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Background This study aimed to determine whether handwriting patterns are altered in individuals experiencing depressive episodes. Additionally, we developed a model for the recognition of major depressive disorder (MDD) based on electronic handwriting in psychological tasks. Methods A total of 130 patients and 117 healthy controls completed 21 psychology-related handwriting tasks. The electronic tablet recorded several handwriting characteristics, including horizontal and vertical coordinates, nib pressure and speed, and inclination angle. The statistical indicators for each handwriting characteristic were calculated. Statistical analyses, including differential analysis, were performed to identify predictors of depression. Furthermore, logistic regression and machine learning models were developed to discriminate MDD. Results The study included 130 patients with onset depression (mean (standard deviation (SD)) age, 20.42 (5.21)) and 117 healthy controls (mean (SD) age, 20.54 (2.60)). The t -test and logistics analysis results indicated that depressed patients exhibited a higher minimum of handwriting pressure, an elevated median of handwriting speed, and greater pen tip jitter. The LightGBM machine learning model exhibited satisfactory performance, with a cross-validated area under the receiver operating curve of mean 0.90 (SD, 0.01). The analysis of variance revealed that the negative question–answer task model exhibited superior performance compared to the neutral and positive task models. Conclusions The present study indicates that depressed patients exhibit modal handwriting changes and developed a cost-effective, rapid, and valid model for identifying MDD. This finding established a strong foundation for developing multimodal recognition models in the future.

Background Brain injury is the main cause of high mortality and disability after successful cardiopulmonary resuscitation (CPR) from sudden cardiac arrest (CA). The transient receptor potential M4 (TRPM4) channel is a novel target for ameliorating blood–brain barrier (BBB) disruption and neuroinflammation. Herein, we tested whether flufenamic acid (FFA), which is reported to block TRPM4 with high potency, could confer neuroprotection against brain injury secondary to CA/CPR and whether its action was exerted by blocking the TRPM4 channel. Methods Wild-type (WT) and Trpm4 knockout ( Trpm4 −/− ) mice subjected to 10-min CA/CPR were randomized to receive FFA or vehicle once daily. Post-CA/CPR brain injuries including neurologic deficits, survival rate, histological damage, edema formation, BBB destabilization and neuroinflammation were assessed. Results In WT mice subjected to CA/CPR, FFA was effective in improving survival and neurologic outcome, reducing neuropathological injuries, attenuating brain edema, lessening the leakage of IgG and Evans blue dye, restoring tight junction protein expression and promoting microglia/macrophages from the pro-inflammatory subtype toward the anti-inflammatory subtype. In comparison to WT mice, Trpm4 −/− mice exhibited less neurologic deficiency, milder histological impairment, more BBB integrity and more anti-inflammatory microglia/macrophage polarization. As expected, FFA did not provide a benefit of superposition compared with vehicle in the Trpm4 −/− mice after CA/CPR. Conclusions FFA mitigates BBB breach and modifies the functional status of microglia/macrophages, thereby improving survival and neurologic deficits following CA/CPR. The neuroprotective effects occur at least partially by interfering with the TRPM4 channel in the neurovascular unit. These results indicate the significant clinical potential of FFA to improve the prognosis for CA victims who are successfully resuscitated.

Delayed radiation-induced brain injury (RIBI) characterized by progressive cognitive decline significantly impacts patient outcomes after radiotherapy. The activation of NLRP3 inflammasome within microglia after brain radiation is involved in the progression of RIBI by mediating inflammatory responses. We have previously shown that sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) mediates microglial NLRP3-related inflammation following global brain ischemia. However, the role of SUR1-TRPM4 in RIBI remains unclear. Here, we found that whole-brain radiation induced up-regulation and assembly of SUR1-TRPM4, which further activated the NLRP3 inflammasome in microglia and caused persistent neuroinflammation in mice. Blocking SUR1-TRPM4 by glibenclamide or gene deletion of Trpm4 effectively prevented NLRP3-mediated neuroinflammation and alleviated RIBI. Utilizing the mouse model of RIBI and irradiated BV2 cells, we further demonstrated that irradiation caused mitochondrial damage to microglia, leading to violent release of reactive oxygen species (ROS), which enhanced the transcription of SUR1, TRPM4, and NLRP3 inflammasome-related molecules. Moreover, ROS up-regulated ten-eleven translocation 2 (TET2) to enhance TRPM4 expression by mediating the demethylation of the gene promoter, thereby facilitating the assembly of SUR1-TRPM4 in microglia. In summary, this study deciphers that SUR1-TRPM4 crucially mediates the persistent activation of microglial NLRP3 inflammasome under the action of ROS after whole-brain radiation, offering novel therapeutic strategies for delayed RIBI as well as other NLRP3-related neurological disorders involving excessive ROS production.

Brain injury represents the leading cause of mortality and disability after cardiopulmonary resuscitation (CPR) from cardiac arrest (CA), in which the accumulation of dying cells aggravate tissue injury by releasing proinflammatory intracellular components. Microglia play an essential role in maintaining brain homeostasis via milk fat globule epidermal growth factor 8 (MFG‐E8)‐opsonized efferocytosis, the engulfment of dying cells and debris. This study investigates whether potentiating microglia efferocytosis by MFG‐E8 provides neuroprotection after CA/CPR. After 8‐minute asphyxial CA/CPR, male adult C57BL/6J mice were randomly assigned to receive recombinant mouse MFG‐E8 (rmMFG‐E8) or vehicle. We evaluated the survival and neurological deficits of mice, along with histological damages, phagocytosis index of dying cells, and microglia polarization. A transcriptome analysis was conducted to explore the downstream molecules modulated by MFG‐E8. In mice resuscitated from CA, rmMFG‐E8 administration significantly enhanced the efferocytosis of apoptotic cells by microglia, improved the survival and neurological function of mice, and attenuated neuropathological injuries. Additionally, rmMFG‐E8 induced a prominent alteration in microglial gene expression and promoted a shift from a proinflammatory phenotype to an anti‐inflammatory phenotype. Moreover, rmMFG‐E8 treatment induced up‐regulation of interferon regulatory factor 7 (IRF7), and IRF7 gene silencing largely reversed the neuroprotective effects of rmMFG‐E8. This study demonstrates that rmMFG‐E8 improves survival and neurological outcomes after CA/CPR by enhancing microglial efferocytosis and reshaping the inflammatory microenvironment in brain tissue. Potentiating MFG‐E8 is a promising strategy to combat post‐CA brain injury. Schematic representation of the effects of rmMFG‐E8 on post‐CA/CPR brain injury. Ischemic/reperfusion injury caused by CA/RCA results in elevated apoptotic cell death in various cells and decreased apoptotic cell clearance by phagocytes, such as microglia. Apoptotic cells, without proper phagocytic clearance, have the potential to release toxic and proinflammatory contents through secondary necrosis, creating a vicious cycle that contributes to further brain injury. MFG‐E8 administration enhances phagocytic activity and induces microglia to switch to an anti‐inflammatory phenotype, effectively attenuating deleterious inflammation and further mitigating neuronal injury, ultimately improving survival and neurological outcome.

Emerging studies underscore the pivotal role of glymphatic system (GS) dysfunction in the pathogenesis of cerebral edema following brain injury. The transient receptor potential vanilloid 4 (TRPV4) channels have been implicated in modulating the polarization of aquaporin‐4 (AQP4), a key protein involved in GS function. This study investigates the potential of targeting TRPV4 to alleviate GS dysfunction and reduce cerebral edema following ischemic stroke. TRPV4 inhibitor HC067047 or a vehicle was administered via lateral ventricle cannulation in a mouse model of middle cerebral artery occlusion and reperfusion (MCAO/R). The function of the GS was assessed through tracer injection experiments, including in vivo transcranial imaging, ex vivo brain tissue and section analysis, and fluorescence retention in deep cervical lymph nodes (dCLNs). Cerebral edema was quantified using magnetic resonance imaging. AQP4 polarization and β‐dystroglycan (β‐DG) expression were evaluated by immunofluorescence. Western blotting was employed to measure protein levels of β‐DG, matrix metalloproteinase‐9 (MMP9), and Ras homolog family member A (RhoA). Long‐term neurological outcomes were assessed via behavioral testing. MCAO/R mice exhibited significant GS dysfunction, cerebral edema, and disrupted AQP4 polarization. Additionally, β‐DG expression was markedly reduced, while TRPV4 expression was elevated in the ischemic penumbra. Western blotting revealed increased expression of MMP9 and RhoA. The inhibition of TRPV4 by HC067047 significantly improved GS function, reduced cerebral edema, and enhanced neurological recovery. Mechanistically, HC067047 partially restored AQP4 polarization, upregulated β‐DG expression, and suppressed the expression of MMP9 and RhoA. These findings highlight the therapeutic potential of TRPV4 inhibition in ischemic stroke by restoring GS function, mitigating cerebral edema, and promoting neurological recovery, thereby positioning TRPV4 as a promising target for future interventions. After ischemic stroke, TRPV4 activation induces cerebral edema through the TRPV4‐RhoA‐MMP9 axis: RhoA upregulates MMP9, which cleaves β‐DG to impair membrane anchoring. Subsequent β‐DG loss triggers AQP4 depolarization, disrupting GS‐mediated water homeostasis. This cascade establishes β‐DG/AQP4 dysregulation as the core pathogenic mechanism of edema.

Brain injury is the leading cause of death and disability in survivors of cardiac arrest, where neuroinflammation triggered by infiltrating macrophages plays a pivotal role. Here, we seek to elucidate the origin of macrophages infiltrating the brain and their mechanism of action after cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Wild-type or photoconvertible Cd68-Cre:R26-LSL-KikGR mice were subjected to 10-min CA/CPR, and the migration of gut-derived macrophages into brain was assessed. Transcriptome sequencing was performed to identify the key proinflammatory signal of macrophages infiltrating the brain, triggering receptor expressed on myeloid cells 1 (TREM1). Upon drug intervention, the effects of TREM1 on post-CA/CPR brain injury were further evaluated. 16S rRNA sequencing was used to detect gut dysbiosis after CA/CPR. Through photoconversion experiments, we found that small intestine-derived macrophages infiltrated the brain and played a crucial role in triggering secondary brain injury after CA/CPR. The infiltrating peripheral macrophages showed upregulated TREM1 levels, and we further revealed the crucial role of gut-derived TREM1 + macrophages in post-CA/CPR brain injury through a drug intervention targeting TREM1. Moreover, a close correlation between upregulated TREM1 expression and poor neurological outcomes was observed in CA survivors. Mechanistically, CA/CPR caused a substantial expansion of Enterobacter at the early stage, which ignited intestinal TREM1 signaling via the activation of Toll-like receptor 4 on macrophages through the release of lipopolysaccharide. Our findings reveal essential crosstalk between the gut and brain after CA/CPR and underscore the potential of targeting TREM1 + small intestine-derived macrophages as a novel therapeutic strategy for mitigating post-CA/CPR brain injury.

During the early mid-1990s, a number of rural farmers across central China were employed to the unregulated plasma- selling-activity and many of them were infected by HIV-1. However, AIDS progression in the former blood donors （FBDs） is various. The aim of this study is to assess human leukocyte antigen （HLA） class I allele distribution in FBDs and evaluate its association with HIV-1 infection and disease progression. A total of 353 FBDs were enrolled in the cohort including 294 ART na＇fve HIV-1 seropositive and 59 HIV-1 seronegative age-matched subjects. The viral load and CD4/CD8 T cell counts were assessed in all subjects. Compared with HIV-seropositive group, the frequency of HLA-A＊03 in control was significantly higher. After classifying the HLA-B alleles of the subjects according to the presence of Bw4/Bw6 serological epitopes, detri- mental effect of HLA Bw6/Bw6 homozygosity was also confirmed in the HIV-seropositive subjects. This study provides nov- el evidence on HLA class I allele distribution and association of HLA-A＊03 frequency with HIV-1 infection and viremia in the HIV-1 infected FBDs, which may throw light on intervention strategy for the HIV-1 infection and our understanding how host immunity and genetic background affect HIV infection and AIDS progression.

It is generally believed that CD8＋ cytotoxic T lymphocytes （CTLs） play a critical role in limiting the replication of human immunodeficiency virus type 1 （HIV-1） and in determining the outcome of the infection, and this effect may partly depend on which HIV product is preferentially targeted. To address the correlation between HIV-l-specific CTL responses and virus replication in a cohort of former plasma donors （FPDs）, 143 antiretroviral therapy naive FPDs infected with HIV-1 clade B＇ strains were assessed for HIV-l-specific CTL responses with an IFN-γ Elispot as- say at single peptide level by using overlapping peptides （OLPs） covering the whole consensus clade B proteome. By using a Spearman＇s rank correlation analysis, we found that the proportion of Gag-specific CTL responses among the total virus-specific CTL activity was inversely correlated with viral loads while being positively correlated to CD4 counts, as opposed to Pol- and Env-speeific responses that were associated with increased viral loads and decreased CD4 counts. In addition, Vpr-specifc CTL responses showed a similar protective effect with Gag responses, but with a much lower frequency of recognition. Significantly, we also observed an association between HLA-A＊30/B＊13/ Cw＊06 haplotype and lower viral loads that was probably due to restricted Gag-specific CTL responses. Thus, our data demonstrate the prominent role of Gag-specific CTL responses in disease control. The advantage of HLA-A＊30/ B＊13/Cw＊06 haplotype in viral control may be associated with the contribution of Gag-specific CTL responses in the studied individuals.

Background: This study aims to design a 3D printed handheld electrospinning device and evaluate its effect on the rapid repair of mouse skin wounds. Methods: The device was developed by Solidworks and printed by Object 350 photosensitive resin printer. The polylactic acid (PLA)/gelatin blend was used as the raw material to fabricate in-situ degradable nanofiber scaffolds. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and water vapor permeability test were used to evaluate the material properties of the scaffolds; cytotoxicity test was performed to evaluate material/residual solvent toxicity, and in situ tissue repair experiments in Balb/c mouse were performed. Results: The 3D printed handheld electrospinning device successfully fabricates PLA/gelatin nanofibrous membrane with uniformly layered nanofibers and good biocompatibility. Animal experiments showed that the mice in the experimental group had complete skin repair. Conclusions: The 3D printed handheld device can achieve in situ repair of full-thickness defects in mouse skin.

Lipopeptide-19, a HIV fusion inhibitor (LP-19), has showed potent anti-HIV activity. However, there is still limited information of the antiviral activity against different subtype clinical isolates and the drug resistance barrier of LP-19. Therefore, 47 HIV clinical isolates were selected for this study. The viral features were identified, in which 43 strains are CCR5 tropisms, and 4 strains are CCR5/CXCR4 tropisms, and there are 6 subtype B’, 15 CRF01_AE, 14 CRF07_BC, 2 CRF08_BC and 10 URF strains. These 47 viruses were used to detected and analyze the inhibitory activities of LP-19. The results showed that the average 50% inhibitory concentration (IC 50 ) and 90% inhibitory concentration (IC 90 ) of LP-19 were 0.50 nM and 1.88 nM, respectively. The average IC 50 of LP-19 to B’, CRF01_AE, CRF07_BC, CRF08_BC, and URF strains was 0.76 nM, 0.29 nM, 0.38 nM, 0.85 nM, and 0.44 nM, respectively. C34 and Enfuvirtide (T-20), two fusion inhibitors, were compared on the corresponding strains simultaneously. The antiviral activity of LP-19 was 16.7-fold and 86-fold higher than that of C34 and T-20. The antiviral activity of LP-19, C34, and T-20 were further detected and showed IC 50 was 0.15 nM, 1.02 nM, and 66.19 nM, respectively. IC 50 of LP-19 was about 7-fold and 441-fold higher compared to C34 and T-20 against HIV-1 NL4-3 strains. NL4-3 strains were exposed to increasing concentrations of LP-19 and C34 in MT-2 cell culture. The culture virus was sequenced and analyzed. The results showed that A243V mutation site identified at weeks 28, 32, 38, and 39 of the cell culture in the gp41 CP (cytoplasmic domain) region. NL4-3/A243V viruses containing A243V mutation were constructed. Comparing the antiviral activities of LP-19 against HIV NL4-3 to HIV strains (only 1.3-fold), HIV did not show drug resistance when LP-19 reached 512-fold of the initial concentration under the drug pressure for 39 weeks. This study suggests that LP-19 has broad-spectrum anti-HIV activity, and high drug resistance barrier.