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Huiqian Guo,1,2,* Jing Luo,1,3,* Suming Chen,1 Ting Yu,4 Xiaofei Mu,4 Fangzhou Chen,4 Xiuhui Lu,4 Jiaqi He,4 Yali Zheng,4 Chunmei Bao,2 Peng Wang,4 Zhe Yin,4 Boan Li1– 3 1Department of Clinical Laboratory, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, People’s Republic of China; 2School of Medical Laboratory, Weifang Medical University, Weifang, 261053, People’s Republic of China; 3Medical School of Chinese PLA, Beijing, 100853, People’s Republic of China; 4State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, People’s Republic of China*These authors contributed equally to this workCorrespondence: Boan Li, Department of Clinical Laboratory, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, People’s Republic of China, Email lba@263.net Zhe Yin, State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, People’s Republic of China, Email jerry9yin@163.comPurpose: To investigate the genetic diversity of IncG plasmids, we have proposed a typing scheme based on replicon repA and performed comparative genomic analysis of five IncG plasmids from China.Methods: p30860-KPC, p116965-KPC, pA1705-KPC, pA1706-KPC and pNY5520-KPC total in five IncG plasmids from clinical isolates of Pseudomonas and Enterobacteriaceae, respectively, were fully sequenced and were compared with the previously collected reference plasmid p10265-KPC.Results: Based on phylogeny, IncG-type plasmids are divided into IncG-I to IncG-VIII, the five plasmids belong to IncG-VIII. A detailed sequence comparison was then presented that the IncG plasmid involved accessory region I (Tn 5563a/b/c/d/e), accessory region II (ISpa19), and accessory region III (blaKPC-2-region). Expect for the pNY5520-KPC, the rest of the plasmids had the same backbone structure as the reference one. Within the plasmids, insertion sequences Tn 5563d and Tn 5563e were identified, a novel unknown insertion region was found in Tn 5563b/c/d/e. In addition, Tn 6376b and Tn 6376c were newly designated in the study.Conclusion: The data presented here including a typing scheme and detailed genetic comparison which provide an insight into the diversification and evolution history of IncG plasmids.Keywords: IncG plasmids, blaKPC-2, phylogenetic tree, multidrug resistance, mobile elements

Shenjiao Wang,1,2,* Xin Zou,3– 5,* Jianguang Fu,1 Fei Deng,1 Huiyan Yu,1 Huan Fan,1 Qigang Dai,1 Qingxiang Shang,5 Ke Xu,1 Changjun Bao1,5 1Acute Infectious Disease Control and Prevention Institute, Jiangsu Provincial Center for Disease Control and Prevention (Jiangsu Provincial Academy of Preventive Medicine), Nanjing, Jiangsu Province, People’s Republic of China; 2Ili Kazakh Autonomous Prefecture Center for Disease Control and Prevention, Ili, Xinjiang, People’s Republic of China; 3Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China; 4Chongqing Key Laboratory of Viral Infectious Diseases, Chongqing, People’s Republic of China; 5School of Public Health, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ke Xu; Changjun Bao, Acute Infectious Disease Control and Prevention Institute, Jiangsu Provincial Center for Disease Control and Prevention (Jiangsu Provincial Academy of Preventive Medicine), No. 172, Jiangsu Road, Gulou District, Nanjing, Jiangsu Province, 210009, People’s Republic of China, Tel +86-18915999237, +86-18118996911, Email xuke923@163.com; bao2000_cn@163.comBackground: Human adenovirus (HAdV) is common pathogens that cause various respiratory diseases. The genetic diversity of viruses caused by recombination is considered to be the main source of emerging outbreaks. The aim of this study is to explore the evolutionary relationship and recombination events of HAdV genome in respiratory tract infections in Jiangsu Province.Methods: Whole-genome sequencing (WGS) technology was used to sequence 66 patients with HAdV infection (37 patients with influenza-like illness (ILI) and 29 hospitalized patients with pneumonia) from Jiangsu Province. Epidemiological analysis was performed on hospitalized pneumonia and ILI patients infected with HAdV. Subsequently, phylogenetic, recombination, and nucleotide and amino acid identity analyses were performed.Results: Epidemiological analysis of patients undergoing WGS showed that 75.7% of ILI patients were infected with the HAdVB strain and 69.0% of hospitalized pneumonia patients were infected with the HAdVC strain. Moreover, the hospitalized pneumonia and ILI patients infected with HAdV were different in region and time. The strains of HAdVB3 and HAdVB7 genotypes were mainly infected in 2015 and 2017, and the strains of HAdVC1 and HAdVC2 genotypes were mainly infected in 2020. The results of histogram analysis showed that the HAdV strain mainly infected children under 5 years old. In addition, 36 novel recombinant strains were identified. The discovery of these recombinant strains may contribute to understanding the epidemiology of HAdV and research on related vaccines. Furthermore, the percentage of nucleotide and amino acid identities revealed a high level of genetic conservation within isolates from HAdVB3, HAdVB7, HAdVC1, HAdVC2 and HAdVC5 genotypes.Conclusion: The WGS analysis reveals the evolutionary relationships and recombination events of HAdV strains in Jiangsu Province, which is helpful to deepen the understanding of HAdV epidemiology and evolution. In addition, it provides a basis for the formulation of public health strategies in Jiangsu Province.Keywords: human adenovirus, whole genome sequencing, phylogenetic analysis, recombination

Chenxuan Bao,1 Huayuan Xiang,1 Qiaoqiao Chen,1,2 Yuxue Zhao,1,2 Qianqian Gao,1 Feng Huang,1 Lingxiang Mao1,2 1Department of Laboratory Medicine, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, People’s Republic of China; 2Department of Laboratory Medicine, the Affiliated People’s Hospital, Jiangsu University, Zhenjiang, Jiangsu, People’s Republic of ChinaCorrespondence: Lingxiang Mao, Department of Laboratory Medicine, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, People’s Republic of China, Tel +86 15358599331, Email maolingxiang@aliyun.comAbstract: Small extracellular vesicles (sEVs), a subset of extracellular vesicles (EVs) originating from the endosomal compartment, are a kind of lipid bilayer vesicles released by almost all types of cells, serving as natural carriers of nucleic acids, proteins, and lipids for intercellular communication and transfer of bioactive molecules. The current findings suggest their vital role in physiological and pathological processes. Various sEVs labeling techniques have been developed for the more advanced study of the function, mode of action, bio-distribution, and related information of sEVs. In this review, we summarize the existing and emerging sEVs labeling techniques, including fluorescent labeling, radioisotope labeling, nanoparticle labeling, chemical contrast agents labeling, and label-free technique. These approaches will pave the way for an in-depth study of sEVs. We present a systematic and comprehensive review of the principles, advantages, disadvantages, and applications of these techniques, to help promote applications of these labeling approaches in future research on sEVs.Keywords: small extracellular vesicles, label, image, tracking, in vivo imaging

This research serves as an initial exploration into a novel zinc carrier derived from gelatin obtained from the skin of featherback fish (Chitala ornata), which is a natural source. The skin was found to contain approximately 63.23 ± 0.51 % moisture, 71.18 ± 1.82 % crude protein, 9.13 ± 3.40 % crude lipid, and 19.69 ± 1.61 % ash (on a dry weight basis). To extract the gelatin, warm water was used, followed by hydrolysis using Alcalase. The gelatin-to-water ratio was 1:4 (w/v), with a pH of 8, temperature of 50 °C, enzyme-to-substrate (E:S) ratio of 40 U/g protein, and a hydrolysis time of 4 h. The resulting hydrolysate exhibited a degree of hydrolysis (DH) of 18.46 ± 1.35 % and a zinc-binding capacity (ZnBC) of 39.66 ± 1.56 % (which was 2.00 times lower than that of ethylenediamine tetraacetic acid disodium salt (Na2EDTA)). The hydrolysate's activity remained above 60 % even after exposure to a wide pH range 1-11 and treatment for 180 min at 100 °C. Notably, the hydrolysate contained a significant amount of hydroxyproline (Hyp), measuring 1550 mg/L. Ultrafiltration was utilized to fractionate the hydrolysate, resulting in five peptide fractions (>30 kDa, 10-30 kDa, 3-10 kDa, 1-3 kDa, and

In this study, featherback (Chitala ornata) skin was used to generate an antioxidant protein hydrolysate with foaming and emulsifying properties. Hydrolysates were obtained by using Alcalase preparation, a skin:water ratio of 1:2 (w/v), a pH 7.5, 55 °C, an enzyme:substrate ratio of 80 U/g protein, and a 5 h hydrolysis time. In terms of antioxidant activity, the hydrolysate showed 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging capacity at 3.00 mg/mL and 1.82 mg/mL as the inhibitory concentration of 50 % free radicals (IC50), which was 731.71 and 27.58 folds higher than those of vitamin C, in order. It also displayed moderate foaming property, with its foaming capacity (FC) and foaming stability (FS) being 1.08 - 1.55 and 1.19 - 2.89 times lower than those of albumin, in that order. In contrast, the hydrolysate exhibited great emulsifying properties with an emulsifying activity index (EAI) and emulsifying stability index (ESI) comparable to those of sodium caseinate at pH 3-8. The hydrolysate contained a high concentration of lipophilic amino acids (AAs) (87.28 % of total AA content). As a result, featherback skin hydrolysate may be considered as a versatile ingredient for the development of natural antioxidants with technological capabilities.

Jinyan Lin,* Yu Zhang,* Chongxi Bao, Huasong Lu, Yun Zhong, Chuanfeng Huang, Qiuping Huang, Dezhen Wang, Jing Luo, Ke Wang, Jinliang Kong Pulmonary and Critical Care Medicine Ward, Guangxi Medical University First Affiliated Hospital, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinliang Kong; Ke Wang, Pulmonary and Critical Care Medicine Ward, Guangxi Medical University First Affiliated Hospital, No. 6 Shuangyong Road, Nanning, 530021, People’s Republic of China, Email kjl071@126.com; 497256113@qq.comBackground: Streptococcus constellatus, a commensal, plays an important role in purulent infections. It has been reported as aggressive pathogen causing pleural empyema. But the role of S. constellatus in empyema has not been taken seriously. There are no studies about clinical characteristics of empyema caused by S. constellatus domestically and abroad. This study aimed to explore the clinical features and management of empyema caused by S. constellatus.Methods: A retrospective review of 9 patients diagnosed with empyema caused by S. constellatus in a hospital between January 2010 and August 2021 was performed.Results: S. constellatus empyema were mostly seen in old males (66.7%) with comorbid diseases. The high-risk factors include diabetes mellitus, oral infection, and oral surgery. All were unilateral encapsulated empyema (right-side, 55.6%), diagnosed with pneumonia (bilateral pneumonia, 88.9%; ipsilateral lung abscess, 44.4%). 33.3% of patients had S. constellatus and anaerobes co-isolated. S. constellatus were sensitive to penicillin G, linezolid, levofloxacin, vancomycin, ceftriaxone, and chloramphenicol, resistant to erythromycin, tetracycline, and clindamycin. 33.3% of the patients needed ventilator support. The primary treatment to S. constellatus empyema was timely pus drainage, intravenous antibiotics, and enough nutrition support, intrapleural fibrinolytics and surgery (VAST recommended first) in necessity.Conclusion: S. constellatus may cause pneumonia and lung abscess first and then spread to cause empyema mainly in old males with comorbid diseases. S. constellatus often co-isolated with anaerobes in empyema. Antibiotics should cover simultaneously both S. constellatus and anaerobes.Keywords: S. constellatus, empyema, clinical features, anaerobes

Jiayao Guan,1,* Chunmei Bao,2,* Peng Wang,3 Ying Jing,3 Lingling Wang,3 Xinyue Li,3 Xiaofei Mu,3 Boan Li,2 Dongsheng Zhou,3 Xuejun Guo,1 Zhe Yin3 1Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, Jilin, 130122, People’s Republic of China; 2Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China; 3State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhe Yin, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, People’s Republic of China, Tel +86-10-66948557, Email jerry9yin@163.com Xuejun Guo, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, Jilin, 130122, People’s Republic of China, Tel +86-431-86985931, Email xuejung2021@163.comPurpose: The aim of this study was to gain a deeper genomics and bioinformatics understanding of diversification of accessory genetic elements (AGEs) in Providencia.Methods: Herein, the complete genome sequences of five Providencia isolates from China were determined, and seven AGEs were identified from the chromosomes. Detailed genetic dissection and sequence comparison were applied to these seven AGEs, together with additional 10 chromosomal ones from GenBank (nine of them came from Providencia).Results: These 17 AGEs were divided into four groups: Tn 6512 and its six derivatives, Tn 6872 and its two derivatives, Tn 6875 and its one derivative, and Tn 7 and its four derivatives. These AGEs display high-level diversification in modular structures that had complex mosaic natures, and particularly different multidrug resistance (MDR) regions were presented in these AGEs. At least 52 drug resistance genes, involved in resistance to 15 different categories of antimicrobials and heavy metal, were found in 15 of these 17 AGEs.Conclusion: Integration of these AGEs into the Providencia chromosomes would contribute to the accumulation and distribution of drug resistance genes and enhance the ability of Providencia isolates to survive under drug selection pressure.Keywords: Providencia, integrative and conjugative elements, integrative and mobilizable elements, unit transposons, multidrug resistance

Xuanxuan Liu,1,2 Xingxing Wang,1 Yan Pan,1 Li Zhao,3 Shuo Sun,1 Ang Luo,3 Changlei Bao,3,4 Haiyang Tang,3,4 Ying Han1 1Key Laboratory of Targeted Intervention for Cardiovascular Disease, Collaborative Innovation Center of Translational Medicine for Cardiovascular Disease, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Physiology and Pathologic Physiology, Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, People’s Republic of China; 3College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, People’s Republic of China; 4State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Ying HanKey Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center of Translational Medicine for Cardiovascular Disease, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, People’s Republic of ChinaTel/Fax +86-25-86869351Email yhancn@njmu.edu.cnHaiyang TangState Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, People’s Republic of ChinaTel +86-15975396262Email tanghy2008@yahoo.comPurpose: Endothelial dysfunction and the subsequent decrease in endothelium-dependent vascular relaxation of small arteries are major features of hypertension. Artemisinin, a well-known antimalarial drug, has been shown to exert protecting roles against endothelial cell injury in cardiac and pulmonary vascular diseases. The current study aimed to investigate the effects of artemisinin on endothelium-dependent vascular relaxation and arterial blood pressure, as well as the potential signalling pathways in spontaneously hypertensive rats (SHRs).Methods: In this study, acetylcholine (ACh)-induced dose-dependent relaxation assays were performed to evaluate vascular endothelial function after treatment with artemisinin. Artemisinin was administered to the rats by intravenous injection or to arteries by incubation for the acute exposure experiments, and it was administered to rats by intraperitoneal injection for 28 days for the chronic experiments.Results: Both acute and chronic administration of artemisinin decreased the heart rate and improved ACh-induced endothelium-dependent relaxation but negligibly affected the arterial blood pressure in SHRs. Incubation with artemisinin decreased basal vascular tension, NAD(P)H oxidase activity and reactive oxygen species (ROS) levels, but it also increased endothelial nitric oxide (NO) synthase (eNOS) activity and NO levels in the mesenteric artery, coronary artery, and pulmonary artery of SHRs. Artemisinin chronic administration to SHRs increased the protein expression of eNOS and decreased the protein expression of the NAD(P)H oxidase subunits NOX-2 and NOX-4 in the mesenteric artery.Conclusion: These results indicate that treatment with artemisinin has beneficial effects on reducing the heart rate and basal vascular tension and improving endothelium-dependent vascular relaxation in hypertension, which might occur by increasing eNOS activation and NO release and inhibiting NAD(P)H oxidase derived ROS production.Keywords: hypertension, artemisinin, vascular function, nitric oxide, reactive oxygen species

Yao Tong,* Chengrong Bao,* Yi-Qiong Xu,* Lei Tao,* Yao Zhou, Lei Zhuang, Ying Meng, Hui Zhang, Jingjing Xue, Weijun Wang, Lele Zhang, Qingbo Pan, Zhenzhen Shao, Tianran Hu, Qian Guo, Qingsheng Xue, Han Lu, Yan Luo Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Luo; Han Lu Email ly11087@rjh.com.cn; luhan0301@163.comBackground: Acute lung injury (ALI) is a severe respiratory disease with high rates of morbidity and mortality. Many mediators regarding endogenous or exogenous are involved in the pathophysiology of ALI. Here, we have uncovered the involvement of integrins and matrix metalloproteinases, as critical determinants of excessive inflammation and endothelial permeability, in the regulation of ALI.Methods: Inflammatory cytokines were measured by quantitative real-time PCR for mRNA levels and ELISA for secretion levels. Endothelial permeability assay was detected by the passage of rhodamine B isothiocyanate-dextran. Mice lung permeability was assayed by Evans blue albumin (EBA). Western blot was used for protein level measurements. The intracellular reactive oxygen species (ROS) were evaluated using a cell-permeable probe, DCFH-DA. Intratracheal injection of lipopolysaccharide (LPS) into mice was conducted to establish the lung injury model.Results: Exogenous MMP-9 significantly aggravated the inflammatory response and permeability in mouse pulmonary microvascular endothelial cells (PMVECs) treated by LPS, whereas knockdown of MMP-9 exhibited the opposite phenotypes. Knockdown of integrin β 3 or β 5 in LPS-treated PMVECs significantly downregulated MMP-9 expression and decreased inflammatory response and permeability in the presence or absence of exogenous MMP-9. Additionally, the interaction of MMP-9 and integrin β 5 was impaired by a ROS scavenger, which further decreased the pro-inflammatory cytokines production and endothelial leakage in PMVECs subjected to co-treatment (LPS with exogenous MMP-9). In vivo studies, exogenous MMP-9 treatment or knockdown β 3 integrin significantly decreased survival in ALI mice. Notably, knockdown of β 5 integrin alone had no remarkable effect on survival, but which combined with anti-MMP-9 treatment significantly improved the survival by ameliorating excessive lung inflammation and permeability in ALI mice.Conclusion: These findings support the β 3/5 integrin-MMP-9 axis as an endogenous signal that could play a pivotal role in regulating inflammatory response and alveolar-capillary permeability in ALI.Keywords: acute lung injury, endothelial cells, integrin, MMP-9

Xiaoning Cen,1,&ast; Yunmei Huang,2,&ast; Zhuangnian Lu,3,&ast; Wenjun Shao,4 Chenyi Zhuo,1 Chongchan Bao,5 Shi Feng,5 Cheng Wei,5 Xiqiang Tang,5 Lijun Cen,5 Wenwen Guo,5 Xinru Tian,5 Qianli Tang,5 Xusen Huang1 1General Surgery, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China; 2Department of Pathology, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China; 3Department of Pediatrics, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China; 4Medical college of Soochow University, Suzhou, Jiangsu, 215000, People’s Republic of China; 5YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qianli TangYouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of ChinaEmail htmgx@163.comXusen HuangGeneral Surgery, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, Guangxi, People’s Republic of ChinaEmail hxsfy@163.comBackground: LncRNAs play an important role in tumor initiation and development. However, the underlying involvement of lncRNA expression in colorectal carcinoma remains to be clarified.Methods: All analyses were performed in R software v4.0, SPSS v13.0, and GraphPad Prism 8. The “limma” package was used to identify differentially expressed lncRNAs between two groups with the threshold of |logFC| > 1 and P < 0.05. The “Survival” package was used to conduct survival analysis. HCT8 and SE480 cell lines were used to conduct further phenotype experiments, including transwell, wound-healing, CCK8 and colony formation assay. Gene set enrichment analysis was used to explore the biological pathway difference in high and low IGFL2-AS1 patients.Results: The lncRNA IGFL2-AS1 was highly expressed in colon adenocarcinoma (COAD) tissue and cell lines (HCT116, HCT8, HCT129, and SW480). The COAD patients with high IGFL2-AS1 were associated with a worse prognosis. Meanwhile, the knockdown of IGFL2-AS1 could significantly suppress the proliferation and invasion of COAD cells. Gene set enrichment analysis showed that the top five biological pathways involving IGFL2-AS1 were angiogenesis, epithelial–mesenchymal transition, KRAS signaling, myogenesis, and coagulation. Western blot results showed that the inhibition of IGFL2-AS1 could significantly reduce the N-cadherin, HIF1A and KRAS protein expression, yet increase the E-cadherin protein level. IGFL2-AS1 was also positively correlated with M0 macrophages, M2 macrophages, and neutrophils but negatively correlated with CD4+ memory T cells and CD8+ T cells.Conclusion: IGFL1-AS1 could seriously worsen patient outcomes and facilitate COAD progression, thus serving as an independent tumor marker.Keywords: IGFL2-AS1, lncRNA, colon cancer, immune

Ning Zhang,1 Changqing Zhang,2 Zhihong Zeng,1 Jiyong Zhang,1 Shengnan Du,1 Chunde Bao,3 Zhe Wang1 1Longwood Biopharmaceuticals, Shanghai, People’s Republic of China; 2Department of Orthopaedics, Shanghai Sixth People’s Hospital, Shanghai, People’s Republic of China; 3Department of Rheumatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaCorrespondence: Zhe Wang Email zhe.wang@lwbiopharma.comBackground: Research on JAK family members as therapeutic targets for autoimmune diseases has brought tofacitinib and baricitinib into clinical for the treatment of rheumatoid arthritis and other autoimmune diseases. Despite the potent efficacy of these first-generation JAK inhibitors, their broad-spectrum JAK inhibition and adverse events warrant development of a JAK1-specific inhibitor to improve their safety profile.Methods: In this study, we characterized a JAK1-specific inhibitor, LW402, on biochemical and human whole-blood assays. We further evaluated the therapeutic efficacy of LW402 in a rat adjuvant-induced arthritis (rAIA) model and a mouse collagen-induced arthritis (mCIA) model. The safety of LW402 was evaluated in both SpragueDawley rats and cynomolgus monkeys.Results: LW402 exhibited potent nanomolar activity against JAK1 and showed a 45-fold selectivity for inhibition of JAK1- over JAK2-dependent signaling induced by either IL6 or GM-CSF in human whole-blood assays. In the rAIA model, oral dosing of LW402 resulted in a dose-dependent improvement in disease symptoms, including reduction in paw swelling, marked reduction in the inflammatory-cell infiltration to synovial tissue, and protection of articular cartilage and bone from damage. The therapeutic efficacy of LW402 correlated well with the plasma exposure of LW402 and the extent of pSTAT3 inhibition in white blood cells. LW402 also effectively eased disease symptoms in the mCIA model. Toxicity studies in the Sprague Dawley rats and cynomolgus monkeys established a ≥ 5x therapeutic window for LW402 as drug exposures of toxicity study NOAEL dose and pharmacology study ED50 dose were compared.Conclusion: We developed a novel JAK1-specific inhibitor LW402 with potent efficacy in rAIA and mCIA models. We established a good safety profile for LW402 in toxicity studies, and the overall superiority of LW402 should translated well to the clinical setting for the treatment of RA and other autoimmune diseases.Keywords: rheumatoid arthritis, JAK1 inhibitor, rat-AIA model, mouse CIA

Yuzheng Xue,1,* Yao Zhong,1,* Tielong Wu,1 Yingyue Sheng,1 Yuanyuan Dai,1 Lingling Xu,1 Chuanqing Bao2 1Department of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi 214041, Jiangsu, People’s Republic of China; 2Department of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi 214041, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuzheng XueDepartment of Gastroenterology, Affiliated Hospital of Jiangnan University, No. 585, Xingyuan North Road, Wuxi 214041, Jiangsu, People’s Republic of ChinaEmail xueyz001@163.comPurpose: The expression of microRNA-125b (miR-125b) is low in a variety of cancers, including gastric, lung, bladder, thyroid, and esophageal cancers. However, its specific mechanism in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study is aimed to explore the role of miR-125b in PDAC.Methods: PDAC tissues and adjacent tissues were collected for miR-125b analysis by qRT-PCR. Different PDAC cell lines were cultured for miR-125b detection by qRT-PCR, and CAPAN1 cells were selected for the downstream experiments. Cell proliferation was characterized by methyl thiazolyl tetrazolium (MTT) and 5-bromo-2-deoxyUridine (BrdU) staining. Flow cytometry was utilized for apoptosis and cell cycle changes. Cell invasion was determined by the Transwell assay and the dual-luciferase assay was utilized for validating the target gene. Western blotting was used to detect apoptosis related and PI3K/AKT signaling proteins.Results: miR-125b was significantly down-regulated in human PDAC tissues and cell lines (P < 0.05). miR-125b inhibited the growth and invasion of CAPAN1 cells, facilitated apoptosis, and blocked the cell cycle at the G0/G1 phase. Furthermore, miR-125 directly targeted NEDD9. The high expression of NEDD9 impaired the anti-proliferative and anti-apoptotic activity of miR-125b. miR-125b also inhibited apoptosis-related proteins and PI3K/AKT signaling pathways via NEDD9.Conclusion: miR-125b decreased cell growth and invasion, and facilitated apoptosis in CAPAN1 cells through PI3K/AKT inhibition via targeting NEDD9.Keywords: miR-125b, pancreatic ductal adenocarcinoma, apoptosis, NEDD9, PI3K/AKT

Models test our understanding of processes and can reach beyond the spatial and temporal scales of measurements. Multi-component Reactive Transport Models (RTMs), initially developed more than three decades ago, have been used extensively to explore the interactions of geothermal, hydrologic, geochemical, and geobiological processes in subsurface systems. Driven by extensive data sets now available from intensive measurement efforts, there is a pressing need to couple RTMs with other community models to explore non-linear interactions among the atmosphere, hydrosphere, biosphere, and geosphere. Here we briefly review the history of RTM development, summarize the current state of RTM approaches, and identify new research directions, opportunities, and infrastructure needs to broaden the use of RTMs. In particular, we envision the expanded use of RTMs in advancing process understanding in the Critical Zone, the veneer of the Earth that extends from the top of vegetation to the bottom of groundwater. We argue that, although parsimonious models are essential at larger scales, process-based models offer tools to explore the highly nonlinear coupling that characterizes natural systems. We present seven testable hypotheses that emphasize the unique capabilities of process-based RTMs for (1) elucidating chemical weathering and its physical and biogeochemical drivers; (2) understanding the interactions among roots, micro-organisms, carbon, water, and minerals in the rhizosphere; (3) assessing the effects of heterogeneity across spatial and temporal scales; and (4) integrating the vast quantity of novel data, including “omics” data (genomics, transcriptomics, proteomics, metabolomics), elemental concentration and speciation data, and isotope data into our understanding of complex earth surface systems. With strong support from data-driven sciences, we are now in an exciting era where integration of RTM framework into other community models will facilitate process understanding across disciplines and across scales.

A ligature-induced periodontitis model was established in wild-type and CD146CreERT2; RosatdTomato mice to explore the function of pericytes in alveolar bone formation. We found that during periodontitis progression and periodontal wound healing, CD146+/NG2+ pericytes were enriched in the periodontal tissue areas, which could migrate to the alveolar bone surface and colocalize with ALP+/OCN+ osteoblasts. Chemokine C-X-C motif receptor 4 (CXCR4) inhibition using AMD3100 blocked CD146-Cre+ pericyte migration and osteogenesis, as well as further exacerbated periodontitis-associated bone loss. Next, primary pericytes were sorted out by magnetic-activated cell sorting and demonstrated that C-X-C motif chemokine ligand 12 (CXCL12) promotes pericyte migration and osteogenesis via CXCL12-CXCR4-Rac1 signaling. Finally, the local administration of an adeno-associated virus for Rac1 overexpression in NG2+ pericytes promotes osteoblast differentiation of pericytes and increases alveolar bone volume in periodontitis. Thus, our results provided the evidence that pericytes may migrate and osteogenesis via the CXCL12-CXCR4-Rac1 axis during the pathological process of periodontitis. [ABSTRACT FROM AUTHOR]