Digital Commons Network^™

Peripheral Huntingtin Silencing Does Not Ameliorate Central Signs Of Disease In The B6.Httq111/+ Mouse Model Of Huntington's Disease., Sydney R Coffey, Robert M Bragg, Shawn Minnig, Seth A Ament, Jeffrey P Cantle, Anne Glickenhaus, Daniel Shelnut, José M Carrillo, Dominic D Shuttleworth, Julie-Anne Rodier, Kimihiro Noguchi, C Frank Bennett, Nathan D Price, Holly B Kordasiewicz, Jeffrey B Carroll

Articles, Abstracts, and Reports

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease whose predominant neuropathological signature is the selective loss of medium spiny neurons in the striatum. Despite this selective neuropathology, the mutant protein (huntingtin) is found in virtually every cell so far studied, and, consequently, phenotypes are observed in a wide range of organ systems both inside and outside the central nervous system. We, and others, have suggested that peripheral dysfunction could contribute to the rate of progression of striatal phenotypes of HD. To test this hypothesis, we lowered levels of huntingtin by treating mice with antisense oligonucleotides (ASOs) targeting the murine …

An Indicator Cell Assay For Blood-Based Diagnostics., Samuel A Danziger, Leslie R Miller, Karanbir Singh, G Adam Whitney, Elaine R Peskind, Ge Li, Robert J Lipshutz, John D Aitchison, Jennifer J Smith

Articles, Abstracts, and Reports

We have established proof of principle for the Indicator Cell Assay Platform™ (iCAP™), a broadly applicable tool for blood-based diagnostics that uses specifically-selected, standardized cells as biosensors, relying on their innate ability to integrate and respond to diverse signals present in patients' blood. To develop an assay, indicator cells are exposed in vitro to serum from case or control subjects and their global differential response patterns are used to train reliable, disease classifiers based on a small number of features. In a feasibility study, the iCAP detected pre-symptomatic disease in a murine model of amyotrophic lateral sclerosis (ALS) with 94% …

Spina Bifida: Pathogenesis, Mechanisms, And Genes In Mice And Humans, S.W. Mohd-Zin, A.I. Marwan, M.K. Abou Chaar, A. Ahmad-Annuar, N.M. Abdul-Aziz

Research Publications (2016 to 2020)

Spina bifida is among the phenotypes of the larger condition known as neural tube defects (NTDs). It is the most common central nervous system malformation compatible with life and the second leading cause of birth defects after congenital heart defects. In this review paper, we define spina bifida and discuss the phenotypes seen in humans as described by both surgeons and embryologists in order to compare and ultimately contrast it to the leading animal model, the mouse. Our understanding of spina bifida is currently limited to the observations we make in mouse models, which reflect complete or targeted knockouts of …

Identifying Novel Transcription Factors Involved In The Inflammatory Response By Using Binding Site Motif Scanning In Genomic Regions Defined By Histone Acetylation., Peter S Askovich, Stephen A Ramsey, Alan H Diercks, Kathleen A Kennedy, Theo A Knijnenburg, Alan Aderem

Articles, Abstracts, and Reports

The innate immune response to pathogenic challenge is a complex, multi-staged process involving thousands of genes. While numerous transcription factors that act as master regulators of this response have been identified, the temporal complexity of gene expression changes in response to pathogen-associated molecular pattern receptor stimulation strongly suggest that additional layers of regulation remain to be uncovered. The evolved pathogen response program in mammalian innate immune cells is understood to reflect a compromise between the probability of clearing the infection and the extent of tissue damage and inflammatory sequelae it causes. Because of that, a key challenge to delineating the …

Cd26 As A Novel Marker For Identifying T Cells With Potent Antitumor Activity, Stefanie Renae Bailey

MUSC Theses and Dissertations

Cancer immunotherapies engage the immune system to elicit antitumor responses. The discovery of cell-intrinsic inhibitory pathways and cancer-specific antigens has allowed for the advancement of immune checkpoint blockades and a cellular therapy called adoptive cell transfer (ACT), respectively. ACT is an innovative therapy that entails the acquisition, expansion and infusion of autologous T cells back into the patient to eradicate tumors. The development of this field has yielded exciting results for patients with advanced malignancies, particularly blood-based cancers. Defined as a living drug, ACT has the unique potential to elicit long-term responses if transferred T cells are capable of persisting. …

Annotation Of Alternatively Spliced Proteins And Transcripts With Protein-Folding Algorithms And Isoform-Level Functional Networks., Hongdong Li, Yang Zhang, Yuanfang Guan, Rajasree Menon, Gilbert S Omenn

Articles, Abstracts, and Reports

Tens of thousands of splice isoforms of proteins have been catalogued as predicted sequences from transcripts in humans and other species. Relatively few have been characterized biochemically or structurally. With the extensive development of protein bioinformatics, the characterization and modeling of isoform features, isoform functions, and isoform-level networks have advanced notably. Here we present applications of the I-TASSER family of algorithms for folding and functional predictions and the IsoFunc, MIsoMine, and Hisonet data resources for isoform-level analyses of network and pathway-based functional predictions and protein-protein interactions. Hopefully, predictions and insights from protein bioinformatics will stimulate many experimental validation studies.

Wall Tension Regulates The Abundance Of Mir-133a In The Thoracic Aorta, Adam William Akerman

MUSC Theses and Dissertations

A reduction in microRNA (miR)-133a is associated with dilation of the thoracic aorta (TA). Since wall tension increases with vessel diameter, this study tested the hypothesis that elevated mechanical tension induces the loss of miR-133a in the TA. Elevated tension (1.5g, 3hrs) applied to murine TA ex vivo reduced miR-133a (0.31±0.17 vs 1.00±0.25 fold; p<0.05 vs normotension (0.7g)). Cyclic stretch (12%, 1Hz, 3hrs) reduced miR-133a in TA fibroblasts (0.21±0.02 vs 1.00±0.27 fold; p<0.05 vs static control), with no change in smooth muscle cells. Neither transcription of miR-133a nor mRNA/protein levels of three microRNA-specific exoribonucleases were altered with stretching of the fibroblasts. However, stretch induced exosome secretion of miR-133a. Two in vivo models of hypertension were utilized to determine the effect of elevated wall tension on miR-133a in the TA: Angiotensin-II infusion (1.44mg/kg/day, 28 days) and a spontaneous hypertensive mouse line (BPH2). In both models, blood pressures were elevated and miR-133a was decreased in the TA compared to normotensive mice (0.69±0.06 and 0.52±0.04 vs 1.00±0.13 fold respectively; p<0.05 for both). Plasma miR-133a was elevated in the BPH2 mice (3.39±0.77 vs 1.00±0.41 fold; p<0.05 vs normotensive). Plasma miR-133a was also elevated in hypertensive human subjects (1.55±0.26 vs 1.00±0.18 fold, p<0.05 vs normotensive). These findings demonstrate that the reduction in miR-133a levels that occurred with increased mechanical stretch of the TA was likely driven by exosome secretion from TA fibroblasts, and may provide a novel target for detrimental remodeling of the vasculature in the setting of hypertension.

Mc-Ppea As A New And More Potent Inhibitor Of Clp-Induced Sepsis And Pulmonary Inflammation Than Fk866., Peixin Huang, Mark W Lee, Keivan Sadrerafi, Daniel P. Heruth, Li Q. Zhang, Dev Maulik, Shui Qing Ye

Manuscripts, Articles, Book Chapters and Other Papers

Our previous study indicated that overexpression of nicotinamide phosphoribosyltransferase (NAMPT) aggravated acute lung injury, while knockdown of NAMPT expression attenuated ventilator-induced lung injury. Recently, we found that meta-carborane-butyl-3-(3-pyridinyl)-2E-propenamide (MC-PPEA, MC4), in which the benzoylpiperidine moiety of FK866 has been replaced by a carborane, displayed a 100-fold increase in NAMPT inhibition over FK866. Here, we determined the effects of MC4 and FK866 on cecal ligation and puncture (CLP) surgery-induced sepsis in C57BL/6J mice. MC4 showed stronger inhibitory effects than FK866 on CLP-induced mortality, serum tumor necrosis factor α (TNFα) levels, pulmonary myeloperoxidase activity, alveolar injury, and interleukin 6 and interleukin1β messenger …

Altered Gut Microbiome In A Mouse Model Of Gulf War Illness Causes Neuroinflammation And Intestinal Injury Via Leaky Gut And Tlr4 Activation, Firas Alhasson, Suvarthi Das, Ratanesh K. Seth, Diptadip Dattaroy, Varun Chandrashekaran, Caitlin N. Ryan, Luisa S. Chan, Traci Testerman, James Burch, Lorne J. Hofseth, Ronnie Horner, Mitzi Nagarkatti, Prakash Nagarkatti, Stephen M. Lasley, Saurabh Chatterjee

Faculty Publications

Many of the symptoms of Gulf War Illness (GWI) that include neurological abnormalities, neuroinflammation, chronic fatigue and gastrointestinal disturbances have been traced to Gulf War chemical exposure. Though the association and subsequent evidences are strong, the mechanisms that connect exposure to intestinal and neurological abnormalities remain unclear. Using an established rodent model of Gulf War Illness, we show that chemical exposure caused significant dysbiosis in the gut that included increased abundance of phylum Firmicutes and Tenericutes, and decreased abundance of Bacteroidetes. Several gram negative bacterial genera were enriched in the GWI-model that included Allobaculum sp. Altered microbiome caused significant decrease …

Targeted Calcium Influx Boosts Cytotoxic T Lymphocyte Function In The Tumour Microenvironment, Kyun-Do Kim, Seyeon Bae, Tara Capece, Hristina Nedelkovska, Rafael G. De Rubio, Alan V. Smrcka, Jun Chang-Duk, Jung Woojin, Byeonghak Park, Minsoo Kim, Tae-Il Kim, Minsoo Kim

Biology

Adoptive cell transfer utilizing tumour-targeting cytotoxic T lymphocytes (CTLs) is one of the most effective immunotherapies against haematological malignancies, but significant clinical success has not yet been achieved in solid tumours due in part to the strong immunosuppressive tumour microenvironment. Here, we show that suppression of CTL killing by CD4+CD25+Foxp+ regulatory T cell (Treg) is in part mediated by TGFβ-induced inhibition of inositol trisphosphate (IP3) production, leading to a decrease in T cell receptor (TCR)-dependent intracellular Ca2+ response. Highly selective optical control of Ca2+ signalling in adoptively transferred CTLs enhances T cell activation and IFN-γ production in vitro, leading to …

Mononuclear-Macrophages But Not Neutrophils Act As Major Infiltrating Anti-Leptospiral Phagocytes During Leptospirosis., Xu Chen, Shi-Jun Li, David M. Ojcius, Ai-Hua Sun, Wei-Lin Hu, Xu'ai Lin, Jie Yan

All Dugoni School of Dentistry Faculty Articles

OBJECTIVE: To identify the major infiltrating phagocytes during leptospirosis and examine the killing mechanism used by the host to eliminate Leptospira interrogans.

METHODS: Major infiltrating phagocytes in Leptospira-infected C3H/HeJ mice were detected by immunohistochemistry. Chemokines and vascular endothelial cell adhesion molecules (VECAMs) of Leptospira-infected mice and leptospirosis patients were detected by microarray and immunohistochemistry. Leptospira-phagocytosing and -killing abilities of human or mouse macrophages and neutrophils, and the roles of intracellular ROS, NO and [Ca2+]i in Leptospira-killing process were evaluated by confocal microscopy and spectrofluorimetry.

RESULTS: Peripheral blood mononuclear-macrophages rather than neutrophils were the main infiltrating phagocytes in the lungs, liver …

Advances In The Creation And Use Of Genetically Modified Rodent Models, Laura Lambert

All ETDs from UAB

Rodents have been the model of choice for decades in biomedical research due to their relatively high physiological similarity to humans and amenability to genomic modification. While transgenic constructs were first used in mouse blastocysts in 1974 and the first mouse embryonic stem (ES) cell line created in 1981, the lack of reliable methods to produce ES cells or culture embryos from the rat led to the limitation of its use in spite of several advantages such as larger size and higher genetic homology with humans. Use of genetic modification has recently expanded due to the advent of tailored nucleases …

Aav-Mediated Expression Of Anti-Tau Scfvs Decreases Tau Accumulation In A Mouse Model Of Tauopathy, Christina Ising, Gilbert Gallardo, Cheryl E.G. Leyns, Connie H. Wong, Hong Jiang, Floy Stewart, Lauren J. Koscal, Joseph Roh, Grace O. Robinson, Javier Remolina Serrano, David M. Holtzman

Open Access Publications

Tauopathies are characterized by the progressive accumulation of hyperphosphorylated, aggregated forms of tau. Our laboratory has previously demonstrated that passive immunization with an anti-tau antibody, HJ8.5, decreased accumulation of pathological tau in a human P301S tau-expressing transgenic (P301S-tg) mouse model of frontotemporal dementia/tauopathy. To investigate whether the F

Analyzing And Modeling The Dysfunction Of Inhibitory Neurons In Alzheimer’S Disease, Carlos Perez, Jokubas Ziburkus, Ghamim Ullah

Physics Faculty Publications

Alzheimer’s disease (AD) is characterized by the abnormal proteolytic processing of amyloid precursor protein, resulting in increased production of a self-aggregating form of beta amyloid (Aβ). Several lines of work on AD patients and transgenic mice with high Aβ levels exhibit altered rhythmicity, aberrant neuronal network activity and hyperexcitability reflected in clusters of hyperactive neurons, and spontaneous epileptic activity. Recent studies highlight that abnormal accumulation of Aβ changes intrinsic properties of inhibitory neurons, which is one of the main reasons underlying the impaired network activity. However, specific cellular mechanisms leading to interneuronal dysfunction are not completely …

Fibroblast Growth Requires Ct10 Regulator Of Kinase (Crk) And Crk-Like (Crkl)., Taeju Park, Mateusz Koptyra, Tom Curran

Manuscripts, Articles, Book Chapters and Other Papers

CT10 regulator of kinase (Crk) and Crk-like (CrkL) are the cellular counterparts of the viral oncogene v-Crk Elevated levels of Crk and CrkL have been observed in many human cancers; inhibition of Crk and CrkL expression reduced the tumor-forming potential of cancer cell lines. Despite a close relationship between the Crk family proteins and tumorigenesis, how Crk and CrkL contribute to cell growth is unclear. We ablated endogenous Crk and CrkL from cultured fibroblasts carrying floxed alleles of Crk and CrkL by transfection with synthetic Cre mRNA (synCre). Loss of Crk and CrkL induced by synCre transfection blocked cell proliferation …

Recombinant Listeria Adhesion Protein Expressing Probiotics Protect Against Listeria Monocytogenes Infection In Animal Models, Valerie E. Ryan

Open Access Theses

Listeria monocytogenes (Lm) is a foodborne pathogen, found ubiquitously in nature, and has a high morbidity rate among immunocompromised individuals, the elderly, and especially pregnant women and their fetuses resulting in abortion, stillbirth, and neonatal infection. There are currently no preventative medical interventions against Lm infection. The Listeria adhesion protein (LAP) is present in both pathogenic and non-pathogenic Listeria (i.e., L. innocua) and has shown to interact with host epithelial proteins causing tight junction dysregulation aiding in pathogen attachment and paracellular translocation across the host intestinal epithelium. Our lab has demonstrated that recombinant probiotics, Lactobacillus casei (LbcWT) expressing LAP …

Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2 Regulates Lps-Induced Inflammation And Alveolar Remodeling In The Developing Lung., Heather Menden, Sheng Xia, Sherry M. Mabry, Angels Navarro, Michael F. Nyp, Venkatesh Sampath

Manuscripts, Articles, Book Chapters and Other Papers

In premature infants, sepsis is associated with alveolar simplification manifesting as bronchopulmonary dysplasia. The redox-dependent mechanisms underlying sepsis-induced inflammation and alveolar remodeling in the immature lung remain unclear. We developed a neonatal mouse model of sepsis-induced lung injury to investigate whether nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) regulates Toll-like receptor (TLR)-mediated inflammation and alveolar remodeling. Six-day-old NOX2

Development Of Activity In The Mouse Visual Cortex., Jing Shen, Matthew T Colonnese

Pharmacology and Physiology Faculty Publications

No abstract provided.

Effect Of The Butyrate Prodrug Pivaloyloxymethyl Butyrate (An9) On A Mouse Model For Spinal Muscular Atrophy., Jonathan D. Edwards, Matthew E.R. Butchbach

Department of Pediatrics Faculty Papers

Spinal muscular atrophy (SMA) is an early-onset motor neuron disease that leads to loss of muscle function. Butyrate (BA)-based compounds markedly improve the survival and motor phenotype of SMA mice. In this study, we examine the protective effects of the BA prodrug pivaloyloxymethyl butyrate (AN9) on the survival of SMNΔ7 SMA mice. Oral administration of AN9 beginning at PND04 almost doubled the average lifespan of SMNΔ7 SMA mice. AN9 treatment also increased the growth rate of SMNΔ7 SMA mice when compared to vehicle-treated SMNΔ7 SMA mice. In conclusion, BA prodrugs like AN9 have ameliorative effects on SMNΔ7 SMA mice.

Respective Contributions Of Single And Compound Granule Fusion To Secretion By Activated Platelets, Anita Eckly, Jean-Yves Rinckel, Fabienne Proamer, Neslihan Ulas, Smita Joshi, Sidney W. Whiteheart, Christian Gachet

Molecular and Cellular Biochemistry Faculty Publications

Although granule secretion is pivotal in many platelet responses, the fusion routes of α and δ granule release remain uncertain. We used a 3D reconstruction approach based on electron microscopy to visualize the spatial organization of granules in unstimulated and activated platelets. Two modes of exocytosis were identified: a single mode that leads to release of the contents of individual granules and a compound mode that leads to the formation of granule-to-granule fusion, resulting in the formation of large multigranular compartments. Both modes occur during the course of platelet secretion. Single fusion events are more visible at lower levels of …

V-Src Oncogene Induces Trop2 Proteolytic Activation Via Cyclin D1., Xiaoming Ju, Xuanmao Jiao, Adam Ertel, Mathew C. Casimiro, Gabriele Disante, Shengqiong Deng, Zhiping Li, Agnese Di Rocco, Tingting Zhan, Adam Hawkins, Tanya Stoyanova, Sebastiano Andò, Alessandro Fatatis, Michael P. Lisanti, Leonard G. Gomella, Lucia R. Languino, Richard G. Pestell

Department of Cancer Biology Faculty Papers

Proteomic analysis of castration-resistant prostate cancer demonstrated the enrichment of Src tyrosine kinase activity in approximately 90% of patients. Src is known to induce cyclin D1, and a cyclin D1-regulated gene expression module predicts poor outcome in human prostate cancer. The tumor-associated calcium signal transducer 2 (TACSTD2/Trop2/M1S1) is enriched in the prostate, promoting prostate stem cell self-renewal upon proteolytic activation via a γ-secretase cleavage complex (PS1, PS2) and TACE (ADAM17), which releases the Trop2 intracellular domain (Trop2 ICD). Herein, v-Src transformation of primary murine prostate epithelial cells increased the proportion of prostate cancer stem cells as characterized by gene expression, …

Quantitative Proteomic Profiling Reveals Hepatic Lipogenesis And Liver X Receptor Activation In The Pander Transgenic Model., Mark G. Athanason, Whitney A. Ratliff, Dale Chaput, Catherine B. Marelia, Melanie N. Kuehl, Stanley M. Stevens Jr., Brant R. Burkhardt

Molecular Biosciences Faculty Publications

PANcreatic-DERived factor (PANDER) is a member of a superfamily of FAM3 proteins modulating glycemic levels by metabolic regulation of the liver and pancreas. The precise PANDER-induced hepatic signaling mechanism is still being elucidated and has been very complex due to the pleiotropic nature of this novel hormone. Our PANDER transgenic (PANTG) mouse displays a selective hepatic insulin resistant (SHIR) phenotype whereby insulin signaling is blunted yet lipogenesis is increased, a phenomena observed in type 2 diabetes. To examine the complex PANDER-induced mechanism of SHIR, we utilized quantitative mass spectrometry-based proteomic analysis using Stable Isotope Labeling by Amino Acids in Cell …

Plant Expression Of Cocaine Hydrolase-Fc Fusion Protein For Treatment Of Cocaine Abuse, Guojun Wang, Ting Zhang, Haifeng Huang, Shurong Hou, Xiabin Chen, Fang Zheng, Chang-Guo Zhan

Molecular Modeling and Biopharmaceutical Center Faculty Publications

BACKGROUND: A recently reported cocaine hydrolase (CocH3) fused with fragment crystallizable (Fc) region of human immunoglobulin G1, denoted as CocH3-Fc, is known as a promising therapeutic candidate for the treatment of cocaine overdose and addiction. A challenge for practical therapeutic use of this enzyme exists in the large-scale protein production and, therefore, it is interesting to identify a low-cost and feasible, sustainable source of CocH3-Fc production.

RESULTS: CocH3-Fc was transiently expressed in plant Nicotiana benthamiana leaves. The plant-expressed protein, denoted as pCocH3-Fc, was as active as that expressed in mammalian cells both in vitro and in vivo. However, compared to …

Pleckstrin Homology (Ph) Domain Leucine-Rich Repeat Protein Phosphatase Controls Cell Polarity By Negatively Regulating The Activity Of Atypical Protein Kinase C, Xiaopeng Xiong, Xin Li, Yang-An Wen, Tianyan Gao

Markey Cancer Center Faculty Publications

The proper establishment of epithelial polarity allows cells to sense and respond to signals that arise from the microenvironment in a spatiotemporally controlled manner. Atypical PKCs (aPKCs) are implicated as key regulators of epithelial polarity. However, the molecular mechanism underlying the negative regulation of aPKCs remains largely unknown. In this study, we demonstrated that PH domain leucine-rich repeat protein phosphatase (PHLPP), a novel family of Ser/Thr protein phosphatases, plays an important role in regulating epithelial polarity by controlling the phosphorylation of both aPKC isoforms. Altered expression of PHLPP1 or PHLPP2 disrupted polarization of Caco2 cells grown in 3D cell cultures …

Tumor Vessel Normalization After Aerobic Exercise Enhances Chemotherapeutic Efficacy., Keri L Schadler, Nicholas J Thomas, Peter Galie, Dong Ha Bhang, Kerry C Roby, Prince Addai, Jacob E Till, Kathleen Sturgeon, Alexander Zaslavsky, Christopher S Chen, Sandra Ryeom

Henry M. Rowan College of Engineering Departmental Research

Targeted therapies aimed at tumor vasculature are utilized in combination with chemotherapy to improve drug delivery and efficacy after tumor vascular normalization. Tumor vessels are highly disorganized with disrupted blood flow impeding drug delivery to cancer cells. Although pharmacologic anti-angiogenic therapy can remodel and normalize tumor vessels, there is a limited window of efficacy and these drugs are associated with severe side effects necessitating alternatives for vascular normalization. Recently, moderate aerobic exercise has been shown to induce vascular normalization in mouse models. Here, we provide a mechanistic explanation for the tumor vascular normalization induced by exercise. Shear stress, the mechanical …

Epithelial Cell Integrin Β1 Is Required For Developmental Angiogenesis In The Pituitary Gland, Kathleen M. Scully, Dorota Skowronska-Krawczyk, Michal Krawczyk, Daria Merkurjev, Havilah Taylor, Antonia Livolsi, Jessica Tollkuhn, Radu V. Stan, Michael G. Rosenfeld

Dartmouth Scholarship

As a key component of the vertebrate neuroendocrine system, the pituitary gland relies on the progressive and coordinated development of distinct hormone-producing cell types and an invading vascular network. The molecular mechanisms that drive formation of the pituitary vasculature, which is necessary for regulated synthesis and secretion of hormones that maintain homeostasis, metabolism, and endocrine function, remain poorly understood. Here, we report that expression of integrin β1 in embryonic pituitary epithelial cells is required for angiogenesis in the developing mouse pituitary gland. Deletion of pituitary epithelial integrin β1 before the onset of angiogenesis resulted in failure of invading endothelial cells …

M-Track: A New Software For Automated Detection Of Grooming Trajectories In Mice, Annalisa Scimemi, Lin Zhang, Kelsey E. Fleming, Sheldon L. Reeves

Biological Sciences Faculty Scholarship

Grooming is a complex and robust innate behavior, commonly performed by most vertebrate species. In mice, grooming consists of a series of stereotyped patterned strokes, performed along the rostro-caudal axis of the body. The frequency and duration of each grooming episode is sensitive to changes in stress levels, social interactions and pharmacological manipulations, and is therefore used in behavioral studies to gain insights into the function of brain regions that control movement execution and anxiety. Traditional approaches to analyze grooming rely on manually scoring the time of onset and duration of each grooming episode, and are often performed on grooming …

Conditional Ablation Of Hdac3 In Islet Beta Cells Results In Glucose Intolerance And Enhanced Susceptibility To Stz-Induced Diabetes, Wen-Bin Chen, Ling Gao, Jie Wang, Yan-Gang Wang, Zheng Dong, Jiajun Zhao, Qing-Sheng Mi, Li Zhou

Dermatology Articles

Histone deacetylases (HDACs) are enzymes that regulate gene expression by modifying chromatin structure through removal of acetyl groups from target histones or non-histone proteins. Previous in vitro studies suggest that HDACs may be novel pharmacological targets in immune-mediated islet β-cell destruction. However, the role of specific HDAC in islet β-cell development and function remain unclear. Here, we generated a conditional islet β-cells specific HDAC3 deletion mouse model to determine the consequences of HDAC3 depletion on islet β-cell differentiation, maintenance and function. Islet morphology, insulin secretion, glucose tolerance, and multiple low-dose streptozotocin (STZ)-induced diabetes incidence were evaluated and compared between HDAC3 …

Chemical Modification Of Extracellular Matrix By Cold Atmospheric Plasma-Generated Reactive Species Affects Chondrogenesis And Bone Formation., Peter Eisenhauer, Natalie Chernets, You Song, Danil Dobrynin, Nancy Pleshko, Marla J Steinbeck, Theresa A. Freeman

Department of Orthopaedic Surgery Faculty Papers

The goal of this study was to investigate whether cold plasma generated by dielectric barrier discharge (DBD) modifies extracellular matrices (ECM) to influence chondrogenesis and endochondral ossification. Replacement of cartilage by bone during endochondral ossification is essential in fetal skeletal development, bone growth and fracture healing. Regulation of this process by the ECM occurs through matrix remodelling, involving a variety of cell attachment molecules and growth factors, which influence cell morphology and protein expression. The commercially available ECM, Matrigel, was treated with microsecond or nanosecond pulsed (μsp or nsp, respectively) DBD frequencies conditions at the equivalent frequencies (1 kHz) or …

Adam17 Substrate Release In Proximal Tubule Drives Kidney Fibrosis, Eirini Kefaloyianni, Muthu Lakshmi Muthu, Jakob Kaeppler, Xiaoming Sun, Venkata Sabbisetti, Athena Chalaris, Stefan Rose-John, Eitan Wong, Irit Sagi, Sushrut S. Waikar, Helmut Rennke, Benjamin D. Humphreys, Joseph V. Bonventre, Andreas Herrlich

Open Access Publications

Kidney fibrosis following kidney injury is an unresolved health problem and causes significant morbidity and mortality worldwide. In a study into its molecular mechanism, we identified essential causative features. Acute or chronic kidney injury causes sustained elevation of a disintegrin and metalloprotease 17 (ADAM17); of its cleavage-activated proligand substrates, in particular of pro-TNFα and the EGFR ligand amphiregulin (pro-AREG); and of the substrates' receptors. As a consequence, EGFR is persistently activated and triggers the synthesis and release of proinflammatory and profibrotic factors, resulting in macrophage/neutrophil ingress and fibrosis. ADAM17 hypomorphic mice, specific ADAM17 inhibitor-treated WT mice, or mice with inducible …