Identification and mutational analyses of phosphorylation sites of the calcineurin-binding protein CbpA and the identification of domains required for calcineurin binding in Aspergillus fumigatus.

Calcineurin is a key protein phosphatase required for hyphal growth and virulence in Aspergillus fumigatus, making it an attractive antifungal target. However, currently available calcineurin inhibitors, FK506 and cyclosporine A, are immunosuppressive, limiting usage in the treatment of patients with invasive aspergillosis. Therefore, the identification of endogenous inhibitors of calcineurin belonging to the calcipressin family is an important parallel strategy. We previously identified the gene cbpA as the A. fumigatus calcipressin member and showed its involvement in hyphal growth and calcium homeostasis. However, the mechanism of its activation/inhibition through phosphorylation and its interaction with calcineurin remains unknown. Here we show that A. fumigatus CbpA is phosphorylated at three distinct domains, including the conserved SP repeat motif (phosphorylated domain-I; PD-I), a filamentous fungal-specific domain (PD-II), and the C-terminal CIC motif (Calcipressin Inhibitor of Calcineurin; PD-III). While mutation of three phosphorylated residues (Ser208, Ser217, Ser223) in the PD-II did not affect CbpA function in vivo, mutation of the two phosphorylated serines (Ser156, Ser160) in the SP repeat motif caused reduced hyphal growth and sensitivity to oxidative stress. Mutational analysis in the key domains in calcineurin A (CnaA) and proteomic interaction studies confirmed the requirement of PxIxIT motif-binding residues (352-NIR-354) and the calcineurin B (CnaB)-binding helix residue (V371) for the binding of CbpA to CnaA. Additionally, while the calmodulin-binding residues (442-RVF-444) did not affect CbpA binding to CnaA, three mutations (T359P, H361L, and L365S) clustered between the CnaA catalytic and the CnaB-binding helix were also required for CbpA binding. This is the first study to analyze the phosphorylation status of calcipressin in filamentous fungi and identify the domains required for binding to calcineurin

The High Redshift Integrated Sachs-Wolfe Effect

In this paper we rely on the quasar (QSO) catalog of the Sloan Digital Sky Survey Data Release Six (SDSS DR6) of about one million photometrically selected QSOs to compute the Integrated Sachs-Wolfe (ISW) effect at high redshift, aiming at constraining the behavior of the expansion rate and thus the behaviour of dark energy at those epochs. This unique sample significantly extends previous catalogs to higher redshifts while retaining high efficiency in the selection algorithm. We compute the auto-correlation function (ACF) of QSO number density from which we extract the bias and the stellar contamination. We then calculate the cross-correlation function (CCF) between QSO number density and Cosmic Microwave Background (CMB) temperature fluctuations in different subsamples: at high z>1.5 and low z<1.5 redshifts and for two different choices of QSO in a conservative and in a more speculative analysis. We find an overall evidence for a cross-correlation different from zero at the 2.7\sigma level, while this evidence drops to 1.5\sigma at z>1.5. We focus on the capabilities of the ISW to constrain the behaviour of the dark energy component at high redshift both in the \LambdaCDM and Early Dark Energy cosmologies, when the dark energy is substantially unconstrained by observations. At present, the inclusion of the ISW data results in a poor improvement compared to the obtained constraints from other cosmological datasets. We study the capabilities of future high-redshift QSO survey and find that the ISW signal can improve the constraints on the most important cosmological parameters derived from Planck CMB data, including the high redshift dark energy abundance, by a factor \sim 1.5.Comment: 20 pages, 18 figures, and 7 table

The institutional shaping of management: in the tracks of English individualism

Globalisation raises important questions about the shaping of economic action by cultural factors. This article explores the formation of what is seen by some as a prime influence on the formation of British management: individualism. Drawing on a range of historical sources, it argues for a comparative approach. In this case, the primary comparison drawn is between England and Scotland. The contention is that there is a systemic approach to authority in Scotland that can be contrasted to a personal approach in England. An examination of the careers of a number of Scottish pioneers of management suggests the roots of this systemic approach in practices of church governance. Ultimately this systemic approach was to take a secondary role to the personal approach engendered by institutions like the universities of Oxford and Cambridge, but it found more success in the different institutional context of the USA. The complexities of dealing with historical evidence are stressed, as is the value of taking a comparative approach. In this case this indicates a need to take religious practice as seriously as religious belief as a source of transferable practice. The article suggests that management should not be seen as a simple response to economic imperatives, but as shaped by the social and cultural context from which it emerges

CTCF genetic alterations in endometrial carcinoma are pro-tumorigenic

CTCF is a haploinsufficient tumour suppressor gene with diverse normal functions in genome structure and gene regulation. However the mechanism by which CTCF haploinsufficiency contributes to cancer development is not well understood. CTCF is frequently mutated in endometrial cancer. Here we show that most CTCF mutations effectively result in CTCF haploinsufficiency through nonsense-mediated decay of mutant transcripts, or loss-of-function missense mutation. Conversely, we identified a recurrent CTCF mutation K365T, which alters a DNA binding residue, and acts as a gain-of-function mutation enhancing cell survival. CTCF genetic deletion occurs predominantly in poor prognosis serous subtype tumours, and this genetic deletion is associated with poor overall survival. In addition, we have shown that CTCF haploinsufficiency also occurs in poor prognosis endometrial clear cell carcinomas and has some association with endometrial cancer relapse and metastasis. Using shRNA targeting CTCF to recapitulate CTCF haploinsufficiency, we have identified a novel role for CTCF in the regulation of cellular polarity of endometrial glandular epithelium. Overall, we have identified two novel pro-tumorigenic roles (promoting cell survival and altering cell polarity) for genetic alterations of CTCF in endometrial cance

Constraining Primordial Non-Gaussianity with High-Redshift Probes

We present an analysis of the constraints on the amplitude of primordial non-Gaussianity of local type described by the dimensionless parameter $f_{\rm NL}$. These constraints are set by the auto-correlation functions (ACFs) of two large scale structure probes, the radio sources from NRAO VLA Sky Survey (NVSS) and the quasar catalogue of Sloan Digital Sky Survey Release Six (SDSS DR6 QSOs), as well as by their cross-correlation functions (CCFs) with the cosmic microwave background (CMB) temperature map (Integrated Sachs-Wolfe effect). Several systematic effects that may affect the observational estimates of the ACFs and of the CCFs are investigated and conservatively accounted for. Our approach exploits the large-scale scale-dependence of the non-Gaussian halo bias. The derived constraints on {$f_{\rm NL}$} coming from the NVSS CCF and from the QSO ACF and CCF are weaker than those previously obtained from the NVSS ACF, but still consistent with them. Finally, we obtain the constraints on $f_{\rm NL}=53\pm25$ ($1\,\sigma$) and $f_{\rm NL}=58\pm24$ ($1\,\sigma$) from NVSS data and SDSS DR6 QSO data, respectively.Comment: 16 pages, 8 figures, 1 table, Accepted for publication on JCA

Implementing NICE guidelines for the psychological treatment of depression and anxiety disorders: The IAPT experience

The Improving Access to Psychological Therapies (IAPT) programme is a large-scale initiative that aims to greatly increase the availability of NICE recommended psychological treatment for depression and anxiety disorders within the National Health Service in England. This article describes the background to the programme, the arguments on which it is based, the therapist training scheme, the clinical service model, and a summary of progress to date. At mid-point in a national roll-out of the programme progress is generally in line with expectation, and a large number of people who would not otherwise have had the opportunity to receive evidence-based psychological treatment have accessed, and benefited from, the new IAPT services. Planned future developments and challenges for the programme are briefly described

Optical and spin properties of localized and free excitons in GaBi ₓAs₁-ₓ /GaAs multiple quantum wells

Raman spectroscopy and magneto-photoluminescence measurements under high magnetic fields were used to investigate the optical and spin properties of GaBiAs/GaAs multiple quantum wells (MQWs). An anomalous negative diamagnetic energy shift was observed at higher temperatures and higher laser intensities, which was associated to a sign inversion of hole effective mass in these structures. In addition, an enhancement of the polarization degree with decreasing of laser intensity was observed (experimental condition where the emission is dominated by localized excitons). This effect was explained by changes of spin relaxation and exciton recombination times due to exciton localization by disorder

Ethnicity and prediction of cardiovascular disease: performance of QRISK2 and Framingham scores in a U.K. tri-ethnic prospective cohort study (SABRE--Southall And Brent REvisited).

OBJECTIVE: To evaluate QRISK2 and Framingham cardiovascular disease (CVD) risk scores in a tri-ethnic U.K. population. DESIGN: Cohort study. SETTING: West London. PARTICIPANTS: Randomly selected from primary care lists. Follow-up data were available for 87% of traced participants, comprising 1866 white Europeans, 1377 South Asians, and 578 African Caribbeans, aged 40-69 years at baseline (1998-1991). MAIN OUTCOME MEASURES: First CVD events: myocardial infarction, coronary revascularisation, angina, transient ischaemic attack or stroke reported by participant, primary care or hospital records or death certificate. RESULTS: During follow-up, 387 CVD events occurred in men (14%) and 78 in women (8%). Both scores underestimated risk in European and South Asian women (ratio of predicted to observed risk: European women: QRISK2: 0.73, Framingham: 0.73; South Asian women: QRISK2: 0.52, Framingham: 0.43). In African Caribbeans, Framingham over-predicted in men and women and QRISK2 over-predicted in women. Framingham classified 28% of participants as high risk, predicting 54% of all such events. QRISK2 classified 19% as high risk, predicting 42% of all such events. Both scores performed poorly in identifying high risk African Caribbeans; QRISK2 and Framingham identified as high risk only 10% and 24% of those who experienced events. CONCLUSIONS: Neither score performed consistently well in all ethnic groups. Further validation of QRISK2 in other multi-ethnic datasets, and better methods for identifying high risk African Caribbeans and South Asian women, are required

Opportunistic, human-pathogenic species in the Herpotrichiellaceae are phenotypically similar to saprobic or phytopathogenic species in the Venturiaceae

Although morphologically similar, species of Cladophialophora (Herpotrichiellaceae) were shown to be phylogenetically distinct from Pseudocladosporium (Venturiaceae), which was revealed to be synonymous with the older genus, Fusicladium. Other than being associated with human disorders, species of Cladophialophora were found to also be phytopathogenic, or to occur as saprobes on organic material, or in water, fruit juices, or sports drinks, along with species of Exophiala. Caproventuria and Metacoleroa were confirmed to be synonyms of Venturia, which has Fusicladium (= Pseudocladosporium) anamorphs. Apiosporina, based on A. collinsii, clustered basal to the Venturia clade, and appears to represent a further synonym. Several species with a pseudocladosporium-like morphology in vitro represent a sister clade to the Venturia clade, and are unrelated to Polyscytalum. These taxa are newly described in Fusicladium, which is morphologically close to Anungitea, a heterogeneous genus with unknown phylogenetic affinity. In contrast to the Herpotrichiellaceae, which were shown to produce numerous synanamorphs in culture, species of the Venturiaceae were morphologically and phylogenetically more uniform. Several new species and new combinations were introduced in Cladophialophora, Cyphellophora (Herpotrichiellaceae), Exophiala, Fusicladium, Venturia (Venturiaceae), and Cylindrosympodium (incertae sedis)

Measurement of the Bs0→J/ψKS0B_s^0\to J/\psi K_S^0 branching fraction

The $B_s^0\to J/\psi K_S^0$ branching fraction is measured in a data sample corresponding to 0.41$fb^{-1}$ of integrated luminosity collected with the LHCb detector at the LHC. This channel is sensitive to the penguin contributions affecting the sin2$\beta$ measurement from $B^0\to J/\psi K_S^0$ The time-integrated branching fraction is measured to be $BF(B_s^0\to J/\psi K_S^0)=(1.83\pm0.28)\times10^{-5}$. This is the most precise measurement to date