2,086 research outputs found
Influence of phosphorylation on isoform composition and function of a microtubule-associated protein from developing Artemia
Structural insights into RNA processing by the human RISC-loading complex.
Targeted gene silencing by RNA interference (RNAi) requires loading of a short guide RNA (small interfering RNA (siRNA) or microRNA (miRNA)) onto an Argonaute protein to form the functional center of an RNA-induced silencing complex (RISC). In humans, Argonaute2 (AGO2) assembles with the guide RNA-generating enzyme Dicer and the RNA-binding protein TRBP to form a RISC-loading complex (RLC), which is necessary for efficient transfer of nascent siRNAs and miRNAs from Dicer to AGO2. Here, using single-particle EM analysis, we show that human Dicer has an L-shaped structure. The RLC Dicer's N-terminal DExH/D domain, located in a short 'base branch', interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. A model generated by docking the available atomic structures of Dicer and Argonaute homologs into the RLC reconstruction suggests a mechanism for siRNA transfer from Dicer to AGO2
Spontaneous Gender Categorization in Masking and Priming Studies: Key for Distinguishing Jane from John Doe but Not Madonna from Sinatra
Facial recognition is key to social interaction, however with unfamiliar faces only generic information, in the form of facial stereotypes such as gender and age is available. Therefore is generic information more prominent in unfamiliar versus familiar face processing? In order to address the question we tapped into two relatively disparate stages of face processing. At the early stages of encoding, we employed perceptual masking to reveal that only perception of unfamiliar face targets is affected by the gender of the facial masks. At the semantic end; using a priming paradigm, we found that while to-be-ignored unfamiliar faces prime lexical decisions to gender congruent stereotypic words, familiar faces do not. Our findings indicate that gender is a more salient dimension in unfamiliar relative to familiar face processing, both in early perceptual stages as well as later semantic stages of person construal
Use cases, best practice and reporting standards for metabolomics in regulatory toxicology
Metabolomics is a widely used technology in academic research, yet its application to regulatory science has been limited. The most commonly cited barrier to its translation is lack of performance and reporting standards. The MEtabolomics standaRds Initiative in Toxicology (MERIT) project brings together international experts from multiple sectors to address this need. Here, we identify the most relevant applications for metabolomics in regulatory toxicology and develop best practice guidelines, performance and reporting standards for acquiring and analysing untargeted metabolomics and targeted metabolite data. We recommend that these guidelines are evaluated and implemented for several regulatory use cases
Impact of age norms and stereotypes on managers' hiring decisions of retirees
Purpose -Our study investigates the role of managers in the re-employment of early retirees and asks what the effect is of managers’ age norms and stereotypes on managers’ employment decisions.
Design/methodology/approach- A combination of a factorial study and a survey was conducted. First, information on the age norms and stereotypes was collected. Secondly, profiles of hypothetical retired job applicants were presented to the employers, who were asked to make a specific hiring decision. The information collected during both studies was combined in the analysis and multilevel models were estimated.
Findings -The results indicate that higher age norms result in a higher propensity to hire an early retiree. Stereotypes, by contrast, do not influence managers’ decisions. Early retirees’ chances for re-employment are also related to their own circumstances (physical appearance and relevant experience) and organisational forces, as they are hired when organisations face labour force shortages.
Research limitation / implications – with the use of vignettes study we deal with hypothetical hiring situation.
Originality value- Although the effect of age norms and age stereotypes has been often suggested, not much empirical evidence was presented to support this notion. Our study estimates the effect of age norms and stereotypes on hiring decision.
key words: bridge employment; early retirees; age norms; age stereotypes; multilevel models.
Enhanced insulin sensitivity associated with provision of mono and polyunsaturated fatty acids in skeletal muscle cells involves counter modulation of PP2A
International audienceAims/Hypothesis: Reduced skeletal muscle insulin sensitivity is a feature associated with sustained exposure to excess saturated fatty acids (SFA), whereas mono and polyunsaturated fatty acids (MUFA and PUFA) not only improve insulin sensitivity but blunt SFA-induced insulin resistance. The mechanisms by which MUFAs and PUFAs institute these favourable changes remain unclear, but may involve stimulating insulin signalling by counter-modulation/repression of protein phosphatase 2A (PP2A). This study investigated the effects of oleic acid (OA; a MUFA), linoleic acid (LOA; a PUFA) and palmitate (PA; a SFA) in cultured myotubes and determined whether changes in insulin signalling can be attributed to PP2A regulation. Principal Findings: We treated cultured skeletal myotubes with unsaturated and saturated fatty acids and evaluated insulin signalling, phosphorylation and methylation status of the catalytic subunit of PP2A. Unlike PA, sustained incubation of rat or human myotubes with OA or LOA significantly enhanced Akt-and ERK1/2-directed insulin signalling. This was not due to heightened upstream IRS1 or PI3K signalling nor to changes in expression of proteins involved in proximal insulin signalling, but was associated with reduced dephosphorylation/inactivation of Akt and ERK1/2. Consistent with this, PA reduced PP2Ac demethylation and tyrosine 307 phosphorylation-events associated with PP2A activation. In contrast, OA and LOA strongly opposed these PA-induced changes in PP2Ac thus exerting a repressive effect on PP2A.Conclusions/Interpretation: Beneficial gains in insulin sensitivity and the ability of unsaturated fatty acids to oppose palmitate-induced insulin resistance in muscle cells may partly be accounted for by counter-modulation of PP2A
From wormhole to time machine: Comments on Hawking's Chronology Protection Conjecture
The recent interest in ``time machines'' has been largely fueled by the
apparent ease with which such systems may be formed in general relativity,
given relatively benign initial conditions such as the existence of traversable
wormholes or of infinite cosmic strings. This rather disturbing state of
affairs has led Hawking to formulate his Chronology Protection Conjecture,
whereby the formation of ``time machines'' is forbidden. This paper will use
several simple examples to argue that the universe appears to exhibit a
``defense in depth'' strategy in this regard. For appropriate parameter regimes
Casimir effects, wormhole disruption effects, and gravitational back reaction
effects all contribute to the fight against time travel. Particular attention
is paid to the role of the quantum gravity cutoff. For the class of model
problems considered it is shown that the gravitational back reaction becomes
large before the Planck scale quantum gravity cutoff is reached, thus
supporting Hawking's conjecture.Comment: 43 pages,ReV_TeX,major revision
Regularizing Portfolio Optimization
The optimization of large portfolios displays an inherent instability to
estimation error. This poses a fundamental problem, because solutions that are
not stable under sample fluctuations may look optimal for a given sample, but
are, in effect, very far from optimal with respect to the average risk. In this
paper, we approach the problem from the point of view of statistical learning
theory. The occurrence of the instability is intimately related to over-fitting
which can be avoided using known regularization methods. We show how
regularized portfolio optimization with the expected shortfall as a risk
measure is related to support vector regression. The budget constraint dictates
a modification. We present the resulting optimization problem and discuss the
solution. The L2 norm of the weight vector is used as a regularizer, which
corresponds to a diversification "pressure". This means that diversification,
besides counteracting downward fluctuations in some assets by upward
fluctuations in others, is also crucial because it improves the stability of
the solution. The approach we provide here allows for the simultaneous
treatment of optimization and diversification in one framework that enables the
investor to trade-off between the two, depending on the size of the available
data set
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