Inhibition of phosphoinositide 3-kinase/protein kinase B signaling hampers the vasopressin-dependent stimulation of myogenic differentiation

Arginine-vasopressin (AVP) promotes muscle differentiation, hypertrophy, and regeneration through the combined activation of the calcineurin and Calcium/Calmodulin-dependent Protein Kinase (CaMK) pathways. The AVP system is impaired in several neuromuscular diseases, suggesting that AVP may act as a physiological factor in skeletal muscle. Since the Phosphoinositide 3-kinases/Protein Kinase B/mammalian Target Of Rapamycin (PI3K/Akt/mTOR) signaling plays a significant role in regulating muscle mass, we evaluated its role in the AVP myogenic effect. In L6 cells AKT1 expression was knocked down, and the AVP-dependent expression of mTOR and Forkhead box O3 (FoxO) was analyzed by Western blotting. The effect of the PI3K inhibitor LY294002 was evaluated by cellular and molecular techniques. Akt knockdown hampered the AVP-dependent mTOR expression while increased the levels of FoxO transcription factor. LY294002 treatment inhibited the AVP-dependent expression of Myocyte Enhancer Factor-2 (MEF2) and myogenin and prevented the nuclear translocation of MEF2. LY294002 also repressed the AVP-dependent nuclear export of histone deacetylase 4 (HDAC4) interfering with the formation of multifactorial complexes on the myogenin promoter. We demonstrate that the PI3K/Akt pathway is essential for the full myogenic effect of AVP and that, by targeting this pathway, one may highlight novel strategies to counteract muscle wasting in aging or neuromuscular disorders

Age Dating Stellar Populations in the Near Infrared: An absolute age indicator from the presence/absence of red supergiants

The determination of age is a critical component in the study of a population of stellar clusters. In this letter we present a new absolute age indicator for young massive star clusters based on J-H colour. This novel method identifies clusters as older or younger than 5.7 +/- 0.8 Myr based on the appearance of the first population of red supergiant stars. We test the technique on the stellar cluster population of the nearby spiral galaxy, M83, finding good agreement with the theoretical predictions. The localisation of this technique to the near-IR promises that it may be used well into the future with space-- and ground--based missions optimised for near-IR observations.Comment: 5 pages, 5 figures. Accepted to MNRAS, November 201

Characterizing spiral arm and interarm star formation

Interarm star formation contributes significantly to a galaxy's star formation budget, and provides an opportunity to study stellar birthplaces unperturbed by spiral arm dynamics. Using optical integral field spectroscopy of the nearby galaxy NGC 628 with VLT/MUSE, we construct Halpha maps including detailed corrections for dust extinction and stellar absorption to identify 391 HII regions at 35pc resolution over 12 kpc^2. Using tracers sensitive to the underlying gravitational potential, we associate HII regions with either arm (271) or interarm (120) environments. Using our full spectral coverage of each region, we find that most HII region physical properties (luminosity, size, metallicity, ionization parameter) are independent of environment. We calculate the fraction of Halpha luminosity due to the diffuse ionized gas (DIG) background contaminating each HII region, and find the DIG surface brightness to be higher within HII regions compared to the surroundings, and slightly higher within arm HII regions. Use of the temperature sensitive [SII]/Halpha line ratio map instead of the Halpha surface brightness to identify HII region boundaries does not change this result. Using the dust attenuation as a tracer of the gas, we find depletion times consistent with previous work (2 x 10^9 yr) with no differences between the arm and interarm, however this is very sensitive to the DIG correction. Unlike molecular clouds, which can be dynamically affected by the galactic environment, we see fairly consistent HII region properties in both arm and interarm environments. This suggests either a difference in arm star formation and feedback, or a decoupling of dense star forming clumps from the more extended surrounding molecular gas.Comment: 10 pages, 4 figures, 1 table, accepted for publication in Ap

The effect of spatial resolution on optical and near-IR studies of stellar clusters: Implications for the origin of the red excess

Recent ground based near-IR studies of stellar clusters in nearby galaxies have suggested that young clusters remain embedded for 7-10Myr in their progenitor molecular cloud, in conflict with optical based studies which find that clusters are exposed after 1-3Myr. Here, we investigate the role that spatial resolution plays in this apparent conflict. We use a recent catalogue of young ($5000$~\msun) clusters in the nearby spiral galaxy, M83, along with Hubble Space Telescope (HST) imaging in the optical and near-IR, and ground based near-IR imaging, to see how the colours (and hence estimated properties such as age and extinction) are affected by the aperture size employed, in order to simulate studies of differing resolution. We find that the near-IR is heavily affected by the resolution, and when aperture sizes $>40$~pc are used, all young/blue clusters move red-ward in colour space, which results in their appearance as heavily extincted clusters. However, this is due to contamination from nearby sources and nebular emission, and is not an extinction effect. Optical colours are much less affected by resolution. Due to the larger affect of contamination in the near-IR, we find that, in some cases, clusters will appear to show near-IR excess when large ($>20$~pc) apertures are used. Our results explain why few young ($<6$~Myr), low extinction (\av < 1~mag) clusters have been found in recent ground based near-IR studies of cluster populations, while many such clusters have been found in higher resolution HST based studies. Additionally, resolution effects appear to (at least partially) explain the origin of the near-IR excess that has been found in a number of extragalactic YMCs.Comment: 8 pages, 5 figures, accepted for publication in MNRA

MYOGENIC DIFFERENTIATION AND MUSCLE HOMEOSTASIS: NOVEL ROLES OF VASOPRESSIN

The neurohypophyseal nonapeptide arg-vasopressin (AVP) and related peptides constitute a novel family of positive regulators of terminal differentiation of myogenic cell lines and primary satellite cells. By interacting with V1 type receptor, AVP induces activation of phospholipases C and D, regulates cAMP levels, increases cytosolic Ca2+ concentration and up-regulates Myf-5 and myogenin expression, both at the mRNA and at the protein level. In a chemically defined medium, which eliminates the interference of serum components, AVP activates both the calcineurin and the CaMK signaling pathways, whose combined activation leads to the formation of multifactor complexes and is required for the full expression of the differentiated phenotype in vitro. To better clarify the physiological role of AVP in skeletal muscle, we analyzed the AVP effects on muscle regeneration induced by cardiotoxin injection. In particular, to increase skeletal muscle sensibility to circulating AVP, in the absence of systemic effects related to administration of the hormone itself, we over-expressed the V1a AVP receptor in mouse tibialis anterior muscle by electroporation-mediated gene delivery in vivo. The local over-expression of the V1aR in injured muscle results in enhanced regeneration. V1aR over-expressing muscle exhibits: early activation of satellite cells and regeneration markers, accelerated differentiation, increased cell population expressing hematopoietic stem cell markers and its conversion to the myogenic lineage. We demonstrate that V1aR over-expressing muscle increases calcineurin and IL-4 expression levels, and induces the phosphorylation of FOXO trascription factors, inhibiting the expression of atrophic genes. This study highlights a novel in vivo role for the AVP-dependent pathways which may represent a potential gene therapy approach for many diseases affecting muscle homeostasis

Deep near-infrared imaging of W3 Main: constraints on stellar cluster formation

Embedded clusters like W3 Main are complex and dynamically evolving systems that represent an important phase of the star formation process. We aim at the characterization of the entire stellar content of W3 Main in a statistical sense to identify possible differences in evolutionary phase of the stellar populations and find clues about the formation mechanism of this massive embedded cluster. Methods. Deep JHKs imaging is used to derive the disk fraction, Ks-band luminosity functions and mass functions for several subregions in W3 Main. A two dimensional completeness analysis using artificial star experiments is applied as a crucial ingredient to assess realistic completeness limits for our photometry. We find an overall disk fraction of 7.7 $\pm$ 2.3%, radially varying from 9.4 $\pm$ 3.0 % in the central 1 pc to 5.6 $\pm$ 2.2 % in the outer parts of W3 Main. The mass functions derived for three subregions are consistent with a Kroupa and Chabrier mass function. The mass function of IRSN3 is complete down to 0.14 Msun and shows a break at M $\sim$ 0.5 Msun. We interpret the higher disk fraction in the center as evidence for a younger age of the cluster center. We find that the evolutionary sequence observed in the low-mass stellar population is consistent with the observed age spread among the massive stars. An analysis of the mass function variations does not show evidence for mass segregation. W3 Main is currently still actively forming stars, showing that the ionizing feedback of OB stars is confined to small areas ($\sim$ 0.5 pc). The FUV feedback might be influencing large regions of the cluster as suggested by the low overall disk fraction.Comment: 15 pages, 13 figures, accepted by A&

The Curse of Copying , 7 J. Marshall Rev. Intell. Prop. L. 296 (2008)

The concept of “copying” has long been involved with various aspects of intellectual property law, particularly in regard to patents and trademarks. In the absence of legally determined exclusive rights, “copying” is permitted, and is in fact, encouraged. However, because the term “copying” carries an undercurrent of disapproval and unfavorable practices, it is a favorite of patentees looking to portray an accused infringer in the most negative light, especially before a jury. Hence, the curse of “copying.” This article will review the current state of “copying” by addressing the substantive precedent in areas where “copying” has traditionally had a substantive effect—willfulness of any accused infringing conduct and obviousness of the patented invention. With respect to “copying” and willful infringement, this article outlines two important considerations that the precedent is weak upon—“‘copying’ what?” and “‘copying’ when?” Lifting the curse requires care and some courage at trial, in view of a precedential framework that is less than favorable to the accused infringer and the pejorative impact the term “copying” will likely have on the jury and the court. These issues will be discussed and suggestions are advanced throughout as to how one might lift the curse once it is pronounced

Evaluation of immunization practices in Naples, Italy.

This paper reports the results of a survey on vaccination coverage among children born in January 1995 and residing at the beginning of the study (March 1998) in the city of Naples, Italy. The percentages vaccinated, at various times from birth, with oral polio vaccine (OPV), have been compared with those found in a similar survey conducted at the end of 1985 regarding the cohort of children born in June 1983. By the fourth month of life 67% of the 1995 cohort were vaccinated with the first doses of OPV, an increase of about 26% on that found in the 1983 cohort. Similar results were found with the second doses. Among the 1995 cohort 49% were vaccinated with the third dose of OPV within the thirteenth month of life; the corresponding value for the 1983 cohort was 33%. Within the twenty-fourth month of life, in the 1995 cohort, 86% completed the primary cycle of vaccination with OPV; the corresponding figure for the 1983 cohort was 65%. At the end of the third year of life 80% of the 1995 cohort received the fourth dose of OPV. A significant association has been found between socioeconomic status and coverage level

Spin and lattice excitations of a BiFeO3 thin film and ceramics

We present a comprehensive study of polar and magnetic excitations in BiFeO3 ceramics and a thin film epitaxially grown on an orthorhombic (110) TbScO3 substrate. Infrared reflectivity spectroscopy was performed at temperatures from 5 to 900 K for the ceramics and below room temperature for the thin film. All 13 polar phonons allowed by the factor-group analysis were observed in theceramic samples. The thin-film spectra revealed 12 phonon modes only and an additional weak excitation, probably of spin origin. On heating towards the ferroelectric phase transition near 1100 K, some phonons soften, leading to an increase in the static permittivity. In the ceramics, terahertz transmission spectra show five low-energy magnetic excitations including two which were not previously known to be infrared active; at 5 K, their frequencies are 53 and 56 cm-1. Heating induces softening of all magnetic modes. At a temperature of 5 K, applying an external magnetic field of up to 7 T irreversibly alters the intensities of some of these modes. The frequencies of the observed spin excitations provide support for the recently developed complex model of magnetic interactions in BiFeO3 (R.S. Fishman, Phys. Rev. B 87, 224419 (2013)). The simultaneous infrared and Raman activity of the spin excitations is consistent with their assignment to electromagnons

Safety and activity of trastuzumab-containing therapies for the treatment of metastatic breast cancer: our long-term clinical experience (GOIM study).

Background: Trastuzumab is widely used as the treatment of choice for HER2-positive metastatic breast cancer (MBC). Patients and methods: Seventy patients, median age 57 years and range 31–81 years, were included in our retrospective analysis with the aim to evaluate safety and activity of trastuzumab-containing therapies. Results: We observed for first-line treatment response rate (RR) 41%, stable disease (SD) 47% and time to progression (TTP) 8 months (range 1–44). Corresponding numbers for second line were RR 23%, SD 62% and (TTP) 9 months (range 3–23) and beyond second line RR 22%, SD 78% and (TTP) 9 months (range 4–19). Overall survival was 19.2 months (3–62 months). The median cumulative dose of trastuzumab administrated was 5286 mg (464–17 940 mg). Trastuzumab was well tolerated. Median left ventricular ejection function (LVEF) at baseline was 62% and at the end of treatment was 59%. The more relevant adverse events consisted of an asymptomatic decrease in LVEF to 40% (baseline 60%) and a grade 3 symptomatic increase in bilirubin. Conclusion: Trastuzumab-containing therapies in MBC show a good safety and toxicity profile and a remarkable activity even in heavily pretreated women. Patients should benefit from continued trastuzumab therapy, as shown by the maintenance of (TTP) even beyond second-line treatment