Página 1 dos resultados de 2059 itens digitais encontrados em 0.048 segundos

‣ The intestinal epithelium and its neoplasms: genetic, cellular and tissue interactions.

Dove, W F; Cormier, R T; Gould, K A; Halberg, R B; Merritt, A J; Newton, M A; Shoemaker, A R
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 29/06/1998 Português
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The Min (multiple intestinal neoplasia) strain of the laboratory mouse and its derivatives permit the fundamental study of factors that regulate the transition between normal and neoplastic growth. A gene of central importance in mediating these alternative patterns of growth is Apc, the mouse homologue of the human adenomatous polyposis coli (APC) gene. When adenomas form in the Min mouse, both copies of the Apc gene must be inactivated. One copy is mutated by the nonsense Apc allele carried in heterozygous form in this strain. The other copy can be silenced by any of several mechanisms. These range from loss of the homologue bearing the wild-type Apc allele; to interstitial deletions surrounding the wild-type allele; to intragenic mutation, including nonsense alleles; and finally, to a reduction in expression of the locus, perhaps owing to mutation in a regulatory locus. Each of these proposed mechanisms may constitute a two-hit genetic process as initially posited by Knudson; however, apparently the two hits could involve either a single locus or two loci. The kinetic order for the transition to adenoma may be still higher than two, if polyclonal adenomas require stronger interactions than passive fusion. The severity of the intestinal neoplastic phenotype of the Min mouse is strongly dependent upon loci other than Apc. One of these...

‣ The Nucleosome Remodeling Factor ISWI Functionally Interacts With an Evolutionarily Conserved Network of Cellular Factors

Arancio, Walter; Onorati, Maria C.; Burgio, Giosalba; Collesano, Marianna; Ingrassia, Antonia M. R.; Genovese, Swonild I.; Fanto, Manolis; Corona, Davide F. V.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /05/2010 Português
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ISWI is an evolutionarily conserved ATP-dependent chromatin remodeling factor playing central roles in DNA replication, RNA transcription, and chromosome organization. The variety of biological functions dependent on ISWI suggests that its activity could be highly regulated. Our group has previously isolated and characterized new cellular activities that positively regulate ISWI in Drosophila melanogaster. To identify factors that antagonize ISWI activity we developed a novel in vivo eye-based assay to screen for genetic suppressors of ISWI. Our screen revealed that ISWI interacts with an evolutionarily conserved network of cellular and nuclear factors that escaped previous genetic and biochemical analyses.

‣ The Conserved YAGL Motif in Human Metapneumovirus Is Required for Higher-Order Cellular Assemblies of the Matrix Protein and for Virion Production▿

Sabo, Yosef; Ehrlich, Marcelo; Bacharach, Eran
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /07/2011 Português
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YXXL motifs in cellular and viral proteins have a variety of functions. The matrix (M) protein of the respiratory pathogen human metapneumovirus (hMPV) contains two such conserved motifs—YSKL and YAGL. We mutated these sequences to analyze their contributions to hMPV infectivity. The mutant clones were capable of intracellular replication; however, the YAGL but not YSKL mutants were defective at spreading in infected cultures. We improved the reverse genetics system for hMPV and generated cell lines that stably expressed selectable, replicating full-length genomes for both the wild type and the mutant clones, allowing microscopic and biochemical analyses of these viruses. YAGL mutants produced normal cellular levels of M protein but failed to release virions, while ectopic coexpression of wild-type M generated particles that were restricted to a single cycle of infection. The YAGL motif did not act as a late (L) domain, however, since hMPV budding was independent of the cellular endosomal sorting complex required for transport (ESCRT) machinery and because replacement of the YAGL motif with classical L domains generated defective viruses. Instead, the YAGL mutants had defective M assemblies lacking a normal filamentous appearance and showed poor extractability from the cell compared to the wild-type protein. The mutant proteins were not grossly misfolded...

‣ Combination of Chemical Genetics and Phosphoproteomics for Kinase Signaling Analysis Enables Confident Identification of Cellular Downstream Targets*

Oppermann, Felix S.; Grundner-Culemann, Kathrin; Kumar, Chanchal; Gruss, Oliver J.; Jallepalli, Prasad V.; Daub, Henrik
Fonte: The American Society for Biochemistry and Molecular Biology Publicador: The American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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Delineation of phosphorylation-based signaling networks requires reliable data about the underlying cellular kinase-substrate interactions. We report a chemical genetics and quantitative phosphoproteomics approach that encompasses cellular kinase activation in combination with comparative replicate mass spectrometry analyses of cells expressing either inhibitor-sensitive or resistant kinase variant. We applied this workflow to Plk1 (Polo-like kinase 1) in mitotic cells and induced cellular Plk1 activity by wash-out of the bulky kinase inhibitor 3-MB-PP1, which targets a mutant kinase version with an enlarged catalytic pocket while not interfering with wild-type Plk1. We quantified more than 20,000 distinct phosphorylation sites by SILAC, approximately half of which were measured in at least two independent experiments in cells expressing mutant and wild-type Plk1. Based on replicate phosphorylation site quantifications in both mutant and wild-type Plk1 cells, our chemical genetic proteomics concept enabled stringent comparative statistics by significance analysis of microarrays, which unveiled more than 350 cellular downstream targets of Plk1 validated by full concordance of both statistical and experimental data. Our data point to hitherto poorly characterized aspects in Plk1-controlled mitotic progression and provide a largely extended resource for functional studies. We anticipate the described strategies to be of general utility for systematic and confident identification of cellular protein kinase substrates.

‣ Interactions between oxygen homeostasis, food availability, and hydrogen sulfide signaling

Iranon, Nicole N.; Miller, Dana L.
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 27/11/2012 Português
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46.78189%
The ability to sense and respond to stressful conditions is essential to maintain organismal homeostasis. It has long been recognized that stress response factors that improve survival in changing conditions can also influence longevity. In this review, we discuss different strategies used by animals in response to decreased O2 (hypoxia) to maintain O2 homeostasis, and consider interactions between hypoxia responses, nutritional status, and H2S signaling. O2 is an essential environmental nutrient for almost all metazoans as it plays a fundamental role in development and cellular metabolism. However, the physiological response(s) to hypoxia depend greatly on the amount of O2 available. Animals must sense declining O2 availability to coordinate fundamental metabolic and signaling pathways. It is not surprising that factors involved in the response to hypoxia are also involved in responding to other key environmental signals, particularly food availability. Recent studies in mammals have also shown that the small gaseous signaling molecule hydrogen sulfide (H2S) protects against cellular damage and death in hypoxia. These results suggest that H2S signaling also integrates with hypoxia response(s). Many of the signaling pathways that mediate the effects of hypoxia...

‣ The Metabolic Status Drives Acclimation of Iron Deficiency Responses in Chlamydomonas reinhardtii as Revealed by Proteomics Based Hierarchical Clustering and Reverse Genetics*

Höhner, Ricarda; Barth, Johannes; Magneschi, Leonardo; Jaeger, Daniel; Niehues, Anna; Bald, Till; Grossman, Arthur; Fufezan, Christian; Hippler, Michael
Fonte: The American Society for Biochemistry and Molecular Biology Publicador: The American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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Iron is a crucial cofactor in numerous redox-active proteins operating in bioenergetic pathways including respiration and photosynthesis. Cellular iron management is essential to sustain sufficient energy production and minimize oxidative stress. To produce energy for cell growth, the green alga Chlamydomonas reinhardtii possesses the metabolic flexibility to use light and/or carbon sources such as acetate. To investigate the interplay between the iron-deficiency response and growth requirements under distinct trophic conditions, we took a quantitative proteomics approach coupled to innovative hierarchical clustering using different “distance-linkage combinations” and random noise injection. Protein co-expression analyses of the combined data sets revealed insights into cellular responses governing acclimation to iron deprivation and regulation associated with photosynthesis dependent growth. Photoautotrophic growth requirements as well as the iron deficiency induced specific metabolic enzymes and stress related proteins, and yet differences in the set of induced enzymes, proteases, and redox-related polypeptides were evident, implying the establishment of distinct response networks under the different conditions. Moreover, our data clearly support the notion that the iron deficiency response includes a hierarchy for iron allocation within organelles in C. reinhardtii. Importantly...

‣ The Relationship Between Midlife and Late Life Alcohol Consumption, APOE e4 and the Decline in Learning and Memory Among Older Adults

Downer, Brian; Zanjani, Faika; Fardo, David W.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Aims: The aim of the study was to determine whether the trajectory of learning and memory is modified according to an interaction between midlife or late life alcohol consumption status and the presence of one or more APOE e4 alleles. Methods: This was a secondary analysis of cognitive, genetic and alcohol consumption data collected from members of the Framingham Heart Study Offspring Cohort. Results: Light and moderate alcohol consumption during late life was associated with greater decline in learning and memory among APOE e4 carriers, whereas light and moderate alcohol consumption was associated with an increase in learning and memory among non-APOE e4 carriers. There was not a significant interaction between midlife alcohol consumption status and APOE e4 on the trajectory of learning and memory. Conclusion: Light to moderate alcohol consumption during late life may protect against a decline in learning and memory for non-APOE e4 allele carriers, but not for older adults who carry one or more APOE e4 alleles.

‣ A GABRA2 Variant Is Associated with Increased Stimulation and ‘High’ Following Alcohol Administration

Arias, Albert J.; Covault, Jonathan; Feinn, Richard; Pond, Timothy; Yang, Bao-Zhu; Ge, Wenjing; Oncken, Cheryl; Kranzler, Henry R.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
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Aims: Variation in genes encoding GABAA receptor subunits has been implicated in the risk of alcohol dependence (AD). We sought to replicate and extend previous findings of a moderating effect of single nucleotide polymorphisms (SNPs) in GABRA2 (which encodes the GABAA α-2 subunit) on the subjective effects of alcohol by examining SNPs in this and the adjacent GABRG1 gene on chromosome 4. Methods: Fifty-two European-Americans (22 males, 28 light drinkers and 24 heavy drinkers) completed 3 laboratory sessions, during which they drank low-dose, high-dose, or placebo alcohol prior to undergoing periodic assessments of stimulation, sedation and drug enjoyment. We genotyped subjects for three SNPs previously associated with AD: rs279858 in GABRA2, and rs7654165 and rs6447493 in GABRG1. Results: Two SNPs were associated with altered stimulatory effects of alcohol as measured on the Biphasic Alcohol Effects Scale, (rs279858: P = 0.0046; rs6447493: P = 0.0023); both effects were in the opposite direction of previous findings. Carriers of the rs279858 C allele experienced greater stimulation from alcohol. Further inspection of the rs6447493 interaction did not support a pharmacogenetic effect. The effects of rs279858 (but not the other two SNPs) on items from a secondary outcome measure...

‣ Domain Specificity of MAP3K Family Members, MLK and Tak1, for JNK Signaling in Drosophila

Stronach, Beth; Lennox, Ashley L.; Garlena, Rebecca A.
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Português
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A highly diverse set of protein kinases functions as early responders in the mitogen- and stress-activated protein kinase (MAPK/SAPK) signaling pathways. For instance, humans possess 14 MAPK kinase kinases (MAP3Ks) that activate Jun kinase (JNK) signaling downstream. A major challenge is to decipher the selective and redundant functions of these upstream MAP3Ks. Taking advantage of the relative simplicity of Drosophila melanogaster as a model system, we assessed MAP3K signaling specificity in several JNK-dependent processes during development and stress response. Our approach was to generate molecular chimeras between two MAP3K family members, the mixed lineage kinase, Slpr, and the TGF-β activated kinase, Tak1, which share 32% amino acid identity across the kinase domain but otherwise differ in sequence and domain structure, and then test the contributions of various domains for protein localization, complementation of mutants, and activation of signaling. We found that overexpression of the wild-type kinases stimulated JNK signaling in alternate contexts, so cells were capable of responding to both MAP3Ks, but with distinct outcomes. Relative to wild-type, the catalytic domain swaps compensated weakly or not at all, despite having a shared substrate...

‣ Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) Study

Hägg, Sara; Skogsberg, Josefin; Lundström, Jesper; Noori, Peri; Nilsson, Roland; Zhong, Hua; Maleki, Shohreh; Shang, Ming-Mei; Brinne, Björn; Bradshaw, Maria; Bajic, Vladimir B.; Samnegård, Ann; Silveira, Angela; Gigante, Bruna; Leander, Karin; de Fai
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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46.73514%
Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n = 66/tissue) and atherosclerotic and unaffected arterial wall (n = 40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n = 15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n = 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n = 49/48) and one visceral fat (n = 59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P = 0.008 and P = 0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably...

‣ An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits

Zillikens, M. Carola; Farber, Charles R.; Demissie, Serkalem; Soranzo, Nicole; Bianchi, Estelle N.; Grundberg, Elin; Estrada, Karol; Zhou, Yanhua; van Nas, Atila; Moffatt, Miriam F.; Zhai, Guangju; van Meurs, Joyce B.; Pols, Huibert A. P.; Price, Roger I.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.661028), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them...

‣ Filamin B Regulates Chondrocyte Proliferation and Differentiation through Cdk1 Signaling

Hu, Jianjun; Lu, Jie; Lian, Gewei; Zhang, Jingping; Hecht, Jonathan L.; Sheen, Volney L.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Humans who harbor loss of function mutations in the actin-associated filamin B (FLNB) gene develop spondylocarpotarsal syndrome (SCT), a disorder characterized by dwarfism (delayed bone formation) and premature fusion of the vertebral, carpal and tarsal bones (premature differentiation). To better understand the cellular and molecular mechanisms governing these seemingly divergent processes, we generated and characterized FlnB knockdown ATDC5 cell lines. We found that FlnB knockdown led to reduced proliferation and enhanced differentiation in chondrocytes. Within the shortened growth plate of postnatal FlnB−/− mice long bone, we observed a similarly progressive decline in the number of rapidly proliferating chondrocytes and premature differentiation characterized by an enlarged prehypertrophic zone, a widened Col2a1+/Col10a1+ overlapping region, but relatively reduced hypertrophic zone length. The reduced chondrocyte proliferation and premature differentiation were, in part, attributable to enhanced G2/M phase progression, where fewer FlnB deficient ATDC5 chondrocytes resided in the G2/M phase of the cell cycle. FlnB loss reduced Cdk1 phosphorylation (an inhibitor of G2/M phase progression) and Cdk1 inhibition in chondrocytes mimicked the null FlnB...

‣ Deletion of Prepl Causes Growth Impairment and Hypotonia in Mice

Lone, Anna Mari; Leidl, Mathias; McFedries, Amanda K.; Horner, James W.; Creemers, John; Saghatelian, Alan
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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Genetic studies of rare diseases can identify genes of unknown function that strongly impact human physiology. Prolyl endopeptidase-like (PREPL) is an uncharacterized member of the prolyl peptidase family that was discovered because of its deletion in humans with hypotonia-cystinuria syndrome (HCS). HCS is characterized by a number of physiological changes including diminished growth and neonatal hypotonia or low muscle tone. HCS patients have deletions in other genes as well, making it difficult to tease apart the specific role of PREPL. Here, we develop a PREPL null (PREPL−/−) mouse model to address the physiological role of this enzyme. Deletion of exon 11 from the Prepl gene, which encodes key catalytic amino acids, leads to a loss of PREPL protein as well as lower Prepl mRNA levels. PREPL−/− mice have a pronounced growth phenotype, being significantly shorter and lighter than their wild type (PREPL+/+) counterparts. A righting assay revealed that PREPL−/− pups took significantly longer than PREPL+/+ pups to right themselves when placed on their backs. This deficit indicates that PREPL−/− mice suffer from neonatal hypotonia. According to these results, PREPL regulates growth and neonatal hypotonia in mice, which supports the idea that PREPL causes diminished growth and neonatal hypotonia in humans with HCS. These animals provide a valuable asset in deciphering the underlying biochemical...

‣ Optical control of mammalian endogenous transcription and epigenetic states

Brigham, Mark Daniel
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation
Português
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The dynamic nature of gene expression enables cellular programming, homeostasis and environmental adaptation in living systems. Dissection of causal gene functions in cellular and organismal processes therefore necessitates approaches that enable spatially and temporally precise modulation of gene expression. Recently, a variety of microbial and plant-derived light-sensitive proteins have been engineered as optogenetic actuators, enabling high-precision spatiotemporal control of many cellular functions. However, versatile and robust technologies that enable optical modulation of transcription in the mammalian endogenous genome remain elusive. Here we describe the development of light-inducible transcriptional effectors (LITEs), an optogenetic two-hybrid system integrating the customizable TALE DNA-binding domain with the light-sensitive cryptochrome 2 protein and its interacting partner CIB1 from Arabidopsis thaliana. LITEs do not require additional exogenous chemical cofactors, are easily customized to target many endogenous genomic loci, and can be activated within minutes with reversibility. LITEs can be packaged into viral vectors and genetically targeted to probe specific cell populations. We have applied this system in primary mouse neurons...

‣ Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations

Demirkan, Ayşe; van Duijn, Cornelia M.; Ugocsai, Peter; Isaacs, Aaron; Pramstaller, Peter P.; Liebisch, Gerhard; Wilson, James F.; Johansson, Åsa; Rudan, Igor; Aulchenko, Yurii S.; Kirichenko, Anatoly V.; Janssens, A. Cecile J. W.; Jansen, Ritsert C.; G
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids \((smallest P-value = 9.88×10^{−204})\) and 10 loci for sphingolipids \((smallest P-value = 3.10 \times 10^{-57})\). After a correction for multiple comparisons \((P-value<2.2×10^{−9})\), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2...

‣ Neuronal and Molecular Basis of Nociception and Thermosensation in Drosophila melanogaster

Zhong, Lixian
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2011 Português
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46.67689%

From insects to mammals, the ability to constantly sense environmental stimuli is essential for the survival of most living organisms. Most animals have nocifensive behaviors towards extreme temperatures, mechanical stimuli or irritant chemicals that are considered to be noxious. Nociception is defined as the neural encoding and processing of noxious stimuli. This process starts from the activation of pain detecting peripheral sensory neurons (nociceptors) that can detect noxious mechanical, thermal or chemical stimuli. On the other hand, animals also have the ability to discriminate innocuous temperatures and to direct their locomotions to their favorable environmental temperatures and this behavior is called thermotaxis.

In this study, I used Drosophila melanogasteras a genetic model organism to study the molecular and cellular basis of nociception and thermotaxis. Drosophila larvae exhibit a stereotyped defensive behavior in response to nociceptive stimuli (termed nocifensive escape locomotion behavior, NEL). Using this behavior as a readout, we manipulated the neuronal activities of periphery sensory Type II multidendritic neurons and have identified a specific class of neurons, class IV multidendritic neurons...

‣ Structural Dynamics and Novel Biological Function of Topoisomerase 2

Chen, Yu-tsung Shane
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2015 Português
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Eukaryotic Topoisomerase 2 is an essential enzyme that solves DNA topological problems such as DNA knotting, catenation, and supercoiling. It alters the DNA topology by introducing transient double strand break in one DNA duplex as a gate for the passage of another DNA duplex. Two different aspects of studies about eukaryotic Topoisomerase 2 will be covered in this thesis. In the first half of the thesis, we investigated conformational changes of human Topoisomerase 2 (hsTop2) in the presence of cofactors and inhibitors. In the second half, we focused on an unknown regulatory function in the C-terminal domain (CTD) of Drosophila Topoisomerase 2 (Top2).

In the project of studying enzyme conformational changes, we adapted a previously developed methodology, Pulse-Alkylation Mass Spectrometry, with monobromobimane to study the protein dynamics of hsTop2. Using this method, we captured the evidence of conformational changes in the presence of ATP and Mg2+ or the Top2 inhibitor, ICRF-193 which were not previously observed. Last, by using CTD truncated hsTop2, the increasing reactivity of Cys427 suggested the CTD domain might be tethered adjacent to the core enzyme.

Following the study of enzyme conformational changes...

‣ The Origin and Evolution of Viruses as Molecular Organisms

Claudiu I. Bandea
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
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Viruses are the most abundant life forms and the repertoire of viral genes is greater than that of cellular genes. It is also evident that viruses have played a major role in driving cellular evolution, and yet, viruses are not part of mainstream biology, nor are they included in the Tree of Life. A reason for this major paradox in biology is the misleading dogma of viruses as viral particles and their enigmatic evolutionary origin. This article presents an alternative view about the nature of viruses based on their properties during the intracellular stage of their life cycle, when viruses express features comparable to those of many parasitic cellular species. Supporting this view about the nature of viruses is a novel hypothetical evolutionary model for their origin from parasitic cellular species that fused with their host cells. By losing their membrane and cellular structure within the host cell, these new types of parasitic species gained full access to precursors for the synthesis of their specific molecules and to the host’s information processing machineries, such as translation, which created unique parasitic and evolutionary opportunities. To identify viruses during their intracellular stage of their life cycle, in which their specific molecules are free or dispersed within the host cell...

‣ A Unifying Scenario on the Origin and Evolution of Cellular and Viral Domains

Claudiu I. Bandea
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
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The cellular theory on the nature of life has been one of the first major advancements in biology. Viruses, however, are the most abundant life forms, and their exclusion from mainstream biology and the Tree of Life (TOL) is a major paradox in biology. This article presents a broad, unifying scenario on the origin and evolution of cellular and viral domains that challenges the conventional views about the history of life and supports a TOL that includes viruses. Co-evolution of viruses and their host cells has led to some of the most remarkable developments and transitions in the evolution of life, including the origin of non-coding DNA as a genomic protective device against viral insertion damage. However, one of the major fundamental evolutionary developments driven by viruses was probably the origin of cellular domains - Bacteria, Archaea and Eukarya - from the Last Universal Common Ancestor (LUCA) lineage, by evolving anti-fusion mechanisms. Consistent with a novel fusion/fission model for the population mode of evolution of LUCA, this paper presents a “cell-like world” model for the origin of life. According to this model the evolution of coupled replication, transcription and translation system (RT&T) occurred within non-living cell-like compartments (CCs). In this model...

‣ The genetics of mental illness: implications for practice

Hyman,Steven E.
Fonte: World Health Organization Publicador: World Health Organization
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2000 Português
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Many of the comfortable and relatively simple models of the nature of mental disorders, their causes and their neural substrates now appear quite frayed. Gone is the idea that symptom clusters, course of illness, family history and treatment response would coalesce in a simple way to yield valid diagnoses. Also too simple was the concept, born of early pharmacological successes, that abnormal levels of one or more neurotransmitters would satisfactorily explain the pathogenesis of depression or schizophrenia. Gone is the notion that there is a single gene that causes any mental disorder or determines any behavioural variant. The concept of the causative gene has been replaced by that of genetic complexity, in which multiple genes act in concert with non-genetic factors to produce a risk of mental disorder. Discoveries in genetics and neuroscience can be expected to lead to better models that provide improved representation of the complexity of the brain and behaviour and the development of both. There are likely to be profound implications for clinical practice. The complex genetics of risk should reinvigorate research on the epidemiology and classification of mental disorders and explain the complex patterns of disease transmission within families. Knowledge of the timing of the expression of risk genes during brain development and of their function should not only contribute to an understanding of gene action and the pathophysiology of disease but should also help to direct the search for modifiable environmental risk factors that convert risk into illness. The function of risk genes can only become comprehensible in the context of advances at the molecular...