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Neutrino-induced charged-current single π+ production in the Δ(1232) resonance region is of considerable interest to accelerator-based neutrino oscillation experiments. In this Letter, high statistic differential cross sections are reported for the semiexclusive reaction νμA→μ−π++ nucleon(s) on scintillator, carbon, water, iron, and lead targets recorded by MINERvA using a wideband νμ beam with ⟨Eν⟩≈6 GeV. Suppression of the cross section at low Q2 and enhancement of low Tπ are observed in both light and heavy nuclear targets compared with phenomenological models used in current neutrino interaction generators. The cross sections per nucleon for iron and lead compared with CH across the kinematic variables probed are 0.8 and 0.5 respectively, a scaling which is also not predicted by current generators.

Timely and accurate socioeconomic indicators are the prerequisite for smart social governance. For example, the level of economic development and the structure of population are important statistics for regional or national policy-making. However, the collection of these characteristics usually depends on demographic and social surveys, which are time- and labor-intensive. To address these issues, we propose a machine learning-based approach to estimate and map the economic development from multi-source open available geospatial data, including remote sensing imagery and OpenStreetMap road networks. Specifically, we first extract knowledge-based features from different data sources; then the multi-view graphs are constructed through different perspectives of spatial adjacency and feature similarity; and a multi-view graph neural network (MVGNN) model is built on them and trained in a self-supervised learning manner. Then, the handcrafted features and the learned graph representations are combined to estimate the regional economic development indicators via random forest models. Taking China’s county-level gross domestic product (GDP) as an example, extensive experiments have been conducted and the results demonstrate the effectiveness of the proposed method, and the combination of the knowledge-based and learning-based features can significantly outperform baseline methods. Our proposed approach can advance the goal of acquiring timely and accurate socioeconomic variables through widely accessible geospatial data, which has the potential to extend to more social indicators and other geographic regions to support smart governance and policy-making in the future.

Black-carbon (BC) aerosol can strongly influence planetary boundary layer (PBL) development and thus severe haze formation, but its distinct role compared with scattering aerosols is not yet fully understood. Here, combining numerical simulation and field observation, we found a “tipping point,” where the daily maximum PBL height decreases abruptly when exceeding a critical threshold of aerosol optical depth (AOD), due to a BC-induced decoupling of mixing zones. Because the threshold AOD decreases with increasing BC mass fraction, our results suggest that the abrupt transition of PBL development to adverse conditions can be avoided by reducing the AOD below the threshold but can be avoided more efficiently by reducing the BC mass fraction to increase the threshold (e.g., up to four to six times more effective in extreme haze events in Beijing). To achieve co-benefits for air quality and climate change, our findings clearly demonstrate that high priority should be given to controlling BC emissions.

Nitrogen oxides affect health and climate. Their emissions, in the form of nitric oxide, from inland waters such as lakes are generally considered negligible and are absent in air quality and climate models. Here we find unexpected high emissions of nitric oxide from remote lakes on the Tibetan Plateau, based on satellite observations of tropospheric nitrogen dioxide vertical column densities and subsequent emission inversion at a fine resolution of 5 km. The total emissions from 135 lakes larger than 50 km2 reach 1.9 metric tons N h−1, comparable to anthropogenic emissions in individual megacities worldwide or the Tibet Autonomous Region. On average, the emissions per unit area reach 63.4 μg N m−2 h−1, exceeding those from crop fields. Such strong natural emissions from inland waters have not been reported, to the best of our knowledge. The emissions are derived from microbial processes in association with substantial warming and melting of glacier and permafrost on the plateau, constituting a previously unknown feedback between climate, lake ecology and nitrogen emissions.

This Letter presents the first simultaneous measurement of the quasielasticlike neutrino-nucleus cross sections on C, water, Fe, Pb, and scintillator (hydrocarbon or CH) as a function of longitudinal and transverse muon momentum. The ratio of cross sections per nucleon between Pb and CH is always above unity and has a characteristic shape as a function of transverse muon momentum that evolves slowly as a function of longitudinal muon momentum. The ratio is constant versus longitudinal momentum within uncertainties above a longitudinal momentum of 4.5 GeV/c. The cross section ratios to CH for C, water, and Fe remain roughly constant with increasing longitudinal momentum, and the ratios between water or C to CH do not have any significant deviation from unity. Both the overall cross section level and the shape for Pb and Fe as a function of transverse muon momentum are not reproduced by current neutrino event generators. These measurements provide a direct test of nuclear effects in quasielasticlike interactions, which are major contributors to long-baseline neutrino oscillation data samples.

Prior work has examined associations between cardiometabolic pregnancy complications and autism spectrum disorder (ASD) but not how these complications may relate to social communication traits more broadly. We addressed this question within the Environmental Influences on Child Health Outcomes program, with 6,778 participants from 40 cohorts conducted from 1998–2021 with information on ASD-related traits via the Social Responsiveness Scale. Four metabolic pregnancy complications were examined individually, and combined, in association with Social Responsiveness Scale scores, using crude and adjusted linear regression as well as quantile regression analyses. We also examined associations stratified by ASD diagnosis, and potential mediation by preterm birth and low birth weight, and modification by child sex and enriched risk of ASD. Increases in ASD-related traits were associated with obesity (β = 4.64, 95% confidence interval: 3.27, 6.01) and gestational diabetes (β = 5.21, 95% confidence interval: 2.41, 8.02), specifically, but not with hypertension or preeclampsia. Results among children without ASD were similar to main analyses, but weaker among ASD cases. There was not strong evidence for mediation or modification. Results suggest that common cardiometabolic pregnancy complications may influence child ASD-related traits, not only above a diagnostic threshold relevant to ASD but also across the population.

Hao Su,* Yueheng Tang,* Kexin Nie, Zhi Wang, Hongzhan Wang, Hui Dong, Gang Chen Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gang ChenDepartment of Integration Traditional Chinese Medicine and Western Medicine, TongJi Hospital, Huazhong University of Science and Technology, 1095Jiefang Avenue, Wuhan, Hubei Province, 430030, People’s Republic of China, Email dragonchengang@sina.comBackground: Hepatocellular carcinoma (HCC) is one of the most common and mortality types of malignant tumors in the world. The Tripartite-Motif (TRIM) protein family consists of more than 80 proteins with E3 ubiquitin ligase activity. Increasing studies have found that TRIM family proteins play an extremely important role in the occurrence and development of tumors. However, the expression and prognostic values of TRIMs in HCC have not been clarified.Methods: We used bioinformatic methods to explore the potential function of TRIM family genes in the HCC. Web servers ONCOMINE, UALCAN, GEPIA, cBioPortal, STRING, DAVID 6.8 and TIMER were used in this research.Results: We screened TRIM1-76 and found the expressions of TRIM6, TRIM11, TRIM16, TRIM18(MID1), TRIM24, TRIM28, TRIM31, TRIM37, TRIM45, TRIM52, TRIM59, TRIM66 were significantly changed in HCC. Among them, TRIM24, TRIM28, TRIM37, TRIM45 and TRIM59 had significant effects on pathological stages, overall survival and disease free survival. Functions of these genes are primarily related to transcriptional misregulation in cancer, p53 signaling pathway, alcoholism and viral carcinogenesis, FoxO signal pathway, PI3K-AKT pathway, cell cycle, microRNAs in cancer. Our results showed the significant correlation between TRIMs expression and infiltration of innate immune cells (macrophages, neutrophils, and dendritic cells).Conclusion: Our result provides novel insights into the function of TRIM family genes, which may be used as potential references for drug targets and accurate survival predictions in patients with HCC.Keywords: hepatocellular carcinoma, bioinformatics analysis, TRIM, survival, tumor immunology

Hongqiong Meng,1 Qionghua Long,1 Ruiping Wang,1 Xian Zhou,1 Huipeng Su,1 Tingting Wang,1 Ya Li2 1Department of General Medicine, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Yan’an Hospital Affiliated to Kunming Medical University, Kunming, People’s Republic of ChinaCorrespondence: Ya LiDepartment of Respiratory and Critical Care Medicine, Yan’an Hospital Affiliated to Kunming Medical University, 245 Renmin East Road, Kunming, Yunnan Province, People’s Republic of ChinaEmail 563825085@qq.comPurpose: Chronic obstructive pulmonary disease (COPD) is a major cause of death and morbidity worldwide. A better understanding of new biomarkers for COPD patients and their complex mechanisms in the progression of COPD are needed.Methods: An algorithm was conducted to reveal the proportions of 22 subsets of immune cells in COPD samples. Differentially expressed immune-related genes (DE-IRGs) were obtained based on the differentially expressed genes (DEGs) of the GSE57148 dataset, and 1509 immune-related genes (IRGs) were downloaded from the ImmPort database. Functional enrichment analyses of DE-IRGs were conducted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses and Ingenuity Pathway Analysis (IPA). We defined the DE-IRGs that had correlations with immune cells as hub genes. The potential interactions among the hub genes were explored by a protein–protein interaction (PPI) network.Results: The CIBERSORT results showed that lung tissue of COPD patients contained a greater number of resting NK cells, activated dendritic cells, and neutrophils than normal samples. However, the fractions of follicular helper T cells and resting dendritic cells were relatively lower. Thirty-eight DE-IRGs were obtained for further analysis. Functional enrichment analysis revealed that these DE-IRGs were significantly enriched in several immune-related biological processes and pathways. Notably, we also observed that DE-IRGs were associated with the coronavirus disease COVID-19 in the progression of COPD. After correlation analysis, six DE-IRGs associated with immune cells were considered hub genes, including AHNAK, SLIT2 TNFRRSF10C, CXCR1, CXCR2, and FCGR3B.Conclusion: In the present study, we investigated immune-related genes as novel diagnostic biomarkers and explored the potential mechanism for COPD based on CIBERSORT analysis, providing a new understanding for COPD treatment.Keywords: chronic obstructive pulmonary disease, COPD, immune-related genes, IRGs, CIBERSORT, diagnosis

RATIONALE: Current guidelines do not sufficiently capture the heterogeneous nature of asthma; a more detailed molecular classification is needed. Metabolomics represents a novel and compelling approach to derive asthma endotypes (i.e., subtypes defined by functional and/or pathobiological mechanisms). OBJECTIVES: To validate metabolomic-driven endotypes of asthma and explore their underlying biology. METHODS: In the Genetics of Asthma in Costa Rica Study (GACRS), untargeted metabolomic profiling, similarity network fusion, and spectral clustering was used to identify metabo-endotypes of asthma, and differences in asthma-relevant phenotypes across these metabo-endotypes were explored. The metabo-endotypes were recapitulated in the Childhood Asthma Management Program (CAMP), and clinical differences were determined. Metabolomic drivers of metabo-endotype membership were investigated by meta-analyzing findings from GACRS and CAMP. MEASUREMENTS AND MAIN RESULTS: Five metabo-endotypes were identified in GACRS with significant differences in asthma-relevant phenotypes, including prebronchodilator (p-ANOVA = 8.3 × 10(−5)) and postbronchodilator (p-ANOVA = 1.8 × 10(−5)) FEV(1)/FVC. These differences were validated in the recapitulated metabo-endotypes in CAMP. Cholesterol esters, trigylcerides, and fatty acids were among the most important drivers of metabo-endotype membership. The findings suggest dysregulation of pulmonary surfactant homeostasis may play a role in asthma severity. CONCLUSIONS: Clinically meaningful endotypes may be derived and validated using metabolomic data. Interrogating the drivers of these metabo-endotypes has the potential to help understand their pathophysiology.

Fewer than half of the world's infants have access to the birth dose of hepatitis B vaccine (HBV), which prevents mother-to-child transmission of HBV and subsequent liver cancer. Now is the time to expand access for infants born in low-resource settings.

Processes with precisely known cross sections, like neutrino-electron elastic scattering (νe−→νe−) and inverse muon decay (νμe−→μ−νe) have been used by MINERνA to constrain the uncertainty on the neutrinos at the main injector (NuMI) neutrino beam flux. This work presents a new measurement of neutrino elastic scattering with electrons using the medium energy ν¯μ-enhanced NuMI beam. A sample of 578 events after background subtraction is used in combination with the previous measurement on the νμ beam and the inverse muon decay measurement to reduce the uncertainty on the νμ flux in the νμ-enhanced beam from 7.6% to 3.3% and the ν¯μ flux in the ν¯μ-enhanced beam from 7.8% to 4.7%.

This paper presents the first simultaneous measurement of the quasielastic-like neutrino-nucleus cross sections on C, water, Fe, Pb and scintillator (hydrocarbon or CH) as a function of longitudinal and transverse muon momentum. The ratio of cross sections per nucleon between Pb and CH is always above unity and has a characteristic shape as a function of transverse muon momentum that evolves slowly as a function of longitudinal muon momentum. The ratio is constant versus longitudinal momentum within uncertainties above a longitudinal momentum of 4.5GeV/c. The cross section ratios to CH for C, water, and Fe remain roughly constant with increasing longitudinal momentum, and the ratios between water or C to CH do not have any significant deviation from unity. Both the overall cross section level and the shape for Pb and Fe as a function of transverse muon momentum are not reproduced by current neutrino event generators. These measurements provide a direct test of nuclear effects in quasielastic-like interactions, which are major contributors to long-baseline neutrino oscillation data samples., 9 pages, 8 flgures, including supplemental material

Процес глобалізації та прийняття нової парадигми світового розвитку, спрямованої на досягнення сталого розвитку, вимагають розширення концепції належного управління, що дозволяє покращити інституційну якість. У той же час ефективність управління залежить від корупції та участі громадськості в національних аудитах. Документ мав на меті проаналізувати вплив участі громадськості в національних аудитах на управління корупцією. Об’єктом дослідження були 30 провінцій Китаю за 2008–2017 рр. У дослідженні застосовувалася регресійна модель із запобіжною, викривальною та захисною функціями аудиту. Висновки показали, що «бачення управління» аудиту є основною причиною аудиту. Крім того, функція «імунної системи» національного аудиту має гальмівний вплив на корупцію, серед яких стримуючий ефект функції захисту є найвпливовішим. Вплив участі громадськості в національних аудитах на управління корупцією в основному відображається у функції стримування та опору національним аудитам. Стаття робить внесок у теорію аудиту шляхом включення механізму участі громадськості, покращення шляху управління «національний аудит – участь громадськості – управління корупцією». Це дозволяє покращити функцію «імунної системи» національного аудиту шляхом врахування демократичного відтінку прийняття рішень та розвитку середовища належного управління. Процесс глобализации и принятие новой парадигмы мирового развития, направленной на достижение устойчивого развития, требуют расширения концепции благого управления, что позволяет повысить институциональное качество. В то же время эффективность управления зависит от коррупции и участия общественности в национальных аудитах. Документ был направлен на анализ влияния участия общественности в национальных аудитах на управление коррупцией. Объектом исследования стали 30 провинций Китая за 2008–2017 гг. В исследовании применялась регрессионная модель с профилактической, выявленной и защитной функциями аудита. Результаты показали, что «точка зрения руководства» на аудит является первопричиной аудита. Кроме того, сдерживающее влияние на коррупцию оказывает функция «иммунной системы» национальных аудиторов, среди которых наиболее влиятельным является сдерживающий эффект функции защиты. Влияние участия общественности в национальных аудитах на управление коррупцией в основном отражается в функции национальных аудитов по сдерживанию и сопротивлению. Документ вносит вклад в теорию аудита, включив механизм участия общественности, улучшив путь управления «национальный аудит — участие общественности — управление коррупцией». Это позволяет улучшить функцию «иммунной системы» национального аудита, принимая во внимание демократическую коннотацию принятия решений и создавая среду для эффективного управления. The globalization process and acceptance of a new paradigm for world development aimed at attaining sustainable development require extending the concept of good governance, which allows the improvement of institutional quality. At the same time, governance performance depends on corruption and public participation in national audits. The paper aimed to analyze the impact of public participation in national audits on corruption governance. The object of investigation was 30 Chinese provinces for 2008–2017. The study applied a regression model with the preventive, exposed, and defensive functions of audits. The findings showed that the “governance view” of the audit is the root cause of the audit. In addition, the “immune system” function of national audits has an inhibitory effect on corruption, among which the deterrent effect of the defense function is the most-influential. The influence of public participation in national audits on corruption governance is mainly reflected in the deterrence and resistance function of national audits. The paper contributes to audit theory by incorporating the public participation mechanism, improving the governance path of “national audit—public participation—corruption governance”. It allows improving the national audit “immune system” function by considering the democratic connotation of decision-making and developing a good governance environment. Це дослідження було профінансовано Дослідженням з питань бухгалтерського обліку та аудиту раптових великих громадських подій (FJ2020JDZ068), великими проектами Бази соціальних наук Фуцзянь у 2020 році, дослідженням шляху поглиблення реформи науково-технологічної інноваційної системи в нашій провінції зі стратегічної точки зору «самозабезпечення та самовдосконалення в науці та техніці» (2021R0164), ключові проекти спільного проекту стратегічного плану досліджень інновацій Фуцзянь у 2021 році, дослідження з оцінки ефективності екологічного врядування місцевого самоврядування ( MCZ [2020] № 822), основні проекти Департаменту фінансів провінції Фуцзянь у 2020 році, Дослідження державного аудиту та фінансової безпеки з точки зору нагляду за ЗМІ (MCZ [2022] № 639), основні проекти Департаменту фінансів провінції Фуцзянь у 2022 році.

Snow properties and their changes are crucial to a better understanding of hydrological processes, soil thermal regimes, and surface energy balances. Reliable data and information on snow depth and snow water equivalent (SWE) are also crucial for water resource assessments and socio-economic development at local and regional scales. However, these data are extremely limited and unreliable in northern Xinjiang, China. This study thus aims to investigate spatial variations of snow depth, SWE, and snow density based on winter snowfield surveys from 2015 through 2017 in the Altai Mountains, northwestern China. The results indicated that snow depth and SWE were greater in the alpine Kanas-Hemu region, and shallow snow accumulated on the piedmont sloping plain. Snow property distributions were strongly controlled by topography and vegetation. Elevation and latitude were the most important factors affecting snow depth and SWE, while snow density was strongly affected by longitude. Leeward slopes were easier to accumulate snow cover, especially on the north-, east-, and southeast-facing slopes. Canopy interception was also the cause of the difference in snow distribution. Snow depth, SWE, and snow density in forests were reduced by 8%‒53%, 2%‒67% and –4% to +48%, respectively, compared with surrounding open areas. Especially when snow depth was less than 40 cm, snow depth and SWE differences in forests were more exaggerated. This study provides a basic data set of spatial distributions and variations of snow properties in the Altai Mountains, which can be used as an input parameter in climate or hydrological models., The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

Ying Liu,1,2,&ast; Dao-Hai Cheng,3,&ast; Ke-Dao Lai,1 Hua Su,1 Guo-Shou Lu,1 Li Wang,1 Ji-Hua Lv1 1Department of Pharmacology, Guangxi Institute of Chinese Medicine & Pharmaceutical Science, Nanning, 530022, People’s Republic of China; 2Guangxi Key Laboratory of Traditional Chinese Medicine Quality Standards, Nanning, 530022, People’s Republic of China; 3Department of Pharmacy, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Liu; Ke-Dao Lai Email shenghuakai_1997@163.com; laikedao@163.comObjective: Inhibition of tumor metastasis is a useful strategy to improve the efficacy of cancer therapy. Ventilagolin, a natural 1, 4-naphthoquinone derivative extracted from Ventilago leiocarpa Benth, has shown promising antitumor effects in previous studies. However, the effects and underlying mechanisms of Ventilagolin against migration, invasion and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) remain unclear. The present study has examined these effects and determined whether the proto-oncogene Pim-1 is involved.Methods: The effects of Ventilagolin on migration, invasion, Pim-1 and EMT-related proteins (eg, E-cadherin, N-cadherin, Vimentin) expression were assessed by scratch wound healing, Transwell, qRT-PCR and Western blot assays, respectively. Pim-1 stably overexpressed HepG2 and SMMC-7721 cells were generated to explore whether Ventilagolin inhibited migration, invasion and EMT of HCC cells via regulating Pim-1. Subcutaneous xenograft tumor model in nude mice was established. Histopathological changes of tumor tissues were examined by H&E staining and expressions of Pim-1 and EMT-related proteins were detected by immunohistochemistry.Results: Ventilagolin significantly (P < 0.01) reduced the expression of Pim-1 levels in HepG2 and SMMC-7721 cells. Compared with the control group, the migration and invasion abilities of Pim-1-overexpressing HepG2 and SMMC-7721 cells were significantly (P < 0.05, P < 0.01) enhanced, the expression of E-cadherin was decreased (P < 0.01), and the levels of N-cadherin and Vimentin were upregulated (P < 0.05, P < 0.01). Ventilagolin treatment effectively reversed these effects of Pim-1 overexpression. In vivo experiments showed that Ventilagolin could effectively suppress HCC tumor growth, downregulate Pim-1, N-cadherin and Vimentin expression, and upregulate E-cadherin expression.Conclusion: Ventilagolin suppresses HCC cell proliferation, migration and invasion and reverses EMT process by downregulating Pim-1, suggesting Ventilagolin is a potential therapeutic agent for treatment of HCC.Keywords: Ventilagolin, Pim-1, hepatocellular carcinoma, epithelial-mesenchymal transition

Leying Xi,1 Shuang Xu,2 Yingying Jiang,2 Hang Su,2 Yuying Sun,2 Yingying Wen,2 Jingjing Wu,2 Xianqing Ren2 1Department of Pediatrics, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 2Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Xianqing RenDepartment of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, No. 9 Renmin Road, Jinshui District, Zhengzhou, Henan Province, 450000, People’s Republic of ChinaTel +86 13673712698Email Renxq723@163.comObjective: Henoch–Schönlein purpura (HSP) is the most common vasculitis in children. Renal involvement is the main long-term complication of HSP, and presently there is no way to predict which children may have irreversible renal damage from the outset. This study aimed to explore the prediction value of laboratory indexes on renal involvement in children with HSP, which could help the early identification and intervention.Methods: Children with HSP hospitalized at the First Affiliated Hospital of Henan University of Chinese Medicine from June 2019 to December 2020 were included. The demographic findings, clinical features, laboratory findings including blood routine examination, serum immunoglobulin, complement, T cell subsets levels, liver and kidney function, coagulation function were recorded. Laboratory indexes were analyzed, logistic regression analysis was performed to identify the independent predictors in HSP patients with renal involvement, and receiver operating characteristic (ROC) curves were further used to assess the value of prediction indexes, as well as the efficacy of combined diagnosis.Results: The study included 146 HSP patients, among them, 50 patients (34.2%) had renal involvement. Age, platelet distribution width (PDW), CD3+ and fibrinogen (FIB) were positively correlated with renal involvement, while the levels of Immunoglobulin G (IgG), C-reactive protein (CRP), and neutrophil/lymphocyte ratio (NLR) were negatively correlated with renal involvement. The area under the ROC Curve (AUC) of these biomarkers ranged from 0.6284 to 0.7009, and among the combinations, a combination of NLR, CRP, CD3+, FIB, PDW, IgG and age had the best AUC value (0.9774).Conclusion: Age, PDW, CD3+, FIB, CRP, NLR and IgG were prediction indexes for renal involvement in HSP patients, and these indexes can be combined appropriately to improve the diagnostic efficacy.Keywords: Henoch–Schönlein purpura, laboratory indexes, renal involvement, diagnosis

Yixuan Zhang,1,&ast; Haochen Su,2,&ast; Haibo Wang,3,&ast; Chenghu Xu,1 Siqi Zhou,4 Jing Zhao,1 Shanshan Shen,1 Guifang Xu,1 Lei Wang,1 Xiaoping Zou,1 Shu Zhang,1 Ying Lv1 1Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 2Department of Gastroenterology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China; 3Cyttelbio Corporation, Beijing, People’s Republic of China; 4Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated of Jiangsu University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shu Zhang; Ying Lv Email zhangsgastro@nju.edu.cn; lvying@njglyy.comBackground: Circulating tumor cells (CTCs) were a promising liquid biopsy for pancreatic cancer (PC) but circulate in low counts in peripheral blood. We evaluated the diagnostic and prognostic values of portal vein (PoV) CTCs in PC patients.Methods: PoV was aspirated under EUS guidance from 40 patients with suspected pancreaticobiliary cancers. Epithelial–mesenchymal-transition-related subtypes of CTCs were identified via immunofluorescence using EpCAM and Twist antibodies. The diagnostic and prognostic performance of PoV CTCs was investigated by receiver-operating characteristic (AUC) curve and Kaplan–Meier survival analysis.Results: In total, 40 patients including 31 with PC, 4 with non-pancreatic periampullary cancer and 5 with benign pancreatic diseases (BPD) were enrolled. CTCs were detected more in PoV compared with peripheral blood. PoV CTC numbers in BPD patients were lower than in PC patients. The number of PoV CTCs, especially mesenchymal-CTCs (M-CTCs), was positively correlated with the tumor burden, instead of epithelial-CTCs (E-CTCs). The combination of PoV CTC numbers and CA19-9 demonstrated better diagnostic efficiency (AUC value 0.987) than either alone in differentiating PC with BPD. Moreover, the diagnostic efficacy of PoV CTCs and M-CTCs were obviously better than that of E-CTCs and CA19-9 in distinguishing early and late stage PC. Lastly, high PoV CTC and M-CTC numbers were both associated with shorter overall survival.Conclusion: Acquisition of the PoV samples in PC patients via EUS-guided procedures has been proved safe and feasible. PoV CTCs, especially M-CTCs, have great potentials in diagnosing and predicting the prognosis of PC, especially in combination with CA19-9.Keywords: circulating tumor cell, endoscopic ultrasound, portal vein blood, diagnosis, prognosis

Maternal infection and stress during the prenatal period have been associated with adverse neurodevelopmental outcomes in offspring, suggesting that biomarkers of increased inflammation in the mothers may associate with poorer developmental outcomes. In 491 mother–child pairs from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we investigated the association between maternal levels of two inflammatory biomarkers; interleukin-8 (IL-8) and C-Reactive Protein (CRP) during early (10–18 wks) and late (32–38 wks) pregnancy with offspring scores in the five domains of the Ages and Stages Questionnaire, a validated screening tool for assessing early life development. We identified a robust association between early pregnancy IL-8 levels and decreased fine-motor (β: −0.919, 95%CI: −1.425, −0.414, p = 3.9 × 10−4) and problem-solving skills at age two (β: −1.221, 95%CI: −1.904, −0.414, p = 4.9 × 10−4). Associations between IL-8 with other domains of development and those for CRP did not survive correction for multiple testing. Similarly, while there was some evidence that the detrimental effects of early pregnancy IL-8 were strongest in boys and in those who were not breastfed, these interactions were not robust to correction for multiple testing. However, further research is required to determine if other maternal inflammatory biomarkers associate with offspring neurodevelopment and work should continue to focus on the management of factors leading to increases in IL-8 levels in pregnant women.

Identifying prognostic factors for disease progression is a cornerstone of medical research. Repeated assessments of a marker outcome are often used to evaluate disease progression, and the primary research question is to identify factors associated with the longitudinal trajectory of this marker. Our work is motivated by diabetic kidney disease (DKD), where serial measures of estimated glomerular filtration rate (eGFR) are the longitudinal measure of kidney function, and there is notable interest in identifying factors, such as metabolites, that are prognostic for DKD progression. Linear mixed models (LMM) with serial marker outcomes (e.g., eGFR) are a standard approach for prognostic model development, namely by evaluating the time and prognostic factor (e.g., metabolite) interaction. However, two-stage methods that first estimate individual-specific eGFR slopes, and then use these as outcomes in a regression framework with metabolites as predictors are easy to interpret and implement for applied researchers. Herein, we compared the LMM and two-stage methods, in terms of bias and mean squared error via analytic methods and simulations, allowing for irregularly spaced measures and missingness. Our findings provide novel insights into when two-stage methods are suitable longitudinal prognostic modeling alternatives to the LMM. Notably, our findings generalize to other disease studies.

MINERvA has measured the $\nu_{\mu}$-induced coherent $\pi^{+}$ cross section simultaneously in hydrocarbon (CH), graphite (C), iron (Fe) and lead (Pb) targets using neutrinos from 2 to 20 GeV. The measurements exceed the predictions of the Rein-Sehgal and Berger-Sehgal PCAC based models at multi-GeV $\nu_{\mu}$ energies and at produced $\pi^{+}$ energies and angles, $E_{\pi}>1$ GeV and $\theta_{\pi}10$ GeV., Comment: 8 pages, 6 figures and 60 pages of supplemental material. Updated to accepted version, with ancillary files of the cross section data

The Polycomb group (PcG) protein Enhancer of Zeste Homolog 2 (EZH2) is one of the three core subunits of the Polycomb Repressive Complex 2 (PRC2). It harbors histone methyltransferase activity (MTase) that specifically catalyze histone 3 lysine 27 (H3K27) methylation on target gene promoters. As such, PRC2 are epigenetic silencers that play important roles in cellular identity and embryonic stem cell maintenance. In the past two decades, mounting evidence supports EZH2 mutations and/or over-expression in a wide array of hematological cancers and solid tumors, including prostate cancer. Further, EZH2 is among the most up-regulated genes in neuroendocrine prostate cancers, which become abundant due to the clinical use of high-affinity androgen receptor pathway inhibitors. While numerous studies have reported epigenetic functions of EZH2 that inhibit tumor suppressor genes and promote tumorigenesis, discordance between EZH2 and H3K27 methylation has been reported. Further, enzymatic EZH2 inhibitors have shown limited efficacy in prostate cancer, warranting a more comprehensive understanding of EZH2 functions. Here we first review how canonical functions of EZH2 as a histone MTase are regulated and describe the various mechanisms of PRC2 recruitment to the chromatin. We further outline non-histone substrates of EZH2 and discuss post-translational modifications to EZH2 itself that may affect substrate preference. Lastly, we summarize non-canonical functions of EZH2, beyond its MTase activity and/or PRC2, as a transcriptional cofactor and discuss prospects of its therapeutic targeting in prostate cancer.

Jiandong Shi, Piaoyan Zhang, Huarong Su, Lingyi Cai, Liang Zhao, Haixia Zhou Department of Hematology, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Haixia ZhouDepartment of Hematology, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Xueyuanxi Load No. 109, Wenzhou City, Zhejiang Province, People’s Republic of ChinaEmail e-mail:zhxcrystal@126.comObjective: To analyze the changes in downstream genes, signaling pathways, and proteins based on the difference of microRNA (miRNA) expression in neuroblastoma (NB).Methods: GSE128004 second-generation sequencing expression data were downloaded from GEO, and Limma package of R language was used to analyze differential expression, and a volcano map and heat map were drawn; the target genes corresponding to the differential miRNA were found using the miWalk web tool, and GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) were performed. The key genes were identified and verified in the TCGA database.Results: A total of 34 differentially expressed miRNAs were screened out. Among them, 22 up-regulated miRNAs predicted 1163 target genes and 12 down-regulated miRNAs predicted 1474 target genes. Target genes were enriched and analyzed by KEGG to find the FOXO signal pathway, mTOR signal pathway, AMPK signal pathway, and other signal pathways. After GO analysis, axon formation, regulation of chemical synaptic transmitters, regulation of nerve synapses, regulation of cross-synaptic signals, and other physiological processes were assessed. A total of 16 key genes were obtained by PPI analysis, and the survival analysis of TP53 and ATM genes verified in the TCGA database showed statistical significance.Conclusion: The 34 differential miRNAs may be related to the occurrence and development of NB. TP53 and ATM are related to the prognosis of NB. The role and mechanism of TP53 and ATM in NB need to be further verified.Keywords: neuroblastoma, miRNA, bioinformatics

The T2K experiment widely uses plastic scintillator as a target for neutrino interactions and an active medium for the measurement of charged particles produced in neutrino interactions at its near detector complex. Over 10 years of operation the measured light yield recorded by the scintillator based subsystems has been observed to degrade by 0.9--2.2\% per year. Extrapolation of the degradation rate through to 2040 indicates the recorded light yield should remain above the lower threshold used by the current reconstruction algorithms for all subsystems. This will allow the near detectors to continue contributing to important physics measurements during the T2K-II and Hyper-Kamiokande eras. Additionally, work to disentangle the degradation of the plastic scintillator and wavelength shifting fibres shows that the reduction in light yield can be attributed to the ageing of the plastic scintillator., Comment: 29 pages, 18 figures. Prepared for submission to JINST

More than a century after the performance of the oil drop experiment, the possible existence of fractionally charged particles FCP still remains unsettled. The search for FCPs is crucial for some extensions of the Standard Model in particle physics. Most of the previously conducted searches for FCPs in cosmic rays were based on experiments underground or at high altitudes. However, there have been few searches for FCPs in cosmic rays carried out in orbit other than AMS-01 flown by a space shuttle and BESS by a balloon at the top of the atmosphere. In this study, we conduct an FCP search in space based on on-orbit data obtained using the DArk Matter Particle Explorer (DAMPE) satellite over a period of five years. Unlike underground experiments, which require an FCP energy of the order of hundreds of GeV, our FCP search starts at only a few GeV. An upper limit of $6.2\times 10^{-10}~~\mathrm{cm^{-2}sr^{-1} s^{-1}}$ is obtained for the flux. Our results demonstrate that DAMPE exhibits higher sensitivity than experiments of similar types by three orders of magnitude that more stringently restricts the conditions for the existence of FCP in primary cosmic rays., Comment: 19 pages, 6 figures, accepted by PRD

The human immunoglobulin heavy chain (IGH) locus on chromosome 14 includes more than 40 functional copies of the variable gene (IGHV).

Shuangcheng Yu,1,* Haiqing Su,2,* Jianchang Lu,1 Fanyu Zhao,1 Fangyan Jiang2 1Department of Radiology, Minzu Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530001, People’s Republic of China; 2Department of Medical Ultrasound, Minzu Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fangyan JiangDepartment of Medical Ultrasound, Minzu Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530001, People’s Republic of ChinaEmail jiangfy1984@hotmail.comBackground: Myofascial trigger points (MTrPs) are defined as very small and hypersensitive points in skeletal muscle that are palpable, and produce localized pain on compression. The aim of this study was to explore the feasibility of combining T2 mapping with diffusion tensor imaging (DTI) for assessing MTrPs in a rat model and to investigate properties of the pathophysiological mechanisms.Methods: Twenty-four Sprague-Dawley rats (model group, n = 14; control group, n = 10) underwent a magnetic resonance imaging (MRI) examination on a 3 T-MRI-scanner with a protocol consisting of T2 mapping and DTI. The MTrPs were established by blunt strike in combination with eccentric exercise. Enzyme-linked immunosorbent assays (ELISAs) were used to detect the levels of interleukin-1ß (IL-1ß) and interleukin-2 (IL-2) and their results were correlated with T2 values. Parameters from MRI including T2 values, fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) were compared between the two groups. Histological analysis was applied to provide an additional supply for MRI findings.Results: The MTrPs of rats displayed significantly increased T2 values and FA (= 0.000) compared with normal controls, whereas MD and RD values were significantly lower (P= 0.031, = 0.000, respectively). There was no statistically significant difference in AD between the two groups (P= 0.400). These differences were accompanied by elevated levels of IL-1ß and interleukin-2 IL-2 in the MTrP group compared with controls. T2 values were positively correlated with elevated IL-1ß levels (r = 0.543, P < 0.05) but were not correlated with IL-2 levels (P > 0.05).Conclusion: Combining T2 and DTI sequences creates a sensitive tool to assess MTrPs in a rat model. These data clarify a hypothesis that a trigger point is a chronic and mild muscle injury with inflammation.Keywords: magnetic resonance imaging, gastrocnemius muscle, myofascial pain syndrome, diagnosis, inflammatory cytokines

Xi Chen,1,* Ping Tu,2,* Xing-Lan Sun,1 Ting-Ying Hu,1 Jia Wan,1 Yi-Wei Hu,1 Hui-Ling Zhou,1 Hai Su1 1Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 2Department of Post Anesthesia Care Unit, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xing-Lan SunDepartment of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, No. 1 of Minde Road, Donghu District, Nanchang, 330006, People’s Republic of ChinaTel +86 791-86312182Fax +86 791-86312182Email sunxinglan_99dr@163.comObjective: The aim of this study is to evaluate the impact on blood pressure (BP) of a 10°C change in room temperature (between 18°C and 28°C).Methods: A total of 112 volunteers, 56 males and 56 females, 55 with and 57 without hypertension, were enrolled in the study. First, the participants were placed in a 25°C room. Second, they were randomly assigned to either a 28°C (group A) or an 18°C room (group B). Finally, they were moved from the 28°C to the 18°C room, or vice versa. They stayed in each room for 20 minutes. Seated BP was measured at the 17th and 19th minute in each room, and the average was used. The difference in the subject’s BP between the second two rooms was recorded as delta BP.Results: The baseline systolic BP (SBP), age, gender distribution, and incidence of hypertension were similar between the two groups. In group A, the decrease in room temperature of 10°C induced a mean rise in SBP of 4.1 mmHg. In group B, the increase of 10°C caused SBP to decrease by 4.0 mmHg. When compared with the group without hypertension, the group with hypertension had a significantly higher rise in mean SBP (6.8 vs 1.2 mmHg) as a result of the decrease in temperature and a significantly higher drop in SBP (7.3 vs 1.2 mmHg) as a result of the increase in temperature. The participants in the group with hypertension were older.Conclusion: A 10°C change in room temperature, from 18°C to 28°C, for 20 min can cause a significant change in SBP. The extent of this change is more obvious in the older group.Keywords: room, temperature, BP, hypertension, change

Neutrino-induced charged-current single $\pi^+$ production in the $\Delta(1232)$ resonance region is of considerable interest to accelerator-based neutrino oscillation experiments. In this work, high statistics differential cross sections are reported for the semi-exclusive reaction $\nu_\mu A \to \mu^- \pi^+ +$ nucleon(s) on scintillator, carbon, water, iron, and lead targets recorded by MINERvA using a wide-band $\nu_\mu$ beam with $\left< E_\nu \right> \approx 6$~GeV. Suppression of the cross section at low $Q^2$ and enhancement of low $T_\pi$ are observed in both light and heavy nuclear targets compared to phenomenological models used in current neutrino interaction generators. The cross-section ratios for iron and lead compared to CH across the kinematic variables probed are 0.8 and 0.5 respectively, a scaling which is also not predicted by current generators., Comment: 6 pages, 6 figures, 117 pages of supplementary material; updated to accepted version and added ancillary files with cross section data; updated again to add ancillary files with neutrino flux used for result

Processes with precisely known cross sections, like neutrino electron elastic scattering ($\nu e^{-} \!\rightarrow \nu e^{-}$) and inverse muon decay ($\nu_\mu e^{-} \!\rightarrow \mu^{-} \nu_e$) have been used by MINERvA to constrain the uncertainty on the NuMI neutrino beam flux. This work presents a new measurement of neutrino elastic scattering with electrons using the medium energy \numubar enhanced NuMI beam. A sample of 578 events after background subtraction is used in combination with the previous measurement on the \numu beam and the inverse muon decay measurement to reduce the uncertainty on the \numu flux in the \numu-enhanced beam from 7.6\% to 3.3\% and the \numubar flux in the \numubar-enhanced beam from 7.8\% to 4.7\%., Comment: 12 pages, 16 figures

Black carbon (BC) plays an important role in the climate system due to its strongwarming effect, yet the magnitude of this effect is highly uncertain due to the complex mixingstate of aerosols. Here we build a unified theoretical framework to describe BC’s mixing states,linking dynamic processes to BC coating thickness distribution, and show its self-similarity for sites in diverse environments. The size distribution of BC-containing particles is found to followan exponential pattern and is independent of BC core size. A mixing state module is establishedbased on this finding and successfully applied in global and regional models, which increases theaccuracy of aerosol climate effect estimations. Our theoretical framework can bridge the gap be-tween observation and model simulation in both mixing state description and light absorption quantification

Intratumoral hypoxia is associated with castration-resistant prostate cancer (CRPC), a lethal disease. FOXA1 is an epithelial transcription factor that is down-regulated in CRPC. We have previously reported that FOXA1 loss induces epithelial-mesenchymal transition (EMT) and cell motility through elevated TGFβ signaling. However, whether FOXA1 directly regulates hypoxia pathways of CRPC tumors has not been previously studied. Here we report that FOXA1 down-regulation induces hypoxia transcriptional programs, and FOXA1 level is negatively correlated with hypoxia markers in clinical prostate cancer (PCa) samples. Mechanistically, FOXA1 directly binds to an intragenic enhancer of HIF1A to inhibit its expression, and HIF1A, in turn, is critical in mediating FOXA1 loss-induced hypoxia gene expression. Further, we identify CCL2, a chemokine ligand that modulates tumor microenvironment and promotes cancer progression, as a crucial target of the FOXA1-HIF1A axis. We found that FOXA1 loss leads to immunosuppressive macrophage infiltration and increased cell invasion, dependent on HIF1A expression. Critically, therapeutic targeting of HIF1A-CCL2 using pharmacological inhibitors abolishes FOXA1 loss-induced macrophage infiltration and PCa cell invasion. In summary, our study reveals an essential role of FOXA1 in controlling the hypoxic tumor microenvironment and establishes the HIF1A-CCL2 axis as one mechanism of FOXA1 loss-induced CRPC progression.

The MINERνA experiment reports double-differential cross-section measurements for νμ-carbon interactions with three-momentum transfer |q→|<1.2 GeV obtained with medium energy exposures in the NuMI beam. These measurements are performed as a function of the three-momentum transfer and an energy transfer estimator called the available energy defined as the energy that would be visible in the detector. The double-differential cross sections are compared to the genie and nuwro predictions along with the modified version of genie which incorporates new models for better agreement with earlier measurements from MINERνA. In these measurements, the quasielastic, resonance, and multinucleon knockout processes appear at different kinematics in this two-dimensional space. The results can be used to improve models for neutrino interactions needed by neutrino oscillation experiments.

Graph neural network(GNN) has obtained outstanding achievements in relational data. However, these data have uncertain properties, for example, spurious edges may be included. Recently, Variational graph autoencoder(VGAE) has been proposed to solve this problem. However, the distributional assumptions in the variational family restrict the variational inference (VI) flexibility and they define variational families using mean-field, which can not capture complex posterior distributional. To solve the above question, in this paper, we proposed a novel GNN model based on semi-implicit variational inference (SIVI), which can embed the node to the latent space to improve VI flexibility and enhance VI expressiveness with mixing distribution. Specifically, to approximate the true posterior, a variational posterior was given utilizing a semi-implicit hierarchical variational framework, which can model complex posterior. Moreover, an iterative decoder is used to better capture graph properties. Besides, due to the hierarchical structure in our model, it can incorporation neighbour information between nodes. Experiments on multiple data sets, our method has achieved state-of-the-art results compared to other similar methods. Particularly, on the citation dataset Citeseer without features, our method outperforms VGAE by nine percentage.

Neutrino charged-current quasielastic-like scattering, a reaction category extensively used in neutrino oscillation measurements, probes nuclear effects that govern neutrino-nucleus interactions. This Letter reports the first measurement of the triple-differential cross section for ν_{μ} quasielastic-like reactions using the hydrocarbon medium of the MINERvA detector exposed to a wideband beam spanning 2≤E_{ν}≤20 GeV. The measurement maps the correlations among transverse and longitudinal muon momenta and summed proton kinetic energies, and compares them to predictions from a state-of-art simulation. Discrepancies are observed that likely reflect shortfalls with modeling of pion and nucleon intranuclear scattering and/or spectator nucleon ejection from struck nuclei. The separate determination of leptonic and hadronic variables can inform experimental approaches to neutrino-energy estimation.

Neutrino charged-current quasielastic-like scattering, a reaction category extensively used in neutrino oscillation measurements, probes nuclear effects that govern neutrino-nucleus interactions. This Letter reports the first measurement of the triple-differential cross section for νμ quasielastic-like reactions using the hydrocarbon medium of the MINERvA detector exposed to a wideband beam spanning 2≤Eν≤20 GeV. The measurement maps the correlations among transverse and longitudinal muon momenta and summed proton kinetic energies, and compares them to predictions from a state-of-art simulation. Discrepancies are observed that likely reflect shortfalls with modeling of pion and nucleon intranuclear scattering and/or spectator nucleon ejection from struck nuclei. The separate determination of leptonic and hadronic variables can inform experimental approaches to neutrino-energy estimation.

ObjectivesWe sought to identify metabolic changes potentially related to rheumatoid arthritis (RA) pathogenesis occurring in the blood prior to its diagnosis.MethodsIn a US military biorepository, serum samples collected at two timepoints prior to a diagnosis of RA were identified. These were matched to controls who did not develop RA by subject age, race and time between sample collections and RA diagnosis time to stored serum samples. Relative abundances of 380 metabolites were measured using liquid chromatography–tandem mass spectrometry. We determined whether pre-RA case versus control status predicted metabolite concentration differences and differences over time (trajectories) using linear mixed models, assessing for interactions between time, pre-RA status and metabolite concentrations. We separately examined pre-RA and pre-seropositive RA cases versus matched controls and adjusted for smoking. Multiple comparison adjustment set the false discovery rate to 0.05.Results291 pre-RA cases (80.8% pre seropositive RA) were matched to 292 controls, all with two serum samples (2.7±1.6 years; 1.0±0.9 years before RA/matched date). 52.0% were women; 52.8% were White, 26.8% Black and 20.4% other race. Mean age was 31.2 (±8.1) years at earliest blood draw. Fourteen metabolites had statistically significant trajectory differences among pre-RA subjects versus controls, including sex steroids, amino acid/lipid metabolism and xenobiotics. Results were similar when limited to pre seropositive RA and after adjusting for smoking.ConclusionsIn this military case–control study, metabolite concentration trajectory differences in pre-RA cases versus controls implicated steroidogenesis, lipid/amino acid metabolism and xenobiotics in RA pathogenesis. Metabolites may have potential as biomarkers and/or therapeutic targets preceding RA diagnosis.

Guohua Zhu,1,2,* Jukun Song,2,3,* Weimin Chen,3,* Dongbo Yuan,2,3 Wei Wang,2 Xiaoyue Chen,3 Hen Liu,2,4 Hao Su,2,4 Jianguo Zhu1– 4 1Guizhou Medical University, Guiyang, Guizhou Province 550002, People’s Republic of China; 2Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province 550002, People’s Republic of China; 3Guizhou University School of Medicine, Guiyang, Guizhou Province 550025, People’s Republic of China; 4Zunyi Medical University, Zunyi, Guizhou Province 563000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianguo ZhuDepartment of Urology, Guizhou Provincial People’s Hospital,, Guiyang, Guizhou Province 550002, People’s Republic of ChinaTel/Fax +86-851-85925503Email doctorzhujianguo@163.comAbstract: Dickkopf-1 (Dkk1) is a secretory antagonist of the classical Wnt signaling pathway. Many studies have reported that Dkk1 is abnormally expressed in tumor cells, and abnormal expression of Dkk1 can inhibit cell proliferation or induce apoptosis through pro-apoptotic factors, However, due to the differences in tumor environment and the complex regulatory mechanisms in different tumors, Dkk1 has different effects on the progression of different tumors. In many tumors, high expression of Dkk1 may promote tumor metastasis. However, Dkk1, which is highly expressed in other tumors, can inhibit tumor invasion and metastasis. More and more evidence shows that Dkk1 plays a complex and different role in tumor occurrence, development and metastasis in different tumor environments and through a variety of complex regulatory mechanisms. Therefore, Dkk1 may not only be a useful biomarker of metastasis, but also a target for studying the metabolic mechanism of tumor cells and treating tumors in many tumor types. Therefore, this article reviews the research progress on the expression, mechanism and function of Dkk1 in different tumors, and at the same time, based on the public database data, we made a further analysis of the expression of Dkk1 in different tumors.Keywords: dickkopf-1, Dkk1, Wnt signaling pathway, tumor mechanism, metastasis, biomarker, in vitro, in vivo

PURPOSE This Provisional Clinical Opinion update presents a clinically pragmatic approach to hepatitis B virus (HBV) screening and management. PROVISIONAL CLINICAL OPINION All patients anticipating systemic anticancer therapy should be tested for HBV by 3 tests—hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc) total immunoglobulin (Ig) or IgG, and antibody to hepatitis B surface antigen—but anticancer therapy should not be delayed. Findings of chronic HBV (HBsAg-positive) or past HBV (HBsAg-negative and anti-HBc–positive) infection require HBV reactivation risk assessment. Patients with chronic HBV receiving any systemic anticancer therapy should receive antiviral prophylactic therapy through and for minimum 12 months following anticancer therapy. Hormonal therapy alone should not pose a substantial risk of HBV reactivation in patients with chronic HBV receiving hormonal therapy alone; these patients may follow noncancer HBV monitoring and treatment guidance. Coordination of care with a clinician experienced in HBV management is recommended for patients with chronic HBV to determine HBV monitoring and long-term antiviral therapy after completion of anticancer therapy. Patients with past HBV infection undergoing anticancer therapies associated with a high risk of HBV reactivation, such as anti-CD20 monoclonal antibodies or stem-cell transplantation, should receive antiviral prophylaxis during and for minimum 12 months after anticancer therapy completion, with individualized management thereafter. Careful monitoring may be an alternative if patients and providers can adhere to frequent, consistent follow-up so antiviral therapy may begin at the earliest sign of reactivation. Patients with past HBV undergoing other systemic anticancer therapies not clearly associated with a high risk of HBV reactivation should be monitored with HBsAg and alanine aminotransferase during cancer treatment; antiviral therapy should commence if HBV reactivation occurs. Additional information is available at www.asco.org/supportive-care-guidelines .

Hao Su,1 Chen Chang,2 Jiajie Hao,2 Xin Xu,2 Mandula Bao,1 Shou Luo,1 Chuanduo Zhao,1 Qian Liu,1 Xishan Wang,1 Zhixiang Zhou,1 Haitao Zhou1 1Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 2State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Zhixiang Zhou; Haitao ZhouNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, People’s Republic of ChinaTel/Fax +861087787110Email zhouzhixiangdoctor@126.com; zhouhaitao01745@163.comPurpose: The molecular mechanism of perineural invasion (PNI) in stage II colorectal cancer (CRC) remains not to be defined clearly. This study aims to identify the genomic aberrations related to PNI in stage II CRC.Patients and Methods: Using array-based comparative genomic hybridization (array-CGH), primary tumor tissues and paracancerous normal tissues of stage II CRC with PNI and without PNI were analyzed. We identified genomic aberrations by using Genomic Workbench and MD-SeeGH and validated the aberrations of selected genes by real-time polymerase chain reaction (PCR). Gene ontology (GO) and pathway analysis were performed to determine the most likely biological effects of these genes.Results: The most frequent gains in stage II CRC were at 7q11.21-q11.22, 8p11.21, 8p12-p11.23, 8q11.1-q11.22, 13q12.13-q12.2, and 20q11.21-q11.23 and the most frequent losses were at 17p13.1-p12, 8p23.2, and 118q11.2-q23. Four high-level amplifications at 8p11.23-p11.22, 18q21.1, 19q11-q12, and 20q11.21-q13.32 and homozygous deletions at 20p12.1 were discovered in Stage II CRC. Gains at 7q11.21-q22.1, 16p11.2, 17q23.3-q25.3, 19p13.3-p12, and 20p13-p11.1, and losses at 11q11-q12.1, 11p15.5-p15.1, 18p11.21, and 18q21.1-q23 were more commonly found in patients with PNI by frequency plot comparison together with detailed genomic analysis. It is also observed that gains at 8q11.1-q24.3, 9q13-q34.3, and 13q12.3-q13.1, and losses at 8p23.3-p12, 17p13.3-p11.2, and 21q22.12 occurred more frequently in patients without PNI. Further validation showed that the expression of FLT1, FBXW7, FGFR1, SLC20A2 and SERPINI1 was significantly up-regulated in the NPNI group compared to the PNI group. GO and pathway analysis revealed some genes enriched in specific pathways.Conclusion: These involved genomic changes in the PNI of stage II CRC may be useful to reveal the mechanisms underlying PNI and provide candidate biomarkers.Keywords: array CGH, colorectal cancer, perineural invasion, biomarker

Lin Deng,1,* Shikong Guo,2,* Hong Li,1 Xianghui You,1 Yang Song,1 Haichuan Su1 1Department of Oncology, Tangdu Hospital, Air Force Military Medical University, Xi’an, Shaanxi, China; 2Department of Orthopedics, Tangdu Hospital, Air Force Military Medical University, Xi’an, Shaanxi, China*These authors contributed equally to this workCorrespondence: Yang Song; Haichuan Su Email songyang212212@163.com; suhaic_1@163.comBackground: This study explored the value of ascites and serum CA125, CEA, and CA19-9 levels and ascites DNA ploidy analysis for the diagnosis of peritoneal carcinomatosis (PC) in patients with gastrointestinal and ovarian malignancies, which can cause ascites and may disseminate peritoneally.Methods: We measured ascites and serum levels of CA125, CEA, CA19-9 and performed an ascites DNA ploidy analysis in 58 patients with PC and 44 patients without PC.Results: We found that a high expression level of CA125 in ascites fluid was associated with the occurrence of PC in patients with gastrointestinal and ovarian malignancies (P< 0.001), and that high CEA and CA19- 9 levels in ascites fluid were associated with PC in patients with gastrointestinal malignancies (P=0.001, P=0.002). But, these tumor marker expression levels in ascites fluid were not significantly associated with the PC stage (P> 0.05). We found similar serum levels of CA125, CEA, and CA19-9 between patients with gastrointestinal and ovarian malignancies and PC and those without PC (P> 0.05). We found that the presence of three or more cells with heteroploid in the ascites samples was significantly associated with PC in gastrointestinal and ovarian malignancies (P< 0.001). In addition, the best ROC curves and highest AUCs were achieved by combining the CA125 level and heteroploid cell analysis results (AUC for gastrointestinal and ovarian malignancies, 0.815, AUC for gastrointestinal malignancies, 0.873). Moreover, the combined ascites CA125 level and result of heteroploid cell analysis provided the best diagnostic sensitivity and specificity for PC (75.9% and 79.5%, respectively, in gastrointestinal and ovarian malignancies; 85.0% and 86.7%, respectively, in gastrointestinal malignancies).Conclusion: Ascites levels of CA125, CEA, CA19-9, and heteroploid cells can be considered valuable markers for the diagnosis of PC in patients with gastrointestinal and ovarian cancer.Keywords: peritoneal carcinomatosis, tumor marker, ascites, heteroploid cell

Because they deliver outstanding energy density, next-generation lithium metal batteries (LMBs) are essential to the advancement of both electric mobility and portable electronic devices. However, the high reactivity of metallic lithium surfaces leads to the low electrochemical performance of many secondary batteries. Besides, Li deposition is not uniform, which has been attributed to the low ionic conductivity of the anode surface. In particular, lithium exposure to CO2 gas is considered detrimental due to the formation of carbonate on the solid electrolyte interphase (SEI). In this work, we explored the interaction of Li metal with CO2 gas as a function of time using ambient pressure X-ray photoelectron spectroscopy to clarify the reaction pathway and main intermediates involved in the process during which oxalate formation has been detected. Furthermore, when O2 gas is part of the surrounding environment with CO2 gas, the reaction pathway is bypassed to directly promote carbonate as a single product.

Xiaohua Chen, Zhuxiang Zhang, Yan Ma, Hongxin Su, Peng Xie, Juntao Ran Department Of Radiation Therapy, First Hospital Of Lanzhou University, Lanzhou City, Gansu Province 730000, People’s Republic of ChinaCorrespondence: Juntao RanDepartment Of Radiation Therapy, First Hospital Of Lanzhou University, No. 1 Donggang West Road, Chengguan District, Lanzhou City, Gansu Province 730000, People’s Republic of ChinaTel +86 931-8356435Email kyxfjedpjge1@163.comBackground: It has been proved that lncRNAs could function as CeRNA for miRNAs in tumor growth and metastasis for cervical cancer. This paper aims to identify the role of LINC02381 in cervical cancer cells.Materials and Methods: RT-qPCR was utilized to measure the expression levels of LINC02381 in cervical cancer tissues and cells. MTT, colony formation assay, transwell assay, RT-qPCR, and Western blotting were performed to investigate the roles of LINC02381 in cervical cancer cells. RegRNA 2.0 was used to predict the miRNA-binding sites of LINC02381. Luciferase reporter assay and RT-qPCR were employed to confirm the sponging effect between miR-133b and LINC02381.Results: This study showed that LINC02381 was up-regulated in cervical cancer cells and acted as an oncogene in the development of cervical cancer. LINC02381 promoted cell viability and metastasis via sponging miR-133b. Moreover, miR-133b could target its downstream mediator of RhoA and inhibit its expression.Conclusion: Overall, our results indicated that LINC02381 functions as an oncogene in cervical cancer and could serve as a novel target for cervical cancer therapies in the future.Keywords: LINC02381, miR-133b, RhoA, cervical cancer, cell viability

Objectives RA develops slowly over years. We tested for metabolic changes prior to RA onset using a large non-targeted metabolomics platform to identify novel pathways and advance understanding of RA development. Methods Two hundred and fifty-four incident RA cases with plasma samples drawn pre-RA onset in the Nurses’ Health Study (NHS) cohorts were matched 1:2 to 501 controls on age, race, menopause/post-menopausal hormone use and blood collection features. Relative abundances of 360 unique, known metabolites were measured. Conditional logistic regression analyses assessed associations between metabolites and incidence of RA, adjusted for age, smoking and BMI, accounting for multiple comparisons. Subgroup analyses investigated seropositive (sero+) RA and RA within 5 years of sample collection. Significant metabolites were then tested in a female military pre-RA case–control study (n = 290). Results In the NHS, metabolites associated with RA and sero+RA in multivariable models included 4-acetamidobutanoate (odds ratio (OR) = 0.80/S.d., 95% CI: 0.66, 0.95), N-acetylputrescine (OR = 0.82, 95% CI: 0.69, 0.96), C5 carnitine (OR = 0.84, 95% CI: 0.71, 0.99) and C5:1 carnitine (OR = 0.81, 95% CI: 0.68, 0.95). These were involved primarily in polyamine and leucine, isoleucine and valine metabolism. Several metabolites associated with sero+RA within 5 years of diagnosis were replicated in the independent military cohort: C5 carnitine (OR = 0.55, 95% CI: 0.33, 0.92), C5:1 carnitine (OR = 0.62, 95% CI: 0.39, 0.99) and C3 carnitine (OR = 0.57, 95% CI: 0.36, 0.91). Conclusion Several metabolites were inversely associated with incidence of RA among women. Three short-chain acylcarnitines replicated in a smaller dataset and may reflect inflammation in the 5-year period prior to sero+RA diagnosis.

OBJECTIVE Inflamed airways are hypothesized to contribute to rheumatoid arthritis (RA) pathogenesis due to RA-related autoantibody production, and smoking is the strongest environmental RA risk factor. However, the role of chronic airway diseases in RA development is unclear. We undertook this study to investigate whether asthma and chronic obstructive pulmonary disease (COPD) were each associated with RA. METHODS We performed a prospective cohort study of 205,153 women in the Nurses' Health Study (NHS, 1988-2014) and NHSII (1991-2015). Exposures were self-reported physician-diagnosed asthma or COPD confirmed by validated supplemental questionnaires. The primary outcome was incident RA confirmed by medical record review by 2 rheumatologists. Covariates (including smoking pack-years/status) were assessed via biennial questionnaires. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for RA were estimated using Cox regression. RESULTS We identified 15,148 women with confirmed asthma, 3,573 women with confirmed COPD, and 1,060 incident RA cases during 4,384,471 person-years (median 24.0 years/participant) of follow-up in the NHS and NHSII. Asthma was associated with increased RA risk (HR 1.53 [95% CI 1.24-1.88]) compared to no asthma/COPD after adjustment for covariates, including smoking pack-years/status. Asthma remained associated with increased RA risk when analyzing only never-smokers (HR 1.53 [95% CI 1.14-2.05]). COPD was also associated with increased RA risk (HR 1.89 [95% CI 1.31-2.75]). The association of COPD with RA was most pronounced in the subgroup of ever-smokers age >55 years (HR 2.20 [95% CI 1.38-3.51]). CONCLUSION Asthma and COPD were each associated with increased risk of incident RA, independent of smoking status/intensity and other potential confounders. These results provide support for the hypothesis that chronic airway inflammation may be crucial in RA pathogenesis.

Background: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.Research Question: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma?Study Design and Methods: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10–6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2).Results: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10–8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent.Interpretation: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

The application of large-scale metabolomic profiling provides new opportunities for realizing the potential of omics-based precision medicine for asthma. By leveraging data from over 14,000 individuals in four distinct cohorts, this study identifies and independently replicates 17 steroid metabolites whose levels were significantly reduced in individuals with prevalent asthma. Although steroid levels were reduced among all asthma cases regardless of medication use, the largest reductions were associated with inhaled corticosteroid (ICS) treatment, as confirmed in a 4-year low-dose ICS clinical trial. Effects of ICS treatment on steroid levels were dose dependent; however, significant reductions also occurred with low-dose ICS treatment. Using information from electronic medical records, we found that cortisol levels were substantially reduced throughout the entire 24-hour daily period in patients with asthma who were treated with ICS compared to those who were untreated and to patients without asthma. Moreover, patients with asthma who were treated with ICS showed significant increases in fatigue and anemia as compared to those without ICS treatment. Adrenal suppression in patients with asthma treated with ICS might, therefore, represent a larger public health problem than previously recognized. Regular cortisol monitoring of patients with asthma treated with ICS is needed to provide the optimal balance between minimizing adverse effects of adrenal suppression while capitalizing on the established benefits of ICS treatment.

Biological soil crusts (biocrusts) release the reactive nitrogen gases (Nr) nitrous acid (HONO) and nitric oxide (NO) into the atmosphere, but the underlying microbial process controls have not yet been resolved. In this study, we analyzed the activity of microbial consortia relevant in Nr emissions during desiccation using transcriptome and proteome profiling and fluorescence in situ hybridization. We observed that < 30 min after wetting, genes encoding for all relevant nitrogen (N) cycling processes were expressed. The most abundant transcriptionally active N-transforming microorganisms in the investigated biocrusts were affiliated with Rhodobacteraceae, Enterobacteriaceae, and Pseudomonadaceae within the Alpha- and Gammaproteobacteria. Upon desiccation, the nitrite (NO2-) content of the biocrusts increased significantly, which was not the case when microbial activity was inhibited. Our results confirm that NO2- is the key precursor for biocrust emissions of HONO and NO. This NO2- accumulation likely involves two processes related to the transition from oxygen-limited to oxic conditions in the course of desiccation: (i) a differential regulation of the expression of denitrification genes; and (ii) a physiological response of ammonia-oxidizing organisms to changing oxygen conditions. Thus, our findings suggest that the activity of N-cycling microorganisms determines the process rates and overall quantity of Nr emissions.