Conformational landscape of small ligands: a multilevel strategy to determine the conformational penalty of bioactive ligands

Determining the conformational penalty required for adopting the bioactive conformation is still a challenging question in drug design, because a small uncertainty in this free energy component can lead to significant errors in the predicted activities. Herein, we use the Multilevel strategy, a methodology recently developed by our group, to explore the conformational preferences of ligands in solution, and to estimate the conformational cost of selecting the bioactive conformation

Lutein and the C/N as tracers of organic matter in the Palmones River estuary

Los pigmentos vegetales han sido usados como bioindicadores de la presencia de organismos fototrópicos en ríos, estuarios y sedimentos marinos actuales y en estudios paleolimnológicos. En el sedimento del estuario río Palmones (Bahía de Algeciras, Sur de España) se ha estudiado las concentraciones de clorofila a y luteína, el índice C/N y el contenido en materia orgánica. Utilizando la concentración de estos dos pigmentos en diferentes profundidades así como el índice de sedimentación(determinado por Rubio et al. En 2003 por el método del 210Pb), se ha determinado el índice de degradación de la luteína y clorofila a en la marisma. La permanencia de la luteína en el sedimento es mayor que la de la clorofila a. Según estos resultados se ha podido discriminar las fuentes de materia orgánicaPlant pigments have been used as biomarkers of the presence of phototrophic organisms in rivers, estuaries and sea sediments in present and in paleolimnological studies. Chlorophyll a and lutein concentration, C/N ratio and organic matter content have been studied in the sediment of the Palmones River estuary (Algeciras Bay, Southern Spain). Using the concentration of these two pigments at different depths, as well as the sedimentation rate (determined by Rubio et al. in 2003 by means of the 210Pb method), lutein and chlorophyll a degradation rate has been determined, in the saltmarsh. Lutein persistence in the sediment was higher than the persistence of chlorophyll a. According to these results, it was possible to discriminate the organic matter source

Relationship between physicochemical variables and productivity in open ponds for the production of Spirulina: a predictive model of algal yield,”

Abstract Spirulina is one of the most extensively used microalgae for animal and human nutrition; its main interest is centered in its high protein content, 60 -65% on a dry weight basis. In this study, Spirulina was grown in open raceway ponds, and several physicochemical (e.g., pH, dissolved oxygen concentration, temperature, conductivity and irradiance) and biological (e.g., biomass concentration and yield) variables were studied. The variables were correlated in order to implement a mathematical model to predict algal yield. Dissolved oxygen concentration in the cultivation ponds ranged between 10 mg l À 1 in winter (115% of O 2 saturation) and 30 mg l À 1 in summer (375% of O 2 saturation); a clear decrease of biomass concentration was found when dissolved oxygen was >25 mg l À 1 . Neither biomass concentration nor productivity was saturated at the maximum temperature achieved in the open pond during this study (approximately 28 jC). The pH seemed to control both the maximal algal density in the pond and the productivity that were found to be maximum at pH values below 10.5. Finally, all the variables were positively correlated with irradiance. Principal component analysis (PCA) allowed recognition of different sets of samples characterized by a combination of temperature, dissolved oxygen concentration, pH, biomass, productivity, irradiance and conductivity. This method helped to predict a significant loss of productivity in the open ponds in mid-summer due to high pH and high-dissolved O 2 concentration.

Unveiling a Novel Transient Druggable Pocket in BACE-1 through Molecular Simulations: Conformational Analysis and Binding Mode of Multisite Inhibitors

The critical role of BACE-1 in the formation of neurotoxic ß-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimer's disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challenging. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination of two fragments - huprine and rhein - that individually are endowed with very low activity against BACE-1. Examination of crystal structures reveals no appropriate binding site large enough to accommodate 1. Therefore we have examined the conformational flexibility of BACE-1 through extended molecular dynamics simulations, paying attention to the highly flexible region shaped by loops 8-14, 154-169 and 307-318. The analysis of the protein dynamics, together with studies of pocket druggability, has allowed us to detect the transient formation of a secondary binding site, which contains Arg307 as a key residue for the interaction with small molecules, at the edge of the catalytic cleft. The formation of this druggable 'floppy' pocket would enable the binding of multisite inhibitors targeting both catalytic and secondary sites. Molecular dynamics simulations of BACE-1 bound to huprine-rhein hybrid compounds support the feasibility of this hypothesis. The results provide a basis to explain the high inhibitory potency of the two enantiomeric forms of 1, together with the large dependence on the length of the oligomethylenic linker. Furthermore, the multisite hypothesis has allowed us to rationalize the inhibitory potency of a series of tacrine-chromene hybrid compounds, specifically regarding the apparent lack of sensitivity of the inhibition constant to the chemical modifications introduced in the chromene unit. Overall, these findings pave the way for the exploration of novel functionalities in the design of optimized BACE-1 multisite inhibitors

New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode

Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.02,10.03,7.09,11]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.02,5.03,11.04,9.06,17.012,16]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant

Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies

Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5bd have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5ad has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5ad, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities

Heritage, conflict and historical relevance. An experience in teacher education

Partiendo de los resultados de investigación de proyectos participativos y comunitarios en los espacios de la Batalla del Ebro, desarrollados por la Asociación Lo Riu y el grupo de investigación DIDPATRI, se han llevado a distintas acciones de divulgación y difusión del patrimonio de la Guerra Civil española, con especial énfasis en la formación inicial del profesorado. Entre 2012 y 2014 se ha desarrollado una experiencia formativa en el marco de la asignatura de Didáctica de la Historia (Grado de Educación Primaria, Universidad de Barcelona) para romper con ideas y estereotipos que tradicionalmente se asocian a éste tipo de espacios patrimoniales. En estas actuaciones, centradas en la Guerra Civil (con marcada naturaleza conflictiva), permiten que el profesorado en formación inicial se vaya adentrando en cuestiones sobre ciudadanía que reflejan la complejidad de la enseñanza de la historia, introduciendo aspectos más competenciales en la enseñanza y aprendizaje de la disciplina

Local Sensitivity Analysis of Kinetic Models for Cellulose Pyrolysis

Abstract: The first and nth order kinetic models are usually used to describe cellulose pyrolysis. In this work, the local sensitivities of the conversion and derivative conversion with respect to the frequency factor, the logarithm of the frequency factor, the activation energy and the reaction order for the first and nth order kinetic models are calculated by using the finite difference method. The results show that the sensitivities of the first and nth order kinetic models with respect to the activation energy and the logarithm of the frequency factor are significant, while the frequency factor and the reaction order affect the nth order kinetic model slightly. Compared with the frequency factor, the natural logarithm of the frequency factor is a better choice in the parameter estimation of the first and nth order kinetic models. Graphical Abstract: [Figure not available: see fulltext.

Long-term Responders after autologous stem cell transplantation in multiple myeloma

Introduction: Multiple myeloma (MM) is considered an incurable hematological neoplasm. For transplant-eligible patients, initial treatment includes an induction phase followed by an autologous stem cell transplantation (ASCT). Despite the introduction of several drugs in the past years, relapses still occur. Nevertheless, some patients achieve sustained responses after successful induction treatment and ASCT. Methods: We retrospectively evaluated all patients diagnosed with MM in our institution who underwent induction treatment and ASCT between 1990 and 2015. The subset of patients who achieved a sustained response (any degree) for 5 or more years after ASCT without further treatment or signs of progression were distinguished as 'long-term responders' (LTRs). In the non-LTR group, a cohort referred to as 'prolonged responders' (PLRs) showed sustained response of at least 5 years after ASCT but eventually relapsed. We collected and analyzed clinical and laboratory data. Results: Two hundred and fifty patients were diagnosed with MM and received induction treatment and ASCT at our institution in the study period. Among them, 54 (21.6%) patients met the criteria for LTR. Some diagnostic features such as a younger age, female gender, ECOG performance status of 0, lower International Staging System (ISS) stage, lower bone marrow plasma cell infiltration, and lower serum levels of calcium, C-reactive protein, and lactate dehydrogenase (LDH) were found to be more prevalent in LTR. Female gender, an ECOG performance status of 0, a localized Durie-Salmon stage, an ISS of I-II, the absence of bone disease, and an LDH within normal range were also predictive of longer progression-free survival (PFS) and overall survival (OS) in the whole cohort. The depth of the response achieved after induction and ASCT as well as the administration of an IMID-based maintenance regimen may play a role in the differences observed on PFS between cohorts. A detectable M-protein with a monoclonal gammopathy of undetermined significance (MGUS)-like behavior was detected in one-third of LTR after ASCT. Although relapses continue to occur in patients who achieve a 5-year treatment-free period after ASCT, a plateau is observed in the survival curves at approximately 21 years of follow-up

MicroRNA-654-5p suppresses ovarian cancer development impacting on MYC, WNT and AKT pathways

Ovarian cancer is the most lethal gynecological malignancy due to the silent nature on its early onset and the rapid acquisition of drug resistance. Histologically heterogeneous, it includes several subtypes with different mutational landscapes, hampering the development of effective targeted therapies. Non-coding RNAs are emerging as potential new therapeutic targets in cancer. To search for a microRNA signature related to ovarian carcinomas and study its potential as effective targeted therapy, we examined the expression of 768 miRNA in a large collection of tumor samples and found miR-654-5p to be infraexpressed in ovarian serous carcinomas, the most common and aggressive type. Restoration of miR-654-5p levels reduced tumor cell viability in vitro and in vivo and impaired sphere formation capacity and viability of ovarian cancer patient-derived ascitic cells ex vivo. CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AKT pathways. Together, we unveiled the tumor suppressor function of miR-654-5p, suggesting that its restoration or co-targeting of CDCP1 and PLAGL2 may be an effective therapeutic approach for ovarian cancer.This work was supported in part by grants from Instituto de la Mujer Dexeus (DEXEUS-B29/012), CIBER (CB16/12/00328), SGR (2017 SGR 1661), the Ministerio de Economia y Competitividad and Fondos FEDER (RTC-2015-3821-1), Instituto Carlos III (PI15/00238 to A.S. and PI17/00564 to M.F.S) and the Miguel Servet Program (CP13/00158 and CPII18/00027 to AS. and CPII16/00006 to MFS). AP and LS were supported by predoctoral VHIR fellowships and CJ by an AGAUR predoctoral fellowship (VHIR: PRED-VHIR-2014-11 and PRED-VHIR-2017; AGAUR: 2017FI_B_00095, respectively)