Digital Commons Network^™

Viral-Immune Cell Interactions At The Maternal-Fetal Interface In Human Pregnancy, Elaine L Parker, Rachel B Silverstein, Sonam Verma, Indira U Mysorekar

Open Access Publications

The human decidua and placenta form a distinct environment distinguished for its promotion of immunotolerance to infiltrating semiallogeneic trophoblast cells to enable successful pregnancy. The maternal-fetal interface also successfully precludes transmission of most pathogens. This barrier function occurs in conjunction with a diverse influx of decidual immune cells including natural killer cells, macrophages and T cells. However, several viruses, among other microorganisms, manage to escape destruction by the host adaptive and innate immune system, leading to congenital infection and adverse pregnancy outcomes. In this review, we describe mechanisms of pathogenicity of two such viral pathogens, Human cytomegalovirus (HCMV) and Zika …

Lung Secretoglobin Scgb1a1 Influences Alveolar Macrophage-Mediated Inflammation And Immunity, Min Xu, Wei Yang, Xuanchuan Wang, Deepak Kumar Nayak

Open Access Publications

Alveolar macrophage (AM) is a mononuclear phagocyte key to the defense against respiratory infections. To understand AM's role in airway disease development, we examined the influence of Secretoglobin family 1a member 1 (SCGB1A1), a pulmonary surfactant protein, on AM development and function. In a murine model, high-throughput RNA-sequencing and gene expression analyses were performed on purified AMs isolated from mice lacking in

A Novel Method For High-Dimensional Anatomical Mapping Of Extra-Axial Cerebrospinal Fluid: Application To The Infant Brain, Mahmoud Mostapha, Sun Hyung Kim, Alan C Evans, Stephen R Dager, Annette M Estes, Robert C Mckinstry, Kelly N Botteron, Guido Gerig, Stephen M Pizer, Robert T Schultz, Heather C Hazlett, Joseph Piven, Jessica B Girault, Mark D Shen, Martin A Styner

Open Access Publications

Cerebrospinal fluid (CSF) plays an essential role in early postnatal brain development. Extra-axial CSF (EA-CSF) volume, which is characterized by CSF in the subarachnoid space surrounding the brain, is a promising marker in the early detection of young children at risk for neurodevelopmental disorders. Previous studies have focused on global EA-CSF volume across the entire dorsal extent of the brain, and not regionally-specific EA-CSF measurements, because no tools were previously available for extracting local EA-CSF measures suitable for localized cortical surface analysis. In this paper, we propose a novel framework for the localized, cortical surface-based analysis of EA-CSF. The proposed …

Characterization Of The Complete Mitochondrial Genomes Of Two Sibling Species Of Parasitic Roundworms, Haemonchus Contortus And Teladorsagia Circumcincta, Nikola Palevich, Paul H Maclean, Young-Jun Choi, Makedonka Mitreva

Open Access Publications

No abstract provided.

Phase I Study Of Vemurafenib In Children With Recurrent Or Progressive Brafv600e Mutant Brain Tumors: Pacific Pediatric Neuro-Oncology Consortium Study (Pnoc-002), Theodore Nicolaides, Karen Gauvain, Et Al

Open Access Publications

No abstract provided.

Deconstructing Tumor Heterogeneity: The Stromal Perspective, Renee E. Vickman, Douglas V. Faget, Sheila A. Stewart, Et Al

Open Access Publications

Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive

Orsay Virus Cp-Δ Adopts A Novel Β-Bracelet Structural Fold And Incorporates Into Virions As A Head Fiber, Yusong R. Guo, Yanlin Fan, Ying Zhou, Miao Jin, Jim L. Zhang, Hongbing Jiang, Matthew V. Holt, Tao Wang, Nicolas L. Young, David Wang, Weiwei Zhong, Yizhi J. Tao

Open Access Publications

Fiber proteins are commonly found in eukaryotic and prokaryotic viruses, where they play important roles in mediating viral attachment and host cell entry. They typically form trimeric structures and are incorporated into virions via noncovalent interactions. Orsay virus, a small RNA virus which specifically infects the laboratory model nematode

Isg15 Fast-Tracks Dna Replication, Alice Meroni, Alessandro Vindigni

Open Access Publications

In this issue, Raso et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.202002175) uncover a novel replication fork speed regulatory network controlled by the ubiquitin-like modifier interferon-stimulated gene 15 (ISG15), which plays a central role in the innate immune response and regulates tumorigenesis as well as chemotherapy response.

Cadmium Activates Ampa And Nmda Receptors With M3 Helix Cysteine Substitutions, Timothy J. Wilding, James E. Huettner

Open Access Publications

AMPA and NMDA receptors are ligand-gated ion channels that depolarize postsynaptic neurons when activated by the neurotransmitter L-glutamate. Changes in the distribution and activity of these receptors underlie learning and memory, but excessive change is associated with an array of neurological disorders, including cognitive impairment, developmental delay, and epilepsy. All of the ionotropic glutamate receptors (iGluRs) exhibit similar tetrameric architecture, transmembrane topology, and basic framework for activation; conformational changes induced by extracellular agonist binding deform and splay open the inner helix bundle crossing that occludes ion flux through the channel. NMDA receptors require agonist binding to all four subunits, whereas …

Identification Of New Helicobacter Pylori Subpopulations In Native Americans And Mestizos From Peru, Andrés Julián Gutiérrez-Escobar, Douglas E Berg, Et Al

Open Access Publications

Region-specific

Atacgraph: Profiling Genome-Wide Chromatin Accessibility From Atac-Seq, Rita Jui-Hsien Lu, Yen-Ting Liu, Chih Wei Huang, Ming-Ren Yen, Chung-Yen Lin, Pao-Yang Chen

Open Access Publications

Assay for transposase-accessible chromatin using sequencing data (ATAC-seq) is an efficient and precise method for revealing chromatin accessibility across the genome. Most of the current ATAC-seq tools follow chromatin immunoprecipitation sequencing (ChIP-seq) strategies that do not consider ATAC-seq-specific properties. To incorporate specific ATAC-seq quality control and the underlying biology of chromatin accessibility, we developed a bioinformatics software named ATACgraph for analyzing and visualizing ATAC-seq data. ATACgraph profiles accessible chromatin regions and provides ATAC-seq-specific information including definitions of nucleosome-free regions (NFRs) and nucleosome-occupied regions. ATACgraph also allows identification of differentially accessible regions between two ATAC-seq datasets. ATACgraph incorporates the docker image …

Campylobacter Colonization, Environmental Enteric Dysfunction, Stunting, And Associated Risk Factors Among Young Children In Rural Ethiopia: A Cross-Sectional Study From The Campylobacter Genomics And Environmental Enteric Dysfunction (Caged) Project, Dehao Chen, Mark J Manary, Et Al

Open Access Publications

Livestock farming provides a possible mechanism by which smallholder farmers can meet their household need for animal source foods (ASF), which may reduce the risk of stunting. However, direct/indirect contacts with domestic animals may increase colonization by

Cd4 Inhibits Helper T Cell Activation At Lower Affinity Threshold For Full-Length T Cell Receptors Than Single Chain Signaling Constructs, Deborah K Johnson, Wyatt Magoffin, Sheldon J Myers, Jordan G Finnell, John C Hancock, Taylor S Orton, Stephen P Persaud, Kenneth A Christensen, K Scott Weber

Open Access Publications

CD4

Insights From Genetic Studies Of Cerebral Palsy, Sara A Lewis, Sheetal Shetty, Bryce A Wilson, Aris J Huang, Sheng Chih Jin, Hayley Smithers-Sheedy, Michael C Fahey, Michael C Kruer

Open Access Publications

Cohort-based whole exome and whole genome sequencing and copy number variant (CNV) studies have identified genetic etiologies for a sizable proportion of patients with cerebral palsy (CP). These findings indicate that genetic mutations collectively comprise an important cause of CP. We review findings in CP genomics and propose criteria for CP-associated genes at the level of gene discovery, research study, and clinical application. We review the published literature and report 18 genes and 5 CNVs from genomics studies with strong evidence of for the pathophysiology of CP. CP-associated genes often disrupt early brain developmental programming or predispose individuals to known …

Nonmicrobial Activation Of Tlrs Controls Intestinal Growth, Wound Repair, And Radioprotection, William F Stenson, Matthew A Ciorba

Open Access Publications

TLRs, key components of the innate immune system, recognize microbial molecules. However, TLRs also recognize some nonmicrobial molecules. In particular, TLR2 and TLR4 recognize hyaluronic acid, a glycosaminoglycan in the extracellular matrix. In neonatal mice endogenous hyaluronic acid binding to TLR4 drives normal intestinal growth. Hyaluronic acid binding to TLR4 in pericryptal macrophages results in cyclooxygenase2- dependent PGE

Apurinic/Apyrimidinic Endonuclease 1 Restricts The Internalization Of Bacteria Into Human Intestinal Epithelial Cells Through The Inhibition Of Rac1, Gerco Den Hartog, Lindsay D Butcher, Amber L Ablack, Laura A Pace, Jailal N G Ablack, Richard Xiong, Soumita Das, Thaddeus S Stappenbeck, Lars Eckmann, Peter B Ernst, Sheila E Crowe

Open Access Publications

Pathogenic intestinal bacteria lead to significant disease in humans. Here we investigated the role of the multifunctional protein, Apurinic/apyrimidinic endonuclease 1 (APE1), in regulating the internalization of bacteria into the intestinal epithelium. Intestinal tumor-cell lines and primary human epithelial cells were infected with

Regulatory T Cells Developing Peri-Weaning Are Continually Required To Restrain Th2 Systemic Responses Later In Life, Kathryn A. Knoop, Keely G Mcdonald, Chyi-Song Hsieh, Phillip I Tarr, Rodney D Newberry

Open Access Publications

Atopic disorders including allergic rhinitis, asthma, food allergy, and dermatitis, are increasingly prevalent in Western societies. These disorders are largely characterized by T helper type 2 (Th2) immune responses to environmental triggers, particularly inhaled and dietary allergens. Exposure to such stimuli during early childhood reduces the frequency of allergies in at-risk children. These allergic responses can be restrained by regulatory T cells (Tregs), particularly Tregs arising in the gut. The unique attributes of how early life exposure to diet and microbes shape the intestinal Treg population is a topic of significant interest. While imprinting during early life promotes the development …

Rna Based Approaches To Profile Oncogenic Pathways From Low Quantity Samples To Drive Precision Oncology Strategies, Anja Van De Stolpe, Wim Verhaegh, Jean-Yves Blay, Cynthia X Ma, Patrick Pauwels, Mark Pegram, Hans Prenen, Dirk De Ruysscher, Nabil F Saba, Susan F Slovin, Karen Willard-Gallo, Hatim Husain

Open Access Publications

Precision treatment of cancer requires knowledge on active tumor driving signal transduction pathways to select the optimal effective targeted treatment. Currently only a subset of patients derive clinical benefit from mutation based targeted treatment, due to intrinsic and acquired drug resistance mechanisms. Phenotypic assays to identify the tumor driving pathway based on protein analysis are difficult to multiplex on routine pathology samples. In contrast, the transcriptome contains information on signaling pathway activity and can complement genomic analyses. Here we present the validation and clinical application of a new knowledge-based mRNA-based diagnostic assay platform (OncoSignal) for measuring activity of relevant signaling …

Using The Zebrafish Lateral Line To Understand The Roles Of Mitochondria In Sensorineural Hearing Loss, Melanie Holmgren, Lavinia Sheets

Open Access Publications

Hair cells are the mechanosensory receptors of the inner ear and can be damaged by noise, aging, and ototoxic drugs. This damage often results in permanent sensorineural hearing loss. Hair cells have high energy demands and rely on mitochondria to produce ATP as well as contribute to intracellular calcium homeostasis. In addition to generating ATP, mitochondria produce reactive oxygen species, which can lead to oxidative stress, and regulate cell death pathways. Zebrafish lateral-line hair cells are structurally and functionally analogous to cochlear hair cells but are optically and pharmacologically accessible within an intact specimen, making the zebrafish a good model …

Advances In Modeling The Immune Microenvironment Of Colorectal Cancer, Paul Sukwoo Yoon, Nuala Del Piccolo, Venktesh S Shirure, Yushuan Peng, Amanda Kirane, Robert J Canter, Ryan C Fields, Steven C George, Sepideh Gholami

Open Access Publications

Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the US. CRC frequently metastasizes to the liver and these patients have a particularly poor prognosis. The infiltration of immune cells into CRC tumors and liver metastases accurately predicts disease progression and patient survival. Despite the evident influence of immune cells in the CRC tumor microenvironment (TME), efforts to identify immunotherapies for CRC patients have been limited. Here, we argue that preclinical model systems that recapitulate key features of the tumor microenvironment-including tumor, stromal, and immune cells; the extracellular matrix; and the vasculature-are …

Nab-Paclitaxel Plus Durvalumab In Patients With Previously Treated Advanced Stage Non-Small Cell Lung Cancer (Abound.2l+), Daniel Morgensztern, Manuel Cobo Dols, Santiago Ponce Aix, Pieter E Postmus, Jaafar Bennouna, Jürgen R Fischer, Oscar Juan-Vidal, David J Stewart, Andrea Ardizzoni, Rafia Bhore, Marianne Wolfsteiner, Martin Reck, Denis Talbot, Ramaswamy Govindan, Teng Jin Ong

Open Access Publications

No abstract provided.

Treatment-Emergent Neuroendocrine Prostate Cancer: A Clinicopathological And Immunohistochemical Analysis Of 94 Cases, Qingfu Zhang, Yunan Han, Yao Zhang, Dan Liu, Jian Ming, Bo Huang, Xueshan Qiu

Open Access Publications

Purpose: This study aimed to evaluate the pathological characteristics, immunophenotype, and prognosis of treatment-emergent neuroendocrine prostate cancer (T-NEPC).

Materials and Methods: We collected 231 repeated biopsy specimens of castration-resistant prostate cancer (CRPC) cases between 2008 and 2019. We used histopathological and immunohistochemical evaluations of Synaptophysin (SYN), ChromograninA (CgA), CD56, androgen receptor (AR), and prostate

Results: Among the 231 CRPC cases, 94 (40.7%) cases were T-NEPC. T-NEPC were more likely to present with negative immunohistochemistry for AR (30.9%) and PSA (47.9%) than that of CRPC (8.8% and 17.5%, respectively). Kaplan-Meier analysis revealed that patients with T-NEPC (median overall survival [OS]: 17.6 …

Randomized Controlled Crossover Trials Of The Pharmacokinetics Of Prc-063, A Novel Multilayer Extended-Release Formulation Of Methylphenidate, In Healthy Adults, Martin A. Katzman, Greg Mattingly, Larry J. Klassen, Marc J. Cataldo, Graeme A. E. Donnelly

Open Access Publications

No abstract provided.

The Impact Of Sars-Cov-2 In Dementia Across Latin America: A Call For An Urgent Regional Plan And Coordinated Response, Agustin Ibanez, Jorge Llibre-Guerra, Et Al

Open Access Publications

The SARS-CoV-2 global pandemic will disproportionately impact countries with weak economies and vulnerable populations including people with dementia. Latin American and Caribbean countries (LACs) are burdened with unstable economic development, fragile health systems, massive economic disparities, and a high prevalence of dementia. Here, we underscore the selective impact of SARS-CoV-2 on dementia among LACs, the specific strain on health systems devoted to dementia, and the subsequent effect of increasing inequalities among those with dementia in the region. Implementation of best practices for mitigation and containment faces particularly steep challenges in LACs. Based upon our consideration of these issues, we urgently …

Killing The Pathogen And Sparing The Placenta, Indira U. Mysorekar

Open Access Publications

No abstract provided.

Effects Of Diet Versus Gastric Bypass On Metabolic Function In Diabetes, Mihoko Yoshino, Brandon D. Kayser, Jun Yoshino, Richard I. Stein, Dominic Reeds, J. Christopher Eagon, Shaina R. Eckhouse, Jeramie D. Watrous, Mohit Jain, Rob Knight, Kenneth Schechtman, Bruce W. Patterson, Samuel Klein

Open Access Publications

No abstract provided.

Krasg12c Inhibition With Sotorasib In Advanced Solid Tumors, David S. Hong, Ramaswamy Govindan, Et Al

Open Access Publications

No abstract provided.

Trial Of Sodium Phenylbutyrate–Taurursodiol For Amyotrophic Lateral Sclerosis, Sabrina Paganoni, Timothy M. Miller, Et Al

Open Access Publications

No abstract provided.

Context Is Key: Delineating The Unique Functions Of Ifnα And Ifnβ In Disease, Lindsey E Fox, Marissa C Locke, Deborah J Lenschow

Open Access Publications

Type I interferons (IFNs) are critical effector cytokines of the immune system and were originally known for their important role in protecting against viral infections; however, they have more recently been shown to play protective or detrimental roles in many disease states. Type I IFNs consist of IFNα, IFNβ, IFNϵ, IFNκ, IFNω, and a few others, and they all signal through a shared receptor to exert a wide range of biological activities, including antiviral, antiproliferative, proapoptotic, and immunomodulatory effects. Though the individual type I IFN subtypes possess overlapping functions, there is growing appreciation that they also have unique properties. In …

Hematopoeitic Cell Transplantation And Car T-Cell Therapy: Complements Or Competitors?, Scott R Goldsmith, Armin Ghobadi, John F Dipersio

Open Access Publications

Allogeneic hematopoietic cell transplantation (allo-HCT) and chimeric antigen receptor T cell (CAR T) therapy are the main modalities of adoptive cellular immunotherapy that have widely permeated the clinical space. The advent of both technologies revolutionized treatment of many hematologic malignancies, both offering the chance at sustained remissions for patients who would otherwise invariably succumb to their diseases. The understanding and exploitation of the nonspecific alloreactivity of allo-HCT and the graft-versus-tumor effect is contrasted by the genetically engineered precision of CAR T therapy. Historically, those with relapsed and refractory hematologic malignancies have often been considered for allo-HCT, although outcomes vary dramatically …