Transforming Activity of the Rho Family GTPase, Wrch-1, a Wnt-regulated Cdc42 Homolog, Is Dependent on a Novel Carboxyl-terminal Palmitoylation Motif

Wrch-1 is a Rho family GTPase that shares strong sequence and functional similarity with Cdc42. Like Cdc42, Wrch-1 can promote anchorage-independent growth transformation. We determined that activated Wrch-1 also promoted anchorage-dependent growth transformation of NIH 3T3 fibroblasts. Wrch-1 contains a distinct carboxyl-terminal extension not found in Cdc42, suggesting potential differences in subcellular location and function. Consistent with this, we found that Wrch-1 associated extensively with plasma membrane and endosomes, rather than with cytosol and perinuclear membranes like Cdc42. Like Cdc42, Wrch-1 terminates in a CAAX tetrapeptide (where C is cysteine, A is aliphatic amino acid, and X is any amino acid) motif (CCFV), suggesting that Wrch-1 may be prenylated similarly to Cdc42. Most surprisingly, unlike Cdc42, Wrch-1 did not incorporate isoprenoid moieties, and Wrch-1 membrane localization was not altered by inhibitors of protein prenylation. Instead, we showed that Wrch-1 is modified by the fatty acid palmitate, and pharmacologic inhibition of protein palmitoylation caused mislocalization of Wrch-1. Most interestingly, mutation of the second cysteine of the CCFV motif (CCFV > CSFV), but not the first, abrogated both Wrch-1 membrane localization and transformation. These results suggest that Wrch-1 membrane association, subcellular localization, and biological activity are mediated by a novel membrane-targeting mechanism distinct from that of Cdc42 and other isoprenylated Rho family GTPases

Relevance of collagen piezoelectricity to "Wolff's Law": A critical review

According to “Wolff's Law”, bone is deposited and reinforced at areas of greatest stress. From a clinical perspective, this “law” is supported by the strong association between bone density and physical activity. From a mechanistic standpoint, however, the law presents a challenge to scientists seeking to understand how osteocytes and osteoblasts sense the mechanical load. In the 1960s, collagen piezoelectricity was invoked as a potential mechanism by which osteocytes could detect areas of greater stress but piezoelectricity diminished in importance as more compelling mechanisms, such as streaming potential, were identified. In addition, accumulating evidence for the role of fluid-related shear stress in osteocyte's mechanosensory function has made piezoelectricity seemingly more obsolete in bone physiology. This review critically evaluates the role of collagen piezoelectricity (if any) in Wolff's Law—specifically, the evidence regarding its involvement in strain-generated potentials, existing alternate mechanisms, the present understanding of bone mechanosensation, and whether piezoelectricity serves an influential role within the context of this newly proposed mechanism. In addition to reviewing the literature, this review generates several hypotheses and proposes future research to fully address the relevance of piezoelectricity in bone physiology.National Center for Complementary and Alternative Medicine (U.S.) (grant K23-AT003238

Illness perceptions and explanatory models of viral hepatitis B & C among immigrants and refugees: a narrative systematic review.

© 2015 Owiti et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BACKGROUND: Hepatitis B and C (HBV, HCV) infections are associated with high morbidity and mortality. Many countries with traditionally low prevalence (such as UK) are now planning interventions (screening, vaccination, and treatment) of high-risk immigrants from countries with high prevalence. This review aimed to synthesise the evidence on immigrants' knowledge of HBV and HCV that might influence the uptake of clinical interventions. The review was also used to inform the design and successful delivery of a randomised controlled trial of targeted screening and treatment. METHODS: Five databases (PubMed, CINHAL, SOCIOFILE, PsycINFO & Web of Science) were systematically searched, supplemented by reference tracking, searches of selected journals, and of relevant websites. We aimed to identify qualitative and quantitative studies that investigated knowledge of HBV and HCV among immigrants from high endemic areas to low endemic areas. Evidence, extracted according to a conceptual framework of Kleinman's explanatory model, was subjected to narrative synthesis. We adapted the PEN-3 model to categorise and analyse themes, and recommend strategies for interventions to influence help-seeking behaviour. RESULTS: We identified 51 publications including quantitative (n = 39), qualitative (n = 11), and mixed methods (n = 1) designs. Most of the quantitative studies included small samples and had heterogeneous methods and outcomes. The studies mainly concentrated on hepatitis B and ethnic groups of South East Asian immigrants residing in USA, Canada, and Australia. Many immigrants lacked adequate knowledge of aetiology, symptoms, transmission risk factors, prevention strategies, and treatment, of hepatitis HBV and HCV. Ethnicity, gender, better education, higher income, and English proficiency influenced variations in levels and forms of knowledge. CONCLUSION: Immigrants are vulnerable to HBV and HCV, and risk life-threatening complications from these infections because of poor knowledge and help-seeking behaviour. Primary studies in this area are extremely diverse and of variable quality precluding meta-analysis. Further research is needed outside North America and Australia

Combined Simulation and Experimental Study of Large Deformation of Red Blood Cells in Microfluidic Systems

Author manuscript; available in PMC 2012 March 1.We investigate the biophysical characteristics of healthy human red blood cells (RBCs) traversing microfluidic channels with cross-sectional areas as small as 2.7 × 3 μm. We combine single RBC optical tweezers and flow experiments with corresponding simulations based on dissipative particle dynamics (DPD), and upon validation of the DPD model, predictive simulations and companion experiments are performed in order to quantify cell deformation and pressure–velocity relationships for different channel sizes and physiologically relevant temperatures. We discuss conditions associated with the shape transitions of RBCs along with the relative effects of membrane and cytosol viscosity, plasma environments, and geometry on flow through microfluidic systems at physiological temperatures. In particular, we identify a cross-sectional area threshold below which the RBC membrane properties begin to dominate its flow behavior at room temperature; at physiological temperatures this effect is less profound.Singapore-MIT Alliance for Research and TechnologyUnited States. National Institutes of Health (National Heart, Lung, and Blood Institute Award R01HL094270

The higher-level phylogeny of Archosauria (Tetrapoda:Diapsida)

Crown group Archosauria, which includes birds, dinosaurs, crocodylomorphs, and several extinct Mesozoic groups, is a primary division of the vertebrate tree of life. However, the higher-level phylogenetic relationships within Archosauria are poorly resolved and controversial, despite years of study. The phylogeny of crocodile-line archosaurs (Crurotarsi) is particularly contentious, and has been plagued by problematic taxon and character sampling. Recent discoveries and renewed focus on archosaur anatomy enable the compilation of a new dataset, which assimilates and standardizes character data pertinent to higher-level archosaur phylogeny, and is scored across the largest group of taxa yet analysed. This dataset includes 47 new characters (25% of total) and eight taxa that have yet to be included in an analysis, and total taxonomic sampling is more than twice that of any previous study. This analysis produces a well-resolved phylogeny, which recovers mostly traditional relationships within Avemetatarsalia, places Phytosauria as a basal crurotarsan clade, finds a close relationship between Aetosauria and Crocodylomorpha, and recovers a monophyletic Rauisuchia comprised of two major subclades. Support values are low, suggesting rampant homoplasy and missing data within Archosauria, but the phylogeny is highly congruent with stratigraphy. Comparison with alternative analyses identifies numerous scoring differences, but indicates that character sampling is the main source of incongruence. The phylogeny implies major missing lineages in the Early Triassic and may support a Carnian-Norian extinction event.Marshall Scholarship for study in the United KingdomJurassic FoundationUniversity of BristolPaleontological Societ

Skeletal Adaptation to Intramedullary Pressure-Induced Interstitial Fluid Flow Is Enhanced in Mice Subjected to Targeted Osteocyte Ablation

Interstitial fluid flow (IFF) is a potent regulatory signal in bone. During mechanical loading, IFF is generated through two distinct mechanisms that result in spatially distinct flow profiles: poroelastic interactions within the lacunar-canalicular system, and intramedullary pressurization. While the former generates IFF primarily within the lacunar-canalicular network, the latter generates significant flow at the endosteal surface as well as within the tissue. This gives rise to the intriguing possibility that loading-induced IFF may differentially activate osteocytes or surface-residing cells depending on the generating mechanism, and that sensation of IFF generated via intramedullary pressurization may be mediated by a non-osteocytic bone cell population. To begin to explore this possibility, we used the Dmp1-HBEGF inducible osteocyte ablation mouse model and a microfluidic system for modulating intramedullary pressure (ImP) to assess whether structural adaptation to ImP-driven IFF is altered by partial osteocyte depletion. Canalicular convective velocities during pressurization were estimated through the use of fluorescence recovery after photobleaching and computational modeling. Following osteocyte ablation, transgenic mice exhibited severe losses in bone structure and altered responses to hindlimb suspension in a compartment-specific manner. In pressure-loaded limbs, transgenic mice displayed similar or significantly enhanced structural adaptation to Imp-driven IFF, particularly in the trabecular compartment, despite up to ∼50% of trabecular lacunae being uninhabited following ablation. Interestingly, regression analysis revealed relative gains in bone structure in pressure-loaded limbs were correlated with reductions in bone structure in unpressurized control limbs, suggesting that adaptation to ImP-driven IFF was potentiated by increases in osteoclastic activity and/or reductions in osteoblastic activity incurred independently of pressure loading. Collectively, these studies indicate that structural adaptation to ImP-driven IFF can proceed unimpeded following a significant depletion in osteocytes, consistent with the potential existence of a non-osteocytic bone cell population that senses ImP-driven IFF independently and potentially parallel to osteocytic sensation of poroelasticity-derived IFF

The patriotism of gentlemen with red hair: European Jews and the liberal state, 1789–1939

European Jewish history from 1789–1939 supports the view that construction of national identities even in secular liberal states was determined not only by modern considerations alone but also by ancient patterns of thought, behaviour and prejudice. Emancipation stimulated unprecedented patriotism, especially in wartime, as Jews strove to prove loyalty to their countries of citizenship. During World War I, even Zionists split along national lines, as did families and friends. Jewish patriotism was interchangeable with nationalism inasmuch as Jews identified themselves with national cultures. Although emancipation implied acceptance and an end to anti-Jewish prejudice in the modern liberal state, the kaleidoscopic variety of Jewish patriotism throughout Europe inadvertently undermined the idea of national identity and often provoked anti-Semitism. Even as loyal citizens of separate states, the Jews, however scattered, disunited and diverse, were made to feel, often unwillingly, that they were one people in exile

Dynamics of Mechanical Signal Transmission through Prestressed Stress Fibers

Transmission of mechanical stimuli through the actin cytoskeleton has been proposed as a mechanism for rapid long-distance mechanotransduction in cells; however, a quantitative understanding of the dynamics of this transmission and the physical factors governing it remains lacking. Two key features of the actin cytoskeleton are its viscoelastic nature and the presence of prestress due to actomyosin motor activity. We develop a model of mechanical signal transmission through prestressed viscoelastic actin stress fibers that directly connect the cell surface to the nucleus. The analysis considers both temporally stationary and oscillatory mechanical signals and accounts for cytosolic drag on the stress fibers. To elucidate the physical parameters that govern mechanical signal transmission, we initially focus on the highly simplified case of a single stress fiber. The results demonstrate that the dynamics of mechanical signal transmission depend on whether the applied force leads to transverse or axial motion of the stress fiber. For transverse motion, mechanical signal transmission is dominated by prestress while fiber elasticity has a negligible effect. Conversely, signal transmission for axial motion is mediated uniquely by elasticity due to the absence of a prestress restoring force. Mechanical signal transmission is significantly delayed by stress fiber material viscosity, while cytosolic damping becomes important only for longer stress fibers. Only transverse motion yields the rapid and long-distance mechanical signal transmission dynamics observed experimentally. For simple networks of stress fibers, mechanical signals are transmitted rapidly to the nucleus when the fibers are oriented largely orthogonal to the applied force, whereas the presence of fibers parallel to the applied force slows down mechanical signal transmission significantly. The present results suggest that cytoskeletal prestress mediates rapid mechanical signal transmission and allows temporally oscillatory signals in the physiological frequency range to travel a long distance without significant decay due to material viscosity and/or cytosolic drag

Impact of Prison Status on HIV-Related Risk Behaviors

Baseline data were collected to evaluate the effectiveness of interventions on completion of the hepatitis A and B vaccine series among 664 sheltered and street-based homeless adults who were: (a) homeless; (b) recently (<1 year) discharged from prison; (c) discharged 1 year or more; and (d) never incarcerated. Group differences at baseline were assessed for socio–demographic characteristics, drug and alcohol use, sexual activity, mental health and public assistance. More than one-third of homeless persons (38%) reported prison time and 16% of the sample had been recently discharged from prison. Almost half of persons who were discharged from prison at least 1 year ago reported daily use of drugs and alcohol over the past 6 months compared to about 1 in 5 among those who were recently released from prison. As risk for HCV and HIV co-infection continues among homeless ex-offenders, HIV/HCV prevention efforts are needed for this population