Cardiomyocyte specific overexpression of a 37 amino acid domain of regulator of G protein signalling 2 inhibits cardiac hypertrophy and improves function in response to pressure overload in mice

Regulator of G protein signalling 2 (RGS2) is known to play a protective role in maladaptive cardiac hypertrophy and heart failure via its ability to inhibit Gq- and Gs- mediated GPCR signalling. We previously demonstrated that RGS2 can also inhibit protein translation and can thereby attenuate cell growth. This G protein-independent inhibitory effect has been mapped to a 37 amino acid domain (RGS2eb) within RGS2 that binds to eukaryotic initiation factor 2B (eIF2B). When expressed in neonatal rat cardiomyocytes, RGS2eb attenuates both protein synthesis and hypertrophy induced by Gq- and Gs- activating agents. In the current study, we investigated the potential cardioprotective role of RGS2eb by determining whether RGS2eb transgenic (RGS2eb TG) mice with cardiomyocyte specific overexpression of RGS2eb show resistance to the development of hypertrophy in comparison to wild-type (WT) controls. Using transverse aortic constriction (TAC) in a pressure-overload hypertrophy model, we demonstrated that cardiac hypertrophy was inhibited in RGS2eb TG mice compared to WT controls following four weeks of TAC. Expression of the hypertrophic markers atrial natriuretic peptide (ANP) and β-myosin heavy chain (MHC-β) was also reduced in RGS2eb TG compared to WT TAC animals. Furthermore, cardiac function in RGS2eb TG TAC mice was significantly improved compared to WT TAC mice. Notably, cardiomyocyte cell size was significantly decreased in TG compared to WT TAC mice. These results suggest that RGS2 may limit pathological cardiac hypertrophy at least in part via the function of its eIF2B-binding domain

Functional rescue of dystrophin deficiency in mice caused by frameshift mutations using Campylobacter jejuni Cas9

Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle wasting disease caused by mutations in the DMD gene. In 51% of DMD cases, a reading frame is disrupted because of deletion of several exons. Here, we show that CjCas9 derived from Campylobacter jejuni can be used as a gene editing tool to correct an out-of-frame Dmd exon in Dmd knockout mice. Herein, we used Cas9 derived from S. pyogenes to generate Dmd knockout (KO) mice with a frameshift mutation in Dmd gene. Then, we expressed CjCas9, its single-guide RNA, and the eGFP gene in the tibialis anterior muscle of the Dmd KO mice using an all-in-one adeno-associated virus (AAV) vector. CjCas9 cleaved the target site in the Dmd gene efficiently in vivo and induced small insertions or deletions at the target site. This treatment resulted in conversion of the disrupted Dmd reading frame from out-of-frame to in-frame, leading to the expression of dystrophin in the sarcolemma. Importantly, muscle strength was enhanced in the CjCas9-treated muscles, without off-target mutations, indicating high efficiency and specificity of CjCas9. This work suggests that in vivo DMD frame correction, mediated by CjCas9 has great potential for the treatment of DMD and other neuromuscular diseases

HerMES: The submillimeter spectral energy distributions of Herschel/SPIRE-detected galaxies

We present colours of sources detected with the Herschel/SPIRE instrument in deep extragalactic surveys of the Lockman Hole, Spitzer-FLS, and GOODS-N fields in three photometric bands at 250, 350 and 500 μm. We compare these with expectations from the literature and discuss associated uncertainties and biases in the SPIRE data. We identify a 500 μm flux limited selection of sources from the HerMES point source catalogue that appears free from neighbouring/blended sources in all three SPIRE bands. We compare the colours with redshift tracks of various contemporary models. Based on these spectral templates we show that regions corresponding to specific population types and redshifts can be identified better in colour-flux space. The redshift tracks as well as the colour-flux plots imply a majority of detected objects with redshifts at 1 < z < 3.5, somewhat depending on the group of model SEDs used. We also find that a population of sources with S_(250)/S_(350) < 0.8 at fluxes above 50 mJy as observed by SPIRE are not well represented by contemporary models and could consist of a mix of cold and lensed galaxies

Submillimetre galaxies reside in dark matter haloes with masses greater than 3 × 10^(11) solar masses

The extragalactic background light at far-infrared wavelengths comes from optically faint, dusty, star-forming galaxies in the Universe with star formation rates of a few hundred solar masses per year. These faint, submillimetre galaxies are challenging to study individually because of the relatively poor spatial resolution of far-infrared telescopes. Instead, their average properties can be studied using statistics such as the angular power spectrum of the background intensity variations. A previous attempt at measuring this power spectrum resulted in the suggestion that the clustering amplitude is below the level computed with a simple ansatz based on a halo model. Here we report excess clustering over the linear prediction at arcminute angular scales in the power spectrum of brightness fluctuations at 250, 350 and 500 µm. From this excess, we find that submillimetre galaxies are located in darkmatter haloes with a minimum mass, M_(min), such that log_(10)[M_(min)/M_⊙] = 11.5^(+0.7)_(-0.2) at 350 µm, where M_⊙ is the solar mass. This minimum dark matter halo mass corresponds to the most efficient mass scale for star formation in the Universe, and is lower than that predicted by semi-analytical models for galaxy formation

HerMES: deep galaxy number counts from a P(D) fluctuation analysis of SPIRE Science Demonstration Phase observations

Dusty, star-forming galaxies contribute to a bright, currently unresolved cosmic far-infrared background. Deep Herschel-Spectral and Photometric Imaging Receiver (SPIRE) images designed to detect and characterize the galaxies that comprise this background are highly confused, such that the bulk lies below the classical confusion limit. We analyse three fields from the Herschel Multi-tiered Extragalactic Survey (HerMES) programme in all three SPIRE bands (250, 350 and 500 μm); parametrized galaxy number count models are derived to a depth of ~2 mJy beam^(−1), approximately four times the depth of previous analyses at these wavelengths, using a probability of deflection [P(D)] approach for comparison to theoretical number count models. Our fits account for 64, 60 and 43 per cent of the far-infrared background in the three bands. The number counts are consistent with those based on individually detected SPIRE sources, but generally inconsistent with most galaxy number count models, which generically overpredict the number of bright galaxies and are not as steep as the P(D)-derived number counts. Clear evidence is found for a break in the slope of the differential number counts at low flux densities. Systematic effects in the P(D) analysis are explored. We find that the effects of clustering have a small impact on the data, and the largest identified systematic error arises from uncertainties in the SPIRE beam