ALBERT

Description: Vertical ocean-bottom seismograph (OBS) data at frequencies below 0.05 Hz are contaminated by noise induced by infragravity waves. We constructed the transfer function between pressure and velocity data from OBSs deployed in Taiwan waters to remove the wave pressure-induced noise from seismic recordings. Data were analyzed from five portable broadband OBSs deployed each for 10 months at water depths from 1740 to 4600 m and from a cabled, shallow-buried seismograph (EOS1) installed on the seafloor at 300 m depth. Removing long-period noise from these OBS data improves the identification of teleseismic phases such as P , S , SS , P diff , and PKIKP that are otherwise ambiguous or unidentifiable. For EOS1, infragravity-wave signals completely mask the P and S waveforms in the 10–50 s period band suitable for centroid moment tensor (CMT) solutions for most of the local events. Application of the transfer functions to predict and remove wave deformation yielded clean prominent P and S waveforms at these periods and aided in the CMT determination for small events jointly with land stations. The relative amplitudes of the wavenumber-normalized transfer function for some of the OBSs are mostly determined by the thickness of the sediment at the OBS site.

Description: G-protein-coupled receptors (GPCRs) are critically regulated by beta-arrestins, which not only desensitize G-protein signalling but also initiate a G-protein-independent wave of signalling. A recent surge of structural data on a number of GPCRs, including the beta2 adrenergic receptor (beta2AR)-G-protein complex, has provided novel insights into the structural basis of receptor activation. However, complementary information has been lacking on the recruitment of beta-arrestins to activated GPCRs, primarily owing to challenges in obtaining stable receptor-beta-arrestin complexes for structural studies. Here we devised a strategy for forming and purifying a functional human beta2AR-beta-arrestin-1 complex that allowed us to visualize its architecture by single-particle negative-stain electron microscopy and to characterize the interactions between beta2AR and beta-arrestin 1 using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and chemical crosslinking. Electron microscopy two-dimensional averages and three-dimensional reconstructions reveal bimodal binding of beta-arrestin 1 to the beta2AR, involving two separate sets of interactions, one with the phosphorylated carboxy terminus of the receptor and the other with its seven-transmembrane core. Areas of reduced HDX together with identification of crosslinked residues suggest engagement of the finger loop of beta-arrestin 1 with the seven-transmembrane core of the receptor. In contrast, focal areas of raised HDX levels indicate regions of increased dynamics in both the N and C domains of beta-arrestin 1 when coupled to the beta2AR. A molecular model of the beta2AR-beta-arrestin signalling complex was made by docking activated beta-arrestin 1 and beta2AR crystal structures into the electron microscopy map densities with constraints provided by HDX-MS and crosslinking, allowing us to obtain valuable insights into the overall architecture of a receptor-arrestin complex. The dynamic and structural information presented here provides a framework for better understanding the basis of GPCR regulation by arrestins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134437/" 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/PMC4134437/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shukla, Arun K -- Westfield, Gerwin H -- Xiao, Kunhong -- Reis, Rosana I -- Huang, Li-Yin -- Tripathi-Shukla, Prachi -- Qian, Jiang -- Li, Sheng -- Blanc, Adi -- Oleskie, Austin N -- Dosey, Anne M -- Su, Min -- Liang, Cui-Rong -- Gu, Ling-Ling -- Shan, Jin-Ming -- Chen, Xin -- Hanna, Rachel -- Choi, Minjung -- Yao, Xiao Jie -- Klink, Bjoern U -- Kahsai, Alem W -- Sidhu, Sachdev S -- Koide, Shohei -- Penczek, Pawel A -- Kossiakoff, Anthony A -- Woods, Virgil L Jr -- Kobilka, Brian K -- Skiniotis, Georgios -- Lefkowitz, Robert J -- DK090165/DK/NIDDK NIH HHS/ -- GM072688/GM/NIGMS NIH HHS/ -- GM087519/GM/NIGMS NIH HHS/ -- GM60635/GM/NIGMS NIH HHS/ -- HL075443/HL/NHLBI NIH HHS/ -- HL16037/HL/NHLBI NIH HHS/ -- HL70631/HL/NHLBI NIH HHS/ -- MOP-93725/Canadian Institutes of Health Research/Canada -- NS028471/NS/NINDS NIH HHS/ -- R01 DK090165/DK/NIDDK NIH HHS/ -- R01 GM060635/GM/NIGMS NIH HHS/ -- R01 GM072688/GM/NIGMS NIH HHS/ -- R01 HL016037/HL/NHLBI NIH HHS/ -- R01 HL070631/HL/NHLBI NIH HHS/ -- R01 NS028471/NS/NINDS NIH HHS/ -- UL1 TR000430/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Aug 14;512(7513):218-22. doi: 10.1038/nature13430. Epub 2014 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India. [3]. ; 1] Life Sciences Institute and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2]. ; 1] Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA [2]. ; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Chemistry, University of California at San Diego, La Jolla, California 92093, USA. ; Life Sciences Institute and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; School of Pharmaceutical &Life Sciences, Changzhou University, Changzhou, Jiangsu 213164, China. ; Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. ; Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA. ; Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas 77054, USA. ; 1] Department of Chemistry, University of California at San Diego, La Jolla, California 92093, USA [2]. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA. ; 1] Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA [3] Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043026" target="_blank"〉PubMed〈/a〉

Description: Alzheimer’s disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-β (Aβ) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary...

Description: We investigated the effects of the time course of addition of osteogenic supplements dexamethasone, beta-glycerolphosphate, and L-ascorbic acid to rat marrow stromal cells, and the exposure time on the proliferation and differentiation of the cells. It was the goal of these experiments to determine the time point for supplement addition to optimize marrow stromal cell proliferation and osteoblastic differentiation. To determine this, two studies were performed; one study was based on the age of the cells from harvest, and the other study was based on the duration of exposure to supplemented medium. Cells were seen to proliferate rapidly at early time points in the presence and absence of osteogenic supplements as determined by 3H-thymidine incorporation into the DNA of replicating cells. These results were supported by cell counts ascertained through total DNA analysis. Alkaline phosphatase (ALP) activity and osteocalcin production at 21 days were highest for both experimental designs when the cells were exposed to supplemented medium immediately upon harvest. The ALP levels at 21 days were six times greater for cells maintained in supplements throughout than for control cells cultured in the absence of supplements for both studies, reaching an absolute value of 75 x 10(-7) micromole/min/cell. Osteocalcin production reached 20 x 10(-6) ng/cell at 21 days in both studies for cells maintained in supplemented medium throughout the study, whereas the control cells produced an insignificant amount of osteocalcin. These results suggest that the addition of osteogenic supplements to marrow-derived cells early in the culture period did not inhibit proliferation and greatly enhanced the osteoblastic phenotype of cells in a rat model.