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HIV-specific chimeric antigen receptor-T cell (CAR T cell) therapies are candidates to functionally cure HIV infection in people with HIV (PWH) by eliminating reactivated HIV-infected cells derived from latently infected cells within the HIV reservoir. Paramount to translating such therapeutic candidates successfully into the clinic will require anti-HIV CAR T cells to localize to lymphoid tissues in the body and eliminate reactivated HIV-infected cells such as CD4+ T cells and monocytes/macrophages. Here we show that i.v. injected anti-HIV duoCAR T cells, generated using a clinical-grade anti-HIV duoCAR lentiviral vector, localized to the site of active HIV infection in the spleen of humanized mice and eliminated HIV-infected PBMCs. CyTOF analysis of preinfusion duoCAR T cells revealed an early memory phenotype composed predominantly of CCR7+ stem cell-like/central memory T cells (TSCM/TCM) with expression of some effector-like molecules. In addition, we show that anti-HIV duoCAR T cells effectively sense and kill HIV-infected CD4+ T cells and monocytes/macrophages. Furthermore, we demonstrate efficient genetic modification of T cells from PWH on suppressive ART into anti-HIV duoCAR T cells that subsequently kill autologous PBMCs superinfected with HIV. These studies support the safety and efficacy of anti-HIV duoCAR T cell therapy in our presently open phase I/IIa clinical trial (NCT04648046).

Epigenetics is a biological process that modifies and regulates gene expression, affects neuronal function, and contributes to pain. However, the mechanism by which epigenetics facilitates and maintains chronic pain is poorly understood. We aimed to determine whether [N.sup.6]-methyladenosine (m6A) specifically modified by methyltransferase-like 14 (METTL14) alters neuronal activity and governs pain by sensitizing the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR) in the dorsal root ganglion (DRG) neurons in a model of chemotherapy-induced neuropathic pain (CINP). Using dot blotting, immunofluorescence, gain/loss-of-function, and behavioral assays, we found that m6A levels were upregulated in L4-L6 DRG neurons in CINP in a DBP/METTL14-dependent manner, which was also confirmed in human DRGs. Blocking METTL14 reduced m6A methylation and attenuated pain hypersensitivity. Mechanistically, METTL14-mediated m6A modification facilitated the synaptic plasticity of DRG neurons by enhancing the GluN2A subunit of NMDAR, and inhibiting METTL14 blocked this effect. In contrast, overexpression of METTL14 upregulated m6A modifications, enhanced presynaptic NMDAR activity in DRG neurons, and facilitated pain sensation. Our findings reveal a previously unrecognized mechanism of METTL14-mediated m6A modification in DRG neurons to maintain neuropathic pain. Targeting these molecules may provide a new strategy for pain treatment., Introduction Chemotherapy-induced neuropathic pain (CINP) is a debilitating complication caused by damage to the peripheral nervous system by chemotherapeutic agents, including paclitaxel (1). CINP occurs in approximately 50% to 90% [...]

Objective To investigate the clinical features of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. Methods We collected and analyzed the clinical and laboratory data and obtained the clinical characteristics of diagnosis and treatment from fifteen patients with positive GFAP antibody tested by cerebrospinal fluid and diagnosed autoimmune GFAP astrocytopathy by the multi-centers. Results The mean age of the first onset of autoimmune GFAP astrocytopathy was 39.73 years old (range 4-65 years), with no significant gender difference. In terms of clinical manifestations, we found the whole brain symptoms including abnormal mental behavior, disturbance of consciousness, epileptic attack accounting for more than 50, , meningitis accounting for 66.7%, myelitis (53.3%), limb tremor (53.3%), vision loss (33.3%); systemic symptoms including fever(100%) and fatigue(86.7%). 46.7% of patients were initially diagnosed with tuberculous meningoencephalitis and were treated with diagnostic antituberculous therapy. The MRI showed 46.7% of patients showed brain linear perivascular radial gadolinium enhancement in the white matter perpendicular to the ventricle. Conclusions Autoimmune GFAP astrocytopathy are acute or subacute dieases and the main clinical features include encephalitis, meningitis, myelitis and optic neuritis. They are likely to be misdiagnosed as tuberculous meningoencephalitis and can manifest progressive loss of consciousness in early phase, which is even life threatening.

County's level economic disparities remain as a key policy issue for sustainable and healthy regional development, particularly for their spatiotemporal dynamics. This research adopted Geographic Information Systems software and spatial econometric analysis methods to analyze the temporal and spatial disparities, spatial structures, and dynamic evolution processes of the Xizang Autonomous Region's county-level economy. With the application of the coefficient of variation and spatial autocorrelation methods, the research identified a significant trend of narrowing economic differences among the 74 counties. The study also observes a growing spatial autocorrelation, pointing towards a more clustered economic growth pattern, particularly influenced by the Lhasa economic circle's expanding regional radiation capacity. The findings underscore the importance of strategic development planning, including the integrated development of Lhasa and Shannan. This study contributes to the literature on regional economic development and offers insights for policy formulation aimed at sustainable and equitable growth in Xizang, which could also benefit future development of counties in developing countries with comparable economic environments. [ABSTRACT FROM AUTHOR]

The considerable increase in train velocity has intensified mutual aerodynamic effects between a train and a tunnel. How to effectively reduce the micro-pressure wave (MPW) amplitude at the high-speed railway tunnel exit is significantly important and has been recognized as an extremely challenging study, especially for the high-speed maglev tunnel when the train travels through it at 400 km/h or even more. To effectively mitigate the phenomenon of "sound explosion" caused by micro-pressure waves, this study provided a newly novel solution to mitigate the micro-pressure wave amplitude, which breaks up the traditional design idea and introduces a completely new arch lattice-shell structure inside the tunnel hood. In addition, the effect of the arch lattice-shell length on initial compression waves at high-speed maglev tunnel entrance and MPWs at exit were analyzed. The findings indicate that compared to the typical section-expanded tunnel hood, the new section-expanded lattice-shell hoods have a positive effect on the mitigation of micro-pressure waves emitted at the high-speed maglev tunnel exit. As the hood length increases, the alleviating effect is strengthened, resulting in a substantial decrease in the peak of the pressure gradient (Pg) and amplitudes of MPWs. When the section-expanded lattice-shell hoods are 50, 80, and 100 m in length, the pressure gradient peaks (Pg) are decreased by 6.2%, 34.9%, and 41.8%, respectively, while the corresponding amplitudes of MPWs are reduced by 9.4%, 46.8%, and 51.9%, respectively. Therefore, the new arch lattice-shell structure added inside the section-expanded tunnel hood can significantly mitigate the amplitudes of MPWs, which provides a newly novel solution for the tunnel hood design during the high-speed train passing through the tunnel at a higher speed. [ABSTRACT FROM AUTHOR]