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11.
Cederwall B Moradi FG Bäck T Johnson A Blomqvist J Clément E de France G Wadsworth R Andgren K Lagergren K Dijon A Jaworski G Liotta R Qi C Nyakó BM Nyberg J Palacz M Al-Azri H Algora A de Angelis G Ataç A Bhattacharyya S Brock T Brown JR Davies P Di Nitto A Dombrádi Z Gadea A Gál J Hadinia B Johnston-Theasby F Joshi P Juhász K Julin R Jungclaus A Kalinka G Kara SO Khaplanov A Kownacki J La Rana G Lenzi SM Molnár J Moro R Napoli DR Singh BS Persson A Recchia F Sandzelius M Scheurer JN Sletten G 《Nature》2011,469(7328):68-71
Shell structure and magic numbers in atomic nuclei were generally explained by pioneering work that introduced a strong spin-orbit interaction to the nuclear shell model potential. However, knowledge of nuclear forces and the mechanisms governing the structure of nuclei, in particular far from stability, is still incomplete. In nuclei with equal neutron and proton numbers (N = Z), enhanced correlations arise between neutrons and protons (two distinct types of fermions) that occupy orbitals with the same quantum numbers. Such correlations have been predicted to favour an unusual type of nuclear superfluidity, termed isoscalar neutron-proton pairing, in addition to normal isovector pairing. Despite many experimental efforts, these predictions have not been confirmed. Here we report the experimental observation of excited states in the N = Z = 46 nucleus (92)Pd. Gamma rays emitted following the (58)Ni((36)Ar,2n)(92)Pd fusion-evaporation reaction were identified using a combination of state-of-the-art high-resolution γ-ray, charged-particle and neutron detector systems. Our results reveal evidence for a spin-aligned, isoscalar neutron-proton coupling scheme, different from the previous prediction. We suggest that this coupling scheme replaces normal superfluidity (characterized by seniority coupling) in the ground and low-lying excited states of the heaviest N = Z nuclei. Such strong, isoscalar neutron-proton correlations would have a considerable impact on the nuclear level structure and possibly influence the dynamics of rapid proton capture in stellar nucleosynthesis. 相似文献
12.
Zuber J Shi J Wang E Rappaport AR Herrmann H Sison EA Magoon D Qi J Blatt K Wunderlich M Taylor MJ Johns C Chicas A Mulloy JC Kogan SC Brown P Valent P Bradner JE Lowe SW Vakoc CR 《Nature》2011,478(7370):524-528
Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. 相似文献
13.
Paul D. Taylor Silviu O. Martha Dennis P. Gordon 《Journal of Natural History》2018,52(25-26):1657-1721
Genera assigned to the cheilostome bryozoan family Onychocellidae are revised based on the skeletal morphology of the type species and, when possible, the type material of these species. All genera are illustrated using scanning electron micrographs, some for the first time. Onychocellidae, which ranges from the Cenomanian stage of the Cretaceous to the Recent, has been a particularly troublesome family because of poorly defined generic concepts correlating at least in part with a paucity of morphological characters. Thirty-five genera are described in this review. Of these, two are recognised as subjective synonyms of other onychocellid genera (Rhebasia and Semieschara), one cannot be sufficiently characterised from the type material (Collura), and two are new: Aechmellina gen. nov. (type species Aechmella falcifera) and Kamilocella gen. nov. (type species Eschara latilabris). A neotype is chosen for Rhagasostoma hexagonum, the type species of Rhagasostoma. A key is provided to assist in the identification of onychocellid genera. Phylogenetic relationships between genera remain obscure and are unlikely to be fully resolved based on skeletal morphology alone. The family as an entity is loosely circumscribed and almost certainly paraphyletic, containing stem genera of other anascan familes such as Lunulitidae, Coscinopleuridae and Aspidostomatidae.
www.zoobank.org/urn:lsid:org:pub:63A31AD2-F049-42CB-A45B-557014DC286E 相似文献
14.
RK Koenekoop H Wang J Majewski X Wang I Lopez H Ren Y Chen Y Li GA Fishman M Genead J Schwartzentruber N Solanki EI Traboulsi J Cheng CV Logan M McKibbin BE Hayward DA Parry CA Johnson M Nageeb;Finding of Rare Disease Genes 《Nature genetics》2012,44(9):1035-1039
Leber congenital amaurosis (LCA) is a blinding retinal disease that presents within the first year after birth. Using exome sequencing, we identified mutations in the nicotinamide adenine dinucleotide (NAD) synthase gene NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 in eight families with LCA, including the family in which LCA was originally linked to the LCA9 locus. Notably, all individuals with NMNAT1 mutations also have macular colobomas, which are severe degenerative entities of the central retina (fovea) devoid of tissue and photoreceptors. Functional assays of the proteins encoded by the mutant alleles identified in our study showed that the mutations reduce the enzymatic activity of NMNAT1 in NAD biosynthesis and affect protein folding. Of note, recent characterization of the slow Wallerian degeneration (Wld(s)) mouse model, in which prolonged axonal survival after injury is observed, identified NMNAT1 as a neuroprotective protein when ectopically expressed. Our findings identify a new disease mechanism underlying LCA and provide the first link between endogenous NMNAT1 dysfunction and a human nervous system disorder. 相似文献
15.
Kalay E Yigit G Aslan Y Brown KE Pohl E Bicknell LS Kayserili H Li Y Tüysüz B Nürnberg G Kiess W Koegl M Baessmann I Buruk K Toraman B Kayipmaz S Kul S Ikbal M Turner DJ Taylor MS Aerts J Scott C Milstein K Dollfus H Wieczorek D Brunner HG Hurles M Jackson AP Rauch A Nürnberg P Karagüzel A Wollnik B 《Nature genetics》2011,43(1):23-26
Functional impairment of DNA damage response pathways leads to increased genomic instability. Here we describe the centrosomal protein CEP152 as a new regulator of genomic integrity and cellular response to DNA damage. Using homozygosity mapping and exome sequencing, we identified CEP152 mutations in Seckel syndrome and showed that impaired CEP152 function leads to accumulation of genomic defects resulting from replicative stress through enhanced activation of ATM signaling and increased H2AX phosphorylation. 相似文献
16.
Wright FA Strug LJ Doshi VK Commander CW Blackman SM Sun L Berthiaume Y Cutler D Cojocaru A Collaco JM Corey M Dorfman R Goddard K Green D Kent JW Lange EM Lee S Li W Luo J Mayhew GM Naughton KM Pace RG Paré P Rommens JM Sandford A Stonebraker JR Sun W Taylor C Vanscoy LL Zou F Blangero J Zielenski J O'Neal WK Drumm ML Durie PR Knowles MR Cutting GR 《Nature genetics》2011,43(6):539-546
A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder. 相似文献
17.
18.
Trinidad Montero-Melendez Rachel A. E. Forfar Jennifer M. Cook Jeffrey C. Jerman Debra L. Taylor Mauro Perretti 《Cellular and molecular life sciences : CMLS》2017,74(7):1335-1345
The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC3, MC4, and MC5 receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r?/? mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC3 PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases. 相似文献
19.
Georgette Taylor 《Annals of science》2013,70(4):465-486
This paper presents a case study that contributes to the current debate among historians of chemistry concerning the role and influence of pedagogy in science. Recently, Bernadette Bensaude-Vincent and her colleagues concluded that in nineteenth-century France, ‘textbooks played an important role in discipline building and in creating theories’.1 Developing this idea further, this paper examines the dissemination of knowledge through face-to-face chemical lectures, showing that the influence of pedagogical strategy on theoretical content of the science is far from negligible. The pedagogy of William Cullen was essentially responsible for the prevalence of the doctrine of affinity in British chemistry from the 1760s onwards. Cullen used his affinity theory as a pedagogical tool that to a large extent defined his discipline, and the pedagogical pyramid that he headed similarly ensured that the doctrine would remain at the heart of British chemistry. From a pedagogical tool, the doctrine of affinity was transformed over time into a chemical tool, offering British chemists a disciplinary common ground that both set and reinforced the boundaries to their discipline. 相似文献
20.
MicroRNA Mirn140 modulates Pdgf signaling during palatogenesis 总被引:2,自引:0,他引:2
Eberhart JK He X Swartz ME Yan YL Song H Boling TC Kunerth AK Walker MB Kimmel CB Postlethwait JH 《Nature genetics》2008,40(3):290-298
Disruption of signaling pathways such as those mediated by sonic hedgehog (Shh) or platelet-derived growth factor (Pdgf) causes craniofacial abnormalities, including cleft palate. The role that microRNAs play in modulating palatogenesis, however, is completely unknown. We show that, in zebrafish, the microRNA Mirn140 negatively regulates Pdgf signaling during palatal development, and we provide a mechanism for how disruption of Pdgf signaling causes palatal clefting. The pdgf receptor alpha (pdgfra) 3' UTR contained a Mirn140 binding site functioning in the negative regulation of Pdgfra protein levels in vivo. pdgfra mutants and Mirn140-injected embryos shared a range of facial defects, including clefting of the crest-derived cartilages that develop in the roof of the larval mouth. Concomitantly, the oral ectoderm beneath where these cartilages develop lost pitx2 and shha expression. Mirn140 modulated Pdgf-mediated attraction of cranial neural crest cells to the oral ectoderm, where crest-derived signals were necessary for oral ectodermal gene expression. Mirn140 loss of function elevated Pdgfra protein levels, altered palatal shape and caused neural crest cells to accumulate around the optic stalk, a source of the ligand Pdgfaa. These results suggest that the conserved regulatory interactions of mirn140 and pdgfra define an ancient mechanism of palatogenesis, and they provide candidate genes for cleft palate. 相似文献