Metallocene catalysts for the ring-opening co-polymerisation of epoxides and cyclic anhydrides

The ring-opening co-polymerisation (ROCOP) of epoxides and cyclic anhydrides is a versatile route to new polyesters. The vast number of monomers that are readily available means that an effectively limitless number of unique polymeric materials can be prepared using a common synthetic route, thereby paving the way to polymers that are more recyclable and could be used in applications that currently lie exclusively within the remit of polyolefins. Metallocene complexes [Cp2MCl2] (M = Ti, Zr, Hf, Cp = η5-C5H5) are known to be excellent pre-catalysts for olefin polymerisation and yet have not been reported for ROCOP, despite their supreme pedigree in the polymerisation realm. Herein, we report the first application of [Cp2MCl2] as catalysts for the ROCOP of epoxides and anhydrides and show that they are effective catalysts for this reaction. The catalytic performances are good with standard epoxides such as cyclohexene oxide but are excellent with more challenging sterically demanding limonene oxide, and this therefore represents a highly effective catalyst system for the preparation of bio-derived recyclable polymers

LGR5 regulates pro-survival MEK/ERK and proliferative Wnt/β-catenin signalling in neuroblastoma.

LGR5 is a marker of normal and cancer stem cells in various tissues where it functions as a receptor for R-spondins and increases canonical Wnt signalling amplitude. Here we report that LGR5 is also highly expressed in a subset of high grade neuroblastomas. Neuroblastoma is a clinically heterogenous paediatric cancer comprising a high proportion of poor prognosis cases (~40%) which are frequently lethal. Unlike many cancers, Wnt pathway mutations are not apparent in neuroblastoma, although previous microarray analyses have implicated deregulated Wnt signalling in high-risk neuroblastoma. We demonstrate that LGR5 facilitates high Wnt signalling in neuroblastoma cell lines treated with Wnt3a and R-spondins, with SK-N-BE(2)-C, SK-N-NAS and SH-SY5Y cell-lines all displaying strong Wnt induction. These lines represent MYCN-amplified, NRAS and ALK mutant neuroblastoma subtypes respectively. Wnt3a/R-Spondin treatment also promoted nuclear translocation of β-catenin, increased proliferation and activation of Wnt target genes. Strikingly, short-interfering RNA mediated knockdown of LGR5 induces dramatic Wnt-independent apoptosis in all three cell-lines, accompanied by greatly diminished phosphorylation of mitogen/extracellular signal-regulated kinases (MEK1/2) and extracellular signal-regulated kinases (ERK1/2), and an increase of BimEL, an apoptosis facilitator downstream of ERK. Akt signalling is also decreased by a Rictor dependent, PDK1-independent mechanism. LGR5 expression is cell cycle regulated and LGR5 depletion triggers G1 cell-cycle arrest, increased p27 and decreased phosphorylated retinoblastoma protein. Our study therefore characterises new cancer-associated pathways regulated by LGR5, and suggest that targeting of LGR5 may be of therapeutic benefit for neuroblastomas with diverse etiologies, as well as other cancers expressing high LGR5

Correction: LGR5 regulates pro-survival MEK/ERK and proliferative Wnt/β-catenin signalling in neuroblastoma.

Present: The originally supplied Figure 5 contains duplicate total-ERK panels. Correct: The proper Figure 5 appears below. The authors sincerely apologize for this error

Omission of surgery in older women with early breast cancer has an adverse impact on breast cancer specific survival

Background: Primary endocrine therapy (PET) is used as an alternative to surgery in up to 40% of UK women with early breast cancer over age 70. This study has investigated the impact of surgery versus PET on breast cancer specific survival (BCSS) in older women. Methods: Cancer registration data were obtained from two English regions from 2002 to 2010 (n=23,961). A retrospective analysis was performed for women with ER positive disease, using statistical modelling to show the effect of treatment (surgery or PET) and age/health status on BCSS. Missing data was handled using multiple imputation. Results: After data pre-processing, 18,730 (78.5%) were identified as having ER positive disease; of these, 10,087 (54%) had surgery and 8,643 (46%) had PET. BCSS was worse in the PET group compared with the surgical group (5 year BCSS: 69% v 90% respectively). This was true for all strata considered, though the differential was lessened in the cohort with the greatest degree of comorbidity. For older, frailer patients the hazard of breast cancer death has less relative impact on overall survival. Selection for surgery on the basis of predicted life expectancy may permit selection of women for whom surgery confers little benefit. This model is being used to develop an on-line algorithm to aid management of older women with early breast cancer (Age Gap Risk Prediction Tool). Conclusion: BCSS in older women with ER positive disease is worse if surgery is omitted. This treatment choice may, therefore, contribute to inferior cancer outcomes

Size constancy in bat biosonar?

Perception and encoding of object size is an important feature of sensory systems. In the visual system object size is encoded by the visual angle (visual aperture) on the retina, but the aperture depends on the distance of the object. As object distance is not unambiguously encoded in the visual system, higher computational mechanisms are needed. This phenomenon is termed "size constancy". It is assumed to reflect an automatic re-scaling of visual aperture with perceived object distance. Recently, it was found that in echolocating bats, the 'sonar aperture', i.e., the range of angles from which sound is reflected from an object back to the bat, is unambiguously perceived and neurally encoded. Moreover, it is well known that object distance is accurately perceived and explicitly encoded in bat sonar. Here, we addressed size constancy in bat biosonar, recruiting virtual-object techniques. Bats of the species Phyllostomus discolor learned to discriminate two simple virtual objects that only differed in sonar aperture. Upon successful discrimination, test trials were randomly interspersed using virtual objects that differed in both aperture and distance. It was tested whether the bats spontaneously assigned absolute width information to these objects by combining distance and aperture. The results showed that while the isolated perceptual cues encoding object width, aperture, and distance were all perceptually well resolved by the bats, the animals did not assign absolute width information to the test objects. This lack of sonar size constancy may result from the bats relying on different modalities to extract size information at different distances. Alternatively, it is conceivable that familiarity with a behaviorally relevant, conspicuous object is required for sonar size constancy, as it has been argued for visual size constancy. Based on the current data, it appears that size constancy is not necessarily an essential feature of sonar perception in bats

The use of surgery in the treatment of ER+ early stage breast cancer in England: variation by time, age and patient characteristics

AIM: To assess whether the proportion of patients aged 70 and over with ER+ operable breast cancer in England who are treated with surgery has changed since 2002, and to determine whether age and individual level factors including tumour characteristics and co-morbidity influence treatment choice. METHODS: A retrospective cohort analysis of routinely collected cancer registration data from two English regions (West Midlands, Northern & Yorkshire) was carried out (n = 17,129). Trends in surgical use over time for different age groups were assessed graphically and with linear regression. Uni- and multivariable logistic regressions were used to assess the effects of age, comorbidity, deprivation and disease characteristics on treatment choice. Missing data was handled using multiple imputation. RESULTS: There is no evidence of a change in the proportion of patients treated surgically over time. The multivariable model shows that age remains an important predictor of whether or not a woman with ER+ operable breast cancer receives surgery after covariate adjustment (Odds ratio of surgery vs no surgery, 0.82 (per year over 70)). Co-morbidity, deprivation, symptomatic presentation, later stage at diagnosis and low grade are also associated with increased probability of non-surgical treatment. CONCLUSION: Contrary to current NICE guidance in England, age appears to be an important factor in the decision to treat operable ER+ breast cancer non-surgically. Further research is needed to assess the role of other age-related factors on treatment choice, and the effect that current practice has on survival and mortality from breast cancer for older women

Numerical Algebraic Geometry: A New Perspective on String and Gauge Theories

The interplay rich between algebraic geometry and string and gauge theories has recently been immensely aided by advances in computational algebra. However, these symbolic (Gr\"{o}bner) methods are severely limited by algorithmic issues such as exponential space complexity and being highly sequential. In this paper, we introduce a novel paradigm of numerical algebraic geometry which in a plethora of situations overcomes these short-comings. Its so-called 'embarrassing parallelizability' allows us to solve many problems and extract physical information which elude the symbolic methods. We describe the method and then use it to solve various problems arising from physics which could not be otherwise solved.Comment: 36 page

Middle and Late Pleistocene environmental history of the Marsworth area, south-central England

To elucidate the Middle and Late Pleistocene environmental history of south-central England, we report the stratigraphy, sedimentology, palaeoecology and geochronology of some deposits near the foot of the Chiltern Hills scarp at Marsworth, Buckinghamshire. The Marsworth site is important because its sedimentary sequences contain a rich record of warm stages and cold stages, and it lies close to the Anglian glacial limit. Critical to its history are the origin and age of a brown pebbly silty clay (diamicton) previously interpreted as weathered till. The deposits described infill a river channel incised into chalk bedrock. They comprise clayey, silty and gravelly sediments, many containing locally derived chalk and some with molluscan, ostracod and vertebrate remains. Most of the deposits are readily attributed to periglacial and fluvial processes, and some are dated by optically stimulated luminescence to Marine Isotope Stage (MIS) 6. Although our sedimentological data do not discriminate between a glacial or periglacial interpretation of the diamicton, amino-acid dating of three molluscan taxa from beneath it indicates that it is younger than MIS 9 and older than MIS 5e. This makes a glacial interpretation unlikely, and we interpret the diamicton as a periglacial slope deposit. The Pleistocene history reconstructed for Marsworth identifies four key elements: (1) Anglian glaciation during MIS 12 closely approached Marsworth, introducing far-travelled pebbles such as Rhaxella chert and possibly some fine sand minerals into the area. (2) Interglacial environments inferred from fluvial sediments during MIS 7 varied from fully interglacial conditions during sub-stages 7e and 7c, cool temperate conditions during sub-stage 7b or 7a, temperate conditions similar to those today in central England towards the end of the interglacial, and cool temperate conditions during sub-stage 7a. (3) Periglacial activity during MIS 6 involved thermal contraction cracking, permafrost development, fracturing of chalk bedrock, fluvial activity, slopewash, mass movement and deposition of loess and coversand. (4) Fully interglacial conditions during sub-stage 5e led to renewed fluvial activity, soil formation and acidic weathering

Spectrum and Morphology of the Two Brightest Milagro Sources in the Cygnus Region: MGRO J2019+37 and MGRO J2031+41

The Cygnus region is a very bright and complex portion of the TeV sky, host to unidentified sources and a diffuse excess with respect to conventional cosmic-ray propagation models. Two of the brightest TeV sources, MGRO J2019+37 and MGRO J2031+41, are analyzed using Milagro data with a new technique, and their emission is tested under two different spectral assumptions: a power law and a power law with an exponential cutoff. The new analysis technique is based on an energy estimator that uses the fraction of photomultiplier tubes in the observatory that detect the extensive air shower. The photon spectrum is measured in the range 1 to 200 TeV using the last 3 years of Milagro data (2005-2008), with the detector in its final configuration. MGRO J2019+37 is detected with a significance of 12.3 standard deviations ($\sigma$), and is better fit by a power law with an exponential cutoff than by a simple power law, with a probability $>98$% (F-test). The best-fitting parameters for the power law with exponential cutoff model are a normalization at 10 TeV of $7^{+5}_{-2}\times10^{-10}$ $\mathrm{s^{-1}\: m^{-2}\: TeV^{-1}}$, a spectral index of $2.0^{+0.5}_{-1.0}$ and a cutoff energy of $29^{+50}_{-16}$ TeV. MGRO J2031+41 is detected with a significance of 7.3$\sigma$, with no evidence of a cutoff. The best-fitting parameters for a power law are a normalization of $2.4^{+0.6}_{-0.5}\times10^{-10}$ $\mathrm{s^{-1}\: m^{-2}\: TeV^{-1}}$ and a spectral index of $3.08^{+0.19}_{-0.17}$. The overall flux is subject to an $\sim$30% systematic uncertainty. The systematic uncertainty on the power law indices is $\sim$0.1. A comparison with previous results from TeV J2032+4130, MGRO J2031+41 and MGRO J2019+37 is also presented.Comment: 11 pages, 10 figure