Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

Weighted gene co-expression network analysis reveals key biomarkers and immune infiltration characteristics for bronchial epithelial cells from asthmatic patients.

BACKGROUND: Asthma ranks among the most prevalent non-communicable diseases worldwide. Previous studies have elucidated the significant role of the immune system in its pathophysiology. Nevertheless, the immune-related mechanisms underlying asthma are complex and still inadequately understood. Thus, our objective was to investigate novel key biomarkers and immune infiltration characteristics associated with asthma by employing integrated bioinformatics tools. METHODS: In this study, we conducted a weighted gene co-expression network analysis (WGCNA) to identify key modules and genes potentially implicated in asthma. Functional annotation of these key modules and genes was carried out through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Additionally, we constructed a protein-protein interaction (PPI) network using the STRING database to identify 10 hub genes. Furthermore, we evaluated the relative proportion of immune cells in bronchial epithelial cell samples from 20 healthy individuals and 88 asthmatic patients using CIBERSORT. Finally, we validated the hub genes and explored their correlation with immune infiltration. RESULTS: Furthermore, 20 gene expression modules and 10 hub genes were identified herein. Among them, complement component 3 (C3), prostaglandin I2 receptor (PTGIR), parathyroid hormone-like hormone (PTHLH), and C-X3-C motif chemokine ligand 1 (CX3CL1) were closely correlated with the infiltration of immune cells. They may be novel candidate biomarkers or therapeutic targets for asthma. Furthermore, B cells memory, and plasma cells might play an important role in immune cell infiltration after asthma. CONCLUSIONS: C3, PTGIR, CX3CL1, and PTHLH have important clinical diagnostic values and are correlated with infiltration of multiple immune cell types in asthma. These hub genes, B cells memory, and plasma cells may become important biological targets for therapeutic asthma drug screening and drug design.

Immunotherapy efficacy prediction through a feature re-calibrated 2.5D neural network.

BACKGROUND AND OBJECTIVE: Lung cancer continues to be a leading cause of cancer-related mortality worldwide, with immunotherapy emerging as a promising therapeutic strategy for advanced non-small cell lung cancer (NSCLC). Despite its potential, not all patients experience benefits from immunotherapy, and the current biomarkers used for treatment selection possess inherent limitations. As a result, the implementation of imaging-based biomarkers to predict the efficacy of lung cancer treatments offers a promising avenue for improving therapeutic outcomes. METHODS: This study presents an automatic system for immunotherapy efficacy prediction on the subjects with lung cancer, facilitating significant clinical implications. Our model employs an advanced 2.5D neural network that incorporates 2D intra-slice feature extraction and 3D inter-slice feature aggregation. We further present a lesion-focused prior to guide the re-calibration for intra-slice features, and a attention-based re-calibration for the inter-slice features. Finally, we design an accumulated back-propagation strategy to optimize network parameters in a memory-efficient fashion. RESULTS: We demonstrate that the proposed method achieves impressive performance on an in-house clinical dataset, surpassing existing state-of-the-art models. Furthermore, the proposed model exhibits increased efficiency in inference for each subject on average. To further validate the effectiveness of our model and its components, we conducted comprehensive and in-depth ablation experiments and discussions. CONCLUSION: The proposed model showcases the potential to enhance physicians' diagnostic performance due to its impressive performance in predicting immunotherapy efficacy, thereby offering significant clinical application value. Moreover, we conduct adequate comparison experiments of the proposed methods and existing advanced models. These findings contribute to our understanding of the proposed model's effectiveness and serve as motivation for future work in immunotherapy efficacy prediction.

Effects of intrathecal pemetrexed on the survival of patients with leptomeningeal metastasis from lung adenocarcinoma: a propensity score matching analysis.

PURPOSE: To explore the impact of intrathecal pemetrexed (IP) on the survival of lung adenocarcinoma (LUAC) patients with leptomeningeal metastasis (LM). METHODS: We analyzed patients with LUAC and LM who received systemic therapy after LM diagnosis at the Fujian Cancer Hospital between July 2018 and March 2022. Patients who underwent IP were assigned to the IP group; those without IP treatment were designated as the non-IP group. Propensity score matching (PSM) was performed between the two groups. RESULTS: 165 patients were enrolled: 83 and 82 in the IP and non-IP groups, respectively. After 1:1 PSM, we included 114 patients in the matched cohort. Median overall survival (OS) was 13.2 months (95% CI 10.8-15.6 months) in the IP group versus 10.1 months (95% CI 5.3-14.9 months) in the non-IP group (P = 0.488). Only Eastern Cooperative Oncology Group Performance Status (ECOG PS) was confirmed as an independent predictor for OS in the matched cohort (hazard ratio (HR) 2.03; P = 0.023). Multivariate competing-risks analysis showed that IP significantly correlated with central nervous system-related death (HR 0.31; P = 0.046). When stratified by ECOG PS, IP improved survival in patients with poor ECOG PS (PS = 2) (14.3 months vs. 1.6 months; P = 0.003). CONCLUSIONS: Intrathecal pemetrexed did not enhance OS for the entire LUAC patient with LM compared to non-intrathecal chemotherapy. However, it exhibited the potential to reduce the risk of central nervous system-related mortality and improve survival in patients with poor ECOG PS.

The integrated production of hydrochar and methane from lignocellulosic fermentative residue coupling hydrothermal carbonization with anaerobic digestion.

The popularization of large-scale biogas project makes the disposal of fermentative residue an urgent issue to be solved. Hydrothermal carbonization (HTC) technology is suitable for treating wet biomass to produce carbonaceous materials. In this study, the solid residue from the two-phase anaerobic digestion (AD) was hydrothermally converted in the range of 180-240 °C, and the hydrochar and aqueous components were characterized for subsequent utilization. The heating values of hydrochar were indicated to be increased by 14.2% and 16.6% at 210 °C and 240 °C as compared with feedstock, and also the specific surface areas were 34.8 m2/g and 27.1 m2/g with 17.4- and 13.3-fold enhancement, respectively. The migration of elements such as S, Cl, K to aqueous phase was beneficial for fuel application. The mesoporous pores were dominant in hydrochars with ample oxygenated functional groups. In addition, the wastewater involved organic acids, phenols, and nitrogen-containing compounds, etc. Evaluating the biodegradability by AD, it was found that when the initial concentration was ≤8 g COD/L, the maximum methane yields up to 275.9 mL CH4/g CODremoval and 277.6 mL CH4/g CODremoval were obtained. The enhanced toxicity/inhibition of representative pollutants on microorganisms was significant at higher organic loading, which could be indicated in the microbial structure and diversity. As a conclusion, the integrated production of hydrochar and methane will provide an extended route for further processing of lignocellulosic fermentative residue.

Soft Robotics Enables Neuroprosthetic Hand Design.

Development and implementation of neuroprosthetic hands is a multidisciplinary field at the interface between humans and artificial robotic systems, which aims at replacing the sensorimotor function of the upper-limb amputees as their own. Although prosthetic hand devices with myoelectric control can be dated back to more than 70 years ago, their applications with anthropomorphic robotic mechanisms and sensory feedback functions are still at a relatively preliminary and laboratory stage. Nevertheless, a recent series of proof-of-concept studies suggest that soft robotics technology may be promising and useful in alleviating the design complexity of the dexterous mechanism and integration difficulty of multifunctional artificial skins, in particular, in the context of personalized applications. Here, we review the evolution of neuroprosthetic hands with the emerging and cutting-edge soft robotics, covering the soft and anthropomorphic prosthetic hand design and relating bidirectional neural interactions with myoelectric control and sensory feedback. We further discuss future opportunities on revolutionized mechanisms, high-performance soft sensors, and compliant neural-interaction interfaces for the next generation of neuroprosthetic hands.

Identification and validation of synapse-related hub genes after spinal cord injury by bioinformatics analysis.

BACKGROUND: Spinal cord injury (SCI) is a neurological disease with high morbidity and mortality. Previous studies have shown that abnormally expressed synapse-related genes are closely related to the occurrence and development of SCI. However, little is known about the interaction of these aberrantly expressed genes and the molecular mechanisms that play a role in the injury response. Therefore, deeply exploring the correlation between synapse-related genes and functional recovery after spinal cord injury and the molecular regulation mechanism is of great significance. METHODS: First, we selected the function GSE45006 dataset to construct three clinically meaningful gene modules by hierarchical clustering analysis in 4 normal samples and 20 SCI samples. Subsequently, we performed functional and pathway enrichment analyses of key modules. RESULTS: The results showed that related module genes were significantly enriched in synaptic structures and functions, such as the regulation of synaptic membranes and membrane potential. A protein-protein interaction network (PPI) was constructed to identify 10 hub genes of SCI, and the results showed that Snap25, Cplx1, Stxbp1, Syt1, Rims1, Rab3a, Syn2, Syn1, Cask, Lin7b were most associated with SCI. Finally, these hub genes were further verified by quantitative real-time fluorescence polymerase chain reaction (qRT-PCR) in the spinal cord tissues of the blank group and SCI rats, and it was found that the expression of these hub genes was significantly decreased in the spinal cord injury compared with the blank group (P ≤ 0.05). CONCLUSION: These results suggest that the structure and function of synapses play an important role after spinal cord injury. Our study helps to understand the underlying pathogenesis of SCI patients further and identify new targets for SCI treatment.

EA participates in pain transition through regulating KCC2 expression by BDNF-TrkB in the spinal cord dorsal horn of male rats.

The pathogenesis of chronic pain is complex and poorly treated, seriously affecting the quality of life of patients. Electroacupuncture (EA) relieves pain by preventing the transition of acute pain into chronic pain, but its mechanism of action is still unclear. Here, we aimed to investigate whether EA can inhibit pain transition by increasing KCC2 expression via BDNF-TrkB. We used hyperalgesic priming (HP) model to investigate the potential central mechanisms of EA intervention on pain transition. HP model male rats showed significant and persistent mechanically abnormal pain. Brain derived neurotrophic factor (BDNF) expression and Tropomyosin receptor kinase B (TrkB) phosphorylation were upregulated in the affected spinal cord dorsal horn (SCDH) of HP model rats, accompanied by K+-Cl-- Cotransporter-2 (KCC2) expression was down-regulated. EA significantly increased the mechanical pain threshold in HP model male rats and decreased BDNF and p-TrkB overexpression and upregulated KCC2 expression. Blockade of BDNF with BDNF neutralizing antibody attenuated mechanical abnormal pain in HP rats. Finally, administration of exogenous BDNF by pharmacological methods reversed the EA-induced resistance to abnormal pain. In all, these results suggest that BDNF-TrkB contributes to mechanical abnormal pain in HP model rats and that EA ameliorates mechanical abnormal pain through upregulation of KCC2 by BDNF-TrkB in SCDH. Our study further supports EA as an effective treatment to prevent the transition of acute pain into chronic pain.

Construction of Covalent Organic Frameworks via a Visible-Light-Activated Photocatalytic Multicomponent Reaction.

Multicomponent reactions (MCRs), as a powerful one-pot combinatorial synthesis tool, have been recently applied to the synthesis of covalent organic frameworks (COFs). Compared with the thermally driven MCRs, the photocatalytic MCR-based COF synthesis has not yet been investigated. Herein, we first report the construction of COFs by a photocatalytic multicomponent reaction. Upon visible-light irradiation, a series of COFs with excellent crystallinity, stability, and permanent porosity are successfully synthesized via photoredox-catalyzed multicomponent Petasis reaction under ambient conditions. Additionally, the obtained Cy-N3-COF exhibits excellent photoactivity and recyclability for the visible-light-driven oxidative hydroxylation of arylboronic acids. The concept of photocatalytic multicomponent polymerization not only enriches the methodology for COF synthesis but also opens a new avenue for the construction of COFs that might not be possible with the existing synthetic methods based on thermally driven MCRs.

In situ utilization of photogenerated hydrogen for hydrogenation reaction over a covalent organic framework.

A fully sp2-carbon conjugated COF (Py-FTP-COF) was designed and synthesized, exhibiting excellent hydrogen evolution rate of 5.22 mmol g-1 h-1. More importantly, in situ hydrogenation of nitroarenes under visible-light irradiation without any additional hydrogen source was successfully accomplished for the first time over COF-based materials.

A soft neuroprosthetic hand providing simultaneous myoelectric control and tactile feedback.

Neuroprosthetic hands are typically heavy (over 400 g) and expensive (more than US$10,000), and lack the compliance and tactile feedback of human hands. Here, we report the design, fabrication and performance of a soft, low-cost and lightweight (292 g) neuroprosthetic hand that provides simultaneous myoelectric control and tactile feedback. The neuroprosthesis has six active degrees of freedom under pneumatic actuation, can be controlled through the input from four electromyography sensors that measure surface signals from residual forearm muscles, and integrates five elastomeric capacitive sensors on the fingertips to measure touch pressure so as to enable tactile feedback by eliciting electrical stimulation on the skin of the residual limb. In a set of standardized tests performed by two individuals with transradial amputations, we show that the soft neuroprosthetic hand outperforms a conventional rigid neuroprosthetic hand in speed and dexterity. We also show that one individual with a transradial amputation wearing the soft neuroprosthetic hand can regain primitive touch sensation and real-time closed-loop control.

Involvement of kynurenine pathway between inflammation and glutamate in the underlying etiopathology of CUMS-induced depression mouse model.

Inflammation and glutamate (GLU) are widely thought to participate in the pathogenesis of depression, and current evidence suggests that the development of depression is associated with the activation of the kynurenine pathway (KP). However, the exact mechanism of KP among the inflammation, GLU and depression remain poorly understood. In this study, we examined the involvement of KP, inflammation and GLU in depressive phenotype induced by chronic unpredictable mild stress (CUMS) in C57B/6 J mice. Our results showed that CUMS caused depressive like-behavior in the sucrose preference test, tail suspension test and forced swimming test. From a molecular perspective, CUMS upregulated the peripheral and central inflammatory response and activated indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of KP, which converts tryptophan (TRP) into kynurenine (KYN). KYN is a precursor for QA in microglia, which could activate the N-methyl-D-aspartate receptor (NMDAR), increasing the GLU release, mirrored by increased IDO activity, quinolinic acid and GLU levels in the hippocampus, prefrontal cortex and serum. However, intervention with IDO inhibitor 1-methyl-DL-tryptophan (50 mg/kg/s.c.) and 1-methyl-L-tryptophan (15 mg/kg/i.p.) reversed the depressive-like behaviors and adjusted central and peripheral KP's metabolisms levels as well as GLU content, but the inflammation levels were not completely affected. These results provide certain evidence that KP may be a vital pathway mediated by IDO linking inflammation and glutamate, contributing to depression.

CD8+ T cell/cancer-associated fibroblast ratio stratifies prognostic and predictive responses to immunotherapy across multiple cancer types.

Background: Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) are critical for immune suppression by restricting immune cell infiltration in the tumor stromal zones from penetrating tumor islands and changing their function status, particularly for CD8+ T cells. However, assessing and quantifying the impact of CAFs on immune cells and investigating how this impact is related to clinical outcomes, especially the efficacy of immunotherapy, remain unclear. Materials and methods: The TME was characterized using immunohistochemical (IHC) analysis using a large-scale sample size of gene expression profiles. The CD8+ T cell/CAF ratio (CFR) association with survival was investigated in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) lung cancer cohorts. The correlation between CFR and immunotherapeutic efficacy was computed in five independent cohorts. The correlation between CFR and objective response rates (ORRs) following pembrolizumab monotherapy was investigated in 20 solid tumor types. To facilitate clinical translation, the IHC-detected CD8/α-SMA ratio was applied as an immunotherapeutic predictive biomarker in a real-world lung cancer cohort. Results: Compared with normal tissue, CAFs were enriched in cancer tissue, and the amount of CAFs was overwhelmingly higher than that in other immune cells. CAFs are positively correlated with the extent of immune infiltration. A higher CFR was strongly associated with improved survival in lung cancer, melanoma, and urothelial cancer immunotherapy cohorts. Within most cohorts, there was no clear evidence for an association between CFR and programmed death-ligand 1 (PD-L1) or tumor mutational burden (TMB). Compared with TMB and PD-L1, a higher correlation coefficient was observed between CFR and the ORR following pembrolizumab monotherapy in 20 solid tumor types (Spearman's r = 0.69 vs. 0.44 and 0.21). In a real-world cohort, patients with a high CFR detected by IHC benefited considerably from immunotherapy as compared with those with a low CFR (hazard ratio, 0.37; 95% confidence interval, 0.19-0.75; p < 0.001). Conclusions: CFR is a newly found and simple parameter that can be used for identifying patients unlikely to benefit from immunotherapy. Future studies are needed to confirm this finding.

Integrated bioinformatics analysis identifies the effects of Sema3A/NRP1 signaling in oligodendrocytes after spinal cord injury in rats.

Objective: To investigate the effect of Sema3A/NRP1 signaling in oligodendrocytes (OLs) after spinal cord injury. Methods: Three analysis strategies, namely differential expression gene analysis, Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, were applied. The protein-protein interaction (PPI) network was constructed using the STRING website to explore the correlation between Sema3A/NRP1 and oligodendrocytes. Then, the T10 spinal cord segment of rats was injured by the Allen method to establish a spinal cord injury (SCI) model. Real-time quantitative PCR, Western blotting, Nissl staining and immunofluorescence staining were used to detect the effect of Sema3A/NRP1 signaling on oligodendrocytes in vivo. Results: After the SCI model was established, significantly fewer oligodendrocytes were observed. At the same time, R software was used to analyze the expression of related genes, and NRP1 expression was increased. PCR also demonstrated similar results, and NRP1 ligand Sema3A was also upregulated. KEGG and GO functional enrichment analysis indicated that the SCI model was mainly related to cytokine interaction, cell proliferation, differentiation and maturation. Interestingly, we found that NRP1 was involved in semaphorin-plexin signaling pathway neuronal projection guidance and axon guidance, mediating cell growth and migration. Moreover, Sema3A/NRP1 signaling was closely associated with platelet-derived growth factor receptor α (PDGFRα) in the PPI network. When Sema3A/NRP1 signaling was specifically blocked at early stages, PDGFRα expression was effectively inhibited, and the expression of OLs was promoted. Furthermore, inhibition of Sema3A/NRP1 signaling increased the Basso-Beattie-Bresnahan (BBB) score of lower limb motor function in SCI rats and promoted the survival of motor neurons in the ventral horn of the injured spinal cord. Conclusion: Our data suggest that Sema3A/NRP1 signaling may regulate the development of OPCs and OLs after SCI, thereby affecting functional recovery.

Energy recovery from high ash-containing sewage sludge: Focusing on performance evaluation of bio-fuel production.

Hydrothermal liquefaction (HTL) has shown great potential to convert sewage sludge (SS) with high moisture into bio-crude. However, the disposal and reutilization of hydrothermal liquefaction wastewater (HTLWW) is a critical issue. Anaerobic digestion (AD) is proven to be an alternative to treat organic wastewater. Therefore, energy recovery from high ash-containing SS was studied by integrating AD with HTL. The effect of temperature on HTL efficiency was investigated and then methane production from HTLWW was conducted by AD with organic loading increasing from 2 g COD/L to 6 g COD/L. Results showed that the maximum bio-crude yield of 23.5 % was obtained at 350 °C. Methane yield of 309.4 mL CH4/g CODremoved was achieved at 2 g COD/L with COD removal rate of 72.5 %. Meanwhile, the microbial structure and abundance showed great shifts resulting from the adaptation to complex compounds. JGI-000079-D21, Aminicenantales, and Bacteroidetes_ vadinHA17 predominated in the bacterial community. Due to the presence of the toxic substances in HTLWW, such as phenolic and nitrogenous heterocyclic compounds, there was a decrease in methane yield when the organic loading was higher than 4 g COD/L. The organic matters in extracellular polymeric substances (EPS) were rich in fulvic acid-like and humic acid-like substances due to the attack and stimulation of toxicants. Under the condition of unstable fermentation, Advenella and Bacillus first appeared as phenol and pyridine degrading bacteria, respectively. The microbial diversity declined sharply to demonstrate the toxic effect of the refractory organics existing at high organic loading. The enrichment of Methanosaeta in methanogens meant that acetotrophic metabolism is the dominant pathway in methanogenesis. In this study, the profile of bio-fuel production from high ash-containing SS would provide an integrated reference to treat wet biomass and recover energy simultaneously.

Hsa_circ_0006692 Promotes Lung Cancer Progression via miR-205-5p/CDK19 Axis.

Circular RNA (CircRNA) is related to tumor development. Nevertheless, the regulation and function of hsa_circ_0006692 and its interactions with miR-205-5p and CDK19 in the development of non-small-cell lung cancer (NSCLC) were un-explored. The correlations of expression levels of hsa_circ_0006692 in NSCLC specimens and cells with pathological characteristics were studied. The interactions of hsa_circ_0006692 with miR-205-5p and CDK19 were assessed with real-time PCR, RNA-binding protein immunoprecipitation (RIP), luciferase reporter, RNA pull-down, and fluorescence in situ hybridization (FISH). The roles of hsa_circ_0006692 on cell growth, invasion, and migration in vitro and metastasis in vivo were evaluated. Hsa_circ_0006692 was over-expressed in 60 cases of NSCLC specimens and cells, which was positively correlated with TNM stage, tumor size, and invasion of the lung basal layer. The results of the in vitro and in vivo studies revealed that the over-expression of hsa_circ_0006692 facilitated NSCLC cell growth, migration, and invasion, cell cycle arrest at the S phase, and the activation of BCL-2, CCND1, and PCNA. The results of the dual-luciferase reporter assay, RNA immunoprecipitation, and pull-down assays indicated that hsa_circ_0006692 sponged miR-205-5p, which targeted CDK19 and facilitated the malignant behaviors of lung cancer cells. Hsa_circ_0006692 modulated EMT of lung cancer cells via the stimulation of CDH1, CDH2, VIMENTIN, and MMP7. This study revealed that hsa_circ_0006692 promoted NSCLC progression via enhancing cell growth, invasion, and metastasis through sponging mir-205-5p, up-regulating the downstream oncogene CDK19 and modulating EMT of lung cancer cells. The circ-0006692/mir-205-5p/CDK19 axis might serve as a prognosis biomarker and target for drugs aimed against NSCLC.

Identifying Key Biomarkers and Immune Infiltration in Female Patients with Ischemic Stroke Based on Weighted Gene Co-Expression Network Analysis.

Stroke is one of the leading causes of death and disability worldwide. Evidence shows that ischemic stroke (IS) accounts for nearly 80 percent of all strokes and that the etiology, risk factors, and prognosis of this disease differ by gender. Female patients may bear a greater burden than male patients. The immune system may play an important role in the pathophysiology of females with IS. Therefore, it is critical to investigate the key biomarkers and immune infiltration of female IS patients to develop effective treatment methods. Herein, we used weighted gene co-expression network analysis (WGCNA) to determine the key modules and core genes in female IS patients using the GSE22255, GSE37587, and GSE16561 datasets from the GEO database. Subsequently, we performed functional enrichment analysis and built a protein-protein interaction (PPI) network. Ten genes were selected as the true central genes for further investigation. After that, we explored the specific molecular and biological functions of these hub genes to gain a better understanding of the underlying pathogenesis of female IS patients. Moreover, the "Cell type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT)" was used to examine the distribution pattern of immune subtypes in female patients with IS and normal controls, revealing a new potential target for clinical treatment of the disease.

Electroacupuncture Inhibits NLRP3 Activation by Regulating CMPK2 After Spinal Cord Injury.

Objectives: This study aimed to evaluate the expression of cytosine monophosphate kinase 2 (CMPK2) and activation of the NLRP3 inflammasome in rats with spinal cord injury (SCI) and to characterize the effects of electroacupuncture on CMPK2-associated regulation of the NLRP3 inflammasome. Methods: An SCI model was established in Sprague-Dawley (SD) rats. The expression levels of NLRP3 and CMPK2 were measured at different time points following induction of SCI. The rats were randomly divided into a sham group (Sham), a model group (Model), an electroacupuncture group (EA), an adeno-associated virus (AAV) CMPK2 group, and an AAV NC group. Electroacupuncture was performed at jiaji points on both sides of T9 and T11 for 20 min each day for 3 consecutive days. In the AAV CMPK2 and AAV NC groups, the viruses were injected into the T9 spinal cord via a microneedle using a microscope and a stereotactic syringe. The Basso-Beattie-Bresnahan (BBB) score was used to evaluate the motor function of rats in each group. Histopathological changes in spinal cord tissue were detected using H&E staining, and the expression levels of NLRP3, CMPK2, ASC, caspase-1, IL-18, and IL-1ß were quantified using Western blotting (WB), immunofluorescence (IF), and RT-PCR. Results: The expression levels of NLRP3 and CMPK2 in the spinal cords of the model group were significantly increased at day 1 compared with those in the sham group (p < 0.05). The expression levels of NLRP3 and CMPK2 decreased gradually over time and remained low at 14 days post-SCI. We successfully constructed AAV CMPK2 and showed that CMPK2 was significantly knocked down following 2 dilutions. Finally, treatment with EA or AAV CMPK2 resulted in significantly increased BBB scores compared to those in the model group and the AAV NC group (p < 0.05). The histomorphology of the spinal cord in the EA and AAV CMPK2 groups was significantly different than that in the model and AAV NC groups. WB, IF, and PCR analyses showed that the expression levels of CMPK2, NLRP3, ASC, caspase-1, IL-18, and IL-1ß were significantly lower in the EA and AAV CMPK2 groups compared with those in the model and AAV NC groups (p < 0.05). Conclusion: Our study showed that CMPK2 regulated NLRP3 expression in rats with SCI. Activation of NLRP3 is a critical mechanism of inflammasome activation and the inflammatory response following SCI. Electroacupuncture downregulated the expression of CMPK2 and inhibited activation of NLRP3, which could improve motor function in rats with SCI.

Study of the Immediate Effects of Autostereoscopic 3D Visual Training on the Accommodative Functions of Myopes.

Purpose: Stereoscopic viewing has an impact on ocular dynamics, but its effects on accommodative functions are not fully understood, especially for autostereoscopic viewing. This study aimed to investigate the changes in dynamic accommodative response, accommodative amplitude, and accommodative facility of myopes after autostereoscopic visual training. Methods: We enrolled 46 adults (men = 22 and women = 24; age = 21.5 ± 2.5 [range = 18-25] years, spherical equivalent: -4.52 ± 1.89 [-8.88 to -1.75] diopters [D]) who visited the Eye & ENT Hospital of Fudan University. The study population was randomly divided into three-dimensional (3D) and two-dimensional (2D) viewing groups to watch an 11-minute training video displayed in 3D or 2D mode. Dynamic accommodative response, accommodative facility, and accommodative amplitude were measured before, during, and immediately after the training. Accommodative lag and the variability of accommodation were also analyzed. Visual fatigue was evaluated subjectively using a questionnaire. Results: Accommodative lag decreased from 0.54 ± 0.29 D to 0.42 ± 0.32 D (P = 0.004), whereas accommodative facility increased from 10.83 ± 4.55 cycles per minute (cpm) to 13.15 ± 5.25 cpm (P < 0.001) in the 3D group. In the 2D group, there was no significant change in the accommodative lag (P = 0.163) or facility (P = 0.975), but a decrease in accommodative amplitude was observed (from 13.88 ± 3.17 D to 12.71 ± 2.23 D, P = 0.013). In the 3D group, the accommodative response changed with the simulated target distance. Visual fatigue was relatively mild in both groups. Conclusions: The immediate impact of autostereoscopic training included a decrease in the accommodative lag and an increase in the accommodative facility. However, the long-term effects of autostereoscopic training require further exploration.