SAP97 and dystrophin macromolecular complexes determine two pools of cardiac sodium channels Nav1.5 in cardiomyocytes

The cardiac sodium channel Na(v)1.5 plays a key role in excitability and conduction. The 3 last residues of Na(v)1.5 (Ser-Ile-Val) constitute a PDZ-domain binding motif that interacts with the syntrophin-dystrophin complex. As dystrophin is absent at the intercalated discs, Na(v)1.5 could potentially interact with other, yet unknown, proteins at this site.

Dimorphism in Shell Shape and Strength in Two Species of Emydid Turtle

This study investigates the mechanical implications of shell shape differences between males and females of two North American turtle species: Chrysemys picta and Glyptemys insculpta. These species show patterns of sexual dimorphism that are common to many species of turtle. Females have wider and more highly domed shells, whereas males tend to have flatter, more streamlined shells. In addition, the males of many terrestrial species have concave plastra, most likely to accommodate the domed shells of the females while mating. The purpose of this study was to determine whether the known morphological differences in male and female turtle shells are also associated with differences in shell strength. Landmark coordinate data were collected from the shells of males and females of both species. These data were used to create digital models of each shell for finite-element (FE) analysis. FE models were generated by transforming a single base model of a turtle shell to match the shapes of each specimen examined in this study. All models were assigned the same material properties and restraints. Twelve load cases, each representing a predator’s bite at a different location on the carapace, were applied separately to the models. Subsequently, Von Mises stresses were extracted for each element of each model. Overall, the shells of females of both species exhibited significantly lower maximum and average stresses for a given load than those of their male counterparts. Male G. insculpta exhibited significant increases in stresses because of the concave shape of their plastra. We suggest that the mechanical implications of shell shape differences between males and females may have a large impact on many aspects of the biology of these turtle species.

The interface between morphology and action planning: a comparison of two species of New World monkeys

Recent research with several species of nonhuman primates suggests sophisticated motor-planning abilities observed in human adults may be ubiquitous among primates. However, there is considerable variability in the extent to which these abilities are expressed across primate species. In the present experiment, we explore whether the variability in the expression of anticipatory motor-planning abilities may be attributed to cognitive differences (such as tool use abilities) or whether they may be due to the consequences of morphological differences (such as being able to deploy a precision grasp). We compared two species of New World monkeys that differ in their tool use abilities and manual dexterity: squirrel monkeys, Saimiri sciureus (less dexterous with little evidence for tool use) and tufted capuchins, Sapajus apella (more dexterous and known tool users). The monkeys were presented with baited cups in an untrained food extraction task. Consistent with the morphological constraint hypothesis, squirrel monkeys frequently showed second-order motor planning by inverting their grasp when picking up an inverted cup, while capuchins frequently deployed canonical upright grasping postures. Findings suggest that the lack of ability for precision grasping may elicit more consistent second-order motor planning, as the squirrel monkeys (and other species that have shown a high rate of second-order planning) have fewer means of compensating for inefficient initial postures. Thus, the interface between morphology and motor planning likely represents an important factor for understanding both the ontogenetic and phylogenetic origins of sophisticated motor-planning abilities.

The Interface Between Morphology and Action Planning: a Comparison of Two Species of New World Monkeys

Recent research with several species of nonhuman primates suggests sophisticated motor-planning abilities observed in human adults may be ubiquitous among primates. However, there is considerable variability in the extent to which these abilities are expressed across primate species. In the present experiment, we explore whether the variability in the expression of anticipatory motor-planning abilities may be attributed to cognitive differences (such as tool use abilities) or whether they may be due to the consequences of morphological differences (such as being able to deploy a precision grasp). We compared two species of New World monkeys that differ in their tool use abilities and manual dexterity: squirrel monkeys, Saimiri sciureus (less dexterous with little evidence for tool use) and tufted capuchins, Sapajus apella (more dexterous and known tool users). The monkeys were presented with baited cups in an untrained food extraction task. Consistent with the morphological constraint hypothesis, squirrel monkeys frequently showed second-order motor planning by inverting their grasp when picking up an inverted cup, while capuchins frequently deployed canonical upright grasping postures. Findings suggest that the lack of ability for precision grasping may elicit more consistent second-order motor planning, as the squirrel monkeys (and other species that have shown a high rate of second-order planning) have fewer means of compensating for inefficient initial postures. Thus, the interface between morphology and motor planning likely represents an important factor for understanding both the ontogenetic and phylogenetic origins of sophisticated motor-planning abilities. (C) 2013 The Association for the Study of Animal Behaviour. Published by Elsevier Ltd. All rights reserved.

Planetary Gear Modal Vibration Experiments and Correlation against Lumped-Parameter and Finite Element Models

Experimental modal analysis techniques are applied to characterize the planar dynamic behavior of two spur planetary gears. Rotational and translational vibrations of the sun gear, carrier, and planet gears are measured. Experimentally obtained natural frequencies, mode shapes, and dynamic response are compared to the results from lumped-parameter and finite element models. Two qualitatively different classes of mode shapes in distinct frequency ranges are observed in the experiments and confirmed by the lumped-parameter model, which considers the accessory shafts and fixtures in the system to capture all of the natural frequencies and modes. The finite element model estimates the high-frequency modes that have significant tooth mesh deflection without considering the shafts and fixtures. The lumped-parameter and finite element models accurately predict the natural frequencies and modal properties established by experimentation. Rotational, translational, and planet mode types presented in published mathematical studies are confirmed experimentally. The number and types of modes in the low-frequency and high-frequency bands depend on the degrees of freedom in the central members and planet gears, respectively. The accuracy of natural frequency prediction is improved when the planet bearings have differing stiffnesses in the tangential and radial directions, consistent with the bearing load direction. (C) 2012 Elsevier Ltd. All rights reserved.

Tempering the EU? NGO Advocacy in the Area of Freedom, Security, and Justice

The European Union’s (EU) area of Freedom, Security and Justice (AFSJ) portfolio comprises policy areas such as immigration and asylum, and police and judicial cooperation. Steps were taken to bring this field into the mandate of the EU first by the Maastricht Treaty, followed by changes implemented by the Amsterdam and Lisbon Treaties, the last one ‘normalizing’ the EU’s erstwhile Third Pillar. As the emergent EU regime continues to consolidate in this field, NGOs of various kinds continue to seek to influence policy-making and implementation, with varying success. This article seeks to establish the context in which NGOs carry out their work and argues that the EU-NGO interface is impacted both by the institutional realities of the European Union and the capacities of EU-oriented NGOs to seize and expand opportunities for access and input into the policy cycle. Using EU instruments representing three different policy bundles in AFSJ (immigration, asylum and judicial cooperation in criminal matters), the article seeks to map out NGO strategies in engaging and oftentimes resisting European Union policy instruments.

Investigating the Effects of Various Crowd Characteristics on the Dynamic Properties of an Occupied Structure

One of the challenges for structural engineers during design is considering how the structure will respond to crowd-induced dynamic loading. It has been shown that human occupants of a structure do not simply add mass to the system when considering the overall dynamic response of the system, but interact with it and may induce changes of the dynamic properties from those of the empty structure. This study presents an investigation into the human-structure interaction based on several crowd characteristics and their effect on the dynamic properties of an empty structure. The dynamic properties including frequency, damping, and mode shapes were estimated for a single test structure by means of experimental modal analysis techniques. The same techniques were utilized to estimate the dynamic properties when the test structure was occupied by a crowd with different combinations of size, posture, and distribution. The goal of this study is to isolate the occupant characteristics in order to determine the significance of each to be considered when designing new structures to avoid crowd serviceability issues. The results are presented and summarized based on the level of influence of each characteristic. The posture that produces the most significant effects based on the scope of this research is standing with bent knees with a maximum decrease in frequency of the first mode of the empty structure by 32 percent atthe highest mass ratio. The associated damping also increased 36 times the damping of the empty structure. In addition to the analysis of the experimental data, finite element models and a two degree-of-freedom model were created. These models were used to gain an understanding of the test structure, model a crowd as an equivalent mass, and also to develop a single degree-of-freedom (SDOF) model to best represent a crowd of occupants based on the experimental results. The SDOF models created had an averagefrequency of 5.0 Hz, within the range presented in existing biomechanics research, and combined SDOF systems of the test structure and crowd were able to reproduce the frequency and damping ratios associated with experimental tests. Results of this study confirmed the existence of human-structure interaction andthe inability to simply model a crowd as only additional mass. The two degree-offreedom model determined was able to predict the change in natural frequency and damping ratio for a structure occupied by multiple group sizes in a single posture. These results and model are the preliminary steps in the development of an appropriate methodfor modeling a crowd in combination with a more complex FE model of the empty structure.

Plato and Frankfurt: Two Theories of the Relations Between Love and Living Well

This thesis provides a comparison of the ideas of caring and love as they appear in the works of Plato and Frankfurt. Frankfurt, a contemporary philosopher, maintains that an individual arrives at the most meaningful life through understanding what it is that heor she cares about the most. Interestingly, the instances of eros in Plato's Symposium and Phaedrus resonate with this idea. We see throughout these erotic dialogues similarities to Frankfurt's notions of care and love.Throughout his many works, Frankfurt provides us with several distinct features of care and love. This thesis offers an in depth discussion of each of these features andalso provides commentary from other contemporary philosophers who are familiar with Frankfurt's work. In addition, this thesis applies these features of care and love to Plato's erotic dialogues, and emphasizes areas in which Plato and Frankfurt agree and those inwhich they disagree. In essence, it becomes apparent that while there are many similarities between the ideas of these two prominent thinkers, Plato and Frankfurt do not agree about what constitutes the best human life. Plato maintains that the best life is onespent dedicated to philosophy and in pursuit of the 'good'. Frankfurt, on the other hand,imposes no such limitations on what we should consider the best life because people are likely to have different life experiences that lead them to care about and love different things. Instead he suggests that the best or most meaningful human life is one in which a person spends his or her life caring about the things he or she does, indeed, care aboutand loving those things he or she does, indeed, love.

Two patterns of adipokine and other biomarker dynamics in a long-term weight loss intervention

Long-term dietary intervention frequently induces a rapid weight decline followed by weight stabilization/regain. Here, we sought to identify adipokine biomarkers that may reflect continued beneficial effects of dieting despite partial weight regain.

Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation

Human sexual determination is initiated by a cascade of genes that lead to the development of the fetal gonad. Whereas development of the female external genitalia does not require fetal ovarian hormones, male genital development requires the action of testicular testosterone and its more potent derivative dihydrotestosterone (DHT). The "classic" biosynthetic pathway from cholesterol to testosterone in the testis and the subsequent conversion of testosterone to DHT in genital skin is well established. Recently, an alternative pathway leading to DHT has been described in marsupials, but its potential importance to human development is unclear. AKR1C2 is an enzyme that participates in the alternative but not the classic pathway. Using a candidate gene approach, we identified AKR1C2 mutations with sex-limited recessive inheritance in four 46,XY individuals with disordered sexual development (DSD). Analysis of the inheritance of microsatellite markers excluded other candidate loci. Affected individuals had moderate to severe undervirilization at birth; when recreated by site-directed mutagenesis and expressed in bacteria, the mutant AKR1C2 had diminished but not absent catalytic activities. The 46,XY DSD individuals also carry a mutation causing aberrant splicing in AKR1C4, which encodes an enzyme with similar activity. This suggests a mode of inheritance where the severity of the developmental defect depends on the number of mutations in the two genes. An unrelated 46,XY DSD patient carried AKR1C2 mutations on both alleles, confirming the essential role of AKR1C2 and corroborating the hypothesis that both the classic and alternative pathways of testicular androgen biosynthesis are needed for normal human male sexual differentiation.

Two domains of the V protein of virulent canine distemper virus selectively inhibit STAT1 and STAT2 nuclear import

Canine distemper virus (CDV) causes in dogs a severe systemic infection, with a high frequency of demyelinating encephalitis. Among the six genes transcribed by CDV, the P gene encodes the polymerase cofactor protein (P) as well as two additional nonstructural proteins, C and V; of these V was shown to act as a virulence factor. We investigated the molecular mechanisms by which the P gene products of the neurovirulent CDV A75/17 strain disrupt type I interferon (IFN-alpha/beta)-induced signaling that results in the establishment of the antiviral state. Using recombinant knockout A75/17 viruses, the V protein was identified as the main antagonist of IFN-alpha/beta-mediated signaling. Importantly, immunofluorescence analysis illustrated that the inhibition of IFN-alpha/beta-mediated signaling correlated with impaired STAT1/STAT2 nuclear import, whereas the phosphorylation state of these proteins was not affected. Coimmunoprecipitation assays identified the N-terminal region of V (VNT) responsible for STAT1 targeting, which correlated with its ability to inhibit the activity of the IFN-alpha/beta-mediated antiviral state. Conversely, while the C-terminal domain of V (VCT) could not function autonomously, when fused to VNT it optimally interacted with STAT2 and subsequently efficiently suppressed the IFN-alpha/beta-mediated signaling pathway. The latter result was further supported by a single mutation at position 110 within the VNT domain of CDV V protein, resulting in a mutant that lost STAT1 binding while retaining a partial STAT2 association. Taken together, our results identified the CDV VNT and VCT as two essential modules that complement each other to interfere with the antiviral state induced by IFN-alpha/beta-mediated signaling. Hence, our experiments reveal a novel mechanism of IFN-alpha/beta evasion among the morbilliviruses.

Detecting BRAF Mutations in Formalin-Fixed Melanoma: Experiences with Two State-of-the-Art Techniques

Melanoma is characterized by a high frequency of BRAF mutations. It is unknown if the BRAF mutation status has any predictive value for therapeutic approaches such as angiogenesis inhibition.

Comparing the demonstration of freedom from Trichinella infection of domestic pigs by traditional and risk-based surveillance

Traditionally, the routine artificial digestion test is applied to assess the presence of Trichinella larvae in pigs. However, this diagnostic method has a low sensitivity compared to serological tests. The results from artificial digestion tests in Switzerland were evaluated over a time period of 15 years to determine by when freedom from infection based on these data could be confirmed. Freedom was defined as a 95% probability that the prevalence of infection was below 0.0001%. Freedom was demonstrated after 12 years at the latest. A new risk-based surveillance approach was then developed based on serology. Risk-based surveillance was also assessed over 15 years, starting in 2010. It was shown that by using this design, the sample size could be reduced by at least a factor of 4 when compared with the traditional testing regimen, without lowering the level of confidence in the Trichinella-free status of the pig population.