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The Snakeskin-Mesh Complex Of Smooth Septate Junction Restricts Yorkie To Regulate Intestinal Homeostasis In Drosophila, Hsi-Ju Chen, Qi Li, Niraj K. Nirala, Y. Tony Ip May 2020

The Snakeskin-Mesh Complex Of Smooth Septate Junction Restricts Yorkie To Regulate Intestinal Homeostasis In Drosophila, Hsi-Ju Chen, Qi Li, Niraj K. Nirala, Y. Tony Ip

Open Access Articles

Tight junctions in mammals and septate junctions in insects are essential for epithelial integrity. We show here that, in the Drosophila intestine, smooth septate junction proteins provide barrier and signaling functions. During an RNAi screen for genes that regulate adult midgut tissue growth, we found that loss of two smooth septate junction components, Snakeskin and Mesh, caused a hyperproliferation phenotype. By examining epitope-tagged endogenous Snakeskin and Mesh, we demonstrate that the two proteins are present in the cytoplasm of differentiating enteroblasts and in cytoplasm and septate junctions of mature enterocytes. In both enteroblasts and enterocytes, loss of Snakeskin and Mesh ...


The Coordinate Actions Of Calcineurin And Hog1 Mediate The Stress Response Through Multiple Nodes Of The Cell Cycle Network, Cassandra M. Leech, Mackenzie J. Flynn, Heather E. Arsenault, Jianhong Ou, Haibo Liu, Lihua Julie Zhu, Jennifer A. Benanti Apr 2020

The Coordinate Actions Of Calcineurin And Hog1 Mediate The Stress Response Through Multiple Nodes Of The Cell Cycle Network, Cassandra M. Leech, Mackenzie J. Flynn, Heather E. Arsenault, Jianhong Ou, Haibo Liu, Lihua Julie Zhu, Jennifer A. Benanti

Open Access Articles

Upon exposure to environmental stressors, cells transiently arrest the cell cycle while they adapt and restore homeostasis. A challenge for all cells is to distinguish between stress signals and coordinate the appropriate adaptive response with cell cycle arrest. Here we investigate the role of the phosphatase calcineurin (CN) in the stress response and demonstrate that CN activates the Hog1/p38 pathway in both yeast and human cells. In yeast, the MAPK Hog1 is transiently activated in response to several well-studied osmostressors. We show that when a stressor simultaneously activates CN and Hog1, CN disrupts Hog1-stimulated negative feedback to prolong Hog1 ...


Transcriptomic Profiling Reveals Extraordinary Diversity Of Venom Peptides In Unexplored Predatory Gastropods Of The Genus Clavus, Aiping Lu, Maren Watkins, Qing Li, Samuel D. Robinson, Gisela P. Concepcion, Mark Yandell, Zhiping Weng, Baldomero M. Olivera, Helena Safavi-Hemami, Alexander E. Fedosov Apr 2020

Transcriptomic Profiling Reveals Extraordinary Diversity Of Venom Peptides In Unexplored Predatory Gastropods Of The Genus Clavus, Aiping Lu, Maren Watkins, Qing Li, Samuel D. Robinson, Gisela P. Concepcion, Mark Yandell, Zhiping Weng, Baldomero M. Olivera, Helena Safavi-Hemami, Alexander E. Fedosov

Open Access Articles

Predatory gastropods of the superfamily Conoidea number over 12,000 living species. The evolutionary success of this lineage can be explained by the ability of conoideans to produce complex venoms for hunting, defense and competitive interactions. Whereas venoms of cone snails (family Conidae) have become increasingly well studied, the venoms of most other conoidean lineages remain largely uncharacterized. In the present study we present the venom gland transcriptomes of two species of the genus Clavus that belong to the family Drilliidae. Venom gland transcriptomes of two specimens of Clavus canalicularis, and two specimens of Cv. davidgilmouri were analyzed, leading to ...


Chemical Modifications Of Adenine Base Editor Mrna And Guide Rna Expand Its Application Scope, Tingting Jiang, Xiao-Ou Zhang, Yueying Cao, Zhiping Weng, Wen Xue Apr 2020

Chemical Modifications Of Adenine Base Editor Mrna And Guide Rna Expand Its Application Scope, Tingting Jiang, Xiao-Ou Zhang, Yueying Cao, Zhiping Weng, Wen Xue

Open Access Articles

CRISPR-Cas9-associated base editing is a promising tool to correct pathogenic single nucleotide mutations in research or therapeutic settings. Efficient base editing requires cellular exposure to levels of base editors that can be difficult to attain in hard-to-transfect cells or in vivo. Here we engineer a chemically modified mRNA-encoded adenine base editor that mediates robust editing at various cellular genomic sites together with moderately modified guide RNA, and show its therapeutic potential in correcting pathogenic single nucleotide mutations in cell and animal models of diseases. The optimized chemical modifications of adenine base editor mRNA and guide RNA expand the applicability of ...


Dolphinnext: A Distributed Data Processing Platform For High Throughput Genomics, Onur Yukselen, Osman Turkyilmaz, Ahmet R. Ozturk, Manuel Garber, Alper Kucukural Apr 2020

Dolphinnext: A Distributed Data Processing Platform For High Throughput Genomics, Onur Yukselen, Osman Turkyilmaz, Ahmet R. Ozturk, Manuel Garber, Alper Kucukural

Open Access Articles

BACKGROUND: The emergence of high throughput technologies that produce vast amounts of genomic data, such as next-generation sequencing (NGS) is transforming biological research. The dramatic increase in the volume of data, the variety and continuous change of data processing tools, algorithms and databases make analysis the main bottleneck for scientific discovery. The processing of high throughput datasets typically involves many different computational programs, each of which performs a specific step in a pipeline. Given the wide range of applications and organizational infrastructures, there is a great need for highly parallel, flexible, portable, and reproducible data processing frameworks. Several platforms currently ...


Dbf4-Dependent Kinase (Ddk)-Mediated Proteolysis Of Cenp-A Prevents Mislocalization Of Cenp-A In Saccharomyces Cerevisiae, Jessica R. Eisenstatt, Lars Boeckmann, Wei-Chun Au, Valerie Garcia, Levi Bursch, Josefina Ocampo, Michael Costanzo, Michael Weinreich, Robert A. Sclafani, Anastasia Baryshnikova, Chad L. Myers, Charles Boone, David J. Clark, Richard E. Baker, Munira A. Basrai Apr 2020

Dbf4-Dependent Kinase (Ddk)-Mediated Proteolysis Of Cenp-A Prevents Mislocalization Of Cenp-A In Saccharomyces Cerevisiae, Jessica R. Eisenstatt, Lars Boeckmann, Wei-Chun Au, Valerie Garcia, Levi Bursch, Josefina Ocampo, Michael Costanzo, Michael Weinreich, Robert A. Sclafani, Anastasia Baryshnikova, Chad L. Myers, Charles Boone, David J. Clark, Richard E. Baker, Munira A. Basrai

Open Access Articles

The evolutionarily conserved centromeric histone H3 variant (Cse4 in budding yeast, CENP-A in humans) is essential for faithful chromosome segregation. Mislocalization of CENP-A to non-centromeric chromatin contributes to chromosomal instability (CIN) in yeast, fly, and human cells and CENP-A is highly expressed and mislocalized in cancers. Defining mechanisms that prevent mislocalization of CENP-A is an area of active investigation. Ubiquitin-mediated proteolysis of overexpressed Cse4 (GALCSE4) by E3 ubiquitin ligases such as Psh1 prevents mislocalization of Cse4, and psh1Delta strains display synthetic dosage lethality (SDL) with GALCSE4. We previously performed a genome-wide screen and identified five alleles of CDC7 and DBF4 ...


Trim34 Restricts Hiv-1 And Siv Capsids In A Trim5alpha-Dependent Manner, Molly Ohainle, Kyusik Kim, Sevnur Komurlu Keceli, Abby Felton, Ed Campbell, Jeremy Luban, Michael Emerman Apr 2020

Trim34 Restricts Hiv-1 And Siv Capsids In A Trim5alpha-Dependent Manner, Molly Ohainle, Kyusik Kim, Sevnur Komurlu Keceli, Abby Felton, Ed Campbell, Jeremy Luban, Michael Emerman

Open Access Articles

The HIV-1 capsid protein makes up the core of the virion and plays a critical role in early steps of HIV replication. Due to its exposure in the cytoplasm after entry, HIV capsid is a target for host cell factors that act directly to block infection such as TRIM5alpha and MxB. Several host proteins also play a role in facilitating infection, including in the protection of HIV-1 capsid from recognition by host cell restriction factors. Through an unbiased screening approach, called HIV-CRISPR, we show that the CPSF6-binding deficient, N74D HIV-1 capsid mutant is sensitive to restriction mediated by human TRIM34 ...


Interpretation Of The Epigenetic Signature Of Facioscapulohumeral Muscular Dystrophy In Light Of Genotype-Phenotype Studies, Ana Nikolic, Louise Maranda, Rossella Ginevra Tupler Apr 2020

Interpretation Of The Epigenetic Signature Of Facioscapulohumeral Muscular Dystrophy In Light Of Genotype-Phenotype Studies, Ana Nikolic, Louise Maranda, Rossella Ginevra Tupler

Open Access Articles

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by incomplete penetrance and intra-familial clinical variability. The disease has been associated with the genetic and epigenetic features of the D4Z4 repetitive elements at 4q35. Recently, D4Z4 hypomethylation has been proposed as a reliable marker in the FSHD diagnosis. We exploited the Italian Registry for FSHD, in which FSHD families are classified using the Clinical Comprehensive Evaluation Form (CCEF). A total of 122 index cases showing a classical FSHD phenotype (CCEF, category A) and 110 relatives were selected to test with the receiver operating characteristic (ROC) curve, the diagnostic and predictive value of D4Z4 ...


Identification And Characterization Of The Lactating Mouse Mammary Gland Citrullinome, Guangyuan Li, Coleman H. Young, Bryce Snow, Amanda O. Christensen, M. Kristen Demoruelle, Venkatesh V. Nemmara, Paul R. Thompson, Heather M. Rothfuss, Brian D. Cherrington Apr 2020

Identification And Characterization Of The Lactating Mouse Mammary Gland Citrullinome, Guangyuan Li, Coleman H. Young, Bryce Snow, Amanda O. Christensen, M. Kristen Demoruelle, Venkatesh V. Nemmara, Paul R. Thompson, Heather M. Rothfuss, Brian D. Cherrington

Open Access Articles

Citrullination is a post-translational modification (PTM) in which positively charged peptidyl-arginine is converted into neutral peptidyl-citrulline by peptidylarginine deiminase (PAD or PADI) enzymes. The full protein citrullinome in many tissues is unknown. Herein, we used mass spectrometry and identified 107 citrullinated proteins in the lactation day 9 (L9) mouse mammary gland including histone H2A, alpha-tubulin, and beta-casein. Given the importance of prolactin to lactation, we next tested if it stimulates PAD-catalyzed citrullination using mouse mammary epithelial CID-9 cells. Stimulation of CID-9 cells with 5 microg/mL prolactin for 10 min induced a 2-fold increase in histone H2A citrullination and a ...


Histone Deacetylases 1 And 2 Silence Cryptic Transcription To Promote Mitochondrial Function During Cardiogenesis, Zachary J. Milstone, Sherin Saheera, Lauren Bourke, Tomer Shpilka, Cole M. Haynes, Chinmay M. Trivedi Apr 2020

Histone Deacetylases 1 And 2 Silence Cryptic Transcription To Promote Mitochondrial Function During Cardiogenesis, Zachary J. Milstone, Sherin Saheera, Lauren Bourke, Tomer Shpilka, Cole M. Haynes, Chinmay M. Trivedi

Open Access Articles

Cryptic transcription occurs widely across the eukaryotic genome; however, its regulation during vertebrate development is not understood. Here, we show that two class I histone deacetylases, Hdac1 and Hdac2, silence cryptic transcription to promote mitochondrial function in developing murine hearts. Mice lacking Hdac1 and Hdac2 in heart exhibit defective developmental switch from anaerobic to mitochondrial oxidative phosphorylation (OXPHOS), severe defects in mitochondrial mass, mitochondrial function, and complete embryonic lethality. Hdac1/Hdac2 promotes the transition to OXPHOS by enforcing transcriptional fidelity of metabolic gene programs. Mechanistically, Hdac1/Hdac2 deacetylates histone residues including H3K23, H3K14, and H4K16 to suppress cryptic transcriptional initiation ...


Innate Immunity In The C. Elegans Intestine Is Programmed By A Neuronal Regulator Of Awc Olfactory Neuron Development, Kyle J. Foster, Hilary K. Cheesman, Pengpeng Liu, Nicholas D. Peterson, Sarah M. Anderson, Read Pukkila-Worley Apr 2020

Innate Immunity In The C. Elegans Intestine Is Programmed By A Neuronal Regulator Of Awc Olfactory Neuron Development, Kyle J. Foster, Hilary K. Cheesman, Pengpeng Liu, Nicholas D. Peterson, Sarah M. Anderson, Read Pukkila-Worley

Open Access Articles

Olfactory neurons allow animals to discriminate nutritious food sources from potential pathogens. From a forward genetic screen, we uncovered a surprising requirement for the olfactory neuron gene olrn-1 in the regulation of intestinal epithelial immunity in Caenorhabditis elegans. During nematode development, olrn-1 is required to program the expression of odorant receptors in the AWC olfactory neuron pair. Here, we show that olrn-1 also functions in AWC neurons in the cell non-autonomous suppression of the canonical p38 MAPK PMK-1 immune pathway in the intestine. Low activity of OLRN-1, which activates the p38 MAPK signaling cassette in AWC neurons during larval development ...


Biomarker Exploration In Human Peripheral Blood Mononuclear Cells For Monitoring Sulforaphane Treatment Responses In Autism Spectrum Disorder, Hua Liu, Andrew W. Zimmerman, Kanwaljit Singh, Susan Connors, Eileen Diggins, Katherine K. Stephenson, Albena T. Dinkova-Kostova, Jed W. Fahey Apr 2020

Biomarker Exploration In Human Peripheral Blood Mononuclear Cells For Monitoring Sulforaphane Treatment Responses In Autism Spectrum Disorder, Hua Liu, Andrew W. Zimmerman, Kanwaljit Singh, Susan Connors, Eileen Diggins, Katherine K. Stephenson, Albena T. Dinkova-Kostova, Jed W. Fahey

Open Access Articles

Autism Spectrum Disorder (ASD) is one of the most common neurodevelopmental disorders with no drugs treating the core symptoms and no validated biomarkers for clinical use. The multi-functional phytochemical sulforaphane affects many of the biochemical abnormalities associated with ASD. We investigated potential molecular markers from three ASD-associated physiological pathways that can be affected by sulforaphane: redox metabolism/oxidative stress; heat shock response; and immune dysregulation/inflammation, in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with ASD. We first analyzed the mRNA levels of selected molecular markers in response to sulforaphane ex vivo treatment in PBMCs from healthy ...


Are Dietary Fish Oil Supplements Appropriate For Dyslipidemia Management? A Review Of The Evidence, Samuel C. R. Sherratt, Michael Lero, R. Preston Mason Apr 2020

Are Dietary Fish Oil Supplements Appropriate For Dyslipidemia Management? A Review Of The Evidence, Samuel C. R. Sherratt, Michael Lero, R. Preston Mason

Open Access Articles

PURPOSE OF REVIEW: The purpose of this review is to assess whether dietary fish oil supplements can be appropriate for patients with elevated triglycerides and cardiovascular risk based on a comprehensive analysis of their composition, and level of regulatory oversight.

RECENT FINDINGS: Approximately 19 million people in the United States take fish oil supplements, many for the purpose of treating or preventing heart disease. Unlike prescription products, fish oil supplements are classified as food by the Food and Drug Administration (FDA) and are not required to undergo manufacturing oversight or clinical testing. Analysis of widely used dietary fish oil supplements ...


Mechanisms Of Insulin Resistance Related To White, Beige, And Brown Adipocytes, Michael P. Czech Apr 2020

Mechanisms Of Insulin Resistance Related To White, Beige, And Brown Adipocytes, Michael P. Czech

Open Access Articles

BACKGROUND: The diminished glucose lowering effect of insulin in obesity, called "insulin resistance," is associated with glucose intolerance, type 2 diabetes, and other serious maladies. Many publications on this topic have suggested numerous hypotheses on the molecular and cellular disruptions that contribute to the syndrome. However, significant uncertainty remains on the mechanisms of its initiation and long-term maintenance.

SCOPE OF REVIEW: To simplify insulin resistance analysis, this review focuses on the unifying concept that adipose tissue is a central regulator of systemic glucose homeostasis by controlling liver and skeletal muscle metabolism. Key aspects of adipose function related to insulin resistance ...


Comparisons Of Antibody Populations In Different Pre-Fusion F Vlp-Immunized Cotton Rat Dams And Their Offspring, Lori Mcginnes Cullen, Marina S. Boukhvalova, Jorge C. G. Blanco, Trudy G. Morrison Mar 2020

Comparisons Of Antibody Populations In Different Pre-Fusion F Vlp-Immunized Cotton Rat Dams And Their Offspring, Lori Mcginnes Cullen, Marina S. Boukhvalova, Jorge C. G. Blanco, Trudy G. Morrison

Open Access Articles

Respiratory syncytial virus (RSV) infection poses a significant risk for infants. Since the direct vaccination of infants is problematic, maternal vaccination may provide a safer, more effective approach to their protection. In the cotton rat (CR) model, we have compared the immunization of pregnant CR dams with virus-like particles assembled with the prototype mutation stabilized pre-fusion F protein, DS-Cav1, as well two alternative mutation stabilized pre-fusion proteins (UC-2 F, UC-3 F) and showed that the alternative pre-fusion F VLPs protected the offspring of immunized dams significantly better than DS-Cav1 F VLPs (Blanco, et al. J. Virol. 93: e00914). Here, we ...


Humanity's Best Friend: A Dog-Centric Approach To Addressing Global Challenges, Naomi Sykes, Elinor K. Karlsson, Greger Larson Mar 2020

Humanity's Best Friend: A Dog-Centric Approach To Addressing Global Challenges, Naomi Sykes, Elinor K. Karlsson, Greger Larson

Open Access Articles

No other animal has a closer mutualistic relationship with humans than the dog (Canis familiaris). Domesticated from the Eurasian grey wolf (Canis lupus), dogs have evolved alongside humans over millennia in a relationship that has transformed dogs and the environments in which humans and dogs have co-inhabited. The story of the dog is the story of recent humanity, in all its biological and cultural complexity. By exploring human-dog-environment interactions throughout time and space, it is possible not only to understand vital elements of global history, but also to critically assess our present-day relationship with the natural world, and to begin ...


Beta-Amyloid Clustering Around Asc Fibrils Boosts Its Toxicity In Microglia, Lea L. Friker, Hannah Scheiblich, Inga V. Hochheiser, Rebecca Brinkschulte, Dietmar Riedel, Eicke Latz, Matthias Geyer, Michael T. Heneka Mar 2020

Beta-Amyloid Clustering Around Asc Fibrils Boosts Its Toxicity In Microglia, Lea L. Friker, Hannah Scheiblich, Inga V. Hochheiser, Rebecca Brinkschulte, Dietmar Riedel, Eicke Latz, Matthias Geyer, Michael T. Heneka

Open Access Articles

Alzheimer's disease is the world's most common neurodegenerative disorder. It is associated with neuroinflammation involving activation of microglia by beta-amyloid (Abeta) deposits. Based on previous studies showing apoptosis-associated speck-like protein containing a CARD (ASC) binding and cross-seeding extracellular Abeta, we investigate the propagation of ASC between primary microglia and the effects of ASC-Abeta composites on microglial inflammasomes and function. Indeed, ASC released by a pyroptotic cell can be functionally built into the neighboring microglia NOD-like receptor protein (NLRP3) inflammasome. Compared with protein-only application, exposure to ASC-Abeta composites amplifies the proinflammatory response, resulting in pyroptotic cell death, setting free ...


A Systematic Re-Examination Of Processing Of Mhci-Bound Antigenic Peptide Precursors By Er Aminopeptidase 1, George Mavridis, Richa Arya, Alexander Domnick, Jerome Zoidakis, Manousos Makridakis, Antonia Vlahou, Anastasia Mpakali, Angelos Lelis, Dimitris Georgiadis, Robert Tampe, Athanasios Papakyriakou, Lawrence J. Stern, Efstratios Stratikos Mar 2020

A Systematic Re-Examination Of Processing Of Mhci-Bound Antigenic Peptide Precursors By Er Aminopeptidase 1, George Mavridis, Richa Arya, Alexander Domnick, Jerome Zoidakis, Manousos Makridakis, Antonia Vlahou, Anastasia Mpakali, Angelos Lelis, Dimitris Georgiadis, Robert Tampe, Athanasios Papakyriakou, Lawrence J. Stern, Efstratios Stratikos

Open Access Articles

Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims antigenic peptide precursors to generate mature antigenic peptides for presentation by major histocompatibility complex class I (MHCI) molecules and regulates adaptive immune responses. ERAP1 has been proposed to trim peptide precursors both in solution and in pre-formed MHCI-peptide complexes, but which mode is more relevant to its biological function remains controversial. Here, we compared ERAP1-mediated trimming of antigenic peptide precursors in solution or when bound to three MHCI alleles, HLA-B*58, HLA-B*08 and HLA-A*02. For all MHCI-peptide combinations, peptide binding onto MHCI protected against ERAP1-mediated trimming. In only a single MHCI-peptide combination ...


Epstein-Barr Virus Epitope-Major Histocompatibility Complex Interaction Combined With Convergent Recombination Drives Selection Of Diverse T Cell Receptor Alpha And Beta Repertoires, Anna Gil, Larisa Kamga, Ramakanth Chirravuri-Venkata, Nuray Aslan, Fransenio G. Clark, Dario Ghersi, Katherine Luzuriaga, Liisa K. Selin Mar 2020

Epstein-Barr Virus Epitope-Major Histocompatibility Complex Interaction Combined With Convergent Recombination Drives Selection Of Diverse T Cell Receptor Alpha And Beta Repertoires, Anna Gil, Larisa Kamga, Ramakanth Chirravuri-Venkata, Nuray Aslan, Fransenio G. Clark, Dario Ghersi, Katherine Luzuriaga, Liisa K. Selin

Open Access Articles

Recognition modes of individual T cell receptors (TCRs) are well studied, but factors driving the selection of TCR repertoires from primary through persistent human virus infections are less well understood. Using deep sequencing, we demonstrate a high degree of diversity of Epstein-Barr virus (EBV)-specific clonotypes in acute infectious mononucleosis (AIM). Only 9% of unique clonotypes detected in AIM persisted into convalescence; the majority (91%) of unique clonotypes detected in AIM were not detected in convalescence and were seeming replaced by equally diverse "de novo" clonotypes. The persistent clonotypes had a greater probability of being generated than nonpersistent clonotypes due ...


Premature Termination Codon Readthrough Upregulates Progranulin Expression And Improves Lysosomal Function In Preclinical Models Of Grn Deficiency, Jonathan Frew, Fen-Biao Gao, Haakon B. Nygaard Mar 2020

Premature Termination Codon Readthrough Upregulates Progranulin Expression And Improves Lysosomal Function In Preclinical Models Of Grn Deficiency, Jonathan Frew, Fen-Biao Gao, Haakon B. Nygaard

Open Access Articles

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a devastating and progressive disorder, and a common cause of early onset dementia. Progranulin (PGRN) haploinsufficiency due to autosomal dominant mutations in the progranulin gene (GRN) is an important cause of FTLD (FTLD-GRN), and nearly a quarter of these genetic cases are due to a nonsense mutation. Premature termination codons (PTC) can be therapeutically targeted by compounds allowing readthrough, and aminoglycoside antibiotics are known to be potent PTC readthrough drugs. Restoring endogenous PGRN through PTC readthrough has not previously been explored as a therapeutic intervention in FTLD.

METHODS: We studied whether the aminoglycoside G418 ...


Liver-Directed But Not Muscle-Directed Aav-Antibody Gene Transfer Limits Humoral Immune Responses In Rhesus Monkeys, Sebastian P. Fuchs, Jose M. Martinez-Navio, Eva G. Rakasz, Guangping Gao, Ronald C. Desrosiers Mar 2020

Liver-Directed But Not Muscle-Directed Aav-Antibody Gene Transfer Limits Humoral Immune Responses In Rhesus Monkeys, Sebastian P. Fuchs, Jose M. Martinez-Navio, Eva G. Rakasz, Guangping Gao, Ronald C. Desrosiers

Open Access Articles

A number of publications have described the use of adeno-associated virus (AAV) for the delivery of anti-HIV and anti-simian immunodeficiency virus (SIV) monoclonal antibodies (mAbs) to rhesus monkeys. Anti-drug antibodies (ADAs) have been frequently observed, and long-term AAV-mediated delivery has been inconsistent. Here, we investigated different AAV vector strategies and delivery schemes to rhesus monkeys using the rhesus monkey mAb 4L6. We compared 4L6 immunoglobulin G1 (IgG1) delivery using the AAV1 versus the AAV8 serotype with a cytomegalovirus (CMV) promoter and the use of a muscle-specific versus a liver-specific promoter. Long-term expression levels of 4L6 IgG1 following AAV8-mediated gene transfer ...


Exogenous Gdf11, But Not Gdf8, Reduces Body Weight And Improves Glucose Homeostasis In Mice, Ryan G. Walker, Hye Lim Noh, Taekyoon Kim, Jason K. Kim, Richard T. Lee Mar 2020

Exogenous Gdf11, But Not Gdf8, Reduces Body Weight And Improves Glucose Homeostasis In Mice, Ryan G. Walker, Hye Lim Noh, Taekyoon Kim, Jason K. Kim, Richard T. Lee

Open Access Articles

Insulin resistance is associated with aging in mice and humans. We have previously shown that administration of recombinant GDF11 (rGDF11) to aged mice alters aging phenotypes in the brain, skeletal muscle, and heart. While the closely related protein GDF8 has a role in metabolism, limited data are available on the potential metabolic effects of GDF11 or GDF8 in aging. To determine the metabolic effects of these two ligands, we administered rGDF11 or rGDF8 protein to young or aged mice fed a standard chow diet, short-term high-fat diet (HFD), or long-term HFD. Under nearly all of these diet conditions, administration of ...


Canine Models Of Inherited Musculoskeletal And Neurodegenerative Diseases, Brett D. Story, Matthew E. Miller, Allison M. Bradbury, Emily D. Million, Dongsheng Duan, Toloo Taghian, Dominik Faissler, Deborah Fernau, Sidney J. Beecy, Heather Gray-Edwards Mar 2020

Canine Models Of Inherited Musculoskeletal And Neurodegenerative Diseases, Brett D. Story, Matthew E. Miller, Allison M. Bradbury, Emily D. Million, Dongsheng Duan, Toloo Taghian, Dominik Faissler, Deborah Fernau, Sidney J. Beecy, Heather Gray-Edwards

Open Access Articles

Mouse models of human disease remain the bread and butter of modern biology and therapeutic discovery. Nonetheless, more often than not mouse models do not reproduce the pathophysiology of the human conditions they are designed to mimic. Naturally occurring large animal models have predominantly been found in companion animals or livestock because of their emotional or economic value to modern society and, unlike mice, often recapitulate the human disease state. In particular, numerous models have been discovered in dogs and have a fundamental role in bridging proof of concept studies in mice to human clinical trials. The present article is ...


Tumor Cell-Organized Fibronectin Maintenance Of A Dormant Breast Cancer Population, Lauren E. Barney, Christopher L. Hall, Alyssa D. Schwartz, Akia N. Parks, Christopher Sparages, Sualyneth Galarza, Manu O. Platt, Arthur M. Mercurio, Shelly R. Peyton Mar 2020

Tumor Cell-Organized Fibronectin Maintenance Of A Dormant Breast Cancer Population, Lauren E. Barney, Christopher L. Hall, Alyssa D. Schwartz, Akia N. Parks, Christopher Sparages, Sualyneth Galarza, Manu O. Platt, Arthur M. Mercurio, Shelly R. Peyton

Open Access Articles

Tumors can undergo long periods of dormancy, with cancer cells entering a largely quiescent, nonproliferative state before reactivation and outgrowth. To understand the role of the extracellular matrix (ECM) in regulating tumor dormancy, we created an in vitro cell culture system with carefully controlled ECM substrates to observe entrance into and exit from dormancy with live imaging. We saw that cell populations capable of surviving entrance into long-term dormancy were heterogeneous, containing quiescent, cell cycle-arrested, and actively proliferating cells. Cell populations capable of entering dormancy formed an organized, fibrillar fibronectin matrix via alphavbeta3 and alpha5beta1 integrin adhesion, ROCK-generated tension, and ...


Evaluation Of Pre-Processing On The Meta-Analysis Of Dna Methylation Data From The Illumina Humanmethylation450 Beadchip Platform, Claudia Sala, Pietro Di Lena, Danielle Fernandes Durso, Andrea Prodi, Gastone Castellani, Christine Nardini Mar 2020

Evaluation Of Pre-Processing On The Meta-Analysis Of Dna Methylation Data From The Illumina Humanmethylation450 Beadchip Platform, Claudia Sala, Pietro Di Lena, Danielle Fernandes Durso, Andrea Prodi, Gastone Castellani, Christine Nardini

Open Access Articles

INTRODUCTION: Meta-analysis is a powerful means for leveraging the hundreds of experiments being run worldwide into more statistically powerful analyses. This is also true for the analysis of omic data, including genome-wide DNA methylation. In particular, thousands of DNA methylation profiles generated using the Illumina 450k are stored in the publicly accessible Gene Expression Omnibus (GEO) repository. Often, however, the intensity values produced by the BeadChip (raw data) are not deposited, therefore only pre-processed values -obtained after computational manipulation- are available. Pre-processing is possibly different among studies and may then affect meta-analysis by introducing non-biological sources of variability.

MATERIAL AND ...


Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, And Metabolism, Informing The Pathogenesis Of Hypertrophic Cardiomyopathy, Christopher N. Toepfer, Raul Padron, Christine E. Seidman Mar 2020

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, And Metabolism, Informing The Pathogenesis Of Hypertrophic Cardiomyopathy, Christopher N. Toepfer, Raul Padron, Christine E. Seidman

Open Access Articles

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations.

METHODS: We assayed myosin ATP binding to define the proportion of myosins in ...


Diabetes Mellitus Type 2 Is Associated With Increased Tumor Expression Of Programmed Death-Ligand 1 (Pd-L1) In Surgically Resected Non-Small Cell Lung Cancer - A Matched Case-Control Study, Christopher A. Febres-Aldana, Robert Poppiti, John M. Varlotto, Rick Voland, Michael Zaleski, Setareh Sharzehi, Negar Rassaei Mar 2020

Diabetes Mellitus Type 2 Is Associated With Increased Tumor Expression Of Programmed Death-Ligand 1 (Pd-L1) In Surgically Resected Non-Small Cell Lung Cancer - A Matched Case-Control Study, Christopher A. Febres-Aldana, Robert Poppiti, John M. Varlotto, Rick Voland, Michael Zaleski, Setareh Sharzehi, Negar Rassaei

Open Access Articles

OBJECTIVES: Programmed death-ligand 1 (PD-L1) expression is a biomarker for cancer immunotherapy. Diabetes mellitus type-2 is a comorbid disease associated with adverse outcomes in Non-Small Cell Lung Cancer (NSCLC). We aimed to investigate the differences in PD-L1 expression in diabetics.

METHODS: A matched case-control cohort of surgically-resected NSCLC was assembled from an early multicenter study (PMID: 19152440). PD-L1 immunohistochemistry (Clone 22C3) was graded by a tumor positive score (TPS) system (TPS0: no staining; TPS1: < 1%; TPS2: 1-49%; TPS3: > /=50%). Variables showing significance at univariate survival analysis were fit in a Cox regression survival model.

RESULTS: Diabetics (n=40) and nondiabetics (n=39) showed no ...


Methylation Of Srd5a2 Promoter Predicts A Better Outcome For Castration-Resistant Prostate Cancer Patients Undergoing Androgen Deprivation Therapy, Zongwei Wang, Tuo Deng, Xingbo Long, Xueming Lin, Shulin Wu, Hongbo Wang, Rongbin Ge, Zhenwei Zhang, Chin-Lee Wu, Mary-Ellen Taplin, Aria F. Olumi Mar 2020

Methylation Of Srd5a2 Promoter Predicts A Better Outcome For Castration-Resistant Prostate Cancer Patients Undergoing Androgen Deprivation Therapy, Zongwei Wang, Tuo Deng, Xingbo Long, Xueming Lin, Shulin Wu, Hongbo Wang, Rongbin Ge, Zhenwei Zhang, Chin-Lee Wu, Mary-Ellen Taplin, Aria F. Olumi

Open Access Articles

PURPOSE: To determine whether SRD5A2 promoter methylation is associated with cancer progression during androgen deprivation therapy (ADT) in CRPC.

PATIENTS AND METHODS: In a Local CRPC cohort, 42 prostatic specimens were collected from patients who were diagnosed as CRPC and underwent transurethral resection of the prostate (TURP) at Massachusetts General Hospital (MGH). In a metastatic CRPC (Met CRPC) cohort, 12 metastatic biopsies were collected from CRPC patients who would be treated with abiraterone plus dutasteride (Clinical Trial NCT01393730). As controls, 36 benign prostatic specimens were collected from patients undergoing prostate reduction surgery for symptoms of bladder outlet obstruction secondary to ...


Muscle-Directed Delivery Of An Aav1 Vector Leads To Capsid-Specific T Cell Exhaustion In Nonhuman Primates And Humans, Gwladys Gernoux, Alisha M. Gruntman, Meghan Blackwood, Marina Zieger, Terence R. Flotte, Christian Mueller Mar 2020

Muscle-Directed Delivery Of An Aav1 Vector Leads To Capsid-Specific T Cell Exhaustion In Nonhuman Primates And Humans, Gwladys Gernoux, Alisha M. Gruntman, Meghan Blackwood, Marina Zieger, Terence R. Flotte, Christian Mueller

Open Access Articles

With the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approvals for Zolgensma, Luxturna, and Glybera, recombinant adeno-associated viruses (rAAVs) are considered efficient tools for gene transfer. However, studies in animals and humans demonstrate that intramuscular (IM) AAV delivery can trigger immune responses to AAV capsids and/or transgenes. IM delivery of rAAV1 in humans has also been described to induce tolerance to rAAV characterized by the presence of capsid-specific regulatory T cells (Tregs) in periphery. To understand mechanisms responsible for tolerance and parameters involved, we tested 3 muscle-directed administration routes in rhesus monkeys: IM delivery, venous ...


Comprehensive Fitness Maps Of Hsp90 Show Widespread Environmental Dependence, Julia M. Flynn, Ammeret Rossouw, Pamela A. Cote-Hammarlof, Ines Fragata, David Mavor, Carl Hollins Iii, Claudia Bank, Daniel N. Bolon Mar 2020

Comprehensive Fitness Maps Of Hsp90 Show Widespread Environmental Dependence, Julia M. Flynn, Ammeret Rossouw, Pamela A. Cote-Hammarlof, Ines Fragata, David Mavor, Carl Hollins Iii, Claudia Bank, Daniel N. Bolon

Open Access Articles

Gene-environment interactions have long been theorized to influence molecular evolution. However, the environmental dependence of most mutations remains unknown. Using deep mutational scanning, we engineered yeast with all 44,604 single codon changes encoding 14,160 amino acid variants in Hsp90 and quantified growth effects under standard conditions and under five stress conditions. To our knowledge, these are the largest determined comprehensive fitness maps of point mutants. The growth of many variants differed between conditions, indicating that environment can have a large impact on Hsp90 evolution. Multiple variants provided growth advantages under individual conditions; however, these variants tended to exhibit ...