A novel TRPC6 mutation in a family with podocytopathy and clinical variability

Abstract Background Mutation in several podocyte-specific genes have been noted to result in phenotypic heterogeneity. Herein, we report a novel, autosomal dominant TRPC6 mutation in a family with disease ranging from asymptomatic minimal change disease to end-stage kidney disease. Case presentation A 35 year old woman developed asymptomatic, nephrotic range proteinuria during pregnancy that did not resolve after delivery. Her mother had end-stage kidney disease of unknown etiology and her brother had asymptomatic proteinuria. Kidney biopsy revealed minimal change disease in both the proband and her brother. Genetic testing was performed in the proband and mother, revealing a novel frameshift mutation in TRPC6, D873fsX878. The proband continues to have subnephrotic range proteinuria and normal creatinine but her brother has since developed progressive chronic kidney disease. Conclusions The current case report underscores the heterogeneity of disease in podocytopathies and related genes. Genetic testing of podocyte genes is useful in order to understand the pathophysiologic processes underlying these overlapping diseases

A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase

l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL

Correlates and Consequences of Spanking and Verbal Punishment for Low-Income White, African American, and Mexican American Toddlers

This study examined the prevalence, predictors, and outcomes of spanking and verbal punishment in 2,573 low-income White, African American, and Mexican American toddlers at ages 1, 2, and 3. Both spanking and verbal punishment varied by maternal race/ethnicity. Child fussiness at age 1 predicted spanking and verbal punishment at all three ages. Cross-lagged path analyses indicated that spanking (but not verbal punishment) at age 1 predicted child aggressive behavior problems at age 2 and lower Bayley mental development scores at age 3. Neither child aggressive behavior problems nor Bayley scores predicted later spanking or verbal punishment. In some instances, maternal race/ethnicity and/or emotional responsiveness moderated the effects of spanking and verbal punishment on child outcomes

The food superstore revolution: changing times, changing research agendas in the UK

This paper considers the changing scope of research into UK food superstores over a 30-year period. Rather than catalogue changing market shares by format, we seek instead to show how change links to national policy agendas. Academic research has evolved to address the growing complexities of the social, technological, economic and political impacts of the superstore format. We exemplify this by tracing the progression of retail change in Portsmouth, Hampshire, over 30 years. We discover that academic research can conflict with the preconceptions of some public policymakers. The position is exacerbated by a progressive decline in public information – and a commensurate rise in factual data held by commercial data companies – that leaves policymakers with a choice of which data to believe. This casts a shadow over the objectivity of macro-policy as currently formulated. Concerns currently arise because the UK Competition Commission (2008 but ongoing) starts each inquiry afresh with a search for recent data. Furthermore, it has recently called for changes to retail planning – the very arena in which UK superstore research commenced

Baseline age and time to major fracture in younger postmenopausal women

To estimate the incidence of first hip or clinical vertebral fracture or major osteoporotic (hip, clinical vertebral, proximal humerus or wrist) fracture in postmenopausal women receiving their first bone mineral density (BMD) test before age 65

Globally, functional traits are weak predictors of juvenile tree growth, and we do not know why

1. Plant functional traits, in particular specific leaf area (SLA), wood density and seed mass, are often good predictors of individual tree growth rates within communities. Individuals and species with high SLA, low wood density and small seeds tend to have faster growth rates. 2. If community-level relationships between traits and growth have general predictive value, then similar relationships should also be observed in analyses that integrate across taxa, biogeographic regions and environments. Such global consistency would imply that traits could serve as valuable proxies for the complex suite of factors that determine growth rate, and, therefore, could underpin a new generation of robust dynamic vegetation models. Alternatively, growth rates may depend more strongly on the local environment or growth–trait relationships may vary along environmental gradients. 3. We tested these alternative hypotheses using data on 27 352 juvenile trees, representing 278 species from 27 sites on all forested continents, and extensive functional trait data, 38% of which were obtained at the same sites at which growth was assessed. Data on potential evapotranspiration (PET), which summarizes the joint ecological effects of temperature and precipitation, were obtained from a global data base. 4. We estimated size-standardized relative height growth rates (SGR) for all species, then related them to functional traits and PET using mixed-effect models for the fastest growing species and for all species together. 5. Both the mean and 95th percentile SGR were more strongly associated with functional traits than with PET. PET was unrelated to SGR at the global scale. SGR increased with increasing SLA and decreased with increasing wood density and seed mass, but these traits explained only 3.1% of the variation in SGR. SGR–trait relationships were consistently weak across families and biogeographic zones, and over a range of tree statures. Thus, the most widely studied functional traits in plant ecology were poor predictors of tree growth over large scales. 6. Synthesis. We conclude that these functional traits alone may be unsuitable for predicting growth of trees over broad scales. Determining the functional traits that predict vital rates under specific environmental conditions may generate more insight than a monolithic global relationship can offer

The Role of the State in the Financialisation of the UK Economy

This article looks at the role of UK governments in the financialisation of the British economy and its industry. It argues two things. First, the UK state has had a rather more active role here than most observers have acknowledged. Successive governments since the 1970s have not merely abandoned industry, they have handed much of its control to the financial sector. Second, a key part of this policy shift was linked to the rising power of the Treasury and its reshaping of the former Department of Trade and Industry in its own ideal economic policy image. This both boosted the City and disadvantaged industry, thus propelling the UK towards financialisation at a faster pace than almost all rival economies. The arguments are based on evidence from a mix of interviews with central actors, published insider accounts and an analysis of budget statements in the period 1976–2010

Context and Crowding in Perceptual Learning on a Peripheral Contrast Discrimination Task: Context-Specificity in Contrast Learning

Perceptual learning is an improvement in sensitivity due to practice on a sensory task and is generally specific to the trained stimuli and/or tasks. The present study investigated the effect of stimulus configuration and crowding on perceptual learning in contrast discrimination in peripheral vision, and the effect of perceptual training on crowding in this task. 29 normally-sighted observers were trained to discriminate Gabor stimuli presented at 9° eccentricity with either identical or orthogonally oriented flankers with respect to the target (ISO and CROSS, respectively), or on an isolated target (CONTROL). Contrast discrimination thresholds were measured at various eccentricities and target-flanker separations before and after training in order to determine any learning transfer to untrained stimulus parameters. Perceptual learning was observed in all three training stimuli; however, greater improvement was obtained with training on ISO-oriented stimuli compared to CROSS-oriented and unflanked stimuli. This learning did not transfer to untrained stimulus configurations, eccentricities or target-flanker separations. A characteristic crowding effect was observed increasing with viewing eccentricity and decreasing with target-flanker separation before and after training in both configurations. The magnitude of crowding was reduced only at the trained eccentricity and target-flanker separation; therefore, learning for contrast discrimination and for crowding in the present study was configuration and location specific. Our findings suggest that stimulus configuration plays an important role in the magnitude of perceptual learning in contrast discrimination and suggest context-specificity in learning

The Targeting of Plasmalemmal Ceramide to Mitochondria during Apoptosis

Ceramide is a key lipid mediator of cellular processes such as differentiation, proliferation, growth arrest and apoptosis. During apoptosis, ceramide is produced within the plasma membrane. Although recent data suggest that the generation of intracellular ceramide increases mitochondrial permeability, the source of mitochondrial ceramide remains unknown. Here, we determine whether a stress-mediated plasmalemmal pool of ceramide might become available to the mitochondria of apoptotic cells. We have previously established annexin A1—a member of a family of Ca2+ and membrane-binding proteins—to be a marker of ceramide platforms. Using fluorescently tagged annexin A1, we show that, upon its generation within the plasma membrane, ceramide self-associates into platforms that subsequently invaginate and fuse with mitochondria. An accumulation of ceramide within the mitochondria of apoptotic cells was also confirmed using a ceramide-specific antibody. Electron microscopic tomography confirmed that upon the formation of ceramide platforms, the invaginated regions of the plasma membrane extend deep into the cytoplasm forming direct physical contacts with mitochondrial outer membranes. Ceramide might thus be directly transferred from the plasma membrane to the mitochondrial outer membrane. It is conceivable that this “kiss-of-death” increases the permeability of the mitochondrial outer membrane thereby triggering apoptosis