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Evidence For Dissociable Cognitive And Neural Pathways From Poverty Versus Maltreatment To Deficits In Emotion Regulation, Nourhan M Elsayed, Brent I Rappaport, Joan L. Luby, Deanna M Barch

Open Access Publications

Poverty and threat exposure (TE) predict deficits in emotion regulation (ER). Effective cognitive ER (i.e., reappraisal) may be supported by: (1) cognitive processes implicated in generating and implementing cognitive reappraisal, supported by activation in brain regions involved in cognitive control (e.g., frontal, insular, and parietal cortices) and (2) emotion processing and reactivity, involving identification, encoding, and maintenance of emotional states and related variation in brain activity of regions involved in emotional reactivity (i.e., amygdala). Poverty is associated with deficits in cognitive control, and TE with alterations in emotion processing and reactivity. Our goal was to identify dissociable emotional and cognitive …

Shock In The Setting Of Diamond-Blackfan Anemia Relapse, Metri Haddaden, Samir Husami, Modar Alom, Yifan Pang, Zaid Imam, Daniel Keena

Open Access Publications

Adult intensivists have increasing exposure to individuals with congenital diseases surviving into adulthood. Solid knowledge bases and early recognition of the possible sequelae of congenital disorders are crucial in caring for these patients. We present a challenging case of shock and relapse of Diamond-Blackfan anemia in a 42-year-old man lost to follow-up for 18 years and highlighted the importance of healthcare transitions into adulthood and the challenges faced by health care systems to develop new strategies successfully transitioning complex pediatric patients to adult care.

Membrane Transporter Dimerization Driven By Differential Lipid Solvation Energetics Of Dissociated And Associated States, Rahul Chadda, Nathan Bernhardt, Elizabeth G. Kelley, Susana C.M. Teixeira, Kacie Griffith, Alejandro Gil-Ley, Tuğba N. Öztürk, Lauren E. Hughes, Ana Forsythe, Venkatramanan Krishnamani, José D. Faraldo-Gómez, Janice L. Robertson

Open Access Publications

Over two-thirds of integral membrane proteins of known structure assemble into oligomers. Yet, the forces that drive the association of these proteins remain to be delineated, as the lipid bilayer is a solvent environment that is both structurally and chemically complex. In this study, we reveal how the lipid solvent defines the dimerization equilibrium of the CLC-ec1 Cl

The Structure, Function And Evolution Of A Complete Human Chromosome 8, Glennis A Logsdon, Milinn Kremitzki, Tina A Graves-Lindsay, Et Al

Open Access Publications

The complete assembly of each human chromosome is essential for understanding human biology and evolution

Genomic Context Differs Between Human Dilated Cardiomyopathy And Hypertrophic Cardiomyopathy, Megan J Puckelwartz, Gerald W Dorn Ii, Et Al

Open Access Publications

Background Inherited cardiomyopathies display variable penetrance and expression, and a component of phenotypic variation is genetically determined. To evaluate the genetic contribution to this variable expression, we compared protein coding variation in the genomes of those with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Methods and Results Nonsynonymous single-nucleotide variants (nsSNVs) were ascertained using whole genome sequencing from familial cases of HCM (n=56) or DCM (n=70) and correlated with echocardiographic information. Focusing on nsSNVs in 102 genes linked to inherited cardiomyopathies, we correlated the number of nsSNVs per person with left ventricular measurements. Principal component analysis and generalized linear models …

Sex And Race-Ethnic Disparities In Door-To-Ct Time In Acute Ischemic Stroke: The Florida Stroke Registry, Sai P Polineni, Enmanuel J Perez, Kefeng Wang, Carolina M Gutierrez, Jeffrey Walker, Dianne Foster, Chuanhui Dong, Negar Asdaghi, Jose G Romano, Ralph L Sacco, Tatjana Rundek, Florida Stroke Registry

Open Access Publications

Background Less than 40% of acute stroke patients have computed tomography (CT) imaging performed within 25 minutes of hospital arrival. We aimed to examine the race-ethnic and sex differences in door-to-CT (DTCT) ≤25 minutes in the FSR (Florida Stroke Registry). Methods and Results Data were collected from 2010 to 2018 for 63 265 patients with acute ischemic stroke from the FSR and secondary analysis was performed on 15 877 patients with intravenous tissue plasminogen activator-treated ischemic stroke. Generalized estimating equation models were used to determine predictors of DTCT ≤25. DTCT ≤25 was achieved in 56% of cases of suspected acute …

Metabolic Modulation By Cdk4/6 Inhibitor Promotes Chemokine-Mediated Recruitment Of T Cells Into Mammary Tumors, Roman V Uzhachenko, Vijaya Bharti, Zhufeng Ouyang, Ashlyn Blevins, Stacey Mont, Nabil Saleh, Hunter A Lawrence, Chengli Shen, Sheau-Chiann Chen, Gregory D Ayers, David G Denardo, Carlos Arteaga, Ann Richmond, Anna E Vilgelm

Open Access Publications

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Here, we show that CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models. This effect is driven by the induction of chemokines CCL5, CXCL9, and CXCL10 in CDK4/6i-treated tumor cells facilitating recruitment of activated CD8

Nox1-Dependent Redox Signaling Potentiates Colonic Stem Cell Proliferation To Adapt To The Intestinal Microbiota By Linking Egfr And Tlr Activation, Sjoerd Van Der Post, George M H Birchenough, Jason M Held

Open Access Publications

The colon epithelium is a primary point of interaction with the microbiome and is regenerated by a few rapidly cycling colonic stem cells (CSCs). CSC self-renewal and proliferation are regulated by growth factors and the presence of bacteria. However, the molecular link connecting the diverse inputs that maintain CSC homeostasis remains largely unknown. We report that CSC proliferation is mediated by redox-dependent activation of epidermal growth factor receptor (EGFR) signaling via NADPH oxidase 1 (NOX1). NOX1 expression is CSC specific and is restricted to proliferative CSCs. In the absence of NOX1, CSCs fail to generate ROS and have a reduced …

The Mechanistic Basis Of Protection By Non-Neutralizing Anti-Alphavirus Antibodies, James T Earnest, Autumn C Holmes, Katherine Basore, Matthias Mack, Daved H Fremont, Michael S Diamond

Open Access Publications

Although neutralizing monoclonal antibodies (mAbs) against epitopes within the alphavirus E2 protein can protect against infection, the functional significance of non-neutralizing mAbs is poorly understood. Here, we evaluate the activity of 13 non-neutralizing mAbs against Mayaro virus (MAYV), an emerging arthritogenic alphavirus. These mAbs bind to the MAYV virion and surface of infected cells but fail to neutralize infection in cell culture. Mapping studies identify six mAb binding groups that localize to discrete epitopes within or adjacent to the A domain of the E2 glycoprotein. Remarkably, passive transfer of non-neutralizing mAbs protects against MAYV infection and disease in mice, and …

Adversity Is Linked With Decreased Parent-Child Behavioral And Neural Synchrony, Caroline P Hoyniak, Laura E Quiñones-Camacho, M Catalina Camacho, Jenna H Chin, Elizabeth M Williams, Lauren S Wakschlag, Susan B Perlman

Open Access Publications

Parent-child synchrony-parent-child interaction patterns characterized by contingent social responding, mutual responsivity, and co-regulation-has been robustly associated with adaptive child outcomes. Synchrony has been investigated in both behavioral and biological frameworks. While it has been demonstrated that adversity can influence behavioral parent-child synchrony, the neural mechanisms by which this disruption occurs are understudied. The current study examined the association between adversity, parent-child behavioral synchrony, and parent-child neural synchrony across lateral prefrontal cortical regions using functional near-infrared spectroscopy hyperscanning during a parent-child interaction task that included a mild stress induction followed by a recovery period. Participants included 115 children (ages 4-5) and …

Non-Canonical Metabolic Pathways In The Malaria Parasite Detected By Isotope-Tracing Metabolomics, Simon A Cobbold, Madel V Tutor, Philip Frasse, Emma Mchugh, Markus Karnthaler, Darren J Creek, Audrey Odom John, Leann Tilley, Stuart A Ralph, Malcolm J Mcconville

Open Access Publications

The malaria parasite, Plasmodium falciparum, proliferates rapidly in human erythrocytes by actively scavenging multiple carbon sources and essential nutrients from its host cell. However, a global overview of the metabolic capacity of intraerythrocytic stages is missing. Using multiplex

Ambient Fine Particulate Matter Air Pollution And Risk Of Weight Gain And Obesity In United States Veterans: An Observational Cohort Study, Benjamin Bowe, Andrew K. Gibson, Yan Xie, Yan Yan, Aaron Van Donkelaar, Randall V. Martin, Ziyad Al-Aly

Open Access Publications

BACKGROUND: Experimental evidence and studies of children and adolescents suggest that ambient fine particulate matter [particulate matter

OBJECTIVES: Our goal was to characterize the association between

METHODS: We followed 3,902,440 U.S. Veterans from 2010 to 2018 (median 8.1 y, interquartile range: 7.3-8.4) and assigned time-updated

RESULTS: A

DISCUSSION:

Sars-Cov-2 Infects Human Engineered Heart Tissues And Models Covid-19 Myocarditis, Adam L Bailey, Oleksandr Dmytrenko, Lina Greenberg, Andrea L Bredemeyer, Pan Ma, Jing Liu, Vinay Penna, Emma S Winkler, Sanja Sviben, W Tom Stump, James A Fitzpatrick, Chieh-Yu Lin, Michael S Diamond, Michael J Greenberg, Kory J Lavine, Et Al

Open Access Publications

There is ongoing debate as to whether cardiac complications of coronavirus disease-2019 (COVID-19) result from myocardial viral infection or are secondary to systemic inflammation and/or thrombosis. We provide evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis and are susceptible to severe acute respiratory syndrome coronavirus 2. We establish an engineered heart tissue model of COVID-19 myocardial pathology, define mechanisms of viral pathogenesis, and demonstrate that cardiomyocyte severe acute respiratory syndrome coronavirus 2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death. These findings implicate direct infection of cardiomyocytes in the pathogenesis of COVID-19 myocardial pathology …

Multimodal Examination Of Emotion Processing Systems Associated With Negative Affectivity Across Early Childhood, M Catalina Camacho, Elizabeth M Williams, Keya Ding, Susan B Perlman

Open Access Publications

High Temperamental Negative Affectivity in early childhood has been found to predict later emotion dysregulation. While much work has been conducted to separately probe bio-behavioral systems associated with Negative Affectivity, very little work has examined the relations among multiple systems across age. In this study, we use multi-modal methods to index neurobiological systems associated with Negative Affectivity in 53 4-7-year-old children. Prefrontal activation during emotion regulation was measured using functional near-infrared spectroscopy over the lateral prefrontal cortex (PFC) while children played a game designed to elicit frustration in Social (Happy and Angry faces) and Nonsocial contexts. Gaze behaviors while free-viewing …

A Clinician’S Guide For Navigating The World Of Attention Deficit Hyperactivity Disorder Medications, Gregory W. Mattingly, Joel Young

Open Access Publications

No abstract provided.

Variant Recurrence Confirms The Existence Of A Fbxo31-Related Spastic-Dystonic Cerebral Palsy Syndrome, Ivana Dzinovic, Matej Škorvánek, Petra Pavelekova, Chen Zhao, Boris Keren, Sandra Whalen, Somayeh Bakhtiari, Sheng Chih Jin, Michael C Kruer, Robert Jech, Juliane Winkelmann, Michael Zech

Open Access Publications

The role of genetics in the causation of cerebral palsy has become the focus of many studies aiming to unravel the heterogeneous etiology behind this frequent neurodevelopmental disorder. A recent paper reported two unrelated children with a clinical diagnosis of cerebral palsy, who carried the same de novo c.1000G > A (p.Asp334Asn) variant in FBXO31, encoding a widely studied tumor suppressor not previously implicated in monogenic disease. We now identified a third individual with the recurrent FBXO31 de novo missense variant, featuring a spastic-dystonic phenotype. Our data confirm a link between variant FBXO31 and an autosomal dominant neurodevelopmental disorder characterized by …

Idiopathic Non-Cirrhotic Portal Hypertension And Porto-Sinusoidal Vascular Disease: Review Of Current Data, Michel Kmeid, Xiuli Liu, Samuel Ballentine, Hwajeong Lee

Open Access Publications

Idiopathic non-cirrhotic portal hypertension (INCPH) is a clinicopathologic disease entity characterized by the presence of clinical signs and symptoms of portal hypertension (PH) in the absence of liver cirrhosis or known risk factors accountable for PH. Multiple hematologic, immune-related, infectious, hereditary and metabolic risk factors have been associated with this disorder. Still, the exact etiopathogenesis is largely unknown. The recently proposed porto-sinusoidal vascular disease (PSVD) scheme broadens the spectrum of the disease by also including patients without clinical PH who are found to have similar histopathologic findings on core liver biopsies. Three histomorphologic lesions have been identified as specific for …

Endogenous And Combination Retinoids Are Active In Myelomonocytic Leukemias, Orsola Di Martino, Haixia Niu, Gayla Hadwiger, Heikki Kuusanmaki, Margaret A. Ferris, Anh Vu, Jeremy Beales, Carl Wagner, María P. Menéndez-Gutiérrez, Mercedes Ricote, Caroline Heckman, John S. Welch

Open Access Publications

Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The presence of natural retinoids in vivo could influence the efficacy of pharmacologic agonists and antagonists. We found that natural RXRA ligands, but not RARA ligands, were present in murine MLL-AF9-derived myelomonocytic leukemias in vivo and that the concurrent presence of receptors and ligands acted as tumor suppressors. Pharmacologic retinoid responses could be optimized by concurrent targeting RXR ligands (e.g. bexarotene) and RARA ligands (e.g. all-trans retinoic acid, ATRA), which induced either leukemic maturation …

The Epidemiology And Biology Of Pulmonary Metastases, William D Gerull, Varun Puri, Benjamin D Kozower

Open Access Publications

Our goal in this chapter is to explore the complex processes of metastasis and why there is a predisposition for this to occur in the lung. In addition, we aim to describe the incidence of pulmonary metastases in various contexts and based on the origin of the primary tumor. There are unique characteristics of the pulmonary system that make metastases more likely to occur in the lung than anywhere else in the body. Some of these characteristics include receiving the entire cardiac output every minute, having the densest capillary bed in the body, and being the first reservoir of most …

An Open-Source Device For Measuring Food Intake And Operant Behavior In Rodent Home-Cages, Bridget A. Matikainen-Ankney, Thomas Earnest, Eric Casey, Justin G. Wang, Alex A. Legaria, Kia M. Barclay, Makenzie R. Norris, Yu-Hsuan Chang, Eric Lin, Sineadh M. Conway, Ream Al-Hasani, Jordan G. Mccall, Meaghan C. Creed, Alexxai V. Kravitz, Et Al

Open Access Publications

Feeding is critical for survival, and disruption in the mechanisms that govern food intake underlies disorders such as obesity and anorexia nervosa. It is important to understand both food intake and food motivation to reveal mechanisms underlying feeding disorders. Operant behavioral testing can be used to measure the motivational component to feeding, but most food intake monitoring systems do not measure operant behavior. Here, we present a new solution for monitoring both food intake and motivation in rodent home-cages: the Feeding Experimentation Device version 3 (FED3). FED3 measures food intake and operant behavior in rodent home-cages, enabling longitudinal studies of …

Epb41l5 Controls Podocyte Extracellular Matrix Assembly By Adhesome-Dependent Force Transmission, Jasmin I Maier, Manuel Rogg, Martin Helmstädter, Alena Sammarco, Oliver Schilling, Benedikt Sabass, Jeffrey H Miner, Jörn Dengjel, Gerd Walz, Martin Werner, Tobias B Huber, Christoph Schell

Open Access Publications

The integrity of the kidney filtration barrier essentially relies on the balanced interplay of podocytes and the glomerular basement membrane (GBM). Here, we show by analysis of in vitro and in vivo models that a loss of the podocyte-specific FERM-domain protein EPB41L5 results in impaired extracellular matrix (ECM) assembly. By using quantitative proteomics analysis of the secretome and matrisome, we demonstrate a shift in ECM composition characterized by diminished deposition of core GBM components, such as LAMA5. Integrin adhesome proteomics reveals that EPB41L5 recruits PDLIM5 and ACTN4 to integrin adhesion complexes (IACs). Consecutively, EPB41L5 knockout podocytes show insufficient maturation of …

Crosstalk Between Nonclassical Monocytes And Alveolar Macrophages Mediates Transplant Ischemia-Reperfusion Injury Through Classical Monocyte Recruitment, Chitaru Kurihara, Wenjun Li, Daniel Kreisel, Et Al

Open Access Publications

Primary graft dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular nonclassical monocytes (NCM) initiate neutrophil recruitment. Simultaneously, host-origin classical monocytes (CM) permeabilize the vascular endothelium to allow neutrophil extravasation necessary for PGD. Here, we show that a CCL2-CCR2 axis is necessary for CM recruitment. Surprisingly, although intravital imaging and multichannel flow cytometry revealed that depletion of donor NCM abrogated CM recruitment, single cell RNA sequencing identified donor alveolar macrophages (AM) as predominant CCL2 secretors. Unbiased transcriptomic analysis of murine tissues combined with murine KOs and chimeras indicated that …

Laminin Β2 Variants Associated With Isolated Nephropathy That Impact Matrix Regulation, Yamato Kikkawa, Helen Liapis, Jeffrey H. Miner, Et Al.

Open Access Publications

Mutations in LAMB2, encoding laminin β2, cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense mutations that have been identified affect primarily the N-terminus of laminin β2. On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the β2 LEa-LF-LEb domains are exclusively found in cases with isolated nephropathy. Here we report the clinical features of mild isolated nephropathy associated with 3 LAMB2 variants in the LEa-LF-LEb domains (p.R469Q, p.G699R, and p.R1078C) and their biochemical characterization. Although Pierson syndrome missense mutations often inhibit laminin β2 secretion, the …

Chromosome 8 Gain Is Associated With High-Grade Transformation In Mpnst, Carina Dehner, Chang In Moon, Zhaohe Zhou, Chris Miller, Hua Xu, Xiaodan Wan, Kuangying Yang, Jay Mashl, Yuxi Wang, Xiaochun Zhang, Abigail Godec, Paul A. Jones, Sonika Dahiya, Himanshi Bhatia, Tina Primeau, Shunqiang Li, Li Ding, Angela C. Hirbe, Et Al.

Open Access Publications

One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma that commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven successful in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared with the primary tumors from which they were derived using copy …

Evaluating The Rapid Emergence Of Daptomycin Resistance In Corynebacterium: A Multicenter Study, Kaitlin F Mitchell, Erin Mcelvania, Meghan A Wallace, Lauren E Droske, Amy E Robertson, Lars F Westblade, Carey-Ann D. Burnham

Open Access Publications

Members of the genus

Analysis Workflow To Assess De Novo Genetic Variants From Human Whole-Exome Sequencing, Nicholas S Diab, Spencer King, Weilai Dong, Garrett Allington, Amar Sheth, Samuel T Peters, Kristopher T Kahle, Sheng Chih Jin

Open Access Publications

Here, we present a protocol to analyze

Flow Cytometry-Based Ex Vivo Murine Nk Cell Cytotoxicity Assay, Pamela Wong, Julia A Wagner, Melissa M Berrien-Elliott, Timothy Schappe, Todd A Fehniger

Open Access Publications

Direct killing of diseased cells is a hallmark function of NK cells. This protocol describes a flow-based assay to measure

Sequin: An Imaging And Analysis Platform For Quantification And Characterization Of Synaptic Structures In Mouse, Sydney J Reitz, Andrew D Sauerbeck, Terrance T Kummer

Open Access Publications

Synapses are crucial to brain function and frequent disease targets, but current analysis methods cannot report on individual synaptic components

Cryo-Em Structure Of The Rous Sarcoma Virus Octameric Cleaved Synaptic Complex Intasome, Krishan K Pandey, Sibes Bera, Ke Shi, Michael J Rau, Amarachi V Oleru, James A J Fitzpatrick, Alan N Engelman, Hideki Aihara, Duane P Grandgenett

Open Access Publications

Despite conserved catalytic integration mechanisms, retroviral intasomes composed of integrase (IN) and viral DNA possess diverse structures with variable numbers of IN subunits. To investigate intasome assembly mechanisms, we employed the Rous sarcoma virus (RSV) IN dimer that assembles a precursor tetrameric structure in transit to the mature octameric intasome. We determined the structure of RSV octameric intasome stabilized by a HIV-1 IN strand transfer inhibitor using single particle cryo-electron microscopy. The structure revealed significant flexibility of the two non-catalytic distal IN dimers along with previously unrecognized movement of the conserved intasome core, suggesting ordered conformational transitions between intermediates that …

Polθ Promotes The Repair Of 5'-Dna-Protein Crosslinks By Microhomology-Mediated End-Joining, Gurushankar Chandramouly, Shuren Liao, Timur Rusanov, Nikita Borisonnik, Marissa L Calbert, Tatiana Kent, Katherine Sullivan-Reed, Umeshkumar Vekariya, Ekaterina Kashkina, Tomasz Skorski, Hong Yan, Richard T Pomerantz

Open Access Publications

DNA polymerase θ (Polθ) confers resistance to chemotherapy agents that cause DNA-protein crosslinks (DPCs) at double-strand breaks (DSBs), such as topoisomerase inhibitors. This suggests Polθ might facilitate DPC repair by microhomology-mediated end-joining (MMEJ). Here, we investigate Polθ repair of DSBs carrying DPCs by monitoring MMEJ in Xenopus egg extracts. MMEJ in extracts is dependent on Polθ, exhibits the MMEJ repair signature, and efficiently repairs 5' terminal DPCs independently of non-homologous end-joining and the replisome. We demonstrate that Polθ promotes the repair of 5' terminal DPCs in mammalian cells by using an MMEJ reporter and find that Polθ confers resistance to …