Optimal Monte Carlo Updating

Based on Peskun's theorem it is shown that optimal transition matrices in Markov chain Monte Carlo should have zero diagonal elements except for the diagonal element corresponding to the largest weight. We will compare the statistical efficiency of this sampler to existing algorithms, such as heat-bath updating and the Metropolis algorithm. We provide numerical results for the Potts model as an application in classical physics. As an application in quantum physics we consider the spin 3/2 XY model and the Bose-Hubbard model which have been simulated by the directed loop algorithm in the stochastic series expansion framework.Comment: 6 pages, 5 figures, replaced with published versio

Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing

ER stress results in activation of the unfolded protein response and has been implicated in the development of fibrotic diseases. In this study, we show that inhibition of the ER stress-induced IRE1α signaling pathway, using the inhibitor 4μ8C, blocks TGFβ-induced activation of myofibroblasts in vitro, reduces liver and skin fibrosis in vivo, and reverts the fibrotic phenotype of activated myofibroblasts isolated from patients with systemic sclerosis. By using IRE1α(-/-) fibroblasts and expression of IRE1α-mutant proteins lacking endoribonuclease activity, we confirmed that IRE1α plays an important role during myofibroblast activation. IRE1α was shown to cleave miR-150 and thereby to release the suppressive effect that miR-150 exerted on αSMA expression through c-Myb. Inhibition of IRE1α was also demonstrated to block ER expansion through an XBP-1-dependent pathway. Taken together, our results suggest that ER stress could be an important and conserved mechanism in the pathogenesis of fibrosis and that components of the ER stress pathway may be therapeutically relevant for treating patients with fibrotic diseases

Naturalness in Cosmological Initial Conditions

We propose a novel approach to the problem of constraining cosmological initial conditions. Within the framework of effective field theory, we classify initial conditions in terms of boundary terms added to the effective action describing the cosmological evolution below Planckian energies. These boundary terms can be thought of as spacelike branes which may support extra instantaneous degrees of freedom and extra operators. Interactions and renormalization of these boundary terms allow us to apply to the boundary terms the field-theoretical requirement of naturalness, i.e. stability under radiative corrections. We apply this requirement to slow-roll inflation with non-adiabatic initial conditions, and to cyclic cosmology. This allows us to define in a precise sense when some of these models are fine-tuned. We also describe how to parametrize in a model-independent way non-Gaussian initial conditions; we show that in some cases they are both potentially observable and pass our naturalness requirement.Comment: 35 pages, 8 figure

Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension

BACKGROUND AND AIMS: Hepatic stellate cells (HSCs) are vital to hepatocellular function and the liver response to injury. They share a phenotypic homology with astrocytes that are central in the pathogenesis of hepatic encephalopathy, a condition in which hyperammonemia plays a pathogenic role. This study tested the hypothesis that ammonia modulates human HSC activation in vitro and in vivo, and evaluated whether ammonia lowering, by using l-ornithine phenylacetate (OP), modifies HSC activation in vivo and reduces portal pressure in a bile duct ligation (BDL) model. METHODS: Primary human HSCs were isolated and cultured. Proliferation (BrdU), metabolic activity (MTS), morphology (transmission electron, light and immunofluorescence microscopy), HSC activation markers, ability to contract, changes in oxidative status (ROS) and endoplasmic reticulum (ER) were evaluated to identify effects of ammonia challenge (50 μM, 100 μM, 300 μM) over 24–72 h. Changes in plasma ammonia levels, markers of HSC activation, portal pressure and hepatic eNOS activity were quantified in hyperammonemic BDL animals, and after OP treatment. RESULTS: Pathophysiological ammonia concentrations caused significant and reversible changes in cell proliferation, metabolic activity and activation markers of hHSC in vitro. Ammonia also induced significant alterations in cellular morphology, characterised by cytoplasmic vacuolisation, ER enlargement, ROS production, hHSC contraction and changes in pro-inflammatory gene expression together with HSC-related activation markers such as α-SMA, myosin IIa, IIb, and PDGF-Rβ. Treatment with OP significantly reduced plasma ammonia (BDL 199.1 μmol/L ± 43.65 vs. BDL + OP 149.27 μmol/L ± 51.1, p <0.05) and portal pressure (BDL 14 ± 0.6 vs. BDL + OP 11 ± 0.3 mmHg, p <0.01), which was associated with increased eNOS activity and abrogation of HSC activation markers. CONCLUSIONS: The results show for the first time that ammonia produces deleterious morphological and functional effects on HSCs in vitro. Targeting ammonia with the ammonia lowering drug OP reduces portal pressure and deactivates hHSC in vivo, highlighting the opportunity for evaluating ammonia lowering as a potential therapy in cirrhotic patients with portal hypertension

Reactive gamma-ketoaldehydes as novel activators of hepatic stellate cells in vitro

Aims: Products of lipid oxidation, such as 4-hydroxynonenal (4-HNE), are key activators of hepatic stellate cells (HSC) to a pro-fibrogenic phenotype. Isolevuglandins (IsoLG) are a family of acyclic γ-ketoaldehydes formed through oxidation of arachidonic acid or as by-products of the cyclooxygenase pathway. IsoLGs are highly reactive aldehydes which are efficient at forming protein adducts and cross-links at concentrations 100-fold lower than 4-hydroxynonenal. Since the contribution of IsoLGs to liver injury has not been studied, we synthesized 15-E2-IsoLG and used it to investigate whether IsoLG could induce activation of HSC. / Results: Primary human HSC were exposed to 15-E2-IsoLG for up to 48 hours. Exposure to 5 μM 15-E2-IsoLG in HSCs promoted cytotoxicity and apoptosis. At non-cytotoxic doses (50 pM-500 nM) 15-E2-IsoLG promoted HSC activation, indicated by increased expression of α-SMA, sustained activation of ERK and JNK signaling pathways, and increased mRNA and/or protein expression of cytokines and chemokines, which was blocked by inhibitors of JNK and NF-kB. In addition, IsoLG promoted formation of reactive oxygen species, and induced an early activation of ER stress, followed by autophagy. Inhibition of autophagy partially reduced the pro-inflammatory effects of IsoLG, suggesting that it might serve as a cytoprotective response. / Innovation: This study is the first to describe the biological effects of IsoLG in primary HSC, the main drivers of hepatic fibrosis. / Conclusions: IsoLGs represent a newly identified class of activators of HSC in vitro, which are biologically active at concentrations as low as 500 pM, and are particularly effective at promoting a pro-inflammatory response and autophagy

A Sub-Picojoule per Bit Integrated Magneto-Optic Modulator on Silicon: Modeling and Experimental Demonstration

Integrated magneto-optic (MO) modulators are an attractive but not fully explored alternative to electro-optic (EO) modulators. They are current driven, structurally simple, and could potentially achieve high efficiency in cryogenic and room temperature environments where fJ bit−1 optical interfaces are needed. In this paper, the performance and energy efficiency of a novel MO modulator at room temperature are for the first time assessed. First, a model of the micro-ring-based modulator is implemented to investigate the design parameters and their influence on the performance. Then, a fabricated device is experimentally characterized to assess its performance in terms of bit rate and energy efficiency. The model shows efficient operation at 1.2 Gbps using a 16 mA drive current, consuming only 155 fJ bit−1. The experimental results show that the MO effect is suitable for modulation, achieving error-free operation above 16 mA with a power consumption of 258 fJ bit−1 at a transient limited data rate of 1.2 Gbps

SHRIMP ion probe zircon geochronology and Sr and Nd isotope geochemistry for southern Longwood Range and Bluff Peninsula intrusive rocks of Southland, New Zealand

Permian–Jurassic ultramafic to felsic intrusive complexes at Bluff Peninsula and in the southern Longwood Range along the Southland coast represent a series of intraoceanic magmatic arcs with ages spanning a time interval of 110 m.y. New SHRIMP U-Pb zircon data for a quartz diorite from the Flat Hill complex, Bluff Peninsula, yield an age of 259 ± 4 Ma, consistent with other geochronological and paleontological evidence confirming a Late Permian age. The new data are consistent with an age of c. 260 Ma for the intrusive rocks of the Brook Street Terrane. SHRIMP U-Pb zircon ages for the southern Longwood Range confirm that intrusions become progressively younger from east to west across the complex. A gabbro at Oraka Point (eastern end of coastal section) has an age of 245 ± 4 Ma and shows virtually no evidence of zircon inheritance. The age is significantly different from that of the Brook Street Terrane intrusives. Zircon ages from the western parts of the section are younger and more varied (203–227 Ma), indicating more complex magmatic histories. A leucogabbro dike from Pahia Point gives the youngest emplacement age of 142 Ma, which is similar to published U-Pb zircon ages for the Anglem Complex and Paterson Group on Stewart Island

Regional White Matter Integrity Differentiates Between Vascular Dementia and Alzheimer Disease

BACKGROUND AND PURPOSE: Considerable clinical and radiological overlap between vascular dementia (VaD) and Alzheimer disease (AD) often makes the diagnosis difficult. Diffusion-tensor imaging studies showed that fractional anisotropy (FA) could be a useful marker for white matter changes. This study aimed to identify regional FA changes to identify a biomarker that could be used to differentiate VaD from AD. METHODS: T1-weighted and diffusion-tensor imaging scans were obtained in 13 VaD patients, 16 AD patients, and 22 healthy elderly controls. We used tract-based spatial statistics to study regional changes in fractional anisotropy in AD, VaD, and elderly controls. We then used probabilistic tractography to parcel the corpus callosum in 7 regions according to its connectivity with major cerebral cortices using diffusion-tensor imaging data set. We compared the volume and mean FA in each set of transcallosal fibers between groups using ANOVA and then applied a discriminant analysis based on FA and T2-weighted imaging measures. RESULTS: FA reduction in forceps minor was the most significant area of difference between AD and VaD. Segmentation of the corpus callosum using tractography and comparison of FA changes of each segment confirmed the FA changes in transcallosal prefrontal tracts of patients with VaD when compared to AD. The best discriminant model was the combination of transcallosal prefrontal FA and Fazekas score with 87.5% accuracy, 100% specificity, and 93% sensitivity (P&lt;0.0001). CONCLUSIONS: Integrating mean FA in the forceps minor to the Fazekas score provides a useful quantitative marker for differentiating AD from VaD

Clusterwise Independent Component Analysis (C-ICA): using fMRI resting state networks to cluster subjects and find neurofunctional subtypes

Background: FMRI resting state networks (RSNs) are used to characterize brain disorders. They also show extensive heterogeneity across patients. Identifying systematic differences between RSNs in patients, i.e. discovering neurofunctional subtypes, may further increase our understanding of disease heterogeneity. Currently, no methodology is available to estimate neurofunctional subtypes and their associated RSNs simultaneously.New method: We present an unsupervised learning method for fMRI data, called Clusterwise Independent Component Analysis (C-ICA). This enables the clustering of patients into neurofunctional subtypes based on differences in shared ICA-derived RSNs. The parameters are estimated simultaneously, which leads to an improved estimation of subtypes and their associated RSNs.Results: In five simulation studies, the C-ICA model is successfully validated using both artificially and realistically simulated data (N = 30-40). The successful performance of the C-ICA model is also illustrated on an empirical data set consisting of Alzheimer's disease patients and elderly control subjects (N = 250). C-ICA is able to uncover a meaningful clustering that partially matches (balanced accuracy = .72) the diagnostic labels and identifies differences in RSNs between the Alzheimer and control cluster. Comparison with other methods: Both in the simulation study and the empirical application, C-ICA yields better results compared to competing clustering methods (i.e., a two step clustering procedure based on single subject ICA's and a Group ICA plus dual regression variant thereof) that do not simultaneously estimate a clustering and associated RSNs. Indeed, the overall mean adjusted Rand Index, a measure for cluster recovery, equals 0.65 for C-ICA and ranges from 0.27 to 0.46 for competing methods.Conclusions: The successful performance of C-ICA indicates that it is a promising method to extract neuro-functional subtypes from multi-subject resting state-fMRI data. This method can be applied on fMRI scans of patient groups to study (neurofunctional) subtypes, which may eventually further increase understanding of disease heterogeneity.Multivariate analysis of psychological dat

Macrophage MerTK promotes profibrogenic cross-talk with hepatic stellate cells via soluble mediators

Background & Aims: Activation of Kupffer cells and recruitment of monocytes are key events in fibrogenesis. These cells release soluble mediators which induce the activation of hepatic stellate cells (HSCs), the main fibrogenic cell type within the liver. Mer tyrosine kinase (MerTK) signaling regulates multiple processes in macrophages and has been implicated in the pathogenesis of non-alcoholic steatohepatitis-related fibrosis. In this study, we explored if MerTK activation in macrophages influences the profibrogenic phenotype of HSCs. Methods: Macrophages were derived from THP-1 cells or differentiated from peripheral blood monocytes towards MerTK+/CD206+/CD163+/CD209- macrophages. The role of MerTK was assessed by pharmacologic and genetic inhibition. HSC migration was determined in Boyden chambers, viability was measured by the MTT assay, and proliferation was evaluated by the BrdU incorporation assay. Results: Gas-6 induced MerTK phosphorylation and Akt activation in macrophages, and these effects were inhibited by UNC569. During polarization, MerTK+/CD206+/CD163+/CD209- macrophages exhibited activation of STAT3, ERK1/2, p38 and increased expression of VEGF-A. Activation of MerTK in THP-1 macrophages induced a secretome which promoted a significant increase in migration, proliferation, viability and expression of profibrogenic factors in HSCs. Similarly, conditioned medium from MerTK+ macrophages induced a significant increase in cell migration, proliferation, STAT3 and p38 phosphorylation and upregulation of IL-8 expression in HSCs. Moreover, conditioned medium from Gas-6-stimulated Kupffer cells induced a significant increase in HSC proliferation. These effects were specifically related to MerTK expression and activity in macrophages, as indicated by pharmacologic inhibition and knockdown experiments. Conclusions: MerTK activation in macrophages modifies the secretome to promote profibrogenic features in HSCs, implicating this receptor in the pathogenesis of hepatic fibrosis. Lay summary: Fibrosis represents the process of scarring occurring in patients with chronic liver diseases. This process depends on production of scar tissue components by a specific cell type, named hepatic stellate cells, and is regulated by interaction with other cells. Herein, we show that activation of MerTK, a receptor present in a population of macrophages, causes the production of factors that act on hepatic stellate cells, increasing their ability to produce scar tissue