Glucocorticoid Regulation of Elastin Synthesis in Human Fibroblasts: Down-Regulation in Fibroblasts from Normal Dermis But Not From Keloids

Keloids arise as benign connective tissue masses at sites of injury in genetically predisposed individuals, In addition to excessive collagen accumulation, there is biochemical and histologic evidence of elastic tissue. Previous studies showed that glucocorticoid regulation of collagen synthesis differs in fibroblasts from normal adult dermis and keloids, To define further the abnormal regulation of matrix synthesis in keloid fibroblasts, we examined glucocorticoid regulation of elastin synthesis. The basal level of elastin synthesis was significantly higher in keloid than in normal cells, and hydrocortisone reduced synthesis of elastin and elastin mRNA in normal but not in keloid fibroblasts. We had shown previously that fibroblasts from fetal dermis resembled keloid fibroblasts in glucocorticoid regulation of growth and collagen synthesis. In this study, glucocorticoids failed to down-regulate elastin synthesis in fetal cells that had not differentiated to produce normal levels of elastin, whereas fetal cells with normal elastin production exhibited glucocorticoid down-regulation. Abnormal regulation in keloid cells was independent of cell density and was confined to fibroblasts cultured from the keloid nodule. These findings reinforce the conclusion that a matrix-regulatory pathway is deranged in these focal lesions. Coordinate down-regulation of collagen and elastin by hydrocortisone in normal adult denial fibroblasts and the failure of hydrocortisone to down-regulate synthesis of either protein in keloid cells support the existence of common elements in the regulatory pathways of these two matrix proteins

HabEx polarization ray trace and aberration analysis

The flux difference between a terrestrial exoplanet and a much brighter nearby star creates an enormous optical design challenge for space-based imaging systems. Coronagraphs are designed to block the star’s flux and obtain a high-dynamic-range image of the exoplanet. The contrast of an optical system is calculated using the point spread function (PSF). Contrast quantifies starlight suppression of an imaging system at a given separation of the two objects. Contrast requirements can be as small as 10^(−10) for earth-like planets. This work reports an analysis of the September 2017 Habitable Exoplanet Imaging Mission (HabEx) end-to-end optical system prescription for geometric and polarization aberrations across the 450 to 550 nm channel. The Lyot coronagraph was modeled with a vector vortex charge 6 mask but without adaptive optics (AO) to correct the phase of the Jones pupil. The detector plane irradiance was calculated for three states of the telescope/coronagraph system: (1) free of geometric and polarization aberrations; (2) isotropic mirror coatings throughout the end-toend system; and (3) isotropic mirrors with form birefringence on the primary mirror. For each of these three states the system response both with and without a coronagraph mask was calculated. Two merit functions were defined to quantify the system’s ability to attenuate starlight: (1) normalized polychromatic irradiance (NPI), and (2) starlight suppression factor (SSF). Both of these are dimensionless and their values are functions of position across the focal plane. The NPI is defined as the irradiance point-by-point across the detector plane with a coronagraph mask divided by the value of the on-axis irradiance without a coronagraph mask. The SSF is the irradiance point-by-point across the detector plane with a coronagraph mask divided by the pointby-point value of the irradiance across the detector plane without a coronagraph mask. Both the NPI and the SSF provide insights into coronagraph performance. Deviations from the aberration-free case are calculated and summarized in table 2. The conclusions are: (1) the HabEx optical system is well-balanced for both geometric and polarization aberrations; (2) the spatially dependent polarization reflectivity for the HabEx primary mirror should be specified to ensure the coating is isotropic; (3) AO to correct the two orthogonal polarization-dependent wavefront errors is essential

Colours of Bulges and Discs within Galaxy Clusters and the Signature of Disc Fading on Infall

The origins of the bulge and disc components of galaxies are of primary importance to understanding galaxy formation. Here bulge–disc decomposition is performed simultaneously in B and R bands for 922 bright galaxies in eight nearby (z \u3c 0.06) clusters with deep redshift coverage using photometry from the National Optical Astronomy Observatory (NOAO) Fundamental Plane Survey. The total galaxy colours follow a universal colour–magnitude relation (CMR). The discs of L* galaxies are 0.24 mag bluer in B−R than bulges. Bulges have a significant CMR slope while the CMR slope of discs is flat. Thus the slope of the CMR of the total light is driven primarily (60 per cent) by the bulge CMR, and to a lesser extent (40 per cent) by the change in the bulge‐to‐total ratio as a function of magnitude. The colours of the bulge and disc components do not depend on the bulge‐to‐total ratio, for galaxies with bulge‐to‐total ratios greater than 0.2. While the colours of the bulge components do not depend significantly on environment, the median colours of discs vary significantly, with discs in the cluster centre redder by 0.10 mag than those at the virial radius. Thus while star formation in bulges appears to be regulated primarily by mass‐dependent, and hence presumably internal, processes, that of discs is affected by the cluster environment

Sequential Extensions of Causal and Evidential Decision Theory

Moving beyond the dualistic view in AI where agent and environment are separated incurs new challenges for decision making, as calculation of expected utility is no longer straightforward. The non-dualistic decision theory literature is split between causal decision theory and evidential decision theory. We extend these decision algorithms to the sequential setting where the agent alternates between taking actions and observing their consequences. We find that evidential decision theory has two natural extensions while causal decision theory only has one.Comment: ADT 201

Regulation of Peroxisome Proliferator-Activated Receptors by E6-Associated Protein

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors (NRs) that regulate genes involved in lipid and glucose metabolism. PPAR activity is regulated by interactions with cofactors and of interest are cofactors with ubiquitin ligase activity. The E6-associated protein (E6-AP) is an E3 ubiquitin ligase that affects the activity of other NRs, although its effects on PPARs have not been examined. E6-AP inhibited the ligand-independent transcriptional activity of PPARα and PPARβ, with marginal effects on PPARγ, and decreased basal mRNA levels of PPARα target genes. Inhibition of PPARα activity required the ubiquitin ligase function of E6-AP, but occurred in a proteasome-independent manner. PPARα interacted with E6-AP, and in mice treated with PPARα agonist clofibrate, mRNA and protein levels of E6-AP were increased in wildtype, but not in PPARα null mice, indicating a PPARα-dependent regulation. These studies suggest coordinate regulation of E6-AP and PPARα, and contribute to our understanding of the role of PPARs in cellular metabolism

DEAD-Box Helicase Proteins Disrupt RNA Tertiary Structure Through Helix Capture

DEAD-box helicase proteins accelerate folding and rearrangements of highly structured RNAs and RNA–protein complexes (RNPs) in many essential cellular processes. Although DEAD-box proteins have been shown to use ATP to unwind short RNA helices, it is not known how they disrupt RNA tertiary structure. Here, we use single molecule fluorescence to show that the DEAD-box protein CYT-19 disrupts tertiary structure in a group I intron using a helix capture mechanism. CYT-19 binds to a helix within the structured RNA only after the helix spontaneously loses its tertiary contacts, and then CYT-19 uses ATP to unwind the helix, liberating the product strands. Ded1, a multifunctional yeast DEAD-box protein, gives analogous results with small but reproducible differences that may reflect its in vivo roles. The requirement for spontaneous dynamics likely targets DEAD-box proteins toward less stable RNA structures, which are likely to experience greater dynamic fluctuations, and provides a satisfying explanation for previous correlations between RNA stability and CYT-19 unfolding efficiency. Biologically, the ability to sense RNA stability probably biases DEAD-box proteins to act preferentially on less stable misfolded structures and thereby to promote native folding while minimizing spurious interactions with stable, natively folded RNAs. In addition, this straightforward mechanism for RNA remodeling does not require any specific structural environment of the helicase core and is likely to be relevant for DEAD-box proteins that promote RNA rearrangements of RNP complexes including the spliceosome and ribosome

Independent evaluation of a simple clinical prediction rule to identify right ventricular dysfunction in patients with shortness of breath

BACKGROUND: Many patients have unexplained persistent dyspnea after negative computed tomographic pulmonary angiography (CTPA). We hypothesized that many of these patients have isolated right ventricular (RV) dysfunction from treatable causes. We previously derived a clinical decision rule (CDR) for predicting RV dysfunction consisting of persistent dyspnea and normal CTPA, finding that 53% of CDR-positive patients had isolated RV dysfunction. Our goal is to validate this previously derived CDR by measuring the prevalence of RV dysfunction and outcomes in dyspneic emergency department patients. METHODS: A secondary analysis of a prospective observational multicenter study that enrolled patients presenting with suspected PE was performed. We included patients with persistent dyspnea, a nonsignificant CTPA, and formal echo performed. Right ventricular dysfunction was defined as RV hypokinesis and/or dilation with or without moderate to severe tricuspid regurgitation. RESULTS: A total of 7940 patients were enrolled. Two thousand six hundred sixteen patients were analyzed after excluding patients without persistent dyspnea and those with a significant finding on CTPA. One hundred ninety eight patients had echocardiography performed as standard care. Of those, 19% (95% confidence interval [CI], 14%-25%) and 33% (95% CI, 25%-42%) exhibited RV dysfunction and isolated RV dysfunction, respectively. Patients with isolated RV dysfunction or overload were more likely than those without RV dysfunction to have a return visit to the emergency department within 45 days for the same complaint (39% vs 18%; 95% CI of the difference, 4%-38%). CONCLUSION: This simple clinical prediction rule predicted a 33% prevalence of isolated RV dysfunction or overload. Patients with isolated RV dysfunction had higher recidivism rates and a trend toward worse outcomes

Ordered Assembly of the Adhesive and Electrochemical Connections within Newly Formed Intercalated Disks in Primary Cultures of Adult Rat Cardiomyocytes

The intercalated disk (ID) is a complex structure that electromechanically couples adjoining cardiac myocytes into a functional syncitium. The integrity of the disk is essential for normal cardiac function, but how the diverse elements are assembled into a fully integrated structure is not well understood. In this study, we examined the assembly of new IDs in primary cultures of adult rat cardiac myocytes. From 2 to 5 days after dissociation, the cells flatten and spread, establishing new cell-cell contacts in a manner that recapitulates the in vivo processes that occur during heart development and myocardial remodeling. As cells make contact with their neighbors, transmembrane adhesion proteins localize along the line of apposition, concentrating at the sites of membrane attachment of the terminal sarcomeres. Cx43 gap junctions and ankyrin-G, an essential cytoskeletal component of voltage gated sodium channel complexes, were secondarily recruited to membrane domains involved in cell-cell contacts. The consistent order of the assembly process suggests that there are specific scaffolding requirements for integration of the mechanical and electrochemical elements of the disk. Defining the relationships that are the foundation of disk assembly has important implications for understanding the mechanical dysfunction and cardiac arrhythmias that accompany alterations of ID architecture

Shared decision making in patients with low risk chest pain: prospective randomized pragmatic trial.

OBJECTIVE: To compare the effectiveness of shared decision making with usual care in choice of admission for observation and further cardiac testing or for referral for outpatient evaluation in patients with possible acute coronary syndrome. DESIGN: Multicenter pragmatic parallel randomized controlled trial. SETTING: Six emergency departments in the United States. PARTICIPANTS: 898 adults (aged \u3e17 years) with a primary complaint of chest pain who were being considered for admission to an observation unit for cardiac testing (451 were allocated to the decision aid and 447 to usual care), and 361 emergency clinicians (emergency physicians, nurse practitioners, and physician assistants) caring for patients with chest pain. INTERVENTIONS: Patients were randomly assigned (1:1) by an electronic, web based system to shared decision making facilitated by a decision aid or to usual care. The primary outcome, selected by patient and caregiver advisers, was patient knowledge of their risk for acute coronary syndrome and options for care; secondary outcomes were involvement in the decision to be admitted, proportion of patients admitted for cardiac testing, and the 30 day rate of major adverse cardiac events. RESULTS: Compared with the usual care arm, patients in the decision aid arm had greater knowledge of their risk for acute coronary syndrome and options for care (questions correct: decision aid, 4.2 v usual care, 3.6; mean difference 0.66, 95% confidence interval 0.46 to 0.86), were more involved in the decision (observing patient involvement scores: decision aid, 18.3 v usual care, 7.9; 10.3, 9.1 to 11.5), and less frequently decided with their clinician to be admitted for cardiac testing (decision aid, 37% v usual care, 52%; absolute difference 15%; P CONCLUSIONS: Use of a decision aid in patients at low risk for acute coronary syndrome increased patient knowledge about their risk, increased engagement, and safely decreased the rate of admission to an observation unit for cardiac testing.Trial registration ClinicalTrials.gov NCT01969240

HabEx polarization ray trace and aberration analysis

The flux difference between a terrestrial exoplanet and a much brighter nearby star creates an enormous optical design challenge for space-based imaging systems. Coronagraphs are designed to block the star’s flux and obtain a high-dynamic-range image of the exoplanet. The contrast of an optical system is calculated using the point spread function (PSF). Contrast quantifies starlight suppression of an imaging system at a given separation of the two objects. Contrast requirements can be as small as 10^(−10) for earth-like planets. This work reports an analysis of the September 2017 Habitable Exoplanet Imaging Mission (HabEx) end-to-end optical system prescription for geometric and polarization aberrations across the 450 to 550 nm channel. The Lyot coronagraph was modeled with a vector vortex charge 6 mask but without adaptive optics (AO) to correct the phase of the Jones pupil. The detector plane irradiance was calculated for three states of the telescope/coronagraph system: (1) free of geometric and polarization aberrations; (2) isotropic mirror coatings throughout the end-toend system; and (3) isotropic mirrors with form birefringence on the primary mirror. For each of these three states the system response both with and without a coronagraph mask was calculated. Two merit functions were defined to quantify the system’s ability to attenuate starlight: (1) normalized polychromatic irradiance (NPI), and (2) starlight suppression factor (SSF). Both of these are dimensionless and their values are functions of position across the focal plane. The NPI is defined as the irradiance point-by-point across the detector plane with a coronagraph mask divided by the value of the on-axis irradiance without a coronagraph mask. The SSF is the irradiance point-by-point across the detector plane with a coronagraph mask divided by the pointby-point value of the irradiance across the detector plane without a coronagraph mask. Both the NPI and the SSF provide insights into coronagraph performance. Deviations from the aberration-free case are calculated and summarized in table 2. The conclusions are: (1) the HabEx optical system is well-balanced for both geometric and polarization aberrations; (2) the spatially dependent polarization reflectivity for the HabEx primary mirror should be specified to ensure the coating is isotropic; (3) AO to correct the two orthogonal polarization-dependent wavefront errors is essential