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The scientific production in health and biological sciences of the top 20 Brazilian universities

Zorzetto,R.; Razzouk,D.; Dubugras,M.T.B.; Gerolin,J.; Schor,N.; Guimarães,J.A.; Mari,J.J.
Fonte: Associação Brasileira de Divulgação Científica Publicador: Associação Brasileira de Divulgação Científica
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2006 Português
Relevância na Pesquisa
55.88%
Brazilian scientific output exhibited a 4-fold increase in the last two decades because of the stability of the investment in research and development activities and of changes in the policies of the main funding agencies. Most of this production is concentrated in public universities and research institutes located in the richest part of the country. Among all areas of knowledge, the most productive are Health and Biological Sciences. During the 1998-2002 period these areas presented heterogeneous growth ranging from 4.5% (Pharmacology) to 191% (Psychiatry), with a median growth rate of 47.2%. In order to identify and rank the 20 most prolific institutions in these areas, searches were made in three databases (DataCAPES, ISI and MEDLINE) which permitted the identification of 109,507 original articles produced by the 592 Graduate Programs in Health and Biological Sciences offered by 118 public universities and research institutes. The 20 most productive centers, ranked according to the total number of ISI-indexed articles published during the 1998-2003 period, produced 78.7% of the papers in these areas and are strongly concentrated in the Southern part of the country, mainly in São Paulo State.

Nuclear localization of cyclin B1 mediates its biological activity and is regulated by phosphorylation

Li, Jianke; Meyer, April N.; Donoghue, Daniel J.
Fonte: The National Academy of Sciences of the USA Publicador: The National Academy of Sciences of the USA
Tipo: Artigo de Revista Científica
Publicado em 21/01/1997 Português
Relevância na Pesquisa
55.87%
M-phase promoting factor or maturation promoting factor, a key regulator of the G2 → M transition of the cell cycle, is a complex of cdc2 and a B-type cyclin. We have previously shown that Xenopus cyclin B1 has five sites of Ser phosphorylation, four of which map to a recently identified cytoplasmic retention signal (CRS). The CRS appears to be responsible for the cytoplasmic localization of B-type cyclins, although the underlying mechanism is still unclear. Phosphorylation of cyclin B1 is not required for cdc2 binding or cdc2 kinase activity. However, when all of the Ser phosphorylation sites in the CRS are mutated to Ala to abolish phosphorylation, the mutant cyclin B1Ala is inactivated; activity can be enhanced by mutation of these residues to Glu to mimic phosphoserine, suggesting that phosphorylation of cyclin B1 is required for its biological activity. Here we show that biological activity can be restored to cyclin B1Ala by appending either a nuclear localization signal (NLS), or a second CRS domain with the Ser phosphorylation sites mutated to Glu, while fusion of a second CRS domain with the Ser phosphorylation sites mutated to Ala inactivates wild-type cyclin B1. Nuclear histone H1 kinase activity was detected in association with cyclin B1Ala targeted to the nucleus by a wild-type NLS...

STAT3 complements defects in an interferon-resistant cell line: Evidence for an essential role for STAT3 in interferon signaling and biological activities

Yang, Chuan-He; Murti, Aruna; Pfeffer, Lawrence M.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 12/05/1998 Português
Relevância na Pesquisa
55.85%
STAT proteins play critical roles in the signal transduction pathways for various cytokines. The type I interferons (IFNα/β) promote the DNA-binding activity of the transcription factors STAT1, STAT2, and STAT3. Although the requirement for STAT1 and STAT2 in IFNα/β signaling and action is well documented, the biological importance of STAT3 to IFN action has not yet been addressed. We found that STAT3 plays a critical role in signal transduction by IFNα/β. A human cell line that is resistant to the antiviral and antiproliferative activities of IFN but is still IFN-responsive by virtue of STAT1 and STAT2 activation was found to be defective in STAT3 activation and in induction of NF-κB DNA-binding activity. Expression of STAT3 in these resistant cells complemented these signaling defects and also markedly increased cellular sensitivity to the antiviral and antiproliferative effects of IFN. Because STAT3 is involved in the induction of NF-κB DNA-binding activity and in the induction of antiviral and antiproliferative activity, our results place STAT3 as an important upstream element in type I IFN signal transduction and in the induction of biological activities. Therefore, our results indicate that STAT1 and STAT2 are not the only STATs required for the expression of the key biological activities of IFNα/β.

Proposal for a standardized temporal scheme of biological classification for extant species

Avise, John C.; Johns, Glenn C.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 22/06/1999 Português
Relevância na Pesquisa
55.85%
With respect to conveying useful comparative information, current biological classifications are seriously flawed because they fail to (i) standardize criteria for taxonomic ranking and (ii) equilibrate assignments of taxonomic rank across disparate kinds of organisms. In principle, these problems could be rectified by adopting a universal taxonomic yardstick based on absolute dates of the nodes in evolutionary trees. By using procedures of temporal banding described herein, a simple philosophy of biological classification is proposed that would retain a manageable number of categorical ranks yet apply them in standardized fashion to time-dated phylogenies. The phylogenetic knowledge required for a time-standardized nomenclature arguably may emerge in the foreseeable future from vast increases in multilocus DNA sequence information (coupled with continued attention to phylogeny estimation from traditional systematic data). By someday encapsulating time-dated phylogenies in a familiar yet modified hierarchical ranking scheme, a temporal-banding approach would improve the comparative information content of biological classifications.

Perceptual deficits in patients with impaired recognition of biological motion after temporal lobe lesions

Vaina, Lucia M.; Gross, Charles G.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.88%
“Biological motion” may be defined by the pattern of movement of a small number of lights attached to the major joints of a human performing simple actions. Normal observers watching such displays immediately recognize a person and his or her actions. In the present study, we investigated the effects of lesions of anterior cortical regions on the perception of biological motion. We measured the performance on psychophysical static and motion tasks and on object and action recognition tests in four stroke patients who presented with a disorder of recognition of biological motion. We relate our results to the finding that neurons in the rostral part of the superior temporal gyrus (the superior temporal polysensory area) respond selectively to biological motion, and to the idea that the superior temporal polysensory area integrates the late stages of the dorsal and ventral cortical visual streams, as well as to recent functional MRI studies on biological motion.

Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries

Inglese, James; Auld, Douglas S.; Jadhav, Ajit; Johnson, Ronald L.; Simeonov, Anton; Yasgar, Adam; Zheng, Wei; Austin, Christopher P.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.85%
High-throughput screening (HTS) of chemical compounds to identify modulators of molecular targets is a mainstay of pharmaceutical development. Increasingly, HTS is being used to identify chemical probes of gene, pathway, and cell functions, with the ultimate goal of comprehensively delineating relationships between chemical structures and biological activities. Achieving this goal will require methodologies that efficiently generate pharmacological data from the primary screen and reliably profile the range of biological activities associated with large chemical libraries. Traditional HTS, which tests compounds at a single concentration, is not suited to this task, because HTS is burdened by frequent false positives and false negatives and requires extensive follow-up testing. We have developed a paradigm, quantitative HTS (qHTS), tested with the enzyme pyruvate kinase, to generate concentration–response curves for >60,000 compounds in a single experiment. We show that this method is precise, refractory to variations in sample preparation, and identifies compounds with a wide range of activities. Concentration–response curves were classified to rapidly identify pyruvate kinase activators and inhibitors with a variety of potencies and efficacies and elucidate structure–activity relationships directly from the primary screen. Comparison of qHTS with traditional single-concentration HTS revealed a high prevalence of false negatives in the single-point screen. This study demonstrates the feasibility of qHTS for accurately profiling every compound in large chemical libraries (>105 compounds). qHTS produces rich data sets that can be immediately mined for reliable biological activities...

Predicting interpretability of metabolome models based on behavior, putative identity, and biological relevance of explanatory signals

Enot, David P.; Beckmann, Manfred; Overy, David; Draper, John
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.85%
Powerful algorithms are required to deal with the dimensionality of metabolomics data. Although many achieve high classification accuracy, the models they generate have limited value unless it can be demonstrated that they are reproducible and statistically relevant to the biological problem under investigation. Random forest (RF) generates models, without any requirement for dimensionality reduction or feature selection, in which individual variables are ranked for significance and displayed in an explicit manner. In metabolome fingerprinting by mass spectrometry, each metabolite can be represented by signals at several m/z. Exploiting a prior understanding of expected biochemical differences between sample classes, we aimed to develop meaningful metrics relevant to the significance both of the overall RF model and individual, potentially explanatory, signals. Pair-wise comparison of related plant genotypes with strong phenotypic differences demonstrated that robust models are not only reproducible but also logically structured, highlighting correlated m/z derived from just a small number of explanatory metabolites reflecting the biological differences between sample classes. RF models were also generated by using groupings of samples known to be increasingly phenotypically similar. Although classification accuracy was often reasonable...

Multiple ERK substrates execute single biological processes in Caenorhabditis elegans germ-line development

Arur, Swathi; Ohmachi, Mitsue; Nayak, Sudhir; Hayes, Matthew; Miranda, Alejandro; Hay, Amanda; Golden, Andy; Schedl, Tim
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.87%
RAS-extracellular signal regulated kinase (ERK) signaling governs multiple aspects of cell fate specification, cellular transitions, and growth by regulating downstream substrates through phosphorylation. Understanding how perturbations to the ERK signaling pathway lead to developmental disorders and cancer hinges critically on identification of the substrates. Yet, only a limited number of substrates have been identified that function in vivo to execute ERK-regulated processes. The Caenorhabditis elegans germ line utilizes the well-conserved RAS–ERK signaling pathway in multiple different contexts. Here, we present an integrated functional genomic approach that identified 30 ERK substrates, each of which functions to regulate one or more of seven distinct biological processes during C. elegans germ-line development. Our results provide evidence for three themes that underlie the robustness and specificity of biological outcomes controlled by ERK signaling in C. elegans that are likely relevant to ERK signaling in other organisms: (i) multiple diverse ERK substrates function to control each individual biological process; (ii) different combinations of substrates function to control distinct biological processes; and (iii) regulatory feedback loops between ERK and its substrates help reinforce or attenuate ERK activation. Substrates identified here have conserved orthologs in humans...

Structure of deviations from optimality in biological systems

Pérez-Escudero, Alfonso; Rivera-Alba, Marta; de Polavieja, Gonzalo G.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.85%
Optimization theory has been used to analyze evolutionary adaptation. This theory has explained many features of biological systems, from the genetic code to animal behavior. However, these systems show important deviations from optimality. Typically, these deviations are large in some particular components of the system, whereas others seem to be almost optimal. Deviations from optimality may be due to many factors in evolution, including stochastic effects and finite time, that may not allow the system to reach the ideal optimum. However, we still expect the system to have a higher probability of reaching a state with a higher value of the proposed indirect measure of fitness. In systems of many components, this implies that the largest deviations are expected in those components with less impact on the indirect measure of fitness. Here, we show that this simple probabilistic rule explains deviations from optimality in two very different biological systems. In Caenorhabditis elegans, this rule successfully explains the experimental deviations of the position of neurons from the configuration of minimal wiring cost. In Escherichia coli, the probabilistic rule correctly obtains the structure of the experimental deviations of metabolic fluxes from the configuration that maximizes biomass production. This approach is proposed to explain or predict more data than optimization theory while using no extra parameters. Thus...

Reverse engineering dynamic temporal models of biological processes and their relationships

Ramakrishnan, Naren; Tadepalli, Satish; Watson, Layne T.; Helm, Richard F.; Antoniotti, Marco; Mishra, Bud
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.88%
Biological processes such as circadian rhythms, cell division, metabolism, and development occur as ordered sequences of events. The synchronization of these coordinated events is essential for proper cell function, and hence the determination of critical time points in biological processes is an important component of all biological investigations. In particular, such critical time points establish logical ordering constraints on subprocesses, impose prerequisites on temporal regulation and spatial compartmentalization, and situate dynamic reorganization of functional elements in preparation for subsequent stages. Thus, building temporal phenomenological representations of biological processes from genome-wide datasets is relevant in formulating biological hypotheses on: how processes are mechanistically regulated; how the regulations vary on an evolutionary scale, and how their inadvertent disregulation leads to a diseased state or fatality. This paper presents a general framework (GOALIE) to reconstruct temporal models of cellular processes from time-course gene expression data. We mathematically formulate the problem as one of optimally segmenting datasets into a succession of “informative” windows such that time points within a window expose concerted clusters of gene action whereas time points straddling window boundaries constitute points of significant restructuring. We illustrate here how GOALIE successfully brings out the interplay between multiple yeast processes...

Biological role of noise encoded in a genetic network motif

Kittisopikul, Mark; Süel, Gürol M.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.85%
Genetic circuits that regulate distinct cellular processes can differ in their wiring pattern of interactions (architecture) and susceptibility to stochastic fluctuations (noise). Whether the link between circuit architecture and noise is of biological importance remains, however, poorly understood. To investigate this problem, we performed a computational study of gene expression noise for all possible circuit architectures of feed-forward loop (FFL) motifs. Results revealed that FFL architectures fall into two categories depending on whether their ON (stimulated) or OFF (unstimulated) steady states exhibit noise. To explore the biological importance of this difference in noise behavior, we analyzed 858 documented FFLs in Escherichia coli that were divided into 39 functional categories. The majority of FFLs were found to regulate two subsets of functional categories. Interestingly, these two functional categories associated with FFLs of opposite noise behaviors. This opposite noise preference revealed two noise-based strategies to cope with environmental constraints where cellular responses are either initiated or terminated stochastically to allow probabilistic sampling of alternative states. FFLs may thus be selected for their architecture-dependent noise behavior...

Quantifying the Waddington landscape and biological paths for development and differentiation

Wang, Jin; Zhang, Kun; Xu, Li; Wang, Erkang
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.88%
We developed a theoretical framework to prove the existence and quantify the Waddington landscape as well as chreode-biological paths for development and differentiation. The cells can have states with the higher probability ones giving the different cell types. Different cell types correspond to different basins of attractions of the probability landscape. We study how the cells develop from undifferentiated cells to differentiated cells from landscape perspectives. We quantified the Waddington landscape through construction of underlying probability landscape for cell development. We show the developmental process proceeds as moving from undifferentiated to the differentiated basins of attractions. The barrier height of the basins of attractions correlates with the escape time that determines the stability of cell types. We show that the developmental process can be quantitatively described and uncovered by the biological paths on the quantified Waddington landscape from undifferentiated to the differentiated cells. We found the dynamics of the developmental process is controlled by a combination of the gradient and curl force on the landscape. The biological paths often do not follow the steepest descent path on the landscape. The landscape framework also quantifies the possibility of reverse differentiation process such as cell reprogramming from differentiated cells back to the original stem cell. We show that the biological path of reverse differentiation is irreversible and different from the one for differentiation process. We found that the developmental process described by the underlying landscape and the associated biological paths is relatively stable and robust against the influences of environmental perturbations.

Separating intrinsic from extrinsic fluctuations in dynamic biological systems

Hilfinger, Andreas; Paulsson, Johan
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.85%
From molecules in cells to organisms in ecosystems, biological populations fluctuate due to the intrinsic randomness of individual events and the extrinsic influence of changing environments. The combined effect is often too complex for effective analysis, and many studies therefore make simplifying assumptions, for example ignoring either intrinsic or extrinsic effects to reduce the number of model assumptions. Here we mathematically demonstrate how two identical and independent reporters embedded in a shared fluctuating environment can be used to identify intrinsic and extrinsic noise terms, but also how these contributions are qualitatively and quantitatively different from what has been previously reported. Furthermore, we show for which classes of biological systems the noise contributions identified by dual-reporter methods correspond to the noise contributions predicted by correct stochastic models of either intrinsic or extrinsic mechanisms. We find that for broad classes of systems, the extrinsic noise from the dual-reporter method can be rigorously analyzed using models that ignore intrinsic stochasticity. In contrast, the intrinsic noise can be rigorously analyzed using models that ignore extrinsic stochasticity only under very special conditions that rarely hold in biology. Testing whether the conditions are met is rarely possible and the dual-reporter method may thus produce flawed conclusions about the properties of the system...

Direct and indirect effects of biological factors on extinction risk in fossil bivalves

Harnik, Paul G.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.85%
Biological factors, such as abundance and body size, may contribute directly to extinction risk and indirectly through their influence on other biological characteristics, such as geographic range size. Paleontological data can be used to explicitly test many of these hypothesized relationships, and general patterns revealed through analysis of the fossil record can help refine predictive models of extinction risk developed for extant species. Here, I use structural equation modeling to tease apart the contributions of three canonical predictors of extinction—abundance, body size, and geographic range size—to the duration of bivalve species in the early Cenozoic marine fossil record of the eastern United States. I find that geographic range size has a strong direct effect on extinction risk and that an apparent direct effect of abundance can be explained entirely by its covariation with geographic range. The influence of geographic range on extinction risk is manifest across three ecologically disparate bivalve clades. Body size also has strong direct effects on extinction risk but operates in opposing directions in different clades, and thus, it seems to be decoupled from extinction risk in bivalves as a whole. Although abundance does not directly predict extinction risk...

Optimization criteria and biological process enrichment in homologous multiprotein modules

Hodgkinson, Luqman; Karp, Richard M.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.89%
Biological process enrichment is a widely used metric for evaluating the quality of multiprotein modules. In this study, we examine possible optimization criteria for detecting homologous multiprotein modules and quantify their effects on biological process enrichment. We find that modularity, linear density, and module size are the most important criteria considered, complementary to each other, and that graph theoretical attributes account for 36% of the variance in biological process enrichment. Variations in protein interaction similarity within module pairs have only minor effects on biological process enrichment. As random modules increase in size, both biological process enrichment and modularity tend to improve, although modularity does not show this upward trend in modules with size at most 50 proteins. To adjust for these trends, we recommend a size correction based on random sampling of modules when using biological process enrichment or other attributes to evaluate module boundaries. Characteristics of homologous multiprotein modules optimized for each of the optimization criteria are examined.

Childhood abuse, parental warmth, and adult multisystem biological risk in the Coronary Artery Risk Development in Young Adults study

Carroll, Judith E.; Gruenewald, Tara L.; Taylor, Shelley E.; Janicki-Deverts, Denise; Matthews, Karen A.; Seeman, Teresa E.
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.88%
Adverse social relations in early life are thought to negatively influence health throughout the lifespan. The present findings provide a biological link regarding why negative early life experiences affect health and further suggest that a loving parental figure may provide protection. It is well recognized that providing children in adverse circumstances with a nurturing relationship is beneficial for their overall wellbeing. Our findings suggest that a loving relationship may also prevent the rise in biomarkers indicative of disease risk across numerous physiological systems, impacting adverse health outcomes decades later. The results contribute in a meaningful way to several biological literatures and to the social sciences and, as such, will have a substantial impact.

Avaliação dos futuros professores em ciências biológicas sobre a polêmica criacionismo e evolucionismo; Evaluation of student teachers in the biological sciences over the controversial creationism and evolutionism

CARVALHO, Rodolfo
Fonte: Universidade Federal de Goiás; BR; UFG; Mestrado em Educação em Ciências e Matemática; Ciências Exatas e da Terra Publicador: Universidade Federal de Goiás; BR; UFG; Mestrado em Educação em Ciências e Matemática; Ciências Exatas e da Terra
Tipo: Dissertação Formato: application/pdf
Português
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55.87%
This paper has as its main purpose to highlight what are the concepts of future Science and Biology teachers from UFG about the controversy caused by the debate between the ideas of creationism and biological evolution concerning the origin and diversity of life. The study subjects were licensed teachers from the initial and final grades of the Biological Sciences course UFG. This study is based on the questions of quantitative and qualitative research. It was used as a method, case study and, as the main instrument for data collection, the questionnaire comprising two parts: 1) Licensed teachers socio-cultural profile and 2) A dilemma simulating a debate situation on the controversy analyzed. Analyzing the data collected and the bibliographies referred to the topic under this study, as results, the following scores / categories were obtained: a) With respect to subjects perceptions about the controversy creationism x biological evolution, it was evident that this dilemma is related to students familiar/religious formation; b) For future Biology teachers all ideas on the origin and diversity of life should be discussed and taught in the classroom and c) The justification to deal with these ideas in the classroom has a connection with a respect towards creationists opinions. From these three categories...

A predisposition for biological motion in the newborn baby

Simion, Francesca; Regolin, Lucia; Bulf, Hermann
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.88%
An inborn predisposition to attend to biological motion has long been theorized, but had so far been demonstrated only in one animal species (the domestic chicken). In particular, no preference for biological motion was reported for human infants of <3 months of age. We tested 2-day-old babies' discrimination after familiarization and their spontaneous preferences for biological vs. nonbiological point-light animations. Newborns were shown to be able to discriminate between two different patterns of motion (Exp. 1) and, when first exposed to them, selectively preferred to look at the biological motion display (Exp. 2). This preference was also orientation-dependent: newborns looked longer at upright displays than upside-down displays (Exp. 3). These data support the hypothesis that detection of biological motion is an intrinsic capacity of the visual system, which is presumably part of an evolutionarily ancient and nonspecies-specific system predisposing animals to preferentially attend to other animals.

Targeting angiogenesis: Structural characterization and biological properties of a de novo engineered VEGF mimicking peptide

D'Andrea, Luca Domenico; Iaccarino, Guido; Fattorusso, Roberto; Sorriento, Daniela; Carannante, Concetta; Capasso, Domenica; Trimarco, Bruno; Pedone, Carlo
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.87%
Modulating angiogenesis is an attractive goal because many pathological conditions depend on the growth of new vessels. Angiogenesis is mainly regulated by the VEGF, a mitogen specific for endothelial cells. In the last years, many efforts have been pursued to modulate the angiogenic response targeting VEGF and its receptors. Based on the x-ray structure of VEGF bound to the receptor, we designed a peptide, QK, reproducing a region of the VEGF binding interface: the helix region 17–25. NMR conformation analysis of QK revealed that it adopts a helical conformation in water, whereas the peptide corresponding to the α-helix region of VEGF, VEGF15, is unstructured. Biological assays in vitro and on bovine aorta endothelial cells suggested that QK binds to the VEGF receptors and competes with VEGF. VEGF15 did not bind to the receptors indicating that the helical structure is necessary for the biological activity. Furthermore, QK induced endothelial cells proliferation, activated cell signaling dependent on VEGF, and increased the VEGF biological response. QK promoted capillary formation and organization in an in vitro assay on matrigel. These results suggested that the helix region 17–25 of VEGF is involved in VEGF receptor activation. The peptide designed to resemble this region shares numerous biological properties of VEGF...

Inhibition of macrophage migration inhibitory factor (MIF) tautomerase and biological activities by acetaminophen metabolites

Senter, Peter D.; Al-Abed, Yousef; Metz, Christine N.; Benigni, Fabio; Mitchell, Robert A.; Chesney, J.; Han, Jianlin; Gartner, Carlos G.; Nelson, Sidney D.; Todaro, George J.; Bucala, Richard
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
55.88%
The cytokine macrophage migration inhibitory factor (MIF) has emerged to be an important regulator of the inflammatory response and is critically involved in the development of septic shock, arthritis, and glomerulonephritis. Although the biological activities of MIF are presumed to require a receptor-based mechanism of action, the protein is also a tautomerase and has a catalytically active N-terminal proline that is invariant in structurally homologous bacterial isomerases. This observation raises the possibility that MIF may exert its biological action via an enzymatic reaction. Physiologically relevant substrates for MIF have not been identified, nor have site-directed mutagenesis studies consistently supported the requirement for a functional catalytic site. Small molecule inhibitors of MIF's isomerase activity also have been developed, but none have been shown yet to inhibit MIF biological activity. We report herein that the iminoquinone metabolite of acetaminophen, N-acetyl-p-benzoquinone imine (NAPQI), inhibits both the isomerase and the biological activities of MIF. The reaction between NAPQI and MIF is covalent and produces a NAPQI-modified MIF species with diminished cell binding activity and decreased recognition by anti-MIF mAb. These data are consistent with a model by which the NAPQI reacts with the catalytic Pro-1 of MIF to disrupt the integrity of epitope(s) critical to MIF's biological activity and point to the importance of the catalytic domain...