Accelerated epigenetic aging in Werner syndrome.

Individuals suffering from Werner syndrome (WS) exhibit many clinical signs of accelerated aging. While the underlying constitutional mutation leads to accelerated rates of DNA damage, it is not yet known whether WS is also associated with an increased epigenetic age according to a DNA methylation based biomarker of aging (the "Epigenetic Clock"). Using whole blood methylation data from 18 WS cases and 18 age matched controls, we find that WS is associated with increased extrinsic epigenetic age acceleration (p=0.0072) and intrinsic epigenetic age acceleration (p=0.04), the latter of which is independent of age-related changes in the composition of peripheral blood cells. A multivariate model analysis reveals that WS is associated with an increase in DNA methylation age (on average 6.4 years, p=0.011) even after adjusting for chronological age, gender, and blood cell counts. Further, WS might be associated with a reduction in naïve CD8+ T cells (p=0.025) according to imputed measures of blood cell counts. Overall, this study shows that WS is associated with an increased epigenetic age of blood cells which is independent of changes in blood cell composition. The extent to which this alteration is a cause or effect of WS disease phenotypes remains unknown

Growing season CH4 and N2O fluxes from a subarctic landscape in northern Finland; from chamber to landscape scale

Subarctic and boreal emissions of CH4 are important contributors to the atmospheric greenhouse gas (GHG) balance and subsequently the global radiative forcing. Whilst N2O emissions may be lower, the much greater radiative forcing they produce justifies their inclusion in GHG studies. In addition to the quantification of flux magnitude, it is essential that we understand the drivers of emissions to be able to accurately predict climate-driven changes and potential feedback mechanisms. Hence this study aims to increase our understanding of what drives fluxes of CH4 and N2O in a subarctic forest/wetland landscape during peak summer conditions and into the shoulder season, exploring both spatial and temporal variability, and uses satellite-derived spectral data to extrapolate from chamber-scale fluxes to a 2 km  ×  2 km landscape area. From static chamber measurements made during summer and autumn campaigns in 2012 in the Sodankylä region of northern Finland, we concluded that wetlands represent a significant source of CH4 (3.35 ± 0.44 mg C m−2 h−1 during the summer campaign and 0.62 ± 0.09 mg C m−2 h−1 during the autumn campaign), whilst the surrounding forests represent a small sink (−0.06 ± < 0.01 mg C m−2 h−1 during the summer campaign and −0.03 ± < 0.01 mg C m−2 h−1 during the autumn campaign). N2O fluxes were near-zero across both ecosystems. We found a weak negative relationship between CH4 emissions and water table depth in the wetland, with emissions decreasing as the water table approached and flooded the soil surface and a positive relationship between CH4 emissions and the presence of Sphagnum mosses. Temperature was also an important driver of CH4 with emissions increasing to a peak at approximately 12 °C. Little could be determined about the drivers of N2O emissions given the small magnitude of the fluxes. A multiple regression modelling approach was used to describe CH4 emissions based on spectral data from PLEIADES PA1 satellite imagery across a 2 km  ×  2 km landscape. When applied across the whole image domain we calculated a CH4 source of 2.05 ± 0.61 mg C m−2 h−1. This was significantly higher than landscape estimates based on either a simple mean or weighted by forest/wetland proportion (0.99 ± 0.16, 0.93 ± 0.12 mg C m−2 h−1, respectively). Hence we conclude that ignoring the detailed spatial variability in CH4 emissions within a landscape leads to a potentially significant underestimation of landscape-scale fluxes. Given the small magnitude of measured N2O fluxes a similar level of detailed upscaling was not needed; we conclude that N2O fluxes do not currently comprise an important component of the landscape-scale GHG budget at this site

Antifungal Chemical Compounds Identified Using a C. elegans Pathogenicity Assay

There is an urgent need for the development of new antifungal agents. A facile in vivo model that evaluates libraries of chemical compounds could solve some of the main obstacles in current antifungal discovery. We show that Candida albicans, as well as other Candida species, are ingested by Caenorhabditis elegans and establish a persistent lethal infection in the C. elegans intestinal track. Importantly, key components of Candida pathogenesis in mammals, such as filament formation, are also involved in nematode killing. We devised a Candida-mediated C. elegans assay that allows high-throughput in vivo screening of chemical libraries for antifungal activities, while synchronously screening against toxic compounds. The assay is performed in liquid media using standard 96-well plate technology and allows the study of C. albicans in non-planktonic form. A screen of 1,266 compounds with known pharmaceutical activities identified 15 (∼1.2%) that prolonged survival of C. albicans-infected nematodes and inhibited in vivo filamentation of C. albicans. Two compounds identified in the screen, caffeic acid phenethyl ester, a major active component of honeybee propolis, and the fluoroquinolone agent enoxacin exhibited antifungal activity in a murine model of candidiasis. The whole-animal C. elegans assay may help to study the molecular basis of C. albicans pathogenesis and identify antifungal compounds that most likely would not be identified by in vitro screens that target fungal growth. Compounds identified in the screen that affect the virulence of Candida in vivo can potentially be used as “probe compounds” and may have antifungal activity against other fungi

Multiple Autism-Linked Genes Mediate Synapse Elimination via Proteasomal Degradation of a Synaptic Scaffold PSD-95

SummaryThe activity-dependent transcription factor myocyte enhancer factor 2 (MEF2) induces excitatory synapse elimination in mouse neurons, which requires fragile X mental retardation protein (FMRP), an RNA-binding protein implicated in human cognitive dysfunction and autism. We report here that protocadherin 10 (Pcdh10), an autism-spectrum disorders gene, is necessary for this process. MEF2 and FMRP cooperatively regulate the expression of Pcdh10. Upon MEF2 activation, PSD-95 is ubiquitinated by the ubiquitin E3 ligase murine double minute 2 (Mdm2) and then binds to Pcdh10, which links it to the proteasome for degradation. Blockade of the Pcdh10-proteasome interaction inhibits MEF2-induced PSD-95 degradation and synapse elimination. In FMRP-lacking neurons, elevated protein levels of eukaryotic translation elongation factor 1 α (EF1α), an Mdm2-interacting protein and FMRP target mRNA, sequester Mdm2 and prevent MEF2-induced PSD-95 ubiquitination and synapse elimination. Together, our findings reveal roles for multiple autism-linked genes in activity-dependent synapse elimination

Spectral and morphological analysis of the remnant of Supernova 1987A with ALMA & ATCA

We present a comprehensive spectral and morphological analysis of the remnant of Supernova (SN) 1987A with the Australia Telescope Compact Array (ATCA) and the Atacama Large Millimeter/submillimeter Array (ALMA). The non-thermal and thermal components of the radio emission are investigated in images from 94 to 672 GHz ($\lambda$ 3.2 mm to 450 $\mu$m), with the assistance of a high-resolution 44 GHz synchrotron template from the ATCA, and a dust template from ALMA observations at 672 GHz. An analysis of the emission distribution over the equatorial ring in images from 44 to 345 GHz highlights a gradual decrease of the east-to-west asymmetry ratio with frequency. We attribute this to the shorter synchrotron lifetime at high frequencies. Across the transition from radio to far infrared, both the synchrotron/dust-subtracted images and the spectral energy distribution (SED) suggest additional emission beside the main synchrotron component ($S_{\nu}\propto\nu^{-0.73}$) and the thermal component originating from dust grains at $T\sim22$ K. This excess could be due to free-free flux or emission from grains of colder dust. However, a second flat-spectrum synchrotron component appears to better fit the SED, implying that the emission could be attributed to a pulsar wind nebula (PWN). The residual emission is mainly localised west of the SN site, as the spectral analysis yields $-0.4\lesssim\alpha\lesssim-0.1$ across the western regions, with $\alpha\sim0$ around the central region. If there is a PWN in the remnant interior, these data suggest that the pulsar may be offset westward from the SN position.Comment: ApJ accepted. 21 pages, emulateapj. References update