Digital Commons Network^™

Adaptations To An Implementation Study For Integrating Hypertension Management Into Hiv Care In Lagos, Nigeria: Application Of The Frame, Chioma Hope Nwankwo, Juliet Iwelunmor, Et Al.

2020-Current year OA Pubs

BACKGROUND: Implementation strategies are dynamic and multi-faceted, and may require adaptations to fit implementation contexts, especially in lower-and-middle income countries. We report the adaptations for an ongoing late-stage implementation science trial (R01HL147811) that integrates hypertension management into HIV care in Lagos, Nigeria - a country with a high dual-disease burden - through the Task Strengthening Strategy for Hypertension (TASSH) intervention and Practice Facilitation implementation strategy.

METHODS: FRAME (Framework for Reporting Adaptations and Modifications-Enhanced) modules were used to record adaptations to the intervention (i.e., TASSH) respectively, enhance participant recruitment and retention rates, and increase frequency of trainings. Data collection sources included …

Recommendations For The Diagnosis And Management Of Cln3 Disease (Batten Disease) Using The Delphi Consensus Methodology, Jonathan W Mink, Jonathan D Cooper, Et Al.

2020-Current year OA Pubs

BACKGROUND: CLN3 disease, also called Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), or Batten disease, is an ultra‑rare, neurodegenerative lysosomal storage disorder generally affecting individuals during the first decade of life. There can be a delay in diagnosis or misdiagnosis due to a lack of awareness, and when the most common presenting symptom of visual loss is attributed to more common conditions affecting vision. METHODS: We used a previously published Expert Mapping Tool (EMT) to identify multidisciplinary professionals with diagnostic or clinical management expertise, as well as patient advocates with experience of CLN3 disease. A systematic literature review of published evidence using …

A Practice-Based Implementation Strategy Bundle For Integrating Behavioral Health In Primary Care: A Matrixed Multiple Case Study, Gretchen Buchanan, Kelley Mccall, Lorella Palazzo, Michelle Bagwell, Shivani Patel, Shravya Allena, Byron J Powell

2020-Current year OA Pubs

BACKGROUND: Integrated behavioral health (IBH) is an evidence-based approach to addressing mental health in primary care settings. It typically involves augmenting a primary care team with a behavioral health professional (e.g., psychologist, licensed clinical social worker) who sees patients for brief, focused concerns; can function as a bridge to specialty care; and provides medical providers with support and education about patient behavioral health concerns. IBH has slowly begun to disseminate across the United States, but practices encounter significant implementation barriers. How IBH is implemented has not been systematically studied outside of trials, yet this study could provide a rich foundation …

Ultrasound-Guided Skeletal Muscle Biopsy Technique Permits Measurement Of Structural, Functional, Cellular And Biochemical Properties, Addison Barber, Amber Willbanks, Guadalupe Meza, Jeremie L A Ferey, Gretchen A Meyer, Sudarshan Dayanidhi, W David Arnold, Richard L Lieber, Ishan Roy

2020-Current year OA Pubs

Human muscle biopsies are often required to study or diagnose diseases. However, traditional approaches are challenging due to limited sample size, quality, or participant discomfort. Fine-gauge needle biopsies (≥ 14-gauge), present an alternative but may yield insufficient tissue for comprehensive analysis. Ultrasound guidance, coupled with vacuum-assisted, single needle-insertion multiple sampling addresses these challenges. In 19 healthy participants (mean age: 30.1 ± 10 years, 42% male), 2-3 samples were collected from a single needle insertion into the vastus lateralis (VL) and tibialis anterior (TA). Summed VL and TA sample masses averaged 148 ± 38 mg and 166 ± 64 mg, with …

Hematopoietic Cell Transplantation For Wiskott-Aldrich Syndrome: A Pidtc Report, Jessie L Alexander, Jeffrey J Bednarski, Et Al.

2020-Current year OA Pubs

Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and …

Patient And Healthcare Professionals' Perceptions Of Educational Tools To Reduce Urine Culture Contamination In Outpatient Clinics: A Qualitative Study., Ashley Collazo, Trenton M Haltom, Johanan Luna Rodriguez, Kiara Olmeda, Azalia Mancera, Fabrizia Faustinella, Michael K Paasche-Orlow, Zach Landis-Lewis, Roger Zoorob, Barbara W Trautner, Larissa Grigoryan

2020-Current year OA Pubs

OBJECTIVE: Iteratively develop educational tools (instructional video and flyer) to improve midstream clean catch (MSCC) urine sample collection using patient and healthcare professionals' input.

DESIGN: Multi-method qualitative study.

SETTING: Outpatient clinics in Houston, Texas, United States.

PARTICIPANTS: Adult patients recruited from public and private clinics (

METHODS: Twelve patient interviews and three focus groups with HCPs (May 2024-November 2024). Interviews discussed patient experiences using the educational tools to guide urine specimen collection. Focus groups elicited HCPs' perspectives on the comprehensibility and utility of the tools in their respective clinics. We identified themes using directed content analysis.

RESULTS: We garnered insight …

Crossing The Finish Line Towards A Disease-Modifying Treatment For Angelman Syndrome, Matthew C Judson, Jason J Yi, Et Al.

2020-Current year OA Pubs

Recent progress in the development of genetic therapies promises that impactful treatments for single-gene neurodevelopmental disorders are imminent. But can derailed neurodevelopmental processes be mended after broken genes are replaced or otherwise restored? The results of ongoing clinical trials for Angelman syndrome will soon yield answers to this pressing question, yet the trials face significant obstacles. Here we identify insights needed to aid the quest for a disease-modifying Angelman syndrome therapy, which could serve as a roadmap for the expeditious development of genetic therapies for other single-gene neurodevelopmental disorders.

Blood And Body Fluid Exposure And Reporting Behaviors Among Healthcare Workers: A Decade-Long Comparative Study At A Tertiary Medical Center, Ziad Kaddour, Rami Abdul-Halim, Zeina Al-Khalil, Lea Al Zoghby, Raafat Alameddine, Reem Mansour, Jack El Sawda, Zeina A Kanafani

2020-Current year OA Pubs

BACKGROUND: Occupational exposure to blood and body fluids (BBFE) remains a significant risk for healthcare workers (HCWs), yet underreporting persists despite the implementation of institutional policies. This study aimed to compare BBFE prevalence, reporting practices, and HCWs' knowledge, perceptions, attitudes, and behaviors, and identify predictors of BBFE and failure to report incidents over a ten-year period at a tertiary medical center.

METHODS: Two cross-sectional surveys were conducted at the American University of Beirut Medical Center (AUBMC) in 2013-2014 and 2023-2024. In 2013-2014, all participants completed paper-based questionnaires, whereas in 2023-2024, medical students, residents, and nurses completed online surveys, and housekeeping/laundry …

Translation Of Expanded Cgg Repeats In Lrp12 Associated Oculopharyngodistal Myopathy, Chengcheng Li, Jil A Daw, Sara K Pittman, Connor J Maltby, Hidetoshi Sakurai, Peter K Todd, Conrad C Weihl

2020-Current year OA Pubs

Oculopharyngodistal myopathy (OPDM) is characterized by ptosis, ophthalmoparesis, dysphagia, and distal weakness. Myopathological features include rimmed vacuoles and intranuclear inclusions. OPDM is associated with a pathogenic CGG repeat expansions in the 5'UTR of LRP12, NOTCH2NLC, GIPC1, RILPL1 and ABCD3. Translation of the repeat in the glycine reading frame has been demonstrated for expansions in FMR1, NOTCH2NLC and GIPC1. To assess for a similar phenomenon with LRP12, we expressed normal or expanded CGG repeats in the context of the 5'UTR of LRP12, upstream of a green fluorescent protein (GFP) in the three repeat reading frames. Repeat dependent translation occurs exclusively in …

A New Chromosome-Level Genome Assembly For Western Painted Turtle Chrysemys Picta Bellii, A Model For Extreme Physiological Adaptations, Junhao Chen, John R Bermingham Jr, Patrick Minx, Milinn Kremitzky, Zhenguo Lin, Daniel E Warren

2020-Current year OA Pubs

The western painted turtle, Chrysemys picta bellii, has the greatest tolerance to anoxia of any tetrapod studied to date. These turtles reside in the northern United States and southern Canada, and survive months of anoxia while submerged in ice-locked ponds and bogs. Reference genomes provide an important resource for elucidating the molecular bases for such unique physiological traits. The initial reference genome for this species, published in 2013, is highly fragmented, thereby limiting downstream analyses and biological interpretation. We created a new and improved assembly by combining PacBio HiFi, 10 × Genomics Chromium, Hi-C sequence data and Bionano optical mapping …

Integrating Interferon Gamma Receptor Pathways, Antigenicity, And Immune Contexture As Predictors Of Immunotherapeutic Strategies For Mucosal Melanomas, Matilde Monti, Jinglun Li, Obi Griffith, Malachi Griffith, William Vermi, Et Al.

2020-Current year OA Pubs

BACKGROUND: Mucosal melanomas (MM) arise from mucosal melanocytes at various anatomical sites. These tumors are rare, highly aggressive, and often associated with poor outcomes. Current treatments, including immune checkpoint inhibitors, show limited efficacy in advanced disease. Compared with cutaneous melanomas, there is a lack of data on the immunogenicity and interferon (IFN)-γ sensitivity of MM. In this study, we examined these features in sino-nasal melanomas (SN-MM) cell lines and clinical samples using microscopy and functional genomics.

METHODS: The immune contexture of SN-MM was analyzed by immunohistochemistry on 48 tumor biopsies. RNA sequencing and mass spectrometry-based proteomic approaches were used to …

Development Of A Sustainable Blended Food Aid Product Using Local Ingredients For Nutritionally Vulnerable Populations In Haiti, Sherlie Jean Louis Dulience, Rachel Zimmerman, Michelle Dorce, Ilana Seff, Andrea Spray Bulungu, Patricia Kohl, Carolyn Lesorogol, Bazelais Dulience, Lora Iannotti

2020-Current year OA Pubs

OBJECTIVES: This study aimed to: (1) identify optimal blended food recipe options using local flours; (2) assess behaviors, attitudes, and practices around the use of blended foods among nutritionally vulnerable groups in Haiti; and (3) evaluate the nutrient composition of prototype blended food product relative to nutrient requirements for vulnerable populations.

METHODS: Blended food recipes made from local flours were identified through matrix scoring and stakeholder consensus. Focus groups (n = 7) assessed behaviors and attitudes toward blended foods. Prototype recipes were selected based on matrix scoring, program participant feedback, and feasibility of bringing to scale. Nutrient composition of the …

Brd4-Mediated Er Membrane Contact Creates Functionally Distinct Mitochondrial Subtypes, Brandon Chen, Rachel M Guerra, David J Pagliarini, Et Al.

2020-Current year OA Pubs

Inter-organellar communication is critical for cellular metabolism. One of the most abundant inter-organellar interactions occurs at the endoplasmic reticulum and mitochondria contact sites (ERMCSs). However, an understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism is limited by a lack of tools that permit temporal induction and reversal. Through screening approaches, we identified fedratinib, an FDA-approved drug that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology, induces a distinct ER-mitochondria envelopment structure, and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondrial electron transport chain …

Single-Center Experience Of Voclosporin Use For Pediatric Lupus Nephritis: A Case Series, Ran Hazan, Nazlican Tang Civilibal, Kevin Baszis, Tarin M Bigley

2020-Current year OA Pubs

No abstract provided.

Longitudinal Profiling Of Tumor And Immune Compartments Uncovers Patterns Of Dysregulation And Associations With Response In Multiple Myeloma, Denis J Ohlstrom, Reyka G Jayasinghe, Yizhe Song, Ravi Vij, Li Ding, Et Al.

2020-Current year OA Pubs

UNLABELLED: Multiple myeloma is a malignancy of clonally expanded plasma cells shaped by complex interactions with the immune microenvironment (IME). To investigate immune correlates of treatment response and disease progression, we conducted multi-omics profiling including CD138neg single-cell RNA sequencing of 243 bone marrow samples from 102 patients (631,226 cells) and CD138pos bulk RNA and whole-genome sequencing from 209 samples. In longitudinal analyses, interferon-γ signaling associated with markers of impaired T-cell memory after autologous stem cell transplant, whereas naïve B-cell abundance and immunoglobulin diversity correlated with improved progression-free survival (HR = 0.48; P = 2.3e-4). At disease progression, multiple myeloma cells …

An Acetylation-Dependent Switch Underlies Host Disease Tolerance During Streptococcal Infection, Sumit Kumar Paudel, Sowmya Gannavaram, Michael G Caparon, Wei Xu

2020-Current year OA Pubs

Building on our finding that Streptococcus pyogenes pyruvate dehydrogenase (PDH) suppresses host disease tolerance (DT) via short-chain fatty acid (SCFA)-mediated modulation of host acetyl-CoA and IL-10 levels, we characterize the global transcriptomic and epigenetic mechanisms underlying this immunometabolic manipulation. Combining new histological and ultrastructural analyses with an in-depth re-analysis of single-cell and bulk RNA-seq datasets to more comprehensively characterize the DT response, we show that PDH deficiency is associated with broad immunologic rewiring, characterized by intracellular bacterial containment within phagocytes, expansion of pro-resolving myeloid cells, and altered cell-cell communication. Metabolic analysis of ΔPdh-infected tissues revealed a shift away from acetyl-CoA …

Decreased Metallothionein-3 Expression In The Human Spinal Cord Is A Common Feature Of Amyotrophic Lateral Sclerosis And Multiple Sclerosis, Adam P Gunn, James B W Hilton, Soumya Mukherjee, Jeffrey R Liddell, Stephen W Mercer, Catriona A Mclean, Colin L Masters, Peter J Crouch, Blaine R Roberts

2020-Current year OA Pubs

Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are devastating adult-onset neurological diseases with distinct pathological manifestations. Although growing evidence implicates copper dysregulation in both diseases, our understanding of this connection remains incomplete. In this study, we investigated metallothionein-3 (MT3), which is a key regulator of copper metabolism in the central nervous system (CNS), and its relationship to copper in the ALS and MS spinal cord. Using combined quantitative mass spectrometry approaches and immunohistochemical observations, we found a significant decrease in ALS and MS spinal cord MT3 levels compared to controls. This was correlated with levels of copper and MT3-copper …

Glucagon-Like Peptide-1 Receptor Agonists And Risk Of Substance Use Disorders Among Us Veterans With Type 2 Diabetes: Cohort Study, Miao Cai, Taeyoung Choi, Yan Xie, Ziyad Al-Aly

2020-Current year OA Pubs

OBJECTIVES: To investigate whether initiation of glucagon-like peptide-1 (GLP-1) receptor agonists is associated with both reduced risks of incident alcohol, cannabis, cocaine, nicotine, opioid, and other substance use disorders (SUDs) in people with no history of SUDs (protocol 1) and with reduced risk of SUD related adverse clinical outcomes among people with a pre-existing SUD (protocol 2).

DESIGN: Emulation of eight parallel, new user, active comparator target trials using electronic health records: seven trials for each incident SUD outcome (protocol 1) and one trial for adverse outcomes in people with pre-existing SUD (protocol 2).

SETTING: US Department of Veterans Affairs. …

Sodium Content Of Packaged Foods And Beverages In Nigeria: A Cross-Sectional Comparative Study With Who Global Sodium Benchmarks, Kenya, And South Africa, Adedayo E Ojo, Alexandra Jones, Kylie Howes, Vanessa Alfa, Anthony Orji, Oluwafemi A Stephen, Carla Pool, Alex Kibet, Fraser Taylor, Diederick E Grobbee, Bruce Neal, Mark D Huffman, Dike B Ojji, Sanne A E Peters

2020-Current year OA Pubs

High intake of processed foods, especially those with high sodium content, is a contributor to hypertension and cardiovascular disease. This study aimed to compare the sodium content of packaged foods and beverages in Nigeria to WHO Global Sodium Benchmarks and similar products in Kenya and South Africa. The study examined packaged foods from major retail stores in the capital cities of the Federal Capital Territory, Kano, and Ogun states in Nigeria from November 2020 to March 2021. Benchmark values were based on the 2021 WHO Global Sodium Benchmarks. We used secondary data from packaged food surveys conducted in South Africa …

A Neural Circuit Framework For Economic Choice: From Building Blocks Of Valuation To Compositionality In Multitasking, Aldo Battista, Camillo Padoa-Schioppa, Xiao-Jing Wang

2020-Current year OA Pubs

Value-guided decisions are a cornerstone of cognition, yet the underlying circuit-level mechanisms remain elusive. We used reinforcement learning to train recurrent neural network models endowed with Dale's law on a battery of economic choice tasks, which revealed a two-stage computational framework. First, value estimation occurs at the input level, where learned weights store subjective preferences and approximate the non-linear multiplication of reward magnitude and probability to yield expected values. This feedforward mechanism enables generalization to novel choice options. Second, option values are compared within the recurrent network, where specific connectivity patterns mediate robust winner-take-all decisions, with both excitatory and inhibitory …

Exploring The Role Of Social Networks In Youth Mental Health, Nicholas Szoko, Alexander Riley, Jacquelin Rankine, Alison J Culyba

2020-Current year OA Pubs

Social network analysis (SNA) offers an innovative approach to understand youths' complex social support systems. Growing work highlights links between youths' social networks and mental health. We used SNA to examine associations between social network characteristics and psychological empowerment, depression, anxiety, and post-traumatic stress among youth living in areas with concentrated disadvantage. We administered egocentric social network surveys in which youth (i.e., egos) enumerated individuals in their social network (i.e., alters), answered questions about each alter, and described how alters were connected. We measured psychological empowerment and mental health symptoms with validated instruments. There were 111 youth in the analytic …

Sex-Related Differences In Clinical Profile, Management, And Outcomes Of Patients With Type A And B Acute Aortic Dissection: Observations From Irad, Elizabeth Jackson, Andreina Carbone, Sherene Shalhub, Chih-Wen Pai, Marek Ehrlich, Toru Suzuki, G Chad Hughes, Anil Bhan, Rumi Faizer, Antonio Cittadini, Alan Braverman, Eric Isselbacher, Kim Eagle, Christoph Nienaber, Eduardo Bossone

2020-Current year OA Pubs

BACKGROUND: Available data about sex differences in patients with acute aortic dissection (AAD) are scant and conflicting. The aim of this study is to assess sex-related differences in clinical characteristics, presentation, diagnostic findings, management, and outcomes among patients with type A (TA-AAD) and type B AAD (TB-AAD).

METHODS: Data about 11 586 patients enrolled in the IRAD (International Registry of Acute Aortic Dissection) from 1996 to 2022, were analyzed; 7819 (67.5%) experienced TA-AAD and 3867 (33.0%) TB-AAD. Men and women were compared with regard to diagnosis, treatment, and in-hospital and long-term survival.

RESULTS: One third of patients were women (TA-AAD, …

Building Capacity On Hypertension Management In Nigeria, Shivani Mishra, Daphne Lew, Et Al.

2020-Current year OA Pubs

No abstract provided.

Shiga Toxin-Producing Escherichia Coli Outbreak In Canadian Daycare Centers, Mohamed Eltorki, Oluwatimilehin O Ajayi, Jina Seok, Jianling Xie, Francesco A Rizzuti, Byron M Berenger, Phillip I Tarr, Andrew T Pavia, Kate Snedeker, Silviu Grisaru, Otto G Vanderkooi, Linda Chui, Gillian A M Tarr, Gemma Vomiero, Stephen B Freedman

2020-Current year OA Pubs

IMPORTANCE: Shiga toxin-producing Escherichia coli (STEC) infections have significant morbidity, with 15% to 20% of children developing hemolytic uremic syndrome (HUS), more than half of whom require kidney replacement therapy (KRT).

OBJECTIVE: To describe health care resource utilization, clinical outcomes, and outcomes associated with daily laboratory monitoring for thrombotic microangiopathy (TMA) in a large point-source STEC outbreak.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was conducted among a population-based cohort of individuals exposed to a contaminated food item served in 11 childcare centers in Calgary, Alberta, Canada, on August 29, 2023. Children and adults with confirmed STEC infection linked …

Cell Type-Specific Gene Regulatory Atlas Prioritizes Drug Targets And Repurposable Medicines In Alzheimer's Disease, Yunxiao Ren, Ming Hu, Yang E Li, Andrew A Pieper, Jeffrey Cummings, Feixiong Cheng

2020-Current year OA Pubs

Alzheimer's disease (AD) is a complex and poorly understood neurodegenerative disorder that lacks sufficiently effective treatments. Computational and integrative analyses that leverage multiomic data provide a promising strategy to uncover disease mechanisms and identify therapeutic opportunities. Here, we develop a cell type-specific regulatory atlas of the human middle temporal gyrus via leveraging single-nucleus RNA-seq (1,197,032 nuclei) and ATAC-seq (740,875 nuclei) data sets from 84 donors across four stages of AD neuropathological change (ADNC). We observe differential gene expression for six major cell types intensified at severe ADNC. Integrating peak-to-gene linkages and motif enrichment analyses, we reconstruct transcription factor (TF)-target gene …

The Relationship Between Apparent Potentiation And The Magnitude Of The Control Response, Joe Henry Steinbach, Gustav Akk

2020-Current year OA Pubs

The effect of a potentiating drug on ion channel function is typically evaluated by comparing current responses to the control agonist in the presence and absence of the potentiator. Differences in ratios of responses are then taken as proof of distinct potentiation properties when comparing modulation by different compounds. In these experiments, the concentration of the agonist is typically kept low to generate a small fractional control response. The precise relative magnitude of the control response is, however, not standardized among labs and can range from a concentration producing a response equal to just 2% of maximal (EC2) to over …

Trends In Mammography Use Among Women Aged 40 To 74 Years In The Us, 2002-2022, Syed Mahfuz Al Hasan, Debbie L Bennett, Adetunji T Toriola

2020-Current year OA Pubs

IMPORTANCE: Understanding how prior policies, systemic factors, and public health events have shaped mammography use among US women is essential for interpreting the 2024 US Preventive Services Task Force (USPSTF) recommendation update and identifying gaps to inform equitable public health strategies.

OBJECTIVE: To analyze mammography use trends in US women aged 40 to 49 and 50 to 74 years from 2002 to 2022 and assess variation by sociodemographic, health care access, behavioral, and geographic factors, including associations with the 2009 USPSTF recommendation and the COVID-19 pandemic.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data from the Behavioral Risk Factor …

Media Reporting Of The 2024 Us Preventive Services Task Force Mammography Guideline Update, Tamar Parmet, Yue Li, Joseph Cappella, Laura D Scherer, Erika A Waters, Ashley J Housten

2020-Current year OA Pubs

No abstract provided.

Cholecalciferol (Vitamin D3) Is An Agonist Of The Alzheimer's Disease-Associated Immune Receptor Trem2, Hunter B Dean, Ryan A Tuckey, Rory A Greer, Jessica A Greven, Shan-Zhong Yang, Daniel S Elston, Gunnar N Eastep, Yuwei Song, Thomas J Brett, Yuhua Song, Erik D Roberson

2020-Current year OA Pubs

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is one of the strongest genetic risk factors for late-onset Alzheimer's disease (AD). Several TREM2 ligands are known, including charged lipids and AD-associated proteins like apolipoprotein E and amyloid-β, but the full range of endogenous ligands for TREM2 remains unknown. Here we combined virtual screening of the Human Metabolome Database with molecular dynamics simulations, binding free energy estimation, and biolayer interferometry to identify novel TREM2 ligands and map their binding sites. Cholecalciferol, the unmodified parent form of vitamin D3, emerged as a top candidate. Structural modeling indicated that cholecalciferol binds TREM2 at …

Astrocyte-Specific Deletion Of Lrrc8a Causes Neurological Dysfunction But Not Chronic White Matter Edema, Sven Kerst, Leoni Hoogterp, Marjolein Breur, Gemma M Van Rooijen-Van Leeuwen, Marianna Bugiani, Rajan Sah, Huibert D Mansvelder, Marjo S Van Der Knaap, Rogier Min

2020-Current year OA Pubs

Volume-regulated anion channels (VRACs) are central to cell volume homeostasis. They mediate swelling-induced efflux of chloride and organic osmolytes to drive regulatory volume decrease. In the brain, VRACs have been proposed to play a key role in astrocytic volume regulation. Genetic defects in astrocytic VRAC modulating proteins (MLC1, GlialCAM, Aquaporin-4, GPRC5B) cause the leukodystrophy Megalencephalic leukoencephalopathy with subcortical cysts (MLC), characterized by chronic white matter edema and myelin vacuolization. Disrupted VRAC activity in MLC-patient-derived lymphoblasts and primary astrocytes from MLC mice further supports a pathogenic link between defective VRAC activity and MLC. Here, we studied the physiological and pathological consequences …