Digital Commons Network^™

Repair Of Thoracic Aortic Aneurysm With Bilateral Aberrant Subclavian Artery, Yuki Ikeno, Akiko Tanaka, Francesco Brandini, Anthony L Estrera

Faculty, Staff and Student Publications

We present a rare anatomical configuration of a 19-year-old woman, characterized by descending thoracic aortic aneurysm with right aberrant subclavian arteries with a Kommerell's diverticulum in a left aortic arch. The complexity of this vascular anomaly was accompanied by an anomalous origin of left subclavian artery. The patient underwent a single-stage open surgical repair via left thoracotomy under deep hypothermic circulatory arrest. The bilateral aberrant subclavian arteries were separately reconstructed in situ using hand-sewn branched grafts.

Structure And Function Are Not The Same: The Case For Restoring Mechanoreceptor Continuity Following Anterior Cruciate Ligament Injury, Jillian E Beveridge, Payam Zandiyeh, Brett D Owens, Ata M Kiapour, Braden C Fleming

Faculty, Staff and Student Publications

Anterior cruciate ligament (ACL) injury, particularly in increasingly young and active adolescents, continues to pose a clinical challenge with re-injury rates reported as high as 30%. Evidence also suggests that current standard-of-care ACL reconstruction (ACLR) does not mitigate post-traumatic osteoarthritis (PTOA) risk. Bridge- enhanced ACL restoration (BEAR) is a recently developed and tested ACL surgery that promotes primary healing of the native ACL with excellent early results. BEAR has shown to reduce signs of early PTOA compared to ACLR in an animal model. Here, we describe a theoretical framework related to re-innervation that can clarify why the outcomes of ACLR …

Vertebrate And Invertebrate Animal Infection Models Of Candida Auris Pathogenicity, Melissa Martinez, Danielle A Garsin, Michael C Lorenz

Faculty, Staff and Student Publications

Candida auris is an emerging fungal pathogen with several concerning qualities. First recognized in 2009, it has arisen in multiple geographically distinct genomic clades nearly simultaneously. C. auris strains are typically multidrug resistant and colonize the skin much better than most other pathogenic fungi; it also persists on abiotic surfaces, enabling outbreaks due to transmission in health care facilities. All these suggest a biology substantially different from the 'model' fungal pathogen, Candida albicans and support intensive investigation of C. auris biology directly. To uncover novel virulence mechanisms in this species requires the development of appropriate animal infection models. Various studies …

Tumoral Interferon Beta Induces An Immune-Stimulatory Phenotype In Tumor-Associated Macrophages In Melanoma Brain Metastases, Julia Gellert, Dennis A Agardy, Swaminathan Kumar, Alexandros Kourtesakis, Tamara Boschert, Kristine Jähne, Michael O Breckwoldt, Lukas Bunse, Wolfgang Wick, Michael A Davies, Michael Platten, Theresa Bunse

Faculty, Staff and Student Publications

Type I interferons (IFN) are immune-stimulatory cytokines involved in antiviral and antitumor immune responses. They enhance the efficacy of immunogenic anticancer therapies such as radiotherapy by activating both innate and adaptive immune cells. Macrophages are one of the most abundant innate immune cells in the immune microenvironment of melanoma brain metastases (MBM) and can exert potent immune-suppressive functions. Here, we investigate the potential of tumoral type I IFNs to repolarize tumor-associated macrophages (TAM) in two murine MBM models and assess the effects of radiotherapy-induced type I IFN on TAMs in a transcriptomic MBM patient dataset. In mice, we describe a …

Targeting Adenosine A2b Receptor Promotes Penile Rehabilitation Of Refractory Erectile Dysfunction, Yang Xiong, Feng Qin, Shanzun Wei, Xingliang Yang, Jun Li, Changjing Wu, Fuxun Zhang, Jiuhong Yuan

Faculty, Staff and Student Publications

The mechanisms of adenosine and specific adenosine receptor subtypes in promoting penile rehabilitation remain unclear. Single‐cell RNA sequencing of human corpus cavernosum,  adenosine deaminase (ADA) and adenosine receptors knock‐out mice (ADA−/−, A1−/−, A2a−/−, A2b−/−, and A3−/−), and primary corpus cavernosum smooth muscle cells are used to determine receptor subtypes responsible for adenosine‐induced erection. Three rat models are established to characterize refractory erectile dysfunction (ED): age‐related ED, bilateral cavernous nerve crush related ED (BCNC), and diabetes mellitus‐induced ED. In single‐cell RNA sequencing data, the corpus cavernosum of ED patients show a decrease in adenosine A1, A2a and A2b receptors. In vivo, …

Proteomics In Orthopedic Research: Recent Studies And Their Translational Implications, George Li, Argyrios Stampas, Yoshihiro Komatsu, Xueqin Gao, Johnny Huard, Sheng Pan

Faculty, Staff and Student Publications

Proteomics is a growing field that offers insights into various aspects of disease processes and therapy responses. Within the field of orthopedics, there are a variety of diseases that have a poor prognosis due to a lack of targeted curative therapy or disease modifying therapy. Other diseases have been difficult to manage in part due to lack of clinical biomarkers that offer meaningful insight into disease progression or severity. As an emerging technology, proteomics has been increasingly applied in studying bone biology and an assortment of orthopedics related diseases, such as osteoarthritis, osteosarcoma and bone tumors, osteoporosis, traumatic bone injury, …

Enolase Inhibitors As Therapeutic Leads For Naegleria Fowleri Infection, Jillian E Milanes, Victoria C Yan, Cong-Dat Pham, Florian Muller, Samuel Kwain, Kerrick C Rees, Brian N Dominy, Daniel C Whitehead, Steven W Millward, Madison Bolejack, Roger Shek, Logan Tillery, Isabelle Q Phan, Bart Staker, E Ashley Moseman, Xiang Zhang, Xipeng Ma, Audriy Jebet, Xinmin Yin, James C Morris

Faculty, Staff and Student Publications

Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used …

T-Bet Suppresses Proliferation Of Malignant B Cells In Chronic Lymphocytic Leukemia, Philipp M Roessner, Isabelle Seufert, Vicente Chapaprieta, Ruparoshni Jayabalan, Hannah Briesch, Ramon Massoni-Badosa, Pavle Boskovic, Julian Benckendorff, Tobias Roider, Lavinia Arseni, Mariana Coelho, Supriya Chakraborty, Alicia M Vaca, Mariela Sivina, Markus Muckenhuber, Sonia Rodriguez-Rodriguez, Alice Bonato, Sophie A Herbst, Marc Zapatka, Clare Sun, Helene Kretzmer, Thomas Naake, Peter-Martin Bruch, Felix Czernilofsky, Elisa Ten Hacken, Martin Schneider, Dominic Helm, Deyan Y Yosifov, Joseph Kauer, Alexey V Danilov, Moritz Bewarder, Kristina Heyne, Christof Schneider, Stephan Stilgenbauer, Adrian Wiestner, Jan-Philipp Mallm, Jan A Burger, Dimitar G Efremov, Peter Lichter, Sascha Dietrich, José I Martin-Subero, Karsten Rippe, Martina Seiffert

Faculty, Staff and Student Publications

The T-box transcription factor T-bet is known as a master regulator of the T-cell response but its role in malignant B cells has not been sufficiently explored. Here, we conducted single-cell resolved multi-omics analyses of malignant B cells from patients with chronic lymphocytic leukemia (CLL) and studied a CLL mouse model with a genetic knockout of Tbx21. We found that T-bet acts as a tumor suppressor in malignant B cells by decreasing their proliferation rate. NF-κB activity, induced by inflammatory signals provided by the microenvironment, triggered T-bet expression, which affected promoter-proximal and distal chromatin coaccessibility and controlled a specific gene …

Nf1 Mutation Disrupts Activity-Dependent Oligodendroglial Plasticity And Motor Learning In Mice, Yuan Pan, Corina Anastasaki, Jit Chatterjee, Suzanne Scheaffer, David H Gutmann, Et Al.

2020-Current year OA Pubs

Neurogenetic disorders, such as neurofibromatosis type 1 (NF1), can cause cognitive and motor impairments, traditionally attributed to intrinsic neuronal defects such as disruption of synaptic function. Activity-regulated oligodendroglial plasticity also contributes to cognitive and motor functions by tuning neural circuit dynamics. However, the relevance of oligodendroglial plasticity to neurological dysfunction in NF1 is unclear. Here we explore the contribution of oligodendrocyte progenitor cells (OPCs) to pathological features of the NF1 syndrome in mice. Both male and female littermates (4-24 weeks of age) were used equally in this study. We demonstrate that mice with global or OPC-specific Nf1 heterozygosity exhibit defects …

Neoantigen-Specific Cytotoxic Tr1 Cd4 T Cells Suppress Cancer Immunotherapy, Hussein Sultan, Yoshiko Takeuchi, Jeffrey P Ward, Tian-Tian Liu, Vladimir Sukhov, Yuang Song, Samuel Ameh, Simone Brioschi, Darya Khantakova, Cora D Arthur, J Michael White, Heather Kohlmiller, Kathleen C F Sheehan, Marco Colonna, Kenneth M Murphy, Maxim N Artyomov, Robert D Schreiber, Et Al.

2020-Current year OA Pubs

CD4

Cholesterol Accumulation Promotes Photoreceptor Senescence And Retinal Degeneration, Ryo Terao, Brian S Sohn, Taku Yamamoto, Tae Jun Lee, Jason Colasanti, Charles W Pfeifer, Joseph B Lin, Andrea Santeford, Shinobu Yamaguchi, Mitsukuni Yoshida, Rajendra S Apte

2020-Current year OA Pubs

PURPOSE: Dysregulated cholesterol metabolism is critical in the pathogenesis of AMD. Cellular senescence contributes to the development of numerous age-associated diseases. In this study, we investigated the link between cholesterol burden and the cellular senescence of photoreceptors.

METHODS: Retinas from rod-specific ATP binding cassette subfamily A member 1 (Abca1) and G member 1 (Abcg1) (Abca1/g1-rod/-rod) knockout mice fed with a high-fat diet were analyzed for the signs of cellular senescence. Real-time quantitative PCR and immunofluorescence were used to characterize the senescence profile of the retina and cholesterol-treated photoreceptor cell line (661W). Inducible elimination of p16(Ink4a)-positive senescent cells (INK-ATTAC) mice or …

Local Complement Activation And Modulation In Mucosal Immunity, Devesha H Kulkarni, Marick Starick, Rafael Aponte Alburquerque, Hrishikesh S Kulkarni

2020-Current year OA Pubs

The complement system is an evolutionarily conserved arm of innate immunity, which forms one of the first lines of host response to pathogens and assists in the clearance of debris. A deficiency in key activators/amplifiers of the cascade results in recurrent infection, whereas a deficiency in regulating the cascade predisposes to accelerated organ failure, as observed in colitis and transplant rejection. Given that there are over 60 proteins in this system, it has become an attractive target for immunotherapeutics, many of which are United States Food and Drug Administration-approved or in multiple phase 2/3 clinical trials. Moreover, there have been …

Deletion Of Mipep In Adipocytes Protects Against Obesity And Insulin Resistance By Boosting Muscle Metabolism, Alexis Diaz-Vegas, Kristen C Cooke, Harry B Cutler, Belinda Yau, Stewart W C Masson, Dylan Harney, Oliver K Fuller, Meg Potter, Søren Madsen, Niamh R Craw, Yiju Zhang, Cesar L Moreno, Melkam A Kebede, G Gregory Neely, Jacqueline Stöckli, James G Burchfield, David E James

Faculty, Staff and Students Publications

Mitochondria facilitate thousands of biochemical reactions, covering a broad spectrum of anabolic and catabolic processes. Here we demonstrate that the adipocyte mitochondrial proteome is markedly altered across multiple models of insulin resistance and reveal a consistent decrease in the level of the mitochondrial processing peptidase miPEP.

OBJECTIVE: To determine the role of miPEP in insulin resistance.

METHODS: To experimentally test this observation, we generated adipocyte-specific miPEP knockout mice to interrogate its role in the aetiology of insulin resistance.

RESULTS: We observed a strong phenotype characterised by enhanced insulin sensitivity and reduced adiposity, despite normal food intake and physical activity. Strikingly, …

Fine-Tuning Ampk In Physiology And Disease Using Point-Mutant Mouse Models, Naghmana Ashraf, Jeanine L Van Nostrand

Faculty, Staff and Students Publications

AMP-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that monitors the cellular energy status to adapt it to the fluctuating nutritional and environmental conditions in an organism. AMPK plays an integral part in a wide array of physiological processes, such as cell growth, autophagy and mitochondrial function, and is implicated in diverse diseases, including cancer, metabolic disorders, cardiovascular diseases and neurodegenerative diseases. AMPK orchestrates many different physiological outcomes by phosphorylating a broad range of downstream substrates. However, the importance of AMPK-mediated regulation of these substrates in vivo remains an ongoing area of investigation to better understand its precise …

Human Platelet Lysate Enhances In Vivo Activity Of Car-Vδ2 T Cells By Reducing Cellular Senescence And Apoptosis, Feiyan Mo, Chiou-Tsun Tsai, Rong Zheng, Chonghui Cheng, Helen E Heslop, Malcolm K Brenner, Maksim Mamonkin, Norihiro Watanabe

Faculty, Staff and Students Publications

BACKGROUND AIMS: Vγ9Vδ2 T cells are an attractive cell platform for the off-the-shelf cancer immunotherapy as the result of their lack of alloreactivity and inherent multi-pronged cytotoxicity, which could be further amplified with chimeric antigen receptors (CARs). In this study, we sought to enhance the in vivo longevity of CAR-Vδ2 T cells by modulating ex vivo manufacturing conditions and selecting an optimal CAR costimulatory domain.

METHODS: Specifically, we compared the anti-tumor activity of Vδ2 T cells expressing anti-CD19 CARs with costimulatory endodomains derived from CD28, 4-1BB or CD27 and generated in either standard fetal bovine serum (FBS)- or human platelet …

Aging-Associated Metabolite Methylmalonic Acid Increases Susceptibility To Pulmonary Fibrosis, Kai Xu, Linke Ding, Wenwen Li, Yaxuan Wang, Shuaichen Ma, Hui Lian, Xiaoyue Pan, Ruyan Wan, Weiming Zhao, Juntang Yang, Ivan Rosas, Lan Wang, Guoying Yu

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by pulmonary fibroblast overactivation, resulting in the accumulation of abnormal extracellular matrix and lung parenchymal damage. Although the pathogenesis of IPF remains unclear, aging was proposed as the most prominent nongenetic risk factor. Propionate metabolism undergoes reprogramming in the aging population, leading to the accumulation of the by-product methylmalonic acid (MMA). This study aimed to explore alterations in propionate metabolism in IPF and the impact of the by-product MMA on pulmonary fibrosis. It revealed alterations in the expression of enzymes involved in propionate metabolism within IPF lung tissues, characterized …

Histone Serotonylation Regulates Ependymoma Tumorigenesis, Hsiao-Chi Chen, Peihao He, Malcolm Mcdonald, Michael R Williamson, Srinidhi Varadharajan, Brittney Lozzi, Junsung Woo, Dong-Joo Choi, Debosmita Sardar, Emmet Huang-Hobbs, Hua Sun, Siri M Ippagunta, Antrix Jain, Ganesh Rao, Thomas E Merchant, David W Ellison, Jeffrey L Noebels, Kelsey C Bertrand, Stephen C Mack, Benjamin Deneen

Faculty, Staff and Students Publications

Bidirectional communication between tumors and neurons has emerged as a key facet of the tumor microenvironment that drives malignancy1,2. Another hallmark feature of cancer is epigenomic dysregulation, where alterations in gene expression influences cell states and interactions with the tumor microenvironment3. Ependymoma (EPN) is a pediatric brain tumor that relies on epigenomic remodeling to engender malignancy4,5; how these epigenetic mechanisms intersect with extrinsic neuronal signaling during EPN tumor progression is unknown. Here we show that activity of serotonergic neurons regulates EPN tumorigenesis, while serotonin itself also serves as an activating …

Glutathione Dynamics In Subcellular Compartments And Implications For Drug Development, Hanfeng Lin, Lingfei Wang, Xiqian Jiang, Jin Wang

Faculty, Staff and Students Publications

Glutathione (GSH) is a pivotal tripeptide antioxidant essential for maintaining cellular redox homeostasis and regulating diverse cellular processes. Subcellular compartmentalization of GSH underscores its multifaceted roles across various organelles including the cytosol, mitochondria, endoplasmic reticulum, and nucleus, each exhibiting distinct regulatory mechanisms. Perturbations in GSH dynamics contribute to pathophysiological conditions, emphasizing the clinical significance of understanding its intricate regulation. This review consolidates current knowledge on subcellular GSH dynamics, highlighting its implications in drug development, particularly in covalent drug design and antitumor strategies targeting intracellular GSH levels. Challenges and future directions in deciphering subcellular GSH dynamics are discussed, advocating for innovative …

A Group 3 Medulloblastoma Stem Cell Program Is Maintained By Otx2-Mediated Alternative Splicing, Olivier Saulnier, Jamie Zagozewski, Lisa Liang, Liam D Hendrikse, Paul Layug, Victor Gordon, Kimberly A Aldinger, Parthiv Haldipur, Stephanie Borlase, Ludivine Coudière-Morrison, Ting Cai, Emma Martell, Naomi M Gonzales, Gareth Palidwor, Christopher J Porter, Stéphane Richard, Tanveer Sharif, Kathleen J Millen, Brad W Doble, Michael D Taylor, Tamra E Werbowetski-Ogilvie

Faculty, Staff and Students Publications

OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein-protein interactions and regulates a stem cell splicing program. OTX2 can directly or indirectly bind RNA and this may be partially independent of its DNA regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in human cerebellar rhombic lip origins. Among …

Intermittent Mechanical Loading On Mouse Tibia Accelerates Longitudinal Bone Growth By Inducing Pthrp Expression In The Female Tibial Growth Plate., Sarah Mcgarry, Karen Kover, Daniel P. Heruth, Mark Dallas, Xinxin Jin, Shufang Wu, Francesco De Luca

Manuscripts, Articles, Book Chapters and Other Papers

It is not clear as to whether weight bearing and ambulation may affect bone growth. Our goal was to study the role of mechanical loading (one of the components of ambulation) on endochondral ossification and longitudinal bone growth. Thus, we applied cyclical, biologically relevant strains for a prolonged time period (4 weeks) to one tibia of juvenile mice, while using the contralateral one as an internal control. By the end of the 4-week loading period, the mean tibial growth of the loaded tibiae was significantly greater than that of the unloaded tibiae. The mean height and the mean area of …

Intestinal Crypt Apoptosis As An Orchestrator Of Necrotizing Enterocolitis: A New Mechanism?, Wei Yu, Aparna Venkatraman, Venkatesh Sampath

Manuscripts, Articles, Book Chapters and Other Papers

No abstract provided.

Complement C3ar Signaling: Immune And Metabolic Modulation And Its Impact On Alzheimer’S Disease, Manasee Gedam, Hui Zheng

Center on Aging Staff Publications

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia among the elderly population. Despite its widespread prevalence, our comprehension of the intricate mechanisms governing the pathogenesis of the disease remains incomplete, posing a challenge for the development of efficient therapies. Pathologically characterized by the presence of amyloid β plaques and neurofibrillary tau tangles, AD is also accompanied by the hyperactivation of glial cells and the immune system. The complement cascade, the evolutionarily conserved innate immune pathway, has emerged as a significant contributor to AD. This review focuses on one of the complement components, the …

Chick Embryo Chorioallantoic Membrane As A Platform For Assessing The In Vivo Efficacy Of Chimeric Antigen Receptor T-Cell Therapy In Solid Tumors, Allison J Nipper, Emilie A K Warren, Kershena S Liao, Hsuan-Chen Liu, Chieko Michikawa, Caroline E Porter, Gabrielle A Wells, Mariana Villanueva, Fabio Henrique Brasil Da Costa, Ratna Veeramachaneni, Hugo Villanueva, Masataka Suzuki, Andrew G Sikora

Faculty, Staff and Student Publications

The fertilized chicken egg chorioallantoic membrane (CAM), a highly vascularized membrane nourishing the developing embryo, also supports rapid growth of three-dimensional vascularized tumors from engrafted cells and tumor explants. Because murine xenograft models suffer limitations of time, cost, and scalability, we propose CAM tumors as a rapid, efficient screening tool for assessing anti-tumor efficacy of chimeric Ag receptor (CAR) T cells against solid tumors. We tested the efficacy of human epidermal growth factor receptor 2 (HER2)-specific CAR T cells against luminescent, HER2-expressing (FaDu, SCC-47) or HER2-negative (MDA-MB-468) CAM-engrafted tumors. Three days after tumor engraftment, HER2-specific CAR T cells were applied …

Cerebellar Functions Beyond Movement And Learning, Linda H Kim, Detlef H Heck, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

The cerebellum has a well-established role in controlling motor functions, including coordination, posture, and the learning of skilled movements. The mechanisms for how it carries out motor behavior remain under intense investigation. Interestingly though, in recent years the mechanisms of cerebellar function have faced additional scrutiny since nonmotor behaviors may also be controlled by the cerebellum. With such complexity arising, there is now a pressing need to better understand how cerebellar structure, function, and behavior intersect to influence behaviors that are dynamically called upon as an animal experiences its environment. Here, we discuss recent experimental work that frames possible neural …

Nlrp1 Inflammasome Promotes Senescence And Senescence-Associated Secretory Phenotype, Inés Muela-Zarzuela, Juan Miguel Suarez-Rivero, Andrea Gallardo-Orihuela, Chun Wang, Kumi Izawa, Marta De Gregorio-Procopio, Isabelle Couillin, Bernhard Ryffel, Jiro Kitaura, Alberto Sanz, Thomas Von Zglinicki, Gabriel Mbalaviele, Mario D Cordero

2020-Current year OA Pubs

BACKGROUND: Senescence is a cellular aging-related process triggered by different stresses and characterized by the secretion of various inflammatory factors referred to as senescence-associated secretory phenotype (SASP), some of which are produced by the NLRP3 inflammasome. Here, we present evidence that the NLRP1 inflammasome is a DNA damage sensor and a key mediator of senescence.

METHODS: Senescence was induced in fibroblasts in vitro and in mice. Cellular senescence was assessed by Western blot analysis of several proteins, including p16, p21, p53, and SASP factors, released in the culture media or serum. Inflammasome components, including NLRP1, NLRP3 and GSDMD were knocked …

Mitochondrial Ca2+-Coupled Generation Of Reactive Oxygen Species, Peroxynitrite Formation, And Endothelial Dysfunction In Cantú Syndrome, Elsayed Metwally, Alfredo Sanchez Solano, Boris Lavanderos, Evan Yamasaki, Pratish Thakore, Conor Mcclenaghan, Natalia Rios, Rafael Radi, Yumei Feng Earley, Colin G. Nichols, Scott Earley

2020-Current year OA Pubs

Cantú syndrome is a multisystem disorder caused by gain-of-function (GOF) mutations in KCNJ8 and ABCC9, the genes encoding the pore-forming inward rectifier Kir6.1 and regulatory sulfonylurea receptor SUR2B subunits, respectively, of vascular ATP-sensitive K+ (KATP) channels. In this study, we investigated changes in the vascular endothelium in mice in which Cantú syndrome-associated Kcnj8 or Abcc9 mutations were knocked in to the endogenous loci. We found that endothelium-dependent dilation was impaired in small mesenteric arteries from Cantú mice. Loss of endothelium-dependent vasodilation led to increased vasoconstriction in response to intraluminal pressure or treatment with the adrenergic receptor agonist phenylephrine. We also …

Augustus Waller's Foresight Realized: Sarm1 In Peripheral Neuropathies, Stefanie Geisler

2020-Current year OA Pubs

Peripheral neuropathy is a common neurodegenerative condition characterized by numbness, tingling, pain, and weakness that frequently starts in the distal limbs. Arising from multiple etiologies, many peripheral neuropathies exhibit a slowly progressive course due to axon degeneration for which no effective treatments exist. During the past decade, numerous crucial insights into mechanisms of axon degeneration in peripheral neuropathies emerged from experiments involving nerve-cutting procedures, revealing the central role of the SARM1 axon degeneration pathway in both. Here I review commonalities and differences in the role of SARM1 after nerve cut and in several acquired and inherited peripheral neuropathies. This new …

Synaptic Fidelity For Drug Development: Is It Time To Move Beyond Glutamate Release And Receptors?, Chadi G Abdallah, Amanda J F Tamman

Faculty, Staff and Students Publications

No abstract provided.

A Rare Variant In Mrc2 Associated With Familial Supraventricular Tachycardia And Wolff-Parkinson-White Syndrome, Adam S Potter, Christina Y Miyake, Claudia Gonzaga-Jauregui, Yuriana Aguilar-Sanchez, Mohit M Hulsurkar, Satadru K Lahiri, Lucia M Moreira, Neelam Mehta, Mahshid S Azamian, James R Lupski, Svetlana Reilly, Seema R Lalani, Xander H T Wehrens

Faculty, Staff and Students Publications

Background: Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated with Wolff-Parkinson-White syndrome. The goal of this study was to identify genetic variants within a large family with structurally normal hearts affected by SVT and Wolff-Parkinson-White syndrome and determine causality of the gene deficit in a corresponding mouse model.

Methods: Whole exome sequencing performed on 2 distant members of a 3-generation family in which multiple members were affected by SVT or Wolff-Parkinson-White pattern (preexcitation) on ECG identified MRC2 as a candidate gene. Serial electrocardiograms, …

Ca2+/Calmodulin-Dependent Kinase Iiδc-Induced Chronic Heart Failure Does Not Depend On Sarcoplasmic Reticulum Ca2+ Leak, Matthias Dewenter, Tilmann Seitz, Julia H Steinbrecher, B Daan Westenbrink, Haiyun Ling, Stephan E Lehnart, Xander H T Wehrens, Johannes Backs, Joan Heller Brown, Lars S Maier, Stefan Neef

Faculty, Staff and Students Publications

Aims: Hyperactivity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) has emerged as a central cause of pathologic remodelling in heart failure. It has been suggested that CaMKII-induced hyperphosphorylation of the ryanodine receptor 2 (RyR2) and consequently increased diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) is a crucial mechanism by which increased CaMKII activity leads to contractile dysfunction. We aim to evaluate the relevance of CaMKII-dependent RyR2 phosphorylation for CaMKII-induced heart failure development in vivo.

Methods and results: We crossbred CaMKIIδC overexpressing [transgenic (TG)] mice with RyR2-S2814A knock-in mice that are resistant to CaMKII-dependent RyR2 phosphorylation. Ca2+-spark measurements on isolated ventricular …