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2006

University of Massachusetts Medical School

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Articles 1 - 30 of 95

Full-Text Articles in Life Sciences

Activated Checkpoint Kinase 2 Provides A Survival Signal For Tumor Cells, Jagadish C. Ghosh, Takehiko Dohi, Christopher M. Raskett, Timothy F. Kowalik, Dario C. Altieri Dec 2006

Activated Checkpoint Kinase 2 Provides A Survival Signal For Tumor Cells, Jagadish C. Ghosh, Takehiko Dohi, Christopher M. Raskett, Timothy F. Kowalik, Dario C. Altieri

Open Access Articles

Tumor cells often become resistant to DNA damage-based therapy; however, the underlying mechanisms are not yet understood. Here, we show that tumor cells exposed to DNA damage counteract cell death by releasing the antiapoptotic protein, survivin, from mitochondria. This is independent of p53, and requires activated checkpoint kinase 2 (Chk2), a putative tumor suppressor. Molecular or genetic targeting of Chk2 prevents the release of survivin from mitochondria, enhances DNA damage-induced tumor cell apoptosis, and inhibits the growth of resistant in vivo tumors. Therefore, activated Chk2 circumvents its own tumor-suppressive functions by promoting tumor cell survival. Inhibiting Chk2 in combination with ...


Modulating Role Of Rna Structure In Alternative Splicing Of A Critical Exon In The Spinal Muscular Atrophy Genes, Natalia N. Singh, Ravindra N. Singh, Elliot J. Androphy Dec 2006

Modulating Role Of Rna Structure In Alternative Splicing Of A Critical Exon In The Spinal Muscular Atrophy Genes, Natalia N. Singh, Ravindra N. Singh, Elliot J. Androphy

Open Access Articles

Humans have two nearly identical copies of the survival motor neuron (SMN ) gene, SMN1 and SMN2. Homozygous loss of SMN1 causes spinal muscular atrophy (SMA). SMN2 is unable to prevent the disease due to skipping of exon 7. Using a systematic approach of in vivo selection, we have previously demonstrated that a weak 5' splice site (ss) serves as the major cause of skipping of SMN2 exon 7. Here we show the inhibitory impact of RNA structure on the weak 5' ss of exon 7. We call this structure terminal stem-loop 2 (TSL2). Confirming the inhibitory nature of TSL2, point ...


Structure Of The Yeast Histone H3-Asf1 Interaction: Implications For Chaperone Mechanism, Species-Specific Interactions, And Epigenetics, Andrew J. Antczak, Toshiaki Tsubota, Paul D. Kaufman, James M. Berger Dec 2006

Structure Of The Yeast Histone H3-Asf1 Interaction: Implications For Chaperone Mechanism, Species-Specific Interactions, And Epigenetics, Andrew J. Antczak, Toshiaki Tsubota, Paul D. Kaufman, James M. Berger

Program in Gene Function and Expression Publications and Presentations

BACKGROUND: The histone H3/H4 chaperone Asf1 (anti-silencing function 1) is required for the establishment and maintenance of proper chromatin structure, as well as for genome stability in eukaryotes. Asf1 participates in both DNA replication-coupled (RC) and replication-independent (RI) histone deposition reactions in vitro and interacts with complexes responsible for both pathways in vivo. Asf1 is known to directly bind histone H3, however, high-resolution structural information about the geometry of this interaction was previously unknown. RESULTS: Here we report the structure of a histone/histone chaperone interaction. We have solved the 2.2 A crystal structure of the conserved N-terminal ...


A Prospective Study Of The Transient Decrease In Ovarian Cancer Risk Following Childbirth, Qin Liu, Mats Lambe, Inkyung Baik, Sven Cnattingius, Tomas Riman, Anders R. Ekbom, Hans-Olov Adami, Chung-Cheng Hsieh Dec 2006

A Prospective Study Of The Transient Decrease In Ovarian Cancer Risk Following Childbirth, Qin Liu, Mats Lambe, Inkyung Baik, Sven Cnattingius, Tomas Riman, Anders R. Ekbom, Hans-Olov Adami, Chung-Cheng Hsieh

Open Access Articles

Epidemiologic evidence shows that the risk of ovarian cancer is decreased following childbirth. We examined the time points when the decreased risk of postpartum maternal ovarian cancer reaches the lowest point and whether the protective effect diminishes over time. A case-control study nested within the Swedish Fertility Register included 10,086 cases of epithelial ovarian cancer recorded in the Swedish Cancer Register from 1961 to 2001. From the Fertility Register, 49,249 eligible subjects matched to the cases by age were selected as controls. The analysis contrasted risk between adjacent parities through logistic regression models that included indicator variables representing ...


Interaction Of Papillomavirus E2 Protein With The Brm Chromatin Remodeling Complex Leads To Enhanced Transcriptional Activation, R. Ajay Kumar, Samisubbu R. Naidu, Xiaoyu Wang, Anthony N. Imbalzano, Elliot J. Androphy Dec 2006

Interaction Of Papillomavirus E2 Protein With The Brm Chromatin Remodeling Complex Leads To Enhanced Transcriptional Activation, R. Ajay Kumar, Samisubbu R. Naidu, Xiaoyu Wang, Anthony N. Imbalzano, Elliot J. Androphy

Open Access Articles

Papillomavirus E2 is a sequence-specific DNA binding protein that regulates transcription and replication of the viral genome. The transcriptional activities of E2 are typically evaluated by transient transfection of nonreplicating E2-dependent reporters. We sought to address whether E2 activates transcription in an episomal context and its potential interaction with the chromatin remodeling proteins. Using an Epstein-Barr virus-based episomal reporter, we demonstrate that E2 stimulates transcription from an E2-dependent promoter in a chromatin context. This activation is enhanced by the presence of proteins associated with SWI/SNF complexes, which are ATP-dependent chromatin remodeling enzymes. We show that exogenous expression of the ...


Virus-Induced Decline In Soluble Vascular Endothelial Growth Receptor 2 Is Associated With Plasma Leakage In Dengue Hemorrhagic Fever, Anon Srikiatkhachorn, Chuanpis Ajariyakhajorn, Timothy P. Endy, Siripen Kalayanarooj, Daniel H. Libraty, Sharone Green, Francis A. Ennis, Alan L. Rothman Dec 2006

Virus-Induced Decline In Soluble Vascular Endothelial Growth Receptor 2 Is Associated With Plasma Leakage In Dengue Hemorrhagic Fever, Anon Srikiatkhachorn, Chuanpis Ajariyakhajorn, Timothy P. Endy, Siripen Kalayanarooj, Daniel H. Libraty, Sharone Green, Francis A. Ennis, Alan L. Rothman

Open Access Articles

Some individuals infected with dengue virus develop dengue hemorrhagic fever (DHF), a viral hemorrhagic disease characterized by a transient period of localized plasma leakage. To determine the importance of vascular endothelial growth factor A (VEGF-A) in this syndrome, we compared plasma levels of VEGF-A and the soluble forms of its receptors in patients with DHF to patients with dengue fever (DF), a milder form of dengue virus infection without plasma leakage. We observed a rise in the plasma levels of free, but not total VEGF-A in DHF patients at the time of plasma leakage. This was associated with a decline ...


Brca1 Foci In Normal S-Phase Nuclei Are Linked To Interphase Centromeres And Replication Of Pericentric Heterochromatin, Gayle Jeannette Pageau, Jeanne B. Lawrence Dec 2006

Brca1 Foci In Normal S-Phase Nuclei Are Linked To Interphase Centromeres And Replication Of Pericentric Heterochromatin, Gayle Jeannette Pageau, Jeanne B. Lawrence

Open Access Articles

Breast cancer-associated protein 1 (BRCA1) forms foci at sites of induced DNA damage, but any significance of these normal S-phase foci is unknown. BRCA1 distribution does not simply mirror or overlap that of replicating DNA; however, BRCA1 foci frequently abut sites of BrdU incorporation, mostly at mid-to-late S phase. Although BRCA1 does not overlap XIST RNA across the inactive X chromosome, BRCA1 foci position overwhelmingly in heterochromatic regions, particularly the nucleolar periphery where many centromeres reside. In humans and mice, including early embryonic cells, BRCA1 commonly associates with interphase centromere-kinetochore complexes, including pericentric heterochromatin. Proliferating cell nuclear antigen or BrdU ...


Cbfbeta Reduces Cbfbeta-Smmhc-Associated Acute Myeloid Leukemia In Mice, Susan Ann Heilman, Ya-Huei Kuo, Chantal S. Goudswaard, Peter J. Valk, Lucio H. Castilla Dec 2006

Cbfbeta Reduces Cbfbeta-Smmhc-Associated Acute Myeloid Leukemia In Mice, Susan Ann Heilman, Ya-Huei Kuo, Chantal S. Goudswaard, Peter J. Valk, Lucio H. Castilla

Open Access Articles

The gene encoding for core-binding factor beta (CBFbeta) is altered in acute myeloid leukemia samples with an inversion in chromosome 16, expressing the fusion protein CBFbeta-SMMHC. Previous studies have shown that this oncoprotein interferes with hematopoietic differentiation and proliferation and participates in leukemia development. In this study, we provide evidence that Cbfbeta modulates the oncogenic function of this fusion protein. We show that Cbfbeta plays an important role in proliferation of hematopoietic progenitors expressing Cbfbeta-SMMHC in vitro. In addition, Cbfbeta-SMMHC-mediated leukemia development is accelerated in the absence of Cbfbeta. These results indicate that the balance between Cbfbeta and Cbfbeta-SMMHC directly ...


Inhibition Of Bach1 (Fancj) Helicase By Backbone Discontinuity Is Overcome By Increased Motor Atpase Or Length Of Loading Strand, Rigu Gupta, Sudha Sharma, Kevin M. Doherty, Joshua A. Sommers, Sharon B. Cantor, Robert M. Brosh Dec 2006

Inhibition Of Bach1 (Fancj) Helicase By Backbone Discontinuity Is Overcome By Increased Motor Atpase Or Length Of Loading Strand, Rigu Gupta, Sudha Sharma, Kevin M. Doherty, Joshua A. Sommers, Sharon B. Cantor, Robert M. Brosh

Cancer Biology Publications and Presentations

The BRCA1 associated C-terminal helicase (BACH1) associated with breast cancer has been implicated in double strand break (DSB) repair. More recently, BACH1 (FANCJ) has been genetically linked to the chromosomal instability disorder Fanconi Anemia (FA). Understanding the roles of BACH1 in cellular DNA metabolism and how BACH1 dysfunction leads to tumorigenesis requires a comprehensive investigation of its catalytic mechanism and molecular functions in DNA repair. In this study, we have determined that BACH1 helicase contacts with both the translocating and the non-translocating strands of the duplex are critical for its ability to track along the sugar phosphate backbone and unwind ...


Intranuclear Binding Kinetics And Mobility Of Single Native U1 Snrnp Particles In Living Cells, David Grunwald, Beatrice Spottke, Volker Buschmann, Ulrich Kubitscheck Dec 2006

Intranuclear Binding Kinetics And Mobility Of Single Native U1 Snrnp Particles In Living Cells, David Grunwald, Beatrice Spottke, Volker Buschmann, Ulrich Kubitscheck

Biochemistry and Molecular Pharmacology Publications and Presentations

Uridine-rich small nuclear ribonucleoproteins (U snRNPs) are splicing factors, which are diffusely distributed in the nucleoplasm and also concentrated in nuclear speckles. Fluorescently labeled, native U1 snRNPs were microinjected into the cytoplasm of living HeLa cells. After nuclear import single U1 snRNPs could be visualized and tracked at a spatial precision of 30 nm at a frame rate of 200 Hz employing a custom-built microscope with single-molecule sensitivity. The single-particle tracks revealed that most U1 snRNPs were bound to specific intranuclear sites, many of those presumably representing pre-mRNA splicing sites. The dissociation kinetics from these sites showed a multiexponential decay ...


Mitotic Kinesin-Like Protein 2 Binds And Colocalizes With Papillomavirus E2 During Mitosis, Ting Yu, Yu-Cai Peng, Elliot J. Androphy Dec 2006

Mitotic Kinesin-Like Protein 2 Binds And Colocalizes With Papillomavirus E2 During Mitosis, Ting Yu, Yu-Cai Peng, Elliot J. Androphy

Open Access Articles

MKlp2 is a kinesin-like motor protein of the central mitotic spindle required for completion of cytokinesis. Papillomavirus E2 is a sequence specific DNA binding protein that regulates viral transcription and replication and is responsible for partitioning viral episomes into daughter cells during cell division. We demonstrate that MKlp2 specifically associates with the E2 protein during mitosis. Using chromatin immunoprecipitation, we show viral genomes are in complex with MKlp2 only within this stage of cell cycle. By immunofluorescence, a subpopulation of papillomavirus E2 colocalizes with MKlp2 in the midbody/midplate during late mitosis. We conclude that during specific stages of mitosis ...


Cellular And Molecular Regulation Of The Primate Endometrium: A Perspective, William C. Okulicz Nov 2006

Cellular And Molecular Regulation Of The Primate Endometrium: A Perspective, William C. Okulicz

Open Access Articles

This contribution will trace some of the many seminal studies on the female uterus (endometrium) over the centuries and conclude with a description of some current research initiatives in our laboratory. Numerous contributions from many investigators over the years have contributed to our current understanding of endometrial function. The historical section of this chapter is intended to be a brief overall description of some of these efforts and not exhaustive. Additional information can be found in the review articles and books cited herein.


Quantitative Analysis Of Hedgehog Gradient Formation Using An Inducible Expression System: A Dissertation, Vivian F. Su Nov 2006

Quantitative Analysis Of Hedgehog Gradient Formation Using An Inducible Expression System: A Dissertation, Vivian F. Su

GSBS Dissertations and Theses

The Hedgehog (Hh) family of proteins are secreted growth factors that play an essential role in the embryonic development of all organisms and the main components in the pathway are conserved from insects to humans. These proteins affect patterning and morphogenesis of multiple tissues. Therefore, mutations in the Hh pathway can result in a wide range of developmental defects and oncogenic diseases. Because the main components in the pathway are conserved from insects to humans, Drosophilahas been shown to provide a genetically tractable system to gain insight into the processes that Hh is involved in.

In this study, the ...


Trefoil Family Factor 2 Is Expressed In Murine Gastric And Immune Cells And Controls Both Gastrointestinal Inflammation And Systemic Immune Responses, Evelyn A. Kurt-Jones, Lucheng Cao, Frantisek Sandor, Arlin B. Rogers, Mark T. Whary, Prashant R. Nambiar, Anna M. Cerny, Glennice N. Bowen, Jing Yan, Shigeo Takaishi, Alfred L. Chi, George W. Reed, Jeanmarie Houghton, James G. Fox, Timothy C. Wang Nov 2006

Trefoil Family Factor 2 Is Expressed In Murine Gastric And Immune Cells And Controls Both Gastrointestinal Inflammation And Systemic Immune Responses, Evelyn A. Kurt-Jones, Lucheng Cao, Frantisek Sandor, Arlin B. Rogers, Mark T. Whary, Prashant R. Nambiar, Anna M. Cerny, Glennice N. Bowen, Jing Yan, Shigeo Takaishi, Alfred L. Chi, George W. Reed, Jeanmarie Houghton, James G. Fox, Timothy C. Wang

Open Access Articles

Trefoil family factor 2 (TFF2), also known as spasmolytic peptide, is a low-molecular-weight protein that is upregulated in gastric tissues infected with Helicobacter or having other inflammatory conditions, but a precise function is yet to be elucidated. The role of TFF2 in the development of gastritis, colitis, and inflammatory cytokine responses was examined both in vivo and in vitro using wild-type and TFF2 knockout mice. TFF2 knockout and wild-type mice were infected with Helicobacter felis (H. felis) to induce gastritis. Colitis was induced in TFF2 knockout and wild-type mice by administering dextran sodium sulfate (DSS) in drinking water. Histopathology, clinical ...


The Drosophila Radish Gene Encodes A Protein Required For Anesthesia-Resistant Memory, Elisabeth Folkers, Scott Waddell, William G. Quinn Nov 2006

The Drosophila Radish Gene Encodes A Protein Required For Anesthesia-Resistant Memory, Elisabeth Folkers, Scott Waddell, William G. Quinn

Neurobiology Publications and Presentations

Long-term memory in Drosophila is separable into two components: consolidated, anesthesia-resistant memory and long-lasting, protein-synthesis-dependent memory. The Drosophila memory mutant radish is specifically deficient in anesthesia-resistant memory and so represents the only molecular avenue to understanding this memory component. Here, we have identified the radish gene by positional cloning and comparative sequencing, finding a mutant stop codon in gene CG15720 from the Drosophila Genome Project. Induction of a wild-type CG15720 transgene in adult flies acutely rescues the mutant's memory defect. The phospholipase A2 gene, previously identified as radish [Chiang et al. (2004) Curr. Biol. 14:263-272], maps 95 kb ...


M1 Muscarinic Receptors Inhibit L-Type Ca2+ Current And M-Current By Divergent Signal Transduction Cascades, Liwang Liu, Rubing Zhao, Yan Bai, Lee F. Stanish, James E. Evans, Michael J. Sanderson, Joseph V. Bonventre, Ann R. Rittenhouse Nov 2006

M1 Muscarinic Receptors Inhibit L-Type Ca2+ Current And M-Current By Divergent Signal Transduction Cascades, Liwang Liu, Rubing Zhao, Yan Bai, Lee F. Stanish, James E. Evans, Michael J. Sanderson, Joseph V. Bonventre, Ann R. Rittenhouse

Open Access Articles

Ion channels reside in a sea of phospholipids. During normal fluctuations in membrane potential and periods of modulation, lipids that directly associate with channel proteins influence gating by incompletely understood mechanisms. In one model, M(1)-muscarinic receptors (M(1)Rs) may inhibit both Ca(2+) (L- and N-) and K(+) (M-) currents by losing a putative interaction between channels and phosphatidylinositol-4,5-bisphosphate (PIP(2)). However, we found previously that M(1)R inhibition of N-current in superior cervical ganglion (SCG) neurons requires loss of PIP(2) and generation of a free fatty acid, probably arachidonic acid (AA) by phospholipase ...


P38 Mitogen-Activated Protein Kinase: A Novel Modulator Of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels And Neuronal Excitability, Patricia M. Wynne Nov 2006

P38 Mitogen-Activated Protein Kinase: A Novel Modulator Of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels And Neuronal Excitability, Patricia M. Wynne

Open Access Articles

No abstract provided.


Protection Against Vaccinia Virus Challenge By Cd8 Memory T Cells Resolved By Molecular Mimicry, Markus Cornberg, Brian S. Sheridan, Frances M. Saccoccio, Michael A. Brehm, Liisa K. Selin Nov 2006

Protection Against Vaccinia Virus Challenge By Cd8 Memory T Cells Resolved By Molecular Mimicry, Markus Cornberg, Brian S. Sheridan, Frances M. Saccoccio, Michael A. Brehm, Liisa K. Selin

Open Access Articles

Live vaccinia virus (VV) vaccination has been highly successful in eradicating smallpox. However, the mechanisms of immunity involved in mediating this protective effect are still poorly understood, and the roles of CD8 T-cell responses in primary and secondary VV infections are not clearly identified. By applying the concept of molecular mimicry to identify potential CD8 T-cell epitopes that stimulate cross-reactive T cells specific to lymphocytic choriomeningitis virus (LCMV) and VV, we identified after screening only 115 peptides two VV-specific immunogenic epitopes that mediated protective immunity against VV. An immunodominant epitope, VV-e7r130, did not generate cross-reactive T-cell responses to LCMV, and ...


Rna Silencing Pathways In Schizosaccharomyces Pombe And Drosophila Melanogaster: A Dissertation, Alla A. Sigova Nov 2006

Rna Silencing Pathways In Schizosaccharomyces Pombe And Drosophila Melanogaster: A Dissertation, Alla A. Sigova

GSBS Dissertations and Theses

RNA silencing is an evolutionary conserved sequence-specific mechanism of regulation of gene expression. RNA interference (RNAi), a type of RNA silencing in animals, is based on recognition and endonucleolytic cleavage of target mRNA complimentary in sequence to 21-nucleotide (nt) small RNA guides, called small interfering RNAs (siRNAs). Another class of 21-nt small RNAs, called micro RNAs (miRNAs), is endogenously encoded in eukaryotic genomes. Both production of siRNAs from long double-stranded RNA (dsRNA) and biogenesis of miRNAs from hairpin structures are governed by the ribonuclease III enzyme Dicer. Although produced as duplex molecules, siRNAs and miRNAs are assembled into effector complex ...


Requirements For Assembly And Release Of Newcastle Disease Virus-Like Particles: A Dissertation, Homer Dadios Pantua Oct 2006

Requirements For Assembly And Release Of Newcastle Disease Virus-Like Particles: A Dissertation, Homer Dadios Pantua

GSBS Dissertations and Theses

The final step of paramyxovirus infection requires the assembly of viral structural components at the plasma membrane of infected cells followed by budding of virions. While the matrix (M) protein of some paramyxoviruses has been suggested to play a central role in the assembly and release of virus particles, the specific viral and host protein requirements are still unclear. Using Newcastle disease virus (NDV) as a prototype paramyxovirus, we explored the role of each of the NDV structural proteins in virion assembly and release. For these studies, we established a virus-like particle (VLP) system for NDV. The key viral proteins ...


Unraveling Transcription Regulatory Networks By Protein-Dna And Protein-Protein Interaction Mapping, Albertha J. M. Walhout Oct 2006

Unraveling Transcription Regulatory Networks By Protein-Dna And Protein-Protein Interaction Mapping, Albertha J. M. Walhout

Open Access Articles

Metazoan genomes contain thousands of protein-coding and noncoding RNA genes, most of which are differentially expressed, i.e., at different locations or at different times during development, function, or pathology of the organism. Differential gene expression is achieved in part by the action of regulatory transcription factors (TFs) that bind to cis-regulatory elements that are often located in or near their target genes. Each TF likely regulates many targets in the context of intricate transcription regulatory networks. Up to 10% of a genome may encode TFs, but only a handful of these have been studied in detail. Here, I will ...


Cpeb Controls Oocyte Growth And Follicle Development In The Mouse, Racki J. Waldemar, Joel D. Richter Oct 2006

Cpeb Controls Oocyte Growth And Follicle Development In The Mouse, Racki J. Waldemar, Joel D. Richter

Open Access Articles

CPEB is a sequence-specific RNA-binding protein that regulates polyadenylation-induced translation. In Cpeb knockout mice, meiotic progression is disrupted at pachytene due to inhibited translation of synaptonemal complex protein mRNAs. To assess the function of CPEB after pachytene, we used the zona pellucida 3 (Zp3) promoter to generate transgenic mice expressing siRNA that induce the destruction of Cpeb mRNA. Oocytes from these animals do not develop normally; they undergo parthenogenetic cell division in the ovary, exhibit abnormal polar bodies, are detached from the cumulus granulosa cell layer, and display spindle and nuclear anomalies. In addition, many follicles contain apoptotic granulosa cells ...


Autophagy Is Activated For Cell Survival After Endoplasmic Reticulum Stress, Maiko Ogata, Shin-Ichiro Hino, Atsushi Saito, Keisuke Morikawa, Shinichi Kondo, Soshi Kanemoto, Tomohiko Murakami, Manabu Taniguchi, Ichiro Tanii, Kazuya Yoshinaga, Sadao Shiosaka, James A. Hammarback, Fumihiko Urano, Kazunori Imaizumi Oct 2006

Autophagy Is Activated For Cell Survival After Endoplasmic Reticulum Stress, Maiko Ogata, Shin-Ichiro Hino, Atsushi Saito, Keisuke Morikawa, Shinichi Kondo, Soshi Kanemoto, Tomohiko Murakami, Manabu Taniguchi, Ichiro Tanii, Kazuya Yoshinaga, Sadao Shiosaka, James A. Hammarback, Fumihiko Urano, Kazunori Imaizumi

Program in Gene Function and Expression Publications and Presentations

Eukaryotic cells deal with accumulation of unfolded proteins in the endoplasmic reticulum (ER) by the unfolded protein response, involving the induction of molecular chaperones, translational attenuation, and ER-associated degradation, to prevent cell death. Here, we found that the autophagy system is activated as a novel signaling pathway in response to ER stress. Treatment of SK-N-SH neuroblastoma cells with ER stressors markedly induced the formation of autophagosomes, which were recognized at the ultrastructural level. The formation of green fluorescent protein (GFP)-LC3-labeled structures (GFP-LC3 "dots"), representing autophagosomes, was extensively induced in cells exposed to ER stress with conversion from LC3-I to ...


The Lrs And Sin Domains: Two Structurally Equivalent But Functionally Distinct Nucleosomal Surfaces Required For Transcriptional Silencing, Christopher J. Fry, Anne Norris, Michael S. Cosgrove, Jef D. Boeke, Craig L. Peterson Oct 2006

The Lrs And Sin Domains: Two Structurally Equivalent But Functionally Distinct Nucleosomal Surfaces Required For Transcriptional Silencing, Christopher J. Fry, Anne Norris, Michael S. Cosgrove, Jef D. Boeke, Craig L. Peterson

Open Access Articles

Genetic experiments have identified two structurally similar nucleosomal domains, SIN and LRS, required for transcriptional repression at genes regulated by the SWI/SNF chromatin remodeling complex or for heterochromatic gene silencing, respectively. Each of these domains consists of histone H3 and H4 L1 and L2 loops that form a DNA-binding surface at either superhelical location (SHL) +/-2.5 (LRS) or SHL +/-0.5 (SIN). Here we show that alterations in the LRS domain do not result in Sin(-) phenotypes, nor does disruption of the SIN domain lead to loss of ribosomal DNA heterochromatic gene silencing (Lrs(-) phenotype). Furthermore, whereas disruption ...


Chromosome Conformation Capture Carbon Copy (5c): A Massively Parallel Solution For Mapping Interactions Between Genomic Elements, Josee Dostie, Todd A. Richmond, Ramy A. Arnaout, Rebecca R. Selzer, William L. Lee, Tracey A. Honan, Eric D. Rubio, Anton Krumm, Justin Lamb, Chad Nusbaum, Roland D. Green, Job Dekker Oct 2006

Chromosome Conformation Capture Carbon Copy (5c): A Massively Parallel Solution For Mapping Interactions Between Genomic Elements, Josee Dostie, Todd A. Richmond, Ramy A. Arnaout, Rebecca R. Selzer, William L. Lee, Tracey A. Honan, Eric D. Rubio, Anton Krumm, Justin Lamb, Chad Nusbaum, Roland D. Green, Job Dekker

Open Access Articles

Physical interactions between genetic elements located throughout the genome play important roles in gene regulation and can be identified with the Chromosome Conformation Capture (3C) methodology. 3C converts physical chromatin interactions into specific ligation products, which are quantified individually by PCR. Here we present a high-throughput 3C approach, 3C-Carbon Copy (5C), that employs microarrays or quantitative DNA sequencing using 454-technology as detection methods. We applied 5C to analyze a 400-kb region containing the human beta-globin locus and a 100-kb conserved gene desert region. We validated 5C by detection of several previously identified looping interactions in the beta-globin locus. We also ...


Impact Of Cyclooxygenase Inhibitors In The Women's Health Initiative Hormone Trials: Secondary Analysis Of A Randomized Trial, Judith Hsia, Joann E. Manson, Lewis H. Kuller, Mary B. Pettinger, John H. Choe, Robert D. Langer, Marian C. Limacher, Albert Oberman, Judith K. Ockene, Mary Jo O'Sullivan, Jennifer G. Robinson Sep 2006

Impact Of Cyclooxygenase Inhibitors In The Women's Health Initiative Hormone Trials: Secondary Analysis Of A Randomized Trial, Judith Hsia, Joann E. Manson, Lewis H. Kuller, Mary B. Pettinger, John H. Choe, Robert D. Langer, Marian C. Limacher, Albert Oberman, Judith K. Ockene, Mary Jo O'Sullivan, Jennifer G. Robinson

Women’s Health Research Faculty Publications

OBJECTIVES: We evaluated the hypothesis that cyclooxygenase (COX) inhibitor use might have counteracted a beneficial effect of postmenopausal hormone therapy, and account for the absence of cardioprotection in the Women's Health Initiative hormone trials. Estrogen increases COX expression, and inhibitors of COX such as nonsteroidal anti-inflammatory agents appear to increase coronary risk, raising the possibility of a clinically important interaction in the trials.

DESIGN: The hormone trials were randomized, double-blind, and placebo-controlled. Use of nonsteroidal anti-inflammatory drugs was assessed at baseline and at years 1, 3, and 6.

SETTING: The Women's Health Initiative hormone trials were conducted at ...


Identification Of Novel (RNai DeFicient) Genes In C. Elegans: A Dissertation, Chun-Chieh G. Chen Sep 2006

Identification Of Novel (RNai DeFicient) Genes In C. Elegans: A Dissertation, Chun-Chieh G. Chen

GSBS Dissertations and Theses

RNA interference or RNAi was first discovered as an experimental approach that induces potent sequence-specific gene silencing. Remarkably, subsequent studies on dissecting the molecular mechanism of the RNAi pathway reveal that RNAi is conserved in most eukaryotes. In addition, genes and mechanisms related to RNAi are employed to elicit the regulation of endogenous gene expression that controls a variety of important biological processes. To investigate the mechanism of RNAi in the nematode C. elegans, we performed genetic screens in search of RNAi deficient mutants (rde). Here I report the summary of the genetic screens in search of rde ...


Hemagglutinin (Ha) Proteins From H1 And H3 Serotypes Of Influenza A Viruses Require Different Antigen Designs For The Induction Of Optimal Protective Antibody Responses As Studied By Codon-Optimized Ha Dna Vaccines, Shixia Wang, Jessica Taaffe, Christopher S. Parker, Alicia Solorzano, Hong Cao, Adolfo Garcia-Sastre, Shan Lu Sep 2006

Hemagglutinin (Ha) Proteins From H1 And H3 Serotypes Of Influenza A Viruses Require Different Antigen Designs For The Induction Of Optimal Protective Antibody Responses As Studied By Codon-Optimized Ha Dna Vaccines, Shixia Wang, Jessica Taaffe, Christopher S. Parker, Alicia Solorzano, Hong Cao, Adolfo Garcia-Sastre, Shan Lu

Open Access Articles

Effective antibody responses provide crucial immunity against influenza virus infection. The hemagglutinin (HA) protein is the major target of protective antibody responses induced by viral infection and by vaccination with both inactivated and live-attenuated flu vaccines, but knowledge about the optimal designs of protective HA antigens from different flu serotypes is still limited. In this study, we have significantly improved the immunogenicity of HA-expressing DNA vaccines by using codon-optimized HA sequences for either an H1 serotype (A/NewCal/20/99) or an H3 serotype (A/Panama/2007/99) human influenza A virus and then used these constructs as model antigens ...


Rapid Quantification Of Naive Alloreactive T Cells By Tnf-Alpha Production And Correlation With Allograft Rejection In Mice, Michael A. Brehm, Julie A. Mangada, Thomas G. Markees, Todd Pearson, Keith A. Daniels, Thomas B. Thornley, Raymond M. Welsh, Aldo A. Rossini, Dale L. Greiner Sep 2006

Rapid Quantification Of Naive Alloreactive T Cells By Tnf-Alpha Production And Correlation With Allograft Rejection In Mice, Michael A. Brehm, Julie A. Mangada, Thomas G. Markees, Todd Pearson, Keith A. Daniels, Thomas B. Thornley, Raymond M. Welsh, Aldo A. Rossini, Dale L. Greiner

Open Access Articles

Allograft transplantation requires chronic immunosuppression, but there is no effective strategy to evaluate the long-term maintenance of immunosuppression other than assessment of graft function. The ability to monitor naive alloreactive T cells would provide an alternative guide for drug therapy at early, preclinical stages of graft rejection and for evaluating tolerance-inducing protocols. To detect and quantify naive alloreactive T cells directly ex vivo, we used the unique ability of naive T cells to rapidly produce TNF-alpha but not IFN-gamma. Naive alloreactive T cells were identified by the production of TNF-alpha after a 5-hour in vitro stimulation with alloantigen and were ...


Probing Protein Dynamics Through Mutational And Computational Studies Of Hiv-1 Protease: A Dissertation, Jennifer E. Murzycki Sep 2006

Probing Protein Dynamics Through Mutational And Computational Studies Of Hiv-1 Protease: A Dissertation, Jennifer E. Murzycki

GSBS Dissertations and Theses

How proteins undergo conformational changes to bind a ligand is one of the most fundamental questions of protein biology. MD simulations provide a useful computational tool for studying the theoretical movements of protein in solution on nanosecond timescales. The results of these simulations can be used to guide experimental design. By correlating the theoretical models with the results of experimental studies, we can obtain a significant amount of information about protein dynamics. This study represents the application of both computational and traditional experimental techniques to study protein dynamics in HIV-1 protease. The results provide a novel mechanism for the conformational ...