Graph 'texture' features as novel metrics that can summarize complex biological graphs.

Objective.Image texture features, such as those derived by Haralicket al, are a powerful metric for image classification and are used across fields including cancer research. Our aim is to demonstrate how analogous texture features can be derived for graphs and networks. We also aim to illustrate how these new metrics summarize graphs, may aid comparative graph studies, may help classify biological graphs, and might assist in detecting dysregulation in cancer.Approach.We generate the first analogies of image texture for graphs and networks. Co-occurrence matrices for graphs are generated by summing over all pairs of neighboring nodes in the graph. We generate metrics for fitness landscapes, gene co-expression and regulatory networks, and protein interaction networks. To assess metric sensitivity we varied discretization parameters and noise. To examine these metrics in the cancer context we compare metrics for both simulated and publicly available experimental gene expression and build random forest classifiers for cancer cell lineage.Main results.Our novel graph 'texture' features are shown to be informative of graph structure and node label distributions. The metrics are sensitive to discretization parameters and noise in node labels. We demonstrate that graph texture features vary across different biological graph topologies and node labelings. We show how our texture metrics can be used to classify cell line expression by lineage, demonstrating classifiers with 82% and 89% accuracy.Significance.New metrics provide opportunities for better comparative analyzes and new models for classification. Our texture features are novel second-order graph features for networks or graphs with ordered node labels. In the complex cancer informatics setting, evolutionary analyses and drug response prediction are two examples where new network science approaches like this may prove fruitful.

The conformations and basal conformational dynamics of translocation factor SecDF vary with translocon SecYEG interaction.

The general secretory, or Sec, system is a primary protein export pathway from the cytosol of Escherichia coli and all eubacteria. Integral membrane protein complex SecDF is a translocation factor that enhances polypeptide secretion, which is driven by the Sec translocase, consisting of translocon SecYEG and ATPase SecA. SecDF is thought to utilize a proton gradient to effectively pull precursor proteins from the cytoplasm into the periplasm. Working models have been developed to describe the structure and function of SecDF, but important mechanistic questions remain unanswered. Atomic force microscopy (AFM) is a powerful technique for studying the dynamics of single-molecule systems including membrane proteins in near-native conditions. The sharp tip of the AFM provides direct access to membrane-external protein conformations. Here, we acquired AFM images and kymographs (∼100 ms resolution) to visualize SecDF protrusions in near-native supported lipid bilayers and compared the experimental data to simulated AFM images based on static structures. When studied in isolation, SecDF exhibited a stable and compact conformation close to the lipid bilayer surface, indicative of a resting state. Interestingly, upon SecYEG introduction, we observed changes in both SecDF conformation and conformational dynamics. The population of periplasmic protrusions corresponding to an intermediate form of SecDF, which is thought to be active in precursor protein handling, increased more than ninefold. In conjunction, our dynamics measurements revealed an enhancement in the transition rate between distinct SecDF conformations when the translocon was present. Together, this work provides a novel vista of basal-level SecDF conformational dynamics in near-native conditions.

Runoff and leaching of dissolved phosphorus in streams from a rainfed mixed cropping and grazing catchment under a Mediterranean climate in Australia.

Managing phosphorus (P) is a global priority for environmental water quality due to P lost from agricultural land through leaching, runoff and subsurface flow. In Western Australia (WA), following decades of P fertiliser application to crops and pastures in low rainfall regions, questions have been raised about this region's contribution to environmental P loss. This study was conducted on the Fitzgerald River catchment in the south Western Australia (WA) with mixed cropping and grazing land uses and a Mediterranean climate with low mean rainfall (~350 mm yr-1). Phosphorus forms were monitored continuously over a three-year period in five separate streams, each draining a defined sub-catchment. The P concentrations in streams consistently exceeded Australian and New Zealand Environment Conservation Council (ANZECC) trigger values throughout the monitoring period. Of the measured total P concentration, ~75% was dissolved P (DRP; <0.45 µm) and 80% of that fraction was in the filterable reactive form (FRP). These water quality measurements and other independent soil investigations at this site, suggest that transport of dissolved P rather than erosion of sediment-bound P was dominant in this environment. Based on extractable soil P (Colwell P) and the P buffering index (PBI), predicted concentrations of dissolved reactive P (DRP) in soil solution in topsoils (0-10 cm) across this catchment, generally exceeded ANZECC's values of 0.07 mg PL-1. The level of exceedance was spatially variable. Streams draining areas with the lowest predicted DRP concentrations also had the lowest measured FRP concentrations. Elsewhere stream water FRP concentrations depended on both DRP concentration and the PBI of the land being drained. Our findings suggest that deployment of practices that physically filter runoff, for example riparian vegetation, would be ineffective in restricting P transport into stream in this environment. This conclusion is consistent with previous findings of the ineffectiveness of riparian buffers on coarse textured sandy soils in higher rainfall areas of southwest WA. A reduction in DRP losses without yield loss could be achieved by following evidence-based fertiliser advice from soil testing to limit losses of legacy P".

The Bingo Card Sign as an Early Symptom of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized pathologically by irreversible protein misfolding-induced neuronal loss, and clinically by progressive impairments in memory, judgment, decision making, literacy and numeracy. We report a patient referred to Memory Clinic with a single complaint, "reduced capacity to play bingo." We suggest that the capacity to successfully play bingo may afford clinical clues indicating an early symptom of dementia and inquiries about bingo participation may be a useful when assessing individuals for dementia. Bingo requires the use of multiple cognitive skills which are impaired by AD, including number recognition, letter recognition, short term memory and concentration. With the game of bingo steadily gaining in popularity it may become an easily utilized line of questioning to detect indications of dementia prior to the development of currently recognized clinical symptoms.

Phenotypic and Haplotype Diversity among Tetraploid and Hexaploid Wheat Accessions with Potentially Novel Insect Resistance Genes for Wheat Stem Sawfly.

Genetic diversity in breeding programs can be impaired by fixation of alleles derived from a limited number of founder lines. This is demonstrated with the use of a solid-stem trait derived from the Portuguese landrace 'S-615' over 70 yrs ago that is widely used to resist the wheat stem sawfly ( Norton, WSS) in North America. The objective of this study was to evaluate haplotype diversity underlying the quantitative trait locus (QTL) that controls the majority of the S-615 derived solid-stem genetic variation using single-nucleotide polymorphism (SNP) assays in a diverse set of 228 solid-stem tetraploid and hexaploid wheat accessions originating from areas of the world infested with various species of WSS. Haplotype analysis showed all WSS-resistant hexaploid wheat varieties in North America, except 'Conan', evaluated in this study contain a haplotype associated with the S-615 solid-stem allele. In total, 26 haplotypes were identified among the hexaploid and tetraploid accessions at . Prevalence of most haplotypes were skewed toward either the hexaploid or tetraploid wheat accessions. The haplotype found in the S-615- hexaploid wheat landrace was not found in the solid-stem tetraploid landrace accessions evaluated in this study. Haplotype analysis revealed several new haplotypes that have potential to contain novel alleles for solid-stems at , which may form the basis for introducing genetic diversity into breeding programs aimed at WSS resistance.

Chlamydia pneumoniae Induces Interferon Gamma Responses in Peripheral Blood Mononuclear Cells in Children with Allergic Asthma.

Respiratory infections caused by Chlamydia pneumoniae have been associated with exacerbations of asthma. Cell-mediated immunity (CMI) is critical for maintaining immunity. We compared interferon (IFN)-γ responses in C. pneumoniae-infected peripheral blood mononuclear cells (PBMC) in paediatric patients ± asthma. Presence of C. pneumoniae was tested from asthma patients (N = 17) and non-asthmatic controls (N = 16) (PCR). PBMC were infected for 1 h ± C. pneumoniae AR-39 (MOI = 0.1) and cultured for 48 h. IFN-γ levels were measured in supernatants (ELISA). C. pneumoniae-IgG antibodies in serum were determined (MIF). All subjects tested negative for C. pneumoniae (PCR). C. pneumoniae-induced IFN-γ production in vitro was more prevalent in asthma compared with non-asthma; levels of IFN-γ were higher in asthma compared with non-asthma (P = 0.003). There was no association between recent respiratory infection and positive IFN-γ responses. These data show that C. pneumoniae modulates IFN-γ responses in patients with asthma, even in absence of active infection.

Increased seroprevalence of Enterovirus 71 IgE antibodies in asthmatic compared with non-asthmatic children.

BACKGROUND: Asthma is a common pediatric chronic inflammatory airway disease. Respiratory viral infections are frequent infectious triggers for exacerbations of asthma. OBJECTIVE: We sought to determine whether Enterovirus 71 (EV71), a ubiquitous virus that causes systemic inflammatory responses in children but is not a known respiratory pathogen, can also serve as an infectious trigger for asthma. METHODS: Specific EV71 IgE and IgM antibodies (Abs), total serum IgE, and IL-2 and IL-4 cytokine levels in serum of asthmatic and non-asthmatic children (N = 42, ages 5-19; N = 35, ages 1-20, respectively) were measured (ELISA). RESULTS: Asthmatic children had higher EV71 IgE Ab levels than non-asthmatic (P < 0.001). Non-asthmatic children had significantly higher EV71 IgM Ab levels than asthmatic (P < 0.001). Despite low serum IgE levels of non-asthmatic, compared with asthmatic (P < 0.001), the non-asthmatic children produced significantly more IL-2 and IL-4 than asthmatic (P < 0.001; P < 0.001). The ages of the asthmatics, but not the non-asthmatics had a significant effect on the levels of EV 71 IgE Abs (P = 0.02; P = 0.356). A test of difference between these two slopes was significant. However, the ages of the non-asthmatic, but not the asthmatic children had a significant effect on the levels of EV 71 IgM Abs; a test of difference between these two slopes was significant. CONCLUSIONS: Increased specific EV71 IgE Ab responses may indicate that EV71 infection may also be an infectious trigger in asthma. However, the role of specific EV71 IgM Abs, Th2 cytokines, and age in non-asthmatic children should be further studied.

Evaluation of a "walk-through" ladder top design during ladder-roof transitioning tasks.

This study evaluated the effect of an extension ladder "walk-through" top design on kinetic and kinematic behaviors and the outward destabilizing forces induced on the ladder during transitioning at elevation. Thirty-two male participants performed stepping tasks between a ladder top and a roof at simulated elevation in a surround-screen virtual-reality system. The experimental conditions included a "walk-through" and a standard ladder top section supported on flat and sloped roof surfaces. Three force platforms were placed under the ladder section and in the roof to measure propulsion forces during transitions. A motion measurement system was used to record trunk kinematics. The frictional demand at the virtual ladder base was also calculated. The results indicate that under optimal ladder setup (angle 75.5 °), the frictional demand at the ladder base remains relatively small for all experimental conditions. Also, the "walk through" ladder top eased the ladder-to-roof transitions but not the roof-to-ladder transitions.

Estimating farm to catchment nutrient fluxes using dynamic simulation modelling--can agri-environmental BMPs really do the job?

A dynamic model of Phosphorus (P) movement through the Peel-Harvey catchment in South Western Australia was developed using system dynamics modelling software. The model was developed to illustrate watershed P flux and to predict future P loss rates under a range of management scenarios. Model input parameters were sourced from extensive surveys of local agricultural practices and regional soil testing data. Model P-routing routines were developed from the known interactions between the various watershed P compartments and fluxes between the various P stores. Phosphorus-retention characteristics of a variety of management practices were determined from local field trials where available and published values where not. The model simulated a 200 year time frame to reflect 100 years to the present day since initial land development, and forecast 100 years into the future. Although the catchment has an annual P-loss target of 70 tonnes per annum (tpa), the measured (and modelled) present-day loss is double this amount (140 tpa) and this is projected to rise to 1300 tpa if current land management practices continue. Broad implementation of neither "biological" BMPs such as perennial pastures and managed riparian zones, or of "chemical" BMPs such as reduced water solubility fertilisers and P-retentive soil amendments, produces reductions in P-loss from present-day levels. Even if broad-scale implementation of the large suite of BMPs tested in this research occurs, catchment P-losses are likely to increase from the present level of 140 tpa to approximately 200 tpa over the next 100 years. This has significant implications for both future land use and subsequent water quality in the catchment as well as questioning the wisdom and perceptions of efficacy of past and future BMP implementation strategies.

Odorant receptors of a primitive hymenopteran pest, the wheat stem sawfly.

The wheat stem sawfly, Cephus cinctus, is an herbivorous hymenopteran that feeds exclusively on members of the Graminae family. Synanthropically, it has become one of the most important insect pests of wheat grown in the northern Great Plains region of the USA and Canada. Insecticides are generally ineffective because of the wheat stem sawfly's extended adult flight period and its inaccessible larval stage, during which it feeds within the wheat stems, making it virtually intractable to most pest management strategies. While research towards integrated pest management strategies based on insect olfaction has proved promising, nothing is known about the molecular basis of olfaction in this important pest species. In this study we identified 28 unique odorant receptor (Or) transcripts from an antennal transcriptome. A phylogenetic analysis with the predicted Ors from the honey bee and jewel wasp genomes revealed at least four clades conserved amongst all three Hymenoptera species. Antennal expression levels were analysed using quantitative real-time PCR, and one male-biased and five female-biased Ors were identified. This study provides the basis for future functional analyses to identify behaviourally active odours that can be used to help develop olfactory-mediated pest management tools.

Overabundant FANCD2, alone and combined with NQO1, is a sensitive marker of adverse prognosis in breast cancer.

BACKGROUND: Defective DNA repair is central to the progression and treatment of breast cancer. Immunohistochemically detected DNA repair markers may be good candidates for novel prognostic and predictive factors that could guide the selection of individualized treatment strategies. PATIENTS AND METHODS: We have analyzed nuclear immunohistochemical staining of BRCA1, FANCD2, RAD51, XPF, and PAR in relation to clinicopathological and survival data among 1240 paraffin-embedded breast tumors, and additional gene expression microarray data from 76 tumors. The antioxidant enzyme NQO1 was analyzed as a potential modifier of prognostic DNA repair markers. RESULTS: RAD51 [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.70-0.94, P = 0.0050] and FANCD2 expression (HR 1.50, 95% CI 1.28-1.76, P = 1.50 × 10(-7)) were associated with breast cancer survival. High FANCD2 expression correlated with markers of adverse prognosis but remained independently prognostic in multivariate analysis (HR 1.27, 95% CI 1.08-1.49, P = 0.0043). The FANCD2-associated survival effect was most pronounced in hormone receptor positive, HER2-negative tumors, and in tumors with above-median NQO1 expression. In the NQO1-high subset, patients belonging to the highest quartile of FANCD2 immunohistochemical scores had a threefold increased risk of metastasis or death (HR 3.10, 95% CI 1.96-4.92). Global gene expression analysis indicated that FANCD protein overabundance is associated with the upregulation of proliferation-related genes and a downregulated nucleotide excision repair pathway. CONCLUSION: FANCD2 immunohistochemistry is a sensitive, independent prognostic factor in breast cancer, particularly when standard markers indicate relatively favorable prognosis. Taken together, our results suggest that the prognostic effect is linked to proliferation, DNA damage, and oxidative stress; simultaneous detection of FANCD2 and NQO1 provides additional prognostic value.

Research to improve extension ladder angular positioning.

A leading cause for extension ladder fall incidents is a slide-out event usually related to suboptimal ladder inclination. An improved ladder positioning method or procedure could reduce the risk of ladder stability failure and the related fall injury. The objective of the study was to comparatively evaluate the effectiveness of a multimodal angle indicator with other existing methods for extension ladder angular positioning. Twenty experienced and 20 inexperienced ladder users participated in the study. Four ladder positioning methods were tested in a controlled laboratory environment with 4.88 m (16 ft) and 7.32 m (24 ft) ladders in extended and retracted positions. The positioning methods included a no-instruction method, the current standard anthropometric method, and two instrumental methods - a bubble level indicator, and a multimodal indicator providing direct feedback with visual and sound signals. Performance measures included positioning angle and time. The results indicated that the anthropometric method was effective in improving the extension ladder positioning angle (p < 0.001); however, it was associated with considerable variability and required 50% more time than no-instruction. The bubble level indicator was an accurate positioning method (with very low variability), but required more than double the time of the no-instruction method (p < 0.001). The multimodal indicator improved the ladder angle setting as compared to the no-instruction and anthropometry methods (p < 0.001) and required the least time for ladder positioning among the tested methods (p < 0.001). An indicator with direct multimodal feedback is a viable approach for quick and accurate ladder positioning. The main advantage of the new multimodal method is that it provides continuous feedback on the angle of the device and hence does not require repositioning of the ladder. Furthermore, this indicator can be a valuable tool for training ladder users to correctly apply the current ANSI A14 standard anthropometric method in ladder angular positioning. The multimodal indicator concept has been further developed to become a hand-held tool in the form of a smart phone application.

Albedo and atmospheric constraints of dwarf planet Makemake from a stellar occultation.

Pluto and Eris are icy dwarf planets with nearly identical sizes, comparable densities and similar surface compositions as revealed by spectroscopic studies. Pluto possesses an atmosphere whereas Eris does not; the difference probably arises from their differing distances from the Sun, and explains their different albedos. Makemake is another icy dwarf planet with a spectrum similar to Eris and Pluto, and is currently at a distance to the Sun intermediate between the two. Although Makemake's size (1,420 ± 60 km) and albedo are roughly known, there has been no constraint on its density and there were expectations that it could have a Pluto-like atmosphere. Here we report the results from a stellar occultation by Makemake on 2011 April 23. Our preferred solution that fits the occultation chords corresponds to a body with projected axes of 1,430 ± 9 km (1σ) and 1,502 ± 45 km, implying a V-band geometric albedo p(V) = 0.77 ± 0.03. This albedo is larger than that of Pluto, but smaller than that of Eris. The disappearances and reappearances of the star were abrupt, showing that Makemake has no global Pluto-like atmosphere at an upper limit of 4-12 nanobar (1σ) for the surface pressure, although a localized atmosphere is possible. A density of 1.7 ± 0.3 g cm(-3) is inferred from the data.

Cisplatin benefit is predicted by immunohistochemical analysis of DNA repair proteins in squamous cell carcinoma but not adenocarcinoma: theranostic modeling by NSCLC constituent histological subclasses.

BACKGROUND: Most non-small-cell lung cancer (NSCLC) patients receive cisplatin-based chemotherapy though clinical response is restricted to a subset of patients. DNA repair protein levels are possible surrogates for cisplatin-induced DNA adduct (and subsequent cell death) repair efficiency and thus molecular determinants of therapeutic efficacy. The International Adjuvant Lung Trial (IALT)-Bio study previously suggested ERCC1 and MSH2 as predictive of cisplatin-based therapeutic benefit. PATIENTS AND METHODS: DNA repair protein expression (XPF, BRCA1, ERCC1, MSH2, p53, PARP1, and ATM) was assessed by immunohistochemistry on a large subset of patients (N = 769) from the IALT trial. Tissue Microarray slides were digitally scanned and signal quantified by user-defined macros. Statistical analyses (univariate and multivariate) of 5-year disease-free survival (DFS) and 5-year overall survival used binary cut-offs (H score low/high expression). RESULTS: In patients with squamous cell carcinoma (SCC), ATM, p53, PARP1, ERCC1, and MSH2 displayed significant (borderline) predictive values, mainly on DFS with chemotherapy efficacy limited to low marker levels. Adenocarcinoma (ADC) results were not significant. BRCA1 and XPF were not significant for predictive modeling in either SCC or ADCs. CONCLUSION: Here predictive utility of DNA repair enzymes co-segregates with SCC histology, focusing their predictive value to this histological subclass of NSCLC. Distinct mechanisms of chemotherapeutic response or resistance might exist among histological subclasses of solid tumors.

Genomic evolution in Barrett's adenocarcinoma cells: critical roles of elevated hsRAD51, homologous recombination and Alu sequences in the genome.

A prominent feature of most cancers including Barrett's adenocarcinoma (BAC) is genetic instability, which is associated with development and progression of disease. In this study, we investigated the role of recombinase (hsRAD51), a key component of homologous recombination (HR)/repair, in evolving genomic changes and growth of BAC cells. We show that the expression of RAD51 is elevated in BAC cell lines and tissue specimens, relative to normal cells. HR activity is also elevated and significantly correlates with RAD51 expression in BAC cells. The suppression of RAD51 expression, by short hairpin RNA (shRNA) specifically targeting this gene, significantly prevented BAC cells from acquiring genomic changes to either copy number or heterozygosity (P<0.02) in several independent experiments employing single-nucleotide polymorphism arrays. The reduction in copy-number changes, following shRNA treatment, was confirmed by Comparative Genome Hybridization analyses of the same DNA samples. Moreover, the chromosomal distributions of mutations correlated strongly with frequencies and locations of Alu interspersed repetitive elements on individual chromosomes. We conclude that the hsRAD51 protein level is systematically elevated in BAC, contributes significantly to genomic evolution during serial propagation of these cells and correlates with disease progression. Alu sequences may serve as substrates for elevated HR during cell proliferation in vitro, as they have been reported to do during the evolution of species, and thus may provide additional targets for prevention or treatment of this disease.

The development of new therapeutics for Alzheimer's disease.

Existing treatments for Alzheimer's disease (AD) fail to address the underlying pathology of the disease; they merely provide short-lived symptomatic relief. Consequently, the progression of AD is unrelenting, leading to a continual decrease in cognitive abilities. Recent advances in understanding the genetic factors that predispose to AD, as well as in biomarker development, have brought with them the promise of earlier and more reliable diagnosis of this disease. As improvements continue to be made in these areas, the shortcomings of current AD treatments appear all the more acute because opportunities for early intervention are hindered by a lack of "curative" or even disease-modifying drugs. This State of the Art report reviews existing AD therapeutics and highlights recent progress made in the design and development of drugs that are aimed at disrupting AD disease progression by inhibition of the protein misfolding of ß-amyloid (Aß) into neurotoxic oligomeric aggregates.

Effect of previous benign breast biopsy on the interpretive performance of subsequent screening mammography.

BACKGROUND: Most breast biopsies will be negative for cancer. Benign breast biopsy can cause changes in the breast tissue, but whether such changes affect the interpretive performance of future screening mammography is not known. METHODS: We prospectively evaluated whether self-reported benign breast biopsy was associated with reduced subsequent screening mammography performance using examination data from the mammography registries of the Breast Cancer Surveillance Consortium from January 2, 1996, through December 31, 2005. A positive interpretation was defined as a recommendation for any additional evaluation. Cancer was defined as any invasive breast cancer or ductal carcinoma in situ diagnosed within 1 year of mammography screening. Measures of mammography performance (sensitivity, specificity, and positive predictive value 1 [PPV1]) were compared both at woman level and breast level in the presence and absence of self-reported benign biopsy history. Referral to biopsy was considered a positive interpretation to calculate positive predictive value 2 (PPV2). Multivariable analysis of a correct interpretation on each performance measure was conducted after adjusting for registry, year of examination, patient characteristics, months since last mammogram, and availability of comparison film. Accuracy of the mammogram interpretation was measured using area under the receiver operating characteristic curve (AUC). All statistical tests were two-sided. RESULTS: A total of 2,007,381 screening mammograms were identified among 799,613 women, of which 14.6% mammograms were associated with self-reported previous breast biopsy. Multivariable adjusted models for mammography performance showed reduced specificity (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.73 to 0.75, P < .001), PPV2 (OR = 0.85, 95% CI = 0.79 to 0.92, P < .001), and AUC (AUC 0.892 vs 0.925, P < .001) among women with self-reported benign biopsy. There was no difference in sensitivity or PPV1 in the same adjusted models, although unadjusted differences in both were found. Specificity was lowest among women with documented fine needle aspiration-the least invasive biopsy technique (OR = 0.58, 95% CI = 0.55 to 0.61, P < .001). Repeating the analysis among women with documented biopsy history, unilateral biopsy history, or restricted to invasive cancers did not change the results. CONCLUSIONS: Self-reported benign breast biopsy history was associated with statistically significantly reduced mammography performance. The difference in performance was likely because of tissue characteristics rather than the biopsy itself.

Beta-alanine as a small molecule neurotransmitter.

This review discusses the role of beta-alanine as a neurotransmitter. Beta-alanine is structurally intermediate between alpha-amino acid (glycine, glutamate) and gamma-amino acid (GABA) neurotransmitters. In general, beta-alanine satisfies a number of the prerequisite classical criteria for being a neurotransmitter: beta-alanine occurs naturally in the CNS, is released by electrical stimulation through a Ca(2+) dependent process, has binding sites, and inhibits neuronal excitability. beta-Alanine has 5 recognized receptor sites: glycine co-agonist site on the NMDA complex (strychnine-insensitive); glycine receptor site (strychnine sensitive); GABA-A receptor; GABA-C receptor; and blockade of GAT protein-mediated glial GABA uptake. Although beta-alanine binding has been identified throughout the hippocampus, limbic structures, and neocortex, unique beta-alaninergic neurons with no GABAergic properties remain unidentified, and it is impossible to discriminate between beta-alaninergic and GABAergic properties in the CNS. Nevertheless, a variety of data suggest that beta-alanine should be considered as a small molecule neurotransmitter and should join the ranks of the other amino acid neurotransmitters. These realizations open the door for a more comprehensive evaluation of beta-alanine's neurochemistry and for its exploitation as a platform for drug design.

Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia.

BACKGROUND: Mutations in the JARID1C (Jumonji AT-rich interactive domain 1C) gene were recently associated with X-linked mental retardation (XLMR). Mutations in this gene are reported to be one of the relatively more common causes of XLMR with a frequency of approximately 3% in males with proven or probable XLMR. The JARID1C protein functions as a histone 3 lysine 4 (H3K4) demethylase and is involved in the demethylation of H3K4me3 and H3K4me2. METHODS: Mutation analysis of the JARID1C gene was conducted in the following cohorts: probands from 23 XLMR families linked to Xp11.2, 92 males with mental retardation and short stature, and 172 probands from small XLMR families with no linkage information. RESULTS: Four novel mutations consisting of two missense mutations, p.A77T and p.V504M, and two frame shift mutations, p.E468fsX2 and p.R1481fsX9, were identified in males with mental retardation. Two of the mutations, p.V504M and p.E468fsX2, are located in the JmjC domain of the JARID1C gene where no previous mutations have been reported. Additional studies showed that the missense mutation, p.V504M, was a de novo event on the grandpaternal X chromosome of the family. Clinical findings of the nine affected males from the four different families included mental retardation (100%), short stature (55%), hyperreflexia (78%), seizures (33%) and aggressive behaviour (44%). The degree of mental retardation consisted of mild (25%), moderate (12%) and severe (63%). CONCLUSION: Based on the clinical observations, male patients with mental retardation, short stature and hyperreflexia should be considered candidates for mutations in the JARID1C gene.

Guiding BMP adoption to improve water quality in various estuarine ecosystems in Western Australia.

The Australian Government's Coastal Catchment Initiative (CCI) seeks to achieve targeted reductions in nutrient pollution to key coastal water quality hotspots, reducing algal blooms and fish kills. Under the CCI a Water Quality Improvement Plan (WQIP) is being prepared for targeted estuaries (Swan-Canning, near Perth, and the Vasse-Geographe, 140 km south of Perth) to address nutrient pollution issues. A range of projects are developing, testing and implementing agricultural Best Management Practices (BMPs) to reduce excessive loads of nutrients reaching the receiving waters. This work builds on progress-to-date achieved in a similar project in the Peel-Harvey Catchment (70 km south of Perth). It deals with the necessary steps of identifying the applicability of BMPs for nutrient attenuation, developing and promoting BMPs in the context of nutrient use and attenuation on farm and through catchments and estimating the degree to which BMP implementation can protect receiving waters. With a range of BMPs available with varying costs and effectiveness, a Decision Support System (DSS) to guide development of the WQIP and implementation of BMPs to protect receiving waters, is under development. As new information becomes available the DSS will be updated to ensure relevance and accuracy for decision-making and planning purposes. The DSS, calibrated for application in the catchments, will play a critical role in adaptive implementation of the WQIP by assessing the effect of land use change and management interventions on pollutant load generation and by providing a tool to guide priority setting and investment planning to achieve agreed WQIP load targets.