Cerebrovascular and blood-brain barrier impairments in Huntington's disease: Potential implications for its pathophysiology: Vascular impairments in HD

ObjectiveAlthough the underlying cause of Huntington's disease (HD) is well established, the actual pathophysiological processes involved remain to be fully elucidated. In other proteinopathies such as Alzheimer's and Parkinson's diseases, there is evidence for impairments of the cerebral vasculature as well as the blood–brain barrier (BBB), which have been suggested to contribute to their pathophysiology. We investigated whether similar changes are also present in HD.MethodsWe used 3‐ and 7‐Tesla magnetic resonance imaging as well as postmortem tissue analyses to assess blood vessel impairments in HD patients. Our findings were further investigated in the R6/2 mouse model using in situ cerebral perfusion, histological analysis, Western blotting, as well as transmission and scanning electron microscopy.ResultsWe found mutant huntingtin protein (mHtt) aggregates to be present in all major components of the neurovascular unit of both R6/2 mice and HD patients. This was accompanied by an increase in blood vessel density, a reduction in blood vessel diameter, as well as BBB leakage in the striatum of R6/2 mice, which correlated with a reduced expression of tight junction‐associated proteins and increased numbers of transcytotic vesicles, which occasionally contained mHtt aggregates. We confirmed the existence of similar vascular and BBB changes in HD patients.InterpretationTaken together, our results provide evidence for alterations in the cerebral vasculature in HD leading to BBB leakage, both in the R6/2 mouse model and in HD patients, a phenomenon that may, in turn, have important pathophysiological implications. Ann Neurol 2015;78:160–17

Unsupervised markovian segmentation on graphics hardware

Abstract. This contribution shows how unsupervised Markovian segmentation techniques can be accelerated when implemented on graphics hardware equipped with a Graphics Processing Unit (GPU). Our strategy exploits the intrinsic properties of local interactions between sites of a Markov Random Field model with the parallel computation ability of a GPU. This paper explains how classical iterative site-wise-update algorithms commonly used to optimize global Markovian cost functions can be efficiently implemented in parallel by fragment shaders driven by a fragment processor. This parallel programming strategy significantly accelerates optimization algorithms such as ICM and simulated annealing. Good acceleration are also achieved for parameter estimation procedures such as K-means and ICE. The experiments reported in this paper have been obtained with a mid-end, affordable graphics card available on the market.

Markovian Energy-Based Computer Vision Algorithms on Graphics Hardware

Abstract. This paper shows how Markovian segmentation algorithms used to solve well known computer vision problems such as motion estimation, motion detection and stereovision can be significantly accelerated when implemented on programmable graphics hardware. More precisely, this contribution exposes how the parallel abilities of a standard Graphics Processing Unit (usually devoted to image synthesis) can be used to infer the labels of a label field. The computer vision problems addressed in this paper are solved in the maximum a posteriori (MAP) sense with an optimization algorithm such as ICM or simulated annealing. To do so, the fragment processor is used to update in parallel every labels of the segmentation map while rendering passes and graphics textures are used to simulate optimization iterations. Results show that impressive acceleration factors can be reached, especially when the size of the scene, the number of labels or the number of iterations is large. Hardware results have been obtained with programs running on a mid-end affordable graphics card.

Ratchet vs Blasé Investors and Asset Markets * Ratchet vs Blasé Investors and Asset Markets

Abstract This paper proposes a new wealth-dependent utility function for the intertemporal consumption and portfolio problem, in which the subsistance (marginal utility bliss) consumption level is a function of wealth. Ratchet effects obtain when higher wealth increases the subsistance consumption level; blasé behavior occurs when higher wealth reduces it. We have three contributions: (i) we identify closedform solutions for optimal consumption and portfolio rules; (ii) we use the optimal rules to estimate the model using aggregate portfolio data, and (iii) we derive and discuss the pricing implications of our results. When financial assets and wealth are considered, our estimates are consistent with blasé behavior and counter-cyclical risk aversion. JEL classification: G11, G12

A positive feedback loop links opposing functions of P-TEFb/Cdk9 and histone H2B ubiquitylation to regulate transcript elongation in fission yeast.

Transcript elongation by RNA polymerase II (RNAPII) is accompanied by conserved patterns of histone modification. Whereas histone modifications have established roles in transcription initiation, their functions during elongation are not understood. Mono-ubiquitylation of histone H2B (H2Bub1) plays a key role in coordinating co-transcriptional histone modification by promoting site-specific methylation of histone H3. H2Bub1 also regulates gene expression through an unidentified, methylation-independent mechanism. Here we reveal bidirectional communication between H2Bub1 and Cdk9, the ortholog of metazoan positive transcription elongation factor b (P-TEFb), in the fission yeast Schizosaccharomyces pombe. Chemical and classical genetic analyses indicate that lowering Cdk9 activity or preventing phosphorylation of its substrate, the transcription processivity factor Spt5, reduces H2Bub1 in vivo. Conversely, mutations in the H2Bub1 pathway impair Cdk9 recruitment to chromatin and decrease Spt5 phosphorylation. Moreover, an Spt5 phosphorylation-site mutation, combined with deletion of the histone H3 Lys4 methyltransferase Set1, phenocopies morphologic and growth defects due to H2Bub1 loss, suggesting independent, partially redundant roles for Cdk9 and Set1 downstream of H2Bub1. Surprisingly, mutation of the histone H2B ubiquitin-acceptor residue relaxes the Cdk9 activity requirement in vivo, and cdk9 mutations suppress cell-morphology defects in H2Bub1-deficient strains. Genome-wide analyses by chromatin immunoprecipitation also demonstrate opposing effects of Cdk9 and H2Bub1 on distribution of transcribing RNAPII. Therefore, whereas mutual dependence of H2Bub1 and Spt5 phosphorylation indicates positive feedback, mutual suppression by cdk9 and H2Bub1-pathway mutations suggests antagonistic functions that must be kept in balance to regulate elongation. Loss of H2Bub1 disrupts that balance and leads to deranged gene expression and aberrant cell morphologies, revealing a novel function of a conserved, co-transcriptional histone modification

H2Bub1 depends on Cdk9 activity and Spt5 phosphorylation.

<p>(A) Immunoblots of whole-cell extracts from wild-type (wt) (JS78) or AS mutant strains (LV7, LV77, LV42), as indicated, grown in the absence (−) or presence (+) of 20 µM 3-MB-PP1, added 20 min prior to harvest. Antibodies are indicated at right. (B) Immunoblots of extracts from indicated strains probed for total histone H2B and H2Bub1, as indicated at right. “T212A” and “T212E” denote strains <i>cdk9-T212A</i> (HD7-24) and <i>cdk9-T212E</i> (HG127). (C) Immunoblots of extracts from wild-type (JS78) or indicated <i>spt5</i> mutant strains.</p

Opposing effects of H2Bub1 and Cdk9 activity on RNAPII distribution revealed by ChIP–chip.

<p>(A) Average distribution of RNAPII at 540 <i>S. pombe</i> genes, as determined by ChIP-chip in a <i>cdk9-T212A</i> strain (JTB325). Genes were grouped according to total levels of RNAPII enrichment. (B) As in (A) for <i>cdk9-T212A htb1-K119R</i> (JTB326). (C) Average distributions of differences between <i>cdk9-T212A</i> (JTB325) and wild-type (JTB62-1) RNAPII enrichment grouped according to RNAPII enrichment in wild-type cells. (D) As in (C) for differences between <i>cdk9-T212A htb1-K119R</i> and wild-type RNAPII enrichment. (E) As in (C) for differences between <i>cdk9-T212A htb1-K119R</i> and <i>cdk9-T212A</i> RNAPII enrichment. (F) As in (C) for differences between <i>cdk9-T212A htb1-K119R</i> and <i>htb1-K119R</i> RNAPII enrichment. The keys below C-F illustrate the statistical significance of the differences for each group at 50 positions along the average gene. The rows of the key are color-coded according to the graph. Open squares denote p>0.01; light shading denotes 0.01>p>10exp-5; dark shading denotes p<10exp-5 (one-sample t-tests; μ₀ = 0). Note that there is only light shading for the last row (corresponding to the blue curve).</p