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Abstract Dapagliflozin (DAPA) demonstrates promise in the management of diabetic mellitus (DM) and cardiomyopathy. Trimethylamine N-oxide (TMAO) is synthesized by the gut microbiota through the metabolic conversion of choline and phosphatidylcholine. Ferroptosis may offer novel therapeutic avenues for the management of diabetes and myocardial ischemia–reperfusion injury (IRI). However, the precise mechanism underlying ferroptosis in cardiomyocytes and the specific role of TMAO generated by gut microbiota in the therapeutic approach for DM and myocardial IRI utilizing DAPA need to be further explored. Nine male SD rats with specific pathogen-free (SPF) status were randomly divided equally into the normal group, the DM + IRI (DIR) group, and the DAPA group. The diversity of the gut microbiota was analyzed using 16S rRNA gene sequencing. Additionally, the Wekell technique was employed to measure the levels of TMAO in the three groups. Application of network pharmacology to search for intersection targets of DAPA, DIR, and ferroptosis, and RT-PCR experimental verification. Ultimately, the overlapping targets that were acquired were subjected to molecular docking analysis with TMAO. The changes of Bacteroidetes and Firmicutes in the gut microbiota of DIR rats were most significantly affected by DAPA. Escherichia-Shigella and Prevotella_9 within the phylum Bacteroidetes could be identified as the primary effects of DAPA on DIR. Compared with the normal group, the TMAO content in the DIR group was significantly increased, while the TMAO content in the DAPA group was decreased compared to the DIR group. For the network pharmacology analysis, DAPA and DIR generated 43 intersecting target genes, and then further intersected with ferroptosis-related genes, resulting in 11 overlapping target genes. The mRNA expression of ALB, HMOX1, PPARG, CBS, LCN2, and PPARA decreased in the DIR group through reverse transcription polymerase chain reaction (RT-PCR) validation, while the opposite trend was observed in the DAPA group. The docking score between TMAO and DPP4 was − 5.44, and the MM-GBSA result of − 22.02 kcal/mol. It epitomizes the finest docking performance among all the target genes with the lowest score. DAPA could reduce the levels of metabolite TMAO produced by gut microbiota, thereby regulating related target genes to decrease ferroptosis in DIR cardiomyocytes.

Abstract Background Ischemic postconditioning (IPostC) has been reported as a promising method for protecting against myocardial ischemia-reperfusion (MI/R) injury. Our previous study found that the infarct-limiting effect of IPostC is abolished in the heart of diabetes whose cardiac expression of DJ-1 (also called PARK7, Parkinsonism associated deglycase) is reduced. However, the role and in particular the underlying mechanism of DJ-1 in the loss of sensitivity to IPostC-induced cardioprotection in diabetic hearts remains unclear. Methods Streptozotocin-induced type 1 diabetic rats were subjected to MI/R injury by occluding the left anterior descending artery (LAD) and followed by reperfusion. IPostC was induced by three cycles of 10s of reperfusion and ischemia at the onset of reperfusion. AAV9-CMV-DJ-1, AAV9-CMV-C106S-DJ-1 or AAV9-DJ-1 siRNA were injected via tail vein to either over-express or knock-down DJ-1 three weeks before inducing MI/R. Results Diabetic rats subjected to MI/R exhibited larger infarct area, more severe oxidative injury concomitant with significantly reduced cardiac DJ-1 expression and increased PTEN expression as compared to non-diabetic rats. AAV9-mediated cardiac DJ-1 overexpression, but not the cardiac overexpression of DJ-1 mutant C106S, restored IPostC-induced cardioprotection and this effect was accompanied by increased cytoplasmic DJ-1 translocation toward nuclear and mitochondrial, reduced PTEN expression, and increased Nrf-2/HO-1 transcription. Our further study showed that AAV9-mediated targeted DJ-1 gene knockdown aggravated MI/R injury in diabetic hearts, and this exacerbation of MI/R injury was partially reversed by IPostC in the presence of PTEN inhibition or Nrf-2 activation. Conclusions These findings suggest that DJ-1 preserves the cardioprotective effect of IPostC against MI/R injury in diabetic rats through nuclear and mitochondrial DJ-1 translocation and that inhibition of cardiac PTEN and activation of Nrf-2/HO-1 may represent the major downstream mechanisms whereby DJ-1 preserves the cardioprotective effect of IPostC in diabetes. Graphical abstract

Abstract Background Chronic obstructive pulmonary disease (COPD) is a frequently diagnosed yet treatable condition, provided it is identified early and managed effectively. This study aims to develop an advanced COPD diagnostic model by integrating deep learning and radiomics features. Methods We utilized a dataset comprising CT images from 2,983 participants, of which 2,317 participants also provided epidemiological data through questionnaires. Deep learning features were extracted using a Variational Autoencoder, and radiomics features were obtained using the PyRadiomics package. Multi-Layer Perceptrons were used to construct models based on deep learning and radiomics features independently, as well as a fusion model integrating both. Subsequently, epidemiological questionnaire data were incorporated to establish a more comprehensive model. The diagnostic performance of standalone models, the fusion model and the comprehensive model was evaluated and compared using metrics including accuracy, precision, recall, F1-score, Brier score, receiver operating characteristic curves, and area under the curve (AUC). Results The fusion model exhibited outstanding performance with an AUC of 0.952, surpassing the standalone models based solely on deep learning features (AUC = 0.844) or radiomics features (AUC = 0.944). Notably, the comprehensive model, incorporating deep learning features, radiomics features, and questionnaire variables demonstrated the highest diagnostic performance among all models, yielding an AUC of 0.971. Conclusion We developed and implemented a data fusion strategy to construct a state-of-the-art COPD diagnostic model integrating deep learning features, radiomics features, and questionnaire variables. Our data fusion strategy proved effective, and the model can be easily deployed in clinical settings. Trial registration Not applicable. This study is NOT a clinical trial, it does not report the results of a health care intervention on human participants.

Stress granules (SGs) will be produced when the body is under external stimuli, and SGs play an important role in the pathogenesis of more and more diseases. The study on SGs has generally grown to a comprehensive subject in the past 35 years (from 1988 to 2022). The bibliometric analysis was used to comprehensively analyze the progress and development trend of SGs research. The literature output in the field of peritoneal dialysis showed a fluctuating growth in the past 35 years, and the last five years were the peak period of literature output. Journal of virology was the most widely published journal on SGs. And the most common research category was Biochemistry Molecular Biology. No matter in terms of the number of papers, citation frequency, H-index, or the distribution of journals and funding sources, the United States was far away from leading. With the enhancement of economic and scientific research strength, China has gradually carried out research on SGs. However, the citation frequency and H-index of Chinese papers were relatively low. Research cooperation between research institutions was relatively close, but domestic research institutions had less cooperation with relevant international institutions. The cooperation among authors was relatively scattered, and further exchanges and cooperation between scholars were needed for Chinese scholars. There are more and more reports about SGs, but there was still a big gap between China and the United States in the study of SGs.

Abstract The blood urea nitrogen to albumin ratio (BAR) has been demonstrated as a prognostic factor in sepsis and respiratory diseases, yet its role in severe coronary heart disease (CHD) remains unexplored. This retrospective study, utilizing data from the Medical Information Mart for Intensive Care-IV database, included 4254 CHD patients, predominantly male (63.54%), with a median age of 74 years (IQR 64–83). Primary outcomes included in-hospital, 28-day and 1-year all-cause mortality after ICU admission. The Kaplan–Meier curves, Cox regression analysis, multivariable restricted cubic spline regression were employed to assess association between BAR index and mortality. In-hospital, within 28-day and 1-year mortality rates were 16.93%, 20.76% and 38.11%, respectively. Multivariable Cox proportional hazards analysis revealed associations between the increased BAR index and higher in-hospital mortality (HR 1.11, 95% CI 1.02–1.21), 28-day mortality (HR 1.17, 95% CI 1.08–1.27) and 1-year mortality (HR 1.23, 95% CI 1.16–1.31). Non-linear relationships were observed for 28-day and 1-year mortality with increasing BAR index (both P for non-linearity

Abstract Machine learning‐based approaches demonstrate a significant potential in radar quantitative precipitation estimation (QPE) applications. In contrast to conventional methods that depend on local raindrop size distributions, deep learning (DL) can establish an effective mapping from three‐dimensional radar observations to ground rain rates. However, the lack of transparency in DL models poses challenges toward understanding the underlying physical mechanisms that drive their outcomes. This study aims to develop a DL‐based QPE system and provide a physical explanation of radar precipitation estimation process. This research is designed by employing a deep neural network consisting of two modules. The first module is a quantitative precipitation estimation network that has the capability to learn precipitation patterns and spatial distribution from multidimensional polarimetric radar observations. The second module introduces a quantitative precipitation estimation shapley additive explanations method to quantify the influence of each radar observable on the model estimate across various precipitation intensities.

Background: Ventilator-associated pneumonia (VAP) causes heavy losses in terms of finances, hospitalization, and death for elderly patients in the intensive care unit (ICU); however, the risk is difficult to evaluate due to a lack of reliable assessment tools. We aimed to create and validate a nomogram to estimate VAP risk to provide early intervention for high-risk patients. Methods: Between January 2016 and March 2021, 293 patients from a tertiary hospital in China were retrospectively reviewed as a training set. Another 84 patients were enrolled for model validation from April 2021 to February 2022. Least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression analysis were employed to select predictors, and a nomogram model was constructed. The calibration, discrimination, and clinical utility of the nomogram were verified. Finally, a web-based online scoring system was created to make the model more practical. Results: The predictors were hypoproteinemia, long-term combined antibiotic use, intubation time, length of mechanical ventilation, and tracheotomy/intubation. The area under the curve (AUC) was 0.937 and 0.925 in the training and validation dataset, respectively, suggesting the model exhibited effective discrimination. The calibration curve demonstrated high consistency with the observed result and the estimated values. Decision curve analysis (DCA) demonstrated that the nomogram was clinically applicable. Conclusions: We have created a novel nomogram model that can be utilized to anticipate VAP risk in elderly ICU patients, which is helpful for healthcare professionals to detect patients at high risk early and adopt protective interventions.

Abstract CRISPR-mediated knock-in (KI) technology opens a new era of fluorescent-protein labeling in zebrafish, a preferred model organism for in vivo imaging. We described here an optimized zebrafish gene-tagging strategy, which enables easy and high-efficiency KI, ensures high odds of obtaining seamless KI germlines and is suitable for wide applications. Plasmid donors for 3′-labeling were optimized by shortening the microhomologous arms and by reducing the number and reversing the sequence of the consensus Cas9/sgRNA binding sites. To allow for scar-less KI across the genome, linearized dsDNA donors with 5′-chemical modifications were generated and successfully incorporated into our method. To refine the germline screen workflow and expedite the screen process, we combined fluorescence enrichment and caudal-fin junction-PCR. Furthermore, to trace proteins expressed at a low abundance, we developed a fluorescent signal amplifier using the transcriptional activation strategy. Together, our strategies enable efficient gene-tagging and sensitive expression detection for almost every gene in zebrafish.

Summary: Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality, with metastasis being the primary determinant of poor prognosis in patients. Investigating the molecular mechanisms underlying CRC metastasis is currently a prominent and challenging area of research. Exosomes, as crucial intercellular communication mediators, facilitate the transfer of metabolic and genetic information from cells of origin to recipient cells. Their roles in mediating information exchange between CRC cells and immune cells, fibroblasts, and other cell types are pivotal in reshaping the tumor microenvironment, regulating key biological processes such as invasion, migration, and formation of pre-metastatic niche. This article comprehensively examines the communication function and mechanism of exosomes derived from different cells in cancer metastasis, while also presenting an outlook on current research advancements and future application prospects. The aim is to offer a distinctive perspective that contributes to accurate diagnosis and rational treatment strategies for CRC.

Melittin, a classical antimicrobial peptide, is a highly potent antitumor agent. However, its significant toxicity seriously hampers its application in tumor therapy. In this study, we developed novel melittin analogs with pH-responsive, cell-penetrating and membrane-lytic activities by replacing arginine and lysine with histidine. After conjugation with camptothecin (CPT), CPT-AAM-1 and CPT-AAM-2 were capable of killing tumor cells by releasing CPT at low concentrations and disrupting cell membranes at high concentrations under acidic conditions. Notably, we found that the C-terminus of the melittin analogs was more suitable for drug conjugation than the N-terminus. CPT-AAM-1 significantly suppressed melanoma growth in vivo with relatively low toxicity. Collectively, the present study demonstrates that the development of antitumor drugs based on pH-responsive antimicrobial peptide-drug conjugates is a promising strategy.

Abstract Fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) are key indicators reflecting blood glucose control in type 2 diabetes mellitus (T2DM) patients. The purpose of this study is to establish a predictive model for blood glucose changes in T2DM patients after 3 months of treatment, achieving personalized treatment.A retrospective study was conducted on type 2 diabetes mellitus real-world medical data from 4 cities in Sichuan Province, China from January 2015 to December 2020. After data preprocessing, data inputting, data sampling, and feature screening, 16 kinds of machine learning methods were used to construct prediction models, and 5 prediction models with the best prediction performance were screened respectively. A total of 100,000 cases were included to establish the FBG model, and 2,169 cases were established to establish the HbA1c model. The best prediction model both of FBG and HbA1c finally obtained are realized by ensemble learning and modified random forest inputting, the AUC values are 0.819 and 0.970, respectively. The most important indicators of the FBG and HbA1c prediction model were FBG and HbA1c. Medication compliance, follow-up outcome, dietary habits, BMI, and waist circumference also had a greater impact on FBG levels. The prediction accuracy of the models of the two blood glucose control indicators is high and has certain clinical applicability.HbA1c and FBG are mutually important predictors, and there is a close relationship between them.

Abstract Background Aging is a dynamic and heterogeneous process that may better be captured by trajectories of aging biomarkers. Biological age has been advocated as a better biomarker of aging than chronological age, and plant-based dietary patterns have been found to be linked to aging. However, the associations of biological age trajectories with mortality and plant-based dietary patterns remained unclear. Methods Using group-based trajectory modeling approach, we identified distinctive aging trajectory groups among 12,784 participants based on a recently developed biological aging measure acquired at four-time points within an 8-year period. We then examined associations between aging trajectories and quintiles of plant-based dietary patterns assessed by overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI) among 10,191 participants who had complete data on dietary intake, using multivariable multinomial logistics regression adjusting for sociodemographic and lifestyles factors. Cox proportional hazards regression models were applied to investigate the association between aging trajectories and all-cause mortality. Results We identified three latent classes of accelerated aging trajectories: slow aging, medium-degree, and high-degree accelerated aging trajectories. Participants who had higher PDI or hPDI had lower odds of being in medium-degree (OR = 0.75, 95% CI: 0.65, 0.86 for PDI; OR = 0.73, 95% CI: 0.62, 0.85 for hPDI) or high-degree (OR = 0.63, 95% CI: 0.46, 0.86 for PDI; OR = 0.62, 95% CI: 0.44, 0.88 for hPDI) accelerated aging trajectories. Participants in the highest quintile of uPDI were more likely to be in medium-degree (OR = 1.72, 95% CI: 1.48, 1.99) or high-degree (OR = 1.70, 95% CI: 1.21, 2.38) accelerated aging trajectories. With a mean follow-up time of 8.40 years and 803 (6.28%) participants died by the end of follow-up, we found that participants in medium-degree (HR = 1.56, 95% CI: 1.29, 1.89) or high-degree (HR = 3.72, 95% CI: 2.73, 5.08) accelerated aging trajectory groups had higher risks of death than those in the slow aging trajectory. Conclusions We identified three distinctive aging trajectories in a large Asian cohort and found that adopting a plant-based dietary pattern, especially when rich in healthful plant foods, was associated with substantially lowered pace of aging.

Abstract Background Higher fasting plasma glucose (FPG) levels were associated with an increased risk of all-cause mortality; however, the associations between long-term FPG trajectory groups and mortality were unclear, especially among individuals with a normal FPG level at the beginning. The aims of this study were to examine the associations of FPG trajectories with the risk of mortality and identify modifiable lifestyle factors related to these trajectories. Methods We enrolled 50,919 individuals aged ≥ 20 years old, who were free of diabetes at baseline, in the prospective MJ cohort. All participants completed at least four FPG measurements within 6 years after enrollment and were followed until December 2011. FPG trajectories were identified by group-based trajectory modeling. We used Cox proportional hazards models to examine the associations of FPG trajectories with mortality, adjusting for age, sex, marital status, education level, occupation, smoking, drinking, physical activity, body mass index, baseline FPG, hypertension, dyslipidemia, cardiovascular disease or stroke, and cancer. Associations between baseline lifestyle factors and FPG trajectories were evaluated using multinomial logistic regression. Results We identified three FPG trajectories as stable (n = 32,481), low-increasing (n = 17,164), and high-increasing (n = 1274). Compared to the stable group, both the low-increasing and high-increasing groups had higher risks of all-cause mortality (hazard ratio (HR) = 1.18 (95% CI 0.99–1.40) and 1.52 (95% CI 1.09–2.13), respectively), especially among those with hypertension. Compared to participants with 0 to 1 healthy lifestyle factor, those with 6 healthy lifestyle factors were more likely to be in the stable group (ORlow-increasing = 0.61, 95% CI 0.51–0.73; ORhigh-increasing = 0.20, 95% CI 0.13–0.32). Conclusions Individuals with longitudinally increasing FPG had a higher risk of mortality even if they had a normal FPG at baseline. Adopting healthy lifestyles may prevent individuals from transitioning into increasing trajectories.

Abstract Background The cause of aggravation of diabetic myocardial damage is yet to be elucidated; damage to mitochondrial function has been a longstanding focus of research. During diabetic myocardial ischaemia–reperfusion (MI/R), it remains unclear whether reduced mitochondrial fusion exacerbates myocardial injury by generating free damaged mitochondrial DNA (mitoDNA) and activating the cGAS-STING pathway. Methods In this study, a mouse model of diabetes was established (by feeding mice a high-fat diet (HFD) plus a low dose of streptozotocin (STZ)), a MI/R model was established by cardiac ischaemia for 2 h and reperfusion for 30 min, and a cellular model of glycolipid toxicity induced by high glucose (HG) and palmitic acid (PA) was established in H9C2 cells. Results We observed that altered mitochondrial dynamics during diabetic MI/R led to increased mitoDNA in the cytosol, activation of the cGAS-STING pathway, and phosphorylation of the downstream targets TBK1 and IRF3. In the cellular model we found that cytosolic mitoDNA was the result of reduced mitochondrial fusion induced by HG and PA, which also resulted in cGAS-STING signalling and activation of downstream targets. Moreover, inhibition of STING by H-151 significantly ameliorated myocardial injury induced by MFN2 knockdown in both the cell and mouse models. The use of a fat-soluble antioxidant CoQ10 improved cardiac function in the mouse models. Conclusions Our study elucidated the critical role of cGAS-STING activation, triggered by increased cytosolic mitoDNA due to decreased mitochondrial fusion, in the pathogenesis of diabetic MI/R injury. This provides preclinical insights for the treatment of diabetic MI/R injury. Video Abstract Graphical Abstract

The endoplasmic reticulum (ER) played an important role in the folding, assembly and post-translational modification of proteins. ER homeostasis could be disrupted by the accumulation of misfolded proteins, elevated reactive oxygen species (ROS) levels, and abnormal Ca2+ signaling, which was referred to ER stress (ERS). Ferroptosis was a unique programmed cell death model mediated by iron-dependent phospholipid peroxidation and multiple signaling pathways. The changes of mitochondrial structure, the damage of glutathione peroxidase 4 (GPX4) and excess accumulation of iron were the main characteristics of ferroptosis. ROS produced by ferroptosis can interfere with the activity of protein-folding enzymes, leading to the accumulation of large amounts of unfolded proteins, thus causing ERS. On the contrary, the increase of ERS level could promote ferroptosis by the accumulation of iron ion and lipid peroxide, the up-regulation of ferroptosis related genes. At present, the studies on the relationship between ferroptosis and ERS were one-sided and lack of in-depth studies on the interaction mechanism. This review aimed to explore the molecular mechanism of cross-talk between ferroptosis and ERS, and provide new strategies and targets for the treatment of liver diseases.

Kermesite (Sb2S2O), a needle-like unstable secondary oxysulfide, has made visible advancements in optimizing its triclinic crystal system through twinning discovery. However, research on twinning behavior at micro and nano scales, including its growth mechanisms and impact on kermesite morphologies, remains notably scarce. Our study focuses on kermesite crystal clusters from a private collection in Yunnan, China, confirming the chemical formula as Sb2S1.97O1.03 through EPMA. Single-crystal XRD yielded refined unit cell parameters (a = 8.153(5) Å, b = 10.717(7) Å, c = 5.796(3) Å; α = 102.836(10)°, β = 110.556(8)°, γ = 100.999(12)°), revealing space group P1¯ with Z = 4 and indicating twinning with a ratio of 27.4%. Remarkably, a Transmission Electron Microscope (TEM) provided the first direct observation of twinning in natural kermesite, revealing rotational twins with varying widths and lengths (ranging from 100 nm to several millimeters). Analysis and simulation elucidated that rotational twins, generated by a 180° rotation, align with the mineral’s elongation direction along the [Sb2S2O4]n chains (a-axis), challenging the conventional long-axis direction (b-axis) for crystal growth. This study proposes a symbiotic relationship between kermesite growth and twinning, suggesting that the observed X-shaped growth in crystal clusters results from the collaboration of single crystals (growing along b) and twins (growing along a) in the unit cell. These findings contribute to our understanding of kermesite’s structural complexities and the potential growth and formation mechanism of crystal clusters.

Background: Greenness surrounding residential places has been found to significantly reduce the risk of diseases such as hypertension, obesity, and metabolic syndrome (MetS). However, it is unclear whether visible greenness exposure at the workplace has any impact on the risk of MetS. Methods: Visible greenness exposure was assessed using a Green View Index (GVI) based on street view images through a convolutional neural network model. We utilized logistic regression to examine the cross-sectional association between GVI and MetS as well as its components among 51,552 adults aged 18–60 in the city of Hangzhou, China, from January 2018 to December 2021. Stratified analyses were conducted by age and sex groups. Furthermore, a scenario analysis was conducted to investigate the risks of having MetS among adults in different GVI scenarios. Results: The mean age of the participants was 40.1, and 38.5% were women. We found a statistically significant association between GVI and having MetS. Compared to the lowest quartile of GVI, participants in the highest quartile of GVI had a 17% (95% CI: 11–23%) lower odds of having MetS. The protective association was stronger in the males, but we did not observe such differences in different age groups. Furthermore, we found inverse associations between GVI and the odds of hypertension, low high-density lipoprotein cholesterol, obesity, and high levels of FPG. Conclusions: Higher exposure to outdoor visible greenness in the workplace environment might have a protective effect against MetS.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is considered a “multisystem” disease that simultaneously suffers from metabolic diseases and hepatic steatosis. Some may develop into liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Given the close connection between metabolic diseases and fatty liver, it is urgent to identify drugs that can control metabolic diseases and fatty liver as a whole and delay disease progression. Ferroptosis, characterized by iron overload and lipid peroxidation resulting from abnormal iron metabolism, is a programmed cell death mechanism. It is an important pathogenic mechanism in metabolic diseases or fatty liver, and may become a key direction for improving MASLD. In this article, we have summarized the physiological and pathological mechanisms of iron metabolism and ferroptosis, as well as the connections established between metabolic diseases and fatty liver through ferroptosis. We have also summarized MASLD therapeutic drugs and potential active substances targeting ferroptosis, in order to provide readers with new insights. At the same time, in future clinical trials involving subjects with MASLD (especially with the intervention of the therapeutic drugs), the detection of serum iron metabolism levels and ferroptosis markers in patients should be increased to further explore the efficacy of potential drugs on ferroptosis.

Objective: To explore the regulating function of the dietary fiber of Agaricus bisporus and the powder of Agaricus bisporus on the human gut microbiota. Methods: Dietary fiber of Agaricus bisporus were extracted by water extraction and alcohol precipitation for human gut microbial fermentation in vitro. The pH, gas production and short-chain fatty acid contents of metabolites were determined. The V4 region of fecal microorganisms was enriched and sequenced by IlluminaPE250 sequencing platform. Results: Taking fructo-oligosaccharide as the positive control group and without dietary fiber as the blank control group, during the in vitro fermentation process, with the increase of time, the pH value of the Agaricus bisporus dietary fiber group decreased from 6.93 to 4.48, and the pH value of the powder of Agaricus bisporus decreased from 6.93 to 4.86. With the increasing of time, compared with the blank group, the gas production of the Agaricus bisporus dietary fiber group and the powder of Agaricus bisporus group increased by 3.4 and 1.9 mL. After 24 hours of in vitro fermentation, it was found that compared with the positive control group, the richness and diversity of the human gut microbiota in the Agaricus bisporus dietary fiber group and the powder of Agaricus bisporus group were relatively higher. Compared with the blank group, dietary fiber of Agaricus bisporus group was more conducive to the production of acetic acid (34.3 mmol/L) and propionic acid (7.6 mmol/L) by human gut microbiota and promoted the growth of beneficial bacteria of Bifidobacterium. The powder of Agaricus bisporus group was more conducive to producing acetic acid (39.4 mmol/L) and promoting the growth of Enterobacter. Compared with the positive control group, the production of propionic acid in the Agaricus bisporus dietary fiber group and the powder of Agaricus bisporus group was relatively higher. Conclusion: Both the dietary fiber of the Agaricus bisporus and the powder of Agaricus bisporus could be effectively utilized by the human gut microbiota to produce short-chain fatty acids and increase the relative abundance of beneficial bacteria. Compared with blank group, dietary fiber of Agaricus bisporus added in experimental group had the best results, which had an effective prebiotic regulation function on human gut microbiota.

Succinate, one of the intermediates of the tricarboxylic acid cycle, is now recognized to play a role in a broad range of physiological and pathophysiological settings, but its role in adipogenesis is unclear. Our study used Bama miniature pigs as a model to explore the effects of succinate on performance, meat quality, and fat formation. The results showed that adding 1% succinate significantly increased the average daily gain, feed/gain ratio, eye muscle area, and body fat content (p < 0.05), but had no effect on feed intake. Further meat quality analysis showed that succinate increased the marbling score and intramuscular fat content of longissimus dorsi muscle (LM), while decreasing the shear force and the cross-sectional area of LM (p < 0.05). Metabolomics analysis of LM revealed that succinate reshaped levels of fatty acids, triglycerides, glycerophospholipids, and sphingolipids in LM. Succinate promotes adipogenic differentiation in porcine primary preadipocytes. Finally, dietary succinate supplementation increased succinylation modification rather than acetylation modification in the adipose tissue pool. This study elucidated the effects of succinate on the growth and meat quality of pigs and its mechanism of action and provided a reference for the role of succinate in the nutrition and metabolism of pigs.

Abstract Background Standardized patient (SP) simulations are well-recognized patterns for practicing clinical skills and interactions. Our previous study showed that a simulation program using occupational SP for Traditional Chinese Medicine (OSP-TCMs) was efficient, however, a high cost and time-intensive nature have limited its use. TCM postgraduates trained as student SPs (SSP-TCMs) present a potentially cost-effective alternative. The purpose of this study was to examine and determine whether SSP simulation offered more benefits over didactic training alone for improving clinical competency among TCM medical students, and conduct a multifaceted analysis comparing SSP-TCMs and OSP-TCMs. Methods This was a prospective, single-blinded, randomized controlled trial. Fourth-year TCM undergraduates were recruited as trainees from the Clinical Medical School, Chengdu University of TCM. Data were collected from September 2018 to December 2020. Trainees were randomly divided into the three following groups: traditional method training group, OSP-TCM training group, and SSP-TCM training group (1:1:1). At the end of a 10-week curriculum, trainees received a two-station examination comprising a systematic online knowledge test and an offline clinical performance examination. Post-training and post-exam questionnaires were administered to collect feedback from these trainees. Results Students assigned to the SSP-TCM training and OSP-TCM training groups received favorable marks for the “systematic knowledge test” and “TCM clinical skills” (2018, Pa=0.018, Pb=0.042; 2019, Pa=0.01, Pb=0.033; 2020, Pa=0.035, Pb=0.039) compared to the TM trainees. Additionally, trainees in the intervention groups demonstrated a positive post-training edge in scores of “medical records” (2018, Pa=0.042, Pb=0.034; 2019, Pa=0.032, Pb=0.042; 2020, Pa=0.026, Pb=0.03) and “TCM syndrome differentiation and therapeutic regimen” (2018, Pb=0.032; 2019, Pa=0.037, Pb=0.024; 2020, Pa=0.036, Pb=0.043). For the simulation encounter assessment given by SP-TCMs, OSP-TCM trainees and SSP-TCM trainees scored higher than TM trainees (2018, Pa=0.038, Pb=0.037; 2019, Pa=0.024, Pb=0.022; 2020, Pa=0.019, Pb=0.021). For the feedback questionnaires, the students in TM group provided less positive feedback for training efficacy and test performance compared to those in the SSP-TCM and OSP-TCM groups. The trainees responded that the training effect of clinical simulations was similar between the SSP-TCM and OSP-TCM groups. SSP-TCMs were more responsive to unexpected emergencies (Pa=0.022, Pb>0.05) and more likely to encourage questioning (Pa=0.029, Pb>0.05) but tended to provide implied hints (Pc=0.015) and utilize medical jargon (Pc=0.007) as compared to OSP-TCMs. Conclusion Simulation training for SSP-TCMs and OSP-TCMs showed great benefits for enhancing clinical competency. SSP-TCM simulation was feasible, practical, and cost-effective, and may serve as an alternative method to OSP-TCM simulation.

Since wolframite is usually associated with calcite, the separation and enrichment of wolframite by froth flotation remains a great challenge. Herein, a novel trisiloxane surfactant N-(2-aminoethyl)-3-aminopropyltrisiloxane (AATS) was successful synthesized, which was used for the separation of wolframite from calcite for the first time. The flotation separation performance of AATS was studied by flotation test, and its adsorption mechanism was explored based on contact angle, infrared spectrum analysis (FTIR), zeta potential and density functional theory (DFT) calculation. The results of micro-flotation test and binary mixed ore flotation test pointed that AATS had excellent selectivity and more prominent collection capacity for the flotation of wolframite when compared with industrial reagent sodium oleate (NaOL). The measurement results of contact angle proved that AATS improved the hydrophobicity of the wolframite surface. The highly selective adsorption mechanism of AATS surfactant on mineral surfaces were further researched and analyzed by FTIR and zeta potential. The results revealed that AATS surfactant had significant adsorption effect on wolframite, yet almost no adsorption on calcite. DFT calculation indicated that AATS produced electrostatic adsorption with wolframite surface through —N+H3 group.

Wind power converter (WPC) is a key part of a wind power unit which delivers electric energy to power grid. Because of a large number of semiconductors, WPC has a high failure rate. This paper proposes a method to accurately evaluate the reliability of WPC, which is crucial for the design and maintenance of wind turbines. Firstly, the index of effective temperature (ET) is presented to quantify the effects of temperature and humidity on the semiconductor operation. A novel method is proposed to evaluate the lifetime and calculate the aging failure rates of the semiconductors considering the fluctuations of ET. Secondly, the failure mode and effect analysis (FMEA) of WPC is investigated based on the topology and control scheme. The conventional two-state reliability model of the WPC is extended to the multi-state reliability model where the partial working state under the fault-tolerant control scheme is allowed. Finally, a reliability evaluation framework is established to calculate the parameters of the WPC reliability model considering the variable failure rates and repair activities of semiconductors. Case studies are designed to verfify the proposed method using a practical wind turbine.

Abstract Introduction Trastuzumab, as the gold standard for HER2-positive BC treatment, was the first-line HER2 targeted drug. However, some studies reported patients benefited more from lapatinib and lapatinib plus trastuzumab therapy than standard trastuzumab therapy. This study presents an update of a systematic review and meta-analysis involving comparison of lapatinib and lapatinib plus trastuzumab therapy versus trastuzumab therapy. Aim We determined whether trastuzumab plus lapatinib or lapatinib therapy is not inferior to trastuzumab therapy in HER2-positive breast cancer patients. Methods Relevant trials were searched in CNKI, Wanfang, VIP, Sinomed, PubMed, Embase, and Cochrane CENTRAL databases from inception until October 25, 2021. Primary outcomes were OS, DFS/EFS, and PFS while secondary outcomes were pCR (ypT0/is ypN0), pCR (ypT0/is ypN0/+), ORR, DCR, rate of BCS, RFS, cardiac toxicities, and other toxicities. Results Thirteen randomized controlled trials were included in this study. Trastuzumab combined with lapatinib therapy was found to be superior to standard trastuzumab therapy alone with regard to overall survival, disease-free survival/event-free survival, pathologic complete response (ypT0/is ypN0), pathologic complete response (ypT0/is ypN0/+), recurrence-free survival, higher incidences of diarrhea, and rash/skin toxicity. Lapatinib therapy was established to be inferior to trastuzumab therapy in overall survival, progression-free survival, disease-free survival/event-free survival, pathologic complete response (ypT0/is ypN0) and pathologic complete response (ypT0/is ypN0/+), diarrhea, and rash/skin toxicity and had a low incidence of left ventricular ejection fraction decline. Conclusions The efficacy of trastuzumab combined with lapatinib therapy is superior to standard trastuzumab therapy alone; however, it has more non-cardiac grade III/IV toxicities. Moreover, the efficacy of lapatinib therapy is inferior to that of standard trastuzumab therapy alone.

Discovery of the Siah Diq porphyry (Cu–Au) prospect in the foothill of Dam Koh volcano is a recent exploration success story of mineralization buried under a 46 m alluvium cover in an exploratory mature Chagai belt. Acquisition of geophysical data followed by drilling and logging was key in the discovery. Integrated magnetics and induced polarization (IP) surveys in an area of 7.5 km2, pointed out magnetic-low, IP-high, and resistivity-low anomalies corresponding to porphyry Cu–Au type sulfide mineralization. Three bore holes were drilled to test the geophysical anomalies. After careful observation and geoscientific logging of core, porphyry style Cu–Au mineralization was revealed. The porphyry prospect was further characterized based on host rock lithology, petrography, alteration mineralogy, ore vein characterization, and Cu/Au geochemical assays based on core samples. Rocks hosting the mineralization include andesite, granodiorite, coarse, as well as fine grained diorite and pink granite, all highly altered, mineralized and porphyritic. Propylitic alteration was dominant in all the three bore holes and developed earlier followed by phyllic, potassic, and argillic alterations. Sulfide mineralization is present as cross-cutting stockwork veins and disseminations. Average copper and gold assays of drill core are 0.17% Cu and 0.78 ppm Au, respectively. Economically insignificant values of molybdenum and silver have been noted in some samples.

Eukaryotic cells are stimulated by external pressure such as that derived from heat shock, oxidative stress, nutrient deficiencies, or infections, which induce the formation of stress granules (SGs) that facilitates cellular adaptation to environmental pressures. As aggregated products of the translation initiation complex in the cytoplasm, SGs play important roles in cell gene expression and homeostasis. Infection induces SGs formation. Specifically, a pathogen that invades a host cell leverages the host cell translation machinery to complete the pathogen life cycle. In response, the host cell suspends translation, which leads to SGs formation, to resist pathogen invasion. This article reviews the production and function of SGs, the interaction between SGs and pathogens, and the relationship between SGs and pathogen-induced innate immunity to provide directions for further research into anti-infection and anti-inflammatory disease strategies.

BackgroundTai Chi Chuan (TCC) may have a positive impact on physical and psychological well-being in breast cancer patients, but the evidence remains limited and inconclusive. This systematic review aims to evaluate the effects of TCC on the quality of life (QoL) and psychological symptoms in women patients with breast cancer.MethodsThis review has been registered on PROSPERO (ID: CRD42019141977). Randomized controlled trials (RCTs) of TCC for breast cancer were searched from eight major English and Chinese databases. All trials included were analyzed in accordance with the Cochrane Handbook. The primary outcomes were QoL, anxiety, and depression in patients with breast cancer. Fatigue, sleep quality, cognitive function, and inflammatory cytokine were the secondary outcomes.ResultsFifteen RCTs involving a total of 1,156 breast cancer participants were included in this review. The methodological quality of included trials was generally poor. The pooled results suggested that TCC-based exercise could significantly improve QoL [standardized mean difference (SMD)=0.35, 95%CI: 0.15–0.55, I2 = 0, model: fixed, IV], anxiety [weighted mean difference (WMD)=−4.25, 95%CI: −5.88 to −2.63, I2 = 0, model: fixed, IV], and fatigue (SMD=−0.87, 95%CI: −1.50 to −0.24, I2 = 80.9%, model: random, DL) compared other controls, with moderate to low certainty of evidence. The improvement of QoL and fatigue by TCC was also clinically meaningful. However, TCC-based exercise failed to show any between-group differences in depression, sleep quality, cognitive function, and inflammatory cytokine. Post-hoc analysis revealed that TCC-based exercise outperformed the other exercise in improving shoulder function with very low certainty of evidence.ConclusionOur findings manifested that TCC-based exercise is helpful for improving the QoL, anxiety, and fatigue in patients with breast cancer within the range of comparisons covered in this study. However, the results must be treated with great caution because of the methodological flaws of included trials. Larger, well-designed, and conducted randomized controlled trials with longer follow-up is warranted in the future to evaluate the important outcomes of TCC for breast cancer.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019141977, identifier, CRD42019141977.

Abstract Background Our study aimed to explore the associations between solid fuels burning for either heating or cooking and all-cause mortality based on 2859 participants from the China Health and Retirement Longitudinal Study during 2011–2018. Methods Logistic regression models were performed to estimate the risk for all-cause mortality between different types of fuels in the current longitudinal study. Furthermore, the combined impacts of applying solid fuels for both cooking and heating and the effect among those who switched types of fuels in cooking or heating during follow-up were also analyzed. Interaction and stratification analysis by covariables was applied further to explore the relationship between fuel burning and all-cause mortality. Results After full-adjustment, usage of solid fuels was associated with higher all-cause mortality (for heating: OR = 1.93, 95% CI = 1.25, 3.00; for cooking: OR = 1.76, 95% CI = 1.10, 2.82). Using solid fuels for both cooking and heating (OR = 2.36; 95% CI, 1.38, 4.03) was associated with a higher risk of all-cause mortality, while using solid fuels with a single purpose was not (OR = 1.52; 95% CI, 0.90, 2.55). Protective tendencies were detected in switching solid to clean fuel for cooking (OR = 0.62; 95% CI, 0.32, 1.17) and heating (OR = 0.62; 95% CI, 0.35, 1.10). Conclusion Either cooking or heating with solid fuels increases the risk of all-cause mortality among Chinese mid-aged and aging people in the urban area of China.

Abstract Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our approach to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, allowing us to learn new features and expand to other cancer types as training cohorts grow.

Abstract Background Current data indicate that supplements such as folic acid and vitamin B may be beneficial in halting and even reversing atrophic gastritis, intestinal metaplasia and intraepithelial neoplasia, generally referred to as gastric precancerous conditions(GPC). However, there is no Meta-analysis article to evaluate the prevention and treatment of folic acid in the gastric precancerous conditions. We therefore conducted a meta-analysis to confirm the efficacy of folic acid in treating GPC. Methods Using a systematic review method, consider randomized controlled trials (RCT), including clinical trial reports, unpublished clinical trial data, and conference papers. The search time was been set from the database’s establishment to June 2, 2021. The language was not limited, using PubMed, SinoMed, Lancet, Web of Science, CNKI, Cochrane, Ovid, Science Direct, Embase, and EBSCO databases. Data were extracted using a pre-designed extraction tool and analysis was undertaken using RevMan5.2.Besides,we use Origin software to construct the Time-dose interval analysis. Results Of the 225 records identified, 13 studies involving 1252 patients (including 11 clinical controlled trials, 1 conference paper report and 1 unpublished research report) met the inclusion conditions. Folic acid dose maintained at 20–30 mg / d for 3–6 months may be beneficial to pathological changes of GPC. Moreover, in the 3 month treatment of 5 trials, the effect was more obvious when the folic acid dose was maintained at 30 mg / d. In the 7 trials, the symptom ineffective rate of GPC treated with folic acid was 32% (RR:0.32, 95% confidence interval CI:0.21–0.48), which was combined using a fixed analysis model; The effect of folic acid on gastric mucosal atrophy in 5 trials (RR: 1.61, 95%CI 1.07–2.41). The changes of folic acid on intestinal metaplasia in the 2 experiments (RR: 1.77, 95% CI: 1.32–2.37).The 2 results are combined using a fixed analytical model. However, the subgroup analysis of 9 trials revealed no significant effectiveness of symptom. Conclusions Our research showed that folic acid supplementation brings benefits in preventing and even reversing the progression of GPC in the stomach, and provided evidence for its potential clinical use in management of GPC. Registration: The logn number of our Meta-anlysis on PROSPERO is CRD420223062.

Abstract Overhead line conductors can generate audible noise across a wide frequency spectrum as a result of elevated electric fields at the conductor surface. Such fields are enhanced by the presence of surface defects, insects, water drops and pollution. Within this paper, the impact of a superhydrophobic coating on the audible noise produced by an overhead line conductor is examined. Noise levels from a conductor coated with a superhydrophobic coating were compared to those from a bare conductor in a semi‐anechoic chamber. The conductors were energised at voltages to provide surface electric fields ranging from 6 kV/cm to 21 kV/cm (rms). With a continuous water spray system depositing droplets on the conductor surface, the frequency domain sound pressure level, overall sound pressure levels and corona discharge magnitude were measured. It is demonstrated that the use of a superhydrophobic coating reduced audible noise levels and corona discharge magnitude, especially at electric fields above 14 kV/cm. The image analysis suggests that the water drop size distribution and the position of surface droplets on the conductor circumference play an important role in the magnitude of audible noise.

Abstract In this study, we investigated immunoreactivity of peanut (Arachis hypogaea) oil using the silkworm (Bombyx mori) model. The peanut oil induced melanin formation when injected to the silkworm hemocoel. We then purified the active substance and identified the triacylglycerols (TAGs) as the responsible molecule for the melanin-forming effect of peanut oil. Also, the peanut TAGs induced the muscle contraction of the silkworm (i.e., cleavage of the insect cytokine BmPP) and the TNF-α production by cultured mouse macrophage cells. The muscle contraction activity of the peanut TAGs was reduced by saponification reaction, indicating that the TAG (not the degraded fatty acids) moiety is responsible for the activity. The muscle contraction effects of other TAGs of olive, lard, and beef oil were comparable with that of peanut TAGs. Nevertheless, for the melanin formation, the effect of peanut TAGs was outstanding. The fatty acid composition of peanut TAGs was distinct from that of olive TAGs. These results suggest that TAGs are immunoreactive and induces cytokines both in insect and mammalian immune systems. Also, the differential effects of peanut and olive TAGs for the melanin formation may suggest that TAGs with different fatty acid compositions are distinguished by the immune system.

Abstract Background A lack of sleep or disorder in sleep–wake cycles has been associated with metabolic impairments. However, few studies have investigated the association between daytime napping duration and the risk of non-alcoholic fatty liver disease. This study aimed to investigate the association of daytime napping duration with the risk of non-alcoholic fatty liver disease in a Chinese population. Methods This cross-sectional study analyzed data from the Health Management Center of Nanfang Hospital, Guangdong Province. A total of 3363 participants aged 20–79 years were recruited and admitted from January 20, 2018, to October 16, 2020. Non-alcoholic fatty liver disease was diagnosed using abdominal ultrasonography. The outcome was the association between daytime sleep duration and the risk of non-alcoholic fatty liver disease. Results Compared with non-nappers, long daytime nappers (≥ 60 min) were associated with a higher risk of non-alcoholic fatty liver disease in the crude model (odds ratio 2.138; 95% confidence interval 1.88–2.61, P

IntroductionIt is critical to select subsequent treatments for patients after the failure of trastuzumab therapy. Following the failure of standard trastuzumab therapy guidelines in the Chinese Society of Clinical Oncology, pyrotinib and capecitabine is a grade I recommended regimen for treating patients with HER2-positive metastatic breast cancer. Concurrently, in treating patients with HER2-positive metastatic breast cancer, lapatinib and capecitabine are also recommended regimens for those who have previously received taxanes, anthracyclines, and trastuzumab therapy. However, there is currently no systematic review and meta-analysis comparing pyrotinib with lapatinib among HER2+ MBC patients. Therefore, this study aims to perform a systematic review and meta-analysis and assess whether pyrotinib is superior to lapatinib in efficacy and safety.MethodsRelevant trials were searched in CNKI, Wanfang, VIP, PubMed, Embase, and Cochrane CENTRAL databases from inception until March 27th, 2022. The primary outcomes were PFS and OS, and the secondary outcomes were ORR and grade ≥3 AEs.ResultsFive relevant studies were included in this study, including 2 RCTs and 3 retrospective cohort studies. Pyrotinib combined with chemotherapy is superior to lapatinib combined with chemotherapy among HER2+ metastatic breast cancer patients, with a significant improvement in PFS (prior trastuzumab therapy) (HR: 0.47, 95% CI: 0.39-0.57, pConclusionsThe efficacy of pyrotinib combined with chemotherapy is superior to lapatinib combined with chemotherapy but has more safety risks.

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized metastatic melanoma (MM) treatment in just a few years. Ultraviolet (UV) in sunlight is the most significant environmental cause of melanoma, which is considered to be the main reason for tumor mutation burden (TMB) increase in melanoma. High TMB usually predicts that PD-1 inhibitors are effective. The sunlight exposure pattern of MM might be a clinical feature that matches TMB. The relationship between sunlight exposure patterns and immunotherapy response in MM is unclear. This study aims to investigate the correlation between sunlight exposure patterns and immunotherapy response in MM and establish nomograms that predict 3- and 5-year overall survival (OS) rate.MethodsWe searched the Surveillance, Epidemiology, and End Results (SEER) database and enrolled MM cases from 2005-2016. According to the advent of ICIs in 2011, the era was divided into the non-ICIs era (2005-2010) and the ICIs era (2011-2016). Patients were divided into three cohorts according to the primary site sunlight exposure patterns: head and neck in the first cohort, trunk arms and legs in the second cohort, and acral sites in the third cohort. We compared survival differences for each cohort between the two eras, performed stratified analysis, established nomograms for predicting 3- and 5-year OS rate, and performed internal validation.ResultsComparing the survival difference between the ICIs and non-ICIs era, head and neck melanoma showed the greatest improvement in survival, with 3- and 5-year OS rate increasing by 10.2% and 9.1%, respectively (P=0.00011). In trunk arms and legs melanoma, the 3- and 5-year OS rate increased by 4.6% and 3.9%, respectively (P

ObjectiveBesides breast and gastric cancer, HER2 amplification/mutation are also found in lung adenocarcinoma (LUAD). However, the correlation between HER2 variations and the phenotype of immunogenicity and tumor immune microenvironment (TIME) in LUAD compared with breast and gastric cancer has yet to be fully elucidated.MethodsWe integrated public databases (discovery set) and internal data (validated set) of 288 patients representing three distinct HER2-altered tumors. Genomic data were used to identify somatic mutations, copy number variations, and calculate tumor mutational burden (TMB) and microsatellite instability score. RNA sequencing was conducted to estimate immune gene signatures and contents of tumor-infiltrating immune cell populations. Finally, IHC was used to determine PD-L1 expression and the tumoral-infiltration of immune cells in 50 HER2-variant tumor specimens with no prior therapeutic regimens.ResultsCompared with HER2-amplified breast and gastric cancers, patients with HER2-amplified LUAD showed higher immunogenicity, mainly manifested in immune checkpoints expression and tissue/blood TMB. Additionally, HER2-amplified LUAD exhibited an inflamed TIME with remarkably increased genes encoding HLAs, T-cell activity and immune cell-type, and accompanied with tumor‐infiltrating lymphocytes. In LUAD, patients with HER2 amplification possessed higher tissue TMB than HER2 mutation, whereas no difference was observed in PD-L1 expression. HER2 amplification (primary) was associated with significantly higher PD-L1 expression and TMB than acquired HER2 amplification after resistance to EGFR-TKIs.ConclusionPatients with HER2-amplified LUAD have better immunogenicity and/or an inflamed TIME among HER2-aberrant tumors. Our study may provide clues for establishing the benefits and uses of ICIs for patients with this disease.

Abstract Background Psychological risk factors have been recognised as potential, modifiable risk factors in the development and progression of cardiovascular disease (CVD). Tai Chi, a mind-body exercise, has the potential to improve psychological well-being and quality of life. We aim to assess the effects and safety of Tai Chi on psychological well-being and quality of life in people with CVD and/or cardiovascular risk factors. Methods We searched for randomised controlled trials evaluating Tai Chi for psychological well-being and quality of life in people with CVD and cardiovascular risk factors, from major English and Chinese databases until 30 July 2021. Two authors independently conducted study selection and data extraction. Methodological quality was evaluated using the Cochrane Risk of Bias tool. Review Manager software was used for meta-analysis. Results We included 37 studies (38 reports) involving 3525 participants in this review. The methodological quality of the included studies was generally poor. Positive effects of Tai Chi on stress, self-efficacy, and mood were found in several individual studies. Meta-analyses demonstrated favourable effects of Tai Chi plus usual care in reducing anxiety (SMD − 2.13, 95% confidence interval (CI): − 2.55, − 1.70, 3 studies, I 2 = 60%) and depression (SMD -0.86, 95% CI: − 1.35, − 0.37, 6 studies, I 2 = 88%), and improving mental health (MD 7.86, 95% CI: 5.20, 10.52, 11 studies, I 2 = 71%) and bodily pain (MD 6.76, 95% CI: 4.13, 9.39, 11 studies, I 2 = 75%) domains of the 36-Item Short Form Survey (scale from 0 to 100), compared with usual care alone. Tai Chi did not increase adverse events (RR 0.50, 95% CI: 0.21, 1.20, 5 RCTs, I 2 = 0%), compared with control group. However, less than 30% of included studies reported safety information. Conclusions Tai Chi seems to be beneficial in the management of anxiety, depression, and quality of life, and safe to practice in people with CVD and/or cardiovascular risk factors. Monitoring and reporting of safety information are highly recommended for future research. More well-designed studies are warranted to determine the effects and safety of Tai Chi on psychological well-being and quality of life in this population. Systematic review registration International Prospective Register for Systematic Reviews (PROSPERO), CRD42016042905. Registered on 26 August 2016.

Abstract Background Adipsin has been identified as a secreted adipokine that plays a critical pathogenic role in metabolic disorders. However, it is not clear regarding the association of circulating adipsin with cardiovascular disease (CVD). This study will explore the association between circulating adipsin and asymptomatic carotid atherosclerosis in Chinese obese adults. Methods A total of 483 obese adult subjects (aged 40 years or older) were enrolled in this study. Serum adipsin concentrations and carotid intima-media thickness (CIMT) were measured to determine these associations. Results Individuals with increased CIMT and asymptomatic carotid atherosclerosis had lower levels of circulating adipsin than controls (both p

Abstract The purpose of this study was to investigate whether inhibition of DNA (cytosine-5)-methyltransferase 1 (DNMT-1) alleviated ferroptosis through nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy during diabetes myocardial (DM) ischemia/reperfusion (I/R) injury (IRI). Rat DM + sham (DS), I/R, and DM + I/R (DIR), H9c2 cell high glucose (HG), hypoxia reoxygenation (H/R), and high-glucose hypoxia reoxygenation (HH/R) models were established. DNMT-1 inhibitor 5-Aza-2’-deoxycytidine (5-aza-CdR) was administered to rat and cell models. The protein level of DNMT-1, NCOA4, FTH, GPX4, Beclin-1, and P62 was detected by western blotting. Compared with normal sham (NS) group, myocardial tissue was injured in DS and I/R models. The level of DNMT-1, NCOA4, and ferroptosis was increased. Moreover, the cell injury was more serious in rat DIR or HH/R model. 5-Aza-CdR could reduce NCOA4-mediated ferritinophagy and myocardial injury in DIR and HH/R models. Moreover, the siRNA for NCOA4 could also reduce the level of ferritinophagy and cell injury in HH/R model. 5-Aza-CdR enhanced the protective effect for NCOA4-siRNA in the process of cell injury. Inhibition of DNMT-1 could reduce ferroptosis during DIR, which the NCOA4-mediated ferritinophagy might be regulated.

Abstract Introduction Suboptimal health status (SHS), an intermediate state between chronic disease and health, is characterized by chronic fatigue, non-specific pain, headaches, dizziness, anxiety, depression, and functional system disorders with a high prevalence worldwide. Although some lifestyle factors (e.g. smoking, alcohol consumption, physical exercise) and environmental factors (e.g. air quality, noise, living conditions) have already been studied, few studies can comprehensively illustrate the associations of lifestyle and environment factors with general, physical, mental, and social SHS. Methods A cross-sectional study was conducted among 6750 urban residents aged 14 years or over in five random cities from September 2017 to September 2018 through face-to-face questionnaires. There were 5881 valid questionnaires with a response rate of 87%. A general linear model and structural equation model were developed to quantify the effects of lifestyle behaviors and environment factors on SHS. Results The detection rates of general, physical, mental, and social SHS were 66.7, 67.0, 65.5, and 70.0%, respectively. Good lifestyle behaviors and favorable environment factors positively affected SHS (P

Objective(s): Ischemia/reperfusion (I/R) is a leading cause of myocardial infarction (MI) injury, contributing to excess injury to cardiac tissues involved in inflammation, apoptosis, and oxidative stress. The present study was conducted to examine the effects of combined thymoquinone (TQ) with ischemic postconditioning (IPostC) therapy on apoptosis and inflammation due to I/R injury in diabetic rat hearts. Materials and Methods: A single dose injection of streptozotocin (STZ; 60 mg/kg) was administered to thirty-two Wistar male rats to induce diabetes. Hearts were fixed on a Langendorff setting and exposed to a 30 min regional ischemia subsequently to 60 min reperfusion. IPostC was induced at the onset of reperfusion by 3 cycles of 30 sec R/I. ELISA, Western blotting assay, and TUNEL staining were applied to assess the cardioprotective effect of IPostC and TQ against I/R injury in diabetic and non-diabetic rats.Results: Administration of TQ alone in non-diabetic isolated hearts significantly diminished CK-MB, TNF-α, IL-1β, and apoptosis and enhanced p-GSK-3β and Bcl-2 (p

It is possible to call single-nucleotide variant (SNV) in cell-free DNA (cfDNA), but the accuracy of detection is often affected by low tumour cfDNA content. Here, the authors develop a method, cfSNV, and show that it can be used even for medium-coverage whole exome sequencing of cfDNA.

Although analysis of maternal plasma cell-free content has been employed for screening of genetic abnormalities within a pregnancy, limited attention has been paid to its use for the detection of adverse pregnancy outcomes (APOs) based on placental function. Here we investigated cell-free DNA and RNA content of 102 maternal and 25 cord plasma samples. Employing a novel deconvolution methodology, we found that during the first trimester, placenta-specific DNA increased prior to the subsequent development of gestational diabetes with no change in patients with preeclampsia while decreasing with maternal obesity. Moreover, using cell-free RNA sequencing, APOs revealed 71 differentially expressed genes early in pregnancy. We noticed the upregulation of S100A8, MS4A3, and MMP8 that have been already associated with APOs but also the upregulation of BCL2L15 and the downregulation of ALPL that have never been associated with APOs. We constructed a classifier with a positive predictive ability (AUC) of 0.91 for APOs, 0.86 for preeclampsia alone and 0.64 for GDM. We conclude that placenta-specific cell-free nucleic acids during early gestation provide the possibility of predicting APOs prior to the emergence of characteristic clinical features.

Background: Some Western medicine schools in China established standardized patient (SP) programs for medical education. However, SP programs are rarely applied to the education of traditional Chinese medicine (TCM). In this study, we evaluated the effectiveness of using standardized patient traditional Chinese medicine (SP-TCM) to improve clinical competency among TCM medical students. Methods: This study was a prospective, 2-group, parallel-training randomized trial over the course of 5 years. Data were collected from September 2016 to December 2020. Participants in each year were randomly allocated into the traditional-method training group or the SP-TCM training group (1:1) for a 3-month curriculum. Measurement of clinical competency among all trainees was based on a standardized examination composed of scores of medical record documentation, scores of TCM syndrome differentiation and therapeutic regimen, and checklist assessment from both SP-TCMs and TCM professionals. Feedback was collected using semi-constructive questionnaires from both groups. Results: Compared with those assigned to traditional-method training, those assigned to SP-TCM training demonstrated significantly greater post-training improvement in medical record documentation and TCM syndrome differentiation and therapeutic regimen. Moreover, SP-TCM trainees outscored those assigned to traditional training in the assessment for encounter performance given by independent SP-TCMs and TCM professionals. The SP-TCM method gained higher satisfaction of training efficacy and test performance than the traditional method. Conclusion: This SP-TCM program demonstrated great benefits for improving clinical competency among TCM medical students.

Abstract Background As a secreted adipokine, adipsin has been recently shown to play a pivotal role in metabolic disorders. However, information regarding the association of circulating adipsin with non-alcoholic fatty liver disease (NAFLD) in humans is scant. Methods We recruited 1163 obese adult subjects with waist circumference at least 90 cm in men and 80 cm in women from the community. Circulating adipsin levels were measured by enzyme-linked immunosorbent assay. Results Circulating adipsin levels of NAFLD subjects was decreased compared to those in non-NAFLD (p

BackgroundThis study aims to explore the key targets and signaling pathways of the traditional Chinese medicine Phellodendron and Anemarrhena drug pair (PADP) for the treatment of liver cancer.MethodsFirstly, bioinformatics technology was used to analyze GSE62232 gene chip to obtain the differential genes of liver cancer. A network pharmacology technology was used to find the active components of PADP and their targets. Secondly, the differential genes were imported into STRING database to draw a PPI network, and network topology structure map combined with Cytoscape software. And the R language was used to identify differential gene targets and pathways through GO and KEGG pathway enrichment analysis. In addition, AutoDock Vina was used for molecular docking of core targets and core compounds. Moreover, GEPIA online analysis tool was used to perform survival analysis of the core target genes. Finally, RT-PCR was used to verify the changes of key target genes. CCK−8 assay was performed to detect cell proliferation. Flow cytometry was performed to detect the cell cycle and apoptotic. Transwell invasion assay was performed to detect cell invasion.ResultsFirstly, a total of 21,654 genes were obtained. After screening, 1019 differential genes were obtained, including 614 down-regulated genes and 405 up-regulated genes. Furthermore, after screening by ADME standards, 52 active ingredients were obtained, of which 37 were Phellodendron and 15 were Anemarrhena. And a total of 36 differential genes have been identified, including 13 up-regulated genes and 23 down-regulated genes. Moreover, through enrichment analysis, we found that PADP may treat liver cancer through multiple channels and multiple pathways including the p53 signaling pathway, IL-17 signaling pathway, TNF signaling pathway, Toll-like receptor signaling pathway and so on. Secondly, the molecular docking results showed that there was certain affinity between the core compounds and core target genes. In addition, GEPIA online analysis showed that ESR1, AR, CCNB1, CDK1, AKR1C3 and CCNA2 might become potential target genes for the survival and prognosis of PADP for the treatment of liver cancer. Finally, it was found that PADP could up regulate genes ESR1 and AR, down regulate genes CCNB1, CDK1, AKR1C3, and CCNA2. PADP could promote the apoptosis of liver cancer cells, shorten the cell cycle, and inhibit the proliferation and invasion of liver cancer cells.ConclusionPADP may treat liver cancer through multiple targets, multiple channels, and multiple pathways, thereby suppressing cancer cells and improving the living quality of patients.

Background: Anti-silencing function 1B (ASF1B), a histone H3-H4 chaperone, is crucial for S-phase progression and cell proliferation. Recent studies have shown that ASF1B may be used as a new proliferation marker for cancer prognosis. However, the prognostic value and effect of ASF1B on tumor cells and the immune microenvironment in hepatocellular carcinoma (HCC) remain unclear.Methods: We analyzed the expression of ASF1B and its prognostic value using The Cancer Genome Atlas (TCGA) database (as a training set) and other databases, and we validated the findings by immunohistochemistry in our clinical database, containing 141 HCC patients (as a validation set). Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed to probe the tumor-associated biological processes of ASF1B in HCC. The interrelationships between ASF1B expression and tumor immunological characteristics were analyzed by multiple databases. The Imvigor210 cohort was retrieved to assess the ability of ASF1B to predict immunotherapy efficacy.Results: ASF1B was highly expressed in tumor tissue compared to paracancerous tissue. High ASF1B expression was associated with worse overall survival (OS) and progression-free survival (PFS) in the training set (p = 0.005, p < 0.001) and validation set (p < 0.001, p < 0.001). Multivariate analysis revealed that ASF1B was an independent prognostic factor associated with OS and PFS. GSEA and GSVA suggested that ASF1B was involved in tumor-associated biological processes, including the cell cycle, DNA replication, base excision repair, mismatch repair, RNA degradation, ubiquitin-mediated proteolysis, and nucleotide excision repair. Further analysis revealed that the levels of ASF1B were positively correlated with the immune cells infiltration of B cells, CD8+ T cells, CD4+ T cells, neutrophils, and dendritic cells. However, ASF1B was positively correlated with Treg cell infiltration and inhibitory immune checkpoints in exhausted T cells. Patients who received anti-PD-L1 immunotherapy with high ASF1B expression had a higher objective response.Conclusion: The ASF1B level is an independent prognostic factor and may serve as a potential immunotherapeutic target.

Liver failure is characterized by serious liver decompensation and high mortality. The activation of systemic immune responses and systemic inflammation are widely accepted as the core pathogenesis of liver failure. Glucocorticoids (GCs) are most regularly utilized to suppress excessive inflammatory reactions and immunological responses. GCs have been used in the clinical treatment of liver failure for nearly 60 years. While there has been no unanimity on the feasibility and application of GC treatment in liver failure until recently. The most recent trials have produced conflicting results when it comes to the dose and time for GC therapy of different etiology of liver failure. Our review outlines the issues and options in managing GC treatment in liver failure based on an investigation of the molecular mechanism that GC may give in the treatment.