MolE: a molecular foundation model for drug discovery

Models that accurately predict properties based on chemical structure are valuable tools in drug discovery. However, for many properties, public and private training sets are typically small, and it is difficult for the models to generalize well outside of the training data. Recently, large language models have addressed this problem by using self-supervised pretraining on large unlabeled datasets, followed by fine-tuning on smaller, labeled datasets. In this paper, we report MolE, a molecular foundation model that adapts the DeBERTa architecture to be used on molecular graphs together with a two-step pretraining strategy. The first step of pretraining is a self-supervised approach focused on learning chemical structures, and the second step is a massive multi-task approach to learn biological information. We show that fine-tuning pretrained MolE achieves state-of-the-art results on 9 of the 22 ADMET tasks included in the Therapeutic Data Commons.Comment: Accepted at Learning Meaningful Representations of Life workshop, NeurIPS 202

Avian influenza: genetic evolution under vaccination pressure

Antigenic drift of avian influenza viruses (AIVs) has been observed in chickens after extended vaccination program, similar to those observed with human influenza viruses. To evaluate the evolutionary properties of endemic AIV under high vaccination pressure (around 2 billion doses used in the last 12 years), we performed a pilot phylogenic analysis of the hemagglutinin (HA) gene of AIVs isolated from 1994 to 2006. This study demonstrates that Mexican low pathogenicity (LP) H5N2-AIVs are constantly undergoing genetic drifts. Recent AIV isolates (2002–2006) show significant molecular drifts when compared with the H5N2 vaccine-strain or other field isolates (1994–2000). This study also demonstrates that molecular drifts in the HA gene lineages follow a yearly trend, suggesting gradually cumulative sequence mutations. These findings might explain the increasing incidence of LP H5N2 AIV isolated from commercial avian farms. These findings support recent concerns about the challenge of AIV antigenic drift and influenza epidemics

Diseño y Emprendimiento: su enseñanza y complejidad en una universidad pública

La presente investigación aborda cómo ha sido el proceso de enseñanza del emprendimiento en las licenciaturas de diseño en la UACJ. Los resultados sugieren que el cambio de paradigma hacia una formación emprendedora ha iniciado, no sin diversos obstáculos: inexactitud de una estrategia institucional que soporte aún más dicho cambio en donde se proporcionen mejores herramientas y competencias en emprendimiento para generar en los estudiantes áreas de oportunidad; sin demeritar los esfuerzos que para dicho cambio ya se realizan, como el decidido apoyo hacia eventos emprendedores, a la Academia Transversal del Emprendimiento y el carácter obligatorio de la materia Formación Empresarial

Modelling ligand selectivity of serine proteases using integrative proteochemometric approaches improves model performance and allows the multi-target dependent interpretation of features.

Serine proteases, implicated in important physiological functions, have a high intra-family similarity, which leads to unwanted off-target effects of inhibitors with insufficient selectivity. However, the availability of sequence and structure data has now made it possible to develop approaches to design pharmacological agents that can discriminate successfully between their related binding sites. In this study, we have quantified the relationship between 12,625 distinct protease inhibitors and their bioactivity against 67 targets of the serine protease family (20,213 data points) in an integrative manner, using proteochemometric modelling (PCM). The benchmarking of 21 different target descriptors motivated the usage of specific binding pocket amino acid descriptors, which helped in the identification of active site residues and selective compound chemotypes affecting compound affinity and selectivity. PCM models performed better than alternative approaches (models trained using exclusively compound descriptors on all available data, QSAR) employed for comparison with R(2)/RMSE values of 0.64 ± 0.23/0.66 ± 0.20 vs. 0.35 ± 0.27/1.05 ± 0.27 log units, respectively. Moreover, the interpretation of the PCM model singled out various chemical substructures responsible for bioactivity and selectivity towards particular proteases (thrombin, trypsin and coagulation factor 10) in agreement with the literature. For instance, absence of a tertiary sulphonamide was identified to be responsible for decreased selective activity (by on average 0.27 ± 0.65 pChEMBL units) on FA10. Among the binding pocket residues, the amino acids (arginine, leucine and tyrosine) at positions 35, 39, 60, 93, 140 and 207 were observed as key contributing residues for selective affinity on these three targets.Q.A. thanks the Islamic Development Bank and Cambridge Commonwealth Trust for Funding. O.M.L. is grateful to CONACyT (No. 217442/312933) and the Cambridge Overseas Trust for funding. G.v.W. thanks EMBL 90 (EIPOD) and Marie Curie (COFUND) for funding. A.B. thanks Unilever and the ERC (Starting Grant RC-2013-StG 336159 MIXTURE) for funding. ICC thanks the Institut Pasteur and the Pasteur-Paris International PhD programme for funding. TM thanks the Institut Pasteur for funding.This is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C4IB00175

Ser historiador del arte

Este artículo está firmado por cuatro historiadores del arte que proporcionan un punto de vista conjunto formado por las experiencias y reflexiones que han vivido, tanto en común como por separado, con el fin de ofrecer al lector una visión general sobre la profesión del historiador del arte.This article is signed by four art historians who provide a joint point of view formed by the experiences and reflections they have lived, both together and separately, in order to offer the reader an overview of the profession of art historian

Data-driven approaches used for compound library design, hit triage and bioactivity modeling in high-throughput screening

High-throughput screening (HTS) campaigns are routinely performed in pharmaceutical companies to explore activity profiles of chemical libraries for the identification of promising candidates for further investigation. With the aim of improving hit rates in these campaigns, data-driven approaches have been used to design relevant compound screening collections, enable effective hit triage and perform activity modeling for compound prioritization. Remarkable progress has been made in the activity modeling area since the recent introduction of large-scale bioactivity-based compound similarity metrics. This is evidenced by increased hit rates in iterative screening strategies and novel insights into compound mode of action obtained through activity modeling. Here, we provide an overview of the developments in data-driven approaches, elaborate on novel activity modeling techniques and screening paradigms explored and outline their significance in HTS.Medicinal Chemistr

IMPLEMENTACIÓN DE UN SISTEMA POKA-YOKE PARA ENSAMBLE DE SELLO EN BOMBA PARA DIRECCIÓN HIDRÁULICA (IMPLEMENTATION OF A POKA-YOKE SYSTEM FOR PUMP SEAL ASSEMBLY FOR HYDRAULIC STEERING)

Resumen Con este diseño se espera contribuir a la disminución de las garantías en la línea de producción Domestic Power Steering (DPS), con el objetivo de reducir los efectos de la variación de presión en el ensamble del sello de la bomba del sistema de la dirección hidráulica para diferentes modelos en una empresa automotriz de la región. En la primera fase se realizó un análisis para encontrar la causa de la falla y determinar las razones de las variaciones de presión en el proceso y su impacto en el sistema de producción. En la segunda fase se diseñó, fabricó e implementó el sistema Poka-Yoke con el cual se espera contribuir a la disminución de estas garantías en un 30%. Con este, se eliminará la variación de la presión del equipo al momento del ensamble, se aumentará la seguridad para el operador, obteniendo resultados satisfactorios en el producto final. Palabras Clave: Ensamble, Implementación, Poka-Yoke, Sello, Variación de presión. Abstract This design is expected to contribute to the reduction of warranties in the Domestic Power Steering (DPS) production line, with the aim of reducing the effects of pressure variation in the hydraulic steering system pump seal assembly. for different models in an automotive company in the region. In the first phase, an analysis was carried out to find the cause of the failure and determine the reasons for the pressure variations in the process and their impact on the production system. In the second phase, the Poka-Yoke system was designed, manufactured and implemented, with which it is expected to contribute to the reduction of these guarantees by 30%. With this, the variation in the pressure of the equipment at the time of assembly will be eliminated, the safety for the operator will be increased, obtaining satisfactory results in the final product. Keywords: Assembly, Implementation, Poka-Yoke, Seal, Pressure Variation

On the Efficiency of the Tidal Stirring Mechanism for the Origin of Dwarf Spheroidals: Dependence on the Orbital and Structural Parameters of the Progenitor Disky Dwarfs

(Abridged) The tidal stirring model posits the formation of dSph galaxies via the tidal interactions between rotationally-supported dwarfs and MW-sized host galaxies. Using a set of collisionless N-body simulations, we investigate the efficiency of the tidal stirring mechanism. We explore a wide variety of dwarf orbital configurations and initial structures and demonstrate that in most cases the disky dwarfs experience significant mass loss and their stellar components undergo a dramatic morphological and dynamical transformation: from disks to bars and finally to pressure-supported spheroidal systems with kinematic and structural properties akin to those of the classic dSphs in the Local Group (LG). Our results suggest that such tidal transformations should be common occurrences within the currently favored cosmological paradigm and highlight the key factor responsible for an effective metamorphosis to be the strength of the tidal shocks at the pericenters of the orbit. We demonstrate that the combination of short orbital times and small pericenters, characteristic of dwarfs being accreted at high redshift, induces the strongest transformations. Our models also indicate that the transformation efficiency is affected significantly by the structure of the progenitor disky dwarfs. Lastly, we find that the dwarf remnants satisfy the relation Vmax = \sqrt{3} * sigma, where sigma is the 1D, central stellar velocity dispersion and Vmax is the maximum halo circular velocity, with intriguing implications for the missing satellites problem. Overall, we conclude that the action of tidal forces from the hosts constitutes a crucial evolutionary mechanism for shaping the nature of dwarf galaxies in environments such as that of the LG. Environmental processes of this type should thus be included as ingredients in models of dwarf galaxy formation and evolution.Comment: submitted to ApJ, 34 pages, 15 figures, LaTeX (uses emulateapj.cls

Analyzing multitarget activity landscapes using protein-ligand interaction fingerprints: interaction cliffs.

This is the original submitted version, before peer review. The final peer-reviewed version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/ci500721x.Activity landscape modeling is mostly a descriptive technique that allows rationalizing continuous and discontinuous SARs. Nevertheless, the interpretation of some landscape features, especially of activity cliffs, is not straightforward. As the nature of activity cliffs depends on the ligand and the target, information regarding both should be included in the analysis. A specific way to include this information is using protein-ligand interaction fingerprints (IFPs). In this paper we report the activity landscape modeling of 507 ligand-kinase complexes (from the KLIFS database) including IFP, which facilitates the analysis and interpretation of activity cliffs. Here we introduce the structure-activity-interaction similarity (SAIS) maps that incorporate information on ligand-target contact similarity. We also introduce the concept of interaction cliffs defined as ligand-target complexes with high structural and interaction similarity but have a large potency difference of the ligands. Moreover, the information retrieved regarding the specific interaction allowed the identification of activity cliff hot spots, which help to rationalize activity cliffs from the target point of view. In general, the information provided by IFPs provides a structure-based understanding of some activity landscape features. This paper shows examples of analyses that can be carried out when IFPs are added to the activity landscape model.M-L is very grateful to CONACyT (No. 217442/312933) and the Cambridge Overseas Trust for funding. AB thanks Unilever for funding and the European Research Council for a Starting Grant (ERC-2013- StG-336159 MIXTURE). J.L.M-F. is grateful to the School of Chemistry, Department of Pharmacy of the National Autonomous University of Mexico (UNAM) for support. This work was supported by a scholarship from the Secretariat of Public Education and the Mexican government