Donepezil-based hybrids as multifunctional anti-Alzheimer's disease chelating agents: Effect of positional isomerization

The intricate and multifactorial nature of Alzheimer's disease (AD) requires the development of compounds able to hit different pathophysiological targets, such as cholinergic dysfunction, deposits of amyloid beta (A beta) peptide and metal dyshomeostasis. In order to continue the search for new anti-AD drugs, a design strategy was once more followed based on repositioning donepezil (DNP) drug, by ortho-attaching a benzylpiperidine mimetic of DNP moiety to a hydroxyphenyl-benzimidazole (BIM) chelating unit (compound 1). Herein, compound 1 and a positional isomer 2 are compared in terms of their potential multiple properties: both present good acetylcholinesterase (AChE) inhibition (low mu molar range) and are moderate/good inhibitors of A beta self- and Cu-mediated aggregation, the inhibition process being mainly due to ligand intercalation between the p-sheets of the fibrils; compound 1 has a higher chelating capacity towards Cu2+ and Zn2+ (pCu = 14.3, pZn = 6.4, pH 7.4, C-I/C-M = 10, C-M = 10(-6) M) than 2 (pCu = 10.7, pZn = 6.3), attributed to its ability to establish a tridentate (N,O,O) coordination to the metal ion. Both compounds are eligible as drug candidates for oral administration but compound 1 shows improved neuroprotective role by completely preventing Ali-induced cell toxicity

Gestión de la cadena de suministro para incrementar la rentabilidad en la empresa Lubricentro S&P, Végueta 2021

Objetivo: Evaluar de qué manera la Gestión de la cadena de suministro contribuye al incremento de la rentabilidad en la empresa Lubricentro S&P. Materiales y métodos: El diseño de la investigación es pre-experimental; de tipo aplicada, explicativa con alcance longitudinal, con carácter de medida cuantitativa. La población estuvo comprendida por población objeto, productos que ingresen a almacén en periodo septiembre 2020-agosto del 2021 y población sujeto, que está constituido por 20 personas dueños de empresas existentes en el área de influencia. Resultados: Se realizó el análisis a la situación actual, por medio de un diagrama de flujo y un diagrama de análisis de procesos, reduciendo el tiempo de abastecimiento en 0:28 min. Se estableció contacto con más proveedores pasando de 9 a 16 proveedores de las cuales el 18,75% son locales y el 81,25% nacionales, se estableció un lote económico de pedido, se aplicó la metodología de las 5S, mejorando el orden y limpieza del almacén, reduciendo los productos de rotación “C” en un 22,58%; el uso de un kardex y una plantilla mejorada en Excel permitió obtener datos reales, de esa manera se calculó el stock minino, y punto de reorden de los aceites. Los costos de almacén muestran una diferencia de S/169,26 a favor del segundo año La Gestión de la cadena de suministro logró incrementar la rentabilidad en un 1,3 %. Conclusión: La gestión de la cadena de suministro contribuyó en el incremento de la rentabilidad en la empresa Lubricentro S&P

Literatura Infantil como Estrategia Metodológica en el Proceso de Aprendizaje de la Comunicación en la niñez, de multinivel, preescolar San Miguel, municipio El Tuma–La Dalia, ll semestre 2020

Esta investigación se realizó con el propósito analizar la literatura infantil como estrategia metodológica con el proceso de aprendizaje de la comunicación en la niñez, multinivel preescolar san miguel El Tuma La Dalia ll semestre 2020,se hizo uso de elementos dentro del diseño metodológico, empleando métodos teóricos y empíricos , con una población de 22 niños y 1 maestra, los instrumentos utilizados 1 entrevista a la docente, 1 guía de observación a estudiantes ;los principales hallazgos que se discutieron fueron proceso de aprendizaje, estrategia metodológica, literatura infantil y comunicación. Algunas de las conclusiones fueron estas: se identificó que la docente aplica estas estrategias lectura de cuentos, rimas, cantos y adivinanzascon los niños se determinó que no existen factores que intervengan en el desarrollo de la literatura infantil.Palabras claves: proceso de aprendizaje, literatura infantil, comunicación

Closing gaps to our origins : EUVO: the ultraviolet-visible window into the Universe

This article reproduces the contents of the White Paper entitled by the same name submitted to the call issued by the European Space Agency soliciting ideas from the scientific community for the science themes that should be covered during the Voyage 2050 planning cycle. This contribution focus in the investigation of the emergence of life and the role that astronomy has to play in it. Three fundamental areas of activity are identified: [1] measuring the chemical enrichment of the Universe, [2] investigating planet formation and searching for exoplanets with signatures of life and, [3] determining the abundance of amino acids and the chemical routes to amino acid and protein growth in astronomical bodies. This proposal deals with the first two. The building blocks of life in the Universe began as primordial gas processed in stars and mixed at galactic scales. The mechanisms responsible for this development are not well-understood and have changed over the intervening 13 billion years. To follow the evolution of matter over cosmic time, it is necessary to study the strongest (resonance) transitions of the most abundant species in the Universe. Most of them are in the ultraviolet (UV; 950 Å - 3000 Å ) spectral range that is unobservable from the ground; the “missing” metals problem cannot be addressed without this access. Habitable planets grow in protostellar discs under ultraviolet irradiation, a by-product of the accretion process that drives the physical and chemical evolution of discs and young planetary systems. The electronic transitions of the most abundant molecules are pumped by this UV field that is the main oxidizing agent in the disc chemistry and provides unique diagnostics of the planet-forming environment that cannot be accessed from the ground. Knowledge of the variability of the UV radiation field is required for the astrochemical modelling of protoplanetary discs, to understand the formation of planetary atmospheres and the photochemistry of the precursors of life. Earth’s atmosphere is in constant interaction with the interplanetary medium and the solar UV radiation field. The exosphere of the Earth extends up to 35 planetary radii providing an amazing wealth of information on our planet’s winds and the atmospheric compounds. To access to it in other planetary systems, observation of the UV resonance transitions is required. The investigation for the emergence of life calls for the development of large astronomical facilities, including instrumentation in optical and UV wavelengths. In this contribution, the need to develop a large observatory in the optical and in the UV is revealed, in order to complete the scientific goals to investigate the origin of life, inaccessible through other frequencies in the electromagnetic spectrum

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

LINE-1 retrotransposon in chronic myeloid leukemia

Le gène hybride BCR-ABL1, responsable de la leucémie myéloïde chronique (LMC), code une protéine à activité tyrosine kinase constitutive. Lors d’une étude transcriptomique menée au laboratoire sur des patients résistants secondaires à l’imatinib, les deux gènes codant les protéines des rétrotransposons LINE-1 ont été trouvés sous exprimés d’environ 20 fois lorsque les patients rechutent. Le rôle des transposons n’a jamais été clairement défini, ils assurent certainement une fonction importante puisqu’ils sont conservés au cours de l’évolution et présents chez tous les organismes. Le but de ce travail a été d’étudier l’implication de LINE-1 dans la LMC. La sous-expression de LINE-1 est-elle une conséquence de la présence de BCR-ABL1 ou une cause de son apparition ? Différents groupes ont montré que les rétrotransposons LINE-1 possédent la capacité de réparation des cassures double-brin de l’ADN. Nous avons fait l’hypothèse qu’une diminution de l’expression des gènes codés par les rétrotransposons LINE-1 entraînerait l’instabilité génétique observée dans la LMC. Une étude réalisée chez des patients atteints de LMC et des sujets contrôles a montré une correlation inverse entre l’expression de LINE-1 et celle de l’oncogène BCR-ABL1. Parallèlement, une étude sur des lignées cellulaires leucémiques humaines BCR-ABL positives et négatives a été réalisée. Nous avons recherché le lien qui existe entre l’expression de LINE 1, de BCR-ABL1 et la réparation des cassures double-brin de l’ADN. Nous avons montré d’une part qu’une inhibition de l’expression de BCR-ABL1 induit une augmentation de l’expression des transposons LINE-1 D’autre part, une diminution de l’expression de LINE-1 entraîne une apparition du transcrit BCR-ABL1 dans les cellules BCR-ABL negatives.BCR-ABL1 fusion gene, responsible of the chronic myeloid leukemia (CML) encodes a constitutively activated tyrosine kinase protein. Expression of both LINE-1 retrotransposon ORFs were found decreased at the time of imatinib resistance in a comparative transcriptional study focused on secondary resistant patients. The role of retrotransposons is unclear. They are conserved through evolution. This project focuses on the involvement of LINE-1 in CML. Is LINE-1 under expression a result of BCR-ABL1 expression or is it at the origin of BCR ABL1? Different groups have shown that LINE-1 retrotransposons were able to repair DNA double strands breaks. We suggest that LINE-1 under expression could be responsible of genetic instability observed in CML. We show in a study on CML patients and healthy subjects that LINE-1 expression is inverse correlated to BCR-ABL1 expression. Moreover, study on BCR-ABL+ and BCR-ABL- human leukemic cell lines was carried on. First, we show that decrease of BCR-ABL1 expression induces increase of LINE-1 expression. Then that decrease of LINE-1 expression generates BCR-ABL1 transcript in BCR-ABL negatives cell lines

LINE-1 retrotransposon in chronic myeloid leukemia

Le gène hybride BCR-ABL1, responsable de la leucémie myéloïde chronique (LMC), code une protéine à activité tyrosine kinase constitutive. Lors d’une étude transcriptomique menée au laboratoire sur des patients résistants secondaires à l’imatinib, les deux gènes codant les protéines des rétrotransposons LINE-1 ont été trouvés sous exprimés d’environ 20 fois lorsque les patients rechutent. Le rôle des transposons n’a jamais été clairement défini, ils assurent certainement une fonction importante puisqu’ils sont conservés au cours de l’évolution et présents chez tous les organismes. Le but de ce travail a été d’étudier l’implication de LINE-1 dans la LMC. La sous-expression de LINE-1 est-elle une conséquence de la présence de BCR-ABL1 ou une cause de son apparition ? Différents groupes ont montré que les rétrotransposons LINE-1 possédent la capacité de réparation des cassures double-brin de l’ADN. Nous avons fait l’hypothèse qu’une diminution de l’expression des gènes codés par les rétrotransposons LINE-1 entraînerait l’instabilité génétique observée dans la LMC. Une étude réalisée chez des patients atteints de LMC et des sujets contrôles a montré une correlation inverse entre l’expression de LINE-1 et celle de l’oncogène BCR-ABL1. Parallèlement, une étude sur des lignées cellulaires leucémiques humaines BCR-ABL positives et négatives a été réalisée. Nous avons recherché le lien qui existe entre l’expression de LINE 1, de BCR-ABL1 et la réparation des cassures double-brin de l’ADN. Nous avons montré d’une part qu’une inhibition de l’expression de BCR-ABL1 induit une augmentation de l’expression des transposons LINE-1 D’autre part, une diminution de l’expression de LINE-1 entraîne une apparition du transcrit BCR-ABL1 dans les cellules BCR-ABL negatives.BCR-ABL1 fusion gene, responsible of the chronic myeloid leukemia (CML) encodes a constitutively activated tyrosine kinase protein. Expression of both LINE-1 retrotransposon ORFs were found decreased at the time of imatinib resistance in a comparative transcriptional study focused on secondary resistant patients. The role of retrotransposons is unclear. They are conserved through evolution. This project focuses on the involvement of LINE-1 in CML. Is LINE-1 under expression a result of BCR-ABL1 expression or is it at the origin of BCR ABL1? Different groups have shown that LINE-1 retrotransposons were able to repair DNA double strands breaks. We suggest that LINE-1 under expression could be responsible of genetic instability observed in CML. We show in a study on CML patients and healthy subjects that LINE-1 expression is inverse correlated to BCR-ABL1 expression. Moreover, study on BCR-ABL+ and BCR-ABL- human leukemic cell lines was carried on. First, we show that decrease of BCR-ABL1 expression induces increase of LINE-1 expression. Then that decrease of LINE-1 expression generates BCR-ABL1 transcript in BCR-ABL negatives cell lines

Etude des rétrotransposons LINE-1 dans la leucémie myéloïde chronique

Le gène hybride BCR-ABL1, responsable de la leucémie myéloïde chronique (LMC), code une protéine à activité tyrosine kinase constitutive. Lors d une étude transcriptomique menée au laboratoire sur des patients résistants secondaires à l imatinib, les deux gènes codant les protéines des rétrotransposons LINE-1 ont été trouvés sous exprimés d environ 20 fois lorsque les patients rechutent. Le rôle des transposons n a jamais été clairement défini, ils assurent certainement une fonction importante puisqu ils sont conservés au cours de l évolution et présents chez tous les organismes. Le but de ce travail a été d étudier l implication de LINE-1 dans la LMC. La sous-expression de LINE-1 est-elle une conséquence de la présence de BCR-ABL1 ou une cause de son apparition ? Différents groupes ont montré que les rétrotransposons LINE-1 possédent la capacité de réparation des cassures double-brin de l ADN. Nous avons fait l hypothèse qu une diminution de l expression des gènes codés par les rétrotransposons LINE-1 entraînerait l instabilité génétique observée dans la LMC. Une étude réalisée chez des patients atteints de LMC et des sujets contrôles a montré une correlation inverse entre l expression de LINE-1 et celle de l oncogène BCR-ABL1. Parallèlement, une étude sur des lignées cellulaires leucémiques humaines BCR-ABL positives et négatives a été réalisée. Nous avons recherché le lien qui existe entre l expression de LINE 1, de BCR-ABL1 et la réparation des cassures double-brin de l ADN. Nous avons montré d une part qu une inhibition de l expression de BCR-ABL1 induit une augmentation de l expression des transposons LINE-1 D autre part, une diminution de l expression de LINE-1 entraîne une apparition du transcrit BCR-ABL1 dans les cellules BCR-ABL negatives.BCR-ABL1 fusion gene, responsible of the chronic myeloid leukemia (CML) encodes a constitutively activated tyrosine kinase protein. Expression of both LINE-1 retrotransposon ORFs were found decreased at the time of imatinib resistance in a comparative transcriptional study focused on secondary resistant patients. The role of retrotransposons is unclear. They are conserved through evolution. This project focuses on the involvement of LINE-1 in CML. Is LINE-1 under expression a result of BCR-ABL1 expression or is it at the origin of BCR ABL1? Different groups have shown that LINE-1 retrotransposons were able to repair DNA double strands breaks. We suggest that LINE-1 under expression could be responsible of genetic instability observed in CML. We show in a study on CML patients and healthy subjects that LINE-1 expression is inverse correlated to BCR-ABL1 expression. Moreover, study on BCR-ABL+ and BCR-ABL- human leukemic cell lines was carried on. First, we show that decrease of BCR-ABL1 expression induces increase of LINE-1 expression. Then that decrease of LINE-1 expression generates BCR-ABL1 transcript in BCR-ABL negatives cell lines.BORDEAUX2-Bib. électronique (335229905) / SudocSudocFranceF

ABT-737 increases tyrosine kinase inhibitor–induced apoptosis in chronic myeloid leukemia cells through XIAP downregulation and sensitizes CD34+ CD38− population to imatinib

International audienceChronic myeloid leukemia (CML) tumorigenicity is driven by the oncogenic BCR-ABL tyrosine kinase. Specific tyrosine kinase inhibitors (TKI) have been designed and are now used for the treatment of CML. These TKI induce apoptosis in leukemic cells in a BIM-dependent mechanism. We hypothesized that an increase in BIM activity could sensitize CML cells to TKI. We blocked the anti-apoptotic proteins of the Bcl-2 family by using ABT-737, a Bcl-2 and Bcl-XL inhibitor. ABT-737 modified Bcl-2 protein interactions toward a pro-apoptotic phenotype. Its combination with TKI resulted in a strong synergism in CML cell lines. The association also induced a large decrease in X-linked inhibitor of apoptosis (XIAP), followed by caspase-3 activation. This XIAP decrease was due to post-translational events. The mitochondrial serine protease HtrA2/Omi was identified as being responsible for this off-target effect. Then, ABT-737 and TKI cooperate at several levels to induce apoptosis of CML cells lines, and the benefit of this association was also observed in CML hematopoietic progenitors. Interestingly, a lethal effect was also observed in the more immature CD34(+)CD38(-) TKI-insensitive population. Combination therapy might by an interesting strategy for the treatment of CML patients

Stepwise Biogenesis of Subpopulations of Lipid Droplets in Nitrogen Starved Phaeodactylum tricornutum Cells

International audienceDiatoms are unicellular heterokonts, living in oceans and freshwaters, exposed to frequent environmental variations. They have a sophisticated membrane compartmentalization and are bounded by a siliceous cell-wall. Formation of lipid droplets (LDs), filled with triacylglycerol (TAG), is a common response to stress. The proteome of mature-LDs from Phaeodactylum tricornutum highlighted the lack of proteins involved in early-LD formation, TAG biosynthesis or LD-to-LD connections. These features suggest that cytosolic LDs might reach a size limit. We analyzed the dynamics of LD formation in P. tricornutum (Pt1 8.6; CCAP 1055/1) during 7 days of nitrogen starvation, by monitoring TAG by mass spectrometry-based lipidomics, and LD radius using epifluorescence microscopy and pulse field gradient nuclear magnetic resonance. We confirmed that mature LDs reach a maximal size. Based on pulse field gradient nuclear magnetic resonance, we did not detect any LD-LD fusion. Three LD subpopulations were produced, each with a different maximal size, larger-sized LDs (radius 0.675 ± 0.125 µm) being generated first. Mathematical modeling showed how smaller LDs are produced once larger LDs have reached their maximum radius. In a mutant line having larger cells, the maximal size of the first LD subpopulation was higher (0.941 ± 0.169 µm), while the principle of stepwise formation of distinct LD populations was maintained. Results suggest that LD size is determined by available cytosolic space and sensing of an optimal size reached in the previous LD subpopulation. Future perspectives include the unraveling of LD-size control mechanisms upon nitrogen shortage. This study also provides novel prospects for the optimization of oleaginous microalgae for biotechnological applications