Medicine and Health Sciences Commons^™

Rapid And Accurate Remethylation Of Dna In Dnmt3a- Deficient Hematopoietic Cells With Restoration Of Dnmt3a Activity, Yang Li, Haley J Abel, Michelle Cai, Taylor A Lavalle, Tiankai Yin, Nichole M Helton, Amanda M Smith, Christopher A Miller, Timothy J Ley

2020-Current year OA Pubs

Here, we characterize the DNA methylation phenotypes of bone marrow cells from mice with hematopoietic deficiency of

Semaglutide Improves Metabolic Dysfunction-Associated Steatohepatitis: A 10-Year Retrospective Study, Parth Shah, Megan White, Alex Sievert, Alexander Conway, Adam Kneepkens, Gregory Sayuk, Mauricio Lisker-Melman, Jill Elwing

2020-Current year OA Pubs

BACKGROUND AND AIMS: Semaglutide has been studied in patients with metabolic dysfunction-associated steatohepatitis (MASH) due to potential benefit from weight loss on liver inflammation. However, preclinical studies suggest that MASH improvement may be independent of weight loss. We aim to assess the impact of semaglutide on MASH in relation to weight loss.

METHODS: This retrospective study included 420 patients with diabetes on semaglutide for at least 12 months between 2011 and 2022. Exclusion criteria were liver disease other than MASH, decompensated cirrhosis, malignancy, and bariatric surgery. Primary endpoints were clinically significant improvements in AST or ALT (mean difference > 6.3 U/L …

"We Need A Little Strength As Well": Examining The Social Context Of Informal Caregivers For Black Women With Breast Cancer, Tess Thompson, Jacquelyn Coats, Merriah Croston, Robert O Motley Jr, Vetta Sanders Thompson, Aimee S James, Lashaune P Johnson

2020-Current year OA Pubs

BACKGROUND: Informal caregivers (e.g., partners, other family members, friends) often provide social support to Black women with breast cancer, and caregivers find both benefits and challenges in their caregiving role.

METHODS: In this qualitative study, twenty-four caregivers for Black women with breast cancer participated in focus groups and interviews. Participants responded to a brief close-ended questionnaire as well as semi-structured questions about their experiences as cancer caregivers. Demographic information was collected, and relationship satisfaction was measured by the Relationship Assessment Scale-General scale (RAS-G). Focus groups and interviews were recorded, transcribed verbatim, and coded by two independent coders. Using an iterative, …

Circadian Immunity From Bench To Bedside: A Practical Guide, Huram Mok, Elaine Ostendorf, Alex Ganninger, Avi J. Adler, Guy Hazan, Jeffrey A. Haspel

2020-Current year OA Pubs

The immune system is built to counteract unpredictable threats, yet it relies on predictable cycles of activity to function properly. Daily rhythms in immune function are an expanding area of study, and many originate from a genetically based timekeeping mechanism known as the circadian clock. The challenge is how to harness these biological rhythms to improve medical interventions. Here, we review recent literature documenting how circadian clocks organize fundamental innate and adaptive immune activities, the immunologic consequences of circadian rhythm and sleep disruption, and persisting knowledge gaps in the field. We then consider the evidence linking circadian rhythms to vaccination, …

Current Understanding Of The Alzheimer's Disease-Associated Microbiome And Therapeutic Strategies, Dong-Oh Seo, David M Holtzman

2020-Current year OA Pubs

Alzheimer's disease (AD) is a fatal progressive neurodegenerative disease. Despite tremendous research efforts to understand this complex disease, the exact pathophysiology of the disease is not completely clear. Recently, anti-Aβ antibodies have been shown to remove amyloid from the brain and slow the clinical progression of mild dementia by ~30%. However, exploring alternative strategies is crucial to understanding and developing more effective therapeutic interventions. In recent years, the microbiota-gut-brain axis has received significant attention in the AD field. Numerous studies have suggested that alterations in the gut microbiota composition are associated with the progression of AD, and several underlying mechanisms …

The Bethesda Ercp Skills Assessment Tool (Besat) Can Reliably Differentiate Endoscopists Of Different Experience Levels, Kevin Liu, Vladimir Kushnir, Et Al.

2020-Current year OA Pubs

No abstract provided.

Disease Characteristics, Treatments, And Outcomes Of Patients With Pulmonary Arterial Hypertension Treated With Selexipag In Real-World Settings From The Sphere Registry (Selexipag: The Users Drug Registry), Vallerie Mclaughlin, Harrison W Farber, Kristin B Highland, Anna R Hemnes, Murali M Chakinala, Kelly M Chin, Michelle Han, Michelle Cho, Tobore Tobore, Mohammad Rahman, Nick H Kim

2020-Current year OA Pubs

BACKGROUND: Selexipag is an oral prostacyclin receptor agonist, indicated for pulmonary arterial hypertension to delay disease progression and reduce the risk of pulmonary arterial hypertension-related hospitalization. SelexiPag: tHe usErs dRug rEgistry (NCT03278002) was a US-based, prospective, real-world registry of selexipag-treated patients.

METHODS: Adults with pulmonary hypertension (enrolled 2016-2020) prescribed selexipag were followed for ≤18 months, with data collected at routine clinic visits. Patients were defined as newly or previously initiated if they had started selexipag ≤60 days or >60 days, respectively, before enrollment.

RESULTS: The registry included 829 patients (430 newly initiated, 399 previously initiated; 759 with pulmonary arterial hypertension), …

Pycallingcards: An Integrated Environment For Visualizing, Analyzing, And Interpreting Calling Cards Data, Juanru Guo, Wenjin Zhang, Xuhua Chen, Allen Yen, Lucy Chen, Christian A Shively, Daofeng Li, Ting Wang, Joseph D Dougherty, Robi D Mitra

2020-Current year OA Pubs

MOTIVATION: Unraveling the transcriptional programs that control how cells divide, differentiate, and respond to their environments requires a precise understanding of transcription factors' (TFs) DNA-binding activities. Calling cards (CC) technology uses transposons to capture transient TF binding events at one instant in time and then read them out at a later time. This methodology can also be used to simultaneously measure TF binding and mRNA expression from single-cell CC and to record and integrate TF binding events across time in any cell type of interest without the need for purification. Despite these advantages, there has been a lack of dedicated …

Influences Of Specialty Identity When Implementing A New Emergency Department In Denmark: A Qualitative Study, Jeanette Wassar Kirk, Mette Bendtz Lindstroem, Nina Thórný Stefánsdóttir, Ove Andersen, Byron J Powell, Per Nilsen, Tine Tjørnhøj-Thomsen

2020-Current year OA Pubs

BACKGROUND: The Danish Health Authority recommended the implementation of new types of emergency departments. Organizational changes in the hospital sector challenged the role, identity, and autonomy of medical specialists. They tend to identify with their specialty, which can challenge successful implementation of change. However, investigations on specialty identity are rare in implementation science, and how the co-existence of different specialty identities influences the implementation of new emergency departments needs to be explored for the development of tailored implementation strategies. The aim of this study was to examine how medical specialty identity influences collaboration between physicians when implementing a new emergency …

Bullous Pemphigoid With Prominent Mucosal Involvement In The Setting Of Renal Allograft Rejection, Wesley T Hodges, Ahmed H Badawi, Ilana S Rosman, Amy C Musiek, Leonid Shmuylovich

2020-Current year OA Pubs

No abstract provided.

Assessment Of Bovine Cortical Bone Fracture Behavior Using Impact Microindentation As A Surrogate Of Fracture Toughness, Babak Jahani, Rachana Vaidya, James M Jin, Donald A Aboytes, Kaitlyn S Broz, Siva Krothapalli, Bhanuteja Pujari, Walee M Baig, Simon Y Tang

2020-Current year OA Pubs

The fracture behavior of bone is critically important for evaluating its mechanical competence and ability to resist fractures. Fracture toughness is an intrinsic material property that quantifies a material's ability to withstand crack propagation under controlled conditions. However, properly conducting fracture toughness testing requires the access to calibrated mechanical load frames and the destructive testing of bone samples, and therefore fracture toughness tests are clinically impractical. Impact microindentation mimicks certain aspects of fracture toughness measurements, but its relationship with fracture toughness remains unknown. In this study, we aimed to compare measurements of notched fracture toughness and impact microindentation in fresh …

Bintrafusp Alfa With Ccrt Followed By Bintrafusp Alfa Versus Placebo With Ccrt Followed By Durvalumab In Patients With Unresectable Stage Iii Nsclc: A Phase 2 Randomized Study, Everett E Vokes, Clifford G Robinson, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Preclinical evaluation of bintrafusp alfa (BA) combined with radiotherapy revealed greater antitumor effects than BA or radiotherapy alone. In a phase 1 study, BA exhibited encouraging clinical activity in patients with stage IIIB or IV NSCLC who had received previous treatment.

METHODS: This multicenter, double-blind, controlled phase 2 study (NCT03840902) evaluated the safety and efficacy of BA with concurrent chemoradiotherapy (cCRT) followed by BA (BA group) versus placebo with cCRT followed by durvalumab (durvalumab group) in patients with unresectable stage III NSCLC. The primary end point was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 …

A 3'Utr Insertion Is A Candidate Causal Variant At The Tmem106b Locus Associated With Increased Risk For Ftld-Tdp, Augustine Chemparathy, Chengran Yang, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

BACKGROUND AND OBJECTIVES: Single-nucleotide variants near

METHODS: An exploratory analysis identified structural variants on neurodegeneration-related genes. Subsequent analyses focused on an

RESULTS: The primary analysis included 432 participants (52.5% female, age range 45-92 years). We identified a 316 bp

DISCUSSION: We identified a novel

Multiomic Profiling Reveals Metabolic Alterations Mediating Aberrant Platelet Activity And Inflammation In Myeloproliferative Neoplasms, Fan He, Angelo Ba Laranjeira, Tim Kong, Shuyang Lin, Katrina J. Ashworth, Alice Liu, Nina M. Lasky, Daniel Ac Fisher, Maggie J. Cox, Mary C. Fulbright, Lilian Antunes-Heck, Layow Yu, Molly Brakhane, Bei Gao, Stephen M. Sykes, Angelo D'Alessandro, Jorge Di Paola, Stephen T. Oh

2020-Current year OA Pubs

Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single-cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR, and oxidative phosphorylation in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation accompanied by increases in the levels of multiple intermediates of the tricarboxylic acid cycle, but lower α-ketoglutarate (α-KG) in MPN patients. Inhibition of PI3K/AKT/mTOR signaling significantly reduced metabolic responses and …

Evidence That Anemia Accelerates As Progression Via Shear-Induced Tgf-Β1 Activation: Heyde's Syndrome Comes Full Circle, Kumar Subramani, Jeffrey Bander, Sixia Chen, Mayte Suárez-Fariñas, Thamizhiniyan Venkatesan, Sandeep Subrahmanian, Rohan Varshney, Annapoorna Kini, Samin Sharma, Daniel B Rifkin, Jaehyung Cho, Barry S Coller, Jasimuddin Ahamed

2020-Current year OA Pubs

The severity of aortic stenosis (AS) is associated with acquired von Willebrand syndrome (AVWS) and gastrointestinal bleeding, leading to anemia (Heyde's syndrome). We investigated how anemia is linked with AS and AVWS using the LA100 mouse model and patients with AS. Induction of anemia in LA100 mice increased transforming growth factor (TGF)-β1 activation, AVWS, and AS progression. Patients age >75 years with severe AS had higher plasma TGF-β1 levels and more severe anemia than AS patients age <75 years, and there was a correlation between TGF-β1 and anemia. These data are compatible with the hypothesis that the blood loss anemia of Heyde's syndrome contributes to AS progression via WSS-induced activation of platelet TGF-β1 and additional gastrointestinal bleeding via WSS-induced AVWS.

Structural Biases In Disordered Proteins Are Prevalent In The Cell, David Moses, Karina Guadalupe, Feng Yu, Eduardo Flores, Anthony R Perez, Ralph Mcanelly, Nora M Shamoon, Gagandeep Kaur, Estefania Cuevas-Zepeda, Andrea D Merg, Erik W Martin, Alex S Holehouse, Shahar Sukenik

2020-Current year OA Pubs

Intrinsically disordered proteins and protein regions (IDPs) are prevalent in all proteomes and are essential to cellular function. Unlike folded proteins, IDPs exist in an ensemble of dissimilar conformations. Despite this structural plasticity, intramolecular interactions create sequence-specific structural biases that determine an IDP ensemble's three-dimensional shape. Such structural biases can be key to IDP function and are often measured in vitro, but whether those biases are preserved inside the cell is unclear. Here we show that structural biases in IDP ensembles found in vitro are recapitulated inside human-derived cells. We further reveal that structural biases can change in a sequence-dependent …

Children's Neural Reactivity To Maternal Praise And Criticism: Associations With Early Depressive Symptoms And Maternal Depression, Matthew R J Vandermeer, Pan Liu, Ola Mohamed Ali, Andrew R Daoust, Marc F Joanisse, Deanna M Barch, Elizabeth P Hayden

2020-Current year OA Pubs

Caregiving experiences are implicated in children's depression risk; however, children's neural reactivity to positive and negative feedback from mothers, a potential mediator of depression risk, is poorly understood. In a sample of 81 children (

Longitudinal Predictors Of Health-Related Quality Of Life In Isolated Dystonia, Johanna Junker, Joel S Perlmutter, Et Al.

2020-Current year OA Pubs

OBJECTIVE: To determine longitudinal predictors of health-related quality of life (HR-QoL) in an international multicenter cohort of patients with isolated dystonia.

METHODS: Out of 603 dystonia patients prospectively enrolled in the Natural History Dystonia Coalition study, 155 were assessed three times within 2 years for HR-QoL, symptoms of depression, generalized anxiety disorder (GAD), and social anxiety disorder (SAD), as well as dystonia severity and dystonic tremor. In addition, the impact of botulinum neurotoxin (BoNT) injections on HR-QoL was evaluated after 1 year.

RESULTS: Depressive symptoms at baseline predicted lower HR-QoL on all subscales after 2 years (all p ≤ 0.001). …

The Impact Of Patterns In Linkage Disequilibrium And Sequencing Quality On The Imprint Of Balancing Selection, Tristan J Hayeck, Yang Li, Timothy L Mosbruger, Jonathan P Bradfield, Adam G Gleason, George Damianos, Grace Tzun-Wen Shaw, Jamie L Duke, Laura K Conlin, Tychele N Turner, Marcelo A Fernández-Viña, Mahdi Sarmady, Dimitri S Monos

2020-Current year OA Pubs

Regions under balancing selection are characterized by dense polymorphisms and multiple persistent haplotypes, along with other sequence complexities. Successful identification of these patterns depends on both the statistical approach and the quality of sequencing. To address this challenge, at first, a new statistical method called LD-ABF was developed, employing efficient Bayesian techniques to effectively test for balancing selection. LD-ABF demonstrated the most robust detection of selection in a variety of simulation scenarios, compared against a range of existing tests/tools (Tajima's D, HKA, Dng, BetaScan, and BalLerMix). Furthermore, the impact of the quality of sequencing on detection of balancing selection was …

Outcomes Of Ceftriaxone Compared With Cefazolin Or Nafcillin/Oxacillin For Outpatient Therapy For Methicillin-Sensitive Staphylococcus Aureus Bloodstream Infections: Results From A Large United States Claims Database, Yasir Hamad, Katelin B Nickel, Margaret A Olsen, Ige A George

2020-Current year OA Pubs

BACKGROUND: Ceftriaxone is a convenient option for methicillin-sensitive

METHODS: In this retrospective cohort, a large insurance claims database was queried from 2010 to 2018 for adults with MSSA bloodstream infection (BSI). Patients discharged on OPAT on cefazolin or oxacillin/nafcillin were compared with ceftriaxone with respect to 90-day hospital readmission with the same infection category and 90-day all-cause readmission using logistic regression models.

RESULTS: Of 1895 patients with MSSA BSI, 1435 (75.7%) patients received cefazolin, oxacillin, or nafcillin and 460 (24.3%) ceftriaxone. Readmission due to the same infection category occurred in 366 (19.3%), and all-cause readmission occurred in 535 (28.3%) within …

Quantification Of Enteric Dysfunction In Cystic Fibrosis: Inter- And Intraindividual Variability, Laura A Duckworth, Kimberly A Sutton, Nurmohammad Shaikh, Jinli Wang, Carla Hall-Moore, Lori R Holtz, Phillip I Tarr, Ronald C Rubenstein

2020-Current year OA Pubs

OBJECTIVES: To test the utility of various biomarkers as indicators of gut dysfunction in cystic fibrosis (CF) and determine whether intraindividual variations in these measures are repeatable over short intervals and whether interindividual variations correlate with clinical outcomes.

STUDY DESIGN: We performed a cross-sectional, limited longitudinal study of children with CF aged 1-21 years who provided blood and stool samples at 2 or 3 visits, 2 weeks and 3 months apart, which were assayed for markers of intestinal inflammation (fecal calprotectin [fCal], lipocalin-2 [fLcn2], neopterin), and permeability (plasma lipopolysaccharide [LPS] antibodies, LPS-binding protein) by enzyme immunoassays. Control specimens were obtained …

Legionella Pneumophila Usurps Host Cell Lipids For Vacuole Expansion And Bacterial Growth, Soma Ghosh, Saumya Bandyopadhyay, Danielle M. Smith, Sangeeta Adak, Clay F. Semenkovich, Laszlo Nagy, Michael J. Wolfgang, Tamara J. O'Connor

2020-Current year OA Pubs

Vacuolar pathogens reside in membrane-bound compartments within host cells. Maintaining the integrity of this compartment is paramount to bacterial survival and replication as it protects against certain host surveillance mechanisms that function to eradicate invading pathogens. Preserving this compartment during bacterial replication requires expansion of the vacuole membrane to accommodate the increasing number of bacteria, and yet, how this is accomplished remains largely unknown. Here, we show that the vacuolar pathogen Legionella pneumophila exploits multiple sources of host cell fatty acids, including inducing host cell fatty acid scavenging pathways, in order to promote expansion of the replication vacuole and bacteria …

Changes In Bone Marrow Fibrosis During Momelotinib Or Ruxolitinib Therapy Do Not Correlate With Efficacy Outcomes In Patients With Myelofibrosis, Stephen T Oh, Et Al.

2020-Current year OA Pubs

Bone marrow fibrosis (BMF) is a pathological feature of myelofibrosis, with higher grades associated with poor prognosis. Limited data exist on the association between outcomes and BMF changes. We present BMF data from Janus kinase (JAK) inhibitor-naive patients from SIMPLIFY-1 (NCT01969838), a double-blind, randomized, phase 3 study of momelotinib vs ruxolitinib. Baseline and week 24 bone marrow biopsies were graded from 0 to 3 as per World Health Organization criteria. Other assessments included Total Symptom Score, spleen volume, transfusion independence status, and hemoglobin levels. Paired samples were available from 144 and 160 patients randomized to momelotinib and ruxolitinib. With momelotinib …

Core Requirements Of Frailty Screening In The Emergency Department: An International Delphi Consensus Study, Elizabeth Moloney, Christopher R Carpenter, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Frailty is associated with adverse outcomes among patients attending emergency departments (EDs). While multiple frailty screens are available, little is known about which variables are important to incorporate and how best to facilitate accurate, yet prompt ED screening. To understand the core requirements of frailty screening in ED, we conducted an international, modified, electronic two-round Delphi consensus study.

METHODS: A two-round electronic Delphi involving 37 participants from 10 countries was undertaken. Statements were generated from a prior systematic review examining frailty screening instruments in ED (logistic, psychometric and clinimetric properties). Reflexive thematic analysis generated a list of 56 statements …

Mousevuer: Video Based Open-Source System For Laboratory Mouse Home-Cage Monitoring, Ghadi Salem, Niall Cope, Marcial Garmendia, Alex Pu, Abhishek Somenhalli, Jonathan Krynitsky, Noah Cubert, Thomas Jones, George Dold, Anthony Fletcher, Alexxai Kravitz, Thomas Pohida, John Dennis

2020-Current year OA Pubs

Video monitoring of mice in the home-cage reveals behavior profiles without the disruptions caused by specialized test setups and makes it possible to quantify changes in behavior patterns continually over long time frames. Several commercial home-cage monitoring systems are available with varying costs and capabilities; however there are currently no open-source systems for home-cage monitoring. We present an open-source system for top-down video monitoring of research mice in a slightly modified home-cage. The system is designed for integration with Allentown NexGen ventilated racks and allows unobstructed view of up to three mice, but can also be operated outside the rack. …

Epidemiology And Preventability Of Hospital-Onset Bacteremia And Fungemia In 2 Hospitals In India, Sumanth Gandra, Dorothy Sinclair, Dustin Stwalley, Jacaranda Van Rheenen, David K Warren, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Studies evaluating the incidence, source, and preventability of hospital-onset bacteremia and fungemia (HOB), defined as any positive blood culture obtained after 3 calendar days of hospital admission, are lacking in low- and middle-income countries (LMICs).

DESIGN, SETTING, AND PARTICIPANTS: All consecutive blood cultures performed for 6 months during 2020-2021 in 2 hospitals in India were reviewed to assess HOB and National Healthcare Safety Network (NHSN) reportable central-line-associated bloodstream infection (CLABSI) events. Medical records of a convenience sample of 300 consecutive HOB events were retrospectively reviewed to determine source and preventability. Univariate and multivariable logistic regression analyses were performed to …

Control Intervention Design For Preclinical And Clinical Trials: Consensus-Based Core Recommendations From The Third Stroke Recovery And Rehabilitation Roundtable, Kathryn S Hayward, Emily J Dalton, Jessica Barth, Marian Brady, Leora R Cherney, Leonid Churilov, Andrew N Clarkson, Jesse Dawson, Sean P Dukelow, Peter Feys, Maree Hackett, Steve R Zeiler, Catherine E Lang

2020-Current year OA Pubs

Control comparator selection is a critical trial design issue. Preclinical and clinical investigators who are doing trials of stroke recovery and rehabilitation interventions must carefully consider the appropriateness and relevance of their chosen control comparator as the benefit of an experimental intervention is established relative to a comparator. Establishing a strong rationale for a selected comparator improves the integrity of the trial and validity of its findings. This Stroke Recovery and Rehabilitation Roundtable (SRRR) taskforce used a graph theory voting system to rank the importance and ease of addressing challenges during control comparator design. "Identifying appropriate type of control" was …

Surgically Implanted Endovascular, Microaxial Left Ventricular Assist Device: A Single Institution Study, Erin M Schumer, Yun Zhu Bai, Kunal D Kotkar, M Faraz Masood, Akinobu Itoh, Joel D Schilling, Gregory A Ewald, Marci S Damiano, Irene Fischer, Tsuyoshi Kaneko, Ralph J Damiano, Amit Pawale

2020-Current year OA Pubs

OBJECTIVE: The Impella 5.5 (Abiomed, Inc), a surgically implanted endovascular microaxial left ventricular assist device, is increasingly used worldwide and there have been more than 10,000 implants. The purpose of this study is to describe a large-volume, single-center experience with the use of the Impella 5.5.

METHODS: Data were obtained retrospectively from patients supported with the Impella 5.5 implanted at our institution from May 1, 2020, to December 31, 2022. Demographic, operative, and postoperative outcomes for each group are described. Results are reported in median (interquartile range) or n (%). The entire cohort was divided into 5 main groups based …

Fertility Management In Cystinosis: A Clinical Perspective, Craig B Langman, Rowena B Delos Santos, Cybele Ghossein, Andrea M Atherton, Elena N Levtchenko, Aude Servais

2020-Current year OA Pubs

Cystinosis is a rare, inherited, lysosomal storage disorder characterized by the progressive accumulation of intralysosomal cystine and subsequent organ and tissue damage. The kidneys are the first and most severely impacted organ. Although cystinosis was once considered a fatal pediatric disease, patients with cystinosis are living well into adulthood with advances in medical care, including kidney transplant and early and continuous use of cysteamine therapy. This increase in life expectancy has revealed an extrarenal phenotype of cystinosis that emerges in adolescence and adulthood, affecting nearly all body systems, including the endocrine and reproductive systems. As individuals with cystinosis are planning …

Conditional Hepatocyte Ablation Of Pdia1 Uncovers Indispensable Roles In Both Apob And Mttp Folding To Support Vldl Secretion, Zhouji Chen, Shiyu Wang, Anita Pottekat, Alec Duffey, Insook Jang, Benny H Chang, Jaehyung Cho, Brian N Finck, Nicholas O Davidson, Randal J Kaufman

2020-Current year OA Pubs

OBJECTIVES: The assembly and secretion of hepatic very low-density lipoprotein (VLDL) plays pivotal roles in hepatic and plasma lipid homeostasis. Protein disulfide isomerase A1 (PDIA1/P4HB) is a molecular chaperone whose functions are essential for protein folding in the endoplasmic reticulum. Here we investigated the physiological requirement in vivo for PDIA1 in maintaining VLDL assembly and secretion.

METHODS: Pdia1/P4hb was conditionally deleted in adult mouse hepatocytes and the phenotypes characterized. Mechanistic analyses in primary hepatocytes determined how PDIA1 ablation alters MTTP synthesis and degradation as well as altering synthesis and secretion of Apolipoprotein B (APOB), along with complementary expression of intact …