LncRNA SOX9-AS1 triggers a transcriptional program involved in lipid metabolic reprogramming, cell migration and invasion in triple-negative breast cancer.

At the molecular level, triple-negative breast cancer (TNBC) is frequently categorized as PAM50 basal-like subtype, but despite the advances in molecular analyses, the clinical outcome for these subtypes is uncertain. Long non-coding RNAs (lncRNAs) are master regulators of genes involved in hallmarks of cancer, which makes them suitable biomarkers for breast cancer (BRCA) diagnosis and prognosis. Here, we evaluated the regulatory role of lncRNA SOX9-AS1 in these subtypes. Using the BRCA-TCGA cohort, we observed that SOX9-AS1 was significantly overexpressed in basal-like and TNBC in comparison with other BRCA subtypes. Survival analyzes showed that SOX9-AS1 overexpression was associated with a favorable prognosis in TNBC and basal-like patients. To study the functions of SOX9-AS1, we determined the expression levels in a panel of nine BRCA cell lines finding increased levels in MDA-MB-468 and HCC1187 TNBC. Using subcellular fractionation in these cell lines, we ascertained that SOX9-AS1 was located in the cytoplasmic compartment. In addition, we performed SOX9-AS1 gene silencing using two short-harping constructs, which were transfected in both cell models and performed a genome-wide RNA-seq analysis. Data showed that 351 lncRNAs and 740 mRNAs were differentially expressed in MDA-MB-468 while 56 lncRNAs and 100 mRNAs were modulated in HCC1187 cells (Log2FC < - 1.5 and > 1.5, p.adj value < 0.05). Pathway analysis revealed that the protein-encoding genes potentially regulate lipid metabolic reprogramming, and epithelial-mesenchymal transition (EMT). Expression of lipid metabolic-related genes LIPE, REEP6, GABRE, FBP1, SCD1, UGT2B11, APOC1 was confirmed by RT-qPCR. Functional analysis demonstrated that the knockdown of SOX9-AS1 increases the triglyceride synthesis, cell migration and invasion in both two TNBC cell lines. In conclusion, high SOX9-AS1 expression predicts an improved clinical course in patients, while the loss of SOX9-AS1 expression enhances the aggressiveness of TNBC cells.

Differential Predictive Effect of Self-Regulation Behavior and the Combination of Self- vs. External Regulation Behavior on Executive Dysfunctions and Emotion Regulation Difficulties, in University Students.

The aim of this research was to establish linear relations (association and prediction) and inferential relations between three constructs at different levels of psychological research - executive dysfunction (microanalysis), self-regulation (molecular level), and self- vs. external regulation (molar level), in the prediction of emotion regulation difficulties. We hypothesized that personal and contextual regulatory factors would be negatively related to levels of executive dysfunction and emotion regulation difficulties; by way of complement, non-regulatory and dysregulatory personal, and contextual factors would be positively related to these same difficulties. To establish relationships, we used a retrospective, ex post facto design, where 298 university students voluntarily participated by completing standardized self-reports. Linear and structural correlational, predictive analyses were performed, as well as inferential analyses. Results were consistent and validated the proposed hypotheses, for both association and prediction. The most important result refers to the discriminant value of the five-level combination heuristic for predicting Executive Function and External (contextual) Dys-Regulation. In conclusion: (1) both personal and contextual regulation factors must be analyzed in order to better understand the variation in executive functions and emotion regulation difficulties; (2) it is important to continue connecting the different levels of the constructs referring to self-regulation, given their complementary role in the behavioral analysis of regulation difficulties.

Analysis of Psychosocial Adjustment in the Family During Confinement: Problems and Habits of Children and Youth and Parental Stress and Resilience.

The COVID-19 health crisis has led to a dramatic change in dynamics and habits of families, which may be a factor involved in the development and maintenance of problems and difficulties in children. The present study is a cross-sectional study that aims to describe and analyze the relationship between the difficulties in psychological adjustment and the change of habits of the infant-juvenile population as perceived by their parents and their stress and resilience during the total confinement of the first wave of the COVID-19 pandemic in Spain, as well as analyzing the course of the changes and the relationships between weeks 3 to 6, that is, the score of different participants in each week of the confinement. The sample is comprised of 883 parents of children and adolescents between 3 and 18 years of age. Children's psychological adjustment, children's habits, parental stress, and parental resilience were assessed by parents. The results show that parents perceive a change in the habits and psychological difficulties in their children. At the same time, our results describe parents with a high level of stress and resilience, with differences depending on the children's ages. The time of confinement accentuates the perception of parents about the psychological difficulties of their children and parental stress, as well as a decrease in resilience. These difficulties are reduced when the parent has resilience competencies. These results show that the resilience of parents mediate the relationship between parental stress and psychological problems of their children. These results shows that COVID-19 lockdown had a considerable effect on families, both on children and parents. Some practical implications based on results are provided.

Antivaccine Movement and COVID-19 Negationism: A Content Analysis of Spanish-Written Messages on Twitter.

During the COVID-19 pandemic, different conspiracies have risen, with the most dangerous being those focusing on vaccines. Today, there exists a social media movement focused on destroying the credibility of vaccines and trying to convince people to ignore the advice of governments and health organizations on vaccination. Our aim was to analyze a COVID-19 antivaccination message campaign on Twitter that uses Spanish as the main language, to find the key elements in their communication strategy. Twitter data were retrieved from 14 to 28 December using NodeXL software. We analyzed tweets in Spanish, focusing on influential users, most influential tweets, and content analysis of tweets. The results revealed ordinary citizens who 'offer the truth' as the most important profile in this network. The content analysis showed antivaccine tweets (31.05%) as the most frequent. The analysis of anti-COVID19 tweets showed that attacks against vaccine safety were the most important (79.87%) but we detected a new kind of message presenting the vaccine as a means of manipulating the human genetic code (8.1%). We concluded that the antivaccine movement and its tenets have great influence in the COVID-19 negationist movement. We observed a new topic in COVID-19 vaccine hoaxes that must be considered in our fight against misinformation.

[COVID-19 and vaccination: analysis of public institution's role in information spread through Twitter.] / COVID-19 y vacunación: Análisis del papel de las instituciones públicas en la difusión de información a través de Twitter.

OBJECTIVE: The COVID-19 pandemic has been a time where social media allows increased conversations about it. These conversations have spread various conspiracies about vaccines against COVID-19. It is, therefore, necessary to develop communication strategies, led by official accounts, that offer accessible information on vaccination as a preventive public health strategy. The aim of this study was to analyze the role of public institutions on Twitter campaign #yomevacuno to deal with misinformation about vaccination against COVID-19. METHODS: This paper performs a social network analysis and content analysis of Twitter data, using NodeXL software, from December 8th to 23rd, 2020. Tweets included content #yomevacuno hashtag. RESULTS: A total of 6,080 interactions were collected, 82% were tweets. Data shows that public institutions generate 53.36% of traffic information, the most important was the Ministerio de Sanidad from Spain. Content analysis revealed that 48% of a sample of 50 Tweets the message was focused on vaccination as a social responsibility to defeat COVID-19 pandemic. CONCLUSIONS: The communication strategy of #yomevacuno hashtag, has been led by the Ministerio de Sanidad of Spain, by comparison to other campaigns in which there was no large presence of public institutions. This case represents the importance of social media as a way to spread information and prevention, even in public health and the need for them to be led by public organizations rather than by individual users.

OBJETIVO: Durante la pandemia de COVID-19, las redes sociales han servido de medio para difundir mensajes a favor y en contra de las vacunas. Es por tanto necesario desarrollar estrategias de comunicación, lideradas por organismos oficiales, que ofrezcan información accesible sobre la vacunación como medida preventiva de Salud Pública. El objetivo de este estudio fue analizar el papel en Twitter de las instituciones públicas en la campaña de concienciación sobre la vacunación frente a la COVID-19. METODOS: Se desarrolló un análisis de los mensajes enviados a través de Twitter que contuvieran el hashtag #yomevacuno, entre los días 8 y 23 de diciembre de 2020, utilizando el software NodeXL. Se analizó tanto el flujo de información como los usuarios más influyentes en la red #yomevacuno, así como el contenido de los tuits. RESULTADOS: Se recopilaron 6.080 interacciones, donde el 8,2% fueron contenidos originales (tuits). Se observó que las instituciones oficiales generaron el 53,36% del tráfico total, siendo la más activa el Ministerio de Sanidad. El análisis de contenidos mostró que el mensaje principal fue el de la apelación a la vacunación frente a la COVID-19 como responsabilidad social (48%). CONCLUSIONES: En este estudio se observa la estrategia de comunicación del hashtag #yomevacuno a favor de la campaña de vacunación frente a la COVID-19. Esta campaña muestra como, en contraposición a otras campañas de fomento de estrategias de prevención de Salud Pública, una institución pública (el Ministerio de Sanidad) lidera el flujo de información ofrecida a los usuarios de la red social Twitter. Este caso representa la importancia de las redes sociales como medio de información y prevención en Salud Pública y la necesidad de que sean lideradas por organizaciones públicas más que por usuarios individuales.

LINC00460 Is a Dual Biomarker That Acts as a Predictor for Increased Prognosis in Basal-Like Breast Cancer and Potentially Regulates Immunogenic and Differentiation-Related Genes.

Breast cancer (BRCA) is a serious public health problem, as it is the most frequent malignant tumor in women worldwide. BRCA is a molecularly heterogeneous disease, particularly at gene expression (mRNAs) level. Recent evidence shows that coding RNAs represent only 34% of the total transcriptome in a human cell. The rest of the 66% of RNAs are non-coding, so we might be missing relevant biological, clinical or regulatory information. In this report, we identified two novel tumor types from TCGA with LINC00460 deregulation. We used survival analysis to demonstrate that LINC00460 expression is a marker for poor overall (OS), relapse-free (RFS) and distant metastasis-free survival (DMFS) in basal-like BRCA patients. LINC00460 expression is a potential marker for aggressive phenotypes in distinct tumors, including HPV-negative HNSC, stage IV KIRC, locally advanced lung cancer and basal-like BRCA. We show that the LINC00460 prognostic expression effect is tissue-specific, since its upregulation can predict poor OS in some tumors, but also predicts an improved clinical course in BRCA patients. We found that the LINC00460 expression is significantly enriched in the Basal-like 2 (BL2) TNBC subtype and potentially regulates the WNT differentiation pathway. LINC00460 can also modulate a plethora of immunogenic related genes in BRCA, such as SFRP5, FOSL1, IFNK, CSF2, DUSP7 and IL1A and interacts with miR-103-a-1, in-silico, which, in turn, can no longer target WNT7A. Finally, LINC00460:WNT7A ratio constitutes a composite marker for decreased OS and DMFS in Basal-like BRCA, and can predict anthracycline therapy response in ER-BRCA patients. This evidence confirms that LINC00460 is a master regulator in BRCA molecular circuits and influences clinical outcome.

FAM83H-AS1 is a potential modulator of cancer driver genes across different tumors and a prognostic marker for ER/PR + BRCA patients.

Breast cancer (BRCA) is a serious public health problem, as it is the most frequent malignant tumor in women worldwide. BRCA is a molecularly heterogenic disease, particularly at gene expression (mRNAs) level. Recent evidence shows that coding RNAs represent only 34% of the total transcriptome in a human cell. The rest of the 66% of RNAs are non-coding, so we might be missing relevant biological, clinical or regulatory information. In this report, we identified nine novel tumor types from TCGA with FAM83H-AS1 deregulation. We used survival analysis to demonstrate that FAM83H-AS1 expression is a marker for poor survival in IHC-detected ER and PR positive BRCA patients and found a significant correlation between FAM83H-AS1 overexpression and tamoxifen resistance. Estrogen and Progesterone receptor expression levels interact with FAM83H-AS1 to potentiate its effect in OS prediction. FAM83H-AS1 silencing impairs two important breast cancer related pathways: cell migration and cell death. Among the most relevant potential FAM83H-AS1 gene targets, we found p63 and claudin 1 (CLDN1) to be deregulated after FAM83H-AS1 knockdown. Using correlation analysis, we show that FAM83H-AS1 can regulate a plethora of cancer-related genes across multiple tumor types, including BRCA. This evidence suggests that FAM83H-AS1 is a master regulator in different cancer types, and BRCA in particular.

A lncRNA landscape in breast cancer reveals a potential role for AC009283.1 in proliferation and apoptosis in HER2-enriched subtype.

Breast cancer is the most commonly diagnosed neoplasm in women worldwide with a well-recognized heterogeneous pathology, classified into four molecular subtypes: Luminal A, Luminal B, HER2-enriched and Basal-like, each one with different biological and clinical characteristics. Long non-coding RNAs (lncRNAs) represent 33% of the human transcriptome and play critical roles in breast carcinogenesis, but most of their functions are still unknown. Therefore, cancer research could benefit from continued exploration into the biology of lncRNAs in this neoplasm. We characterized lncRNA expression portraits in 74 breast tumors belonging to the four molecular subtypes using transcriptome microarrays. To infer the biological role of the deregulated lncRNAs in the molecular subtypes, we performed co-expression analysis of lncRNA-mRNA and gene ontology analysis. We identified 307 deregulated lncRNAs in tumor compared to normal tissue and 354 deregulated lncRNAs among the different molecular subtypes. Through co-expression analysis between lncRNAs and protein-coding genes, along with gene enrichment analysis, we inferred the potential function of the most deregulated lncRNAs in each molecular subtype, and independently validated our results taking advantage of TCGA data. Overexpression of the AC009283.1 was observed in the HER2-enriched subtype and it is localized in an amplification zone at chromosome 17q12, suggesting it to be a potential tumorigenic lncRNA. The functional role of lncRNA AC009283.1 was examined through loss of function assays in vitro and determining its impact on global gene expression. These studies revealed that AC009283.1 regulates genes involved in proliferation, cell cycle and apoptosis in a HER2 cellular model. We further confirmed these findings through ssGSEA and CEMITool analysis in an independent HER2-amplified breast cancer cohort. Our findings suggest a wide range of biological functions for lncRNAs in each breast cancer molecular subtype and provide a basis for their biological and functional study, as was conducted for AC009283.1, showing it to be a potential regulator of proliferation and apoptosis in the HER2-enriched subtype.

Expression of long non-coding RNA ENSG00000226738 (LncKLHDC7B) is enriched in the immunomodulatory triple-negative breast cancer subtype and its alteration promotes cell migration, invasion, and resistance to cell death.

Triple negative breast cancer (TNBC) represents an aggressive phenotype with poor prognosis compared with ER, PR, and HER2-positive tumors. TNBC is a heterogeneous disease, and gene expression analysis has identified seven molecular subtypes. Accumulating evidence demonstrates that long non-coding RNA (lncRNA) are involved in regulation of gene expression and cancer biology, contributing to essential cancer cell functions. In this study, we analyzed the expression profile of lncRNA in TNBC subtypes from 156 TNBC samples, and then characterized the functional role of LncKLHDC7B (ENSG00000226738). A total of 710 lncRNA were found to be differentially expressed between TNBC subtypes, and a subset of these altered lncRNA were independently validated. We discovered that LncKLHDC7B (ENSG00000226738) acts as a transcriptional modulator of its neighboring coding gene KLHDC7B in the immunomodulatory subtype. Furthermore, LncKLHDC7B knockdown enhanced migration and invasion, and promoted resistance to cellular death. Our findings confirmed the contribution of LncKLHDC7B to induction of apoptosis and inhibition of cell migration and invasion, suggesting that TNBC tumors with enrichment of LncKLHDC7B may exhibit distinct regulatory activity, or that this may be a generalized process in breast cancer. Additionally, in silico analysis confirmed for the first time that the low expression of KLHDC7B and LncKLHDC7B is associated with poor prognosis in patients with breast cancer.

University students' food consumption assessment and the relation with their academic profile / Evaluación del consumo de alimentos de una población de estudiantes universitarios y su relación con el perfil académico

Objective: The purpose of this research is to assess the quality of the diet taken by the students of Universidad Alfonso X El Sabio (Madrid) and to learn whether having a specific knowledge about nutrition produce positive effects in food behavior. Methods: 390 students were tested, 72.63% of them studied degrees in relation to health sciences whereas the remaining 27.37% did not. The students were between 18 and 25 years old. The information was gathered through a questionnaire. This information dealt with frequency of food consumption as well as weight and height in order to get the body mass index. Results: The breakdown of the population according to their body mass index was the following: 75.54% normal weight, 11.06% low weight, 13.4% obesity. These figures are considered normal and they are similar to other groups of students. Both groups (health science students and the others) showed a lower cereal, vegetable and fruit consumption in comparison with the recommended percentage; whereas the consumption of pulses was higher than the average in Spain and the average from other groups, almost reaching the recommendable minimum. In addition, both groups showed a high consumption of dairies. No striking differences have been found between both groups. When comparing both of them in relation to gender, women showed better food behavior since they ate more fruit, vegetables and white fish. Conclusion: No differences have been found between the group studying health sciences and the students studying other kind of degree. The obtained results show that the food consumption of the population is far from the stipulated recommendations; therefore, it would be necessary to design a new action plan regarding nutrition.

Objetivo: el propósito de este estudio ha sido evaluar la calidad de la alimentación de los estudiantes de la Universidad Alfonso X El Sabio (Madrid) y establecer si tener una formación específica sobre temas de nutrición produce efectos positivos en los comportamientos alimentarios. Métodos: la muestra estuvo formada por 390 estudiantes, 72,63% de Ciencias de la Salud (CS) y 27,37% de otras carreras (No CS), con edades comprendidas entre 18 y 25 años. A través de un cuestionario se recabó información sobre frecuencia de consumo de alimentos. También se obtuvieron datos sobre el peso y la talla para calcular el índice de masa corporal (IMC). Resultados: la distribución de la población según el IMC fue la siguiente: 75,54% normopeso, 11,06% bajo peso, 13,4% obesidad; valores dentro de la normalidad y similares a los de otros grupos de estudiantes. Los dos grupos presentaron un consumo inferior al recomendado de cereales, verduras, hortalizas y fruta; a su vez, el consumo de legumbres fue superior a la media española y a la de otros jóvenes, llegando casi al mínimo recomendado. También se dio, en ambos grupos, un elevado consumo de lácteos. No se ha encontrado diferencias significativas entre titulaciones. Al comparar los datos para la variable sexo, el grupo de mujeres presentó un patrón de consumo más adecuado, con una mayor ingesta de fruta, verdura y pescado blanco. Conclusión: no se han visto diferencias en el comportamiento alimentario entre los dos grupos analizados (CS y No CS). Los resultados obtenidos indican que el consumo de alimentos de esta población se aleja de las recomendaciones establecidas, por lo que convendría diseñar un plan de actuación en materia nutricional.

Evaluación del consumo de alimentos de una población de estudiantes universitarios y su relación con el perfil académico / University students’ food consumption assessment and the relation with their academic profile

Objetivo: el propósito de este estudio ha sido evaluar la calidad de la alimentación de los estudiantes de la Universidad Alfonso X El Sabio (Madrid) y establecer si tener una formación específica sobre temas de nutrición produce efectos positivos en los comportamientos alimentarios. Métodos: la muestra estuvo formada por 390 estudiantes, 72,63% de Ciencias de la Salud (CS) y 27,37% de otras carreras (No CS), con edades comprendidas entre 18 y 25 años. A través de un cuestionario se recabó información sobre frecuencia de consumo de alimentos. También se obtuvieron datos sobre el peso y la talla para calcular el índice de masa corporal (IMC). Resultados: la distribución de la población según el IMC fue la siguiente: 75,54% normopeso, 11,06% bajo peso, 13,4% obesidad; valores dentro de la normalidad y similares a los de otros grupos de estudiantes. Los dos grupos presentaron un consumo inferior al recomendado de cereales, verduras, hortalizas y fruta; a su vez, el consumo de legumbres fue superior a la media española y a la de otros jóvenes, llegando casi al mínimo recomendado. También se dio, en ambos grupos, un elevado consumo de lácteos. No se ha encontrado diferencias significativas entre titulaciones. Al comparar los datos para la variable sexo, el grupo de mujeres presentó un patrón de consumo más adecuado, con una mayor ingesta de fruta, verdura y pescado blanco. Conclusión: no se han visto diferencias en el comportamiento alimentario entre los dos grupos analizados (CS y No CS). Los resultados obtenidos indican que el consumo de alimentos de esta población se aleja de las recomendaciones establecidas, por lo que convendría diseñar un plan de actuación en materia nutricional (AU)

Objective: The purpose of this research is to assess the quality of the diet taken by the students of Universidad Alfonso X El Sabio (Madrid) and to learn whether having a specific knowledge about nutrition produce positive effects in food behavior. Methods: 390 students were tested, 72.63% of them studied degrees in relation to health sciences whereas the remaining 27.37% did not. The students were between 18 and 25 years old. The information was gathered through a questionnaire. This information dealt with frequency of food consumption as well as weight and height in order to get the body mass index. Results: The breakdown of the population according to their body mass index was the following: 75.54% normal weight, 11.06% low weight, 13.4% obesity. These figures are considered normal and they are similar to other groups of students. Both groups (health science students and the others) showed a lower cereal, vegetable and fruit consumption in comparison with the recommended percentage; whereas the consumption of pulses was higher than the average in Spain and the average from other groups, almost reaching the recommendable minimum. In addition, both groups showed a high consumption of dairies. No striking differences have been found between both groups. When comparing both of them in relation to gender, women showed better food behavior since they ate more fruit, vegetables and white fish. Conclusion: No differences have been found between the group studying health sciences and the students studying other kind of degree. The obtained results show that the food consumption of the population is far from the stipulated recommendations; therefore, it would be necessary to design a new action plan regarding nutrition (AU)

GHEP-ISFG collaborative simulated exercise for DVI/MPI: Lessons learned about large-scale profile database comparisons.

The GHEP-ISFG Working Group has recognized the importance of assisting DNA laboratories to gain expertise in handling DVI or missing persons identification (MPI) projects which involve the need for large-scale genetic profile comparisons. Eleven laboratories participated in a DNA matching exercise to identify victims from a hypothetical conflict with 193 missing persons. The post mortem database was comprised of 87 skeletal remain profiles from a secondary mass grave displaying a minimal number of 58 individuals with evidence of commingling. The reference database was represented by 286 family reference profiles with diverse pedigrees. The goal of the exercise was to correctly discover re-associations and family matches. The results of direct matching for commingled remains re-associations were correct and fully concordant among all laboratories. However, the kinship analysis for missing persons identifications showed variable results among the participants. There was a group of laboratories with correct, concordant results but nearly half of the others showed discrepant results exhibiting likelihood ratio differences of several degrees of magnitude in some cases. Three main errors were detected: (a) some laboratories did not use the complete reference family genetic data to report the match with the remains, (b) the identity and/or non-identity hypotheses were sometimes wrongly expressed in the likelihood ratio calculations, and (c) many laboratories did not properly evaluate the prior odds for the event. The results suggest that large-scale profile comparisons for DVI or MPI is a challenge for forensic genetics laboratories and the statistical treatment of DNA matching and the Bayesian framework should be better standardized among laboratories.

[Epigenetic alterations in cervical cancer progression]. / Alteraciones epigenéticas en la progresión del cáncer cervicouterino.

Despite the use of the screening test, such as Papanicolaou, and the detection of human papillomavirus (HPV), cervical cancer remains as a public health problem in México and it is the second leading cause of death for malignant neoplasias among women. High-risk HPV infection is the main risk factor for the development of premalignant lesions and cervical cancer; however, HPV infection is not the only factor; there are various genetic and epigenetic alterations required for the development of neoplasias; some of them have been described and even in some cases they have been suggested as biomarkers for prognosis. However, in contrast with other cancer types, such as breast cancer, in cervical cancer the use of biomarkers has not been established for clinical applications. Unlike genetic alterations, epigenetic alterations are potentially reversible; in this sense, their characterization is important, since they have not only a potential use as biomarkers, but they also could represent new therapeutic targets for treatment of cervical cancer. This review describes some of the more common epigenetic alterations in cervical cancer and its potential use in routine clinical practice.

A pesar del empleo de los métodos de tamizaje como el Papanicolaou y la detección de virus del papiloma humano (VPH), el cáncer cervicouterino (CaCU) sigue siendo un problema de salud pública en México, ya que es la segunda causa de muerte por neoplasias malignas en mujeres. La infección por VPH de alto potencial oncogénico es el principal factor de riesgo para el desarrollo de lesiones precursoras y CaCU; sin embargo, no es suficiente, dado que se requiere de diversas alteraciones genéticas y epigenéticas para el desarrollo de la neoplasia y un gran número de ellas han sido descritas, incluso en algunos casos se ha sugerido su uso como biomarcadores en la progresión o predictivos de respuesta. A diferencia de lo que sucede con otros tipos de cáncer, como el de mama, en el CaCU no se ha establecido el uso de marcadores para su aplicación en la clínica. A diferencia de las alteraciones genéticas, las alteraciones epigenéticas son potencialmente reversibles y su caracterización no solo tiene potencial para el uso como biomarcadores, sino como blancos de nuevas terapias. En esta revisión se describen algunas de las alteraciones epigenéticas más características en el CaCU, con potencial uso para la clínica.

Ancestry informative markers: inference of ancestry in aged bone samples using an autosomal AIM-Indel multiplex.

Ancestry informative markers (AIMs) can be useful to infer ancestry proportions of the donors of forensic evidence. The probability of success typing degraded samples, such as human skeletal remains, is strongly influenced by the DNA fragment lengths that can be amplified and the presence of PCR inhibitors. Several AIM panels are available amongst the many forensic marker sets developed for genotyping degraded DNA. Using a 46 AIM Insertion Deletion (Indel) multiplex, we analyzed human skeletal remains of post mortem time ranging from 35 to 60 years from four different continents (Sub-Saharan Africa, South and Central America, East Asia and Europe) to ascertain the genetic ancestry components. Samples belonging to non-admixed individuals could be assigned to their corresponding continental group. For the remaining samples with admixed ancestry, it was possible to estimate the proportion of co-ancestry components from the four reference population groups. The 46 AIM Indel set was informative enough to efficiently estimate the proportion of ancestry even in samples yielding partial profiles, a frequent occurrence when analyzing inhibited and/or degraded DNA extracts.

Peptidoglycan from Staphylococcus aureus has an anti-apoptotic effect in HaCaT keratinocytes mediated by the production of the cellular inhibitor of apoptosis protein-2.

Colonization of epithelium by microorganisms leads to inflammatory responses. In some cases an anti-apoptotic response involving the cellular inhibitor of apoptosis protein-2 (cIAP-2) also occurs. Although strong expression of cIAP-2 has been observed in lesional skin from psoriatic patients and in HaCaT keratinocytes treated with peptidoglycan (PGN) from Staphylococcus aureus, anti-apoptotic responses induced in the skin by cIAP-2 have seldom been studied. In this study, the effect of PGN on TNF-α-induced apoptotic HaCaT keratinocytes was assessed. Morphological analysis, quantification of cells with DNA fragmentation and active caspase-3 detection was performed to assess apoptotic cell death. Greater LL-37 and cIAP-2 production was found in keratinocytes stimulated with PGN than in non-treated cells (P < 0.05). In comparison with cells treated with TNF-α only, a significant reduction in apoptotic cell death was observed when HaCaT were pretreated with PGN before inducing apoptosis with TNF-α (P < 0.05). In addition, an inhibitor of cIAP-2 activity (LCL161) stopped the PGN effect. These findings show that PGN from S. aureus has an anti-apoptotic effect in keratinocytes mediated by cIAP-2 production, suggesting that this anti-apoptotic activity could favor proliferation of keratinocytes in psoriasis.

Characterization of the reproductive effects of the Vgf-derived peptide TLQP-21 in female rats: in vivo and in vitro studies.

BACKGROUND: VGF (non-acronymic), a protein expressed in the hypothalamus and pituitary, is involved in the control of metabolism and body weight homeostasis. Different active peptide fragments are generated from VGF, including TLQP-21. Previous studies of our group reported that this molecule participates also in the regulation of reproductive function in male rats, with predominant stimulatory effects. METHODS: We report herein a series of studies on the reproductive effects of TLQP-21 in female rats, as evaluated by a combination of in vivo and in vitro analyses. RESULTS: TLQP-21 modestly increased serum LH levels after systemic administration and directly stimulated pituitary LH and FSH secretion in prepubertal female rats, while acute central injection of TLQP-21 was unable to modify LH secretion at this age. Repeated central administration of TLQP-21 during the pubertal transition (between PND-28 and -35) to female rats fed ad libitum advanced the timing of vaginal opening and increased the percentage of animals with signs of ovulation. Moreover, an analogous treatment slightly enhanced ovarian maturation in pubertal female rats subjected to chronic undernutrition, but was unable to rescue the delay of vaginal opening induced by food deprivation. In addition, TLQP-21 oppositely modified LH secretion in adult female rats depending on the stage of the ovarian cycle: it stimulated LH secretion when injected in the morning of diestrus and decreased the magnitude of the preovulatory LH (but not FSH) surge when injected in the afternoon of proestrus. CONCLUSIONS: Our data are the first to document the potential involvement of TLQP-21 in the control of reproductive function in female rats.

Early metabolic programming of puberty onset: impact of changes in postnatal feeding and rearing conditions on the timing of puberty and development of the hypothalamic kisspeptin system.

Kiss1 neurons have recently emerged as a putative conduit for the metabolic gating of reproduction, with leptin being a regulator of hypothalamic Kiss1 expression. Early perturbations of the nutritional status are known to predispose to different metabolic disorders later in life and to alter the timing of puberty; however, the potential underlying mechanisms remain poorly defined. Here we report how changes in the pattern of postnatal feeding affect the onset of puberty and evaluate key hormonal and neuropeptide [Kiss1/kisspeptin (Kp)] alterations linked to these early nutritional manipulations. Female rats were raised in litters of different sizes: small (four pups per dam: overfeeding), normal (12 pups per dam), and large litters (20 pups per litter: underfeeding). Postnatal overfeeding resulted in persistently increased body weight and earlier age of vaginal opening, as an external sign of puberty, together with higher levels of leptin and hypothalamic Kiss1 mRNA. Conversely, postnatal underfeeding caused a persistent reduction in body weight, lower ovarian and uterus weights, and delayed vaginal opening, changes that were paralleled by a decrease in leptin and Kiss1 mRNA levels. Kisspeptin-52 immunoreactivity (Kp-IR) in the hypothalamus displayed similar patterns, with lower numbers of Kp-IR neurons in the arcuate nucleus of postnatally underfed animals, and a trend for increased Kp-positive fibers in the periventricular area of early overfed rats. Yet, gonadotropin responses to Kp at puberty were similar in all groups, except for enhanced responsiveness to low doses of Kp-10 in postnatally underfed rats. In conclusion, our data document that the timing of puberty is sensitive to both overfeeding and subnutrition during early (postnatal) periods and suggest that alterations in hypothalamic expression of Kiss1/kisspeptin may underlie at least part of such programming phenomenon.

Characterization of the reproductive effects of the anorexigenic VGF-derived peptide TLQP-21: in vivo and in vitro studies in male rats.

VGF (nonacronymic) is a 68-kDa protein encoded by the homonymous gene, which is expressed abundantly at the hypothalamus and has been involved in the control of metabolism and body weight homeostasis. Different active peptide fragments are generated from VGF, including TLQP-21. Circumstantial evidence has suggested that VGF might also participate in the control of reproduction. Yet its mechanisms of action and the eventual role of specific VGF-derived peptides on the hypothalamic-pituitary-gonadal (HPG) axis remain unknown. Herein we report a series of studies on the reproductive effects of TLQP-21 as evaluated in male rats by a combination of in vivo and in vitro analyses. Central administration of TLQP-21 induced acute gonadotropin responses in pubertal and adult male rats, likely via stimulation of GnRH secretion, as documented by static incubations of hypothalamic tissue. In addition, in pubertal (but not adult) males, TLQP-21 stimulated LH secretion directly at the pituitary level. Repeated central administration of TLQP-21 to pubertal males subjected to chronic undernutrition was able to ameliorate the hypogonadotropic state induced by food deprivation. In contrast, chronic administration of TLQP-21 to fed males at puberty resulted in partial desensitization and puberty delay. Finally, in adult (but not pubertal) males, TLQP-21 enhanced hCG-stimulated testosterone secretion by testicular tissue in vitro. In summary, our data are the first to document a complex and multifaceted mode of action of TLQP-21 at different levels of the male HPG axis with predominant stimulatory effects, thus providing a tenable basis for the (direct) reproductive role of this VGF-derived peptide.

The anorexigenic neuropeptide, nesfatin-1, is indispensable for normal puberty onset in the female rat.

The hypothalamic peptide, nesfatin-1, derived from the precursor NEFA/nucleobindin 2 (NUCB2), was recently identified as anorexigenic signal, acting in a leptin-independent manner. Yet its participation in the regulation of other biological functions gated by body energy status remains unexplored. We show herein that NUCB2/nesfatin-1 is involved in the control of female puberty. NUCB2/nesfatin mRNA and protein were detected at the hypothalamus of pubertal female rats, with prominent signals at lateral hypothalamus (LHA), paraventricular (PVN), and supraoptic (SON) nuclei. Hypothalamic NUCB2 expression raised along pubertal transition, with detectable elevations of its mRNA levels at LHA, PVN, and SON, and threefold increase of its total protein content between late-infantile and peripubertal periods. Conditions of negative energy balance, such as 48 h fasting or sustained subnutrition, decreased hypothalamic NUCB2 mRNA and/or protein levels in pubertal females. At this age, central administration of nesfatin-1 induced modest but significant elevations of circulating gonadotropins, whose magnitude was notably augmented in conditions of food deprivation. Continuous intracerebroventricular infusion of antisense morpholino oligonucleotides (as-MONs) against NUCB2 along pubertal maturation, which markedly reduced hypothalamic NUCB2 protein content, delayed vaginal opening and decreased ovarian weights and serum luteinizing hormone (LH) levels. In contrast, in adult female rats, intracerebroventricular injection of nesfatin did not stimulate LH or follicle-stimulating hormone secretion; neither did central as-MON infusion alter preovulatory gonadotropin surges, despite suppression of hypothalamic NUCB2. In sum, our data are the first to disclose the indispensable role of NUCB2/nesfatin-1 in the central networks driving puberty onset, a function that may contribute to its functional coupling to energy homeostasis.