Adaptive approximate Bayesian computation for complex models

Approximate Bayesian computation (ABC) is a family of computational techniques in Bayesian statistics. These techniques allow to fi t a model to data without relying on the computation of the model likelihood. They instead require to simulate a large number of times the model to be fi tted. A number of re finements to the original rejection-based ABC scheme have been proposed, including the sequential improvement of posterior distributions. This technique allows to de- crease the number of model simulations required, but it still presents several shortcomings which are particu- larly problematic for costly to simulate complex models. We here provide a new algorithm to perform adaptive approximate Bayesian computation, which is shown to perform better on both a toy example and a complex social model.Comment: 14 pages, 5 figure

Biomolecular condensation of the microtubule-associated protein tau.

Cells contain multiple compartments dedicated to the regulation and control of biochemical reactions. Cellular compartments that are not surrounded by membranes can rapidly form and dissolve in response to changes in the cellular environment. The physicochemical processes that underlie the formation of non-membrane-bound compartments in vivo are connected to liquid-liquid phase separation of proteins and nucleic acids in vitro. Recent evidence suggests that the protein tau, which plays an important role in Alzheimer's disease and other neurodegenerative disorders, phase separates in solution, forms tau phases with microtubules, and associates with phase-separated RNA-binding protein granules in cells. Here we review the experimental evidence that supports the ability of tau to phase separate in solution and form biomolecular condensates in cells. As for other disease-relevant proteins, the physiological and pathological functions of tau are tightly connected - through loss of normal function or gain of toxic function - and we therefore discuss how tau phase separation plays a role for both, and with respect to different cellular functions of tau

Combined SIMS-SPM Instrument For High Sensitivity And High Resolution Elemental 3D Analysis

Extended abstract of a paper presented at Microscopy and Microanalysis 2012 in Phoenix, Arizona, USA, July 29 - August 2, 201

In situ stress tensor measured in an Alaskan glacier

An experimental program at Worthington Glacier, Alaska, U.S.A., has yielded the first in situ measurements of the full stress tensor in glacier ice. Measurements were made with an array of stiff (low-compliance) normal-force sensors frozen into a borehole at 120 m depth. Freezing in temperate ice was accomplished by a down-hole heat exchanger which extracted heat at the rate of 15 W. Under slowly varying stress conditions, relaxation of stress anomalies by viscous creep following drilling of the hole and installation of the sensors allows for equilibration of measured stresses with far-field stresses. Equilibration of local and far-field stresses was confirmed and pressure sensor calibrated in laboratory experiments prior to the field program. Results of the stress measurements show principal axes of the stress tensor oriented in directions consistent with the geometry of the glacier and broadly consistent with measured englacial strain rate. The magnitudes of stress-tensor components are more error-prone and more sensitive to uncertainty in sensor magnitude than uncertainty in sensor orientation. Mean stress determined by pressure measurements agrees with estimated lithostatic overburden with within approximately 15%. Unexpected results include a stress perturbation lasted about 5 days that caused a rotation of the orientations of the principal stress axes of approximately 5 degrees about an axis pointing in the down-flow direction

Fifty-kDa Hyaluronic Acid Upregulates Some Epidermal Genes without Changing TNF-α Expression in Reconstituted Epidermis

Background: Due to its strong water binding potential, hyaluronic acid (HA) is a well-known active ingredient for cosmetic applications. However, based on its varying molecular size, skin penetration of HA may be limited. Recent studies have demonstrated that low-molecular-weight HA (LMW HA) may show a certain proinflammatory activity. We thus aimed to characterize an LMW-sized HA molecule that combines strong anti-aging abilities with efficient skin penetration but lacks potential proinflammatory effects. Methods: Total RNA and total protein were isolated from reconstituted human epidermis following incubation with HAs of various molecular weights (20, 50, 130, 300, 800 and 1,500 kDa). Tumor necrosis factor-alpha expression was determined using quantitative PCR. Genonnic and proteomic expression of various junctional proteins was determined using Affymetrix and common Western blotting techniques. Results: LMW HA of approximately 50 kDa did not significantly alter tumor necrosis factor-alpha expression compared to 20-kDa HA, but revealed significantly higher skin penetration rates than larger sized HA associated with increased expression of genes and proteins known to be involved in tight junction formation and keratinocyte cohesion. Conclusion: LMW HA of approximately 50 kDa shows better penetration abilities than larger-sized HA. In addition, LMW HA influences the expression of various genes including those contributing to keratinocyte differentiation and formation of intercellular tight junction complexes without showing proinflammatory activity. These observations contribute to current knowledge on the effects of LMW HA on keratinocyte biology and cutaneous physiology. Copyright (C) 2011 S. Karger AG, Base

Spectral Analysis of the Chandra Comet Survey

We present results of the analysis of cometary X-ray spectra with an extended version of our charge exchange emission model (Bodewits et al. 2006). We have applied this model to the sample of 8 comets thus far observed with the Chandra X-ray observatory and ACIS spectrometer in the 300-1000 eV range. The surveyed comets are C/1999 S4 (LINEAR), C/1999 T1 (McNaught-Hartley), C/2000 WM1 (LINEAR), 153P/2002 (Ikeya-Zhang), 2P/2003 (Encke), C/2001 Q4 (NEAT), 9P/2005 (Tempel 1) and 73P/2006-B (Schwassmann-Wachmann 3) and the observations include a broad variety of comets, solar wind environments and observational conditions. The interaction model is based on state selective, velocity dependent charge exchange cross sections and is used to explore how cometary X-ray emission depend on cometary, observational and solar wind characteristics. It is further demonstrated that cometary X-ray spectra mainly reflect the state of the local solar wind. The current sample of Chandra observations was fit using the constrains of the charge exchange model, and relative solar wind abundances were derived from the X-ray spectra. Our analysis showed that spectral differences can be ascribed to different solar wind states, as such identifying comets interacting with (I) fast, cold wind, (II), slow, warm wind and (III) disturbed, fast, hot winds associated with interplanetary coronal mass ejections. We furthermore predict the existence of a fourth spectral class, associated with the cool, fast high latitude wind.Comment: 16 pages, 16 figures, and 7 Tables; accepted A&A (Due to space limits, this version has lower resolution jpeg images.

Propagation of tau pathology in Alzheimer’s disease: identification of novel therapeutic targets

Accumulation and aggregation of the microtubule-associated protein tau are a pathological hallmark of neurodegenerative disorders such as Alzheimer’s disease (AD). In AD, tau becomes abnormally phosphorylated and forms inclusions throughout the brain, starting in the entorhinal cortex and progressively affecting additional brain regions as the disease progresses. Formation of these inclusions is thought to lead to synapse loss and cell death. Tau is also found in the cerebrospinal fluid (CSF), and elevated levels are a biomarker for AD. Until recently, it was thought that the presence of tau in the CSF was due to the passive release of aggregated tau from dead or dying tangle-bearing neurons. However, accumulating evidence from different AD model systems suggests that tau is actively secreted and transferred between synaptically connected neurons. Transgenic mouse lines with localized expression of aggregating human tau in the entorhinal cortex have demonstrated that, as these animals age, tau becomes mislocalized from axons to cell bodies and dendrites and that human tau-positive aggregates form first in the entorhinal cortex and later in downstream projection targets. Numerous in vitro and in vivo studies have provided insight into the mechanisms by which tau may be released and internalized by neurons and have started to provide insight into how tau pathology may spread in AD. In this review, we discuss the evidence for regulated tau release and its specific uptake by neurons. Furthermore, we identify possible therapeutic targets for preventing the propagation of tau pathology, as inhibition of tau transfer may restrict development of tau tangles in a small subset of neurons affected in early stages of AD and therefore prevent widespread neuron loss and cognitive dysfunction associated with later stages of the disease

High power arcjet

The activities on the development of the high power arc jet HIPARC, the thrust balance, and plasma diagnostic probes are discussed. Modifications of the HIPARC design and a synopsis of the materials used are given. Further experimental results with the TT30 thruster in the 50 kW range are presented. Some first calibration measurements of the thrust balance are also included. Progress concerning the development of plasma diagnostic devices is documented

Low Dose Rapamycin Exacerbates Autoimmune Experimental Uveitis

Rapamycin, a potent immune modulator, is used to treat transplant rejection and some autoimmune diseases. Uveitis is a potentially severe inflammatory eye disease, and 2 clinical trials of treating uveitis with rapamycin are under way. Unexpectedly, recent research has demonstrated that low dose rapamycin enhances the memory T cell population and function. However, it is unclear how low dose rapamycin influences the immune response in the setting of uveitis.B10.RIII mice were immunized to induce experimental autoimmune uveitis (EAU). Ocular inflammation of control and rapamycin-treated mice was compared based on histological change. ELISPOT and T cell proliferation assays were performed to assess splenocyte response to ocular antigen. In addition, we examined the effect of rapamycin on activation-induced cell death (AICD) using the MitoCapture assay and Annexin V staining.Administration of low dose rapamycin exacerbated EAU, whereas treating mice with high dose rapamycin attenuated ocular inflammation. The progression of EAU by low dose rapamycin coincided with the increased frequency of antigen-reactive lymphocytes. Lastly, fewer rapamycin-treated T cells underwent AICD, which might contribute to exaggerated ocular inflammation and the uveitogenic immune response.These data reveal a paradoxical role for rapamycin in uveitis in a dose-dependent manner. This study has a potentially important clinical implication as rapamycin might cause unwanted consequences dependent on dosing and pharmacokinetics. Thus, more research is needed to further define the mechanism by which low dose rapamycin augments the immune response