Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.

Keratin 16 (K16) is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad. It can be induced in hyperproliferative states such as wound healing, inflammation and cancer. Here we show that the inactive rhomboid protease RHBDF2 (iRHOM2) regulates thickening of the footpad epidermis through its interaction with K16. K16 expression is absent in the thinned footpads of irhom2-/- mice compared with irhom2+/+mice, due to reduced keratinocyte proliferation. Gain-of-function mutations in iRHOM2 underlie Tylosis with oesophageal cancer (TOC), characterized by palmoplantar thickening, upregulate K16 with robust downregulation of its type II keratin binding partner, K6. By orchestrating the remodelling and turnover of K16, and uncoupling it from K6, iRHOM2 regulates the epithelial response to physical stress. These findings contribute to our understanding of the molecular mechanisms underlying hyperproliferation of the palmoplantar epidermis in both physiological and disease states, and how this 'stress' keratin is regulated

Cell motility: the integrating role of the plasma membrane

The plasma membrane is of central importance in the motility process. It defines the boundary separating the intracellular and extracellular environments, and mediates the interactions between a motile cell and its environment. Furthermore, the membrane serves as a dynamic platform for localization of various components which actively participate in all aspects of the motility process, including force generation, adhesion, signaling, and regulation. Membrane transport between internal membranes and the plasma membrane, and in particular polarized membrane transport, facilitates continuous reorganization of the plasma membrane and is thought to be involved in maintaining polarity and recycling of essential components in some motile cell types. Beyond its biochemical composition, the mechanical characteristics of the plasma membrane and, in particular, membrane tension are of central importance in cell motility; membrane tension affects the rates of all the processes which involve membrane deformation including edge extension, endocytosis, and exocytosis. Most importantly, the mechanical characteristics of the membrane and its biochemical composition are tightly intertwined; membrane tension and local curvature are largely determined by the biochemical composition of the membrane and the biochemical reactions taking place; at the same time, curvature and tension affect the localization of components and reaction rates. This review focuses on this dynamic interplay and the feedbacks between the biochemical and biophysical characteristics of the membrane and their effects on cell movement. New insight on these will be crucial for understanding the motility process

Mechanisms of T cell organotropism

F.M.M.-B. is supported by the British Heart Foundation, the Medical Research Council of the UK and the Gates Foundation

Polygenic risk and hazard scores for Alzheimer's disease prediction

OBJECTIVE: Genome‐wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age‐specific genetic risk for AD. The aim of this study was to quantify the age‐specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. // METHODS: Quantification of individual differences in age‐specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age‐specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P‐value thresholds for disease association. // RESULTS: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10−12) was observed for PRS based upon genome‐wide significant SNPs (P ≤ 5 × 10−8). The strength of association was weaker with less stringent SNP selection thresholds. // INTERPRETATION: Both PRS and PHS can be used to predict an age‐specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10−3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10−3, the age‐specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study)

Sources and fate of manganese in a tidal basin of the German Wadden Sea

Dissolved and particulate Mn concentrations were investigated on a seasonal scale in surface waters of the NW German Wadden Sea (Spiekeroog Island) in 2002 and 2003. As the Wadden Sea forms the transition zone between the terrestrial and marine realms, Mn was analysed in coastal freshwater tributaries and in the adjoining German Bight as well. Additionally, sediments and porewaters of the tidal flat sediments were analysed for Mn partitioning and microbial activity. Dissolved Mn concentrations show strong tidal and seasonal variation with elevated concentrations during summer at low tide. Summer values in the Wadden Sea (av. 0.7 μM) are distinctly higher than in the central areas of the German Bight (av. 0.02 μM), suggesting a possible impact of the Wadden Sea environment on the Mn budget of the North Sea. Seasonality is also observed for particulate Mn in the Wadden Sea (winter av. 800 mg kg− 1; summer av. 1360 mg kg− 1). Although particles are relatively Mn-poor during winter, the high SPM load during this season causes elevated excess concentrations of particulate Mn, which in part exceed those of the dissolved phase. Therefore, winter values cannot be ignored in balance calculations for the Wadden Sea system. Porewater Mn concentrations differ depending on sediment type and season. Maximum concentrations are found in surface sediments at a mixed flat site (190 μM) during summer, while winter values are distinctly lower. This indicates that enhanced microbial activity owing to higher temperature during summer leads to increased reduction of Mn-oxides in surface sediments and enhances the corresponding diffusive and advective Mn flux across the sediment-water interface. Draining of Mn-rich porewaters from sediments is also documented by analyses of tidal creek waters, which are highly enriched in Mn during summer. Furthermore, an important Mn source is freshwater discharged into the Wadden Sea via a flood-gate. The concentration of dissolved Mn in freshwater was highly variable during the sampling campaigns in 2002 and 2003, averaging 4 μM. In contrast, particulate Mn displayed a seasonal behaviour with increasing contents during summer. On the basis of salinity variations in the Wadden Sea, the total amount of Mn contributed to the Wadden Sea via freshwater was estimated. This balance shows the importance of the freshwater environment for the Mn inventory of the Wadden Sea. During winter the total Mn inventory of the Wadden Sea water column may be explained almost completely by freshwater discharge, whereas in summer the porewater system forms the dominating source

User-Defined Gestures for Augmented Reality

Abstract. Recently there has been an increase in research towards using hand gestures for interaction in the field of Augmented Reality (AR). These works have primarily focused on researcher designed gestures, while little is known about user preference and behavior for gestures in AR. In this paper, we present our guessability study for hand gestures in AR in which 800 gestures were elicited for 40 selected tasks from 20 participants. Using the agreement found among gestures, a user-defined gesture set was created to guide designers to achieve consistent user-centered gestures in AR. Wobbrock’s surface taxonomy has been extended to cover dimensionalities in AR and with it, characteristics of collected gestures have been derived. Common motifs which arose from the empirical findings were applied to obtain a better understanding of users’ thought and behavior. This work aims to lead to consistent user-centered designed gestures in AR