Description: Assisted reproductive technologies (ART) are associated with several complications including low birth weight, abnormal placentation and increased risk for rare imprinting disorders. Indeed, experimental studies demonstrate ART procedures independent of existing infertility induce epigenetic perturbations in the embryo and extraembryonic tissues. To test the hypothesis that these epigenetic perturbations persist and result in adverse outcomes at term, we assessed placental morphology and methylation profiles in E18.5 mouse concepti generated by in vitro fertilization (IVF) in two different genetic backgrounds. We also examined embryo transfer (ET) and superovulation procedures to ascertain if they contribute to developmental and epigenetic effects. Increased placental weight and reduced fetal-to-placental weight ratio were observed in all ART groups when compared with naturally conceived controls, demonstrating that non-surgical embryo transfer alone can impact placental development. Furthermore, superovulation further induced overgrowth of the placental junctional zone. Embryo transfer and superovulation defects were limited to these morphological changes, as we did not observe any differences in epigenetic profiles. IVF placentae, however, displayed hypomethylation of imprinting control regions of select imprinted genes and a global reduction in DNA methylation levels. Although we did not detect significant differences in DNA methylation in fetal brain or liver samples, rare IVF concepti displayed very low methylation and abnormal gene expression from the normally repressed allele. Our findings suggest that individual ART procedures cumulatively increase placental morphological abnormalities and epigenetic perturbations, potentially causing adverse neonatal and long-term health outcomes in offspring.

Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138491/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138491/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉H3Africa Consortium -- Rotimi, Charles -- Abayomi, Akin -- Abimiku, Alash'le -- Adabayeri, Victoria May -- Adebamowo, Clement -- Adebiyi, Ezekiel -- Ademola, Adebowale D -- Adeyemo, Adebowale -- Adu, Dwomoa -- Affolabi, Dissou -- Agongo, Godfred -- Ajayi, Samuel -- Akarolo-Anthony, Sally -- Akinyemi, Rufus -- Akpalu, Albert -- Alberts, Marianne -- Alonso Betancourt, Orlando -- Alzohairy, Ahmed Mansour -- Ameni, Gobena -- Amodu, Olukemi -- Anabwani, Gabriel -- Andersen, Kristian -- Arogundade, Fatiu -- Arulogun, Oyedunni -- Asogun, Danny -- Bakare, Rasheed -- Balde, Naby -- Baniecki, Mary Lynn -- Beiswanger, Christine -- Benkahla, Alia -- Bethke, Lara -- Boehnke, Micheal -- Boima, Vincent -- Brandful, James -- Brooks, Andrew I -- Brosius, Frank C -- Brown, Chester -- Bucheton, Bruno -- Burke, David T -- Burnett, Barrington G -- Carrington-Lawrence, Stacy -- Carstens, Nadia -- Chisi, John -- Christoffels, Alan -- Cooper, Richard -- Cordell, Heather -- Crowther, Nigel -- Croxton, Talishiea -- de Vries, Jantina -- Derr, Leslie -- Donkor, Peter -- Doumbia, Seydou -- Duncanson, Audrey -- Ekem, Ivy -- El Sayed, Ahmed -- Engel, Mark E -- Enyaru, John C K -- Everett, Dean -- Fadlelmola, Faisal M -- Fakunle, Eyitayo -- Fischbeck, Kenneth H -- Fischer, Anne -- Folarin, Onikepe -- Gamieldien, Junaid -- Garry, Robert F -- Gaseitsiwe, Simani -- Gbadegesin, Rasheed -- Ghansah, Anita -- Giovanni, Maria -- Goesbeck, Parham -- Gomez-Olive, F Xavier -- Grant, Donald S -- Grewal, Ravnit -- Guyer, Mark -- Hanchard, Neil A -- Happi, Christian T -- Hazelhurst, Scott -- Hennig, Branwen J -- Hertz-, Christiane -- Fowler -- Hide, Winston -- Hilderbrandt, Friedhelm -- Hugo-Hamman, Christopher -- Ibrahim, Muntaser E -- James, Regina -- Jaufeerally-Fakim, Yasmina -- Jenkins, Carolyn -- Jentsch, Ute -- Jiang, Pan-Pan -- Joloba, Moses -- Jongeneel, Victor -- Joubert, Fourie -- Kader, Mukthar -- Kahn, Kathleen -- Kaleebu, Pontiano -- Kapiga, Saidi H -- Kassim, Samar Kamal -- Kasvosve, Ishmael -- Kayondo, Jonathan -- Keavney, Bernard -- Kekitiinwa, Adeodata -- Khan, Sheik Humarr -- Kimmel, Paul -- King, Mary-Claire -- Kleta, Robert -- Koffi, Mathurin -- Kopp, Jeffrey -- Kretzler, Matthias -- Kumuthini, Judit -- Kyobe, Samuel -- Kyobutungi, Catherine -- Lackland, Daniel T -- Lacourciere, Karen A -- Landoure, Guida -- Lawlor, Rita -- Lehner, Thomas -- Lesosky, Maia -- Levitt, Naomi -- Littler, Katherine -- Lombard, Zane -- Loring, Jeanne F -- Lyantagaye, Sylvester -- Macleod, Annette -- Madden, Ebony B -- Mahomva, Chengetai R -- Makani, Julie -- Mamven, Manmak -- Marape, Marape -- Mardon, Graeme -- Marshall, Patricia -- Martin, Darren P -- Masiga, Daniel -- Mason, Robin -- Mate-Kole, Michael -- Matovu, Enock -- Mayige, Mary -- Mayosi, Bongani M -- Mbanya, Jean Claude -- McCurdy, Sheryl A -- McCarthy, Mark I -- McIlleron, Helen -- Mc'Ligeyo, S O -- Merle, Corrine -- Mocumbi, Ana Olga -- Mondo, Charles -- Moran, John V -- Motala, Ayesha -- Moxey-Mims, Marva -- Mpoloka, Wata Sununguko -- Msefula, Chisomo L -- Mthiyane, Thuli -- Mulder, Nicola -- Mulugeta, Gebregziab her -- Mumba, Dieuodonne -- Musuku, John -- Nagdee, Mo -- Nash, Oyekanmi -- Ndiaye, Daouda -- Nguyen, Anh Quynh -- Nicol, Mark -- Nkomazana, Oathokwa -- Norris, Shane -- Nsangi, Betty -- Nyarko, Alexander -- Nyirenda, Moffat -- Obe, Eileen -- Obiakor, Reginald -- Oduro, Abraham -- Ofori-Acquah, Solomon F -- Ogah, Okechukwu -- Ogendo, Stephen -- Ohene-Frempong, Kwaku -- Ojo, Akinlolu -- Olanrewaju, Timothy -- Oli, John -- Osafo, Charlotte -- Ouwe Missi Oukem-Boyer, Odile -- Ovbiagele, Bruce -- Owen, Andrew -- Owolabi, Mayowa Ojo -- Owolabi, Lukman -- Owusu-Dabo, Ellis -- Pare, Guillaume -- Parekh, Rulan -- Patterton, Hugh G -- Penno, Margaret B -- Peterson, Jane -- Pieper, Rembert -- Plange-Rhule, Jacob -- Pollak, Martin -- Puzak, Julia -- Ramesar, Rajkumar S -- Ramsay, Michele -- Rasooly, Rebekah -- Reddy, Shiksha -- Sabeti, Pardis C -- Sagoe, Kwamena -- Salako, Tunde -- Samassekou, Oumar -- Sandhu, Manjinder S -- Sankoh, Osman -- Sarfo, Fred Stephen -- Sarr, Marie -- Shaboodien, Gasnat -- Sidibe, Issa -- Simo, Gustave -- Simuunza, Martin -- Smeeth, Liam -- Sobngwi, Eugene -- Soodyall, Himla -- Sorgho, Hermann -- Sow Bah, Oumou -- Srinivasan, Sudha -- Stein, Dan J -- Susser, Ezra S -- Swanepoel, Carmen -- Tangwa, Godfred -- Tareila, Andrew -- Tastan Bishop, Ozlem -- Tayo, Bamidele -- Tiffin, Nicki -- Tinto, Halidou -- Tobin, Ekaete -- Tollman, Stephen Meir -- Traore, Mahamadou -- Treadwell, Marsha J -- Troyer, Jennifer -- Tsimako-Johnstone, Masego -- Tukei, Vincent -- Ulasi, Ifeoma -- Ulenga, Nzovu -- van Rooyen, Beverley -- Wachinou, Ablo Prudence -- Waddy, Salina P -- Wade, Alisha -- Wayengera, Misaki -- Whitworth, James -- Wideroff, Louise -- Winkler, Cheryl A -- Winnicki, Sarah -- Wonkam, Ambroise -- Yewondwos, Mengistu -- sen, Tadase -- Yozwiak, Nathan -- Zar, Heather -- 085349/Wellcome Trust/United Kingdom -- 095009/Wellcome Trust/United Kingdom -- 095201/Wellcome Trust/United Kingdom -- 098504/Wellcome Trust/United Kingdom -- 104111/Wellcome Trust/United Kingdom -- MC_U123292700/Medical Research Council/United Kingdom -- P20 MD006899/MD/NIMHD NIH HHS/ -- R01 AI104621/AI/NIAID NIH HHS/ -- RG/08/012/25941/British Heart Foundation/United Kingdom -- U01 HG007044/HG/NHGRI NIH HHS/ -- U41 HG006941/HG/NHGRI NIH HHS/ -- U54 AI110398/AI/NIAID NIH HHS/ -- U54 HG006938/HG/NHGRI NIH HHS/ -- U54 HG006939/HG/NHGRI NIH HHS/ -- U54 HG007479/HG/NHGRI NIH HHS/ -- UH2 HG007051/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 20;344(6190):1346-8. doi: 10.1126/science.1251546.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24948725" target="_blank"〉PubMed〈/a〉

Description: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Description: Arthritis is a leading cause of disability, and when nonoperative methods have failed, a prosthetic implant is a cost-effective and clinically successful treatment. Metal-on-metal replacements are an attractive implant technology, a lower-wear alternative to metal-on-polyethylene devices. Relatively little is known about how sliding occurs in these implants, except that proteins play a critical role and that there is a tribological layer on the metal surface. We report evidence for graphitic material in the tribological layer in metal-on-metal hip replacements retrieved from patients. As graphite is a solid lubricant, its presence helps to explain why these components exhibit low wear and suggests methods of improving their performance; simultaneously, this raises the issue of the physiological effects of graphitic wear debris.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liao, Y -- Pourzal, R -- Wimmer, M A -- Jacobs, J J -- Fischer, A -- Marks, L D -- 1RC2AR058993-01/AR/NIAMS NIH HHS/ -- New York, N.Y. -- Science. 2011 Dec 23;334(6063):1687-90. doi: 10.1126/science.1213902.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60201, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22194573" target="_blank"〉PubMed〈/a〉

Description: The genetic contribution to the variation in human lifespan is ~25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (〈65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 x 10 –8 ). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 x 10 –36 ), representing the TOMM40 / APOE / APOC1 locus. In a prospective meta-analysis ( n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Description: Plectin, a versatile 500-kDa cytolinker protein, is essential for muscle fiber integrity and function. The most common disease caused by mutations in the human plectin gene, epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), is characterized by severe skin blistering and progressive muscular dystrophy. Besides displaying pathological desmin-positive protein aggregates and degenerative changes in the myofibrillar apparatus, skeletal muscle specimens of EBS-MD patients and plectin-deficient mice are characterized by massive mitochondrial alterations. In this study, we demonstrate that structural and functional alterations of mitochondria are a primary aftermath of plectin deficiency in muscle, contributing to myofiber degeneration. We found that in skeletal muscle of conditional plectin knockout mice (MCK-Cre/cKO), mitochondrial content was reduced, and mitochondria were aggregated in sarcoplasmic and subsarcolemmal regions and were no longer associated with Z-disks. Additionally, decreased mitochondrial citrate synthase activity, respiratory function and altered adenosine diphosphate kinetics were characteristic of plectin-deficient muscles. To analyze a mechanistic link between plectin deficiency and mitochondrial alterations, we comparatively assessed mitochondrial morphology and function in whole muscle and teased muscle fibers of wild-type, MCK-Cre/cKO and plectin isoform-specific knockout mice that were lacking just one isoform (either P1b or P1d) while expressing all others. Monitoring morphological alterations of mitochondria, an isoform P1b-specific phenotype affecting the mitochondrial fusion–fission machinery and manifesting with upregulated mitochondrial fusion-associated protein mitofusin-2 could be identified. Our results show that the depletion of distinct plectin isoforms affects mitochondrial network organization and function in different ways.

Description: Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-delta syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110delta protein, the catalytic subunit of phosphoinositide 3-kinase delta (PI3Kdelta), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110delta. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110delta inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930011/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930011/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Angulo, Ivan -- Vadas, Oscar -- Garcon, Fabien -- Banham-Hall, Edward -- Plagnol, Vincent -- Leahy, Timothy R -- Baxendale, Helen -- Coulter, Tanya -- Curtis, James -- Wu, Changxin -- Blake-Palmer, Katherine -- Perisic, Olga -- Smyth, Deborah -- Maes, Mailis -- Fiddler, Christine -- Juss, Jatinder -- Cilliers, Deirdre -- Markelj, Gasper -- Chandra, Anita -- Farmer, George -- Kielkowska, Anna -- Clark, Jonathan -- Kracker, Sven -- Debre, Marianne -- Picard, Capucine -- Pellier, Isabelle -- Jabado, Nada -- Morris, James A -- Barcenas-Morales, Gabriela -- Fischer, Alain -- Stephens, Len -- Hawkins, Phillip -- Barrett, Jeffrey C -- Abinun, Mario -- Clatworthy, Menna -- Durandy, Anne -- Doffinger, Rainer -- Chilvers, Edwin R -- Cant, Andrew J -- Kumararatne, Dinakantha -- Okkenhaug, Klaus -- Williams, Roger L -- Condliffe, Alison -- Nejentsev, Sergey -- 095198/Wellcome Trust/United Kingdom -- 095198/Z/10/Z/Wellcome Trust/United Kingdom -- 095691/Wellcome Trust/United Kingdom -- BB/J004456/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U105184308/Medical Research Council/United Kingdom -- U105184308/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2013 Nov 15;342(6160):866-71. doi: 10.1126/science.1243292. Epub 2013 Oct 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Cambridge, Cambridge, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24136356" target="_blank"〉PubMed〈/a〉

Description: We introduce a spectroscopic method that determines nonlinear quantum mechanical response functions beyond the optical diffraction limit and allows direct imaging of nanoscale coherence. In established coherent two-dimensional (2D) spectroscopy, four-wave-mixing responses are measured using three ingoing waves and one outgoing wave; thus, the method is diffraction-limited in spatial resolution. In coherent 2D nanoscopy, we use four ingoing waves and detect the final state via photoemission electron microscopy, which has 50-nanometer spatial resolution. We recorded local nanospectra from a corrugated silver surface and observed subwavelength 2D line shape variations. Plasmonic phase coherence of localized excitations persisted for about 100 femtoseconds and exhibited coherent beats. The observations are best explained by a model in which coupled oscillators lead to Fano-like resonances in the hybridized dark- and bright-mode response.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aeschlimann, Martin -- Brixner, Tobias -- Fischer, Alexander -- Kramer, Christian -- Melchior, Pascal -- Pfeiffer, Walter -- Schneider, Christian -- Struber, Christian -- Tuchscherer, Philip -- Voronine, Dmitri V -- New York, N.Y. -- Science. 2011 Sep 23;333(6050):1723-6. doi: 10.1126/science.1209206. Epub 2011 Aug 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Fachbereich Physik and Research Center OPTIMAS, Technische Universitat Kaiserslautern, Erwin-Schrodinger-Str. 46, 67663 Kaiserslautern, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21835982" target="_blank"〉PubMed〈/a〉