Digital Commons Network^™

Reproducibility Of Cognitive Endpoints In Clinical Trials: Lessons From Neurofibromatosis Type 1, Jonathan M Payne, David H Gutmann, Et Al

Open Access Publications

OBJECTIVE: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility.

METHODS: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, …

Nonlinear Z-Score Modeling For Improved Detection Of Cognitive Abnormality, John Kornak, Nupur Ghoshal, Lynne Jones, Et Al

Open Access Publications

Introduction: Conventional Z-scores are generated by subtracting the mean and dividing by the standard deviation. More recent methods linearly correct for age, sex, and education, so that these "adjusted" Z-scores better represent whether an individual's cognitive performance is abnormal. Extreme negative Z-scores for individuals relative to this normative distribution are considered indicative of cognitive deficiency.

Methods: In this article, we consider nonlinear shape constrained additive models accounting for age, sex, and education (correcting for nonlinearity). Additional shape constrained additive models account for varying standard deviation of the cognitive scores with age (correcting for heterogeneity of variance).

Results: Corrected Z-scores based …

Signal Regulatory Protein Alpha Initiates Cachexia Through Muscle To Adipose Tissue Crosstalk, Jiao Wu, Jiangling Dong, Daniela Verzola, Keith Hruska, Giacomo Garibotto, Zhaoyong Hu, William E Mitch, Sandhya S Thomas

Open Access Publications

BACKGROUND: Muscle wasting from chronic kidney disease (CKD) or from defective insulin signalling results in morbidity and, ultimately, mortality. We have identified an endogenous mediator of insulin resistance, signal regulatory protein alpha (SIRPα), which leads to cachexia in mice and is associated with cachexia in patients with CKD.

METHODS: We assessed insulin signalling and mechanisms causing muscle atrophy plus white adipose tissue (WAT) metabolism in mouse models of CKD or acute diabetes (streptozotocin treatment). We then examined these factors in mice with global knockout (KO) of SIRPα and sought mediators of metabolic responses in muscle and adipose tissues of mice …

Linking The Effects Of Helminth Infection, Diet And The Gut Microbiota With Human Whole-Blood Signatures, Soo Ching Lee, Mei San Tang, Alice V. Easton, Joseph Cooper Devlin, Ling Ling Chua, Ilseung Cho, Foong Ming Moy, Tsung Fei Khang, Yvonne A. L. Lim, P'Ng Loke

Open Access Publications

Helminth infection and dietary intake can affect the intestinal microbiota, as well as the immune system. Here we analyzed the relationship between fecal microbiota and blood profiles of indigenous Malaysians, referred to locally as Orang Asli, in comparison to urban participants from the capital city of Malaysia, Kuala Lumpur. We found that helminth infections had a larger effect on gut microbial composition than did dietary intake or blood profiles. Trichuris trichiura infection intensity also had the strongest association with blood transcriptional profiles. By characterizing paired longitudinal samples collected before and after deworming treatment, we determined that changes in serum zinc …

Standard Operating Procedure For Curation And Clinical Interpretation Of Variants In Cancer, Arpad M Danos, Kilannin Krysiak, Erica K Barnell, Adam C Coffman, Joshua F Mcmichael, Susanna Kiwala, Nicholas C Spies, Lana M Sheta, Shahil P Pema, Lynzey Kujan, Kaitlin A Clark, Amber Z Wollam, Alex H Wagner, Malachi Griffith, Obi L Griffith, Et Al

Open Access Publications

Manually curated variant knowledgebases and their associated knowledge models are serving an increasingly important role in distributing and interpreting variants in cancer. These knowledgebases vary in their level of public accessibility, and the complexity of the models used to capture clinical knowledge. CIViC (Clinical Interpretation of Variants in Cancer - www.civicdb.org) is a fully open, free-to-use cancer variant interpretation knowledgebase that incorporates highly detailed curation of evidence obtained from peer-reviewed publications and meeting abstracts, and currently holds over 6300 Evidence Items for over 2300 variants derived from over 400 genes. CIViC has seen increased adoption by, and also undertaken collaboration …

Entry By Multiple Picornaviruses Is Dependent On A Pathway That Includes Tnk2, Wasl, And Nck1, Hongbing Jiang, Christian Leung, Stephen Tahan, David Wang

Open Access Publications

Comprehensive knowledge of the host factors required for picornavirus infection would facilitate antiviral development. Here we demonstrate roles for three human genes,

Gut Microbiota: From The Forgotten Organ To A Potential Key Player In The Pathology Of Alzheimer's Disease, Dong-Oh Seo, David M Holtzman

Open Access Publications

More than 300 years ago, Antony van Leewenhoeck first described observing single-celled microorganisms, which he termed "animalcules," examining his saliva under a microscope. Although the idea of the coexistence of microorganisms in our body is not new, we have only recently been able to investigate their ecological relationship to our body, with the development of high-throughput molecular techniques. The diverse microorganism communities residing in our guts are established and maintained by complex interactions among microorganisms and their host. Notably, their alteration has been implicated in influencing various diseases including neurological diseases. Alzheimer's disease (AD) is the most common cause of …

Direct Binding Of Phosphatidylglycerol At Specific Sites Modulates Desensitization Of A Ligand-Gated Ion Channel, Ailing Tong, John T. Petroff Ii, Fong-Fu Hsu, Philipp A.M. Schmidpeter, Crina M. Nimigean, Liam Sharp, Grace Brannigan, Wayland W.L. Cheng

Open Access Publications

Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC …

Elliot Krane Oral History.

Pediatric Palliative Care Oral History Project

Dr. Elliot Krane begins the interview by describing his early career and observations that pain in pediatrics was not meaningfully managed. After Dr. Krane took a position at the University of Washington, he developed his career path at the intersection of pediatrics and pain/anesthesiology. At his post in Seattle, Dr. Krane worked within a small, close knit pain department that were at the "world's nexus of [Starbucks] coffee and pain management," where he helped advance early pediatric pain practices. Dr. Krane then describes in depth some of the barriers he encountered, such as the myth that children did not meaningfully …

Molecular Game Theory For A Toxin-Dominant Food Chain Model, Bowen Li, Jonathan R Silva, Jianmin Cui, Et Al.

2010-2019 OA Pubs

Animal toxins that are used to subdue prey and deter predators act as the key drivers in natural food chains and ecosystems. However, the predators of venomous animals may exploit feeding adaptation strategies to overcome toxins their prey produce. Much remains unknown about the genetic and molecular game process in the toxin-dominant food chain model. Here, we show an evolutionary strategy in different trophic levels of scorpion-eating amphibians, scorpions and insects, representing each predation relationship in habitats dominated by the paralytic toxins of scorpions. For scorpions preying on insects, we found that the scorpion α-toxins irreversibly activate the skeletal muscle …

Defining Components Of Early Functional Rehabilitation For Acute Achilles Tendon Rupture: A Systematic Review, Jennifer A Zellers, Marianne Christensen, Inge Lunding Kjær, Michael Skovdal Rathleff, Karin Grävare Silbernagel

Open Access Publications

Background: Early functional rehabilitation is frequently discussed in treating Achilles tendon rupture. A consistent definition of what constitutes early functional rehabilitation has not been established across the literature, despite studies supporting its efficacy. A standardized definition would be helpful to pool data across studies, allow for between-study comparisons, and ultimately work toward developing clinical guidelines.

Purpose: To define early functional rehabilitation (including when it is initiated and what it entails) when used to treat Achilles tendon rupture and to identify outcome measures for evaluating the effect of treatment.

Study Design: Systematic review; Level of evidence, 4.

Methods: Ovid MEDLINE, EMBASE, …

Immune Globulin Subcutaneous, Human - Klhw 20% For Primary Humoral Immunodeficiency: An Open-Label, Phase Iii Study, John W Sleasman, William R Lumry, Iftikhar Hussain, H James Wedner, James B Harris, Kecia L Courtney, Elsa Mondou, Jiang Lin, Mark R Stein

2010-2019 OA Pubs

No abstract provided.

Noda-Like Rna Viruses Infecting Caenorhabditis Nematodes: Sympatry, Diversity, And Reassortment, Lise Frézal, Hyeim Jung, Stephen Tahan, David Wang, Marie-Anne Félix

Open Access Publications

Three RNA viruses related to nodaviruses were previously described to naturally infect the nematode

Maternal Fluoxetine Exposure Alters Cortical Hemodynamic And Calcium Response Of Offspring To Somatosensory Stimuli, Rachel M Rahn, Susan E Maloney, Lindsey M Brier, Joseph D Dougherty, Joseph P Culver

Open Access Publications

Epidemiological studies have found an increased incidence of neurodevelopmental disorders in populations prenatally exposed to selective serotonin reuptake inhibitors (SSRIs). Optical imaging provides a minimally invasive way to determine if perinatal SSRI exposure has long-term effects on cortical function. Herein we probed the functional neuroimaging effects of perinatal SSRI exposure in a fluoxetine (FLX)-exposed mouse model. While resting-state homotopic contralateral functional connectivity was unperturbed, the evoked cortical response to forepaw stimulation was altered in FLX mice. The stimulated cortex showed decreased activity for FLX versus controls, by both hemodynamic responses [oxyhemoglobin (HbO

Diffusion Basis Spectrum Imaging For Identifying Pathologies In Ms Subtypes, Afsaneh Shirani, Peng Sun, Kathryn Trinkaus, Dana C Perantie, Ajit George, Robert T Naismith, Robert E Schmidt, Sheng-Kwei Song, Anne H Cross

Open Access Publications

Diffusion basis spectrum imaging (DBSI) combines discrete anisotropic diffusion tensors and the spectrum of isotropic diffusion tensors to model the underlying multiple sclerosis (MS) pathologies. We used clinical MS subtypes as a surrogate of underlying pathologies to assess DBSI as a biomarker of pathology in 55 individuals with MS. Restricted isotropic fraction (reflecting cellularity) and fiber fraction (representing apparent axonal density) were the most important DBSI metrics to classify MS using brain white matter lesions. These DBSI metrics outperformed lesion volume. When analyzing the normal-appearing corpus callosum, the most significant DBSI metrics were fiber fraction, radial diffusivity (reflecting myelination), and …

Human Monoclonal Antibodies Against Chikungunya Virus Target Multiple Distinct Epitopes In The E1 And E2 Glycoproteins, Jose A. Quiroz, Ryan J. Malonis, Larissa B. Thackray, Courtney A. Cohen, Jesper Pallesen, Rohit K. Jangra, Rebecca S. Brown, Daniel Hofmann, Frederick W. Holtsberg, Sergey Shulenin, Elisabeth K. Nyakatura, Lorellin A. Durnell, Vinayak Rayannavar, Johanna P. Daily, Andrew B. Ward, M. Javad Aman, John M. Dye, Kartik Chandran, Michael S. Diamond, Margaret Kielian, Jonathan R. Lai

Open Access Publications

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes persistent arthritis in a subset of human patients. We report the isolation and functional characterization of monoclonal antibodies (mAbs) from two patients infected with CHIKV in the Dominican Republic. Single B cell sorting yielded a panel of 46 human mAbs of diverse germline lineages that targeted epitopes within the E1 or E2 glycoproteins. MAbs that recognized either E1 or E2 proteins exhibited neutralizing activity. Viral escape mutations localized the binding epitopes for two E1 mAbs to sites within domain I or the linker between domains I and III; and for two …

Dc-Script Deficiency Delays Mouse Mammary Gland Development And Branching Morphogenesis, Chunling Tang, Renske J E Van Den Bijgaart, Maaike W G Looman, Nina Tel-Karthaus, Annemarie M A De Graaf, Susan Gilfillan, Marco Colonna, Marleen Ansems, Gosse J Adema

Open Access Publications

Mammary glands are unique organs in which major adaptive changes occur in morphogenesis and development after birth. Breast cancer is the most common cancer and a major cause of mortality in females worldwide. We have previously identified the loss of expression of the transcription regulator DC-SCRIPT (Zfp366) as a prominent prognostic event in estrogen receptor positive breast cancer patients. DC-SCRIPT affects multiple transcriptional events in breast cancer cells, including estrogen and progesterone receptor-mediated transcription, and promotes CDKN2B-related cell cycle arrest. As loss of DC-SCRIPT expression appears an early event in breast cancer development, we here investigated the role of DC-SCRIPT …

Vav1 Inhibits Rankl-Induced Osteoclast Differentiation And Bone Resorption., Jin Sun Jang, In Soon Kang, Young-Nam Cha, Zang Hee Lee, Mary C Dinauer, Young-June Kim, Chaekyun Kim

Open Access Publications

Vav1 is a Rho/Rac guanine nucleotide exchange factor primarily expressed in hematopoietic cells. In this study, we investigated the potential role of Vav1 in osteoclast (OC) differentiation by comparing the ability of bone marrow mononuclear cells (BMMCs) obtained from Vav1-deficient (Vav1-/-) and wild-type (WT) mice to differentiate into mature OCs upon stimulation with macrophage colony stimulating factor and receptor activator of nuclear kappa B ligand in vitro. Our results suggested that Vav1 deficiency promoted the differentiation of BMMCs into OCs, as indicated by the increased expression of tartrate-resistant acid phosphatase, cathepsin K, and calcitonin receptor. Therefore, Vav1 may play a …

Tfeb Activation In Macrophages Attenuates Postmyocardial Infarction Ventricular Dysfunction Independently Of Atg5-Mediated Autophagy, Ali Javaheri, Geetika Bajpai, Antonino Picataggi, Smrithi Mani, Layla Foroughi, Hosannah Evie, Attila Kovacs, Carla J Weinheimer, Krzystztof Hyrc, Qingli Xiao, Andrea Ballabio, Jin-Moo Lee, Scot J Matkovich, Babak Razani, Joel D Schilling, Kory J Lavine, Abhinav Diwan

Open Access Publications

Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages. Inflammasome activation and IL-1β secretion are implicated in myocardial infarction (MI) and resultant heart failure; however, little is known about how macrophage lysosomes regulate these processes. In mice subjected to cardiac ischemia/reperfusion (IR) injury and humans with ischemic cardiomyopathy, we observed evidence of lysosomal impairment in macrophages. Inducible macrophage-specific overexpression of transcription factor EB (TFEB), a master regulator of lysosome biogenesis (Mϕ-TFEB), attenuated postinfarction remodeling, decreased abundance of proinflammatory macrophages, and reduced levels of myocardial IL-1β compared with controls. Surprisingly, neither inflammasome suppression nor Mϕ-TFEB-mediated attenuation …

Targeting Tauopathy With Engineered Tau-Degrading Intrabodies, Gilbert Gallardo, Connie H Wong, Sara M Ricardez, Carolyn N Mann, Kent H Lin, Cheryl E G Leyns, Hong Jiang, David M Holtzman

Open Access Publications

BACKGROUND: The accumulation of pathological tau is the main component of neurofibrillary tangles and other tau aggregates in several neurodegenerative diseases, referred to as tauopathies. Recently, immunotherapeutic approaches targeting tau have been demonstrated to be beneficial in decreasing tauopathy in animal models. We previously found that passive immunotherapy with anti-tau antibody to human tau or expression of an anti-tau secreted single-chain variable fragment (scFv) in the central nervous system of a mouse model of tauopathy decreased but did not remove all tau-associated pathology. Although these and other studies demonstrate that conventional immunotherapeutic approaches targeting tau can influence tau pathogenesis, the …

Cis-Regulatory Basis Of Sister Cell Type Divergence In The Vertebrate Retina, Daniel P Murphy, Andrew Eo Hughes, Karen A Lawrence, Connie A Myers, Joseph C Corbo

2010-2019 OA Pubs

Multicellular organisms evolved via repeated functional divergence of transcriptionally related sister cell types, but the mechanisms underlying sister cell type divergence are not well understood. Here, we study a canonical pair of sister cell types, retinal photoreceptors and bipolar cells, to identify the key

Redefining Noradrenergic Neuromodulation Of Behavior: Impacts Of A Modular Locus Coeruleus Architecture, Dan J. Chandler, Patricia Jensen, Jordan G. Mccall, Anthony E. Pickering, Lindsay A. Schwarz, Nelson K. Totah

Open Access Publications

The locus coeruleus (LC) is a seemingly singular and compact neuromodulatory nucleus that is a prominent component of disparate theories of brain function due to its broad noradrenergic projections throughout the CNS. As a diffuse neuromodulatory system, noradrenaline affects learning and decision making, control of sleep and wakefulness, sensory salience including pain, and the physiology of correlated forebrain activity (ensembles and networks) and brain hemodynamic responses. However, our understanding of the LC is undergoing a dramatic shift due to the application of state-of-the-art methods that reveal a nucleus of many modules that provide targeted neuromodulation. Here, we review the evidence …

Staphylococcus Aureus Infects Osteoclasts And Replicates Intracellularly, Jennifer L Krauss, Philip M Roper, Anna Ballard, Chien-Cheng Shih, James A J Fitzpatrick, James E Cassat, Pei Ying Ng, Nathan J Pavlos, Deborah J Veis

Open Access Publications

Osteomyelitis (OM), or inflammation of bone tissue, occurs most frequently as a result of bacterial infection and severely perturbs bone structure. OM is predominantly caused by

Chitosan Biosynthesis And Virulence In The Human Fungal Pathogen Cryptococcus Gattii, Woei C Lam, Rajendra Upadhya, Charles A Specht, Abigail E Ragsdale, Camaron R Hole, Stuart M Levitz, Jennifer K Lodge

Open Access Publications

No abstract provided.

Mutation Of The Co-Chaperone Tsc1 In Bladder Cancer Diminishes Hsp90 Acetylation And Reduces Drug Sensitivity And Selectivity, Mark R. Woodford, Michael Hughes, Rebecca A. Sager, Sarah J. Backe, Alexander J. Baker-Williams, Michael S. Bratslavsky, Joseph M. Jacob, Oleg Shapiro, Michael Wong, Gennady Bratslavsky, Dimitra Bourboulia, Mehdi Mollapour

Open Access Publications

The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that affects Hsp90 binding to its inhibitors. Highly variable mutations of TSC1 have been previously identified in bladder cancer and correlate with sensitivity to the Hsp90 inhibitors. Here we showed loss of TSC1 leads to hypoacetylation of Hsp90-K407/K419 …

Structured Inhibitory Activity Dynamics In New Virtual Environments, Moises Arriaga, Edward B. Han

Open Access Publications

Inhibition plays a powerful role in regulating network excitation and plasticity; however, the activity of defined interneuron types during spatial exploration remain poorly understood. Using two-photon calcium imaging, we recorded hippocampal CA1 somatostatin- and parvalbumin-expressing interneurons as mice performed a goal-directed spatial navigation task in new visual virtual reality (VR) contexts. Activity in both interneuron classes was strongly suppressed but recovered as animals learned to adapt the previously learned task to the new spatial context. Surprisingly, although there was a range of activity suppression across the population, individual somatostatin-expressing interneurons showed consistent levels of activity modulation across exposure to multiple …

Stimulation Of Piezo1 By Mechanical Signals Promotes Bone Anabolism, Xuehua Li, Li Han, Intawat Nookaew, Erin Mannen, Matthew J. Silva, Maria Almeida, Jinhu Xiong

Open Access Publications

Mechanical loading, such as caused by exercise, stimulates bone formation by osteoblasts and increases bone strength, but the mechanisms are poorly understood. Osteocytes reside in bone matrix, sense changes in mechanical load, and produce signals that alter bone formation by osteoblasts. We report that the ion channel Piezo1 is required for changes in gene expression induced by fluid shear stress in cultured osteocytes and stimulation of Piezo1 by a small molecule agonist is sufficient to replicate the effects of fluid flow on osteocytes. Conditional deletion of

Ilc3s Integrate Glycolysis And Mitochondrial Production Of Reactive Oxygen Species To Fulfill Activation Demands, Blanda Di Luccia, Susan Gilfillan, Marina Cella, Marco Colonna, Stanley Ching-Cheng Huang

Open Access Publications

Group 3 innate lymphoid cells (ILC3s) are the innate counterparts of Th17 that require the transcription factor RORγt for development and contribute to the defense against pathogens through IL-22 and IL-17 secretion. Proliferation and effector functions of Th17 require a specific mTOR-dependent metabolic program that utilizes high-rate glycolysis, while mitochondrial lipid oxidation and production of reactive oxygen species (mROS) support alternative T reg cell differentiation. Whether ILC3s employ a specific metabolic program is not known. Here, we find that ILC3s rely on mTOR complex 1 (mTORC1) for proliferation and production of IL-22 and IL-17A after in vitro activation and Citrobacter …

Htlv-1 Viral Oncogene Hbz Drives Bone Destruction In Adult T Cell Leukemia, Jingyu Xiang, Daniel A Rauch, Devra D Huey, Amanda R Panfil, Xiaogang Cheng, Alison K Esser, Xinming Su, John C Harding, Yalin Xu, Gregory C Fox, Francesca Fontana, Takayuki Kobayashi, Junyi Su, Hemalatha Sundaramoorthi, Wing Hing Wong, Yizhen Jia, Thomas J Rosol, Deborah J Veis, Patrick L Green, Stefan Niewiesk, Lee Ratner, Katherine N Weilbaecher

Open Access Publications

Osteolytic bone lesions and hypercalcemia are common, serious complications in adult T cell leukemia/lymphoma (ATL), an aggressive T cell malignancy associated with human T cell leukemia virus type 1 (HTLV-1) infection. The HTLV-1 viral oncogene HBZ has been implicated in ATL tumorigenesis and bone loss. In this study, we evaluated the role of HBZ on ATL-associated bone destruction using HTLV-1 infection and disease progression mouse models. Humanized mice infected with HTLV-1 developed lymphoproliferative disease and continuous, progressive osteolytic bone lesions. HTLV-1 lacking HBZ displayed only modest delays to lymphoproliferative disease but significantly decreased disease-associated bone loss compared with HTLV-1-infected mice. …

Irak4 Mediates Colitis-Induced Tumorigenesis And Chemoresistance In Colorectal Cancer, Qiong Li, Yali Chen, Daoxiang Zhang, Julie Grossman, Lin Li, Namrata Khurana, Hongmei Jiang, Patrick M Grierson, John Herndon, David G Denardo, Grant A Challen, Jingxia Liu, Marianna B Ruzinova, Ryan C Fields, Kian-Huat Lim

Open Access Publications

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor-associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have …