CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis

Macrophages abundantly found in the tumor microenvironment enhance malignancy(1). At metastatic sites a distinct population of metastasis associated macrophages (MAMs) promote tumor cell extravasation, seeding and persistent growth(2). Our study has defined the origin of these macrophages by showing Gr1+ inflammatory monocytes (IMs) are preferentially recruited to pulmonary metastases but not primary mammary tumors, a process also found for human IMs in pulmonary metastases of human breast cancer cells. The recruitment of these CCR2 (receptor for chemokine CCL2) expressing IMs and subsequently MAMs and their interaction with metastasizing tumor cells is dependent on tumor and stromal synthesized CCL2 (FigS1). Inhibition of CCL2/CCR2 signaling using anti-CCL2 antibodies blocks IM recruitment and inhibits metastasis in vivo and prolongs the survival of tumor-bearing mice. Depletion of tumor cell-derived CCL2 also inhibits metastatic seeding. IMs promote tumor cell extravasation in a process that requires monocyte-derived VEGF. CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer (Fig S2)(3-6). Our data provides the mechanistic link between these two clinical associations and indicates new therapeutic targets for treating metastatic breast disease

Eyetracking Metrics in Young Onset Alzheimer’s Disease: A Window into Cognitive Visual Functions

Young onset Alzheimer’s disease (YOAD) is defined as symptom onset before the age of 65 years and is particularly associated with phenotypic heterogeneity. Atypical presentations, such as the clinic-radiological visual syndrome posterior cortical atrophy (PCA), often lead to delays in accurate diagnosis. Eyetracking has been used to demonstrate basic oculomotor impairments in individuals with dementia. In the present study, we aim to explore the relationship between eyetracking metrics and standard tests of visual cognition in individuals with YOAD. Fifty-seven participants were included: 36 individuals with YOAD (n =  26 typical AD; n =  10 PCA) and 21 age-matched healthy controls. Participants completed three eyetracking experiments: fixation, pro-saccade, and smooth pursuit tasks. Summary metrics were used as outcome measures and their predictive value explored looking at correlations with visuoperceptual and visuospatial metrics. Significant correlations between eyetracking metrics and standard visual cognitive estimates are reported. A machine-learning approach using a classification method based on the smooth pursuit raw eyetracking data discriminates with approximately 95% accuracy patients and controls in cross-validation tests. Results suggest that the eyetracking paradigms of a relatively simple and specific nature provide measures not only reflecting basic oculomotor characteristics but also predicting higher order visuospatial and visuoperceptual impairments. Eyetracking measures can represent extremely useful markers during the diagnostic phase and may be exploited as potential outcome measures for clinical trials

ApoE influences regional white-matter axonal density loss in Alzheimer's disease

Mechanisms underlying phenotypic heterogeneity in young onset Alzheimer disease (YOAD) are poorly understood. We used diffusion tensor imaging and neurite orientation dispersion and density imaging (NODDI) with tract-based spatial statistics to investigate apolipoprotein (APOE) ε4 modulation of white-matter damage in 37 patients with YOAD (22, 59% APOE ε4 positive) and 23 age-matched controls. Correlation between neurite density index (NDI) and neuropsychological performance was assessed in 4 white-matter regions of interest. White-matter disruption was more widespread in ε4+ individuals but more focal (posterior predominant) in the absence of an ε4 allele. NODDI metrics indicate fractional anisotropy changes are underpinned by combinations of axonal loss and morphological change. Regional NDI in parieto-occipital white matter correlated with visual object and spatial perception battery performance (right and left, both p = 0.02), and performance (nonverbal) intelligence (WASI matrices, right, p = 0.04). NODDI provides tissue-specific microstructural metrics of white-matter tract damage in YOAD, including NDI which correlates with focal cognitive deficits, and APOEε4 status is associated with different patterns of white-matter neurodegeneration

Navigational cue effects in Alzheimer's disease and posterior cortical atrophy.

OBJECTIVE: Deficits in spatial navigation are characteristic and disabling features of typical Alzheimer's disease (tAD) and posterior cortical atrophy (PCA). Visual cues have been proposed to mitigate such deficits; however, there is currently little empirical evidence for their use. METHODS: The effect of visual cues on visually guided navigation was assessed within a simplified real-world setting in individuals with tAD (n = 10), PCA (n = 8), and healthy controls (n = 12). In a repeated-measures design comprising 36 trials, participants walked to a visible target destination (an open door within a built environment), with or without the presence of an obstacle. Contrast and motion-based cues were evaluated; both aimed to facilitate performance by applying perceptual changes to target destinations without carrying explicit information. The primary outcome was completion time; secondary outcomes were measures of fixation position and walking path directness during consecutive task phases, determined using mobile eyetracking and motion capture methods. RESULTS: Results illustrate marked deficits in patients' navigational ability, with patient groups taking an estimated two to three times longer to reach target destinations than controls and exhibiting tortuous walking paths. There were no significant differences between tAD and PCA task performance. Overall, patients took less time to reach target destinations under cue conditions (contrast-cue: 11.8%; 95% CI: [2.5, 20.3]) and were more likely initially to fixate on targets. INTERPRETATION: The study evaluated navigation to destinations within a real-world environment. There is evidence that introducing perceptual changes to the environment may improve patients' navigational ability

Contrasting environmental drivers of adult and juvenile growth in a marine fish: implications for the effects of climate change

Many marine fishes have life history strategies that involve ontogenetic changes in the use of coastal habitats. Such ontogenetic shifts may place these species at particular risk from climate change, because the successive environments they inhabit can differ in the type, frequency and severity of changes related to global warming. We used a dendrochronology approach to examine the physical and biological drivers of growth of adult and juvenile mangrove jack (Lutjanus argentimaculatus) from tropical north-western Australia. Juveniles of this species inhabit estuarine environments and adults reside on coastal reefs. The Niño-4 index, a measure of the status of the El Niño-Southern Oscillation (ENSO) had the highest correlation with adult growth chronologies, with La Niña years (characterised by warmer temperatures and lower salinities) having positive impacts on growth. Atmospheric and oceanographic phenomena operating at ocean-basin scales seem to be important correlates of the processes driving growth in local coastal habitats. Conversely, terrestrial factors influencing precipitation and river runoff were positively correlated with the growth of juveniles in estuaries. Our results show that the impacts of climate change on these two life history stages are likely to be different, with implications for resilience and management of populations

Variability of coastal and ocean water temperature in the upper 700 m along the western Iberian Peninsula from 1975 to 2006

Temperature is observed to have different trends at coastal and ocean locations along the western Iberian Peninsula from 1975 to 2006, which corresponds to the last warming period in the area under study. The analysis was carried out by means of the Simple Ocean Data Assimilation (SODA). Reanalysis data are available at monthly scale with a horizontal resolution of 0.5° × 0.5° and a vertical resolution of 40 levels, which allows obtaining information beneath the sea surface. Only the first 21 vertical levels (from 5.0 m to 729.35 m) were considered here, since the most important changes in heat content observed for the world ocean during the last decades, correspond to the upper 700 m. Warming was observed to be considerably higher at ocean locations than at coastal ones. Ocean warming ranged from values on the order of 0.3 °C dec(-1) near surface to less than 0.1 °C dec(-1) at 500 m, while coastal warming showed values close to 0.2 °C dec(-1) near surface, decreasing rapidly below 0.1 °C dec(-1) for depths on the order of 50 m. The heat content anomaly for the upper 700 m, showed a sharp increase from coast (0.46 Wm(-2)) to ocean (1.59 Wm(-2)). The difference between coastal and ocean values was related to the presence of coastal upwelling, which partially inhibits the warming from surface of near shore water.publishe

The functional neuroanatomy of musical memory in Alzheimer's disease

BACKGROUND: Memory for music has attracted much recent interest in Alzheimer's disease but the underlying brain mechanisms have not been defined in patients directly. Here we addressed this issue in an Alzheimer's disease cohort using activation fMRI of two core musical memory systems. METHODS: We studied 34 patients with younger onset Alzheimer's disease led either by episodic memory decline (typical Alzheimer's disease) or by visuospatial impairment (posterior cortical atrophy) in relation to 19 age-matched healthy individuals. We designed a novel fMRI paradigm based on passive listening to melodies that were either previously familiar or unfamiliar (musical semantic memory) and either presented singly or repeated (incidental musical episodic memory). RESULTS: Both syndromic groups showed significant functional neuroanatomical alterations relative to the healthy control group. For musical semantic memory, disease-associated activation group differences were localised to right inferior frontal cortex (reduced activation in the group with memory-led Alzheimer's disease); while for incidental musical episodic memory, disease-associated activation group differences were localised to precuneus and posterior cingulate cortex (abnormally enhanced activation in the syndromic groups). In post-scan behavioural testing, both patient groups had a deficit of musical episodic memory relative to healthy controls whereas musical semantic memory was unimpaired. CONCLUSIONS: Our findings define functional neuroanatomical substrates for the differential involvement of musical semantic and incidental episodic memory in major phenotypes of Alzheimer's disease. The complex dynamic profile of brain activation group differences observed suggests that musical memory may be an informative probe of neural network function in Alzheimer's disease. These findings may guide the development of future musical interventions in dementia

Feasibility Study of Dual Energy Radiographic Imaging for Target Localization in Radiotherapy for Lung Tumors

Purpose Dual-energy (DE) radiographic imaging improves tissue discrimination by separating soft from hard tissues in the acquired images. This study was to establish a mathematic model of DE imaging based on intrinsic properties of tissues and quantitatively evaluate the feasibility of applying the DE imaging technique to tumor localization in radiotherapy. Methods We investigated the dependence of DE image quality on the radiological equivalent path length (EPL) of tissues with two phantoms using a stereoscopic x-ray imaging unit. 10 lung cancer patients who underwent radiotherapy each with gold markers implanted in the tumor were enrolled in the study approved by the hospital's Ethics Committee. The displacements of the centroids of the delineated gross tumor volumes (GTVs) in the digitally reconstructed radiograph (DRR) and in the bone-canceled DE image were compared with the averaged displacements of the centroids of gold markers to evaluate the feasibility of using DE imaging for tumor localization. Results The results of the phantom study indicated that the contrast-to-noise ratio (CNR) was linearly dependent on the difference of EPL and a mathematical model was established. The objects and backgrounds corresponding to ΔEPL less than 0.08 are visually indistinguishable in the bone-canceled DE image. The analysis of patient data showed that the tumor contrast in the bone-canceled images was improved significantly as compared with that in the original radiographic images and the accuracy of tumor localization using the DE imaging technique was comparable with that of using fiducial makers. Conclusion It is feasible to apply the technique for tumor localization in radiotherapy

Corals record long-term Leeuwin current variability including Ningaloo Niño/Niña since 1795

Variability of the Leeuwin current (LC) off Western Australia is a footprint of interannual and decadal climate variations in the tropical Indo-Pacific. La Niña events often result in a strengthened LC, high coastal sea levels and unusually warm sea surface temperatures (SSTs), termed Ningaloo Niño. The rarity of such extreme events and the response of the southeastern Indian Ocean to regional and remote climate forcing are poorly understood owing to the lack of long-term records. Here we use well-replicated coral SST records from within the path of the LC, together with a reconstruction of the El Niño-Southern Oscillation to hindcast historical SST and LC strength from 1795 to 2010. We show that interannual and decadal variations in SST and LC strength characterized the past 215 years and that the most extreme sea level and SST anomalies occurred post 1980. These recent events were unprecedented in severity and are likely aided by accelerated global ocean warming and sea-level rise. © 2014 Macmillan Publishers Limited

Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model

Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures