Digital Commons Network^™

Vps13b Is Localized At The Interface Between Golgi Cisternae And Is A Functional Partner Of Fam177a1, Berrak Ugur, Florian Schueder, Jimann Shin, Michael G Hanna, Yumei Wu, Marianna Leonzino, Maohan Su, Anthony R Mcadow, Catherine Wilson, John Postlethwait, Lilianna Solnica-Krezel, Joerg Bewersdorf, Pietro De Camilli

2020-Current year OA Pubs

Mutations in VPS13B, a member of a protein family implicated in bulk lipid transport between adjacent membranes, cause Cohen syndrome. VPS13B is known to be concentrated in the Golgi complex, but its precise location within this organelle and thus the site(s) where it achieves lipid transport remains unclear. Here, we show that VPS13B is localized at the interface between proximal and distal Golgi subcompartments and that Golgi complex reformation after Brefeldin A (BFA)-induced disruption is delayed in VPS13B KO cells. This delay is phenocopied by the loss of FAM177A1, a Golgi complex protein of unknown function reported to be a …

Heterozygous Btnl8 Variants In Individuals With Multisystem Inflammatory Syndrome In Children (Mis-C), Evangelos Bellos, Erica G Schmitt, Et Al.

2020-Current year OA Pubs

Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, "burdenMC," which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5-5.3, P < 10-6). BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2.

Pathogenicity And Virulence Of Human Respiratory Syncytial Virus: Multifunctional Nonstructural Proteins Ns1 And Ns2, Trudy N Merritt, Jingjing Pei, Daisy W Leung

2020-Current year OA Pubs

Human respiratory syncytial virus (hRSV) is a major cause of lower respiratory tract infections in young children, the elderly, and immunocompromised. Despite its discovery over 60 years ago and the global impact on human health, limited effective prophylactic or therapeutic options have been available for hRSV infections. This has largely been attributed to the legacy of vaccine failure in the 1960s using a formalin-inactivated RSV , which led to enhancement of disease post exposure to hRSV infection and hampered subsequent development of vaccine candidates. Recent FDA approval of vaccines for older adults and pregnant individuals are major advancements but leaves …

Development And Validation Of A Prechiasmatic Mouse Model Of Subarachnoid Hemorrhage To Measure Long-Term Cognitive Deficits, Deepti Diwan, Jogender Mehla, James W Nelson, James D Quirk, Sheng-Kwei Song, Sarah Cao, Benjamin Meron, Aminah Mostofa, Gregory J Zipfel

2020-Current year OA Pubs

Controllable and reproducible animal models of aneurysmal subarachnoid hemorrhage (SAH) are crucial for the systematic study of the pathophysiology and treatment of this debilitating condition. However, current animal models have not been successful in replicating the pathology and disabilities seen in SAH patients, especially the long-term neurocognitive deficits that affect the survivor's quality of life. Therefore, there is an unmet need to develop experimental models that reliably replicate the long-term clinical ramifications of SAH - especially in mice where genetic manipulations are straightforward and readily available. To address this need, a standardized mouse SAH model is developed that reproducibly produced …

Subcutaneous Ocrelizumab In Multiple Sclerosis: Results Of The Phase 1b Ocarina I Study, Scott D Newsome, Robert T Naismith, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Subcutaneous ocrelizumab is being developed to provide treatment flexibility and additional choice to patients with multiple sclerosis. OCARINA I (NCT03972306) is an open-label, multicenter, Phase 1b, dose-finding study to investigate the pharmacokinetics, safety, tolerability, and immunogenicity of subcutaneous ocrelizumab and to select a dose for the Phase 3 OCARINA II study (NCT05232825).

METHODS: Patients with relapsing or primary progressive multiple sclerosis (aged 18-65 years; Expanded Disability Status Scale score 0.0-6.5) were enrolled into two groups: previously treated with intravenous ocrelizumab (Group A) or naïve to ocrelizumab (Group B). Patients received single ascending doses of subcutaneous ocrelizumab up to 1200 …

Cxcr3-Cxcl11 Signaling Restricts Angiogenesis And Promotes Pericyte Recruitment, Jihui Lee, Megan E. Goeckel, Allison Levitas, Sarah Colijn, Jimann Shin, Anna Hindes, Geonyoung Mun, Zarek Burton, Bharadwaj Chintalapati, Ying Yin, Javier Abello, Lilianna Solnica-Krezel, Amber N. Stratman

2020-Current year OA Pubs

BACKGROUND: Endothelial cell (EC)-pericyte interactions are known to remodel in response to hemodynamic forces; yet there is a lack of mechanistic understanding of the signaling pathways that underlie these events. Here, we have identified a novel signaling network regulated by blood flow in ECs-the chemokine receptor CXCR3 (CXC motif chemokine receptor 3) and one of its ligands, CXCL11 (CXC motif chemokine ligand 11)-that delimits EC angiogenic potential and promotes pericyte recruitment to ECs during development.

METHODS: We investigated the role of CXCR3 on vascular development using both 2- and 3-dimensional in vitro assays, to study EC-pericyte interactions and EC behavioral …

Dysfunctional Alpha Modulation As A Mechanism Of Working Memory Impairment In Serious Mental Illness, Molly A Erickson, Megan A Boudewyn, Kurt Winsler, Charlotte Li, Deanna M Barch, Cameron S Carter, Michael J Frank, James M Gold, Angus W Macdonald 3rd, John D Ragland, Steven M Silverstein, Andrew Yonelinas, Steven J Luck

2020-Current year OA Pubs

BACKGROUND: People with psychosis and mood disorders experience disruptions in working memory; however, the underlying mechanism remains unknown. We focused on 2 potential mechanisms: poor attentional engagement should be associated with elevated levels of prestimulus alpha-band activity within the electroencephalogram (EEG), whereas impaired working memory encoding should be associated with reduced poststimulus alpha suppression.

METHODS: We collected EEG data from 68 people with schizophrenia, 43 people with bipolar disorder with a history of psychosis, 53 people with major depressive disorder, and 90 healthy comparison subjects while they completed a spatial working memory task. We quantified attention lapsing, memory precision, and …

The Effects Of Mosaicism On Biological And Clinical Markers Of Alzheimer's Disease In Adults With Down Syndrome, Laura Xicota, Rachel L Henson, Beau Ances, Et Al.

2020-Current year OA Pubs

BACKGROUND: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.

METHODS: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma …

Quantifying Brain Development In The Healthy Brain And Child Development (Hbcd) Study: The Magnetic Resonance Imaging And Spectroscopy Protocol, Douglas C Dean 3rd, Chad M Sylvester, Michael P Harms, Christopher D Smyser, Et Al.

2020-Current year OA Pubs

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. The acquisition of multimodal magnetic resonance-based brain development data is central to the study's core protocol. However, application of Magnetic Resonance Imaging (MRI) methods in this population is complicated by technical challenges and difficulties of imaging in early life. Overcoming these challenges requires an innovative and harmonized approach, combining age-appropriate acquisition protocols together with specialized pediatric neuroimaging strategies. The HBCD MRI Working Group aimed to establish a core acquisition …

Emergent Microenvironments Of Nucleoli, Matthew R King, Kiersten M Ruff, Rohit V Pappu

2020-Current year OA Pubs

In higher eukaryotes, the nucleolus harbors at least three sub-phases that facilitate multiple functionalities including ribosome biogenesis. The three prominent coexisting sub-phases are the fibrillar center (FC), the dense fibrillar component (DFC), and the granular component (GC). Here, we review recent efforts in profiling sub-phase compositions that shed light on the types of physicochemical properties that emerge from compositional biases and territorial organization of specific types of macromolecules. We highlight roles played by molecular grammars which refers to protein sequence features including the substrate binding domains, the sequence features of intrinsically disordered regions, and the multivalence of these distinct types …

Inflammation, Physical Activity, And Disease-Free Survival In Stage Iii Colon Cancer: Cancer And Leukemia Group B-Southwest Oncology Group 80702 (Alliance), Justin C Brown, Chao Ma, Qian Shi, Felix Couture, Philip Kuebler, Pankaj Kumar, Benjamin Tan, Smitha Krishnamurthi, Victor Chang, Richard M Goldberg, Eileen M O'Reilly, Anthony F Shields, Jeffrey A Meyerhardt

2020-Current year OA Pubs

BACKGROUND: Inflammation and insufficient physical inactivity contribute to individual-level risk of disease recurrence and death in stage III colon cancer. The extent to which increased inflammatory risk can be offset by sufficient physical activity remains unknown.

METHODS: This cohort study was nested within the Cancer and Leukemia Group B (now part of the Alliance for Clinical Trials in Oncology) and Southwest Oncology Group randomized trial. Inflammatory burden was quantified by high-sensitivity C-reactive protein, interleukin-6, and soluble tumor necrosis factor-α receptor 2 after recovery from tumor resection. Physical activity was measured during and after postoperative chemotherapy. The primary endpoint was disease-free …

The Sodium-Proton Exchangers Snhe And Nhe1 Control Plasma Membrane Hyperpolarization In Mouse Sperm, Analia G Novero, Celia M Santi, Et Al.

2020-Current year OA Pubs

Sperm capacitation is a complex process that takes place in the female reproductive tract and empowers mammalian sperm with the competence to fertilize an egg. It consists of an intricate cascade of events that can be mimicked in vitro through incubation in a medium containing essential components, such as bicarbonate, albumin, Ca

Solid-State Nmr Compositional Analysis Of Sputum From People With Cystic Fibrosis, Kathy Duong, Evan Moss, Courtney Reichhardt

2020-Current year OA Pubs

People with the genetic disease cystic fibrosis (CF) often have chronic airway infections and produce airway secretions called sputum. A better understanding of sputum composition is desired in order to track changes in response to CF therapeutics and to improve laboratory models for the study of CF airway infections. The glycosylated protein mucin is a primary component. Along with extracellular DNA, mucin gives rise to the high viscoelasticity of sputum, which inhibits airway clearance and is thought to promote chronic airway infections in people with CF. Past studies of sputum composition identified additional biomolecular components of sputum including other proteins, …

Spatial, Transcriptomic, And Epigenomic Analyses Link Dorsal Horn Neurons To Chronic Pain Genetic Predisposition, Cynthia M Arokiaraj, Alexander Chamessian, Et Al.

2020-Current year OA Pubs

Key mechanisms underlying chronic pain occur within the dorsal horn. Genome-wide association studies (GWASs) have identified genetic variants predisposed to chronic pain. However, most of these variants lie within regulatory non-coding regions that have not been linked to spinal cord biology. Here, we take a multi-species approach to determine whether chronic pain variants impact the regulatory genomics of dorsal horn neurons. First, we generate a large rhesus macaque single-nucleus RNA sequencing (snRNA-seq) atlas and integrate it with available human and mouse datasets to produce a single unified, species-conserved atlas of neuron subtypes. Cellular-resolution spatial transcriptomics in mouse shows the precise …

Metabolite Signatures Of Chronological Age, Aging, Survival, And Longevity, Paola Sebastiani, Mary F Feitosa, Mary K Wojczynski, Gary J Patti, Et Al.

2020-Current year OA Pubs

Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies. By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic …

A Circular Engineered Sortase For Interrogating Histone H3 In Chromatin, Samuel D Whedon, Emily Zahn, Benjamin A Garcia, Et Al.

2020-Current year OA Pubs

Reversible modification of the histone H3 N-terminal tail is critical in regulating chromatin structure, gene expression, and cell states, while its dysregulation contributes to disease pathogenesis. Understanding the crosstalk between H3 tail modifications in nucleosomes constitutes a central challenge in epigenetics. Here we describe an engineered sortase transpeptidase, cW11, that displays highly favorable properties for introducing scarless H3 tails onto nucleosomes. This approach significantly accelerates the production of both symmetrically and asymmetrically modified nucleosomes. We demonstrate the utility of asymmetrically modified nucleosomes produced in this way in dissecting the impact of multiple modifications on eraser enzyme processing and molecular recognition …

Lymphocytic Choriomeningitis Arenavirus Utilises Intercellular Connections For Cell To Cell Spread, Owen Byford, Amelia B Shaw, Hiu Nam Tse, Alex Moon-Walker, Erica Ollmann Saphire, Sean P J Whelan, Martin Stacey, Roger Hewson, Juan Fontana, John N Barr

2020-Current year OA Pubs

The Arenaviridae family of segmented RNA viruses contains nearly 70 species with several associated with fatal haemorrhagic fevers, including Lassa, Lujo and Junin viruses. Lymphocytic choriomeningitis arenavirus (LCMV) is associated with fatal neurologic disease in humans and additionally represents a tractable model for studying arenavirus biology. Within cultured cells, a high proportion of LCMV spread is between directly neighbouring cells, suggesting infectivity may pass through intercellular connections, bypassing the canonical extracellular route involving egress from the plasma membrane. Consistent with this, we visualized abundant actin- and tubulin-rich connections conjoining LCMV-infected and uninfected cells within cultures, resembling tunnelling nanotubes (TNTs). Within …

A Proteogenomic Analysis Of Cervical Cancer Reveals Therapeutic And Biological Insights, Jing Yu, Li Ding, Et Al.

2020-Current year OA Pubs

Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women's health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes. EP300 is found to enhance the acetylation of FOSL2-K222, consequently accelerating the malignant proliferation of CC cells. Proteomic stratification identifies three patient subgroups with distinct features in prognosis, …

Effectiveness And Safety Of Irreversible Electroporation When Used For The Ablation Of Stage 3 Pancreatic Adenocarcinoma: Initial Results From The Direct Registry Study, Robert C G Martin, Rebekah Ruth White, Malcolm M Bilimoria, Michael D Kluger, David A Iannitti, Patricio M Polanco, Chet W Hammil, Sean P Cleary, Robert Evans Heithaus, Theodore Welling, Carlos H F Chan

2020-Current year OA Pubs

BACKGROUND/OBJECTIVES: Overall survival for patients with Stage 3 pancreatic ductal adenocarcinoma (PDAC) remains limited, with a median survival of 12 to 15 months. Irreversible electroporation (IRE) is a local tumor ablation method that induces cancerous cell death by disrupting cell membrane homeostasis. The DIRECT Registry study was designed to assess the effectiveness and safety of IRE when combined with standard of care (SOC) treatment for Stage 3 PDAC versus SOC alone in a real-world setting after at least 3 months of induction chemotherapy; Methods: Patients with Stage 3 PDAC treated with IRE plus SOC or SOC alone were prospectively enrolled …

Does Muscle Pain Induce Alterations In The Pelvic Floor Motor Unit Activity Properties In Interstitial Cystitis/Bladder Pain Syndrome? A High-Density Semg-Based Study, Monica Albaladejo-Belmonte, Michael Houston, Nicholas Dias, Theresa Spitznagle, Henry Lai, Yingchun Zhang, Javier Garcia-Casado

2020-Current year OA Pubs

Several studies have shown interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic condition that poses challenges in both diagnosis and treatment, is associated with painful pelvic floor muscles (PFM) and altered neural drive to these muscles. However, its pathophysiology could also involve other alterations in the electrical activity of PFM motor units (MUs). Studying these alterations could provide novel insights into IC/BPS and help its clinical management. This study aimed to characterize PFM activity at the MU level in women with IC/BPS and pelvic floor myalgia using high-density surface electromyography (HD-sEMG). Signals were recorded from 15 patients and 15 healthy controls …

Samd7 Represses Short-Wavelength Cone Genes To Preserve Long-Wavelength Cone And Rod Photoreceptor Identity, Leo I Volkov, Yohey Ogawa, Ramiz Somjee, Hannah E Vedder, Hannah E Powell, Deepak Poria, Sam Meiselman, Vladimir J Kefalov, Joseph C Corbo

2020-Current year OA Pubs

The role of transcription factors in photoreceptor gene regulation is fairly well understood, but knowledge of the cell-type-specific function of transcriptional cofactors remains incomplete. Here, we show that the transcriptional corepressor

Disordered Proteins Interact With The Chemical Environment To Tune Their Protective Function During Drying, Shraddha Kc, Kenny H Nguyen, Vincent Nicholson, Annie Walgren, Tony Trent, Edith Gollub, Paulette Sofia Romero-Perez, Alex S Holehouse, Shahar Sukenik, Thomas C Boothby

2020-Current year OA Pubs

The conformational ensemble and function of intrinsically disordered proteins (IDPs) are sensitive to their solution environment. The inherent malleability of disordered proteins, combined with the exposure of their residues, accounts for this sensitivity. One context in which IDPs play important roles that are concomitant with massive changes to the intracellular environment is during desiccation (extreme drying). The ability of organisms to survive desiccation has long been linked to the accumulation of high levels of cosolutes such as trehalose or sucrose as well as the enrichment of IDPs, such as late embryogenesis abundant (LEA) proteins or cytoplasmic abundant heat-soluble (CAHS) proteins. …

Reconstitution Of Arp2/3-Nucleated Actin Assembly With Proteins Cp, V-1, And Carmil, Olivia L Mooren, Patrick Mcconnell, James D Debrecht, Anshuman Jaysingh, John A Cooper

2020-Current year OA Pubs

Actin polymerization is often associated with membrane proteins containing capping-protein-interacting (CPI) motifs, such as capping protein, Arp2/3, myosin I linker (CARMIL), CD2AP, and WASHCAP/Fam21. CPI motifs bind directly to actin-capping protein (CP), and this interaction weakens the binding of CP to barbed ends of actin filaments, lessening the ability of CP to functionally cap those ends. The protein V-1/myotrophin binds to the F-actin-binding site on CP and sterically blocks CP from binding barbed ends. CPI-motif proteins also weaken the binding between V-1 and CP, which decreases the inhibitory effects of V-1, thereby freeing CP to cap barbed ends. Here, we …

Mitochondrial Pyruvate Transport Regulates Presynaptic Metabolism And Neurotransmission, Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Marion I Stunault, Hao Zhang, Xiangfeng Niu, Marissa A Laramie, Jasmin Sponagel, Leah P Shriver, Gary J Patti, Vitaly A Klyachko, Ghazaleh Ashrafi

2020-Current year OA Pubs

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal …

A Phase I First-In-Human Study Of Abbv-011, A Seizure-Related Homolog Protein 6-Targeting Antibody-Drug Conjugate, In Patients With Small Cell Lung Cancer, Daniel Morgensztern, Et Al.

2020-Current year OA Pubs

PURPOSE: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy.

PATIENTS AND METHODS: ABBV-011 was administered intravenously once every 3 weeks during dose escalation (0.3-2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by IHC) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated.

RESULTS: As of August 2022, 99 patients received ABBV-011 monotherapy [dose escalation, …

Pvacview: An Interactive Visualization Tool For Efficient Neoantigen Prioritization And Selection, Huiming Xia, My H Hoang, Evelyn Schmidt, Susanna Kiwala, Joshua Mcmichael, Zachary L Skidmore, Bryan Fisk, Jonathan J Song, Jasreet Hundal, Thomas Mooney, Jason R Walker, S Peter Goedegebuure, Christopher A Miller, William E Gillanders, Obi L Griffith, Malachi Griffith

2020-Current year OA Pubs

BACKGROUND: Neoantigen-targeting therapies including personalized vaccines have shown promise in the treatment of cancers, particularly when used in combination with checkpoint blockade therapy. At least 100 clinical trials involving these therapies have been initiated globally. Accurate identification and prioritization of neoantigens is crucial for designing these trials, predicting treatment response, and understanding mechanisms of resistance. With the advent of massively parallel DNA and RNA sequencing technologies, it is now possible to computationally predict neoantigens based on patient-specific variant information. However, numerous factors must be considered when prioritizing neoantigens for use in personalized therapies. Complexities such as alternative transcript annotations, various …

Identification And Characterization Of The Lipoprotein N-Acyltransferase In Bacteroides, Krista M Armbruster, Jiawen Jiang, Mariana G Sartorio, Nichollas E Scott, Jenna M Peterson, Jonathan Z Sexton, Mario F Feldman, Nicole M Koropatkin

2020-Current year OA Pubs

Members of the Bacteroidota compose a large portion of the human gut microbiota, contributing to overall gut health via the degradation of various polysaccharides. This process is facilitated by lipoproteins, globular proteins anchored to the cell surface by a lipidated N-terminal cysteine. Despite their importance, lipoprotein synthesis by these bacteria is understudied. In

Associations Between Dietary Patterns And Quality Of Life In A Longitudinal Cohort Of Colorectal Cancer Survivors, Kristen S Smith, Adetunji T Toriola, Et Al.

2020-Current year OA Pubs

PURPOSE: To characterize dietary patterns and examine associations with cross-sectional and longitudinal changes in quality of life (QOL) over approximately one year after colorectal cancer (CRC) diagnosis.

METHODS: The ColoCare Study is an international, multi-center, prospective cohort study of newly diagnosed CRC survivors of any stage. A subset of participants with CRC in the United States completed patient-reported outcome measures at 6- and 12-months post-enrollment, including the Food Frequency Questionnaire (FFQ) and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Dietary patterns at 6 months (around the time of treatment completion) were identified …

Dilated Cardiomyopathy-Associated Skeletal Muscle Actin (Acta1) Mutation R256h Disrupts Actin Structure And Function And Causes Cardiomyocyte Hypocontractility, Ankit Garg, Silvia Jansen, Lina Greenberg, Rui Zhang, Kory J Lavine, Michael J Greenberg

2020-Current year OA Pubs

Skeletal muscle actin (ACTA1) mutations are a prevalent cause of skeletal myopathies consistent with ACTA1's high expression in skeletal muscle. Rare de novo mutations in ACTA1 associated with combined cardiac and skeletal myopathies have been reported, but ACTA1 represents only ~20% of the total actin pool in cardiomyocytes, making its role in cardiomyopathy controversial. Here we demonstrate how a mutation in an actin isoform expressed at low levels in cardiomyocytes can cause cardiomyopathy by focusing on a unique ACTA1 variant, R256H. We previously identified this variant in a family with dilated cardiomyopathy, who had reduced systolic function without clinical skeletal …

Microglia Drive Diurnal Variation In Susceptibility To Inflammatory Blood-Brain Barrier Breakdown, Jennifer H. Lawrence, Asha Patel, Melvin W. King, Collin J. Nadarajah, Richard Daneman, Erik S. Musiek

2020-Current year OA Pubs

The blood-brain barrier (BBB) is critical for maintaining brain homeostasis but is susceptible to inflammatory dysfunction. While transporter-dependent efflux of some lipophilic substrates across the BBB shows circadian variation due to rhythmic transporter expression, basal transporter-independent permeability and leakage is nonrhythmic. Whether daily timing influences BBB permeability in response to inflammation is unknown. Here, we induced systemic inflammation through repeated LPS injections either in the morning (ZT1) or evening (ZT13) under standard lighting conditions; we then examined BBB permeability to a polar molecule that is not a transporter substrate, sodium fluorescein. We observed clear diurnal variation in inflammatory BBB permeability, …