Digital Commons Network^™

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, …

Protein Phosphatase 4 Controls Circadian Clock Dynamics By Modulating Clock/Bmal1 Activity, Sabrina Klemz, Thomas Wallach, Sandra Korge, Mechthild Rosing, Roman Klemz, Bert Maier, Nicholas C Fiorenza, Irem Kaymak, Anna K Fritzsche, Erik D Herzog, Ralf Stanewsky, Achim Kramer

Open Access Publications

In all organisms with circadian clocks, post-translational modifications of clock proteins control the dynamics of circadian rhythms, with phosphorylation playing a dominant role. All major clock proteins are highly phosphorylated, and many kinases have been described to be responsible. In contrast, it is largely unclear whether and to what extent their counterparts, the phosphatases, play an equally crucial role. To investigate this, we performed a systematic RNAi screen in human cells and identified protein phosphatase 4 (PPP4) with its regulatory subunit PPP4R2 as critical components of the circadian system in both mammals and

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) …

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

Disentangling The Complexity Of The Rumen Microbial Diversity Through Fractionation Using A Sucrose Density Gradient, Ruth Hernández, Hugo Jimenez, Cesar Vargas-Garcia, Alejandro Caro-Quintero, Alejandro Reyes

Open Access Publications

The ruminal microbial community is an important element in health, nutrition, livestock productivity, and climate impact. Despite the historic and current efforts to characterize this microbial diversity, many of its members remain unidentified, making it challenging to associate microbial groups with functions. Here we present a low-cost methodology for rumen sample treatment that separates the microbial community based on cell size, allowing for the identification of subtle compositional changes. In brief, the sample is centrifuged through a series of sucrose density gradients, and cells migrate to their corresponding density fraction. From each fraction, DNA is extracted and

Pattern And Degree Of Individual Brain Atrophy Predicts Dementia Onset In Dominantly Inherited Alzheimer's Disease, Ophir Keret, Randal J Bateman, Tammie L S Benzinger, John C Morris, Beau M Ances, Nelly Joseph-Mathurin, Richard J Perrin, Brian A Gordon, Dominantly Inherited Alzheimer Network, Et Al

Open Access Publications

Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment.

Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally.

Results: Our risk score separated asymptomatic versus demented …

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 …

Structure-Guided Microbial Targeting Of Antistaphylococcal Prodrugs, Justin J. Miller, Ishaan T. Shah, Jayda Hatten, Yasaman Barekatain, Elizabeth A. Mueller, Ahmed M. Moustafa, Rachel L. Edwards, Cynthia S. Dowd, Paul J. Planet, Florian L. Muller, Joseph M. Jez, Audrey R. Odom John

Open Access Publications

Carboxy ester prodrugs are widely employed to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can mask problematic chemical features that prevent cellular uptake and may enable tissue-specific compound delivery. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, limiting their therapeutic potential. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes as microbial esterase-specific promoieties have not been described. Here we identify the bacterial esterases, GloB and FrmB, that activate carboxy ester prodrugs in

Glembatumumab Vedotin For Patients With Metastatic, Gpnmb Overexpressing, Triple-Negative Breast Cancer (“Metric”): A Randomized Multicenter Study, Linda T. Vahdat, Cynthia Ma, Et Al.

Open Access Publications

No abstract provided.

Tailoring Of Arteriovenous Graft‑To‑Vein Anastomosis Angle To Attenuate Pathological Flow Fields, Dillon Williams, Eric C. Leuthardt, Guy M. Genin, Mohamed Zayed

Open Access Publications

No abstract provided.

Quantitative Imaging Of Membrane Contact Sites For Sterol Transfer Between Endo‑Lysosomes And Mitochondria In Living Cells, Alice Dupont Juhl, Christian W. Heegaard, Stephan Werner, Gerd Schneider, Kathiresan Krishnan, Douglas F. Covey, Daniel Wüstner

Open Access Publications

No abstract provided.

Visceral Obesity And Insulin Resistance Associate With Cd36 Deletion In Lymphatic Endothelial Cells, Vincenza Cifarelli, Sila Appak-Baskoy, Vivek S. Peche, Andrew Kluzak, Trevor Shew, Ramkumar Narendran, Kathryn M. Pietka, Marina Cella, Curtis W. Walls, Rafael Czepielewski, Stoyan Ivanov, Gwendalyn J. Randolph, Hellmut G. Augustin, Nada A. Abumrad

Open Access Publications

No abstract provided.

Deep Learning The Structural Determinants Of Protein Biochemical Properties By Comparing Structural Ensembles With Diffnets, Michael D. Ward, Maxwell I. Zimmerman, Artur Meller, Moses Chung, S.J. Swamidass, Gregory R. Bowman

Open Access Publications

No abstract provided.

Selective Sweep For An Enhancer Involucrin Allele Identifies Skin Barrier Adaptation Out Of Africa, Mary Elizabeth Mathyer, Erin A. Brettmann, Alina D. Schmidt, Zane A. Goodwin, Inez Y. Oh, Ashley M. Quiggle, Eric Tycksen, Natasha Ramakrishnan, Scot J. Matkovich, Emma Guttman-Yassky, John R. Edwards, Cristina De Guzman Strong

Open Access Publications

No abstract provided.

Cryo-Em Structure Of Cortical Microtubules From Human Parasite Toxoplasma Gondii Identifies Their Microtubule Inner Proteins, Xiangli Wang, Yong Fu, Wandy L. Beatty, Meisheng Ma, Alan Brown, L. David Sibley, Rui Zhang

Open Access Publications

No abstract provided.

Mapping The Molecular And Structural Specialization Of The Skin Basement Membrane For Inter-Tissue Interactions, Ko Tsutsui, Hiroki Machida, Asako Nakagawa, Kyungmin Ahn, Ritsuko Morita, Kiyotoshi Sekiguchi, Jeffrey H. Miner, Hironobu Fujiwara

Open Access Publications

No abstract provided.

Dopamine D1 + D3 Receptor Density May Correlate With Parkinson Disease Clinical Features, Pengfei Yang, William C Knight, Huifangjie Li, Yingqiu Guo, Joel S Perlmutter, Tammie L S Benzinger, John C Morris, Jinbin Xu

Open Access Publications

OBJECTIVE: Dopamine D2-like receptors - mainly dopamine D2 receptors (D2R) and dopamine D3 receptors (D3R) - are believed to be greatly involved in the pathology of Parkinson disease (PD) progression. However, these receptors have not been precisely examined in PD patients. Our aim was to quantitatively calculate the exact densities of dopamine D1 receptors (D1R), D2R, and D3R in control, Alzheimer disease (AD), and Lewy body disease (LBD) patients (including PD, Dementia with Lewy bodies, and Parkinson disease dementia); and analyze the relationship between dopamine receptors and clinical PD manifestations.

METHODS: We analyzed the densities of D1R, D2R, and D3R …

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

Sevoflurane And Desflurane Exposures Following Aneurysmal Subarachnoid Hemorrhage Confer Multifaceted Protection Against Delayed Cerebral Ischemia, Keshav Jayaraman, Meizi Liu, Gregory J Zipfel, Umeshkumar Athiraman

Open Access Publications

Numerous studies have demonstrated the ability of isoflurane conditioning to provide multifaceted protection against aneurysmal subarachnoid hemorrhage (SAH)-associated delayed cerebral ischemia (DCI); however, preclinical studies have not yet examined whether other commonly used inhalational anesthetics in neurological patients such as sevoflurane or desflurane are also protective against SAH-induced neurovascular deficits. We therefore sought to identify the potential for sevoflurane and desflurane conditioning to protect against DCI in an endovascular perforation mouse model of SAH. Neurological function was assessed daily via neuroscore. Large artery vasospasm and microvessel thrombosis were assessed three days after SAH or sham surgery. Four groups were examined: …

Global Waves Synchronize The Brain's Functional Systems With Fluctuating Arousal, Ryan V Raut, Abraham Z Snyder, Anish Mitra, Dov Yellin, Naotaka Fujii, Rafael Malach, Marcus E Raichle

Open Access Publications

We propose and empirically support a parsimonious account of intrinsic, brain-wide spatiotemporal organization arising from traveling waves linked to arousal. We hypothesize that these waves are the predominant physiological process reflected in spontaneous functional magnetic resonance imaging (fMRI) signal fluctuations. The correlation structure ("functional connectivity") of these fluctuations recapitulates the large-scale functional organization of the brain. However, a unifying physiological account of this structure has so far been lacking. Here, using fMRI in humans, we show that ongoing arousal fluctuations are associated with global waves of activity that slowly propagate in parallel throughout the neocortex, thalamus, striatum, and cerebellum. We …

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.

Genomic And Clinical Characterization Of Early T-Cell Precursor Lymphoblastic Lymphoma, Xinjie Xu, Christian N. Paxton, Robert J. Hayashi, Kimberly P. Dunsmore, Stuart S. Winter, Stephen P. Hunger, Naomi J. Winick, William L. Carroll, Mignon L. Loh, Meenakshi Devidas, Thomas G. Gross, Catherine M. Bollard, Sherrie L. Perkins, Rodney R. Miles

Open Access Publications

No abstract provided.