bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Subtypes Based on DNA Methylation Predict Prognosis in Lung Squamous Cell Carcinoma
Authors: Li XiuShen , Nie Ke-Chao , Zheng Zhi-Hua , Zhou Rui-Sheng , Huang Yu-Sheng , Ye Zeng-Jie , He Fan , Tang Ying 
Published: October 2020

Abstract
Background: Due to tumor heterogeneity, the diagnosis, treatment, and prognosis of patients with lung squamous cell carcinoma (LUSC) are difficult. DNA methylation can affect tumor heterogeneity by participating in gene expression. Methods: In this study, we collected the clinical information of LUSC patients in the Cancer Genome Atlas (TCGA) database and the relevant methylated sequences of the University of California Santa Cruz (UCSC) database to construct methylated subtypes and performed prognostic analysis. Results: 965 potential independent prognosis methylation sites were finally identified and the genes were identified. Based on consensus clustering analysis, seven subtypes were identified by using 965 CpG sites and corresponding survival curves were plotted. The prognostic analysis model was constructed according to the methylation sites’ information of the subtype with the best prognosis. Internal and external verifications were used to evaluate the prediction model. Conclutions: Models based on differences in DNA methylation levels may help to classify the molecular subtypes of LUSC patients, and provide more individualized treatment recommendations and prognostic assessments for different clinical subtypes. GNAS, FZD2, FZD10 are the core three genes that may be related to the prognosis of LUSC patients.
Post Traumatic Stress Disorder and Death Anxiety Symptoms During the Coronavirus Epidemic in 2019: A Cross-Sectional Study Based on the Affected Population
Authors: Zhang Qian , Zheng Rujun , Fu Yan , Mu Qianqian , Li Junying 
Published: October 2020

Abstract
Background Mental health is an important aspect of the management public health emergencies.While extensive research is being conducted on various aspects of the COVID-19 epidemic, one of the factors overlooked is death anxiety. Methods A cross-sectional study based on the results of an online survey. The survey was conducted one month after the outbreak (February 18–29, 2020) and repeated at the time of resuming activity (April 8–14, 2020). The 15-item Death Anxiety Scale (T-DAS) was used to assess the degree of death anxiety, and the revised 23-item Stanford Acute Stress Response Questionnaire (SASRQ) assessed PTSD symptom clusters. Through convenient sampling, a total of 7678 cases were collected. Results: Between the first and second surveys, the number of individuals with high death anxiety rose from 48.1–53.2%, while the incidence of PTSD increased from 7–10.4%. PTSD was found to be significantly associated with living community contact history, poor health status of participants, history of life-threatening experiences, high death anxiety level, and non-medical occupation. Compared with other occupations, medical staff suffer more lasting death anxiety during the COVID-19 epidemic. Conclusions: During the COVID-19 epidemic, adverse psychological symptoms were prevalent among the general population in China.High death anxiety also was an important factor affecting PTSD.Therefore, means to address death anxiety must be included in the plan for the management of psychological effects of public health emergency and high-risk groups such as medical personnel should receive targeted intervention.
Gold Nanoparticles Induce Cell Stress by Interfering with the Cellular Protein Quality Control System
Authors: Zhang Guofang , Song Qingle , Zhang Yuqian , Liang Ruijing , Chen Liang , Monteiro-Riviere Nancy , Boraschi Diana , Chang Yan-Zhong , Li Hongchang , Li Yang 
Published: October 2020

Abstract
The cellular protein quality control (PQC) system ensures the intracellular misfolded/unfolded proteins to be detected and eliminated. ER-associated degradation (ERAD) and unfolded protein response (UPR) are the key mechanisms of PQC, which maintain protein homeostasis and ensure cell survival. Here, we show that after internalization by human epithelial cells, gold (Au) nanoparticles (NPs) localized in endoplasmic reticulum (ER) and induced an accumulation of misfolded/unfolded proteins. Au NPs activated UPR, but suppressed ERAD shown by a reduced degradation rate of the ERAD marker CD3-δ-YFP, which triggered ER stress through IRE1-XBP1-Chaperones and PERK-eIF2α-ATF4-CHOP pathways. The Au NP-dependent ER stress consequently induced the intracellular accumulation of ROS, and caused cell apoptosis/death, concomitant to production/release of inflammatory cytokines and chemokines. This study for the first time shows that NPs can interfere with the cellular PQC system by impairing ERAD activity, which in turn initiates a cascade of events leading to cell death and inflammation.
Anion-Exchange-Mediated Internal Electric Field: Boosting Photogenerated Carrier Separation and Utilization
Authors: Li Yadong , Han Tong , Cao Xing , Sun Kaian , Peng Qing , Cheong Weng-Chon , Chen Zheng , Lin Rui , Zhao Di , Zhuang Zewen , Chen Chen , Wang Dingsheng 
Published: October 2020

Abstract
Constructing heterojunctions is a commonly used method for heterogeneous photocatalysts to modulate the internal electric field (IEF); however, this method suffers from narrow IEF distribution (primarily limited at the heterojunction interface) and long migration paths of photocarriers, and therefore results in suboptimal efficiencies in carrier separation and utilization. In this work, we report for the first time novel basic bismuth nitrate compound nanorods (denoted as BOH NRs) featuring surface-exposed open channels and a simple chemical composition; by simply modifying the bulk anion layers to overcome the limitations of heterojunctions, the bulk IEF could be readily modulated. A low exchange ratio (~10%) with halide anions (I–, Br–, Cl–) would give rise to a prominent elevation in carrier separation efficiency; for the reaction of photocatalytic oxidative coupling of benzylamine, the conversions over the modified catalysts are 1.6–2 times as high as that over pristine BOH. Benefiting from the unique crystal structure and the localization of valence electrons, the IEF intensity increases with the atomic number of introduced halide anions, leading to an enhanced efficiency of carrier separation and utilization. Our work here offers new insights into the design and optimization of semiconductor photocatalysts.
Anthelminthic Efficacy of Fenbendazole and Levamisole in Native Fowl in Northern Iran
Authors: Soudkolaei Saemi , Kalidari Gholam Ali , Borji Hassan 
Published: October 2020

Abstract
Background: With the number of free-range domestic chickens increasing, helminth parasites have potentially become more of a threat in commercial flocks in recent years, and routine poultry worming is needed to improve chicken products. The present study deals with a field trial to study the efficiency of two generally used anthelmintics as fenbendazole and levamisole, against gastrointestinal nematodes of domestic chickens in the north of Iran. Methods: Out of 45 domestic chickens flocks that agreed to the study, 20 flocks were selected to participate in fecal egg count reduction testing based on flock size from April 2017 to September 2018. The infected chickens were randomly distributed into three equal groups of each (n = 30). Ninety chickens in the infected groups received one of the following treatments (d 0 of treatment): Group 1: 5 mg kg−1 body weight (BW) of fenbendazole for three continuous days, Group 2: 16 mg kg−1 BW of Levamisole, and Group 3: placebo; water + DMSO (the control). The efficiency of the treatments was evaluated by comparing fecal egg count in the treated groups and control group.Results: Examination of 3 herds of chickens from the control group showed that the animals were infected with gastrointestinal nematodes by 95.0% with an average geometric value of 361 eggs per gram of feces. The substance fenbendazole at a dose of 5 mg/kg b/w for three days against gastrointestinal nematodes showed an efficiency of 83.7% (P ≥0.05), and the substance levamisole at a dose of 16 mg/kg b/w showed 71.8% (P ≥0.05) with geometric mean eggs in a gram of feces 100 and 199.6, respectively. In general, the initial substances of fenbendazole and leamisole showed significantly lower activity.. The result of this study revealed that fenbendazole was a better effective dewormer than levamisole on the three Iranian domestic chicken flocks, but it is not significant. Capillaria spp., were the most generally resistant nematodes followed by Trichostrongylus spp., and Amidostomum anseris.Conclusion: Our results indicated there is a reduction efficacy in fenbendazole and levamisole in three Iranian domestic chicken flocks. Given the results of our study, it appears possible that resistance may be expected in the helminth parasite of poultry. Additional studies with a larger scale are required to determine the prevalence of anthelminthic resistance in the poultry industry.
Identification of Co-Expressed Genes Promoting CD8+ T Cell Infiltration in Melanoma Tumor Microenvironments
Authors: Yan Kexin , Wang Yutao , Xiao Ting 
Published: October 2020

Abstract
Purpose: To identify CD8+ T cell-related factors and the co-expression network in melanoma, to illustrate the interactions among CD8+ T cell-related genes in the melanoma tumor microenvironment.Method: We obtained melanoma and para-carcinoma tissue mRNA matrices from TCGA-SKCM and GSE65904. The CIBERSORT algorithm was used to assess CD8+ T cell proportions and the “estimate” package was used to assess melanoma tumor microenvironment purity. Weighted gene co-expression network analysis was used to identify the most related co-expression modules in TCGA-SKCM and GSE65904. Subsequently, a co-expression network was built based on the common results in the two cohorts. Results: Nine co-expressed genes (CCL5, GAP5, GZMA, GZMH, IRF1, LAG3, PRF1, NKG7, PSMB10) were identified as CD8+ T cell-related genes that promoted infiltration of CD8+ T cells, which were enriched in the cellular response to interferon−gamma process and antigen processing and presentation of peptide antigen. In the low expression level group, inflammation and immune responses were weaker, and the tumor purity was higher, suggesting that these genes were immune protective factors that improved the prognosis of melanoma. Besides this, co-expression factors negatively correlated with angiogenesis factors and positively correlated with angiogenesis inhibitors. Conclusion: These nine co-expressed genes promote high levels of infiltration of CD8+ T cells by the cellular response to the interferon−gamma process. The mechanism might provide new pathways for treatment of patients who are insensitive to PD-1 immunotherapy due to low degrees of CD8+ T cell infiltration.
Genomic Characterization of A Multidrug-Resistant Citrobacter Freundii Strain ZT01-0079 Co-Producing blaNDM-1&nbsp;and&nbsp;blaSHV-12&nbsp;Using MiSeq and MinION
Authors: Zhang Tingyan , Lin Yanfeng , Li Zhonghong , Liu Xiong , Li Jinhui , Li Lizhong , Wang Kaiying , Liu Zhongdong , Lu Lanfen , Li Peng , Wang Hongyan 
Published: October 2020

Abstract
Background: The emergence of multi-drug resistant Citrobacter freundii poses daunting challenges to the treatment of clinical infections. The purpose of this study was to characterize the genome of a C. freundii strain with an IncX3 plasmid encoding both the blaNDM-1 and blaSHV-12 genes.Methods: Strain ZT01-0079 was isolated from a clinical urine sample. The Vitek2 system was used for identification and antimicrobial susceptibility testing. The presence of blaNDM-1 was detected by PCR and sequencing. Conjugation experiments and Southern blotting were performed to determine the transferability of the blaNDM-1- carrying plasmid. Nanopore and Illumina sequencing were performed to better understand the genomic characteristics of the strain.Results: Strain ZT01-0079 was identified as C. freundii, and the coexistence of blaNDM-1 and multiple drug resistance genes was confirmed. Electrophoresis and Southern blotting showed that blaNDM-1 was located on a ~53kb IncX3 plasmid. The NDM-1-encoding plasmid was successfully transferred at a frequency of 1.68×10−3. Both blaNDM-1 and blaSHV-12 were located on the self-transferable IncX3 plasmid.Conclusion: The rapid spread of the IncX3 plasmid highlights the importance of continuous monitoring of the prevalence of NDM-1-encoding Enterobacteriaceae. Mutations of existing carbapenem resistance genes will bring formidable challenges to clinical treatment.
How Can We Improve Patients’ Access to New Drugs Under Uncertainties? : South Korea’s Experience with Risk Sharing Arrangements
Authors: Lee Boram , Bae Eun-Young , Bae SeungJin , Choi HyunJin , Son Kyung-Bok , Lee Young-Sil , Jang Suhyun , Lee Tae-Jin 
Published: October 2020

Abstract
Background: New drugs including cancer drugs and orphan drugs are becoming increasingly more expensive. Risk sharing arrangements (RSAs) could manage the risk based on both financial impact and the health outcome of new drugs if reimbursed. To improve patients’ access to new drugs under uncertainties, many developed countries have adopted RSAs. In this study, we aimed to understand the effects of RSAs in South Korea on patients’ access.Methods: We reviewed current status of RSA drugs in South Korea. The number of appraisals and time gap between market approval and reimbursement per RSA drug were considered to quantify improvement of patients’ access as they showed how rapidly decisions on reimbursement of RSA drugs were derived. Then, we applied a comparative analysis to determine whether the RSA drugs in South Korea were reimbursed in the UK, Italy, and Australia. Most data for this study were obtained from websites of the governmental department/agencies responsible for appraisal of drug reimbursement in each country. And literatures related to RSAs were investigated as well.Results: The eligibility for Korean RSAs had two key components - drugs for cancer and rare diseases and not having other alternative treatments. As of the first half of 2019, there were 39 RSA drugs reimbursed in South Korea, the majority of which were financial-based schemes. Refund and expenditure cap were the representative types (89.7%). After introduction of RSAs, the time gap and number of appraisals were decreased. Based on the indications of RSA drugs, the level of drug coverage in South Korea was found lower than Italy, similar to the UK, and higher than Australia.Conclusions: RSAs in South Korea significantly enhanced patients’ access to new drugs and led to the alleviation of patients’ out-of-pocket expenses. The drug coverage of South Korea had a level comparable to that of other countries. This study provides implications for countries that have a dual mission of containing pharmaceutical expenditure and improving access to new drugs.
Synaptosomes: New Vesicles for Neuronal Mitochondrial Transplantation
Authors: Picone Pasquale , Porcelli Gaetana , Bavisotto Celeste Caruso , Nuzzo Domenico , Galizzi Giacoma , Biagio Pier Luigi San , Bulone Donatella , Carlo Marta Di 
Published: October 2020

Abstract
Background: Mitochondrial dysfunction is a critical factor in the onset and progression of neurodegenerative diseases. Recently, mitochondrial transplantation has been advised as an innovative and attractive strategy to transfer and replace damaged mitochondria. Here we propose, for the first time, to use rat brain extracted synaptosomes, subcellular fraction of isolated synaptic terminal that contain mitochondria, as mitochondrial delivery systems. Results: Synaptosomes preparation was validated by the presence of Synaptophysin and PSD95. Syn aptosomes were characterized in terms of dimension, zeta potential, polydispersity index and number of particles/mL. Nile Red or CTX-FITCH labeled synaptosomes were internalized in LAN5 recipient cells by a mechanism involving specific protein-protein interaction, as demonstrated by loss of fusion ability after trypsin treatment and using different cell lines. The loading and release ability of the synaptosomes was proved by the presence of curcumin both into synaptosomes and LAN5 cells. The vitality of mitochondria transferred by Synaptosomes was demonstrated by the presence of Opa1, Fis1 and TOM40 mitochondrial proteins and JC-1 measurements. Further, synaptosomes deliver vital mitochondria into the cytoplasm of neuronal cells as demonstrated by microscopic images, increase of TOM 40, cytochrome c, Hexokinase II mitochondrial proteins, and presence of rat mitochondrial DNA. Finally, by using synaptosomes as vehicle, healthy mitochondria restored mitochondrial function in cells containing rotenone or CCCp damaged mitochondria. Conclusions: Taken together these results suggest that synaptosomes can be a natural vehicle for the delivery of molecules and organelles to neuronal cells. Further, replacement of affected mitochondria with healthy ones could be a potential therapy for the treatment of neuronal mitochondrial dysfunction-related diseases.
Novel hyaluronic acid-coated polymeric micelles with ROS scavenging to encapsulate statins for alleviating atherosclerosis
Authors: Mu Dan , Li Jianhui , Qi Yu , Sun Xuan , Liu Yihai , Shen Song , Li Yuyu , Xu Biao , Zhang Bing 
Published: October 2020

Abstract
Inflammation and oxidative stress are two major factors that are involved in the pathogenesis of atherosclerosis. A smart drug delivery system that responds to the oxidative microenvironment of atherosclerotic plaques was constructed in the present study. Simvastatin (SIM)-loaded biodegradable polymeric micelles were constructed from hyaluronic acid (HA)-coated poly(ethylene glycol)-poly(tyrosine-ethyl oxalyl) (PEG-Ptyr-EO) for the purpose of simultaneously inhibiting macrophages and decreasing the level of reactive oxygen species (ROS) to treat atherosclerosis. HA coating endows the micelle system the ability of targeting CD44-positive inflammatory macrophages. Owing to the ROS-responsive nature of PEG-Ptyr-EO, the micelles can not only be degraded by enzymes, but also consumes ROS by itself at the pathologic sites, upon which the accumulation of pro-inflammatory macrophages is effectively suppressed and oxidative stress is alleviated. Consequently, the SIM-loaded micelles demonstrated remarkable therapeutic effects. In conclusion, the SIM-loaded micelle system can synchronically alleviate the accumulation of macrophages and oxidative stress, providing a promising and innovative option against atherosclerosis.
Attitudes of Junior Faculty Members Towards The Role of Faculty Development Program on Their Scholar Activities: The Experience in A Developing Country
Authors: Dabbagh Ali , Ahmadizadeh Seyyedeh Narjes , Behnaz Faranak , Fani Kamal , Ghasemi Mahshid , Goharani Reza , Jahangirifard Alireza , Malekianzadeh Bita , Massoudi Nilofar , Memary Elham , Moshari Mohammad Reza , Sabouri A. Sassan , Salaarian Sara , Sezari Parissa 
Published: October 2020

Abstract
The authors have requested that this preprint be removed from Research Square.
A Global Genome-wide Scan with Optimal Cutoff Mining for Emerging Biomarkers in Head and Neck Squamous Cell Carcinoma
Authors: Chi Li-Hsing , Wu Alexander TH , Hsiao Michael , Li Yu-Chuan (Jack) 
Published: October 2020

Abstract
BackgroundThe survival analysis of the Cancer Genome Atlas (TCGA) dataset is a well-known method to discover the gene expression-based prognostic biomarkers of head and neck squamous cell carcinoma (HNSCC). In order to utilize a continuous gene expression for survival analysis, it is necessary to determine a cutoff point by the dichotomization of the patients. There is some optimization software for cutoff determination. However, those predetermined cutoffs by software usually set at the median, 1/4 quantile, or 3/4 quantile of RNA sequencing (RNA-Seq) value to find a significant P-value of the Kaplan-Meier curve. There are few clinicopathological features available on their pre-processed data sets.MethodsWe developed a comprehensive workflow by R script, running on the Rstudio platform. It includes data retrieving and pre-processing, feature selection, cutoff mining engine, Kaplan-Meier survival analysis, Cox proportional hazard modeling, and biomarker discovery.ResultsUsing this workflow on the TCGA HNSCC cohort, we scanned human protein-coding genes (20,500) programmatically. After adjustment with other confounders, we found that the clinical tumor stage and the surgical margin involvement are independent risk factors in patient survival. According to the resulting tables with Bonferroni adjusted P-value under optimal cutoff as well as hazard ratio (>=1.5), there were ten candidate biomarkers, named as DKK1, CAMK2N1, STC2, PGK1, SURF4, USP10, NDFIP1, FOXA2, STIP1, and DKC1, which are significantly associated with the poor prognosis of overall survival (OS). At the same time, the other ten genes were over-expressed in the better survival patients (with hazard ratio <=0.5), named as ZNF557, ZNF266, IL19, MYO1H, FCGBP, LOC148709, EVPLL, PNMA5, IQCN (previous name as KIAA1683), and NPB. Further validations are warranted. ConclusionsWe suggested this analysis tool equipped with an optimal cutoff finder will help with biomarker discovery of protein-coding genes, in terms of tumor-agnostic therapy.
Can Two supercutaneous locking plates be final treatment for complex&nbsp;tibia&nbsp;fracture? ----Clinical result of 39 cases and a finite element study
Authors: Ma Zhongyuan , Pei Zhiyong , Qu Yanzhen , Wu Hongbin 
Published: October 2020

Abstract
BackgroundSupercutaneous locking plate (SLP) has been tried to treat tibia fracture with certain success, but some inevitable problems: such as insufficient stability, screw tract inflammation and the impingement on knee and ankle joint movement have got in the way of its application. Few literature have focused on the possible solution for the above-mentioned problems, and few reports have tried the method of two SLPs.Methods43 patients received two SLPs as final treatment and 39 finished follow-up. 25 patients were open fracture and 18 of them needed skin graft, 11 patients had severe skin contusion, 3 patients had nearby soft tissue infection. Moore and Dahl pin site classification was used to record screw tract inflammation. Lysholm knee score and Kofoed ankle score were used to assess the knee and ankle function. An FE tibial fracture model was reconstructed to analyze the stiffness of different fixation.Results38 of 39 patients had bony union, the other one had clinical union. No bone infection or plate breakage was found while two screws were found broken at the rod-cap junction. FE analysis showed the structure axial stiffness (N/mm2) decreased with the plate-bone distance increased for one SLP, but two SLPs could greatly increase axial stiffness with the stiffness of SLP-2/4(364) was stronger than that of SLP-0(360.6). Function of knee and ankle was well accepted by most patients even with two plates on tibia, the lysholm knee score and kofoed ankle score was 78.9士5.0 and 72.3士7.0 respectively for two plates. When the number of plate decreased, lysholm knee score and kofoed ankle score further increased significantly. All patients had screw site inflammation: grade 2 in 25 cases; grade 3 in 14 cases. ConclusionsTwo SLPs can provide enough strength for bone union. Screw tract inflammation is inevitable, but infection could be foreseen and controlled. The impingement of SLP on knee and ankle joint movement is limited. Two SLPs maybe a good supplement treatment for complex tibia fracture.