Engineering tyrosine-based electron flow pathways in proteins: The case of aplysia myoglobin

Tyrosine residues can act as redox cofactors that provide an electron transfer ("hole-hopping") route that enhances the rate of ferryl heme iron reduction by externally added reductants, for example, ascorbate. Aplysia fasciata myoglobin, having no naturally occurring tyrosines but 15 phenylalanines that can be selectively mutated to tyrosine residues, provides an ideal protein with which to study such through-protein electron transfer pathways and ways to manipulate them. Two surface exposed phenylalanines that are close to the heme have been mutated to tyrosines (F42Y, F98Y). In both of these, the rate of ferryl heme reduction increased by up to 3 orders of magnitude. This result cannot be explained in terms of distance or redox potential change between donor and acceptor but indicates that tyrosines, by virtue of their ability to form radicals, act as redox cofactors in a new pathway. The mechanism is discussed in terms of the Marcus theory and the specific protonation/deprotonation states of the oxoferryl iron and tyrosine. Tyrosine radicals have been observed and quantified by EPR spectroscopy in both mutants, consistent with the proposed mechanism. The location of each radical is unambiguous and allows us to validate theoretical methods that assign radical location on the basis of EPR hyperfine structure. Mutation to tyrosine decreases the lipid peroxidase activity of this myoglobin in the presence of low concentrations of reductant, and the possibility of decreasing the intrinsic toxicity of hemoglobin by introduction of these pathways is discussed. © 2012 American Chemical Society

Fine forecasts: encouraging the media to include ultraviolet radiation information in summertime weather forecasts

Melanoma and skin cancer are largely attributable to over-exposure to solar ultraviolet radiation (UVR). Reports of UVR levels within media weather forecasts appear to be well received by the public and have good potential to communicate the need for appropriate sun protection to a broad audience. This study describes provision of UVR messages by New Zealand newspapers, radio and TV stations over a 4-year period, and examines the impact of an intervention which aimed to address media concerns about the financial costs of accessing UVR information for broadcast. Newspaper and radio presentation of UVR information increased immediately after these costs were removed; however, among radio stations it dropped in subsequent years. Among those media that were presenting UVR, this information was broadcast throughout the summer period and repeated throughout the day. Furthermore, most reports included concomitant, behavioral sun protection messages. At the final assessment (summer 2001/02), 66% of radio stations, both TV channels and 48% of newspapers reported UVR information in summertime weather reports. Efforts to further increase UVR presentation will need to address media concerns about time constraints on weather forecasts and media perceptions of poor audience demand or understanding of some UVR message

On the geometry of mixed states and the Fisher information tensor

In this paper, we will review the co-adjoint orbit formulation of finite dimensional quantum mechanics, and in this framework, we will interpret the notion of quantum Fisher information index (and metric). Following previous work of part of the authors, who introduced the definition of Fisher information tensor, we will show how its antisymmetric part is the pullback of the natural Kostant-Kirillov-Souriau symplectic form along some natural diffeomorphism. In order to do this, we will need to understand the symmetric logarithmic derivative as a proper 1-form, settling the issues about its very definition and explicit computation. Moreover, the fibration of co-adjoint orbits, seen as spaces of mixed states, is also discussed.Comment: 27 pages; Accepted Manuscrip

Political activity for physical activity: health advocacy for active transport

Effective health advocacy is a priority for efforts to increase population participation in physical activity. Local councils are an important audience for this advocacy. The aim of the current study was to describe features of advocacy for active transport via submissions to city council annual plans in New Zealand, and the impact of an information sheet to encourage the health sector to be involved in this process. Written submissions to city council's annual consultation process were requested for 16 city councils over the period of three years (2007/08, 2008/09, and 2009/10). Submissions were reviewed and categories of responses were created. An advocacy information sheet encouraging health sector participation and summarising some of the evidence-base related to physical activity, active transport and health was released just prior to the 2009/10 submission time. Over the period of the study, city councils received 47,392 submissions, 17% of which were related to active transport. Most submissions came from city residents, with a small proportion (2%) from the health sector. The largest category of submissions was in support of pedestrian and cycling infrastructure, design and maintenance of facilities and additional features to support use of these transport modes. Health arguments featured prominently in justifications for active transport initiatives, including concerns about injury risk, obesity, physical inactivity, personal safety and facilities for people with disabilities. There was evidence that the information sheet was utilised by some health sector submitters (12.5%), providing tentative support for initiatives of this nature. In conclusion, the study provides novel information about the current nature of health advocacy for active transport and informs future advocacy efforts about areas for emphasis, such as health benefits of active transport, and potential alliances with other sectors such as environmental sustainability, transport and urban planning and local communities

Geometric Satake, Springer correspondence, and small representations

For a simply-connected simple algebraic group $G$ over \C, we exhibit a subvariety of its affine Grassmannian that is closely related to the nilpotent cone of $G$, generalizing a well-known fact about $GL_n$. Using this variety, we construct a sheaf-theoretic functor that, when combined with the geometric Satake equivalence and the Springer correspondence, leads to a geometric explanation for a number of known facts (mostly due to Broer and Reeder) about small representations of the dual group.Comment: Version 2: minor revisions, 33 page

The project data sphere initiative: accelerating cancer research by sharing data

Background. In this paper, we provide background and context regarding the potential for a new data-sharing platform, the Project Data Sphere (PDS) initiative, funded by financial and in-kind contributions from the CEO Roundtable on Cancer, to transform cancer research and improve patient outcomes. Given the relatively modest decline in cancer death rates over the past several years, a new research paradigm is needed to accelerate therapeutic approaches for oncologic diseases. Phase III clinical trials generate large volumes of potentially usable information, often on hundreds of patients, including patients treated with standard of care therapies (i.e., controls). Both nationally and internationally, a variety of stakeholders have pursued data-sharing efforts to make individual patient-level clinical trial data available to the scientific research community. Potential Benefits and Risks of Data Sharing. For researchers, shared data have the potential to foster a more collaborative environment, to answer research questions in a shorter time frame than traditional randomized control trials, to reduce duplication of effort, and to improve efficiency. For industry participants, use of trial data to answer additional clinical questions could increase research and development efficiency and guide future projects through validation of surrogate end points, development of prognostic or predictive models, selection of patients for phase II trials, stratification in phase III studies, and identification of patient subgroups for development of novel therapies. Data transparency also helps promote a public image of collaboration and altruism among industry participants. For patient participants, data sharing maximizes their contribution to public health and increases access to information that may be used to develop better treatments. Concerns about data-sharing efforts include protection of patient privacy and confidentiality. To alleviate these concerns, data sets are deidentified to maintain anonymity. To address industry concerns about protection of intellectual property and competitiveness, we illustrate several models for data sharing with varying levels of access to the data and varying relationships between trial sponsors and data access sponsors. The Project Data Sphere Initiative. PDS is an independent initiative of the CEO Roundtable on Cancer Life Sciences Consortium, built to voluntarily share, integrate, and analyze comparator arms of historical cancer clinical trial data sets to advance future cancer research. The aim is to provide a neutral, broad-access platform for industry and academia to share raw, deidentified data from late-phase oncology clinical trials using comparator-arm data sets. These data are likely to be hypothesis generating or hypothesis confirming but, notably, do not take the place of performing a well-designed trial to address a specific hypothesis. Prospective providers of data to PDS complete and sign a data sharing agreement that includes a description of the data they propose to upload, and then they follow easy instructions on the website for uploading their deidentified data. The SAS Institute has also collaborated with the initiative to provide intrinsic analytic tools accessible within the website itself. As of October 2014, the PDS website has available data from 14 cancer clinical trials covering 9,000 subjects, with hopes to further expand the database to include more than 25,000 subject accruals within the next year. PDS differentiates itself from other data-sharing initiatives by its degree of openness, requiring submission of only a brief application with background information of the individual requesting access and agreement to terms of use. Data from several different sponsors may be pooled to develop a comprehensive cohort for analysis. In order to protect patient privacy, data providers in the U.S. are responsible for deidentifying data according to standards set forth by the Privacy Rule of the U.S. Health Insurance Portability and Accountability Act of 1996. Using Data Sharing to Improve Outcomes in Cancer: The “Prostate Cancer Challenge.” Control-arm data of several studies among patients with metastatic castration-resistant prostate cancer (mCRPC) are currently available through PDS. These data sets have multiple potential uses. The “Prostate Cancer Challenge” will ask the cancer research community to use clinical trial data deposited in the PDS website to address key research questions regarding mCRPC. General themes that could be explored by the cancer community are described in this article: prognostic models evaluating the influence of pretreatment factors on survival and patient-reported outcomes; comparative effectiveness research evaluating the efficacy of standard of care therapies, as illustrated in our companion article comparing mitoxantrone plus prednisone with prednisone alone; effects of practice variation in dose, frequency, and duration of therapy; level of patient adherence to elements of trial protocols to inform the design of future clinical trials; and age of subjects, regional differences in health care, and other confounding factors that might affect outcomes. Potential Limitations and Methodological Challenges. The number of data sets available and the lack of experimental arm data limit the potential scope of research using the current PDS. The number of trials is expected to grow exponentially over the next year and may include multiple cancer settings, such as breast, colorectal, lung, hematologic malignancy, and bone marrow transplantation. Other potential limitations include the retrospective nature of the data analyses performed using PDS and its generalizability, given that clinical trials are often conducted among younger, healthier, and less racially diverse patient populations. Methodological challenges exist when combining individual patient data from multiple clinical trials; however, advancements in statistical methods for secondary database analysis offer many tools for reanalyzing data arising from disparate trials, such as propensity score matching. Despite these concerns, few if any comparable data sets include this level of detail across multiple clinical trials and populations. Conclusion. Access to large, late-phase, cancer-trial data sets has the potential to transform cancer research by optimizing research efficiency and accelerating progress toward meaningful improvements in cancer care. This type of platform provides opportunities for unique research projects that can examine relatively neglected areas and that can construct models necessitating large amounts of detailed data.The full potential of PDS will be realized only when multiple tumor types and larger numbers of data sets are available through the website

Annexin A2 Binds RNA and Reduces the Frameshifting Efficiency of Infectious Bronchitis Virus

Annexin A2 (ANXA2) is a protein implicated in diverse cellular functions, including exocytosis, DNA synthesis and cell proliferation. It was recently proposed to be involved in RNA metabolism because it was shown to associate with some cellular mRNA. Here, we identified ANXA2 as a RNA binding protein (RBP) that binds IBV (Infectious Bronchitis Virus) pseudoknot RNA. We first confirmed the binding of ANXA2 to IBV pseudoknot RNA by ultraviolet crosslinking and showed its binding to RNA pseudoknot with ANXA2 protein in vitro and in the cells. Since the RNA pseudoknot located in the frameshifting region of IBV was used as bait for cellular RBPs, we tested whether ANXA2 could regulate the frameshfting of IBV pseudoknot RNA by dual luciferase assay. Overexpression of ANXA2 significantly reduced the frameshifting efficiency from IBV pseudoknot RNA and knockdown of the protein strikingly increased the frameshifting efficiency. The results suggest that ANXA2 is a cellular RBP that can modulate the frameshifting efficiency of viral RNA, enabling it to act as an anti-viral cellular protein, and hinting at roles in RNA metabolism for other cellular mRNAs

Thermodynamically Consistent Force Field for Molecular Dynamics Simulations of Alkaline-Earth Carbonates and Their Aqueous Speciation

In recent years atomistic simulations have become increasingly important in providing molecular insight to complement experiments. Even for the seemingly simple case of ion-pair formation a detailed atomistic picture of the structure and relative stability of the contact, solvent-shared and solvent-separated ion pairs can only be readily achieved by computer simulation. Here a new force field parametrization for the alkaline-earth carbonate interactions in water has been developed by fitting against experimental thermodynamic and structural data. We demonstrate that the present force field can accurately reproduce the dynamics and thermodynamics of the ions in solution, which is the key to producing quantitatively accurate data that can be compared against experiment

Initial Results from the CHOOZ Long Baseline Reactor Neutrino Oscillation Experiment

Initial results are presented from CHOOZ, a long-baseline reactor-neutrino vacuum-oscillation experiment. Electron antineutrinos were detected by a liquid scintillation calorimeter located at a distance of about 1 km. The detector was constructed in a tunnel protected from cosmic rays by a 300 MWE rock overburden. This massive shielding strongly reduced potentially troublesome backgrounds due to cosmic-ray muons, leading to a background rate of about one event per day, more than an order of magnitude smaller than the observed neutrino signal. From the statistical agreement between detected and expected neutrino event rates, we find (at 90% confidence level) no evidence for neutrino oscillations in the electron antineutrino disappearance mode for the parameter region given approximately by deltam**2 > 0.9 10**(-3) eV**2 for maximum mixing and (sin(2 theta)**2) > 0.18 for large deltam**2.Comment: 13 pages, Latex, submitted to Physics Letters