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Si-Yu Long,* Lin Shang,* Huijuan Shi, Siqi Zhao, Jiali Cao, Yanling He Department of Dermatology, Beijing Chao-Yang Hospital, Capital Medical University, National Clinical Research Center for Skin and Immune Diseases, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiali Cao; Yanling He, Department of Dermatology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 10020, People’s Republic of China, Email cnsk2008@126.com; hylchaoyang@163.comBackground: Psoriasis is a global health concern as a chronic inflammatory skin disease. Endothelial dysfunction has been implicated in psoriasis pathogenesis.Objective: This study aims to explore the scientific literature on the relationship between psoriasis and endothelial cells using bibliometric analysis, identifying research trends and public interest in this topic.Methods: We analyzed articles on the topic of endothelial cells and psoriasis in the Web of Science (WoS) Core Collection from 1987 to 2022, examining their distribution by publication year, country, organization, author, and journal. We used bibliometric software, including CiteSpace and R package bibliometrix, to visualize co-authorship relations, keyword citation burst analysis, co citation networks, keyword time zone map, burst references and cluster analysis.Results: Our analysis included 993 publications. The bibliometric analysis revealed a steady increase in the number of publications on psoriasis and endothelial cells over the past decade. The United States was the leading contributor to this field. The Journal of Investigative Dermatology was the most high-yield publication journal. Burst references analysis identified key articles that have significantly influenced the field, including studies on the role of endothelial dysfunction in psoriasis pathogenesis and the association between psoriasis severity and cardiovascular outcomes. 9 clusters were grouped in the key-word citation network. “Expression”, “inflammation”, “endothelial growth factor” and “angiogenesis” were the research focuses, while “cardiovascular disease”, “atherosclerosis”, “endothelial dysfunction”, and “oxidative stress” might be the future research hotspots.Conclusion: This bibliometric analysis sheds light on the growing acknowledgement of the involvement of endothelial cells in psoriasis, with the United States taking the lead. It also emphasizes the necessity for additional research to unravel the underlying mechanisms connecting psoriasis, endothelial dysfunction, and cardiovascular comorbidities. Ultimately, this research will contribute to the development of enhanced management strategies for psoriasis patients.Keywords: bibliometric analysis, endothelial cells, psoriasis, inflammation, cardiovascular risk, molecular mechanisms

Si-Yu Long,1 Le Wang,1,2 Hai-Qin Jiang,1 Ying Shi,1 Wen-Yue Zhang,1 Jing-Shu Xiong,1 Pei-Wen Sun,1,2 Yan-Qing Chen,1 You-Ming Mei,1 Chun Pan,1 Gai Ge,1 Zhen-Zhen Wang,1 Zi-Wei Wu,1 Mei-Wen Yu,1,2 Hong-Sheng Wang1– 3 1Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, People’s Republic of China; 2National Centre for Leprosy Control, China CDC, Nanjing, People’s Republic of China; 3Centre for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of ChinaCorrespondence: Hong-Sheng Wang; Mei-Wen YuJiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, St 12 Jiangwangmiao, Nanjing, Jiangsu, 210042, People’s Republic of ChinaEmail whs33@vip.sina.com; yumeiwen@163.comBackground: Genome-wide association studies (GWASs) have identified some immune-related single-nucleotide polymorphisms (SNPs) to be associated with leprosy.Methods: This study investigated the association of 17 SNPs based on previously published GWAS studies with susceptibility to leprosy, different polar forms and immune states of leprosy in a case–control study from southwestern China, including 1344 leprosy patients and 2732 household contacts (HHCs) (1908 relatives and 824 genetically unrelated contact individuals). The differences of allele distributions were analyzed using chi-squared analysis and logistic regression.Results: After adjusting covariate factors, rs780668 and rs3764147 polymorphisms influenced susceptibilities to genetically related or unrelated leprosy contact individuals. rs142179458 was associated with onset early cases, rs73058713 A allele and rs3764147 A allele increased the risk of reversal reaction, while rs3764147 G allele had higher risk to present lepromatous leprosy and erythema nodosum leprosum.Conclusion: Our results demonstrated that genetic variants in the LACC1, HIF1A, SLC29A3 and CDH18 genes were positively correlated with the occurrence of leprosy and leprosy clinical phenotypes, providing new insights into the immunogenetics of the disease.Keywords: leprosy, association study, susceptibility gene, polymorphisms

Shu-Yu Long, Qiong Yang, Rui Chi, Li Luo, Xi Xiong, Zheng-Qiong Chen Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, People’s Republic of ChinaCorrespondence: Zheng-Qiong Chen Email chenzhengqiong75@163.comPurpose: Antepartum hemorrhage (APH) in women with placenta previa (PP) has been associated with increased perinatal complications. The present study aims to evaluate the maternal and neonatal outcomes, and risk factors related to this condition.Methods: This retrospective study was conducted in the Obstetrics and Gynecology Department of the Second Affiliated Hospital of Army Military Medical University from January 2016 to September 2019, which included all women with PP. The clinical and ultrasound features in patients with or without APH were compared.Results: There were 233 women with APH and 302 women without APH in the cohort. Most of the women with APH were prone to adverse maternal and neonatal outcomes. In the logistic regression analysis, cervical length was inversely correlated to APH (OR: 0.972, 95% CI: 0.952∼ 0.993), while complete PP increased the risk for APH (OR: 2.121, 95% CI: 1.208∼ 3.732). Furthermore, the anterior placenta increased the risk for APH (OR: 1.664, 95% CI: 1.139∼ 2.430), the partial absence of the over lying myometrium increased the risk for APH (OR: 2.015, 95% CI: 1.293∼ 3.141), and the previous history of uterine artery embolization (UAE) increased the highest risk for APH (OR: 11.706, 95% CI: 1.424∼ 96.195).Conclusion: Obstetricians should be aware of the increased risk of adverse pregnancy outcomes related to APH in women with complete PP, short cervical length, anterior placenta, and partially absent over lying myometrium. Prior UAE is a novel risk factor associated with increased prevalence of APH.Keywords: placenta previa, antepartum hemorrhage, bleeding, pregnancy complications, risk factor

Yun-Liang Shen,1,* Si-Yu Long,2,* Wen-Ming Kong,1 Li-Mei Wu,1 Li-Juan Fei,1 Qiang Yao,1 Hong-Sheng Wang2 1Department of Leprosy Control, Zhejiang Provincial Institute of Dermatology, Huzhou, People’s Republic of China; 2Laboratory of Leprosy and Other Mycobacterial Infections, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong-Sheng WangLaboratory of Leprosy and Other Mycobacterial Infections, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, St 12 Jiangwangmiao, Nanjing, Jiangsu 210042, People’s Republic of ChinaEmail whs33@vip.sina.comQiang YaoDepartment of Leprosy Control, Zhejiang Provincial Institute of Dermatology, St 61, Wuyuan, Huzhou, Zhejiang 313200, People’s Republic of ChinaEmail 7793908@qq.comPurpose: Genome-wide association studies (GWAS) have identified multiple genetic variants associated with leprosy. To investigate the single and combined associations between single-nucleotide polymorphisms (SNPs) and the development of leprosy, we therefore performed generalized multi-analytical (GMDR) analysis in Chinese leprosy household contacts and constructed a risk prediction model.Patients and Methods: This case–control study included 229 leprosy cases and 233 healthy household contacts in Zhejiang province, China. Participants were genotyped for 17 polymorphisms selected from GWAS. The Pearson χ2 test, logistic regression and GMDR analysis were performed to investigate gene–gene interactions and construct a risk prediction model for leprosy.Results: The genotype and the allele distributions of rs142179458, rs2275606, rs663743 and rs73058713 were significantly different between patients and controls. rs2275606, rs6478108, rs663743 and rs73058713 showed an association after adjusting for sex and age in the logistic regression. A five-way interaction model consisting of rs2058660, rs2275606, rs4720118, rs6478108 and rs780668 was chosen as the optimal model for determining leprosy susceptibility. The model classified 237 (51.3%) into the low-risk group and 225 (48.7%) individuals into the high-risk group. The area under the curve (AUC) of this model was 0.757 (95% CI: 0.712– 0.803), and the odds ratio for leprosy between the high- and low-risk groups was 9.733 (95% CI: 6.384– 14.960; P< 0.001). The sensitivity and specificity of the model were observed to be 74.7% and 76.8%, respectively.Conclusion: Our results suggest that rs2058660, rs2275606, rs4720118, rs6478108 and rs780668, five SNPs with a significant sole effect on leprosy, interact to confer a higher risk for the disease in leprosy household contacts (HHCs).Keywords: leprosy, gene–gene interactions, generalized multi-analytical, risk stratification

Recent advances in bioanalytical and imaging technologies have revolutionized our ability to assess complex biological and pathological changes within tissue samples. Spatial omics, a rapidly evolving technology, enables the simultaneous detection of multiple biomolecules in tissue sections, allowing for high-dimensional molecular profiling within tissue microanatomical contexts. This offers a powerful opportunity for precise, multidimensional exploration of complex disease pathophysiology. The Pathology 2.0 working group within the European Society of Toxicologic Pathology (ESTP) includes a subgroup dedicated to spatial omics technologies. Their primary goal is to raise awareness about these emerging technologies and their potential applications in discovery and toxicologic pathology. This review provides an overview of commonly used, commercially available platforms for transcriptomic, proteomic, and multiomic analysis, discussing technical aspects and illustrative examples of their applications. To harness the power of spatial omics for translational drug discovery and human safety risk assessment, we emphasize the important role of pathologists at every stage of the workflow-from hypothesis generation to sample preparation, data analysis, and interpretation. Spatial omics technologies offer novel opportunities in target discovery, lead selection, preclinical assessment, and clinical development in compound development., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KH, BA, JMR, BP, AV, NK, JAG, MR, NG, LK, IV, MB and BJ are employed by Roche Pharma Research and Early Development. MV, HW, SAY are employed by Johnson & Johnson. DSB is employed by Sanofi Global Discovery Pathology. CS, BK and SYL are employed by Novartis Biomedical Research. SJ is a co-founder of Elucidate Bio Inc, and serves on its Board of Directors and Scientific Advisory Board, and acknowledges research support from F. Hoffmann-La Roche, Ltd. RK is employed by AnaPath Services GmbH. EV is employed by Idorsia Pharmaceuticals Ltd. SY is employed by Boehringer Ingelheim Pharma GmbH & Co. KG. The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The delayed healing of infected wounds can be attributed to the increased production of reactive oxygen species (ROS) and consequent damages to vascellum and tissue, resulting in a hypoxic wound environment that further exacerbates inflammation. Current clinical treatments including hyperbaric oxygen therapy and antibiotic treatment fail to provide sustained oxygenation and drug-free resistance to infection. To propose a dynamic oxygen regulation strategy, this study develops a composite hydrogel with ROS-scavenging system and oxygen-releasing microspheres in the wound dressing. The hydrogel itself reduces cellular damage by removing ROS derived from immune cells. Simultaneously, the sustained release of oxygen from microspheres improves cell survival and migration in hypoxic environments, promoting angiogenesis and collagen regeneration. The combination of ROS scavenging and oxygenation enables the wound dressing to achieve drug-free anti-infection through activating immune modulation, inhibiting the secretion of pro-inflammatory cytokines interleukin-6, and promoting tissue regeneration in both acute and infected wounds of rat skins. Thus, the composite hydrogel dressing proposed in this work shows great potential for dynamic redox regulation of infected wounds and accelerates wound healing without drugs., (© 2024 Wiley‐VCH GmbH.)

As ubiquitous components among fruits, polyphenols, including flavonoids and phenolic acids, are somewhat embarrassed on their health benefits but low bioavailability, triggering a hotspot on their interaction with microbiota. Due to its structural characteristics similar to flavonoids and phenolic acids, dihydrochalcone phlorizin (PHZ) was selected as a reference, to illustrate its step-by-step metabolic fate associated with microbiota. The results confirmed that the metabolic flux of PHZ starts with its conversion to phloretin (PHT), sequentially followed by the formation of 3-(4-hydroxyphenyl) propionic acid (PHA), and 4-hydroxyphenylacetic acid (4-HPAA). Catabolic characteristics was comparatively elucidated by introducing apparent and potential kinetics. Besides, coupling catabolic processes with microbial changes suggested several potential bacteria involving in PHZ metabolism, as well as those regulated by PHZ and its metabolites. In particular, seven strains from Lactobacillus were selectively isolated and confirmed to be essential for deglycosylation of PHZ, implying a potential synergistic effect between PHZ and Lactobacillus., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Psoriasis is a global health concern, and biological therapies have proven to be highly effective in treating psoriatic patients in many countries. We performed a bibliometric analysis of current research on biological agents for the treatments of psoriasis, investigating research patterns and public interest in this area. We conducted a thorough review of articles on biological agents for psoriasis in the Web of Science Core Collection spanning from 2000 to 2022. Our study involved examining the distribution of these articles based on publication year, affiliations, countries, authors, and journals. To visualize this data effectively, we employed bibliometric tools like CiteSpace and the R package bibliometrix. Our analysis encompassed 8,047 publications. The number of papers published sharply increased from 2009, either reaching its peak in 2022 or not yet reaching it. The United States (n = 2,292), Kristian Reich (n = 166), and British Journal of Dermatology (n = 368) emerged as the top countries, author, and journal, respectively, in terms of publication productivity. The burst references predominantly focused on evaluating the safety and efficacy of biological treatments. The keyword citation network identified 11 clusters, with research themes revolving around "double blind", "efficacy", "therapy", "safety", and "psoriatic arthritis" were the research focuses. Additionally, potential future research areas such as "multicenter," "drug survival," and "severity" were emphasized. This study sheds light on the evolving research landscape and public interest in biological agents for psoriasis. The results suggest rapid expansion in this field, with the United States at the forefront. Enhanced international collaboration is recommended, and forthcoming research endeavors may concentrate on predicting treatment outcomes and adverse effects. Researching new biological agents, broadening the indications for biological agent treatment, and creating personalized treatment plans may pave the way for further research., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Background: Idiopathic scoliosis significantly affects the physical and mental health of children and adolescents, with varying prevalence rates in different regions. The occurrence of idiopathic scoliosis is associated with genetic regulation and biochemical factors, but the changes in exosome-derived miRNA profiles among idiopathic scoliosis patients remain unclear. This study aimed to determine the prevalence of idiopathic scoliosis in Yunnan Province, China, and identify key exosome-derived miRNAs in idiopathic scoliosis through a cohort study., Methods: From January 2018 to December 2020, a cross-sectional study on idiopathic scoliosis in children and adolescents was conducted in Yunnan Province. A total of 84,460 students from 13 cities and counties in Yunnan Province participated in a scoliosis screening program, with ages ranging from 7 to 19 years. After confirmation through screening and imaging results, patients with severe idiopathic scoliosis and normal control individuals were selected using propensity matching. Subsequently, plasma exosome-derived miRNA sequencing and RT-qPCR validation were performed separately. Based on the validation results, diagnostic performance analysis and target gene prediction were conducted for differential plasma exosome-derived miRNAs., Results: The overall prevalence of idiopathic scoliosis in children and adolescents in Yunnan Province was 1.10%, with a prevalence of 0.87% in males and 1.32% in females. The peak prevalence was observed at age 13. Among patients diagnosed with idiopathic scoliosis, approximately 12.8% had severe cases, and there were more cases of double curvature than of single curvature, with thoracolumbar curvature being the most common in the single-curvature group. Sequencing of plasma exosome-derived miRNAs associated with idiopathic scoliosis revealed 56 upregulated and 153 downregulated miRNAs. Further validation analysis confirmed that hsa-miR-27a-5p, hsa-miR-539-5p, and hsa-miR-1246 have potential diagnostic value., Conclusions: We gained insights into the epidemiological characteristics of idiopathic scoliosis in Yunnan Province and conducted further analysis of plasma exosome-derived miRNA changes in patients with severe idiopathic scoliosis. This study has provided new insights for the prevention and diagnosis of idiopathic scoliosis, paving the way for exploring clinical biomarkers and molecular regulatory mechanisms. However, further validation and elucidation of the detailed biological mechanisms underlying these findings will be required in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Yuan, Wang, Jiang, Wang, Yang, Li, Wang, Chen, Li, Long, Zhang, He and Wang.)

Background: Curcumin nicotinate (Curtn), derived from curcumin and niacin, reduces serum LDL-C levels, partly due to its influence on PCSK9. This study investigates IDOL's role in Curtn's lipid-lowering effects., Objective: To elucidate Curtn's regulation of the IDOL/LDLR pathway and potential molecular mechanisms in hepatocytes., Methods: Differential metabolites in Curtn-treated HepG2 cells were identified via LC-MS. Molecular docking assessed Curtn's affinity with IDOL. Cholesterol content and LDLR expression effects were studied in high-fat diet Wistar rats. In vitro evaluations determined Curtn's influence on IDOL overexpression's LDL-C uptake and LDLR expression in hepatocytes., Results: Lipids were the main differential metabolites in Curtn-treated HepG2 cells. Docking showed Curtn's higher affinity to IDOL's FERM domain compared to curcumin, suggesting potential competitive inhibition of IDOL's binding to LDLR. Curtn decreased liver cholesterol in Wistar rats and elevated LDLR expression. During in vitro experiments, Curtn significantly enhanced the effects of IDOL overexpression in HepG2 cells, leading to increased LDL-C uptake and elevated expression of LDL receptors., Conclusion: Curtn modulates the IDOL/LDLR pathway, enhancing LDL cholesterol uptake in hepatocytes. Combined with its PCSK9 influence, Curtn emerges as a potential hyperlipidemia therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hard carbon has been widely used in anode of lithium/sodium ion battery, electrode of supercapacitor, and carbon molecular sieve for CO 2 capture and hydrogen storage. In this study the lignin derived hard carbon products are investigated, and the conclusions are abstracted as follows. (1) The lignin derived hard carbon products consist of microcrystal units of sp 2 graphene fragments, jointed by sp 3 carbon atoms and forming sp 2 -sp 3 hybrid hard carbon family. (2) From the lignin precursors to the sp 2 -sp 3 hybrid hard carbon products, most carbon atoms retain their original electron configurations (sp 2 or sp 3 ) and keep their composition in lignin. (3) The architectures of lignin-derived hard carbon materials are closely dependent on the forms of their lignin precursors, and could be preformed by different pretreatment techniques. (4) The carbonization of lignin precursors follows the mechanism "carbonization in situ and recombination nearby". (5) Due to the high carbon ratio and abundant active functional groups in lignin, new activation techniques could be developed for control of pore size and pore volume. In general lignin is an excellent raw material for sp 2 -sp 3 hybrid hard carbon products, a green and sustainable alternative resource for phenolic resin, and industrial production for lignin derived hard carbon products would be feasible., (© 2024. The Author(s).)

Hepatitis B virus (HBV) infection is a serious global health problem. After the viruses infect the human body, the host can respond to the virus infection by coordinating various cellular responses, in which mitochondria play an important role. Evidence has shown that mitochondrial proteins are involved in host antiviral responses. In this study, we found that the overexpression of TIM22 and TIM29, the members of the inner membrane translocase TIM22 complex, significantly reduced the level of intracellular HBV DNA and RNA and secreted HBV surface antigens and E antigen. The effects of TIM22 and TIM29 on HBV replication and transcription is attributed to the reduction of core promoter activity mediated by the increased expression of SRSF1 which acts as a suppressor of HBV replication. This study provides new evidence for the critical role of mitochondria in the resistance of HBV infection and new targets for the development of treatment against HBV infection., (© 2024 Wiley Periodicals LLC.)

Microcrystal cellulose (MCC) is a green and sustainable resource that widely exists in various lignocellulose species in percentage 10% to 30%. The fine powder of MCC is often discarded in industrial productions that use lignocellulose as feedstock. The crystal structure of two types of MCC (sugarcane pith and bamboo pith) and their derived carbon materials are studied, and the key findings are summarized as follows. (1) In the MCC refined from sugarcane pith, there are large amount of cellulose 2D crystal, which can be converted to valuable 2D graphene crystal. (2) In the MCC refined from bamboo pith there are large amount of cluster microcrystal cellulose, which can be converted to soft and elastic graphene microcrystal (GMC). (3) The 2D cellulose in MCC of sugarcane pith has large surface area and is easily to be degraded to sugars by acid-base hydrolysis reaction, which can be carbonized to Fullerenes-like carbon spheres. (4) The crystal structures of MCC derived carbon materials are strongly impacted by the crystal structures of MCC, and the carbonization reaction of MCC follows "in situ carbonization" and "nearby recombination" mechanism. In general, the results from this study may open a new way for value-added applications of microcrystal cellulose., (© 2023. The Author(s).)

Unhealthy diets rich in fats and/or sugar are considered as the major external cause of the obesity epidemic, which is often accompanied by a significant decrease in gut hormone glucagon-like peptide-1 (GLP1) levels. Numerous studies have demonstrated notable contributions of the gut microbiota in this process. Nevertheless, the underlying mechanism still needs further investigation. The role of epigenetic modifications in gene expression and metabolism has been well demonstrated, with m6A methylation on RNAs being the most prevalent modification throughout their metabolism. In the present study, we found that the expressions of small intestinal Gcg and Pc3 , two key genes regulating GLP1 expression, were significantly downregulated in obese mice, associated with reduced GLP1 level. Immunohistochemistry analysis indicated that a high-fat diet slightly increased the density of enteroendocrine L cells in the small intestine, implying that decreased GLP1 levels were not caused by the changes in L cell intensity. Instead, the small intestinal m6A level as well as the expression of known "writers", mettl3/14 and wtap , were found to be positively correlated with the expression of Gcg and Pc3 . Fecal microbiota transplantation with feces from normal and obese mice daily to antibiotic-treated mice revealed that dysbiosis in diet-induced obesity was sufficient to reduce serum GLP1, small intestinal m6A level, and intestinal expressions of Gcg , Pc3 , and writer genes ( mettl3/14 , wtap ). However, as the most direct and universal methyl donor, the production of fecal S-adenosylmethionine was neither affected by the different dietary patterns nor their shaped microbiota. These results suggested that microbial modulation of the epitranscriptome may be involved in regulating GLP1 expression, and highlighted epitranscriptomic modifications as an additional level of interaction between diet and individual health.

Objectives: Cutaneous tuberculosis with various manifestations can be divided into several clinical types according to the host's immune status and infective route. However, the etiological factors of this disease remain unclear. The objective of this study is to investigate the pathogens associated with the occurrence and different types of cutaneous tuberculosis., Methods: 58 Mycobacterium tuberculosis strains isolated from cutaneous tuberculosis over the last 20 years were sequenced and analyzed for genomic characteristics including lineage distribution, drug-resistance mutations, and mutations potentially associated with different sites of infection., Results: The M. tuberculosis strains from four major types of cutaneous tuberculosis and pulmonary tuberculosis shared similar genotypes and genomic composition. The strains isolated from cutaneous tuberculosis had a lower rate of drug resistance. Phylogenic analysis showed cutaneous tuberculosis and pulmonary tuberculosis isolates scattered on the three. Several SNPs in metabolism related genes exhibited a strong correlation with different infection sites., Conclusions: The different infection sites of TB may barely be affected by large genomic changes in M. tuberculosis isolates, but the significant difference in SNPs of drug resistance gene and metabolism-related genes still deserves more attention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mei, Zhang, Sun, Jiang, Shi, Xiong, Wang, Chen, Long, Pan, Luo and Wang.)

One of the most desirable targets for HBV medications is the sodium taurocholate cotransporting polypeptide (NTCP), an entry receptor for the hepatitis B virus (HBV). N-myristoylated preS1 2-48 (Myrcludex B or Hepcludex), an NTCP-binding peptide from the large surface protein of HBV, has been developed as the first-in-class entry inhibitor. However, its relatively large molecular weight contributes to increased immunogenicity and antibody production. As a result, it is preferable to look for an NTCP-binding peptide with a smaller size. To do this, we developed a human cell surface display strategy and screened peptides based on preS1-21. PreS1-21 (genotype D) was extended by 7 random amino acids and fused with mCherry and FasL transmembrane domain. The pooled constructs were transfected into HEK293 cells by using the transposon/transposase system to create a library displaying various peptides on the cell surface with red fluorescence. On the other hand, we expressed NTCP protein fused with EGFP on HEK293 and used the membrane lysate containing NTCP-GFP as the bait protein to select peptides with increased NTCP affinity. After 7 cycles of selection, the deep sequencing results revealed that some polypeptides were more than 1,000 times enriched. Further screening of the mostly enriched 10 peptides yields the peptide preS1-21-pep3. Replacing the preS1-21 sequence of preS1-21-pep3 with those from different genotypes demonstrated that the consensus sequence of genotype A-F had the best performance. The peptide (Myr-preS1-21-pep3) was synthesized and tested on the HepG2-NTCP cell model. The results showed that Myr-preS1-21-pep3 is approximately 10 times more potent than the initial peptide Myr-preS1-21 in preventing HBV infection. In conclusion, we developed a new strategy for screening peptides binding to membrane proteins and identified a new NTCP-binding peptide with a much smaller size than Hepcludex., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Yang, Guo, Wang, Zhang, Sun, Li, Gan, Long, Liu, Fan, Huang and Hu.)

Chronic hepatitis B virus (HBV) infection can lead to fibrosis, liver cirrhosis, and primary hepatocellular carcinoma. Investigating host factors that regulate HBV replication helps to identify antiviral targets. In the current study, we identified Nicotinamide N-Methyltransferase gene (NNMT) as a novel factor that regulates HBV transcription. NNMT is up-regulated at both the mRNA and protein levels in HepG2.2.15 cells compared to HepG2 cells. Overexpression of NNMT reduces HBV replication in several cell models, while knockdown of NNMT enhances HBV DNA levels. Mechanistically, NNMT suppresses HBV DNA replication by inhibiting HBV RNA transcription. The region required for the inhibitory effect of NNMT was narrowed to nt 1672-1708 in enhancer II by luciferase assays. On the other hand, ChIP assays and EMSA results showed that NNMT does not bind to this region substantially, either directly or indirectly. Next, a collection of hepatic nuclear receptor transcription factors was screened to determine whether they were affected by NNMT overexpression. NR5A1, a positive regulator of HBV replication, decreased significantly after NNMT overexpression. Collectively, the findings of this study shed light on the regulation of HBV transcription., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The epididymis is a common site of obstruction in obstructive azoospermia (OA). Vasoepididymostomy has become an important method for the treatment of epididymal OA since 2000. There are two challenges in classic microscopic vasoepididymostomy. First, anastomosis of the vas deferens and epididymis is performed with double-needle sutures. However, there is a lack of good-quality and cost-effective double-needle sutures in China, which leads to increased difficulty and poor success rates of anastomosis. Second, the separation of the vas deferens does not retain vasculature, although the vas deferens vasculature plays an important role in the blood supply to the vas deferens, epididymis, and testis. This affects the blood supply to the anastomotic area and epididymis. Therefore, this team has made innovative improvements to address these problems. Good-quality, cost-effective, single-needle sutures, which are easy to purchase in China and other countries, were used in microsurgical longitudinal intussusception vasoepididymostomy. This can optimize the operation procedure and shorten the operation time while ensuring the success rate of the anastomosis. The surgical method of preserving the vas deferens vessels was innovatively proposed because the etiology of epididymal OA is mostly inflammatory in China. The protection of the blood supply to the vas deferens and epididymis is maximized using microsurgical forceps to separate and protect the vasculature. Patency reached 81.7% in the postoperative follow-up, indicating a better surgical treatment effect.

The core promoter (CP) of hepatitis B virus (HBV) is critical for HBV replication by controlling the transcription of pregenomic RNA (pgRNA). Host factors regulating the activity of the CP can be identified by different methods. Biotin-based proximity labeling, a powerful method with the capability to capture weak or dynamic interactions, has not yet been used to map proteins interacting with the CP. Here, we established a strategy, based on the newly evolved promiscuous enzyme TurboID, for interrogating host factors regulating the activity of HBV CP. Using this strategy, we identified STAU1 as an important factor involved in the regulation of HBV CP. Mechanistically, STAU1 indirectly binds to CP mediated by TARDBP, and recruits the SAGA transcription coactivator complex to the CP to upregulate its activity. Moreover, STAU1 binds to HBx and enhances the level of HBx by stabilizing it in a ubiquitin-independent manner., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Eastern equine encephalitis virus (EEEV) is mosquito-borne virus that produces fatal encephalitis in humans. We recently conducted a first of its kind study to investigate EEEV clinical disease course following aerosol challenge in a cynomolgus macaque model utilizing the state-of-the-art telemetry to measure critical physiological parameters. Here, we report the results of a comprehensive pathology study of NHP tissues collected at euthanasia to gain insights into EEEV pathogenesis. Viral RNA and proteins as well as microscopic lesions were absent in the visceral organs. In contrast, viral RNA and proteins were readily detected throughout the brain including autonomic nervous system (ANS) control centers and spinal cord. However, despite presence of viral RNA and proteins, majority of the brain and spinal cord tissues exhibited minimal or no microscopic lesions. The virus tropism was restricted primarily to neurons, and virus particles (~61-68 nm) were present within axons of neurons and throughout the extracellular spaces. However, active virus replication was absent or minimal in majority of the brain and was limited to regions proximal to the olfactory tract. These data suggest that EEEV initially replicates in/near the olfactory bulb following aerosol challenge and is rapidly transported to distal regions of the brain by exploiting the neuronal axonal transport system to facilitate neuron-to-neuron spread. Once within the brain, the virus gains access to the ANS control centers likely leading to disruption and/or dysregulation of critical physiological parameters to produce severe disease. Moreover, the absence of microscopic lesions strongly suggests that the underlying mechanism of EEEV pathogenesis is due to neuronal dysfunction rather than neuronal death. This study is the first comprehensive investigation into EEEV pathology in a NHP model and will provide significant insights into the evaluation of countermeasure., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate the value of the correlation coefficient between the ICP wave amplitude and the mean ICP level (RAP) and the resistance to CSF outflow (Rout) in predicting the outcome of patients with post-traumatic hydrocephalus (PTH) selected for shunting., Materials and Methods: As a training set, a total of 191 patients with PTH treated with VP shunting were retrospectively analyzed to evaluate the potential predictive value of Rout, collected from pre-therapeutic CSF infusion test, for a desirable recovery level (dRL), standing for the modified rankin scale (mRS) of 0-2. Eventually, there were 70 patients with PTH prospectively included as a validation set to evaluate the value of Rout-combined RAP as a predictor of dRL. We calculated Rout from a CSF infusion test and collected RAP during continuous external lumbar drainage (ELD). Maximum RAP (RAPmax) and its changes relative to the baseline (ΔRAPmax%) served as specific parameters of evaluation., Results: In the training set, Rout was proved to be a significant predictor of dRL to shunting, with the area under the curve (AUC) of 0.686 ( p < 0.001) in receiver-operating characteristic (ROC) analysis. In the validation set, Rout alone did not present a significant value in the prediction of desirable recovery level (dRL). ΔRAPmax% after 1st or 2nd day of ELD both showed significance in predicting of dRL to shunting with the AUC of 0.773 ( p < 0.001) and 0.786 ( p < 0.001), respectively. Significantly, Rout increased the value of ΔRAPmax% in the prediction of dRL with the AUC of 0.879 ( p < 0.001), combining with ΔRAPmax% after the 1st and 2nd days of ELD. RAPmax after the 1st and 2nd days of ELD showed a remarkable predictive value for non-dRL (Levels 3-6 in Modified Rankin Scale) with the AUC of 0.891 ( p < 0.001) and 0.746 ( p < 0.001)., Conclusion: Both RAP and Rout can predict desirable recovery level (dRL) to shunting in patients with PTH in the early phases of treatment. A RAP-combined Rout is a better dRL predictor for a good outcome to shunting. These findings help the neurosurgeon predict the probability of dRL and facilitate the optimization of the individual treatment plan in the event of ineffective or unessential shunting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Long, You, Xu, Gao and Yang.)

We investigated a case of cutaneous infection in an immunocompromised patient in China that was caused by a novel species within the Mycobacterium gordonae complex. Results of whole-genome sequencing indicated that some strains considered to be M. gordonae complex are actually polyphyletic and should be designated as closely related species.

Background: Dilated cardiomyopathy (DCM) is one of the most common types of cardiomyopathies. Various genes have been verified to be related to DCM, but the pathogenesis remains unclear. Cyclin-dependent-kinase 8 (CDK8), encoded by the CDK8 gene, is a transcriptional factor that regulates the phosphorylation of RNA polymerase II. It plays an important role in the transcription process and different signaling pathways. This study aimed to investigate the potential role of CDK8 gene polymorphisms in DCM susceptibility and prognosis in a Chinese Han population., Methods: Two single nucleotide polymorphisms (SNPs) of CDK8 , rs17083838 (A/G) and rs7992670 (A/G), were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 341 DCM patients and 381 healthy controls. Survival analysis was performed using Kaplan-Meier curves and Cox regression analysis., Results: The frequencies of allele A of both SNPs rs17083838 and rs7992670 were increased in DCM patients compared to healthy controls (P<0.05). Genotypic frequencies of rs17083838 and rs7992670 were associated with the susceptibility to DCM in the codominant, and recessive models (P<0.05), and AA/AG genotypes of rs17083838 were also related to DCM susceptibility in the dominant model. AA/AG genotypes of rs17083838 and the AA genotype of rs7992670 in the dominant and recessive genetic models presented a correlation with the poor prognosis of DCM patients in both univariate (P<0.05) and multivariate analyses (P<0.05) after adjusting for age, gender, left ventricular end-diastolic diameter (LVEDD), and left ventricular ejection fraction (LVEF)., Conclusions: This research is the first to reveal that CDK8 gene polymorphisms might be related to DCM susceptibility and prognosis in the Chinese Han population., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/cdt-21-323). The authors have no conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Background: There is a high incidence of leprosy among house-contacts compared with the general population. We aimed to establish a predictive model using these genetic factors along with epidemiological factors to predict leprosy risk of leprosy household contacts (HHCs)., Methods: Weighted genetic risk score (wGRS) encompassing genome wide association studies (GWAS) variants and five non-genetic factors were examined in a case-control design associated with leprosy risk including 589 cases and 647 controls from leprosy HHCs. We constructed a risk prediction nomogram and evaluated its performance by concordance index (C-index) and calibration curve. The results were validated using bootstrap resampling with 1000 resamples and a prospective design including 1100 HHCs of leprosy patients., Finding: The C-index for the risk model was 0·792 (95% confidence interval [CI] 0·768-0·817), and was confirmed to be 0·780 through bootstrapping validation. The calibration curve for the probability of leprosy showed good agreement between the prediction of the nomogram and actual observation. HHCs were then divided into the low-risk group (nomogram score ≤ 81) and the high-risk group (nomogram score > 81). In prospective analysis, 12 of 1100 participants had leprosy during 63 months' follow-up. We generated the nomogram for leprosy in the validation cohort (C-index 0·773 [95%CI 0·658-0·888], sensitivity75·0%, specificity 66·8%). Interpretation The nomogram achieved an effective prediction of leprosy in HHCs. Using the model, the risk of an individual contact developing leprosy can be determined, which can lead to a rational preventive choice for tracing higher-risk leprosy contacts., Funding: The ministry of health of China, ministry of science and technology of China, Chinese academy of medical sciences, Jiangsu provincial department of science and technology, Nanjing municipal science and technology bureau., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Dispersion is one of the most important issues in see-through near eye displays with waveguide technology. In particular, the nanophotonics design is challenging but demanding. In this paper, we propose a design method for a multilayer achromatic metasurface structure for near eye display application by a physics-driven generative neural network. Two in-coupling metagratings under different projector illuminations are presented and numerically verified with the absolute diffraction efficiency over 89%. A beam splitter, which provides a balance between compactness and visual comfort in a single-projector-binocular display, is also designed. Finally, we apply this method to an out-coupling metasurface with the capability of enlarging the visible region by threefold.

Purpose: The effect of mifepristone for treatment of low-risk cesarean scar pregnancy (CSP) was monitored by contrast-enhanced ultrasound (CEUS)., Methods: Data were collected from 23 CSP patients with a 10-point risk score <5 (low-risk CSP) and from 23 intrauterine pregnancy (IUP) patients with a scar from a previous cesarean delivery. All patients were prescribed 75 mg mifepristone daily for 2 days and underwent transvaginal CEUS before and after administration of mifepristone. On the third day, uterine curettage was performed after transvaginal CEUS. Arrival time (AT), peak intensity (PI), and area under the curve (AUC) around the gestational sac were monitored by CEUS before and after application of mifepristone, and the rate of effective treatment was compared between the two patient groups., Results: No patients experienced side effects from either the CEUS procedure or the mifepristone treatment. Changes in AT, PI, and AUC index from before vs. after mifepristone treatment did not differ significantly between the two groups (all p values >0.05). There was also no significant difference in the rate of effective treatment between the two groups (95.65% in the CSP group vs. 100% in the IUP group; p > 0.05)., Conclusions: Based on monitoring by CEUS, the effect of mifepristone in low-risk CSP was comparable to that in IUP., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Xi Xiong et al.)

Oxidative stress induces the formation of oxidized low‑density lipoprotein (ox‑LDL), which accelerates the development of atherosclerosis and the rupture of atherosclerotic plaques by promoting lipid accumulation and inhibiting autophagy in vascular cells. Lipophagy is known to be involved in maintaining the balance of neutral lipid metabolism; however, the phenomenon of lipophagy deficiency in ox‑LDL‑treated endothelial cells (ECs) remains to be elucidated. It has been demonstrated that lipid accumulation caused by ox‑LDL inhibits autophagy, which promotes apoptosis in ECs. The aim of the present study was to investigate the association between decreased autophagy and lipid accumulation in ECs treated with ox‑LDL. Electron microscopy demonstrated that the formation of autolipophagosomes was decreased in ox‑LDL‑treated human umbilical vein ECs compared with that in the LDL‑treated group and was accompanied by a decrease in the autophagy‑associated proteins via western blotting analysis. Using laser focal colocalization detection, decreased lipid processing was observed in the lysosomes of ox‑LDL‑treated ECs, which indicated that lipophagy may be attenuated and subsequently result in lipid accumulation in ox‑LDL‑treated ECs.

The goal of this study is to provide quantitative data on the ideal volume for intramuscular (IM) injections into the semimembranosus muscle of guinea pigs weighing between 320 to 410 grams. This evaluation comprised 2 experiments. The first was to assess dispersion leakage of intramuscularly injected iohexol, a radiocontrast agent commonly used in Computed Tomography (CT), based on analysis of in vivo imaging. The second used varying volumes of intramuscularly injected sodium chloride (0.9% NaCl) to assess pain and pathology associated with IM injection. Hartley guinea pigs were injected IM with varying volumes of either iohexol or sodium chloride (150, 300, 500, 1000 and 1500 μL). In the iohexol experiment, results suggest IM volumes of 150 and 300 μL remain within the target muscle. In the experiment using sodium chloride, pain and pathology did not increase as IM volume increased. The pathology noted was related to needle tract through the musculature rather than the volume size of the injectate. The results did not reveal a correlation between volume of IM 0.9% NaCl and pain levels. We conclude that volume size correlates more with precision and accuracy of delivery into the intended muscle tissue. Regarding tissue distribution, our findings also suggest that the optimal capacity for IM injection in the semimembranosus muscle should be less than 500 μL.

As a member of the kinesin-3 family, kinesin family member 16B (KIF16B) has a characteristic PhoX homology (PX) domain that binds to membranes containing phosphatidylinositol-3-phosphate (PI(3)P) and moves along microtubule filaments to the plus end via a process regulated by coiled coils in the stalk region in various cell types. The physiological function of KIF16B supports the transport of intracellular cargo and the formation of endosomal tubules. Ras-related protein (Rab) coordinates many steps of membrane transport and are involved in the regulation of KIF16B-mediated vesicle trafficking. Data obtained from clinical research suggest that KIF16B has a potential effect on the disease processes in intellectual disability, abnormal lipid metabolism, and tumor brain metastasis. In this review, we summarize recent advances in the structural and physiological characteristics of KIF16B as well as diseases associated with KIF16B disorders, and speculating its role as a potential adaptor for intracellular cholesterol trafficking.

Human health is threatened by obesity which causes the increasing incidence of various diseases, especially stroke. Ischemic stroke (IS) is mostly caused by the rupture of arterial plaque, whose instability is positively associated with matrix metalloproteinases (MMPs) that degrades extracellular matrix components. Studies have shown that matrix metalloproteinase-12 (MMP-12) may be involved in the pathogenesis of IS. Because of the higher incidence of stroke in obese patients than that in normal weight people, it is urgent for obesity to forecast stroke early. Considering high levels MMP-12 in obesity, we put forward that MMP-12 may be a potential biomarker for IS in obese patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The SREBP2/LDLR pathway is sensitive to cholesterol content in the endoplasmic reticulum (ER), while membrane low-density lipoprotein receptor (LDLR) is influenced by sterol response element binding protein 2 (SREBP2), pro-protein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of LDLR (IDOL). LDL-C, one of the risk factors in cardiovascular disease, is cleared through endocytosis recycling of LDLR. Therefore, we propose that a balance between LDLR endocytosis recycling and PCSK9-mediated and IDOL-mediated lysosomal LDLR degradation is responsible for cholesterol homeostasis in the ER. For statins that decrease serum LDL-C levels via cholesterol synthesis inhibition, the mechanism by which the statins increase the membrane LDLR may be regulated by cholesterol homeostasis in the ER., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Nipah virus (NiV) is an emerging zoonotic paramyxovirus that causes highly lethal henipavirus encephalitis in humans. Survivors develop various neurologic sequelae, including late-onset and relapsing encephalitis, several months up to several years following initial infection. However, the underlying pathology and disease mechanisms of persistent neurologic complications remain unknown. Here, we demonstrate persistent NiV infection in the brains of grivets that survived experimental exposure to NiV. Encephalitis affected the entire brains, with the majority of NiV detected in the neurons and microglia of the brainstems, cerebral cortices, and cerebella. We identified the vascular endothelium in the brain as an initial target of NiV infection during the acute phase of disease, indicating a primary path of entry for NiV into the brain. Notably, we were unable to detect NiV anywhere else except the brains in the examined survivors. Our findings indicate that late-onset and relapsing encephalitis of NiV in human survivors may be due to viral persistence in the brain and shed light on the pathogenesis of chronic henipavirus encephalitis.

Objective: To explore the expression of the N-methyl-D-aspartate (NMDA) receptor in the rat model of orchialgia and its possible mechanisms., Methods: According to Yoshioka's method, the male rats in the control group were injected with 0.2 ml saline, and those in the experimental group with 0.2 ml 2% acetic acid solution. Then we tested the behavioral responses of the rats and determined the expressions of the subunits NR1 and NR2B of the NMDA receptor in the dorsal root ganglion and spinal dorsal horn by Western blot, RT-qPCR and immunofluorescence staining., Results: The withdrawal latency was decreased in the model rats, reaching the lowest value at 4 hours after modeling, significantly lower than in the controls (［4.15 ± 0.84］ vs ［12.32 ± 1.05］, P < 0.05). Compared with the controls, the model rats showed remarkably increased mRNA and protein expressions of NR2B in the dorsal root ganglion (P < 0.05) but not in the spinal dorsal horn at 4 hours. However, no statistically significant difference was found in the expression of NR1 either in the dorsal root ganglion or in the spinal dorsal horn between the two groups (P > 0.05)., Conclusions: The NMDA receptor plays an important role in pathogenesis of orchialgia in rats. In the early stage of pain, upregulating the expression of the subunit NR2B of the NMDA receptor can mediate peripheral hyperalgesia and consequently orchialgia.

A chemical investigation on the 80% EtOH extract of the aerial parts of Kopsia fruticosa led to five new indole alkaloids, kopsifolines G-K (1-5), and one known alkaloid, kopsifoline A (6). Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D ( 1 H- 1 H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated components were evaluated in vitro for cytotoxic activities against seven tumor cell lines, antimicrobial activities against two Gram-positive bacteria and five Gram-negative bacteria, and antifungal activities against five pathogens. As a result, alkaloids 3-5 exhibited some cytotoxicity against all of seven tested tumor cell lines (HS-1, HS-4, SCL-1, A431, BGC-823, MCF-7, and W480) with IC 50 values of 11.8-13.8, 10.3-12.5, and 7.3-9.5 μM, respectively. Alkaloids 3-5 also possessed significant antimicrobial and antifungal activities which was reported for the first time for the alkaloids isolated from Kopsia genus., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Thirteen new lethal cases of acute hemorrhagic disease (HD) with typical histopathogical features were identified in young Asian elephants (Elephas maximus indicus) in India between 2013 and 2017. Eight occurred amongst free-ranging wild herds, with three more in camp-raised orphans and two in captive-born calves. All were confirmed to have high levels of Elephant Endotheliotropic Herpesvirus type 1A (EEHV1A) DNA detected within gross pathological lesions from necropsy tissue by multi-locus PCR DNA sequencing. The strains involved were all significantly different from one another and from nine previously described cases from Southern India (which included one example of EEHV1B). Overall, eight selected dispersed PCR loci totaling up to 6.1-kb in size were analyzed for most of the 22 cases, with extensive subtype clustering data being obtained at four hypervariable gene loci. In addition to the previously identified U48(gH-TK) and U51(vGPCR1) gene loci, these included two newly identified E5(vGPCR5) and E54(vOX2-1) loci mapping far outside of the classic EEHV1A versus EEHV1B subtype chimeric domains and towards the novel end segments of the genome that had not been evaluated previously. The high levels of genetic divergence and mosaic scrambling observed between adjacent loci match closely to the overall range of divergence found within 45 analyzed North American and European cases, but include some common relatively unique polymorphic features and preferred subtypes that appear to distinguish most but not all Indian strains from both those in Thailand and those outside range countries. Furthermore, more than half of the Indian cases studied here involved calves living within wild herds, whereas nearly all other cases identified in Asia so far represent rescued camp orphans or captive-born calves., Competing Interests: The authors have declared that no competing interests exist.

Graphene microcrystal (GMC) is a type of glassy carbon fabricated from lignin, in which the microcrystals of graphene are chemically bonded by sp³ carbon atoms, forming a glass-like microcrystal structure. The lignin is refined from sugarcane bagasse using an ethanol-based organosolv technique which is used for the fabrication of GMC by two technical schemes: The pyrolysis reaction of lignin in a tubular furnace at atmospheric pressure; and the hydrothermal carbonization (HTC) of lignin at lower temperature, followed by pyrolysis at higher temperature. The existence of graphene nanofragments in GMC is proven by Raman spectra and XRD patterns; the ratio of sp² carbon atoms to sp³ carbon atoms is demonstrated by XPS spectra; and the microcrystal structure is observed in the high-resolution transmission electron microscope (HRTEM) images. Temperature and pressure have an important impact on the quality of GMC samples. With the elevation of temperature, the fraction of carbon increases, while the fraction of oxygen decreases, and the ratio of sp² to sp³ carbon atoms increases. In contrast to the pyrolysis techniques, the HTC technique needs lower temperatures because of the high vapor pressure of water. In general, with the help of biorefinery, the biomass material, lignin, is found to be qualified and sustainable material for the manufacture of GMC. Lignin acts as a renewable substitute for the traditional raw materials of glassy carbon, copolymer resins of phenol formaldehyde, and furfuryl alcohol-phenol.

Sugarcane bagasse was refined into cellulose, hemicellulose, and lignin using an ethanol-based organosolv technique. The hydrothermal carbonization (HTC) reactions were applied for bagasse and its two components cellulose and lignin. Based on GC-MS analysis, 32 (13+19) organic byproducts were derived from cellulose and lignin, more than the 22 byproducts from bagasse. Particularly, more valuable catechol products were obtained from lignin with 56.8% share in the total GC-MS integral area, much higher than the 2.263% share in the GC-MS integral areas of bagasse. The organic byproducts from lignin make up more than half of the total mass of lignin, indicating that lignin is a chemical treasure storage. In general, bio-refinery and HTC are two effective techniques for the valorization of bagasse and other biomass materials from agriculture and forest industry. HTC could convert the inferior biomass to superior biofuel with higher energy quantity of combustion, at the same time many valuable organic byproducts are produced. Bio-refinery could promote the HTC reaction of biomass more effective. With the help of bio-refinery and HTC, bagasse and other biomass materials are not only the sustainable energy resource, but also the renewable and environment friendly chemical materials, the best alternatives for petroleum, coal and natural gas., Competing Interests: The authors have declared that no competing interests exist.

A phytochemical study on the whole plant of Spermacoce latifolia led to the isolation of a new anthraquinone, 1,2,6-trihydroxy-5-methoxy-9,10-anthraquinone (1), and a new naphthoquinone, (2R)-6-hydroxy-7-methoxy-dehydroiso-α-lapachone (2), together with three known anthraquinones (3-5). Their structures were established on the basis of detailed spectroscopic analysis, including one- and two-dimensional NMR, ESI-MS, and HR-ESI-MS techniques. All the compounds were isolated from S. latifolia for the first time. Compounds 1, 2, 4, and 5 showed significant antibacterial activity toward Bacillus subtilis with MIC values ranging from 0.9 to 31.2 μg/ml, and compound 4 aslo exhibited antibacterial activity against Bacillus cereus with a MIC value 62.5 μg/ml. Compound 1 was further revealed to show significant in vitro α-glucosidase inhibitory activity with IC 50 value of 0.653 mM.

A new two-dimensional (2D) carbon crystal, different from graphene, has been prepared from 1,3,5-trihydroxybenzene, consisting of 4-carbon and 6-carbon rings in 1:1 ratio, named 4-6 carbophene by authors, in which all carbon atoms possess sp 2 hybrid orbitals with some distortion, forming an extensive conjugated π-bonding planar structure. The angles between the three σ-bonds of the carbon sp 2 orbitals are roughly 120°, 90°, and 150°. Each of the three non-adjacent sides of a 6C-ring is shared with a 4C-ring; and each of the two opposite sides of a 4C-ring is shared with a 6C-ring. Dodecagonal holes with a diameter of approximate 5.8 Å are regularly located throughout the 2D carbon crystal. Even though the bond energies in 4-6 carbophene are weaker than those in the graphene, the new planar crystal is quite stable in ambient conditions. The 4-6 carbophene can be synthetized from 1,3,5-trihydroxybenzene or other benzene derivatives through dehydration and polymerization reactions, and may possess several possible patterns that form a family of 2D carbon crystals. A possible side reaction involving 1,3,5-trihydroxybenzene is also discussed, which may produce a carbon-oxygen two dimensional crystal.

A novel group of mammalian DNA viruses called elephant endotheliotropic herpesviruses (EEHVs) belonging to the Proboscivirus genus has been associated with nearly 100 cases of highly lethal acute hemorrhagic disease in young Asian elephants worldwide. The complete 180-kb genomes of prototype strains from three AT-rich branch viruses, EEHV1A, EEHV1B, and EEHV5, have been published. However, less than 6 kb of DNA sequence each from EEHV3, EEHV4, and EEHV7 showed them to be a hugely diverged second major branch with GC-rich characteristics. Here, we determined the complete 206-kb genome of EEHV4(Baylor) directly from trunk wash DNA by next-generation sequencing and de novo assembly procedures. Among a total of 119 genes with an overall colinear organization similar to those of the AT-rich EEHVs, major features of EEHV4 include a family of 26 paralogous 7xTM and vGPCR-like genes plus 25 novel or missing genes. The genome also contains an unusual distribution of tracts of 5 to 11 successive A or T nucleotides in intergenic domains between the mostly much higher GC content protein coding regions. Furthermore, an extremely high GC-rich bias in the third wobble position of codons clearly delineates the coding regions for many but not all proteins. There are also two novel captured cellular genes, including a C-type lectin (vECTL) and an O-linked acetylglucosamine transferase (vOGT), as well as an unusually large and complex Ori-Lyt dyad symmetry domain. Finally, 30 kb from a second strain proved to include three small chimeric domains, indicating the existence of distinct EEHV4A and EEHV4B subtypes. IMPORTANCE Multiple species of herpesviruses from three different lineages of the Proboscivirus genus (EEHV1/6, EEHV2/5, and EEHV3/4/7) infect both Asian and African elephants, but lethal hemorrhagic disease is largely confined to Asian elephant calves and is predominantly associated with EEHV1. Milder disease caused by EEHV5 or EEHV4 is being increasingly recognized as well, but little is known about the latter, which is estimated to have diverged at least 35 million years ago from the others within a distinctive GC-rich branch of the Proboscivirus genus. Here, we have determined the complete genomic DNA sequence of a strain of EEHV4 obtained from a trunk wash sample collected from a surviving Asian elephant calf undergoing asymptomatic shedding during convalescence after an acute hemorrhagic disease episode. This represents the first example from among the three known GC-rich branch Proboscivirus species to be assembled and fully annotated. Several distinctive features of EEHV4 compared to AT-rich branch genomes are described.

Nearly 100 cases of lethal acute hemorrhagic disease in young Asian elephants have been reported worldwide. All tested cases contained high levels of elephant endotheliotropic herpesvirus (EEHV) DNA in pathological blood or tissue samples. Seven known major types of EEHVs have been partially characterized and shown to all belong to the novel Proboscivirus genus. However, the recently determined 206-kb EEHV4 genome proved to represent the prototype of a GC-rich branch virus that is very distinct from the previously published 180-kb EEHV1A, EEHV1B, and EEHV5A genomes, which all fall within an alternative AT-rich branch. Although EEHV4 retains the large family of 7xTM and vGPCR-like genes, six are unique to either just one or the other branch. While both branches display a highly enriched distribution of A and T tracts in intergenic domains, they are generally much larger within the GC-rich branch. Both branches retain the vGCNT1 acetylglucosamine transferase and at least one vOX-2 gene, but the two branches differ by 25 genes overall, with the AT-rich branch encoding a fucosyl transferase (vFUT9) plus two or three more vOX2 proteins and an immunoglobulin-like gene family that are all absent from the GC-rich branch. Several envelope glycoproteins retain only 15 to 20% protein identity or less across the two branches. Finally, the two plausible predicted transcriptional regulatory proteins display no homology at all to those in the alpha-, beta-, or gammaherpesvirus subfamilies. These results reinforce our previous proposal that the probosciviruses should be designated a new subfamily of mammalian herpesviruses. IMPORTANCE Multiple species of herpesviruses from three different lineages of the Proboscivirus genus (EEHV1/6, EEHV2/5, and EEHV3/4/7) infect either Asian or African elephants, but the highly lethal hemorrhagic disease is largely confined to Asian elephant calves and is predominantly associated with EEHV1. In the accompanying paper [P. D. Ling et al., mSphere 1(3):e00081-15, 10.1128/mSphere.00081-15], we report the complete 206-kb genome of EEHV4, the third different species causing disease in Asian elephants and the first example of a GC-rich branch proboscivirus. To gain insights into the nature and differential properties of these two very anciently diverged lineages of elephant herpesviruses, we describe here several additional unusual features found in the complete GC-rich genome of EEHV4 with particular emphasis on patterns of divergence as well as common unique features that are distinct from those of all other herpesviruses, such as the enlarged AT-rich intergenic domains and gene families, including the large number of vGPCR-like proteins.

This article summarizes the physiology and anatomy of reptiles, highlighting points relevant for emergency room veterinarians. Other systems, such as the endocrine and immune systems, have not been covered. The many other aspects of reptile species variation are too numerous to be covered. This article provides an overview but encourages clinicians to seek additional species-specific information to better medically diagnose and treat their reptile patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

More than 100 young captive and wild Asian elephants are known to have died from a rapid-onset, acute hemorrhagic disease caused primarily by multiple distinct strains of two closely related chimeric variants of a novel herpesvirus species designated elephant endotheliotropic herpesvirus (EEHV1A and EEHV1B). These and two other species of Probosciviruses (EEHV4 and EEHV5) are evidently ancient and likely nearly ubiquitous asymptomatic infections of adult Asian elephants worldwide that are occasionally shed in trunk wash secretions. Although only a handful of similar cases have been observed in African elephants, they also have proved to harbor their own multiple and distinct species of Probosciviruses-EEHV2, EEHV3, EEHV6, and EEHV7-found in lung and skin nodules or saliva. For reasons that are not yet understood, approximately 20% of Asian elephant calves appear to be susceptible to the disease when primary infections are not controlled by normal innate cellular and humoral immune responses. Sensitive specific polymerase chain reaction (PCR) DNA blood tests have been developed, routine monitoring has been established, the complete large DNA genomes of each of the four Asian EEHV species have now been sequenced, and PCR gene subtyping has provided unambiguous evidence that this is a sporadic rather than epidemic disease that it is not being spread among zoos or other elephant housing facilities. Nevertheless, researchers have not yet been able to propagate EEHV in cell culture, determine whether or not human antiherpesvirus drugs are effective inhibitors, or develop serology assays that can distinguish between antibodies against the multiple different EEHV species., (© The Author 2016. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Unlabelled: More than 80 cases of lethal hemorrhagic disease associated with elephant endotheliotropic herpesviruses (EEHVs) have been identified in young Asian elephants worldwide. Diagnostic PCR tests detected six types of EEHV in blood of elephants with acute disease, although EEHV1A is the predominant pathogenic type. Previously, the presence of herpesvirus virions within benign lung and skin nodules from healthy African elephants led to suggestions that African elephants may be the source of EEHV disease in Asian elephants. Here, we used direct PCR-based DNA sequencing to detect EEHV genomes in necropsy tissue from five healthy adult African elephants. Two large lung nodules collected from culled wild South African elephants contained high levels of either EEHV3 alone or both EEHV2 and EEHV3. Similarly, a euthanized U.S. elephant proved to harbor multiple EEHV types distributed nonuniformly across four small lung nodules, including high levels of EEHV6, lower levels of EEHV3 and EEHV2, and a new GC-rich branch type, EEHV7. Several of the same EEHV types were also detected in random lung and spleen samples from two other elephants. Sanger PCR DNA sequence data comprising 100 kb were obtained from a total of 15 different strains identified, with (except for a few hypervariable genes) the EEHV2, EEHV3, and EEHV6 strains all being closely related to known genotypes from cases of acute disease, whereas the seven loci (4.0 kb) obtained from EEHV7 averaged 18% divergence from their nearest relative, EEHV3. Overall, we conclude that these four EEHV species, but probably not EEHV1, occur commonly as quiescent infections in African elephants., Importance: Acute hemorrhagic disease characterized by high-level viremia due to infection by members of the Proboscivirus genus threatens the future breeding success of endangered Asian elephants worldwide. Although the genomes of six EEHV types from acute cases have been partially or fully characterized, lethal disease predominantly involves a variety of strains of EEHV1, whose natural host has been unclear. Here, we carried out genotype analyses by partial PCR sequencing of necropsy tissue from five asymptomatic African elephants and identified multiple simultaneous infections by several different EEHV types, including high concentrations in lymphoid lung nodules. Overall, the results provide strong evidence that EEHV2, EEHV3, EEHV6, and EEHV7 represent natural ubiquitous infections in African elephants, whereas Asian elephants harbor EEHV1A, EEHV1B, EEHV4, and EEHV5. Although a single case of fatal cross-species infection by EEHV3 is known, the results do not support the previous concept that highly pathogenic EEHV1A crossed from African to Asian elephants in zoos., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Human cytosolic sulfotransferases (hSULTs) are important phase II metabolic enzymes. They catalyze transfer of the sulfuryl-group (-SO3) from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the hydroxyl or primary amine moieties of a large number of endogenous and xenobiotic substrates. Broad selectivity and specificity of binding and activity within the sulfortransferases family could be detected by thermal denaturation assays, which have been made more and more suitable for high throughput screening based on recent technical advances. Here molecular dynamics simulations were used to explore the effect of the cofactor (PAPS) and substrate (LCA) on the thermal stability of the enzyme. It was found that the apo-enzyme unfolded fastest upon heating. The holo-enzyme with bound substrate LCA unfolded slowest. This thermo-denaturation order is consistent with that observed in experiments. Further it was found that the cofactor and substrate will pronouncedly increase the thermal stability of the active pocket regions that interact directly with the ligands. In addition, cofactor and substrate show noticeable synergy effect on the thermal stability of the enzyme.

The concept of generalized ratiometric indicator based surface-enhanced Raman spectroscopy was first introduced and successfully implemented in the detection of Cd(2+) in environmental water samples using Au nanoparticles (AuNPs) modified by trithiocyanuric acid (TMT). Without the use of any internal standard, the proposed method achieved accurate concentration predictions for Cd(2+) in environmental water samples with recoveries in the ranges of 91.8-108.1%, comparable to the corresponding values obtained by atomic absorption spectroscopy. The limit of detection and limit of quantification were estimated to be 2.9 and 8.7 nM, respectively. More importantly, other species present in water samples which cannot react with TMT and have weaker binding ability to AuNPs than TMT do not interfere with the quantification of Cd(2+). Therefore, it is expected that the combination of the generalized ratiometric indicator based surface-enhanced Raman spectroscopy with the proposed AuNP-TMT probing system can be a competitive alternative for the primary screening of Cd(2+) pollution.

Unlabelled: The genomes of three types of novel endotheliotropic herpesviruses (elephant endotheliotropic herpesvirus 1A [EEHV1A], EEHV1B, and EEHV2) associated with lethal hemorrhagic disease in Asian elephants have been previously well characterized and assigned to a new Proboscivirus genus. Here we have generated 112 kb of DNA sequence data from segments of four more types of EEHV by direct targeted PCR from blood samples or necropsy tissue samples from six viremic elephants. Comparative phylogenetic analysis of nearly 30 protein-encoding genes of EEHV5 and EEHV6 show that they diverge uniformly by nearly 20% from their closest relatives, EEHV2 and EEHV1A, respectively, and are likely to have similar overall gene content and genome organization. In contrast, seven EEHV3 and EEHV4 genes analyzed differ from those of all other EEHVs by 37% and have a G+C content of 63% compared to just 42% for the others. Three strains of EEHV5 analyzed clustered into two partially chimeric subgroups EEHV5A and EEHV5B that diverge by 19% within three small noncontiguous segments totaling 6.2 kb. We conclude that all six EEHV types should be designated as independent species within a proposed new fourth Deltaherpesvirinae subfamily of mammalian herpesviruses. These virus types likely initially diverged close to 100 million years ago when the ancestors of modern elephants split from all other placental mammals and then evolved into two major branches with high- or low-G+C content about 35 million years ago. Later additional branching events subsequently generated three paired sister taxon lineages of which EEHV1 plus EEHV6, EEHV5 plus EEHV2, and EEHV4 plus EEHV3 may represent Asian and African elephant versions, respectively., Importance: One of the factors threatening the long-term survival of endangered Asian elephants in both wild range countries and in captive breeding populations in zoos is a highly lethal hemorrhagic herpesvirus disease that has killed at least 70 young Asian elephants worldwide. The genomes of the first three types of EEHVs (or probosciviruses) identified have been partially characterized in the preceding accompanying paper (L. K. Richman, J.-C. Zong, E. M. Latimer, J. Lock, R. C. Fleischer, S. Y. Heaggans, and G. S. Hayward, J. Virol. 88:13523-13546, 2014, http://dx.doi.org/10.1128/JVI.01673-14). Here we have used PCR DNA sequence analysis from multiple segments of DNA amplified directly from blood or necropsy tissue samples of six more selected cases of hemorrhagic disease to partially characterize four other types of EEHVs from either Asian or African elephants. We propose that all six types and two chimeric subtypes of EEHV belong to multiple lineages of both AT-rich and GC-rich branches within a new subfamily to be named the Deltaherpesvirinae, which evolved separately from all other mammalian herpesviruses about100 million years ago., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Pancreatic β-cell survival remains poorly understood despite decades of research. GATA transcription factors broadly regulate embryogenesis and influence survival of several cell types, but their role in adult β-cells remains undefined. To investigate the role of GATA factors in adult β-cells, we derived β-cell-inducible Gata4- and Gata6-knockout mice, along with whole-body inducible Gata4 knockouts. β-Cell Gata4 deletion modestly increased the proportion of dying β-cells in situ with ultrastructural abnormalities suggesting endoplasmic reticulum (ER) stress. Notably, glucose homeostasis was not grossly altered in Gata4- and Gata6-knockout mice, suggesting that GATA factors do not have essential roles in β-cells. Several ER stress signals were up-regulated in Gata4 and Gata6 knockouts, most notably CHOP, a known regulator of ER stress-induced apoptosis. However, ER stress signals were not elevated to levels observed after acute thapsigargin administration, suggesting that GATA deficiency only caused mild ER stress. Simultaneous deletion of Gata4 and CHOP partially restored β-cell survival. In contrast, whole-body inducible Gata4 knockouts displayed no evidence of ER stress in other GATA4-enriched tissues, such as heart. Indeed, distinct GATA transcriptional targets were differentially expressed in islets compared with heart. Such β-cell-specific findings prompted study of a large meta-analysis dataset to investigate single nucleotide polymorphisms harbored within the human GATA4 locus, revealing several variants significantly associated with type 1 diabetes mellitus. We conclude that GATA factors have important but nonessential roles to promote ER integrity and β-cell survival in a tissue-specific manner and that GATA factors likely contribute to type 1 diabetes mellitus pathogenesis.

Up to 65% of deaths of young Asian elephants (Elephas maximus) between 3 mo and 15 yr of age in Europe and North America over the past 20 yr have been attributed to hemorrhagic disease associated with a novel DNA virus called elephant endotheliotropic herpesvirus (EEHV). To evaluate the potential role of EEHV in suspected cases of a similar lethal acute hemorrhagic disease occurring in southern India, we studied pathologic tissue samples collected from field necropsies. Nine cases among both orphaned camp and wild Asian elephants were identified by diagnostic PCR. These were subjected to detailed gene subtype DNA sequencing at multiple PCR loci, which revealed seven distinct strains of EEHV1A and one of EEHV1B. Two orphan calves that died within 3 days of one another at the same training camp had identical EEHV1A DNA sequences, indicating a common epidemiologic source. However, the high level of EEHV1 subtype genetic diversity found among the other Indian strains matches that among over 30 EEHV1 strains that have been evaluated from Europe and North America. These results argue against the previous suggestions that this is just a disease of captive elephants and that the EEHV1 virus has crossed recently from African elephant (Loxodonta africana) hosts to Asian elephants. Instead, both the virus and the disease are evidently widespread in Asia and, despite the disease severity, Asian elephants appear to be the ancient endogenous hosts of both EEHV1A and EEHV1B.