A small-molecule activation mechanism that directly opens the KCNQ2 channel.

Pharmacological activation of voltage-gated ion channels by ligands serves as the basis for therapy and mainly involves a classic gating mechanism that augments the native voltage-dependent open probability. Through structure-based virtual screening, we identified a new scaffold compound, Ebio1, serving as a potent and subtype-selective activator for the voltage-gated potassium channel KCNQ2 and featuring a new activation mechanism. Single-channel patch-clamp, cryogenic-electron microscopy and molecular dynamic simulations, along with chemical derivatives, reveal that Ebio1 engages the KCNQ2 activation by generating an extended channel gate with a larger conductance at the saturating voltage (+50 mV). This mechanism is different from the previously observed activation mechanism of ligands on voltage-gated ion channels. Ebio1 caused S6 helices from residues S303 and F305 to perform a twist-to-open movement, which was sufficient to open the KCNQ2 gate. Overall, our findings provide mechanistic insights into the activation of KCNQ2 channel by Ebio1 and lend support for KCNQ-related drug development.

Anti-angiogenesis in colorectal cancer therapy.

The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence increases annually. Angiogenesis plays an important role in the development of tumors because it can bring the nutrients that cancer cells need and take away metabolic waste. Various mechanisms are involved in the formation of neovascularization, and vascular endothelial growth factor is a key mediator. Meanwhile, angiogenesis inhibitors and drug resistance (DR) are challenges to consider when formulating treatment strategies for patients with different conditions. Thus, this review will discuss the molecules, signaling pathways, microenvironment, treatment, and DR of angiogenesis in CRC.

M2 macrophage-derived exosomes induce angiogenesis and increase skin flap survival through HIF1AN/HIF-1α/VEGFA control.

BACKGROUND: Skin flap transplantation is a routine strategy in plastic and reconstructive surgery for skin-soft tissue defects. Recent research has shown that M2 macrophages have the potential for pro-angiogenesis during tissue healing. METHODS: In our research, we extracted the exosomes from M2 macrophages(M2-exo) and applied the exosomes in the model of skin flap transplantation. The flap survival area was measured, and the choke vessels were assessed by morphological observation. Hematoxylin and eosin (H&E) staining and Immunohistochemistry were applied to assess the neovascularization. The effect of M2-exo on the function of Human umbilical vein endothelial cells (HUVECs) was also investigated. We also administrated 2-methoxyestradiol (2-ME2, an inhibitor of HIF-1α) to explore the underlying mechanism. We tested the effects of M2-Exo on the proliferation of HUVECs through CCK8 assay and EdU staining assay. RESULTS: The survival area and number of micro-vessels in the skin flaps were increased in the M2-exo group. Besides, the dilation rate of choke vessels was also enhanced in the M2-exo group. Additionally, compared with the control group, M2-exo could accelerate the proliferation, migration and tube formation of HUVECs in vitro. Furthermore, the expression of the pro-angiogenesis factors, HIF-1α and VEGFA, were overexpressed with the treatment of the M2-exo. The expression of HIF1AN protein level was decreased in the M2-exo group. Finally, treatment with HIF-1α inhibitor reverses the pro-survival effect of M2-exo on skin flaps by interfering with the HIF1AN/HIF-1α/VEGFA signaling pathway. CONCLUSION: This study showed that M2-exosomes promote skin flap survival by enhancing angiogenesis, with HIF1AN/HIF-1α/VEGFA playing a crucial role in this process.

Acidithiobacillus acidisediminis sp. nov., an acidophilic sulphur-oxidizing chemolithotroph isolated from acid mine drainage sediment.

Strain S30A2T, isolated from the acid mine drainage sediment of Mengzi Copper Mine, Yunnan, is proposed to represent a novel species of the sulphur-oxidizing genus Acidithiobacillus. Cells were Gram-stain-negative, non-endospore forming, highly motile with one or two monopolar flagella and rod-shaped. The strain was mesophilic, growing at 30-50 °C (optimum, 38 °C), acidophilic, growing at pH 2.0-4.5 (optimum, pH 2.5), and tolerant of 0-4 % (w/v; 684 mol l-1) NaCl. The 16S rRNA gene-based sequence analysis showed that strain S30A2T belongs to the genus Acidithiobacillus and shows the largest similarity of 96.6 % to the type strain Acidithiobacillus caldus KUT. The genomic DNA G+C content of strain S30A2T was 59.25 mol%. The average nucleotide identity ANIb and ANIm values between strain S30A2T and A. caldus KUT were 70.95 and 89.78 %, respectively and the digital DNA-DNA hybridization value was 24.9 %. Strain S30A2T was strictly aerobic and could utilize elementary sulphur and tetrathionate to support chemolithotrophic growth. The major cellular fatty acid of S30A2T was C19 : 1ω7c. The respiratory quinones were ubiquinone-8 and ubiquinone-7. Based upon its phylogenetic, genetic, phenotypic, physiologic and chemotaxonomic characteristics, strain S30A2T is considered to represent a novel species of the genus Acidithiobacillus, for which the name Acidithiobacillus acidisediminis sp. nov. is proposed. The type strain is S30A2T (=CGMCC 1.17059T=KCTC 72580T).

Exploratory analysis of predictors of ventricular aneurysm in a cohort of 291 patients with acute myocardial infarction.

OBJECTIVE: In this study, we explored the determinants of ventricular aneurysm development following acute myocardial infarction (AMI), thereby prompting timely interventions to enhance patient prognosis. METHODS: In this retrospective cohort analysis, we evaluated 297 AMI patients admitted to the First People's Hospital of Changzhou. The study was structured as follows. Comprehensive baseline data collection included hematological evaluations, ECG, echocardiography, and coronary angiography upon admission. Within 3 months post-AMI, cardiac ultrasounds were administered to detect ventricular aneurysm development. Univariate and multivariate logistic regression analysis were employed to pinpoint the determinants of ventricular aneurysm formation. Subsequently, a predictive model was formulated for ventricular aneurysm post-AMI. Moreover, the diagnostic efficacy of this model was appraised using the ROC curves. RESULTS: In our analysis of 291 AMI patients, spanning an age range of 32-91 years, 247 were male (84.9%). At the conclusion of a 3-month observational period, the cohort bifurcated into two subsets: 278 patients without ventricular aneurysm and 13 with evident ventricular aneurysm. Distinguishing features of the ventricular aneurysm subgroup were markedly higher values for age, B-type natriuretic peptide(BNP), Left atrium(LA), Left ventricular end-diastolic dimension (LEVDD), left ventricular end systolic diameter (LVEWD), E-wave velocity (E), Left atrial volume (LAV), E/A ratio (E/A), E/e ratio (E/e), ECG with elevated adjacent four leads(4 ST-Elevation), and anterior wall myocardial infarction(AWMI) compared to their counterparts (p < 0.05). Among the singular predictive factors, total cholesterol (TC) emerged as the most significant predictor for ventricular aneurysm development, exhibiting an AUC of 0.704. However, upon crafting a multifactorial model that incorporated gender, TC, an elevated ST-segment in adjacent four leads, and anterior wall infarction, its diagnostic capability: notably surpassed that of the standalone TC, yielding an AUC of 0.883 (z = -9.405, p = 0.000) as opposed to 0.704. Multivariate predictive model included gender, total cholesterol, ST elevation in 4 adjacent leads, anterior myocardial infarction, the multivariate predictive model showed better diagnostic efficacy than single factor index TC (AUC: 0. 883 vs. 0.704,z =-9.405, p = 0.000), it also improved predictive power for correctly reclassifying ventricular aneurysm occurrence in patients with AMI, NRI = 28.42% (95% CI: 6.29-50.55%; p = 0.012). Decision curve analysis showed that the use of combination model had a positive net benefit. CONCLUSION: Lipid combined with ECG model after myocardial infarction could be used to predict the formation of ventricular aneurysm and aimed to optimize and adjust treatment strategies.

Voltage-gated potassium channels KCNQs: Structures, mechanisms, and modulations.

KCNQ (Kv7) channels are voltage-gated, phosphatidylinositol 4,5-bisphosphate- (PIP2-) modulated potassium channels that play essential roles in regulating the activity of neurons and cardiac myocytes. Hundreds of mutations in KCNQ channels are closely related to various cardiac and neurological disorders, such as long QT syndrome, epilepsy, and deafness, which makes KCNQ channels important drug targets. During the past several years, the application of single-particle cryo-electron microscopy (cryo-EM) technique in the structure determination of KCNQ channels has greatly advanced our understanding of their molecular mechanisms. In this review, we summarize the currently available structures of KCNQ channels, analyze their special voltage gating mechanism, and discuss their activation mechanisms by both the endogenous membrane lipid and the exogenous synthetic ligands. These structural studies of KCNQ channels will guide the development of drugs targeting KCNQ channels.

A pH-Stable Tb-MOF as Luminescence Sensor for Highly Sensitive Detection of Amino Acids through Diverse Sensing Mechanism.

A luminescent Tb-MOF with excellent stability and dual-emitting properties was constructed with an amide-functionalized tetracarboxylate ligand. Tb-MOFs were initially assembled on one-dimensional Tb3+ chains, then formed a two-dimensional double-decker layer through the synergistic linking of organic ligands and bridging formic acid anions, and further fabricated the final three-dimensional structure through the connection of the organic ligands. Powder X-ray diffraction experiments revealed that Tb-MOFs not only exhibited excellent stability in water but also maintained structural integrity in the pH range of 2-12. Importantly, this Tb-MOF provided the first example of a metal-organic framework (MOF)-based luminescence sensor that can simultaneously detect two acid amino acids (aspartic and glutamic acids) through a turn-off sensing mechanism and two basic amino acids (lysine and arginine acids) through unusual turn-on and turn-off-on sensing mechanisms. Moreover, high sensitivity, low detection limit, and excellent recyclability of this sensor endow Tb-MOFs with great potential as a highly efficient amino acid fluorescence sensor in chemical detection and biological environments.

Construction and Validation of a Reliable Disulfidptosis-Related LncRNAs Signature of the Subtype, Prognostic, and Immune Landscape in Colon Cancer.

Disulfidptosis, a novel form of regulated cell death (RCD) associated with metabolism, represents a promising intervention target in cancer therapy. While abnormal lncRNA expression is associated with colon cancer development, the prognostic potential and biological characteristics of disulfidptosis-related lncRNAs (DRLs) remain unclear. Consequently, the research aimed to discover a novel indication of DRLs with significant prognostic implications, and to investigate their possible molecular role in the advancement of colon cancer. Here, we acquired RNA-seq data, pertinent clinical data, and genomic mutations of colon adenocarcinoma (COAD) from the TCGA database, and then DRLs were determined through Pearson correlation analysis. A total of 434 COAD patients were divided in to three subgroups through clustering analysis based on DRLs. By utilizing univariate Cox regression, the least absolute shrinkage and selection operator (LASSO) algorithm, and multivariate Cox regression analysis, we ultimately created a prognostic model consisting of four DRLs (AC007728.3, AP003555.1, ATP2B1.AS1, and NSMCE1.DT), and an external database was used to validate the prognostic features of the risk model. According to the Kaplan-Meier curve analysis, patients in the low-risk group exhibited a considerably superior survival time in comparison to those in the high-risk group. Enrichment analysis revealed a significant association between metabolic processes and the genes that were differentially expressed in the high- and low-risk groups. Additionally, significant differences in the tumor immune microenvironment landscape were observed, specifically pertaining to immune cells, function, and checkpoints. High-risk patients exhibited a low likelihood of immune evasion, as indicated by the Tumor Immune Dysfunction and Exclusion (TIDE) analysis. Patients who exhibit both a high risk and high Tumor Mutational Burden (TMB) experience the least amount of time for survival, whereas those belonging to the low-risk and low-TMB category demonstrate the most favorable prognosis. In addition, the risk groups determined by the 4-DRLs signature displayed distinct drug sensitivities. Finally, we confirmed the levels of expression for four DRLs through rt-qPCR in both tissue samples from colon cancer patients and cell lines. Taken together, the first 4-DRLs-based signature we proposed may serve for a hopeful instrument for forecasting the prognosis, immune landscape, and therapeutic responses in colon cancer patients, thereby facilitating optimal clinical decision-making.

New insights into the link between pro-environmental attitudes and household food waste behaviours in China: Moderating effect of shopping distance.

Environmental attitude, value and awareness are widely believed to help reach the goal of cutting global food waste, but these psychological and cognitive factors are not always good predictors of wasteful behaviours. Notably, it is still unclear how the role of pro-environmental attitude (PEA) in reducing household food waste (HFW) changes with grocery shopping distance. To this end, using 7319 households survey data from China, this study investigates the moderating effect of shopping distance on the link between PEA and HFW behaviour. The results of Tobit regressions show that PEA is an important predictor of actual HFW behaviour in the absence of the constraint of shopping distance. However, the expansion of shopping distance will weaken the positive role of PEA in reducing HFW. It indicates that, due to the temporal and financial constraints generated by shopping distance, there is a certain degree of hypothetical deviation between the wasteful behaviours that individuals actually exhibit and their stated PEA. Our findings, from the perspective of the moderating effect of shopping distance, explain why some individuals deviate from their stated PEA in HFW behaviour, which provides a new insight into the generation of 'attitude-behaviour' gap. Therefore, policy interventions that merely enhancing environmental education may have limited effect on reducing food waste; instead, the promotion of citizen environmental ethics should be combined with efforts to improve the accessibility of retail infrastructures.

A prediction model based on functional mitral regurgitation for the recurrence of paroxysmal atrial fibrillation (PAF) after post-circular pulmonary vein radiofrequency ablation (CPVA).

AIM: To construct a prediction model based on functional mitral regurgitation (FMR) in patients with paroxysmal atrial fibrillation (PAF) to predict atrial fibrillation recurrence after the post-circular pulmonary vein radiofrequency ablation (CPVA). METHODS: We retrospectively analyzed 289 patients with PAF who underwent CPVA for the first time. The patients were randomly divided into modeling group and verification group at the ratio of 75:25. In the modeling group, the multivariate logistic regression was used to analyze and construct a prediction model for post-CPVA recurrence in PAF patients, which was then validated in the verification group. RESULTS: (1) After 3-6 months of follow-up, the patients were divided into sinus rhythm group (252 cases) and recurrence group (24 cases); (2) In the modeling group, the age, left atrial diameter (LAD), and the degree of MR (mild, moderate, severe) were higher in recurrence group than that of the sinus rhythm group, and the left atrial appendage emptying velocity (LAAV) was lower in recurrence group (all p < .05). (3) A model for predicting the recurrence of PAF after radiofrequency ablation was constructed in the modeling group. The equation was: Logit(P) = -3.253 + .092 × age + 1.263 × mild MR + 2.325 × moderate MR + 5.111 × severe MR -.113 × LAAV. The area under the curve (AUC) of the model was .889 in modeling group and .866 in verification group, and the difference was not statistically significant (p > .05). CONCLUSION: The prediction model of atrial fibrillation (AF) recurrence after CPVA in PAF patients has good predictive efficacy, specificity, and accuracy.

Low strength wastewater anammox start-up and stable operation by inoculating sponge-iron sludge: Cooperation of biological iron and iron bacteria.

The application of anaerobic ammonium oxidation (Anammox) technology in low-strength wastewater treatment still faces difficult in-situ start-ups and unstable operations. Sponge-iron sludge (R1) was used as a novel inoculum to provide a promising solution. Conventional activated sludge (R0) was used as the control. However, little is known about the feasibility and performance during the start-up and operation of Anammox combined with biological iron and iron bacteria in an iron sludge system. Anammox was successfully started both in R1 (87 days) and R0 (89 days) with a low-strength influent (with a nitrogen loading rate (NLR) of 43.64 ± 0.41 g N/(m3⋅d)). During long-term operation, the R0 nevertheless produced higher nitrates (9.7 ± 0.1 mg/L) than expected. In contrast, R1 presented no excess nitrate production (2.1 ± 0.06 mg/L). The total inorganic nitrogen (TIN) removal efficiency increased from 78.2 ± 7.1% in R0 to 86.1 ± 4.3% in R1. The iron sludge in R1 was divided equally into three parts and three different nitrogen-feeding methods were used over the 34 days of operation, as follows: first using a mixture of ammonium (27.15 ± 1.0 mg/L) and nitrite (32.7 ± 1.7 mg/L), then only ammonium (27.15 ± 1.0 mg/L) and lastly only nitrite (32.7 ± 1.7 mg/L) as the influent. R1 was a coupled system composed of Anammox, Feammox, and NOx--dependent Fe(II) oxidation (NDFO). The contribution of Feammox and NDFO to TIN removal was 27.1 ± 1.2% and 31.9 ± 0.7%. However, Anammox was the primary nitrogen transformation pathway. X-ray diffraction (XRD) analysis shows that iron hydroxide (Fe(OH)3) and iron oxide hydroxide (FeOOH) were generated in R1. The produced Fe(OH)3 and FeOOH were capable of participating in Feammox and formed a Fe(II)/Fe(III) cycle which further removed nitrogen. Therefore, a highly stable and impressive nitrogen removal performance was demonstrated in the iron sludge Anammox system under the cooperation of biological iron and iron bacteria. The study considered the enrichment of norank_c_OM190, Desulfuromonas, and Thiobacillus and their contribution to the Anammox, Feammox, and NDFO processes, respectively. This study provides a new perspective for the start-up and stable operation of low-strength wastewater Anammox engineering applications.

Insights into palladium nanoparticles produced by Shewanella oneidensis MR-1: Roles of NADH dehydrogenases and hydrogenases.

Biologically synthesized palladium nanoparticles (bio-Pd) have attracted considerable interest as promising green catalysts for environmental remediation. However, the mechanisms by which microorganisms produce bio-Pd remain unclear. In the present study, we investigated the roles of Shewanella oneidensis MR-1 and its NADH dehydrogenases and hydrogenases (HydA and HyaB) in bio-Pd production using formate as the electron donor. The roles of NADH dehydrogenases and hydrogenases were studied by inhibiting NADH dehydrogenases and using hydrogenase mutants (ΔhydA, ΔhyaB, and ΔhydAΔhyaB), respectively. The results showed ~97% reduction of palladium by S. oneidensis MR-1 after 24 h using 250 µM palladium and 500 µM formate. Electron microscopy images showed the presence of bio-Pd on both the outer and cytoplasmic membranes of S. oneidensis MR-1. However, the inhibition of NADH dehydrogenases in S. oneidensis MR-1 resulted in only ~61% reduction of palladium after 24 h, and bio-Pd were not found on the outer membrane. The mutants lacking one or two hydrogenases removed 91-96% of palladium ions after 24 h and showed more cytoplasmic bio-Pd but less periplasmic bio-Pd. To the best of our knowledge, this is the first study to demonstrate the role of NADH dehydrogenases of S. oneidensis MR-1 in the formation of bio-Pd on the outer membrane. It also demonstrates that the hydrogenases (especially HyaB) of S. oneidensis MR-1 contribute to the formation of bio-Pd in the periplasmic space. This study provides mechanistic insights into the production of biogenic metal nanoparticles towards their possible use in industrial and environmental applications.

Shewanella oneidensis MR-1 self-assembled Pd-cells-rGO conductive composite for enhancing electrocatalysis.

Biosynthesized noble metal nanoparticles (NPs) as promising green catalysts for electrochemical application has invited a lot of attention. However, effective electron transfer between biosynthesized NPs and electrode remains a challenge due to the uncontrollable and poor conductive property of cell substrates. In this study, graphene oxide (GO) was introduced into a bio-Pd synthesis process governed by Shewanella oneidensis MR-1, which was demonstrated to be simultaneously reduced with Pd(II) and transformed to reduced GO (rGO), resulting in the formation of a Pd-cells-rGO composite. Compared to the control without rGO (Pd-cells), the electrochemical conductivity of Pd-cells-rGO composite increased from almost zero to 196 µS cm-1, indicating the rGO facilities the electron transport across the composite. Electrochemical characterizations revealed the electrochemical active surface area (ECSA) of Pd in Pd-cells-rGO was enlarged by increasing the amount of rGO in the composite, clearly indicating that the conductive network created by rGO enable the Pd NPs receive electrons from electrode and become electrochemical active. A considerable enhancement of electrocatalytic activity was further confirmed for Pd-cells-rGO as indicated by 36.7- and 17.2-fold increase (Pd-cells-rGO with Pd/GO ratio of 5/1 vs Pd-cells) of steady state current density toward hydrogen evolution and nitrobenzene reduction at -0.7 V and -0.55 V vs Ag/AgCl, respectively. We also compared the electrocatalytic performance with MWCNTs hybrids Pd-cells-CNTs. It was found that the association of Pd, cells and rGO creates an interactive and synergistic environment to allow higher conductivity and catalytic activity under the same amount of carbon nanomaterial. The strategy developed in this work activates a highly reactive NPs and proposed a designable protocol for enhancing electrocatalytic activity of biocatalysts.

LLPS of FXR proteins drives replication organelle clustering for ß-coronaviral proliferation.

ß-Coronaviruses remodel host endomembranes to form double-membrane vesicles (DMVs) as replication organelles (ROs) that provide a shielded microenvironment for viral RNA synthesis in infected cells. DMVs are clustered, but the molecular underpinnings and pathophysiological functions remain unknown. Here, we reveal that host fragile X-related (FXR) family proteins (FXR1/FXR2/FMR1) are required for DMV clustering induced by expression of viral non-structural proteins (Nsps) Nsp3 and Nsp4. Depleting FXRs results in DMV dispersion in the cytoplasm. FXR1/2 and FMR1 are recruited to DMV sites via specific interaction with Nsp3. FXRs form condensates driven by liquid-liquid phase separation, which is required for DMV clustering. FXR1 liquid droplets concentrate Nsp3 and Nsp3-decorated liposomes in vitro. FXR droplets facilitate recruitment of translation machinery for efficient translation surrounding DMVs. In cells depleted of FXRs, SARS-CoV-2 replication is significantly attenuated. Thus, SARS-CoV-2 exploits host FXR proteins to cluster viral DMVs via phase separation for efficient viral replication.

Association of body mass index and smoking on outcome of Chinese patients with colorectal cancer.

BACKGROUND: The impact of body mass index (BMI) on the prognosis of patients with colorectal cancer remains largely unknown, particularly in Asian populations. Therefore, the aim of this study was to examine the influence of BMI on clinicopathological characteristics and mortality of Chinese colorectal cancer patients. METHODS: The study cohort consisted of 525 patients who were diagnosed with colorectal cancer and underwent radical surgery at the second hospital of Harbin Medical University between June 2004 and August 2011. Study participants were divided into two BMI categories: normal weight (BMI <23 kg/m²) and overweight (BMI ≥23 kg/m²). RESULTS: Of 525 patients, 208 patients (39.6%) were included in the normal-weight group and 317 patients were included in the overweight group. During the mean follow-up period of 48.8 months, 89 patients had disease recurrence and 131 deaths occurred. High BMI was significantly correlated with younger age, presence of diabetes, alcohol consumption, distal colon tumors, amount of lymph node harvested and pathological stage. No statistically significant correlation was found between high BMI and progression-free survival (PFS) or overall survival (OS) when the total group of patients was considered (P = 0.077 and P = 0.701, respectively). Cigarette-smoking patients had significantly shorter OS than patients who had never smoked (hazard ratio = 1.613, 95% confidence interval = 1.133 to 2.296; P = 0.008), and this difference in OS remained significant in multivariate analysis. Cigarette-smoking patients did not have significantly different PFS compared with patients who had never smoked. CONCLUSION: There was no significant correlation between obesity and outcomes of patients with colorectal cancer. In addition, our findings support the claims that cigarette smoking may be partially responsible for the divergent mortality of patients with colorectal cancer.

Left ventricular longitudinal strain in patients with type 2 diabetes mellitus is independently associated with glycated hemoglobin level.

OBJECTIVE: Left ventricular and left atrial strain are sensitive and reliable markers for evaluating cardiac function in patients with type 2 diabetes mellitus (T2DM), with interactions between the two parameters. The present study aimed to analyze the correlation between global longitudinal strain (GLS) of the left ventricle and glycated hemoglobin (HbA1c) levels in patients with T2DM. METHODS: A total of 292 patients clinically diagnosed with T2DM were selected and divided into three groups according to HbA1c level. The strains of the left atrium and left ventricle in the three groups of T2DM patients with different HbA1c levels were compared. Univariate and multivariate (including left atrial functional indicators) linear regression analyses were performed to assess the relationship between strain indicators and HbA1c levels. Generalized additive models were used to examine the relationship between strain indicators and HbA1c levels. RESULTS: There were significant differences among the three groups in terms of age, microalbuminuria, total cholesterol, fasting blood glucose, postprandial blood glucose, and HbA1c level, and left atrial conduit longitudinal strain (LAScd) and GLS (p < .05). Univariate and multivariate linear regression analyses revealed that, as HbA1c levels increased, the absolute value of GLS gradually decreased (p < .001). Curve fitting revealed a positive correlation between HbA1c level and GLS, which was not affected by left atrial function. CONCLUSION: Left ventricular GLS was independently correlated with HbA1c level in patients with T2DM and was not affected by left atrial function.

Metagenomic analysis characterizes resistomes of an acidic, multimetal(loid)-enriched coal source mine drainage treatment system.

Heavy metal(loid) contaminations caused by mine activities are potential hot spots of antibiotic resistance genes (ARGs) because of heavy metal(loid)-induced co-selection of ARGs and heavy metal(loid) resistance genes (MRGs). This study used high-throughput metagenomic sequencing to analyze the resistome characteristics of a coal source acid mine drainage passive treatment system. The multidrug efflux mechanism dominated the antibiotic resistome, and a highly diverse heavy metal(loid) resistome was dominated by mercury-, iron-, and arsenic--associated resistance. Correlation analysis indicated that mobile gene elements had a greater influence on the dynamic of MRGs than ARGs. Among the metagenome-assembled genomes, six potential pathogens carrying multiple resistance genes resistant to several antibiotics and heavy metal(loid)s were recovered. Pseudomonas spp. contained the highest numbers of resistance genes, with resistance to two types of antibiotics and 12 types of heavy metal(loid)s. Thus, high contents of heavy metal(loid)s drove the co-selection of ARGs and MRGs. The occurrence of potential pathogens containing multiple resistance genes might increase the risk of ARG dissemination in the environment.

Microbial Risks Caused by Livestock Excrement: Current Research Status and Prospects.

Livestock excrement is a major pollutant yielded from husbandry and it has been constantly imported into various related environments. Livestock excrement comprises a variety of microorganisms including certain units with health risks and these microorganisms are transferred synchronically during the management and utilization processes of livestock excrement. The livestock excrement microbiome is extensively affecting the microbiome of humans and the relevant environments and it could be altered by related environmental factors as well. The zoonotic microorganisms, extremely zoonotic pathogens, and antibiotic-resistant microorganisms are posing threats to human health and environmental safety. In this review, we highlight the main feature of the microbiome of livestock excrement and elucidate the composition and structure of the repertoire of microbes, how these microbes transfer from different spots, and they then affect the microbiomes of related habitants as a whole. Overall, the environmental problems caused by the microbiome of livestock excrement and the potential risks it may cause are summarized from the microbial perspective and the strategies for prediction, prevention, and management are discussed so as to provide a reference for further studies regarding potential microbial risks of livestock excrement microbes.

Coal-source acid mine drainage reduced the soil multidrug-dominated antibiotic resistome but increased the heavy metal(loid) resistome and energy production-related metabolism.

A recent global scale study found that mining-impacted environments have multi-antibiotic resistance gene (ARG)-dominated resistomes with an abundance similar to urban sewage but much higher than freshwater sediment. These findings raised concern that mining may increase the risk of ARG environmental proliferation. The current study assessed how typical multimetal(loid)-enriched coal-source acid mine drainage (AMD) contamination affects soil resistomes by comparing with background soils unaffected by AMD. Both contaminated and background soils have multidrug-dominated antibiotic resistomes attributed to the acidic environment. AMD-contaminated soils had a lower relative abundance of ARGs (47.45 ± 23.34 ×/Gb) than background soils (85.47 ± 19.71 ×/Gb) but held high-level heavy metal(loid) resistance genes (MRGs, 133.29 ± 29.36 ×/Gb) and transposase- and insertion sequence-dominated mobile genetic elements (MGEs, 188.51 ± 21.81 ×/Gb), which was 56.26 % and 412.12 % higher than background soils, respectively. Procrustes analysis showed that the microbial community and MGEs exerted more influence on driving heavy metal(loid) resistome variation than antibiotic resistome. The microbial community increased energy production-related metabolism to fulfill the increasing energy needs required by acid and heavy metal(loid) resistance. Horizontal gene transfer (HGT) events primarily exchanged energy- and information-related genes to adapt to the harsh AMD environment. These findings provide new insight into the risk of ARG proliferation in mining environments.

Mechanosensitive channel MscL induces non-apoptotic cell death and its suppression of tumor growth by ultrasound.

Mechanosensitive channel of large conductance (MscL) is the most thoroughly studied mechanosensitive channel in prokaryotes. Owing to its small molecular weight, clear mechanical gating mechanism, and nanopore forming ability upon opening, accumulating studies are implemented in regulating cell function by activating mechanosensitive channel of large conductance in mammalian cells. This study aimed to investigate the potentials of mechanosensitive channel of large conductance as a nanomedicine and a mechano-inducer in non-small cell lung cancer (NSCLC) A549 cells from the view of molecular pathways and acoustics. The stable cytoplasmic vacuolization model about NSCLC A549 cells was established via the targeted expression of modified mechanosensitive channel of large conductance channels in different subcellular organelles. Subsequent morphological changes in cellular component and expression levels of cell death markers are analyzed by confocal imaging and western blots. The permeability of mitochondrial inner membrane (MIM) exhibited a vital role in cytoplasmic vacuolization formation. Furthermore, mechanosensitive channel of large conductance channel can be activated by low intensity focused ultrasound (LIFU) in A549 cells, and the suppression of A549 tumors in vivo was achieved by LIFU with sound pressure as low as 0.053 MPa. These findings provide insights into the mechanisms underlying non-apoptotic cell death, and validate the nanochannel-based non-invasive ultrasonic strategy for cancer therapy.