Inhibitory Fcγ receptor deletion enhances CD8 T cell stemness increasing anti-PD-1 therapy responsiveness against glioblastoma.

BACKGROUND: Certain cancers present challenges for treatment because they are resistant to immune checkpoint blockade (ICB), attributed to low tumor mutational burden and the absence of T cell-inflamed features. Among these, glioblastoma (GBM) is notoriously resistant to ICB. To overcome this resistance, the identification of T cells with heightened stemness marked by T-cell factor 1 (TCF1) expression has gained attention. Several studies have explored ways to preserve stem-like T cells and prevent terminal exhaustion. In this study, we investigate a target that triggers stem-like properties in CD8 T cells to enhance the response to ICB in a murine GBM model. METHODS: Using Fcgr2b-/- mice and a murine GL261 GBM model, we confirmed the efficacy of anti-programmed cell death protein-1 (PD-1) immunotherapy, observing improved survival. Analysis of immune cells using fluorescence-activated cell sorting and single-cell RNA sequencing delineated distinct subsets of tumor-infiltrating CD8 T cells in Fcgr2b-/- mice. The crucial role of the stem-like feature in the response to anti-PD-1 treatment for reinvigorating CD8 T cells was analyzed. Adoptive transfer of OT-I cells into OVA-expressing GL261 models and CD8 T cell depletion in Fcgr2b-/- mice confirmed the significance of Fcgr2b-/- CD8 T cells in enhancing the antitumor response. Last, S1P1 inhibitor treatment confirmed that the main source of tumor antigen-specific Fcgr2b-/- CD8 T cells is the tumor-draining lymph nodes (TdLNs). RESULTS: In a murine GBM model, anti-PD-1 monotherapy and single-Fc fragment of IgG receptor IIb (FcγRIIB) deletion exhibit limited efficacy. However, their combination substantially improves survival by enhancing cytotoxicity and proliferative capacity in tumor-infiltrating Fcgr2b-/- CD8 T cells. The improved response to anti-PD-1 treatment is associated with the tumor-specific memory T cells (Ttsms) exhibiting high stemness characteristics within the tumor microenvironment (TME). Ttsms in the TdLN thrives in a protective environment, maintaining stem-like characteristics and serving as a secure source for tumor infiltration. This underscores the significance of FcγRIIB ablation in triggering Ttsms and enhancing ICB therapy against GBM. CONCLUSIONS: Deletion of FcγRIIB on CD8 T cells leads to the generation of a Ttsms, which is localized in TdLN and protected from the immunosuppressive TME. Incorporating these highly stemness-equipped Ttsms enhances the response to anti-PD-1 therapy in immune-suppressed brain tumors.

Cardiometabolic benefits of fenofibrate in heart failure related to obesity and diabetes.

BACKGROUND: Heart failure (HF) is a serious and common condition affecting millions of people worldwide, with obesity being a major cause of metabolic disorders such as diabetes and cardiovascular disease. This study aimed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, on the obese- and diabetes-related cardiomyopathy. METHODS AND RESULTS: We used db/db mice and high fat diet-streptozotocin induced diabetic mice to investigate the underlying mechanisms of fenofibrate's beneficial effects on heart function. Fenofibrate reduced fibrosis, and lipid accumulation, and suppressed inflammatory and immunological responses in the heart via TNF signaling. In addition, we investigated the beneficial effects of fenofibrate on HF hospitalization. The Korean National Health Insurance database was used to identify 427,154 fenofibrate users and 427,154 non-users for comparison. During the 4.22-year follow-up, fenofibrate use significantly reduced the risk of HF hospitalization (hazard ratio, 0.907; 95% CI 0.824-0.998). CONCLUSIONS: The findings suggest that fenofibrate may be a useful therapeutic agent for obesity- and diabetes-related cardiomyopathy.

Advanced Flexible Physical Sensors with Independent Detection Mechanisms of Pressure and Strain Stimuli for Overcoming Signal Interference.

Flexible and wearable physical sensors have gained significant interest owing to their potential in attachable devices, electronic skin, and multipurpose sensors. The physical stimuli of these sensors typically consist of vertically and horizontally applied pressures and strains, respectively. However, owing to their similar response characteristics, interference occurs between the two types of signals detected, complicating the distinction between pressure and strain stimuli, leading to inaccurate data interpretation and reduced sensor specificity. Therefore, we developed a dual-sensing-mode physical sensor with separate response mechanisms for the two types of physical stimuli based on a unique structural design that can independently induce changes in the piezocapacitance and piezoresistance for pressure and strain stimuli, respectively. The asterisk-shaped piezoresistive pathway (electrode), designed for multifunctionality, effectively detected the intensity and direction of tensile deformation, and an elastomeric sponge structure positioned between the two electrodes detected the pressure signals via changes in capacitance. This dual-sensing-mode sensor offers clearer signal differentiation and enhanced multifunctionality compared to those of traditional single-mode sensors. Additionally, extensive experimentation demonstrated that our sensor has a good sensitivity, high linearity, and stability in detecting signals, proving its applicability for sophisticated monitoring and control tasks that require the differential detection between pressure and deformation signals.

Type I interferon signaling regulates myeloid and T cell crosstalk in the glioblastoma tumor microenvironment.

Downstream interferon signaling through the type I interferon (IFN) receptor, IFNAR, is crucial for the proper production of type I IFNs in mounting anti-tumor immune responses. Our study investigates the role of type I IFN signaling in the glioblastoma (GBM) tumor microenvironment by leveraging single-cell RNA sequencing to analyze tumor-infiltrating lymphocytes. We investigate how type I IFN signaling within the myeloid compartment contributes to the crosstalk with T cells in the tumor microenvironment. Through the use of the Gl261 murine GBM model, we find that the lack of proper type I IFN response results in enhanced PD-L1 interactions among myeloid cells, thereby affecting T cell functionality. Additionally, we also characterize how anti-PD1 treatment induces transcriptional changes in tumor-associated monocytes and macrophages by analyzing intercellular communication networks and propose how immune checkpoint blockade therapy could possibly relieve some of the immunosuppression derived from the lack of proper type I IFN production.

Efficacy of Antibiotic Regimens for Pneumonia in Young Infants Aged 0-59 Days: A Systematic Review.

CONTEXT: Pneumonia is a leading cause of death in young infants. OBJECTIVES: To evaluate the efficacy of different antibiotic regimens to treat young infant pneumonia on critical clinical outcomes. DATA SOURCES: MEDLINE, Embase, CINAHL, World Health Organization (WHO) Global Index Medicus, Cochrane Central Registry of Trials. STUDY SELECTION: We included randomized controlled trials of young infants aged 0 to 59 days with pneumonia (population) comparing the efficacy of antibiotic regimens (intervention) with alternate regimens or management (control) on clinical outcomes. DATA EXTRACTION: We extracted data and assessed risk of bias in duplicate. We used Grading of Recommendations, Assessment, Development, and Evaluation to assess certainty of evidence. LIMITATIONS: Trials were heterogeneous, which precluded data pooling. RESULTS: Of 2601 publications screened, 10 randomized controlled trials were included. Seven trials were hospital-based (n = 869) and 3 were nonhospital-based (n = 4329). No hospital-based trials evaluated WHO-recommended first-choice regimens. One trial found the WHO-recommended second-choice antibiotic, cefotaxime, to have similar rates of treatment success as non-WHO-recommended regimens of either amoxicillin-clavulanate (RR 0.99, 95% confidence interval 0.82-1.10) or amoxicillin-clavulanate/cefotaxime (RR 1.02, 95% confidence interval 0.86-1.12). Among 3 nonhospital-based trials comparing oral amoxicillin to alternate regimens to treat isolated tachypnea among infants aged 7-59 days, there were no differences in treatment failure between amoxicillin and alternate regimens. Certainty of evidence was low or very low for all primary outcomes. CONCLUSIONS: We found limited evidence to support the superiority of any single antibiotic regimen over alternate regimens to treat young infant pneumonia.

Efficacy of Antibiotic Regimens for Sepsis or Possible Serious Bacterial Infection in Young Infants Aged 0 to 59 Days: A Systematic Review and Meta-analysis.

CONTEXT: Sepsis is a leading cause of young infant mortality. OBJECTIVE: To evaluate the efficacy of different antibiotic regimens to treat young infant sepsis or possible serious bacterial infection (PSBI) on clinical outcomes. DATA SOURCES: MEDLINE, Embase, CINAHL, World Health Organization Global Index Medicus, Cochrane Central Registry of Trials. STUDY SELECTION: We included randomized controlled trials (RCTs) of young infants 0 to 59 days with sepsis or PBSI (population) comparing the efficacy of antibiotic regimens (intervention) with alternate regimens or management (control) on clinical outcomes. DATA EXTRACTION: We extracted data and assessed risk of bias in duplicate. We performed random-effects meta-analysis, and used Grading of Recommendations, Assessment, Development, and Evaluation to assess certainty of evidence. RESULTS: Of 2390 publications, we included 41 RCTs (n = 18 054). Thirty-five trials were hospital-based and 6 were nonhospital-based. Meta-analysis of 4 trials demonstrated similar rates of treatment success with intramuscular/intravenous third generation cephalosporins versus intramuscular/intravenous penicillin or ampicillin + gentamicin (RR 1.03, 95% CI 0.93-1.13]; n = 1083; moderate certainty of evidence). Meta-analysis of 3 trials demonstrated similar rates of treatment failure with oral amoxicillin + intramuscular gentamicin versus intramuscular penicillin + gentamicin for nonhospital treatment of clinical severe illness (RR 0.86, 95% CI 0.72-1.02]; n = 5054; low certainty of evidence). Other studies were heterogeneous. LIMITATIONS: RCTs evaluated heterogeneous regimens, limiting our ability to pool data. CONCLUSIONS: We found limited evidence to support any single antibiotic regimen as superior to alternate regimens to treat young infant sepsis or PSBI.

Spatial profiling of non-small cell lung cancer provides insights into tumorigenesis and immunotherapy response.

Lung cancer is the second most common cancer worldwide and a leading cause of cancer-related deaths. Despite advances in targeted therapy and immunotherapy, the prognosis remains unfavorable, especially in metastatic cases. This study aims to identify molecular changes in non-small cell lung cancer (NSCLC) patients based on their response to treatment. Using tumor and matched immune cell rich peritumoral tissues, we perform a retrospective, comprehensive spatial transcriptomic analysis of a proven malignant NSCLC sample treated with immune checkpoint inhibitor (ICI). In addition to T cells, other immune cell types, such as B cells and macrophages, were also activated in responders to ICI treatment. In particular, B cells and B cell-mediated immunity pathways are consistently found to be activated. Analysis of the histologic subgroup (lung squamous cell carcinoma, LUSC; lung adenocarcinoma, LUAD) of NSCLC also confirms activation of B cell mediated immunity. Analysis of B cell subtypes shows that B cell subtypes were more activated in immune cell-rich tissues near tumor tissue. Furthermore, increased expression of B cell immunity-related genes is associated with better prognosis. These findings provide insight into predicting ICI treatment responses and identifying appropriate candidates for immunotherapy in NSCLC patients.

γδ T cells as a potential therapeutic agent for glioblastoma.

Although γδ T cells comprise a small population of T cells, they perform important roles in protecting against infection and suppressing tumors. With their distinct tissue-localizing properties, combined with their various target recognition mechanisms, γδ T cells have the potential to become an effective solution for tumors that do not respond to current therapeutic procedures. One such tumor, glioblastoma (GBM), is a malignant brain tumor with the highest World Health Organization grade and therefore the worst prognosis. The immune-suppressive tumor microenvironment (TME) and immune-evasive glioma stem cells are major factors in GBM immunotherapy failure. Currently, encouraged by the strong anti-tumoral function of γδ T cells revealed at the preclinical and clinical levels, several research groups have shown progression of γδ T cell-based GBM treatment. However, several limitations still exist that block effective GBM treatment using γδ T cells. Therefore, understanding the distinct roles of γδ T cells in anti-tumor immune responses and the suppression mechanism of the GBM TME are critical for successful γδ T cell-mediated GBM therapy. In this review, we summarize the effector functions of γδ T cells in tumor immunity and discuss current advances and limitations of γδ T cell-based GBM immunotherapy. Additionally, we suggest future directions to overcome the limitations of γδ T cell-based GBM immunotherapy to achieve successful treatment of GBM.

Integrative single-cell transcriptome analysis provides new insights into post-COVID-19 pulmonary fibrosis and potential therapeutic targets.

The global COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 virus has resulted in a significant number of patients experiencing persistent symptoms, including post-COVID pulmonary fibrosis (PCPF). This study aimed to identify novel therapeutic targets for PCPF using single-cell RNA-sequencing data from lung tissues of COVID-19 patients, idiopathic pulmonary fibrosis (IPF) patients, and a rat transforming growth factor beta-1-induced fibrosis model treated with antifibrotic drugs. Patients with COVID-19 had lower alveolar macrophage counts than healthy controls, whereas patients with COVID-19 and IPF presented with elevated monocyte-derived macrophage counts. A comparative transcriptome analysis showed that macrophages play a crucial role in IPF and COVID-19 development and progression, and fibrosis- and inflammation-associated genes were upregulated in both conditions. Functional enrichment analysis revealed the upregulation of inflammation and proteolysis and the downregulation of ribosome biogenesis. Cholesterol efflux and glycolysis were augmented in both macrophage types. The study suggests that antifibrotic drugs may reverse critical lung fibrosis mediators in COVID-19. The results help clarify the molecular mechanisms underlying pulmonary fibrosis in patients with severe COVID-19 and IPF and highlight the potential efficacy of antifibrotic drugs in COVID-19 therapy. Collectively, all these findings may have significant implications for the development of new treatment strategies for PCPF.

Supplementation with a high-glucose drink stimulates anti-tumor immune responses to glioblastoma via gut microbiota modulation.

A high-sugar diet induces lifestyle-associated metabolic diseases, such as obesity and diabetes, which may underlie the pro-tumor effects of a high-sugar diet. We supply GL261 syngeneic glioblastoma (GBM) mice with a short-term high-glucose drink (HGD) and find an increased survival rate with no evidence of metabolic disease. Modulation of the gut microbiota through HGD supplementation is critical for enhancing the anti-tumor immune response. Single-cell RNA sequencing shows that gut microbiota modulation by HGD supplementation increases the T cell-mediated anti-tumor immune response in GBM mice. We find that the cytotoxic CD4+ T cell population in GBM is increased due to synergy with anti-programmed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors, but this effect depends upon HGD supplementation. Thus, we determine that HGD supplementation enhances anti-tumor immune responses in GBM mice through gut microbiota modulation and suggest that the role of HGD supplementation in GBM should be re-examined.

Effectiveness and Safety of Fufang Danshen Dripping Pill (Cardiotonic Pill) on Blood Viscosity and Hemorheological Factors for Cardiovascular Event Prevention in Patients with Type 2 Diabetes Mellitus: Systematic Review and Meta-Analysis.

Background and Objectives: Diabetes can cause various vascular complications. The Compounded Danshen-Dripping-Pill (CDDP) is widely used in China. This study aimed to analyze the effectiveness and safety of CDDP in the blood viscosity (BV) with type 2 diabetes mellitus (T2DM). Materials and Methods: We conducted a systematic search of seven databases from their inception to July 2022 for randomized controlled trials that used CDDP to treat T2DM. To evaluate BV, we measured low shear rate (LSR), high shear rate (HSR), and plasma viscosity (PV). Homocysteine and adiponectin levels were also assessed as factors that could affect BV. Results: We included 18 studies and 1532 patients with T2DM. Meta-analysis revealed that CDDP significantly reduced LSR (mean difference [MD] -2.74, 95% confidence interval [CI] -3.77 to -1.72), HSR (MD -0.86, 95% CI -1.08 to -0.63), and PV (MD -0.37, 95% CI -0.54 to -0.19) compared to controls. CDDP also reduced homocysteine (MD -8.32, 95% CI -9.05 to -7.58), and increased plasma adiponectin (MD 2.72, 95% CI 2.13 to 3.32). Adverse events were reported less frequently in the treatment groups than in controls. Conclusions: CDDP is effective in reducing BV on T2DM. However, due to the poor design and quality of the included studies, high-quality, well-designed studies are required in the future.

Integrative analysis of mitochondrial metabolic reprogramming in early-stage colon and liver cancer.

Gastrointestinal malignancies, including colon adenocarcinoma (COAD) and liver hepatocellular carcinoma (LIHC), remain leading causes of cancer-related deaths worldwide. To better understand the underlying mechanisms of these cancers and identify potential therapeutic targets, we analyzed publicly accessible Cancer Genome Atlas datasets of COAD and LIHC. Our analysis revealed that differentially expressed genes (DEGs) during early tumorigenesis were associated with cell cycle regulation. Additionally, genes related to lipid metabolism were significantly enriched in both COAD and LIHC, suggesting a crucial role for dysregulated lipid metabolism in their development and progression. We also identified a subset of DEGs associated with mitochondrial function and structure, including upregulated genes involved in mitochondrial protein import and respiratory complex assembly. Further, we identified mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) as a crucial regulator of cancer cell metabolism. Using a genome-scale metabolic model, we demonstrated that HMGCS2 suppression increased glycolysis, lipid biosynthesis, and elongation while decreasing fatty acid oxidation in colon cancer cells. Our study highlights the potential contribution of dysregulated lipid metabolism, including ketogenesis, to COAD and LIHC development and progression and identifies potential therapeutic targets for these malignancies.

Double-edged sword: γδ T cells in mucosal homeostasis and disease.

The mucosa is a tissue that covers numerous body surfaces, including the respiratory tract, digestive tract, eye, and urogenital tract. Mucosa is in direct contact with pathogens, and γδ T cells perform various roles in the tissue. γδ T cells efficiently defend the mucosa from various pathogens, such as viruses, bacteria, and fungi. In addition, γδ T cells are necessary for the maintenance of homeostasis because they select specific organisms in the microbiota and perform immunoregulatory functions. Furthermore, γδ T cells directly facilitate pregnancy by producing growth factors. However, γδ T cells can also play detrimental roles in mucosal health by amplifying inflammation, thereby worsening allergic responses. Moreover, these cells can act as major players in autoimmune diseases. Despite their robust roles in the mucosa, the application of γδ T cells in clinical practice is lacking because of factors such as gaps between mice and human cells, insufficient knowledge of the target of γδ T cells, and the small population of γδ T cells. However, γδ T cells may be attractive targets for clinical use due to their effector functions and low risk of inducing graft-versus-host disease. Therefore, robust research on γδ T cells is required to understand the crucial features of these cells and apply these knowledges to clinical practices.

LY6D is crucial for lipid accumulation and inflammation in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a serious metabolic disorder characterized by excess fat accumulation in the liver. Over the past decade, NAFLD prevalence and incidence have risen globally. There are currently no effective licensed drugs for its treatment. Thus, further study is required to identify new targets for NAFLD prevention and treatment. In this study, we fed C57BL6/J mice one of three diets, a standard chow diet, high-sucrose diet, or high-fat diet, and then characterized them. The mice fed a high-sucrose diet had more severely compacted macrovesicular and microvesicular lipid droplets than those in the other groups. Mouse liver transcriptome analysis identified lymphocyte antigen 6 family member D (Ly6d) as a key regulator of hepatic steatosis and the inflammatory response. Data from the Genotype-Tissue Expression project database showed that individuals with high liver Ly6d expression had more severe NAFLD histology than those with low liver Ly6d expression. In AML12 mouse hepatocytes, Ly6d overexpression increased lipid accumulation, while Ly6d knockdown decreased lipid accumulation. Inhibition of Ly6d ameliorated hepatic steatosis in a diet-induced NAFLD mouse model. Western blot analysis showed that Ly6d phosphorylated and activated ATP citrate lyase, which is a key enzyme in de novo lipogenesis. In addition, RNA- and ATAC-sequencing analyses revealed that Ly6d drives NAFLD progression by causing genetic and epigenetic changes. In conclusion, Ly6d is responsible for the regulation of lipid metabolism, and inhibiting Ly6d can prevent diet-induced steatosis in the liver. These findings highlight Ly6d as a novel therapeutic target for NAFLD.

Harnessing type I interferon-mediated immunity to target malignant brain tumors.

Type I interferons have long been appreciated as a cytokine family that regulates antiviral immunity. Recently, their role in eliciting antitumor immune responses has gained increasing attention. Within the immunosuppressive tumor microenvironment (TME), interferons stimulate tumor-infiltrating lymphocytes to promote immune clearance and essentially reshape a "cold" TME into an immune-activating "hot" TME. In this review, we focus on gliomas, with an emphasis on malignant glioblastoma, as these brain tumors possess a highly invasive and heterogenous brain TME. We address how type I interferons regulate antitumor immune responses against malignant gliomas and reshape the overall immune landscape of the brain TME. Furthermore, we discuss how these findings can translate into future immunotherapies targeting brain tumors in general.

Protocol for analyzing γδ T cells from the vagina of diet-induced obese mice using single-cell RNA sequencing and flow cytometry.

Obesity affects susceptibility to sexually transmitted diseases like genital herpes, caused by herpes simplex virus (HSV) 2. The γδ T cells in the vagina play a major role in HSV-2 suppression. Here, we present a protocol for inducing HSV-2 infection intravaginally in high-fat diet-induced obese mice. We describe steps for isolating single cells from vaginal tissue and analyzing cells using single-cell RNA sequencing and flow cytometry. We then detail confirmation of the γδ T cell phenotype in vitro. For complete details on the use and execution of this protocol, please refer to Park et al.1.

Pharmacologic Activation of Angiotensin-Converting Enzyme II Alleviates Diabetic Cardiomyopathy in db/db Mice by Reducing Reactive Oxidative Stress.

BACKGRUOUND: Diabetes mellitus is one of the most common chronic diseases worldwide, and cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients. Diabetic cardiomyopathy (DCM) is a phenomenon characterized by a deterioration in cardiac function and structure, independent of vascular complications. Among many possible causes, the renin-angiotensin-aldosterone system and angiotensin II have been proposed as major drivers of DCM development. In the current study, we aimed to investigate the effects of pharmacological activation of angiotensin-converting enzyme 2 (ACE2) on DCM. METHODS: The ACE2 activator diminazene aceturate (DIZE) was administered intraperitoneally to male db/db mice (8 weeks old) for 8 weeks. Transthoracic echocardiography was used to assess cardiac mass and function in mice. Cardiac structure and fibrotic changes were examined using histology and immunohistochemistry. Gene and protein expression levels were examined using quantitative reverse transcription polymerase chain reaction and Western blotting, respectively. Additionally, RNA sequencing was performed to investigate the underlying mechanisms of the effects of DIZE and identify novel potential therapeutic targets for DCM. RESULTS: Echocardiography revealed that in DCM, the administration of DIZE significantly improved cardiac function as well as reduced cardiac hypertrophy and fibrosis. Transcriptome analysis revealed that DIZE treatment suppresses oxidative stress and several pathways related to cardiac hypertrophy. CONCLUSION: DIZE prevented the diabetes mellitus-mediated structural and functional deterioration of mouse hearts. Our findings suggest that the pharmacological activation of ACE2 could be a novel treatment strategy for DCM.

Regulation of c-SMAC formation and AKT-mTOR signaling by the TSG101-IFT20 axis in CD4+ T cells.

CD4+ T cells play major roles in the adaptive immune system, which requires antigen recognition, costimulation, and cytokines for its elaborate orchestration. Recent studies have provided new insight into the importance of the supramolecular activation cluster (SMAC), which comprises concentric circles and is involved in the amplification of CD4+ T cell activation. However, the underlying mechanism of SMAC formation remains poorly understood. Here, we performed single-cell RNA sequencing of CD4+ T cells left unstimulated and stimulated with anti-CD3 and anti-CD28 antibodies to identify novel proteins involved in their regulation. We found that intraflagellar transport 20 (IFT20), previously known as cilia-forming protein, was upregulated in antibody-stimulated CD4+ T cells compared to unstimulated CD4+ T cells. We also found that IFT20 interacted with tumor susceptibility gene 101 (TSG101), a protein that endocytoses ubiquitinated T-cell receptors. The interaction between IFT20 and TSG101 promoted SMAC formation, which led to amplification of AKT-mTOR signaling. However, IFT20-deficient CD4+ T cells showed SMAC malformation, resulting in reduced CD4+ T cell proliferation, aerobic glycolysis, and cellular respiration. Finally, mice with T-cell-specific IFT20 deficiency exhibited reduced allergen-induced airway inflammation. Thus, our data suggest that the IFT20-TSG101 axis regulates AKT-mTOR signaling via SMAC formation.

A single-center prospective study regarding time to return to activities of daily living after craniotomy for brain tumors.

BACKGROUND: There are few studies on the time to return to activities of daily living (ADL) after craniotomy in patients with brain tumors. This study aimed to investigate the duration before returning to ADLs after craniotomy for brain tumors and present data that can provide information and guidelines on the appropriate time needed. METHODS: Patients (n = 183 of 234) who underwent craniotomy for brain tumors between April 2021 and July 2021 capable of self-care upon discharge were enrolled, and data of 158 were collected. The start time of 85 ADL items was prospectively investigated for 4 months postoperatively, using the self-recording sheet. RESULTS: Over 89% and 87% of the patients performed basic ADL items within a month and instrumental ADL items within 2 months (medians: within 18 days), except for a few. Regarding work, 50% of the patients returned within 4 months. Washing hair with a wound was performed at 18 days of median value, after 4 months of dyeing/perming hair, 6 days of drinking coffee/tea, after 4 months of air travel, and 40 days of complementary and alternative medicine. In patients with infratentorial tumors or surgical problems, return times were much later for various items. CONCLUSIONS: It is possible to provide practical information and guidelines on the duration to return to ADL after craniotomy in brain tumor patients. These study findings also reduce uncertainty about recovery and daily life and help patients return to their daily life at the appropriate time, thereby maintaining function and daily well-being after surgery.

Integrated analysis of the microbiota-gut-brain axis in response to sleep deprivation and diet-induced obesity.

Introduction: Sleep deprivation (SD) and obesity are common in modern societies. SD and obesity frequently coexist, but research on the combined consequences of SD and obesity has been limited. In this study, we investigated the gut microbiota and host responses to SD and high-fat diet (HFD)-induced obesity. In addition, we attempted to identify key mediators of the microbiota-gut-brain axis. Methods: C57BL/6J mice were divided into four groups based on whether they were sleep deprived and whether they were fed a standard chow diet (SCD) or HFD. We then performed fecal microbiome shotgun sequencing, gut transcriptome analysis using RNA sequencing, and brain mRNA expression analysis using the nanoString nCounter Mouse Neuroinflammation Panel. Results: The gut microbiota was significantly altered by the HFD, whereas the gut transcriptome was primarily influenced by SD. Sleep and diet are both important in the inflammatory system of the brain. When SD and the HFD were combined, the inflammatory system of the brain was severely disrupted. In addition, inosine-5' phosphate may be the gut microbial metabolite that mediates microbiota-gut-brain interactions. To identify the major drivers of this interaction, we analyzed the multi-omics data. Integrative analysis revealed two driver factors that were mostly composed of the gut microbiota. We discovered that the gut microbiota may be the primary driver of microbiota-gut-brain interactions. Discussion: These findings imply that healing gut dysbiosis may be a viable therapeutic target for enhancing sleep quality and curing obesity-related dysfunction.