Mouse strain determines cardiac growth potential

RATIONALE: The extent of heart disease varies from person to person, suggesting that genetic background is important in pathology. Genetic background is also important when selecting appropriate mouse models to study heart disease. This study examines heart growth as a function of strain, specifically C57BL/6 and DBA/2 mouse strains. OBJECTIVE: In this study, we test the hypothesis that two strains of mice, C57BL/6 and DBA/2, will produce varying degrees of heart growth in both physiological and pathological settings. METHODS AND RESULTS: Differences in heart dimensions are detectable by echocardiography at 8 weeks of age. Percentages of cardiac progenitor cells (c-kit+ cells) and mononucleated cells were found to be in a higher percentage in DBA/2 mice, and more tri- and quad-nucleated cells were in C57BL/6 mice. Cardiomyocyte turnover shows no significant changes in mitotic activity, however, there is more apoptotic activity in DBA/2 mice. Cardiomyocyte cell size increased with age, but increased more in DBA/2 mice, although percentages of nucleated cells remained the same in both strains. Two-week isoproterenol stimulation showed an increase in heart growth in DBA/2 mice, both at cardiomyocyte and whole heart level. In isoproterenol-treated DBA/2 mice, there was also a greater expression level of the hypertrophy marker, ANF, compared to C57BL/6 mice. CONCLUSION: We conclude that the DBA/2 mouse strain has a more immature cardiac phenotype, which correlates to a cardiac protective response to hypertrophy in both physiological and pathological stimulations

Mycobacterium tuberculosis CarD, an essential global transcriptional regulator forms amyloid-like fibrils

CarD is an essential global transcription regulator from Mycobacterium tuberculosis (Mtb) that binds RNA polymerase and activates transcription by stabilizing the transcription initiation complex. Available crystal structures have captured two distinct, monomeric and domain-swapped homodimeric, oligomeric states of CarD. However, the actual oligomeric state of CarD in solution and its biological relevance has remained unclear. Here, we confirm the presence of the homodimeric state of CarD in solution by using synchrotron-based small-angle X-ray scattering. Furthermore, by using biochemical and biophysical experiments, in addition to mass-spectrometry, transmission electron microscopy, and confocal imaging, we show that CarD is the first soluble cytosolic protein in Mtb which displays the tendency to form amyloid-like fibrils both in vitro as well as in vivo. We demonstrate that the deletion of the fourteen N-terminal residues involved in domain-swapping hampers amyloid formation, thus, suggesting that domain-swapping is crucial in amyloidogenesis. The discovery of the amyloidogenic property of an essential cytosolic global transcription regulator, CarD, in a pathogenic bacteria will further open up new frontiers in research.Peer reviewe

Crystallization and preliminary crystallographic analysis of the major capsid proteins VP16 and VP17 of bacteriophage P23-77

The major capsid proteins VP16 and VP17 of bacteriophage P23-77 have been crystallized using both recombinant and purified virus and preliminary diffraction analyses have been performed

The Structure of an RNAi Polymerase Links RNA Silencing and Transcription

RNA silencing refers to a group of RNA-induced gene-silencing mechanisms that developed early in the eukaryotic lineage, probably for defence against pathogens and regulation of gene expression. In plants, protozoa, fungi, and nematodes, but apparently not insects and vertebrates, it involves a cell-encoded RNA-dependent RNA polymerase (cRdRP) that produces double-stranded RNA triggers from aberrant single-stranded RNA. We report the 2.3-Å resolution crystal structure of QDE-1, a cRdRP from Neurospora crassa, and find that it forms a relatively compact dimeric molecule, each subunit of which comprises several domains with, at its core, a catalytic apparatus and protein fold strikingly similar to the catalytic core of the DNA-dependent RNA polymerases responsible for transcription. This evolutionary link between the two enzyme types suggests that aspects of RNA silencing in some organisms may recapitulate transcription/replication pathways functioning in the ancient RNA-based world

A Deep HST Search for Escaping Lyman Continuum Flux at z~1.3: Evidence for an Evolving Ionizing Emissivity

We have obtained deep Hubble Space Telescope far-UV images of 15 starburst galaxies at z~1.3 in the GOODS fields to search for escaping Lyman continuum photons. These are the deepest far-UV images m_{AB}=28.7, 3\sigma, 1" diameter) over this large an area (4.83 arcmin^2) and provide the best escape fraction constraints for any galaxy at any redshift. We do not detect any individual galaxies, with 3\sigma limits to the Lyman Continuum (~700 \AA) flux 50--149 times fainter (in f_nu) than the rest-frame UV (1500 \AA) continuum fluxes. Correcting for the mean IGM attenuation (factor ~2), as well as an intrinsic stellar Lyman Break (~3), these limits translate to relative escape fraction limits of f_{esc,rel}<[0.03,0.21]. The stacked limit is f_{esc,rel}(3\sigma)<0.02. We use a Monte Carlo simulation to properly account for the expected distribution of IGM opacities. When including constraints from previous surveys at z~1.3 we find that, at the 95% confidence level, no more than 8% of star--forming galaxies at z~1.3 can have relative escape fractions greater than 0.50. Alternatively, if the majority of galaxies have low, but non-zero, escaping Lyman Continuum, the escape fraction can not be more than 0.04. Both the stacked limits, and the limits from the Monte Carlo simulation suggest that the average ionizing emissivity (relative to non-ionizing UV emissivity) at z~1.3 is significantly lower than has been observed in Lyman Break Galaxies (LBGs) at z~3. If the ionizing emissivity of star-forming galaxies is in fact increasing with redshift, it would help to explain the high photoionization rates seen in the IGM at z>4 and reionization of the intergalactic medium at z>6. [Abridged]Comment: Submitted to ApJ (Nov. 6) Comments Welcome. 11 pages, 8 figure

Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis

We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2−/− mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim+/−Bcl-2−/− mice, but were largely restored in Bim−/−Bcl-2−/− mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim−/−, T cells. Further, T cells from Bim+/−Bcl-2−/− mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8+ T cells required Bcl-2 to combat Bim to maintain peripheral survival, whereas naive CD4+ T cells did not. In contrast, Bim+/−Bcl-2−/− mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim+/−Bcl-2−/− mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for a balance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells

Dietary salt intake and discretionary salt use in two general population samples in Australia: 2011 and 2014

The limited Australian measures to reduce population sodium intake through national initiatives targeting sodium in the food supply have not been evaluated. The aim was, thus, to assess if there has been a change in salt intake and discretionary salt use between 2011 and 2014 in the state of Victoria, Australia. Adults drawn from a population sample provided 24 h urine collections and reported discretionary salt use in 2011 and 2014. The final sample included 307 subjects who participated in both surveys, 291 who participated in 2011 only, and 135 subjects who participated in 2014 only. Analysis included adjustment for age, gender, metropolitan area, weekend collection and participation in both surveys, where appropriate. In 2011, 598 participants: 53% female, age 57.1(12.0)(SD) years and in 2014, 442 participants: 53% female, age 61.2(10.7) years provided valid urine collections, with no difference in the mean urinary salt excretion between 2011: 7.9 (7.6, 8.2) (95% CI) g/salt/day and 2014: 7.8 (7.5, 8.1) g/salt/day (p = 0.589), and no difference in discretionary salt use: 35% (2011) and 36% (2014) reported adding salt sometimes or often/always at the table (p = 0.76). Those that sometimes or often/always added salt at the table and when cooking had 0.7 (0.7, 0.8) g/salt/day (p = 0.0016) higher salt excretion. There is no indication over this 3-year period that national salt reduction initiatives targeting the food supply have resulted in a population reduction in salt intake. More concerted efforts are required to reduce the salt content of manufactured foods, together with a consumer education campaign targeting the use of discretionary salt

Accelerated volume loss in glacier ablation zones of NE Greenland, Little Ice Age to present

Mountain glaciers at the periphery of the Greenland ice sheet are a crucial freshwater and sediment source to the North Atlantic and strongly impact Arctic terrestrial, fjord, and coastal biogeochemical cycles. In this study we mapped the extent of 1,848 mountain glaciers in NE Greenland at the Little Ice Age. We determined area and volume changes for the time periods Little Ice Age to 1980s and 1980s to 2014 and equilibrium line altitudes. There was at least 172.76 ± 34.55‐km3 volume lost between 1910 and 1980s, that is, a rate of 2.61 ± 0.52 km3/year. Between 1980s and 2014 the volume lost was 90.55 ± 18.11 km3, that is, a rate of 3.22 ± 0.64 km3/year, implying an increase of ~23% in the rate of ice volume loss. Overall, at least ~7% of mass loss from Greenland mountain glaciers and ice caps has come from the NE sector

Accelerated volume loss in glacier ablation zones of NE Greenland, Little Ice Age to present

Mountain glaciers at the periphery of the Greenland ice sheet are a crucial freshwater and sediment source to the North Atlantic and strongly impact Arctic terrestrial, fjord, and coastal biogeochemical cycles. In this study we mapped the extent of 1,848 mountain glaciers in NE Greenland at the Little Ice Age. We determined area and volume changes for the time periods Little Ice Age to 1980s and 1980s to 2014 and equilibrium line altitudes. There was at least 172.76 ± 34.55‐km3 volume lost between 1910 and 1980s, that is, a rate of 2.61 ± 0.52 km3/year. Between 1980s and 2014 the volume lost was 90.55 ± 18.11 km3, that is, a rate of 3.22 ± 0.64 km3/year, implying an increase of ~23% in the rate of ice volume loss. Overall, at least ~7% of mass loss from Greenland mountain glaciers and ice caps has come from the NE sector