bluuebunny/crossref_metadata_2025_split huggingface dataset:
Knockdown of Interleukin 17 Receptor A (IL‐17RA) in Paraventricular Nucleus of Hypothalamus Attenuates IL‐17‐induced Pressor Responses and Sympathetic Excitation
Authors: Yu Yang , Cao Yiling , Felder Robert B. , Wei Shun-Guang 
Published: April 2020

Inflammation contributes significantly to cardiovascular and autonomic dysfunction in hypertension and heart failure. Over the years, the pro‐inflammatory cytokine interleukin (IL)‐17 (also known as IL‐17A) has been recognized as a critical inflammatory regulator bridging immune responses and tissue inflammation. Our previous studies have demonstrated that peripherally or centrally administrated IL‐17A dramatically elevates blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in rats, and that its receptors IL‐17RA are richly expressed in the brain. The present work sought to determine whether IL‐17RA in the hypothalamic paraventricular nucleus (PVN), a key cardiovascular/autonomic brain center, mediate hemodynamic and sympathetic responses to systemically administered IL‐17A. In urethane anesthetized male SD rats, Mean BP (MBP, mmHg), HR (beats/min) and RSNA (% change) were recorded before and for 6–8 hours after an intravenous (IV) injection of IL‐17A (500 ng). In age‐matched control rats, IV IL‐17A induced a large and long‐lasting increase (*p<0.001 vs. baseline) in MBP (16.2 ± 2.3*), HR (49.8 ± 5.1*) and RSNA (165.6 ± 13.2 %*), beginning within 120 mins and peaking 6–8 hours after the injection. However, in rats pretreated with bilateral PVN microinjections of an IL‐17RA siRNA AAV virus and studied one week later, the IV IL‐17A‐elicited pressor responses in MBP (10.1 ± 2.1*), HR (22.1 ± 4.0*) and RSNA (68.5 ± 7.8 %*) were significantly (p<0.05) attenuated. mRNA for tumor necrosis factor‐α (TNF‐α), IL‐1β, monocyte chemoattractant protein‐1 (MCP‐1) and IL‐17RA in the PVN was measured by real‐time qPCR. Knockdown efficiency of IL‐17RA siRNA was confirmed by a reduction (−55%) of IL‐17RA mRNA level in the PVN. Additionally, the mRNA levels of TNF‐α (1.12 ± 0.24 vs. 0.51 ± 0.11*), IL‐1β (1.05 ± 0.16 vs. 0.64 ± 0.09*), and MCP‐1 (1.01 ± 0.10 vs. 0.60 ± 0.10*) induced by IV IL‐17A were significantly reduced in the PVN in rats pretreated with IL‐17RA siRNA. These data indicate that systemically administered IL‐17A acts upon IL‐17RA in the PVN to increase the expression of inflammatory mediators that drive sympathetic excitation, suggesting that PVN plays an important role in mediating the effects of circulating IL‐17A on sympathetic drive and cardiovascular function in inflammatory conditions such as hypertension and heart failure. IL‐17RA in the PVN is a potential target for therapeutic intervention in these diseases.Support or Funding InformationThis research was supported by NIH/NHLBI RO1 HL139521.
Seasonal Cytotoxic Effects of Urban Watersheds in the Greater Houston Area
Authors: Abdullah-Smoot Dayana Attiya 
Published: April 2020

Steadily rising populations are turning Houston, Texas to the urban concrete jungle it is today. With communities growing and searching for homes, the need for new construction and establishments only increases the amount of impermeable surfaces relying heavily on the native waterways. Houston is known for its complex network of waterways surrounding and interweaving throughout the city, which are referred to as bayous. They work as a storm water runoff system to help prevent flooding, but many communities use the watersheds for recreational purposes. Local patrons boat, fish and swim in the bayous, unaware of the chemicals and pollutants lurking in the water. Due to the extensive flood history in Houston and the surrounding areas, communities do not have to be near the bayou to be inundated with the polluted water. Heavy rain for only an hour or two can cause bayous to rise, streets flood and water can make the find its way into low‐lying homes. Current studies have shown that there are high concentrations of As, Hg, Cr, Pb and Zn in the water. We hypothesize that the metals and chemical compounds identified could cause the water to have deleterious effects on living organisms occupying the watersheds or using its resources. My study objectives include observing the cellular response when the cells are subjected to the bayou water samples collected during the summer and fall of 2018 to compare cellular viability and to determine which of the watersheds has the greatest over cytotoxic effects.Water samples were collected in triplicates from Mustang Bayou, Dickinson Bayou, Horsepen Bayou, Houston Clear Lake, Cypress Creek and Cypress Creek Lake, which are six major waterways in the surrounding Houston area. The methods included buffering the water sample that will not be detrimental to the cells, then serial dilute the samples in media for varying concentrations (control or 0%, 12%, 25%, 50%, 100%) and tested the bayou water samples on the HT29 colon cells using a cytotoxicity assay and proliferation assays at 12, 24, and 48‐hour time points.We observed a linear decrease in viable cells as the treatment time points of bayou water increased. Cytotoxic effects were observed at every time point no matter the concentration of bayou water in the sample and the highest overall cellular viability was observed in the fall 2018 samples, because the overall viability percentages were roughly 20% higher than summer samples for both the 12hr and 24hr treatments although the 48hr results stayed consistent. Future studies include treating FHC colon cells with the same bayou water concentrations to compare to the HT29 cellular response and investigate the cytotoxic cellular effect with media containing the chemical elements at the concentrations determined from the chemical analysis.Support or Funding InformationThis research was primarily supported by the National Science Foundation (NSF) through Texas Southern University (TSU) under the award numbers HRD‐1622993, BCS‐1831205, and HRD‐1829184
Loss of colonic epithelial NCOR1 aggravates experimental colitis chronicity
Authors: Boudreau Francois , Lecours Mia , Di Castro Ariane Cristina , Nicolas Vilcy Reyes , Jones Christine , Perreault Nathalie 
Published: April 2020

The nuclear co‐repressor NCOR1 orchestrates the assembly of a large transcriptional repression complex that is involved in the negative regulation of pro‐inflammatory genes. Chronic intestinal inflammation is associated with sustained activation of pro‐inflammatory molecules. Since NCOR1 is considered as a potent repressor of pro‐inflammatory genes in macrophages, we aimed to investigate the role of intestinal epithelial NCOR1 during inflammatory stresses. Conditional deletion of Ncor1 in the whole intestinal epithelium was achieved by crossing Villin‐Cre and Ncor1loxP/loxP C57BL/6 mouse models. DSS‐induced colitis in NCOR1ΔIEC mice was more severe than control mice according to survival as well as clinical observations. A gene profiling analysis in the colon of non‐diseased NCOR1ΔIEC and control mice identified 85 unique and mapped transcripts being significantly modulated between NCOR1ΔIEC and control mice. An Ingenuity Pathway Analysis from these predicted target genes identified gastrointestinal disease (79 transcripts) as top disease and biofunction. Analysis of enriched targets in specific canonical pathways predicted an increase in the tryptophan degradation pathway (P = 3.2E‐02), a pathway recently demonstrated to be strongly relevant to inflammatory bowel disease severity. Indoleamine‐pyrrole 2,3‐dioxygenase (IDO1), that catalyzes the first and rate‐limiting step of tryptophan oxidation, was induced more than 7 times in the colon of NCOR1ΔIEC mice. IDO1 was also significantly more elevated in NCOR1ΔIEC mice when compared to control mice both subjected to chronic inflammation (3 cycles of DSS). Spontaneous induction of Ido1 gene expression was also confirmed in cultured ex vivo colon organoids deleted for Ncor1. In conclusion, our results highlight the critical role of NCOR1 to maintain intestinal inflammatory homeostasis during experimental colitis and uncover a novel function for NCOR1 in the regulation of Ido1 expression and potentially tryptophan metabolism.Support or Funding InformationCanadian Institutes of Health Research
Secondary Analysis of Premature Respiratory Outcomes Program (PROP) Clinical Trial to Identify Correlations of Risk Factors for Respiratory Morbidity and Mortality in Premature Infants
Authors: Torres Juliet , Otero Jose Javier 
Published: April 2020

BackgroundThe Premature Respiratory Outcomes Program (PROP) was a collaborative, multi‐disciplinary clinical study that sought to analyze the factors that could predict future risk for respiratory morbidity and mortality for 835 premature infants with gestational ages 23 0/7 to 28 6/7 weeks. PROP investigators conducted physiologic challenges called Room Air Challenges (RAC) and Hypoxic Challenges Tests (HCT) to determine whether the premature infants could maintain their SpO2 in the target range of ≥90% and to assess pulmonary reserve in former premature infants without Bronchopulmonary Dysplasia(BPD) at 36 weeks’ premenstrual age (PMA). This project was funded by the National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI) for 5 years through a $18.5 million research initiative.ObjectiveWe are interested in understanding the relationship between brain imaging data and respiration outcomes, and infection or chorioamnionitis and respiration outcomes. In addition, the RAC and HCT provides the opportunity to analyze the outcomes of physiologic challenges in preterm infants compared to term infants undergoing the same challenges in studies that conducted preflight HCT.Statement of the methodsWe utilized machine learning tools such as random forest, support vector machines, gradient boosted machines, and logistic regression to generate predictive models of the aforementioned features.Summary of resultsPreliminary data analysis of key variables to be included in our future data analytics includes standard deviations for birth weight (gm) (235.98), the baby’s head circumference (cm) (83.05), APGAR for one minute (scored 1–10) (2.47), and APGAR 5 minutes (2.10).Statement of conclusionsThis PROP clinical study encapsulates an immense amount of multidisciplinary data from 835 premature infants, which is an extremely special population to include in research as approximately 1 out of every 9 births in the United States occurs prematurely.Support or Funding InformationR01HL132355
Temporal RNA Integrity Analysis of Archived Spaceflight Biological Samples
Authors: Scott Ryan T. , Talburt Elizabeth Delgadillo , French Alison J. , Lopez Danielle , Polo San-Huei Lai , Boyko Valery , Dinh Marie T. , Rask Jon C. , Chakravarty Kaushik , Stewart Helen , Del Alto Martha E. 
Published: April 2020

Spaceflight experiments have utilized model organisms for decades to assess effects of microgravity on biological systems. In many of those experiments, obtaining and assessing tissues from only a few biological systems are of interest to their Principal Investigators. To maximize scientific return from space flown experiments, the remaining tissues are captured, curated, and preserved in the Institutional Scientific Collection (ISC) at NASA Ames Research Center. The international scientific community is encouraged to request these available tissues through NASA’s ISC Biospecimen Sharing Program, and conduct research furthering insights into the field of space biology. The purpose of this study is to evaluate viability of tissues which have been archived for differing lengths of time within the NASA ISC. Garnering information from the NASA ISC tissues – such as downstream functional analysis for the generation of omics datasets – is partly dependent on the state of sample preservation. RNA integrity number (RIN) values were calculated for rodent liver tissues that were part of spaceflight scientific payloads. Rat livers were tested from Spacelab Life Sciences 1 (SLS‐1; 1991), as were mouse livers from Commercial Biomedical Test Module 3 (CBTM‐3; 2011), Rodent Research 1 (RR1; 2014), and Rodent Research 3 (RR3; 2016). It was found that mean RIN values from CBTM‐3, RR1, and RR3 were suitable for downstream functional analysis (RIN > 5), while the mean RIN value for SLS‐1 was not (RIN = 2.5 ± 0.1). This work to analyze RIN values of NASA ISC liver tissues will inform future investigators in their tissue and assay selections. This study lays the foundation for future efforts to understand the quality and viability of different tissues archived within the NASA ISC biospecimen repository.Support or Funding InformationNASA Ames Research Center
Mouse Trophoblasts Can Provide Antiviral Protection to Embryonic Stem Cells
Authors: Fendereski Mona , Neupane Biswas , Bai Fengwei , Guo YanLin 
Published: April 2020

The blastocyst is the preimplantation embryo that consists of two major components: the inner cell mass (ICM) and the trophectoderm, which give rise to the fetus and placenta, respectively. We have previously reported that embryonic stem cells (ESCs), the major component of the ICM of blastocyst, do not express type I interferons (IFNs) and lack response to inflammatory cytokines. One would assume that this could make ESCs susceptible to infection. Surprisingly ESCs are less susceptible to immunological cytotoxicity and are not hypersensitive to viral infection. These findings led to our hypothesis that the lack of antiviral responses could be a protective mechanism that allows ESCs to avoid negative impact of immune responses, but how ESCs deal with pathogen infection and immunological challenges is not known. In this study, we investigated IFN‐based antiviral innate immunity of the trophectoderm by using mouse trophoblast stem cells (TSCs) and their in vitro differentiated trophoblasts (TSC‐TBs). Unlike ESCs, our data indicated that both TSCs and TSC‐TBs have a functional IFN system as indicated by their ability to express IFNα, IFNβ, and IFNλ in respond to viral stimuli. They express IFN‐stimulated genes when treated with IFNα and IFNβ. We further showed that the conditioned medium from TSCs and TSC‐FBs stimulated with polyinosinic:polycytidylic acid (poly I:C), a synthetic viral RNA analog, contains antiviral activity that could inhibit infection of ESCs by Chikungunya and Zika virus, similar to the effect of purified IFNβ. These findings indicate that embryonic cell lineages in the blastocyst have different immunological properties at the same developmental stage. Although ESCs are deficient in producing IFNs, they can gain IFN antiviral protection from the trophectoderm via a paracrine signaling mechanism in the blastocyst. Therefore, lacking the production of IFN in ESCs could be a protective mechanism that allows ESCs to avoid the potential harmful impact of immune responses without compromising their antiviral innate immunity.Support or Funding InformationThis work was in part supported by the National Institute of General Medical Sciences (R15GM128196‐01). We thank Mississippi‐IDeA Network of Biomedical Research Excellence for the use of the imaging facility (funded by the National Institute of General Medical Sciences P20 GM103476‐11).
Low concentrations of nicotine increase frequency and decrease amplitude of respiratory bursts recorded from the hypoglossal nerve, with no change in amplitude of bursts recorded from the phrenic nerve, in the neonatal rat brainstem spinal cord preparation
Authors: Wollman Lila Buls , Flannigan Emily Gayle , Fregosi Ralph Frank 
Published: April 2020

Nicotinic acetylcholine receptors (nAChRs) are expressed throughout the central respiratory network, including postsynaptically on pattern generating neurons and motor neurons, and presynaptically on both excitatory and inhibitory inputs to these neurons. Normally, specific populations of nAChRs are briefly activated by the endogenous neurotransmitter acetylcholine, which is then rapidly hydrolyzed by acetylcholinesterase. However, with active or passive nicotine exposure, low circulating concentrations of nicotine results in global and prolonged activation of nAChRs, the effects of which are largely unknown. Here, we used the brainstem spinal cord preparation and rhythmic brainstem slice from nicotine‐naïve neonatal rats on postnatal days 1–4 to study the effects of prolonged, global nAChR activation on respiratory motor output. In the brainstem spinal cord preparation, bath application of 250 nM nicotine for 30 minutes resulted in an increase in respiratory burst frequency (21 % above baseline) accompanied by a decrease in hypoglossal nerve amplitude (62 % below baseline), but no change in phrenic nerve amplitude. In the rhythmic brainstem slice, bath application of nicotine concentrations as low as 50 nM caused an increase in frequency (35 % above baseline) and a decrease in amplitude (33 % below baseline) of respiratory bursts recorded from the hypoglossal nerve. These results indicate that low concentrations of nicotine are sufficient to cause changes in the respiratory network, including profound inhibition of hypoglossal motor output.Support or Funding Information5R01HD071302‐07
Characterization of Amplified Malate Dehydrogenase 1 (MDH1) in the Context of Squamous Cell Lung Cancer
Authors: Alexander Sati Amrita , Weeks Joi , Hoang An , Sohl Christal 
Published: April 2020

Cancer cells often reroute or stimulate their metabolism to support proliferation, which requires a change in the activity or regulation of key metabolic residues. Malate dehydrogenase 1 (MDH1) catalyzes the NADH‐dependent conversion of oxaloacetate to malate, which can help drive glycolysis through the production of NAD+. MDH1 is amplified in many squamous cell lung carcinomas, the second leading cause of cancer related death, and this amplification is associated with a poor prognosis of 50% reduced survival. The precise role of MDH1 in driving squamous cell lung cancer and the mechanisms that regulate this protein are not yet well understood.Here, we develop a tool to examine the effect of MDH1 amplification in an in vitro model. We aim to examine MDH1 amplification in squamous cell lung carcinoma with an isogenic control. It has been previously shown that MDH1 methylation can suppress glutamine metabolism in pancreatic cancers, and that acetylation of MDH1 alters its activity. We will examine how MDH1 amplification affects squamous cell carcinomas by using biochemical kinetics and cellular methods. We have found that MDH1 amplification influences the production of metabolites in the TCA cycle. Through monoclonal single cell isolation, we will generate a squamous epithelial lung cancer cell line stably overexpressing MDH1. We hypothesize that MDH1 has cysteine residues that can be sensitive to oxidative stress which can alter the normal enzymatic activities of MDH1. Through site‐directed mutagenesis, we will mutate a cysteine residue to a serine residue at the 137 position to examine the possible effect of oxidative stress on MDH1. This residue has been shown to be sensitive to oxidation in the mouse form of MDH1. We will also heterologously express and purify MDH1 mutants and perform kinetic assays to examine the impact of amplified MDH1. By understanding the regulatory strategies of MDH1, we hope to identify new pathways that may be targeted therapeutically.Support or Funding InformationThis work was funded by a Research Scholar Grant, RSG‐19‐075‐01‐TBE, from the American Cancer Society (C.D.S.), National Institutes of Health R00 CA187594 (C.D.S.), U54CA132384 (SDSU) & U54CA132379 (UC San Diego), and IMSD 5R25GM058906 (SDSU), as well as the California Metabolic Research Foundation (SDSU).
Oxidative Susceptibility and Degradation of Calmodulin Cardiac Mutants
Authors: Moen Rebecca Jane , Julian Jordan , Isehak Imad , Thomas David Dale 
Published: April 2020

Mutations within the ubiquitous calcium‐sensing protein calmodulin (CaM) have been linked to congenital arrhythmia disorders including long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). In cardiomyocytes, CaM is critical for regulating excitation‐contraction coupling by binding calcium as well as binding a diverse set of targets including the ryanodine receptor (RyR2) to regulate intracellular calcium levels. The vertebrate CaM primary sequence contains nine methionine (Met) amino acid residues which are highly conserved. All nine Met are susceptible to oxidation to methionine sulfoxide (MetO). These methionine residues are solvent‐exposed upon binding calcium and facilitate CaM binding its targets. CaM also contains a potential PEST sequence, an internal signal for rapid proteolytic degradation. We have investigated the oxidative and proteolytic susceptibility of four calmodulinopathy mutants: D96V and D130G, which are linked to LQTS and N54I and N98S, which are associated with CPVT. The goal of this research is to establish a correlation of CaM disease mutants and oxidative susceptibility, with an emphasis on the compounding and detrimental functional and structural effects these two types of modifications may cause.Support or Funding InformationThis work is supported by a NIH grant AG26160 to DDT and a Minnesota State University, Mankato Undergraduate Research Center Foundation Grant to JJ.
Long OPA1 isoforms mediate a membrane potential‐dependent threshold for mitochondrial fusion in AC16 cardiomyocytes
Authors: Gilkerson Robert , Maynard Kristen , De La Torre Patrick , Keniry Megan 
Published: April 2020

The bioenergetic function of mitochondria is linked to its organellar structural dynamics by optic atrophy‐1 (OPA1), a nuclear‐encoded protein that mediates fusion of the mitochondrial inner membrane. OPA1‐mediated inner membrane fusion is dependent on the transmembrane potential across the mitochondrial inner membrane (Δψm): long (L‐OPA1) isoforms accomplish fusion for an interconnected reticular morphology when Δψm is intact. Upon loss of Δψm, L‐OPA1 is cleaved by the OMA1 metalloprotease, causing accumulation of short S‐OPA1 and collapse of mitochondrial fusion to a fragmented morphology. We examined Δψm‐sensitive mitochondrial fusion in human AC16 cardiomyocytes treated with carbonyl cyanide m‐chlorophenyl hydrazone (CCCP), an uncoupler of Δψm. Upon increasing titration with CCCP, mitochondrial fusion collapses at [CCCP] > 2 μM, as determined using blinded ImageJ quantification of mitochondrial morphology. Similarly, OPA1 Western blotting revealed that AC16s show a significant loss of fusion‐active L‐OPA1 at [CCCP] > 2 μM. Taken together, these findings indicate that L‐OPA1 maintains mitochondrial fusion, but that OMA1 is activated at [CCCP] > 2 μM, causing L‐OPA1 cleavage and collapse of mitochondrial fusion. Experiments in progress are examining OMA1 activation at this Δψm breakpoint, as well as impact of altered OPA1 and OMA1 expression.Support or Funding InformationNIGMS 5SC3GM116669 (to R.G.)NIGMS 1SC3GM132053 (to M.K.)UTRGV Presidential Graduate Research Assistantship (to P. D.)