Medicine and Health Sciences Commons^™

Obesity Is Associated With Muscle Atrophy In Rotator Cuff Tear, Simone D Herzberg, Robert H Brophy, Matthew V Smith, Et Al.

2020-Current year OA Pubs

OBJECTIVE: The primary goal of this study is to evaluate the relationship between Body Mass Index (BMI) and muscle atrophy in individuals with rotator cuff tears.

METHODS: This study consists of patients with rotator cuff tears identified by MRI from two independent cohorts, the Rotator Cuff Outcomes Workgroup (ROW) and the Multicenter Orthopaedic Outcomes Network (MOON). Presence of atrophy (yes/no) and severity of atrophy (as an ordinal variable) were assessed on MRI by expert physicians. We used multivariable regression models to evaluate the relationship between BMI and muscle atrophy while adjusting for age and sex in each study, conducted sensitivity …

Detection Of Early-Stage Nash Using Non-Invasive Hyperpolarized 13c Metabolic Imaging, Cornelius Von Morze, Tyler Blazey, Ashley Shaw, William M Spees, Kooresh I Shoghi, Michael A Ohliger

2020-Current year OA Pubs

Non-alcoholic steatohepatitis (NASH) is characterized from its early stages by a profound remodeling of the liver microenvironment, encompassing changes in the composition and activities of multiple cell types and associated gene expression patterns. Hyperpolarized (HP)

Real-World And Clinical Trial Outcomes In Large B-Cell Lymphoma With Axicabtagene Ciloleucel Across Race And Ethnicity, Frederick L Locke, Armin Ghobadi, Et Al.

2020-Current year OA Pubs

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival …

Examining Associations Between Smartphone Use And Clinical Severity In Frontotemporal Dementia: Proof-Of-Concept Study, Emily W Paolillo, Nupur Ghoshal, Et Al.

2020-Current year OA Pubs

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown.

OBJECTIVE: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD.

METHODS: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional …

Airy-Beam Holographic Sonogenetics For Advancing Neuromodulation Precision And Flexibility, Zhongtao Hu, Yaoheng Yang, Leqi Yang, Yan Gong, Chinwendu Chukwu, Dezhuang Ye, Yimei Yue, Jinyun Yuan, Alexxai V Kravitz, Hong Chen

2020-Current year OA Pubs

Advancing our understanding of brain function and developing treatments for neurological diseases hinge on the ability to modulate neuronal groups in specific brain areas without invasive techniques. Here, we introduce Airy-beam holographic sonogenetics (AhSonogenetics) as an implant-free, cell type-specific, spatially precise, and flexible neuromodulation approach in freely moving mice. AhSonogenetics utilizes wearable ultrasound devices manufactured using 3D-printed Airy-beam holographic metasurfaces. These devices are designed to manipulate neurons genetically engineered to express ultrasound-sensitive ion channels, enabling precise modulation of specific neuronal populations. By dynamically steering the focus of Airy beams through ultrasound frequency tuning, AhSonogenetics is capable of modulating neuronal populations …

Myeloablative Vs Nonmyeloablative Consolidation For Primary Central Nervous System Lymphoma: Results Of Alliance 51101, Tracy T Batchelor, Brad S Kahl, Nancy L Bartlett, Nina Wagner-Johnston, Et Al.

2020-Current year OA Pubs

Although it is evident that standard-dose whole-brain radiotherapy as consolidation is associated with significant neurotoxicity, the optimal consolidative strategy for primary central nervous system lymphoma (PCNSL) is not defined. We performed a randomized phase 2 clinical trial via the US Alliance cancer cooperative group to compare myeloablative consolidation supported by autologous stem cell transplantation with nonmyeloablative consolidation after induction therapy for PCNSL. To our knowledge, this is the first randomized trial to be initiated that eliminates whole-brain radiotherapy as a consolidative approach in newly diagnosed PCNSL. Patients aged 18 to 75 years were randomly assigned in a 1:1 manner to …

Injury-Induced Foxm1 Expression In The Mouse Kidney Drives Epithelial Proliferation By A Cyclin F-Dependent Mechanism, Megan L. Noonan, Yoshiharu Muto, Yasuhiro Yoshimura, Aidan Leckie-Harre, Haojia Wu, Vladimir V. Kalinichenko, Benjamin D. Humphreys, Monica Chang-Panesso

2020-Current year OA Pubs

Acute kidney injury (AKI) strongly upregulates the transcription factor Foxm1 in the proximal tubule in vivo, and Foxm1 drives epithelial proliferation in vitro. Here, we report that deletion of Foxm1 either with a nephron-specific Cre driver or by inducible global deletion reduced proximal tubule proliferation after ischemic injury in vivo. Foxm1 deletion led to increased AKI to chronic kidney disease transition, with enhanced fibrosis and ongoing tubule injury 6 weeks after injury. We report ERK mediated FOXM1 induction downstream of the EGFR in primary proximal tubule cells. We defined FOXM1 genomic binding sites by cleavage under targets and release using …

Dorsal Raphe Neurons Integrate The Values Of Reward Amount, Delay, And Uncertainty In Multi-Attribute Decision-Making, Yang-Yang Feng, Ethan S Bromberg-Martin, Ilya E Monosov

2020-Current year OA Pubs

The dorsal raphe nucleus (DRN) is implicated in psychiatric disorders that feature impaired sensitivity to reward amount, impulsivity when facing reward delays, and risk-seeking when confronting reward uncertainty. However, it has been unclear whether and how DRN neurons signal reward amount, reward delay, and reward uncertainty during multi-attribute value-based decision-making, where subjects consider these attributes to make a choice. We recorded DRN neurons as monkeys chose between offers whose attributes, namely expected reward amount, reward delay, and reward uncertainty, varied independently. Many DRN neurons signaled offer attributes, and this population tended to integrate the attributes in a manner that reflected …

Role Of The Afferent Lymph As An Immunological Conduit To Analyze Tissue Antigenic And Inflammatory Load, Padma P Nanaware, Cheryl F Lichti, Xiaoxiao Wan, Emil R Unanue, Et Al.

2020-Current year OA Pubs

The lymphatic fluid is the conduit by which part of the tissue "omics" is transported to the draining lymph node for immunosurveillance. Following cannulation of the pre-nodal cervical and mesenteric afferent lymphatics, herein we investigate the lymph proteomic composition, uncovering that its composition varies according to the tissue of origin. Tissue specificity is also reflected in the dendritic cell-major histocompatibility complex class II-eluted immunopeptidome harvested from the cervical and mesenteric nodes. Following inflammatory disruption of the gut barrier, the lymph antigenic and inflammatory loads are analyzed in both mice and subjects with inflammatory bowel diseases. Gastrointestinal tissue damage reflects the …

A Shared Group Of Bacterial Taxa In The Duodenal Microbiota Of Undernourished Pakistani Children With Environmental Enteric Dysfunction, Najeeha T Iqbal, Robert Y Chen, Nicholas W Griffin, Matthew C Hibberd, Michael J Barratt, Jeffrey I Gordon, Et Al.

2020-Current year OA Pubs

Environmental enteric dysfunction (EED) is a subclinical syndrome of altered small intestinal function postulated to be an important contributor to childhood undernutrition. The role of small intestinal bacterial communities in the pathophysiology of EED is poorly defined due to a paucity of studies where there has been a direct collection of small intestinal samples from undernourished children. Sixty-three members of a Pakistani cohort identified as being acutely malnourished between 3 and 6 months of age and whose wasting (weight-for-length

The Vaginal Immunoproteome For The Prediction Of Spontaneous Preterm Birth: A Retrospective Longitudinal Study, Zachary Shaffer, Roberto Romero, Adi L Tarca, Jose Galaz, Marcia Arenas-Hernandez, Dereje W Gudicha, Tinnakorn Chaiworapongsa, Eunjung Jung, Manaphat Suksai, Kevin R Theis, Nardhy Gomez-Lopez

2020-Current year OA Pubs

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm birth occur spontaneously and result from preterm labor with intact (spontaneous preterm labor [sPTL]) or ruptured (preterm prelabor rupture of membranes [PPROM]) membranes. The prediction of spontaneous preterm birth (sPTB) remains underpowered due to its syndromic nature and the dearth of independent analyses of the vaginal host immune response. Thus, we conducted the largest longitudinal investigation targeting vaginal immune mediators, referred to herein as the immunoproteome, in a population at high risk for sPTB.

METHODS: Vaginal swabs were collected across gestation from pregnant …

Effectiveness Of An Online Text-Based Stress Management Program For Employees Who Work In Micro- And Small-Sized Enterprises: A Randomized Controlled Trial, Natsu Sasaki, Sayaka Ogawa, Utako Sawada, Taichi Shimazu, Byron J Powell, Hajime Takeno, Akizumi Tsutsumi, Kotaro Imamura

2020-Current year OA Pubs

BACKGROUND: Internet psychoeducational interventions improve employees' mental health. However, implementing them for employees in micro- and small-sized enterprises (MSEs) is challenging.

OBJECTIVES: This randomized controlled trial examined the effectiveness of a fully automated text-based stress management program, "WellBe-LINE," in improving mental health and job-related outcomes for employees in workplaces with fewer than 50 employees.

METHODS: The program was developed based on stakeholder interviews and surveys of 1000 employees at MSEs. Adult full-time employees at an enterprise with fewer than 50 employees were recruited from registered members of a web survey company in Japan. Participants were randomly allocated to the intervention …

Noninvasive Assessment Of The Lung Inflammation-Fibrosis Axis By Targeted Imaging Of Cmklr1, Philip Z Mannes, Taylor S Adams, Samaneh Farsijani, Clayton E Barnes, Joseph D Latoche, Kathryn E Day, Jessie R Nedrow, Farida Ahangari, Naftali Kaminski, Janet S Lee, Sina Tavakoli

2020-Current year OA Pubs

Precision management of fibrotic lung diseases is challenging due to their diverse clinical trajectories and lack of reliable biomarkers for risk stratification and therapeutic monitoring. Here, we validated the accuracy of CMKLR1 as an imaging biomarker of the lung inflammation-fibrosis axis. By analyzing single-cell RNA sequencing datasets, we demonstrated

Defining Cis-Regulatory Elements And Transcription Factors That Control Human Cortical Interneuron Development, Gareth Chapman, Julianna Determan, Haley Jetter, Komal Kaushik, Ramachandran Prakasam, Kristen L Kroll

2020-Current year OA Pubs

Although human cortical interneurons (cINs) are a minority population in the cerebral cortex, disruption of interneuron development is a frequent contributor to neurodevelopmental disorders. Here, we utilized a model for deriving cINs from human embryonic stem cells to profile chromatin state changes and generate an atlas of

Clinical Prediction For Surgical Versus Nonsurgical Interventions In Patients With Vertebral Osteomyelitis And Discitis, Jennifer Lee, Miguel A. Ruiz-Cardozo, Rujvee P. Patel, Saad Javeed, Raj Swaroop Lavadi, Catherine Newsom-Stewart, Anton Alyakin, Camilo A. Molina, Nitin Agarwal, Wilson Z. Ray, Michele Santacatterina, Brenton H. Pennicooke

2020-Current year OA Pubs

BACKGROUND: Vertebral osteomyelitis and discitis (VOD), an infection of intervertebral discs, often requires spine surgical intervention and timely management to prevent adverse outcomes. Our study aims to develop a machine learning (ML) model to predict the indication for surgical intervention (during the same hospital stay) versus nonsurgical management in patients with VOD.

METHODS: This retrospective study included adult patients (≥18 years) with VOD (ICD-10 diagnosis codes M46.2,3,4,5) treated at a single institution between 01/01/2015 and 12/31/2019. The primary outcome studied was surgery. Candidate predictors were age, sex, race, Elixhauser comorbidity index, first-recorded lab values, first-recorded vital signs, and admit diagnosis. …

Harmonized Cross-Species Cell Atlases Of Trigeminal And Dorsal Root Ganglia, Shamsuddin A Bhuiyan, Lite Yang, Lisa A Mcilvried, Bryan A Copits, Zachariah Bertels, John S Del Rosario, Allie J Widman, Richard A Slivicki, Jiwon Yi, Robert W Gereau Iv, Et Al.

2020-Current year OA Pubs

Sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli to the central nervous system. Single-cell RNA sequencing has provided insights into the diversity of sensory ganglia cell types in rodents, nonhuman primates, and humans, but it remains difficult to compare cell types across studies and species. We thus constructed harmonized atlases of the DRG and TG that describe and facilitate comparison of 18 neuronal and 11 non-neuronal cell types across six species and 31 datasets. We then performed single-cell/nucleus RNA sequencing of DRG from both human and the …

Advanced Hiv Disease And Associated Factors Among Young People Aged 15-24 Years At A Tertiary Hospital In Sierra Leone: A Cross-Sectional Study, Mamadu Baldeh, Samuel Kizito, Sulaiman Lakoh, Daniel Sesay, Samuel Adeyemi Williams, Umu Barrie, Frida Dennis, Dimbintsoa Rakotomalala Robinson, Franck Lamontagne, Franck Amahowe, Patrick Turay, Ozge Sensoy Bahar, Elvin Geng, Fred M Ssewamala

2020-Current year OA Pubs

BACKGROUND: Advanced HIV disease (AHD) in young people living with HIV (PLHIV) is an increasingly pressing public health issue in sub-Saharan Africa. Despite global progress in early HIV testing and reducing HIV-related deaths, many youths experience increased rates of HIV disease progression in sub-Saharan Africa. This study describes the burden, clinical manifestations, and factors for disease progression among young PLHIV aged 15 - 24 years seeking medical services at a major public hospital in Sierra Leone.

METHODS: We performed a cross-sectional analysis of routinely collected data for PLHIV patients aged 15 to 24 seen at Connaught Hospital in Sierra Leone …

Enabling Tobacco Treatment For Gastroenterology Patients Via A Novel Low-Burden Point-Of-Care Model, Suha Abushamma, Li-Shiun Chen, Jingling Chen, Nina Smock, Giang Pham, Chien-Huan Chen

2020-Current year OA Pubs

BACKGROUND & AIM: Smoking is a major risk factor for multiple gastrointestinal cancers, and adversely affects peptic ulcer disease, gastroesophageal reflux, pancreatitis and Crohn's disease. Despite key recommendations for diagnosing and treating tobacco use disorder in healthcare settings, the degree to which this is implemented in Gastroenterology (GI) clinics is unknown. We aimed to assess our providers' practices, identify barriers for implementing evidence-based smoking cessation treatments, and address these barriers by implementing a novel low-burden point of care Electronic health record-enabled evidence-based tobacco treatment (ELEVATE), in GI clinics.

METHODS: An online survey was distributed to clinic gastroenterologists. ELEVATE module training …

Improving Emergency Medicine Resident Pediatric Lumbar Puncture Procedural Performance Through A Brief Just-In-Time Video Intervention, Sarayna S Mcguire, Alexander S Finch, Jenna M Thomas, Octavio Lazaro, Sara A Hevesi, Aidan F Mullan, Jim L Homme

2020-Current year OA Pubs

BACKGROUND: Emergency medicine (EM) trainee comfort level with lumbar puncture (LP) has decreased over time due to changing practice guidelines, particularly amongst pediatric patients. We implemented a "just in time" (JIT) brief educational video based on a previously published LP Performance Scoring Checklist to improve trainee efficiency and competence in LP performance.

METHODS: Our pilot quasi-experimental study took place January-June 2022 within a large, academic Midwestern emergency department (ED) with an established 3-year EM residency program. All 9 interns performed a timed diagnostic LP on an infant LP model in January, scored according to the LP Performance Scoring Checklist. In …

Antibiotic Dispensing Practices Among Informal Healthcare Providers In Low-Income And Middle-Income Countries: A Scoping Review Protocol, Meera Tandan, Poshan Thapa, Buna Bhandari, Sumanth Gandra, Diwash Timalsina, Shweta Bohora, Swostika Thapaliya, Anupama Bhusal, Genevieve C Gore, Surbhi Sheokand, Prachi Shukla, Chandrashekhar Joshi, Nitin Mudgal, Madhukar Pai, Giorgia Sulis

2020-Current year OA Pubs

INTRODUCTION: The rise of antimicrobial resistance represents a critical threat to global health, exacerbated by the excessive and inappropriate dispensing and use of antimicrobial drugs, notably antibiotics, which specifically target bacterial infections. The surge in antibiotic consumption globally is particularly concerning in low-income and middle-income countries (LMICs), where informal healthcare providers (IPs) play a vital role in the healthcare landscape. Often the initial point of contact for healthcare-seeking individuals, IPs play a crucial role in delivering primary care services in these regions. Despite the prevalent dispensing of antibiotics by IPs in many LMICs, as highlighted by existing research, there remains …

Impact Of Cognitive Impairment On Driving Behaviour And Route Choices Of Older Drivers: A Real-World Driving Study, Reihaneh Derafshi, Ganesh M Babulal, Sayeh Bayat

2020-Current year OA Pubs

Maintaining driving independence is important for older adults. However, cognitive decline, a common issue in older populations, can impair older adults' driving abilities and overall safety on the roads. This study explores how cognitive impairment influences driving patterns and driving choices among older adults. We analyzed real-world driving patterns of 246 older adults using GPS dataloggers. Our sample included 230 cognitively normal older adults (CN; Clinical Dementia Rating

Incidence And Risk Factors For New And Recurrent Infarcts In Adults With Sickle Cell Disease, Lori C Jordan, Allison A King, Andria L Ford, Taniya E Varughese, Lisa Garrett, Et Al.

2020-Current year OA Pubs

BACKGROUND: Most adults with sickle cell disease will experience a silent cerebral infarction (SCI) or overt stroke. Identifying patient subgroups with increased stroke incidence is important for future clinical trials focused on stroke prevention. Our 3-center prospective cohort study tested the primary hypothesis that adults with sickle cell disease and SCIs have a greater incidence of new stroke or SCI compared with those without SCI. A secondary aim focused on identifying additional risk factors for progressive infarcts, particularly traditional risk factors for stroke in adults.

METHODS AND RESULTS: This observational study included adults with sickle cell disease and no history …

Protein Restriction Slows The Development And Progression Of Pathology In A Mouse Model Of Alzheimer's Disease, Reji Babygirija, Natalie M Niemi, Et Al.

2020-Current year OA Pubs

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also …

Structural Basis For Hyperpolarization-Dependent Opening Of Human Hcn1 Channel, Verena Burtscher, Jonathan Mount, Jian Huang, John Cowgill, Yongchang Chang, Kathleen Bickel, Jianhan Chen, Peng Yuan, Baron Chanda

2020-Current year OA Pubs

Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 corresponding to Closed, Open, and a putative Intermediate state. Our structures reveal that the downward motion of the gating …

Seeding Activity Of Human Superoxide Dismutase 1 Aggregates In Familial And Sporadic Amyotrophic Lateral Sclerosis Postmortem Neural Tissues By Real-Time Quaking-Induced Conversion, Justin K Mielke, Mikael Klingeborn, Eric P Schultz, Erin L Markham, Emily D Reese, Parvez Alam, Ian R Mackenzie, Cindy V Ly, Byron Caughey, Neil R Cashman, Moses J Leavens

2020-Current year OA Pubs

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2-5 years after diagnosis. The identification of novel prognostic and pharmacodynamic biomarkers are needed to facilitate therapeutic development. Metalloprotein human superoxide dismutase 1 (SOD1) is known to accumulate and form aggregates in patient neural tissue with familial ALS linked to mutations in their SOD1 gene. Aggregates of SOD1 have also been detected in other forms of ALS, including the sporadic form and the most common familial form linked to abnormal hexanucleotide repeat expansions in the Chromosome 9 open reading frame 72 (C9ORF72) gene. Here, we report …

Development Of A Method For Making Optimal Decisions For Intervention Flexibility During Implementation (Modifi): A Modified Delphi Study, Stephanie K Brewer, Catherine M Corbin, Ana A Baumann, Shannon Wiltsey Stirman, Janine M Jones, Michael D Pullmann, Aaron R Lyon, Modifi Expert Panel

2020-Current year OA Pubs

BACKGROUND: Intervention adaptation is often necessary to improve the fit between evidence-based practices/programs and implementation contexts. Existing frameworks describe intervention adaptation processes but do not provide detailed steps for prospectively designing adaptations, are designed for researchers, and require substantial time and resources to complete. A pragmatic approach to guide implementers through developing and assessing adaptations in local contexts is needed. The goal of this project was to develop Making Optimal Decisions for Intervention Flexibility during Implementation (MODIFI), a method for intervention adaptation that leverages human centered design methods and is tailored to the needs of intervention implementers working in applied …

Structural Characterization Of Ligand Binding And Ph-Specific Enzymatic Activity Of Mouse Acidic Mammalian Chitinase, Roberto Efraín Díaz, Andrew K Ecker, Galen J Correy, Pooja Asthana, Iris D Young, Bryan Faust, Michael C Thompson, Ian B Seiple, Steven Van Dyken, Richard M Locksley, James S Fraser

2020-Current year OA Pubs

Chitin is an abundant biopolymer and pathogen-associated molecular pattern that stimulates a host innate immune response. Mammals express chitin-binding and chitin-degrading proteins to remove chitin from the body. One of these proteins, Acidic Mammalian Chitinase (AMCase), is an enzyme known for its ability to function under acidic conditions in the stomach but is also active in tissues with more neutral pHs, such as the lung. Here, we used a combination of biochemical, structural, and computational modeling approaches to examine how the mouse homolog (mAMCase) can act in both acidic and neutral environments. We measured kinetic properties of mAMCase activity across …

Cancer-Associated Histone H3 N-Terminal Arginine Mutations Disrupt Prc2 Activity And Impair Differentiation, Benjamin A Nacev, Benjamin A Garcia, Et Al.

2020-Current year OA Pubs

Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants is exclusively observed on the minor fraction of histone tails harboring the mutations, …

A Longitudinal Mri And Tspo Pet-Based Investigation Of Brain Region-Specific Neuroprotection By Diazepam Versus Midazolam Following Organophosphate-Induced Seizures, Brad A Hobson, Douglas J Rowland, Yimeng Dou, Naomi Saito, Zachary T Harmany, Donald A Bruun, Danielle J Harvey, Abhijit J Chaudhari, Joel R Garbow, Pamela J Lein

2020-Current year OA Pubs

Acute poisoning with organophosphorus cholinesterase inhibitors (OPs), such as OP nerve agents and pesticides, can cause life threatening cholinergic crisis and status epilepticus (SE). Survivors often experience significant morbidity, including brain injury, acquired epilepsy, and cognitive deficits. Current medical countermeasures for acute OP poisoning include a benzodiazepine to mitigate seizures. Diazepam was long the benzodiazepine included in autoinjectors used to treat OP-induced seizures, but it is now being replaced in many guidelines by midazolam, which terminates seizures more quickly, particularly when administered intramuscularly. While a direct correlation between seizure duration and the extent of brain injury has been widely reported, …

Prevalence Of Anti-Myelin Oligodendrocyte Glycoprotein Antibodies Across Neuroinflammatory And Neurodegenerative Diseases, Ritu R Trivedi, Angela S Archambault, Clarice Pavlak, Matteo Gastaldi, Claudia Cantoni, Laura Ghezzi, Anne H Cross, Timothy M Miller, Gregory F Wu

2020-Current year OA Pubs

Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in …