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The intricate side of systems biology

Voit, Eberhard; Neves, Ana Rute; Santos, Helena
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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The combination of high-throughput methods of molecular biology with advanced mathematical and computational techniques has propelled the emergent field of systems biology into a position of prominence. Unthinkable a decade ago, it has become possible to screen and analyze the expression of entire genomes, simultaneously assess large numbers of proteins and their prevalence, and characterize in detail the metabolic state of a cell population. Although very important, the focus on comprehensive networks of biological components is only one side of systems biology. Complementing large-scale assessments, and sometimes at the risk of being forgotten, are more subtle analyses that rationalize the design and functioning of biological modules in exquisite detail. This intricate side of systems biology aims at identifying the specific roles of processes and signals in smaller, fully regulated systems by computing what would happen if these signals were lacking or organized in a different fashion. We exemplify this type of approach with a detailed analysis of the regulation of glucose utilization in Lactococcus lactis. This organism is exposed to alternating periods of glucose availability and starvation. During starvation, it accumulates an intermediate of glycolysis...

Identifying genes important for spermatogonial stem cell self-renewal and survival

Oatley, Jon M.; Avarbock, Mary R.; Telaranta, Aino I.; Fearon, Douglas T.; Brinster, Ralph L.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Spermatogonial stem cells (SSCs) are the foundation for spermatogenesis and, thus, preservation of a species. Because of stem cell rarity, studying their self-renewal is greatly facilitated by in vitro culture of enriched biologically active cell populations. A recently developed culture method identified glial cell line-derived neurotrophic factor (GDNF) as the essential growth factor that supports in vitro self-renewal of SSCs and results in an increase in their number. This system is a good model to study mechanisms of stem cell self-renewal because of the well defined culture conditions, enriched cell population, and available transplantation assay. By withdrawing and replacing GDNF in culture medium, we identified regulated expression of many genes by using microarray analysis. The expression levels of six of these genes were dramatically decreased by GDNF withdrawal and increased by GDNF replacement. To demonstrate the biological significance of the identified GDNF-regulated genes, we examined the importance of the most responsive of the six, bcl6b, a transcriptional repressor. By using siRNA to reduce transcript levels, Bcl6b was shown to be crucial for SSC maintenance in vitro. Moreover, evaluation of Bcl6b-null male testes revealed degeneration and/or absence of active spermatogenesis in 24 ± 7% of seminiferous tubules. These data suggest that Bcl6b is an important molecule in SSC self-renewal and validate the biological relevance of the GDNF-regulated genes identified through microarray analysis. In addition...

Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells

Fish, Jennifer L.; Kosodo, Yoichi; Enard, Wolfgang; Pääbo, Svante; Huttner, Wieland B.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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The ASPM (abnormal spindle-like microcephaly-associated) protein has previously been implicated in the determination of human cerebral cortical size, but the cell biological basis of this regulation has not been studied. Here we investigate the role of Aspm in mouse embryonic neuroepithelial (NE) cells, the primary stem and progenitor cells of the mammalian brain. Aspm was found to be concentrated at mitotic spindle poles of NE cells and to be down-regulated with their switch from proliferative to neurogenic divisions. Upon RNA interference in telencephalic NE cells, Aspm mRNA is reduced, mitotic spindle poles lack Aspm protein, and the cleavage plane of NE cells is less frequently oriented perpendicular to the ventricular surface of the neuroepithelium. The alteration in the cleavage plane orientation of NE cells increases the probability that these highly polarized cells undergo asymmetric division, i.e., that apical plasma membrane is inherited by only one of the daughter cells. Concomitant with the resulting increase in abventricular cells in the ventricular zone, a larger proportion of NE cell progeny is found in the neuronal layer, implying a reduction in the number of NE progenitor cells upon Aspm knock-down relative to control. Our results demonstrate that Aspm is crucial for maintaining a cleavage plane orientation that allows symmetric...

Macromolecular-scale resolution in biological fluorescence microscopy

Donnert, Gerald; Keller, Jan; Medda, Rebecca; Andrei, M. Alexandra; Rizzoli, Silvio O.; Lührmann, Reinhard; Jahn, Reinhard; Eggeling, Christian; Hell, Stefan W.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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We demonstrate far-field fluorescence microscopy with a focal-plane resolution of 15–20 nm in biological samples. The 10- to 12-fold multilateral increase in resolution below the diffraction barrier has been enabled by the elimination of molecular triplet state excitation as a major source of photobleaching of a number of dyes in stimulated emission depletion microscopy. Allowing for relaxation of the triplet state between subsequent excitation–depletion cycles yields an up to 30-fold increase in total fluorescence signal as compared with reported stimulated emission depletion illumination schemes. Moreover, it enables the reduction of the effective focal spot area by up to ≈140-fold below that given by diffraction. Triplet-state relaxation can be realized either by reducing the repetition rate of pulsed lasers or by increasing the scanning speed such that the build-up of the triplet state is effectively prevented. This resolution in immunofluorescence imaging is evidenced by revealing nanoscale protein patterns on endosomes, the punctuated structures of intermediate filaments in neurons, and nuclear protein speckles in mammalian cells with conventional optics. The reported performance of diffraction-unlimited fluorescence microscopy opens up a pathway for addressing fundamental problems in the life sciences.

A family of conserved noncoding elements derived from an ancient transposable element

Xie, Xiaohui; Kamal, Michael; Lander, Eric S.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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The evolutionary origin of the conserved noncoding elements (CNEs) in the human genome remains poorly understood but may hold important clues to their biological functions. Here, we report the discovery of a CNE family with ≈124 instances in the human genome that demonstrates a clear signature of having been derived from an ancient transposon. The CNE family is also present in the chicken genome, although typically not at orthologous locations. The CNE family is closely related to the active transposon SINE3 in zebrafish and also to a previously uncharacterized transposon in the coelacanth, the so-called “living fossil” belonging to the lobe-finned fish lineage. The mammal, bird, zebrafish, and coelacanth families all share a highly similar core element of ≈180 bp but have important differences in their 5′ and 3′ ends. The core element has thus been preserved over 450 million years of evolution, implying an important biological function. In addition, we identify 95 additional CNE families that likely predate the mammalian radiation. The results highlight both the creative role of transposons and the importance of CNE families.

A microrotary motor powered by bacteria

Hiratsuka, Yuichi; Miyata, Makoto; Tada, Tetsuya; Uyeda, Taro Q. P.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Biological molecular motors have a number of unique advantages over artificial motors, including efficient conversion of chemical energy into mechanical work and the potential for self-assembly into larger structures, as is seen in muscle sarcomeres and bacterial and eukaryotic flagella. The development of an appropriate interface between such biological materials and synthetic devices should enable us to realize useful hybrid micromachines. Here we describe a microrotary motor composed of a 20-μm-diameter silicon dioxide rotor driven on a silicon track by the gliding bacterium Mycoplasma mobile. This motor is fueled by glucose and inherits some of the properties normally attributed to living systems.

Anomalous resonance in a nanomechanical biosensor

Gupta, Amit K.; Nair, Pradeep R.; Akin, Demir; Ladisch, Michael R.; Broyles, Steve; Alam, Muhammad A.; Bashir, Rashid
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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The decrease in resonant frequency (−Δωr) of a classical cantilever provides a sensitive measure of the mass of entities attached on its surface. This elementary phenomenon has been the basis of a new class of bio-nanomechanical devices as sensing components of integrated microsystems that can perform rapid, sensitive, and selective detection of biological and biochemical entities. Based on classical analysis, there is a widespread perception that smaller sensors are more sensitive (sensitivity ≈ −0.5ωr/mC, where mC is the mass of the cantilever), and this notion has motivated scaling of biosensors to nanoscale dimensions. In this work, we show that the response of a nanomechanical biosensor is far more complex than previously anticipated. Indeed, in contrast to classical microscale sensors, the resonant frequencies of the nanosensor may actually decrease or increase after attachment of protein molecules. We demonstrate theoretically and experimentally that the direction of the frequency change arises from a size-specific modification of diffusion and attachment kinetics of biomolecules on the cantilevers. This work may have broad impact on microscale and nanoscale biosensor design, especially when predicting the characteristics of bio-nanoelectromechanical sensors functionalized with biological capture molecules.

Combinations of biomarkers predictive of later life mortality

Gruenewald, Tara L.; Seeman, Teresa E.; Ryff, Carol D.; Karlamangla, Arun S.; Singer, Burton H.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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A wide range of biomarkers, reflecting activity in a number of biological systems (e.g., neuroendocrine, immune, cardiovascular, and metabolic), have been found to prospectively predict disability, morbidity, and mortality outcomes in older adult populations. Levels of these biomarkers, singly or in combination, may serve as an early warning system of risk for future adverse health outcomes. In the current investigation, 13 biomarkers were examined as predictors of mortality occurrence over a 12-year period in a sample of men and women (n = 1,189) 70–79 years of age at enrollment into the study. Biomarkers examined in analyses included markers of neuroendocrine functioning (epinephrine, norepinephrine, cortisol, and dehydroepiandrosterone), immune activity (C-reactive protein, fibrinogen, IL-6, and albumin), cardiovascular functioning (systolic and diastolic blood pressure), and metabolic activity [high-density lipoprotein (HDL) cholesterol, total to HDL cholesterol ratio, and glycosylated hemoglobin]. Recursive partitioning techniques were used to identify a set of pathways, composed of combinations of different biomarkers, that were associated with a high-risk of mortality over the 12-year period. Of the 13 biomarkers examined...

Evolution of complexity in signaling pathways

Soyer, Orkun S.; Bonhoeffer, Sebastian
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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It is not clear how biological pathways evolve to mediate a certain physiological response and why they show a level of complexity that is generally above the minimum required to achieve such a response. One possibility is that pathway complexity increases due to the nature of evolutionary mechanisms. Here, we analyze this possibility by using mathematical models of biological pathways and evolutionary simulations. Starting with a population of small pathways of three proteins, we let the population evolve with mutations that affect pathway structure through duplication or deletion of existing proteins, deletion or creation of interactions among them, or addition of new proteins. Our simulations show that such mutational events, coupled with a selective pressure, leads to growth of pathways. These results indicate that pathways could be driven toward complexity via simple evolutionary mechanisms and that complexity can arise without any specific selective pressure for it. Furthermore, we find that the level of complexity that pathways evolve toward depends on the selection criteria. In general, we find that final pathway size tends to be lower when pathways evolve under stringent selection criteria. This leads to the counterintuitive conclusion that simple response requirements on a pathway would facilitate its evolution toward higher complexity.

A tunable algorithm for collective decision-making

Pratt, Stephen C.; Sumpter, David J. T.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Complex biological systems are increasingly understood in terms of the algorithms that guide the behavior of system components and the information pathways that link them. Much attention has been given to robust algorithms, or those that allow a system to maintain its functions in the face of internal or external perturbations. At the same time, environmental variation imposes a complementary need for algorithm versatility, or the ability to alter system function adaptively as external circumstances change. An important goal of systems biology is thus the identification of biological algorithms that can meet multiple challenges rather than being narrowly specified to particular problems. Here we show that emigrating colonies of the ant Temnothorax curvispinosus tune the parameters of a single decision algorithm to respond adaptively to two distinct problems: rapid abandonment of their old nest in a crisis and deliberative selection of the best available new home when their old nest is still intact. The algorithm uses a stepwise commitment scheme and a quorum rule to integrate information gathered by numerous individual ants visiting several candidate homes. By varying the rates at which they search for and accept these candidates, the ants yield a colony-level response that adaptively emphasizes either speed or accuracy. We propose such general but tunable algorithms as a design feature of complex systems...

Modern proteomes contain putative imprints of ancient shifts in trace metal geochemistry

Dupont, Christopher L.; Yang, Song; Palenik, Brian; Bourne, Philip E.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Because of the rise in atmospheric oxygen 2.3 billion years ago (Gya) and the subsequent changes in oceanic redox state over the last 2.3–1 Gya, trace metal bioavailability in marine environments has changed dramatically. Although theorized to have influenced the biological usage of metals leaving discernable genomic signals, a thorough and quantitative test of this hypothesis has been lacking. Using structural bioinformatics and whole-genome sequences, the Fe-, Zn-, Mn-, and Co-binding metallomes of 23 Archaea, 233 Bacteria, and 57 Eukarya were constructed. These metallomes reveal that the overall abundances of these metal-binding structures scale to proteome size as power laws with a unique set of slopes for each Superkingdom of Life. The differences in the power describing the abundances of Fe-, Mn-, Zn-, and Co-binding proteins in the proteomes of Prokaryotes and Eukaryotes are similar to the theorized changes in the abundances of these metals after the oxygenation of oceanic deep waters. This phenomenon suggests that Prokarya and Eukarya evolved in anoxic and oxic environments, respectively, a hypothesis further supported by structures and functions of Fe-binding proteins in each Superkingdom. Also observed is a proliferation in the diversity of Zn-binding protein structures involved in protein–DNA and protein–protein interactions within Eukarya...

A fully integrated microfluidic genetic analysis system with sample-in–answer-out capability

Easley, Christopher J.; Karlinsey, James M.; Bienvenue, Joan M.; Legendre, Lindsay A.; Roper, Michael G.; Feldman, Sanford H.; Hughes, Molly A.; Hewlett, Erik L.; Merkel, Tod J.; Ferrance, Jerome P.; Landers, James P.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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We describe a microfluidic genetic analysis system that represents a previously undescribed integrated microfluidic device capable of accepting whole blood as a crude biological sample with the endpoint generation of a genetic profile. Upon loading the sample, the glass microfluidic genetic analysis system device carries out on-chip DNA purification and PCR-based amplification, followed by separation and detection in a manner that allows for microliter samples to be screened for infectious pathogens with sample-in–answer-out results in <30 min. A single syringe pump delivers sample/reagents to the chip for nucleic acid purification from a biological sample. Elastomeric membrane valving isolates each distinct functional region of the device and, together with resistive flow, directs purified DNA and PCR reagents from the extraction domain into a 550-nl chamber for rapid target sequence PCR amplification. Repeated pressure-based injections of nanoliter aliquots of amplicon (along with the DNA sizing standard) allow electrophoretic separation and detection to provide DNA fragment size information. The presence of Bacillus anthracis (anthrax) in 750 nl of whole blood from living asymptomatic infected mice and of Bordetella pertussis in 1 μl of nasal aspirate from a patient suspected of having whooping cough are confirmed by the resultant genetic profile.

Fusicoccins are biosynthesized by an unusual chimera diterpene synthase in fungi

Toyomasu, Tomonobu; Tsukahara, Mai; Kaneko, Akane; Niida, Rie; Mitsuhashi, Wataru; Dairi, Tohru; Kato, Nobuo; Sassa, Takeshi
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Fusicoccins are a class of diterpene glucosides produced by the plant-pathogenic fungus Phomopsis amygdali. As modulators of 14-3-3 proteins, fusicoccins function as potent activators of plasma membrane H+-ATPase in plants and also exhibit unique biological activity in animal cells. Despite their well studied biological activities, no genes encoding fusicoccin biosynthetic enzymes have been identified. Cyclic diterpenes are commonly synthesized via cyclization of a C20 precursor, geranylgeranyl diphosphate (GGDP), which is produced through condensation of the universal C5 isoprene units dimethylallyl diphosphate and isopentenyl diphosphate by prenyltransferases. We found that (+)-fusicocca-2,10 (14)-diene, a tricyclic hydrocarbon precursor for fusicoccins, is biosynthesized from the C5 isoprene units by an unusual multifunctional enzyme, P. amygdali fusicoccadiene synthase (PaFS), which shows both prenyltransferase and terpene cyclase activities. The functional analysis of truncated mutants and site-directed mutagenesis demonstrated that PaFS consists of two domains: a terpene cyclase domain at the N terminus and a prenyltransferase domain at the C terminus. These findings suggest that fusicoccadiene can be produced efficiently in the fungus by using the C5 precursors...

HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1

Schröfelbauer, Bärbel; Hakata, Yoshiyuki; Landau, Nathaniel R.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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The Vpr accessory protein of HIV-1 induces a response similar to that of DNA damage. In cells expressing Vpr, the DNA damage sensing kinase, ATR, is activated, resulting in G2 arrest and apoptosis. In addition, Vpr causes rapid degradation of the uracil-DNA glycosylases UNG2 and SMUG1. Although several cellular proteins have been reported to bind to Vpr, the mechanism by which Vpr mediates its biological effects is unknown. Using tandem affinity purification and mass spectrometry, we identified a predominant cellular protein that binds to Vpr as the damage-specific DNA-binding protein 1 (DDB1). In addition to its role in the repair of damaged DNA, DDB1 is a component of an E3 ubiquitin ligase that degrades numerous cellular substrates. Interestingly, DDB1 is targeted by specific regulatory proteins of other viruses, including simian virus 5 and hepatitis B. We show that the interaction with DDB1 mediates Vpr-induced apoptosis and UNG2/SMUG1 degradation and impairs the repair of UV-damaged DNA, which could account for G2 arrest and apoptosis. The interaction with DDB1 may explain several of the diverse biological functions of Vpr and suggests potential roles for Vpr in HIV-1 replication.

Accurate, conformation-dependent predictions of solvent effects on protein ionization constants

Barth, P.; Alber, T.; Harbury, P. B.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Predicting how aqueous solvent modulates the conformational transitions and influences the pKa values that regulate the biological functions of biomolecules remains an unsolved challenge. To address this problem, we developed FDPB_MF, a rotamer repacking method that exhaustively samples side chain conformational space and rigorously calculates multibody protein–solvent interactions. FDPB_MF predicts the effects on pKa values of various solvent exposures, large ionic strength variations, strong energetic couplings, structural reorganizations and sequence mutations. The method achieves high accuracy, with root mean square deviations within 0.3 pH unit of the experimental values measured for turkey ovomucoid third domain, hen lysozyme, Bacillus circulans xylanase, and human and Escherichia coli thioredoxins. FDPB_MF provides a faithful, quantitative assessment of electrostatic interactions in biological macromolecules.

Predicting protein–protein interactions based only on sequences information

Shen, Juwen; Zhang, Jian; Luo, Xiaomin; Zhu, Weiliang; Yu, Kunqian; Chen, Kaixian; Li, Yixue; Jiang, Hualiang
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Protein–protein interactions (PPIs) are central to most biological processes. Although efforts have been devoted to the development of methodology for predicting PPIs and protein interaction networks, the application of most existing methods is limited because they need information about protein homology or the interaction marks of the protein partners. In the present work, we propose a method for PPI prediction using only the information of protein sequences. This method was developed based on a learning algorithm-support vector machine combined with a kernel function and a conjoint triad feature for describing amino acids. More than 16,000 diverse PPI pairs were used to construct the universal model. The prediction ability of our approach is better than that of other sequence-based PPI prediction methods because it is able to predict PPI networks. Different types of PPI networks have been effectively mapped with our method, suggesting that, even with only sequence information, this method could be applied to the exploration of networks for any newly discovered protein with unknown biological relativity. In addition, such supplementary experimental information can enhance the prediction ability of the method.

Directing macromolecular conformation through halogen bonds

Voth, Andrea Regier; Hays, Franklin A.; Ho, P. Shing
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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The halogen bond, a noncovalent interaction involving polarizable chlorine, bromine, or iodine molecular substituents, is now being exploited to control the assembly of small molecules in the design of supramolecular complexes and new materials. We demonstrate that a halogen bond formed between a brominated uracil and phosphate oxygen can be engineered to direct the conformation of a biological molecule, in this case to define the conformational isomer of a four-stranded DNA junction when placed in direct competition against a classic hydrogen bond. As a result, this bromine interaction is estimated to be ≈2–5 kcal/mol stronger than the analogous hydrogen bond in this environment, depending on the geometry of the halogen bond. This study helps to establish halogen bonding as a potential tool for the rational design and construction of molecular materials with DNA and other biological macromolecules.

Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling networks

Wolf-Yadlin, Alejandro; Hautaniemi, Sampsa; Lauffenburger, Douglas A.; White, Forest M.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Although recent developments in MS have enabled the identification and quantification of hundreds of phosphorylation sites from a given biological sample, phosphoproteome analysis by MS has been plagued by inconsistent reproducibility arising from automated selection of precursor ions for fragmentation, identification, and quantification. To address this challenge, we have developed a new MS-based strategy, based on multiple reaction monitoring of stable isotope-labeled peptides, that enables highly reproducible quantification of hundreds of nodes (phosphorylation sites) within a signaling network and across multiple conditions simultaneously. We have applied this strategy to quantify temporal phosphorylation profiles of 222 tyrosine phosphorylated peptides across seven time points following EGF treatment, including 31 tyrosine phosphorylation sites not previously known to be regulated by EGF stimulation. With this approach, 88% of the signaling nodes were reproducibly quantified in four analyses, as compared with only 34% by typical information-dependent analysis. As a result of the improved reproducibility, full temporal phosphorylation profiles were generated for an additional 104 signaling nodes with the multiple reaction monitoring strategy...

Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities

Qian, Xiaolan; Li, Guorong; Asmussen, Holly K.; Asnaghi, Laura; Vass, William C.; Braverman, Richard; Yamada, Kenneth M.; Popescu, Nicholas C.; Papageorge, Alex G.; Lowy, Douglas R.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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The three deleted in liver cancer genes (DLC1–3) encode Rho-GTPase-activating proteins (RhoGAPs) whose expression is frequently down-regulated or silenced in a variety of human malignancies. The RhoGAP activity is required for full DLC-dependent tumor suppressor activity. Here we report that DLC1 and DLC3 bind to human tensin1 and its chicken homolog. The binding has been mapped to the tensin Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains at the C terminus of tensin proteins. Distinct DLC1 sequences are required for SH2 and PTB binding. DCL binding to both domains is constitutive under basal conditions. The SH2 binding depends on a tyrosine in DCL1 (Y442) but is phosphotyrosine-independent, a highly unusual feature for SH2 binding. DLC1 competed with the binding of other proteins to the tensin C terminus, including β3-integrin binding to the PTB domain. Point mutation of a critical tyrosine residue (Y442F) in DLC1 rendered the protein deficient for binding the tensin SH2 domain and binding full-length tensin. The Y442F protein was diffusely cytoplasmic, in contrast to the localization of wild-type DLC1 to focal adhesions, but it retained the ability to reduce the intracellular levels of Rho-GTP. The Y442F mutant displayed markedly reduced biological activity...

Drift and breakup of spiral waves in reaction–diffusion–mechanics systems

Panfilov, A. V.; Keldermann, R. H.; Nash, M. P.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
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Rotating spiral waves organize excitation in various biological, physical, and chemical systems. They underpin a variety of important phenomena, such as cardiac arrhythmias, morphogenesis processes, and spatial patterns in chemical reactions. Important insights into spiral wave dynamics have been obtained from theoretical studies of the reaction–diffusion (RD) partial differential equations. However, most of these studies have ignored the fact that spiral wave rotation is often accompanied by substantial deformations of the medium. Here, we show that joint consideration of the RD equations with the equations of continuum mechanics for tissue deformations (RD–mechanics systems), yield important effects on spiral wave dynamics. We show that deformation can induce the breakup of spiral waves into complex spatiotemporal patterns. We also show that mechanics leads to spiral wave drift throughout the medium approaching dynamical attractors, which are determined by the parameters of the model and the size of the medium. We study mechanisms of these effects and discuss their applicability to the theory of cardiac arrhythmias. Overall, we demonstrate the importance of RD–mechanics systems for mathematics applied to life sciences.