Novel natural osthole-inspired amphiphiles as membrane targeting antibacterials against methicillin-resistant Staphylococcus aureus (MRSA).

Methicillin-resistant Staphylococcus aureus (MRSA) is a widespread pathogen causing clinical infections and is multi-resistant to many antibiotics, making it urgent need to develop novel antibacterials to combat MRSA. Herein, we designed and prepared a series of novel osthole amphiphiles 6a-6ad by mimicking the structures and function of antimicrobial peptides (AMPs). Antibacterial assays showed that osthole amphiphile 6aa strongly inhibited S. aureus and 10 clinical MRSA isolates with MIC values of 1-2 µg/mL, comparable to that of the commercial antibiotic vancomycin. Additionally, 6aa had the advantages of rapid bacteria killing without readily developing drug resistance, low toxicity, good membrane selectivity, and good plasma stability. Mechanistic studies indicated that 6aa possesses good membrane-targeting ability to bind to phosphatidylglycerol (PG) on the bacterial cell membranes, thereby disrupting the cell membranes and causing an increase in intracellular ROS as well as leakage of proteins and DNA, and accelerating bacterial death. Notably, in vivo activity results revealed that 6aa exhibits strong anti-MRSA efficacy than vancomycin as well as a substantial reduction in MRSA-induced proinflammatory cytokines, including TNF-α and IL-6. Given the impressive in vitro and in vivo anti-MRSA efficacy of 6aa, which makes it a potential candidate against MRSA infections.

Campylotropis xinfeniae (Fabaceae, Papilionoideae), a new species from Yunnan, China, based on morphological and molecular evidence.

Campylotropis xinfeniae, a new species from the dry-hot valley of the Jinsha River in the Yunnan province, China, is described and illustrated. It is morphologically similar to C. wilsonii and C. brevifolia in having glabrescent old branches, absent stipels, 3-foliolate leaves, and adaxially puberulent leaflets, while it differs from the latter two in having often paniculate inflorescences, obviously white standard, not incurved sickle keel, larger narrowly oblique legumes, and longer legume beak. The complete chloroplast genome of this new species is 149,073 bp in length and exhibits a typical quadripartite structure. Phylogenetic analyses based on the complete chloroplast genome also supported C. xinfeniae as a new species located at the basal distinct clade of the genus Campylotropis, clearly separated from the remaining members of the genus and its allied genera. A conservation assessment of data deficient (DD) is recommended for the new species without extensive exploring of similar habitats according to the IUCN Categories and Criteria.

Mitogenomic phylogeny, biogeography, and cryptic divergence of the genus Silurus (Siluriformes: Siluridae).

The genus Silurus, an important group of catfish, exhibits heterogeneous distribution in Eurasian freshwater systems. This group includes economically important and endangered species, thereby attracting considerable scientific interest. Despite this interest, the lack of a comprehensive phylogenetic framework impedes our understanding of the mechanisms underlying the extensive diversity found within this genus. Herein, we analyzed 89 newly sequenced and 20 previously published mitochondrial genomes (mitogenomes) from 13 morphological species to reconstruct the phylogenetic relationships, biogeographic history, and species diversity of Silurus. Our phylogenetic reconstructions identified eight clades, supported by both maximum-likelihood and Bayesian inference. Sequence-based species delimitation analyses yielded multiple molecular operational taxonomic units (MOTUs) in several taxa, including the Silurus asotus complex (four MOTUs) and Silurus microdorsalis (two MOTUs), suggesting that species diversity is underestimated in the genus. A reconstructed time-calibrated tree of Silurus species provided an age estimate of the most recent common ancestor of approximately 37.61 million years ago (Ma), with divergences among clades within the genus occurring between 11.56 Ma and 29.44 Ma, and divergences among MOTUs within species occurring between 3.71 Ma and 11.56 Ma. Biogeographic reconstructions suggested that the ancestral area for the genus likely encompassed China and the Korean Peninsula, with multiple inferred dispersal events to Europe and Central and Western Asia between 21.78 Ma and 26.67 Ma and to Japan between 2.51 Ma and 18.42 Ma. Key factors such as the Eocene-Oligocene extinction event, onset and intensification of the monsoon system, and glacial cycles associated with sea-level fluctuations have likely played significant roles in shaping the evolutionary history of the genus Silurus.

In vitro and in vivo activity of ceftazidime/avibactam and aztreonam alone or in combination against mcr-9, serine- and metallo-ß-lactamases-co-producing carbapenem-resistant Enterobacter cloacae complex.

PURPOSE: Enterobacteriaceae carrying mcr-9, in particularly those also co-containing metallo-ß-lactamase (MBL) and TEM type ß-lactamase, present potential transmission risks and lack adequate clinical response methods, thereby posing a major threat to global public health. The aim of this study was to assess the antimicrobial efficacy of a combined ceftazidime/avibactam (CZA) and aztreonam (ATM) regimen against carbapenem-resistant Enterobacter cloacae complex (CRECC) co-producing mcr-9, MBL and TEM. METHODS: The in vitro antibacterial activity of CZA plus ATM was evaluated using a time-kill curve assay. Furthermore, the in vivo interaction between CZA plus ATM was confirmed using a Galleria mellonella (G. mellonella) infection model. RESULTS: All eight clinical strains of CRECC, co-carrying mcr-9, MBL and TEM, exhibited high resistance to CZA and ATM. In vitro time-kill curve analysis demonstrated that the combination therapy of CZA + ATM exerted significant bactericidal activity against mcr-9, MBL and TEM-co-producing Enterobacter cloacae complex (ECC) isolates with a 100% synergy rate observed in our study. Furthermore, in vivo survival assay using Galleria mellonella larvae infected with CRECC strains co-harboring mcr-9, MBL and TEM revealed that the CZA + ATM combination significantly improved the survival rate compared to the drug-treatment alone and untreated control groups. CONCLUSION: To our knowledge, this study represents the first report on the in vitro and in vivo antibacterial activity of CZA plus ATM against CRECC isolates co-harboring mcr-9, MBL and TEM. Our findings suggest that the combination regimen of CZA + ATM provides a valuable reference for clinicians to address the increasingly complex antibiotic resistance situation observed in clinical microorganisms.

Transcriptomic analysis of induced resistance to polymyxin in carbapenem-resistant Enterobacter cloacae complex isolate carrying mcr-9.

OBJECTIVES: Polymyxins are currently the last-resort treatment against multi-drug resistant Gram-negative bacterial infections, but plasmid-mediated mobile polymyxin resistance genes (mcr) threaten its efficacy, especially in carbapenem-resistant Enterobacter cloacae complex (CRECC). The objective of this study was to provide insights into the mechanism of polymyxin-induced bacterial resistance and the effect of overexpression of mcr-9. METHODS: The clinical strain CRECC414 carrying the mcr-9 gene was treated with a gradient concentration of polymyxin. Subsequently, the broth microdilution was used to determine the minimum inhibitory concentration (MIC) and RT-qPCR was utilized to assess mcr-9 expression. Transcriptome sequencing and Whole genome sequencing (WGS) was utilized to identify alterations in strains resulting from increased polymyxin resistance, and significant transcriptomic differences were analyzed alongside a comprehensive examination of metabolic networks at the genomic level. RESULTS: Polymyxin treatment induced the upregulation of mcr-9 expression and significantly elevated the MIC of the strain. Furthermore, the WGS and transcriptomic results revealed a remarkable up-regulation of arnBCADTEF gene cassette, indicating that the Arn/PhoPQ system-mediated L-Ara4N modification is the preferred mechanism for achieving high levels of resistance. Additionally, significant alterations in bacterial gene expression were observed with regards to multidrug efflux pumps, oxidative stress and repair mechanisms, cell membrane biosynthesis, as well as carbohydrate metabolic pathways. CONCLUSION: Polymyxin greatly disrupts the transcription of vital cellular pathways. A complete PhoPQ two-component system is a prerequisite for polymyxin resistance of Enterobacter cloacae, even though mcr-9 is highly expressed. These findings provide novel and important information for further investigation of polymyxin resistance of CRECC.

Age-related changes after intracerebral hemorrhage: a comparative proteomics analysis of perihematomal tissue.

The risk factors and causes of intracerebral hemorrhage (ICH) and the degree of functional recovery after ICH are distinct between young and elderly patients. The increasing incidence of ICH in young adults has become a concern; however, research on the molecules and pathways involved ICH in subjects of different ages is lacking. In this study, tandem mass tag (TMT)-based proteomics was utilized to examine the protein expression profiles of perihematomal tissue from young and aged mice 24 h after collagenase-induced ICH. Among the 5,129 quantified proteins, ICH induced 108 and 143 differentially expressed proteins (DEPs) in young and aged mice, respectively; specifically, there were 54 common DEPs, 54 unique DEPs in young mice and 89 unique DEPs in aged mice. In contrast, aging altered the expression of 58 proteins in the brain, resulting in 39 upregulated DEPs and 19 downregulated DEPs. Bioinformatics analysis indicated that ICH activated different proteins in complement pathways, coagulation cascades, the acute phase response, and the iron homeostasis signaling pathway in mice of both age groups. Protein-protein interaction (PPI) analysis and ingenuity pathway analysis (IPA) demonstrated that the unique DEPs in the young and aged mice were related to lipid metabolism and carbohydrate metabolism, respectively. Deeper paired-comparison analysis demonstrated that apolipoprotein M exhibited the most significant change in expression as a result of both aging and ICH. These results help illustrate age-related protein expression changes in the acute phase of ICH.

H*ads dynamics engineering via bimetallic Pd-Cu@MXene catalyst for enhanced electrocatalytic hydrodechlorination.

Electrocatalytic hydrodechlorination (EHDC) is a promising approach to safely remove halogenated emerging contaminants (HECs) pollutants. However, sluggish production dynamics of adsorbed atomic H (H*ads) limit the applicability of this green process. In this study, bimetallic Pd-Cu@MXene catalysts were synthesized to achieve highly efficient removal of HECs. The alloy electrode (Pd-Cu@MX/CC) exhibited better EHDC performance in comparison to Pd@MX/CC electrode, resulting in diclofenac degradation efficiency of 93.3 ± 0.1%. The characterization analysis revealed that the Pd0/PdII ratio decreased by forming bimetallic Pd-Cu alloy. Density functional theory calculations further demonstrated the electronic configuration modulation of the Pd-Cu@MXene catalysts, optimizing binging energies for H* and thereby facilitating H*ads production and tuning the reduction capability of H*ads. Noteably, the amounts and reduction potential of H*ads for Pd-Cu@MXene catalysts were 1.5 times higher and 0.37 eV lower than those observed for the mono Pd electrode. Hence, the introduction of Cu into the Pd catalyst optimized the dynamics of H*ads production, thereby conferring significant advantages to EHDC reactions. This augmentation was underscored by the successful application of the alloy catalysts supported by MXene in EHDC experiments involving other HECs, which represented a new paradigm for EHDC for efficient recalcitrant pollutant removal by H*ads.

Vascularized fascial flap for reconstruction of combined oral mucosa-mandibular defects: The multi-modal biological assessment.

OBJECTIVE: The reconstruction of composite defects in the oral and maxillofacial region using vascularized fascial flaps, such as the fibular, iliac, and temporal fascial flaps, has gained increasing attention among surgeons. However, there remains uncertainty regarding the suitability of fascial flaps as transplants, as well as their healing processes and outcomes, due to their non-mucosal nature. This study aims to comprehensively assess the biological aspects of vascularized fascial flaps at clinical, histological, and genetic levels, with the goal of providing essential biological references for their clinical application. STUDY DESIGN: This study enrolled three patients who underwent reconstruction of combined oral mucosa-mandibular defects using fibular vascularized fascial flaps between 2020 and 2023. Data regarding changes in the appearance of the fascial flaps, bulk-RNA sequencing, and histological slices of initial fascia, initial gingiva, and transformed fascia were collected and analyzed. RESULTS: Within three months, the fascial flaps exhibited rapid epithelial coverage and displayed distinct characteristics resembling mucosa. High-throughput RNA sequencing analyses and histological slices revealed that the transformed fascia exhibited tissue structures similar to mucosa and demonstrated unique advantages in promoting blood vessel formation and reducing scarring through the high-level expression of relevant genes. CONCLUSION: These findings emphasize the potential and feasibility of utilizing vascularized fascial flaps for oral mucosa reconstruction, establishing their unique advantage as transplant materials, and providing significant biological information and references for their selection and clinical application.

Huntington's Disease: Complex Pathogenesis and Therapeutic Strategies.

Huntington's disease (HD) arises from the abnormal expansion of CAG repeats in the huntingtin gene (HTT), resulting in the production of the mutant huntingtin protein (mHTT) with a polyglutamine stretch in its N-terminus. The pathogenic mechanisms underlying HD are complex and not yet fully elucidated. However, mHTT forms aggregates and accumulates abnormally in neuronal nuclei and processes, leading to disruptions in multiple cellular functions. Although there is currently no effective curative treatment for HD, significant progress has been made in developing various therapeutic strategies to treat HD. In addition to drugs targeting the neuronal toxicity of mHTT, gene therapy approaches that aim to reduce the expression of the mutant HTT gene hold great promise for effective HD therapy. This review provides an overview of current HD treatments, discusses different therapeutic strategies, and aims to facilitate future therapeutic advancements in the field.

A Multidrug-Resistant Extended-Spectrum Beta-Lactamase (ESBL)-Producing Enterobacter hormaechei Strain from Mixed Sprouts.

Fresh vegetables can harbor antibiotic-resistant bacteria, including extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales. Enterobacter hormaechei is a bacterium belonging to the Enterobacterales order and the most commonly identified nosocomial pathogen of Enterobacter cloacae complex. The purpose of this study was to characterize a multi-drug resistant ESBL-producing E. hormaechei strain isolated from a sample of mixed sprouts. Vegetable samples were pre-enriched in buffered peptone water, followed by enrichment in Enterobacteria Enrichment Broth, and isolation on Chromagar™ ESBL plates. One isolate from a sprout sample was confirmed to produce both ESBL and AmpC ß-lactamases through the combination disk diffusion assay using antibiotic disks containing cefotaxime and ceftazidime with or without clavulanate, and with or without cloxacillin, respectively. The isolate was also resistant to multiple antibiotics, including cefotaxime, ceftazidime, chloramphenicol, trimethoprim-sulfamethoxazole, tetracycline, gentamicin, ampicillin, and amoxicillin-clavulanate, as determined by antimicrobial susceptibility testing. Through whole genome sequencing, the isolate was identified as E. hormaechei 057-E1, which carried multiple antibiotic resistance (AR) genes and a sul2-aph(3″)-Ib-aph(6)-Id-blaTEM-1-ISEcp1 -blaCTX-M-15 gene cluster. Our results further demonstrate the important role of fresh vegetables in AR and highlight the need to develop strategies for AR mitigation in fresh vegetables.

High-throughput sequencing and fatty acid profile analyses of the Black Amur bream (Megalobrama terminalis) reveal variation in dietary niche associated with geographic segregation.

Fish dietary niche is a core focus, and it reflects the diversity of resources, habitats, or environments occupied by a species. However, whether geographic segregation among different populations triggers dietary diversification and concomitant fish niche shift remains unknown. In the present study, we selected the Black Amur bream (Megalobrama terminalis) is a migratory fish species that plays an important role in the material transfer and energy cycling of river ecosystems, inhabiting southern China drainage with multiple geographic populations. Here, we utilized the combined analyses of 18S rDNA high-throughput sequencing in fish gut contents and fatty acid (FA) in muscle tissues to evaluate potential spatial patterns of habitat and resource use for M. terminalis in three rivers of southern China. Our results showed that prey items of the Xijiang (XR) population (Pearl River) exhibited the highest species diversity and richness among the three geographic populations. Moreover, diet composition of M. terminalis was affected by spatial differences associated with geographic segregation. Analyses of FA biomarkers indicated that the highest levels of C16:0, C18:3n-3, and C18:2n-6c were found in Wanquan (WS) population (Wanquan River). The XR population exhibited a distinct FA profile characterized by higher amounts of arachidonic acid (ARA) and docosahexaenoic acid (DHA). The Moyang (MY) population (Moyang River) acted as the linkage between WS and XR populations and consisted of middle levels of saturated FAs (SFAs) and polyunsaturated FAs (PUFAs). The XR population displayed a greater FA niche width compared with WS population. Furthermore, we observed a close positive relationship between the niche width and α-diversity indices of dietary resources for FA proflies. Our study provides valued information to develop different conservation strategies among different populations and improve fisheries management for M. terminalis and other endemic species in local rivers.

The skin circadian clock gene F3 as a potential marker for psoriasis severity and its bidirectional relationship with IL-17 signaling in keratinocytes.

OBJECTIVE: Psoriasis is an immune-mediated skin disease where the IL-17 signaling pathway plays a crucial role in its development. Chronic circadian rhythm disorder in psoriasis pathogenesis is gaining more attention. The relationship between IL and 17 signaling pathway and skin clock genes remains poorly understood. METHODS: GSE121212 with psoriatic lesion and healthy controls was used as the exploration cohort for searching analysis. Datasets GSE54456, GSE13355, GSE14905, GSE117239, GSE51440, and GSE137218 were applied to validation analysis. Single-cell RNA sequencing (scRNA-seq) dataset GSE173706 was used to explore the F3 expression and related pathway activities in single-cell levels. Through intersecting with high-expression DEGs, F3 was selected as the signature skin circadian gene in psoriasis for further investigation. Functional analyses, including correlation analyses, prediction of transcription factors, protein-protein interaction, and single gene GSEA to explore the potential roles of F3. ssGSEA algorithm was performed to uncover the immune-related characteristics of psoriasis. We further explored F3 expression in the specific cell population in scRNA-seq dataset, besides this, AUCell analysis was performed to explore the pathway activities and the results were further compared between the specific cell cluster. Immunohistochemistry experiment, RT-qPCR was used to validate the location and expression of F3, small interfering RNA (siRNA) transfection experiment in HaCaT, and transcriptome sequencing analysis were applied to explore the potential function of F3. RESULTS: F3 was significantly down-regulated in psoriasis and interacted with IL-17 signaling pathway. Low expression of F3 could upregulate the receptor of JAK-STAT signaling, thereby promoting keratinocyte inflammation. CONCLUSION: Our research revealed a bidirectional link between the skin circadian gene F3 and the IL-17 signaling pathway in psoriasis, suggesting that F3 may interact with the IL-17 pathway by activating JAK-STAT within keratinocytes and inducing abnormal intracellular inflammation.

Activities of aztreonam in combination with several novel ß-lactam-ß-lactamase inhibitor combinations against carbapenem-resistant Klebsiella pneumoniae strains coproducing KPC and NDM.

Isolates coproducing serine/metallo-carbapenems are a serious emerging public health threat, given their rapid dissemination and the limited number of treatment options. The purposes of this study were to evaluate the in vitro antibacterial activity of novel ß-lactam-ß-lactamase inhibitor combinations (BLBLIs) against carbapenem-resistant Klebsiella pneumoniae (CRKP) coproducing metallo-ß-lactamase and serine-ß-lactamase, and to explore their effects in combination with aztreonam, meropenem, or polymyxin in order to identify the best therapeutic options. Four CRKP isolates coproducing K. pneumoniae carbapenemase (KPC) and New Delhi metallo-ß-lactamase (NDM) were selected, and a microdilution broth method was used to determine their susceptibility to antibiotics. Time-kill assay was used to detect the bactericidal effects of the combinations of antibiotics. The minimum inhibitory concentration (MIC) values for imipenem and meropenem in three isolates did not decrease after the addition of relebactam or varbobactam, but the addition of avibactam to aztreonam reduced the MIC by more than 64-fold. Time-kill assay demonstrated that imipenem-cilastatin/relebactam (ICR) alone exerted a bacteriostatic effect against three isolates (average reduction: 1.88 log10 CFU/mL) and ICR combined with aztreonam exerted an additive effect. Aztreonam combined with meropenem/varbobactam (MEV) or ceftazidime/avibactam (CZA) showed synergistic effects, while the effect of aztreonam combined with CZA was inferior to that of MEV. Compared with the same concentration of aztreonam plus CZA combination, aztreonam/avibactam had a better bactericidal effect (24 h bacterial count reduction >3 log10CFU/mL). These data indicate that the combination of ATM with several new BLBLIs exerts powerful bactericidal activity, which suggests that these double ß-lactam combinations might provide potential alternative treatments for infections caused by pathogens coproducing-serine/metallo-carbapenems.

Development of Membrane-Targeting Fluorescent 2-Phenyl-1H-phenanthro[9,10-d]imidazole-Antimicrobial Peptide Mimic Conjugates against Methicillin-Resistant Staphylococcus aureus.

The escalation of multidrug-resistant bacterial infections, especially infections caused by methicillin-resistant Staphylococcus aureus (MRSA), underscores the urgent need for novel antimicrobial drugs. Here, we synthesized a series of amphiphilic 2-phenyl-1H-phenanthro[9,10-d]imidazole-antimicrobial peptide (AMP) mimic conjugates (III1-30). Among them, compound III13 exhibited excellent antibacterial activity against G+ bacteria and clinical MRSA isolates (MIC = 0.5-2 µg/mL), high membrane selectivity, and low toxicity. Additionally, compared with traditional clinical antibiotics, III13 demonstrated rapid bactericidal efficacy and was less susceptible to causing bacterial resistance. Mechanistic studies revealed that III13 targets phosphatidylglycerol (PG) on bacterial membranes to disrupt membrane integrity, leading to an increase in intracellular ROS and leakage of proteins and DNA, ultimately causing bacterial cell death. Furthermore, III13 possessed good fluorescence properties with potential for further dynamic monitoring of the antimicrobial process. Notably, III13 showed better in vivo efficacy against MRSA compared to vancomycin, suggesting its potential as a promising candidate for anti-MRSA medication.

RNA processing modification mediated subtypes illustrate the distinctive features of tumor microenvironment in hepatocellular carcinoma.

Multiple transcript isoforms of genes can be formed by processing and modifying the 5' and 3' ends of RNA. Herein, the aim of this study is to uncover the characteristics of RNA processing modification (RPM) in hepatocellular carcinoma (HCC), and to identify novel biomarkers and potential targets for treatment. Firstly, integrated bioinformatics analysis was carried out to identify risk prognostic RPM regulators (RPMRs). Then, we used these RPMRs to identify subtypes of HCC and explore differences in immune microenvironment and cellular function improvement pathways between the sub-types. Finally, we used the principal component analysis algorithms to estimate RPMscore, which were applied to 5 cohorts. Lower RPMscore among patients correlated with a declined survival rate, increased immune infiltration, and raised expression of immune checkpoints, aligning with the "immunity tidal model theory". The RPMscore exhibited robust, which was validated in multiple datasets. Mechanistically, low RPMscore can create an immunosuppressive microenvironment in HCC by manipulating tumor-associated macrophages. Preclinically, patients with high RPMscore might benefit from immunotherapy. The RPMscore is helpful in clustering HCC patients with distinct prognosis and immunotherapy. Our RPMscore model can help clinicians to select personalized therapy for HCC patients, and RPMscore may act a part in the development of HCC.

MSF-PFP: A Novel Multisource Feature Fusion Model for Protein Function Prediction.

Protein function prediction is essential for disease treatment and drug development; yet, traditional biological experimental methods are less efficient in annotating protein function, and existing automated methods fail to fully leverage protein multisource data. Here, we present MSF-PFP, a computational framework that fuses multisource data features to predict protein function with high accuracy. Our framework designs specific models for feature extraction based on the characteristics of various data sources, including a global-local-individual strategy for local location features. MSF-PFP then integrates extracted features through a multisource feature fusion model, ultimately categorizing protein functions. Experimental results demonstrate that MSF-PFP outperforms eight state-of-the-art models, achieving FMax scores of 0.542, 0.675, and 0.624 for the biological process (BP), molecular function (MF), and cellular component (CC), respectively. The source code and data set for MSF-PFP are available at https://swanhub.co/TianGua/MSF-PFP, facilitating further exploration and validation of the proposed framework. This study highlights the potential of multisource data fusion in enhancing protein function prediction, contributing to improved disease therapy and medication discovery strategies.

Quantitative catalogue of mammalian mitotic chromosome-associated RNAs.

The faithful transmission of a cell's identity and functionality to its daughters during mitosis requires the proper assembly of mitotic chromosomes from interphase chromatin in a process that involves significant changes in the genome-bound material, including the RNA. However, our understanding of the RNA that is associated with the mitotic chromosome is presently limited. Here, we present complete and quantitative characterizations of the full-length mitotic chromosome-associated RNAs (mCARs) for 3 human cell lines, a monkey cell line, and a mouse cell line derived from high-depth RNA sequencing (3 replicates, 47 M mapped read pairs for each replicate). Overall, we identify, on average, more than 20,400 mCAR species per cell-type (including isoforms), more than 5,200 of which are enriched on the chromosome. Notably, overall, more than 2,700 of these mCARs were previously unknown, which thus also expands the annotated genome of these species. We anticipate that these datasets will provide an essential resource for future studies to better understand the functioning of mCARs on the mitotic chromosome and in the cell.

Mechanism for transmission and pathogenesis of carbapenem-resistant Enterobacterales harboring the carbapenemase IMP and clinical countermeasures.

Carbapenem-resistant Enterobacterales (CRE) are some of the most important pathogens causing infections, which can be challenging to treat. We identified four blaIMP-carrying CRE isolates and collected clinical data. The transferability and stability of the plasmid were verified by conjugation, successive passaging, and plasmid elimination assays. The IncC blaIMP-4-carrying pIMP4-ECL42 plasmid was successfully transferred into the recipient strain, and the high expression of traD may have facilitated the conjugation transfer of the plasmid. Interestingly, the plasmid showed strong stability in clinical isolates. Whole-genome sequencing was performed on all isolates. We assessed the sequence similarity of blaIMP -harboring plasmid from our institution and compared it to plasmids for which sequence data are publicly available. We found that four blaIMP-carrying CRE belonged to four different sequence types. The checkerboard technique and time-kill assays were used to investigate the best antimicrobial therapies for blaIMP-carrying CRE. The time-kill assay showed that the imipenem of 1× minimum inhibitory concentration (MIC) alone had the bactericidal or bacteriostatic effect against IMP-producing strains at 4-12 h in vitro. Moreover, the combination of tigecycline (0.5/1/2 × MIC) and imipenem (0.5/1 × MIC) showed a bactericidal effect against the blaIMP-26-carrying CRECL60 strain.IMPORTANCECarbapenem-resistant Enterobacterales (CRE) are an urgent public health threat, and infections caused by these microorganisms are often associated with high mortality and limited treatment options. This study aimed to determine the clinical features, molecular characteristics, and plasmid transmissible mechanisms of blaIMP carriage as well as to provide a potential treatment option. Here, we demonstrated that conjugated transfer of the IncC blaIMP-4-carrying plasmid promotes plasmid stability, so inhibition of conjugated transfer and enhanced plasmid loss may be potential ways to suppress the persistence of this plasmid. The imipenem alone or tigecycline-imipenem combination showed a good bactericidal effect against IMP-producing strains. In particular, our study revealed that imipenem alone or tigecycline-imipenem combination may be a potential therapeutic option for patients who are infected with IMP-producing strains. Our study supports further trials of appropriate antibiotics to determine optimal treatment and emphasizes the importance of continued monitoring of IMP-producing strains in the future.

Innovative principle of implant-oriented fibula placement in mandibular reconstruction using double-barrel fibula and simultaneous implants: A technical note.

Simultaneous or secondary inserted implants with double-barrel fibula to reconstruct the mandible have become a common method. However, difficulties in later restoration caused by placement errors of fibula or incipiently placed implants have also been reported in some studies. This note describes a novel technique of implant-oriented guide plates helpful for mandible ablation, fibula segmentation and positioning, and implant placement. We design a series of guide plates especially an implant-fibula placing guide plate, and record and fix the relative spatial positions of the remaining teeth, the simultaneous implants and upper fibula. During surgery, the placement of upper fibula is oriented towards appropriate placement of implants. Therefore, the position of upper fibula can meet the requirements of simultaneous implant as much as possible. Within the limits of present observation, we believe that this technique may increase the manipuility while reducing the errors and the risk of complications.

A Brainwide Risk Score for Psychiatric Disorder Evaluated in a Large Adolescent Population Reveals Increased Divergence Among Higher-Risk Groups Relative to Control Participants.

BACKGROUND: Accurate psychiatric risk assessment requires biomarkers that are both stable and adaptable to development. Functional network connectivity (FNC), which steadily reconfigures over time, potentially contains abundant information to assess psychiatric risks. However, the absence of suitable analytical methodologies has constrained this area of investigation. METHODS: We investigated the brainwide risk score (BRS), a novel FNC-based metric that contrasts the relative distances of an individual's FNC to that of psychiatric disorders versus healthy control references. To generate group-level disorder and healthy control references, we utilized a large brain imaging dataset containing 5231 total individuals diagnosed with schizophrenia, autism spectrum disorder, major depressive disorder, and bipolar disorder and their corresponding healthy control individuals. The BRS metric was employed to assess the psychiatric risk in 2 new datasets: Adolescent Brain Cognitive Development (ABCD) Study (n = 8191) and Human Connectome Project Early Psychosis (n = 170). RESULTS: The BRS revealed a clear, reproducible gradient of FNC patterns from low to high risk for each psychiatric disorder in unaffected adolescents. We found that low-risk ABCD Study adolescent FNC patterns for each disorder were strongly present in over 25% of the ABCD Study participants and homogeneous, whereas high-risk patterns of each psychiatric disorder were strongly present in about 1% of ABCD Study participants and heterogeneous. The BRS also showed its effectiveness in predicting psychosis scores and distinguishing individuals with early psychosis from healthy control individuals. CONCLUSIONS: The BRS could be a new image-based tool for assessing psychiatric vulnerability over time and in unaffected individuals, and it could also serve as a potential biomarker, facilitating early screening and monitoring interventions.