Mapping chemical structure-activity information of HAART-drug cocktails over complex networks of AIDS epidemiology and socioeconomic data of U.S. counties

[Abstract] Using computational algorithms to design tailored drug cocktails for highly active antiretroviral therapy (HAART) on specific populations is a goal of major importance for both pharmaceutical industry and public health policy institutions. New combinations of compounds need to be predicted in order to design HAART cocktails. On the one hand, there are the biomolecular factors related to the drugs in the cocktail (experimental measure, chemical structure, drug target, assay organisms, etc.); on the other hand, there are the socioeconomic factors of the specific population (income inequalities, employment levels, fiscal pressure, education, migration, population structure, etc.) to study the relationship between the socioeconomic status and the disease. In this context, machine learning algorithms, able to seek models for problems with multi-source data, have to be used. In this work, the first artificial neural network (ANN) model is proposed for the prediction of HAART cocktails, to halt AIDS on epidemic networks of U.S. counties using information indices that codify both biomolecular and several socioeconomic factors. The data was obtained from at least three major sources. The first dataset included assays of anti-HIV chemical compounds released to ChEMBL. The second dataset is the AIDSVu database of Emory University. AIDSVu compiled AIDS prevalence for >2300 U.S. counties. The third data set included socioeconomic data from the U.S. Census Bureau. Three scales or levels were employed to group the counties according to the location or population structure codes: state, rural urban continuum code (RUCC) and urban influence code (UIC). An analysis of >130,000 pairs (network links) was performed, corresponding to AIDS prevalence in 2310 counties in U.S. vs. drug cocktails made up of combinations of ChEMBL results for 21,582 unique drugs, 9 viral or human protein targets, 4856 protocols, and 10 possible experimental measures. The best model found with the original data was a linear neural network (LNN) with AUROC > 0.80 and accuracy, specificity, and sensitivity ≈ 77% in training and external validation series. The change of the spatial and population structure scale (State, UIC, or RUCC codes) does not affect the quality of the model. Unbalance was detected in all the models found comparing positive/negative cases and linear/non-linear model accuracy ratios. Using synthetic minority over-sampling technique (SMOTE), data pre-processing and machine-learning algorithms implemented into the WEKA software, more balanced models were found. In particular, a multilayer perceptron (MLP) with AUROC = 97.4% and precision, recall, and F-measure >90% was found

Prediction of multi-target networks of neuroprotective compounds with entropy indices and synthesis, assay, and theoretical study of new asymmetric 1,2-rasagiline carbamates

In a multi-target complex network, the links (Lij) represent the interactions between the drug (di) and the target (tj), characterized by different experimental measures (Ki, Km, IC50, etc.) obtained in pharmacological assays under diverse boundary conditions (cj). In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%–90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular OPEN ACCESS Int. J. Mol. Sci. 2014, 15 17036 targets on 11 different organisms (including human). Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1) assay in absence of neurotoxic agents; (2) in the presence of glutamate; and (3) in the presence of H2O2. Lastly, we used the new Assessing Links with Moving Averages (ALMA)-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentallyThe authors thank the Xunta de Galicia for financial support of this work under project 07CSA008203PRS

M.A.B. Revestimientos vítreos con propiedades bactericidas y fungicidas

This report describes the mosaic M.A.B. (bactericide and fungicide) produced by Togama S.A. belonging to the group Fluidra S.A., which has been awarded with the Silver Alfa Award by the Spanish Society of Ceramics and Glass at the International Fair Cevisama 2012. This award recognizes the R & D efforts developed by Togama, SA, already started with participation in the Alpha Awards 2009 and 201

STIM1 deficiency is linked to Alzheimer’s disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca2+ entry

La STIM1 es una proteína del retículo endoplásmico con un papel en la movilización y señalización del Ca2+. Como sensor de los niveles intraluminales de Ca2+, STIM1 modula los canales de Ca2+ de la membrana plasmática para regular la entrada de Ca2+. En las células de neuroblastoma SH-SY5Y y en los fibroblastos cutáneos familiares de pacientes con la enfermedad de Alzheimer, STIM1 se divide en el dominio transmembrana por la presenilina-1-asociada a γ-secretase, lo que lleva a una desregulación de la homeostasis del Ca2+. En este informe, investigamos los niveles de expresión de STIM1 en los tejidos cerebrales (giro frontal medio) de pacientes con enfermedad de Alzheimer confirmada patológicamente, y observamos que el nivel de expresión de la proteína STIM1 disminuyó con la progresión de la neurodegeneración. Para estudiar el papel de STIM1 en la neurodegeneración, se diseñó una estrategia para eliminar la expresión del gen STIM1 en la línea de células de neuroblastoma SH-SY5Y mediante la edición del genoma mediado por CRISPR/Cas9, como un modelo in vitro para examinar el fenotipo de las células neuronales deficientes de STIM1. Se demostró que, si bien la STIM1 no es necesaria para la diferenciación de las células SH-SY5Y, es absolutamente esencial para la supervivencia de las células en la diferenciación. Las células STIM1-KO diferenciadas mostraron una disminución significativa de la actividad del complejo I de la cadena respiratoria mitocondrial, la despolarización de la membrana interna de la mitocondria, la reducción de la concentración de Ca2+ libre en la mitocondria y mayores niveles de senescencia en comparación con las células de tipo salvaje. En paralelo, las células STIM1-KO mostraron una entrada de Ca2+ potenciada en respuesta a la despolarización, que era sensible a la nifedipina, apuntando a los canales de Ca2+ operados por voltaje de tipo L como mediadores de la entrada de Ca2+ aumentada. El derribo estable de las transcripciones de CACNA1C restauró la función mitocondrial, aumentó los niveles mitocondriales de Ca2+ y redujo la senescencia a los niveles basales, demostrando el papel esencial de la regulación de la entrada de Ca2+ operada por voltaje a través de los canales Cav1.2 en la muerte celular deficiente de STIM1 SHSY5Y.STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer’s disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca2+ homeostasis. In this report, we investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer’s disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression of STIM1 gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca2+ concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca2+ entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca2+ channels as mediators of the upregulated Ca2+ entry. The stable knocking-down of CACNA1C transcripts restored mitocondrial function, increased mitochondrial Ca2+ levels, and dropped senescence to basal levels, emonstrating the essential role of the upregulation of voltage-operated Ca2+ entry through Cav1.2 channels in STIM1-deficient SHSY5Y cell death.• Ministerio de Educación, Cultura y Deporte. Beca FPU13/03430 • The Company of Biologists. Ayuda JCSTF-170507 • Ministerio de Economía, y Competitividad. Proyectos BFU2014-52401-P y BFU2017-82716, para Francisco Javier Martín Romero • Ministerio de Economía, y Competitividad. Proyectos BFU2014-53641-P y BFU2017-85723-P, para Ana María Mata Durán y Carlos Gutiérrez Merino • Junta de Extremadura. Ayudas GRU15077 e IB16088, para Francisco Javier Martín Romero • Junta de Extremadura. Ayuda GRU15139, para Ana María Mata DuránpeerReviewe

Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: A longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects

[Background and Aim] Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD).[Methods] Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years).[Results] Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non-NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these.[Conclusions] The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death.This project has been partially funded by the ‘Consejería de Salud de la Junta de Andalucía’ (PI-0075-2014) and the ‘Spanish Ministry of Economy, Innovation and Competition, Instituto de Salud Carlos III’ (PI19/01404, PI16/01842, PI17/00535 and GLD19/00100).Peer reviewe

Expansion of Signal Transduction Pathways in Fungi by Extensive Genome Duplication

Plants and fungi use light and other signals to regulate development, growth, and metabolism. The fruiting bodies of the fungus Phycomyces blakesleeanus are single cells that react to environmental cues, including light, but the mechanisms are largely unknown [1]. The related fungus Mucor circinelloides is an opportunistic human pathogen that changes its mode of growth upon receipt of signals from the environment to facilitate pathogenesis [2]. Understanding how these organisms respond to environmental cues should provide insights into the mechanisms of sensory perception and signal transduction by a single eukaryotic cell, and their role in pathogenesis. We sequenced the genomes of P. blakesleeanus and M. circinelloides and show that they have been shaped by an extensive genome duplication or, most likely, a whole-genome duplication (WGD), which is rarely observed in fungi [3–6]. We show that the genome duplication has expanded gene families, including those involved in signal transduction, and that duplicated genes have specialized, as evidenced by differences in their regulation by light. The transcriptional response to light varies with the developmental stage and is still observed in a photoreceptor mutant of P. blakesleeanus. A phototropic mutant of P. blakesleeanus with a heterozygous mutation in the photoreceptor gene madA demonstrates that photosensor dosage is important for the magnitude of signal transduction. We conclude that the genome duplication provided the means to improve signal transduction for enhanced perception of environmental signals. Our results will help to understand the role of genome dynamics in the evolution of sensory perception in eukaryotes.Office of Science (USA) DE-AC02-05CH11231Ministerio de Economía y Competitividad BIO2005-25029-E , BIO2015-67148-RJunta de Andalucía P06-CVI-0165

Propiedades de la cal en pasta obtenida a partir del tratamiento de fosfoyesos de la industria de fertilizantes

El proceso industrial de fabricación de ácido fosfórico tiene como materia prima principal la roca fosf orita, compue sta mayoritariamente por apatito (Ca 5 (PO 4 ) 3 OH); produciéndose el ácido fosfórico por un lado y por otro un subproducto formado principalmente por sulfato hidratado de calcio, denominado fosfoyeso. La producción de ácido fosfórico en Huelva (SO España) ha sido objeto de controversia por la formación de balsas de este subproducto, sin suficiente control, en las marismas de la desembocadura del río Tinto. Un grupo de investigadores liderados desde el Dpto. de Física de la Materia Condensada de la Universidad de Sevilla ha desarrollado un procedimiento sencillo y muy eficiente de obtención de portlandita, en forma de pasta de cal, como producto de la reacción química de u na disolución de fosfoyesos con una solución de sosa alcalina: CaSO 4 ·2H 2 O + 2NaOH Ca(OH) 2 + Na 2 SO 4 + 2H 2 O Como es previsible, la portlandita obtenida es susceptible de carbonatación, actuando como sumidero para el secuestro mineral de CO 2 . Esta metodolog ía tiene el potencial de reducir simultáneamente dos problemas ambientales: la gestión de los residuos industriales peligrosos; y las emisiones de gases de efecto invernadero. Este trabajo presenta la caracterización química, mineralógica, morfología y granulométrica del producto obtenido de cara su potencial utilización en aplicaciones relacionadas con el sector de la construcción, considerando inicialmente sus posibilidades como conglomerante y consolidant

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis.

Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS-/-) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS-/- mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS-/- livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease

A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy

Background: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. Methods: alb-myctg mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Results: Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myctg mice. Middle-aged alb-myctg exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myctg mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. Conclusions: A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategies

A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy

Background: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. Methods: alb-myctg mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Results: Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myctg mice. Middle-aged alb-myctg exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myctg mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. Conclusions: A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategies