Swift Observations of GRB 050603: An afterglow with a steep late time decay slope

We report the results of Swift observations of the Gamma Ray Burst GRB 050603. With a V magnitude V=18.2 about 10 hours after the burst the optical afterglow was the brightest so far detected by Swift and one of the brightest optical afterglows ever seen. The Burst Alert Telescope (BAT) light curves show three fast-rise-exponential-decay spikes with $T_{90}$=12s and a fluence of 7.6$\times 10^{-6}$ ergs cm$^{-2}$ in the 15-150 keV band. With an $E_{\rm \gamma, iso} = 1.26 \times 10^{54}$ ergs it was also one of the most energetic bursts of all times. The Swift spacecraft began observing of the afterglow with the narrow-field instruments about 10 hours after the detection of the burst. The burst was bright enough to be detected by the Swift UV/Optical telescope (UVOT) for almost 3 days and by the X-ray Telescope (XRT) for a week after the burst. The X-ray light curve shows a rapidly fading afterglow with a decay index $\alpha$=1.76$^{+0.15}_{-0.07}$. The X-ray energy spectral index was $\beta_{\rm X}$=0.71\plm0.10 with the column density in agreement with the Galactic value. The spectral analysis does not show an obvious change in the X-ray spectral slope over time. The optical UVOT light curve decays with a slope of $\alpha$=1.8\plm0.2. The steepness and the similarity of the optical and X-ray decay rates suggest that the afterglow was observed after the jet break. We estimate a jet opening angle of about 1-2$^{\circ}$Comment: 14 pages, accepted for publication in Ap

Angular Diameters of the G Subdwarf μ\mu Cassiopeiae A and the K Dwarfs σ\sigma Draconis and HR 511 from Interferometric Measurements with the CHARA Array

Using the longest baselines of the CHARA Array, we have measured the angular diameter of the G5 V subdwarf $\mu$ Cas A, the first such determination for a halo population star. We compare this result to new diameters for the higher metallicity K0 V stars, $\sigma$ Dra and HR 511, and find that the metal-poor star, $\mu$ Cas A, has an effective temperature ($T_{\rm eff}=5297\pm32$ K), radius ($R=0.791\pm0.008 R_{\rm \odot}$), and absolute luminosity ($L=0.442\pm0.014 L_{\rm \odot}$) comparable to the other two stars with later spectral types. We show that stellar models show a discrepancy in the predicted temperature and radius for $\mu$ Cas A, and we discuss these results and how they provide a key to understanding the fundamental relationships for stars with low metallicity.Comment: Accepted for publication in The Astrophysical Journa

The highly surprising behaviour of diphosphine ligands in iron-catalysed Negishi cross-coupling

Iron-catalysed cross-coupling is undergoing explosive development, but mechanistic understanding lags far behind synthetic methodology. Here, we find that the activity of iron–diphosphine pre-catalysts in the Negishi coupling of benzyl halides is strongly dependent on the diphosphine, but the ligand does not appear to be coordinated to the iron during turnover. This was determined using time-resolved in operando X-ray absorption fine structure spectroscopy employing a custom-made flow cell and confirmed by 31P NMR spectroscopy. While the diphosphine ligands tested are all able to coordinate to iron(II), in the presence of excess zinc(II)—as in the catalytic reaction—they coordinate predominantly to the zinc. Furthermore, combined synthetic and kinetic investigations implicate the formation of a putative mixed Fe–Zn(dpbz) species before the rate-limiting step of catalysis. These unexpected findings may not only impact the field of iron-catalysed Negishi cross-coupling, but potentially beyond to reactions catalysed by other transition metal/diphosphine complexes

Frequency-dependent selection can forecast evolution in Streptococcus pneumoniae

Predicting how pathogen populations will change over time is challenging. Such has been the case withStreptococcus pneumoniae, an important human pathogen, and the pneumococcal conjugate vaccines (PCVs), which target only a fraction of the strains in the population. Here, we use the frequencies of accessory genes to predict changes in the pneumococcal population after vaccination, hypothesizing that these frequencies reflect negative frequency-dependent selection (NFDS) on the gene products. We find that the standardized predicted fitness of a strain, estimated by an NFDS-based model at the time the vaccine is introduced, enables us to predict whether the strain increases or decreases in prevalence following vaccination. Further, we are able to forecast the equilibrium post-vaccine population composition and assess the invasion capacity of emerging lineages. Overall, we provide a method for predicting the impact of an intervention on pneumococcal populations with potential application to other bacterial pathogens in which NFDS is a driving force.Peer reviewe

Silver(I)-Catalyzed Synthesis of Cuneanes from Cubanes and their Investigation as Isosteres

Bridged or caged polycyclic hydrocarbons have rigid structures that project substituents into precise regions of 3D space, making them attractive as linking groups in materials science and as building blocks for medicinal chemistry. The efficient synthesis of new or underexplored classes of such compounds is, therefore, an important objective. Herein, we describe the silver(I)-catalyzed rearrangement of 1,4-disubstituted cubanes to cuneanes, which are strained hydrocarbons that have not received much attention since they were first described in 1970. The synthesis of 2,6-disubstituted or 1,3-disubstituted cuneanes can be achieved with high regioselectivities, with the regioselectivity being dependent on the electronic character of the cubane substituents. A preliminary assessment of cuneanes as scaffolds for medicinal chemistry suggests cuneanes could serve as isosteric replacements of trans-1,4-disubstituted cyclohexanes and 1,3-disubstituted benzenes. An analogue of the anticancer drug sonidegib was synthesized, in which the 1,2,3-trisubstituted benzene was replaced with a 1,3-disubstituted cuneane

Rates of self-reported delinquency among Western Australian male and female high school students: the malefemale gender gap

The Adapted Self-Report Delinquency Scale (ASDS) was administered to 328 adolescents (174 males and 154 females) from eight high schools in Perth, Western Australia. The ages of the sample ranged from 13 to 17 years. Males reported a greater percentage level of involvement than females in 36 of 40 individual delinquent behaviours comprising the ASDS. A between-subjects multivariate analysis of variance using a Bonferroni adjusted alpha revealed a significant multivariate main effect of gender, F(6, 318) = 3.98, p < 0.001, partial η2 = 0.08. No significant main effect of age was evident. Univariate F-tests revealed that males scored significantly higher than females on only one of seven delinquent factors (physical aggression). These data are discussed in light of established evidence showing male predominance in delinquency, recent reports suggesting a male-female gender gap, and theories that have attempted to explain this disparity in offending among males and females

The role and function of IκKα/β in monocyte impairment

Following major trauma, sepsis or surgery, some patients exhibit an impaired monocyte inflammatory response that is characterized by a decreased response to a subsequent bacterial challenge. To investigate this poorly understood phenomenon, we adopted an in-vitro model of endotoxin tolerance utilising primary human CD14 + monocytes to focus on the effect of impairment on IκKα/β, a critical part of the NFκB pathway. Impaired monocytes had decreased IκKα mRNA and protein expression and decreased phosphorylation of the IκKα/β complex. The impaired monocyte secretome demonstrated a distinct cytokine/chemokine footprint from the naïve monocyte, and that TNF-α was the most sensitive cytokine or chemokine in this setting of impairment. Inhibition of IκKα/β with a novel selective inhibitor reproduced the impaired monocyte phenotype with decreased production of TNF-α, IL-6, IL-12p70, IL-10, GM-CSF, VEGF, MIP-1β, TNF-β, IFN-α2 and IL-7 in response to an LPS challenge. Surgical patients with infection also exhibited an impaired monocyte phenotype and had decreased SITPEC, TAK1 and MEKK gene expression, which are important for IκKα/β activation. Our results emphasize that impaired monocyte function is, at least in part, related to dysregulated IκKα/β activation, and that IκKα/β is likely involved in mounting a sufficient monocyte inflammatory response. Future studies may wish to focus on adjuvant therapies that augment IκKα/β function to restore monocyte function in this clinically important problem

Preclinical efficacy studies of a novel nanoparticle-based formulation of paclitaxel that out-performs Abraxane

Poly-(γ-l-glutamylglutamine)–paclitaxel (PGG–PTX) is a novel polymer-based formulation of paclitaxel (PTX) in which the PTX is linked to the polymer via ester bonds. PGG–PTX is of interest because it spontaneously forms very small nanoparticles in plasma. In mouse models, PGG–PTX increased tumor exposure to PTX by 7.7-fold relative to that produced by PTX formulated in Cremophor. In this study, the efficacy of PGG–PTX was compared to that of Abraxane, an established nanoparticular formulation of PTX, in three different tumor models. Efficacy was quantified by delay in tumor growth of NCI H460 human lung cancer, 2008 human ovarian cancer and B16 melanoma xenografts growing in athymic mice following administration of equitoxic doses of PGG–PTX and Abraxane administered on either a single dose or every 7 day schedule. Toxicity was assessed by change in total body weight. The efficacy and toxicity of PGG–PTX was shown to increase with dose in the H460 model. PGG–PTX was ~1.5-fold less potent than Abraxane. PGG–PTX produced statistically significantly greater inhibition of tumor growth than Abraxane in all three tumor models when mice were given single equitoxic doses of drug. When given every 7 days for 3 doses, PGG–PTX produced greater inhibition of tumor growth while generating much less weight loss in mice bearing H460 tumors. PGG–PTX has activity that is superior to that of Abraxane in multiple tumor models. PGG–PTX has the potential to out-perform Abraxane in enhancing the delivery of PTX tumors while at the same time further reducing the toxicity of both single dose and weekly treatment regimens

A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case–control study

Funder: Pancreatic Cancer Research Fund; funder-id: http://dx.doi.org/10.13039/100011704Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with around 9% of patients surviving >5 years. Asymptomatic in its initial stages, PDAC is mostly diagnosed late, when already a locally advanced or metastatic disease, as there are no useful biomarkers for detection in its early stages, when surgery can be curative. We have previously described a promising biomarker panel (LYVE1, REG1A, and TFF1) for earlier detection of PDAC in urine. Here, we aimed to establish the accuracy of an improved panel, including REG1B instead of REG1A, and an algorithm for data interpretation, the PancRISK score, in additional retrospectively collected urine specimens. We also assessed the complementarity of this panel with CA19-9 and explored the daily variation and stability of the biomarkers and their performance in common urinary tract cancers. Methods and findings: Clinical specimens were obtained from multiple centres: Barts Pancreas Tissue Bank, University College London, University of Liverpool, Spanish National Cancer Research Center, Cambridge University Hospital, and University of Belgrade. The biomarker panel was assayed on 590 urine specimens: 183 control samples, 208 benign hepatobiliary disease samples (of which 119 were chronic pancreatitis), and 199 PDAC samples (102 stage I–II and 97 stage III–IV); 50.7% were from female individuals. PDAC samples were collected from patients before treatment. The samples were assayed using commercially available ELISAs. Statistical analyses were performed using non-parametric Kruskal–Wallis tests adjusted for multiple comparisons, and multiple logistic regression. Training and validation datasets for controls and PDAC samples were obtained after random division of the whole available dataset in a 1:1 ratio. The substitution of REG1A with REG1B enhanced the performance of the panel to detect resectable PDAC. In a comparison of controls and PDAC stage I–II samples, the areas under the receiver operating characteristic curve (AUCs) increased from 0.900 (95% CI 0.843–0.957) and 0.926 (95% CI 0.843–1.000) in the training (50% of the dataset) and validation sets, respectively, to 0.936 in both the training (95% CI 0.903–0.969) and the validation (95% CI 0.888–0.984) datasets for the new panel including REG1B. This improved panel showed both sensitivity (SN) and specificity (SP) to be >85%. Plasma CA19-9 enhanced the performance of this panel in discriminating PDAC I–II patients from controls, with AUC = 0.992 (95% CI 0.983–1.000), SN = 0.963 (95% CI 0.913–1.000), and SP = 0.967 (95% CI 0.924–1.000). We demonstrate that the biomarkers do not show significant daily variation, and that they are stable for up to 5 days at room temperature. The main limitation of our study is the low number of stage I–IIA PDAC samples (n = 27) and lack of samples from individuals with hereditary predisposition to PDAC, for which specimens collected from control individuals were used as a proxy. Conclusions: We have successfully validated our urinary biomarker panel, which was improved by substituting REG1A with REG1B. At a pre-selected cutoff of >80% SN and SP for the affiliated PancRISK score, we demonstrate a clinically applicable risk stratification tool with a binary output for risk of developing PDAC (‘elevated’ or ‘normal’). PancRISK provides a step towards precision surveillance for PDAC patients, which we will test in a prospective clinical study, UroPanc