Imaging surface structure and premelting of ice Ih with atomic resolution.

Ice surfaces are closely relevant to many physical and chemical properties, such as melting, freezing, friction, gas uptake and atmospheric reaction1-8. Despite extensive experimental and theoretical investigations9-17, the exact atomic structures of ice interfaces remain elusive owing to the vulnerable hydrogen-bonding network and the complicated premelting process. Here we realize atomic-resolution imaging of the basal (0001) surface structure of hexagonal water ice (ice Ih) by using qPlus-based cryogenic atomic force microscopy with a carbon monoxide-functionalized tip. We find that the crystalline ice-Ih surface consists of mixed Ih- and cubic (Ic)-stacking nanodomains, forming 19 × 19 periodic superstructures. Density functional theory reveals that this reconstructed surface is stabilized over the ideal ice surface mainly by minimizing the electrostatic repulsion between dangling OH bonds. Moreover, we observe that the ice surface gradually becomes disordered with increasing temperature (above 120 Kelvin), indicating the onset of the premelting process. The surface premelting occurs from the defective boundaries between the Ih and Ic domains and can be promoted by the formation of a planar local structure. These results put an end to the longstanding debate on ice surface structures and shed light on the molecular origin of ice premelting, which may lead to a paradigm shift in the understanding of ice physics and chemistry.

Collaborative deep learning improves disease-related circRNA prediction based on multi-source functional information.

Emerging studies have shown that circular RNAs (circRNAs) are involved in a variety of biological processes and play a key role in disease diagnosing, treating and inferring. Although many methods, including traditional machine learning and deep learning, have been developed to predict associations between circRNAs and diseases, the biological function of circRNAs has not been fully exploited. Some methods have explored disease-related circRNAs based on different views, but how to efficiently use the multi-view data about circRNA is still not well studied. Therefore, we propose a computational model to predict potential circRNA-disease associations based on collaborative learning with circRNA multi-view functional annotations. First, we extract circRNA multi-view functional annotations and build circRNA association networks, respectively, to enable effective network fusion. Then, a collaborative deep learning framework for multi-view information is designed to get circRNA multi-source information features, which can make full use of the internal relationship among circRNA multi-view information. We build a network consisting of circRNAs and diseases by their functional similarity and extract the consistency description information of circRNAs and diseases. Last, we predict potential associations between circRNAs and diseases based on graph auto encoder. Our computational model has better performance in predicting candidate disease-related circRNAs than the existing ones. Furthermore, it shows the high practicability of the method that we use several common diseases as case studies to find some unknown circRNAs related to them. The experiments show that CLCDA can efficiently predict disease-related circRNAs and are helpful for the diagnosis and treatment of human disease.

Metformin use correlated with lower risk of cardiometabolic diseases and related mortality among US cancer survivors: evidence from a nationally representative cohort study.

BACKGROUND: In the USA, the prolonged effective survival of cancer population has brought significant attention to the rising risk of cardiometabolic morbidity and mortality in this population. This heightened risk underscores the urgent need for research into effective pharmacological interventions for cancer survivors. Notably, metformin, a well-known metabolic regulator with pleiotropic effects, has shown protective effects against cardiometabolic disorders in diabetic individuals. Despite these promising indications, evidence supporting its efficacy in improving cardiometabolic outcomes in cancer survivors remains scarce. METHODS: A prospective cohort was established using a nationally representative sample of cancer survivors enrolled in the US National Health and Nutrition Examination Survey (NHANES), spanning 2003 to 2018. Outcomes were derived from patient interviews, physical examinations, and public-access linked mortality archives up to 2019. The Oxidative Balance Score was utilized to assess participants' levels of oxidative stress. To evaluate the correlations between metformin use and the risk of cardiometabolic diseases and related mortality, survival analysis of cardiometabolic mortality was performed by Cox proportional hazards model, and cross-sectional analysis of cardiometabolic diseases outcomes was performed using logistic regression models. Interaction analyses were conducted to explore the specific pharmacological mechanism of metformin. RESULTS: Among 3995 cancer survivors (weighted population, 21,671,061, weighted mean [SE] age, 62.62 [0.33] years; 2119 [53.04%] females; 2727 [68.26%] Non-Hispanic White individuals), 448 reported metformin usage. During the follow-up period of up to 17 years (median, 6.42 years), there were 1233 recorded deaths, including 481 deaths from cardiometabolic causes. Multivariable models indicated that metformin use was associated with a lower risk of all-cause (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.47-0.81) and cardiometabolic (HR, 0.65; 95% CI, 0.44-0.97) mortality compared with metformin nonusers. Metformin use was also correlated with a lower risk of total cardiovascular disease (odds ratio [OR], 0.41; 95% CI, 0.28-0.59), stroke (OR, 0.44; 95% CI, 0.26-0.74), hypertension (OR, 0.27; 95% CI, 0.14-0.52), and coronary heart disease (OR, 0.41; 95% CI, 0.21-0.78). The observed inverse associations were consistent across subgroup analyses in four specific cancer populations identified as cardiometabolic high-risk groups. Interaction analyses suggested that metformin use as compared to non-use may counter-balance oxidative stress. CONCLUSIONS: In this cohort study involving a nationally representative population of US cancer survivors, metformin use was significantly correlated with a lower risk of cardiometabolic diseases, all-cause mortality, and cardiometabolic mortality.

Plunge-Freezing Cryopreservation of Tendons.

Allograft transplantation is an important method for tendon reconstruction after injury, and its clinical success highly relies on the storage and transportation of the grafts. Cryopreservation is a promising strategy for tendon storage. In this study, we report a novel cryopreservation agent (CPA) formulation with a high biocompatibility for tendon cryopreservation. Mainly composed of natural zwitterionic betaine and the biocompatible polymer poly(vinylpyrrolidone) (PVP), it exhibited ideal abilities to depress the freezing point and inhibit ice growth and recrystallization. Notably, after cryopreservation via plunge-freezing for 1 month, Young's modulus (144 MPa, 98% of fresh tendons) and ultimate stress (46.7 MPa, 99% of fresh tendons) remained stable, and the cross-linking of collagen microfibers, protein structures, and glycosaminoglycan (GAG) contents changed slightly. These results indicate that the formulation (5 wt % betaine and 5 wt % PVP in phosphate-buffered saline, PBS solution) effectively maintains the biomechanical properties and tissue structure. This work offers a novel cryopreservation method for tendons and may also provide insights into the long-term preservation of various other tissues.

Molecular Characteristics of an NDM-4 and OXA-181 Co-Producing K51-ST16 Carbapenem-Resistant Klebsiella pneumoniae: Study of Its Potential Dissemination Mediated by Conjugative Plasmids and Insertion Sequences.

The carbapenem-resistant Klebsiella pneumoniae (CRKP) strain GX34 was recovered from the respiratory tract of an elderly male with severe pneumonia, and only susceptible to amikacin, tigecycline, and colistin. Complete genome suggested that it belonged to K51-ST16 and harbored plasmid-encoded NDM-4 and OXA-181, located on IncFIB plasmid GX34p1_NDM-4 and ColKP3/IncX3 plasmid GX34p4_OXA-181, respectively. A series of transconjugants generated in the plasmid conjugation assays, including Escherichia coli J53-N1 (harboring a self-transmissible and blaNDM-1-producing plasmid Eco-N-1-p), J53-N2 (harboring a blaNDM-4-producing plasmid and a helper plasmid GX34p5), and J53-O (harboring a blaOXA-181-producing plasmid), could be stably inherited after 10 days of serial passage and no significant biological fitness costs were detected. Furthermore, we first reported the blaNDM-1 gene, derived from blaNDM-4 mutation (460C>A) under meropenem pressure, could be in vitro transferred into a self-conjugative, recombined plasmid Eco-N-1-p of J53-N1. Eco-N-1-p was mainly recombined by GX34p4_OXA-181 (40,449 bp, 75.16%) and GX34p1_NDM-4 (8,553 bp, 15.89%), in which IS26 and IS5-like probably played a major role. Eco-N-1-p could be transferred into the conjugation recipient K. pneumoniae KP54 and make the latter sacrifice fitness. The retention rates of blaNDM-1 remained high stability (>80% after 200 generations). The comparative genomic analysis of GX34 and those carrying blaNDM-4 or blaOXA-181 genes retrieved from the NCBI RefSeq database showed all blaNDM-4 (26/26, 100.00%) and blaOXA-181 (13/13, 100.00%) were surrounded by IS26. The immediate environment of blaNDM-4 and blaOXA-181 in GX34 and some retrieved strains shared identical features, hinting at their possible dissemination. Effective measures should be taken to monitor the spread of this clone.

In vitro activity of cefiderocol, a siderophore cephalosporin, against carbapenem-resistant hypervirulent Klebsiella pneumoniae in China.

Cefiderocol is a siderophore cephalosporin that binds ferric iron and utilizes iron transporters to cross the cell membrane. Hypervirulent Klebsiella pneumoniae (hvKp) is known to produce more siderophores; in this case, the uptake of cefiderocol may be decreased. Therefore, the objective of this study was to evaluate the in vitro activity of cefiderocol against hvKp isolates. A total of 320 carbapenem-resistant K. pneumoniae (CRKp) isolates were collected in China between 2014 and 2022, including 171 carbapenem-resistant hvKp (CR-hvKp) and 149 carbapenem-resistant classical K. pneumoniae (CR-cKp). Quantitative detection of siderophores showed that the average siderophore production of CR-hvKp (234.6 mg/L) was significantly higher than that of CR-cKp (68.9 mg/L, P < 0.001). The overall cefiderocol resistance rate of CR-hvKp and CR-cKp was 5.8% (10/171) and 2.7% (4/149), respectively. The non-susceptible rates of both cefiderocol and siderophore production of CR-hvKp isolates were higher than those of CR-cKp in either NDM-1- or KPC-2-producing groups. The MIC90 and MIC50 for CR-hvKp and CR-cKp were 8 mg/L and 2 mg/L and 4 mg/L and 1 mg/L, respectively. The cumulative cefiderocol MIC distribution for CR-hvKp was significantly lower than that of CR-cKp isolates (P = 0.003). KL64 and KL47 consisted of 53.9% (83/154) and 75.7% (53/70) of the ST11 CR-hvKp and CR-cKp, respectively, and the former had significantly higher siderophore production. In summary, cefiderocol might be less effective against CR-hvKp compared with CR-cKp isolates, highlighting the need for caution regarding the prevalence of cefiderocol-resistant K. pneumoniae strains, particularly in CR-hvKp isolates.

Inhibition of RNA degradation integrates the metabolic signals induced by osmotic stress into the Arabidopsis circadian system.

The circadian clock system acts as an endogenous timing reference that coordinates many metabolic and physiological processes in plants. Previous studies have shown that the application of osmotic stress delays circadian rhythms via 3'-phospho-adenosine 5'-phosphate (PAP), a retrograde signalling metabolite that is produced in response to redox stress within organelles. PAP accumulation leads to the inhibition of exoribonucleases (XRNs), which are responsible for RNA degradation. Interestingly, we are now able to demonstrate that post-transcriptional processing is crucial for the circadian response to osmotic stress. Our data show that osmotic stress increases the stability of specific circadian RNAs, suggesting that RNA metabolism plays a vital role in circadian clock coordination during drought. Inactivation of XRN4 is sufficient to extend circadian rhythms as part of this response, with PRR7 and LWD1 identified as transcripts that are post-transcriptionally regulated to delay circadian progression.

Empagliflozin attenuates doxorubicin-impaired cardiac contractility by suppressing reactive oxygen species in isolated myocytes.

In animal studies, sodium-glucose co-transporter-2 inhibitors-such as empagliflozin-have been shown to improve heart failure and impaired cardiac contractility induced by anthracyclines-including doxorubicin-although the therapeutic mechanism remains unclear. Moreover, abnormalities in Ca2+ handling within ventricular myocytes are the predominant feature of heart failure. Accordingly, this study aimed to investigate whether empagliflozin can alleviate Ca2+ handling disorders induced by acute doxorubicin exposure and elucidate the underlying mechanisms. To this end, ventricular myocytes were isolated from C57BL/6 mice. Contraction function, Ca2+ handling, and mitochondrial reactive oxygen species (ROS) generation were then evaluated using IonOptix or confocal microscopy. Ca2+ handling proteins were detected by western blotting. Results show that incubation with 1 µmol/L of doxorubicin for 120-min impaired cardiac contractility in isolated myocytes, which was significantly alleviated by pretreatment with 1 µmol/L of empagliflozin. Doxorubicin also markedly induced Ca2+ handling disorders, including decreased Ca2+ transients, prolonged Ca2+ transient decay time, enhanced frequency of Ca2+ sparks, and decreased Ca2+ content in the sarcoplasmic reticulum. These dysregulations were improved by pretreatment with empagliflozin. Moreover, empagliflozin effectively inhibited doxorubicin-induced mitochondrial ROS production in isolated myocytes and rescued doxorubicin-induced oxidation of Ca2+/calmodulin-dependent protein kinase II (ox-CaMKII) and CaMKII-dependent phosphorylation of RyR2. Similarly, preincubation with 10 µmol/L Mito-TEMPO mimicked the protective effects of empagliflozin. Collectively, Empagliflozin ameliorated the doxorubicin-induced contraction malfunction and Ca2+-handling disorders. These findings suggest that empagliflozin alleviates Ca2+-handling disorders by improving ROS production in the mitochondria and alleviating the enhanced oxidative CaMKII signaling pathway induced by doxorubicin.

Visualization and mapping of the right phrenic nerve by intracardiac echocardiography during atrial fibrillation ablation.

OBJECTIVE: This study aimed to evaluate the feasibility of real-time visualization and mapping of the right phrenic nerve (RPN) by using intracardiac echocardiography (ICE) during atrial fibrillation (AF) ablation. BACKGROUND: RPN injury is a complication associated with the ablation of AF. Multiple approaches are currently being used to prevent and detect RPN injuries. However, none of these approaches can directly visualize the RPN in real-time during the ablation procedure. METHODS AND RESULTS: The RPN was detected using ICE. The RPN and its adjacent structures were analysed. The relationship between the RPN's distance from the superior vena cava (SVC) and its pacing capture threshold was quantified. The safety of SVC isolation guided by the ICE-visualized RPN was evaluated. Thirty-eight people were enrolled in this study. The RPN was visualized by ICE in 92% of patients. It ran through the space between the SVC and the mediastinal pleura and had a 'straw'-like appearance upon ICE imaging. The course of the RPN was close to the SVC (minimum 1.0 ± 0.4 mm) and the right superior pulmonary vein (minimum 14.1 ± 7.3 mm). There was a positive linear correlation between the RPN's capture threshold and its distance from the SVC (Spearman's correlation coefficient = 0.728, < 0.001). SVC isolation was guided by the RPN; none of the patients developed an RPN injury. CONCLUSIONS: RPN can be visualized by ICE in most patients, thus providing a novel approach for the real-time detection of RPN during AF ablation.

Empagliflozin Ameliorates Ouabain-Induced Na+ and Ca2+ Dysregulations in Ventricular Myocytes in an Na+-Dependent Manner.

PURPOSE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of glucose-lowering agents that have improved clinical outcomes in patients with heart failure; however, their therapeutic mechanisms remain elusive. Although contradictory results have been reported, it has been proposed that improving Na+ homeostasis may be the underlying mechanism of action of SGLT2 inhibitors in heart failure treatment. This study explored whether empagliflozin ameliorates Na+ and Ca2+ handling disorders induced by ouabain in an Na+-dependent manner. METHODS: Isolated ventricular myocytes of mice were incubated with ouabain to establish a cellular model of Na+ overload. Effects of empagliflozin on Na+ and Ca2+ handling were evaluated using an ionOptix system and a confocal microscope. Distinct cytosolic Na+ levels were established by incubating different ouabain concentrations (10, 50, and 100 µmol/L). RESULTS: In the absence of ouabain, 1 µmol/L empagliflozin had a negligible impact on Na+ and Ca2+ handling in ventricular myocytes. Ouabain (50 µmol/L) significantly enhanced cytosolic Na+ levels and dysregulated Ca2+ handling, including an increased Ca2+ transient amplitude, elevated Ca2+ content in the sarcoplasmic reticulum, and enhanced spontaneous Ca2+ release normalized by treatment with 1 µmol/L empagliflozin within 10 min. All Na+ and Ca2+ handling abnormalities induced by ouabain were reversed by 1 µmol/L empagliflozin. The efficacy of empagliflozin was more potent at higher cytosolic Na+ levels. Pretreatment with the Na+/H+ exchanger (NHE) inhibitor (1 µmol/L cariporide) abolished the effects of empagliflozin. CONCLUSION: Empagliflozin ameliorates ouabain-induced Na+ and Ca2+ handling disorders in a cytosolic Na+-dependent manner, potentially by inhibiting the NHE.

Association of shift work and dietary inflammatory potential with all-cause death among us hypertensive population: national health and nutrition examination study, 2005-2010.

BACKGROUND & AIMS: The individual effect of working schedule on survival in the hypertensive population has not been adequately studied. Shiftworkers are also prone to unhealthy lifestyles like pro-inflammatory diet. Therefore, we assessed the effect of shift work and its joint association with dietary inflammatory potential on mortality risk among the large US nationally representative sample of adult hypertensive population. METHODS: Data were from a nationally representative prospective cohort among US hypertensive population (n = 3680; weighted population, 54,192,988). The participants were linked to the 2019 public-access linked mortality archives. The working schedule were self-reported using the Occupation Questionnaire Section. Dietary inflammatory index (DII) scores were equally calculated using the 24-hour dietary recall (24 h) interviews. Multivariable Cox proportional hazards regression models were used to estimate hazard ratio and 95% confidence intervals (95%CI) for survival of hypertension individuals by work schedule and dietary inflammatory potential. The joint effect of work schedule and dietary inflammatory potential was then examined. RESULTS: Among the 3680 hypertension individuals (39.89% female [n = 1479] and 71.42% white [n = 1707]; weighted mean [SE] age, 47.35 [0.32] years), 592 individuals reported shift work status. 474 (10.76%) reported shift work status with pro-inflammatory dietary pattern (DII scores > 0). 118 (3.06%) reported shift work status with anti-inflammatory dietary pattern (DII scores < 0). 646 (19.64%) reported a non-shift working schedule with anti-inflammatory dietary pattern, while 2442 (66.54%) reported non-shift working schedule with pro-inflammatory dietary pattern. After a median follow-up of 11.67 years (140 months), 317 deaths (cardiovascular diseases (CVD), 65; cancer, 104) were registered. Cox regression analysis showed that shift work was associated with higher risk of all-cause mortality (hazard ratio [HR], 1.48; 95% CI, 1.07-2.06) compared with non-shift workers. In the joint analysis, shift work status combined with pro-inflammatory dietary pattern was associated with the highest all-cause mortality risk. Moreover, adopting the anti-inflammatory diet significantly attenuates the deleterious effect of shift work on mortality risk. CONCLUSIONS: In this large representative sample of adults with hypertension in the U.S., the combination of shift work status with pro-inflammatory dietary pattern was highly prevalent and was associated with the highest risks of death from all causes.

Interfacial water intercalation-induced metal-insulator transition in NbS2/BN heterostructure.

Interfacial engineering, such as molecule intercalation, can modify properties and optimize performance of van der Waals heterostructures and their devices. Here, we investigated the pristine and water molecule intercalated heterointerface of niobium disulphide (NbS2) on hexagonal boron nitride (h-BN) (NbS2/BN) using advanced atomic force microscopy (AFM), and observed the metal-insulator transition (MIT) of first layer (1L-) of NbS2 induced by water molecule intercalation. In pristine sample, interfacial charge transfers were confirmed by the direct detection of trapped static charges at the post-exposed h-BN surface, produced by mechanically peeling off the 1L-NbS2 from the substrate. The interfacial charge transfers facilitate the intercalation of water molecules at the heterointerface. The intercalated water layers make a MIT of 1L-NbS2, while the pristine metallic state of the following NbS2 layers remains preserved. This work is of great significance to help understand the interfacial properties of 2D metal/insulator heterostructures and can pave the way for further preparation of an ultrathin transistor.

Nanoscale charge transfer and diffusion at the MoS2/SiO2 interface by atomic force microscopy: contact injection versus triboelectrification.

Understanding the process of charge generation, transfer, and diffusion between two-dimensional (2D) materials and their supporting substrates is very important for potential applications of 2D materials. Compared with the systematic studies of triboelectric charging in a bulk sample, a fundamental understanding of the triboelectrification of the 2D material/insulator system is rather limited. Here, the charge transfer and diffusion of both the SiO2 surface and MoS2/SiO2 interface through contact electrification and frictional electrification are investigated systematically in situ by scanning Kelvin probe microscopy and dual-harmonic electrostatic force microscopy. Different from the simple static charge transfer between SiO2 and the PtSi alloy atomic force microscope (AFM) tip, the charge transfer between the tip and the MoS2/SiO2 system is complicated. Triboelectric charges, generated by contact or frictional electrification with the AFM tip, are trapped at the MoS2/SiO2 interface and act as floating gates. The local charge discharge processes can be obtained by monitoring the surface potential. The charge decay time (τ) of the MoS2/SiO2 interface is one (or two) orders of magnitude larger than the decay time τ of the SiO2 surface. This work facilitates an understanding of the triboelectric and de-electrification of the interface between 2D materials and substrates. In addition to the charge transfer and diffusion, we demonstrate the nanopatterns of surface and interfacial charges, which have great potential for the application of self-assembly of charged nanostructures.

Up-regulated fractalkine (FKN) and its receptor CX3CR1 are involved in fructose-induced neuroinflammation: Suppression by curcumin.

Recent studies suggest that diet-induced fractalkine (FKN) stimulates neuroinflammation in animal models of obesity, yet how it occurs is unclear. This study investigated the role of FKN and it receptor, CX3CR1, in fructose-induced neuroinflammation, and examined curcumin's beneficial effect. Fructose feeding was found to induce hippocampal microglia activation with neuroinflammation through the activation of the Toll-like receptor 4 (TLR4)/nuclear transcription factor κB (NF-κB) signaling, resulting in the reduction of neurogenesis in the dentate gyrus (DG) of mice. Serum FKN levels, as well as hypothalamic FKN and CX3CR1 gene expression, were significantly increased in fructose-fed mice with hypothalamic microglia activation. Hippocampal gene expression of FKN and CX3CR1 was also up-regulated at 14d and normalized at 56d in mice fed with fructose, which were consistent with the change of GFAP. Furthermore, immunostaining showed that GFAP and FKN expression was increased in cornu amonis 1, but decreased in DG in fructose-fed mice. In vitro studies showed that GFAP and FKN expression was stimulated in astrocytes, and suppressed in mixed glial cells exposed to 48h-fructose, with the continual increase of pro-inflammatory cytokines. Thus, increased FKN and CX3CR1 may cause a cross-talk between activated glial cells and neurons, playing an important role in the development of neuroinflammation in fructose-fed mice. Curcumin protected against neuronal damage in hippocampal DG of fructose-fed mice by inhibiting microglia activation and suppressed FKN/CX3CR1 up-regulation in the neuronal network. These results suggest a new therapeutic approach to protect against neuronal damage associated with dietary obesity-associated neuroinflammation.

Loss and gain of ceftazidime-avibactam susceptibility in a non-carbapenemase-producing K1-ST23 hypervirulent Klebsiella pneumoniae.

OBJECTIVES: This study aimed at revealing the underlying mechanisms of the loss and gain of ceftazidime-avibactam susceptibility in a non-carbapenemase-producing hypervirulent Klebsiella pneumoniae (hvKp). METHODS: Here we longitudinally recovered 3 non-carbapenemase-producing K1-ST23 hvKp strains at a one-month interval (KP29105, KP29499 and KP30086) from an elderly male. Antimicrobial susceptibility testing, whole genome sequencing, transcriptomic sequencing, gene cloning, plasmid conjugation, quantitative real-time PCR (qRT-PCR), and SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) were conducted. RESULTS: Among the 3 hvKp strains, KP29105 was resistant to the third- and fourth-generation cephalosporins, KP29499 acquired resistance to both ceftazidime-avibactam and carbapenems, while KP30086 restored its susceptibility to ceftazidime-avibactam, imipenem and meropenem but retained low-level resistance to ertapenem. KP29105 and KP29499 carried plasmid-encoded genes blaCTX-M-15 and blaCTX-M-71, respectively, but KP30086 lost both. Cloning of gene blaCTX-M-71 and conjugation experiment of blaCTX-M-71-carrying plasmid showed that the transformant and transconjugant were susceptible to ceftazidime-avibactam but had a more than 8-fold increase in MICs. Supplementation with an outer membrane permeabilizer could reduce the MIC of ceftazidime-avibactam by 32 folds, indicating that porins play a key role in ceftazidime-avibactam resistance. The OmpK35 of the 3 isolates was not expressed, and the OmpK36 of KP29499 and KP30086 had a novel amino acid substitution (L359R). SDS-PAGE and qRT-PCR showed that the expression of porin OmpK36 of KP29499 and KP30086 was significantly down-regulated compared with KP29105. CONCLUSIONS: In summary, we reported the rare ceftazidime-avibactam resistance in a non-carbapenemase-producing hvKp strain. Resistance plasmid carrying blaCTX-M-71 and mutated OmpK36 had a synergetic effect on the resistance.

Coexistence of virulent and multidrug-resistant plasmids in an uropathogenic Escherichia coli.

OBJECTIVES: The emergence of pathogens co-harbouring multiple mobile resistance and virulence elements is of great concern in clinical settings. Herein, we report an O101: H10-ST167 Escherichia coli Hu106 strain isolated from the urinary tract of a female in China. METHODS: Antibiotic susceptibility testing was used to present the antimicrobial resistance spectrum. Whole-genome sequencing (WGS) and bioinformatic analysis were used to clarify the virulent and resistance mechanisms. Furthermore, the virulence of this strain was tested by the Greater wax moth larvae and siderophore production experiment. RESULTS: The strain E. coli Hu106 was resistant to almost all antimicrobials tested, and only susceptible to aztreonam, amikacin, and tigecycline. WGS analysis revealed that the strain Hu106 co-harboured blaNDM-9 and mcr-1 on p2-Hu106, belonging to IncHI2/IncHI2A (256,000 bp). The co-existence of both resistance genes, blaNDM-9 and mcr-1, on the plasmid p2-Hu106 was mainly acquired by transposition recombination of mobile antibiotic elements mediated by IS26 and/or IS1 on IncHI2/IncHI2A type plasmid. In addition, the virulence clusters aerobactin (iutA-iucABCD) and salmochelin (iroBCDEN) were identified on an IncFIB/IncFIC(IncFII) type plasmid p1-Hu106, flanked by small mobile elements such as IS1A, ISkpn28, and IS3, respectively. After performing genomic comparison of p1-Hu106 with the WGS in NCBI, we identified that the virulent plasmid p1-Hu106-like could spread in different clones of E. coli and Klebsiella pneumoniae, revealing its underlying dissemination mechanism between Enterobacterales. Furthermore, the strain caused a decreased survival rate of larvae and produced high siderophore units (62.33%), similar to hypervirulent K. pneumoniae NTUH-K2044. CONCLUSIONS: The strains co-carrying the multidrug-resistant plasmid p2-Hu106 and virulent plasmid p1-Hu106 should be closely monitored to prevent its further spreading.

A survey on blockchain sharding.

As a promising technology, blockchain has found widespread application in numerous decentralized systems. However, the scalability problem of blockchain has drawn considerable criticism. Sharding, an effective technology, offers a solution to enhance blockchain scalability by enabling parallel validation and confirmation of transactions or new block generation. Although extensive research has been conducted on sharding, the existing literature still lacks a thorough review on its current state of arts with comprehensive analysis and evaluation. In this paper, we propose a series of evaluation criteria regarding scalability, applicability, and reliability. Additionally, we classify the cutting-edge sharding schemes based on blockchain type and sharding techniques. We then provide a comprehensive overview of these existing schemes by analyzing their respective advantages and disadvantages according to the proposed criteria. At the end of the survey, we highlight open issues and suggest future research directions based on the results of our meticulous analysis.

Globular adiponectin ameliorates insulin resistance in skeletal muscle by enhancing the LKB1-mediated AMPK activation via SESN2.

Adiponectin has been demonstrated to be a mediator of insulin sensitivity; however, the underlined mechanisms remain unclear. SESN2 is a stress-inducible protein that phosphorylates AMPK in different tissues. In this study, we aimed to validate the amelioration of insulin resistance by globular adiponectin (gAd) and to reveal the role of SESN2 in the improvement of glucose metabolism by gAd. We used a high-fat diet-induced wild-type and SESN2-/- C57BL/6J insulin resistance mice model to study the effects of six-week aerobic exercise or gAd administration on insulin resistance. In vitro study, C2C12 myotubes were used to determine the potential mechanism by overexpressing or inhibiting SESN2. Similar to exercise, six-week gAd administration decreased fasting glucose, triglyceride and insulin levels, reduced lipid deposition in skeletal muscle and reversed whole-body insulin resistance in mice fed on a high-fat diet. Moreover, gAd enhanced skeletal muscle glucose uptake by activating insulin signaling. However, these effects were diminished in SESN2-/- mice. We found that gAd administration increased the expression of SESN2 and Liver kinase B1 (LKB1) and increased AMPK-T172 phosphorylation in skeletal muscle of wild-type mice, while in SESN2-/- mice, LKB1 expression was also increased but the pAMPK-T172 was unchanged. At the cellular level, gAd increased cellular SESN2 and pAMPK-T172 expression. Immunoprecipitation experiment suggested that SESN2 promoted the formation of complexes of AMPK and LKB1 and hence phosphorylated AMPK. In conclusion, our results revealed that SESN2 played a critical role in gAd-induced AMPK phosphorylation, activation of insulin signaling and skeletal muscle insulin sensitization in mice with insulin resistance.

Evaluation of BACTEC MGIT 960 system for recovery of Nocardia from clinical specimens.

Nocardia spp. is an aerobic Gram-positive bacillus responsible for nocardiosis. Herein, we performed a retrospective study to evaluate the performance of BACTEC MGIT 960 system, in comparison with smear microscopy and blood agar plate (BAP) culture, to recover Nocardia from different clinical specimens. Furthermore, the inhibitory effect of antibiotics contained in MGIT 960 tube on Nocardia was also evaluated. The sensitivities for Nocardia recovery using smear microscopy, BAP culture, and MGIT 960 were 39.4% (54/137), 46.1% (99/215), and 81.3% (156/192), respectively. N. farcinica was the most detected species (60.4%, 136/225). In MGIT 960-recovered Nocardia strains, N. farcinica accounted for 76.9%. Furthermore, trimethoprim in MGIT 960 tube inhibited less N. farcinica growth than that of other Nocardia species, partially explaining why MGIT 960 recovered more N. farcinica from sputa. The current study demonstrated that MGIT 960 could recover Nocardia strains from heavily-contaminated samples if its components and antibiotics are redesigned.

Gender-specific prevalence and trend of heart failure in China from 1990 to 2019.

AIMS: Heart failure (HF) is one of the leading causes of the global burden of disability and mortality. However, the comprehensive epidemic status of HF in China is unclear. Notably, the gender-specific survey for HF prevalence is lacking. The present study aimed to analyse the gender-specific prevalence and temporal trend of HF in China and explore the attributable aetiology and risk factors. METHODS AND RESULTS: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 was used to evaluate the age-standardized prevalence and years lived with disability of HF in China by gender. The temporal trend of HF and attributable risk factors were analysed by Joinpoint regression models from 1990 to 2019. The total age-standardized prevalence rate of HF steadily decreased over the past two decades from 1079.4 to 1032.8 per 100 000 individuals. Since 2017, the prevalence trend of HF has significantly increased [annual percentage change (APC) of 2.72 for females and 0.61 for males, P < 0.05]. In 2019, the age-standardized rate of HF prevalence in females surpassed that of males, and hypertensive heart disease was the leading cause of HF for females (42.65% of cases) and males (41.19% of cases). From 2017 to 2019, high systolic pressure contributed to most cases of HF-related hypertensive heart disease, with an APC of 2.68 for females and 0.48 for males (P < 0.05). CONCLUSIONS: Although HF prevalence has steadily decreased over the past two decades, an increasing trend has occurred since 2017, especially for females. The leading cause of HF was hypertensive heart disease. Metabolic risks, particularly high systolic pressure, consistently contribute to the prevalence of heart diseases leading to HF. Promoting HF screening and controlling metabolic risks at the population level are imperative. Gender differences in HF prevalence should be considered.