Digital Commons Network^™

An Inducible Cre Mouse Line To Sparsely Target Nervous System Cells, Including Remak Schwann Cells, Darshan Sapkota, Joseph D Dougherty

Open Access Publications

Nerves of the peripheral nervous system contain two classes of Schwann cells: myelinating Schwann cells that ensheath large caliber axons and generate the myelin sheath, and Remak Schwann cells that surround smaller axons and do not myelinate. While tools exist for genetic targeting of Schwann cell precursors and myelinating Schwann cells, such reagents have been challenging to generate specifically for the Remak population, in part because many of the genes that mark this population in maturity are also robustly expressed in Schwann cell precursors. To circumvent this challenge, we utilized BAC transgenesis to generate a mouse line expressing a tamoxifen-inducible …

Combining Stage Specificity And Metabolomic Profiling To Advance Antimalarial Drug Discovery, James M Murithi, Edward S Owen, Eva S Istvan, Marcus C S Lee, Sabine Ottilie, Kelly Chibale, Daniel E Goldberg, Elizabeth A Winzeler, Manuel Llinás, David A Fidock, Manu Vanaerschot

Open Access Publications

We report detailed susceptibility profiling of asexual blood stages of the malaria parasite Plasmodium falciparum to clinical and experimental antimalarials, combined with metabolomic fingerprinting. Results revealed a variety of stage-specific and metabolic profiles that differentiated the modes of action of clinical antimalarials including chloroquine, piperaquine, lumefantrine, and mefloquine, and identified late trophozoite-specific peak activity and stage-specific biphasic dose-responses for the mitochondrial inhibitors DSM265 and atovaquone. We also identified experimental antimalarials hitting previously unexplored druggable pathways as reflected by their unique stage specificity and/or metabolic profiles. These included several ring-active compounds, ones affecting hemoglobin catabolism through distinct pathways, and mitochondrial inhibitors …

Cryptococcus Neoformans Chitin Synthase 3 Plays A Critical Role In Dampening Host Inflammatory Responses, Camaron R Hole, Woei C Lam, Rajendra Upadhya, Jennifer K Lodge

Open Access Publications

No abstract provided.

Proof-Of-Concept Study Of The Efficacy Of A Microbiota-Directed Complementary Food Formulation (Mdcf) For Treating Moderate Acute Malnutrition, Ishita Mostafa, Naila Nurun Nahar, Md Munirul Islam, Sayeeda Huq, Mahfuz Mustafa, Michael Barratt, Jeffrey I Gordon, Tahmeed Ahmed

Open Access Publications

BACKGROUND: Childhood undernutrition remains a significant global health challenge accounting for over half of all under 5 child mortality. Moderate acute malnutrition (MAM), which leads to wasting [weight-for-length z-scores (WLZ) between - 2 and - 3], affects 33 million children under 5 globally and more than 2 million in Bangladesh alone. We have previously reported that acute malnutrition in this population is associated with gut microbiota immaturity, and in a small, 1-month pre-proof-of-concept (POC) study demonstrated that a microbiota-directed complementary food formulation (MDCF-2) was able to repair this immaturity, promote weight gain and increase plasma biomarkers and mediators of healthy …

Dnmt3b Ablation Impairs Fracture Repair Through Upregulation Of Notch Pathway, Jun Ying, Taotao Xu, Cuicui Wang, Hongting Jin, Peijian Tong, Jianjun Guan, Yousef Abu-Amer, Regis O'Keefe, Jie Shen

Open Access Publications

We previously established that DNA methyltransferase 3b (Dnmt3b) is the sole Dnmt responsive to fracture repair and that Dnmt3b expression is induced in progenitor cells during fracture repair. In the current study, we confirmed that Dnmt3b ablation in mesenchymal progenitor cells (MPCs) resulted in impaired endochondral ossification, delayed fracture repair, and reduced mechanical strength of the newly formed bone in Prx1-Cre;Dnmt3bf/f (Dnmt3bPrx1) mice. Mechanistically, deletion of Dnmt3b in MPCs led to reduced chondrogenic and osteogenic differentiation in vitro. We further identified Rbpjκ as a downstream target of Dnmt3b in MPCs. In fact, we located 2 Dnmt3b binding sites in the …

Myocardial B Cells Are A Subset Of Circulating Lymphocytes With Delayed Transit Through The Heart, Luigi Adamo, Cibele Rocha-Resende, Chieh-Yu Lin, Sarah Evans, Jesse Williams, Hao Dun, Wenjun Li, Cedric Mpoy, Prabhakar S Andhey, Buck E Rogers, Kory Lavine, Daniel Kreisel, Maxim Artyomov, Gwendalyn J Randolph, Douglas L Mann

Open Access Publications

Current models of B lymphocyte biology posit that B cells continuously recirculate between lymphoid organs, without accumulating in peripheral healthy tissues. Nevertheless, B lymphocytes are one of the most prevalent leukocyte populations in the naive murine heart. To investigate this apparent inconsistency in the literature, we conducted a systematic analysis of myocardial B cell ontogeny, trafficking dynamics, histology, and gene expression patterns. We found that myocardial B cells represent a subpopulation of circulating B cells that make close contact with the microvascular endothelium of the heart and arrest their transit as they pass through the heart. The vast majority ( …

Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis At The Blood-Brain Barrier For Central Nervous System Entry, Hamid Salimi, Matthew D Cain, Xiaoping Jiang, Robyn A Roth, Wandy L Beatty, Chengqun Sun, William B Klimstra, Jianghui Hou, Robyn S Klein

Open Access Publications

Venezuelan and western equine encephalitis viruses (VEEV and WEEV, respectively) invade the central nervous system (CNS) early during infection, via neuronal and hematogenous routes. While viral replication mediates host shutoff, including expression of type I interferons (IFN), few studies have addressed how alphaviruses gain access to the CNS during established infection or the mechanisms of viral crossing at the blood-brain barrier (BBB). Here, we show that hematogenous dissemination of VEEV and WEEV into the CNS occurs via caveolin-1 (Cav-1)-mediated transcytosis (Cav-MT) across an intact BBB, which is impeded by IFN and inhibitors of RhoA GTPase. Use of reporter and nonreplicative …

Synthetic And Genomic Regulatory Elements Reveal Aspects Of Cis-Regulatory Grammar In Mouse Embryonic Stem Cells, Dana M King, Clarice Kit Yee Hong, James L Shepherdson, David M Granas, Brett B Maricque, Barak A Cohen

2020-Current year OA Pubs

In embryonic stem cells (ESCs), a core transcription factor (TF) network establishes the gene expression program necessary for pluripotency. To address how interactions between four key TFs contribute to

Spatiotemporal Dynamics Of Multi-Vesicular Release Is Determined By Heterogeneity Of Release Sites Within Central Synapses, Dario Maschi, Vitaly A. Klyachko

Open Access Publications

A synaptic active zone (AZ) can release multiple vesicles in response to an action potential. This multi-vesicular release (MVR) occurs at most synapses, but its spatiotemporal properties are unknown. Nanoscale-resolution detection of individual release events in hippocampal synapses revealed unprecedented heterogeneity among vesicle release sites within a single AZ, with a gradient of release probability decreasing from AZ center to periphery. Parallel to this organization, MVR events preferentially overlap with uni-vesicular release (UVR) events at sites closer to an AZ center. Pairs of fusion events comprising MVR are also not perfectly synchronized, and the earlier event tends to occur closer …

Quantitative Trait Variation In Asd Probands And Toddler Sibling Outcomes At 24 Months, Jessica B Girault, Kelly N Botteron, John N Constantino, Et Al

Open Access Publications

BACKGROUND: Younger siblings of children with autism spectrum disorder (ASD) are at increased likelihood of receiving an ASD diagnosis and exhibiting other developmental concerns. It is unknown how quantitative variation in ASD traits and broader developmental domains in older siblings with ASD (probands) may inform outcomes in their younger siblings.

METHODS: Participants included 385 pairs of toddler siblings and probands from the Infant Brain Imaging Study. ASD probands (mean age 5.5 years, range 1.7 to 15.5 years) were phenotyped using the Autism Diagnostic Interview-Revised (ADI-R), the Social Communication Questionnaire (SCQ), and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). Siblings …

Prevalence And Family-Related Factors Associated With Suicidal Ideation, Suicide Attempts, And Self-Injury In Children Aged 9 To 10 Years, Danielle C. Deville, Diana Whalen, Florence J. Breslin, Amanda S. Morris, Sahib S. Khalsa, Martin P. Paulus, Deanna M. Barch

Open Access Publications

Importance: Although suicide is a leading cause of death for children in the United States, and the rate of suicide in childhood has steadily increased, little is known about suicidal ideation and behaviors in children.

Objective: To assess the overall prevalence of suicidal ideation, suicide attempts, and nonsuicidal self-injury, as well as family-related factors associated with suicidality and self-injury among preadolescent children.

Design, Setting, and Participants: Cross-sectional study using retrospective analysis of the baseline sample from the Adolescent Brain Cognitive Development (ABCD) study. This multicenter investigation used an epidemiologically informed school-based recruitment strategy, with consideration of the demographic composition of …

Mechanism Of Differential Zika And Dengue Virus Neutralization By A Public Antibody Lineage Targeting The Diii Lateral Ridge, Haiyan Zhao, Lily Xu, Robin Bombardi, Rachel Nargi, Zengqin Deng, John M. Errico, Christopher A. Nelson, Kimberly A. Dowd, Theodore C. Pierson, James E. Crowe, Michael S. Diamond, Daved H. Fremont

Open Access Publications

We previously generated a panel of human monoclonal antibodies (mAbs) against Zika virus (ZIKV) and identified one, ZIKV-116, that shares germline usage with mAbs identified in multiple donors. Here we show that ZIKV-116 interferes with ZIKV infection at a post-cellular attachment step by blocking viral fusion with host membranes. ZIKV-116 recognizes the lateral ridge of envelope protein domain III, with one critical residue varying between the Asian and African strains responsible for differential binding affinity and neutralization potency (E393D). ZIKV-116 also binds to and cross-neutralizes some dengue virus serotype 1 (DENV1) strains, with genotype-dependent inhibition explained by variation in a …

Hypothalamic Orexin And Mechanistic Target Of Rapamycin Activation Mediate Sleep Dysfunction In A Mouse Model Of Tuberous Sclerosis Complex, Bo Zhang, Dongjun Guo, Lirong Han, Nicholas Rensing, Akiko Satoh, Michael Wong

2020-Current year OA Pubs

Tuberous sclerosis complex (TSC) is a genetic disease related to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and manifested by neurological symptoms, such as epilepsy and sleep disorders. The pathophysiology of sleep dysfunction is poorly understood and is likely multifactorial, but may involve intrinsic biological regulators in the brain. Here, we characterized a mouse model of sleep disorders in TSC and investigated mechanisms of sleep dysfunction in this conditional knockout model involving inactivation of the Tsc1 gene in neurons and astrocytes (Tsc1

Toward Actionable Practice Parameters For "Dual Diagnosis": Principles Of Assessment And Management For Co-Occurring Psychiatric And Intellectual/Developmental Disability, John N Constantino, Shae Strom, Michael Bunis, Cy Nadler, Teresa Rodgers, Julia Lepage, Connie Cahalan, Amber Stockreef, Lucas Evans, Rachel Jones, Alyssa Wilson

2020-Current year OA Pubs

PURPOSE OF REVIEW: Although treatment algorithms and parameters for best practice are readily available for all major syndromes of psychiatric impairment, the occurrence of psychiatric syndromes in individuals with intellectual and developmental disability (IDD) invokes serious contextual challenges for interpretation of symptoms, diagnosis, and optimization of treatment, both for clinicians and for the service sectors in which care and support of individuals with IDD are delivered. Recognizing that there exist very few definitive resources for best practice under the circumstance of this form of "dual diagnosis," the Missouri Department of Mental Health convened an expert panel to conduct a focused …

Inhibition Of Rev-Erbs Stimulates Microglial Amyloid-Beta Clearance And Reduces Amyloid Plaque Deposition In The 5xfad Mouse Model Of Alzheimer's Disease, Jiyeon Lee, Do Eon Kim, Percy Griffin, Patrick W Sheehan, Dong-Hou Kim, Erik S Musiek, Seung-Yong Yoon

Open Access Publications

A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aβ

Comparison Of Symptomatic And Functional Responses To Vagus Nerve Stimulation In Anthem-Hf, Inovate-Hf, And Nectar-Hf, Inder S Anand, Marvin A Konstam, Helmut U Klein, Douglas L Mann, Jeffrey L Ardell, Douglas D Gregory, Joseph M Massaro, Imad Libbus, Lorenzo A Dicarlo, John James E Udelson, Javed Butler, John D Parker, John R Teerlink

Open Access Publications

AIMS: Clinical studies of vagal nerve stimulation (VNS) for heart failure with reduced ejection fraction have had mixed results to date. We sought to compare VNS delivery and associated changes in symptoms and function in autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure (ANTHEM-HF), increase of vagal tone in heart failure (INOVATE-HF), and neural cardiac therapy for heart failure (NECTAR-HF) for hypothesis generation.

METHODS AND RESULTS: Descriptive statistics were used to analyse data from the public domain for differences in proportions using Pearson's chi-square test, differences in mean values using Student's …

Perioperative Care Of The Geriatric Patient For Noncardiac Surgery, Jonathan D Wolfe, Natasha K Wolfe, Michael W Rich

Open Access Publications

Adults age 65 and over are the fastest growing segment of the population in the United States and around the world. As the size of this population expands, the number of older adults referred for surgical procedures will continue to increase. Due to the physiologic changes of aging and the increased frequency of comorbidities, older adults are at increased risk for adverse outcomes, and perioperative care is inherently more complex than in younger individuals. In this review, we discuss the physiologic changes of aging relevant to the surgical patient, comprehensive preoperative assessment, and postoperative management of common complications in older …

Circulating Ceramide Ratios And Risk Of Vascular Brain Aging And Dementia, Emer R Mcgrath, Jayandra J Himali, Vanessa Xanthakis, Meredith S Duncan, Jean E Schaffer, Daniel S Ory, Linda R Peterson, Charles Decarli, Matthew P Pase, Claudia L Satizabal, Ramachandran S Vasan, Alexa S Beiser, Sudha Seshadri

Open Access Publications

BACKGROUND: We determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer's disease (AD) dementia in a large, community-based sample.

METHODS: We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia-free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes.

RESULTS: During a median 6.5 year follow-up, 81 participants developed dementia, of whom 60 were …

The Prevalence And Clinical Implications Of Comorbid Back Pain In Shoulder Instability: A Multicenter Orthopaedic Outcomes Network (Moon) Shoulder Instability Cohort Study, Kevin Cronin, Robert Brophy, Matthew Smith, Rick Wright, Et Al

Open Access Publications

Background: Understanding predictors of pain is critical, as recent literature shows that comorbid back pain is an independent risk factor for worse functional and patient-reported outcomes (PROs) as well as increased opioid dependence after total joint arthroplasty.

Purpose/Hypothesis: The purpose of this study was to evaluate whether comorbid back pain would be predictive of pain or self-reported instability symptoms at the time of stabilization surgery. We hypothesized that comorbid back pain will correlate with increased pain at the time of surgery as well as with worse scores on shoulder-related PRO measures.

Study Design: Cross-sectional study; Level of evidence, 3.

Methods: …

Targeting Refractory Sarcomas And Malignant Peripheral Nerve Sheath Tumors In A Phase I/Ii Study Of Sirolimus In Combination With Ganetespib (Sarc023), Aerang Kim, Brian A. Van Tine, Et Al

Open Access Publications

No abstract provided.

Analysis Of Neurodegenerative Disease-Causing Genes In Dementia With Lewy Bodies, Tatiana Orme, Nigel J Cairns, John C Morris, Et Al

Open Access Publications

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, …

Clinical Controversies In Anticoagulation Monitoring And Antithrombin Supplementation For Ecmo, Meghan M Chlebowski, Sirine Baltagi, Mel Carlson, Jerrold H Levy, Philip C Spinella

Open Access Publications

During extracorporeal membrane oxygenation (ECMO), a delicate balance is required to titrate systemic anticoagulation to prevent thrombotic complications within the circuit and prevent bleeding in the patient. Despite focused efforts to achieve this balance, the frequency of both thrombotic and bleeding events remains high. Anticoagulation is complicated to manage in this population due to the complexities of the hemostatic system that are compounded by age-related developmental hemostatic changes, variable effects of the etiology of critical illness on hemostasis, and blood-circuit interaction. Lack of high-quality data to guide anticoagulation management in ECMO patients results in marked practice variability among centers. One …

Perfect Timing: Circadian Rhythms, Sleep, And Immunity - An Nih Workshop Summary, Jeffrey A Haspel, Andrew E Gelman, Brian S Kim, Et Al

Open Access Publications

Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses - ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation -are mediated in a time of day-dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, "Sleep Insufficiency, Circadian Misalignment, and the Immune Response," to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential. This Review summarizes topics discussed and highlights immediate opportunities for delineating clinically relevant connections among biological rhythms, …

Lxrs Regulate Features Of Age-Related Macular Degeneration And May Be A Potential Therapeutic Target, Mayur Choudhary, Ebraheim N Ismail, Pei-Li Yao, Faryan Tayyari, Roxana A Radu, Steven Nusinowitz, Michael E Boulton, Rajendra S Apte, Jeffrey W Ruberti, James T Handa, Peter Tontonoz, Goldis Malek

Open Access Publications

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry …

The Tip Of The Vgrg Spike Is Essential To Functional Type Vi Secretion System Assembly In Acinetobacter Baumannii, Juvenal Lopez, Pek Man Ly, Mario F Feldman

Open Access Publications

The type VI secretion system (T6SS) is a critical weapon in bacterial warfare between Gram-negative bacteria. Although invaluable for niche establishment, this machine represents an energetic burden to its host bacterium.

Wormbase: A Modern Model Organism Information Resource, Todd W. Harris, Tim Schedl, Et Al

Open Access Publications

WormBase (https://wormbase.org/) is a mature Model Organism Information Resource supporting researchers using the nematode Caenorhabditis elegans as a model system for studies across a broad range of basic biological processes. Toward this mission, WormBase efforts are arranged in three primary facets: curation, user interface and architecture. In this update, we describe progress in each of these three areas. In particular, we discuss the status of literature curation and recently added data, detail new features of the web interface and options for users wishing to conduct data mining workflows, and discuss our efforts to build a robust and scalable architecture by …

Mirdb: An Online Database For Prediction Of Functional Microrna Targets, Yuhao Chen, Xiaowei Wang

Open Access Publications

MicroRNAs (miRNAs) are small noncoding RNAs that act as master regulators in many biological processes. miRNAs function mainly by downregulating the expression of their gene targets. Thus, accurate prediction of miRNA targets is critical for characterization of miRNA functions. To this end, we have developed an online database, miRDB, for miRNA target prediction and functional annotations. Recently, we have performed major updates for miRDB. Specifically, by employing an improved algorithm for miRNA target prediction, we now present updated transcriptome-wide target prediction data in miRDB, including 3.5 million predicted targets regulated by 7000 miRNAs in five species. Further, we have implemented …

Are We Ready To Share Qualitative Research Data? Knowledge And Preparedness Among Qualitative Researchers, Irb Members, And Data Repository Curators, Jessica Mozersky, Heidi Walsh, Meredith Parsons, Tristan Mcintosh, Kari Baldwin, James M Dubois

Open Access Publications

Data sharing maximizes the value of data, which is time and resource intensive to collect. Major funding bodies in the United States (US), like the National Institutes of Health (NIH), require data sharing and researchers frequently share de-identified quantitative data. In contrast, qualitative data are rarely shared in the US but the increasing trend towards data sharing and open science suggest this may be required in future. Qualitative methods are often used to explore sensitive health topics raising unique ethical challenges regarding protecting confidentiality while maintaining enough contextual detail for secondary analyses. Here, we report findings from semi-structured in-depth interviews …

Atomistic Basis Of Opening And Conduction In Mammalian Inward Rectifier Potassium (Kir2.2) Channels, Eva-Maria Zangerl-Plessl, Sun-Joo Lee, Grigory Maksaev, Harald Bernsteiner, Feifei Ren, Peng Yuan, Anna Stary-Weinzinger, Colin G. Nichols

Open Access Publications

Potassium ion conduction through open potassium channels is essential to control of membrane potentials in all cells. To elucidate the open conformation and hence the mechanism of K+ ion conduction in the classic inward rectifier Kir2.2, we introduced a negative charge (G178D) at the crossing point of the inner helix bundle, the location of ligand-dependent gating. This "forced open" mutation generated channels that were active even in the complete absence of phosphatidylinositol-4,5-bisphosphate (PIP2), an otherwise essential ligand for Kir channel opening. Crystal structures were obtained at a resolution of 3.6 Å without PIP2 bound, or 2.8 Å in complex with …

Toward Improving Practices For Submission Of Diagnostic Tissue Blocks For National Cancer Institute Clinical Trials, Hala Makhlouf, Mark A Watson, Heather A Lankes, Carol Weil, Maura Dickler, Michael Birrer, Christopher Moskaluk, Nilsa C Ramirez, Nader Okby, Edgar Alonsozana, Mark Barnes, Edward B Goldman, Rebecca Enos, Irina Lubensky

2020-Current year OA Pubs

OBJECTIVES: The National Cancer Institute (NCI) National Clinical Trials Network performs phase II and III clinical trials, which increasingly rely on the submission of diagnostic formalin-fixed, paraffin-embedded tissue blocks for biomarker assessment. Simultaneously, advances in precision oncology require that clinical centers maintain diagnostic specimens for ancillary, standard-of-care diagnostics. This has caused tissue blocks to become a limited resource for advancing the NCI clinical trial enterprise and the practice of modern molecular pathology.

METHODS: The NCI convened a 1-day workshop of multidisciplined experts to discuss barriers and strategic solutions to facilitate diagnostic block submission for clinical trial science, from the perspective …