CARMIL family proteins as multidomain regulators of actin-based motility

CARMILs are large multidomain proteins that regulate the actin-binding activity of capping protein (CP), a major capper of actin filament barbed ends in cells. CARMILs bind directly to CP and induce a conformational change that allosterically decreases but does not abolish its actin-capping activity. The CP-binding domain of CARMIL consists of the CP-interaction (CPI) and CARMIL-specific interaction (CSI) motifs, which are arranged in tandem. Many cellular functions of CARMILs require the interaction with CP; however, a more surprising result is that the cellular function of CP in cells appears to require binding to a CARMIL or another protein with a CPI motif, suggesting that CPI-motif proteins target CP and modulate its actin-capping activity. Vertebrates have three highly conserved genes and expressed isoforms of CARMIL with distinct and overlapping localizations and functions in cells. Various domains of these CARMIL isoforms interact with plasma membranes, vimentin intermediate filaments, SH3-containing class I myosins, the dual-GEF Trio, and other adaptors and signaling molecules. These biochemical properties suggest that CARMILs play a variety of membrane-associated functions related to actin assembly and signaling. CARMIL mutations and variants have been implicated in several human diseases. We focus on roles for CARMILs in signaling in addition to their function as regulators of CP and actin. </jats:p

The properties of the Galactic bar implied by gas kinematics in the inner Milky Way

Longitude-velocity (l-V) diagrams of H I and CO gas in the inner Milky Way have long been known to be inconsistent with circular motion in an axisymmetric potential. Several lines of evidence suggest that the Galaxy is barred, and gas flow in a barred potential could be consistent with the observed ``forbidden'' velocities and other features in the data. We compare the H I observations to l-V diagrams synthesized from 2-D fluid dynamical simulations of gas flows in a family of barred potentials. The gas flow pattern is very sensitive to the parameters of the assumed potential, which allows us to discriminate among models. We present a model that reproduces the outer contour of the H I l-V diagram reasonably well; this model has a strong bar with a semimajor axis of 3.6 kpc, an axis ratio of approximately 3:1, an inner Lindblad resonance (ILR), and a pattern speed of 42 km/s/kpc, and matches the data best when viewed from 34\deg to the bar major axis. The behavior of the models, combined with the constraint that the shocks in the Milky Way bar should resemble those in external barred galaxies, leads us to conclude that wide ranges of parameter space are incompatible with the observations. In particular we suggest that the bar must be fairly strong, must have an ILR, and cannot be too end-on, with the bar major axis at 35\deg +/- 5\deg to the line of sight. The H I data exhibit larger forbidden velocities over a wider longitude range than are seen in molecular gas; this important difference is the reason our favored model differs so significantly from other recently proposed models.Comment: 23 pages, 14 figures, 1 table, uses emulateapj and psfig, 640 kb. Submitted to Ap

Brokerage in commercialised healthcare systems:A conceptual framework and empirical evidence from Uttar Pradesh

In many contexts there are a range of individuals and organisations offering healthcare services that differ widely in cost, quality and outcomes. This complexity is exacerbated by processes of healthcare commercialisation. Yet reliable information on healthcare provision is often limited, and progress to and through the healthcare system may depend on knowledge drawn from prior experiences, social networks and the providers themselves. It is in these contexts that healthcare brokerage emerges and third-party actors facilitate access to healthcare. This article presents a novel framework for studying brokerage of access to healthcare, and empirical evidence on healthcare brokerage in urban slums in Lucknow, Uttar Pradesh. The framework comprises six areas of interest that have been derived from sociological and political science literature on brokerage. A framework approach was used to group observational and interview data into six framework charts (one for each area of interest) to facilitate close thematic analysis. A cadre of women in Lucknow's urban slums performed healthcare brokerage by encouraging use of particular healthcare services, organising travel, and mediating communications and fee negotiations with providers. The women emphasised their personal role in facilitating access to care and encouraged dependency on their services by withholding information from users. They received commission payments from healthcare programmes, and sometimes from users and hospitals as well, but were blamed for issues beyond their control. Disruption to their ability to facilitate low-cost healthcare meant some women lost their positions as brokers, while others adapted by leveraging old and new relationships with hospital managers. Brokerage analysis reveals how people capitalise on the complexity of healthcare systems by positioning themselves as intermediaries. Commercialised healthcare systems offer a fertile environment for such behaviours, which can undermine attainment of healthcare entitlements and exacerbate inequities in healthcare access

Everyday life and locative play: an exploration of Foursquare and playful engagements with space and place

Foursquare is a location-based social network (LBSN) that combines gaming elements with features conventionally associated with social networking sites (SNSs). Following two qualitative studies, this article sets out to explore what impact this overlaying of physical environments with play has on everyday life and experiences of space and place. Drawing on early understandings of play, alongside the flâneur and ‘phoneur’ as respective methods for conceptualizing play in the context of mobility and urbanity, this article examines whether the suggested division between play and ordinary life is challenged by Foursquare, and if so, how this reframing of play is experienced. Second, this article investigates what effect this LBSN has on mobility choices and spatial relationships. Finally, the novel concept of the ‘phoneur’ is posited as a way of understanding how pervasive play through LBSNs acts as a mediating influence on the experience of space and place

Obesity inhibits the osteogenic differentiation of human adipose-derived stem cells

Additional file 3: Figure S3. No observable differences in lnASCs and obASCs during early bone regeneration. Critical size calvarial defects were created in the parietal bone of nude mice and assessed after 2 weeks. (A) Representative images of microCT scanning. (B) Quantification of microCT. Scale bar represents 1 mm. Bars, Âą SEM

A Bayesian method for evaluating and discovering disease loci associations

Background: A genome-wide association study (GWAS) typically involves examining representative SNPs in individuals from some population. A GWAS data set can concern a million SNPs and may soon concern billions. Researchers investigate the association of each SNP individually with a disease, and it is becoming increasingly commonplace to also analyze multi-SNP associations. Techniques for handling so many hypotheses include the Bonferroni correction and recently developed Bayesian methods. These methods can encounter problems. Most importantly, they are not applicable to a complex multi-locus hypothesis which has several competing hypotheses rather than only a null hypothesis. A method that computes the posterior probability of complex hypotheses is a pressing need. Methodology/Findings: We introduce the Bayesian network posterior probability (BNPP) method which addresses the difficulties. The method represents the relationship between a disease and SNPs using a directed acyclic graph (DAG) model, and computes the likelihood of such models using a Bayesian network scoring criterion. The posterior probability of a hypothesis is computed based on the likelihoods of all competing hypotheses. The BNPP can not only be used to evaluate a hypothesis that has previously been discovered or suspected, but also to discover new disease loci associations. The results of experiments using simulated and real data sets are presented. Our results concerning simulated data sets indicate that the BNPP exhibits both better evaluation and discovery performance than does a p-value based method. For the real data sets, previous findings in the literature are confirmed and additional findings are found. Conclusions/Significance: We conclude that the BNPP resolves a pressing problem by providing a way to compute the posterior probability of complex multi-locus hypotheses. A researcher can use the BNPP to determine the expected utility of investigating a hypothesis further. Furthermore, we conclude that the BNPP is a promising method for discovering disease loci associations. © 2011 Jiang et al

The RMS Survey: Distribution and properties of a sample of massive young stars

The Red MSX Source (RMS) survey has identified a large sample of massive young stellar objects (MYSOs) and ultra compact (UC) HII regions from a sample of ~2000 MSX and 2MASS colour selected sources. Using a recent catalogue of molecular clouds derived from the Boston University-Five College Radio Astronomy Observatory Galactic Ring Survey (GRS), and by applying a Galactic scaleheight cut off of 120 pc, we solve the distance ambiguity for RMS sources located within 18\degr 54\degr. These two steps yield kinematic distances to 291 sources out of a possible 326 located within the GRS longitude range. Combining distances and integrated fluxes derived from spectral energy distributions, we estimate luminosities to these sources and find that > 90% are indicative of the presence of a massive star. We find the completeness limit of our sample is ~10^4 Lsun, which corresponds to a zero age main sequence (ZAMS) star with a mass of ~12 Msun. Selecting only these sources, we construct a complete sample of 196 sources. Comparing the properties of the sample of young massive stars with the general population, we find the RMS-clouds are generally larger, more massive, and more turbulent. We examine the distribution of this sub-sample with respect to the location of the spiral arms and the Galactic bar and find them to be spatially correlated. We identify three significant peaks in the source surface density at Galactocentric radii of approximately 4, 6 and 8 kpc, which correspond to the proposed positions of the Scutum, Sagittarius and Perseus spiral arms, respectively. Fitting a scale height to the data we obtain an average value of ~29+-0.5 pc, which agrees well with other reported values in the literature, however, we note a dependence of the scale height on galactocentric radius with it increases from 30 pc to 45 pc between 2.5 and 8.5 kpc.Comment: Accepted for publication by MNRAS. Paper consists of 15 pages including 12 figures and four tables. Full versions of Tables 2 and 3 will only be available online. The resolution of Figure 9 has been reduced - a full resolution version of the paper can be download from here: http://www.ast.leeds.ac.uk/cgi-bin/RMS/RMS_PUBLICATIONS.cg

Development of High Temperature SiC Based Hydrogen/Hydrocarbon Sensors with Bond Pads for Packaging

This paper describes efforts towards the transition of existing high temperature hydrogen and hydrocarbon Schottky diode sensor elements to packaged sensor structures that can be integrated into a testing system. Sensor modifications and the technical challenges involved are discussed. Testing of the sensors at 500 C or above is also presented along with plans for future development