Dihydromyricetin reverses capecitabine-induced peripheral myelin dysfunction through modulation of oxidative stress.

Previous clinical reports have shown that capecitabine, an oral prodrug of 5-fluorouracil (5-Fu), can induce peripheral neuropathy, resulting in numbness, paresthesia and hypoesthesia. However, the mechanism through which capecitabine causes peripheral nerve injury remains unclear. Here, we demonstrate that systemic administration of capecitabine leads to myelin abnormalities in the peripheral nerves of mice, which are possibly attributed to the death of Schwann cells, the myelinating cells in the peripheral nervous system. Furthermore, our results show that 5-Fu induces significant oxidative stress in Schwann cells by inhibiting the expression of the anti-oxidative protein DJ-1, leading to a decrease in Schwann cell markers. We found that the anti-oxidant dihydromyricetin (DMY) reverses 5-Fu-induced Schwann cell death and oxidative stress and alleviates capecitabine-induced myelin abnormalities. Taken together, our data indicate that capecitabine induces peripheral myelin dysfunction by regulating DJ-1-mediated oxidative stress in Schwann cells and reveal DMY as a potential therapeutic strategy for capecitabine-induced peripheral neuropathy.

BmRRS1 Protein Inhibits the Proliferation of Baculovirus Autographa californica Nucleopolyhedrovirus in Silkworm, Bombyx mori.

The study of functional genes involved in baculovirus infection is vital for its wide application in pest biocontrol. This study utilized the Autographa californica nucleopolyhedrovirus (AcMNPV) and silkworm as models to elucidate the role of BmRRS1, which has been found to exhibit notable differential expression between resistant and susceptible silkworm strains. The results showed that it was evolutionarily conserved in selected species. Among different tissues, it was expressed at the highest level in the gonads, followed by the hemolymph and silk glands; among the different developmental stages, it was the highest in the second instar, followed by the pupae and adults. Moreover, its vital role in suppressing AcMNPV infection was verified by the decreased expression of lef3 and vp39 protein after overexpression of BmRRS1 as well as by the increased expression of the viral gene lef3 and the viral protein vp39 after siRNA treatment against BmRRS1 expression in BmN cells. Additionally, the direct interaction between BmRRS1 and AcMNPV was detected by the GST pull-down assay. Finally, the homologue of BmRRS1 in Spodoptera frugiperda was found to be involved in larval resistance to AcMNPV. In a word, BmRRS1 plays a vital role in AcMNPV resistance in silkworms, and this might be related to the direct interaction with AcMNPV. The results of this study provide a potential target for protecting silkworm larvae from virus infection and controlling agricultural and forestry pests.

Chemical Rules for Stacked Kagome and Honeycomb Topological Semimetals.

The chemical rules for predicting and understanding topological states in stacked kagome and honeycomb lattices are studied in both analytical and numerical ways. Starting with a minimal five-band tight-binding model, all the topological states are sorted into five groups, which are determined by the interlayer and intralayer hopping parameters. Combined with the model, an algorithm is designed to obtain a series of experimentally synthesized topological semimetals with kagome and honeycomb layers, i.e., IAMX family (IA = Alkali metal element, M = Rare earth metal element, X = Carbon group element), in the inorganic crystal structure database. A follow-up high-throughput calculation shows that IAMX family materials are all nodal-line semimetals and they will be Weyl semimetals after taking spin-orbit coupling into consideration. To have further insights into the topology of the IAMX family, a detailed chemical rule analysis is carried out on the high-throughput calculations, including the lattice constants of the structure, intralayer and interlayer couplings, bond strengths, electronegativity, and so on, which are consistent with the tight-binding model. This study provides a way to discover and modulate topological properties in stacked kagome and honeycomb crystals and offers candidates for studying topology-related properties like topological superconductors and axion insulators.

Peripheral Mechanisms of Mechanical Itch.

Mechanical itch, which is defined as an itch sensation caused by innocuous mechanical force, may warn of the potential risk in the skin. The increased mechanosensitivity in sensory neurons may cause scratch-induced itch and promote the transition from acute itch to chronic itch. Recent studies have not only expanded our knowledge about the neuronal circuits in the CNS but have also highlighted the importance of the peripheral epithelia-immune-neuronal crosstalk in the development of mechanical itch. In this review, we will summarize related findings about the molecular and cellular mechanisms of mechanical itch in the skin.

Orienting role of the putative human posterior infero-temporal area in visual attention.

The dorsal attention network (DAN) is a network of brain regions essential for attentional orienting, which includes the lateral intraparietal area (LIP) and frontal eye field (FEF). Recently, the putative human dorsal posterior infero-temporal area (phPITd) has been identified as a new node of the DAN. However, its functional relationship with other areas of the DAN and its specific role in visual attention remained unclear. In this study, we analyzed a large publicly available neuroimaging dataset to investigate the intrinsic functional connectivities (FCs) of the phPITd with other brain areas. The results showed that the intrinsic FCs of the phPITd with the areas of the visual network and the DAN were significantly stronger than those with the ventral attention network (VAN) areas and areas of other networks. We further conducted individual difference analyses with a sample size of 295 participants and a series of attentional tasks to investigate which attentional components each phPITd-based DAN edge predicts. Our findings revealed that the intrinsic FC of the left phPITd with the LIPv could predict individual ability in attentional orienting, but not in alerting, executive control, and distractor suppression. Our results not only provide direct evidence of the phPITd's functional relationship with the LIPv, but also offer a comprehensive understanding of its specific role in visual attention.

The distinct development of stimulus and response serial dependence.

Serial dependence (SD) is a phenomenon wherein current perceptions are biased by the previous stimulus and response. This helps to attenuate perceptual noise and variability in sensory input and facilitates stable ongoing perceptions of the environment. However, little is known about the developmental trajectory of SD. This study investigates how the stimulus and response biases of the SD effect develop across three age groups. Conventional analyses, in which previous stimulus and response biases were assessed separately, revealed significant changes in the biases over time. Previous stimulus bias shifted from repulsion to attraction, while previous response bias evolved from attraction to greater attraction. However, there was a strong correlation between stimulus and response orientations. Therefore, a generalized linear mixed-effects (GLME) analysis that simultaneously considered both previous stimulus and response, outperformed separate analyses. This revealed that previous stimulus and response resulted in two distinct biases with different developmental trajectories. The repulsion bias of previous stimulus remained relatively stable across all age groups, whereas the attraction bias of previous response was significantly stronger in adults than in children and adolescents. These findings demonstrate that the repulsion bias towards preceding stimuli is established early in the developing brain (at least by around 10 years old), while the attraction bias towards responses is not fully developed until adulthood. Our findings provide new insights into the development of the SD phenomenon and how humans integrate two opposing mechanisms into their perceptual responses to external input during development.

The influence of eight cognitive training regimes upon cognitive screening tool performance in post-stroke survivors: a network meta-analysis.

Background: Traditional meta-analysis offers only direct comparative evidence. The optimal cognitive training for poststroke cognitive impairment (PSCI) remains largely undetermined. Objectives: This study aims to assess and compare the effectiveness of selected cognitive training methods for PSCI patients and to identify and rank the most effective intervention programs. Methods: Searches were conducted in PubMed, Embase, Cochrane Library, Web of science, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and China Biomedical Database for randomized controlled trials up to September 30, 2023. Two researchers independently performed literature screening, data extraction, and quality assessment. Network meta-analysis was utilized to synthesize the main findings. The primary outcome focused on the intervention's impact on subjective cognitive function, with secondary outcomes including effects on activities of daily living, motor function, and functional independence. This study is registered with PROSPERO (CRD42023463282). Results: Fifty eligible randomized controlled trials were identified, revealing eight distinct interventions. These interventions collectively demonstrate efficacy in enhancing cognition. Traditional cognitive training significantly improves overall cognitive function, daily living function, motor function, and functional independence. In Loewenstein Occupational Therapy Cognitive Assessment, Barthel Index, Fugl-Meyer Assessment, and Functional Independence Measure scales, a combination of computer-based and traditional cognitive training outperformed the conventional control group MD = 29.97 (95%CI: 16.3, 44.2), MD = 18.67 (95%CI: 9.78, 27.45), MD = 28.76 (95%CI: 5.46, 51.79) and MD = 42.2 (95%CI: 5.25, 78.99). In the MMSE scale, virtual reality cognitive training combined with traditional training was most effective MD = 8.01 (95%CI: 3.6, 12.4). On the MoCA scale, the combination of exercise and cognitive training showed superior results MD = 6.68 (95%CI: 2.55, 10.78). Only the combined computer-based and traditional cognitive training, as well as traditional cognitive training alone, significantly enhanced functional independence, with no notable differences in other pairwise interventions. Conclusion: The network meta-analysis suggests that augmenting traditional training with other modalities may enhance overall effectiveness. Specifically, interventions incorporating computer-based cognitive training appear to surpass other methods in improving cognition, daily living function, motor skills, and functional independence. The findings of this network meta-analysis provide evidence-based guidance for clinical decision-making. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier in PROSPERO (CRD42023463282).

Depression and hepatobiliary diseases: a bidirectional Mendelian randomization study.

Background: More and more evidence suggests a close association between depression and hepatobiliary diseases, but its causal relationship is not yet clear. Method: Using genome-wide association studies (GWAS) to summarize data, independent genetic variations associated with depression were selected as instrumental variables. Firstly, we designed a univariate Mendelian randomization (UVMR) analysis with two samples and simultaneously conducted reverse validation to evaluate the potential bidirectional causal relationship between depression and various hepatobiliary diseases. Secondly, we conducted a multivariate Mendelian randomization (MVMR) analysis on diseases closely related to depression, exploring the mediating effects of waist to hip ratio, hypertension, and daytime nap. The mediating effects were obtained through MVMR. For UVMR and MVMR, inverse variance weighted method (IVW) is considered the most important analytical method. Sensitivity analysis was conducted using Cochran'Q, MR Egger, and Leave-one-out methods. Results: UVMR analysis showed that depression may increase the risk of non-alcoholic fatty liver disease (OR, 1.22; 95% CI, 1.03-1.46; p=0.0248) in liver diseases, while depression does not increase the risk of other liver diseases; In biliary and pancreatic related diseases, depression may increase the risk of cholelithiasis (OR, 1.26; 95% CI, 1.05-1.50; p=0.0120), chronic pancreatitis (OR, 1.61; 95% CI, 1.10-2.35; p=0.0140), and cholecystitis (OR, 1.23; 95% CI, 1.03-1.48; p=0.0250). In addition, through reverse validation, we found that non-alcoholic fatty liver disease, cholelithiasis, chronic pancreatitis, cholecystitis, or the inability to increase the risk of depression (p>0.05). The waist to hip ratio, hypertension, and daytime nap play a certain role in the process of depression leading to non-alcoholic fatty liver disease, with a mediating effect of 35.8%. Conclusion: Depression is a susceptibility factor for non-alcoholic fatty liver disease, and the causal effect of genetic susceptibility to depression on non-alcoholic fatty liver disease is mediated by waist-hip ratio, hypertension, and daytime nap.

Identification and preliminary validation of differently expressed genes as candidate biomarkers associated with atherosclerosis.

OBJECTIVE: Atherosclerosis (AS) is the primary cause of deadly cardio-cerebro vascular diseases globally. This study aims to explore the key differentially expressed genes (DEGs), potentially serving as predictive biomarkers for AS. METHODS: Microarray datasets were retrieved from the GEO database for DEGs and DE-miRNAs identification. Then biological function of DEGs were elucidated based on gene ontology (GO) and KEGG pathway enrichment analysis. The protein-protein interaction (PPI) network and DEGs-DE-miRNAs network were constructed, with emphasis on hub DEGs selection and their interconnections. Additionally, receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic precision of hub DEGs for AS. More importantly, an AS Syrian Golden hamster model was established to validate the expression levels of hub DEGs in AS. RESULTS: A total of 203 DEGs and 10 DE-miRNAs were screened, with six genes were chosen as hub DEGs. These DEGs were significantly enriched in AS-related biological processes and pathways, such as immune and inflammatory response, cellular response to IL-1 and TNF, positive regulation of angiogenesis, Type I diabetes mellitus, Cytokine-cytokine receptor interaction, TLR signaling pathway. Also, these DEGs and DE-miRNAs formed a closely-interacted DE-miRNAs - DEGs - KEGG pathway network. Besides, hub DEGs presented promising diagnostic potential for AS (AUC: 0.781 âˆ¼ 0.887). In addition, the protein expression levels of TNF-α, CXCL8, CCL4, IL-1ß, CCL3 and CCR8 were significantly increased in AS group Syrian Golden hamsters. CONCLUSION: The identified candidate genes TNF, CXCL8, CCL4, IL1B, CCL3 and CCR8 may have the potential to serve as prognostic biomarker in diagnosing AS.

Evidence that a Novel Chalcone Derivative, Compound 27, Acts on the Epithelium Via the PI3K/AKT/Nrf2-Keap1 Signaling Pathway, to Mitigate LPS-Induced Acute Lung Injury in Mice.

Acute lung injury (ALI) is a highly heterogeneous clinical syndrome and an important cause of mortality in critically ill patients, with limited treatment options currently available. Chalcone, an essential secondary metabolite found in edible or medicinal plants, exhibits good antioxidant activity and simple structure for easy synthesis. In our study, we synthesized a novel chalcone derivative, compound 27 (C27). We hypothesized that C27 could be a potential treatment for acute respiratory distress syndrome (ARDS). Therefore, the protective effects of C27 on lung epithelial cells during ALI and the underlying molecular mechanisms were investigated. In vivo, Intratracheal instillation of LPS (10 mg/kg) was used to induce acute lung injury in mice. In vitro, the bronchial epithelial cell line (Beas-2b) was treated with 30 µM tert-butyl hydroperoxide (t-BHP) to simulate oxidative stress. Our findings demonstrate that pretreatment with C27 reduces LPS-induced oxidative destruction and cellular apoptosis in lung tissues of mice. Furthermore, it significantly attenuates t-BHP-induced cellular reactive oxygen species (ROS) generation, mitochondrial damage, and apoptosis in vitro. Mechanistically, the signaling pathway involving Nrf2-Keap1 and the downstream antioxidative proteins were activated by C27 in vivo. Additionally, PI3K inhibitor LY294002 and Nrf2 inhibitor ML385 abolished the effect of C27 in vitro, indicating that the protective effect of C27 is mediated via the PI3K/AKT/Nrf2-Keap1 pathway. Our study provides evidence that C27 protects against LPS-induced ALI by mitigating oxidative stress via activation of the PI3K/AKT/Nrf2-Keap1 signaling pathway. Therefore, we hypothesize that C27 represents a viable alternative for ALI therapy.

Reviving Bistable Perception in Patients With Depression by Decreasing the Overestimation of Prior Precision.

Slower perceptual alternations, a notable perceptual effect observed in psychiatric disorders, can be alleviated by antidepressant therapies that affect serotonin levels in the brain. While these phenomena have been well documented, the underlying neurocognitive mechanisms remain to be elucidated. Our study bridges this gap by employing a computational cognitive approach within a Bayesian predictive coding framework to explore these mechanisms in depression. We fitted a prediction error (PE) model to behavioral data from a binocular rivalry task, uncovering that significantly higher initial prior precision and lower PE led to a slower switch rate in patients with depression. Furthermore, serotonin-targeting antidepressant treatments significantly decreased the prior precision and increased PE, both of which were predictive of improvements in the perceptual alternation rate of depression patients. These findings indicated that the substantially slower perception switch rate in patients with depression was caused by the greater reliance on top-down priors and that serotonin treatment's efficacy was in its recalibration of these priors and enhancement of PE. Our study not only elucidates the cognitive underpinnings of depression, but also suggests computational modeling as a potent tool for integrating cognitive science with clinical psychology, advancing our understanding and treatment of cognitive impairments in depression.

Dual chemical bonding construction of electrochemical peptide sensor based on GDY/MOFs(Fe) composite for ultra-low determination of prostate-specific antigen.

A novel "double chemical bonding" electrochemical peptide biosensor 2FcP-GA-GDY(Fe)@NMIL-B was developed for highly selective, ultrasensitive, and ultrastable identification of prostate-specific antigen (PSA). The C-Fe-O chemical bond linking Fe-Graphdiyne (Fe-GDY) with NH2-MIL88B(Fe) (NMIL88B) as the first chemical bonding of electrode carrier Fe-GDY@NH2-MIL88B(Fe) (GDY(Fe)@NMIL) significantly accelerates electron transport. With glutaraldehyde (GA) as a crosslinking agent, the Schiff-base -NC- formed by GDY(Fe)@NMIL nanocomposites links the two Fc molecules labeled peptides (2FcP) as the second chemical bonding, facilitating high-density attachment of peptides to the electrode carrier in a firm manner. When the PSA analyte is introduced to identify and cleave the specific peptide, the release of ferrocene from its head leads to a decrease in the electrical signal, enabling sensitive detection. The prepared sensing platform exhibits exceptional analytical performance for PSA with an extended linear response range from 10 fg mL-1 to 50 ng mL-1. Additionally, the detection limit has been significantly reduced to an ultra-low level of only 0.94 fg mL-1, surpassing those reported in most literature by several orders of magnitude. Moreover, the 2FcP-GA-GDY(Fe)@NMIL-B sensor has excellent selectivity and stability while also showcasing great potential for practical application of PSA detection in human serum using the standard addition method.