A

Abstract:  Non-Alcoholic Fatty Liver Disease (NAFLD) is considered a clinical manifestation of Metabolic Syndrome (MS). The hepatic lipid overload generates an excesive production of reactive oxygen species inducing oxidative stress (OS), there are still no standardized studies on effective treatments or consensus on the appropriate drug for each patient. Assess in MS the pharmacological response of atorvastatin and metformin on levels of inflammatory and OS biomarkers and possible liver modifications. 40 Male Wistar rats were used (8 per group): (A)Control, (B)MS, C) MS+Atorvastatin, D) MS+Metformin, E) MS+Atorvastatin+Metformin. MS was induced by 10% fructose for 6 week. The inflammatory and OS state were verify by Fibrinogen (mg/dL), Nitric oxide (NO)(µM) and superoxide dismutase (SOD)(U/mL) by means of spectrophotometry. The liver tissue was analyzed by optical microscopy(OM). ANOVA and hotelling as a post hoc test, p significance level<0.05. Fibrinogen concentration increased in (B)(288.83±6.8) with respect to (A)(203.33±6.8)(p<0.001), and in groups (C)(196±7.45), (D)(242±7.45) and (E)(104,33±6,8) showed significant regression of hyperfibrinogenemia (p<0.001). Levels of NO significantly decreased in (B)(14.76±1.86) compared to (A)(27.09±1.95)(p<0.001) and normalized their levels in the groups (C)(25.48±2.06), (D)(22.2±2,33) and (E)(31.25±2,18)(p<0,001). SOD activity in (B)(178.64±10.23) increased significantly contrasted with (A)(134.5±10.73)(p<0.001), (D)(195.71±12,82) and (E)(222,17±15.17)(p<0.001), however in group (C)(145.71±12.82) there was a significant decreased from (B)(p<0.001). In the hepatic OM (B), centrilobular and sinusoidal congestion with the presence of binucleated hepatocytes and vacuolization phenomena was evidenced. Our results indicated a pro-oxidative and inflammatory state with hepatic repercussion in (B). Atorvastatin normalizing biomarkers and retrograde the liver injury. Metformin achieves the reversal of inflammation and OS with restoration of liver tissue by showing the absence of cellular and inflammatory lesions. The pharmacological combination demonstrated superior efficacy than monotherapy, each drug acting on its biological targets, achieving greater effectiveness in normalizing biochemical variables and in regression of histological lesions. The current evidence on MS shows that in the face of a complex etiopathogenic mechanism, therapeutic approaches with multiple objectives are necessary such as the implementation of these drugs instead of waiting for an ideal drug that includes all the altered molecular pathways.Resumen:  Enfermedad del hígado graso asociada a disfunción metabólica(MAFLD, siglas inglés),es considerada una manifestación clínica del Síndrome Metabólico(SM). La sobrecarga hepática de lípidos genera producción excesiva de especies reactivas de oxígeno induciendo Estrés Oxidativo(EO), aún no hay estudios estandarizados sobre tratamientos efectivos ni consenso sobre el fármaco adecuado para cada paciente. Valorar en SM la respuesta farmacológica de atorvastatina y metformina sobre niveles de biomarcadores inflamatorios, de EO y las posibles modificaciones hepáticas. Utilizamos 40 ratas machos Wistar (n=8 por grupo): A)Control, B)SM, C)SM+Atorvastatina, D)SM+Metformina y E)SM+Atorvastatina+Metformina. SM inducido mediante fructuosa al 10% diluida en agua durante 6 semanas. Atorvastatina 0,035mg/día/rata y 1,78mg/día/rata de metformina durante 45 días. El estado inflamatorio y EO se constató por Fibrinógeno (mg/dL), óxido nítrico (NO)(µM) y superóxido dismutasa(SOD)(U/mL) por espectrofotometría. Se analizó histología hepática por microscopía óptica(MO). ANOVA y Hotelling como test post-hoc, significación p<0.05. Fibrinógeno aumentó en (B)(288,83±6,8) respecto a (A)(203,33±6,8)(p<0,001), los grupos (C)(196±7,45), (D)(242±7,45) y (E)(104,33±6,8) evidenciaron una regresión significativa de hiperfibrinogenemia(p<0,001). Los niveles de NO disminuyeron en (B)(14,76±1,86) comparado con (A)(27,09±1,95)(p<0,001), su concentración se normalizó en los grupos (C)(25,48±2,06), (D)(22,2±2,33) y (E)(31,25±2,18)(p<0,001). SOD aumentó en (B)(178,64±10,23), (D)(195,71±12,82) y  (E)(222,17±15,17)(p<0,001) contrastado con (A)(134,5±10,73)(p<0,001), sin embargo en (C)(145,71±12,82) evidenció disminución significativa respecto a (B)(p<0,001). MO hepática en (B) evidencio congestión centrolobulillar y leve congestión sinusoidales con presencia de hepatocitos binucleados y fenómenos de vacuolización. Los grupos (C), (D) y (E) demostraron regresión de las lesiones descriptas en (B).  Nuestros resultados indicaron un estado prooxidativo e inflamatorio con repercusión hepática en (B).Atorvastatina normalizando los biomarcadores analizados y retrogradando las lesiones hepáticas. Metformina logra una reversión de inflamación y EO, con restitución del tejido hepático al evidenciar ausencia de lesiones celulares e inflamatorias. La combinación farmacológica demostró eficacia superior que la monoterapia, actuando cada fármaco en sus blancos biológicos logrando una mayor efectividad en la normalización de las variables bioquímicas y en la regresión de lesiones histológicas. La evidencia actual sobre MAFLD demuestra que ante un mecanismo etiopatogénico complejo es necesario enfoques terapéuticos con múltiples objetivos, la implementación de estos fármacos en lugar de esperar un fármaco ideal que contemple todas las vías moleculares alteradas.

The Edinburgh Social Cognition Test (ESCoT):Examining the effects of age on a new measure of theory of mind and social norm understanding

<div><p>Current measures of social cognition have shown inconsistent findings regarding the effects of healthy aging. Moreover, no tests are currently available that allow clinicians and researchers to examine cognitive and affective theory of mind (ToM) and understanding of social norms within the same test. To address these limitations, we present the Edinburgh Social Cognition Test (ESCoT) which assesses cognitive and affective ToM and inter- and intrapersonal understanding of social norms. We examined the effects of age, measures of intelligence and the Broader Autism Phenotype (BAP) on the ESCoT and established tests of social cognition. Additionally, we investigated the convergent validity of the ESCoT based on traditional social cognition measures. The ESCoT was administered alongside Reading the Mind in Films (RMF), Reading the Mind in Eyes (RME), Judgement of Preference and Social Norm Questionnaire to 91 participants (30 aged 18–35 years, 30 aged 45–60 years and 31 aged 65–85 years). Poorer performance on the cognitive and affective ToM ESCoT subtests were predicted by increasing age. The affective ToM ESCoT subtest and RMF were predicted by gender, where being female predicted better performance. Unlike the ESCoT, better performance on the RMF was predicted by higher verbal comprehension and perceptual reasoning abilities, while better performance on the RME was predicted by higher verbal comprehension scores. Lower scores on inter-and intrapersonal understanding of social norms were both predicted by the presence of more autism-like traits while poorer interpersonal understanding of social norms performance was predicted by increasing age. These findings show that the ESCoT is a useful measure of social cognition and, unlike established tests of social cognition, performance is not predicted by measures of verbal comprehension and perceptual reasoning. This is particularly valuable to obtain an accurate assessment of the influence of age on our social cognitive abilities.</p></div

Evolutionary Changes in the Complexity of the Tectum of Nontetrapods: A Cladistic Approach

Background: The tectum is a structure localized in the roof of the midbrain in vertebrates, and is taken to be highly conserved in evolution. The present article assessed three hypotheses concerning the evolution of lamination and citoarchitecture of the tectum of nontetrapod animals: 1) There is a significant degree of phylogenetic inertia in both traits studied (number of cellular layers and number of cell classes in tectum); 2) Both traits are positively correlated accross evolution after correction for phylogeny; and 3) Different developmental pathways should generate different patterns of lamination and cytoarchitecture. Methodology/Principal Findings: The hypotheses were tested using analytical-computational tools for phylogenetic hypothesis testing. Both traits presented a considerably large phylogenetic signal and were positively associated. However, no difference was found between two clades classified as per the general developmental pathways of their brains. Conclusions/Significance: The evidence amassed points to more variation in the tectum than would be expected by phylogeny in three species from the taxa analysed; this variation is not better explained by differences in the main course of development, as would be predicted by the developmental clade hypothesis. Those findings shed new light on th

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition.

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage–fusion–bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors

Modern tests of Lorentz invariance

Motivated by ideas about quantum gravity, a tremendous amount of effort over the past decade has gone into testing Lorentz invariance in various regimes. This review summarizes both the theoretical frameworks for tests of Lorentz invariance and experimental advances that have made new high precision tests possible. The current constraints on Lorentz violating effects from both terrestrial experiments and astrophysical observations are presented.Comment: Modified and expanded discussions of various points. Numerous references added. Version matches that accepted by Living Reviews in Relativit

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Funder: Ludwig Center at HarvardFunder: National Cancer Institute: K22CA193848Funder: US National Institutes of Health Intramural Research Program Project Z1AES103266Abstract: Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer