A study on the determination of the metabolites of 2,4,6-Trinitrotoluene using a dual-drift tube ion mobility spectrometer.

2,4,6-Trinitrotoluene (TNT) and its four metabolites, namely 2-ADNT, 4-ADNT, 2,4-DANT, and 2,6-DANT, are highly toxic substances. These metabolites also serve as biomarkers for assessing the health of individuals exposed to TNT. In this study, a homemade DDT-IMS apparatus was utilized to detect these metabolites. Under negative detection mode, the drift times of 2-ADNT and 4-ADNT showed subtle shifts within a drift tube temperature range of 100 °C-120 °C, aiding in their differentiation. In positive detection mode for 2,4-DANT and 2,6-DANT, significant variations were observed in both the number and drift time of their positive product ions across a drift tube temperature range of 80 °C-120 °C. Consequently, optimal analytical performance for these metabolites was achieved at approximately 100 °C. Evaluation of the instrumental response during the measurement of the four metabolites in both positive and negative modes revealed that negative detection mode offered greater advantages of detecting these compounds. The working ranges for measuring the four metabolites spanned two orders of magnitude, with detection limits for each metabolite nearly below 1 ng. Notably, clear identification of the signals for these metabolites was achieved even when samples were mixed in urine, highlighting the ability of the DDT-IMS in detecting TNT metabolites. The developed DDT-IMS detection method has significant potential for enhancing environmental risk assessment and biological hazard evaluation, particularly in relation to human exposure to TNT.

Association of polychlorinated biphenyls with vitamin D among rural Chinese adults with normal glycaemia and type 2 diabetes mellitus.

BACKGROUND: Endocrine function in patients with type 2 diabetes (T2DM) typically differs from those with normal glucose tolerance (NGT). However, few epidemiologic studies have explored how these differences impact the association between exposure to polychlorinated biphenyls (PCBs) and vitamin D levels. METHODS: This study included 1,705 subjects aged 18-79 years from the Henan Rural Cohort [887 NGT and 818 T2DM]. Linear regression was applied to evaluate the associations between PCB exposure and vitamin D levels. Quantile g-computation regression (QG) and Bayesian kernel machine regression (BKMR) were applied to evaluate the impact of PCB mixtures on vitamin D levels. Interaction effects of ΣPCBs with HOMA2-%ß and HOMA2-IR on vitamin D levels were assessed. RESULTS: Plasma ΣPCBs was positively associated with 25(OH)D2 in the NGT group (ß = 0.060, 95% CI: 0.028, 0.092). Conversely, in T2DM group, ΣPCBs was negatively associated with 25(OH)D3 and 25(OH)D (ß = -0.049, 95% CI: -0.072, -0.026; ß = -0.043, 95% CI: -0.063, -0.023). Similarly, both QG and BKMR analysis revealed a negative association between PCB mixture exposure and vitamin D levels in the T2DM group, contrary to the results observed in the NGT groups. Furthermore, the negative association of ΣPCBs with 25(OH)D2 and 25(OH)D disappeared or changed to a positive association with the increase of HOMA2-%ß levels. CONCLUSIONS: These findings suggest that decreased ß cell function may exacerbate the negative effects of PCB exposure on vitamin D levels. Recognizing T2DM patients' sensitivity to PCBs is vital for protecting chronic disease health.

Molecular mechanisms underlying the neural correlates of working memory.

BACKGROUND: Working memory (WM), a core component of executive functions, relies on a dedicated brain system that maintains and stores information in the short term. While extensive neuroimaging research has identified a distributed set of neural substrates relevant to WM, their underlying molecular mechanisms remain enigmatic. This study investigated the neural correlates of WM as well as their underlying molecular mechanisms. RESULTS: Our voxel-wise analyses of resting-state functional MRI data from 502 healthy young adults showed that better WM performance (higher accuracy and shorter reaction time of the 3-back task) was associated with lower functional connectivity density (FCD) in the left inferior temporal gyrus and higher FCD in the left anterior cingulate cortex. A combination of transcriptome-neuroimaging spatial correlation and the ensemble-based gene category enrichment analysis revealed that the identified neural correlates of WM were associated with expression of diverse gene categories involving important cortical components and their biological processes as well as sodium channels. Cross-region spatial correlation analyses demonstrated significant associations between the neural correlates of WM and a range of neurotransmitters including dopamine, glutamate, serotonin, and acetylcholine. CONCLUSIONS: These findings may help to shed light on the molecular mechanisms underlying the neural correlates of WM.

Effects of a back-assist exosuit in lab-based approximations of construction tasks performed by novices and experienced construction workers.

Passive back-assist exosuits may be beneficial for construction workers, but few evaluations have been conducted with actual workers and construction-relevant tasks. This paper presents a laboratory study of the HeroWear Apex exosuit with 35 participants: 15 with significant construction experience and 20 without it. Participants completed several approximations of brief construction tasks (lifting, carrying, raising boards) and three 3-min tasks (hunched standing, kneeling, hunched walking with a nail gun) with and without the exosuit. During brief tasks, erector spinae electromyograms were reduced in all tasks (Cohen's d up to -0.58), kinematics suggested load shifting from the back to the legs, and the exosuit was perceived as helpful. During 3-min tasks, the exosuit was perceived as helpful in all tasks, but only reduced erector spinae electromyograms during kneeling. Thus, the exosuit may benefit workers during several construction-related tasks, though objective benefits could not be shown in 3-min standing or walking.

This study explored how a passive back-assist exosuit affects back muscle activity and kinematics in lab-based approximations of construction tasks performed by both novices and experienced construction workers. Quantitative and qualitative results indicated potential benefits in several brief load lifting and carrying tasks, but not during 3-min standing or walking.

The role of the gut microbiota in neurodegenerative diseases targeting metabolism.

In recent years, the incidence of neurodegenerative diseases (NDs) has gradually increased over the past decades due to the rapid aging of the global population. Traditional research has had difficulty explaining the relationship between its etiology and unhealthy lifestyle and diets. Emerging evidence had proved that the pathogenesis of neurodegenerative diseases may be related to changes of the gut microbiota's composition. Metabolism of gut microbiota has insidious and far-reaching effects on neurodegenerative diseases and provides new directions for disease intervention. Here, we delineated the basic relationship between gut microbiota and neurodegenerative diseases, highlighting the metabolism of gut microbiota in neurodegenerative diseases and also focusing on treatments for NDs based on gut microbiota. Our review may provide novel insights for neurodegeneration and approach a broadly applicable basis for the clinical therapies for neurodegenerative diseases.

Effect of Ginkgo tablets on the pharmacokinetics of metoprolol in rats: liquid chromatography-tandem mass spectrometry-based study.

OBJECTIVES: This study aimed to assess the interaction between metoprolol and Ginkgo tablets during their co-administration to provide a reference for clinical prescribing. METHODS: The co-administration of metoprolol (20 mg/kg) and Ginkgo tablets (2.4 mg/kg) was conducted in adult Sprague Dawley (SD) rats (n = 8). An optimized liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the analysis of plasma metoprolol to evaluate its pharmacokinetics. In vitro, the rat liver microsomes were employed to assess the effect of Ginkgo tablets on the metabolic stability of metoprolol and the activity of Cytochrome P450 2D6 (CYP2D6). RESULTS: The developed LC-MS/MS method was demonstrated of high sensitivity, accuracy, and precision. When co-administered with Ginkgo tablets, it increased the area under the curve (AUC, 59.01 ± 10.11 vs. 39.19 ± 10.21 µg/mL × min), the maximum plasma concentration (Cmax, 461.72 ± 44.64 vs. 276.35 ± 118.09 ng/mL), and the half-life (t1/2, 302.83 ± 91.52 vs. 262.34 ± 111.12 min) of metoprolol in rats and reduced the clearance rate (0.346 ± 0.057 vs. 0.539 ± 0.145 L/min/kg). In vitro, Ginkgo tablets improved the metabolic stability of metoprolol and suppressed the activity of CYP2D6 in a concentration-dependent manner with the IC50 value of 11.17 µM. CONCLUSION: Co-administration of metoprolol with Ginkgo tablets resulted in increasing its systemic exposure through inhibiting CYP2D6 activity.

Optimizing the combination of chemotherapeutic drugs along with radiotherapy for extranodal NK/T-cell lymphoma.

Background: Extranodal natural killer/T-cell lymphoma (ENKTCL) has a unique treatment principle. However, the optimal combination of drugs along with radiotherapy (RT) is unknown. Design: Retrospective cohort study. Objectives: We screened multiple drug combinations to identify the most efficacious therapeutic combinations. Methods: We reviewed 3105 patients who received 40 chemotherapy regimens with different combinations of 9 drug classes and/or RT. Least absolute shrinkage and selection operator and multivariable Cox regression analyses were used to screen efficacious single drugs and identify optimal combinations for overall survival (OS). Inverse probability of treatment weighting (IPTW) and multivariable analyses were used to compare survival between treatment regimens. Results: Screening and validation revealed RT, asparaginase (ASP), and gemcitabine (GEM) to be the most efficacious single modality/drug. RT remained an important component of first-line treatment, whereas ASP was a fundamental drug of non-anthracycline (ANT)-based regimens. Addition of RT to non-ANT-based or ASP/GEM-based regimens, or addition of an ASP-drug into ANT-based or GEM/platinum-based regimens, improved 5-year OS significantly. Use of ASP/GEM-based regimens was associated with significantly higher 5-year OS (79.9%) compared with ASP/ANT-based (69.2%, p = 0.001), ASP/methotrexate-based (63.5%, p = 0.011), or ASP/not otherwise specified-based (63.2%, p < 0.001) regimens. The survival benefit of ASP/GEM-based regimens over other ASP-based regimens was substantial across risk-stratified and advanced-stage subgroups. The survival benefits of a combination of RT, ASP, and GEM were consistent after adjustment for confounding factors by IPTW. Conclusion: These results suggest that combining ASP/GEM with RT for ENKTCL is an efficacious and feasible therapeutic option and provides a rationale and strategy for developing combination therapies.

Immunocytes do not mediate food intake and the causal relationship with allergic rhinitis: a comprehensive Mendelian randomization.

Background: Observational studies indicate a correlation between food intake and allergic rhinitis. The potential interplay between the immune system and allergic rhinitis might contribute causally to both food intake and allergic rhinitis, providing promising therapeutic avenues. However, elucidating the causal relationship and immune-mediated mechanisms between food intake and allergic rhinitis remains a pending task. Methods: We utilized a two-sample Mendelian randomization (MR) methodology to explore the causal relationship between food intake and allergic rhinitis. Furthermore, we investigated the potential causal relationship of immune cell signals with allergic rhinitis, as well as the potential causal relationship between food intake and immune cell signals. Moreover, employing both two-step Mendelian randomization and multivariable Mendelian randomization, we delved into the mediating role of immune cell signals in the causal relationship between food intake and allergic rhinitis. Leveraging publicly accessible genetic datasets, our analysis encompassed 903 traits, comprising 171 food intake features, 731 immune cell features, and one trait related to allergic rhinitis. Result: We found causal relationships between seven types of food intake and allergic rhinitis, as well as between 30 immune cell phenotypes and allergic rhinitis. Furthermore, our two-step Mendelian randomization analysis and multivariable Mendelian randomization analysis indicate that immune cells do not mediate the causal relationship between food intake and allergic rhinitis. Conclusion: To the best of our knowledge, we are the first to incorporate a large-scale dataset integrating immune cell features, food intake features, and allergic rhinitis into Mendelian randomization analysis. Our research findings indicate that there are causal relationships between six types of food intake and allergic rhinitis, as well as between 30 immune cell phenotypes and allergic rhinitis. Additionally, immune cells do not mediate these relationships.

TRIM21 induces selective autophagic degradation of c-Myc and sensitizes regorafenib therapy in colorectal cancer.

Kirsten rat sarcoma virus (KRAS) mutation is associated with malignant tumor transformation and drug resistance. However, the development of clinically effective targeted therapies for KRAS-mutant cancer has proven to be a formidable challenge. Here, we report that tripartite motif-containing protein 21 (TRIM21) functions as a target of extracellular signal-regulated kinase 2 (ERK2) in KRAS-mutant colorectal cancer (CRC), contributing to regorafenib therapy resistance. Mechanistically, TRIM21 directly interacts with and ubiquitinates v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) at lysine 148 (K148) via K63-linkage, enabling c-Myc to be targeted to the autophagy machinery for degradation, ultimately resulting in the downregulation of enolase 2 expression and inhibition of glycolysis. However, mutant KRAS (KRAS/MT)-driven mitogen-activated protein kinase (MAPK) signaling leads to the phosphorylation of TRIM21 (p-TRIM21) at Threonine 396 (T396) by ERK2, disrupting the interaction between TRIM21 and c-Myc and thereby preventing c-Myc from targeting autophagy for degradation. This enhances glycolysis and contributes to regorafenib resistance. Clinically, high p-TRIM21 (T396) is associated with an unfavorable prognosis. Targeting TRIM21 to disrupt KRAS/MT-driven phosphorylation using the antidepressant vilazodone shows potential for enhancing the efficacy of regorafenib in treating KRAS-mutant CRC in preclinical models. These findings are instrumental for KRAS-mutant CRC treatment aiming at activating TRIM21-mediated selective autophagic degradation of c-Myc.

Wafer-Scale Freestanding Monocrystalline Chalcogenide Membranes by Strain-Assisted Epitaxy and Spalling.

Monocrystalline chalcogenide thin films in freestanding forms are very much needed in advanced electronics such as flexible phase change memories (PCMs). However, they are difficult to manufacture in a scalable manner due to their growth and delamination challenges. Herein, we report a viable strategy for a wafer-scale epitaxial growth of monocrystalline germanium telluride (GeTe) membranes and their deterministic integrations onto flexible substrates. GeTe films are epitaxially grown on Ge wafers via a tellurization reaction accompanying a formation of confined dislocations along GeTe/Ge interfaces. The as-grown films are subsequently delaminated off the wafers, preserving their wafer-scale structural integrity, enabled by a strain-engineered spalling method that leverages the stress-concentrated dislocations. The versatility of this wafer epitaxy and delamination approach is further expanded to manufacture other chalcogenide membranes, such as germanium selenide (GeSe). These materials exhibit phase change-driven electrical switching characteristics even in freestanding forms, opening up unprecedented opportunities for flexible PCM technologies.

ER-mitochondria contact sites regulate hepatic lipogenesis via Ip3r-Grp75-Vdac complex recruiting Seipin.

BACKGROUND: Mitochondria and endoplasmic reticulum (ER) contact sites (MERCS) constitute a functional communication platform for ER and mitochondria, and they play a crucial role in the lipid homeostasis of the liver. However, it remains unclear about the exact effects of MERCs on the neutral lipid synthesis of the liver. METHODS: In this study, the role and mechanism of MERCS in palmitic acid (PA)-induced neutral lipid imbalance in the liver was explored by constructing a lipid metabolism animal model based on yellow catfish. Given that the structural integrity of MERCS cannot be disrupted by the si-mitochondrial calcium uniporter (si-mcu), the MERCS-mediated Ca2+ signaling in isolated hepatocytes was intercepted by transfecting them with si-mcu in some in vitro experiments. RESULTS: The key findings were: (1) Hepatocellular MERCs sub-proteome analysis confirmed that, via activating Ip3r-Grp75-voltage-dependent anion channel (Vdac) complexes, excessive dietary PA intake enhanced hepatic MERCs. (2) Dietary PA intake caused hepatic neutral lipid deposition by MERCs recruiting Seipin, which promoted lipid droplet biogenesis. (3) Our findings provide the first proof that MERCs recruited Seipin and controlled hepatic lipid homeostasis, depending on Ip3r-Grp75-Vdac-controlled Ca2+ signaling, apart from MERCs's structural integrity. Noteworthy, our results also confirmed these mechanisms are conservative from fish to mammals. CONCLUSIONS: The findings of this study provide a new insight into the regulatory role of MERCS-recruited SEIPIN in hepatic lipid synthesis via Ip3r-Grp75-Vdac complex-mediated Ca2+ signaling, highlighting the critical contribution of MERCS in hepatic lipid homeostasis.

A transcriptomic analysis of dental pulp stem cell senescence in vitro.

BACKGROUND/PURPOSE: The use of human dental pulp stem cells (hDPSCs) as autologous stem cells for tissue repair and regenerative techniques is a significant area of global research. The objective of this study was to investigate the effects of long-term in vitro culture on the multidifferentiation potential of hDPSCs and the potential molecular mechanisms involved. MATERIALS AND METHODS: The tissue block method was used to extract hDPSCs from orthodontic-minus-extraction patients, which were then expanded and cultured in vitro for 12 generations. Stem cells from passages three, six, nine, and twelve were selected. Flow cytometry was used to detect the expression of stem cell surface markers, and CCK-8 was used to assess cell proliferation. ß-Galactosidase staining was employed to detect cellular senescence, Alizarin Red S staining to assess osteogenic potential, and Oil Red O staining to evaluate lipogenic capacity. RNA sequencing (RNA-seq) was conducted to identify differentially expressed genes in DPSCs and investigate their potential mechanisms. RESULTS: With increasing passage numbers, pulp stem cells showed an increase in senescence and a decrease in proliferative capacity and osteogenic-lipogenic multidifferentiation potential. The expression of stem cell surface markers CD34 and CD45 was stable, whereas the expression of CD73, CD90, and CD105 decreased with increasing passages. According to the RNA-seq analysis, the differentially expressed genes CFH, WNT16, HSD17B2, IDI1, and COL5A3 may be associated with stem cell senescence. CONCLUSION: Increased in vitro expansion induced cellular senescence in pulp stem cells, which resulted in a reduction in their proliferative capacity and osteogenic-lipogenic differentiation potential. The differential expression of genes such as CFH, WNT16, HSD17B2, IDI1, and COL5A3 may represent a potential mechanism for the induction of cellular senescence in pulp stem cells.

Akt inhibitors prevent CyHV-2 infection in vitro.

Cyprinid herpesvirus 2 (CyHV-2) is a double-stranded DNA virus that infects goldfish (Carassius auratus) and crucian carp (C. carassius), resulting in substantial mortality rates and significant epidemiological implications. To gain deeper insights into CyHV-2-host interactions and identify potential therapeutic targets, quantitative proteomics analysis was conducted on CyHV-2-infected Ryukin goldfish fin (RyuF-2) cells. Our findings revealed significant alterations in the expression of proteins associated with the PI3K/Akt signaling pathway, which were up-regulated upon viral infection. Building on these observations, we employed LY294002, a specific inhibitor of PI3K, to investigate its impact on viral replication by inhibiting the PI3K/Akt pathway in GiCF cell line derived from the caudal fin of Carassius auratus gibelio (Bloch). Our results demonstrated the inhibition of both CyHV-2 replication and Akt phosphorylation within this pathway. Quercetin, a plant-derived analogue of LY294002, was further investigated for its anti-CyHV-2 effects in vitro as well as its underlying mechanism. The results suggested that quercetin exhibits antiviral properties against CyHV-2 and may exert its effects through mechanisms similar to those observed with LY294002. Given that aquaculture water serves as a vector for aquaculture viral diseases and the release of chemical compounds can lead to pollution of the aquatic environment, our study shifted focus to crude extracts obtained from plants. We confirmed crude quercetin extract derived from Cuminum anisum has antiviral activity against CyHV-2 in vitro. Therefore, based on our identification of the involvement of PI3K/Akt signaling pathway in CyHV-2 replication, along with verification of its antiviral mechanism using LY294002, we propose natural dietary quercetin as a promising candidate for development into a novel anti-CyHV-2 drug.

Three hepcidins from the spotted knifejaw (Oplegnathus punctatus) promote antimicrobial activity via TLR/NFκB pathway.

Hepcidin belongs to a class of small cationic antimicrobial peptides rich in cysteine. It is synthesized by liver and is widely involved in host antimicrobial, antiviral and other immune responses. We identified and characterized three hepcidin genes (OpHep1, OpHep2 and OpHep3) in spotted knifejaw. All the OpHeps shared high identities with hepcidins in other teleost, containing alpha helix and ß-sheets. Three OpHeps were all detected in healthy tissues, with the abundant expression in liver. They were significantly increased after Vibrio harveyi infection in the six immune-relevant tissues (liver, kidney, spleen, gill, skin and intestine). OpHeps knockdown in spotted knifejaw liver cells affected the mRNA levels of inflammation-related genes, including il1ß, il6, il8, and nfκb. Further, the recombinant hepcidin proteins were effective in suppressing the growth of both Gram-negative and Gram-positive bacteria. To identify the function of OpHeps in vivo, we performed the overexpression of three OpHeps in zebrafish, and found OpHeps could significantly induce immune-related genes expression in transgenic zebrafish, including myd88, il10, il21, il16, tlr1, tlr3 and lysozyme. When infected with V. harveyi, OpHeps transgenic zebrafishes had a higher survival rate than wild-type zebrafishes. The expression of myd88, il10, il8, il1ß, nfκb and lysozyme were all significantly up-regulated in transgenic fishes during bacterial infection. In summary, these results indicated that hepcidin could protect fish fight against pathogen through TLR/NFκB signaling cascade and Lysozyme. Three OpHeps would be potential targets for prevention of bacterial infections in aquaculture industry of spotted knifejaw, which provided a new idea for the molecular breeding of fish disease resistance.

Lipid-lowering drugs and risk of rapid renal function decline: a mendelian randomization study.

BACKGROUND: Chronic kidney disease (CKD) patients face the risk of rapid kidney function decline leading to adverse outcomes like dialysis and mortality. Lipid metabolism might contribute to acute kidney function decline in CKD patients. Here, we utilized the Mendelian Randomization approach to investigate potential causal relationships between drug target-mediated lipid phenotypes and rapid renal function decline. METHODS: In this study, we utilized two methodologies: summarized data-based Mendelian randomization (SMR) and inverse variance-weighted Mendelian randomization (IVW-MR), to approximate exposure to lipid-lowering drugs. This entailed leveraging expression quantitative trait loci (eQTL) for drug target genes and genetic variants proximal to drug target gene regions, which encode proteins associated with low-density lipoprotein (LDL) cholesterol, as identified in genome-wide association studies. The objective was to investigate causal associations with the progression of rapid kidney function decline. RESULTS: The SMR analysis revealed a potential association between high expression of PCSK9 and rapid kidney function decline (OR = 1.11, 95% CI= [1.001-1.23]; p = 0.044). Similarly, IVW-MR analysis demonstrated a negative association between LDL cholesterol mediated by HMGCR and kidney function decline (OR = 0.74, 95% CI = 0.60-0.90; p = 0.003). CONCLUSION: Genetically predicted inhibition of HMGCR is linked with the progression of kidney function decline, while genetically predicted PCSK9 inhibition is negatively associated with kidney function decline. Future research should incorporate clinical trials to validate the relevance of PCSK9 in preventing kidney function decline.

3D bioprinted in vitro epilepsy models for pharmacological evaluation in temporal lobe epilepsy.

This study introduces a novel in vitro model for intractable temporal lobe epilepsy (TLE) utilizing 3D bioprinting technology, aiming to replicate the complex neurobiological characteristics of TLE more accurately . Primary neural cell constructs were fabricated and subjected to epileptiform-inducing conditions, fostering synaptic proliferation and neuronal loss. Systematically electrophysiological and immunofluorescent analyses indicated that significant synaptic connectivity and sustained epileptiform activities within the constructs akin to those observed in human epilepsy models. Notably, the model responded to treatments with phenytoin and tetrodotoxin, illustrating its potential utility in drug response kinetics studies. Furthermore, we performed drug permeability simulations using COMSOL Multiphysics to analyze the diffusion characteristics of these drugs within the constructs. These results confirm that our 3D bioprinted neural model provides a physiologically relevant and ethically sustainable platform, which is beneficial for studying TLE mechanisms and developing therapeutic strategies with high accuracy and clinical relevance. .

Early prediction of sepsis in emergency department patients using various methods and scoring systems.

BACKGROUND: Early recognition of sepsis, a common life-threatening condition in intensive care units (ICUs), is beneficial for improving patient outcomes. However, most sepsis prediction models were trained and assessed in the ICU, which might not apply to emergency department (ED) settings. AIMS: To establish an early predictive model based on basic but essential information collected upon ED presentation for the follow-up diagnosis of sepsis observed in the ICU. STUDY DESIGN: This study developed and validated a reliable model of sepsis prediction among ED patients by comparing 10 different methods based on retrospective electronic health record data from the MIMIC-IV database. In-ICU sepsis was identified as the primary outcome. The potential predictors encompassed baseline demographics, vital signs, pain scale, chief complaints and Emergency Severity Index (ESI). 80% and 20% of the total of 425 737 ED visit records were randomly selected for the train set and the test set for model development and validation, respectively. RESULTS: Among the methods evaluated, XGBoost demonstrated an optimal predictive performance with an area under the curve (AUC) of 0.90 (95% CI: 0.90-0.91). Logistic regression exhibited a comparable predictive ability to XGBoost, with an AUC of 0.89 (95% CI: 0.89-0.90), along with a sensitivity and specificity of 85% (95% CI: 0.83-0.86) and 78% (95% CI: 0.77-0.80), respectively. Neither of the five commonly used severity scoring systems demonstrated satisfactory performance for sepsis prediction. The predictive ability of using ESI as the sole predictor (AUC: 0.79, 95% CI: 0.78-0.80) was also inferior to the model integrating ESI and other basic information. CONCLUSIONS: The use of ESI combined with basic clinical information upon ED presentation accurately predicted sepsis among ED patients, strengthening its application in ED. RELEVANCE TO CLINICAL PRACTICE: The proposed model may assist nurses in risk stratification management and prioritize interventions for potential sepsis patients, even in low-resource settings.

Diallyl disulfide alleviates hepatic steatosis by the conservative mechanism from fish to tetrapod: Augment Mfn2/Atgl-Mediated lipid droplet-mitochondria coupling.

Despite increasing evidences has highlighted the importance of mitochondria-lipid droplet (LD) coupling in maintaining lipid homeostasis, little progress in unraveling the role of mitochondria-LD coupling in hepatic lipid metabolism has been made. Additionally, diallyl disulfide (DADS), a garlic organosulfur compound, has been proposed to prevent hepatic steatosis; however, no studies have focused on the molecular mechanism to date. To address these gaps, this study investigated the systemic control mechanisms of mitochondria-LD coupling regulating hepatic lipid metabolism, and also explored their function in the process of DADS alleviating hepatic steatosis. To this end, an animal model of lipid metabolism, yellow catfish Pelteobagrus fulvidraco were fed four different diets (control, high-fat, DADS and high-fat + DADS diet) in vivo for 8 weeks; in vitro experiments were conducted to inhibit Mfn2/Atgl-mediated mitochondria-LD coupling in isolated hepatocytes. The key findings are: (1) the activations of hepatic LDs lipolysis and mitochondrial ß-oxidation are likely the major drivers for DADS alleviating hepatic steatosis; (2) the underlying mechanism is that DADS enhances mitochondria-LD coupling by promoting the interaction between mitochondrion-localized Mfn2 with LD-localized Atgl, which facilitates the hepatic LDs lipolysis and the transfer of fatty acids (FAs) from LDs to mitochondria for subsequent ß-oxidation; (3) Mfn2-mediated mitochondrial fusion facilitates mitochondria to form more PDM, which possess higher ß-oxidation capacity in hepatocytes. Significantly, the present research unveils a previously undisclosed mechanism by which Mfn2/Atgl-mitochondria-LD coupling relieves hepatic LDs accumulation, which is a conserved strategy from fish to tetrapod. This study provides another dimension for mitochondria-LD coupling and opens up new avenues for the therapeutic interventions in hepatic steatosis.

Identification of Genetic Associations of IDH2, LDHA, and LDHB Genes with Milk Yield and Compositions in Dairy Cows.

Previous study revealed that isocitrate dehydrogenase (NADP (+)) 2, mitochondrial (IDH2), lactate dehydrogenase A (LDHA), and lactate dehydrogenase B (LDHB) genes were significantly differentially expressed in liver tissues of Holstein cows among different lactation periods and associated with lipid and protein metabolism; hence, they were considered as candidates for milk production traits. Herein, the genetic effects of the three genes on milk yield, fat, and protein traits were studied by association analysis using 926 Chinese Holstein cows from 45 sire families. As a result, five single nucleotide polymorphisms (SNPs) in IDH2, one in LDHA, and three in LDHB were identified by re-sequencing, and subsequently, they were genotyped in 926 Chinese Holstein cows by genotyping by target sequencing (GBTS). With the animal model, single-locus association analysis revealed that four SNPs in IDH2 and one SNP in LDHA were significantly associated with milk, fat, and protein yields (p ≤ 0.0491), and three SNPs in LDHB were associated with milk yield, milk fat yield, and fat percentage (p ≤ 0.0285). Further, four IDH2 SNPs were found to form a haplotype block significantly associated with milk yield, fat yield, protein yield, and protein percentage (p ≤ 0.0249). In addition, functional predictions indicated that one SNP in LDHA, g.26304153G>A, may affect transcription factor binding and two SNPs, g.88544541A>G and g.88556310T>C could alter LDHB mRNA secondary structure. In summary, this study profiled the significant genetic effects of IDH2, LDHA, and LDHB on milk yield and composition traits and provided referable genetic markers for genomic selection programs in dairy cattle.

Prevalence and association of uncorrected refractive error among Chinese adolescents: a cross-sectional study.

BACKGROUND: Uncorrected refractive error (URE) is one of the main causes of visual impairments. URE may reduce interaction and learning in the classroom, leading to social isolation, irreversible amblyopia, lack of external knowledge, and restrictions on education and employment opportunities. Our aim was to investigate the prevalence and related factors of URE in adolescents using epidemiological surveys and questionnaire surveys related to lifestyle habits. METHODS: A cross-sectional school-based study was conducted in Nantong, China, including adolescents 12-19 years of age from 16 schools. URE was defined as presenting visual acuity worse than 6/12 and improving to ≥ 1 lines after correction in either eye. Univariate and multivariate logistic regression analyses were used to investigate specific correlations between URE and related lifestyle parameters. Non-cycloplegic autorefraction was assessed for each adolescent. RESULTS: A total of 2,910 adolescents were analyzed, of which 50.3% (n = 1,465) were male, and 49.7% (n = 1,445) were female. The mean age was 15.23 ± 1.77 years. The overall prevalence of URE was 23.7%. The total prevalence of REC and eREC was 85.1% and 71.7%, respectively, and both of them showed an increasing trend with age (Ptrend = 0.018 and Ptrend = 0.019, respectively). A higher prevalence of URE was related to myopia, anisometropia, and increased daily use of electronic products. Timely visual examination by medical institutions, more extracurricular homework, and older age were protective factors for URE. Among the 689 adolescents with URE, 362 (52.5%) did not receive any refractive correction, and 327 (47.5%) used corrected glasses. CONCLUSION: URE was highly prevalent among adolescents in China. Myopia was the most important risk factor for URE. The impact of anisometropia and increased daily use of electronic devices on URE was significant. Timely visual examinations by medical institutions served as an effective protective factor against URE. Further research on adjusting intervention strategies is therefore needed to eliminate preventable visual impairments.