Focal adhesion kinase is a load-dependent governor of the slow contractile and oxidative muscle phenotype

Striated muscle exhibits a pronounced structural-functional plasticity in response to chronic alterations in loading. We assessed the implication of focal adhesion kinase (FAK) signalling in mechano-regulated differentiation of slow-oxidative muscle. Load-dependent consequences of FAK signal modulation were identified using a multi-level approach after electrotransfer of rat soleus muscle with FAK-expression plasmid vs. empty plasmid-transfected contralateral controls. Muscle fibre-targeted over-expression of FAK in anti-gravitational muscle for 9 days up-regulated transcript levels of gene ontologies underpinning mitochondrial metabolism and contraction in the transfected belly portion. Concomitantly, mRNA expression of the major fast-type myosin heavy chain (MHC) isoform, MHC2A, was reduced. The promotion of the slow-oxidative expression programme by FAK was abolished after co-expression of the FAK inhibitor FAK-related non-kinase (FRNK). Elevated protein content of MHC1 (+9%) and proteins of mitochondrial respiration (+165-610%) with FAK overexpression demonstrated the translation of transcript differentiation in targeted muscle fibres towards a slow-oxidative muscle phenotype. Coincidentally MHC2A protein was reduced by 50% due to protection of muscle from de-differentiation with electrotransfer. Fibre cross section in FAK-transfected muscle was elevated by 6%. The FAK-modulated muscle transcriptome was load-dependent and regulated in correspondence to tyrosine 397 phosphorylation of FAK. In the context of overload, the FAK-induced gene expression became manifest at the level of contraction by a slow transformation and the re-establishment of normal muscle force from the lowered levels with transfection. These results highlight the analytic power of a systematic somatic transgene approach by mapping a role of FAK in the dominant mechano-regulation of muscular motor performance via control of gene expression.

Male reproductive pattern in a polygynous ungulate with a slow life-history: the role of age, social status and alternative mating tactics

According to life-history theory age-dependent investments into reproduction are thought to co-vary with survival and growth of animals. In polygynous species, in which size is an important determinant of reproductive success, male reproduction via alternative mating tactics at young age are consequently expected to be the less frequent in species with higher survival. We tested this hypothesis in male Alpine ibex (Capra ibex), a highly sexually dimorphic mountain ungulate whose males have been reported to exhibit extremely high adult survival rates. Using data from two offspring cohorts in a population in the Swiss Alps, the effects of age, dominance and mating tactic on the likelihood of paternity were inferred within a Bayesian framework. In accordance with our hypothesis, reproductive success in male Alpine ibex was heavily biased towards older, dominant males that monopolized access to receptive females by adopting the 'tending' tactic, while success among young, subordinate males via the sneaking tactic 'coursing' was in general low and rare. In addition, we detected a high reproductive skew in male Alpine ibex, suggesting a large opportunity for selection. Compared with other ungulates with higher mortality rates, reproduction among young male Alpine ibex was much lower and more sporadic. Consistent with that, further examinations on the species level indicated that in polygynous ungulates the significance of early reproduction appears to decrease with increasing survival. Overall, this study supports the theory that survival prospects of males modulate the investments into reproduction via alternative mating tactics early in life. In the case of male Alpine ibex, the results indicate that their life-history strategy targets for long life, slow and prolonged growth and late reproduction.

Case of "slow" stroke from carotid artery occlusion treated by delayed but cautious endovascular intervention.

In a challenging case of carotid occlusion with slowly evolving stroke, we used brain imaging to facilitate endovascular revascularization resulting in the relief of the patient's symptoms. Patients with carotid occlusion and continued neurological worsening or fluctuations present enormous treatment challenges. These patients may present "slow" strokes with subacute infarcts that present significant challenges and risks during attempts at revascularization of the occluded artery. We present such a case in which we used multimodal imaging techniques, including MR-perfusion, to facilitate endovascular revascularization. Our approach of delayed but cautious intra-arterial thrombolytic therapy, guided by brain imaging, and followed by stent placement across the residual stenosis, enabled revascularization of the occluded artery without overt in-hospital complications.

Ar-40/Ar-39 Evidence for Middle Proterozoic (1300-1500 Ma) Slow Cooling of the Southern Black Hills, South Dakota, Midcontinent, North America: Implications for Early Proterozoic P-T Evolution and Posttectonic Magmatism

Ar-40/Ar-39 total gas and plateau dates from muscovite and biotite in the southern Black Hills, South Dakota, provide evidence for a period of Middle Proterozoic slow cooling. Early Proterozoic (1600-1650 Ma) mica dates were obtained from metasedimentary rocks located in a synformal structure between the Harney Peak and Bear Mountain domes and also south of Bear Mountain. Metamorphic rocks from the dome areas and undeformed samples of the similar to 1710 Ma Harney Peak Granite (HPG) yield Middle Proterozoic mica dates (similar to 1270-1500 Ma). Two samples collected between the synform and Bear Mountain dome yield intermediate total gas mica dates of similar to 1550 Ma. We suggest two end-member interpretations to explain the map pattern of cooling ages: (1) subhorizontal slow cooling of an area which exhibits variation in mica Ar retention intervals or (2) mild folding of a Middle Proterozoic (similar to 1500 Ma) similar to 300 degrees C isotherm. According to the second interpretation, the preservation of older dates between the domes may reflect reactivation of a preexisting synformal structure (and downwarping of relatively cold rocks) during a period of approximately east-west contraction and slow uplift during the Middle Proterozoic. The mica data, together with hornblende data from the Black Hills published elsewhere, indicate that the ambient country-rock temperature at the 3-4 kbar depth of emplacement of the HPG was between 350 degrees C and 500 degrees C, suggesting that the average upper crustal geothermal gradient was 25 degrees-40 degrees C/km prior to intrusion. The thermochronologic data suggest HPG emplacement was followed by a similar to 200 m.y. period of stability and tectonic quiescence with little uplift. We propose that crust thickened during the Early Proterozoic was uplifted and erosionally(?) thinned prior to similar to 1710 Ma and that the HPG magma was emplaced into isostatically stable crust of relatively normal thickness. We speculate that uplift and crustal thinning prior to HPG intrusion was the result of differential thinning of the subcrustal lithosphere beneath the Black Hills. If so, this process would have also caused an increase in mantle heat flux across the Moho and triggered vapor-absent melting of biotite to produce the HPG magma. This scenario for posttectonic granite generation is supported, in part, by the fact that in the whole of the Black Hills, the HPG is spatially associated with the deepest exposed Early Proterozoic country rock.

Growth and Persistence of Diverse Intertidal Crusts: Survival of the Slow in a Fast-Paced World

Encrusting algae are conspicuous components of hard-substratum benthic communities in the photic zone despite being poor competitors and slow growers. Little is known about their growth rates or about mechanisms controlling key processes such as wound healing and surviving overgrowth. We manipulated 12 crustose species (including red and brown algae and a lichen) from the intertidal zone of Washington, USA, studying their varying responses to identical experimental conditions. Three of 8 crust species tested showed increased growth rates with size. Species healed from standardized wounds at different rates and using different mechanisms (e.g. lateral vs vertical regeneration) as seen in cross-sections. Three species showed altered growth rates at unwounded margins of wounded crusts, suggesting intrathallus communication. Year-long experiments involving simulated overgrowth showed that some species can maintain healthy tissue in a covered area, and one (the coralline Lithothamnion phymatodeum) even grew new tissue there. Other species gradually lost color, thickness, and area in covered areas. Hildenbrandia occidentalis survived remarkably well when covered, possibly due to its very slow growth and low metabolic demand. One suggested mechanism underlying the high variation in responses among crusts is the degree to which their thalli may be anatomically integrated by features such as cell fusions; physiological work testing translocation via these features is needed. Other mechanisms allowing persistence include rapid wound healing and frequent recruitment.

Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence

Opioid substitution treatment (OST) for opioid dependence may be limited by adverse events (AEs). Increasing the range of therapeutic options optimizes outcomes and facilitates patient management. An international, multi-center, two-phase study investigated the efficacy and safety of slow-release oral morphine (SROM) versus methadone in patients receiving methadone therapy for opioid dependence. In phase 1 (two way cross-over, 11 weeks each period) patients were randomized to SROM or methadone oral solution. In phase 2 (25 weeks), patients continued treatment with SROM (group A) or switched from methadone to SROM (group B). In total, 211 out of 276 completed phase 1 and 198 entered phase 2 (n = 95 group A, n = 103 group B). Treatment with both SROM and methadone was well tolerated. However, the mean QTc-interval associated with methadone was significantly longer than that under SROM. Higher treatment satisfaction, fewer cravings for heroin, and lower mental stress were reported with SROM. This study adds a significant further weight of evidence that SROM is an effective and well tolerated long-term maintenance treatment for opioid dependence with a beneficial risk profile compared to methadone regarding cardiac effects and supports its clinical utility.

The FgfrL1 receptor is required for development of slow muscle fibers.

FgfrL1, which interacts with Fgf ligands and heparin, is a member of the fibroblast growth factor receptor (Fgfr) family. FgfrL1-deficient mice show two significant alterations when compared to wildtype mice: They die at birth due to a malformed diaphragm and they lack metanephric kidneys. Utilizing gene arrays, qPCR and in situ hybridization we show here that the diaphragm of FgfrL1 knockout animals lacks any slow muscle fibers at E18.5 as indicated by the absence of slow fiber markers Myh7, Myl2 and Myl3. Similar lesions are also found in other skeletal muscles that contain a high proportion of slow fibers at birth, such as the extraocular muscles. In contrast to the slow fibers, fast fibers do not appear to be affected as shown by expression of fast fiber markers Myh3, Myh8, Myl1 and MylPF. At early developmental stages (E10.5, E15.5), FgfrL1-deficient animals express slow fiber genes at normal levels. The loss of slow fibers cannot be attributed to the lack of kidneys, since Wnt4 knockout mice, which also lack metanephric kidneys, show normal expression of Myh7, Myl2 and Myl3. Thus, FgfrL1 is specifically required for embryonic development of slow muscle fibers.

Quick divergence but slow convergence during ecotype formation in lake and stream stickleback pairs of variable age

When genetic constraints restrict phenotypic evolution, diversification can be predicted to evolve along so-called lines of least resistance. To address the importance of such constraints and their resolution, studies of parallel phenotypic divergence that differ in their age are valuable. Here, we investigate the parapatric evolution of six lake and stream threespine stickleback systems from Iceland and Switzerland, ranging in age from a few decades to several millennia. Using phenotypic data, we test for parallelism in ecotypic divergence between parapatric lake and stream populations and compare the observed patterns to an ancestral-like marine population. We find strong and consistent phenotypic divergence, both among lake and stream populations and between our freshwater populations and the marine population. Interestingly, ecotypic divergence in low-dimensional phenotype space (i.e. single traits) is rapid and seems to be often completed within 100 years. Yet, the dimensionality of ecotypic divergence was highest in our oldest systems and only there parallel evolution of unrelated ecotypes was strong enough to overwrite phylogenetic contingency. Moreover, the dimensionality of divergence in different systems varies between trait complexes, suggesting different constraints and evolutionary pathways to their resolution among freshwater systems.

Slow Cities: Sustainable Places in a Fast World

This article examines the Slow Food and Slow City movement as an alternative approach to urban development that focuses on local resources, economic and cultural strengths, and the unique historical context of a town. Following recent discussions about the politics of alternative economic development, the study examines the Slow City movement as a strategy to address the interdependencies between goals for economic, environmental, and equitable urban development. In particular, we draw on the examples of two Slow Cities in Germany—Waldkirch and Hersbruck, and show how these towns are retooling their urban policies. The study is placed in the context of alternative urban development agendas as opposed to corporate-centered development. We conclude the article by offering some remarks about the institutional and political attributes of successful Slow Cities and the transferability of the concept.