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Shuang Lv,1 Yiming Li,2 Bojian Sun,1 Yu Jing,1 Xing Wang,3 Zhanqing Gu,1 Bailiang Wang,4 Cheng Xiao3 1Department of Rheumatology, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Cardiovascular, the First Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 3Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 4Department of Orthopaedic Surgery, China-Japan Friendship Hospital, Beijing, People’s Republic of ChinaCorrespondence: Bailiang Wang; Cheng Xiao, Email orthopaedic_wang@126.com; xc2002812@126.comObjects: Rheumatoid arthritis (RA) is a systemic autoimmune disease with an obscure pathogenesis. This study aims to identify the susceptibility conferred by specific single nucleotide polymorphisms (SNPs), namely rs17548629 within the RIPK1 gene and rs10094579 within the RIPK2 gene, in RA. Additionally, it investigates the associations between inflammatory markers and biochemical parameters at various stages of the disease.Methods: We analyzed 394 patients with RA and 258 normal controls (NCs), examining SNPs within the RIPK1 (rs17548629) and RIPK2 (rs10094579) genes using polymerase chain reaction (PCR) and sequencing techniques. Profiles of RA patients were evaluated for inflammatory markers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), as well as biochemical parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, glucose, uric acid, and creatinine. Additionally, disease-specific indicators included cyclic citrullinated peptide (CCP), rheumatoid factor (RF), antinuclear antibodies (ANA), and anti-keratin antibodies. The Disease Activity Score 28 (DAS28), based on ESR, was used to categorize RA patients into groups of high, moderate, or low disease activity.Results: We found a significant association between the RIPK1 rs17548629 genotype and RA in the additive model (p < 0.001; OR = 3.23), over-dominant model (p < 0.001; OR = 0.27), and dominant model (p < 0.001; OR = 3.94). The frequency of the C allele at rs17548629 was significantly higher in NCs than in RA patients (p < 0.001; OR = 0.322). When compared with normal controls, the RIPK1 rs17548629 genotype demonstrated significant associations with both anti-CCP-positive RA patients (p < 0.001) and anti-CCP-negative RA patients (p < 0.001). Similarly, this genotype was associated with RF-positive RA patients (p < 0.001). Furthermore, the RIPK2 rs10094579 genotype was significantly associated with CRP levels in RA patients with low disease activity in the over-dominant model (p = 0.029; OR = 0.065, adjusted for age and sex).Conclusion: The presence of the RIPK1 rs17548629 genotype is associated with RA under additive, co-dominant, and dominant models. The T allele mutation at rs17548629 increases the risk of RA in the Chinese population. The RIPK1 rs17548629 genotype was identified as being associated with RF-positive RA patients, whereas no significant association was observed in RF-negative individuals. These findings suggest that this SNP may modulate the risk of RA in an RF-dependent manner. Furthermore, the RIPK2 rs10094579 genotype correlates with CRP levels in RA patients exhibiting low disease activity. This association underscores the necessity for caution when reducing the dosage of therapy in RA patients with low disease activity who carry the CA genotype at RIPK2 rs10094579. Additional research is warranted to explore other genotypes that may influence RA susceptibility and to refine potential treatment strategies.keywords: receptor-interacting protein kinase, rheumatoid arthritis, polymorphism, single nucleotide, biochemical parameters

Yawan Jing,1,2 Ruixin Cheng,3 Hao Zeng,1 Qin Huang,1 Dongyu He,1 Jiayi Sun,1 Panwen Tian,1,4 Yalun Li1,4 1Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Respiratory Health and Multimorbidity, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, Precision Medicine Center/Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Gerontology and Geriatrics, Tibet Autonomous Region People’s Hospital, Lhasa, Tibet Autonomous Region, People’s Republic of China; 3Department of Radiation Oncology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, 510080, People’s Republic of China; 4Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Yalun Li; Panwen Tian, Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu, Sichuan Province, 610041, People’s Republic of China, Tel/Fax +86 28 85423660, Email lunlunhx@qq.com; mrascend@163.comBackground: KRAS mutation is one of the most common driver oncogenes in non-small cell lung cancer (NSCLC), and the most common mutation subtype is G12C. However, there is still a lack of efficacy and prognosis data related to immunotherapy, which hinders the promotion of new strategies.Methods: Clinical characteristics and treatment outcomes were collected and analyzed for patients with NSCLC harboring KRAS mutations at West China Hospital of Sichuan University from June 2013 to March 2023.Results: Among the 231 patients with KRAS-mutated NSCLC, 29.4% had KRAS G12C mutations. Compared to the KRAS non-G12C NSCLC group, the KRAS G12C NSCLC group had a greater number of pack-years. The programmed death ligand 1 expression and the proportion of patients with a high tumor mutational burden were not significantly different between the two groups. Similar patterns of TP53, STK11, and CDKN2A mutations were observed between KRAS G12C and KRAS non-G12C NSCLC groups. The median progression-free survival (PFS) (8.4 vs 7.0 months, p=0.100) and overall survival (OS) (12.1 vs 18.1 months, p=0.590) were not statistically different between KRAS G12C and KRAS non-G12C. Compared to patients with KRAS G12C NSCLC who did not receive immunotherapy, patients who received immunotherapy had a better objective response rate (46.2% vs 0%, p=0.002), PFS (12.2 vs 7.5 months, p=0.087) and OS (49.9 vs 11.1 months, p=0.12).Conclusion: Patients with KRAS G12C were more likely to be smokers. Advanced KRAS G12C NSCLC patients who received immunotherapy had a better ORR than those who did not, suggesting that patients with G12C mutations are more likely to benefit from immunotherapy.Keywords: non-small cell lung cancer, KRAS G12C mutation, KRAS mutation, immunotherapy, overall survival

Xiaochun Chen,1,&ast; Benhong Zhang,2,&ast; Jin He,3,&ast; Xiaohong Rui,4 Tian He,4 Lizhu Zhang,5 Junfeng Bao,6 Yanfei Jing,7 Futao Cao8 1Department of Laboratory Medicine, Taizhou Second People’s Hospital, Taizhou, People’s Republic of China; 2Department of Laboratory Medicine, Hangzhou Gongshu District Integrated Traditional Chinese and Western Medicine Hospital, Hangzhou, People’s Republic of China; 3Department of Laboratory Medicine, Hangzhou Yuhang Jiamu Nursing Home, Hangzhou, People’s Republic of China; 4Department of Laboratory Medicine, Affiliated Wuxi Fifth Hospital of Jiangnan University, Wuxi, People’s Republic of China; 5Department of Research, Nanxin Pharm, Nanjing, People’s Republic of China; 6Department of Laboratory Medicine, Wuxi Maternal and Child Health Care Hospital, Women’s Hospital of Jiangnan University, Wuxi, People’s Republic of China; 7Department of Function, Affiliated Wuxi Fifth Hospital of Jiangnan University, Wuxi, People’s Republic of China; 8Department of Emergency, Jiangnan University Medical Center, Wuxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanfei Jing, Department of Function, Affiliated Wuxi Fifth Hospital of Jiangnan University, Wuxi, Jiangsu, 214005, People’s Republic of China, Email tengfeiba0002@163.com Futao Cao, Department of Emergency, Jiangnan University Medical Center, Wuxi, Jiangsu, 214000, People’s Republic of China, Email caofutao999@163.comIntroduction: The emergence of multidrug-resistant Klebsiella pneumoniae (K. pneumoniae) and the decline of effective antibiotics lead to the urgent need for new antibacterial agents. The aim of this study is to investigate the therapeutic effect of antimicrobial peptides against gentamicin-resistant (RT) K. pneumoniae and to screen effective antimicrobial peptides.Methods: In this study, the RT strains were induced by gradient gentamicin, and the RT strains were selected by detecting the expression levels of efflux pump genes, porin genes, and biofilm formation genes of the strains combined with their effects on the cells. Then the effects of four antimicrobial peptides on the efflux pump activity, biofilm formation level and cell condition after infection were detected to explore the effects of antimicrobial peptides on RT strains. Finally, the RT strain was used to induce a mouse model of pneumonia, and the four antimicrobial peptides were used to treat pneumonia mice for in vivo experiments. The pathological changes in lung tissues in each group were detected to explore the antimicrobial peptide with the most significant effect on the RT strain in vivo.Results: The results showed that the minimal inhibitory concentrations of the RT strains (strain C and strain I) were significantly higher than those of the wild-type strain, and the expression of efflux pump, porin and biofilm formation genes was significantly increased. The antimicrobial peptides could effectively inhibit the biofilm formation and efflux pump protein function of the RT strains. In addition, the antimicrobial peptides showed promising antibacterial effects both in vitro and in vivo.Discussion: Our study provided a theoretical basis for the treatment of gentamicin resistant K. pneumoniae infection with antimicrobial peptides, and found that KLA was significantly superior to LL37, Magainin I, KLA and Dermaseptin (10 μg/mL in cells, 50 μg in mice).Keywords: Klebsiella pneumoniae, K. pneumoniae, antibiotics, antimicrobial peptide, gentamicin-resistant, RT, microenvironment

Qing Lin,1,2,&ast; Yafei Jing,2,3,&ast; Cailing Yan,2 Xinyi Chen,2 Qiong Zhang,2 Xinhua Lin,2,3 Yunlu Xu,2,4 Bing Chen2,3 1Department of Pharmacy, Affiliated Fuzhou First Hospital of Fujian Medical University, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 2School of Pharmacy, Fujian Medical University, Fujian, People’s Republic of China; 3Key Laboratory of Nanomedical Technology (Education Department of Fujian Province), Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 4Center of Translational Hematology, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bing Chen, School of Pharmacy, Fujian Medical University, Fuzhou, 350122, People’s Republic of China, Email BingChen_001@126.com; BingChen_001@fjmu.edu.cn Yunlu Xu, Center of Translational Hematology, Fujian Medical University Union Hospital, Fujian Medical University, Fuzhou, 350122, People’s Republic of China, Email xuyunlu3578@126.comBackground: Current immunotherapies with unexpected severe side effects and treatment resistance have not resulted in the desired outcomes for patients with melanoma, and there is a need to discover more effective medications. Cytotoxin (CTX) from Cobra Venom has been established to have favorable cytolytic activity and antitumor efficacy and is regarded as a promising novel anticancer agent. However, amphiphilic CTX with excellent anionic phosphatidylserine lipid-binding ability may also damage normal cells.Methods: We developed pH-responsive liposomes with a high CTX load (CTX@PSL) for targeted acidic-stimuli release of drugs in the tumor microenvironment. The morphology, size, zeta potential, drug-release kinetics, and preservation stability were characterized. Cell uptake, apoptosis-promoting effects, and cytotoxicity were assessed using MTT assay and flow cytometry. Finally, the tissue distribution and antitumor effects of CTX@PSL were systematically assessed using an in vivo imaging system.Results: CTX@PSL exhibited high drug entrapment efficiency, drug loading, stability, and a rapid release profile under acidic conditions. These nanoparticles, irregularly spherical in shape and small in size, can effectively accumulate at tumor sites (six times higher than free CTX) and are rapidly internalized into cancer cells (2.5-fold higher cell uptake efficiency). CTX@PSL displayed significantly stronger cytotoxicity (IC50 0.25 μg/mL) and increased apoptosis in than the other formulations (apoptosis rate 71.78± 1.70%). CTX@PSL showed considerably better tumor inhibition efficacy than free CTX or conventional liposomes (tumor inhibition rate 79.78± 5.93%).Conclusion: Our results suggest that CTX@PSL improves tumor-site accumulation and intracellular uptake for sustained and targeted CTX release. By combining the advantages of CTX and stimuli-responsive nanotechnology, the novel CTX@PSL nanoformulation is a promising therapeutic candidate for cancer treatment.Keywords: cobra venom cytotoxin, tumor microenvironment, pH-responsive, targeted delivery, liposomes

Ziyu Ren,1 Jiangchuan Long,1 Wenzhen Deng,1 Yuanyuan Jing,1 Jingwen Qiu,1 Wei Ren,2 Dongfang Liu1 1Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Endocrinology and Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Wei Ren, Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, No. 1. You-Yi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-23-89012755, Email renwei67@sina.com Dongfang Liu, Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, No. 74, Linjiang Road, Yuzhong District, Chongqing, 400010, People’s Republic of China, Tel +86-23-63832133, Email 300306@hospital.cqmu.edu.cn; ldf023023@qq.comBackground: In recent years, multiple observational studies have confirmed the association between sleep traits and various human physiopathological states. However, the causal relationship between sleep traits and hypothalamic-pituitary-target gland axis (HPTGA) function remains unknown.Methods: We obtained summary statistics on sleep traits (insomnia, chronotype, and sleep duration (long and short)) from the UK Biobank database. Data related to the HPTGA functions were obtained from the publicly available database. Subsequently, a two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationship between different sleep traits and the HPTGA function. Reverse MR analysis was conducted to examine the direction of causality.Results: The MR analysis results suggested that chronotype is associated with decreased levels of six hormones in HPTGA. Sleep duration was causally associated with decreased levels of free thyroxine and progesterone. Both long and short sleep durations are detrimental to the secretion of prolactin-releasing peptide, somatostatin, and plasma cortisol, while short sleep duration can promote progesterone secretion. After gender stratification, we found that female reproductive function is more susceptible to the influence of unfavorable sleep traits.Conclusion: Our MR analysis indicated a significant causal association between chronotype and suppressed gonadal function in healthy adult humans, with no apparent gender-specific effect. Extreme sleep durations were also found to be detrimental to the maintenance of normal HPTGA secretion function. Compared to males, gonadal function in the female cohort is more susceptible to extreme sleep habits. Subsequent observational studies are urgently needed to confirm the underlying mechanisms.Keywords: hypothalamo-hypophyseal-target gland axis, sleep traits, causal inference, Mendelian randomization

Xuehui Jiang,1,2 Qun Fu,3 Yan Jing,4 Ying Kong,2 Hong Liu,2 Hongwei Peng,2 Kaisaner Rexiti,1,2 Xiaohua Wei2 1School of Pharmacy, Nanchang University, Nanchang, People’s Republic of China; 2Department of Pharmacy, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 3Jiangxi Provincial Drug Inspector Center, Jiangxi Provincial Drug Administration, Nanchang, People’s Republic of China; 4Department of Pharmacy, Linyi Central Hospital, Linyi, People’s Republic of ChinaCorrespondence: Xiaohua Wei, Department of Pharmacy, The First Affiliated Hospital of Nanchang University, No. 17 Yong Wai Zheng Street, Nanchang, 330006, People’s Republic of China, Tel +86 13803523639, Email wxh-hello@163.comPurpose: Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population.Patients and Methods: A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens.Results: A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 1012/L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 1012/L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 1012/L and 4.9 × 1012/L.Conclusion: RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.Keywords: imatinib, PPK, rs2231142, RBC, personalized dose, GIST, postoperative

Jiayao Guan,1,&ast; Chunmei Bao,2,&ast; 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&ast;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

Yanan Xu,1,&ast; Ying Jing,2,&ast; Lingfei Hu,2 Qiaoxiang Cheng,1 Huixia Gao,3 Zhi Zhang,3 Huiying Yang,2 Yuee Zhao,2 Dongsheng Zhou,2 Zhe Yin,2 Erhei Dai1,3 1Department of Clinical Laboratory Medicine, Hebei Medical University, Shijiazhuang, Hebei, 050011, People’s Republic of China; 2State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, People’s Republic of China; 3Department of Laboratory Medicine, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei, 050021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Erhei Dai; Zhe Yin, Tel +86-311-85814612 ; +86-10-66948557, Email daieh2008@126.com; jerry9yin@163.comPurpose: To establish a typing scheme for IncFIB replicon and to dissect genomic features of IncFIB-4.1/4.2 single-replicon plasmids.Methods: A total of 146 representative fully sequenced IncFIB-replicon-containing plasmids were selected to construct a phylogenetic tree of repBIncFIB sequences. A collection of nine IncFIB-4.1/4.2 single-replicon plasmids from China were fully sequenced here and compared with the first sequenced IncFIB-4.1/4.2 single-replicon plasmids from GenBank to dissect their genomic diversity.Results: In this study, a repB sequence-based scheme was proposed for grouping IncFIB replicon into seven primary types and further into 70 subtypes. A collection of nine IncFIB-4.1/4.2 single-replicon plasmids were fully sequenced here and compared with the first sequenced IncFIB-4.1/4.2 single-replicon plasmids from GenBank. These 11 plasmids had small backbones and shared only three key backbone markers repB together with its iterons, parABC, and stbD. Each plasmid contained one large accessory region (LAR) inserted into the backbone, and these 11 LARs had significantly distinct profiles of mobile genetic elements (MGEs) and resistance/metabolism gene loci. Antibiotic resistance regions (ARRs; the antibiotic resistance gene-containing genetic elements) were found in seven of these 11 LARs. Besides resistance genes, ARRs carried unit or composite transposons, integrons, and putative resistance units. IncFIB-4.1/4.2 single-replicon plasmids were important vectors of drug resistance genes. This was the first report of three novel MGEs: In1776, Tn 6755, and Tn 6857.Conclusion: Data presented here provided a deeper insight into diversity and evolution of IncFIB replicon and IncFIB-4.1/4.2 single-replicon plasmids.Keywords: IncFIB, IncFIB-4 single-replicon plasmids, large accessory regions, antibiotic resistance regions, In1776, Tn 6755, Tn 6857

Wantong Han,1– 3 Lingzhong Xu,1– 3 Aimin Niu,4 Yurong Jing,1– 3 Wenzhe Qin,1– 3 Jiao Zhang,1– 3 Xiang Jing,5 Yali Wang6 1Centre for Health Management and Policy Research, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2NHC Key Laboratory of Health Economics and Policy Research, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 3Center for Health Economics Experiment and Public Policy Research, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 4Department of Public Health, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 5Yuncheng Central Hospital, Yuncheng, Shanxi, People’s Republic of China; 6Henan Provincial Center for Disease Control and Prevention, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Lingzhong XuSchool of Public Health, Cheeloo College of Medicine, Shandong University, Mailbox No. 110, 44 Wenhuaxi Road, Jinan, 250012, Shandong, People’s Republic of ChinaTel +86-0531-8838-2648Fax +86-0531-88382533Email lzxu@sdu.edu.cnAimin NiuDepartment of Public Health, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwu Road, Huaiyin District, Jinan, 250021, People’s Republic of ChinaTel +86-1866-370-2722Fax +86-0531-87921022Email nam1106@163.comPurpose: Studies have suggested that public health emergencies can have many psychological effects on college students, therefore, the aim of this study is to investigate current situation of college students’ anxiety and its determinants in the time of an unexpected pandemic.Patients and Methods: We conducted convenience sampling to collect the data through network-based online questionnaires in February 2020, a total of 17,876 college students were included in the analysis. Chi-square test and multivariate logistic were used to identify the associations between the outbreak experiences and anxiety detection.Results: This study found that detection rate of anxiety among college students was 18.2%. The differences in male students, students whose self-perceived risk of infection were high, who were greatly affected by the outbreak, eager to go back to school, reluctant to leave home and stay at home enough were of statistical significance among different anxiety level (OR> 1, P< 0.05). And the severe anxiety rate of students who living in cities was significantly higher (2.337[1.468, 3.721]).Conclusion: Although our results show that anxiety among college students was at a low level, various universities should focus on the online activities and develop appropriate epidemic management plans to prevent their feelings of worry, tension and panic.Keywords: anxiety, college students, network-based, COVID-19

Betula alnoides is a fast-growing and native timber species prevalently planted in tropical and subtropical areas of southern China. Despite the large-scale development of B. alnoides plantations, knowledge of its association with arbuscular mycorrhizal fungi (AMF) is limited. In the present study, we chose young (3-year-old sapling, P3y) and middle-aged (12-year-old stand, P12y) B. alnoides plantations and adjacent native forest (N) in the Puwen Tropical Forest Experimental Station located in Xishuangbanna prefecture of Yunnan Province, southwestern China, as study materials and explored the change in AMF community composition in the plantation chronosequence. In addition, we combined morphological methods and Illumina MiSeq sequencing techniques to analyze rhizosphere soil AMF. The results indicated that the AMF richness and diversity indexes of B. alnoides at two ages tended to be similar to those of natural growing trees in native forest. However, the specific AM fungal compositions were distinctly different, providing evidence of the conservation value of the native forest, which harbors a unique AMF diversity. Hierarchical cluster analysis further revealed that the AMF community composition of trees in the mid-aged stand (P12y) was more similar to that of naturally growing B. alnoides (N) than that of the young-aged trees (P3y), which proved the considerable resilience of AMF to the establishment of the B. alnoides plantation. A set of at least five soil properties (available phosphorus, available nitrogen, organic matter, total nitrogen and silt content) was found to play a significant role in shaping the AMF communities. These results contribute to the understanding of the impacts of B. alnoides plantations on AMF diversity and composition. Such information is critical for the efficient planting and sustainable management of B. alnoides plantations.

Abstract Background Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non‐healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease‐free survival (DFS), and overall survival (OS). Methods In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin‐antithrombin (TAT) and D‐dimer were correlated with clinicopathological data, and 5‐year survival. Results Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ≤ .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER‐ (vs ER+), and HER2+ (vs HER2‐) (all P 3‐fold mortality risk compared to low TAT. Conclusion This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.

Shujie Wang1,*, Erhei Dai2,*, Xiaoyuan Jiang3, Lijun Zeng3, Qiaoxiang Cheng2,3, Ying Jing3, Lingfei Hu3, Zhe Yin3, Bo Gao3, Jinglin Wang3, Guixin Duan4, Xuehui Cai1, Dongsheng Zhou3 1State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, People’s Republic of China; 2Department of Laboratory Medicine, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei 050021, 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; 4Animal Science and Technology College, Heilongjiang Bayi Agricultural University, Daqing 163000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongsheng ZhouState Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, No. 20 Dongdajie Street, Fengtai District, Beijing 100071, People’s Republic of ChinaTel +86 106 694 8503Email dongshengzhou1977@gmail.comXuehui CaiState Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, No. 678 Haping Road, Xiangfang District, Harbin 150069, People’s Republic of ChinaTel +86 4 515 105 1766Email aci139@sina.comBackground: Multiple incompatibility (Inc) groups of plasmids have been identified in Enterobacteriaceae species, but there are still quite a few sequenced plasmids that could not be assigned to any known Inc groups.Methods: One IncFIIpKF727591β plasmid p205880-qnrS and two IncpKPHS1 plasmids p11219-CTXM and p205880-NR1 were fully sequenced in this work. Detailed genomic comparison was applied to all available sequenced plasmids of IncFIIpKF727591 or IncpKPHS1 group.Results: p205880-qnrS carried a novel transposon Tn6396, which was an ISKpn19-compsite transposon and represented a prototype transposable element carrying a minimum core qnrS1 module. p11219-CTXM harbored a novel transposon Tn6559, which was generated from integration of a truncated IS903D–blaCTX-M-14–ISEcp1 unit into the Tn3-family cryptic unit transposon Tn1722. Two Inc groups, IncFIIpKF727591 and IncpKPHS1, of plasmids from Enterobacteriaceae species were proposed, and IncFIIpKF727591 was further grouped into two subgroups IncFIIpKF727591α and IncFIIpKF727591β. Each of the 11 IncFIIpKF727591 plasmids carried multiple accessory modules including at least one resistance module, and the relatively small IncFIIpKF727591 backbones could acquire a wealth of foreign genetic contents. The modular structures of plasmid backbones were conserved within each of IncFIIpKF727591α and IncFIIpKF727591β subgroups but dramatically different, although with similar gene organizations, between these two subgroups. The IncpKPHS1 backbones were conserved with respect to modular structures, and only four of the 14 IncpKPHS1 plasmids carried accessory modules, two of which contained resistance genes.Conclusion: A genomic comparison of sequenced IncpKPHS1 or IncFIIpKF727591 plasmids provides insights into modular differences and genetic diversification of these plasmids, some of which carries antimicrobial resistance genes.Keywords: plasmids, IncFIIpKF727591, IncpKPHS1, Tn6396, Tn6559

Abstract Background Porcine deltacoronavirus (PDCoV) is a novel coronavirus that can cause diarrhea in nursing piglets. This study was aimed to investigate the roles of host differentially expressed genes on metabolic pathways in PDCoV infections. Results Twenty thousand six hundred seventy-four differentially expressed mRNAs were identified in 5-day-old piglets responded to PDCoV experimental infections. Many of these genes were correlated to the basic metabolism, such as the peroxisome proliferator-activated receptor (PPAR) signaling pathway which plays a critical role in digestion. At the same time, in the PPAR pathway genes of fatty acid-binding protein (FABP) family members were observed with remarkably differential expressions. The differential expressed genes were associated with appetite decrease and weight loss of PDCoV- affected piglets. Discussion Fatty acid-binding protein 1 (FABP1) and fatty acid-binding protein 3 (FABP3) were found to be regulated by PDCoV. These two genes not only mediate fatty acid transportation to different cell organelles such as mitochondria, peroxisome, endoplasmic reticulum and nucleus, but also modulate fatty acid metabolism and storage as a signaling molecule outside the cell. Therefore, it can be preliminarily concluded that PPAR differential expression caused by PDCoV was mostly associated with weight loss and death from emaciation. Conclusions The host differentially expressed genes were associated with infection response, metabolism signaling and organismal systems signaling pathways. The genes of FABP family members in the PPAR signaling pathway were the most highly altered and played important roles in metabolism. Alteration of these genes were most likely the reason of weight loss and other clinical symptoms. Our results provided new insights into the metabolic mechanisms and pathogenesis of PDCoV infection. Methods Animal experiment, Determination of viral growth by real-time RT-PCR, Histopathology, Immunohistochemical staining, Microarray analysis.

Collagen hydrogels have been extensively applied in biomedical applications. However, their mechanical properties are insufficient for such applications. Our previous study showed improved mechanical properties when collagen was blended with alginate. The current study aims to analyze the physico-chemical properties of collagen-alginate (CA) films such as swelling, porosity, denaturation temperature (Td), and rheology properties. Collagen was prepared from discarded fish skin of Ikan Belida (Notopterus lopis) that was derived from fish ball manufacturing industries and cross-linked with alginate from brown seaweed (Sargasum polycystum) of a local species as a means to benefit the downstream production of marine industries. CA hydrogels were fabricated with ratios (v/v) of 1:1, 1:4, 3:7, 4:1, and 7:3 respectively. FTIR spectrums of CA film showed an Amide I shift of 1636.12 cm−1 to 1634.64 cm−1, indicating collagen-alginate interactions. SEM images of CA films show a porous structure that varied from pure collagen. DSC analysis shows Td was improved from 61.26 °C (collagen) to 83.11 °C (CA 3:7). CA 4:1 swelled nearly 800% after 48 h, correlated with the of hydrogels porosity. Most CA demonstrated visco-elastic solid characteristics with greater storage modulus (G′) than lost modulus (G″). Shear thinning and non-Newtonian behavior was observed in CA with 0.4% to 1.0% (w/v) CaCl2. CA hydrogels that were derived from discarded materials shows promising potential to serve as a wound dressing or ink for bio printing in the future.

Objectives: To investigate whether there is an elevated neoplasm risk in patients with rheumatic diseases treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).Methods: A population-based nested case–control study was performed by retrieving all patients newly diagnosed with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriatic arthritis (PsA) or psoriasis vulgaris (PsO) from the 2000 Longitudinal Health Insurance Database (LHID 2000) in Taiwan. Two hundred and sixty-one patients with neoplasm from 1997 to 2013 were enrolled in this study, and controls were matched in a 1:1 ratio with age, sex, and year of enrollment. Composition of demographic indices, comorbidities, medication usage, and differences in days of prescription of different medications between neoplasm and neoplasm-free (control) groups were compared.Results: Between the control and neoplasm groups, no differences in ratio were observed in the usage of hydroxychloroquine (50.96 vs. 49.04%, p = 0.6616), methotrexate (26.82 vs. 27.59%, p = 0.8441), azathioprine (3.45 vs. 3.07%, p = 0.8052), and cyclophosphamide (1.15 vs. 2.30%, p = 0.3131) from enrollment to index date. Medications within 3 years before the index date in patients that had ≥3 months of comparable duration also showed no difference (hydroxychloroquine: 33.06 vs. 30.25%, p = 0.6404; methotrexate: 20.66 vs. 25.21%, p = 0.4018; azathioprine: 2.48 vs. 2.52%, p = 0.9835; cyclophosphamide: 0.83 vs. 0.84%, p = 0.9906). We also made a subgroup analysis focusing on RA and SLE patients; no difference between control and neoplasm group in both the ratio of usage and days of prescription of hydroxychloroquine, methotrexate, azathioprine, and cyclophosphamide was observed.Conclusion: Neoplasm risk in patients with rheumatic diseases has no correlation with csDMARD usage.

David R Walker, Timothy R Juday, Shivaji R Manthena, Yonghua Jing, Vipan Sood Health Economics and Outcomes Research, AbbVie Inc., North Chicago, IL, USA Background: Combination therapy with sofosbuvir (SOF) and simeprevir (SIM) is used to treat patients with hepatitis C virus infection. It is currently unknown whether adding ribavirin (RBV) to SOF + SIM, which raises the pill count from two up to eight pills a day, impacts adherence. The aim of this study is to examine the impact of pill count on real-world adherence rates in patients treated with SOF + SIM with and without RBV. Methods: This retrospective study assessed composite adherence to SOF and SIM over 12 weeks of treatment for two cohorts of hepatitis C patients: one initiating SOF + SIM therapy, and the other initiating SOF + SIM + RBV therapy. Analyses were conducted using MarketScan® and Optum US commercial pharmacy claims and enrollment data. Adherence was adjusted by treatment regimen, age, sex, co-pay, presence/absence of cirrhosis, treatment history, and Charlson Comorbidity Index. Results: There was a significant difference in composite unadjusted and adjusted adherence rates for SOF and SIM for the SOF + SIM vs SOF + SIM + RBV cohorts based on MarketScan data (unadjusted, 92.6% and 89.7%, respectively; P=0.0423; adjusted, 92.2% and 88.7%, respectively; P=0.0176), but not based on Optum data (unadjusted, 94.8% and 95.6%, respectively; P=0.5618; adjusted, 94.8% and 95.1%, respectively; P=0.8589). In the MarketScan and Optum databases, there were no statistical differences in unadjusted and adjusted adherence rates for SOF. Unadjusted and adjusted adherence rates for SIM were mixed, as they were for composite adherence. Conclusion: The impact of the addition of RBV to SOF + SIM therapy was mixed. The impact of RBV on SOF adherence was not significant in either database. Keywords: adherence, hepatitis C, direct acting antiviral, sofosbuvir, simeprevir, ribavirin

Leaf day respiration is one of the most fundamental plant physiological processes and plays a vital role in the plant carbon cycle. However, day respiration is inherently complex and difficult to measure. In this study, the Kok method and the Laisk method were used to measure leaf day respiration for the saplings of one evergreen conifer species (Pinus koraiensis) and two deciduous broadleaved species (Tilia amurensis and Fraxinus mandshurica) in a temperate forest. Results show that discrepancy between the corrected day respiration values estimated by the Kok and Laisk methods was only 4% for the three tree species. On average, day respiration was 55.9% and 52.6% lower compared to night respiration for the three tree species, as measured by the Kok and Laisk method, respectively. Day respiration of the evergreen conifer species estimated by the Kok method was 31.7% lower while that estimated by the Laisk method was 36.8% lower than that of the deciduous broadleaved species. Night respiration of the evergreen conifer trees was 40.7% lower than those of the deciduous broadleaved trees. Day respiration rate is positively correlated with night respiration rate. Notably, day respiration rate decreased with increased photosynthetic photon flux density, and even a small amount of light significantly inhibited leaf day respiration in all three species.

Levodopa is considered to be the most effective symptomatic drug for Parkinson's disease (PD). As the disease progresses, however, the patients are likely to experience a reduced response to levodopa and develop motor fluctuations (i.e., end-of-dose wearing off and unpredictable “on-off”). Protein-rich diets and elevated plasma concentrations of large neutral amino acids have been proved to impair the therapeutic effect of levodopa by reducing its absorption and influx into the brain. On the other hand, the protein-restricted diets including low-protein diet (LPD), protein-redistribution diet (PRD) and PRD with use of low-protein products can all improve the efficacy of levodopa in patients with motor fluctuations. However, it should be noted that protein-restricted diets may also contribute to several side effects, including dyskinesia, weight loss, and malnutrition (e.g., protein and calcium insufficiency). Together, protein-restricted diets are an effective approach to improve motor fluctuations in PD patients, while long-term adherence to these diets requires monitoring for side effects.

A fast-growing alder species native to the eastern Himalayas, Nepalese alder (Alnus nepalensis), has recently received considerable attention in the restoration of contaminated lands due to its significant economic benefits and ecological functions. The bioaccumulation characteristics and phytoremediation potential of naturally regenerated Nepalese alder were evaluated in a lead-zinc spoil heap located in Lancang county, Yunnan province, south-western China. Results showed that bioaccumulation factors (BFs) of A. nepalensis for Zn and Pb were always >1 in slightly contaminated soils (extractable Zn, Pb of 4.2-17.9 and 3.4-13.1 mg kg-1, respectively) and >1 for Cd in contaminated soils (extractable Cd 0.3- 6.8 mg kg-1). By contrast, translocation factors (TFs) for Zn were 1 for Pb in soil slightly contaminated by 13.1 mg kg-1 extractable Pb and >1 for Cd in contaminated soils (extractable Cd 2.6- 6.8 mg kg-1). Significant positive correlations were found between heavy metals (HMs) in roots and extractable HMs in soils (p

A Master Sintering Curve (MSC) for rutile TiO2 was constructed for Pressure-less sintering using constant heating rate dilatometry data based on the combined-stage sintering model. Construction of the master sintering curve is described and the validation is proved with rutile TiO2 under different thermal histories. The concept of master sintering can be used to predict the sintering shrinkage and final density and calculate the activation energy, and a value of 105 KJ/mol for TiO2 was obtained. With one temperature dependent parameter determined experimentally, it became possible to describe accurately the densification behavior of TiO2 from the initial to final stages of sintering. .

Workstations and electronic display devices in a picture archiving and communication system (PACS) provide a convenient and efficient platform for medical diagnosis. The performance of display devices has to be verified to ensure that image quality is not degraded. In this study, we designed a set of randomized object test patterns (ROTPs) consisting of randomly located spheres with various image characteristics to evaluate the performance of a 2.5 mega-pixel (MP) commercial color LCD and a 3 MP diagnostic monochrome LCD in several aspects, including the contrast, resolution, point spread effect, and noise. The ROTPs were then merged into 120 abdominal CT images. Five radiologists were invited to review the CT images, and receiver operating characteristic (ROC) analysis was carried out using a five-point rating scale. In the high background patterns of ROTPs, the sensitivity performance was comparable between both monitors in terms of contrast and resolution, whereas, in the low background patterns, the performance of the commercial color LCD was significantly poorer than that of the diagnostic monochrome LCD in all aspects. The average area under the ROC curve (AUC) for reviewing abdominal CT images was 0.717±0.0200 and 0.740±0.0195 for the color monitor and the diagnostic monitor, respectively. The observation time (OT) was 145±27.6 min and 127±19.3 min, respectively. No significant differences appeared in AUC (p = 0.265) and OT (p = 0.07). The overall results indicate that ROTPs can be implemented as a quality control tool to evaluate the intrinsic characteristics of display devices. Although there is still a gap in technology between different types of LCDs, commercial color LCDs could replace diagnostic monochrome LCDs as a platform for reviewing abdominal CT images after monitor calibration.