Constraining the variation of fundamental constants using 18cm OH lines

We describe a new technique to estimate variations in the fundamental constants using 18cm OH absorption lines. This has the advantage that all lines arise in the same species, allowing a clean comparison between the measured redshifts. In conjunction with one additional transition (for example, an HCO$^+$ line), it is possible to simultaneously measure changes in $\alpha$, $g_p$ and $y \equiv m_e/m_p$. At present, only the 1665 MHz and 1667 MHz lines have been detected at cosmological distances; we use these line redshifts in conjunction with those of HI 21cm and mm-wave molecular absorption in a gravitational lens at $z\sim 0.68$ to constrain changes in the above three parameters over the redshift range $0 < z \lesssim 0.68$. While the constraints are relatively weak ($\lesssim$ 1 part in $10^3$), this is the first simultaneous constraint on the variation of all three parameters. We also demonstrate that either one (or more) of $\alpha$, $g_p$ and $y$ must vary with cosmological time or there must be systematic velocity offsets between the OH, HCO$^+$ and HI absorbing clouds.Comment: 5 pages, no figures. Accepted for publication in Phys. Rev. Let

A phase II study of capecitabine and oxalplatin combination chemotherapy in patients with inoperable adenocarcinoma of the gall bladder or biliary tract

Background: Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. Methods: This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Com mittee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecit abine (1000 mg/m2 po, twice daily, days 1–14) and oxaliplatin (130 mg/m2 i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. Results: Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8 % (95 % CI 12.05–39.5 %). Stable disease was observed in a further 13 patients (31 %) and progressive disease observed in 12 (28.6 %) of patients. The median progression-free survival was 4.6 months (95 % CI 2.8–6.4 months; Fig. 1) and the median overall survival 7.9 months (95 % CI 5.3–10.4 months; Fig. 2). Conclusion: Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease. How ever, capecitabine in combination with oxaliplatin does have modest activity in this disease, and can be considered as an alternative treatment option for patients in whom cisplatin and/or gemcitabine are contra-indicated

National evaluation of the neighbourhood nurseries: integrated report

Report description: The NNI was launched in 2001 to provide high quality childcare in the most disadvantaged neighbourhoods of England, to help parents into employment, reduce child poverty and boost children’s development. By 2005 45,000 new childcare places had been created in approximately 1,400 neighbourhood nurseries. This report brings together the findings of the four individual strands of the National Evaluation of Neighbourhood Nurseries Initiative as shown above and makes a number of recommendations. The report shows the rationale for the government’s strategy in targeting disadvantaged neighbourhoods and in focusing on high quality childcare to provide the link between raising parental employment and income and improving children’s life chances

A novel framework for discharge uncertainty quantification applied to 500 UK gauging stations

Benchmarking the quality of river discharge data and understanding its information content for hydrological analyses is an important task for hydrologic science. There is a wide variety of techniques to assess discharge uncertainty. However, few studies have developed generalized approaches to quantify discharge uncertainty. This study presents a generalized framework for estimating discharge uncertainty at many gauging stations with different errors in the stage‐discharge relationship. The methodology utilizes a nonparametric LOWESS regression within a novel framework that accounts for uncertainty in the stage‐discharge measurements, scatter in the stage‐discharge data and multisection rating curves. The framework was applied to 500 gauging stations in England and Wales and we evaluated the magnitude of discharge uncertainty at low, mean and high flow points on the rating curve. The framework was shown to be robust, versatile and able to capture place‐specific uncertainties for a number of different examples. Our study revealed a wide range of discharge uncertainties (10–397% discharge uncertainty interval widths), but the majority of the gauging stations (over 80%) had mean and high flow uncertainty intervals of less than 40%. We identified some regional differences in the stage‐discharge relationships, however the results show that local conditions dominated in determining the magnitude of discharge uncertainty at a gauging station. This highlights the importance of estimating discharge uncertainty for each gauging station prior to using those data in hydrological analyses

4mu spectra of AGB stars I: Observations

We present times series of high resolution spectra of AGB variables at 4mu. Line profiles from the major contributors to the spectra of oxygen rich stars at 4mu, OH, H$_2$O, HCl and SiO, are examined. The velocity as well as shape variations of these profiles with time are discussed. The line profiles investigated frequently have emission and multiple absorption components. The changes with time of the 4mu region lines do not always follow the cyclic variability seen in NIR spectra and in the photometric light curve. We interpret and discuss the results qualitatively considering comparing the spectral variability with that of the well behaved 1.6mu region and of dynamical model atmospheres. Miras and semiregular variables are compared. The origins of non-periodic behavior are discussed, including the role of spatial inhomogeneities in the stellar atmosphere.Comment: 14 pages, 12 figures, accepted for publication in A&

Thioredoxin Inhibitors Attenuate Platelet Function and Thrombus Formation.

Thioredoxin (Trx) is an oxidoreductase with important physiological function. Imbalances in the NADPH/thioredoxin reductase/thioredoxin system are associated with a number of pathologies, particularly cancer, and a number of clinical trials for thioredoxin and thioredoxin reductase inhibitors have been carried out or are underway. Due to the emerging role and importance of oxidoreductases for haemostasis and the current interest in developing inhibitors for clinical use, we thought it pertinent to assess whether inhibition of the NADPH/thioredoxin reductase/thioredoxin system affects platelet function and thrombosis. We used small molecule inhibitors of Trx (PMX 464 and PX-12) to determine whether Trx activity influences platelet function, as well as an unbiased proteomics approach to identify potential Trx substrates on the surface of platelets that might contribute to platelet reactivity and function. Using LC-MS/MS we found that PMX 464 and PX-12 affected the oxidation state of thiols in a number of cell surface proteins. Key surface receptors for platelet adhesion and activation were affected, including the collagen receptor GPVI and the von Willebrand factor receptor, GPIb. To experimentally validate these findings we assessed platelet function in the presence of PMX 464, PX-12, and rutin (a selective inhibitor of the related protein disulphide isomerase). In agreement with the proteomics data, small molecule inhibitors of thioredoxin selectively inhibited GPVI-mediated platelet activation, and attenuated ristocetin-induced GPIb-vWF-mediated platelet agglutination, thus validating the findings of the proteomics study. These data reveal a novel role for thioredoxin in regulating platelet reactivity via proteins required for early platelet responses at sites of vessel injury (GPVI and GPIb). This work also highlights a potential opportunity for repurposing of PMX 464 and PX-12 as antiplatelet agents.CM is funded by Medical Research Council Grant No G9826026. AR was funded by a British Heart Foundation Centre of Research Excellence-funded Vacation Studentship. CHC is funded by British Heart Foundation Fellowship FS/11/49/28751.This is the final version of the article. It first appeared from PLOS via https://doi.org/10.1371/journal.pone.016300

Graphene-wrapped sulfur/metal organic framework-derived microporous carbon composite for lithium sulfur batteries

A three-dimensional hierarchical sandwich-type graphene sheet-sulfur/carbon (GS-S/CZIF8-D) composite for use in a cathode for a lithium sulfur (Li-S) battery has been prepared by an ultrasonic method. The microporous carbon host was prepared by a one-step pyrolysis of Zeolitic Imidazolate Framework-8 (ZIF-8), a typical zinc-containing metal organic framework (MOF), which offers a tunable porous structure into which electro-active sulfur can be diffused. The thin graphene sheet, wrapped around the sulfur/zeolitic imidazolate framework-8 derived carbon (S/CZIF8-D) composite, has excellent electrical conductivity and mechanical flexibility, thus facilitating rapid electron transport and accommodating the changes in volume of the sulfur electrode. Compared with the S/CZIF8-D sample, Li-S batteries with the GS-S/CZIF8-D composite cathode showed enhanced capacity, improved electrochemical stability, and relatively high columbic efficiency by taking advantage of the synergistic effects of the microporous carbon from ZIF-8 and a highly interconnected graphene network. Our results demonstrate that a porous MOF-derived scaffold with a wrapped graphene conductive network structure is a potentially efficient design for a battery electrode that can meet the challenge arising from low conductivity and volume change.National Science Foundation of China (21373028)This is the final version of the article. It first appeared from American Institute of Physics Publishing via http://dx.doi.org/10.1063/1.490175

Trading places: Peptide and small molecule alternatives to oligonucleotide-based modulation of microRNA expression

It is well established that microRNA (miRNA) dysregulation is involved in the development and progression of various diseases, especially cancer. Emerging evidence suggests that small molecule and peptide agents can interfere with miRNA disease pathways. Despite this, very little is known about structural features that drive drug–miRNA interactions and subsequent inhibition. In this review, we highlight the advances made in the development of small molecule and peptide inhibitors of miRNA processing. Specifically, we attempt to draw attention to peptide features that may be critical for interaction with the miRNA secondary structure to regulate miRNA expression. We hope that this review will help to establish peptides as exciting miRNA expression modulators and will contribute towards the development of the first miRNA-targeting peptide therapy