344 research outputs found

    Molecular Analysis of a Major Carpel Developmental Regulator: CRABS CLAW’s Protein Domains and Non-Cell-Autonomous Action

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    CRABS CLAW is a small protein belonging to the YABBY family, a plant specific protein family. In Arabidopsis thaliana it is expressed in the developing carpels and regulates the apical fusion of the two carpels, transmitting tract development, lateral growth, and nectary formation. The expression of CRC is rather complex with multiple expression domains throughout the young gynoecium and as for other YABBY proteins a non-cell-autonomous action has been described. However, only few regulators of CRC expression and target genes are described and the mode of non-cell-autonomous action is still unknown. This dissertation aims to identify transcriptional regulators, responsible for the proper temporal and spatial expression of CRC, the specification of CRC’s place in the adaxial-abaxial regulatory network and to clarify the means of its non-cell-autonomous action. The regulation of CRC expression has been analyzed via a large scale Yeast-1-Hybrid screen and identified over 100 potential regulators of CRC expression, integrating CRC tightly into the carpel developmental regulatory protein network. Further analysis of CRC function through expression analysis led to the identification of target genes of CRC like mir165/166, members of the KANADI gene family, and the HD ZIP III gene family. Both gene families are major players in the adaxial-abaxial regulatory network, involved in the development of all lateral plant organs such as leaves and floral organs. CRC supports KANADI action and activates the expression of other involved factors. In addition, CRC directly targets members of the HD ZIP III family. However, CRC’s position in the adaxial- abaxial regulatory network seems to be not conserved in other eudicots. CRC exhibits a non- cell-autonomous action which is conferred by at least two signaling pathways. Abaxial polarity is regulated by the activation of the mobile miRNA165/166. At the same time, localizations of GFP tagged CRC revealed the CRC protein to be mobile as it migrates into the adaxial domain in young gynoecia. In older gynoecia it was excluded from the adaxial domain. This study identified multiple unique features of CRC compared to its relatives. Its thightly controlled expression by over 100 putative regulators, integration in complex co-expression networks, adaxial and abaxial target genes, and its two mode non-cell-autonomous action indicate the important role in the complicated carpel development.CRABS CLAW ist ein kleines Protein der pflanzenspezifischen YABBY Protein Familie. In Arabidopsis thaliana ist es in den entwickelnden FruchtblĂ€ttern exprimiert und reguliert die apikale Fusion der FruchtblĂ€tter, die Entwicklung des Transmissionskanal (einem Bereich des Septums), die Begrenzung des lateralen Wachstums des Gynoeceums, und die Bildung der Nektarien. Die Expression von CRC ist auf mehrere Bereiche im Fruchtblatt aufgeteilt und ebenso wurde ein nicht-zell-autonomer Effekt wie fĂŒr andere YABBY Proteine beschrieben. Jedoch sind nur einige wenige Regulatoren der CRC Expression und Zielgene von CRC bekannt, sowie die Natur des mobilen Signals des nicht-zell-autonomen Effektes unbekannt ist. Daher zielt diese Dissertation darauf, zusĂ€tzliche transkriptionelle Regulatoren, die fĂŒr die korrekte zeitliche und rĂ€umliche Expression von CRC nötig sind, zu identifizieren, sowie CRCs Position im adaxialen-abaxialen Netzwerk zu identifizieren und die Art und Weise des nicht-zell-autonomen Effektes zu klĂ€ren. Die Expression von CRC wurde durch eine groß angelegte Hefe-1-Hybrid Analyse nĂ€her untersucht und ĂŒber 100 mögliche Regulatoren der CRC Expression wurden identifiziert. Dies festigt CRCs Position im gen-regulatorischen Netzwerk der Fruchtblattentwicklung. Eine weitere Analyse der CRC Funktionen mittels Expressionsanalyse fĂŒhrte zu der Identifikation mehrerer Zielgene wie mir165/166, Mitglieder der KANADI Genfamilie und Mitglieder der HD ZIP III Genfamilie. Beide Genfamilien sind Hauptkomponenten des adaxial–abaxialen Regulationsnetzwerkes. Dabei unterstĂŒtzt CRC die Funktion der KAN Proteine und reguliert die Expression anderer involvierter Gene. ZusĂ€tzlich reguliert CRC direkt die Expression einiger HD ZIP III Gene. Wobei die Regulation der adaxial-abaxialen Regulatoren durch CRC zwischen verschiedenen Eudikotylen nicht komplett konserviert ist. CRC weist eine nicht-zell-autonome Funktion auf, die durch mindestens zwei SignalĂŒbertragungswege vermittelt wird. Zum einen reguliert CRC die abaxiale PolaritĂ€t durch die Aktivierung der mobilen miRNA165/166 und zum anderen durch direkten Transport des CRC Proteins. Lokalisierungen von mit GFP markierten CRC zeigten, dass das CRC Protein in den frĂŒhen Stadien des Gyneoceums von der abaxialen DomĂ€ne in die adaxiale wandert. In spĂ€teren Stadien ist CRC auf die abaxiale DomĂ€ne begrenzt. Diese Studie konnte mehrere einzigartige CRC Charakteristika identifizieren, die CRC von den anderen Mitgliedern der YABBY Familie unterscheidet. Seine stark kontrollierte Expression durch mehr als 100 mögliche Regulatoren, die Integration in ein kompliziertes Co- Expressions Netzwerk, adaxiale und abaxiale Zielgene, und mindestens zwei Möglichkeiten zur nicht-zell-autonomen Regulation, zeigen eindringlich die wichtige Rolle CRCs in der komplexen Karpellentwicklung auf

    Reproducibility in the absence of selective reporting : An illustration from large-scale brain asymmetry research

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    Altres ajuts: Max Planck Society (Germany).The problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p-hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multisite collaborative study, we mapped brain anatomical left-right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we revisited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta-analytic effect from the 98 other datasets, in terms of effect direction and significance threshold. In this sense, the results within each dataset were viewed as coming from separate studies in an "ideal publishing environment," that is, free from selective reporting and p hacking. We found an average reproducibility rate of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. Reproducibility was not obviously related to the age of participants, scanner field strength, FreeSurfer software version, cortical regional measurement reliability, or regional size. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically-used sample sizes

    Novel genetic loci associated with hippocampal volume

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    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

    The genetic architecture of the human cerebral cortex

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    INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

    Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

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    BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362
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