Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Keywords: BLOOD-PRESSURE ; HOMOLOGOUS RECOMBINATION ; CHROMOSOMAL INSTABILITY ; BODY-MASS INDEX ; NATURAL MENOPAUSE ; LOCI ; WIDE ASSOCIATION ; BRCA2 MUTATION CARRIERS ; CELL-TYPES ; PREMATURE OVARIAN FAILURE
    Abstract: Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in approximately 70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk ( approximately 6% increase in risk per year; P = 3 x 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
    Type of Publication: Journal article published
    PubMed ID: 26414677
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Publication Date: 2014-11-14
    Description: Topology, with its abstract mathematical constructs, often manifests itself in physics and has a pivotal role in our understanding of natural phenomena. Notably, the discovery of topological phases in condensed-matter systems has changed the modern conception of phases of matter. The global nature of topological ordering, however, makes direct experimental probing an outstanding challenge. Present experimental tools are mainly indirect and, as a result, are inadequate for studying the topology of physical systems at a fundamental level. Here we employ the exquisite control afforded by state-of-the-art superconducting quantum circuits to investigate topological properties of various quantum systems. The essence of our approach is to infer geometric curvature by measuring the deflection of quantum trajectories in the curved space of the Hamiltonian. Topological properties are then revealed by integrating the curvature over closed surfaces, a quantum analogue of the Gauss-Bonnet theorem. We benchmark our technique by investigating basic topological concepts of the historically important Haldane model after mapping the momentum space of this condensed-matter model to the parameter space of a single-qubit Hamiltonian. In addition to constructing the topological phase diagram, we are able to visualize the microscopic spin texture of the associated states and their evolution across a topological phase transition. Going beyond non-interacting systems, we demonstrate the power of our method by studying topology in an interacting quantum system. This required a new qubit architecture that allows for simultaneous control over every term in a two-qubit Hamiltonian. By exploring the parameter space of this Hamiltonian, we discover the emergence of an interaction-induced topological phase. Our work establishes a powerful, generalizable experimental platform to study topological phenomena in quantum systems.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roushan, P -- Neill, C -- Chen, Yu -- Kolodrubetz, M -- Quintana, C -- Leung, N -- Fang, M -- Barends, R -- Campbell, B -- Chen, Z -- Chiaro, B -- Dunsworth, A -- Jeffrey, E -- Kelly, J -- Megrant, A -- Mutus, J -- O'Malley, P J J -- Sank, D -- Vainsencher, A -- Wenner, J -- White, T -- Polkovnikov, A -- Cleland, A N -- Martinis, J M -- England -- Nature. 2014 Nov 13;515(7526):241-4. doi: 10.1038/nature13891.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics, University of California, Santa Barbara, California 93106-9530, USA. ; Department of Physics, Boston University, Boston, Massachusetts 02215, USA. ; 1] Department of Physics, University of California, Santa Barbara, California 93106-9530, USA [2] Google Inc., Santa Barbara, California 93117, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25391961" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    Publication Date: 2015-03-06
    Description: Quantum computing becomes viable when a quantum state can be protected from environment-induced error. If quantum bits (qubits) are sufficiently reliable, errors are sparse and quantum error correction (QEC) is capable of identifying and correcting them. Adding more qubits improves the preservation of states by guaranteeing that increasingly larger clusters of errors will not cause logical failure-a key requirement for large-scale systems. Using QEC to extend the qubit lifetime remains one of the outstanding experimental challenges in quantum computing. Here we report the protection of classical states from environmental bit-flip errors and demonstrate the suppression of these errors with increasing system size. We use a linear array of nine qubits, which is a natural step towards the two-dimensional surface code QEC scheme, and track errors as they occur by repeatedly performing projective quantum non-demolition parity measurements. Relative to a single physical qubit, we reduce the failure rate in retrieving an input state by a factor of 2.7 when using five of our nine qubits and by a factor of 8.5 when using all nine qubits after eight cycles. Additionally, we tomographically verify preservation of the non-classical Greenberger-Horne-Zeilinger state. The successful suppression of environment-induced errors will motivate further research into the many challenges associated with building a large-scale superconducting quantum computer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kelly, J -- Barends, R -- Fowler, A G -- Megrant, A -- Jeffrey, E -- White, T C -- Sank, D -- Mutus, J Y -- Campbell, B -- Chen, Yu -- Chen, Z -- Chiaro, B -- Dunsworth, A -- Hoi, I-C -- Neill, C -- O'Malley, P J J -- Quintana, C -- Roushan, P -- Vainsencher, A -- Wenner, J -- Cleland, A N -- Martinis, John M -- England -- Nature. 2015 Mar 5;519(7541):66-9. doi: 10.1038/nature14270.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics, University of California, Santa Barbara, California 93106, USA. ; 1] Department of Physics, University of California, Santa Barbara, California 93106, USA [2] Centre for Quantum Computation and Communication Technology, School of Physics, The University of Melbourne, Victoria 3010, Australia. ; 1] Department of Physics, University of California, Santa Barbara, California 93106, USA [2] Department of Materials, University of California, Santa Barbara, California 93106, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25739628" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    Publication Date: 2014-04-25
    Description: A quantum computer can solve hard problems, such as prime factoring, database searching and quantum simulation, at the cost of needing to protect fragile quantum states from error. Quantum error correction provides this protection by distributing a logical state among many physical quantum bits (qubits) by means of quantum entanglement. Superconductivity is a useful phenomenon in this regard, because it allows the construction of large quantum circuits and is compatible with microfabrication. For superconducting qubits, the surface code approach to quantum computing is a natural choice for error correction, because it uses only nearest-neighbour coupling and rapidly cycled entangling gates. The gate fidelity requirements are modest: the per-step fidelity threshold is only about 99 per cent. Here we demonstrate a universal set of logic gates in a superconducting multi-qubit processor, achieving an average single-qubit gate fidelity of 99.92 per cent and a two-qubit gate fidelity of up to 99.4 per cent. This places Josephson quantum computing at the fault-tolerance threshold for surface code error correction. Our quantum processor is a first step towards the surface code, using five qubits arranged in a linear array with nearest-neighbour coupling. As a further demonstration, we construct a five-qubit Greenberger-Horne-Zeilinger state using the complete circuit and full set of gates. The results demonstrate that Josephson quantum computing is a high-fidelity technology, with a clear path to scaling up to large-scale, fault-tolerant quantum circuits.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barends, R -- Kelly, J -- Megrant, A -- Veitia, A -- Sank, D -- Jeffrey, E -- White, T C -- Mutus, J -- Fowler, A G -- Campbell, B -- Chen, Y -- Chen, Z -- Chiaro, B -- Dunsworth, A -- Neill, C -- O'Malley, P -- Roushan, P -- Vainsencher, A -- Wenner, J -- Korotkov, A N -- Cleland, A N -- Martinis, John M -- England -- Nature. 2014 Apr 24;508(7497):500-3. doi: 10.1038/nature13171.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Physics, University of California, Santa Barbara, California 93106, USA [2]. ; Department of Physics, University of California, Santa Barbara, California 93106, USA. ; Department of Electrical Engineering, University of California, Riverside, California 92521, USA. ; 1] Department of Physics, University of California, Santa Barbara, California 93106, USA [2] Centre for Quantum Computation and Communication Technology, School of Physics, The University of Melbourne, Victoria 3010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24759412" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    Publication Date: 2018-10-24
    Description: Bottom trawlers land around 19 million tons of fish and invertebrates annually, almost one-quarter of wild marine landings. The extent of bottom trawling footprint (seabed area trawled at least once in a specified region and time period) is often contested but poorly described. We quantify footprints using high-resolution satellite vessel...
    Keywords: Sustainability Science
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    Publication Date: 2014-05-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Campbell, Bruce -- England -- Nature. 2014 May 15;509(7500):288. doi: 10.1038/509288c.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CGIAR, Copenhagen, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24828180" target="_blank"〉PubMed〈/a〉
    Keywords: Climate Change/*statistics & numerical data ; Environmental Policy/*legislation & jurisprudence ; Food Supply/economics/*legislation & jurisprudence/*statistics & numerical data ; United Nations/*legislation & jurisprudence
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Publication Date: 2018-03-06
    Description: Tumors defective for DNA polymerase (Pol) ε proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ε proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol ε proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ε proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol ε mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol ε.
    Electronic ISSN: 2050-084X
    Topics: Natural Sciences in General
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    Publication Date: 2018-01-25
    Description: Background Diagnostic use of gene panel next-generation sequencing (NGS) techniques is commonplace for individuals with inherited retinal dystrophies (IRDs), a highly genetically heterogeneous group of disorders. However, these techniques have often failed to capture the complete spectrum of genomic variation causing IRD, including CNVs. This study assessed the applicability of introducing CNV surveillance into first-tier diagnostic gene panel NGS services for IRD. Methods Three read-depth algorithms were applied to gene panel NGS data sets for 550 referred individuals, and informatics strategies used for quality assurance and CNV filtering. CNV events were confirmed and reported to referring clinicians through an accredited diagnostic laboratory. Results We confirmed the presence of 33 deletions and 11 duplications, determining these findings to contribute to the confirmed or provisional molecular diagnosis of IRD for 25 individuals. We show that at least 7% of individuals referred for diagnostic testing for IRD have a CNV within genes relevant to their clinical diagnosis, and determined a positive predictive value of 79% for the employed CNV filtering techniques. Conclusion Incorporation of CNV analysis increases diagnostic yield of gene panel NGS diagnostic tests for IRD, increases clarity in diagnostic reporting and expands the spectrum of known disease-causing mutations.
    Keywords: Open access
    Print ISSN: 0022-2593
    Electronic ISSN: 1468-6244
    Topics: Medicine
    Published by BMJ Publishing Group
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    Publication Date: 2018-07-07
    Description: Endothelium-derived epoxyeicosatrienoic acids (EETs) have numerous vascular activities mediated by G protein–coupled receptors. Long-chain free fatty acids and EETs activate GPR40, prompting us to investigate the role of GPR40 in some vascular EET activities. 14,15-EET, 11,12-EET, arachidonic acid, and the GPR40 agonist GW9508 increase intracellular calcium concentrations in human GPR40–overexpressing HEK293 cells (EC50 = 0.58 ± 0.08 μm, 0.91 ± 0.08 μm, 3.9 ± 0.06 μm, and 19 ± 0.37 nm, respectively). EETs with cis- and trans-epoxides had similar activities, whereas substitution of a thiirane sulfur for the epoxide oxygen decreased the activities. 8,9-EET, 5,6-EET, and the epoxide hydrolysis products 11,12- and 14,15-dihydroxyeicosatrienoic acids were less active than 11,12-EET. The GPR40 antagonist GW1100 and siRNA-mediated GPR40 silencing blocked the EET- and GW9508-induced calcium increases. EETs are weak GPR120 agonists. GPR40 expression was detected in human and bovine endothelial cells (ECs), smooth muscle cells, and arteries. 11,12-EET concentration-dependently relaxed preconstricted coronary arteries; however, these relaxations were not altered by GW1100. In human ECs, 11,12-EET increased MAP kinase (MAPK)-mediated ERK phosphorylation, phosphorylation and levels of connexin-43 (Cx43), and expression of cyclooxygenase-2 (COX-2), all of which were inhibited by GW1100 and the MAPK inhibitor U0126. Moreover, siRNA-mediated GPR40 silencing decreased 11,12-EET–induced ERK phosphorylation. These results indicated that GPR40 is a low-affinity EET receptor in vascular cells and arteries. We conclude that epoxidation of arachidonic acid to EETs enhances GPR40 agonist activity and that 11,12-EET stimulation of GPR40 increases Cx43 and COX-2 expression in ECs via ERK phosphorylation.
    Print ISSN: 0021-9258
    Electronic ISSN: 1083-351X
    Topics: Biology , Chemistry and Pharmacology
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    Publication Date: 2014-12-05
    Description: Activation of mechanosensitive ion channels by physical force underlies many physiological processes including the sensation of touch, hearing and pain. TRAAK (also known as KCNK4) ion channels are neuronally expressed members of the two-pore domain K(+) (K2P) channel family and are mechanosensitive. They are involved in controlling mechanical and temperature nociception in mice. Mechanosensitivity of TRAAK is mediated directly through the lipid bilayer--it is a membrane-tension-gated channel. However, the molecular mechanism of TRAAK channel gating and mechanosensitivity is unknown. Here we present crystal structures of TRAAK in conductive and non-conductive conformations defined by the presence of permeant ions along the conduction pathway. In the non-conductive state, a lipid acyl chain accesses the channel cavity through a 5 A-wide lateral opening in the membrane inner leaflet and physically blocks ion passage. In the conductive state, rotation of a transmembrane helix (TM4) about a central hinge seals the intramembrane opening, preventing lipid block of the cavity and permitting ion entry. Additional rotation of a membrane interacting TM2-TM3 segment, unique to mechanosensitive K2Ps, against TM4 may further stabilize the conductive conformation. Comparison of the structures reveals a biophysical explanation for TRAAK mechanosensitivity--an expansion in cross-sectional area up to 2.7 nm(2) in the conductive state is expected to create a membrane-tension-dependent energy difference between conformations that promotes force activation. Our results show how tension of the lipid bilayer can be harnessed to control gating and mechanosensitivity of a eukaryotic ion channel.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682367/" 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/PMC4682367/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brohawn, Stephen G -- Campbell, Ernest B -- MacKinnon, Roderick -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 4;516(7529):126-30. doi: 10.1038/nature14013.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Neurobiology and Biophysics and Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25471887" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallization ; Humans ; Ion Channel Gating/*physiology ; *Models, Molecular ; Mutation ; Oxidation-Reduction ; Potassium Channels/*chemistry/genetics/*metabolism ; Protein Structure, Tertiary
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...