Digital Commons Network^™

Early Aberrant Angiogenesis Due To Elastic Fiber Fragmentation In Aortic Valve Disease, Robert B Hinton, Amy L Juraszek, Amy M Opoka, Benjamin J Landis, J Michael Smith, Robert P Mecham, Kevin E Bove

Open Access Publications

Elastic fiber fragmentation (EFF) is a hallmark of aortic valve disease (AVD), and neovascularization has been identified as a late finding related to inflammation. We sought to characterize the relationship between early EFF and aberrant angiogenesis. To examine disease progression, regional anatomy and pathology of aortic valve tissue were assessed using histochemistry, immunohistochemistry, and electron microscopy from early-onset (<40 yo) and late-onset (≥40 yo) non-syndromic AVD specimens. To assess the effects of EFF on early AVD processes, valve tissue from Williams and Marfan syndrome patients was also analyzed. Bicuspid aortic valve was more common in early-onset AVD, and cardiovascular comorbidities were more common in late-onset AVD. Early-onset AVD specimens demonstrated angiogenesis without inflammation or atherosclerosis. A distinct pattern of elastic fiber components surrounded early-onset AVD neovessels, including increased emilin-1 and decreased fibulin-5. Different types of EFF were present in Williams syndrome (WS) and Marfan syndrome (MFS) aortic valves; WS but not MFS aortic valves demonstrated angiogenesis. Aberrant angiogenesis occurs in early-onset AVD in the absence of inflammation, implicating EFF. Elucidation of underlying mechanisms may inform the development of new pharmacologic treatments.

Models Of Distal Arthrogryposis And Lethal Congenital Contracture Syndrome, Julia Whittle, Aaron Johnson, Matthew B Dobbs, Christina A Gurnett

Open Access Publications

Distal arthrogryposis and lethal congenital contracture syndromes describe a broad group of disorders that share congenital limb contractures in common. While skeletal muscle sarcomeric genes comprise many of the first genes identified for Distal Arthrogyposis, other mechanisms of disease have been demonstrated, including key effects on peripheral nerve function. While Distal Arthrogryposis and Lethal Congenital Contracture Syndromes display superficial similarities in phenotype, the underlying mechanisms for these conditions are diverse but overlapping. In this review, we discuss the important insights gained into these human genetic diseases resulting from in vitro molecular studies and in vivo models in fruit fly, zebrafish, …

Developmental Variation In Testosterone: Cortisol Ratio Alters Cortical- And Amygdala-Based Cognitive Processes, Jimin Lew, Sherri Lee Jones, Christina Caccese, Isobel Orfi, Charlotte Little, Kelly N Botteron, James T Mccracken, Tuong-Vi Nguyen

Open Access Publications

Testosterone (T) and cortisol (C) are the end products of neuroendocrine axes that interact with the process of shaping brain structure and function. Relative levels of T:C (TC ratio) may alter prefrontal-amygdala functional connectivity in adulthood. What remains unclear is whether TC-related effects are rooted to childhood and adolescence. We used a healthy cohort of 4-22-year-olds to test for associations between TC ratios, brain structure (amygdala volume, cortical thickness (CTh), and their coordinated growth), as well as cognitive and behavioral development. We found greater TC ratios to be associated with the growth of specific brain structures: 1) parietal CTh; 2) …

Genomic Risk Prediction For Breast Cancer In Older Women, Paul Lacaze, Yin Cao, Et Al

Open Access Publications

Genomic risk prediction models for breast cancer (BC) have been predominantly developed with data from women aged 40-69 years. Prospective studies of older women aged ≥70 years have been limited. We assessed the effect of a 313-variant polygenic risk score (PRS) for BC in 6339 older women aged ≥70 years (mean age 75 years) enrolled into the ASPREE trial, a randomized double-blind placebo-controlled clinical trial investigating the effect of daily 100 mg aspirin on disability-free survival. We evaluated incident BC diagnoses over a median follow-up time of 4.7 years. A multivariable Cox regression model including conventional BC risk factors was …

Bioactivation Of Isoxazole-Containing Bromodomain And Extra-Terminal Domain (Bet) Inhibitors, Noah R Flynn, Michael D Ward, Mary A Schleiff, Corentine M C Laurin, Rohit Farmer, Stuart J Conway, Gunnar Boysen, S Joshua Swamidass, Grover P Miller

Open Access Publications

The 3,5-dimethylisoxazole motif has become a useful and popular acetyl-lysine mimic employed in isoxazole-containing bromodomain and extra-terminal (BET) inhibitors but may introduce the potential for bioactivations into toxic reactive metabolites. As a test, we coupled deep neural models for quinone formation, metabolite structures, and biomolecule reactivity to predict bioactivation pathways for 32 BET inhibitors and validate the bioactivation of select inhibitors experimentally. Based on model predictions, inhibitors were more likely to undergo bioactivation than reported non-bioactivated molecules containing isoxazoles. The model outputs varied with substituents indicating the ability to scale their impact on bioactivation. We selected OXFBD02, OXFBD04, and I-BET151 …

Rp11-362k2.2:Rp11-767i20.1 Genetic Variation Is Associated With Post-Reperfusion Therapy Parenchymal Hematoma. A Gwas Meta-Analysis, Elena Muiño, Laura Heitsch, Laura Ibañez, Carlos Cruchaga, Rajat Dhar, Jin-Moo Lee, Et Al

Open Access Publications

Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing …

Ser 71 Phosphorylation Inhibits Actin-Binding Of Profilin-1 And Its Apoptosis-Sensitizing Activity, Faliang Wang, Cuige Zhu, Shirong Cai, Aaron Boudreau, Sun-Joong Kim, Mina Bissell, Jieya Shao

Open Access Publications

The essential actin-binding factor profilin-1 (Pfn1) is a non-classical tumor suppressor with the abilities toboth inhibit cellular proliferation and augment chemotherapy-induced apoptosis. Besides actin, Pfn1 interacts with proteins harboring the poly-L-proline (PLP) motifs. Our recent work demonstrated that both nuclear localization and PLP-binding are required for tumor growth inhibition by Pfn1, and this is at least partially due to Pfn1 association with the PLP-containing ENL protein in the Super Elongation Complex (SEC) and the transcriptional inhibition of pro-cancer genes. In this paper, by identifying a phosphorylation event of Pfn1 at Ser

Using Monozygotic Twins To Dissect Common Genes In Posttraumatic Stress Disorder And Migraine, Charlotte K Bainomugisa, Heidi G Sutherland, Richard Parker, Allan F Mcrae, Larisa M Haupt, Lyn R Griffiths, Andrew Heath, Elliot C Nelson, Margaret J Wright, Ian B Hickie, Nicholas G Martin, Dale R Nyholt, Divya Mehta

Open Access Publications

Epigenetic mechanisms have been associated with genes involved in Posttraumatic stress disorder (PTSD). PTSD often co-occurs with other health conditions such as depression, cardiovascular disorder and respiratory illnesses. PTSD and migraine have previously been reported to be symptomatically positively correlated with each other, but little is known about the genes involved. The aim of this study was to understand the comorbidity between PTSD and migraine using a monozygotic twin disease discordant study design in six pairs of monozygotic twins discordant for PTSD and 15 pairs of monozygotic twins discordant for migraine. DNA from peripheral blood was run on Illumina EPIC …

Neuropilin-2 Is Associated With Increased Hepatoblastoma Cell Viability And Motility, Katja Eloranta, Ruth Nousiainen, Stefano Cairo, Mikko P Pakarinen, David B Wilson, Marjut Pihlajoki, Markku Heikinheimo

Open Access Publications

The neuropilins NRP1 and NRP2 are multifunctional glycoproteins that have been implicated in several cancer-related processes including cell survival, migration, and invasion in various tumor types. Here, we examine the role of neuropilins in hepatoblastoma (HB), the most common pediatric liver malignancy. Using a combination of immunohistochemistry, RNA analysis and western blotting, we observed high level expression of

The Stroke Neuro-Imaging Phenotype Repository: An Open Data Science Platform For Stroke Research, Hossein Mohammadian Foroushani, Rajat Dhar, Yasheng Chen, Jenny Gurney, Ali Hamzehloo, Jin-Moo Lee, Daniel S Marcus

Open Access Publications

Stroke is one of the leading causes of death and disability worldwide. Reducing this disease burden through drug discovery and evaluation of stroke patient outcomes requires broader characterization of stroke pathophysiology, yet the underlying biologic and genetic factors contributing to outcomes are largely unknown. Remedying this critical knowledge gap requires deeper phenotyping, including large-scale integration of demographic, clinical, genomic, and imaging features. Such big data approaches will be facilitated by developing and running processing pipelines to extract stroke-related phenotypes at large scale. Millions of stroke patients undergo routine brain imaging each year, capturing a rich set of data on stroke-related …

Loureirin B Exerts Its Immunosuppressive Effects By Inhibiting Stim1/Orai1 And K V 1.3 Channels, Shujuan Shi, Qianru Zhao, Caihua Ke, Siru Long, Feng Zhang, Xu Zhang, Yi Li, Xinqiao Liu, Hongzhen Hu, Shijin Yin

Open Access Publications

Loureirin B (LrB) is a constituent extracted from traditional Chinese medicine Resina Draconis. It has broad biological functions and an impressive immunosuppressive effect that has been supported by numerous studies. However, the molecular mechanisms underlying Loureirin B-induced immune suppression are not fully understood. We previously reported that Loureirin B inhibited K

Functional Disruptions Of The Brain In Low Back Pain: A Potential Imaging Biomarker Of Functional Disability, Bidhan Lamichhane, Dinal Jayasekera, Rachel Jakes, Wilson Z Ray, Eric C Leuthardt, Ammar H Hawasli

Open Access Publications

Chronic low back pain (LBP) is one of the leading causes of disability worldwide. While LBP research has largely focused on the spine, many studies have demonstrated a restructuring of human brain architecture accompanying LBP and other chronic pain states. Brain imaging presents a promising source for discovering noninvasive biomarkers that can improve diagnostic and prognostication outcomes for chronic LBP. This study evaluated graph theory measures derived from brain resting-state functional connectivity (rsFC) as prospective noninvasive biomarkers of LBP. We also proposed and tested a hybrid feature selection method (Enet-subset) that combines Elastic Net and an optimal subset selection method. …

Predicting Self-Intercepted Medication Ordering Errors Using Machine Learning, Christopher Ryan King, Joanna Abraham, Bradley A. Fritz, Zhicheng Cui, William Galanter, Yixin Chen, Thomas Kannampallil

Open Access Publications

Current approaches to understanding medication ordering errors rely on relatively small manually captured error samples. These approaches are resource-intensive, do not scale for computerized provider order entry (CPOE) systems, and are likely to miss important risk factors associated with medication ordering errors. Previously, we described a dataset of CPOE-based medication voiding accompanied by univariable and multivariable regression analyses. However, these traditional techniques require expert guidance and may perform poorly compared to newer approaches. In this paper, we update that analysis using machine learning (ML) models to predict erroneous medication orders and identify its contributing factors. We retrieved patient demographics (race/ethnicity, …

Microglia In Alzheimer's Disease At Single-Cell Level. Are There Common Patterns In Humans And Mice?, Yun Chen, Marco Colonna

Open Access Publications

Alzheimer's disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation of microglia. Because variants of genes expressed in microglia correlate with AD risk, microglial response to pathology plausibly impacts disease course. In mouse AD models, single-cell RNA sequencing (scRNA-seq) analyses delineated this response as progressive conversion of homeostatic microglia into disease-associated microglia (DAM); additional reactive microglial populations have been reported in other models of neurodegeneration and neuroinflammation. We review all of these microglial signatures, highlighting four fundamental patterns: DAM, IFN-microglia, MHC-II microglia, and proliferating microglia. We propose that …

A Phase 2 Study Of Isatuximab Monotherapy In Patients With Multiple Myeloma Who Are Refractory To Daratumumab, Joseph Mikhael, Ravi Vij, Et Al.

Open Access Publications

No abstract provided.

A Decade In Review After Idiopathic Scoliosis Was First Called A Complex Trait-A Tribute To The Late Dr. Yves Cotrel For His Support In Studies Of Etiology Of Scoliosis, Nelson L S Tang, Matthew B Dobbs, Christina A Gurnett, Yong Qiu, T P Lam, Jack C Y Cheng, Nancy Hadley-Miller

Open Access Publications

Adolescent Idiopathic Scoliosis (AIS) is a prevalent and important spine disorder in the pediatric age group. An increased family tendency was observed for a long time, but the underlying genetic mechanism was uncertain. In 1999, Dr. Yves Cotrel founded the Cotrel Foundation in the Institut de France, which supported collaboration of international researchers to work together to better understand the etiology of AIS. This new concept of AIS as a complex trait evolved in this setting among researchers who joined the annual Cotrel meetings. It is now over a decade since the first proposal of the complex trait genetic model …

Molecular Genetics And Complex Inheritance Of Congenital Heart Disease, Nicholas S Diab, Syndi Barish, Weilai Dong, Shujuan Zhao, Garrett Allington, Xiaobing Yu, Kristopher T Kahle, Martina Brueckner, Sheng Chih Jin

Open Access Publications

Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. …

Consequences Of Sur2[A478v] Mutation In Skeletal Muscle Of Murine Model Of Cantu Syndrome, Rosa Scala, Fatima Maqoud, Nicola Zizzo, Giuseppe Passantino, Antonietta Mele, Giulia Maria Camerino, Conor Mcclenaghan, Theresa M Harter, Colin G Nichols, Domenico Tricarico

Open Access Publications

(1) Background: Cantu syndrome (CS) arises from gain-of-function (GOF) mutations in the

The Top 100 Cited Papers In The Field Of Iron Deficiency In Humans: A Bibliometric Study, John L. Frater

Open Access Publications

No abstract provided.

Autosomal Dominant Ano5-Related Disorder Associated With Myopathy And Gnathodiaphyseal Dysplasia, Aziz Shaibani, Shaida Khan, Marwan Shinawi

Open Access Publications

No abstract provided.

Impact Of Breast Reconstruction Patients On Cosmetic Practice, Danielle C. Cooper, Ali A. Qureshi, Ketan Sharma, Marissa M. Tenenbaum, Terence M. Myckatyn

Open Access Publications

No abstract provided.

Effect Of Clinical Isolate Or Cleavage Site Mutations In The Sars-Cov-2 Spike Protein On Protein Stability, Cleavage, And Cell–Cell Fusion, Chelsea T. Barrett, Hadley E. Neal, Kearstin Edmonds, Carole L. Moncman, Rachel Thompson, Jean M. Branttie, Kerri Beth Boggs, Cheng-Yu Wu, Daisy W. Leung, Rebecca E. Dutch

Open Access Publications

No abstract provided.

Progress In Diagnosing Primary Ciliary Dyskinesia: The North American Perspective, Michael Glenn O'Connor, Amjad Horani, Adam J Shapiro

Open Access Publications

Primary Ciliary Dyskinesia (PCD) is a rare, under-recognized disease that affects respiratory ciliary function, resulting in chronic oto-sino-pulmonary disease. The PCD clinical phenotype overlaps with other common respiratory conditions and no single diagnostic test detects all forms of PCD. In 2018, PCD experts collaborated with the American Thoracic Society (ATS) to create a clinical diagnostic guideline for patients across North America, specifically considering the local resources and limitations for PCD diagnosis in the United States and Canada. Nasal nitric oxide (nNO) testing is recommended for first-line testing in patients ≥5 years old with a compatible clinical phenotype; however, all low …

Stk39 Promotes Breast Cancer Invasion And Metastasis By Increasing Snai1 Activity Upon Phosphorylation, Zhaoping Qiu, Bo Dong, Weijie Guo, Rychahou Piotr, Greg Longmore, Xiuwei Yang, Zhiyong Yu, Jiong Deng, B. Mark Evers, Yadi Wu

Open Access Publications

No abstract provided.

Psychedelics For Brain Injury: A Mini-Review, Shariq Mansoor Khan, Gregory T Carter, Sunil K Aggarwal, Julie Holland

Open Access Publications

No abstract provided.

Gene Therapy For Aromatic L-Amino Acid Decarboxylase Deficiency By Mr-Guided Direct Delivery Of Aav2-Aadc To Midbrain Dopaminergic Neurons, Toni S. Pearson, Et Al.

Open Access Publications

No abstract provided.

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

Open Access Publications

No abstract provided.

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

Open Access Publications

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

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

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

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

Open Access Publications

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

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

Open Access Publications

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