Transforming growth factor-beta enables NFATc1 expression during osteoclastogenesis.

Osteoclastogenesis is dependent on distinct stimuli that prime and activate osteoclast differentiation. One cytokine needed to prime monocytes for osteoclastogenesis is TGF-beta, which enables and augments RANKL and TNF-alpha-induced osteoclast differentiation. However, the precise time-period during which this occurs and the molecular mechanism mediating this action are unknown. We report here TGF-beta prime monocytes for osteoclast formation within 24h by regulating expression of NFATc1, a key osteoclastic transcription factor. TGF-beta directly induces cytoplasmic NFATc1 expression within 24h, but is unable to stimulate NFATc1 nuclear translocation. Furthermore, RANKL-induced NFATc1 expression is dependent on the presence of TGF-beta during the early stages of osteoclastogenesis. Similarly, TNF-alpha activates osteoclastogenesis by stimulating translocation of TGF-beta-induced NFATc1. In light of these findings, it is apparent that osteoclast formation is dependent on coordinated interactions between TGF-beta and RANKL/TNF-alpha that regulate the expression and intracellular distribution of NFATc1 during early stages of osteoclast differentiation

Spatial evolution of friction of a textured wafer surface

Abstract Mechanical failure of integrated circuits and micro-electro-mechanical systems (MEMS) demands new understanding of friction in small devices. In present research, we demonstrated an in situ approach to measure sliding friction of a patterned surface composing multi-materials and structures. The effects of materials and surface morphology on friction and electrical contact resistance were investigated. The material transfer at the interface of dissimilar materials was found to play dominating roles in friction. The current work provides important insights from the fundamentals of friction that benefit the design of new micro-devices.</jats:p

COP21 climate negotiators' responses to climate model forecasts

Policymakers involved in climate change negotiations are key users of climate science. It is therefore vital to understand how to communicate scientific information most effectively to this group. We tested how a unique sample of policymakers and negotiators at the Paris COP21 conference update their beliefs on year 2100 global mean temperature increases in response to a statistical summary of climate models' forecasts. We randomized the way information was provided across participants using three different formats similar to those used in Intergovernmental Panel on Climate Change reports. In spite of having received all available relevant scientific information, policymakers adopted such information very conservatively, assigning it less weight than their own prior beliefs. However, providing individual model estimates in addition to the statistical range was more effective in mitigating such inertia. The experiment was repeated with a population of European MBA students who, despite starting from similar priors, reported conditional probabilities closer to the provided models' forecasts than policymakers. There was also no effect of presentation format in the MBA sample. These results highlight the importance of testing visualization tools directly on the population of interest

6 Ma age of carving Westernmost Grand Canyon: Reconciling geologic data with combined AFT, (U-Th)/He, and He-4/He-3 thermochronologic data

Conflicting hypotheses about the timing of carving of the Grand Canyon involve either a 70 Ma (“old”) or <6 Ma (“young”) Grand Canyon. This paper evaluates the controversial westernmost segment of the Grand Canyon where the following lines of published evidence firmly favor a “young” Canyon. 1) North-derived Paleocene Hindu Fanglomerate was deposited across the present track of the westernmost Grand Canyon, which therefore was not present at ∼55 Ma. 2) The 19 Ma Separation Point basalt is stranded between high relief side canyons feeding the main stem of the Colorado River and was emplaced before these tributaries and the main canyon were incised. 3) Geomorphic constraints indicate that relief generation in tributaries and on plateaus adjacent to the westernmost Grand Canyon took place after 17 Ma. 4) The late Miocene–Pliocene Muddy Creek Formation constraint shows that no river carrying far-traveled materials exited at the mouth of the Grand Canyon until after 6 Ma. Interpretations of previously-published low-temperature thermochronologic data conflict with these lines of evidence, but are reconciled in this paper via the integration of three methods of analyses on the same sample: apatite (U–Th)/He ages (AHe), 4He/3He thermochronometry (4He/3He), and apatite fission-track ages and lengths (AFT). HeFTy software was used to generate time–temperature (t–T) paths that predict all new and published 4He/3He, AHe, and AFT data to within assumed uncertainties. These t–T paths show cooling from ∼100 °C to 40–60 °C in the Laramide (70–50 Ma), long-term residence at 40–60 °C in the mid-Tertiary (50–10 Ma), and cooling to near-surface temperatures after 10 Ma, and thus support young incision of the westernmost Grand Canyon. A subset of AHe data, when interpreted alone (i.e. without 4He/3He or AFT data), are better predicted by t–T paths that cool to surface temperatures during the Laramide, consistent with an “old” Grand Canyon. However, the combined AFT, AHe, and 4He/3He analysis of a key sample from Separation Canyon can only be reconciled by a “young” Canyon. Additional new AFT (5 samples) and AHe data (3 samples) in several locations along the canyon corridor also support a “young” Canyon. This inconsistency, which mimics the overall controversy of the age of the Grand Canyon, is reconciled here by optimizing cooling paths so they are most consistent with multiple thermochronometers from the same rocks. To do this, we adjusted model parameters and uncertainties to account for uncertainty in the rate of radiation damage annealing in these apatites during sedimentary burial and the resulting variations in He retentivity. In westernmost Grand Canyon, peak burial conditions (temperature and duration) during the Laramide were likely insufficient to fully anneal radiation damage that accumulated during prolonged, near-surface residence since the Proterozoic. We conclude that application of multiple thermochronometers from common rocks reconciles conflicting thermochronologic interpretations and the data presented here are best explained by a “young” westernmost Grand Canyon. Samples spread along the river corridor also suggest the possibility of variable mid-Tertiary thermal histories beneath north-retreating cliffs

Differential hippocampal shapes in posterior cortical atrophy patients: A comparison with control and typical AD subjects.

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by predominant visual deficits and parieto-occipital atrophy, and is typically associated with Alzheimer's disease (AD) pathology. In AD, assessment of hippocampal atrophy is widely used in diagnosis, research, and clinical trials; its utility in PCA remains unclear. Given the posterior emphasis of PCA, we hypothesized that hippocampal shape measures may give additional group differentiation information compared with whole-hippocampal volume assessments. We investigated hippocampal volume and shape in subjects with PCA (n = 47), typical AD (n = 29), and controls (n = 48). Hippocampi were outlined on MRI scans and their 3D meshes were generated. We compared hippocampal volume and shape between disease groups. Mean adjusted hippocampal volumes were ∼8% smaller in PCA subjects (P < 0.001) and ∼22% smaller in tAD subject (P < 0.001) compared with controls. Significant inward deformations in the superior hippocampal tail were observed in PCA compared with controls even after adjustment for hippocampal volume. Inward deformations in large areas of the hippocampus were seen in tAD subjects compared with controls and PCA subjects, but only localized shape differences remained after adjusting for hippocampal volume. The shape differences observed, even allowing for volume differences, suggest that PCA and tAD are each associated with different patterns of hippocampal tissue loss that may contribute to the differential range and extent of episodic memory dysfunction in the two groups. Hum Brain Mapp, 2015. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc

Rich Situated Attitudes

We outline a novel theory of natural language meaning, Rich Situated Semantics [RSS], on which the content of sentential utterances is semantically rich and informationally situated. In virtue of its situatedness, an utterance’s rich situated content varies with the informational situation of the cognitive agent interpreting the utterance. In virtue of its richness, this content contains information beyond the utterance’s lexically encoded information. The agent-dependence of rich situated content solves a number of problems in semantics and the philosophy of language (cf. [14, 20, 25]). In particular, since RSS varies the granularity of utterance contents with the interpreting agent’s informational situation, it solves the problem of finding suitably fine- or coarse-grained objects for the content of propositional attitudes. In virtue of this variation, a layman will reason with more propositions than an expert

Formulation, inflammation, and RNA sensing impact the immunogenicity of self-amplifying RNA vaccines

To be effective, RNA vaccines require both in situ translation and the induction of an immune response to recruit cells to the site of immunization. These factors can pull in opposite directions with the inflammation reducing expression of the vaccine antigen. We investigated how formulation affects the acute systemic cytokine response to a self-amplifying RNA (saRNA) vaccine. We compared a cationic polymer (pABOL), a lipid emulsion (nanostructured lipid carrier, NLC), and three lipid nanoparticles (LNP). After immunization, we measured serum cytokines and compared the response to induced antibodies against influenza virus. Formulations that induced a greater cytokine response induced a greater antibody response, with a significant correlation between IP-10, MCP-1, KC, and antigen-specific antibody titers. We then investigated how innate immune sensing and signaling impacted the adaptive immune response to vaccination with LNP-formulated saRNA. Mice that lacked MAVS and are unable to signal through RIG-I-like receptors had an altered cytokine response to saRNA vaccination and had significantly greater antibody responses than wild-type mice. This indicates that the inflammation induced by formulated saRNA vaccines is not solely deleterious in the induction of antibody responses and that targeting specific aspects of RNA vaccine sensing might improve the quality of the response

Interpreting population reach of a large, successful physical activity trial delivered through primary care.

Abstract Background Failure to include socio-economically deprived or ethnic minority groups in physical activity (PA) trials may limit representativeness and could lead to implementation of interventions that then increase health inequalities. Randomised intervention trials often have low recruitment rates and rarely assess recruitment bias. A previous trial by the same team using similar methods recruited 30% of the eligible population but was in an affluent setting with few non-white residents and was limited to those over 60 years of age. Methods PACE-UP is a large, effective, population-based walking trial in inactive 45-75 year-olds that recruited through seven London general practices. Anonymised practice demographic data were available for all those invited, enabling investigation of inequalities in trial recruitment. Non-participants were invited to complete a questionnaire. Results From 10,927 postal invitations, 1150 (10.5%) completed baseline assessment. Participation rate ratios (95% CI), adjusted for age and gender as appropriate, were lower in men 0.59 (0.52, 0.67) than women, in those under 55 compared with those ≥65, 0.60 (0.51, 0.71), in the most deprived quintile compared with the least deprived 0.52 (0.39, 0.70) and in Asian individuals compared with whites 0.62 (0.50, 0.76). Black individuals were equally likely to participate as white individuals. Participation was also associated with having a co-morbidity or some degree of health limitation. The most common reasons for non-participation were considering themselves as being too active or lack of time. Conclusions Conducting the trial in this diverse setting reduced overall response, with lower response in socio-economically deprived and Asian sub-groups. Trials with greater reach are likely to be more expensive in terms of recruitment and gains in generalizability need to be balanced with greater costs. Differential uptake of successful trial interventions may increase inequalities in PA levels and should be monitored