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1.  The bending of cell sheets - from folding to rolling 
BMC Biology  2011;9:90.
The bending of cell sheets plays a major role in multicellular embryonic morphogenesis. Recent advances are leading to a deeper understanding of how the biophysical properties and the force-producing behaviors of cells are regulated, and how these forces are integrated across cell sheets during bending. We review work that shows that the dynamic balance of apical versus basolateral cortical tension controls specific aspects of invagination of epithelial sheets, and recent evidence that tissue expansion by growth contributes to neural retinal invagination in a stem cell-derived, self-organizing system. Of special interest is the detailed analysis of the type B inversion in Volvox reported in BMC Biology by Höhn and Hallmann, as this is a system that promises to be particularly instructive in understanding morphogenesis of any monolayered spheroid system.
See research article: http://www.biomedcentral.com/1741-7007/9/89
doi:10.1186/1741-7007-9-90
PMCID: PMC3248374  PMID: 22206439
2.  Difficult phylogenetic questions: more data, maybe; better methods, certainly 
BMC Biology  2011;9:91.
Contradicting the prejudice that endosymbiosis is a rare phenomenon, Husník and co-workers show in BMC Biology that bacterial endosymbiosis has occured several times independently during insect evolution. Rigorous phylogenetic analyses, in particular using complex models of sequence evolution and an original site removal procedure, allow this conclusion to be established after eschewing inference artefacts that usually plague the positioning of highly divergent endosymbiont genomic sequences.
See research article http://www.biomedcentral.com/1741-7007/9/87
doi:10.1186/1741-7007-9-91
PMCID: PMC3248379  PMID: 22206462
3.  There is more than one way to turn a spherical cellular monolayer inside out: type B embryo inversion in Volvox globator 
BMC Biology  2011;9:89.
Background
Epithelial folding is a common morphogenetic process during the development of multicellular organisms. In metazoans, the biological and biomechanical processes that underlie such three-dimensional (3D) developmental events are usually complex and difficult to investigate. Spheroidal green algae of the genus Volvox are uniquely suited as model systems for studying the basic principles of epithelial folding. Volvox embryos begin life inside out and then must turn their spherical cell monolayer outside in to achieve their adult configuration; this process is called 'inversion.' There are two fundamentally different sequences of inversion processes in Volvocaceae: type A and type B. Type A inversion is well studied, but not much is known about type B inversion. How does the embryo of a typical type B inverter, V. globator, turn itself inside out?
Results
In this study, we investigated the type B inversion of V. globator embryos and focused on the major movement patterns of the cellular monolayer, cell shape changes and changes in the localization of cytoplasmic bridges (CBs) connecting the cells. Isolated intact, sectioned and fragmented embryos were analyzed throughout the inversion process using light microscopy, confocal laser scanning microscopy, scanning electron microscopy and transmission electron microscopy techniques. We generated 3D models of the identified cell shapes, including the localizations of CBs. We show how concerted cell-shape changes and concerted changes in the position of cells relative to the CB system cause cell layer movements and turn the spherical cell monolayer inside out. The type B inversion of V. globator is compared to the type A inversion in V. carteri.
Conclusions
Concerted, spatially and temporally coordinated changes in cellular shapes in conjunction with concerted migration of cells relative to the CB system are the causes of type B inversion in V. globator. Despite significant similarities between type A and type B inverters, differences exist in almost all details of the inversion process, suggesting analogous inversion processes that arose through parallel evolution. Based on our results and due to the cellular biomechanical implications of the involved tensile and compressive forces, we developed a global mechanistic scenario that predicts epithelial folding during embryonic inversion in V. globator.
doi:10.1186/1741-7007-9-89
PMCID: PMC3324393  PMID: 22206406
4.  Endothelio-hematopoietic relationship: getting closer to the beginnings 
BMC Biology  2011;9:88.
The close association between hematopoietic and endothelial cells during embryonic development led to the proposal that they may originate from a common ancestor - the hemangioblast. Due to a lack of unique specific markers for in vivo cell fate tracking studies, evidence supporting this theory derives mainly from in vitro differentiation studies. Teixeira and colleagues describe a novel enhancer that drives specific eGFP expression in blood islands of the electroporated chick embryo, thereby presenting a tool potentially suitable for analysis of hemangioblast differentiation and development of blood islands.
See research article: http://www.biomedcentral.com/1471-213X/11/76
doi:10.1186/1741-7007-9-88
PMCID: PMC3247189  PMID: 22204560
5.  Multiple origins of endosymbiosis within the Enterobacteriaceae (γ-Proteobacteria): convergence of complex phylogenetic approaches 
BMC Biology  2011;9:87.
Background
The bacterial family Enterobacteriaceae gave rise to a variety of symbiotic forms, from the loosely associated commensals, often designated as secondary (S) symbionts, to obligate mutualists, called primary (P) symbionts. Determination of the evolutionary processes behind this phenomenon has long been hampered by the unreliability of phylogenetic reconstructions within this group of bacteria. The main reasons have been the absence of sufficient data, the highly derived nature of the symbiont genomes and lack of appropriate phylogenetic methods. Due to the extremely aberrant nature of their DNA, the symbiotic lineages within Enterobacteriaceae form long branches and tend to cluster as a monophyletic group. This state of phylogenetic uncertainty is now improving with an increasing number of complete bacterial genomes and development of new methods. In this study, we address the monophyly versus polyphyly of enterobacterial symbionts by exploring a multigene matrix within a complex phylogenetic framework.
Results
We assembled the richest taxon sampling of Enterobacteriaceae to date (50 taxa, 69 orthologous genes with no missing data) and analyzed both nucleic and amino acid data sets using several probabilistic methods. We particularly focused on the long-branch attraction-reducing methods, such as a nucleotide and amino acid data recoding and exclusion (including our new approach and slow-fast analysis), taxa exclusion and usage of complex evolutionary models, such as nonhomogeneous model and models accounting for site-specific features of protein evolution (CAT and CAT+GTR). Our data strongly suggest independent origins of four symbiotic clusters; the first is formed by Hamiltonella and Regiella (S-symbionts) placed as a sister clade to Yersinia, the second comprises Arsenophonus and Riesia (S- and P-symbionts) as a sister clade to Proteus, the third Sodalis, Baumannia, Blochmannia and Wigglesworthia (S- and P-symbionts) as a sister or paraphyletic clade to the Pectobacterium and Dickeya clade and, finally, Buchnera species and Ishikawaella (P-symbionts) clustering with the Erwinia and Pantoea clade.
Conclusions
The results of this study confirm the efficiency of several artifact-reducing methods and strongly point towards the polyphyly of P-symbionts within Enterobacteriaceae. Interestingly, the model species of symbiotic bacteria research, Buchnera and Wigglesworthia, originated from closely related, but different, ancestors. The possible origins of intracellular symbiotic bacteria from gut-associated or pathogenic bacteria are suggested, as well as the role of facultative secondary symbionts as a source of bacteria that can gradually become obligate maternally transferred symbionts.
doi:10.1186/1741-7007-9-87
PMCID: PMC3271043  PMID: 22201529
7.  Putting the pH into phosphatidic acid signaling 
BMC Biology  2011;9:85.
The lipid phosphatidic acid (PA) has important roles in cell signaling and metabolic regulation in all organisms. New evidence indicates that PA also has an unprecedented role as a pH biosensor, coupling changes in pH to intracellular signaling pathways. pH sensing is a property of the phosphomonoester headgroup of PA. A number of other potent signaling lipids also contain headgroups with phosphomonoesters, implying that pH sensing by lipids may be widespread in biology.
doi:10.1186/1741-7007-9-85
PMCID: PMC3229452  PMID: 22136116
8.  Pit-bull reviewing, the pursuit of perfection and the victims of success 
BMC Biology  2011;9:84.
doi:10.1186/1741-7007-9-84
PMCID: PMC3229515  PMID: 22133126
9.  Notch1 binds and induces degradation of Snail in hepatocellular carcinoma 
BMC Biology  2011;9:83.
Background
Hepatocellular carcinoma (HCC) is a common, highly invasive malignant tumor associated with a high mortality rate. We previously reported that the aberrant expression of Snail via activation of reactive oxygen species contributes to the invasive property of HCC, in part by downregulation of E-cadherin through both transcriptional repression and epigenetic modification of the E-cadherin promoter. Having demonstrated the ability of Snail to bind and recruit histone deacetylase 1 and DNA methyltransferase 1 in this context, we set out to look for other interactions that could affect its ability to promote oncogenic transformation and cancer cell invasion.
Results
Using cells that stably expressed Snail, we characterized Snail protein interactors by tandem affinity purification and mass spectrometry. Immunoprecipitation and subcellular colocalization studies were performed to confirm our identification of the Notch1 intracellular domain (NICD) as a novel Snail-binding partner. NICD interaction with Snail was found to induce ubiquitination and MDM2-dependent degradation of Snail. Interestingly, NICD inhibited Snail-dependent invasive properties in both HCC cells and mouse embryonic fibroblasts.
Conclusions
Our study demonstrates that NICD can oppose Snail-dependent HCC cell invasion by binding and inducing proteolytic degradation of Snail. Although Notch signaling and Snail are both widely considered tumor-promoting factors, our findings indicate that the individual oncogenic contribution of Notch1 and Snail in malignant systems should be interpreted carefully, particularly when they are conjointly expressed.
doi:10.1186/1741-7007-9-83
PMCID: PMC3247845  PMID: 22128911
Snail; Notch1 intracellular domain; degradation; invasion; hepatocellular carcinoma
10.  Bidirectional remodeling of β1-integrin adhesions during chemotropic regulation of nerve growth 
BMC Biology  2011;9:82.
Background
Chemotropic factors in the extracellular microenvironment guide nerve growth by acting on the growth cone located at the tip of extending axons. Growth cone extension requires the coordination of cytoskeleton-dependent membrane protrusion and dynamic adhesion to the extracellular matrix, yet how chemotropic factors regulate these events remains an outstanding question. We demonstrated previously that the inhibitory factor myelin-associated glycoprotein (MAG) triggers endocytic removal of the adhesion receptor β1-integrin from the growth cone surface membrane to negatively remodel substrate adhesions during chemorepulsion. Here, we tested how a neurotrophin might affect integrin adhesions.
Results
We report that brain-derived neurotropic factor (BDNF) positively regulates the formation of substrate adhesions in axonal growth cones during stimulated outgrowth and prevents removal of β1-integrin adhesions by MAG. Treatment of Xenopus spinal neurons with BDNF rapidly triggered β1-integrin clustering and induced the dynamic formation of nascent vinculin-containing adhesion complexes in the growth cone periphery. Both the formation of nascent β1-integrin adhesions and the stimulation of axon extension by BDNF required cytoplasmic calcium ion signaling and integrin activation at the cell surface. Exposure to MAG decreased the number of β1-integrin adhesions in the growth cone during inhibition of axon extension. In contrast, the BDNF-induced adhesions were resistant to negative remodeling by MAG, correlating with the ability of BDNF pretreatment to counteract MAG-inhibition of axon extension. Pre-exposure to MAG prevented the BDNF-induced formation of β1-integrin adhesions and blocked the stimulation of axon extension by BDNF.
Conclusions
Altogether, these findings demonstrate the neurotrophin-dependent formation of integrin-based adhesions in the growth cone and reveal how a positive regulator of substrate adhesions can block the negative remodeling and growth inhibitory effects of MAG. Such bidirectional remodeling may allow the growth cone to rapidly adjust adhesiveness to the extracellular matrix as a general mechanism for governing axon extension. Techniques for manipulating integrin internalization and activation state may be important for overcoming local inhibitory factors after traumatic injury or neurodegenerative disease to enhance regenerative nerve growth.
doi:10.1186/1741-7007-9-82
PMCID: PMC3283487  PMID: 22126462
11.  Motion dazzle and camouflage as distinct anti-predator defenses 
BMC Biology  2011;9:81.
Background
Camouflage patterns that hinder detection and/or recognition by antagonists are widely studied in both human and animal contexts. Patterns of contrasting stripes that purportedly degrade an observer's ability to judge the speed and direction of moving prey ('motion dazzle') are, however, rarely investigated. This is despite motion dazzle having been fundamental to the appearance of warships in both world wars and often postulated as the selective agent leading to repeated patterns on many animals (such as zebra and many fish, snake, and invertebrate species). Such patterns often appear conspicuous, suggesting that protection while moving by motion dazzle might impair camouflage when stationary. However, the relationship between motion dazzle and camouflage is unclear because disruptive camouflage relies on high-contrast markings. In this study, we used a computer game with human subjects detecting and capturing either moving or stationary targets with different patterns, in order to provide the first empirical exploration of the interaction of these two protective coloration mechanisms.
Results
Moving targets with stripes were caught significantly less often and missed more often than targets with camouflage patterns. However, when stationary, targets with camouflage markings were captured less often and caused more false detections than those with striped patterns, which were readily detected.
Conclusions
Our study provides the clearest evidence to date that some patterns inhibit the capture of moving targets, but that camouflage and motion dazzle are not complementary strategies. Therefore, the specific coloration that evolves in animals will depend on how the life history and ontogeny of each species influence the trade-off between the costs and benefits of motion dazzle and camouflage.
doi:10.1186/1741-7007-9-81
PMCID: PMC3257203  PMID: 22117898
12.  Clustered ChIP-Seq-defined transcription factor binding sites and histone modifications map distinct classes of regulatory elements 
BMC Biology  2011;9:80.
Background
Transcription factor binding to DNA requires both an appropriate binding element and suitably open chromatin, which together help to define regulatory elements within the genome. Current methods of identifying regulatory elements, such as promoters or enhancers, typically rely on sequence conservation, existing gene annotations or specific marks, such as histone modifications and p300 binding methods, each of which has its own biases.
Results
Herein we show that an approach based on clustering of transcription factor peaks from high-throughput sequencing coupled with chromatin immunoprecipitation (Chip-Seq) can be used to evaluate markers for regulatory elements. We used 67 data sets for 54 unique transcription factors distributed over two cell lines to create regulatory element clusters. By integrating the clusters from our approach with histone modifications and data for open chromatin, we identified general methylation of lysine 4 on histone H3 (H3K4me) as the most specific marker for transcription factor clusters. Clusters mapping to annotated genes showed distinct patterns in cluster composition related to gene expression and histone modifications. Clusters mapping to intergenic regions fall into two groups either directly involved in transcription, including miRNAs and long noncoding RNAs, or facilitating transcription by long-range interactions. The latter clusters were specifically enriched with H3K4me1, but less with acetylation of lysine 27 on histone 3 or p300 binding.
Conclusion
By integrating genomewide data of transcription factor binding and chromatin structure and using our data-driven approach, we pinpointed the chromatin marks that best explain transcription factor association with different regulatory elements. Our results also indicate that a modest selection of transcription factors may be sufficient to map most regulatory elements in the human genome.
doi:10.1186/1741-7007-9-80
PMCID: PMC3239327  PMID: 22115494
transcription factor; ChIP-Seq; histone modification; chromatin
13.  How plants cope with temperature stress 
BMC Biology  2011;9:79.
A cold night can follow a hot day, and because they cannot move, plants subjected to such temperature fluctuations must acclimate on the basis mainly of pre-existing proteins. Zhang et al. report in a paper in BMC Plant Biology, however, that heat-induced cell death results from transcriptional activation of a kinase related to disease resistance factors and leading to a localized hypersensitive response. This specialized response reflects the failure of adaptations that normally enable plants to survive over a remarkable temperature range, by mechanisms that are not fully understood.
doi:10.1186/1741-7007-9-79
PMCID: PMC3219733  PMID: 22093487
14.  Following the genes: a framework for animal modeling of psychiatric disorders 
BMC Biology  2011;9:76.
The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans.
doi:10.1186/1741-7007-9-76
PMCID: PMC3214139  PMID: 22078115
autism; schizophrenia; rare mutations; synaptic; interneurons; EEG; functional connectivity; microcircuits; Cre; allelic heterogeneity
15.  Genes, animal models and the current understanding of psychiatric disease  
BMC Biology  2011;9:78.
doi:10.1186/1741-7007-9-78
PMCID: PMC3214146  PMID: 22085652
16.  Two patients walk into a clinic...a genomics perspective on the future of schizophrenia 
BMC Biology  2011;9:77.
Progress is being made in schizophrenia genomics, suggesting that this complex brain disorder involves rare, moderate to high-risk mutations and the cumulative impact of small genetic effects, coupled with environmental factors. The genetic heterogeneity underlying schizophrenia and the overlap with other neurodevelopmental disorders suggest that it will not continue to be viewed as a single disease. This has radical implications for clinical practice, as diagnosis and treatment will be guided by molecular etiology rather than clinical diagnostic criteria.
doi:10.1186/1741-7007-9-77
PMCID: PMC3214150  PMID: 22078159
17.  Requirement for Pdx1 in specification of latent endocrine progenitors in zebrafish 
BMC Biology  2011;9:75.
Background
Insulin-producing beta cells emerge during pancreas development in two sequential waves. Recently described later-forming beta cells in zebrafish show high similarity to second wave mammalian beta cells in developmental capacity. Loss-of-function studies in mouse and zebrafish demonstrated that the homeobox transcription factors Pdx1 and Hb9 are both critical for pancreas and beta cell development and discrete stage-specific requirements for these genes have been uncovered. Previously, exocrine and endocrine cell recovery was shown to follow loss of pdx1 in zebrafish, but the progenitor cells and molecular mechanisms responsible have not been clearly defined. In addition, interactions of pdx1 and hb9 in beta cell formation have not been addressed.
Results
To learn more about endocrine progenitor specification, we examined beta cell formation following morpholino-mediated depletion of pdx1 and hb9. We find that after early beta cell reduction, recovery occurs following loss of either pdx1 or hb9 function. Unexpectedly, simultaneous knockdown of both hb9 and pdx1 leads to virtually complete and persistent beta cell deficiency. We used a NeuroD:EGFP transgenic line to examine endocrine cell behavior in vivo and developed a novel live-imaging technique to document emergence and migration of late-forming endocrine precursors in real time. Our data show that Notch-responsive progenitors for late-arising endocrine cells are predominantly post mitotic and depend on pdx1. By contrast, early-arising endocrine cells are specified and differentiate independent of pdx1.
Conclusions
The nearly complete beta cell deficiency after combined loss of hb9 and pdx1 suggests functional cooperation, which we clarify as distinct roles in early and late endocrine cell formation. A novel imaging approach permitted visualization of the emergence of late endocrine cells within developing embryos for the first time. We demonstrate a pdx1-dependent progenitor population essential for the formation of duct-associated, second wave endocrine cells. We further reveal an unexpectedly low mitotic activity in these progenitor cells, indicating that they are set aside early in development.
doi:10.1186/1741-7007-9-75
PMCID: PMC3215967  PMID: 22034951
18.  Molecular dynamics simulations and drug discovery 
BMC Biology  2011;9:71.
This review discusses the many roles atomistic computer simulations of macromolecular (for example, protein) receptors and their associated small-molecule ligands can play in drug discovery, including the identification of cryptic or allosteric binding sites, the enhancement of traditional virtual-screening methodologies, and the direct prediction of small-molecule binding energies. The limitations of current simulation methodologies, including the high computational costs and approximations of molecular forces required, are also discussed. With constant improvements in both computer power and algorithm design, the future of computer-aided drug design is promising; molecular dynamics simulations are likely to play an increasingly important role.
doi:10.1186/1741-7007-9-71
PMCID: PMC3203851  PMID: 22035460
molecular dynamics simulations; computer-aided drug discovery; cryptic binding sites; allosteric binding sites; virtual screening, free-energy prediction
19.  Proteasome inhibition, the pursuit of new cancer therapeutics, and the adaptor molecule p130Cas 
BMC Biology  2011;9:72.
Current interest in proteasome inhibitors for cancer therapy has stimulated considerable research efforts to identify the molecular pathway to their cytotoxicity with a view to identifying the mechanisms of sensitivity and resistance as well as informing the development of new drugs. Zhao and Vuori describe this month in BMC Biology experiments indicating a novel role of the adaptor protein p130Cas in sensitivity to apoptosis induced not only by proteasome inhibitors but also by the unrelated drug doxorubicin.
See research article: http:// http://www.biomedcentral.com/1741-7007/9/73
doi:10.1186/1741-7007-9-72
PMCID: PMC3203852  PMID: 22034840
20.  The docking protein p130Cas regulates cell sensitivity to proteasome inhibition 
BMC Biology  2011;9:73.
Background
The focal adhesion protein p130Cas (Cas) activates multiple intracellular signaling pathways upon integrin or growth factor receptor ligation. Full-length Cas frequently promotes cell survival and migration, while its C-terminal fragment (Cas-CT) produced upon intracellular proteolysis is known to induce apoptosis in some circumstances. Here, we have studied the putative role of Cas in regulating cell survival and death pathways upon proteasome inhibition.
Results
We found that Cas-/- mouse embryonic fibroblasts (MEFs), as well as empty vector-transfected Cas-/- MEFs (Cas-/- (EV)) are significantly resistant to cell death induced by proteasome inhibitors, such as MG132 and Bortezomib. As expected, wild-type MEFs (WT) and Cas-/- MEFs reconstituted with full-length Cas (Cas-FL) were sensitive to MG132- and Bortezomib-induced apoptosis that involved activation of a caspase-cascade, including Caspase-8. Cas-CT generation was not required for MG132-induced cell death, since expression of cleavage-resistant Cas mutants effectively increased sensitivity of Cas-/- MEFs to MG132. At the present time, the domains in Cas and the downstream pathways that are required for mediating cell death induced by proteasome inhibitors remain unknown. Interestingly, however, MG132 or Bortezomib treatment resulted in activation of autophagy in cells that lacked Cas, but not in cells that expressed Cas. Furthermore, autophagy was found to play a protective role in Cas-deficient cells, as inhibition of autophagy either by chemical or genetic means enhanced MG132-induced apoptosis in Cas-/- (EV) cells, but not in Cas-FL cells. Lack of Cas also contributed to resistance to the DNA-damaging agent Doxorubicin, which coincided with Doxorubicin-induced autophagy in Cas-/- (EV) cells. Thus, Cas may have a regulatory role in cell death signaling in response to multiple different stimuli. The mechanisms by which Cas inhibits induction of autophagy and affects cell death pathways are currently being investigated.
Conclusion
Our study demonstrates that Cas is required for apoptosis that is induced by proteasome inhibition, and potentially by other death stimuli. We additionally show that Cas may promote such apoptosis, at least partially, by inhibiting autophagy. This is the first demonstration of Cas being involved in the regulation of autophagy, adding to the previous findings by others linking focal adhesion components to the process of autophagy.
doi:10.1186/1741-7007-9-73
PMCID: PMC3215977  PMID: 22034875
21.  Sumo-dependent substrate targeting of the SUMO protease Ulp1 
BMC Biology  2011;9:74.
Background
In the yeast Saccharomyces cerevisiae, the essential small ubiquitin-like modifier (SUMO) protease Ulp1 is responsible for both removing SUMO/Smt3 from specific target proteins and for processing precursor SUMO into its conjugation-competent form. Ulp1 localizes predominantly to nuclear pore complexes but has also been shown to deconjugate sumoylated septins at the bud-neck of dividing cells. How Ulp1 is directed to bud-neck localized septins and other cytoplasmic deconjugation targets is not well understood.
Results
Using a structure/function approach, we set out to elucidate features of Ulp1 that are required for substrate targeting. To aid our studies, we took advantage of a catalytically inactive mutant of Ulp1 that is greatly enriched at the septin ring of dividing yeast cells. We found that the localization of Ulp1 to the septins requires both SUMO and specific structural features of Ulp1's catalytic domain. Our analysis identified a 218-amino acid, substrate-trapping mutant of the catalytic domain of Ulp1, Ulp1(3)(C580S), that is necessary and sufficient for septin localization. We also used the targeting and SUMO-binding properties of Ulp1(3)(C580S) to purify Smt3-modified proteins from cell extracts.
Conclusions
Our study provides novel insights into how the Ulp1 SUMO protease is actively targeted to its substrates in vivo and in vitro. Furthermore, we found that a substrate-trapping Ulp1(3)(C580S) interacts robustly with human SUMO1, SUMO2 and SUMO2 chains, making it a potentially useful tool for the analysis and purification of SUMO-modified proteins.
doi:10.1186/1741-7007-9-74
PMCID: PMC3216068  PMID: 22034919
22.  Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast 
BMC Biology  2011;9:70.
Background
The uptake of drugs into cells has traditionally been considered to be predominantly via passive diffusion through the bilayer portion of the cell membrane. The recent recognition that drug uptake is mostly carrier-mediated raises the question of which drugs use which carriers.
Results
To answer this, we have constructed a chemical genomics platform built upon the yeast gene deletion collection, using competition experiments in batch fermenters and robotic automation of cytotoxicity screens, including protection by 'natural' substrates. Using these, we tested 26 different drugs and identified the carriers required for 18 of the drugs to gain entry into yeast cells.
Conclusions
As well as providing a useful platform technology, these results further substantiate the notion that the cellular uptake of pharmaceutical drugs normally occurs via carrier-mediated transport and indicates that establishing the identity and tissue distribution of such carriers should be a major consideration in the design of safe and effective drugs.
doi:10.1186/1741-7007-9-70
PMCID: PMC3280192  PMID: 22023736
23.  Appetite for destruction: the inhibition of glycolysis as a therapy for tuberous sclerosis complex-related tumors 
BMC Biology  2011;9:69.
The elevated metabolic requirements of cancer cells reflect their rapid growth and proliferation and are met through mutations in oncogenes and tumor suppressor genes that reprogram cellular processes. For example, in tuberous sclerosis complex (TSC)-related tumors, the loss of TSC1/2 function causes constitutive mTORC1 activity, which stimulates glycolysis, resulting in glucose addiction in vitro. In research published in Cell and Bioscience, Jiang and colleagues show that pharmacological restriction of glucose metabolism decreases tumor progression in a TSC xenograft model.
See research article: http://www.cellandbioscience.com/content/1/1/34
doi:10.1186/1741-7007-9-69
PMCID: PMC3198763  PMID: 22018140
24.  Toward a comprehensive language for biological systems 
BMC Biology  2011;9:68.
Rule-based modeling has become a powerful approach for modeling intracellular networks, which are characterized by rich molecular diversity. Truly comprehensive models of cell behavior, however, must address spatial complexity at both the intracellular level and at the level of interacting populations of cells, and will require richer modeling languages and tools. A recent paper in BMC Systems Biology represents a signifcant step toward the development of a unified modeling language and software platform for the development of multi-level, multiscale biological models.
See research article: http://www.biomedcentral.com/1752-0509/5/166
doi:10.1186/1741-7007-9-68
PMCID: PMC3195790  PMID: 22005092
25.  Host-parasite relationships in the genome 
BMC Biology  2011;9:67.
Transposable elements are best interpreted as genomic parasites, proliferating in genomes through their over-replication relative to the rest of the genome. A new study examining correlations across Drosophila species between transposable element numbers and rates of host evolution has brought into focus one of the most complex questions in transposable element biology-what it is that determines the proportion of the genome that is transposable elements.
See research article: http://www.biomedcentral.com/1471-2148/11/258/
doi:10.1186/1741-7007-9-67
PMCID: PMC3189907  PMID: 21985691

Results 1-25 (91)