Construction of global optimization constrained NLP test cases from unconstrained problems

This paper presents a novel construction technique for constrained nonconvex Nonlinear Programming Problem (NLP) test cases, derived from the evaluation tree structure of standardized bound constrained problems for which the global solution is known. It is demonstrated in a step-by-step procedure how first an equality constrained problem can be derived from an unconstrained one, with bounds imposed on all variables, using the Directed Acyclic Graph (DAG) of the unconstrained objective function and the use of interval arithmetic to derive bounds for the new variables introduced. An advantage of the proposed methodology is that several standard unconstrained global optimization test cases can be constructed for varying number of optimization variables, thus leading to adjustable size derived NLP’s. Further to this in a second step it is demonstrated how any subset of the equalities derived can be relaxed into inequalities giving an equivalent optimization problem. Finally, in a third step it is demonstrated how, by reducing the number of equality constraints derived, it is possible to obtain more complex expressions in the constraints and objective function. The methodology is highlighted throughout by motivating examples and a sample code in Mathematica TM is provided in the Appendix.This is the author accepted manuscript. The final version is available from Elsevier via https://doi.org/https://doi.org/10.1016/j.cherd.2016.03.01

Regulation of markers of synaptic function in mouse models of depression: chronic mild stress and decreased expression of VGLUT1

Depression has been linked to failure in synaptic plasticity originating from environmental and/or genetic risk factors. The chronic mild stress (CMS) model regulates the expression of synaptic markers of neurotransmitter function and associated depressive-like behaviour. Moreover, mice heterozygous for the synaptic vesicle protein (SVP) vesicular glutamate transporter 1 (VGLUT1), have been proposed as a genetic model of deficient glutamate function linked to depressive-like behaviour. Here, we aimed to identify, in these two experimental models, mechanisms of failure in synaptic plasticity, common to stress and impaired glutamate function. First, we show that CMS induced a transient decrease of different plasticity markers (VGLUT1, synapsin 1, sinaptophysin, rab3A and activity regulated cytoskeletal protein Arc) but a long-lasting decrease of the brain derived neurotrophic factor (BDNF) as well as depressive-like behaviour. The immediate early gene (IEG) Arc was also downregulated in VGLUT1+/- heterozygous mice. In contrast, an opposite regulation of synapsin 1 was observed. Finally, both models showed a marked increase of cortical Arc response to novelty. Increased Arc response to novelty could be suggested as a molecular mechanism underlying failure to adapt to environmental changes, common to chronic stress and altered glutamate function. Further studies should investigate whether these changes are associated to depressive-like behaviour both in animal models and in depressed patients

The Cadiz Contourite Channel: Sandy contourites, bedforms and dynamic current interaction

The Cadiz Contourite Channel is the largest and most prominent contourite channel in the middle slope of the Gulf of Cadiz, and is known to channelise the southern branch of the Lower Core of Mediterranean Outflow Water (MOW) as it flows westwards from the Gibraltar Gateway. The channel lies in water depth between 650 and 1500 m, is 150 km long, 2–12 km wide, up to 120 m deep, and broadly s-shaped in plan view. It has several associated subparallel marginal channels and shorter spillover channel segments. Its geometry is controlled by the interaction of a strong bottom current with the seafloor morphology, affected by neotectonic deformation and diapiric intrusion. Bottom photographs and dredge hauls reveal a channel floor shaped by high-energy flow, in places with bare rock, boulders and gravel, and elsewhere covered with sandy contourites. The rocky substrate and derived clasts are formed of authigenic iron-rich carbonates, testifying the high degree of fluid escape from adjacent diapiric ridges and mud volcanoes. The sandy substrate shows a wide range of current-induced bedforms including small, straight-crested ripples, large sinuous sand waves and dunes (wavelength 3.5–5 m, height 0.3–0.9 m), weak surface lineation on sands, and aligned gravel stringers and deep erosive scours around large boulders. Bedform orientation indicates flows directed to the south/south-west (main channel) and west (spillover channel), which can be related to MOW bottom currents, and current velocities that vary between about 0.2 and 0.8 m s− 1, even in the same channel location. However, current vane orientation was clearly responding, at least in part, to tidal effects and periodicity in the Gulf of Cadiz at the time the photographs were taken. Maximum current velocities are achieved by a combination of barotropic and internal tides (probably generated at the continental slope) that reinforce the normal MOW flow. In addition, meteorologically-induced internal waves with periods shorter than tidal ones may exert an even greater influence on current intensity, especially when they occur at times of sudden changes of meteorological forcing. This effect further influences MOW variability. In all cases, the funnelling effect of the Cadiz Channel amplifies tidal or meteorologically-induced bottom currents

Clusterin deficiency is associated with a lack of response to teriflunomide in multiple sclerosis

Clusterin deficiency; Teriflunomide; Multiple sclerosisDeficiència de clusterina; Teriflunomida; Esclerosi múltipleDeficiencia de clusterina; Teriflunomida; Esclerosis múltipleThis research was conducted using Departmental funds for Medical Research

Mechanisms of Natural Gene Therapy in Dystrophic Epidermolysis Bullosa

Item does not contain fulltextRevertant mosaicism has been reported in several inherited diseases, including the genetic skin fragility disorder epidermolysis bullosa (EB). Here, we describe the largest cohort of seven patients with revertant mosaicism and dystrophic EB (DEB), associated with mutations in the COL7A1 gene, and determine the underlying molecular mechanisms. We show that revertant mosaicism occurs both in autosomal dominantly and recessively inherited DEB. We found that null mutations resulting in complete loss of collagen VII and severe disease, as well as missense or splice-site mutations associated with some preserved collagen VII function and a milder phenotype, were corrected by revertant mosaicism. The mutation, subtype, and severity of the disease are thus not decisive for the presence of revertant mosaicism. Although collagen VII is synthesized and secreted by both keratinocytes and fibroblasts, evidence for reversion was only found in keratinocytes. The reversion mechanisms included back mutations/mitotic recombinations in 70% of the cases and second-site mutations affecting splicing in 30%. We conclude that revertant mosaicism is more common than previously assumed in patients with DEB, and our findings will have implications for future therapeutic strategies using the patient's naturally corrected cells as a source for cell-based therapies

YSOVAR: Six pre-main-sequence eclipsing binaries in the Orion Nebula Cluster

Eclipsing binaries (EBs) provide critical laboratories for empirically testing predictions of theoretical models of stellar structure and evolution. Pre-main-sequence (PMS) EBs are particularly valuable, both due to their rarity and the highly dynamic nature of PMS evolution, such that a dense grid of PMS EBs is required to properly calibrate theoretical PMS models. Analyzing multi-epoch, multi-color light curves for 2400 candidateOrion Nebula Cluster (ONC) members from our Warm Spitzer Exploration Science Program YSOVAR, we have identified 12 stars whose light curves show eclipse features. Four of these 12 EBs are previously known. Supplementing our light curves with follow-up optical and near-infrared spectroscopy, we establish two of the candidates as likely field EBs lying behind the ONC. We confirm the remaining six candidate systems, however, as newly identified ONC PMS EBs. These systems increase the number of known PMS EBs by over 50% and include the highest mass (Theta1 Ori E, for which we provide a complete set of well-determined parameters including component masses of 2.807 and 2.797 solar masses) and longest period (ISOY J053505.71-052354.1, P \sim 20 days) PMS EBs currently known. In two cases (Theta1 Ori E and ISOY J053526.88-044730.7), enough photometric and spectroscopic data exist to attempt an orbit solution and derive the system parameters. For the remaining systems, we combine our data with literature information to provide a preliminary characterization sufficient to guide follow-up investigations of these rare, benchmark systems.Comment: Accepted by Ap

Changes in the treatment of Enterococcus faecalis infective endocarditis in Spain in the last 15 years: from ampicillin plus gentamicin to ampicillin plus ceftriaxone

AbstractThe aim of this study was to assess changes in antibiotic resistance, epidemiology and outcome among patients with Enterococcus faecalis infective endocarditis (EFIE) and to compare the efficacy and safety of the combination of ampicillin and gentamicin (A+G) with that of ampicillin plus ceftriaxone (A+C). The study was a retrospective analysis of a prospective cohort of EFIE patients treated in our centre from 1997 to 2011. Thirty patients were initially treated with A+G (ampicillin 2 g/4 h and gentamicin 3 mg/kg/day) and 39 with A+C (ampicillin 2 g/4 h and ceftriaxone 2 g/12 h) for 4–6 weeks. Increased rates of high-level aminoglycoside resistance (HLAR; gentamicin MIC ≥512 mg/L, streptomycin MIC ≥1024 mg/L or both) were observed in recent years (24% in 1997–2006 and 49% in 2007–2011; p 0.03). The use of A+C increased over time: 1997–2001, 4/18 (22%); 2002–2006, 5/16 (31%); 2007–2011, 30/35 (86%) (p <0.001). Renal failure developed in 65% of the A+G group and in 34% of the A+C group (p 0.014). Thirteen patients (43%) in the A+G group had to discontinue treatment, whereas only one patient (3%) treated with A+C had to discontinue treatment (p <0.001). Only development of heart failure and previous chronic renal failure were independently associated with 1-year mortality, while the individual antibiotic regimen (A+C vs. A+G) did not affect outcome (OR, 0.7; 95% CI, 0.2–2.2; p 0.549). Our study shows that the prevalence of HLAR EFIE has increased significantly in recent years and that alternative treatment with A+C is safer than A+G, with similar clinical outcomes, although the sample size is too small to draw firm conclusions. Randomized controlled studies are needed to confirm these results

Ventilatory drive and the apnea-hypopnea index in six-to-twelve year old children

BACKGROUND: We tested the hypothesis that ventilatory drive in hypoxia and hypercapnia is inversely correlated with the number of hypopneas and obstructive apneas per hour of sleep (obstructive apnea hypopnea index, OAHI) in children. METHODS: Fifty children, 6 to 12 years of age were studied. Participants had an in-home unattended polysomnogram to compute the OAHI. We subsequently estimated ventilatory drive in normoxia, at two levels of isocapnic hypoxia, and at three levels of hyperoxic hypercapnia in each subject. Experiments were done during wakefulness, and the mouth occlusion pressure measured 0.1 seconds after inspiratory onset (P(0.1)) was measured in all conditions. The slope of the relation between P(0.1 )and the partial pressure of end-tidal O(2 )or CO(2 )(P(ET)O(2 )and P(ET)CO(2)) served as the index of hypoxic or hypercapnic ventilatory drive. RESULTS: Hypoxic ventilatory drive correlated inversely with OAHI (r = -0.31, P = 0.041), but the hypercapnic ventilatory drive did not (r = -0.19, P = 0.27). We also found that the resting P(ET)CO(2 )was significantly and positively correlated with the OAHI, suggesting that high OAHI values were associated with resting CO(2 )retention. CONCLUSIONS: In awake children the OAHI correlates inversely with the hypoxic ventilatory drive and positively with the resting P(ET)CO(2). Whether or not diminished hypoxic drive or resting CO(2 )retention while awake can explain the severity of sleep-disordered breathing in this population is uncertain, but a reduced hypoxic ventilatory drive and resting CO(2 )retention are associated with sleep-disordered breathing in 6–12 year old children

Exponential Decay of Correlations Implies Area Law

We prove that a finite correlation length, i.e. exponential decay of correlations, implies an area law for the entanglement entropy of quantum states defined on a line. The entropy bound is exponential in the correlation length of the state, thus reproducing as a particular case Hastings proof of an area law for groundstates of 1D gapped Hamiltonians. As a consequence, we show that 1D quantum states with exponential decay of correlations have an efficient classical approximate description as a matrix product state of polynomial bond dimension, thus giving an equivalence between injective matrix product states and states with a finite correlation length. The result can be seen as a rigorous justification, in one dimension, of the intuition that states with exponential decay of correlations, usually associated with non-critical phases of matter, are simple to describe. It also has implications for quantum computing: It shows that unless a pure state quantum computation involves states with long-range correlations, decaying at most algebraically with the distance, it can be efficiently simulated classically. The proof relies on several previous tools from quantum information theory - including entanglement distillation protocols achieving the hashing bound, properties of single-shot smooth entropies, and the quantum substate theorem - and also on some newly developed ones. In particular we derive a new bound on correlations established by local random measurements, and we give a generalization to the max-entropy of a result of Hastings concerning the saturation of mutual information in multiparticle systems. The proof can also be interpreted as providing a limitation on the phenomenon of data hiding in quantum states.Comment: 35 pages, 6 figures; v2 minor corrections; v3 published versio