An Expert Systems for Homeopatic Glaucoma Treatment (SEHO)

In this article, an Expert System for Homeopathic Glaucoma Treatment (SEHO) is presented, the task of which is to assist ophthalmologists in selecting the most appropriate therapy for a patient diagnosed as having glaucoma. It is based on techniques proper to homeopathic medicine, a trend that is gaining more and more supporters all over the world, but in which real experts are few and far between. After a brief overview of the state of the art, the authors describe in detail on the development of the system, for which the IDEAL methodology, designed for knowledge-based system development, was used

Curved dilatonic brane-worlds and the cosmological constant problem

We construct a model for dilatonic brane worlds with constant curvature on the brane, i.e. a non-zero four-dimensional cosmological constant, given in function of the dilaton coupling and the cosmological constant of the bulk. We compare this family of solutions to other known dilatonic domain wall solutions and apply a self-tunning mechanism to check the stability of our solutions under quantum fluctuations living on the brane.Comment: latex, 6 pages. (v2): considerable changes in the conclusion. (v3): added new discussion on the solutions and some references; version to appear in CQ

Obesity dependent metabolic signatures associated with nonalcoholic fatty liver disease progression

Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultra-performance liquid chromatography coupled to mass spectrometry (UPLCMS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual’s level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values = 0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention

Functional correlates of response inhibition in impulse control disorders in Parkinson’s disease

Available online 11 September 2021.Impulse control disorder is a prevalent side-effect of Parkinson’s disease (PD) medication, with a strong negative impact on the quality of life of those affected. Although impulsivity has classically been associated with response inhibition deficits, previous evidence from PD patients with impulse control disorder (ICD) has not revealed behavioral dysfunction in response inhibition. In this study, 18 PD patients with ICD, 17 PD patients without this complication, and 15 healthy controls performed a version of the conditional Stop Signal Task during functional magnetic resonance imaging. Whole-brain contrasts, regions of interest, and functional connectivity analyses were conducted. Our aim was to investigate the neural underpinnings of two aspects of response inhibition: proactive inhibition, inhibition that has been prepared beforehand, and restrained inhibition, inhibition of an invalid inhibitory tendency. We observed that, in respect to the other two groups, PD patients with ICD exhibited hyperactivation of the stopping network bilaterally while performing proactive inhibition. When engaged in restrained inhibition, they showed hyperactivation of the left inferior frontal gyrus, an area linked to action monitoring. Restrained inhibition also resulted in changes to the functional co-activation between inhibitory regions and left inferior parietal cortex and right supramarginal gyrus. Our findings indicate that PD patients with ICD completed the inhibition task correctly, showing altered engagement of inhibitory and attentional areas. During proactive inhibition they showed bilateral hyperactivation of two inhibitory regions, while during restrained inhibition they showed additional involvement of attentional areas responsible for alerting and orienting.This work was supported by grants from the Carlos III Institute of Health (PI11/02109) and the ERA-Neuron program (PIM2010ERN- 0033). Additionally, the authors received the following grants and honoraria: T.E.-P. received a grant from the Spanish Ministry of Economy and Competitiveness (BES-2016-079489). P.M.P.-A. was supported by grants from the Spanish Ministry of Economy and Competitiveness (RYC-2014-15440), the Spanish Ministry of Science and Innovation (PGC2018-093408-B-I00), and the Fundación Tatiana Pérez de Guzmán el Bueno. I.N.-G. was the recipient of a Rio Hortega grant (CM16/00033) from the Carlos III Institute of Health. I.N.-G. received honoraria from Zambon and TEVA for travel and accommodation to attend scientific meetings. M.C.R.-O. received financial support for her research from national and local government institutions in Spain (Carlos III Institute of Health, Basque Country Government, Diputacion Foral Guipuzcoa, and CIBERNED). M.C.R.-O. received honoraria from Zambon, Bial, and Boston Scientific for lectures, travel, and accommodation to attend scientific meetings. BCBL acknowledges support from the Basque Government through the BERC 2018-2021 program

Functional correlates of response inhibition in impulse control disorders in Parkinson’s disease

Available online 11 September 2021.Impulse control disorder is a prevalent side-effect of Parkinson’s disease (PD) medication, with a strong negative impact on the quality of life of those affected. Although impulsivity has classically been associated with response inhibition deficits, previous evidence from PD patients with impulse control disorder (ICD) has not revealed behavioral dysfunction in response inhibition. In this study, 18 PD patients with ICD, 17 PD patients without this complication, and 15 healthy controls performed a version of the conditional Stop Signal Task during functional magnetic resonance imaging. Whole-brain contrasts, regions of interest, and functional connectivity analyses were conducted. Our aim was to investigate the neural underpinnings of two aspects of response inhibition: proactive inhibition, inhibition that has been prepared beforehand, and restrained inhibition, inhibition of an invalid inhibitory tendency. We observed that, in respect to the other two groups, PD patients with ICD exhibited hyperactivation of the stopping network bilaterally while performing proactive inhibition. When engaged in restrained inhibition, they showed hyperactivation of the left inferior frontal gyrus, an area linked to action monitoring. Restrained inhibition also resulted in changes to the functional co-activation between inhibitory regions and left inferior parietal cortex and right supramarginal gyrus. Our findings indicate that PD patients with ICD completed the inhibition task correctly, showing altered engagement of inhibitory and attentional areas. During proactive inhibition they showed bilateral hyperactivation of two inhibitory regions, while during restrained inhibition they showed additional involvement of attentional areas responsible for alerting and orienting.This work was supported by grants from the Carlos III Institute of Health (PI11/02109) and the ERA-Neuron program (PIM2010ERN- 0033). Additionally, the authors received the following grants and honoraria: T.E.-P. received a grant from the Spanish Ministry of Economy and Competitiveness (BES-2016-079489). P.M.P.-A. was supported by grants from the Spanish Ministry of Economy and Competitiveness (RYC-2014-15440), the Spanish Ministry of Science and Innovation (PGC2018-093408-B-I00), and the Fundación Tatiana Pérez de Guzmán el Bueno. I.N.-G. was the recipient of a Rio Hortega grant (CM16/00033) from the Carlos III Institute of Health. I.N.-G. received honoraria from Zambon and TEVA for travel and accommodation to attend scientific meetings. M.C.R.-O. received financial support for her research from national and local government institutions in Spain (Carlos III Institute of Health, Basque Country Government, Diputacion Foral Guipuzcoa, and CIBERNED). M.C.R.-O. received honoraria from Zambon, Bial, and Boston Scientific for lectures, travel, and accommodation to attend scientific meetings. BCBL acknowledges support from the Basque Government through the BERC 2018-2021 program

RhI/RhIII catalyst-controlled divergent aryl/heteroaryl C-H bond functionalization of picolinamides with alkynes

The ability to establish switchable site-selectivity through catalyst control in the direct functionalization of molecules that contain distinct C-H bonds remains a demanding challenge that would enable the construction of diverse scaffolds from the same starting materials. Herein we describe the realization of this goal, namely a divergent heteroaryl/aryl C-H functionalization of aromatic picolinamide derivatives, targeting two distinct C-H sites, either at the pyridine ring or at the arene unit, to afford isoquinoline or ortho-olefinated benzylamine (or phenethylamine) derivatives. This complementary reactivity has been achieved on the basis of a RhIII/RhI switch in the catalyst, resulting in different mechanistic outcomes. Notably, a series of experimental and DFT mechanistic studies revealed important insights about the mechanism of the reaction and reasons behind the divergent regiochemical outcomeWe thank the Spanish Government (MINECO, CTQ2012-35790) for financial support. N. R. thanks the MICINN for a Ramón y Cajal contract and the European Commission for a Marie Curie Career Integration Grant (CIG: CHAAS-304085). We also thank the Centro de Computación Científica de la UAM for their generous allocation of computer tim

Palladium-Catalyzed Carbonylative Cyclization of Amines via γ-C(sp3)-H Activation: Late-Stage Diversification of Amino Acids and Peptides

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Catalysis, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acscatal.6b01987The selective γ-C(sp3)-H carbonylation of N-(2-pyridyl)sulfonyl (N-SO2Py)-protected amines has been accomplished by using palladium catalysis and Mo(CO)6 as carbonyl source. The reaction provides a powerful approach for derivatization of amine-based moieties, including amino acids, into richly functionalized γ-lactams. Not only methyl groups, but also methylene C-H bonds of cyclopropanes and conformationally biased molecules can be activated to provide ring-fused γ-lactam derivatives. This carbonylation protocol is also amenable to the late-stage diversification of more-complex multifunctional molecules such as dipeptides and tripeptides, demonstrating the key role of the N-SO2Py as directing group and its capacity to override other inherent substrate coordinating elements. In addition to providing an attractive solution to the difficulties in handling hazardous CO gas, the use of Mo(CO)6 as an air-stable solid source of CO in substoichiometric amount (0.33 equiv) ensures PdII-catalytic activity by preventing its decomposition or deactivation under excess of CO via reduction of PdII to Pd0 or saturation of the metal coordination sphere. Indeed, significantly lower efficiency is observed when the reactions are carried out under CO atmosphere (1 atm), or in the presence of increased amounts of Mo(CO)6. A series of experimental and DFT mechanistic studies provide important insights about the reaction mechanismWe thank the Spanish Ministerio de Economía y Competitividad (MINECO, Project No. CTQ2012-35790), and MINECO/FEDER, UE (Project No. CTQ2015-66954-P) for financial support. E.H. thanks the Gobierno Vasco for a predoctoral fellowship. N.R. thanks the MICINN for a Ramón y Cajal contract and the European Commission for a Marie Curie Foundation (CIG: CHAAS-304085

Antioxidant responses related to temozolomide resistance in glioblastoma

Ministerio de Ciencia, Innovación y Universidades; Universidad de Málaga CBUA.Glioblastoma remains one of the most challenging and devastating cancers, with only a very small proportion of patients achieving 5-year survival. The current standard of care consists of surgery, followed by radiation therapy with concurrent and maintenance chemotherapy with the alkylating agent temozolomide. To date, this drug is the only one that provides a significant survival benefit, albeit modest, as patients end up acquiring resistance to this drug. As a result, tumor progression and recurrence inevitably occur, leading to death. Several factors have been proposed to explain this resistance, including an upregulated antioxidant system to keep the elevated intracellular ROS levels, a hallmark of cancer cells, under control. In this review, we discuss the mechanisms of chemoresistance -including the important role of glioblastoma stem cells-with emphasis on antioxidant defenses and how agents that impair redox balance (i.e.: sulfasalazine, erastin, CB-839, withaferin, resveratrol, curcumin, chloroquine, and hydroxychloroquine) might be advantageous in combined therapies against this type of cancer.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech