Developing World Users as Lead Users: A Case Study in Engineering Reverse Innovation

This paper examines the “reverse innovation” of the leveraged freedom chair (LFC), a high-performance, low-cost, off-road wheelchair originally designed for developing countries. A needs study of 71 developed world wheelchair users was conducted through three different data collection efforts. These data were contrasted with studies of 125 developing world wheelchair users, who were shown to be lead users for their developed world counterparts. The GRIT freedom chair (GFC), the developed world version of the LFC, was designed based on results of the study. By recognizing developing country users as lead users, designers can reveal latent needs and create globally disruptive innovations.Singapore University of Technology and DesignMassachusetts Institute of Technology. Department of Mechanical EngineeringRobert N. Noyce Career Development Chair at MITGlobal Research Innovation and Technology (GRIT

Anatomical regulation of ice nucleation and cavitation helps trees to survive freezing and drought stress

Peer reviewe

Management of congenital nephrotic syndrome: consensus recommendations of the ERKNet-ESPN Working Group

Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders characterized by nephrotic-range proteinuria, hypoalbuminaemia and oedema, which manifest in utero or during the first 3 months of life. The main cause of CNS is genetic defects in podocytes; however, it can also be caused, in rare cases, by congenital infections or maternal allo-immune disease. Management of CNS is very challenging because patients are prone to severe complications, such as haemodynamic compromise, infections, thromboses, impaired growth and kidney failure. In this consensus statement, experts from the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Paediatric Nephrology (ESPN) summarize the current evidence and present recommendations for the management of CNS, including the use of renin–angiotensin system inhibitors, diuretics, anticoagulation and infection prophylaxis. Therapeutic management should be adapted to the clinical severity of the condition with the aim of maintaining intravascular euvolaemia and adequate nutrition, while preventing complications and preserving central and peripheral vessels. We do not recommend performing routine early nephrectomies but suggest that they are considered in patients with severe complications despite optimal conservative treatment, and before transplantation in patients with persisting nephrotic syndrome and/or a WT1-dominant pathogenic variant

A single dose of the γ-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans

Abstract Background In Alzheimer’s disease, beta-amyloid peptides in the brain aggregate into toxic oligomers and plaques, a process which is associated with neuronal degeneration, memory loss, and cognitive decline. One therapeutic strategy is to decrease the production of potentially toxic beta-amyloid species by the use of inhibitors or modulators of the enzymes that produce beta-amyloid from amyloid precursor protein (APP). The failures of several such drug candidates by lack of effect or undesired side-effects underscore the importance to monitor the drug effects in the brain on a molecular level. Here we evaluate if peptidomic analysis in cerebrospinal fluid (CSF) can be used for this purpose. Methods Fifteen human healthy volunteers, divided into three groups, received a single dose of placebo or either 140 mg or 280 mg of the γ-secretase inhibitor semagacestat (LY450139). Endogenous peptides in CSF, sampled prior to administration of the drug and at six subsequent time points, were analyzed by liquid chromatography coupled to mass spectrometry, using isobaric labeling based on the tandem mass tag approach for relative quantification. Results Out of 302 reproducibly detected peptides, 11 were affected by the treatment. Among these, one was derived from APP and one from amyloid precursor-like protein 1. Nine peptides were derived from proteins that may not be γ-secretase substrates per se, but that are regulated in a γ-secretase-dependent manner. Conclusions These results indicate that a CSF peptidomic approach may be a valuable tool both to verify target engagement and to identify other pharmacodynamic effects of the drug. Data are available via ProteomeXchange with identifier PXD003075. Trial registration NCT00765115, registered 30/09/2008. </jats:sec

PNPLA3 mediates hepatocyte triacylglycerol remodeling

Peer reviewe

PNPLA3 mediates hepatocyte triacylglycerol remodeling

Peer reviewe

Normal growth and intravascular volume status with good metabolic control during peritoneal dialysis in infancy

Peer reviewe

A single dose of the gamma-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans

Background: In Alzheimer’s disease, beta-amyloid peptides in the brain aggregate into toxic oligomers and plaques, a process which is associated with neuronal degeneration, memory loss, and cognitive decline. One therapeutic strategy is to decrease the production of potentially toxic beta-amyloid species by the use of inhibitors or modulators of the enzymes that produce beta-amyloid from amyloid precursor protein (APP). The failures of several such drug candidates by lack of effect or undesired side-effects underscore the importance to monitor the drug effects in the brain on a molecular level. Here we evaluate if peptidomic analysis in cerebrospinal fluid (CSF) can be used for this purpose. Methods: Fifteen human healthy volunteers, divided into three groups, received a single dose of placebo or either 140 mg or 280 mg of the γ-secretase inhibitor semagacestat (LY450139). Endogenous peptides in CSF, sampled prior to administration of the drug and at six subsequent time points, were analyzed by liquid chromatography coupled to mass spectrometry, using isobaric labeling based on the tandem mass tag approach for relative quantification. Results: Out of 302 reproducibly detected peptides, 11 were affected by the treatment. Among these, one was derived from APP and one from amyloid precursor-like protein 1. Nine peptides were derived from proteins that may not be γ-secretase substrates per se, but that are regulated in a γ-secretase-dependent manner. Conclusions: These results indicate that a CSF peptidomic approach may be a valuable tool both to verify target engagement and to identify other pharmacodynamic effects of the drug. Data are available via ProteomeXchange with identifier PXD00307

Management of children with congenital nephrotic syndrome: challenging treatment paradigms

Background: Management of children with congenital nephrotic syndrome (CNS) is challenging. Bilateral nephrectomies followed by dialysis and transplantation are practiced in most centres, but conservative treatment may also be effective. / Methods: We conducted a 6-year review across members of the European Society for Paediatric Nephrology Dialysis Working Group to compare management strategies and their outcomes in children with CNS. / Results: Eighty children (50% male) across 17 tertiary nephrology units in Europe were included (mutations in NPHS1, n = 55; NPHS2, n = 1; WT1, n = 9; others, n = 15). Excluding patients with mutations in WT1, antiproteinuric treatment was given in 42 (59%) with an increase in S-albumin in 70% by median 6 (interquartile range: 3–8) g/L (P < 0.001). Following unilateral nephrectomy, S-albumin increased by 4 (1–8) g/L (P = 0.03) with a reduction in albumin infusion dose by 5 (2–9) g/kg/week (P = 0.02). Median age at bilateral nephrectomies (n = 29) was 9 (7–16) months. Outcomes were compared between two groups of NPHS1 patients: those who underwent bilateral nephrectomies (n = 25) versus those on conservative management (n = 17). The number of septic or thrombotic episodes and growth were comparable between the groups. The response to antiproteinuric treatment, as well as renal and patient survival, was independent of NPHS1 mutation type. At final follow-up (median age 34 months) 20 (80%) children in the nephrectomy group were transplanted and 1 died. In the conservative group, 9 (53%) remained without dialysis, 4 (24%; P < 0.001) were transplanted and 2 died. / Conclusion: An individualized, stepwise approach with prolonged conservative management may be a reasonable alternative to early bilateral nephrectomies and dialysis in children with CNS and NPHS1 mutations. Further prospective studies are needed to define indications for unilateral nephrectomy

Tamarindus indica Extract Alters Release of Alpha Enolase, Apolipoprotein A-I, Transthyretin and Rab GDP Dissociation Inhibitor Beta from HepG2 Cells

Background: The plasma cholesterol and triacylglycerol lowering effects of Tamarindus indica extract have been previously described. We have also shown that the methanol extract of T. indica fruit pulp altered the expression of lipid-associated genes including ABCG5 and APOAI in HepG2 cells. In the present study, effects of the same extract on the release of proteins from the cells were investigated using the proteomics approach. Methodology/Principal Findings: When culture media of HepG2 cells grown in the absence and presence of the methanol extract of T. indica fruit pulp were subjected to 2-dimensional gel electrophoresis, the expression of seven proteins was found to be significantly different (p<0.03125). Five of the spots were subsequently identified as alpha enolase (ENO1), transthyretin (TTR), apolipoprotein A-I (ApoA-I; two isoforms), and rab GDP dissociation inhibitor beta (GDI-2). A functional network of lipid metabolism, molecular transport and small molecule biochemistry that interconnects the three latter proteins with the interactomes was identified using the Ingenuity Pathways Analysis software. Conclusion/Significance: The methanol extract of T. indica fruit pulp altered the release of ENO1, ApoA-I, TTR and GDI-2 from HepG2 cells. Our results provide support on the effect of T. indica extract on cellular lipid metabolism, particularly that of cholesterol