Hydrogel-based therapeutic strategies for spinal cord injury repair: Recent advances and future prospects.

Spinal cord injury (SCI) is a debilitating condition that can result in significant functional impairment and loss of quality of life. There is a growing interest in developing new therapies for SCI, and hydrogel-based multimodal therapeutic strategies have emerged as a promising approach. They offer several advantages for SCI repair, including biocompatibility, tunable mechanical properties, low immunogenicity, and the ability to deliver therapeutic agents. This article provides an overview of the recent advances in hydrogel-based therapy strategies for SCI repair, particularly within the past three years. We summarize the SCI hydrogels with varied characteristics such as phase-change hydrogels, self-healing hydrogel, oriented fibers hydrogel, and self-assembled microspheres hydrogel, as well as different functional hydrogels such as conductive hydrogels, stimuli-responsive hydrogels, adhesive hydrogel, antioxidant hydrogel, sustained-release hydrogel, etc. The composition, preparation, and therapeutic effect of these hydrogels are briefly discussed and comprehensively evaluated. In the end, the future development of hydrogels in SCI repair is prospected to inspire more researchers to invest in this promising field.

A Local Search Algorithm with Vertex Weighting Strategy and Two-Level Configuration Checking for the Minimum Connected Dominating Set Problem.

The minimum connected dominating set problem is a combinatorial optimization problem with a wide range of applications in many fields. We propose an efficient local search algorithm to solve this problem. In this work, first, we adopt a new initial solution construction method based on three simplification rules. This method can reduce the size of the original graph and thus obtain a high-quality initial solution. Second, we propose an approach based on a two-level configuration checking strategy and a tabu strategy to reduce the cycling problem. Third, we introduce a perturbation strategy and a vertex weighting strategy to help the algorithm be able to jump out of the local optimum effectively. Fourth, we combine the scoring functions Cscore and Mscore with the aforementioned strategies to propose effective methods for selecting vertices. These methods assist the algorithm in selecting vertices that are suitable for addition to or removal from the current candidate solution. Finally, we verify the performance advantages of the local search algorithm by comparing it with existing optimal heuristic algorithms on two sets of instances. The experimental results show that the algorithm exhibits better performance on two sets of classical instances.

Clinical and laboratory insights into the threat of hypervirulent Klebsiella pneumoniae.

Hypervirulent Klebsiella pneumoniae (hvKP) typically causes severe invasive infections affecting multiple sites in healthy individuals. In the past, hvKP was characterized by a hypermucoviscosity phenotype, susceptibility to antimicrobial agents, and its tendency to cause invasive infections in healthy individuals within the community. However, there has been an alarming increase in reports of multidrug-resistant hvKP, particularly carbapenem-resistant strains, causing nosocomial infections in critically ill or immunocompromised patients. This presents a significant challenge for clinical treatment. Early identification of hvKP is crucial for timely infection control. Notably, identifying hvKP has become confusing due to its prevalence in nosocomial settings and the limited predictive specificity of the hypermucoviscosity phenotype. Novel virulence predictors for hvKP have been discovered through animal models or machine learning algorithms, while standardization of identification criteria is still necessary. Timely source control and antibiotic therapy have been widely employed for the treatment of hvKP infections. Additionally, phage therapy is a promising alternative approach due to escalating antibiotic resistance. In summary, this narrative review highlights the latest research progress in the development, virulence factors, identification, epidemiology of hvKP, and treatment options available for hvKP infection.

Curcumin improves atrial fibrillation susceptibility by regulating tsRNA expression in aging mouse atrium.

Age is an independent risk factor for atrial fibrillation (AF), and curcumin can delay aging related disease through reducing oxidative stress and inflammation. However, its target in aging-related AF remains unclear. Transfer RNA-derived small RNA (tsRNA) is a novel short non-coding RNA (sncRNA), and exerts a potential regulatory function in aging. This study was to explore the therapeutic targets of curcumin in atrium of aged mice by PANDORA-seq. Aged mice (18 month) were treated with curcumin (100 mg/kg). Rapid transjugular atrial pacing was performed to observe AF inducibility. SA-ß-gal staining, reactive oxygen species (ROS) detection and qRT-PCR were used to assess the degree of aging and oxidative stress/inflammation levels. PANDORA-seq was performed to reveal the differentially expressed sncRNAs in the atrium of mice. The results showed that curcumin reduced the susceptibility AF of aged mice by improving aging-related atrial fibrosis. Compared to young mice (5 month) group, aged mice yielded 473 significantly altered tsRNA sequences, while 947 tsRNA sequences were significantly altered after treated with curcumin. Enrichment analysis revealed that the target genes were mainly related to DNA damage and protein modification. Compared with the 5 month group, the expression levels of mature-mt_tRNA-Val-TAC_CCA_end, mature-mt_tRNA-Glu-TTC_CCA_end, and mature-tRNA-Asp-GTC_CCA_end were up-regulated in the 18 month group, while the expression of mature-mt_tRNA-Thr-TGT_5_end was down-regulated. This trend was reversed in the 18 month + curcumin group. Increased cellular ROS levels, inflammation expression and senescence in aged mice atrium were improved by the down-regulation of mature-mt_tRNA-Val-TAC_CCA_end. In conclusion, our findings identified mature-mt_tRNA-Val-TAC_CCA_end participated in the mechanism of aging-related atrial fibrosis, providing new intervention target of aging-related AF.

Fitness effects of synthetic and natural diet preservatives on the edible insect Bombyx mori.

Silkworm pupae as widely consumed insect products are good biosources of protein and micronutrients. Silkworm rearing throughout the year can be achieved by feeding them an artificial diet instead of native plants, facilitating extensive pupa production. However, artificial diets are prone to spoilage caused by bacterial contamination. Here, we evaluated the antiseptic effect of ethylparaben (EP, chemical preservative) and medium-chain fatty acids (MCFA, natural preservative) in a silkworm artificial diet. Results showed that both preservatives effectively inhibited pathogenic bacterial growth. Furthermore, the addition of EP or MCFA did not negatively impact the production capacity of silkworms and the homeostasis of gut microbiota. However, the expression of genes involved in detoxification such as Ugt2, and immune response such as Cecropin B, were upregulated after EP consumption. Therefore, natural preservative MCFA emerges as a suitable option from a safety perspective. These findings highlight future directions for improving insect artificial diet formulation.

A panel of genotypically and phenotypically diverse clinical Acinetobacter baumannii strains for novel antibiotic development.

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. IMPORTANCE: Acinetobacter 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.

Lighting up endogenous H2O2 in the tumor microenvironment using a dual-mode nanoprobe for long afterglow and MR bioimaging.

Persistent luminescent nanoparticles (PLNPs) are excellent luminescent materials, and near-infrared PLNPs are efficiently applied for biosensing and bioimaging due to their advantages of no excitation, excellent light stability and long afterglow. However, due to interference from the complex environment within organisms, single-mode imaging methods often face limitations in selectivity, sensitivity, and accuracy. Therefore, it is desirable to construct a dual-mode imaging probe strategy with higher specificity and sensitivity for bioimaging. Magnetic resonance imaging (MRI) has been widely used in the field of bioimaging due to its advantages of high resolution, non-radiation and non-invasiveness. Here, by combining near-infrared PLNPs and manganese dioxide (MnO2) nanosheets, a sensitive and convenient dual-mode "turn on" bioimaging nanoprobe ZGC@MnO2 has been developed for long afterglow imaging and MRI of endogenous hydrogen peroxide (H2O2) in the tumor microenvironment (TME). The monitoring of H2O2 has garnered significant attention due to its crucial role in human pathologies. For the dual-mode "turn on" bioimaging nanoprobe, the near-infrared PLNPs of quasi-spherical ZnGa2O4:Cr (ZGC) nanoparticles were synthesized as luminophores, and MnO2 nanosheets were utilized as a fluorescence quencher, carrier and H2O2 recognizer. H2O2 in the TME could reduce MnO2 nanosheets to Mn2+ for MRI, and ZGC nanoparticles were released for long afterglow imaging. Finally, the ZGC@MnO2 nanoprobe exhibited a rapid response, an excellent signal-to-noise ratio and a limit of detection of 3.67 nM for endogenous H2O2 in the TME. This dual-mode approach enhances the detection sensitivity for endogenous H2O2, thereby facilitating the research of endogenous H2O2-associated diseases and clinical diagnostics.

Dissemination of Ceftriaxone-Resistant Salmonella Enteritidis Harboring Plasmids Encoding blaCTX-M-55 or blaCTX-M-14 Gene in China.

Salmonella Enteritidis was the primary foodborne pathogen responsible for acute gastroenteritis. The growing ceftriaxone resistance poses a significant threat to public health. Infection with S. Enteritidis has emerged as a major public health concern, particularly in developing countries. However, research on ceftriaxone-resistant S. Enteritidis (CRO-RSE) remains limited, particularly concerning its resistance mechanism, plasmid structure, and transmission characteristics. This study aims to address these gaps comprehensively. We collected 235 S. Enteritidis isolates from Hangzhou First People's Hospital between 2010 and 2020. Among these, 8.51% (20/235) exhibited resistance to ceftriaxone. Whole-genome analysis revealed that 20 CRO-RSE isolates harbored blaCTX-M-55 or blaCTX-M-14 on the plasmid. Moreover, the dissemination of the blaCTX-M-type gene was associated with IS26 and ISEcp1. Plasmid fusion entailing the integration of the p1 plasmid with antibiotic resistance genes and the p2 (pSEV) virulence plasmid was observed in certain CRO-RSE. Additionally, the structural analysis of the plasmids unveiled two types carrying the blaCTX-M-type gene: type A with multiple replicons and type B with IncI1 (Alpha) replicon. Type B plasmids exhibited superior adaptability and stability compared to type A plasmids within Enterobacteriaceae. Interestingly, although the type B (S808-p1) plasmid displayed the potential to spread to Acinetobacter baumannii, it failed to maintain stability in this species.

Genetic characterization of plasmid-borne blaOXA-58 and blaOXA-72 in Acinetobacter pittii in Shaanxi, China.

OBJECTIVES: Acinetobacter pittii has emerged as an opportunistic nosocomial pathogen associated with hospital-acquired infections. The purpose of this study was to investigate the genetic structures of plasmids carrying carbapenemase genes blaOXA-58 and blaOXA-72 in A. pittii strains AR3676 and AR3651 isolated from patients. METHODS: Antimicrobial susceptibility testing was performed using broth microdilution. Whole-genome sequencing and bioinformatics analysis were performed to characterize the genome of A. pittii AR3676 and AR3651. Conjugation experiments were conducted to evaluate plasmid transferability. Phylogenetic and comparative genomic analysis were performed to explore the characteristics of carbapenem-resistant A. pittii isolates worldwide. RESULTS: The AR3676 strain showed resistance to imipenem. The 19 700-bp plasmid pAR3676-OXA-58 harboured blaOXA-58 with genetic contexts consisting of a truncated ISAba3-like-blaOXA58-ISAba3. Additionally, the AR3651 strain showed resistance to imipenem and meropenem. The AR3651 genome comprised one 9,837-bp RepA_AB plasmid pAR3651-OXA-72 harbouring blaOXA-72. This blaOXA-72 was flanked by XerC/XerD recombination sites. The conjugation of plasmids pAR3676-OXA-58 and pAR3651-OXA-72 from A. pittii to Acinetobacter baumannii ATCC 17978RIFR failed three independent times. Phylogenetic analysis of A. pittii strains AR3676, AR3651, and a further 504 A. pittii strains collected between 1966 and 2022 from various geographic localities revealed genetic diversity with a heterogeneous distribution of carbapenemase genes. CONCLUSIONS: A. pittii strains with a plasmid carrying blaOXA-58 or blaOXA-72 may serve as an important reservoir of carbapenemase genes. Carbapenemase genes on a single plasmid may facilitate their dissemination and persistence. Additionally, pdif sites and mobile elements play an important role in the mobilization of resistance genes and plasmid evolution.

Assessing the quality and eco-beneficial microbes in the use of silkworm excrement compost.

Sericulture has become widespread globally, and the utilization of artificial diets produces a substantial quantity of silkworm excrement. Although silkworm excrement can be composted for environmentally friendly disposal, the potential utility of the resulting compost remains underexplored. The aim of this study was to assess the quality of this unique compost and screen for eco-beneficial microbes, providing a new perspective on microbial research in waste management, especially in sustainable agriculture. The low-concentration compost application exhibited a greater plant growth-promoting effect, which was attributed to an appropriate nutritional value (N, P, K, and dissolved organic matter) and the presence of plant growth-promoting bacteria (PGPB) within the compost. Encouraged by the "One Health" concept, the eco-benefits of potent PGPB, namely, Klebsiella pneumoniae and Bacillus licheniformis, in sericulture were further evaluated. For plants, K. pneumoniae and B. licheniformis increased plant weight by 152.44 % and 130.91 %, respectively. We also found that even a simple synthetic community composed of the two bacteria performed better than any single bacterium. For animals, K. pneumoniae significantly increased the silkworm (Qiufeng × Baiyu strain) cocoon shell weight by 111.94 %, which could increase sericulture profitability. We also elucidated the mechanism by which K. pneumoniae assisted silkworms in degrading tannic acid, a common plant-derived antifeedant, thereby increasing silkworm feed efficiency. Overall, these findings provide the first data revealing multiple beneficial interactions among silkworm excrement-derived microbes, plants, and animals, highlighting the importance of focusing on microbes in sustainable agriculture.

Current trends and possibilities of typical microbial protein production approaches: a review.

Global population growth and demographic restructuring are driving the food and agriculture sectors to provide greater quantities and varieties of food, of which protein resources are particularly important. Traditional animal-source proteins are becoming increasingly difficult to meet the demand of the current consumer market, and the search for alternative protein sources is urgent. Microbial proteins are biomass obtained from nonpathogenic single-celled organisms, such as bacteria, fungi, and microalgae. They contain large amounts of proteins and essential amino acids as well as a variety of other nutritive substances, which are considered to be promising sustainable alternatives to traditional proteins. In this review, typical approaches to microbial protein synthesis processes were highlighted and the characteristics and applications of different types of microbial proteins were described. Bacteria, fungi, and microalgae can be individually or co-cultured to obtain protein-rich biomass using starch-based raw materials, organic wastes, and one-carbon compounds as fermentation substrates. Microbial proteins have been gradually used in practical applications as foods, nutritional supplements, flavor modifiers, and animal feeds. However, further development and application of microbial proteins require more advanced biotechnological support, screening of good strains, and safety considerations. This review contributes to accelerating the practical application of microbial proteins as a promising alternative protein resource and provides a sustainable solution to the food crisis facing the world.

Formation mechanism of a novel core-shell with tetradecyl dimethyl benzyl ammonium-modified montmorillonite interlayer nanofibrous membrane and its antimicrobial properties.

A novel core-shell with a tetradecyl dimethyl benzyl ammonium chloride-modified montmorillonite (TDMBA/MMT) interlayer silk fibroin (SF)/poly(lactic acid) (PLLA) nanofibrous membrane was fabricated using a simple conventional electrospinning method. Scanning electron microscopy and pore size analyses revealed that this core-shell with TDMBA/MMT interlayer maintained its nanofibrous morphology and larger pore structure more successfully than SF/PLLA nanofibrous membranes after treatment with 75% ethanol vapor. Transmission electron microscopy and energy-dispersive X-ray spectroscopy analyses testified that the SF/PLLA-TDMBA/MMT nanofibers exhibited a core-shell with an interlayer structure, with SF/PLLA in the core-shell layer and TDMBA/MMT in the interlayer. The formation of a core-shell with interlayer nanofibers was primarily attributed to the uniform dispersion of TDMBA/MMT nanosheets in a solution owing to its exfoliation using hexafluoroisopropanol and then preparing a stable spinning solution similar to an emulsion. Compared to SF/PLLA nanofibrous membranes, the core-shell structure with TDMBA/MMT interlayers of SF/PLLA nanofibrous membranes exhibited enhanced hydrophilicity, thermal stability, mechanical properties as well as improved and long-lasting antimicrobial performance against Escherichia coli and Staphylococcus aureus without cytotoxicity.

Multifunctional Interface Modification Enables Efficient and Stable HTL-Free Carbon-Electroded CsPbI2Br Perovskite Solar Cells.

In recent years, hole transport layer-free all-inorganic CsPbI2Br carbon-electroded perovskite solar cells (C-PSCs) have garnered significant attention due to a trade-off between stability and photovoltaic performance. However, there are inevitably many defects generated at the surfaces or grain boundaries of CsPbI2Br perovskite films, which will serve as carrier non-radiative recombination centers, and CsPbI2Br perovskite films are sensitive to water molecules to degrade, together with energy level mismatch between CsPbI2Br perovskite and carbon electrodes. Herein, 1-benzyl-3-methylimidazolium hexafluorophosphate (1-B-3-MIMPF6), an imidazolium-based ionic liquid simultaneously containing benzene ring and fluorine atoms, was introduced for the modification of the perovskite/carbon interface. The results showed that it could effectively reduce defects, enhance carrier transfer, mitigate carrier non-radiative recombination, facilitate energy alignment, and block moisture intrusion. Therefore, the photovoltaic performance of the modified PSCs with ITO/SnO2/CsPbI2Br/1-B-3-MIMPF6/carbon architecture has been boosted with a champion power conversion efficiency (PCE) of 13.47 %, open circuit voltage of 1.20 V, short circuit current density of 14.69 mA/cm2, and fill factor of 76 %. Moreover, the unencapsulated modified devices exhibited an improved stability and the PCE maintained 78 % of their initial PCE after 24 h storage at room temperature in a 30 %-35 % humidity environment, whereas that of the pristine devices dropped to almost zero.

Neoadjuvant savolitinib targeted therapy for stage IIIB-N3 lung adenocarcinoma harboring mesenchymal-epithelial transition exon 14 skipping mutation: a case report and literature review.

Savolitinib is a selective inhibitor that specifically targets the phosphorylation of mesenchymal-epithelial transition (MET) kinase. It has demonstrated significant inhibitory effects on the proliferation of tumor cells with METex14 skipping mutation, making it a promising treatment option. While it is the first approved small-molecule inhibitor specifically targeting MET kinase in China, there is limited information about its efficacy as neoadjuvant therapy for patients with supraclavicular lymph node metastasis (N3). In this case report, we presented the successful outcome of a 48-year-old male patient who was diagnosed with stage IIIB (T2bN3M0) lung adenocarcinoma originating from the left upper lobe. The patient exhibited the METex14 skipping alteration. Following two months of neoadjuvant savolitinib treatment, the patient achieved partial remission, with a significant reduction in the size of the primary tumor and metastatic lymph nodes. Postoperative pathological confirmation revealed a pathological complete response, and subsequent imaging examinations, including computed tomography scan and circulating tumor DNA-based molecular residual disease detection, showed no sign of recurrence at 7 months after surgery. Based on this case, neoadjuvant and adjuvant savolitinib therapy may be considered as a favorable alternative to chemotherapy for marginally resectable nonsmall cell lung cancer patients with METex14 skipping mutation.

Genomic epidemiology and ceftazidime-avibactam high-level resistance mechanisms of Pseudomonas aeruginosa in China from 2010 to 2022.

Ceftazidime-avibactam (CZA) resistance is a huge threat in the clinic; however, the underlying mechanism responsible for high-level CZA resistance in Pseudomonas aeruginosa (PA) isolates remains unknown. In this study, a total of 5,763 P. aeruginosa isolates were collected from 2010 to 2022 to investigate the ceftazidime-avibactam (CZA) high-level resistance mechanisms of Pseudomonas aeruginosa (PA) isolates in China. Fifty-six PER-producing isolates were identified, including 50 isolates carrying blaPER-1 in PA, and 6 isolates carrying blaPER-4. Of these, 82.1% (46/56) were classified as DTR-PA isolates, and 76.79% (43/56) were resistant to CZA. Importantly, blaPER-1 and blaPER-4 overexpression led to 16-fold and >1024-fold increases in the MICs of CZA, respectively. WGS revealed that the blaPER-1 gene was located in two different transferable IncP-2-type plasmids and chromosomes, whereas blaPER-4 was found only on chromosomes and was carried by a class 1 integron embedded in a Tn6485-like transposon. Overexpression of efflux pumps may be associated with high-level CZA resistance in blaPER-1-positive strains. Kinetic parameter analysis revealed that PER-4 exhibited a similar kcat/Km with ceftazidime and a high (∼3359-fold) IC50 value with avibactam compared to PER-1. Our study found that overexpression of PER-1 combined with enhanced efflux pump expression and the low affinity of PER-4 for avibactam contributes to high-level resistance to CZA. Additionally, the Tn6485-like transposon plays a significant role in disseminating blaPER. Urgent active surveillance is required to prevent the further spread of high-level CZA resistance in DTR-PA isolates.

Boron-Doped Engineering for Carbon Quantum Dots-Based Memristors with Controllable Memristance Stability.

Carbon quantum dots-based memristors (CQDMs) have emerged as a rising star in data storage and computing. The key constraint to their commercialization is memristance variability, which mainly arises from the disordered conductive paths. Doping methodology can optimize electron and ion transport to help construct a stable conductive mode. Herein, based on boron (B)-doped engineering strategy, three kinds of comparable quantum dots are synthesized, including carbon quantum dots (CQDs), a series of boron-doped CQDs (BCQDs) with different B contents, and boron quantum dots. The corresponding device performances highlight the superiority of BCQDs-based memristors, exhibiting a ternary flash-type memory behavior with longer retention time and more controllable memristance stability. The comprehensive analysis results, including device performance, functional layer morphology, and material simulated calculation, illustrate that the doped B elements can directionally guide the migration of aluminum ions by enhancing the capture of free electrons, resulting in ordered conductive filaments and stable ternary memory behavior. Finally, the conceptual applications of logic display and logic gate are discussed, indicating a bright prospect for BCQDs-based memristors. This work proves that modest B doping can optimize memristance property, establishing a theoretical foundation and template scheme for developing effective and stable CQDMs.

Multiomics analysis reveals the molecular basis for increased body weight in silkworms (Bombyx mori) exposed to environmental concentrations of polystyrene micro- and nanoplastics.

INTRODUCTION: Micro- and nanoplastics (MNPs) are emerging environmental pollutants that have raised serious concerns about their potential impact on ecosystem and organism health. Despite increasing efforts to investigate the impacts of micro- and nanoplastics (MNPs) on biota little is known about their potential impacts on terrestrial organisms, especially insects, at environmental concentrations. OBJECTIVES: To address this gap, we used an insect model, silkworm Bombyx mori to examine the potential long-term impacts of different sizes of polystyrene (PS) MNPs at environmentally realistic concentrations (0.25 to 1.0 µg/mL). METHODS: After exposure to PS-MNPs over most of the larval lifetime (from second to last instar), the endpoints were examined by an integrated physiological (growth and survival) and multiomics approach (metabolomics, 16S rRNA, and transcriptomics). RESULTS: Our results indicated that dietary exposures to PS-MNPs had no lethal effect on survivorship, but interestingly, increased host body weight. Multiomics analysis revealed that PS-MNPs exposure significantly altered multiple pathways, particularly lipid metabolism, leading to enriched energy reserves. Furthermore, the exposure changed the structure and composition of the gut microbiome and increased the abundance of gut bacteria Acinetobacter and Enterococcus. Notably, the predicted functional profiles and metabolite expressions were significantly correlated with bacterial abundance. Importantly, these observed effects were particle size-dependent and were ranked as PS-S (91.92 nm) > PS-M (5.69 µm) > PS-L (9.7 µm). CONCLUSION: Overall, PS-MNPs at environmentally realistic concentrations exerted stimulatory effects on energy metabolism that subsequently enhanced body weight in silkworms, suggesting that chronic PS-MNPs exposure might trigger weight gain in animals and humans by influencing host energy and microbiota homeostasis.

Emergence and plasmid cointegration-based evolution of NDM-1-producing ST107 Citrobacter freundii high-risk resistant clone in China.

Carbapenem-resistant Citrobacter freundii (CRCF) poses an enormous challenge in the health care setting. However, the epidemiology and plasmid dynamic evolution of this species have not been well studied, especially for the novel high-risk resistant clones in the intensive care units (ICUs). Here, we characterised the cointegration-based plasmid dynamic evolution of the emerging ST107 CRCF clone in China. Twenty CRCF strains were identified, including ST22 (30%), ST107 (25%), ST396 (10%) and ST116 (10%). Interestingly, the tigecycline (TGC) resistance gene cluster tmexCD2-toprJ2 and blaNDM-1 and blaKPC-2 were simultaneously found in one ST107 strain. Epidemiological analysis showed that ST107 clone contained human- and environment-derived strains from five countries. Notably, 93.75% (15/16) of the isolates harboured blaNDM-1 or blaKPC-2. Plasmid fusion among various ST107 strains of two patients occurred in the same ICU, mediated by Tn5403 and IS26-based insertion and deletion events. pCF1807-2 carried blaNDM-1 while pCF1807-3 carried both tmexCD2-toprJ2 and blaKPC-2 in the CF1807 strain. Importantly, the cointegrate plasmid pCF1807-2 exhibited higher transfer efficiency and could remain stable after serial passage. Notably, no fitness cost was observed for the host. In conclusion, ST107 CRCF is a high-risk resistant clone due to its ability to integrate resistant plasmids. Our findings elucidated the potential threat and global transmission of the ST107 lineage, and reasonable monitoring should be performed to prevent its further spread in hospitals.

Involvement of plasminogen activator inhibitor-1 in p300/p53-mediated age-related atrial fibrosis.

Plasminogen activator inhibitor-1 (PAI-1), a key regulator of the fibrinolytic system, is also intimately involved in the fibrosis. Although PAI-1 may be involved in the occurrence of atrial fibrillation (AF) and thrombosis in the elderly, but whether it participated in aging-related atrial fibrosis and the detailed mechanism is still unclear. We compared the transcriptomics data of young (passage 4) versus senescent (passage 14) human atrial fibroblasts and found that PAI-1 was closely related to aging-related fibrosis. Aged mice and senescent human and mouse atrial fibroblasts underwent electrophysiological and biochemical studies. We found that p300, p53, and PAI-1 protein expressions were increased in the atrial tissue of aged mice and senescent human and mouse atrial fibroblasts. Curcumin or C646 (p300 inhibitor), or p300 knockdown inhibited the expression of PAI-1 contributing to reduced atrial fibroblasts senescence, atrial fibrosis, and the AF inducibility. Furthermore, p53 knockdown decreased the protein expression of PAI-1 and p21 in senescent human and mouse atrial fibroblasts. Our results suggest that p300/p53/PAI-1 signaling pathway participates in the mechanism of atrial fibrosis induced by aging, which provides new sights into the treatment of elderly AF.

IS26 mediated blaCTX-M-65 amplification in Escherichia coli increase the antibiotic resistance to cephalosporin in vivo.

OBJECTIVES: To characterize two Escherichia coli strains isolated from a patient pre- and post-treatment, using ß-lactams and ß-lactam/ß-lactamase inhibitor combinations (BLBLIs). METHODS: A combination of antibiotic susceptibility testing (AST) with whole genome sequencing using Illumina and Oxford Nanopore platforms. Long-read sequencing and reverse transcription-quantitative PCR were performed to determine the copy numbers and expression levels of antibiotic resistance genes (ARGs), respectively. Effect on fitness costs were assessed by growth rate determination. RESULTS: The strain obtained from the patient after the antibiotic treatment (XH989) exhibited higher resistance to cefepime, BLBLIs and quinolones compared with the pre-treatment strain (XH987). Sequencing revealed IS26-mediated duplications of a IS26-fosA3-blaCTX-M-65 plasmid-embedded element in strain XH989. Long-read sequencing (7.4 G data volume) indicated a variation in copy numbers of blaCTX-M-65 within one single culture of strain XH989. Increased copy numbers of the IS26-fosA3-blaCTX-M-65 element were correlated with higher CTX-M-65 expression level and did not impose fitness costs, while facilitating faster growth under high antibiotic concentrations. CONCLUSION: Our study is an example from the clinic how BLBLIs and ß-lactams exposure in vivo possibly promoted the amplification of an IS26-multiple drug resistance (MDR) region. The observation of a copy number variation seen with the blaCTX-M-65 gene in the plasmid of the post-treatment strain expands our knowledge of insertion sequence dynamics and evolution during treatment.