Digital Commons Network^™

Nerve-Associated Macrophages Control Adipose Homeostasis Across Lifespan And Restrain Age-Related Inflammation, Elsie Gonzalez-Hurtado, Maxim N Artyomov, Et Al.

2020-Current year OA Pubs

Age-related inflammation or 'inflammaging' increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice. Aging led to depletion of vessel-associated macrophages, expansion of lipid-associated macrophages and emergence of a unique subset of CD38

Aberrant Expression Of Nuclear Prothymosin Α Contributes To Epithelial-Mesenchymal Transition In Lung Cancer, Liyun Chen, Chung-Teng Wang, Jia-Ming Chang, Ai-Li Shiau, Gia-Shing Shieh, Yau-Lin Tseng, Yi-Ting Yen, Tang-Hsiu Huang, Li-Hsin Cheng, Yu-Chih Wu, Chao-Liang Wu, Bing-Hua Su, Pensee Wu

2020-Current year OA Pubs

Elevated expression of prothymosin α (ProT) is frequently observed in cancers, but the underlying molecular mechanism remains poorly understood. Here, we report the clinical relevance of ProT expression and its correlation with lung cancer progression. We have shown that ProT was highly expressed in early-stage lung cancer, exhibiting nuclear localization; on the contrary, a loss of nuclear ProT expression was detected in late-stage tumor specimens. Furthermore, the expression of nuclear ProT impaired lung cancer cell migration, suppressed TGF-β-induced epithelial-to-mesenchymal transition (EMT)-associated transcription factor expression, and inhibited in vivo tumor metastasis. The suppressive effect of ProT was further found to trigger …

The Impact Of Waitlisting After A Weekend On Transplant-Related Outcomes For Patients With Acute Liver Failure In The Us, Melis G Celdir, Qianyi Shi, Tomohiro Tanaka

2020-Current year OA Pubs

INTRODUCTION: Potential delays in patient care during weekends have not been studied in liver transplantation (LT) for acute liver failure (ALF). We evaluated the impact of listing after a weekend on waitlist (WL) and post-LT outcomes in ALF patients.

METHODS: In a retrospective cohort study of adult ALF patients from February 2002 to May 2023 in the United Network for Organ Sharing (UNOS) database, the primary exposure was listing after a weekend. Multinomial regression and Cox models assessed WL outcomes and post-LT mortality, respectively, adjusting for potential confounders. Inverse probability censoring weighting addressed censoring bias.

RESULTS: Among 6600 adults listed …

Variation In Recommended Treatment Strategies Among American Surgeons For Actual Adult Traumatic Brachial Plexus Injury Cases, Michele N Christy, Christopher J Dy, R Glenn Gaston, Bryan J Loeffler, Mihir J Desai, Steve K Lee, Harvey Chim, Jeffrey B Friedrich, Sameer K Puri, Jason H Ko, Planet Study Group

2020-Current year OA Pubs

PURPOSE: The surgical management of adult traumatic brachial plexus injuries (BPI) is challenging, with no consensus on optimal strategies. This study aimed to gather preferred reconstructive strategies from BPI surgeons for actual cases from a multicenter cohort to identify areas of agreement.

METHODS: Four case files (history, physical examination, and imaging and electrodiagnostic testing results) were distributed to eight self-designated Level IV expert BPI surgeons in the United States. Each surgeon independently reviewed the cases and provided a preferred reconstructive plan via free text response.

RESULTS: For a pan-plexus case after blunt trauma (67 years old; 3 months from injury): …

S1pr1 Regulates Lymphatic Valve Development And Tertiary Lymphoid Organ Formation In The Ileum, Xin Geng, Gwendalyn J Randolph, Et Al.

2020-Current year OA Pubs

Efficient lymph flow is ensured by lymphatic valves (LVs). The mechanisms that regulate LV development are incompletely understood. Here, we show that the deletion of the GPCR sphingosine 1-phosphate receptor-1 (S1PR1) from lymphatic endothelial cells (LECs) results in fewer LVs. Interestingly, LVs that remained in the terminal ileum-draining lymphatic vessels were specifically dysfunctional. Furthermore, tertiary lymphoid organs (TLOs) formed in the terminal ileum of the mutant mice. TLOs in this location are associated with ileitis in humans and mice. However, mice lacking S1PR1 did not develop obvious characteristics of ileitis. Mechanistically, S1PR1 regulates shear stress signaling and the expression of …

Neutrophils Drive Vascular Occlusion, Tumour Necrosis And Metastasis, Jose M Adrover, Xiao Han, Lijuan Sun, Takeo Fujii, Nicole Sivetz, Juliane Daßler-Plenker, Clary Evans, Jessica Peters, Xue-Yan He, Courtney D Cannon, Won Jin Ho, George Raptis, R Scott Powers, Mikala Egeblad

2020-Current year OA Pubs

Tumour necrosis is associated with poor prognosis in cancer

Walking Interventions And Cognitive Health In Older Adults: A Systematic Review Of Randomized Controlled Trials, Jongwon Lee, Delia West, Christine Pellegrini, Jingkai Wei, Sara Wilcox, Jean Neils-Strunjas, A Caroline Rudisill, Daniela B Friedman, David X Marquez, Jenna Dzwierzynski, Joyce Balls-Berry, Rachelle Gajadhar, Chih-Hsiang Yang

2020-Current year OA Pubs

ObjectiveThis systematic review summarizes the effectiveness and the dose of walking interventions on specific cognition domains in older adults, including executive function, memory, attention, processing speed, and global cognition.Data sourcePublished randomized controlled trials in PubMed, Embase, and Web of Science until 10 May 2023.Study Inclusion and Exclusion CriteriaStudies include older adults without Alzheimer's or related dementias, involving a walking intervention and performance-based neuropsychological assessments for executive function, memory, processing speed, attention, or global cognition.Data ExtractionTwo independent research assistants reviewed 8424 studies and included 17 studies.Data SynthesisParticipant demographics, intervention features (type, intensity, time, frequency, duration, format, and context), cognitive assessment tools, …

Rezafungin Versus Caspofungin For The Treatment Of Candidemia And Invasive Candidiasis: Results From The Double-Blind, Randomized, Phase 3 Restore Trial Including The China Extension Study, George R Thompson, Haihui Huang, Sizhou Feng, Yunsong Yu, Alex Soriano, Oliver A Cornely, Bart Jan Kullberg, Peter G Pappas, Marin Kollef, Jose A Vazquez, Patrick M Honore, Laura Cox, Matteo Bassetti

2020-Current year OA Pubs

BACKGROUND: Rezafungin is approved for use in adults with candidemia and/or invasive candidiasis (IC) based on data from the ReSTORE trial (NCT03667690), which demonstrated noninferior efficacy to caspofungin. For regulatory purposes, an additional cohort of patients from China was recruited to ReSTORE. Here, we compared rezafungin and caspofungin in patients with candidemia and/or IC through analysis of the ReSTORE global data plus the China extension study.

METHODS: Adults with candidemia/IC were randomized (1:1) to receive weekly rezafungin (400/200 mg) or daily caspofungin (70/50 mg) for ≤28 days. Noninferiority was concluded for primary efficacy endpoints if the upper bound of the …

Identifying Care Gaps Along The Hiv Treatment Failure Cascade: A Multistate Analysis Of Viral Load Monitoring, Re-Suppression, And Regimen Switches In Zambia, Kombatende Sikombe, Noelle Le Tourneau, Brian Rice, Jake M. Pry, Sandra Simbeza, Laura K. Beres, Anjali Sharma, Njekwa Mukamba, Alison Wringe, James R. Hargreaves, Jacob Mutale, Carolyn Bolton Moore, Izukanji Sikazwe, Elvin Geng, Aaloke Mody

2020-Current year OA Pubs

BACKGROUND: Timely response to treatment failure is critical for improved outcomes and viral re-suppression among people living with HIV, but care gaps along the treatment failure cascade can occur due to delays by both clients (e.g., retention and adherence) and health systems (e.g., fidelity to viral load [VL] monitoring guidelines). We used multistate analysis to identify drivers of implementation gaps in the treatment failure cascade, including time to HIV VL monitoring, re-suppression, and regimen switches, in Zambia.

METHODS AND FINDINGS: We used national electronic HIV health records to identify adults on antiretroviral therapy (ART) for more than 6 months who …

Acinetobacter Phages Use Distinct Strategies To Breach The Capsule Barrier, Alexis J. Mccalla, Forrest C. Walker, Fabiana Bisaro, Miguel Rodriguez-Anavitate, Anna Johannesman, Gisela Di Venanzio, Mario F. Feldman, Michele Leroux

2020-Current year OA Pubs

Acinetobacter baumannii is an opportunistic pathogen that is a growing threat in hospital settings due to its alarmingly high rates of antibiotic resistance. Alternative therapies are urgently needed to manage the growing burden of untreatable A. baumannii infections. Phage therapy is a promising avenue that has already seen some success in isolated compassionate-use cases, including the famous "Patterson case". Bacterial surface structures are the first determinants of susceptibility to phage infection and play a major role in phage host range. Most A. baumannii strains produce a protective capsule that is highly diverse both in structure and composition, and provides the …

Characterization Of A Mouse Model Of Osteoarticular Infection Using Clinical Isolates Of Staphylococcus Aureus, Philip M Roper, Jessica Beetner, Jennifer L Davis, Christine Shao, Jason Zhang, Linda Cox, Nitin Kumar Pokhrel, James E Cassat, Javier Rangel-Moreno, Gowrishankar Muthukrishnan, Deborah J Veis

2020-Current year OA Pubs

Osteoarticular infection, most commonly due to

Associations Of Biomarkers Of Systemic Inflammation, Angiogenesis, And Cell-To-Cell Adhesion With Tumor Budding Among Early-Onset And Later-Onset Colorectal Cancer Patients, Oda Hausmann, Adetunji T Toriola, Et Al.

2020-Current year OA Pubs

BACKGROUND: High tumor budding and elevated systemic inflammation are adverse prognostic indicators in colorectal cancer. Its underlying mechanisms remain poorly understood. It is unclear whether systemic inflammation, angiogenesis, and cell-to-cell adhesion influence tumor budding.

METHODS: We investigated n = 132 stage I-III colorectal cancer patients recruited at Huntsman Cancer Institute enrolled in the ColoCare Study. Tumor budding was evaluated using an evidence-based scoring system, and patient sera were analyzed for nine circulating biomarkers using the Meso Scale Discovery platform. We examined associations between biomarkers and tumor budding using multivariable linear regression models adjusted for age, sex, neoadjuvant treatment, stage, and …

Minimally Invasive, Bioadaptive Multimodal Sensor Probe With Safe Deployment For Real-Time Acute Compartment Syndrome Diagnosis, Seung Gi Seo, Amanda M Westman, William Moritz, Joseph Ribaudo, Mitchell A Pet, Et Al.

2020-Current year OA Pubs

Acute Compartment Syndrome (ACS) is a serious medical condition that arises from increased pressure within osteofascial compartments, leading to impaired blood flow and potential tissue damage. Early and accurate diagnosis is critical for preventing permanent damage. Current methods rely largely on qualitative assessments with limited accuracy, and those that exploit invasive pressure measurements often prove inadequate. Herein, a soft materials-based multimodal sensor probe is introduced, as well as the mechanical and thermal influences to monitor intra-compartmental pressure, tissue oxygen saturation (StO

Machine Learning Feasibility In Cochlear Implant Speech Perception Outcomes-Moving Beyond Single Biomarkers For Cochlear Implant Performance Prediction, Matthew A. Shew, Cole Pavelchek, Andrew Michelson, Amanda Ortmann, Shannon Lefler, Amit Walia, Nedim Durakovic, Alisa Phillips, Ayna Rejepova, Jacques A. Herzog, Phillip Payne, Jay F. Piccirillo, Craig A. Buchman

2020-Current year OA Pubs

OBJECTIVES: Machine learning (ML) is an emerging discipline centered around complex pattern matching and large data-based prediction modeling and can improve precision medicine healthcare. Cochlear implants (CI) are highly effective, however, outcomes vary widely, and accurately predicting speech perception performance outcomes between patients remains a challenge. This study aims to evaluate the ability of ML to predict speech perception performance among CI recipients at 6-month post-implantation using only preoperative variables on one of the largest CI datasets to date, with an emphasis placed on identification of poor performers.

DESIGN: All patients enrolled in the national CI outcome tracking database, HERMES, …

Acad10 And Acad11 Enable Mammalian 4-Hydroxy Acid Lipid Catabolism, Edrees H Rashan, Abigail K Bartlett, Jingying Zhang, Andrew J Smith, Zakery N Baker, Patrick Forny, Peng Yuan, David J Pagliarini, Et Al.

2020-Current year OA Pubs

Fatty acid β-oxidation is a central catabolic pathway with broad health implications. However, various fatty acids, including 4-hydroxy acids (4-HAs), are largely incompatible with β-oxidation machinery before being modified. Here we reveal that two atypical acyl-CoA dehydrogenases, ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains that phosphorylate the 4-hydroxy position as a requisite step in converting 4-hydroxyacyl-CoAs into conventional 2-enoyl-CoAs. Through cryo-electron microscopy and molecular modeling, we identified an atypical dehydrogenase binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain …

Assessing Stages Of Objective Memory Impairment And Neuroimaging As Risk Factors Of Incident Cognitive Impairment, Kellen K Petersen, Ali Ezzati, Bhargav T Nallapu, Richard B Lipton, Reisa A Sperling, Kathryn V Papp, Dorene M Rentz, Keith A Johnson, Ellen Grober

2020-Current year OA Pubs

OBJECTIVE: The Stages of Objective Memory Impairment (SOMI) system, based on the Free and Cued Selective Reminding Test (FCSRT), is a potential marker of subtle cognitive impairment in cognitively normal persons defined by a Clinical Dementia Rating (CDR) = 0. We investigated SOMI's ability to predict incident cognitive impairment (CDR >0) in combination with demographic features and neuroimaging biomarkers.

METHODS: Cognitively unimpaired participants (CDR = 0) from the Harvard Aging Brain Study had baseline FCSRT scores, MRI, FDG-PET, and PiB-PET as well as follow-up CDRs for 5 years. Cox proportional hazards models with correction for multiple testing assessed the predictive …

Drug-Drug Interaction Between Dolutegravir And Artemether-Lumefantrine In Hiv And Malaria Mono- And Co-Infections: A Pharmacogenetic Analysis From Ghana, Nicholas Ekow Thomford, Tracy Kellermann, Joel Adu Twum, John Anyimadu, Charné Dixon, Dennis Sappor, Dee Blackhurst, Prince Amoah Barnie, Oksana Ryabinina, Samuel Badu Nyarko, Robert Peter Biney, Martins Ekor, George B Kyei

2020-Current year OA Pubs

BACKGROUND: Human Immunodeficiency Virus and malaria are significant public health challenges in sub-Saharan Africa, contributing substantially to morbidity and mortality in the region. The trajectory of HIV and malaria mono- and coinfections may be different with presentations of drug-drug and disease-disease interactions. Current medications of artemether-lumefantrine and dolutegravir (DTG) -based anti-retroviral therapy which are the preferred drugs are metabolised by CYP2B6, CYP3A4/5 and UGTs which are polymorphic and may contribute to drug disposition and clinical outcomes. This study investigated the pharmacogenetic effects of co-administration of arthemeter-lumfantrine and DTG in HIV-malaria mono and coinfection.

METHODS: Malaria and HIV mono- and coinfected …

Factors Associated With Erectile Dysfunction In Men With Lower Urinary Tract Symptoms (Luts): A Symptoms Of Lower Urinary Tract Dysfunction Research Network (Lurn) Study, Devin Boehm, Abigail R. Smith, Sarah A. Mansfield, Kathryn E. Flynn, Richard J. Fantus, Alexander P. Glaser, Brian T. Helfand, Margaret Helmuth, Tara N. Morgan, H. Henry Lai, Aruna V. Sarma, Claire C. Yang, Ziya Kirkali, James W. Griffith

2020-Current year OA Pubs

BACKGROUND: Erectile function (EF) and its associated covariates have not been extensively studied in a large covariate of patients seeking treatment for lower urinary tract symptoms (LUTS). Our objective is to determine the relationship between urinary symptoms and comorbidities with erectile dysfunction (ED) in 447 treatment-seeking men with LUTS.

METHODS: Data from the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) observational cohort study were analyzed using multivariable logistic regression models to quantify the relationship between LUTS and ED. Models also included anxiety, depression, obesity, cardiovascular disease (CVD), diabetes, and medication use.

RESULTS: Men reporting sexual activity were younger …

The Caribbean American Dementia And Aging Study: Protocol For A Population-Based Study Of Older Adult Health And Dementia In Cuba, The Dominican Republic, And Puerto Rico, Mao-Mei Liu, Jorge Llibre-Guerra, Chris Soria, Jing Li, Tania Zayas Llerena, Guillermina Rodriguez, Daisy Acosta, Ivonne Jiménez Velázquez, Juan J Llibre-Rodriguez, William H Dow

2020-Current year OA Pubs

BACKGROUND: The Hispanic Caribbean region is rapidly aging but national population-based aging surveys are rare. The Caribbean American Dementia and Aging Study (CADAS) is a multi-purpose household study of aging with a particular focus on the life course determinants and consequences of health and dementia in three countries with many similarities but divergent recent histories: Puerto Rico, Dominican Republic, and Cuba. METHODS: CADAS will survey population-based samples of adults ages 65 and over. In Puerto Rico and Dominican Republic these will be nationally representative samples of 1,500 adults each; the Cuban survey will include 1,500 adults from purposively selected urban …

Excitotoxic Neuronal Death Requires Superoxide Entry Into Neurons Through Volume-Regulated Anion Channels, Kate Harris, Seok Joon Won, Gokhan Uruk, Nguyen Mai, Devran Ogut, Yonghui Zhao, Litao Xie, Paul Baxter, Katharina Everaerts, Rajan Sah, Raymond A Swanson

2020-Current year OA Pubs

Neuronal death in stroke and other conditions stems in part from stimulation of

Prefoldin Complex Promotes Interferon-Stimulated Gene Expression And Is Inhibited By Rotavirus Vp3, Yinxing Zhu, Yanhua Song, Dilip Kumar, Peter K Jackson, B V Venkataram Prasad, Siyuan Ding

2020-Current year OA Pubs

Timely induction of interferons and interferon-stimulated genes (ISGs) is critical for successful host defense against viral infections. VP3 encoded by rotavirus is implicated in interferon antagonism. However, the precise mechanisms remain incompletely understood. By conducting tandem-affinity purification coupled with high-resolution mass spectrometry, we identify the prefoldin complex as the top cellular binding partner of VP3. Rotavirus infection is significantly enhanced in prefoldin subunit knockout cells. Using proteome-wide label-free quantification, we find that prefoldin assists in folding ubiquitin-like-modifier-activating-enzyme-3 (UBA3), both of which positively regulate ISG expression. Through direct and competitive binding, VP3 interferes with the chaperone activity of prefoldin, leading to …

Adapt-3d: Accelerated Deep Adaptable Processing Of Tissue For 3-Dimensional Fluorescence Tissue Imaging For Research And Clinical Settings, Daniel D Lee, Kevin A Telfer, Deanna L Davis, Leon C D Smyth, Rahul Ravindran, Rafael S Czepielewski, Christopher G Huckstep, Siling Du, Kento Kurashima, Ajay K Jain, Jonathan Kipnis, Bernd H Zinselmeyer, Gwendalyn J Randolph

2020-Current year OA Pubs

Light sheet microscopy and preparative clearing methods that improve light penetration in 3D tissues have revolutionized imaging in biomedical research. Here we present ADAPT-3D, a streamlined 3-step approach to turn tissues optically transparent while preserving tissue architecture with the versatility to handle diverse tissue sizes and types across species. Unlike extensive lipid removal utilized by existing protocols, ADAPT-3D only partially removes lipids to preserve cell membranes, yet the non-toxic aqueous refractive indexing solution still rapidly turns tissues transparent while preserving the fluorescence of endogenous and antibody conjugated fluorophores. ADAPT-3D prepares whole mouse brains for light sheet microscopy in a 4-hour …

Whf Roadmap On Single Pill Combination Therapies, Enrico G Ferro, Mark Huffman, Orly Vardeny, Et Al.

2020-Current year OA Pubs

Cardiovascular diseases (CVDs) are the leading global cause of mortality, with treatment adherence posing a major barrier to effective prevention and control. Single pill combinations (SPCs), also known as fixed-dose combinations, simplify treatment by combining multiple agents into one pill, improving adherence and reducing cardiovascular risk. This World Heart Federation Roadmap synthesizes the latest clinical evidence and identifies key barriers to SPC implementation, including limited manufacturing, affordability, regulatory complexity, and inconsistent guideline inclusion. Drawing on global expert input and health systems analysis, the Roadmap outlines practical, context-specific solutions to improve access, scale-up, and integration of SPCs into national strategies, especially …

Bi-5756 Reduces Graft-Versus-Host Disease Through Cb1-Mediated Treg Upregulation, Sena Kim, Abdul-Jalil Dania, Sora Lim, Jaebok Choi

2020-Current year OA Pubs

Cannabinoid receptor 1 (CB1) has been implicated in multiple inflammatory diseases by regulating pro-inflammatory mediators or altering immune cell polarization. However, the expression and direct functional role of CB1 in T cells remain largely unexplored. Here, we demonstrate that primary murine T cells express CB1 and that its novel agonist, BI-5756, directly increases the frequencies of regulatory T cells (Tregs) in primary murine pan T cells after activation. In addition, BI-5756 exhibits an in vivo protective effect against graft-versus-host disease (GvHD), an allogeneic T cell-mediated inflammatory complication after allogeneic hematopoietic cell transplantation (allo-HCT), resulting in an improved overall survival with …

Conventional Versus Advanced Imaging Selection For Endovascular Treatment Of Basilar Artery Occlusion Strokes, Huanwen Chen, Joshua Osbun, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Endovascular thrombectomy (EVT) is an effective treatment for basilar artery occlusion (BAO) stroke in select patients. While there is a growing body of literature suggesting that advanced imaging modalities such as computed tomography perfusion (CTP) and magnetic resonance (MR) may not be necessary for selecting anterior circulation large vessel occlusion stroke patients for EVT, whether advanced imaging may be superior to conventional imaging (non-contrast CT and CT angiography) in identifying good treatment candidates among BAO patients is less clear.

PATIENTS AND METHODS: This was a multicenter retrospective cohort study of BAO EVT patients treated from 2013 to 2022 in …

Loss Of Dihydroceramide Desaturase Drives Neurodegeneration By Disrupting Endoplasmic Reticulum And Lipid Droplet Homeostasis In Glial Cells, Yuqing Zhu, Kevin Cho, Haluk Lacin, Yi Zhu, Jose T Dipaola, Beth A Wilson, Gary Patti, James B Skeath

2020-Current year OA Pubs

Dihydroceramide desaturases convert dihydroceramides to ceramides, the precursors of all complex sphingolipids. Reduction of DEGS1 dihydroceramide desaturase function causes pediatric neurodegenerative disorder hypomyelinating leukodystrophy-18 (HLD-18). We discovered that

Defrnd: Detergent-Free Reconstitution Into Native Nanodiscs With Designer Membrane Scaffold Peptides, Qian Ren, Vinay Idikuda, Baron Chanda, Et Al.

2020-Current year OA Pubs

Membrane scaffold protein-based nanodiscs have facilitated unprecedented structural and biophysical analysis of membrane proteins in a near-native lipid environment. However, successful reconstitution of membrane proteins in nanodiscs requires prior solubilization and purification in detergents, which may impact their physiological structure and function. Furthermore, the detergent-mediated reconstitution of nanodiscs is unlikely to recapitulate the precise composition or asymmetry of native membranes. To circumvent this fundamental limitation of traditional nanodisc technology, we herein describe the development of membrane-solubilizing peptides to directly extract membrane proteins from native cell membranes into nanoscale discoids. By systematically protein engineering and screening, we create a class of …

Danicamtiv Reduces Myosin's Working Stroke But Activates The Thin Filament By Accelerating Actomyosin Attachment, Brent Scott, Lina Greenberg, Caterina Squarci, Kenneth S Campbell, Michael J Greenberg

2020-Current year OA Pubs

Heart failure is a leading cause of death worldwide, and even with current treatments, the 5-y transplant-free survival rate is only ~50 to 70%. As such, there is a need to develop new treatments for patients that improve survival and quality of life. Recently, there have been efforts to develop small molecules for heart failure that directly target components of the sarcomere, including cardiac myosin. Danicamtiv is one of these molecules; however, its direct effects on myosin's single molecule mechanics and kinetics are not well understood. Using optical trapping techniques, stopped flow transient kinetics, and in vitro reconstitution assays, we …

Phosphorylation Toggles The Sars-Cov-2 Nucleocapsid Protein Between Two Membrane-Associated Condensate States, Bruna Favetta, Huan Wang, Jasmine Cubuk, Arjun Singh, Mayur Barai, Cesar Ramirez, Haiyan Zheng, Adam J Gormley, N Sanjeeva Murthy, Gregory Dignon, Andrea Soranno, Zheng Shi, Benjamin S Schuster

2020-Current year OA Pubs

The Nucleocapsid protein (N) of SARS-CoV-2 plays a critical role in the viral lifecycle by regulating RNA replication and by packaging the viral genome. N and RNA phase separate to form condensates that may be important for these functions. Both functions occur at membrane surfaces, but how N toggles between these two membrane-associated functional states is unclear. Here, we reveal that phosphorylation switches how N condensates interact with membranes, in part by modulating condensate material properties. Our studies also show that phosphorylation alters N's interaction with viral membrane proteins. We gain mechanistic insight through structural analysis and molecular simulations, which …

Single-Neuron Datasets For Linguistic And Semantic Processing In The Human Amygdala And Hippocampus, Yue Wang, Runnan Cao, Jon T Willie, Peter Brunner, Shuo Wang

2020-Current year OA Pubs

Understanding linguistic and semantic processing in the human brain involves exploring intricate neural networks. However, it remains unclear whether and how the amygdala and hippocampus are involved in these processes. Here, we recorded single-neuron activity from the human amygdala and hippocampus while neurosurgical patients with intractable epilepsy performed various language tasks. Specifically, we recorded from 68 neurons in 7 patients for the visual language localizer task, 115 neurons in 12 patients for the auditory language localizer task, 88 neurons in 9 patients for the TIMIT task, and 51 neurons in 4 patients for the natural story task. Together, our comprehensive …