Genome-Wide Linkage Analysis of Human Auditory Cortical Activation Suggests Distinct Loci on Chromosomes 2, 3, and 8

Neural processes are explored through macroscopic neuroimaging and microscopic molecular measures, but the two levels remain primarily detached. The identification of direct links between the levels would facilitate use of imaging signals as probes of genetic function and, vice versa, access to molecular correlates of imaging measures. Neuroimaging patterns have been mapped for a few isolated genes, chosen based on their connection with a clinical disorder. Here we propose an approach that allows an unrestricted discovery of the genetic basis of a neuroimaging phenotype in the normal human brain. The essential components are a subject population that is composed of relatives and selection of a neuroimaging phenotype that is reproducible within an individual and similar between relatives but markedly variable across a population. Our present combined magnetoencephalography and genome-wide linkage study in 212 healthy siblings demonstrates that auditory cortical activation strength is highly heritable and, specifically in the right hemisphere, regulated oligogenically with linkages to chromosomes 2q37, 3p12, and 8q24. The identified regions delimit as candidate genes TRAPPC9, operating in neuronal differentiation, and ROBO1, regulating projections of thalamocortical axons. Identification of normal genetic variation underlying neurophysiological phenotypes offers a non-invasive platform for an in-depth, concerted capitalization of molecular and neuroimaging levels in exploring neural function.Peer reviewe

Understanding the evolution of native pinewoods in Scotland will benefit their future management and conservation

Scots pine (Pinus sylvestris L.) is a foundation species in Scottish highland forests and a national icon. Due to heavy exploitation, the current native pinewood coverage represents a small fraction of the postglacial maximum. To reverse this decline, various schemes have been initiated to promote planting of new and expansion of old pinewoods. This includes the designation of seed zones for control of the remaining genetic resources. The zoning was based mainly on biochemical similarity among pinewoods but, by definition, neutral molecular markers do not reflect local phenotypic adaptation. Environmental variation within Scotland is substantial and it is not yet clear to what extent this has shaped patterns of adaptive differentiation among Scottish populations. Systematic, rangewide common-environment trials can provide insights into the evolution of the native pinewoods, indicating how environment has influenced phenotypic variation and how variation is maintained. Careful design of such experiments can also provide data on the history and connectivity among populations, by molecular marker analysis. Together, phenotypic and molecular datasets from such trials can provide a robust basis for refining seed transfer guidelines for Scots pine in Scotland and should form the scientific basis for conservation action on this nationally important habitat

Glomerular sclerosis in kidneys with congenital nephrotic syndrome (NPHS1)

Congenital nephrotic syndrome of the Finnish type (NPHS1) is a rare genetic disease caused by mutations in the NPHS1 gene encoding a major podocyte slit-diaphragm protein, nephrin. Patients with NPHS1 have severe nephrotic syndrome from birth and develop renal fibrosis in early childhood. In this work, we studied the development of glomerular sclerosis in kidneys removed from 4- to 44-month-old NPHS1 patients. The pathological lesions and expression of glomerular cell markers were studied in nephrectomized NPHS1 and control kidneys using light and electron microscopy and immunohistochemistry. An analysis of 1528 glomeruli from 20 patients revealed progressive mesangial sclerosis and capillary obliteration. Although few inflammatory cells were detected in the mesangial area, paraglomerular inflammation and fibrosis was common. The podocytes showed severe ultrastructural changes and hypertrophy with the upregulation of cyclins A and D1. Podocyte proliferation, however, was rare. Apoptosis was hardly detected and the expression of antiapoptotic B-cell lymphoma-2 and proapoptotic p53 were comparable to controls. Moderate amounts of podocytes were secreted into the urine of NPHS1 patients. Shrinkage of the glomerular tuft was common, whereas occlusion of tubular opening or protrusion of the glomerular tuft into subepithelial space or through the Bowman's capsule were not detected. The results indicate that, in NPHS1 kidneys, the damaged podocytes induce progressive mesangial expansion and capillary obliteration. Podocyte depletion, glomerular tuft adhesion, and misdirected filtration, however, seem to play a minor role in the nephron destruction

Graft Neutrophil Sequestration and Concomitant Tissue Plasminogen Activator Release During Reperfusion in Clinical Kidney Transplantation

Background. Inflammation, coagulation, and fibrinolysis are tightly linked together. Reperfusion after transient ischemia activates both neutrophils, coagulation, and fibrinolysis. Experimental data suggest that tissue plasminogen activator (tPA) regulates renal neutrophil influx in kidney ischemia and reperfusion injury. Methods. In 30 patients undergoing kidney transplantation, we measured renal neutrophil sequestration and tPA release from blood samples drawn from the supplying artery and renal vein early after reperfusion. tPA antigen levels were measured using a commercial enzyme-linked immunosorbent assay kit. For each parameter, transrenal difference (Delta) was calculated by subtracting the value of the arterial sample (ingoing blood) from the value of the venous sample (outgoing blood). Results. Positive transrenal gradients of tPA antigen occurred at 1 minute [Delta = 14 (3-46) ng/mL, P <.01] and 5 minutes [Delta = 5 (-3 to 27) ng/mL, P <.01] after reperfusion. At 5 minutes after reperfusion, a negative transrenal gradient of neutrophils was observed [Delta = -0.17 (-1.45 to 0.24) x 10E9 cells/L, P <.001]. At 1 minute after reperfusion, neutrophil sequestration into the kidney (ie, negative transrenal neutrophil count) correlated significantly with tPA release from the kidney (ie, positive transrenal tPA concentration), (R = -0.513 and P = .006). Conclusions. The findings suggest a proinflammatory role for tPA in ischemia and reperfusion injury in human kidney transplantation.Peer reviewe

Genotypes exhibit no variation in precision foraging in mycorrhizal Norway spruce seedlings

Aims Fine roots, that comprise the adjustable part of the root system, are important in spatially heterogeneous boreal forest soils. We investigated the soil exploring patterns of Norway spruce (Picea abies) seedlings of equal height belonging to families representing two contrasting growth phenotypes that have shown fast and slow growth rates in long-term experiments. We hypothesised that seedlings of the fast-growing phenotype would show a more explorative root growth strategy, intense branching, and root proliferation in response to the nutrient patch, and that slow-growing phenotypes would be more tolerant to drought stress. Methods Seedlings were grown in flat Perspex microcosms with a clod of humus placed in the mid-bottom part of each microcosm for eight months. The order-based and functional classification, branching topology, and size of seedling root systems were studied with WinRHIZO (TM) image-analysis software and root exploration patterns with LIGNUM-model simulations. In addition, transpiration, stomatal conductance, net assimilation rate responses were measured. Results No differences were found in the early foraging of roots for the humus clod nor net assimilation rate and transpiration between the phenotype groups. Seedlings were favouring exploitation over exploration in the early phases of development regardless of growth phenotype group. However, in fast-growing phenotypes, the main roots were longer, and the lateral root pool favoured long and bifurcated laterals that formed larger absorptive root area. Conclusions Our results indicate that in nutrient-poor conditions, better growth of lateral roots precedes future differences in the aboveground growth rate of Norway spruce.Peer reviewe

Football in the community schemes: Exploring the effectiveness of an intervention in promoting healthful behaviour change

This study aims to examine the effectiveness of a Premier League football club’s Football in the Community (FitC) schemes intervention in promoting positive healthful behaviour change in children. Specifically, exploring the effectiveness of this intervention from the perspectives of the participants involved (i.e. the researcher, teachers, children and coaches). A range of data collection techniques were utilized including the principles of ethnography (i.e. immersion, engagement and observations), alongside conducting focus groups with the children. The results allude to the intervention merely ‘keeping active children active’ via (mostly) fun, football sessions. Results highlight the important contribution the ‘coach’ plays in the effectiveness of the intervention. Results relating to working practice (i.e. coaching practice and coach recruitment) are discussed and highlighted as areas to be addressed. FitC schemes appear to require a process of positive organizational change to increase their effectiveness in strategically attending to the health agenda

How does it really feel to act together? : Shared emotions and the phenomenology of we-agency

Research on the phenomenology of agency for joint action has so far focused on the sense of agency and control in joint action, leaving aside questions on how it feels to act together. This paper tries to fill this gap in a way consistent with the existing theories of joint action and shared emotion. We first reconstruct Pacherie’s (Phenomenology and the Cognitive Sciences, 13, 25–46, 2014) account on the phenomenology of agency for joint action, pointing out its two problems, namely (1) the necessary trade-off between the sense of self- and we-agency; and (2) the lack of affective phenomenology of joint action in general. After elaborating on these criticisms based on our theory of shared emotion, we substantiate the second criticism by discussing different mechanisms of shared affect—feelings and emotions—that are present in typical joint actions. We show that our account improves on Pacherie’s, first by introducing our agentive model of we-agency to overcome her unnecessary dichotomy between a sense of self- and we-agency, and then by suggesting that the mechanisms of shared affect enhance not only the predictability of other agents’ actions as Pacherie highlights, but also an agentive sense of we-agency that emerges from shared emotions experienced in the course and consequence of joint action.Peer reviewe

Novel pyrimidine-2,4-diamine derivative suppresses the cell viability and spindle assembly checkpoint activity by targeting Aurora kinases

Mitosis represents a clinically important determination point in the life cycle of proliferating cells. One potential drug target within the mitotic machinery is the spindle assembly checkpoint (SAC), an evolutionarily conserved signaling pathway that monitors the connections between microtubules (MTs) and chromosomes. Mistakes in SAC signaling may lead to cell division errors that can trigger elimination of cancer cells at M phase or soon after exit from mitosis. In this study, we describe the cellular effects of a novel pyrimidine-2,4-diamine derivative that we discovered to inhibit the activity of SAC. The compound caused rapid escape from the mitotic arrest induced by lack of interkinetochore tension but not by lack of MT-kinetochore attachments. In cycling cells, the compound disrupted the architecture of mitotic spindle that triggered a transient M-phase arrest that was rapidly followed by a forced mitotic exit. The premature termination of M phase was found to be a consequence of precocious inactivation of SAC caused by a direct inhibitory effect of the compound on Aurora B kinase in vitro and in cells. The compound also targets Aurora A kinase and tubulin in vitro and in cells, which can explain the observed spindle anomalies. The reduced activity of Aurora B kinase resulted in polyploidy and suppression of cancer cell viability. Our data suggest that this new pharmacophore possesses interesting anticancer properties that could be exploited in development of mitosis-targeting therapies