompanied by a higher VPT. A significant positive association was observed between increased step time and the highest VPT group [odds ratio (OR) = 1.83, 95% CI: 1.32-2.55, p< 0.01]. In female patients, this OR value elevated to 2.16 (95% CI: 1.25-3.73, p< 0.01). Conclusions: In addition to sex, age, and leg length, VPT was a distinct factor that associated with altered gait parameters. DPN is associated with increased step time, and the step time increases with worsening VPT in type 2 diabetes.

Regulation of lnc-TLCD2-1 on Radiation Sensitivity of Colorectal Cancer and Comprehensive Analysis of Its Mechanism.

As is well known that colorectal cancer is the third most common cancer in the world, and radiation treatment plays a vital role in colorectal cancer therapy, but radiation resistance is a significant problem in the treatment of colorectal cancer. As an important member of the non-coding RNA family, long non-coding RNAs (lncRNAs) have been found that it plays a role in the occurrence and progression of colorectal cancer in recent years. However, little is known about the effect of lncRNA on colorectal cancer sensitivity to radiotherapy. We found that lnc-TLCD2-1 was significantly differentially expressed in radiation-tolerant CCL244 cell lines and radiation-sensitive HCT116 cell lines, suggesting that lnc-TLCD2-1 may regulate the radiosensitivity of colorectal cancer, and the relevant underlying mechanism was investigated. Cell clone formation assay, flow cytometry, and cell counting kit 8 (CCK8) were used to detect radiation sensitivity, apoptosis, and proliferation of colorectal cancer cells, respectively; Quantitative real-time PCR and western blot were used to detect the expression of genes; the direct interaction between lnc-TLCD2-1 and hsa-miR-193a-5p was verified by dual luciferase reporter assays; GEPIA, Starbase, TIMER and DAVID were used to complete expression of lnc-TLCD2-1, miR-193a-5p,YY1 and NF-кB-P65 in colorectal cancer, correlation, immune cell infiltration, GO and KEGG enrichment analysis. Clinical prognostic analysis data were obtained from GSE17536 dataset. After radiotherapy for HCT116, the expression of lnc-TLCD2-1 was increased, and the expression of hsa-miR-193a-5p was significantly decreased, while that of CCL244 was the opposite, and the change range of lnc-TLCD2-1 was relatively small. HCT116 with overexpression of lnc-TLCD2-1 after radiation treatment, the number of cell colonies significantly increased, and cell apoptosis decreased compared with the negative control group. The cell colonies and apoptosis of CCL244 with disturbed expression of lnc-TLCD2-1 were opposite to those of HCT116. Lnc-TLCD2-1 can regulate the expression of YY1/NF-кB-P65 by targeting miR-193a-5p. Lnc-TLCD2-1 can promote the proliferation of colorectal cancer. High expression of lnc-TLCD2-1 independently predicted a shorter survival. Lnc-TLCD2-1 is associated with radiation resistance and short survival in colorectal cancer patients. In addition, Lnc-TLCD2-1 can promote the proliferation of colorectal cancer. Our study provides a scientific basis for targeting lnc-TLCD2-1 in colorectal cancer radiation resistance interventions and selection of prognostic biomarker.

Non-Native Peptides Capable of Pan-Activating the agr Quorum Sensing System across Multiple Specificity Groups of Staphylococcus epidermidis.

Staphylococcus epidermidis is a leading cause of hospital-acquired infections. Traditional antibiotics have significantly reduced efficacy against this pathogen due to its ability to form biofilms on abiotic surfaces and drug resistance. The accessory gene regulator (agr) quorum sensing system is directly involved in S. epidermidis pathogenesis. Activation of agr is achieved via binding of the autoinducing peptide (AIP) signal to the extracellular sensor domain of its cognate receptor, AgrC. Divergent evolution has given rise to four agr specificity groups in S. epidermidis defined by the unique AIP sequence used by each group (AIPs-I-IV) with observed cross-group activities. As agr agonism has been shown to reduce biofilm growth in S. epidermidis, the development of pan-group activators of the agr system is of interest as a potential antivirulence strategy. To date, no synthetic compounds have been identified that are capable of appreciably activating the agr system of more than one specificity group of S. epidermidis or, to our knowledge, of any of the other Staphylococci. Here, we report the characterization of the structure-activity relationships for agr agonism by S. epidermidis AIP-II and AIP-III and the application of these new SAR data and those previously reported for AIP-I for the design and synthesis of the first multigroup agr agonists. These non-native peptides were capable of inducing the expression of critical biofilm dispersal agents (i.e., phenol-soluble modulins) in cell culture and represent new tools to study the role of quorum sensing in S. epidermidis infections.

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing.

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption 1,2 . There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

The efficacy and safety of cold atmospheric plasma as a novel therapy for diabetic wound in vitro and in vivo.

Cold atmospheric plasma (CAP) is a group of various chemical active species, such as ozone and nitric oxide, generated by working gas. CAP was demonstrated to have an effect on tissue regeneration and wound healing. We conducted this study to evaluate the efficacy and safety of CAP as a novel therapy for diabetic wounds in vitro and in vivo. The plasma consists of ionised helium gas that is produced by a high-voltage and high-frequency power supply. Eight-week-old male db/db mice and C57BL mice were treated with helium gas (control group), 90s' CAP (low-dose group), and 180s' CAP (high-dose group). Mice were treated and observed for 2 weeks. Skin samples from around the wound and blood samples were collected. Our in vitro analysis included scratch wound-healing assays by using human HaCaT immortalised human epidermal cells. After 14 days of treatment, CAP could obviously promote diabetic wound healing. Wound closure rates were significantly higher in the low-dose group and high-dose groups compared with the control group. Meanwhile, compared with the control group, the protein expression of IL-6, tumour necrosis factor-α, inducible nitric oxide synthase, and superoxide dismutase in two CAP groups significantly decreased, while the protein expression of vascular endothelial growth factor and transforming growth factor-ß in two CAP groups significantly increased (all P < .05); these data show good agreement with the change in mRNA level (all P < .05). In vitro, scratch wound-healing assays showed that plasma treatment could effectively ensure healing within 3 minutes of exposure (all P < .05). In addition, no difference was found in histological observations of normal skin and the level of serum alanine transaminase, aspartate aminotransferase, blood urea nitrogen, creatinine, and white blood cells among the CAP groups and control group. CAP treatment for 3 minutes every day improves wound healing in diabetic mice by suppressing inflammation, reducing oxidative stress, and enhancing angiogenesis, involving several proteins signalling, and it is safe for the liver and kidney.

Forecasting incidence of infectious diarrhea using random forest in Jiangsu Province, China.

BACKGROUND: Infectious diarrhea can lead to a considerable global disease burden. Thus, the accurate prediction of an infectious diarrhea epidemic is crucial for public health authorities. This study was aimed at developing an optimal random forest (RF) model, considering meteorological factors used to predict an incidence of infectious diarrhea in Jiangsu Province, China. METHODS: An RF model was developed and compared with classical autoregressive integrated moving average (ARIMA)/X models. Morbidity and meteorological data from 2012 to 2016 were used to construct the models and the data from 2017 were used for testing. RESULTS: The RF model considered atmospheric pressure, precipitation, relative humidity, and their lagged terms, as well as 1-4 week lag morbidity and time variable as the predictors. Meanwhile, a univariate model ARIMA (1,0,1)(1,0,0)52 (AIC = - 575.92, BIC = - 558.14) and a multivariable model ARIMAX (1,0,1)(1,0,0)52 with 0-1 week lag precipitation (AIC = - 578.58, BIC = - 578.13) were developed as benchmarks. The RF model outperformed the ARIMA/X models with a mean absolute percentage error (MAPE) of approximately 20%. The performance of the ARIMAX model was comparable to that of the ARIMA model with a MAPE reaching approximately 30%. CONCLUSIONS: The RF model fitted the dynamic nature of an infectious diarrhea epidemic well and delivered an ideal prediction accuracy. It comprehensively combined the synchronous and lagged effects of meteorological factors; it also integrated the autocorrelation and seasonality of the morbidity. The RF model can be used to predict the epidemic level and has a high potential for practical implementation.

A case-control study on the risk factors for hemorrhagic fever with renal syndrome.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is an endemic communicable disease in China, accounting for 90% of total reported cases worldwide. In this study, the authors want to investigate the risk factors for HFRS in recent years to provide the prevention and control advices. METHODS: A community-based, 1:2 matched case-control study was carried out to investigate the risk factors for HFRS. Cases were defined as laboratory-confirmed cases that tested positive for hantavirus-specific IgM antibodies. Two neighbourhood controls of each case were selected by sex, age and occupation. Standardized questionnaires were used to collect information and identify the risk factors for HFRS. RESULTS: Eighty-six matched pairs were investigated in the study. The median age of the cases was 55.0 years, 72.09% were male, and 73.26% were farmers. In the multivariate logistic regression analysis, cleaning spare room at home (OR = 3.310, 95%CI 1.335-8.210) was found to be risk factor for infection; storing food and crops properly (OR = 0.279 95%CI 0.097-0.804) provided protection from infection. CONCLUSION: Storing food and crops properly seemed to be protective factor, which was important for HFRS prevention and control. More attention should be paid to promote comprehensive health education and behaviour change among high-risk populations in the HFRS endemic area.

Epidemiology of infectious diarrhoea and the relationship with etiological and meteorological factors in Jiangsu Province, China.

We depicted the epidemiological characteristics of infectious diarrhoea in Jiangsu Province, China. Generalized additive models were employed to evaluate the age-specific effects of etiological and meteorological factors on prevalence. A long-term increasing prevalence with strong seasonality was observed. In those aged 0-5 years, disease risk increased rapidly with the positive rate of virus (rotavirus, norovirus, sapovirus, astrovirus) in the 20-50% range. In those aged > 20 years, disease risk increased with the positive rate of adenovirus and bacteria (Vibrio parahaemolyticus, Salmonella, Escherichia coli, Campylobacter jejuni) until reaching 5%, and thereafter stayed stable. The mean temperature, relative humidity, temperature range, and rainfall were all related to two-month lag morbidity in the group aged 0-5 years. Disease risk increased with relative humidity between 67-78%. Synchronous climate affected the incidence in those aged >20 years. Mean temperature and rainfall showed U-shape associations with disease risk (with threshold 15 °C and 100 mm per month, respectively). Meanwhile, disease risk increased gradually with sunshine duration over 150 hours per month. However, no associations were found in the group aged 6-19 years. In brief, etiological and meteorological factors had age-specific effects on the prevalence of infectious diarrhoea in Jiangsu. Surveillance efforts are needed to prevent its spread.