Synthesis of Ultrathin High-Entropy Oxides with Phase Controllability.

High-entropy oxides (HEOs) with an ultrathin geometric structure are especially expected to exhibit extraordinary performance in different fields. The phase structure is deemed as a key factor in determining the properties of HEOs, rendering their phase control synthesis tempting. However, the disparity in intrinsic phase structures and physicochemical properties of multiple components makes it challenging to form single-phase HEOs with the target phase. Herein, we proposed a self-lattice framework-guided strategy to realize the synthesis of ultrathin HEOs with desired phase structures, including rock-salt, spinel, perovskite, and fluorite phases. The participation of the Ga assistor was conducive to the formation of the high-entropy mixing state by decreasing the formation energy. The as-prepared ultrathin spinel HEOs were demonstrated to be an excellent catalyst with high activity and stability for the oxygen evolution reaction in water electrolysis. Our work injects new vitality into the synthesis of HEOs for advanced applications and undoubtedly expedites their phase engineering.

Gallium-Based Liquid Metals in Rechargeable Batteries: From Properties to Applications.

Gallium-based (Ga-based) liquid metals have attracted considerable interest due to their low melting points, enabling them to feature both liquid properties and metallic properties at room temperature. In light of this, Ga-based liquid metals also possess excellent deformability, high electrical and thermal conductivity, superior metal affinity, and unique self-limited surface oxide, making them popular functional materials in energy storage. This provides a possibility to construct high-performance rechargeable batteries that are deformable, free of dendrite growth, and so on. This review primarily starts with the property of Ga-based liquid metal, and then focuses on the potential applications in rechargeable batteries by exploiting these advantages, aiming to construct the correlation between properties and structures. The glorious applications contain interface protection, self-healing electrode construction, thermal management, and flexible batteries. Finally, the opportunities and obstacles for the applications of liquid metal in batteries are presented.

Targeted ablation of the left middle cervical ganglion prevents ventricular arrhythmias and cardiac injury induced by AMI.

Cardiac sympathetic overactivation is a critical driver in the progression of acute myocardial infarction (AMI). The left middle cervical ganglion (LMCG) is an important extracardiac sympathetic ganglion. However, the regulatory effects of LMCG on AMI have not yet been fully documented. In the present study, we detected that the LMCG was innervated by abundant sympathetic components and exerted an excitatory effect on the cardiac sympathetic nervous system in response to stimulation. In canine models of AMI, targeted ablation of LMCG reduced the sympathetic indexes of heart rate variability and serum norepinephrine, resulting in suppressed cardiac sympathetic activity. Moreover, LMCG ablation could improve ventricular electrophysiological stability, evidenced by the prolonged ventricular effective refractory period, elevated action potential duration, increased ventricular fibrillation threshold, and enhanced connexin43 expression, consequently showing antiarrhythmic effects. Additionally, compared with the control group, myocardial infarction size, circulating cardiac troponin I, and myocardial apoptosis were significantly reduced, accompanied by preserved cardiac function in canines subjected to LMCG ablation. Finally, we performed the left stellate ganglion (LSG) ablation and compared its effects with LMCG destruction. The results indicated that LMCG ablation prevented ventricular electrophysiological instability, cardiac sympathetic activation, and AMI-induced ventricular arrhythmias with similar efficiency as LSG denervation. In conclusion, this study demonstrated that LMCG ablation suppressed cardiac sympathetic activity, stabilized ventricular electrophysiological properties and mitigated cardiomyocyte death, resultantly preventing ischemia-induced ventricular arrhythmias, myocardial injury, and cardiac dysfunction. Neuromodulation therapy targeting LMCG represented a promising strategy for the treatment of AMI.

Tumor necrosis factor receptor-associated factor 5 protects against intimal hyperplasia by regulation of macrophage polarization via directly targeting PPARγ.

OBJECTIVES: Intimal hyperplasia is a serious clinical problem associated with the failure of therapeutic methods in multiple atherosclerosis-related coronary heart diseases, which are initiated and aggravated by the polarization of infiltrating macrophages. The present study aimed to determine the effect and underlying mechanism by which tumor necrosis factor receptor-associated factor 5 (TRAF5) regulates macrophage polarization during intimal hyperplasia. METHODS: TRAF5 expression was detected in mouse carotid arteries subjected to wire injury. Bone marrow-derived macrophages, mouse peritoneal macrophages and human myeloid leukemia mononuclear cells were also used to test the expression of TRAF5 in vitro. Bone marrow-derived macrophages upon to LPS or IL-4 stimulation were performed to examine the effect of TRAF5 on macrophage polarization. TRAF5-knockout mice were used to evaluate the effect of TRAF5 on intimal hyperplasia. RESULTS: TRAF5 expression gradually decreased during neointima formation in carotid arteries in a time-dependent manner. In addition, the results showed that TRAF5 expression was reduced in classically polarized macrophages (M1) subjected to LPS stimulation but was increased in alternatively polarized macrophages (M2) in response to IL-4 administration, and these changes were demonstrated in three different types of macrophages. An in vitro loss-of-function study with TRAF5 knockdown plasmids or TRAF5-knockout mice revealed high expression of markers associated with M1 macrophages and reduced expression of genes related to M2 macrophages. Subsequently, we incubated vascular smooth muscle cells with conditioned medium of polarized macrophages in which TRAF5 expression had been downregulated or ablated, which promoted the proliferation, migration and dedifferentiation of VSMCs. Mechanistically, TRAF5 knockdown inhibited the activation of anti-inflammatory M2 macrophages by directly inhibiting PPARγ expression. More importantly, TRAF5-deficient mice showed significantly aggressive intimal hyperplasia. CONCLUSIONS: Collectively, this evidence reveals an important role of TRAF5 in the development of intimal hyperplasia through the regulation of macrophage polarization, which provides a promising target for arterial restenosis-related disease management.

Nek6 knockdown polarized macrophages into a pro-inflammatory phenotype via inhibiting STAT3 expression.

Recently macrophage polarization has emerged as playing an essential role in the oathogenesis of atherosclerosis, which is the most important underlying process in many types of cardiovascular diseases. Although Nek6 has been reported to be involved in various cellular processes, the effect of Nek6 on macrophage polarization remains unknown. Macrophages exposed to lipopolysaccharide (LPS) or IL-4 were used to establish an in vitro model for the study of regulation of classically (M1) or alternatively (M2) activated macrophage. Bone marrow-derived macrophages (BMDMs) transfected with short hairpin RNA-targeting Nek6 were then in functional studies. We observed that Nek6 expression was decreased in both peritoneal macrophages (PMs) and BMDMs stimulated by LPS. This effect was seen at both mRNA and protein level. The opposite results were obtained after administration of IL-4. Macrophage-specific Nek6 knockdown significantly exacerbated pro-inflammatory M1 polarized macrophage gene expression in response to LPS challenge, but the anti-inflammatory response gene expression that is related to M2 macrophages was attenuated by Nek6 silencing followed by treatment with IL-4. Mechanistic studies exhibited that Nek6 knockdown inhibited the phosphorylated STAT3 expression that mediated the effect on macrophage polarization regulated by AdshNek6. Moreover, decreased Nek6 expression was also observed in atherosclerotic plaques. Collectively, these evidences suggested that Nek6 acts as a crucial site in macrophage polarization, and that this operates in a STAT3-dependent manner.

Genomic and functional analysis of phage-mediated horizontal gene transfer in Pseudomonas syringae on the plant surface.

Many strains of Pseudomonas colonise plant surfaces, including the cherry canker pathogens, Pseudomonas syringae pathovars syringae and morsprunorum. We have examined the genomic diversity of P. syringae in the cherry phyllosphere and focused on the role of prophages in transfer of genes encoding Type 3 secreted effector (T3SE) proteins contributing to the evolution of virulence. Phylogenomic analysis was carried out on epiphytic pseudomonads in the UK orchards. Significant differences in epiphytic populations occurred between regions. Nonpathogenic strains were found to contain reservoirs of T3SE genes. Members of P. syringae phylogroups 4 and 10 were identified for the first time from Prunus. Using bioinformatics, we explored the presence of the gene encoding T3SE HopAR1 within related prophage sequences in diverse P. syringae strains including cherry epiphytes and pathogens. Results indicated that horizontal gene transfer (HGT) of this effector between phylogroups may have involved phage. Prophages containing hopAR1 were demonstrated to excise, circularise and transfer the gene on the leaf surface. The phyllosphere provides a dynamic environment for prophage-mediated gene exchange and the potential for the emergence of new more virulent pathotypes. Our results suggest that genome-based epidemiological surveillance of environmental populations will allow the timely application of control measures to prevent damaging diseases.

Bacteriophage host range evolution through engineered enrichment bias, exploiting heterologous surface receptor expression.

Research on the initial phage-host interaction has been conducted on a limited repertoire of phages and their cognate receptors, such as phage λ and the Escherichia coli LamB (EcLamB) protein. Apart from phage λ, little is known about other phages that target EcLamB. Here, we developed a simple method for isolating novel environmental phages in a predictable way, i.e. isolating phages that target a particular receptor(s) of a bacterium, in this case, the EcLamB protein. A plasmid (pMUT13) encoding the EcLamB porin was transferred into three different enterobacterial genera. By enrichment with these engineered bacteria, a number of phages (ZZ phages) that targeted EcLamB were easily isolated from the environment. Interestingly, although EcLamB-dependent in their recombinant heterologous hosts, these newly isolated ZZ phages also targeted OmpC as an alternative receptor when infecting E. coli. Moreover, the phage host range was readily extended within three different bacterial genera with heterologously expressed EcLamB. Unlike phage λ, which is a member of the Siphoviridae family, these newly isolated EcLamB-dependent phages were more commonly members of the Myoviridae family, based on transmission electron microscopy and genomic sequences. Modifications of this convenient and efficient phage enrichment method could be useful for the discovery of novel phages.

The Prophages of Citrobacter rodentium Represent a Conserved Family of Horizontally Acquired Mobile Genetic Elements Associated with Enteric Evolution towards Pathogenicity.

Prophage-mediated horizontal gene transfer (HGT) plays a key role in the evolution of bacteria, enabling access to new environmental niches, including pathogenicity. Citrobacter rodentium is a host-adapted intestinal mouse pathogen and important model organism for attaching and effacing (A/E) pathogens, including the clinically significant enterohaemorrhagic and enteropathogenic Escherichia coli (EHEC and EPEC, respectively). Even though C. rodentium contains 10 prophage genomic regions, including an active temperate phage, ΦNP, little was known regarding the nature of C. rodentium prophages in the bacterium's evolution toward pathogenicity. In this study, our characterization of ΦNP led to the discovery of a second, fully functional temperate phage, named ΦSM. We identify the bacterial host receptor for both phages as lipopolysaccharide (LPS). ΦNP and ΦSM are likely important mediators of HGT in C. rodentium Bioinformatic analysis of the 10 prophage regions reveals cargo genes encoding known virulence factors, including several type III secretion system (T3SS) effectors. C. rodentium prophages are conserved across a wide range of pathogenic enteric bacteria, including EPEC and EHEC as well as pathogenic strains of Salmonella enterica, Shigella boydii, and Klebsiella pneumoniae Phylogenetic analysis of core enteric backbone genes compared against prophage evolutionary models suggests that these prophages represent an important, conserved family of horizontally acquired enteric-bacterium-associated pathogenicity determinants. In addition to highlighting the transformative role of bacteriophage-mediated HGT in C. rodentium's evolution toward pathogenicity, these data suggest that the examination of conserved families of prophages in other pathogenic bacteria and disease outbreaks might provide deeper evolutionary and pathological insights otherwise obscured by more classical analysis.IMPORTANCE Bacteriophages are obligate intracellular parasites of bacteria. Some bacteriophages can confer novel bacterial phenotypes, including pathogenicity, through horizontal gene transfer (HGT). The pathogenic bacterium Citrobacter rodentium infects mice using mechanisms similar to those employed by human gastrointestinal pathogens, making it an important model organism. Here, we examined the 10 prophages of C. rodentium, investigating their roles in its evolution toward virulence. We characterized ΦNP and ΦSM, two endogenous active temperate bacteriophages likely important for HGT. We showed that the 10 prophages encode predicted virulence factors and are conserved within other intestinal pathogens. Phylogenetic analysis suggested that they represent a conserved family of horizontally acquired enteric-bacterium-associated pathogenic determinants. Consequently, similar analysis of prophage elements in other pathogens might further understanding of their evolution and pathology.

N-Acetylcysteine Alleviates Phenylephrine-Induced Cardiomyocyte Dysfunction via Engaging PI3K/AKT Signaling Pathway.

BACKGROUND: Increased reactive oxygen species (ROS) and oxidative stress response lead to cardiomyocyte hypertrophy and apoptosis, which play crucial roles in the pathogenesis of heart failure. The purpose of current research was to explore the role of antioxidant N-acetylcysteine (NAC) on cardiomyocyte dysfunction and the underlying molecular mechanisms. METHODS AND RESULTS: Compared with control group without NAC treatment, NAC dramatically inhibited the cell size of primary cultured neonatal rat cardiomyocytes (NRCMs) tested by immunofluorescence staining and reduced the expression of representative markers associated with hypertrophic, fibrosis and apoptosis subjected to phenylephrine administration examined by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. Moreover, enhanced ROS expression was attenuated, whereas activities of makers related to oxidative stress response examined by individual assay Kits, including total antioxidation capacity (T-AOC), glutathione peroxidase (GSH-Px), and primary antioxidant enzyme Superoxide dismutase (SOD) were induced by NAC treatment in NRCMs previously treated with phenylephrine. Mechanistically, we noticed that the protein expression levels of phosphorylated phosphatidylinositol 3-kinase (PI3K) and AKT were increased by NAC stimulation. More importantly, we identified that the negative regulation of NAC in cardiomyocyte dysfunction was contributed by PI3K/AKT signaling pathway through further utilization of PI3K/AKT inhibitor (LY294002) or agonist (SC79). CONCLUSIONS: Collected, NAC could attenuate cardiomyocyte dysfunction subjected to phenylephrine, partially by regulating the ROS-induced PI3K/AKT-dependent signaling pathway.

14-3-3ε/YWHAE regulates the transcriptional expression of cardiac sodium channel NaV1.5.

BACKGROUND: Cardiac voltage-gated sodium channel alpha subunit 5 (NaV1.5) encoded by SCN5A is associated with arrhythmia disorders. However, the molecular mechanism underlying NaV1.5 expression remains to be fully elucidated. Previous studies have reported that the 14-3-3 family acts as an adaptor involved in regulating kinetic characteristics of cardiac ion channels. OBJECTIVE: The purpose of this study was to establish 14-3-3ε/YWHAE, a member of the 14-3-3 family, as a crucial regulator of NaV1.5 and to explore the potential role of 14-3-3ε in the heart. METHODS: Western blotting, patch clamping, real-time reverse transcription-polymerase chain reaction, RNA immunoprecipitation, electrocardiogram recording, echocardiography, and histologic analysis were performed. RESULTS: YWHAE overexpression significantly reduced the expression level of SCN5A mRNA and sodium current density, whereas YWHAE knockdown significantly increased SCN5A mRNA expression and sodium current density in HEK293/NaV1.5 and H9c2 cells. Similar results were observed in mice injected with adeno-associated virus serotype 9-mediated YWHAE knockdown. The effect of 14-3-3ε on NaV1.5 expression was abrogated by knockdown of TBX5, a transcription factor of NaV1.5. An interaction between 14-3-3ε protein and TBX5 mRNA was identified, and YWHAE overexpression significantly decreased TBX5 mRNA stability without affecting SCN5A mRNA stability. In addition, mice subjected to adeno-associated virus serotype 9-mediated YWHAE knockdown exhibited shorter R-R intervals and higher prevalence of premature ventricular contractions. CONCLUSION: Our data unveil a novel regulatory mechanism of NaV1.5 by 14-3-3ε and highlight the significance of 14-3-3ε in transcriptional regulation of NaV1.5 expression and cardiac arrhythmias.

Interlayer Biatomic Pair Bridging the van der Waals Gap for 100% Activation of 2D Layered Material.

2D layered materials are regarded as prospective catalyst candidates due to their advantageous atomic exposure ratio. Nevertheless, the predominant population of atoms residing on the basal plane with saturated coordination, exhibit inert behavior, while a mere fraction of atoms located at the periphery display reactivity. Here, a novel approach is reported to attain complete atom activation in 2D layered materials through the construction of an interlayer biatomic pair bridge. The atoms in question have been strategically optimized to achieve a highly favorable state for the adsorption of intermediates. This optimization results from the introduction of new gap states around the Fermi level. Moreover, the presence of the interlayer bridge facilitates the electron transfer across the van der Waals gap, thereby enhancing the reaction kinetics. The hydrogen evolution reaction exhibits an impressive ultrahigh current density of 2000 mA cm-2 at 397 mV, surpassing the pristine MoS2 by approximately two orders of magnitude (26 mA cm-2 at 397 mV). This study provides new insights for enhancing the efficacy of 2D layered catalysts.

Genetic dissection of the tissue-specific roles of type III effectors and phytotoxins in the pathogenicity of Pseudomonas syringae pv. syringae to cherry.

When compared with other phylogroups (PGs) of the Pseudomonas syringae species complex, P. syringae pv. syringae (Pss) strains within PG2 have a reduced repertoire of type III effectors (T3Es) but produce several phytotoxins. Effectors within the cherry pathogen Pss 9644 were grouped based on their frequency in strains from Prunus as the conserved effector locus (CEL) common to most P. syringae pathogens; a core of effectors common to PG2; a set of PRUNUS effectors common to cherry pathogens; and a FLEXIBLE set of T3Es. Pss 9644 also contains gene clusters for biosynthesis of toxins syringomycin, syringopeptin and syringolin A. After confirmation of virulence gene expression, mutants with a sequential series of T3E and toxin deletions were pathogenicity tested on wood, leaves and fruits of sweet cherry (Prunus avium) and leaves of ornamental cherry (Prunus incisa). The toxins had a key role in disease development in fruits but were less important in leaves and wood. An effectorless mutant retained some pathogenicity to fruit but not wood or leaves. Striking redundancy was observed amongst effector groups. The CEL effectors have important roles during the early stages of leaf infection and possibly acted synergistically with toxins in all tissues. Deletion of separate groups of T3Es had more effect in P. incisa than in P. avium. Mixed inocula were used to complement the toxin mutations in trans and indicated that strain mixtures may be important in the field. Our results highlight the niche-specific role of toxins in P. avium tissues and the complexity of effector redundancy in the pathogen Pss 9644.

Sintilimab-Induced Myocarditis in a Patient with Gastric Cancer: A Case Report and Literature Review.

Immune checkpoint inhibitors (ICIs) have emerged as a powerful and efficacious therapeutic approach for many cancer patients. Sintilimab is a fully human IgG4 monoclonal antibody that binds with programmed cell death receptor-1 (PD-1) to block its interaction with ligands, thereby enhancing the antitumor effects of T cells. However, ICIs may induce immune-related adverse events (irAEs) in various systems and organs, with fulminant myocarditis being the most severe one. We report the case of a 45-year-old female with gastric cancer who developed chest pain two weeks after chemotherapy with sintilimab; she was diagnosed with immune-associated fulminant myocarditis and experienced an Adams-Stokes syndrome attack in the hospital. Eventually, she was discharged after being treated with methylprednisolone, immunoglobulin, and an IABP.

Coaxial Electrospun Tai Chi-Inspired Lithium-Ion Battery Separator with High Performance and Fireproofing Capacity.

Organic flame-retardant-loaded battery separator offers a new opportunity for battery safety. However, its poor thermal stability still poses serious safety issues. Inspired by Tai Chi, an "internal-cultivating and external-practicing" core-shell nanofibrous membrane was prepared by coaxial electrospinning, wherein the shell layer was a mixture of polyvinylidene fluoride, silicon dioxide (SiO2), and graphene oxide (GO) and the core layer contained triphenyl phosphate (TPP). SiO2 and GO enhanced the thermal stability and electrochemical performance. The encapsulated TPP prevented heat transfer and the degradation of electrochemical performance caused by its direct dissolution. This separator exhibited outstanding thermal stability and flame retardancy: it did not burn and remained relatively intact (91.2%) in an open flame for 15 s. The battery assembled with a composite separator showed excellent performance: the initial capacity reached 164 mA h/g and maintained 95% after 100 charge-discharge cycles. This novel strategy endows high-performance lithium batteries with relatively higher safety.

A Monolayer High-Entropy Layered Hydroxide Frame for Efficient Oxygen Evolution Reaction.

High-entropy materials with tailored geometric and elemental compositions provide a guideline for designing advanced electrocatalysts. Layered double hydroxides (LDHs) are the most efficient oxygen evolution reaction (OER) catalyst. However, due to the huge difference in ionic solubility product, an extremely strong alkali environment is necessary to prepare high-entropy layered hydroxides (HELHs), which results in an uncontrollable structure, poor stability, and scarce active sites. Here, a universal synthesis of monolayer HELH frame in a mild environment is presented, regardless of the solubility product limit. Mild reaction conditions allow this study to precisely control the fine structure and elemental composition of the final product. Consequently, the surface area of the HELHs is up to 380.5 m2  g-1 . The current density of 100 mA cm-2 is achieved in 1 m KOH at an overpotential of 259 mV, and, after 1000 h operation at the current density of 20 mA cm-2 , the catalytic performance shows no obvious deterioration. The high-entropy engineering and fine nanostructure control open opportunities to solve the problems of low intrinsic activity, very few active sites, instability, and low conductance during OER for LDH catalysts.

Transcriptome analysis reveals the mechanism of pyroptosis-related genes in septic cardiomyopathy.

Background: Septic cardiomyopathy (SC) is characterized by myocardial dysfunction caused by sepsis and constitutes one of the serious complications of sepsis. Pyroptosis is a unique proinflammatory programmed cell death process. However, the role of pyroptosis in the development of SC remains unclear, and further study is required. The purpose of this study is to identify pyroptosis-related genes (PRGs) in SC and explore the mechanism of pyroptosis involved in the regulation of SC formation and progression. Methods: Differential expression analysis and enrichment analysis were performed on the SC-related dataset GSE79962 to identify differentially expressed genes (DEGs). PRGs were screened by intersecting genes associated with pyroptosis in previous studies with the DEGs obtained from GSE79962. The expression pattern of them was studied based on their raw expression data. Additionally, corresponding online databases were used to predict miRNAs, transcription factors (TFs) and therapeutic agents of PRGs. Lipopolysaccharide (LPS)-induced cell damage models in H9C2 and AC16 cell lines were constructed, cell activity was detected by CCK-8 and cell pyroptosis were detected by Hoechst33342/PI staining. Furthermore, these PRGs were verified in the external datasets (GSE53007 and GSE142615) and LPS-induced cell damage model. Finally, the effect of siRNA-mediated PRGs knockdown on the pyroptosis phenotype was examined. Results: A total of 1,206 DEGs were screened, consisting of 663 high-expressed genes and 543 low-expressed genes. Among them, ten PRGs (SOD2, GJA1, TIMP3, TAP1, TIMP1, NOD1, TP53, CPTP, CASP1 and SAT1) were identified, and they were mainly enriched in "Pyroptosis", "Ferroptosis", "Longevity regulating pathway", and "NOD-like receptor signaling pathway". A total of 147 miRNAs, 31 TFs and 13 therapeutic drugs were predicted targeting the PRGs. The expression trends of SOD2 were confirmed in both the external datasets and LPS-induced cell damage models. Knockdown of SOD2 induced increased pyroptosis in the AC16 LPS-induced cell damage model. Conclusions: In this study, we demonstrated that SOD2 is highly expressed in both the SC and LPS-induced cell damage models. Knockdown of SOD2 led to a significant increase in pyroptosis in the AC16 LPS-induced cell damage model. These findings suggest that SOD2 may serve as a potential target for the diagnosis and treatment of SC.

Projected changes in terrestrial water storage and associated flood potential across the Yangtze River basin.

Terrestrial water storage is a crucial component in water cycle and plays an important role in flood formations process, particularly in a changing environment. In this study, we aim to examine the future variation of terrestrial water storage anomaly (TWSA) and associated flood potential in one of the most flood-prone regions, the Yangtze River basin in China. Using the Gravity Recovery and Climate Experiment (GRACE) data, we perform bias correction for seven general circulation models (GCMs) from the Coupled Model Intercomparison Project Phase 6 under three Shared Socio-economic Pathway (SSP) scenarios: SSP126, SSP245, and SSP585. The spatiotemporal characteristics of changes in future Flood Potential Index are projected and compared between the near (2031-2060) and far (2071-2100) future with reference to the historical period (1985-2014). The results show that GCMs-simulated TWSA generally agrees well with the GRACE results after downscaling and bias correction with the average correlation coefficient of 0.86, Nash-Sutcliffe efficiency of 0.73 and the root mean square error of 21.68 mm. We found that the total variance of projected TWSA is mainly sourced from the internal variability and model uncertainties, while the uncertainties in scenarios contribute relatively less. Moreover, the flood potential is projected to decline during the near future under various scenarios and even lower during the far future under SSP585 scenario. Our findings provide implications for flood control and management under climate change over high flood risk regions worldwide.

Emergence of the resistance-nodulation-division efflux pump tmexCD3-toprJ3 gene confers resistance to tigecycline in Pseudomonas juntendi and Proteus terrae isolated from a pig farm in China.

BACKGROUND: Tigecycline is regarded as a last-resort antimicrobial agent against multidrug resistance (MDR). However, resistance-nodulation-division efflux pump resistance genes, such as tmexCD3-toprJ3, that confer resistance to tigecycline have emerged. OBJECTIVES: This study aimed to characterise the tmexCD3-toprJ3 gene cluster in Pseudomonas juntendi and Proteus terrae isolated from a pig farm. METHODS: Samples were obtained from a Chinese piggery and included 92 pig faecal samples, 56 wastewater samples, 23 drinking water samples, 28 sow vagina samples and nine sow uterus swabs. The presence of tmexCD3-toprJ3 was detected using a polymerase chain reaction assay, and the antimicrobial susceptibility profile of the tmexCD3-toprJ3-positive isolates was determined using the broth dilution method. Genomic locations were identified using whole-genome sequencing and bioinformatics. RESULTS: We identified two tmexCD3-toprJ3-positive isolates, and both isolates were highly resistant to antibiotics such as tigecycline. In addition, we identified several mobile elements (ISPa7, ISCfr1, ISVsa3) and insertion sequences (TnAs2, TnAs3) in tmexCD3-toprJ3-positive isolates that could increase the potential for the spread of MDR. CONCLUSIONS: To the best of our knowledge, this study is the first to report the detection of tmexCD3-toprJ3 in P. juntendi and P. terrae isolated from a pig farm.

Suppressive Effects of Gelsemine on Anxiety-like Behaviors Induced by Chronic Unpredictable Mild Stress in Mice.

Gelsemine is an active principle and a major alkaloid found in Gelsemium genus of plants belonging to the Loganiaceae family. The aim of the present study was to explore whether gelsemine exerts anxiolytic effects on a mouse model of chronic-unpredictable-mild-stress (CUMS)-induced anxiety-like behaviors. NOD-like receptor protein 3 (NLRP3) inflammasome, downregulated cAMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were also evaluated as potential mechanisms. First, gelsemine reversed a CUMS-induced decrease in body-weight gain in mice. Next, gelsemine alleviated CUMS-induced anxiety-like behaviors, as evidenced by the increased distance traveled in the central zone of the open-field test, both the increased percentage of time spent and distance traveled in the light compartment, the increased number of transitions between compartments in the light/dark-transition test, and the increased percentage of entries and time spent in the open arm of the elevated plus-maze. In addition, gelsemine decreased the levels of pro-inflammatory cytokines, including interleukin (IL)-1ß and IL-6, in the hypothalamus and hippocampus of CUMS mice. Interestingly, further investigations revealed that gelsemine inhibited the CUMS-induced activation of NLRP3-inflammasome pathways and downregulated CREB and BDNF overexpression in the hypothalamus. In summary, gelsemine alleviated anxiety-like behaviors in the CUMS-induced mouse model. Gelsemine exerted its anxiolytic effects by modulating the NLRP3 and CREB/BDNF pathways.

Toxicity assessment of gelsenicine and the search for effective antidotes.

BACKGROUND: Gelsenicine, one of the most toxic alkaloids of Gelsemium elegans Benth (G. elegans), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available. OBJECTIVE: This study aimed to analyse the toxicity characteristics of gelsenicine. METHODS: Both acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened. RESULTS: In the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD50 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood-brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice. CONCLUSIONS: Gelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicine-related poisoning and its toxicity mechanisms.