Physiological role for GABAA receptor desensitization in the induction of long-term potentiation at inhibitory synapses.

GGABAA receptors (GABAARs) are pentameric ligand-gated ion channels distributed throughout the brain where they mediate synaptic and tonic inhibition. Following activation, these receptors undergo desensitization which involves entry into long-lived agonist-bound closed states. Although the kinetic effects of this state are recognised and its structural basis has been uncovered, the physiological impact of desensitization on inhibitory neurotransmission remains unknown. Here we describe an enduring form of long-term potentiation at inhibitory synapses that elevates synaptic current amplitude for 24 h following desensitization of GABAARs in response to agonist exposure or allosteric modulation. Using receptor mutants and allosteric modulators we demonstrate that desensitization of GABAARs facilitates their phosphorylation by PKC, which increases the number of receptors at inhibitory synapses. These observations provide a physiological relevance to the desensitized state of GABAARs, acting as a signal to regulate the efficacy of inhibitory synapses during prolonged periods of inhibitory neurotransmission

Chandrasekhar-Kendall functions in astrophysical dynamos

Some of the contributions of Chandrasekhar to the field of magnetohydrodynamics are highlighted. Particular emphasis is placed on the Chandrasekhar-Kendall functions that allow a decomposition of a vector field into right- and left-handed contributions. Magnetic energy spectra of both contributions are shown for a new set of helically forced simulations at resolutions higher than what has been available so far. For a forcing function with positive helicity, these simulations show a forward cascade of the right-handed contributions to the magnetic field and nonlocal inverse transfer for the left-handed contributions. The speed of inverse transfer is shown to decrease with increasing value of the magnetic Reynolds number.Comment: 10 pages, 5 figures, proceedings of the Chandrasekhar Centenary Conference, to be published in PRAMANA - Journal of Physic

Evidence for niche adaptation in the genome of the bovine pathogen Streptococcus uberis.

BACKGROUND: Streptococcus uberis, a Gram positive bacterial pathogen responsible for a significant proportion of bovine mastitis in commercial dairy herds, colonises multiple body sites of the cow including the gut, genital tract and mammary gland. Comparative analysis of the complete genome sequence of S. uberis strain 0140J was undertaken to help elucidate the biology of this effective bovine pathogen. RESULTS: The genome revealed 1,825 predicted coding sequences (CDSs) of which 62 were identified as pseudogenes or gene fragments. Comparisons with related pyogenic streptococci identified a conserved core (40%) of orthologous CDSs. Intriguingly, S. uberis 0140J displayed a lower number of mobile genetic elements when compared with other pyogenic streptococci, however bacteriophage-derived islands and a putative genomic island were identified. Comparative genomics analysis revealed most similarity to the genomes of Streptococcus agalactiae and Streptococcus equi subsp. zooepidemicus. In contrast, streptococcal orthologs were not identified for 11% of the CDSs, indicating either unique retention of ancestral sequence, or acquisition of sequence from alternative sources. Functions including transport, catabolism, regulation and CDSs encoding cell envelope proteins were over-represented in this unique gene set; a limited array of putative virulence CDSs were identified. CONCLUSION: S. uberis utilises nutritional flexibility derived from a diversity of metabolic options to successfully occupy a discrete ecological niche. The features observed in S. uberis are strongly suggestive of an opportunistic pathogen adapted to challenging and changing environmental parameters.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

An Open Access Database of Genome-wide Association Results

<p>Abstract</p> <p>Background</p> <p>The number of genome-wide association studies (GWAS) is growing rapidly leading to the discovery and replication of many new disease loci. Combining results from multiple GWAS datasets may potentially strengthen previous conclusions and suggest new disease loci, pathways or pleiotropic genes. However, no database or centralized resource currently exists that contains anywhere near the full scope of GWAS results.</p> <p>Methods</p> <p>We collected available results from 118 GWAS articles into a database of 56,411 significant SNP-phenotype associations and accompanying information, making this database freely available here. In doing so, we met and describe here a number of challenges to creating an open access database of GWAS results. Through preliminary analyses and characterization of available GWAS, we demonstrate the potential to gain new insights by querying a database across GWAS.</p> <p>Results</p> <p>Using a genomic bin-based density analysis to search for highly associated regions of the genome, positive control loci (e.g., MHC loci) were detected with high sensitivity. Likewise, an analysis of highly repeated SNPs across GWAS identified replicated loci (e.g., <it>APOE</it>, <it>LPL</it>). At the same time we identified novel, highly suggestive loci for a variety of traits that did not meet genome-wide significant thresholds in prior analyses, in some cases with strong support from the primary medical genetics literature (<it>SLC16A7, CSMD1, OAS1</it>), suggesting these genes merit further study. Additional adjustment for linkage disequilibrium within most regions with a high density of GWAS associations did not materially alter our findings. Having a centralized database with standardized gene annotation also allowed us to examine the representation of functional gene categories (gene ontologies) containing one or more associations among top GWAS results. Genes relating to cell adhesion functions were highly over-represented among significant associations (p < 4.6 × 10^-14), a finding which was not perturbed by a sensitivity analysis.</p> <p>Conclusion</p> <p>We provide access to a full gene-annotated GWAS database which could be used for further querying, analyses or integration with other genomic information. We make a number of general observations. Of reported associated SNPs, 40% lie within the boundaries of a RefSeq gene and 68% are within 60 kb of one, indicating a bias toward gene-centricity in the findings. We found considerable heterogeneity in information available from GWAS suggesting the wider community could benefit from standardization and centralization of results reporting.</p

Promiscuous Expression of α-Tubulin II in Maturing Male and Female Plasmodium falciparum Gametocytes

BACKGROUND: Antimalarial interventions designed to impact on the transmissible sexual stages of Plasmodium falciparum are evaluated by measurement of peripheral gametocyte carriage in vivo and infectivity to mosquitoes. Drug or vaccine-elicited effects may differentially affect the relative abundance of mature male and female sexual forms, and this can be measured by estimation of sex ratios before and after intervention in vivo and in vitro. Measuring the impact of anti-gametocyte drugs on sexual commitment of immature gametocyte stages in vitro is not currently possible as male and female parasites cannot be distinguished by morphology alone prior to stage IV. METHODOLOGY/PRINCIPAL FINDINGS: We have modified an existing immunofluorescence-based approach for distinguishing male and female gametocytes during development in vitro, by using highly synchronised magnetically-enriched gametocyte preparations at different stages of maturity. Antibodies recognising α-tubulin II (males) and Pfg377 (females) were used to attempt to discriminate the sexes. Transcription of these two proteins was not coordinated during in vitro development, with pfg377 transcripts accumulating only late in development, immediately prior to immunofluorescent signals from the PfG377 protein appearing in stage IV gametocytes. Contrary to previous descriptions of this protein as male-specific in P. falciparum, α-tubulin II recognised both male and female gametocytes at stages I to IV, but evidence of differential expression levels of this protein in late stage male and female gametocytes was found. Using antibodies recognising PfG377 as the primary marker and α-tubulin II as a secondary marker, robust estimates of sex ratio in in vitro cultures were obtained for gametocytes at stage IV or later, and validated by light microscopic counts. However, sex ratio estimation was not possible for early stage gametocytes due to the promiscuity of α-tubulin II protein expression, and the relatively late accumulation of PfG377 during the development process. CONCLUSIONS/SIGNIFICANCE: This approach is a feasible method for the evaluation of drug impacts on late-stage gametocyte sex ratio in in vitro studies. Additional sex-specific antigens need to be evaluated for sex ratio estimation in early stage gametocyte preparations

Seasonal differences in leaf-level physiology give lianas a competitive advantage over trees in a tropical seasonal forest

Lianas are an important component of most tropical forests, where they vary in abundance from high in seasonal forests to low in aseasonal forests. We tested the hypothesis that the physiological ability of lianas to fix carbon (and thus grow) during seasonal drought may confer a distinct advantage in seasonal tropical forests, which may explain pan-tropical liana distributions. We compared a range of leaf-level physiological attributes of 18 co-occurring liana and 16 tree species during the wet and dry seasons in a tropical seasonal forest in Xishuangbanna, China. We found that, during the wet season, lianas had significantly higher CO2 assimilation per unit mass (Amass), nitrogen concentration (Nmass), and δ13C values, and lower leaf mass per unit area (LMA) than trees, indicating that lianas have higher assimilation rates per unit leaf mass and higher integrated water-use efficiency (WUE), but lower leaf structural investments. Seasonal variation in CO2 assimilation per unit area (Aarea), phosphorus concentration per unit mass (Pmass), and photosynthetic N-use efficiency (PNUE), however, was significantly lower in lianas than in trees. For instance, mean tree Aarea decreased by 30.1% from wet to dry season, compared with only 12.8% for lianas. In contrast, from the wet to dry season mean liana δ13C increased four times more than tree δ13C, with no reduction in PNUE, whereas trees had a significant reduction in PNUE. Lianas had higher Amass than trees throughout the year, regardless of season. Collectively, our findings indicate that lianas fix more carbon and use water and nitrogen more efficiently than trees, particularly during seasonal drought, which may confer a competitive advantage to lianas during the dry season, and thus may explain their high relative abundance in seasonal tropical forests

Search for Kaluza-Klein Graviton Emission in ppˉp\bar{p} Collisions at s=1.8\sqrt{s}=1.8 TeV using the Missing Energy Signature

We report on a search for direct Kaluza-Klein graviton production in a data sample of 84 ${pb}^{-1}$ of \ppb collisions at $\sqrt{s}$ = 1.8 TeV, recorded by the Collider Detector at Fermilab. We investigate the final state of large missing transverse energy and one or two high energy jets. We compare the data with the predictions from a $3+1+n$-dimensional Kaluza-Klein scenario in which gravity becomes strong at the TeV scale. At 95% confidence level (C.L.) for $n$=2, 4, and 6 we exclude an effective Planck scale below 1.0, 0.77, and 0.71 TeV, respectively.Comment: Submitted to PRL, 7 pages 4 figures/Revision includes 5 figure

The Role of Pre- and Postnatal Timing of Family Risk Factors on Child Behavior at 36 months

Children growing up in disharmonious families with anxious/depressed mothers are at risk for emotional and behavioral difficulties, however whether these associations reflect postnatal environment, prenatal exposure, or an overall liability is still unclear. This study used prospectively collected data from 24,259 participants of the Norwegian Mother and Child Cohort Study (MoBa). Mothers reported on anxiety/depression and family disharmony twice in pregnancy and twice post pregnancy, as well as on their child’s physical aggression and crying behavior at age 36 months. First, results from an autoregressive cross-lagged model showed a substantial stability in both maternal anxiety/depression and family disharmony from pregnancy to 18 months postnatal, but there was no indication that family disharmony led to maternal anxiety/depression, or the other way around. Second, structural equation models further suggests that the main risk derived from an overall liability, that is, a lasting effect of family risks that spanned the two time periods

M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis

BACKGROUND: The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis. METHODS: M6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months. RESULTS: M6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/IGF2R loss of heterozygosity. CONCLUSIONS: This study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy