Niemann-Pick Type C Disease Reveals a Link between Lysosomal Cholesterol and PtdIns(4,5)P2 That Regulates Neuronal Excitability.

There is increasing evidence that the lysosome is involved in the pathogenesis of a variety of neurodegenerative disorders. Thus, mechanisms that link lysosome dysfunction to the disruption of neuronal homeostasis offer opportunities to understand the molecular underpinnings of neurodegeneration and potentially identify specific therapeutic targets. Here, using a monogenic neurodegenerative disorder, NPC1 disease, we demonstrate that reduced cholesterol efflux from lysosomes aberrantly modifies neuronal firing patterns. The molecular mechanism linking alterations in lysosomal cholesterol egress to intrinsic tuning of neuronal excitability is a transcriptionally mediated upregulation of the ABCA1 transporter, whose PtdIns(4,5)P2-floppase activity decreases plasma membrane PtdIns(4,5)P2. The consequence of reduced PtdIns(4,5)P2 is a parallel decrease in a key regulator of neuronal excitability, the voltage-gated KCNQ2/3 potassium channel, which leads to hyperexcitability in NPC1 disease neurons. Thus, cholesterol efflux from lysosomes regulates PtdIns(4,5)P2 to shape the electrical and functional identity of the plasma membrane of neurons in health and disease

Fingering Instability in Combustion

A thin solid (e.g., paper), burning against an oxidizing wind, develops a fingering instability with two decoupled length scales. The spacing between fingers is determined by the P\'eclet number (ratio between advection and diffusion). The finger width is determined by the degree two dimensionality. Dense fingers develop by recurrent tip splitting. The effect is observed when vertical mass transport (due to gravity) is suppressed. The experimental results quantitatively verify a model based on diffusion limited transport

Efficient Computation of Three-Dimensional Flow in Helically Corrugated Hoses Including Swirl

In this article we propose an efficient method to compute the friction factor of helically corrugated hoses carrying flow at high Reynolds numbers. A comparison between computations of several turbulence models is made with experimental results for corrugation sizes that fall outside the range of validity of the Moody diagram. To do this efficiently we implement quasi-periodicity. Using the appropriate boundary conditions and matching body force, we only need to simulate a single period of the corrugation to find the friction factor for fully developed flow. A second technique is introduced by the construction of an appropriately twisted wedge, which allows us to furthermore reduce the problem by a further dimension while accounting for the Beltrami symmetry that is present in the full three-dimensional problem. We make a detailed analysis of the accuracy and time-saving that this novelty introduces. We show that the swirl inside the flow, which is introduced by the helical boundary, has a positive effect on the friction factor. Furthermore, we give a prediction for which corrugation angles the assumption of axisymmetry is no longer valid. It then has to make place for Beltrami-symmetry if accurate results are required

Perceived barriers to children’s active commuting to school: a systematic review of empirical, methodological and theoretical evidence

Active commuting to school (ACS) may increase children’s daily physical activity and help them maintain a healthy weight. Previous studies have identified various perceived barriers related to children’s ACS. However, it is not clear whether and how these studies were methodologically sound and theoretically grounded. The purpose of this review was to critically assess the current literature on perceived barriers to children’s ACS and provide recommendations for future studies. Empirically based literature on perceived barriers to ACS was systematically searched from six databases. A methodological quality scale (MQS) and a theory utilization quality scale (TQS) were created based on previously established instruments and tailored for the current review. Among the 39 studies that met the inclusion criteria, 19 (48.7%) reported statistically significant perceived barriers to child’s ACS. The methodological and theory utilization qualities of reviewed studies varied, with MQS scores ranging between 7 and 20 (Mean =12.95, SD =2.95) and TQS scores from 1 to 7 (Mean =3.62, SD =1.74). A detailed appraisal of the literature suggests several empirical, methodological, and theoretical recommendations for future studies on perceived barriers to ACS. Empirically, increasing the diversity of study regions and samples should be a high priority, particularly in Asian and European countries, and among rural residents; more prospective and interventions studies are needed to determine the causal mechanism liking the perceived factors and ACS; future researchers should include policy-related barriers into their inquiries. Methodologically, the conceptualization of ACS should be standardized or at least well rationalized in future studies to ensure the comparability of results; researchers’ awareness need to be increased for improving the methodological rigor of studies, especially in regard to appropriate statistical analysis techniques, control variable estimation, multicollinearity testing, and reliability and validity reporting. Theoretically, future researchers need to first ground their investigations in theoretical foundations; efforts should be devoted to make sure theories are used thoroughly and correctly; important theoretical constructs, in particular, need to be conceptualized and operationalized appropriately to ensure accurate measurement. By reviewing what has been achieved, this review offered insights for more sophisticated ACS studies in the future