Medicine and Health Sciences Commons^™

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 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 …

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 …

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 …

Optimal Approaches To Analyzing Functional Mri Data In Glioma Patients, Ki Yun Park, Joshua S Shimony, Satrajit Chakrabarty, Aaron B Tanenbaum, Carl D Hacker, Kara M Donovan, Patrick H Luckett, Mikhail Milchenko, Aristeidis Sotiras, Daniel S Marcus, Eric C Leuthardt, Abraham Z Snyder

2020-Current year OA Pubs

BACKGROUND: Resting-state fMRI is increasingly used to study the effects of gliomas on the functional organization of the brain. A variety of preprocessing techniques and functional connectivity analyses are represented in the literature. However, there so far has been no systematic comparison of how alternative methods impact observed results.

NEW METHOD: We first surveyed current literature and identified alternative analytical approaches commonly used in the field. Following, we systematically compared alternative approaches to atlas registration, parcellation scheme, and choice of graph-theoretical measure as regards differentiating glioma patients (N = 59) from age-matched reference subjects (N = 163).

RESULTS: Our results …

Creation Of A National Emergency Medicine Medical Education Journal Club, Jessica Pelletier, James Ahn, Andrew Golden, Caroline Astemborski, Michelle D. Lall, Albert Kim, Sara Dimeo

2020-Current year OA Pubs

Background There are a relatively limited number of emergency medicine (EM) medical education (MedEd) fellowships with few trainees at each program, creating barriers to local collaboration and networking. While best practices for developing MedEd journal clubs exist, there has not been an established national EM MedEd journal club. To address this need, we created a national journal club, the Council of Residency Directors (CORD) MedEd Journal Club (MEJC), to facilitate collaboration and networking opportunities by providing a synchronous online journal club. Objectives Our primary objective was to create a network for collaboration across geographical barriers to form a virtual community …

Spatial And Amplitude Dynamics Of Neurostimulation: Insights From The Acute Intrahippocampal Kainate Seizure Mouse Model, Thomas J Foutz, Nicholas Rensing, Lirong Han, Dominique M Durand, Michael Wong

2020-Current year OA Pubs

OBJECTIVE: Neurostimulation is an emerging treatment for patients with drug-resistant epilepsy, which is used to suppress, prevent, and terminate seizure activity. Unfortunately, after implantation and despite best clinical practice, most patients continue to have persistent seizures even after years of empirical optimization. The objective of this study is to determine optimal spatial and amplitude properties of neurostimulation in inhibiting epileptiform activity in an acute hippocampal seizure model.

METHODS: We performed high-throughput testing of high-frequency focal brain stimulation in the acute intrahippocampal kainic acid mouse model of status epilepticus. We evaluated combinations of six anatomic targets and three stimulus amplitudes.

RESULTS: …

Serological Assays For Differentiating Natural Covid-19 Infection From Vaccine Induced Immunity, Samuel M S Cheng, Gaya K Amarasinghe, Et Al.

2020-Current year OA Pubs

BACKGROUND: Natural SARS-CoV-2 infection may elicit antibodies to a range of viral proteins including non-structural protein ORF8. RNA, adenovirus vectored and sub-unit vaccines expressing SARS-CoV-2 spike would be only expected to elicit S-antibodies and antibodies to distinct domains of nucleocapsid (N) protein may reliably differentiate infection from vaccine-elicited antibody. However, inactivated whole virus vaccines may potentially elicit antibody to wider range of viral proteins, including N protein. We hypothesized that antibody to ORF8 protein will discriminate natural infection from vaccination irrespective of vaccine type.

METHODS: We optimized and validated the anti-ORF8 and anti-N C-terminal domain (NCTD) ELISA assays using sera …

Stereotactic Mr-Guided On-Table Adaptive Radiation Therapy (Smart) For Borderline Resectable And Locally Advanced Pancreatic Cancer: A Multi-Center, Open-Label Phase 2 Study, Michael D Chuong, Hyun Kim, Lauren E Henke, Alex T Price, Et Al.

2020-Current year OA Pubs

BACKGROUND AND PURPOSE: Radiation dose escalation may improve local control (LC) and overall survival (OS) in select pancreatic ductal adenocarcinoma (PDAC) patients. We prospectively evaluated the safety and efficacy of ablative stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for borderline resectable (BRPC) and locally advanced pancreas cancer (LAPC). The primary endpoint of acute grade ≥ 3 gastrointestinal (GI) toxicity definitely related to SMART was previously published with median follow-up (FU) 8.8 months from SMART. We now present more mature outcomes including OS and late toxicity.

MATERIALS AND METHODS: This prospective, multi-center, single-arm open-label phase 2 trial (NCT03621644) enrolled 136 …

Stem Cell Modeling Of Nervous System Tumors, Frank B Furnari, Corina Anastasaki, Shan Bian, Howard A Fine, Tomoyuki Koga, Lu Q Le, Fausto J Rodriguez, David H Gutmann

2020-Current year OA Pubs

Nervous system tumors, particularly brain tumors, represent the most common tumors in children and one of the most lethal tumors in adults. Despite decades of research, there are few effective therapies for these cancers. Although human nervous system tumor cells and genetically engineered mouse models have served as excellent platforms for drug discovery and preclinical testing, they have limitations with respect to accurately recapitulating important aspects of the pathobiology of spontaneously arising human tumors. For this reason, attention has turned to the deployment of human stem cell engineering involving human embryonic or induced pluripotent stem cells, in which genetic alterations …

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 …

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 (

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 …

Public Platform With 39,472 Exome Control Samples Enables Association Studies Without Genotype Sharing, Mykyta Artomov, Alexander A Loboda, Maxim N Artyomov, Mark J Daly

2020-Current year OA Pubs

Acquiring a sufficiently powered cohort of control samples matched to a case sample can be time-consuming or, in some cases, impossible. Accordingly, an ability to leverage genetic data from control samples that were already collected elsewhere could dramatically improve power in genetic association studies. Sharing of control samples can pose significant challenges, since most human genetic data are subject to strict sharing regulations. Here, using the properties of singular value decomposition and subsampling algorithm, we developed a method allowing selection of the best-matching controls in an external pool of samples compliant with personal data protection and eliminating the need for …

A Fluid Biomarker Reveals Loss Of Tdp-43 Splicing Repression In Presymptomatic Als-Ftd, Katherine E Irwin, Timothy Miller, Et Al.

2020-Current year OA Pubs

Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs …

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). …

Mucosal Boosting Enhances Vaccine Protection Against Sars-Cov-2 In Macaques, Katherine Mcmahan, Adrianus C M Boon, Et Al.

2020-Current year OA Pubs

A limitation of current SARS-CoV-2 vaccines is that they provide minimal protection against infection with current Omicron subvariants

Aapm Medical Physics Practice Guideline 14.A: Yttrium-90 Microsphere Radioembolization, Nathan C Busse, Nichole M Maughan, Et Al.

2020-Current year OA Pubs

Radioembolization using Yttrium-90 (

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 …

Racial Differences In Treatment And Survival Among Older Patients With Multiple Myeloma, Rong Wang, Natalia Neparidze, Xiaomei Ma, Graham A Colditz, Su-Hsin Chang, Shi-Yi Wang

2020-Current year OA Pubs

BACKGROUND: Treatments for multiple myeloma (MM) have evolved over time and improved MM survival. While racial differences in MM treatment and prognosis between non-Hispanic African American (NHAA) and non-Hispanic White (NHW) patients are well-established, it is unclear whether they have persisted after the introduction of novel agents.

METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare linked database, our study investigated racial difference in the receipt of treatment within 1 year following diagnosis and assessed survival outcomes among Medicare beneficiaries (≥66 years) diagnosed with MM from 2007 to 2017. We applied multivariable Cox proportional hazards models to estimate the association between …

Caregiver Descriptions Of Dystonia In Cerebral Palsy, Fayza Jaleel, Alyssa Rust, Shirley Cheung, Toni S Pearson, Keisuke Ueda, Amy Robichaux-Viehoever, Katie Leger, Keerthana Chintalapati, Danielle Guez-Barber, Michele Shusterman, Bhooma Aravamuthan

2020-Current year OA Pubs

OBJECTIVE: To determine how caregivers describe dystonia in people with cerebral palsy (CP).

METHODS: In this prospective cohort study, paper surveys were administered to caregivers between September 7, 2021 and October 28, 2021 during CP Center visits at a large tertiary care center. Caregivers were asked to describe involuntary movements triggered by voluntary movement or triggered by tactile stimulation in the people with CP they cared for. Their CP Center medical provider separately assessed people with CP for dystonia. Movement features described exclusively by caregivers of people with CP and dystonia were determined using conventional content analysis.

RESULTS: 113 caregivers …

A Deep Learning Approach To Remove Contrast From Contrast-Enhanced Ct For Proton Dose Calculation, Xu Wang, Yao Hao, Ye Duan, Deshan Yang

2020-Current year OA Pubs

PURPOSE: Non-Contrast Enhanced CT (NCECT) is normally required for proton dose calculation while Contrast Enhanced CT (CECT) is often scanned for tumor and organ delineation. Possible tissue motion between these two CTs raises dosimetry uncertainties, especially for moving tumors in the thorax and abdomen. Here we report a deep-learning approach to generate NCECT directly from CECT. This method could be useful to avoid the NCECT scan, reduce CT simulation time and imaging dose, and decrease the uncertainties caused by tissue motion between otherwise two different CT scans.

METHODS: A deep network was developed to convert CECT to NCECT. The network …

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 …

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 …

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 …

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 …