bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anomalous Origin in the Left Circumflex Artery from the Right Coronary Artery
Authors: Kruse Amelia , Connell Rachel , Harley Jackson , Rehman Rafey , Heintschel Alyssa , Barremkala Malli 
Published: June 2021

The typical branching pattern of the right coronary artery (RCA) consists of a marginal branch and a continuation as the posterior interventricular artery. The left coronary artery classically consists of an anterior interventricular artery and a circumflex branch, the latter of which courses around the left auricle and joins with the right coronary artery. According to past case reports, anomalies in this standard pattern are observed on angiograms with a 0.6% to 1.5% rate of occurrence (Dursunoğlu et al. 2007). Specific anomalies are found to occur at a lower rate, or are unreported due to insufficient studies and publications. Our team analyzed 23 human heart specimens (average age of 82 years) during routine cadaver dissection by undergraduate medical students and discovered an anomalous origin in the left circumflex artery (AOLCX). On the specified cadaver heart (71 year old male), an absence of the circumflex branch from the left coronary artery was noted; and upon further examination AOLCX was arising from a super‐dominant right coronary artery. After arising from the right proximal coronary artery, AOLCX wrapped around the posterior aspect of the aorta before arising anteriorly and circumflexing around the left auricle towards the posterior surface of the heart. The significance of this abnormality is that systolic compression of the AOLCX produced by the aorta and left atrium during daily activities may result in a transient reduction in coronary flow (Carboni). AOLCX from RCA has an incidence of 0.7 % (Roberts WC) and is associated with sudden death (Edwards, et al).Support or Funding InformationN/AThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Structural Insight into the Activin Receptor Assembly Mechanism
Authors: Goebel Erich J , Thompson Thomas 
Published: June 2021

Ligands of the TGFB family, which include BMPs and activins have been implicated to play critical roles in development, cardiac disease, and aging. Upon reaching the cell surface, each ligand signals by forming a ternary complex with type I and type II serine‐threonine kinase receptors. For TGFB and BMP ligands, crystal structures of ternary complexes have revealed differences in receptor assembly, providing context for differential receptor preferences. However, structural information for how activin class ligands assemble both receptors has been lacking. Along this, we have resolved the ternary crystal structure of an activin class member, GDF11, in complex with the type II receptor, ActRIIB, and the type I receptor, Alk5. The structure reveals that receptor positioning is similar to the BMP class with no inter‐receptor interactions, however, the location of the type I receptor is shifted toward the ligand fingertips away from the dimer interface. Since Alk5 serves as a low affinity receptor for both TGFB ligands and GDF11, the first activin receptor complex structure also reveals that different mechanisms have evolved to bind the same type I receptor. While TGFB utilizes inter‐receptor interactions and a cooperative mechanism to bind Alk5, GDF11 cradles Alk5 to form additional contacts at the fingertip region, which are shown, through mutagenesis analysis, to play a role in type I receptor specificity within the activin class. The structure of GDF11/ActRIIB/Alk5 shows that, across the TGFB family, different mechanisms have evolved to regulate type I receptor binding and specificity and provides a molecular explanation for how the activin class accommodates low affinity type I interactions without the requirement of cooperative receptor interactions.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Enzyme Kinetic Characterization and Substrate Specificity of Schizophyllum commune Metacaspases
Authors: Nguyen Le Minh , Fox Kristin M. 
Published: June 2021

Metacaspases are heterodimeric enzymes that belong to the family of cysteine‐dependent proteases, making them distantly related to metazoan caspases and potentially involved in programmed cell death in fungi, protozoa, and plants. Although metacaspases share structural characteristics with caspases, they lack aspartate specificity and instead show a preference for cleaving peptide bonds after arginine or lysine residues at P1. In our research, the five Type 1 Schizophyllum commune metacaspases 1–5 (ScMc1‐5) exhibit arginine and lysine specificity. However, the question of whether the enzymes show preference towards any specific amino acids that come before the cleavage site remains unanswered. To investigate the importance of substrate amino acid sequence for substrate specificity, we performed in‐vitro fluorescent activity assays comparing how ScMC1‐5 cleave various synthetic peptide substrates. Specifically, we examined the effect of amino acid size, charge and polarity on peptide cleavage. The results indicate that ScMC1‐5 demonstrate a preference to cleave more readily after arginine than lysine. They also exhibit significantly higher hydrolytic activity before small residues like glycine relative to larger residues like phenylalanine. Studying such differences in substrate specificity can be relevant for determining the types of proteins metacaspases cleave in vivo. In addition, we conducted enzymatic characterization to analyze ScMC1‐5 kinetics. ScMC1 showed a significantly larger Km, but the Vmax values for all the S. commune metacaspases were similar. Examining the differences among the metacaspases can further our understanding of their individual, physiological functions.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Using Ketoreductases for the Chemoenzymatic Synthesis of a Stereotriad
Authors: Kumru Kaan 
Published: June 2021

Polyketides are diverse natural products of high biological activity produced from complex molecular assembly lines called polyketide synthases (PKSs). Some of the most important bioactive molecules are polyketides, including geldanamycin, doxycycline, tetracycline, and erythromycin. Other polyketides have been shown to have antifungal, antiparasitic, immunosuppressive, and even anticancer properties. Of particular focus here is the ketoreductase (KR), one of the many possible domains within PKSs. The KR reduces carbonyl groups stereoselectively and controls the majority of stereocenters in the polyketide product. KRs have been used in a bottom‐up approach here, harnessing their stereoselective reductions to produce products that would traditionally be difficult and time‐consuming to synthesize. A diketide was first synthesized chemically and reduced with a tylosin KR from Streptomyces fradiae (TylKR2). This reduced diketide was then extended into a triketide through the Masamune C‐acylation reaction. Finally, TylKR2 and a mycolactone KR from a bacterial artificial chromosome (MycKR6) were found to reduce S‐(2‐acetamidoethyl)(4R,5R)‐5‐methoxy‐4‐methyl‐3‐oxoheptanethioate to S‐(2‐acetamidoethyl) (3S,4S,5R)‐3‐hydroxy‐5‐methoxy‐4‐methylheptanethioate in the case of TylKR2 and to S‐(2‐acetamidoethyl) (3R,4S,5R)‐3‐hydroxy‐5‐methoxy‐4‐methylheptanethioate in the case of MycKR6. The reductions were performed in vitro using the glucose dehydrogenase regeneration system with NADP+. In this way, each of the 3 stereocenters was set chemoenzymatically using KRs to form a stereotriad. With similar KRs, it is likely that all 8 possible stereoisomers could be synthesized. Ultimately, these di‐ and triketide building blocks could be extremely useful functional groups to experiment with in drug synthesis and may result in more potent or effective medicines. Additionally, this work could be extended into a methodology for setting as many stereocenters as desired ‐ possibly one day allowing for customizable polyketide synthesis in the same way oligonucleotides and polypeptides can be made today.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Purification, Isolation and Inhibition of Entamoeba histolytica's bifunctional alcohol/aldehyde dehydrogenase (EHADH2)
Authors: Gabrielle Matthew Lee , Espinosa Avelina 
Published: June 2021

Entamoeba histolytica is a unicellular eukaryote that is the causative agent for amebiasis in humans. There are ~100,000 fatalities annually, distributed mostly in developing countries. Cyst‐contaminated food and water disproportionately present in conflict zones. Additionally, lack of resources, clean water, sanitation, and limited access to education and health contribute to the rate of disease worldwide. The current treatment is metronidazole which is effective but has toxic and neurological side effects. The bifunctional alcohol‐aldehyde dehydrogenase (EhADH2) has been suggested as a target for anti‐amebic inhibitors, because it is essential for E. histolytica trophozoite growth. Entamoeba spp use EhADH2 to convert (anaerobically) acetyl‐CoA to acetaldehyde and acetaldehyde to ethanol. Substrate and cofactor (NADH, Fe) cofactor binding sites could be targeted for inhibition. Cyclic carbinol molecules such as cyclobutyl and cyclopropyl inhibit E. histolytica growth by affecting EhADH2 activities. Pyrazoline molecules have also showed inhibitory effects on E. histolytica growth. Three series of pyrazoline inhibitors previously synthesized and preliminarily selected by trophozoite growth inhibition will be tested for their ability to inhibit EhADH2 bifunctional activities. Establishing the mechanism of action for anti‐amebic inhibitors through restriction of EhADH2 activity may provide an alternative treatment to current toxic drugs such as metronidazole.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ginger provides neuroprotection in experimental model of traumatic brain injury
Authors: Sahin Kazim , Kilic Ertugrul , Balcikanli Zeynep , Ates Nilay , Orhan Cemal , Tuzcu Mehmet , Juturu Vijaya 
Published: June 2021

Ginger (Zingiberaceae family) containing gingerols, shogaols, zingerone and volatile oils active compounds, exerts anti‐inflammatory, antioxidant, antiplatelet, fat loss, prevention of cardiovascular disease and anticancer activity. In spite of these known effects, the underlying mechanisms in the signaling pathways that ginger protects the brain after brain trauma are largely unknown. Therefore, the objective of this study was to examine the administration of ginger extract (Gingever®) to improve histopathological results and to demonstrate neuroprotective activity with antioxidative and anti‐inflammatory properties following TBI. Brain injury was induced using a cold trauma model in male mice that were treated with ginger extract (50 mg/kg) or vehicle via intraperitoneal administration just after TBI. Mice were divided into two groups: TBI+vehicle group and TBI+ ginger extract group. Our results show that ginger administration decreased infarct volume by decreasing nuclear factor‐κB (NF‐κB), interleukin 1‐beta (IL‐1b), and glial fibrillary acidic protein (GFAP) and by increasing neurotrophic factor BDNF, growth‐associated protein‐43 (GAP‐43), neural cell adhesion molecule (ICAM) and nuclear factor erythroid 2‐related factor 2 (Nrf2) in the brain. Our findings suggested that ginger promotes neuroprotection following TBI by inhibiting the levels of inflammation, NFkB, and GFAP, and increasing GAP‐43 and Nrf2 levels.Support or Funding InformationThis research was funded by the OmniActive Health Technologies Inc, NJ, USA and partly supported by the Turkish Academy of Sciences (Ankara, Turkey, KS).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Modulation of EGF‐R signaling by desmoglein 2 in pancreatic cancer cells
Authors: Hoffmann Jan , Schinner Camilla , Dietrich Niclas , Zeiler Julian , Spindler Volker 
Published: June 2021

Desmogleins are cell adhesion molecules located both in desmosomes and extradesmosomal regions in the membrane with well‐established roles for intercellular adhesion and signaling. We have previously shown that loss of the most widespread desmoglein, Dsg2, increases malignant behavior and induces a non‐epithelial phenotype through dysregulation of Erk signaling in pancreatic cancer cell lines. Here, we further explored the interdependence of Dsg2 and EGFR/Erk signaling by using Dsg2 knockouts of the pancreatic cancer cell line AsPC‐1. Dsg2 knockout clones showed reduced cell adhesion, enhanced migration and augmented invasion in extracellular matrix. Dsg2 interacted with EGFR as demonstrated in immunoprecipitation experiments. However, upon serum depletion, the increased migratory capacity of Dsg2 knockouts was abrogated and not restored upon EGF treatment. This indicates that increased migration in response to Dsg2 loss is agonist‐dependent but independent of EGF. Furthermore, inhibition of EGFR tyrosin kinase activity using erlotinib was significantly less effective in reducing migration of knockouts compared to wildtype controls. In line with this, erlotinib treatment reduced ERK activity in wildtype controls but not in Dsg2 knockout cells and only partially reverted the non‐epithelial phenotype in response to Dsg2 loss. These data indicate that Dsg2 modulates the activity of EGFR signaling in an agonist‐dependent manner.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of acetazolamide on brain swelling and aquaporin‐4 expression in rats brain after ischemic stroke
Authors: Duan Hubin , Hao Chunyan , Duan Shengqiang , Wang suping , Gao Weiqing , Zhang Ce 
Published: June 2021

ObjectiveTo study the effect of acetazolamide(AZA) on cerebral edema and aquaporin‐ 4 (AQP4) expression after cerebral infarction in rats. To explore the relations between ischemic cerebral edema and AQP4 expression.Methods150 male SD rats were randomly divided into three groups: sham operation group, non‐intervention group, AZA treatment group. Each group was divided into five subgroups according to the time of cerebral ischemia (6h, 1d, 3d, 5d and 7d), and there were 10 rats in each subgroup . The rats model of cerebral infarction was adopted by means of bilateral carotid arteries ligation(2‐VO) method. The treatment group was given intraperitoneal injection of AZA, while the sham operation group and the non‐intervention group were injected the same amount of normal saline at the corresponding time point above. The cerebral edema was measured by dry‐wet weight method. The expression of AQP4 in cerebral infarction was detected by immunohistochemistry.ResultsThe brain water content(BWC) and the expression of AQP4 in non‐intervention group and AZA treatment group began to increase at 6h after cerebral infarction, it reached the peak at 3d, and then decreased gradually.(P<0.05). The BWC and the expression of AQP4 in sham operation group had not change significantly at any time point above (P>0.05). At different time points, the BWC and the expression of AQP4 in non‐intervention group and AZA treatment group was higher than that in sham operation group.(P<0.05). The BWC and the expression of AQP4 in AZA treatment group was lower than that in non‐intervention group.(P<0.05). The expression of AQP4 in sham operation group had not change significantly at any time point above (P>0.05).ConclusionsAcetazolamide can alleviate rats cerebral edema and the expression of AQP4 after rats cerebral infarction, and it may alleviate rats cerebral edema by reducing the expression of AQP4 in rats brain.Support or Funding InformationThis study was supported by the National Natural Science Foundation Youth Fund (30600637), China Postdoctral Foundation(2014M561207), the Shanxi Province Basic Research Program ( 2010021034‐4, 201601D011119), the Shanxi Scholarship Council of China (2011‐096 and Key Projects No.4), Department of Human Resources and Social Security of Shanxi province, The science and technology research projects of health department of Shanxi Province(2016D011119), The Teaching Reform Program of Shanxi Higher Education , The Education Reform Project of Postgraduate Students in Shanxi Province. The Project of “131” Leading Talents of Shanxi Higher Education, The Education Reform Project of Shanxi Medical University.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A New Family of Imidazoline I2 Receptor Ligands Improves Behavior and Cognition in SAMP8 Mice
Authors: Escolano Carmen , Griñán‐Ferré Christian , Vasilopoulou Foetini , Abas Sonia , Rodriguez‐Arevalo Sergio , Bagan Andrea , Perez Belen , Callado Luis F , Garcia‐Sevilla Jesus A , Garcia‐Fuster M. Julia , Pallas Merce , Brea Jose M. , Loza Maria Isabel 
Published: June 2021

Imidazoline I2 receptors (I2‐IR) are widely distributed in the central nervous system. I2‐IR are associated with human brain disorders and I2‐IR proteins are increased in the patients that suffered from Alzheimer's disease (AD). Since structural data for I2‐IR remains unknown, the discovery of selective I2‐IR ligands devoid of alfa2‐adrenoceptor affinity is likely to provide valuable tools to define the pharmacological characterization of these receptors.We reported a new family of (2‐imidazoline‐4‐yl)phosphonates that showed, in radioligand binding studies, higher affinity and selectivity for I2‐IR than idazoxan and other standard I2‐IR ligands. New compounds exhibit good blood‐brain‐barrier properties (PAMPA assay). In vivo studies in mice showed that acute treatments with two of the new ligands induces hypothermia, significantly increases p‐FADD/FADD ratio, an index of cell survival, and reduced hippocampal p35 cleavage into neurotoxic p25, indicating a neuroprotective role.Herein, we present the cognitive and molecular analysis of the treatment of female senescence accelerated mouse‐prone 8 mice (SAMP8) with two leads of our new family of I2‐IR ligands. In particular, 12 months‐old SAMP8 (n=26) were divided randomly into three groups (control, n=10), SAMP8 treated with I2‐IR ligands (compound 1, n= 8 and compound 2, n= 8). Compounds were administered through drinking water and concentration dose adjusted to reach a 5 mg/kg/day during 4 weeks. Behavior and cognitive effects were investigated through three well‐established tests, OFT, EPM and NORT, showing beneficial effects on treated animals. These results were supported by the assessment of key molecular markers for oxidative stress, inflammation indicators, synapsis and apoptosis, parameters related with cognitive decline and AD.Further, in vitro selectivity and ADME‐TOX profiling (human and mice microsomal stability, cytotoxicity, cytochromes inhibition, Caco‐2 permeability, hERG inhibition) and pharmacokinetics will be presented for a lead candidate.In summary, here we present the effectiveness of two new I2‐IR ligands in an in vivo model (SAMP8) for cognitive decline. Although different authors reported the relationship between I2‐ IR and cognitive decline, this study is the first experimental evidence that propose I2‐IR as a new therapeutic target to face AD, an unmet medical need.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Mechanism of Ligand‐Induced Activation of the Tie Family of Receptor Tyrosine Kinases
Authors: MADUKWE JERRY , FERGUSON KATHRYN 
Published: June 2021

Tie1 and Tie2, members of the tyrosine kinase family with immunoglobulin and EGF homology domains, are receptor tyrosine kinases found primarily in endothelial cells with key roles in development and maintenance of the vasculature and in angiogenesis. They are attractive targets for therapeutic intervention in tumor angiogenesis, inflammation, and sepsis. Tie2 is regulated directly by the multimeric angiopoietin (Ang) ligands, with Ang1 being its primary activator. We have previously shown that the Tie2 extracellular region (ECR) forms strong dimers even in the absence of bound ligand and that dimerization is mediated by membrane‐proximal fibronectin type III (FNIII) domains that were omitted in previous structural studies as revealed in the 2.5‐Å resolution X‐ray crystal structure of the membrane‐proximal three Tie2 FNIII domains. However, it is not known whether the membrane proximal FNIII domains of Tie receptors mediate homo‐ and heteromeric interactions that are key in determining the signaling outcome of ligand binding to Tie2. We propose to elucidate the role of the membrane proximal FNIII domains of Tie2 receptors on ligand binding using purified proteins in biophysical and cell‐based experiments. We have successfully purified significant yields of Tie2 and Tie1 ECR lacking or containing the proximal FNIII domains. We are currently optimizing our yields of purified angiopoietin ligands of defined oligomeric states. The oligomeric states of the Ang ligands will be confirmed by size exclusion chromatography and small angle x‐ray scattering analysis. We will use surface plasmon resonance to assess binding of the Ang ligands to the Tie2 ECR variants. We will examine the size of the complex formed between the Ang ligands and Tie2 variants using size exclusion chromatography/multi angle laser light scattering analysis. In addition, we will determine a high‐resolution structure of the complete ECR of Tie2 with or without Ang ligands bound. Taken together, these studies will reveal the effect of the Tie2 extracellular proximal FNIII domain on ligand binding and complex formation. Finally, we will assess the importance of our biophysical experiments findings on cellular signaling using cell‐based assays. We will test the ability of Ang ligands with defined oligomeric states to activate Tie2. Phosphorylation status of Tie2 and downstream signaling molecules such as Akt will serve as a measure of Tie2 activation.Support or Funding InformationNIH grant R01 CA214704This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.