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Dynamics of different-sized solid-state nanocrystals as tracers for a drug-delivery system in the interstitium of a human tumor xenograft

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BREAST CANCER RESEARCH 2009年第4期11卷 1-9页

作者： Kawai, Masaaki Higuchi, Hideo Takeda, Motohiro Kobayashi, Yoshio Ohuchi, Noriaki Tohoku Univ Div Surg Oncol Grad Sch Med Aoba Ku Sendai Miyagi 9808574 Japan Univ Tokyo Dept Phys Grad Sch Sci Bunkyo Ku Tokyo 1130033 Japan Tohoku Univ Grad Sch Med Dept Nanomed Sci Aoba Ku Sendai Miyagi 9808574 Japan Ibaraki Univ Coll Engn Dept Biomol Funct Engn Hitachi Ibaraki 3168511 Japan

Introduction Recent anticancer drugs have been made larger to pass selectively through tumor vessels and stay in the interstitium. Understanding drug movement in association with its size at the single-molecule level and estimating the time needed to reach the targeted organ is indispensable for optimizing drug delivery because single cell-targeted therapy is the ongoing paradigm. This report describes the tracking of single solid nanoparticles in tumor xenografts and the estimation of arrival time. Methods Different-sized nanoparticles measuring 20, 40, and 100 nm were injected into the tail vein of the female Balb/c nu/nu mice bearing human breast cancer on their backs. The movements of the nanoparticles were visualized through the dorsal skin-fold chamber with the high-speed confocal microscopy that we manufactured. Results An analysis of the particle trajectories revealed diffusion to be inversely related to the particle size and position in the tumor, whereas the velocity of the directed movement was related to the position. The difference in the velocity was the greatest for 40-nm particles in the perivascular to the intercellular region: difference = 5.8 nm/s. The arrival time of individual nanoparticles at tumor cells was simulated. The estimated times for the 20-, 40-, and 100-nm particles to reach the tumor cells were 158.0, 218.5, and 389.4 minutes, respectively, after extravasation. Conclusions This result suggests that the particle size can be individually designed for each goal. These data and methods are also important for understanding drug pharmacokinetics. Although this method may be subject to interference by surface molecules attached on the particles, it has the potential to elucidate the pharmacokinetics involved in constructing novel drug-delivery systems involving cell-targeted therapy.

关键词： additional data file Tumor Vasculature Interstitial Region Piezo Actuator Random Diffusion

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Genome-wide deletion mutant analysis reveals genes required for respiratory growth, mitochondrial genome maintenance and mitochondrial protein synthesis in Saccharomyces cerevisiae

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GENOME BIOLOGY 2009年第9期10卷 1-18页

作者： Merz, Sandra Westermann, Benedikt Univ Bayreuth Inst Zellbiol D-95440 Bayreuth Germany Univ Bayreuth BZMB D-95440 Bayreuth Germany

Background: The mitochondrial respiratory chain produces metabolic energy by oxidative phosphorylation. Biogenesis of the respiratory chain requires the coordinated expression of two genomes: the nuclear genome encoding the vast majority of mitochondrial proteins, and the mitochondrial genome encoding a handful of mitochondrial proteins. The understanding of the molecular processes contributing to respiratory chain assembly and maintenance requires the systematic identification and functional analysis of the genes involved. Results: We pursued a systematic, genome-wide approach to define the sets of genes required for respiratory activity and maintenance and expression of the mitochondrial genome in yeast. By comparative gene deletion analysis we found an unexpected phenotypic plasticity among respiratory-deficient mutants, and we identified ten previously uncharacterized genes essential for respiratory growth (RRG1 through RRG10). Systematic functional analysis of 319 respiratory-deficient mutants revealed 16 genes essential for maintenance of the mitochondrial genome, 88 genes required for mitochondrial protein translation, and 10 genes required for expression of specific mitochondrial gene products. A group of mutants acquiring irreversible damage compromising respiratory capacity includes strains defective in assembly of the cytochrome c oxidase that were found to be particularly sensitive to aging. Conclusions: These data advance the understanding of the molecular processes contributing to maintenance of the mitochondrial genome, mitochondrial protein translation, and assembly of the respiratory chain. They revealed a number of previously uncharacterized components, and provide a comprehensive picture of the molecular processes required for respiratory activity in a simple eukaryotic cell.

关键词： Mitochondrial Genome additional data file Respiratory Growth Mitochondrial Protein Synthesis Mitochondrial Translation

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Clustering of genes into regulons using integrated modeling-COGRIM

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GENOME BIOLOGY 2007年第1期8卷 1-14页

作者： Chen, Guang Jensen, Shane T. Stoeckert, Christian J., Jr. Univ Penn Ctr Bioinformat Philadelphia PA 19104 USA Univ Penn Dept Bioengn Philadelphia PA 19104 USA Univ Penn Dept Stat Wharton Sch Philadelphia PA 19104 USA Univ Penn Dept Genet Sch Med Philadelphia PA 19104 USA

We present a Bayesian hierarchical model and Gibbs Sampling implementation that integrates gene expression, ChlP binding, and transcription factor motif data in a principled and robust fashion. COGRIM was applied to both unicellular and mammalian organisms under different scenarios of available data. In these applications, we demonstrate the ability to predict gene-transcription factor interactions with reduced numbers of false-positive findings and to make predictions beyond what is obtained when single types of data are considered.

关键词： Transcription Factor Binding Site additional data file Serum Response Factor Position Weight Matrix Network Component Analysis

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Many LINE1 elements contribute to the transcriptome of human somatic cells

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GENOME BIOLOGY 2009年第9期10卷 1-18页

作者： Rangwala, Sanjida H. Zhang, Lili Kazazian, Haig H., Jr. Univ Penn Sch Med Dept Genet Philadelphia PA 19104 USA

Background: While LINE1 (L1) retroelements comprise nearly 20% of the human genome, the majority are thought to have been rendered transcriptionally inactive, due to either mutation or epigenetic suppression. How many L1 elements 'escape' these forms of repression and contribute to the transcriptome of human somatic cells? We have cloned out expressed sequence tags corresponding to the 5' and 3' flanks of L1 elements in order to characterize the population of elements that are being actively transcribed. We also examined expression of a select number of elements in different individuals. Results: We isolated expressed sequence tags from human lymphoblastoid cell lines corresponding to 692 distinct L1 element sites, including 410 full-length elements. Four of the expression tagged sites corresponding to full-length elements from the human specific L1Hs subfamily were examined in European-American individuals and found to be differentially expressed in different family members. Conclusions: A large number of different L1 element sites are expressed in human somatic tissues, and this expression varies among different individuals. Paradoxically, few elements were tagged at high frequency, indicating that the majority of expressed L1s are transcribed at low levels. Based on our preliminary expression studies of a limited number of elements in a single family, we predict a significant degree of inter-individual transcript-level polymorphism in this class of sequence.

关键词： additional data file Cytosine Methylation Lymphoblastoid Cell Line Picotiter Plate Sense Promoter

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Large scale variation in Enterococcus faecalis illustrated by the genome analysis of strain OGIRF

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GENOME BIOLOGY 2008年第7期9卷 1-16页

作者： Bourgogne, Agathe Garsin, Danielle A. Qin, Xiang Singh, Kavindra V. Sillanpaa, Jouko Yerrapragada, Shailaja Ding, Yan Dugan-Rocha, Shannon Buhay, Christian Shen, Hua Chen, Guan Williams, Gabrielle Muzny, Donna Maadani, Arash Fox, Kristina A. Gioia, Jason Chen, Lei Shang, Yue Arias, Cesar A. Nallapareddy, Sreedhar R. Zhao, Meng Prakash, Vittal P. Chowdhury, Shahreen Jiang, Huaiyang Gibbs, Richard A. Murray, Barbara E. Highlander, Sarah K. Weinstock, George M. Univ Texas Houston Sch Med Dept Med Div Infect Dis Houston TX 77030 USA Univ Texas Houston Sch Med Ctr Study Emerging & Reemerging Pathogens Houston TX 77030 USA Univ Texas Houston Sch Med Dept Microbiol & Mol Genet Houston TX 77030 USA Baylor Coll Med Human Genome Sequencing Ctr Houston TX 77030 USA Baylor Coll Med Dept Mol & Human Genet Houston TX 77030 USA Baylor Coll Med Dept Mol Virol & Microbiol Houston TX 77030 USA

Background: Enterococcus faecalis has emerged as a major hospital pathogen. To explore its diversity, we sequenced E. faecalis strain OGIRF, which is commonly used for molecular manipulation and virulence studies. Results: The 2,739,625 base pair chromosome of OGIRF was found to contain approximately 232 kilobases unique to this strain compared to V583, the only publicly available sequenced strain. Almost no mobile genetic elements were found in OGIRF. The 64 areas of divergence were classified into three categories. First, OGIRF carries 39 unique regions, including 2 CRISPR loci and a new WxL locus. Second, we found nine replacements where a sequence specific to V583 was substituted by a sequence specific to OGIRF. For example, the iol operon of OGIRF replaces a possible prophage and the vanB transposon in V583. Finally, we found 16 regions that were present in V583 but missing from OGIRF, including the proposed pathogenicity island, several probable prophages, and the cpsCDEFGHIJK capsular polysaccharide operon. OGIRF was more rapidly but less frequently lethal than V583 in the mouse peritonitis model and considerably outcompeted V583 in a murine model of urinary tract infections. Conclusion: E. faecalis OGIRF carries a number of unique loci compared to V583, but the almost complete lack of mobile genetic elements demonstrates that this is not a defining feature of the species. additionally, OGIRF's effects in experimental models suggest that mediators of virulence may be diverse between different E. faecalis strains and that virulence is not dependent on the presence of mobile genetic elements.

关键词： additional data file Brain Heart Infusion Mobile Genetic Element Fusidic Acid Brain Heart Infusion Agar

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Estrogen, not intrinsic aging, is the major regulator of delayed human wound healing in the elderly

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GENOME BIOLOGY 2008年第5期9卷 1-17页

作者： Hardman, Matthew J. Ashcroft, Gillian S. Univ Manchester Fac Life Sci Manchester M13 9PT Lancs England

Background: Multiple processes have been implicated in age-related delayed healing, including altered gene expression, intrinsic cellular changes, and changes in extracellular milieu (including hormones). To date, little attempt has been made to assess the relative contribution of each of these processes to a human aging phenomenon. The objective of this study is to determine the contribution of estrogen versus aging in age-associated delayed human wound healing. Results: Using an Affymetrix microarray-based approach we show that the differences in gene expression between male elderly and young human wounds are almost exclusively estrogen regulated. Expression of 78 probe sets was significantly decreased and 10 probe sets increased in wounds from elderly subjects (with a fold change greater than 7). A total of 83% of down-regulated probe sets and 80% of up-regulated probe sets were estrogen-regulated. Differentially regulated genes were validated at the level of gene and protein expression, with genes identified as estrogen-regulated in human confirmed as estrogen-dependent in young estrogen depleted mice in vivo. Moreover, direct estrogen regulation is demonstrated for three array-identified genes, Sele, Lypd3 and Arg1, in mouse cells in vitro. Conclusion: These findings have clear implications for our understanding of age-associated cellular changes in the context of wound healing, the latter acting as a paradigm for other age-related repair and maintenance processes, and suggest estrogen has a more profound influence on aging than previously thought.

关键词： Elderly Subject additional data file Arginase Secretory Leukocyte Protease Inhibitor Expression Analysis Systematic Explorer

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Cross genome phylogenetic analysis of human and Drosophila G protein-coupled receptors:: application to functional annotation of orphan receptors -: art. no. 106

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BMC GENOMICS 2005年第1期6卷 1-20页

作者： Metpally, RPR Sowdhamini, R Tata Inst Fundamental Res Natl Ctr Biol Sci Bangalore 560065 Karnataka India

Background: The cell-membrane G-protein coupled receptors (GPCRs) are one of the largest known superfamilies and are the main focus of intense pharmaceutical research due to their key role in cell physiology and disease. A large number of putative GPCRs are 'orphans' with no identified natural ligands. The first step in understanding the function of orphan GPCRs is to identify their ligands. Phylogenetic clustering methods were used to elucidate the chemical nature of receptor ligands, which led to the identification of natural ligands for many orphan receptors. We have clustered human and Drosophila receptors with known ligands and orphans through cross genome phylogenetic analysis and hypothesized higher relationship of co-clustered members that would ease ligand identification, as related receptors share ligands with similar structure or class. Results: Cross-genome phylogenetic analyses were performed to identify eight major groups of GPCRs dividing them into 32 clusters of 371 human and 113 Drosophila proteins (excluding olfactory, taste and gustatory receptors) and reveal unexpected levels of evolutionary conservation across human and Drosophila GPCRs. We also observe that members of human chemokine receptors, involved in immune response, and most of nucleotide-lipid receptors (except opsins) do not have counterparts in Drosophila. Similarly, a group of Drosophila GPCRs (methuselah receptors), associated in aging, is not present in humans. Conclusion: Our analysis suggests ligand class association to 52 unknown Drosophila receptors and 95 unknown human GPCRs. A higher level of phylogenetic organization was revealed in which clusters with common domain architecture or cellular localization or ligand structure or chemistry or a shared function are evident across human and Drosophila genomes. Such analyses will prove valuable for identifying the natural ligands of Drosophila and human orphan receptors that can lead to a better understanding of physiological and p

关键词： additional data file Octopamine Orphan Receptor Separate Branch Frizzle Receptor

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Coverage and error models of protein-protein interaction data by directed graph analysis

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GENOME BIOLOGY 2007年第9期8卷 1-14页

作者： Chiang, Tony Scholtens, Denise Sarkar, Deepayan Gentleman, Robert Huber, Wolfgang European Bioinformat Inst EMBL Cambridge CB10 1SD England Fred Hutchinson Canc Res Ctr Computat Biol Grp Seattle WA 98109 USA Northwestern Univ Dept Prevent Med Chicago IL 60611 USA

Using a directed graph model for bait to prey systems and a multinomial error model, we assessed the error statistics in all published large-scale datasets for Saccharomyces cerevisiae and characterized them by three traits: the set of tested interactions, artifacts that lead to false-positive or false-negative observations, and estimates of the stochastic error rates that affect the data. These traits provide a prerequisite for the estimation of the protein interactome and its modules.

关键词： additional data file Protein Pair Stochastic Error Protein Interaction data Bait Protein

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Broad network-based predictability of Saccharomyces cerevisiae gene loss-of-function phenotypes

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GENOME BIOLOGY 2007年第12期8卷 1-20页

作者： McGary, Kriston L. Lee, Insuk Marcotte, Edward M. Univ Texas Austin Inst Cellular & Mol Biol Ctr Syst & Synthet Biol Austin TX 78712 USA Univ Texas Austin Dept Chem & Biochem Austin TX 78712 USA

We demonstrate that loss-of-function yeast phenotypes are predictable by guilt-by-association in functional gene networks. Testing 1,102 loss-of-function phenotypes from genome-wide assays of yeast reveals predictability of diverse phenotypes, spanning cellular morphology, growth, metabolism, and quantitative cell shape features. We apply the method to extend a genome-wide screen by predicting, then verifying, genes whose disruption elongates yeast cells, and to predict human disease genes. To facilitate network-guided screens, a web server is available http://***.

关键词： additional data file Functional Network Yeast Gene Human Disease Gene Functional Coherence

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Insertion bias and purifying selection of retrotransposons in the Arabidopsis thaliana genome -: art. no. R79

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GENOME BIOLOGY 2004年第10期5卷 1-10页

作者： Pereira, V Univ London Imperial Coll Sci Technol & Med Ascot SL5 7PY Berks England

Background: Genome evolution and size variation in multicellular organisms are profoundly influenced by the activity of retrotransposons. In higher eukaryotes with compact genomes retrotransposons are found in lower copy numbers than in larger genomes, which could be due to either suppression of transposition or to elimination of insertions, and are non-randomly distributed along the chromosomes. The evolutionary mechanisms constraining retrotransposon copy number and chromosomal distribution are still poorly understood. Results: I investigated the evolutionary dynamics of long terminal repeat ( LTR)-retrotransposons in the compact Arabidopsis thaliana genome, using an automated method for obtaining genomewide, age and physical distribution profiles for different groups of elements, and then comparing the distributions of young and old insertions. Elements of the Pseudoviridae family insert randomly along the chromosomes and have been recently active, but insertions tend to be lost from euchromatic regions where they are less likely to fix, with a half-life estimated at approximately 470,000 years. In contrast, members of the Metaviridae ( particularly Athila) preferentially target heterochromatin, and were more active in the past. Conclusion: Diverse evolutionary mechanisms have constrained both the copy number and chromosomal distribution of retrotransposons within a single genome. In A. thaliana, their nonrandom genomic distribution is due to both selection against insertions in euchromatin and preferential targeting of heterochromatin. Constant turnover of euchromatic insertions and a decline in activity for the elements that target heterochromatin have both limited the contribution of retrotransposon DNA to genome size expansion in A. thaliana.

关键词： Long Terminal Repeat additional data file Pericentromeric Region Pericentromeric Heterochromatin Long Terminal Repeat Sequence

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