Protein Design Using Continuous Rotamers

Optimizing amino acid conformation and identity is a central problem in computational protein design. Protein design algorithms must allow realistic protein flexibility to occur during this optimization, or they may fail to find the best sequence with the lowest energy. Most design algorithms implement side-chain flexibility by allowing the side chains to move between a small set of discrete, low-energy states, which we call rigid rotamers. In this work we show that allowing continuous side-chain flexibility (which we call continuous rotamers) greatly improves protein flexibility modeling. We present a large-scale study that compares the sequences and best energy conformations in 69 protein-core redesigns using a rigid-rotamer model versus a continuous-rotamer model. We show that in nearly all of our redesigns the sequence found by the continuous-rotamer model is different and has a lower energy than the one found by the rigid-rotamer model. Moreover, the sequences found by the continuous-rotamer model are more similar to the native sequences. We then show that the seemingly easy solution of sampling more rigid rotamers within the continuous region is not a practical alternative to a continuous-rotamer model: at computationally feasible resolutions, using more rigid rotamers was never better than a continuous-rotamer model and almost always resulted in higher energies. Finally, we present a new protein design algorithm based on the dead-end elimination (DEE) algorithm, which we call iMinDEE, that makes the use of continuous rotamers feasible in larger systems. iMinDEE guarantees finding the optimal answer while pruning the search space with close to the same efficiency of DEE. Availability: Software is available under the Lesser GNU Public License v3. Contact the authors for source code

The medicalization of current educational research and its effects on education policy and school reforms

Este artículo parte del supuesto de la aparición de una cultura pedagogizada durante los últimos 200 años, según la cual los problemas sociales percibidos se traducen en desafíos educativos. En consecuencia, tanto la investigación como las instituciones educativas crecieron, y una política educativa surgió como resultado de las negociaciones entre los profesionales, los investigadores y los responsables políticos. El documento mantiene que algunas experiencias específicas ocurridas durante la Segunda Guerra Mundial, provocaron un cambio fundamental en el papel social y cultural de los círculos académicos, que condujo a una cultura tecnocrática caracterizada por una mayor confianza mostrada hacia los expertos en lugar de a la práctica profesional (es decir, los maestros y administradores). Bajo este cambio tecnocrático, en primer lugar surgió un sistema tecnológico de razonamiento, que luego fue sustituido por un “paradigma” médico. El nuevo paradigma condujo a una medicalización de la investigación social, en el cual se da por sentado un particular entendimiento organicista de la realidad social, y su investigación se realiza bajo las más discutibles premisas. El resultado es que pese a la creciente importancia de la investigación en general, este cambio expertocrático y médico de la investigación social dio lugar a una reducción drástica de las oportunidades reformistas al privar a las partes interesadas de una amplia gama de investigación educativa, experiencia profesional, sentido común, y debate político.This paper starts from the assumption of the emergence of an educationalized culture over the last 200 years according to which perceived social problems are translated into educational challenges. As a result, both educational institutions and educational research grew, and educational policy resulted from negotiations between professionals, researchers, and policy makers. The paper argues that specific experiences in the Second World War triggered a fundamental shift in the social and cultural role of academia, leading up to a technocratic culture characterized by confidence in experts rather than in practicing professionals (i.e., teachers and administrators). In this technocratic shift, first a technological system of reasoning emerged, and it was then replaced by a medical “paradigm.” The new paradigm led to a medicalization of social research, in which a particular organistic understanding of the social reality is taken for granted and research is conducted under the mostly undiscussed premises of this particular understanding. The result is that despite the increased importance of research in general, this expertocratic and medical shift of social research led to a massive reduction in reform opportunities by depriving the reform stakeholders of abroad range of education research, professional experience, common sense, and political deliberation.Grupo FORCE (HUM-386). Departamento de Didáctica y Organización Escolar de la Universidad de Granad

Taiwanese nursing students' attitudes toward older people

The aim of this research was to establish Taiwanese undergraduate nursing students’ attitudes toward older people. This study involved a cross-sectional survey of 362 nursing students in a university in southern Taiwan. Overall, the results showed that nursing students had positive attitudes toward older people. Moreover, the findings suggested that nursing students’ intention to work with older people and gender were important factors influencing their attitudes toward older people. The findings of this study indicate that efforts are required to maintain these positive attitudes. In addition, provision of nursing courses related to older people that place greater emphasis on attitudes about aging and that take into account students’ working experience and career intention will lead to higher quality of care for older people

Extracellular phosphorylation of a receptor tyrosine kinase controls synaptic localization of NMDA receptors and regulates pathological pain

<div><p>Extracellular phosphorylation of proteins was suggested in the late 1800s when it was demonstrated that casein contains phosphate. More recently, extracellular kinases that phosphorylate extracellular serine, threonine, and tyrosine residues of numerous proteins have been identified. However, the functional significance of extracellular phosphorylation of specific residues in the nervous system is poorly understood. Here we show that synaptic accumulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) and pathological pain are controlled by ephrin-B-induced extracellular phosphorylation of a single tyrosine (p*Y504) in a highly conserved region of the fibronectin type III (FN3) domain of the receptor tyrosine kinase EphB2. Ligand-dependent Y504 phosphorylation modulates the EphB-NMDAR interaction in cortical and spinal cord neurons. Furthermore, Y504 phosphorylation enhances NMDAR localization and injury-induced pain behavior. By mediating inducible extracellular interactions that are capable of modulating animal behavior, extracellular tyrosine phosphorylation of EphBs may represent a previously unknown class of mechanism mediating protein interaction and function.</p></div