Digital Commons Network^™

Hippocampus Guides Adaptive Learning During Dynamic Social Interactions, Oriel Feldmanhall, David F. Montez, Elizabeth A. Phelps, Lila Davachi, Vishnu P. Murty

Open Access Publications

How do we evaluate whether someone will make a good friend or collaborative peer? A hallmark of human cognition is the ability to make adaptive decisions based on information garnered from limited prior experiences. Using an interactive social task measuring adaptive choice (deciding who to reengage or avoid) in male and female participants, we find the hippocampus supports value-based social choices following single-shot learning. These adaptive choices elicited a suppression signal in the hippocampus, revealing sensitivity for the subjective perception of a person and how well they treat you during choice. The extent to which the hippocampus was suppressed was …

Rates Of Gene Conversions Between Escherichia Coli Ribosomal Operons, Isaac Gifford, Aurko Dasgupta, Jeffrey E Barrick

Open Access Publications

Due to their universal presence and high sequence conservation, ribosomal RNA (rRNA) sequences are used widely in phylogenetics for inferring evolutionary relationships between microbes and in metagenomics for analyzing the composition of microbial communities. Most microbial genomes encode multiple copies of rRNA genes to supply cells with sufficient capacity for protein synthesis. These copies typically undergo concerted evolution that keeps their sequences identical, or nearly so, due to gene conversion, a type of intragenomic recombination that changes one copy of a homologous sequence to exactly match another. Widely varying rates of rRNA gene conversion have previously been estimated by comparative …

Controlling Opioid Receptor Functional Selectivity By Targeting Distinct Subpockets Of The Orthosteric Site, Rajendra Uprety, Tao Che, Balázs R. Varga, Abdelfattah Faouzi, Sarah M. Bernhard, Susruta Majumdar, Et Al

Open Access Publications

Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here, we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with

Treatment Of Patients With Chronic Pruritus Of Unknown Origin With Dupilumab, Jiehyun Jeon, Fang Wang, Asima Badic, Brian S Kim

Open Access Publications

BACKGROUND: Chronic pruritus of unknown origin (CPUO) is a highly debilitating disease that lacks effective treatments. This study explores a new therapeutic strategy with dupilumab.

OBJECTIVES: To examine whether patients with CPUO demonstrate clinical response to dupilumab.

PATIENTS AND METHODS: This is a retrospective case series examining all patients with CPUO who were treated with dupilumab from March 2017 to December 2019 at a tertiary referral clinic at Washington University School of Medicine in St. Louis, MO. Numerical rating scale (NRS) itch score changes over time were recorded and analyzed.

RESULTS: Fifteen patients (67% women; mean [SD] age, 68.7 [12.6] …

Gut Helicobacter Presentation By Multiple Dendritic Cell Subsets Enables Context-Specific Regulatory T Cell Generation, Emilie V. Russler-Germain, Jaeu Yi, Shannon Young, Katherine Nutsch, Harikesh S. Wong, Teresa L. Ai, Jiani N. Chai, Vivek Durai, Daniel H. Kaplan, Ronald N. Germain, Kenneth M. Murphy, Chyi-Song Hsieh

Open Access Publications

Generation of tolerogenic peripheral regulatory T (pTreg) cells is commonly thought to involve CD103

Satb2 Induction Of A Neural Crest Mesenchyme-Like Program Drives Melanoma Invasion And Drug Resistance, Maurizio Fazio, Charles K. Kaufman, Et Al

Open Access Publications

Recent genomic and scRNA-seq analyses of melanoma demonstrated a lack of recurrent genetic drivers of metastasis, while identifying common transcriptional states correlating with invasion or drug resistance. To test whether transcriptional adaptation can drive melanoma progression, we made use of a zebrafish mitfa:

The Role Of Endometrial Sampling For Surveillance Of Recurrence In Postmenopausal Patients With Medically Inoperable Stage I Endometrial Cancer, Angelina Carey-Love, Mary M Mullen, Abigail Zamorano, Stephanie Markovina, Andrea R Hagemann, Katherine C Fuh, Premal H Thaker, David G Mutch, Matthew A Powell, Lindsay M Kuroki

Open Access Publications

It is unclear if surveillance for postmenopausal women with medically inoperable stage 1 endometrial cancer (EC) should differ depending on their management strategy. Thus, we investigated the utility of surveillance endometrial sampling among 53 postmenopausal women with medically inoperable, clinical stage I, grade 1 endometrioid EC who received either progestin therapy or radiation between 2009 and 2018, at a single academic institution. Frequency and results of endometrial sampling, as well as recurrence and survival rates were studied. Of 53 patients, 18 (34.0%) received progestin therapy and 35 (66.0%) radiation. Medically managed patients were treated with megestrol acetate (27.7%), a levonorgestrel …

Polygenic Burden Has Broader Impact On Health, Cognition, And Socioeconomic Outcomes Than Most Rare And High-Risk Copy Number Variants, Elmo Christian Saarentaus, Lei Chen, Ira M Hall, Et Al

Open Access Publications

Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on …

Capsule Carbohydrate Structure Determines Virulence In Acinetobacter Baumannii, Yuli Talyansky, Travis B. Nielsen, Jun Yan, Ulrike Carlino-Macdonald, Gisela Di Venanzio, Somnath Chakravorty, Amber Ulhaq, Mario F. Feldman, Thomas A. Russo, Evgeny Vinogradov, Brian Luna, Meredith S. Wright, Mark D. Adams, Brad Spellberg

Open Access Publications

Acinetobacter baumannii is a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and …

Liver Transplantation: Expanding The Donor And Recipient Pool, Ola Ahmed, M. B. Majella Doyle

Open Access Publications

Liver transplantation is an exemplar model of complex surgery and the only curative option for patients with end-stage liver disease. Although historically associated with poor outcomes, liver cancer management has also been revolutionised with liver transplantation and in some instances, survival outcomes are comparable to surgical resection. As such, the key elements underpinning the major advances in surgical technique, immunological therapies and allocation policies combined with improved patient and graft survival outcomes have created a huge demand for organ donation. Despite improvements in donor and recipient selection, there is a persistent disparity between organ supply and demand. Candidate wait-list mortality …

Prognostic And Predictive Effect Of Kras Gene Copy Number And Mutation Status In Early Stage Non-Small Cell Lung Cancer Patients, Andrea S. Fung, Maryam Karimi, Stefan Michiels, Lesley Seymour, Elisabeth Brambilla, Thierry Le-Chevalier, Jean-Charles Soria, Robert Kratzke, Stephen L. Graziano, Siddhartha Devarakonda, Ramaswamy Govindan, Ming-Sound Tsao, Frances A. Shepherd, Lace-Bio Collaborative Group

Open Access Publications

Background: In the current analysis, we characterize the prognostic significance of

Methods: Clinical and genomic data from the LACE (Lung Adjuvant Cisplatin Evaluation)-Bio consortium was utilized. CNAs were categorized as Gain (CN ≥2) or Neutral (Neut)/Loss;

Results: Of the 946 (399 adenocarcinoma) NSCLC patients, 41 [30] had MUT + Gain, 145 [99] MUT + Neut/Loss, 125 [16] WT + Gain, and 635 [254] WT + Neut/Loss. A non-significant trend towards worse lung cancer-specific survival (LCSS; HR =1.34; 95% CI, 0.83-2.17, P=0.232), DFS (HR =1.34; 95% CI, 0.86-2.09, P=0.202) and OS (HR =1.59; 95% CI, 0.99-2.54, P=0.055) was seen in

Conclusions: …

Flortaucipir (Tau) Pet In Lgi1 Antibody Encephalitis, Gregory S Day, Brian A Gordon, Austin Mccullough, Robert C Bucelli, Richard J Perrin, Tammie L S Benzinger, Beau M Ances

Open Access Publications

The contributors to persistent cognitive impairment and hippocampal atrophy in leucine-rich glioma-inactivated 1 antibody encephalitis (LGI1) patients are unknown. We evaluated whether tau neuropathology measured with [

Global, Cell Non-Autonomous Gene Regulation Drives Individual Lifespan Among Isogenic C. Elegans, Holly E. Kinser, Matthew C. Mosley, Isaac B. Plutzer, Zachary Pincus

Open Access Publications

Across species, lifespan is highly variable among individuals within a population. Even genetically identical

Progress Towards Onchocerciasis Elimination In Côte D'Ivoire: A Geospatial Modelling Study, Obiora A. Eneanya, Benjamin G. Koudou, Meite Aboulaye, Aba Ange Elvis, Yeo Souleymane, Marie-Madeleine Kouakou, Gary J. Weil, Peter U. Fischer

Open Access Publications

BACKGROUND: Côte d'Ivoire has had 45 years of intervention for onchocerciasis by vector control (from 1975 to 1991), ivermectin mass drug administration (MDA) (from 1992 to 1994) and community directed treatment with ivermectin (CDTi) from 1995 to the present. We modeled onchocerciasis endemicity during two time periods that correspond to the scale up of vector control and ivermectin distribution, respectively. This analysis illustrates progress towards elimination during these periods, and it has identified potential hotspots areas that are at risk for ongoing transmission.

METHODS AND FINDINGS: The analysis used Ministry of Health skin snip microfilaria (MF) prevalence and intensity data …

Mapping The Immune Environment In Clear Cell Renal Carcinoma By Single-Cell Genomics, Nicholas Borcherding, Ajaykumar Vishwakarma, Andrew P Voigt, Andrew Bellizzi, Jacob Kaplan, Kenneth Nepple, Aliasger K Salem, Russell W Jenkins, Yousef Zakharia, Weizhou Zhang

Open Access Publications

Clear cell renal cell carcinoma (ccRCC) is one of the most immunologically distinct tumor types due to high response rate to immunotherapies, despite low tumor mutational burden. To characterize the tumor immune microenvironment of ccRCC, we applied single-cell-RNA sequencing (SCRS) along with T-cell-receptor (TCR) sequencing to map the transcriptomic heterogeneity of 25,688 individual CD45

Genomic Characterization Of Emerging Bacterial Uropathogen Neisseria Meningitidis, Which Was Misidentified As Neisseria Gonorrhoeae By Nucleic Acid Amplification Testing, Kimberley V Sukhum, Sophonie Jean, Meghan Wallace, Neil Anderson, C A Burnham, Gautam Dantas

Open Access Publications

No abstract provided.

Short-Term Effects Of Appropriate Empirical Antimicrobial Treatment With Ceftolozane/Tazobactam In A Swine Model Of Nosocomial Pneumonia, Ana Motos, Marin Kollef, Et Al

Open Access Publications

The rising frequency of multidrug-resistant and extensively drug-resistant (MDR/XDR) pathogens is making more frequent the inappropriate empirical antimicrobial therapy (IEAT) in nosocomial pneumonia, which is associated with increased mortality. We aim to determine the short-term benefits of appropriate empirical antimicrobial treatment (AEAT) with ceftolozane/tazobactam (C/T) compared with IEAT with piperacillin/tazobactam (TZP) in MDR

Naturalistic Language Input Is Associated With Resting-State Functional Connectivity In Infancy, Lucy S. King, M. Catalina Camacho, David F. Montez, Kathryn L. Humphreys, Ian H. Gotlib

Open Access Publications

The quantity and quality of the language input that infants receive from their caregivers affects their future language abilities; however, it is unclear how variation in this input relates to preverbal brain circuitry. The current study investigated the relation between naturalistic language input and the functional connectivity (FC) of language networks in human infancy using resting-state functional magnetic resonance imaging (rsfMRI). We recorded the naturalistic language environments of five- to eight-month-old male and female infants using the Linguistic ENvironment Analysis (LENA) system and measured the quantity and consistency of their exposure to adult words (AWs) and adult-infant conversational turns (CTs). …

Sars-Cov-2 Infection Severity Is Linked To Superior Humoral Immunity Against The Spike, Jenna J Guthmiller, Ya-Nan Dai, Christopher A Nelson, Paige D Hall, Daved H Fremont, Et Al

Open Access Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a global pandemic. The antigen specificity of the antibody response mounted against this novel virus is not understood in detail. Here, we report that subjects with a more severe SARS-CoV-2 infection exhibit a larger antibody response against the spike and nucleocapsid protein and epitope spreading to subdominant viral antigens, such as open reading frame 8 and nonstructural proteins. Subjects with a greater antibody response mounted a larger memory B cell response against the spike, but not the nucleocapsid protein. Additionally, we revealed that antibodies against the spike are still capable …

Coxsackievirus B3 Infection Early In Pregnancy Induces Congenital Heart Defects Through Suppression Of Fetal Cardiomyocyte Proliferation, Vipul Sharma, Lisa S Goessling, Anoop K Brar, Chetanchandra S Joshi, Indira U Mysorekar, Pirooz Eghtesady

Open Access Publications

Background Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. Methods and Results We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose-response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of …

Death And Myocardial Infarction Following Initial Revascularization Versus Optimal Medical Therapy In Chronic Coronary Syndromes With Myocardial Ischemia: A Systematic Review And Meta-Analysis Of Contemporary Randomized Controlled Trials, Andrea Soares, William E Boden, Whady Hueb, Maria M Brooks, Helen E A Vlachos, Kevin O'Fee, Angela Hardi, David L Brown

Open Access Publications

Background In chronic coronary syndromes, myocardial ischemia is associated with a greater risk of death and nonfatal myocardial infarction (MI). We sought to compare the effect of initial revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) plus optimal medical therapy (OMT) with OMT alone in patients with chronic coronary syndrome and myocardial ischemia on long-term death and nonfatal MI. Methods and Results Ovid Medline, Embase, Scopus, and Cochrane Library databases were searched for randomized controlled trials of PCI or CABG plus OMT versus OMT alone for patients with chronic coronary syndromes. Studies were screened and data …

Zika Virus Oncolytic Activity Requires Cd8+ T Cells And Is Boosted By Immune Checkpoint Blockade, Sharmila Nair, Luciano Mazzoccoli, Arijita Jash, Jennifer Govero, Sachendra S Bais, Tong Hu, Camila R Fontes-Garfias, Chao Shan, Hideho Okada, Sujan Shresta, Jeremy N Rich, Pei-Yong Shi, Michael S Diamond, Milan G Chheda

Open Access Publications

Glioblastoma multiforme (GBM) is a fatal human cancer in part because GBM stem cells are resistant to therapy and recurrence is inevitable. Previously, we demonstrated Zika virus (ZIKV) targets GBM stem cells and prevents death of mice with gliomas. Here, we evaluated the immunological basis of ZIKV-mediated protection against GBM. Introduction of ZIKV into the brain tumor increased recruitment of CD8+ T and myeloid cells to the tumor microenvironment. CD8+ T cells were required for ZIKV-dependent tumor clearance because survival benefits were lost with CD8+ T cell depletion. Moreover, while anti-PD-1 antibody monotherapy moderately improved tumor survival, when coadministered with …

The Dark Kinase Knowledgebase: An Online Compendium Of Knowledge And Experimental Results Of Understudied Kinases, Matthew E. Berginski, Nienke Moret, Changchang Liu, Dennis Goldfarb, Peter K. Sorger, Shawn M. Gomez

Open Access Publications

Kinases form the backbone of numerous cell signaling pathways, with their dysfunction similarly implicated in multiple pathologies. Further facilitated by their druggability, kinases are a major focus of therapeutic development efforts in diseases such as cancer, infectious disease and autoimmune disorders. While their importance is clear, the role or biological function of nearly one-third of kinases is largely unknown. Here, we describe a data resource, the Dark Kinase Knowledgebase (DKK; https://darkkinome.org), that is specifically focused on providing data and reagents for these understudied kinases to the broader research community. Supported through NIH's Illuminating the Druggable Genome (IDG) Program, the DKK …

Oct4 Cooperates With Distinct Atp-Dependent Chromatin Remodelers In Naïve And Primed Pluripotent States In Human, Xin Huang, Kyoung-Mi Park, Paul Gontarz, Bo Zhang, Laura A. Fischer, Chen Dong, Sabine Dietmann, Xiaoyun Xing, Shafqat A. Khan, Nick Jensen, Ting Wang, Thorold W. Theunissen, Et Al

Open Access Publications

No abstract provided.

Improving Hindlimb Locomotor Function By Non-Invasive Aav-Mediated Manipulations Of Propriospinal Neurons In Mice With Complete Spinal Cord Injury, Benedikt Brommer, Miao He, Zicong Zhang, Zhiyun Yang, Jessica C. Page, Junfeng Su, Yu Zhang, Junjie Zhu, Emilia Gouy, Jing Tang, Philip Williams, Wei Dai, Qi Wang, Ryan Solinsky, Bo Chen, Zhigang He

Open Access Publications

No abstract provided.

A Synthetic Mechanogenetic Gene Circuit For Autonomous Drug Delivery In Engineered Tissues, Robert J Nims, Lara Pferdehirt, Noelani B Ho, Alireza Savadipour, Jeremiah Lorentz, Sima Sohi, Jordan Kassab, Alison K Ross, Christopher J O'Conor, Wolfgang B Liedtke, Bo Zhang, Amy L Mcnulty, Farshid Guilak

Open Access Publications

Mechanobiologic signals regulate cellular responses under physiologic and pathologic conditions. Using synthetic biology and tissue engineering, we developed a mechanically responsive bioartificial tissue that responds to mechanical loading to produce a preprogrammed therapeutic biologic drug. By deconstructing the signaling networks induced by activation of the mechanically sensitive ion channel transient receptor potential vanilloid 4 (TRPV4), we created synthetic TRPV4-responsive genetic circuits in chondrocytes. We engineered these cells into living tissues that respond to mechanical loading by producing the anti-inflammatory biologic drug interleukin-1 receptor antagonist. Chondrocyte TRPV4 is activated by osmotic loading and not by direct cellular deformation, suggesting that tissue …

Optimal Method For Fetal Brain Age Prediction Using Multiplanar Slices From Structural Magnetic Resonance Imaging, Jinwoo Hong, Hyuk Jin Yun, Gilsoon Park, Seonggyu Kim, Yangming Ou, Lana Vasung, Caitlin K Rollins, Cynthia M Ortinau, Emiko Takeoka, Shizuko Akiyama, Tomo Tarui, Judy A Estroff, Patricia Ellen Grant, Jong-Min Lee, Kiho Im

Open Access Publications

The accurate prediction of fetal brain age using magnetic resonance imaging (MRI) may contribute to the identification of brain abnormalities and the risk of adverse developmental outcomes. This study aimed to propose a method for predicting fetal brain age using MRIs from 220 healthy fetuses between 15.9 and 38.7 weeks of gestational age (GA). We built a 2D single-channel convolutional neural network (CNN) with multiplanar MRI slices in different orthogonal planes without correction for interslice motion. In each fetus, multiple age predictions from different slices were generated, and the brain age was obtained using the mode that determined the most …

Parental Factors Associated With The Decision To Participate In A Neonatal Clinical Trial, Elliott Mark Weiss, Rakesh Rao, Et Al

Open Access Publications

Importance: It remains poorly understood how parents decide whether to enroll a child in a neonatal clinical trial. This is particularly true for parents from racial or ethnic minority populations. Understanding factors associated with enrollment decisions may improve recruitment processes for families, increase enrollment rates, and decrease disparities in research participation.

Objective: To assess differences in parental factors between parents who enrolled their infant and those who declined enrollment for a neonatal randomized clinical trial.

Design, Setting, and Participants: This survey study conducted from July 2017 to October 2019 in 12 US level 3 and 4 neonatal intensive care units …

Killing The Invaders: Nk Cell Impact In Tumors And Anti-Tumor Therapy, Martina Molgora, Victor S Cortez, Marco Colonna

Open Access Publications

Natural Killer cells belong to group 1 innate lymphoid cells, which also includes ILC1s. NK/ILC1s are highly heterogeneous cell types showing distinct phenotypes across tissues and conditions. NK cells have long been described as innate lymphocytes able to directly and rapidly kill tumor cells without antigen-restriction. Different mechanisms were shown to modulate NK cell activation and tumor resistance, mainly based on cytokine stimulation and receptor-ligand interactions, and several strategies have been developed to target NK cells in tumor immunotherapy to promote NK cell function and overcome tumor evasion. The characterization of ILC1 distinct phenotype and function and the specific role …

Von Willebrand Disease: Proposing Definitions For Future Research, Nathan T. Connell, Jorge Di Paola, Et Al.

Open Access Publications

No abstract provided.