PubMed Central (PMC3 - NLM DTD)
(2,081,148 recursos)
Archive of life sciences journal literature at the U.S. National Institutes of Health (NIH), developed and managed by NIH's National Center for Biotechnology Information (NCBI) in the National Library of Medicine (NLM).
Mostrando recursos 161 - 180 de 184,040
161.
Sampling motifs on phylogenetic trees - Li, Xiaoman; Wong, Wing H.
We present a method to find motifs by simultaneously using the overrepresentation property and the evolutionary conservation property of motifs. This method is applicable to divergent species where alignment is unreliable, which overcomes a major limitation of the current methods. The method has been applied to search regulatory motifs in four yeast species based on ChIP-chip data in Saccharomyces cerevisiae and obtained 20% higher accuracy than the best current methods. We also discovered cis-regulatory elements that govern the tight regulation of ribosomal protein genes in two distantly related insects by using this method. These results demonstrate that our method will...
162.
Efficient synthetic inhibitors of anthrax lethal factor - Forino, Martino; Johnson, Sherida; Wong, Thiang Y.; Rozanov, Dmitri V.; Savinov, Alexei Y.; Li, Wei; Fattorusso, Roberto; Becattini, Barbara; Orry, Andrew J.; Jung, Dawoon; Abagyan, Ruben A.; Smith, Jeffrey W.; Alibek, Ken; Liddington, Robert C.; Strongin, Alex Y.; Pellecchia, Maurizio
Inhalation anthrax is a deadly disease for which there is currently no effective treatment. Bacillus anthracis lethal factor (LF) metalloproteinase is an integral component of the tripartite anthrax lethal toxin that is essential for the onset and progression of anthrax. We report here on a fragment-based approach that allowed us to develop inhibitors of LF. The small-molecule inhibitors we have designed, synthesized, and tested are highly potent and selective against LF in both in vitro tests and cell-based assays. These inhibitors do not affect the prototype human metalloproteinases that are structurally similar to LF. Initial in vivo evaluation of postexposure...
163.
Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene - Shu, Weiguo; Cho, Julie Y.; Jiang, Yuhui; Zhang, Minhua; Weisz, Donald; Elder, Gregory A.; Schmeidler, James; De Gasperi, Rita; Sosa, Miguel A. Gama; Rabidou, Donald; Santucci, Anthony C.; Perl, Daniel; Morrisey, Edward; Buxbaum, Joseph D.
Neurobiology of speech and language has previously been studied in the KE family, in which half of the members have severe impairment in both speech and language. The gene responsible for the phenotype was mapped to chromosome 7q31 and identified as the FOXP2 gene, coding for a transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain. Because of linkage studies implicating 7q31 in autism, where language impairment is a component of the disorder, and in specific language impairment, FOXP2 has also been considered as a potential susceptibility locus for the language deficits in autism and/or specific language impairment....
164.
Cardiac glycosides inhibit TNF-?/NF-?B signaling by blocking recruitment of TNF receptor-associated death domain to the TNF receptor - Yang, Qingfeng; Huang, Wei; Jozwik, Catherine; Lin, Yong; Glasman, Mirta; Caohuy, Hung; Srivastava, Meera; Esposito, Dominic; Gillette, William; Hartley, James; Pollard, Harvey B.
Digitoxin and structurally related cardiac glycoside drugs potently block activation of the TNF-?/NF-?B signaling pathway. We have hypothesized that the mechanism might be discovered by searching systematically for selective inhibitory action through the entire pathway. We report that the common action of these drugs is to block the TNF-?-dependent binding of TNF receptor 1 to TNF receptor-associated death domain. This drug action can be observed with native cells, such as HeLa, and reconstituted systems prepared in HEK293 cells. All other antiinflammatory effects of digitoxin on NF-?B and c-Jun N-terminal kinase pathways appear to follow from the blockade of this initial...
165.
High-resolution genomic profiles of human lung cancer - Tonon, Giovanni; Wong, Kwok-Kin; Maulik, Gautam; Brennan, Cameron; Feng, Bin; Zhang, Yunyu; Khatry, Deepak B.; Protopopov, Alexei; You, Mingjian James; Aguirre, Andrew J.; Martin, Eric S.; Yang, Zhaohui; Ji, Hongbin; Chin, Lynda; DePinho, Ronald A.
Lung cancer is the leading cause of cancer mortality worldwide, yet there exists a limited view of the genetic lesions driving this disease. In this study, an integrated high-resolution survey of regional amplifications and deletions, coupled with gene-expression profiling of non-small-cell lung cancer subtypes, adenocarcinoma and squamous-cell carcinoma (SCC), identified 93 focal copy-number alterations, of which 21 span <0.5 megabases and contain a median of five genes. Whereas all known lung cancer genes/loci are contained in the dataset, most of these recurrent copy-number alterations are previously uncharacterized and include high-amplitude amplifications and homozygous deletions. Notably, despite their distinct histopathological phenotypes,...
166.
A modular microfluidic architecture for integrated biochemical analysis - Shaikh, Kashan A.; Ryu, Kee Suk; Goluch, Edgar D.; Nam, Jwa-Min; Liu, Juewen; Thaxton, C. Shad; Chiesl, Thomas N.; Barron, Annelise E.; Lu, Yi; Mirkin, Chad A.; Liu, Chang
Microfluidic laboratory-on-a-chip (LOC) systems based on a modular architecture are presented. The architecture is conceptualized on two levels: a single-chip level and a multiple-chip module (MCM) system level. At the individual chip level, a multilayer approach segregates components belonging to two fundamental categories: passive fluidic components (channels and reaction chambers) and active electromechanical control structures (sensors and actuators). This distinction is explicitly made to simplify the development process and minimize cost. Components belonging to these two categories are built separately on different physical layers and can communicate fluidically via cross-layer interconnects. The chip that hosts the electromechanical control structures is...
167.
Analyzing a bioterror attack on the food supply: The case of botulinum toxin in milk - Wein, Lawrence M.; Liu, Yifan
We developed a mathematical model of a cows-to-consumers supply chain associated with a single milk-processing facility that is the victim of a deliberate release of botulinum toxin. Because centralized storage and processing lead to substantial dilution of the toxin, a minimum amount of toxin is required for the release to do damage. Irreducible uncertainties regarding the doseresponse curve prevent us from quantifying the minimum effective release. However, if terrorists can obtain enough toxin, and this may well be possible, then rapid distribution and consumption result in several hundred thousand poisoned individuals if detection from early symptomatics is not timely. Timely...
168.
The structural basis of androgen receptor activation: Intramolecular and intermolecular aminocarboxy interactions - Schaufele, Fred; Carbonell, Xavier; Guerbadot, Martin; Borngraeber, Sabine; Chapman, Mark S.; Ma, Aye Aye K.; Miner, Jeffrey N.; Diamond, Marc I.
Nuclear receptors (NRs) are ligand-regulated transcription factors important in human physiology and disease. In certain NRs, including the androgen receptor (AR), ligand binding to the carboxy-terminal domain (LBD) regulates transcriptional activation functions in the LBD and amino-terminal domain (NTD). The basis for NTDLBD communication is unknown but may involve NTDLBD interactions either within a single receptor or between different members of an AR dimer. Here, measurement of FRET between fluorophores attached to the NTD and LBD of the AR established that agonist binding initiated an intramolecular NTDLBD interaction in the nucleus and cytoplasm. This intramolecular folding was followed by AR...
169.
Single-molecule studies of repressorDNA interactions show long-range interactions - Wang, Y. M.; Tegenfeldt, Jonas O.; Reisner, W.; Riehn, R.; Guan, Xiao-Juan; Guo, Ling; Golding, Ido; Cox, Edward C.; Sturm, James; Austin, Robert H.
We have performed single-molecule studies of GFPLacI repressor proteins bound to bacteriophage ? DNA containing a 256 tandem lac operator insertion confined in nanochannels. An integrated photon molecular counting method was developed to determine the number of proteins bound to DNA. By using this method, we determined the saturated mean occupancy of the 256 tandem lac operators to be 13, which constitutes only 2.5% of the available sites. This low occupancy level suggests that the repressors influence each other even when they are widely separated, at distances on the order of 200 nm, or several DNA persistence lengths.
170.
Soluble epoxide hydrolase is a therapeutic target for acute inflammation - Schmelzer, Kara R.; Kubala, Lukas; Newman, John W.; Kim, In-Hae; Eiserich, Jason P.; Hammock, Bruce D.
As of 2004, >73 million people were prescribed antiinflammatory medication. Despite the extensive number of current products, many people still suffer from their diseases or the pharmacological properties (side effects) of the medications. Therefore, developing therapeutic strategies to treat inflammation remains an important endeavor. Here, we demonstrate that the soluble epoxide hydrolase (sEH) is a key pharmacologic target for treating acute systemic inflammation. Lipopolysaccharide-induced mortality, systemic hypotension, and histologically evaluated tissue injury were substantially diminished by administration of urea-based, small-molecule inhibitors of sEH to C57BL/6 mice. Moreover, sEH inhibitors decreased plasma levels of proinflammatory cytokines and nitric oxide metabolites while...
171.
An integrated functional genomics and metabolomics approach for defining poor prognosis in human neuroendocrine cancers - Ippolito, Joseph E.; Xu, Jian; Jain, Sanjay; Moulder, Krista; Mennerick, Steven; Crowley, Jan R.; Townsend, R. Reid; Gordon, Jeffrey I.
Human neuroendocrine (NE) cancers range from relatively indolent to highly aggressive. In this study, we combine functional genomics with metabolomics to identify features of NE cancers associated with a poor outcome. Analysis of GeneChip datasets of primary prostate tumors, as well as lymph node and liver metastases from transgenic mice with a NE cell cancer, plus derived NE cell lines yielded a signature of 446 genes whose expression is enriched in neoplastic mouse prostatic NE cells. This signature was used for in silico metabolic reconstructions of NE cell metabolism, directed liquid chromatography/tandem MS analysis of metabolites in prostatic NE tumors...
172.
Ephrin-B2 ligand is a functional receptor for Hendra virus and Nipah virus - Bonaparte, Matthew I.; Dimitrov, Antony S.; Bossart, Katharine N.; Crameri, Gary; Mungall, Bruce A.; Bishop, Kimberly A.; Choudhry, Vidita; Dimitrov, Dimiter S.; Wang, Lin-Fa; Eaton, Bryan T.; Broder, Christopher C.
Hendra virus (HeV) and Nipah virus (NiV) belong to the genus Henipavirus of the family Paramyxoviridae and are unique in that they exhibit a broad species tropism and cause fatal disease in both animals and humans. They infect cells through a pH-independent membrane fusion process mediated by their fusion and attachment glycoproteins. Previously, we demonstrated identical cell fusion tropisms for HeV and NiV and the protease-sensitive nature of their unknown cell receptor and identified a human cell line (HeLa-USU) that was nonpermissive for fusion and virus infection. Here, a microarray analysis was performed on the HeLa-USU cells, permissive HeLa-CCL2 cells,...
173.
APOBEC3G hypermutates genomic DNA and inhibits Ty1 retrotransposition in yeast - Schumacher, April J.; Nissley, Dwight V.; Harris, Reuben S.
Human cells harbor a variety of factors that function to block the proliferation of foreign nucleic acid. The APOBEC3G enzyme inhibits the replication of retroviruses by deaminating nascent retroviral cDNA cytosines to uracils, lesions that can result in lethal levels of hypermutation. Here, we demonstrate that APOBEC3G is capable of deaminating genomic cytosines in Saccharomyces cerevisiae. APOBEC3G expression caused a 20-fold increase in frequency of mutation to canavanine-resistance, which was further elevated in a uracil DNA glycosylase-deficient background. All APOBEC3G-induced base substitution mutations mapped to the nuclear CAN1 gene and were exclusively C/G ? T/A transition mutations within a 5?-CC...
174.
Restriction mapping in nanofluidic devices - Riehn, Robert; Lu, Manchun; Wang, Yan-Mei; Lim, Shuang Fang; Cox, Edward C.; Austin, Robert H.
We have performed restriction mapping of DNA molecules using restriction endonucleases in nanochannels with diameters of 100-200 nm. The location of the restriction reaction within the device is controlled by electrophoresis and diffusion of Mg2+ and EDTA. We have successfully used the restriction enzymes SmaI, SacI, and PacI, and have been able to measure the positions of restriction sites with a precision of ?1.5 kbp in 1 min using single DNA molecules.
175.
Adult mouse brain gene expression patterns bear an embryologic imprint - Zapala, Matthew A.; Hovatta, Iiris; Ellison, Julie A.; Wodicka, Lisa; Del Rio, Jo A.; Tennant, Richard; Tynan, Wendy; Broide, Ron S.; Helton, Rob; Stoveken, Barbara S.; Winrow, Christopher; Lockhart, Daniel J.; Reilly, John F.; Young, Warren G.; Bloom, Floyd E.; Lockhart, David J.; Barlow, Carrolee
The current model to explain the organization of the mammalian nervous system is based on studies of anatomy, embryology, and evolution. To further investigate the molecular organization of the adult mammalian brain, we have built a gene expression-based brain map. We measured gene expression patterns for 24 neural tissues covering the mouse central nervous system and found, surprisingly, that the adult brain bears a transcriptional imprint consistent with both embryological origins and classic evolutionary relationships. Embryonic cellular position along the anteriorposterior axis of the neural tube was shown to be closely associated with, and possibly a determinant of, the gene...
176.
Identification of mammalian arginyltransferases that modify a specific subset of protein substrates - Rai, Reena; Kashina, Anna
Posttranslational N-terminal protein arginylation, mediated by Arg-tRNA-protein transferase 1 (ATE1), is essential for cardiovascular development and angiogenesis in mammals but is nonessential in yeast. Evidence suggests that many proteins are arginylated in vivo in both mammals and yeast; however, in yeast, N-terminal arginylation can occur only on proteins bearing an N-terminal Asp or Glu, whereas in mammals, N-terminal Cys residues are also arginylation targets, suggesting that Cys arginylation contributes to the essential role of ATE1 in mammals. To date, all of the characterized forms of ATE1 in yeast and mammals have been shown to arginylate only Asp and Glu, leaving...
177.
Genetic interactions between [PSI+] and nonstop mRNA decay affect phenotypic variation - Wilson, Marenda A.; Meaux, Stacie; Parker, Roy; van Hoof, Ambro
Yeast strains can reversibly interconvert between [PSI+] and [psi-] states. The [PSI+] state is caused by a prion form of the translation termination factor eRF3. The [PSI+] state causes read-through at stop codons and can lead to phenotypic variation, although the molecular mechanisms causing those phenotypic changes remain unknown. We identify an interaction between [PSI+]-induced phenotypic variation and defects in nonstop mRNA decay. Nonstop mRNA decay is triggered when a ribosome reaches the 3? end of the transcript. In contrast, we observed little interaction between [PSI+]-induced phenotypic variation and defects in nonsense-mediated decay, which lead to suppression of premature stop...
178.
Dynamic pattern evolution on scale-free networks - Zhou, Haijun; Lipowsky, Reinhard
A general class of dynamic models on scale-free networks is studied by analytical methods and computer simulations. Each network consists of N vertices and is characterized by its degree distribution, P(k), which represents the probability that a randomly chosen vertex is connected to k nearest neighbors. Each vertex can attain two internal states described by binary variables or Ising-like spins that evolve in time according to local majority rules. Scale-free networks, for which the degree distribution has a power law tail P(k) ? k-?, are shown to exhibit qualitatively different dynamic behavior for ? < 5/2 and ? > 5/2,...
179.
Epigenetic differences arise during the lifetime of monozygotic twins - Fraga, Mario F.; Ballestar, Esteban; Paz, Maria F.; Ropero, Santiago; Setien, Fernando; Ballestar, Maria L.; Heine-Suñer, Damia; Cigudosa, Juan C.; Urioste, Miguel; Benitez, Javier; Boix-Chornet, Manuel; Sanchez-Aguilera, Abel; Ling, Charlotte; Carlsson, Emma; Poulsen, Pernille; Vaag, Allan; Stephan, Zarko; Spector, Tim D.; Wu, Yue-Zhong; Plass, Christoph; Esteller, Manel
Monozygous twins share a common genotype. However, most monozygotic twin pairs are not identical; several types of phenotypic discordance may be observed, such as differences in susceptibilities to disease and a wide range of anthropomorphic features. There are several possible explanations for these observations, but one is the existence of epigenetic differences. To address this issue, we examined the global and locus-specific differences in DNA methylation and histone acetylation of a large cohort of monozygotic twins. We found that, although twins are epigenetically indistinguishable during the early years of life, older monozygous twins exhibited remarkable differences in their overall content...
180.
Rational design of aggregation-resistant bioactive peptides: Reengineering human calcitonin - Fowler, Susan B.; Poon, Stephen; Muff, Roman; Chiti, Fabrizio; Dobson, Christopher M.; Zurdo, Jesús
A high propensity to aggregate into intractable deposits is a common problem limiting the production and use of many peptides and proteins in a wide range of biotechnological and pharmaceutical applications. Many therapeutic polypeptides are frequently abandoned at an early stage in their development because of problems with stability and aggregation. It has been shown recently that parameters describing the physicochemical properties of polypeptides can be used as predictors of protein aggregation. Here we demonstrate that these and similar tools can be applied to the rational redesign of bioactive molecules with a significantly reduced aggregation propensity without loss of physiological...
161.
