Associations between regular physical exercise and physical, emotional, and cognitive health of older adults in China: an 8-year longitudinal study with propensity score matching.

Background: The importance of healthy aging is growing in China as it has the largest number of older adults in the world and is one of the fastest-aging countries. This study aimed to examine the predictive value of regular physical exercise in relation to the physical, emotional, and cognitive health among samples of adults aged ≥60 years in China during an 8-year period. Methods: A total of 10,691 older adults were extracted from two waves of national data from the China Family Panel Studies in 2010 and 2018. To minimize the impact of selection bias on the findings, a longitudinal propensity score matching (LPSM) method was used to examine the relationships between regular physical exercise and emotional health (depression), between regular physical exercise and physical health (instrumental activities of daily living), and between regular physical exercise and cognitive health (cognitive ability) of older adults. After LPSM, 856 older adults were included in the study. In the regular physical exercise group, the average age of participants at baseline year was 65.67 years, with an average age of 65.90 years for 238 men and 65.45 years for 190 women, and in the non-physical exercise group, their average age at baseline year was 65.70 years, with an average age of 65.45 years for 253 men and 65.98 years for 175 women. Results: LPSM indicated that regular physical exercise has been found to be effective in improving physical function and reducing depressive symptoms in old adults, even after controlling for background differences. However, the sensitivity analysis suggests that the positive association between regular physical exercise and cognitive function may not be sufficiently valid. Conclusion: The findings of this study indicate that engaging in long-term structured and repetitive physical exercise can have a significant positive effect on reducing depressive symptoms and improving the physical function of older adults. As a result, incorporating regular physical exercise into the lifestyle of older adults is recognized as an effective strategy for promoting healthy aging and reducing the strain on public health resources.

Bioinformatics-based screening and analysis of the key genes involved in the influence of antiangiogenesis on myeloid-derived suppressor cells and their effects on the immune microenvironment.

This study aimed to screen differentially expressed genes (DEGs) involved in the influence of antiangiogenic therapy on myeloid-derived suppressor cell (MDSC) infiltration and investigate their mechanisms of action. Data on DEGs after the action of antiangiogenic drugs in a pan-cancer context were obtained from the Gene Expression Omnibus (GEO) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the clusterProfiler package in R software. Single-sample gene set enrichment analysis was performed using the gene set variation analysis package to evaluate the levels of immune cells and the activity of immune-related pathways. The relationships of DEGs with the infiltration levels of MDSCs and specific immune cell subpopulations were investigated via gene module analysis. The top 10 key genes were subsequently obtained from PPI network analysis using the cytoHubba plugin of the Cytoscape platform. When the DEGs of the four datasets were intersected, a DEG in the intersection of three datasets and 12 DEGs in the intersection of two datasets were upregulated, and 28 DEGs in the intersection of two datasets were downregulated. GO and KEGG pathway enrichment analyses revealed that the DEGs were associated with multiple important signaling pathways closely related to tumor onset and development, including cell differentiation, cell proliferation, the cell cycle, and immune responses. Most downregulated genes in lung adenocarcinoma (LUAD) were positively correlated with MDSC expression. Only MGP was negatively correlated; the correlation between CACNG6 and MDSC expression was statistically insignificant. In lung squamous cell carcinoma (LUSC), the relationships of PMEPA1, PCDH7, NEURL1B, and CACNG6 with MDSC expression were statistically insignificant; MGP was negatively correlated with MDSC expression. The top 10 key genes with the highest degree scores obtained using the cytoHubba plugin of Cytoscape were AURKB, RRM2, BUB1, NUSAP1, PRC1, TOP2A, NCAPH, CENPA, KIF2C, and CCNA2. Most of these genes were upregulated in LUAD and associated with immune cell infiltration and prognosis in tumors. An analysis of the relationships between DEGs and infiltration by other specific immune cells revealed the presence of consistent patterns in the downregulated genes, which exhibited positive correlations with the levels of Th2 cells, γδ T cells, and CD56dim NK cells, and negative correlations with other infiltrating immune cells. Antiangiogenic therapy may regulate MDSC infiltration through multiple important signaling pathways closely associated with tumor onset and development, such as cell differentiation, cell proliferation, the cell cycle, and immune responses. Antiangiogenic drugs may exert effects by affecting various types of infiltrating cells associated with immune suppression.

Novel automated antifungal susceptibility testing system for yeasts based on dual-detection algorithm of turbidimetry and colorimetry.

Introduction. The increasing prevalence and growing resistance of fungi present a significant peril to public health. There are only four classes of antifungal medicines available today, and few candidates are in clinical trials.Hypothesis/Gap Statement. Rapid and sensitive diagnostic techniques are lacking for most fungal pathogens, and those that do exist are expensive or hard to obtain.Aim. This study aimed to evaluate the feasibility of a novel automated antifungal susceptibility testing system, Fungus AST, in comparison to the broth microdilution method (BMD) recommended by the Clinical and Laboratory Standards Institute (CLSI).Methodology. A total of 101 clinical Candida spp. isolates were collected from the Zengcheng Branch of Nanfang Hospital and subjected to antifungal susceptibility testing. Antifungal susceptibility was assessed using the Fungus AST method and the BMD.Results. In this study, we introduce a novel automated antifungal susceptibility testing system, Fungus AST, which detects the turbidity and/or colour intensity of microdilution wells using a four-wavelength detection technology in real time and is designed to match the growth characteristics of strains over time. Based on our analysis, all reportable ranges of Fungus AST were suitable for clinical fungal isolates in PR China. Within ±twofold dilutions, reproducibility was 100 %. Considering the BMD as a referenced method, ten antifungal agents (anidulafungin, caspofungin, micafungin, fluconazole, voriconazole, posaconazole, itraconazole, amphotericin B, 5-flucytosine and nystatin) showed an essential agreement of >95 %. The category agreement of five antifungal agents (anidulafungin, caspofungin, micafungin, fluconazole and voriconazole) was excellent at >90 %. One Candida albicans isolate and voriconazole showed a major error (ME) (1.7 %), and no other ME or very ME agents were found.Conclusion. Given the above, it can be argued that the utilization of Fungus AST is a discretionary automated approach. More improvements are needed in Fungus AST compared to the BMD system for a wider range of clinical isolates, including different types of fungi.

A novel mouse model of calcific aortic valve stenosis.

BACKGROUND: Calcific aortic valve stenosis (CAVS) is one of the most challenging heart diseases in clinical with rapidly increasing prevalence. However, study of the mechanism and treatment of CAVS is hampered by the lack of suitable, robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposition. Here, we aim to establish a mouse model to mimic the development and features of CAVS. METHODS: The model was established via aortic valve wire injury (AVWI) combined with vitamin D subcutaneous injected in wild type C57/BL6 mice. Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradient. Histopathological specimens were collected and examined in respect of valve thickening, calcium deposition, collagen accumulation, osteogenic differentiation and inflammation. RESULTS: Serial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time dependent manner and tended to be stable at 28 days. Compared with the sham group, simple AVWI or the vitamin D group, the hybrid model group showed typical pathological features of CAVS, including hemodynamic alterations, increased aortic valve thickening, calcium deposition, collagen accumulation at 28 days. In addition, osteogenic differentiation, fibrosis and inflammation, which play critical roles in the development of CAVS, were observed in the hybrid model. CONCLUSIONS: We established a novel mouse model of CAVS that could be induced efficiently, robustly and economically, and without genetic intervention. It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effective pharmacological targets.

Decade Milestone Advancement of Defect-Engineered g-C3N4 for Solar Catalytic Applications.

Over the past decade, graphitic carbon nitride (g-C3N4) has emerged as a universal photocatalyst toward various sustainable carbo-neutral technologies. Despite solar applications discrepancy, g-C3N4 is still confronted with a general fatal issue of insufficient supply of thermodynamically active photocarriers due to its inferior solar harvesting ability and sluggish charge transfer dynamics. Fortunately, this could be significantly alleviated by the "all-in-one" defect engineering strategy, which enables a simultaneous amelioration of both textural uniqueness and intrinsic electronic band structures. To this end, we have summarized an unprecedently comprehensive discussion on defect controls including the vacancy/non-metallic dopant creation with optimized electronic band structure and electronic density, metallic doping with ultra-active coordinated environment (M-Nx, M-C2N2, M-O bonding), functional group grafting with optimized band structure, and promoted crystallinity with extended conjugation π system with weakened interlayered van der Waals interaction. Among them, the defect states induced by various defect types such as N vacancy, P/S/halogen dopants, and cyano group in boosting solar harvesting and accelerating photocarrier transfer have also been emphasized. More importantly, the shallow defect traps identified by femtosecond transient absorption spectra (fs-TAS) have also been highlighted. It is believed that this review would pave the way for future readers with a unique insight into a more precise defective g-C3N4 "customization", motivating more profound thinking and flourishing research outputs on g-C3N4-based photocatalysis.

Utility of Goal Attainment Scaling (GAS) in evaluating a multicomponent exercise programme for community-dwelling pre-frail older adults.

OBJECTIVES: This study aimed to investigate the effectiveness of Goal Attainment Scaling (GAS) in assessing an intervention for pre-frail senior citizens. Additionally, the study aimed to explain how the GAS goals were established based on the International Classification of Functioning, Disability and Health (ICF) categories, including body function, activity and participation and environmental factors. METHODS: In this study, 220 pre-frail older adults were randomly selected to participate in a controlled trial. The intervention group engaged in multicomponent exercise three times a week, once at a community health service location and twice at home. The control group received advice on physical activity but did not have supervised exercise. Participants in both groups selected individualised GAS goals from 23 goals developed based on ICF by focus group discussion. The study used generalised estimating equations to analyse the differences between the groups. RESULTS: The study included 144 participants, 72 in the exercise group and 72 in the control group. The top three individualised goals for all participants were vestibular functions (53.5%), pain management (43.1%) and lifting and carrying objects (31.9%). Both groups saw a significant increase in GAS scores at week 8 and week 24 of the intervention (p<0.05), but the exercise group showed a more significant improvement (p<0.05). The participants living alone were associated with lower postintervention improvements in the GAS scores. In contrast, the participants who were using a smartphone were likely to get higher postintervention improvements in the GAS scores. CONCLUSIONS: GAS can be a valuable tool for setting and evaluating individualised and meaningful goals in body functions, activity and participation and environmental factors. The multicomponent exercise interventions can help pre-frail older adults achieve their expected goals as measured by the GAS.

Isorhamnetin as a novel inhibitor of pneumolysin against Streptococcus pneumoniae infection in vivo/in vitro.

The increasing incidence of Streptococcus pneumoniae (S. pneumoniae) infection severely threatened the global public heath, causing a significant fatality in immunocompromised hosts. Notably, pneumolysin (PLY) as a pore-forming cytolysin plays a crucial role in the pathogenesis of pneumococcal pneumonia and lung injury. In this study, a natural flavonoid isorhamnetin was identified as a PLY inhibition to suppress PLY-induced hemolysis by engaging the predicted residues and attenuate cytolysin PLY-mediated A549 cells injury. Underlying mechanisms revealed that PLY inhibitor isorhamnetin further contributed to decrease the formation of bacterial biofilms without affecting the expression of PLY. In vivo S. pneumoniae infection confirmed that the pathological injury of lung tissue evoked by S. pneumoniae was ameliorated by isorhamnetin treatment. Collectively, these results presented that isorhamnetin could inhibit the biological activity of PLY, thus reducing the pathogenicity of S. pneumoniae. In summary, our study laid a foundation for the feasible anti-virulence strategy targeting PLY, and provided a promising PLY inhibitor for the treatment of S. pneumoniae infection.

Nmr-VSM: Non-Touch Motion-Robust Vital Sign Monitoring via UWB Radar Based on Deep Learning.

In recent years, biometric radar has gained increasing attention in the field of non-touch vital sign monitoring due to its high accuracy and strong ability to detect fine-grained movements. However, most current research on biometric radar can only achieve heart rate or respiration rate monitoring in static environments, which have strict monitoring requirements and single monitoring parameters. Moreover, most studies have not applied the collected data despite their significant potential for applications. In this paper, we introduce a non-touch motion-robust vital sign monitoring system via ultra-wideband (UWB) radar based on deep learning. Nmr-VSM not only enables multi-dimensional vital sign monitoring under human motion environments but also implements cardiac anomaly detection. The design of Nmr-VSM includes three key components. Firstly, we design a UWB radar that can perform multi-dimensional vital sign monitoring, including heart rate, respiratory rate, distance, and motion status. Secondly, we collect real experimental data and analyze the impact of eight factors, such as motion status and distance, on heart rate monitoring. We then propose a deep neural network (DNN)-based heart rate data correction model that achieves high robustness in motion environments. Finally, we model the heart rate variability (HRV) of the human body and propose a convolutional neural network (CNN)-based anomaly detection model that achieves low-latency detection of heart diseases, such as ventricular tachycardia and ventricular fibrillation. Experimental results in a real environment demonstrate that Nmr-VSM can not only accurately monitor heart rate but also achieve anomaly detection with low latency.

Human antigen R regulates autophagic flux by stabilizing autophagy-associated mRNA in calcific aortic valve disease.

AIMS: The incidence of calcific aortic valve disease (CAVD) has risen over the last decade and is expected to continue rising; however, pharmacological approaches have proven ineffective. In this study, we evaluated the role and underlying mechanisms of human antigen R (HuR)-mediated post-transcriptional regulation in CAVD. METHODS AND RESULTS: We found that HuR was significantly upregulated in human calcified aortic valves and primary aortic valvular interstitial cells (VICs) following osteogenic stimulation. Subsequent functional studies revealed that HuR silencing ameliorated calcification both in vitro and in vivo. For the first time, we demonstrated that HuR directly interacted with the transcript of phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP4K2A), which mediates phosphatidylinositol signalling, facilitates autophagy, and acts as an mRNA stabilizer. HuR positively modulated PIP4K2A expression at the post-transcriptional level and consequently influenced the AKT/mTOR/ATG13 pathway to regulate autophagy and CAVD progression. CONCLUSION: Our study provides new insights into the post-transcriptional regulatory role of HuR in modulating autophagy-positive factors to regulate the pathogenesis of CAVD. Our findings highlight the potential of HuR as an innovative therapeutic target in CAVD treatment.

Porphyromonas gingivalis Gingipains Destroy the Vascular Barrier and Reduce CD99 and CD99L2 Expression To Regulate Transendothelial Migration.

Porphyromonas gingivalis is an important periodontal pathogen that can cause vascular injury and invade local tissues through the blood circulation, and its ability to evade leukocyte killing is critical to its distal colonization and survival. Transendothelial migration (TEM) is a series of that enable leukocytes to squeeze through endothelial barriers and migrate into local tissues to perform immune functions. Several studies have shown that P. gingivalis-mediated endothelial damage initiates a series of proinflammatory signals that promote leukocyte adhesion. However, whether P. gingivalis is involved in TEM and thus influences immune cell recruitment remains unknown. In our study, we found that P. gingivalis gingipains could increase vascular permeability and promote Escherichia coli penetration by downregulating platelet/endothelial cell adhesion molecule 1 (PECAM-1) expression in vitro. Furthermore, we demonstrated that although P. gingivalis infection promoted monocyte adhesion, the TEM capacity of monocytes was substantially impaired, which might be due to the reduced CD99 and CD99L2 expression on gingipain-stimulated endothelial cells and leukocytes. Mechanistically, gingipains mediate CD99 and CD99L2 downregulation, possibly through the inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway. In addition, our in vivo model confirmed the role of P. gingivalis in promoting vascular permeability and bacterial colonization in the liver, kidney, spleen, and lung and in downregulating PECAM-1, CD99, and CD99L2 expression in endothelial cells and leukocytes. IMPORTANCE P. gingivalis is associated with a variety of systemic diseases and colonizes in distal locations in the body. Here, we found that P. gingivalis gingipains degrade PECAM-1 to promote bacterial penetration while simultaneously reducing leukocyte TEM capacity. A similar phenomenon was also observed in a mouse model. These findings established P. gingivalis gingipains as the key virulence factor in modulating the permeability of the vascular barrier and TEM processes, which may provide a new rationale for the distal colonization of P. gingivalis and its associated systemic diseases.

Analysis of spatial pattern and influencing factors of private clinics in the main urban area of Guiyang in China from 2021 to 2022 based on multi-source data.

BACKGROUND: Private clinics are important places for residents to obtain daily medical care. However, previous researches mainly focused on public medical institutions but ignored the issue of systematic allocation of social medical resources such as clinics. It is critical to understand the private clinics distribution to analyze the rational allocation of medical resources and the spatial difference. METHODS: Based on the field survey, land census, population density, and economic data from Guiyang, this study analyzes the spatial pattern of private clinics in the main urban area of Guiyang and the influencing factors by using spatial analysis methods such as kernel density, standard deviation ellipses, and geo-detector. RESULTS: The private clinics in the main urban area of Guiyang are characterized by "inner dense, outer sparse dense," showing an overall spatial clustering feature of "four cores and two belts with many points" and "dense inside and sparse outside." Different types of private clinics have distinct spatial distribution characteristics and agglomeration forms. The growth of private clinics is closely linked to the population growth of mountainous cities. The most important factors influencing the spatial pattern of private clinics are residential land factors, followed by traffic factors and population density. The impact of economic, natural, and spatial factors is minimal. When using a geo-detector, the results of multi-factor interaction differ from those of single factors, and factor interactions have greater explanatory power than single factors in clinic distribution. CONCLUSION: This study investigates the geographic distribution and influencing variables of private clinics in typical mountain cities and identifies the causes of the current disparity in the distribution of healthcare resources. It is necessary to gradually develop the primary healthcare system in mountainous cities with legislation, counterpart support, and social resources. While ensuring equal access to health care for low-income people and mobile populations, various medical needs of community members should be fully considered and implemented as soon as possible.

Investigation of Nanoscale Tungsten Carbide Enhanced Surface Carbon as a Platinum Support for the Hydrogen Evolution Reaction.

Finding new supports and reducing the amount of platinum are key steps in the development of fuel cells. Herein, nanoscale WC is used as the support for a Pt catalyst, which was prepared by an improved strategy based on solution combustion and chemical reduction. After high-temperature carbonization, the synthesized Pt/WC catalyst displayed a well-distributed size distribution and relatively fine particles, which consisted of WC and modified Pt nanoparticles. Meanwhile, the excess carbon of the precursor transformed into amorphous carbon in the high-temperature process. The formation carbon layer on the surface of the WC nanoparticles had a significant effect on the microstructure of the Pt/WC catalyst, improving the conductivity and stability of Pt. Linear sweep voltammetry and Tafel plots were used to evaluate the catalytic activity and mechanism for the hydrogen evolution reaction. As compared with the WC and commercial Pt/C catalysts, the Pt/WC catalyst showed the highest activity with η10 of 32.3 mV and a Tafel slope of 30 mV·dec-1 towards HER in acidic solution. These studies confirm that the formation of surface carbon can increase material stability and conductivity, improving the synergistic relationships between Pt and WC catalysts, leading to an increase of catalytic activity.

Hybrid Optimization Algorithm Based on Double Particle Swarm in 3D NoC Mapping.

Increasing the number of cores on a chip is one way to solve the bottleneck of exponential growth but an excessive number of cores can lead to problems such as communication blockage and overheating of the chip. Currently, networks-on-chip (NoC) can offer an effective solution to the problem of the communication bottleneck within the chip. With current advancements in IC manufacturing technology, chips can now be 3D-stacked in order to increase chip throughput as well as reduce power consumption while reducing the area of the chip. Automating the mapping of applications into 3D NoC topologies is an important new direction for research in the field of 3D NoC. In this paper, a 3D NoC partitioning algorithm is proposed, which can delineate the 3D NoC region to be mapped. Additionally, a double particle swarm optimization (DPSO) based heuristic algorithm is proposed, which can integrate the characteristics of neighborhood search and genetic algorithms, and thus solve the problem of a particle swarm algorithm falling into local optimal solutions. It is experimentally demonstrated that this DPSO-based hybrid optimization algorithm has a higher throughput rate and lower energy loss than the traditional heuristic algorithm.

The Roles of Riblet and Superhydrophobic Surfaces in Energy Saving Using a Spatial Correlation Analysis.

Riblet and superhydrophobic surfaces are two typical passive control technologies used to save energy. In this study, three microstructured samples-a micro-riblet surface (RS), a superhydrophobic surface (SHS), and a novel composite surface of micro-riblets with superhydrophobicity (RSHS)-were designed to improve the drag reduction rate of water flows. Aspects of the flow fields of microstructured samples, including the average velocity, turbulence intensity, and coherent structures of water flows, were investigated via particle image velocimetry (PIV) technology. A two-point spatial correlation analysis was used to explore the influence of the microstructured surfaces on coherent structures of water flows. Our results showed that the velocity on microstructured surface samples was higher than that on the smooth surface (SS) samples, and the turbulence intensity of water on the microstructured surface samples decreased compared with that on the SS samples. The coherent structures of the water flow on microstructured samples were restricted by length and structural angles. The drag reduction rates of the SHS, RS, and RSHS samples were -8.37 %, -9.67 %, and -17.39 %, respectively. The novel established RSHS demonstrated a superior drag reduction effect and could improve the drag reduction rate of water flows.

A single F153Sß3 mutation causes constitutive integrin αIIbß3 activation in a variant form of Glanzmann thrombasthenia.

This report identifies a novel variant form of the inherited bleeding disorder Glanzmann thrombasthenia, exhibiting only mild bleeding in a physically active individual. The platelets cannot aggregate ex vivo with physiologic agonists of activation, although microfluidic analysis with whole blood displays moderate ex vivo platelet adhesion and aggregation consistent with mild bleeding. Immunocytometry shows reduced expression of αIIbß3 on quiescent platelets that spontaneously bind/store fibrinogen, and activation-dependent antibodies (ligand-induced binding site-319.4 and PAC-1) report ß3 extension suggesting an intrinsic activation phenotype. Genetic analysis reveals a single F153Sß3 substitution within the ßI-domain from a heterozygous T556C nucleotide substitution of ITGB3 exon 4 in conjunction with a previously reported IVS5(+1)G>A splice site mutation with undetectable platelet messenger RNA accounting for hemizygous expression of S153ß3. F153 is completely conserved among ß3 of several species and all human ß-integrin subunits suggesting that it may play a vital role in integrin structure/function. Mutagenesis of αIIb-F153Sß3 also displays reduced levels of a constitutively activated αIIb-S153ß3 on HEK293T cells. The overall structural analysis suggests that a bulky aromatic, nonpolar amino acid (F,W)153ß3 is critical for maintaining the resting conformation of α2- and α1-helices of the ßI-domain because small amino acid substitutions (S,A) facilitate an unhindered inward movement of the α2- and α1-helices of the ßI-domain toward the constitutively active αIIbß3 conformation, while a bulky aromatic, polar amino acid (Y) hinders such movements and restrains αIIbß3 activation. The data collectively demonstrate that disruption of F153ß3 can significantly alter normal integrin/platelet function, although reduced expression of αIIb-S153ß3 may be compensated by a hyperactive conformation that promotes viable hemostasis.

Evaluation of Commercial Products for Colistin and Polymyxin B Susceptibility Testing for mcr-Positive and Negative Escherichia coli and Klebsiella pneumoniae in China.

Purpose: To evaluate the performance of five widespread commercial products for colistin and polymyxin B susceptibility testing in China for mcr-positive and -negative Escherichia coli and Klebsiella pneumoniae. Methods: A total of 132 E. coli and 83 K. pneumoniae strains (including 68 mcr-1-positive E. coli and 28 mcr-8-positive K. pneumoniae) were collected. We analysed the performance of colistin susceptibility (with Vitek 2 and Phoenix M50) and the performance of polymyxin B susceptibility (with DL-96II, MA120, and a Polymyxin B Susceptibility Test strip; POL E-strip). Broth microdilution was used as the gold standard. Categorical agreement (CA), essential agreement (EA), major error (ME), and very major error (VME) were calculated for comparisons. Results: For E. coli, the total CA, EA, ME, and VME to colistin were as follows: Vitek 2, 98.5%/98.5%/0%/2.9%; and Phoenix M50, 98.5%/97.7%/0%/2.9%. The total CA, EA, ME, and VME to polymyxin B were as follows: POL E-strip, 99.2%/63.6%/1.6%/0%; MA120, 70.0%/-/0%/58.8%; and DL-96II, 80.2%/-/1.6%/36.8%. Only Vitek 2 and Phoenix M50 presented satisfactory performances for mcr-1-positive E. coli. For K. pneumoniae, the total CA, EA, ME, and VME to colistin were as follows: Vitek 2, 73.2%/72.0%/0%/61.6%; and Phoenix M50, 74.7%/74.7%/0%/58.3%. The total CA, EA, ME, and VME to polymyxin B were as follows: POL E-strip, 91.6%/74.7%/2.1%/16.7%; MA120, 92.8%/-/2.1%/13.9%; and DL-96II, 92.2%/-/2.1%/8.3%. All systems were unsatisfactory for mcr-8-positive K. pneumoniae. When the susceptibility of mcr-negative strains was tested, all systems presented excellent performance. Conclusion: Vitek 2 and Phoenix M50 with colistin for E. coli showed acceptable performance regardless of mcr-1 expression, while DL-96II, MA120, and the POL E-strip performed worse for mcr-1-positive strains. Furthermore, mcr-8 greatly affected the performance of all systems with both colistin and polymyxin B for K. pneumoniae isolates.

Augmentation of Histone Deacetylase 6 Activity Impairs Mitochondrial Respiratory Complex I in Ischemic/Reperfused Diabetic Hearts.

BACKGROUND: Diabetes augments activity of histone deacetylase 6 (HDAC6) and generation of tumor necrosis factor α (TNFα) and impairs the physiological function of mitochondrial complex I (mCI) which oxidizes reduced nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide to sustain the tricarboxylic acid cycle and ß-oxidation. Here we examined how HDAC6 regulates TNFα production, mCI activity, mitochondrial morphology and NADH levels, and cardiac function in ischemic/reperfused diabetic hearts. METHODS: HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent myocardial ischemia/reperfusion injury in vivo or ex vivo in a Langendorff-perfused system. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. We compared the activities of HDAC6 and mCI, TNFα and mitochondrial NADH levels, mitochondrial morphology, myocardial infarct size, and cardiac function between groups. RESULTS: Myocardial ischemia/reperfusion injury and diabetes synergistically augmented myocardial HDCA6 activity, myocardial TNFα levels, and mitochondrial fission and inhibited mCI activity. Interestingly, neutralization of TNFα with an anti-TNFα monoclonal antibody augmented myocardial mCI activity. Importantly, genetic disruption or inhibition of HDAC6 with tubastatin A decreased TNFα levels, mitochondrial fission, and myocardial mitochondrial NADH levels in ischemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and ameliorated cardiac dysfunction. In H9c2 cardiomyocytes cultured in high glucose, hypoxia/reoxygenation augmented HDAC6 activity and TNFα levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown. CONCLUSIONS: Augmenting HDAC6 activity inhibits mCI activity by increasing TNFα levels in ischemic/reperfused diabetic hearts. The HDAC6 inhibitor, tubastatin A, has high therapeutic potential for acute myocardial infarction in diabetes.

Splice site m6A methylation prevents binding of DGCR8 to suppress KRT4 pre-mRNA splicing in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the 11th most prevalent tumor worldwide. Despite advantages of therapeutic approaches, the 5-year survival rate of patients with OSCC is less than 50%. It is urgent to elucidate mechanisms underlying OSCC progression for developing novel treatment strategies. Our recent study has revealed that Keratin 4 (KRT4) suppresses OSCC development, which is downregulated in OSCC. Nevertheless, the mechanism downregulating KRT4 in OSCC remains unknown. In this study, touchdown PCR was utilized to detect KRT4 pre-mRNA splicing, while m6A RNA methylation was identified by methylated RNA immunoprecipitation (MeRIP). Besides, RNA immunoprecipitation (RIP) was used to determine RNA-protein interaction. Herein, this study indicated that intron splicing of KRT4 pre-mRNA was suppressed in OSCC. Mechanistically, m6A methylation of exon-intron boundaries prevented intron splicing of KRT4 pre-mRNA in OSCC. Besides, m6A methylation suppressed the binding of splice factor DGCR8 microprocessor complex subunit (DGCR8) to exon-intron boundaries in KRT4 pre-mRNA to prohibit intron splicing of KRT4 pre-mRNA in OSCC. These findings revealed the mechanism downregulating KRT4 in OSCC and provided potential therapeutic targets for OSCC.

Therapeutic potential of kaempferol on Streptococcus pneumoniae infection.

Co-infections with pathogens and secondary bacterial infections play significant roles during the pandemic coronavirus disease 2019 (COVID-19) pathogenetic process, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Notably, co-infections with Streptococcus pneumoniae (S. pneumoniae), as a major Gram-positive pathogen causing pneumonia or meningitis, severely threaten the diagnosis, therapy, and prognosis of COVID-19 worldwide. Accumulating evidences have emerged indicating that S. pneumoniae evolves multiple virulence factors, including pneumolysin (PLY) and sortase A (SrtA), which have been extensively explored as alternative anti-infection targets. In our study, natural flavonoid kaempferol was identified as a potential candidate drug for infection therapeutics via anti-virulence mechanisms. We found that kaempferol could interfere with the pore-forming activity of PLY by engaging with catalytic active sites and consequently inhibit PLY-mediated cytotoxicity. Additionally, exposed to kaempferol significantly reduced the SrtA peptidase activity by occupying the active sites of SrtA. Further, the biofilms formation and bacterial adhesion to the host cells could be significantly thwarted by kaempferol incubation. In vivo infection model by S. pneumoniae highlighted that kaempferol oral administration exhibited notable treatment benefits, as evidenced by decreased bacterial burden, suggesting that kaempferol has tremendous potential to attenuate S. pneumoniae pathogenicity. Scientifically, our study implies that kaempferol is a promising therapeutic option by targeting bacterial virulence factors.