Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness

Mutation of the 3β-hydroxysterol Δ7-reductase gene (Dhcr7−/−) results in Smith-Lemli-Opitz syndrome (SLOS). Patients, and genetically altered mice, are unable to produce cholesterol and accumulate 7-dehydrocholesterol (DHC) in serum and tissue. This causes multiple growth and developmental abnormalities as well as immune system anomalies including allergy. Because cholesterol is a key component of liquid-ordered membranes (lipid rafts) and these domains have been implicated in regulating mast cell activation, we examined whether mast cell responsiveness is altered in this model. Mast cells derived from Dhcr7−/− mice (DHCR KO) showed constitutive cytokine production and hyper-degranulation after stimulation of the high affinity IgE receptor (FcɛRI). DHCR KO mast cells, but not wild-type mast cells, accumulated DHC in lipid rafts. DHC partially disrupted lipid raft stability and displaced Lyn kinase protein and activity from lipid rafts. This led to down-regulation of some Lyn-dependent signaling events but increased Fyn kinase activity and Akt phosphorylation. The Lyn-dependent phosphorylation of Csk-binding protein, which negatively regulates Fyn activity, was decreased. This phenotype reproduces some of the characteristics of Lyn-null mast cells, which also demonstrate hyper-degranulation. These findings provide the first evidence of lipid raft dysfunction in SLOS and may explain the observed association of allergy with SLOS

In vivo hypothalamic regional volumetry across the frontotemporal dementia spectrum

BACKGROUND: Frontotemporal dementia (FTD) is a spectrum of diseases characterised by language, behavioural and motor symptoms. Among the different subcortical regions implicated in the FTD symptomatology, the hypothalamus regulates various bodily functions, including eating behaviours which are commonly present across the FTD spectrum. The pattern of specific hypothalamic involvement across the clinical, pathological, and genetic forms of FTD has yet to be fully investigated, and its possible associations with abnormal eating behaviours have yet to be fully explored. METHODS: Using an automated segmentation tool for volumetric T1-weighted MR images, we measured hypothalamic regional volumes in a cohort of 439 patients with FTD (197 behavioural variant FTD [bvFTD]; 7 FTD with associated motor neurone disease [FTD-MND]; 99 semantic variant primary progressive aphasia [svPPA]; 117 non-fluent variant PPA [nfvPPA]; 19 PPA not otherwise specified [PPA-NOS]) and 118 age-matched controls. We compared volumes across the clinical, genetic (29 MAPT, 32 C9orf72, 23 GRN), and pathological diagnoses (61 tauopathy, 40 TDP-43opathy, 4 FUSopathy). We correlated the volumes with presence of abnormal eating behaviours assessed with the revised version of the Cambridge Behavioural Inventory (CBI-R). RESULTS: On average, FTD patients showed 14% smaller hypothalamic volumes than controls. The groups with the smallest hypothalamic regions were FTD-MND (20%), MAPT (25%) and FUS (33%), with differences mainly localised in the anterior and posterior regions. The inferior tuberal region was only significantly smaller in tauopathies (MAPT and Pick’s disease) and in TDP-43 type C compared to controls and was the only regions that did not correlate with eating symptoms. PPA-NOS and nfvPPA were the groups with the least frequent eating behaviours and the least hypothalamic involvement. CONCLUSIONS: Abnormal hypothalamic volumes are present in all the FTD forms, but different hypothalamic regions might play a different role in the development of abnormal eating behavioural and metabolic symptoms. These findings might therefore help in the identification of different underlying pathological mechanisms, suggesting the potential use of hypothalamic imaging biomarkers and the research of potential therapeutic targets within the hypothalamic neuropeptides

ojoplano-mediated basal constriction is essential for optic cup morphogenesis

11 páginas, 7 figuras. To the memory of Dr José-Santiago Martínez-Vinjoy. Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/136/13/2165/DC1Although the vertebrate retina is a well-studied paradigm for organogenesis, the morphogenetic mechanisms that carve the architecture of the vertebrate optic cup remain largely unknown. Understanding how the hemispheric shape of an eye is formed requires addressing the fundamental problem of how individual cell behaviour is coordinated to direct epithelial morphogenesis. Here, we analyze the role of ojoplano (opo), an uncharacterized gene whose human ortholog is associated with orofacial clefting syndrome, in the morphogenesis of epithelial tissues. Most notably, when opo is mutated in medaka fish, optic cup folding is impaired. We characterize optic cup morphogenesis in vivo and determine at the cellular level how opo affects this process. opo encodes a developmentally regulated transmembrane protein that localizes to compartments of the secretory pathway and to basal end-feet of the neuroepithelial precursors. We show that Opo regulates the polarized localization of focal adhesion components to the basal cell surface. Furthermore, tissue-specific interference with integrin-adhesive function impairs optic cup folding, resembling the ocular phenotype observed in opo mutants. We propose a model of retinal morphogenesis whereby opo-mediated formation of focal contacts is required to transmit the mechanical tensions that drive the macroscopic folding of the vertebrate optic cup.This work was supported by grants from the Deutsche Forschungsgemeinschaft, Collaborative Research Centre 488, the EU and HFSPO to J.W.; and MEC:BFU2008-04362/BMC to J.R.M.-M.Peer reviewe

Accurate Bayesian segmentation of thalamic nuclei using diffusion MRI and an improved histological atlas

The human thalamus is a highly connected brain structure, which is key for the control of numerous functions and is involved in several neurological disorders. Recently, neuroimaging studies have increasingly focused on the volume and connectivity of the specific nuclei comprising this structure, rather than looking at the thalamus as a whole. However, accurate identification of cytoarchitectonically designed histological nuclei on standard in vivo structural MRI is hampered by the lack of image contrast that can be used to distinguish nuclei from each other and from surrounding white matter tracts. While diffusion MRI may offer such contrast, it has lower resolution and lacks some boundaries visible in structural imaging. In this work, we present a Bayesian segmentation algorithm for the thalamus. This algorithm combines prior information from a probabilistic atlas with likelihood models for both structural and diffusion MRI, allowing segmentation of 25 thalamic labels per hemisphere informed by both modalities. We present an improved probabilistic atlas, incorporating thalamic nuclei identified from histology and 45 white matter tracts surrounding the thalamus identified in ultra-high gradient strength diffusion imaging. We present a family of likelihood models for diffusion tensor imaging, ensuring compatibility with the vast majority of neuroimaging datasets that include diffusion MRI data. The use of these diffusion likelihood models greatly improves identification of nuclear groups versus segmentation based solely on structural MRI. Dice comparison of 5 manually identifiable groups of nuclei to ground truth segmentations show improvements of up to 10 percentage points. Additionally, our chosen model shows a high degree of reliability, with median test-retest Dice scores above 0.85 for four out of five nuclei groups, whilst also offering improved detection of differential thalamic involvement in Alzheimer’s disease (AUROC 81.98%). The probabilistic atlas and segmentation tool will be made publicly available as part of the neuroimaging package FreeSurfer

Supporting Nature-Based Solutions via Nature-Based Thinking across European and Latin American cities

Nature-Based Solutions concepts and practices are being used worldwide as part of attempts to address societal challenges but have also been criticised for not dealing with deeper transformations needed to face urgent issues including biodiversity loss, climate change and inclusion. In this paper, we explore how an inclusive, integrated and long-sighted approach, emphasising a more radical integration of nature within cities, might support the transformations needed to endure major contemporary challenges. Addressing important emerging critiques of Nature-Based Solutions, we consider the potential of a more incisive form of Nature-Based Thinking (NBT) in cities, based on more holistic perspectives. The paper draws on a reflective and iterative research process that engaged both the research and practice communities through a symposium and a series of futures workshops that together explored the potential of NBT to develop future nature-cities relations in Europe and Latin America. The results of the reflective process suggest that notions of nature with people-not for people- new organisational structures, and the intention and capacity to apply long-term perspectives, are needed when planning for NBS interventions aimed at sustainable urban development. This includes developing a cultural-structural change based on new and inclusive understandings of human-nature relations, and novel governance paradigms that allow cross-sectoral coordination and engagement of local stakeholders beyond formal organisational structures

Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

This corrects the article DOI: 10.1038/sdata.2017.179

Inflation and Dark Energy from spectroscopy at z > 2

The expansion of the Universe is understood to have accelerated during two epochs: in its very first moments during a period of Inflation and much more recently, at z < 1, when Dark Energy is hypothesized to drive cosmic acceleration. The undiscovered mechanisms behind these two epochs represent some of the most important open problems in fundamental physics. The large cosmological volume at 2 < z < 5, together with the ability to efficiently target high-$z$ galaxies with known techniques, enables large gains in the study of Inflation and Dark Energy. A future spectroscopic survey can test the Gaussianity of the initial conditions up to a factor of ~50 better than our current bounds, crossing the crucial theoretical threshold of $\sigma(f_{NL}^{\rm local})$ of order unity that separates single field and multi-field models. Simultaneously, it can measure the fraction of Dark Energy at the percent level up to $z = 5$, thus serving as an unprecedented test of the standard model and opening up a tremendous discovery space

MiR-34b is associated with clinical outcome in triple-negative breast cancer patients

<p>Abstract</p> <p>Background</p> <p>Breast cancer is the most common malignancy with the highest incidence rates among women worldwide. Triple-negative breast cancer (TNBC) represents the major phenotype of basal-like molecular subtype of breast cancer, characterized by higher incidence in young women and a very poor prognosis. MicroRNAs (miRNAs) are small non-coding RNAs playing significant role in the pathogenesis of many cancers including breast cancer. Therefore, miRNAs are also potential prognostic and/or predictive biomarkers in triple-negative breast cancer patients.</p> <p>Methods</p> <p>Thirty-nine TNBC patients with available formalin-fixed paraffin-embedded (FFPE) tissues were enrolled in the study. MiR-34a, miR-34b, and miR-34c were analyzed using qRT-PCR and correlated to clinico-pathological features of TNBC patients.</p> <p>Results</p> <p>Expression levels of miR-34b significantly correlate with disease free survival (DFS) (<it>p </it>= 0.0020, log-rank test) and overall survival (OS) (<it>p </it>= 0.0008, log-rank test) of TNBC patients. No other significant associations between miR-34a, miR-34b, and miR-34c with available clinical pathological data were observed.</p> <p>Conclusions</p> <p>MiR-34b expression negatively correlates with disease free survival and overall survival in TNBC patients. Thus, miR-34b may present a new promising prognostic biomarker in TNBC patients, but independent validations are necessary.</p

Quantifying and addressing the prevalence and bias of study designs in the environmental and social sciences

Building trust in science and evidence-based decision-making depends heavily on the credibility of studies and their findings. Researchers employ many different study designs that vary in their risk of bias to evaluate the true effect of interventions or impacts. Here, we empirically quantify, on a large scale, the prevalence of different study designs and the magnitude of bias in their estimates. Randomised designs and controlled observational designs with pre-intervention sampling were used by just 23% of intervention studies in biodiversity conservation, and 36% of intervention studies in social science. We demonstrate, through pairwise within-study comparisons across 49 environmental datasets, that these types of designs usually give less biased estimates than simpler observational designs. We propose a model-based approach to combine study estimates that may suffer from different levels of study design bias, discuss the implications for evidence synthesis, and how to facilitate the use of more credible study designs.Fil: Christie, Alec P.. University of Cambridge; Reino UnidoFil: Abecasis, David. Universidad de Algarve. Centro de Ciencias del Mar; PortugalFil: Adjeroud, Mehdi. Université de Perpignan; Francia. Institut de Recherche Pour Le Developpement; FranciaFil: Alonso, Juan Carlos. Consejo Superior de Investigaciones Científicas. Museo Nacional de Ciencias Naturales; EspañaFil: Amano, Tatsuya. University of Queensland; AustraliaFil: Anton, Alvaro. Universidad del País Vasco. Facultad de Educación de Bilbao; EspañaFil: Baldigo, Barry P.. United States Geological Survey; Estados UnidosFil: Barrientos, Rafael. Universidad Complutense de Madrid; EspañaFil: Bicknell, Jake E.. University of Kent; Reino UnidoFil: Buhl, Deborah A.. United States Geological Survey; Estados UnidosFil: Cebrian, Just. Mississippi State University; Estados UnidosFil: Ceia, Ricardo S.. Universidad de Coimbra; PortugalFil: Cibils Martina, Luciana. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Ciencias Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Clarke, Sarah. Marine Institute; IrlandaFil: Claudet, Joachim. Universite de Paris; Francia. Centre National de la Recherche Scientifique; FranciaFil: Craig, Michael D.. University of Western Australia; Australia. Murdoch University; AustraliaFil: Davoult, Dominique. Sorbonne University; FranciaFil: De Backer, Annelies. Flanders Research Institute for Agriculture, Fisheries and Food; BélgicaFil: Donovan, Mary K.. University of California; Estados Unidos. University of Hawaii at Manoa; Estados UnidosFil: Eddy, Tyler D.. University of South Carolina; Estados Unidos. Memorial University of Newfoundland; Canadá. Victoria University of Wellington; Nueva ZelandaFil: França, Filipe M.. Lancaster University; Reino UnidoFil: Gardner, Jonathan P. A.. Victoria University of Wellington; Nueva ZelandaFil: Harris, Bradley P.. Alaska Pacific University; Estados UnidosFil: Huusko, Ari. Natural Resources Institute Finland; FinlandiaFil: Jones, Ian L.. Memorial University of Newfoundland; CanadáFil: Kelaher, Brendan P.. Southern Cross University; AustraliaFil: Kotiaho, Janne S.. Universidad de Jyvaskyla; FinlandiaFil: López Baucells, Adrià. Universidad de Lisboa; Portugal. Smithsonian Tropical Research Institute; Panamá. Universidad Nacional de Colombia. Instituto de Investigaciones Amazonicas; Colombia. Museo de Ciencias Naturales de Granollers; EspañaFil: Major, Heather L.. University of New Brunswick; CanadáFil: Mäki Petäys, Aki. Voimalohi Oy; Finlandia. University of Oulu; Finlandi