4 resultados para MAP kinase

em Archivo Digital para la Docencia y la Investigación - Repositorio Institucional de la Universidad del País Vasco


Relevância:

20.00% 20.00%

Publicador:

Resumo:

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disease characterized by the lack of reaction to noxious stimuli and anhidrosis. It is caused by mutations in the NTRK1 gene, which encodes the high affinity tyrosine kinase receptor I for Neurotrophic Growth Factor (NGF). -- Case Presentation: We present the case of a female patient diagnosed with CIPA at the age of 8 months. The patient is currently 6 years old and her psychomotor development conforms to her age (RMN, SPECT and psychological study are in the range of normality). PCR amplification of DNA, followed by direct sequencing, was used to investigate the presence of NTRK1 gene mutations. Reverse transcriptase (RT)-PCR amplification of RNA, followed by cloning and sequencing of isolated RT-PCR products was used to characterize the effect of the mutations on NTRK1 mRNA splicing. The clinical diagnosis of CIPA was confirmed by the detection of two splice-site mutations in NTRK1, revealing that the patient was a compound heterozygote at this gene. One of these alterations, c.574+1G > A, is located at the splice donor site of intron 5. We also found a second mutation, c.2206-2 A > G, not previously reported in the literature, which is located at the splice acceptor site of intron 16. Each parent was confirmed to be a carrier for one of the mutations by DNA sequencing analysis. It has been proposed that the c.574+1G > A mutation would cause exon 5 skipping during NTRK1 mRNA splicing. We could confirm this prediction and, more importantly, we provide evidence that the novel c.2206-2A > G mutation also disrupts normal NTRK1 splicing, leading to the use of an alternative splice acceptor site within exon 17. As a consequence, this mutation would result in the production of a mutant NTRK1 protein with a seven aminoacid in-frame deletion in its tyrosine kinase domain. --Conclusions: We present the first description of a CIPA-associated NTRK1 mutation causing a short interstitial deletion in the tyrosine kinase domain of the receptor. The possible phenotypical implications of this mutation are discussed.

Relevância:

20.00% 20.00%

Publicador:

Resumo:

The notion of information processing has dominated the study of the mind for over six decades. However, before the advent of cognitivism, one of the most prominent theoretical ideas was that of Habit. This is a concept with a rich and complex history, which is again starting to awaken interest, following recent embodied, enactive critiques of computationalist frameworks. We offer here a very brief history of the concept of habit in the form of a genealogical network-map. This serves to provide an overview of the richness of this notion and as a guide for further re-appraisal. We identify 77 thinkers and their influences, and group them into seven schools of thought. Two major trends can be distinguished. One is the associationist trend, starting with the work of Locke and Hume, developed by Hartley, Bain, and Mill to be later absorbed into behaviorism through pioneering animal psychologists (Morgan and Thorndike). This tradition conceived of habits atomistically and as automatisms (a conception later debunked by cognitivism). Another historical trend we have called organicism inherits the legacy of Aristotle and develops along German idealism, French spiritualism, pragmatism, and phenomenology. It feeds into the work of continental psychologists in the early 20th century, influencing important figures such as Merleau-Ponty, Piaget, and Gibson. But it has not yet been taken up by mainstream cognitive neuroscience and psychology. Habits, in this tradition, are seen as ecological, self-organizing structures that relate to a web of predispositions and plastic dependencies both in the agent and in the environment. In addition, they are not conceptualized in opposition to rational, volitional processes, but as transversing a continuum from reflective to embodied intentionality. These are properties that make habit a particularly attractive idea for embodied, enactive perspectives, which can now re-evaluate it in light of dynamical systems theory and complexity research.

Relevância:

20.00% 20.00%

Publicador:

Resumo:

[EN] Protein Kinase G (PKG) or cGMP-dependent protein kinases (PKG) have been shown to play an important role in resistance to abiotic stressors such as high temperatures or oxygen deprivation in Drosophila melanogaster. In Drosophila, the foraging gene encodes a PKG; natural variants for this gene exist, which differ in the level of expression of PKG: rovers (forR allele) which express high PKG levels, and sitters (forS allele) which express lower PKG levels. This project explores the differences in recovery from short periods of anoxia between natural variants (focusing on forS2, flies with a sitter gene in a rover background), as well as mutants with insertions in the foraging gene and RNAi recombinants that show a reduced PKG expression. The parameters measured were time to recovery and level of activity after anoxia. The results showed lower activity after anoxia in sitters than in rovers, reflecting a worse recovery from the anoxic coma in flies with lower PKG levels.

Relevância:

20.00% 20.00%

Publicador:

Resumo:

Adenylate Kinase (AK) is a signal transducing protein that regulates cellular energy homeostasis balancing between different conformations. An alteration of its activity can lead to severe pathologies such as heart failure, cancer and neurodegenerative diseases. A comprehensive elucidation of the large-scale conformational motions that rule the functional mechanism of this enzyme is of great value to guide rationally the development of new medications. Here using a metadynamics-based computational protocol we elucidate the thermodynamics and structural properties underlying the AK functional transitions. The free energy estimation of the conformational motions of the enzyme allows characterizing the sequence of events that regulate its action. We reveal the atomistic details of the most relevant enzyme states, identifying residues such as Arg119 and Lys13, which play a key role during the conformational transitions and represent druggable spots to design enzyme inhibitors. Our study offers tools that open new areas of investigation on large-scale motion in proteins.