115 research outputs found
Frequency Tracking and Parameter Estimation for Robust Quantum State-Estimation
In this paper we consider the problem of tracking the state of a quantum
system via a continuous measurement. If the system Hamiltonian is known
precisely, this merely requires integrating the appropriate stochastic master
equation. However, even a small error in the assumed Hamiltonian can render
this approach useless. The natural answer to this problem is to include the
parameters of the Hamiltonian as part of the estimation problem, and the full
Bayesian solution to this task provides a state-estimate that is robust against
uncertainties. However, this approach requires considerable computational
overhead. Here we consider a single qubit in which the Hamiltonian contains a
single unknown parameter. We show that classical frequency estimation
techniques greatly reduce the computational overhead associated with Bayesian
estimation and provide accurate estimates for the qubit frequencyComment: 6 figures, 13 page
Focal adhesion kinase is essential for cardiac looping and multichamber heart formation
Focal adhesion kinase (FAK) is a critical mediator of matrix- and growth factor-induced signaling during development. Myocyte-restricted FAK deletion in mid-gestation mice results in impaired ventricular septation and cardiac compaction. However, whether FAK regulates early cardiogenic steps remains unknown. To explore a role for FAK in multi-chambered heart formation, we utilized anti-sense morpholinos to deplete FAK in Xenopus laevis. Xenopus FAK morphants exhibited impaired cardiogenesis, pronounced pericardial edema, and lethality by tadpole stages. Spatial-temporal assessment of cardiac marker gene expression revealed that FAK was not necessary for midline migration, differentiation, fusion of cardiac precursors, or linear heart tube formation. However, myocyte proliferation was significantly reduced in FAK morphant heart tubes and these tubes failed to undergo proper looping morphogenesis. Collectively our data imply that FAK plays an essential role in chamber outgrowth and looping morphogenesis likely stimulated by fibroblast growth factors (and possibly other) cardiotrophic factors
Adhesion Stimulates Direct PAK1/ERK2 Association and Leads to ERK-dependent PAK1 Thr 212 Phosphorylation
The Rac1/Cdc42 effector p21-activated kinase (PAK) is activated by various signaling cascades including receptor-tyrosine kinases and integrins and regulates a number of processes such as cell proliferation and motility. PAK activity has been shown to be required for maximal activation of the canonical Ras/Raf/MEK/ERK Map kinase signaling cascade, likely because of PAK co-activation of Raf and MEK. Herein, we found that adhesion signaling also stimulates an association between PAK1 and ERK1/2. PAK1 and ERK1/2 co-immunoprecipitated from rat aortic smooth muscle cells (SMC) plated on fibronectin, and the two proteins co-localized in membrane ruffles and adhesion complexes following PDGF-BB or sphingosine 1-phosphate treatment, respectively. Far Western analysis demonstrated a direct association between the two proteins, and peptide mapping identified an ERK2 binding site within the autoinhibitory domain of PAK1. Interestingly, deletion of a major ERK binding site in PAK attenuates activation of an ERK-dependent serum-responsive element (SRE)-luciferase reporter gene, indicating that association between PAK and ERK is required to facilitate ERK signaling. We also show that ERK2 phosphorylates PAK1 on Thr(212) in vitro and that Thr(212) is phosphorylated in smooth muscle cells following PDGF-BB treatment in an adhesion- and MEK/ERK-dependent fashion. Expression of a phosphomimic variant, PAK-T212E, does not alter ERK association, but markedly attenuates downstream ERK signaling. Taken together, these data suggest that PAK1 may facilitate ERK signaling by serving as a scaffold to recruit Raf, MEK, and ERK to adhesion complexes, and that subsequent growth factor-stimulated phosphorylation of PAK-Thr(212) by ERK may serve to provide a negative feedback signal to control coordinate activation of ERK by growth factor- and matrix-induced signals
Phenology largely explains taller grass at successful nests in greater sage-grouse
Much interest lies in the identification of manageable habitat variables that affect key vital rates for species of concern. For ground-nesting birds, vegetation surrounding the nest may play an important role in mediating nest success by providing concealment from predators. Height of grasses surrounding the nest is thought to be a driver of nest survival in greater sage-grouse (Centrocercus urophasianus; sage-grouse), a species that has experienced widespread population declines throughout their range. However, a growing body of the literature has found that widely used field methods can produce misleading inference on the relationship between grass height and nest success. Specifically, it has been demonstrated that measuring concealment following nest fate (failure or hatch) introduces a temporal bias whereby successful nests are measured later in the season, on average, than failed nests. This sampling bias can produce inference suggesting a positive effect of grass height on nest survival, though the relationship arises due to the confounding effect of plant phenology, not an effect on predation risk. To test the generality of this finding for sage-grouse, we reanalyzed existing datasets comprising \u3e800 sage-grouse nests from three independent studies across the range where there was a positive relationship found between grass height and nest survival, including two using methods now known to be biased. Correcting for phenology produced equivocal relationships between grass height and sage-grouse nest survival. Viewed in total, evidence for a ubiquitous biological effect of grass height on sage-grouse nest success across time and space is lacking. In light of these findings, a reevaluation of land management guidelines emphasizing specific grass height targets to promote nest success may be merited
Skeletal Muscle Differentiation and Fusion Are Regulated by the BAR-containing Rho-GTPase-activating Protein (Rho-GAP), GRAF1
Although RhoA activity is necessary for promoting myogenic mesenchymal stem cell fates, recent studies in cultured cells suggest that down-regulation of RhoA activity in specified myoblasts is required for subsequent differentiation and myotube formation. However, whether this phenomenon occurs in vivo and which Rho modifiers control these later events remain unclear. We found that expression of the Rho-GTPase-activating protein, GRAF1, was transiently up-regulated during myogenesis, and studies in C2C12 cells revealed that GRAF1 is necessary and sufficient for mediating RhoA down-regulation and inducing muscle differentiation. Moreover, forced expression of GRAF1 in pre-differentiated myoblasts drives robust muscle fusion by a process that requires GTPase-activating protein-dependent actin remodeling and BAR-dependent membrane binding or sculpting. Moreover, morpholino-based knockdown studies in Xenopus laevis determined that GRAF1 expression is critical for muscle development. GRAF1-depleted embryos exhibited elevated RhoA activity and defective myofibrillogenesis that resulted in progressive muscle degeneration, defective motility, and embryonic lethality. Our results are the first to identify a GTPase-activating protein that regulates muscle maturation and to highlight the functional importance of BAR domains in myotube formation
Myocyte-Restricted Focal Adhesion Kinase Deletion Attenuates Pressure Overload-Induced Hypertrophy
Focal adhesion kinase (FAK) is a ubiquitously expressed cytoplasmic tyrosine kinase strongly activated by integrins and neurohumoral factors. Previous studies have shown that cardiac FAK activity is enhanced by hypertrophic stimuli before the onset of overt hypertrophy. Herein, we report that conditional deletion of FAK from the myocardium of adult mice did not affect basal cardiac performance, myocyte viability, or myofibrillar architecture. However, deletion of FAK abolished the increase in left ventricular posterior wall thickness, myocyte cross-sectional area, and hypertrophy-associated atrial natriuretic factor induction following pressure overload. Myocyte-restricted deletion of FAK attenuated the initial wave of extracellular signal-regulated kinase activation and cFos expression induced by adrenergic agonists and biomechanical stress. In addition, we found that persistent challenge of mice with myocyte-restricted FAK inactivation leads to enhanced cardiac fibrosis and cardiac dysfunction in comparison to challenged genetic controls. These studies show that loss of FAK impairs normal compensatory hypertrophic remodeling without a concomitant increase in apoptosis in response to cardiac pressure overload and highlight the possibility that FAK activation may be a common requirement for the initiation of this compensatory response
Introductory programming: a systematic literature review
As computing becomes a mainstream discipline embedded in the school curriculum and acts as an enabler for an increasing range of academic disciplines in higher education, the literature on introductory programming is growing. Although there have been several reviews that focus on specific aspects of introductory programming, there has been no broad overview of the literature exploring recent trends across the breadth of introductory programming.
This paper is the report of an ITiCSE working group that conducted a systematic review in order to gain an overview of the introductory programming literature. Partitioning the literature into papers addressing the student, teaching, the curriculum, and assessment, we explore trends, highlight advances in knowledge over the past 15 years, and indicate possible directions for future research
LSST: from Science Drivers to Reference Design and Anticipated Data Products
(Abridged) We describe here the most ambitious survey currently planned in
the optical, the Large Synoptic Survey Telescope (LSST). A vast array of
science will be enabled by a single wide-deep-fast sky survey, and LSST will
have unique survey capability in the faint time domain. The LSST design is
driven by four main science themes: probing dark energy and dark matter, taking
an inventory of the Solar System, exploring the transient optical sky, and
mapping the Milky Way. LSST will be a wide-field ground-based system sited at
Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m
effective) primary mirror, a 9.6 deg field of view, and a 3.2 Gigapixel
camera. The standard observing sequence will consist of pairs of 15-second
exposures in a given field, with two such visits in each pointing in a given
night. With these repeats, the LSST system is capable of imaging about 10,000
square degrees of sky in a single filter in three nights. The typical 5
point-source depth in a single visit in will be (AB). The
project is in the construction phase and will begin regular survey operations
by 2022. The survey area will be contained within 30,000 deg with
, and will be imaged multiple times in six bands, ,
covering the wavelength range 320--1050 nm. About 90\% of the observing time
will be devoted to a deep-wide-fast survey mode which will uniformly observe a
18,000 deg region about 800 times (summed over all six bands) during the
anticipated 10 years of operations, and yield a coadded map to . The
remaining 10\% of the observing time will be allocated to projects such as a
Very Deep and Fast time domain survey. The goal is to make LSST data products,
including a relational database of about 32 trillion observations of 40 billion
objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures
available from https://www.lsst.org/overvie
Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer
Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance
Loss of interferon regulatory factor 5 (IRF5) expression in human ductal carcinoma correlates with disease stage and contributes to metastasis
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