Structural Analysis of the CDK-Cyclin Complex of Pho85-Pho80 and Genome-Wide Characterization of the Phosphate Starvation Response in Schizosaccharomyces pombe

Inorganic phosphate is an essential nutrient required by all organisms for optimal growth. During phosphate starvation, Saccharomyces cerevisiae induces a set of genes responsible for the regulation of inorganic phosphate acquisition. The phosphate-responsive signaling (PHO) pathway controls this response, with the CDK-cyclin complex Pho85-Pho80 playing a prominent role. Here we report the X-ray structure of the Pho85-Pho80 complex, identifying the unique structural features that distinguish it from other cell cycle associated CDK-cyclin complexes. The structure reveals a specific salt bridge between a Pho85 arginine and a Pho80 aspartate that maintains a Pho80 loop confirmation important for substrate recognition and makes phosphorylation of the Pho85 activation loop dispensible. We show that a cluster of residues distal to the kinase active site are involved in a high affinity interaction between the Pho80 cyclin and the transcription factor substrate (Pho4). The structure also reveals a separate high affinity binding site for the CDK inhibitor (Pho81). The fission yeast, Schizosaccharomyces pombe, regulates expression of the secreted acid phosphatase $(pho1^+)$ via a non-orthologous PHO pathway. The genes induced by phosphate limitation and the molecular mechanism by which the genetically identified positive $(pho7^+)$ and negative $(csk1^+)$ regulators function are not known. Here we use a combination of molecular biology, expression microarrays, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq), and global transcriptome sequencing (RNA-Seq) to characterize the role of $pho7^+$ and $csk1^+$ in the PHO response. We show that there is a fast and slow response to phosphate starvation, each with defined regulatory roles. We use ChIP-Seq to identify members of the Pho7 regulon and characterize Pho7 binding dynamics in response to phosphate-limitation and Csk1 activity. We identify a conserved PHO response for the PHO5 $(pho1^+)$, PHO84 $(spbc8e4.01c^+)$, and GIT1 $(spbc1271.09^+)$ orthologs. We show that activation of $pho1^+$ requires Pho7 binding to a UAS in the $pho1^+$ promoter and that a URS is necessary for Csk1 repression. We find that Pho7-dependent activation is not limited to phosphate-starvation, as additional environmental stress response pathways require $pho7^+$ for maximal induction. Using RNA-Seq we show that Pho7 is also involved in regulating non-coding transcription and is a bi-functional transcription factor

We can’t afford to turn a blind eye to myopia

Background Myopia is becoming increasingly prevalent throughout the world. It is an overlooked but leading cause of blindness, particularly among the working aged population. Myopia is often considered benign because it is easily corrected with glasses, contact lenses, or refractive surgery. Traditionally myopia has been classified into physiological and pathological subtypes based on the degree of myopia present. Higher levels of myopia are associated with increased risk of pathological complications but it is important to note that there is no safe level of myopia. Even low levels of myopia increase the risk of retinal detachment and other ocular comorbidities which will be discussed in detail later. The most serious complication, myopic maculopathy, is the only leading cause of blindness without an established treatment and therefore leads to inevitable loss of vision in some myopes, even at a young age. Aim: To highlight the current myopia epidemic and the sight threatening complications associated with it Design: This is a comissioned review article. Data was gathered by performing a literature review, searching the PubMed database for recent articles regarding myopia. Conclusions: Myopia is a potentially blinding disease. By identifying at risk individuals and intervening before they become myopic, eye care practitioners can prevent or delay spectacle use, reduce the risk of the myriad of myopic complications and thereby improve the patient’s quality of life and positively impact its socio-economic effects

Long-Term Estrogen Therapy Improves Vascular Function in Male to Female Transsexuals

AbstractObjectives. This study sought to examine the effects of long-term estrogen therapy on vascular function in male to female transsexuals and to compare the findings with those observed in men and premenopausal women.Background. Gender differences in coronary artery disease have largely been attributed to the beneficial effects of estrogen on vascular function and plasma lipids in women. However, the effects of estrogen on the male vasculature have not been widely studied.Methods. We compared the effects of estrogen on vascular function in 14 male to female transsexuals, 14 age-matched men and 15 premenopausal women. Flow-mediated vasodilation and response to nitroglycerin were assessed in the brachial artery using noninvasive ultrasound.Results. Flow-mediated vasodilation was similar in transsexuals and women but greater than that in men ([mean ± SE] 11.5 ± 1.3% and 9.4 ± 1.1% vs. 5.2 ± 1.0% respectively, p < 0.005). Responses to nitroglycerin were also greater in transsexuals and women than in men (21.6 ± 1.7% and 21.0 ± 0.9% vs. 14.5 ± 1.2%, respectively, p = 0.0005). These differences persisted even after adjusting for vessel size. Despite similar total cholesterol levels, transsexuals had high density lipoprotein cholesterol levels similar to those in women and greater than those observed in men (1.76 ± 0.12 and 1.82 ± 0.11 mmol/liter vs. 1.35 ± 0.07 mmol/liter, respectively, p < 0.005). Moreover, triglyceride levels were greater in transsexuals than in men and women, and low density lipoprotein cholesterol (LDL-C) particle size was smaller (25.7 ± 0.2 nm vs. 26.2 ± 0.1 and 26.6 ± 0.1 nm, respectively, p = 0.0001). Serum testosterone (an index of estrogen therapy in transsexuals) was markedly suppressed in transsexuals and similar to that in women. Univariate analysis revealed that there was a strong inverse correlation between serum testosterone and flow-mediated vasodilation (rs= −0.48, p < 0.005). Multivariate analysis revealed that the best combination of predictors of flow-mediated vasodilation was serum testosterone, vessel size and LDL-C (R2= 0.3, p < 0.005).Conclusions. Long-term estrogen therapy appears to improve vascular function in male to female transsexuals and occurs despite higher triglyceride levels and the presence of small, dense LDL-C. The beneficial effects of estrogen are not gender specific or solely mediated through endothelium-derived nitric oxide.(J Am Coll Cardiol 1997;29:1437–44

Laser Welding of a Stent

We consider the problem of modelling the manufacture of a cylindrical Stent, in which layers of a plastic material are welded together by a Laser beam. We firstly set up the equations for this system and solve them by using a Finite Element method. We then look at various scalings which allow the equations to be simplified. The resulting equations are then solved analytically to obtain approximate solutions to the radial temperature profile and the averaged axial temperature profile

Nudging art lovers to donate.

Many nonprofit organizations face revenue uncertainty due to funding cuts. It is crucial for them to supplement existing revenue streams by private donations, and apply thoughtful market segmentation in their pursuit of donors. We introduce the behavioral concept of ‘nudge’ based on the possibility of loss aversion affecting willingness-to-donate, and investigate its implications for fundraising strategies. Potential donors are nudged to donate by the hypothetical scenario of ‘losing’ an existing exhibition, and also by that of ‘gaining’ an additional exhibition. We observe significant loss aversion effects as frequent gallery-goers donate more in order to avoid losing an exhibition. While both prospective gain and loss scenarios are effective in nudging non-frequent gallery-goers, the prospect of enjoying ‘one more’ event is observed to be stronger. We argue that there may be scope to increase support for nonprofit organizations, particularly in the cultural sector, by exploiting the psychological characteristics of prospective donors

The long road to adaptation: micro and small hospitality firms after the GFC

This study examines the journey of micro and small firm owners/managers of hospitality firms through the global financial crisis. This journey includes measures of firm success and performance supporting firms in the aftermath of the event. The study draws on a sample of mainly hospitality firms in Greece and Cyprus, and considers conceptual tenets of the dynamic capabilities framework. Key dimensions associated with firm success and firm performance following the crisis were revealed. For instance, the ‘value’ dimension emerged through measures of financial management, intrinsic, knowledge-based, strategic, and by adding value to consumers’ experience. Furthermore, strong firm performance was mainly perceived as a result of learning from mistakes or managing time efficiently, while counting on government or financial institutions was associated with poor firm performance. The study has various practical and theoretical implications, including through the proposal of a conceptual framework, where the findings and dynamic capabilities approach converge

OpenFermion: The Electronic Structure Package for Quantum Computers

Quantum simulation of chemistry and materials is predicted to be an important application for both near-term and fault-tolerant quantum devices. However, at present, developing and studying algorithms for these problems can be difficult due to the prohibitive amount of domain knowledge required in both the area of chemistry and quantum algorithms. To help bridge this gap and open the field to more researchers, we have developed the OpenFermion software package (www.openfermion.org). OpenFermion is an open-source software library written largely in Python under an Apache 2.0 license, aimed at enabling the simulation of fermionic models and quantum chemistry problems on quantum hardware. Beginning with an interface to common electronic structure packages, it simplifies the translation between a molecular specification and a quantum circuit for solving or studying the electronic structure problem on a quantum computer, minimizing the amount of domain expertise required to enter the field. The package is designed to be extensible and robust, maintaining high software standards in documentation and testing. This release paper outlines the key motivations behind design choices in OpenFermion and discusses some basic OpenFermion functionality which we believe will aid the community in the development of better quantum algorithms and tools for this exciting area of research.Comment: 22 page

Nature of orchestral noise

Professional orchestral musicians are at risk of exposure to excessive noise when at work. This is an industry-wide problem that threatens not only the hearing of orchestral musicians but also the way orchestras operate. The research described in this paper recorded noise levels within a professional orchestra over three years in order to provide greater insight to the orchestral noise environment; to guide future research into orchestral noise management and hearing conservation strategies; and to provide a basis for the future education of musicians and their managers. Every rehearsal, performance, and recording from May 2004 to May 2007 was monitored, with the woodwind, brass, and percussion sections monitored in greatest detail. The study recorded dBALEQ and dBC peak data, which are presented in graphical form with accompanying summarized data tables. The findings indicate that the principal trumpet, first and third horns, and principal trombone are at greatest risk of exposure to excessive sustained noise levels and that the percussion and timpani are at greatest risk of exposure to excessive peak noise levels. However, the findings also strongly support the notion that the true nature of orchestral noise is a great deal more complex than this simple statement would imply

Potential of Australian Bermudagrasses (\u3cem\u3eCynodon\u3c/em\u3e spp.) for Pasture in Subtropical Australia

In Australia, little work has been carried out on the improvement of tropical or subtropical pastures in recent years. There seems to be an increasing demand for pastures that can withstand heavy grazing, while producing high yields of high quality forage in the humid subtropical regions of Australia. Most graziers, who live in these areas, have small acreages, which they graze intensively. Cynodon spp. represent a potential source of grasses with these attributes. This study will evaluate the pasture potential of a large number of bermudagrass (Cynodon spp.) ecotypes collected from across Australia

Whey protein lowers blood pressure and improves endothelial function and lipid biomarkers in adults with prehypertension and mild hypertension: results from the chronic Whey2Go randomized 1,2 controlled trial

Background: Cardiovascular diseases (CVDs) are the greatest cause of death globally, and their reduction is a key public-health target. High blood pressure (BP) affects 1 in 3 people in the United Kingdom, and previous studies have shown that milk consumption is associated with lower BP. Objective: We investigated whether intact milk proteins lower 24-h ambulatory blood pressure (AMBP) and other risk markers of CVD. Design: The trial was a double-blinded, randomized, 3-way–crossover, controlled intervention study. Forty-two participants were randomly assigned to consume 2 × 28 g whey protein/d, 2 × 28 g Ca caseinate/d, or 2 × 27 g maltodextrin (control)/d for 8 wk separated by a 4-wk washout. The effects of these interventions were examined with the use of a linear mixed-model ANOVA. Results: Thirty-eight participants completed the study. Significant reductions in 24-h BP [for systolic blood pressure (SBP): −3.9 mm Hg; for diastolic blood pressure (DBP): −2.5 mm Hg; P = 0.050 for both)] were observed after whey-protein consumption compared with control intake. After whey-protein supplementation compared with control intake, peripheral and central systolic pressures [−5.7 mm Hg (P = 0.007) and −5.4 mm Hg (P = 0.012), respectively] and mean pressures [−3.7 mm Hg (P = 0.025) and −4.0 mm Hg (P = 0.019), respectively] were also lowered. Flow-mediated dilation (FMD) increased significantly after both whey-protein and calcium-caseinate intakes compared with control intake [1.31% (P < 0.001) and 0.83% (P = 0.003), respectively]. Although both whey protein and calcium caseinate significantly lowered total cholesterol [−0.26 mmol/L (P = 0.013) and −0.20 mmol/L (P = 0.042), respectively], only whey protein decreased triacylglycerol (−0.23 mmol/L; P = 0.025) compared with the effect of the control. Soluble intercellular adhesion molecule 1 and soluble vascular cell adhesion molecule 1 were reduced after whey protein consumption (P = 0.011) and after calcium-caseinate consumption (P = 0.039), respectively, compared with after control intake. Conclusions: The consumption of unhydrolyzed milk proteins (56 g/d) for 8 wk improved vascular reactivity, biomarkers of endothelial function, and lipid risk factors. Whey-protein supplementation also lowered 24-h ambulatory SBP and DBP. These results may have important implications for public health. This trial was registered at clinicaltrials.gov as NCT02090842