Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation

The goal of the current work was to profile positive (mTORC1 activation, autocrine/paracrine growth factors) and negative [AMPK, unfolded protein response (UPR)] pathways that might regulate overload-induced mTORC1 (mTOR complex 1) activation with the hypothesis that a number of negative regulators of mTORC1 will be engaged during a supraphysiological model of hypertrophy. To achieve this, mTORC1- IRS-1/2 signaling, BiP/CHOP/IRE1, and AMPK activation were determined in rat plantaris muscle following synergist ablation (SA). SA resulted in significant increases in muscle mass of 4% per day throughout the 21 days of the experiment. The expression of the insulin-like growth factors (IGF) were high throughout the 21st day of overload. However, IGF signaling was limited, since IRS-1 and -2 were undetectable in the overloaded muscle from day 3 to day 9. The decreases in IRS-1/2 protein were paralleled by increases in GRB10 Ser501/503 and S6K1 Thr389 phosphorylation, two mTORC1 targets that can destabilize IRS proteins. PKB Ser473 phosphorylation was higher from 3– 6 days, and this was associated with increased TSC2 Thr939 phosphorylation. The phosphorylation of TSC2 Thr1345 (an AMPK site) was also elevated, whereas phosphorylation at the other PKB site, Thr1462, was unchanged at 6 days. In agreement with the phosphorylation of Thr1345, SA led to activation of AMPK1 during the initial growth phase, lasting the first 9 days before returning to baseline by day 12. The UPR markers CHOP and BiP were elevated over the first 12 days following ablation, whereas IRE1 levels decreased. These data suggest that during supraphysiological muscle loading at least three potential molecular brakes engage to downregulate mTORC1. m

OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation

The dynamin-related GTPase OPA1 is mutated in autosomal dominant optic atrophy (DOA) (Kjer type), an inherited neuropathy of the retinal ganglion cells. OPA1 is essential for the fusion of the inner mitochondrial membranes, but its mechanism of action remains poorly understood. Here we show that OPA1 has a low basal rate of GTP hydrolysis that is dramatically enhanced by association with liposomes containing negative phospholipids such as cardiolipin. Lipid association triggers assembly of OPA1 into higher order oligomers. In addition, we find that OPA1 can promote the protrusion of lipid tubules from the surface of cardiolipin-containing liposomes. In such lipid protrusions, OPA1 assemblies are observed on the outside of the lipid tubule surface, a protein-membrane topology similar to that of classical dynamins. The membrane tubulation activity of OPA1 is suppressed by GTPγS. OPA1 disease alleles associated with DOA display selective defects in several activities, including cardiolipin association, GTP hydrolysis and membrane tubulation. These findings indicate that interaction of OPA1 with membranes can stimulate higher order assembly, enhance GTP hydrolysis and lead to membrane deformation into tubules

The MOSDEF Survey: Kinematic and Structural Evolution of Star-Forming Galaxies at 1.4≤z≤3.81.4\leq z\leq 3.8

We present ionized gas kinematics for 681 galaxies at $z\sim 1.4-3.8$ from the MOSFIRE Deep Evolution Field survey, measured using models which account for random galaxy-slit misalignments together with structural parameters derived from CANDELS Hubble Space Telescope (HST) imaging. Kinematics and sizes are used to derive dynamical masses. Baryonic masses are estimated from stellar masses and inferred gas masses from dust-corrected star formation rates (SFRs) and the Kennicutt-Schmidt relation. We measure resolved rotation for 105 galaxies. For the remaining 576 galaxies we use models based on HST imaging structural parameters together with integrated velocity dispersions and baryonic masses to statistically constrain the median ratio of intrinsic ordered to disordered motion, $V/\sigma_{V,0}$. We find that $V/\sigma_{V,0}$ increases with increasing stellar mass and decreasing specific SFR (sSFR). These trends may reflect marginal disk stability, where systems with higher gas fractions have thicker disks. For galaxies with detected rotation we assess trends between their kinematics and mass, sSFR, and baryon surface density ($\Sigma_{\mathrm{bar},e}$). Intrinsic dispersion correlates most with $\Sigma_{\mathrm{bar},e}$ and velocity correlates most with mass. By comparing dynamical and baryonic masses, we find that galaxies at $z\sim 1.4-3.8$ are baryon dominated within their effective radii ($R_E$), with Mdyn/Mbaryon increasing over time. The inferred baryon fractions within $R_E$, $f_{\mathrm{bar}}$, decrease over time, even at fixed mass, size, or surface density. At fixed redshift, $f_{\mathrm{bar}}$ does not appear to vary with stellar mass but increases with decreasing $R_E$ and increasing $\Sigma_{\mathrm{bar},e}$. For galaxies at $z\geq2$, the median inferred baryon fractions generally exceed 100%. We discuss possible explanations and future avenues to resolve this tension.Comment: Accepted to ApJ. Added Figure 9, corrected sample size (main results unchanged). 28 pages, 13 figure

Mindfulness as predictor of itch catastrophizing in patients with atopic dermatitis: eesults of a cross-sectional questionnaire study

Itch and worry about itch are predominant symptoms in atopic dermatitis (AD). Mindfulness refers to paying attention in a certain way, non-judgementally and on purpose. In patients with chronic pain, which shares several similarities with chronic itch, a significant relationship between pain intensity, mindfulness and pain catastrophizing has been found. The aim of this study was to investigate whether itch intensity and mindfulness are related to itch catastrophizing in AD patients. Participants receiving treatment for AD (n = 155; 58 male; mean age: 46.5 ± 12 years) completed measures of itch-related catastrophizing (Itch Cognitions Questionnaire; ICQ) and mindfulness (Comprehensive Inventory of Mindfulness; CHIME) during their stay at a rehabilitation center in Borkum, Germany. In addition to other variables, their average itch intensity during the last 2 weeks was assessed by means of a visual analog scale. A positive relationship between itch intensity and itch catastrophizing was found (r = 0.409; p < 0.01). Moreover, the mindfulness scales “acting with awareness,” “accepting and non-judgemental orientation,” and “non-reactive orientation” were negatively related to itch catastrophizing. A linear regression analysis revealed that itch intensity in combination with “acting with awareness” was able to explain more than 27 % (corrected R2 = 0.274; p < 0.001) of the variance of itch catastrophizing. Thus, itch intensity and certain facets of mindfulness were associated with itch catastrophizing in AD patients. Psychological interventions aiming to increase acting with awareness might have a buffering effect on itch catastrophizing, which in turn could lead to lower itch intensity in patients with AD. Future RCTs should test this hypothesis

OPA1 and cardiolipin team up for mitochondrial fusion

Fusion between the inner membranes of two mitochondria requires the GTPase optic atrophy 1 (OPA1), but the molecular mechanism is poorly understood. A study now shows that fusion of two liposomes can be performed by OPA1 tethered to just one liposome, through an interaction with the phospholipid cardiolipin on the opposing liposome

Mercury Exposure and Antinuclear Antibodies among Females of Reproductive Age in the United States: NHANES

Background: Immune dysregulation associated with mercury has been suggested, though data in the general population are lacking. Chronic exposure to low levels of methylmercury (organic) and inorganic mercury is common, such as through fish consumption and dental amalgams. Objective: To examine associations between mercury biomarkers and antinuclear antibody (ANA) positivity and titer strength. Methods: Among females 16-49 years (n=1352) from the National Health and Nutrition Examination Survey (NHANES) 1999-2004, we examined cross-sectional associations between mercury and ANAs (indirect immunofluorescence; cutoff ≥1:80). Three biomarkers of mercury exposure were utilized: hair (available 1999-2000) and total blood (1999-2004) predominantly represented methylmercury, and urinary (1999-2002) inorganic. Survey statistics were used. Multivariable modeling adjusted for several covariates, including age and omega-3 fatty acids. Results: 16% of females were ANA-positive; 96% of ANA-positives had a nuclear staining pattern of speckled. Mercury geometric means (standard deviations) were: 0.22 (0.03) ppm hair, 0.92 (0.05) µg/L blood, and 0.62 (0.04) µg/L urinary. Hair and blood, but not urinary, mercury were associated with ANA positivity (sample sizes 452, 1352, and 804, respectively), adjusting for confounders: hair odds ratio (OR)=4.10 (95% CI: 1.66, 10.13); blood OR=2.32 (95% CI: 1.07, 5.03) comparing highest versus lowest quantiles. Magnitudes of association were strongest for high-titer (≥1:1280) ANA: hair OR=11.41 (95% CI: 1.60, 81.23); blood OR=5.93 (95% CI: 1.57, 22.47). Conclusions: Methylmercury, at low levels generally considered safe, was associated with subclinical autoimmunity among reproductive-age females. Autoantibodies may predate clinical disease by years, thus methylmercury exposure may be relevant to future autoimmune disease risk.This work was supported by NIH/NIEHS K01ES019909, NIH/NIEHS P30ES017885, and NIH/NCRR UL1RR024986. ECS was supported in part by an Arthritis Foundation Health Professional New Investigator Award.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110512/1/SOMERS_EHP.AdvancePubl 02102015.acco.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/110512/2/Somers_EHP Suppl-1408751.s001.508.pdf114Description of SOMERS_EHP.AdvancePubl 02102015.acco.pdf : Main ArticleDescription of Somers_EHP Suppl-1408751.s001.508.pdf : Supplementary Materia

Dietary Omega Polyunsaturated Fatty Acid Intake and Patient‐Reported Outcomes in Systemic Lupus Erythematosus: The Michigan Lupus Epidemiology and Surveillance Program

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155937/1/acr23925_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155937/2/acr23925.pd

The MOSDEF Survey: The First Direct Measurements of the Nebular Dust Attenuation Curve at High Redshift

We use a sample of 532 star-forming galaxies at redshifts z ≃ 1.4–2.6 with deep rest-frame optical spectra from the MOSFIRE Deep Evolution Field (MOSDEF) survey to place the first constraints on the nebular attenuation curve at high redshift. Based on the first five low-order Balmer emission lines detected in the composite spectra of these galaxies (Hα through Hε), we derive a nebular attenuation curve that is similar in shape to that of the Galactic extinction curve, suggesting that the dust covering fraction and absorption/scattering properties along the lines of sight to massive stars at high redshift are similar to those of the average Milky Way sight line. The curve derived here implies nebular reddening values that are, on average, systematically larger than those derived for the stellar continuum. In the context of stellar population synthesis models that include the effects of stellar multiplicity, the difference in reddening of the nebular lines and stellar continuum may imply molecular cloud crossing timescales that are a factor of ≳ 3x longer than those inferred for local molecular clouds, star formation rates that are constant or increasing with time such that newly formed and dustier OB associations always dominate the ionizing flux, and/or that the dust responsible for reddening the nebular emission may be associated with nonmolecular (i.e., ionized and neutral) phases of the interstellar medium. Our analysis points to a variety of investigations of the nebular attenuation curve that will be enabled with the next generation of ground- and space-based facilities