The Tissue-Specific Rep8/UBXD6 Tethers p97 to the Endoplasmic Reticulum Membrane for Degradation of Misfolded Proteins

The protein known as p97 or VCP in mammals and Cdc48 in yeast is a versatile ATPase complex involved in several biological functions including membrane fusion, protein folding, and activation of membrane-bound transcription factors. In addition, p97 plays a central role in degradation of misfolded secretory proteins via the ER-associated degradation pathway. This functional diversity of p97 depends on its association with various cofactors, and to further our understanding of p97 function it is important that these cofactors are identified and analyzed. Here, we isolate and characterize the human protein named Rep8 or Ubxd6 as a new cofactor of p97. Mouse Rep8 is highly tissue-specific and abundant in gonads. In testes, Rep8 is expressed in post-meiotic round spermatids, whereas in ovaries Rep8 is expressed in granulosa cells. Rep8 associates directly with p97 via its UBX domain. We show that Rep8 is a transmembrane protein that localizes to the ER membrane with its UBX domain facing the cytoplasm. Knock-down of Rep8 expression in human cells leads to a decreased association of p97 with the ER membrane and concomitantly a retarded degradation of misfolded ER-derived proteasome substrates. Thus, Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Photolyse et photo-oxydation d'aldéhydes satures normaux

Le niveau triplet T1 (nπ*) d'aldéhydes saturés à chaîne droite se désactive essentiellement par un processus bimoléculaire d'autodésactivation, lorsque la concentration de l'aldéhyde est comprise entre 10–2 et 10–1 M. Le rendement quantique de population du niveau triplet T1 (nπ*) de l’aldéhyde est alors égal à la moitié du rendement quantique de disparition réelle. La photo-oxydation du n-propanal, du n-butanal et du n-hexanal implique un processus d’amorçage des chaînes d'oxydation issu du niveau excité singulet plus efficace que celui issu de l'état excité triplet

Photolyse et photo-oxydation d'aldéhydes saturés ramifiés

L’étude cinétique de la photolyse d'aldéhydes saturés à chaîne ramifiée et de son inhibition par le napthalène permet de préciser le comportement de ces molécules dans le domaine de concentration 10–2M – 10–1M ; on peut déduire du mécanisme un procédé simple de mesure du rendement quantique de transition inter-systèmes S1 → T1, l'état excité triplet T1 (nπ*) se désactivant essentiellement par un processus bimoléculaire d'autodésactivation. Le rendement quantique de population du triplet est égal à 0,295, 0,34 et 0,41 respectivement pour l'éthyl-2 butanal, le diméthyl-2,2 propanai et l'isobutanal.L'étude cinétique de la photo-oxydation de ces mêmes aldéhydes, inhibée par le napthalène montre que la durée de vie de l'état triplet n'est pas perturbée par l'oxygène dissous dans le n-heptane. La comparaison entre photolyse et photo-oxydation permet de préciser les processus d'amorçage de la réaction en chaînes d'oxydation

Mechanisms of kidney disease in Sneddon's syndrome: Case report and literature review .

Sneddon's syndrome is a rare, noninflammatory thrombotic vasculopathy characterized by the combination of livedo racemosa, recurrent stroke, and histopathological skin lesions of endarteritis obliterans. Although multiorgan involvement suggests its systemic nature, detailed pathological description of affected organs - including the kidney - is exceptional. We report a case of Sneddon's syndrome with chronic kidney disease, associated with features of endarteritis obliterans in the skin and the kidney. The clinical presentation of our patient is compared to previously reported cases of Sneddon's syndrome with biopsy-proven kidney disease. We also discuss the differential diagnosis, pathophysiological mechanisms, relationship with antiphospholipid syndrome, and management of patients with Sneddon's syndrome and kidney disease. This clinical observation supports the systemic nature of Sneddon's syndrome and provides insights into the mechanisms by which this rare but probably underdiagnosed disease alters kidney function.


Construction of Francophone families health literacy in a linguistic-minority situation

With the increase in international mobility, healthcare systems should no longer be ignoring language barriers. In addition to the benefit of reducing long‐term costs, immigrant‐friendly organizations should be concerned with mitigating the way language barriers increase individuals’ social vulnerabilities and inequities in health care and health status. This paper reports the findings of a qualitative, exploratory study of the health literacy of 28 Francophone families living in a linguistic‐minority situation in Canada. Analysis of interviews revealed that participants’ social vulnerability, mainly due to their limited social and informational networks, influenced the construction of family health literacy. Disparities in access to healthcare services could be decreased by having health professionals’ work in alliance with Francophone community groups and by hiring bilingual health professionals. Linguistic isolation and lack of knowledge about local cultural organizations among Francophone immigrants were two important findings of this stud

L'évaluation des habiletés cliniques

Le présent chapitre s’adresse principalement aux enseignants en sciences de la santé qui ont envie d’innover dans leurs modalités d’évaluation. L’étudiant tirera aussi bénéfice de la lecture du chapitre, puisqu’elle lui permettra de se familiariser avec ces modes d’évaluation et d’orienter ses apprentissages. Nous traiterons surtout de l’évaluation du raisonnement clinique ainsi que de l’application des connaissances médicales à la résolution de problèmes cliniques. Pour ce faire, nous vous proposons des modalités d’apprentissage et d’évaluation parfois méconnues de la communauté médicale. Le chapitre s’inspire de l’expérience des auteurs dans l’utilisation de ces modalités d’évaluation pour évaluer le parcours d’étudiants en médecine et en sciences infirmières. La dernière section porte sur les questions de prises de décision thérapeutiques. Elle servira, nous l’espérons, d’outil complémentaire à la préparation des externes à cette modalité d’évaluation pour l’examen du licencié du Conseil médical du Canada (LCMC). Vous trouverez, à la fin du chapitre, un tableau comparatif des modalités d’évaluation quant à leur forme et à leur contenu, ainsi que des exemples de questions supplémentaires