Genetic associations between gut microbiota and type 2 diabetes mediated by plasma metabolites: a Mendelian randomization study.

Background: Numerous research studies have indicated a possible association between type 2 diabetes (T2DM) and gut microbiota. To explore specific metabolic pathways connecting gut microbiota and T2DM, we employed Mendelian randomization (MR) and linkage disequilibrium score regression (LDSC) techniques. Methods: This research utilized data from genome-wide association studies (GWAS) that are publicly accessible. We evaluated the genetic correlation between gut microbiota and T2DM using LDSC. Causality was primarily determined through the inverse variance weighted (IVW) method. To verify the robustness of our results, we conducted sensitivity analyses using several approaches, including the weighted median, MR-Egger, and MR-PRESSO. We integrated summary effect estimates from LDSC, along with forward and reverse MR, into a meta-analysis for T2DM using various data sources. Additionally, mediation analysis was performed to explore the impact of plasma metabolites on the relationship between gut microbiota and T2DM. Results: Our study indicated a significant genetic correlation between genus RuminococcaceaeUCG005 (Rg = -0.26, Rg_P = 2.07×10-4) and T2DM. Moreover, the forward MR analysis identified genus RuminococcaceaeUCG010 (OR = 0.857, 95% CI 0.795, 0.924; P = 6.33×10-5) and order Clostridiales (OR = 0.936, 95% CI 0.878, 0.997; P = 0.039) as being significantly associated with a decreased risk of T2DM. The analysis also highlighted several plasma metabolites as significant mediators in these relationships, with metabolites like octadecadienedioate (C18:2-DC) and branched chain 14:0 dicarboxylic acid being notably involved. Conclusion: The findings demonstrate a significant impact of gut microbiota on T2DM via plasma metabolites, suggesting potential metabolic pathways for therapeutic targeting. This study enhances our understanding of the microbiota's role in T2DM pathogenesis and supports the development of microbiota-based interventions.

Simultaneous Mapping of the Nanoscale Organization and Redox State of Extracellular Space in Living Brain Tissue.

The spatial organization characteristics and redox status of the extracellular space (ECS) are crucial in the development of brain diseases. However, it remains a challenge to simultaneously capture dynamic changes in microstructural features and redox states at the submicron level within the ECS. Here, we developed a reversible glutathione (GSH)-responsive nanoprobe (RGN) for mapping the spatial organization features and redox status of the ECS in brain tissues with nanoscale resolution. The RGN is composed of polymer nanoparticles modified with GSH-responsive molecules and amino-functionalized methoxypoly(ethylene glycol), which exhibit exceptional single-particle brightness and excellent free diffusion capability in the ECS of brain tissues. Tracking single RGNs in acute brain slices allowed us to dynamically map spatial organizational features and redox levels within the ECS of brain tissues in disease models. This provides a powerful super-resolution imaging method that offers a potential opportunity to study the dynamic changes in the ECS microenvironment and to understand the physiological and pathological roles of the ECS in vivo.

Label-Free Imaging of Mesenchymal Stem Cell Spheroid Differentiation with Flexible-Probe SECM and a Microfluidic Device.

Mesenchymal stem cells (MSCs) have emerged as an indispensable source for stem cell research and preclinical studies due to their capacity for in vitro proliferation and their potential to differentiate into mesodermal lineages, particularly into osteoblasts. This capability has propelled their application in the fields of bone regeneration and osteochondral repair. Traditional methodologies for assessing the differentiation status of MSCs necessitate invasive procedures such as cell lysis or fixation. In this study, we introduce a nondestructive technique that utilizes an integrated label-free approach to evaluate the osteogenic maturation of MSC spheroid aggregates. This method employs scanning electrochemical microscopy (SECM) with a flexible probe in conjunction with a top-removable microfluidic device designed for easy SECM access. By tracking the production rate of p-aminophenol (PAP) in the generation/collection mode and assessing morphological changes via the negative feedback mode using [Ru(NH3)6]Cl3 (Ruhex), we can discern variations in the alkaline phosphatase (ALP) activity indicative of osteogenic differentiation. This innovative strategy enables the direct evaluation of osteogenic differentiation in MSC spheroids cultured within microwell arrays without necessitating any labeling procedures. The utilization of a flexible microelectrode as the probe that scans in contact mode (with probe-substrate distances potentially as minimal as 0 µm) affords enhanced resolution compared to the traditional stiff-probe technique. Furthermore, this method is compatible with subsequent molecular biology assays, including gene expression analysis and immunofluorescence, thereby confirming the electrochemical findings and establishing the validity of this integrative approach.

Effects of mono- or di-fluoro-substitution on spin crossover behavior in a pair of Schiff base-like FeII-coordination polymers.

Spin crossover (SCO) has long been a hot topic in the field of molecular magnetism owing to its unique bistability character. Rational control of thermal hysteresis and transition temperature (T1/2) is crucial for their practical applications, which rely on precise manipulation of the substituents of SCO coordinating ligands and molecular packing interactions. In this study, we designed two different bridging ligands (2-FDPB: 4,4'-(2-fluoro-1,4-phenylene)dipyridine; 2,3-FDPB: 4,4'-(2,3-difluoro-1,4-phenylene)dipyridine) featuring one and two fluoro substitution on the central benzene ring and applied a Schiff base-like equatorial tetradentate ligand {diethyl(E,E)-2,2'-[4,5-difluoro-1,2-phenyl-bis(iminomethylidyne)]bis(3-oxobutanoate)-(2-)-N,N',O3,O3'} (H2L) to coordinate with the FeII ion. Two FeII-coordination chain polymers [FeII(L)(2,3-FDPB)]·0.25CH2Cl2 (1) and [FeII(L)(2-FDPB)]·0.5CH3OH (2) were obtained. 1 crystallizes in the monoclinic P21/n space group with only one FeII center, while 2 crystallizes in the triclinic P1̄ space group with two independent FeII centers. Unlike the identical 2D layer stacking in 1, 2 exhibited alternating stacking of the extending 2D layers and meshed chains. Magnetic measurements revealed the typical thermally induced spin crossover behavior (SCO): 1 exhibited a 41 K-wide thermal hysteresis with transition temperatures of T1/2↑ = 245 K and T1/2↓ = 204 K, while 2 showed a higher transition temperature (T1/2 = 330 K) with no thermal hysteresis. Magneto-structural correlation studies suggest that the electron-withdrawing effect present in the fluoro substituents does not have a significant impact on the SCO behaviors. Despite the fluoro substituents having a similar atomic radius of hydrogen atoms, variations in the number of these substituents can alter the crystallization behavior of these complexes, which in turn affects the solvents, molecular stacking patterns, and intermolecular interactions, ultimately influencing the SCO behaviors.

Assessing the influences of ß-glucan on highland barley starch: Insights into gelatinization and molecular interactions.

Developing highland barley products is complex, possibly due to the presence of ß-glucan in highland barley. This study aims to investigate the impact of ß-glucan on the physicochemical properties, microstructure, and molecular interactions of highland barley starch (HBS) during gelatinization and aging. Increasing the ß-glucan content significantly reduced peak viscosity, setback viscosity, and breakdown viscosity, indicating altered gelatinization behavior. The ß-glucan content increase caused a significant drop in peak viscosity. With 20% ß-glucan addition, it reduced by 883 mPa·s, nearly 38%. Rheological analysis showed a transition from a solid-like to a liquid-like texture or quality, ultimately leading to a shear-thinning behavior. Fourier-transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) confirmed the interaction between HBS and ß-glucan via intermolecular hydrogen bonding, promoting the formation of double helical structures in starch. These findings provide a deeper understanding of the role of ß-glucan in the processing of highland barley, highlighting its influence on the starch's properties.

Ozone-Assisted Cu-Based Catalysts for the Efficient Electro-Reforming Glycerol to Formic Acid.

Glycerol electrooxidation reaction (GOR) to produce value-added chemicals, such as formic acid, could make more efficient use of abundant glycerol and meet future demand for formic acid as a fuel for direct or indirect formic acid fuel cells. Non-noble metal Cu-based catalysts have great potential in electro-reforming glycerol to formic acid. However, the high activity, selectivity and stability of Cu based catalysts in GOR cannot be achieved simultaneously. Here, we used ozone-assisted electrocatalyst to convert glycerol to formic acid under alkaline conditions, the onset potential was reduced by 60 mV, the Faraday efficiency (FE) reached 95%. The catalyst has excellent stability within 300 h at the current density of 10 mA cm-2. The electron spin resonance proved that ozone produced superoxide anion during the GOR. In situ Raman spectroscopy, electrochemical studies showed that glycerol can be activated with ozone in GOR, and the C-C bond can be broken to reduce the polymerization of glycerol on the catalyst surface, so as to produce more formic acid at a lower voltage. Moreover, the removal of dissolved O3 from water can be up to 100% after 30 minutes of GOR reaction at a solubility of 50 mg L-1 as measured by UV-VIS spectrophotometry.

Development of [177Lu]Lu-LNC1010 for peptide receptor radionuclide therapy of nasopharyngeal carcinoma.

PURPOSE: Somatostatin Receptor 2 (SSTR2)-targeted radiopharmaceutical [68Ga]Ga-DOTATATE has potential advantages in the diagnosis of nasopharyngeal carcinoma (NPC). This study introduces a novel long-lasting SSTR2 analogue, LNC1010, based on DOTATATE, a truncated Evans blue-binding moiety, and a polyethylene-glycol linker. We hypothesised that peptide receptor radionuclide therapy (PRRT) is more effective with [177Lu]Lu-LNC1010 than with [177Lu]Lu-DOTATATE in treating metastatic NPC. METHODS: We assessed binding characteristics of LNC1010 in vitro using C666-1 NPC cells and in-vivo pharmacokinetics of [68Ga]Ga/[177Lu]Lu-LNC1010 in C666-1 NPC xenografts via PET and SPECT imaging, biodistribution studies, and PRRT, and compared them with [68Ga]Ga/[177Lu] Lu-labelled DOTATATE. Furthermore, a proof-of-concept approach for imaging and therapy was conducted in a patient with metastatic NPC. RESULTS: LNC1010 exhibited strong uptake and specific affinity for SSTR2 in C666-1 NPC cells. PET and SPECT imaging demonstrated higher uptake and longer tumour retention of [68Ga]Ga/[177Lu]Lu-LNC1010 than [68Ga]Ga/[177Lu]Lu-DOTATATE in C666-1 NPC xenografts, indicating its suitability for PRRT applications in NPCs. Biodistribution studies confirmed the higher uptake and prolonged retention of [177Lu]Lu-LNC1010 than [177Lu]Lu-DOTATATE. In preclinical PRRT studies, [177Lu]Lu-LNC1010 showed greater inhibition of tumour growth in C666-1 NPC xenografts than [177Lu]Lu-DOTATATE. In a subsequent pilot clinical study, PRRT with [177Lu]Lu-LNC1010 achieved favourable therapeutic and negligible side effects in a patient with metastatic NPC. CONCLUSION: [177Lu]Lu-LNC1010 demonstrated increased tumour uptake and prolonged retention in SSTR2-positive NPCs, with superior anti-tumour efficacy to that of [177Lu]Lu-DOTATATE in preclinical studies. These findings suggest that PRRT with [177Lu]Lu-LNC1010 is a promising treatment for advanced NPC, extending the clinical scope of PRRT beyond neuroendocrine tumours.

A CT-based radiomics tumor quality and quantity model to predict early recurrence after radical surgery for colorectal liver metastases.

PURPOSE: This study aimed to develop a tumor radiomics quality and quantity model (RQQM) based on preoperative enhanced CT to predict early recurrence after radical surgery for colorectal liver metastases (CRLM). METHODS: A retrospective analysis was conducted on 282 cases from 3 centers. Clinical risk factors were examined using univariate and multivariate logistic regression (LR) to construct the clinical model. Radiomics features were extracted using the least absolute shrinkage and selection operator (LASSO) for dimensionality reduction. The LR learning algorithm was employed to construct the radiomics model, RQQM (radiomics-TBS), combined model (radiomics-clinical), clinical risk score (CRS) model and tumor burden score (TBS) model. Inter-model comparisons were made using area under the curve (AUC), decision curve analysis (DCA) and calibration curve. Log-rank tests assessed differences in disease-free survival (DFS) and overall survival (OS). RESULTS: Clinical features screening identified CRS, KRAS/NRAS/BRAF and liver lobe distribution as risk factors. Radiomics model, RQQM, combined model demonstrated higher AUC values compared to CRS and TBS model in training, internal and external validation cohorts (Delong-test P < 0.05). RQQM outperformed the radiomics model, but was slightly inferior to the combined model. Survival curves revealed statistically significant differences in 1-year DFS and 3-year OS for the RQQM (P < 0.001). CONCLUSIONS: RQQM integrates both "quality" (radiomics) and "quantity" (TBS). The radiomics model is superior to the TBS model and has a greater impact on patient prognosis. In the absence of clinical data, RQQM, relying solely on imaging data, shows an advantage in predicting early recurrence after radical surgery for CRLM.

Umbilical Artery Thrombosis Causing Fetal Distress: A Case Report.

The umbilical cord (UC) is vital to maintain blood circulation between the mother and the growing fetus, which is sometimes disrupted. The umbilical artery thrombosis (UAT) is an infrequent complication of pregnancy that can lead to extreme perinatal outcomes, ranging from intrauterine growth restriction stillbirth to neonatal death. The prenatal diagnosis of UAT is essential and sometimes challenging to detect in clinical practice. Once it is detected, the emergent delivery through a cesarean section is considered after the steroidal lung maturity of the fetus. We report a primigravida diagnosed with this rare pregnancy complication, the UAT at delivery, along with the nuchal cord and abnormally coiled UC. The patient had an uneventful course of pregnancy except for the premature rupture of membranes and continuous fetal distress in the second stage of labor. As the labor progression was optimal, and prioritizing the patient's desire, she was vigilantly observed under the premise of continuous electronic fetal monitoring (EFM) to facilitate any emergency, ultimately resulting in the spontaneous vaginal delivery of an alive and healthy baby boy. The fetal distress detected through EFM is an indicator of several stressors predisposing the fetus to some unknown danger that carries an increased risk of perinatal mortality. Based on our experience, it is suggested that radiologists should routinely conduct UC sonographic studies on regular antenatal scans; obstetricians should also have a brief and precise awareness of the critical lifesaving sonographic parameters to measure. The UAT, nuchal cord, and abnormal UC coiling, as found in our case, are all rare factors and related to some extent of fetal morbidity and mortality; once such complications are prenatally suspected, one should manage it through close monitoring and timely decision of appropriate delivery time.

Dose rate correction for the novel 2D diode array MapCHECK 3.

PURPOSE: To investigate the dose rate dependence of MapCHECK3 and its influence on measurement accuracy, as well as the effect of dose rate correction. MATERIALS AND METHODS: The average and instantaneous dose rate dependence of MapCHECK2 and MapCHECK3 were studied. The accuracy of measurements was investigated where the dose rate differed significantly between dose calibration of the MapCHECK and the measurement. Measurements investigated include: the central axis dose for different fields at different depths, off-axis doses outside the field, and off-axis doses along the wedge direction. Measurements using an ion chamber were taken as the reference. Exponential functions were fit to account for average and instantaneous dose rate dependence for MapCHECK3 and used for dose rate correction. The effect of the dose rate correction was studied by comparing the differences between the measurements for MapCHECK (with and without the correction) and the reference. RESULTS: The maximum dose rate dependence of MapCHECK3 is greater than 2.5%. If the dose calibration factor derived from a 10 × 10 cm2 open field at 10 cm depth was used for measurements, the average differences in central diode dose were 0.8% ± 1.0% and 1.0% ± 0.8% for the studied field sizes and measurement depths, respectively. The introduction of wedge would not only induce -1.8% ± 1.3% difference in central diode dose, but also overestimate the effective wedge angle. After the instantaneous dose rate correction, above differences can be changed to 1.9% ± 8.1%, 0.2% ± 0.1%, and 0.0% ± 0.9%. The pass rate can be improved from 98.4% to 98.8%, 98.3%-100.0%, and 96.3%-100.0%, respectively. CONCLUSION: Compared with MapCHECK2 (SunPoint1 diodes), the more pronounced dose rate dependence of MapCHECK3 (SunPoint2 diodes) should be carefully considered. To ensure highly accurate measurement, it is suggested to perform the dose calibration at the same condition where measurement will be performed. Otherwise, the dose rate correction should be applied.

Regulation mechanism of GPS2 on PGC-1α/Drp1-mediated mitochondrial dynamics in inflammation of acute lung injury.

Acute lung injury (ALI) has been a hot topic in the field of critical care research in recent years. Mitochondrial dynamics consists of mitochondrial fusion and mitochondrial fission. Dynamin-related protein 1 (Drp1), a key molecule that regulates mitochondrial fission, is important in the oxidative stress and inflammatory response to ALI. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a core protein that mediates mitochondrial biogenesis. G-protein pathway suppressor 2 (GPS2) acts as a transcriptional cofactor with regulatory effects on nuclear-encoded mitochondrial genes. This study aimed to investigate the mechanism of PGC-1α/Drp1-mediated mitochondrial dynamics involved in ALI and to demonstrate the protective mechanism of GPS2 in regulating mitochondrial structure and function and inflammation in ALI. The ALI model was constructed using LPS-induced wild-type mice and human pulmonary microvascular endothelial cells (HPMVECs). It was found that lung injury, oxidative stress and inflammation were exacerbated in the mice ALI model and that mitochondrial structure and function were disrupted in HPMVECs. In vitro studies revealed that LPS led to the upregulated expression of Drp1 and the downregulated expression of PGC-1α and GPS2. Mitochondrial division was reduced and respiratory function was restored in Drp1 knockdown cells, which inhibited oxidative stress and inflammatory response. In addition, the overexpression of PGC-1α and GPS2 significantly inhibited the expression of Drp1, mitochondrial function was restored, and inhibited reactive oxygen species (ROS) production and inflammatory factor release. Moreover, the overexpression of GPS2 promoted the upregulated expression of PGC-1α. This mechanism was also validated in vivo, in which the low expression of GPS2 in mice resulted in the upregulated expression of Drp1 and the downregulated expression of PGC-1α, and further exacerbated LPS-induced ALI. In the present study, we also found that LPS-induced the downregulated expression of GPS2 may be associated with its increased degradation by the proteasome. Therefore, these findings revealed that GPS2 inhibited oxidative stress and inflammation by modulating PGC-1α/Drp1-mediated mitochondrial dynamics to alleviate LPS-induced ALI, which may provide a new approach to the therapeutic orientation for LPS-induced ALI.

The CCR6-CCL20 axis promotes regulatory T cell glycolysis and immunosuppression in tumors.

Regulatory T cells (Tregs) are important players in the tumor microenvironment. However, the mechanisms behind their immunosuppressive effects are poorly understood. We found that CCR6-CCL20 activity in tumor-infiltrating Tregs is associated with greater glycolytic activity and ablation of Ccr6 reduced glycolysis and lactic acid production while increasing compensatory glutamine metabolism. Immunosuppressive activity towards CD8+ T cells was abrogated in Ccr6-/- Tregs due to reduction in activation-induced glycolysis. Furthermore, Ccr6-/- mice exhibited improved survival across multiple tumor models compared to wildtype mice, and Treg and CD8+ T-cell depletion abrogated the improvement. In addition, Ccr6 ablation further promoted the efficacy of anti-PD-1 therapy in a preclinical glioma model. Follow-up knockdown of Ccl20 with siRNA also demonstrated improvement in antitumor efficacy. Our results unveil CCR6 as a marker and regulator of Treg-induced immunosuppression and identify approaches to target the metabolic determinants of Treg immunosuppressive activity.

Landscape of glycolytic metabolites and their regulating proteins in myocardium from human heart failure with preserved ejection fraction.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) reflects half of all clinical HF yet has few therapies. Obesity and diabetes are now common comorbidities which have focused attention towards underlying myocardial metabolic defects. The profile of a major metabolic pathway, glycolytic intermediates and their regulating enzymes and ancillary pathways, remains unknown. METHODS AND RESULTS: Endomyocardial biopsies from HFpEF (n = 37) and non-failing controls (n = 21) were assayed by non-targeted or targeted metabolomics and immunoblot to determine glycolytic and ancillary pathway metabolites and protein expression of their regulating enzymes. Glucose and GLUT1 expression were higher in HFpEF, but prominent glycolytic metabolites: glucose-6-phosphate, fructose-1,6-biphosphate (F1,6bP), and 3-phosphoglycerate were reduced by -78%, -91%, and -73%, respectively, versus controls. Expression of their corresponding synthesizing enzymes hexokinase, phospho-fructokinase, and phosphoglycerate kinase were also significantly lower (all p < 0.0005). Pentose phosphate and hexosamine biosynthetic pathway metabolites were reduced while glycogen content increased. Despite proximal reduction in key glycolytic intermediates, pyruvate increased but mitochondrial pyruvate transporter (MPC1) expression was reduced. Pyruvate dehydrogenase converting pyruvate to acetyl-CoA was more activated but some Krebs cycle intermediates were reduced. This HFpEF glycolytic profile persisted after adjusting for body mass index (BMI), diabetes, age, and sex, or in subgroup analysis with controls and HFpEF matched for BMI and diabetes/insulin history. In HFpEF, BMI but not glycated haemoglobin negatively correlated with F1,6bP (p = 7e-5, r = -0.61) and phosphoenolpyruvate (p = 0.006, r = -0.46). CONCLUSIONS: Human HFpEF myocardium exhibits reduced glycolytic and ancillary pathway intermediates and expression of their synthesizing proteins. This combines features reported in HF with reduced ejection fraction and obesity/diabetes that likely exacerbate metabolic inflexibility.

Development and comparison of model-integrated evidence approaches for bioequivalence studies with pharmacokinetic end points.

By applying nonlinear mixed-effect (NLME) models, model-integrated evidence (MIE) approaches are able to analyze bioequivalence (BE) data with pharmacokinetic end points that have sparse sampling, which is problematic for non-compartmental analysis (NCA). However, MIE approaches may suffer from inflation of type I error due to underestimation of parameter uncertainty and to the assumption of asymptotic normality. In this study, we developed a MIE BE analysis method that is based on a pre-defined model and consists of several steps including model fitting, uncertainty assessment, simulation, and BE determination. The presented MIE approach has several improvements compared with the previously reported model-integrated methods: (1) treatment, sequence, and period effects are only added to absorption parameters (such as relative bioavailability and rate of absorption) instead of all PK parameters; (2) a simulation step is performed to generate confidence intervals of the pharmacokinetic metrics for BE assessment; and (3) in an effort to maintain type I error, two more advanced parameter uncertainty evaluation approaches are explored, a nonparametric (case resampling) bootstrap, and sampling importance resampling (SIR). To evaluate the developed method and compare the uncertainty assessment methods, simulation experiments were performed for BE studies using a two-way crossover design with different amounts of information (sparse to rich designs) and levels of variability. Based on the simulation results, the method using SIR for parameter uncertainty quantification controls type I error at the nominal level of 0.05 (i.e., the significance level set for BE evaluation) even for studies with small sample size and/or sparse sampling. As expected, our MIE approach for BE assessment exhibited higher power than the NCA-based method, especially as the data becomes sparser and/or more variable.

Ameliorative impacts of Sinapic acid against monosodium urate crystal-induced gouty arthritis and inflammation through different signaling pathways.

As known, gout a metabolic disease due to the urate crystals deposition in the joints and affect human health and state. Humans are looking for safe natural remedies from plants with safe, low cost and high effect on their health. Sinapic acid (SA) is found in plants and used as phytoconstituent in human diets. SA has strong antioxidant activity, bone-regenerative, anti-cancer, anti-allergic, and antidiabetic effects. The current study was outlined to confirm the anti-gout potential of SA against monosodium urate crystals (MSU)-induced gouty arthritis in mice. Positive gouty arthritis was conducted by administration of colchicine and MSU in the hind paw. SA was orally administered to negative and positive MSU arthritic mice at 25 and 50 mg/kg, one-hour before MSU injection (100 µg/kg intra-articular). At the end of the experiment, sampling was done for serum, histopathology, oxidative stress and gene expression analysis. The results showed that SA significantly recovered the joint edema and recovered MSU crystals-showed histopathological changes. The production of cytokines, leukocyte recruitment, oxidative stress, and nucleotide-binding domain, leucinerich-containing family, pyrin domain-containing-3 (NLRP3)-inflammasome genes expressions were increased in positive arthritic mice and ameliorated significantly by SA administration. Moreover, SA showed ameliorative impacts on air pouch model of mice as reported by the down regulation in the expression of inflammation related blood cells, proinflammatory cytokines and other transcriptional genes. In conclusion, sinapic acid showed a potential therapeutic use against side effects accompanying gouty arthritis and is good as a supplement against inflammation associated disorders.

Case report: A therapeutic attempt to treat Morbihan disease with Baricitinib.

A woman in her thirties who had been diagnosed with Morbihan disease did not notice a significant improvement in her condition after receiving years of treatment. Our decision to use Baricitinib helped her to achieve a better outcome. To our knowledge, this is the first study to use Baricitinib in Morbihan disease, although JAK inhibitors have already been successfully used before. It is hoped that our case report will provide new treatment options for Morbihan disease therapy.

Smoking behaviors, physical activities, pulmonary diseases and COVID-19 severity: A Mendelian randomization study.

Smoking behaviors, physical activities, and pulmonary diseases have been revealed to be associated with COVID-19 severity through observational research. The possible causative effect remains undetermined. To investigate this, we thus carried out a Mendelian randomization (MR) analysis. We chose genetic variants from genome-wide association studies that are strongly linked to 5 exposures related to smoking, 1 exposure related to drinking, 3 levels of physical activity, and 3 pulmonary diseases. The COVID-19 Host Genetics Initiative provided summary-level data for severe COVID-19 (13,769 cases and 1,072,442 noncases), hospitalized COVID-19 (32,519 cases and 2,062,805 noncases), and COVID-19 susceptibility (122,616 cases and 2,475,240 noncases). Univariate and multivariate MR analyses were carried out. Significant associations were found between severe COVID-19 and cigarette smoking per day (OR = 1.357, 95% CI: 1.087-1.694), lifetime smoking index (OR = 2.277, 95% CI: 1.602-3.325), and interstitial lung disease (OR = 1.23, 95% CI: 1.112-1.362), hospitalized COVID-19 and lifetime smoking index (OR = 2.199, 95% CI: 1.738-2.781), smoking initiation (OR = 1.419, 95% CI: 1.230-1.637), and interstitial lung disease (OR = 1.146, 95% CI: 1.082-1.214), as well as COVID-19 susceptibility and lifetime smoking index (OR = 1.39, 95% CI: 1.252-1.543), smoking initiation (OR = 1.235, 95% CI: 1.163-1.311), and duration of vigorous activity per day (OR = 0.733, 95% CI: 0.574-0.935). Duration of vigorous activity per day was suggestively inversely linked to hospitalized COVID-19 (OR = 0.434, 95% CI: 0.221-0.853) and severe COVID-19 (OR = 0.323, 95% CI: 0.123-0.850). The association for lifetime smoking index remained consistent with severe COVID-19, hospitalized COVID-19, and COVID-19 susceptibility in multivariable MR analysis. Genetic liability to lifetime smoking index mediated the interstitial lung disease effects on severe COVID-19 risk (21.0%) and hospitalized COVID-19 risk (14.4%). This study identified several smoking behaviors, duration of vigorous activity per day, and interstitial lung disease that may be causally related to COVID-19 severity.

The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.

Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.