Genes mirror geography within Europe.

Understanding the genetic structure of human populations is of fundamental interest to medical, forensic and anthropological sciences. Advances in high-throughput genotyping technology have markedly improved our understanding of global patterns of human genetic variation and suggest the potential to use large samples to uncover variation among closely spaced populations. Here we characterize genetic variation in a sample of 3,000 European individuals genotyped at over half a million variable DNA sites in the human genome. Despite low average levels of genetic differentiation among Europeans, we find a close correspondence between genetic and geographic distances; indeed, a geographical map of Europe arises naturally as an efficient two-dimensional summary of genetic variation in Europeans. The results emphasize that when mapping the genetic basis of a disease phenotype, spurious associations can arise if genetic structure is not properly accounted for. In addition, the results are relevant to the prospects of genetic ancestry testing; an individual's DNA can be used to infer their geographic origin with surprising accuracy-often to within a few hundred kilometres.

The Tea4-PP1 landmark promotes local growth by dual Cdc42 GEF recruitment and GAP exclusion.

Cell polarization relies on small GTPases, such as Cdc42, which can break symmetry through self-organizing principles, and landmarks that define the axis of polarity. In fission yeast, microtubules deliver the Tea1-Tea4 complex to mark cell poles for growth, but how this complex activates Cdc42 is unknown. Here, we show that ectopic targeting of Tea4 to cell sides promotes the local activation of Cdc42 and cell growth. This activity requires that Tea4 binds the type I phosphatase (PP1) catalytic subunit Dis2 or Sds21, and ectopic targeting of either catalytic subunit is similarly instructive for growth. The Cdc42 guanine-nucleotide-exchange factor Gef1 and the GTPase-activating protein Rga4 are required for Tea4-PP1-dependent ectopic growth. Gef1 is recruited to ectopic Tea4 and Dis2 locations to promote Cdc42 activation. By contrast, Rga4 is locally excluded by Tea4, and its forced colocalization with Tea4 blocks ectopic growth, indicating that Rga4 must be present, but at sites distinct from Tea4. Thus, a Tea4-PP1 landmark promotes local Cdc42 activation and growth both through Cdc42 GEF recruitment and by creating a local trough in a Cdc42 GAP.

Local selection rules that can determine specific pathways of DNA unknotting by type II DNA topoisomerases.

We performed numerical simulations of DNA chains to understand how local geometry of juxtaposed segments in knotted DNA molecules can guide type II DNA topoisomerases to perform very efficient relaxation of DNA knots. We investigated how the various parameters defining the geometry of inter-segmental juxtapositions at sites of inter-segmental passage reactions mediated by type II DNA topoisomerases can affect the topological consequences of these reactions. We confirmed the hypothesis that by recognizing specific geometry of juxtaposed DNA segments in knotted DNA molecules, type II DNA topoisomerases can maintain the steady-state knotting level below the topological equilibrium. In addition, we revealed that a preference for a particular geometry of juxtaposed segments as sites of strand-passage reaction enables type II DNA topoisomerases to select the most efficient pathway of relaxation of complex DNA knots. The analysis of the best selection criteria for efficient relaxation of complex knots revealed that local structures in random configurations of a given knot type statistically behave as analogous local structures in ideal geometric configurations of the corresponding knot type.

State power and protected areas: Dynamics and contradictions of forest conservation in Madhya Pradesh, India

The traditionally coercive and state-controlled governance of protected areas for nature conservation in developing countries has in many cases undergone change in the context of widespread decentralization and liberalization. This article examines an emerging "mixed" (coercive, community- and market-oriented) conservation approach in managed-resource protected areas and its effects on state power through a case study on forest protection in the central Indian state of Madhya Pradesh. The findings suggest that imperfect decentralization and partial liberalization resulted in changed forms, rather than uniform loss, of state power. A forest co-management program paradoxically strengthened local capacity and influence of the Forest Department, which generally maintained its territorial and knowledge-based control over forests and timber management. Furthermore, deregulation and reregulation enabled the state to withdraw from uneconomic activities but also implied reduced place-based control of non-timber forest products. Generally, the new policies and programs contributed to the separation of livelihoods and forests in Madhya Pradesh. The article concludes that regulatory, community- and market-based initiatives would need to be better coordinated to lead to more effective nature conservation and positive livelihood outcomes.

Regional coronary endothelial function is closely related to local early coronary atherosclerosis in patients with mild coronary artery disease: pilot study.

BACKGROUND: Coronary endothelial function is abnormal in patients with established coronary artery disease and was recently shown by MRI to relate to the severity of luminal stenosis. Recent advances in MRI now allow the noninvasive assessment of both anatomic and functional (endothelial function) changes that previously required invasive studies. We tested the hypothesis that abnormal coronary endothelial function is related to measures of early atherosclerosis such as increased coronary wall thickness. METHODS AND RESULTS: Seventeen arteries in 14 healthy adults and 17 arteries in 14 patients with nonobstructive coronary artery disease were studied. To measure endothelial function, coronary MRI was performed before and during isometric handgrip exercise, an endothelial-dependent stressor, and changes in coronary cross-sectional area and flow were measured. Black blood imaging was performed to quantify coronary wall thickness and indices of arterial remodeling. The mean stress-induced change in cross-sectional area was significantly higher in healthy adults (13.5%±12.8%, mean±SD, n=17) than in those with mildly diseased arteries (-2.2%±6.8%, P<0.0001, n=17). Mean coronary wall thickness was lower in healthy subjects (0.9±0.2 mm) than in patients with coronary artery disease (1.4±0.3 mm, P<0.0001). In contrast to healthy subjects, stress-induced changes in cross-sectional area, a measure of coronary endothelial function, correlated inversely with coronary wall thickness in patients with coronary artery disease (r=-0.73, P=0.0008). CONCLUSIONS: There is an inverse relationship between coronary endothelial function and local coronary wall thickness in patients with coronary artery disease but not in healthy adults. These findings demonstrate that local endothelial-dependent functional changes are related to the extent of early anatomic atherosclerosis in mildly diseased arteries. This combined MRI approach enables the anatomic and functional investigation of early coronary disease.

Geoheritage popularisation and cartographic visualisation in the Tsanfleuron-Sanetsch area (Valais, Switzerland)

This paper presents the underlying concepts developed by the Institute of Geography of the University of Lausanne (Switzerland) for a popularisation project of the geoheritage in the Tsanfleuron-Sanetsch area (Valais, Switzerland). Due to its wide scientific interest, the local geoheritage is of great value (Reynard, 2008). The article details the complementary links existing between the different parts of a geotourist project - databases, educational panels, educational material and geotourist map - developed for popularising the geoheritage value of the area. Each element of the project is briefly presented. Special focus is set on mapping questions: how cartographic design and information structure can be set in order to facilitate map's use and comprehension. In this way, the Tsanfleuron-Sanetsch map is presented as an applied example of the guiding principles proposed by Coratza and Regolini-Bissig (2009).

A surface-based approach to quantify local cortical gyrification.

The high complexity of cortical convolutions in humans is very challenging both for engineers to measure and compare it, and for biologists and physicians to understand it. In this paper, we propose a surface-based method for the quantification of cortical gyrification. Our method uses accurate 3-D cortical reconstruction and computes local measurements of gyrification at thousands of points over the whole cortical surface. The potential of our method to identify and localize precisely gyral abnormalities is illustrated by a clinical study on a group of children affected by 22q11 Deletion Syndrome, compared to control individuals.

The effects of physiologically plausible connectivity structure on local and global dynamics in large scale brain models.

Functionally relevant large scale brain dynamics operates within the framework imposed by anatomical connectivity and time delays due to finite transmission speeds. To gain insight on the reliability and comparability of large scale brain network simulations, we investigate the effects of variations in the anatomical connectivity. Two different sets of detailed global connectivity structures are explored, the first extracted from the CoCoMac database and rescaled to the spatial extent of the human brain, the second derived from white-matter tractography applied to diffusion spectrum imaging (DSI) for a human subject. We use the combination of graph theoretical measures of the connection matrices and numerical simulations to explicate the importance of both connectivity strength and delays in shaping dynamic behaviour. Our results demonstrate that the brain dynamics derived from the CoCoMac database are more complex and biologically more realistic than the one based on the DSI database. We propose that the reason for this difference is the absence of directed weights in the DSI connectivity matrix.

Local acquisition of methicillin-resistance in predominant Staphylococcus aureus clones of western Switzerland.

Objectives: Recent population genetic studies suggest that the Staphylococcal Chromosome Cassettes mec (SCCmec) was acquired at a global scale much more frequently than previously thought. We hypothesized that such acquisitions can also be observed at a local level. In the present study, we aimed at investigating the diversity of SCCmec in a local MRSA population, where the dissemination of four MRSA clones has been observed (JCM 2007, 45: 3729). Methods: All the MRSA isolates (one per patient) recovered in the Vaud canton of Switzerland from January 2005 to December 2008 were analyzed in this study. We used the Double Locus Sequence Typing (DLST) method, based on clfB and spa loci, and the e-BURST algorithm to group the types with one allele in common (i.e. clone). To increase the discriminatory power of the DLST method, a third polymorphic marker (clfA) was further analyzed on a sub-sample of isolates. The SCCmec type of each isolate was determined with the first two PCRs of the Kondo scheme. Results: DLST analysis indicated that 1884/2036 isolates (92.5%) belong to the four predominant clones. A majority of isolates in each clone harboured an identical SCCmec type: 61/64 (95%) isolates to DLST clone 1−1 SCCmec IV, 1282/1323 (97%) to clone 2−2 SCCmec II, 237/288 (82%) to clone 3−3 SCCmec IV, and 192/209 (92%) to clone 4−4 SCCmec I. Unexpectedly, different SCCmec types were present in a single predominant DLST clone: SCCmec V plus one unusual type in 3 isolates of clone 1−1; SCCmec I, IV, V, VI plus two unusual types in 41 isolates of clone 2−2; SCCmec I, II, VI plus three unusual types in 51 isolates of clone 3−3; and SCCmec II, IV, V plus one unusual type in 17 isolates of clone 4−4. Interestingly, adding a third locus generally did not change the classification of incongruent SCCmec types, suggesting that these SCCmec elements have been acquired locally during the dissemination of the clones. Conclusion: Although the SCCmec diversity within clones was relatively low at a local level, a significant proportion of isolates with different SCCmec have been identified in the four major clones. This suggests that the local acquisition of SCCmec elements is not a rare event and illustrates the great capacity of S. aureus to quickly adapt to its environment by acquiring new genetic elements.

Local increase of arginase activity in lesions of patients with cutaneous leishmaniasis in ethiopia.

BACKGROUND: Cutaneous leishmaniasis is a vector-borne disease that is in Ethiopia mainly caused by the parasite Leishmania aethiopica. This neglected tropical disease is common in rural areas and causes serious morbidity. Persistent nonhealing cutaneous leishmaniasis has been associated with poor T cell mediated responses; however, the underlying mechanisms are not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We have recently shown in an experimental model of cutaneous leishmaniasis that arginase-induced L-arginine metabolism suppresses antigen-specific T cell responses at the site of pathology, but not in the periphery. To test whether these results translate to human disease, we recruited patients presenting with localized lesions of cutaneous leishmaniasis and assessed the levels of arginase activity in cells isolated from peripheral blood and from skin biopsies. Arginase activity was similar in peripheral blood mononuclear cells (PBMCs) from patients and healthy controls. In sharp contrast, arginase activity was significantly increased in lesion biopsies of patients with localized cutaneous leishmaniasis as compared with controls. Furthermore, we found that the expression levels of CD3ζ, CD4 and CD8 molecules were considerably lower at the site of pathology as compared to those observed in paired PBMCs. CONCLUSION: Our results suggest that increased arginase in lesions of patients with cutaneous leishmaniasis might play a role in the pathogenesis of the disease by impairing T cell effector functions.

International Standardisation and Local Participatory Dynamics : The INTERNORM Project

This paper presents a pilot project (INTERNORM) funded by the University of Lausanne (2010 - 2013) to support the involvement of civil society organisations (CSO) in international standard setting bodies such as the ISO. It analyses how a distinct participatory mechanism can influence the institutional environment of technical diplomacy in which standards are shaped. The project is an attempt to respond to the democratic deficit attested in the field of international standardisation, formally open to civil society participation, but still largely dominated by expert knowledge and market players. Many international standards have direct implications on society as a whole, but CSOs (consumers and environmental associations, trade unions) are largely under-represented in negotiation arenas. The paper draws upon international relations literature on new institutional forms in global governance and studies of participation in science and technology. It argues that there are significant limitations to the rise of civil society participation in such global governance mechanisms. The INTERNORM project has been designed as a platform of knowledge exchange between CSO and academic experts, with earmarked funding and official membership to a national standardisation body. But INTERNORM cannot substitute for a long- established lack of resources in time, money and expertise of CSOs. Despite high entry costs into technical diplomacy, participation thus appears as less a matter of upstream engagement, or of procedure only, than of dedicated means to shift the geometry of actors and the framing of socio-technical change.