bluuebunny/crossref_metadata_2025 huggingface dataset:
Circular RNA EPB41 Expression Predicts Unfavorable Prognoses in NSCLC by Regulating miR-486-3p/eIF5A Axis-Mediated Stemness
Authors: Liu Xiyu , Wu Yue , Lou Yuqing , Jin Mingming , Li Xue , Huang Gang
Published: September 2021

Dysregulation of circular RNAs (circRNAs) has recently been found to play an important role in the progression and development of cancers such as non-small cell lung cancer (NSCLC). Yet the functions of many circRNAs in NSCLC remain unclear. In this study, the circRNA expression profiles in NSCLC tumor tissues and adjacent non-tumorous tissues were detected by high-throughput sequencing. Bioinformatics analyses, the dual-luciferase reporter system, fluorescence in situ hybridization (FISH) and miRNA/mRNA high-throughput sequencing were used to identify circ-EPB41 and its downstream target. The subcutaneous tumor/caudal vein transfer mouse model was used for tumor growth and invasion analysis. The results show that the circ-EPB41 was upregulated in NSCLC tissues and cell lines. Increased circ-EPB41 expression in NSCLC was significantly correlated with malignant characteristics, and positive to post-surgical overall survival of NSCLC patients. Reduced circ-EPB41 expression in NSCLC decreased cell proliferation and invasion in both in vitro and in vivo experiments. The miRNA/mRNA high-throughput sequencing suggested that downregulation of circ-EPB41 promoted microRNA (miR)-486-3p and suppressed eukaryotic translation initiation factor 5A (eIF5A) expression. Luciferase reporter experiments confirmed that miR-486-3p/eIF5A were downstream targets of circ-EPB41. In addition, we also found that downregulation of circ-EPB41 suppressed self-renewal and decreased expression of stemness markers SOX2, OCT-4, Nanog and CD133 by sponging miR-486-3p to enhance eIF5A expression. Taken togeter, these data revealed the important role of circ-EPB41 in regulating NSCLC cell invasion and proliferation by modifying miR-486-3p/eIF5A axis-mediated stemness. We believe our study provides a novel perspective regarding the role of circRNAs in NSCLC progression.
Metagenomic survey of agricultural water using long read sequencing: considerations for a successful analysis
Authors: Maguire Meghan , Kase Julie A. , Brown Eric W. , Allard Marc , Musser Steve , González-Escalona Narjol
Published: September 2021

Background

Leafy greens are responsible for nearly half of the produce-related Shiga toxin-producing Escherichia coli (STEC) outbreaks in the United States and recent investigations have implicated agricultural water as a potential source. Current FDA detection protocols require extensive analysis time. Development of methods for rapid detection of STECs in the field are imperative to maintain food safety. We aimed to use Oxford Nanopore rapid sequencing kits for an in-field determination of agricultural water microbiome and possible detection and characterization of STECs strain(s) in these samples.
Results

We tested the performance of the nanopore rapid sequencing kit (RAD004) for fast microbiome determination using the well characterized ZymoBIOMICS mock microbial community and the number of reads for each identified species was present in the expected proportion. Rapid sequencing kit (LRK001 and RAD004) library preparation of DNA extracted from agricultural water resulted in poor nanopore sequencing reactions, with low output (0.3–1.7 M reads), a high proportion of failed reads (50–60%), and highly sheared DNA before and after a magnetic bead clean up. To improve performance, we prepared a DNA library with the ligation kit (LSK109), which includes multiple cleaning steps, reducing inherent inhibitors and producing a better outcome (2.2 M reads, 15% failed reads). Metagenomic composition of four sample sites determined using the ligation kit, showed a highly diverse bacterial community for each site, with 11 total genera identified, including Synechococcus and Cyanobium. No definitive presence of STEC could be confirmed in any of the sites. Approximately 100 reads from each site (0.02% of total reads) were identified as Escherichia coli, but the specific strain or their virulence genes could not be detected. Sites 9, 10, and 12 were found to be positive for STEC presence by microbiological techniques after enrichment.
Conclusions

The rapid sequencing kits can be appropriate for genus or species level microbial identification, but we recommend the use of the ligation kit for increased sequencing depth and removal of contaminants in agricultural water. However, we were not able to identify any STEC strains in these nanopore microbiome samples, due to low initial concentrations. The results from this pilot study provide preliminary evidence that MinION sequencing of agricultural water using the ligation kit has the potential to be used for rapid microbiome determination in the field with optimal results for water quality surveillance.
Publication Landscape on Cushing's Disease: From the Past 40 Years to Future Directions
Authors: Luo Ming-Jie , Du Kelei , Guo Xiaopeng , Wang Zihao , Xing Bing
Published: September 2021

PurposeThough literature related to Cushing's disease (CD) has grown significantly, previous reviews exclusively focused on specific research areas and were biased towards highly cited articles. This study aims to systemically analyze the research landscapes and trends using unbiased methods. MethodsWe queried all the CD-related publications in PubMed and clinical trials registered on clinicaltrials.gov. Latent Dirichlet allocation (LDA), a machine learning method, was used to derive research hotspots from article texts. The research topic clusters and country-level collaboration were revealed by network analysis.Results5015 articles were published since 1981, currently growing at 155 per year, with more retrospective studies but fewer prospective studies. Interestingly, the most popular LDA research topics were complications and comorbidities, endocrine hormone tests and surgical therapy, and they formed a remarkable triangle relationship in the research topic network. These topics had numerous international studies and were supported by most funding. In addition, many topics in the basic research domain were proliferating, including mutation, biomarkers, endopeptidases, and other molecular genetics and pathology of CD. Out of 63 registered clinical trials, over 25% were withdrawn due to inadequate patient recruitment or lack of funding.ConclusionsThis publication landscape analysis provided a systemic representation of CD literature regarding the history, current challenges, and future directions, enabling clinicians a rapid and comprehensive insight into the disease.
Patients’ Perspectives on User Involvement in General Practice. A Qualitative Analysis of Free-Text Comments
Authors: Nørgaard Birgitte , Titlestad Signe Beck , Marcussen Michael
Published: September 2021

Background: General practice plays a core role in managing the pathways of patients with chronic diseases. Despite the increased focus on patient involvement in healthcare practice and well-established knowledge of the benefits of involvement and personalized care, involvement in general practice appears to be challenged. This study aimed to explore patient involvement in general practice from the patients’ perspectives. Method: The study involved a questionnaire survey investigating patient involvement in general practice from the patients’ perspectives. The validated questionnaire includes an open-ended question encouraging responders to provide additional comments regarding their involvement in general practice. The results from these comments are presented in this paper. A thematic analysis was applied. Results: Of the 468 responses, 139 included additional comments to the free-text question. Through our analysis, six analytic themes were generated—To be seen, met, or heard, To feel safe or not, To be involved or dictated to, Accessibility, COVID-19, and For the resourceful—across 116 codings and 25 descriptive themes. The themes’ interwovenness underscores the complexity of both involvement and how it is to live with a chronic disease. Our analysis indicates that involvement in general practice is for the resourceful.Conclusion: The six themes describing involvement in general practice from the perspectives of patients with T2DM and/or COPD were deeply intertwined. Involvement is dependent on being seen, met, and heard, all of which contribute to the patients’ sense of feeling safe (or not). These aspects are dependent on accessibility to a general practitioner; thus, COVID-19 was a barrier during the data-collection period. Furthermore, it appeared that being resourceful not only contributed to a sense of being involved in general practice but was perhaps even a prerequisite for being involved.
From Each According to Means, to Each According to Needs? Distributional Effects of Abolishing Asset-Based Payments for Residential Care in Austria
Authors: Rodrigues Ricardo , Simmons Cassandra , Premrov Tamara , Böhler Christian , Leichsenring Kai
Published: September 2021

BackgroundMost countries in Europe require out-of-pocket payments (OPPs) for nursing homes based on users’ income and often assets. This was also the case in Austria until 2018 when asset-based contributions to residential care —denoted the ‘Pflegeregress’ – were abolished, leaving a shortfall in revenue. We aim to determine how the Pflegeregress was distributed across different groups in Austria prior to 2018, what the distributional consequences of its abolishment were, and what the distributional impact of different financing alternatives would be.MethodsCircumventing data availability issues, we construct a micro-simulation model using a matched administrative dataset on residential care users receiving the Austrian care allowance (Pflegegeldinformation, PFIF, HVB, and Pflegedienstleistungsstatistik, Statistik Austria) and survey data (SHARE, wave 6). Using this model, we estimate the expected duration of residential care and OPPs under the Pflegeregress of a representative sample of older people aged 65+ in Austria, as well as OPPs under budgetary neutral financing alternatives to the abolished asset-based contribution, namely an inheritance tax and a social insurance scheme. The distributional impact of abolishing the Pflegeregress and these alternative scenarios is assessed through a number of measures, such as ability to pay, Concentration Indices (CI) and a needs-standardized measure.ResultsWe find that lower income individuals and homeowners disproportionately contributed to asset-based OPPs for residential care prior to 2018 due in large part to their higher use of residential care and the low asset-exemption thresholds. These groups were therefore the largest beneficiaries of its abolishment. The alternative financing scenarios tested would result in a more progressive distribution of payments (i.e. concentrated on more affluent individuals). ConclusionOur findings indicate the limited ability of asset-based OPPs to target those with higher assets, thus questioning the fairness of these instruments for financing residential care facilities for older people in Austria. Findings also suggest that the parameterization of such OPPs (such as asset exemption thresholds) and patterns of residential care use are key variables for assessing the distribution of asset-based OPPs for residential care use. Policy alternatives that decouple payments from use would entail greater transfers from healthy to less healthier individuals.
Targeting miR-9 in Glioma Stem Cell-Derived Extracellular Vesicles: A Novel Diagnostic and Therapeutic Biomarker
Authors: Geng Liangyuan , Xu Jinjin , Zhu Yihao , Hu Xinhua , Liu Yong , Yang Kun , Xiao Hong , Zou Yuanjie , Liu Hongyi , Ji Jing , Liu Ning
Published: September 2021

Background Glioblastoma, the lethal brain tumor with undesirable prognosis, still has no effective strategies in early diagnosis and treatment. Extracellular vesicles (EVs) isolated from cerebrospinal fluid (CSF) are a potential liquid biopsy source. This study was performed to assess the miRNA expression profiles in EVs from CSF and tissue of GBM patients to identify significantly upregulated miRNAs and investigate the underlying neoplastic mechanisms.Methods EVs were measured by TEM and NTA assays. Differentially regulated miRNAs were measured using RNA sequencing in GBM CSF EVs and in GBM tissues compared with controls. RT-qPCR was employed to analyze certain miRNA and gene expression. Luciferase report assay was used in investigate downstream gene target of miR-9. The proliferation ability was detected by EdU and CCK-8 experiment while cell migration was measured by transwell and wound healing assay.Results The expression level of miR-9 was significantly higher in GBM CSF EVs and tissues than controls (p = 0.038). The area under curve for CSF EV miR-9 was 0.080 (95% CI: 0.583–1.000, p = 0.033). The expression of miR-9 was significantly higher in GSCs and GSC-derived EVs compared with glioblastoma cells. GSC culture medium, which contained the GSC-derives EVs, could promote GBM growth and migration after administration to GBM cells. Moreover, inhibition of miR-9 in GSCs showed the reverse anti-tumor effects. MiR-9 could bind to the 3’UTR region of DACT3 and suppress its expression. The miR-9/DACT3 axis might attribute to GBM malignant phenotype.Conclusion MiR-9 in CSF EVs might act as a novel diagnostic biomarker for GBM and targeting miR-9 by GSC-derived EVs may be a specific and efficient strategy for GBM biotherapy.
Edaravone Ameliorates Depressive and Anxiety-like Behaviors via Sirt1/Nrf2/HO-1/Gpx4 Pathway
Authors: Dang Ruozhi , Wang Mingyang , Li Xinhui , Wang Haiyang , Liu Lanxiang , Wu Qingyuan , Zhao Jianting , Ji Ping , Zhong Lianmei , Licinio Julio , Xie Peng
Published: September 2021

Background: The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression. Edaravone (EDA), a free radical scavenger, processes strong biological activities including antioxidant, anti-inflammatory and neuroprotective properties. However, its role and potential molecular mechanisms in depression remain unclear. The present study aimed to investigate the antidepressant activity of EDA and its underlying mechanisms.Methods: A chronic social defeat stress (CSDS) depression model was performed to explore whether EDA could produce antidepressant effects. C57BL/6J mice were intraperitoneally injected with EDA or Vehicle daily for 10 days. Behaviors tests were then carried out to examine depressive, anxiety-like and cognitive behaviors including social interaction (SI) test, sucrose preference test (SPT), open field test (OFT), elevated plus maze (EPM), novel object recognition (NOR), tail suspension test (TST) and forced swim test (FST). Hippocampal and medial prefrontal cortex (mPFC) tissues were collected for Nissl staining, immunofluorescence, targeted energy metabolomics analysis, measurement of MDA, SOD, GSH and transmission electron microscopy (TEM). Western blotting (WB) and quantitative real time polymerase chain reaction (qRT-PCR) detected the Sirt1/Nrf2/HO-1/Gpx4 signaling pathway. Knockdown experiments were performed to determine the effects of Gpx4 on CSDS mice with EDA treatment by an adeno-associated virus (AAV) vector containing miRNAi(GPX4)-EGFP infusion.Results: The administrated of EDA dramatically ameliorated CSDS-induced depressive and anxiety-like behaviors. Additionally, EDA notably attenuated neuronal loss, microglial activation, astrocyte dysfunction, oxidative stress damage and energy metabolism in the hippocampus (Hip) and mPFC of CSDS-induced mice. Further examination indicated that the application of EDA after the CSDS model significantly increased the protein expressions of Sirt1, Nrf2, HO-1 and Gpx4 in the Hip. In addition, Gpx4 knockdown in CSDS mice abolished EDA-generated efficacy on depressive and anxiety-like behaviors.Conclusion: These findings suggest that EDA possesses potent antidepressant and anxiolytic properties through Sirt1/Nrf2/HO-1/Gpx4 axis and Gpx4-mediated ferroptosis may play a key role in this effect.
Sleep and Alzheimer’s Disease: Shared Genetic Risk Factors, Drug Targets, Molecular Mechanisms, and Causal Effects
Authors: Chen Dongze , Wang Xinpei , Jia Jinzhu , Huang Tao
Published: September 2021

Background: Alzheimer’s disease (AD) was associated with sleep-related phenotypes (SRPs). Whether they share common genetic etiology remains largely unknown. We explored the shared genetics and causality between AD and SRPs by using high-definition likelihood (HDL), cross phenotype association study (CPASSOC), transcriptome wide association study (TWAS), and bidirectional Mendelian randomization (MR) in summary-level data for AD (n = 79145) and summary-level data for seven SRPs (sample size ranges from 345552 to 386577). Results: AD shared strong genetic basis with insomnia (rg = 0.20; P = 9.70×10-5), snoring (rg = 0.13; P = 2.45×10-3), and sleep duration (rg = -0.11; P = 1.18×10-3). CPASSOC identifies 31 independent loci shared between AD and SRPs, including four novel shared loci. Functional analysis and TWAS showed shared genes were enriched in liver, brain, breast, and heart tissues, and highlighted the regulatory role of immunological disorders, very-low-density lipoprotein particle clearance, triglyceride-rich lipoprotein particle clearance, chylomicron remnant clearance and positive regulation of T cell mediated cytotoxicity pathways. Protein-protein interaction analysis provided three potential drug target genes (APOE, MARK4 and HLA-DRA) that interacted with known FDA-approved drug target genes. CPASSOC and TWAS demonstrated three regions 11p11.2, 6p22.3 and 16p11.2 may account for the shared basis between AD and sleep duration or snoring. MR showed AD had causal effect on sleep duration (βIVW = -0.056, PIVW = 1.03×10-3). Conclusion: Our findings provide strong evidence of shared genetics and causation between AD and sleep, and advance our understanding the genetic overlap between them. Identifying shared drug targets and molecular pathways can be beneficial to treat AD and sleep disorders more efficiently.
Comprehensive Analysis and Validation of Solute Carrier Family 25 (SLC25) in Pan-Cancer
Authors: Liu Ao-ran , Liu Ying-nan , Shen Shi-xuan , Yan Li-rong , Lv Zhi , Ding Han-xi , Wang Ang , Yuan Yuan , Xu Qian
Published: September 2021

BackgroundAs the largest gene family functioning in protein transport among human solute carriers, the SLC25 family (mitochondrial carrier family) has been reported to be associated with the genesis and development of many diseases. However, acomprehensiveexplorationfor the roles of SLC family in cancer remains lacking. MethodIn the present study, a total of 15 functional SLC25 family genes were retrieved from all current publications. And multi-dimensional analyses were systematically performed based on the transcriptome and genome data of SLC25 family from a variety of online databases for their expression, mutation and copy number variation, cancer prognosis, signaling pathways and immune cell infiltration. Validation by qPCR was further conducted for the expression of partial SLC25 family members in some tumor tissue.ResultsWe found that SLC25A7 was highly expressed in stomach adenocarcinoma, kidney chromophobeand colon adenocarcinoma, while low expressed in lung adenocarcinoma， thyroid carcinomaas well as head and neck squamous cell carcinoma. SLC25A23 was decreased in colon adenocarcinoma andhead and neck squamous cell carcinoma. SLC25A4 was down-regulated instomach adenocarcinoma,colon adenocarcinoma, kidney renal clear cell carcinoma and head and neck squamous cell carcinoma. Validation results of stomach adenocarcinoma and colon adenocarcinoma were consistent with our bioinformatic prediction. The analysis in regard to cancer-related pathways indicated that SLC25A5 was more likely to be positively associated with carcinogenic pathways such as PI3K-AKT-MTOR, MYC-TARGETS-V2 and E2F-TARGETS. Immune cells including Macrophages M2 and B cells naïve had significant association with SLC25s expression. Survival analysis demonstrated that SLC25A8 was linked to a high-risk effect on the prognosis of cervical squamous cell carcinoma and adenocarcinoma significantly. The majority of SLC25 genes showed high mutation frequency in uterine corpus endometrial carcinoma withan overall average mutation rateof 0.100189. SLC25A8 had extensive copy number variation in different cancer tissue. And SLC25A25 showed high mutation frequency in breast cancer cell lines. As forthe influence of mutation on gene expression and cancer prognosis, SLC25A4 mutation could alter its expression in uterine corpus endometrial carcinoma. Most SLC25 gene mutationmadeprominent effects on the prognosis of patients with uterine corpus endometrial carcinoma. ConclusionAll these findings suggested that the SLC25 family might be crucial to the occurrence, progression and prognosis of tumor. They had the potential to be predictive biomarkers for early diagnosis and prognosis as well as novel targets for individualized treatment of cancer.
Reduced Order Model-based Observer Design for Online Temperature Distribution Estimation in Lithium-ion Batteries
Authors: Fan Bi , Zhuang Yufen , Liu Zhen , Gan Min , Xu KangKang
Published: September 2021

Time/space separation-based modeling methods have been widely researched for estimating lithium-ion battery (LIB) thermal dynamics. However, these methods have been developed in an offline environment and may not perform well in real-time application since the battery systems in electric vehicles (EVs) are usually subject to external disturbances. Furthermore, the onboard measurements of temperature are often corrupted by significant error. To address these problems, we present a reduced model-based observer design for online temperature distribution estimation in LIBs. First, an extreme learning machine (ELM) based offline spatiotemporal model is constructed to approximate the thermal dynamics of LIB. Second, an adaptive reduced order observer is designed based on the offline model developed in the previous step. The offline model is then updated with the estimation results of the observer. As the performance of the estimator is highly related to the placement of sensors, a genetic algorithm (GA) based integrated optimization strategy is also developed to determine the optimal sensor location for online estimation. Finally, the whole temperature distribution is estimated in real time using the observer, the measured voltage, current and the limited available temperature data. Simulation results on a battery thermal system verify the effectiveness of this developed model.
Determinants of Infant and Young Child Feeding Practices in Lower Egypt: A Community- Based Cross-Sectional Survey
Authors: koofy Nehal El , Moawad Eman Mohamed Ibraheim , Tawfik Safaa , El-Sabakhawi Doaa Hamed Mohamed
Published: September 2021

Background: The optimal feeding practice in infants and young children is the key in shaping their adequate growth and development. Methods: The study aimed to explore the multiple interactions that influence the complexity of infant feeding in Egypt and acknowledge the common beliefs, attitudes and practices regarding breastfeeding and weaning process. Energy and nutrients daily intake provided by complementary foods was also investigated. Structured interview survey gathering data on maternal feeding practices related to infants and young children, clinical and nutritional status of infants and their nutrient daily intake was administered to 235 mother-infant pairs recruited from Nile Delta. Results: Exclusive breastfeeding was significantly reported in 55.8% (p < 0.001), being optimum in only 8.9 % of infants and significantly predicted in mothers aged 25-29 years. The complementary feeding started at ≥ 6 months in 58.3 % of infants and significantly based on commercial recipes ((p < 0.001). Cessation of breastfeeding (34.5 %) was mainly associated with maternal perception of insufficient breast milk (16.2 %) and significantly associated with female gender (p<0.001), rural residence (p<0.001), maternal age (25-29 years), parental occupation and paternal education (p<0.001). Calcium (58.7 %), vitamin B2 (45.1 %) and vitamin C (55.7 %) were the only nutrients adequately consumed. Conclusions: In Egypt, infant and young feeding practices are still far from the recommended levels. Collaboration between government entities and non-profit organizations is required to improve maternal knowledge, beliefs, attitudes and practices.
HSPA5 Repressed Ferroptosis to Promote Colorectal Cancer Development by Maintaining GPX4 Stability
Authors: Wang Ronglin , Hua Lei , Ma Peixiang , Song Yang , Min Jie , Zhao Ting , Shi Jingjie , Guo Yongdong , Li Shanshan , Zhang Chao , Yang Cheng , Zhu Liaoliao , Gan Dongxue , Li Junqiang , Su Haichuan
Published: September 2021

Background:Colorectal cancer (CRC) is one of the most malignant cancers and its pathological mechanism is largely unknown.Unfolded protein response and ferroptosis are both critical factors involved in CRC development. However, their relationship in CRC remains to be explored. Methods:In this study, erastin was used to induce ferroptosis in CRC cells. Cell viability and apoptosis were assessed by CCK-8 and colony formation assayand annexin V/propidium iodide staining, respectively. Ferroptosis was confirmed by the detection of glutathione, malondialdehyde, and lipid reactive oxygen species. Unfolded protein response-related proteins and GPX4 protein were analyzed by western blotting. The CRC datasetswere analyzed using the R software, GEPIA2 and TIMER2.0. Results:The results indicated that GPX4 was decreased when treated with the ferroptosis inducer erastin. As an intrinsic protective pathway, the unfolded protein response was activated and HSPA5 was increasedduring ferroptosis. HSPA5 was found to attenuateerastin-induced GPX4 decrease, repress ferroptosis, and promote CRC cell growth both in vitro and in vivo. Mechanistically, HSPA5 bounddirectly to GPX4 andthe interaction between HSPA5 and GPX4increased when treated with erastinfor a short time period. Although the HSPA5-GPX4 interaction failed to completely reverse erastin-induced GPX4 decrease, HSPA5 slowed down GPX4 degradation process and gave CRC cells more time to adjust to erastin toxicity. Additionally, HSPA5 was demonstrated to play a diagnostic role and correlated to immune microenvironment in CRC patients.Conclusion:Our study demonstrates that increased HSPA5 was an intrinsic protective strategy to resist ferroptosis. Specifically, HSPA5 restrained ferroptosis to promote colorectal cancer development by maintaining GPX4 stability. Our study provides potential diagnostic and therapeutic targets for patients with CRC.
Epigenetic Dysregulation of the Expression of PRSS3 Splice Variants Increases the Heterogeneity of Transcripts and Functionality in Human Hepatocellular Carcinoma
Authors: Lin Shuye , Xu Hanli , Pang Mengdi , Zhou Xiaomeng , Pan Yuanming , Zhang Lishu , Guan Xin , Wang Xiaoyue , Lin Bonan , Tian Rongmeng , Chen Keqiang , Zhang Xiaochen , Yang Zijiang , Ji Fengmin , Huang Yingying , Wei Wu , Gong Wanghua , Ren Jianke , Wang Ji Ming , Guo Mingzhou , Huang Jiaqiang
Published: September 2021

Background

Hepatocellular carcinoma (HCC) is one of the most lethal human tumors with extensive heterogeneity. Serine protease 3 (PRSS3) is an indispensable member of the trypsin family and has been implicated in the pathogenesis of several malignancies including HCC. However, paradoxical effects of PPRSS3 on carcinogenesis impede the utilization of its biomarker potential. We hereby systematically dissected the expression of four known splice variants of PRSS3 (PRSS3-SVs) and their functional relevance to HCC.
Methods

The expression and DNA methylation of PRSS3 transcripts and their associated clinical relevance in HCC were analyzed using several publicly available datasets and were validated using qPCR-based assays. Functional assays were performed on gain- and loss-of-function cell models, in which PRSS3 transcript constructs were separately transfected after PRSS3 expression was knocked out by CRISPR-Cas9 editing.
Results

PRSS3 expression was differentially decreased in HCC cell lines and tissues attributable to aberrant expression of PRSS3-SVs towards bipolarity, in which PRSS3-V2 and then -V1 were dominantly expressed whereas PRSS3-V3 and -V4 were rarely or minimally expressed. The expression of PRSS3-V2 or -V1 was reversely associated with site-specific CpG methylation and was distinct between lowly-expressed PRSS3-SVs with hypermethylation (mPRSS3Low) and highly-expressed PRSS3-SVs with hypomethylation (umPRSS3High). Function analysis revealed that PRSS3-V2 exhibited oncogenic functions distinct from a tumor-suppressive role of ectopic PRSS3-V1 or -V3, or PRSS3-V4 with inhibitory effects in PRSS3 knockout HCC cells. Clinically, aberrant expression of PRSS3-SVs was translated into divergent relevance in patients with HCC, in which significant epigenetic downregulation of PRSS3-V2 was seen in early HCC and was associated with favorable patient outcome.
Conclusions

Aberrant expression of divergent PRSS3-SVs disrupted by CpG methylation may integrate the effects of oncogenic PRSS3-V2 and tumor-suppressive PRSS3-V1, resulting in the molecular diversity and functional plasticity of HCC. Dysregulated expression of PRSS3-V2 by site-specific CpG methylation may have potential diagnostic value for patients with early HCC.
miR-133a targets YES1 to reduce cisplatin resistance in ovarian cancer by regulating cell autophagy
Authors: Zhou Yang , Wang Chunyan , Ding Jinye , Sun Yaoqi , Cheng Zhongping
Published: September 2021

Background
Accumulating evidences reveal that aberrant microRNAs (miRNAs) expression can affect the development of chemotherapy drug resistance by modulating the expression of relevant target proteins. Emerging evidences have demonstrated that miR-133a participates in tumorigenesis of various cancers. However, whether miR-133a is associated with cisplatin resistance in ovarian cancer remains unclear.
Objective
To investigate the role of miR-133a in the development of cisplatin resistance in ovarian cancer.
Methods
MiR-133a expression in cisplatin-resistant ovarian cancer cell lines was assessed by reverse-transcription quantitative PCR (RT-qPCR). Cell counting kit-8 (CCK-8) assay was used to evaluate cell viability of tumor cells treated with cisplatin in the presence or absence of miR-133a. Luciferase reporter assay was used to analyze binding of miR-133a with 3’ untranslated regions (3’UTR) of YES proto-oncogene 1 (YES1). The YES1 expression level was analyzed using the dataset from the international cancer genome consortiu (ICGC) and assessed by RT-qPCR and western blotting in vitro. The roles and mechanisms of YES1 on cell functions were further probed via gain- and loss-of-function analysis.
Results
The expression of miR-133a was significantly decreased in cisplatin resistant ovarian cancer cell lines (A2780-DDP and SKOV3-DDP), and the overexpression of miR-133a mimic reduced cisplatin resistance in A2780-DDP and SKOV3-DDP cells and the treatment of miR-133a inhibitor increased cisplatin sensitive in normal A2780 and SKOV3 cells. MiR-133a binds 3’UTR of YES1 and down-regulates its expression. Bioinformatics analysis revealed that YES1 expression was upregulated in recurrent cisplatin resistance ovarian cancer tissue and in vitro experiments also verified its upregulating in cisplatin resistance cell lines. Furthermore, we discovered that miR-133a down-regulated the expression of YES1 and thus inhibited the cell autophagy to reduce cisplatin resistance. Yes1 knockdown significantly suppressed the cisplatin resistance of ovarian cancer cells through inhibiting autophagy in vitro. Xenograft tumor implantation further demonstrated that Yes1 overexpression promoted ovarian tumor development and cisplatin resistance.
Conclusion
Our results suggest that miR-133a/YES1 axis plays a critical role in cisplatin resistance in human ovarian cancer by regulating cell autophagy, which might serve as a promising therapeutic target for ovarian cancer chemotherapy treatment in the future.
Diversity of cultivable bacteria from deep-Sea sediments of the Colombian Caribbean and their Potential in Bioremediation
Authors: Blandon Lina , Marín Mario Alejandro , Quintero Marynes , Jutinico-Shubach Laura Marcela , Montoya-Giraldo Manuela , Santos Marisol , Gómez-León Javier
Published: September 2021

The diversity of deep-sea cultivable bacteria was studied in seven sediment samples of the Colombian Caribbean. Three hundred and fifty two marine bacteria were isolated according to its distinct morphological character on the solid media, then DNA sequences of the 16S rRNA were amplified to identify the isolated strains. The identified bacterial were arranged in three phylogenetic groups, Firmicutes, Proteobacteria, and Actinobacteria, with 34 different OTUs defined at ≥97% of similarity and 70 OTUs at ≥98.65%, being the 51% Firmicutes, 34% Proteobacteria and 15% Actinobacteria. Bacillus and Fictibacillus were the dominant genera in Firmicutes, Halomonas and Pseudomonas in Proteobacteria and Streptomyces and Micromonospora in Actinobacteria. In addition, the strains were tested for biosurfactants and lipases production, with 120 biosurfactant producing strains (mainly Firmicutes) and, 56 lipases producing strains (Proteobacteria). This report contributes to the understanding of the detailed physiology and the complex environmental processes associated with the marine deep-sea cultivable bacteria from the Colombian Caribbean.
Genetic Relationship and Structural Analysis of Resident Pacific Salmon Oncorhynchus Masou in Mijiang River, China
Authors: Liang Shan , Song Bizeng , Chong Xiangyu , Zheng Wei , Yin Xuwang , Nie Hongtao
Published: September 2021

Masu salmon Oncorhynchus masou has been listed as national second-class protected species in China, and many of its local populations have been under threats of decline because of environmental deterioration by human activity, such as habitat loss, water pollution, or dams. Genetic characteristics should be clarified in wild masu salmon population for an effective protection and recovery. In the present study, we explained genetic relationship and structure of masu salmon population in Mijaing River by sequencing the COI gene and analyzing microsatellite makers. Results of COI sequences analysis revealed 15 gene variable sites in approximately 696 bp, which defined 12 haplotypes, including some haplotypes related to geographic regions. The NJ tree indicated genetic relationship that we preliminarily inferred, that is, the masu salmon from Mijiang River belonged to the cherry salmon family (O. masoumasou). Results based on 14 microsatellite loci showed high haplotype diversity and low nucleotide diversity, indicating low genetic diversity of wild masu population in Mijaing River. The observed genetic structure was influenced primarily by bottlenecks due to overfishing and habitat loss. Since masu salmon has become highly vulnerable in China, we recommend to strengthen the protection of resident masu salmon population.
Understanding the Abrupt Effect of Spousal Bereavement on Mortality: an Application of Complex Dynamic Systems Theory
Authors: Katsiferis Alexandros , Nielsen Pernille Yde , Jensen Majken K. , Westendorp Rudi G.J
Published: September 2021

BackgroundThe process of aging renders older people susceptible for adverse outcomes upon stress. Various indicators derived from complex systems theory have been proposed for quantifying resilience in living organisms, including humans. We investigated the ability of system-based indicators in capturing the dynamics of resilience in humans who suffer the adversity of spousal bereavement and tested their predictive power in mortality as a finite health transition.MethodsUsing longitudinal register data on weekly healthcare consumption of all Danish citizens over the age of 65 from January 1st, 2011, throughout December 31st, 2016, we performed statistical comparisons of the indicators ‘average’, ‘slope’, ‘mean squared error’, and ‘lag-1 autocorrelation’ one year before and after spousal bereavement, stratified for age and sex. The relation between levels of these indicators before bereavement and mortality hazards thereafter was determined by time to event analysis and the added value for mortality prediction was estimated by the time dependent area under the receiver operating characteristic curve.ResultsThe study included 934,003 citizens of whom 51,890 experienced spousal bereavement and 2862 died in the first year thereafter. Values of all dynamic indicators were significantly higher with increasing age, in men compared to women, and except lag-1 autocorrelation, higher in the year after bereavement (all p-values < 0.001). All dynamic indicators before bereavement were positively related with mortality hazards thereafter (all p-values < 0.001). The area under the curve of the final model to predict mortality, including all relevant indicators, was 77.7% for males and it was 81.8% for females.ConclusionsIt is concluded that healthcare consumption is increased, more volatile and accelerating with aging and in men compared to women. High values of these dynamic indicators before bereavement indicate loss of resilience as manifested by their predictive value to predict mortality when mourning after spousal loss.
Nascent alt-protein chemoproteomics reveals a repressor of ribosome biogenesis
Authors: Slavoff Sarah , Cao Xiongwen , Khitun Alexandra , Harold Cecelia , Bryant Carson , Zheng Shu-Jian , Baserga Susan
Published: September 2021

Many unannotated microproteins and alternative proteins (alt-proteins) have recently been found to be co-encoded with canonical proteins, but few of their functions are known. Motivated by the hypothesis that alt-proteins undergoing active or stress-induced synthesis could play important cellular roles, here, we developed a chemoproteomic pipeline to identify nascent alt-proteins in human cells. We identified 22 actively translated unannotated alt-proteins, one of which is upregulated after DNA damage stress. We further defined MINAS-60 (MIcroprotein that Negatively regulates ASsembly of the pre-60S ribosomal subunit), a nucleolar localized alt-protein co-encoded with human RBM10. Depletion of MINAS-60 increases the amount of the mature 60S ribosomal subunit, consequently upregulating global protein synthesis and cell proliferation by repressing late-stage pre-60S assembly and export of the 60S ribosome subunit to the cytoplasm. Together, these results implicate MINAS-60 as a repressor of ribosome biogenesis, and demonstrate that chemoproteomics can enable generation of functional hypotheses for uncharacterized alt-proteins.
Analysis of nuclear fusion exists inside earth
Authors: Dong Shupeng
Published: September 2021

Using the falsification method, it is proved that "There are three main sources of heat in the deep earth: (1) heat from when the planet formed and accreted, which has not yet been lost; (2) frictional heating, caused by denser core material sinking to the center of the planet; and (3) heat from the decay of radioactive elements" is a false proposition, it is inferred that the source of heat in the deep earth must have an unknown exothermic factor, and this exothermic factor is the heat from intermolecular nuclear fusion. Then, using the quantum tunneling effect of proton and the observed continental plate drift facts, it is determined that there must be nuclear fusion inside the earth. Through the diagram of temperature of planet Earth, it can be determined that the endothermic nuclear fusion reaction occurs in the core of the earth, and because the water becomes solid and cannot ionize hydrogen ions, nuclear fusion cannot occur, so as to determine that the temperature at Earth's center is the freezing point of the saline solution at the center of the earth's core.
Complexity Measure based on Sensitivity Analysis Applied to an Intensive Care Unit system
Authors: Paiva Joao R. B. , Gomes Viviane M. , Barbosa Poliana S. , Almeida Fabiana R. , Wainer Gabriel A. , Gomes Flavio A. , Calixto Wesley P.
Published: September 2021

This work proposes a system complexity metric and its application to Intensive Care Unit (ICU) system. The methodology for applying said complexity metric comprises: (i) parameters sensitivity indices calculation, (ii) mapping connections dynamics between system components, and (iii) system’s complexity calculation. After simulating the ICU computer model and using the proposed methodology, we obtained results regarding: number of admissions, number of patients in queue, length of stay, beds in use, ICU performance, and system complexity values (in regular or overloaded operation). As the number of patients in queue increased, the ICU system complexity also increased, indicating a need for policies to promote system robustness.
Pharmacological Modulation of TRPM2 Channels via TRPM2 Pathway Leads to Neuroprotection in MPTP-induced Parkinson’s Disease in Sprague Dawley Rats
Authors: Vaidya Bhupesh , Kaur Harpinder , Thapak Pavan , Sharma Shyam Sunder , Singh Jitendra N
Published: September 2021

Transient receptor potential melastatin-2 (TRPM2) channels are cation channels activated by oxidative stress and adenosine di-phosphate ribose (ADPR). Role of TRPM2 channels has been postulated in several neurological disorders, but, it has not been explored in animal models of Parkinson’s disease (PD). Thus, the role of TRPM2 and its associated poly (ADP-ribose) polymerase (PARP) signalling pathways were investigated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model using TRPM2 inhibitor, 2-aminoethyl diphenyl borinate (2-APB) and PARP inhibitor, N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino) acetamide hydrochloride (PJ-34). PD was induced by using a bilateral intranigral administration of MPTP in Sprague-Dawley rats, and different parameters were evaluated. An increase in the oxidative stress was observed, leading to the locomotor and cognitive deficits in the PD rats. PD rats also showed an increased TRPM2 expression in striatum and mid brain accompanied by reduced expression of tyrosine-hydroxylase (TH) in comparison to sham animals. Intraperitoneal administration of 2-aminoethyl diphenyl borinate (2-APB) and N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino) acetamide hydrochloride (PJ-34) led to an improvement in the locomotor and cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and an increase in TH levels in striatum and mid brain. In addition, these pharmacological interventions also led to a decrease in the expression of TRPM2 in PD in striatum and mid brain. Our results provide a rationale for the development of potent pharmacological agents targeting TRPM2-PARP pathway to provide therapeutic benefits for the treatment of neurological disease like PD.
Quantitative Proteomics Reveals Protein Dysregulation During T Cell Activation in Multiple Sclerosis Patients Compared to Healthy Controls
Authors: Cappelletti Chiara , Eriksson Anna Maria , Brorson Ina Skaara , Leikfoss Ingvild S. , Kråbøl Oda Glomstad , Høgestøl Einar August , Vitelli Valeria , Mjaavatten Olav , Harbo Hanne F. , Berven Frode Steingrimsen , Bos Steffan D. , Berge Tone
Published: September 2021

Background: Multiple sclerosis (MS) is an autoimmune, neurodegenerative disorder with a strong genetic component that acts in a complex interaction with environmental factors for disease development. CD4 + T cells are pivotal players in MS pathogenesis, where peripherally activated T cells migrate to the central nervous system leading to demyelination and axonal degeneration. Through a proteomic approach, we aim at identifying dysregulated pathways in activated T cells from MS patients as compared to healthy controls. Methods: CD4 + T cells were purified from peripheral blood from MS patients and healthy controls by magnetic separation. Cells were left unstimulated or stimulated in vitro through the TCR and costimulatory CD28 receptor for 24 hours prior to sampling. Electrospray liquid chromatographytandem mass spectrometry was used to measure protein abundances. Results: Upon T cell activation the abundance of 1,801 proteins was changed. Among these proteins, we observed an enrichment of proteins expressed by MS-susceptibility genes. When comparing protein abundances in T cell samples from healthy controls and MS patients, 18 and 33 proteins were differentially expressed in unstimulated and stimulated CD4 + T cells, respectively. Moreover, 353 and 304 proteins were identified as proteins exclusively induced upon T cell activation in healthy controls and MS patients, respectively and dysregulation of the Nur77 pathway was observed only in samples from MS patients. Conclusions: Our study highlights the importance of CD4 + T cell activation for MS, as proteins that change in abundance upon T cell activation are enriched for proteins encoded by MS susceptibility genes. The results provide evidence for proteomic disturbances in T cell activation in MS, and pinpoint to dysregulation of the Nur77 pathway, a biological pathway known to limit aberrant effector T cell responses.
Shortening of Leucocyte Telomerase Length Is Independently Correlated With High Body Mass Index and Subcutaneous Obesity (Predominantly Truncal), in Asian Indian Women With Prediabetes
Authors: Bhatt Surya Prakash , Misra Anoop , Pandey Ravindra Mohan , Upadhyay Ashish Datt
Published: September 2021

Introduction: Leucocyte telomerase length (LTL) are inked to accelerate aging and premature mortality. In this research, we aimed to explore the relations between biochemical and anthropometry markers and LTL in Asian Indian women with prediabetes.Methods: In this study, 797 prediabetic women (aged 20-60 years, obese, 492; non obese, 305) were recruited. Demographic and clinical profiles, medical history, skin exposure and duration of sunlight exposure were determined. Anthropometry, fasting blood glucose and serum 25-hydroxyvitamin D [25(OH) D] were evaluated. LTL was quantified by a quantitative polymerase chain reaction (qPCR). The study subjects were separated into quartiles groups according to the LTL.Results: The average telomerase length (T/S) ratio was significantly decreased with increasing age. The average telomerase length (T/S) ratio was significantly shorter in obese women with prediabetes (p<0.05). Univariate and multivariable linear regression analysis after adjustment for age, family income, education and hypertension showed that LTL was inversely correlated with body mass index (BMI), waist and hip circumference, waist-hip and waist-to-height ratio, and truncal skinfolds (subscapular, lateral thoracic, and subscapular/triceps ratio, central and total). Multivariable linear regression analysis identified BMI (93%, p<0.0001), central (92%, p<0.0001) and total skinfolds (90%, p<0.0001) as independent predictors of LTL. Conclusions: Besides age, obesity, and subcutaneous adiposity (predominantly truncal) are major contributors to telomerase shortening in Asian Indian women with prediabetes.