Structural and biochemical characterization of the exopolysaccharide deacetylase Agd3 required for Aspergillus fumigatus biofilm formation

The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Deletion of a gene encoding a putative deacetylase, Agd3, leads to defects in GAG deacetylation, biofilm formation, and virulence. Here, we show that Agd3 deacetylates GAG in a metal-dependent manner, and is the founding member of carbohydrate esterase family CE18. The active site is formed by four catalytic motifs that are essential for activity. The structure of Agd3 includes an elongated substrate-binding cleft formed by a carbohydrate binding module (CBM) that is the founding member of CBM family 87. Agd3 homologues are encoded in previously unidentified putative bacterial exopolysaccharide biosynthetic operons and in other fungal genomes. The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Here, the authors study an A. fumigatus enzyme that deacetylates GAG in a metal-dependent manner and constitutes a founding member of a new carbohydrate esterase family.Bio-organic Synthesi

Galaxy And Mass Assembly (GAMA): refining the local galaxy merger rate using morphological information

We use the Galaxy And Mass Assembly (GAMA) survey to measure the local Universe mass dependent merger fraction and merger rate using galaxy pairs and the CAS structural method, which identifies highly asymmetric merger candidate galaxies. Our goals are to determine which types of mergers produce highly asymmetrical galaxies, and to provide a new measurement of the local galaxy major merger rate. We examine galaxy pairs at stellar mass limits down to M∗ = 108M⊙ with mass ratios of 4:1) the lower mass companion becomes highly asymmetric, while the larger galaxy is much less affected. The fraction of highly asymmetric paired galaxies which have a major merger companion is highest for the most massive galaxies and drops progressively with decreasing mass. We calculate that the mass dependent major merger fraction is fairly constant at _ 1.3 − 2% between 109.5 < M∗ < 1011.5M⊙, and increases to _ 4% at lower masses. When the observability time scales are taken into consideration, the major merger rate is found to approximately triple over the mass range we consider. The total co-moving volume major merger rate over the range 108.0 < M∗ < 1011.5M⊙ is (1.2 ± 0.5) × 10−3 h3 70 Mpc−3 Gyr−1

Galaxy And Mass Assembly (GAMA): refining the local galaxy merger rate using morphological information

We use the Galaxy And Mass Assembly (GAMA) survey to measure the local Universe mass dependent merger fraction and merger rate using galaxy pairs and the CAS structural method, which identifies highly asymmetric merger candidate galaxies. Our goals are to determine which types of mergers produce highly asymmetrical galaxies, and to provide a new measurement of the local galaxy major merger rate. We examine galaxy pairs at stellar mass limits down to M∗ = 108M⊙ with mass ratios of 4:1) the lower mass companion becomes highly asymmetric, while the larger galaxy is much less affected. The fraction of highly asymmetric paired galaxies which have a major merger companion is highest for the most massive galaxies and drops progressively with decreasing mass. We calculate that the mass dependent major merger fraction is fairly constant at _ 1.3 − 2% between 109.5 < M∗ < 1011.5M⊙, and increases to _ 4% at lower masses. When the observability time scales are taken into consideration, the major merger rate is found to approximately triple over the mass range we consider. The total co-moving volume major merger rate over the range 108.0 < M∗ < 1011.5M⊙ is (1.2 ± 0.5) × 10−3 h3 70 Mpc−3 Gyr−1

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

Stroke prevalence among the Spanish elderly: an analysis based on screening surveys

BACKGROUND: This study sought to describe stroke prevalence in Spanish elderly populations and compare it against that of other European countries. METHODS: We identified screening surveys -both published and unpublished- in Spanish populations, which fulfilled specific quality requirements and targeted prevalence of stroke in populations aged 70 years and over. Surveys covering seven geographically different populations with prevalence years in the period 1991–2002 were selected, and the respective authors were then asked to provide descriptions of the methodology and raw age-specific data by completing a questionnaire. In addition, five reported screening surveys in European populations furnished useful data for comparison purposes. Prevalence data were combined, using direct adjustment and logistic regression. RESULTS: The overall study population, resident in central and north-eastern Spain, totalled 10,647 persons and yielded 715 cases. Age-adjusted prevalences, using the European standard population, were 7.3% for men, 5.6% for women, and 6.4% for both sexes. Prevalence was significantly lower in women, OR 0.79 95% CI 0.68–0.93, increased with age, particularly among women, and displayed a threefold spatial variation with statistically significant differences. Prevalences were highest, 8.7%, in suburban, and lowest, 3.8%, in rural populations. Compared to pooled Spanish populations, statistically significant differences were seen in eight Italian populations, OR 1.39 95%CI (1.18–1.64), and in Kungsholmen, Sweden, OR 0.40 95%CI (0.27–0.58). CONCLUSION: Prevalence in central and north-eastern Spain is higher in males and in suburban areas, and displays a threefold geographic variation, with women constituting the majority of elderly stroke sufferers. Compared to reported European data, stroke prevalence in Spain can be said to be medium and presents similar age- and sex-specific traits

A new approach to treatment of resistant gram-positive infections: potential impact of targeted IV to oral switch on length of stay

BACKGROUND: Patients prescribed intravenous (IV) glycopeptides usually remain in hospital until completion of this treatment. Some of these patients could be discharged earlier if a switch to an oral antibiotic was made. This study was designed to identify the percentage of inpatients currently prescribed IV glycopeptides who could be discharged earlier if a switch to an oral agent was used, and to estimate the number of bed days that could be saved. We also aimed to identify the patient group(s) most likely to benefit, and to estimate the number of days of IV therapy that could be prevented in patients who remained in hospital. METHODS: Patients were included if they were prescribed an IV glycopeptide for 5 days or more. Predetermined IV to oral antibiotic switch criteria and discharge criteria were applied. A multiple logistic regression model was used to identify the characteristics of the patients most likely to be suitable for earlier discharge. RESULTS: Of 211 patients, 62 (29%) could have had a reduced length of stay if they were treated with a suitable oral antibiotic. This would have saved a total of 649 inpatient days (median 5 per patient; range 1–54). A further 31 patients (15%) could have switched to oral therapy as an inpatient thus avoiding IV line use. The patients most likely to be suitable for early discharge were those with skin and soft tissue infection, under the cardiology, cardiothoracic surgery, orthopaedics, general medical, plastic surgery and vascular specialities, with no high risk comorbidity and less than five other regularly prescribed drugs. CONCLUSION: The need for glycopeptide therapy has a significant impact on length of stay. Effective targeting of oral antimicrobials could reduce the need for IV access, allow outpatient treatment and thus reduce the length of stay in patients with infections caused by antibiotic resistant gram-positive bacteria

High Throughput Interrogation of Somatic Mutations in High Grade Serous Cancer of the Ovary

BACKGROUND:Epithelial ovarian cancer is the most lethal of all gynecologic malignancies, and high grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. The objective of this study was to determine the frequency and types of point somatic mutations in HGSC using a mutation detection protocol called OncoMap that employs mass spectrometric-based genotyping technology. METHODOLOGY/PRINCIPAL FINDINGS:The Center for Cancer Genome Discovery (CCGD) Program at the Dana-Farber Cancer Institute (DFCI) has adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. The mutation detection protocol, termed OncoMap has been expanded to detect more than 1000 mutations in 112 oncogenes in formalin-fixed paraffin-embedded (FFPE) tissue samples. We performed OncoMap on a set of 203 FFPE advanced staged HGSC specimens. We isolated genomic DNA from these samples, and after a battery of quality assurance tests, ran each of these samples on the OncoMap v3 platform. 56% (113/203) tumor samples harbored candidate mutations. Sixty-five samples had single mutations (32%) while the remaining samples had ≥ 2 mutations (24%). 196 candidate mutation calls were made in 50 genes. The most common somatic oncogene mutations were found in EGFR, KRAS, PDGRFα, KIT, and PIK3CA. Other mutations found in additional genes were found at lower frequencies (<3%). CONCLUSIONS/SIGNIFICANCE:Sequenom analysis using OncoMap on DNA extracted from FFPE ovarian cancer samples is feasible and leads to the detection of potentially druggable mutations. Screening HGSC for somatic mutations in oncogenes may lead to additional therapies for this patient population

Which factors explain variation in intention to disclose a diagnosis of dementia? A theory-based survey of mental health professionals

Background: For people with dementia, patient-centred care should involve timely explanation of the diagnosis and its implications. However, this is not routine. Theoretical models of behaviour change offer a generalisable framework for understanding professional practice and identifying modifiable factors to target with an intervention. Theoretical models and empirical work indicate that behavioural intention represents a modifiable predictor of actual professional behaviour. We identified factors that predict the intentions of members of older people's mental health teams (MHTs) to perform key behaviours involved in the disclosure of dementia. Design: Postal questionnaire survey. Participants: Professionals from MHTs in the English National Health Service. Methods: We selected three behaviours: Determining what patients already know or suspect about their diagnosis; using explicit terminology when talking to patients; and exploring what the diagnosis means to patients. The questionnaire was based upon the Theory of Planned Behaviour (TPB), Social Cognitive Theory (SCT), and exploratory team variables. Main outcomes: Behavioural intentions. Results: Out of 1,269 professionals working in 85 MHTs, 399 (31.4%) returned completed questionnaires. Overall, the TPB best explained behavioural intention. For determining what patients already know, the TPB variables of subjective norm, perceived behavioural control and attitude explained 29.4% of the variance in intention. For the use of explicit terminology, the same variables explained 53.7% of intention. For exploring what the diagnosis means to patients, subjective norm and perceived behavioural control explained 48.6% of intention. Conclusion: These psychological models can explain up to half of the variation in intention to perform key disclosure behaviours. This provides an empirically- supported, theoretical basis for the design of interventions to improve disclosure practice by targeting relevant predictive factors. Trial Registration: ISRCTN15871014

3,3′-Diindolylmethane Induces G1 Arrest and Apoptosis in Human Acute T-Cell Lymphoblastic Leukemia Cells

Certain bioactive food components, including indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) from cruciferous vegetables, have been shown to target cellular pathways regulating carcinogenesis. Previously, our laboratory showed that dietary I3C is an effective transplacental chemopreventive agent in a dibenzo[def,p]chrysene (DBC)-dependent model of murine T-cell lymphoblastic lymphoma. The primary objective of the present study was to extend our chemoprevention studies in mice to an analogous human neoplasm in cell culture. Therefore, we tested the hypothesis that I3C or DIM may be chemotherapeutic in human T-cell acute lymphoblastic leukemia (T-ALL) cells. Treatment of the T-ALL cell lines CCRF-CEM, CCRF-HSB2, SUP-T1 and Jurkat with DIM in vitro significantly reduced cell proliferation and viability at concentrations 8- to 25-fold lower than the parent compound I3C. DIM (7.5 µM) arrested CEM and HSB2 cells at the G1 phase of the cell cycle and 15 µM DIM significantly increased the percentage of apoptotic cells in all T-ALL lines. In CEM cells, DIM reduced protein expression of cyclin dependent kinases 4 and 6 (CDK4, CDK6) and D-type cyclin 3 (CCND3); DIM also significantly altered expression of eight transcripts related to human apoptosis (BCL2L10, CD40LG, HRK, TNF, TNFRSF1A, TNFRSF25, TNFSF8, TRAF4). Similar anticancer effects of DIM were observed in vivo. Dietary exposure to 100 ppm DIM significantly decreased the rate of growth of human CEM xenografts in immunodeficient SCID mice, reduced final tumor size by 44% and increased the apoptotic index compared to control-fed mice. Taken together, our results demonstrate a potential for therapeutic application of DIM in T-ALL

Galaxy and mass assembly: the G02 field, Herschel–ATLAS target selection and data release 3

We describe data release 3 (DR3) of the Galaxy And Mass Assembly (GAMA) survey. The GAMA survey is a spectroscopic redshift and multiwavelength photometric survey in three equatorial regions each of 60.0 deg2 (G09, G12, and G15), and two southern regions of 55.7 deg2 (G02) and 50.6 deg2 (G23). DR3 consists of: the first release of data covering the G02 region and of data on H-ATLAS (Herschel – Astrophysical Terahertz Large Area Survey) sources in the equatorial regions; and updates to data on sources released in DR2. DR3 includes 154 809 sources with secure redshifts across four regions. A subset of the G02 region is 95.5 per cent redshift complete to r < 19.8 mag over an area of 19.5 deg2, with 20 086 galaxy redshifts, that overlaps substantially with the XXL survey (X-ray) and VIPERS (redshift survey). In the equatorial regions, the main survey has even higher completeness (98.5 per cent), and spectra for about 75 per cent of H-ATLAS filler targets were also obtained. This filler sample extends spectroscopic redshifts, for probable optical counterparts to HATLAS submillimetre sources, to 0.8 mag deeper (r < 20.6 mag) than the GAMA main survey. There are 25 814 galaxy redshifts for H-ATLAS sources from the GAMA main or filler surveys. GAMA DR3 is available at the survey website (www.gama-survey.org/dr3/)