Miscible displacement fronts of shear thinning fluids inside rough fractures

The miscible displacement of a shear-thinning fluid by another of same rheological properties is studied experimentally in a transparent fracture by an optical technique imaging relative concentration distributions. The fracture walls have complementary self-affine geometries and are shifted laterally in the direction perpendicular to the mean flow velocity {\bf U} : the flow field is strongly channelized and macro dispersion controls the front structure for P\'{e}clet numbers above a few units. The global front width increases then linearly with time and reflects the velocity distribution between the different channels. In contrast, at the local scale, front spreading is similar to Taylor dispersion between plane parallel surfaces. Both dispersion mechanisms depend strongly on the fluid rheology which shifts from Newtonian to shear-thinning when the flow rate increases. In the latter domain, increasing the concentration enhances the global front width but reduces both Taylor dispersion (due to the flattening of the velocity profile in the gap of the fracture) and the size of medium scale front structures

A multilevel intervention to increase physical activity and improve healthy eating and physical literacy among young children (ages 3-5) attending early childcare centres: the Healthy Start-Départ Santé cluster randomised controlled trial study protocol

Abstract: Background: Childhood obesity is a growing concern for public health. Given a majority of children in many countries spend approximately 30 h per week in early childcare centers, this environment represents a promising setting for implementing strategies to foster healthy behaviours for preventing and controlling childhood obesity. Healthy Start-Départ Santé was designed to promote physical activity, physical literacy, and healthy eating among preschoolers. The objectives of this study are to assess the effectiveness of the Healthy Start-Départ Santé intervention in improving physical activity levels, physical literacy, and healthy eating among preschoolers attending early childcare centers. Methods/Design: This study follows a cluster randomized controlled trial design in which the childcare centers are randomly assigned to receive the intervention or serve as usual care controls. The Healthy Start-Départ Santé intervention is comprised of interlinked components aiming to enable families and educators to integrate physical activity and healthy eating in the daily lives of young children by influencing factors at the intrapersonal, interpersonal, organizational, community, physical environment and policy levels. The intervention period, spanning 6-8 months, is preceded and followed by data collections. Participants are recruited from 61 childcare centers in two Canadian provinces, New Brunswick and Saskatchewan. Centers eligible for this study have to prepare and provide meals for lunch and have at least 20 children between the ages of 3 and 5. Centers are excluded if they have previously received a physical activity or nutrition promoting intervention. Eligible centers are stratified by province, geographical location (urban or rural) and language (English or French), then recruited and randomized using a one to one protocol for each stratum. Data collection is ongoing. The primary study outcomes are assessed using accelerometers (physical activity levels), the Test of Gross Motor Development-II (physical literacy), and digital photography-assisted weighted plate waste (food intake). Discussion: The multifaceted approach of Healthy Start-Départ Santé positions it well to improve the physical literacy and both dietary and physical activity behaviors of children attending early childcare centers. The results of this study will be of relevance given the overwhelming prevalence of overweight and obesity in children worldwide. Trial registration: NCT02375490 (ClinicalTrials.gov registry)

Modeling non-hereditary mechanisms of Alzheimer disease during apoptosis in yeast

Impaired protein degradation and mitochondrial dysfunction are believed to contribute to neurodegenerative disorders, including Alzheimer disease (AD). In patients suffering from non-hereditary AD, UBB+1, the frameshift variant of ubiquitin B, accumulated in neurons affected by neurofibrillary tangles, which is a pathological hallmark. We established a yeast model expressing high levels of UBB+1, and could demonstrate that UBB+1 interfered with both the ubiquitin-proteasome system (UPS) and mitochondrial function. More precisely, UBB+1 promoted the mitochondrion-localized production of the basic amino acids arginine, ornithine, and lysine, which we identified as the decisive toxic event culminating in apoptosis. Inducing the UPS activity at mitochondria prevented the lethal basic amino acid accumulation and avoided UBB+1-triggered cell loss. The arginine/ornithine metabolism is altered in brains of AD patients, and VMS1, the mitochondrion-specific UPS component, co-existed with UBB+1 in neurofibrillary tangles. Therefore, our data suggest that aberrant basic amino acid synthesis is a crucial link between UPS dysfunction and mitochondrial damage during AD progression

Accumulation of Basic Amino Acids at Mitochondria Dictates the Cytotoxicity of Aberrant Ubiquitin

Neuronal accumulation of UBB+1, a frameshift variant of ubiquitin B, is a hallmark of Alzheimer’s disease (AD). How UBB+1 contributes to neuronal dysfunction remains elusive. Here, we show that in brain regions of AD patients with neurofibrillary tangles UBB+1 co-exists with VMS1, the mitochondrion-specific component of the ubiquitin-proteasome system (UPS). Expression of UBB+1 in yeast disturbs the UPS, leading to mitochondrial stress and apoptosis. Inhibiting UPS activity exacerbates while stimulating UPS by the transcription activator Rpn4 reduces UBB+1-triggered cytotoxicity. High levels of the Rpn4 target protein Cdc48 and its cofactor Vms1 are sufficient to relieve programmed cell death. We identified the UBB+1-induced enhancement of the basic amino acids arginine, ornithine, and lysine at mitochondria as a decisive toxic event, which can be reversed by Cdc48/Vms1-mediated proteolysis. The fact that AD-induced cellular dysfunctions can be avoided by UPS activity at mitochondria has potentially far-reaching pathophysiological implications

Long-term proteasomal inhibition in transgenic mice by UBB⁺¹ expression results in dysfunction of central respiration control reminiscent of brainstem neuropathology in Alzheimer patients.

Aging and neurodegeneration are often accompanied by a functionally impaired ubiquitin-proteasome system (UPS). In tauopathies and polyglutamine diseases, a mutant form of ubiquitin B (UBB(+1)) accumulates in disease-specific aggregates. UBB(+1) mRNA is generated at low levels in vivo during transcription from the ubiquitin B locus by molecular misreading. The resulting mutant protein has been shown to inhibit proteasome function. To elucidate causative effects and neuropathological consequences of UBB(+1) accumulation, we used a UBB(+1) expressing transgenic mouse line that models UPS inhibition in neurons and exhibits behavioral phenotypes reminiscent of Alzheimer's disease (AD). In order to reveal affected organs and functions, young and aged UBB(+1) transgenic mice were comprehensively phenotyped for more than 240 parameters. This revealed unexpected changes in spontaneous breathing patterns and an altered response to hypoxic conditions. Our findings point to a central dysfunction of respiratory regulation in transgenic mice in comparison to wild-type littermate mice. Accordingly, UBB(+1) was strongly expressed in brainstem regions of transgenic mice controlling respiration. These regions included, e.g., the medial part of the nucleus of the tractus solitarius and the lateral subdivisions of the parabrachial nucleus. In addition, UBB(+1) was also strongly expressed in these anatomical structures of AD patients (Braak stage #6) and was not expressed in non-demented controls. We conclude that long-term UPS inhibition due to UBB(+1) expression causes central breathing dysfunction in a transgenic mouse model of AD. The UBB(+1) expression pattern in humans is consistent with the contribution of bronchopneumonia as a cause of death in AD patients