A short in-frame deletion in NTRK1 tyrosine kinase domain caused by a novel splice site mutation in a patient with congenital insensitivity to pain with anhidrosis

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.

El contexto universitario español para la creación de spin-off académicas: la actividad de I+D+I en la universidad española

La creación, consolidación y proliferación de empresas de spin-offs académicas requiere que se cumplan una serie de requisitos previos:inversión en I+D que contribuya a crear nuevas oportunidades tecnológicas; capital-riesgo para financiar las primeras etapas de desarrollo de una spin-off; una cultura favorable al emprendizaje en el entorno universitario; programas específicos de apoyo a la creación de spin-offs; un marco regulatorio-institucional que favorezca la I+D, la protección de la propiedad intelectual y la aproximación de los investigadores al mundo empresarial. En este artículo se pretende analizar la actividad de I+D+I universitaria española. Se trata de resaltar las principales características diferenciadoras de la situación española con respecto a la Unión Europea, a algún país europeo significativo y a Estados Unidos, como país de referencia en la transferencia de tecnología a través de spin-off académicas.

Determinants of self-reported smoking and misclassification during pregnancy, and analysis of optimal cut-off points for urinary cotinine: a cross-sectional study

10 p.

Design, Construction and Testing of a Hydraulic Power Take-Off for Wave Energy Converters

This paper presents the construction, mathematical modeling and testing of a scaled universal hydraulic Power Take-Off (PTO) device for Wave Energy Converters (WECs). A specific prototype and test bench were designed and built to carry out the tests. The results obtained from these tests were used to adjust an in-house mathematical model. The PTO was initially designed to be coupled to a scaled wave energy capture device with a low speed and high torque oscillating motion and high power fluctuations. Any Energy Capture Device (ECD) that fulfils these requirements can be coupled to this PTO, provided that its scale is adequately defined depending on the rated power of the full scale prototype. The initial calibration included estimation of the pressure drops in the different components, the pressurization time of the oil inside the hydraulic cylinders and the volumetric efficiency of the complete circuit. Since the overall efficiency measured during the tests ranged from 0.69 to 0.8 and the dynamic performance of the PTO was satisfactory, the results are really promising and it is believed that this solution might prove effective in real devices.

Valuing a Natura 2000 network site to inform land use options using a discrete choice experiment: An illustration from the Basque Country

One of the main problems that public institutions face in the management of protected areas, such as the European Natura 2000 network, is determining how to design and implement sustainable management plans that account for the wide range of marketed and non-marketed benefits they provide to society. This paper presents an application of a stated preference valuation approach aimed at evaluating the social preferences of the population of the Basque Country, Spain, for the key attributes of a regional Natura 2000 network site. According to our results, individuals’ willingness-to-pay (WTP) is higher for attributes associated with non-use values (native tree species and biodiversity conservation) than for attributes associated with use values (agricultural development and commercial forestry). The paper concludes that management policies related to Natura 2000 network sites should account for both for the importance of non-use values and the heterogeneity of the population's preferences in order to minimize potential land use conflicts.

Diseño de programas de apoyo a la creación de spin-off académicas

En el presente trabajo, por medio de una revisión de la literatura, identificamos una serie de variables que condicionan las características de los programas de apoyo a la creación de spin-off académicas, establecemos las condiciones bajo las cuales parece que deberían ir en un sentido u otro y perfilamos cuatro modelos básicos de programas.Los resultados del estudio pueden ser una buena guía para las autoridades académicas interesadas en la implantación de un programa de apoyo a la creación de spin-off o para la mejora de la eficiencia de programas ya existentes.

Modelling the Effect of Climate Change on Environmental Pollution Losses from Dairy Systems in the UK

21 p.

La spin-off universitaria como mecanismo para la transferencia de conocimiento

En los últimos años, ha crecido el número de publicaciones existentes sobre el fenómeno de las spin-offs apareciendo así como un mecanismo revolucionario en el cumplimiento de la tercera misión de la universidad. El presente trabajo analiza la creación de spin-offs universitarias como método para la transferencia de conocimiento universidad-empresa, analizando en un principio la historia de la universidad, los modelos y mecanismos para la transferencia de conocimiento. El análisis continúa con una conceptualización del fenómeno una diferenciación de los tipos de spin-offs, además de destacar sus beneficios y factores condicionantes. Por último, se realiza una síntesis del marco legal vigente y un estudio aplicado sobre esta realidad en la UPV/EHU.

Modeling Innovative Power Take-Off Based on Double-Acting Hydraulic Cylinders Array for Wave Energy Conversion

One of the key systems of a Wave Energy Converter for extraction of wave energy is the Power Take-Off (PTO) device. This device transforms the mechanical energy of a moving body into electrical energy. This paper describes the model of an innovative PTO based on independently activated double-acting hydraulic cylinders array. The model has been developed using a simulation tool, based on a port-based approach to model hydraulics systems. The components and subsystems used in the model have been parameterized as real components and their values experimentally obtained from an existing prototype. In fact, the model takes into account most of the hydraulic losses of each component. The simulations show the flexibility to apply different restraining torques to the input movement depending on the geometrical configuration and the hydraulic cylinders on duty, easily modified by a control law. The combination of these two actions allows suitable flexibility to adapt the device to different sea states whilst optimizing the energy extraction. The model has been validated using a real test bench showing good correlations between simulation and experimental tests.

Structure-function analysis of USP1: insights into the role of Ser313 phosphorylation site and the effect of cancer-associated mutations on autocleavage

Background: In complex with its cofactor UAF1, the USP1 deubiquitinase plays an important role in cellular processes related to cancer, including the response to DNA damage. The USP1/UAF1 complex is emerging as a novel target in cancer therapy, but several aspects of its function and regulation remain to be further clarified. These include the role of the serine 313 phosphorylation site, the relative contribution of different USP1 sequence motifs to UAF1 binding, and the potential effect of cancer-associated mutations on USP1 regulation by autocleavage. Methods: We have generated a large set of USP1 structural variants, including a catalytically inactive form (C90S), non-phosphorylatable (S313A) and phosphomimetic (S313D) mutants, deletion mutants lacking potential UAF1 binding sites, a mutant (GG/AA) unable to undergo autocleavage at the well-characterized G670/G671 diglycine motif, and four USP1 mutants identified in tumor samples that cluster around this cleavage site (G667A, L669P, K673T and A676T). Using cell-based assays, we have determined the ability of these mutants to bind UAF1, to reverse DNA damage-induced monoubiquitination of PCNA, and to undergo autocleavage. Results: A non-phosphorylatable S313A mutant of USP1 retained the ability to bind UAF1 and to reverse PCNA ubiquitination in cell-based assays. Regardless of the presence of a phosphomimetic S313D mutation, deletion of USP1 fragment 420-520 disrupted UAF1 binding, as determined using a nuclear relocation assay. The UAF1 binding site in a second UAF1-interacting DUB, USP46, was mapped to a region homologous to USP1(420-520). Regarding USP1 autocleavage, co-expression of the C90S and GG/AA mutants did not result in cleavage, while the cancer-associated mutation L669P was found to reduce cleavage efficiency. Conclusions: USP1 phosphorylation at S313 is not critical for PCNA deubiquitination, neither for binding to UAF1 in a cellular environment. In this context, USP1 amino acid motif 420-520 is necessary and sufficient for UAF1 binding. This motif, and a homologous amino acid segment that mediates USP46 binding to UAF1, map to the Fingers sub-domain of these DUBs. On the other hand, our results support the view that USP1 autocleavage may occur in cis, and can be altered by a cancer-associated mutation.