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Cancer-secreted exosomal miRNAs are emerging mediators of cancer-stromal cross-talk in the tumor environment. Our previous miRNAs array of cervical squamous cell carcinoma (CSCC) clinical specimens identified upregulation of miR-221-3p. Here, we show that miR-221-3p is closely correlated with peritumoral lymphangiogenesis and lymph node (LN) metastasis in CSCC. More importantly, miR-221-3p is characteristically enriched in and transferred by CSCC-secreted exosomes into human lymphatic endothelial cells (HLECs) to promote HLECs migration and tube formation in vitro, and facilitate lymphangiogenesis and LN metastasis in vivo according to both gain-of-function and loss-of-function experiments. Furthermore, we identify vasohibin-1 (VASH1) as a novel direct target of miR-221-3p through bioinformatic target prediction and luciferase reporter assay. Re-expression and knockdown of VASH1 could respectively rescue and simulate the effects induced by exosomal miR-221-3p. Importantly, the miR-221-3p-VASH1 axis activates the ERK/AKT pathway in HLECs independent of VEGF-C. Finally, circulating exosomal miR-221-3p levels also have biological function in promoting HLECs sprouting in vitro and are closely associated with tumor miR-221-3p expression, lymphatic VASH1 expression, lymphangiogenesis, and LN metastasis in CSCC patients. In conclusion, CSCC-secreted exosomal miR-221-3p transfers into HLECs to promote lymphangiogenesis and lymphatic metastasis via downregulation of VASH1 and may represent a novel diagnostic biomarker and therapeutic target for metastatic CSCC patients in early stages.

Butyrate has a bioactive function to reduce carcinogenesis. To achieve targeted cancer therapy, this study developed bacterial cancer therapy (BCT) with butyrate as a payload. By metabolic engineering, Escherichia coli Nissle 1917 (EcN) was reprogrammed to synthesize butyrate (referred to as biobutyrate) and designated EcN-BUT. The adopted strategy includes construction of a synthetic pathway for biobutyrate and the rational design of central metabolism to increase the production of biobutyrate at the expense of acetate. With glucose, EcN-BUT produced primarily biobutyrate under the hypoxic condition. Furthermore, human colorectal cancer cell was administrated with the produced biobutyrate. It caused the cell cycle arrest at the G1 phase and induced the mitochondrial apoptosis pathway independent of p53. In the tumor-bearing mice, the injected EcN-BUT exhibited tumor-specific colonization and significantly reduced the tumor volume by 70%. Overall, this study opens a new avenue for BCT based on biobutyrate.

With the rapid advancement of cyber-physical systems, Digital Twin (DT) is gaining ever-increasing attention owing to its great capabilities to realize Industry 4.0. Enterprises from different fields are taking advantage of its ability to simulate real-time working conditions and perform intelligent decision-making, where a cost-effective solution can be readily delivered to meet individual stakeholder demands. As a hot topic, many approaches have been designed and implemented to date. However, most approaches today lack a comprehensive review to examine DT benefits by considering both engineering product lifecycle management and business innovation as a whole. To fill this gap, this work conducts a state-of-the art survey of DT by selecting 123 representative items together with 22 supplementary works to address those two perspectives, while considering technical aspects as a fundamental. The systematic review further identifies eight future perspectives for DT, including modular DT, modeling consistency and accuracy, incorporation of Big Data analytics in DT models, DT simulation improvements, VR integration into DT, expansion of DT domains, efficient mapping of cyber-physical data and cloud/edge computing integration. This work sets out to be a guide to the status of DT development and application in today’s academic and industrial environment.

Lactate has long been considered an intermediate by-product of glucose metabolism. However, in recent years, accumulating evidence reveals that lactate has unique biological activities. In previous studies, lactate signaling was shown to inhibit inflammation. Furthermore, experiments have shown that lactate can promote the transformation of pro-inflammatory macrophages into anti-inflammatory macrophages. However, no studies have shown whether lactate can alleviate inflammation. RAW 264.7 macrophages were stimulated by LPS to induce an M1 phenotype, and cultured with low and high concentrations of lactate. The cells were then observed for phenotypic transformations and expression of inflammatory mediators and surface markers. The expression of inflammatory factors was also analyzed in the cell-free supernatant fraction. Further, a mouse model of DSS-induced colitis was established and treated with lactate. Colonic tissue injury was monitored by histopathological examinations. The experiments showed that lactate promoted the transformation of activated macrophages to M2 phenotype and decreased the expression of TLR4-mediated NF-κB signaling proteins and inflammatory factors. In the DSS-induced colitis mouse model, lactate promoted the phenotypic transformation of macrophages in colonic tissue, reduced inflammation and organ damage, inhibited the activation of TLR4/NF-κB signaling pathway, decreased the serum levels of pro-inflammatory factors, increased the expression of anti-inflammatory factors, promoted the repair of the intestinal mucosal barrier and reduced the severity of colitis. Lactate inhibits the TLR/NF-κB signaling pathway and the production of pro-inflammatory factors by promoting polarization of macrophages. In addition, lactate promotesthe repair of the intestinal mucosal barrier and protects intestinal tissue in inflammation. Furthermore, lactate is relatively safe. Therefore, lactate is a promising and effective drug for treating inflammation through immunometabolism regulation.

Background Parkinson’s disease (PD) is a neurodegenerative disorder with no absolute cure. The evidence of the involvement of gut microbiota in PD pathogenesis suggests the need to identify certain molecule(s) derived from the gut microbiota, which has the potential to manage PD. Osteocalcin (OCN), an osteoblast-secreted protein, has been shown to modulate brain function. Thus, it is of interest to investigate whether OCN could exert protective effect on PD and, if yes, whether the underlying mechanism lies in the subsequent changes in gut microbiota. Results The intraperitoneal injection of OCN can effectively ameliorate the motor deficits and dopaminergic neuronal loss in a 6-hydroxydopamine-induced PD mouse model. The further antibiotics treatment and fecal microbiota transplantation experiments confirmed that the gut microbiota was required for OCN-induced protection in PD mice. OCN elevated Bacteroidetes and depleted Firmicutes phyla in the gut microbiota of PD mice with elevated potential of microbial propionate production and was confirmed by fecal propionate levels. Two months of orally administered propionate successfully rescued motor deficits and dopaminergic neuronal loss in PD mice. Furthermore, AR420626, the agonist of FFAR3, which is the receptor of propionate, mimicked the neuroprotective effects of propionate and the ablation of enteric neurons blocked the prevention of dopaminergic neuronal loss by propionate in PD mice. Conclusions Together, our results demonstrate that OCN ameliorates motor deficits and dopaminergic neuronal loss in PD mice, modulating gut microbiome and increasing propionate level might be an underlying mechanism responsible for the neuroprotective effects of OCN on PD, and the FFAR3, expressed in enteric nervous system, might be the main action site of propionate. CoKvBsES-WQ_2hkhyhEj9X Video abstract

Background Tuberculosis (TB) poses a severe public health challenge in China and worldwide. This study evaluated the effects of age, period, and birth cohort on reported incidence trends of TB based on population and refined the characteristics of high-risk groups. Methods Aggregate data that reported pulmonary tuberculosis (PTB) cases from China Tuberculosis Management Information System (TBIMS) from 2006 to 2020 were used to analyze effect coefficients through the age–period–cohort (APC) model based on intrinsic estimator (IE) method, and converted them into relative risk ( RR ) to estimate trends. Results A total of 14.82 million cases of PTB were reported in China from 2006 to 2020, showing a continuous downward trend. The reporting rate increased with age by age group, with 70–74 years old being 2–3 times higher than that in 20–24 years old. APC analysis model showed that age effects were bimodal in 20–24 years old [ RR  = 2.29, 95% confidence interval ( CI ): 1.73–3.03] and 70–74 years old ( RR  = 1.95, 95% CI: 1.67–2.27), and lower than the overall average in the groups under 15 years old. Stratified results showed that the risk was higher for women under age 40 than men and higher for men over 40. The risk was higher in urban than in rural areas under 30 years old and slightly higher in rural than in urban between 30 and 64 years old. The risk for 15–34 years old was significantly higher in the east than in other regions. The period effects showed a decreasing trend, and the risk was higher in rural in recent years. Except for cohorts born in 1961–1965 and 2001–2005, where the RR increased, the later the cohort was born, the lower the risk. The cohort 1926–1930 in eastern had the highest risk ( RR  = 3.49, 95% CI: 2.44–4.98). Conclusions The reported incidence of PTB continued to decline in China from 2006 to 2020. The young (20–24 years old) and the elderly (70–74 years old) were equally at high risk. There were differences in the age, period and cohort effects on PTB incidence among gender, urban–rural and regions. Our findings better reflected the characteristics of high-risk populations, thus contributing to the development of timely and effective intervention strategies, and providing clues for etiological research. Graphical abstract

In this research, the antifungal role of hydrogen sulfide (H2S) on the postharvest pathogens Aspergillus niger and Penicillium italicum growing on fruits and under culture conditions on defined media was investigated. Our results show that H2S, released by sodium hydrosulfide (NaHS) effectively reduced the postharvest decay of fruits induced by A. niger and P. italicum. Furthermore, H2S inhibited spore germination, germ tube elongation, mycelial growth, and produced abnormal mycelial contractions when the fungi were grown on defined media in Petri plates. Further studies showed that H2S could cause an increase in intracellular reactive oxygen species (ROS) in A. niger. In accordance with this observation we show that enzyme activities and the expression of superoxide dismutase (SOD) and catalase (CAT) genes in A. niger treated with H2S were lower than those in control. Moreover, H2S also significantly inhibited the growth of Saccharomyces cerevisiae, Rhizopus oryzae, the human pathogen Candida albicans, and several food-borne bacteria. We also found that short time exposure of H2S showed a microbicidal role rather than just inhibiting the growth of microbes. Taken together, this study suggests the potential value of H2S in reducing postharvest loss and food spoilage caused by microbe propagation.

Background Mesophilic alkaline serine proteases from various bacteria have been commercially applied in a range of industries owing to their high catalytic efficiency and wide substrate specificity. However, these proteases have an optimal catalytic temperature of approximately 50 °C, and their activity decreases significantly at low temperature. Therefore, to enhance their cold activity, it is necessary to improve the catalytic performance of these proteases at low temperature. The alkaline serine protease (DHAP) from Bacillus pumilus BA06 is a typical mesophilic enzyme, which has demonstrated great potential in various industrial applications. Here we attempted to improve the cold activity of DHAP via directed evolution. Results Seven variants (P9S, A1G/K27Q, A38V, A116T, T162I, S182R, and T243S) of DHAP from B. pumilus were obtained via directed evolution. The results showed that all of the variants had increased proteolytic activity at 15 °C towards both the casein and synthetic peptide substrates. With the exception of variant T243S, the thermostability of these variants did not decrease in comparison with the wild-type enzyme. Kinetic analysis indicated that the increase in catalytic efficiency was largely attributed to the increase in turnover number ( k cat ). Furthermore, the combined variants generated by site-directed mutagenesis showed a further increase in specific caseinolytic activity and the k cat value for hydrolysis of the synthetic peptide. The combined variants of P9S/K27Q and P9S/T162I exhibited an approximate 5-fold increase in caseinolytic activity at 15 °C and almost no loss of thermostability. Finally, the possible mechanism responsible for the change in catalytic properties for these variants was interpreted based on structural modeling. Conclusions Directed evolution and site-directed mutagenesis were combined to engineer variants of the DHAP from B. pumilus . All of the variants exhibited an increase in hydrolytic efficiency at low temperature towards both of the substrates, casein and synthetic peptide, without any loss of thermostability compared with the wild-type. These data suggest that engineering low-temperature activity for a bacterial protease is not always associated with the loss of thermostability. Furthermore, our findings demonstrate that enhanced cold activity and thermostability could be integrated into a single variant.

Objective To conduct a comprehensive systematic review and meta-analysis to estimate the relationship between endocrine-disrupting chemicals (EDCs), including polychlorinated biphenyls (PCBs), poly-brominated diphenyl ethers (PBDEs), phthalates (PAEs), and per- and polyfluoroalkyl substances (PFAS) exposure and risk of gestational diabetes mellitus (GDM). Methods Relevant studies from their inception to November 2021 were identified by searching EMBASE, PubMed, and Web of Science. The cohort and case–control studies that reported effect size with 95% confidence intervals (CIs) of EDC exposure and GDM were selected. The heterogeneity among the included studies was quantified by I 2 statistic. Publication bias was evaluated through the Begg and Egger tests. Results Twenty-five articles with a total of 23,796 participants were found. Results indicated that exposure to PCBs has a significant influence on the incidence of GDM (OR = 1.14; 95% CI = 1.00-–1.31; n  = 8). The risk of GDM was found to be associated with PBDE exposure (OR = 1.32; 95% CI = 1.15–1.53; n  = 4). PAEs and PFASs exposure were also positively associated with the risk of GDM, with summary ORs of 1.10 (95% CI = 1.03–1.16; n  = 7 for PAEs) and 1.09 (95% CI = 1.02–1.16; n  = 11 for PFASs), respectively. When only cohort studies were considered, the summary OR between PCBs exposure and the risk of GDM was 0.99 (95% CI = 0.91–1.09; n  = 5). Meanwhile, the summary ORs from cohort studies for PBDEs, PAEs, and PFASs exposure were 1.12 (95% CI = 1.00–1.26; n  = 2), 1.08 (95% CI = 1.02–1.15; n  = 5), and 1.06 (95% CI = 1.00–1.12; n  = 8), respectively. The Beggs and Egger tests did not show publication bias, and the sensitivity analyses did not change the results in this meta-analysis. Conclusion These results support that exposure to certain EDCs, including PCBs, PBDEs, PAEs, and PFAS, increase the risk of GDM. Further large-sample epidemiologic researches and mechanistic studies are needed to verify the potential relationship and biological mechanisms. These results are of public health significance because the daily EDC exposure is expected to increase the risk of GDM development. Graphical Abstract

The objective of this research was to analyse whether ameliorating drought stress through exogenously applied spermine (Spm) was related to carbohydrate metabolism, dehydrins accumulation and the transcription of genes encoding dehydrins in two white clovers (drought-susceptible cv. 'Ladino' and drought-resistant cv. 'Haifa') under controlled drying conditions for 10 days. The results show that the application of Spm effectively alleviates negative effects caused by drought stress in both cultivars. Exogenous Spm led to accumulation of more water-soluble carbohydrates (WSC), sucrose, fructose and sorbitol in both cultivars under drought stress, and also significantly elevated glucose content in leaves of drought-resistant cv. 'Haifa', but had no effect on drought-susceptible cv. 'Ladino'. Accordingly, the key enzyme activities of sucrose and sorbitol metabolism changed along with the application of Spm under drought stress. Spm induced a significant increase in sucrose phosphate synthase (SPS) or sorbitol dehydrogenase (SDH) activity, but decrease in sucrose synthetase (SS) activity when two cultivars were subjected to drought. In addition, the improved accumulation of dehydrins induced by exogenous Spm coincided with three genes expression which was responsible for dehydrins synthesis. But Spm-induced transcript level of dehydrin genes increased earlier in cv. 'Ladino' than that in cv. 'Haifa'. Thus, these results suggest that ameliorating drought stress through exogenously applied Spm may be associated with increased carbohydrate accumulation and dehydrins synthesis. There are differences between drought-susceptible and -resistant white clover cultivars related to Spm regulation of WSC metabolism and dehydrins expression.