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The effects of blood benzene, toluene, ethylbenzene, and xylenes (BTEX) on lung function among general adults remain unknown. We enrolled 5,519 adults with measured blood BTEX concentrations and lung function from the US National Health and Nutrition Examination Survey 2007–2012. Weighted linear models were fitted to assess the associations of BTEX with lung function and inflammation parameters (white blood cell five-part differential count and C-reactive protein). The mediating effect of inflammation between BTEX and lung function was also examined. Blood BTEX concentrations decreased yearly from 1999 and were extremely low from 2007–2012. Benzene and toluene exerted the greatest influence on lung function in terms of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), calculated FEV1:FVC ratio, peak expiratory flow rate (PEFR), and forced mid expiratory flow (FEF25%–75%). Both ethylbenzene and all xylene isomers had no effects on FVC but reduced FEV1, FEV1:FVC ratio, PEFR, and FEF25–75%. Weighted quantile analyses demonstrated that BTEX mixture was associated with decreases in FVC, FEV1, FEV1:FVC ratio, PEFR, and FEF25–75%, with benzene weighted most heavily for all lung function parameters. BTEX also increased the levels of inflammation indicated by white blood cell five-part differential count and C-reactive protein, and increased levels of inflammation also reduced lung function. From multiple mediation analysis, inflammation mediated the effects of benzene on FEV1 and PEFR, the effects of toluene on FEV1, and the effects of ethylbenzene on FEV1 and PEFR. Low-dose exposure to BTEX was associated with reduced pulmonary function both in large and small airways. Inflammation could be involved in this pathogenesis.

Kuzushiji, as characters written in a cursive style, had been continuously used for both publishing and handwriting in Japan before the end of the 19th century. However, well into the twentieth century, most modern Japanese lost the ability to read Kuzushiji due to changes in writing systems. Therefore, how to develop advanced machine learning algorithms to identify Japanese historical characters has great significance in preserving cultural knowledge and promoting sustainable development in urban living. Unlike traditional digit image recognition, Kuzushiji image recognition is a more challenging task due to the complex script for cursive handwriting, multiple variations between characters, and imbalanced data. To address such issues, a novel deep learning-based character recognition method called residual shrinkage balanced network (RSBN) is developed for classifying Japanese historical characters. A novel residual shrinkage structure with a soft threshold function is constructed to reduce redundant features using specially designed skip-connected subnetworks. Then, multiple residual shrinkage modules are stacked together to learn hierarchical features from raw input. Furthermore, a novel class rebalancing strategy is further designed to improve learning performance from imbalanced data. The experiments are conducted on Japanese classical literature datasets. The results demonstrate that the proposed method obtains more than 89.01% testing accuracy on Kuzushiji-MNIST dataset, which outperforms the existing deep learning-based character image recognition methods. Moreover, without additional data augmentation techniques, the proposed approach also achieves 97.16% balanced accuracy on Kuzushiji-49 dataset, which is the best one compared with existing published results. When considering the computational performance, the number of trainable parameters of the proposed method is competitive with that of the typical ResNet-18.

Question and answer cold joke (QACJ) is a language phenomenon with particular formal, semantic, and pragmatic features. Its existing analytical mode remains relatively simple, and rarely involves its conceptual basis and implicature inferring. The current study aimed to dig out its inferential model based on its conceptual basis under a comprehensive perspective. The particular formal and semantic features of the QACJ have laid the foundation for its four conceptual bases (i.e., intersected question and answer form, indirectly correlated logic, garden-path inferring, cold but humorous effect). Gudied by an integrated analytical framework, its forward and backward inferring models based on its conceptual bases have been proposed. The garden-path relevance inferring mechanisms are the red-light and the crossroad mechanisms, both relating to the presupposition entailing, optimal-relevance verification, and context shifting, all aiming at a phase in cold humor effect.

To solve the problem of stall warning for axial compressors, this paper proposes a stall warning algorithm based on the sparrow search algorithm, which optimizes the deep belief network. The deep belief network is trained by using deep learning to extract the FFT spectrum of compressor stall experiment data directly as the feature vector. To improve the accuracy of DBN classification, parameters of hidden layer nodes n and initial weights w of DBN were optimized by SSA algorithm, and stall warning algorithm model of SSA-DBN axial-flow compressor was established. The experimental results of the algorithms show that the stall data at each speed is at least 0.1～0.3s in advance for early warning. This method is 0.075~0.281s ahead of the various models from the past to the present, and noise is superimposed on the experimental data to verify the Robustness of the way, better surge warning margin performance, and engineering practicability. &nbsp

Background Multiple neonatal exposures to sevoflurane induce neurocognitive dysfunctions in rodents. The lack of cell type–specific information after sevoflurane exposure limits the mechanistic understanding of these effects. In this study, the authors tested the hypothesis that sevoflurane exposures alter the atlas of hippocampal cell clusters and have neuronal and nonneuronal cell type–specific effects in mice of both sexes. Methods Neonatal mice were exposed to 3% sevoflurane for 2 h at postnatal days 6, 8, and 10 and analyzed for the exposure effects at postnatal day 37. Single-nucleus RNA sequencing was performed in the hippocampus followed by in situ hybridization to validate the results of RNA sequencing. The Morris Water Maze test was performed to test neurocognitive function. Results The authors found sex-specific distribution of hippocampal cell types in control mice alongside cell type– and sex-specific effects of sevoflurane exposure on distinct hippocampal cell populations. There were important changes in male but not in female mice after sevoflurane exposure regarding the proportions of cornu ammonis 1 neurons (control vs. sevoflurane, males: 79.9% vs. 32.3%; females: 27.3% vs. 24.3%), dentate gyrus (males: 4.2% vs. 23.4%; females: 36.2% vs. 35.8%), and oligodendrocytes (males: 0.6% vs. 6.9%; females: 5.9% vs. 7.8%). In male but not in female mice, sevoflurane altered the number of significantly enriched ligand–receptor pairs in the cornu ammonis 1, cornu ammonis 3, and dente gyrus trisynaptic circuit (control vs. sevoflurane, cornu ammonis 1–cornu ammonis 3: 18 vs. 42 in males and 15 vs. 21 in females; cornu ammonis 1–dentate gyrus: 21 vs. 35 in males and 12 vs. 20 in females; cornu ammonis 3–dentate gyrus: 25 vs. 45 in males and 17 vs. 20 in females), interfered with dentate gyrus granule cell neurogenesis, hampered microglia differentiation, and decreased cornu ammonis 1 pyramidal cell diversity. Oligodendrocyte differentiation was specifically altered in females with increased expressions of Mbp and Mag. In situ hybridization validated the increased expression of common differentially expressed genes. Conclusions This single-nucleus RNA sequencing study reveals the hippocampal atlas of mice, providing a comprehensive resource for the neuronal and nonneuronal cell type– and sex-specific effects of sevoflurane during development. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations affect the epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 interacted with KDM6A to activate genes instructing urothelial differentiation. KDM6A-deficient cells displayed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn repressed FOXA1-target genes and activated cell-cycle progression genes. Importantly, ATF3 depletion reversed the cell proliferation phenotype induced by KDM6A deficiency. These data establish that KDM6A loss engenders an epigenetic state that drives tumor growth in an ATF3-dependent manner, creating a potentially targetable molecular vulnerability.Significance:A gain-of-function epigenetic switch that disrupts differentiation is triggered by inactivating KDM6A mutations in bladder cancer and can serve as a potential target for novel therapies.

This paper studies a stochastic two-species Schoener's competitive model with regime switching. We first investigate the sufficient conditions for the existence of a unique stationary distribution of the model. Then we prove that the convergence of transition probability to the stationary distribution is exponentially under some mild assumptions. Moreover, we also introduce several numerical simulations to validate the model against the biological significance.

Objectives This study was to explore the potential relationship between the fibrinogen-to-albumin ratio (FAR) and the presence and severity of coronary artery disease (CAD) in stage 3–5 predialysis chronic kidney disease (CKD) patients. Design This study included 978 patients undergoing coronary angiography (CAG). CAD was defined as the presence of obstructive stenosis > 50% of the lumen diameter in any of the four main coronary arteries. Gensini scores (GSs), left main coronary artery (LMCA) and three-vessel coronary artery disease (TVD) were used to elevate the severity of CAD. Results The adjusted odds ratios of CAD were 3.059 (95% CI: 1.859–5.032) and 2.670 (95% CI: 1.605–4.441) in the third and fourth quartiles of FAR compared with the first quartile, respectively. Among 759 patients diagnosed with CAD, multivariate logistic regression analysis showed that FAR (at the 0.01 level) was significantly positively associated with the presence of LMCA (adjusted OR = 1.177, 95% CI 1.067–1.299, P = 0.001) or TVD (adjusted OR = 1.154, 95% CI 1.076–1.238, P Conclusions FAR levels were independently associated with the presence and severity of CAD in stage 3–5 predialysis CKD patients.

This study aimed to investigate the long-term biocompatibility, safety, and degradation of the ultrathin nitrided iron bioresorbable scaffold (BRS) in vivo, encompassing the whole process of bioresorption in porcine coronary arteries. Fifty-two nitrided iron scaffolds (strut thickness of 70 μm) and 28 Vision Co-Cr stents were randomly implanted into coronary arteries of healthy mini-swine. The efficacy and safety of the nitrided iron scaffold were comparable with those of the Vision stentwithin 52 weeks after implantation. In addition, the long-term biocompatibility, safety, and bioresorption of the nitrided iron scaffold were evaluated by coronary angiography, optical coherence tomography, micro-computed tomography, scanning electron microscopy, energy dispersive spectrometry and histopathological evaluations at 4, 12, 26, 52 weeks and even at 7 years after implantation. In particular, a large number of struts were almost completely absorbed in situ at 7 years follow-up, which were first illustrated in this study. The lymphatic drainage pathway might serve as the potential clearance way of iron and its corrosion products.

BackgroundSomatic mutation contributes to clonal haematopoiesis of indeterminate potential (CHIP) is related to age and associated with a higher risk of stroke and atherosclerotic cardiovascular disease. Here, we investigated the prognostic significance of CHIP in a large first-ever acute ischaemic stroke (AIS) cohort and explored the underlying mechanisms.MethodsWe studied a prospective cohort of 6016 patients who had a first-ever AIS in China. Whole-genome sequencing was performed to identify CHIP. High-sensitivity C reactive protein (hs-CRP) levels above 3 mg/L at baseline were defined as hyperinflammation. Recurrent stroke during the 3-month follow-up was the primary outcome.ResultsAmong the 6016 patients who had a first-ever AIS, with a median age was 62 years (IQR, 54.0‒70.0), 3.70% were identified as CHIP carriers. The most common mutations occurred in theDNMT3A(30.0%) andTET2(11.4%) genes. During a follow-up of 3 months, the presence of CHIP was associated with recurrent stroke (HR 1.62, 95% CI 1.04 to 2.51, p=0.03), recurrent ischaemic stroke (HR 1.64, 95% CI 1.04 to 2.58, p=0.03) and combined vascular events (HR 1.58, 95% CI 1.02 to 2.44, p=0.04) after adjusting for hsCRP levels at baseline in patients who had a first-ever AIS. Subgroup analysis demonstrated that CHIP was only associated with recurrent stroke when patients under hyperinflammation (OR 3.10, 95% CI 1.92 to 5.00, pinteraction=0.002).ConclusionOur results suggest that somatic mutations contributing to CHIP increase the risk of short-term recurrent stroke in patients who had a first-ever AIS. Hyperinflammation may be important in the relationship between CHIP and recurrent stroke.

Evidence shows that rehabilitation is the most effective strategy to reduce the disability rate of patients with stroke. However, there is limited understanding about the factors associated with rehabilitation assessment among patients with intracerebral hemorrhage (ICH) in China. We aimed to investigate the factors associated with rehabilitation assessment in patients with ICH and the relationship between rehabilitation assessment and hospitalization outcomes.Data from 85,664 patients with ICH admitted to 1,312 hospitals between 1 August 2015 and 31 July 2019 were analyzed. A multivariable logistic regression model accounting for in-hospital clustering was used to identify patient and hospital factors associated with rehabilitation assessment during acute hospitalization.A total of 62,228 (72.6%) patients with ICH underwent rehabilitation assessments. In multivariable analyses, factors associated with an increased likelihood of undergoing a rehabilitation assessment (P .05) included a higher Glasgow Coma Scale score on admission, a history of hypertension, a history of peripheral vascular disease, dysphagia screening, carotid vessel imaging, and a longer length of hospital stay. Conversely, patients admitted to the intensive care unit and tertiary-grade hospitals were less likely to undergo rehabilitation assessments during hospitalization for ICH.This study showed that the rate of rehabilitation assessment was 74.2%, which is low. Rehabilitation assessment was associated with longer hospital stays and lower mortality. Therefore, patients with acute cerebral haemorrhage should undergo comprehensive and professional rehabilitation assessment.

Gene fusions can drive tumor development for multiple types of cancer. Currently, many drugs targeting gene fusions are being approved for clinical application. At present, tyrosine receptor kinase (TRK) inhibitors targeting neurotrophic tyrosine receptor kinase (NTRK) gene fusions are among the first "tumor agnostic" drugs approved for pan-cancer use. Representative TRK inhibitors, including larotrectinib and entrectinib, have shown high efficacy for many types of cancer. At the same time, several second-generation drugs designed to overcome first-generation drug resistance are undergoing clinical development. Due to the rarity of NTRK gene fusions in common cancer types and technical issues regarding the complexity of fusion patterns, effectively screening patients for TRK inhibitor treatment in routine clinical practice is challenging. Different detection methods including immunohistochemistry, fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and (DNA and/or RNA-based) next-generation sequencing have pros and cons. As such, recommending suitable tests for individual patients and ensuring the quality of tests is essential. Moreover, at present, there is a lack of systematic review for the clinical efficacy and development status of first- and second-generation TRK inhibitors. To resolve the above issues, our expert group has reached a consensus regarding the diagnosis and treatment of NTRK gene fusion solid tumors, aiming to standardize clinical practice with the goal of benefiting patients with NTRK gene fusions treated with TRK inhibitors.

Aiming at the problem that the existing assembly sequence planning methods are difficult to meet the multi-station assembly requirements of assembly line, an assembly sequence planning method of assembly line considering the constraints of station sequence and station capability is proposed. The multi-station assembly sequence model is established to describe the allocation scheme and assembly sequence of parts. The conditions and generating rules of feasible assembly sequence are given. The assembly time variance of each station is used as the fitness function, and the particle swarm optimization (PSO) algorithm is designed. Taking an engineering vehicle assembly as an example, the optimal integration solution of multi-station assembly sequence and job assignment is obtained by using this algorithm, and the validity of the model is verified. &nbsp

Protein citrullination is one type of protein post-translational modification. Previous methods entail the use of a strongly acidic condition (pH1), which impedes its exploration under physiological and pathological conditions. Here, we developed a biocompatible method based on

The aim of this prospective multi-center study was to investigate the diagnostic value of myocardial blood flow (MBF) quantification using NaI(Tl)-based single-photon emission computed tomography (SPECT) for determining coronary artery disease (CAD) defined by quantitative coronary angiography (QCA).Absolute quantitation of MBF and myocardial flow reserve (MFR) using SPECT is clinically feasible; however, whether flow quantification using NaI(Tl) SPECT is superior to commonly performed SPECT myocardial perfusion imaging (MPI) in determining CAD has not been evaluated.Patients with suspected or known CAD underwent pharmacological stress/rest dynamic SPECT imaging and routine SPECT MPI followed by QCA. Obstructive disease was defined as ≥ 50% reduction in luminal diameter on QCA.One hundred fifty-four patients (462 vessels) were included in the analysis. Obstructive CAD was detected in 76/154 patients (49.4%) and 112/462 vessels (24.2%). Optimal cut-off values were 1.86 mL/min/g for stress MBF and 1.95 for MFR, respectively. Stress MBF and MFR were more sensitive than MPI in both individual patients (stress MBF vs MPI: 81.6% vs 51.3%; MFR vs MPI: 72.4% vs 51.3%) and in coronary vascular regions (stress MBF vs MPI: 78.6% vs 31.3%; MFR vs MPI: 75.9% vs 31.3%; all P .01). In receiver operating characteristic curve analysis, quantification revealed a significantly greater area under the curve than MPI at the patient (stress MBF vs MPI: 0.761 vs 0.641; MFR vs MPI: 0.770 vs 0.641) and the vessel (stress MBF vs MPI: 0.745 vs 0.613; MFR vs MPI: 0.756 vs 0.613; all P .05) levels. Integrating quantitative SPECT measures with MPI significantly increased the area under the curve and improved the discriminatory and reclassification capacity.Flow quantification using NaI(Tl) SPECT provides superior sensitivity and discriminatory capacity to MPI in detecting significant stenosis. Clinical trial registration NCT03637725.

A one-pot, three-component reaction involving SNAr-decarboxylative redox isomerization starting from an electron-withdrawing group bearing fluorobenzaldehyde or fluorothiophenecarbaldehyde (electron-pair diacceptor), secondary amine, and trans-4-hydroxy-l-proline or indoline-2-carboxylic acid (electron-pair donor) has been developed to give N-[(pyrrolylmethyl)-substituted (het)aryl]- and N-[(indolyl­methyl)-substituted (het)aryl]pyrrolidines, -piperidines, -morpholines, and -azocanes. The highlights of this protocol are its great convenience in the simultaneous construction of a C(sp2)–N bond and a C(sp3)–N bond with simple operation; the reaction can be performed on a gram scale. This efficient one-pot multicomponent reaction has potential as a novel method for drug synthesis, especially involving polycyclic compounds.

Objectives: To investigate the association between hyperhomocysteinemia (HHcy) and in-hospital mortality following ischemic stroke (IS), transient ischemic attack (TIA), or intracerebral hemorrhage (ICH). Methods: Data on patients with ischemic cerebrovascular disease (IS/TIA) or ICH enrolled in the Chinese Stroke Center Alliance (CSCA) from 2015 to 2019 were extracted. Patient characteristics and in-hospital mortality were analyzed and multiple adjusted logistic regression analyses performed to investigate the association between blood tHcy (total homocysteine) and in-hospital mortality in patients with HHcy (tHcy ⩾ 15 µmol) and patients with normohomocysteinemia (nHcy) (tHcy Results: A total of 823,622 participants were included. Mean (SD) age was 65.9 (12.1), and 62.5% (n = 514,888) were male. A total of 379,807 (46.0%) patients were identified as having HHcy, and 70,364 (8.5%) patients had an estimated glomerular filtration rate (eGFR) 2. An eGFR 2 was the strongest independent risk factor for HHcy in both patients with IS/TIA (adjusted odds ratio (aOR) 2.67, 95% confidence interval (CI): 2.49–2.86), and those with ICH (2.94, 2.46–3.50). On multivariable logistic regression, after adjusting for potential confounding factors, HHcy was associated with in-hospital mortality (aOR: 1.25, 95% CI: 1.13–1.37 for patients with IS/TIA; aOR: 1.40, 95% CI: 1.12–1.76 for patients with ICH). However, after additionally adjusting for eGFR, this association disappeared among patients with both IS/TIA (aOR: 1.09, 95% CI: 0.99–1.20) and those with ICH (aOR: 1.17, 9% CI: 0.96–1.43). Conclusion: HHcy was associated with in-hospital mortality among the patients with IS/TIA or ICH but this association disappeared after controlling for eGFR, suggesting HHcy was acting as a marker of poor renal function which itself was the predictor of poor outcome. Our results suggest the prevention and management of renal impairment may be an important measure in the reduction of mortality in patients with HHcy after IS/TIA or ICH.

Background: Fine particulate matter (PM2.5) is a risk factor for stroke, and patients with pre-existing diseases appear to be particularly susceptible. We conducted a case-crossover study to examine the association between short-term exposure to fine particulate matter (PM2.5) and hospital admission for stroke in individuals with atrial fibrillation (AF), hypertension, diabetes, or hyperlipidemia. Methods: Patients diagnosed with acute ischemic stroke (AIS) were recruited from 2015 to 2017 in Chinese Stroke Center Alliances. We estimated daily PM2.5 average exposures with a spatial resolution of 0.1° using a data assimilation approach combining satellite measurements, air model simulations, and monitoring values. Conditional logistic regression was used to assess PM2.5-related stroke risk in patients with pre-existing medical co-morbidities. Results: A total of 155,616 patients diagnosed with AIS were admitted. Patients with a history of AF ( n = 15,430), hypertension ( n = 138,220), diabetes ( n = 43,737), or hyperlipidemia ( n = 16,855) were assessed separately. A 10 µg/m3 increase in daily PM2.5 was associated with a significant increase in AIS for individuals with AF at lag 4 (odds ratio (OR), 1.008; 95% confidence interval (CI), 1.002–1.014), and with hypertension (OR, 1.008; 95% CI, 1.006–1.010), diabetes (OR, 1.006; 95% CI, 1.003–1.010), and hyperlipidemia (OR, 1.007; 95% CI, 1.001–1.012) at lags 0–7. Elderly (⩾ 65 years old) and female patients with AF had significantly higher associations at lag 5 (OR, 1.009; 95% CI, 1.002–1.015) and lag 5 (OR, 1.010; 95% CI, 1.002–1.018), respectively. Conclusion: Short-term exposure to PM2.5 is significantly associated with hospital admission for stroke in individuals with pre-existing medical histories, especially in older or female patients with AF. Preventive measures to reduce PM2.5 concentrations are particularly important in individuals with other medical co-morbidities.

The heparin polysaccharide nanoparticles block the interaction between heparan sulfate/S protein and inhibit the infection of both wild-type SARS-CoV-2 pseudovirus and the mutated strains through pulmonary delivery.Image 1.

Three new Clavulina species, C. baiyunensis, C. minor and C.lilaceorosea were described from specimens collected from Baiyun Mountain, Guangzhou, China based on detain morphological studies and phylogenetic analyses of three gene fragments ITS, LSU and RPB2. C. baiyunensis is characterized by light brown to brown basidiomata with hyaline tramal hyphae. C. minor has diminutive, dull white to pale brown basidiomata with hyaline tramal hyphae. C. lilaceorosea has pale brown to ochre brown basidiomata with palmate branches, tramal hyphae walls light brown. Both three new species have abundant clamp connections, basidia with two cornuted sterigmata, postpartal septa common, and cystidia absent. A key of known Clavulinaspecies original from China is presence.

Purpose To estimate and compare annual prevalence and incidence, and demographic characteristics of patients with ulcerative colitis (UC) in Japan and the United States (US). Methods All patients with UC were identified from large employment-based healthcare claims databases (Japan Medical Data Center [JMDC] in Japan and IBM MarketScan Commercial Claims and Encounters database [CCAE] in the US), from 2010 to 2019. Cases were confirmed using International Classification of Disease-9/10 codes with/without Anatomical Therapeutic Chemical codes. Annual age-standardized prevalence and incidence rates were estimated for the JMDC by direct standardization using the CCAE as the standard population. Results Patients with UC were younger in Japan than in the US and men were affected more than women, whereas the reverse was true in the US. Annual prevalence per 100,000 population increased significantly from 5 in 2010 to 98 in 2019 in Japan and from 158 to 233 in the US. Prevalence increased in men more than in women and in all age groups in Japan, whereas increases were observed similarly in men and women, and in the 6 to Conclusion Ten-year trends in epidemiology of UC differ between Japan and the US. The data point to a growing disease burden in both countries that warrants investigation of measures for prevention and treatment.

BackgroundThe pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is complex and multifactorial, with growing evidence indicating the involvement of hematologic disorders. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with increased risks of both hematologic malignancies and cardiovascular diseases. The CHIP in patients with CTEPH and its clinical relevance remain undetermined.MethodsWe performed a step-wise calling method on the next-generation sequencing data from 499 CTEPH patients referred to three centers between October 2006 and December 2021 to identify CHIP mutations. We associated CHIP with all-cause mortality in patients with CTEPH. To provide potential mechanistic insights, the associations between CHIP and inflammation characteristics reflected by circulating cytokines and IgG galactosylation, a hallmark of inflammatory state in diseases were also determined.ResultsTotal 51 (10.2%) patients with CTEPH carried at least one CHIP mutation at a variant allele frequency of ≥ 2%, and the most common mutations were amongDNMT3A,RUN1andSTAG2. During a mean follow-up time of 55 months, deaths occurred in 21 patients (42.9%) in the CHIP group and 105 patients (24.3%) in the non-CHIP group, contributing to the 5-year survival rate of 65.3% in the CHIP group and 81.9% in the non-CHIP group (P< 0.001 for log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (HR: 3.447; 95% CI: 1.747 – 6.803;P< 0.001). Besides, patients in the CHIP group showed higher circulating IL-1beta and IL-6 and lower IL-4 and IgG galactosylation compared with the non-CHIP group.ConclusionsCHIP is enriched in CTEPH patients and is associated with a worse prognosis in CTEPH. Mechanically, patients in the CHIP group showed a more severe inflammatory state.Clinical PerspectiveWhat is new?Clonal hematopoiesis of indeterminate potential (CHIP) mutations are enriched in chronic thromboembolic pulmonary hypertension (CTEPH) patients, with most common mutated genes beingDNMT3A,RUN1andSTAG2.CHIP is associated with worse clinical outcomes in CTEPH.CHIP is associated with more severe inflammation state mediated by myeloid as well as lymphoid cells in patients with CTEPH.What are the clinical implications?CHIP might be a risk factor for CTEPH, suggesting a relationship between CTEPH and hematopoietic disorders.CHIP represented an additional disease component in CTEPH that independently impacts prognosis.CHIP might be a potential target for personalized medicine and an indicator of benefit from anti-inflammatory therapies for CTEPH patients.

Fengyun-3E is an early-morning orbit meteorological satellite which provided more opportunity to observe solar activities and was launched on July 5, 2021. The total solar irradiance is measured by Solar Irradiance Monitor-II (SIM-II) which has been improved on degradation monitor compared to earlier Fengyun satellite. The spectral solar irradiance is observed by the new payload Solar Spectral Irradiance Monitor (SSIM) which could provide continuous spectra from 165nm~2400nm. The SSIM instrument has three wavebands: UV band from 165 nm to 320 nm, VIS band from 285 nm to 700 nm, NIR band from 650 nm to 2400 nm, with spectral resolution as 1nm, 1nm and 8nm, respectively. In this work, we will present the design of solar observation, instruments on-orbit performance and preliminary results of FY-3E solar measurement.

NSMC/CMA has been continuously pushing forward the reprocessing of Fengyun series dataset for better quality, especially L1 product. A comprehensive Fengyun historical data rescue and reprocessing task has been completed. At present, the early historical data of FY-1 archive was rescued and L1 data was reproduced providing full data record since 1988. The long-term L1 data reprocessing includes 7 instrument series on 13 satellites in FY-1, FY-2 and FY-3 missions. There are 3 optical imagers with 2 in polar orbit and 1 in geostationary orbit, 1 infrared sounder, 1 microwave imager, and 2 microwave sounders. After reprocessing, the sensor related instability issues caused by instrument degradation and instrument status changes are solved. The inter-platform consistency is also improved by radiometric reference transfer correction in each instrument series. The Fengyun fundamental climate data records (FCDRs) for 7 instruments have been evaluated by radiometric comparison with reference instruments or RTM simulations. The reprocessed L1 dataset has also supported long-term dataset generation for several geophysical parameters. This paper gives an overview of the data reprocessing efforts.

Earth Radiation Budget (ERB) measurement is one of the main missions of Chinese second generation of polar orbiting meteorological satellites ---FengYun-3 (FY-3) series. There are two instruments, the Solar Irradiance Monitor(SIM) and the Earth Radiation Budget (ERB), on board FY-3 satellite to observe the earth incoming and reflected solar radiance and the emitted radiance. The ERMs on FY-3/A/B/C observe the Earth atmosphere within a narrow scanning field of view (NFOV）and a wide non-scanning field of view (WFOV). For each field of view, the measurements are made from two broadband channels: a total waveband channel covering 0.2 – 50 μm and a Short Wave (SW) band covering 0.2 - 4.3 μm. Because the sudden degradation happened that the SW channel of NFOV has stopped working after 20 months for FY-3A and 8 months for FY-3B in orbit. The observation from ERM on FY-3C has been in good condition for 9 years In this presentation the performance of ERMs calibration in orbit is evaluated with CERES from EOS/Aqua and GERB-3 from Meteosat. The ERM LW and SW unfiltered radiance produced with spectral correction based on atmospheric transfer modelling has a good consistence with the other data. The new ERM instrument(ERM-II), which has a broadband LW channel covering 5-50 μm besides the Total and SW channels with a NFOV scanning mode, will be launch in the coming 2023 and provide 8 years global ERB observation from next FY-3 morning satellite.

Despite the rapid progress of organic solar cells based on non-fullerene acceptors, simultaneously achieving high power conversion efficiency and long-term stability for commercialization requires sustainable research effort. Here, we demonstrate stable devices by integrating a wide bandgap electron-donating polymer (namely PTzBI-dF) and two acceptors (namely L8BO and Y6) that feature similar structures yet different thermal and morphological properties. The organic solar cell based on PTzBI-dF:L8BO:Y6 could achieve a promising efficiency of 18.26% in the conventional device structure. In the inverted structure, excellent long-term thermal stability over 1400 h under 85 °C continuous heating is obtained. The improved performance can be ascribed to suppressed charge recombination along with appropriate charge transport. We find that the morphological features in terms of crystalline coherence length of fresh and aged films can be gradually regulated by the weight ratio of L8BO:Y6. Additionally, the occurrence of melting point decrease and reduced enthalpy in PTzBI-dF:L8BO:Y6 films could prohibit the amorphous phase to cluster, and consequently overcome the energetic traps accumulation aroused by thermal stress, which is a critical issue in high efficiency non-fullerene acceptors-based devices. This work provides insight into understanding non-fullerene acceptors-based organic solar cells for improved efficiency and stability.

Methionine restriction (MR) provides metabolic benefits in many organisms. However, mechanisms underlying the MR-induced effect remain incompletely understood. Here, we show in the budding yeast S. cerevisiae that MR relays a signal of S-adenosylmethionine (SAM) deprivation to adapt bioenergetic mitochondria to nitrogenic anabolism. In particular, decreases in cellular SAM constrain lipoate metabolism and protein lipoylation required for the operation of the tricarboxylic acid (TCA) cycle in the mitochondria, leading to incomplete glucose oxidation with an exit of acetyl-CoA and α-ketoglutarate from the TCA cycle to the syntheses of amino acids, such as arginine and leucine. This mitochondrial response achieves a trade-off between energy metabolism and nitrogenic anabolism, which serves as an effector mechanism promoting cell survival under MR.

IntroductionThe aim of this study is to establish a prognostic risk model based on ferroptosis to prognosticate the severity of Alzheimer’s disease (AD) through gene expression changes.MethodsThe GSE138260 dataset was initially downloaded from the Gene expression Omnibus database. The ssGSEA algorithm was used to evaluate the immune infiltration of 28 kinds of immune cells in 36 samples. The up-regulated immune cells were divided into Cluster 1 group and Cluster 2 group, and the differences were analyzed. The LASSO regression analysis was used to establish the optimal scoring model. Cell Counting Kit-8 and Real Time Quantitative PCR were used to verify the effect of different concentrations of Aβ1–42 on the expression profile of representative genes in vitro.ResultsBased on the differential expression analysis, there were 14 up-regulated genes and 18 down-regulated genes between the control group and Cluster 1 group. Cluster 1 and Cluster 2 groups were differentially analyzed, and 50 up-regulated genes and 101 down-regulated genes were obtained. Finally, nine common differential genes were selected to establish the optimal scoring model. In vitro, CCK-8 experiments showed that the survival rate of cells decreased significantly with the increase of Aβ1–42 concentration compared with the control group. Moreover, RT-qPCR showed that with the increase of Aβ1–42 concentration, the expression of POR decreased first and then increased; RUFY3 was firstly increased and then decreased.DiscussionThe establishment of this research model can help clinicians make decisions on the severity of AD, thus providing better guidance for the clinical treatment of Alzheimer’s disease.

Background Human adenoviruses (HAdV) can cause various diseases, but there is limited information about the genotype diversity and epidemiology of HAdV associated with respiratory tract infections (RTIs) in Nanning.Methods From Jun 2019 to December 2021, throat swab, nasal swab, or nasopharyngeal swab samples were collected from hospitalized patients with RTIs, and Epidemiological data were analyzed using statistical software. HAdV were detected using a qPCR assay targeting a highly conserved 132-bp gene region of the HAdV hexon, and phylogenetic analysis was performed on the 875-bp hexon gene fragment.Results The age and sex distribution of HAdV-positive patients showed significant differences (P = 0.014 and P = 0.025, respectively). The majority of HAdV-positive patients were in the 0–6 age group (67.89%). The HAdV detection rate showed the highest prevalence in spring and autumn, peaking in February. In addition, a total of 37 HAdV-positive samples with 875-bp fragments were successfully genotyped and found to be circulating in Nanning from 2019 to 2021 with HAdV species B, C, and E.Conclusions HAdV prevalence is associated with age and season, with HAdV-B, HAdV-C, and HAdV-E co-circulating among hospitalized patients with RTIs in Nanning. The most frequent genotypes were HAdV-C1, HAdV-C6, and HAdV-E4.

Acrylamide is widely found in various types of fried foods and cigarettes, and is not only neurotoxic and carcinogenic, but also has many potential toxic effects. The current assessment of acrylamide intake through dietary questionnaires is confounded by a variety of factors, which poses limitations to safety assessment. In this review, we focus on the levels of AAMA, the urinary metabolite of acrylamide in humans, and its association with other diseases, and discuss the current research gaps in AAMA and the future needs. We reviewed a total of 25 studies from eight countries. In the general population, urinary AAMA levels were higher in smokers than in nonsmokers, and higher in children than in adults; the highest levels of AAMA were found in the population from Spain compared with the general population from other countries. In addition, AAMA is associated with several diseases, especially cardiovascular system diseases. Therefore, AAMA, as a biomarker of internal human exposure, can reflect acrylamide intake in the short term, which is of great significance for tracing acrylamide-containing foods and setting the allowable intake of acrylamide in foods.

Supplementary Figure from A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study)

Supplementary Data from A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study)

Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations affect the epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 interacted with KDM6A to activate genes instructing urothelial differentiation. KDM6A-deficient cells displayed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn repressed FOXA1-target genes and activated cell-cycle progression genes. Importantly, ATF3 depletion reversed the cell proliferation phenotype induced by KDM6A deficiency. These data establish that KDM6A loss engenders an epigenetic state that drives tumor growth in an ATF3-dependent manner, creating a potentially targetable molecular vulnerability.Significance:A gain-of-function epigenetic switch that disrupts differentiation is triggered by inactivating KDM6A mutations in bladder cancer and can serve as a potential target for novel therapies.

Supplementary Figure 3

ATF3 target genes downregulated in K2 that harbor FOXA1 peaks in RT4

Supplementary Figure 5