Neural approach to estimate the stress intensity factor of semi‐elliptical cracks in rotating cracked shafts in bending

In the last decades, neural network approach has often been used to study various and complex engineering problems, such as optimization or prediction. In this paper, a methodology founded on artificial neural networks (ANNs) was used to calculate the stress intensity factor (SIF) in different points of the front of a semi‐elliptical crack present in a rotating shaft, taking into account the shape and depth of the crack, the angle of rotation, and the location of the point in the front. In the event of rotating machines, such as shafts, it is crucial to know the SIF along the crack front because this parameter, according to the Paris Law, is related to the performance of the crack during its propagation. Previously, it was necessary to achieve the data for the ANN training, for this a quasi‐static numerical model was made, which simulates a rotating cracked shaft with a semi‐elliptical crack. The numerical solutions cover a wide range of crack depths and shapes, and rotation angles. The values of the SIF estimated by the ANNs were contrasted with other solutions available in the literature finding a good agreement between them. The proposed neural network methodology is an alternative that offers a very good option for the SIF estimation, because it is efficient and easy to use, does not require high computational costs, and can be used to analyse the propagation of cracks contained in rotating shafts by means of the Paris Law taking into account the nonlinear behaviour of the shaft.The authors would like to thank the Spanish Ministerio de Economía y Competitividad for the support for this work through the projects DPI2009-13264 and DPI2013-45406-

A closed expression for the stress intensity factor of concave fatigue cracks in rotating shafts

A new analytical model is developed that allows us to obtain the Stress Intensity Factor (SIF) in a point on a concave shaped crack contained in a rotating shaft as a function of the characteristics of the crack (depth and aspect), the point position on the crack front, and the rotation angle. The model can be used for all kinds of linear elastic materials. The Finite Element Method (FEM) has been used to make a tridimensional quasi-static model of a shaft that contains a concave shaped crack in its central section, subjected to rotary bending. Different rotation angles are taken into account in order to simulate the rotation of the shaft. The SIF is determined in every position of the front of the concave crack, for each crack geometry and for each rotation angle. Then an analytical model is developed using all the results of SIF obtained with the numerical model, and is verified comparing its results with solutions found in the literature. The proposed model may be very useful to study the dynamic behavior of shafts with concave shaped cracks, and can be employed to analyze the propagation of these types of cracks.The authors would like to thank the Spanish Ministerio de Economía y Competitividad for the support for this work through the projects DPI2009-13264 and DPI2013-45406-

Elliptical Crack Identification in a Nonrotating Shaft

It is known that fatigue cracks are one of the most important problems of the mechanical components, since their propagation can cause severe loss, both personal and economic. So, it is essential to know deeply the behavior of the cracked element to have tools that allow predicting the breakage before it happens. The shafts are elements that are specially affected by the described problem, because they are subjected to alternative compression and tension stresses., is work presents, firstly, an analytical expression that allows determining the first four natural frequencies of bending vibration of a nonrotating cracked shaft, assumed as an Euler-Bernoulli beam, with circular cross section under pinned-pinned conditions, taking into account the elliptical shape of the crack. Second, once the direct problem is known, the inverse problem is approached. Genetic Algorithm technique has been used to estimate the crack parameters assuming known the natural frequencies of the cracked shaft.The authors would like to thank the Spanish Ministerio de Economía y Competitividad for the support for this work through the project DPI2013-45406-P

Utilización de la red social Instagram para fomentar la práctica continuada del alumnado en la nomenclatura y formulación de compuestos orgánicos

Introducción El aprendizaje de la formulación y nomenclatura de compuestos orgánicos constituye una de las competencias más importantes en la asignatura de Química Orgánica I. Para ello, la resolución de ejercicios constituye una herramienta fundamental que actualmente se integra en el aula. Sin embargo, el grado de implicación del alumnado en la realización de estos ejercicios es, en muchas ocasiones, escaso, lo que lleva a que exista un alto porcentaje de alumnos y alumnas que tienen dificultades para aprobar satisfactoriamente esta parte de la materia. Objetivo La implementación de un Proyecto de Innovación Docente (PID) que propone la creación de un recurso didáctico para mejorar la adquisición de las competencias relativas a formulación orgánica y fomentar la implicación del alumnado de forma interactiva mediante el empleo de la red social Instagram. Metodología A partir de un banco de preguntas previamente elaborado por los integrantes del equipo docente, se prepararon una serie de cuestionarios que fueron compartidos a modo de stories en el perfil de una cuenta de Instagram creada a tal fin. Estos cuestionarios proporcionaron al alumnado una retroalimentación instantánea al completar el ejercicio, mostrando la respuesta correcta así como una explicación acorde con las reglas de la IUPAC. Resultados El impacto de la intervención fue evaluado tanto cualitativamente, mediante encuestas de percepción, como cuantitativamente, mediante el análisis de los datos derivados de la plataforma Instagram, así como de las calificaciones obtenidas en los exámenes de formulación parcial, final y extraordinario, mostrando una alta aceptación por parte del alumnado y una mejora de los resultados académicos. Conclusiones Instagram es una herramienta útil para la práctica de la formulación en la asignatura de Química Orgánica I que mejora la eficacia del proceso de transferencia de información entre profesor y alumno/a. La implantación de este recurso proporciona una herramienta atractiva e innovadora que, al mismo tiempo, refuerza los conocimientos adquiridos en clase en un contexto más cercano y mejora los resultados académicos

Recent advances in the design of Choline kinase α inhibitors and the molecular basis of their inhibition

Up-regulated choline metabolism, characterized by an increase in phosphocholine (PCho), is a hallmark of oncogenesis and tumor progression. Choline kinase (ChoK), the enzyme responsible for PCho synthesis, has consequently become of a promising drug target for cancer therapy and as such a significant number of ChoK inhibitors have been developed over the last few decades. More recently, due to the role of this enzyme in other pathologies, ChoK inhibitors have also been used in new therapeutic approaches against malaria and rheumatoid arthritis. Here, we review research results in the field of ChoKα inhibitors from their synthesis to the molecular basis of their binding mode. Strategies for the development of inhibitors and their selectivity on ChoKα over ChoKβ, the plasticity of the choline-binding site, the discovery of new exploitable binding sites, and the allosteric properties of this enzyme are highlighted. The outcomes summarized in this review will be a useful guide to develop new multi-functional potent drugs for the treatment of various human diseases

Efficient Palladium-Triggered Release of Vorinostat from a Bioorthogonal Precursor

Bioorthogonal uncaging strategies have recently emerged as an experimental therapeutic approach to control drug release. Herein we report a novel masking strategy that enables to modulate the metal chelating properties of hydroxamic acid groups by bioorthogonal chemistry using Pd-functionalized resins. This novel approach allowed to devise an inactive precursor of the histone deacetylase inhibitor vorinostat that was efficiently uncaged by heterogeneous Pd catalysis in cell culture models of glioma and lung cancer

Design and manufacture of functional catalyst-carrier structures for the bioorthogonal activation of anticancer agents

Novel palladium (Pd)-loaded titanium (Ti) devices with high biocompatibility and catalytic activity were prepared using a range of fabrication methods such as powder metallurgy (i.e. sintering with and without space-holder), sputtering, pulsed laser deposition and supersonic cluster beam deposition. The surface of the Ti-[Pd] devices were physico-chemically characterised to confirm the non-alloyed state of the Pd coating onto the titanium substrate. The Pd thickness was optimised to achieve maximum surface area (i.e. maximum catalytic effect) using the minimum amount of material in each method for cost effective production. The catalytic response of the different Ti-[Pd] devices was evaluated under biocompatible conditions by employing an off-on Pd-activatable fluorescent probe. The most robust coating of Pd was produced by an optimised magnetron sputtering method. The sputtered Ti-[Pd] devices were selected to induce the bioorthogonal uncaging of the anticancer drug Vorinostat from a pharmacologically-inactive Pd-activatable precursor in cancer cell culture, demonstrating the capacity of these devices to mediate a local anti-tumour effect via in-situ release of a clinically approved drug. This approach is the first step towards surgically implantable devices that could facilitate targeting affected areas with high spatial selectivity, improving pharmacological activity and reducing systemic side effects through localised treatment directly at the cancer site

Estudio comparativo de los enfoques de aprendizaje de los estudiantes de los Grados en Pedagogía y Educación Primaria

The European Higher Education Areaallowed the introduction of significantchanges in universities at the structural,academic, organizational and manage-ment levels, although for the students tho-se changes were materialised in changesrelated to their learning processes and inthe ways of dealing with the demands as-ked by the institution and professors.Once the Horizon 2010 has passed andfocusing on the Horizon 2020, while stillbeing in the middle of the process of re-novating the certification of bachelor andmaster titles, the necessity of reflecting onthe results obtained after the whole reformcomes in order to prove if those results arethe ones expected or new reforms shouldbe undertaken.From this perspective, an investigationthat analysed the profile and learning approaches of 416 students of the bachelorsof Primary Education and Pedagogy du-ring three academic years is presented.The design followed in this investigationis a non-experimental quantitative studycarried out through a survey. The StudyProcess Questionnaire-2 Factors (SPQ) inits revised and Spanish version (R-CPE-2F)has been used for the data collection. Theresults were analysed with the statisticpackage SPSS in its 23 rd version.The results showed that the predominantlearning approach is the deep approachand that its percentage of use increaseswith the courses. These results are rela-ted to the quality of learning and the aca-demic performance, both being, a priori,adequate.El Espacio Europeo de Educación Superiorpermitió introducir profundos cambios enlas Universidades a nivel estructural, académico,organizativo y de gestión, aunquepara los estudiantes se materializaron encambios relacionados con sus procesosde aprendizaje y los modos de abordar lasdemandas que la institución y el profesoradoles realizó.Una vez superado el horizonte del 2010 ycon la mirada puesta en el horizonte 2020,pero en pleno proceso de renovación delas acreditaciones de los títulos universitariosde grado y máster, surge la necesidadde reflexionar si los resultados obtenidostras toda esta reforma han sido los esperados,o deberían acometerse nuevas reformas.Desde esta perspectiva se presenta unainvestigación que analizó el perfil y losenfoques de aprendizaje de 416 estudiantesuniversitarios del grado de EducaciónPrimaria y del Grado de Pedagogía, a lolargo de los tres primeros cursos.El diseño de investigación seguido fuecuantitativo no experimental tipo encuesta.Para la recogida de información se empleóes Cuestionario de Proceso de Estudioen su versión revisada a dos factores(CPE-R-2F). Los datos fueron analizadoscon el paquete estadístico SPSS versión 23.Los resultados obtenidos apuntan a queel enfoque de aprendizaje más empleadopor los estudiantes es el profundo y queademás, su porcentaje de uso se incrementacurso a curso. Estos datos están relacionadoscon la calidad del aprendizajey el rendimiento académico que, a priori,debería ser adecuado

N-Aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: design, synthesis, computational studies, and antitumor effect

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejmech.2023.115570.Funding This research was funded by the Consejería de Universidad, Inves- tigaci´on e Innovaci´on of the Junta de Andalucía and FEDER, Una manera de hacer Europa (P18-RT-1679, PT18-TP-4160, B-FQM-475- UGR18 and PAIDI-TC-PVT-PSETC-2.0.), the Research Results Transfer Office (OTRI) of the University of Granada (PR/17/006), the Spanish Ministry of Economy and Competitiveness (PID2019.110987RB.I00 and PID2021.128109OB.I00) and the Health Institute Carlos III (DTS18/ 00121). C.D. thanks HECBioSim, the UK High End Computing Con- sortium for Biomolecular Simulation (hecbiosim.ac.uk), which is sup- ported by the EPSRC (EP/L000253/1) for awarding computing time in Jade, a UK Tier-2 resource. B.R.-R. gratefully acknowledges funding from the European Union’s Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant Agreement no. 754446 and UGR Research and Knowledge Transfer Fund—Athenea3i. J.M.E.-R. thanks the Spanish Ministry of Education for a studentship (FPU 16/ 02061). A.M.-M. gratefully acknowledges funding from the HPC- Europa3 Transnational Access programme supported by the European Commission H2020 Research & Innovation GA # 730897 (application number HPC17ARM6V). Funding for open access charge: Universidad de Granada / CBUA.Hyaluronic acid (HA) plays a crucial role in tumor growth and invasion through its interaction with cluster of differentiation 44 (CD44), a non-kinase transmembrane glycoprotein, among other hyaladherins. CD44 expression is elevated in many solid tumors, and its interaction with HA is associated with cancer and angiogenesis. Despite efforts to inhibit HA-CD44 interaction, there has been limited progress in the development of small molecule inhibitors. As a contribution to this endeavour, we designed and synthesized a series of N-aryltetrahydroisoquinoline derivatives based on existing crystallographic data available for CD44 and HA. Hit 2e was identified within these structures for its antiproliferative effect against two CD44+ cancer cell lines, and two new analogs (5 and 6) were then synthesized and evaluated as CD44-HA inhibitors by applying computational and cell-based CD44 binding studies. Compound 2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-5-ol (5) has an EC50 value of 0.59 μM against MDA-MB-231 cells and is effective to disrupt the integrity of cancer spheroids and reduce the viability of MDA-MB-231 cells in a dose-dependent manner. These results suggest lead 5 as a promising candidate for further investigation in cancer treatment.Consejería de Universidad, Investigación e Innovación of the Junta de Andalucía and FEDER, Una manera de hacer Europa (P18-RT-1679, PT18-TP-4160, B-FQM-475- UGR18 and PAIDI-TC-PVT-PSETC-2.0.)Research Results Transfer Office (OTRI) of the University of Granada (PR/17/006),panish Ministry of Economy and Competitiveness (PID2019.110987RB.I00 and PID2021.128109OB.I0)Health Institute Carlos III (DTS18/ 00121)EPSRC (EP/L000253/1)European Union’s Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant Agreement no. 754446HPC-Europa3 Transnational Access programme supported by the European Commission H2020 Research & Innovation GA # 730897Funding for open access charge: Universidad de Granada / CBUA

143 PRINCIPAL COMPONENT CLUSTERING OF FRONTAL PLANE KNEE KINEMATICS

Replication forks stall at different DNA obstacles such as those originated by transcription. Fork stalling can lead to DNA double-strand breaks (DSBs) that will be preferentially repaired by homologous recombination when the sister chromatid is available. The Rrm3 helicase is a replisome component that promotes replication upon fork stalling, accumulates at highly transcribed regions and prevents not only transcription-induced replication fork stalling but also transcription-associated hyper-recombination. This led us to explore the possible role of Rrm3 in the repair of DSBs when originating at the passage of the replication fork. Using a mini-HO system that induces mainly single-stranded DNA breaks, we show that rrm3Δ cells are defective in DSB repair. The defect is clearly seen in sister chromatid recombination, the major repair pathway of replication-born DSBs. Our results indicate that Rrm3 recruitment to replication-born DSBs is crucial for viability, uncovering a new role for Rrm3 in the repair of broken replication forks.This work was supported by grants from the Spanish Ministry of Economy and Innovation (BFU2013-42918), the European Union (FEDER), the European Research Council (ERC2014 AdG669898 TARLOOP), and the Junta de Andalucía (BIO1238). SMG was funded by a predoctoral training fellowship from the Spanish National Research Council (CSIC) and BGG by a postdoctoral grant from the Scientific Foundation of the Spanish Association Against Cancer (AECC). Funding for open access charge: Grants from the Spanish Ministry of Economy and Innovation (BFU2013-42918).Peer Reviewe