Use of machine learning approaches to predict transition of retention in care among people living with HIV in South Carolina: a real-world data study.

Maintaining retention in care (RIC) for people living with HIV (PLWH) helps achieve viral suppression and reduce onward transmission. This study aims to identify the best machine learning model that predicts the RIC transition over time. Extracting from the enhanced HIV/AIDS reporting system, this study included 9765 PLWH from 2005 to 2020 in South Carolina. Transition of RIC was defined as the change of RIC status in each two-year time window. We applied seven classifiers, such as Random Forest, Support Vector Machine, eXtreme Gradient Boosting and Long-short-term memory, for each lagged response to predict the subsequent year's RIC transition. Classification performance was assessed using balanced prediction accuracy, the area under the curve (AUC), recall, precision and F1 scores. The proportion of the four categories of RIC transition was 13.59%, 29.78%, 9.06% and 47.57%, respectively. Support Vector Machine was the best approach for every lag model based on both the F1 score (0.713, 0.717 and 0.719) and AUC (0.920, 0.925 and 0.928). The findings could facilitate the risk augment of PLWH who are prone to follow-up so that clinicians and policymakers could come up with more specific strategies and relocate resources for intervention to keep them sustained in HIV care.

A novel XNA-based Luminex assay to detect UBA1 somatic mutations associated with VEXAS syndrome.

Objectives: Patients with VEXAS syndrome carry mutations of UBA1 gene coding for the E1 enzyme. The three most frequent mutations are p.M41T(122T > C), p.M41V (c.121A > G), and p.M41L (c.121A > C) in codon 41 of exon 3. Currently, sanger sequencing was mainly used to detect these mutations, which has low sensitivity and low throughput. There is a need of high sensitivity, simple and high throughput method to characterize patients with VEXAS syndrome. Methods: Based on our proprietary XNA technology, we have developed a QClamp® Plex platform to detect eight mutations in a single reaction using the Luminex xMap technology. The assay sensitivity, specificity and precision were subsequently evaluated. Furthermore, the reference interval and clinical sensitivity/specificity were estimated using clinical healthy/positive DNA samples and the sanger sequencing method was used for comparison. Results: With spiking synthetic mutant DNA in wildtype GM24385 cell line DNA, this assay can detect UBA1 mutations with a detection limit of variant allele frequency (VAF) at 0.1-5%. Our assay shows 100% concordance with Sanger sequencing results when used for analyzing 15 positive and 19 negative clinical samples. Conclusions: The QClamps® Plex UBA1 Mutation Detection Assay is a quicker, simpler, and more sensitive assay that can accurately detect the UBA1 mutations even at early stages with low mutation frequency.

Elevated KDM4D Expression in Pterygium: Impact and Potential Inhibition by Lycium Barbarum Polysaccharide.

Purpose: This study aimed to explore the effects of elevated KDM4D expression and potential therapeutic effects of Lycium barbarum polysaccharide (LBP) on pterygium. Methods: The expression levels of KDM4D in the primary pterygium (n = 29) and normal conjunctiva (n = 14) were detected by immunohistochemistry. The effects of KDM4D on pterygium fibroblasts were detected by the CCK-8 assay, liquid chromatography-mass spectrometry assay, flow cytometry, and scratch wound healing assay. The relative expression of KDM4D in pterygium fibroblasts stimulated by interleukin (IL)-1ß, IL-6, IL-8, and LBP was detected by quantitative real-time PCR and Western blot. The effects of LBP on pterygium fibroblasts were detected using flow cytometry and scratch wound healing assays. Results: The expression level of KDM4D in pterygium was higher than that in normal conjunctiva. KDM4D increased the cell viability of pterygium fibroblasts. The differentially expressed genes identified in the LM-MS assay enriched in "actin filament organization" and "apoptosis." KDM4D promoted migration and inhibited apoptosis of pterygium fibroblasts in vitro. Inflammatory cytokines, including IL-1ß, IL-6, and IL-8, enhanced the expression of KDM4D in pterygium fibroblasts. LBP inhibited the expression of KDM4D in pterygium fibroblasts and decreased their cell viability. Moreover, LBP attenuated the KDM4D effects on migration and apoptosis of pterygium fibroblasts. Conclusions: Elevated KDM4D expression is a risk factor for pterygium formation. LBP inhibits the expression of KDM4D in pterygium fibroblasts and may be a potential drug for delaying pterygium development.

Solutal Marangoni force controls lateral motion of electrolytic gas bubbles.

Electrochemical gas-evolving reactions have been widely used for industrial energy conversion and storage processes. Gas bubbles form frequently at the electrode surface due to a small gas solubility, thereby reducing the effective reaction area and increasing the over-potential and ohmic resistance. However, the growth and motion mechanisms for tiny gas bubbles on the electrode remains elusive. Combining molecular dynamics (MD) and fluid dynamics simulations (CFD), we show that there exists a lateral solutal Marangoni force originating from an asymmetric distribution of dissolved gas near the bubble. Both MD and CFD simulations deliver a similar magnitude of the Marangoni force of ∼0.01 nN acting on the bubble. We demonstrate that this force may lead to lateral bubble oscillations and analyze the phenomenon of dynamic self-pinning of bubbles at the electrode boundary.

Protein language models-assisted optimization of a uracil-N-glycosylase variant enables programmable T-to-G and T-to-C base editing.

Current base editors (BEs) use DNA deaminases, including cytidine deaminase in cytidine BE (CBE) or adenine deaminase in adenine BE (ABE), to facilitate transition nucleotide substitutions. Combining CBE or ABE with glycosylase enzymes can induce limited transversion mutations. Nonetheless, a critical demand remains for BEs capable of generating alternative mutation types, such as T>G corrections. In this study, we leveraged pre-trained protein language models to optimize a uracil-N-glycosylase (UNG) variant with altered specificity for thymines (eTDG). Notably, after two rounds of testing fewer than 50 top-ranking variants, more than 50% exhibited over 1.5-fold enhancement in enzymatic activities. When eTDG was fused with nCas9, it induced programmable T-to-S (G/C) substitutions and corrected db/db diabetic mutation in mice (up to 55%). Our findings not only establish orthogonal strategies for developing novel BEs but also demonstrate the capacities of protein language models for optimizing enzymes without extensive task-specific training data.

The cerebral lymphatic drainage system and its implications in epilepsy.

The central nervous system has long been thought to lack a clearance system similar to the peripheral lymphatic system. Therefore, the clearance of metabolic waste in the central nervous system has been a subject of great interest in neuroscience. Recently, the cerebral lymphatic drainage system, including the parenchymal clearance system and the meningeal lymphatic network, has attracted considerable attention. It has been extensively studied in various neurological disorders. Solute accumulation and neuroinflammation after epilepsy impair the blood-brain barrier, affecting the exchange and clearance between cerebrospinal fluid and interstitial fluid. Restoring their normal function may improve the prognosis of epilepsy. However, few studies have focused on providing a comprehensive overview of the brain clearance system and its significance in epilepsy. Therefore, this review addressed the structural composition, functions, and methods used to assess the cerebral lymphatic system, as well as the neglected association with epilepsy, and provided a theoretical basis for therapeutic approaches in epilepsy.

NEXMIF variants are associated with epilepsy with or without intellectual disability.

OBJECTIVES: Variants in NEXMIF had been reported associated with intellectual disability (ID) without epilepsy or developmental epileptic encephalopathy (DEE). It is unkown whether NEXMIF variants are associated with epilepsy without ID. This study aims to explore the phenotypic spectrum of NEXMIF and the genotype-phenotype correlations. MATERIALS AND METHODS: Trio-based whole-exome sequencing was performed in patients with epilepsy. Previously reported NEXMIF variants were systematically reviewed to analyze the genotype-phenotype correlations. RESULTS: Six variants were identified in seven unrelated cases with epilepsy, including two de novo null variants and four hemizygous missense variants. The two de novo variants were absent in all populations of gnomAD and four hemizygous missense variants were absent in male controls of gnomAD. The two patients with de novo null variants exhibited severe developmental epileptic encephalopathy. While, the patients with hemizygous missense variants had mild focal epilepsy with favorable outcome. Analysis of previously reported cases revealed that males with missense variants presented significantly higher percentage of normal intellectual development and later onset age of seizure than those with null variants, indicating a genotype-phenotype correlation. CONCLUSION: This study suggested that NEXMIF variants were potentially associated with pure epilepsy with or without intellectual disability. The spectrum of epileptic phenotypes ranged from the mild epilepsy to severe developmental epileptic encephalopathy, where the epileptic phenotypes variability are potentially associated with patients' gender and variant type.

Mitochondrial-regulated Tregs: potential therapeutic targets for autoimmune diseases of the central nervous system.

Regulatory T cells (Tregs) can eliminate autoreactive lymphocytes, induce self-tolerance, and suppress the inflammatory response. Mitochondria, as the energy factories of cells, are essential for regulating the survival, differentiation, and function of Tregs. Studies have shown that patients with autoimmune diseases of the central nervous system, such as multiple sclerosis, neuromyelitis optica spectrum disorder, and autoimmune encephalitis, have aberrant Tregs and mitochondrial damage. However, the role of mitochondrial-regulated Tregs in autoimmune diseases of the central nervous system remains inconclusive. Therefore, this study reviews the mitochondrial regulation of Tregs in autoimmune diseases of the central nervous system and investigates the possible mitochondrial therapeutic targets.

Efficient exon skipping by base-editor-mediated abrogation of exonic splicing enhancers.

Duchenne muscular dystrophy (DMD) is a severe genetic disease caused by the loss of the dystrophin protein. Exon skipping is a promising strategy to treat DMD by restoring truncated dystrophin. Here, we demonstrate that base editors (e.g., targeted AID-mediated mutagenesis [TAM]) are able to efficiently induce exon skipping by disrupting functional redundant exonic splicing enhancers (ESEs). By developing an unbiased and high-throughput screening to interrogate exonic sequences, we successfully identify novel ESEs in DMD exons 51 and 53. TAM-CBE (cytidine base editor) induces near-complete skipping of the respective exons by targeting these ESEs in patients' induced pluripotent stem cell (iPSC)-derived cardiomyocytes. Combined with strategies to disrupt splice sites, we identify suitable single guide RNAs (sgRNAs) with TAM-CBE to efficiently skip most DMD hotspot exons without substantial double-stranded breaks. Our study thus expands the repertoire of potential targets for CBE-mediated exon skipping in treating DMD and other RNA mis-splicing diseases.

Association of CD4 + cell count and HIV viral load with risk of non-AIDS-defining cancers.

OBJECTIVES: HIV-induced immunodeficiency contributes to an increased risk of non-AIDS-defining cancers (NADC). This study aims to identify the most predictive viral load (VL) or CD4 + measures of NADC risk among people with HIV (PWH). DESIGN: Extracted from South Carolina electronic HIV reporting system, we studied adult PWH who were cancer-free at baseline and had at least 6 months of follow-up since HIV diagnosis between January 2005 and December 2020. METHODS: Using multiple proportional hazards models, risk of NADC was investigated in relation to 12 measures of VL and CD4 + cell count at three different time intervals before NADC diagnosis. The best VL/CD4 + predictor(s) and final model were determined using Akaike's information criterion. RESULTS: Among 10 413 eligible PWH, 449 (4.31%) developed at least one type of NADC. After adjusting for potential confounders, the best predictors of NADC were the proportion of days with viral suppression (hazard ratio [HR]: 0.47 (>25% and ≤50% vs. 0), 95% confidence interval [CI]: [0.28, 0.79]) and proportion of days with low CD4 + cell count (AIC = 7201.35) (HR: 12.28 (>75% vs. = 0), 95% CI: [9.29, 16.23]). CONCLUSIONS: VL and CD4 + measures are strongly associated with risk of NADC. In analyses examining three time windows, proportion of days with low CD4 + cell count was the best CD4 + predictor for each time window. However, the best VL predictor varied across time windows. Thus, using the best combination of VL and CD4 + measures for a specific time window should be considered when predicting NADC risk.

Mechanical influence of periacetabular osteotomy on late total hip arthroplasty.

Periacetabular osteotomy (PAO) is an effective technique to treat symptomatic hip dysplasia. However, following PAO, some patients still experience persistent pain or development of hip arthritis, requiring total hip arthroplasty (THA). Issues such as whether patients with PAO are necessarily at increased risk of post-THA complications and revision of the prosthesis remain debatable. The purpose of this study was to evaluate the biomechanical influence of PAO on the acetabulum after THA by finite element analysis. Eight patients with developmental dysplasia of the hip (DDH) diagnosed in the Fourth Medical Center of the PLA General Hospital were enrolled in this research. Patient-specific hip joint models were reconstructed from computed tomography scans, and the hip prosthesises, were established via computer-aided design (CAD) modeling technology. The finite element analysis was conducted to compare the surface and internal stress through the process mapping of the model due to the THA. Compared with the THA after PAO, the position of the high-stress area of the acetabular fossa of patients without PAO decreased, and the high-stress area developed toward the lower edge of the acetabulum. Although the high-stress area of the suprapubic branch did not change significantly, the peak stress was higher (t = .00237). The analysis of the section plane showed that the high-stress area of cancellous bone had a large distribution. The acetabular size and vertical distance of rotation center (VDRC) were significantly correlated with the maximum postoperative acetabular equivalent stress (p = .011, p = .001). In the Post group, both the horizontal distance of rotation center (HDRC) and A-ASA were significantly correlated with postoperative maximal acetabular equivalent stress, with a significance of 0.014 and 0.035, respectively. The risk of postoperative prosthetic revision following THA is not increased by PAO, although the risk of postoperative suprapubic branch fracture is increased.

NLRP3 upregulation related to sleep deprivation-induced memory and emotional behavior changes in TRPV1-/- mice.

Sleep deprivation, which is a common problem in modern society, impairs memory function and emotional behavior. TRPV1, a subfamily of transient receptor potential cation channels, is abundantly expressed in the central nervous system and is associated with animal behavior. In this article, we report that TRPV1 deficiency in mice alleviates sleep deprivation-induced abnormal behaviors. We found that in the sleep-deprived mice, TRPV1 knockout increased the duration and visits in the central area in the open field task and increased visits to the open arms in the elevated plus maze. The TRPV1-/- mice performed better during the test stage in the Morris water maze phase after sleep deprivation. In the mPFC and hippocampus regions, western blotting results showed that TRPV1-/- attenuated sleep deprivation-induced increases in GFAP, NLRP3, and ASC and increased the expression of the mitochondrial marker Tom20. Immunofluorescence results showed that the action of TRPV1 knockout on NLRP3 was negatively correlated with Tom20 after sleep deprivation. Our results confirm that TRPV1 knockout attenuates sleep deprivation-induced behavioral disorders. The effect of TRPV1 on the behavior of sleep-deprived mice may be related to the neuroinflammation associated with mitochondria in the mPFC and hippocampus.

Parental Rejection and School-aged Children's Externalizing Behavior Problems in China: The Roles of Executive Function and Callous-unemotional Traits.

This study examined the mediating role of children's executive function (EF) in the relation between parental rejection and children's externalizing behavior problems and whether this mediation varies depending on their callous-unemotional (CU) trait levels. Two hundred and eighty-four Chinese school-aged children and their fathers and mothers participated. Both fathers and mothers reported on parental rejection, children's externalizing behavior problems, EF, and CU traits. The results showed that EF mediated the association between parental rejection and externalizing behavior problems. Moreover, the negative link between EF and externalizing behavior problems was moderated by CU traits; in particular, the combination of higher-level CU traits and lower-level EF predicted more externalizing behavior problems. Our findings point to the importance of considering family context and multiple personal factors simultaneously to decrease children's behavior problems.

Direct measuring of single-heterogeneous bubble nucleation mediated by surface topology.

Heterogeneous bubble nucleation is one of the most fundamental interfacial processes ranging from nature to technology. There is excellent evidence that surface topology is important in directing heterogeneous nucleation; however, deep understanding of the energetics by which nanoscale architectures promote nucleation is still challenging. Herein, we report a direct and quantitative measurement of single-bubble nucleation on a single silica nanoparticle within a microsized droplet using scanning electrochemical cell microscopy. Local gas concentration at nucleation is determined from finite element simulation at the corresponding faradaic current of the peak-featured voltammogram. It is demonstrated that the criteria gas concentration for nucleation first drops and then rises with increasing nanoparticle radius. An optimum nanoparticle radius around 10 nm prominently expedites the nucleation by facilitating the special topological nanoconfinements that consequently catalyze the nucleation. Moreover, the experimental result is corroborated by our theoretical calculations of free energy change based on the classic nucleation theory. This study offers insights into the impact of surface topology on heterogenous nucleation that have not been previously observed.

Single-cell sequencing reveals the antifibrotic effects of YAP/TAZ in systemic sclerosis.

Systemic sclerosis (SSc) is a heterogeneous disease with skin fibrosis. Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) is associated with fibrotic response. This work attempted to determine the precise mechanism of YAP/TAZ in SSc. Single-cell sequencing (scRNA-seq) was used to analyse the differential gene expression between SSc patients and healthy volunteers, showing that the YAP/TAZ signalling pathway was enriched in the fibroblasts of SSc patients. Subsequently, enzyme-linked immunosorbent assay and immunohistochemical analyses were conducted to examine the levels of YAP and TAZ in mild and severe SSc patients. YAP and TAZ were highly expressed in the serum and skin tissues of mild and severe SSc patients, especially severe SSc patients. Additionally, an SSc mouse model was induced by bleomycin, and the impacts of YAP/TAZ knockdown on the pathological changes in skin and lung tissues were detected by haematoxylin and eosin staining and Masson staining. Knockdown of YAP and TAZ inhibited α-SMA mRNA and protein expression in skin and lung tissues of SSc mice. Inhibition of YAP and TAZ reduced skin inflammation and thickness and repressed lung inflammation and fibrosis in SSc mice. Importantly, knockdown of YAP and TAZ synergistically inhibited inflammation and fibrosis in skin and lung tissues in SSc mice. In conclusion, this work demonstrated that knockdown of YAP and TAZ exerted a synergistic effect on alleviating SSc in mice. Thus, this work suggests that YAP/TAZ is a potential target for SSc treatment.

Investigation on the etiology of patients undergoing non-traumatic total hip arthroplasty in China.

BACKGROUND: China has neither a nationwide joint replacement registry similar to Sweden and New Zealand nor a universal healthcare (medical insurance) registry similar to Hong Kong and Singapore to check. The purpose was to initially understand the distribution characteristics of gender, age and etiology of patients undergoing total hip replacement for non-traumatic reasons nationwide. METHODS: The clinical data of patients who underwent initial artificial total hip replacement due to non-traumatic reasons in joint surgery of 13 large general first-class hospitals at Grade 3 in northern, western, eastern, southern, and southwestern China were collected. After the classification of patients by gender, the etiological characteristics and age distribution of male and female patients were compared, as well as male to female ratio and disease composition ratio of patients of different ages, distribution of causes in different regions, composition ratio, and age distribution characteristics of patients of different ethnic groups. RESULTS: In this study, the data of a total of 7663 patients in joint surgery of 13 general first-class hospitals at Grade 3 from 2015 to 2017 were collected, and 7622 patients were finally included in the study after excluding missing age, gender and some foreign patients. The main causes of diagnosis in male patients were AVN, DDH, and OA, and top 3 causes in female patients were DDH, AVN, and OA. CONCLUSIONS: This study initially understand the distribution characteristics of gender, age and etiology of patients undergoing total hip replacement for non-traumatic reasons nationwide, and further guide the clinical diagnosis, early prevention and treatment of the disease and provide data.

Targeted and activatable nanosystem for fluorescent and optoacoustic imaging of immune-mediated inflammatory diseases and therapy via inhibiting NF-κB/NLRP3 pathways.

Immune-mediated inflammatory diseases (IMIDs) represent a diverse group of diseases and challenges remain for the current medications. Herein, we present an activatable and targeted nanosystem for detecting and imaging IMIDs foci and treating them through blocking NF-κB/NLRP3 pathways. A ROS-activatable prodrug BH-EGCG is synthesized by coupling a near-infrared chromophore with the NF-κB/NLRP3 inhibitor epigallocatechin-3-gallate (EGCG) through boronate bond which serves as both the fluorescence quencher and ROS-responsive moiety. BH-EGCG molecules readily form stable nanoparticles in aqueous medium, which are then coated with macrophage membrane to ensure the actively-targeting capability toward inflammation sites. Additionally, an antioxidant precursor N-acetylcysteine is co-encapsulated into the coated nanoparticles to afford the nanosystem BH-EGCG&NAC@MM to further improve the anti-inflammatory efficacy. Benefiting from the inflammation-homing effect of the macrophage membrane, the nanosystem delivers payloads (diagnostic probe and therapeutic drugs) to inflammatory lesions more efficiently and releases a chromophore and two drugs upon being triggered by the overexpressed in-situ ROS, thus exhibiting better theranostic performance in the autoimmune hepatitis and hind paw edema mouse models, including more salient imaging signals and better therapeutic efficacy via inhibiting NF-κB pathway and suppressing NLRP3 inflammasome activation. This work may provide perceptions for designing other actively-targeting theranostic nanosystems for various inflammatory diseases.

Upregulation of TRPC5 in hippocampal excitatory synapses improves memory impairment associated with neuroinflammation in microglia knockout IL-10 mice.

BACKGROUND: Members of the transient receptor potential canonical (TRPC) protein family are widely distributed in the hippocampus of mammals and exert respective and cooperative influences on the functions of neurons. The relationship between specific TRPC subtypes and neuroinflammation is receiving increasing attention. METHODS: Using Cx3cr1CreERIL-10-/- transgenic mice and their littermates to study the relationship between TRPC channels and memory impairment. RESULTS: We demonstrated that Cx3cr1CreERIL-10-/- mice displayed spatial memory deficits in object location recognition (OLR) and Morris water maze (MWM) tasks. The decreased levels of TRPC4 and TRPC5 in the hippocampal regions were verified via reverse transcription polymerase chain reaction, western blotting, and immunofluorescence tests. The expression of postsynaptic density protein 95 (PSD95) and synaptophysin in the hippocampus decreased with an imbalance in the local inflammatory environment in the hippocampus. The number of cells positive for ionized calcium-binding adaptor molecule 1 (Iba1), a glial fibrillary acidic protein (GFAP), increased with the high expression of interleukin 6 (IL-6) in Cx3cr1CreERIL-10-/- mice. The nod-like receptor protein 3 (NLRP3) inflammasome was also involved in this process, and the cytokines IL-1ß and IL-18 activated by NLRP3 were also elevated by western blotting. The co-localization of TRPC5 and calmodulin-dependent protein kinase IIα (CaMKIIα) significantly decreased TRPC5 expression in excitatory neurons. AAV9-CaMKIIα-TRPC5 was used to upregulate TRPC5 in excitatory neurons in the hippocampus. CONCLUSIONS: The results showed that the upregulation of TRPC5 improved the memory performance of Cx3cr1CreERIL-10-/- mice related to inhibiting NLRP3 inflammasome-associated neuroinflammation.

BRUCE silencing leads to axonal dystrophy by repressing autophagosome-lysosome fusion in Alzheimer's disease.

Axonal dystrophy is a swollen and tortuous neuronal process that contributes to synaptic alterations occurring in Alzheimer's disease (AD). Previous study identified that brain-derived neurotrophic factor (BDNF) binds to tropomyosin-related kinase B (TrkB) at the axon terminal and then the signal is propagated along the axon to the cell body and affects neuronal function through retrograde transport. Therefore, this study was designed to identify a microRNA (miRNA) that alters related components of the transport machinery to affect BDNF retrograde signaling deficits in AD. Hippocampus tissues were isolated from APP/PS1 transgenic (AD-model) mice and C57BL/6J wild-type mice and subject to nicotinamide adenine dinucleotide phosphate and immunohistochemical staining. Autophagosome-lysosome fusion and nuclear translocation of BDNF was detected using immunofluorescence in HT22 cells. The interaction among miR-204, BIR repeat containing ubiquitin-conjugating enzyme (BRUCE) and Syntaxin 17 (STX17) was investigated using dual luciferase reporter gene assay and co-immunoprecipitation assay. The expression of relevant genes and proteins were determined by RT-qPCR and Western blot analysis. Knockdown of STX17 or BRUCE inhibited autophagosome-lysosome fusion and impacted axon growth in HT22 cells. STX17 immunoprecipitating with BRUCE and co-localization of them demonstrated BRUCE interacted with STX17. BRUCE was the target of miR-204, and partial loss of miR-204 by inhibitor promoted autophagosome-lysosome fusion to prevent axon dystrophy and accumulated BDNF nuclear translocation to rescue BDNF/TrkB signaling deficits in HT22 cells. The overall results demonstrated that inhibition of miR-204 prevents axonal dystrophy by blocking BRUCE interaction with STX17, which unraveled potential novel therapeutic targets for delaying AD.

Depression-like behavior associated with E/I imbalance of mPFC and amygdala without TRPC channels in mice of knockout IL-10 from microglia.

Depression has a growing impact on public health. Accumulating evidence supports an association between depression and increased immune system activity. IL-10 is a key cytokine that inhibits excessive inflammatory responses and is related to the anti-inflammatory and protective functions of the central nervous system (CNS). Cx3cr1CreERIL-10-/- mice were used in our study. We aimed to identify the role of IL-10 in microglia in depression and anxiety-like behavior. We performed a series of behavioral tests on the mice; the Cx3cr1CreERIL-10-/- male mice showed depression- and anxiety-like behavior compared with the littermates. The expression of transient receptor potential canonical 5 (TRPC5) decreased in both the medial prefrontal cortex (mPFC) and amygdala regions. The cytokines IL-1ß and IL-6 increased, and IL-10 was decreased by western blotting. The knockout mice showed different trends in the effects of synaptic proteins. In the mPFC, IL-10 knockout induced a decrease in NR2B and synaptophysin; in the amygdala region, there was a significant increase in NR2B and PSD95. IL-10 knockout from microglia induced a decrease in GAD67 and parvalbumin (Pv) in the mPFC, but not in the amygdala. Our results showed enhanced depression and anxiety-like behavior in the Cx3cr1CreER IL-10-/- mice, which could be related to an imbalance in local excitatory and inhibitory transmission, as well as neuroinflammation in the mPFC and amygdala. This imbalance was associated with increased local inflammation. Although many studies have demonstrated the role of TRPC channels in emotional responses, our study showed that TRPC was not involved in this process in Cx3cr1CreERIL-10-/- mice.