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The Material Properties Of A Bacterial-Derived Biomolecular Condensate Tune Biological Function In Natural And Synthetic Systems, Keren Lasker, Steven Boeynaems, Vinson Lam, Daniel Scholl, Emma Stainton, Adam Briner, Maarten Jacquemyn, Dirk Daelemans, Ashok Deniz, Elizabeth Villa, Alex S Holehouse, Aaron D Gitler, Lucy Shapiro

2020-Current year OA Pubs

Intracellular phase separation is emerging as a universal principle for organizing biochemical reactions in time and space. It remains incompletely resolved how biological function is encoded in these assemblies and whether this depends on their material state. The conserved intrinsically disordered protein PopZ forms condensates at the poles of the bacterium Caulobacter crescentus, which in turn orchestrate cell-cycle regulating signaling cascades. Here we show that the material properties of these condensates are determined by a balance between attractive and repulsive forces mediated by a helical oligomerization domain and an expanded disordered region, respectively. A series of PopZ mutants disrupting this …

Trending Anti-E7 Serology Predicts Mortality And Recurrence Of Hpv-Associated Cancers Of The Oropharynx, Luke Johnson, Dat T Ha, Melissa B Hall, Gregory Shoemaker, Paul A Bevins, John Strickley, Shadmehr Demehri, Rebecca A Redman, Joongho Joh

2020-Current year OA Pubs

High-risk human papillomavirus (HPV) is among the most common causes of head and neck cancer (HNC) with increasing incidence. HPV-associated HNC patients' clinical response to treatment varies drastically, which has made treatment de-escalation clinical trials challenging. To address the need for noninvasive biomarkers that differentiate patient outcomes, serum antibodies to E7 oncoprotein levels were evaluated in serial serum specimens from HPV-positive HNC patients (

Islet Primary Cilia Motility Controls Insulin Secretion, Jung Hoon Cho, Zipeng A Li, Lifei Zhu, Brian D Muegge, Henry F Roseman, Eun Young Lee, Toby Utterback, Louis G Woodhams, Philip V Bayly, Jing W Hughes

2020-Current year OA Pubs

Primary cilia are specialized cell-surface organelles that mediate sensory perception and, in contrast to motile cilia and flagella, are thought to lack motility function. Here, we show that primary cilia in human and mouse pancreatic islets exhibit movement that is required for glucose-dependent insulin secretion. Islet primary cilia contain motor proteins conserved from those found in classic motile cilia, and their three-dimensional motion is dynein-driven and dependent on adenosine 5'-triphosphate and glucose metabolism. Inhibition of cilia motion blocks beta cell calcium influx and insulin secretion. Human beta cells have enriched ciliary gene expression, and motile cilia genes are altered in …

Non-Sedative Cortical Eeg Signatures Of Allopregnanolone And Functional Comparators, Peter M Lambert, Richard Ni, Ann Benz, Nicholas R Rensing, Michael Wong, Charles F Zorumski, Steven Mennerick

2020-Current year OA Pubs

Neurosteroids that positively modulate GABA

Multidimensional Analysis And Therapeutic Development Using Patient Ipsc-Derived Disease Models Of Wolfram Syndrome, Rie Asada Kitamura, Kristina G. Maxwell, Kelly Kries, Cris M. Brown, Punn Augsornworawat, Jeffrey R Millman, Fumihiko Urano, Et Al

2020-Current year OA Pubs

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C>T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with …

Current Understanding Of Osteoarthritis Pathogenesis And Relevant New Approaches, Liping Tong, Huan Yu, Xingyun Huang, Jie Shen, Guozhi Xiao, Lin Chen, Huaiyu Wang, Lianping Xing, Di Chen

2020-Current year OA Pubs

Osteoarthritis (OA) is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body. The molecular mechanisms of OA are currently unknown. OA is a heterogeneous disease that affects the entire joint, and multiple tissues are altered during OA development. To better understand the pathological mechanisms of OA, new approaches, methods, and techniques need to be used to understand OA pathogenesis. In this review, we first focus on the epigenetic regulation of OA, with a particular focus on DNA methylation, histone modification, and microRNA regulation, followed by a summary of several key …

Regulation Of Human Cortical Interneuron Development By The Chromatin Remodeling Protein Chd2, E M A Lewis, G Chapman, K Kaushik, J Determan, I Antony, K Meganathan, M Narasimhan, P Gontarz, B Zhang, K L Kroll

2020-Current year OA Pubs

Mutations in the chromodomain helicase DNA binding protein 2 (CHD2) gene are associated with neurodevelopmental disorders. However, mechanisms by which CHD2 regulates human brain development remain largely uncharacterized. Here, we used a human embryonic stem cell model of cortical interneuron (hcIN) development to elucidate its roles in this process. We identified genome-wide CHD2 binding profiles during hcIN differentiation, defining direct CHD2 targets related to neurogenesis in hcIN progenitors and to neuronal function in hcINs. CHD2 bound sites were frequently coenriched with histone H3 lysine 27 acetylation (H3K27ac) and associated with high gene expression, indicating roles for CHD2 in promoting gene …

Systemic Chemotherapies Retain Antitumor Activity In Desmoid Tumors Independent Of Specific Mutations In Ctnnb1 Or Apc: A Multi-Institutional Retrospective Study, Michael J Nathenson, Katharina Feister, Et Al

2020-Current year OA Pubs

PURPOSE: Determine whether specific CTNNB1 or APC mutations in patients with desmoid tumor were associated with differences in clinical responses to systemic treatments.

EXPERIMENTAL DESIGN: We established a multi-institutional dataset of previously treated patients with desmoid tumor across four U.S. sarcoma centers, including demographic and clinicopathologic characteristics, treatment regimens, and clinical and radiographic responses. CTNNB1 or APC mutation status was determined from prior pathology records, or archival tissue was requested and analyzed by Sanger sequencing and/or next-generation sequencing. Evaluable patients with mutation results were analyzed to determine clinical progression-free survival (cPFS), RECIST 1.1 PFS (rPFS), time to next treatment (TTNT), …

Intracellular Connections Between Basal Bodies Promote The Coordinated Behavior Of Motile Cilia, Adam W J Soh, Louis G Woodhams, Anthony D Junker, Cassidy M Enloe, Benjamin E Noren, Adam Harned, Christopher J Westlake, Kedar Narayan, John S Oakey, Philip V Bayly, Chad G Pearson

2020-Current year OA Pubs

Hydrodynamic flow produced by multiciliated cells is critical for fluid circulation and cell motility. Hundreds of cilia beat with metachronal synchrony for fluid flow. Cilia-driven fluid flow produces extracellular hydrodynamic forces that cause neighboring cilia to beat in a synchronized manner. However, hydrodynamic coupling between neighboring cilia is not the sole mechanism that drives cilia synchrony. Cilia are nucleated by basal bodies (BBs) that link to each other and to the cell's cortex via BB-associated appendages. The intracellular BB and cortical network is hypothesized to synchronize ciliary beating by transmitting cilia coordination cues. The extent of intracellular ciliary connections and …

Ehrlich Tumor Induces Trpv1-Dependent Evoked And Non-Evoked Pain-Like Behavior In Mice, Mariana M Bertozzi, Telma Saraiva-Santos, Tiago H Zaninelli, Felipe A Pinho-Ribeiro, Victor Fattori, Larissa Staurengo-Ferrari, Camila R Ferraz, Talita P Domiciano, Cassia Calixto-Campos, Sergio M Borghi, Ana C Zarpelon, Thiago M Cunha, Rubia Casagrande, Waldiceu A Verri

2020-Current year OA Pubs

We standardized a model by injecting Ehrlich tumor cells into the paw to evaluate cancer pain mechanisms and pharmacological treatments. Opioid treatment, but not cyclooxygenase inhibitor or tricyclic antidepressant treatments reduces Ehrlich tumor pain. To best use this model for drug screening it is essential to understand its pathophysiological mechanisms. Herein, we investigated the contribution of the transient receptor potential cation channel subfamily V member 1 (TRPV1) in the Ehrlich tumor-induced pain model. Dorsal root ganglia (DRG) neurons from the Ehrlich tumor mice presented higher activity (calcium levels using fluo-4 fluorescent probe) and an increased response to capsaicin (TRPV1 agonist) …

Innexin Function Dictates The Spatial Relationship Between Distal Somatic Cells In The Caenorhabditis Elegans Gonad Without Impacting The Germline Stem Cell Pool, Theadora Tolkin, Ariz Mohammad, Todd A Starich, Ken C Q Nguyen, David H Hall, Tim Schedl, E Jane Albert Hubbard, David Greenstein

2020-Current year OA Pubs

Gap-junctional signaling mediates myriad cellular interactions in metazoans. Yet, how gap junctions control the positioning of cells in organs is not well understood. Innexins compose gap junctions in invertebrates and affect organ architecture. Here, we investigate the roles of gap-junctions in controlling distal somatic gonad architecture and its relationship to underlying germline stem cells in

Tissue Rotation Of The Xenopus Anterior–Posterior Neural Axis Reveals Profound But Transient Plasticity At The Mid-Gastrula Stage, Lyuba Bolkhovitinov, Bryan T Weselman, Gladys A Shaw, Chen Dong, Janhavi Giribhattanavar, Margaret S Saha

2020-Current year OA Pubs

The establishment of anterior-posterior (AP) regional identity is an essential step in the appropriate development of the vertebrate central nervous system. An important aspect of AP neural axis formation is the inherent plasticity that allows developing cells to respond to and recover from the various perturbations that embryos continually face during the course of development. While the mechanisms governing the regionalization of the nervous system have been extensively studied, relatively less is known about the nature and limits of early neural plasticity of the anterior-posterior neural axis. This study aims to characterize the degree of neural axis plasticity in

The Ifn-Γ Receptor Promotes Immune Dysregulation And Disease In Sting Gain-Of-Function Mice, W. Alexander Stinson, Cathrine A. Miner, Fang R. Zhao, Annena Jane Lundgren, Subhajit Poddar, Jonathan J. Miner

2020-Current year OA Pubs

STING gain-of-function mutations cause STING-associated vasculopathy with onset in infancy (SAVI) in humans, a disease characterized by spontaneous lung inflammation and fibrosis. Mice with STING gain-of-function mutations (SAVI mice) develop αβ T cell-dependent lung disease and also lack lymph nodes. Although SAVI has been regarded as a type I interferonopathy, the relative contributions of the three interferon receptors are incompletely understood. Here, we show that STING gain of function led to upregulation of IFN-γ-induced chemokines in the lungs of SAVI mice and that deletion of the type II IFN receptor (IFNGR1), but not the type I IFN receptor (IFNAR1) or …

Validation Of Blood-Based Transcriptomic Circadian Phenotyping In Older Adults, S Kendall Smith, Peter Tran, Katherine A Madden, Jill Boyd, Rosemary Braun, Erik S Musiek, Yo-El S Ju

2020-Current year OA Pubs

No abstract provided.

Feasibility And Sensitivity Study Of Radiomic Features In Photoacoustic Imaging Of Patient-Derived Xenografts, Lorena Escudero Sanchez, Emma Brown, Leonardo Rundo, Stephan Ursprung, Evis Sala, Sarah E Bohndiek, Ignacio Xavier Partarrieu

2020-Current year OA Pubs

Photoacoustic imaging is an increasingly popular method of exploring the tumour microenvironment, which can provide insight into tumour oxygenation status and potentially treatment response assessment. Currently, the measurements most commonly performed on such images are the mean and median of the pixel values of the tumour volumes of interest. We investigated expanding the set of measurements that can be extracted from these images by adding radiomic features. In particular, we found that Skewness was sensitive to differences between basal and luminal patient derived xenograft cancer models with an [Formula: see text] of 0.86, and that it was robust to variations …

Genome-Wide Association Analyses Of Physical Activity And Sedentary Behavior Provide Insights Into Underlying Mechanisms And Roles In Disease Prevention, Zhe Wang, Mary F. Feitosa, Et Al

2020-Current year OA Pubs

No abstract provided.

Multimodal Single Cell Sequencing Implicates Chromatin Accessibility And Genetic Background In Diabetic Kidney Disease Progression, Parker C Wilson, Yoshiharu Muto, Haojia Wu, Anil Karihaloo, Sushrut S Waikar, Benjamin D Humphreys

2020-Current year OA Pubs

The proximal tubule is a key regulator of kidney function and glucose metabolism. Diabetic kidney disease leads to proximal tubule injury and changes in chromatin accessibility that modify the activity of transcription factors involved in glucose metabolism and inflammation. Here we use single nucleus RNA and ATAC sequencing to show that diabetic kidney disease leads to reduced accessibility of glucocorticoid receptor binding sites and an injury-associated expression signature in the proximal tubule. We hypothesize that chromatin accessibility is regulated by genetic background and closely-intertwined with metabolic memory, which pre-programs the proximal tubule to respond differently to external stimuli. Glucocorticoid excess …

Novel Antiinflammatory Biologics Shaped By Parasite-Host Coevolution, Stephanie M Ryan, Makedonka Mitreva, Et Al

2020-Current year OA Pubs

Parasitic helminth infections, while a major cause of neglected tropical disease burden, negatively correlate with the incidence of immune-mediated inflammatory diseases such as inflammatory bowel diseases (IBD). To evade expulsion, helminths have developed sophisticated mechanisms to regulate their host's immune responses. Controlled experimental human helminth infections have been assessed clinically for treating inflammatory conditions; however, such a radical therapeutic modality has challenges. An alternative approach is to harness the immunomodulatory properties within the worm's excretory-secretory (ES) complement, its secretome. Here, we report a biologics discovery and validation pipeline to generate and screen in vivo a recombinant cell-free secretome library of …

Issues With Variability In Electronic Health Record Data About Race And Ethnicity: Descriptive Analysis Of The National Covid Cohort Collaborative Data Enclave, Lily Cook, Juan Espinoza, Nicole G Weiskopf, Nisha Mathews, David A Dorr, Kelly L Gonzales, Adam Wilcox, Charisse Madlock-Brown, N3c Consoritium

2020-Current year OA Pubs

BACKGROUND: The adverse impact of COVID-19 on marginalized and under-resourced communities of color has highlighted the need for accurate, comprehensive race and ethnicity data. However, a significant technical challenge related to integrating race and ethnicity data in large, consolidated databases is the lack of consistency in how data about race and ethnicity are collected and structured by health care organizations.

OBJECTIVE: This study aims to evaluate and describe variations in how health care systems collect and report information about the race and ethnicity of their patients and to assess how well these data are integrated when aggregated into a large …

Exit Rates Of Accountable Care Organizations That Serve High Proportions Of Beneficiaries Of Racial And Ethnic Minority Groups, Sunny C Lin, Karen E Joynt Maddox, Andrew M Ryan, Nicholas Moloci, Addison Shay, John Malcolm Hollingsworth

2020-Current year OA Pubs

Importance: The Medicare Shared Savings Program provides financial incentives for accountable care organizations (ACOs) to reduce costs of care. The structure of the shared savings program may not adequately adjust for challenges associated with caring for patients with high medical complexity and social needs, a population disproportionately made up of racial and ethnic minority groups. If so, ACOs serving racial and ethnic minority groups may be more likely to exit the program, raising concerns about the equitable distribution of potential benefits from health care delivery reform efforts.

Objective: To evaluate whether ACOs with a high proportion of beneficaries of racial …

An Ex Vivo Culture Model Of Kidney Podocyte Injury Reveals Mechanosensitive, Synaptopodin-Templating, Sarcomere-Like Structures, Shumeng Jiang, Farid Alisafaei, Yin-Yuan Huang, Yuan Hong, Xiangjun Peng, Chengqing Qu, Pongpratch Puapatanakul, Sanjay Jain, Jeffrey H Miner, Guy M Genin, Hani Y Suleiman

2020-Current year OA Pubs

Chronic kidney diseases are widespread and incurable. The biophysical mechanisms underlying them are unclear, in part because material systems for reconstituting the microenvironment of relevant kidney cells are limited. A critical question is how kidney podocytes (glomerular epithelial cells) regenerate foot processes of the filtration apparatus following injury. Recently identified sarcomere-like structures (SLSs) with periodically spaced myosin IIA and synaptopodin appear in injured podocytes in vivo. We hypothesized that SLSs template synaptopodin in the initial stages of recovery in response to microenvironmental stimuli and tested this hypothesis by developing an ex vivo culture system that allows control of the podocyte …

An Ips-Derived In Vitro Model Of Human Atrial Conduction, Sherri M Biendarra-Tiegs, Sergey Yechikov, Bhupinder Shergill, Brittany Brumback, Kentaro Takahashi, Venktesh S Shirure, Ruth Estelle Gonzalez, Laura Houshmand, Denise Zhong, Kuo-Chan Weng, Jon Silva, Timothy W Smith, Stacey L Rentschler, Steven C George

2020-Current year OA Pubs

Atrial fibrillation (AF) is the most common arrhythmia in the United States, affecting approximately 1 in 10 adults, and its prevalence is expected to rise as the population ages. Treatment options for AF are limited; moreover, the development of new treatments is hindered by limited (1) knowledge regarding human atrial electrophysiological endpoints (e.g., conduction velocity [CV]) and (2) accurate experimental models. Here, we measured the CV and refractory period, and subsequently calculated the conduction wavelength, in vivo (four subjects with AF and four controls), and ex vivo (atrial slices from human hearts). Then, we created an in vitro model of …

Real-World Evidence Of Axicabtagene Ciloleucel For The Treatment Of Large B Cell Lymphoma In The United States, Caron A Jacobson, Armin Ghobadi, Et Al.

2020-Current year OA Pubs

Axicabtagene ciloleucel (axi-cel) is a standard-of-care for patients with relapsed or refractory (r/r) large B cell lymphoma who have received 2 or more lines of prior therapy. Patients receiving axi-cel in the real world could have broader a demographic, disease, and treatment profile compared with that of the cohort in the pivotal ZUMA-1 trial. The present study was conducted to evaluate the outcomes of axi-cel therapy in the real-world setting. A total of 1297 patients receiving commercial axi-cel between 2017 and 2020 were selected from the Center for International Blood and Marrow Transplant Research's data registry, of whom 739 (57%) …

Disease Burden Affects Aging Brain Function, Lori L Beason-Held, Danielle Fournier, Andrea T Shafer, Elisa Fabbri, Yang An, Chiung-Wei Huang, Murat Bilgel, Dean F Wong, Luigi Ferrucci, Susan M Resnick

2020-Current year OA Pubs

BACKGROUND: Most older adults live with multiple chronic disease conditions, yet the effect of multiple diseases on brain function remains unclear.

METHODS: We examine the relationship between disease multimorbidity and brain activity using regional cerebral blood flow (rCBF) 15O-water PET scans from 97 cognitively normal participants (mean baseline age 76.5) in the Baltimore Longitudinal Study of Aging (BLSA). Multimorbidity index scores, generated from the presence of 13 health conditions, were correlated with PET data at baseline and in longitudinal change (n = 74) over 5.05 (2.74 SD) years.

RESULTS: At baseline, voxel-based analysis showed that higher multimorbidity scores were associated …

Efficacy And Safety Of Ofatumumab In Recently Diagnosed, Treatment-Naive Patients With Multiple Sclerosis: Results From Asclepios I And Ii, Jutta Gärtner, Stephen L Hauser, Amit Bar-Or, Xavier Montalban, Jeffrey A Cohen, Anne H Cross, Kumaran Deiva, Habib Ganjgahi, Dieter A Häring, Bingbing Li, Ratnakar Pingili, Krishnan Ramanathan, Wendy Su, Roman Willi, Bernd Kieseier, Ludwig Kappos

2020-Current year OA Pubs

BACKGROUND: In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes than those receiving teriflunomide.

OBJECTIVES: To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, treatment-naive (RDTN) participants from ASCLEPIOS.

METHODS: Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the protocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening (CDW), progression independent of relapse activity (PIRA) and …

World Guidelines For Falls Prevention And Management For Older Adults: A Global Initiative, Manuel Montero-Odasso, Susan Stark, Et Al.

2020-Current year OA Pubs

No abstract provided.

Accumulation Of Copy-Back Viral Genomes During Respiratory Syncytial Virus Infection Is Preceded By Diversification Of The Copy-Back Viral Genome Population Followed By Selection, Sébastien A Felt, Emna Achouri, Sydney R Faber, Carolina B López

2020-Current year OA Pubs

RNA viruses generate nonstandard viral genomes during their replication, including viral genomes of the copy-back (cbVGs) type that cannot replicate in the absence of a standard virus. cbVGs play a crucial role in shaping virus infection outcomes due to their ability to interfere with virus replication and induce strong immune responses. However, despite their critical role during infection, the principles that drive the selection and evolution of cbVGs within a virus population are poorly understood. As cbVGs are dependent on the virus replication machinery to be generated and replicated, we hypothesized that host factors that affect virus replication exert selective …

Consensus-Based Recommendations On Priority Activities To Address Acute Kidney Injury In Children: A Modified Delphi Consensus Statement, Stuart L Goldstein, Tara M Neumayr, Et Al.

2020-Current year OA Pubs

Importance: Increasing evidence indicates that acute kidney injury (AKI) occurs frequently in children and young adults and is associated with poor short-term and long-term outcomes. Guidance is required to focus efforts related to expansion of pediatric AKI knowledge.

Objective: To develop expert-driven pediatric specific recommendations on needed AKI research, education, practice, and advocacy.

Evidence Review: At the 26th Acute Disease Quality Initiative meeting conducted in November 2021 by 47 multiprofessional international experts in general pediatrics, nephrology, and critical care, the panel focused on 6 areas: (1) epidemiology; (2) diagnostics; (3) fluid overload; (4) kidney support therapies; (5) biology, pharmacology, and …

Tumor Immune Contexture Is A Determinant Of Anti-Cd19 Car T Cell Efficacy In Large B Cell Lymphoma, Nathalie Scholler, Armin Ghobadi, Et Al

2020-Current year OA Pubs

No abstract provided.

First-In-Human Phase I/Ii Iconic Trial Of The Icos Agonist Vopratelimab Alone And With Nivolumab: Icos-High Cd4 T-Cell Populations And Predictors Of Response, Timothy A Yap, Russell K Pachynski, Haeseong Park, Et Al

2020-Current year OA Pubs

PURPOSE: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors.

PATIENTS AND METHODS: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed.

RESULTS: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was …