1,064 research outputs found
A dedication to Alfred L. Goldberg
No full textThis article belongs to a special issue Molecular Basis of Muscle Wasting - Dedicated to Alfred L. Goldberg Edited By Didier Attaix and William E. Mitch - Document Type: Biographical-Itemabsen
Binding of hydrophobic peptides to several non-catalytic sites promotes peptide hydrolysis by all active sites of 20 S proteasomes: Evidence for peptide-induced channel opening in the alpha-rings
No full textThe eukaryotic 20 S proteasome contains the following 6 active sites: 2 chymotrypsin-like, 2 trypsin-like, and 2 caspase-like. We previously showed that hydrophobic peptide substrates of the chymotrypsin-like sites allosterically stimulate peptide hydrolysis by the caspase-like sites and their own cleavage. More thorough analysis revealed that these peptides also stimulate peptide hydrolysis by the trypsin-like site. This general activation by hydrophobic peptides occurred even if the chymotrypsin-like sites were occupied by a covalent inhibitor and was highly cooperative, with an average Hill coefficient of 7. Therefore, this stimulation of peptide hydrolysis at all active sites occurs upon binding of hydrophobic peptides to several non-catalytic sites. The stimulation by hydrophobic peptides was not observed in the yeast Delta N alpha 3 mutant 20 S proteasomes, in 20 S-PA26 complexes, or SDS-activated proteasomes and was significantly lower in 26 S proteasomes, all of which appear to have the gated channel in the alpha-rings in an open conformation and hydrolyze peptides at much faster rates than 20 S proteasomes. Also the hydrophobic peptides altered K(m), V(max) of active sites in a similar fashion as PA26 and the Delta N alpha 3 mutation. The activation by hydrophobic peptides was decreased in K(+)-containing buffer, which favors the closed state of the channels. Therefore, hydrophobic peptides stimulate peptide hydrolysis most likely by promoting the opening of the channels in the alpha-rings. During protein breakdown, this peptide-induced channel opening may function to facilitate the release of products from the proteasome
Docking of the Proteasomal ATPases' Carboxyl Termini in the 20S Proteasome's α Ring Opens the Gate for Substrate Entry
No full textFoxo Transcription Factors Induce the Atrophy-Related Ubiquitin Ligase Atrogin-1 and Cause Skeletal Muscle Atrophy
No full textAbstractSkeletal muscle atrophy is a debilitating response to fasting, disuse, cancer, and other systemic diseases. In atrophying muscles, the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced, and this response is necessary for rapid atrophy. Here, we show that in cultured myotubes undergoing atrophy, the activity of the PI3K/AKT pathway decreases, leading to activation of Foxo transcription factors and atrogin-1 induction. IGF-1 treatment or AKT overexpression inhibits Foxo and atrogin-1 expression. Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers. When Foxo activation is blocked by a dominant-negative construct in myotubes or by RNAi in mouse muscles in vivo, atrogin-1 induction during starvation and atrophy of myotubes induced by glucocorticoids are prevented. Thus, forkhead factor(s) play a critical role in the development of muscle atrophy, and inhibition of Foxo factors is an attractive approach to combat muscle wasting
Bilateral and unilateral arm training improve motor function through differing neuroplastic mechanisms: a single-blinded randomized controlled trial
No full textBACKGROUND AND PURPOSE:
This randomized controlled trial tests the efficacy of bilateral arm training with rhythmic auditory cueing (BATRAC) versus dose-matched therapeutic exercises (DMTEs) on upper-extremity (UE) function in stroke survivors and uses functional magnetic resonance imaging (fMRI) to examine effects on cortical reorganization.
METHODS:
A total of 111 adults with chronic UE paresis were randomized to 6 weeks (3×/week) of BATRAC or DMTE. Primary end points of UE assessments of Fugl-Meyer UE Test (FM) and modified Wolf Motor Function Test Time (WT) were performed 6 weeks prior to and at baseline, after training, and 4 months later. Pretraining and posttraining, fMRI for UE movement was evaluated in 17 BATRAC and 21 DMTE participants.
RESULTS:
The improvements in UE function (BATRAC: FM Δ = 1.1 + 0.5, P = .03; WT Δ = -2.6 + 0.8, P < .00; DMTE: FM Δ = 1.9 + 0.4, P < .00; WT Δ = -1.6 + 0.7; P = .04) were comparable between groups and retained after 4 months. Satisfaction was higher after BATRAC than DMTE (P = .003). BATRAC led to significantly higher increase in activation in ipsilesional precentral, anterior cingulate and postcentral gyri, and supplementary motor area and contralesional superior frontal gyrus (P < .05). Activation change in the latter was correlated with improvement in the WMFT (P = .01).
CONCLUSIONS:
BATRAC is not superior to DMTE, but both rehabilitation programs durably improve motor function for individuals with chronic UE hemiparesis and with varied deficit severity. Adaptations in brain activation are greater after BATRAC than DMTE, suggesting that given similar benefits to motor function, these therapies operate through different mechanisms
The Internal Sequence of the Peptide-Substrate Determines Its N-Terminus Trimming by ERAP1
No full textBackground: Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims N-terminally extended antigenic peptide precursors down to mature antigenic peptides for presentation by major histocompatibility complex (MHC) class I molecules. ERAP1 has unique properties for an aminopeptidase being able to trim peptides in vitro based on their length and the nature of their C-termini. Methodology/Principal Findings: In an effort to better understand the molecular mechanism that ERAP1 uses to trim peptides, we systematically analyzed the enzyme's substrate preferences using collections of peptide substrates. We discovered strong internal sequence preferences of peptide N-terminus trimming by ERAP1. Preferences were only found for positively charged or hydrophobic residues resulting to trimming rate changes by up to 100 fold for single residue substitutions and more than 40,000 fold for multiple residue substitutions for peptides with identical N-termini. Molecular modelling of ERAP1 revealed a large internal cavity that carries a strong negative electrostatic potential and is large enough to accommodate peptides adjacent to the enzyme's active site. This model can readily account for the strong preference for positively charged side chains. Conclusions/Significance: To our knowledge no other aminopeptidase has been described to have such strong preferences for internal residues so distal to the N-terminus. Overall, our findings indicate that the internal sequence of the peptide can affect its trimming by ERAP1 as much as the peptide's length and C-terminus. We therefore propose that ERAP1 recognizes the full length of its peptide-substrate and not just the N- and C- termini. It is possible that ERAP1 trimming preferences influence the rate of generation and the composition of antigenic peptides in vivo.Version of Recor
The importance of pairwork in educational and interdisciplinary initiatives
No full textAn early and prominent employee of Google, Georges Harik, recently made the assertion that pairs working together in startups are 20 times more productive than individuals working alone. The author has also personally experienced the boost of what is here termed pairwork in a university setting during the startup phase of several educational and interdisciplinary initiatives. The paper briefly explores pairwork in the history of technology and constructs both qualitative and little quantitative models of pairwork. The quantitative model under reasonable assumptions easily recovers Harik’s 20x boost. The paper also briefly examines the author’s recent experiences with pairwork in four interdisciplinary and educational initiatives
Goldner, Alfred (Death, 1893-03-19)
No full textAddress: 141 Pleasant St.Age at death: 7 wks.Pg 28/1893/301/MW S/City/Dr. L. A. Querner/Gildehaus/Carthage Rd.Original record filed in drawer labeled 'GOLDBERG-GR'
Study of K* production in tau decay
No full textcomplete author list:
Goldberg M.; Haupt T.; Horwitz N.; Jain V.; Mestayer M.; Moneti G.; Rozen Y.; Rubin P.; Sharma V.; Skwarnicki T.; Thulasidas M.; Zhu G.; Csorna S.; Letson T.; Alexander J.; Artuso M.; Bebek C.; Berkelman K.; Browder T.; Cassel D.; Cheu E.; Coffman D.; Crawford G.; DeWire J.; Drell P.; Ehrlich R.; Galik R.; Garcia-Sciveres M.; Geiser B.; Gittelman B.; Gray S.; Halling A.; Hartill D.; Heltsley B.; Honscheid K.; Kandaswamy J.; Katayama N.; Kreinick D.; Lewis J.; Ludwig G.; Masui J.; Mistry N.; Mevissen J.; Nandi S.; Nordberg E.; O'Grady C.; Peterson D.; Pisharody M.; Riley D.; Sapper M.; Selen M.; Silverman A.; Stone S.; Worden H.; Worris M.; Sadoff A.; Avery P.; Besson D.; Garren L.; Yelton J.; Kinoshita K.; Pipkin F.; Procario M.; Wilson R.; Wolinski J.; Xiao D.; Zhu Y.; Ammar R.; Baringer P.; Coppage D.; Haas P.; Kwak N.; Lam H.; Ro S.; Kubota Y.; Nelson J.; Perticone D.; Poling R.; Fulton R.; Jensen T.; Johnson D.; Kagan H.; Kass R.; Morrow F.; Whitmore J.; Wilson P.; Bortoletto D.; Chen W.; Dominick J.; McIlwain R.; Miller D.; Ng C.; Schaffner S.; Shibata E.; Shipsey I.; Yao W.; Sparks K.; Thorndike E.; Wang C.; Alam M.; Kim I.; Li W.; Romero V.; Sun C.; Wang P.; Zoeller M.; Goldberg M.; Zoeller M.; Goldberg M
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