Alpha-defensin binding expands human adenovirus tropism.

Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins can increase rather than block infection by certain prominent bacterial and viral pathogens in cell culture and in vivo. We have shown previously that exposure of mouse and human adenoviruses (HAdVs) to α-defensins is able to overcome competitive inhibitors that block cell binding, leading us to hypothesize a defensin-mediated binding mechanism that is independent of known viral receptors. To test this hypothesis, we used genetic approaches to demonstrate that none of several primary receptors nor integrin co-receptors are needed for human α-defensin-mediated binding of HAdV to cells; however, infection remains integrin dependent. Thus, our studies have revealed a novel pathway for HAdV binding to cells that bypasses viral primary receptors. We speculate that this pathway functions in parallel with receptor-mediated entry and contributes to α-defensin-enhanced infection of susceptible cells. Remarkably, we also found that in the presence of α-defensins, HAdV tropism is expanded to non-susceptible cells, even when viruses are exposed to a mixture of both susceptible and non-susceptible cells. Therefore, we propose that in the presence of sufficient concentrations of α-defensins, such as in the lung or gut, integrin expression rather than primary receptor expression will dictate HAdV tropism in vivo. In summary, α-defensins may contribute to tissue tropism not only through the neutralization of susceptible viruses but also by allowing certain defensin-resistant viruses to bind to cells independently of previously described mechanisms.

Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses.

Major depressive disorder, a prevalent and severe psychiatric condition, necessitates development of new and fast-acting antidepressants. Genetic suppression of astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula ameliorates depression-like phenotypes in mice. However, Kir4.1 remains an elusive drug target for depression. Here, we discovered a series of Kir4.1 inhibitors through high-throughput screening. Lys05, the most potent one thus far, effectively suppressed native Kir4.1 channels while displaying high selectivity against established targets for rapid-onset antidepressants. Cryogenic-electron microscopy structures combined with electrophysiological characterizations revealed Lys05 directly binds in the central cavity of Kir4.1. Notably, a single dose of Lys05 reversed the Kir4.1-driven depression-like phenotype and exerted rapid-onset (as early as 1 hour) antidepressant actions in multiple canonical depression rodent models with efficacy comparable to that of (S)-ketamine. Overall, we provided a proof of concept that Kir4.1 is a promising target for rapid-onset antidepressant effects.

α-ketoglutarate preconditioning extends the survival of engrafted adipose-derived mesenchymal stem cells to accelerate healing of burn wounds.

The application of adipose-derived stem cells (ADSCs) in treating hard-to-heal wounds has been widely accepted, while the short-term survival rate remains an obstacle in stem cell therapy. The aim of this study is to investigate the effect of preconditioning ADSCs with α-ketoglutarate (α-KG) on the healing of acid burn wounds and cell survival within wounds. Preconditioning of ADSCs was performed by treating cells at passage 3 with 3.5 mM DM-αKG for 24 h. Proliferation and migration of ADSCs was examined. An acid burn wound was created on the dorsal skin of mice. Cell suspension of ADSCs (2 × 106 cells/ml), either pre-treated with α-KG or not, was injected subcutaneously around the margin of wound. At 1,4,7,10,14 days after injection, the percentage of wound closure was evaluated. Expression of pro-angiogenic factors, matrix molecules and HIF1-α in pretreated ADSCs or in wounds was evaluated by qRT-PCR and immunohistochemistry staining, respectively. The survival rate of DiO-labelled ADSCs was determined with the in vivo bioluminescent imaging system. Treating with α-KG induced an enhancement in migration of ADSCs, while their proliferation was not affected. Expression of Vegf and Fgf-2 was significantly increased. With injection of pretreated ADSCs, healing of wounds was remarkably accelerated, along with increased ECM deposition and microvessel density. Moreover, pretreatment with α-KG resulted a prolonged survival of engrafted ADSCs was observed. Expression of HIF-1α was significantly increased in ADSCs treated with α-KG and in wounds injected with preconditioned ADSCs. Our results revealed that healing of acid burn wound was accelerated with administration of ADSCs pretreated with α-KG, which induced elevated expression of HIF-1α and prolonged survival of engrafted stem cells.

Predictive Mapping of Antimicrobial Resistance for Escherichia coli, Salmonella, and Campylobacter in Food-Producing Animals, Europe, 2000-2021.

In Europe, systematic national surveillance of antimicrobial resistance (AMR) in food-producing animals has been conducted for decades; however, geographic distribution within countries remains unknown. To determine distribution within Europe, we combined 33,802 country-level AMR prevalence estimates with 2,849 local AMR prevalence estimates from 209 point prevalence surveys across 31 countries. We produced geospatial models of AMR prevalence in Escherichia coli, nontyphoidal Salmonella, and Campylobacter for cattle, pigs, and poultry. We summarized AMR trends by using the proportion of tested antimicrobial compounds with resistance >50% and generated predictive maps at 10 × 10 km resolution that disaggregated AMR prevalence. For E. coli, predicted prevalence rates were highest in southern Romania and southern/eastern Italy; for Salmonella, southern Hungary and central Poland; and for Campylobacter, throughout Spain. Our findings suggest that AMR distribution is heterogeneous within countries and that surveillance data from below the country level could help with prioritizing resources to reduce AMR.

Augmented drug resistance of osteosarcoma cells within decalcified bone matrix scaffold: The role of glutamine metabolism.

Due to the lack of a precise in vitro model that can mimic the nature microenvironment in osteosarcoma, the understanding of its resistance to chemical drugs remains limited. Here, we report a novel three-dimensional model of osteosarcoma constructed by seeding tumor cells (MG-63 and MNNG/HOS Cl no. 5) within demineralized bone matrix scaffolds. Demineralized bone matrix scaffolds retain the original components of the natural bone matrix (hydroxyapatite and collagen type I), and possess good biocompatibility allowing osteosarcoma cells to proliferate and aggregate into clusters within the pores. Growing within the scaffold conferred elevated resistance to doxorubicin on MG-63 and MNNG/HOS Cl no. 5 cell lines as compared to two-dimensional cultures. Transcriptomic analysis showed an increased enrichment for drug resistance genes along with enhanced glutamine metabolism in osteosarcoma cells in demineralized bone matrix scaffolds. Inhibition of glutamine metabolism resulted in a decrease in drug resistance of osteosarcoma, which could be restored by α-ketoglutarate supplementation. Overall, our study suggests that microenvironmental cues in demineralized bone matrix scaffolds can enhance osteosarcoma drug responses and that targeting glutamine metabolism may be a strategy for treating osteosarcoma drug resistance.

Tumor cell-derived LC3B+extracellular vesicles mediate the crosstalk between tumor microenvironment and immunotherapy efficacy in hepatocellular carcinoma via the HSP90α-IL-6/IL-8 signaling axis.

BACKGROUND: Inflammatory factors are being recognized as critical modulators of host antitumor immunity in liver cancer. We have previously shown that tumor cell-released LC3B positive extracellular vesicles (LC3B+ EVs) are responsible for malignant progression by dampening antitumor immunity. However, the relationship between LC3B+ EVs and inflammatory factors in the regulation of the liver cancer microenvironment remains unclear. METHODS: Flow cytometry analyses were performed to examine the panel of 12 cytokines, the main source of positive cytokines, and plasma LC3B+ EVs carrying HSP90α in peripheral blood of liver cancer patients. We correlated the levels of plasma IL-6, IL-8 with LC3B+ EVs carrying HSP90α and with prognosis. In vitro culture of healthy donor leukocytes with liver cancer-derived LC3B+ EVs was performed to evaluate the potential effect of blocking HSP90α, IL-6 or IL-8 alone or in combination with PD-1 inhibitor on CD8+ T cell function. We also investigated the potential associations of MAP1LC3B, HSP90AA1, IL6 or IL8 with immunotherapy efficacy using the TCGA databases. RESULTS: In liver cancer patients, plasma IL-6 and IL-8 levels were significantly higher than in healthy controls and associated with poor clinical outcome. In peripheral blood, levels of plasma LC3B+ EVs carrying HSP90α were significantly elevated in HCC patients and positively associated with IL-6 and IL-8 levels, which are predominantly secreted by monocytes and neutrophils. Moreover, LC3B+ EVs from human liver cancer cells promoted the secretion of IL-6 and IL-8 by leukocytes through HSP90α. Besides, we show that the cytokines IL-6 and IL-8 secreted by LC3B+ EVs-induced leukocytes were involved in the inhibition of CD8+ T-cell function, while blockade of the HSP90α on the LC3B+ EVs, IL-6, or IL-8 could enhance anti-PD-1-induced T cell reinvigoration. Finally, patients who received anti-PD-1/PD-L1 immunotherapy with high MAP1LC3B, HSP90AA1, IL6, or IL8 expression had a lower immunotherapy efficacy. CONCLUSIONS: Our data suggest that liver cancer-derived LC3B+ EVs promote a pro-oncogenic inflammatory microenvironment by carrying membrane-bound HSP90α. Targeting HSP90α on the LC3B+ EVs, IL-6, or IL-8 may synergize with anti-PD-1 treatment to enhance the CD8+ T-cell functions, which may provide novel combination strategies in the clinic for the treatment of liver cancer.

Proper application of DNA dyes in agarose gel electrophoresis.

Various dyes are used to visualize DNA bands in agarose gel electrophoresis (AGE) by the methods of pre- or post-staining. The DNA dye user's guides generally state that the binding of the dye to DNA will affect DNA mobility in electrophoresis, thus recommending post-staining for accurate measurement of DNA size. However, many AGE performers prefer pre-staining procedures for reasons such as convenience, real-time observation of DNA bands, and/or the use of a minimal amount of dye. The detrimental effect of the dye on DNA mobility and the associated risk for inaccurate measurement of DNA size are often overlooked by AGE performers. Here we quantitatively determine the impact on DNA migration imposed by frequently used dyes, including GelRed, ethidium bromide (EB), and Gold View. It was observed that pre-staining with GelRed and EB significantly slowed down DNA migration to cause as much as 39.1% overestimation on the size of sample DNA, whereas Gold View had little effect. The slowdown of DNA migration increased with dye concentration until it plateaued when the dye concentration reached a saturated level. Thus, to take advantage of pre-staining, saturated levels of DNA dyes should always be applied for both DNA samples and DNA markers to ensure a fair comparison of DNA sizes. In addition, GelRed and EB display much higher sensitivity than Gold View in the detection of DNA bands in post-staining. The saturated concentrations, cost considerations, and other useful features of these frequently used dyes are summarized for the information of AGE performers.

Interferon-α induces differentiation of cancer stem cells and immunosuppression in hepatocellular carcinoma by upregulating CXCL8 secretion.

Interferon-alpha (IFN-α) is widely used in the clinical treatment of patients with chronic hepatitis B and hepatocellular carcinoma (HCC). However, high levels of CXCL8 are associated with resistance to IFN-α therapy and poorer prognosis in advanced cancers. In this study, we investigated whether IFN-α could directly induce the production of CXCL8 in HCC cells and whether CXCL8 could antagonize the antitumor activity of IFN-α. We found that IFN-α not only upregulated the expression of the inducible genes CXCL9, CXCL10, CXCL11 and PD-L1, but also significantly stimulated CXCL8 secretion in HCC cells. Mechanically, IFN-α induces CXCL8 expression by activating the AKT and JNK pathways. In addition, our results demonstrate that IFN-α exposure significantly increases the differentiation of HCC stem cells, but this effect is reversed by the addition of the CXCL8 receptor CXCR1/2 inhibitor Reparixin and STAT3 inhibitor Stattic. Besides, our study reveals that the cytokine CXCL8 secreted by IFN-α-induced HCC cells inhibits T-cell function. Conversely, inhibition of CXCL8 promotes TNF-α and IFN-γ secretion by T cells. Finally, liver cancer patients who received anti-PD-1/PD-L1 immunotherapy with high CXCL8 expression had a lower immunotherapy efficacy. Overall, our findings clarify that IFN-α triggers immunosuppression and cancer stem cell differentiation in hepatocellular carcinoma by upregulating CXCL8 secretion. This discovery provides a novel approach to enhance the effectiveness of HCC treatment in the future.

The dual roles of dissimilatory iron reduction in the carbon cycle: The "iron mesh" effect can increase inorganic carbon sequestration.

Dissimilatory iron reduction (DIR) can drive the release of organic carbon (OC) as carbon dioxide (CO2 ) by mediating electron transfer between organic compounds and microbes. However, DIR is also crucial for carbon sequestration, which can affect inorganic-carbon redistribution via iron abiotic-phase transformation. The formation conditions of modern carbonate-bearing iron minerals (ICFe ) and their potential as a CO2 sink are still unclear. A natural environment with modern ICFe , such as karst lake sediment, could be a good analog to explore the regulation of microbial iron reduction and sequential mineral formation. We find that high porosity is conducive to electron transport and dissimilatory iron-reducing bacteria activity, which can increase the iron reduction rate. The iron-rich environment with high calcium and OC can form a large sediment pore structure to support rapid DIR, which is conducive to the formation and growth of ICFe . Our results further demonstrate that the minimum DIR threshold suitable for ICFe formation is 6.65 µmol g-1 dw day-1 . DIR is the dominant pathway (average 66.93%) of organic anaerobic mineralization, and the abiotic-phase transformation of Fe2+ reduces CO2 emissions by ~41.79%. Our findings indicate that as part of the carbon cycle, DIR not only drives mineralization reactions but also traps carbon, increasing the stability of carbon sinks. Considering the wide geographic distribution of DIR and ICFe , our findings suggest that the "iron mesh" effect may become an increasingly important vector of carbon sequestration.

Impacts of Left Atrial Appendage Treatments on Mitral Valve Diseases during Surgical Ablations.

Background: Left atrial appendages (LAAs) play an important role in regulating left atrial function, and much evidence supports the possibility that changes in left atrial structure may cause or worsen mitral regurgitation. This study intended to investigate the outcomes of patients with mitral regurgitation who underwent left atrial appendage closure (resection or endocardial closure) during isolated surgical ablations. Methods: Patients with mild or moderate mitral regurgitation who received isolated surgical ablations for atrial fibrillation (AF) in our center from 2013 to 2022 were referred. During follow-up, each clinical visit was composed of medical interrogation, a 24 h Holter, and echocardiographic evaluation. Death, atrial fibrillation, worsening of mitral regurgitation, and stroke were evaluated as outcomes. Freedom from outcomes whose results were adjusted by inverse probability of treatment weighting for causal effects after acquiring propensity scores. Results: A total of 456 patients were enrolled in this study. During a median follow-up of 48 months, 30 deaths and 11 cases of stroke were observed. After adjustments, no significant differences in terms of death or stroke were observed among the three groups. Patients who underwent resection or endocardial closure during surgical ablations had a higher risk of mitral regurgitation worsening during follow-up (p < 0.05). During the whole follow-up, patients who underwent left atrial appendage interventions showed significantly larger left atrial and mitral annular diameters, as well as lower tethering height than those who had left atrial appendage preserved (all p < 0.05). Conclusions: Mitral regurgitation was more likely to get worse when patients with fundamental mitral diseases underwent LAA interventions during isolated surgical AF ablations. In the absence of LAA, the dilation of the left atrium and mitral annulus may ultimately lead to worsening of regurgitation.

Outcomes of Mitral Valve Repair for Posterior Leaflet Prolapse, Anterior Leaflet Prolapse, and Bileaflet Prolapse.

Background: Mitral valve repair (MVr) is an effective treatment for degenerative mitral regurgitation (DMR).And the outcomes and repair rates for posterior leaflet prolapse (PLP), anterior leaflet prolapse (ALP), and bileaflet prolapse (BLP) vary. This study aimed to compare the outcomes of mitral valve repair for patients with PLP, ALP, and BLP. Methods: From 2010 to 2019, 1192 patients with degenerative mitral valve regurgitation underwent surgery at our hospital. And 1069 patients were identified. The average age of all patients was (54.74 ± 12.17) years old for all patients. 273 patients (25.5%) had ALP, 148 patients (13.8%) had BLP, and 648 patients (60.6%) had PLP. All patients were followed up for an average duration of 5.1 years. We compared the outcomes of patients with ALP, PLP, and BLP. Results: Patients with ALP were the youngest of the 3 groups and had the highest prevalence of atrial fibrillation. Patients with PLP had the highest prevalence of hypertension, whereas patients with BLP and ALP had larger left ventricular end-diastolic and left ventricular end-systolic diameters. ALP and BLP repairs had a longer cardiopulmonary bypass and aortic cross-clamp time.10 patients dead in-hospital, 5 patients had PLP, 3 had ALP, and 2 had BLP. The 10-year survival cumulative incidences of reoperation among ALP, BLP, and PLP repairs were not significantly different. ALP repair still had higher cumulative incidences of recurrent mitral regurgitation (MR) compared to PLP. Conclusions: The rates of long-term survival and freedom from reoperation were not significantly different among patients with ALP, BLP, and PLP. ALP repair has higher cumulative incidences of recurrent MR compared to PLP.

Clinically compliant cryopreservation of differentiated retinal pigment epithelial cells.

BACKGROUND AIMS: Age-related macular degeneration (AMD) is the most common cause of blindness in elderly patients within developed countries, affecting more than 190 million worldwide. In AMD, the retinal pigment epithelial (RPE) cell layer progressively degenerates, resulting in subsequent loss of photoreceptors and ultimately vision. There is currently no cure for AMD, but therapeutic strategies targeting the complement system are being developed to slow the progression of the disease. METHODS: Replacement therapy with pluripotent stem cell-derived (hPSC) RPEs is an alternative treatment strategy. A cell therapy product must be produced in accordance with Good Manufacturing Practices at a sufficient scale to facilitate extensive pre-clinical and clinical testing. Cryopreservation of the final cell product is therefore highly beneficial, as the manufacturing, pre-clinical and clinical testing can be separated in time and location. RESULTS: We found that mature hPSC-RPE cells do not survive conventional cryopreservation techniques. However, replating the cells 2-5 days before cryopreservation facilitates freezing. The replated and cryopreserved hPSC-RPE cells maintained their identity, purity and functionality as characteristic RPEs, shown by cobblestone morphology, pigmentation, transcriptional profile, RPE markers, transepithelial resistance and pigment epithelium-derived factor secretion. Finally, we showed that the optimal replating time window can be tracked noninvasively by following the change in cobblestone morphology. CONCLUSIONS: The possibility of cryopreserving the hPSC-RPE product has been instrumental in our efforts in manufacturing and performing pre-clinical testing with the aim for clinical translation.

A novel method for synthesizing authentic SARS-CoV-2 main protease.

The SARS-CoV-2 main protease (Mpro) plays a crucial role in virus amplification and is an ideal target for antiviral drugs. Currently, authentic Mpro is prepared through two rounds of proteolytic cleavage. In this method, Mpro carries a self-cleavage site at the N-terminus and a protease cleavage site followed by an affinity tag at the C-terminus. This article proposes a novel method for producing authentic Mpro through single digestion. Mpro was constructed by fusing a His tag containing TEV protease cleavage sites at the N-terminus. The expressed recombinant protein was digested by TEV protease, and the generated protein had a decreased molecular weight and significantly increased activity, which was consistent with that of authentic Mpro generated by the previous method. These findings indicated that authentic Mpro was successfully obtained. Moreover, the substrate specificity of Mpro was investigated. Mpro had a strong preference for Phe at position the P2, which suggested that the S2 subsite was an outstanding target for designing inhibitors. This article also provides a reference for the preparation of Mpro for sudden coronavirus infection in the future.

Tofacitinib versus thalidomide for mucocutaneous lesions of systemic lupus erythematosus: A real-world CSTAR cohort study XXVII.

OBJECTIVE: Thalidomide is an effective medication for refractory mucocutaneous lesions of systemic lupus erythematosus (SLE) and can treat arthritis in some autoimmune diseases, but it has some adverse reactions. Recently, the effectiveness of tofacitinib in treating mucocutaneous lesions of SLE has been reported. We aimed to compare the efficacy and safety of tofacitinib with thalidomide in treating mucocutaneous and musculoskeletal lesions in patients with SLE. METHODS: This study was a real-world cohort study based on the Chinese SLE Treatment and Research group (CSTAR) registry. SLE patients who manifested mucocutaneous and/or musculoskeletal symptoms and were prescribed tofacitinib or thalidomide were included. We retrospectively conducted comparisons between the tofacitinib and thalidomide groups regarding clinical improvements, SLE disease activity, serological indicators, glucocorticoid doses, and adverse events at the 1, 3, and 6-months time points. RESULTS: At 3 and 6 months, the tofacitinib group exhibited a higher proportion of patients with improvement in mucocutaneous and musculoskeletal issues. Additionally, a greater percentage of patients in the tofacitinib group achieved remission or a low disease activity state (LLDAS) at these time points. No significant serological improvements were observed in either the tofacitinib or thalidomide groups. Fewer adverse events were observed in the tofacitinib group than in the thalidomide group. CONCLUSIONS: Tofacitinib might be superior to thalidomide in the improvement of mucocutaneous and musculoskeletal lesions in SLE, and had a good safety profile.

Association between perioperative self-reported sleep disturbances and delirium risk in elderly patients following total joint arthroplasty: a cohort study.

Perioperative sleep disturbance may increase delirium risk. However, the role of perioperative sleep disturbance in delirium following total joint arthroplasty remains unclear. This prospective cohort study aimed to observe the delirium risk in patients with sleep disturbances. After excluding pre-existing sleep disturbances, older patients scheduled for total joint arthroplasty from July 17, 2022, to January 12, 2023, were recruited. Preoperative sleep disturbance or postoperative sleep disturbance was defined as a Chinese version of the Richards-Campbell Sleep Questionnaire (RCSQ) score of <50 during hospitalisation. A cut-off score of 25 was used to classify the severity of sleep disturbance. The primary outcome was the incidence of postoperative delirium. In all, 11.6% of cohort patients (34/294) developed delirium. After multivariate analysis, a preoperative Day 1 RCSQ score of ≤25 (odds ratio [OR] 3.62, 95% confidence interval [CI] 1.19-10.92; p = 0.02), occurrence of sleep disturbances (OR 2.76, 95% CI 1.19-6.38; p = 0.02) and RCSQ score of ≤25(OR 2.91, 95% CI 1.33-6.37; p = 0.007) postoperatively were strong independent predictors of delirium. After sensitivity analysis for daily delirium, a postoperative Day 1 RCSQ score of ≤25 (OR 9.27, 95% CI 2.72-36.15; p < 0.001) was associated with a greater risk of delirium on postoperative Day 1, with a reasonable discriminative area under the curve of 0.730. We concluded that postoperative but not preoperative sleep disturbances may be an independent factor for delirium risk. Sleep disturbance on the first night after surgery was a good predictor of subsequent delirium, no matter the nature of self-reported sleep disturbance.

Influence of increasing acclimation temperature on growth, digestion, antioxidant capacity, liver transcriptome and intestinal microflora of Ussruri whitefish Coregonus ussuriensis Berg.

For effective restoration, conservation of Ussruri whitefish Coregonus ussuriensis Berg and coping with global climate change, effects of environmental temperature on Ussruri whitefish urgently need to be explored. In current study, the effects of different acclimation temperatures on the growth, digestive physiology, antioxidant ability, liver transcriptional responses and intestinal microflora patterns of Ussruri whitefish were investigated. Ussruri whitefish (15.20 g ± 1.23 g) were reared for 42 days under different acclimation temperatures, i.e., 10, 13, 16, 19, 22 and 25 °C, respectively. Result first determined 28 °C as the semi-lethal temperature in order to design the temperature gradient test. Highest main gain rate (MGR) and specific growth rate (SGR) were observed in fish group having acclimation temperature of 19 °C. Significantly decrease (P < 0.05) in triglyceride (TG) content appeared at 19 °C as compared to the 10 °C and 13 °C temperature groups. 19 °C notablely increased protease activities of stomach and intestine and intestinal lipase and amylase activities. 19 °C group obtained the highest activities of chloramphnicol acetyltransferase (CAT) and total antioxidant capacity (T-AOC) and higher activities of superoxide dismutase (SOD). The intestinal microflora composition was most conducive to maintaining overall intestinal health when the temperature was 19 °C, compared to 10 °C and 25 °C. Ussruri whitefish exposed to 10 °C and 25 °C possessed the lower Lactobacillus abundance compared to exposure to 19 °C. Temperature down to 10 °C or up to 25 °C, respectively, triggered cold stress and heat stress, which leading to impairment in intestinal digestion, liver antioxidant capacity and intestinal microflora structure. Liver transcriptome response to 10 °C, 19 °C and 25 °C revealed that Ussruri whitefish might require the initiation of endoplasmic reticulum stress to correct protein damage from cold-temperature and high-temperature stress, and it was speculated that DNAJB11 could be regarded as a biomarker of cold stress response.Based on the quadratic regression analysis of MGR and SGR against temperature, the optimal acclamation temperature were, respectively, 18.0 °C and 18.1 °C. Our findings provide valuable theoretical insights for an in-depth understanding of temperature acclimation mechanisms and laid the foundation for conservation and development of Ussruri whitefish germplasm resources.

"Simmer pus and grow flesh" method promotes chronic wound healing in rats via bFGF-Wnt ß-catenin signaling pathway.

The purpose of this study was to explore the mechanism of "simmer pus and grow meat" method based on bFGF regulating WNT / ß-Catenin signaling pathway. Of 100 SPF rats, 25 were randomly selected as blank group, and 75 rats were established chronic infectious wound model and divided into blank group, model group (normal saline treatment, n = 25), experimental group (purple and white ointment treatment, n = 25), and wet burn ointment group (wet burn treatment, n = 25). The wound healing rate of rats was compared. The protein expressions of PCAN, VEGF, bFGF, ß-Catenin, GSK-3ß and C-Myc in granulation tissues were detected. On the 7th day, the wound healing rate of the model group was lower than that of the other 3 groups (P<0.05), and the wound healing rate of the positive control group was higher than that of the experimental group and the control group (P<0.05). The expressions of bFGF, GSK-3ß and C-MyC in model group were higher than those in control group (P<0.05). The ß-catenin protein expression in the model group was lower than that in the control group (P<0.05), and the ß-catenin protein expression in the experimental group and the positive control group was higher than that in the model group (P<0.05). The expressions of PCAN and VEGF in model group were lower than those in model group (P<0.05). We found that Zibai ointment promotes chronic wound healing by modulating the bFGF/Wnt/ß-Catenin signaling pathway.

Association between heatwaves and risk and economic burden of injury related hospitalizations in China.

BACKGROUND: Public health is greatly affected by heatwaves, especially as a result of climate change. It is unclear whether heatwaves affect injury hospitalization, especially as developing countries facing the impact of climate change. OBJECTIVES: To assess the impact of heatwaves on injury-related hospitalization and the economic burden. METHODS: The daily hospitalizations and meteorological data from 2014 to 2019 were collected from 23 study sites in 11 meteorological geographic zones in China. We conducted a two-stage time series analysis based on a time-stratified case-crossover design, combined with DLNM to assess the association between heatwaves and daily injury hospitalization, and to further assess the regional and national economic losses resulting from hospitalization by calculating excess hospitalization costs (direct economic losses) and labor losses (indirect economic losses). To determine the vulnerable groups and areas, we also carried out stratified analyses by age, sex, and region. RESULTS: We found that 6.542% (95%CI: 3.939%, 9.008 %) of injury hospitalization were attributable to heatwaves during warm season (May to September) from 2014 to 2019. Approximately 361,447 injury hospitalizations were attributed to heatwaves each year in China, leading to an excess economic loss of 5.173 (95%CI: 3.104, 7.196) billion CNY, of which 3.114 (95%CI: 1.454, 4.720) billion CNY for males and 4.785 (95%CI: 3.203, 6.321) billion CNY for people aged 15-64 years. The attributable fraction (AF) of injury hospitalizations due to heatwaves was the highest in the plateau mountain climate zone, followed by the subtropical monsoon climate zone and the temperate monsoon climate zone. CONCLUSIONS: Heatwaves significantly increase the disease and economic burden of injury hospitalizations, and vary across populations and regions. Our findings implicate the necessity for targeted measures, including raising public awareness, improving healthcare infrastructure, and developing climate resilience policies, to reduce the threat of heatwaves to vulnerable populations and the associated disease and economic burden.

Comparison of recurrence and survival between patients with pathological stage I epithelial ovarian cancer after laparoscopic or laparotomic surgery: retrospective analysis of a propensity-matched cohort.

OBJECTIVE: To compare oncologic outcomes after laparoscopic or laparotomic surgery to treat epithelial ovarian carcinoma in FIGO stage I. DESIGN: Retrospective cohort study. SETTING: Gynecological cancer ward in a tertiary hospital. PARTICIPANTS: A total of 85 patients with FIGO stage I epithelial ovarian carcinoma who underwent laparoscopic staging surgery and 206 who underwent laparotomic staging surgery at West China Second Hospital, Sichuan University (Chengdu, China) between January 1, 2013 and December 31, 2019. INTERVENTIONS: laparoscopic surgery or laparotomic staging surgery. RESULTS: Before propensity score-based matching, the laparotomy group showed higher prevalence of preoperative elevated CA125 level (48.5% vs 35.3%, p = .045) and tumors > 15 cm (27.2% vs 5.9%, p < .001). Multivariate analysis associated higher body mass index with better overall survival (adjusted HR 0.83, 95%CI 0.70-0.99, p = .043). Among propensity score-matched patients (82 per group) who were matched to each other according to propensity scoring based on age, body mass index, CA125 level, largest tumor diameter, FIGO stage, history of abdominal surgery, and American Society of Anesthesiologists grade, the rate of progression-free survival at 5 years was similar between the laparoscopy group (87.1%, 95%CI 79.3-95.7%) and the laparotomy group (90.9%, 95%CI 84.7-97.6%, p = .524), as was the rate of overall survival at 5 years (93.9%, 95%CI 88.0-100.0% vs 94.7%, 95%CI 89.8-99.9%, p = .900). Regardless of whether patients were matched, the two groups showed similar rates of recurrence of 9-11% during follow-up lasting a median of 54.9 months. CONCLUSIONS: Rates of recurrence and survival may be similar between laparoscopy or laparotomy to treat stage I epithelial ovarian cancer. Since laparoscopy is associated with less bleeding and faster recovery, it may be a safe, effective alternative to laparotomy for appropriate patients.

An effective treatment for diabetic foot necrosis with traditional Chinese and Western medicine: a case report.

Patients with diabetes who undergo a kidney transplant are at a great risk of undergoing amputations, usually associated with severe infection and necrosis. The treatment of severe diabetic foot necrosis is challenging in clinic, and the function of the limb is often hugely compromised. A 74-year-old male who had been diagnosed with severe post-renal transplant diabetic foot necrosis refused the option of below-knee amputation from previous surgeons, and requested to keep his left foot. The patient was treated with integrated traditional Chinese medicine (TCM) and Western medicine, with positive results. TCM therapeutic principles included 'clearing heat, removing toxicity, regulating Qi, resolving dampness, activating stagnant blood and nourishing yin as well as tonifying Qi and blood'. Treatment with Western medicine included wound debridement, internal fixation or joint fusion, and use of insulin, antibiotics and vasodilators. The patient was treated with a staged and diverse approach (i.e., a combination of TCM and Western medicine, surgical management and education for diabetic foot care), which ultimately helped the patient achieve limb salvage and regain normal function. A combination therapy of Western medicine and TCM may be a promising approach to heal diabetic foot ulcers.