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This work extends an automatic energy-norm $hp$-adaptive strategy based on performing quasi-optimal unrefinements to the case of non-elliptic problems and goal-oriented adaptivity. The proposed approach employs a multi-level hierarchical data structure and alternates global $h$- and $p$-refinements with a coarsening step. Thus, at each unrefinement step, we eliminate the basis functions with the lowest contributions to the solution. When solving elliptic problems using energy-norm adaptivity, the removed basis functions are those with the lowest contributions to the energy of the solution. For non-elliptic problems or goal-oriented adaptivity, we propose an upper bound of the error representation expressed in terms of an inner product of the specific equation, leading to error indicators that deliver quasi-optimal $hp$-unrefinements. This unrefinement strategy removes unneeded unknowns possibly introduced during the pre-asymptotical regime. In addition, the grids over which we perform the unrefinements are arbitrary, and thus, we can limit their size and associated computational costs. We numerically analyze our algorithm for energy-norm and goal-oriented adaptivity. In particular, we solve two-dimensional ($2$D) Poisson, Helmholtz, convection-dominated equations, and a three-dimensional ($3$D) Helmholtz-like problem. In all cases, we observe \revb{exponential} convergence rates. Our algorithm is robust and straightforward to implement; therefore, it can be easily adapted for industrial applications., BERC.2022-2025

28th EADV Congress, Madrid, Spain, 9-13 October 2019. -- https://eadvmadrid2019.org/

27th EADV, París, 12-14 September 2018, Photodynamic therapy vs Intense pulsed light for onychomycosis treatment

Pigment epithelium-derived factor (PEDF), a neurotrophic protein, is a secreted serpin identified in extracellular matrixes. We show that PEDF extractions from the interphotoreceptor matrix are more efficient with increasing NaCl concentrations, indicating that ionic interactions mediate its association with this polyanionic matrix. We have used affinity chromatography and ultrafiltration to probe for direct binding of PEDF to glycosaminoglycans/polyanions. Correctly folded PEDF bound to immobilized heparin, chondroitin sulfate-A, -B, -C, and dextran sulfate columns and eluted from each with an increase in NaCl concentration. However, in the presence of urea, the protein lost its affinity for heparin. Binding of PEDF to heparan sulfate proteoglycan in solution was in a concentration-dependent fashion (half-maximal specific binding EC50 = 40 micrograms/mL) and was sensitive to increasing NaCl concentrations. The glycosaminoglycan-binding region was analyzed using chemical modification and limited proteolysis. PEDF chemically modified on lysine residues by biotinylation lost its capacity for interacting with heparin, implicating the involvement of PEDF lysine residues in heparin binding. Cleavage of the serpin-exposed loop with chymotrypsin did not affect the heparin-binding property. A limited proteolysis product containing residues 21-approximately 260 bound to heparin with similar affinity as the intact PEDF. Homology modeling of PEDF based on the X-ray crystal structures of antithrombin III and ovalbumin shows a region at the center of beta-sheet A-strands 2 and 3- and helix F that has a basic electrostatic surface potential and is densely populated with lysines exposed to the surface (K134, K137, K189, K191, H212, and K214) that are available to interact with various glycosaminoglycans/polyanions. This region represents a novel site for glycosaminoglycan binding in a serpin, which in PEDF, is distinct and nonoverlapping from the PEDF neurotrophic active region.

1–42 β-Amyloid (Aβ1–42) peptide is a key molecule involved in the development of Alzheimer's disease. Some of its effects are manifested at the neuronal morphological level. These morphological changes involve loss of neurites due to cytoskeleton alterations. However, the mechanism of Aβ1–42 peptide activation of the neurodegenerative program is still poorly understood. Here, Aβ1–42 peptide-induced transduction of cellular death signals through the phosphatidylinositol 3-kinase (PI3K)/phosphoinositol-dependent kinase (PDK)/novel protein kinase C (nPKC)/Rac 1 axis is described. Furthermore, pharmacological inhibition of PDK1 and nPKC activities blocks Rac 1 activation and neuronal cell death. Our results provide insights into an unsuspected connection between PDK1, nPKCs and Rac 1 in the same signal-transduction pathway and points out nPKCs and Rac 1 as potential therapeutic targets to block the toxic effects of Aβ1–42 peptide in neurons. Fil: Manterola, L.. Biodonostia Institute, Hospital Donostia; España Fil: Hernando Rodriguez, M.. National Cancer Research Center; España Fil: Ruiz, A.. Universidad del Pais Vasco; España. Achucarro Basque Center for Neuroscience; España Fil: Apraiz, A.. Universidad del Pais Vasco; España Fil: Arrizabalaga, O.. Universidad del Pais Vasco; España Fil: Vellon, L.. Fundación Instituto de Investigación Biomédica y Desarrollo Tecnológico (INBIOMED); España Fil: Alberdi, E.. Universidad del Pais Vasco; España Fil: Cavaliere, F.. Universidad del Pais Vasco; España Fil: Lacerda, H.M.. Università degli Studi di Torino; Italia Fil: Jimenez, S.. Universidad de Sevilla; España. Consejo Superior de Investigaciones Cientificas; España Fil: Parada, Luis Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Salta. Instituto de Patología Experimental; Argentina. Universidad Nacional de Salta; Argentina Fil: Matute, C.. Universidad del Pais Vasco; España Fil: Zugaza, Jose Luis. Universidad del Pais Vasco; España. Bizkaia Science and Technology Park; España

In many applications of computerised decision support, a recognised source of undesired outcomes is operators' apparent over-reliance on automation. For instance, an operator may fail to react to a potentially dangerous situation because a computer fails to generate an alarm. However, the very use of terms like "over-reliance" betrays possible misunderstandings of these phenomena and their causes, which may lead to ineffective corrective action (e.g. training or procedures that do not counteract all the causes of the apparently "over-reliant" behaviour). We review relevant literature in the area of "automation bias" and describe the diverse mechanisms that may be involved in human errors when using computer support. We discuss these mechanisms, with reference to errors of omission when using "alerting systems", with the help of examples of novel counterintuitive findings we obtained from a case study in a health care application, as well as other examples from the literature.

Dermatofibroma (DF) is a common benign cutaneous tumor with many variants based on alterations in the morphology and composition of its diverse elements. One very infrequent type is sclerotic fibromalike DF (SF-DF). We report 7 new cases of SF-DF. In addition, their main clinicopathological and immunohistochemical features were compared with 14 unselected common DFs and with 3 sclerotic fibromas (SFs). Microscopically, the 7 cases of SF-DFs showed an unencapsulated, well-circumscribed, hypocellular central nodule with thick collagen bundles arranged in a storiform pattern with prominent clefts. The overlying epidermis was attenuated. The periphery of this nodule was more cellular with histopathologic features of common DF. The 7 SF-DFs patients were 4 women and 3 men with a mean (±SD) age of 44.8 (±15.5) years. These 7 patients were younger than those suffering from SFs [71.0 (±17.3) years; (p=0.04)] and older than those presenting common DFs [30.5 (±12.3) years; (p=0.03)]. Immunohistochemically, spindle cells in all 7 SF-DFs were negative for CD34 and CD99. On the contrary, the 3 cases of SF were positive for CD34 and CD99. All of the common DFs were negative for CD34 and only 4 (28.6%) of them were positive for CD99. In conclusion, SF-DF is an uncommon variant of DF with similar clinicopathological and immunohistochemical features. SF-DF shares certain histopathologic features with SF but they are immunophenotypically different. Therefore, both entities should be differentiated.

This paper reports results from a cognitive engineering study that looked at the role of computerised monitoring in neonatal intensive care. A range of methodologies was used: interviews with neonatal staff, ward observations, and experimental techniques. The purpose was to investigate the sources of information used by clinicians when making decisions in the neonatal ICU. It was found that, although it was welcomed by staff, computerised monitoring played a secondary role in the clinicians' decision making (especially for junior and nursing staff) and that staff used the computer less often than indicated by self-reports. Factors that seemed to affect staff use of the computer were the lack (or shortage) of training on the system, the specific clinical conditions involved, and the availability of alternative sources of information. These findings have relevant repercussions for the design of computerised decision support in intensive care and suggest ways in which computerised monitoring can be enhanced, namely: by systematic staff training, by making available online certain types of clinical information, by adapting the user interface, and by developing intelligent algorithms.

CADMIUM II is a system for the interpretation of mammograms. A novel aspect of the system is that it combines symbolic reasoning with image processing, in contrast with most other approaches, which use only image processing and rely on artificial neural networks (ANNs) to classify mammograms. A problem of ANNs is that the advice they give cannot be traced back to communicable diagnostic inferences. Our approach is to provide advice based on explicit knowledge about the diagnostic process. To this end, we have conducted a knowledge elicitation study which looked at the descriptors used by expert radiologists when making diagnostic decisions about mammograms. The analysis of the radiologists' reports yielded a set of salient diagnostic features. These were used to inform the advice provided by the symbolic decision making component of CADMIUM II.

The synthesis and preliminary evaluation of new quinoline and quinoxaline derivatives (obtained by applying the original Reissert method, conveniently modified) as HIV-1 Reverse Transcriptase (RT) inhibitors are presented in this paper; likewise, the first structure-activity relationships are also proposed. Propyl 2-cyano-1(2H)-quinolin-carboxylate 2e, isopropyl 2-cyano-1 (2H)-quinolincarboxylate 2f, butyl 2-cyano-1 (2H)-quinolincarboxylate 2g and isobutyl 2-cyano-1 (2H)-quinolincarboxylate 2h have been selected as lead compounds. These compounds are active against the HIV-1 RT mutant type P236L (2f, IC50 = 1.2 microM) and present activity as anti-infective agents in HLT41acZ-1IIIB cells, showing no cytotoxicity at the active concentrations.