Medicine and Health Sciences Commons^™

Silencing Alanine Transaminase 2 In Diabetic Liver Attenuates Hyperglycemia By Reducing Gluconeogenesis From Amino Acids, Michael R. Martino, Manuel Gutiérrez-Aguilar, Nicole K. H. Yiew, Andrew J. Lutkewitte, Jason M. Singer, Kyle S. Mccommis, Daniel Ferguson, Kim H. H. Liss, Jun Yoshino, M. Katie Renkemeyer, Gordon I. Smith, Kevin Cho, Justin A. Fletcher, Samuel Klein, Gary J. Patti, Shawn C. Burgess, Brian N. Finck

2020-Current year OA Pubs

Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation of

Ptsd Is Associated With Impaired Event Processing And Memory For Everyday Events, Barbara L Pitts, Michelle L Eisenberg, Heather R Bailey, Jeffrey M Zacks

2020-Current year OA Pubs

Current theories of posttraumatic stress disorder (PTSD) propose that memory abnormalities are central to the development and persistence of symptoms. While the most notable memory disturbances in PTSD involve memory for the trauma itself, individuals often have trouble remembering aspects of everyday life. Further, people with PTSD may have difficulty segmenting ongoing activity into discrete units, which is important for our perception and later memory of the activity. The current study investigated whether PTSD diagnosis and symptom severity predicted event segmentation and memory for everyday activities. To do so, 63 people with PTSD and 64 controls with a trauma history …

A Somatic Mutation In Moesin Drives Progression Into Acute Myeloid Leukemia, Ouyang Yuan, Jeffrey A Magee, Et Al.

Open Access Publications

Acute myeloid leukemia (AML) arises when leukemia-initiating cells, defined by a primary genetic lesion, acquire subsequent molecular changes whose cumulative effects bypass tumor suppression. The changes that underlie AML pathogenesis not only provide insights into the biology of transformation but also reveal novel therapeutic opportunities. However, backtracking these events in transformed human AML samples is challenging, if at all possible. Here, we approached this question using a murine in vivo model with an MLL-ENL fusion protein as a primary molecular event. Upon clonal transformation, we identified and extensively verified a recurrent codon-changing mutation (Arg

A Proposed Role For Interactions Between Argonautes, Mirisc, And Rna Binding Proteins In The Regulation Of Local Translation In Neurons And Glia, Sarah K Koester, Joseph D Dougherty

2020-Current year OA Pubs

The first evidence of local translation in the CNS appeared nearly 40 years ago, when electron microscopic studies showed polyribosomes localized to the base of dendritic spines. Since then, local translation has been established as an important regulatory mechanism for gene expression in polarized or functionally compartmentalized cells. While much attention has been placed on characterizing the local transcriptome and regulatory "grammar" directing mRNA localization in neurons and glia, less is understood about how these cells subsequently de-repress mRNA translation in their peripheral processes to produce a rapid translational response to stimuli. MicroRNA-mediated translation regulation offers a possible solution to …

Directed Mutational Scanning Reveals A Balance Between Acidic And Hydrophobic Residues In Strong Human Activation Domains, Max V Staller, Eddie Ramirez, Sanjana R Kotha, Alex S Holehouse, Rohit V Pappu, Barak A Cohen

2020-Current year OA Pubs

Acidic activation domains are intrinsically disordered regions of the transcription factors that bind coactivators. The intrinsic disorder and low evolutionary conservation of activation domains have made it difficult to identify the sequence features that control activity. To address this problem, we designed thousands of variants in seven acidic activation domains and measured their activities with a high-throughput assay in human cell culture. We found that strong activation domain activity requires a balance between the number of acidic residues and aromatic and leucine residues. These findings motivated a predictor of acidic activation domains that scans the human proteome for clusters of …

Calgb 40603 (Alliance): Long-Term Outcomes And Genomic Correlates Of Response And Survival After Neoadjuvant Chemotherapy With Or Without Carboplatin And Bevacizumab In Triple-Negative Breast Cancer, Jonathan H Shepherd, Cynthia Ma, Et Al.

2020-Current year OA Pubs

PURPOSE: CALGB 40603 (NCT00861705), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points.

PATIENTS AND METHODS: The Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose …

Centrosome-Dependent Microtubule Modifications Set The Conditions For Axon Formation, Durga Praveen Meka, Ewelina Betleja, Tao Cheng, Moe R Mahjoub, Et Al.

2020-Current year OA Pubs

Microtubule (MT) modifications are critical during axon development, with stable MTs populating the axon. How these modifications are spatially coordinated is unclear. Here, via high-resolution microscopy, we show that early developing neurons have fewer somatic acetylated MTs restricted near the centrosome. At later stages, however, acetylated MTs spread out in soma and concentrate in growing axon. Live imaging in early plated neurons of the MT plus-end protein, EB3, show increased displacement and growth rate near the MTOC, suggesting local differences that might support axon selection. Moreover, F-actin disruption in early developing neurons, which show fewer somatic acetylated MTs, does not …

Relationship Between Age At Menopause, Obesity, And Incident Heart Failure: The Atherosclerosis Risk In Communities Study, Imo A Ebong, Machelle D Wilson, Duke Appiah, Erin D Michos, Susan B Racette, Amparo Villablanca, Khadijah Breathett, Pamela L Lutsey, Melissa Wellons, Karol E Watson, Patricia Chang, Alain G Bertoni

2020-Current year OA Pubs

Background The mechanisms linking menopausal age and heart failure (HF) incidence are controversial. We investigated for heterogeneity by obesity on the relationship between menopausal age and HF incidence. Methods and Results Using postmenopausal women who attended the Atherosclerosis Risk in Communities Study Visit 4, we estimated hazard ratios of incident HF associated with menopausal age using Cox proportional hazards models, testing for effect modification by obesity and adjusting for HF risk factors. Women were categorized by menopausal age: <45 years, 45 to 49 years, 50 to 54 years, and ≥55 years. Among 4441 postmenopausal women, aged 63.5±5.5 years, there were 903 incident HF events over a mean follow-up of 16.5 years. The attributable risk of generalized and central obesity for HF incidence was greatest among women who experienced menopause at age ≥55 years: 11.09/1000 person-years and 7.38/1000 person-years, respectively. There were significant interactions of menopausal age with body mass index and waist circumference for HF incidence,

Need For Better And Broader Training In Cardio-Obstetrics: A National Survey Of Cardiologists, Cardiovascular Team Members, And Cardiology Fellows In Training, Natalie A Bello, Akanksha Agrawal, Melinda B Davis, Colleen M Harrington, Kathryn J Lindley, Margo B Minissian, Garima Sharma, Mary Norine Walsh, Ki Park

2020-Current year OA Pubs

Background Team-based models of cardio-obstetrics care have been developed to address the increasing rate of maternal mortality from cardiovascular diseases. Cardiovascular clinician and trainee knowledge and comfort with this topic, and the extent of implementation of an interdisciplinary approach to cardio-obstetrics, are unknown. Methods and Results We aimed to assess the current state of cardio-obstetrics knowledge, practices, and services provided by US cardiovascular clinicians and trainees. A survey developed in conjunction with the American College of Cardiology was circulated to a representative sample of cardiologists (N=311), cardiovascular team members (N=51), and fellows in training (N=139) from June 18, 2020, to …

Comprehensive Cross-Sectional And Longitudinal Analyses Of Plasma Neurofilament Light Across Ftd Spectrum Disorders, Tania F. Gendron, Nupur Ghoshal, Et Al.

2020-Current year OA Pubs

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with …

Somatic Dnmt3a Inactivation Leads To Slow, Canonical Dna Methylation Loss In Murine Hematopoietic Cells, Amanda M. Smith, Angela M. Verdoni, Haley J. Abel, David Y. Chen, Shamika Ketkar, Elizabeth R. Leight, Christopher A. Miller, Timothy J. Ley

2020-Current year OA Pubs

Mutations in the gene encoding DNA methyltransferase 3A (

Heat-Induced Sirt1-Mediated H4k16ac Deacetylation Impairs Resection And Smarcad1 Recruitment To Double Strand Breaks, Sharmistha Chakraborty, Raj K. Pandita, Nobuo Horikoshi, Eduardo G Moros, Clayton Hunt, Tej K. Pandita, Et Al.

2020-Current year OA Pubs

Hyperthermia inhibits DNA double-strand break (DSB) repair that utilizes homologous recombination (HR) pathway by a poorly defined mechanism(s); however, the mechanisms for this inhibition remain unclear. Here we report that hyperthermia decreases H4K16 acetylation (H4K16ac), an epigenetic modification essential for genome stability and transcription. Heat-induced reduction in H4K16ac was detected in humans,

Anatomical Variability, Multi-Modal Coordinate Systems, And Precision Targeting In The Marmoset Brain, Takayuki Ose, David C Van Essen, Matthew F Glasser, Et Al.

2020-Current year OA Pubs

Localising accurate brain regions needs careful evaluation in each experimental species due to their individual variability. However, the function and connectivity of brain areas is commonly studied using a single-subject cranial landmark-based stereotactic atlas in animal neuroscience. Here, we address this issue in a small primate, the common marmoset, which is increasingly widely used in systems neuroscience. We developed a non-invasive multi-modal neuroimaging-based targeting pipeline, which accounts for intersubject anatomical variability in cranial and cortical landmarks in marmosets. This methodology allowed creation of multi-modal templates (MarmosetRIKEN20) including head CT and brain MR images, embedded in coordinate systems of anterior and …

Nuclear Morphometry And Chromatin Texture Changes In Hepatocellular Carcinoma Samples May Predict Outcomes Of Liver Transplanted Patients, Jordan Boeira Dos Santos, Rodrigo Tzovenos Starosta, Emily Ferreira Salles Pilar, Jefferson Daniel Kunz, Joelson Tomedi, Carlos Thadeu Schmidt Cerski, Rúbia Denise Ruppenthal

2020-Current year OA Pubs

BACKGROUND: Nuclear changes are typical in the carcinogenesis of hepatocellular carcinoma (HCC). Morphometry and chromatin texture analysis are quantitative methods for their quantification. In this study, we analyzed nuclear morphometry and chromatin texture parameters in samples of hepatocellular carcinoma from liver transplant patients and their associations with clinicopathologic variables.

METHODS: Samples of HCC and adjacent tissue from 34 individuals were collected in tissue microarray blocks. Stained slides were microphotographed using an optical microscope and nuclear parameters analyzed in ImageJ (FracLac plug-in). ROC curve analysis was used to find accurate cut-offs for differentiation of neoplastic and non-neoplastic cells. The inter-rater agreement …

Hormone And Receptor Activator Of Nf-Κb (Rank) Pathway Gene Expression In Plasma And Mammographic Breast Density In Postmenopausal Women, Rachel Mintz, Mei Wang, Shuai Xu, Graham A Colditz, Chris Markovic, Adetunji T Toriola

2020-Current year OA Pubs

BACKGROUND: Hormones impact breast tissue proliferation. Studies investigating the associations of circulating hormone levels with mammographic breast density have reported conflicting results. Due to the limited number of studies, we investigated the associations of hormone gene expression as well as their downstream mediators within the plasma with mammographic breast density in postmenopausal women.

METHODS: We recruited postmenopausal women at their annual screening mammogram at Washington University School of Medicine, St. Louis. We used the NanoString nCounter platform to quantify gene expression of hormones (prolactin, progesterone receptor (PGR), estrogen receptor 1 (ESR1), signal transducer and activator of transcription (STAT1 and STAT5), …

Cs1 Car-T Targeting The Distal Domain Of Cs1 (Slamf7) Shows Efficacy In High Tumor Burden Myeloma Model Despite Fratricide Of Cd8+Cs1 Expressing Car-T Cells, Julie O'Neal, Julie K Ritchey, Matthew L Cooper, Jessica Niswonger, L Sofía González, Emily Street, Michael P Rettig, Susan W Gladney, Leah Gehrs, Ramzi Abboud, Julie L Prior, Gabriel J Haas, Reyka G Jayasinghe, Li Ding, Armin Ghobadi, Ravi Vij, John F Dipersio

2020-Current year OA Pubs

Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains - the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- …

Neuronal Origins Of Reduced Accuracy And Biases In Economic Choices Under Sequential Offers, Weikang Shi, Sebastien Ballesta, Camillo Padoa-Schioppa

2020-Current year OA Pubs

Economic choices are characterized by a variety of biases. Understanding their origins is a long-term goal for neuroeconomics, but progress on this front has been limited. Here, we examined choice biases observed when two goods are offered sequentially. In the experiments, rhesus monkeys chose between different juices offered simultaneously or in sequence. Choices under sequential offers were less accurate (higher variability). They were also biased in favor of the second offer (order bias) and in favor of the preferred juice (preference bias). Analysis of neuronal activity recorded in the orbitofrontal cortex revealed that these phenomena emerged at different computational stages. …

Collaboration Networks Of The Implementation Science Centers For Cancer Control: A Social Network Analysis, Rebekah R Jacob, Ariella R Korn, Grace C Huang, Douglas Easterling, Daniel A Gundersen, Shoba Ramanadhan, Thuy Vu, Heather Angier, Ross C Brownson, Debra Haire-Joshu, April Y Oh, Robert Schnoll

2020-Current year OA Pubs

BACKGROUND: Multi-center research initiatives offer opportunities to develop and strengthen connections among researchers. These initiatives often have goals of increased scientific collaboration which can be examined using social network analysis.

METHODS: The National Cancer Institute (NCI)-funded Implementation Science Centers in Cancer Control (ISC

RESULTS: Of the 192 invitees, 182 network members completed the survey (95%). The most prevalent roles were faculty (60%) and research staff (24%). Almost one-quarter (23%) of members reported advanced expertise in IS, 42% intermediate, and 35% beginner. Most members were female (69%) and white (79%). One-third (33%) of collaboration ties were among members from different centers. …

Washu Epigenome Browser Update 2022, Daofeng Li, Deepak Purushotham, Jessica K Harrison, Silas Hsu, Xiaoyu Zhuo, Changxu Fan, Shane Liu, Vincent Xu, Samuel Chen, Jason Xu, Shinyi Ouyang, Angela S Wu, Ting Wang

2020-Current year OA Pubs

WashU Epigenome Browser (https://epigenomegateway.wustl.edu/browser/) is a web-based genomic data exploration tool that provides visualization, integration, and analysis of epigenomic datasets. The newly renovated user interface and functions have enabled researchers to engage with the browser and genomic data more efficiently and effectively since 2018. Here, we introduce a new integrated panel design in the browser that allows users to interact with 1D (genomic features), 2D (such as Hi-C), 3D (genome structure), and 4D (time series) data in a single web page. The browser can display three-dimensional chromatin structures with the 3D viewer module. The 4D tracks, called 'Dynamic' tracks, animatedly …

Revisiting Concepts Of Evidence In Implementation Science, Ross C Brownson, Rachel C Shelton, Elvin H Geng, Russell E Glasgow

2020-Current year OA Pubs

BACKGROUND: Evidence, in multiple forms, is a foundation of implementation science. For public health and clinical practice, evidence includes the following: type 1 evidence on etiology and burden; type 2 evidence on effectiveness of interventions; and type 3: evidence on dissemination and implementation (D&I) within context. To support a vision for development and use of evidence in D&I science that is more comprehensive and equitable (particularly for type 3 evidence), this article aims to clarify concepts of evidence, summarize ongoing debates about evidence, and provide a set of recommendations and tools/resources for addressing the "how-to" in filling evidence gaps most …

Vcp Suppresses Proteopathic Seeding In Neurons, Jiang Zhu, Sara Pittman, Dhruva Dhavale, Jessica N Patterson, Mohamed Salman Kaleelurrrahuman, William J Buscher, Paul Kotzbauer, Albert A Davis, Conrad Weihl, Et Al.

2020-Current year OA Pubs

BACKGROUND: Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43.

METHODS: We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary …

Acute And Persistent Effects Of Commonly Used Antibiotics On The Gut Microbiome And Resistome In Healthy Adults, Winston E Anthony, Bin Wang, Kimberley V Sukhum, Alaric W D'Souza, Tiffany Hink, Candice Cass, Sondra Seiler, Kimberly A Reske, Christopher Coon, Erik R Dubberke, Carey-Ann D Burnham, Gautam Dantas, Jennie H Kwon

2020-Current year OA Pubs

Antibiotics are deployed against bacterial pathogens, but their targeting of conserved microbial processes means they also collaterally perturb the commensal microbiome. To understand acute and persistent effects of antibiotics on the gut microbiota of healthy adult volunteers, we quantify microbiome dynamics before, during, and 6 months after exposure to 4 commonly used antibiotic regimens. We observe an acute decrease in species richness and culturable bacteria after antibiotics, with most healthy adult microbiomes returning to pre-treatment species richness after 2 months, but with an altered taxonomy, resistome, and metabolic output, as well as an increased antibiotic resistance burden. Azithromycin delays the …

Selective Hypermethylation Is Evident In Small Intestine Samples From Infants With Necrotizing Enterocolitis, Misty Good, Tianjiao Chu, Patricia Shaw, Lila S Nolan, Joseph Wrobleski, Carlos Castro, Qingqing Gong, Olivia Dewitt, David N Finegold, David Peters

2020-Current year OA Pubs

OBJECTIVE: Necrotizing enterocolitis (NEC) is the most common and lethal gastrointestinal disease affecting preterm infants. NEC develops suddenly and is characterized by gut barrier destruction, an inflammatory response, intestinal necrosis and multi-system organ failure. There is currently no method for early NEC detection, and the pathogenesis of NEC remains unclear.

DESIGN: To further understand the molecular mechanisms that support NEC, we used solution phase hybridization and next-generation DNA sequencing of bisulfite converted DNA to perform targeted genome-wide analysis of DNA methylation at high read depth.

RESULTS: We found that ileal samples from surgical NEC infants (n = 5) exist in …

An Imaging Biomarker Of Tumor-Infiltrating Lymphocytes To Risk-Stratify Patients With Hpv-Associated Oropharyngeal Cancer, Germán Corredor, Wade Thorstad, Et Al.

2020-Current year OA Pubs

BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has excellent control rates compared to nonvirally associated OPSCC. Multiple trials are actively testing whether de-escalation of treatment intensity for these patients can maintain oncologic equipoise while reducing treatment-related toxicity. We have developed OP-TIL, a biomarker that characterizes the spatial interplay between tumor-infiltrating lymphocytes (TILs) and surrounding cells in histology images. Herein, we sought to test whether OP-TIL can segregate stage I HPV-associated OPSCC patients into low-risk and high-risk groups and aid in patient selection for de-escalation clinical trials.

METHODS: Association between OP-TIL and patient outcome was explored on whole slide …

Quality Of Life Impact And Recovery After Ureteroscopy And Stent Insertion: Insights From Daily Surveys In Stents, Jonathan D Harper, Alana C Desai, Jodi A Antonelli, Gregory E Tasian, Justin B Ziemba, Hussein R Al-Khalidi, H Henry Lai, Naim M Maalouf, Peter P Reese, Hunter B Wessells, Ziya Kirkali, Charles D Scales, Niddk Urinary Stone Disease Research Network (Usdrn)

2020-Current year OA Pubs

BACKGROUND: Our objective was to describe day-to-day evolution and variations in patient-reported stent-associated symptoms (SAS) in the STudy to Enhance uNderstanding of sTent-associated Symptoms (STENTS), a prospective multicenter observational cohort study, using multiple instruments with conceptual overlap in various domains.

METHODS: In a nested cohort of the STENTS study, the initial 40 participants having unilateral ureteroscopy (URS) and stent placement underwent daily assessment of self-reported measures using the Brief Pain Inventory short form, Patient-Reported Outcome Measurement Information System measures for pain severity and pain interference, the Urinary Score of the Ureteral Stent Symptom Questionnaire, and Symptoms of Lower Urinary Tract …

Left Ventricular Hypertrophy And Biomarkers Of Cardiac Damage And Stress In Aortic Stenosis, Elliot J Stein, Nishath Quader, Alan Zajarias, Anna Vatterott, Et Al

2020-Current year OA Pubs

Background Left ventricular hypertrophy (LVH) is associated with increased mortality risk and rehospitalization after transcatheter aortic valve replacement among those with severe aortic stenosis. Whether cardiac troponin (cTnT) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) risk stratify patients with aortic stenosis and without LVH is unknown. Methods and Results In a multicenter prospective registry of 923 patients with severe aortic stenosis undergoing transcatheter aortic valve replacement, we included 674 with core-laboratory-measured LV mass index, cTnT, and NT-proBNP. LVH was defined by sex-specific guideline cut-offs and elevated biomarker levels were based on age and sex cut-offs. Adjusted Cox proportional hazards models evaluated …

Implementing A New Emergency Department: A Qualitative Study Of Health Professionals' Change Responses And Perceptions, Nina Thórný Stefánsdóttir, Per Nilsen, Mette Bendtz Lindstroem, Ove Andersen, Byron J Powell, Tine Tjørnhøj-Thomsen, Jeanette Wassar Kirk

2020-Current year OA Pubs

BACKGROUND: The aim of the study is two-fold. It explores how managers and key employees at the Emergency Department (ED) and specialist departments in a university hospital in the Capital Region of Denmark respond to the planned change to a new ED, and how they perceive the change involved in the implementation of the new ED. The study investigates what happens when health professionals are confronted with implementation of policy that changes their organization and everyday work lives. Few studies provide in-depth investigations of health professionals' reactions to the implementation of new EDs, and particularly how they influence the implementation …

Neutralizing Antibodies Protect Mice Against Venezuelan Equine Encephalitis Virus Aerosol Challenge, Natasha M Kafai, Soila Sukupolvi-Petty, Jaclyn Liu, Samantha Mackin, Arthur S Kim, Ana Jung, Lindsay Droit, Scott A Handley, Michael S Diamond, Et Al.

2020-Current year OA Pubs

Venezuelan equine encephalitis virus (VEEV) remains a risk for epidemic emergence or use as an aerosolized bioweapon. To develop possible countermeasures, we isolated VEEV-specific neutralizing monoclonal antibodies (mAbs) from mice and a human immunized with attenuated VEEV strains. Functional assays and epitope mapping established that potently inhibitory anti-VEEV mAbs bind distinct antigenic sites in the A or B domains of the E2 glycoprotein and block multiple steps in the viral replication cycle including attachment, fusion, and egress. A 3.2-Å cryo-electron microscopy reconstruction of VEEV virus-like particles bound by a human Fab suggests that antibody engagement of the B domain may …

Hoil1 Regulates Group 2 Innate Lymphoid Cell Numbers And Type 2 Inflammation In The Small Intestine, Matthew J Wood, Jeffrey N Marshall, Victoria L Hartley, Ta-Chiang Liu, Kazuhiro Iwai, Thaddeus S Stappenbeck, Donna A Macduff

2020-Current year OA Pubs

Patients with mutations in HOIL1 experience a complex immune disorder including intestinal inflammation. To investigate the role of HOIL1 in regulating intestinal inflammation, we employed a mouse model of partial HOIL1 deficiency. The ileum of HOIL1-deficient mice displayed features of type 2 inflammation including tuft cell and goblet cell hyperplasia, and elevated expression of Il13, Il5 and Il25 mRNA. Inflammation persisted in the absence of T and B cells, and bone marrow chimeric mice revealed a requirement for HOIL1 expression in radiation-resistant cells to regulate inflammation. Although disruption of IL-4 receptor alpha (IL4Rα) signaling on intestinal epithelial cells ameliorated tuft …

Clinical Outcomes From The Assessing Donor-Derived Cell-Free Dna Monitoring Insights Of Kidney Allografts With Longitudinal Surveillance (Admiral) Study, Lihong Bu, Haris Murad, Tarek Alhamad, Et Al.

2020-Current year OA Pubs

The use of routine monitoring of donor-derived cell-free DNA (dd-cfDNA) after kidney transplant may allow clinicians to identify subclinical allograft injury and intervene prior to development of clinically evident graft injury. To evaluate this, data from 1092 kidney transplant recipients monitored for dd-cfDNA over a three-year period was analyzed to assess the association of dd-cfDNA with histologic evidence of allograft rejection. Elevation of dd-cfDNA (0.5% or more) was significantly correlated with clinical and subclinical allograft rejection. dd-cfDNA values of 0.5% or more were associated with a nearly three-fold increase in risk development of de novo donor-specific antibodies (hazard ratio 2.71) …