An improved crow search algorithm applied to the phase swapping problem in asymmetric distribution systems

This paper discusses the power loss minimization problem in asymmetric distribution systems (ADS) based on phase swapping. This problem is presented using a mixed-integer nonlinear programming model, which is resolved by applying a master–slave methodology. The master stage consists of an improved version of the crow search algorithm. This stage is based on the generation of candidate solutions using a normal Gaussian probability distribution. The master stage is responsible for providing the connection settings for the system loads using integer coding. The slave stage uses a power flow for ADSs based on the three-phase version of the iterative sweep method, which is used to determine the network power losses for each load connection supplied by the master stage. Numerical results on the 8-, 25-, and 37-node test systems show the efficiency of the proposed approach when compared to the classical version of the crow search algorithm, the Chu and Beasley genetic algorithm, and the vortex search algorithm. All simulations were obtained using MATLAB and validated in the DigSILENT power system analysis software

Activities in the natural environment and experiential methodology as tools for the integral development of individuals

Los procesos de enseñanza-aprendizaje se pueden desarrollar en contextos diversos y con metodologías educativas diferentes, pero no todas ellas, ni todos los espacios, tienen el mismo potencial para conseguir que los estudiantes adquieran los conocimientos tratados ni para lograr un desarrollo de todas sus capacidades (físicas, cognitivas, psicológicas). Esta es la base desde la que surge el siguiente estudio. El objetivo principal es comparar los beneficios que se producen en los estudiantes en relación a los procesos de enseñanza-aprendizaje y a su desarrollo integral, en función del aula y de la metodología educativa empleada. Para ello, se han pasado dos cuestionarios, uno después de las sesiones en aula y otro después de las sesiones prácticas en el medio natural, a un grupo de 124 estudiantes de la asignatura de Actividades en el Medio Natural, de la Facultad de Ciencias de la Actividad Física y del Deporte-INEF de Madrid. A la vista de los resultados, destacan el 17,05% de diferencia entre la adquisición de aprendizajes tras las sesiones en la naturaleza en comparación con las sesiones en aula. Se concluye que las actividades en el medio natural, llevadas a cabo con una metodología experiencial, suponen mayores beneficios en cuanto al grado de conocimientos adquiridos y en cuanto al desarrollo de competencias sociales y personales de los participantes

Nonsurgical Procedures for Keratoconus Management

Objectives. To describe the past 20 years’ correction modalities for keratoconus and their visual outcomes and possible complications. Methods. A review of the published literature related to the visual outcomes and possible complications in the context of keratoconus management using nonsurgical procedures for the last 20 years (glasses and contact lenses) was performed. Original articles that reported the outcome of any correction modalities of keratoconus management were reviewed. Results. The most nonsurgical procedure used on keratoconus management is the contact lens fitting. Soft contact lenses and soft toric contact lenses, rigid gas-permeable contact lenses, piggyback contact lens system, hybrid contact lenses, and scleral and corneoscleral contact lenses form the contemporary range of available lens types for keratoconus management with contact lenses. All of them try to restore the vision, improve the quality of life, and delay surgical procedures in patients with this disease. Complications are derived from the intolerance of using contact lens, and the use of each depends on keratoconus severity. Conclusions. In the context of nonsurgical procedures, the use of contact lenses for the management of keratoconic patients represents a good alternative to restore vision and improve the quality of live in this population

Embolization therapy with microspheres for the treatment of liver cancer: State-of-the-art of clinical translation

Embolization with microspheres is a therapeutic strategy based on the selective occlusion of the blood vessels feeding a tumor. This procedure is intraarterially performed in the clinical setting for the treatment of liver cancer. The practice has evolved over the last decade through the incorporation of drug loading ability, biodegradability and imageability with the subsequent added functionality for the physicians and improved clinical outcomes for the patients. This review highlights the evolution of the embolization systems developed through the analysis of the marketed embolic microspheres for the treatment of malignant hepatocellular carcinoma, namely the most predominant form of liver cancer. Embolic microspheres for the distinct modalities of embolization (i.e., bland embolization, chemoembolization and radioembolization) are here comprehensively compiled with emphasis on material characteristics and their impact on microsphere performance. Moreover, the future application of the embolics under clinical investigation is discussed along with the scientific and regulatory challenges ahead in the field

Thermal decomposition of the acetone cyclic diperoxide in 1-octanol solution

The thermal decomposition reaction of acetone cyclic diperoxide (ACDP) in 1-octanol (OCT) solution, at the temperatures and initial concentration ranges of 130° -166 ºC and (0.94-3.00) x 10-2 mol/L , respectively, follows a pseudo-first order kinetic law. Acetone is the main organic decomposition product observed. The activation parameters values of the initial reaction step (ΔH# = 25.8 ± 0.3 kcal/mol; ΔS# = -19.1 ± 0.6 cal/mol K; Ea = 26.6 ± 0.3 kcal/mol), support a reaction mechanism which includes a homolytic rupture of one peroxidic bond of the ACDP molecule with participation of the solvent and involving a biradical intermediate.La reacción de descomposición térmica del diperóxido de acetona cíclico (ACDP) en solución de 1-octanol (OCT), en los rangos de temperatura y concentraciones iniciales de 130° -166 ºC y (0.94-3.00) x 10-2 mol/L respectivamente, sigue una ley cinética de seudo primer orden. La acetona es el principal producto de descomposición observado. Loa valores de activación de la etapa inicial (ΔH# = 25.8 ± 0.3 kcal/mol; ΔS# = -19.1 ± 0.6 cal/mol K; Ea = 26.6 ± 0.3 kcal/mol) apoyan un mecanismo de reacción que incluye una ruptura homolítica de un enlace peroxídico en la molécula del ACDP con participación del solvente y que involucra un birradical intermediario.Laboratorio de Estudio de Compuestos OrgánicosInstituto de Investigaciones Fisicoquímicas Teóricas y Aplicada

Thermal decomposition reaction of 3,3,6,6-tetramethyl- 1,2,4,5-tetroxane in 2-methoxy- ethanol solution

The thermal decomposition study of 3,3,6,6-tetramethyl-1,2,4,5-tetroxane (acetone cyclic diperoxide) was carried out in 2-methoxyethanol solution in the 130-166 °C temperature range. The overall reaction follows a first-order kinetic law up to at least 75% diperoxide conversion. The activation parameters (ΔH# = 22.5 ± 0.7 kcal⋅mol–1 and ΔS# = -25.6 ± 0.5 cal⋅mol–1⋅K–1) for the unimolecular rupture of the O–O bond in the diperoxide molecule were obtained by measuring the remnant diperoxide at different reaction times by the CG technique. Acetone was detected by GC as the major organic product of the reaction.Facultad de Ciencias ExactasInstituto de Investigaciones Fisicoquímicas Teóricas y Aplicada

NF-κB-direct activation of microRNAs with repressive effects on monocyte-specific genes is critical for osteoclast differentiation

Monocyte-to-osteoclast conversion is a unique terminal differentiation process that is exacerbated in rheumatoid arthritis and bone metastasis. The mechanisms implicated in upregulating osteoclast-specific genes involve transcription factors, epigenetic regulators and microRNAs (miRNAs). It is less well known how downregulation of osteoclast-inappropriate genes is achieved. RESULTS: In this study, analysis of miRNA expression changes in osteoclast differentiation from human primary monocytes revealed the rapid upregulation of two miRNA clusters, miR-212/132 and miR-99b/let-7e/125a. We demonstrate that they negatively target monocyte-specific and immunomodulatory genes like TNFAIP3, IGF1R and IL15. Depletion of these miRNAs inhibits osteoclast differentiation and upregulates their targets. These miRNAs are also upregulated in other inflammatory monocytic differentiation processes. Most importantly, we demonstrate for the first time the direct involvement of Nuclear Factor kappa B (NF-κB) in the regulation of these miRNAs, as well as with their targets, whereby NF-κB p65 binds the promoters of these two miRNA clusters and NF-κB inhibition or depletion results in impaired upregulation of their expression. CONCLUSIONS:Our results reveal the direct involvement of NF-κB in shutting down certain monocyte-specific genes, including some anti-inflammatory activities, through a miRNA-dependent mechanism for proper osteoclast differentiation

In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone

The development of resistance to therapy is unavoidable in the history of multiple myeloma patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclinical models, especially those mimicking acquired resistance. Here we present an in vivo model of acquired resistance based on the continuous treatment of mice bearing subcutaneous MM1S plasmacytomas. Xenografts acquired resistance to two generations of immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide) in combination with dexamethasone, that was reversible after a wash-out period. Furthermore, lenalidomide-dexamethasone (LD) or pomalidomide-dexamethasone (PD) did not display cross-resistance, which could be due to the differential requirements of the key target Cereblon and its substrates Aiolos and Ikaros observed in cells resistant to each combination. Differential gene expression profiles of LD and PD could also explain the absence of cross-resistance. Onset of resistance to both combinations was accompanied by upregulation of the mitogen-activated protein kinaseextracellular signal-regulated kinase (ERK) kinase (MEK)ERK pathway and addition of selumetinib, a small-molecule MEK inhibitor, could resensitize resistant cells. Our results provide insights into the mechanisms of acquired resistance to LD and PD combinations and offer possible therapeutic approaches to addressing IMiD resistance in the clinic.Peer Reviewe

Distinct GSDMB protein isoforms and protease cleavage processes differentially control pyroptotic cell death and mitochondrial damage in cancer cells

Gasdermin (GSDM)-mediated pyroptosis is functionally involved in multiple diseases, but Gasdermin-B (GSDMB) exhibit cell death-dependent and independent activities in several pathologies including cancer. When the GSDMB pore-forming N-terminal domain is released by Granzyme-A cleavage, it provokes cancer cell death, but uncleaved GSDMB promotes multiple pro-tumoral effects (invasion, metastasis, and drug resistance). To uncover the mechanisms of GSDMB pyroptosis, here we determined the GSDMB regions essential for cell death and described for the first time a differential role of the four translated GSDMB isoforms (GSDMB1-4, that differ in the alternative usage of exons 6-7) in this process. Accordingly, we here prove that exon 6 translation is essential for GSDMB mediated pyroptosis, and therefore, GSDMB isoforms lacking this exon (GSDMB1-2) cannot provoke cancer cell death. Consistently, in breast carcinomas the expression of GSDMB2, and not exon 6-containing variants (GSDMB3-4), associates with unfavourable clinical-pathological parameters. Mechanistically, we show that GSDMB N-terminal constructs containing exon-6 provoke cell membrane lysis and a concomitant mitochondrial damage. Moreover, we have identified specific residues within exon 6 and other regions of the N-terminal domain that are important for GSDMB-triggered cell death as well as for mitochondrial impairment. Additionally, we demonstrated that GSDMB cleavage by specific proteases (Granzyme-A, Neutrophil Elastase and caspases) have different effects on pyroptosis regulation. Thus, immunocyte-derived Granzyme-A can cleave all GSDMB isoforms, but in only those containing exon 6, this processing results in pyroptosis induction. By contrast, the cleavage of GSDMB isoforms by Neutrophil Elastase or caspases produces short N-terminal fragments with no cytotoxic activity, thus suggesting that these proteases act as inhibitory mechanisms of pyroptosis. Summarizing, our results have important implications for understanding the complex roles of GSDMB isoforms in cancer or other pathologies and for the future design of GSDMB-targeted therapies.This study has been supported by the Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (MICINN-AEI, PID2019-104644RB-I00, PDC2022-133252-I00) -GMB-, (PID2021-126625OB-I00-MCIN/AEI/10.13039/501100011033 FEDER, EU.2022- and DTS20-00024 -ISCIII-) -PGP-, the Instituto de Salud Carlos III (CIBERONC, CB16/12/00295 -GMB- and CB16/12/00241 -JA-, and AC21_2/00020 ERA PerMed ERA-NET, PMP22/00054 Immune4ALL Personalized Medicine -GMB-, cofunded by NextGenerationEU), I “Semilla” CIBERONC-GEICAM Grant -GMB- and the AECC Scientific Foundation (FCAECC PROYE19036MOR and GCTRA18014MATI -GMB-), the National Institutes of Health (NIH, USA) (R01-DK123475) -J-KK- and it has been also supported by a startup fund to -J-KK- from the Ohio State University, the College of Medicine, Department of Surgery. DS contract is funded by CIBERONC partly supported by FEDER funds. SO is funded by the FCAECC (POSTD20028OLTR), SC is funded by the MICINN-AEI PRE2020-095658

Zalypsis has in vitro activity in acute myeloid blasts and leukemic progenitor cells through the induction of a DNA damage response

[EN]Although the majority of patients with acute myeloid leukemia initially respond to conventional chemotherapy, relapse is still the leading cause of death, probably because of the presence of leukemic stem cells that are insensitive to current therapies. We investigated the antileukemic activity and mechanism of action of zalypsis, a novel alkaloid of marine origin. The activity of zalypsis was studied in four acute myeloid leukemia cell lines and in freshly isolated blasts taken from patients with acute myeloid leukemia before they started therapy. Zalypsis-induced apoptosis of both malignant and normal cells was measured using flow cytometry techniques. Gene expression profiling and western blot studies were performed to assess the mechanism of action of the alkaloid. Zalypsis showed a very potent antileukemic activity in all the cell lines tested and potentiated the effect of conventional antileukemic drugs such as cytarabine, fludarabine and daunorubicin. Interestingly, zalypsis showed remarkable ex vivo potency, including activity against the most immature blast cells (CD34(+) CD38(-) Lin(-)) which include leukemic stem cells. Zalypsis-induced apoptosis was the result of an important deregulation of genes involved in the recognition of double-strand DNA breaks, such as Fanconi anemia genes and BRCA1, but also genes implicated in the repair of double-strand DNA breaks, such as RAD51 and RAD54. These gene findings were confirmed by an increase in several proteins involved in the pathway (pCHK1, pCHK2 and pH2AX). The potent and selective antileukemic effect of zalypsis on DNA damage response mechanisms observed in acute myeloid leukemia cell lines and in patients' samples provides the rationale for the investigation of this compound in clinical trials