Inflammation-Mediated Memory Dysfunction and Effects of a Ketogenic Diet in a Murine Model of Multiple Sclerosis

A prominent clinical symptom in multiple sclerosis (MS), a progressive disorder of the central nervous system (CNS) due to heightened neuro-inflammation, is learning and memory dysfunction. Here, we investigated the effects of a ketogenic diet (KD) on memory impairment and CNS-inflammation in a murine model of experimental autoimmune encephalomyelitis (EAE), using electrophysiological, behavioral, biochemical and in vivo imaging approaches. Behavioral spatial learning deficits were associated with motor disability in EAE mice, and were observed concurrently with brain inflammation. The KD improved motor disability in the EAE model, as well as CA1 hippocampal synaptic plasticity (long-term potentiation) and spatial learning and memory (assessed with the Morris Water Maze). Moreover, hippocampal atrophy and periventricular lesions in EAE mice were reversed in KD-treated EAE mice. Finally, we found that the increased expression of inflammatory cytokines and chemokines, as well as the production of reactive oxygen species (ROS), in our EAE model were both suppressed by the KD. Collectively, our findings indicate that brain inflammation in EAE mice is associated with impaired spatial learning and memory function, and that KD treatment can exert protective effects, likely via attenuation of the robust immune response and increased oxidative stress seen in these animals

MindShift: Leveraging Large Language Models for Mental-States-Based Problematic Smartphone Use Intervention

Problematic smartphone use negatively affects physical and mental health. Despite the wide range of prior research, existing persuasive techniques are not flexible enough to provide dynamic persuasion content based on users' physical contexts and mental states. We first conduct a Wizard-of-Oz study (N=12) and an interview study (N=10) to summarize the mental states behind problematic smartphone use: boredom, stress, and inertia. This informs our design of four persuasion strategies: understanding, comforting, evoking, and scaffolding habits. We leverage large language models (LLMs) to enable the automatic and dynamic generation of effective persuasion content. We develop MindShift, a novel LLM-powered problematic smartphone use intervention technique. MindShift takes users' in-the-moment physical contexts, mental states, app usage behaviors, users' goals & habits as input, and generates high-quality and flexible persuasive content with appropriate persuasion strategies. We conduct a 5-week field experiment (N=25) to compare MindShift with baseline techniques. The results show that MindShift significantly improves intervention acceptance rates by 17.8-22.5% and reduces smartphone use frequency by 12.1-14.4%. Moreover, users have a significant drop in smartphone addiction scale scores and a rise in self-efficacy. Our study sheds light on the potential of leveraging LLMs for context-aware persuasion in other behavior change domains

Central nervous system (CNS)–resident natural killer cells suppress Th17 responses and CNS autoimmune pathology

Natural killer (NK) cells of the innate immune system can profoundly impact the development of adaptive immune responses. Inflammatory and autoimmune responses in anatomical locations such as the central nervous system (CNS) differ substantially from those found in peripheral organs. We show in a mouse model of multiple sclerosis that NK cell enrichment results in disease amelioration, whereas selective blockade of NK cell homing to the CNS results in disease exacerbation. Importantly, the effects of NK cells on CNS pathology were dependent on the activity of CNS-resident, but not peripheral, NK cells. This activity of CNS-resident NK cells involved interactions with microglia and suppression of myelin-reactive Th17 cells. Our studies suggest an organ-specific activity of NK cells on the magnitude of CNS inflammation, providing potential new targets for therapeutic intervention

Evaluation and Hydrological Application of CMADS Reanalysis Precipitation Data against Four Satellite Precipitation Products in the Upper Huaihe River Basin, China

Satellite- and reanalysis-based precipitation products are important data source for precipitation, particularly in areas with a sparse gauge network. Here, five open-access precipitation products, including the newly released China Meteorological Assimilation Driving Datasets for the Soil and Water Assessment Tool (SWAT) model (CMADS) reanalysis dataset and four widely used bias-adjusted satellite precipitation products [SPPs; i.e., Tropical Rainfall Measuring Mission (TRMM) Multisatellite Precipitation Analysis 3B42 Version 7 (TMPA 3B42V7), Climate Prediction Center (CPC) morphing technique satellite-gauge blended product (CMORPH-BLD), Climate Hazards Group Infrared Precipitation with Station Data (CHIRPS), and Precipitation Estimation from Remotely Sensed Information using Artificial Neural Networks-Climate Data Record (PERSIANN-CDR)], were assessed. These products were first compared with the gauge observed data collected for the upper Huaihe River basin, and then were used as forcing data for streamflow simulation by the Xin’anjiang (XAJ) hydrological model under two scenarios with different calibration procedures. The performance of CMADS precipitation product for the Chinese mainland was also assessed. The results show that: (1) for the statistical assessment, CMADS and CMORPH-BLD perform the best, followed by TMPA 3B42V7, CHIRPS, and PERSIANN-CDR, among which the correlation coefficient (CC) and root-mean-square error (RMSE) values of CMADS are optimal, although it exhibits certain significant negative relative bias (BIAS; −22.72%); (2) CMORPH-BLD performs the best in capturing and detecting rainfall events, while CMADS tends to underestimate heavy and torrential precipitation; (3) for streamflow simulation, the performance of using CMADS as input is very good, with the highest Nash-Sutcliffe efficiency (NSE) values (0.85 and 0.75 for calibration period and validation period, respectively); and (4) CMADS exhibits high accuracy in eastern China while with significant negative BIAS, and the performance declines from southeast to northwest. The statistical and hydrological evaluations show that CMADS and CMORPH-BLD have high potential for observing precipitation. As high negative BIAS values showed up in CMADS evaluation, further study on the error sources from original data and calibration algorithms is necessary. This study can serve as a reference for selecting precipitation products in data-scarce regions with similar climates and topography in the Global Precipitation Measurement (GPM) era

The Effects of Annealing at Different Temperatures on Microstructure and Mechanical Properties of Cold-Rolled Al0.3CoCrFeNi High-Entropy Alloy

In this work, cold-rolling was utilized to induce a high density of crystal defects in Al0.3CoCrFeNi high-entropy alloys. The effects of annealing temperature on static recrystallization, precipitation behavior and mechanical properties were investigated. With increasing annealing temperature from 590 °C to 800 °C, the area fraction of recrystallized region increases from 26.9% to 93.9%. Cold-rolling deformation largely promotes the precipitation of B2 phases during annealing, and the characteristics of the precipitates are linked to recrystallization level. The coarse and equiaxed B2 phases exist in the recrystallized region and the fine and elongated B2 phases occupy the non-recrystallized region. Combined use of cold-rolling and annealing can remarkably enhance the strength and toughness. A partially recrystallized microstructure in a cold-rolled sample annealed at 700 °C exhibits a better combination of strength and toughness than a fully recrystallized microstructure in a cold-rolled sample annealed at 800 °C. Finally, related mechanisms are discussed

Overexpression of CD99 is associated with tumor adaptiveness and indicates the tumor recurrence and therapeutic responses in gliomas

Glioma undergoes adaptive changes, leading to poor prognosis and resistance to treatment. CD99 influences the migration and invasion of glioma cells and plays an oncogene role. However, whether CD99 can affect the adaptiveness of gliomas is still lacking in research, making its clinical value underestimated. Here, we enrolled our in-house and public multiomics datasets for bioinformatic analysis and conducted immunohistochemistry staining to investigate the role of CD99 in glioma adaptive response and its clinical implications.CD99 is expressed in more adaptative glioma subtypes and cell states. Under hypoxic conditions, CD99 is upregulated in glioma cells and is associated with angiogenesis and metabolic adaptations. Gliomas with over-expressed CD99 also increased the immunosuppressive tumor-associated macrophages. The relevance with tumor adaptiveness of CD99 presented clinical significance. We discovered that CD99 overexpression is associated with short-time recurrence and validated its prognostic value. Additionally, Glioma patients with high expression of CD99 were resistant to chemotherapy and radiotherapy. The CD99 expression was also related to anti-angiogenic and immune checkpoint inhibitor therapy response. Inhibitors of the PI3K-AKT pathway have therapeutic potential against CD99-overexpressing gliomas.Our study identified CD99 as a biomarker characterizing the adaptive response in glioma. Gliomas with high CD99 expression are highly tolerant to stress conditions such as hypoxia and antitumor immunity, making treatment responses dimmer and tumor progression. Therefore, for patients with CD99-overexpressing gliomas, tumor adaptiveness should be fully considered during treatment to avoid drug resistance, and closer clinical monitoring should be carried out to improve the prognosis

Long COVID: The latest manifestations, mechanisms, and potential therapeutic interventions

Abstract COVID‐19 caused by SARS‐CoV‐2 infection affects humans not only during the acute phase of the infection, but also several weeks to 2 years after the recovery. SARS‐CoV‐2 infects a variety of cells in the human body, including lung cells, intestinal cells, vascular endothelial cells, olfactory epithelial cells, etc. The damages caused by the infections of these cells and enduring immune response are the basis of long COVID. Notably, the changes in gene expression caused by viral infection can also indirectly contribute to long COVID. We summarized the occurrences of both common and uncommon long COVID, including damages to lung and respiratory system, olfactory and taste deficiency, damages to myocardial, renal, muscle, and enduring inflammation. Moreover, we provided potential treatments for long COVID symptoms manifested in different organs and systems, which were based on the pathogenesis and the associations between symptoms in different organs. Importantly, we compared the differences in symptoms and frequency of long COVID caused by breakthrough infection after vaccination and infection with different variants of concern, in order to provide a comprehensive understanding of the characteristics of long COVID and propose improvement for tackling COVID‐19

The KD ameliorates EAE-mediated CNS-inflammation and oxidative stress.

<p>Comparison of the frequencies of (A) CD4⁺/CD8⁺ T cells, (B) CD11b⁺/CD45⁺ cells on gated lymphocyte populations in EAE with and without KD treatment. (C) Frequencies of CD4⁺CD25⁺ Foxp3⁺ regulatory T cells. The KD suppressed CNS cellular infiltration and myelin-reactive T cell responses in EAE. Groups of mice (receiving standard diet [SD] and KD diet) were immunized with MOG/CFA/PT, and sacrificed between day 16–19 p.i. Lymph node, spleen and CNS cells were isolated. (D) Lymphoid (LN) or CNS cells were re-stimulated with MOG_35–55 peptide overnight and IFN-γ- and IL-17-expressing CD4⁺ T cells were measured by intracellular staining. The number seen in the box indicated the average percentage of individual markers on the cells. (E) Summary data of the percentage of individual marker in the cells (LN <i>vs.</i> CNS) in SD-treated EAE mice or KD-treated EAE mice. Data are representative of two independent experiments (n = 4–8/group). P values, Student’s <i>t</i>-test; *, <i>p</i><0.05. (E) Visualization and quantification of brain inflammation by <i>in vivo</i> bioluminescence imaging. This is achieved by imaging reactive oxygen species (ROS) levels in the brain. Bioluminescent images in live mice were captured during a 1 min acquisition time using the Xenogen IVIS system at several time points after injection of 27 mg/kg dihydroethidium. Representative images of ROS seen in the left panel were captured in naïve mice and EAE mice with and without KD treatment. All experiments were conducted on groups of mice (n = 4–8) between days 14–19 p.i. Data are representative of two independent experiments (mean and SEM). P values, one way ANOVA; **, <i>p</i><0.01; ***, <i>p</i><0.001.</p

Central nervous system (CNS)-resident natural killer cells suppress Th17 responses and CNS autoimmune pathology.

Natural killer (NK) cells of the innate immune system can profoundly impact the development of adaptive immune responses. Inflammatory and autoimmune responses in anatomical locations such as the central nervous system (CNS) differ substantially from those found in peripheral organs. We show in a mouse model of multiple sclerosis that NK cell enrichment results in disease amelioration, whereas selective blockade of NK cell homing to the CNS results in disease exacerbation. Importantly, the effects of NK cells on CNS pathology were dependent on the activity of CNS-resident, but not peripheral, NK cells. This activity of CNS-resident NK cells involved interactions with microglia and suppression of myelin-reactive Th17 cells. Our studies suggest an organ-specific activity of NK cells on the magnitude of CNS inflammation, providing potential new targets for therapeutic intervention