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As a widely spread Gram-negative bacteria, Klebsiella pneumoniae (KP) mainly causes acquired infections in hospitals, such as lung infections, urinary tract infections, and bloodstream infections. In recent years, the number of multidrug-resistant KP strains has increased dramatically, posing a great threat to human health. Carbapenem-resistant KP (CRKP) can be colonized in human body, especially in gastrointestinal tract, and some colonized patients can be infected during hospitalization, among which invasive operation, underlying disease, admission to intensive care unit, antibiotic use, severity of the primary disease, advanced age, operation, coma, and renal failure are common risk factors for secondary infection. Active screening and preventive measures can effectively prevent the occurrence of CRKP infection. Based on the epidemiological status, this study aims to discuss the correlation between colonization and secondary infection induced by CRKP and risk factors for their happening and provide some reference for nosocomial infection prevention and control.

Abstract Colorectal carcinogenesis and progression are associated with aberrant alternative splicing, yet its molecular mechanisms remain largely unexplored. Here, we find that Microrchidia family CW-type zinc finger 2 (MORC2) binds to RRM1 domain of RNA binding motif protein 39 (RBM39), and RBM39 interacts with site 1 of pre-CDK5RAP2 exon 32 via its UHM domain, resulting in a splicing switch of cyclin-dependent kinase 5 regulatory subunit associated protein 2 (CDK5RAP2) L to CDK5RAP2 S. CDK5RAP2 S promotes invasion of colorectal cancer cells in vitro and metastasis in vivo. Mechanistically, CDK5RAP2 S specifically recruits the PHD finger protein 8 to promote Slug transcription by removing repressive histone marks at the Slug promoter. Moreover, CDK5RAP2 S, but not CDK5RAP2 L, is essential for the promotion of epithelial-mesenchymal transition induced by MORC2 or RBM39. Importantly, high protein levels of MORC2, RBM39 and Slug are strongly associated with metastasis and poor clinical outcomes of colorectal cancer patients. Taken together, our findings uncover a novel mechanism by which MORC2 promotes colorectal cancer metastasis, through RBM39-mediated pre-CDK5RAP2 alternative splicing and highlight the MORC2/RBM39/CDK5RAP2 axis as a potential therapeutic target for colorectal cancer.

Objective The aim of this study was to evaluate the effect of random route multi-directional sprint training (MDST) compared to fixed route MDST on change-of-direction speed (CODS) and reactive agility (RA), and to investigate the correlation between CODS, RA and short-distance straight sprint speed (SDSS). Method A total of 19 collegiate tennis players from Beijing Sport University were randomly assigned to either the random route MDST group (RR group, N = 9, age: 22.22 ± 2.22 years) or the fixed route MDST group (FR group, N = 10, age: 21.90 ± 1.66 years). Both groups completed a progressive load intervention training for 3 weeks, three times a week. The RR group’s random route, mirroring the distance and number of change-of-direction (COD) in the FR group’s fixed route, was specifically designed. The spider run, T-drill, RA test and 5-m straight line sprint test were performed before and after the intervention. Results Both groups showed improved performance in the spider run (p < 0.05), T-drill (p < 0.01) and 5-m straight (p < 0.001) line sprint test after the intervention. Additionally, there was no significant difference in the improvement of CODS and SDSS between the two groups (p > 0.05). The RA of the RR and FR groups after the intervention was significantly higher than before intervention (p < 0.001), and RR group showed greater improvement in RA compared to the FR group. There was a moderate correlation between spider run and T-drill (r = 0.523), RA (r = 0.388), and no significant correlation between spider run and 5-m straight sprint (p > 0.05). T-drill was moderately correlated with RA (r = 0.347) and 5-m straight sprint (r = 0.321). RA was moderately correlated with 5-m straight sprint (r = 0.551). Conclusion Three-week multi-directional sprint training can effectively improve the change-of-direction speed, reactive agility and short-distance straight sprint speed of collegiate tennis players. And random route multi-directional sprint training has better effect on improving reactive agility.

In order to further improve the utility of unmanned aerial vehicle (UAV) remote-sensing for quickly and accurately monitoring the growth of winter wheat under film mulching, this study examined the treatments of ridge mulching, ridge–furrow full mulching, and flat cropping full mulching in winter wheat. Based on the fuzzy comprehensive evaluation (FCE) method, four agronomic parameters (leaf area index, above-ground biomass, plant height, and leaf chlorophyll content) were used to calculate the comprehensive growth evaluation index (CGEI) of the winter wheat, and 14 visible and near-infrared spectral indices were calculated using spectral purification technology to process the remote-sensing image data of winter wheat obtained by multispectral UAV. Four machine learning algorithms, partial least squares, support vector machines, random forests, and artificial neural network networks (ANN), were used to build the winter wheat growth monitoring model under film mulching, and accuracy evaluation and mapping of the spatial and temporal distribution of winter wheat growth status were carried out. The results showed that the CGEI of winter wheat under film mulching constructed using the FCE method could objectively and comprehensively evaluate the crop growth status. The accuracy of remote-sensing inversion of the CGEI based on the ANN model was higher than for the individual agronomic parameters, with a coefficient of determination of 0.75, a root mean square error of 8.40, and a mean absolute value error of 6.53. Spectral purification could eliminate the interference of background effects caused by mulching and soil, effectively improving the accuracy of the remote-sensing inversion of winter wheat under film mulching, with the best inversion effect achieved on the ridge–furrow full mulching area after spectral purification. The results of this study provide a theoretical reference for the use of UAV remote-sensing to monitor the growth status of winter wheat with film mulching.

Abstract Background This meta-analysis aims to investigate the efficacy of early rehabilitation on patients who have undergone surgery for distal radius fractures (DRFs) with palmar plating, focusing on multiple outcome measures including upper limb function, wrist function, back extension mobility, pain levels, and complications. Methods A rigorous search strategy adhering to the PRISMA guidelines was employed across four major databases, including PubMed, Embase, Web of Science, and the Cochrane Library. Studies were included based on stringent criteria, and data extraction was performed independently by two reviewers. Meta-analysis was conducted employing both fixed-effect and random-effects models as dictated by heterogeneity, assessed by the I2 statistic and chi-square tests. A total of 7 studies, encompassing diverse demographic groups and timelines, were included for the final analysis. Results The meta-analysis disclosed that early rehabilitation yielded a statistically significant improvement in upper limb function (SMD -0.27; 95% CI -0.48 to -0.07; P

ABSTRACT Acinetobacter baumannii is one of the most important pathogens worldwide. The intrinsic and acquired resistance of A. baumannii, coupled with the slow pace of novel antimicrobial drug development, poses an unprecedented and enormous challenge to clinical anti-infective therapy of A. baumannii. Recent studies in the field of pathogenicity, antibiotic resistance, and biofilms of A. baumannii have focused on the model strains, including ATCC 17978, ATCC 19606, and AB5075. However, these model strains represent only a limited portion of the heterogeneity in A. baumannii. Furthermore, variants of these model strains have emerged that show significant diversity not only at the genotypic level but also reflected in differences at the phenotypic levels of capsule, virulence, pathogenicity, and antibiotic resistance. Research on A. baumannii, a key pathogen, would benefit from a standardized approach, which characterizes heterogeneous strains in order to facilitate rapid diagnosis, discovery of new therapeutic targets, and efficacy assessment. Our study provides and describes a standardized, genomically and phenotypically heterogeneous panel of 45 different A. baumannii strains for the research community. In addition, we performed comparative analyses of several phenotypes of this panel. We found that the sequence type 2 (ST2) group showed significantly higher rates of resistance, lower fitness cost for adaptation, and yet less biofilm formation. The Macrocolony type E (MTE, flat center and wavy edge phenotype reported in the literature) group showed a less clear correlation of resistance rates and growth rate, but was observed to produce more biofilms. Our study sheds light on the complex interplay of resistance fitness and biofilm formation within distinct strains, offering insights crucial for combating A. baumannii infection.IMPORTANCEAcinetobacter baumannii is globally notorious, and in an effort to combat the spread of such pathogens, several emerging candidate therapies have already surfaced. However, the strains used to test these therapies vary across studies (the sources and numbers of test strains are varied and often very large, with little heterogeneity). The variation complicates the studies. Furthermore, the limited standardized resources of A. baumannii strains have greatly restricted the research on the physiology, pathogenicity, and antibiotic resistance. Therefore, it is crucial for the research community to acquire a standardized and heterogeneous panel of A. baumannii. Our study meticulously selected 45 diverse A. baumannii strains from a total of 2,197 clinical isolates collected from 64 different hospitals across 27 provinces in China, providing a scientific reference for the research community. This assistance will significantly facilitate scientific exchange in academic research.

Objective: To investigate the effects of 8-week aquatic and land high intensity interval training (HIIT) on hemodynamics and vascular function in middle-aged men.Methods: Thirty middle-aged men with low physical activity were selected and divided into 15 men (52.43 ± 4.11) in aquatic group and 15 men (52.74 ± 5.62) in land group by random number table. They performed HIIT exercise in aquatic and land 3 times a week for 8 weeks. Pre-test, inter-test and post-test respectively measure hemodynamics and blood vessel function.Results: (1) Body composition: After 8 weeks of exercise, weight, body mass index (BMI) and body fat rate (BF) were lower than before exercise (aquatic group: p < 0.01, land group: p < 0.05). The improvement of BF in the aquatic group was better than that in the land group (p < 0.05); (2) Cardiac function: After 8 weeks of exercise, stroke volume (SV), left ventricular end-diastolic volume (EDV), cardiac output (CO), and left ventricular fractional shortening (FS), were higher than before exercise (aquatic group: p < 0.01, land group: p < 0.05), heart rate (HR) and left ventricular end-systolic volume (ESV) were lower than before exercise (aquatic group: p < 0.01, land group: p < 0.05). The improvement of SV, HR, EDV, ESV, CO and FS in the aquatic group was better than that in the land group (p < 0.05); (3) Hemodynamics: After 8 weeks of exercise, systolic blood pressure (SBP), diastolic blood pressure (DBP) were lower than before exercise (aquatic group: p < 0.01, land group: p < 0.05), wall shear stress (WSS) and peak systolic velocity (PSV) were higher than before exercise (aquatic group: p < 0.01, land group: p < 0.05). The improvement of SBP, WSS and PSV in the aquatic group was better than that in the land group (p < 0.05); (4) Vascular function: basal diameter and brachial artery flow-mediated dilatation (FMD) level in aquatic group and land group was higher than before exercise, pulse wave velocity (PWV) level was lower than before exercise (aquatic and land group: p < 0.05). The improvement of FMD in the aquatic group was better than that in the land group.Conclusion: The body composition, hemodynamics and vascular function of middle-aged men were improved by 8-week aquatic and land HIIT. Aquatic HIIT has better effect on body fat rate, hemodynamics and vascular endothelial function in middle-aged men due to the effect of aquatic pressure and temperature.

Abstract FBXO31, a member of F-box family to comprise of SCF complex, contributes to a pivotal role in cancer progression. However, the possible involvements of FBXO31 in PC are unelucidated. Here, we reported that FBXO31 was overexpressed in PC patients, which was negatively associated with survival in PC patients. Furthermore, FBXO31 significantly enhanced growth, migration and invasion of PC cells in vitro. Consistently, FBXO31 overexpression promoted tumor growth in nude mice. Mechanistically, SIRT2 was a target of FBXO31 and interacted with FBXO31. Protein half-life and ubiquitination analysis demonstrated that FBXO31 promoted proteasome-dependent degradation of SIRT2. In addition, FBXO31 binds to sirtuin-type domain of SIRT2. Moreover, SIRT2 is required for the oncogenic role of FBXO31 in PC progression. Impressively, METTL3 induced m6A modification of FBXO31 and up-regulated FBXO31 expression, subsequently leading to SIRT2 down-regulation in PC cells. The results showed that METTL3 enhanced FBXO31 mRNA translation in YTHDF1-dependent manner. Taken together, we suggest that METTL3–FBXO31–SIRT2 axis was involved in PC tumorigenesis, which could identify new targets for PC treatment.

Acinetobacter baumannii is an important nosocomial pathogen. Upon colonizing a host, A. baumannii are subjected to selective pressure by immune defenses as they adapt to the host environment. However, the mechanism of this pathoadaptation is unknown. Here, we established an in vitro system to evolve A. baumannii driven by the continuous selective pressure exerted by epithelial cells, and we used a combination of experimental evolution, phenotypic characterization and multi-omics analysis to address the underlying mechanism. When continuously exposed to selective pressure by pulmonary epithelial cells, A. baumannii showed ptk mutation-mediated mucoid conversion (reduced adhesion and increased anti-phagocytic ability) by enhancement of capsular exopolysaccharide chain length; rsmG mutation-mediated deficiency of 7-methylguanosine modification in the 524th nucleotide of 16S rRNA, which increased ribosome translation efficiency; and rnaseI mutation-mediated changes in outer membrane permeability and efflux pump expression. Together, these mutations altered susceptibility to a variety of antimicrobial agents, including the novel antibiotic cefiderocol, by regulating siderophore and siderophore-receptor biosynthesis. In conclusion, pulmonary epithelial cells modulate A. baumannii pathoadaptation, implicating the host–microbe interaction in the survival and persistence of A. baumannii.

ABSTRACT: Objectives: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a prevalent pathogen contributing to hospital infections. Pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST) and core-genome MLST (cgMLST) are frequently used methods to illuminate the nosocomial transmission of CRAB. In this study, we compared the discriminatory power of the three typing methods. Methods: Antimicrobial susceptibility tests were performed by the broth microdilution and Vitek2 methods. PFGE, MLST and cgMLST were conducted to determine the clonality and phylogenetic relationship of the strains. Whole-genome sequence data were acquired by an Illumina HiSeq 2000, and cgMLST was analysed by the Ridom SeqSphere+ v.7.2.3 software. Results: A total of 149 carbapenem-resistant A. baumannii isolates had 15 different PFGE profiles (A-O type), and 73 of the isolates had related subtypes (A1 and A2), accounting for the majority of type A isolates. The maximum-likelihood phylogenetic analysis based on the cgMLST genes grouped the same PFGE clonal pattern A into nine different clusters. ST_Pasteur grouped all the strains into ST2, whereas ST_Oxford grouped the PFGE clonal pattern A isolates into six STs. In addition, the gdhB allele in the ST_Oxford scheme had two copies in five strains, which complicated the ST_Oxford typing. Conclusions: cgMLST was more discriminant than PFGE and MLST. CgMLST is the most suitable and comprehensive method for genotyping A. baumannii in surveillance and epidemiological research.

Summary: How pathogens manipulate host UPRER to mediate immune evasion is largely unknown. Here, we identify the host zinc finger protein ZPR1 as an interacting partner of the enteropathogenic E. coli (EPEC) effector NleE using proximity-enabled protein crosslinking. We show that ZPR1 assembles via liquid-liquid phase separation (LLPS) in vitro and regulates CHOP-mediated UPRER at the transcriptional level. Interestingly, in vitro studies show that the ZPR1 binding ability with K63-ubiquitin chains, which promotes LLPS of ZPR1, is disrupted by NleE. Further analyses indicate that EPEC restricts host UPRER pathways at the transcription level in a NleE-ZPR1 cascade-dependent manner. Together, our study reveals the mechanism by which EPEC interferes with CHOP-UPRER via regulating ZPR1 to help pathogens escape host defense.

Membrane-anchored PD-L1 homodimerizes in cells. N-glycosylation of PD-L1 regulates its homodimerization. The formation of PD-L1 homodimers further regulates their glycan processing, localization to the plasma membrane, and binding to PD-1.

Introduction: Polymyxin B is a last-line therapy for carbapenem-resistant microorganisms. However, a lack of clinical pharmacokinetic/pharmacodynamic (PK/PD) data has substantially hindered dose optimization and breakpoint setting.Methods: A prospective, multi-center clinical trial was undertaken with polymyxin B [2.5 mg/kg loading dose (3-h infusion), 1.25 mg/kg/12 h maintenance dose (2-h infusion)] for treatment of carbapenem-resistant K. pneumoniae (CRKP) bloodstream infections (BSI). Safety, clinical and microbiological efficacy were evaluated. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to determine the concentrations of polymyxin B in blood samples. Population pharmacokinetic (PK) modeling and Monte Carlo simulations were conducted to examine the susceptibility breakpoint for polymyxin B against BSI caused by CRKP.Results: Nine patients were enrolled and evaluated for safety. Neurotoxicity (5/9), nephrotoxicity (5/9), and hyperpigmentation (1/9) were recorded. Blood cultures were negative within 3 days of commencing therapy in all 8 patients evaluated for microbiological efficacy, and clinical cure or improvement occurred in 6 of 8 patients. Cmax and Cmin following the loading dose were 5.53 ± 1.80 and 1.62 ± 0.41 mg/L, respectively. With maintenance dosing, AUCss,24 h was 79.6 ± 25.0 mg h/L and Css,avg 3.35 ± 1.06 mg/L. Monte Carlo simulations indicated that a 1 mg/kg/12-hourly maintenance dose could achieve >90% probability of target attainment (PTA) for isolates with minimum inhibitory concentration (MIC) ≤1 mg/L. PTA dropped substantially for MICs ≥2 mg/L, even with a maximally recommended daily dose of 1.5 mg/kg/12-hourly.Conclusion: This is the first clinical PK/PD study evaluating polymyxin B for BSI. These results will assist to optimize polymyxin B therapy and establish its breakpoints for CRKP BSI.

Cryptococcus spp. is a complex species that often causes cryptococcosis, which is one of the most common opportunistic infections in adults living with HIV and has very high morbidity and mortality rates. This study aimed to investigate the antifungal susceptibility profiles and epidemiological characteristics of the Cryptococcus neoformans species complex (CNSC) and the Cryptococcus gattii species complex (CGSC) in Zhejiang Province, China. A total of 177 CNSC and 3 CGSC isolates were collected, and antifungal susceptibility was tested by FUNGUS 3 and verified with an E-test. Moreover, multiple classification methods and genomic analyses were performed. The majority of the isolates (96.11%) were C. neoformans (formerly C. neoformans var. grubii) (ST5-VNI-A-α). Our study highlights that most of the patients with cryptococcosis were non-HIV patients in China, and nearly half of them did not have underlying diseases that led to immune insufficiency. Most of the Cryptococcus spp. isolates in this study were sensitive to common antifungal drugs. Two 5-flucytosine (5-FC)-resistant strains were identified, and FUR1 mutation was detected in the 5-FC-resistant isolates. Typing based on whole-genome sequencing (WGS) showed better discrimination than that achieved with multilocus sequence typing (MLST) and indicated a clear population structure. A phylogenetic analysis based on WGS included more genomic information than traditional classification methods.

Microalgae cultivation using wastewater is a combined process for pollutant removal and lipid production that has been widely studied in recent years. In this study, the effects of anaerobic membrane effluent (AME) and municipal wastewater (MW) ratios on microalgae growth and pollutant removal processes were investigated, and the lipid production properties were also explored. Results show that microalgae can grow in all AME/WW ratios, and a 40% AME content is the optimal condition for microalgal biomass accumulation (52.9 mg/L·d) and lipid production (0.378 g/L). Higher AME addition would inhibit microalgae growth. In addition, high ammonia (approximately 97%) and phosphate (around 90%) removal efficiencies can be achieved in all AME/WW ratio conditions, while the total nitrogen removal efficiencies decreased with the addition of AME. Total nitrogen and phosphate are the limiting factors in treating water to meet the requirements of the integrated wastewater discharge standard. This study provided a new method for anaerobic digestion and municipal wastewater treatment and also realized green energy production based on the sustainable development principles.

A reliable finite element procedure to simulate shear-dominated ductile fractures in large-scale, thin-walled steel structures is still evolving primarily due to the challenges in determining the failure criterion of metal materials under complex stress states. This paper aims to examine the accuracy of the modified Gurson–Tvergaard–Needleman (GTN) model considering the shear failure in simulating the ductile fracture of steel plate structures under quasi-static punch loading. The modified GTN damage models are performed by the ABAQUS user-defined material subroutine (VUMAT). The void-related parameters and shear damage parameters of Xue’s and the N-H modified GTN models are calibrated from test specimens with various geometries corresponding to different stress triaxiality and shearing conditions. The damage evolution associated with shearing of voids in the modified GTN models has strong influences on the stress triaxiality versus plastic strain under complex stress states, especially for the shear-dominated loading conditions. Based on the original GTN model, Xue’s and the N-H modified GTN model with calibrated material parameters, a numerical comparative study examines the ductile fracture of steel non-stiffened plates and stiffened plates under punch loading. Benchmarked against the experimental studies, the numerical simulations demonstrate that the shear-driven void evolution in the modified GTN model imposes significant effects on the load–displacement responses as well as the onset and extension of ductile fractures in steel plates under punch actions. The N-H modified model with calibrated shear damage parameters shows a better correlation with the ductile fractures in steel plates observed in the experiment than the original GTN model and Xue’s modified GTN model. As a result of this study, the modified GTN model considering shear action can be applied for practical applications in the crashworthiness assessment of ship collision and grounding.

The optimization of drug properties in the process of cancer drug development is very important to save research and development time and cost. In order to make the anti-breast cancer drug candidates with good biological activity, this paper collected 1974 compounds, firstly, the top 20 molecular descriptors that have the most influence on biological activity were screened by using XGBoost-based data feature selection; secondly, on this basis, take pIC50 values as feature data and use a variety of machine learning algorithms to compare, soas to select a most suitable algorithm to predict the IC50 and pIC50 values. It is preliminarily found that the effects of Random Forest, XGBoost and Gradient-enhanced algorithms are good and have little difference, and the Support vector machine is the worst. Then, using the Semi-automatic parameter adjustment method to adjust the parameters of Random Forest, XGBoost and Gradient-enhanced algorithms to find the optimal parameters. It is found that the Random Forest algorithm has high accuracy and excellent anti over fitting, and the algorithm is stable. Its prediction accuracy is 0.745. Finally, the accuracy of the results is verified by training the model with the preliminarily selected data, which provides an innovative solution for the optimization of the properties of anti- breast cancer drugs, and can provide better support for the early research and development of anti-breast cancer drugs.

Callus browning heavily affects indica rice transformation regeneration. Here, the authors show transposon insertion in the promoter of BOC1 gene, encoding a SIMILAR TO RADICAL-INDUCED CELL DEATH ONE protein, can upregulate its expression and decrease callus browning in cultivated rice by releasing oxidative stress.

With the rapid development of smart cities, intelligent navigation, and autonomous driving, how to quickly obtain 3D spatial information of urban buildings and build a high-precision 3D fine model has become a key problem to be solved. As the two-dimensional mapping results have constrained various needs in people’s social life, coupled with the concept of digital city and advocacy, making three-dimensional, virtualization and actualization become the common pursuit of people’s goals. However, the original point cloud obtained is always incomplete due to reasons such as occlusion during acquisition and data density decreasing with distance, resulting in extracted boundaries that are often incomplete as well. In this paper, based on the study of current mainstream 3D model data organization methods, geographic grids and map service specifications, and other related technologies, an intelligent urban 3D modeling model based on multisource data point cloud algorithm is designed for the two problems of unified organization and expression of urban multisource 3D model data. A point cloud preprocessing process is also designed: point cloud noise reduction and downsampling to ensure the original point cloud geometry structure remain unchanged, while improving the point cloud quality and reducing the number of point clouds. By outputting to a common 3D format, the 3D model constructed in this paper can be applied to many fields such as urban planning and design, architectural landscape design, urban management, emergency disaster relief, environmental protection, and virtual tourism.

Carbapenem-resistant Acinetobacter baumannii (CRAB) isolates of global clone 1 (GC1) and global clone 2 (GC2) have been widely reported. Nevertheless, non-GC1 and non-GC2 CRAB strains have been studied less. In particular, no reports concerning sequence type 46 (ST46Pas) CRAB strains have been described thus far. In this work, the genomic features and possible evolution mechanism of ST46Pas OXA-23-producing CRAB isolates from clinical specimens are reported for the first time. Antimicrobial susceptibility testing of three ST46Pas strains revealed identical resistance profiles (resistance to imipenem, meropenem, ciprofloxacin and the combination of cefoperazone/sulbactam at a 2:1 ratio). They were found to belong to ST46Pas and ST462Oxf with capsular polysaccharide 28 (KL28) and lipooligosaccharide 1 (OCL1), respectively. Whole-genome sequencing (WGS) revealed that all contained one copy of chromosomal blaOXA-23, which was located in a novel ISAba1-based Tn7534 composite transposon. In particular, another copy of the Tn7534 composite transposon was identified in an Hgz_103-type plasmid with 9 bp target site duplications (TSDs, ACAACATGC) in the A. baumannii ZHOU strain. As the strains originated from two neighboring intensive care units (ICUs), ST46Pas OXA-23-producing CRAB strains may have evolved via transposition events or a pdif module. Based on the GenBank database, ST46Pas strains were collected from various sources; however, most were collected in Hangzhou (China) from 2014 to 2021. Pan-genome analysis revealed 3276 core genes, 0 soft-core genes, 768 shell genes and 443 cloud genes shared among all ST46Pas strains. In conclusion, the emergence of ST46Pas CRAB strains might present a new threat to healthcare settings; therefore, effective surveillance is required to prevent further dissemination.

To study the contamination of microorganisms in the food industry, pharmaceutical industry, clinical diagnosis, or bacterial taxonomy, accurate identification of species is a key starting point of further investigation. The conventional method of identification by the 16S rDNA gene or other marker gene comparison is not accurate, because it uses a tiny part of the genomic information. The average nucleotide identity calculated between two whole bacterial genomes was proven to be consistent with DNA–DNA hybridization and adopted as the gold standard of bacterial species delineation. Furthermore, there are more bacterial genomes available in public databases recently. All of those contribute to a genome era of bacterial species identification. However, wrongly labeled and low-quality bacterial genome assemblies, especially from type strains, greatly affect accurate identification. In this study, we employed a multi-step strategy to create a type-strain genome database, by removing the wrongly labeled and low-quality genome assemblies. Based on the curated database, a fast bacterial genome identification platform (fIDBAC) was developed (http://fbac.dmicrobe.cn/). The fIDBAC is aimed to provide a single, coherent, and automated workflow for species identification, strain typing, and downstream analysis, such as CDS prediction, drug resistance genes, virulence gene annotation, and phylogenetic analysis.

Autophagy acts as a pivotal innate immune response against infection. Some virulence effectors subvert the host autophagic machinery to escape the surveillance of autophagy. The mechanism by which pathogens interact with host autophagy remains mostly unclear. However, traditional strategies often have difficulty identifying host proteins that interact with effectors due to the weak, dynamic, and transient nature of these interactions. Here, we found that Enteropathogenic Escherichia coli (EPEC) regulates autophagosome formation in host cells dependent on effector NleE. The 26S Proteasome Regulatory Subunit 10 (PSMD10) was identified as a direct interaction partner of NleE in living cells by employing genetically incorporated crosslinkers. Pairwise chemical crosslinking revealed that NleE interacts with the N-terminus of PSMD10. We demonstrated that PSMD10 homodimerization is necessary for its interaction with ATG7 and promotion of autophagy, but not necessary for PSMD10 interaction with ATG12. Therefore, NleE-mediated PSMD10 in monomeric state attenuates host autophagosome formation. Our study reveals the mechanism through which EPEC attenuates host autophagy activity.

The study aimed to investigate the effect of combined balance and plyometric training on the change of direction (COD) performance of badminton athletes. Sixteen elite male badminton players volunteered to participate and were randomly assigned to a balance-plyometric group (BP: n = 8) and plyometric group (PL: n = 8). The BP group performed balance combined with plyometric training three times a week over 6 weeks; while the PL group undertook only plyometric training three times a week during the same period. Meanwhile, both groups were given the same technical training. All participants were tested to assess the COD ability before and after the training period: Southeast Missouri (SEMO) test and 5-0-5 test, dynamic balance ability (Y-Balance test, YBT), and reactive strength index (RSI). Repeated-measure ANOVA revealed that after the intervention there was a significant time × group interaction for 5-0-5 COD test, YBT of both legs and RSI (p < 0.05, partial η2 = 0.26–0.58) due to the better performance observed at post-test compared with a pre-test for the BP group [effect size (ES) = 1.20–1.76], and the improvement was higher than that of the PL group. The change in SEMO test did not differ between BP and PL (p < 0.159, partial η2= 0.137), but the magnitude of the with-group improvement for BP (ES = 1.55) was higher than that of PL (ES = 0.81). These findings suggest that combined training could further improve the COD performance of badminton athletes than plyometric training alone and might provide fitness trainers a more efficient COD training alternative.

Background: Oral Chinese patent medicine (OCPM) combined with western medicine (WM) are believed to be effective for the therapy of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) with sexual dysfunction (SD). These western medicines mainly involve antibiotics, phosphodiesterase type-5 inhibitor (PDE-5i), α-blockers. But there is no randomized controlled trial (RCT) that directly compares the efficacy of different OCPM. Hence, we operated a network meta-analysis (NMA) to contrast the efficacy of different OCPM for CP/CPPS with SD.Methods: Relevant studies were searched in PubMed, Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wanfang database. All of the RCTs concentrated on the use of OCPM to cure CP/CPPS with SD from the inception of the databases to November 2020. We appraised the risk of bias under the Cochrane Handbook and CONSORT statement. The data were statistically analyzed via STATA 13.0 and WinBUGS 1.4.3 instrument.Results: Altogether, 30 pieces of literature with 2,996 participants containing 11 oral Chinese patent medicine and 11 interventions were included in the NMA. In terms of The National Institutes of Health chronic prostatitis symptom index (NIH-CPSI), Qianlie Shutong Capsules (QLSTC) + WM had the most possible of being the optimal treatment. In the light of the International Index of Erectile Function (IIEF-5), Congrong Yishen Granules (CRYSG) + WM had the most possible of being the optimal treatment. Shugan Yiyang Capsules (SGYYC) + WM performed the highest likelihood efficacy under cluster rank graph combined NIH-CPSI and IIEF-5. Liuwei Dihuang Pills/Yougui capsules (LWDHP/YGC) + WM had highly possible to be the optimal treatment not only for the clinical effective rate of CP/CPPS but also for the clinical effective rate of SD. Considering four outcomes, QLSTC, CRYSG, SGYYC, LWDHP/YGC, Qianlie Beixi Capsules (QLBXC) plus WM were the best therapy approach for CP/CPPS with SD, especially LWDHP/YGC + WM and QLBXC + WM.Conclusion: Based on the NMA, QLSTC, CRYSG, SGYYC, LWDHP/YGC, QLBXC plus WM demonstrated the maximum probability of being the optimal therapies. Owing to the limitations of this research, these results should be confirmed by elaborate RCTs.Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021224060].

Objective: Acinetobacter baumannii has emerged as a problematic hospital pathogen and tigecycline is among the few remaining antibiotics retaining activity against multidrug-resistant A. baumannii. This study was aimed to elucidate the tigecycline resistance mechanisms in 28 unique clinical A. baumannii strains from nine provinces in China. Methods: Whole genome sequences were obtained via Illumina HiSeq sequencing and regulatory genes of efflux pumps were analyzed. Minimal inhibitory concentrations (MICs) were determined by agar/microbroth dilution according to the guidelines recommended by Clinical and Laboratory Standards Institute (CLSI). Tigecycline susceptibility data was interpreted using breakpoints for Enterobacterales recommended by EUCAST v8.1. Results: The majority of isolates belonged to the international clonal lineage IC2 (n = 27, 96.4%). Four isolates were considered tigecycline-intermediate (MIC = 2 mg/L), twenty-four isolates were tigecycline-resistant. The insertion of ISAba1 in adeS was found in six isolates and was the most prevalent insertion element (IS). In four isolates we observed an insertion of ISAba1 in adeN, and two of them had IS26 insertions. Two mutations in adeN (deletion and premature stop codon) were observed only in the MIC = 4 mg/L isolates. Other mutations in adeRS (amino acid insertion/substitutions and premature stop codons) were only detected in the MIC ≥ 8 group. The novel substitutions E219 K in adeR and A130 T in adeS were observed in five and four isolates respectively, suggesting a mutational hotspot. Conclusions: This study demonstrates that changes in transcription regulators were important mechanisms in tigecycline resistance in A. baumannii. Also, we identified several chromosomal hotspots that can be used for prediction of tigecycline resistance.

Eperythrozoonosis is a zoonosis transmitted from animals to humans. It is caused by bacteria in the genus Eperythrozoon . These bacteria have a high infection rate and can cause varying degrees of damage. This is the first case report of infective endocarditis caused by Eperythrozoon . The patient had a 30-day history of remittent fever accompanied by chills and progressive weakness and gradually recovered after 6 weeks of minocycline treatment.

Tubulin inhibitors can interfere with normal cell mitosis and inhibit cell proliferation through interfering with the normal structure and function of microtubules, forming spindle filaments. Indole, as a privileged pharmacological skeleton, has been widely used in anti-cancer inhibitors. A variety of alkaloids containing an indole core obtained from natural sources have been proven to inhibit tubulin polymerization, and an ever-increasing number of synthetic indole-based tubulin inhibitors have been reported. Among these, several kinds of indole-based derivatives, such as TMP analogues, aroylindoles, arylthioindoles, fused indole, carbazoles, azacarbolines, alkaloid nortopsentin analogues and bis-indole derivatives, have shown good inhibition activities towards tubulin polymerization. The binding modes and SARs investigations of synthetic indole derivatives, along with a brief mechanism on their anti-tubulin activity, are presented in this review.

Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii. However, polymyxin resistance can emerge with monotherapy, highlighting the need for synergistic combination therapies. Polymyxins in combination with β-lactams have shown remarkable synergy against multidrug-resistant A. baumannii.Methods: Liquid chromatography–mass spectrometry-based metabolomics was conducted to investigate the metabolic perturbations in an A. baumannii clinical isolate, AB090342, in response to colistin (1 mg/L), sulbactam (128 mg/L), and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics, and metabolites showing ≥2-fold changes were subjected to pathway analysis.Results: The synergistic activity of colistin–sulbactam combination was initially driven by colistin through perturbation of fatty acid and phospholipid levels at 1 h. Cell wall biosynthesis was perturbed by sulbactam alone and the combination over 24 h; this was demonstrated by the decreased levels of two important precursors, uridine diphosphate-N-acetylglucosamine and uridine diphosphate-N-acetylmuramate, together with perturbed lysine and amino sugar metabolism. Moreover, sulbactam alone and the combination significantly depleted nucleotide metabolism and the associated arginine biosynthesis, glutamate metabolism, and pentose phosphate pathway. Notably, the colistin–sulbactam combination decreased amino acid and nucleotide levels more dramatically at 4 h compared with both monotherapies.Conclusions: This is the first metabolomics study revealing the time-dependent synergistic activity of colistin and sulbactam against A. baumannii, which was largely driven by sulbactam through the inhibition of cell wall biosynthesis. Our mechanistic findings may help optimizing synergistic colistin combinations in patients.

Objective Liver biopsy is the gold standard test for assessment of liver pathology. This study was performed to assess the predictive value of spleen thickness for liver pathology and the role of routine follow-up procedures in significant liver pathology for patients with chronic hepatitis B (CHB) with persistently normal alanine aminotransferase (PNALT) or minimally raised alanine aminotransferase (ALT). Methods Patients with CHB who underwent percutaneous liver biopsy were retrospectively reviewed. The relationship of liver pathology with age, ALT, hepatitis B e-antigen, and spleen thickness was statistically analyzed, and the predictive accuracy of spleen thickness was evaluated. Results In total, 80.65% of patients had significant necroinflammation and/or fibrosis. Nearly 60% of patients had splenomegaly, of which 89.12% had a histopathological grade of ≥G2 and/or S2. Spleen thickness was predictive of liver pathology, and significant histological findings increased as the hepatitis B virus (HBV) DNA level increased. Conclusions Spleen thickness is an effective predictor of liver pathology in patients with PNALT or minimally raised ALT. Additionally, the prevalence of significant histological findings tended to increase as the HBV DNA level increased. Patients with CHB and splenomegaly and a high HBV DNA level should be treated early with antivirals to improve liver pathology.

Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii; however, polymyxin resistance can emerge with monotherapy. Therefore, synergistic combination therapy is a crucial strategy to reduce polymyxin resistance.Methods: This study conducted untargeted metabolomics to investigate metabolic responses of a multidrug-resistant (MDR) A. baumannii clinical isolate, AB090342, to colistin and aztreonam alone, and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics; metabolites showing ≥ 2-fold changes were subjected to bioinformatics analysis.Results: The synergistic action of colistin-aztreonam combination was initially driven by colistin via significant disruption of bacterial cell envelope, with decreased phospholipid and fatty acid levels at 1 h. Cell wall biosynthesis was inhibited at 4 and 24 h by aztreonam alone and the combination as shown by the decreased levels of two amino sugars, UDP-N-acetylglucosamine and UDP-N-acetylmuramate; these results suggested that aztreonam was primarily responsible for the synergistic killing at later time points. Moreover, aztreonam alone and the combination significantly depleted pentose phosphate pathway, amino acid, peptide and nucleotide metabolism, but elevated fatty acid and key phospholipid levels. Collectively, the combination synergy between colistin and aztreonam was mainly due to the inhibition of cell envelope biosynthesis via different metabolic perturbations.Conclusion: This metabolomics study is the first to elucidate multiple cellular pathways associated with the time-dependent synergistic action of colistin-aztreonam combination against MDR A. baumannii. Our results provide important mechanistic insights into optimizing synergistic colistin combinations in patients.

The Type VI Secretion System (T6SS) is an important virulence system that exists in many bacterial pathogens, and has emerged as a potent mediator of pathogenicity in Acinetobacter baumannii. In this study, we inactivated one of the T6SS components vgrG (valine-glycine repeat G) gene in A. baumannii ATCC 19606 and constructed a complementation strain. BEAS-2b human alveolar epithelial cells was adopted to assess bacterial adhesion, and wild female BALB/c mice were used for in vivo experiments to assess the bacterial killing ability to host. Upon deletion of the vgrG gene, increased antimicrobial resistance to ampicillin/sulbactam, but reduced resistance to chloramphenicol were observed. The vgrG mutant strain showed lower growth rate, reduced eukaryotic cell adherence and impaired lethality in mice. However, the vgrG mutant strain is not implicated in biofilm formation. Our study suggests that the Type VI Secretion System core component VgrG contributes to both virulence and antimicrobial resistance in A. baumannii ATCC 19606.

Acinetobacter baumannii is an important nosocomial pathogen worldwide. A more comprehensive understanding of the within-host genomic evolution of A. baumannii would provide a molecule basis for improving treatment of A. baumannii infection. To understand the evolutionary mechanism facilitating A. baumannii survived in human body, we here reported the genomic analysis of A. baumannii isolated sampled from Chinese patients. We used whole-genome sequence of A. baumannii isolates from the same patient to determine single-nucleotide variants, insertion sequence mapping, and gene change. The MICs for 10 antimicrobial agents were determined. Motility assay and microscopy were performed on the isolated pairs harboring ptk mutations. The gene ptk encoded a putative protein tyrosine kinase involved in the production of capsular polysaccharide. Approximately half (39/86) of the strains isolated from the same patient harbored the same MLST patterns, and during the replacement of international clonal lineage II (ICL-II) and non-ICL-II strains, most of the alteration was that non-ICL-II strain was replaced by ICL-II strain (10/12). A. baumannii was resistant to major antimicrobial agents, whereas the strains were more resistant to ceftazidime, azithromycin, and sulfonamides after within-host evolution. Isolates from the ICL-II lineage displayed greater resistance to antimicrobial agents than non-ICL-II isolates. Isolates from ICL-II harbored more resistance genes and mobile elements than non-ICL-II strains. Several lineages evolved a more mucoid phenotype. Genome sequencing revealed that the phenotype was achieved by genetic changes in the ptk gene. ICL-II (especially ST195 and ST208) was the terminal destination for bacteria after within-host evolution. These results indicate that the molecular basis and the treatment for ICL-II strains needed further investigation.

Acinetobacter baumannii had emerged as an important nosocomial and opportunistic pathogen worldwide. To determine the evolutionary pathway of colistin resistance in A. baumannii and its influence on bacterial fitness, five independent colonies of A. baumannii ATCC 17978 were exposed to colistin in agar (4/5) and liquid media (1/5) with increasing and constant concentrations. Stable resistance isolates were sent for whole genome sequencing. All strains were colistin resistant after exposure to colistin. In addition to the previously reported lpxCAD and pmrAB mutations, we detected four novel putative colistin resistance genes: A1S_1983, hepA, A1S_3026, and rsfS. Lipopolysaccharide (LPS) loss mutants exhibited higher fitness costs than the pmrB mutant in nutrient-rich medium. The colistin-resistant mutants showed higher inhibition ratio in the serum growth experiment than the wild type strain in 100% serum. The MIC results showed that the LPS-deficient but not the pmrB mutant altered the antibiotic resistance profile. The compensatory mutations partially or completely recovered the LPS-deficient’s fitness, suggesting that compensatory mutations played an important role in the emergence and spread of colistin resistant A. baumannii.

Single Nucleotide Polymorphisms (SNPs) found in Genome-Wide Association Study (GWAS) mainly influence the susceptibility of complex diseases, but they still could not comprehensively explain the relationships between mutations and diseases. Interactions between SNPs are considered so important for deeply understanding of those relationships that several strategies have been proposed to explore such interactions. However, part of those methods perform poorly when marginal effects of disease loci are weak or absent, others may lack of considering high-order SNPs interactions, few methods have achieved the requirements in both performance and accuracy. Considering the above reasons, not only low-order, but also high-order SNP interactions as well as main-effect SNPs, should be taken into account in detection methods under an acceptable computational complexity. In this paper, a new pairwise (or low-order) interaction detection method IG (Interaction Gain) is introduced, in which disease models are not required and parallel computing is utilized. Furthermore, high-order SNP interactions were proposed to be detected by finding closely connected function modules of the network constructed from IG detection results. Tested by a wide range of simulated datasets and four WTCCC real datasets, the proposed methods accurately detected both low-order and high-order SNP interactions as well as disease-associated main-effect SNPS and it surpasses all competitors in performances. The research will advance complex diseases research by providing more reliable SNP interactions.