Digital Commons Network^™

Tp53 Mutation Status Divides Myelodysplastic Syndromes With Complex Karyotypes Into Distinct Prognostic Subgroups, Detlef Haase, Matthew J. Walter, Et Al.

Open Access Publications

No abstract provided.

Determining Population Stratification And Subgroup Effects In Association Studies Of Rare Genetic Variants For Nicotine Dependence, Ai-Ru Hsieh, Li-Shiun Chen, Ying-Ju Li, Cathy S. J. Fann

Open Access Publications

No abstract provided.

Challenges To Curing Primary Brain Tumours, Kenneth Aldape, David H. Gutmann, Et Al.

Open Access Publications

No abstract provided.

Clinical Performance Of A Novel Fully Synthetic Dura Substitute, Umang Khandpur, Wilson Ray, Matthew Macewan

Open Access Publications

No abstract provided.

A Strategy For Building And Using A Human Reference Pangenome, Bastien Llamas, Allison Regier, Et Al

Open Access Publications

In March 2019, 45 scientists and software engineers from around the world converged at the University of California, Santa Cruz for the first pangenomics codeathon. The purpose of the meeting was to propose technical specifications and standards for a usable human pangenome as well as to build relevant tools for genome graph infrastructures. During the meeting, the group held several intense and productive discussions covering a diverse set of topics, including advantages of graph genomes over a linear reference representation, design of new methods that can leverage graph-based data structures, and novel visualization and annotation approaches for pangenomes. Additionally, the …

Differential In Vitro Infection Of Neural Cells By Astroviruses, Andrew B. Janowski, Robyn S. Klein, David Wang

Open Access Publications

No abstract provided.

Aberrant Structural And Functional Connectivity And Neurodevelopmental Impairment In Preterm Children, Cynthia E Rogers, Rachel E Lean, Muriah D Wheelock, Christopher D Smyser

Open Access Publications

BACKGROUND: Despite advances in antenatal and neonatal care, preterm birth remains a leading cause of neurological disabilities in children. Infants born prematurely, particularly those delivered at the earliest gestational ages, commonly demonstrate increased rates of impairment across multiple neurodevelopmental domains. Indeed, the current literature establishes that preterm birth is a leading risk factor for cerebral palsy, is associated with executive function deficits, increases risk for impaired receptive and expressive language skills, and is linked with higher rates of co-occurring attention deficit hyperactivity disorder, anxiety, and autism spectrum disorders. These same infants also demonstrate elevated rates of aberrant cerebral structural and …

Association Of Alcohol Consumption After Development Of Heart Failure With Survival Among Older Adults In The Cardiovascular Health Study, Justin S. Sadhu, Eric Novak, Kenneth J. Mukamal, Jorge R. Kizer, Bruce M. Psaty, Phyllis K. Stein, David L. Brown

Open Access Publications

Importance: More than 1 million older adults develop heart failure annually. The association of alcohol consumption with survival among these individuals after diagnosis is unknown.

Objective: To determine whether alcohol use is associated with increased survival among older adults with incident heart failure.

Design, Setting, and Participants: This prospective cohort study included 5888 community-dwelling adults aged 65 years or older who were recruited to participate in the Cardiovascular Health Study between June 12, 1989, and June 1993, from 4 US sites. Of the total participants, 393 individuals had a new diagnosis of heart failure within the first 9 years of …

Lrrk1 Regulation Of Actin Assembly In Osteoclasts Involves Serine 5 Phosphorylation Of L-Plastin, Mingjue Si, Helen Goodluck, Canjun Zeng, Songqin Pan, Elizabeth M Todd, Sharon Celeste Morley, Xuezhong Qin, Subburaman Mohan, Weirong Xing

Open Access Publications

Mice with disruption of Lrrk1 and patients with nonfunctional mutant Lrrk1 exhibit severe osteopetrosis phenotypes because of osteoclast cytoskeletal dysfunction. To understand how Lrrk1 regulates osteoclast function by modulating cytoskeleton rearrangement, we examined the proteins that are differentially phosphorylated in wild-type mice and Lrrk1-deficient osteoclasts by metal affinity purification coupled liquid chromatography/mass spectrometry (LC/MS) analyses. One of the candidates that we identified by LC/MS is L-plastin, an actin bundling protein. We found that phosphorylation of L-plastin at serine (Ser) residues 5 was present in wild-type osteoclasts but not in Lrrk1-deficient cells. Western blot analyses with antibodies specific for Ser5 phosphorylated …

Reengineering Workflow For Curation Of Dicom Datasets, William Bennett, Kirk Smith, Quasar Jarosz, Tracy Nolan, Walter Bosch

Open Access Publications

Reusable, publicly available data is a pillar of open science and rapid advancement of cancer imaging research. Sharing data from completed research studies not only saves research dollars required to collect data, but also helps insure that studies are both replicable and reproducible. The Cancer Imaging Archive (TCIA) is a global shared repository for imaging data related to cancer. Insuring the consistency, scientific utility, and anonymity of data stored in TCIA is of utmost importance. As the rate of submission to TCIA has been increasing, both in volume and complexity of DICOM objects stored, the process of curation of collections …

In Vivo Characterization Of Connective Tissue Remodeling Using Infrared Photoacoustic Spectra, Yuan Qu, Peng Hu, Junhui Shi, Konstantin Maslov, Peinan Zhao, Chiye Li, Jun Ma, Alejandro Garcia-Uribe, Karen Meyers, Emily Diveley, Stephanie Pizzella, Lisa Muench, Nina Punyamurthy, Naomi Goldstein, Oji Onwumere, Mariana Alisio, Kaytelyn Meyenburg, Jennifer Maynard, Kristi Helm, Emma Altieri, Janessia Slaughter, Sabrina Barber, Tracy Burger, Christine Kramer, Jessica Chubiz, Monica Anderson, Ronald Mccarthy, Sarah K England, George A Macones, Molly J Stout, Methodius Tuuli, Lihong V Wang

Open Access Publications

Premature cervical remodeling is a critical precursor of spontaneous preterm birth, and the remodeling process is characterized by an increase in tissue hydration. Nevertheless, current clinical measurements of cervical remodeling are subjective and detect only late events, such as cervical effacement and dilation. Here, we present a photoacoustic endoscope that can quantify tissue hydration by measuring near-infrared cervical spectra. We quantify the water contents of tissue-mimicking hydrogel phantoms as an analog of cervical connective tissue. Applying this method to pregnant women in vivo, we observed an increase in the water content of the cervix throughout pregnancy. The application of this …

A Rare Regulatory Variant In The Mef2d Gene Affects Gene Regulation And Splicing And Is Associated With A Sle Sub-Phenotype In Swedish Cohorts, Fabiana H G Farias, Et Al

Open Access Publications

Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron …

Dysregulated Nk Cell Plcγ2 Signaling And Activity In Juvenile Dermatomyositis, Allison A Throm, Joshua B Alinger, Jeanette T Pingel, Allyssa L Daugherty, Lauren M Pachman, Anthony R French

Open Access Publications

Juvenile dermatomyositis (JDM) is a debilitating pediatric autoimmune disease manifesting with characteristic rash and muscle weakness. To delineate signaling abnormalities in JDM, mass cytometry was performed with PBMCs from treatment-naive JDM patients and controls. NK cell percentages were lower while frequencies of naive B cells and naive CD4+ T cells were higher in JDM patients than in controls. These cell frequency differences were attenuated with cessation of active disease. A large number of signaling differences were identified in treatment-naive JDM patients compared with controls. Classification models incorporating feature selection demonstrated that differences in phospholipase Cγ2 (PLCγ2) phosphorylation comprised 10 of …

Novel Pleiotropic Risk Loci For Melanoma And Nevus Density Implicate Multiple Biological Pathways, David L Duffy, Gu Zhu, Xin Li, Marianna Sanna, Mark M Iles, Leonie C Jacobs, David M Evans, Seyhan Yazar, Jonathan Beesley, Matthew H Law, Peter Kraft, Alessia Visconti, John C Taylor, Fan Liu, Margaret J Wright, Anjali K Henders, Lisa Bowdler, Dan Glass, M Arfan Ikram, André G Uitterlinden, Pamela A Madden, Andrew C Heath, Elliot C Nelson, Adele C Green, Stephen Chanock, Jennifer H Barrett, Matthew A Brown, Nicholas K Hayward, Stuart Macgregor, Richard A Sturm, Alex W Hewitt, Manfred Kayser, David J Hunter, Julia A Newton Bishop, Timothy D Spector, Grant W Montgomery, David A Mackey, George Davey Smith, Tamar E Nijsten, D Timothy Bishop, Veronique Bataille, Mario Falchi, Jiali Han, Nicholas G Martin

Open Access Publications

No abstract provided.

A Web-Based Calculator For The Prediction Of Severe Neurodevelopmental Impairment In Preterm Infants Using Clinical And Imaging Characteristics, Zachary A Vesoulis, Nathalie M El Ters, Maja Herco, Halana V Whitehead, Amit M Mathur

Open Access Publications

Although the most common forms of brain injury in preterm infants have been associated with adverse neurodevelopmental outcomes, existing MRI scoring systems lack specificity, do not incorporate clinical factors, and are technically challenging to perform. The objective of this study was to develop a web-based, clinically-focused prediction system which differentiates severe neurodevelopmental outcomes from normal-moderate outcomes at two years. Infants were retrospectively identified as those who were born ≤30 weeks gestation and who had MRI imaging at term-equivalent age and neurodevelopmental testing at 18⁻24 months. Each MRI was scored on injury in three domains (intraventricular hemorrhage, white matter injury, and …

Lymph Nodes Go With The Flow, Rafael S. Czepielewski, Gwendalyn J. Randolph

Open Access Publications

In this issue, Bovay et al. (https://doi.org/10.1084/jem.20180217) invoke a compelling model of interplay between the venous and lymphatic vasculature in regulating the developmental genesis and early expansion of LNs. This work supports an emerging model that lymph-venous crosstalk supports LN functionality at all stages.

Dietary Protein Restriction Reduces Circulating Vldl Triglyceride Levels Via Crebh-Apoa5-Dependent And -Independent Mechanisms, J Humberto Treviño-Villarreal, Valeria Tosti, Nicola Veronese, Beatrice Bertozzi, Arnold D Bullock, Robert S Figenshau, Gerald L Andriole, Luigi Fontana, Et Al

Open Access Publications

Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Dietary interventions based on protein restriction (PR) reduce circulating triglycerides (TGs), but underlying mechanisms and clinical relevance remain unclear. Here, we show that 1 week of a protein-free diet without enforced calorie restriction significantly lowered circulating TGs in both lean and diet-induced obese mice. Mechanistically, the TG-lowering effect of PR was due, in part, to changes in very low-density lipoprotein (VLDL) metabolism both in liver and peripheral tissues. In the periphery, PR stimulated VLDL-TG consumption by increasing VLDL-bound APOA5 expression and promoting VLDL-TG hydrolysis and clearance from circulation. The PR-mediated increase …

Trex1 Is Expressed By Microglia In Normal Human Brain And Increases In Regions Affected By Ischemia, Parul H Kothari, Grant R Kolar, Joanna C Jen, Rula Hajj-Ali, Paula Bertram, Robert E Schmidt, John P Atkinson

Open Access Publications

BACKGROUND: Mutations in the three-prime repair exonuclease 1 (TREX1) gene have been associated with neurological diseases, including Retinal Vasculopathy with Cerebral Leukoencephalopathy (RVCL). However, the endogenous expression of TREX1 in human brain has not been studied.

METHODS: We produced a rabbit polyclonal antibody (pAb) to TREX1 to characterize TREX1 by Western blotting (WB) of cell lysates from normal controls and subjects carrying an RVCL frame-shift mutation. Dual staining was performed to determine cell types expressing TREX1 in human brain tissue. TREX1 distribution in human brain was further evaluated by immunohistochemical analyses of formalin-fixed, paraffin-embedded samples from normal controls and patients …

Glasdegib In Combination With Cytarabine And Daunorubicin In Patients With Aml Or High-Risk Mds: Phase 2 Study Results, Jorge E Cortes, Mark A Schroeder, Et Al

Open Access Publications

Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open-label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28-day cycles from day -3, with intravenous cytarabine 100 mg/m

Adapting Crowdsourced Clinical Cancer Curation In Civic To The Clingen Minimum Variant Level Data Community-Driven Standards, Arpad M Danos, Alex H Wagner, Kilannin Krysiak, Erica K Barnell, Joshua F Mcmichael, Susanna Kiwala, Adam C Coffman, Lynzey Kujan, Malachi Griffith, Obi L Griffith, Et Al

Open Access Publications

Harmonization of cancer variant representation, efficient communication, and free distribution of clinical variant-associated knowledge are central problems that arise with increased usage of clinical next-generation sequencing. The Clinical Genome Resource (ClinGen) Somatic Working Group (WG) developed a minimal variant level data (MVLD) representation of cancer variants, and has an ongoing collaboration with Clinical Interpretations of Variants in Cancer (CIViC), an open-source platform supporting crowdsourced and expert-moderated cancer variant curation. Harmonization between MVLD and CIViC variant formats was assessed by formal field-by-field analysis. Adjustments to the CIViC format were made to harmonize with MVLD and support ClinGen Somatic WG curation activities, …

Mouse Models Of Preterm Birth: Suggested Assessment And Reporting Guidelines, Ronald Mccarthy, Carmel Martin-Fairey, Dorothy K. Sojka, Erik D. Herzog, Emily S. Jungheim, Molly J. Stout, Justin C. Fay, Mala Mahendroo, Jeff Reese, Jennifer L. Herington, Erin J. Plosa, Elaine L. Shelton, Sarah K. England

Open Access Publications

Preterm birth affects approximately 1 out of every 10 births in the United States, leading to high rates of mortality and long-term negative health consequences. To investigate the mechanisms leading to preterm birth so as to develop prevention strategies, researchers have developed numerous mouse models of preterm birth. However, the lack of standard definitions for preterm birth in mice limits our field's ability to compare models and make inferences about preterm birth in humans. In this review, we discuss numerous mouse preterm birth models, propose guidelines for experiments and reporting, and suggest markers that can be used to assess whether …

Genome-Wide Association Study Of Brain Amyloid Deposition As Measured By Pittsburgh Compound-B (Pib)-Pet Imaging, Qi Yan, Jorge L Del-Aguila, Carlos Cruchaga, Et Al

Open Access Publications

Deposition of amyloid plaques in the brain is one of the two main pathological hallmarks of Alzheimer's disease (AD). Amyloid positron emission tomography (PET) is a neuroimaging tool that selectively detects in vivo amyloid deposition in the brain and is a reliable endophenotype for AD that complements cerebrospinal fluid biomarkers with regional information. We measured in vivo amyloid deposition in the brains of ~1000 subjects from three collaborative AD centers and ADNI using

A Novel Mode Of Capping Protein-Regulation By Twinfilin, Adam B. Johnston, Denise M. Hilton, Patrick Mcconnell, Britney Johnson, Meghan T. Harris, Avital Simone, Gaya K. Amarasinghe, John A. Cooper, Bruce L. Goode

Open Access Publications

Cellular actin assembly is controlled at the barbed ends of actin filaments, where capping protein (CP) limits polymerization. Twinfilin is a conserved in vivo binding partner of CP, yet the significance of this interaction has remained a mystery. Here, we discover that the C-terminal tail of Twinfilin harbors a CP-interacting (CPI) motif, identifying it as a novel CPI-motif protein. Twinfilin and the CPI-motif protein CARMIL have overlapping binding sites on CP. Further, Twinfilin binds competitively with CARMIL to CP, protecting CP from barbed-end displacement by CARMIL. Twinfilin also accelerates dissociation of the CP inhibitor V-1, restoring CP to an active …

Simulation Of Spontaneous G Protein Activation Reveals A New Intermediate Driving Gdp Unbinding, Xianqiang Sun, Sukrit Singh, Kendall J. Blumer, Gregory R. Bowman

Open Access Publications

Activation of heterotrimeric G proteins is a key step in many signaling cascades. However, a complete mechanism for this process, which requires allosteric communication between binding sites that are ~30 Å apart, remains elusive. We construct an atomically detailed model of G protein activation by combining three powerful computational methods: metadynamics, Markov state models (MSMs), and CARDS analysis of correlated motions. We uncover a mechanism that is consistent with a wide variety of structural and biochemical data. Surprisingly, the rate-limiting step for GDP release correlates with tilting rather than translation of the GPCR-binding helix 5. β-Strands 1 - 3 and …

Genetically Engineered Minipigs Model The Major Clinical Features Of Human Neurofibromatosis Type 1, Sara H Isakson, Sonika Dahiya, David H Gutmann, Et Al

Open Access Publications

Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in

Haptoglobin Improves Shock, Lung Injury, And Survival In Canine Pneumonia, Kenneth E. Remy, Irene Cortés-Puch, Steven B. Solomon, Junfeng Sun, Benjamin M. Pockros, Jing Feng, Juan J. Lertora, Roy R. Hantgan, Xiaohua Liu, Andreas Perlegas, H. Shaw Warren, Mark T. Gladwin, Daniel B. Kim-Shapiro, Harvey G. Klein, Charles Natanson

Open Access Publications

During the last half-century, numerous antiinflammatory agents were tested in dozens of clinical trials and have proven ineffective for treating septic shock. The observation in multiple studies that cell-free hemoglobin (CFH) levels are elevated during clinical sepsis and that the degree of increase correlates with higher mortality suggests an alternative approach. Human haptoglobin binds CFH with high affinity and, therefore, can potentially reduce iron availability and oxidative activity. CFH levels are elevated over approximately 24-48 hours in our antibiotic-treated canine model of S. aureus pneumonia that simulates the cardiovascular abnormalities of human septic shock. In this 96-hour model, resuscitative treatments, …

Impaired Monocyte Cholesterol Clearance Initiates Age-Related Retinal Degeneration And Vision Loss, Norimitsu Ban, Tae Jun Lee, Abdoulaye Sene, Mayur Choudhary, Michael Lekwuwa, Zhenyu Dong, Andrea Santeford, Jonathan B. Lin, Goldis Malek, Daniel S. Ory, Rajendra S. Apte

Open Access Publications

Advanced age-related macular degeneration (AMD), the leading cause of blindness among people over 50 years of age, is characterized by atrophic neurodegeneration or pathologic angiogenesis. Early AMD is characterized by extracellular cholesterol-rich deposits underneath the retinal pigment epithelium (RPE) called drusen or in the subretinal space called subretinal drusenoid deposits (SDD) that drive disease progression. However, mechanisms of drusen and SDD biogenesis remain poorly understood. Although human AMD is characterized by abnormalities in cholesterol homeostasis and shares phenotypic features with atherosclerosis, it is unclear whether systemic immunity or local tissue metabolism regulates this homeostasis. Here, we demonstrate that targeted deletion …

Bezlotoxumab For Prevention Of Recurrent Clostridium Difficile Infection In Patients At Increased Risk For Recurrence, Dale N. Gerding, Ciaran P. Kelly, Galia Rahav, Christine Lee, Erik R. Dubberke, Princy N. Kumar, Bruce Yacyshyn, Dina Kao, Karen Eves, Misoo C. Ellison, Mary E. Hanson, Dalya Guris, Mary Beth Dorr

Open Access Publications

Background: Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B indicated to prevent C. difficile infection (CDI) recurrence (rCDI) in adults at high risk for rCDI. This post hoc analysis of pooled monocolonal antibodies for C.difficile therapy (MODIFY) I/II data assessed bezlotoxumab efficacy in participants with characteristics associated with increased risk for rCDI.

Methods: The analysis population was the modified intent-to-treat population who received bezlotoxumab or placebo (n = 1554) by risk factors for rCDI that were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244. The proportion …

Identification Of Enhanced Ifn-Γ Signaling In Polyarticular Juvenile Idiopathic Arthritis With Mass Cytometry, Allison A Throm, Halima Moncrieffe, Amir B Orandi, Jeanette T Pingel, Theresa L Geurs, Hannah L Miller, Allyssa L Daugherty, Olga N Malkova, Daniel J Lovell, Susan D Thompson, Alexei A Grom, Megan A Cooper, Stephen T Oh, Anthony R French

Open Access Publications

Polyarticular juvenile idiopathic arthritis (JIA) is among the most challenging of the JIA subtypes to treat. Even with current biologic therapies, the disease remains difficult to control in a substantial subset of patients, highlighting the need for new therapies. The aim of this study was to use the high dimensionality afforded by mass cytometry with phospho-specific antibodies to delineate signaling abnormalities in immune cells from treatment-naive polyarticular JIA patients. Peripheral blood mononuclear cells were isolated from 17 treatment-naive polyarticular JIA patients, 10 of the patients after achieving clinical remission, and 19 healthy controls. Samples were stimulated for 15 minutes with …

Cardiovascular Consequences Of Katp Overactivity In Cantu Syndrome, Yan Huang, Conor Mcclenaghan, Theresa M Harter, Kristina Hinman, Carmen M Halabi, Scot J Matkovich, Haixia Zhang, G Schuyler Brown, Robert P Mecham, Sarah K England, Attila Kovacs, Maria S Remedi, Colin G Nichols

Open Access Publications

Cantu syndrome (CS) is characterized by multiple vascular and cardiac abnormalities including vascular dilation and tortuosity, systemic hypotension, and cardiomegaly. The disorder is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits. However, there is little understanding of the link between molecular dysfunction and the complex pathophysiology observed, and there is no known treatment, in large part due to the lack of appropriate preclinical disease models in which to test therapies. Notably, expression of Kir6.1 and SUR2 does not fully overlap, and the relative contribution of KATP GOF in …