Mutations in CLCN6 as a Novel Genetic Cause of Neuronal Ceroid Lipofuscinosis in a Murine Model.

OBJECTIVE: The aim of this study was to explore the pathogenesis of CLCN6-related disease and to assess whether its Cl-/H+-exchange activity is crucial for the biological role of ClC-6. METHODS: We performed whole-exome sequencing on a girl with development delay, intractable epilepsy, behavioral abnormities, retinal dysfunction, progressive brain atrophy, suggestive of neuronal ceroid lipofuscinoses (NCLs). We generated and analyzed the first knock-in mouse model of a patient variant (p.E200A) and compared it with a Clcn6-/- mouse model. Additional functional tests were performed with heterologous expression of mutant ClC-6. RESULTS: We identified a de novo heterozygous p.E200A variant in the proband. Expression of disease-causing ClC-6E200A or ClC-6Y553C mutants blocked autophagic flux and activated transcription factors EB (TFEB) and E3 (TFE3), leading to autophagic vesicle and cholesterol accumulation. Such alterations were absent with a transport-deficient ClC-6E267A mutant. Clcn6E200A/+ mice developed severe neurodegeneration with typical features of NCLs. Mutant ClC-6E200A, but not loss of ClC-6 in Clcn6-/- mice, increased lysosomal biogenesis by suppressing mTORC1-TFEB signaling, blocked autophagic flux through impairing lysosomal function, and increased apoptosis. Carbohydrate and lipid deposits accumulated in Clcn6E200A/+ brain, while only lipid storage was found in Clcn6-/- brain. Lysosome dysfunction, autophagy defects, and gliosis were early pathogenic events preceding neuron loss. INTERPRETATION: CLCN6 is a novel genetic cause of NCLs, highlighting the importance of considering CLCN6 mutations in the diagnostic workup for molecularly undefined forms of NCLs. Uncoupling of Cl- transport from H+ countertransport in the E200A mutant has a dominant effect on the autophagic/lysosomal pathway. ANN NEUROL 2024;96:608-624.

Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. METHODS: This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. RESULTS: Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 28 (46.7%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. CLINICALTRIALS: gov NCT04169672.

Long-term survivals of immune checkpoint inhibitors as neoadjuvant and adjuvant therapy in dMMR/MSI-H colorectal and gastric cancers.

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Streak tube imaging lidar with kilohertz laser pulses and few-photons detection capability.

Lidar using active light illumination is capable of capturing depth and reflectivity information of target scenes. Among various technologies, streak tube imaging lidar (STIL) has garnered significant attention due to its high resolution and excellent precision. The echo signals of a STIL system using single laser pulse are often overwhelmed by noise in complex environments, making it difficult to discern the range of the target. By combining high-frequency laser pulses with the repetitive sweep circuit, the STIL system enables efficient detection of few-photons signal in weak-light environments. Additionally, we have developed a robust algorithm for estimating the depth and reflectivity images of targets. The results demonstrate that this lidar system achieves a depth resolution better than 0.5 mm and a ranging accuracy of 95 um. Furthermore, the imaging of natural scenes also validates the exceptional 3D imaging capability of this system.

Ligand binding properties of three odorant-binding proteins in striped flea beetle Phyllotreta striolata towards two phthalate esters.

Odorant-binding proteins (OBPs) initiate insect olfactory perception and mediate specific binding and selection of odorants via uncertain binding mechanisms. We characterized the binding characteristics of four OBPs from the striped flea beetle Phyllotreta striolata (SFB), a major cruciferous crop pest. Tissue expression analysis revealed that the two ABPII OBPs (PstrOBP12 and PstrOBP19) were highly expressed mainly in the antenna, whereas the two minus-C OBPs (PstrOBP13 and PstrOBP16) showed a broad expression pattern. Competitive binding assays of cruciferous plant volatiles showed that PstrOBP12, PstrOBP16 and PstrOBP19 had very strong binding capacities for only two phthalate esters (Ki < 20 µM), and PstrOBP13 specifically bound to four aromatic volatiles (Ki < 11 µM). Fluorescence quenching assays displayed that two phthalate esters bound to three PstrOBPs via different quenching mechanisms. PstrOBP12/PstrOBP16-diisobutyl phthalate and PstrOBP19-bis(6-methylheptyl) phthalate followed static quenching, while PstrOBP12/PstrOBP16-bis(6-methylheptyl) phthalate and PstrOBP19-diisobutyl phthalate followed dynamic quenching. Homology modelling and molecular docking displayed that PstrOBP12-diisobutyl phthalate was driven by H-bonding and van der Waals interactions, while PstrOBP16-diisobutyl phthalate and PstrOBP19-bis(6-methylheptyl) phthalate followed hydrophobic interactions. Finally, behavioural activity analysis demonstrated that phthalate esters exhibited different behavioural activities of SFB at different doses, with low doses attracting and high doses repelling. Overall, we thus revealed the different binding properties of the three PstrOBPs to two phthalate esters, which was beneficial in shedding light on the ligand-binding mechanisms of OBPs.

Combination of transcriptome and Mendelian inheritance reveals novel prognostic biomarker of CTLA-4-related lncRNAs and protective role of nitrogen metabolism pathway in lung adenocarcinoma development.

OBJECTIVE: Since in the cancer setting, tumor cells may use cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to evade the immune system. This study aimed to identify CTLA-4-related long non-coding RNAs (lncRNAs) and assess their roles in lung adenocarcinoma (LUAD) development. METHODS: Clinical and genomic data were obtained from The Cancer Genome Atlas (TCGA), MSigDB and Gene Weaver. CTLA-4-related lncRNA-based gene signatures (CTLA4LncSigs) were identified using Cox regression, establishing a risk score model and an independent prognostic model. Enrichment analysis (GO/KEGG) was performed. Mendelian randomization (MR) analysis investigated the nitrogen metabolism and lung cancer relationship, with Bayesian weighted MR (BWMR) addressing uncertainties. Correlations with tumor microenvironment and drug sensitivity were explored. RESULTS: Nineteen CTLA4LncSigs significantly influenced LUAD prognosis. The risk score demonstrated independence as a prognostic factor. Functional analysis revealed lncRNAs' impact on nitrogen metabolism. MR and BWMR confirmed the protective role of the nitrogen metabolism pathway in lung cancer. CONCLUSION: Our study identifies CTLA-4-related lncRNAs associated with LUAD prognosis and uncovers a previously undiscovered protective role of the nitrogen metabolism pathway in combating LUAD development, providing new insights into potential therapeutic targets and prognostic biomarkers for this aggressive cancer subtype.

Associations of pyrethroid exposure with bone mineral density and osteopenia in adults.

INTRODUCTION: This study was to investigate the correlations between pyrethroid exposure and bone mineral density (BMD) and osteopenia. MATERIALS AND METHODS: This cross-sectional study included 1389 participants over 50 years of age drawn from the 2007-2010 and 2013-2014 National Health and Nutrition Examination Survey (NHANES). Three pyrethroid metabolites, 3-phenoxybenzoic acid (3-PBA), trans-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid (trans-DCCA), and 4-fluoro-3-phenoxybenzoic acid (4-F-3PBA) were used as indicators of pyrethroid exposure. Low BMD was defined as T-score < - 1.0, including osteopenia. Weighted multivariable linear regression analysis or logistic regression analysis was utilized to evaluate the correlation between pyrethroid exposure and BMD and low BMD. Bayesian kernel machine regression (BKMR) model was utilized to analyze the correlation between pyrethroids mixed exposure and low BMD. RESULTS: There were 648 (48.41%) patients with low BMD. In individual pyrethroid metabolite analysis, both tertile 2 and tertile 3 of trans-DCCA were negatively related to total femur, femur neck, and total spine BMD [coefficient (ß) = - 0.041 to - 0.028; all P < 0.05]. Both tertile 2 and tertile 3 of 4-F-3PBA were negatively related to total femur BMD (P < 0.05). Only tertile 2 [odds ratio (OR) = 1.63; 95% CI = 1.07, 2.48] and tertile 3 (OR = 1.65; 95% CI = 1.10, 2.50) of trans-DCCA was correlated with an increased risk of low BMD. The BKMR analysis indicated that there was a positive tendency between mixed pyrethroids exposure and low BMD. CONCLUSION: In conclusion, pyrethroids exposure was negatively correlated with BMD levels, and the associations of pyrethroids with BMD and low BMD varied by specific pyrethroids, pyrethroid concentrations, and bone sites.

Evaluation of the safety, immunogenicity and protective effect of an attenuated Pseudomonas plecoglossicida strain ΔgacS as the live vaccine for the large yellow croaker (Larimichthys crocea).

Pseudomonas plecoglossicida is one of most important pathogenic bacterial species in large yellow croaker and several other commercially valuable fish species. In our previous study, a GacS deficient mutant (ΔgacS) was constructed and its virulence showed substantially attenuated. In present study, the safety, immunogenicity and protective effect of the ΔgacS were evaluated in large yellow croaker as a live-attenuated vaccine candidate. It was shown that the ΔgacS strain exhibited good safety to large yellow croaker and there was no mortality or clinical symptoms observed in all fish that infected by ΔgacS strain with the doses range from 2×105～107 CFU per fish via intraperitoneal injection (IP) or immersion (IM), and almost all bacteria were cleaned up in the spleen of the fish at 14-day post infection. Specific antibodies could be detected at 7-day and 14-day post infection by direct agglutination method, and the valences of antibodies and bactericidal activities of the serum were significant increased with vaccination doses and vaccination time. Moreover, the expressions of some molecules and cytokines involved in specific immune responses were detected in the ΔgacS strain immunization group and control group. After challenged by the wild-type (WT) strain XSDHY-P, the relative percentage survival (RPS) showed highly correlated with the immunized dosage regardless of vaccination methods. It showed that the RPS of the IP groups were 39.47%, 57.89%, 71.05% with the immune dosage in a descending order, respectively, and the RPS of the IM groups were 26.31%, 36.84%, 76.31% with the immune dosage in a descending order, respectively. In summary, the ΔgacS strain exhibited safety and good protective effect to large yellow croaker and was a potential live vaccine candidate.

Cellular localization and potential ligands of a novel scavenger receptor class B/CD36 protein homolog (Pt-SRB2) identified in the marine crab, Portunustrituberculatus.

The scavenger receptor class B family proteins (SRB) are multiligand membrane receptor proteins. Herein, a novel SRB homolog (Pt-SRB2) was identified in Portunus trituberculatus. The open reading frame of Pt-SRB2 was predicted to encode 520 amino acid residues comprising a typical CD36 domain. Phylogenetic analysis showed that Pt-SRB2 distinctly clustered with the SRB homologs of most crustaceans and Drosophila but was separate from all vertebrate CD36/SRB. Semi-quantitative and Real-time quantitative PCR revealed that the abundance of Pt-SRB2 transcripts was the highest in hepatopancreas than in other tested tissues. Overexpressed Pt-SRB2 was distributed primarily in the cell membrane and cytoplasm of HEK293T or Drosophila Schneider 2 cells. In crab hemocytes, Pt-SRB2 was distributed primarily in the cell membrane by immunofluorescence staining. In addition, the immunofluorescence staining showed that green fluorescence signals were mainly located in the inner lumen membrane of the hepatopancreatic tubules. Moreover, solid-phase enzyme-linked immunosorbent assay revealed that rPt-SRB2-L exhibited relative high affinity with lipopolysaccharides, and relative moderate binding affinity with lipoteichoic acid or peptidoglycan. Of note, rPt-SRB2-L showed high binding affinity with eicosapentaenoic acid among a series of long-chain polyunsaturated fatty acids. Taken together, this study provided valuable data for understanding the functions of the crab CD36/SRB.

MolLoG: A Molecular Level Interpretability Model Bridging Local to Global for Predicting Drug Target Interactions.

Developing new pharmaceuticals is a costly and time-consuming endeavor fraught with significant safety risks. A critical aspect of drug research and disease therapy is discerning the existence of interactions between drugs and proteins. The evolution of deep learning (DL) in computer science has been remarkably aided in this regard in recent years. Yet, two challenges remain: (i) balancing the extraction of profound, local cohesive characteristics while warding off gradient disappearance and (ii) globally representing and understanding the interactions between the drug and target local attributes, which is vital for delivering molecular level insights indispensable to drug development. In response to these challenges, we propose a DL network structure, MolLoG, primarily comprising two modules: local feature encoders (LFE) and global interactive learning (GIL). Within the LFE module, graph convolution networks and leap blocks capture the local features of drug and protein molecules, respectively. The GIL module enables the efficient amalgamation of feature information, facilitating the global learning of feature structural semantics and procuring multihead attention weights for abstract features stemming from two modalities, providing biologically pertinent explanations for black-box results. Finally, predictive outcomes are achieved by decoding the unified representation via a multilayer perceptron. Our experimental analysis reveals that MolLoG outperforms several cutting-edge baselines across four data sets, delivering superior overall performance and providing satisfactory results when elucidating various facets of drug-target interaction predictions.

A novel method to select time-varying multivariate time series models for the surveillance of infectious diseases.

BACKGROUND: Describing the transmission dynamics of infectious diseases across different regions is crucial for effective disease surveillance. The multivariate time series (MTS) model has been widely adopted for constructing cross-regional infectious disease transmission networks due to its strengths in interpretability and predictive performance. Nevertheless, the assumption of constant parameters frequently disregards the dynamic shifts in disease transmission rates, thereby compromising the accuracy of early warnings. This study investigated the applicability of time-varying MTS models in multi-regional infectious disease monitoring and explored strategies for model selection. METHODS: This study focused on two prominent time-varying MTS models: the time-varying parameter-stochastic volatility-vector autoregression (TVP-SV-VAR) model and the time-varying VAR model using the generalized additive framework (tvvarGAM), and intended to explore and verify their applicable conditions for the surveillance of infectious diseases. For the first time, this study proposed the time delay coefficient and spatial sparsity indicators for model selection. These indicators quantify the temporal lags and spatial distribution of infectious disease data, respectively. Simulation study adopted from real-world infectious disease surveillance was carried out to compare model performances under various scenarios of spatio-temporal variation as well as random volatility. Meanwhile, we illustrated how the modelling process could help the surveillance of infectious diseases with an application to the influenza-like case in Sichuan Province, China. RESULTS: When the spatio-temporal variation was small (time delay coefficient: 0.1-0.2, spatial sparsity:0.1-0.3), the TVP-SV-VAR model was superior with smaller fitting residuals and standard errors of parameter estimation than those of the tvvarGAM model. In contrast, the tvvarGAM model was preferable when the spatio-temporal variation increased (time delay coefficient: 0.2-0.3, spatial sparsity: 0.6-0.9). CONCLUSION: This study emphasized the importance of considering spatio-temporal variations when selecting appropriate models for infectious disease surveillance. By incorporating our novel indicators-the time delay coefficient and spatial sparsity-into the model selection process, the study could enhance the accuracy and effectiveness of infectious disease monitoring efforts. This approach was not only valuable in the context of this study, but also has broader implications for improving time-varying MTS analyses in various applications.

Evaluating the adverse effects and mechanisms of nanomaterial exposure on longevity of C. elegans: A literature meta-analysis and bioinformatics analysis of multi-transcriptome data.

Exposure to large-size particulate air pollution (PM2.5 or PM10) has been reported to increase risks of aging-related diseases and human death, indicating the potential pro-aging effects of airborne nanomaterials with ultra-fine particle size (which have been widely applied in various fields). However, this hypothesis remains inconclusive. Here, a meta-analysis of 99 published literatures collected from electronic databases (PubMed, EMBASE and Cochrane Library; from inception to June 2023) was performed to confirm the effects of nanomaterial exposure on aging-related indicators and molecular mechanisms in model animal C. elegans. The pooled analysis by Stata software showed that compared with the control, nanomaterial exposure significantly shortened the mean lifespan [standardized mean difference (SMD) = -2.30], reduced the survival rate (SMD = -4.57) and increased the death risk (hazard ratio = 1.36) accompanied by upregulation of ced-3, ced-4 and cep-1, while downregulation of ctl-2, ape-1, aak-2 and pmk-1. Furthermore, multi-transcriptome data associated with nanomaterial exposure were retrieved from Gene Expression Omnibus (GSE32521, GSE41486, GSE24847, GSE59470, GSE70509, GSE14932, GSE93187, GSE114881, and GSE122728) and bioinformatics analyses showed that pseudogene prg-2, mRNAs of abu, car-1, gipc-1, gsp-3, kat-1, pod-2, acdh-8, hsp-60 and egrh-2 were downregulated, while R04A9.7 was upregulated after exposure to at least two types of nanomaterials. Resveratrol (abu, hsp-60, pod-2, egrh-2, acdh-8, gsp-3, car-1, kat-1, gipc-1), naringenin (kat-1, egrh-2), coumestrol (egrh-2) or swainsonine/niacin/ferulic acid (R04A9.7) exerted therapeutic effects by reversing the expression levels of target genes. In conclusion, our study demonstrates the necessity to use phytomedicines that target hub genes to delay aging for populations with nanomaterial exposure.

How multiple air pollutants affect hand, foot, and mouth disease incidence in children: assessing effect modification by geographical context in multicity of Sichuan, southwest China.

BACKGROUND: Several studies have suggested a significant association of hand, foot, and mouth disease (HFMD) with ambient air pollutants. Existing studies have characterized the role of air pollutants on HFMD using only risk ratio measures while ignoring the attributable burden. And whether the geographical context (i.e., diverse topographic features) could modulate the relationships is unclear. METHODS: Daily reported childhood HFMD counts, ambient air pollution, and meteorological data during 2015-2017 were collected for each of 21 cities in Sichuan Province. A multistage analysis was carried out in different populations based on geographical context to assess effect modification by topographic conditions. We first constructed a distributed lag nonlinear model (DLNM) for each city to describe the relationships with risk ratio measures. Then, we applied a multivariate meta-regression to estimate the pooled effects of multiple air pollutants on HFMD from the exposure and lagged dimensions. Finally, attributable risks measures were calculated to quantify HFMD burden by air pollution. RESULTS: Based on 207554 HFMD cases in Sichuan Province, significant associations of HFMD with ambient air pollutants were observed mainly at relatively high exposure ranges. The effects of ambient air pollutants on HFMD are most pronounced on lag0 or around lag7, with relative risks gradually approaching the reference line thereafter. The attributable risks of O3 were much greater than those of other air pollutants, particularly in basin and mountain regions. CONCLUSIONS: This study revealed significant pooled relationships between multiple air pollutants and HFMD incidence from both exposure and lag dimensions. However, the specific effects, including RRs and ARs, differ depending on the air pollution variable and geographical context. These findings provide local authorities with more evidence to determine key air pollutants and regions for devising and implementing targeted interventions.

Melatonin intervention to prevent nanomaterial exposure-induced damages: A systematic review and meta-analysis of in vitro and in vivo studies.

Given its antioxidant, anti-inflammatory, and antiapoptotic properties, melatonin (MEL), a health-caring food to improve sleep disorders, is hypothesized to protect against nanomaterial exposure-induced toxicity. However, the conclusion derived from different studies seemed inconsistent. A meta-analysis of all available preclinical studies was performed to examine the effects of MEL on nanomaterial-induced damages. Eighteen relevant studies were retrieved through searching five electronic databases up to December 2023. The meta-analysis showed that relative to control, MEL treatment significantly increased cell viability (standardized mean difference [SMD = 1.27]) and alleviated liver function (lowered AST [SMD = -3.89] and ALT [SMD = -5.89]), bone formation (enhanced BV/TV [SMD = 4.13] and lessened eroded bone surface [SMD = -5.40]), and brain nerve (inhibition of AChE activity [SMD = -3.60]) damages in animals. The protective mechanisms of MEL against damages caused by nanomaterial exposure were associated with its antiapoptotic (decreased Bax/Bcl-2 ratio [SMD = -4.50] and caspase-3 levels [dose <100 µM: SMD = -3.66]), antioxidant (decreased MDA [in vitro: SMD = -2.84; in vivo: SMD = -4.27]), and anti-inflammatory (downregulated TNF-α [in vitro: SMD = -5.41; in vivo: SMD = -3.21] and IL-6 [in vitro: SMD = -5.90; in vivo: SMD = -2.81]) capabilities. In conclusion, our study suggests that MEL should be supplemented to prevent damages in populations exposed to nanomaterials.

Lipid changes and molecular mechanism inducing cuproptosis in Cryptocaryon irritans after copper-zinc alloy exposure.

Cryptocaryons irritans is a ciliate parasite responsible for cryptocaryoniasis, leading to considerable economic losses in aquaculture. It is typically managed using a copper-zinc alloy (CZA), effectively diminishing C. irritans infection rates while ensuring the safety of aquatic organisms. Nevertheless, the precise mechanism underlying cuproptosis induced C. irritans mortality following exposure to CZA remains enigmatic. Therefore, this study delves into assessing the efficacy of CZA, investigate cuproptosis as a potential mechanism of CZA action against C. irritans, and determine the alterations in antioxidant enzymes, peroxidation, and lipid metabolism. The mRNA expression of dihydrolipoamide S-acetyltransferase was upregulated after 40 and 70 min, while aconitase 1 was implicated in cuproptosis following 70 min of CZA exposure. Furthermore, the relative mRNA levels of glutathione reductase experienced a significant increase after 40 and 70 min of CZA exposure. In contrast, the relative mRNA levels of glutathione S-transferase and phospholipid-hydroperoxide glutathione peroxidase were significantly decreased after 70 min, suggesting a disruption in antioxidant defense and an imbalance in copper ions. Lipidomics results also unveiled an elevation in glycerophospholipids metabolism and the involvement of the lipoic acid pathway, predominantly contributing to cuproptosis. In summary, exposure to CZA induces cuproptosis in C. irritans, impacts glutathione-related enzymes, and alters glycerophospholipids, consequently triggering lipid oxidation.

Social anxiety modulating early processing for social threat words: an ERP study.

Even though some recent research revealed individuals with HSA typically display enhanced processing in the early stages of emotional information processing due to hypervigilance and vulnerability to negative stimuli, it is still unclear whether social anxiety affects the time course underlying processing bias for emotional stimuli. Therefore, the present study aimed to explore the early stage of processing social threat stimuli in high social anxiety (HSA) individuals by recording RTs and EEG data in the emotional Stroop task. Behavioral data showed that the HSA group responded to the threat words faster than neutral words (i.e. negative bias), but no emotional effects in the low social anxiety (LSA) group. Although the P1 component did not show any early effects, ERP data exhibited an enhanced N170 for HSA than for LSA groups. Threat words elicited larger N170 than neutral words in the LSA group only; this emotion effect was not evident in the HSA group. These findings indicated that social anxiety modulates early processing for social threat words. This study revealed the neural mechanisms underlying early emotional processing in individuals with social anxiety, providing insights for the evaluation and intervention of social anxiety.

Novel modified semi-carbonized fiber prepared using discarded clothes for derisking Cu(II) and Pb(II) contaminated water.

We report a novel modified semi-carbonized fiber (CF) prepared using cotton and acrylic clothes for derisking contaminated water to realize the resource utilization of discarded clothes in wastewater treatment. In this study, amphoteric and auxiliary modifiers were used to modify CFs for preparing amphoteric and amphoteric-auxiliary CFs. The basic physicochemical properties of different modified CFs were determined, and the microscopic morphology of modified CFs was detected. The isothermal adsorption characteristics of Cu(II) and Pb(II) on different modified CFs were investigated by the batch method, and the effect mechanisms of temperature, pH, ionic strength, and material dose were compared. Physicochemical properties and microscopic morphology results proved that amphoteric and auxiliary modifiers were modified on the CF surface and changed the surface properties of CF. The adsorption capacities of Cu(II) and Pb(II) on modified CFs increased with the increase in equilibrium concentration of Cu(II) and Pb(II), and the isotherm was more suitable for Freundlich model fitting than that of the Langmuir model. The maximum adsorption capacities (qm) of Cu(II) and Pb(II) on different modified CFs were 60.72-81.26 mg/g and 102.58-161.72 mg/g, respectively, and presented the trend of amphoteric-auxiliary CFs > amphoteric CFs > CFs. Increasing pH and temperature and decreasing ionic strength and material dose were beneficial to Cu(II) and Pb(II) adsorption. The Cu(II) and Pb(II) adsorption process was a spontaneous, endothermic, and entropy-increasing reaction, and the adsorption rate was controlled by chemisorption. The adsorption amount of amphoteric-auxiliary CFs maintained about 65% of original materials after 3 times of regeneration. Electrostatic attraction, precipitation, complexation, and ion exchange were the main adsorption mechanisms. The cation exchange capacity and total pore volume of modified CFs were key to determining qm of Cu(II) and Pb(II).

[Developmental and epileptic encephalopathy 33 caused by EEF1A2 gene mutation: a case report]. / EEF1A2åŸºå› å˜å¼‚è‡´å‘è‚²æ€§ç™«ç—«æ€§è„‘ç— 33型1例.

A boy, aged 7 months, presented with severe global developmental delay (GDD), refractory epilepsy, hypotonia, nystagmus, ocular hypertelorism, a broad nasal bridge, everted upper lip, a high palatal arch, and cryptorchidism. Genetic testing revealed a de novo heterozygous missense mutation of c.364G>A(p.E122K) in the EEF1A2 gene, and finally the boy was diagnosed with autosomal dominant developmental and epileptic encephalopathy 33 caused by the EEF1A2 gene mutation. This case report suggests that for children with unexplained infancy-onset severe to profound GDD/intellectual disability and refractory epilepsy, genetic testing for EEF1A2 gene mutations should be considered. This is particularly important for those exhibiting hypotonia, nonverbal communication, and craniofacial deformities, to facilitate a confirmed diagnosis.

Roles of KCNA2 in Neurological Diseases: from Physiology to Pathology.

Potassium voltage-gated channel subfamily a member 2 (Kv1.2, encoded by KCNA2) is highly expressed in the central and peripheral nervous systems. Based on the patch clamp studies, gain-of function (GOF), loss-of-function (LOF), and a mixed type (GOF/LOF) variants can cause different conditions/disorders. KCNA2-related neurological diseases include epilepsy, intellectual disability (ID), attention deficit/hyperactive disorder (ADHD), autism spectrum disorder (ASD), pain as well as autoimmune and movement disorders. Currently, the molecular mechanisms for the reported variants in causing diverse disorders are unknown. Consequently, this review brings up to date the related information regarding the structure and function of Kv1.2 channel, expression patterns, neuronal localizations, and tetramerization as well as important cell and animal models. In addition, it provides updates on human genetic variants, genotype-phenotype correlations especially highlighting the deep insight into clinical prognosis of KCNA2-related developmental and epileptic encephalopathy, mechanisms, and the potential treatment targets for all KCNA2-related neurological disorders.

Association between albumin-corrected anion gap and in-hospital mortality of intensive care patients with trauma: A retrospective study based on MIMIC-â ¢ and â £ databases.

BACKGROUND: To investigate the correlation between albumin-corrected anion gap(ACAG) within the first 24 hours of admission and in-hospital mortality in trauma patients in intensive care unit(ICU). MATERIALS AND METHODS: We utilized the MIMIC-Ⅲ and MIMIC-Ⅳ databases to examine trauma patients admitted to the ICU. The relationship between ACAG and in-hospital mortality in trauma patients was analyzed using Receiver Operating Characteristic(ROC) curve, Kaplan-Meier (K-M) survival curve, and Cox regression model. Propensity score matching (PSM) and subgroup analysis were conducted to enhance stability and reliability of the findings. Mortality at 30-day and 90-day served as secondary outcomes. RESULTS: The study enrolled a total of 1038 patients. The AUC for ACAG (0.701, 95%CI: 0.652-0.749) was notably higher than that for anion gap and albumin. The Log-rank test revealed that the optimal cut-off point of ACAG for predicting in-hospital mortality was determined to be 20.375mmol/L. The multivariate Cox regression analysis demonstrated an independent association between high ACAG level and a higher risk of in-hospital mortality (HR = 3.128, 95% CI: 1.615-6.059). After PSM analysis, a matched cohort consisting of 291 subjects was obtained. We found no signifcant interaction in most stratas. Finally, The in-hospital, 30-day, and 90-day survival rates in the high ACAG group exhibited a statistically decrease compared to those in the low ACAG group both pre- and post-matching. CONCLUSION: The elevated level of ACAG was found to be independently associated with increased in-hospital mortality among trauma patients in the ICU.