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University of Massachusetts Medical School

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Articles 1 - 30 of 3738

Full-Text Articles in Life Sciences

Enhanced Cas12a Editing In Mammalian Cells And Zebrafish, Pengpeng Liu, Kevin Luk, Masahiro Shin, Feston Idrizi, Samantha F. Kwok, Benjamin P. Roscoe, Esther Mintzer, Sneha Suresh, Kyle Morrison, Josias B. Frazao, Mehmet Fatih Bolukbasi, Karthikeyan Ponnienselvan, Jeremy Luban, Lihua Julie Zhu, Nathan D. Lawson, Scot A. Wolfe May 2019

Enhanced Cas12a Editing In Mammalian Cells And Zebrafish, Pengpeng Liu, Kevin Luk, Masahiro Shin, Feston Idrizi, Samantha F. Kwok, Benjamin P. Roscoe, Esther Mintzer, Sneha Suresh, Kyle Morrison, Josias B. Frazao, Mehmet Fatih Bolukbasi, Karthikeyan Ponnienselvan, Jeremy Luban, Lihua Julie Zhu, Nathan D. Lawson, Scot A. Wolfe

Open Access Articles

Type V CRISPR-Cas12a systems provide an alternate nuclease platform to Cas9, with potential advantages for specific genome editing applications. Here we describe improvements to the Cas12a system that facilitate efficient targeted mutagenesis in mammalian cells and zebrafish embryos. We show that engineered variants of Cas12a with two different nuclear localization sequences (NLS) on the C terminus provide increased editing efficiency in mammalian cells. Additionally, we find that pre-crRNAs comprising a full-length direct repeat (full-DR-crRNA) sequence with specific stem-loop G-C base substitutions exhibit increased editing efficiencies compared with the standard mature crRNA framework. Finally, we demonstrate in zebrafish embryos that the ...


Brown Fat Organogenesis And Maintenance Requires Akt1 And Akt2, Joan Sanchez-Gurmaches, Camila Martinez Calejman, Su Myung Jung, Huawei Li, David A. Guertin May 2019

Brown Fat Organogenesis And Maintenance Requires Akt1 And Akt2, Joan Sanchez-Gurmaches, Camila Martinez Calejman, Su Myung Jung, Huawei Li, David A. Guertin

Open Access Articles

OBJECTIVE: Understanding the signaling mechanisms that control brown adipose tissue (BAT) development is relevant to understanding energy homeostasis and obesity. The AKT kinases are insulin effectors with critical in vivo functions in adipocytes; however, their role in adipocyte development remains poorly understood. The goal of this study was to investigate AKT function in BAT development.

METHODS: We conditionally deleted Akt1 and Akt2 either individually or together with Myf5-Cre, which targets early mesenchymal precursors that give rise to brown adipocytes. Because Myf5-Cre also targets skeletal muscle and some white adipocyte lineages, comparisons were made between AKT function in BAT versus white ...


Regulation Of The Drosophila Imd Pathway By Signaling Amyloids, Anni Kleino, Neal S. Silverman May 2019

Regulation Of The Drosophila Imd Pathway By Signaling Amyloids, Anni Kleino, Neal S. Silverman

Open Access Articles

Fruit flies elicit effective defense responses against numerous microbes. The responses against Gram-negative bacteria are mediated by the Imd pathway, an evolutionarily conserved NF-kappaB pathway recognizing meso-diaminopimelic acid (DAP)-type peptidoglycan from bacterial cell walls. Several reviews already provide a detailed view of ligand recognition and signal transduction during Imd signaling, but the formation and regulation of the signaling complex immediately downstream of the peptidoglycan-sensing receptors is still elusive. In this review, we focus on the formation of the Imd amyloidal signaling center and post-translational modifications in the assembly and disassembly of the Imd signaling complex.


Transfer Rna Genes Affect Chromosome Structure And Function Via Local Effects, Omar Hamdani, Tsung-Han S. Hsieh, Oliver J. Rando, Rohinton T. Kamakaka Apr 2019

Transfer Rna Genes Affect Chromosome Structure And Function Via Local Effects, Omar Hamdani, Tsung-Han S. Hsieh, Oliver J. Rando, Rohinton T. Kamakaka

Open Access Articles

The genome is packaged and organized in an ordered, non-random manner and specific chromatin segments contact nuclear substructures to mediate this organization. Transfer RNA genes (tDNAs) are binding sites for transcription factors and architectural proteins and are thought to play an important role in the organization of the genome. In this study, we investigate the role of tDNAs in genomic organization and chromosome function by editing a chromosome so that it lacks any tDNAs. Surprisingly our analyses of this tDNA-less chromosome show that loss of tDNAs does not grossly affect chromatin architecture or chromosome tethering and mobility. However, loss of ...


Or14i1 Is A Receptor For The Human Cytomegalovirus Pentameric Complex And Defines Viral Epithelial Cell Tropism, Xiaofei E, Paul Meraner, Ping Lu, Jill M. Perreira, Aaron M. Aker, William M. Mcdougall, Ronghua Zhuge, Gary C. Chan, Rachel M. Gerstein, Patrizia Caposio, Andrew D. Yurochko, Abraham L. Brass, Timothy F. Kowalik Apr 2019

Or14i1 Is A Receptor For The Human Cytomegalovirus Pentameric Complex And Defines Viral Epithelial Cell Tropism, Xiaofei E, Paul Meraner, Ping Lu, Jill M. Perreira, Aaron M. Aker, William M. Mcdougall, Ronghua Zhuge, Gary C. Chan, Rachel M. Gerstein, Patrizia Caposio, Andrew D. Yurochko, Abraham L. Brass, Timothy F. Kowalik

Open Access Articles

A human cytomegalovirus (HCMV) pentameric glycoprotein complex (PC), gH-gL-UL128-UL130-UL131A, is necessary for viral infection of clinically relevant cell types, including epithelial cells, which are important for interhost transmission and disease. We performed genome-wide CRISPR/Cas9 screens of different cell types in parallel to identify host genes specifically required for HCMV infection of epithelial cells. This effort identified a multipass membrane protein, OR14I1, as a receptor for HCMV infection. This olfactory receptor family member is required for HCMV attachment, entry, and infection of epithelial cells and is dependent on the presence of viral PC. OR14I1 is required for AKT activation and ...


Head And Neck Cancers, James Liebmann, Ali Akalin, Liana Puscas, Andrew Chen, Richard S. Pieters Mar 2019

Head And Neck Cancers, James Liebmann, Ali Akalin, Liana Puscas, Andrew Chen, Richard S. Pieters

Cancer Concepts: A Guidebook for the Non-Oncologist

This chapter in Cancer Concepts: A Guidebook for the Non-Oncologist presents an overview of head and neck cancers, including epidemiology, etiology, screening, pathology, staging, and treatment. The chapter focuses on cancers of the upper aerodigestive tract which are most often squamous cell carcinomas arising from the squamous epithelium that lines the tract.


Next Steps From A School Gardening Partnership Conference (Ages: Academic Gardening To Enrich Our Students): Expanding The Impact Of School Gardens Through Higher Education, K-12 School And Community Coalitions, Martha Assefa, Pat Barnosky, Michelle Beaulieu, Amy Borg, Casey Burns, Marguerite Cawley, Jennifer De Jordy, Daina Harvey, Kelsey Hopkins, Sue Hunt, Joanne Jaber Gauvin, Isabelle Jenkins, Eliza Lawrence, Anna Marinescu, Mackenzie May, Gina Plata-Nino, Grace Sliwoski, Adam Saltsman Mar 2019

Next Steps From A School Gardening Partnership Conference (Ages: Academic Gardening To Enrich Our Students): Expanding The Impact Of School Gardens Through Higher Education, K-12 School And Community Coalitions, Martha Assefa, Pat Barnosky, Michelle Beaulieu, Amy Borg, Casey Burns, Marguerite Cawley, Jennifer De Jordy, Daina Harvey, Kelsey Hopkins, Sue Hunt, Joanne Jaber Gauvin, Isabelle Jenkins, Eliza Lawrence, Anna Marinescu, Mackenzie May, Gina Plata-Nino, Grace Sliwoski, Adam Saltsman

Community Engagement and Research Symposia

Research suggests that there are many benefits of school gardens for students, teachers and community. Not only can they help children eat more fruits and vegetables and be more physically active, they can help to create learning opportunities and increase teacher satisfaction. In Worcester, Massachusetts, a city with high poverty and food insecurity rates, a broad community coalition formed to brainstorm novel implementation models to improve the use and sustainability of school gardens. The group decided to foster new collaborations among higher education, K-12 schools and community organizations. The innovative idea was that higher education could meet their need for ...


Streptolysin O Induces The Ubiquitination And Degradation Of Pro-Il-1beta, Dora Hancz, Elsa Westerlund, Christine Valfridsson, Getachew Melkamu Aemero, Benedicte Bastiat-Sempe, M. Pontus A. Orning, Egil Lien, Michael R. Wessels, Jenny J. Persson Mar 2019

Streptolysin O Induces The Ubiquitination And Degradation Of Pro-Il-1beta, Dora Hancz, Elsa Westerlund, Christine Valfridsson, Getachew Melkamu Aemero, Benedicte Bastiat-Sempe, M. Pontus A. Orning, Egil Lien, Michael R. Wessels, Jenny J. Persson

Open Access Articles

Group A Streptococcus (GAS) is a common and versatile human pathogen causing a variety of diseases. One of the many virulence factors of GAS is the secreted pore-forming cytotoxin streptolysin O (SLO), which has been ascribed multiple properties, including inflammasome activation leading to release of the potent inflammatory cytokine IL-1beta from infected macrophages. IL-1beta is synthesized as an inactive pro-form, which is activated intracellularly through proteolytic cleavage. Here, we use a macrophage infection model to show that SLO specifically induces ubiquitination and degradation of pro-IL-1beta. Ubiquitination was dependent on SLO being released from the infecting bacterium, and pore formation by ...


Multi-Dimensional Transcriptional Remodeling By Physiological Insulin In Vivo, Thiago M. Batista, Ruben Garcia-Martin, Weikang Cai, Masahiro Konishi, Brian T. O'Neill, Masaji Sakaguchi, Jong Hun Kim, Dae Young Jung, Jason K. Kim, C. Ronald Kahn Mar 2019

Multi-Dimensional Transcriptional Remodeling By Physiological Insulin In Vivo, Thiago M. Batista, Ruben Garcia-Martin, Weikang Cai, Masahiro Konishi, Brian T. O'Neill, Masaji Sakaguchi, Jong Hun Kim, Dae Young Jung, Jason K. Kim, C. Ronald Kahn

Open Access Articles

Regulation of gene expression is an important aspect of insulin action but in vivo is intertwined with changing levels of glucose and counter-regulatory hormones. Here we demonstrate that under euglycemic clamp conditions, physiological levels of insulin regulate interrelated networks of more than 1,000 transcripts in muscle and liver. These include expected pathways related to glucose and lipid utilization, mitochondrial function, and autophagy, as well as unexpected pathways, such as chromatin remodeling, mRNA splicing, and Notch signaling. These acutely regulated pathways extend beyond those dysregulated in mice with chronic insulin deficiency or insulin resistance and involve a broad network of ...


Measuring The Reproducibility And Quality Of Hi-C Data, Galip Gurkan Yardimci, Hakan Ozadam, Bryan R. Lajoie, Ye Zhan, Job Dekker, William S. Noble Mar 2019

Measuring The Reproducibility And Quality Of Hi-C Data, Galip Gurkan Yardimci, Hakan Ozadam, Bryan R. Lajoie, Ye Zhan, Job Dekker, William S. Noble

Open Access Articles

BACKGROUND: Hi-C is currently the most widely used assay to investigate the 3D organization of the genome and to study its role in gene regulation, DNA replication, and disease. However, Hi-C experiments are costly to perform and involve multiple complex experimental steps; thus, accurate methods for measuring the quality and reproducibility of Hi-C data are essential to determine whether the output should be used further in a study.

RESULTS: Using real and simulated data, we profile the performance of several recently proposed methods for assessing reproducibility of population Hi-C data, including HiCRep, GenomeDISCO, HiC-Spector, and QuASAR-Rep. By explicitly controlling noise ...


Entosis Controls A Developmental Cell Clearance In C. Elegans, Yongchan Lee, Jens C. Hamann, Mark Pellegrino, Joanne Durgan, Marie-Charlotte Domart, Lucy M. Collinson, Cole M. Haynes, Oliver Florey, Michael Overholtzer Mar 2019

Entosis Controls A Developmental Cell Clearance In C. Elegans, Yongchan Lee, Jens C. Hamann, Mark Pellegrino, Joanne Durgan, Marie-Charlotte Domart, Lucy M. Collinson, Cole M. Haynes, Oliver Florey, Michael Overholtzer

Open Access Articles

Metazoan cell death mechanisms are diverse and include numerous non-apoptotic programs. One program called entosis involves the invasion of live cells into their neighbors and is known to occur in cancers. Here, we identify a developmental function for entosis: to clear the male-specific linker cell in C. elegans. The linker cell leads migration to shape the gonad and is removed to facilitate fusion of the gonad to the cloaca. We find that the linker cell is cleared in a manner involving cell-cell adhesions and cell-autonomous control of uptake through linker cell actin. Linker cell entosis generates a lobe structure that ...


The Tlr4 Adaptor Tram Controls The Phagocytosis Of Gram-Negative Bacteria By Interacting With The Rab11-Family Interacting Protein 2, Astrid Skjesol, Douglas T. Golenbock, Harald Husebye Mar 2019

The Tlr4 Adaptor Tram Controls The Phagocytosis Of Gram-Negative Bacteria By Interacting With The Rab11-Family Interacting Protein 2, Astrid Skjesol, Douglas T. Golenbock, Harald Husebye

Open Access Articles

Phagocytosis is a complex process that eliminates microbes and is performed by specialised cells such as macrophages. Toll-like receptor 4 (TLR4) is expressed on the surface of macrophages and recognizes Gram-negative bacteria. Moreover, TLR4 has been suggested to play a role in the phagocytosis of Gram-negative bacteria, but the mechanisms remain unclear. Here we have used primary human macrophages and engineered THP-1 monocytes to show that the TLR4 sorting adapter, TRAM, is instrumental for phagocytosis of Escherichia coli as well as Staphylococcus aureus. We find that TRAM forms a complex with Rab11 family interacting protein 2 (FIP2) that is recruited ...


Optimization Of Ribosome Profiling Using Low-Input Brain Tissue From Fragile X Syndrome Model Mice, Botao Liu, Gemma Molinaro, Huan Shu, Emily E. Stackpole, Kimberly M. Huber, Joel D. Richter Mar 2019

Optimization Of Ribosome Profiling Using Low-Input Brain Tissue From Fragile X Syndrome Model Mice, Botao Liu, Gemma Molinaro, Huan Shu, Emily E. Stackpole, Kimberly M. Huber, Joel D. Richter

Open Access Articles

Dysregulated protein synthesis is a major underlying cause of many neurodevelopmental diseases including fragile X syndrome. In order to capture subtle but biologically significant differences in translation in these disorders, a robust technique is required. One powerful tool to study translational control is ribosome profiling, which is based on deep sequencing of mRNA fragments protected from ribonuclease (RNase) digestion by ribosomes. However, this approach has been mainly applied to rapidly dividing cells where translation is active and large amounts of starting material are readily available. The application of ribosome profiling to low-input brain tissue where translation is modest and gene ...


Gait Mechanics Contribute To Exercise Induced Pain Flares In Knee Osteoarthritis, Katherine A. Boyer, Jocelyn F. Hafer Mar 2019

Gait Mechanics Contribute To Exercise Induced Pain Flares In Knee Osteoarthritis, Katherine A. Boyer, Jocelyn F. Hafer

Open Access Articles

BACKGROUND: Exercise-induced pain flares represent a significant barrier for individuals with knee osteoarthritis to meet physical activity recommendations. There is a need to understand factors that contribute to pain flares and the potential for the motor system to adapt and reduce joint loading should a flare occur. The study aim was to examine the impact of a bout of exercise on self-reported pain, walking mechanics and muscle co-contraction for participants with knee osteoarthritis.

METHODS: Thirty-six adults (17 healthy older and 19 knee osteoarthritis) participated in this study. Self-reported pain, joint mechanics and muscle co-activation during gait at two self-selected speeds ...


A Note On Misspecification In General Linear Models With Correlated Errors For The Analysis Of Crossover Clinical Trials, Wei Wang, Ning Cong, Tian Chen, Hui Zhang, Bo Zhang Mar 2019

A Note On Misspecification In General Linear Models With Correlated Errors For The Analysis Of Crossover Clinical Trials, Wei Wang, Ning Cong, Tian Chen, Hui Zhang, Bo Zhang

Open Access Articles

Among various approaches to the repeated measures analysis in crossover clinical trials, the general linear models (GLMs) with correlated errors attract substantial attention due to their simplicity in model specification, implementation, and interpretation. The goal of this research note is to conduct simulation studies to numerically investigate the impact of model misspecification in the GLMs with correlated errors in the analysis of crossover trials. A series of synthetic two-treatment and three-treatment crossover trials were designed, and simulation studies were conducted to assess how treatment effect estimation, type I error rates, and power can be affected by misspecified period effects, carryover ...


Genome Analysis Identifies The Mutant Genes For Common Industrial Silverblue And Hedlund White Coat Colours In American Mink, Andrey D. Manakhov, Tatiana V. Andreeva, Oleg V. Trapezov, Nikolay A. Kolchanov, Evgeny I. Rogaev Mar 2019

Genome Analysis Identifies The Mutant Genes For Common Industrial Silverblue And Hedlund White Coat Colours In American Mink, Andrey D. Manakhov, Tatiana V. Andreeva, Oleg V. Trapezov, Nikolay A. Kolchanov, Evgeny I. Rogaev

Open Access Articles

The fur colour of American mink (Neovison vison) involves over 35 traits, but only three of these have been linked to specific genes. Despite being the most popular, coat colours Silverblue and Hedlund white remain uncharacterized genetically. The former is the first genetic mutant of fur colour identified in minks, while the latter is a commercially valuable phenotype that can be dyed easily. Here, we performed the whole genome sequencing for two American mink breeds with Silverblue and Hedlund white coats. We identified mutations in splice donor sites of genes coding melanophilin (MLPH) and microphthalmia-associated transcription factor (MITF) that regulate ...


Transforming Growth Factor-Beta Renders Ageing Microglia Inhibitory To Oligodendrocyte Generation By Cns Progenitors, Roey Baror, Bjorn Neumann, Michael Segel, Kevin J. Chalut, Stephen P.J. Fancy J, Dorothy P. Schafer, Robin J.M. Franklin Mar 2019

Transforming Growth Factor-Beta Renders Ageing Microglia Inhibitory To Oligodendrocyte Generation By Cns Progenitors, Roey Baror, Bjorn Neumann, Michael Segel, Kevin J. Chalut, Stephen P.J. Fancy J, Dorothy P. Schafer, Robin J.M. Franklin

Neurobiology Publications and Presentations

It is now well-established that the macrophage and microglial response to CNS demyelination influences remyelination by removing myelin debris and secreting a variety of signaling molecules that influence the behaviour of oligodendrocyte progenitor cells (OPCs). Previous studies have shown that changes in microglia contribute to the age-related decline in the efficiency of remyelination. In this study, we show that microglia increase their expression of the proteoglycan NG2 with age, and that this is associated with an altered micro-niche generated by aged, but not young, microglia that can divert the differentiation OPCs from oligodendrocytes into astrocytes in vitro. We further show ...


The Immune Checkpoint Molecules Pd-1, Pd-L1, Tim-3 And Lag-3 In Diffuse Large B-Cell Lymphoma, Benjamin J. Chen, Ravi Dashnamoorthy, Pallavi Galera, Vladislav Makarenko, Hong Chang, Srimoyee Ghosh, Andrew M. Evens Mar 2019

The Immune Checkpoint Molecules Pd-1, Pd-L1, Tim-3 And Lag-3 In Diffuse Large B-Cell Lymphoma, Benjamin J. Chen, Ravi Dashnamoorthy, Pallavi Galera, Vladislav Makarenko, Hong Chang, Srimoyee Ghosh, Andrew M. Evens

Open Access Articles

Signaling through immune checkpoint receptors may lead to T-cell exhaustion and function as immune escape mechanisms in cancer. For diffuse large B-cell lymphoma (DLBCL), the mechanistic and prognostic importance of these markers on tumor cells and the tumor microenvironment remains unclear. We determined the immunohistochemical expression of PD-1, PD-L1, TIM-3, and LAG-3 on tumor cells and on tumor infiltrating lymphocytes (TILs) among 123 DLBCL patients. TIM-3 showed positive staining on tumor cells in 39% of DLBCL cases and PD-L1 expression was noted in 15% of cases. Both PD-1 and LAG-3 were positive on tumor cells in a minority of DLBCL ...


Genome-Wide Prediction Of Synthetic Rescue Mediators Of Resistance To Targeted And Immunotherapy, Avinash Das Sahu, Olga Ponomarova, Eytan Ruppin Mar 2019

Genome-Wide Prediction Of Synthetic Rescue Mediators Of Resistance To Targeted And Immunotherapy, Avinash Das Sahu, Olga Ponomarova, Eytan Ruppin

Open Access Articles

Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here, we perform a genome-wide in silico prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients' response and emerging ...


Classification And Monomer-By-Monomer Annotation Dataset Of Suprachromosomal Family 1 Alpha Satellite Higher-Order Repeats In Hg38 Human Genome Assembly, L. I. Uralsky, V. A. Shepelev, A. A. Alexandrov, Y. B. Yurov, Evgeny I. Rogaev, I. A. Alexandrov Mar 2019

Classification And Monomer-By-Monomer Annotation Dataset Of Suprachromosomal Family 1 Alpha Satellite Higher-Order Repeats In Hg38 Human Genome Assembly, L. I. Uralsky, V. A. Shepelev, A. A. Alexandrov, Y. B. Yurov, Evgeny I. Rogaev, I. A. Alexandrov

Open Access Articles

In the latest hg38 human genome assembly, centromeric gaps has been filled in by alpha satellite (AS) reference models (RMs) which are statistical representations of homogeneous higher-order repeat (HOR) arrays that make up the bulk of the centromeric regions. We analyzed these models to compose an atlas of human AS HORs where each monomer of a HOR was represented by a number of its polymorphic sequence variants. We combined these data and HMMER sequence analysis platform to annotate AS HORs in the assembly. This led to discovery of a new type of low copy number highly divergent HORs which were ...


Understanding The Role Of Prdm12b In Zebrafish Development, Ozge Yildiz Mar 2019

Understanding The Role Of Prdm12b In Zebrafish Development, Ozge Yildiz

GSBS Dissertations and Theses

Function of the adult nervous system relies on the appropriate establishment of neural circuits during embryogenesis. In vertebrates, the neurons that make up motor circuits form in distinct domains along the dorsoventral (DV) axis of the neural tube. Each domain is characterized by a unique combination of transcription factors (TFs) that promote a specific fate, while repressing the fates of adjacent domains. The prdm12 TF is required for the expression of eng1b and the generation of V1 interneurons in the p1 domain, but the details of its function remain unclear.

We used CRISPR/Cas9 genome editing technology to generate the ...


Anti-Drug Antibody Responses Impair Prophylaxis Mediated By Aav-Delivered Hiv-1 Broadly Neutralizing Antibodies, Matthew R. Gardner, Ina Fetzer, Lisa M. Kattenhorn, Meredith E. Davis-Gardner, Amber S. Zhou, Barnett Alfant, Jesse A. Weber, Hema R. Kondur, Jose M. Martinez-Navio, Sebastian P. Fuchs, Ronald C. Desrosiers, Guangping Gao, Jeffrey D. Lifson, Michael Farzan Mar 2019

Anti-Drug Antibody Responses Impair Prophylaxis Mediated By Aav-Delivered Hiv-1 Broadly Neutralizing Antibodies, Matthew R. Gardner, Ina Fetzer, Lisa M. Kattenhorn, Meredith E. Davis-Gardner, Amber S. Zhou, Barnett Alfant, Jesse A. Weber, Hema R. Kondur, Jose M. Martinez-Navio, Sebastian P. Fuchs, Ronald C. Desrosiers, Guangping Gao, Jeffrey D. Lifson, Michael Farzan

Open Access Articles

Adeno-associated virus (AAV) delivery of potent and broadly neutralizing antibodies (bNAbs is a promising approach for the prevention of HIV-1 infection. The immunoglobulin G (IgG)1 subtype is usually selected for this application, because it efficiently mediates antibody effector functions and has a somewhat longer half-life. However, the use of IgG1-Fc has been associated with the generation of anti-drug antibodies (ADAs) that correlate with loss of antibody expression. In contrast, we have shown that expression of the antibody-like molecule eCD4-Ig bearing a rhesus IgG2-Fc domain showed reduced immunogenicity and completely protected rhesus macaques from simian-HIV (SHIV)-AD8 challenges. To directly ...


Adenosine Triphosphate Is Co-Secreted With Glucagon-Like Peptide-1 To Modulate Intestinal Enterocytes And Afferent Neurons, Van B. Lu, Juraj Rievaj, Elisabeth A. O'Flaherty, Christopher A. Smith, Ramona Pais, Luke A. Pattison, Gwen Tolhurst, Andrew B. Leiter, David C. Bulmer, Fiona M. Gribble, Frank Reimann Mar 2019

Adenosine Triphosphate Is Co-Secreted With Glucagon-Like Peptide-1 To Modulate Intestinal Enterocytes And Afferent Neurons, Van B. Lu, Juraj Rievaj, Elisabeth A. O'Flaherty, Christopher A. Smith, Ramona Pais, Luke A. Pattison, Gwen Tolhurst, Andrew B. Leiter, David C. Bulmer, Fiona M. Gribble, Frank Reimann

Open Access Articles

Enteroendocrine cells are specialised sensory cells located in the intestinal epithelium and generate signals in response to food ingestion. Whilst traditionally considered hormone-producing cells, there is evidence that they also initiate activity in the afferent vagus nerve and thereby signal directly to the brainstem. We investigate whether enteroendocrine L-cells, well known for their production of the incretin hormone glucagon-like peptide-1 (GLP-1), also release other neuro-transmitters/modulators. We demonstrate regulated ATP release by ATP measurements in cell supernatants and by using sniffer patches that generate electrical currents upon ATP exposure. Employing purinergic receptor antagonists, we demonstrate that evoked ATP release from ...


Correction Of Pseudoexon Splicing Caused By A Novel Intronic Dysferlin Mutation, Janice A. Dominov, Ozgun Uyan, Diane Mckenna-Yasek, Babi Ramesh Reddy Nallamilli, Virginie Kergourlay, Marc Bartoli, Nicolas Levy, Judith Hudson, Teresinha Evangelista, Hanns Lochmuller, Martin Krahn, Laura Rufibach, Madhuri Hegde, Robert H. Brown Jr. Mar 2019

Correction Of Pseudoexon Splicing Caused By A Novel Intronic Dysferlin Mutation, Janice A. Dominov, Ozgun Uyan, Diane Mckenna-Yasek, Babi Ramesh Reddy Nallamilli, Virginie Kergourlay, Marc Bartoli, Nicolas Levy, Judith Hudson, Teresinha Evangelista, Hanns Lochmuller, Martin Krahn, Laura Rufibach, Madhuri Hegde, Robert H. Brown Jr.

Open Access Articles

Objective: Dysferlin is a large transmembrane protein that functions in critical processes of membrane repair and vesicle fusion. Dysferlin-deficiency due to mutations in the dysferlin gene leads to muscular dystrophy (Miyoshi myopathy (MM), limb girdle muscular dystrophy type 2B (LGMD2B), distal myopathy with anterior tibial onset (DMAT)), typically with early adult onset. At least 416 pathogenic dysferlin mutations are known, but for approximately 17% of patients, one or both of their pathogenic variants remain undefined following standard exon sequencing methods that interrogate exons and nearby flanking intronic regions but not the majority of intronic regions.

Methods: We sequenced RNA from ...


Receptor Interacting Protein Kinase 3 (Rip3) Regulates Ipscs Generation Through Modulating Cell Cycle Progression Genes, Ahmad Al-Moujahed, Bo Tian, Nikolaos E. Efstathiou, Eleni K. Konstantinou, Mien Hoang, Haijiang Lin, Joan W. Miller, Demetrios G. Vavvas Mar 2019

Receptor Interacting Protein Kinase 3 (Rip3) Regulates Ipscs Generation Through Modulating Cell Cycle Progression Genes, Ahmad Al-Moujahed, Bo Tian, Nikolaos E. Efstathiou, Eleni K. Konstantinou, Mien Hoang, Haijiang Lin, Joan W. Miller, Demetrios G. Vavvas

Open Access Articles

The molecular mechanisms involved in induced pluripotent stem cells (iPSCs) generation are poorly understood. The cell death machinery of apoptosis-inducing caspases have been shown to facilitate the process of iPSCs reprogramming. However, the effect of other cell death processes, such as programmed necrosis (necroptosis), on iPSCs induction has not been studied. In this study, we investigated the role of receptor-interacting protein kinase 3 (RIP3), an essential regulator of necroptosis, in reprogramming mouse embryonic fibroblast cells (MEFs) into iPSCs. RIP3 was found to be upregulated in iPSCs compared to MEFs. Deletion of RIP3 dramatically suppressed the reprogramming of iPSCs (~82%). RNA-seq ...


Antimicrobial Resistance In Neisseria Gonorrhoeae: Proceedings Of The Star Sexually Transmitted Infection-Clinical Trial Group Programmatic Meeting, Anthony D. Cristillo, Peter A. Rice Mar 2019

Antimicrobial Resistance In Neisseria Gonorrhoeae: Proceedings Of The Star Sexually Transmitted Infection-Clinical Trial Group Programmatic Meeting, Anthony D. Cristillo, Peter A. Rice

Open Access Articles

The goal of the Sexually Transmitted Infection Clinical Trial Group's Antimicrobial Resistance (AMR) in Neisseria gonorrhoeae (NG) meeting was to assemble experts from academia, government, nonprofit and industry to discuss the current state of research, gaps and challenges in research and technology and priorities and new directions to address the continued emergence of multidrug-resistant NG infections. Topics discussed at the meeting, which will be the focus of this article, include AMR NG global surveillance initiatives, the use of whole genome sequencing and bioinformatics to understand mutations associated with AMR, mechanisms of AMR, and novel antibiotics, vaccines and other methods ...


An Observational Study With The Janssen Autism Knowledge Engine (Jake((R))) In Individuals With Autism Spectrum Disorder, Seth L. Ness, Jean A. Frazier Feb 2019

An Observational Study With The Janssen Autism Knowledge Engine (Jake((R))) In Individuals With Autism Spectrum Disorder, Seth L. Ness, Jean A. Frazier

Open Access Articles

Objective: The Janssen Autism Knowledge Engine (JAKE(R)) is a clinical research outcomes assessment system developed to more sensitively measure treatment outcomes and identify subpopulations in autism spectrum disorder (ASD). Here we describe JAKE and present results from its digital phenotyping (My JAKE) and biosensor (JAKE Sense) components.

Methods: An observational, non-interventional, prospective study of JAKE in children and adults with ASD was conducted at nine sites in the United States. Feedback on JAKE usability was obtained from caregivers. JAKE Sense included electroencephalography, eye tracking, electrocardiography, electrodermal activity, facial affect analysis, and actigraphy. Caregivers of individuals with ASD reported behaviors ...


Targeting Lipooligosaccharide (Los) For A Gonococcal Vaccine, Sunita Gulati, Jutamas Shaughnessy, Sanjay Ram, Peter A. Rice Feb 2019

Targeting Lipooligosaccharide (Los) For A Gonococcal Vaccine, Sunita Gulati, Jutamas Shaughnessy, Sanjay Ram, Peter A. Rice

Open Access Articles

The increasing incidence of gonorrhea worldwide and the global spread of multidrug-resistant strains of Neisseria gonorrhoeae, constitute a public health emergency. With dwindling antibiotic treatment options, there is an urgent need to develop safe and effective vaccines. Gonococcal lipooligosaccharides (LOSs) are potential vaccine candidates because they are densely represented on the bacterial surface and are readily accessible as targets of adaptive immunity. Less well-understood is whether LOSs evoke protective immune responses. Although gonococcal LOS-derived oligosaccharides (OSs) are major immune targets, often they undergo phase variation, a feature that seemingly makes LOS less desirable as a vaccine candidate. However, the identification ...


Zebrafish Prdm12b Acts Independently Of Nkx6.1 Repression To Promote Eng1b Expression In The Neural Tube P1 Domain, Ozge Yildiz, Gerald B. Downes, Charles G. Sagerstrom Feb 2019

Zebrafish Prdm12b Acts Independently Of Nkx6.1 Repression To Promote Eng1b Expression In The Neural Tube P1 Domain, Ozge Yildiz, Gerald B. Downes, Charles G. Sagerstrom

Open Access Articles

BACKGROUND: Functioning of the adult nervous system depends on the establishment of neural circuits during embryogenesis. In vertebrates, neurons that make up motor circuits form in distinct domains along the dorsoventral axis of the neural tube. Each domain is characterized by a unique combination of transcription factors (TFs) that promote a specific fate, while repressing fates of adjacent domains. The prdm12 TF is required for the expression of eng1b and the generation of V1 interneurons in the p1 domain, but the details of its function remain unclear.

METHODS: We used CRISPR/Cas9 to generate the first germline mutants for prdm12 ...


Mutations In The Glycosyltransferase Domain Of Glt8d1 Are Associated With Familial Amyotrophic Lateral Sclerosis, Johnathan Cooper-Knock, John E. Landers, Pamela J. Shaw Feb 2019

Mutations In The Glycosyltransferase Domain Of Glt8d1 Are Associated With Familial Amyotrophic Lateral Sclerosis, Johnathan Cooper-Knock, John E. Landers, Pamela J. Shaw

Open Access Articles

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways, including RNA processing, axonal transport, and protein homeostasis. We report ALS-causing mutations within the gene encoding the glycosyltransferase GLT8D1. Exome sequencing in an autosomal-dominant ALS pedigree identified p.R92C mutations in GLT8D1, which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site, and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro ...