ALBERT

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pearson, Helen -- England -- Nature. 2015 Oct 22;526(7574):492-6. doi: 10.1038/526492a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26490601" target="_blank"〉PubMed〈/a〉

Description: Improvements in nitrogen use efficiency in crop production are critical for addressing the triple challenges of food security, environmental degradation and climate change. Such improvements are conditional not only on technological innovation, but also on socio-economic factors that are at present poorly understood. Here we examine historical patterns of agricultural nitrogen-use efficiency and find a broad range of national approaches to agricultural development and related pollution. We analyse examples of nitrogen use and propose targets, by geographic region and crop type, to meet the 2050 global food demand projected by the Food and Agriculture Organization while also meeting the Sustainable Development Goals pertaining to agriculture recently adopted by the United Nations General Assembly. Furthermore, we discuss socio-economic policies and technological innovations that may help achieve them.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Xin -- Davidson, Eric A -- Mauzerall, Denise L -- Searchinger, Timothy D -- Dumas, Patrice -- Shen, Ye -- England -- Nature. 2015 Dec 3;528(7580):51-9. doi: 10.1038/nature15743. Epub 2015 Nov 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Woodrow Wilson School of Public and International Affairs, Princeton University, Princeton, New Jersey 08544, USA. ; Princeton Environmental Institute, Princeton University, Princeton, New Jersey 08544, USA. ; Appalachian Laboratory, University of Maryland Center for Environmental Science, Frostburg, Maryland 21532, USA. ; Department of Civil and Environmental Engineering, Princeton University, Princeton, New Jersey 08544, USA. ; Centre de Cooperation Internationale en Recherche Agronomique pour le Developpement (CIRAD), 75116, Paris, France. ; Centre International de Recherche sur l'Environnement et le Developpement (CIRED), 94736 Nogent-sur-Marne, France. ; Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia, Athens, Georgia 30602, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26595273" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Jan 29;517(7536):527. doi: 10.1038/517527a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25631406" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DeWeerdt, Sarah -- England -- Nature. 2015 Dec 17;528(7582):S124-5. doi: 10.1038/528S124a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26672783" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pearson, Helen -- England -- Nature. 2015 Feb 26;518(7540):463-4. doi: 10.1038/518463a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25719641" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scholkopf, Bernhard -- England -- Nature. 2015 Feb 26;518(7540):486-7. doi: 10.1038/518486a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Intelligent Systems, 72076 Tubingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25719660" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DeWeerdt, Sarah -- England -- Nature. 2015 May 21;521(7552):S50-1. doi: 10.1038/521S50a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25992671" target="_blank"〉PubMed〈/a〉

Description: Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions. The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton alpha-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial alpha-synuclein (alpha-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal alpha-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies. The discovery of alpha-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinico-pathological traits within synucleinopathies. In this study we show that alpha-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined alpha-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that alpha-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that alpha-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct alpha-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peelaerts, W -- Bousset, L -- Van der Perren, A -- Moskalyuk, A -- Pulizzi, R -- Giugliano, M -- Van den Haute, C -- Melki, R -- Baekelandt, V -- England -- Nature. 2015 Jun 18;522(7556):340-4. doi: 10.1038/nature14547. Epub 2015 Jun 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, 3000 Leuven, Belgium. ; Paris-Saclay Institute of Neuroscience, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France. ; Theoretical Neurobiology &Neuroengineering Laboratory, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium. ; 1] Theoretical Neurobiology &Neuroengineering Laboratory, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium [2] Department of Computer Science, University of Sheffield, S1 4DP Sheffield, UK [3] Brain Mind Institute, Swiss Federal Institute of Technology of Lausanne, 1015 Lausanne, Switzerland [4] Neuro-Electronics Research Flanders (NERF), 3001 Leuven, Belgium. ; 1] KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, 3000 Leuven, Belgium [2] KU Leuven, Leuven Viral Vector Core, 3000 Leuven, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26061766" target="_blank"〉PubMed〈/a〉

Description: Long-standing evidence indicates that human immunodeficiency virus type 1 (HIV-1) preferentially integrates into a subset of transcriptionally active genes of the host cell genome. However, the reason why the virus selects only certain genes among all transcriptionally active regions in a target cell remains largely unknown. Here we show that HIV-1 integration occurs in the outer shell of the nucleus in close correspondence with the nuclear pore. This region contains a series of cellular genes, which are preferentially targeted by the virus, and characterized by the presence of active transcription chromatin marks before viral infection. In contrast, the virus strongly disfavours the heterochromatic regions in the nuclear lamin-associated domains and other transcriptionally active regions located centrally in the nucleus. Functional viral integrase and the presence of the cellular Nup153 and LEDGF/p75 integration cofactors are indispensable for the peripheral integration of the virus. Once integrated at the nuclear pore, the HIV-1 DNA makes contact with various nucleoporins; this association takes part in the transcriptional regulation of the viral genome. These results indicate that nuclear topography is an essential determinant of the HIV-1 life cycle.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marini, Bruna -- Kertesz-Farkas, Attila -- Ali, Hashim -- Lucic, Bojana -- Lisek, Kamil -- Manganaro, Lara -- Pongor, Sandor -- Luzzati, Roberto -- Recchia, Alessandra -- Mavilio, Fulvio -- Giacca, Mauro -- Lusic, Marina -- England -- Nature. 2015 May 14;521(7551):227-31. doi: 10.1038/nature14226. Epub 2015 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy. ; Protein Structure and Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy. ; 1] Struttura Complessa Malattie Infettive, Azienda Ospedaliero-Universitaria, 34134 Trieste, Italy [2] Department of Medical, Surgical and Health Sciences, University of Trieste, 34129 Trieste, Italy. ; Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy. ; 1] Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy [2] Genethon, 91002 Evry, France. ; 1] Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy [2] Department of Medical, Surgical and Health Sciences, University of Trieste, 34129 Trieste, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25731161" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Butler, Declan -- England -- Nature. 2015 Dec 3;528(7580):20-1. doi: 10.1038/528020a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26632570" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DeWeerdt, Sarah -- England -- Nature. 2015 May 14;521(7551):S10-1. doi: 10.1038/521S10a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970451" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Jan 22;517(7535):411-2. doi: 10.1038/517411b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25612014" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grammer, Karl -- Sainani, Kristin Lynn -- England -- Nature. 2015 Oct 8;526(7572):S11. doi: 10.1038/526S11a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26444367" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Jan 15;517(7534):244. doi: 10.1038/517244b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25592497" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kiser, Barbara -- England -- Nature. 2015 Jul 16;523(7560):286-9. doi: 10.1038/523286a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26178952" target="_blank"〉PubMed〈/a〉

Description: The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Ling -- Chen, Xiang-Jun -- Zhu, Jie -- Xi, Yi-Bo -- Yang, Xu -- Hu, Li-Dan -- Ouyang, Hong -- Patel, Sherrina H -- Jin, Xin -- Lin, Danni -- Wu, Frances -- Flagg, Ken -- Cai, Huimin -- Li, Gen -- Cao, Guiqun -- Lin, Ying -- Chen, Daniel -- Wen, Cindy -- Chung, Christopher -- Wang, Yandong -- Qiu, Austin -- Yeh, Emily -- Wang, Wenqiu -- Hu, Xun -- Grob, Seanna -- Abagyan, Ruben -- Su, Zhiguang -- Tjondro, Harry Christianto -- Zhao, Xi-Juan -- Luo, Hongrong -- Hou, Rui -- Perry, J Jefferson P -- Gao, Weiwei -- Kozak, Igor -- Granet, David -- Li, Yingrui -- Sun, Xiaodong -- Wang, Jun -- Zhang, Liangfang -- Liu, Yizhi -- Yan, Yong-Bin -- Zhang, Kang -- England -- Nature. 2015 Jul 30;523(7562):607-11. doi: 10.1038/nature14650. Epub 2015 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. ; BGI-Shenzhen, Shenzhen 518083, China. ; 1] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [2] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China. ; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. ; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] CapitalBio Genomics Co., Ltd., Dongguan 523808, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China. ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA. ; Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China. ; Department of Biochemistry, University of California Riverside, Riverside, California 92521, USA. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA. ; King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia. ; Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China. ; Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [4] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA [5] Veterans Administration Healthcare System, San Diego, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26200341" target="_blank"〉PubMed〈/a〉

Description: The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Lan -- Oliver, Eduardo -- Maratou, Klio -- Atanur, Santosh S -- Dubois, Olivier D -- Cotroneo, Emanuele -- Chen, Chien-Nien -- Wang, Lei -- Arce, Cristina -- Chabosseau, Pauline L -- Ponsa-Cobas, Joan -- Frid, Maria G -- Moyon, Benjamin -- Webster, Zoe -- Aldashev, Almaz -- Ferrer, Jorge -- Rutter, Guy A -- Stenmark, Kurt R -- Aitman, Timothy J -- Wilkins, Martin R -- 098424/Wellcome Trust/United Kingdom -- 101033/Wellcome Trust/United Kingdom -- MR/J0003042/1/Medical Research Council/United Kingdom -- P01 HL014985/HL/NHLBI NIH HHS/ -- PG/04/035/16912/British Heart Foundation/United Kingdom -- PG/10/59/28478/British Heart Foundation/United Kingdom -- PG/12/61/29818/British Heart Foundation/United Kingdom -- PG/2000137/British Heart Foundation/United Kingdom -- PG/95170/British Heart Foundation/United Kingdom -- PG/98018/British Heart Foundation/United Kingdom -- RG/10/16/28575/British Heart Foundation/United Kingdom -- WT098424AIA/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Aug 20;524(7565):356-60. doi: 10.1038/nature14620. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. ; Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. ; Section of Epigenomics and Disease, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. ; Department of Pediatrics and Medicine, Division of Critical Care Medicine and Cardiovascular Pulmonary Research Laboratories, University of Colorado Denver, Denver, Colorado 80045, USA. ; Transgenics and Embryonic Stem Cell Laboratory, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. ; Institute of Molecular Biology and Medicine, 3 Togolok Moldo Street, Bishkek 720040, Kyrgyzstan. ; Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258299" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Butler, Declan -- England -- Nature. 2015 Jun 11;522(7555):139-40. doi: 10.1038/522139a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26062490" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Graves, Jennifer A Marshall -- England -- Nature. 2015 Dec 17;528(7582):343-4. doi: 10.1038/528343a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Life Science, La Trobe University, Melbourne, Victoria 3086, Australia, and at the Research School of Biology, Australian National University, Canberra.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26672550" target="_blank"〉PubMed〈/a〉

Description: The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pemovska, Tea -- Johnson, Eric -- Kontro, Mika -- Repasky, Gretchen A -- Chen, Jeffrey -- Wells, Peter -- Cronin, Ciaran N -- McTigue, Michele -- Kallioniemi, Olli -- Porkka, Kimmo -- Murray, Brion W -- Wennerberg, Krister -- England -- Nature. 2015 Mar 5;519(7541):102-5. doi: 10.1038/nature14119. Epub 2015 Feb 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00290 Helsinki, Finland. ; La Jolla Laboratories, Pfizer Worldwide Research &Development, San Diego, California 92121, USA. ; Hematology Research Unit Helsinki, University of Helsinki, and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, 00290 Helsinki, Finland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686603" target="_blank"〉PubMed〈/a〉

Description: The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413024/" 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/PMC4413024/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schoors, Sandra -- Bruning, Ulrike -- Missiaen, Rindert -- Queiroz, Karla C S -- Borgers, Gitte -- Elia, Ilaria -- Zecchin, Annalisa -- Cantelmo, Anna Rita -- Christen, Stefan -- Goveia, Jermaine -- Heggermont, Ward -- Godde, Lucica -- Vinckier, Stefan -- Van Veldhoven, Paul P -- Eelen, Guy -- Schoonjans, Luc -- Gerhardt, Holger -- Dewerchin, Mieke -- Baes, Myriam -- De Bock, Katrien -- Ghesquiere, Bart -- Lunt, Sophia Y -- Fendt, Sarah-Maria -- Carmeliet, Peter -- 269073/European Research Council/International -- England -- Nature. 2015 Apr 9;520(7546):192-7. doi: 10.1038/nature14362. Epub 2015 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium [2] Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium. ; 1] Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium [2] Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, B-3000 Leuven, Belgium. ; Center for Molecular &Vascular Biology, Department of Cardiovascular Research, KU Leuven; Division of Clinical Cardiology, UZ Leuven, B-3000 Leuven, Belgium. ; Laboratory of Lipid Biochemistry and Protein Interactions, KU Leuven, B-3000 Leuven, Belgium. ; 1] Vascular Patterning Laboratory, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium [2] Vascular Patterning Laboratory, Vesalius Research Center, VIB, B-3000 Leuven, Belgium [3] Integrative Vascular Biology Laboratory, Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. ; Laboratory of Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, B-3000 Leuven, Belgium. ; 1] Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium [2] Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium [3] Exercise Physiology Research Group, Department of Kinesiology, KU Leuven, B-3001 Leuven, Belgium. ; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25830893" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gravitz, Lauren -- England -- Nature. 2015 May 21;521(7552):S60-1. doi: 10.1038/521S60a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25992675" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Klein, Harvey G -- Cortes-Puch, Irene -- Natanson, Charles -- England -- Nature. 2015 May 21;521(7552):289. doi: 10.1038/521289b.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Institutes of Health, Bethesda, Maryland, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25993950" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schork, Nicholas J -- England -- Nature. 2015 Apr 30;520(7549):609-11. doi: 10.1038/520609a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉J. Craig Venter Institute in La Jolla, California, USA. He is also professor at the University of California, San Diego, and at the Translational Genomics Research Institute (TGen) in Phoenix, Arizona, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25925459" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Butler, Declan -- England -- Nature. 2015 May 21;521(7552):269. doi: 10.1038/nature.2015.17560.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25993935" target="_blank"〉PubMed〈/a〉

Description: Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779053/" 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/PMC4779053/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peng, Dongjun -- Kryczek, Ilona -- Nagarsheth, Nisha -- Zhao, Lili -- Wei, Shuang -- Wang, Weimin -- Sun, Yuqing -- Zhao, Ende -- Vatan, Linda -- Szeliga, Wojciech -- Kotarski, Jan -- Tarkowski, Rafal -- Dou, Yali -- Cho, Kathleen -- Hensley-Alford, Sharon -- Munkarah, Adnan -- Liu, Rebecca -- Zou, Weiping -- 5P30CA46592/CA/NCI NIH HHS/ -- CA099985/CA/NCI NIH HHS/ -- CA123088/CA/NCI NIH HHS/ -- CA152470/CA/NCI NIH HHS/ -- CA156685/CA/NCI NIH HHS/ -- CA171306/CA/NCI NIH HHS/ -- CA190176/CA/NCI NIH HHS/ -- CA193136/CA/NCI NIH HHS/ -- R01 CA099985/CA/NCI NIH HHS/ -- R01 CA123088/CA/NCI NIH HHS/ -- R01 CA152470/CA/NCI NIH HHS/ -- R01 CA156685/CA/NCI NIH HHS/ -- R01 CA171306/CA/NCI NIH HHS/ -- R01 CA190176/CA/NCI NIH HHS/ -- R01 CA193136/CA/NCI NIH HHS/ -- England -- Nature. 2015 Nov 12;527(7577):249-53. doi: 10.1038/nature15520. Epub 2015 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. ; Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. ; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. ; The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland. ; The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202, USA. ; Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. ; Graduate Program in Tumor Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26503055" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gravitz, Lauren -- England -- Nature. 2015 May 14;521(7551):S6-8. doi: 10.1038/521S6a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970457" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Jan 8;517(7533):121. doi: 10.1038/517121a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25567246" target="_blank"〉PubMed〈/a〉

Description: Cytosine methylation is a DNA modification generally associated with transcriptional silencing. Factors that regulate methylation have been linked to human disease, yet how they contribute to malignances remains largely unknown. Genomic maps of DNA methylation have revealed unexpected dynamics at gene regulatory regions, including active demethylation by TET proteins at binding sites for transcription factors. These observations indicate that the underlying DNA sequence largely accounts for local patterns of methylation. As a result, this mark is highly informative when studying gene regulation in normal and diseased cells, and it can potentially function as a biomarker. Although these findings challenge the view that methylation is generally instructive for gene silencing, several open questions remain, including how methylation is targeted and recognized and in what context it affects genome readout.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schubeler, Dirk -- England -- Nature. 2015 Jan 15;517(7534):321-6. doi: 10.1038/nature14192.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. [2] University of Basel, Faculty of Science, Petersplatz 1, CH-4003 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25592537" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Jan 8;517(7533):121. doi: 10.1038/517121b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25567245" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grayson, Michelle -- England -- Nature. 2015 Sep 24;525(7570):S1. doi: 10.1038/525S1a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26398730" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kling, Jim -- England -- Nature. 2015 Feb 19;518(7539):439-43. doi: 10.1038/518439a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25693572" target="_blank"〉PubMed〈/a〉

Description: Although CRISPR-Cas9 nucleases are widely used for genome editing, the range of sequences that Cas9 can recognize is constrained by the need for a specific protospacer adjacent motif (PAM). As a result, it can often be difficult to target double-stranded breaks (DSBs) with the precision that is necessary for various genome-editing applications. The ability to engineer Cas9 derivatives with purposefully altered PAM specificities would address this limitation. Here we show that the commonly used Streptococcus pyogenes Cas9 (SpCas9) can be modified to recognize alternative PAM sequences using structural information, bacterial selection-based directed evolution, and combinatorial design. These altered PAM specificity variants enable robust editing of endogenous gene sites in zebrafish and human cells not currently targetable by wild-type SpCas9, and their genome-wide specificities are comparable to wild-type SpCas9 as judged by GUIDE-seq analysis. In addition, we identify and characterize another SpCas9 variant that exhibits improved specificity in human cells, possessing better discrimination against off-target sites with non-canonical NAG and NGA PAMs and/or mismatched spacers. We also find that two smaller-size Cas9 orthologues, Streptococcus thermophilus Cas9 (St1Cas9) and Staphylococcus aureus Cas9 (SaCas9), function efficiently in the bacterial selection systems and in human cells, suggesting that our engineering strategies could be extended to Cas9s from other species. Our findings provide broadly useful SpCas9 variants and, more importantly, establish the feasibility of engineering a wide range of Cas9s with altered and improved PAM specificities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540238/" 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/PMC4540238/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kleinstiver, Benjamin P -- Prew, Michelle S -- Tsai, Shengdar Q -- Topkar, Ved V -- Nguyen, Nhu T -- Zheng, Zongli -- Gonzales, Andrew P W -- Li, Zhuyun -- Peterson, Randall T -- Yeh, Jing-Ruey Joanna -- Aryee, Martin J -- Joung, J Keith -- DP1 GM105378/DP/NCCDPHP CDC HHS/ -- DP1 GM105378/GM/NIGMS NIH HHS/ -- R01 GM088040/GM/NIGMS NIH HHS/ -- R01 GM107427/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jul 23;523(7561):481-5. doi: 10.1038/nature14592. Epub 2015 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Pathology Unit &Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [2] Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [3] Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Molecular Pathology Unit &Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [2] Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. ; 1] Molecular Pathology Unit &Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [2] Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden. ; 1] Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [2] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Broad Institute, Cambridge, Massachusetts 02142, USA. ; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. ; 1] Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Molecular Pathology Unit &Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA [2] Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26098369" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Jan 1;517(7532):15-7. doi: 10.1038/517015a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25557702" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Butler, Declan -- England -- Nature. 2015 Mar 12;519(7542):137. doi: 10.1038/519137a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25762259" target="_blank"〉PubMed〈/a〉

Description: Autophagy, an important catabolic pathway implicated in a broad spectrum of human diseases, begins by forming double membrane autophagosomes that engulf cytosolic cargo and ends by fusing autophagosomes with lysosomes for degradation. Membrane fusion activity is required for early biogenesis of autophagosomes and late degradation in lysosomes. However, the key regulatory mechanisms of autophagic membrane tethering and fusion remain largely unknown. Here we report that ATG14 (also known as beclin-1-associated autophagy-related key regulator (Barkor) or ATG14L), an essential autophagy-specific regulator of the class III phosphatidylinositol 3-kinase complex, promotes membrane tethering of protein-free liposomes, and enhances hemifusion and full fusion of proteoliposomes reconstituted with the target (t)-SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) syntaxin 17 (STX17) and SNAP29, and the vesicle (v)-SNARE VAMP8 (vesicle-associated membrane protein 8). ATG14 binds to the SNARE core domain of STX17 through its coiled-coil domain, and stabilizes the STX17-SNAP29 binary t-SNARE complex on autophagosomes. The STX17 binding, membrane tethering and fusion-enhancing activities of ATG14 require its homo-oligomerization by cysteine repeats. In ATG14 homo-oligomerization-defective cells, autophagosomes still efficiently form but their fusion with endolysosomes is blocked. Recombinant ATG14 homo-oligomerization mutants also completely lose their ability to promote membrane tethering and to enhance SNARE-mediated fusion in vitro. Taken together, our data suggest an autophagy-specific membrane fusion mechanism in which oligomeric ATG14 directly binds to STX17-SNAP29 binary t-SNARE complex on autophagosomes and primes it for VAMP8 interaction to promote autophagosome-endolysosome fusion.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442024/" 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/PMC4442024/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Diao, Jiajie -- Liu, Rong -- Rong, Yueguang -- Zhao, Minglei -- Zhang, Jing -- Lai, Ying -- Zhou, Qiangjun -- Wilz, Livia M -- Li, Jianxu -- Vivona, Sandro -- Pfuetzner, Richard A -- Brunger, Axel T -- Zhong, Qing -- 5P30CA142543/CA/NCI NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 CA133228/CA/NCI NIH HHS/ -- R01 R37-MH63105/MH/NIMH NIH HHS/ -- R37 MH063105/MH/NIMH NIH HHS/ -- T32 GM007232/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 23;520(7548):563-6. doi: 10.1038/nature14147. Epub 2015 Feb 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular and Cellular Physiology, Stanford University, Stanford, California 94305, USA [2] Department of Structural Biology, Stanford University, Stanford, California 94305, USA [3] Department of Photon Science, Stanford University, Stanford, California 94305, USA [4] Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, USA [5] Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA. ; 1] Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [3] College of Food Science &Nutritional Engineering, China Agricultural University, Beijing 100083, China. ; 1] Center for Autophagy Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Division of Biochemistry, Biophysics and Structural Biology, Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686604" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kloor, Keith -- England -- Nature. 2015 Aug 13;524(7564):145-6. doi: 10.1038/nature.2015.18146.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26268173" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grayson, Michelle -- England -- Nature. 2015 May 21;521(7552):S47. doi: 10.1038/521S47a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25992669" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Butler, Declan -- England -- Nature. 2015 Feb 12;518(7538):148-9. doi: 10.1038/518148a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25673392" target="_blank"〉PubMed〈/a〉

Description: The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF 〈/= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755714/" 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/PMC4755714/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Hou-Feng -- Forgetta, Vincenzo -- Hsu, Yi-Hsiang -- Estrada, Karol -- Rosello-Diez, Alberto -- Leo, Paul J -- Dahia, Chitra L -- Park-Min, Kyung Hyun -- Tobias, Jonathan H -- Kooperberg, Charles -- Kleinman, Aaron -- Styrkarsdottir, Unnur -- Liu, Ching-Ti -- Uggla, Charlotta -- Evans, Daniel S -- Nielson, Carrie M -- Walter, Klaudia -- Pettersson-Kymmer, Ulrika -- McCarthy, Shane -- Eriksson, Joel -- Kwan, Tony -- Jhamai, Mila -- Trajanoska, Katerina -- Memari, Yasin -- Min, Josine -- Huang, Jie -- Danecek, Petr -- Wilmot, Beth -- Li, Rui -- Chou, Wen-Chi -- Mokry, Lauren E -- Moayyeri, Alireza -- Claussnitzer, Melina -- Cheng, Chia-Ho -- Cheung, Warren -- Medina-Gomez, Carolina -- Ge, Bing -- Chen, Shu-Huang -- Choi, Kwangbom -- Oei, Ling -- Fraser, James -- Kraaij, Robert -- Hibbs, Matthew A -- Gregson, Celia L -- Paquette, Denis -- Hofman, Albert -- Wibom, Carl -- Tranah, Gregory J -- Marshall, Mhairi -- Gardiner, Brooke B -- Cremin, Katie -- Auer, Paul -- Hsu, Li -- Ring, Sue -- Tung, Joyce Y -- Thorleifsson, Gudmar -- Enneman, Anke W -- van Schoor, Natasja M -- de Groot, Lisette C P G M -- van der Velde, Nathalie -- Melin, Beatrice -- Kemp, John P -- Christiansen, Claus -- Sayers, Adrian -- Zhou, Yanhua -- Calderari, Sophie -- van Rooij, Jeroen -- Carlson, Chris -- Peters, Ulrike -- Berlivet, Soizik -- Dostie, Josee -- Uitterlinden, Andre G -- Williams, Stephen R -- Farber, Charles -- Grinberg, Daniel -- LaCroix, Andrea Z -- Haessler, Jeff -- Chasman, Daniel I -- Giulianini, Franco -- Rose, Lynda M -- Ridker, Paul M -- Eisman, John A -- Nguyen, Tuan V -- Center, Jacqueline R -- Nogues, Xavier -- Garcia-Giralt, Natalia -- Launer, Lenore L -- Gudnason, Vilmunder -- Mellstrom, Dan -- Vandenput, Liesbeth -- Amin, Najaf -- van Duijn, Cornelia M -- Karlsson, Magnus K -- Ljunggren, Osten -- Svensson, Olle -- Hallmans, Goran -- Rousseau, Francois -- Giroux, Sylvie -- Bussiere, Johanne -- Arp, Pascal P -- Koromani, Fjorda -- Prince, Richard L -- Lewis, Joshua R -- Langdahl, Bente L -- Hermann, A Pernille -- Jensen, Jens-Erik B -- Kaptoge, Stephen -- Khaw, Kay-Tee -- Reeve, Jonathan -- Formosa, Melissa M -- Xuereb-Anastasi, Angela -- Akesson, Kristina -- McGuigan, Fiona E -- Garg, Gaurav -- Olmos, Jose M -- Zarrabeitia, Maria T -- Riancho, Jose A -- Ralston, Stuart H -- Alonso, Nerea -- Jiang, Xi -- Goltzman, David -- Pastinen, Tomi -- Grundberg, Elin -- Gauguier, Dominique -- Orwoll, Eric S -- Karasik, David -- Davey-Smith, George -- AOGC Consortium -- Smith, Albert V -- Siggeirsdottir, Kristin -- Harris, Tamara B -- Zillikens, M Carola -- van Meurs, Joyce B J -- Thorsteinsdottir, Unnur -- Maurano, Matthew T -- Timpson, Nicholas J -- Soranzo, Nicole -- Durbin, Richard -- Wilson, Scott G -- Ntzani, Evangelia E -- Brown, Matthew A -- Stefansson, Kari -- Hinds, David A -- Spector, Tim -- Cupples, L Adrienne -- Ohlsson, Claes -- Greenwood, Celia M T -- UK10K Consortium -- Jackson, Rebecca D -- Rowe, David W -- Loomis, Cynthia A -- Evans, David M -- Ackert-Bicknell, Cheryl L -- Joyner, Alexandra L -- Duncan, Emma L -- Kiel, Douglas P -- Rivadeneira, Fernando -- Richards, J Brent -- G1000143/Medical Research Council/United Kingdom -- K01 AR062655/AR/NIAMS NIH HHS/ -- MC_UU_12013/3/Medical Research Council/United Kingdom -- R01 AG005394/AG/NIA NIH HHS/ -- R01 AG005407/AG/NIA NIH HHS/ -- R01 AG027574/AG/NIA NIH HHS/ -- R01 AG027576/AG/NIA NIH HHS/ -- R01 AR035582/AR/NIAMS NIH HHS/ -- R01 AR035583/AR/NIAMS NIH HHS/ -- RC2 AR058973/AR/NIAMS NIH HHS/ -- U01 AG018197/AG/NIA NIH HHS/ -- U01 AG042140/AG/NIA NIH HHS/ -- U01 AG042143/AG/NIA NIH HHS/ -- U01 AR045580/AR/NIAMS NIH HHS/ -- U01 AR045583/AR/NIAMS NIH HHS/ -- U01 AR045614/AR/NIAMS NIH HHS/ -- U01 AR045632/AR/NIAMS NIH HHS/ -- U01 AR045647/AR/NIAMS NIH HHS/ -- U01 AR045654/AR/NIAMS NIH HHS/ -- U01 AR066160/AR/NIAMS NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):112-7. doi: 10.1038/nature14878. Epub 2015 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal H3A 1A2, Canada. ; Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal H3T 1E2, Canada. ; Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA. ; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA. ; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA. ; The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia. ; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA. ; Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York 10021, USA. ; Rheumatology Divison, Hospital for Special Surgery New York, New York 10021, USA. ; School of Clinical Science, University of Bristol, Bristol BS10 5NB, UK. ; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Department of Research, 23andMe, Mountain View, California 94041, USA. ; Department of Population Genomics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. ; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; California Pacific Medical Center Research Institute, San Francisco, California 94158, USA. ; Department of Public Health and Preventive Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Bone &Mineral Unit, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK. ; Departments of Pharmacology and Clinical Neurosciences, Umea University, Umea S-901 87, Sweden. ; Department of Public Health and Clinical Medicine, Umea University, Umea SE-901 87, Sweden. ; Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; McGill University and Genome Quebec Innovation Centre, Montreal H3A 0G1, Canada. ; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Oregon Clinical and Translational Research Institute, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Department of Medical and Clinical Informatics, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK. ; Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. ; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA. ; Department of Human Genetics, McGill University, Montreal H3A 1B1, Canada. ; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands. ; Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA. ; Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal H3G 1Y6, Canada. ; Department of Computer Science, Trinity University, San Antonio, Texas 78212, USA. ; Musculoskeletal Research Unit, University of Bristol, Bristol BS10 5NB, UK. ; Department of Radiation Sciences, Umea University, Umea S-901 87, Sweden. ; School of Public Health, University of Wisconsin, Milwaukee, Wisconsin 53726, USA. ; School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK. ; Department of Statistics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1007 MB, The Netherlands. ; Department of Human Nutrition, Wageningen University, Wageningen 6700 EV, The Netherlands. ; Department of Internal Medicine, Section Geriatrics, Academic Medical Center, Amsterdam 1105, The Netherlands. ; Nordic Bioscience, Herlev 2730, Denmark. ; Cordeliers Research Centre, INSERM UMRS 1138, Paris 75006, France. ; Institute of Cardiometabolism and Nutrition, University Pierre &Marie Curie, Paris 75013, France. ; Departments of Medicine (Cardiovascular Medicine), Centre for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Genetics, University of Barcelona, Barcelona 08028, Spain. ; U-720, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona 28029, Spain. ; Department of Human Molecular Genetics, The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain. ; Women's Health Center of Excellence Family Medicine and Public Health, University of California - San Diego, San Diego, California 92093, USA. ; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. ; Osteoporosis &Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia. ; School of Medicine Sydney, University of Notre Dame Australia, Sydney 6959, Australia. ; St. Vincent's Hospital &Clinical School, NSW University, Sydney 2010, Australia. ; Musculoskeletal Research Group, Institut Hospital del Mar d'Investigacions Mediques, Barcelona 08003, Spain. ; Cooperative Research Network on Aging and Fragility (RETICEF), Institute of Health Carlos III, 28029, Spain. ; Department of Internal Medicine, Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona 08193, Spain. ; Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Icelandic Heart Association, Kopavogur IS-201, Iceland. ; Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland. ; Genetic epidemiology unit, Department of Epidemiology, Erasmus MC, Rotterdam 3000CA, The Netherlands. ; Department of Orthopaedics, Skane University Hospital Malmo 205 02, Sweden. ; Department of Medical Sciences, University of Uppsala, Uppsala 751 85, Sweden. ; Department of Surgical and Perioperative Sciences, Umea Unviersity, Umea 901 85, Sweden. ; Department of Molecular Biology, Medical Biochemistry and Pathology, Universite Laval, Quebec City G1V 0A6, Canada. ; Axe Sante des Populations et Pratiques Optimales en Sante, Centre de recherche du CHU de Quebec, Quebec City G1V 4G2, Canada. ; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia. ; Department of Medicine, University of Western Australia, Perth 6009, Australia. ; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C 8000, Denmark. ; Department of Endocrinology, Odense University Hospital, Odense C 5000, Denmark. ; Department of Endocrinology, Hvidovre University Hospital, Hvidovre 2650, Denmark. ; Clinical Gerontology Unit, University of Cambridge, Cambridge CB2 2QQ, UK. ; Medicine and Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. ; Institute of Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK. ; Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida MSD 2080, Malta. ; Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmo, Lund University, 205 02, Sweden. ; Department of Medicine and Psychiatry, University of Cantabria, Santander 39011, Spain. ; Department of Internal Medicine, Hospital U.M. Valdecilla- IDIVAL, Santander 39008, Spain. ; Department of Legal Medicine, University of Cantabria, Santander 39011, Spain. ; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. ; Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA. ; Department of Medicine and Physiology, McGill University, Montreal H4A 3J1, Canada. ; Department of Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13010, Israel. ; Laboratory of Epidemiology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia. ; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece. ; Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island 02903, USA. ; deCODE Genetics, Reykjavik IS-101, Iceland. ; Framingham Heart Study, Framingham, Massachusetts 01702, USA. ; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal H3A 1A2, Canada. ; Department of Oncology, Gerald Bronfman Centre, McGill University, Montreal H2W 1S6, Canada. ; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA. ; The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA. ; Department of Diabetes and Endocrinology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26367794" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grayson, Michelle -- England -- Nature. 2015 Apr 30;520(7549):S10-2. doi: 10.1038/520S10a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25924192" target="_blank"〉PubMed〈/a〉

Description: Understanding the diversity of human tissues is fundamental to disease and requires linking genetic information, which is identical in most of an individual's cells, with epigenetic mechanisms that could have tissue-specific roles. Surveys of DNA methylation in human tissues have established a complex landscape including both tissue-specific and invariant methylation patterns. Here we report high coverage methylomes that catalogue cytosine methylation in all contexts for the major human organ systems, integrated with matched transcriptomes and genomic sequence. By combining these diverse data types with each individuals' phased genome, we identified widespread tissue-specific differential CG methylation (mCG), partially methylated domains, allele-specific methylation and transcription, and the unexpected presence of non-CG methylation (mCH) in almost all human tissues. mCH correlated with tissue-specific functions, and using this mark, we made novel predictions of genes that escape X-chromosome inactivation in specific tissues. Overall, DNA methylation in several genomic contexts varies substantially among human tissues.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499021/" 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/PMC4499021/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schultz, Matthew D -- He, Yupeng -- Whitaker, John W -- Hariharan, Manoj -- Mukamel, Eran A -- Leung, Danny -- Rajagopal, Nisha -- Nery, Joseph R -- Urich, Mark A -- Chen, Huaming -- Lin, Shin -- Lin, Yiing -- Jung, Inkyung -- Schmitt, Anthony D -- Selvaraj, Siddarth -- Ren, Bing -- Sejnowski, Terrence J -- Wang, Wei -- Ecker, Joseph R -- F32 HL110473/HL/NHLBI NIH HHS/ -- F32HL110473/HL/NHLBI NIH HHS/ -- K99 HL119617/HL/NHLBI NIH HHS/ -- K99 NS080911/NS/NINDS NIH HHS/ -- K99HL119617/HL/NHLBI NIH HHS/ -- R00 NS080911/NS/NINDS NIH HHS/ -- R00NS080911/NS/NINDS NIH HHS/ -- R01 ES024984/ES/NIEHS NIH HHS/ -- T32 GM008666/GM/NIGMS NIH HHS/ -- U01 ES017166/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jul 9;523(7559):212-6. doi: 10.1038/nature14465. Epub 2015 Jun 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Bioinformatics Program, University of California, San Diego, La Jolla, California 92093, USA [2] Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA. ; Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; 1] Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Department of Cognitive Science, University of California, San Diego, La Jolla, California 92037, USA. ; Ludwig Institute for Cancer Research, La Jolla, California 92093, USA. ; Department of Genetics, Stanford University, 300 Pasteur Drive, M-344 Stanford, California 94305, USA. ; Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8109, St Louis, Missouri 63110, USA. ; Bioinformatics Program, University of California, San Diego, La Jolla, California 92093, USA. ; 1] Ludwig Institute for Cancer Research, La Jolla, California 92093, USA [2] University of California, San Diego School of Medicine, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, La Jolla, California 92093, USA. ; 1] Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Division of Biological Sciences, University of California at San Diego, La Jolla, California 92037, USA [3] Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. ; 1] Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA [2] Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA. ; 1] Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26030523" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Veiseh, Omid -- Langer, Robert -- England -- Nature. 2015 Aug 6;524(7563):39-40. doi: 10.1038/524039a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Engineering, and at the David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA, and in the Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245577" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Knight, Rob -- England -- Nature. 2015 Feb 26;518(7540):S5. doi: 10.1038/518S5a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of California, San Diego.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25715279" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Butler, Declan -- England -- Nature. 2015 Jan 1;517(7532):9-10. doi: 10.1038/517009a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25557698" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2015 Dec 3;528(7580):15-6. doi: 10.1038/528015a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26632565" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Velasquez-Manoff, Moises -- England -- Nature. 2015 Nov 19;527(7578):S116-7. doi: 10.1038/527S116a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26580161" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2015 Oct 8;526(7572):171-2. doi: 10.1038/526171a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26450035" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Green, Eric D -- Watson, James D -- Collins, Francis S -- England -- Nature. 2015 Oct 1;526(7571):29-31. doi: 10.1038/526029a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉US National Human Genome Research Institute at the US National Institutes of Health, Bethesda, Maryland, USA. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA, and former director of the US National Center for Human Genome Research. ; US National Institutes of Health, Bethesda, Maryland, USA, and former director of the US National Human Genome Research Institute.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26432225" target="_blank"〉PubMed〈/a〉

Description: Higher-order chromatin structure is emerging as an important regulator of gene expression. Although dynamic chromatin structures have been identified in the genome, the full scope of chromatin dynamics during mammalian development and lineage specification remains to be determined. By mapping genome-wide chromatin interactions in human embryonic stem (ES) cells and four human ES-cell-derived lineages, we uncover extensive chromatin reorganization during lineage specification. We observe that although self-associating chromatin domains are stable during differentiation, chromatin interactions both within and between domains change in a striking manner, altering 36% of active and inactive chromosomal compartments throughout the genome. By integrating chromatin interaction maps with haplotype-resolved epigenome and transcriptome data sets, we find widespread allelic bias in gene expression correlated with allele-biased chromatin states of linked promoters and distal enhancers. Our results therefore provide a global view of chromatin dynamics and a resource for studying long-range control of gene expression in distinct human cell lineages.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515363/" 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/PMC4515363/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dixon, Jesse R -- Jung, Inkyung -- Selvaraj, Siddarth -- Shen, Yin -- Antosiewicz-Bourget, Jessica E -- Lee, Ah Young -- Ye, Zhen -- Kim, Audrey -- Rajagopal, Nisha -- Xie, Wei -- Diao, Yarui -- Liang, Jing -- Zhao, Huimin -- Lobanenkov, Victor V -- Ecker, Joseph R -- Thomson, James A -- Ren, Bing -- R01 ES024984/ES/NIEHS NIH HHS/ -- T32 GM007198/GM/NIGMS NIH HHS/ -- U01 ES017166/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Feb 19;518(7539):331-6. doi: 10.1038/nature14222.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093-0653, USA [2] Medical Scientist Training Program, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093-0653, USA. ; 1] Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093-0653, USA [2] Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA. ; The Morgridge Institute for Research, 309 North Orchard Street, Madison, Wisconsin 53715, USA. ; Tsinghua University-Peking University Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Twinbrook I NIAID Facility, Room 1417, 5640 Fishers Lane, Rockville, Maryland 20852, USA. ; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. ; 1] The Morgridge Institute for Research, 309 North Orchard Street, Madison, Wisconsin 53715, USA [2] Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA [3] Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California 93106, USA. ; 1] Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093-0653, USA [2] University of California, San Diego School of Medicine, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25693564" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Knouse, Kristin A -- Amon, Angelika -- T32 GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jun 11;522(7555):162-3. doi: 10.1038/nature14528. Epub 2015 May 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Koch Institute for Integrative Cancer Research, Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26017308" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Velasquez-Manoff, Moises -- England -- Nature. 2015 Feb 26;518(7540):S3-11. doi: 10.1038/518S3a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25715278" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cahill, Thomas J -- Stables, Rod -- England -- Nature. 2015 Sep 17;525(7569):321. doi: 10.1038/525321b.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Oxford University Hospitals NHS Trust, Oxford, UK. ; Liverpool Heart and Chest Hospital, Liverpool, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26381974" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2015 Sep 10;525(7568):165-6. doi: 10.1038/525165a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26354460" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dolgin, Elie -- England -- Nature. 2015 Oct 8;526(7572):S14-5. doi: 10.1038/526S14a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26444369" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Velculescu, Victor -- Bender, Eric -- England -- Nature. 2015 May 14;521(7551):S9. doi: 10.1038/521S9a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970458" target="_blank"〉PubMed〈/a〉

Description: Infectious agents develop intricate mechanisms to interact with host cell pathways and hijack their genetic and epigenetic machinery to change host cell phenotypic states. Among the Apicomplexa phylum of obligate intracellular parasites, which cause veterinary and human diseases, Theileria is the only genus that transforms its mammalian host cells. Theileria infection of bovine leukocytes induces proliferative and invasive phenotypes associated with activated signalling pathways, notably JNK and AP-1 (ref. 2). The transformed phenotypes are reversed by treatment with the theilericidal drug buparvaquone. We used comparative genomics to identify a homologue of the peptidyl-prolyl isomerase PIN1 in T. annulata (TaPIN1) that is secreted into the host cell and modulates oncogenic signalling pathways. Here we show that TaPIN1 is a bona fide prolyl isomerase and that it interacts with the host ubiquitin ligase FBW7, leading to its degradation and subsequent stabilization of c-JUN, which promotes transformation. We performed in vitro and in silico analysis and in vivo zebrafish xenograft experiments to demonstrate that TaPIN1 is directly inhibited by the anti-parasite drug buparvaquone (and other known PIN1 inhibitors) and is mutated in a drug-resistant strain. Prolyl isomerization is thus a conserved mechanism that is important in cancer and is used by Theileria parasites to manipulate host oncogenic signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401560/" 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/PMC4401560/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marsolier, J -- Perichon, M -- DeBarry, J D -- Villoutreix, B O -- Chluba, J -- Lopez, T -- Garrido, C -- Zhou, X Z -- Lu, K P -- Fritsch, L -- Ait-Si-Ali, S -- Mhadhbi, M -- Medjkane, S -- Weitzman, J B -- 08-0111/Worldwide Cancer Research/United Kingdom -- R01 CA167677/CA/NCI NIH HHS/ -- R01CA167677/CA/NCI NIH HHS/ -- England -- Nature. 2015 Apr 16;520(7547):378-82. doi: 10.1038/nature14044. Epub 2015 Jan 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite Paris Diderot, Sorbonne Paris Cite, Epigenetics and Cell Fate, UMR 7216 CNRS, 75013 Paris, France. ; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, USA. ; Universite Paris Diderot, Sorbonne Paris Cite, Molecules Therapeutiques in silico, INSERM UMR-S 973, 75013 Paris, France. ; 1] INSERM, UMR 866, Equipe labellisee Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, 21000 Dijon, France [2] University of Burgundy, Faculty of Medicine and Pharmacy, 21000 Dijon, France. ; 1] INSERM, UMR 866, Equipe labellisee Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, 21000 Dijon, France [2] University of Burgundy, Faculty of Medicine and Pharmacy, 21000 Dijon, France [3] Centre anticancereux George Francois Leclerc, CGFL, 21000 Dijon, France. ; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Laboratoire de Parasitologie, Ecole Nationale de Medecine Veterinaire, Universite de la Manouba, 2020 Sidi Thabet, Tunisia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25624101" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dolgin, Elie -- England -- Nature. 2015 Jul 23;523(7561):398-9. doi: 10.1038/523398a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26201580" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marteau, Theresa M -- Mantzari, Eleni -- England -- Nature. 2015 Jul 2;523(7558):40-1. doi: 10.1038/523040a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Behaviour and Health Research Unit, University of Cambridge, Cambridge CB2 0SR, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26135443" target="_blank"〉PubMed〈/a〉

Description: Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. Here we show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins--MITF, TFE3 and TFEB--are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. These results identify the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perera, Rushika M -- Stoykova, Svetlana -- Nicolay, Brandon N -- Ross, Kenneth N -- Fitamant, Julien -- Boukhali, Myriam -- Lengrand, Justine -- Deshpande, Vikram -- Selig, Martin K -- Ferrone, Cristina R -- Settleman, Jeff -- Stephanopoulos, Gregory -- Dyson, Nicholas J -- Zoncu, Roberto -- Ramaswamy, Sridhar -- Haas, Wilhelm -- Bardeesy, Nabeel -- DP2 CA195761/CA/NCI NIH HHS/ -- P01 CA117969/CA/NCI NIH HHS/ -- P01 CA117969-07/CA/NCI NIH HHS/ -- P50CA1270003/CA/NCI NIH HHS/ -- R01 CA133557-05/CA/NCI NIH HHS/ -- England -- Nature. 2015 Aug 20;524(7565):361-5. doi: 10.1038/nature14587. Epub 2015 Jul 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA. ; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26168401" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dolgin, Elie -- England -- Nature. 2015 Jun 25;522(7557):S60-1. doi: 10.1038/522S60a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26107099" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Yingying -- England -- Nature. 2015 Dec 17;528(7582):S170-3. doi: 10.1038/528S170a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26673023" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2015 Jul 2;523(7558):17-8. doi: 10.1038/523017a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26135428" target="_blank"〉PubMed〈/a〉

Description: Deregulated expression of the MYC transcription factor occurs in most human cancers and correlates with high proliferation, reprogrammed cellular metabolism and poor prognosis. Overexpressed MYC binds to virtually all active promoters within a cell, although with different binding affinities, and modulates the expression of distinct subsets of genes. However, the critical effectors of MYC in tumorigenesis remain largely unknown. Here we show that during lymphomagenesis in Emicro-myc transgenic mice, MYC directly upregulates the transcription of the core small nuclear ribonucleoprotein particle assembly genes, including Prmt5, an arginine methyltransferase that methylates Sm proteins. This coordinated regulatory effect is critical for the core biogenesis of small nuclear ribonucleoprotein particles, effective pre-messenger-RNA splicing, cell survival and proliferation. Our results demonstrate that MYC maintains the splicing fidelity of exons with a weak 5' donor site. Additionally, we identify pre-messenger-RNAs that are particularly sensitive to the perturbation of the MYC-PRMT5 axis, resulting in either intron retention (for example, Dvl1) or exon skipping (for example, Atr, Ep400). Using antisense oligonucleotides, we demonstrate the contribution of these splicing defects to the anti-proliferative/apoptotic phenotype observed in PRMT5-depleted Emicro-myc B cells. We conclude that, in addition to its well-documented oncogenic functions in transcription and translation, MYC also safeguards proper pre-messenger-RNA splicing as an essential step in lymphomagenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koh, Cheryl M -- Bezzi, Marco -- Low, Diana H P -- Ang, Wei Xia -- Teo, Shun Xie -- Gay, Florence P H -- Al-Haddawi, Muthafar -- Tan, Soo Yong -- Osato, Motomi -- Sabo, Arianna -- Amati, Bruno -- Wee, Keng Boon -- Guccione, Ernesto -- England -- Nature. 2015 Jul 2;523(7558):96-100. doi: 10.1038/nature14351. Epub 2015 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore. ; 1] Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore [2] Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore. ; Cancer Science Institute of Singapore (CSI), National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore. ; Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Via Adamello 16, 20139 Milan, Italy. ; 1] Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Via Adamello 16, 20139 Milan, Italy [2] Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy. ; 1] Institute of High Performance Computing (IHPC), A*STAR (Agency for Science, Technology and Research), Connexis, Singapore 138632, Singapore [2] Bioinformatics Institute (BII), A*STAR (Agency for Science, Technology and Research), Singapore 138671, Singapore. ; 1] Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore [2] Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore [3] Cancer Science Institute of Singapore (CSI), National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970242" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martikainen, Mika -- Pedersen, Ole -- England -- Nature. 2015 Apr 30;520(7549):623. doi: 10.1038/520623a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Newcastle University, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25925472" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grinnell, Frederick -- England -- Nature. 2015 Jun 18;522(7556):257. doi: 10.1038/522257a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26085235" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dolgin, Elie -- England -- Nature. 2015 Jun 4;522(7554):26-8. doi: 10.1038/522026a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26040878" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Komarova, Natalia L -- England -- Nature. 2015 Sep 10;525(7568):198-9. doi: 10.1038/nature15210. Epub 2015 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Mathematics and Ecology and Evolutionary Biology, University of California, Irvine, Irvine, California 92697, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26308890" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dolgin, Elie -- England -- Nature. 2015 Mar 19;519(7543):276-8. doi: 10.1038/519276a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25788077" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grogan, David -- England -- Nature. 2015 Feb 26;518(7540):S2. doi: 10.1038/518S2a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25715277" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2015 Sep 10;525(7568):172-4. doi: 10.1038/525172a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26354465" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gronke, Konrad -- Diefenbach, Andreas -- England -- Nature. 2015 Dec 24;528(7583):488-9. doi: 10.1038/nature16325. Epub 2015 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Centre for Immunology, University of Mainz Medical Centre, and at the Institute of Medical Microbiology and Hygiene, 55131 Mainz, Germany. ; Max-Planck-Institute of Immunobiology and Epigenetics, Freiburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26649826" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scudellari, Megan -- England -- Nature. 2015 May 14;521(7551):S12-4. doi: 10.1038/521S12a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970452" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scudellari, Megan -- England -- Nature. 2015 Dec 17;528(7582):322-5. doi: 10.1038/528322a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26672537" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2015 Mar 26;519(7544):397-8. doi: 10.1038/519397a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25810182" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2015 Jul 30;523(7562):512-3. doi: 10.1038/523512a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26223605" target="_blank"〉PubMed〈/a〉

Description: TP53 (which encodes p53 protein) is the most frequently mutated gene among all human cancers. Prevalent p53 missense mutations abrogate its tumour suppressive function and lead to a 'gain-of-function' (GOF) that promotes cancer. Here we show that p53 GOF mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1 (also known as KMT2A), MLL2 (also known as KMT2D), and acetyltransferase MOZ (also known as KAT6A or MYST3), resulting in genome-wide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas shows specific upregulation of MLL1, MLL2, and MOZ in p53 GOF patient-derived tumours, but not in wild-type p53 or p53 null tumours. Cancer cell proliferation is markedly lowered by genetic knockdown of MLL1 or by pharmacological inhibition of the MLL1 methyltransferase complex. Our study reveals a novel chromatin mechanism underlying the progression of tumours with GOF p53, and suggests new possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent GOF p53 mutations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568559/" 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/PMC4568559/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhu, Jiajun -- Sammons, Morgan A -- Donahue, Greg -- Dou, Zhixun -- Vedadi, Masoud -- Getlik, Matthaus -- Barsyte-Lovejoy, Dalia -- Al-awar, Rima -- Katona, Bryson W -- Shilatifard, Ali -- Huang, Jing -- Hua, Xianxin -- Arrowsmith, Cheryl H -- Berger, Shelley L -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- P30 ES013508/ES/NIEHS NIH HHS/ -- R01 CA078831/CA/NCI NIH HHS/ -- R01 GM069905/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Sep 10;525(7568):206-11. doi: 10.1038/nature15251. Epub 2015 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Biomedical Graduate Studies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada. ; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada. ; Abramson Family Cancer Research Institute, Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, 320 E. Superior Street, Chicago, Illinois 60611, USA. ; Cancer and Stem Cell Epigenetics, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. ; Princess Margaret Cancer Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C4, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26331536" target="_blank"〉PubMed〈/a〉

Description: Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer's disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term 'cistauosis', appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer's disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718588/" 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/PMC4718588/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kondo, Asami -- Shahpasand, Koorosh -- Mannix, Rebekah -- Qiu, Jianhua -- Moncaster, Juliet -- Chen, Chun-Hau -- Yao, Yandan -- Lin, Yu-Min -- Driver, Jane A -- Sun, Yan -- Wei, Shuo -- Luo, Man-Li -- Albayram, Onder -- Huang, Pengyu -- Rotenberg, Alexander -- Ryo, Akihide -- Goldstein, Lee E -- Pascual-Leone, Alvaro -- McKee, Ann C -- Meehan, William -- Zhou, Xiao Zhen -- Lu, Kun Ping -- P30 AG013846/AG/NIA NIH HHS/ -- P30AG13846/AG/NIA NIH HHS/ -- R01AG029385/AG/NIA NIH HHS/ -- R01AG046319/AG/NIA NIH HHS/ -- R01CA167677/CA/NCI NIH HHS/ -- R01HL111430/HL/NHLBI NIH HHS/ -- S10RR017927/RR/NCRR NIH HHS/ -- T32HD040128/HD/NICHD NIH HHS/ -- U01 NS086659/NS/NINDS NIH HHS/ -- U01NS086659-01/NS/NINDS NIH HHS/ -- England -- Nature. 2015 Jul 23;523(7561):431-6. doi: 10.1038/nature14658. Epub 2015 Jul 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Division of Emergency Medicine, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Alzheimer's Disease Center, CTE Program, Boston University School of Medicine, Boston, Massachusetts 02118, USA. ; 1] Division of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Geriatric Research Education and Clinical Center, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts 02130, USA. ; Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Microbiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan. ; Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Micheli Center for Sports Injury Prevention, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26176913" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gross, Susan J -- Kareht, Stephanie -- Ryan, Allison -- England -- Nature. 2015 Jul 16;523(7560):290. doi: 10.1038/523290d.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Natera, San Carlos, California, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26178955" target="_blank"〉PubMed〈/a〉

Description: Eukaryotic transcription factors (TFs) are key determinants of gene activity, yet they bind only a fraction of their corresponding DNA sequence motifs in any given cell type. Chromatin has the potential to restrict accessibility of binding sites; however, in which context chromatin states are instructive for TF binding remains mainly unknown. To explore the contribution of DNA methylation to constrained TF binding, we mapped DNase-I-hypersensitive sites in murine stem cells in the presence and absence of DNA methylation. Methylation-restricted sites are enriched for TF motifs containing CpGs, especially for those of NRF1. In fact, the TF NRF1 occupies several thousand additional sites in the unmethylated genome, resulting in increased transcription. Restoring de novo methyltransferase activity initiates remethylation at these sites and outcompetes NRF1 binding. This suggests that binding of DNA-methylation-sensitive TFs relies on additional determinants to induce local hypomethylation. In support of this model, removal of neighbouring motifs in cis or of a TF in trans causes local hypermethylation and subsequent loss of NRF1 binding. This competition between DNA methylation and TFs in vivo reveals a case of cooperativity between TFs that acts indirectly via DNA methylation. Methylation removal by methylation-insensitive factors enables occupancy of methylation-sensitive factors, a principle that rationalizes hypomethylation of regulatory regions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Domcke, Silvia -- Bardet, Anais Flore -- Adrian Ginno, Paul -- Hartl, Dominik -- Burger, Lukas -- Schubeler, Dirk -- England -- Nature. 2015 Dec 24;528(7583):575-9. doi: 10.1038/nature16462. Epub 2015 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH 4058 Basel, Switzerland. ; University of Basel, Faculty of Sciences, Petersplatz 1, CH 4003 Basel, Switzerland. ; Swiss Institute of Bioinformatics, Maulbeerstrasse 66, CH 4058 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26675734" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2015 Jul 16;523(7560):263-4. doi: 10.1038/523263a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26178940" target="_blank"〉PubMed〈/a〉

Description: Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections, and comprise nearly 8% of the human genome. The most recently acquired human ERV is HERVK(HML-2), which repeatedly infected the primate lineage both before and after the divergence of the human and chimpanzee common ancestor. Unlike most other human ERVs, HERVK retained multiple copies of intact open reading frames encoding retroviral proteins. However, HERVK is transcriptionally silenced by the host, with the exception of in certain pathological contexts such as germ-cell tumours, melanoma or human immunodeficiency virus (HIV) infection. Here we demonstrate that DNA hypomethylation at long terminal repeat elements representing the most recent genomic integrations, together with transactivation by OCT4 (also known as POU5F1), synergistically facilitate HERVK expression. Consequently, HERVK is transcribed during normal human embryogenesis, beginning with embryonic genome activation at the eight-cell stage, continuing through the emergence of epiblast cells in preimplantation blastocysts, and ceasing during human embryonic stem cell derivation from blastocyst outgrowths. Remarkably, we detected HERVK viral-like particles and Gag proteins in human blastocysts, indicating that early human development proceeds in the presence of retroviral products. We further show that overexpression of one such product, the HERVK accessory protein Rec, in a pluripotent cell line is sufficient to increase IFITM1 levels on the cell surface and inhibit viral infection, suggesting at least one mechanism through which HERVK can induce viral restriction pathways in early embryonic cells. Moreover, Rec directly binds a subset of cellular RNAs and modulates their ribosome occupancy, indicating that complex interactions between retroviral proteins and host factors can fine-tune pathways of early human development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503379/" 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/PMC4503379/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grow, Edward J -- Flynn, Ryan A -- Chavez, Shawn L -- Bayless, Nicholas L -- Wossidlo, Mark -- Wesche, Daniel J -- Martin, Lance -- Ware, Carol B -- Blish, Catherine A -- Chang, Howard Y -- Pera, Renee A Reijo -- Wysocka, Joanna -- 1F30CA189514-01/CA/NCI NIH HHS/ -- 1S10RR02678001/RR/NCRR NIH HHS/ -- 1S10RR02933801/RR/NCRR NIH HHS/ -- DP2 AI112193/AI/NIAID NIH HHS/ -- DP2AI11219301/AI/NIAID NIH HHS/ -- F30 CA189514/CA/NCI NIH HHS/ -- P01GM099130/GM/NIGMS NIH HHS/ -- P50-HG007735/HG/NHGRI NIH HHS/ -- R01 GM112720/GM/NIGMS NIH HHS/ -- T32 HG000044/HG/NHGRI NIH HHS/ -- U01 HL100397/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jun 11;522(7555):221-5. doi: 10.1038/nature14308. Epub 2015 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA. ; Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA. ; 1] Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [2] Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [3] Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health &Science University, Beaverton, Oregon 97006, USA. ; Stanford Immunology, Stanford University School of Medicine, Stanford, California 94305, USA. ; 1] Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA [2] Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [3] Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA. ; Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA. ; Department of Comparative Medicine, University of Washington, Seattle, Washington 98195-8056, USA. ; Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. ; 1] Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA [2] Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [3] Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [4] Department of Cell Biology and Neurosciences, Montana State University, Bozeman, Montana 59717, USA. ; 1] Institute for Stem Cell Biology &Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA [2] Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA [3] Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25896322" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2015 Feb 5;518(7537):24-6. doi: 10.1038/518024a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Nature's senior European correspondent.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25652979" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scudellari, Megan -- England -- Nature. 2015 Jan 22;517(7535):426-9. doi: 10.1038/517426a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25612035" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perkel, Jeffrey M -- England -- Nature. 2015 Aug 13;524(7564):257-8.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26273714" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Victor, David G -- Ramanathan, V -- Zaelke, Durwood -- England -- Nature. 2015 Jan 1;517(7532):21. doi: 10.1038/517021b.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of California San Diego, California, USA. ; Institute for Governance and Sustainable Development, Washington DC, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25557706" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2015 Jun 25;522(7557):406-8. doi: 10.1038/522406a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Nature from London.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26108834" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2015 Jan 29;517(7536):537-8. doi: 10.1038/517537a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25631423" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2015 Jun 25;522(7557):404-5. doi: 10.1038/nature.2015.17797.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26108832" target="_blank"〉PubMed〈/a〉

Description: At the onset of metazoan cell division the nuclear envelope breaks down to enable capture of chromosomes by the microtubule-containing spindle apparatus. During anaphase, when chromosomes have separated, the nuclear envelope is reassembled around the forming daughter nuclei. How the nuclear envelope is sealed, and how this is coordinated with spindle disassembly, is largely unknown. Here we show that endosomal sorting complex required for transport (ESCRT)-III, previously found to promote membrane constriction and sealing during receptor sorting, virus budding, cytokinesis and plasma membrane repair, is transiently recruited to the reassembling nuclear envelope during late anaphase. ESCRT-III and its regulatory AAA (ATPase associated with diverse cellular activities) ATPase VPS4 are specifically recruited by the ESCRT-III-like protein CHMP7 to sites where the reforming nuclear envelope engulfs spindle microtubules. Subsequent association of another ESCRT-III-like protein, IST1, directly recruits the AAA ATPase spastin to sever microtubules. Disrupting spastin function impairs spindle disassembly and results in extended localization of ESCRT-III at the nuclear envelope. Interference with ESCRT-III functions in anaphase is accompanied by delayed microtubule disassembly, compromised nuclear integrity and the appearance of DNA damage foci in subsequent interphase. We propose that ESCRT-III, VPS4 and spastin cooperate to coordinate nuclear envelope sealing and spindle disassembly at nuclear envelope-microtubule intersection sites during mitotic exit to ensure nuclear integrity and genome safeguarding, with a striking mechanistic parallel to cytokinetic abscission.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vietri, Marina -- Schink, Kay O -- Campsteijn, Coen -- Wegner, Catherine Sem -- Schultz, Sebastian W -- Christ, Liliane -- Thoresen, Sigrid B -- Brech, Andreas -- Raiborg, Camilla -- Stenmark, Harald -- England -- Nature. 2015 Jun 11;522(7555):231-5. doi: 10.1038/nature14408. Epub 2015 Jun 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway [2] Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway. ; 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, N-0379 Oslo, Norway [2] Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379 Oslo, Norway [3] Centre of Molecular Inflammation Research, Faculty of Medicine, Norwegian University of Science and Technology, N-7491 Trondheim, Norway.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26040712" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marx, Vivien -- England -- Nature. 2015 Aug 27;524(7566):503-5. doi: 10.1038/524503a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Nature and Nature Methods.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26310768" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vihinen, Mauno -- England -- Nature. 2015 May 21;521(7552):261. doi: 10.1038/521261a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lund University, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25993922" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marx, Vivien -- England -- Nature. 2015 Jun 18;522(7556):373-7. doi: 10.1038/522373a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Nature and Nature Methods.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26085275" target="_blank"〉PubMed〈/a〉

Description: Psoriasis is a chronic inflammatory skin disorder that affects approximately 2-3% of the population worldwide and has severe effects on patients' physical and psychological well-being. The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg(-1) groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg(-1) group and 13 out of 14 subjects in the 10 mg kg(-1) group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kopp, Tamara -- Riedl, Elisabeth -- Bangert, Christine -- Bowman, Edward P -- Greisenegger, Elli -- Horowitz, Ann -- Kittler, Harald -- Blumenschein, Wendy M -- McClanahan, Terrill K -- Marbury, Thomas -- Zachariae, Claus -- Xu, Danlin -- Hou, Xiaoli Shirley -- Mehta, Anish -- Zandvliet, Anthe S -- Montgomery, Diana -- van Aarle, Frank -- Khalilieh, Sauzanne -- England -- Nature. 2015 May 14;521(7551):222-6. doi: 10.1038/nature14175. Epub 2015 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, University of Vienna Medical School, 1090 Vienna, Austria [2] Juvenis Medical Center, 1010 Vienna, Austria. ; Department of Dermatology, Division of General Dermatology, University of Vienna Medical School, 1090 Vienna, Austria. ; Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, University of Vienna Medical School, 1090 Vienna, Austria. ; Merck &Co., Inc., Whitehouse Station, New Jersey 08889, USA. ; Orlando Clinical Research Center, Orlando, Florida 32809, USA. ; Department of Dermato-allergology, Gentofte Hospital, University of Copenhagen, Kildegaardsvej 28, DK-2900 Hellerup, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25754330" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2015 Jun 11;522(7555):140-1. doi: 10.1038/522140a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26062491" target="_blank"〉PubMed〈/a〉