Increased serum asprosin is correlated with diabetes mellitus-induced erectile dysfunction.

OBJECTIVE: Asprosin, a newly identified adipokine, is pathologically increased in type 2 diabetes. The aim of this study is to see whether serum asprosin concentrations are linked to diabetes mellitus-induced erectile dysfunction (DMED). METHODS: 90 male patients with type 2 diabetes were included. According to the International Index of Erectile Function (IIEF-5) score, they were classified into two groups: 45 type 2 diabetes patients without erectile dysfunction (DM group) (IIEF-5 > 21),45 patients with diabetes induced erectile dysfunction (DMED group) (IIEF-5 ≤ 21)0.45 healthy male volunteers with normal blood glucose, IIEF-5 score > 21 points, and age matched with the DMED group were included as the control group. Anthropometric and biochemical variables were determined in all participants. RESULTS: When compared to the controls, T2DM ( Type 2 Diabetes Mellitus)patients had higher serum asprosin levels. The DMED group had significantly higher serum asprosin than the T2DM groups(p < 0.001). After adjusting for multiple variables considered traditional risk factors for ED(erectile dysfunction), Asprosin can still be used as an independent risk factor for ED; The ROC(Receive Operating Characteristic Curve) indicates that asprosin has good sensitivity (97.8%) and specificity (62.2%) in predicting ED, with an area under the curve of 0.843.Correlation analysis shows that asprosin is negatively correlated with SOD(superoxide dismutase ) and positively correlated with MDA (malondialdehyde). CONCLUSION: Serum asprosin concentrations are increased in patients with DMED. Also, asprosin is correlated with oxidative stress indexes (MDA, SOD).

Association of cardiometabolic multimorbidity with all-cause and cardiovascular disease mortality among Chinese hypertensive patients.

BACKGROUND: Hypertension usually clusters with multiple comorbidities. However, the association between cardiometabolic multimorbidity (CMM) and mortality in hypertensive patients is unclear. This study aimed to investigate the association between CMM and all-cause and cardiovascular disease (CVD) mortality in Chinese patients with hypertension. METHODS: The data used in this study were from the China National Survey for Determinants of Detection and Treatment Status of Hypertensive Patients with Multiple Risk Factors (CONSIDER), which comprised 5006 participants aged 19-91 years. CMM was defined as the presence of one or more of the following morbidities: diabetes mellitus, dyslipidemia, chronic kidney disease, coronary heart disease, and stroke. Cox proportional hazard models were used to calculate the hazard ratios (HR) with 95% CI to determine the association between the number of CMMs and both all-cause and CVD mortality. RESULTS: Among 5006 participants [mean age: 58.6 ± 10.4 years, 50% women (2509 participants)], 76.4% of participants had at least one comorbidity. The mortality rate was 4.57, 4.76, 8.48, and 16.04 deaths per 1000 person-years in hypertensive patients without any comorbidity and with one, two, and three or more morbidities, respectively. In the fully adjusted model, hypertensive participants with two cardiometabolic diseases (HR = 1.52, 95% CI: 1.09-2.13) and those with three or more cardiometabolic diseases (HR = 2.44, 95% CI: 1.71-3.48) had a significantly elevated risk of all-cause mortality. The findings were similar for CVD mortality but with a greater increase in risk magnitude. CONCLUSIONS: In this study, three-fourths of hypertensive patients had CMM. Clustering with two or more comorbidities was associated with a significant increase in the risk of all-cause and cardiovascular mortality among hypertensive patients, suggesting more intensive treatment and control in this high-risk patient group.

Hydrogen production and solar energy storage with thermo-electrochemically enhanced steam methane reforming.

Hydrogen is widely regarded as a sustainable energy carrier with tremendous potential for low-carbon energy transition. Solar photovoltaic-driven water electrolysis (PV-E) is a clean and sustainable approach of hydrogen production, but with major barriers of high hydrogen production costs and limited capacity. Steam methane reforming (SMR), the state-of-the-art means of hydrogen production, has yet to overcome key obstacles of high reaction temperature and CO2 emission for sustainability. This work proposes a solar thermo-electrochemical SMR approach, in which solar-driven mid/low-temperature SMR is combined with electrochemical H2 separation and in-situ CO2 capture. The feasibility of this method is verified experimentally, achieving an average methane conversion of 96.8% at a dramatically reduced reforming temperature of 400-500 °C. The underlying mechanisms of this method are revealed by an experimentally calibrated model, which is further employed to predict its performance for thermo-electrochemical hydrogen production. Simulation results show that a net solar-to-H2 efficiency of 26.25% could be obtained at 500 °C, which is over 11 percentage points higher than that of PV-E; the first-law thermodynamic efficiency reaches up to 63.27% correspondingly. The enhanced efficiency also leads to decreased fuel consumption and lower CO2 emission of the proposed solar-driven SMR system. Such complementary conversion of solar PV electricity, solar thermal energy, and low-carbon fuel provides a synergistic and efficient means of sustainable H2 production with potentially long-term solar energy storage on a vast scale.

Guadecitabine vs TC in relapsed/refractory AML after intensive chemotherapy: a randomized phase 3 ASTRAL-2 trial.

ABSTRACT: Guadecitabine is a novel hypomethylating agent (HMA) resistant to deamination by cytidine deaminase. Patients with relapsed/refractory acute myeloid leukemia (AML) were randomly assigned to guadecitabine or a preselected treatment choice (TC) of high-intensity chemotherapy, low-intensity treatment with HMAs or low-dose cytarabine, or best supportive care (BSC). The primary end point was overall survival (OS). A total of 302 patients were randomly assigned to guadecitabine (n = 148) or TC (n = 154). Preselected TCs were low-intensity treatment (n = 233 [77%; mainly HMAs]), high-intensity chemotherapy (n = 63 [21%]), and BSC (n = 6 [2%]). The median OS were 6.4 and 5.4 months for guadecitabine and TC, respectively (hazard ratio 0.88 [95% confidence interval, 0.67-1.14]; log-rank P = .33). Survival benefit for guadecitabine was suggested in several prospective subgroups, including age <65 years, Eastern Cooperative Oncology Group performance status 0 to 1, refractory AML, and lower peripheral blood blasts ≤30%. Complete response (CR) + CR with partial hematologic recovery rates were 17% for guadecitabine vs 8% for TC (P < .01); CR+CR with incomplete count recovery rates were 27% for guadecitabine vs 14% for TC (P < .01). Safety was comparable for the 2 arms, but guadecitabine had a higher rate of grade ≥3 neutropenia (32% vs 17%; P < .01). This study did not demonstrate an OS benefit for guadecitabine. Clinical response rates were higher for guadecitabine, with comparable safety to TC. There was an OS benefit for guadecitabine in several prespecified subgroups. This study was registered at www.clinicaltrials.gov as #NCT02920008.

Immunosuppressive therapy and COVID-19 infection in patients with NMOSD.

INTRODUCTION: To evaluate whether treated with immunosuppressants in neuromyelitis optica spectrum disorder (NMOSD) shows an effect on the severity and outcomes of COVID-19 Omicron variant. METHODS: This is a substudy of a single-center clinical trial involving human umbilical cord mesenchymal stem cells (hUC-MSCs) in NMOSD patients. NMOSD patients with hUC-MSCs treatment, NMOSD patients without hUC-MSCs treatment, and matched healthy controls (HC) were included. Demographic information, NMOSD-related clinical features, comorbidities, use of disease-modifying therapy, COVID-19 vaccination status, COVID-19 clinical features, COVID-19 clinical outcomes, and NMOSD-related disease activity were obtained through online questionnaires or phone calls. RESULTS: The majority of NMOSD patients received long-term treatment with mycophenolate mofetil (68.8%) or azathioprine (22.9%), and 50% received oral glucocorticoid. During the epidemic, 97.4% of NMOSD patients infected with COVID-19 had asymptomatic or mild forms, with only two patients (2.6%) requiring hospitalization. None of these patients required tracheal intubation or admission to the intensive care unit. Clinical symptoms were found to be more prevalent in HC groups. Additionally, the HC groups had higher fever-recorded temperatures. NMOSD patients who received hUC-MSCs treatment had shorter disease duration than patients who did not receive hUC-MSCs treatment. DISCUSSION: Immunosuppressant-treated patients with NMOSD have a similar risk of COVID-19 infection as the general population, but the disease duration is shorter and the clinical symptoms are less severe. Among our NMOSD patients who received hUC-MSCs treatment, COVID-19 outcomes were favorable, with no increased risk of severe COVID-19. Prospective studies on immunotherapies are needed to help determine best treatment practices.

The effect of double filtration plasmapheresis and corticosteroids on patients with anti-dipeptidyl-peptidase-like protein 6 encephalitis.

INTRODUCTION: Anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis is a rare condition with varied symptoms including gastrointestinal issues, weight loss, cognitive and mental dysfunction, and hyperexcitability of the central nervous system. METHODS: We studied five patients with anti-DPPX encephalitis who received immunotherapy, specifically DFPP, at our hospital. We analyzed their clinical symptoms, lab results, electrophysiological and imaging findings, and outcomes with immunotherapy. RESULTS: Patients presented with cognitive dysfunction, tremor, seizures, psychiatric disturbances, and cerebellar and brainstem dysfunction. Magnetic resonance imaging (MRI) showed brain abnormalities in one patient and elevated cerebrospinal fluid (CSF) protein levels in two patients. Antibodies against DPPX were detected in all patients and in CSF in two patients. One patient had antibodies against anti-CV2/contactin response mediator protein 5 (CRMP5). All patients responded well to DFPP and corticosteroids. CONCLUSION: DFPP may be an effective treatment for anti-DPPX encephalitis. Further research is needed to understand disease progression and evaluate immunotherapy efficacy.

Site-Selective C-O Bond Editing of Unprotected Saccharides.

Glucose and its polyhydroxy saccharide analogs are complex molecules that serve as essential structural components in biomacromolecules, natural products, medicines, and agrochemicals. Within the expansive realm of saccharides, a significant area of research revolves around chemically transforming naturally abundant saccharide units to intricate or uncommon molecules such as oligosaccharides or rare sugars. However, partly due to the presence of multiple hydroxyl groups with similar reactivities and the structural complexities arising from stereochemistry, the transformation of unprotected sugars to the desired target molecules remains challenging. One such formidable challenge lies in the efficient and selective activation and modification of the C-O bonds in saccharides. In this study, we disclose a modular 2-fold "tagging-editing" strategy that allows for direct and selective editing of C-O bonds of saccharides, enabling rapid preparation of valuable molecules such as rare sugars and drug derivatives. The first step, referred to as "tagging", involves catalytic site-selective installation of a photoredox active carboxylic ester group to a specific hydroxyl unit of an unprotected sugar. The second step, namely, "editing", features a C-O bond cleavage to form a carbon radical intermediate that undergoes further transformations such as C-H and C-C bond formations. Our strategy constitutes the most effective and shortest route in direct transformation and modification of medicines and other molecules bearing unprotected sugars.

Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study.

BACKGROUND: The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and pharmacokinetics of oral decitabine plus the cytidine deaminase inhibitor cedazuridine versus intravenous decitabine. METHODS: We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 days of oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m2 per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine-cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over 5 days with oral decitabine-cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC0-24 for both oral decitabine-cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with ClinicalTrials.gov, NCT03306264. FINDINGS: Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and five [4%] not reported) received treatment. Median follow-up was 966 days (IQR 917-1050). Primary endpoint of total exposure of oral decitabine-cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66-105·60), indicating equivalent pharmacokinetic exposure on the basis of area under the curve. The safety profiles of oral decitabine-cedazuridine and intravenous decitabine were similar. The most frequent adverse events of grade 3 or worse were thrombocytopenia (81 [61%] of 133 participants), neutropenia (76 [57%] participants), and anaemia (67 [50%] participants). The incidence of serious adverse events in cycles 1-2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with intravenous decitabine. There were five treatment-related deaths; two deemed related to oral therapy (sepsis and pneumonia) and three to intravenous treatment (septic shock [n=2] and pneumonia [n=1]). INTERPRETATION: Oral decitabine-cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. The results support use of oral decitabine-cedazuridine as a safe and effective alternative to intravenous decitabine for treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia. FUNDING: Astex Pharmaceuticals.

[Health Impact Analysis of Fine Particulate Pollution from Vehicles in the Beijing-Tianjin-Hebei Region].

Vehicle exhaust emissions are posing an increasingly adverse impact on urban air quality. The emission characteristics analysis and health effect assessment of specific air pollution sources can provide scientific evidence for environmental air quality management. The characteristics and health effects of PM2.5 emissions from vehicles and economic losses caused by them in the Beijing-Tianjin-Hebei Region were analyzed from 2010 to 2020. From 2010 to 2020, PM2.5 emissions from vehicles in the Beijing-Tianjin-Hebei Region showed an annual increase at first, followed by a slow decrease. According to the emission sharing ratios of different vehicle types, heavy-duty trucks and buses were the main contributors to PM2.5, with a total contribution rate of over 65.27%. The emission characteristics of vehicle pollutants varied in different cities. The contribution rate of pollutants in Beijing decreased significantly, and the emission reduction in other cities was also dramatic. The evaluation results of the impact of PM2.5 emissions from vehicles on human health showed that the number of health endpoints in the Beijing-Tianjin-Hebei Region was on the rise. In 2020, PM2.5 pollution caused approximately 34337 premature deaths (95% CI:9025-57209), 45500 hospitalizations (95% CI:10800-80200), 282300 outpatients (95% CI:140500-416300), and 439000 people to fall ill (95% CI:160300-679200). Beijing had the largest number of patients that presented different health endpoints. The total health and economic losses caused by PM2.5 emissions from vehicles in 2010, 2015, and 2020 were 27.742 billion yuan (95% CI:8.616-44.643 billion yuan), 90.608 billion yuan (95% CI:28.476-144.050 billion yuan), and 129.965 billion yuan (95% CI:40.829-205.245 billion yuan), respectively. In addition, due to the differences in vehicle ownership, PM2.5 concentrations, population, and economic losses per case of health outcome, the health effects and economic losses varied in different cities within the region. Among these cities, Beijing, Tianjin, Baoding, and Tangshan were at higher health risks and suffered more economic losses. The results of this study will help reduce the adverse effects on health and economic losses caused by pollution discharge and provide scientific evidence for environmental protection authorities to implement targeted pollution prevention and control.

Dual effect of tacrolimus on mast cell-mediated allergy and inflammation through Mas-related G protein-coupled receptor X2.

BACKGROUND: Topical tacrolimus, although widely used in the treatment of dermatoses, presents with an immediate irritation on initial application resembling a pseudo-allergic reaction. Mas-related G protein-coupled receptor X2 (MRGPRX2) in mast cells (MCs) mediates drug-induced pseudo-allergic reaction and immunoglobulin E (IgE)-independent pruritis in chronic skin diseases. However, the immunosuppression mechanism of tacrolimus on MCs via MRGPRX2 has not been reported. OBJECTIVE: To investigate the role of MRGPRX2 and the mechanism of action of tacrolimus on its short-term and long-term applications. METHODS: Wild-type mice, KitW-sh/W-sh mice, and MrgprB2-deficient (MUT) mice were used to study the effect of tacrolimus on in vivo anaphylaxis model. LAD2 cells and MRGPRX2-knockdown LAD2 cells were specifically used to derive the associated mechanism of the tacrolimus effect. RESULTS: Short-term application of tacrolimus triggers IgE-independent activation of MCs via MRGPRX2/B2 in both in vivo and in vitro experiments. Tacrolimus binds to MRGPRX2, which was verified by fluorescently labeled tacrolimus in cells. On long-term treatment with tacrolimus, the initial allergic reaction fades away corresponding with the downregulation of MRGPRX2, which leads to decreased release of inflammatory cytokines (P < 0.05 to P < 0.001). CONCLUSION: Short-term treatment with tacrolimus induces pseudo-allergic reaction via MRGPRX2/B2 in MCs, whereas long-term treatment downregulates expression of MRGPRX2/B2, which may contribute to its potent immunosuppressive effect in the treatment of various skin diseases.

Comprehensive Metabolic Fingerprints Characterize Neuromyelitis Optica Spectrum Disorder by Nanoparticle-Enhanced Laser Desorption/Ionization Mass Spectrometry.

Timely screening of neuromyelitis optica spectrum disorder (NMOSD) and differential diagnosis from myelin oligodendrocyte glycoprotein associated disorder (MOGAD) are the keys to improving the quality of life of patients. Metabolic disturbance occurs with the development of NMOSD. Still, advanced tools are required to probe the metabolic phenotype of NMOSD. Here, we developed a fast nanoparticle-enhanced laser desorption/ionization mass spectrometry assay for multiplexing metabolic fingerprints (MFs) from trace plasma and cerebrospinal fluid (CSF) samples in 30 s. Machine learning of the plasma MFs achieved the timely screening of NMOSD from healthy donors with an area under receiver operator characteristic curve (AUROC) of 0.998, and it comprehensively revealed the dysregulated neurotransmitter and energy metabolisms. Combining comprehensive MFs from both plasma and CSF, we constructed an integrated panel for differential diagnosis of NMOSD versus MOGAD with an AUROC of 0.923. This approach demonstrated performance superior to that of human experts in classifying two diseases, especially in antibody assay-limited regions. Together, this approach provides an advanced nanomaterial-based tool for identifying vulnerable populations below the antibody threshold of aquaporin-4 positivity.

Improving prediction model robustness with virtual sample construction for near-infrared spectra analysis.

In a qualitative analysis of near-infrared spectroscopy (NIRS), when the samples to be analyzed are difficult to obtain or there are few counterexamples, the robustness of the models is poor, resulting in the decline of the generalization ability of the models. In this case, the effective method is to construct virtual samples to achieve the balance of categories. In this contribution, three virtual spectrum construction strategies including Synthetic Minority Oversampling Technique (SMOTE), Adaptive Synthetic Sampling (ADASYN), and Deep Convolutional Generative Adversarial Network (DCGAN) were explored to deal with the problem of insufficient or imbalanced sample numbers in NIRS analysis. The strategies were tested with the melamine and Yali pears two spectral datasets. The PLS-DA and Correct Recognition Rate (CRR) were used for discriminant model construction and accuracy evaluation, respectively. The results show that SMOTE, ADASYN, and DCGAN processing strategies can all improve the global CRR (CRRglob). The SMOTE and ADASYN can improve the CRR for majority class sample (CRRmaj), but the CRR for minority class sample (CRRmin) has decreased. For the DCGAN method, the CRRglob, CRRmaj, and CRRmin were all improved. The standard deviation of the results of the multiple parallel calculations demonstrates the robustness of DCGAN generation method. Therefore, the DCGAN method has good reliability and practicability, and can increase the robustness and generalization ability of the NIRS model.

Asymptomatic atrial fibrillation among hospitalized patients: clinical correlates and in-hospital outcomes in Improving Care for Cardiovascular Disease in China-Atrial Fibrillation.

AIMS: The clinical correlates and outcomes of asymptomatic atrial fibrillation (AF) in hospitalized patients are largely unknown. We aimed to investigate the clinical correlates and in-hospital outcomes of asymptomatic AF in hospitalized Chinese patients. METHODS AND RESULTS: We conducted a cross-sectional registry study of inpatients with AF enrolled in the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation Project between February 2015 and December 2019. We investigated the clinical characteristics of asymptomatic AF and the association between the clinical correlates and the in-hospital outcomes of asymptomatic AF. Asymptomatic and symptomatic AF were defined according to the European Heart Rhythm Association score. Asymptomatic patients were more commonly males (56.3%) and had more comorbidities such as hypertension (57.4%), diabetes mellitus (18.6%), peripheral artery disease (PAD; 2.3%), coronary artery disease (55.5%), previous history of stroke/transient ischaemic attack (TIA; 17.9%), and myocardial infarction (MI; 5.4%); however, they had less prevalent heart failure (9.6%) or left ventricular ejection fractions ≤40% (7.3%). Asymptomatic patients were more often hospitalized with a non-AF diagnosis as the main diagnosis and were more commonly first diagnosed with AF (23.9%) and long-standing persistent/permanent AF (17.0%). The independent determinants of asymptomatic presentation were male sex, long-standing persistent AF/permanent AF, previous history of stroke/TIA, MI, PAD, and previous treatment with anti-platelet drugs. The incidence of in-hospital clinical events such as all-cause death, ischaemic stroke/TIA, and acute coronary syndrome (ACS) was higher in asymptomatic patients than in symptomatic patients, and asymptomatic clinical status was an independent risk factor for in-hospital all-cause death, ischaemic stroke/TIA, and ACS. CONCLUSION: Asymptomatic AF is common among hospitalized patients with AF. Asymptomatic clinical status is associated with male sex, comorbidities, and a higher risk of in-hospital outcomes. The adoption of effective management strategies for patients with AF should not be solely based on clinical symptoms.

[Spatial Distribution, Source Analysis, and Health Risk Assessment of Metal Elements in Karst Water in Southeastern Chongqing].

Dispersed karst water is an important water supply source, or even the only water supply source, for some districts and counties in Chongqing City. It is particularly necessary to understand the distribution characteristics of metal elements in karst water and the health risks exposed. In this study, the scattered karst water in the southeastern part of Chongqing was taken as the main research object, and the concentrations of Al, Cu, Pb, Zn, Cr, Cd, Ni, Mn, As, and Hg in 42 groups of karst spring water samples were determined. The spatial distribution of metal elements with a high detection rate was revealed using the ordinary kriging interpolation method, and the spatial distribution characteristics, sources, and health risks of metal elements were analyzed using multivariate statistical methods and health risk models. The results showed that the quality of dispersed karst water in southeastern Chongqing was generally good, and the spatial scale variability in the occurrence of metal elements in karst water was strong, especially for Ni and As. The sources of Cu, Pb, As, Zn, and Cr were mainly affected by the regional geological background; Al and Mn were mainly affected by human industrial, agricultural, and mining activities; and Ni was affected by both the natural background and human activities. The total health risk of exposure through the drinking route was higher than that of the skin infiltration route, which was the main exposure route of the human body. The total health risk of children exposed through the drinking route was higher than that of adults, and the total health risk of adults exposed through the skin infiltration route was higher than that of children. It is worth noting that Cr was the determinant of total health risk. From the perspective of drinking water safety, local residents need to pay certain attention to water quality when drinking distributed karst groundwater, in order to reduce the health risk of the population.

Functional screening and rational design of compounds targeting GPR132 to treat diabetes.

Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes.

[Hydrochemical Characteristics and Formation Causes of Ground Karst Water Systems in Gudui Spring Catchment].

As one of the famous karst springs in Shanxi Province, the Gudui spring is the only medium-low temperature hot spring, with a long history of development and a rich cultural accumulation. The karst groundwater in the Gudui spring catchment was taken as the research object. Through systematic sample collection and isotope analysis, hydrochemistry (Durov map, ion ratio, Gibbs map, and hydrogen and oxygen isotope) methods were comprehensively used to analyze groundwater hydrochemistry and groundwater system runoff characteristics. The87Sr/86Sr value of karst groundwater in the Gudui spring catchment was 0.709 to 0.717, and the Mg/(Mg+Ca) value was 0.27 to 0.74. By analyzing the Sr isotope composition and Mg/(Mg+Ca) and 1/Sr variation characteristics, it was concluded that the karst groundwater in the Gudui spring catchment was a mixture of deep hot water and shallow cold water. The karst water subsystem of Nanliang spring presented the characteristics of carbonate stratum runoff. The karst water subsystem of Fuling Mountain Gaoxian Haitou spring and the deep circulation subsystem of Houma Basin exhibited the runoff characteristics of carbonate rock and igneous rock strata. The karst water subsystem of Taiershan Jiuyuanshan Gudui spring presented the runoff characteristics of carbonate rock and ancient silicoaluminate strata. The δ18O value in karst groundwater of Guodui spring area ranged from -11.46‰ to -7.81‰, and the average value was -10.08‰. The range of the δD value was -83.7‰ to -60.8‰, and the average value was -73.6‰. This showed that karst groundwater in the spring area was the result of mixing of various types of water. Through comparative analysis of hydrogen and oxygen isotopes of 2014 and 2021 sampling points at the same location, it was concluded that the change in water samples at the Guduiquan resulted from the gradual accumulation of water supplied by Sanquan Reservoir. The change in Sanquan Reservoir was due to the influence of Yellow River diversion. The karst groundwater in the spring area were characterized by large calcium ion, magnesium ion, and sodium ion values; a small potassium ion value; a large sulfate value; and a small chloride value. The hydrochemical types of karst groundwater in Gudui spring catchment could be divided into SO4-Na, SO4-Ca, HCO3-Na, HCO3-Mg, HCO3-Ca, and Cl-Na. The hydrochemical types of karst groundwater showed evident hydrochemical composition zoning from HCO3-Ca·Mg→HCO3·SO4-Ca·Mg→SO4·HCO3-Na·Ca→SO4·Cl-Na·Ca. According to the comprehensive analysis of hydrochemical isotope and hydrogeological conditions, the karst water subsystem of Nanliang spring was primarily recharged by rainfall infiltration in the exposed limestone area and river infiltration, and its karst groundwater was recharged by runoff from south to north to the karst water subsystem of Fuling Mountain Gaoxian Haitou spring and the deep circulation subsystem of Houma Basin. The karst water subsystem of Taier Jiuyuan Mountain Gudui spring received rainfall infiltration supplement and upstream runoff supplement from the exposed limestone area. Its karst groundwater flowed from north to south and received the supply of Sanquan Reservoir from Yellow River water in the natural discharge area of Gudui spring.

Clinical impact of the genomic landscape and leukemogenic trajectories in non-intensively treated elderly acute myeloid leukemia patients.

To characterize the genomic landscape and leukemogenic pathways of older, newly diagnosed, non-intensively treated patients with AML and to study the clinical implications, comprehensive genetics analyses were performed including targeted DNA sequencing of 263 genes in 604 patients treated in a prospective Phase III clinical trial. Leukemic trajectories were delineated using oncogenetic tree modeling and hierarchical clustering, and prognostic groups were derived from multivariable Cox regression models. Clonal hematopoiesis-related genes (ASXL1, TET2, SRSF2, DNMT3A) were most frequently mutated. The oncogenetic modeling algorithm produced a tree with five branches with ASXL1, DDX41, DNMT3A, TET2, and TP53 emanating from the root suggesting leukemia-initiating events which gave rise to further subbranches with distinct subclones. Unsupervised clustering mirrored the genetic groups identified by the tree model. Multivariable analysis identified FLT3 internal tandem duplications (ITD), SRSF2, and TP53 mutations as poor prognostic factors, while DDX41 mutations exerted an exceptionally favorable effect. Subsequent backwards elimination based on the Akaike information criterion delineated three genetic risk groups: DDX41 mutations (favorable-risk), DDX41wildtype/FLT3-ITDneg/TP53wildtype (intermediate-risk), and FLT3-ITD or TP53 mutations (high-risk). Our data identified distinct trajectories of leukemia development in older AML patients and provide a basis for a clinically meaningful genetic outcome stratification for patients receiving less intensive therapies.

Exogenous Easily Extractable Glomalin-Related Soil Protein Stimulates Plant Growth by Regulating Tonoplast Intrinsic Protein Expression in Lemon.

Arbuscular mycorrhizal fungi (AMF) have the function of promoting water absorption for the host plant, whereas the role of easily extractable glomalin-related soil protein (GRSP), an N-linked glycoprotein secreted by AMF hyphae and spores, is unexplored for citrus plants. In this study, the effects on plant growth performance, root system characteristics, and leaf water status, along with the changes of mineral element content and relative expressions of tonoplast intrinsic protein (TIP) genes in lemon (Citrus limon L.) seedlings, were investigated under varying strengths of exogenous EE-GRSP application under potted conditions. The results showed that 1/2, 3/4, and full-strength exogenous EE-GRSP significantly promoted plant growth performance, as well as increased the biomass and root system architecture traits including root surface area, volume, taproot length, and lateral root numbers of lemon seedlings. The four different strengths of exogenous GRSP displayed differential effects on mineral element content: notably increased the content of phosphorus (P) and iron (Fe) in both leaves and roots, as well as magnesium (Mg) and zinc (Zn) content in the roots, but dramatically decreased the content of calcium (Ca) and manganese (Mn) in the roots, as well as Zn and Mn in the leaves. Exogenous EE-GRSP improved leaf water status, manifesting as decreases in leaf water potential, which was associated with the upregulated expressions of tonoplast intrinsic proteins (TIPs), including ClTIP1;1, ClTIP1;2, ClTIP1;3, ClTIP2;1, ClTIP2;2, ClTIP4;1, and ClTIP5;1 both in leaves and roots, and TIPs expressions exhibited diverse responses to EE-GRSP application. It was concluded that exogenous EE-GRSP exhibited differential responses on plant growth performance, which was related to its strength, and the effects were associated with nutrient concentration and root morphology, especially in the improvement in water status related to TIPs expressions. Therefore, EE-GRSP can be used as a biological promoter in plant cultivation, especially in citrus.

Amphiphysin-IgG autoimmune sciatic neuropathy and facial neuropathy related to primary central nervous system lymphoma: A case report.

We reported a 61-year-old man presented with 10-month progressing left sciatic neuropathy and 10-day right facial neuropathy. Serum amphiphysin-IgG was positive. 18F-FDG PET/CT of the whole body showed no signs of malignancy. Treatment with plasma exchange and oral prednisone relieved the symptoms. Nine months later, right hemiparesis and seizure of right limbs developed. 18F-FDG and 18F-PBR06 (18 kDa translocator protein, TSPO) radioligand PET/MRI of the whole body revealed intense uptake in the intracranial lesions. Intracranial lymphoma was diagnosed by stereotactic needle brain biopsy. Mononeuropathies could be paraneoplastic syndromes. TSPO shows high uptake in intracranial lymphoma on 18F-PBR06 PET images.