Open Access. Powered by Scholars. Published by Universities.®

Life Sciences Commons

Open Access. Powered by Scholars. Published by Universities.®

Genetics

Medical Sciences

Institution
Publication Year
Publication
Publication Type
File Type

Articles 1 - 30 of 96

Full-Text Articles in Life Sciences

Mutations In The Sptlc1 Gene Are A Cause Of Amyotrophic Lateral Sclerosis That May Be Amenable To Serine Supplementation, Janel O. Johnson, Ruth Chia, Robert H. Brown Jr., John E. Landers Sep 2019

Mutations In The Sptlc1 Gene Are A Cause Of Amyotrophic Lateral Sclerosis That May Be Amenable To Serine Supplementation, Janel O. Johnson, Ruth Chia, Robert H. Brown Jr., John E. Landers

University of Massachusetts Medical School Faculty Publications

SPTLC1 encodes a critical subunit of serine palmitoyltransferase, the enzyme catalyzing the first and rate-limiting step in de novo sphingolipid biosynthesis, and mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A. Using exome sequencing, we identified a de novo variant in SPTLC1 resulting in a p.Ala20Ser amino acid change in an individual diagnosed with juvenile-onset amyotrophic lateral sclerosis (ALS) and confirmed its pathogenicity by showing elevated plasma levels of neurotoxic deoxymethyl-sphinganine. A second case of juvenile-onset ALS arising again from a p.Ala20Ser mutation was later identified, confirming the association of SPTLC1 with this ...


Signaling To Trp53 And Tap63 From Chk1/Chk2 Is Responsible For Elimination Of Most Oocytes Defective For Either Chromosome Synapsis Or Recombination, Vera D. Rinaldi, Jordana C. Bloom, John C. Schimenti Sep 2019

Signaling To Trp53 And Tap63 From Chk1/Chk2 Is Responsible For Elimination Of Most Oocytes Defective For Either Chromosome Synapsis Or Recombination, Vera D. Rinaldi, Jordana C. Bloom, John C. Schimenti

University of Massachusetts Medical School Faculty Publications

Eukaryotic organisms have evolved mechanisms to prevent the accumulation of cells bearing genetic aberrations. This is especially crucial for the germline, because fecundity, and fitness of progeny would be adversely affected by an excessively high mutational incidence. The process of meiosis poses unique problems for mutation avoidance, due to the requirement for SPO11-induced programmed double strand breaks (DSBs) in recombination-driven pairing and segregation of homologous chromosomes. Mouse meiocytes bearing unrepaired meiotic DSBs or unsynapsed chromosomes are eliminated before completing meiotic prophase I. In previous work, we showed that checkpoint kinase 2 (CHK2; CHEK2), a canonical DNA damage response protein, is ...


Gain-Of-Function Mutations In The Unc-2/Cav2alpha Channel Lead To Excitation-Dominant Synaptic Transmission In C. Elegans, Yung-Chi Huang, Jennifer K. Pirri, Diego Rayes, Shangbang Gao, Ben Mulcahy, Jeff Grant, Yasunori Saheki, Michael M. Francis, Mei Zhen, Mark J. Alkema Aug 2019

Gain-Of-Function Mutations In The Unc-2/Cav2alpha Channel Lead To Excitation-Dominant Synaptic Transmission In C. Elegans, Yung-Chi Huang, Jennifer K. Pirri, Diego Rayes, Shangbang Gao, Ben Mulcahy, Jeff Grant, Yasunori Saheki, Michael M. Francis, Mei Zhen, Mark J. Alkema

Neurobiology Publications and Presentations

Mutations in pre-synaptic voltage gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the Caenorhabditis elegans CaV2 channel alpha1 subunit, UNC-2, which leads to increased calcium currents. unc-2(zf35gf) mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the unc-2 gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of unc-2(zf35gf) mutants. unc-2 ...


Common Variants In The Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy, Michelle M. Bellerose, Seung-Hun Baek, Chuan-Chin Huang, Caitlin E. Moss, Eun-Ik Koh, Megan K. Proulx, Clare M. Smith, Richard E. Baker, Jong Seok Lee, Seokyong Eum, Sung Jae Shin, Sang-Nae Cho, Megan Murray, Christopher M. Sassetti Jul 2019

Common Variants In The Glycerol Kinase Gene Reduce Tuberculosis Drug Efficacy, Michelle M. Bellerose, Seung-Hun Baek, Chuan-Chin Huang, Caitlin E. Moss, Eun-Ik Koh, Megan K. Proulx, Clare M. Smith, Richard E. Baker, Jong Seok Lee, Seokyong Eum, Sung Jae Shin, Sang-Nae Cho, Megan Murray, Christopher M. Sassetti

Open Access Articles

Despite the administration of multiple drugs that are highly effective in vitro, tuberculosis (TB) treatment requires prolonged drug administration and is confounded by the emergence of drug-resistant strains. To understand the mechanisms that limit antibiotic efficacy, we performed a comprehensive genetic study to identify Mycobacterium tuberculosis genes that alter the rate of bacterial clearance in drug-treated mice. Several functionally distinct bacterial genes were found to alter bacterial clearance, and prominent among these was the glpK gene that encodes the glycerol-3-kinase enzyme that is necessary for glycerol catabolism. Growth on glycerol generally increased the sensitivity of M. tuberculosis to antibiotics in ...


Adaptive Evolution Targets A Pirna Precursor Transcription Network, Swapnil S. Parhad, Tianxiong Yu, Gen Zhang, Nicholas P. Rice, Zhiping Weng, William E. Theurkauf Jun 2019

Adaptive Evolution Targets A Pirna Precursor Transcription Network, Swapnil S. Parhad, Tianxiong Yu, Gen Zhang, Nicholas P. Rice, Zhiping Weng, William E. Theurkauf

University of Massachusetts Medical School Faculty Publications

In Drosophila, transposon-silencing piRNAs are derived from heterochromatic clusters and a subset of euchromatic transposon insertions, which are transcribed from internal non-canonical initiation sites and flanking canonical promoters. Rhino binds to Deadlock, which recruits TRF2 to promote non-canonical transcription of these loci. Cuff co-localizes with Rhino and Del. The role of Cuff is less well understood, but the cuff gene shows hallmarks of adaptive evolution, which frequently targets functional interactions within host defense systems. We show that Drosophila simulans cuff is a dominant negative allele when expressed in Drosophila melanogaster, where it traps Deadlock, TRF2 and the transcriptional co-repressor CtBP ...


Using Genetic Diversity To Understand Susceptibility To Cognitive Decline In Aging And Alzheimer’S Disease, Sarah M. Neuner May 2019

Using Genetic Diversity To Understand Susceptibility To Cognitive Decline In Aging And Alzheimer’S Disease, Sarah M. Neuner

Theses and Dissertations (ETD)

An individual's genetic makeup plays an important role in determining susceptibility to cognitive aging and transition to dementia such as Alzheimer's disease (AD). Identifying the specific genetic variants that contribute to cognitive aging and AD may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we turned to genetically diverse mice from the BXD genetic reference panel (GRP) to overcome some ...


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 ...


Hypomorphic Mutations Of Trip11 Cause Odontochondrodysplasia, Anika Wehrle, John A. Follit, Gregory J. Pazour, Andrea Superti-Furga, Martin Lowe, Ekkehart Lausch Feb 2019

Hypomorphic Mutations Of Trip11 Cause Odontochondrodysplasia, Anika Wehrle, John A. Follit, Gregory J. Pazour, Andrea Superti-Furga, Martin Lowe, Ekkehart Lausch

Open Access Articles

Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism ...


The Trim-Nhl Protein Nhl-2 Is A Co-Factor In The Nuclear And Somatic Rnai Pathways In C. Elegans, Gregory M. Davis, Shikui Tu, Jacqueline A. Wilce, Julie M. Claycomb, Zhiping Weng, Peter R. Boag Dec 2018

The Trim-Nhl Protein Nhl-2 Is A Co-Factor In The Nuclear And Somatic Rnai Pathways In C. Elegans, Gregory M. Davis, Shikui Tu, Jacqueline A. Wilce, Julie M. Claycomb, Zhiping Weng, Peter R. Boag

Program in Bioinformatics and Integrative Biology Publications and Presentations

Proper regulation of germline gene expression is essential for fertility and maintaining species integrity. In the C. elegans germline, a diverse repertoire of regulatory pathways promote the expression of endogenous germline genes and limit the expression of deleterious transcripts to maintain genome homeostasis. Here we show that the conserved TRIM-NHL protein, NHL-2, plays an essential role in the C. elegans germline, modulating germline chromatin and meiotic chromosome organization. We uncover a role for NHL-2 as a co-factor in both positively (CSR-1) and negatively (HRDE-1) acting germline 22G-small RNA pathways and the somatic nuclear RNAi pathway. Furthermore, we demonstrate that NHL-2 ...


The Trim-Nhl Protein Nhl-2 Is A Novel Co-Factor Of The Csr-1 And Hrde-1 22g-Rna Pathways, Peter R. Boag, Gregory M. Davis, Shikui Tu, Rhys N. Colson, Joshua W. T. Anderson, Menachem J. Gunzburg, Michelle A. Francisco, Debashish Ray, Tuhin Maity, Monica Z. Wu, Quaid D. Morris, Timothy R. Hughes, Jacqueline A. Wilce, University Of Toronto, Zhiping Weng Feb 2018

The Trim-Nhl Protein Nhl-2 Is A Novel Co-Factor Of The Csr-1 And Hrde-1 22g-Rna Pathways, Peter R. Boag, Gregory M. Davis, Shikui Tu, Rhys N. Colson, Joshua W. T. Anderson, Menachem J. Gunzburg, Michelle A. Francisco, Debashish Ray, Tuhin Maity, Monica Z. Wu, Quaid D. Morris, Timothy R. Hughes, Jacqueline A. Wilce, University Of Toronto, Zhiping Weng

University of Massachusetts Medical School Faculty Publications

Proper regulation of germline gene expression is essential for fertility and maintaining species integrity. In the C. elegans germline, a diverse repertoire of regulatory pathways promote the expression of endogenous germline genes and limit the expression of deleterious transcripts to maintain genome homeostasis. Here we show that the conserved TRIM-NHL protein, NHL-2, plays an essential role in the C. elegans germline, modulating germline chromatin and meiotic chromosome organization. We uncover a role for NHL-2 as a co-factor in both positively (CSR-1) and negatively (HRDE-1) acting germline 22G-small RNA pathways and the somatic nuclear RNAi pathway. Furthermore, we demonstrate that NHL-2 ...


Orbit: A New Paradigm For Genetic Engineering Of Mycobacterial Chromosomes, Kenan C. Murphy, Samantha J. Nelson, Subhalaxmi Nambi, Kadamba Papavinasasundaram, Christina E. Baer, Christopher M. Sassetti Jan 2018

Orbit: A New Paradigm For Genetic Engineering Of Mycobacterial Chromosomes, Kenan C. Murphy, Samantha J. Nelson, Subhalaxmi Nambi, Kadamba Papavinasasundaram, Christina E. Baer, Christopher M. Sassetti

University of Massachusetts Medical School Faculty Publications

Current methods for genome engineering in mycobacteria rely on relatively inefficient recombination systems that require the laborious construction of a long double-stranded DNA substrate for each desired modification. We combined two efficient recombination systems to produce a versatile method for high-throughput chromosomal engineering that obviates the need for the preparation of double-stranded DNA recombination substrates. A synthetic targeting oligonucleotide is incorporated into the chromosome via homologous recombination mediated by the phage Che9c RecT annelase. This oligo contains a site-specific recombination site for the directional Bxb1 integrase (Int), which allows the simultaneous integration of a payload plasmid that contains a cognate ...


Unexpected Crispr Off-Target Mutation Pattern In Vivo Are Not Typically Germline-Like, Zhiting Wei, Funan He, Guohui Chuai, Hanhui Ma, Zhixi Su, Qi Liu Sep 2017

Unexpected Crispr Off-Target Mutation Pattern In Vivo Are Not Typically Germline-Like, Zhiting Wei, Funan He, Guohui Chuai, Hanhui Ma, Zhixi Su, Qi Liu

University of Massachusetts Medical School Faculty Publications

A computationally evolutionary investigation was performed to re-analyze the WGS data of the two studies published in Nature Methods (2015, 2017) with opposite conclusions on CRISPR off-target mutations. Our analysis concluded that the so-called unexpected SNVs pattern obtained by the study of Schaefer et al. are not typically germline-like. Some of unusual and unidentified mutations may arise, but the real reasons remain to be explored. Based on the available data and a direct comparison of the two studies, we presented two possible reasons and future re-analysis directions that may contribute to such different conclusions. To characterize the authentic CRISPR-mediated mutations ...


Clinical And Experimental Studies Of A Novel P525r Fus Mutation In Amyotrophic Lateral Sclerosis, Lisha Kuang, Marisa Kamelgarn, Alexandra Arenas, Jozsef Gal, Deborah Taylor, Weiming Gong, Martin Brown, Daret St. Clair, Edward J. Kasarskis, Haining Zhu Aug 2017

Clinical And Experimental Studies Of A Novel P525r Fus Mutation In Amyotrophic Lateral Sclerosis, Lisha Kuang, Marisa Kamelgarn, Alexandra Arenas, Jozsef Gal, Deborah Taylor, Weiming Gong, Martin Brown, Daret St. Clair, Edward J. Kasarskis, Haining Zhu

Molecular and Cellular Biochemistry Faculty Publications

Objective: To describe the clinical features of a novel fused in sarcoma (FUS) mutation in a young adult female amyotrophic lateral sclerosis (ALS) patient with rapid progression of weakness and to experimentally validate the consequences of the P525R mutation in cellular neuronal models.

Methods: We conducted sequencing of genomic DNA from the index patient and her family members. Immunocytochemistry was performed in various cellular models to determine whether the newly identified P525R mutant FUS protein accumulated in cytoplasmic inclusions. Clinical features of the index patient were compared with 19 other patients with ALS carrying the P525L mutation in the same ...


Project Mine: Study Design And Pilot Analyses Of A Large-Scale Whole-Genome Sequencing Study In Amyotrophic Lateral Sclerosis, Project Mine Consortium, Wouter Van Rheenen, Kevin P. Kenna, John E. Landers, Jan H. Veldink Jun 2017

Project Mine: Study Design And Pilot Analyses Of A Large-Scale Whole-Genome Sequencing Study In Amyotrophic Lateral Sclerosis, Project Mine Consortium, Wouter Van Rheenen, Kevin P. Kenna, John E. Landers, Jan H. Veldink

University of Massachusetts Medical School Faculty Publications

The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility of disease. We have therefore begun Project MinE, an international collaboration that seeks to analyse whole-genome sequence data of at least 15,000 ALS patients and 7,500 controls. Here, we report on the design of Project MinE and pilot analyses of newly whole-genome sequenced 1,264 ALS patients and 611 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1%), the vast majority of which is absent in public data sets. Principal component analysis reveals local geographical clustering of these variants within The Netherlands. We use the whole-genome sequence data to explore the implications of poor geographical matching of cases and controls in a sequence-based disease study and to investigate how ancestry-matched, externally sequenced controls can induce false positive associations. Also, we have publicly released genome-wide minor allele counts in cases and controls, as well as results from genic burden tests.


The Utilization Of Prenatal Microarray: A Survey Of Current Genetic Counseling Practices And Barriers, Leslie N. Durham, Leslie Durham May 2017

The Utilization Of Prenatal Microarray: A Survey Of Current Genetic Counseling Practices And Barriers, Leslie N. Durham, Leslie Durham

UT GSBS Dissertations and Theses (Open Access)

Chromosomal microarray (CMA) assesses chromosome copy number variants (CNVs) missed by standard karyotyping. The American College of Obstetricians and Gynecologists (ACOG) recommends CMA for all patients with fetuses with an ultrasound anomaly and suggests that it be made available to all women undergoing invasive testing. In order to assess prenatal genetic counselors’ (GCs) practices regarding the utilization of CMA we conducted a survey of their current practices, attitudes, and perceived barriers. Of the 192 respondents, 183 (95%) have incorporated CMA into clinical practice with the majority (64%) believing that the benefits of CMA outweigh the harms. However, only half (52 ...


Monkey-Based Research On Human Disease: The Implications Of Genetic Differences, Jarrod Bailey Sep 2016

Monkey-Based Research On Human Disease: The Implications Of Genetic Differences, Jarrod Bailey

Jarrod Bailey, PhD

Assertions that the use of monkeys to investigate human diseases is valid scientifically are frequently based on a reported 90–93% genetic similarity between the species. Critical analyses of the relevance of monkey studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for monkeys to constitute good models for research, and that monkey data do not translate well to progress in clinical practice for humans. Salient examples include the failure of new drugs in clinical trials, the highly different infectivity and pathology of SIV/HIV, and poor extrapolation of research on Alzheimer ...


Lessons From Chimpanzee-Based Research On Human Disease: The Implications Of Genetic Differences, Jarrod Bailey Sep 2016

Lessons From Chimpanzee-Based Research On Human Disease: The Implications Of Genetic Differences, Jarrod Bailey

Jarrod Bailey, PhD

Assertions that the use of chimpanzees to investigate human diseases is valid scientifically are frequently based on a reported 98–99% genetic similarity between the species. Critical analyses of the relevance of chimpanzee studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for the chimpanzee to constitute a good model for research, and furthermore, that chimpanzee data do not translate well to progress in clinical practice for humans. Leading examples include the minimal citations of chimpanzee research that is relevant to human medicine, the highly different pathology of HIV/AIDS and hepatitis ...


The Genetic Basis Of Natural Variation In C. Elegans Telomere Length, Daniel E. Cook, Stefan Zdraljevic, Robyn E. Tanny, Beomseok Seo, David Riccardi, Luke M. Noble, Matthew V. Rockman, Mark J. Alkema, Christian Braendle, Jan Kammenga, John Wang, Leonid Kruglyak, Marie-Anne Felix, Junho Lee, Erik Andersen May 2016

The Genetic Basis Of Natural Variation In C. Elegans Telomere Length, Daniel E. Cook, Stefan Zdraljevic, Robyn E. Tanny, Beomseok Seo, David Riccardi, Luke M. Noble, Matthew V. Rockman, Mark J. Alkema, Christian Braendle, Jan Kammenga, John Wang, Leonid Kruglyak, Marie-Anne Felix, Junho Lee, Erik Andersen

University of Massachusetts Medical School Faculty Publications

Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligosaccharide/oligonucleotide-binding fold of POT-2, a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 ...


A Pilot Study Of The Pharmacogenetics Of Ketamine-Induced Emergence Phenomena: A Dissertation, Edwin N. Aroke Apr 2016

A Pilot Study Of The Pharmacogenetics Of Ketamine-Induced Emergence Phenomena: A Dissertation, Edwin N. Aroke

Graduate School of Nursing Dissertations

Background: Up to 55% of patients administered ketamine, experience an emergence phenomena (EP) that closely mimics schizophrenia and increases their risk of injury. While genetics accounts for about 50% of severe adverse drug reactions, no studies have investigated genetic association of ketamine-induced EP in healthy patients. Ketamine is metabolized by CYP 2B6 enzymes and CYP 2B^8^ allele significantly alter ketamine metabolism. In addition, ketamine exerts most of its effects by inhibiting the N-methyl-D-aspartate receptor (NMADR), and NMDAR genes (GRIN2B) are associated with learning and memory impairment and schizophrenia.

Purpose: To investigate the relationship between CYP2B6*6 and GRIN2B single ...


The Intersection Of Neuroimaging And Genomics On Complex Traits And Perception, Helena C. Yardley Jan 2016

The Intersection Of Neuroimaging And Genomics On Complex Traits And Perception, Helena C. Yardley

Integrative Physiology Graduate Theses & Dissertations

Thoughts, feelings and complex behavioral patterns are represented through neural patterns. These neural patterns have molecular and genetic underpinnings, but the connection between the two isn’t always clear. In this manuscript, we evaluate a possible neuroendophenotype for behavioral disinhibition in a sample collected from the Center on Antisocial Drug Dependence, who were selected based upon their degree of behavioral disinhibition. We obtained genome-wide data on the 1,901 participants, and generated a composite polygenic risk score for each of the 80 subjects from 1,876 single nucleotide polymorphisms shown to be associated with the behavioral disinhibition phenotype. We then ...


Role Of The Dna Sensor Sting In Protection From Lethal Infection Following Corneal And Intracerebral Challenge With Herpes Simplex Virus 1, Zachary M. Parker, Aisling A. Murphy, David. A. Leib Aug 2015

Role Of The Dna Sensor Sting In Protection From Lethal Infection Following Corneal And Intracerebral Challenge With Herpes Simplex Virus 1, Zachary M. Parker, Aisling A. Murphy, David. A. Leib

Open Dartmouth: Faculty Open Access Scholarship

STING is a protein in the cytosolic DNA and cyclic dinucleotide sensor pathway that is critical for the initiation of innate responses to infection by various pathogens. Consistent with this, herpes simplex virus 1 (HSV-1) causes invariable and rapid lethality in STING-deficient (STING(-/-)) mice following intravenous (i.v.) infection. In this study, using real-time bioluminescence imaging and virological assays, as expected, we demonstrated that STING(-/-) mice support greater replication and spread in ocular tissues and the nervous system. In contrast, they did not succumb to challenge via the corneal route even with high titers of a virus that was routinely ...


Selective Involvement Of The Checkpoint Regulator Vista In Suppression Of B-Cell, But Not T-Cell, Responsiveness By Monocytic Myeloid-Derived Suppressor Cells From Mice Infected With An Immunodeficiency-Causing Retrovirus, Kathy A. Green, Li Wang, Randolph J. Noelle, William R. Green Jul 2015

Selective Involvement Of The Checkpoint Regulator Vista In Suppression Of B-Cell, But Not T-Cell, Responsiveness By Monocytic Myeloid-Derived Suppressor Cells From Mice Infected With An Immunodeficiency-Causing Retrovirus, Kathy A. Green, Li Wang, Randolph J. Noelle, William R. Green

Open Dartmouth: Faculty Open Access Scholarship

Inhibition of T-cell responses in tumor microenvironments by myeloid-derived suppressor cells (MDSCs) is widely accepted. We demonstrated augmentation of monocytic MDSCs whose suppression of not only T-cell, but also B-cell, responsiveness paralleled the immunodeficiency during LP-BM5 retrovirus infection. MDSCs inhibited T cells by inducible nitric oxide synthase (iNOS)/nitric oxide (NO), but uniquely, inhibition of B cells was ~50% dependent each on iNOS/NO and the MDSC-expressed negative-checkpoint regulator VISTA. Blockade with a combination of iNOS/NO and VISTA caused additive or synergistic abrogation of MDSC-mediated suppression of B-cell responsiveness.


Combining Magnetic Resonance Imaging And Genome-Wide Genetic Mapping In Epilepsy, Christopher D. Whelan Jun 2015

Combining Magnetic Resonance Imaging And Genome-Wide Genetic Mapping In Epilepsy, Christopher D. Whelan

PhD theses

Recent attempts to elucidate the genetic architecture of complex epilepsies have been limited by a variety of issues including phenotypic ambiguities, small sample sizes and restricted genetic scope. This thesis employed a diverse array of genetic mapping and MRI techniques to help improve the power of genetic mapping efforts and thus our understanding of the neurobiological factors contributing towards common forms of the disorder.

As part of a collaborative meta-analysis of GWAS data on complex epilepsies, we contributed to the identification of loci at 2q24.3 (implicating the SCN1A gene) and 4p15.1 (implicating the PCDH7 gene) as risk factors ...


Systems Level Analysis Of Systemic Sclerosis Shows A Network Of Immune And Profibrotic Pathways Connected With Genetic Polymorphisms, J. Matthew Mahoney, Jaclyn Taroni, Viktor Martyanov, Tammara A. A. Wood, Casey S. Greene, Patricia A. Pioli, Monique E. Hinchcliff, Michael L. Whitfield Jan 2015

Systems Level Analysis Of Systemic Sclerosis Shows A Network Of Immune And Profibrotic Pathways Connected With Genetic Polymorphisms, J. Matthew Mahoney, Jaclyn Taroni, Viktor Martyanov, Tammara A. A. Wood, Casey S. Greene, Patricia A. Pioli, Monique E. Hinchcliff, Michael L. Whitfield

Open Dartmouth: Faculty Open Access Scholarship

Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of patients with SSc. Analysis of longitudinal skin biopsies suggests that a patient's subset assignment is stable over 6-12 months. Genetically, SSc is multi-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations. Here we identify the genes consistently associated with the intrinsic subsets across three independent cohorts, show the relationship between these ...


Development Of Gold Nanoparticle-Based Antigen Delivery Platform For Vaccines Against Hiv-1, Feng Lin Jan 2015

Development Of Gold Nanoparticle-Based Antigen Delivery Platform For Vaccines Against Hiv-1, Feng Lin

Graduate Theses and Dissertations

As one of the world’s most devastating viruses, HIV-1 has killed more than 39 million people, and around two million cases of newly infected individuals are recorded every year. However, no effective vaccine has been developed to stop this pandemic since its onset in the 1980s. Since vaccine development is moving slowly, delivery platforms as an essential element to enhance both the efficiency and efficacy of vaccines have drawn increased attention. Gold nanoparticles (GNPs) as a novel delivery platform has been studied in drug and vaccine delivery. My research goal is to apply this delivery platform in the AIDS ...


Mcl1 Enhances The Survival Of Cd8+ Memory T Cells After Viral Infection, Jingang Gui, Zhuting Hu, Ching-Yi Tsai, Tian Ma, Yan Song, Amanda Morales, Li-Hao Huang, Ethan Dmitrovsky, Ruth Craig, Edward Usherwood Jan 2015

Mcl1 Enhances The Survival Of Cd8+ Memory T Cells After Viral Infection, Jingang Gui, Zhuting Hu, Ching-Yi Tsai, Tian Ma, Yan Song, Amanda Morales, Li-Hao Huang, Ethan Dmitrovsky, Ruth Craig, Edward Usherwood

Open Dartmouth: Faculty Open Access Scholarship

Viral infection results in the generation of massive numbers of activated effector CD8+ T cells that recognize viral components. Most of these are short-lived effector T cells (SLECs) that die after clearance of the virus. However, a small proportion of this population survives and forms antigen-specific memory precursor effector cells (MPECs), which ultimately develop into memory cells. These can participate in a recall response upon reexposure to antigen even at protracted times postinfection. Here, antiapoptotic myeloid cell leukemia 1 (MCL1) was found to prolong survival upon T cell stimulation, and mice expressing human MCL1 as a transgene exhibited a skewing ...


Monkey-Based Research On Human Disease: The Implications Of Genetic Differences, Jarrod Bailey Nov 2014

Monkey-Based Research On Human Disease: The Implications Of Genetic Differences, Jarrod Bailey

Laboratory Experiments Collection

Assertions that the use of monkeys to investigate human diseases is valid scientifically are frequently based on a reported 90–93% genetic similarity between the species. Critical analyses of the relevance of monkey studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for monkeys to constitute good models for research, and that monkey data do not translate well to progress in clinical practice for humans. Salient examples include the failure of new drugs in clinical trials, the highly different infectivity and pathology of SIV/HIV, and poor extrapolation of research on Alzheimer ...


Structural Features Of The Pseudomonas Fluorescens Biofilm Adhesin Lapa Required For Lapg-Dependent Cleavage, Biofilm Formation, And Cell Surface Localization, Chelsea D. Boyd, T. Jarrod Smith, Sofiane El-Kirat-Chatel, Peter D. Newell, Yves F. Dufrêne, George A. O'Toole May 2014

Structural Features Of The Pseudomonas Fluorescens Biofilm Adhesin Lapa Required For Lapg-Dependent Cleavage, Biofilm Formation, And Cell Surface Localization, Chelsea D. Boyd, T. Jarrod Smith, Sofiane El-Kirat-Chatel, Peter D. Newell, Yves F. Dufrêne, George A. O'Toole

Open Dartmouth: Faculty Open Access Scholarship

The localization of the LapA protein to the cell surface is a key step required by Pseudomonas fluorescens Pf0-1 to irreversibly attach to a surface and form a biofilm. LapA is a member of a diverse family of predicted bacterial adhesins, and although lacking a high degree of sequence similarity, family members do share common predicted domains. Here, using mutational analysis, we determine the significance of each domain feature of LapA in relation to its export and localization to the cell surface and function in biofilm formation. Our previous work showed that the N terminus of LapA is required for ...


Probiotics: Finding The Right Regulatory Balance, Diane E. Hoffmann, Claire M. Fraser-Liggett, Frank B. Palumbo, Jacques Ravel, Karen H. Rothenberg, Virginia Rowthorn May 2014

Probiotics: Finding The Right Regulatory Balance, Diane E. Hoffmann, Claire M. Fraser-Liggett, Frank B. Palumbo, Jacques Ravel, Karen H. Rothenberg, Virginia Rowthorn

Karen H. Rothenberg

Some products marketed as drugs should be excused from Phase I trials, but safety and efficacy claims for dietary supplements should be more tightly regulated.


Linking Molecular, Electrical And Anatomical Properties Of Human Epileptic Brain, Shruti Bagla Jan 2014

Linking Molecular, Electrical And Anatomical Properties Of Human Epileptic Brain, Shruti Bagla

Wayne State University Dissertations

Epilepsy is a common neurological disorder of recurrent unprovoked seizures. It affects almost 1% of the world population. Although there is a wide range of anti-epileptic drugs (AEDs) available, they only treat the seizure symptoms and do not cure the disease itself. The poor role of AEDs can be attributed to the lack of knowledge of exact mechanisms and networks that produce epileptic activities in the neocortex. At present, the best cure for epilepsy is surgical removal of electrically localized epileptic brain tissue. Surgically removed brain tissue presents an excellent opportunity to discover the molecular and cellular basis of human ...