Últimos itens adicionados do Acervo: Proceedings Nature

Nature é uma das mais prestigiosas e antigas revistas científicas do mundo: sua primeira edição é de 4 de novembro de 1869. Entre as inúmeras descobertas científicas publicadas na Nature estão a dos raios X, da estrutura em dupla hélice do ADN e o buraco na camada de ozônio.

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‣ The 'consciousness' of the living state: Extending the Baars global broadcast model across physiological subsystems

Rodrick Wallace
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
For the broad spectrum of cognitive biological phenomena having 'dual' information sources, isolation from crosstalk between them requires more metabolic free energy than permitting correlation. This allows an evolutionary exaptation leading to dynamic global broadcasts at multiple scales, similar to the well-studied exaptation of noise to trigger stochastic resonance amplification in physiological systems. Entropy gradient models adapted from nonequilibrium thermodynamics lead to an index theorem in which analytic solutions of empirical equations describe different possible topological modes. Not only is the living state characterized by cognition at every scale and level of organization, but by multiple, shifting, tunable, cooperative broadcasts that link selected subsets of those structures to address problems. As for animal consciousness, the 'stream' of cognitive physiological broadcast is constrained by the riverbanks of embedding context, expressed in terms of systematic regularities of an enveloping environmental information source and the limitations imposed by developmental trajectory.

‣ Disruptive Strategies for Removing Drug Discovery Bottlenecks

Sean Ekins; Chris L. Waller; Mary P. Bradley; Antony J. Williams
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
Drug Discovery is shifting focus from the industry to outside partners and in the process creating new bottlenecks, suggesting the need for a more disruptive overhaul. Technologies like high throughput screening (HTS) have moved to a larger number of academic and institutional laboratories in the US, with little apparent coordination or consideration of the outputs and creating a translational gap. While there have been collaborative public private partnerships in Europe to share pharmaceutical data, the USA has lagged behind. Sharing precompetitive computational models may be the next frontier to provide more confidence in the quality of the leads produced and attract investment. We suggest there needs to be an awareness of what research is going on in the screening centers, more collaboration and coordination. These efforts will shift the focus to finding the best researchers to fund and require a rethink of how to reward their collaborative efforts.

‣ Docking studies to explore novel inhibitors against human beta-site APP cleaving enzyme (BACE-1) involved in Alzheimer’s disease

S Anjum Mobeen; Manne Munikumar; Amineni Umamaheswari
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Poster
Português
Alzheimer’s disease (AD) is one of the most prominent neurodegenerative disorders, particularly in elder persons over 65 age. It is characterized by progressive cognitive deterioration together with declining activities. Amyloid precursor protein (APP) cleaves at A-beta (Aβ) peptide by rate limiting factor of Beta-site APP cleaving enzyme (BACE-1) in amyloidogenic pathway. Elevated level of BACE-1 leads to the accumulation of an insoluble form of Aβ peptides (Senile Plaques), an important hallmark in the pathogenesis of Alzheimer disease. Five published inhibitors of BACE-1, thiazolidinediones, rosiglitazone, pioglitazone, Sc7 and tartaric acid are available with poor pharmacological properties and intolerable side effects. Therefore, a computational approach was undertaken to design novel inhibitors against human BACE-1. The crystal structure of human BACE-1 was retrieved from the protein data bank and optimized by applying OPLS force field in Maestro v9.2. An ASINEX database (115,000 ligands) was downloaded and compounds were prepared using LigPrep. The optimized ligand dataset was docked into the BACE-1 through sequential application of Glide HTVS, SP and XP methods that penalizes more stringently for minor steric classes subsequently. Finally...

‣ Quantitative Models for Efficient Cloning of Different Vectors with Various Clone sites

Gang Zhang; Anurag Tandon
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
We developed an efficient "Combinatorial Strategy” for cloning different vectors with various clone sites. 1) Using originally existed clone sites from circular vectors to prepare the inserts, and if no appropriate sites are available, performing SDM to create compatible sites, to achieve maximal correct digestion of the inserts. 2) Different vectors were digested with various restriction endonucleases, and then dephosphorylated with CIP. 3) Top10 competent cells were used for transformation to increase the transformant colonies. Our results showed that, when blunt sites, or a Xba I site was adopted for ligation, the percentages of positive clones were about 50%. Whereas, when different sites, including one blunt and another Pst I sites, Not I and Xho I sites, the percentages of positive clones were nearly 100%. Using this strategy, most vectors could be successfully cloned through “one ligation, one transformation, three to five minipreps."

‣ A Quantitative Model for Human Olfactory Receptors

Sk. Sarif Hassan; Pabitra Pal Choudhury; Aritra Bose
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
A wide variety of chemicals having distinct odors are smelled by humans. Odor perception initiates in the nose, where it is detected by a large family of olfactory receptors (ORs). Based on divergence of evolutionary model a sequence of human ORs database has been proposed by D. Lancet et al (2000, 2006). It is quite impossible to infer whether a given sequence of nucleotides is a human OR or not, without any biological experimental validation. In our perspective, a proper quantitative understanding of these ORs is required to justify or nullify whether a given sequence is a human OR or not. In this paper, all human OR sequences have been quantified, and a set of clusters have been made using the quantitative results based on two different metrics. Using this proposed quantitative model, one can easily make probable justification or deterministic nullification whether a given sequence of nucleotides is a probable human OR homologue or not, without seeking any biological experiment. Of course a further biological experiment is essential to validate the probable human OR homologue.

‣ A Quantitative Model for Human Olfactory Receptors

Sk. Sarif Hassan; Pabitra Pal Choudhury; Aritra Bose
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
A wide variety of chemicals having distinct odors are smelled by humans. Odor perception initiates in the nose, where it is detected by a large family of olfactory receptors (ORs). Based on divergence of evolutionary model, a sequence of human ORs database has been proposed by D. Lancet et al (2000, 2006). It is quite impossible to infer whether a given sequence of nucleotides is a human OR or not, without any biological experimental validation. In our perspective, a proper quantitative understanding of these ORs is required to justify or nullify whether a given sequence is a human OR or not. In this paper, all human OR sequences have been quantified, and a set of clusters have been made using the quantitative results based on two different metrics. Using this proposed quantitative model, one can easily make probable justification or deterministic nullification whether a given sequence of nucleotides is a probable human OR homologue or not, without seeking any biological experiment. Of course a further biological experiment is essential to validate the probable human OR homologue.

‣ How the Discovery of Brain Correlates of Consciousness Supports Non-Reductive Physicalism

Alfredo Pereira Jr
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
In this work I attempt to justify the claim that the discovery of statistically relevant brain correlates of consciousness supports Non-Reductive Physicalism. First I distinguish the main varieties of Reductive and Non-Reductive Physicalism, selecting the right one that is benefited by progress in brain sciences. Second, I discuss epistemological problems in the search of brain correlates of consciousness, focusing on the simultaneous occurrence of conscious activity, known by means of subjective report, and the corresponding brain activity, registered with the help of technology. Finally, I argue – using Salmon´s concept of Statistical Explanation - that statistics affords a distinction of causal (physical) from casual (illusory) correlations.

‣ Improving metabolite evaluation in integrated pathway analysis

Rasanpreet Kaur; Anwesha Dutta; Martina Kutmon; Martijn Iersel; Chris Evelo
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Poster
Português
Biological molecules such as proteins and metabolites interact to accomplish a biological function and to respond to environmental stimuli. Pathways capture this information derived through scientific experimentation and data analysis. They contain information about genes that appear in complexes, the interacting genes, the directionality of the interactions (e.g. inhibitors versus activators), the cellular locations where the reactions occur, and the metabolites that are affected by the processes. Using our open-source pathway analysis platform, PathVisio, we will connect pathway analysis to different quantitative approaches already in development for metabolic network modeling, such as flux balance analysis and dynamic simulation. In order to use system-wide measurements to gain insights into this mechanism, we have to integrate large scale data analysis with modeled or measured fluxomics data results. For this we will develop a BridgeDb database for reaction identifiers, develop a PathVisio plugin for visualization of modeling results and architect a flexible, standards-based visualization approach (e.g. using MIM and SBGN) that will enable visualization of any conforming model, including visualization of the model output (e.g. flux changes). The focus here is on visualization of the modeling results...

‣ Gender effects on cytidine analogue metabolism and myelodysplastic syndrome treatment outcomes

Reda Mahfouz; Ania Jankowska; Quteba Ebrahem; Zhenbo Hu; Pramod Terse; Joseph Covey; Kenneth Chan; Yonghua Ling; Kory Engelke; Mikkael Sekeres; Ramon Tiu; Jaroslaw Maciejewski; Tomas Radivoyevitch; Yogen Saunthararajah
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
In vivo, half-lives of cytidine analogues such as 5-azacytidine and decitabine, used to treat myelodysplastic syndromes (MDS), are determined largely by cytidine deaminase (CDA), an enzyme that rapidly metabolizes these drugs into inactive uridine counterparts. Genetic factors influence CDA activity, and hence, could impact 5-azacytidine/decitabine levels and efficacy, a possibility requiring evaluation. Using an HPLC assay, plasma CDA activity was confirmed to be decreased in individuals with the CDA SNP A79C. More interestingly, there was an even larger decrease in females. Explaining the decrease in enzyme activity, liver CDA expression was significantly lower in female versus male mice. As expected, decitabine plasma levels, measured by mass-spectrometry, were significantly higher in females. In mathematical modeling, the detrimental effect of shortening half-life of S-phase specific therapy was amplified in low S-phase fraction disease (e.g., MDS). Accordingly, in multivariate analysis of MDS patients treated with 5-azacytidine/decitabine, overall survival was significantly worse in males.

‣ Lost in translation: Toward a formal model of multilevel, multiscale medicine

Rodrick Wallace
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
For a broad spectrum of low level cognitive regulatory and other biological phenomena, isolation from signal crosstalk between them requires more metabolic free energy than permitting correlation. This allows an evolutionary exaptation leading to dynamic global broadcasts of interacting physiological processes at multiple scales. The argument is similar to the well-studied exaptation of noise to trigger stochastic resonance amplification in physiological subsystems. Not only is the living state characterized by cognition at every scale and level of organization, but by multiple, shifting, tunable, cooperative larger scale broadcasts that link selected subsets of functional modules to address problems. This multilevel dynamical viewpoint has implications for initiatives in translational medicine that have followed the implosive collapse of pharmaceutical industry 'magic bullet' research. In short, failure to respond to the inherently multilevel, multiscale nature of human pathophysiology will doom translational medicine to a similar implosion.

‣ Schizophrenia is a TH2 dominant autoimmune disease possibly against acetylcholine receptors of CNS

Wanchung(Wan-Jiung) Hu
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
Schizophrenia is a very common psychiatric disorder. However, its etiology and pathogenesis is still unknown. Current theory saying that neurotransmitter imbalance such as serotonin or dopamine only provides limited effectiveness in schizophrenia treatment by drugs changing serotonin and dopamine concentration. Despite of such treatment, majority of schizophrenia patients still have very poor prognosis. Thus, the neurotransmitter imbalance theory is not correct. Here, I propose that schizophrenia is actually a TH2 dominant autoimmune disorder. The candidate of autoantigen could be acetylcholine receptors of CNS. My theory can explain the positive as well as negative symptoms of schizophrenia. By microarray analysis of PBMCS, one-tenth of the total 519 significantly expressed genes are immune-related genes. Among them, TH2 related genes are significantly up-regulated including IL-4, histidine decarboxylase, aldehyde dehydrogenase, CCR9, IgE Fc receptor, GATA2, serotonin receptor, phospholipase A2, and prostaglandin D2 synthase. Besides, TH1 and TH17 related genes are down-regulated including CXCL5, cathepsin C, and neutrophil related S100 binding proteins. The new theory sheds a light to better control this detrimental illness. Anti-inflammatory agents could be used to manage schizophrenia in the near future.

‣ Identifying reliable traits across laboratory mouse exploration arenas: A meta-analysis

Michael J. Galsworthy; Rime Madani; Hans-Peter Lipp
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
This study is a meta-analysis of 367 mice from a collection of behaviour neuroscience and behaviour genetic studies run in the same lab in Zurich, Switzerland. We employed correlation-based statistics to confirm and quantify consistencies in behaviour across the testing environments. All 367 mice ran exactly the same behavioural arenas: the light/dark box, the null maze, the open field arena, an emergence task and finally an object exploration task. We analysed consistency of three movement types across those arenas (resting, scanning, progressing), and their relative preference for three zones of the arenas (home, transition, exploration). Results were that 5/6 measures showed strong individual-differences consistency across the tests. Mean inter-arena correlations for these five measures ranged from +.12 to +.53. Unrotated principal component factor analysis (UPCFA) and Cronbach’s alpha measures showed these traits to be reliable and substantial (32-63% of variance across the five arenas). UPCFA loadings then indicate which tasks give the best information about these cross-task traits. One measure (that of time spent in “intermediate” zones) was not reliable across arenas. Conclusions centre on the use of individual differences research and behavioural batteries to revise understandings of what measures in one task predict for behaviour in others. Developing better behaviour measures also makes sound scientific and ethical sense.

‣ Translational neuroscience requires better design and analysis of preclinical studies

Stanley E. Lazic
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
Animal models are often used to obtain a better understanding of psychiatric, neurodegenerative, and neurodevelopmental disorders. Despite many years of research, these models have not led to many novel therapies or treatments. Translating results between species will always be difficult, and it is argued that inappropriate statistical analyses, failure to identify the experimental unit, lack of random assignment to treatment conditions, and unblinded assessment of outcomes contribute to the low rate of translating preclinical in vivo studies into successful therapies. It is known that these shortcomings can generate biased estimates, too many false positives and false negatives, and unreproducible results. These issues have been raised repeatedly, but have largely gone unheeded by scientists. Two recommendations are made to improve the situation.

‣ Using causal models to distinguish between neurogenesis-dependent and -independent effects on behaviour

Stanley E. Lazic
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
There has been a substantial amount of research on the relationship between hippocampal neurogenesis and behaviour over the past fifteen years, but the causal role that new neurons have on cognitive and affective behavioural tasks is still far from clear. This is partly due to the difficulty of manipulating levels of neurogenesis without inducing off-target effects, which might also influence behaviour. In addition, the analytical methods typically used do not directly test whether neurogenesis mediates the effect of an intervention on behaviour. Previous studies may have incorrectly attributed changes in behavioural performance to neurogenesis because the role of known (or unknown) neurogenesis-independent mechanisms were not formally taken into consideration during the analysis. Causal models can tease apart complex causal relationships and were used to demonstrate that the effect of exercise on pattern separation is via neurogenesis-independent mechanisms. Many studies in the neurogenesis literature would benefit from the use of statistical methods that can separate neurogenesis-dependent from neurogenesis-independent effects on behaviour.

‣ Mobile Image Ratiometry for the Detection of Botrytis cinerea (Gray Mold)

Donald C. Cooper
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
Mobile Platform Informatics (MPI) and Smartphone Informatics (SPI) methods like Mobile Image Ratiometry (MIR) are potentially transformative point-of-use instantaneous analysis tools that are useful across a variety of industries. In agriculture, MIR-compatible immuno test strips allow early detection of a number of biotic stressors before devastating crop losses occur. Here we describe a low-cost and easy-to-use Smartphone and/or tablet-based protocol (Mobile Assay Inc., www.mobileassay.com) for the detection and on-sight instantaneous analysis of B. cinerea, a fungus that causes significant damage to a variety of plants and flowers. Early detection and tracking of the B. cinerea fungus before the visible gray mold appears has the potential to increase agricultural productivity especially in the developing world.

‣ Inter-Tunneling Mechanism of Colliding Population Waves

Lev V. Kalmykov; Vyacheslav L. Kalmykov
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
Here we show a new interaction mechanism of colliding population waves. It provides a stable coexistence of two similar but different species competing for the same limiting resource during their asexual propagation in a limited homogeneous environment under constant conditions. The revealed mechanism opens new opportunities in conservation biology.

‣ Genomic Replikin Counts of Infectious Salmon Anemia Virus (ISAV) in Canada Exceed the Counts in Lethal Outbreaks in Norway, Chile, and Scotland. Real-Time Tracking of the Evolution of the ISAV Genome and the Resultant Replikins Solid Phase ISAV Vaccine Make ISAV Pandemic Prevention Possible.

Samuel Bogoch; Elenore S. Bogoch
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
Genomic Replikin CountsTM of Infectious Salmon Anemia Virus (ISAV) in Canada Exceed the Counts in Lethal Outbreaks in Norway, Chile, and Scotland. Real-Time Tracking of the Evolution of the ISAV Genome and the Resultant Replikins Solid Phase ISAV Vaccine Make ISAV Pandemic Prevention Possible.

‣ The phyogenetic principles of mma: A hypothetical biostratigraphic model

Alfred Czarnetzki; Dirk von Rautenfeld; Madjid Samii
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
Two erectoid hominids from Sarstedt prompted a detailed examination of the course of the impressions of the Arteria meningea media and their characteristics within the line of hominidae.

‣ AntEpiSeeker2.0: extending epistasis detection to epistasis-associated pathway inference using ant colony optimization

Yupeng Wang; Xinyu Liu; Romdhane Rekaya
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
Genome-wide association studies (GWAS) have become a standard method for finding genetic variations that contribute to common, complex diseases. Recently, it is suggested that these diseases may be caused by epistatic interactions of multiple genetic variations. Although tens of software tools have been developed for epistasis detection, few are able to infer pathway importance from the identified epistatic interactions. AntEpiSeeker is originally an algorithm for detecting epistatic interactions in case-control studies, using a two-stage ant colony optimization (ACO) algorithm. We have developed AntEpiSeeker2.0, which extends the AntEpiSeeker algorithm to inference of epistasis-associated pathways, based on a natural use of the ACO pheromones. By looking at pheromone distribution across pathways, epistasis-associated pathways can be easily identified. The effectiveness of AntEpiSeeker2.0 in inferring epistasis-associated pathways is demonstrated through a simulation study and a real data application. AntEpiSeeker 2.0 was designed to provide efficient inference of epistasis-associated pathways based on ant colony optimization and is freely available at http://lambchop.ads.uga.edu/antepiseeker2/.

‣ HTRIdb: an open-access database for experimentally verified human transcriptional regulation interactions

Luiz A. Bovolenta; Marcio L. Acencio; Ney Lemke
Fonte: Nature Preceedings Publicador: Nature Preceedings
Tipo: Manuscript
Português
Background: The modeling of interactions among transcription factors (TFs) and their respective target genes (TGs) into transcriptional regulatory networks is important for the complete understanding of regulation of biological processes. In the case of human TF-TG interactions, there is no database at present that explicitly provides such information even though many databases containing human TF-TG interaction data have been available. In an effort to provide researchers with a repository of TF-TG interactions from which such interactions can be directly extracted, we present here the Human Transcriptional Regulation Interactions database (HTRIdb). Description: The HTRIdb is an open-access database of experimentally validated interactions among human TFs and their TGs. HTRIdb can be searched via a user-friendly web interface and the retrieved TF-TG interactions data and the associated protein-protein interactions can be downloaded or interactively visualized as a network using the Cytoscape Web software. Moreover, users can improve the database quality by uploading their own interactions and indicating inconsistencies in the data. So far, HTRIdb has been populated with 283 TFs that regulate 11886 genes, totaling 18160 TF-TG interactions. HTRIdb is freely available at http://www.lbbc.ibb.unesp.br/htri. Conclusions: HTRIdb is a powerful user-friendly tool from which human experimentally validated TF-TG interactions can be easily extracted and used to construct transcriptional regulation interaction networks enabling researchers to decipher the regulation of biological processes.