A Molecular Characterization of the Allelic Expression of the BRCA1 Founder Δ9-12 Pathogenic Variant and Its Potential Clinical Relevance in Hereditary Cancer.

Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most common pathogenic variants (PVs) causing HBOC occur in the BRCA1 gene, with more than 3850 reported mutations in the gene sequence. The prevalence of specific PVs in BRCA1 has increased across populations due to the effect of founder mutations. Therefore, when a founder mutation is identified, it becomes key to improving cancer risk characterization and effective screening protocols. The only founder mutation described in the Mexican population is the deletion of exons 9 to 12 of BRCA1 (BRCA1Δ9-12), and its description focuses on the gene sequence, but no transcription profiles have been generated for individuals who carry this gene. In this study, we describe the transcription profiles of cancer patients and healthy individuals who were heterozygous for PV BRCA1Δ9-12 by analyzing the differential expression of both alleles compared with the homozygous BRCA1 control group using RT-qPCR, and we describe the isoforms produced by the BRCA1 wild-type and BRCA1Δ9-12 alleles using nanopore long-sequencing. Using the Kruskal-Wallis test, our results showed a similar transcript expression of the wild-type allele between the healthy heterozygous group and the homozygous BRCA1 control group. An association between the recurrence and increased expression of both alleles in HBOC patients was also observed. An analysis of the sequences indicated four wild-type isoforms with diagnostic potential for discerning individuals who carry the PV BRCA1Δ9-12 and identifying which of them has developed cancer.

Proteasome inhibition alters mitotic progression through the upregulation of centromeric α-Satellite RNAs.

Cell cycle progression requires control of the abundance of several proteins and RNAs over space and time to properly transit from one phase to the next and to ensure faithful genomic inheritance in daughter cells. The proteasome, the main protein degradation system of the cell, facilitates the establishment of a proteome specific to each phase of the cell cycle. Its activity also strongly influences transcription. Here, we detected the upregulation of repetitive RNAs upon proteasome inhibition in human cancer cells using RNA-seq. The effect of proteasome inhibition on centromeres was remarkable, especially on α-Satellite RNAs. We showed that α-Satellite RNAs fluctuate along the cell cycle and interact with members of the cohesin ring, suggesting that these transcripts may take part in the regulation of mitotic progression. Next, we forced exogenous overexpression and used gapmer oligonucleotide targeting to demonstrate that α-Sat RNAs have regulatory roles in mitosis. Finally, we explored the transcriptional regulation of α-Satellite DNA. Through in silico analyses, we detected the presence of CCAAT transcription factor-binding motifs within α-Satellite centromeric arrays. Using high-resolution three-dimensional immuno-FISH and ChIP-qPCR, we showed an association between the α-Satellite upregulation and the recruitment of the transcription factor NFY-A to the centromere upon MG132-induced proteasome inhibition. Together, our results show that the proteasome controls α-Satellite RNAs associated with the regulation of mitosis.

Novel ureido-dihydropyridine scaffolds as theranostic agents.

In this work, the synthesis of interesting urea derivatives 5 based on 1,4-dihydropyridines 3 is described for the first time. Considering that both families exhibit potential as drugs to treat various diseases, their activity as anticancer agents has been evaluated in HeLa (cervix), Jurkat (leukaemia) and A549 (lung) cancer cell lines as well as on healthy mice in vivo. In general, whereas 1,4-dihydropyridines show a moderate cytotoxic activity, their urea analogues cause an extraordinary increase in their antiproliferative activity, specially towards HeLa cells. Because of the chiral nature of these compounds, enantiomerically enriched samples were also tested, showing different cytotoxic activity than the racemic mixture. Although the reason is not clear, it could be caused by a complex amalgam of physical and chemical contributions. The studied compounds also exhibit luminescent properties, which allow performing a biodistribution study in cancer cells. They have emission maxima between 420 and 471 nm, being the urea derivatives in general red shifted. Emission quenching was observed for those compounds containing a nitro group (3e,f and 5e,f). Fluorescence microscopy showed that 1,4-dihydropyridines 3a and 3g localised in the lysosomes, in contrast to the urea derivatives 5h that accumulated in the cell membrane. This different distribution could be key to explain the differences found in the cytotoxic activity and in the mechanism of action. Interestingly, a preliminary in vivo study regarding the acute toxicity of some of these compounds on healthy mice has been conducted, using a concentration up to 7200 times higher than the corresponding IC50 value. No downgrade in the welfare of the tested mice was observed, which could support their use in preclinical tumour models.

La adiccionología una especialidad médica y subespecialidad de la psiquiatría / Addictionology A Medical Specialty And Sub-Specialty Of Psychiatry

La Adiccionología como componente de las ciencias de la salud, está alcanzando un rápido reconocimiento como disciplina médica, específicamente como subespecialidad de la psiquiatría. El problema de las adicciones es un tema que se extiende y se agrava en la sociedad posmoderna, debido a su multidimensionalidad y multifactorialidad. Las condiciones de salud de los países han mejorado en cuanto a la reducción de la mortalidad y de la incidencia de algunas enfermedades transmisibles. Sin embargo, se está dando una mayor incidencia de enfermedades crónicas no transmisibles relacionadas con los estilos de vida, así como la emergencia de problemas de salud derivados de la violencia, el consumo de drogas, adicciones sociales, lúdicas y adicción digital (conectividad). Los factores familiares, incluyendo el rechazo de los padres y los conflictos familiares, debido al abuso de sustancias y problemas de salud mental, se encuentran entre los predictores más fuertes y consistentes de los problemas de comportamiento de los adolescentes. De otro lado, en el Modelo Holístico Centrado en la Familia, Nizama propone el desarrollo humano integral mediante la organización multidimensional como eje de vida que comprende once dimensiones de la vida humana: corporal, potencial genético, personalidad, esencia humana, cognición, imaginación, estilos de vida, activos, imagen, futuridad y posteridad. En conclusión, la adiccionología es la especialidad médica indicada para el manejo exitoso y esperanzador de esta enfermedad volitiva en todos los grupos de edad, con adherencia familiar comprometida y sostenible.

Addictionology as a component of the health sciences is rapidly becoming recognized as a medical discipline, specifically as a subspecialty of psychiatry. The problem of addictions is a subject that extends and worsens in postmodern society, due to its multidimensionality and multifactoriality. The health conditions of the countries have improved in terms of reducing mortality and the incidence of some communicable diseases. However, there is a greater incidence of chronic noncommunicable diseases related to lifestyles, as well as the emergence of health problems derived from violence, drug consumption, social, recreational addictions and digital addiction (connectivity). Family factors, including rejection by parents and family conflicts, due to substance abuse and mental health problems, are among the strongest and most consistent predictors of adolescent behavior problems. Therefore, in the Holistic Family Centered Model, Nizama proposes integral human development through multidimensional organization as an axis of life that comprises eleven dimensions of human life: body, genetic potential, personality, human essence, cognition, imagination, lifestyles, assets, image, futurity and posterity. In conclusion, addictionology is the medical specialty indicated for the successful and hopeful management of this volitional disease in all age groups, with committed and sustainable family adherence.

Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.

The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs. Metformin bound to the active-site heme of CYP3A4 in a co-crystal structure, establishing CYP3A4 as a biguanide target. Structure-based design led to discovery of N1-hexyl-N5-benzyl-biguanide (HBB), which bound to the CYP3A4 heme with higher affinity than metformin. HBB potently and specifically inhibited CYP3A4 AA epoxygenase activity. HBB also inhibited growth of established ER+ mammary tumors and suppressed intratumoral mTOR. CYP3A4 AA epoxygenase inhibition by biguanides thus demonstrates convergence between eicosanoid activity in mitochondria and biguanide action in cancer, opening a new avenue for cancer drug discovery.

¿existen diferencias entre sexos en las redes atencionales? una revisión sistemática sobre el alerta fásica, vigilancia, orientación y control ejecutivo / Are there sex differences in attentional networks? a systematic review of the phasic alerting, vigilance, orienting and executive control

Resumen Las diferencias entre sexos suelen ser un aspecto crucial a ser tenido en cuenta en ciertos desarrollos en neurociencias cognitivas. En el estudio de las redes neuronales de la atención (alerta fásica, vigilancia, orientación, control atencional), aún no se observa un consenso establecido y esclarecedor sobre las diferencias existentes entre mujeres y hombres. Este trabajo presenta una revisión de las diferencias entre sexos encontradas en las investigaciones de las redes atencionales. Se pretende aportar una discusión que sirva como guía para considerar el sexo como variable de interés en futuros estudios en ciencias cognitivas.

Abstract Sex differences are often a crucial topic to be taken into account in certain developments in cognitive neuroscience. In the study of attention neural networks (phasic alerting, vigilance, orienting, executive control), there is not yet a consensus established and enlightening about the differences between men and women. This paper presents a review of sex differences found in investigations of attentional networks. We plan to bring a discussion to serve as a guide to regard sex as a variable of interest in future studies in cognitive neuroscience.

Frei José Mariano da Conceição Veloso e a divulgação de técnicas industriais no Brasil colonial: discussão de alguns conceitos das ciências químicas / Friar José Mariano da Conceição Veloso and the promotion of industrial techniques in colonial Brazil: discussion of some concepts from the chemical sciences

Na virada para o século XIX, o botânico mineiro frei Veloso desenvolveu intensa atividade de publicação de livros com intuito de divulgar aos colonos do império português técnicas para o melhoramento da produção agrícola e da incipiente indústria química. Este artigo aborda o primeiro tomo da Alographia dos alkalis fixos..., obra que contém artigos, capítulos de livros, cartas e patentes coligidos de uma dezena de autores, especialmente franceses e ingleses, sobre o conhecimento científico e técnico necessário para produção de carbonato de potássio a partir de cinza de plantas autóctones. Alguns conceitos e definições da época da Revolução Química são discutidos, levando em conta como Veloso os traduziu para o português e os introduziu no Brasil por meio de sua obra.

At the turn of the 19th century, Minas Gerais Botanist Friar Veloso worked intensely on the publication of books to promote among settlers from the Portuguese empire techniques for improving agricultural production and from the incipient chemistry industry. This article analyzes the first volume of the "Alographia dos alkalis fixos...", a work that includes articles, book chapters, letters and patents from ten authors, particularly French and English, about the scientific and technical knowledge needed for the production of potassium carbonate from the ash of native plants. Some concepts and definitions used at the time of the Chemical Revolution are discussed, considering that Veloso translated them to Portuguese and introduced them to Brazil through his work.