Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex.

Regulation of enhancer activity is important for controlling gene expression programs. Here, we report that a biochemical complex containing a potential chromatin reader, RACK7, and the histone lysine 4 tri-methyl (H3K4me3)-specific demethylase KDM5C occupies many active enhancers, including almost all super-enhancers. Loss of RACK7 or KDM5C results in overactivation of enhancers, characterized by the deposition of H3K4me3 and H3K27Ac, together with increased transcription of eRNAs and nearby genes. Furthermore, loss of RACK7 or KDM5C leads to de-repression of S100A oncogenes and various cancer-related phenotypes. Our findings reveal a RACK7/KDM5C-regulated, dynamic interchange between histone H3K4me1 and H3K4me3 at active enhancers, representing an additional layer of regulation of enhancer activity. We propose that RACK7/KDM5C functions as an enhancer "brake" to ensure appropriate enhancer activity, which, when compromised, could contribute to tumorigenesis.

Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity.

ABSTRACT: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell-associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.

60Co-γ Irradiation-Induced Shift and Polarity Reversal in the Triboelectric Series of Poly(ether sulfone)s.

The sensitivity of triboelectric nanogenerators (TENGs) to the surface charge density highlights the significance of triboelectric materials and their modifications. Efforts have been directed toward developing effective strategies for increasing the surface charge density, expanding the potential applications of TENGs. This study proposes the use of irradiation technology for grafting to modify the electron-donating capability of poly(ether sulfone) (PES), thereby affording a dual benefit of enhancing the surface charge density and inducing a shift in the position of PES from negative to positive within the triboelectric series. The TENG based on grafted PES has resulted in a significant 3-fold increase in surface charge density compared to that of pristine PES, reaching 263 µC m-2. The surface charge density can be further increased to 502 µC m-2 through charge pumping. Notably, irradiation technology presents advantages over chemical grafting methods, particularly in terms of sustainability and environmental friendliness. This innovative approach shows great potential in advancing the domain of TENGs.

Near-infrared dual-gas sensor for simultaneous detection of CO and CH4 using a double spot-ring plane-concave multipass cell and a digital laser frequency stabilization system.

A novel double spot-ring plane-concave multipass cell (DSPC-MPC) gas sensor was proposed for simultaneous detection of trace gases, which has lower cost and higher mirror utilization than the traditional multipass cell with 129 m, 107 m, 85 m, 63 m and 40 m effective optical path lengths adjustable. The performance of the DSPC-MPC gas sensor was evaluated by measuring CO and CH4 using two narrow linewidth distributed feedback lasers with center wavelengths of 1567 nm and 1653 nm, respectively. An adjustable digital PID laser frequency stabilization system based on LabVIEW platform was developed to continuously stabilize the laser frequency within ∼±30.3 MHz. The Allan deviation results showed that the minimum detection limits for CO and CH4 were 0.07 ppmv and 0.008 ppmv at integration times of 711 s and 245 s, respectively. The proposed concept of DSPC-MPC provides more ideas for the realization of gas detection under different absorption path lengths and the development of multi-component gas sensing systems.

Benefit of axicabtagene ciloleucel versus chemoimmunotherapy in older patients and/or patients with poor ECOG performance status with relapsed or refractory large B-cell lymphoma after 2 or more lines of prior therapy.

Axicabtagene ciloleucel (axi-cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real-world effectiveness of axi-cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi-cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients treated with CIT for R/R LBCL after ≥2 lines of prior therapy were included from SCHOLAR-1 (an international, multicohort, retrospective study). After propensity score matching, at a median follow-up of 24 months for patients receiving axi-cel and 60 months for patients receiving CIT, 12-month overall survival rates were 62% and 28%, respectively (hazard ratio, 0.30 [95% CI, 0.24-0.37]). Objective response rate (ORR) was 76% (complete response [CR] rate 58%) in patients receiving axi-cel versus 28% (CR rate 16%) for those receiving CIT. A 57% difference in ORR (55% difference in CR rate) favoring axi-cel over CIT was observed among patients aged ≥65 years. Increased magnitude of benefit in response rates for axi-cel versus CIT was also observed among patients with ECOG PS = 2. These findings further support the broader use of axi-cel in older patients and patients with ECOG PS = 2 with R/R LBCL.

LysSYL: a broad-spectrum phage endolysin targeting Staphylococcus species and eradicating S. aureus biofilms.

BACKGROUND: Staphylococcus aureus and its single or mixed biofilm infections seriously threaten global public health. Phage therapy, which uses active phage particles or phage-derived endolysins, has emerged as a promising alternative strategy to antibiotic treatment. However, high-efficient phage therapeutic regimens have yet to be established. RESULTS: In this study, we used an enrichment procedure to isolate phages against methicillin-resistant S. aureus (MRSA) XN108. We characterized phage SYL, a new member of the Kayvirus genus, Herelleviridae family. The phage endolysin LysSYL was expressed. LysSYL demonstrated stability under various conditions and exhibited a broader range of efficacy against staphylococcal strains than its parent phage (100% vs. 41.7%). Moreover, dynamic live/dead bacterial observation demonstrated that LysSYL could completely lyse MRSA USA300 within 10 min. Scan and transmission electron microscopy revealed evident bacterial cell perforation and deformation. In addition, LysSYL displayed strong eradication activity against single- and mixed-species biofilms associated with S. aureus. It also had the ability to kill bacterial persisters, and proved highly effective in eliminating persistent S. aureus when combined with vancomycin. Furthermore, LysSYL protected BALB/c mice from lethal S. aureus infections. A single-dose treatment with 50 mg/kg of LysSYL resulted in a dramatic reduction in bacterial loads in the blood, liver, spleen, lungs, and kidneys of a peritonitis mouse model, which resulted in rescuing 100% of mice challenged with 108 colony forming units of S. aureus USA300. CONCLUSIONS: Overall, the data provided in this study highlight the strong therapeutic potential of endolysin LysSYL in combating staphylococcal infections, including mono- and mixed-species biofilms related to S. aureus.

Controls of Mineral Solubility on Adsorption-Induced Molecular Fractionation of Dissolved Organic Matter Revealed by 21 T FT-ICR MS.

Mineral adsorption-induced molecular fractionation of dissolved organic matter (DOM) affects the composition of both DOM and OM adsorbed and thus stabilized by minerals. However, it remains unclear what mineral properties control the magnitude of DOM fractionation. Using a combined technique approach that leverages the molecular composition identified by ultrahigh resolution 21 T Fourier transform ion cyclotron resonance mass spectrometry and adsorption isotherms, we catalogue the compositional differences that occur at the molecular level that results in fractionation due to adsorption of Suwannee River fulvic acid on aluminum (Al) and iron (Fe) oxides and a phyllosilicate (allophane) species of contrasting properties. The minerals of high solubility (i.e., amorphous Al oxide, boehmite, and allophane) exhibited much stronger DOM fractionation capabilities than the minerals of low solubility (i.e., gibbsite and Fe oxides). Specifically, the former released Al3+ to solution (0.05-0.35 mM) that formed complexes with OM and likely reduced the surface hydrophobicity of the mineral-OM assemblage, thus increasing the preference for adsorbing polar DOM molecules. The impacts of mineral solubility are exacerbated by the fact that interactions with DOM also enhance metal release from minerals. For sparsely soluble minerals, the mineral surface hydrophobicity, instead of solubility, appeared to be the primary control of their DOM fractionation power. Other chemical properties seemed less directly relevant than surface hydrophobicity and solubility in fractionating DOM.

Exploring clinical evaluation indicators for predicting coagulation in the extracorporeal circulation circuit in hemodialysis patients receiving individualized regional citrate anticoagulation-A single-center, retrospective clinical study.

BACKGROUND: Citrate anticoagulation is an important anticoagulation method in hemodialysis (HD) but cannot completely prevent the occurrence of coagulation in the extracorporeal circulation (ECC) circuit, and the clinical coagulation status can significantly affect the effect of citrate anticoagulation. In this study, the relationships between clinical coagulation status indicators and coagulation in the ECC circuit in HD patients receiving individualized citrate anticoagulant were studied to explore indicators that may predict coagulation in the ECC circuit. METHODS: This study was a single-center, retrospective clinical study, and clinical data and laboratory tests related to the coagulation status of HD patients receiving individualized regional citrate anticoagulation (RCA) were collected. The relationships between indicators commonly used in clinical practice to evaluate clinical coagulation status and coagulation in the ECC circuit were statistically analyzed to find indicators that can predict the occurrence of coagulation in the ECC circuit. RESULTS: The individualized RCA had a good anticoagulation effect, and the actual citrate infusion rate in nearly 80% of the patients was within ±10% of the theoretical infusion rate. The combined diseases or conditions that affect the coagulation status in vivo may increase the incidence of coagulation in the ECC circuit. The clinical D-dimer level is an independent risk factor that affects and can predict coagulation in the ECC circuit, with a cutoff value of 2.03 mg/L, sensitivity of 59%, and specificity of 78%. CONCLUSION: Individualized RCA can meet the needs of most HD treatments. Abnormal coagulation status in HD patients may increase the incidence of coagulation in the ECC circuit during individualized RCA for HD, and the D-dimer level can predict the occurrence of coagulation in the ECC circuit during this treatment.

The impact of retirement on blood pressure: evidence from a nationwide survey in China.

INTRODUCTION: The health impact of retirement is controversial. Most previous studies have been based on self-reported health indicators or the endpoints of some chronic diseases (e.g., morbidity or mortality), but objective physiological indicators (e.g., blood pressure) have rarely been used. The objective of this study is to elucidate the health effects of retirement on blood pressure, thereby offering empirical evidence to facilitate the health of retirees and to optimize retirement policies. METHODS: From 2012 to 2015, 84,696 participants of the Chinese Hypertension Survey (CHS) were included in this study. We applied the fuzzy regression discontinuity design (FRDD) to identify retirement's causal effect on systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure. We also explored the heterogeneity in the effects of retirement across different sex and education level groups. RESULTS: Based on the fully adjusted model, we estimated that retirement increased SBP by 5.047 mm Hg (95% CI: -2.628-12.723, P value: 0.197), DBP by 0.614 mm Hg (95% CI: -3.879-5.108, P value: 0.789) and pulse pressure by 4.433 mm Hg (95% CI: -0.985-9.851, P value: 0.109). We found that retirement led to a significant increase in male participants' SBP and pulse pressure as well as a possible decrease in female participants' blood pressure. Additionally, the blood pressure levels of low-educated participants were more vulnerable to the shock of retirement. CONCLUSION: Retirement is associated with an increase in blood pressure level. There is a causal relationship between the increase in blood pressure levels of men and retirement. Policy-makers should pay extra attention to the health status of men and less educated people when adjusting retirement policies in the future.

Crocetin protects mouse brain from apoptosis in traumatic brain injury model through activation of autophagy.

BACKGROUND: Autophagy is recognized as a promising therapeutic target for traumatic brain injury (TBI). Crocetin is an aglycone of crocin naturally occurring in saffron and has been found to alleviate brain injury diseases. However, whether crocetin affects autophagy after TBI remains unknown. Therefore, we explore crocetin roles in autophagy after TBI. METHODS: We used a weight-dropped model to induce TBI in C57BL/6J mice. Neurological severity scoring (NSS) and grip tests were used to evaluate the neurological level of injury. Brain edema, neuronal apoptosis, neuroinflammation and autophagy were detected by measurements of brain water content, TUNEL staining, ELISA kits and western blotting. RESULTS: Crocetin ameliorated neurological dysfunctions and brain edema after TBI. Crocetin reduced neuronal apoptosis and neuroinflammation and enhanced autophagy after TBI. CONCLUSION: Crocetin alleviates TBI by inhibiting neuronal apoptosis and neuroinflammation and activating autophagy.

New online dynamic nomograms to predict recurrence-free and overall survival after resection of endometrial cancer: a single-institution retrospective cohort study.

PURPOSE: The significant global burden of endometrial cancer (EC) and the challenges associated with predicting EC recurrence indicate the need for a dynamic prediction model. This study aimed to propose nomograms based on clinicopathological variables to predict recurrence-free survival (RFS) and overall survival (OS) after surgical resection for EC. METHODS: This single-institution retrospective cohort study included patients who underwent surgical resection for EC. Web-based nomograms were developed to predict RFS and OS following resection for EC, and their discriminative and calibration abilities were assessed. RESULTS: This study included 289 patients (median age, 56 years). At a median follow-up of 51.1 (range, 4.1-128.3) months, 13.5% (39/289) of patients showed relapse or died, and 10.7% (31/289) had non-endometrioid tumors (median size: 2.8 cm). Positive peritoneal cytology result (hazard ratio [HR], 35.06; 95% confidence interval [CI], 1.12-1095.64; P = 0.0428), age-adjusted Charlson comorbidity index (AACCI) (HR, 52.08; 95% CI, 12.35-219.61; P < 0.001), and FIGO (Federation of Gynecology and Obstetrics) stage IV (HR, 138.33; 95% CI, 17.38-1101.05; P < 0.001) were predictors of RFS. Similarly, depth of myometrial invasion ≥ 1/2 (HR, 1; 95% CI, 0.46-2.19; P = 0.995), AACCI (HR, 93.63; 95% CI, 14.87-589.44; P < 0.001), and FIGO stage IV (HR, 608.26; 95% CI, 73.41-5039.66; P < 0.001) were predictors of OS. The nomograms showed good predictive capability, positive discriminative ability, and calibration (RFS: 0.895 and OS: 0.891). CONCLUSION: The nomograms performed well in internal validation when patients were stratified into prognostic groups, offering a personalized approach for risk stratification and treatment decision-making.

Magnetic covalent organic frameworks for extraction and determination of endocrine-disrupting chemicals in beverage and water samples.

BACKGROUND: Phenolic endocrine-disrupting chemicals (EDCs) are widespread and easily ingested through the food chain. They pose a serious threat to human health. Magnetic solid-phase extraction (MSPE) is an effective sample pre-treatment technology to determine traces of phenolic EDCs. RESULTS: Magnetic covalent organic framework (COF) (Fe3 O4 @COF) nanospheres were prepared and characterized. The efficient and selective extraction of phenolic EDCs relies on a large specific surface and the inherent porosity of COFs and hydrogen bonding, π-π, and hydrophobic interactions between COF shells and phenolic EDCs. Under optimal conditions, the proposed magnetic solid-phase extraction-high-performance liquid chromatography-ultra violet (MSPE-HPLC-UV) based on the metallic covalent organic framework method for phenolic EDCs shows good linearities (0.002-6 µg mL-1 ), with R2 of 0.995 or higher, and low limits of detection (6-1.200 ng mL-1 ). CONCLUSION: Magnetic covalent organic frameworks (Fe3 O4 @COFs) with good MSPE performance for phenolic EDCs were synthesized by the solvothermal method. The magnetic covalent organic framework-based MSPE-HPLC-UV method was applied successfully to determine phenolic EDCs in beverage and water samples with satisfactory recoveries (90.200%-123%) and relative standard deviations (2.100%-12.100%). © 2023 Society of Chemical Industry.

Current research hotspots and frontier trends on carbon budget of coastal wetlands: A bibliometric analysis.

Coastal wetlands are the main distribution of blue carbon in coastal zones and well known for their high carbon sequestration capacity. Investigating the variation of carbon budget is crucial for understanding the functionality of coastal wetlands and effectively addressing climate change. In this study, a bibliometric analysis of 4,509 articles was conducted to reveal research progress, hot issues, and emerging trends in the coastal wetland carbon budget field. The number of publications and citations in this field increased exponentially from 1991 to 2022. The leading subject category was Environmental Sciences with 1,844 articles (40.9%). At present, studies have been focused on blue carbon, the effects of climate change and man-made disturbances on carbon cycle, and the restoration of coastal wetlands. Based on the hotspots and trends in this field, the future researches should include (1) exploring the functional mechanisms of various factors affecting carbon cycle and establishing a methodological system for the estimation of blue carbon in coastal wetlands; (2) researching restoration techniques of coastal wetland and constructing wetland restoration evaluation index system; and (3) formulating enforceable carbon trading policy and strengthening international cooperation.

Workplace-based primary prevention intervention reduces incidence of hypertension: a post hoc analysis of cluster randomized controlled study.

BACKGROUND: A workplace-based primary prevention intervention be an effective approach to reducing the incidence of hypertension (HTN). However, few studies to date have addressed the effect among the Chinese working population. We assessed the effect of a workplace-based multicomponent prevention interventions program for cardiovascular disease on reducing the occurrence of HTN through encouraging employees to adopt a healthy lifestyle. METHODS: In this post hoc analysis of cluster randomized controlled study, 60 workplaces across 20 urban regions in China were randomized to either the intervention group (n = 40) or control group (n = 20). All employees in each workplace were asked to complete a baseline survey after randomization for obtaining sociodemographic information, health status, lifestyle, etc. Employees in the intervention group were given a 2-year workplace-based primary prevention intervention program for improving their cardiovascular health, including (1) cardiovascular health education, (2) a reasonable diet, (3) tobacco cessation, (4) physical environment promotion, (5) physical activity, (6) stress management, and (7) health screening. The primary outcome was the incidence of HTN, and the secondary outcomes were improvements of blood pressure (BP) levels and lifestyle factors from baseline to 24 months. A mix effect model was used to assess the intervention effect at the end of the intervention in the two groups. RESULTS: Overall, 24,396 participants (18,170 in the intervention group and 6,226 in the control group) were included (mean [standard deviation] age, 39.3 [9.1] years; 14,727 men [60.4%]). After 24 months of the intervention, the incidence of HTN was 8.0% in the intervention groups and 9.6% in the control groups [relative risk (RR) = 0.66, 95% CI, 0.58 ~ 0.76, P < 0.001]. The intervention effect was significant on systolic BP (SBP) level (ß = - 0.7 mm Hg, 95% CI, - 1.06 ~ - 0.35; P < 0.001) and on diastolic BP (DBP) level (ß = - 1.0 mm Hg, 95% CI, - 1.31 ~ - 0.76; P < 0.001). Moreover, greater improvements were reported in the rates of regular exercise [odd ratio (OR) = 1.39, 95% CI, 1.28 ~ 1.50; P < 0.001], excessive intake of fatty food (OR = 0.54, 95% CI, 0.50 ~ 0.59; P < 0.001), and restrictive use of salt (OR = 1.22, 95% CI, 1.09 ~ 1.36; P = 0.001) in intervention groups. People with a deteriorating lifestyle had higher rates of developing HTN than those with the same or improved lifestyle. Subgroup analysis showed that the intervention effect of BP on employees with educational attainment of high school above (SBP: ß = - 1.38/ - 0.76 mm Hg, P < 0.05; DBP: ß = - 2.26/ - 0.75 mm Hg, P < 0.001), manual labor workers and administrative worker (SBP: ß = - 1.04/ - 1.66 mm Hg, P < 0.05; DBP: ß = - 1.85/ - 0.40 mm Hg, P < 0.05), and employees from a workplace with an affiliated hospital (SBP: ß = - 2.63 mm Hg, P < 0.001; DBP: ß = - 1.93 mm Hg, P < 0.001) were significantly in the intervention group. CONCLUSIONS: This post hoc analysis found that workplace-based primary prevention interventions program for cardiovascular disease were effective in promoting healthy lifestyle and reducing the incidence of HTN among employees. TRIAL REGISTRATION: Chinese Clinical Trial Registry No. ChiCTR-ECS-14004641.

Ultrasensitive Self-Driven Terahertz Photodetectors Based on Low-Energy Type-II Dirac Fermions and Related Van der Waals Heterojunctions.

The exotic electronic properties of topological semimetals (TSs) have opened new pathways for innovative photonic and optoelectronic devices, especially in the highly pursuit terahertz (THz) band. However, in most cases Dirac fermions lay far above or below the Fermi level, thus hindering their successful exploitation for the low-energy photonics. Here, low-energy type-II Dirac fermions in kitkaite (NiTeSe) for ultrasensitive THz detection through metal-topological semimetal-metal heterostructures are exploited. Furthermore, a heterostructure combining two Dirac materials, namely, graphene and NiTeSe, is implemented for a novel photodetector exhibiting a responsivity as high as 1.22 A W-1 , with a response time of 0.6 µs, a noise-equivalent power of 18 pW Hz-0.5 , with outstanding stability in the ambient conditions. This work brings to fruition of Dirac fermiology in THz technology, enabling self-powered, low-power, room-temperature, and ultrafast THz detection.

Microbiota-derived tryptophan metabolites indole-3-lactic acid is associated with intestinal ischemia/reperfusion injury via positive regulation of YAP and Nrf2.

BACKGROUND: Lactobacillus has been demonstrated to serve a protective role in intestinal injury. However, the relationship between Lactobacillus murinus (L. murinus)-derived tryptophan metabolites and intestinal ischemia/reperfusion (I/R) injury yet to be investigated. This study aimed to evaluate the role of L. murinus-derived tryptophan metabolites in intestinal I/R injury and the underlying molecular mechanism. METHODS: Liquid chromatograph mass spectrometry analysis was used to measure the fecal content of tryptophan metabolites in mice undergoing intestinal I/R injury and in patients undergoing cardiopulmonary bypass (CPB) surgery. Immunofluorescence, quantitative RT-PCR, Western blot, and ELISA were performed to explore the inflammation protective mechanism of tryptophan metabolites in WT and Nrf2-deficient mice undergoing intestinal I/R, hypoxia-reoxygenation (H/R) induced intestinal organoids. RESULTS: By comparing the fecal contents of three L. murinus-derived tryptophan metabolites in mice undergoing intestinal I/R injury and in patients undergoing cardiopulmonary bypass (CPB) surgery. We found that the high abundance of indole-3-lactic acid (ILA) in the preoperative feces was associated with better postoperative intestinal function, as evidenced by the correlation of fecal metabolites with postoperative gastrointestinal function, serum I-FABP and D-Lactate levels. Furthermore, ILA administration improved epithelial cell damage, accelerated the proliferation of intestinal stem cells, and alleviated the oxidative stress of epithelial cells. Mechanistically, ILA improved the expression of Yes Associated Protein (YAP) and Nuclear Factor erythroid 2-Related Factor 2 (Nrf2) after intestinal I/R. The YAP inhibitor verteporfin (VP) reversed the anti-inflammatory effect of ILA, both in vivo and in vitro. Additionally, we found that ILA failed to protect epithelial cells from oxidative stress in Nrf2 knockout mice under I/R injury. CONCLUSIONS: The content of tryptophan metabolite ILA in the preoperative feces of patients is negatively correlated with intestinal function damage under CPB surgery. Administration of ILA alleviates intestinal I/R injury via the regulation of YAP and Nrf2. This study revealed a novel therapeutic metabolite and promising candidate targets for intestinal I/R injury treatment.

The clinical and functional effects of TERT variants in myelodysplastic syndrome.

Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of a telomere biology disorder who underwent allogeneic transplantation. Patients with a TERT rare variant had shorter telomere length (P < .001) and younger age at MDS diagnosis (52 vs 59 years, P = .03) than patients without a TERT rare variant. In multivariable models, TERT rare variants were associated with inferior overall survival (P = .034) driven by an increased incidence of nonrelapse mortality (NRM; P = .015). Death from a noninfectious pulmonary cause was more frequent among patients with a TERT rare variant. Most variants were missense substitutions and classified as variants of unknown significance. Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 90% of TERT rare variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein-RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized. Routine screening for TERT rare variants in MDS patients regardless of age or clinical suspicion may identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.

First Direct Observation of Collider Neutrinos with FASER at the LHC.

We report the first direct observation of neutrino interactions at a particle collider experiment. Neutrino candidate events are identified in a 13.6 TeV center-of-mass energy pp collision dataset of 35.4 fb^{-1} using the active electronic components of the FASER detector at the Large Hadron Collider. The candidates are required to have a track propagating through the entire length of the FASER detector and be consistent with a muon neutrino charged-current interaction. We infer 153_{-13}^{+12} neutrino interactions with a significance of 16 standard deviations above the background-only hypothesis. These events are consistent with the characteristics expected from neutrino interactions in terms of secondary particle production and spatial distribution, and they imply the observation of both neutrinos and anti-neutrinos with an incident neutrino energy of significantly above 200 GeV.

Therapeutic potential of bacteriophage endolysins for infections caused by Gram-positive bacteria.

Gram-positive (G+) bacterial infection is a great burden to both healthcare and community medical resources. As a result of the increasing prevalence of multidrug-resistant G+ bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), novel antimicrobial agents must urgently be developed for the treatment of infections caused by G+ bacteria. Endolysins are bacteriophage (phage)-encoded enzymes that can specifically hydrolyze the bacterial cell wall and quickly kill bacteria. Bacterial resistance to endolysins is low. Therefore, endolysins are considered promising alternatives for solving the mounting resistance problem. In this review, endolysins derived from phages targeting G+ bacteria were classified based on their structural characteristics. The active mechanisms, efficacy, and advantages of endolysins as antibacterial drug candidates were summarized. Moreover, the remarkable potential of phage endolysins in the treatment of G+ bacterial infections was described. In addition, the safety of endolysins, challenges, and possible solutions were addressed. Notwithstanding the limitations of endolysins, the trends in development indicate that endolysin-based drugs will be approved in the near future. Overall, this review presents crucial information of the current progress involving endolysins as potential therapeutic agents, and it provides a guideline for biomaterial researchers who are devoting themselves to fighting against bacterial infections.

Automatic characterization of stroke patients' posturography based on probability density analysis.

OBJECTIVE: The probability density analysis was applied to automatically characterize the center of pressure (COP) data for evaluation of the stroke patients' balance ability. METHODS: The real-time COP coordinates of 38 stroke patients with eyes open and closed during quiet standing were obtained, respectively, from a precision force platform. The COP data were analyzed and characterized by the commonly used parameters: total sway length (SL), sway radius (SR), envelope sway area (EA), and the probability density analysis based parameters: projection area (PA), skewness (SK) and kurtosis (KT), and their statistical correlations were analyzed. The differences of both conventional parameters and probability density parameters under the conditions of eyes open (EO) and eyes closed (EC) were compared. RESULTS: The PA from probability density analysis is strongly correlated with SL and SR. Both the traditional parameters and probability density parameters in the EC state are significantly different from those in the EO state. The obtained various statokinesigrams were calculated and categorized into typical sway types through probability density function for clinical evaluation of the balance ability of stroke patients. CONCLUSIONS: The probability density analysis of COP data can be used to characterize the posturography for evaluation of the balance ability of stroke patients.