Asymmetry in Signal Propagation between the Soma and Dendrites Plays a Key Role in Determining Dendritic Excitability in Motoneurons

It is widely recognized that propagation of electrophysiological signals between the soma and dendrites of neurons differs depending on direction, i.e. it is asymmetric. How this asymmetry influences the activation of voltage-gated dendritic channels, and consequent neuronal behavior, remains unclear. Based on the analysis of asymmetry in several types of motoneurons, we extended our previous methodology for reducing a fully reconstructed motoneuron model to a two-compartment representation that preserved asymmetric signal propagation. The reduced models accurately replicated the dendritic excitability and the dynamics of the anatomical model involving a persistent inward current (PIC) dispersed over the dendrites. The relationship between asymmetric signal propagation and dendritic excitability was investigated using the reduced models while varying the asymmetry in signal propagation between the soma and the dendrite with PIC density constant. We found that increases in signal attenuation from soma to dendrites increased the activation threshold of a PIC (hypo-excitability), whereas increases in signal attenuation from dendrites to soma decreased the activation threshold of a PIC (hyper-excitability). These effects were so strong that reversing the asymmetry in the soma-to-dendrite vs. dendrite-to-soma attenuation, reversed the correlation between PIC threshold and distance of this current source from the soma. We propose the tight relation of the asymmetric signal propagation to the input resistance in the dendrites as a mechanism underlying the influence of the asymmetric signal propagation on the dendritic excitability. All these results emphasize the importance of maintaining the physiological asymmetry in dendritic signaling not only for normal function of the cells but also for biophysically realistic simulations of dendritic excitability. © 2014 Kim et al.1

Lymphangiogenesis and lymph node metastasis in breast cancer

<p>Abstract</p> <p>Introduction</p> <p>There have been few studies on lymphangiogenesis in the past due to the lack of specific lymphatic endothelial markers, and lymphatic-specific growth factors. Recently, these limitations have been relieved by the discovery of a small number of potential lymphatic-specific markers. The relationship between lymphangiogenesis and regional or distant metastasis has not previously been investigated in humans. Using these lymphatic markers, it is possible to explore the relationship between lymphangiogenesis and tumour metastasis. This study indirectly quantified lymphangiogenesis by measuring mRNA expression of all seven lymphatic markers described above in breast cancers and correlated these markers with lymphatic involvement and survival.</p> <p>The cDNA from 153 frozen archived breast samples were analysed with Q-PCR for all seven lymphangiogenic markers. This was correlated with various prognostic factors as well as patient survival.</p> <p>Results</p> <p>There was significantly greater expression of all 7 markers in malignant compared to benign breast tissue. In addition, there was greater expression in lymph node positive/grade 3 tumours when compared to lymph node negative/grade 1 tumours. In 5 of the markers, there was a greater expression in poor NPI prognostic tumours when compared to favourable prognostic tumours which was not statistically significant. There was no association between recurrence risk and lymphangiogenic marker expression.</p> <p>Conclusion</p> <p>In summary, the findings from this study show that lymphangiogenesis, measured by specific lymphatic marker expression, is higher in breast cancers than in normal breast tissue. Secondly, breast cancers which have metastasised to the regional lymphatics show higher expression compared to those which have not, although the individual differences for all five markers were not statistically significant.</p

The mTOR regulated RNA-binding protein LARP1 requires PABPC1 for guided mRNA interaction.

The mammalian target of rapamycin (mTOR) is a critical regulator of cell growth, integrating multiple signalling cues and pathways. Key among the downstream activities of mTOR is the control of the protein synthesis machinery. This is achieved, in part, via the co-ordinated regulation of mRNAs that contain a terminal oligopyrimidine tract (TOP) at their 5'ends, although the mechanisms by which this occurs downstream of mTOR signalling are still unclear. We used RNA-binding protein (RBP) capture to identify changes in the protein-RNA interaction landscape following mTOR inhibition. Upon mTOR inhibition, the binding of LARP1 to a number of mRNAs, including TOP-containing mRNAs, increased. Importantly, non-TOP-containing mRNAs bound by LARP1 are in a translationally-repressed state, even under control conditions. The mRNA interactome of the LARP1-associated protein PABPC1 was found to have a high degree of overlap with that of LARP1 and our data show that PABPC1 is required for the association of LARP1 with its specific mRNA targets. Finally, we demonstrate that mRNAs, including those encoding proteins critical for cell growth and survival, are translationally repressed when bound by both LARP1 and PABPC1

Galaxy And Mass Assembly (GAMA): the 0.013 < z < 0.1 cosmic spectral energy distribution from 0.1 m to 1 mm

We use the Galaxy And Mass Assembly survey (GAMA) I data set combined with GALEX, Sloan Digital Sky Survey (SDSS) and UKIRT Infrared Deep Sky Survey (UKIDSS) imaging to construct the low-redshift (z < 0.1) galaxy luminosity functions in FUV, NUV, ugriz and YJHK bands from within a single well-constrained volume of 3.4 × 105 (Mpc h−1)3. The derived luminosity distributions are normalized to the SDSS data release 7 (DR7) main survey to reduce the estimated cosmic variance to the 5 per cent level. The data are used to construct the cosmic spectral energy distribution (CSED) from 0.1 to 2.1 μm free from any wavelength-dependent cosmic variance for both the elliptical and non-elliptical populations. The two populations exhibit dramatically different CSEDs as expected for a predominantly old and young population, respectively. Using the Driver et al. prescription for the azimuthally averaged photon escape fraction, the non-ellipticals are corrected for the impact of dust attenuation and the combined CSED constructed. The final results show that the Universe is currently generating (1.8 ± 0.3) × 1035 h W Mpc−3 of which (1.2 ± 0.1) × 1035 h W Mpc−3 is directly released into the inter-galactic medium and (0.6 ± 0.1) × 1035 h W Mpc−3 is reprocessed and reradiated by dust in the far-IR. Using the GAMA data and our dust model we predict the mid- and far-IR emission which agrees remarkably well with available data. We therefore provide a robust description of the pre- and post-dust attenuated energy output of the nearby Universe from 0.1 μm to 0.6 mm. The largest uncertainty in this measurement lies in the mid- and far-IR bands stemming from the dust attenuation correction and its currently poorly constrained dependence on environment, stellar mass and morphology

GAMA: towards a physical understanding of galaxy formation

The Galaxy And Mass Assembly (GAMA) project is the latest in a tradition of large galaxy redshift surveys, and is now underway on the 3.9m Anglo-Australian Telescope at Siding Spring Observatory. GAMA is designed to map extragalactic structures on scales of 1kpc - 1Mpc in complete detail to a redshift of z~0.2, and to trace the distribution of luminous galaxies out to z~0.5. The principal science aim is to test the standard hierarchical structure formation paradigm of Cold Dark Matter (CDM) on scales of galaxy groups, pairs, discs, bulges and bars. We will measure (1) the Dark Matter Halo Mass Function (as inferred from galaxy group velocity dispersions); (2) baryonic processes, such as star formation and galaxy formation efficiency (as derived from Galaxy Stellar Mass Functions); and (3) the evolution of galaxy merger rates (via galaxy close pairs and galaxy asymmetries). Additionally, GAMA will form the central part of a new galaxy database, which aims to contain 275,000 galaxies with multi-wavelength coverage from coordinated observations with the latest international ground- and space-based facilities: GALEX, VST, VISTA, WISE, HERSCHEL, GMRT and ASKAP. Together, these data will provide increased depth (over 2 magnitudes), doubled spatial resolution (0.7"), and significantly extended wavelength coverage (UV through Far-IR to radio) over the main SDSS spectroscopic survey for five regions, each of around 50 deg^2. This database will permit detailed investigations of the structural, chemical, and dynamical properties of all galaxy types, across all environments, and over a 5 billion year timeline.Comment: GAMA overview which appeared in the October 2009 issue of Astronomy & Geophysics, ref: Astron.Geophys. 50 (2009) 5.1

Identification of the RNA polymerase I-RNA interactome.

Ribosome biogenesis is a complex process orchestrated by a host of ribosome assembly factors. Although it is known that many of the proteins involved in this process have RNA binding activity, the full repertoire of proteins that interact with the precursor ribosomal RNA is currently unknown. To gain a greater understanding of the extent to which RNA-protein interactions have the potential to control ribosome biogenesis, we used RNA affinity isolation coupled with proteomics to measure the changes in RNA-protein interactions that occur when rRNA transcription is blocked. Our analysis identified 211 out of 457 nuclear RNA binding proteins with a >3-fold decrease in RNA-protein interaction after inhibition of RNA polymerase I (RNAPI). We have designated these 211 RNA binding proteins as the RNAPI RNA interactome. As expected, the RNAPI RNA interactome is highly enriched for nucleolar proteins and proteins associated with ribosome biogenesis. Selected proteins from the interactome were shown to be nucleolar in location and to have RNA binding activity that was dependent on RNAPI activity. Furthermore, our data show that two proteins, which are required for rRNA maturation, AATF and NGDN, and which form part of the RNA interactome, both lack canonical RNA binding domains and yet are novel pre-rRNA binding proteins

Galaxy and mass assembly (GAMA): dust obscuration in galaxies and their recent star formation histories

We present self-consistent star formation rates derived through pan-spectral analysis of galaxies drawn from the Galaxy and Mass Assembly (GAMA) survey. We determine the most appropriate form of dust obscuration correction via application of a range of extinction laws drawn from the literature as applied to Hα, [O ii] and UV luminosities. These corrections are applied to a sample of 31 508 galaxies from the GAMA survey at z < 0.35. We consider several different obscuration curves, including those of Milky Way, Calzetti and Fischera & Dopita curves and their effects on the observed luminosities. At the core of this technique is the observed Balmer decrement, and we provide a prescription to apply optimal obscuration corrections using the Balmer decrement. We carry out an analysis of the star formation history (SFH) using stellar population synthesis tools to investigate the evolutionary history of our sample of galaxies as well as to understand the effects of variation in the initial mass function (IMF) and the effects this has on the evolutionary history of galaxies. We find that the Fischera & Dopita obscuration curve with an Rv value of 4.5 gives the best agreement between the different SFR indicators. The 2200 Å feature needed to be removed from this curve to obtain complete consistency between all SFR indicators suggesting that this feature may not be common in the average integrated attenuation of galaxy emission. We also find that the UV dust obscuration is strongly dependent on the SF

Contribution of NOTCH1 genetic variants to bicuspid aortic valve and other congenital lesions

INTRODUCTION: Bicuspid aortic valve (BAV) affects 1% of the general population. NOTCH1 was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to NOTCH1 mutations has not been estimated. AIM: The aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to NOTCH1 mutations. METHODS: The population of our study consisted of participants of the University of Leicester Bicuspid aoRtic vAlVe gEnetic research-8 pedigrees with multiple affected family members and 381 sporadic patients. All subjects underwent NOTCH1 sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting NOTCH1 sequencing in context of congenital heart disease. RESULTS: NOTCH1 sequencing in 36 subjects from 8 pedigrees identified one variant c.873C>G/p.Tyr291* meeting the American College of Medical Genetics and Genomics criteria for pathogenicity. No pathogenic or likely pathogenic NOTCH1 variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting NOTCH1 sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic NOTCH1 variants were detected in 9/435 (2.1%; 95% CI: 0.7% to 3.4%) of pedigrees and between 0.05% (95% CI: 0.005% to 0.10%) and 0.08% (95% CI: 0.02% to 0.13%) of sporadic patients. Incomplete penetrance of definitely pathogenic NOTCH1 mutations was observed in almost half of reported pedigrees. CONCLUSIONS: Pathogenic and likely pathogenic NOTCH1 genetic variants explain 2% of familial and <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart

Galaxy and Mass Assembly (GAMA): Optimal Tiling of Dense Surveys with a Multi-Object Spectrograph

A heuristic greedy algorithm is developed for efficiently tiling spatially dense redshift surveys. In its first application to the Galaxy and MassAssembly (GAMA) redshift survey we find it rapidly improves the spatial uniformity of our data, and naturally corrects for any spatial bias introduced by the 2dF multi-object spectrograph. We make conservative predictions for the final state of the GAMA redshift survey after our final allocation of time, and can be confident that even if worse than typical weather affects our observations, all of our main survey requirements will be me