TRAF2 recruitment via T61 in CD30 drives NFκB activation and enhances hESC survival and proliferation.

CD30 (TNFRSF8), a tumor necrosis factor receptor family protein, and CD30 variant (CD30v), a ligand-independent form encoding only the cytoplasmic signaling domain, are concurrently overexpressed in transformed human embryonic stem cells (hESCs) or hESCs cultured in the presence of ascorbate. CD30 and CD30v are believed to increase hESC survival and proliferation through NF kappa B activation, but how this occurs is largely unknown. Here we demonstrate that hESCs that endogenously express CD30v and hESCs that artificially overexpress CD30v exhibit increased ERK phosphorylation levels, activation of the canonical NF kappa B pathway, down-regulation of the noncanonical NF kappa B pathway, and reduced expression of the full-length CD30 protein. We further find that CD30v, surprisingly, resides predominantly in the nucleus of hESC. We demonstrate that alanine substitution of a single threonine residue at position 61 (T61) in CD30v abrogates CD30v-mediated NF kappa B activation, CD30v-mediated resistance to apoptosis, and CD30v-enhanced proliferation, as well as restores normal G2/M-checkpoint arrest upon H2O2 treatment while maintaining its unexpected subcellular distribution. Using an affinity purification strategy and LC-MS, we identified TRAF2 as the predominant protein that interacts with WT CD30v but not the T61A-mutant form in hESCs. The identification of Thr-61 as a critical residue for TRAF2 recruitment and canonical NF kappa B signaling by CD30v reveals the substantial contribution that this molecule makes to overall NF kappa B activity, cell cycle changes, and survival in hESCs

Drug-tubulin interactions interrogated by transient absorption spectroscopy

[EN] Colchicine (COL) is a bioactive molecule with antitumor properties. When COL binds to tubulin (TU), it inhibits microtubule assembly dynamics. We have investigated COL-TU interactions using laser flash photolysis (LFP) technique and performing fully flexible molecular dynamics simulations. Excitation of COL at 355 nm in aqueous medium did not lead to any transient absorption spectrum. By contrast, in the presence of TU a transient peaking at lambda(max) ca. 420 nm was registered and assigned as triplet excited COL complexed with TU ((COL)-C-3*@TU). In aerated medium, the lifetime was tau ca. 160 mu s and the quantum yield was 0.138. Likewise, when the bicyclic COL analog MTC was submitted to LFP in the presence of TU, (MTC)-M-3@TU* was detected with a lifetime of ca. 62 ms and a quantum yield of 0.296, Aqueous solutions of MTC did not produce any signal in the microsecond timescale. The triplet energy of MTC was obtained by means of emission measurements and found to be ca. 200 kJ mol(-1), a value that matches with that previously reported for COL (188 kJ mol(-1)). Molecular dynamic simulations, both with the ground and triplet excited state, reveal a strong interaction between COL and TU to give stabilized complexes with restricted mobility inside the protein binding site. These results demonstrate that LFP is a useful methodology to study the binding of COL derivatives to TU and open a new way to evaluate the interactions of non-fluorescent anticancer drugs with this protein.Financial support from the Spanish Government (grants CTQ2010-19909; BFU2011-23416 and SEV 2012-0267), the Generalitat Valenciana (Prometeo II/2013/005) and Comunidad de Madrid (S2010/BMD-2353) is gratefully acknowledged. G.S. thanks ASIC-UPV for computing time.Bosca Mayans, F.; Sastre Navarro, GI.; Andreu, JM.; Jornet, D.; Tormos Faus, RE.; Miranda Alonso, MÁ. (2015). Drug-tubulin interactions interrogated by transient absorption spectroscopy. RSC Advances. 5(61):49451-49458. https://doi.org/10.1039/C5RA05636ES4945149458561Mitchison, T., & Kirschner, M. (1984). Dynamic instability of microtubule growth. Nature, 312(5991), 237-242. doi:10.1038/312237a0Margolis, R. L., & Wilson, L. (1978). Opposite end assembly and disassembly of microtubules at steady state in vitro. Cell, 13(1), 1-8. doi:10.1016/0092-8674(78)90132-0Desai, A., & Mitchison, T. J. (1997). MICROTUBULE POLYMERIZATION DYNAMICS. Annual Review of Cell and Developmental Biology, 13(1), 83-117. doi:10.1146/annurev.cellbio.13.1.83Howard, J., & Hyman, A. A. (2003). Dynamics and mechanics of the microtubule plus end. Nature, 422(6933), 753-758. doi:10.1038/nature01600Jordan, M. A., & Wilson, L. (2004). Microtubules as a target for anticancer drugs. Nature Reviews Cancer, 4(4), 253-265. doi:10.1038/nrc1317Ravelli, R. B. G., Gigant, B., Curmi, P. A., Jourdain, I., Lachkar, S., Sobel, A., & Knossow, M. (2004). Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature, 428(6979), 198-202. doi:10.1038/nature02393Cormier, A., Marchand, M., Ravelli, R. B. G., Knossow, M., & Gigant, B. (2008). Structural insight into the inhibition of tubulin by vinca domain peptide ligands. EMBO reports, 9(11), 1101-1106. doi:10.1038/embor.2008.171Prota, A. E., Bargsten, K., Diaz, J. F., Marsh, M., Cuevas, C., Liniger, M., … Steinmetz, M. O. (2014). A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs. Proceedings of the National Academy of Sciences, 111(38), 13817-13821. doi:10.1073/pnas.1408124111Prota, A. E., Bargsten, K., Zurwerra, D., Field, J. J., Díaz, J. F., Altmann, K.-H., & Steinmetz, M. O. (2013). Molecular Mechanism of Action of Microtubule-Stabilizing Anticancer Agents. Science, 339(6119), 587-590. doi:10.1126/science.1230582Prota, A. E., Bargsten, K., Northcote, P. T., Marsh, M., Altmann, K.-H., Miller, J. H., … Steinmetz, M. O. (2014). Structural Basis of Microtubule Stabilization by Laulimalide and Peloruside A. Angewandte Chemie International Edition, 53(6), 1621-1625. doi:10.1002/anie.201307749Brossi, A., Yeh, H. J. C., Chrzanowska, M., Wolff, J., Hamel, E., Lin, C. M., … Silverton, J. (1988). Colchicine and its analogues: Recent findings. Medicinal Research Reviews, 8(1), 77-94. doi:10.1002/med.2610080105Imazio, M., Trinchero, R., & Adler, Y. (2008). Colchicine for the treatment of pericarditis. Future Cardiology, 4(6), 599-607. doi:10.2217/14796678.4.6.599Fakih, M., Replogle, T., Lehr, J. E., Pienta, K. J., & Yagoda, A. (1995). Inhibition of prostate cancer growth by estramustine and colchicine. The Prostate, 26(6), 310-315. doi:10.1002/pros.2990260606Lee, R. M., & Gewirtz, D. A. (2008). Colchicine site inhibitors of microtubule integrity as vascular disrupting agents. Drug Development Research, 69(6), 352-358. doi:10.1002/ddr.20267Abad, A., López-Pérez, J. L., del Olmo, E., García-Fernández, L. F., Francesch, A., Trigili, C., … San Feliciano, A. (2012). Synthesis and Antimitotic and Tubulin Interaction Profiles of Novel Pinacol Derivatives of Podophyllotoxins. Journal of Medicinal Chemistry, 55(15), 6724-6737. doi:10.1021/jm2017573Álvarez, R., Puebla, P., Díaz, J. F., Bento, A. C., García-Navas, R., de la Iglesia-Vicente, J., … Peláez, R. (2013). Endowing Indole-Based Tubulin Inhibitors with an Anchor for Derivatization: Highly Potent 3-Substituted Indolephenstatins and Indoleisocombretastatins. Journal of Medicinal Chemistry, 56(7), 2813-2827. doi:10.1021/jm3015603Panda, D., Daijo, J. E., Jordan, M. A., & Wilson, L. (1995). Kinetic Stabilization of Microtubule Dynamics at Steady State in Vitro by Substoichiometric Concentrations of Tubulin-Colchicine Complex. Biochemistry, 34(31), 9921-9929. doi:10.1021/bi00031a014Andreu, J. M., & Timasheff, S. N. (1982). Interaction of tubulin with single ring analogs of colchicine. Biochemistry, 21(3), 534-543. doi:10.1021/bi00532a019Roesner, M., Capraro, H.-G., Jacobson, A. E., Atwell, L., Brossi, A., Iorio, M. A., … Chignell, C. F. (1981). Biological effects of modified colchicines. Improved preparation of 2-demethylcolchicine, 3-demethylcolchicine, and (+)-colchicine and reassignment of the position of the double bond in dehydro-7-deacetamidocolchicines. Journal of Medicinal Chemistry, 24(3), 257-261. doi:10.1021/jm00135a005Pérez-Ramírez, B., Gorbunoff, M. J., & Timasheff, S. N. (1998). Linkages in Tubulin-Colchicine Functions:  The Role of the Ring C (C‘) Oxygens and Ring B in the Controls†. Biochemistry, 37(6), 1646-1661. doi:10.1021/bi971344dDUMORTIER, C., YAN, Q., BANE, S., & ENGELBORGHS, Y. (1997). Mechanism of tubulin–colchicine recognition: a kinetic study of the binding of the colchicine analogues colchicide and isocolchicine. Biochemical Journal, 327(3), 685-688. doi:10.1042/bj3270685Andreu, J. M., Gorbunopff, M. J., Lee, J. C., & Timasheff, S. N. (1984). Interaction of tubulin with bifunctional colchicine analogs: an equilibrium study. Biochemistry, 23(8), 1742-1752. doi:10.1021/bi00303a025Nguyen, T. L., McGrath, C., Hermone, A. R., Burnett, J. C., Zaharevitz, D. W., Day, B. W., … Gussio, R. (2005). A Common Pharmacophore for a Diverse Set of Colchicine Site Inhibitors Using a Structure-Based Approach. Journal of Medicinal Chemistry, 48(19), 6107-6116. doi:10.1021/jm050502tTorin Huzil, J., Winter, P., Johnson, L., Weis, A. L., Bakos, T., Banerjee, A., … Tuszynski, J. A. (2010). Computational Design and Biological Testing of Highly Cytotoxic Colchicine Ring A Modifications. Chemical Biology & Drug Design, 75(6), 541-550. doi:10.1111/j.1747-0285.2010.00970.xCao, R., Liu, M., Yin, M., Liu, Q., Wang, Y., & Huang, N. (2012). Discovery of Novel Tubulin Inhibitors via Structure-Based Hierarchical Virtual Screening. Journal of Chemical Information and Modeling, 52(10), 2730-2740. doi:10.1021/ci300302cLaing, N., Dahllöf, B., Hartley-Asp, B., Ranganathan, S., & Tew, K. D. (1997). Interaction of Estramustine with Tubulin Isotypes†. Biochemistry, 36(4), 871-878. doi:10.1021/bi961445wGireesh, K. K., Rashid, A., Chakraborti, S., Panda, D., & Manna, T. (2012). CIL-102 binds to tubulin at colchicine binding site and triggers apoptosis in MCF-7 cells by inducing monopolar and multinucleated cells. Biochemical Pharmacology, 84(5), 633-645. doi:10.1016/j.bcp.2012.06.008Gunasekera, N., Xiong, G., Musier-Forsyth, K., & Arriaga, E. (2004). A capillary electrophoretic method for monitoring the presence of α-tubulin in nuclear preparations. Analytical Biochemistry, 330(1), 1-9. doi:10.1016/j.ab.2004.03.059Medrano, F. J., Andreu, J. M., Gorbunoff, M. J., & Timasheff, S. N. (1991). Roles of ring C oxygens in the binding of colchicine to tubulin. Biochemistry, 30(15), 3770-3777. doi:10.1021/bi00229a026Morrison, K. C., & Hergenrother, P. J. (2012). Whole cell microtubule analysis by flow cytometry. Analytical Biochemistry, 420(1), 26-32. doi:10.1016/j.ab.2011.08.020Hastie, S. B., & Rava, R. P. (1989). Analysis of the near-ultraviolet absorption band of colchicine and the effect of tubulin binding. Journal of the American Chemical Society, 111(18), 6993-7001. doi:10.1021/ja00200a015Bhattacharyya, B., Kapoor, S., & Panda, D. (2010). Fluorescence Spectroscopic Methods to Analyze Drug–Tubulin Interactions. Microtubules, in vitro, 301-329. doi:10.1016/s0091-679x(10)95017-6Sardar, P. S., Maity, S. S., Das, L., & Ghosh, S. (2007). Luminescence Studies of Perturbation of Tryptophan Residues of Tubulin in the Complexes of Tubulin with Colchicine and Colchicine Analogues†. Biochemistry, 46(50), 14544-14556. doi:10.1021/bi701412kBhattacharyya, B., & Wolff, J. (1974). Promotion of Fluorescence upon Binding of Colchicine to Tubulin. Proceedings of the National Academy of Sciences, 71(7), 2627-2631. doi:10.1073/pnas.71.7.2627Lhiaubet-Vallet, V., Sarabia, Z., Boscá, F., & Miranda, M. A. (2004). Human Serum Albumin-Mediated Stereodifferentiation in the Triplet State Behavior of (S)- and (R)-Carprofen. Journal of the American Chemical Society, 126(31), 9538-9539. doi:10.1021/ja048518gVayá, I., Lhiaubet-Vallet, V., Jiménez, M. C., & Miranda, M. A. (2014). Photoactive assemblies of organic compounds and biomolecules: drug–protein supramolecular systems. Chem. Soc. Rev., 43(12), 4102-4122. doi:10.1039/c3cs60413fBosca, F., & Tormos, R. (2013). Behavior of Drug Excited States within Macromolecules: Binding of Colchicine and Derivatives to Albumin. The Journal of Physical Chemistry B, 117(25), 7528-7534. doi:10.1021/jp402489jFltzgerald, T. J. (1976). Molecular features of colchicine associated with antimitotic activity and inhibition of tubulin polymerization. Biochemical Pharmacology, 25(12), 1383-1387. doi:10.1016/0006-2952(76)90108-8Andreu, J. M. (2007). Large Scale Purification of Brain Tubulin With the Modified Weisenberg Procedure. Microtubule Protocols, 17-28. doi:10.1007/978-1-59745-442-1_2S. L. Murov , I.Carmichael and G. L.Hug, Handbook of Photochemistry, Marcel Dekker, Inc., New York, 2nd edn, 1993Silva, J. N., Bosca, F., Tomé, J. P. C., Silva, E. M. P., Neves, M. G. P. M. S., Cavaleiro, J. A. S., … Santus, R. (2009). Tricationic Porphyrin Conjugates: Evidence for Chain-Structure-Dependent Relaxation of Excited Singlet and Triplet States. The Journal of Physical Chemistry B, 113(52), 16695-16704. doi:10.1021/jp907930wLand, E. J. (1980). Pulse radiolysis and flash photolysis: some applications in biology and medicine. Biochimie, 62(4), 207-221. doi:10.1016/s0300-9084(80)80395-6Bensasson, R. V., & Gramain, J.-C. (1980). Benzophenone triplet properties in acetonitrile and water. Reduction by lactams. Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases, 76(0), 1801. doi:10.1039/f19807601801Plimpton, S. (1995). Fast Parallel Algorithms for Short-Range Molecular Dynamics. Journal of Computational Physics, 117(1), 1-19. doi:10.1006/jcph.1995.1039In ’t Veld, P. J., Plimpton, S. J., & Grest, G. S. (2008). Accurate and efficient methods for modeling colloidal mixtures in an explicit solvent using molecular dynamics. Computer Physics Communications, 179(5), 320-329. doi:10.1016/j.cpc.2008.03.005Rappe, A. K., Casewit, C. J., Colwell, K. S., Goddard, W. A., & Skiff, W. M. (1992). UFF, a full periodic table force field for molecular mechanics and molecular dynamics simulations. Journal of the American Chemical Society, 114(25), 10024-10035. doi:10.1021/ja00051a040MOPAC2009, James J. P. Stewart, Stewart computational chemistry, version 13.207L; web: http://OpenMOPAC.netMaia, J. D. C., Urquiza Carvalho, G. A., Mangueira, C. P., Santana, S. R., Cabral, L. A. F., & Rocha, G. B. (2012). GPU Linear Algebra Libraries and GPGPU Programming for Accelerating MOPAC Semiempirical Quantum Chemistry Calculations. Journal of Chemical Theory and Computation, 8(9), 3072-3081. doi:10.1021/ct3004645Chai, J.-D., & Head-Gordon, M. (2008). Long-range corrected hybrid density functionals with damped atom–atom dispersion corrections. Physical Chemistry Chemical Physics, 10(44), 6615. doi:10.1039/b810189bSchäfer, A., Huber, C., & Ahlrichs, R. (1994). Fully optimized contracted Gaussian basis sets of triple zeta valence quality for atoms Li to Kr. The Journal of Chemical Physics, 100(8), 5829-5835. doi:10.1063/1.467146Jacquemin, D., Wathelet, V., Perpète, E. A., & Adamo, C. (2009). Extensive TD-DFT Benchmark: Singlet-Excited States of Organic Molecules. Journal of Chemical Theory and Computation, 5(9), 2420-2435. doi:10.1021/ct900298eJacquemin, D., Perpète, E. A., Ciofini, I., & Adamo, C. (2010). Assessment of Functionals for TD-DFT Calculations of Singlet−Triplet Transitions. Journal of Chemical Theory and Computation, 6(5), 1532-1537. doi:10.1021/ct100005dPeach, M. J. G., Benfield, P., Helgaker, T., & Tozer, D. J. (2008). Excitation energies in density functional theory: An evaluation and a diagnostic test. The Journal of Chemical Physics, 128(4), 044118. doi:10.1063/1.2831900Bartovský, P., Tormos, R., & Miranda, M. A. (2009). Colchicine–protein interactions revealed by transient absorption spectroscopy after in situ photoisomerization to lumicolchicines. Chemical Physics Letters, 480(4-6), 305-308. doi:10.1016/j.cplett.2009.09.023Vayá, I., Bueno, C. J., Jiménez, M. C., & Miranda, M. A. (2008). Determination of Enantiomeric Compositions by Transient Absorption Spectroscopy using Proteins as Chiral Selectors. Chemistry - A European Journal, 14(36), 11284-11287. doi:10.1002/chem.200801657Marcus, Y. (1993). The properties of organic liquids that are relevant to their use as solvating solvents. Chemical Society Reviews, 22(6), 409. doi:10.1039/cs9932200409Nery, A. L. P., Quina, F. H., Moreira, Jr, P. F., Medeiros, C. E. R., Baader, W. J., Shimizu, K., … Bechara, E. J. H. (2001). Does the Photochemical Conversion of Colchicine into Lumicolchicines Involve Triplet Transients? A Solvent Dependence Study¶. Photochemistry and Photobiology, 73(3), 213. doi:10.1562/0031-8655(2001)0732.0.co;2Perdew, J. P., Burke, K., & Ernzerhof, M. (1996). Generalized Gradient Approximation Made Simple. Physical Review Letters, 77(18), 3865-3868. doi:10.1103/physrevlett.77.3865Perdew, J. P., Burke, K., & Ernzerhof, M. (1997). Generalized Gradient Approximation Made Simple [Phys. Rev. Lett. 77, 3865 (1996)]. Physical Review Letters, 78(7), 1396-1396. doi:10.1103/physrevlett.78.139

Comprehensive annotation of the Parastagonospora nodorum reference genome using next-generation genomics, transcriptomics and proteogenomics

Parastagonospora nodorum, the causal agent of Septoria nodorum blotch (SNB), is an economically important pathogen of wheat (Triticum spp.), and a model for the study of necrotrophic pathology and genome evolution. The reference P. nodorum strain SN15 was the first Dothideomycete with a published genome sequence, and has been used as the basis for comparison within and between species. Here we present an updated reference genome assembly with corrections of SNP and indel errors in the underlying genome assembly from deep resequencing data as well as extensive manual annotation of gene models using transcriptomic and proteomic sources of evidence (https://github.com/robsyme/Parastagonospora_nodorum_SN15). The updated assembly and annotation includes 8,366 genes with modified protein sequence and 866 new genes. This study shows the benefits of using a wide variety of experimental methods allied to expert curation to generate a reliable set of gene models

The Things You Do:Internal Models of Others' Expected Behaviour Guide Action Observation

Predictions allow humans to manage uncertainties within social interactions. Here, we investigate how explicit and implicit person models-how different people behave in different situations-shape these predictions. In a novel action identification task, participants judged whether actors interacted with or withdrew from objects. In two experiments, we manipulated, unbeknownst to participants, the two actors action likelihoods across situations, such that one actor typically interacted with one object and withdrew from the other, while the other actor showed the opposite behaviour. In Experiment 2, participants additionally received explicit information about the two individuals that either matched or mismatched their actual behaviours. The data revealed direct but dissociable effects of both kinds of person information on action identification. Implicit action likelihoods affected response times, speeding up the identification of typical relative to atypical actions, irrespective of the explicit knowledge about the individual's behaviour. Explicit person knowledge, in contrast, affected error rates, causing participants to respond according to expectations instead of observed behaviour, even when they were aware that the explicit information might not be valid. Together, the data show that internal models of others' behaviour are routinely re-activated during action observation. They provide first evidence of a person-specific social anticipation system, which predicts forthcoming actions from both explicit information and an individuals' prior behaviour in a situation. These data link action observation to recent models of predictive coding in the non-social domain where similar dissociations between implicit effects on stimulus identification and explicit behavioural wagers have been reported

Scoring method of a Situational Judgment Test:influence on internal consistency reliability, adverse impact and correlation with personality?

textabstractSituational Judgment Tests (SJTs) are increasingly used for medical school selection. Scoring an SJT is more complicated than scoring a knowledge test, because there are no objectively correct answers. The scoring method of an SJT may influence the construct and concurrent validity and the adverse impact with respect to non-traditional students. Previous research has compared only a small number of scoring methods and has not studied the effect of scoring method on internal consistency reliability. This study compared 28 different scoring methods for a rating SJT on internal consistency reliability, adverse impact and correlation with personality. The scoring methods varied on four aspects: the way of controlling for systematic error, and the type of reference group, distance and central tendency statistic. All scoring methods were applied to a previously validated integrity-based SJT, administered to 931 medical school applicants. Internal consistency reliability varied between .33 and .73, which is likely explained by the dependence of coefficient alpha on the total score variance. All scoring methods led to significantly higher scores for the ethnic majority than for the non-Western minorities, with effect sizes ranging from 0.48 to 0.66. Eighteen scoring methods showed a significant small positive correlation with agreeableness. Four scoring methods showed a significant small positive correlation with conscientiousness. The way of controlling for systematic error was the most influential scoring method aspect. These results suggest that the increased use of SJTs for selection into medical school must be accompanied by a thorough examination of the scoring method to be used

Computer aided diagnosis of coronary artery disease, myocardial infarction and carotid atherosclerosis using ultrasound images: a review

The diagnosis of Coronary Artery Disease (CAD), Myocardial Infarction (MI) and carotid atherosclerosis is of paramount importance, as these cardiovascular diseases may cause medical complications and large number of death. Ultrasound (US) is a widely used imaging modality, as it captures moving images and image features correlate well with results obtained from other imaging methods. Furthermore, US does not use ionizing radiation and it is economical when compared to other imaging modalities. However, reading US images takes time and the relationship between image and tissue composition is complex. Therefore, the diagnostic accuracy depends on both time taken to read the images and experience of the screening practitioner. Computer support tools can reduce the inter-operator variability with lower subject specific expertise, when appropriate processing methods are used. In the current review, we analysed automatic detection methods for the diagnosis of CAD, MI and carotid atherosclerosis based on thoracic and Intravascular Ultrasound (IVUS). We found that IVUS is more often used than thoracic US for CAD. But for MI and carotid atherosclerosis IVUS is still in the experimental stage. Furthermore, thoracic US is more often used than IVUS for computer aided diagnosis systems

Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p <2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.Peer reviewe

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been