Apsidal Motion of the Massive, Benchmark Eclipsing Binary V578 Mon

V578 Mon is a system of two early B-type stars in the Rosette Nebula star-forming region (NGC 2244), and is one of only nine eclipsing binaries with component masses greater than 10 M\odot whose physical parameters have been determined with an accuracy of better than 3%. It is therefore a benchmark system for evolutionary and stellar structure models of newly formed massive stars. Combining our multi-band light curves spanning 40 yr with previous light curve data from the literature, we fit a model light curve that for the first time includes the effects of apsidal motion of the system. We measure an apsidal period of 33.48+0.10-0.06 yr. As a consequence of incorporating the apsidal motion into the modeling of the system's orbital parameters, we determine an updated eccentricity of e = 0.07755+0.00022-0.00027, which differs significantly from the value previously reported in the literature. Evidently, the inclusion of apsidal motion in the light curve modeling significantly affects the eccentricity determination. Incorporating these key parameters into a comprehensive model of the system's physical parameters-including internal structure constraints- will bring V578 Mon to the next level of benchmark precision and utility.Comment: 17 pages, 7 figures, to appear in the Astronomical Journa

Common activation of canonical Wnt signaling in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is an extremely aggressive malignancy, which carries a dismal prognosis. Activating mutations of the Kras gene are common to the vast majority of human PDA. In addition, recent studies have demonstrated that embryonic signaling pathway such as Hedgehog and Notch are inappropriately upregulated in this disease. The role of another embryonic signaling pathway, namely the canonical Wnt cascade, is still controversial. Here, we use gene array analysis as a platform to demonstrate general activation of the canonical arm of the Wnt pathway in human PDA. Furthermore, we provide evidence for Wnt activation in mouse models of pancreatic cancer. Our results also indicate that Wnt signaling might be activated downstream of Hedgehog signaling, which is an early event in PDA evolution. Wnt inhibition blocked proliferation and induced apoptosis of cultured adenocarcinoma cells, thereby providing evidence to support the development of novel therapeutical strategies for Wnt inhibition in pancreatic adenocarcinoma

No Language-Specific Activation during Linguistic Processing of Observed Actions

It has been suggested that cortical neural systems for language evolved from motor cortical systems, in particular from those fronto-parietal systems responding also to action observation. While previous studies have shown shared cortical systems for action--or action observation--and language, they did not address the question of whether linguistic processing of visual stimuli occurs only within a subset of fronto-parietal areas responding to action observation. If this is true, the hypothesis that language evolved from fronto-parietal systems matching action execution and action observation would be strongly reinforced.We used functional magnetic resonance imaging (fMRI) while subjects watched video stimuli of hand-object-interactions and control photo stimuli of the objects and performed linguistic (conceptual and phonological), and perceptual tasks. Since stimuli were identical for linguistic and perceptual tasks, differential activations had to be related to task demands. The results revealed that the linguistic tasks activated left inferior frontal areas that were subsets of a large bilateral fronto-parietal network activated during action perception. Not a single cortical area demonstrated exclusive--or even simply higher--activation for the linguistic tasks compared to the action perception task.These results show that linguistic tasks do not only share common neural representations but essentially activate a subset of the action observation network if identical stimuli are used. Our findings strongly support the evolutionary hypothesis that fronto-parietal systems matching action execution and observation were co-opted for language, a process known as exaptation

Dissociating Object Directed and Non-Object Directed Action in the Human Mirror System; Implications for Theories of Motor Simulation

Mirror neurons are single cells found in macaque premotor and parietal cortices that are active during action execution and observation. In non-human primates, mirror neurons have only been found in relation to object-directed movements or communicative gestures, as non-object directed actions of the upper limb are not well characterized in non-human primates. Mirror neurons provide important evidence for motor simulation theories of cognition, sometimes referred to as the direct matching hypothesis, which propose that observed actions are mapped onto associated motor schemata in a direct and automatic manner. This study, for the first time, directly compares mirror responses, defined as the overlap between action execution and observation, during object directed and meaningless non-object directed actions. We present functional MRI data that demonstrate a clear dissociation between object directed and non-object directed actions within the human mirror system. A premotor and parietal network was preferentially active during object directed actions, whether observed or executed. Moreover, we report spatially correlated activity across multiple voxels for observation and execution of an object directed action. In contrast to predictions made by motor simulation theory, no similar activity was observed for non-object directed actions. These data demonstrate that object directed and meaningless non-object directed actions are subserved by different neuronal networks and that the human mirror response is significantly greater for object directed actions. These data have important implications for understanding the human mirror system and for simulation theories of motor cognition. Subsequent theories of motor simulation must account for these differences, possibly by acknowledging the role of experience in modulating the mirror response

Therapeutic Rescue of Misfolded Mutants: Validation of Primary High Throughput Screens for Identification of Pharmacoperone Drugs

Functional rescue of misfolded mutant receptors by small non-peptide molecules has been demonstrated. These small, target-specific molecules (pharmacological chaperones or "pharmacoperones") serve as molecular templates, promote correct folding and allow otherwise misfolded mutants to pass the scrutiny of the cellular quality control system (QCS) and be expressed at the plasma membrane (PM) where they function similarly to wild type (WT) proteins. In the case of the gonadotropin releasing hormone receptor (GnRHR), drugs that rescue one mutant typically rescue many mutants, even if the mutations are located at distant sites (extracellular loops, intracellular loops, transmembrane helices). This increases the value of these drugs. These drugs are typically identified, post hoc, from "hits" in screens designed to detect antagonists or agonists. The therapeutic utility of pharmacoperones has been limited due to the absence of screens that enable identification of pharmacoperones per se.We describe a generalizable primary screening approach for pharmacoperone drugs based on measurement of gain of activity in stable HeLa cells stably expressing the mutants of two different model G-protein coupled receptors (GPCRs) (hGnRHR[E(90)K] or hV2R[L(83)Q]). These cells turn off expression of the receptor mutant gene of interest in the presence of tetracycline and its analogs, which provides a convenient means to identify false positives.The methods described and characterized here provide the basis of novel primary screens for pharmacoperones that detect drugs that rescue GPCR mutants of specific receptors. This approach will identify structures that would have been missed in screens that were designed to select only agonists or antagonists. Non-antagonistic pharmacoperones have a therapeutic advantage since they will not compete for endogenous agonists and may not have to be washed out once rescue has occurred and before activation by endogenous or exogenous agonists

Bcl-2 protein family: Implications in vascular apoptosis and atherosclerosis

Apoptosis has been recognized as a central component in the pathogenesis of atherosclerosis, in addition to the other human pathologies such as cancer and diabetes. The pathophysiology of atherosclerosis is complex, involving both apoptosis and proliferation at different phases of its progression. Oxidative modification of lipids and inflammation differentially regulate the apoptotic and proliferative responses of vascular cells during progression of the atherosclerotic lesion. Bcl-2 proteins act as the major regulators of extrinsic and intrinsic apoptosis signalling pathways and more recently it has become evident that they mediate the apoptotic response of vascular cells in response to oxidation and inflammation either in a provocative or an inhibitory mode of action. Here we address Bcl-2 proteins as major therapeutic targets for the treatment of atherosclerosis and underscore the need for the novel preventive and therapeutic interventions against atherosclerosis, which should be designed in the light of molecular mechanisms regulating apoptosis of vascular cells in atherosclerotic lesions

Representation of body identity and body actions in extrastriate body area and ventral premotor cortex

Although inherently linked, body form and body action may be represented in separate neural substrates. Using repetitive transcranial magnetic stimulation in healthy individuals, we show that interference with the extrastriate body area impairs the discrimination of bodily forms, and interference with the ventral premotor cortex impairs the discrimination of bodily actions. This double dissociation suggests that whereas extrastriate body area mainly processes actors' body identity, premotor cortex is crucial for visual discriminations of actions

Retinoid Signaling in Pancreatic Cancer, Injury and Regeneration

Background: Activation of embryonic signaling pathways quiescent in the adult pancreas is a feature of pancreatic cancer (PC). These discoveries have led to the development of novel inhibitors of pathways such as Notch and Hedgehog signaling that are currently in early phase clinical trials in the treatment of several cancer types. Retinoid signaling is also essential for pancreatic development, and retinoid therapy is used successfully in other malignancies such as leukemia, but little is known concerning retinoid signaling in PC. Methodology/Principal Findings: We investigated the role of retinoid signaling in vitro and in vivo in normal pancreas, pancreatic injury, regeneration and cancer. Retinoid signaling is active in occasional cells in the adult pancreas but is markedly augmented throughout the parenchyma during injury and regeneration. Both chemically induced and genetically engineered mouse models of PC exhibit a lack of retinoid signaling activity compared to normal pancreas. As a consequence, we investigated Cellular Retinoid Binding Protein 1 (CRBP1), a key regulator of retinoid signaling known to play a role in breast cancer development, as a potential therapeutic target. Loss, or significant downregulation of CRBP1 was present in 70% of human PC, and was evident in the very earliest precursor lesions (PanIN-1A). However, in vitro gain and loss of function studies and CRBP1 knockout mice suggested that loss of CRBP1 expression alone was not sufficient to induce carcinogenesis or to alter PC sensitivity to retinoid based therapies. Conclusions/Significance: In conclusion, retinoid signalling appears to play a role in pancreatic regeneration and carcinogenesis, but unlike breast cancer, it is not mediated directly by CRBP1

The Resident Assessment Instrument-Minimum Data Set 2.0 quality indicators: a systematic review

BackgroundThe Resident Assessment Instrument-Minimum Data Set (RAI-MDS) 2.0 is designed to collect the minimum amount of data to guide care planning and monitoring for residents in long-term care settings. These data have been used to compute indicators of care quality. Use of the quality indicators to inform quality improvement initiatives is contingent upon the validity and reliability of the indicators. The purpose of this review was to systematically examine published and grey research reports in order to assess the state of the science regarding the validity and reliability of the RAI-MDS 2.0 Quality Indicators (QIs).MethodsWe systematically reviewed the evidence for the validity and reliability of the RAI-MDS 2.0 QIs. A comprehensive literature search identified relevant original research published, in English, prior to December 2008. Fourteen articles and one report examining the validity and/or reliability of the RAI-MDS 2.0 QIs were included.ResultsThe studies fell into two broad categories, those that examined individual quality indicators and those that examined multiple indicators. All studies were conducted in the United States and included from one to a total of 209 facilities. The number of residents included in the studies ranged from 109 to 5758. One study conducted under research conditions examined 38 chronic care QIs, of which strong evidence for the validity of 12 of the QIs was found. In response to these findings, the 12 QIs were recommended for public reporting purposes. However, a number of observational studies (n=13), conducted in &quot;real world&quot; conditions, have tested the validity and/or reliability of individual QIs, with mixed results. Ten QIs have been studied in this manner, including falls, depression, depression without treatment, urinary incontinence, urinary tract infections, weight loss, bedfast, restraint, pressure ulcer, and pain. These studies have revealed the potential for systematic bias in reporting, with under-reporting of some indicators and over-reporting of others.ConclusionEvidence for the reliability and validity of the RAI-MDS QIs remains inconclusive. The QIs provide a useful tool for quality monitoring and to inform quality improvement programs and initiatives. However, caution should be exercised when interpreting the QI results and other sources of evidence of the quality of care processes should be considered in conjunction with QI results.<br /