bluuebunny/crossref_metadata_2025 huggingface dataset:
Contribution of sensory memory to speech motor learning
Authors: Ito Takayuki , Bai Jiachuan , Ostry David J.
Published: September 2020

In speech production, almost everyone achieves an exceptionally high level of proficiency. This is remarkable because speech involves some of the smallest and most carefully timed movements of which we are capable. The present paper demonstrates that sensory memory contributes to speech motor learning. Moreover, we report the surprising result that somatic sensory memory predicts speech motor learning, whereas auditory memory does not.
Cardiolipin, Perhydroxyl Radicals, and Lipid Peroxidation in Mitochondrial Dysfunctions and Aging
Authors: Panov Alexander V. , Dikalov Sergey I.
Published: September 2020

Mitochondrial dysfunctions caused by oxidative stress are currently regarded as the main cause of aging. Accumulation of mutations and deletions of mtDNA is a hallmark of aging. So far, however, there is no evidence that most studied oxygen radicals are directly responsible for mutations of mtDNA. Oxidative damages to cardiolipin (CL) and phosphatidylethanolamine (PEA) are also hallmarks of oxidative stress, but the mechanisms of their damage remain obscure. CL is the only phospholipid present almost exclusively in the inner mitochondrial membrane (IMM) where it is responsible, together with PEA, for the maintenance of the superstructures of oxidative phosphorylation enzymes. CL has negative charges at the headgroups and due to specific localization at the negative curves of the IMM, it creates areas with the strong negative charge where local pH may be several units lower than in the surrounding bulk phases. At these sites with the higher acidity, the chance of protonation of the superoxide radical (O2•), generated by the respiratory chain, is much higher with the formation of the highly reactive hydrophobic perhydroxyl radical (HO2•). HO2•specifically reacts with the double bonds of polyunsaturated fatty acids (PUFA) initiating the isoprostane pathway of lipid peroxidation. Because HO2•is formed close to CL aggregates and PEA, it causes peroxidation of the linoleic acid in CL and also damages PEA. This causes disruption of the structural and functional integrity of the respirosomes and ATP synthase. We provide evidence that in elderly individuals with metabolic syndrome (MetS), fatty acids become the major substrates for production of ATP and this may increase several-fold generation of O2•and thus HO2•. We conclude that MetS accelerates aging and the mitochondrial dysfunctions are caused by the HO2•-induced direct oxidation of CL and the isoprostane pathway of lipid peroxidation (IPLP). The toxic products of IPLP damage not only PEA, but also mtDNA and OXPHOS proteins. This results in gradual disruption of the structural and functional integrity of mitochondria and cells.
Interactions between Gut Microbiota and Immunomodulatory Cells in Rheumatoid Arthritis
Authors: Xu Huihui , Zhao Hongyan , Fan Danping , Liu Meijie , Cao Jinfeng , Xia Ya , Ju Dahong , Xiao Cheng , Guan Qingdong
Published: September 2020

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases caused by abnormal immune activation and immune tolerance. Immunomodulatory cells (ICs) play a critical role in the maintenance and homeostasis of normal immune function and in the pathogenesis of RA. The human gastrointestinal tract is inhabited by trillions of commensal microbiota on the mucosal surface that play a fundamental role in the induction, maintenance, and function of the host immune system. Gut microbiota dysbiosis can impact both the local and systemic immune systems and further contribute to various diseases, such as RA. The neighbouring intestinal ICs located in distinct intestinal mucosa may be the most likely intermediary by which the gut microbiota can affect the occurrence and development of RA. However, the reciprocal interaction between the components of the gut microbiota and their microbial metabolites with distinct ICs and how this interaction may impact the development of RA are not well studied. Therefore, a better understanding of the gut microbiota, ICs, and their interactions might improve our knowledge of the mechanisms by which the gut microbiota contribute to RA and facilitate the further development of novel therapeutic approaches. In this review, we have summarized the roles of the gut microbiota in the immunopathogenesis of RA, especially the interactions between the gut microbiota and ICs, and further discussed the strategies for treating RA by targeting/regulating the gut microbiota.
Some Characterizations and Properties of a New Partial Order
Authors: Liu Xiaoji , Gui Fang
Published: September 2020

On the basis of Löwner partial order and core partial order, we introduce a new partial order: LC partial order. By applying matrix decomposition, core inverse, core partial order, and Löwner partial order, we give some characteristics of LC partial order, study the relationship between LC partial order and Löwner partial order under constraint conditions, and illustrate its differences with some classical partial orders, such as minus, CL, and GL partial orders.
Coordination Mechanism of Supply Chain considering the Bullwhip Effect under Digital Technologies
Authors: Ran Wenxue , Wang Yan , Yang Lifan , Liu Sen
Published: September 2020

The bullwhip effect (BWE) and stochastic demand coexist in supply chain operation management, which leads to a lower performance. In recent years, with the development of blockchain, cloud computing, big data, and other digital technologies (DTs), many enterprises hope to use them to weaken the BWE and improve profits. This paper focuses on improving the application level of DTs in the supply chain through coordination for enhancing the performance. We consider a supply chain with one-supplier-one-retailer and coordinate it with the cost-sharing contract and revenue-cost-sharing contract (the improved contract). We find out that the retailer and supplier did not always have the willingness to use DTs to alleviate the BWE. Even if they have the intention to use DTs, their ideal application level is not the same. After coordination, both the application level of DTs and the performance of the supply chain are improved, and we find that the improved contract has a better coordination effect. Finally, we validate our model by numerical simulation.
Finite-Time Stability Criteria for a Class of High-Order Fractional Cohen–Grossberg Neural Networks with Delay
Authors: Yang Zhanying , Zhang Jie , Hu Junhao , Mei Jun
Published: September 2020

This paper focuses on a class of delayed fractional Cohen–Grossberg neural networks with the fractional order between 1 and 2. Two kinds of criteria are developed to guarantee the finite-time stability of networks based on some analytical techniques. This method is different from those in some earlier works. Moreover, the obtained criteria are expressed as some algebraic inequalities independent of the Mittag–Leffler functions, and thus, the calculation is relatively simple in both theoretical analysis and practical applications. Finally, the feasibility and validity of obtained results are supported by the analysis of numerical simulations.
Hall and Ion Slip Effects on Mixed Convection Flow of Eyring-Powell Nanofluid over a Stretching Surface
Authors: Ibrahim Wubshet , Anbessa Temesgen
Published: September 2020

The purpose of this research is to inspect the mixed convection flow of Eyring-Powell nanofluid over a linearly stretching sheet through a porous medium with Cattaneo–Christov heat and mass flux model in the presence of Hall and ion slip, permeability, and Joule heating effects. Proper similarity transforms yield coupled nonlinear differential systems, which are solved using the spectral relaxation method (SRM). The story audits show that the present research problem has not been studied until this point. Efficiency of numerous parameters on velocity, temperature, and concentration curves is exposed graphically. Likewise, the numerical values of skin friction coefficients, local Nusselt, and Sherwood numbers are computed and tabulated for some physical parameters. It is manifested that fluid velocities, skin friction coefficients, local Nusselt, and Sherwood numbers promote with the larger values of Eyring-Powell fluid parameter ε. It is also noticed that primary velocity promotes with larger values of mixed convection parameter λ, Hall parameter βe, and ion slip parameter βi, while the opposite condition is observed for secondary velocity, temperature, and concentration. Furthermore, comparative surveys between the previously distributed writing and the current information are made for explicit cases, which are examined to be in a marvelous understanding.
Dynamical Analyses on Beta Oscillations in a STN-GPE-GPI Model of Parkinson’s Disease
Authors: Bi Yuanhong , Liu Quansheng , Zhao Jingyi , Yang Wuritu
Published: September 2020

Exploring the behaviors of beta oscillations in the basal ganglia is helpful to understand the mechanism of Parkinson’s disease. Studies have shown that the external and internal segments (GPe, GPi) of the globus pallidus receive different intensities of signals from the striatum in Parkinson’s disease and play different roles in the production of beta oscillations, but the relevant mechanism still remains unclear. Based on a model of the subthalamic nucleus (STN) and globus pallidus (GP), we propose an extended STN-GPe-GPi model and analyze the dynamical behaviors of beta oscillations in this model. The stability condition is obtained through theoretical analyses, and the generation of beta oscillations by the inputs from the cortex and striatum is further considered. The influence of some parameters related to GPi on its firing rate oscillations is discussed. The results obtained in this paper are expected to play a guiding role in the medical treatment of Parkinson’s disease.
Global Existence and Decay for a System of Two Singular Nonlinear Viscoelastic Equations with General Source and Localized Frictional Damping Terms
Authors: Boulaaras Salah Mahmoud , Guefaifia Rafik , Mezouar Nadia , Alghamdi Ahmad Mohammed
Published: September 2020

The current paper deals with the proof of a global solution of a viscoelasticity singular one-dimensional system with localized frictional damping and general source terms, taking into consideration nonlocal boundary condition. Moreover, similar to that in Boulaaras’ recent studies by constructing a Lyapunov functional and use it together with the perturbed energy method in order to prove a general decay result.
The Potential of Food Protein-Derived Bioactive Peptides against Chronic Intestinal Inflammation
Authors: Zhu Wanying , Ren Liying , Zhang Li , Qiao Qinqin , Farooq Muhammad Zahid , Xu Qingbiao
Published: September 2020

Inflammation can cause various chronic diseases like inflammatory bowel diseases. Various food protein-derived bioactive peptides (BAPs) with anti-inflammatory activity have the potential to manage these diseases. The aim of this paper is to overview the mechanisms and the molecular targets of BAPs to exert anti-inflammatory activity. In this review, the in vitro and in vivo effects of BAPs on intestinal inflammation are highlighted. The mechanism, pathways, and future perspectives of BAPs as the potential sources of therapeutic treatments to alleviate intestinal inflammation are provided, including nuclear factor-κB, mitogen-activated protein kinase, Janus kinase-signal transducer and activator of transcription, and peptide transporter 1 (PepT1), finding that PepT1 and gut microbiota are the promising targets for BAPs to alleviate the intestinal inflammation. This review provides a comprehensive understanding of the role of dietary BAPs in attenuating inflammation and gives a novel direction in nutraceuticals for people or animals with intestinal inflammation.
The Effect of Smoking on COVID-19 Symptom Severity: Systematic Review and Meta-Analysis
Authors: Gülsen Askin , Yigitbas Burcu Arpinar , Uslu Berat , Drömann Daniel , Kilinc Oguz
Published: September 2020

Background. Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SAR2-COV-2) and was first identified in Wuhan, China, in December of 2019, but quickly spread to the rest of the world, causing a pandemic. While some studies have found no link between smoking status and severe COVID-19, others demonstrated a significant one. The present study aimed to determine the relationship between smoking and clinical COVID-19 severity via a systematic meta-analysis approach. Methods. We searched the Google Scholar, PubMed, Scopus, Web of Science, and Embase databases to identify clinical studies suitable for inclusion in this meta-analysis. Studies reporting smoking status and comparing nonsevere and severe patients were included. Nonsevere cases were described as mild, common type, nonintensive care unit (ICU) treatment, survivors, and severe cases as critical, need for ICU, refractory, and nonsurvivors. Results. A total of 16 articles detailing 11322 COVID-19 patients were included. Our meta-analysis revealed a relationship between a history of smoking and severe COVID-19 cases (OR=2.17; 95% CI: 1.37–3.46; P<.001). Additionally, we found an association between the current smoking status and severe COVID-19 (OR=1.51; 95% CI: 1.12–2.05; P<.008). In 10.7% (978/9067) of nonsmokers, COVID-19 was severe, while in active smokers, severe COVID-19 occurred in 21.2% (65/305) of cases. Conclusion. Active smoking and a history of smoking are clearly associated with severe COVID-19. The SARS-COV-2 epidemic should serve as an impetus for patients and those at risk to maintain good health practices and discontinue smoking. The trial is registered with the International Prospective Register of Systematic Reviews (PROSPERO) CRD42020180173.
Assessing the Performance of Extended Half-Life Coagulation Factor VIII, FC Fusion Protein by Using Chromogenic and One-Stage Assays in Saudi Hemophilia A Patients
Authors: Owaidah Tarek M. , Alzahrani Hazzaa A. , Al-Numair Nouf S. , Alnosair Abdulmjeed O. , Aguilos Amelita M. , Saleh Mahasen
Published: September 2020

Background. The one-stage assay is the most common method to measure factor VIII activity (FVIII : C) in hemophilia A patients. The chromogenic assay is another two-stage test involving purified coagulation factors followed by factor Xa-specific chromogenic substrate. Aim. This study aimed to assess the discrepancy and correlation between the chromogenic and one-stage assays in measuring FVIII : C levels in hemophilia patients receiving Extended Half-Life Elocta® as a recombinant extended half-life coagulation factor. Methods. We performed a study comparing the measurements of FVIII : C levels by the chromogenic versus the one-stage assays at different drug levels. Data of FVIII : C levels, dosage, and the time interval from administration to measurement were retrieved from the hospital records. The correlation, mean differences, and discrepancy between the two assays were calculated. The linear regression analysis was used to predict the time interval till reaching 1% FVIII : C. Results. Fourteen patients with 56 samples were included in the study. Of them, 13 patients were receiving Elocta® as a prophylactic, while one was receiving Elocta® on demand. One-third of these samples showed a discrepancy between the chromogenic and one-stage assays. The two assays were well correlated. Mean differences were significant at the individual and the time interval level. The time since the last Elocta® injection could significantly predict FVIII : C levels (β = 0.366, P<0.001). Conclusion. Our findings suggested a significant difference between both methods; the FVIII : C levels measured by the one-stage assay were less than those estimated by the chromogenic assay. However, the measurements of FVIII levels by the two assays were well correlated but discrepant in one-third of the samples. The levels of FVIII : C reach 1% after 5.4 days since the last Elocta® administration.
Disulfiram-Induced Acute Liver Injury
Authors: Ramer Lucas , Tihy Matthieu , Goossens Nicolas , Frossard Jean-Louis , Rubbia-Brandt Laura , Spahr Laurent
Published: September 2020

Disulfiram is a drug used to treat alcohol dependence since many years. It interferes with the metabolism of alcohol, may be associated with neurological and dermatological symptoms, and can be hepatotoxic. Due to the frequent coexistent liver test alterations due to alcohol, the true incidence of disulfiram-associated liver injury is unclear and severity of injury may vary from mildly elevated liver enzymes to fulminant hepatitis leading to death. There are several reported cases of disulfiram hepatitis in the literature. Liver histology, when available, demonstrates some degree of portal inflammation with eosinophils and hepatocyte necrosis. We present here a well-documented case of acute hepatitis due to disulfiram with typical histological lesions, favorable outcome following drug withdrawal, and a brief steroid course. The risk of hepatotoxicity should be kept in mind when prescribing disulfiram.
Palatal Soft Tissue Thickness on Maxillary Posterior Teeth and Its Relation to Palatal Vault Angle Measured by Cone-Beam Computed Tomography
Authors: Hormdee Doosadee , Yamsuk Thanwarat , Sutthiprapaporn Pipop
Published: September 2020

Objective. Analyzing palatal soft tissue thickness in cone-beam computed tomography (CBCT) images and evaluating the relationship between tissue thickness and palatal vault angulation. Methods. Out of 1,737 CBCT images, fifty-six images met the inclusion criteria and were included in this cross-sectional study. The palatal vault angle on the maxillary first molar was measured and divided the images into 3 groups. The soft tissue thickness between the maxillary first premolar and second molar was measured at a distance of 3, 6, 7, 8, and 9 mm from the cementoenamel junction. All the image measurements were performed using CBCT-viewer software. Result. In this study, 56 CBCT images with full permanent maxillary posterior teeth and absence of light scattering were found. The mean age of the patients was 31.59 ± 13.92 years. The moderate and deep palatal vault angle patterns had the greatest and least prevalence, respectively. The average thickness on shallow, moderate, and deep palatal vault groups was 4.02 ± 0.58, 3.75 ± 0.73, and 3.43 ± 0.38 mm, respectively. Furthermore, the mean palatal mucosal thickness was statistically different between the deep and shallow palatal vault angle groups (p<0.05, power of test 0.8). Based on the Pearson correlation coefficient, there was a negative correlation between the palatal mucosal thickness and palatal vault angle (p<0.05, power of test 0.85). Conclusion. A negative correlation between the palatal mucosal thickness and palatal vault angle was observed. Furthermore, this study suggested that the shape of the palatal vault can be one of the supporting data for evaluating the graft dimensions.
Clinical Characteristics and Management of the Hydatid Cyst of the Liver: A Study from a Tertiary Care Center in Nepal
Authors: Joshi Utsav , Subedi Roshan , Jayswal Amar , Agrawal Vishakha
Published: September 2020

A hydatid cyst of the liver is a significant yet neglected public health problem in Nepal. The present study was carried out to evaluate the demographic characteristics, clinical presentations, and management of the patients of the hydatid cyst of the liver in the setting of a developing country. It was a retrospective, descriptive analysis of 53 patients admitted in the department of surgery with the diagnosis of hydatid cyst of the liver based on clinical manifestations, imaging studies, or serology between 2016 and 2019. The median age of the patients was 36 years, with the age group of 25-45 years being the most commonly affected (23, 43.4%). 58.5% of the patients were female. Abdominal pain (49, 92.5%) and a palpable liver (17, 32.1%) were the most common complaint and physical finding in our study population, respectively. Abdominal ultrasonography and computed tomography scan were the major imaging studies used to establish a diagnosis. A unilocular and anechoic cystic lesion was the most frequent imaging finding. The right lobe of the liver harbored the cysts in the maximum number of patients. Surgery was the preferred modality of treatment (23, 43.4%), with pericystectomy being the most common form of surgical intervention. The hydatid cyst of the liver is a common cause of morbidity in Nepal. Clinical evaluation supplemented by imaging studies is required for diagnosis, and surgery remains the treatment of choice in most cases. To explain the epidemiological pattern of the disease, multicentric studies involving a larger sample of patients should be conducted.
A Comprehensive Model for Estimating Stimulated Reservoir Volume Based on Flowback Data in Shale Gas Reservoirs
Authors: Chen Qi , Wang Shaojun , Zhu Dan , Ren Guoxuan , Zhang Yuan , Hu Jinghong
Published: September 2020

Stimulated reservoir volume (SRV) which is generated by horizontal drilling with multistage hydraulic fracturing governs the production in the shale gas reservoirs. Although microseismic data has been used to estimate the SRV, it is high-priced and sometimes overestimated. Additionally, the effect of stress sensitivity on SRV is not considered in abnormal overpressure areas. Thus, the objective of this work is to characterize subsurface fracture networks with stress sensitivity of permeability through the shale gas well production data of the early flowback stage. The flowback regions are first identified with the flowback data of two shale gas wells in South China. Then, we measured the permeability stress sensitivity of the core after fracturing, coupled to the dynamic relative permeability (DRP) calculation to obtain an accurate and simple DRP curve. After that, a comprehensive model is built considering dynamic two-phase relative permeability function and stress sensitivity. Finally, we compared the calculated results with the microseismic data. The results show that the proposed model could reasonably predict the SRV using the flowback data after fracturing. Additionally, compared with the microseismic data, the stress sensitivity should be included, especially in the abnormal overpressure block. It is believed that this mathematical model is accurate and useful. The work provides an efficient approach to estimate stimulated reservoir volume in the shale gas reservoirs.
Extract of Pogostemon cablin Possesses Potent Anticancer Activity against Colorectal Cancer Cells In Vitro and In Vivo
Authors: Chien Ju-Huei , Lee Shan-Chih , Chang Kai-Fu , Huang Xiao-Fan , Chen Yi-Ting , Tsai Nu-Man
Published: September 2020

Pogostemon cablin (PCa), an herb used in traditional Chinese medicine, is routinely used in the amelioration of different types of gastrointestinal discomfort. However, the mechanisms underlying the cancer suppression activity of PCa in colorectal cancer (CRC) cells have yet to be clarified. The aim of this study was to investigate the anticancer effects of PCa, specifically the induction of apoptosis in CRC cells. The growth inhibition curve of CRC cells following exposure to PCa was detected by an MTT assay. Moreover, PCa combined with 5‐FU revealed a synergic effect of decreased cell viability. PCa inhibited cell proliferation and induced cell cycle arrest at the G0/G1 phase and cell apoptosis through regulation of associated protein expression. An in vivo study showed that PCa suppressed the growth of CRC via induction of cell apoptosis with no significant change in body weight or organ histology. Our results demonstrated that PCa inhibits the growth of CRC cells and induces apoptosis in vitro and in vivo, which suggests the potential applicability of PCa as an anticancer agent.
IPEX Syndrome with Normal FOXP3 Protein Expression in Treg Cells in an Infant Presenting with Intractable Diarrhea as a Single Symptom
Authors: Al Maawali Ali , Derfalvi Beata , Van Limbergen Johan , Issekutz Andrew , Issekutz Thomas , Ghandourah Hasan , Rashid Mohsin
Published: September 2020

IPEX (immune dysregulation-polyendocrinopathy-enteropathy-X-linked) syndrome is a rare, potentially fatal multisystem disorder caused by mutations in the FOXP3 gene. This can lead to quantitative or functional deficiency of regulatory T cells (Treg), thereby affecting their immune-suppressive actions which can in turn cause autoimmune and inflammatory disorders. We describe an infant with IPEX syndrome with unremarkable maternal family history whose only presentations were severe diarrhea and malnutrition. The patient had a normal percentage of Treg cells and FOXP3 protein expression, but further testing revealed a hemizygous missense mutation in the FOXP3 gene. IPEX syndrome should be considered in young children even if severe intractable diarrhea is the only symptom with no other autoimmune manifestations. Sequencing of the FOXP3 gene should always be considered for accurate diagnosis to look for mutations even in the face of normal FOXP3 protein expression in the Treg cell.
A Deep Learning Framework Identifies Pathogenic Noncoding Somatic Mutations from Personal Prostate Cancer Genomes
Authors: Wang Cheng , Li Jingjing
Published: September 2020

Our understanding of noncoding mutations in cancer genomes has been derived primarily from mutational recurrence analysis by aggregating clinical samples on a large scale. These cohort-based approaches cannot directly identify individual pathogenic noncoding mutations from personal cancer genomes. Therefore, although most somatic mutations are localized in the noncoding cancer genome, their effects on driving tumorigenesis and progression have not been systematically explored and noncoding somatic alleles have not been leveraged in current clinical practice to guide personalized screening, diagnosis, and treatment. Here, we present a deep learning framework to capture pathogenic noncoding mutations in personal cancer genomes, which perturb gene regulation by altering chromatin architecture. We deployed the system specifically for localized prostate cancer by integrating large-scale prostate cancer genomes and the prostate-specific epigenome. We exhaustively evaluated somatic mutations in each patient's genome and agnostically identified thousands of somatic alleles altering the prostate epigenome. Functional genomic analyses subsequently demonstrated that affected genes displayed differential expression in prostate tumor samples, were vulnerable to expression alterations, and were convergent onto androgen receptor–mediated signaling pathways. Accumulation of pathogenic regulatory mutations in these affected genes was predictive of clinical observations, suggesting potential clinical utility of this approach. Overall, the deep learning framework has significantly expanded our view of somatic mutations in the vast noncoding genome, uncovered novel genes in localized prostate cancer, and will foster the development of personalized screening and therapeutic strategies for prostate cancer.

Significance:

This study's characterization of the noncoding genome in prostate cancer reveals mutational signatures predictive of clinical observations, which may serve as a powerful prognostic tool in this disease.
Uncovering the Potential Differentially Expressed miRNAs and mRNAs in Ischemic Stroke Based on Integrated Analysis in the Gene Expression Omnibus Database
Authors: Zhu Xiaotun , Liu Xiao , Liu Ying , Chang Wansheng , Song Yanfeng , Zhu Shulai
Published: September 2020

Introduction: Ischemic stroke is the third leading cause of death. There is no known treatment or cure for the disease. Moreover, the pathological mechanism of ischemic stroke remains unclear. Objective: We aimed to identify potential microRNAs (miRNAs) and mRNAs, contributing to understanding the pathology of ischemic stroke. Methods: First, the data of miRNA and mRNA were downloaded for differential expression analysis. Then, the regulatory network between miRNA and mRNAs was constructed. Third, top 100 differentially expressed mRNAs were used to construct a protein-protein interaction network followed by the function annotation of mRNAs. In addition, in vitro experiment was used to validate the expression of mRNAs. Last, receiver operating characteristic diagnostic analysis of differentially methylated genes was performed. Results: Totally, up to 26 differentially expressed miRNAs and 1,345 differentially expressed mRNAs were identified. Several regulatory interaction pairs between miRNA and mRNAs were identified, such as hsa-miR-206-HMGCR/PICALM, hsa-miR-4491-TMEM97, hsa-miR-3622b-5p/hsa-miR-548k-KLF12, and hsa-miR-302a-3p/hsa-miR-3145-3p-CTSS. MAPK signaling pathway (involved DUSP1) and the Notch signaling pathway (involved NUMB and CREBBP) were identified. The expression validation of KLF12, ARG1, ITGAM, SIRT4, SERPINH1, and DUSP1 was consistent with the bioinformatics analysis. Interestingly, hsa-miR-206, hsa-miR-4491, hsa-miR-3622b-5p, hsa-miR-548k, hsa-miR-302a-3p, hsa-miR-3145-3p, KLF12, and ID3 had the potential diagnostic value of ischemic stroke. Conclusions: The identified differentially expressed miRNAs and mRNAs may be associated with the development of ischemic stroke.
Minimizing Individual Learning Curves in a Mature Endoscopic Fetal Surgery Program
Authors: Akuchie Chinonso , Renaud Elizabeth J. , Watson-Smith Debra , Carr Stephen R. , Luks Francois I.
Published: September 2020

Introduction: Twin-to-twin transfusion syndrome affects monochorionic twin pregnancies and can result in fetal death. Endoscopic laser treatment remains a relatively infrequent procedure for this condition. This presents difficulties for maintaining proficiency and for training new personnel. Objective: The dual mentoring program at our institution allows for continuous mentoring of new providers. We hypothesize that this approach stabilizes program proficiency despite the addition of new practitioners. Methods: Query of the fetal treatment program database returned 146 cases of laser ablation between 2000 and 2019. Patient and pregnancy characteristics as well as operative time and outcomes were recorded. The learning curve-cumulative summation method and rolling averages were used to analyze outcomes. Results: Overall survival was 69%, and survival of at least 1 twin was 89%. Mean operative time was 53.6 ± 20.9 min. Overall twin survival stabilized after the first 40 cases. Rolling averages for operative time decreased from 71 to 49 min for the most recent cases. These results were not affected by the introduction of new surgeons. Conclusions: Creative mentoring can maintain stable overall program outcomes despite changes in team composition. This training approach may be applicable to other rare procedures in fetal surgery.
The Role of miR-210 in the Biological System: A Current Overview
Authors: Hui Xu , Al-Ward Hisham , Shaher Fahmi , Liu Chun-Yang , Liu Ning
Published: September 2020

Background: MicroRNAs (miRNAs) represent a group of non-coding RNAs measuring 19–23 nucleotides in length and are recognized as powerful molecules that regulate gene expression in eukaryotic cells. miRNAs stimulate the post-transcriptional regulation of gene expression via direct or indirect mechanisms. Summary: miR-210 is highly upregulated in cells under hypoxia, thereby revealing its significance to cell endurance. Induction of this mRNA expression is an important feature of the cellular low-oxygen response and the most consistent and vigorous target of HIF. Key Message: miR-210 is involved in many cellular functions under the effect of HIF-1α, including the cell cycle, DNA repair, immunity and inflammation, angiogenesis, metabolism, and macrophage regulation. It also plays an important regulatory role in T-cell differentiation and stimulation.
Comparison of the Icare ic100 Rebound Tonometer and the Goldmann Applanation Tonometer in 1,000 Eyes
Authors: Subramaniam Arjun Gopal , Allen Penelope , Toh Tze’Yo
Published: September 2020

Background: Measurement of intraocular pressure (IOP) forms a crucial component in the diagnosis and management of glaucoma. Many devices have been developed to measure IOP with Goldmann applanation tonometry (GAT) considered the gold standard for IOP measurement. Objectives: The objective was to compare the IOP measured using Icare ic100 and GAT. Methods: This cross-sectional study measured IOP in 1,000 eyes (500 left and 500 right) using the Icare ic100 and GAT. Central corneal thickness (CCT) was measured using a hand-held pachymeter. IOP measurements were investigated in all eyes, by IOP substrata, by CCT group, by number of topical glaucoma medications, and diagnosis. Results: There was moderate agreement between ic100 and GAT IOP measurements (intraclass correlation coefficient 0.73). Mean IOP was significantly lower when measured by ic100 than by GAT (12.1 vs. 16.2 mm Hg, p < 0.0001). Mean ic100 IOPs were also significantly lower than mean GAT IOPs within each IOP strata ≤12 (7.9 vs. 9.7 mm Hg, p < 0.0001), 13–21 (12.1 vs. 16.6 mm Hg, p < 0.0001), and ≥22 (18.4 vs. 25.2 mm Hg, p < 0.0001) and within each subanalysis. Conclusions: The Icare tonometer consistently under estimated IOP compared to GAT, irrespective of CCT ranges and other subgroup analyses. The mean difference of 4.2 mm Hg can have significant clinical implications, particularly in the management of glaucoma patients.
Cardiac Computed Tomography for Personalized Management of Patients With Type 2 Diabetes Mellitus
Authors: Cardoso Rhanderson , Dudum Ramzi , Ferraro Richard A. , Bittencourt Marcio , Blankstein Ron , Blaha Michael J. , Nasir Khurram , Rajagopalan Sanjay , Michos Erin D. , Blumenthal Roger S. , Cainzos-Achirica Miguel
Published: September 2020

The incidence and prevalence of type 2 diabetes mellitus are increasing in the United States and worldwide. The individual-level risk of atherosclerotic cardiovascular disease events in primary prevention populations with type 2 diabetes mellitus is highly heterogeneous. Accurate risk stratification in this group is paramount to optimize the use of preventive therapies. Herein, we review the use of the coronary artery calcium score as a decision aid in individuals with type 2 diabetes mellitus without clinical atherosclerotic cardiovascular disease to guide the use of preventive pharmacotherapies, such as aspirin, lipid-lowering mediations, and cardiometabolic agents. The magnitude of expected risk reduction for each of these therapies must be weighed against its cost and potential adverse events. Coronary artery calcium has the potential to improve risk stratification in select individuals beyond clinical and laboratory risk factors, thus providing a more granular assessment of the expected net benefit with each therapy. In patients with diabetes mellitus and stable chest pain, coronary computed tomography angiography increases the sensitivity for coronary artery disease diagnoses compared with functional studies because of the detection of nonobstructive atherosclerosis. Most importantly, this anatomic approach may improve cardiovascular outcomes by increasing the use of evidence-based preventive therapies informed by plaque burden. We therefore provide an updated discussion of the pivotal role of coronary computed tomography angiography in the workup of stable chest pain in patients with diabetes mellitus in the context of recent landmark trials, such as PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), SCOT-HEART trial (Scottish Computed Tomography of the Heart), and ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches). Finally, we also outline the current role of coronary computed tomography angiography in acute chest pain presentations.
Abstract 1: Male Sprague Dawley Rats Exposed To Perinatal Hypoxia Are More Susceptible To Angiotensin II-induced Hypertension In Adulthood Vs Females
Authors: Ramirez Lindsey A , Marin Terri , Snyder Elizabeth , Brands Michael W , Sullivan Jennifer C
Published: September 2020

Preterm infants (born prior to 37 weeks (wks) gestation) are susceptible to hypoxia, which predisposes to hypertension in later life. Underdeveloped organs, including the kidney, prevent preterm infants from effectively regulating blood volume and O
2
delivery. Since rat nephrogenesis completes ~ postnatal day (PND) 8, we hypothesized that exposure to hypoxia before nephrogenesis is complete will promote hypertension in adulthood. Male and female Sprague Dawley pups were randomized to Ctrl (room air) or intermittent hypoxia (IH) at PND 1 (n=6/group). IH pups were exposed to ~10% O
2
three times a day, 10 minutes/session, from PND 1-8. O
2
saturation was measured at PND 6. Mean arterial pressure (MAP) was measured via telemetry from ~14 – 16 wks of age. To determine the MAP response to a cardiovascular challenge, osmotic minipumps containing angiotensin (Ang) II (400 ng/kg/min) were implanted at 15 wks of age. IH pups had lower O
2
saturation vs ctrl (P
O2
<0.05). Light cycle (LC) and dark cycle (DC) MAP were similar in all groups at baseline. Following treatment, LC-MAP was higher in IH-M vs Ctrl-M, but similar among female groups (P
Int
.
= 0.04). IH animals had higher DC-MAP vs ctrl (P
O2
= 0.02). IH decreased blood oxygen, suggesting a global decrease in oxygen delivery to organs, similar to what is seen with hypoxia. Perinatal IH alone did not increase MAP. However, this exposure did increase MAP in response to Ang II. While both males and females exposed to perinatal hypoxia had higher Ang II-induced hypertension vs ctrls in the dark cycle, this effect was preserved only in males in the light cycle. This suggests males are more susceptible to blood pressure effects of perinatal IH.
Abstract 11: Role Of Pro-saas Peptides In Salt Resistance
Authors: Kumar Megha , Capece Gina , Konkalmatt Prasad R , Zheng Xiaoxu , Asico Laureano , Jose Pedro , Armando Ines
Published: September 2020

The recently deorphanized G protein couple receptor 83 (GPR83) is expressed in proximal and distal convoluted tubules of the mouse kidney and in human renal proximal tubule cells (hRPTCs). Peptides derived from the cleavage of the precursor neuroendocrine hormone pro-SAAS (pro serine, alanine, alanine, serine), in particular PEN (proline, glutamic acid, and asparagine), have been proposed as the endogenous ligands of GPR83 but their function in the kidney is unknown. GPR83 is constitutively active; silencing (siRNA, 20 nM, 72h) its expression in hRPTCs decreases the phosphorylation of ERK1/2, p38, p90RSK and AKT (43%, 52%, 65%, and 25% respectively, n=4/group, P<0.05 vs non-silencing siRNA). Conversely, PEN (proline, glutamic acid, and asparagine) treatment of hRPTCs (1 μM, 1h) increases ERK1/2, p38, p90RSK, and AKT phosphorylation (15-fold, 1.7-fold, 2-fold, 18-fold respectively, n=4/group, P<0.05 vs vehicle). We hypothesized that GPR83 and its ligands PEN and pro-SAAS are involved in the regulation of blood pressure. Global deletion or renal-specific silencing of the
Gpr83
gene in mice increased systolic blood pressure (SBP). High salt diet increased Gpr83 transcription 2-fold (P<0.05; n=4/group) in SJL/J and BALB/c salt-resistant mice, relative to C57Bl/6J salt-sensitive mice. Renal-restricted infusion of PEN (1 μg/day; 7 days) did not affect SBP, slightly decreased Na
+
excretion and renal NHE3 expression (P<0.05 all) and did not affect renal Na
+
/K
+
-ATPase expression, suggesting that PEN is only a partial ligand of GPR83. By contrast, the renal specific siRNA-mediated silencing of pro-SAAS in mice increased SBP (130±4 vs control wild-type 100±1 mmHg, n=3/group; P<0.05) that was associated with decreased urinary Na
+
excretion (P<0.05) and increased renal expressions of NHE3, SGLT2, NaPi2, NKCC2, NCC, and Na
+
/K
+
-ATPase (P<0.05 all). Renal expression of GRK4, another regulator of BP was also increased. Renal pro-SAAS expression was increased by a high salt diet (4%NaCl) in non-transgenic mice but was decreased in the salt-sensitive GRK4 486V mice on the same diet. Our results suggest that pro-SAAS peptides may be involved in the development of salt sensitivity through gene-gene interaction between GPR83 and GRK4 486.
Abstract MP21: Suppression Of Reactive Oxygen Species Protects The Dahl Salt-sensitive Rat From Developing Maternal Syndrome
Authors: Dasinger John Henry , Abais-battad Justine M , Cherian-Shaw Mary , Mattson David L
Published: September 2020

The Dahl Salt-Sensitive (SS) rat maintained on a low salt diet exhibits a differential response to pregnancy; approximately half develop maternal syndrome (hypertension and proteinuria) while the other half are protected. The exact mechanisms of maternal syndrome are unclear, but it is proposed that reactive oxygen species (ROS) are involved. Previous studies from our laboratory demonstrated the importance of NADPH oxidase (NOX) 2-derived ROS produced by immune cells in the development of salt-sensitive hypertension and renal disease. Given the role of NOX2-derived ROS in the Dahl SS rat, we tested the hypothesis that genetic deletion of the p67phox subunit of NOX2 (SS
Ncf2-/-
) will result in the protection from developing maternal syndrome. To test this hypothesis, 8 week old female Dahl SS and SS
Ncf2-/-
were instrumented with radio-telemeters for continuous measurement of mean arterial pressure (MAP). After a recovery period, baseline MAP was measured as well as an overnight urine collection for markers of renal damage before females were mated with males of the same strain and age. Virgin litter-mate controls were run in parallel. As expected, MAP and protein excretion levels were comparable at baseline between virgin and mated SS
Ncf2-/-
rats. These parameters remained comparable at the late pregnancy time point (108±3 vs 112±1mmHg, 9±3 vs 16±5mg/day,
p
>0.05). In contrast to the SS preeclamptic pregnancy, the SS
Ncf2-/-
mated rats are protected from the development of maternal syndrome (141±8 vs 112±1mmHg,
p
<0.001; and 98±16 vs 16±5mg/day,
p
<0.001; in the SS vs SS
Ncf2-/-
, respectively). This protection is accompanied with a significant reduction in uterine artery resistance index which is a marker of impaired blood flow, in the SS
Ncf2-/-
(0.85±0.03 vs 0.59±0.02,
p
<0.01). Despite these phenotypic differences, the number of infiltrating immune cells into kidneys or placentas do not differ between these two groups. These results suggest that NOX2-derived ROS contribute to the pathogenesis of maternal syndrome in the Dahl SS rat, and further investigations are necessary to clarify the source of the ROS within key organs such as the kidney and placenta.
Abstract MP23: Vascular Smooth Muscle Rho-related Btb Domain Containing Protein 1 In Hypertension And Arterial Stiffness
Authors: Fang Shi , Wu Jing , Donato Silva Sebastiao , Lu Ko-ting , Sigmund Curt D
Published: September 2020

Rho-related BTB domain containing protein 1 (RhoBTB1) is a transcriptional target of peroxisome proliferator activated receptor γ (PPARγ), but its physiological and molecular function in blood pressure (BP) control remains unclear. We showed that aortic RhoBTB1 expression was decreased in mice expressing vascular smooth muscle (VSM) specific dominant negative PPARγ mutation (S-P467L). Genetic complementation of VSM RhoBTB1 reversed the hypertension, vascular dysfunction, and arterial stiffness in S-P467L mice; and suppressed the elevated enzymatic activity of phosphodiesterase 5 (PDE5) in S-P467L mice. In HEK293 cells, RhoBTB1 increases PDE5 ubiquitination in a Cullin-3-dependent manner. We concluded that VSMC RhoBTB1 mediates the anti-hypertensive effect of PPARγ.

RhoBTB1 expression was decreased in aorta from mice treated with angiotensin II (AngII, 490ng/kg/min, 2-weeks). We hypothesized that restoration of VSM RhoBTB1 would reverse established AngII-mediated hypertension, vascular dysfunction, and arterial stiffness. Transgenic mice expressing inducible VSM-specific RhoBTB1 (S-RhoBTB1) were treated with AngII (490ng/kg/min, 6-weeks) and the transgene was activated by Tamoxifen (Tx) during week 3. ISM-Cre mice expressing VSM Cre-recombinase were similarly treated as controls. AngII equally increased BP, as measured by radiotelemetry in both ISM-Cre and S-RhoBTB1 mice. The vasodilatory and vasoconstrictor responses in the carotid artery were not different in AngII-treated S-RhoBTB1 and ISM-Cre mice. RhoBTB1 did not affect pulse wave velocity (PWV), a measure of arterial stiffness, in mice without AngII (ISM-Cre vs S-RhoBTB1: 2.64±0.08 vs 2.48±0.06 mm/ms, p>0.05, n=6); and AngII increased PWV similarly in both strains before Tx (ISM-Cre vs S-RhoBTB1: 3.54±0.22 vs 3.52±0.18 mm/ms, p>0.05, n=7-9). PWV of S-RhoBTB1 mice started to decrease after the first week whereas it continued to rise in ISM-Cre mice. By the second week of Tx, VSMC RhoBTB1 expression significantly attenuated AngII induced arterial stiffness (ISM-Cre vs S-RhoBTB1: 4.21±0.37 vs 3.17±0.16 mm/ms, p=0.02, n=7-9). These data suggest a mechanism where RhoBTB1 improves vascular compliance independently from BP and is protective against arterial stiffness.
Abstract MP30: Small Molecule Inhibitor Of Chloride Channel Tmem16a Blocks Vascular Smooth Muscle Contraction And Lowers Blood Pressure In Spontaneously Hypertensive Rats
Authors: Cil Onur , Jordan Maria C , Askew Page Henry R , Myat Thwe Pyone , Baldwin Samuel N , Anderson Marc , Greenwood Iain A , Roos Kenneth P , Verkman Alan
Published: September 2020

Hypertension is a major cause of cardiovascular morbidity and mortality, despite the availability of antihypertensive drugs with different targets and mechanisms of action. There is an unmet need for antihypertensive drugs with novel mechanisms of action to better control hypertension and reduce cardiovascular morbidity and mortality. Here, we provide evidence that pharmacological inhibition of TMEM16A (transmembrane member 16A or anoctamin-1), a Ca
2+
-activated Cl
-
channel expressed in vascular smooth muscle cells, reduces in vitro vascular smooth muscle contraction and decreases blood pressure in spontaneously hypertensive rats (SHR). We recently identified by high-throughput screening and subsequent medicinal chemistry, small molecule TMEM16A inhibitor TM
inh
-23 (2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid o-tolylamide) that inhibits TMEM16A current fully, with IC
50
~ 30 nM. TM
inh
-23 pretreatment blocked maximum in vitro vascular smooth muscle contractions induced by a thromboxane mimetic (U46619) in rat mesenteric arteries by 90%. Intraperitoneal (ip) administration of TM
inh
-23 to rodents at 10 mg/kg produced sustained serum concentrations of >10 μM for >4 hours. BP measurements by tail-cuff and telemetry showed a maximum ~45 mmHg reduction in SBP in spontaneously hypertensive rats (SHR) after a single dose (10 mg/kg, ip) TM
inh
-23 administration compared to vehicle treatment, with BP gradually returning to baseline values within 6-8 hours after TM
inh
-23 treatment. Minimal effect on BP (less than 10 mmHg decrease in SBP) was seen in wild-type rats and mice with TM
inh
-23 treatment (10 mg/kg, ip). Chronic 5-day treatment of SHR with TM
inh
-23 (10 mg/kg, ip, twice daily) caused sustained decreases (~20-25 mmHg) in daily average SBP, DBP and MAP during the treatment period. TM
inh
-23 action was reversible, with BP returning to baseline (~170/115 mmHg) by 3 days after discontinuation of treatment. These studies provide validation for TMEM16A as a target for antihypertensive therapy, and demonstrate the proof-of-concept for efficacy of TM
inh
-23 as an antihypertensive with a novel mechanism of action.