CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer's disease pathology.

Neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by innate immune-mediated inflammation, but functional and mechanistic effects of the adaptive immune system remain unclear. Here we identify brain-resident CD8+ T cells that coexpress CXCR6 and PD-1 and are in proximity to plaque-associated microglia in human and mouse AD brains. We also establish that CD8+ T cells restrict AD pathologies, including ß-amyloid deposition and cognitive decline. Ligand-receptor interaction analysis identifies CXCL16-CXCR6 intercellular communication between microglia and CD8+ T cells. Further, Cxcr6 deficiency impairs accumulation, tissue residency programming and clonal expansion of brain PD-1+CD8+ T cells. Ablation of Cxcr6 or CD8+ T cells ultimately increases proinflammatory cytokine production from microglia, with CXCR6 orchestrating brain CD8+ T cell-microglia colocalization. Collectively, our study reveals protective roles for brain CD8+ T cells and CXCR6 in mouse AD pathogenesis and highlights that microenvironment-specific, intercellular communication orchestrates tissue homeostasis and protection from neuroinflammation.

Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke.

The precise mechanisms underlying the beneficial effects of regulatory T (Treg) cells on long-term tissue repair remain elusive. Here, using single-cell RNA sequencing and flow cytometry, we found that Treg cells infiltrated the brain 1 to 5 weeks after experimental stroke in mice. Selective depletion of Treg cells diminished oligodendrogenesis, white matter repair, and functional recovery after stroke. Transcriptomic analyses revealed potent immunomodulatory effects of brain-infiltrating Treg cells on other immune cells, including monocyte-lineage cells. Microglia depletion, but not T cell lymphopenia, mitigated the beneficial effects of transferred Treg cells on white matter regeneration. Mechanistically, Treg cell-derived osteopontin acted through integrin receptors on microglia to enhance microglial reparative activity, consequently promoting oligodendrogenesis and white matter repair. Increasing Treg cell numbers by delivering IL-2:IL-2 antibody complexes after stroke improved white matter integrity and rescued neurological functions over the long term. These findings reveal Treg cells as a neurorestorative target for stroke recovery.

Lipid signalling enforces functional specialization of Treg cells in tumours.

Regulatory T cells (Treg cells) are essential for immune tolerance1, but also drive immunosuppression in the tumour microenvironment2. Therapeutic targeting of Treg cells in cancer will therefore require the identification of context-specific mechanisms that affect their function. Here we show that inhibiting lipid synthesis and metabolic signalling that are dependent on sterol-regulatory-element-binding proteins (SREBPs) in Treg cells unleashes effective antitumour immune responses without autoimmune toxicity. We find that the activity of SREBPs is upregulated in intratumoral Treg cells. Moreover, deletion of SREBP-cleavage-activating protein (SCAP)-a factor required for SREBP activity-in these cells inhibits tumour growth and boosts immunotherapy that is triggered by targeting the immune-checkpoint protein PD-1. These effects of SCAP deletion are associated with uncontrolled production of interferon-γ and impaired function of intratumoral Treg cells. Mechanistically, signalling through SCAP and SREBPs coordinates cellular programs for lipid synthesis and inhibitory receptor signalling in these cells. First, de novo fatty-acid synthesis mediated by fatty-acid synthase (FASN) contributes to functional maturation of Treg cells, and loss of FASN from Treg cells inhibits tumour growth. Second, Treg cells in tumours show enhanced expression of the PD-1 gene, through a process that depends on SREBP activity and signals via mevalonate metabolism to protein geranylgeranylation. Blocking PD-1 or SREBP signalling results in dysregulated activation of phosphatidylinositol-3-kinase in intratumoral Treg cells. Our findings show that metabolic reprogramming enforces the functional specialization of Treg cells in tumours, pointing to new ways of targeting these cells for cancer therapy.

CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity.

Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism2-4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein-protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (Treg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and Treg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse Treg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance.

Daytime eating prevents mood vulnerability in night work.

Shift workers have a 25 to 40% higher risk of depression and anxiety partly due to a misalignment between the central circadian clock and daily environmental/behavioral cycles that may negatively affect mood and emotional well-being. Hence, evidence-based circadian interventions are required to prevent mood vulnerability in shift work settings. We used a stringently controlled 14-d circadian paradigm to assess mood vulnerability during simulated night work with either daytime and nighttime or daytime-only eating as compared with simulated day work (baseline). Simulated night work with daytime and nighttime eating increased depression-like mood levels by 26.2% (p-value adjusted using False Discovery Rates, pFDR = 0.001; effect-size r = 0.78) and anxiety-like mood levels by 16.1% (pFDR = 0.001; effect-size r = 0.47) compared to baseline, whereas this did not occur with simulated night work in the daytime-only eating group. Importantly, a larger degree of internal circadian misalignment was robustly associated with more depression-like (r = 0.77; P = 0.001) and anxiety-like (r = 0.67; P = 0.002) mood levels during simulated night work. These findings offer a proof-of-concept demonstration of an evidence-based meal timing intervention that may prevent mood vulnerability in shift work settings. Future studies are required to establish if changes in meal timing can prevent mood vulnerability in night workers.

Heat-Assisted Magnetization Switching in Flexible Spin-Orbit Torque Devices.

Heat-assisted magnetic anisotropy engineering has been successfully used in selective magnetic writing and microwave amplification due to a large interfacial thermal resistance between the MgO barrier and the adjacent ferromagnetic layers. However, in spin-orbit torque devices, the writing current does not flow through the tunnel barrier, resulting in a negligible heating effect due to efficient heat dissipation. Here, we report a dramatically reduced switching current density of ∼2.59 MA/cm2 in flexible spin-orbit torque heterostructures, indicating a 98% decrease in writing energy consumption compared with that on a silicon substrate. The reduced driving current density is enabled by the dramatically decreased magnetic anisotropy due to Joule dissipation and the lower thermal conductivity of the flexible substrate. The large magnetic anisotropy could be fully recovered after the impulse, indicating retained high stability. These results pave the way for flexible spintronics with the otherwise incompatible advantages of low power consumption and high stability.

New Insight into Bulk Structural Degradation of High-Voltage LiCoO2 at 4.55 V.

The aggravated mechanical and structural degradation of layered oxide cathode materials upon high-voltage charging invariably causes fast capacity fading, but the underlying degradation mechanisms remain elusive. Here we report a new type of mechanical degradation through the formation of a kink band in a Mg and Ti co-doped LiCoO2 cathode charged to 4.55 V (vs Li/Li+). The local stress accommodated by the kink band can impede crack propagation, improving the structural integrity in a highly delithiated state. Additionally, machine-learning-aided atomic-resolution imaging reveals that the formation of kink bands is often accompanied by the transformation from the O3 to O1 phase, which is energetically favorable as demonstrated by first-principles calculations. Our results provide new insights into the mechanical degradation mechanism of high-voltage LiCoO2 and the coupling between electrochemically triggered mechanical failures and structural transition, which may provide valuable guidance for enhancing the electrochemical performance of high-voltage layered oxide cathode materials for lithium-ion batteries.

Facilitation of Behavioral and Cortical Emergence from Isoflurane Anesthesia by GABAergic Neurons in Basal Forebrain.

General anesthesia shares many similarities with natural sleep in behavior and electroencephalogram (EEG) patterns. The latest evidence suggests that general anesthesia and sleep-wake behavior may share overlapping neural substrates. The GABAergic neurons in the basal forebrain (BF) have recently been demonstrated to play a key role in controlling wakefulness. It was hypothesized that BF GABAergic neurons may participate in the regulation of general anesthesia. Here, using in vivo fiber photometry, we found that the activity of BF GABAergic neurons was generally inhibited during isoflurane anesthesia, having obviously decreased during the induction of anesthesia and being gradually restored during the emergence from anesthesia, in Vgat-Cre mice of both sexes. Activation of BF GABAergic neurons with chemogenetic and optogenetic approaches decreased sensitivity to isoflurane, delayed induction, and accelerated emergence from isoflurane anesthesia. Optogenetic activation of BF GABAergic neurons decreased EEG δ power and the burst suppression ratio (BSR) during 0.8% and 1.4% isoflurane anesthesia, respectively. Similar to the effects of activating BF GABAergic cell bodies, photostimulation of BF GABAergic terminals in the thalamic reticular nucleus (TRN) also strongly promoted cortical activation and behavioral emergence from isoflurane anesthesia. Collectively, these results showed that the GABAergic BF is a key neural substrate for general anesthesia regulation that facilitates behavioral and cortical emergence from general anesthesia via the GABAergic BF-TRN pathway. Our findings may provide a new target for attenuating the depth of anesthesia and accelerating emergence from general anesthesia.SIGNIFICANCE STATEMENT The basal forebrain (BF) is a key brain region controlling sleep-wake behavior. Activation of GABAergic neurons in the BF potently promotes behavioral arousal and cortical activity. Recently, many sleep-wake-related brain structures have been reported to participate in the regulation of general anesthesia. However, it is still unclear what role BF GABAergic neurons play in general anesthesia. In this study, we aim to reveal the role of BF GABAergic neurons in behavioral and cortical emergence from isoflurane anesthesia and elucidate the underlying neural pathways. Understanding the specific role of BF GABAergic neurons in isoflurane anesthesia would improve our understanding of the mechanisms of general anesthesia and may provide a new strategy for accelerating emergence from general anesthesia.

FTO Deficiency Alleviates LPS-induced Acute Lung Injury by TXNIP/NLRP3-mediated Alveolar Epithelial Cell Pyroptosis.

N6-methyladenosine (m6A) plays a role in various diseases, but it has rarely been reported in acute lung injury (ALI). The FTO (fat mass and obesity-associated) protein can regulate mRNA metabolism by removing m6A residues. The aim of this study was to examine the role and mechanism of the m6A demethylase FTO in LPS-induced ALI. Lung epithelial FTO-knockout mice and FTO-knockdown/overexpression human alveolar epithelial (A549) cell lines were constructed to evaluate the effects of FTO on ALI. Bioinformatics analysis and a series of in vivo and in vitro assays were used to examine the mechanism of FTO regulation. Rescue assays were conducted to examine whether the impact of FTO on ALI depended on the TXNIP/NLRP3 pathway. In LPS-induced ALI, RNA m6A modification amounts were upregulated, and FTO expression was downregulated. In vivo, lung epithelial FTO knockout alleviated alveolar structure disorder, tissue edema, and pulmonary inflammation and improved the survival of ALI mice. In vitro, FTO knockdown reduced A549 cell damage and death induced by LPS, whereas FTO overexpression exacerbated cell damage and death. Mechanistically, bioinformatics analysis revealed that TXNIP was a downstream target of FTO. FTO deficiency mitigated pyroptosis in LPS-induced ALI via the TXNIP/NLRP3 pathway. Rescue assays confirmed that the impact of FTO on the TXNIP/NLRP3 pathway was significantly reversed by the TXNIP inhibitor SRI-37330. Deficiency of FTO alleviates LPS-induced ALI via TXNIP/NLRP3 pathway-mediated alveolar epithelial cell pyroptosis, which might be a novel therapeutic strategy for combating ALI.

Optimization of Mother-to-Child Hepatitis B Virus Prevention Program: Integration of Maternal Screening and Infant Post-vaccination Serologic Testing.

BACKGROUND: Evaluation of the impact on mother-to-child transmission (MTCT) of a HBV-prevention program that incorporates maternal antiviral prophylaxis is hindered by the limited availability of real-world data. METHODS: This study analyzed data on maternal HBV screening, neonatal immunization, and post-vaccination serologic testing (PVST) for HBsAg among at-risk infants born to HBV carrier mothers from the National Immunization Information System during 01/01/2008-31/12/2022. Through linkage with the National Health Insurance Database, information of maternal antiviral therapy was obtained. Multivariate logistic regression was performed to explore MTCT risk in relation to infant-mother characteristics and prevention strategies. RESULTS: Totally, 2,460,218 deliveries with maternal HBV status were screened. Between 2008 and 2022, the annual HBsAg and HBeAg seropositivity rates among native pregnant women aged 15-49 years decreased from 12.2% to 2.6% and from 2.7% to 0.4%, respectively (p for both trends < 0.0001). Among the 22,859 at-risk infants undergoing PVST, the MTCT rates differed between infants born to HBsAg-positive/HBeAg-negative and HBeAg-positive mothers (0.75% and 6.33%, respectively; p < 0.001). The MTCT rate was 1.72% (11/641) for infants born to HBeAg-positive mothers with antiviral prophylaxis. MTCT risk increased with maternal HBeAg-positivity (OR 9.29, 6.79-12.73) and decreased with maternal antiviral prophylaxis (OR 0.28, 0.16-0.49). For infants with maternal HBeAg-positivity, MTCT risk was associated with mothers born in the immunization era (OR 1.40, 1.17-1.67). CONCLUSIONS: MTCT was related to maternal HBeAg-positivity and effectively prevented by maternal prophylaxis in the immunized population. At-risk infants born to maternal vaccinated cohorts might possibly pose further risk.

Heteroatom-Coordinated Palladium Molecular Catalysts for Sustainable Electrochemical Production of Hydrogen Peroxide.

Currently, hydrogen peroxide (H2O2) manufacturing involves an energy-intensive anthraquinone technique that demands expensive solvent extraction and a multistep process with substantial energy consumption. In this work, we synthesized Pd-N4-CO, Pd-S4-NCO, and Pd-N2O2-C single-atom catalysts via an in situ synthesis approach involving heteroatom-rich ligands and activated carbon under mild reaction conditions. It reveals that palladium atoms interact strongly with heteroatom-rich ligands, which provide well-defined and uniform active sites for oxygen (O2) electrochemically reduced to hydrogen peroxide. Interestingly, the Pd-N4-CO electrocatalyst shows excellent performance for the electrocatalytic reduction of O2 to H2O2 via a two-electron transfer process in a base electrolyte, exhibiting a negligible amount of onset overpotential and >95% selectivity within a wide range of applied potentials. The electrocatalysts based on the activity and selectivity toward 2e- ORR follow the order Pd-N4-CO > Pd-N2O2-C > Pd-S4-NCO in agreement with the pull-push mechanism, which is the Pd center strongly coordinated with high electronegativity donor atoms (N and O atoms) and weakly coordinated with the intermediate *OOH to excellent selectivity and sustainable production of H2O2. According to density functional theory, Pd-N4 is the active site for selectivity toward H2O2 generation. This work provides an emerging technique for designing high-performance H2O2 electrosynthesis catalysts and the rational integration of several active sites for green and sustainable chemical synthesis via electrochemical processes.

Using the Diabetes Care System for a County-Wide Hepatitis C Elimination: An Integrated Community-Based Shared Care Model in Taiwan.

INTRODUCTION: Despite the serious risks of diabetes with hepatitis C virus (HCV) infection, this preventable comorbidity is rarely a priority for HCV elimination. We aim to examine how a shared care model could eliminate HCV in patients with diabetes (PwD) in primary care. METHODS: There were 27 community-based Diabetes Health Promotion Institutes in each township/city of Changhua, Taiwan. PwD from these institutes from January 2018 to December 2020 were enrolled. HCV screening and treatment were integrated into diabetes structured care through collaboration between diabetes care and HCV care teams. Outcome measures included HCV care continuum indicators. Township/city variation in HCV infection prevalence and care cascades were also examined. RESULTS: Of the 10,684 eligible PwD, 9,984 (93.4%) underwent HCV screening, revealing a 6.18% (n = 617) anti-HCV seroprevalence. Among the 597 eligible seropositive individuals, 507 (84.9%) completed the RNA test, obtaining 71.8% positives. Treatment was initiated by 327 (89.8%) of 364 viremic patients, and 315 (86.5%) completed it, resulting in a final cure rate of 79.4% (n = 289). Overall, with the introduction of antivirals in this cohort, the prevalence of viremic HCV infection dropped from 4.44% to 1.34%, yielding a 69.70% (95% credible interval 63.64%-77.03%) absolute reduction. DISCUSSION: Although HCV prevalence varied, the care cascades achieved consistent results across townships/cities. We have further successfully implemented the model in county-wide hospital-based diabetes clinics, eventually treating 89.6% of the total PwD. A collaborative effort between diabetes care and HCV elimination enhanced the testing and treatment in PwD through an innovative shared care model.

SLC10A1 rs2296651 variant (S267F mutation) predicts biochemical traits, hepatitis B virus infection susceptibility and the risk of gallstone disease.

Sodium taurocholate co-transporting polypeptide (NTCP), a bile acid transporter, plays a crucial role in regulating bile acid levels and influencing the risk of HBV infection. Genetic variations in the SLC10A1 gene, which encodes NTCP, affect these functions. However, the impact of SLC10A1 gene variants on the metabolic and biochemical traits remained unclear. We aimed to investigate the association of SLC10A1 gene variants with the clinical and biochemical parameters, and the risk of different HBV infection statuses and gallstone disease in the Taiwanese population. Genotyping data from 117,679 Taiwan Biobank participants were analyzed using the Axiom genome-wide CHB arrays. Regional-plot association analysis demonstrated genome-wide significant association between the SLC10A1 rs2296651 genotypes and lipid profile, gamma glutamyl transferase (γGT) level and anti-HBc-positivity. Genotype-phenotype association analyses revealed significantly lower total cholesterol, low-density lipoprotein (LDL) cholesterol and uric acid levels, a higher γGT level and a higher gallstone incidence in rare rs2296651-A allele carrier. Participants with the rs2296651 AA-genotype exhibited significantly lower rates of anti-HBc-positivity and HBsAg-positivity. Compared to those with the GG-genotype, individuals with non-GG-genotypes had reduced risks for various HBV infection statuses: the AA-genotype showed substantially lower risks, while the GA-genotype demonstrated modestly lower risks. Predictive tools also suggested that the rs2296651 variant potentially induced protein damage and pathogenic effects. In conclusion, our data revealed pleiotropic effects of the SLC10A1 rs2296651 genotypes on the levels of biochemical traits and the risk of HBV infection and gallstone disease. This confirms SLC10A1's versatility and implicates its genotypes in predicting both biochemical traits and disease susceptibility.

TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.

BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment. METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models. RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation. CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.

Strong Interface Coupling Enables Stability of Amorphous Meta-Stable State in CoS/Ni3S2 for Efficient Oxygen Evolution.

Rational design of heterostructure catalysts through phase engineering strategy plays a critical role in heightening the electrocatalytic performance of catalysts. Herein, a novel amorphous/crystalline (a/c) heterostructure (a-CoS/Ni3S2) is manufactured by a facile hydrothermal sulfurization method. Strikingly, the interface coupling between amorphous phase (a-CoS) and crystalline phase (Ni3S2) in a-CoS/Ni3S2 is much stronger than that between crystalline phase (c-CoS) and crystalline phase (Ni3S2) in crystalline/crystalline (c/c) heterostructure (c-CoS/Ni3S2) as control sample, which makes the meta-stable amorphous structure more stable. Meanwhile, a-CoS/Ni3S2 has more S vacancies (Sv) than c-CoS/Ni3S2 because of the presence of an amorphous phase. Eventually, for the oxygen evolution reaction (OER), the a-CoS/Ni3S2 exhibits a significantly lower overpotential of 192 mV at 10 mA cm-2 compared to the c-CoS/Ni3S2 (242 mV). An exceptionally low cell voltage of 1.51 V is required to achieve a current density of 50 mA cm-2 for overall water splitting in the assembled cell (a-CoS/Ni3S2 || Pt/C). Theoretical calculations reveal that more charges transfer from a-CoS to Ni3S2 in a-CoS/Ni3S2 than in c-CoS/Ni3S2, which promotes the enhancement of OER activity. This work will bring into play a fabrication strategy of a/c catalysts and the understanding of the catalytic mechanism of a/c heterostructures.

Elucidation of triacylglycerol catabolism in Yarrowia lipolytica: how cells balance acetyl-CoA and excess reducing equivalents.

Yarrowia lipolytica is an industrial yeast that can convert waste oil to value-added products. However, it is unclear how this yeast metabolizes lipid feedstocks, specifically triacylglycerol (TAG) substrates. This study used 13C-metabolic flux analysis (13C-MFA), genome-scale modeling, and transcriptomics analyses to investigate Y. lipolytica W29 growth with oleic acid, glycerol, and glucose. Transcriptomics data was used to guide 13C-MFA model construction and to validate the 13C-MFA results. The 13C-MFA data was then used to constrain a genome-scale model (GSM), which predicted Y. lipolytica fluxes, cofactor balance, and theoretical yields of terpene products. The three data sources provided new insights into cellular regulation during catabolism of glycerol and fatty acid components of TAG substrates, and how their consumption routes differ from glucose catabolism. We found that (1) over 80% of acetyl-CoA from oleic acid is processed through the glyoxylate shunt, a pathway that generates less CO2 compared to the TCA cycle, (2) the carnitine shuttle is a key regulator of the cytosolic acetyl-CoA pool in oleic acid and glycerol cultures, (3) the oxidative pentose phosphate pathway and mannitol cycle are key routes for NADPH generation, (4) the mannitol cycle and alternative oxidase activity help balance excess NADH generated from ß-oxidation of oleic acid, and (5) asymmetrical gene expressions and GSM simulations of enzyme usage suggest an increased metabolic burden for oleic acid catabolism.

Sirolimus for the treatment of patients with refractory connective tissue disease-related thrombocytopenia: a pilot study.

OBJECTIVE: CTD-related immune thrombocytopenia (CTD-ITP) represents an unmet medical need because the drugs that are available are only partly effective and have considerable side-effects. The aim of this study was to assess the efficacy and safety of sirolimus in refractory CTD-ITP patients. METHODS: We did a single-arm, open-label, pilot study of sirolimus in patients with CTD-ITP unresponsive to, or intolerant of, conventional medications. Patients received oral sirolimus for 6 months at a starting dose of 0.5-1 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6-15 ng/ml. The primary efficacy end point was changes in platelet count, and overall response assessed according to the ITP International Working Group Criteria. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. RESULTS: Between November 2020 and February 2022, 12 consecutively hospitalized patients with refractory CTD-ITP were enrolled and prospectively followed. Of these, six patients (50%) achieved complete response, two (16.7%) achieved partial response, and four (33.3%) were no response under therapy. Three of four patients with primary Sjögren's syndrome and two of three patients with systemic lupus erythematosus achieved overall response. One of two patients with overlapping Sjögren's syndrome and systemic lupus erythematosus achieved complete response at 6 months. No severe drug-related toxicities were observed. CONCLUSION: Our results do support sirolimus as an alternative regimen for refractory CTD-ITP patients, including systemic lupus erythematosus and primary SS.

Lipid metabolism in T cell signaling and function.

T cells orchestrate adaptive immunity against pathogens and other immune challenges, but their dysfunction can also mediate the pathogenesis of cancer and autoimmunity. Metabolic adaptation in response to immunological and microenvironmental signals contributes to T cell function and fate decision. Lipid metabolism has emerged as a key regulator of T cell responses, with selective lipid metabolites serving as metabolic rheostats to integrate environmental cues and interplay with intracellular signaling processes. Here, we discuss how extracellular, de novo synthesized and membrane lipids orchestrate T cell biology. We also describe the roles of lipids as regulators of intracellular signaling at the levels of transcriptional, epigenetic and post-translational regulation in T cells. Finally, we summarize therapeutic targeting of lipid metabolism and signaling, and conclude with a discussion of important future directions. Understanding the molecular and functional interplay between lipid metabolism and T cell biology will ultimately inform therapeutic intervention for human disease.

Efficacy and Safety of Repetitive Transcranial Magnetic Stimulation in Cerebellar Ataxia: a Systematic Review and Meta-analysis.

Cerebellar ataxia(CA) is defined as a degenerative disease of the nervous system. Repetitive transcranial magnetic stimulation (rTMS) has been a promising treatment for neurological and psychiatric diseases. Hence, to find out whether cerebellar rTMS impacts CA as a potential therapy, we performed a systematic review and meta-analysis. Qualified studies through a systematic search were retrieved for randomized controlled trials (RCTs) using acknowledged databases. Review Manager 5.4 software was employed to synthesize the data. A total of seven studies were identified as eligible and included in the quantitative review. Comparing real and sham-rTMS interventions, the utilization of rTMS on cerebellum improved the scale for the assessment and rating of ataxia (SARA) (SMD - 0.87, 95% CI - 1.41 to - 0.34; P = 0.001; I2 = 62%), the International Cooperative Ataxia Rating Scale (ICARS) (SMD - 1.06, 95% CI - 1.47 to - 0.64; P < 0.00001; I2 = 0%) and Berg balance Scale (BBS) (SMD 0.76, 95% CI 0.33 to 1.19; P = 0.0005; I2 = 39%). The subgroup analysis demonstrated high-frequency of rTMS had a positive effect (SMD - 1.28, 95% CI - 1.82 to - 0.74; P < 0.00001; I2 = 0%). For the safety, the incidence of adverse events between the two groups was not significantly different (OR 1.73, 95% CI 0.55 to 5.46; P = 0.35; I2 = 0%). In conclusion, this meta-analysis provided limited evidence, suggesting a possible strategy that rTMS over the cerebellum could be a viable therapy for symptoms associated with CA. Besides, rTMS intervention was well-attended and did not result in unanticipated negative effects.

New endoscopic closure technique, "internal traction-assisted suspended closure," for GI defect closure: a pilot study (with video).

BACKGROUND AND AIMS: After endoscopic full-thickness resection (EFTR), reliable closure of the perforation is critical. However, it is technically difficult to close some defects by using metal clips alone or by purse-string suturing, which may lead to unreliable closure. Inspired by the process of pulling up the 2 ends of the incision in the surgical suture, we developed a new endoscopic closure technique, the "internal traction-assisted suspended closure" technique. This pilot study was performed as an initial evaluation of the feasibility and safety of this new endoscopic closure technique. METHODS: Data from patients in whom this suspended closure technique was used to close full-thickness defects after EFTR were retrospectively reviewed. The primary outcome was successful closure rate. Secondary outcomes were closure time, length of postprocedural hospital stay, and incidence of postprocedural adverse events. Defect size and tumor characteristics were also analyzed. RESULTS: Eight patients who underwent the suspended closure technique after EFTR were included. All patients were successfully treated with the suspended closure technique, and no patient developed serious adverse events. The median length of the defect was 3.25 cm (range, 2.5-9.0) and the median width was 2.8 cm (range, 1.8-6.0). The median closing time was 13 minutes (range, 6-24). CONCLUSIONS: The internal traction-assisted suspended closure technique is a simple, reliable, and easy-to-use technique for large full-thickness defects after endoscopic resection.