Comprehensive assessment on the association of dietary vitamins with all-cause and cardiovascular mortality among individuals with prediabetes: evidence from NHANES 1999-2018.

Background: Prediabetes has become a global health issue, and currently, the relationship between vitamin levels and mortality in prediabetes remains unclear. This study aims to investigate the association between the levels of eleven vitamins and all-cause and cardiovascular disease (CVD) mortality in prediabetes patients. Methods: This cross-sectional study included 14 634 prediabetes patients from 10 cycles of the National Health and Nutrition Examination Survey between 1999 and 2018. Mortality and underlying causes of death were determined by linking records from the National Death Index until December 31, 2019. Multivariable Cox proportional hazards regression models were established to assess hazard ratios and 95% confidence intervals for all-cause, CVD, cancer, and other mortalities. Restricted cubic splines were used to visualize non-linear associations between various vitamins and mortality risk. Results: During the follow-up period, 2316/14 634 prediabetes patients died (12.55%), with 722 deaths (3.68%) attributed to CVD. After multivariable adjustment, vitamin B1, niacin, folate, vitamin C, vitamin E, and vitamin K levels exhibited non-linear associations with all-cause mortality (all p < 0.05). Vitamin B1, niacin, and vitamin E levels showed non-linear associations with CVD mortality (p < 0.05). Vitamin B6 exhibited a linear negative association with all-cause, CVD, and other mortalities (p > 0.05). However, vitamins A and B2 levels were not significantly associated with mortality rates (all p > 0.05). Consistent results were observed in the subgroup analyses after complete adjustment for variables. Conclusions: Higher levels of dietary vitamins B1, B6, niacin, folate, vitamin C, vitamin E, and vitamin K were significantly associated with lower risk of all-cause mortality and CVD mortality in patients with prediabetes. There was no association between vitamin A and B2 levels and all-cause and CVD mortality among individuals with prediabetes. These findings suggest the importance of correcting vitamin deficiencies to prevent mortality in prediabetes patients.

Harnessing ZIKV NS2A RNA for alleviating acute hepatitis and cytokine release storm by targeting translation machinery.

BACKGROUND AND AIMS: Hyperactivated inflammatory responses induced by cytokine release syndrome (CRS) are the primary causes of tissue damage and even death. The translation process is precisely regulated to control the production of proinflammatory cytokines. However, it is largely unknown whether targeting translation can effectively limit the hyperactivated inflammatory responses during acute hepatitis and graft-versus-host disease (GVHD). APPROACH AND RESULTS: By using in vitro translation and cellular overexpression systems, we have found that the non-structural protein gene NS2A of Zika virus (ZIKV) functions as RNA molecules to suppress the translation of both ectopic genes and endogenous proinflammatory cytokines. Mechanistically, results from RNA pulldown and co-immunoprecipitation (Co-IP) assays have demonstrated that NS2A RNA interacts with the translation initiation factor eIF2α to disrupt the dynamic balance of the eIF2/eIF2B complex and translation initiation, which is the rate-limiting step during the translation process. In the acetaminophen (APAP)-, LPS/D-galactosamine (D-GalN)-, viral infection-induced acute hepatitis, and GVHD mouse models, mice with myeloid cell-specific knock-in of NS2A show decreased levels of serum proinflammatory cytokines and reduced tissue damage. CONCLUSIONS: ZIKV NS2A dampens the production of proinflammatory cytokines and alleviates inflammatory injuries by interfering translation process as RNA molecules, which suggests that NS2A RNA is potentially used to treat numerous acute inflammatory diseases characterized by CRS.

Imerslund-Gräsbeck syndrome in a child with a novel compound heterozygous mutations in the AMN gene: a case report.

BACKGROUND: Imerslund-Gräsbeck syndrome (IGS) is an autosomal recessive disorder characterized by selective vitamin B12 malabsorption, resulting in vitamin B12 deficiency and impaired reabsorption of proximal tubular proteins.This case highlights a previously unidentified compound heterozygous variant in the Amnionless (AMN) gene that causes IGS syndrome and underscores the importance of long-term oral vitamin B12 replacement therapy in managing the condition. CASE PRESENTATION: In this retrospective analysis, we present the clinical data of a 3-year and 6-month-old female child diagnosed with IGS at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China, in November 2018. The child was admitted to the hospital due to a history of anemia persisting for over a month. There was no previous significant medical history. The admission examination revealed megaloblastic anemia with proteinuria. Serum vitamin B12 levels were decreased, while folic acid and renal function were normal. The patient was diagnosed with megaloblastic anemia and started long-term oral vitamin B12 replacement therapy. Throughout the follow-up period, blood tests consistently showed normal results, while proteinuria persisted. In November 2019, the child and her parents underwent whole exome sequencing analysis, which revealed a novel compound heterozygous variant in the AMN gene: c.162 + 1G > A and c.922 C > T (p.Q308X) in the child, c.162 + 1G > A in the father, and c.922 C > T (p.Q308X) in the mother. Therefore, this child was further diagnosed with IGS. CONCLUSIONS: In this case, whole exome sequencing proves to be highly practical in daily healthcare for diagnosing and refining rare or ultra-rare diseases with ambiguous phenotypes or genetic diversity. It is also valuable for prognostic evaluation and personalized management. Additionally, the oral vitamin B12 treatment demonstrated positive clinical effects for the child, offering a new option for patients unable to undergo intramuscular vitamin B12 replacement therapy.

Effects of rural hospital closures on nurse staffing levels and health care utilization at nearby hospitals.

Our study examines the causal effect of rural hospital closures on nearby hospitals' nurse staffing levels and health care utilization. We use data from the 2014-2019 American Hospital Association Survey on nurse staffing level outcomes including licensed practical or vocational nurses (LPNs), registered nurses (RNs), and advanced practice nurses (APNs); and health care utilization outcomes, including inpatient and outpatient surgical operations and emergency department (ED) visits. Using propensity score matching and difference-in-differences (DID) methods, we find that rural hospital closures lead to an average increase of 37.3% in the number of nurses in nearby rural hospitals during the 4 years following the closure. This increase is found across all categories of nurses, including LPNs, RNs, and APNs. We also find a substantial increase in the provision of inpatient and outpatient surgical operations but there is no change in ED visits. We do not find any effects for nearby urban hospitals. Our study suggests that a large proportion of the nursing workforce relocates to nearby hospitals after a rural hospital closure, which mitigates the negative consequences of such closures and allows these nearby hospitals to provide a larger volume of highly profitable services.

Mitochondrial Deoxyguanosine Kinase Induces 5-Fluorouracil Chemotherapy Sensitivity through Autophagy.

AIMS: The purpose of this study was to investigate the role of DGUOK in the pro-gression of colorectal cancer (CRC) and its impact on the sensitivity of CRC cells to 5-FU treatment. METHODS: We conducted bioinformatics analysis and qRT-PCR to evaluate DGUOK expression in CRC tissues/cells. Cell viability of CRC cells treated with 5-FU was assessed using CCK-8 and colony formation assays. Autophagy levels were determined through immunofluorescence assays and Western blot analysis. Additionally, the influence of p-p38 on autophagy was inves-tigated via Western blotting. A rescue assay was performed to confirm whether DGUOK/p38 affects 5-FU sensitivity in CRC cells through autophagy. RESULTS: Our findings indicate that DGUOK is upregulated in CRC tissues compared to normal tissues, correlating with increased cell proliferation and migration. Functionally, inhibition of DGUOK enhances autophagy, thereby decreasing the sensitivity of CRC cells to 5-FU. This ef-fect is partly mediated by DGUOK's impact on the mitogen-activated protein kinase (MAPK) pathway, specifically promoting the phosphorylation of p38 MAPK, a crucial regulator in au-tophagy pathways. CONCLUSION: These results suggest that DGUOK could serve as a novel marker for predicting the efficacy of 5-FU in CRC treatment.

Novel GNAI3 mutation in a Chinese family with auriculocondylar syndrome and treatment of severe dentofacial deformities: a 5-year follow-up case report.

BACKGROUND: Auriculocondylar syndrome (ARCND) is an extremely rare autosomal dominant or recessive condition that typically manifests as question mark ears (QMEs), mandibular condyle hypoplasia, and micrognathia. Severe dental and maxillofacial malformations present considerable challenges in patients' lives and clinical treatment. Currently, only a few ARCND cases have been reported worldwide, but most of them are related to genetic mutations, clinical symptoms, and ear correction; there are few reports concerning the treatment of dentofacial deformities. CASE PRESENTATION: Here, we report a rare case of ARCND in a Chinese family. A novel insertional mutation in the guanine nucleotide-binding protein alpha-inhibiting activity polypeptide 3 (GNAI3) was identified in the patient and their brother using whole-exome sequencing. After a multidisciplinary consultation and examination, sequential orthodontic treatment and craniofacial surgery, including distraction osteogenesis and orthognathic surgery, were performed using three-dimensional (3D) digital technology to treat the patient's dentofacial deformity. A good prognosis was achieved at the 5-year follow-up, and the patient returned to normal life. CONCLUSIONS: ARCND is a monogenic and rare condition that can be diagnosed based on its clinical triad of core features. Molecular diagnosis plays a crucial role in the diagnosis of patients with inconspicuous clinical features. We present a novel insertion variation in GNAI3, which was identified in exon 2 of chromosome 110116384 in a Chinese family. Sequential therapy with preoperative orthodontic treatment combined with distraction osteogenesis and orthognathic surgery guided by 3D digital technology may be a practical and effective method for treating ARCND.

Construction and validation of a nomogram prediction model for the progression to septic shock in elderly patients with urosepsis.

Background: Septic shock is a clinical syndrome characterized by the progression of sepsis to a severe stage. Elderly patients with urosepsis in the intensive care unit (ICU) are more likely to progress to septic shock. This study aimed to establish and validate a nomogram model for predicting the risk of progression to septic shock in elderly patients with urosepsis. Methods: We extracted data from the Medical Information Mart for Intensive Care (MIMIC-IV) and the eICU Collaborative Research Database (eICU-CRD). The MIMIC-IV dataset was split into a training set for model development and an internal validation set to assess model performance. Further external validation was performed using a distinct dataset sourced from the eICU-CRD. Predictors were screened using least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression analyses. The evaluation of model performance included discrimination, calibration, and clinical usefulness. Results: The study demonstrated that the Glasgow Coma Scale (GCS), white blood count (WBC), platelet, blood urea nitrogen (BUN), calcium, albumin, congestive heart failure (CHF), and invasive ventilation were closely associated with septic shock in the training cohort. Nomogram prediction, utilizing eight parameters, demonstrated strong predictive accuracy with area under the curve (AUC) values of 0.809 (95 % CI 0.786-0.834), 0.794 (95 % CI 0.756-0.831), and 0.723 (95 % CI 0.647-0.801) in the training, internal validation, and external validation sets, respectively. Additionally, the nomogram demonstrated a promising calibration performance and significant clinical usefulness in both the training and validation sets. Conclusion: The constructed nomogram is a reliable and practical tool for predicting the risk of progression to septic shock in elderly patients with urosepsis. Its implementation in clinical practice may enhance the early identification of high-risk patients, facilitate timely and targeted interventions to mitigate the risk of septic shock, and improve patient outcomes.

Willingness to receive mpox vaccine among men who have sex with men: a systematic review and meta-analysis.

BACKGROUND: Since May 2022, mpox outbreaks have been occurring in non-mpox endemic areas, with the main population affected being men who have sex with men (MSM). Outbreak prevention and control depend not only on the effectiveness of vaccines but also on people's willingness to receive these vaccines. Currently, there is lack of synthesis on the overall rates and influence factors of MSMs' willingness to vaccinate against mpox. Therefore, we systematically reviewed studies that assessed the willingness of MSM to receive mpox vaccine. METHODS: Studies reporting mpox vaccination intentions among MSM were included by searching five databases (PubMed, Web of Science, EMBASE, CINAHL, and SCOPUS) from inception to May 12, 2024. The quality of the included literature was assessed using Joanna Briggs Institute's critical appraisal tool. The data analysis software is Stata17. The systematic review has been registered with Prospero (registration ID: CRD42023452357). RESULTS: Twenty cross-sectional studies were included in the review. Meta-analysis results showed that the pooled willingness rate of vaccinate against mpox was 77.0% (95% CI: 73-81%, I2 = 99.4%). According to subgroup analysis, study countries (P = 0.002), research sample size (P = 0.001), and whether participants were infected with HIV (P = 0.002) may be sources of heterogeneity. The results of the meta-analysis of influencing factors showed that more number of sexual partners (OR: 2.24, 95%CI: 1.86-2.69), pre-exposure prophylaxis use (OR: 6.04, 95%CI: 4.80-7.61), history of sexually transmitted infections (OR: 2.96, 95%CI: 2.33-3.76), confidence in the vaccine's effectiveness (OR: 2.79, 95%CI: 2.04-3.80) and safety (OR: 10.89, 95%CI: 5.22-22.72), fear of mpox infection (OR: 2.47, 95%CI: 2.11-2.89) and epidemics (OR: 2.87, 95%CI: 2.22-3.70), high mpox knowledge (OR: 2.35, 95%CI: 1.51-3.66), and the belief that people at high risk should be prioritized for vaccination (OR: 3.09, 95%CI: 1.40-6.84) were the facilitators of vaccine willingness. In addition, as a secondary outcome, meta-analysis results showed a pooled unwillingness rate of 16% (95% CI: 13-20%, I2 = 98.1%, 9 studies). CONCLUSION: Willingness to vaccinate mpox was high among MSM, but some participants still had negative attitudes towards vaccination. Therefore, the Ministry of Public Health should develop targeted and effective strategies against those influencing factors to prevent and manage mpox outbreaks.

Versatile Patterning of Liquid Metal via Multiphase 3D Printing.

This paper presents a scalable and straightforward technique for the immediate patterning of liquid metal/polymer composites via multiphase 3D printing. Capitalizing on the polymer's capacity to confine liquid metal (LM) into diverse patterns. The interplay between distinctive fluidic properties of liquid metal and its self-passivating oxide layer within an oxidative environment ensures a resilient interface with the polymer matrix. This study introduces an inventive approach for achieving versatile patterns in eutectic gallium indium (EGaIn), a gallium alloy. The efficacy of pattern formation hinges on nozzle's design and internal geometry, which govern multiphase interaction. The interplay between EGaIn and polymer within the nozzle channels, regulated by variables such as traverse speed and material flow pressure, leads to periodic patterns. These patterns, when encapsulated within a dielectric polymer polyvinyl alcohol (PVA), exhibit an augmented inherent capacitance in capacitor assemblies. This discovery not only unveils the potential for cost-effective and highly sensitive capacitive pressure sensors but also underscores prospective applications of these novel patterns in precise motion detection, including heart rate monitoring, and comprehensive analysis of gait profiles. The amalgamation of advanced materials and intricate patterning techniques presents a transformative prospect in the domains of wearable sensing and comprehensive human motion analysis.

diABZI and poly(I:C) inhibit osteoclastic bone resorption by inducing IRF7 and IFIT3.

Type I interferons (IFN-I) are pleiotropic factors endowed with multiple activities that play important roles in innate and adaptive immunity. Although many studies indicate that IFN-I inducers exert favorable effects on broad-spectrum antivirus, immunomodulation, and anti-tumor activities by inducing endogenous IFN-I and IFN-stimulated genes, their function in bone homeostasis still needs further exploration. Here, our study demonstrates 2 distinct IFN-I inducers, diABZI and poly(I:C), as potential therapeutics to alleviate osteolysis and osteoporosis. First, IFN-I inducers suppress the genes that control osteoclast (OC) differentiation and activity in vitro. Moreover, diABZI alleviates bone loss in Ti particle-induced osteolysis and ovariectomized -induced osteoporosis in vivo by inhibiting OC differentiation and function. In addition, the inhibitory effects of IFN-I inducers on OC differentiation are not observed in macrophages derived from Ifnar1-/-mice, which indicate that the suppressive effect of IFN-I inducers on OC is IFNAR-dependent. Mechanistically, RNAi-mediated silencing of IRF7 and IFIT3 in OC precursors impairs the suppressive effect of the IFN-I inducers on OC differentiation. Taken together, these results demonstrate that IFN-I inducers play a protective role in bone turnover by limiting osteoclastogenesis and bone resorption through the induction of OC-specific mediators via the IFN-I signaling pathway.

OCs are responsible for bone resorption, and their excessive differentiation and enhanced activity will lead to bone resorption diseases such as osteoporosis and osteolysis. Here, our study demonstrates 2 distinct IFN-I inducers, diABZI and poly(I:C), as potential therapeutics to alleviate osteolysis and osteoporosis. IFN-I inducers suppress OC differentiation, and particularly diABZI alleviates bone loss in osteolysis and osteoporosis mouse models. Taken together, IFN-I inducers play a protective role in bone turnover by limiting osteoclastogenesis and bone resorption through the induction of OC-specific mediators via the IFN-I signaling pathway. Our in-depth and comprehensive discovery of the IFN-I inducer would provide new insight into OC biology and therapeutic targets for osteoclastic bone resorption diseases.

T Cell-Derived Apoptotic Extracellular Vesicles Hydrolyze cGAMP to Alleviate Radiation Enteritis via Surface Enzyme ENPP1.

Radiation enteritis is the most common complication of pelvic radiotherapy, but there is no effective prevention or treatment drug. Apoptotic T cells and their products play an important role in regulating inflammation and maintaining physiological immune homeostasis. Here it is shown that systemically infused T cell-derived apoptotic extracellular vesicles (ApoEVs) can target mice irradiated intestines and alleviate radiation enteritis. Mechanistically, radiation elevates the synthesis of intestinal 2'3' cyclic GMP-AMP (cGAMP) and activates cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) proinflammatory pathway. After systemic infusion of ApoEVs, the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) enriches on the surface of ApoEVs hydrolyze extracellular cGAMP, resulting in inhibition of the cGAS-STING pathway activated by irradiation. Furthermore, after ApoEVs are phagocytosed by phagocytes, ENPP1 on ApoEVs hydrolyzed intracellular cGAMP, which serves as an intracellular cGAMP hydrolyzation mode, thereby alleviating radiation enteritis. The findings shed light on the intracellular and extracellular hydrolysis capacity of ApoEVs and their role in inflammation regulation.

PFKFB3 controls acinar IP3R-mediated Ca2+ overload to regulate acute pancreatitis severity.

Acute pancreatitis (AP) is among the most common hospital gastrointestinal diagnoses; understanding the mechanisms underlying the severity of AP is critical for development of new treatment options for this disease. Here, we evaluate the biological function of phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in AP pathogenesis in 2 independent genetically engineered mouse models of AP. PFKFB3 was elevated in AP and severe AP (SAP), and KO of Pfkfb3 abrogated the severity of alcoholic SAP (FAEE-SAP). Using a combination of genetic, pharmacological, and molecular studies, we defined the interaction of PFKFB3 with inositol 1,4,5-trisphosphate receptor (IP3R) as a key event mediating this phenomenon. Further analysis demonstrated that the interaction between PFKFB3 and IP3R promotes FAEE-SAP severity by altering intracellular calcium homeostasis in acinar cells. Together, our results support a PFKFB3-driven mechanism controlling AP pathobiology and define this enzyme as a therapeutic target to ameliorate the severity of this condition.

Identification and function analysis of BCL2 in immune response of Pteria penguin.

B-cell lymphoma/leukemia-2 (BCL2), an anti-apoptotic factor in the mitochondrial regulatory pathway of apoptosis, is critically important in immune defenses. In this study, a novel BCL2 gene was characterized from Pteria penguin (P. penguin). The PpBCL2 was 1482 bp long, containing an open reading frame (ORF) of 588 bp encoding 195 amino acids. Four highly conserved BCL-2 homology (BH) domains were found in PpBCL2. Amino acid alignment and phylogenetic tree showed that PpBCL2 had the highest similarity with BCL2 of Crassostrea gigas at 65.24 %. Tissue expression analysis showed that PpBCL2 had high constitutive expression in gill, digestive diverticulum and mantle, and was significantly increased 72 h of Vibrio parahaemolyticus (V. parahaemolyticus) challenge in these immune tissues. Furthermore, PpBCL2 silencing significantly inhibited antimicrobial activity of hemolymph supernatant by 1.4-fold, and significantly reduced the survival rate by 51.7 % at 72 h post infection in P. penguin. These data indicated that PpBCL2 played an important role in immune response of P. penguin against V. parahaemolyticus infection.

The Association Between Rumination and Craving in Chinese Methamphetamine-Dependent Patients: The Masking Effect of Depression.

BACKGROUND: Craving is a core feature of addiction. Rumination and depression play a crucial role in the process of methamphetamine addiction. The aim of this study was to examine the relationship between rumination, depression and craving in methamphetamine patients, which has not been explored yet. METHODS: A total of 778 patients with methamphetamine user disorder (MUD) at the Xinhua Drug Rehabilitation Center, located in Mianyang City, Sichuan Province, China. We used a set of self-administered questionnaires that included socio-demographic, detailed drug use history, rumination, depression and craving information. The Rumination Response Scale (RRS) was used to measure rumination, the Beck Depression Inventory (BDI) to measure depression and the Visual Analogue Scale (VAS) to measure craving. RESULTS: There was a significant positive correlation between rumination and craving, or depression, and between depression and craving. Furthermore, depression mediated between rumination and craving, with a mediation effect of 160%. CONCLUSIONS: Our findings suggest that there is a close interrelationship between rumination, craving and depression in MUD patients, and that depression may play a mediating role between rumination and craving.

This is the first study to investigate the relationship between rumination and craving during withdrawal in methamphetamine dependent patients and the mediating role of depression.Among methamphetamine patients, it was found that reflection was positively correlated with rumination and depression, depression and craving, rumination and craving, and depression plays the mediating role between rumination and craving.These findings suggest that interventions to reduce depression and rumination may also be effective for withdrawal and relapse reduction in methamphetamine patients, providing further rationale for the treatment of methamphetamine patients.

Rapid, Micron-Resolution 3D Printing of Nd:YAG Ceramic with Optical Gain.

Polycrystalline yttrium aluminum garnet (YAG) ceramic doped with neodymium (Nd), referred to as Nd:YAG, is widely used in solid-state lasers. However, conventional powder metallurgy methods suffer from expenses, time consumption, and limitations in customizing structures. This study introduces a novel approach for creating Nd:YAG ceramics with 3D free-form structures from micron (∼70 µm) to centimeter scales. Firstly, sol-gel synthesis is employed to form photocurable colloidal solutions. Subsequently, by utilizing a home-built micro-continuous liquid interface printing process, precursors are printed into 3D poly(acrylic acid) hydrogels containing yttrium, aluminum, and neodymium hydroxides, with a resolution of 5.8 µm pixel-1 at a speed of 10 µm s-1. After the hydrogels undergo thermal dehydration, debinding, and sintering, polycrystalline Nd:YAG ceramics featuring distinguishable grains are successfully produced. By optimizing the concentrations of the sintering aids (tetraethyl orthosilicate) and neodymium trichloride (NdCl3), the resultant samples exhibit satisfactory photoluminescence, emitting light concentrated at 1064 nm when stimulated by a 532 nm laser. Additionally, Nd:YAG ceramics with various 3D geometries (e.g., cone, spiral, and angled pillar) are printed and characterized, which demonstrates the potential for applications, such as laser and amplifier fibers, couplers, and splitters in optical circuits, as well as gain metamaterials or metasurfaces.

Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury.

BACKGROUND: Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) plays a crucial role in metabolizing and detoxifying endogenous and exogenous substances. However, its contribution to the progression of liver damage remains unclear. AIM: To determine the role and mechanism of UGT1A1 in liver damage progression. METHODS: We investigated the relationship between UGT1A1 expression and liver injury through clinical research. Additionally, the impact and mechanism of UGT1A1 on the progression of liver injury was analyzed through a mouse model study. RESULTS: Patients with UGT1A1 gene mutations showed varying degrees of liver damage, while patients with acute-on-chronic liver failure (ACLF) exhibited relatively reduced levels of UGT1A1 protein in the liver as compared to patients with chronic hepatitis. This suggests that low UGT1A1 levels may be associated with the progression of liver damage. In mouse models of liver injury induced by carbon tetrachloride (CCl4) and concanavalin A (ConA), the hepatic levels of UGT1A1 protein were found to be increased. In mice with lipopolysaccharide or liver steatosis-mediated liver-injury progression, the hepatic protein levels of UGT1A1 were decreased, which is consistent with the observations in patients with ACLF. UGT1A1 knockout exacerbated CCl4- and ConA-induced liver injury, hepatocyte apoptosis and necroptosis in mice, intensified hepatocyte endoplasmic reticulum (ER) stress and oxidative stress, and disrupted lipid metabolism. CONCLUSION: UGT1A1 is upregulated as a compensatory response during liver injury, and interference with this upregulation process may worsen liver injury. UGT1A1 reduces ER stress, oxidative stress, and lipid metabolism disorder, thereby mitigating hepatocyte apoptosis and necroptosis.

Genetic Analysis of Two Novel GPI Variants Disrupting H Bonds and Localization Characteristics of 55 Gene Variants Associated with Glucose-6-phosphate Isomerase Deficiency.

OBJECTIVE: Glucose-6-phosphate isomerase (GPI) deficiency is a rare hereditary nonspherocytic hemolytic anemia caused by GPI gene variants. This disorder exhibits wide heterogeneity in its clinical manifestations and molecular characteristics, often posing challenges for precise diagnoses using conventional methods. To this end, this study aimed to identify the novel variants responsible for GPI deficiency in a Chinese family. METHODS: The clinical manifestations of the patient were summarized and analyzed for GPI deficiency phenotype diagnosis. Novel compound heterozygous variants of the GPI gene, c.174C>A (p.Asn58Lys) and c.1538G>T (p.Trp513Leu), were identified using whole-exome and Sanger sequencing. The AlphaFold program and Chimera software were used to analyze the effects of compound heterozygous variants on GPI structure. RESULTS: By characterizing 53 GPI missense/nonsense variants from previous literature and two novel missense variants identified in this study, we found that most variants were located in exons 3, 4, 12, and 18, with a few localized in exons 8, 9, and 14. This study identified novel compound heterozygous variants associated with GPI deficiency. These pathogenic variants disrupt hydrogen bonds formed by highly conserved GPI amino acids. CONCLUSION: Early family-based sequencing analyses, especially for patients with congenital anemia, can help increase diagnostic accuracy for GPI deficiency, improve child healthcare, and enable genetic counseling.

Lactobacillus Reuteri Vesicles Regulate Mitochondrial Function of Macrophages to Promote Mucosal and Cutaneous Wound Healing.

The interplay between bacteria and their host influences the homeostasis of the human immune microenvironment, and this reciprocal interaction also affects the process of tissue damage repair. A variety of immunomodulatory commensal bacteria reside in the body, capable of delivering membrane vesicles (MVs) to host cells to regulate the local immune microenvironment. This research revealed, for the initial time, the significant enhancement of mucosal and cutaneous wound healing by MVs secreted by the human commensal Lactobacillus reuteri (RMVs) through modulation of the inflammatory environment in wound tissue. Local administration of RMVs reduces the proportion of pro-inflammatory macrophages in inflamed tissues and mitigates the level of local inflammation, thereby facilitating the healing of oral mucosa and cutaneous wounds. The elevated oxidative stress levels in activated pro-inflammatory macrophages can be modulated by RMVs, resulting in phenotypic transformation of macrophages. Furthermore, 3-hydroxypropionaldehyde present in RMVs can decrease the mitochondrial permeability of macrophages and stabilize the mitochondrial membrane potential, thereby promoting the conversion of macrophages to an anti-inflammatory phenotype. This study pioneers the significance of commensal bacterial MVs in tissue injury repair and presents a novel concept for the repair of tissue damage.

Nomogram predictive model for in-hospital mortality risk in elderly ICU patients with urosepsis.

BACKGROUND: Urinary tract infection (UTI) is a common cause of sepsis. Elderly patients with urosepsis in intensive care unit (ICU) have more severe conditions and higher mortality rates owing to factors such as advanced age, immunosenescence, and persistent host inflammatory responses. However, comprehensive studies on nomograms to predict the in-hospital mortality risk in elderly patients with urosepsis are lacking. This study aimed to construct a nomogram predictive model to accurately assess the prognosis of elderly patients with urosepsis and provide therapeutic recommendations. METHODS: Data of elderly patients with urosepsis were extracted from the Medical Information Mart for Intensive Care (MIMIC) IV 2.2 database. Patients were randomly divided into training and validation cohorts. A predictive nomogram model was constructed from the training set using logistic regression analysis, followed by internal validation and sensitivity analysis. RESULTS: This study included 1,251 patients. LASSO regression analysis revealed that the Glasgow Coma Scale (GCS) score, red cell distribution width (RDW), white blood count (WBC), and invasive ventilation were independent risk factors identified from a total of 43 variables studied. We then created and verified a nomogram. The area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA) of the nomogram were superior to those of the traditional SAPS-II, APACHE-II, and SOFA scoring systems. The Hosmer-Lemeshow test results and calibration curves suggested good nomogram calibration. The IDI and NRI values showed that our nomogram scoring tool performed better than the other scoring systems. The DCA curves showed good clinical applicability of the nomogram. CONCLUSIONS: The nomogram constructed in this study is a convenient tool for accurately predicting in-hospital mortality in elderly patients with urosepsis in ICU. Improving the treatment strategies for factors related to the model could improve the in-hospital survival rates of these patients.

Breaking the Activity-Selectivity Trade-off for CH4-to-C2H6 Photoconversion.

Photocatalytic conversion of methane (CH4) to ethane (C2H6) has attracted extensive attention from academia and industry. Typically, the traditional oxidative coupling of CH4 (OCM) reaches a high C2H6 productivity, yet the inevitable overoxidation limits the target product selectivity. Although the traditional nonoxidative coupling of CH4 (NOCM) can improve the product selectivity, it still encounters unsatisfied activity, arising from being thermodynamically unfavorable. To break the activity-selectivity trade-off, we propose a conceptually new mechanism of H2O2-triggered CH4 coupling, where the H2O2-derived ·OH radicals are rapidly consumed for activating CH4 into ·CH3 radicals exothermically, which bypasses the endothermic steps of the direct CH4 activation by photoholes and the interaction between ·CH3 and ·OH radicals, affirmed by in situ characterization techniques, femtosecond transient absorption spectroscopy, and density-functional theory calculation. By this pathway, the designed Au-WO3 nanosheets achieve unprecedented C2H6 productivity of 76.3 mol molAu-1 h-1 with 95.2% selectivity, and TON of 1542.7 (TOF = 77.1 h-1) in a self-designed flow reactor, outperforming previously reported photocatalysts regardless of OCM and NOCM pathways. Also, under outdoor natural sunlight irradiation, the Au-WO3 nanosheets exhibit similar activity and selectivity toward C2H6 production, showing the possibility for practical applications. Interestingly, this strategy can be applied to other various photocatalysts (Au-WO3, Au-TiO2, Au-CeO2, Pd-WO3, and Ag-WO3), showing a certain universality. It is expected that the proposed mechanism adds another layer to our understanding of CH4-to-C2H6 conversion.