Medicine and Health Sciences Commons^™

Shared And Unique Heritability Of Hippocampal Subregion Volumes In Children And Adults, Jacob G Pine, Arpana Agrawal, Ryan Bogdan, Sridhar Kandala, Shelly Cooper, Deanna M Barch

2020-Current year OA Pubs

Behavioral genetic analyses have not demonstrated robust, unique, genetic correlates of hippocampal subregion volume. Genetic differentiation of hippocampal longitudinal axis subregion volume has not yet been investigated in population-based samples, although this has been demonstrated in rodent and post-mortem human tissue work. The following study is the first population-based investigation of genetic factors that contribute to gray matter volume along the hippocampal longitudinal axis. Twin-based biometric analyses demonstrated that longitudinal axis subregions are associated with significant, unique, genetic variance, and that longitudinal axis subregions are also associated with significant shared, hippocampus-general, genetic factors. Our study's findings suggest that genetic differences …

The Response Of Dual-Leucine Zipper Kinase (Dlk) To Nocodazole: Evidence For A Homeostatic Cytoskeletal Repair Mechanism, Laura Devault, Chase Mateusiak, John Palucki, Michael Brent, Jeffrey Milbrandt, Aaron Diantonio

2020-Current year OA Pubs

Genetic and pharmacological perturbation of the cytoskeleton enhances the regenerative potential of neurons. This response requires Dual-leucine Zipper Kinase (DLK), a neuronal stress sensor that is a central regulator of axon regeneration and degeneration. The damage and repair aspects of this response are reminiscent of other cellular homeostatic systems, suggesting that a cytoskeletal homeostatic response exists. In this study, we propose a framework for understanding DLK mediated neuronal cytoskeletal homeostasis. We demonstrate that low dose nocodazole treatment activates DLK signaling. Activation of DLK signaling results in a DLK-dependent transcriptional signature, which we identify through RNA-seq. This signature includes genes likely …

Shared Decision-Making During Virtual Care Regarding Rheumatologic And Chronic Conditions: Qualitative Study Of Benefits, Pitfalls, And Optimization, Lisa Zickuhr, Catherine Mccarthy, Emma Nolan-Thomas, Tiffany Westrich-Robertson, Elizabeth A Baker, Janice L Hanson

2020-Current year OA Pubs

OBJECTIVE: Virtual care (VC) is an accepted modality of care delivery, and shared decision-making (SDM) benefits patients with rheumatologic and chronic conditions (RCCs). Unfortunately, research suggests reduced quality of SDM during VC. This study explores the benefits and shortcomings of SDM regarding RCCs during VC with suggestions for optimally using VC during SDM.

METHODS: Following Stiggelbout's framework for SDM, we conducted focus groups of patients with RCCs and providers to understand their experiences with SDM during VC, probing for facilitating and challenging factors. We conducted content analysis of the transcripts, defining themes, and inductively reasoned to identify relationships among themes. …

Arid1a Loss Is Associated With Increased Nrf2 Signaling In Human Head And Neck Squamous Cell Carcinomas, Vinh Nguyen, Travis P. Schrank, Michael B. Major, Bernard E. Weissman

2020-Current year OA Pubs

Prior to the next generation sequencing and characterization of the tumor genome landscape, mutations in the SWI/SNF chromatin remodeling complex and the KEAP1-NRF2 signaling pathway were underappreciated. While these two classes of mutations appeared to independently contribute to tumor development, recent reports have demonstrated a mechanistic link between these two regulatory mechanisms in specific cancer types and cell models. In this work, we expand upon these data by exploring the relationship between mutations in BAF and PBAF subunits of the SWI/SNF complex and activation of NRF2 signal transduction across many cancer types. ARID1A/B mutations were strongly associated with NRF2 transcriptional …

Comparison Of Cerebrospinal Fluid, Plasma And Neuroimaging Biomarker Utility In Alzheimer's Disease, Karin L Meeker, Patrick H Luckett, Nicolas R Barthélemy, Diana A Hobbs, Charles Chen, James Bollinger, Vitaliy Ovod, Shaney Flores, Sarah Keefe, Rachel L Henson, Elizabeth M Herries, Eric Mcdade, Jason J Hassenstab, Chengjie Xiong, Carlos Cruchaga, Tammie L S Benzinger, David M Holtzman, Suzanne E Schindler, Randall J Bateman, John C Morris, Brian A Gordon, Beau M Ances

2020-Current year OA Pubs

Alzheimer's disease biomarkers are crucial to understanding disease pathophysiology, aiding accurate diagnosis and identifying target treatments. Although the number of biomarkers continues to grow, the relative utility and uniqueness of each is poorly understood as prior work has typically calculated serial pairwise relationships on only a handful of markers at a time. The present study assessed the cross-sectional relationships among 27 Alzheimer's disease biomarkers simultaneously and determined their ability to predict meaningful clinical outcomes using machine learning. Data were obtained from 527 community-dwelling volunteers enrolled in studies at the Charles F. and Joanne Knight Alzheimer Disease Research Center at Washington …

Multiple Genes Core To Erad, Macroautophagy And Lysosomal Degradation Pathways Participate In The Proteostasis Response In Α1-Antitrypsin Deficiency, Jie Li, Tunda Hidvegi, Sanja Sviben, James A J Fitzpatrick, Hemalatha Sundaramoorthi, Stephen C Pak, Gary A Silverman, David H Perlmutter, Et Al.

2020-Current year OA Pubs

BACKGROUND & AIMS: In the classic form of α1-antitrypsin deficiency (ATD), the misfolded α1-antitrypsin Z (ATZ) variant accumulates in the endoplasmic reticulum (ER) of liver cells. A gain-of-function proteotoxic mechanism is responsible for chronic liver disease in a subgroup of homozygotes. Proteostatic response pathways, including conventional endoplasmic reticulum-associated degradation and autophagy, have been proposed as the mechanisms that allow cellular adaptation and presumably protection from the liver disease phenotype. Recent studies have concluded that a distinct lysosomal pathway called endoplasmic reticulum-to-lysosome completely supplants the role of the conventional macroautophagy pathway in degradation of ATZ. Here, we used several state-of-the-art approaches …

Factors Associated With Never Treatment And Acceptability Of Mass Drug Administration For The Elimination Of Lymphatic Filariasis In Guyana, 2021, Claudia Duguay, Reza A. Niles-Robin, Charles R. Thickstun, Horace Cox, Annastacia Sampson, Jean Seme-Fils Alexandre, Nathely Caleb-Mars, Charles W. Goss, Ana Morice, Ronaldo G. Carvalho Scholte, Alison Krentel

2020-Current year OA Pubs

Guyana remains one of four countries in the Americas endemic for lymphatic filariasis (LF). Elimination of LF requires repeated annual mass drug administration (MDA) with sufficient levels of coverage for success. This study assesses the acceptability and never treatment of LF MDA using data from a routine assessment survey in 2021. A subset of individuals, over 20 years of age (n = 2498), were selected to receive an expanded questionnaire to examine factors associated with acceptability and never treatment. Assessed factors include respondent demographics, knowledge, risk perceptions of LF, and opinions on the MDA programme. The majority (73%) of those …

Microstructural Analysis Does Not Support Altered Interhemispheric Wiring Of The Human Anterior Commissure In Corpus Callosum Dysgenesis, Timothy J Edwards, Ryan J Dean, Gail A Robinson, Jacquelyn Knight, Simone A Mandelstam, Linda J Richards

2020-Current year OA Pubs

BACKGROUND: Individuals with corpus callosum dysgenesis (CCD) lack the clear disconnection syndrome that is characteristic of individuals in whom the corpus callosum has been surgically severed. One potential explanation for this paradox is that the anterior commissure undergoes neuroplastic remodeling in CCD to improve interhemispheric communication between the brain hemispheres.

METHODS: A cohort of sixteen individuals with CCD (and sixteen sex and age-matched neurotypical controls) underwent multi-shell diffusion magnetic resonance high-field imaging (dMRI) at 7-Tesla to assess the anatomy of the anterior commissure for evidence of neuroplasticity.

RESULTS: No significant group-wise differences in midsagittal anterior commissure volumes were detected between …

Multi-Peptide Characterization Of Plasma Neurofilament Light Chain In Preclinical And Mild Alzheimer's Disease, John B Coulton, Yingxin He, Nicolas R Barthélemy, Hong Jiang, David M Holtzman, Randall J Bateman

2020-Current year OA Pubs

Although neurofilament light chain is a well-known marker of neuronal damage, its characterization at the proteoform level is underdeveloped. Here, we describe a new method to profile and quantify neurofilament light chain in plasma at the peptide level, using three in-house monoclonal antibodies targeting distinct protein domains and nano-liquid chromatography coupled to high-resolution tandem mass spectrometry. This study profiled and compared plasma neurofilament light chain to CSF in 102 older individuals (73.9 ± 6.3 years old), 37 of which had a clinical dementia rating greater than 0. We observed elevated neurofilament light chain in preclinical Alzheimer's disease plasma for two …

The Involvement Of The Piriform Cortex In Non-Lesional Temporal Lobe Epilepsy: An Uncommon Component Of The Epileptogenic Network, Nigel P Pedersen, Ashley Raghu, Veeresh Kumar N Shivamurthy, Joshua J Chern, Robert E Gross, Jon T Willie, Raymond J Dingledine, Ammar Kheder

2020-Current year OA Pubs

The piriform cortex is recognized as highly epileptogenic in rodents, yet its electrophysiological role in human epilepsy remains understudied. Recent surgical outcomes have suggested potential benefits in resecting the piriform cortex for cases of medial temporal lobe epilepsy. However, little is known about its electrophysiological activity in human epilepsy. This case-series study aimed to explore the electrophysiological role of the piriform cortex within the epileptogenic network among patients with suspected temporal lobe epilepsy. Participants were recruited from Emory University Hospital or Children's Healthcare of Atlanta, with non-lesional frontotemporal or temporal lobe hypotheses, undergoing stereoelectroencephalographic studies. Specifically, focus was placed on …

Mosgraphgen: A Novel Tool To Generate Multi-Omics Signaling Graphs To Facilitate Integrative And Interpretable Graph Ai Model Development, Heming Zhang, Dekang Cao, Zirui Chen, Xiuyuan Zhang, Yixin Chen, Cole Sessions, Carlos Cruchaga, Philip Payne, Guangfu Li, Michael Province, Fuhai Li

2020-Current year OA Pubs

MOTIVATION: Multi-omics data, i.e. genomics, epigenomics, transcriptomics, proteomics, characterize cellular complex signaling systems from multi-level and multi-view and provide a holistic view of complex cellular signaling pathways. However, it remains challenging to integrate and interpret multi-omics data for mining critical biomarkers. Graph AI models have been widely used to analyze graph-structure datasets, and are ideal for integrative multi-omics data analysis because they can naturally integrate and represent multi-omics data as a biologically meaningful multi-level signaling graph and interpret multi-omics data via graph node and edge ranking analysis. Nevertheless, it is nontrivial for graph-AI model developers to pre-analyze multi-omics data and …