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Articles 31 - 45 of 45

Full-Text Articles in Molecular Biology

Integrated Genome-Wide Analysis Of Expression Quantitative Trait Loci Aids Interpretation Of Genomic Association Studies, Roby Joehanes, Kahraman Tanriverdi, Jane E. Freedman, Peter J. Munson Jan 2017

Integrated Genome-Wide Analysis Of Expression Quantitative Trait Loci Aids Interpretation Of Genomic Association Studies, Roby Joehanes, Kahraman Tanriverdi, Jane E. Freedman, Peter J. Munson

UMass Metabolic Network Publications

BACKGROUND: Identification of single nucleotide polymorphisms (SNPs) associated with gene expression levels, known as expression quantitative trait loci (eQTLs), may improve understanding of the functional role of phenotype-associated SNPs in genome-wide association studies (GWAS). The small sample sizes of some previous eQTL studies have limited their statistical power. We conducted an eQTL investigation of microarray-based gene and exon expression levels in whole blood in a cohort of 5257 individuals, exceeding the single cohort size of previous studies by more than a factor of 2.

RESULTS: We detected over 19,000 independent lead cis-eQTLs and over 6000 independent lead trans-eQTLs, targeting ...


Comprehensive Essentiality Analysis Of The Mycobacterium Tuberculosis Genome Via Saturating Transposon Mutagenesis, Michael A. Dejesus, Elias R. Gerrick, Weizhen Xu, Sae Woong. Park, Jarukit E. Long, Cara C. Boutte, Eric J. Rubin, Dirk Schnappinger, Sabine Ehrt, Sarah M. Fortune, Christopher M. Sassetti, Thomas R. Ioerger Jan 2017

Comprehensive Essentiality Analysis Of The Mycobacterium Tuberculosis Genome Via Saturating Transposon Mutagenesis, Michael A. Dejesus, Elias R. Gerrick, Weizhen Xu, Sae Woong. Park, Jarukit E. Long, Cara C. Boutte, Eric J. Rubin, Dirk Schnappinger, Sabine Ehrt, Sarah M. Fortune, Christopher M. Sassetti, Thomas R. Ioerger

UMass Metabolic Network Publications

For decades, identifying the regions of a bacterial chromosome that are necessary for viability has relied on mapping integration sites in libraries of random transposon mutants to find loci that are unable to sustain insertion. To date, these studies have analyzed subsaturated libraries, necessitating the application of statistical methods to estimate the likelihood that a gap in transposon coverage is the result of biological selection and not the stochasticity of insertion. As a result, the essentiality of many genomic features, particularly small ones, could not be reliably assessed. We sought to overcome this limitation by creating a completely saturated transposon ...


Central Role Of Il-23 And Il-17 Producing Eosinophils As Immunomodulatory Effector Cells In Acute Pulmonary Aspergillosis And Allergic Asthma, Evelyn V. Santos Guerra, Chrono K. Lee, Charles A. Specht, Bhawna Yadav, Haibin Huang, Ali Akalin, Jun R. Huh, Christian Mueller, Stuart M. Levitz Jan 2017

Central Role Of Il-23 And Il-17 Producing Eosinophils As Immunomodulatory Effector Cells In Acute Pulmonary Aspergillosis And Allergic Asthma, Evelyn V. Santos Guerra, Chrono K. Lee, Charles A. Specht, Bhawna Yadav, Haibin Huang, Ali Akalin, Jun R. Huh, Christian Mueller, Stuart M. Levitz

UMass Metabolic Network Publications

Aspergillus fumigatus causes invasive pulmonary disease in immunocompromised hosts and allergic asthma in atopic individuals. We studied the contribution of lung eosinophils to these fungal diseases. By in vivo intracellular cytokine staining and confocal microscopy, we observed that eosinophils act as local sources of IL-23 and IL-17. Remarkably, mice lacking eosinophils had a >95% reduction in the percentage of lung IL-23p19+ cells as well as markedly reduced IL-23 heterodimer in lung lavage fluid. Eosinophils killed A. fumigatus conidia in vivo. Eosinopenic mice had higher mortality rates, decreased recruitment of inflammatory monocytes, and decreased expansion of lung macrophages after challenge with ...


Amplification Of Adipogenic Commitment By Vstm2a, Blandine Secco, Peter L. Lee, David A. Guertin, Mathieu Laplante Jan 2017

Amplification Of Adipogenic Commitment By Vstm2a, Blandine Secco, Peter L. Lee, David A. Guertin, Mathieu Laplante

UMass Metabolic Network Publications

Despite progress in our comprehension of the mechanisms regulating adipose tissue development, the nature of the factors that functionally characterize adipose precursors is still elusive. Defining the early steps regulating adipocyte development is needed for the generation of tools to control adipose tissue size and function. Here, we report the discovery of V-set and transmembrane domain containing 2A (VSTM2A) as a protein expressed and secreted by committed preadipocytes. VSTM2A expression is elevated in the early phases of adipogenesis in vitro and adipose tissue development in vivo. We show that VSTM2A-producing cells associate with the vasculature and express the common surface ...


Ck2 Inhibitor Cx-4945 Destabilizes Notch1 And Synergizes With Jq1 Against Human T-Acute Lymphoblastic Leukemic Cells, Haiwei Lian, Dun Li, Yun Zhou, Esther Landesman-Bollag, Guanglan Zhang, Nicole M. Anderson, Kevin Charles Tang, Justine E. Roderick, Michelle A. Kelliher, David C. Seldin, Hui Fu, Hui Feng Jan 2017

Ck2 Inhibitor Cx-4945 Destabilizes Notch1 And Synergizes With Jq1 Against Human T-Acute Lymphoblastic Leukemic Cells, Haiwei Lian, Dun Li, Yun Zhou, Esther Landesman-Bollag, Guanglan Zhang, Nicole M. Anderson, Kevin Charles Tang, Justine E. Roderick, Michelle A. Kelliher, David C. Seldin, Hui Fu, Hui Feng

UMass Metabolic Network Publications

Here we show that CK2 inhibition by CX-4945 destabilizes NOTCH1 and synergizes with JQ1 to induce apoptosis in human T-ALL cells, implicating an alternative strategy to target NOTCH1 signaling in refractory/relapsed T-ALL.


Phosphorylation Of The Mdm2 Oncoprotein By The C-Abl Tyrosine Kinase Regulates P53 Tumor Suppression And The Radiosensitivity Of Mice, Michael I. Carr, Justine E. Roderick, Hong Zhang, Bruce A. Woda, Michelle A. Kelliher, Stephen N. Jones Dec 2016

Phosphorylation Of The Mdm2 Oncoprotein By The C-Abl Tyrosine Kinase Regulates P53 Tumor Suppression And The Radiosensitivity Of Mice, Michael I. Carr, Justine E. Roderick, Hong Zhang, Bruce A. Woda, Michelle A. Kelliher, Stephen N. Jones

UMass Metabolic Network Publications

The p53 tumor suppressor acts as a guardian of the genome by preventing the propagation of DNA damage-induced breaks and mutations to subsequent generations of cells. We have previously shown that phosphorylation of the Mdm2 oncoprotein at Ser394 by the ATM kinase is required for robust p53 stabilization and activation in cells treated with ionizing radiation, and that loss of Mdm2 Ser394 phosphorylation leads to spontaneous tumorigenesis and radioresistance in Mdm2S394A mice. Previous in vitro data indicate that the c-Abl kinase phosphorylates Mdm2 at the neighboring residue (Tyr393) in response to DNA damage to regulate p53-dependent apoptosis. In this present ...


Wzb117 (2-Fluoro-6-(M-Hydroxybenzoyloxy) Phenyl M-Hydroxybenzoate) Inhibits Glut1-Mediated Sugar Transport By Binding Reversibly At The Exofacial Sugar Binding Site, Ogooluwa A. Ojelabi, Kenneth P. Lloyd, Andrew Simon, Julie K. De Zutter, Anthony Carruthers Dec 2016

Wzb117 (2-Fluoro-6-(M-Hydroxybenzoyloxy) Phenyl M-Hydroxybenzoate) Inhibits Glut1-Mediated Sugar Transport By Binding Reversibly At The Exofacial Sugar Binding Site, Ogooluwa A. Ojelabi, Kenneth P. Lloyd, Andrew Simon, Julie K. De Zutter, Anthony Carruthers

UMass Metabolic Network Publications

WZB117 (2-fluoro-6-(m-hydroxybenzoyloxy) phenyl m-hydroxybenzoate) inhibits passive sugar transport in human erythrocytes and cancer cell lines and, by limiting glycolysis, inhibits tumor growth in mice. This study explores how WZB117 inhibits the erythrocyte sugar transporter glucose transport protein 1 (GLUT1) and examines the transporter isoform specificity of inhibition. WZB117 reversibly and competitively inhibits erythrocyte 3-O-methylglucose (3MG) uptake with Ki(app) = 6 mum but is a noncompetitive inhibitor of sugar exit. Cytochalasin B (CB) is a reversible, noncompetitive inhibitor of 3MG uptake with Ki(app) = 0.3 mum but is a competitive inhibitor of sugar exit indicating that WZB117 and CB ...


Pgc-1alpha Dictates Endothelial Function Through Regulation Of Enos Expression, Siobhan M. Craige, Swenja Kroller-Schon, Chunying Li, Shashi Kant, Shenghe Cai, Kai Chen, Mayur M. Contractor, Yongmei Pei, Eberhard Schulz, John F. Keaney Jr. Dec 2016

Pgc-1alpha Dictates Endothelial Function Through Regulation Of Enos Expression, Siobhan M. Craige, Swenja Kroller-Schon, Chunying Li, Shashi Kant, Shenghe Cai, Kai Chen, Mayur M. Contractor, Yongmei Pei, Eberhard Schulz, John F. Keaney Jr.

UMass Metabolic Network Publications

Endothelial dysfunction is a characteristic of many vascular related diseases such as hypertension. Peroxisome proliferator activated receptor gamma, coactivator 1alpha (PGC-1alpha) is a unique stress sensor that largely acts to promote adaptive responses. Therefore, we sought to define the role of endothelial PGC-1alpha in vascular function using mice with endothelial specific loss of function (PGC-1alpha EC KO) and endothelial specific gain of function (PGC-1alpha EC TG). Here we report that endothelial PGC-1alpha is suppressed in angiotensin-II (ATII)-induced hypertension. Deletion of endothelial PGC-1alpha sensitized mice to endothelial dysfunction and hypertension in response to ATII, whereas PGC-1alpha EC TG mice were ...


Cancer Metabolism: Fueling More Than Just Growth, Namgyu Lee, Dohoon Kim Dec 2016

Cancer Metabolism: Fueling More Than Just Growth, Namgyu Lee, Dohoon Kim

UMass Metabolic Network Publications

The early landmark discoveries in cancer metabolism research have uncovered metabolic processes that support rapid proliferation, such as aerobic glycolysis (Warburg effect), glutaminolysis, and increased nucleotide biosynthesis. However, there are limitations to the effectiveness of specifically targeting the metabolic processes which support rapid proliferation. First, as other normal proliferative tissues also share similar metabolic features, they may also be affected by such treatments. Secondly, targeting proliferative metabolism may only target the highly proliferating "bulk tumor" cells and not the slower-growing, clinically relevant cancer stem cell subpopulations which may be required for an effective cure. An emerging body of research indicates ...


Structural And Genetic Analyses Of The Mycobacterium Tuberculosis Protein Kinase B Sensor Domain Identify A Potential Ligand-Binding Site, Daniil M. Prigozhin, Kadamba Papavinasasundaram, Christina E. Baer, Kenan C. Murphy, Alisa Moskaleva, Tony Y. Chen, Tom Alber, Christopher M. Sassetti Oct 2016

Structural And Genetic Analyses Of The Mycobacterium Tuberculosis Protein Kinase B Sensor Domain Identify A Potential Ligand-Binding Site, Daniil M. Prigozhin, Kadamba Papavinasasundaram, Christina E. Baer, Kenan C. Murphy, Alisa Moskaleva, Tony Y. Chen, Tom Alber, Christopher M. Sassetti

UMass Metabolic Network Publications

Monitoring the environment with serine/threonine protein kinases is critical for growth and survival of Mycobacterium tuberculosis, a devastating human pathogen. Protein kinase B (PknB) is a transmembrane serine/threonine protein kinase that acts as an essential regulator of mycobacterial growth and division. The PknB extracellular domain (ECD) consists of four repeats homologous to penicillin-binding protein and serine/threonine kinase associated (PASTA) domains, and binds fragments of peptidoglycan. These properties suggest that PknB activity is modulated by ECD binding to peptidoglycan substructures, however, the molecular mechanisms underpinning PknB regulation remain unclear. In this study, we report structural and genetic characterization ...


Cxcr4 Identifies Transitional Bone Marrow Premonocytes That Replenish The Mature Monocyte Pool For Peripheral Responses, Shu Zhen Chong, Maximilien Evrard, John E. Harris, Lai Guan Ng Oct 2016

Cxcr4 Identifies Transitional Bone Marrow Premonocytes That Replenish The Mature Monocyte Pool For Peripheral Responses, Shu Zhen Chong, Maximilien Evrard, John E. Harris, Lai Guan Ng

UMass Metabolic Network Publications

It is well established that Ly6Chi monocytes develop from common monocyte progenitors (cMoPs) and reside in the bone marrow (BM) until they are mobilized into the circulation. In our study, we found that BM Ly6Chi monocytes are not a homogenous population, as current data would suggest. Using computational analysis approaches to interpret multidimensional datasets, we demonstrate that BM Ly6Chi monocytes consist of two distinct subpopulations (CXCR4hi and CXCR4lo subpopulations) in both mice and humans. Transcriptome studies and in vivo assays revealed functional differences between the two subpopulations. Notably, the CXCR4hi subset proliferates and is immobilized in the BM for the ...


Cxcr4 Identifies Transitional Bone Marrow Premonocytes That Replenish The Mature Monocyte Pool For Peripheral Responses, Shu Zhen Chong, John E. Harris, Lai Guan Ng Oct 2016

Cxcr4 Identifies Transitional Bone Marrow Premonocytes That Replenish The Mature Monocyte Pool For Peripheral Responses, Shu Zhen Chong, John E. Harris, Lai Guan Ng

UMass Metabolic Network Publications

It is well established that Ly6Chi monocytes develop from common monocyte progenitors (cMoPs) and reside in the bone marrow (BM) until they are mobilized into the circulation. In our study, we found that BM Ly6Chi monocytes are not a homogenous population, as current data would suggest. Using computational analysis approaches to interpret multidimensional datasets, we demonstrate that BM Ly6Chi monocytes consist of two distinct subpopulations (CXCR4hi and CXCR4lo subpopulations) in both mice and humans. Transcriptome studies and in vivo assays revealed functional differences between the two subpopulations. Notably, the CXCR4hi subset proliferates and is immobilized in the BM for the ...


Fine-Tuning Of Substrate Affinity Leads To Alternative Roles Of Mycobacterium Tuberculosis Fe2+-Atpases, Sarju J. Patel, Brianne E. Lewis, Jarukit E. Long, Subhalaxmi Nambi, Christopher M. Sassetti, Timothy L. Stemmler, Jose M. Arguello May 2016

Fine-Tuning Of Substrate Affinity Leads To Alternative Roles Of Mycobacterium Tuberculosis Fe2+-Atpases, Sarju J. Patel, Brianne E. Lewis, Jarukit E. Long, Subhalaxmi Nambi, Christopher M. Sassetti, Timothy L. Stemmler, Jose M. Arguello

UMass Metabolic Network Publications

Little is known about iron efflux transporters within bacterial systems. Recently, the participation of Bacillus subtilis PfeT, a P1B4-ATPase, in cytoplasmic Fe(2+) efflux has been proposed. We report here the distinct roles of mycobacterial P1B4-ATPases in the homeostasis of Co(2+) and Fe(2+) Mutation of Mycobacterium smegmatis ctpJ affects the homeostasis of both ions. Alternatively, an M. tuberculosis ctpJ mutant is more sensitive to Co(2+) than Fe(2+), whereas mutation of the homologous M. tuberculosis ctpD leads to Fe(2+) sensitivity but no alterations in Co(2+) homeostasis. In vitro, the three enzymes are activated by both ...


Spatially Distinct And Metabolically Active Membrane Domain In Mycobacteria, Jennifer M. Hayashi, John D. Leszyk, Christina E. Baer, Scott A. Shaffer, Christopher M. Sassetti, Yasu S. Morita May 2016

Spatially Distinct And Metabolically Active Membrane Domain In Mycobacteria, Jennifer M. Hayashi, John D. Leszyk, Christina E. Baer, Scott A. Shaffer, Christopher M. Sassetti, Yasu S. Morita

UMass Metabolic Network Publications

Protected from host immune attack and antibiotic penetration by their unique cell envelope, mycobacterial pathogens cause devastating human diseases such as tuberculosis. Seamless coordination of cell growth with cell envelope elongation at the pole maintains this barrier. Unraveling this spatiotemporal regulation is a potential strategy for controlling mycobacterial infections. Our biochemical analysis previously revealed two functionally distinct membrane fractions in Mycobacterium smegmatis cell lysates: plasma membrane tightly associated with the cell wall (PM-CW) and a distinct fraction of pure membrane free of cell wall components (PMf). To provide further insight into the functions of these membrane fractions, we took the ...


No Current Evidence For Widespread Dosage Compensation In S. Cerevisiae, Eduardo M. Torres, Michael Springer, Angelika Amon Mar 2016

No Current Evidence For Widespread Dosage Compensation In S. Cerevisiae, Eduardo M. Torres, Michael Springer, Angelika Amon

UMass Metabolic Network Publications

Previous studies of laboratory strains of budding yeast had shown that when gene copy number is altered experimentally, RNA levels generally scale accordingly. This is true when the copy number of individual genes or entire chromosomes is altered. In a recent study, Hose et al. (2015) reported that this tight correlation between gene copy number and RNA levels is not observed in recently isolated wild Saccharomyces cerevisiae variants. To understand the origins of this proposed difference in gene expression regulation between natural variants and laboratory strains of S. cerevisiae, we evaluated the karyotype and gene expression studies performed by Hose ...