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Antigen-specific, MHC-restricted αβ T cells are necessary for protective immunity against Mycobacterium tuberculosis, but the ability to broadly study these responses has been limited. In the present study, we used single-cell and bulk T cell receptor (TCR) sequencing and the GLIPH2 algorithm to analyze M. tuberculosis-specific sequences in two longitudinal cohorts, comprising 166 individuals with M. tuberculosis infection who progressed to either tuberculosis (n = 48) or controlled infection (n = 118). We found 24 T cell groups with similar TCR-β sequences, predicted by GLIPH2 to have common TCR specificities, which were associated with control of infection (n = 17), and others that were associated with progression to disease (n = 7). Using a genome-wide M. tuberculosis antigen screen, we identified peptides targeted by T cell similarity groups enriched either in controllers or in progressors. We propose that antigens recognized by T cell similarity groups associated with control of infection can be considered as high-priority targets for future vaccine development.

The LUX-ZEPLIN experiment recently reported limits on WIMP-nucleus interactions from its initial science run, down to 9.2×10−48 cm2 for the spin-independent interaction of a 36 GeV/c2 WIMP at 90% confidence level. In this paper, we present a comprehensive analysis of the backgrounds important for this result and for other upcoming physics analyses, including neutrinoless double-beta decay searches and effective field theory interpretations of LUX-ZEPLIN data. We confirm that the in-situ determinations of bulk and fixed radioactive backgrounds are consistent with expectations from the ex-situ assays. The observed background rate after WIMP search criteria were applied was (6.3±0.5)×10−5 events/keVee/kg/day in the low-energy region, approximately 60 times lower than the equivalent rate reported by the LUX experiment.

Background Epidemiological evidence on the relationship between fish consumption and chronic obstructive pulmonary disease (COPD) is limited, especially among Chinese. Objectives To explore the prospective association between fish consumption and COPD among a large population-based Chinese cohort. Methods The China Kadoorie Biobank (CKB) recruited over 0.5 million participants from ten geographically diverse regions across China from 2004 to 2008. Consumption frequency of fish at baseline was assessed by a validated food frequency questionnaire. 169,188 men and 252,238 women who had no prior COPD and other major chronic diseases at baseline were included in our analyses. Cox proportional hazard models were employed to estimate the hazard ratio (HR) and 95% confidence interval (CI) for fish consumption categories in relation to incident COPD. Results During a median follow-up of 11.1 years, 5542 incident COPD cases were documented. Fish consumption was inversely associated with COPD risk among women, with a 17% reduction in risk for participants who consumed fish ≥4 days/week compared with non-consumption (HR: 0.83; 95% CI: 0.70, 0.99; p for trend = 0.017), whereas we did not observe such a dose-response relationship among men (HR: 0.89; 95% CI: 0.76, 1.05; p for trend = 0.373). The joint analysis showed that COPD risk was 38% and 48% lower in men and women who consumed fish ≥4 days/week and had a healthy lifestyle (having ≥4 of the following healthy lifestyle factors: not smoking currently, never or rarely drinking alcohol, adequate physical activity, BMI 18.5-23.9 kg/m2, normal waist circumference, reasonable diet), compared with participants with fish consumption

General background: Obesity (defined as body mass index [BMI] ‚Äöv¢‚Ä¢30 kg/m2) is an escalating global epidemic. Obesity poses significant health risks to the lives of affected people. Moreover, obesity imposes substantial economic burdens on individuals, healthcare payers and societies due to, for example, direct healthcare costs and numerous indirect costs including productivity losses. Among various types of surgical and non-surgical treatments, bariatric (metabolic or weight loss) surgery was found to be the most efficacious and the only long-lasting reliable option to severe and resistant obesity. Despite the clinical benefits of bariatric surgery being confirmed, the health economic impacts of bariatric surgery remain under-researched, particularly in Australia. Principal objectives: The overarching aim of this thesis was to investigate and generate health economic evidence for bariatric surgery, which could be used to populate future economic models. The specific aims of this thesis were to: 1) for the first time systematically summarize and meta-analyse the impact of bariatric surgery on utility-based quality of life (i.e., health state utilities [HSUs]) and explore the predictors of HSU changes; 2) systematically synthesise and for the first time meta-analyse all evidence regarding the economic value of bariatric surgery across the depth and breadth of the health economics literature; 3) for the first time investigate the scale, disaggregated profile, and determinants of healthcare costs associated with primary bariatric surgery within Tasmanian public health system; and 4) further investigate the critical care unit (CCU) utilisation after bariatric surgery and its relevant predictors within Tasmanian public health system; and finally 5) validate the economic impact of bariatric surgery compared with matched controls using a large population-based cohort in Australia. Methods & Main findings: To address these objectives, five papers were developed. The first paper (Chapter 3) presented a comprehensive systematic review with meta-analysis to investigate the impact of bariatric surgery on HSUs. The synthesised results suggested that HSUs increased (particularly one-year) after surgery. This study substantially overcomes the challenges associated with systematically selecting HSU data that could be used as more reliable inputs to future bariatric surgery-related cost-utility models. The second paper (Chapter 4) provided another comprehensive systematic review with meta-analysis to investigate the economic evidence of bariatric surgery. This study found that bariatric surgery is a cost-saving treatment for obesity over the life course, particularly when indirect costs were considered. Health economists therefore should consider a broad range of direct and indirect costs to evaluate the true economic impact of bariatric surgery. The third paper (Chapter 5) presented the first detailed characterisation of the scale, disaggregated profile, and determinants of bariatric-related costs, and examined the evolution of resource utilisation patterns and costs. This study complements previous exploratory findings with the disaggregated (micro-level) bariatric-related costs and their contributions over time, concluding that resource utilisation patterns and costs for bariatric are changing, which is as expected from the changing incidence of surgery type in Australia over time. Further, the micro-costing approach provides precise cost inputs that can be used in future health economic evaluations of bariatric surgery to facilitate decision making in alternative contextual settings. The fourth paper (Chapter 6) presented the first mixed-methods research to investigate CCU utilisation after bariatric surgery in Tasmanian publich healthcare system. In addition to the healthcare utilisation and cost data, this study has identified several predictors associated with planned and unplanned CCU admission. The identified risk factors could be used in the development of a risk tool or decision tree that would likely add a greater degree of precision to current clinical guidelines for allocating CCU resources for bariatric eligible patients in Australia. The fifth paper (Chapter 7) presented the first contemporary large population-based longitudinal cohort study to validate the economic impacts of bariatric surgery in an Australian population aged 45 year and over. By utilizing the linear mixed-effects model and the difference-in-differences approach to map the healthcare costs of 8 years before and 8 years after bariatric surgery, and considering an approximation of indirect costs, we found that the economic benefits of bariatric surgery increase when a longer horizon was considered, whilst cost-savings were not achieved during the study period even after the consideration of indirect costs in this middle-aged-to-elderly population sample. Future longer-term research is needed to validate our findings in younger population cohorts in Australia. Results of Chapters 4 to 7 also pointed out the strictly limited availability of bariatric surgery in Australian public healthcare system causing long wait times and other complications. This thesis highlights the need for appropriate strategies to eliminate restrictive and burdensome bariatric surgery-related preoperative requirements to relieve the prolonged wait time for bariatric surgery in public healthcare system to optimally tackle the obesity pandemic, especially in the post-COVID-19 world. Conclusions: In summary, the body of work presented in this thesis (which armed with a comprehensive structure of the statistical theories and methods) has substantially added to our understanding of the health economic impacts of bariatric surgery. Health-economic evidence is more robust for decision making process compared to the evidence solely based on clinical outcomes or economics research. The costs and HSU estimates generated from this thesis will contribute to the future bariatric surgery-related health economic evaluations. Our important recommendation for the healthcare policy makers is to devise appropriate strategies to relieve the long waitlist for bariatric surgery in public healthcare system.

A new search for two-neutrino double-beta ($2\nu\beta\beta$) decay of $^{136}\rm Xe$ to the $0^+_1$ excited state of $^{136}\rm Ba$ is performed with the full EXO-200 dataset. A deep learning-based convolutional neural network is used to discriminate signal from background events. Signal detection efficiency is increased relative to previous searches by EXO-200 by more than a factor of two. With the addition of the Phase II dataset taken with an upgraded detector, the median 90$\%$ confidence level half-life sensitivity of $2\nu\beta\beta$ decay to the $0^+_1$ state of $^{136}\rm Ba$ is $2.9 \times 10^{24}~\rm yr$ using a total $^{136}\rm Xe$ exposure of $234.1~\rm kg~yr$. No statistically significant evidence for $2\nu\beta\beta$ decay to the $0^+_1$ state is observed, leading to a lower limit of $T^{2\nu}_{1/2}(0^+ \rightarrow 0^+_1) > 1.4\times10^{24}~\rm yr$ at 90$\%$ confidence level, a factor of $1.7$ improvement over the current world's best constraint., Comment: 9 pages, 6 figures, 2 tables

Hao Yang,1,&ast; Qing Xia,2,&ast; Yan Shen,2 Ting-Li Chen,3 Jing Wang,3 Ya-Yun Lu2 1Department of Stomatology, Huadong Sanatorium, Wuxi, 214065, People’s Republic of China; 2Health Examination Center, Huadong Sanatorium, Wuxi, 214065, People’s Republic of China; 3Department of Ophthalmology, Huadong Sanatorium, Wuxi, 214065, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ya-Yun LuHealth Examination Center, Huadong Sanatorium, Wuxi, 214065, People’s Republic of China, Tel +86 13763384379, Email luyy28@163.comBackground: Hashimoto’s thyroiditis (HT) is recognized as the most common autoimmune thyroid disease, often accompanied by the diffuse enlargement of thyroid with abundant blood flow and elevated level of thyroid autoantibodies. As obesity had a positive association with the risk of HT. Thus, this retrospective study was established to further explore the gender relationship between metabolic obesity phenotypes and the risk of Hashimoto’s thyroiditis (HT).Materials and Methods: Data for 3697 subjects aged ≥ 18 years were randomly collected from a Health check-up database from April to December 2019. Obesity was defined by general obesity (GO; body mass index [BMI] ≥ 28 kg/m2) and abdominal obesity (AO; waist circumstance, male ≥ 90 cm, female ≥ 85 cm). Metabolic unhealthy was defined as having at least one metabolic syndrome component and a homeostasis model assessment of insulin resistance ≥ 2.5. Obesity phenotypes were divided into three groups: GO, AO, compound obesity (GO+AO). After adjustment for potential confounding factors, multivariate logistic regression was used to assess the association between metabolic obesity phenotypes and risk of HT by sex and explore the correlation between different obesity patterns and HT risk by metabolic health status.Results: The incidence of HT was 23.5% and significantly higher among females than males with different metabolic phenotypes (26.2% vs 20.5%, p< 0.05), except metabolically healthy AO. Compared with non-obese subjects, different metabolic obesity phenotypes were independent risk factors among males (p< 0.05). Among females, unhealthy metabolic status with GO (adjusted odds ratio [OR]=2.62) or AO (adjusted OR=2.87) and metabolically healthy non-GO (adjusted OR=2.05) were risk factors of HT (p< 0.05). Increasing BMI categories and waist circumstance quartiles were positively correlated with HT risk (p for trend < 0.05). Subgroup analyses indicated that GO+AO (adjusted OR=2.52) or only AO (adjusted OR=2.41) were risk factors for HT for those with unhealthy metabolic status. Moreover, GO+AO (adjusted OR=2.37) was an independent risk factor for HT under healthy metabolic status.Conclusion: GO+AO was associated with an increased risk of HT, identifying higher BMI/WC as a significant risk factor for HT. Males with unhealthy metabolic state or obesity and metabolically unhealthy females with obesity are high-risk group for HT. Additionally, only AO and GO+AO conferred increased risk of HT for individuals with metabolic abnormalities.Keywords: Hashimoto’s thyroiditis, metabolic obesity phenotypes, general obesity, abdominal obesity, retrospective data

Ni Zeng,1,2 Liwen Ma,3 Yuxin Cheng,1 Qingyue Xia,1 Yueyue Li,1 Yihe Chen,1 Zhiyu Lu,1 Qian Lu,1 Feng Jiang,4 Dan Luo1 1Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, People’s Republic of China; 2Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 3Department of Dermatology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210000, People’s Republic of China; 4Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, People’s Republic of ChinaCorrespondence: Dan LuoDepartment of Dermatology, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Road, Nanjing, 210000, People’s Republic of ChinaEmail daniluo2005@163.comFeng JiangDepartment of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, 200011, People’s Republic of ChinaEmail dxyjiang@163.comObjective: In this research, we studied the genes associated with ferroptosis to develop a prognostic model and find out an association with tumor immune microenvironment in skin cutaneous melanoma (SKCM) patients.Methods: To find SKCM-related ferroptosis genes, we used Cox regression and LASSO approach on 60 genes related to ferroptosis and SKCM-related RNA-seq. Following that, a ferroptosis-related gene signature was created. Time-dependent ROC curve and Kaplan–Meier analysis were calculated to determine its capability of prediction. Besides, several assessments were used to evaluate overall survival (OS), accompanied by the creation of a nomogram for the clinicopathologic factors and the ferroptosis-related gene signature we established. We also investigated the relationship between ferroptosis-related gene signature with three immune checkpoints and immune cell infiltration.Results: Our prognostic model included two genes (ALOX5, CHAC1). In both TCGA and GEO cohorts, OS was lower in high-risk category. Using our gene signature, we can reliably predict OS. Additionally, our gene signature can predict immune cell infiltration and SKCM immunotherapy response.Conclusion: Our gene signature has shown to be a reliable predictor of OS, reflect the immune microenvironment, and predict the effectiveness of immunotherapy for SKCM patients.Keywords: skin cutaneous melanoma, SKCM, ferroptosis, immune microenvironment, immune checkpoint

The LUX-ZEPLIN experiment recently reported limits on WIMP-nucleus interactions from its initial science run, down to $9.2\times10^{-48}$ cm$^2$ for the spin-independent interaction of a 36 GeV/c$^2$ WIMP at 90% confidence level. In this paper, we present a comprehensive analysis of the backgrounds important for this result and for other upcoming physics analyses, including neutrinoless double-beta decay searches and effective field theory interpretations of LUX-ZEPLIN data. We confirm that the in-situ determinations of bulk and fixed radioactive backgrounds are consistent with expectations from the ex-situ assays. The observed background rate after WIMP search criteria were applied was $(6.3\pm0.5)\times10^{-5}$ events/keV$_{ee}$/kg/day in the low-energy region, approximately 60 times lower than the equivalent rate reported by the LUX experiment., 25 pages, 15 figures

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for Weakly Interacting Massive Particles (WIMPs), while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector., 77 pages, 40 figures, 1262 references

Background Burkholderia pseudomallei is a tropical pathogen that causes melioidosis. Its intrinsic drug-resistance is a leading cause of treatment failure, and the few available antibiotics require prolonged use to be effective. This study aimed to assess the clinical potential of B. pseudomallei phages isolated from Hainan, China. Methods Burkholderia pseudomallei strain (HNBP001) was used as the isolation host, and phages were recovered from domestic environmental sources, which were submitted to the host range determination, lytic property assays, and stability tests. The best candidate was examined via the transmission electron microscope for classification. With its genome sequenced and analyzed, its protective efficacy against B. pseudomallei infection in A549 cells and Caenorhabditis elegans was evaluated, in which cell viability and survival rates were compared using the one-way ANOVA method and the log-rank test. Results A phage able to lyse 24/25 clinical isolates was recovered. It was classified in the Podoviridae family and was found to be amenable to propagation. Under the optimal multiplicity of infection (MOI) of 0.1, an eclipse period of around 20 min and a high titer (1012 PFU/ml) produced within 1 h were demonstrated. This phage was found stabile at a wide range of temperatures (24, 37, 40, 50, and 60 °C) and pH values (3–12). After being designated as vB_BpP_HN01, it was fully sequenced, and the 71,398 bp linear genome, containing 93 open reading frames and a tRNA-Asn, displayed a low sequence similarity with known viruses. Additionally, protective effects of applications of vB_BpP_HN01 (MOI = 0.1 and MOI = 1) alone or in combination with antibiotics were found to improve viability of infected cells (70.6 ± 6.8%, 85.8 ± 5.7%, 91.9 ± 1.8%, and 96.8 ± 1.8%, respectively). A significantly reduced mortality (10%) and a decreased pathogen load were demonstrated in infected C. elegans following the addition of this phage. Conclusions As the first B. pseudomallei phage was isolated in Hainan, China, phage vB_BpP_HN01 was characterized by promising lytic property, stability, and efficiency of bacterial elimination during the in vitro/vivo experiments. Therefore, we can conclude that it is a potential alternative agent for combating melioidosis. Graphical Abstract

This research project benefitted from Ministry of Education (Singapore) Tier 1 Grant R-313-000-131-115 (to A. Delios), National Science Foundation of China Grants 72002158 (to H.T.) and 71810107002 (to H.T.), grants from the Knut and Alice Wallenberg Foundation (to A. Dreber) and the Marianne and Marcus Wallenberg Foundation (through a Wallenberg Scholar grant; to A. Dreber), Austrian Science Fund (FWF) Grant SFB F63 (to A. Dreber), grants from the Jan Wallander and Tom Hedelius Foundation (Svenska Handelsbankens Forskningsstiftelser; to A. Dreber), and an Research & Development (R&D) research grant from Institut Européen d'Administration des Affaires (INSEAD) (to E.L.U.). Dmitrii Dubrov, of the G.T.F.C., was supported by the National Research University Higher School of Economics (HSE University) Basic Research Program. This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability—for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples. Publisher PDF

Ke Rong,1 Xiaoliu Li,2 Weimin Jiang,1 Xuhua Wu,1 Qingquan Xia,2 Jie Chen,1 Xiaofan Yin2 1Department of Orthopedics, The First Affiliated Hospital of Soochow University, Soochow, 215006, People’s Republic of China; 2Department of Orthopedics, Minhang Hospital, Fudan University, Shanghai, 201199, People’s Republic of ChinaCorrespondence: Weimin JiangDepartment of Orthopedics, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Soochow, 215006, People’s Republic of ChinaTel +86-512-65223637Email min_jw@21cn.comBackground: Osteonecrosis of the femoral head (ONFH) seriously affects the quality of life and labor ability of patients. It is urgent and vital to find the methods for necrosis clinical treatment.Objective: This study aims to study the potential protective effects of Alendronate in the early stage of femur head necrosis.Methods: Ten clinal ONFH tissue samples were employed. H&E staining was employed for the observation of the pathological characteristics of ONFH. The rat model (n=12) was established by the treatment of liquid nitrogen and then treated with Alendronate. The protein expression of BMP2, EIF2AK3, EIF2A and ATF4 were detected via Western blotting and IHC.Results: Fibrin and necrotizing granulation tissue were observed in ONFH tissues with lymphocytes and plasma cells infiltrating in the necrotic area, exhibiting the inflammatory muscle with abnormal shape and color. In the Model group, the BMP2 and ATF4 were mainly distributed in the cell boundaries. The relative protein expression of BMP2, EIF2AK3, EIF2A, ATF4 was decreased in the Model group, compared to the NC group, which was partially recovered by the Alendronate application.Conclusion: Alendronate application partially reversed the suppression of expression of BMP2, EIF2AK3, EIF2A, ATF4 caused by liquid nitrogen. Alendronate could be a promising strategy of curing ONFH via targeting BMP2/EIF2AK3/EIF2A/ATF4 pathway.Keywords: femoral head necrosis, alendronate, BMP2, ATF4

We estimate the amount of Ar37 produced in natural xenon via cosmic-ray-induced spallation, an inevitable consequence of the transportation and storage of xenon on the Earth’s surface. We then calculate the resulting Ar37 concentration in a 10-tonne payload (similar to that of the LUX-ZEPLIN experiment) assuming a representative schedule of xenon purification, storage, and delivery to the underground facility. Using the spallation model by Silberberg and Tsao, the sea-level production rate of Ar37 in natural xenon is estimated to be 0.024 atoms/kg/day. Assuming the xenon is successively purified to remove radioactive contaminants in 1-tonne batches at a rate of 1 tonne/month, the average Ar37 activity after 10 tons are purified and transported underground is 0.058−0.090 μBq/kg, depending on the degree of argon removal during above-ground purification. Such cosmogenic Ar37 will appear as a noticeable background in the early science data, while decaying with a 35-day half-life. This newly noticed production mechanism of Ar37 should be considered when planning for future liquid-xenon-based experiments.

Xiangtian Ling,1 Xinqi Ma,1 Xielan Kuang,1 Yuxiu Zou,1 Han Zhang,1 Han Tang,1 Han Du,1 Binbin Zhu,1 Hao Huang,1 Qing Xia,1 Minghao Chen,1 Danyi Mao,1 Dongli Chen,1 Huangxuan Shen,1,2 Jianhua Yan1 1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, People’s Republic of China; 2Biobank of Eye, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, People’s Republic of ChinaCorrespondence: Huangxuan Shen; Jianhua YanZhongshan Ophthalmic Center, Sun Yat-Sen University, 54 Xianlie Road, Guangzhou, 510060, People’s Republic of ChinaTel +8620-8733-5261; +8620-8733-0484Fax +8620-8733-3271Email shenhx@mail.sysu.edu.cn; yanjh2011@126.comPurpose: To assess the cellular and molecular effects of lidocaine on muscles/myoblasts.Methods: Cultured myogenic precursor (C2C12) cells were treated with varying concentrations of lidocaine.Results: Cell viability of C2C12 cells was inhibited by lidocaine in a concentration-dependent manner, with concentrations ≥ 0.08%, producing a dramatic reduction in cell viability. These ≥ 0.08% concentrations of lidocaine arrested cell cycles of C2C12 cells in the G0/G1 phase. Moreover, lidocaine inhibited cell migration and myogenic processes in C2C12 cells at low concentrations. Results from QRT-PCR assays revealed that following treatment with lidocaine, Notch1, Notch2, Hes1, Csl and Dll4 all showed higher levels of expression, while no changes were observed in Mmal1, Hey1, Dll1 and Jag1.Conclusion: This work provides the first description of the effects of lidocaine upon the regeneration of muscles and maintenance of satellite cells at the cellular and molecular levels. In specific, we found that the Dll4-Notch-Csl-Hes1 axis was up-regulated suggesting that the Notch signaling pathway was involved in producing these effects of lidocaine. These findings provide a new and important foundation for future investigations into the effects of drug therapies in muscle diseases.Keywords: local anesthetics, C2C12 cells, myogenic differentiation, strabismus, Notch signaling pathway

Yang Liu,1,2,* Jun Liang,2,* Qingrong Xia,2 Xin Zhou,1 Xuefeng Xie1 1Department of Basic and Clinical Pharmacology, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui, People’s Republic of China; 2Department of Pharmacy, Hefei Fourth People’s Hospital, Hefei 230000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xuefeng XieDepartment of Basic and Clinical Pharmacology, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui, People’s Republic of ChinaTel/Fax +86 551 65172137Email xiexuefeng@ahmu.edu.cnObjective: To explore the therapeutic effects of lithium combined with second-generation antipsychotics (SGAs) of quetiapine, clozapine, olanzapine, and risperidone for the treatment of manic episodes in patients with bipolar disorder (BD) to guide the selection of medications.Methods: We examined the case data of patients with BD who experienced manic episodes and were hospitalized in a Class 3A Psychiatric Hospital in Anhui Province from January 2015 to October 2019. The enrolled patients were rated using the Bech–Rafaelsen Mania Rating Scale (BRMS) before and after treatment, and relevant adverse effects were monitored.Results: Analysis of the collected case data of 182 patients showed significant differences in the BRMS scores on admission and at discharge of patients treated with lithium combined with each SGA. The chi-square test showed no obvious difference in the final therapeutic effects of lithium combined with each of the four SGAs (χ2 = 7.365, P = 0.146). However, there were differences in the incidence of adverse effects (χ2 = 10.604, P = 0.014) and remission rate after 2 weeks of treatment (χ2 = 10.174, P = 0.017). Logistic regression analysis revealed that the incidence of adverse effects was related to the length of stay in hospital and clozapine treatment. The remission rate after 2 weeks was associated with the length of stay in hospital, clozapine treatment, and age of onset.Conclusion: Lithium combined with SGAs (quetiapine, clozapine, olanzapine, and risperidone) effectively improves the manic symptoms of patients with BD who experience manic episodes. Lithium combined with quetiapine for the treatment of bipolar manic episode has advantages with respect to the speed of effective and incidence of adverse effects.Keywords: bipolar mania, atypical antipsychotic, mood stabilizers, remission rate

Ying Liu,1,* Xiaojie Li,1,* Shuwen Xiao,1 Xinyi Liu,1 Xuanming Chen,1 Qiyue Xia,1 Song Lei,2 Hongxia Li,1 Zhihui Zhong,3 Kai Xiao1 1National Chengdu Center for Safety Evaluation of Drugs and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2Department of Pathology, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 3Laboratory of Non-Human Primate Disease Model Research, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kai Xiao Tel +86-28-83326313Email xiaokaikaixiao@scu.edu.cnBackground: Gold nanoparticles (AuNPs) have shown great promise in various biomedical applications, but their effects on male reproductive function remain to be ascertained. The aim of this study was to investigate the uptake, cytotoxicity and testosterone production inhibition of AuNPs in mouse Leydig cells, as well as their accumulation in the testes of male mice and their effects on male reproductive function.Results: AuNPs (5 nm) were able to be internalized into the endosomes/lysosomes of TM3 Leydig cells, induce the formation of autophagosomes, increase the production of reactive oxygen species (ROS), and disrupt the cell cycle in S phase, resulting in concentration-dependent cytotoxicity and DNA damage. Interestingly, AuNPs significantly reduced testosterone production in TM3 cells by inhibiting the expression of 17α-hydroxylase, an important enzyme in androgen synthesis. After repeated intravenous injection, AuNPs gradually accumulated and retained in the testes of male BALB/c mice in a dose-dependent manner. One week after withdrawal, the level of plasma testosterone in the 0.5 mg/kg AuNPs group was significantly reduced compared to that in the PBS control group, accompanied by the decreased expression of 17α-hydroxylase in the testes. In addition, AuNPs treatment significantly increased the rate of epididymal sperm malformation, but without affecting fertility.Conclusion: Our results suggest that AuNPs can accumulate in the testes and reduce testosterone production in Leydig cells by down-regulating the expression of 17α-hydroxylase, thus affecting the quality of epididymal sperm.Keywords: gold nanoparticles, Leydig cells, testosterone, reproductive toxicity, fertility

We estimate the amount of 37 Ar produced in natural xenon via cosmic-ray-induced spallation, an inevitable consequence of the transportation and storage of xenon on the Earth’s surface. We then calculate the resulting 37 Ar concentration in a 10-tonne payload (similar to that of the LUX-ZEPLIN experiment) assuming a representative schedule of xenon purification, storage, and delivery to the underground facility. Using the spallation model by Silberberg and Tsao, the sea-level production rate of 37 Ar in natural xenon is estimated to be 0.024 atoms / kg / day . Assuming the xenon is successively purified to remove radioactive contaminants in 1-tonne batches at a rate of 1 tonne / month , the average 37 Ar activity after 10 tons are purified and transported underground is 0.058 − 0.090 μ Bq / kg , depending on the degree of argon removal during above-ground purification. Such cosmogenic 37 Ar will appear as a noticeable background in the early science data, while decaying with a 35-day half-life. This newly noticed production mechanism of 37 Ar should be considered when planning for future liquid-xenon-based experiments.

Sodium-ion batteries (NIBs) are considered a complementary or even an alternative energy storage technology to lithium-ion batteries (LIBs). Current technological development of NIBs is hindered by fundamental challenges, such as sluggish charge transport kinetics, short cycling lifespan, and low energy density. Electrode materials hold the key to any success in commercialising NIBs. While the past decade has witnessed rapid advances in design and synthesis of various electrode materials with different structures and microcosmic morphologies, there are still critical issues associated with electrode materials, especially anode materials, that need to be addressed before the NIB technology becomes commercially viable. For battery electrode materials, their surface properties play a critical role in determining cell performance. As a forefront of an electrode material where Na ion storage and charge transfer initiate, the electrode surface has a fundamental influence on the charge storage properties of the electrode. In this article, we review recent research progress towards modification/functionalisation of the surface structure of NIB anode materials for improving charge transport kinetics, charge storage capacity, and cycling durability. We aim to provide a concise summary of strategies for surface engineering, along with an insightful analysis of the critical role of the surface structure of NIB anode materials in determining their electrochemical performance. This journal is

We have built and operated a crystalline/vapor xenon TPC, with the goal of improving searches for dark matter. The motivation for this instrument is the fact that beta decays from the radon decay chain to the ground state presently limit the state-of-the-art liquid/vapor xenon experiments. In contrast, a crystalline xenon target has the potential to exclude, or tag and reject radon-chain backgrounds. As a preamble to demonstrating such capabilities, the present article makes a first demonstration of the operation of a crystalline/vapor xenon TPC with electroluminescence (gas gain) for the electron signal readout. It also shows that the scintillation yield in crystalline xenon appears to be identical to that in liquid xenon, in contrast to previous results.

We present a search for electron-recoil signatures from the charged-current absorption of fermionic dark matter using the EXO-200 detector. We report an average electron recoil background rate of $6.8 \times 10^{-4}\, \mathrm{cts}\,\mathrm{kg}^{-1}\mathrm{yr}^{-1}\mathrm{keV}^{-1}$ above $4\,\mathrm{MeV}$ and find no statistically significant excess over our background projection. Using a total ${}^{136}\mathrm{Xe}$ exposure of $234.1\,\mathrm{kg}\,\mathrm{yr}$ we exclude new parameter space for the charged-current absorption cross-section for dark matter masses between $m_\chi = 2.6\,\mathrm{MeV} - 11.6\,\mathrm{MeV}$ with a minimum of $6\times 10^{-51}\,\mathrm{cm}^2$ at $8.3\,\mathrm{MeV}$ at the $90\%$ confidence level., Comment: 9 pages, 6 figures, 1 table

The Early Cretaceous Jehol Biota evolution has remarkable spatiotemporal correlation with the destruction of the North China craton though the coupling mechanism remains enigmatic. The craton destruction was accompanied by intense magmatic activity and the released volatiles and nutrients might have had climatic and environmental impacts on the biotic evolution. In this study, we investigated the mentioned hypothetical causal link by determining concentrations and total emissions of volatile elements (S, F, Cl) and bulk-rock P contents of volcanic rocks that were erupted during the pre-flourishing, flourishing and post-flourishing stages of the Jehol Biota. Our results show that the volcanism near the flourishing stage has lower S (1,083–2,370 ppm), Cl (1,277–5,608 ppm) and higher P₂O₅ contents (0.48–0.84 wt.%) than that in the non-flourishing stages with S of 1,991–3,288 ppm, Cl of 7,915–12,315 ppm and P₂O₅ of 0.17–0.23 wt.%. Fluorine contents in the three stages vary from 893 to 3,746 ppm. The total volatile emissions are minor in the flourishing stage (1–14 Gt S, 0.6–10 Gt Cl, 0.6–9 Gt F) but elevated in the non-flourishing stages (2–766 Gt S, 4–1,168 Gt Cl, 1–175 Gt F). Our data suggest that regional climatic and environmental impacts of volcanism in the non-flourishing stages probably hindered the species diversification. The high P flux released from lithospheric mantle-derived lavas during the peak time of craton destruction might have enhanced primary productivity and contributed to the flourishing of the Jehol Biota. Our study provides insights into the relationship between the biosphere and deep geodynamic processes driven by volcanism.

Initiation of large igneous provinces (LIPs) and temporal and spatial variations in their chemical compositions provide unique opportunities to understand mantle dynamics. It has been recently revealed that water-rich reservoirs in the mantle sources have played a significant role in the production of LIPs. However, the dominant causes for the chemical variations in primitive magmas of LIPs remain debated. In the Emeishan LIP (ELIP), there are several places where picrites accompany more abundant flood basalts. These picrites span a large range of Ti/Y, Sm/Yb, and TiO₂/Al₂O₃. In this work, we have determined the water contents of picrites with Ti/Y > 500 from the ELIP, based on the water content of clinopyroxene phenocrysts and water partitioning coefficients. We have also calculated the water content of the mantle sources by applying batch and fractional partial melting models. We show that the chemical compositions of picrites in the ELIP closely correlate with the calculated water content in their mantle sources. Our model suggests that the variation in the chemical composition of the primary magmas of the ELIP both on a local and regional scale can be mainly explained by the complementary roles of relatively dry recycled pyroxenite and hydrated components in the mantle plume, without requiring catastrophic thinning of the lithospheric mantle. Our model thus implies that both the initiation and chemical variation of the ELIP are affected by water from the deep mantle.

Tengteng Wang, Qinghua Xia, Xiude Chen, Xunbo Jin Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Xiude ChenDepartment of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250014, People’s Republic of ChinaTel +86 15168863866Email scistone_2019@163.comBackground and Aim: Baidu, currently the top online search tool in China, has developed an internet search trends gathering and analysis tool called the Baidu Index. The aim of this study was to explore the value of the Baidu Index for monitoring online kidney stones-related information-seeking behavior and understanding of population features and priorities in China.Materials and Methods: The Baidu Index was queried using the term “kidney stones” for the period 2014– 2018. The search volume was recorded as well as a demand graph, with a geographic and demographic distribution. For surgical treatment modalities, the medical term “extracorporeal shock wave lithotripsy (ESWL)” was analyzed and then compared to the term “kidney stone surgery” to assess changes.Results: The search trend for the term “kidney stones” remained sustained growth over time. Searches were mostly presented by the age 20– 49, in males in the south of China. The demand graph indicated that the diagnosis, followed by the treatment, and dietary control of kidney stones had received the most attention. The search volume related to ESWL showed a similar increasing trend, but was searched with a greater volume than the term “kidney stone surgery” for most of the last 5 years.Conclusion: The Baidu Index is a useful tool to track online health information-seeking behavior of internet users in China. The geographic and demographic characteristics in kidney stones seem to be reflected in online search trend data to some extent.Keywords: search engine, Baidu Index, kidney stones, kidney stone surgery, extracorporeal shock wave lithotripsy

Xi Cao,1,2 Tingfei Tan,1,2 Dongchun Zhu,1,2 Haixia Yu,1,2 Yaru Liu,1,2 Haiyun Zhou,1,2 Yong Jin,3,4 Quan Xia1,2 1Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, People’s Republic of China; 3Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, Hefei, People’s Republic of China; 4The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Quan Xia Tel +86 551 62922154Email xiaquan2010@163.comBackground: Melanoma is the most common symptom ofaggressive skin cancer, and it has become a serious health concern worldwide in recent years. The metastasis rate of malignant melanoma remains high, and it is highly difficult to cure with the currently available treatment options. Effective yet safe therapeutic options are still lacking. Alternative treatment options are in great demand to improve the therapeutic outcome against advanced melanoma. This study aimed to develop albumin nanoparticles (ANPs) coated with macrophage plasma membranes (RANPs) loaded with paclitaxel (PTX) to achieve targeted therapy against malignant melanoma.Methods: Membrane derivations were achieved by using a combination of hypotonic lysis, mechanical membrane fragmentation, and differential centrifugation to empty the harvested cells of their intracellular contents. The collected membrane was then physically extruded through a 400 nm porous polycarbonate membrane to form macrophage cell membrane vesicles. Albumin nanoparticles were prepared through a well-studied nanoprecipitation process. At last, the two components were then coextruded through a 200 nm porous polycarbonate membrane.Results: Using paclitaxel as the model drug, PTX-loaded RANPs displayed significantly enhanced cytotoxicity and apoptosis rates compared to albumin nanoparticles without membrane coating in the murine melanoma cell line B16F10. RANPs also exhibited significantly higher internalization efficiency in B16F10 cells than albumin nanoparticles without a membrane coating. Next, a B16F10 tumor xenograft mouse model was established to explore the biodistribution profiles of RANPs, which showed prolonged blood circulation and selective accumulation at the tumor site. PTX-loaded RANPs also demonstrated greatly improved antitumor efficacy in B16F10 tumor-bearing mouse xenografts.Conclusion: Albumin-based nanoscale delivery systems coated with macrophage plasma membranes offer a highly promising approach to achieve tumor-targeted therapy following systemic administration.Keywords: macrophage membrane, albumin nanoparticles, melanoma, paclitaxel, tumor-targeted therapy

Qian-qian Chen,1–3 Jia-min Shi,1,2 Zhou Ding,1,2 Qing Xia,1,2 Tian-sheng Zheng,1,2 Yan-bei Ren,1,2 Ming Li,1,2 Li-hong Fan1,2 1Department of Respiratory Medicine, Shanghai 10th People’s Hospital, Tongji University, Shanghai 200072, People’s Republic of China; 2Institute of Energy Metabolism and Health, Tongji University School of Medicine, Shanghai 200072, People’s Republic of China; 3Medical School of Nantong University, Nantong, Jiangsu 22601, People’s Republic of ChinaCorrespondence: Li-hong Fan; Ming LiDepartment of Respiratory Medicine, Shanghai 10th People’s Hospital, Tongji University, #301 Mid Yianchang Road, Shanghai 200072, People’s Republic of ChinaTel/fax +86 1 800 176 3288; +86 1 339 135 8760Email 18260626371@163.com; mlid163@163.comBackground: Berberine (BBR) from the widely used Chinese herbal medicine Huanglian has an array of pharmacological and biochemical properties, including anti-neoplastic activity. However, the specific mechanisms underlying these properties are unknown. The aim of this study was to explore the anti-tumor mechanisms of BBR in non-small cell lung cancer (NSCLC).Methods: The effects of BBR on NSCLC tumor development and programmed cell death were investigated both in vivo and in vitro. Luciferase reporter assays were used to determine whether tissue factor (TF) was a target of miR-19a.Results: BBR suppressed NSCLC growth and promoted apoptosis in NSCLC cells by modulating miR-19a and TF expression. Luciferase assays showed that TF was a direct inhibitory target of miR-19a in NSCLC cells. BBR induced apoptosis through the miR-19a/TF/MAPK axis.Conclusion: The results suggest that BBR induces apoptosis of NSCLC cells via the miR-19a/TF/MAPK signaling pathway.Keywords: non-small-cell lung carcinoma, NSCLC, berberine, miR-19a, tissue factor, TF, MAPK

Guiding neuronal cell growth is desirable for neural tissue engineering but is very challenging. In this work, a self-assembling ultra-short surfactant-like peptide I3K which possesses positively charged lysine head groups, and hydrophobic isoleucine tails, was chosen to investigate its potential for guiding neuronal cell growth. The peptides were able to self-assemble into nanofibrous structures and interact strongly with silk fibroin (SF) scaffolds, providing a niche for neural cell attachment and proliferation. SF is an excellent biomaterial for tissue engineering. However neuronal cells, such as rat PC12 cells, showed poor attachment on pure regenerated SF (RSF) scaffold surfaces. Patterning of I3K peptide nanofibers on RSF surfaces significantly improved cellular attachment, cellular density, as well as morphology of PC12 cells. The live / dead assay confirmed that RSF and I3K have negligible cytotoxicity against PC12 cells. Atomic force microscopy (AFM) was used to image the topography and neurite formation of PC12 cells, where results revealed that self-assembled I3K nanofibers can support the formation of PC12 cell neurites. Immunolabelling also demonstrated that coating of I3K nanofibers onto the RSF surfaces not only increased the percentage of cells bearing neurites but also increased the average maximum neurite length. Therefore, the peptide I3K could be used as an alternative to poly-l-lysine for cell culture and tissue engineering applications. As micro-patterning of neural cells to guide neurite growth is important for developing nerve tissue engineering scaffolds, inkjet printing was used to pattern self-assembled I3K peptide nanofibers on RSF surfaces for directional control of PC12 cell growth. The results demonstrated that inkjet-printed peptide micro-patterns can effectively guide the cell alignment and organization on RSF scaffold surfaces, providing great potential for nerve regeneration applications.

Hepatocellular carcinoma (HCC) patients suffer from few treatment options and poor survival rates. Here we report that endonuclease VIII-like protein 3 (NEIL3) is overexpressed in HCC and correlates with poor survival. All six HCC cell lines investigated were dependent on NEIL3 catalytic activity for survival and prevention of senescence, while NEIL3 was dispensable for non-transformed cells. NEIL3-depleted HCC cell lines accumulated oxidative DNA lesions specifically at telomeres, resulting in telomere dysfunctional foci and 53BP1 foci formation. Following oxidative DNA damage during mitosis, NEIL3 relocated to telomeres and recruited apurinic endonuclease 1 (APE1), indicating activation of base excision repair. META-FISH revealed that NEIL3, but not NEIL1 or NEIL2, is required to initiate APE1 and Polβ-dependent base excision repair at oxidized telomeres. Repeated exposure of NEIL3-depleted cells to oxidizing damage induced chromatin bridges and damaged telomeres. These results demonstrate a novel function for NEIL3 in repair of oxidative DNA damage at telomeres in mitosis, which is important to prevent senescence of HCC cells. Furthermore, these data suggest that NEIL3 could be a target for therapeutic intervention for HCC.

Purposes: The purposes of this study were to use noninvasive Left ventricular pressure-strain loops (LV-PSLs) to compare the various myocardial work indices in patients with noninvasive hypertrophic cardiomyopathy (NHCM) and to evaluate the clinical application of myocardial work to the evaluation of NHCM patients.Method: 80 NHCM patients and 45 healthy subjects were enrolled. All the selectors underwent Echocardiography examination. Dynamic images of standard apical three-chamber, four-chamber, and two-chamber view were collected, the myocardial work indices of left ventricle were measured by LV-PSLs. The difference in myocardial work indices between two groups and various myocardial work indices in different types of hypertrophic cardiomyopathy were compared.Results: There were no significant difference in the general clinical data between the NHCM group and control; myocardial work indices of HCM were lower compared with control group except global work waste (GWW); The myocardial work between all three types of NHCMs was also different, particularly in global construction work (GCW); the intra- and inter observer consistency of myocardial work indices were good.Conclusion: Myocardial work assessed by the LV-PSLs could reflect myocardial work in NHCM patients at the early stage and quantitatively assess regional and global myocardial function, providing an accurate and convenient imaging method for early detection of the subclinical status of NHCM patients.

As the importance of gut microbiota in health is increasingly recognized, the interest in interventions that can modulate the microbiota and its interactions with its host has soared. The survival status of the probiotics in the gastrointestinal environment and the microbial interactions between the LAB have also received considerable attention. In the present research, the gastrointestinal environment tolerance, adhesion ability, and biofilm formation of the lactobacillus strains in the co-culture system were explored, through the real-time fluorescence-based quantitative PCR, UPLC-MS/MS metabolic profiling analysis and Live/Dead® BacLight™ cell staining methods. The results show that the co-culture system can promote the release of signal molecules and can effectively protect the liability of the Lactobacillus acidophilus in the gastrointestinal environment. Meanwhile, amino acid-derived quorum sensing molecule L-alanine (1 %) can effectively enhance the communication of the cells in the complex fermentation model, which leads to the increase of the liability of the L. acidophilus in the gastrointestinal environment.ImportanceThe findings of this study provide a clue to the amino acid-derived metabolites in the communication among cells in the GIT environment, which can enhance the communication of the lactobacillus strains in the complex fermentation model. Meanwhile, the liability of Lactobacillus acidophilus could be enhanced in the co-culture system during the gastrointestinal environment stress with the amino acid-derived quorum sensing (QS) components, and it will shed some light to the application of the amino acid-derived QS molecules in the fermentation stater industry.

Qiyue Xia,1,2,* Jinxing Huang,1,* Qiyi Feng,1 Xuanming Chen,1 Xinyi Liu,1 Xiaojie Li,1 Ting Zhang,3 Shuwen Xiao,1 Hongxia Li,1 Zhihui Zhong,3,4 Kai Xiao1,41National Chengdu Center for Safety Evaluation of Drugs and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan Province, China; 2Toxicology Department, Sichuan Center for Disease Control and Prevention, Chengdu, Sichuan Province, China; 3Laboratory of Nonhuman Primate Disease Modeling Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; 4Sichuan Kangcheng Biotech Co., Ltd, Chengdu, Sichuan Province, ChinaCorrespondence: Kai XiaoNational Chengdu Center for Safety Evaluation of Drugs and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, 28 Gaopeng Ave, High-Tech Development Zone, Chengdu 610041, Sichuan Province, People’s Republic of ChinaTel +86 288 332 6313Fax +86 288 517 3043Email xiaokaikaixiao@scu.edu.cn*These authors contributed equally to this workBackground: Gold nanoparticles (AuNPs) have shown great promise in biomedical applications. However, the interaction of AuNPs with biological systems, its underlying mechanisms and influencing factors need to be further elucidated.Purpose: The aim of this study was to systematically investigate the effects of particle size on the uptake and cytotoxicity of AuNPs in normal cells and cancer cells as well as their biological distribution in vivo.Results: Our data demonstrated that the uptake of AuNPs increased in HepG2 cancer cells but decreased in L02 normal cells, with the increase of particle size (5-50 nm). In both cancer cells and normal cells, small (5 nm) AuNPs exhibited greater cytotoxicity than large ones (20 and 50 nm). Interestingly, 5 nm AuNPs induced both apoptosis and necrosis in HepG2 cells through the production of reactive oxygen species (ROS) and the activation of pro-caspase3, whereas it mainly induced necrosis in L02 cells through the overexpression of TLR2 and the release of IL-6 and IL-1a cytokines. Among them, 50 nm AuNPs showed the longest blood circulation and highest distribution in liver and spleen, and the treatment of 5 nm AuNPs but not 20 nm and 50 nm AuNPs resulted in the increase of neutrophils and slight hepatotoxicity in mice.Conclusion: Our results indicate that the particle size of AuNPs and target cell type are critical determinants of cellular uptake, cytotoxicity and underlying mechanisms, and biological distribution in vivo, which deserves careful consideration in the future biomedical applications.Keywords: gold nanoparticles, particle size, uptake, toxicity, biodistribution

Yuhuan Yang,1,* Shuna Yao,1,* Jiuyang Zhang,1 Zheng Yan,1 Junfeng Chu,1 Haiying Wang,1 Zhihua Yao,1 Fan Zhang,2 Qingxin Xia,3 Yanyan Liu11Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Department of Central Laboratory, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Pathology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Yanyan LiuDepartment of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, 127 Dong Ming Road, Zhengzhou, Henan 450008, People’s Republic of ChinaEmail yyliu@zzu.edu.cnQingxin XiaDepartment of Pathology, Affiliated Cancer Hospital of Zhengzhou University, 127 Dong Ming Road, Zhengzhou, Henan 450008, People’s Republic of ChinaEmail 13838173710@139.com*These authors contributed equally to this workAbstract: Early T-cell precursor (ETP) leukemia represents a new subtype of T-lymphoblastic leukemia/lymphoma with unique immunophenotypes expressing T-cell and one or more of the myeloid/stem cell markers. Here, we report a young patient who had primary mediastinal mass and pleural effusion without bone marrow involvement. A CT-guided mediastinal biopsy and flow cytometry analysis of the pleural effusion revealed the blast cells to have complicated immunophenotypes: strongly expressed T-cell antigen CD7, myeloid-lineage antigens CD33 and CD13 and stem cell markers cTdT, CD34, and HLA-DR; dimly expressed myeloid-lineage specific antigen cMPO and B-cell antigen cCD79a; but did not express T-cell specific antigen cytoplasmic CD3 and B-cell specific antigen CD19. Clonal T-cell receptor rearrangement eventually determined the cell of origin from ETPs, not myeloblasts. The patient showed primary resistance to lymphoid and myeloid-directed induction therapy. Finally, low-dose decitabine combined with modified-CAG regimen induced a complete remission and allogeneic stem cell transplantation was performed as consolidation. The case indicates a primary mediastinal neoplasm from ETP with distinctive immunophenotype from leukemia type. Low-dose decitabine and modified-CAG regimen in combination with allogeneic stem cell transplantation may improve the outcome of patient.Keywords: early T-cell precursor, decitabine, G-CSF priming, T-lymphoblastic lymphoma

A search for Majoron-emitting modes of the neutrinoless double-beta decay of $^{136}$Xe is performed with the full EXO-200 dataset. This dataset consists of a total $^{136}$Xe exposure of 234.1 kg$\cdot$yr, and includes data with detector upgrades that have improved the energy threshold relative to previous searches. A lower limit of T$_{1/2}^{\rm{^{136}Xe}}>$4.3$\cdot$10$^{24}$ yr at 90\% C.L. on the half-life of the spectral index $n=1$ Majoron decay was obtained, a factor of 3.6 more stringent than the previous limit from EXO-200, corresponding to a constraint on the Majoron-neutrino coupling constant of $|\langle g_{ee}^{M}\rangle|$$

The existing scholarly literature on EU-China relations is characterised by a dichotomous distinction between material and ideational factors and overemphasises the ‘interest versus values’ motif undergirding EU-China relations. The enigma of EU-China diplomatic relationship-building is compounded with a ‘relational gap’ in diplomatic studies. There is a dearth of a systemic theoretical framework that integrates the various dimensions of diplomatic relationship-building to interpret the dynamics of the process of diplomatic relationship-building. This study advances a novel theoretical model of diplomatic relationship-building and an associated social-network based research methodology to explore the making of EU-China relations through two in-depth case studies: the negotiations of the EU-China landmark agreement – the Agreement on Cooperation on, and Protection of, Geographical Indications (2009-2019) and the flagship EU-China climate-related bilateral cooperation – the EU-China Emission Trading System Project (2010-2019). The study purports that the making of EU-China relations is a process influenced by three essential elements – structural coordination, negotiations of technical and political substance, and the dialogue between the EU’s ‘walk the talk’ diplomatic style and China’s ‘shoulder responsibility’ diplomatic style. The process of EU-China diplomatic relationship-building is shaped by the fundamental underpinning of the relationship, encapsulated in EU-China shared intentions, which endow the EU and China with a ‘we-feeling’ that invokes shared vision and conveys the potential to unite the two parties. In so doing, the work provides a new theoretical arsenal to understand EU-China relations in a way that captures not only the ‘relational’ nature of diplomatic relationship-building but also takes us beyond the binary understanding of interests and values as sole motives in fostering international diplomacy, by integrating the social layer of ‘intentions’ in understanding diplomatic relationship-building. This work transcends traditional research in International Relations and has broader implications for exploring means by which the EU-China relationship can be better evaluated, managed and enhanced.

© 2020 Wiley-VCH GmbH Sodium-ion batteries have attracted ever-increasing attention in view of the natural abundance of sodium resources. Sluggish sodiation kinetics, nevertheless, remain a tough challenge, in terms of achieving high rate capability and high energy density. Herein, a sheet-in-sphere nanoconfiguration of 2D titania–carbon superlattices vertically aligned inside of mesoporous TiO2@C hollow nanospheres is constructed. In such a design, the ultrathin 2D superlattices consist of ordered alternating monolayers of titania and carbon, enabling interpenetrating pathways for rapid transport of electrons and Na+ ions as well as a 2D heterointerface for Na+ storage. Kinetics analysis discloses that the combination of 2D heterointerface and mesoporosity results an intercalation pseudocapacitive charge storage mechanism, which triggers ultrafast sodiation kinetics. In situ transmission electron microscope imaging and in situ synchrotron X-ray diffraction techniques elucidate that the sheet-in-sphere architecture can maintain robust mechanical and crystallographic structural stability, resulting an extraordinary high rate capability, remarkable stable cycling with a low capacity fading ratio of 0.04% per cycle over 500 cycles at 0.2 C, and exceptionally long-term cyclability up to 20 000 cycles at 50 C. This study offers a method for the realization of a high power density and long-term cyclability battery by designing of a hierarchical nanoarchitecture.

We report on a comparison between the theoretically predicted and experimentally measured spectra of the first-forbidden nonunique β-decay transition ¹³⁷Xe(7/2⁻)→¹³⁷Cs(7/2⁺). The experimental data were acquired by the EXO-200 experiment during a deployment of an AmBe neutron source. The ultralow background environment of EXO-200, together with dedicated source deployment and analysis procedures, allowed for collection of a pure sample of the decays, with an estimated signal to background ratio of more than 99 to 1 in the energy range from 1075 to 4175 keV. In addition to providing a rare and accurate measurement of the first-forbidden nonunique β-decay shape, this work constitutes a novel test of the calculated electron spectral shapes in the context of the reactor antineutrino anomaly and spectral bump.

Applications of room-temperature-sodium sulfur (RT-Na/S) batteries are currently impeded by the insulating nature of sulfur, the slow redox kinetics of sulfur with sodium, and the dissolution and migration of sodium polysulfides. Herein, a novel micrometer-sized hierarchical S cathode supported by FeS2 electrocatalyst, which is grown in situ in well-confined carbon nanocage assemblies, is presented. The hierarchical carbon matrix can provide multiple physical entrapment to polysulfides, and the FeS2 nanograins exhibit a low Na-ion diffusion barrier, strong binding energy, and high affinity for sodium polysulfides. Their combination makes it an ideal sulfur host to immobilize the polysulfides and achieve reversible conversion of polysulfides toward Na2 S. Importantly, the hierarchical S cathode is suitable for large-scale production via the inexpensive and green spray-drying method. The porous hierarchical S cathode offers a high sulfur content of 65.5 wt%, and can deliver high reversible capacity (524 mAh g-1 over 300 cycles at 0.1 A g-1 ) and outstanding rate capability (395 mAh g-1 at 1 A g-1 for 850 cycles), holding great promise for both scientific research and real application.

We report on a comparison between the theoretically predicted and experimentally measured spectra of the first-forbidden non-unique $\beta$-decay transition $^{137}\textrm{Xe}(7/2^-)\to\,^{137}\textrm{Cs}(7/2^+)$. The experimental data were acquired by the EXO-200 experiment during a deployment of an AmBe neutron source. The ultra-low background environment of EXO-200, together with dedicated source deployment and analysis procedures, allowed for collection of a pure sample of the decays, with an estimated signal-to-background ratio of more than 99-to-1 in the energy range from 1075 to 4175 keV. In addition to providing a rare and accurate measurement of the first-forbidden non-unique $\beta$-decay shape, this work constitutes a novel test of the calculated electron spectral shapes in the context of the reactor antineutrino anomaly and spectral bump., Comment: Version as accepted by PRL

Shuang-xiang Tan,1,2 Rui-cheng Hu,1,2 Qian Xia,2 Yong-li Tan,1 Jing-jing Liu,1 Gui-xiang Gan,1 Li-le Wang1 1Hunan Province Institute of Gerontology, Hunan Provincial People’s Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, China; 2Department of Respiratory Medicine, Hunan Provincial People’s Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, China Background: Non–small cell lung cancer (NSCLC) is one of the leading malignant tumors worldwide. Aberrant gene promoter methylation contributes to NSCLC, and PRDM is a tumor suppressor gene family that possesses histone methyltransferase activity. This study aimed to investigate whether aberrant methylation of PRDM promoter is involved in NSCLC. Materials and methods: Primary tumor tissues, adjacent nontumorous tissues, and distant lung tissues were collected from 75 NSCLC patients including 52 lung squamous cell carcinoma (LSCC) patients and 23 lung adenocarcinoma patients. The expression of PRDMs was detected by polymerase chain reaction (PCR), Western blot, and immunohistochemical analysis. The methylation of PRDM promoters was detected by methylation-specific PCR. The correlation of methylation and expression of PRDMs with clinicopathological characteristics of patients were analyzed. Results: mRNA expression of PRDM2, PRDM5, and PRDM16 was low or absent in tumor tissues compared to distant lung tissues. The methylation frequencies of PRDM2, PRDM5, and PRDM16 in tumor tissues were significantly higher than those in distal lung tissues. In LSCC patients, methylation of PRDM2 and PRDM16 was correlated with smoking status and methylation of PRDM5 was correlated with tumor differentiation. Conclusion: The expression of PRDM2, PRDM5, and PRDM16 is low or absent in NSCLC, and this is mainly due to gene promoter methylation. Smoking may be an important cause of PRDM2 and PRDM16 methylation in NSCLC. Keywords: lung tumor, PR domain zinc finger protein, epigenetics, methylation, gene expression

Quansong Xia,1,* Wei Wang,2,* Juan Xu,3 Xue Chen,2 Zhaoming Zhong,2 Chuanzheng Sun2 1Department of Clinical Laboratory, 2Department of Head and Neck Surgery, The Third Affiliated Hospital of Kunming Medical University, 3Department of Internal Medicine, The People’s Hospital of Guandu District, Kunming, People’s Republic of China *These authors contributed equally to this work Background: Radiotherapy and chemotherapy are the two important postoperative management approaches for anaplastic thyroid carcinoma (ATC), and several studies have suggested that postoperative radiotherapy and chemotherapy can prolong the survival of patients with ATC. However, the results remain inconsistent. Objective: A meta-analysis was performed to address whether postoperative radiotherapy and chemotherapy could prolong the survival of patients with ATC. Methods: Relevant studies were included, and pooled hazard ratios (HRs) together with 95% confidence intervals (CIs) were calculated. Results: Ten relevant studies on factors that affect the prognosis for ATC were included in this meta-analysis, evaluating a total of 1,163 patients. The pooled HR for overall survival (OS) was calculated using a random-effects model. The pooled results demonstrated that for all patients with resectable ATC, the combination of surgery and radiotherapy significantly reduced the risk of death compared with surgery alone (HR =0.51, 95% CI: 0.36–0.73, Z=3.66, P=0.0002). To investigate the prognostic impacts of chemotherapy in patients with ATC, we also calculated the pooled HR of chemotherapy for OS using a random-effects model; however, the pooled results suggested that chemotherapy did not prolong the survival of ATC patients compared with controls (HR =0.63, 95% CI: 0.33–1.21, Z=1.39, P=0.17). Conclusion: This study provided evidence that currently, for patients with ATC, postoperative radiotherapy may prolong survival; in contrast, chemotherapy did not improve long-term survival. Keywords: anaplastic thyroid carcinoma, postoperative radiotherapy, chemotherapy, prognosis, meta-analysis

OBJECTIVE To examine the clinical outcomes and associated prognostic factors among patients with multidrug-resistant tuberculosis (MDR-TB) in China. METHODS This retrospective study involved 243 patients with MDR-TB. All patients received standard regimens containing para-amino salicylic acid (PAS) and/or cycloserine (CS). The demographic, social and clinical characteristics of patients were recorded and the patients were followed up for 24 months. RESULTS Treatment success was closely associated with young age, non-farming occupations, shorter history or smoking, normal urine results, initial MDR-TB treatment regimen, increased haemoglobin, direct bilirubin, uric acid and thyroid stimulating hormone (TSH) levels, and lower white blood cell, neutrophil and blood platelet counts (all P < 0.05). On multivariable analysis, increased haemoglobin (hazard ratio [HR] 1.019, 95%CI 1.007-1.032, P = 0.002) and TSH levels (HR 1.002, 95%CI 1.006-1.039, P = 0.008), normal urine results (HR 1.541, 95%CI 1.008-2.358, P = 0.046) and initial MDR-TB treatment regimen (HR 2.238, 95%CI 1.090-4.597, P = 0.028) were prognostic factors for treatment success in MDR-TB. CONCLUSIONS Higher haemoglobin and TSH levels, normal urine results and initial MDR-TB treatment regimen might predict successful treatment of MDR-TB.

Danting Cui,1 Xiaodan Lu,1 Chenggong Yan,1 Xiang Liu,1 Meirong Hou,1 Qi Xia,2 Yikai Xu,1 Ruiyuan Liu2,3 1Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, People’s Republic of China; 3School of Biomedical Engineering, Southern Medical University, Guangzhou, People’s Republic of China Abstract: Bombesin (BBN), an analog of gastrin-releasing peptide (GRP), specifically binds to GRP receptors, which are overexpressed in human prostate cancer (PC). Here, we synthesized a BBN-modified gadolinium oxide (Gd2O3) nanoprobe containing fluorescein (Gd2O3-5(6)-carboxyfluorescein [FI]-polyethylene glycol [PEG]-BBN) for targeted magnetic resonance (MR)/optical dual-modality imaging of PC. The Gd2O3-FI-PEG-BBN nanoparticles exhibited a relatively uniform particle size with an average diameter of 52.3nm and spherical morphology as depicted by transmission electron microscopy. The longitudinal relaxivity (r1) of Gd2O3-FI-PEG-BBN (r1 =4.23mM–1s–1) is comparable to that of clinically used Magnevist (Gd-DTPA). Fluorescence microscopy and in vitro cellular MRI demonstrated GRP receptor-specific and enhanced cellular uptake of the Gd2O3-FI-PEG-BBN in PC-3 tumor cells. Moreover, Gd2O3-FI-PEG-BBN showed more remarkable contrast enhancement than the corresponding nontargeted Gd2O3-FI-PEG according to in vivo MRI and fluorescent imaging. Tumor immunohistochemical analysis further demonstrated improved accumulation of the targeted nanoprobe in tumors. BBN-conjugated Gd2O3 may be a promising nanoplatform for simultaneous GRP receptor-targeted molecular cancer diagnosis and antitumor drug delivery in future clinical applications. Keywords: magnetic resonance imaging, gadolinium oxide, bombesin, gastrin-releasing peptide receptor, molecular imaging

Background Although neutrophil-to-lymphocyte ratio (NLR) and a high platelet-to-lymphocyte ratio (PLR) have been reported to be an inverse prognostic predictor of survival in patients with pancreatic cancer (PC), the comparison of their prognostic roles in patients with PC undergoing gemcitabine-based chemotherapy and 5-fluorouracil (5-FU) remains unclear. Methods This study was designed and performed to determine the predictive role of NLR and PLR in patients diagnosed with PC who underwent one of these two regimens. We retrospectively enrolled 95 patients diagnosed with PC undergoing supportive care, gemcitabine-based chemotherapy or 5-FU therapy from January 2015 to October 2018. Univariate and multivariate Cox regression analyses were done to identify clinicopathological predictors of time to treatment failure (TTF) and overall survival (OS), including pretreatment NLR and PLR. Results Pretreatment NLR was significantly associated with metastasis. Pretreatment NLR was an independent prognostic predictor of both TTF and OS for patients with PC, with NLR>4.0 predicting worse survival. PLR, however, didn’t independently predict TTF or OS. There were no significant difference in the OS of patients undergoing gemcitabine-based regimens and 5-FU regimens when divided into two subgroups: NLR≤4.0 and >4.0. Conclusions Pretreatment NLR is a promising independent outcome predictor for patients with PC. The predictive value of PLR might not be as good as NLR. NLR might not be a suitable factor in the selection of regimens for patients with PC in term of gemcitabine and 5-FU.

© 2019 Chin. Soc. for Elec. Eng. Nonintrusive load monitoring (NILM) is one of the key applications of big data analytics in smart power distribution systems for end-use customers. A successful implementation of nonintrusive load monitoring can improve the knowledge of load, and has great potential in increasing demand side response. Traditional nonintrusive load monitoring algorithms have long suffered from the problems of high misjudgment rate and low accuracy of disaggregated power value. To address these problems, the deep learning framework was adopted. Specifically, a nonintrusive load monitoring model based on sequence-to-sequence (seq2seq) model with attention mechanism was proposed. The model first embeds the input active power time sequence into a high dimensional vector, extracts information with a long short term memory (LSTM)-based encoder, and then selects the most relevant information to decode and reaches the final disaggregation results with a decoder wrapped by attention mechanism. Compared with existing models, the proposed deep learning network structure increases model's ability to extract and utilize information dramatically. The proposed model was tested on the REFITPowerData dataset, and compared with the state-of-the-art model.

For the field of high energy physics to continue to have a bright future, priority within the field must be given to investments in the development of both evolutionary and transformational detector development that is coordinated across the national laboratories and with the university community, international partners and other disciplines. While the fundamental science questions addressed by high energy physics have never been more compelling, there is acute awareness of the challenging budgetary and technical constraints when scaling current technologies. Furthermore, many technologies are reaching their sensitivity limit and new approaches need to be developed to overcome the currently irreducible technological challenges. This situation is unfolding against a backdrop of declining funding for instrumentation, both at the national laboratories and in particular at the universities. This trend has to be reversed for the country to continue to play a leadership role in particle physics, especially in this most promising era of imminent new discoveries that could finally break the hugely successful, but limited, Standard Model of fundamental particle interactions. In this challenging environment it is essential that the community invest anew in instrumentation and optimize the use of the available resources to develop new innovative, cost-effective instrumentation, as this is our best hope to successfully accomplish the mission of high energy physics. This report summarizes the current status of instrumentation for high energy physics, the challenges and needs of future experiments and indicates high priority research areas., Comment: A report of the 2018 DPF Coordinating Panel for Advanced Detectors (CPAD) Community Workshop (101 pages)

Active antimicrobial peptide HI-3 was isolated and purified from the 5th instar larvae of Hermetia illucens L., and its effects on proliferation, apoptosis and migration of nasopharyngeal carcinoma (CNE2) cells were investigated. The expressions of telomerase reverse transcriptase (hTERT) in CNE2 cells were also studied in vitro to elucidate the mechanism involved in the action of HI-3 on CNE2 cells. Results showed that three fractions (HI-1, HI-2, HI-3) were isolated from the hemolymph of H. illucens larvae. After purified by RP-HPLC, only HI-3 showed the inhibitory activities to four strains of bacteria. It was also showed that HI-3 could effectively inhibit the proliferation of CNE2 cells in a dose- and time-dependent manner. Apoptosis of CNE2 cells was observed in the treatment with 160 μg/ml HI-3, and the early apoptosis rate up to 27.59 ± 1.14%. However, no significantly inhibitory effects and apoptosis were found on human umbilical vein endothelial cells (HUV-C). Moreover, HI-3 could significantly reduce the migration ability of CNE2 cells when compared with that of the control. On the other hand, the levels of mRNA and protein of hTERT in the HI-3 treatment were all significantly lower than that of the control. Results indicated that HI-3 could inhibit the proliferation of CNE2 cells and induce the apoptosis of CNE2 cells by down-regulating the telomerase activity in CNE2 cells, while no obvious effect was occurred on HUV-C. It inferred that HI-3 is a potential anti-tumor drug with low toxicity to normal cells.Summary StatementAn active antimicrobial peptide HI-3 was isolated and purified.Inhibitory proliferation of CNE2 cells, but no effect on normal cells.A potential antitumoral drug.

The 2D cell culture is the predominant in vitro model for numerous studies. However, 2D cell cultures may not accurately reflect the functions of three-dimensional (3D) tissues, which have extensive cell–cell and cell–matrix interactions; thus, using 2D cell cultures may lead to inaccurate experimental results. Therefore, to obtain adequate and detailed information about the antioxidant activity of cyanidin-3-O-glucoside (C3G) and C3G liposomes in the 2D and 3D cell culture models, we used in this study H2O2to construct the cell damage model and assess the antioxidant activity of C3G and C3G liposomes on Caco-2 cells cultured in the 3D model. We also measured the cell viability, cell morphology, and activity of glutathione (GSH), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) content of Caco-2 cells treated with H2O2, C3G, and C3G liposomes. Results showed that cells cultured in the 3D culture model formed a 3D structure and tight spheroids and showed increased cell activity and IC50. The C3G and C3G liposomes can enhance the activity of GSH, SOD, and T-AOC but decrease the MDA content. At the same time, the effect was more obvious in the 3D cell culture model than in the cells cultured in the 2D model. This study revealed that the results obtained from the 2D cell model may be inaccurate compared with the results obtained from the 3D cell model. A realistic mechanism study of antioxidant activity of C3G and C3G liposomes in the 3D cell model, which acts as an intermediate stage bridging the in vitro 2D and in vivo models, was observed.