Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

/pdf/gene-discovery-and-polygenic-prediction-from-a-genome-wide-28jxdgwqo5.pdf

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

Recent advances in the field of electron cryomicroscopy (cryo-EM) have resulted in a rapidly increasing number of atomic models of biomacromolecules that have been solved using this technique and deposited in the Protein Data Bank and the Electron Microscopy Data Bank. Similar to macromolecular crystallography, validation tools for these models and maps are required. While some of these validation tools may be borrowed from crystallography, new methods specifically designed for cryo-EM validation are required. Here, new computational methods and tools implemented in PHENIX are discussed, including d99 to estimate resolution, phenix.auto_sharpen to improve maps and phenix.mtriage to analyze cryo-EM maps. It is suggested that cryo-EM half-maps and masks should be deposited to facilitate the evaluation and validation of cryo-EM-derived atomic models and maps. The application of these tools to deposited cryo-EM atomic models and maps is also presented.

/pdf/new-tools-for-the-analysis-and-validation-of-cryo-em-maps-3ffig255jn.pdf

New tools for the analysis and validation of cryo-EM maps and atomic models

Recent advances in the field of electron cryo-microscopy (cryo-EM) have resulted in a rapidly increasing number of atomic models of bio-macromolecules solved using this technique and deposited in the Protein Data Bank and the Electron Microscopy Data Bank. Similar to macromolecular crystallography, validation tools for these models and maps are required. While some of these validation tools may be borrowed from crystallography, new methods specifically for cryo-EM validation are required. We discuss new computational methods and tools implemented in Phenix, including d99 to estimate resolution, phenix.auto_sharpen to improve maps, and phenix.mtriage to analyze cryo-EM maps. We suggest that cryo-EM half-maps and masks are deposited to facilitate evaluation and validation of cryo-EM derived atomic models and maps. We also present the application of these tools to deposited cryo-EM atomic models and maps.

/pdf/new-tools-for-the-analysis-and-validation-of-cryo-em-maps-ku7zoyoznd.pdf

New tools for the analysis and validation of Cryo-EM maps and atomic models

Histone deacetylases (HDACs) are evolutionary conserved enzymes which operate by removing acetyl groups from histones and other protein regulatory factors, with functional consequences on chromatin remodeling and gene expression profiles. We provide here a review on the recent knowledge accrued on the zinc-dependent HDAC protein family across different species, tissues, and human pathologies, specifically focusing on the role of HDAC inhibitors as anti-cancer agents. We will investigate the chemical specificity of different HDACs and discuss their role in the human interactome as members of chromatin-binding and regulatory complexes.

Histone deacetylases (HDACs): Evolution, specificity, role in transcriptional complexes, and pharmacological actionability

Extracellular vesicles (EVs) are produced by all known organisms and are important for cell communication and physiology. Great morphological diversity has been described regarding EVs found in body fluids such as blood plasma, breast milk, and ejaculate. However, a detailed morphological analysis has never been performed on exosomes when purified from a single cell type. In this study we analysed and quantified, via multiple electron microscopy techniques, the morphology of exosomes purified from the human mast cell line HMC-1. The results revealed a wide diversity in exosome morphology, suggesting that subpopulations of exosomes with different and specific functions may exist. Our findings imply that a new, more efficient way of defining exosome subpopulations is necessary. A system was proposed where exosomes were classified into nine different categories according to their size and shape. Three additional morphological features were also found in exosomes regardless of their morphological classification. These findings show that exosomes purified from a single cell line are also morphologically diverse, similar to previous observations for EVs in body fluids. This knowledge can help to improve the interpretation of experimental results and widen our general understanding of the biological functions of exosomes.

https://www.tandfonline.com/doi/pdf/10.1080/20013078.2017.1329476

Exosomes purified from a single cell type have diverse morphology

Transcription regulation through chromatin compaction and decompaction is regulated through various chromatin-remodeling complexes such as nucleosome remodeling and histone deacetylation (NuRD) complex NuRD is a 1 MDa multi-subunit protein complex which comprises many different subunits, among which histone deacetylases HDAC1/2, ATP-dependent remodeling enzymes CHD3/4, histone chaperones RbAp46/48, CpG-binding proteins MBD2/3, the GATAD2a (p66α) and/or GATAD2b (p66β) and specific DNA-binding proteins MTA1/2/3 Here, we review the currently known crystal and NMR structures of these subunits, the functional data and their relevance for biomedical research considering the implication of NuRD subunits in cancer and various other diseases The complexity of this macromolecular assembly, and its poorly understood mode of interaction with the nucleosome, the repeating unit of chromatin, illustrate that this complex is a major challenge for structure-function relationship studies which will be tackled best by an integrated biology approach

Structure and function insights into the NuRD chromatin remodeling complex

https://onlinelibrary.wiley.com/doi/pdf/10.1111/boc.201600042

The integrative role of cryo electron microscopy in molecular and cellular structural biology.

10 Integrative structure-function analysis of large nucleoprotein complexes

An integrative structural biology approach has been used to study the structural organization of the NuRD complex.My work focused especially on three subunits of this complex: MBD3, RbAp46 and RbAp48. I set up the preparation of the individual subunits and characterized them by various biophysical methods. We next carried out binding assays with homemade human nucleosomes. For MBD3, optimization of the complex led to crystals diffracting up to 7 A. In parallel, a preliminary 3-D reconstruction at 25 A resolution has been solved in cryo-EM. For RbAp46/48, crystal we were able to show that these proteins form stable complexes with the nucleosome, paving the way for future structural analysis by cryo-EM or X-ray crystallography.

Structure-Function study of the chromatin remodelling complex NuRD

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Structure and function insights into the NuRD chromatin remodeling complex

The integrative role of cryo electron microscopy in molecular and cellular structural biology.

10 Integrative structure-function analysis of large nucleoprotein complexes

Structure-Function study of the chromatin remodelling complex NuRD