PTEN Enters the Nuclear Age

Regulation of the PTEN tumor suppressor protein is poorly understood. In this issue, Wang et al. (2007) and Trotman et al. (2007) describe how ubiquitination regulates PTEN stability and its nuclear localization. Additionally, Shen et al. (2007) report that a nuclear pool of PTEN helps to maintain chromosomal stability

Cortical tau deposition follows patterns of entorhinal functional connectivity in aging.

Tau pathology first appears in the transentorhinal and anterolateral entorhinal cortex (alEC) in the aging brain. The transition to Alzheimer's disease (AD) is hypothesized to involve amyloid-β (Aβ) facilitated tau spread through neural connections. We contrasted functional connectivity (FC) of alEC and posteromedial EC (pmEC), subregions of EC that differ in functional specialization and cortical connectivity, with the hypothesis that alEC-connected cortex would show greater tau deposition than pmEC-connected cortex. We used resting state fMRI to measure FC, and PET to measure tau and Aβ in cognitively normal older adults. Tau preferentially deposited in alEC-connected cortex compared to pmEC-connected or non-connected cortex, and stronger connectivity was associated with increased tau deposition. FC-tau relationships were present regardless of Aβ, although strengthened with Aβ. These results provide an explanation for the anatomic specificity of neocortical tau deposition in the aging brain and reveal relationships between normal aging and the evolution of AD

Time Course of Dichoptic Masking in Normals and Suppression in Amblyopes

Purpose: To better understand the relationship between dichoptic masking in normal vision and suppression in amblyopia we address three questions: First, what is the time course of dichoptic masking in normals and amblyopes? Second, is interocular suppression low-pass or band-pass in its spatial dependence? And third, in the above two regards, is dichoptic masking in normals different from amblyopic suppression? Methods: We measured the dependence of dichoptic masking in normal controls and amblyopes on the temporal duration of presentation under three conditions; monocular (the nontested eye—i.e., dominant eye of normals or nonamblyopic eye of amblyopes, being patched), dichoptic-luminance (the nontested eye seeing a mean luminance—i.e., a DC component) and dichoptic-contrast (the nontested eye seeing high-contrast visual noise). The subject had to detect a letter in the other eye, the contrast of which was varied. Results: We found that threshold elevation relative to the patched condition occurred in both normals and amblyopes when the nontested eye saw either 1/f or band-pass filtered noise, but not just mean luminance (i.e., there was no masking from the DC component that corresponds to a channel responsive to a spatial frequency of 0 cyc/deg); longer presentation of the target (corresponding to lower temporal frequencies) produced greater threshold elevation. Conclusions: Dichoptic masking exhibits similar properties in both subject groups, being low-pass temporally and band-pass spatially, so that masking was greatest at the longest presentation durations and was not greatly affected by mean luminance in the nontested eye

Tau deposition is associated with functional isolation of the hippocampus in aging.

The tau protein aggregates in aging and Alzheimer disease and may lead to memory loss through disruption of medial temporal lobe (MTL)-dependent memory systems. Here, we investigated tau-mediated mechanisms of hippocampal dysfunction that underlie the expression of episodic memory decline using fMRI measures of hippocampal local coherence (regional homogeneity; ReHo), distant functional connectivity and tau-PET. We show that age and tau pathology are related to higher hippocampal ReHo. Functional disconnection between the hippocampus and other components of the MTL memory system, particularly an anterior-temporal network specialized for object memory, is also associated with higher hippocampal ReHo and greater tau burden in anterior-temporal regions. These associations are not observed in the posteromedial network, specialized for context/spatial information. Higher hippocampal ReHo predicts worse memory performance. These findings suggest that tau pathology plays a role in disconnecting the hippocampus from specific MTL memory systems leading to increased local coherence and memory decline

Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma

High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis

Pediatric high-grade glioma: biologically and clinically in need of new thinking.

High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace. It is important to avoid therapeutic strategies developed purely using data obtained from studies on adult glioblastoma. This approach has resulted in repetitive trials and ineffective treatments being applied to these children, with limited improvement in clinical outcome. The authors of this perspective, comprising biology and clinical expertise in the disease, recently convened to discuss the most effective ways to translate the emerging molecular insights into patient benefit. This article reviews our current understanding of pediatric high-grade glioma and suggests approaches for innovative clinical management

Analysis of and workarounds for element reversal for a finite element-based algorithm for warping triangular and tetrahedral meshes

We consider an algorithm called FEMWARP for warping triangular and tetrahedral finite element meshes that computes the warping using the finite element method itself. The algorithm takes as input a two- or three-dimensional domain defined by a boundary mesh (segments in one dimension or triangles in two dimensions) that has a volume mesh (triangles in two dimensions or tetrahedra in three dimensions) in its interior. It also takes as input a prescribed movement of the boundary mesh. It computes as output updated positions of the vertices of the volume mesh. The first step of the algorithm is to determine from the initial mesh a set of local weights for each interior vertex that describes each interior vertex in terms of the positions of its neighbors. These weights are computed using a finite element stiffness matrix. After a boundary transformation is applied, a linear system of equations based upon the weights is solved to determine the final positions of the interior vertices. The FEMWARP algorithm has been considered in the previous literature (e.g., in a 2001 paper by Baker). FEMWARP has been succesful in computing deformed meshes for certain applications. However, sometimes FEMWARP reverses elements; this is our main concern in this paper. We analyze the causes for this undesirable behavior and propose several techniques to make the method more robust against reversals. The most successful of the proposed methods includes combining FEMWARP with an optimization-based untangler.Comment: Revision of earlier version of paper. Submitted for publication in BIT Numerical Mathematics on 27 April 2010. Accepted for publication on 7 September 2010. Published online on 9 October 2010. The final publication is available at http://www.springerlink.co

The Atacama Cosmology Telescope: The LABOCA/ACT Survey of Clusters at All Redshifts

We present a multi-wavelength analysis of eleven Sunyaev Zel'dovich effect (SZE)-selected galaxy clusters (ten with new data) from the Atacama Cosmology Telescope (ACT) southern survey. We have obtained new imaging from the Large APEX Bolometer Camera (345GHz; LABOCA) on the Atacama Pathfinder EXperiment (APEX) telescope, the Australia Telescope Compact Array (2.1GHz; ATCA), and the Spectral and Photometric Imaging Receiver (250, 350, and $500\,\rm\mu m$; SPIRE) on the Herschel Space Observatory. Spatially-resolved 345GHz SZE increments with integrated S/N > 5 are found in six clusters. We compute 2.1GHz number counts as a function of cluster-centric radius and find significant enhancements in the counts of bright sources at projected radii $\theta < \theta_{2500}$. By extrapolating in frequency, we predict that the combined signals from 2.1GHz-selected radio sources and 345GHz-selected SMGs contaminate the 148GHz SZE decrement signal by ~5% and the 345GHz SZE increment by ~18%. After removing radio source and SMG emission from the SZE signals, we use ACT, LABOCA, and (in some cases) new Herschel SPIRE imaging to place constraints on the clusters' peculiar velocities. The sample's average peculiar velocity relative to the cosmic microwave background is $153\pm 383\,\rm km\,s^{-1}$.Comment: 19 pages, 11 figures, Accepted for Publication in The Astrophysical Journa

Tau PET and multimodal brain imaging in patients at risk for chronic traumatic encephalopathy.

ObjectiveTo characterize individual and group-level neuroimaging findings in patients at risk for Chronic Traumatic Encephalopathy (CTE).MethodsEleven male patients meeting criteria for Traumatic Encephalopathy Syndrome (TES, median age: 64) underwent neurologic evaluation, 3-Tesla MRI, and PET with [18F]-Flortaucipir (FTP, tau-PET) and [11C]-Pittsburgh compound B (PIB, amyloid-PET). Six patients underwent [18F]-Fluorodeoxyglucose-PET (FDG, glucose metabolism). We assessed imaging findings at the individual patient level, and in group-level comparisons with modality-specific groups of cognitively normal older adults (CN). Tau-PET findings in patients with TES were also compared to a matched group of patients with mild cognitive impairment or dementia due to Alzheimer's disease (AD).ResultsAll patients with TES sustained repetitive head injury participating in impact sports, ten in American football. Three patients met criteria for dementia and eight had mild cognitive impairment. Two patients were amyloid-PET positive and harbored the most severe MRI atrophy, FDG hypometabolism, and FTP-tau PET binding. Among the nine amyloid-negative patients, tau-PET showed either mildly elevated frontotemporal binding, a "dot-like" pattern, or no elevated binding. Medial temporal FTP was mildly elevated in a subset of amyloid-negative patients, but values were considerably lower than in AD. Voxelwise analyses revealed a convergence of imaging abnormalities (higher FTP binding, lower FDG, lower gray matter volumes) in frontotemporal areas in TES compared to controls.ConclusionsMildly elevated tau-PET binding was observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with CTE pathology stages III-IV. FTP-PET may be useful as a biomarker of tau pathology in CTE but is unlikely to be sensitive to early disease stages