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

Distinguishing the cold conveyor belt and sting jet air streams in an intense extratropical cyclone

Strong winds equatorwards and rearwards of a cyclone core have often been associated with two phenomena, the cold conveyor belt (CCB) jet and sting jets. Here, detailed observations of the mesoscale structure in this region of an intense cyclone are analysed. The {\it in-situ} and dropsonde observations were obtained during two research flights through the cyclone during the DIAMET (DIAbatic influences on Mesoscale structures in ExTratropical storms) field campaign. A numerical weather prediction model is used to link the strong wind regions with three types of ``air streams'', or coherent ensembles of trajectories: two types are identified with the CCB, hooking around the cyclone center, while the third is identified with a sting jet, descending from the cloud head to the west of the cyclone. Chemical tracer observations show for the first time that the CCB and sting jet air streams are distinct air masses even when the associated low-level wind maxima are not spatially distinct. In the model, the CCB experiences slow latent heating through weak resolved ascent and convection, while the sting jet experiences weak cooling associated with microphysics during its subsaturated descent. Diagnosis of mesoscale instabilities in the model shows that the CCB passes through largely stable regions, while the sting jet spends relatively long periods in locations characterized by conditional symmetric instability (CSI). The relation of CSI to the observed mesoscale structure of the bent-back front and its possible role in the cloud banding is discussed

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

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

Sting jets in intense winter North-Atlantic windstorms

Extratropical cyclones dominate autumn and winter weather over western Europe. The strongest cyclones, often termed windstorms, have a large socio-economic impact due to the strong surface winds and associated storm surges in coastal areas. Here we show that sting jets are a common feature of windstorms; up to a third of the 100 most intense North Atlantic winter windstorms over the last two decades satisfy conditions for sting jets. The sting jet is a mesoscale descending airstream that can cause strong near-surface winds in the dry slot of the cyclone, a region not usually associated with strong winds. Despite their localized transient nature these sting jets can cause significant damage, a prominent example being the storm that devastated southeast England on 16 October 1987. We present the first regional climatology of windstorms with sting jets. Previously analysed sting jet cases appear to have been exceptional in their track over northwest Europe rather than in their strength

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

Asymmetric triplex metallohelices with high and selective activity against cancer cells

Small cationic amphiphilic α-helical peptides are emerging as agents for the treatment of cancer and infection, but they are costly and display unfavourable pharmacokinetics. Helical coordination complexes may offer a three-dimensional scaffold for the synthesis of mimetic architectures. However, the high symmetry and modest functionality of current systems offer little scope to tailor the structure to interact with specific biomolecular targets, or to create libraries for phenotypic screens. Here, we report the highly stereoselective asymmetric self-assembly of very stable, functionalized metallohelices. Their anti-parallel head-to-head-to-tail ‘triplex’ strand arrangement creates an amphipathic functional topology akin to that of the active sub-units of, for example, host-defence peptides and ​p53. The metallohelices display high, structure-dependent toxicity to the human colon carcinoma cell-line HCT116 ​p53++, causing dramatic changes in the cell cycle without DNA damage. They have lower toxicity to human breast adenocarcinoma cells (MDA-MB-468) and, most remarkably, they show no significant toxicity to the bacteria methicillin-resistant Staphylococcus aureus and Escherichia coli. At a glanc