Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages.

A key event in atherogenesis is the formation of lipid-loaded macrophages, lipidotic cells, which exhibit irreversible accumulation of undigested modified low-density lipoproteins (LDL) in lysosomes. This event culminates in the loss of cell homeostasis, inflammation, and cell death. Nevertheless, the exact chemical etiology of atherogenesis and the molecular and cellular mechanisms responsible for the impairment of lysosome function in plaque macrophages are still unknown. Here, we demonstrate that macrophages exposed to cholesteryl hemiazelate (ChA), one of the most prevalent products of LDL-derived cholesteryl ester oxidation, exhibit enlarged peripheral dysfunctional lysosomes full of undigested ChA and neutral lipids. Both lysosome area and accumulation of neutral lipids are partially irreversible. Interestingly, the dysfunctional peripheral lysosomes are more prone to fuse with the plasma membrane, secreting their undigested luminal content into the extracellular milieu with potential consequences for the pathology. We further demonstrate that this phenotype is mechanistically linked to the nuclear translocation of the MiT/TFE family of transcription factors. The induction of lysosome biogenesis by ChA appears to partially protect macrophages from lipid-induced cytotoxicity. In sum, our data show that ChA is involved in the etiology of lysosome dysfunction and promotes the exocytosis of these organelles. This latter event is a new mechanism that may be important in the pathogenesis of atherosclerosis.

FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.

CAG repeat expansion in the HTT gene drives Huntington's disease (HD) pathogenesis and is modulated by DNA damage repair pathways. In this context, the interaction between FAN1, a DNA-structure-specific nuclease, and MLH1, member of the DNA mismatch repair pathway (MMR), is not defined. Here, we identify a highly conserved SPYF motif at the N terminus of FAN1 that binds to MLH1. Our data support a model where FAN1 has two distinct functions to stabilize CAG repeats. On one hand, it binds MLH1 to restrict its recruitment by MSH3, thus inhibiting the assembly of a functional MMR complex that would otherwise promote CAG repeat expansion. On the other hand, it promotes accurate repair via its nuclease activity. These data highlight a potential avenue for HD therapeutics in attenuating somatic expansion.

Derivation and maintenance of mouse haploid embryonic stem cells.

Ploidy represents the number of chromosome sets in a cell. Although gametes have a haploid genome (n), most mammalian cells have diploid genomes (2n). The diploid status of most cells correlates with the number of probable alleles for each autosomal gene and makes it difficult to target these genes via mutagenesis techniques. Here, we describe a 7-week protocol for the derivation of mouse haploid embryonic stem cells (hESCs) from female gametes that also outlines how to maintain the cells once derived. We detail additional procedures that can be used with cell lines obtained from the mouse Haplobank, a biobank of >100,000 individual mouse hESC lines with targeted mutations in 16,970 genes. hESCs can spontaneously diploidize and can be maintained in both haploid and diploid states. Mouse hESCs are genomically and karyotypically stable, are innately immortal and isogenic, and can be derived in an array of differentiated cell types; they are thus highly amenable to genetic screens and to defining molecular connectivity pathways.

Estudio de la prevalencia del sobrepeso y la obesidad en un centro penitenciario español / Study of the prevalence of overweight and obesity in a Spanish prison

Introducción: El sobrepeso y la obesidad constituyen un problema de salud extendido a lo largo de todo el mundo. Existen pocas investigaciones sobre su prevalencia en centros penitenciarios, por ello, este estudio tiene por objetivo determinar dicha prevalencia en una muestra de internos en un centro penitenciario español. Material y métodos: 122 internos de un centro penitenciario español participaron voluntariamente en la investigación, 99 hombres (81.1%) y 23 mujeres (18.9%), con una edad promedio de 36.2 años (DT 11.03). A todos ellos se les pesó y midió, calculando su índice de masa corporal (IMC). Resultados: El 56.6 % de los internos tienen sobrepeso u obesidad, lo cual está ligeramente por debajo de los valores de prevalencia en la población española. No se observan diferencias significativas en la prevalencia de sobrepeso u obesidad entre hombre y mujeres. Discusión: Los resultados obtenidos indican que las personas internas en centros penitenciarios tienen niveles altos de prevalencia de sobrepeso y/u obesidad, como en otras investigaciones internacionales, lo que debe incitar a realizar programas preventivos y/o de intervención (AU)

Background: Overweight and obesity are a worldwide health problem. There are few researches about the prevalence of these conditions in penitentiaries; that is why this study aims at determining prevalence in a sample of inmates at a Spanish penitentiary. Methods and materials: 122 inmates from a Spanish penitentiary volunteered for this research in which 99 were men (81.1%) and 23 were women (18.9%), and the average age was 36.2 (DT 11.03). Weight and size measures were collected, and the body mass index (BMI) was assessed. Results: 56.6 % of inmates are overweighed or obese, which is slightly below the prevalence values among the Spanish population. No significant differences can be observed in the prevalence of overweight or obesity between men and women. Debate: The results show that there are high levels of overweight and/or obesity prevalence among penitentiary inmates, matching the results from other international studies. This should encourage the implementation of prevention and/or intervention programs (AU)

[Study of the prevalence of overweight and obesity in a spanish prison]. / Estudio de la prevalencia del sobrepeso y la obesidad en un centro penitenciario español.

BACKGROUND: Overweight and obesity are a worldwide health problem. There are few researches about the prevalence of these conditions in penitentiaries; that is why this study aims at determining prevalence in a sample of inmates at a Spanish penitentiary. METHODS AND MATERIALS: 122 inmates from a Spanish penitentiary volunteered for this research in which 99 were men (81.1%) and 23 were women (18.9%), and the average age was 36.2 (DT 11.03). Weight and size measures were collected, and the body mass index (BMI) was assessed. RESULTS: 56.6 % of inmates are overweighed or obese, which is slightly below the prevalence values among the Spanish population. No significant differences can be observed in the prevalence of overweight or obesity between men and women. DEBATE: The results show that there are high levels of overweight and/or obesity prevalence among penitentiary inmates, matching the results from other international studies. This should encourage the implementation of prevention and/or intervention programs.

INTRODUCCIÓN: El sobrepeso y la obesidad constituyen un problema de salud extendido a lo largo de todo el mundo. Existen pocas investigaciones sobre su prevalencia en centros penitenciarios, por ello, este estudio tiene por objetivo determinar dicha prevalencia en una muestra de internos en un centro penitenciario español. MATERIAL Y MÉTODOS: 122 internos de un centro penitenciario español participaron voluntariamente en la investigación, 99 hombres (81.1%) y 23 mujeres (18.9%), con una edad promedio de 36.2 años (DT 11.03). A todos ellos se les pesó y midió, calculando su índice de masa corporal (IMC). RESULTADOS: El 56.6 % de los internos tienen sobrepeso u obesidad, lo cual está ligeramente por debajo de los valores de prevalencia en la población española. No se observan diferencias significativas en la prevalencia de sobrepeso u obesidad entre hombre y mujeres. DISCUSIÓN: Los resultados obtenidos indican que las personas internas en centros penitenciarios tienen niveles altos de prevalencia de sobrepeso y/u obesidad, como en otras investigaciones internacionales, lo que debe incitar a realizar programas preventivos y/o de intervención.

Luxaçäo traumática anterior do quadril. Relato de caso / Late anterior traumatic dislocation of the hip

Os autores apresentam caso de luxaçäo traumática anterior inveterada do quadril direito em paciente masculino de 22 anos que apresentava luxaçäo näo reduzida de 30 dias. O tratamento cirúrgico chegou a ser indicado, depois que algumas tentativas de reduçäo incruenta näo alcançaram sucesso. A reduçao foi conseguida incruentamente, mesmo após decorrido esse longo período.