Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion.

Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+ mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.

Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8+ T cell effector functions.

Concentrations of the secondary bile acid, deoxycholic acid (DCA), are aberrantly elevated in colorectal cancer (CRC) patients, but the consequences remain poorly understood. Here, we screened a library of gut microbiota-derived metabolites and identified DCA as a negative regulator for CD8+ T cell effector function. Mechanistically, DCA suppressed CD8+ T cell responses by targeting plasma membrane Ca2+ ATPase (PMCA) to inhibit Ca2+-nuclear factor of activated T cells (NFAT)2 signaling. In CRC patients, CD8+ T cell effector function negatively correlated with both DCA concentration and expression of a bacterial DCA biosynthetic gene. Bacteria harboring DCA biosynthetic genes suppressed CD8+ T cells effector function and promoted tumor growth in mice. This effect was abolished by disrupting bile acid metabolism via bile acid chelation, genetic ablation of bacterial DCA biosynthetic pathway, or specific bacteriophage. Our study demonstrated causation between microbial DCA metabolism and anti-tumor CD8+ T cell response in CRC, suggesting potential directions for anti-tumor therapy.

Clinical trial links oncolytic immunoactivation to survival in glioblastoma.

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).

The field-free Josephson diode in a van der Waals heterostructure.

The superconducting analogue to the semiconducting diode, the Josephson diode, has long been sought with multiple avenues to realization being proposed by theorists1-3. Showing magnetic-field-free, single-directional superconductivity with Josephson coupling, it would serve as the building block for next-generation superconducting circuit technology. Here we realized the Josephson diode by fabricating an inversion symmetry breaking van der Waals heterostructure of NbSe2/Nb3Br8/NbSe2. We demonstrate that even without a magnetic field, the junction can be superconducting with a positive current while being resistive with a negative current. The ΔIc behaviour (the difference between positive and negative critical currents) with magnetic field is symmetric and Josephson coupling is proved through the Fraunhofer pattern. Also, stable half-wave rectification of a square-wave excitation was achieved with a very low switching current density, high rectification ratio and high robustness. This non-reciprocal behaviour strongly violates the known Josephson relations and opens the door to discover new mechanisms and physical phenomena through integration of quantum materials with Josephson junctions, and provides new avenues for superconducting quantum devices.

SEC61G assists EGFR-amplified glioblastoma to evade immune elimination.

Amplification of chromosome 7p11 (7p11) is the most common alteration in primary glioblastoma (GBM), resulting in gains of epidermal growth factor receptor (EGFR) copy number in 50 to 60% of GBM tumors. However, treatment strategies targeting EGFR have thus far failed in clinical trials, and the underlying mechanism remains largely unclear. We here demonstrate that EGFR amplification at the 7p11 locus frequently encompasses its neighboring genes and identifies SEC61G as a critical regulator facilitating GBM immune evasion and tumor growth. We found that SEC61G is always coamplified with EGFR and is highly expressed in GBM. As an essential subunit of the SEC61 translocon complex, SEC61G promotes translocation of newly translated immune checkpoint ligands (ICLs, including PD-L1, PVR, and PD-L2) into the endoplasmic reticulum and promotes their glycosylation, stabilization, and membrane presentation. Depletion of SEC61G promotes the infiltration and cytolytic activity of CD8+ T cells and thus inhibits GBM occurrence. Further, SEC61G inhibition augments the therapeutic efficiency of EGFR tyrosine kinase inhibitors in mice. Our study demonstrates a critical role of SEC61G in GBM immune evasion, which provides a compelling rationale for combination therapy of EGFR-amplified GBMs.

Association of pre-existing depression and anxiety with Omicron variant infection.

Pre-existing psychiatric disorders were linked to an increased susceptibility to COVID-19 during the initial outbreak of the pandemic, while evidence during Omicron prevalence is lacking. Leveraging data from two prospective cohorts in China, we identified incident Omicron infections between January 2023 and April 2023. Participants with a self-reported history or self-rated symptoms of depression or anxiety before the Omicron pandemic were considered the exposed group, whereas the others were considered unexposed. We employed multivariate logistic regression models to examine the association of pre-existing depression or anxiety with the risk of any or severe Omicron infection indexed by medical interventions or severe symptoms. Further, we stratified the analyses by polygenic risk scores (PRSs) for COVID-19 and repeated the analyses using the UK Biobank data. We included 10,802 individuals from the Chinese cohorts (mean age = 51.1 years, 45.6% male), among whom 7841 (72.6%) were identified as cases of Omicron infection. No association was found between any pre-existing depression or anxiety and the overall risk of Omicron infection (odds ratio [OR] =1.04, 95% confidence interval [CI] 0.95-1.14). However, positive associations were noted for severe Omicron infection, either as infections requiring medical interventions (1.26, 1.02-1.54) or with severe symptoms (≥3: 1.73, 1.51-1.97). We obtained comparable estimates when stratified by COVID-19 PRS level. Additionally, using clustering method, we identified eight distinct symptom patterns and found associations between pre-existing depression or anxiety and the patterns characterized by multiple or complex severe symptoms including cough and taste and smell decline (ORs = 1.42-2.35). The results of the UK Biobank analyses corroborated findings of the Chinese cohorts. In conclusion, pre-existing depression and anxiety was not associated with the risk of Omicron infection overall but an elevated risk of severe Omicron infection, supporting the continued efforts on monitoring and possible early intervention in this high-risk population during Omicron prevalence.

Click display: a rapid and efficient in vitro protein display method for directed evolution.

We describe a novel method for in vitro protein display-click display-that does not depend on maintaining RNA integrity during biopanning and yields covalently linked protein-cDNA complexes from double-stranded input DNA within 2 h. The display is achieved in a one-pot format encompassing transcription, translation and reverse transcription reactions in series. Stable linkage between proteins and the encoding cDNA is mediated by a modified DNA linker-ML-generated via a click chemistry reaction between a puromycin-containing oligo and a cDNA synthesis primer. Biopanning of a click-displayed mock library coupled with next-generation sequencing analysis revealed >600-fold enrichment of target binders within a single round of panning. A synthetic library of Designed Ankyrin Repeat Proteins (DARPins) with ∼1012 individual members was generated using click display in a 25-µl reaction and six rounds of library panning against a model protein yielded a panel of nanomolar binders. This study establishes click display as a powerful tool for protein binder discovery/engineering and provides a convenient platform for in vitro biopanning selection even in RNase-rich environments such as on whole cells.

Deficiency of leucine-rich repeat kinase 2 aggravates thioacetamide-induced acute liver failure and hepatic encephalopathy in mice.

BACKGROUND: Hepatic encephalopathy (HE) is closely associated with inflammatory responses. However, as a crucial regulator of the immune and inflammatory responses, the role of leucine-rich repeat kinase 2 (LRRK2) in the pathogenesis of HE remains unraveled. Herein, we investigated this issue in thioacetamide (TAA)-induced HE following acute liver failure (ALF). METHODS: TAA-induced HE mouse models of LRRK2 wild type (WT), LRRK2 G2019S mutation (Lrrk2G2019S) and LRRK2 knockout (Lrrk2-/-) were established. A battery of neurobehavioral experiments was conducted. The biochemical indexes and pro-inflammatory cytokines were detected. The prefrontal cortex (PFC), striatum (STR), hippocampus (HIP), and liver were examined by pathology and electron microscopy. The changes of autophagy-lysosomal pathway and activity of critical Rab GTPases were analyzed. RESULTS: The Lrrk2-/--HE model reported a significantly lower survival rate than the other two models (24% vs. 48%, respectively, p < 0.05), with no difference found between the WT-HE and Lrrk2G2019S-HE groups. Compared with the other groups, after the TAA injection, the Lrrk2-/- group displayed a significant increase in ammonium and pro-inflammatory cytokines, aggravated hepatic inflammation/necrosis, decreased autophagy, and abnormal phosphorylation of lysosomal Rab10. All three models reported microglial activation, neuronal loss, disordered vesicle transmission, and damaged myelin structure. The Lrrk2-/--HE mice presented no severer neuronal injury than the other genotypes. CONCLUSIONS: LRRK2 deficiency may exacerbate TAA-induced ALF and HE in mice, in which inflammatory response is evident in the brain and aggravated in the liver. These novel findings indicate a need of sufficient clinical awareness of the adverse effects of LRRK2 inhibitors on the liver.

Design and Fabrication of Biomass Derived Black Carbon Modified g-C3N4/FeIn2S4 Heterojunction as Highly Efficient Photocatalyst for Wastewater Treatment.

The environmental deterioration caused by dye wastewater discharge has received considerable attention in recent decades. One of the most promising approaches to addressing the aforementioned environmental issue is the development of photocatalysts with high solar energy consumption efficiency for the treatment of dye-contaminated water. In this study, a novel low-cost π-π biomass-derived black carbon modified g-C3N4 coupled FeIn2S4 composite (i.e., FeInS/BC-CN) photocatalyst is successfully designed and fabricated that reveals significantly improved photocatalytic performance for the degradation of Eosin Yellow (EY) dye in aqueous solution. Under dark and subsequent visible light irradiation, the amount optimized composite reveals 99% removal performance for EY dye, almost three-fold compared to that of the pristine FeInS and BC-CN counterparts. Further, it is confirmed by means of the electron spin resonance spectrometry, quenching experiments, and density functional theory (DFT) calculations, that the hydroxyl radicals (•OH) and superoxide radicals (•O2 -) are the dominant oxidation species involved in the degradation process of EY dye. In addition, a systematic photocatalytic degradation route is proposed based on the resultant degradation intermediates detectedduring liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. This work provides an innovative idea for the development of advanced photocatalysts to mitigate water pollution.

Electron Transport Layer Engineering Induced Carrier Dynamics Optimization for Efficient Cd-Free Sb2 Se3 Thin-Film Solar Cells.

Antimony selenide (Sb2 Se3 ) is a highly promising photovoltaic material thanks to its outstanding optoelectronic properties, as well as its cost-effective and eco-friendly merits. However, toxic CdS is widely used as an electron transport layer (ETL) in efficient Sb2 Se3 solar cells, which largely limit their development toward market commercialization. Herein, an effective green Cd-free ETL of SnOx is introduced and deposited by atomic layer deposition method. Additionally, an important post-annealing treatment is designed to further optimize the functional layers and the heterojunction interface properties. Such engineering strategy can optimize SnOx ETL with higher nano-crystallinity, higher carrier density, and less defect groups, modify Sb2 Se3 /SnOx heterojunction with better interface performance and much desirable "spike-like" band alignment, and also improve the Sb2 Se3 light absorber layer quality with passivated bulk defects and prolonged carrier lifetime, and therefore to enhance carrier separation and transport while suppressing non-radiative recombination. Finally, the as-fabricated Cd-free Mo/Sb2 Se3 /SnOx /ITO/Ag thin-film solar cell exhibits a stimulating efficiency of 7.39%, contributing a record value for Cd-free substrate structured Sb2 Se3 solar cells reported to date. This work provides a viable strategy for developing and broadening practical applications of environmental-friendly Sb2 Se3 photovoltaic devices.

Roles of very long-chain fatty acids in compound leaf patterning in Medicago truncatula.

Plant cuticles are composed of hydrophobic cuticular waxes and cutin. Very long-chain fatty acids (VLCFAs) are components of epidermal waxes and the plasma membrane and are involved in organ morphogenesis. By screening a barrelclover (Medicago truncatula) mutant population tagged by the transposable element of tobacco (Nicotiana tabacum) cell type1 (Tnt1), we identified two types of mutants with unopened flower phenotypes, named unopened flower1 (uof1) and uof2. Both UOF1 and UOF2 encode enzymes that are involved in the biosynthesis of VLCFAs and cuticular wax. Comparative analysis of the mutants indicated that the mutation in UOF1, but not UOF2, leads to the increased number of leaflets in M. truncatula. UOF1 was specifically expressed in the outermost cell layer (L1) of the shoot apical meristem (SAM) and leaf primordia. The uof1 mutants displayed defects in VLCFA-mediated plasma membrane integrity, resulting in the disordered localization of the PIN-FORMED1 (PIN1) ortholog SMOOTH LEAF MARGIN1 (SLM1) in M. truncatula. Our work demonstrates that the UOF1-mediated biosynthesis of VLCFAs in L1 is critical for compound leaf patterning, which is associated with the polarization of the auxin efflux carrier in M. truncatula.

Remnant cholesterol and the risk of aortic valve calcium progression: insights from the MESA study.

BACKGROUND: Remnant cholesterol (RC) is implicated in the risk of cardiovascular disease. However, comprehensive population-based studies elucidating its association with aortic valve calcium (AVC) progression are limited, rendering its precise role in AVC ambiguous. METHODS: From the Multi-Ethnic Study of Atherosclerosis database, we included 5597 individuals (61.8 ± 10.1 years and 47.5% men) without atherosclerotic cardiovascular disease at baseline for analysis. RC was calculated as total cholesterol minus high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), as estimated by the Martin/Hopkins equation. Using the adjusted Cox regression analyses, we examined the relationships between RC levels and AVC progression. Furthermore, we conducted discordance analyses to evaluate the relative AVC risk in RC versus LDL-C discordant/concordant groups. RESULTS: During a median follow-up of 2.4 ± 0.9 years, 568 (10.1%) participants exhibited AVC progression. After adjusting for traditional cardiovascular risk factors, the HRs (95% CIs) for AVC progression comparing the second, third, and fourth quartiles of RC levels with the first quartile were 1.195 (0.925-1.545), 1.322 (1.028-1.701) and 1.546 (1.188-2.012), respectively. Notably, the discordant high RC/low LDL-C group demonstrated a significantly elevated risk of AVC progression compared to the concordant low RC/LDL-C group based on their medians (HR, 1.528 [95% CI 1.201-1.943]). This pattern persisted when clinical LDL-C threshold was set at 100 and 130 mg/dL. The association was consistently observed across various sensitivity analyses. CONCLUSIONS: In atherosclerotic cardiovascular disease-free individuals, elevated RC is identified as a residual risk for AVC progression, independent of traditional cardiovascular risk factors. The causal relationship of RC to AVC and the potential for targeted RC reduction in primary prevention require deeper exploration.

Phytic acid/tannic acid reinforced hydrogels with ultra-high strength for human motion monitoring and arrays.

Conductive hydrogels have been widely researched for their potential applications in soft electronic devices. Creating environmentally friendly and multifunctional high-strength hydrogels for high-performance devices remains a significant challenge. This study employs the biodegradable material polyvinyl alcohol (PVA) as the primary component, with phytic acid (PA) and tannic acid (TA) as reinforcing phases, to create a multifunctional, high-strength "green" hydrogel. Through the multiple complexations of two bio-enhancing phases with the PVA main chain, this hydrogel attains ultra-high tensile strength (9.341 MPa), substantial toughness (4.262 MJ m-3), and extensive fracture strain (> 1000%), making it a representative with both mechanical performance and antibacterial capabilities. Additionally, it exhibits a low strain sensing limit (0.5%) and excellent durability (500 cycles under 50% strain). This work introduces a novel strategy of combining biodegradable materials with biomass to fabricate multifunctional hydrogels suitable for human motion monitoring and 2D pressure distribution.

Disease trajectory of high neuroticism and the relevance to psychiatric disorders: A retro-prospective cohort study.

BACKGROUND: Neuroticism is a psychological personality trait that has a significant impact on public health and is also a potential predisposing factor for adverse disease outcomes; however, comprehensive studies of the subsequently developed conditions are lacking. The starting point of disease trajectory in terms of genetic variation remains unclear. METHOD: Our study included 344,609 adult participants from the UK Biobank cohort who were virtually followed up from January 1, 1997. Neuroticism levels were assessed using 12 items from the Eysenck Personality Questionnaire. We performed a phenome-wide association analysis of neuroticism and subsequent diseases. Binomial tests and logistic regression models were used to test the temporal directionality and association between disease pairs to construct disease trajectories. We also investigated the association between polygenic risk scores (PRSs) for five psychiatric traits and high neuroticism. RESULTS: The risk for 59 diseases was significantly associated with high neuroticism. Depression, anxiety, irritable bowel syndrome, migraine, spondylosis, and sleep disorders were the most likely to develop, with hazard ratios of 6.13, 3.66, 2.28, 1.74, 1.74, and 1.71, respectively. The disease trajectory network revealed two major disease clusters: cardiometabolic and chronic inflammatory diseases. Medium/high genetic risk groups stratified by the PRSs of four psychiatric traits were associated with an elevated risk of high neuroticism. We further identified eight complete phenotypic trajectory clusters of medium or high genetic risk for psychotic, anxiety-, depression-, and stress-related disorders. CONCLUSION: Neuroticism plays an important role in the development of somatic and mental disorders. The full picture of disease trajectories from the genetic risk of psychiatric traits and neuroticism in early life to a series of diseases later provides evidence for future research to explore the etiological mechanisms and precision management.

Evaluation of the causal effects of blood metabolites on irritable bowel syndrome: Mendelian randomization.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal pain, discomfort, and changes in bowel habits. The mechanism underlying IBS remains unclear, and little evidence exists for clarifying the causal relationship between blood metabolites and IBS. METHODS: We conducted a Mendelian randomization (MR) study using two samples. Exposure data for 7824 Europeans were extracted from a genome-wide association study (GWAS) on metabolite levels. The IBS GWAS data from the GWAS database were used for the initial analysis. The primary analysis of causal relationships was conducted using inverse-variance weighting (IVW) with MR-Egger and weighted medians as supplementary analyses. Sensitivity analyses were performed using a combination of the Cochran's Q test, MR-Egger intercept test, Mendelian randomization pleiotropy residual sum and outlier, and leave-one-out analysis. For significant associations, replication and meta-analyses were performed using additional independent IBS case GWAS data released by the FinnGen Consortium R9. To identify the metabolites, score regression, confounding analysis, and reverse MR were performed to further assess the causal relationships between the metabolites. RESULTS: After rigorous screening, we identified four known metabolites to be associated with IBS (stearate, odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.59-0.92; arginine, OR: 1.36, 95% CI: 1.07-1.74; 1-palmitoylglycerol, OR:1.49, 95% CI: 1.07-2.07; 1-palmitoylglycerophosphoinositol, OR: 0.84, 95% CI: 0.71-0.99). CONCLUSIONS: MR analysis revealed a causal relationship between the four metabolites and IBS, providing preliminary evidence for the pathogenesis of IBS. Our results provide novel insights into the potential biomarkers of IBS.

Microbial creation of ß-Nicotinamide mononucleotide and its regulation of lipid metabolism in the liver of high-fat diet mice.

ß-Nicotinamide mononucleotide (NMN) is a biologically active nucleotide that regulates the physiological metabolism of the body by rapidly increasing nicotinamide adenine dinucleotide (NAD+). To determine the safety and biological activity of NMN resources, we constructed a recombinant strain of P. pastoris that heterologously expresses nicotinamide-phosphate ribosyltransferase (NAMPT), and subsequently catalyzed and purified the expressed product to obtain NMN. Consequently, this study established a high-fat diet (HFD) obese model to investigate the lipid-lowering activity of NMN. The findings showed that NMN supplementation directly increased the NAD+ levels, and reduced HFD-induced liver injury and lipid deposition. NMN treatment significantly decreased total cholesterol (TC) and triglyceride (TG) in serum and liver, as well as alanine aminotransferase (ALT) and insulin levels in serum (p < .05 or p < .01). In conclusion, this study combined synthetic biology with nutritional evaluation to confirm that P. pastoris-generated NMN modulated lipid metabolism in HFD mice, offering a theoretical framework and evidence for the application of microbially created NMN.

Numerical analysis of on-chip acousto-optic modulators for visible wavelengths.

On-chip acousto-optic modulators that operate at an optical wavelength of 780 nm and a microwave frequency of 6.835 GHz are proposed. The modulators are based on a lithium-niobate-on-sapphire platform and efficiently excite surface acoustic waves and exhibit strong interactions with tightly confined optical modes in waveguides. In particular, a high-efficiency phase modulator and single-sideband mode converter are designed. We found that for both microwave and optical wavelengths below 1 µm, the interactions at the cross-sections of photonic waveguides are sensitive to the waveguide width and are significantly different from those in previous studies. Our designed devices have small footprints and high efficiencies, making them suitable for controlling rubidium atoms and realizing hybrid photonic-atomic chips. Furthermore, our devices have the potential to extend the acousto-optic modulators to other visible wavelengths for other atom transitions and for visible light applications, including imaging and sensing.

Aeromonas spp. from hospital sewage act as a reservoir of genes resistant to last-line antibiotics.

BACKGROUND: Aeromonas species are opportunistic pathogens distributed widely in the ecosystem. They are known to be capable of acquiring antibiotic resistance genes, including those encoding proteins against last-line antibiotics, such as the tmexCD-toprJ, mcr and carbapenemase genes. We investigated the genomic and phenotypic characteristics of tmexCD-toprJ-positive Aeromonas strains collected from human, animals, and water samples, particularly those from hospital wastewater in China. METHODS: Samples were collected from living animals, meat, water and human. Aeromonas strains in these samples were isolated in selective media. Antimicrobial resistance profiles of all Aeromonas strains were tested by the broth microdilution method. The presence of tmexCD-toprJ was verified by polymerase chain reaction (PCR). All tmexCD-toprJ-positive (n = 36) and selected tmexCD-toprJ-negative (n = 18) Aeromonas strains were subjected to whole genome sequencing. Carriage of antimicrobial resistance genes, the genetic environment of tmexCD-toprJ and genetic diversity of tmexCD-toprJ-positive Aeromonas strains were determined by bioinformatics analysis. Phylogenetic tree of the Aeromonas strains was built by using the Harvest Suite. FINDINGS: Among the 636 Aeromonas strains isolated from different sources, 36 were positive for tmexCD-toprJ, with the highest prevalence of tmexCD-toprJ being found in fishes (8.8%, 95 CI% 3.6-17.2%), followed by hospital wastewater (6.5%, 95 CI% 4.3-9.3%), river water (2.0%, 0.1-10.9) and duck (1.2%, 95 CI% 3.6-17.2%). All tmexCD-toprJ-positive Aeromonas strains carried multiple antimicrobial resistance genes and exhibited resistance to different classes of antibiotics. Co-existence of tmexCD-toprJ, mcr and blaKPC-2 were identified in 21 strains. The tmexCD-toprJ-positive Aeromonas strains were genetically diverse and found to belong to four different species that could be clustered into three major lineages. The tmexCD-toprJ gene clusters were predominantly located in the chromosome (35/36) of Aeromonas spp., with only one strain carrying the plasmid-borne tmexCD-toprJ cluster. The tmexCD-toprJ genes were associated with seven different types of genetic environments, each of which carried distinct types of mobile elements that may be responsible for mediating transmission of this gene cluster.

Continuous Right Ventricular Pressure Monitoring in Cardiac Surgery.

OBJECTIVE: Right ventricular (RV) dysfunction in cardiac surgery can lead to RV failure, which is associated with increased morbidity and mortality. Abnormal RV function can be identified using RV pressure monitoring. The primary objective of the study is to determine the proportion of patients with abnormal RV early to end-diastole diastolic pressure gradient (RVDPG) and abnormal RV end-diastolic pressure (RVEDP) before initiation and after cardiopulmonary bypass (CPB) separation. The secondary objective is to evaluate if RVDPG before CPB initiation is associated with difficult and complex separation from CPB, RV dysfunction, and failure at the end of cardiac surgery. DESIGN: Prospective study. SETTING: Tertiary care cardiac institute. PARTICIPANTS: Cardiac surgical patients. INTERVENTION: Cardiac surgery. MEASUREMENTS AND MAIN RESULTS: Automated electronic quantification of RVDPG and RVEDP were obtained. Hemodynamic measurements were correlated with cardiac and extracardiac parameters from transesophageal echocardiography and postoperative complications. Abnormal RVDPG was present in 80% of the patients (n = 105) at baseline, with a mean RVEDP of 14.2 ± 3.9 mmHg. Patients experienced an RVDPG > 4 mmHg for a median duration of 50.2% of the intraoperative period before CPB initiation and 60.6% after CPB separation. A total of 46 (43.8%) patients had difficult/complex separation from CPB, 18 (38.3%) patients had RV dysfunction, and 8 (17%) had RV failure. Abnormal RVDPG before CPB was not associated with postoperative outcome. CONCLUSION: Elevated RVDPG and RVEDP are common in cardiac surgery. RVDPG and RVEDP before CPB initiation are not associated with RV dysfunction and failure but can be used to diagnose them.

Isaridin E Protects against Sepsis by Inhibiting Von Willebrand Factor-Induced Endothelial Hyperpermeability and Platelet-Endothelium Interaction.

Endothelial hyperpermeability is pivotal in sepsis-associated multi-organ dysfunction. Increased von Willebrand factor (vWF) plasma levels, stemming from activated platelets and endothelium injury during sepsis, can bind to integrin αvß3, exacerbating endothelial permeability. Hence, targeting this pathway presents a potential therapeutic avenue for sepsis. Recently, we identified isaridin E (ISE), a marine-derived fungal cyclohexadepsipeptide, as a promising antiplatelet and antithrombotic agent with a low bleeding risk. ISE's influence on septic mortality and sepsis-induced lung injury in a mouse model of sepsis, induced by caecal ligation and puncture, is investigated in this study. ISE dose-dependently improved survival rates, mitigating lung injury, thrombocytopenia, pulmonary endothelial permeability, and vascular inflammation in the mouse model. ISE markedly curtailed vWF release from activated platelets in septic mice by suppressing vesicle-associated membrane protein 8 and soluble N-ethylmaleide-sensitive factor attachment protein 23 overexpression. Moreover, ISE inhibited healthy human platelet adhesion to cultured lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), thereby significantly decreasing vWF secretion and endothelial hyperpermeability. Using cilengitide, a selective integrin αvß3 inhibitor, it was found that ISE can improve endothelial hyperpermeability by inhibiting vWF binding to αvß3. Activation of the integrin αvß3-FAK/Src pathway likely underlies vWF-induced endothelial dysfunction in sepsis. In conclusion, ISE protects against sepsis by inhibiting endothelial hyperpermeability and platelet-endothelium interactions.