Explosive Nucleosynthesis: What we learned and what we still do not understand

This review touches on historical aspects, going back to the early days of nuclear astrophysics, initiated by B$^2$FH and Cameron, discusses (i) the required nuclear input from reaction rates and decay properties up to the nuclear equation of state, continues (ii) with the tools to perform nucleosynthesis calculations and (iii) early parametrized nucleosynthesis studies, before (iv) reliable stellar models became available for the late stages of stellar evolution. It passes then through (v) explosive environments from core-collapse supernovae to explosive events in binary systems (including type Ia supernovae and compact binary mergers), and finally (vi) discusses the role of all these nucleosynthesis production sites in the evolution of galaxies. The focus is put on the comparison of early ideas and present, very recent, understanding.Comment: 11 pages, to appear in Springer Proceedings in Physics (Proc. of Intl. Conf. "Nuclei in the Cosmos XV", LNGS Assergi, Italy, June 2018

Comprehensive assessment of estrogen receptor beta antibodies in cancer cell line models and tissue reveals critical limitations in reagent specificity

Estrogen Receptor-β (ERβ) has been implicated in many cancers. In prostate and breast cancer its function is controversial, but genetic studies implicate a role in cancer progression. Much of the confusion around ERβ stems from antibodies that are inadequately validated, yet have become standard tools for deciphering its role. Using an ERβ-inducible cell system we assessed commonly utilized ERβ antibodies and show that one of the most commonly used antibodies, NCL-ER-BETA, is non-specific for ERβ. Other antibodies have limited ERβ specificity or are only specific in one experimental modality. ERβ is commonly studied in MCF-7 (breast) and LNCaP (prostate) cancer cell lines, but we found no ERβ expression in either, using validated antibodies and independent mass spectrometry-based approaches. Our findings question conclusions made about ERβ using the NCL-ER-BETA antibody, or LNCaP and MCF-7 cell lines. We describe robust reagents, which detect ERβ across multiple experimental approaches and in clinical samples.The authors acknowledge the Breast Cancer Research Foundation, Cancer Research UK, ERC Consolidator award (grant number 646876), Cambridge Biomedical Research Campus and Cambridge Cancer Centre, which fund the tissue bank and the Urology Biorepository

Multi-scale evolution of Kelvin–Helmholtz waves at the earth's magnetopause during southward IMF periods

At the Earth's low-latitude magnetopause, the Kelvin–Helmholtz instability (KHI), driven by the velocity shear between the magnetosheath and magnetosphere, has been frequently observed during northward interplanetary magnetic field (IMF) periods. However, the signatures of the KHI have been much less frequently observed during southward IMF periods, and how the KHI develops under southward IMF has been less explored. Here, we performed a series of realistic 2D and 3D fully kinetic simulations of a KH wave event observed by the Magnetospheric Multiscale (MMS) mission at the dusk-flank magnetopause during southward IMF on September 23, 2017. The simulations demonstrate that the primary KHI bends the magnetopause current layer and excites the Rayleigh–Taylor instability (RTI), leading to penetration of high-density arms into the magnetospheric side. This arm penetration disturbs the structures of the vortex layer and produces intermittent and irregular variations of the surface waves which significantly reduces the observational probability of the periodic KH waves. The simulations further demonstrate that in the non-linear growth phase of the primary KHI, the lower-hybrid drift instability (LHDI) is induced near the edge of the primary vortices and contributes to an efficient plasma mixing across the magnetopause. The signatures of the large-scale surface waves by the KHI/RTI and the small-scale fluctuations by the LHDI are reasonably consistent with the MMS observations. These results indicate that the multi-scale evolution of the magnetopause KH waves and the resulting plasma transport and mixing as seen in the simulations may occur during southward IM

Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

PURPOSE: The ferret cisplatin emesis model has been used for ~30 years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT(3) receptor antagonists to assess its translational validity. METHODS: A systematic review identified available evidence and was used to perform meta-analyses. RESULTS: Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n = 53) used a 10 mg kg(−1) dose to induce acute emesis, which peaked after 2 h. More recent studies (n = 11) also used 5 mg kg(−1), which induced a biphasic response peaking at 12 h and 48 h. Overall, 5-HT(3) receptor antagonists reduced cisplatin (5 mg kg(−1)) emesis by 68% (45–91%) during the acute phase (day 1) and by 67% (48–86%) and 53% (38–68%, all P < 0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin. CONCLUSION: Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT(3) receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret

Causal hierarchy within the thalamo-cortical network in spike and wave discharges

Background: Generalised spike wave (GSW) discharges are the electroencephalographic (EEG) hallmark of absence seizures, clinically characterised by a transitory interruption of ongoing activities and impaired consciousness, occurring during states of reduced awareness. Several theories have been proposed to explain the pathophysiology of GSW discharges and the role of thalamus and cortex as generators. In this work we extend the existing theories by hypothesizing a role for the precuneus, a brain region neglected in previous works on GSW generation but already known to be linked to consciousness and awareness. We analysed fMRI data using dynamic causal modelling (DCM) to investigate the effective connectivity between precuneus, thalamus and prefrontal cortex in patients with GSW discharges. Methodology and Principal Findings: We analysed fMRI data from seven patients affected by Idiopathic Generalized Epilepsy (IGE) with frequent GSW discharges and significant GSW-correlated haemodynamic signal changes in the thalamus, the prefrontal cortex and the precuneus. Using DCM we assessed their effective connectivity, i.e. which region drives another region. Three dynamic causal models were constructed: GSW was modelled as autonomous input to the thalamus (model A), ventromedial prefrontal cortex (model B), and precuneus (model C). Bayesian model comparison revealed Model C (GSW as autonomous input to precuneus), to be the best in 5 patients while model A prevailed in two cases. At the group level model C dominated and at the population-level the p value of model C was ∼1. Conclusion: Our results provide strong evidence that activity in the precuneus gates GSW discharges in the thalamo-(fronto) cortical network. This study is the first demonstration of a causal link between haemodynamic changes in the precuneus - an index of awareness - and the occurrence of pathological discharges in epilepsy. © 2009 Vaudano et al

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis

Background Ultrasound (US) has largely replaced contrast venography as the definitive diagnostic test for deep vein thrombosis (DVT). We aimed to derive a definitive estimate of the diagnostic accuracy of US for clinically suspected DVT and identify study-level factors that might predict accuracy. Methods We undertook a systematic review, meta-analysis and meta-regression of diagnostic cohort studies that compared US to contrast venography in patients with suspected DVT. We searched Medline, EMBASE, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, Database of Reviews of Effectiveness, the ACP Journal Club, and citation lists (1966 to April 2004). Random effects meta-analysis was used to derive pooled estimates of sensitivity and specificity. Random effects meta-regression was used to identify study-level covariates that predicted diagnostic performance. Results We identified 100 cohorts comparing US to venography in patients with suspected DVT. Overall sensitivity for proximal DVT (95% confidence interval) was 94.2% (93.2 to 95.0), for distal DVT was 63.5% (59.8 to 67.0), and specificity was 93.8% (93.1 to 94.4). Duplex US had pooled sensitivity of 96.5% (95.1 to 97.6) for proximal DVT, 71.2% (64.6 to 77.2) for distal DVT and specificity of 94.0% (92.8 to 95.1). Triplex US had pooled sensitivity of 96.4% (94.4 to 97.1%) for proximal DVT, 75.2% (67.7 to 81.6) for distal DVT and specificity of 94.3% (92.5 to 95.8). Compression US alone had pooled sensitivity of 93.8 % (92.0 to 95.3%) for proximal DVT, 56.8% (49.0 to 66.4) for distal DVT and specificity of 97.8% (97.0 to 98.4). Sensitivity was higher in more recently published studies and in cohorts with higher prevalence of DVT and more proximal DVT, and was lower in cohorts that reported interpretation by a radiologist. Specificity was higher in cohorts that excluded patients with previous DVT. No studies were identified that compared repeat US to venography in all patients. Repeat US appears to have a positive yield of 1.3%, with 89% of these being confirmed by venography. Conclusion Combined colour-doppler US techniques have optimal sensitivity, while compression US has optimal specificity for DVT. However, all estimates are subject to substantial unexplained heterogeneity. The role of repeat scanning is very uncertain and based upon limited data

A generic method for estimating and smoothing multispecies biodiversity indices using intermittent data

Biodiversity indicators summarise extensive, complex ecological data sets and are important in influencing government policy. Component data consist of time-varying indices for each of a number of different species. However, current biodiversity indicators suffer from multiple statistical shortcomings. We describe a state-space formulation for new multispecies biodiversity indicators, based on rates of change in the abundance or occupancy probability of the contributing individual species. The formulation is flexible and applicable to different taxa. It possesses several advantages, including the ability to accommodate the sporadic unavailability of data, incorporate variation in the estimation precision of the individual species’ indices when appropriate, and allow the direct incorporation of smoothing over time. Furthermore, model fitting is straightforward in Bayesian and classical implementations, the latter adopting either efficient Hidden Markov modelling or the Kalman filter. Conveniently, the same algorithms can be adopted for cases based on abundance or occupancy data—only the subsequent interpretation differs. The procedure removes the need for bootstrapping which can be prohibitive. We recommend which of two alternatives to use when taxa are fully or partially sampled. The performance of the new approach is demonstrated on simulated data, and through application to three diverse national UK data sets on butterflies, bats and dragonflies. We see that uncritical incorporation of index standard errors should be avoided