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Fetal Cortical Plate Segmentation Using Fully Convolutional Networks With Multiple Plane Aggregation, Jinwoo Hong, Hyuk Jin Yun, Gilsoon Park, Seonggyu Kim, Cynthia T Laurentys, Leticia C Siqueira, Tomo Tarui, Caitlin K Rollins, Cynthia M Ortinau, P Ellen Grant, Jong-Min Lee, Kiho Im

Open Access Publications

Fetal magnetic resonance imaging (MRI) has the potential to advance our understanding of human brain development by providing quantitative information of cortical plate (CP) development

Smoking-By-Genotype Interaction In Type 2 Diabetes Risk And Fasting Glucose, Peitao Wu, Mary F. Feitosa, Yize Li, Michael M. Province, D C Rao, Et Al.

Open Access Publications

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in …

Integration Of Mobile Health Into Sickle Cell Disease Care To Increase Hydroxyurea Utilization: Protocol For An Efficacy And Implementation Study, Jane S Hankins, Cecelia Calhoun, Ana Baumann, Lisa Klesges, Et Al

Open Access Publications

BACKGROUND: Hydroxyurea prevents disease complications among patients with sickle cell disease (SCD). Although its efficacy has been endorsed by the National Health Lung and Blood Institute evidence-based guidelines, its adoption is low, both by patients with SCD and providers. Mobile health (mHealth) apps provide benefits in improving medication adherence and self-efficacy among patients with chronic diseases and have facilitated prescription among medical providers. However, mHealth has not been systematically tested as a tool to increase hydroxyurea adherence nor has the combination of mHealth been assessed at both patient and provider levels to increase hydroxyurea utilization.

OBJECTIVE: This study aims to …

Comparing Sensitivity To Change Using The 6-Item Versus The 17-Item Hamilton Depression Rating Scale In The Guided Randomized Controlled Trial, Boadie W Dunlop, Sagar V Parikh, Anthony J Rothschild, Michael E Thase, Charles Debattista, Charles R Conway, Brent P Forester, Francis M Mondimore, Richard C Shelton, Matthew Macaluso, Jennifer Logan, Paul Traxler, James Li, Holly Johnson, John F Greden

Open Access Publications

BACKGROUND: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown.

METHODS: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. …

Multicenter Clinical Evaluation Of Etest Meropenem-Vaborbactam (Biomérieux) For Susceptibility Testing Of Enterobacterales (Enterobacteriaceae) And Pseudomonas Aeruginosa, Sophonie Jean, Sheri Garrett, Claire Anglade, Laurence Bridon, Leanne Davies, Omai B Garner, Jennifer Richards, Meghan Wallace, Mandy Wootton, Carey-Ann D. Burnham

Open Access Publications

Meropenem-vaborbactam (MEV) is a novel carbapenem-beta-lactamase inhibitor combination antibiotic approved by the U.S. Food and Drug Administration (FDA) for treatment of complicated urinary tract infections, including pyelonephritis, in adults. In this study, we evaluated the performance of Etest MEV (bioMérieux, Marcy l'Etoile, France) compared to that of broth microdilution for 629

A Qualitative Study Of Older Adults' Perspectives On Initiating Exercise And Mindfulness Practice, Diana C Parra, Julie Loebach Wetherell, Alexandria Van Zandt, Ross C Brownson, Janardan Abhishek, Eric J Lenze

Open Access Publications

BACKGROUND: Mindfulness practice and exercise are ways by which older adults can improve and maintain their physical, emotional and cognitive health.

METHODS: This single-site qualitative study gathered insights of older adults' perceptions about initiating and maintaining mindfulness and exercise practices. We carried out focus groups with 41 adults aged 65-85 who had recently initiated Mindfulness Based Stress Reduction (MBSR), structured exercise, or their combination as part of participation in a clinical trial. We used a semi-structured interview to ask them open-ended questions regarding the benefits, barriers and facilitators of participating in mindfulness and/or exercise interventions. The interview also included questions …

Humanized Zebrafish Enhance Human Hematopoietic Stem Cell Survival And Promote Acute Myeloid Leukemia Clonal Diversity, Vinothkumar Rajan, Nicole Melong, Wing Hing Wong, Benjamin King, R. Spencer Tong, Nithin Mahajan, Daniel Gaston, Troy Lund, David Rittenberg, Graham Dellaire, Clinton J. V. Campbell, Todd Druley, Jason N. Berman

Open Access Publications

Xenograft models are invaluable tools in establishing the current paradigms of hematopoiesis and leukemogenesis. The zebrafish has emerged as a robust alternative xenograft model but, like mice, lack specific cytokines that mimic the microenvironment found in human patients. To address this critical gap, we generated the first humanized zebrafish that express human hematopoietic-specific cytokines (GM-CSF, SCF, and SDF1α). Termed GSS fish, these zebrafish promote survival, self-renewal and multilineage differentiation of human hematopoietic stem and progenitor cells and result in enhanced proliferation and hematopoietic niche-specific homing of primary human leukemia cells. Using error-corrected RNA sequencing, we determined that patient-derived leukemias transplanted …

Immunomodulatory Activity Of Humanized Anti-Il-7r Monoclonal Antibody Rn168 In Subjects With Type 1 Diabetes, Kevan C Herold, Jing Hughes, Janet B Mcgill, Et Al

Open Access Publications

BACKGROUND: The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses.

METHODS: Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study.

RESULTS: Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central …

Comparison Of Reproducibility, Accuracy, Sensitivity, And Specificity Of Mirna Quantification Platforms, Paula M Godoy, Andrea J Barczak, Peter Dehoff, Srimeenakshi Srinivasan, Alton Etheridge, David Galas, Saumya Das, David J Erle, Louise C Laurent

Open Access Publications

Given the increasing interest in their use as disease biomarkers, the establishment of reproducible, accurate, sensitive, and specific platforms for microRNA (miRNA) quantification in biofluids is of high priority. We compare four platforms for these characteristics: small RNA sequencing (RNA-seq), FirePlex, EdgeSeq, and nCounter. For a pool of synthetic miRNAs, coefficients of variation for technical replicates are lower for EdgeSeq (6.9%) and RNA-seq (8.2%) than for FirePlex (22.4%); nCounter replicates are not performed. Receiver operating characteristic analysis for distinguishing present versus absent miRNAs shows small RNA-seq (area under curve 0.99) is superior to EdgeSeq (0.97), nCounter (0.94), and FirePlex (0.81). …

The Aminoalkylindole Bml-190 Negatively Regulates Chitosan Synthesis Via The Cyclic Amp/Protein Kinase A1 Pathway In Cryptococcus Neoformans, Brian T Maybruck, Woei C Lam, Charles A Specht, Ma Xenia G Ilagan, Maureen J Donlin, Jennifer K Lodge

Open Access Publications

No abstract provided.

The Role Of Glia In Epilepsy, Intellectual Disability, And Other Neurodevelopmental Disorders In Tuberous Sclerosis Complex, Michael Wong

Open Access Publications

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by severe neurological manifestations, including epilepsy, intellectual disability, autism, and a range of other behavioral and psychiatric symptoms, collectively referred to as TSC-associated neuropsychiatric disorders (TAND). Various tumors and hamartomas affecting different organs are the pathological hallmarks of the disease, especially cortical tubers of the brain, but specific cellular and molecular abnormalities, such as involving the mechanistic target of rapamycin (mTOR) pathway, have been identified that also cause or contribute to neurological manifestations of TSC independent of gross structural lesions. In particular, while neurons are immediate mediators of neurological symptoms, …

Adaptation Of The Clinical Dementia Rating Scale For Adults With Down Syndrome, Christina N Lessov-Schlaggar, Olga L Del Rosario, John C Morris, Beau M Ances, Bradley L Schlaggar, John N Constantino

Open Access Publications

BACKGROUND: Adults with Down syndrome (DS) are at increased risk for Alzheimer disease dementia, and there is a pressing need for the development of assessment instruments that differentiate chronic cognitive impairment, acute neuropsychiatric symptomatology, and dementia in this population of patients.

METHODS: We adapted a widely used instrument, the Clinical Dementia Rating (CDR) Scale, which is a component of the Uniform Data Set used by all federally funded Alzheimer Disease Centers for use in adults with DS, and tested the instrument among 34 DS patients recruited from the community. The participants were assessed using two versions of the modified CDR-a …

Regional Gene Repression By Dna Double-Strand Breaks In G1 Phase Cells, Caitlin E. Purman, Patrick L. Collins, Sofia I. Porter, Ankita Saini, Harshath Gupta, Barry P. Sleckman, Eugene M. Oltz

Open Access Publications

DNA damage responses (DDR) to double-strand breaks (DSBs) alter cellular transcription programs at the genome-wide level. Through processes that are less well understood, DSBs also alter transcriptional responses locally, which may be important for efficient DSB repair. Here, we developed an approach to elucidate the

Clearance Of Chikungunya Virus Infection In Lymphoid Tissues Is Promoted By Treatment With An Agonistic Anti-Cd137 Antibody, Jun P Hong, Mary K Mccarthy, Bennett J Davenport, Thomas E Morrison, Michael S Diamond

Open Access Publications

CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV …

Cytogps: A Web-Enabled Karyotype Analysis Tool For Cytogenetics, Zachary B Abrams, Lin Zhang, Lynne V Abruzzo, Nyla A Heerema, Suli Li, Tom Dillon, Ricky Rodriguez, Kevin R Coombes, Philip R O Payne

Open Access Publications

SUMMARY: Karyotype data are the most common form of genetic data that is regularly used clinically. They are collected as part of the standard of care in many diseases, particularly in pediatric and cancer medicine contexts. Karyotypes are represented in a unique text-based format, with a syntax defined by the International System for human Cytogenetic Nomenclature (ISCN). While human-readable, ISCN is not intrinsically machine-readable. This limitation has prevented the full use of complex karyotype data in discovery science use cases. To enhance the utility and value of karyotype data, we developed a tool named CytoGPS. CytoGPS first parses ISCN karyotypes …

Dosimetric Feasibility Of Utilizing The Viewray Magnetic Resonance Guided Linac System For Image-Guided Spine Stereotactic Body Radiation Therapy, Gage Redler, Tynan Stevens, Jochen Cammin, Martha Malin, Olga Green, Sasa Mutic, Sean Pitroda, Bulent Aydogan

Open Access Publications

INTRODUCTION: Spine stereotactic body radiation therapy (SBRT) achieves favorable outcomes compared to conventional radiotherapy doses/fractionation. The spinal cord is the principal dose-limiting organ-at-risk (OAR), and safe treatment requires precise immobilization/localization. Therefore, image guidance is paramount to successful spine SBRT. Conventional X-ray imaging and alignment to surrogate bony anatomy may be inadequate, whereas magnetic resonance imaging (MRI) directly visualizes the dose-limiting cord. This work assessed the dosimetric capability of the ViewRay (ViewRay Inc. Oakwood Village, OH) magnetic resonance (MR) guided linac (MR-Linac) for spine SBRT.

METHODS: Eight spine SBRT patients without orthopedic hardware who were previously treated on a TrueBeam using …

Distinct Roles Of Interferon Alpha And Beta In Controlling Chikungunya Virus Replication And Modulating Neutrophil-Mediated Inflammation, Lindsey E Cook, Marissa C Locke, Alissa R Young, Kristen Monte, Matthew L Hedberg, Raeann M Shimak, Kathleen C F Sheehan, Deborah J Veis, Michael S Diamond, Deborah J Lenschow

Open Access Publications

Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice …

Gantenerumab Reduces Amyloid-Β Plaques In Patients With Prodromal To Moderate Alzheimer's Disease: A Pet Substudy Interim Analysis, Gregory Klein, Paul Delmar, Nicola Voyle, Sunita Rehal, Carsten Hofmann, Danielle Abi-Saab, Mirjana Andjelkovic, Smiljana Ristic, Guoqiao Wang, Randall Bateman, Geoffrey A Kerchner, Monika Baudler, Paulo Fontoura, Rachelle Doody

Open Access Publications

BACKGROUND: We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer's disease (AD).

METHODS: A subset of patients enrolled in …

Let-7 Micrornas Regulate Microglial Function And Suppress Glioma Growth Through Toll-Like Receptor 7, Alice Buonfiglioli, David H Gutmann, Et Al

Open Access Publications

Microglia express Toll-like receptors (TLRs) that sense pathogen- and host-derived factors, including single-stranded RNA. In the brain, let-7 microRNA (miRNA) family members are abundantly expressed, and some have recently been shown to serve as TLR7 ligands. We investigated whether let-7 miRNA family members differentially control microglia biology in health and disease. We found that a subset of let-7 miRNA family members function as signaling molecules to induce microglial release of inflammatory cytokines, modulate antigen presentation, and attenuate cell migration in a TLR7-dependent manner. The capability of the let-7 miRNAs to control microglial function is sequence specific, mapping to a let-7 …

Discordant Transmission Of Bacteria And Viruses From Mothers To Babies At Birth, Rabia Maqsood, Rachel Rodgers, Cynthia Rodriguez, Scott A Handley, I. Malick Ndao, Phillip I Tarr, Barbara B Warner, Efrem S Lim, Lori R Holtz

Open Access Publications

BACKGROUND: The earliest microbial colonizers of the human gut can have life-long consequences for their hosts. Precisely how the neonatal gut bacterial microbiome and virome are initially populated is not well understood. To better understand how the maternal gut microbiome influences acquisition of the infant gut microbiome, we studied the early life bacterial microbiomes and viromes of 28 infant twin pairs and their mothers.

RESULTS: Infant bacterial and viral communities more closely resemble those of their related co-twin than unrelated infants. We found that 63% of an infant's bacterial microbiome can be traced to their mother's gut microbiota. In contrast, …

Assessing Somatization In Urologic Chronic Pelvic Pain Syndrome, C S North, B A Hong, H H Lai, D H Alpers

Open Access Publications

BACKGROUND: This study examined the prevalence of somatization disorder in Urological Chronic Pelvic Pain Syndrome (UCPPS) and the utility of two self-report symptom screening tools for assessment of somatization in patients with UCPPS.

METHODS: The study sample included 65 patients with UCPPS who enrolled in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Study at Washington University. Patients completed the PolySymptomatic PolySyndromic Questionnaire (PSPS-Q) (n = 64) and the Patient Health Questionnaire-15 Somatic Symptom Severity Scale (PHQ-15) (n = 50). Review of patient medical records found that only 47% (n = 30) contained sufficient documentation to assess …

Lime-Induced Phytophotodermatitis, Ashraf Abugroun, Safwan Gaznabi, Arjun Natarajan, Hussein Daoud

Open Access Publications

Phytophotodermatitis, also commonly known as phototoxic dermatitis, is a common skin condition that occurs after contact with certain plants and subsequent exposure to sunlight. It is often confused with skin burns due to the blistering nature of its lesions. We herein report a case of phytophotodermatitis that developed in a 26-year-old male following contact with lime and subsequent exposure to sunlight.

The Local Translation Of Kna In Dendritic Projections Of Auditory Neurons And The Roles Of Kna In The Transition From Hidden To Overt Hearing Loss, Jeong Han Lee, Mincheol Kang, Seojin Park, Maria C. Perez-Flores, Xiao-Dong Zhang, Wenying Wang, Michael Anne Gratton, Nipavan Chiamvimonvat, Ebenezer N. Yamoah

Open Access Publications

Local and privileged expression of dendritic proteins allows segregation of distinct functions in a single neuron but may represent one of the underlying mechanisms for early and insidious presentation of sensory neuropathy. Tangible characteristics of early hearing loss (HL) are defined in correlation with nascent hidden hearing loss (HHL) in humans and animal models. Despite the plethora of causes of HL, only two prevailing mechanisms for HHL have been identified, and in both cases, common structural deficits are implicated in inner hair cell synapses, and demyelination of the auditory nerve (AN). We uncovered that Na

Text-Mining Clinically Relevant Cancer Biomarkers For Curation Into The Civic Database, Jake Lever, Martin R Jones, Arpad M Danos, Kilannin Krysiak, Melika Bonakdar, Jasleen K Grewal, Luka Culibrk, Obi L Griffith, Malachi Griffith, Steven J M Jones

Open Access Publications

BACKGROUND: Precision oncology involves analysis of individual cancer samples to understand the genes and pathways involved in the development and progression of a cancer. To improve patient care, knowledge of diagnostic, prognostic, predisposing, and drug response markers is essential. Several knowledgebases have been created by different groups to collate evidence for these associations. These include the open-access Clinical Interpretation of Variants in Cancer (CIViC) knowledgebase. These databases rely on time-consuming manual curation from skilled experts who read and interpret the relevant biomedical literature.

METHODS: To aid in this curation and provide the greatest coverage for these databases, particularly CIViC, we …

A Metastable Subproteome Underlies Inclusion Formation In Muscle Proteinopathies, Prajwal Ciryam, Matthew Antalek, Fernando Cid, Gian Gaetano Tartaglia, Christopher M Dobson, Anne-Katrin Guettsches, Britta Eggers, Matthias Vorgerd, Katrin Marcus, Rudolf A Kley, Richard I Morimoto, Michele Vendruscolo, Conrad C Weihl

Open Access Publications

Protein aggregation is a pathological feature of neurodegenerative disorders. We previously demonstrated that protein inclusions in the brain are composed of supersaturated proteins, which are abundant and aggregation-prone, and form a metastable subproteome. It is not yet clear, however, whether this phenomenon is also associated with non-neuronal protein conformational disorders. To respond to this question, we analyzed proteomic datasets from biopsies of patients with genetic and acquired protein aggregate myopathy (PAM) by quantifying the changes in composition, concentration and aggregation propensity of proteins in the fibers containing inclusions and those surrounding them. We found that a metastable subproteome is present …

Developmental Hypomyelination In Wolfram Syndrome: New Insights From Neuroimaging And Gene Expression Analyses, Amjad Samara, Rachel Rahn, Olga Neyman, Ki Yun Park, Ahmad Samara, Bess Marshall, Joseph Dougherty, Tamara Hershey

Open Access Publications

Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Mutations in WFS1 are responsible for the majority of Wolfram syndrome cases. WFS1 encodes for an endoplasmic reticulum (ER) protein, wolframin. It is proposed that wolframin deficiency triggers the unfolded protein response (UPR) pathway resulting in an increased ER stress-mediated neuronal loss. Recent neuroimaging …

Sik3 Suppresses Neuronal Hyperexcitability By Regulating The Glial Capacity To Buffer K+ And Water, Hailun Li, Alexandra Russo, Aaron Diantonio

Open Access Publications

Glial regulation of extracellular potassium (K

Single-Nucleotide Polymorphism-Based Genetic Risk Score And Patient Age At Prostate Cancer Diagnosis, Rong Na, Craig Labbate, Hongjie Yu, Zhuqing Shi, Richard J. Fantus, Chi-Hsiung Wang, Gerald L. Andriole, William B. Isaacs, S Lilly Zheng, Brian T. Helfand, Jianfeng Xu

Open Access Publications

Importance: Few studies have evaluated the association between a single-nucleotide polymorphism-based genetic risk score (GRS) and patient age at prostate cancer (PCa) diagnosis.

Objectives: To test the association between a GRS and patient age at PCa diagnosis and to compare the performance of a GRS with that of family history (FH) in PCa risk stratification.

Design, Setting, and Participants: A cohort study of 3225 white men was conducted as a secondary analysis of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) chemoprevention trial, a 4-year, randomized, double-blind, placebo-controlled multicenter study conducted from March 2003 to April 2009 to evaluate …

Association Of Aspirin Use With Mortality Risk Among Older Adult Participants In The Prostate, Lung, Colorectal, And Ovarian Cancer Screening Trial, Holli A. Loomans-Kropp, Paul Pinsky, Yin Cao, Andrew T. Chan, Asad Umar

Open Access Publications

Importance: Aspirin use has been associated with reduced risk of cancer mortality, particularly of the colorectum. However, aspirin efficacy may be influenced by biological characteristics, such as obesity and age. With the increasing prevalence of obesity and conflicting data regarding the effect of aspirin in older adults, understanding the potential association of aspirin use with cancer mortality according to body mass index (BMI) and age is imperative.

Objectives: To investigate the association of aspirin use with risk of all-cause, any cancer, gastrointestinal (GI) cancer, and colorectal cancer (CRC) mortality among older adults and to perform an exploratory analysis of the …

Disease-Associated Mutations In Niemann-Pick Type C1 Alter Er Calcium Signaling And Neuronal Plasticity, Scott A. Tiscione, Oscar Vivas, Kenneth S. Ginsburg, Donald M. Bers, Daniel S. Ory, Luis F. Santana, Rose E. Dixon, Eamonn J. Dickson

Open Access Publications

Niemann-Pick type C1 (NPC1) protein is essential for the transport of externally derived cholesterol from lysosomes to other organelles. Deficiency of NPC1 underlies the progressive NPC1 neurodegenerative disorder. Currently, there are no curative therapies for this fatal disease. Given the Ca