Gene dosage compensation: Origins, criteria to identify compensated genes, and mechanisms including sensor loops as an emerging systems-level property in cancer.

The gene dosage compensation hypothesis presents a mechanism through which the expression of certain genes is modulated to compensate for differences in the dose of genes when additional chromosomes are present. It is one of the means through which cancer cells actively cope with the potential damaging effects of aneuploidy, a hallmark of most cancers. Dosage compensation arises through several processes, including downregulation or overexpression of specific genes and the relocation of dosage-sensitive genes. In cancer, a majority of compensated genes are generally thought to be regulated at the translational or post-translational level, and include the basic components of a compensation loop, including sensors of gene dosage and modulators of gene expression. Post-translational regulation is mostly undertaken by a general degradation or aggregation of remaining protein subunits of macromolecular complexes. An increasingly important role has also been observed for transcriptional level regulation. This article reviews the process of targeted gene dosage compensation in cancer and other biological conditions, along with the mechanisms by which cells regulate specific genes to restore cellular homeostasis. These mechanisms represent potential targets for the inhibition of dosage compensation of specific genes in aneuploid cancers. This article critically examines the process of targeted gene dosage compensation in cancer and other biological contexts, alongside the criteria for identifying genes subject to dosage compensation and the intricate mechanisms by which cells orchestrate the regulation of specific genes to reinstate cellular homeostasis. Ultimately, our aim is to gain a comprehensive understanding of the intricate nature of a systems-level property. This property hinges upon the kinetic parameters of regulatory motifs, which we have termed "gene dosage sensor loops." These loops have the potential to operate at both the transcriptional and translational levels, thus emerging as promising candidates for the inhibition of dosage compensation in specific genes. Additionally, they represent novel and highly specific therapeutic targets in the context of aneuploid cancer.

Targeted Expression to Liver of an antimiR-33 Sponge as a Gene Therapy Strategy against Hypercholesterolemia: In Vitro Study.

Atherosclerosis is the leading cause of cardiovascular diseases in Mexico and worldwide. The membrane transporters ABCA1 and ABCG1 are involved in the reverse transport of cholesterol and stimulate the HDL synthesis in hepatocytes, therefore the deficiency of these transporters promotes the acceleration of atherosclerosis. MicroRNA-33 (miR-33) plays an important role in lipid metabolism and exerts a negative regulation on the transporters ABCA1 and ABCG1. It is known that by inhibiting the function of miR-33 with antisense RNA, HDL levels increase and atherogenic risk decreases. Therefore, in this work, a genetic construct, pPEPCK-antimiR-33-IRES2-EGFP, containing a specific antimiR-33 sponge with two binding sites for miR-33 governed under the PEPCK promoter was designed, constructed, and characterized, the identity of which was confirmed by enzymatic restriction, PCR, and sequencing. Hep G2 and Hek 293 FT cell lines, as well as a mouse hepatocyte primary cell culture were transfected with this plasmid construction showing expression specificity of the PEPCK promoter in hepatic cells. An analysis of the relative expression of miR-33 target messengers showed that the antimiR-33 sponge indirectly induces the expression of its target messengers (ABCA1 and ABCG1). This strategy could open new specific therapeutic options for hypercholesterolemia and atherosclerosis, by blocking the miR-33 specifically in hepatocytes.

Estimación de las propiedades psicométricas del instrumento de medición de adicción al sexo (MAS)

Introducción: El instrumento MAS, una prueba para evaluar adicción al sexo, ha presentado inconvenientes en el nivel factorial. Por esto, esta investigación buscó estimar las propiedades psicométricas de dicho instrumento, en población colombiana. Método: Inicialmente, se realizó un juicio de expertos para establecer la validez de contenido, a través de la V de Aiken; luego se aplicó el MAS y la escala de inhibición/excitación sexual (SIS/ SES) a 337 participantes, por medio de un formulario web (Google forms), de los cuales 312 cumplieron con los criterios de inclusión (221 mujeres y 91 hombres) con edades en el rango 18-65 años (x_ = 28.49, DE = 9.77). Mediante SPSS, se calculó el alfa de Cronbach, la correlación de Pearson y se hizo un análisis factorial con rotación Varimax. Resultados: Los análisis reflejaron una buena confiabilidad, una correlación ajustada a lo esperado, en relación con la prueba SIS/SES y el análisis factorial arrojó seis factores que presentan diferencias en comparación con la prueba planteada inicialmente. Conclusión: La prueba MAS presenta un adecuado nivel de confiabilidad, pero no cuenta con una validez de constructo adecuada.

Introduction: The MAS instrument, a test to assess sex addiction, has presented drawbacks at the factorial level. For this reason, this research sought to estimate the psychometric properties of the sex addiction measurement instrument (MAS) in Colombian population. Method: Initially, an expert judgment was carried out to establish the validity of content through Aiken's V, then the MAS and the sexual inhibition/arousal scale (SIS/SES) were applied to 337 participants through a form web (Google forms) of which 312 met the inclusion criteria (221 women and 91 men) aged between 18 and 65 years (x_ = 28.49, SD = 9.77). Using SPSS, Cronbach's alpha, Pearson's correlation, and a factorial analysis with Varimax rotation were calculated. Results: The analyzes showed a good reliability, a correlation adjusted to what was expected in relation to the SIS/SES test and the factorial analysis showed six factors that present differences in comparison with the initially proposed test. Conclusion: The sex addiction measurement test (MAS) has an adequate level of reliability, but does not have adequate construct validity.

MYC dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer.

We hypothesize that dosage compensation of critical genes arises from systems-level properties for cancer cells to withstand the negative effects of aneuploidy. We identified several candidate genes in cancer multiomics data and developed a biocomputational platform to construct a mathematical model of their interaction network with micro-RNAs and transcription factors, where the property of dosage compensation emerged for MYC and was dependent on the kinetic parameters of its feedback interactions with three micro-RNAs. These circuits were experimentally validated using a genetic tug-of-war technique to overexpress an exogenous MYC, leading to overexpression of the three microRNAs involved and downregulation of endogenous MYC. In addition, MYC overexpression or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity in MYC-amplified colon cancer cells. Finally, we identified negative correlation of MYC dosage compensation with patient survival in TCGA breast cancer patients, highlighting the potential of this mechanism to prevent aneuploid cancer progression.

Strategies for Targeting Gene Therapy in Cancer Cells With Tumor-Specific Promoters.

Cancer is the second cause of death worldwide, surpassed only by cardiovascular diseases, due to the lack of early diagnosis, and high relapse rate after conventional therapies. Chemotherapy inhibits the rapid growth of cancer cells, but it also affects normal cells with fast proliferation rate. Therefore, it is imperative to develop other safe and more effective treatment strategies, such as gene therapy, in order to significantly improve the survival rate and life expectancy of patients with cancer. The aim of gene therapy is to transfect a therapeutic gene into the host cells to express itself and cause a beneficial biological effect. However, the efficacy of the proposed strategies has been insufficient for delivering the full potential of gene therapy in the clinic. The type of delivery vehicle (viral or non viral) chosen depends on the desired specificity of the gene therapy. The first gene therapy trials were performed with therapeutic genes driven by viral promoters such as the CMV promoter, which induces non-specific toxicity in normal cells and tissues, in addition to cancer cells. The use of tumor-specific promoters over-expressed in the tumor, induces specific expression of therapeutic genes in a given tumor, increasing their localized activity. Several cancer- and/or tumor-specific promoters systems have been developed to target cancer cells. This review aims to provide up-to-date information concerning targeting gene therapy with cancer- and/or tumor-specific promoters including cancer suppressor genes, suicide genes, anti-tumor angiogenesis, gene silencing, and gene-editing technology, as well as the type of delivery vehicle employed. Gene therapy can be used to complement traditional therapies to provide more effective treatments.

Nivel académico y aplicación de parámetros de seguridad en programas de ejercicio físico en ancianos / Academic background and application of safety parameters in physical exercise programs for the elderly

Introducción: El conocimiento idóneo en ciencias del ejercicio físico de los instructores de los programas ejercicio físico comunitario es importante para garantizar la seguridad y calidad de los programas para adultos mayores. Objetivo: Analizar el nivel de formación de los instructores y la frecuencia de aplicación de dos parámetros de seguridad para la implementación de programas de ejercicio físico para el adulto mayor. Métodos: Estudio transversal, analítico, realizado con 115 instructores de grupos de adultos mayores de Bucaramanga, Colombia. Para la recolección de la información se utilizó un cuestionario ad hoc. Las variables se analizaron en medidas de tendencia central o frecuencias según su naturaleza. Se utilizó la prueba exacta de Fischer para explorar la asociación entre las variables de interés. El nivel de significancia fue de p ≤ 0,05. Resultados: El 18,22 por ciento de los instructores encuestados posee titulación en Ciencias del Ejercicio Físico. Se encontró una mayor frecuencia de aplicación de método de selección de aptitud para la realización de actividad física, con diferencias estadísticamente significativas, en los sujetos titulados (p = 0,032) y en aquellos que recibieron capacitación formal en ejercicio físico en el adulto mayor (p = 0,002). Los sujetos titulados exigieron con mayor frecuencia una valoración médica (p=0,036). Conclusiones: La mayoría de los instructores reportaron no aplicar los parámetros de seguridad para la implementación de un programa de ejercicio físico. Sin embargo, hubo una mayor frecuencia de aplicación en instructores titulados y en aquellos con capacitación formal en ejercicio físico para el adulto mayor(AU)

Introduction: Suitable knowledge about physical culture sciences by community exercise instructors is important to ensure the safety and quality of programs for the elderly. Objective: Analyze the academic background of instructors and the frequency of application of two safety parameters in the implementation of physical exercise programs for the elderly. Methods: An analytical cross-sectional study was conducted of 155 instructors of groups of elderly people in Bucaramanga, Colombia. An ad hoc questionnaire was used to collect the information. The variables were analyzed as measures of central tendency or frequencies, depending on their nature. Fisher's exact test was used to explore the association between the variables of interest. The significance level was p ≤ 0.05. Results: Of the instructors surveyed, 18.22 percent had a degree in Physical Exercise Sciences. A higher frequency was found of the application of the selection method based on aptitude to conduct physical activity, with statistically significant differences between graduated subjects (p = 0.032) and those who had received formal training in physical exercise for the elderly (p = 0.002). Medical assessment was more often requested by graduated subjects (p=0.036). Conclusions: Most instructors reported not to apply the safety parameters for implementation of a physical exercise program. However, application was more frequent by graduated instructors and those with formal training in physical exercise for the elderly(AU)

Bartonella quintana and Typhus Group Rickettsiae Exposure among Homeless Persons, Bogotá, Colombia.

In 2015, we investigated Bartonella quintana and typhus group rickettsiae in body lice from homeless persons in Bogotá, Colombia. We found B. quintana-infected body lice and seroprevalence of this microorganism in 19% of homeless persons and typhus group rickettsiae in 56%. Public health professionals should start preemptive measures and active vector control.