Coherent State Approach to Quantum Clocks

The ``problem of time'' has been a pressing issue in quantum gravity for some time. To help understand this problem, Rovelli proposed a model of a two harmonic oscillators system where one of the oscillators can be thought of as a ``clock'' for the other oscillator thus giving a natural time reference frame for the system. Recently, the author has constructed an explicit form for the coherent states on the reduced phase space of this system in terms of Klauder's projection operator approach. In this paper, by using coherent state representations and other tools from coherent state quantization, I investigate the construction of gauge invariant operators on this reduced phase space, and the ability to use a quantum oscillator as a ``clock.''Comment: 13 pages, Late

Toward a simulation approach for alkene ring-closing metathesis : scope and limitations of a model for RCM

A published model for revealing solvent effects on the ring-closing metathesis (RCM) reaction of di-Et diallylmalonate 7 has been evaluated over a wider range of conditions, to assess its suitability for new applications. Unfortunately, the model is too flexible and the published rate consts. do not agree with exptl. studies in the literature. However, by fixing the values of important rate consts. and restricting the concn. ranges studied, useful conclusions can be drawn about the relative rates of RCM of different substrates, precatalyst concn. can be simulated accurately and the effect of precatalyst loading can be anticipated. Progress has also been made toward applying the model to precatalyst evaluation, but further modifications to the model are necessary to achieve much broader aims

Mid-Miocene cooling and the extinction of tundra in continental Antarctica

A major obstacle in understanding the evolution of Cenozoic climate has been the lack of well dated terrestrial evidence from high-latitude, glaciated regions. Here, we report the discovery of exceptionally well preserved fossils of lacustrine and terrestrial organisms from the McMurdo Dry Valleys sector of the Transantarctic Mountains for which we have established a precise radiometric chronology. The fossils, which include diatoms, palynomorphs, mosses, ostracodes, and insects, represent the last vestige of a tundra community that inhabited the mountains before stepped cooling that first brought a full polar climate to Antarctica. Paleoecological analyses, 40Ar/39Ar analyses of associated ash fall, and climate inferences from glaciological modeling together suggest that mean summer temperatures in the region cooled by at least 8°C between 14.07 ± 0.05 Ma and 13.85 ± 0.03 Ma. These results provide novel constraints for the timing and amplitude of middle-Miocene cooling in Antarctica and reveal the ecological legacy of this global climate transition

Coherently Dedispersed Polarimetry of Millisecond Pulsars

We present a large sample of high-precision, coherently-dedispersed polarization profiles of millisecond pulsars (MSPs) at frequencies between 410 and 1414 MHz. These data include the first polarimetric observations of several of the pulsars, and the first low-frequency polarization profiles for others. Our observations support previous suggestions that the pulse shapes and polarimetry of MSPs are more complex than those of their slower relatives. An immediate conclusion is that polarimetry-based classification schemes proposed for young pulsars are of only limited use when applied to millisecond pulsars.Comment: 28 pages, 10 figures. Text matches version that appeared in ApJS. Full paper with high-resolution figures available at ftp://ftp.jb.man.ac.uk/pub/psr/papers/msppolpton.ps.g

Stillbirth and intrauterine fetal death: contemporary demographic features of >1000 cases from an urban population

OBJECTIVES: Of 780 000 births annually in the UK, around 3300 are stillborn, a rate of approximately 4 per 1000 births. Traditional epidemiological associations are based on historic data. The aim of this study was to document contemporary demographic findings in a large series of > 1000 deaths in utero in London and compare these with national datasets. METHODS: From a dedicated database, including > 400 data fields per case, of fetal, infant and pediatric autopsies performed at Great Ormond Street Hospital and St George's Hospital, London, we extracted information on all intrauterine deaths, excluding terminations of pregnancy, from 2005 to 2013, inclusive. Demographic data were analyzed according to the gestational age at which fetal death occurred (second-trimester intrauterine fetal death (IUFD), subdivided into early (1000 autopsies in cases of intrauterine death, these data highlight the increased risk for fetal loss associated with maternal demographic factors in contemporary clinical practice, particularly associations with increased maternal age and body mass index. Among women in whom an intrauterine death occurs, maternal ethnicity, mode of conception and gynecological history are associated with differing timing of fetal loss. Further research is required to understand the mechanisms involved in such maternal factors in order to develop preventative strategies

Structure-based predictions broadly link transcription factor mutations to gene expression changes in cancers

© 2014 The Author(s). Thousands of unique mutations in transcription factors (TFs) arise in cancers, and the functional and biological roles of relatively few of these have been characterized. Here, we used structure-based methods developed specifically for DNA-binding proteins to systematically predict the consequences of mutations in several TFs that are frequently mutated in cancers. The explicit consideration of protein-DNA interactions was crucial to explain the roles and prevalence of mutations in TP53 and RUNX1 in cancers, and resulted in a higher specificity of detection for known p53-regulated genes among genetic associations between TP53 genotypes and genome-wide expression in The Cancer Genome Atlas, compared to existing methods of mutation assessment. Biophysical predictions also indicated that the relative prevalence of TP53 missense mutations in cancer is proportional to their thermodynamic impacts on protein stability and DNA binding, which is consistent with the selection for the loss of p53 transcriptional function in cancers. Structure and thermodynamics-based predictions of the impacts of missense mutations that focus on specific molecular functions may be increasingly useful for the precise and large-scale inference of aberrant molecular phenotypes in cancer and other complex diseases

Therapeutic Enhancement of Protective Immunity during Experimental Leishmaniasis

Leishmaniasis is an infectious disease that causes a large burden of morbidity and mortality in the tropics. Caused by protozoan parasites of the genus Leishmania that are transmitted by sandflies, leishmaniasis causes a wide spectrum of human disease. The severe end of the spectrum, visceral leishmaniasis, causes an annual mortality of approximately 50,000, largely in India and Sudan. Available therapies for leishmaniasis are problematic due to emerging drug resistance, toxicity and/or the need for lengthy courses of treatment. There is thus an urgent need for novel therapeutic approaches to this neglected tropical disease. To address this problem, the authors examined whether a commercially available drug developed for cancer therapy (Ontak), reported to have immunological activity of relevance to the immunobiology of Leishmania infection, exhibited efficacy in mouse models of leishmaniasis. The study found therapeutic efficacy for the drug alone in these models, as well as additive therapeutic efficacy in combination with standard antimicrobial therapy. Rational reinvestigation of the efficacy of already approved drugs in experimental models of neglected tropical diseases has promise in providing needed new candidates to the drug discovery pipeline

Incidence of community-acquired lower respiratory tract infections and pneumonia among older adults in the United Kingdom: a population-based study.

Community-acquired lower respiratory tract infections (LRTI) and pneumonia (CAP) are common causes of morbidity and mortality among those aged ≥65 years; a growing population in many countries. Detailed incidence estimates for these infections among older adults in the United Kingdom (UK) are lacking. We used electronic general practice records from the Clinical Practice Research Data link, linked to Hospital Episode Statistics inpatient data, to estimate incidence of community-acquired LRTI and CAP among UK older adults between April 1997-March 2011, by age, sex, region and deprivation quintile. Levels of antibiotic prescribing were also assessed. LRTI incidence increased with fluctuations over time, was higher in men than women aged ≥70 and increased with age from 92.21 episodes/1000 person-years (65-69 years) to 187.91/1000 (85-89 years). CAP incidence increased more markedly with age, from 2.81 to 21.81 episodes/1000 person-years respectively, and was higher among men. For both infection groups, increases over time were attenuated after age-standardisation, indicating that these rises were largely due to population aging. Rates among those in the most deprived quintile were around 70% higher than the least deprived and were generally higher in the North of England. GP antibiotic prescribing rates were high for LRTI but lower for CAP (mostly due to immediate hospitalisation). This is the first study to provide long-term detailed incidence estimates of community-acquired LRTI and CAP in UK older individuals, taking person-time at risk into account. The summary incidence commonly presented for the ≥65 age group considerably underestimates LRTI/CAP rates, particularly among older individuals within this group. Our methodology and findings are likely to be highly relevant to health planners and researchers in other countries with aging populations

Klotho and the treatment of human malignancies

Klotho was first discovered as an anti-ageing protein linked to a number of age-related disease processes, including cardiovascular, renal, musculoskeletal, and neurodegenerative conditions. Emerging research has also demonstrated a potential therapeutic role for Klotho in cancer biology, which is perhaps unsurprising given that cancer and ageing share similar molecular hallmarks. In addition to functioning as a tumour suppressor in numerous solid tumours and haematological malignancies, Klotho represents a candidate therapeutic target for patients with these diseases, the majority of whom have limited treatment options. Here, we examine contemporary evidence evaluating the anti-neoplastic effects of Klotho and describe the modulation of downstream oncogenic signalling pathways, including Wnt/β-catenin, FGF, IGF1, PIK3K/AKT, TGFβ, and the Unfolded Protein Response. We also discuss possible approaches to developing therapeutic Klotho and consider technological advances that may facilitate the delivery of Klotho through gene therapy