Indirect Sensitivity to Heavy Z' Bosons at a Multi-TeV e+e- Collider

We compare the phenomenology of two models, the so-called minimal Z' and an effective model for a SM-like Higgs realised as a composite state of a new strong interaction, at a multi-TeV linear collider in the hypothesis that the new physics is at a scale beyond the direct reach of the machine.Comment: 6 pages, 5 figures, to appear in the Proceedings of the International Workshop on Future Linear Colliders LCWS201

Future Electron-Positron Colliders and the 4-Dimensional Composite Higgs Model

In this note we analyse the prospects of a future electron-positron collider in testing a particular realisation of a composite Higgs model encompassing partial compositeness, namely, the 4-Dimensional Composite Higgs Model. We study the main Higgs production channels for three possible energy stages and different luminosity options of such a machine and confront our results to the expected experimental accuracies in the various Higgs decay channels accessible herein and, for comparison, also at the Large Hadron Collider.Comment: 24 pages, 10 figures, minor corrections for publication in JHE

Probing New Scales at a e+e- Linear Collider

Extending the sensitivity to New Physics beyond the anticipated reach of the LHC is a prime aim of future colliders. This paper summarises the potential of an e+e- linear collider, at and beyond 1 TeV, using a realistic simulation of the detector response and the accelerator induced background. The possible LC energy-luminosity trade-offs offered in probing multi-TeV scales for new phenomena with electro-weak observables are also discussed

Effects of cleaning methods upon preservation of stable isotopes and trace elements in shells of Cyprideis torosa (Crustacea, Ostracoda): implications for palaeoenvironmental reconstruction

The trace element (Sr/Ca and Mg/Ca) and stable isotope (δ¹⁸O and δ¹³C) geochemistry of fossil ostracod valves provide valuable information, particularly in lacustrine settings, on palaeo-water composition and palaeotemperature. The removal of sedimentary and organic contamination prior to geochemical analysis is essential to avoid bias of the results. Previous stable isotope and trace element work on ostracod shells has, however, employed different treatments for the removal of contamination beyond simple ‘manual’ cleaning using a paint brush and methanol under a low-power binocular microscope. For isotopic work pre-treatments include chemical oxidation, vacuum roasting and plasma ashing, and for trace element work sonication, chemical oxidation and reductive cleaning. The impact of different treatments on the geochemical composition of the valve calcite has not been evaluated in full, and a universal protocol has not been established. Here, a systematic investigation of the cleaning methods is undertaken using specimens of the ubiquitous euryhaline species, Cyprideis torosa. Cleaning methods are evaluated by undertaking paired analyses on a single carapace (comprising two valves); in modern ostracods, whose valves are assumed to be unaltered, the two valves should have identical geochemical and isotopic composition. Hence, when one valve is subjected to the chosen treatment and the other to simple manual cleaning any difference in composition can confidently be assigned to the treatment method. We show that certain cleaning methods have the potential to cause alteration to the geochemical signal, particularly Mg/Ca and δ¹⁸O, and hence have implications for palaeoenvironmental reconstructions. For trace element determinations we recommend cleaning by sonication and for stable isotope analysis, oxidation by hydrogen peroxide. These methods remove contamination, yet do not significantly alter the geochemical signal

Studies of New Vector Resonances at the CLIC Multi-TeV e+e- Collider

Several models predict the existence of new vector resonances in the multi-TeV region, which can be produced in high energy e+e- collisions in the s-channel. In this paper we review the existing limits on the masses of these resonances from LEP/SLC and TEVATRON data and from atomic parity violation in some specific models. We study the potential of a multi-TeV e+e- collider, such as CLIC, for the determination of their properties and nature.Comment: 17 pages, 16 EPS figures, uses JHEP3.cl

Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks

Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin-positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1-depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons

GPER mediates the angiocrine actions induced by IGF1 through the HIF-1α/VEGF pathway in the breast tumor microenvironment

The G protein estrogen receptor GPER/GPR30 mediates estrogen action in breast cancer cells as well as in breast cancer-associated fibroblasts (CAFs), which are key components of microenvironment driving tumor progression. GPER is a transcriptional target of hypoxia inducible factor 1 alpha (HIF-1α) and activates VEGF expression and angiogenesis in hypoxic breast tumor microenvironment. Furthermore, IGF1/IGF1R signaling, which has angiogenic effects, has been shown to activate GPER in breast cancer cells. We analyzed gene expression data from published studies representing almost 5000 breast cancer patients to investigate whether GPER and IGF1 signaling establish an angiocrine gene signature in breast cancer patients. Next, we used GPER-positive but estrogen receptor (ER)-negative primary CAF cells derived from patient breast tumours and SKBR3 breast cancer cells to investigate the role of GPER in the regulation of VEGF expression and angiogenesis triggered by IGF1. We performed gene expression and promoter studies, western blotting and immunofluorescence analysis, gene silencing strategies and endothelial tube formation assays to evaluate the involvement of the HIF-1α/GPER/VEGF signaling in the biological responses to IGF1. We first determined that GPER is co-expressed with IGF1R and with the vessel marker CD34 in human breast tumors (n = 4972). Next, we determined that IGF1/IGF1R signaling engages the ERK1/2 and AKT transduction pathways to induce the expression of HIF-1α and its targets GPER and VEGF. We found that a functional cooperation between HIF-1α and GPER is essential for the transcriptional activation of VEGF induced by IGF1. Finally, using conditioned medium from CAFs and SKBR3 cells stimulated with IGF1, we established that HIF-1α and GPER are both required for VEGF-induced human vascular endothelial cell tube formation. These findings shed new light on the essential role played by GPER in IGF1/IGF1R signaling that induces breast tumor angiogenesis. Targeting the multifaceted interactions between cancer cells and tumor microenvironment involving both GPCRs and growth factor receptors has potential in future combination anticancer therapies

Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation

BACKGROUND: Liver biopsy is the reference standard for diagnosing the extent of fibrosis in chronic liver disease; however, it is invasive, with the potential for serious complications. Alternatives to biopsy include non-invasive liver tests (NILTs); however, the cost-effectiveness of these needs to be established. OBJECTIVE: To assess the diagnostic accuracy and cost-effectiveness of NILTs in patients with chronic liver disease. DATA SOURCES: We searched various databases from 1998 to April 2012, recent conference proceedings and reference lists. METHODS: We included studies that assessed the diagnostic accuracy of NILTs using liver biopsy as the reference standard. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was conducted using the bivariate random-effects model with correlation between sensitivity and specificity (whenever possible). Decision models were used to evaluate the cost-effectiveness of the NILTs. Expected costs were estimated using a NHS perspective and health outcomes were measured as quality-adjusted life-years (QALYs). Markov models were developed to estimate long-term costs and QALYs following testing, and antiviral treatment where indicated, for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). NILTs were compared with each other, sequential testing strategies, biopsy and strategies including no testing. For alcoholic liver disease (ALD), we assessed the cost-effectiveness of NILTs in the context of potentially increasing abstinence from alcohol. Owing to a lack of data and treatments specifically for fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), the analysis was limited to an incremental cost per correct diagnosis. An analysis of NILTs to identify patients with cirrhosis for increased monitoring was also conducted. RESULTS: Given a cost-effectiveness threshold of £20,000 per QALY, treating everyone with HCV without prior testing was cost-effective with an incremental cost-effectiveness ratio (ICER) of £9204. This was robust in most sensitivity analyses but sensitive to the extent of treatment benefit for patients with mild fibrosis. For HBV [hepatitis B e antigen (HBeAg)-negative)] this strategy had an ICER of £28,137, which was cost-effective only if the upper bound of the standard UK cost-effectiveness threshold range (£30,000) is acceptable. For HBeAg-positive disease, two NILTs applied sequentially (hyaluronic acid and magnetic resonance elastography) were cost-effective at a £20,000 threshold (ICER: £19,612); however, the results were highly uncertain, with several test strategies having similar expected outcomes and costs. For patients with ALD, liver biopsy was the cost-effective strategy, with an ICER of £822. LIMITATIONS: A substantial number of tests had only one study from which diagnostic accuracy was derived; therefore, there is a high risk of bias. Most NILTs did not have validated cut-offs for diagnosis of specific fibrosis stages. The findings of the ALD model were dependent on assuptions about abstinence rates assumptions and the modelling approach for NAFLD was hindered by the lack of evidence on clinically effective treatments. CONCLUSIONS: Treating everyone without NILTs is cost-effective for patients with HCV, but only for HBeAg-negative if the higher cost-effectiveness threshold is appropriate. For HBeAg-positive, two NILTs applied sequentially were cost-effective but highly uncertain. Further evidence for treatment effectiveness is required for ALD and NAFLD. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001561. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Ictal but Not Interictal Epileptic Discharges Activate Astrocyte Endfeet and Elicit Cerebral Arteriole Responses

Activation of astrocytes by neuronal signals plays a central role in the control of neuronal activity-dependent blood flow changes in the normal brain. The cellular pathways that mediate neurovascular coupling in the epileptic brain remain, however, poorly defined. In a cortical slice model of epilepsy, we found that the ictal, seizure-like discharge, and only to a minor extent the interictal discharge, evokes both a Ca2+ increase in astrocyte endfeet and a vasomotor response. We also observed that rapid ictal discharge-induced arteriole responses were regularly preceded by Ca2+ elevations in endfeet and were abolished by pharmacological inhibition of Ca2+ signals in these astrocyte processes. Under these latter conditions, arterioles exhibited after the ictal discharge only slowly developing vasodilations. The poor efficacy of interictal discharges, compared with ictal discharges, to activate endfeet was confirmed also in the intact in vitro isolated guinea pig brain. Although the possibility of a direct contribution of neurons, in particular in the late response of cerebral blood vessels to epileptic discharges, should be taken into account, our study supports the view that astrocytes are central for neurovascular coupling also in the epileptic brain. The massive endfeet Ca2+ elevations evoked by ictal discharges and the poor response to interictal events represent new information potentially relevant to interpret data from diagnostic brain imaging techniques, such as functional magnetic resonance, utilized in the clinic to localize neural activity and to optimize neurosurgery of untreatable epilepsies