bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNA Binding Protein ZFP36L1 Regulates Alcoholic Steatohepatitis in Mice
Authors: Patial Sonika , Saini Yogesh , Bathula Chandra 
Published: April 2020

Zinc finger protein 36 like 1 (ZFP36L1) regulates mRNA levels by binding to AU‐rich elements (ARE’s) on the 3′untranslated regions (3′UTR) of specific mRNAs and enhancing their turnover. While the biochemical function of ZFP36L1 is somewhat understood, its physiological and pathological functions remain unknown. Here, we sought to investigate the roles of ZFP36L1 in liver physiology and pathology by generating liver‐specific deletion of ZFP36L1 (Zfp36l1LKO) using Cre‐loxP approach and subjecting them to alcoholic steatohepatitis. Liver‐specific loss of ZFP36L1 did not result in any aberrant phenotype in mice. However, Zfp36l1LKO mice were significantly protected from developing alcohol‐induced hepatic steatosis in Lieber‐DeCarli liquid diet‐induced model of alcoholic steatohepatitis. Serum levels of ALT did not significantly increase in Zfp36l1LKO mice upon alcohol consumption while serum levels of ALT were significantly upregulated in wild type (WT) alcohol‐treated mice. Transcriptomic analysis showed less than 170 differentially expressed transcripts in alcohol‐treated Zfp36l1LKO mice compared to greater than 500 differentially expressed transcripts in alcohol‐treated WT mice. Mechanistically, the levels of fibroblast growth factor 21 (Fgf21) mRNA were significantly increased and lipoprotein lipase (Lpl) mRNA were significantly reduced in the livers of alcohol‐treated Zfp36l1LKO mice compared to alcohol‐treated WT group. We further found evidence that Fgf21 mRNA is a direct target of ZFP36L1. FGF21 is a metabolic regulator of glucose and lipid metabolism and has been previously found to be significantly induced upon alcohol consumption and protect against alcohol‐induced liver injury. In summary, our results demonstrate that FGF21 is post‐transcriptionally regulated by ZFP36L1 in alcoholic liver injury. Modulation of levels of ZFP36L1 may be beneficial in the prevention or treatment of human alcoholic liver disease.Support or Funding InformationStart Up Funds, LSUSVM
The complete evidence that Starling’s law responsible for many errors and misconceptions on fluid therapy in shock is wrong: The correct replacement is the hydrodynamic phenomenon of the porous orifice (G) tube
Authors: Ghanem Ahmed Nasr , Ghanem Khaled Ahmed 
Published: April 2020

Introduction and objectiveTo report the hydrodynamic of a porous orifice (G) tube as replacement for the wrong Starling’s law.Material and methodsHydrodynamics of the G tube, based on capillary ultra‐structure, were studied. The effect of changing G tube orifice diameter, proximal pressure and distal pressure on the side pressure and chamber (C) pressure were evaluated. The physiological proof that the capillary works as G tube not Poiseuille’s tube is provided.ResultsHydrodynamics of the G tube showed that proximal, akin to arterial, pressure induces a negative side pressure gradient on the G tube wall, which is negative causing suction maximum near the inlet and turn positive near the exit causing filtration. This created the rapid, autonomous magnetic field like fluid circulation phenomenon between G and C. The physiological evidence on the hind limb of sheep proves that the capillary works as G tube.ConclusionHydrodynamic of the G tube challenges the role attributed to arterial pressure as a filtration force in Starling’s law. A literature review shows that oncotic pressure does not work and the law has failed to explain the capillary–ISF transfer. A concept based on the new hydrodynamic phenomenon of the G tube is proposed to replace Starling’s law. A rapid autonomous dynamic magnetic field‐like G–C circulation occurs. Factors which initiate, regulate and affect the G–C circulation, its physiological proof and relevance to clinical importance are given.’ A physiological evidence on capillary working as G tube not Poiseuille’s tube is provided.
Antihyperlipidemic, Antiperoxidative and Hypoglycemic Effects of Saponins from Solanum anguivi Lam. Fruits in Alloxan‐induced Diabetic Rats
Authors: Molehin Olorunfemi Raphael , Elekofehinti Olusola Olalekan , Oyeyemi Ajibade Oluwagbenga 
Published: April 2020

Solanum anguivi Lam. fruit is commonly used in folklore medicine for the management of various diseases including diabetes in Nigeria. The present study evaluates the antihyperlipidemic, antiperoxidative, and hypoglycemic activities of saponins from Solanum anguivi fruits in alloxan‐induced diabetes rats. Diabetic rats were treated with saponin (20 – 100 mg/kg) for 21 days. Results indicated that administration of saponins significantly reduced the elevated levels of glucose, decreased total cholesterol (TC), total triglycerides (TG), low density lipoprotein (LDL) and increased high density lipoprotein (HDL) in the serum towards normalcy when compared to the diabetic control (P< 0.05). In addition, saponins exhibited strong inhibition of lipid peroxidation and increased the levels of antioxidant enzymes (superoxide dismutase and catalase) in the serum, liver and pancreas when compared to the diabetic control (P< 0.05). Our results suggest that saponins from S. anguivi fruit can enhance the hypoglycemic, hypolipidemic and antioxidant properties in alloxan‐induced diabetic rats, and may have the potential to be used in the prevention or in the management of diabetes.Support or Funding InformationThis research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors
Understanding the Interplay between Human Epidermal Growth Factor Receptor 2 and Neuraminidase 1 on the Regulation of Fatty Acid Binding Protein 5 in Breast Cancer Cells
Authors: McCullough Ian , Thulasiraman Padmamalini 
Published: April 2020

Human epidermal growth factor receptor 2 (HER2), a member of the epidermal growth factor receptor (EGFR) family, accounts for 15–20% of breast cancer cases. HER2 is a glycosylated protein with sialic acid groups attached on the surface of the protein. Sialylated proteins can be regulated by enzymes called Neuraminidases 1 (Neu1) that catalyze the removal of sialic acid residues from glycoproteins. One of the oncogenes activated by the downstream signaling effector of the HER2 pathway is a protein called fatty acid binding protein 5 (FABP5). Elevated expression of FABP5 is correlated with poor prognosis in several carcinomas and overexpression of FABP5 prevents retinoic acid‐mediated growth suppression of mammary carcinoma cells. The objective of this study is to examine whether reducing Neu1 activity or its expression decreases HER2 activation and subsequently the downregulation of FABP5 in HER2 positive breast cancer cell line, MDA‐MB‐453. Using sialic acid assay, we quantitated the levels of sialic acid in MDA‐MB‐453 cells treated with oseltamivir phosphate, an inhibitor of Neu1 activity. Oseltamivir phosphate reduced the concentration of sialic acid in a dose‐dependent manner. Through western blot analysis, we demonstrated that suppressing the activity of Neu1 with ostelamivir phosphate in MDA‐MB‐453 cells reduced heregulin‐mediated induction of the active phosphorylated HER2 and its downstream target, FABP5. Furthermore, silencing Neu1 using siRNA reduced the expression of FABP5 protein expression in MDA‐MB‐453. Taken together, this data demonstrated that inhibition of Neu1 prevented heregulin‐induced HER2 activation, and in turn, regulated the expression of FABP5 in MDA‐MB‐453 cell line. We propose that these studies will contribute to the understanding of how Neu1 and HER2 communicate to modulate the expression of FABP5, Thus, Neu1 can be used as clinical target to improve the efficacy or sensitivity of retinoic acid in HER2+ breast cancer patients.Support or Funding InformationFunding was obtained through the Summer Undergraduate Research Fellowship, Office of Undergraduate Research (I.M) and the Pat Capps Covey College of Allied Health Professions Start Up Fund (P.T.) from the University of South Alabama.
Transcriptional Dynamics Underpinning Muscle Senescence in Manduca sexta
Authors: Grosso Avery Del , Wone Beate , Wone Bernard W.M. 
Published: April 2020

Muscle aging is a complex dynamic process that adversely affects whole‐animal metabolism and physiology. The molecular regulation of aging muscle that impacts muscle function, performance, and metabolism remains largely unknown because such studies in model organisms are prohibitively time‐ and resource‐intensive. The hawk moth, Manduca sexta, offers a unique opportunity to identify the genes that coordinate the muscle aging process. With a complete lifespan of about ten days and being similar to vertebrate muscle systems, this non‐vertebrate animal model is ideal to conduct a molecular dissection of the regulatory genes underpinning the senescence process in muscles. Here, we characterize the genome‐wide transcriptional changes by profiling gene expression from a high‐resolution time course sampling of muscle tissue from middle age to advanced age moths. Following RNA‐Sequencing of the time course tissues, we not only report differentially expressed genes across the time and day intervals, but also construct gene regulatory networks to identify candidate genes that direct the aging process. This approach will allow us to uncover novel interactions and generate new hypotheses as to the fundamental processes surrounding muscle aging. We will discuss the genes coordinating muscle senescence which include, but are not limited to, the down‐regulation of ribosome biogenesis, upregulation of Z‐band‐associated‐proteins, and down‐regulation of nicotinic acetylcholine receptors. Our results provide an unprecedented view into the complex molecular regulatory events orchestrating muscle senescence.Support or Funding InformationSouth Dakota Board of Regents Competitive Research Grant #A20‐0013‐001; Nolop Institute of Medical Biology Summer Research Scholarship
Buddleja saligna Willd (Loganiaceae) Inhibits Angiotensin‐Converting Enzyme Activity in Oxidative Cardiopathy with Concomitant Modulation of Nucleotide Hydrolyzing Enzymatic Activities and Dysregulated Lipid Metabolic Pathways
Authors: Erukainure Ochuko Lucky , Matsabisa Motlalepula 
Published: April 2020

Buddleja saligna Willd (Loganiaceae), mostly indigenous to South Africa is traditionally used in the treatment cardio‐dysfunctional related ailments amongst other diseases. The cardio‐protective effect of B. saligna was investigated in ferric‐induced oxidative cardiopathy. Hearts harvested from healthy male SD rats were incubated with 0.1 mM FeSO4 to induce oxidative damage and co‐incubated with B. saligna extract. Reaction mixtures without the extract served as negative control, while tissues without the extract or standard antioxidant (gallic acid) and pro‐oxidant served as the normal control. The tissues were analyzed for levels of glutathione, malondialdehyde, and nitric oxide as well as cholinergic, angiotensin‐converting enzyme (ACE), lipase, and purinergic enzymes activities, lipid profiles, fatty acid metabolic pathways and metabolites. Induction of oxidative damage significantly (p<0.05) depleted the levels of GSH, SOD, catalase, and ENTPDase activities, while concomitantly elevating the levels of MDA, NO, ACE, acetylcholinesterase, lipase and ATPase activities. These levels and activities were significantly reversed on treatment with B. saligna. Treatment with B. saligna also led to depletion of cardiac cholesterol and LDL‐c levels, while elevating triglyceride and HDL‐c level. It also depleted oxidative‐induced lipid metabolites with concomitant generation of thirteen other metabolites. B. saligna also inactivated oxidative‐induced pathways for beta oxidation of very long chain fatty acids, glycerolipid metabolism, and fatty acid elongation in mitochondria. These results suggest that B. saligna protects against ferric‐induced oxidative cardiopathy by mitigating oxidative stress, while concomitantly inhibiting ACE, acetylcholinesterase and lipase activities, and modulating lipid spectrum and dysregulated metabolic pathways.Support or Funding InformationThis work was supported by research funding from the National Research Foundation; and the Department of Science and Innovation (DSI) through the IKS‐Based Technology Innovations, Pretoria, South Africa
Prohibitin‐1 plays a multifaceted role in mediating luteinizing hormone‐induced steroidogenesis in Leydig cells.
Authors: Bassi Geetika , Mishra Suresh 
Published: April 2020

Leydig cells (LCs) present in the interstitium between seminiferous tubules in the testis are responsible for the biosynthesis of testosterone from cholesterol in response to luteinizing hormone (LH) from the pituitary. The principal pathways of testosterone biosynthesis, the identities of the main steroidogenic enzymes, and genetic disorders of most of these enzymes have been elucidated. However, many important questions related to LH signaling and cholesterol transport remain unknown. For example, the mechanisms of StAR‐mediated cholesterol transport from the outer mitochondrial membrane to cytochrome P450 side chain cleavage (P450scc or Cyp11a1) enzyme in the inner mitochondrial membrane, which is a critical step in steroidogenesis, remain elusive. It is conceivable that we are missing some important players involved in this process.Prohibitin‐1 (PHB1) is a pleiotropic protein with cell compartment‐specific functions, including the phosphorylation‐dependent membrane signaling and mitochondrial chaperone, which appears to require heterodimerization with its homologous protein prohibitin‐2 (PHB2) in the inner mitochondrial membrane. Previously, we have reported transgenic mouse models expressing PHB1 (PHB‐Tg) or Y114F‐PHB1 (mPHB‐Tg) from the fatty acid binding protein‐4 (Fabp4) gene promoter. During their phenotypic characterization, unexpectedly, we found that male mPHB‐Tg mice, but not PHB‐Tg mice, have high testosterone levels. Subsequent analysis revealed that it was due to leaky overexpression of m/PHB1 in LCs. This prompted us to investigate whether LH regulates PHB1 in LCs. A dose and time‐dependent effect of human chorionic gonadotropin, hCG (pituitary analog of LH) was found on PHB1 expression levels in LCs. To define the cell compartment‐specific role of PHB1 in LCs, we investigated the functional status of LH signaling in testes/LCs and ultrastructure of LCs from transgenic mice. A difference in phospho‐ERK levels was found between PHB‐Tg and mPHB‐Tg, which was higher in mPHB1 expressing cells. A similar effect was found in PHB1 manipulated MA‐10 cells (a model LC line). A parallel change in ultrastructural features of LCs (mitochondrial structure and lipid droplets) was found in PHB and mPHB overexpressing cells. Moreover, co‐immunoprecipitation experiments showed that PHB1 and PHB2 interact with P450scc and/or StAR. Analysis of PHBs protein sequences revealed the presence of multiple CRAC and/or CARC motifs (cholesterol recognition motifs) in both proteins. In aggregate, this finding suggests that PHB1 is a LH regulated protein in LCs and plays a multifaceted role in LH‐induced steroidogenesis, including ERK activation and potentially in the functional coupling of StAR and P450scc across mitochondrial membrane for steroidogenesis. The scope of our findings is broad because the basics of cholesterol transport across mitochondrial membranes are similar in different steroidogenic tissues.
Enhancing Abiotic Stress Response via a Kalanchoe fedtschenkoi NF‐Y Transcription Factor in C3 Plants
Authors: Malwattage Naleeka Randani Mohotti , Garcia Travis M. , Cushman John C. , Wone Bernard W. M. 
Published: April 2020

Global crop production is expected to decrease because of increasing abiotic stressors including extremes in temperature, water, light intensity, nutrients, and radiation due to climate change and anthropogenic activities. Increased abiotic stressors will alter the metabolism in C3 plants and thus negatively affect their growth and productivity. Developing C3 crop varieties with improved abiotic stress tolerances emerges as the most sustainable solution towards ensuring global food security under the predicted climate change scenario. Crassulacean Acid Metabolism (CAM) plants are considered well‐adapted to drought, heat, increased light intensities, higher UV irradiation, and are far more water‐use efficient compared to C3 photosynthesis plants. The use of abiotic stress‐responsive transcription factors (TFs) from CAM plants is one feasible approach to improve crop production under adverse abiotic stress conditions. We have identified a NF‐YB TF from the heat‐tolerant obligate CAM plant Kalanchoe fedtschenkoi as a possible regulator of abiotic stresses. This NF‐Y is a ubiquitous transcription factor that is expressed as one of three possible isoforms NF‐YA, NF‐YB, or NF‐YC. Their isoforms interact to form a heterotrimeric complex with each subunit playing key roles in the abiotic stress responses including drought, heat, freezing, and salinity. We are functionally characterizing this KfNF‐YB via overexpression in Arabidopsis thaliana to determine its role in abiotic stress responses. Preliminary results following in vitro salinity stress assay of T2 transgenic lines after 12 days in MS media with 200 mM NaCl indicate increased root growth, whereas the wild type had retarded root growth. In addition, transgenic lines had higher biomass dry weight compared to wild type after 12 days. T2 lines also have increased rosette size in two‐week old transgenic A. thaliana compared to wild type. We will discuss the implications of the preliminary results as a potential strategy to enhance multiple abiotic stress tolerance responses in C3 plants.Support or Funding InformationThis work is funded by South Dakota Board of Regents Grant #A18‐0015‐001 to BWM Wone and supported in part by U. S. Department of Energy, Office of Science, Genomic Science Program under award #DE‐SC0008834 to JC Cushman.
WNT Receptor Requirements for Dishevelled Phosphorylation
Authors: Hollis Katie , Zhong Alex , Stevens Payton , Diegel Cassandra , Michalski Megan , Williams Bart 
Published: April 2020

The Dishevelled (DVL) protein is a key component of WNT signaling that relays signals from receptors to downstream effectors. It has been shown that following WNT ligand binding to Frizzled (FZD) receptors, DVL is recruited to the membrane and is phosphorylated. Downstream signals of WNT require the presence of DVL. Since FZD receptors are the known receptor for WNT ligands, it has been assumed, but not shown that Wnt‐stimulated DVL phosphorylation is dependent on a FZD receptor. Since there are 19 WNTs, 10 FZDs, 3 DVLs and co‐receptors, such as LRP5/6 and ROR1/2, that play a role in Wnt signaling, it is suspected that the specific combination that forms the signaling complex determines the downstream signaling output. Most WNTs have been shown to activate canonical, β‐catenin dependent signaling, whereas WNT5a can stimulate multiple non‐canonical effector pathways such as planar cell polarity and calcium signaling. We hypothesize that the specific receptors, whether it be ROR1/2 or a particular FZD, that bind to WNT5a determine the non‐canonical pathway that is activated. In order to look further downstream, our primary objective is to determine which receptors are required in response to WNT5a to activate DVL phosphorylation.By using cellular models missing key proteins in the WNT signaling complex, we can determine their individual functions and redundancies. To study WNT‐FZD‐DVL interactions, we are utilizing cell lines which lack all ten FZDs (FZDless), ROR1/2 (Rorless), or DVL1/2/3 (DVLless) and assessing relative expression and phosphorylation of DVL. DVL expression is decreased in RORless cells and ROR1 and ROR2 expression are decreased in DVLless cells. LGK974 Porcupine inhibitor treatment to inhibit endogenous WNT secretion also reduces DVL expression in wildtype cells. In comparison, overexpression of the FZD2 receptor, results in increased ROR2 expression. FZDless cells show no phosphorylation of DVL under endogenous WNT stimulation or in the presence of WNT conditioned media (CM). In contrast, RORless cells show DVL phosphorylation under endogenous WNT expression, but not with LGK974 and subsequent WNT5a CM treatment.In conclusion, expression and phosphorylation of DVL are dependent on the expression of specific WNT receptors. WNT‐induced DVL phosphorylation is dependent on the presence of FZD receptors but expression of ROR receptors is not necessary. However, these requirements are dependent on the particular WNT ligand in question. WNT5a not only requires FZD receptors to stimulate DVL phosphorylation, but also requires ROR receptors. Overall, these findings demonstrate the intricacies of WNT signaling and lends itself to further investigation of these receptor requirements.Support or Funding InformationVan Andel Institute Graduate School Fellowship
Expression and Crystallization of Adenosine Deaminase Acting on tRNA
Authors: Hurdle Carolyn M. , Macbeth Mark R. 
Published: April 2020

Adenosine Deaminase tRNA Specific 1 (ADAT1) is an enzyme in the adenosine deaminase acting on RNA (ADAR) family that causes site‐specific adenosine mutation in eukaryotic tRNA. tRNA deamination by ADAT1 changes the adenosine nucleotide to an inosine, impacting the control of specific genetic programs. These enzymes do not have double stranded RNA binding motifs like that of the ADARs but instead share the catalytic domain of the ADAR. While structures for several ADAR enzymes have been determined, there are no structures for ADAT1. This research seeks to determine the structure of the ADAT1 enzyme from C. albicans. The enzyme contains conserved residues that are proposed to bind Zn2+and the inositol hexakisphosphate co‐factor, yet it has truncations that are in non‐conserved regions when compared to ADAT1 genes from other organisms. The Candida gene has been subcloned and will be expressed in S. cerevisiae. Through crystallization and X‐ray diffraction, a structure will be determined and the mechanism of substrate recognition and catalysis will be evaluated.Support or Funding InformationHolcomb Awards Committee Grant (MRM, 2019)