Abstract Aims Aging impairs cardiac function and increases susceptibility to myocardial ischaemic injury. Cardiac myosin light chain kinase (MLCK3) phosphorylates cardiac myosin regulatory light chain (MLC2), controlling sarcomere organization and cardiomyocyte contraction. Dysregulation of MLCK3 and phosphorylated MLC2 (p-MLC2) contributes to heart failure after myocardial infarction (MI). We aimed at exploring how the MLCK3–p-MLC2 axis changes in aging hearts post MI and at investigating the underlying regulatory mechanisms. Methods and results We generated adult (3 months) and aged (30 months) MI mouse models to compare their cardiac performance, and then detected MLCK3 expression and MLC2 activity. Aging increased the size of MI-induced infarctions and promoted cardiac contractile dysfunction. Furthermore, MLCK3 expression and MLC2 activity increased in adult hearts after MI, but not in aged hearts. miR-146a was found consistently increased in adult and aged hearts post MI. Mechanistic analyses performed in vitro demonstrated that miR-146a-5p down-regulated matrix metalloprotease (MMP)2/16 expression in cardiomyocytes. This down-regulation in turn increased MLCK3 expression and MLC2 activity. However, miR-146a-5p failed to regulate the MMP2/16–MLCK3–p-MLC2 axis in senescent cardiomyocytes or in cardiac miR-146a conditional knockout mice, with the latter experiencing an exacerbated deterioration of cardiac function post MI. Conclusion These results suggest that an increase of MLCK3 and p-MLC2 contents through decreasing MMP2/16 by miR-146a-5p represents a compensatory mechanism that can protect cardiac contractile function after MI. Aging impairs this miR-146a-5p-regulated MMP2/16–MLCK3–p-MLC2 contractile axis, leading to compromised contractile function and increased susceptibility to heart failure.

Background: Globally lung cancer is one of the most common cancers, and is responsible for almost 20% of all cancer care costs. As a potential treatment for lung cancer, anti-PD-1/ PD-L1 therapy has become a novel scientific hotspot in recent decades. The present study aims at exploring the status and trends of the top frequently cited publications about the anti-PD-1/PD-L1 therapy for lung cancer via bibliometric analysis. Methods: The publications concerning anti-PD-1/PD-L1 therapy for lung cancer were searched on the core collection database of Web of Science, setting the time period for retrieval from 1950 to 2019. The top 100 most frequently cited publications were retrieved, and the bibliometric data were mainly accessed through an open online analysis platform and VOSviewer software. Results: The cited frequencies about the top 100 cited publications ranged from 218 to 6248. These articles were published in 39 publications, which were mainly ranked in Q1. The top journal in terms of the number of the articles was the New England Journal of Medicine (16 articles). The most frequently nominated author was Brahmer, JR from Sidney Kimmel Comprehensive Cancer Center, while the most contributing institution was Memorial Sloan Kettering Cancer. The United States acted as the pioneer in this new field of research and led plentiful of national and international co-operations. Immunotherapy, nivolumab, cell lung-cancer, safety, and docetaxel appeared more frequently as keywords. Discussions: To sum up, high quality journals, influential authors and institutions and research with high quality evidence were apt to attract more attention and possess more public credibility. Moreover, the bibliometric analysis is yielding up its advantage of identifying and analyzing the characteristics and changes in the intellectual structures of a special topic.

1Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, People’s Republic of China; 2Grade 2018 Clinical Medicine, Army Medical University, Chongqing, People’s Republic of China; 3Grade 2017 Nursing, Shenzhen University Health Science Center, Shenzhen, People’s Republic of China; 4Department of Radiology, Affiliated Hospital of Beihua University, Jilin, People’s Republic of China; 5Department of Forensic Science, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, People’s Republic of China; 6Department of Pathology, Shenzhen University Health Science Center, Shenzhen, People’s Republic of China

Substance-related disorders are a group of medical conditions that affect a person's brain and behavior and lead to an inability to control the use of legal or illegal drug(s) or medication. Substance-related disorder is a serious public health and society problem worldwide. Genetic factors have been proven to have an important role. Researchers have carried out a lot of work in this field, and a large number of research results have been published in academic journals around the world. However, there are few overviews of research progress, presentation, and development trends in this field. In this study, a total of 636 articles related to genetic factors of substance-related disorders were retrieved from the Web of Science (WoS) database from 1997 to 2018, and the scientific literatures were analyzed by bibliometrics. The study found that the United States (US) has maintained a leading position in the field of research, with many core institutions and plenty of high-quality research results. Alcohol use disorder is still the most concerning issue in this field. Over the past 20 years, new techniques such as genome-wide association study (GWAS) based on high-throughput sequencing technology have replaced family studies, twin studies, and retrospective studies in this field. We believe that it is urgent to study the genetic factors of substance-related disorders, which can greatly deepen the understanding of the pathogenesis of substance-related disorders and may provide potential targets for precise treatment of such diseases.

生态环境损害问题困扰着大部分发达国家及发展中国家,各国日益重视生态环境损害的评估、赔偿及修复工作,环境损害司法鉴定开始登上历史舞台.通过文献计量学方法应用CiteSpace和VOSviewer软件,针对生态环境损害和司法对策文献的学科、国家、机构及作者分布特征,以及文献的共被引等信息可视化进行研究.研究发现:20世纪70年代起,美国的一些机构持续引领研究热潮,无论是空气颗粒污染、土壤或水体的重金属污染等均受到重视;作为发展中国家的代表,我国相关研究自21世纪初开始迅速崛起,近年发布的一系列针对环境损害司法鉴定相关的法律、法规,不仅承袭了前期成果和客观需求,更为将来的研究成果及司法实践奠定基础.

Editor, We have read with great interest the recently published article by Graziano D.L. Crudele et al. (1), observing the distribution of cases of death according to manner of death and manner of injury and number of fossae involved, for analyzing the frequency of cranial base fractures in lethal head trauma. The authors focused on the proportion of base fractures associated with vault fractures, and the frequency of absence of base fracture in subjects with no vault fractures and concluded the interesting associations of base fractures to age and manner of death. We utterly appreciate the merit of the proposed investigation. Besides, we especially interested in the 69 case records of base fractures but with no vault fractures and the storage conditions before autopsy. Regarding three cases of skull base fractures induced by refrigeration we reported several years ago (2), the cause of death was none of skull–brain injuries associated with and the differential between antemortem and postmortem basilar fractures was concluded. Though we agree with the analyzed conclusion made by Graziano D.L. Crudele et al., additional information on storage conditions and distinguishment and description of base fractures would be better for such occasion. The bone structure is relatively loose and osteoporotic in the sella area. In addition, brain tissue hold “anomalous expansion” factor exhibiting a “cold bilges heat shrink” abnormal phenomenon within 0–4°C due to containing mostly water according to common physical knowledge. Once volume of water increases by 1/10 to the maximum when condensing into ice at 0°C, the brain tissue volume obviously increases. As the cranial cavity is a relatively closed structure, the weak basilar part of the skull ruptures because of the increased volume of brain tissue and the intracranial pressure. Together with another six cases reported cases on Forensic Journals within China, the characteristics of basilar fracture due to frozen corpses can be summarized as following: (1) Usually single and simple shape of basilar fracture was observed, probably a linear fracture, a half ring, or a ring fracture; (2) the fracture is of limited range in especially weak structures, like anterior cranial fossa sieve plate, and orbital plate; (3) because of the direction of the force from encephalic to extracranial, fracture fragment shifts, or collapses in the same direction as for annular or comminuted fractures without bleeding at the fracture site or at surrounding tissue; and (4) other rules include no violence involved, no bleeding or “raccoon sign” around the upper and lower eyelids, and no cerebrospinal fluid leaking out. Furthermore, how antemortem differs from postmortem basilar fracture is concerned. Antemortem basilar fracture would involve either anterior, middle, or posterior cranial fossa, producing a linear fracture, or with any complex variations. The fracture lines are in the same direction of the force, and the fracture zone corresponds to brain tissue rupture, bleeding, and so on.

Background: Methcathinone (CAT) acts as a designer psychostimulant and the beta-keto analog of methamphetamine, is globally abused and cause serious neurological conditions. The aim of this study is to analyze neurotoxicity of Methcathinone (CAT) to verify the hypothesis of unbalanced oxidative stress and the evaluation of apoptotic response and autophagy by sub-acute exposure to high dosage injection. Methods: To address these issues, we measured the body temperature and stereotyped motor activity during rats model setting by CAT injection in 15-day. Biochemical markers of oxidative stress were evaluated, and the activity of anti-oxidative enzymes was found significantly lower in the brains of rats that had different doses of CAT. Findings: The mechanism of the toxicological effect of CAT is proved to be partly induced by apoptotic pathway according to multiple biochemical and immunohistological methods, as well as expression of nNOS, ratios of LC3-II to LC3-I and cleaved caspase3 to procaspase3. Furthermore, we detected the inhibition of NAC to CAT induced-apoptotic and autophagy pathways effected largely compared to the CAT group through activity of SOD, GSH, GSH-PX, CAT and MDA, TUNEL staining and expression of Atg-7, Beclin-1 and ratio of LC3-II to LC3-I, which decreased neurotoxicity. Our results highlight the central role of oxidative stress in CAT neurotoxicity, as high levels of apoptosis and autophagy can promote the progression of neurotoxicity. Funding Statement: This study was supported by National Natural Science Foundation of China (Grant No. 81501632). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All animal procedures were conducted between 8:00 A.M. and 8:00 P.M. in strict accordance with the “Hubei Administration Rule of Laboratory Animal” and were approved by the Institutional Animal Care and Use Committee of Huazhong University of Science and Technology, Tongji Medical College, China (approval No. Y20100377). The description of animal procedures meets the ARRIVE recommended national standard “Laboratory Animal-Requirements of Environment and Housing Facilities”.

HIMF (hypoxia-induced mitogenic factor) is a secreted proinflammatory cytokine with a critical role in cardiac hypertrophy development. Loss of HIMF attenuates transverse aortic constriction-induced cardiac hypertrophy and fibrosis, but the underlying mechanisms are unknown. We show that IL (interleukin)-6 production increases following transverse aortic constriction in wild-type mice; this effect is inhibited in HIMF gene knockout ( Himf −/− ) mice. IL-6 production also increases in cultured cardiac myocytes overexpressing HIMF and neutralizing IL-6 with an anti-IL-6 antibody prohibits HIMF-induced cardiomyocyte hypertrophy. HIMF expression in cardiac fibroblasts cannot be stimulated by transverse aortic constriction or exposure to prohypertrophic factors, including phenylephrine, Ang II (angiotensin II), TGF (transform growth factor)-β, and hypoxia. However, conditioned medium from cardiomyocytes overexpressing HIMF can increase IL-6 production, and cardiac fibroblast proliferation, migration, and myofibroblast differentiation to a similar level as exposure to exogenous rHIMF (recombinant HIMF). Again, neutralizing IL-6 prevented cardiac fibroblasts activation. Finally, the MAPK (mitogen-activated protein kinase) and CaMKII (Ca 2+ /calmodulin-dependent protein kinase II)–STAT3 (signal transducers and activators of transcription 3) pathways are activated in HIMF-overexpressing cardiomyocytes and rHIMF-stimulated cardiac fibroblasts; this effect can be inhibited on neutralizing IL-6. These data support that HIMF induces cardiac fibrosis via a cardiomyocyte-to-fibroblast paracrine effect. IL-6 is a downstream signal of HIMF and has a central role in cardiomyocyte hypertrophy and myocardial fibrosis that is mediated by activating the MAPK and CaMKII-STAT3 pathways.

Journal of Forensic SciencesVolume 65, Issue 2 p. 664-664 Letter To The Editor Commentary on: Zhuo Y, Wang X, Wu J, Zhang S, Deng H, Liu W, et al. Simultaneous quantitative determination of amphetamines, opiates, ketamine, cocaine and metabolites in human hair: application to forensic cases of drug abuse. J Forensic Sci doi: 10.1111/1556-4029.14179. Epub 2019 Sep 9 Jin Hu Ph.D., M.D., Jin Hu Ph.D., M.D. Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei, ChinaAuthors contributed equally.Search for more papers by this authorNa Zheng Ph.D., Na Zheng Ph.D. Department of Pathology, Health Science Center, Shenzhen University, Shenzhen, 518066 Guangdong, ChinaAuthors contributed equally.Search for more papers by this authorMan Liang Ph.D., Corresponding Author Man Liang Ph.D. liangman@hust.edu.cn orcid.org/0000-0002-0543-7362 Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei, ChinaSearch for more papers by this author Jin Hu Ph.D., M.D., Jin Hu Ph.D., M.D. Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei, ChinaAuthors contributed equally.Search for more papers by this authorNa Zheng Ph.D., Na Zheng Ph.D. Department of Pathology, Health Science Center, Shenzhen University, Shenzhen, 518066 Guangdong, ChinaAuthors contributed equally.Search for more papers by this authorMan Liang Ph.D., Corresponding Author Man Liang Ph.D. liangman@hust.edu.cn orcid.org/0000-0002-0543-7362 Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei, ChinaSearch for more papers by this author First published: 25 October 2019 https://doi.org/10.1111/1556-4029.14225 See Original Article here See Authors’ Response here Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume65, Issue2March 2020Pages 664-664 RelatedInformation

HIMF (hypoxia-induced mitogenic factor/found in inflammatory zone 1/resistin like α) is a secretory and cytokine-like protein and serves as a critical stimulator of hypoxia-induced pulmonary hypertension. With a role for HIMF in heart disease unknown, we explored the possible roles for HIMF in cardiac hypertrophy by overexpressing and knocking down HIMF in cardiomyocytes and characterizing HIMF gene (himf) knockout mice. We found that HIMF mRNA and protein levels were upregulated in phenylephrine-stimulated cardiomyocyte hypertrophy and our mouse model of transverse aortic constriction-induced cardiac hypertrophy, as well as in human hearts with dilated cardiomyopathy. Furthermore, HIMF overexpression could induce cardiomyocyte hypertrophy, as characterized by elevated protein expression of hypertrophic biomarkers (ANP [atrial natriuretic peptide] and β-MHC [myosin heavy chain-β]) and increased cell-surface area compared with controls. Conversely, HIMF knockdown prevented phenylephrine-induced cardiomyocyte hypertrophy and himf ablation in knockout mice significantly attenuated transverse aortic constriction-induced hypertrophic remodeling and cardiac dysfunction. HIMF overexpression increased the cytosolic Ca2+ concentration and activated the CaN-NFAT (calcineurin-nuclear factor of activated T cell) and MAPK (mitogen-activated protein kinase) pathways; this effect could be prevented by reducing cytosolic Ca2+ concentration with L-type Ca2+ channel blocker nifedipine or inhibiting the CaSR (Ca2+ sensing receptor) with Calhex 231. Furthermore, HIMF overexpression increased HIF-1α (hypoxia-inducible factor) expression in neonatal rat ventricular myocytes, and HIMF knockout inhibited HIF-1α upregulation in transverse aortic constriction mice. Knockdown of HIF-1α attenuated HIMF-induced cardiomyocyte hypertrophy. In conclusion, HIMF has a critical role in the development of cardiac hypertrophy, and targeting HIMF may represent a potential therapeutic strategy.

A new phthalide derivative, xylarphthalide A (1), along with two known compounds (-)-5-carboxylmellein (2) and (-)-5-methylmellein (3), were isolated from the endophytic fungus Xylaria sp. GDG-102 cultured from the Chinese medicinal plant Sophora tonkinensis. Their structures were identified by MS and NMR experiments, and the absolute configuration of 1 was further confirmed by single-crystal X-ray diffraction analysis. Compound 1–3 showed antibacterial activities against Bacillus megaterium, Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Shigella dysenteriae with MIC values of 12.5–25 μg/mL.

Studies suggest the potential role of a sarcoplasmic reticulum (SR) Ca2+ leak in cardiac contractile dysfunction in sepsis. However, direct supporting evidence is lacking, and the mechanisms underlying this SR leak are poorly understood. Here, we investigated the changes in cardiac Ca2+ handling and contraction in LPS-treated rat cardiomyocytes and a mouse model of polymicrobial sepsis produced by cecal ligation and puncture (CLP). LPS decreased the systolic Ca2+ transient and myocyte contraction as well as SR Ca2+ content. Meanwhile, LPS increased Ca2+ spark–mediated SR Ca2+ leak. Preventing the SR leak with ryanodine receptor (RyR) blocker tetracaine restored SR load and increased myocyte contraction. Similar alterations in Ca2+ handling were observed in cardiomyocytes from CLP mice. Treatment with JTV-519, an anti-SR leak drug, restored Ca2+ handling and improved cardiac function. In the LPS-treated cardiomyocytes, mitochondrial reactive oxygen species and oxidative stress in RyR2 were increased, whereas the levels of the RyR2-associated FK506-binding protein 1B (FKBP12.6) were decreased. The Toll-like receptor 4 (TLR4)–specific inhibitor TAK-242 reduced the oxidative stress in LPS-treated cells, decreased the SR leak, and normalized Ca2+ handling and myocyte contraction. Consistently, TLR4 deletion significantly improved cardiac function and corrected abnormal Ca2+ handling in the CLP mice. This study provides evidence for the critical role of the SR Ca2+ leak in the development of septic cardiomyopathy and highlights the therapeutic potential of JTV-519 by preventing SR leak. Furthermore, it reveals that TLR4 activation-induced mitochondrial reactive oxygen species production and the resulting oxidative stress in RyR2 contribute to the SR Ca2+ leak.

A new compound, 6-heptanoyl-4-methoxy-2H-pyran-2-one (1), was isolated from the endophytic fungus Xylaria sp. GDG-102 from the leaf of Sophora tonkinensis. The structure of the new compound was elucidated on the basis of 1D and 2D NMR spectra. Compound 1 showed antimicrobial activity against E. coli and S. aureus with MIC values 50 μg/mL.

Two new cyclopentapeptides, xylapeptide A (1) with an uncommon L-pipecolinic acid moiety, and xylapeptide B (2) having a common L-proline residue were identified from an associated fungus Xylaria sp. isolated from the Chinese medicinal plant Sophora tonkinensis. Their planar structures were elucidated by a comprehensive analysis of NMR and MS spectroscopic spectra. The absolute configurations were determined by Marfey’s method and single-crystal X-ray diffraction (Cu Kα) analysis. Xylapeptide A (1) is the first example of cyclopentapeptide with L-Pip of terrestrial origin and showed strong antibacterial activity against Bacillus subtilis and B. cereus with MIC value of 12.5 μg/mL.

BACKGROUND:Recent studies highlighted the protective benefits of a Chinese herb extract from polygonum cuspidatum, trans-polydatin, on cardiac disease. We investigated the therapeutic effect of trans-polydatin on myocardial ischemia/reperfusion (IR) injury and the underlying mechanisms related to the renin-angiotensin system (RAS) and RhoA kinase (ROCK) pathway.METHODS AND RESULTS:Experiments were performed on neonatal rats' ventricular myocytes that were subjected to hypoxia-reoxygenation (simulated IR, SIR) and on adult mice which were subjected to left anterior descending coronary artery occlusion for 45 min followed by a one-week reperfusion. trans-Polydatin significantly increased cell viability and reduced apoptosis in SIR cardiomyocytes. It was also observed to reduce the infarct size and increase the cardiac function in IR mice. trans-Polydatin decreased the expression of angiotensin and inhibited the activities of renin and angiotensin-converting enzyme. Furthermore, trans-polydatin inhibited ROCK activity, especially the angiotensin I receptor-activated ROCK pathway.CONCLUSIONS:trans-Polydatin exerts a cardio-protection against myocardial IR injury likely through inhibiting both RAS and the downstream ROCK pathway.