Medicine and Health Sciences Commons^™

Methylgrapher: Genome-Graph-Based Processing Of Dna Methylation Data From Whole Genome Bisulfite Sequencing, Wenjin Zhang, Juan F Macias-Velasco, Xiaoyu Zhuo, Edward A Belter, Chad Tomlinson, John Garza, Nina Tekkey, Daofeng Li, Ting Wang

2020-Current year OA Pubs

Genome graphs, including the recently released draft human pangenome graph, can represent the breadth of genetic diversity and thus transcend the limits of traditional linear reference genomes. However, there are no genome-graph-compatible tools for analyzing whole genome bisulfite sequencing (WGBS) data. To close this gap, we introduce methylGrapher, a tool tailored for accurate DNA methylation analysis by mapping WGBS data to a genome graph. Notably, methylGrapher can reconstruct methylation patterns along haplotype paths precisely and efficiently. To demonstrate the utility of methylGrapher, we analyzed the WGBS data derived from five individuals whose genomes were included in the first Human Pangenome …

Piezo1-Mediated Mechanotransduction Regulates Collagen Synthesis On Nanostructured 2d And 3d Models Of Fibrosis, Neda Rashidi, Natalia S Harasymowicz, Alireza Savadipour, Nancy Steward, Ruhang Tang, Sara Oswald, Farshid Guilak

2020-Current year OA Pubs

Progressive fibrosis can lead to tissue malfunction and organ failure due to the pathologic accumulation of a collagen-rich extracellular matrix. In vitro models provide useful tools for deconstructing the roles of specific biomechanical or biological mechanisms, such as substrate micro- and nanoscale architecture, in these processes for identifying potential therapeutic targets. Here, we investigated how the mechanosensitive ion channel PIEZO1 influences fibrotic gene and protein expression in adipose-derived stem cells (hASCs). Specifically, we examined the role of PIEZO1 and the mechanosensitive transcription factors YAP/TAZ in sensing aligned or non-aligned substrate architecture to regulate collagen formation. We utilized both 2D microphotopatterned …

Common And Specific Gene Regulatory Programs In Zebrafish Caudal Fin Regeneration At Single-Cell Resolution, Yujie Chen, Yiran Hou, Qinglin Zeng, Irene Wang, Meiru Shang, Kwangdeok Shin, Christopher Hemauer, Xiaoyun Xing, Junsu Kang, Guoyan Zhao, Ting Wang

2020-Current year OA Pubs

Following amputation, zebrafish regenerate their injured caudal fin through lineage-restricted reprogramming. Although previous studies have charted various genetic and epigenetic dimensions of this process, the intricate gene regulatory programs shared by, or unique to, different regenerating cell types remain underinvestigated. Here, we mapped the regulatory landscape of fin regeneration by applying paired snRNA-seq and snATAC-seq on uninjured and regenerating fins. This map delineates the regulatory dynamics of predominant cell populations at multiple stages of regeneration. We observe a marked increase in the accessibility of chromatin regions associated with regenerative and developmental processes at 1 dpa, followed by a gradual closure …

Ecological Trait Differences Are Associated With Gene Expression In The Primary Visual Cortex Of Primates, Trisha M Zintel, John J Ely, Mary Ann Raghanti, William D Hopkins, Patrick R Hof, Chet C Sherwood, Jason M Kamilar, Amy L Bauernfeind, Courtney C Babbitt

2020-Current year OA Pubs

UNLABELLED: Primate species differ drastically from most other mammals in how they visually perceive their environments, which is particularly important for foraging, predator avoidance, and detection of social cues.

BACKGROUND/OBJECTIVES: Although it is well established that primates display diversity in color vision and various ecological specializations, it is not understood how visual system characteristics and ecological adaptations may be associated with gene expression levels within the primary visual cortex (V1).

METHODS: We performed RNA-Seq on V1 tissue samples from 28 individuals, representing 13 species of primates, including hominoids, cercopithecoids, and platyrrhines. We explored trait-dependent differential expression (DE) by contrasting species …

Cardiovascular Considerations After Cancer Therapy: Gaps In Evidence And Jacc: Cardiooncology Expert Panel Recommendations, Anne Blaes, Anju Nohria, Saro Armenian, Carmen Bergom, Paaladinesh Thavendiranathan, Ana Barac, Gabriela Sanchez-Petitto, Sanjal Desai, Leah L Zullig, Alicia K Morgans, Joerg Herrmann

2020-Current year OA Pubs

Cancer survivors, particularly those treated with anthracyclines and chest radiation, face an elevated risk of cancer therapy-related cardiovascular toxicity. These complications affect not only physical health, but also life expectancy. Risk factors for cancer therapy-related cardiovascular toxicity include age at which cancer treatment was received, the use of (potentially) cardiotoxic cancer therapies, and the presence of concomitant cardiovascular risk factors. Current guidelines provide recommendations for cardiovascular surveillance after cancer therapy, including type and frequency. All cancer survivors are advised to undergo annual clinical screenings and optimization of cardiovascular risk factors. Those at higher risk should undergo additional cardiovascular testing. This …

Precision Data-Driven Modeling Of Cortical Dynamics Reveals Person-Specific Mechanisms Underpinning Brain Electrophysiology, Matthew F Singh, Todd S Braver, Michael Cole, Shinung Ching

2020-Current year OA Pubs

Task-free brain activity affords unique insight into the functional structure of brain network dynamics and has been used to identify neural markers of individual differences. In this work, we present an algorithmic optimization framework that directly inverts and parameterizes brain-wide dynamical-systems models involving hundreds of interacting neural populations, from single-subject M/EEG time-series recordings. This technique provides a powerful neurocomputational tool for interrogating mechanisms underlying individual brain dynamics ("precision brain models") and making quantitative predictions. We extensively validate the models' performance in forecasting future brain activity and predicting individual variability in key M/EEG metrics. Last, we demonstrate the power of our …

Using Community Engagement To Create A Telecoaching Intervention To Improve Self-Management In Adolescents And Young Adults With Cystic Fibrosis: Qualitative Study, Christina L Duncan, Emily F Muther, Jennifer J Lindwall, Kristine Durkin, Elizabeth Ruvalcaba, Eliza Williamson, Corrine Ahrabi-Nejad, Evelyn Bord, Angela Green, Megan L Harrison, Deepika Polineni

2020-Current year OA Pubs

BACKGROUND: Adolescents and young adults (AYA) with cystic fibrosis (CF) are at risk for deviating from their daily treatment regimen due to significant time burden, complicated daily therapies, and life stressors. Developing patient-centric, effective, engaging, and practical behavioral interventions is vital to help sustain therapeutically meaningful self-management.

OBJECTIVE: This study aimed to devise and refine a patient-centered telecoaching intervention to foster self-management in AYA with CF using a combination of intervention development approaches, including an evidence- and theory-based approach (ie, applying existing theories and research evidence for behavior change) and a target population-centered approach (ie, intervention refinement based on the …

Differences In Risk Appraisal And Neural Activity In Adolescents With A History Of Misconduct, Elizabeth S Escalante, Jessica S Flannery, Michael T Perino, Eva H Telzer

2020-Current year OA Pubs

While much of the prior work examining the behavioural and neural mechanisms of adolescent risk taking has focused on community samples, less is known about whether these mechanisms apply to adolescents engaging in high levels of risky behaviour. The current study examines behavioural and neural differences between adolescents with (N = 24) and without (N = 35) a history of misconduct using a risk perception questionnaire and risk-taking fMRI task. Adolescents with a history of misconduct perceived fewer negative consequences of risk relative to positive consequences and exhibited altered neural tracking of risk and reward in the nucleus accumbens. Specifically, …

Impact Of Stain Variation And Color Normalization For Prognostic Predictions In Pathology, Siyu Lin, Haowen Zhou, Mark Watson, Ramaswamy Govindan, Richard J Cote, Changhuei Yang

2020-Current year OA Pubs

In recent years, deep neural networks (DNNs) have demonstrated remarkable performance in pathology applications, potentially even outperforming expert pathologists due to their ability to learn subtle features from large datasets. One complication in preparing digital pathology datasets for DNN tasks is the variation in tinctorial qualities. A common way to address this is to perform stain normalization on the images. In this study, we show that a well-trained DNN model trained on one batch of histological slides failed to generalize to another batch prepared at a different time from the same tissue blocks, even when stain normalization methods were applied. …

A Data-Driven Latent Variable Approach To Validating The Research Domain Criteria Framework, S K L Quah, B Jo, C Geniesse, L Q Uddin, J A Mumford, D M Barch, D A Fair, I H Gotlib, R A Poldrack, M Saggar

2020-Current year OA Pubs

Despite the widespread use of the Research Domain Criteria (RDoC) framework in psychiatry and neuroscience, recent studies suggest that the RDoC is insufficiently specific or excessively broad relative to the underlying brain circuitry it seeks to elucidate. To address these concerns, we employ a latent variable approach using bifactor analysis. We examine 84 whole-brain task-based fMRI (tfMRI) activation maps from 19 studies with 6192 participants. A curated subset of 37 maps with a balanced representation of RDoC domains constitute the training set, and the remaining held-out maps form the internal validation set. External validation is conducted using 36 peak coordinate …

Comparison Of Sampling And Culture Methods For The Recovery Of Yeast From Hospital Surfaces, Allison R Eberly, Alyssa M Valencia, Kate Peacock, David Mcdonald, Tiffany Hink, Carleigh Samuels, Lucy Vogt, Yao-Peng Xue, Maggie Newberry, Caroline A O'Neil, Gautam Dantas, Jennie H Kwon

2020-Current year OA Pubs

OBJECTIVE: To compare the recovery of yeast from hospital surfaces from two different collection methods: Eswab moistened with molecular water, and premoistened stick-mounted sponge.

DESIGN: Comparison of collection methods for the recovery of yeast in the hospital environment.

SETTING: This study took place at intensive care units of a large academic medical center.

Neutralizing Antibody Immune Correlates In Covail Trial Recipients Of An Mrna Second Covid-19 Vaccine Boost, Bo Zhang, Rachel M Presti, Et Al.

2020-Current year OA Pubs

Neutralizing antibody titer has been a surrogate endpoint for guiding COVID-19 vaccine approval and use, although the pandemic's evolution and the introduction of variant-adapted vaccine boosters raise questions as to this surrogate's contemporary performance. For 985 recipients of an mRNA second bivalent or monovalent booster containing various Spike inserts [Prototype (Ancestral), Beta, Delta, and/or Omicron BA.1 or BA.4/5] in the COVAIL trial (NCT05289037), titers against 5 strains were assessed as correlates of risk of symptomatic COVID-19 ("COVID-19") and as correlates of relative (Pfizer-BioNTech Omicron vs. Prototype) booster protection against COVID-19 over 6 months of follow-up during the BA.2-BA.5 Omicron-dominant period. …

Evolution Of The Umbilical Cord Blood Proteome Across Gestational Development, Leena B Mithal, Nicola Lancki, Ted Ling-Hu, Young Ah Goo, Sebastian Otero, Nathaniel J Rhodes, Byoung-Kyu Cho, William A Grobman, Judd F Hultquist, Denise Scholtens, Karen K Mestan, Patrick C Seed

2020-Current year OA Pubs

Neonatal health is dependent on early risk stratification, diagnosis, and timely management of potentially devastating conditions, particularly in the setting of prematurity. Many of these conditions are poorly predicted in real-time by clinical data and current diagnostics. Umbilical cord blood may represent a novel source of molecular signatures that provides a window into the state of the fetus at birth. In this study, we comprehensively characterized the cord blood proteome of infants born between 25 to 42 weeks using untargeted mass spectrometry and functional enrichment analysis. We determined that the cord blood proteome at birth varies significantly across gestational development. …

Barcoded Sars-Cov-2 Viruses Define The Impact Of Duration And Route Of Exposure On The Transmission Bottleneck In A Hamster Model, Reed Trende, Tamarand L Darling, Tianyu Gan, David Wang, Adrianus C M Boon

2020-Current year OA Pubs

The transmission bottleneck, defined as the number of viruses shed from one host to infect another, is an important determinant of the rate of virus evolution and the level of immunity required to protect against virus transmission. Despite its importance, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission bottleneck remains poorly characterized. We adapted a SARS-CoV-2 reverse genetics system to generate a pool of >200 isogenic SARS-CoV-2 viruses harboring specific 6-nucleotide barcodes, infected donor hamsters with this pool, and exposed contact hamsters to paired infected donors, varying the duration and route of exposure. Following exposure, the nasal turbinates, trachea, …

Recommendations For Interdisciplinary Research Collaboration For Early Career Dissemination And Implementation Researchers: A Multi-Phase Study, Hannah G Lane, Sallie D Allgood, Julie Schexnayder, Hayden B Bosworth, Ana A Baumann, Allison A Lewinski

2020-Current year OA Pubs

INTRODUCTION: Dissemination and implementation (D&I) scientists are key members of collaborative, interdisciplinary clinical and translational research teams. Yet, early career D&I researchers (ECRs) have few guidelines for cultivating productive research collaborations. We developed recommendations for ECRs in D&I when serving as collaborators or co-investigators.

METHODS: We employed a consensus-building approach: (1) group discussions to identify 3 areas of interest: "Marketing yourself" (describing your value to non-D&I collaborators), "Collaboration considerations

RESULTS: Forty-four D&I researchers completed the first survey, 12 of whom attended one of three focus groups. Twenty-nine D&I researchers completed the second survey (

CONCLUSIONS: Research collaborations are essential in …

Germline Predisposition In Multiple Myeloma, Fernanda Martins Rodrigues, Yize Li, Erik Storrs, Michael C Wendl, Reyka G Jayasinghe, Mark Fiala, John F Dipersio, Ravi Vij, Li Ding, Et Al.

2020-Current year OA Pubs

We present a study of rare germline predisposition variants in 954 unrelated individuals with multiple myeloma (MM) and 82 MM families. Using a candidate gene approach, we identified such variants across all age groups in 9.1% of sporadic and 18% of familial cases. Implicated genes included genes suggested in other MM risk studies as potential risk genes (

A Yeast-Based Oral Therapeutic Delivers Immune Checkpoint Inhibitors To Reduce Intestinal Tumor Burden, Olivia N Rebeck, Miranda J Wallace, Jerome Prusa, Jie Ning, Esse M Evbuomwan, Sunaina Rengarajan, Lemoyne Habimana-Griffin, Suryang Kwak, David Zahrah, Jason Tung, James Liao, Bejan Mahmud, Skye R S Fishbein, Erick S Ramirez Tovar, Rehan Mehta, Bin Wang, Mark G Gorelik, Gautam Dantas, Et Al.

2020-Current year OA Pubs

Engineered probiotics are an emerging platform for in situ delivery of therapeutics to the gut. Herein, we developed an orally administered, yeast-based therapeutic delivery system to deliver next-generation immune checkpoint inhibitor (ICI) proteins directly to gastrointestinal tumors. We engineered Saccharomyces cerevisiae var. boulardii (Sb), a probiotic yeast with high genetic tractability and innate anticancer activity, to secrete "miniature" antibody variants that target programmed death ligand 1 (Sb_haPD-1). When tested in an ICI-refractory colorectal cancer (CRC) mouse model, Sb_haPD-1 significantly reduced intestinal tumor burden and resulted in significant shifts to the immune cell profile and microbiome composition. This oral therapeutic platform …

Molecular Determinants Of Condensate Composition, Alex S Holehouse, Simon Alberti

2020-Current year OA Pubs

Cells use membraneless compartments to organize their interiors, and recent research has begun to uncover the molecular principles underlying their assembly. Here, we explore how site-specific and chemically specific interactions shape the properties and functions of condensates. Site-specific recruitment involves precise interactions at specific sites driven by partially or fully structured interfaces. In contrast, chemically specific recruitment is driven by complementary chemical interactions without the requirement for a persistent bound-state structure. We propose that site-specific and chemically specific interactions work together to determine the composition of condensates, facilitate biochemical reactions, and regulate enzymatic activities linked to metabolism, signaling, and gene …

Rsk1 Is An Exploitable Dependency In Myeloproliferative Neoplasms And Secondary Acute Myeloid Leukemia, Tim Kong, Angelo B A Laranjeira, Christopher T Letson, Layow Yu, Shuyang Lin, Jared S Fowles, Daniel A C Fisher, Sherwin Ng, Wei Yang, Fan He, Jingxian Liu, Alexander B Kim, Maggie J Cox, Mary C Fulbright, Stacey L Rentschler, Li Ding, Grant A Challen, Stephen T Oh, Et Al.

2020-Current year OA Pubs

Myeloid malignancies are heterogenous disorders characterized by distinct molecular drivers but share convergence of oncogenic signaling pathways and propagation by ripe pro-inflammatory niches. Here, we establish a comprehensive transcriptional atlas across the spectrum of myeloproliferative neoplasms (MPN) and secondary acute myeloid leukemia (sAML) through RNA-sequencing of 158 primary samples encompassing CD34+ hematopoietic stem/progenitor cells and CD14+ monocytes. Supported by mass cytometry (CyTOF) profiling, we reveal aberrant networks of PI3K/AKT/mTOR signalling and NFκB-mediated hyper-inflammation. Combining ATAC-Seq, CUT&Tag, RNA-seq, and CyTOF, we demonstrate that targeting of ribosomal protein S6 kinase A1 (RSK1) suppresses NFκB activation and diminishes pro-inflammatory mediators including tumor necrosis …

N-Glycosylation In The Serpin Domain Of The C1-Esterase Inhibitor In Hereditary Angioedema, Zhen Ren, John Bao, Shuangxia Zhao, Nicola Pozzi, H. James Wedner, John P. Atkinson

2020-Current year OA Pubs

Hereditary angioedema is an autosomal dominant disorder caused by defects in C1-esterase inhibitor (C1-INH), resulting in poorly controlled activation of the kallikrein-kinin system and bradykinin overproduction. C1-INH is a heavily glycosylated protein in the serine protease inhibitor (SERPIN) family, yet the role of these glycosylation sites remains unclear. To elucidate the functional impact of N-glycosylation in the SERPIN domain of C1-INH, we engineered 4 sets consisting of 26 variants at or near the N-linked sequon (NXS/T). Among these, 6 are reported in patients with hereditary angioedema and 5 are known C1-INH variants without accessible clinical histories. We systematically evaluated their …

A Human Single-Neuron Dataset For Object Recognition, Runnan Cao, Peter Brunner, Nicholas J Brandmeir, Jon T Willie, Shuo Wang

2020-Current year OA Pubs

Object recognition is fundamental to how we interact with and interpret the world around us. The human amygdala and hippocampus play a key role in object recognition, contributing to both the encoding and retrieval of visual information. Here, we recorded single-neuron activity from the human amygdala and hippocampus when neurosurgical epilepsy patients performed a one-back task using naturalistic object stimuli. We employed two sets of naturalistic object images from leading datasets extensively used in primate neural recordings and computer vision models: we recorded 1204 neurons using the ImageNet stimuli, which included broader object categories (10 different images per category for …

Active Learning Of Enhancers And Silencers In The Developing Neural Retina, Ryan Z Friedman, Avinash Ramu, Sara Lichtarge, Yawei Wu, Lloyd Tripp, Daniel Lyon, Connie A Myers, David M Granas, Maria Gause, Joseph C Corbo, Barak A Cohen, Michael A White

2020-Current year OA Pubs

Deep learning is a promising strategy for modeling cis-regulatory elements. However, models trained on genomic sequences often fail to explain why the same transcription factor can activate or repress transcription in different contexts. To address this limitation, we developed an active learning approach to train models that distinguish between enhancers and silencers composed of binding sites for the photoreceptor transcription factor cone-rod homeobox (CRX). After training the model on nearly all bound CRX sites from the genome, we coupled synthetic biology with uncertainty sampling to generate additional rounds of informative training data. This allowed us to iteratively train models on …

Animal Models Of Non-Respiratory, Post-Acute Sequelae Of Covid-19, Abigail Vanderheiden, Michael S Diamond

2020-Current year OA Pubs

Post-acute sequelae of COVID-19 (PASC) are a diverse set of symptoms and syndromes driven by dysfunction of multiple organ systems that can persist for years and negatively impact the quality of life for millions of individuals. We currently lack specific therapeutics for patients with PASC, due in part to an incomplete understanding of its pathogenesis, especially for non-pulmonary sequelae. Here, we discuss three animal models that have been utilized to investigate PASC: non-human primates (NHPs), hamsters, and mice. We focus on neurological, gastrointestinal, and cardiovascular PASC and highlight advances in mechanistic insight that have been made using these animal models, …

Tolerability And Long-Term Disease Control By Ighv Mutation Status Among Patients With Cll On Ibrutinib Arm Of E1912, Tait D Shanafelt, Amanda F Cashen, Et Al.

2020-Current year OA Pubs

No abstract provided.

Engaging Dystonia Networks With Subthalamic Stimulation, Konstantin Butenko, Evan M Gordon, Nico U F Dosenbach, Et Al.

2020-Current year OA Pubs

Deep brain stimulation is an efficacious treatment for dystonia. While the internal pallidum serves as the primary target, recently, stimulation of the subthalamic nucleus (STN) has been investigated. However, optimal targeting within this structure and its surroundings have not been studied in depth. Indeed, historical targets that have been used for surgical treatment of dystonia are directly adjacent to the STN. Further, multiple types of dystonia exist, and outcomes are variable, suggesting that not all types would profit maximally from the same target. Therefore, a thorough investigation of neural substrates underlying stimulation effects on dystonia signs and symptoms is warranted. …

Sialylated Igg Induces The Transcription Factor Rest In Alveolar Macrophages To Protect Against Lung Inflammation And Severe Influenza Disease, Saborni Chakraborty, Derek E Byers, Philip A Mudd, Michael S Diamond, Et Al.

2020-Current year OA Pubs

While most respiratory viral infections resolve with little harm to the host, severe symptoms arise when infection triggers an aberrant inflammatory response that damages lung tissue. Host regulators of virally induced lung inflammation have not been well defined. Here, we show that enrichment for sialylated, but not asialylated immunoglobulin G (IgG), predicted mild influenza disease in humans and was broadly protective against heterologous influenza viruses in a murine challenge model. Mechanistic studies show that sialylated IgG mediated this protection by inducing the transcription factor repressor element-1 silencing transcription factor (REST), which repressed nuclear factor κB (NF-κB)-driven responses, preventing severe lung …

Helminth Infections Affect Host Immune Responses To Viral Infections And Vaccines, Juan García-Bernalt Diego, Pritesh Desai, Stephen T Yeung, Payal Damani-Yokota, Kamal M Khanna, Michael S Diamond, Michael Schotsaert

2020-Current year OA Pubs

Helminths are highly prevalent in many regions of the world. Due to the chronic nature of most helminth infections, these parasites are proficient immunomodulators of their hosts. This modulation often leads to skewed or even impaired immune responses against unrelated antigens, such as viruses and vaccines, which can be both beneficial and detrimental for the host. The extent of these effects and the impact on the outcomes of viral infection depends on a variety of factors including timing and tropism of both infections, pathological mechanisms, genetic background, and environmental factors. In this review, we dissect these complex interactions between virus …

Daily Glucocorticoids Promote Glioblastoma Growth And Circadian Synchrony To The Host, Maria F Gonzalez-Aponte, Anna R Damato, Tatiana Simon, Nigina Aripova, Fabrizio Darby, Myung Sik Jeon, Jingqin Luo, Joshua B Rubin, Erik D Herzog

2020-Current year OA Pubs

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis despite aggressive therapy. Here, we hypothesized that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We find daily glucocorticoids promote or suppress GBM growth through glucocorticoid receptor (GR) signaling depending on time of day and the clock genes, Bmal1 and Cry. Blocking circadian signals, like vasoactive intestinal peptide or glucocorticoids, dramatically slows GBM growth and disease progression. Analysis of human GBM samples from The Cancer Genome Atlas (TCGA) shows that high GR expression significantly increases hazard of mortality. Finally, mouse …

Cannabis Use Characteristics And Associations With Problematic Use Outcomes, Quitting-Related Factors, And Mental Health Among Us Young Adults, Carla J Berg, Cassidy R Loparco, Katelyn F Romm, Yuxian Cui, Darcey M Mccready, Yan Wang, Y Tony Yang, Hannah S Szlyk, Erin Kasson, Rishika Chakraborty, Patricia A Cavazos-Rehg

2020-Current year OA Pubs

OBJECTIVE: Given the changes in trends of cannabis use (e.g., product types), this study examined latent classes of young adult use and associations with use-related outcomes.

METHODS: We analyzed 2023 survey data among 4,031 US young adults (M

RESULTS: LCA identified 4 classes of cannabis use frequency and types used: 'infrequent-herb/edibles' (41.4%), 'frequent-herb' (16.8%), 'moderate-herb' (28.0%), and 'moderate-oil/other' (13.8%). In multivariable analyses (referent group: 'moderate-herb' class), 'frequent-herb' reported less problematic use (B=-0.18, 95%CI=-0.30, -0.07), while 'moderate-oil/other' reported greater (B = 0.39, 95%CI = 0.27, 0.51). 'Infrequent-herb/edibles' had lower odds of driving post-use of cannabis (aOR = 0.28, 95%CI = 0.22, …

Decreased Lipidated Apoe-Receptor Interactions Confer Protection Against Pathogenicity Of Apoe And Its Lipid Cargoes In Lysosomes, Jing L Guo, Alexandra Litvinchuk, David M Holtzman, Et Al.

2020-Current year OA Pubs

While apolipoprotein E (APOE) is the strongest genetic modifier for late-onset Alzheimer's disease (LOAD), the molecular mechanisms underlying isoform-dependent risk and the relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding of lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 and decreases the uptake of cholesteryl esters (CEs), which are lipids linked to neurodegeneration. In human neurons, the addition of ApoE carrying polyunsaturated fatty acids (PUFAs)-CE revealed an allelic series (ApoE4 > ApoE3 > ApoE2) associated with lipofuscinosis, an age-related lysosomal pathology resulting from lipid peroxidation. Lipofuscin increased lysosomal accumulation of tau …