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Qiang Shao,1,2,* Ying Zhang,2,* Zhiyuan Zhang,2 Wei Jiang,2 Yongcheng Yin,3 Yuepeng Fang,1 Ce Zhang,1 Qingfa Chen,2 Bin Ning1,2 1Cheeloo College of Medicine, Jinan Central Hospital, Shandong University, Jinan, People’s Republic of China; 2Central Hospital Affiliated to Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 3School of Clinical Medicine, Shandong Second Medical University, Weifang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bin Ning; Qingfa Chen, Central Hospital Affiliated to Shandong First Medical University, No. 105, Jiefang Road, Jinan, Shandong, 250013, People’s Republic of China, Tel +86-18866510349, Email bning@sdfmu.edu.cn; tsingfachan@163.comBackground: Post-spinal cord injury (SCI) inflammation correlates with neurologic recovery. Through sequencing, we explored the roles of a differentially expressed circRNA in mice after SCI, circGla, on inflammation and recovery of SCI.Methods: The T8–T10 SCI model was established in C57BL6 mice. HE staining and RT-qPCR verified circGla upregulation results after injury obtained through sequencing. RNase R digestion and primer amplification experiments confirmed the circular properties of circGla. Nucleus and cytoplasm isolation experiments and FISH confirmed circGla expression in the astrocyte cytoplasm. AAV was used to establish a circGla knockdown mouse model. Behavioral tests were conducted to assess the recovery of the neurological function. The key inflammatory molecules after SCI were evaluated through MRI, RT-qPCR, and ELISA. For in vitro experiments, circGla was upregulated or knocked down in mouse astrocytes to detect its effect. The binding between miR-488 and circGla was confirmed through RIP and the dual luciferase experiment. RT-qPCR and ELISA confirmed the content correlation of the two molecules and the in vitro inflammatory function of miR-488. The binding experiment in astrocytes confirmed the binding between miR-488 and MEKK1 mRNA. Western blotting of MAPK pathway-related proteins confirmed that MEKK1 is a downstream effector for circGla and miR-488 in astrocytes.Results: Following SCI, the circular RNA circGla levels increased and it existed in the astrocyte cytoplasm. circGla knockdown reduced inflammation and improved neurological recovery in vivo. The correlation between circGla and proinflammatory factors was confirmed in vitro. circGla bound to miR-488, and the high miR-488 level was associated with the low astrocyte inflammatory state. miR-488 bound to MEKK1 mRNA, and upregulation or knockdown of circGla or miR-488 affected MAPK pathway-related protein expression.Conclusion: Following SCI, downregulation of circGla expression in astrocytes can reduce inflammatory manifestations and stimulate long-term functional recovery in mice through miR-488 and MEKK1. Keywords: non-coding RNAs, inflammation, competing endogenous RNAs, traumatic spinal cord injury, secondary injury

Yang Guo,1– 4 Bobin Ning,5 Qunhui Zhang,1– 4 Jing Ma,4 Linlin Zhao,1– 4 QiQin Lu,1– 4 Dejun Zhang1,4 1Research Center for High Altitude Medicine, Medical College of Qinghai University, Xining, 810001, People’s Republic of China; 2Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province, Medical College of Qinghai University, Xining, 810001, People’s Republic of China; 3Qinghai-Utah Joint Research Key Lab for High Altitude Medicine, Medical College of Qinghai University, Xining, 810001, People’s Republic of China; 4Department of Eco-Environmental Engineering, Qinghai University, Xining, 810016, People’s Republic of China; 5Department of Medicine, The General Hospital of the People’s Liberation Army, Beijing, 100038, People’s Republic of ChinaCorrespondence: Dejun ZhangDepartment of Eco-Environmental Engineering, Qinghai University, Qinghai, 810016, People’s Republic of ChinaEmail djzhangqhu@163.comPurpose: The objective of this study was to identify the potential regulatory mechanisms, diagnostic biomarkers, and therapeutic drugs for heart failure (HF).Methods: Differentially expressed genes (DEGs) between HF and non-failing donors were screened from the GSE57345, GSE5406, and GSE3586 datasets. Database for Annotation Visualization and Integrated Discovery and Metascape were used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses respectively. The GSE57345 dataset was used for weighted gene co-expression network analysis (WGCNA). The intersecting hub genes from the DEGs and WGCNA were identified and verified with the GSE5406 and GSE3586 datasets. The diagnostic value of the hub genes was calculated through receiver operating characteristic analysis and net reclassification index (NRI). Gene set enrichment analysis (GSEA) was used to filter out the signaling pathways associated with the hub genes. SYBYL 2.1 was used for molecular docking of hub targets and potential HF drugs obtained from the connection map.Results: Functional annotation of the DEGs showed enrichment of negative regulation of angiogenesis, endoplasmic reticulum stress response, and heart development. PTN, LUM, ISLR, and ASPN were identified as the hub genes of HF. GSEA showed that the key genes were related to the transforming growth factor-β (TGF-β) and Wnt signaling pathways. Sirolimus, LY-294002, and wortmannin have been confirmed as potential drugs for HF.Conclusion: We identified new hub genes and candidate therapeutic drugs for HF, which are potential diagnostic, therapeutic and prognostic targets and warrant further investigation.Keywords: differentially expressed genes, weighted gene co-expression network analysis, diagnostic biomarkers, therapeutic drugs, heart failure

Shuyuan Liu,1,2,&ast; Ling Xing,1,3,&ast; Qian Wang,4 Tianyu Xin,2 Handing Mao,1 Ye Tao,5 Jinbao Zhao,2 Xin Li,4 Cong Li,1 Qinghua Li,6 Yan Dou,7 Yixin Li,8 Wei Zhang,9 Bo Ning,10 Qing Song1 1Medical School of Chinese PLA, Beijing, People’s Republic of China; 2Emergency Department, Sixth Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Department of Emergency, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Emergency Department, Third Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China; 5Health Care Department, Beijing Huangsi Aesthetic Surgery Hospital, Beijing, People’s Republic of China; 6Department of Intensive Care Unit, The 990th Hospital of Chinese PLA, Zhumadian, People’s Republic of China; 7Department of Intensive Care Unit, The 909th Hospital of Chinese PLA, Zhangzhou, People’s Republic of China; 8Department of Intensive Care Unit, The 910th Hospital of Chinese PLA, Quanzhou, People’s Republic of China; 9Emergency Department, The 900th Hospital of Chinese PLA, Fuzhou, People’s Republic of China; 10Department of Intensive Care Unit, Air Force Medical Center of China, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo NingDepartment of Intensive Care Unit, Air Force Medical Center of China, Beijing, 100142, People’s Republic of ChinaTel +86 15611161110Fax +86 1068410099Email boningbn@163.comQing SongMedical School of Chinese PLA, Beijing, 100853, People’s Republic of ChinaTel +86 13911374534Fax +86 1068182255Email songqing_sq87@163.comObjective: The purpose of this study is to evaluate the factors involved in the early stage of exertional heat stroke (EHS) that are associated with mortality.Methods: In this retrospective, case-control study, patients from 11 tertiary medical centers in China were enrolled from January 1, 2012, to December 31, 2019. Demographic information, underlying diseases, ambient temperature, and relative humidity, clinical manifestations, initial body temperature, time from onset to diagnosis of EHS (including suspected), and the duration of body temperature > 38°C of all enrolled patients were recorded. The occurrence of organ dysfunction within 72 h was evaluated, and in-hospital deaths were recorded. The patients were subsequently divided into a survival group and a non-survival group. The “case” refers to patients in the non-survival group, while the “control” refers to patients without death.Results: Of the 214 hospitalized patients with EHS, 183 survived and 31 died, and the overall mortality was 14.49% (31/214). A binary logistic regression showed that only the duration of body temperature > 38°C (OR 1.80, 95% CI 1.34– 2.42) and the number of organs damaged within 72 h of onset (OR 6.54, 95% CI 2.31– 18.56) were statistically significant in terms of risk of death in hospital (p < 0.05). A goodness of fit test produced a p-value of 0.76. According to receiver operating characteristic curve (ROC) analysis, the areas under the curve (AUC) were 0.989 (95% CI 0.978– 1.000; p < 0.05) and 0.936 (95% CI 0.896– 0.976; p < 0.05).Conclusion: Of the various factors involved in the early stage of the disease, the duration of high body temperature and the number of organs damaged within 72 h of onset were independent risk factors and predictors associated with death.Keywords: heat stroke, exertional, cooling, mortality

Songyuan Luo,* Huanyu Ding,* Jianfang Luo, Wei Li, Bing Ning, Yuan Liu, Wenhui Huang, Ling Xue, Ruixin Fan, Jiyan Chen Cardiology Department, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China *These authors contributed equally to this work Background: Thoracic endovascular aortic repair (TEVAR) has become an emerging treatment modality for acute type B aortic dissection (TBAD) patients in recent years. The risk factors and impacts of acute kidney injury (AKI) after percutaneous TEVAR, however, have not been widely established.Methods: We retrospectively studied the clinical records of 305 consecutive patients who admitted to our institution and had TEVAR for TBAD between December 2009 and June 2013. The patients were routinely monitored for their renal functions preoperatively until 7 days after TEVAR. The Kidney Disease Improving Global Guidelines (KDIGO) criteria were used for AKI.Results: Of the total 305 consecutive patients, 84 (27.5%) developed AKI after TEVAR, comprising 66 (21.6%) patients in KDIGO stage 1, 6 (2.0%) patients in stage 2 and 12 (3.9%) patients in stage 3. From the logistic regression analysis, systolic blood pressure (SBP) on admission >140 mmHg (odds ratio [OR], 2.288; 95% CI, 1.319–3.969) and supra-aortic branches graft bypass hybrid surgery (OR, 3.228; 95% CI, 1.526–6.831) were independent risk factors for AKI after TEVAR. Local anesthesia tended to be a protective factor (OR, 0.563; 95% CI, 0.316–1.001). The preoperative renal function, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or statin administration, volume of contrast agent, range of TBAD and false lumen involving renal artery were not associated with post-operation AKI. The in-hospital mortality and major adverse events were markedly increased with the occurrence of AKI (7.1% vs 0.9%, P=0.006; 14.3% vs 3.2%, P

Xuemei Zhang,1 Maosheng Huang,2 Xifeng Wu,2 Susan Kadlubar,1 Jie Lin,2 Xinfeng Yu,1 Chunyang Fan,3 Baitang Ning,4 Fred F Kadlubar1†1University of Arkansas for Medical Sciences, Little Rock, Arkansas, 2The University of Texas MD Anderson Cancer Center, Houston, Texas, 3VA hospital, Little Rock, Arkansas, 4National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas, USA†Fred F Kadlubar passed away on December 4, 2010.Abstract: The objective of this study was to determine copy number variant (CNV) and promoter genetic variants in glutathione S-transferase Mu class 1 (GSTM1) and the risk of recurrence (REC)/second primary tumor (SPT) in patients with previously diagnosed early stage head and neck cancer. Among 441 subjects, 133 experienced REC and/or an SPT, while 308 had single primary disease. TaqMan real-time polymerase chain reaction was used to measure the exact copy number of GSTM1 and direct sequencing was used to determine genetic variants in the GSTM1 promoter region. Multivariate Cox regression analysis was performed to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) associated with copy number and genetic variants. REC/SPT-free survival times were compared by constructing Kaplan–Meier curves and differences between curves were tested by logrank test. Results showed a significantly decreased REC/SPT (HR = 0.57; 95% CI = 0.35–0.95) and longer REC/SPT-free survival in subjects with at least two copies of GSTM1 compared with the GSTM1 homozygous deletion, but not in those with one copy of GSTM1. The −498G, −426G, and −339T alleles were significantly associated with REC/SPT, with HRs of 0.11 (0.02–0.85), 0.28 (0.11–0.74) and 2.02 (1.07–3.82), respectively. Kaplan–Meier survival analysis showed that the −498G, −426G, and −339C alleles were also significantly associated with increased REC/SPT-free survival. Further haplotype analysis showed the haplotype P-498G--426G--339C carriers had decreased REC/SPT with a HR of 0.09 (95% CI 0.01–0.71) and increased REC/SPT-free survival compared with those with haplotype P-498C--426A--339T. The P-498C--426A--339T-containing reporter construct had significantly increased luciferase expression. These results suggest that the GSTM1 CNV and promoter haplotype are better predictors of REC/SPTs of head and neck cancer than just measuring the presence/absence of GSTM1.Keywords: GSTM1, copy number variant, REC, SPT, single nucleotide polymorphism

Vineetha Koroth Edavana1, Xinfeng Yu1, Ishwori B Dhakal1, Suzanne Williams1, Baitang Ning2, Ian T Cook3, David Caldwell1, Charles N Falany3, Susan Kadlubar11Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 2Division of Personalized Nutrition and Medicine, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, USA; 3Department of Pharmacology, University of Alabama, Birmingham, AL, USAAbstract: Fulvestrant (Faslodex™) is a pure antiestrogen that is approved to treat hormone receptor-positive metastatic breast cancer in postmenopausal women. Previous studies have demonstrated that fulvestrant metabolism in humans involves cytochromes P450 and UDP-glucuronosyltransferases (UGTs). To date, fulvestrant sulfation has not been characterized. This study examined fulvestrant sulfation with nine recombinant sulfotransferases and found that only SULT1A1 and SULT1E1 displayed catalytic activity toward this substrate, with Km of 4.2 ± 0.99 and 0.2 ± 0.16 µM, respectively. In vitro assays of 104 human liver cytosols revealed marked individual variability that was highly correlated with β-naphthol sulfation (SULT1A1 diagnostic substrate; r = 0.98, P < 0.0001), but not with 17ß-estradiol sulfation (SULT1E1 diagnostic substrate; r = 0.16, P = 0.10). Fulvestrant sulfation was correlated with both SULT1A1*1/2 genotype (P value = 0.023) and copy number (P < 0.0001). These studies suggest that factors influencing SULT1A1/1E1 tissue expression and/or enzymatic activity could influence the efficacy of fulvestrant therapy.Keywords: fulvestrant, sulfotransferase, genotype, copy number

Abstract We conjecture a multi-parameter generalization of the toric inequalities of [1]. We then extend their proof methods for the generalized toric inequalities in two ways. The first extension constructs the graph corresponding to the toric inequalities and the generalized toric conjectures by tiling the Euclidean space. An entanglement wedge nesting relation then determines the geometric structure of the tiles. In the second extension, we exploit the cyclic nature of the inequalities and conjectures to construct cycle graphs. Then, the graph can be obtained using graph Cartesian products of cycle graphs. In addition, we define a set of knots on the graph by following [1]. These graphs with knots then imply the validity of their associated inequality. We study the case where the graph can be decomposed into disjoint unions of torii. Under the specific case, we explore and prove the conjectures for some ranges of parameters. We also discuss ways to explore the conjectured inequalities whose corresponding geometries are d-dimensional torii (d > 2).

Abstract Background Juvenile hormone (JH) is an insect-exclusive hormone involved in regulating diverse aspects of insect physiology, and the evolution of its diverse function is widely interesting. Studying embryogenesis in basal wingless insects is important to understand the functional evolution of JH; however, experimental studies in this regard are scarce. In this study, we conducted CRISPR/Cas9-mediated knockout (KO) of genes involved in JH biosynthesis and signaling cascades in the ametabolous firebrat, Thermobia domestica. Additionally, we investigated whether the primitive action of JH is conserved in the hemimetabolous cricket, Gryllus bimaculatus. Results We observed that KO of JHAMT, CYP15A1, Met, and Kr-h1 resulted in embryonic lethality in T. domestica. Deprivation of JH or JH signaling arrested the progression of extraembryonic fluid resorption after dorsal closure and hatching, which is consistent with the gene expression pattern showing high Kr-h1 expression in the late embryos of T. domestica. The embryos deficient in JH signaling displayed wrinkled and weak legs. Comparative transcriptome analysis revealed that JH signaling promotes embryonic leg maturation through inducing energy supply and muscle activity, as validated by transmission electron microscopy (TEM). In addition, JH signaling exhibited similar embryonic effects in G. bimaculatus. Conclusions This study reveals the indispensable role of JH signaling in facilitating the maturation of terminal tissues during late embryogenesis, as demonstrated by the regulation of leg development, in ametabolous and hemimetabolous insects. These findings further indicate that the embryonic functions of JH evolved earlier than its anti-metamorphic functions during postembryonic development.

Abstract We present a deterministic way of finding contraction maps for candidate holographic entanglement entropy inequalities modulo choices due to actual degeneracy. We characterize its complexity and give an argument for the completeness of the contraction map proof method as a necessary and sufficient condition for the validity of an entropy inequality for holographic entanglement.

Pharmacologic treatment of orthopedic diseases is a common challenge for clinical orthopedic surgeons, and as an important step in the stepwise treatment of orthopedic diseases, it is often difficult to achieve satisfactory results with existing pharmacologic treatments. Therefore, it is increasingly important to find new ways to effectively improve the treatment pattern of orthopedic diseases as well as to enhance the therapeutic efficacy. It has been found that metal-organic frameworks (MOFs) possess the advantages of high specific surface area, high porosity, chemical stability, tunability of structure and biocompatibility. Therefore, MOFs are expected to improve the conventional traditional treatment modality for bone diseases. This manuscript reviewed the applications of MOFs in the treatment of common clinical bone diseases and look forward to its future development.