Shc depletion stimulates brown fat activity in vivo and in vitro.

Adipose tissue is an important metabolic organ that integrates a wide array of homeostatic processes and is crucial for whole-body insulin sensitivity and energy metabolism. Brown adipose tissue (BAT) is a key thermogenic tissue with a well-established role in energy expenditure. BAT dissipates energy and protects against both hypothermia and obesity. Thus, BAT stimulation therapy is a rational strategy for the looming pandemic of obesity, whose consequences and comorbidities have a huge impact on the aged. Shc-deficient mice (ShcKO) were previously shown to be lean, insulin sensitive, and resistant to high-fat diet and obesity. We investigated the contribution of BAT to this phenotype. Insulin-dependent BAT glucose uptake was higher in ShcKO mice. Primary ShcKO BAT cells exhibited increased mitochondrial respiration; increased expression of several mitochondrial and lipid-oxidative enzymes was observed in ShcKO BAT. Levels of brown fat-specific markers of differentiation, UCP1, PRDM16, ELOVL3, and Cox8b, were higher in ShcKO BAT. In vitro, Shc knockdown in BAT cell line increased insulin sensitivity and metabolic activity. In vivo, pharmacological stimulation of ShcKO BAT resulted in higher energy expenditure. Conversely, pharmacological inhibition of BAT abolished the improved metabolic parameters, that is the increased insulin sensitivity and glucose tolerance of ShcKO mice. Similarly, in vitro Shc knockdown in BAT cell lines increased their expression of UCP1 and metabolic activity. These data suggest increased BAT activity significantly contributes to the improved metabolic phenotype of ShcKO mice

Endurance of SN 2005ip after a decade: X-rays, radio, and H-alpha like SN 1988Z require long-lived pre-supernova mass loss

SN2005ip was a TypeIIn event notable for its sustained strong interaction with circumstellar material (CSM), coronal emission lines, and IR excess, interpreted as shock interaction with the very dense and clumpy wind of an extreme red supergiant. We present a series of late-time spectra of SN2005ip and a first radio detection of this SN, plus late-time X-rays, all of which indicate that its CSM interaction is still strong a decade post-explosion. We also present and discuss new spectra of geriatric SNe with continued CSM interaction: SN1988Z, SN1993J, and SN1998S. From 3-10 yr post-explosion, SN2005ip's H-alpha luminosity and other observed characteristics were nearly identical to those of the radio-luminous SN1988Z, and much more luminous than SNe1993J and 1998S. At 10 yr after explosion, SN2005ip showed a drop in H$\alpha$ luminosity, followed by a quick resurgence over several months. We interpret this variability as ejecta crashing into a dense shell located at around 0.05 pc from the star, which may be the same shell that caused the IR echo at earlier epochs. The extreme H-alpha luminosities in SN2005ip and SN1988Z are still dominated by the forward shock at 10 yr post-explosion, whereas SN1993J and SN1998S are dominated by the reverse shock at a similar age. Continuous strong CSM interaction in SNe~2005ip and 1988Z is indicative of enhanced mass loss for about 1e3 yr before core collapse, longer than Ne, O, or Si burning phases. Instead, the episodic mass loss must extend back through C burning and perhaps even part of He burning.Comment: 14 pages, 8 figs. accepted in MNRA

SN2013fs and SN2013fr: Exploring the circumstellar-material diversity in Type II supernovae

We present photometry and spectroscopy of SN2013fs and SN2013fr in the first 100 days post-explosion. Both objects showed transient, relatively narrow H$\alpha$ emission lines characteristic of SNeIIn, but later resembled normal SNeII-P or SNeII-L, indicative of fleeting interaction with circumstellar material (CSM). SN2013fs was discovered within 8hr of explosion. Its light curve exhibits a plateau, with spectra revealing strong CSM interaction at early times. It is a less luminous version of the transitional SNIIn PTF11iqb, further demonstrating a continuum of CSM interaction intensity between SNeII-P and IIn. It requires dense CSM within 6.5$\times$10$^{14}$~cm of the progenitor, from a phase of advanced pre-SN mass loss shortly before explosion. Spectropolarimetry of SN2013fs shows little continuum polarization, but noticeable line polarization during the plateau phase. SN2013fr morphed from a SNIIn at early times to a SNII-L. After the first epoch its narrow lines probably arose from host-galaxy emission, but the bright, narrow H$\alpha$ emission at early times may be intrinsic. As for SN2013fs, this would point to a short-lived phase of strong CSM interaction if proven to be intrinsic, suggesting a continuum between SNeIIn and II-L. It is a low-velocity SNII-L, like SN2009kr but more luminous. SN2013fr also developed an IR excess at later times, due to warm CSM dust that require a more sustained phase of strong pre-SN mass loss.Comment: MNRAS accepted. 28 pages, 23 figures, 8 table

Deletion of the Basement Membrane Heparan Sulfate Proteoglycan Type XVIII Collagen Causes Hypertriglyceridemia in Mice and Humans

Background: Lipoprotein lipase (Lpl) acts on triglyceride-rich lipoproteins in the peripheral circulation, liberating free fatty acids for energy metabolism or storage. This essential enzyme is synthesized in parenchymal cells of adipose tissue, heart, and skeletal muscle and migrates to the luminal side of the vascular endothelium where it acts upon circulating lipoproteins. Prior studies suggested that Lpl is immobilized by way of heparan sulfate proteoglycans on the endothelium, but genetically altering endothelial cell heparan sulfate had no effect on Lpl localization or lipolysis. The objective of this study was to determine if extracellular matrix proteoglycans affect Lpl distribution and triglyceride metabolism. Methods and Findings: We examined mutant mice defective in collagen XVIII (Col18), a heparan sulfate proteoglycan present in vascular basement membranes. Loss of Col18 reduces plasma levels of Lpl enzyme and activity, which results in mild fasting hypertriglyceridemia and diet-induced hyperchylomicronemia. Humans with Knobloch Syndrome caused by a null mutation in the vascular form of Col18 also present lower than normal plasma Lpl mass and activity and exhibit fasting hypertriglyceridemia. Conclusions: This is the first report demonstrating that Lpl presentation on the lumenal side of the endothelium depends on a basement membrane proteoglycan and demonstrates a previously unrecognized phenotype in patients lacking Col18.National Institute of Health (NIH)[HL087228]National Institute of Health (NIH)[GM33063]National Institute of Health (NIH)[HL67255]CEPID/FAPESPCNPqUniversity of Colorado Denver Department of MedicineLeducq FoundationAmerican Heart Association[0735038N

Combining realist evaluation and transformative evaluation to advance research in palliative care: The case of end of life companionship.

Palliative care requires innovative methods to understand what works, for whom, in what circumstances and why. Realist evaluation has become one prominent approach due to its preoccupation with building, and testing, causal theories to explain the influence of contextual factors on outcomes. Undertaking realist evaluation is not without challenges and may amplify issues of underrepresentation, disempower those working in palliative care, and produce results with poor ecological validity. Complementary approaches are needed which mitigate these challenges, whilst producing credible findings that advances knowledge. In this article it is outlined how realist evaluation provides a toolkit to advance research to explain, and empirically test, the complex contours of palliative care. Moreover, it is proposed that transformative evaluation can provide a catalyst to engage and empower those within palliative care, create the opportunity for care transformation, and produce more informed and authentic theories. Contemporary issues in palliative care pertain to the complexity of palliative care, the insufficiency of experimental designs alone, and the challenges of achieving inclusive research participation. In this article it is argued that theory led, participatory, opportunistic and naturalistic approaches can provide an antidote to the issues in the literature. The combination also mitigates many methodological critiques of the individual approaches, by increasing the transformative potential of realist evaluation, and explanatory potential of transformative evaluation

Combining realist evaluation and transformative evaluation to advance research in palliative care: The case of end of life companionship

Background: Palliative care requires innovative methods to understand what works, for whom, in what circumstances and why. Realist evaluation has become one prominent approach due to its preoccupation with building, and testing, causal theories to explain the influence of contextual factors on outcomes. Undertaking realist evaluation is not without challenges and may amplify issues of underrepresentation, disempower those working in palliative care, and produce results with poor ecological validity. Complementary approaches are needed which mitigate these challenges, whilst producing credible findings that advances knowledge. Purpose: In this article it is outlined how realist evaluation provides a toolkit to advance research to explain, and empirically test, the complex contours of palliative care. Moreover, it is proposed that transformative evaluation can provide a catalyst to engage and empower those within palliative care, create the opportunity for care transformation, and produce more informed and authentic theories. Discussion: Contemporary issues in palliative care pertain to the complexity of palliative care, the insufficiency of experimental designs alone, and the challenges of achieving inclusive research participation. In this article it is argued that theory led, participatory, opportunistic and naturalistic approaches can provide an antidote to the issues in the literature. The combination also mitigates many methodological critiques of the individual approaches, by increasing the transformative potential of realist evaluation, and explanatory potential of transformative evaluation

Investigating harms of testing for ovarian cancer – psychological outcomes and cancer conversion rates in women with symptoms of ovarian cancer:A cohort study embedded in the multicentre ROCkeTS prospective diagnostic study

Objective: To investigate psychological correlates in women referred with suspected ovarian cancer via the fast‐track pathway, explore how anxiety and distress levels change at 12 months post‐testing, and report cancer conversion rates by age and referral pathway. Design: Single‐arm prospective cohort study. Setting: Multicentre. Secondary care including outpatient clinics and emergency admissions. Population: A cohort of 2596 newly presenting symptomatic women with a raised CA125 level, abnormal imaging or both. Methods: Women completed anxiety and distress questionnaires at recruitment and at 12 months for those who had not undergone surgery or a biopsy within 3 months of recruitment. Main outcome measures: Anxiety and distress levels measured using a six‐item short form of the State–Trait Anxiety Inventory (STAI‐6) and the Impact of Event Scale – Revised (IES‐r) questionnaire. Ovarian cancer (OC) conversion rates by age, menopausal status and referral pathway. Results: Overall, 1355/2596 (52.1%) and 1781/2596 (68.6%) experienced moderate‐to‐severe distress and anxiety, respectively, at recruitment. Younger age and emergency presentations had higher distress levels. The clinical category for anxiety and distress remained unchanged/worsened in 76% of respondents at 12 months, despite a non‐cancer diagnosis. The OC rates by age were 1.6% (95% CI 0.5%–5.9%) for ag

Combining realist evaluation and transformative evaluation to advance research in palliative care: The case of end of life companionship

Abstract Background: Palliative care requires innovative methods to understand what works, for whom, in what circumstances and why. Realist evaluation has become one prominent approach due to its preoccupation with building, and testing, causal theories to explain the influence of contextual factors on outcomes. Undertaking realist evaluation is not without challenges and may amplify issues of underrepresentation, disempower those working in palliative care, and produce results with poor ecological validity. Complementary approaches are needed which mitigate these challenges, whilst producing credible findings that advances knowledge. Purpose: In this article it is outlined how realist evaluation provides a toolkit to advance research to explain, and empirically test, the complex contours of palliative care. Moreover, it is proposed that transformative evaluation can provide a catalyst to engage and empower those within palliative care, create the opportunity for care transformation, and produce more informed and authentic theories. Discussion: Contemporary issues in palliative care pertain to the complexity of palliative care, the insufficiency of experimental designs alone, and the challenges of achieving inclusive research participation. In this article it is argued that theory led, participatory, opportunistic, and naturalistic approaches can provide an antidote to the issues in the literature. The combination also mitigates many methodological critiques of the individual approaches, by increasing the transformative potential of realist evaluation, and explanatory potential of transformative evaluation

The slow demise of the long-lived SN 2005ip

The Type IIn supernova (SN IIn) 2005ip is one of the most well-studied and long-lasting examples of an SN interacting with its circumstellar environment. The optical light curve plateaued at a nearly constant level for more than five years, suggesting ongoing shock interaction with an extended and clumpy circumstellar medium (CSM). Here, we present continued observations of the SN from ∼1000 to 5000 d post-explosion at all wavelengths, including X-ray, ultraviolet, near-infrared (NIR), and mid-infrared. The UV spectra probe the pre-explosion mass loss and show evidence for CNO processing. From the bolometric light curve, we find that the total radiated energy is in excess of 10⁵⁰ erg, the progenitor star’s pre-explosion mass-loss rate was ≳1×10⁻²M_⊙ yr⁻¹⁠, and the total mass lost shortly before explosion was ≳1 M_⊙⁠, though the mass lost could have been considerably larger depending on the efficiency for the conversion of kinetic energy to radiation. The ultraviolet through NIR spectrum is characterized by two high-density components, one with narrow high-ionization lines, and one with broader low-ionization H I, He I, [O I], Mg II, and Fe II lines. The rich Fe II spectrum is strongly affected by Lyα fluorescence, consistent with spectral modelling. Both the Balmer and He I lines indicate a decreasing CSM density during the late interaction period. We find similarities to SN 1988Z, which shows a comparable change in spectrum at around the same time during its very slow decline. These results suggest that, at long last, the shock interaction in SN 2005ip may finally be on the decline