bluuebunny/crossref_metadata_2025 huggingface dataset:
Bimodal sequence composition underlies functional duality of transcribed enhancers
Authors: Flores Mario , Ovcharenko Ivan
Published: August 2020

Background:Recent studies have drawn attention to transcribed enhancers (trEs) as important regulatory elements of gene expression; however, their characteristics and mechanisms of action remain poorly understood. Results:We profiled the characteristics of trEs and obtained insights into their mechanisms of action. We found that trEs harbor functional duality related to bimodal sequence composition. TrEs are composed of nonoverlapping cores and flanking regions (flanks): cores function as regular enhancers, while flanks transcribe enhancer RNAs (eRNAs) that can potentially regulate the expression of their target genes in trans. Cores are evolutionarily conserved and compact, while flanks are significantly longer. We observed that approximately 25% of eRNAs transcribed from the flanks likely contribute to trans DNA:RNA triple helix formation, while another 10% likely employ classical mechanisms of RNA-based regulation. We found that the majority of human enhancers are not transcribed, and trEs are strikingly different from regular enhancers in their functional characteristics. In addition, we found evidence for trEs exhibiting functional duality in regulatory locus encapsulation (RLE), effectively providing localized control over the spread of gene expression upregulation by trE cores and other locus enhancers. Conclusions:In summary, our results advocate for enhancer transcription being an uncommon mechanism of gene regulation, and the duality of transcribed enhancer function being a product of additive, not overlapping, DNA sequence encryption.
WITHDRAWN: Transcriptome Sequencing of Trichoderma Koningiopsis Strain Tk1 to Identify and Analyze Differential Gene Expression Patterns
Authors: Luo Mei , Dong Zhangyong , Shu Yongxin , Chen Mobing
Published: August 2020

Background: Trichoderma koningiopsis strain Tk1 shows good biocontrol potential. However, its biocontrol function may differ under different conditions. The objective of this study is to elucidate the biological and transcriptome differences of T. koningiopsis Tk1 under different media. Results: In this study, the mycelium weight and sporulation of T. koningiopsis Tk1 was found to differ in various media. Further, the Tk1 strain inhibited the growth of the pathogen Fusarium oxysporum in the three media tested. Fries3, PD, and PS were collected for RNA sequencing of Tk1 mycelia to identify the genes that are differentially expressed genes (DEGs) between Tk1 grown on different media. De novo transcriptome assembly resulted in identification of 14,208 unigenes. The differential gene expression pattern was more similar between the Fries3 and PS samples, whereas PD samples showed a different expression pattern. The DEGs were enriched in some metabolic and biosynthetic pathways. Additional analysis of the DEGs identified a set of carbohydrate-active enzymes that are upregulated or downregulated under different conditions.Conclusions: These results indicate that the Tk1 strain cultured in Fires3 and PS mediums can produce specific metabolic and carbohydrate-active enzymes to enhance their antimicrobial effect, providing a foundation for the subsequent mining of specific genes.
Acid Sphingomyelinase Deficiency Normalizes Neuronal Function in GCase Deficiency - Unexpected Biological Rescue Effect of Combined Genetic Risk Factors for Parkinson’s Disease
Authors: Keatinge Marcus , Gegg Matthew E , Watson Lisa , Mortiboys Heather , Bui Hai , Lefeber Dirk , Rens Astrid Van , MacDonald Ryan , Schapira Anthony , Bandmann Oliver
Published: August 2020

BackgroundThe additive mechanistic effect of genetic risk variants for Parkinson’s disease (PD) is a plausible but largely unproven hypothesis. We investigated the mechanistic interaction between the two lysosomal PD risk genes glucocerebrosidase 1 (GBA1) and sphingomyelinase 1 (SMPD1) in complementing model systems.MethodsUsing CRISPR/Cas gene editing, smpd1 mutant (smpd1-/-) zebrafish were generated and crossed to our previously characterised gba1-/- zebrafish line, generating double knockouts (gba1-/-;smpd1-/-). Spontaneous motor behaviour and survival were assessed in WT, single mutants and double mutants. HPLC-based sphingolipid quantification was combined with RNAseq based pathway analysis, assessment of the mitochondrial respiratory chain and quantification of lipid membrane oxidation for in-depth assessment of cellular health across all four genotypes. We also determined the effect of combined glucocerebrosidase (GCase) and acid sphingomyelinase (ASM) inactivation on autophagy and alpha-synuclein homeostasis in the human neuronal cell line SH-SY5Y.ResultsUnexpectedly, ASM deficiency rescued the marked behavioural phenotype and prolonged survival in gba1-/-;smpd1-/- double-mutant zebrafish compared to gba1-/-. RNAseq-based pathway analysis confirmed a profound rescue of neuronal function and intracellular homeostasis. We identified complete reciprocal rescue of mitochondrial respiratory chain function and abolished lipid membrane oxidation in gba1-/-;smpd1-/- compared to gba1-/- or smpd1-/- as the underlying rescue mechanism. The complementing in vitro experiments demonstrated an unexpected reduction of α-synuclein levels in human cell lines with combined GCase and ASM deficiency.ConclusionsOur study highlights the importance of functional validation for any putative mechanistic interactions between genetic risk factors and their overall effect on disease-relevant mechanisms rather than readily assuming an additive effect.
Interaction Between Clopidogrel and Panax Notoginseng Saponins
Authors: Hu Yunzhen , Yang Xi
Published: August 2020

Background: Panax notoginseng saponins (PNS) is commonly used in combination with clopidogrel in clinic. This study was to investigate the effect of PNS on the pharmacokinetics of clopidogrel active metabolite CAMD and the effect on the activities of clopidogrel metabolic enzymes in rats. Methods: In pharmacokinetics studies, the rats were divided into clopidogrel and combination groups, and continuously administered for seven days. The concentration of CAMD was determined by LC-MS/MS. In enzymes studies, the rats were divided into control and PNS groups. After administration for seven days, CYP2C19 and CYP3A4 activities were measured by the metabolic rate of the specific substrate in rat liver microsomes. The activity of CES1 enzyme was determined by double antibody sandwich method.Results: PNS significantly increased AUC0-∞ of CAMD from 43.1±11.6 to 72.0±25.1 h·ng/mL (p<0.05). Combination group had lower CL/F and Vd/F than clopidogrel group (p<0.05). PNS significantly decreased the activity of CYP3A4 and CES1 (p<0.01), but no significant effect on CYP2C19.Conclusions: The combination use of PNS and clopidogrel produced a significant increase in the AUC of clopidogrel active metabolite CAMD. PNS could inhibit the activity of CYP3A4 and CES1 enzyme in rat.
Vascular Access Support Team: A Multi-Disciplinary Response to Optimise Patients’ Care during COVID-19 Pandemic
Authors: Sinha Manish , Saha Prakash , Nabil Melhem , Kessaris Nicos , Biasi Lukla , Booth Caroline , Callaghan Chris J. , Donati Tommaso , Ostermann Marliese , Patel Sanjay , Ware Nick , Zayed Hany , Drage Martin , Sallam Morad
Published: August 2020

Background: Vascular access support teams have been set up to help offload procedural tasks from critical care teams during the coronavirus disease 2019 (COVID-19) global pandemic. However, the impact of VAST on clinical outcomes and on workload has not been shown previously with no reports to date from the UK. Our aim was to evaluate clinical outcomes of a multidisciplinary vascular access support team (VAST) and the value of the service to critical care teams. Methods: Prospectively collected data on all patients requiring vascular access at St Thomas’ Hospital, London over a 5-week period during the first wave of the pandemic in the UK. At the end of study period, online anonymised questionnaire administered to critical care team members, including nursing and medical professionals, to evaluate their experience of the service. We report access-related complication until discharge from centre and description of results of online survey.Results: 122 patients aged 52.1 ± 13 years with high rate of pre-existing co-morbidities, underwent line insertion including 190 catheters (central venous n=182, arterial n=8). Median (range) number of 5 (0-17) lines were placed per day in patients of whom 90% tested positive for Severe Acute Respiratory Syndrome Coronavirus-type 2 pathogen (SARS-CoV-2). A single line (n=146) was inserted in 96 out of 122 patients (78.7%) and n=18 patients (14.7%) ‘double puncture’ technique used. 45 line insertions (24%) had complications with minor [bleeding (n=19), line infection (n=10)] and 2 lines (1%) with major complication. The survey respondents, n=54 professionals, highlighted ease of referral and timely access placement (>90% responses); with agreement that VAST service saved them precious time and allow them to focus on other jobs.Conclusions: We describe the successful deployment of a multidisciplinary vascular access team with low complication rates and high rates of satisfaction. We recommend similar models can be considered by health services to optimise patient care and ICU management.
Expression and clinical significance of SARS-COV-2 receptor ACE2 in colon cancer
Authors: Nie Hui , Wang Yutong , Wu Geting , He Xiaoyun , Liao Zhiming , Ou Chunlin , Zhou Jianhua
Published: August 2020

Background: Angiotensin-converting enzyme 2 (ACE2), a crucial cell entry receptor for severe acute respiratory syndrome coronavirus 2, has been identified as an oncogene in some tumour types. However, its role in colon cancer is poorly understood.Methods: Integrative bioinformatics analyses were performed to uncover the role of ACE2 in colon cancer-associated immunology. Results: The results showed that ACE2 was overexpressed in colon cancer tissues and correlated with poor survival. Moreover, ACE2 expression was closely associated with the immune-infiltrating levels of CD4+ T, CD8+ T, and neutrophils. Conclusions: ACE2 is closely associated with colon cancer and may be involved in tumourigenesis and cancer–immune interactions, and could be a promising prognostic and therapeutic biomarker in colon cancer.
Barriers and Facilitators Affecting Implementation of a Clinical Decision aid for the Diagnosis of Acute Aortic Syndrome: A Qualitative Study
Authors: Dmitriew Caitlin , Ohle Robert
Published: August 2020

Background: Acute aortic syndrome (AAS) is an uncommon, life-threatening emergency that is frequently misdiagnosed. The Canadian clinical practice guidelines for the diagnosis of AAS were developed to improve patient outcomes and include a clinical decision aid designed to facilitate clinician decision-making. The objective of this study was to prospectively identify barriers and facilitators among physicians prior to implementation of the decision aid.Methods: We conducted semi-structured interviews with emergency room physicians working at five sites distributed between urban academic and rural settings. We used purposive sampling, contacting physicians until data saturation was reached. Interview questions were designed to understand potential barriers and facilitators to decision aid uptake and use. Responses were analysed according to the Theoretical Domains Framework, and overarching themes describing these barriers and facilitators were identified. Results: A majority of interviewees anticipated that the decision aid would support clinical decision making and risk stratification. Potential facilitators identified included guideline validation and publication and endorsement by peers. Barriers to implementation and application of the aid included the fact that the use of D-dimer and knowledge of the rationale for its use in the investigation of AAS were not widespread. The complexity of the decision aid and insufficient specificity of D-dimer were also identified as potential barriers to use. Conclusion: Physicians were amenable to using the AAS decision aid to support clinical decision-making and to reduce resource use. The barriers identified should be addressed prior to implementation in order to support decision aid uptake and use.
Ultrastructure and Functional Morphology of the Appendages in the Reef-Building Sedentary Polychaete Sabellaria Alveolata (Annelida, Sedentaria, Sabellida)
Authors: Meyer Christian , André Thomas , Purschke Günter
Published: August 2020

Background: The sedentary polychaete Sabellaria alveolata, the sandcastle or honeycomb worm, possesses four different kinds of appendages besides the parapodia: opercular papillae, tentacular filaments, palps, and branchiae. It exhibits a highly specialized anterior end, the operculum, formed by the prostomium, peristomium, and two anterior segments. Besides the median organ, the operculum comprises opercular papillae, tentacular filaments, and palps. Paired branchiae are present from the second thoracic chaetiger onwards on the posteriorly following segments except for the last ones. Only the palps have been studied thus far by transmission electron microscopy in late larvae of a different species. In order to bridge the data gap, we investigated the appendages of S. alveolata by applying light microscopy, confocal laser scanning microscopy, scanning, and transmission electron microscopy. Results: In S. alveolata the entire body is covered by a thin cuticle characterized by the absence of layers of parallel collagen fibers with no differentiation between the various body regions including the branchiae. The opercular papillae bear numerous tufts of receptor cells and lack motile cilia. The tentacular filaments show a distinctive ciliation pattern; their most conspicuous morphological feature is their cell-free cartilaginous endoskeletal structure enclosed by ECM. Besides musculature the filaments include a single coelomic cavity but blood vessels are absent. The palps are ciliated with two coelomic cavities and a single blind-ending blood vessel. Besides external ciliation and receptor cells, the coelomate branchiae are highly vascularized and equipped with numerous blood spaces extending deep into the basal regions of the epidermal cells (diffusion distances: 150–400nm). Conclusions: All appendages, including the branchiae, bear receptor cells and, as such, are sensory. The opercular papillae resemble typical parapodial cirri. In contrast, the tentacular filaments have a double function: sensing, collecting and transporting particles. A similarity to branchiae can be excluded. The palps are typical grooved palps similar to another sabellariid studied. A revised classification of polychaete branchiae is suggested; thereby, the branchiae of S. alveolata belong to the most common type comprising coelom, musculature, and blood vessels. The results indicate that diffusion distances between blood and environment have been underestimated in many cases.
The Discovery of a Recombinant SARS2-like CoV Strain Provides Insight Into SARS and COVID-19 Pandemics
Authors: Li Xin , Jin Xiufeng , Chen Shunmei , Wang Liangge , Yau Tung On , Yang Jianyi , Hong Zhangyong , Ruan Jishou , Duan Guangyou , Gao Shan
Published: August 2020

Background: In December 2019, the world awoke to a new zoonotic strain of coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).Results: In the present study, we classified betacoronavirus subgroup B into the SARS-CoV-2, SARS-CoV and SARS-like CoV clusters, and the ORF8 genes of these three clusters into types 1, 2 and 3, respectively. One important result of our study is that we reported—for the first time—a recombination event of ORF8 at the whole-gene level in a bat, which had been co-infected by two betacoronavirus strains. This result provides substantial proof for long-existing hypotheses regarding the recombination and biological functions of ORF8. Based on the analysis of recombination events in the Spike gene, we propose that the Spike protein of SARS-CoV-2 may have more than one specific receptor for its function as gp120 of HIV has CD4 and CCR5. In the present study, we also found that the ancestor of betacoronavirus had a strong first Internal Ribosome Entry Site (IRES) and at least one furin cleavage site (FCS) in the junction region between S1 and S2 subunits.Conclusions: We concluded that the junction FCS in SARS-CoV-2 may increase the efficiency of its entry into cells, while the type 2 ORF8 acquired by SARS-CoV may increase its replication efficiency. These two most critical events provide the most likely explanation for SARS and COVID-19 pandemics.
Virtual Reality Hypnosis for Anxiety and Pain Management in Intensive Care Units. A Prospective Randomized Trial Among Cardiac Surgery Patients.
Authors: Rousseaux Floriane Marie , Dardenne Nadia , Massion Paul B , Ledoux Didier , Faymonville Marie-Elisabeth , Nyssen Anne-Sophie , Vanhaudenhuyse Audrey
Published: August 2020

Background: Although non-pharmacological tools are nowadays commonly used in medical settings, virtual reality and hypnosis are little studied in complex contexts such as intensive care, where patients need significant physical and psychological assistance. The aim of the project is to evaluate the benefits of hypnosis, virtual reality (VR) and the combination of hypnosis and virtual reality (VRH) on anxiety and pain on patients before and after a cardiac surgery.Methods: This prospective randomized and controlled clinical trial was conducted in the University Hospital of Liege (Belgium). Participants are adults undergoing cardiac surgery, French speaking. Exclusion criteria are patients with psychiatric diseases, claustrophobia, acrophobia, heavy hearing impairment, visual impairment, extreme fatigue, verbal incoherence, surgery cancelled or postponed. The day before the surgery, patients were randomly assigned to four arms (control, hypnosis, VR and VRH) and had 20 minutes of one of the technique. They received the same intervention one day after surgery, in intensive care units. Anxiety, pain, fatigue, relaxation and physiological parameters were evaluated before and after each session.Results: 100 patients (66.38 ± 11.48 years; 76 men, 24 women) were included. Results showed that anxiety decreased from baseline to postoperative day in all groups. Relaxation increased in all groups in preoperative (p = .000) and postoperative period (p = 0.03). There were no significant results for pain and fatigue (p > 0.05). There was no significant difference between control group and hypnosis, VR or VRH.Conclusion: Anxiety decreased and relaxation increased in all groups, including control group. We cannot affirm that one technique is better than another is. Nevertheless, this study helps to expand the knowledge regarding application of virtual reality, hypnosis and virtual reality hypnosis in the specific contexts of cardiac surgery and intensive care units. Additional studies are required to compare and evaluate the costs-effectiveness of these techniques for critical care patients and caregivers (see Figure 1).Trial registration: ClinicalTrials.gov: NCT03820700. https://clinicaltrials.gov/ct2/show/NCT03820700. Registered on January 29 2019. Retrospectively registered.
Stress-related Growth and Perceived Health in Japanese People Living With HIV: Web-based Nationwide Participatory Research.
Authors: Togari Taisuke , Inoue Yoji , Oshima Gaku , Abe Sakurako , Hosokawa Rikuya , Takaku Yosuke
Published: August 2020

Background: For Japanese people living with HIV, this study aimed at the following: verifying the three-factor model of stress-related growth scales; confirming the impact of stress-related growth on mental health and physical symptoms; and determining differences in the effects of stress-related growth on health by time since HIV diagnosis.　Methods: A cross-sectional anonymous self-administered online survey which was prepared on the basis of the participatory research method was conducted from July 2013 to February 2014 and from December 2016 to July 2017 for all Japanese web users living with HIV. We analyzed the data of 1,422 participants who responded regarding the number of years since diagnosis and where transmission was sexual. The mean age (standard deviation) was 38.6 (8.3) years.　Results: Stress-related growth comprises three factors: self-perception, interpersonal relationships, and philosophy of life. In the group over 4 years since diagnosis, logistic and Poisson regression analysis simultaneously including all the scales showed a positive effect; in the group with less than 4 years since diagnosis, such an association was found only for self-perception. In the group with over 4 years since diagnosis, positive growth in interpersonal relationships and self-perception led to reduced somatic symptoms; however, philosophy of life was linked to increased physical symptoms. When the group with less than 4 years since diagnosis was included, no correlation was evident with philosophy of life; positive growth in self-perception led to reduced physical symptoms; positive changes in interpersonal relationships produced increased physical symptoms.　Conclusions: Toward assisting people living with HIV/AIDS, we found that personal and group relationships played an important role in creating positive changes regarding respondents’ perceptions of life and other people.
RNF114 suppresses tumour metastasis through the regulation of PARP10
Authors: Zhao Yahui , Liang Xiao , Wei Li , Liu Yao , Liu Juan , Feng Huan , Zheng Fen , Wang Ying , Ma Haijie , Wu Jiaxue
Published: August 2020

Background

ADP-ribosylation is a multifunctional post-translational modification catalysed by intracellular ADP-ribosyltransferases. Previously, we demonstrated that the mono-ADP-ribosyltransferase PARP10 suppresses tumour metastasis through the negative regulation of Aurora A kinase activity. However, the mechanisms of PARP10 regulation and modification were unclear.
Methods

Interaction of RNF114 and PARP10 was identified by exogenous and endogenous reciprocal immunoprecipitation (IP) assays and pull-down assays. Ubiquitination of PARP10 by RNF114 was analysed by in vivo ubiquitination assays. Potential effects of ubiquitination on PARP10’s activity was detected by western blots and pull-down assays. Potential role of RNF114 in tumour metastasis were determined by migration and invasion assays and in vivo metastasis assay.
Results

That E3 ubiquitin ligase RNF114 is a partner of PARP10 was identified by IP assays. The auto-mono-ADP-ribosylation of PARP10 is required for the interaction of RNF114 and PARP10. RNF114 ubiquitinates PARP10 through K27-linked polyubiquitination, which enhances PARP10 enzymatic activity. Moreover, RNF114 deficiency promotes tumour cell migration and tumour metastasis through the regulation of PARP10 and its downstream signalling pathway.
Conclusions

Our findings identify RNF114 as a novel functional regulator of PARP10 and provide evidence of crosstalk between the components of K27-linked polyubiquitination and mono-ADP ribosylation.
Two Novel PDE11A Genetic Variants Increase Tau Phosphorylations in Early-onset Alzheimer's Disease
Authors: qin wei , Zhou Aihong , Zuo Xiumei , Jia Longfei , Wei Cuibai , Tang Yi , Wang Fen , Li Fangyu , Wang Qi , Li Ying , Wei Yiping , Zhao Lina , Jin Hongmei , cruchaga Carlos , Benitez Bruno A. , Jia jianping
Published: August 2020

Background: Alzheimer’s disease (AD) is a leading cause of dementia in the elderly and has become a major health issue. However, a large number of genetic risk factors remain undiscovered. Methods: To identify novel risk genes and better understand the molecular pathway underlying AD, whole-exome sequencing (WES) was performed in 215 early-onset AD (EOAD) patients and 55 unrelated healthy controls of Han Chinese ethnicity. Subsequent direct sequencing was performed in 4962 individuals to validate the selected rare mutations. Computational annotation and in vitro functional studies were performed to evaluate the role of candidate mutations in EOAD and the underlying mechanisms.Results: We identified two rare missense mutations in the phosphodiesterase 11A (PDE11A) gene, resulting in p.Arg202His, and p.Leu756Gln, in individuals with EOAD. Both mutations are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation, and classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at T181, S404, S202, S416, S214, S396 and AT8 epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cAMP levels, protein kinase A (PKA) activation, and cAMP response element-binding protein (CREB) phosphorylation. Additionally, pretreatment with a PKA inhibitor (H89) suppressed PDE11A mutation-induced p-Tau formation.Conclusions: Our results demonstrate that both PDE11A mutations and PDE11A knockdown increase Tau phosphorylation through the cAMP/PKA pathway, suggesting that PDE11A is a novel risk gene for AD. This study provides insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention.
Light-responsive self-assembly of semi-conducting nanoplatelets
Authors: ARIAS Yesica FLORES , PLAMONT Rémi , Huang He , Ryabchun Alexander , Katsonis Nathalie , fleury Benoit
Published: August 2020

CdSe nanoplatelets are a recently discovered class of colloidal semiconducting nanocrystals. Atomic control over their thickness allows achieving control over quantum size effects, and in particular, these platelets exhibit monochromatic light emission because of the confinement of photo-generated excitons only in their thickness. These nanoplatelets can self-organize into supra-particular polymers, depending on their environment, which means that their shape anisotropy can be expressed at the microscale. Here, the self-assembly of semiconducting nanoplatelets is controlled remotely by light, in a dynamic nanoparticulate system that integrates light-responsive molecular switches covalently. Azobenzene ligands were thus designed to (i) be grafted on the nanoplatelets (ii) ensure their colloidal stability in chloroform when confined on their surface in the E-configuration. Upon irradiation, the ligands isomerize into their Z-configuration, leading to a modification of the dipolar moment of the particles and to the formation of one-dimensional stacks. The self-assembly is reversible, as thermal relaxation of the ligands yields the initial dispersion back. This reversible hybrid system can be used in the design of responsive optical systems, as illustrated by photo-patterning experiments leading to controlled spatial resolution of the luminescence intensity in thin films.
Non-small lung cancer cells-derived exosome miR-3157-3p primes pre-metastatic niche by inducing angiogenesis and vascular permeability
Authors: Ma Zijian , Wei Ke , Yang Fengming , Guo Zizhang , Pan Chunfeng , He Yaozhou , Wang Jun , Li Zhihua , Chen Liang , Xia Yang , Chen Yijiang
Published: August 2020

Background: Cancer-derived exosomes are considered to be the main driving force for cancer-induced metastasis niche formation at foreign sites, but the mechanism is unclear.Methods: Identification of differentially expressed miRNAs in exosomes by miRNA sequencing. Through a series of in vitro and in vivo experiments, it was studied that the tumor-derived exosome miR-3157-3p can be taken up by the endothelium and exert biological functions. The molecular mechanism of miR-3157-3p was confirmed by Western blot, luciferase test and rescue experiment. Finally, real-time fluorescence quantitative PCR and RNA in situ hybridization were used to evaluate the clinical relevance of miR-3157-3p expression.Result: In metastatic NSCLC patients, the expression level of miR-3157-3p in circulating exosomes was significantly higher than that of non-metastatic NSCLC patients. Here, we found that miR-3157-3p can be transferred from NSCLC cells to vascular endothelial cells through exosomes. Exosome miR-3157-3p has regulated the expression of VEGF / MMP2 / MMP9 and occludin in endothelial cells by targeting TIMP / KLF2, thereby promoted angiogenesis and increased vascular permeability. In addition, exosome miR-3157-3p from NSCLC cells enhances NSCLC metastasis in mouse lungs.Conclusion: Our work indicates that exosome miR-3157-3p is involved in the formation of pre-metastatic niche and may be used as a blood-based biomarker for NSCLC metastasis.
NF-κB-Mediated lncRNA AC007271.3 as A ceRNA Promotes Carcinogenesis of Oral Squamous Cell Carcinoma by Regulating Slug
Authors: Zheng Ze-nan , Huang Guang-zhao , Wu Qing-qing , Ye Heng-yu , Zeng Wei-sen , Lv Xiao-zhi
Published: August 2020

Background: Oral squamous cell carcinoma (OSCC) is the most common oral cancer. Our previous studies confirmed that dysregulation function of long non-coding RNA (lncRNA) AC007271.3 was associated with a poor prognosis and overexpression of AC007271.3 promoted cell proliferation, migration, invasion and inhibited cell apoptosis in vitro, and promoted tumor growth in vivo. However, the underlying mechanisms of AC007271.3 dysregulation remained obscure.Methods: Bioinformatics databases were used to predicted the potential down-stream targeted of AC007271.3 and verified by dual luciferase reporter assay. Core promoter region of AC007271.3 was identified by luciferase activity assay and the potential transcription factor on it was verified by ChIP assay. Western blot and qRT-PCR were performed to detect the protein and messenger RNA (mRNA) levels, respectively. Animal experiments confirmed the metastatic ability in vivo.Results: AC007271.3 functioned as competing endogenous RNA (ceRNA) by binding to miR-125b-2-3p and upregulated the expression of Slug, which is a direct target of miR-125b-2-3p. AC007271.3 enhanced the expression of Slug and inhibited the expression of E-cadherin to promote the migration and invasion in OSCC cells. The expression of AC007271.3 was promoted by canonical nuclear factor-κB (NF-κB) pathway. Conclusion: Our study showed that the classical NF-κB pathway-activated AC007271.3 regulates EMT by miR-125b-2-3p / Slug / E-cadherin axis to promote the development of OSCC, implicating it as a novel potential target for therapeutic intervention in this disease.
Effect of the timing of stay-at-home orders on COVID-19 infections in the United States of America
Authors: Trivedi Megh , Das Anirudha
Published: August 2020

The current COVID-19 pandemic has sparked growing global interest in understanding the spread and outcome of the virus. From previous pandemics, we have learned that several demographic, geographic, and socio-economic factors may play a role in increasing risk of infection. Our objective was to examine the association of timing of mandated stay-at-home orders at the county-level with COVID-19 cases, daily case rate and mortality in the United States of America (USA). Publicly available data were used to perform a cross-sectional study of USA counties with > 100,000 population, and at least 50 confirmed cases per 100,000 people as of May 24, 2020. The three outcome variables were: total cases/100,000, daily case rate (DCR), and total deaths/100,000. Out of 3142 USA counties, 569 met the inclusion criteria. Of all variables, the timing of state-mandated stay-at-home order had the most significant effect on all three outcomes after adjusting for multiple socio-demographic, geographic and health related factors. Additional factors with significant association with increased cases and deaths include population density, housing problem, unemployment, African American race, and age > 65. Policymakers at the local level must take this into consideration while planning for interventions to prevent the spread of COVID-19.
Measuring PrEP Preferences Among At-Risk Military Populations: Results of an Adaptive Choice Based Conjoint Analysis Study
Authors: Gutierrez Jose I , Dubov Alex , Altice Frederick , Vlahov David
Published: August 2020

BACKGROUNDPre-exposure prophylaxis (PrEP) effectively prevents HIV infection, yet its uptake remains low among U.S. military men who have sex with men (MSM). Research shows that health services matching preferences produce favorable outcomes. Therefore, an early step for planning program design is to characterize and identify preferences for improved PrEP delivery within this population. METHODSHIV-negative military MSM were recruited through a closed, LGBT military social media group. Participants completed an anonymous survey presenting five experimentally varied attributes of interest related to PrEP administration (dosing method, provider type, visit location, lab work evaluation location, and dispensing venue). Relative importance and part-worth utility scores were generated using Hierarchical Bayes (HB) estimation, and the randomized first choice model was used to examine participation interest across eight possible PrEP program scenarios. RESULTSAmong the 429 participants and the eight scenarios that varied the five attributes into delivery profiles, the most preferred scenario (69.9%) featured a daily pill or long-term PrEP injection, military provider, smartphone/telehealth visit, lab evaluation on-base, and on-base medication pick-up. Responses indicated the need for providers to familiarize themselves with PrEP prescription knowledge and to provide interactions sensitive to sexual identity, mental health, and decision autonomy. CONCLUSIONThese results suggest that a military setting is preferred over a civilian or off-site one, yet more importantly, it points to a high value placed on the quality of clinical interactions. High interest in long-acting implants and injections also suggest potential markets for future PrEP engagement.
Identification of Tumor Mutation Burden and Immune Infiltrates in Hepatocellular Carcinoma Based on Multi-Omics Analysis
Authors: Yin Lu , Zhou Liuzhi , Xu Rujun
Published: August 2020

Background: We aimed to explore the tumor mutational burden (TMB) and immune infiltration in HCC and investigate new biomarkers for immunotherapy.Methods: Transcriptome and gene mutation data were downloaded from the GDC portal, including 374 HCC samples and 50 matched samples. Furthermore, we divided the samples into high and low TMB groups, and analyzed the differential genes between them with GO, KEGG, and GSEA. Cibersort was used to assess the immune cell infiltration in the samples. Finally, univariate and multivariate Cox regression analyses were performed to identify differential genes related to TMB and immune infiltration, and a risk prediction model was constructed.Results: We found 10 frequently mutated genes, including TP53, TTN, CTNNB1, MUC16, ALB, PCLO, MUC, APOB, RYR2, and ABCA. Pathway analysis indicated that these TMB-related differential genes were mainly enriched in PI3K-AKT. Cibersort analysis showed that memory B cells (P=0.02), CD8+ T cells (P=0.09), CD4+ memory activated T cells (P=0.07), and neutrophils (P=0.06) demonstrated a difference in immune infiltration between high and low TMB groups. On multivariate analysis, GABRA3 (P=0.05), CECR7 (P<0.001), TRIM16 (P=0.003), and IL7R (P=0.04) were associated with TMB and immune infiltration. The risk prediction model had an area under the curve (AUC) of 0.69, suggesting that patients with low risk had better survival outcomes.Conclusions: Our study demonstrated for the first time that CECR7, GABRA3, IL7R, and TRIM16L mutations were associated with TMB and promoted antitumor immunity in HCC.
Comparison of clinical data and computed tomography semiotics of the lungs in COVID-19
Authors: Petrikov S. S. , Popugaev K. А. , Barmina T. G. , Zabavskaya O. А. , Sharifullin F. А. , Kokov L. S.
Published: August 2020

The objective of the study: to compare the degree of lung damage according to chest CT data to the clinical state of COVID-19 patient, to analyze the semiotics and changes in CT data. Subjects and methods. 317 CT scans were retrospectively analyzed; those scans belonged to 98 patients with COVID-19 treated at N.V. Sklifosovsky Research Institute for Emergency Medicine. Patients were divided into 4 groups, depending on the degree of the lungs damage detected by CT during the primary examination, their clinical state was assessed at each subsequent CT scan. To determine the relationship between the degree of pulmonary changes and the clinical status of patients, a correlation analysis was performed using the rank correlation method, significance was assessed using the Student's coefficient. Results. It was found that CT allowed to identify changes in the lungs typical of COVID-19 and assess their degree, as well as to analyze progression or regression lung changes, including comparison with clinical data. A significant correlation was revealed (rs = 0.577) between the growing degree of lung damage, as determined by CT and deterioration of the clinical status of patients.
The impact of the infection caused by hepatitis B and C on the characteristics of hepatotoxic reactions in tuberculosis patients
Authors: Dantsev V. V. , Muchaidze R. D. , Levina L. R. , Spitsyn M. G. , Tokmakov V. S. , Balasanyants G. S.
Published: August 2020

The objective of the study: to identify the specific parameters of hepatotoxic reactions in tuberculosis patients depending on the presence of hepatitis B and C markers in the blood. Subjects and methods. The state of the hepatobiliary system was studied in 107 HIV-negative patients with newly diagnosed infiltrative pulmonary tuberculosis in the destructive phase. The main group included 52 people with positive results of the tests for markers of viral hepatitis B and C, the comparison group included 55 people with negative results. The groups were compatible in age, volume of the lung tissue lesions, and drug resistance profile. Results. Even before the start of anti-tuberculosis therapy, in the main group had elevated levels of cholinesterase and blood amylase, ultrasound examination detected hyperechoic liver parenchyma, enlarged right lobe of the liver, liver veins fibrosis, the enlarged diameter of the cystic duct and splenic vein, and splenomegaly (p <0.05), which was statistically significantly more frequent than in the comparison group. In the course of treatment, patients of both groups developed hepatotoxic reactions, however, in the main group they were more frequent versus the comparison group (88.4 and 21.8%, respectively, p <0.05), appeared earlier on average by 14 days and were accompanied by more pronounced clinical manifestations and abnormalities of biochemical parameters.
Epidemiology of extrapulmonary tuberculosis in high-burden regions
Authors: Kulchavenya E. V. , Merganov M. M. , Sharipov F. R.
Published: August 2020

The objective of the study: to assess the structure of extrapulmonary tuberculosis in two high-burden regions (Siberia, the Far East of the Russian Federation, and the Republic of Tajikistan), with the consideration of HIV status, gender, and age of patients. Subjects and methods. A simple cohort open retrospective study was carried out based on the analysis of statistical reports from TB control institutions of the Republic of Tajikistan, Siberian and Far Eastern Federal Districts of the Russian Federation for 2018. Results. In the Siberian Federal District and Far Eastern Federal District, among extrapulmonary forms of tuberculosis, the proportion of bone and joint tuberculosis made 43.6%, urinary tuberculosis – 21.3%, and tuberculosis of central nervous system ranked third and made 17%. In Tajikistan, bone and joint tuberculosis also prevailed and made 46.0%, followed by tuberculosis of peripheral lymph nodes. In Tajikistan, among extrapulmonary tuberculosis patients, HIV positive patients made only 3.5%, while in the Siberian and Far Eastern Federal Districts, they made 36.8%. However, in the Siberian and Far Eastern Federal Districts of the Russian Federation, among HIV positive patients with extrapulmonary tuberculosis, tuberculosis of the central nervous system (38.3%) prevailed, in the Republic of Tajikistan it was tuberculosis of peripheral lymph nodes (37.9%), followed by bone and joint tuberculosis (31.0%) and abdominal tuberculosis (17.2%). Urogenital tuberculosis was in the last place in the structure of extrapulmonary tuberculosis in HIV-positive patients.
Medication management of autonomic nervous system disorders in adolescents with tuberculosis
Authors: Shovkun L. А. , Klimenko N. Yu. , Аksenova V. А. , Kudlay D. А. , Nikolenko N. Yu. , Kampos E. D.
Published: August 2020

To manage autonomic disorders in adolescents with tuberculosis, 100 people from 12 to 15 years old were examined and randomly divided into two groups: Group 1 received standard anti-tuberculosis therapy, and in Group 2, additionally to standard therapy, comprehensive treatment with Magne B6was used for 2 months, and then Valerian extract was used for another 2 months. For comparison, 50 healthy adolescents were examined. Before treatment, all adolescents with tuberculosis experienced a decrease in heart rate variability, a pronounced autonomic imbalance with the prevalence of sympathicotonia and overexertion of compensatory mechanisms. In Group 1, during the comprehensive treatment there were an increase in SDNN and Mo and decrease in AMo and tension index at rest. Active orthostatic test (AOT) was accompanied by a significant increase in SDNN, Mo and a decrease in AMo, which indicated an increase in the activity of the parasympathetic autonomic nervous system and decreased activity of the sympathetic autonomic nervous system. In the group receiving standard therapy, hypersympathycotonia persisted and manifested through significant (p < 0.05) reduction in such parameters as SDNN, increased heart rate, AMo, and Mo shift to short intervals. Medication management resulted in the vegetative balance by increasing heart rate variability, reducing hypersympathicotonia, improving the autonomic support of the cardiovascular system at rest and during AOT.
The multivariate analysis of results of bedaquiline use in the therapy of MDR/XDR pulmonary tuberculosis
Authors: Stavitskaya N. V. , Felker I. G. , Zhukova E. M. , Tlif А. I. , Doktorova N. P. , Kudlay D. А.
Published: August 2020

The objective of the study:to perform the multivariate analysis of treatment outcomes in patients with multiple/extensive drug resistant tuberculosis (MDR/XDR TB), including those with HIV infection, whose chemotherapy regimens included bedaquiline.Subjects and methods:70 patients with MDR/XDR TB were enrolled in the retrospective two-center study, the multivariate analysis of treatment outcomes with bedaquiline-containing regimen was carried out.Results:the performed multivariate analysis demonstrated high efficacy and good tolerability of bedaquiline-containing regimens for MDR/XDR TB treatment even despite the continuous ineffective treatment of patients in the past. The prolonged intake of bedaquiline for more than 24 weeks was not associated with a high level of adverse reactions. It was found that the use of cycloserine/terizidone made a significant contribution to the favorable outcome of chemotherapy. The factors associated with the most unfavorable treatment outcomes were the following: age above 60 years, concurrent chronic obstructive pulmonary disease, alcohol and/or drug addiction, and smoking.
Coronaviruses as causative agents of severe respiratory diseases
Authors: Panova А. E. , Kulikova I. B. , Lagutkin D. А. , Vinokurov А. S. , Shulgina M. V. , Vasilyeva I. А.
Published: August 2020

The review presents 61 publications on the molecular mechanisms of pathogenicity, specific parameters of the infectious process and possibilities of laboratory diagnosis of coronaviruses, including SARS-CoV-2 - of the causative agent of COVID-19.
A clinical case of Kaposi sarcoma in a patient with TB/HIV co-infection
Authors: Kuzmina N. V. , Nelidova N. V.
Published: August 2020

The article describes a clinical case of Kaposi sarcoma in a patient with concurrent tuberculosis, HIV infection with severely compromised T-cell immunity, viral hepatitis B and C, and substances and alcohol abuse. Also, the patient had low adherence to treatment with anti-tuberculosis and antiretroviral drugs.
Development of a Multidimensional Computerized Adaptive Test based on the Bifactor Model
Authors: ŞAHİN Murat Doğan , GELBAL Selahattin
Published: August 2020

The purpose of this study was to conduct a real-time multidimensional computerized adaptive test (MCAT) using data from a previous paper-pencil test (PPT) regarding the grammar and vocabulary dimensions of an end-of-term proficiency exam conducted on students in a preparatory class at a university. An item pool was established through four separate 50-item sets applied in four different semesters. The fit between unidimensional, multi-unidimensional and bifactor IRT models was compared during item calibration, with the bifactor model providing the best fit for all data sets. This was followed by a hybrid simulation for 36 conditions obtained using six item selection methods, two ability estimation methods and three termination rules. The statistics and graphs obtained indicate D-rule item selection, maximum a posteriori (MAP) ability estimation and standard error termination rule as the best algorithm for the real-time MCAT application. With the minimum number of items to be administered determined as 10, the real-time application conducted on 99 examinees yielded an average number of items of 13.4. The PPT format proficiency exam consists of 50 items, leading to the conclusion that the examinees participating in the real-time MCAT are administered an average of 74.4% fewer items than the PPT. Additionally, 86 of the examinees answered between 10-13 items. The item pool use rate is 30%. Lastly, the correlation between the PPT scores and general trait scores of 32 examinees was calculated as .77.
Significance of metabotropic glutamate receptor antagonists in experimental neuropathic pain in animals
Authors: KANIA BOGDAN FELIKS , BRACHA URSZULA , LONC GRZEGORZ , WOJNAR TOMASZ
Published: August 2020

Neuropathic pain is a serious therapeutic problem. Current therapy is often ineffective, and the available drugs have serious side effects. For these reasons, the search for alternative therapeutic solutions is underway. Recent research on metabotropic receptors for glutamic acid (mGluR) gives great hope for the development of a new type of drug in the treatment of neuropathic pain. Particularly promising are antagonists of mGluR group I receptors. There are many studies demonstrating the efficacy of non-competitive mGlu1 and mGlu5 receptor antagonists in animal models of neuropathic pain. The purpose of this study was to gather information obtained from research on the role of mGluR antagonists in neuropathic pain. The blockade of intracellular glutamatergic receptor could represent a new strategy for the development of effective therapies for neuropathic pain.
Amfiprotik ve Dipolar Aprotik Çözücülerde 3-(4-Aril) Propiyonik Asit Türevlerinin Asitlik Kuvvetleri
Authors: OCAK Zafer
Published: August 2020

Beş adet 3-(4-aril) propiyonik asit türevinin asitlik özellikleri incelenmiştir. Bu çalışmada amfiprotik çözücülerden etanol, tert‐butanol ve su, dipolaraprotik çözücülerden N,N dimetilformamid (DMF), aseton kullanılmıştır. Bileşikler tetrabutilamonyum hidroksidin (TBAH) metanoldeki çözeltisi ile titre edilmiş ve titrasyonlarda dönüm noktasının belirlenmesinde potansiyometrik metod, asitliğin belirlenmesinde yarı nötralizasyon metodu kullanılmıştır. Titrasyon eğrilerinin beklendiği gibi S şeklinde olduğu belirlenmiştir. Çizelge ve grafikler kullanılarak propiyonik asit türevlerinin amfiprotik ve dipolar aprotik çözücülerdeki asitlik kuvvetleri hesaplanmıştır. Çözücülerde elde edilen pKa değerlerinin farklandırıldığı görülmüştür. Bileşiklerin asitlik kuvvetlerine çözücü, moleküler yapı, otoprotoliz sabiti, dielektrik sabiti ve çözücünün seviyeleme-farklandırma etkileri tartışılmıştır.