LXR-dependent enhancer activation regulates the temporal organization of the liver's response to refeeding leading to lipogenic gene overshoot.

Transitions between the fed and fasted state are common in mammals. The liver orchestrates adaptive responses to feeding/fasting by transcriptionally regulating metabolic pathways of energy usage and storage. Transcriptional and enhancer dynamics following cessation of fasting (refeeding) have not been explored. We examined the transcriptional and chromatin events occurring upon refeeding in mice, including kinetic behavior and molecular drivers. We found that the refeeding response is temporally organized with the early response focused on ramping up protein translation while the later stages of refeeding drive a bifurcated lipid synthesis program. While both the cholesterol biosynthesis and lipogenesis pathways were inhibited during fasting, most cholesterol biosynthesis genes returned to their basal levels upon refeeding while most lipogenesis genes markedly overshoot above pre-fasting levels. Gene knockout, enhancer dynamics, and ChIP-seq analyses revealed that lipogenic gene overshoot is dictated by LXRα. These findings from unbiased analyses unravel the mechanism behind the long-known phenomenon of refeeding fat overshoot.

Retinoic acid reduces human neuroblastoma cell migration and invasiveness: effects on DCX, LIS1, neurofilaments-68 and vimentin expression.

BACKGROUND: Neuroblastoma is a severe pediatric tumor, histologically characterised by a variety of cellular phenotypes. One of the pharmacological approaches to neuroblastoma is the treatment with retinoic acid. The mechanism of action of retinoic acid is still unclear, and the development of resistance to this differentiating agent is a great therapy problem.Doublecortin, a microtubule-associated protein involved in neuronal migration, has recently been proposed as a molecular marker for the detection of minimal residual disease in human neuroblastoma. Nevertheless, no information is available on the expression of doublecortin in the different cell-types composing human neuroblastoma, its correlation with neuroblastoma cell motility and invasiveness, and the possible modulations exerted by retinoic acid treatment. METHODS: We analysed by immunofluorescence and by Western blot analysis the presence of doublecortin, lissencephaly-1 (another protein involved in neuronal migration) and of two intermediate filaments proteins, vimentin and neurofilament-68, in SK-N-SH human neuroblastoma cell line both in control conditions and under retinoic acid treatment. Migration and cell invasiveness studies were performed by wound scratch test and a modified microchemotaxis assay, respectively. RESULTS: Doublecortin is expressed in two cell subtypes considered to be the more aggressive and that show high migration capability and invasiveness. Vimentin expression is excluded by these cells, while lissencephaly-1 and neurofilaments-68 are immunodetected in all the cell subtypes of the SK-N-SH cell line. Treatment with retinoic acid reduces cell migration and invasiveness, down regulates doublecortin and lissencephaly-1 expression and up regulates neurofilament-68 expression. However, some cells that escape from retinoic acid action maintain migration capability and invasiveness and express doublecortin. CONCLUSION: a) Doublecortin is expressed in human neuroblastoma cells that show high motility and invasiveness;b) Retinoic acid treatment reduces migration and invasiveness of the more aggressive cell components of SK-N-SH cells;c) The cells that after retinoic acid exposure show migration and invasive capability may be identified on the basis of doublecortin expression.

Stem Cell-Specific Mechanisms Ensure Genomic Fidelity within HSCs and upon Aging of HSCs.

Whether aged hematopoietic stem and progenitor cells (HSPCs) have impaired DNA damage repair is controversial. Using a combination of DNA mutation indicator assays, we observe a 2- to 3-fold increase in the number of DNA mutations in the hematopoietic system upon aging. Young and aged hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) do not show an increase in mutation upon irradiation-induced DNA damage repair, and young and aged HSPCs respond very similarly to DNA damage with respect to cell-cycle checkpoint activation and apoptosis. Both young and aged HSPCs show impaired activation of the DNA-damage-induced G1-S checkpoint. Induction of chronic DNA double-strand breaks by zinc-finger nucleases suggests that HSPCs undergo apoptosis rather than faulty repair. These data reveal a protective mechanism in both the young and aged hematopoietic system against accumulation of mutations in response to DNA damage.

Pericarditis tuberculosa: presentación de un caso y revisión de la literatura / Tuberculous pericarditis: a case report and review of the literature

La pericarditis constrictiva crónica es un síndrome clínico causado por la compresión cardíaca ejercida por un pericardio engrosado o rígido. La tuberculosis es una causa rara de pericarditis constrictiva en los países desarrollados. Sin embargo, ésta es una importante condición a considerar en países en desarrollo y en pacientes con infección por VIH. La pericarditis tuberculosa es una forma de tuberculosis extra-pulmonar que puede conducir a la muerte. La dificultad en su diagnóstico y las serias consecuencias de la infección no tratada hacen de esta condición un importante problema de salud tanto en países industrializados como en aquellos en vía de desarrollo. Ayudas diagnósticas como la ecocardiografía son esenciales en el diagnóstico, y ante la sospecha de afección tuberculosa del pericardio se indica la realización de estudios del líquido o del tejido pericárdico. El tratamiento antituberculoso se realiza durante seis meses y se considera la pericardiectomía en pacientes con pericarditis constrictiva calcificada o en quienes la constricción empeora después de seis a ocho semanas de tratamiento.

Constrictive pericarditis is a clinical syndrome caused by the cardiac compression of a thickened or rigid pericardium. Tuberculosis is a rare cause of constrictive pericarditis in developed countries. However, this is an important condition to consider in developing countries and in patients with HVI infection. Tuberculous pericarditis is a form of extra-pulmonary tuberculosis that may lead to death. The difficulty in its diagnosis and the serious consequences of this non-treated infection make this condition an important health problem both in industrialized and developing countries. Diagnostic aids such as echography are essential in the diagnosis, and in front of the suspicion of tuberculous infection of the pericardium, the performance of pericardial fluid or pericardial tissue studies is indicated. Anti TB treatment is carried out for six months and pericardiectomy is considered in patients with calcified constrictive pericarditis or in those in whom the constriction worsens after six to eight weeks of treatment.