Prediction of stroke risk based on left atrial appendage morphology: from pareidolia to artificial intelligence

<jats:title>Abstract</jats:title><jats:p>The global carbon-climate system is a complex dynamical system with multiple feedbacks among components, and to steer this system away from dangerous climate change, it may not be enough to prescribe action according to long-term scenarios of fossil fuel emissions. We introduce here concepts from control theory, a branch of applied mathematics that is effective at steering complex dynamical systems to desired states, and distinguish between open- and closed-loop control. We attempt (1) to show that current scientific work on carbon-climate feedbacks and climate policy more closely resembles the conceptual model of open- than closed-loop control, (2) to introduce a mathematical generalization of the carbon-climate system as a compartmental dynamical system that can facilitate the formal treatment of the closed-loop control problem, and (3) to formulate carbon-climate control as a congestion control problem, discussing important concepts such as observability and controllability. We also show that most previous discussions on climate change mitigation and policy development have relied on an implicit assumption of open-loop control that does not consider frequent corrections due to deviations of goals from observations. Using a reduced complexity model, we illustrate that the problem of managing the global carbon cycle can be abstracted as a network congestion problem, accounting for nonlinear behavior and feedback from a global carbon monitoring system. As opposed to <jats:italic>scenarios</jats:italic>, the goal of closed-loop control is to develop <jats:italic>rules</jats:italic> for continuously steering the global carbon-climate system away from dangerous climate change.</jats:p&gt

Inhibitor binding mode and allosteric regulation of Na+-glucose symporters.

Sodium-dependent glucose transporters (SGLTs) exploit sodium gradients to transport sugars across the plasma membrane. Due to their role in renal sugar reabsorption, SGLTs are targets for the treatment of type 2 diabetes. Current therapeutics are phlorizin derivatives that contain a sugar moiety bound to an aromatic aglycon tail. Here, we develop structural models of human SGLT1/2 in complex with inhibitors by combining computational and functional studies. Inhibitors bind with the sugar moiety in the sugar pocket and the aglycon tail in the extracellular vestibule. The binding poses corroborate mutagenesis studies and suggest a partial closure of the outer gate upon binding. The models also reveal a putative Na+ binding site in hSGLT1 whose disruption reduces the transport stoichiometry to the value observed in hSGLT2 and increases inhibition by aglycon tails. Our work demonstrates that subtype selectivity arises from Na+-regulated outer gate closure and a variable region in extracellular loop EL5

Dose-response relationship of fibrous dusts in intraperitoneal studies.

The relationship between the number of fibers injected intraperitoneally and the occurrence of peritoneal mesotheliomas in rats was investigated using data from a series of carcinogenicity studies with several fibrous dusts. Based on observed tumor incidences ranging between 10 and 90%, the hypothesis of a common slope of dose-response relationships (parallel probit lines in probit analysis) cannot be rejected. In general, parallelism of probit lines is considered an indication of a common mode of action. Analysis of the shape of the dose-response relationship, with one apparent exception, shows virtually linear or superlinear behavior, i.e., from these data, there is no indication of a decrease in carcinogenic potency of an elementary carcinogenic unit at lower doses

PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells

Endothelial pro-inflammatory activation plays a pivotal role in atherosclerosis, and many pro-inflammatory and atherogenic signals converge upon mechanistic target of rapamycin (mTOR). Inhibitors of mTOR complex 1 (mTORC1) reduced atherosclerosis in preclinical studies, but side effects including insulin resistance and dyslipidemia limit their clinical use in this context. Therefore, we investigated PRAS40, a cell type-specific endogenous modulator of mTORC1, as alternative target. Indeed, we previously found PRAS40 gene therapy to improve metabolic profile; however, its function in endothelial cells and its role in atherosclerosis remain unknown. Here we show that PRAS40 negatively regulates endothelial mTORC1 and pro-inflammatory signaling. Knockdown of PRAS40 in endothelial cells promoted TNFα-induced mTORC1 signaling, proliferation, upregulation of inflammatory markers and monocyte recruitment. In contrast, PRAS40-overexpression blocked mTORC1 and all measures of pro-inflammatory signaling. These effects were mimicked by pharmacological mTORC1-inhibition with torin1. In an in vivo model of atherogenic remodeling, mice with induced endothelium-specific PRAS40 deficiency showed enhanced endothelial pro-inflammatory activation as well as increased neointimal hyperplasia and atherosclerotic lesion formation. These data indicate that PRAS40 suppresses atherosclerosis via inhibition of endothelial mTORC1-mediated pro-inflammatory signaling. In conjunction with its favourable effects on metabolic homeostasis, this renders PRAS40 a potential target for the treatment of atherosclerosis

Ablation Lesion Assessment with MRI

Late gadolinium enhancement (LGE) MRI is capable of detecting not only native cardiac fibrosis, but also ablation-induced scarring. Thus, it offers the unique opportunity to assess ablation lesions non-invasively. In the atrium, LGE-MRI has been shown to accurately detect and localise gaps in ablation lines. With a negative predictive value close to 100% it can reliably rule out pulmonary vein reconnection non-invasively and thus may avoid unnecessary invasive repeat procedures where a pulmonary vein isolation only approach is pursued. Even LGE-MRI-guided repeat pulmonary vein isolation has been demonstrated to be feasible as a standalone approach. LGE-MRI-based lesion assessment may also be of value to evaluate the efficacy of ventricular ablation. In this respect the elimination of LGE-MRI-detected arrhythmogenic substrate may serve as a potential endpoint, but validation in clinical studies is lacking. Despite holding great promise, the widespread use of LGE-MRI is still limited by the absence of standardised protocols for image acquisition and post-processing. In particular, reproducibility across different centres is impeded by inconsistent thresholds and internal references to define fibrosis. Thus, uniform methodological and analytical standards are warranted to foster a broader implementation in clinical practice

A New 5 Flavour NLO Analysis and Parametrizations of Parton Distributions of the Real Photon

New, radiatively generated, NLO quark (u,d,s,c,b) and gluon densities in a real, unpolarized photon are presented. We perform three global fits, based on the NLO DGLAP evolution equations for Q^2>1 GeV^2, to all the available structure function F_2^gamma(x,Q^2) data. As in our previous LO analysis we utilize two theoretical approaches. Two models, denoted as FFNS_{CJK}1 & 2 NLO, adopt the so-called Fixed Flavour-Number Scheme for calculation of the heavy-quark contributions to F_2^gamma(x,Q^2), the CJK NLO model applies the ACOT(chi) scheme. We examine the results of our fits by a comparison with the LEP data for the Q^2 dependence of the F_2^gamma, averaged over various x-regions, and the F_2,c^gamma. Grid parametrizations of the parton densities for all fits are provided.Comment: 49 pages, 27 postscript figures; FORTRAN programs available at http://www.fuw.edu.pl/~pjank/param.htm

Transverse momentum spectra of identified particles in high energy collisions with statistical hadronisation model

A detailed analysis is performed of transverse momentum spectra of several identified hadrons in high energy collisions within the framework of the statistical model of hadronisation. The effect of the decay chain following hadron generation is accurately taken into account. The considered centre-of-mass energies range from ~ 10 to 30 GeV in hadronic collisions (pi+ p, pp and Kp) and from ~ 15 to 45 GeV in e+e- collisions. A clear consistency is found between the temperature parameter extracted from the present analysis and that obtained from fits to average hadron multiplicities in the same collision systems. This finding indicates that in the hadronisation, the production of different particle species and their momentum spectra are two closely related phenomenons governed by one parameter.Comment: Talk given by F. Becattini in "Correlations and Fluctuations 2000", 12 pp., 11 figure