The gating mechanism in cyclic nucleotide-gated ion channels

Cyclic nucleotide-gated (CNG) channels mediate transduction in several sensory neurons. These channels use the free energy of CNs' binding to open the pore, a process referred to as gating. CNG channels belong to the superfamily of voltage-gated channels, where the motion of the \uce\ub1-helix S6 controls gating in most of its members. To date, only the open, cGMP-bound, structure of a CNG channel has been determined at atomic resolution, which is inadequate to determine the molecular events underlying gating. By using electrophysiology, site-directed mutagenesis, chemical modification, and Single Molecule Force Spectroscopy, we demonstrate that opening of CNGA1 channels is initiated by the formation of salt bridges between residues in the C-linker and S5 helix. These events trigger conformational changes of the \uce\ub1-helix S5, transmitted to the P-helix and leading to channel opening. Therefore, the superfamily of voltage-gated channels shares a similar molecular architecture but has evolved divergent gating mechanisms

FCC Physics Opportunities: Future Circular Collider Conceptual Design Report Volume 1

We review the physics opportunities of the Future Circular Collider, covering its e+e-, pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics

FCC-hh: The Hadron Collider: Future Circular Collider Conceptual Design Report Volume 3

In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries

FCC-hh: The Hadron Collider: Future Circular Collider Conceptual Design Report Volume 3

In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries

Comparison of region-of-interest analysis with three different histogram analysis methods in the determination of perfusion metrics in patients with brain gliomas

PURPOSE: To compare routine ROI analysis and three different histogram analyses in the grading of glial neoplasms. The hypothesis is that histogram methods can provide a robust and objective technique for quantifying perfusion data in brain gliomas. Current region-of-interest (ROI)-based methods for the analysis of dynamic susceptibility contrast perfusion magnetic resonance imaging (DSC MRI) data are operator-dependent. MATERIALS AND METHODS: A total of 92 patients underwent conventional and DSC MRI. Multiple histogram metrics were obtained for cerebral blood flow (CBF), cerebral blood volume (CBV), and relative CBV (rCBV) maps using tumoral (T), peritumoral (P), and total tumoral (TT) analysis. Results were compared to histopathologic grades. Statistical analysis included Mann-Whitney (MW) tests, Spearman rank correlation coefficients, logistic regression, and McNemar tests. RESULTS: The maximum value of rCBV (rCBV(max)) showed highly significant correlation with glioma grade (r = 0.734, P <0.001). The strongest histogram correlations (P <0.0001) occurred with rCBV(T) SD (r = 0.718), rCBV(P) SD(25) (r = 0.724) and rCBV(TT) SD(50) (r = 0.685). Multiple rCBV(T), rCBV(P), and rCBV(TT) histogram metrics showed significant correlations. CBF and CBV histogram metrics were less strongly correlated with glioma grade than rCBV histogram metrics. CONCLUSION: Histogram analysis of perfusion MR provides prediction of glioma grade, with peritumoral metrics outperforming tumoral and total tumoral metrics. Further refinement may lead to automated methods for perfusion data analysis