Digital Commons Network^™

Substrate Reduction Therapy For Krabbe Disease And Metachromatic Leukodystrophy Using A Novel Ceramide Galactosyltransferase Inhibitor, Michael C. Babcock, Christina R. Mikulka, Hemanth R. Nelvagal, Xuntian Jiang, Mark S. Sands, Et Al

Open Access Publications

No abstract provided.

Pge2-Jnk Signaling Axis Non-Canonically Promotes Gli Activation By Protecting Gli2 From Ubiquitin-Proteasomal Degradation, Jun Yang, Weijun Liu, Et Al.

Open Access Publications

No abstract provided.

Lower Extremity Nerve Transfers In Acute Flaccid Myelitis Patients: A Case Series, Amy M. Moore, Carrie Roth Bettlach, Thomas T. Tung, Julie M. West, Stephanie A. Russo

Open Access Publications

No abstract provided.

Irradiation-Modulated Murine Brain Microenvironment Enhances Gl261-Tumor Growth And Inhibits Anti-Pd-L1 Immunotherapy, Joel R Garbow, Tanner M Johanns, Xia Ge, John A Engelbach, Liya Yuan, Sonika Dahiya, Christina I Tsien, Feng Gao, Keith M Rich, Joseph J H Ackerman

Open Access Publications

Purpose: Clinical evidence suggests radiation induces changes in the brain microenvironment that affect subsequent response to treatment. This study investigates the effect of previous radiation, delivered six weeks prior to orthotopic tumor implantation, on subsequent tumor growth and therapeutic response to anti-PD-L1 therapy in an intracranial mouse model, termed the Radiation Induced Immunosuppressive Microenvironment (RI

Method and Materials: C57Bl/6 mice received focal (hemispheric) single-fraction, 30-Gy radiation using the Leksell GammaKnife

Results: Tumors in previously irradiated brain display aggressive, invasive growth, characterized by viable tumor and large regions of hemorrhage and necrosis. Mice challenged intracranially with GL261 six weeks after prior …

Structure And Function Of Pancreatic Lipase-Related Protein 2 And Its Relationship With Pathological States, Guoying Zhu, Qing Fang, Fengshang Zhu, Dongping Huang, Changqing Yang

Open Access Publications

Pancreatic lipase is critical for the digestion and absorption of dietary fats. The most abundant lipolytic enzymes secreted by the pancreas are pancreatic triglyceride lipase (PTL or PNLIP) and its family members, pancreatic lipase-related protein 1 (PNLIPRP1or PLRP1) and pancreatic lipase-related protein 2 (PNLIPRP2 or PLRP2). Unlike the family's other members, PNLIPRP2 plays an elemental role in lipid digestion, especially for newborns. Therefore, if genetic factors cause gene mutation, or other factors lead to non-expression, it may have an effect on fat digestion and absorption, on the susceptibility to pancreas and intestinal pathogens. In this review, we will summarize what …

Reducing Auditory Nerve Excitability By Acute Antagonism Of Ca2+-Permeable Ampa Receptors, Amit Walia, Choongheon Lee, Jared Hartsock, Shawn S Goodman, Roland Dolle, Alec N Salt, Jeffery T Lichtenhan, Mark A Rutherford

Open Access Publications

Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca

Markers Of Early Changes In Cognition Across Cohorts Of Adults With Down Syndrome At Risk Of Alzheimer's Disease, Andrew J Aschenbrenner, Jason Hassenstab, Et Al

Open Access Publications

Introduction: Down syndrome (DS), a genetic variant of early onset Alzheimer's disease (AD), lacks a suitable outcome measure for prevention trials targeting pre-dementia stages.

Methods: We used cognitive test data collected in several longitudinal aging studies internationally from 312 participants with DS without dementia to identify composites that were sensitive to change over time. We then conducted additional analyses to provide support for the utility of the composites. The composites were presented to an expert panel to determine the most optimal cognitive battery based on predetermined criteria.

Results: There were common cognitive domains across site composites, which were sensitive to …

Distinct Microrna Profiles In The Perilymph And Serum Of Patients With Menière's Disease, Matthew Shew, Helena Wichova, Madeleine St Peter, Athanasia Warnecke, Hinrich Staecker

Open Access Publications

No abstract provided.

Maturation Of Heterogeneity In Afferent Synapse Ultrastructure In The Mouse Cochlea, Shelby A Payne, Matthew S Joens, Heather Chung, Natalie Skigen, Adam Frank, Sonali Gattani, Kya Vaughn, Allison Schwed, Matt Nester, Atri Bhattacharyya, Guhan Iyer, Bethany Davis, Jason Carlquist, Honey Patel, James A J Fitzpatrick, Mark A Rutherford

Open Access Publications

Auditory nerve fibers (ANFs) innervating the same inner hair cell (IHC) may have identical frequency tuning but different sound response properties. In cat and guinea pig, ANF response properties correlate with afferent synapse morphology and position on the IHC, suggesting a causal structure-function relationship. In mice, this relationship has not been fully characterized. Here we measured the emergence of synaptic morphological heterogeneities during maturation of the C57BL/6J mouse cochlea by comparing postnatal day 17 (p17, ∼3 days after hearing onset) with p34, when the mouse cochlea is mature. Using serial block face scanning electron microscopy and three-dimensional reconstruction we measured …

Inhibition Of Discoidin Domain Receptors By Imatinib Prevented Pancreatic Fibrosis Demonstrated In Experimental Chronic Pancreatitis Model, Sapana Bansod, Mohd Aslam Saifi, Chandraiah Godugu

Open Access Publications

No abstract provided.

The Sulfur Microbial Diet And Risk Of Colorectal Cancer By Molecular Subtypes And Intratumoral Microbial Species In Adult Men, Daniel R. Sikavi, Yin Cao, Et Al

Open Access Publications

No abstract provided.

Dysregulation Of Mannose-6-Phosphate-Dependent Cholesterol Homeostasis In Acinar Cells Mediates Pancreatitis, Olga A Mareninova, Yan Xie, Nicholas O Davidson, Et Al

Open Access Publications

Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood. Here, we show that the mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene encoding a key enzyme in the M6P pathway disrupted acinar cell cholesterol turnover, causing accumulation of nonesterified cholesterol in lysosomes/autolysosomes, its depletion in the plasma membrane, and upregulation of cholesterol synthesis and uptake. We found similar dysregulation of acinar cell cholesterol, and a decrease in GNPTAB levels, in both WT experimental pancreatitis and human disease. The …

Listeria Exploits Ifitm3 To Suppress Antibacterial Activity In Phagocytes, Joel M. J. Tan, Michael S. Diamond, Et Al

Open Access Publications

No abstract provided.

Multi-Omics Integration Analysis Identifies Novel Genes For Alcoholism With Potential Overlap With Neurodegenerative Diseases, Manav Kapoor, Michael J. Chao, Emma C. Johnson, Gloriia Novikova, Dongbing Lai, Jacquelyn L. Meyers, Jessica Schulman, John I. Nurnberger Jr., Bernice Porjesz, Yunlong Liu, The Collaborative Study On Genetics Of Alcoholism (Coga), Tatiana Foroud, Howard J. Edenberg, Edoardo Marcora, Arpana Agrawal, Alison Goate

Open Access Publications

No abstract provided.

A Ligand-Insensitive Unc5b Splicing Isoform Regulates Angiogenesis By Promoting Apoptosis, David Pradella, William Vermi, Et Al

Open Access Publications

No abstract provided.

Regulation Of Beta-Amyloid Production In Neurons By Astrocyte-Derived Cholesterol, Hao Wang, Joshua A. Kulas, Chao Wang, David M. Holtzman, Heather A. Ferris, Scott B. Hansen

Open Access Publications

No abstract provided.

Critical Roles Of Calpastatin In Ischemia/Reperfusion Injury In Aged Livers, Joseph Flores-Toro, Sung-Kook Chun, Jun-Kyu Shin, Joan Campbell, Melissa Lichtenberger, William Chapman, Ivan Zendejas, Kevin Behrns, Christiaan Leeuwenburgh, Jae-Sung Kim

Open Access Publications

Ischemia/reperfusion (I/R) injury unavoidably occurs during hepatic resection and transplantation. Aged livers poorly tolerate I/R during surgical treatment. Although livers have a powerful endogenous inhibitor of calpains, calpastatin (CAST), I/R activates calpains, leading to impaired autophagy, mitochondrial dysfunction, and hepatocyte death. It is unknown how I/R in aged livers affects CAST. Human and mouse liver biopsies at different ages were collected during in vivo I/R. Hepatocytes were isolated from 3-month- (young) and 26-month-old (aged) mice, and challenged with short in vitro simulated I/R. Cell death, protein expression, autophagy, and mitochondrial permeability transition (MPT) between the two age groups were compared. …

Parallel Hippocampal-Parietal Circuits For Self- And Goal-Oriented Processing, Annie Zheng, David F. Montez, Scott Marek, Adrian W. Gilmore, Dillan J. Newbold, Timothy O. Laumann, Benjamin P. Kay, Nicole A. Seider, Andrew N. Van, Jacqueline M. Hampton, Dimitrios Alexopoulos, Bradley L. Schlaggar, Chad M. Sylvester, Deanna J. Greene, Joshua S. Shimony, Steven M. Nelson, Gagan S. Wig, Caterina Gratton, Kathleen B. Mcdermott, Marcus E. Raichle, Evan M. Gordon, Nico U. F. Dosenbach

Open Access Publications

No abstract provided.

Ngn3-Positive Cells Arise From Pancreatic Duct Cells, Chiemi Kimura-Nakajima, Kousuke Sakaguchi, Yoshiko Hatano, Masahito Matsumoto, Yasushi Okazaki, Keisuke Tanaka, Takumi Yamane, Yuichi Oishi, Kenji Kamimoto, Ken Iwatsuki

Open Access Publications

The production of pancreatic β cells is the most challenging step for curing diabetes using next-generation treatments. Adult pancreatic endocrine cells are thought to be maintained by the self-duplication of differentiated cells, and pancreatic endocrine neogenesis can only be observed when the tissue is severely damaged. Experimentally, this can be performed using a method named partial duct ligation (PDL). As the success rate of PDL surgery is low because of difficulties in identifying the pancreatic duct, we previously proposed a method for fluorescently labeling the duct in live animals. Using this method, we performed PDL on neurogenin3 (Ngn3)-GFP transgenic mice …

Tyk2 In Cancer Metastases: Genomic And Proteomic Discovery, Dana C Borcherding, Kevin He, Neha V Amin, Angela C Hirbe

Open Access Publications

Advances in genomic analysis and proteomic tools have rapidly expanded identification of biomarkers and molecular targets important to cancer development and metastasis. On an individual basis, personalized medicine approaches allow better characterization of tumors and patient prognosis, leading to more targeted treatments by detection of specific gene mutations, overexpression, or activity. Genomic and proteomic screens by our lab and others have revealed tyrosine kinase 2 (

Exploring Social Media Recruitment Strategies And Preliminary Acceptability Of An Mhealth Tool For Teens With Eating Disorders, Erin Kasson, Melissa M Vázquez, Christine Doroshenko, Ellen E Fitzsimmons-Craft, Denise E Wilfley, C Barr Taylor, Patricia A Cavazos-Rehg

Open Access Publications

(1) Background: The current study leveraged social media to connect with teens with EDs to identify population specific characteristics and to gather feedback on an mHealth intervention. (2) Methods: We recruited teens with EDs from social media in two phases: (1) Discovery Group, (2) Testing Group. The Discovery Group (

Advances In Genetic And Molecular Understanding Of Alzheimer's Disease, Laura Ibanez, Carlos Cruchaga, Maria Victoria Fernández

Open Access Publications

Alzheimer's disease (AD) has become a common disease of the elderly for which no cure currently exists. After over 30 years of intensive research, we have gained extensive knowledge of the genetic and molecular factors involved and their interplay in disease. These findings suggest that different subgroups of AD may exist. Not only are we starting to treat autosomal dominant cases differently from sporadic cases, but we could be observing different underlying pathological mechanisms related to the amyloid cascade hypothesis, immune dysfunction, and a tau-dependent pathology. Genetic, molecular, and, more recently, multi-omic evidence support each of these scenarios, which are …

A Mouse Model Displays Host And Bacterial Strain Differences In Aerococcus Urinae Urinary Tract Infection, Nicole M Gilbert, Brian Choi, Jingjie Du, Christina Collins, Amanda L Lewis, Catherine Putonti, Alan J Wolfe

Open Access Publications

In recent years, the clinical significance of Aerococcus urinae has been increasingly recognized. A. urinae has been implicated in cases of urinary tract infection (UTI; acute cystitis and pyelonephritis) in both male and female patients, ranging from children to older adults. Aerococcus urinae can also be invasive, causing urosepsis, endocarditis, and musculoskeletal infections. Mechanisms of pathogenesis in A. urinae infections are poorly understood, largely due to the lack of an animal model system. In response to this gap, we developed a model of A. urinae urinary tract infection in mice. We compared A. urinae UTI in female C3H/HeN and C57BL/6 …

Functional And Epigenetic Phenotypes Of Humans And Mice With Dnmt3a Overgrowth Syndrome, Amanda M. Smith, Taylor A. Lavalle, Marwan Shinawi, Sai M. Ramakrishnan, Haley J. Abel, Cheryl A. Hill, Nicole M. Kirkland, Michael P. Rettig, Nichole M. Helton, Sharon E. Heath, Francesca Ferraro, David Y. Chen, Sangeeta Adak, Clay F. Semenkovich, Diana L. Christian, Jenna R. Martin, Harrison W. Gabel, Christopher A. Miller, Timothy J. Ley

Open Access Publications

No abstract provided.

Influence Of Mpv17 On Hair-Cell Mitochondrial Homeostasis, Synapse Integrity, And Vulnerability To Damage In The Zebrafish Lateral Line, Melanie Holmgren, Lavinia Sheets

Open Access Publications

Noise exposure is particularly stressful to hair-cell mitochondria, which must produce enough energy to meet high metabolic demands as well as regulate local intracellular Ca

Deletion Of Glut1 In Early Postnatal Cartilage Reprograms Chondrocytes Toward Enhanced Glutamine Oxidation, Cuicui Wang, Jun Ying, Xiangfeng Niu, Xiaofei Li, Gary J. Patti, Jie Shen, Regis J. O'Keefe

Open Access Publications

No abstract provided.

Sequence- And Structure-Specific Cytosine-5 Mrna Methylation By Nsun6, Tommaso Selmi, Shobbir Hussain, Sabine Dietmann, Matthias Heiß, Kayla Borland, Sophia Flad, Jean-Michel Carter, Rebecca Dennison, Ya-Lin Huang, Stefanie Kellner, Susanne Bornelöv, Michaela Frye

Open Access Publications

The highly abundant N6-methyladenosine (m6A) RNA modification affects most aspects of mRNA function, yet the precise function of the rarer 5-methylcytidine (m5C) remains largely unknown. Here, we map m5C in the human transcriptome using methylation-dependent individual-nucleotide resolution cross-linking and immunoprecipitation (miCLIP) combined with RNA bisulfite sequencing. We identify NSUN6 as a methyltransferase with strong substrate specificity towards mRNA. NSUN6 primarily targeted three prime untranslated regions (3'UTR) at the consensus sequence motif CTCCA, located in loops of hairpin structures. Knockout and rescue experiments revealed enhanced mRNA and translation levels when NSUN6-targeted mRNAs were methylated. Ribosome profiling further demonstrated that NSUN6-specific methylation …

Complexity In Genetic Cardiomyopathies And New Approaches For Mechanism-Based Precision Medicine, Michael J. Greenberg, Jil C. Tardiff

Open Access Publications

Genetic cardiomyopathies have been studied for decades, and it has become increasingly clear that these progressive diseases are more complex than originally thought. These complexities can be seen both in the molecular etiologies of these disorders and in the clinical phenotypes observed in patients. While these disorders can be caused by mutations in cardiac genes, including ones encoding sarcomeric proteins, the disease presentation varies depending on the patient mutation, where mutations even within the same gene can cause divergent phenotypes. Moreover, it is challenging to connect the mutation-induced molecular insult that drives the disease pathogenesis with the various compensatory and …

The Association Of Polygenic Risk For Schizophrenia, Bipolar Disorder, And Depression With Neural Connectivity In Adolescents And Young Adults: Examining Developmental And Sex Differences, J.L. Meyers, E.C. Johnson, A. Agrawal, A. Anokhin, M.H. Plawecki, Et Al.

Open Access Publications

No abstract provided.

Intracranial Delivery Of Aav9 Gene Therapy Partially Prevents Retinal Degeneration And Visual Deficits In Cln6-Batten Disease Mice, Katherine A. White, Hemanth R. Nelvagal, Timothy A. Poole, Bin Lu, Tyler B. Johnson, Samantha Davis, Melissa A. Pratt, Jon Brudvig, Ana B. Assis, Shibi Likhite, Kathrin Meyer, Brian K. Kaspar, Jonathan D. Cooper, Shaomei Wang, Jill M. Weimer

Open Access Publications

No abstract provided.