Digital Commons Network^™

Building The Foundation For A Community-Generated National Research Blueprint For Inherited Bleeding Disorders: Research Priorities For Mucocutaneous Bleeding Disorders, Robert F Sidonio Jr, Jorge Di Paola, Et Al.

2020-Current year OA Pubs

BACKGROUND: Excessive or abnormal mucocutaneous bleeding (MCB) may impact all aspects of the physical and psychosocial wellbeing of those who live with it (PWMCB). The evidence base for the optimal diagnosis and management of disorders such as inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD), Ehlers-Danlos syndromes (EDS), and von Willebrand disease (VWD) remains thin with enormous potential for targeted research.

RESEARCH DESIGN AND METHODS: National Hemophilia Foundation and American Thrombosis and Hemostasis Network initiated the development of a National Research Blueprint for Inherited Bleeding Disorders with extensive all-stakeholder consultations to identify the priorities of people with …

Cmpk2 Is A Host Restriction Factor That Inhibits Infection Of Multiple Coronaviruses In A Cell-Intrinsic Manner, Mingjun Zhu, Jiahuang Lv, Wei Wang, Rongli Guo, Chunyan Zhong, Avan Antia, Qiru Zeng, Jizong Li, Qingtao Liu, Jinzhu Zhou, Xuejiao Zhu, Baochao Fan, Siyuan Ding, Bin Li

2020-Current year OA Pubs

Coronaviruses (CoVs) comprise a group of important human and animal pathogens. Despite extensive research in the past 3 years, the host innate immune defense mechanisms against CoVs remain incompletely understood, limiting the development of effective antivirals and non-antibody-based therapeutics. Here, we performed an integrated transcriptomic analysis of porcine jejunal epithelial cells infected with porcine epidemic diarrhea virus (PEDV) and identified cytidine/uridine monophosphate kinase 2 (CMPK2) as a potential host restriction factor. CMPK2 exhibited modest antiviral activity against PEDV infection in multiple cell types. CMPK2 transcription was regulated by interferon-dependent and interferon regulatory factor 1 (IRF1)-dependent pathways post-PEDV infection. We demonstrated …

Single Cell Preparations Of Mycobacterium Tuberculosis Damage The Mycobacterial Envelope And Disrupt Macrophage Interactions, Ekansh Mittal, Andrew T Roth, Anushree Seth, Srikanth Singamaneni, Wandy Beatty, Jennifer A Philips

2020-Current year OA Pubs

For decades, investigators have studied the interaction of

Virology Under The Microscope-A Call For Rational Discourse, Felicia Goodrum, Carolina Lopez, Sean Whelan, Et Al.

2020-Current year OA Pubs

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled …

The Er Protein Translocation Channel Subunit Sbh1 Controls Virulence Of Cryptococcus Neoformans, Felipe H. Santiago-Tirado, Thomas Hurtaux, Jennifer Geddes-Mcalister, Duy Nguyen, Volkhard Helms, Tamara L Doering, Karin Römisch

2020-Current year OA Pubs

The fungal pathogen Cryptococcus neoformans is distinguished by a cell-wall-anchored polysaccharide capsule that is critical for virulence. Biogenesis of both cell wall and capsule relies on the secretory pathway. Protein secretion begins with polypeptide translocation across the endoplasmic reticulum (ER) membrane through a highly conserved channel formed by three proteins: Sec61, Sbh1, and Sss1. Sbh1, the most divergent, contains multiple phosphorylation sites, which may allow it to regulate entry into the secretory pathway in a species- and protein-specific manner. Absence of

Apical Secretory Glycoprotein Complex Contributes To Cell Attachment And Entry By Cryptosporidium Parvum, Marianna E. Akey, Rui Xu, Soumya Ravindran, Lisa Funkhouser-Jones, L. David Sibley

2020-Current year OA Pubs

Cryptosporidium parvum is an enteric pathogen that invades epithelial cells in the intestine, where it resides at the apical surface in a unique epicellular location. Compared with those of related apicomplexan parasites, the processes of host cell attachment and invasion by C. parvum are poorly understood. The streamlined C. parvum genome contains numerous mucin-like glycoproteins, several of which have previously been shown to mediate cell attachment, although the majority are unstudied. Here, we identified the antigens recognized by monoclonal antibody (MAb) 1A5, which stains the apical end of sporozoites and mature merozoites. Immunoprecipitation with MAb 1A5 followed by mass spectrometry …

Care Of Bullet-Related Injuries: A Cross-Sectional Study Of Instructions And Prescriptions Provided On Discharge From The Emergency Department, Jane M. Hayes, L J. Punch, Kristen L. Mueller

2020-Current year OA Pubs

INTRODUCTION: There are more than 80,000 emergency department (ED) visits for non-fatal bullet-related injuries (BRI) per year in the United States. Approximately half of these patients are discharged home from the ED. Our objective in this study was to characterize the discharge instructions, prescriptions, and follow-up plans provided to patients discharged from the ED after BRI.

METHODS: This was a single-center, cross-sectional study of the first 100 consecutive patients who presented to an urban, academic, Level I trauma center ED with an acute BRI beginning on January 1, 2020. We queried the electronic health record for patient demographics, insurance status, …

Long-Term Intensive Endurance Exercise Training Is Associated To Reduced Markers Of Cellular Senescence In The Colon Mucosa Of Older Adults, Marco Demaria, Beatrice Bertozzi, Nicola Veronese, Francesco Spelta, Edda Cava, Valeria Tosti, Laura Piccio, Dayna S Early, Luigi Fontana

2020-Current year OA Pubs

Regular endurance exercise training is an effective intervention for the maintenance of metabolic health and the prevention of many age-associated chronic diseases. Several metabolic and inflammatory factors are involved in the health-promoting effects of exercise training, but regulatory mechanisms remain poorly understood. Cellular senescence-a state of irreversible growth arrest-is considered a basic mechanism of aging. Senescent cells accumulate over time and promote a variety of age-related pathologies from neurodegenerative disorders to cancer. Whether long-term intensive exercise training affect the accumulation of age-associated cellular senescence is still unclear. Here, we show that the classical senescence markers p16 and IL-6 were markedly …

Trpv1-Mediated Sonogenetic Neuromodulation Of Motor Cortex In Freely Moving Mice, Kevin Xu, Yaoheng Yang, Zhongtao Hu, Yimei Yue, Yan Gong, Jianmin Cui, Joseph P Culver, Michael R Bruchas, Hong Chen

2020-Current year OA Pubs

No abstract provided.

Orthodenticle Homeobox 2 Is Transported To Lysosomes By Nuclear Budding Vesicles, Jun Woo Park, Eun Jung Lee, Eunyoung Moon, Hong-Lim Kim, In-Beom Kim, Didier Hodzic, Namsuk Kim, Hee-Seok Kweon, Jin Woo Kim

2020-Current year OA Pubs

Transcription factors (TFs) are transported from the cytoplasm to the nucleus and disappear from the nucleus after they regulate gene expression. Here, we discover an unconventional nuclear export of the TF, orthodenticle homeobox 2 (OTX2), in nuclear budding vesicles, which transport OTX2 to the lysosome. We further find that torsin1a (Tor1a) is responsible for scission of the inner nuclear vesicle, which captures OTX2 using the LINC complex. Consistent with this, in cells expressing an ATPase-inactive Tor1aΔE mutant and the LINC (linker of nucleoskeleton and cytoskeleton) breaker KASH2, OTX2 accumulated and formed aggregates in the nucleus. Consequently, in the mice expressing …

Membrane Phospholipids Control Gating Of The Mechanosensitive Potassium Leak Channel Trek1, Philipp A M Schmidpeter, John T Petroff 2nd, Leila Khajoueinejad, Aboubacar Wague, Cheryl Frankfater, Wayland W L Cheng, Crina M Nimigean, Paul M Riegelhaupt

2020-Current year OA Pubs

Tandem pore domain (K2P) potassium channels modulate resting membrane potentials and shape cellular excitability. For the mechanosensitive subfamily of K2Ps, the composition of phospholipids within the bilayer strongly influences channel activity. To examine the molecular details of K2P lipid modulation, we solved cryo-EM structures of the TREK1 K2P channel bound to either the anionic lipid phosphatidic acid (PA) or the zwitterionic lipid phosphatidylethanolamine (PE). At the extracellular face of TREK1, a PA lipid inserts its hydrocarbon tail into a pocket behind the selectivity filter, causing a structural rearrangement that recapitulates mutations and pharmacology known to activate TREK1. At the cytoplasmic …

Mitochondrial Phosphatidylethanolamine Modulates Ucp1 To Promote Brown Adipose Thermogenesis, Jordan M Johnson, Irfan J Lodhi, Et Al.

2020-Current year OA Pubs

Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of adenosine triphosphate (ATP) synthase. Here, we provide evidence that phosphatidylethanolamine (PE) modulates UCP1-dependent proton conductance across the IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist-induced increase in whole-body oxygen …

Allogeneic Natural Killer Cell Therapy, Melissa M Berrien-Elliott, Miriam T Jacobs, Todd A Fehniger

2020-Current year OA Pubs

Interest in adoptive cell therapy for treating cancer is exploding owing to early clinical successes of autologous chimeric antigen receptor (CAR) T lymphocyte therapy. However, limitations using T cells and autologous cell products are apparent as they (1) take weeks to generate, (2) utilize a 1:1 donor-to-patient model, (3) are expensive, and (4) are prone to heterogeneity and manufacturing failures. CAR T cells are also associated with significant toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and prolonged cytopenias. To overcome these issues, natural killer (NK) cells are being explored as an alternative cell source for allogeneic cell …

Genetic Subgroups Inform On Pathobiology In Adult And Pediatric Burkitt Lymphoma, Nicole Thomas, Nancy L. Bartlett, Lee Ratner, Et Al.

2020-Current year OA Pubs

Burkitt lymphoma (BL) accounts for most pediatric non-Hodgkin lymphomas, being less common but significantly more lethal when diagnosed in adults. Much of the knowledge of the genetics of BL thus far has originated from the study of pediatric BL (pBL), leaving its relationship to adult BL (aBL) and other adult lymphomas not fully explored. We sought to more thoroughly identify the somatic changes that underlie lymphomagenesis in aBL and any molecular features that associate with clinical disparities within and between pBL and aBL. Through comprehensive whole-genome sequencing of 230 BL and 295 diffuse large B-cell lymphoma (DLBCL) tumors, we identified …

Setd2 Regulates Chromatin Accessibility And Transcription To Suppress Lung Tumorigenesis, Yuchen Xie, Merve Sahin, Toru Wakamatsu, Akane Inoue-Yamauchi, Wanming Zhao, Song Han, Amrita M. Nargund, Shaoyuan Yang, Yang Lyu, James J. Hsieh, Christina S. Leslie, Emily H. Cheng

2020-Current year OA Pubs

SETD2, a H3K36 trimethyltransferase, is the most frequently mutated epigenetic modifier in lung adenocarcinoma, with a mutation frequency of approximately 9%. However, how SETD2 loss of function promotes tumorigenesis remains unclear. Using conditional Setd2-KO mice, we demonstrated that Setd2 deficiency accelerated the initiation of KrasG12D-driven lung tumorigenesis, increased tumor burden, and significantly reduced mouse survival. An integrated chromatin accessibility and transcriptome analysis revealed a potentially novel tumor suppressor model of SETD2 in which SETD2 loss activates intronic enhancers to drive oncogenic transcriptional output, including the KRAS transcriptional signature and PRC2-repressed targets, through regulation of chromatin accessibility and histone chaperone recruitment. …

Identifying Factors Which Influence Eating Disorder Risk During Behavioral Weight Management: A Consensus Study, Hiba Jebeile, Caitlin M Mcmaster, Brittany J Johnson, Sarah P Garnett, Susan J Paxton, Anna L Seidler, Rebecca A Jones, Andrew J Hill, Sarah Maguire, Caroline Braet, Genevieve Dammery, Denise E Wilfley, Louise A Baur, Natalie B Lister, On Behalf Of The Eating Disorders In Weight-Related Therapy (Edit) Collaboration

2020-Current year OA Pubs

This study aimed to understand clinician, researcher and consumer views regarding factors which influence eating disorder (ED) risk during behavioral weight management, including individual risk factors, intervention strategies and delivery features. Eighty-seven participants were recruited internationally through professional and consumer organizations and social media and completed an online survey. Individual characteristics, intervention strategies (5-point scale) and delivery features (important/unimportant/unsure) were rated. Participants were mostly women (n = 81), aged 35-49 y, from Australia or United States, were clinicians and/or reported lived experience of overweight/obesity and/or ED. There was agreement (64% to 99%) that individual characteristics were relevant to ED risk, …

The Toxoplasma Micropore Mediates Endocytosis For Selective Nutrient Salvage From Host Cell Compartments, Wenyan Wan, Hui Dong, De-Hua Lai, Jiong Yang, Kai He, Xiaoyan Tang, Qun Liu, Geoff Hide, Xing-Quan Zhu, L David Sibley, Zhao-Rong Lun, Shaojun Long

2020-Current year OA Pubs

Apicomplexan parasite growth and replication relies on nutrient acquisition from host cells, in which intracellular multiplication occurs, yet the mechanisms that underlie the nutrient salvage remain elusive. Numerous ultrastructural studies have documented a plasma membrane invagination with a dense neck, termed the micropore, on the surface of intracellular parasites. However, the function of this structure remains unknown. Here we validate the micropore as an essential organelle for endocytosis of nutrients from the host cell cytosol and Golgi in the model apicomplexan Toxoplasma gondii. Detailed analyses demonstrated that Kelch13 is localized at the dense neck of the organelle and functions as …

Uncovering The Complex Genetic Architecture Of Human Plasma Lipidome Using Machine Learning Methods, Miikael Lehtimäki, Binisha H Mishra, Coral Del-Val, Leo-Pekka Lyytikäinen, Mika Kähönen, C Robert Cloninger, Olli T Raitakari, Reijo Laaksonen, Igor Zwir, Terho Lehtimäki, Pashupati P Mishra

2020-Current year OA Pubs

Genetic architecture of plasma lipidome provides insights into regulation of lipid metabolism and related diseases. We applied an unsupervised machine learning method, PGMRA, to discover phenotype-genotype many-to-many relations between genotype and plasma lipidome (phenotype) in order to identify the genetic architecture of plasma lipidome profiled from 1,426 Finnish individuals aged 30-45 years. PGMRA involves biclustering genotype and lipidome data independently followed by their inter-domain integration based on hypergeometric tests of the number of shared individuals. Pathway enrichment analysis was performed on the SNP sets to identify their associated biological processes. We identified 93 statistically significant (hypergeometric p-value < 0.01) lipidome-genotype relations. Genotype biclusters in these 93 relations contained 5977 SNPs across 3164 genes. Twenty nine of the 93 relations contained genotype biclusters with more than 50% unique SNPs and participants, thus representing most distinct subgroups. We identified 30 significantly enriched biological processes among the SNPs involved in 21 of these 29 most distinct genotype-lipidome subgroups through which the identified genetic variants can influence and regulate plasma lipid related metabolism and profiles. This study identified 29 distinct genotype-lipidome subgroups in the studied Finnish population that may have distinct disease trajectories and therefore could be useful in precision medicine research.

Skeletal Dysplasia-Causing Trpv4 Mutations Suppress The Hypertrophic Differentiation Of Human Ipsc-Derived Chondrocytes, Amanda R Dicks, Grigory I Maksaev, Zainab Harissa, Alireza Savadipour, Ruhang Tang, Nancy Steward, Wolfgang Liedtke, Colin G Nichols, Chia-Lung Wu, Farshid Guilak

2020-Current year OA Pubs

Mutations in the TRPV4 ion channel can lead to a range of skeletal dysplasias. However, the mechanisms by which TRPV4 mutations lead to distinct disease severity remain unknown. Here, we use CRISPR-Cas9-edited human-induced pluripotent stem cells (hiPSCs) harboring either the mild V620I or lethal T89I mutations to elucidate the differential effects on channel function and chondrogenic differentiation. We found that hiPSC-derived chondrocytes with the V620I mutation exhibited increased basal currents through TRPV4. However, both mutations showed more rapid calcium signaling with a reduced overall magnitude in response to TRPV4 agonist GSK1016790A compared to wildtype (WT). There were no differences in …

Hydrogel Encapsulation Of Genome-Engineered Stem Cells For Long-Term Self-Regulating Anti-Cytokine Therapy, Kelsey H Collins, Lara Pferdehirt, Leila S Saleh, Alireza Savadipour, Luke E Springer, Kristin L Lenz, Dominic M Thompson, Sara J Oswald, Christine T N Pham, Farshid Guilak

2020-Current year OA Pubs

Biologic therapies have revolutionized treatment options for rheumatoid arthritis (RA) but their continuous administration at high doses may lead to adverse events. Thus, the development of improved drug delivery systems that can sense and respond commensurately to disease flares represents an unmet medical need. Toward this end, we generated induced pluripotent stem cells (iPSCs) that express interleukin-1 receptor antagonist (IL-1Ra, an inhibitor of IL-1) in a feedback-controlled manner driven by the macrophage chemoattractant protein-1 (Ccl2) promoter. Cells were seeded in agarose hydrogel constructs made from 3D printed molds that can be injected subcutaneously via a blunt needle, thus simplifying implantation …

Tcr-Engineered Adoptive Cell Therapy Effectively Treats Intracranial Murine Glioblastoma, Maximilian O. Schaettler, Rupen Desai, Anthony Z. Wang, Alexandra J. Livingstone, Dale K. Kobayashi, Andrew T. Coxon, Jay A. Bowman-Kirigin, Connor J. Liu, Mao Li, Diane E. Bender, Michael J. White, David M. Kranz, Tanner M. Johanns, Gavin P. Dunn

2020-Current year OA Pubs

BACKGROUND: Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma.

METHODS: We employed single-cell PCR to isolate a TCR specific for the Imp3

RESULTS: We isolated and characterized the 3×1.1C TCR that displayed a high affinity for mImp3 but no wild-type cross-reactivity. To provide a …

Benchmarking The Generalizability Of Brain Age Models: Challenges Posed By Scanner Variance And Prediction Bias, Robert J Jirsaraie, Tobias Kaufmann, Vishnu Bashyam, Guray Erus, Joan L Luby, Lars T Westlye, Christos Davatzikos, Deanna M Barch, Aristeidis Sotiras

2020-Current year OA Pubs

Machine learning has been increasingly applied to neuroimaging data to predict age, deriving a personalized biomarker with potential clinical applications. The scientific and clinical value of these models depends on their applicability to independently acquired scans from diverse sources. Accordingly, we evaluated the generalizability of two brain age models that were trained across the lifespan by applying them to three distinct early-life samples with participants aged 8-22 years. These models were chosen based on the size and diversity of their training data, but they also differed greatly in their processing methods and predictive algorithms. Specifically, one brain age model was …

Svep1 Is An Endogenous Ligand For The Orphan Receptor Pear1, Jared S Elenbaas, Upasana Pudupakkam, Katrina J Ashworth, Chul Joo Kang, Ved Patel, Katherine Santana, In-Hyuk Jung, Paul C Lee, Kendall H Burks, Junedh M Amrute, Robert P Mecham, Carmen M Halabi, Arturo Aliso, Jorge Di Paola, Nathan O Stitziel

2020-Current year OA Pubs

Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that causally promotes vascular disease and associates with platelet reactivity in humans. Here, using a human genomic and proteomic approach, we identify a high affinity, disease-relevant, and potentially targetable interaction between SVEP1 and the orphan receptor Platelet and Endothelial Aggregation Receptor 1 (PEAR1). This interaction promotes PEAR1 phosphorylation and disease associated AKT/mTOR signaling in vascular cells and platelets. Mice lacking SVEP1 have reduced platelet activation, and exogenous SVEP1 induces PEAR1-dependent activation of platelets. SVEP1 and PEAR1 causally and concordantly relate to platelet …

Fmr1 Mutation Alters The Early Development Of Sensory Coding And Hunting And Social Behaviors In Larval Zebrafish, Shuyu I Zhu, Michael H Mccullough, Zac Pujic, Jordan Sibberas, Biao Sun, Thomas Darveniza, Bianca Bucknall, Lilach Avitan, Geoffrey J Goodhill

2020-Current year OA Pubs

Autism spectrum disorders (ASDs) are developmental in origin; however, little is known about how they affect the early development of behavior and sensory coding. The most common inherited form of autism is Fragile X syndrome (FXS), caused by a mutation in

Mrna Vaccine Mitigates Sars-Cov-2 Infections And Covid-19, Christina M. Kackos, Sherri L. Surman, Bart G. Jones, Robert E. Sealy, Trushar Jeevan, Christopher J H Davitt, Sergei Pustylnikov, Tamarand L. Darling, Adrianus C M Boon, Julia L. Hurwitz, Marcelo M. Samsa, Richard J. Webby

2020-Current year OA Pubs

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in December of 2019 and is responsible for millions of infections and deaths across the globe. Vaccination against SARS-CoV-2 has proven effective to contain the spread of the virus and reduce disease. The production and distribution of these vaccines occurred at a remarkable pace, largely through the employment of the novel mRNA platform. However, interruptions in supply chain and high demand for clinical grade reagents have impeded the manufacture and distribution of mRNA vaccines at a time when accelerated vaccine deployment is crucial. Furthermore, the emergence of SARS-CoV-2 …

Apolipoprotein E4 Has Extensive Conformational Heterogeneity In Lipid-Free And Lipid-Bound Forms, Melissa D Stuchell-Brereton, Maxwell I Zimmerman, Justin J Miller, Upasana L Mallimadugula, J Jeremías Incicco, Debjit Roy, Louis G Smith, Jasmine Cubuk, Berevan Baban, Gregory T Dekoster, Carl Frieden, Gregory R Bowman, Andrea Soranno

2020-Current year OA Pubs

The ε4-allele variant of apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer's disease, although it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. Previous studies have led to conflicting models of the C-terminal region positioning with respect to the N-terminal domain across isoforms largely because the data are potentially confounded by the presence of heterogeneous oligomers. Here, we apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct …

Barriers To Using Legally Authorized Representatives In Clinical Research With Older Adults, Jessica Mozersky, Erin D Solomon, Kari Baldwin, Matthew Wroblewski, Meredith Parsons, Melody Goodman, James M Dubois

2020-Current year OA Pubs

BACKGROUND: Older adults are at increased risk of cognitive impairments including Alzheimer's disease dementia. Legally authorized representatives (LARs) can provide informed consent when a participant is no longer able to, but little is known about barriers to incorporating them in research.

OBJECTIVE: Explore reasons for not asking and documenting participant decisions to appoint LARs among researchers conducting clinical intervention trials studying older adults or individuals with cognitive impairments.

METHODS: Mixed method design consisting of a survey (

RESULTS: 37% (

CONCLUSION: Resources and education to increase awareness and knowledge of LARs are needed. Researchers studying older adults should, at minimum, …

Self-Renewing Macrophages In Dorsal Root Ganglia Contribute To Promote Nerve Regeneration, Rui Feng, Vishnu Muraleedharan Saraswathy, Mayssa H Mokalled, Valeria Cavalli

2020-Current year OA Pubs

Sensory neurons located in dorsal root ganglia (DRG) convey sensory information from peripheral tissue to the brain. After peripheral nerve injury, sensory neurons switch to a regenerative state to enable axon regeneration and functional recovery. This process is not cell autonomous and requires glial and immune cells. Macrophages in the DRG (DRGMacs) accumulate in response to nerve injury, but their origin and function remain unclear. Here, we mapped the fate and response of DRGMacs to nerve injury using macrophage depletion, fate-mapping, and single-cell transcriptomics. We identified three subtypes of DRGMacs after nerve injury in addition to a small population of …

Amniotes Co-Opt Intrinsic Genetic Instability To Protect Germ-Line Genome Integrity, Yu H Sun, Xiaoyu Zhuo, Et Al.

2020-Current year OA Pubs

Unlike PIWI-interacting RNA (piRNA) in other species that mostly target transposable elements (TEs), >80% of piRNAs in adult mammalian testes lack obvious targets. However, mammalian piRNA sequences and piRNA-producing loci evolve more rapidly than the rest of the genome for unknown reasons. Here, through comparative studies of chickens, ducks, mice, and humans, as well as long-read nanopore sequencing on diverse chicken breeds, we find that piRNA loci across amniotes experience: (1) a high local mutation rate of structural variations (SVs, mutations ≥ 50 bp in size); (2) positive selection to suppress young and actively mobilizing TEs commencing at the pachytene …

Phase Ib Study Of Telisotuzumab Vedotin In Combination With Erlotinib In Patients With C-Met Protein-Expressing Non-Small-Cell Lung Cancer, D Ross Camidge, Daniel Morgensztern, Et Al.

2020-Current year OA Pubs

PURPOSE: Overexpression of c-Met protein and epidermal growth factor receptor (

PATIENTS AND METHODS: This study evaluated Teliso-V (2.7 mg/kg once every 21 days) plus erlotinib (150 mg once daily) in adult patients (age ≥ 18 years) with c-Met+ NSCLC. Later enrollment required presence of an

RESULTS: As of January 2020, 42 patients were enrolled (N = 36 efficacy-evaluable). Neuropathies were the most common any-grade adverse events reported, with 24 of 42 patients (57%) experiencing at least one event. The pharmacokinetic profile of Teliso-V plus erlotinib was similar to Teliso-V monotherapy. Median PFS for all efficacy-evaluable patients was 5.9 months …