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Abstract Background Muskoxen are important ecosystem components and provide food, economic opportunities, and cultural well-being for Indigenous communities in the Canadian Arctic. Between 2010 and 2021, Erysipelothrix rhusiopathiae was isolated from carcasses of muskoxen, caribou, a seal, and an Arctic fox during multiple large scale mortality events in the Canadian Arctic Archipelago. A single strain (‘Arctic clone’) of E. rhusiopathiae was associated with the mortalities on Banks, Victoria and Prince Patrick Islands, Northwest Territories and Nunavut, Canada (2010–2017). The objectives of this study were to (i) characterize the genomes of E. rhusiopathiae isolates obtained from more recent muskox mortalities in the Canadian Arctic in 2019 and 2021; (ii) identify and compare common virulence traits associated with the core genome and mobile genetic elements (i.e. pathogenicity islands and prophages) among Arctic clone versus other E. rhusiopathiae genomes; and iii) use pan-genome wide association studies (GWAS) to determine unique genetic contents of the Arctic clone that may encode virulence traits and that could be used for diagnostic purposes. Results Phylogenetic analyses revealed that the newly sequenced E. rhusiopathiae isolates from Ellesmere Island, Nunavut (2021) also belong to the Arctic clone. Of 17 virulence genes analysed among 28 Arctic clone isolates, four genes – adhesin, rhusiopathiae surface protein-A (rspA), choline binding protein-B (cbpB) and CDP-glycerol glycerophosphotransferase (tagF) – had amino acid sequence variants unique to this clone when compared to 31 other E. rhusiopathiae genomes. These genes encode proteins that facilitate E. rhusiopathiae to attach to the host endothelial cells and form biofilms. GWAS analyses using Scoary found several unique genes to be overrepresented in the Arctic clone. Conclusions The Arctic clone of E. rhusiopathiae was associated with multiple muskox mortalities spanning over a decade and multiple Arctic islands with distances over 1000 km, highlighting the extent of its spatiotemporal spread. This clone possesses unique gene content, as well as amino acid variants in multiple virulence genes that are distinct from the other closely related E. rhusiopathiae isolates. This study establishes an essential foundation on which to investigate whether these differences are correlated with the apparent virulence of this specific clone through in vitro and in vivo studies.

Xiang Li,1 Mengtian Pan,1 Xinjuan Tian,1 Lele Zixin Yang,2 Jingjing Zhang,1 Dongmei Yan,3 Baohui Xu,4 Li Zhao,1 Weirong Fang1 1Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China; 2The Pennsylvania State University, Eberly College of Science, State College, PA, USA; 3Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, People’s Republic of China; 4Department of Surgery, Stanford University School of Medicine, Stanford, CA, USACorrespondence: Li Zhao; Weirong Fang, Email zhaoli@cpu.edu.cn; weirongfang@cpu.edu.cnBackground: Tripartite motif containing 59 (TRIM59) is a ubiquitin ligase and is involved in the pathogenesis of various diseases, including cancers, sepsis, and other immune-related diseases. However, it has not been defined whether TRIM59 plays a role in ischemic stroke in mice.Methods: This study determined the influence of Trim59 deficiency on experimental stroke outcomes and the cerebral proteomic profile using myeloid cell Trim59 conditional knockout (Trim59-cKO) mice and a label-free quantitative proteomic profiling technique. The possible mechanisms by which TRIM59 affected stroke onset were elucidated by in vivo and in vitro experiments.Results: Immunofluorescence staining results showed that TRIM59 expression was up-regulated after cerebral ischemia and co-localized with macrophages. Myeloid cell Trim59 deficiency exacerbated ischemic injury on day 3 after experimental stroke. In proteomic analysis, 23 differentially expressed proteins were identified in ischemic brain of Trim59-cKO mice as compared to Trim59flox/flox mice. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the differentially expressed proteins were enriched in complement and coagulation cascades. Protein–protein interaction analysis suggested the central role of clusterin in the interaction network. ELISA and Western blot assays confirmed the reduced levels of clusterin protein in the ischemic brains of Trim59-cKO mice. Further experimental results showed that clusterin was expressed in neurons. Conditional co-culture experiments of primary neurons and bone marrow-derived macrophages demonstrated that LPS stimulated macrophages to secrete complement C3. In addition, TRIM59 may affect the changes in clusterin expression in an indirect manner by influencing the secretion of complement C3 in macrophages. In vivo experiments also proved a significant increase in C3 levels in the brains of Trim59-cKO mice after ischemia.Conclusion: Myeloid cell Trim59 deficiency aggravated ischemic stroke outcomes in conjunction with a distinct cerebral proteomic profile, and the underlying mechanism may be related to the regulation of macrophage C3 expression by TRIM59.Keywords: Trim59, ischemic stroke, proteomic profile, complement and coagulation cascades, C3

Baogen Zhang,1,&ast; Biqing Huang,2,&ast; Fan Yang,3,&ast; Jiandong Yang,1 Man Kong,1 Jing Wang,1 Yaoxian Xiang,1 Kangjie Wang,1 Ruchen Peng,4 Kun Yang,4 Chao An,5 Dong Yan1 1Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, People’s Republic of China; 2Department of Interventional Radiology and Vascular Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of China; 3Department of Cardiology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of China; 4Department of Medical Imaging, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, People’s Republic of China; 5Department of Minimal Invasive Intervention, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative, Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dong Yan, Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, 101149, People’s Republic of China, Tel/Fax +86-10-69543901, Email dongyan@mail.ccmu.edu.cn Chao An, Department of Minimal invasive intervention, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative, Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China, Tel/Fax +86-20-87343272, Email anchao-1983@163.comObjective: To compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with transarterial chemoembolization (TACE) for the treatment of high-risk hepatocellular carcinoma (hHCC) patients.Methods: Between January 2014 and August 2022, a total of 1765 consecutive patients with hHCC who underwent initial intra-arterial therapies were reviewed and divided into a TACE group (n, 507) and a HAIC group (n, 426). The study used propensity score matching (PSM) to reduce selectivity bias. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan‒Meier curves with the Log rank test. The objective response rate (ORR), conversion surgery rate (CSR) adverse event (AE) comparison and subgroup analysis were performed between the two groups.Results: After PSM 1:1, 444 patients were divided into two groups. The patients with hHCC who received HAIC had higher median PFS (6.1 vs 3.3 months, P < 0.001) and OS (10.3 vs 8.2 months, P=0.303) than TACE. Higher ORR (24.8% vs 11.7%) and CSR (15.5% vs 8.9%) were found in the HAIC group than in the TACE group (both P < 0.05). The incidence of grade 3/4 AE was 23.9% and 8.1% in the TACE and HAIC groups, respectively. The subgroup analysis suggest that HAIC appeared to particularly benefit patients with tumor diameter of more than 10 centimeters (hazard ratio [HR], 0.6; 95% CI, 0.47– 0.77; p, 0.00) and PVTT Vp4 (HR, 0.56; 95% CI, 0.39– 0.8; P, 0.01) for PFS outperforming TACE.Conclusion: HAIC can provide better disease control for hHCC than cTACE, with a comparable long-term OS and safety.Keywords: hepatocellular carcinoma, transarterial chemoembolization, hepatic artery infusion chemotherapy, high risk

Kun Cao,1,2,&ast; Zehui Wang,1,3,5,6,&ast; Xiaojiao Sun,3– 6,&ast; Di Yan,1– 3 Yanwen Liu,3 Ting Ma,3 Xiaojuan Sun1,2 1Department of Oral and Maxillofacial Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China; 2Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China; 3School of Stomatology, Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China; 4Animal Experiment Center of Ningxia Medical University, Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China; 5Stem Cell Institute, General Hospital, Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China; 6Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zehui Wang, Department of Oral and Maxillofacial Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China, Email wangzehui364@163.com Xiaojuan Sun, Department of Oral and Maxillofacial Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 750004, People’s Republic of China, Email ms_sunxiaojuan@126.comIntroduction: Nano-mesoporous bioactive glass and RGD peptide-coated collagen membranes have great potential in wound healing. However, the application of their compound has not been further studied. Our purpose is to prepare a novel bioactive collagen scaffold containing both NMBG stent and adhesion peptides (BM), which then proves its promising prospect the assessment of physical properties, biocompatibility, GSK-3β/β-catenin signaling axis and toxicological effects.Methods: The structural and morphological changes of BM were analyzed using scanning electron microscopy (SEM) and Energy Dispersive Spectroscopy (EDS). In vivo, wound healing of BM was assessed in SD rats through dynamic monitoring and calculation of wound healing rate. Immunohistofluorescence (IHF), H&E, and Masson staining were utilized; in vitro, primary cell culture, and a variety of assays including CCK-8, Transwell, Scratch, Immunocytofluorescence (ICF), and Western blot (WB) were performed, both for morphology and molecular analysis.Results and Discussion: Preparation of BM involved attaching NMBG to RGD-exposed collagen while avoiding the use of toxic chemical reagents. BM exhibited a distinctive superficial morphology with increased Si content, indicating successful NMBG attachment. In vivo studies on SD rats demonstrated the superior wound healing capability of BM, as evidenced by accelerated wound closure, thicker epithelial layers, and enhanced collagen deposition compared to the NC group. Additionally, BM promoted skin fibroblast migration and proliferation, possibly through activation of the GSK-3β/β-catenin signaling axis, which was crucial for tissue regeneration. This study underscored the potential of BM as an effective wound-healing dressing.Conclusion: A new method for synthesizing ECM-like membranes has been developed using nano-mesoporous bioactive glass and collagen-derived peptides. This approach enhances the bioactivity of biomaterials through surface functionalization and growth factor-free therapy.Keywords: NMBG, proliferation, RGD, migration, wound healing, GSK-3β/β-catenin signaling axis

Sampen HJI, Sharrocks AD, Lin X, et al. Open Access Rheumatol. 2009;1:151–161. We, the Editor and Publisher of the journal Open Access Rheumatology: Research and Reviews are issuing an expression of concern for the published article. Following publication, questions about the scientific integrity of the article were brought to the Publisher and Editors’ attention. We reached out to the corresponding author who has been cooperative and as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution. The corresponding author has been notified about this Expression of Concern.

Background Currently, endovascular treatment of intracranial aneurysms is limited by low complete occlusion rates. The advent of novel endovascular technology has expanded the applicability of endovascular therapies; however, the superiority of novel embolic devices over the traditional Guglielmi detachable coils is still debated. We performed a systematic review of literature that reported the Raymond–Roy occlusion classification (RROC) rates of modern endovascular devices to determine their immediate and follow‐up occlusion effectivenesses for the treatment of unruptured saccular intracranial aneurysms. Methods A search was conducted using electronic databases (PUBMED, Cochrane, ClinicalTrials.gov, and Web of Science). We retrieved studies published between 2000 and 2022, reporting immediate and follow‐up RROC rates of subjects treated with different endovascular intracranial aneurysm therapies. We extracted demographic information of the treated patients and their reported angiographic RROC rates. Results A total of 80 studies from 15 countries were included for data extraction. The RROC rates determined from angiogram were obtained for 21 331 patients (72.5% women, pooled mean age: 58.2 [95% CI]: 56.8–59.6), harboring 22 791 aneurysms. The most frequent aneurysm locations were the internal carotid artery (46.4%, 95% CI: 41.9%–50.9%), the anterior communicating artery (26.4%, 95% CI: 22.5%–30.8%), the middle cerebral artery (24.5%, 95% CI: 19.2%–30.8%), and the basilar tip (14.4%, 95% CI: 11.3%–18.3%). The complete occlusion probability (RROC‐I) was analyzed for Guglielmi detachable coils, the Woven EndoBridge, and flow diverters. The RROC‐I rate was the highest in balloon‐assisted coiling (73.9%, 95% CI: 65.0%–81.2%) and the lowest in the Woven EndoBridge (27.8%, 95% CI: 13.2%–49.2%). The follow‐up RROC‐I probability was homogenous in all analyzed devices. Conclusion We observed that the coil‐based endovascular therapy provides acceptable rates of complete occlusion, and these rates are improved in balloon‐assisted coils. Out of the analyzed devices, the Woven EndoBridge exhibited the shortest time to achieve >90% probability of follow‐up complete occlusion (∼18 months). Overall, the Guglielmi detachable coils remain the gold standard for endovascular treatment of unruptured saccular aneurysms.

Jiewei Yu,1 Lingling Ke,1 Jingjing Zhou,2 Chunyan Ding,1 Hui Yang,1 Dongbiao Yan,3 Chengbi Yu3 1Department of Ophthalmology, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, 332000, People’s Republic of China; 2Image Center, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, 332000, People’s Republic of China; 3Department of Endocrinology, Jiujiang Hospital of Traditional Chinese Medicine, Jiujiang, Jiangxi, 332000, People’s Republic of ChinaCorrespondence: Chengbi Yu, Department of Endocrinology, Jiujiang Hospital of Traditional Chinese Medicine, No. 555 Dehua Road, Lianxi District, Jiujiang, Jiangxi, 332000, People’s Republic of China, Tel +86 792-8188311, Email yuchengbi@126.comBackground: Diabetes retinopathy (DR) is a chronic, progressive, and potentially harmful retinal disease associated with persistent hyperglycemia. Autophagy is a lysosome-dependent degradation pathway that widely exists in eukaryotic cells, which has recently been demonstrated to participate in the DR development. Stachydrine (STA) is a water-soluble alkaloid extracted from Leonurus heterophyllus. This study aimed to explore the effects of STA on the autophagy in DR progression in vivo and in vitro.Methods: High glucose-treated human retinal microvascular endothelial cells (HRMECs) and STA-treated rats were used to establish DR model. The reactive oxygen species (ROS) and inflammatory factor levels (TNF-α, IL-1β, and IL-6) were determined using corresponding kits. Additionally, the cell growth was analyzed using CCK-8 and EdU assays. Besides, LC3BII, p62, p-AMPKα, AMPKα, and SIRT1 protein levels were measured using Western blot. The LC3BII and SIRT1 expressions were also determined using immunofluorescence.Results: The results showed that STZ decreased the ROS and inflammatory factor levels in the HG-treated HRMECs. Besides, after STA treatment, the beclin-1, LC3BII, p-AMPKα, and SIRT1 levels were increased, and p62 was decreased in the HG-treated HRMECs and the retinal tissue of STZ-treated rats.Conclusion: In conclusion, this study demonstrated that STA effectively relieved the inflammation and promoted the autophagy in DR progression in vivo and in vitro through activating the AMPK/SIRT1 signaling pathway.Keywords: diabetes retinopathy, stachydrine, autophagy, AMPK/SIRT1

Xiangjie Fu,1 Yaqiong Ni,2 Guanchen Wang,3 Runda Nie,3 Yang Wang,4 Run Yao,1 Danyang Yan,1 Mingming Guo,3 Ning Li1 1Department of Blood Transfusion, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 2Hunan Provincial Key Laboratory of Micro&Nano Materials Interface Science, College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, People’s Republic of China; 3School of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, People’s Republic of China; 4Institute of Integrative Medicine, Key Laboratory of Hunan Province for Liver Manifestation of Traditional Chinese Medicine, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of ChinaCorrespondence: Ning Li, Tel +86 731 84327436, Email liningxy@csu.edu.cnBackground: Multidrug-resistant staphylococcus aureus infected wounds can lead to nonhealing, systemic infections, and even death. Although advanced dressings are effective in protecting, disinfecting, and maintaining moist microenvironments, they often have limitations such as single functionality, inadequate drug release, poor biosafety, or high rates of drug resistance.Methods: Here, a novel wound dressing comprising glycyrrhizic acid (GA) and tryptophan-sorbitol carbon quantum dots (WS-CQDs) was developed, which exhibit synergistic and long-lasting antibacterial and anti-inflammatory effects. We investigated the characterization, mechanical properties, synergistic antibacterial effects, sustained-release properties, and cytotoxicity of GA/WS-CQDs hydrogels in vitro. Additionally, we performed transcriptome sequence analysis to elucidate the antibacterial mechanism. Furthermore, we evaluated the biosafety, anti-inflammatory effects, and wound healing ability of GA/WS-CQDs dressings using an in vivo mouse model of methicillin-resistant staphylococcus aureus (MRSA)-infected wounds.Results: The prepared GA/WS-CQDs hydrogels demonstrated superior anti-MRSA effects compared to common antibiotics in vitro. Furthermore, the sustained release of WS-CQDs from GA/WS-CQDs hydrogels lasted for up to 60 h, with a cumulative release of exceeding 90%. The sustained-released WS-CQDs exhibited excellent anti-MRSA effects, with low drug resistance attributed to DNA damage and inhibition of bacterial biofilm formation. Notably, in vivo experiments showed that GA/WS-CQDs dressings reduced the expression of inflammatory factors (TNF-α, IL-1β, and IL-6) and significantly promoted the healing of MRSA-infected wounds with almost no systemic toxicity. Importantly, the dressings did not require replacement during the treatment process.Conclusion: These findings emphasize the high suitability of GA/WS-CQDs dressings for MRSA-infected wound healing and their potential for clinical translation.Graphical Abstract: Keywords: tryptophan-sorbitol CQDs, glycyrrhizic acid, wound dressings, synergistic synergism, sustained release, methicillin-resistant staphylococcus aureus-infected wounds healing

Wenhui Zhang,1,2,&ast; Yi Wang,2,3,&ast; Er Li,1 Dingyan Yan,1,2 Jianhua Yu,2 Mingli Zhu,4 Jinchuan Shi,2,&ast; Liping Zheng1,&ast; 1Department of Nursing, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Infection, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Institute of Hepatology and Epidemiology, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Medical Laboratory, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinchuan Shi, Department of Infection, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, No. 2 Hengbu Street, Liuxia Town, Xihu District, Hangzhou, Zhejiang, People’s Republic of China, Email shijinchuan2008@126.com Liping Zheng, Department of Nursing, Affiliated Hangzhou Xixi Hospital, Zhejiang University School of Medicine, No. 2 Hengbu Street, Liuxia Town, Xihu District, Hangzhou, Zhejiang, People’s Republic of China, Email zhengliping512@126.comPurpose: Neuropsychiatric adverse events (NPAEs) occur frequently in people living with human immunodeficiency virus (PLWH) receiving antiretroviral therapy (ART). This study aimed to assess the dynamic trends and risk factors of NPAEs among PLWH in Hangzhou taking efavirenz (EFV)- or dolutegravir (DTG)- or elvitegravir (EVG)-based regimens.Patients and Methods: A total of 287 ART-naive PLWH were included in this study, EFV (400mg)- (n = 122), EFV (600mg)- (n = 37), DTG- (n = 73), EVG-based (n = 47) and other ART regimens (n = 8) as the initial ART regimen were administered for 12 months. All data were collected at five time points within a 12-month follow-up. The Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale were used to evaluate sleep disorders and anxiety and depression symptoms, respectively. The dynamic trends and potential risk factors of NPAEs were investigated using a generalized linear mixed model.Results: Mean age was 29.4 (SD: 7.5) years with 97.2% males. After 12 months of ART, the prevalence of sleep disorders and anxiety decreased significantly, although only a slight improvement was observed for depression. In addition, there was a significant positive correlation between sleep disorders, anxiety, and depression. The risk factors for NPAEs differed slightly depending on the choice of ART regimen, but the seven factors most commonly associated with NPAEs were age, sex, marital status, education level, smoking status, body mass index, and WHO clinical stage. Treatment-induced changes in CD4-positive T-cell count and virological suppression did not depend on the particular choice of ART regimen.Conclusion: The prevalence of sleep disorders and anxiety changed significantly over time on ART and the risks of these disorders were associated with seven common clinical and demographic factors.Keywords: sleep disorders, anxiety, depression, antiretroviral therapy, people living with HIV

Donglei Shi,&ast; Li Wei,&ast; Hongsen Liang, Dongqing Yan, Junhang Zhang, Zhaojun Wang Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhaojun Wang, Department of Thoracic Surgery, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, People’s Republic of China, Email wangzhj55@mail.sysu.edu.cnBackground: Malaria remains a substantial concern in the realm of public health on a worldwide level. Using information from the global burden of disease (GBD) 2019 for 204 countries and territories between 1990 and 2019, we assessed the burden of malaria.Methods: Data on malaria were derived from the GBD 2019 study between 1990 and 2019. We evaluated the number of incidence, deaths, disability-adjusted life years (DALYs), age-standardized incidence rates (ASIR), age-standardized mortality rates (ASMR), and age-standardized DALY rates (ASDR), examining them across variables such as age, year, gender, country, region, and socio-demographic index (SDI).Results: The burden of malaria decreased globally between 1990 and 2019. There were 2313.57× 105 incident cases and 6.43× 105 deaths in 2019, contributing to 464.38× 105 DALYs. Largest incident cases were observed in Western Sub-Saharan Africa [1151.72 (95% UI: 890.01– 1527.17)] × 105 in 2019. The only region where deaths increased between 1990 and 2019 was Western Sub-Saharan Africa. ASRs of malaria are distributed heterogeneously in different regions. The highest ASIR was observed in Central Sub-Saharan Africa [21,557.65 (95% UI: 16,639.4– 27,491.48)] in 2019. From 1990 to 2019, the ASMR of malaria declined. Compared to other age cohorts, the ASIR, ASMR, and ASDR for children aged between 1 to 4 years were found to be higher. Worst-affected regions by malaria infection were the low-middle SDI region and low SDI region.Conclusion: Malaria threatens global public health, especially in Central Sub-Saharan Africa and Western Sub-Saharan Africa. Children 1– 4 years old continue to bear the most significant burden of malaria. The study’s results will guide efforts to reduce malaria’s impact on the global population.Keywords: malaria, global burden of disease, ASIR, ASMR, ASDR

Nowadays it has become possible to develop inexpensive modern control systems for nonlinear complexity electromechanical objects due to the development of microprocessor technology and power electronics. Switched reluctance electric machines are among these devices. It makes it possible to widely use such electric machines in various practical implementations, in particular, in traction drives, electric drives of oil and gas drilling rigs, and in other applications. The switched reluctance electric machine is a non-linear object, and its control methods require formalization and grouping. The manuscript considers the design and functional features of switched reluctance electrical machines. The main methods of controlling these electrical machine types are given. Comparative analysis of the most known methods is carried out. The main classical methods of switched reluctance electric machine control are considered, such as a relay current controller with a limitation, the method of controlling the turn on/off angles and controlling the DC link voltage. Transient responses in the electric drive system are demonstrated using the considered methods. It is shown that by adjusting the on/off angles, it is possible to reduce the torque oscillation coefficient. The identified features of the presented methods will make it possible to simplify and reduce the development time for an effective control system for switched reluctance electrical machines as well as to reduce the torque ripple.

Yaping Yu,1,&ast; Shun Ding,2,&ast; Xiaoqing Xu,1,&ast; Dongming Yan,3 Yonghao Fan,1 Banzhan Ruan,1 Xiaodian Zhang,1 Liping Zheng,1 Wei Jie,1 Shaojiang Zheng1,4 1Department of Oncology of the First Affiliated Hospital & Tumor Institute, Hainan Medical University, Haikou, 570102, People’s Republic of China; 2Department of Otolaryngology, Head and Neck Surgery, the First Affiliated Hospital, Hainan Medical University, Haikou, 570102, People’s Republic of China; 3Department of Neurosurgery, the First Affiliated Hospital of Hainan Medical University, Haikou, 570102, People’s Republic of China; 4Key Laboratory of Emergency and Trauma, Ministry of Education, Hainan Medical University, Haikou, 571199, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Jie; Shaojiang Zheng, Department of Oncology of the First Affiliated Hospital & Tumor Institute, Hainan Medical University, Haikou, 570102, People’s Republic of China, Tel +86-898-66968217 ; +86-898-66568158, Email wei_jie@hainmc.edu.cn; zhengsj2008@163.comPurpose: This study aimed to explore the pharmacological mechanism of Dangshen (Codonopsis pilosula) against hepatocellular carcinoma (HCC) based on network pharmacology and bioinformatics, and to verify the anticancer effect of luteolin, the active ingredient of Codonopsis pilosula, on HCC cells.Methods: The effective compounds and potential targets of Codonopsis pilosula were established using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. The genes related to HCC were obtained through the GeneCards database. The interactive genes were imported into the Visualization and Integrated Discovery database for Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal enrichment, and the hub genes were screened out. The Cancer Genome Atlas database was used to construct a prognosis model, and the prognosis and clinicopathological correlation were analyzed. In in vitro experiments, we verified the effects of luteolin, an active compound of Codonopsis pilosula, on the proliferation, cell cycle, apoptosis and migration of HCC cells.Results: A total of 21 effective compounds of Codonopsis pilosula and 98 potential downstream target genes were screened through the TCMSP database, and 1406 HCC target genes were obtained through the GeneCards database. Finally, 53 interacting genes between the two databases were obtained, among which, the 10 key node genes were CASP3, TP53, MDM2, AKT1, ESR1, BCL2L1, MCL1, HSP90AA1, CASP9, and CCND1, involving 77 typical GO terms and 72 KEGG signals. The Kaplan–Meier survival curve of the model group showed that the overall survival of the low-risk group was significantly higher than that of the high-risk group. Luteolin significantly inhibited the proliferation and migration of HCC cells, induced apoptosis, and increased the G2/M phase ratio. Mechanistically, luteolin significantly inhibited the phosphorylation of MAPK-JNK and Akt (Thr308) and subsequently led to upregulation of ESR1. Pharmacological inhibition of ESR1 with fulvestrant enhanced cell viability and migration and attenuated apoptosis.Conclusion: Codonopsis pilosula has potential for clinical development due to its anti-HCC properties. Luteolin, the effective component of Codonopsis pilosula, plays anti-HCC role through AKT- or MAPK-JNK signaling mediated ESR1.Keywords: Codonopsis pilosula, network pharmacology, bioinformatics, luteolin, hepatocellular carcinoma

Cheng Ma,1– 4,&ast; Yin Cao,1,&ast; Guang Zhang,1– 3,&ast; Jiannan Qiu,2 Yan Zhou,1 Peng Wang,2 Shuo Wang,2 Dongliang Yan,1 Ding Ma,2 Chunping Jiang,1– 3 Zhongxia Wang1– 3 1Department of Hepatobiliary Surgery, Drum Tower Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 3Department of Tissue Engineering, Jinan Microecological Biomedicine Shandong Laboratory, Jinan, People’s Republic of China; 4Department of Gastrointestinal Surgery, Xuzhou Central Hospital, Xuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhongxia Wang; Chunping Jiang, Email freud_t@126.com; chunpingjiang@163.comBackground: The prediction of prognosis of hepatocellular carcinoma (HCC) is of great significance in improving disease outcome and optimizing clinical management, while reliable prognostic indicators are lacking. This study was conducted to develop readily-to-use nomograms for prognosis prediction of HCC after hepatectomy.Materials and Methods: Data of eligible patients were collected and analyzed retrospectively. Independent prognostic factors were identified by Cox regression, and nomograms for the prediction of disease-free survival (DFS) and overall survival (OS) were developed. The performance of the nomograms was evaluated by receiver operating characteristics (ROC) curves, C-indexes and calibration curves and was verified by the validation cohort. The predictive value of the nomograms was also compared with the 8th edition of American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) and the Barcelona Clinic Liver Cancer (BCLC) staging systems.Results: In total, 599 patients were enrolled in the analysis: 420 in the training cohort and 179 in the validation cohort. The optimal cut-off value of Gamma-Glutamyl Transpeptidase-to-Lymphocyte Ratio (GLR) was 19.5. GLR contributed significantly to the nomograms with good predictive power. In ROC analyses, the areas under curve (AUCs) of the nomograms for 1-, 3- and 5-year DFS and OS prediction were 0.758, 0.756, 0.734 and 0.810, 0.799, 0.758, respectively. The C-indexes of the DFS nomogram were 0.697 (95% CI 0.665– 0.729) in the training cohort and 0.710 (95% CI 0.664– 0.756) in the validation cohort. For OS prediction, the C-indexes were 0.741 (95% CI 0.704– 0.778) and 0.758 (95% CI 0.705– 0.811) in the training and validation cohorts, respectively. The calibration curves demonstrated satisfactory agreement between nomogram predictions and actual observations. The nomograms demonstrated superior predictive performance to the TNM and the BCLC staging systems.Conclusion: Our novel nomograms showed adequate performance in the prediction of HCC prognosis after hepatectomy, which may facilitate the risk stratification and individualized management of HCC patients.Keywords: hepatocellular carcinoma, nomogram, gamma-glutamyl transferase, lymphocyte, hepatectomy

Bovine respiratory disease (BRD) is the leading cause of morbidity and mortality in cattle raised in North America. At the feedlot, cattle are subject to metaphylactic treatment with macrolides to prevent BRD, a practice that may promote antimicrobial resistance and has resulted in an urgent need for novel strategies. Mannheimia haemolytica is one of the major bacterial agents of BRD. The inhibitory effects of two amphipathic, α-helical (PRW4, WRL3) and one β-sheet (WK2) antimicrobial peptides were evaluated against multidrug-resistant (MDR) M. haemolytica isolated from Alberta feedlots. WK2 was not cytotoxic against bovine turbinate (BT) cells by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. All three peptides inhibited M. haemolytica, with WK2 being the most efficacious against multiple isolates. At 8–16 µg/mL, WK2 was bactericidal against Mh 330 in broth, and at 32 µg/mL in the presence of BT cells, it reduced the population by 3 logs CFU/mL without causing cytotoxic effects. The membrane integrity of Mh 330 was examined using NPN (1-N-phenylnaphthylamine) and ONPG (o-Nitrophenyl β-D-galactopyranoside), with both the inner and outer membranes being compromised. Thus, WK2 may be a viable alternative to the use of macrolides as part of BRD prevention and treatment strategies.

BackgroundBovine respiratory disease (BRD) is a significant health problem in beef cattle production, resulting in considerable economic losses due to mortalities, cost of treatment, and reduced feed efficiency. The onset of BRD is multifactorial, with numerous stressors being implicated, including transportation from farms to feedlots. In relation to animal welfare, regulations or practices may require mandatory rest times during transportation. Despite this, there is limited information on how transportation and rest stops affect the respiratory microbiota.ResultsThis study evaluated the effect of cattle source (ranch-direct or auction market-derived) and rest stop duration (0 or 8 h of rest) on the upper respiratory tract microbiota and its relationship to stress response indicators (blood cortisol and haptoglobin) of recently weaned cattle transported for 36 h. The community structure of bacteria was altered by feedlot placement. When cattle were off-loaded for a rest, several key bacterial genera associated with BRD (Mannheimia, Histophilus, Pasteurella) were increased for most sampling times after feedlot placement for the ranch-direct cattle group, compared to animals given no rest stop. Similarly, more sampling time points had elevated levels of BRD-associated genera when auction market cattle were compared to ranch-direct. When evaluated across time and treatments several genera including Mannheimia, Moraxella, Streptococcus and Corynebacterium were positively correlated with blood cortisol concentrations.ConclusionThis is the first study to assess the effect of rest during transportation and cattle source on the respiratory microbiota in weaned beef calves. The results suggest that rest stops and auction market placement may be risk factors for BRD, based solely on increased abundance of BRD-associated genera in the upper respiratory tract. However, it was not possible to link these microbiota to disease outcome, due to low incidence of BRD in the study populations. Larger scale studies are needed to further define how transportation variables impact cattle health.

Li Bao,1,2 Ying Zhang,2,3 Sichao Yan,1,2 Dan Yan,2,3 Dechun Jiang1,2 1Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Key Laboratory of Bio-Characteristic Profiling for Evaluation of Rational Drug Use, Beijing, People’s Republic of China; 3Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Dechun Jiang, Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, No. 10 Tieyi-Road, Haidian District, Beijing, 10038, People’s Republic of China, Tel +86-10-63926723, Email jdc@bjsjth.cnPurpose: Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis and insulin sensitivity, resulting in hyperglycemia. The exploration of a complex regulatory network in host metabolism homeostasis may raise a novel strategy for the prevention of T2D. A variety of metabolites serve as the endogenous ligand of G protein-coupled receptors (GPCR) and play an important role in the pathophysiological process of T2D and insulin resistance, however, the roles of remaining endogenous metabolites in insulin resistance and GPCRs still need to be explored.Patients and Methods: The effect of LPC (17:0) on hyperglycemia were proved in high fat diet (HFD) mice, and qPCR with Western blot technology was used to verify the downstream targets.Results: Herein, we found that LPC (17:0) reduced blood glucose and alleviated insulin resistance and related metabolic disorders in high-fat diet induced (HFD) mice through activating GLP-1 and promoting insulin secretion. Further, the LPC (17:0) was found to stimulate intestinal GPR120, GPR35 and CALCR, with potential effect on GLP-1 stimulation.Conclusion: The above observation revealed LPC (17:0) as an endogenous protective factor with potential role on GPCRs, and it provided theoretical support for the development of LPC (17:0) as a potent drug candidate or health food additive for insulin resistance and hyperglycemia.Keywords: lysophosphatidylcholine, hyperglycemia, GPR120, GPR35, CALCR

Chemotherapy and radiotherapy resistance are major obstacles in the long-term efficacy of head and neck squamous cell carcinoma (HNSCC) treatment. Secondhand smoke (SHS) exposure is common and has been proposed as an independent predictor of HNSCC recurrence and disease-free survival. However, the underlying mechanisms responsible for these negative patient outcomes are unknown. To assess the effects of SHS exposure on cisplatin efficacy in cancer cells, three distinct HNSCC cell lines were exposed to sidestream (SS) smoke, the main component of SHS, at concentrations mimicking the nicotine level seen in passive smokers’ saliva and treated with cisplatin (0.01–100 µM) for 48 h. Compared to cisplatin treatment alone, cancer cells exposed to both cisplatin and SS smoke extract showed significantly lower cisplatin-induced cell death and higher cell viability, IC50, and indefinite survival capacity. However, SS smoke extract exposure alone did not change cancer cell viability, cell death, or cell proliferation compared to unexposed control cancer cells. Mechanistically, exposure to SS smoke extract significantly reduced the expression of cisplatin influx transporter CTR1, and increased the expression of multidrug-resistant proteins ABCG2 and ATP7A. Our study is the first to document that exposure to SHS can increase cisplatin resistance by altering the expression of several proteins involved in multidrug resistance, thus increasing the cells’ capability to evade cisplatin-induced cell death. These findings emphasize the urgent need for clinicians to consider the potential role of SHS on treatment outcomes and to advise cancer patients and caregivers on the potential benefits of avoiding SHS exposure.

Bowen Wu,1 Li Tan,2 Weihua Wang,3 Xingzhong Feng,4 Dan Yan1,5,6 1Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Center of Pharmaceutical Technology, Tsinghua University, Beijing, People’s Republic of China; 4Tsinghua University Yuquan Hospital, Beijing, People’s Republic of China; 5Beijing Institute of Clinical Pharmacy, Beijing, People’s Republic of China; 6Beijing Key Laboratory for Evaluation of Rational Drug Use, Beijing, People’s Republic of ChinaCorrespondence: Xingzhong Feng, Tsinghua University Yuquan Hospital, No. 5 Shijingshan Road, Shijingshan District, Beijing, People’s Republic of China, Email fengxz9797@sina.com Dan Yan, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing, People’s Republic of China, Email pharmsci@126.comBackground: Imidazole Propionate (ImP) is a new marker of Type 2 diabetes mellitus (T2DM), which can induce impaired glucose metabolism and weaken the efficacy of metformin. An extensive exploration into literature suggests that ImP may be associated with stool consistency.Purpose: Through an in-depth study of the relationship between stool consistency, bile acids, fecal microbiota and ImP, we intend to explore the mechanism driving the ImP content difference in T2DM.Patients Under Study and Methods: This is a single-center, prospective, cross-sectional study. Plasma ImP and stool consistency were analyzed among 96 diabetic subjects and 45 healthy subjects. All subjects were divided into the stool consistency normal (N) group and the stool consistency abnormal group, of which the abnormal group was sub-divided into the hard stool (H) group and the soft stool (S) group. After identifying the correlation between ImP and stool consistency, we analyzed the influence of bile acids and fecal microbiota on ImP in diabetic subjects.Results: For T2DM patients, the ImP level of the abnormal stool consistency group was significantly higher than that of the normal stool consistency group (P < 0.001). Results were verified in 45 healthy subjects (P = 0.002). ImP was significantly associated with taurocholic acid (TCA) (P = 0.003) in feces, taurodeoxycholate (TDCA) (P = 0.003), glycochenodeoxycholate (GCDCA) (P = 0.021), and glycocholic acid (GCA) (P = 0.031) in plasma. The Shannon index of Group N was significantly higher than that of Group H (P = 0.041) and Group S (P = 0.003).Conclusion: ImP was higher in diabetic patients with abnormal stool consistency than in those with normal stool consistency, which was related to the proportion of bile acids and fecal microbial structure. These findings may improve our understanding of ImP and contribute to the treatment of T2DM by improving stool consistency.Keywords: ImP, T2DM, stool consistency, bile acids

Antecedent group A streptococcal pharyngitis is a well-established cause of acute rheumatic fever (ARF) where rheumatic valvular heart disease (RHD) and Sydenham chorea (SC) are major manifestations. In ARF, crossreactive antibodies and T cells respond to streptococcal antigens, group A carbohydrate, N-acetyl-β-D-glucosamine (GlcNAc), and M protein, respectively, and through molecular mimicry target heart and brain tissues. In this translational human study, we further address our hypothesis regarding specific pathogenic humoral and cellular immune mechanisms leading to streptococcal sequelae in a small pilot study. The aims of the study were to (1) better understand specific mechanisms of pathogenesis in ARF, (2) identify a potential early biomarker of ARF, (3) determine immunoglobulin G (IgG) subclasses directed against GlcNAc, the immunodominant epitope of the group A carbohydrate, by reaction of ARF serum IgG with GlcNAc, M protein, and human neuronal cells (SK-N-SH), and (4) determine IgG subclasses deposited on heart tissues from RHD. In 10 pediatric patients with RHD and 6 pediatric patients with SC, the serum IgG2 subclass reacted significantly with GlcNAc, and distinguished ARF from 7 pediatric patients with uncomplicated pharyngitis. Three pediatric patients who demonstrated only polymigrating arthritis, a major manifestation of ARF and part of the Jones criteria for diagnosis, lacked the elevated IgG2 subclass GlcNAc-specific reactivity. In SC, the GlcNAc-specific IgG2 subclass in cerebrospinal fluid (CSF) selectively targeted human neuronal cells as well as GlcNAc in the ELISA. In rheumatic carditis, the IgG2 subclass preferentially and strongly deposited in valve tissues (n = 4) despite elevated concentrations of IgG1 and IgG3 in RHD sera as detected by ELISA to group A streptococcal M protein. Although our human study of ARF includes a very small limited sample set, our novel research findings suggest a strong IgG2 autoantibody response against GlcNAc in RHD and SC, which targeted heart valves and neuronal cells. Cardiac IgG2 deposition was identified with an associated IL-17A/IFN-γ cooperative signature in RHD tissue which displayed both IgG2 deposition and cellular infiltrates demonstrating these cytokines simultaneously. GlcNAc-specific IgG2 may be an important autoantibody in initial stages of the pathogenesis of group A streptococcal sequelae, and future studies will determine if it can serve as a biomarker for risk of RHD and SC or early diagnosis of ARF.

Abstract Background Screening for maternal anogenital Group B streptococci (GBS) colonization in pregnancy with initiation of intravenous intrapartum antibiotic prophylaxis as indicated has led to a significant reduction in the incidence of neonatal GBS infection. This study aims to evaluate the agreement between vaginal-perianal or vaginal-perineal culture and the more typically used vaginal-rectal culture for screening for maternal anogenital GBS colonization in the third trimester of pregnancy. Methods Eligible English-language studies published until January 2020 were retrieved from Scopus, Web of Science, PubMed, Embase, and ClinicalTrials.gov databases. Studies were compiled that assessed for GBS colonization utilizing vaginal-perianal or vaginal-perineal culture and vaginal-rectal culture during the third trimester of pregnancy. Nonoriginal research articles and studies that did not assess pregnant patients, did not use culture-based screening, or did not compare vaginal-perianal or vaginal-perineal culture with vaginal-rectal culture were excluded. The search identified 559 articles with three prospective cohort studies that met inclusion criteria, including 643 participants. Quality was assessed using the Newcastle–Ottawa Scale, and risk of bias was assessed using the Risk of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Patient characteristics and associated pain with specimen collection were abstracted. Meta-analyses of both the raw agreement and the Cohen’s kappa statistic were performed. Results Within the three included studies, the range of GBS detection was 17.6–34.0%, consistent with the anticipated prevalence of GBS colonization reported in earlier publications. For both raw agreement and Cohen’s kappa coefficient, the test for heterogeneity was not significant, indicating low heterogeneity among studies. The pooled estimate of the raw agreement was 0.97 (95%CI 0.95–0.98) and of the Cohen's kappa coefficient was 0.91 (95% CI: 0.87–0.95), indicating (according to the Landis and Koch criteria) an “almost perfect” agreement between the compared clinical tests. In the two studies that assessed procedure-related patient discomfort, vaginal-rectal swabbing caused more discomfort. Conclusion Use of vaginal-perineal culture for assessment of maternal GBS colonization is comparable to the more typically utilized vaginal-rectal culture and is associated with less discomfort.

Avian pathogenic Escherichia coli (APEC), such as O1, O2 and O78, are important serogroups relating to chicken health, being responsible for colibacillosis. In this study, we isolated and characterized bacteriophages (phages) from hen feces and human sewage in Alberta with the potential for controlling colibacillosis in laying hens. The lytic profile, host range, pH tolerance and morphology of seven APEC-infecting phages (ASO1A, ASO1B, ASO2A, ASO78A, ASO2B, AVIO78A and ASO78B) were assessed using a microplate phage virulence assay and transmission electron microscopy (TEM). The potential safety of phages at the genome level was predicted using AMRFinderPlus and the Virulence Factor Database. Finally, phage genera and genetic relatedness with other known phages from the NCBI GenBank database were inferred using the virus intergenomic distance calculator and single gene-based phylogenetic trees. The seven APEC-infecting phages preferentially lysed APEC strains in this study, with ECL21443 (O2) being the most susceptible to phages (n = 5). ASO78A had the broadest host range, lysing all tested strains (n = 5) except ECL20885 (O1). Phages were viable at a pH of 2.5 or 3.5–9.0 after 4 h of incubation. Based on TEM, phages were classed as myovirus, siphovirus and podovirus. No genes associated with virulence, antimicrobial resistance or lysogeny were detected in phage genomes. Comparative genomic analysis placed six of the seven phages in five genera: Felixounavirus (ASO1A and ASO1B), Phapecoctavirus (ASO2A), Tequatrovirus (ASO78A), Kayfunavirus (ASO2B) and Sashavirus (AVIO78A). Based on the nucleotide intergenomic similarity (Caudoviricetes. The tail fiber protein phylogeny revealed variations within APEC-infecting phages and closely related phages. Diverse APEC-infecting phages harbored in the environment demonstrate the potential to control colibacillosis in poultry.

Bovine mastitis caused by multi-drug resistant (MDR) Klebsiella pneumoniae is difficult to treat with antibiotics, whereas bacteriophages may be a viable alternative. Our objective was to use 2 K. pneumoniae strains, 1 MDR and the other non-MDR, to isolate phages from sewage samples and compare their biological and genomic characteristics. Additionally, phage infected mouse mammary gland was also analyzed by H&E staining and ELISA kits to compare morphology and inflammatory factors, respectively. Based on assessments with double agar plates and transmission electron microscopy, phage CM_Kpn_HB132952 had clear plaques surrounded by translucent halos on the bacterial lawn of K. pneumoniae KPHB132952 and belonged to Siphoviridae, whereas phage CM_Kpn_HB143742 formed a clear plaque on the bacterial lawn of K. pneumoniae KPHB143742 and belonged to Podoviridae. In 1-step growth curves, CM_Kpn_HB132952 and CM_Kpn_HB143742 had burst sizes of 0.34 and 0.73 log10 PFU/mL, respectively. The former had a latent period of 50 min and an optimal multiplicity of infection (MOI) of 0.01, whereas for the latter, the latent period was 30 min (MOI = 1). Phage CM_Kpn_HB132952 had better thermal and acid–base stability than phage CM_Kpn_HB143742. Additionally, both phages had the same host range rate but different host ranges. Based on Illumina NovaSeq, phages CM_Kpn_HB132952 and CM_Kpn_HB143742 had 140 and 145 predicted genes, respectively. Genomic sequencing and phylogenetic tree analysis indicated that both phages were novel phages belonging to the Klebsiella family. Additionally, the histopathological structure and inflammatory factors TNF-α and IL-1β were not significantly different among phage groups and the control group. In conclusion, using 1 MDR and 1 non-MDR strain of K. pneumoniae, we successfully isolated two phages from the same sewage sample, and demonstrated that they had distinct biological and genomic characteristics.

Mingyue Huang,1,2,&ast; Xinyu Yang,2,&ast; Zhenzhen Wang,3 Jianglan Long,3 Aiting Wang,3 Yi Zhang,4 Dan Yan3 1College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, People’s Republic of China; 2Beijing Key Laboratory of Bio-Characteristic Profiling for Evaluation of Rational Drug Use, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, People’s Republic of China; 3Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China; 4Department of Traditional Chinese Medicine and Natural Medicine, Chongqing Institute for Food and Drug Control, Chongqing, 401121, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dan YanDepartment of Pharmacy, Beijing Friendship Hospital, Capital Medical University, No. 95, Yong’an Road, Xicheng District, Beijing, 100050, People’s Republic of ChinaTel +86 10-63139318Email pharmsci@126.comYi ZhangDepartment of Traditional Chinese Medicine and Natural Medicine, Chongqing Institute for Food and Drug Control, No. 1, Chunlan 2nd Road, Yubei District, Chongqing, 401121, People’s Republic of ChinaTel +86 23-86072771Email zhangyi@cqifdc.org.cnAbstract: Autophagy has been reported to involve in the pathogenesis of type 2 diabetes mellitus (T2DM), which protects the insulin target tissues and pancreatic β-cells. However, autophagy is inhibited when the cells are lipid overload. That, in turn, increases the accumulation of fat. Lipotoxicity caused by excessive lipid accumulation contributes to pathogenesis of T2DM. Therefore, it is undeniable to break the vicious circles between lipid excess and autophagy deficiency. Lipophagy, a selective form of autophagy, is characterized by selective breakdown of lipid droplets (LDs). The nutritional status of cells contributes to the way of autophagy (selective or non-selective), while selective autophagy helps to accurately remove excess substances. It seems that lipophagy could be an effective means to decrease abnormal lipid accumulation that leads to insulin resistance and β-cell impairment by removing ectopic LDs. Based on this process, many natural compounds have been reported to decrease lipid accumulation in tissues through autophagy-lysosomal pathway, which gradually highlights the significance of lipophagy. In this review, we focus on the mechanisms that lipophagy improves T2DM and natural products that are applied to induce lipophagy. It is also suggested that natural herbs with rich contents of natural products inducing lipophagy would be potential candidates for alleviating T2DM.Keywords: lipophagy, lipid metabolism, type 2 diabetes mellitus, autophagy, natural products

Xiao-Mei Tao,1– 3,* Peng-Fei Liu,1,* Hong-Yan Gu,1– 3 Dong-Bo Lian,1 Lei Gao,1 Wei-Wei Tao,4 Dan Yan,1– 3 Bin Zhao5 1Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, People’s Republic of China; 2Beijing Key Laboratory of Bio-Characteristic Profiling for Evaluation of Clinical Rational Drug Use, Beijing Municipal Science and Technology Commission, Beijing 100038, People’s Republic of China; 3International Cooperation & Joint Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing Municipal Science & Technology Commission, Beijing 100038, People’s Republic of China; 4College of Nursing, Dalian Medical University, Dalian 116044, People’s Republic of China; 5Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei-Wei Tao; Bin Zhao Tel +86 13610862836; +86 13811825981Email weiweitaomy@126.com; binzhaomyemail@sina.comIntroduction: Osteoarthritis is the most prevalent articular disease in the elderly. We aimed to explore the role of cordycepin (COR) in the progression and development of osteoarthritis and its correlation with TGF-β activity and autophagy.Methods: Sprague Dawley rats were induced by anterior cruciate ligament transection (ACLT) to establish knee osteoarthritis model. To investigate the role of COR in knee osteoarthritis, rats were injected with 5, 10, and 20 mg/kg of COR before joint surgery. After surgery, paw withdrawal mechanical threshold (PWMT) was performed. HE staining and Alcian blue staining were carried out to detect cartilage damage. ELISA was used to detect the level of TGFβ in the serum. Protein expression was analyzed by Western blotting.Results: In this study, we found that the PWMT of rats with osteoarthritis induced by ACLT was decreased significantly, accompanied by obvious histological and cartilage damage. After different doses of COR treatment, the PWMT of osteoarthritis rats induced by ACLT was increased in a dose-dependent manner. In addition, compared with the control group, COR treatment also reversed the effect of ACLT on cartilage injury in rats. Furthermore, the level of TGF-β in serum of ACLT rats was increased significantly, which may be related to the overexpression of TGF-β R1. However, the increase of serum TGF-β level in ACLT rats was reversed by COR treatment in a dose-dependent manner. It is worth noting that TGF-β overexpression reduced the proportion of autophagy-related protein LC3-II/I, thus inhibiting autophagy. In order to further confirm the effect of TGF-β on autophagy, TGF-β was overexpressed or the autophagy inhibitor 3-MA was applied. The results showed that TGF-β overexpression and 3-MA treatment reversed the effect of COR on autophagy.Conclusion: In summary, our findings declared that COR alleviated ACLT-induced osteoarthritis pain and cartilage damage by inhibiting TGF-β activity and inducing autophagy in rat model with knee osteoarthritis.Keywords: cordycepin, anterior cruciate ligament transection, osteoarthritis, TGF-β, autophagy, in vivo

Jiahao Tang,1,2 Liang Chen,1,2 Deyi Yan,1,2 Zijian Shen,1,2 Bingzhang Wang,1,2 Sheji Weng,1,2 Zongyi Wu,1,2 Zhongjie Xie,1,2 Jiancan Shao,1,2 Lei Yang,1,2 Liyan Shen1,2 1The Second School of Medicine Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of China; 2Key Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of ChinaCorrespondence: Lei Yang; Liyan ShenKey Laboratory of Orthopedics of Zhejiang Province, Department of Orthopedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, No. 109, Xueyuan West Road, Lucheng District, Wenzhou, Zhejiang 325000, People’s Republic of ChinaFax +86 577 88002760Email yl190015@hotmail.com; uynixmm@163.comPurpose: Aseptic loosening is a major complication after total joint replacement. Reactive oxygen species generated by local tissue cells and liberated from implant surfaces have been suggested to cause implant failures. Surface modification of titanium (Ti)-based implants with proanthocyanidins (PAC) is a promising approach for the development of anti-oxidant defense mechanism to supplement the mechanical functions of Ti implants. In this study, a controlled PAC release system was fabricated on the surface of Ti substrates using the layer-by-layer (LBL) assembly.Materials and Methods: Polyethyleneimine (PEI) base layer was fabricated to enable layer-by-layer (LBL) deposition of hyaluronic acid/chitosan (HA/CS) multi-layers without or with the PAC. Surface topography and wettability of the fabricated HA/CS-PAC substrates were characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), Fourier-transform infrared spectroscopy (FTIR) and contact angle measurement. PAC release profiles were investigated using drug release assays. MC3T3-E1 pre-osteoblast cells were used to assess the osteo-inductive effects of HA/CS-PAC substrates under conditions H2O2-induced oxidative stress in vitro. A rat model of femoral intramedullary implantation evaluated the osseo-integration and osteo-inductive potential of the HA/CS-PAC coated Ti implants in vivo.Results: SEM, AFM, FTIR and contact angle measurements verified the successful fabrication of Ti surfaces with multi-layered HA/CS-PAC coating. Drug release assays revealed controlled and sustained release of PAC over 14 days. In vitro, cell-based assays showed high tolerability and enhanced the osteogenic potential of MC3T3-E1 cells on HA/CS-PAC substrates when under conditions of H2O2-induced oxidative stress. In vivo evaluation of femoral bone 14 days after femoral intramedullary implantation confirmed the enhanced osteo-inductive potential of the HA/CS-PAC coated Ti implants.Conclusion: Multi-layering of HA/CS-PAC coating onto Ti-based surfaces by the LBL deposition significantly enhances implant osseo-integration and promotes osteogenesis under conditions of oxidative stress. This study provides new insights for future applications in the field of joint arthroplasty.Keywords: proanthocyanidins, anti-oxidant, ROS, layer-by-layer methodology, surface modification of titanium, osteogenesis

Abstract A previously isolated a bacteriophage, vB_EcoS_AKFV33 of T5virus, demonstrated great potential in biocontrol of Shiga toxigenic Escherichia coli (STEC) O157. This study further evaluated its potential as a biocontrol agent in broth culture against other important non-O157 serogroups of STEC and Salmonella. AKFV33 was capable of lysing isolates of STEC serogroups O26 (n = 1), O145 (n = 1) and Salmonella enterica serovars (n = 6). In a broth culture microplate system, efficacy of AKFV33 for killing STEC O26:H11, O145:NM and Salmonella was improved (P

The present study reports on the development and testing of novel bleaching agents containing co-doped metaloxide nanoparticles (NP; 0%, 5%, 10% v/w) and hydrogen peroxide (HP, 0%, 6%, 15%, and 35%). Bovine blocks (n = 200, A = 36 mm2) were obtained and randomly distributed into experimental groups (n = 10/group). NPs were incorporated into gels before bleaching (3 sessions, 7 days apart, 30 min/session, irradiated with violet light-LT). Color changes (ΔE00, ΔWID), mineral content (CO32−, PO43−), and topography were assessed (spectrophotometer, ATR-FTIR, and AFM) before and after bleaching procedures (14 days). Metabolic status and three-dimensional components of non-disrupted Streptococcus mutans biofilms were investigated using a multimode reader and confocal microscopy. The results indicate that ΔE00 and ΔWID significantly increased with NPs’ concentrations and LT. The enamel’s mineral ratio was adversely impacted by HP, but alterations were less pronounced when using NP-containing gels. The enamel’s topography was not damaged by the bleaching protocols tested. The bioluminescence results show that bleaching protocols do not render latent antibacterial properties to enamel, and the confocal microscopy results demonstrate that the 3-dimensional distribution of the components was affected by the protocols. The proposed nanotechnology improved the bleaching efficacy of experimental materials independent of hydrogen peroxide or irradiation and did not adversely impact the enamel’s surface properties or its chemical content.

Dewei Peng,1,2 Jing Dong,1,2 Yunping Zhao,1,2 Xiaomei Peng,1,2 Jingjing Tang,1,2 Xiaoyan Chen,1,2 Lihua Wang,1,2 Dan-Ning Hu,2,3 Peter S Reinach,1,2 Jia Qu,1,2 Dongsheng Yan1,21School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2State Key Laboratory of Ophthalmology, Optometry and Visual Science, Wenzhou, Zhejiang, People’s Republic of China; 3Tissue Culture Center, New York Eye and Ear Infirmary, New York Medical College, New York, NY, USAPurpose: Uveal melanoma (UM) is the most frequent metastatic ocular tumor in adults. Therapeutic intervention remains ineffective since none of the novel procedures used to treat this disease increased survival rates. To deal with this limitation, additional studies are required to clarify its pathogenesis. The current study focused on describing how epigenetic modulation by miR-142-3p affects changes in some cellular functions underlying UM pathogenesis.Methods and results: Microarray analysis identified 374 miRNAs which were differentially expressed between UM cells and uveal melanocytes. miR-142-3p was one of the 10 most downregulated miRNAs. Quantitative RT-PCR analysis confirmed that miR-142-3p expression levels were significantly decreased in both UM cell lines and clinical specimens. The results of the MTS, clone formation, scratch wound, transwell assays, and in vivo biofluorescence imaging showed that miR-142-3p overexpression significantly inhibited cell proliferation, migration, and invasiveness. Nevertheless, miR-142-3p did not affect cell apoptotic activity or sensitivity to doxorubicin. Cell cycle and EdU analysis showed that miR-142-3p overexpression induced G1/G2 cell cycle arrest and reduced DNA synthesis in UM cells. Microarray analysis showed that miR-142-3p mainly regulates the TGFβ signaling pathway, and those in which MAPK and PI3K-Akt are constituents. Functional interactions between miR-142-3p and CDC25C, TGFβR1, GNAQ, WASL, and RAC1 target genes were confirmed based on the results of the luciferase reporter assay and Western blot analysis. CDC25C or RAC1 downregulation is in agreement with cell cycle arrest and DNA synthesis disorder induction, while downregulation of TGFβR1, GNAQ, WASL, or RAC1 accounts for declines in cell migration.Conclusion: miR-143-3p is a potential therapeutic target to treat UM since overriding its declines in expression that occur in this disease reversed the pathogenesis of this disease. Such insight reveals novel biomarker for decreasing UM vitality and for improved tracking of tumor progression.Keywords: miR-142-3p, uveal melanoma, tumor suppressor, molecular mechanisms

Abstract Background The clinical behavior of prostate cancer (PCa) is variable, and while the majority of cases remain indolent, 10% of patients progress to deadly forms of the disease. Current clinical predictors used at the time of diagnosis have limitations to accurately establish progression risk. Here we describe the development of a tumor suppressor regulated, cell-cycle gene expression based prognostic signature for PCa, and validate its independent contribution to risk stratification in several radical prostatectomy (RP) patient cohorts. Methods We used RNA interference experiments in PCa cell lines to identify a gene expression based gene signature associated with Tmeff2, an androgen regulated, tumor suppressor gene whose expression shows remarkable heterogeneity in PCa. Gene expression was confirmed by qRT-PCR. Correlation of the signature with disease outcome (time to recurrence) was retrospectively evaluated in four geographically different cohorts of patients that underwent RP (834 samples), using multivariate logistical regression analysis. Multivariate analyses were adjusted for standard clinicopathological variables. Performance of the signature was compared to previously described gene expression based signatures using the SigCheck software. Results Low levels of TMEFF2 mRNA significantly (p

Effectiveness of bacteriophages AKFV33 (Tequintavirus, T5) and AHP24 (Rogunavirus, T1), wV7 (Tequatrovirus, T4), and AHP24S (Vequintavirus, rV5), as well as 11 cocktails of combinations of the four phages, were evaluated in vitro for biocontrol of six common phage types of Escherichia coli O157 (human and bovine origins) at different multiplicities of infection (MOIs; 0.01–1,000), temperatures (37 or 22°C), and exposure times (10–22 h). Phage efficacy against O157 was highest at MOI 1,000 (P < 0.001) and after 14-18 h of exposure at 22°C (P < 0.001). The activity of individual phages against O157 did not predict the activity of a cocktail of these phages even at the same temperature and MOI. Combinations of phages were neutral (no better or worse than the most effective constituent phages acting alone), displayed facilitation (greater efficacy than the most effective constituent phages acting alone), or antagonistic (lower efficacy than the most effective constituent phages acting alone). Across MOIs, temperatures, exposure time, and O157 strains, a cocktail of T1, T4, and rV5 was most effective (P < 0.05) against O157, although T1 and rV5 were less effective (P < 0.001) than other individual phages. T5 was the most effective individual phages (P < 0.05), but was antagonistic to other phages, particularly rV5 and T4 + rV5. Interactions among phages were influenced by phage genera and phage combination, O157 strains, MOIs, incubation temperatures, and times. Based on this study, future development of phage cocktails should, as a minimum, include confirmation of a lack of antagonism among constituent phages and preferably confirmation of facilitation or synergistic effects.

Multidrug-resistant (MDR; resistance to ≥3 antimicrobial classes) members of the Pasteurellaceae family may compromise the efficacy of therapies used to prevent and treat bovine respiratory disease (BRD) in feedlot cattle. This study examined the prevalence of multidrug resistance in strains of Mannheimia haemolytica and Pasteurella multocida collected from BRD cattle mortalities in North America. Isolates of M. haemolytica (n = 147) and P. multocida (n = 70) spanning 69 Alberta feedlots from 2011 to 2016 and two United States feedlots from 2011 to 2012 were examined for antimicrobial resistance (AMR) in association with integrative and conjugative elements (ICEs). Overall, resistance was high in both bacterial species with an increase in the prevalence of MDR isolates between 2011 and 2016. Resistance to >7 antimicrobial drugs occurred in 31% of M. haemolytica and 83% of P. multocida isolates. Resistance to sulfadimethoxine, trimethoprim/sulfamethoxazole, neomycin, clindamycin oxytetracycline, spectinomycin, tylosin, tilmicosin, and tulathromycin was most common. Although >80% of strains harbored three or more ICE-associated genes, only 12% of M. haemolytica and 77% of P. multocida contained all six, reflecting the diversity of ICEs. There was evidence of clonal spread as P. multocida and M. haemolytica isolates with the same pulsed-field gel electrophoresis profile from the United States in 2011 were isolated in Alberta in 2015–2016. This work highlights that MDR strains of Pasteurellaceae containing ICEs are widespread and may be contributing to BRD therapy failure in feedlot cattle. Given the antimicrobial resistance gene profiles identified, these MDR isolates may be selected for by the use of macrolides, tetracyclines, and/or in-feed supplements containing heavy metals.

Rapid and accurate diagnosis of bovine respiratory disease (BRD) presents a substantial challenge to the North American cattle industry. Here we utilize recombinase polymerase amplification (RPA), a fast and sensitive isothermal DNA-based technology for the detection of four BRD pathogens (Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, Mycoplasma bovis), genes coding antimicrobial resistance (AMR) and integrative conjugative elements (ICE) which can harbor AMR genes. Eleven RPA assays were designed and validated including: a) one conventional species-specific multiplex assay targeting the 4 BRD pathogens, b) two species-specific real-time multiplex RPA assays targeting M. haemolytica/M. bovis and P. multocida/H. somni, respectively with a novel competitive internal amplification control, c) seven conventional assays targeting AMR genes (tetH, tetR, msrE, mphE, sul2, floR, erm42), and d) one real-time assay targeting ICE. Each real-time RPA assay was tested on 100 deep nasopharyngeal swabs (DNPS) collected from feedlot cattle previously assessed for targets using either culture methods and/or polymerase chain reaction (PCR) verification (TC-PCR). The developed RPA assays enabled sensitive and accurate identification of BRD agents and AMR/ICE genes directly from DNPS, in a shorter period than TC-PCR, showing considerable promise as a tool for point-of-care identification of BRD pathogens and antimicrobial resistance genes.

The efficacy of a water quality management strategy highly depends on the analysis of water quality data, which must be intensively analyzed from both spatial and temporal perspectives. This study aims to analyze spatial and temporal trends in water quality in Code River in Indonesia and correlate these with land use and land cover changes over a particular period. Water quality data consisting of 15 parameters and Landsat image data taken from 2011 to 2017 were collected and analyzed. We found that the concentrations of total dissolved solid, nitrite, nitrate, and zinc had increasing trends from upstream to downstream over time, whereas concentrations of parameter biological oxygen demand, cuprum, and fecal coliform consistently undermined water quality standards. This study also found that the proportion of natural vegetation land cover had a positive correlation with the quality of Code River’s water, whereas agricultural land and built-up areas were the most sensitive to water pollution in the river. Moreover, the principal component analysis of water quality data suggested that organic matter, metals, and domestic wastewater were the most important factors for explaining the total variability of water quality in Code River. This study demonstrates the application of a GIS-based multivariate analysis to the interpretation of water quality monitoring data, which could aid watershed stakeholders in developing data-driven intervention strategies for improving the water quality in rivers and streams.

Liming Huang,1 Wenshen Xu,2 Lian Dai,3 Danfang Yan,4 Shu Zhang,1 Xi Shi1 1The First Department of Chemotherapy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China; 2Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China; 3Department of Medicine, The Third Affiliated People’s Hospital, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China; 4Department of Radiation Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China Purpose: O6-methylguanine-DNA methyltransferase (MGMT) plays a crucial role in repairing damaged DNA caused by alkylating agents. A number of cancer susceptibility loci have been recognized as enhancer variants. This study aimed to explore the significance of enhancer variants of MGMT in glioma susceptibility. Patients and methods: A retrospective case-control study consisting of 150 glioma patients and 327 controls was conducted to test whether enhancer variants of MGMT are associated with glioma susceptibility. Genotypes were determined by Sequenom MassARRAY technology. Associations were estimated by logistic regression. Biochemical assays were used to examine the function of glioma susceptibility locus. Results: We found that the A allele of rs10764901, an intronic variant of MGMT, was associated with a significantly decreased risk of glioma. The rs10764901 AA genotype carriers had an OR of 0.49 (95% CI, 0.24–0.98; P=0.045) compared with the rs10764901 GG genotype. When the rs10764901 AG and AA genotypes were pooled for analysis, a significantly decreased risk of glioma was also found (OR, 0.63; 95% CI, 0.43–0.93; P=0.021). Functional analyses showed that the rs10764901 A allele drove a lower luciferase expression and had higher transcription factor binding affinity than the G allele. Conclusion: An enhancer variant of MGMT rs10764901 affects the regulatory activity of enhancer by altering the binding affinity of transcription factors and is associated with glioma susceptibility. Keywords: glioma, MGMT, enhancer, genetic variation, susceptibility

Shiga toxin-producing Escherichia coli (STEC) and Salmonella enterica are important foodborne pathogens capable of forming both single- and multi-species biofilms. In this study, the mono- and dual-species biofilms were formed by STEC O113:H21 and Salmonella enterica serovar Choleraesuis 10708 on stainless steel in the presence of beef juice over 5 d at 22 °C. The dual-species biofilm mass was substantially (p < 0.05) greater than that produced by STEC O113:H21 or S. Choleraesuis 10708 alone. However, numbers (CFU/mL) of S. Choleraesuis 10708 or STEC O113:H21 cells in the dual-species biofilm were (p < 0.05) lower than their respective counts in single-species biofilms. In multi-species biofilms, the sensitivity of S. Choleraesuis 10708 to the antimicrobial peptide WK2 was reduced, but it was increased for STEC O113:H21. Visualization of the temporal and spatial development of dual-species biofilms using florescent protein labeling confirmed that WK2 reduced cell numbers within biofilms. Collectively, our results highlight the potential risk of cross-contamination by multi-species biofilms to food safety and suggest that WK2 may be developed as a novel antimicrobial or sanitizer for the control of biofilms on stainless steel.

Sahil Sekhon, Caleb Jeon, Mio Nakamura, Di Yan, Ladan Afifi, Tina Bhutani, Ethan Levin Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA Abstract: Psoriasis vulgaris is a chronic, immune-mediated systemic disease that affects ~7.5 million people in the US. It can be treated with many therapies, often in combination, which include topicals, phototherapy, oral systemics, and biologics. Biologic agents target specific components of the immune system involved in the pathogenesis of psoriasis including TNF-alpha, IL-12, IL-17, and IL-23. The biologic ixekizumab, approved for the treatment of moderate–severe plaque psoriasis in the US, targets IL-17. This review describes the role of IL-17 in psoriasis, the mechanism by which ixekizumab targets this cytokine, and the clinical utility of ixekizumab. Keywords: ixekizumab, biologics, psoriasis, IL-17, anti-IL-17

Abstract Background Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines which participate in clearing viral infections. Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. Methods We generated a RIG-I transgenic (TG) mouse strain that expresses the RIG-I gene product under the control of the human lung specific surfactant protein C promoter. We compared the mortality and host immune responses of RIG-I TG mice and their litter-matched wild type (WT) mice following challenge with influenza A virus (IAV). Results RIG-I overexpression increased survival of IAV-infected mice. CS exposure increased mortality in WT mice infected with IAV. Remarkably, the effect of RIG-I overexpression on survival during IAV infection was enhanced in CS-exposed animals. CS-exposed IAV-infected WT mice had a suppressed innate response profile in the lung compared to sham-exposed IAV-infected WT mice in terms of the protein concentration, total cell count and inflammatory cell composition in the bronchoalveolar lavage fluid. RIG-I overexpression restored the innate immune response in CS-exposed mice to that seen in sham-exposed WT mice during IAV infection, and is likely responsible for enhanced survival in RIG-I TG mice as restoration preceded death of the animals. Conclusions Our results demonstrate that RIG-I overexpression in mice is protective for CS enhanced susceptibility of smokers to influenza infection, and that CS mediated RIG-I suppression may be partially responsible for the increased morbidity and mortality of the mice exposed to IAV. Thus, optimizing the RIG-I response may be an important treatment strategy for CS-enhanced lung infections, particularly those due to IAV.

Xiaobing Qin,1,2,* Shaorong Yu,1,3,* Leilei Zhou,1,4 Meiqi Shi,3 Yong Hu,1 Xiaoyue Xu,1 Bo Shen,1 Siwen Liu,1 Dali Yan,1 Jifeng Feng1,3 1Research Center for Clinical Oncology, Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, 2Department of Oncology, Xuzhou First People’s Hospital, Xuzhou, 3Department of Oncology, Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, 4Department of Oncology, Affiliated Huai’an Hospital of Nanjing Medical University, Huai’an, Jiangsu, China *These authors have contributed equally to this work Abstract: Exosomes derived from lung cancer cells confer cisplatin (DDP) resistance to other cancer cells. However, the underlying mechanism is still unknown. A549 resistance to DDP (A549/DDP) was established. Microarray was used to analyze microRNA (miRNA) expression profiles of A549 cells, A549/DDP cells, A549 exosomes, and A549/DDP exosomes. There was a strong correlation of miRNA profiles between exosomes and their maternal cells. A total of 11 miRNAs were significantly upregulated both in A549/DDP cells compared with A549 cells and in exosomes derived from A549/DDP cells in contrast to exosomes from A549 cells. A total of 31 downregulated miRNAs were also observed. miR-100–5p was the most prominent decreased miRNA in DDP-resistant exosomes compared with the corresponding sensitive ones. Downregulated miR-100–5p was proved to be involved in DDP resistance in A549 cells, and mammalian target of rapamycin (mTOR) expression was reverse regulated by miR-100–5p. Exosomes confer recipient cells’ resistance to DDP in an exosomal miR-100–5p-dependent manner with mTOR as its potential target both in vitro and in vivo. Exosomes from DDP-resistant lung cancer cells A549 can alter other lung cancer cells’ sensitivity to DDP in exosomal miR-100–5p-dependent manner. Our study provides new insights into the molecular mechanism of DDP resistance in lung cancer. Keywords: lung cancer, cisplatin, exosome, miR-100–5p, drug resistance

Di Yan, Ladan Afifi, Caleb Jeon, Megha Trivedi, Hsin Wen Chang, Kristina Lee, Wilson Liao Department of Dermatology, University of California-San Francisco, San Francisco, CA, USA Abstract: Metabolomics is an emerging new “omics” field involving the systematic analysis of the metabolites in a biologic system. These metabolites provide a molecular snapshot of cellular activity and are thus important for understanding the functional changes in metabolic pathways that drive disease. Recently, metabolomics has been used to study the local and systemic metabolic changes in psoriasis and its cardiometabolic comorbidities. Such studies have revealed novel insights into disease pathogenesis and suggest new biochemical signatures that may be used as a marker of psoriatic disease. This review will discuss common strategies in metabolomics analysis, current findings in the metabolomics of psoriasis, and emerging trends in psoriatic metabolomics. Keywords: metabolome, psoriasis, psoriatic arthritis, skin, urine, metabolites

Background: Resident physicians are frequently uncomfortable ordering enteral nutrition (EN) and are unaware of the variety of formulas and supplements available for different disease processes. Many depend on a clinical dietician to assist with recommending EN formulas and patient energy requirements that may not be readily available on patient admission. This creates a barrier to early initiation of EN and non-compliance with Society of Critical Care Medicine and American Society of Parenteral and Enteral Nutrition clinical guidelines. Objective: Internal medicine resident physicians were provided an iPod with a smart phone/device application (EN application) to assist them in choosing EN formulas for patients during their intensive care unit (ICU) rotation. The primary outcome was improved initiation of EN within 24 hours of admission. Secondary outcomes included the following: time to initiate EN, goal calories reached, infections rates, length of stay, mortality, and concordance with clinical guidelines. Design: The study is a quasi-experimental design to improve delivery of EN at an academic medical center in the medical ICU. Data were collected from a retrospective chart review to evaluate the impact of an EN application to assist resident physicians when ordering EN. Results: Use of the EN application reduced the percent of patients with delayed initiation of EN from 61.2% prior to 37.5% ( P