A heterozygous variant in the human cardiac miR-133 gene, MIR133A2, alters miRNA duplex processing and strand abundance

BACKGROUND MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Sequential cleavage of miRNA precursors results in a ~22 nucleotide duplex of which one strand, the mature miRNA, is typically loaded into the RNA-induced silencing complex (RISC) while the passenger strand is degraded. Very little is known about how genetic variation might affect miRNA biogenesis and function. RESULTS We re-sequenced the MIR1-1, MIR1-2, MIR133A1, MIR133A2, and MIR133B genes, that encode the cardiac-enriched miRNAs, miR-1 and miR-133, in 120 individuals with familial atrial fibrillation and identified 10 variants, including a novel 79T > C MIR133A2 substitution. This variant lies within the duplex at the 3' end of the mature strand, miR-133a-3p, and is predicted to prevent base-pairing and weaken thermostability at this site, favoring incorporation of the passenger strand, miR-133a-5p, into RISC. Genomic DNA fragments containing miR-133a-2 precursor sequences with 79T and 79C alleles were transfected into HeLa cells. On Northern blotting the 79T allele showed strong expression of miR-133a-3p with weak expression of miR-133a-5p. In contrast, the 79C allele had no effect on miR-133a-3p but there was a significant increase (mean 3.6-fold) in miR-133a-5p levels. Deep sequencing of small RNA libraries prepared from normal human and murine atria confirmed that nearly all the mature miR-133a was comprised of miR-133a-3p and that levels of miR-133a-5p were very low. A number of isomiRs with variations at 5' and 3' ends were identified for both miR-133a-3p and miR-133a-5p, with 2 predominant miR-133a-3p isomiRs and one predominant miR-133a-5p isomiR. Bioinformatics analyses indicate that the major miR-133a-3p and 5p isomiRs have numerous predicted target mRNAs, only a few of which are in common. CONCLUSIONS Multiple miR-133a isomiRs with potential different mRNA target profiles are present in the atrium in humans and mice. We identified a human 79T > C MIR133A2 variant that alters miRNA processing and results in accumulation of the miR-133a-5p strand that is usually degraded

Reflexive and preparatory selection and suppression of salient information in the right and left posterior parietal cortex

Attentional cues can trigger activity in the parietal cortex in anticipation of visual displays, and this activity may, in turn, induce changes in other areas of the visual cortex, hence, implementing attentional selection. In a recent TMS study [Mevorach, C., Humphreys, G. W., & Shalev, L. Opposite biases in salience-based selection for the left and right posterior parietal cortex. Nature Neuroscience, 9, 740-742, 2006b], it was shown that the posterior parietal cortex (PPC) can utilize the relative saliency (a nonspatial property) of a target and a distractor to bias visual selection. Furthermore, selection was lateralized so that the right PPC is engaged when salient information must be selected and the left PPC when the salient information must be ignored. However, it is not clear how the PPC implements these complementary forms of selection. Here we used on-line triple-pulse TMS over the right or left PPC prior to or after the onset of global/local displays. When delivered after the onset of the display, TMS to the right PPC disrupted the selection of the more salient aspect of the hierarchical letter. In contrast, left PPC TMS delivered prior to the onset of the stimulus disrupted responses to the lower saliency stimulus. These findings suggest that selection and suppression of saliency, rather than being "two sides of the same coin," are fundamentally different processes. Selection of saliency seems to operate reflexively, whereas suppression of saliency relies on a preparatory phase that "sets up" the system in order to effectively ignore saliency

Ultraviolet spectroscopy of the brightest supergiants in M31 and M33

Ultraviolet spectroscopy from the IUE, in combination with groundbased visual and infrared photometry, are to determine the energy distributions of the luminous blue variables, the Hubble-Sandage variables, in M31 and M33. The observed energy distributions, especially in the ultraviolet, show that these stars are suffering interstellar reddening. When corrected for interstellar extinction, the integrated energy distributions yield the total luminosities and black body temperatures of the stars. The resulting bolometric magnitudes and temperatures confirm that these peculiar stars are indeed very luminous, hot stars. They occupy the same regions of the sub B01 vs. log T sub e diagram as do eta Car, P Cyg and S Dor in our galaxy and the LMC. Many of the Hubble-Sandage variables have excess infrared radiation which is attributed to free-free emission from their extended atmospheres. Rough mass loss estimates from the infrared excess yield rates of 0.00001 M sub annual/yr. The ultraviolet spectra of the H-S variables are also compared with similar spectra of eta Car, P Cyg and S For

Object-guided Spatial Attention in Touch: Holding the Same Object with Both Hands Delays Attentional Selection

Abstract Previous research has shown that attention to a specific location on a uniform visual object spreads throughout the entire object. Here we demonstrate that, similar to the visual system, spatial attention in touch can be object guided. We measured event-related brain potentials to tactile stimuli arising from objects held by observers' hands, when the hands were placed either near each other or far apart, holding two separate objects, or when they were far apart but holding a common object. Observers covertly oriented their attention to the left, to the right, or to both hands, following bilaterally presented tactile cues indicating likely tactile target location(s). Attentional modulations for tactile stimuli at attended compared to unattended locations were present in the time range of early somatosensory components only when the hands were far apart, but not when they were near. This was found to reflect enhanced somatosensory processing at attended locations rather than suppressed processing at unattended locations. Crucially, holding a common object with both hands delayed attentional selection, similar to when the hands were near. This shows that the proprioceptive distance effect on tactile attentional selection arises when distant event locations can be treated as separate and unconnected sources of tactile stimulation, but not when they form part of the same object. These findings suggest that, similar to visual attention, both space- and object-based attentional mechanisms can operate when we select between tactile events on our body surface.</jats:p

Magnetic Fields in Evolved Stars: Imaging the Polarized Emission of High-Frequency SiO Masers

We present Submillimeter Array observations of high frequency SiO masers around the supergiant VX Sgr and the semi-regular variable star W Hya. The J=5-4, v=1 28SiO and v=0 29SiO masers of VX Sgr are shown to be highly linearly polarized with a polarization from ~5-60%. Assuming the continuum emission peaks at the stellar position, the masers are found within ~60 mas of the star, corresponding to ~100 AU at a distance of 1.57 kpc. The linear polarization vectors are consistent with a large scale magnetic field, with position and inclination angles similar to that of the dipole magnetic field inferred in the H2O and OH maser regions at much larger distances from the star. We thus show for the first time that the magnetic field structure in a circumstellar envelope can remain stable from a few stellar radii out to ~1400 AU. This provides further evidence supporting the existence of large scale and dynamically important magnetic fields around evolved stars. Due to a lack of parallactic angle coverage, the linear polarization of masers around W Hya could not be determined. For both stars we observed the 28SiO and 29SiO isotopologues and find that they have a markedly different distribution and that they appear to avoid each other. Additionally, emission from the SO 5_5-4_4 line was imaged for both sources. Around W Hya we find a clear offset between the red- and blue-shifted SO emission. This indicates that W Hya is likely host to a slow bipolar outflow or a rotating disk-like structure.Comment: 8 pages, 7 figures, accepted for publication in ApJ. Online table will be available with published versio

Relationships between Pitch-Matching and Grade Level, Gender, Ethnicity, and Classroom Teachers’ Use of Music in Grades K-3,

The purpose of this study was to examine relationships between pitch-matching and grade level, sex, ethnicity, and classroom teachers’ use of music among K-3 students (N = 289) taught by the same general music teacher. Portions of the data from a pitch-matching exercise that functioned as the music teacher’s roll-taking procedure during the 2005-06 school year were treated as pre- and posttests. There were no significant pretest differences between ethnic groups (Hispanic, White, Other). There were significant pretest differences among classes taught by different classroom teachers, as well as the female students scoring significantly higher than males. Covariance analysis (pretest as covariate) revealed significant improvement by girls over boys on the posttest. There were no significant pretest differences among grade levels, suggesting a lack of carryover of pitch-matching skills from previous years, despite significant improvement (pre-post) for every grade level during the year under study. The boys performed poorly relative to girls in higher grades, though the interaction was not significant. Finally, the study revealed relationships between classroom teachers’ reported use of music and student gain scores (pre-post) in pitch-matching

Global variation in the thermal tolerances of plants

Data availability: The global dataset of gplant thermal tolerances generated for and analysed within this study is appended to Supplementary Information (SI Dataset). Acknowledgments: We thank Mark Adams for providing code to optimise spatial distance kernels, and Jake Alexander, Per-Ola Karis, members of the BES Macroecology SIG, and members of the Bolin Centre for Climate Research (Research Area 8) for helpful discussions.Peer reviewedPostprin

Can continental bogs with stand the pressure due to climate change?

Not all peatlands are alike. Theoretical and process based models suggest that ombrogenic, oligotrophic peatlands can withstand the pressures due to climate change because of the feedbacks among ecosystem production, decomposition and water storage. Although there have been many inductive explanations inferring from paleo-records, there is a lack of deductive empirical tests of the models predictions of these systems’ stability and there are few records of the changes in the net ecosystem carbon balance (NECB) of peatlands that are long enough to examine the dynamics of the NECB in relation to climate variability. Continuous measurements of all the components of the NECB and the associated general climatic and environmental conditions have been made at the Mer Bleue (MB) peatland, a large, 28 km2, 5 m deep, raised ombro-oligotrophic, shrub and Sphagnum covered bog, near Ottawa, Canada from May 1, 1998 until the present. The sixteen-year daily CO2, CH4, and DOC flux and NECB covers a wide range of variability in peatland water storage from very dry to very wet growing seasons. We used the MB data to test the extent of MB peatland’s stability and the strength of the underlying key feedback between the NECB and changes in water storage projected by the models. In 2007 we published a six-year (1999-2004) net ecosystem carbon balance (NECB) for MB of ∼22 ± 40 g C m-2 yr-1, but we have since recalculated the 1998-2004 NECB to be 32 ± 40 g C m-2 yr-1 based on a reanalyzed average NEP of 51 ± 41 g C m-2 yr-1. Over the same period the net loss of C via the CH4 and DOC fluxes were -4 ± 1 and -15 ± 3 g C m-2 yr-1. The 1998-2004 six-year MB average NECB is similar to the long-term C accumulation rate, estimated from MB peat cores, for the last 3,000 years. The post 2004 MB NEP has increased to an average of ∼96 ± 32 g C m-2 yr-1 largely to there being generally wetter growing seasons. The losses of C via DOC (18 ± 1 g C m-2 yr-1) and CH4 (7 ± 4 g C m-2 yr-1) while showing considerable year-to-year variability are not significantly different post 2004. Hence, the proportional loss of C as DOC and CH4 in the MB NECB is slightly less post-2004 than it was before 2004 though the cumulative errors preclude statistically differences. As a result the MB NECB has increased to 79 ± 29 g C m-2 yr-1 post 2004 yielding a 14 year contemporary NECB of 56 ± 36 g C m-2 yr-1, which is double the long-term accumulation rate of C. The variability in the annual NECB and growing season mean NEP for the MB bog can be explained (r2 = 0.35, p \u3c 0.01) by the variability in growing season water table depth. These results suggest the carbon balance – water table feedback is sufficient enough to create stability in continental bogs so they will withstand a considerable amount of climate change

Senescence and host–pathogen interactions

Damage to our genomes triggers cellular senescence characterised by stable cell cycle arrest and a pro-inflammatory secretome that prevents the unrestricted growth of cells with pathological potential. In this way, senescence can be considered a powerful innate defence against cancer and viral infection. However, damage accumulated during ageing increases the number of senescent cells and this contributes to the chronic inflammation and deregulation of the immune function, which increases susceptibility to infectious disease in ageing organisms. Bacterial and viral pathogens are masters of exploiting weak points to establish infection and cause devastating diseases. This review considers the emerging importance of senescence in the host–pathogen interaction: we discuss the pathogen exploitation of ageing cells and senescence as a novel hijack target of bacterial pathogens that deploys senescence-inducing toxins to promote infection. The persistent induction of senescence by pathogens, mediated directly through virulence determinants or indirectly through inflammation and chronic infection, also contributes to age-related pathologies such as cancer. This review highlights the dichotomous role of senescence in infection: an innate defence that is exploited by pathogens to cause disease