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  • 1
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    Time-domain and spectral properties of pulsars at 154 MHz (2016)
    Oxford University Press
    Details
    Publication Date: 2016-07-02
    Description: We present 154 MHz Murchison Widefield Array imaging observations and variability information for a sample of pulsars. Over the declination range –80° 〈  〈 10°, we detect 17 known pulsars with mean flux density greater than 0.3 Jy. We explore the variability properties of this sample on time-scales of minutes to years. For three of these pulsars, PSR J0953+0755, PSR J0437–4715, and PSR J0630–2834, we observe interstellar scintillation and variability on time-scales of greater than 2 min. One further pulsar, PSR J0034–0721, showed significant variability, the physical origins of which are difficult to determine. The dynamic spectra for PSR J0953+0755 and PSR J0437–4715 show discrete time and frequency structure consistent with diffractive interstellar scintillation and we present the scintillation bandwidth and time-scales from these observations. The remaining pulsars within our sample were statistically non-variable. We also explore the spectral properties of this sample and find spectral curvature in pulsars PSR J0835–4510, PSR J1752–2806, and PSR J0437–4715.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 2
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    The 154 MHz radio sky observed by the Murchison Widefield Array: noise, confusion, and first source count analyses (2016)
    Oxford University Press
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    Publication Date: 2016-05-12
    Description: We analyse a 154 MHz image made from a 12 h observation with the Murchison Widefield Array (MWA) to determine the noise contribution and behaviour of the source counts down to 30 mJy. The MWA image has a bandwidth of 30.72 MHz, a field-of-view within the half-power contour of the primary beam of 570 deg 2 , a resolution of 2.3 arcmin and contains 13 458 sources above 5. The rms noise in the centre of the image is 4–5 mJy beam –1 . The MWA counts are in excellent agreement with counts from other instruments and are the most precise ever derived in the flux density range 30–200 mJy due to the sky area covered. Using the deepest available source count data, we find that the MWA image is affected by sidelobe confusion noise at the 3.5 mJy beam –1 level, due to incompletely peeled and out-of-image sources, and classical confusion becomes apparent at 1.7 mJy beam –1 . This work highlights that (i) further improvements in ionospheric calibration and deconvolution imaging techniques would be required to probe to the classical confusion limit and (ii) the shape of low-frequency source counts, including any flattening towards lower flux densities, must be determined from deeper 150 MHz surveys as it cannot be directly inferred from higher frequency data.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 3
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    Influence of electron-acoustic phonon scattering on off-resonant cavity feeding within a strongly coupled quantum-dot cavity system (2011)
    American Physical Society (APS)
    Details
    Publication Date: 2011-04-22
    Description: Author(s): S. Hughes, P. Yao, F. Milde, A. Knorr, D. Dalacu, K. Mnaymneh, V. Sazonova, P. J. Poole, G. C. Aers, J. Lapointe, R. Cheriton, and R. L. Williams We present a quantum optics approach to describe the influence of electron-acoustic phonon coupling on the emission spectra of a strongly coupled quantum-dot cavity system. Using a canonical Hamiltonian for light quantization and a photon Green function formalism, phonons are included to all orders ... [Phys. Rev. B 83, 165313] Published Thu Apr 21, 2011
    Keywords: Semiconductors II: surfaces, interfaces, microstructures, and related topics
    Print ISSN: 1098-0121
    Electronic ISSN: 1095-3795
    Topics: Physics
    Published by American Physical Society (APS)
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  • 4
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    Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit (2007)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2007-07-14
    Description: Many human cancers involve up-regulation of the phosphoinositide 3-kinase PI3Kalpha, with oncogenic mutations identified in both the p110alpha catalytic and the p85alpha regulatory subunits. We used crystallographic and biochemical approaches to gain insight into activating mutations in two noncatalytic p110alpha domains-the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110alpha in a complex with the p85alpha inter-Src homology 2 (inter-SH2) domain shows that oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. We also examined helical domain mutations and found that the Glu545 to Lys545 (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. These studies extend our understanding of the architecture of PI3Ks and provide insight into how two classes of mutations that cause a gain in function can lead to cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miled, Nabil -- Yan, Ying -- Hon, Wai-Ching -- Perisic, Olga -- Zvelebil, Marketa -- Inbar, Yuval -- Schneidman-Duhovny, Dina -- Wolfson, Haim J -- Backer, Jonathan M -- Williams, Roger L -- GM55692/GM/NIGMS NIH HHS/ -- MC_U105184308/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2007 Jul 13;317(5835):239-42.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17626883" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; *Catalytic Domain ; Cattle ; Cell Line ; Cell Transformation, Neoplastic ; Crystallography, X-Ray ; Dimerization ; Humans ; Models, Molecular ; Molecular Sequence Data ; *Mutation ; Neoplasms/*genetics ; Phosphatidylinositol 3-Kinases/antagonists & ; inhibitors/chemistry/*genetics/*metabolism ; Protein Structure, Secondary ; Protein Structure, Tertiary ; src Homology Domains
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    Shaping development of autophagy inhibitors with the structure of the lipid kinase Vps34 (2010)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2010-03-27
    Description: Phosphoinositide 3-kinases (PI3Ks) are lipid kinases with diverse roles in health and disease. The primordial PI3K, Vps34, is present in all eukaryotes and has essential roles in autophagy, membrane trafficking, and cell signaling. We solved the crystal structure of Vps34 at 2.9 angstrom resolution, which revealed a constricted adenine-binding pocket, suggesting the reason that specific inhibitors of this class of PI3K have proven elusive. Both the phosphoinositide-binding loop and the carboxyl-terminal helix of Vps34 mediate catalysis on membranes and suppress futile adenosine triphosphatase cycles. Vps34 appears to alternate between a closed cytosolic form and an open form on the membrane. Structures of Vps34 complexes with a series of inhibitors reveal the reason that an autophagy inhibitor preferentially inhibits Vps34 and underpin the development of new potent and specific Vps34 inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860105/" 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/PMC2860105/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miller, Simon -- Tavshanjian, Brandon -- Oleksy, Arkadiusz -- Perisic, Olga -- Houseman, Benjamin T -- Shokat, Kevan M -- Williams, Roger L -- MC_U105184308/Medical Research Council/United Kingdom -- U.1051.03.014(78824)/Medical Research Council/United Kingdom -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2010 Mar 26;327(5973):1638-42. doi: 10.1126/science.1184429.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20339072" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/*analogs & derivatives/metabolism/pharmacology ; Adenosine Triphosphatases/metabolism ; Animals ; Autophagy/*drug effects ; Binding Sites ; Catalysis ; Catalytic Domain ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Drosophila Proteins/*antagonists & inhibitors/*chemistry/genetics/metabolism ; Drosophila melanogaster ; Enzyme Inhibitors/chemical synthesis/chemistry/*metabolism/pharmacology ; Furans/chemistry/metabolism/pharmacology ; Humans ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Phosphatidylinositol 3-Kinases/*antagonists & ; inhibitors/*chemistry/genetics/metabolism ; Phosphatidylinositols/metabolism ; Point Mutation ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Pyridines/chemistry/metabolism/pharmacology ; Pyrimidines/chemistry/metabolism/pharmacology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 6
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    Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-10-19
    Description: Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-delta syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110delta protein, the catalytic subunit of phosphoinositide 3-kinase delta (PI3Kdelta), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110delta. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110delta inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930011/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930011/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Angulo, Ivan -- Vadas, Oscar -- Garcon, Fabien -- Banham-Hall, Edward -- Plagnol, Vincent -- Leahy, Timothy R -- Baxendale, Helen -- Coulter, Tanya -- Curtis, James -- Wu, Changxin -- Blake-Palmer, Katherine -- Perisic, Olga -- Smyth, Deborah -- Maes, Mailis -- Fiddler, Christine -- Juss, Jatinder -- Cilliers, Deirdre -- Markelj, Gasper -- Chandra, Anita -- Farmer, George -- Kielkowska, Anna -- Clark, Jonathan -- Kracker, Sven -- Debre, Marianne -- Picard, Capucine -- Pellier, Isabelle -- Jabado, Nada -- Morris, James A -- Barcenas-Morales, Gabriela -- Fischer, Alain -- Stephens, Len -- Hawkins, Phillip -- Barrett, Jeffrey C -- Abinun, Mario -- Clatworthy, Menna -- Durandy, Anne -- Doffinger, Rainer -- Chilvers, Edwin R -- Cant, Andrew J -- Kumararatne, Dinakantha -- Okkenhaug, Klaus -- Williams, Roger L -- Condliffe, Alison -- Nejentsev, Sergey -- 095198/Wellcome Trust/United Kingdom -- 095198/Z/10/Z/Wellcome Trust/United Kingdom -- 095691/Wellcome Trust/United Kingdom -- BB/J004456/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U105184308/Medical Research Council/United Kingdom -- U105184308/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2013 Nov 15;342(6160):866-71. doi: 10.1126/science.1243292. Epub 2013 Oct 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Cambridge, Cambridge, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24136356" target="_blank"〉PubMed〈/a〉
    Keywords: Class I Phosphatidylinositol 3-Kinases ; *Genetic Predisposition to Disease ; Humans ; Immunologic Deficiency Syndromes/*genetics/immunology/*pathology ; Lymphocytes/immunology ; Mutation ; Pedigree ; Phosphatidylinositol 3-Kinases/*genetics ; Phosphatidylinositol Phosphates/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Respiratory Tract Infections/*genetics/immunology/*pathology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
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    Limits on Fast Radio Bursts and other transient sources at 182 MHz using the Murchison Widefield Array (2016)
    Oxford University Press
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    Publication Date: 2016-04-04
    Description: We present a survey for transient and variable sources, on time-scales from 28 s to ~1 yr, using the Murchison Widefield Array (MWA) at 182 MHz. Down to a detection threshold of 0.285 Jy, no transient candidates were identified, making this the most constraining low-frequency survey to date and placing a limit on the surface density of transients of 〈4.1 x 10 –7  deg –2 for the shortest time-scale considered. At these frequencies, emission from Fast Radio Bursts (FRBs) is expected to be detectable in the shortest time-scale images without any corrections for interstellar or intergalactic dispersion. At an FRB limiting flux density of 7980 Jy, we find a rate of 〈82 FRBs per sky per day for dispersion measures 〈700 pc cm –3 . Assuming a cosmological population of standard candles, our rate limits are consistent with the FRB rates obtained by Thornton et al. if they have a flat spectral slope. Finally, we conduct an initial variability survey of sources in the field with flux densities 0.5 Jy and identify no sources with significant variability in their light curves. However, we note that substantial further work is required to fully characterize both the short-term and low-level variability within this field.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 8
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    Vesicular and non-vesicular transport feed distinct glycosylation pathways in the Golgi (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-08-06
    Description: Newly synthesized proteins and lipids are transported across the Golgi complex via different mechanisms whose respective roles are not completely clear. We previously identified a non-vesicular intra-Golgi transport pathway for glucosylceramide (GlcCer)--the common precursor of the different series of glycosphingolipids-that is operated by the cytosolic GlcCer-transfer protein FAPP2 (also known as PLEKHA8) (ref. 1). However, the molecular determinants of the FAPP2-mediated transfer of GlcCer from the cis-Golgi to the trans-Golgi network, as well as the physiological relevance of maintaining two parallel transport pathways of GlcCer--vesicular and non-vesicular--through the Golgi, remain poorly defined. Here, using mouse and cell models, we clarify the molecular mechanisms underlying the intra-Golgi vectorial transfer of GlcCer by FAPP2 and show that GlcCer is channelled by vesicular and non-vesicular transport to two topologically distinct glycosylation tracks in the Golgi cisternae and the trans-Golgi network, respectively. Our results indicate that the transport modality across the Golgi complex is a key determinant for the glycosylation pattern of a cargo and establish a new paradigm for the branching of the glycosphingolipid synthetic pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉D'Angelo, Giovanni -- Uemura, Takefumi -- Chuang, Chia-Chen -- Polishchuk, Elena -- Santoro, Michele -- Ohvo-Rekila, Henna -- Sato, Takashi -- Di Tullio, Giuseppe -- Varriale, Antonio -- D'Auria, Sabato -- Daniele, Tiziana -- Capuani, Fabrizio -- Johannes, Ludger -- Mattjus, Peter -- Monti, Maria -- Pucci, Piero -- Williams, Roger L -- Burke, John E -- Platt, Frances M -- Harada, Akihiro -- De Matteis, Maria Antonietta -- MC_U105184308/Medical Research Council/United Kingdom -- PG/11/109/29247/British Heart Foundation/United Kingdom -- TGM11CB1/Telethon/Italy -- England -- Nature. 2013 Sep 5;501(7465):116-20. doi: 10.1038/nature12423. Epub 2013 Aug 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Telethon Institute of Genetics and Medicine, Via Pietro Castellino 111, 80131 Naples, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23913272" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics/metabolism ; Animals ; Biological Transport ; Cell Line ; Globosides/biosynthesis/chemistry/metabolism ; Glucosylceramides/chemistry/*metabolism ; Glycosphingolipids/biosynthesis/chemistry/metabolism ; *Glycosylation ; Golgi Apparatus/*metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Phosphatidylinositol Phosphates/metabolism ; trans-Golgi Network/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 9
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    Structures of PI4KIIIbeta complexes show simultaneous recruitment of Rab11 and its effectors (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-05-31
    Description: Phosphatidylinositol 4-kinases (PI4Ks) and small guanosine triphosphatases (GTPases) are essential for processes that require expansion and remodeling of phosphatidylinositol 4-phosphate (PI4P)-containing membranes, including cytokinesis, intracellular development of malarial pathogens, and replication of a wide range of RNA viruses. However, the structural basis for coordination of PI4K, GTPases, and their effectors is unknown. Here, we describe structures of PI4Kbeta (PI4KIIIbeta) bound to the small GTPase Rab11a without and with the Rab11 effector protein FIP3. The Rab11-PI4KIIIbeta interface is distinct compared with known structures of Rab complexes and does not involve switch regions used by GTPase effectors. Our data provide a mechanism for how PI4KIIIbeta coordinates Rab11 and its effectors on PI4P-enriched membranes and also provide strategies for the design of specific inhibitors that could potentially target plasmodial PI4KIIIbeta to combat malaria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046302/" 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/PMC4046302/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burke, John E -- Inglis, Alison J -- Perisic, Olga -- Masson, Glenn R -- McLaughlin, Stephen H -- Rutaganira, Florentine -- Shokat, Kevan M -- Williams, Roger L -- MC_U105184308/Medical Research Council/United Kingdom -- PG/11/109/29247/British Heart Foundation/United Kingdom -- PG11/109/29247/British Heart Foundation/United Kingdom -- R01AI099245/AI/NIAID NIH HHS/ -- T32 GM064337/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 May 30;344(6187):1035-8. doi: 10.1126/science.1253397.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. jeburke@uvic.ca rlw@mrc-lmb.cam.ac.uk. ; Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. ; Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24876499" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antimalarials/chemistry/pharmacology ; Binding Sites ; Cell Line ; Crystallography, X-Ray ; Drug Design ; Humans ; I-kappa B Kinase/*chemistry ; Molecular Sequence Data ; Mutation ; Phosphotransferases (Alcohol Group Acceptor)/*chemistry/genetics ; Plasmodium/drug effects/growth & development ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; rab GTP-Binding Proteins/*chemistry
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
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    Quantitation of class IA PI3Ks in mice reveals p110-free-p85s and isoform-selective subunit associations and recruitment to receptors [Biochemistry] (2018)
    National Academy of Sciences
    Details
    Publication Date: 2018-11-28
    Description: Class IA PI3Ks have many roles in health and disease. The rules that govern intersubunit and receptor associations, however, remain unclear. We engineered mouse lines in which individual endogenous class IA PI3K subunits were C-terminally tagged with 17aa that could be biotinylated in vivo. Using these tools we quantified PI3K...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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