Glucagon Receptor Antagonist for Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized. METHOD: We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts. RESULTS: In contrast to the post-transverse aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-transverse aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress. CONCLUSIONS: These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.

EGR1-mediated metabolic reprogramming to oxidative phosphorylation contributes to ibrutinib resistance in B-cell lymphoma.

The use of Bruton tyrosine kinase inhibitors, such as ibrutinib, to block B-cell receptor signaling has achieved a remarkable clinical response in several B-cell malignancies, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). Acquired drug resistance, however, is significant and affects the long-term survival of these patients. Here, we demonstrate that the transcription factor early growth response gene 1 (EGR1) is involved in ibrutinib resistance. We found that EGR1 expression is elevated in ibrutinib-resistant activated B-cell-like subtype DLBCL and MCL cells and can be further upregulated upon ibrutinib treatment. Genetic and pharmacological analyses revealed that overexpressed EGR1 mediates ibrutinib resistance. Mechanistically, TCF4 and EGR1 self-regulation induce EGR1 overexpression that mediates metabolic reprogramming to oxidative phosphorylation (OXPHOS) through the transcriptional activation of PDP1, a phosphatase that dephosphorylates and activates the E1 component of the large pyruvate dehydrogenase complex. Therefore, EGR1-mediated PDP1 activation increases intracellular adenosine triphosphate production, leading to sufficient energy to enhance the proliferation and survival of ibrutinib-resistant lymphoma cells. Finally, we demonstrate that targeting OXPHOS with metformin or IM156, a newly developed OXPHOS inhibitor, inhibits the growth of ibrutinib-resistant lymphoma cells both in vitro and in a patient-derived xenograft mouse model. These findings suggest that targeting EGR1-mediated metabolic reprogramming to OXPHOS with metformin or IM156 provides a potential therapeutic strategy to overcome ibrutinib resistance in relapsed/refractory DLBCL or MCL.

Oxidative-Atmosphere-Induced Strong Metal-Support Interaction and Its Catalytic Application.

ConspectusIn 1978, the classical strong metal-support interaction (C-SMSI) was first explored by observing significantly suppressed H2 and CO adsorption on Group-VIII noble-metal-reducible oxide systems after high-temperature treatment. Subsequent studies showed that local electron redistribution and encapsulation overlayers on metal nanoparticles (NPs) are typical features of SMSI, which endows supported metal heterogeneous catalysts with various advantageous properties for catalytic applications. In recent decades, significant advancements have been made in the utilization of SMSI effects via oxidation, adsorbate mediation, wet-chemistry processes, and so on. Oxidative SMSI (O-SMSI) was first observed by Mou et al. for Au/ZnO, wherein encapsulation overlayers were formed on Au NPs after being treated under oxidative conditions. In this system, positively charged Au NPs are formed through electron transfer from the metal to the support, and Au-O-Zn linkages drive the formation of the encapsulation overlayer. O-SMSI and the behavior it imparts in catalyst systems contradict our previous understanding on C-SMSI with respect to the need for a reducing atmosphere and the known encapsulation driving force. Moreover, O-SMSI encapsulation overlayers show considerable stability in oxidizing atmospheres and provide a potential solution to the problem of high-temperature sintering of supported catalysts. To date, O-SMSI has been observed for catalyst systems with various supports, including metal oxides, phosphides, and nitrides, and provides application opportunities for supported metal catalysts in oxidative catalytic process.In this Account, we first briefly introduce the research background of O-SMSI and the motivation for developing new systems exhibiting this effect. In particular, the Au/hydroxyapatite (HAP, nonoxide) system with O-SMSI induced by applying high-temperature oxidation prevents the sintering of Au NPs. Furthermore, Pt and Pd catalysts exhibit O-SMSI with HAP and ZnO supports under oxidizing heat treatment. Based on the composition and structure of HAP, the tetrahedral units ((PO4)3-) and OH- are shown to be responsible for O-SMSI. Importantly, the local electronic redistribution in the metal NPs (i.e., electron transfer from the metal to support), which is a characteristic feature of O-SMSI, can be controlled to tailor the strength of the metal-support interaction. We used exogenous adsorbents to tune the electronic state (Fermi level) of metal NPs to artificially introduce O-SMSI to Au, Pd, Pt, and Rh catalysts supported on TiO2. Moreover, the findings of our study indicate that O-SMSI can be broadly applied to the development of heterogeneous catalysts. Finally, we summarize some common O-SMSI catalysts with different proposed mechanisms and provide insights into the existing challenges and possible research directions in the field.

Modification effects of long-term air pollution levels on the relationship between short-term exposure to meteorological factors and hand, foot, and mouth disease: A distributed lag non-linear model-based study in Shandong Province, China.

The occurrence of hand, foot, and mouth disease (HFMD) is closely related to meteorological factors. However, location-specific characteristics, such as persistent air pollution, may increase the complexity of the impact of meteorological factors on HFMD, and studies across different areas and populations are largely lacking. In this study, a two-stage multisite time-series analysis was conducted using data from 16 cities in Shandong Province from 2015 to 2019. In the first stage, we obtained the cumulative exposure-response curves of meteorological factors and the number of HFMD cases for each city. In the second stage, we merged the estimations from the first stage and included city-specific air pollution variables to identify significant effect modifiers and how they modified the short-term relationship between HFMD and meteorological factors. High concentrations of air pollutants may reduce the risk effects of high average temperature on HFMD and lead to a distinct peak in the cumulative exposure-response curve, while lower concentrations may increase the risk effects of high relative humidity. Furthermore, the effects of average wind speed on HFMD were different at different levels of air pollution. The differences in modification effects between subgroups were mainly manifested in the diversity and quantity of significant modifiers. The modification effects of long-term air pollution levels on the relationship between sunshine hours and HFMD may vary significantly depending on geographical location. The people in age＜3 and male groups were more susceptible to long-term air pollution. These findings contribute to a deepening understanding of the relationship between meteorological factors and HFMD and provide evidence for relevant public health decision-making.

Perovskite Oxide as A New Platform for Efficient Electrocatalytic Nitrogen Oxidation.

Electrocatalytic nitrogen oxidation reaction (NOR) offers an efficient and sustainable approach for conversion of widespread nitrogen (N2 ) into high-value-added nitrate (NO3 - ) under mild conditions, representing a promising alternative to the traditional approach that involves harsh Haber-Bosch and Ostwald oxidation processes. Unfortunately, due to the weak absorption/activation of N2 and the competitive oxygen evolution reaction, the kinetics of NOR process is extremely sluggish accompanied with low Faradaic efficiencies and NO3 - yield rates. In this work, an oxygen-vacancy-enriched perovskite oxide with nonstoichiometric ratio of strontium and ruthenium (denoted as Sr0.9 RuO3 ) was synthesized and explored as NOR electrocatalyst, which can exhibit a high Faradaic efficiency (38.6 %) with a high NO3 - yield rate (17.9 µmol mg-1 h-1 ). The experimental results show that the amount of oxygen vacancies in Sr0.9 RuO3 is greatly higher than that of SrRuO3 , following the same trend as their NOR performance. Theoretical simulations unravel that the presence of oxygen vacancies in the Sr0.9 RuO3 can render a decreased thermodynamic barrier toward the oxidation of *N2 to *N2 OH at the rate-determining step, leading to its enhanced NOR performance.

The care status and factors affecting antiretroviral therapy timing for people living with HIV: a retrospective cohort study in Shandong Province, China.

This study described the care status of People Living with HIV (PLWH) including antiretroviral therapy (ART) and viral suppression from 2018 to 2020. We recognized that immediate ART was associated with improved viral suppression. Therefore, we also aimed to explore the factors affecting the early initiation of ART. We initiated a retrospective cohort study to evaluate the care status of people living with HIV in Shandong Province. From 2018 to 2020, patients infected by homosexual transmission in particular had a higher ART rate (78.82%, 79.69%, and 87.72%, respectively). Of PLWH who received ART, 79.57%, 77.63%, and 67.71% achieved viral suppression, respectively. However, COVID-19 may affect the rate of ART and viral suppression, which we need to explore in our research. From 2018 to 2020, the proportion of immediate antiretroviral therapy within 30 days of diagnosis increased from 48.12% to 65.42%. Multivariate logistic regression demonstrated that patients with junior college degree or above (OR, 1.39 [95%CI, 1.12-1.73]) and key population or medical institutions (OR, 3.62 [95%CI, 2.18-6.16]; OR, 3.88 [95%CI, 2.33-6.59]) were substantially likely to receive ART immediately, while patients outside the province (OR, 0.60 [95%CI, 0.50-0.73]) were less likely to receive ART immediately.

Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice.

Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy.

Longitudinal trajectories of depressive symptoms: the role of multimorbidity, mobility and subjective memory.

BACKGROUND: The high prevalence of depression among older people in China places a heavy burden on the health system. Multimorbidity, mobility limitation and subjective memory impairment are found to be risk indicators for depression. However, most studies on this topic focused on depression at a single point in time, ignoring the dynamic changes in depressive symptoms and the relationship between the trajectories and these three conditions. Therefore, we aimed to identify distinct trajectories of depressive symptoms in older people and investigate their associations with multimorbidity, mobility limitation and subjective memory impairment. METHODS: Data was drawn from China Health and Retirement Longitudinal Study conducted during 2011-2018. A total of 5196 participants who completed 4 visits, conducted every 2-3 years were included in this study. Group-based trajectory modeling was conducted to identify distinct trajectories of depressive symptoms z-scores. Multinomial logistic regression was used to investigate the relationships. RESULTS: Four distinct trajectories of depressive symptoms z-scores were identified, labeled as persistently low symptoms (68.69%, n = 3569), increasing symptoms (12.14%, n = 631), decreasing symptoms (14.05%, n = 730) and persistently high symptoms (5.12%, n = 266). Participants with multimorbidity had unfavorable trajectories of depressive symptoms compared with those without multimorbidity, with adjusted odds ratios (95% CIs) of 1.40 (1.15, 1.70), 1.59 (1.33, 1.90) and 2.19 (1.65, 2.90) for the increasing symptoms, decreasing symptoms and persistently high symptoms, respectively. We also observed a similar trend among participants with mobility limitations. Compared with participants who had poor subjective memory, participants with excellent/very good/good subjective memory had a lower risk of developing unfavorable trajectories of depressive symptoms. The adjusted odds ratios (95% CIs) of the increasing symptoms, decreasing symptoms and persistently high symptoms were 0.54 (0.40, 0.72), 0.50 (0.38, 0.65) and 0.48 (0.31, 0.73), respectively. CONCLUSIONS: Multimorbidity, mobility limitation and subjective memory impairment were found to be potential risk factors for unfavorable depression trajectories.

High Valence State Sites as Favorable Reductive Centers for High-Current-Density Water Splitting.

Electrochemical water splitting is a promising approach for producing sustainable and clean hydrogen. Typically, high valence state sites are favorable for oxidation evolution reaction (OER), while low valence states can facilitate hydrogen evolution reaction (HER). However, here we proposed a high valence state of Co3+ in Ni9.5 Co0.5 -S-FeOx hybrid as the favorable center for efficient and stable HER, while structural analogues with low chemical states showed much worse performance. As a result, the Ni9.5 Co0.5 -S-FeOx catalyst could drive alkaline HER with an ultra-low overpotential of 22 mV for 10 mA cm-2 , and 175 mV for 1000 mA cm-2 at the industrial temperature of 60 °C, with an excellent stability over 300 h. Moreover, this material could work for both OER and HER, with a low cell voltage being 1.730 V to achieve 1000 mA cm-2 for overall water splitting at 60 °C. X-ray absorption spectroscopy (XAS) clearly identified the high valence Co3+ sites, while in situ XAS during HER and theoretical calculations revealed the favorable electron capture at Co3+ and suitable H adsorption/desorption energy around Co3+ , which could accelerate the HER. The understanding of high valence states to drive reductive reactions may pave the way for the rational design of energy-related catalysts.

Long noncoding RNA lnc-H2AFV-1 promotes cell growth by regulating aberrant m6A RNA modification in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor in the oral and maxillofacial regions, and long noncoding RNAs (lncRNAs) play crucial roles in the occurrence and progression of HNSCC. The lncRNA lnc-H2AFV-1 was found to be upregulated in HNSCC tissues; however, the function of lnc-H2AFV-1 in regulating HNSCC proliferation and the potential molecular mechanism is unclear. The present study evaluated the expression of lnc-H2AFV-1 in HNSCC tissues using quantitative real-time PCR (qPCR) and associated abundant lnc-H2AFV-1 expression with tumor size. Functionally, lnc-H2AFV-1 significantly promoted the proliferation of HNSCC cells in vitro and in vivo. Quantified N6-methyladenosine (m6A) RNA methylation and dot blot assays revealed that total m6A methylation in HNSCC cells was accompanied by lnc-H2AFV-1 expression. Western blotting showed that the expression of methyltransferase-like (METTL) 3 and METTL14 was consistent with that of lnc-H2AFV-1, whereas the expression of demethylase fat mass and obesity-associated (FTO) was contrary to that of lnc-H2AFV-1. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and MeRIP-qPCR revealed that lnc-H2AFV-1 overexpression led to the elevated expression and maximal m6A methylation of intraflagellar transport (IFT) 80 in HNSCC. In addition, METTL3/14 knockdown decreased IFT80 expression. Thus, our findings suggested that lnc-H2AFV-1 might be a biomarker that alters m6A modification by regulating the m6A methylases METTL3/14 and FTO and then mediating the downstream target IFT80 to promote HNSCC progression.

Associated factors on physical activity among childhood cancer survivors in Mainland China: a qualitative exploration applied health belief model.

PURPOSE: Regular physical activity (PA) is essential for childhood cancer survivors (CCS), yet most CCS have difficulty participating in it. The level of PA participation among CCS in China is lower than those of western countries, leading to a worse long-term survival of CCS in China. Here, the study aims to explore the associated factors on the PA performance among CCS. METHODS: From September to December 2020, the study used purposive sampling to recruit 35 families (88.9%) as sampling units among two hospitals in Hangzhou City, China. The data collection conducted two designs on semi-structured interviews with different roles under family structure - children (n = 35) and parents (n = 35) - respectively. The design of predetermined questions relied on the health belief model (HBM) as a thematic framework. The qualitative analysis applied codebook thematic analysis and used the deductive approach to finalize the main findings. RESULTS: The study only presented preliminary conclusions from interviews with CCS, which resulted in four themes (changes in PA performance; perceptions on participating PA; cognitions of PA; impacts from others) with eight sub-themes. In particular, CCS replied diversity changes in PA, but most of them mentioned the inactive PA after diagnosis, especially the decline of moderate-to-vigorous PA (MVPA). As for the "perceptions of PA," almost all CCS had substantial perceived benefits about PA, specifically on their physical well-being. All children also expressed perceived barriers to PA, including the side effects of disease and treatment, fatigue, academic burden, changes in psychological status, and lack of companions. On the cognitions of PA, the CCS had limited realizations of regular PA and low self-efficacy on MVPA. Furthermore, CCS expressed their need for support from their parents, school teachers, and healthcare providers. But in reality, they recieved less support on PA from these important people. CONCLUSION: The changes in PA after illness among CCS are apparent and unavoidable because of the interaction impacts from internal factors (e.g., personal characters, cognization, perceptions of PA) and external factors (e.g., disease effects, interpersonal supports). The findings explained the main elements under HBM but also provided explored views as the evidence on developing theories and guiding motivations and practices on PA among CCS. IMPLICATIONS FOR CANCER SURVIVORS: In this exploratory study of 35 CCS, we identified the current situation of PA among CCS in China and explored the associated factors. As the first qualitative study on the CCS in mainland China, the study considered particular effects on social culture and living environment.

MicroRNA-425-5p Is Involved in the Development of Diabetic Retinopathy and Regulates the Proliferation and Migration of Retinal Microvascular Endothelial Cells.

INTRODUCTION: The objective of this article was to detect the expression pattern and clinical value of miR-425-5p in diabetic retinopathy (DR) patients and investigate its effect on the proliferation and migration of human retinal microvascular endothelial cells (HRMECs) in a high glucose (HG) state. METHODS: The serum miR-425-5p level of the subjects was determined using quantitative real-time PCR. The diagnostic value of serum miR-425-5p was validated using the receiver operating characteristic curve. Pearson analysis detected the correlation between clinical indicators and microRNA. The influence of miR-425-5p on cell proliferation and migration under HG conditions was calculated by using Cell Counting Kit-8 and Transwell assay. RESULTS: Serum miR-425-5p levels showed a gradual increasing trend in the healthy control group, the diabetic mellitus patients without DR, and DR patients. Moreover, the levels of miR-425-5p in proliferative DR (PDR) patients were elevated than that of non-PDR (NPDR) patients. Furthermore, upregulated miR-425-5p had a high diagnostic value for DR patients and can distinguish PDR patients from NPDR patients. The expression of miR-425-5p was significantly positively correlated with the fasting plasma glucose, glycosylated hemoglobin (HbA1C), homeostasis model assessment of insulin resistance, and disease course of the patients. Under HG conditions, overexpression of miR-425-5p promoted HRMEC proliferation and migration, while inhibition of miR-425-5p led to opposite results. CONCLUSION: Present research confirmed that serum miR-425-5p levels in DR are marked by elevation. High expression of miR-425-5p can be used as a feasible diagnostic biomarker for DR patients and can predict the development and severity of DR. Moreover, inhibiting the expression of miR-425-5p levels under the condition of hyperglycemia may be used as a valuable therapeutic strategy for preventing the pathogenesis of DR.

Radiomics model based on multi-sequence MR images for predicting preoperative immunoscore in rectal cancer.

PURPOSE: To establish and validate a radiomics model based on multi-sequence magnetic resonance (MR) images for preoperative prediction of immunoscore in rectal cancer. MATERIALS AND METHODS: This retrospective study included 133 patients with pathologically confirmed rectal cancer after surgical resection who underwent MR examination before treatment within two weeks. All patients were randomly divided into training cohort (n = 92) and validation (n = 41) cohort according to a ratio of 7:3. The volumes of interest were manually delineated in the T2-weighted images (T2WI) and apparent diffusion coefficient (ADC) images, from which a total of 804 radiomics features were extracted. Thereafter, we used Spearman correlation analysis and gradient boosting decision tree (GBDT) algorithm to select the strongest features, and the radiomics scores were established using multivariate logistic regression algorithm, including two single-mode models and two dual-mode models. The predictive performance and the clinical usefulness of the model were assessed by the receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA). RESULTS: Integrated model A based on T2WI and ADC images showed a better predictive performance, which yielded an AUC of 0.770 (95% CI 0.673-0.867) in the training cohort and 0.768 (95% CI 0.619-0.917) in the validation cohort. Calibration curve showed good agreement between predicted results of the model and actual events, and DCA indicated good clinical usefulness. Moreover, stratification analysis proved that the integrated model A had strong robustness. CONCLUSIONS: Integrated model A based on T2WI and ADC images has the potential to be used as a non-invasive tool for preoperative prediction of immunoscore in rectal cancer. It may be useful in evaluating prognosis and guiding individualized immunotherapy of patients.

Branched-Chain Amino Acid Catabolism Promotes Thrombosis Risk by Enhancing Tropomodulin-3 Propionylation in Platelets.

BACKGROUND: Branched-chain amino acids (BCAAs), essential nutrients including leucine, isoleucine, and valine, serve as a resource for energy production and the regulator of important nutrient and metabolic signals. Recent studies have suggested that dysfunction of BCAA catabolism is associated with the risk of cardiovascular disease. Platelets play an important role in cardiovascular disease, but the functions of BCAA catabolism in platelets remain unknown. METHODS: The activity of human platelets from healthy subjects before and after ingestion of BCAAs was measured. Protein phosphatase 2Cm specifically dephosphorylates branched-chain α-keto acid dehydrogenase and thereby activates BCAA catabolism. Protein phosphatase 2Cm-deficient mice were used to elucidate the impacts of BCAA catabolism on platelet activation and thrombus formation. RESULTS: We found that ingestion of BCAAs significantly promoted human platelet activity (n=5; P<0.001) and arterial thrombosis formation in mice (n=9; P<0.05). We also found that the valine catabolite α-ketoisovaleric acid and the ultimate oxidation product propionyl-coenzyme A showed the strongest promotion effects on platelet activation, suggesting that the valine/α-ketoisovaleric acid catabolic pathway plays a major role in BCAA-facilitated platelet activation. Protein phosphatase 2Cm deficiency significantly suppresses the activity of platelets in response to agonists (n=5; P<0.05). Our results also suggested that BCAA metabolic pathways may be involved in the integrin αIIbß3-mediated bidirectional signaling pathway that regulates platelet activation. Mass spectrometry identification and immunoblotting revealed that BCAAs enhanced propionylation of tropomodulin-3 at K255 in platelets or Chinese hamster ovary cells expressing integrin αIIbß3. The tropomodulin-3 K255A mutation abolished propionylation and attenuated the promotion effects of BCAAs on integrin-mediated cell spreading, suggesting that K255 propionylation of tropomodulin-3 is an important mechanism underlying integrin αIIbß3-mediated BCAA-facilitated platelet activation and thrombosis formation. In addition, the increased levels of BCAAs and the expression of positive regulators of BCAA catabolism in platelets from patients with type 2 diabetes mellitus are significantly correlated with platelet hyperreactivity. Lowering dietary BCAA intake significantly reduced platelet activity in ob/ob mice (n=4; P<0.05). CONCLUSIONS: BCAA catabolism is an important regulator of platelet activation and is associated with arterial thrombosis risk. Targeting the BCAA catabolism pathway or lowering dietary BCAA intake may serve as a novel therapeutic strategy for metabolic syndrome-associated thrombophilia.

Validation of perceived physical fatigability using the simplified-Chinese version of the Pittsburgh Fatigability Scale.

BACKGROUND: The Pittsburgh Fatigability Scale (PFS) was developed to capture fatigue and demand in a single tool, filling a gap that no validated questionnaire existed to measure perceived fatigability. Since fatigability is a more sensitive measure of a person's susceptibility to fatigue, we validated the simplified-Chinese version of the PFS among Chinese community-dwelling older adults. METHODS: This cross-sectional study was conducted in an urban community in Beijing between November 2018 and July 2019. The PFS was translated into simplified-Chinese by the translation, retro-translation method. Internal consistency of the Physical subscale of the PFS was evaluated by Cronbach's alpha. Convergent validity and discriminant validity were evaluated against physical performance measures (i.e., Short Physical Performance Battery & Timed Up and Go Test) and daily living performance (i.e., Barthel Index & Instrumental activity of daily living). RESULTS: Our study included 457 participants, including 182 men (39.8%) and 275 women (60.2%). The age range of the included participants was 61-96 years (mean = 84.8 years, SD = 5.8 years). The simplified-Chinese version of PFS Physical scores showed strong internal consistency (Cronbach's alpha = 0.81). Higher PFS Physical scores were associated with worse physical performance, and daily living performance (|correlation coefficient| range: 0.36-0.56, p < .001). Age- and sex-adjusted PFS Physical scores had moderate to good overall discrimination for correctly classifying people by their physical performance and daily living performance (AUCs range 0.70-0.87, p < .001). CONCLUSIONS: The PFS simplified-Chinese version is a valid instrument to assess perceived physical fatigability in Chinese-speaking older adults with good convergent validity. Thus, the PFS, with low cost and greater feasibility, is a desired tool to measure fatigability in large population studies.

Associations of sarcopenia and its defining components with cognitive function in community-dwelling oldest old.

BACKGROUND: This study aimed to investigate the associations of sarcopenia and its defining components with cognitive function in community-dwelling oldest old (over 80 years old) in China. METHODS: Sarcopenia was diagnosed by the 2019 Asian Working Group for Sarcopenia (AWGS) criteria. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA). Logistic and linear regression models were used to explore the associations of sarcopenia and its defining components with risk of mild cognitive impairment (MCI), and performance on multiple cognitive domains among 428 adults aged 80 years and older. RESULTS: The overall prevalence of sarcopenia was 35.5%, with 40.34% for men and 32.14% for women. The prevalence of MCI was higher among sarcopenic oldest old than non-sarcopenic oldest old (28.95% vs. 17.39%, p = 0.005). Multivariate logistic regression analyses showed that sarcopenia [odds ratio (OR) = 1.86, 95% confidence interval (CI): 1.04-3.33], low handgrip strength (HS) [OR = 2.33, 95% CI: 1.40-3.87] and slow gait speed (GS) [OR = 2.31, 95% CI: 1.13-4.72] were significantly and independently associated with risk of MCI. Multivariate linear regression analyses showed that low HS was associated with worse performance in global cognitive function, visuospatial and executive function, naming and delayed recall. CONCLUSIONS: Sarcopenia, low HS and low GS was significantly associated with MCI in community-dwelling oldest old. The associations between sarcopenia and its defining components with different cognitive subdomains could be further explored in the future.

Efficient Source Camera Identification with Diversity-Enhanced Patch Selection and Deep Residual Prediction.

Source camera identification has long been a hot topic in the field of image forensics. Besides conventional feature engineering algorithms developed based on studying the traces left upon shooting, several deep-learning-based methods have also emerged recently. However, identification performance is susceptible to image content and is far from satisfactory for small image patches in real demanding applications. In this paper, an efficient patch-level source camera identification method is proposed based on a convolutional neural network. First, in order to obtain improved robustness with reduced training cost, representative patches are selected according to multiple criteria for enhanced diversity in training data. Second, a fine-grained multiscale deep residual prediction module is proposed to reduce the impact of scene content. Finally, a modified VGG network is proposed for source camera identification at brand, model, and instance levels. A more critical patch-level evaluation protocol is also proposed for fair performance comparison. Abundant experimental results show that the proposed method achieves better results as compared with the state-of-the-art algorithms.

Regulating the Local Charge Distribution of Ni Active Sites for the Urea Oxidation Reaction.

In electrochemical energy storage and conversion systems, the anodic oxygen evolution reaction (OER) accounts for a large proportion of the energy consumption. The electrocatalytic urea oxidation reaction (UOR) is one of the promising alternatives to OER, owing to its low thermodynamic potential. However, owing to the sluggish UOR kinetics, its potential in practical use has not been unlocked. Herein, we developed a tungsten-doped nickel catalyst (Ni-WOx ) with superior activity towards UOR. The Ni-WOx catalyst exhibited record fast reaction kinetics (440 mA cm-2 at 1.6 V versus reversible hydrogen electrode) and a high turnover frequency of 0.11 s-1 , which is 4.8 times higher than that without W dopants. In further experiments, we found that the W dopant regulated the local charge distribution of Ni atoms, leading to the formation of Ni3+ sites with superior activity and thus accelerating the interfacial catalytic reaction. Moreover, when we integrated Ni-WOx into a CO2 flow electrolyzer, the cell voltage is reduced to 2.16 V accompanying with ≈98 % Faradaic efficiency towards carbon monoxide.

IFN-α2b inhibits the ethanol enriched-HBV cccDNA through blocking a positive feedback loop of HBx/MSL2/cccDNA/HBV/HBx in liver.

Hepatitis B virus (HBV) is a major risk factor for liver diseases, in which HBV covalently closed circular DNA (cccDNA), as the genomic form that templates viral transcription, plays crucial roles in sustaining viral persistence. Clinically, the excessive ethanol intake accelerates the progression of liver diseases with HBV infection. Here, we supposed that ethanol might trigger HBV cccDNA in the liver. Interestingly, we observed that the ethanol remarkably elevated the levels of HBeAg, HBsAg, HBV DNA and cccDNA in HBV-expressing hepatoma cells. Mechanically, the ethanol increased the levels of HBx and MSL2 in vivo and in HBV-expressing HepG2 cells, but not in HBV-free HepG2 cells. Moreover, the down-regulation of MSL2 by small interference RNA could block the ethanol-promoted HBV cccDNA in HepG2.2.15 cells. As a commonly administered treatment for HBV, the effect of IFNα on ethanol-triggered HBV cccDNA remains poorly understood. Strikingly, we showed that the treatment with IFN-α2b inhibited the ethanol-promoted cccDNA through depressing MSL2 in the cells. Thus, we conclude that IFN-α2b inhibits the ethanol-enriched HBV cccDNA through blocking a positive feedback loop of HBx/MSL2/cccDNA/HBV/HBx. Our finding provides new insights into the mechanism by which IFN-α2b inhibits ethanol-enhanced HBV cccDNA. Therapeutically, IFNα may contribute to the cccDNA induced by ethanol in liver.

A neutron irradiation-induced displacement damage of indium vacancies in α-In2Se3 nanoflakes.

The discovery of layered two-dimensional (2D) ferroelectric materials has promoted the development of miniaturized and highly integrated ferroelectric electronics. The 2D ferroelectric materials can be applied in a radiation environment, in which the effect of radiation on these materials should be considered. However, the effects of radiation on 2D ferroelectric materials may be entirely different from those on traditional ferroelectric materials. Ionization effect-induced domain switching can be recovered by applying an external electric field, whereas the displacement effect initiated by radiation particles produces crystal structure damage. The displacement damage that is extremely difficult to recover may have a negative impact on the application of 2D ferroelectric materials in a radiation environment. In this study, the effect of displacement induced by neutron irradiation on the promising α-In2Se3 nanoflakes was investigated. Neutron irradiation (1 MeV) with a fluence of 1014 cm-2 was used for avoiding ionization effects in a certain range. Although the topography of α-In2Se3 does not change underneutron irradiation, vacancies have been proved to be induced by neutron irradiation; furthermore, it has been identified that the vacancies mostly originate from the loss of In atoms. The out-of-plane (OOP) and in-plane (IP) domain structures of the α-In2Se3 nanoflakes with a few layers only slighlty change. In addition, the polarization of the irradiated nanoflakes could still be reversed. All these findings show that although the vacancies may influence the band structure and polarizaiton values of α-In2Se3, the ferroelectric performance may have a strong resistance to neutron irradiation. Therefore, our investigation implies that α-In2Se3 is an excellent 2D ferroelectric material for application in radiation-resistant electronic devices in the future.