NASTRAN analysis of Tokamak vacuum vessel using interactive graphics

Isoparametric quadrilateral and triangular elements were used to represent the vacuum vessel shell structure. For toroidally symmetric loadings, MPCs were employed across model boundaries and rigid format 24 was invoked. Nonsymmetric loadings required the use of the cyclic symmetry analysis available with rigid format 49. NASTRAN served as an important analysis tool in the Tokamak design effort by providing a reliable means for assessing structural integrity. Interactive graphics were employed in the finite element model generation and in the post-processing of results. It was felt that model generation and checkout with interactive graphics reduced the modelling effort and debugging man-hours significantly

Opposing actions of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) in regulating microtubule stabilization during cardiac hypertrophy

Excessive proliferation and stabilization of the microtubule (MT) array in cardiac myocytes can accompany pathological cardiac hypertrophy, but the molecular control of these changes remains poorly characterized. In this study, we examined MT stabilization in two independent murine models of heart failure and revealed increases in the levels of post-translationally modified stable MTs, which were closely associated with STAT3 activation. To explore the molecular signaling events contributing to control of the cardiac MT network, we stimulated cardiac myocytes with an a-adrenergic agonist phenylephrine (PE), and observed increased tubulin content without changes in detyrosinated (glutubulin) stable MT’s. In contrast, the hypertrophic interleukin-6 (IL6) family cytokines increased both the glu-tubulin content and glu-MT density. When we examined a role for ERK in regulating cardiac MTs, we showed that the MEK/ERK-inhibitor U0126 increased glu-MT density in either control cardiac myocytes or following exposure to hypertrophic agents. Conversely, expression of an activated MEK1 mutant reduced glu-tubulin levels. Thus, ERK signaling antagonizes stabilization of the cardiac MT array. In contrast, inhibiting either JAK2 with AG490, or STAT3 signaling with Stattic or siRNA knockdown, blocked cytokine-stimulated increases in glu-MT density. Furthermore, the expression of a constitutively active STAT3 mutant triggered increased glu-MT density in the absence of hypertrophic stimulation. Thus, STAT3 activation contributes substantially to cytokine-stimulated glu-MT changes. Taken together, our results highlight the opposing actions of STAT3 and ERK pathways in the regulation of MT changes associated with cardiac myocyte hypertrophy

Food Sharing across Borders

Evolutionary models consider hunting and food sharing to be milestones that paved the way from primate to human societies. Because fossil evidence is scarce, hominoid primates serve as referential models to assess our common ancestors’ capacity in terms of communal use of resources, food sharing, and other forms of cooperation. Whereas chimpanzees form male-male bonds exhibiting resource-defense polygyny with intolerance and aggression toward nonresidents, bonobos form male-female and female-female bonds resulting in relaxed relations with neighboring groups. Here we report the first known case of meat sharing between members of two bonobo communities, revealing a new dimension of social tolerance in this species. This observation testifies to the behavioral plasticity that exists in the two Pan species and contributes to scenarios concerning the traits of the last common ancestor of Pan and Homo. It also contributes to the discussion of physiological triggers of in-group/out-group behavior and allows reconsideration of the emergence of social norms in prehuman societies

The evolution of the upright posture and gait—a review and a new synthesis

During the last century, approximately 30 hypotheses have been constructed to explain the evolution of the human upright posture and locomotion. The most important and recent ones are discussed here. Meanwhile, it has been established that all main hypotheses published until the last decade of the past century are outdated, at least with respect to some of their main ideas: Firstly, they were focused on only one cause for the evolution of bipedality, whereas the evolutionary process was much more complex. Secondly, they were all placed into a savannah scenario. During the 1990s, the fossil record allowed the reconstruction of emerging bipedalism more precisely in a forested habitat (e.g., as reported by Clarke and Tobias (Science 269:521–524, 1995) and WoldeGabriel et al. (Nature 412:175–178, 2001)). Moreover, the fossil remains revealed increasing evidence that this part of human evolution took place in a more humid environment than previously assumed. The Amphibian Generalist Theory, presented first in the year 2000, suggests that bipedalism began in a wooded habitat. The forests were not far from a shore, where our early ancestor, along with its arboreal habits, walked and waded in shallow water finding rich food with little investment. In contrast to all other theories, wading behaviour not only triggers an upright posture, but also forces the individual to maintain this position and to walk bipedally. So far, this is the only scenario suitable to overcome the considerable anatomical and functional threshold from quadrupedalism to bipedalism. This is consistent with paleoanthropological findings and with functional anatomy as well as with energetic calculations, and not least, with evolutionary psychology. The new synthesis presented here is able to harmonise many of the hitherto competing theories

Strategies for the Use of Fallback Foods in Apes

Researchers have suggested that fallback foods (FBFs) shape primate food processing adaptations, whereas preferred foods drive harvesting adaptations, and that the dietary importance of FBFs is central in determining the expression of a variety of traits. We examine these hypotheses in extant apes. First, we compare the nature and dietary importance of FBFs used by each taxon. FBF importance appears greatest in gorillas, followed by chimpanzees and siamangs, and least in orangutans and gibbons (bonobos are difficult to place). Next, we compare 20 traits among taxa to assess whether the relative expression of traits expected for consumption of FBFs matches their observed dietary importance. Trait manifestation generally conforms to predictions based on dietary importance of FBFs. However, some departures from predictions exist, particularly for orang-utans, which express relatively more food harvesting and processing traits predicted for consuming large amounts of FBFs than expected based on observed dietary importance. This is probably due to the chemical, mechanical, and phenological properties of the apes’ main FBFs, in particular high importance of figs for chimpanzees and hylobatids, compared to use of bark and leaves—plus figs in at least some Sumatran populations—by orang-utans. This may have permitted more specialized harvesting adaptations in chimpanzees and hylobatids, and required enhanced processing adaptations in orang-utans. Possible intercontinental differences in the availability and quality of preferred and FBFs may also be important. Our analysis supports previous hypotheses suggesting a critical influence of the dietary importance and quality of FBFs on ape ecology and, consequently, evolution

P018 SOCS1 and 3 expression is determined by fibroblast phenotype in IPF

STAT3 signaling is implicated in IPF pathogenesis but the mechanisms regulating STAT3 expression and function are unknown. SOCS1 and SOCS3 inhibit STAT3 signaling and reduced SOCS1 levels have been reported in IPF lung fibroblasts and is also associated with increased collagen production. Using IPF and control lung fibroblasts and tissue, the mechanisms underlying SOCS1 downregulation in IPF were investigated. A significant reduction in basal SOCS1 mRNA in IPF fibroblasts was confirmed and a trend towards reduced SOCS3 demonstrated. However there was no difference in their ability to phosphorylate STAT1 or STAT3 or increase SOCS3 expression following IL-6 stimulation or to phosphorylate STAT1 and increase SOCS1 mRNA after IFNγ treatment. Methylation of SOCS1 in control and IPF fibroblasts was low and unaffected by 5’-aza-2’-deoxycytidine’ treatment. SOCS1 is a target of microRNA (miR)-155 and although the miR155 level was increased in IPF tissue, expression was reduced in IPF fibroblasts. Therefore, SOCS1 is not regulated by mRNA stability, SOCS1 gene methylation or miR155 in these cells. Interestingly, reanalysis of cells based on collagen (COLIA1) and alpha smooth muscle actin (ACTA2) mRNA levels showed that cells classified as fibrotic (high COLIA1 and ACTA2), actually had increased SOCS1 and SOCS3 mRNA levels, opposite to the original findings when grouped based on clinical diagnosis. In conclusion, these findings question the role of SOCS1 in driving lung fibrosis in IPF, and demonstrate that phenotypic characterization, in addition to clinical diagnosis will provide a more complete picture of the differential behaviour between IPF and normal lung fibroblasts

LSC Abstract – Investigating SOCS-mediated regulation of STAT signalling in idiopathic pulmonary fibrosis (IPF)

The STAT inhibitor, SOCS1 is reduced in IPF lung fibroblasts, and has been linked to higher levels of type I collagen. Using IPF (n=6) and control (n=9) lung fibroblast cultures and control (n=4) and IPF (n=8) lung tissue, we investigated the mechanisms underlying SOCS1 down-regulation in IPF. We have demonstrated a significant reduction in basal SOCS1 mRNA in IPF fibroblasts and have observed a trend towards reduced SOCS3. Immunohistochemical analysis of lung tissue revealed an abundance of activated-STAT1 and -STAT3, target molecules of SOCS1 and SOCS3. There was no difference in collagen mRNA between IPF and control fibroblasts but high basal levels of collagen protein were detected in IPF cells. There was no difference in the ability of IPF fibroblasts to express pSTAT1, pSTAT3 or SOCS3 following IL-6 stimulation, although the magnitude of the response varied. Similarly, the kinetics of IFNγ-induced SOCS1 mRNA and pSTAT1 levels were not altered in IPF fibroblasts. SOCS1 has been identified as a target of miR155, so we investigated the capacity of miR155 to regulate SOCS1 in IPF. miR155 levels were significantly increased in IPF lung tissue, providing a possible explanation for reduced SOCS1. However, miR155 was reduced in IPF fibroblasts. Analysis of the methylation pattern at putative STAT1/3 binding sites within the SOCS1 promoter has revealed that these sites are unmethylated. In conclusion SOCS1 expression in human lung fibroblasts is not regulated by methylation at STAT1/3 transcription factor binding sites in the SOCS1 promoter or by miR155

SOCS-Regulation of Jak/STAT Signalling in Idiopathic Pulmonary Fibrosis (IPF)

American Thoracic Society International Conference Abstracts > A73. LUNG FIBROSIS: NEW DIRECTIONS TO INFORM THE FUTUR

Reduced <i>SOCS1</i> Expression in Lung Fibroblasts from Patients with IPF Is Not Mediated by Promoter Methylation or Mir155

The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of transcription (STAT)3 signaling is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis, but the mechanisms regulating STAT3 expression and function are unknown. Suppressor of cytokine signaling (SOCS)1 and SOCS3 block STAT3, and low SOCS1 levels have been reported in IPF fibroblasts and shown to facilitate collagen production. Fibroblasts and lung tissue from IPF patients and controls were used to examine the mechanisms underlying SOCS1 down-regulation in IPF. A significant reduction in basal SOCS1 mRNA in IPF fibroblasts was confirmed. However, there was no difference in the kinetics of activation, and methylation of SOCS1 in control and IPF lung fibroblasts was low and unaffected by 5'-aza-2'-deoxycytidine' treatment. SOCS1 is a target of microRNA-155 and although microRNA-155 levels were increased in IPF tissue, they were reduced in IPF fibroblasts. Therefore, SOCS1 is not regulated by SOCS1 gene methylation or microRNA155 in these cells. In conclusion, we confirmed that IPF fibroblasts had lower levels of SOCS1 mRNA compared with control fibroblasts, but we were unable to determine the mechanism. Furthermore, although SOCS1 may be important in the fibrotic process, we were unable to find a significant role for SOCS1 in regulating fibroblast function