PEX5, the Shuttling Import Receptor for Peroxisomal Matrix Proteins, Is a Redox-Sensitive Protein

Peroxisome maintenance depends on the import of nuclear-encoded proteins from the cytosol. The vast majority of these proteins is destined for the peroxisomal lumen and contains a C-terminal peroxisomal targeting signal, called PTS1. This targeting signal is recognized in the cytosol by the receptor PEX5. After docking at the peroxisomal membrane and release of the cargo into the organelle matrix, PEX5 is recycled to the cytosol through a process requiring monoubiquitination of an N-terminal, cytosolically exposed cysteine residue (Cys11 in the human protein). At present, the reason why a cysteine, and not a lysine residue, is the target of ubiquitination remains unclear. Here, we provide evidence that PTS1 protein import into human fibr oblasts is a redox-sensitive process. We also demonstrate that Cys11 in human PEX5 functions as a redox switch that regulates PEX5 activity in response to intracellular oxidative stress. Finally, we show that exposure of human PEX5 to oxidized glutathione results in a ubiquitination-deficient PEX5 molecule, and that substitution of Cys11 by a lysine can counteract this effect. In summary, these findings reveal that the activity of PEX5, and hence PTS1 import, is controlled by the redox state of the cytosol. The potential physiological implications of these findings are discussed.The authors are grateful to Dr. Ann Moser (Baltimore, USA) for the primary PEX5 null human fibroblasts. This work was supported bygrants from the ‘Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (Onderzoeksproject G.0754.09)’ (to M. F. and P. P.V.V.), by the KU Leuven grants OT/09/045 (toM. F. and P. P. V. V.) and DBOF/10/059 (to P. P. V. V. and M. F.), and by FEDER funds through the Operational Competitiveness Programme – COMPETE and by National Funds through FCT – Fundac¸ão para a Ciência e a Tecnologia under the project FCOMP-01-0124-FEDER-019731 (PTDC/BIA-BCM/118577/2010) (to J. E. A.). M.N. is supported by a FLOF fellowship from the Department of Cellular and Molecular Medicine, KU Leuven. B.W. is a recipient of a DBOF fellowship (DBOF/10/059) from the KU Leuven. C. P. G. is supported by Fundac¸ão para a Ciência e a Tecnologia, Programa Operacional Potencial Humano do QREN, and Fundo Social Europeu

Scale relativity and fractal space-time: theory and applications

In the first part of this contribution, we review the development of the theory of scale relativity and its geometric framework constructed in terms of a fractal and nondifferentiable continuous space-time. This theory leads (i) to a generalization of possible physically relevant fractal laws, written as partial differential equation acting in the space of scales, and (ii) to a new geometric foundation of quantum mechanics and gauge field theories and their possible generalisations. In the second part, we discuss some examples of application of the theory to various sciences, in particular in cases when the theoretical predictions have been validated by new or updated observational and experimental data. This includes predictions in physics and cosmology (value of the QCD coupling and of the cosmological constant), to astrophysics and gravitational structure formation (distances of extrasolar planets to their stars, of Kuiper belt objects, value of solar and solar-like star cycles), to sciences of life (log-periodic law for species punctuated evolution, human development and society evolution), to Earth sciences (log-periodic deceleration of the rate of California earthquakes and of Sichuan earthquake replicas, critical law for the arctic sea ice extent) and tentative applications to system biology.Comment: 63 pages, 14 figures. In : First International Conference on the Evolution and Development of the Universe,8th - 9th October 2008, Paris, Franc

The Genetic Architecture of Depression in Individuals of East Asian Ancestry: A Genome-Wide Association Study

Importance: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations. Objective: To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression. Design, Setting, and Participants: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021. Exposures: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts. Main Outcomes and Measures: Depression status was defined based on health records and self-report questionnaires. Results: There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = -0.018, SE = 0.003, P = 4.43x10-8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (β = 0.028, SE = 0.005, P = 6.48x10-9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = -0.003, SE = 0.005, P = .53 for rs4656484 and β = -0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent. Conclusions and Relevance: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping

Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue

Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD

The peroxisomal protein import machinery displays a preference for monomeric substrates

Peroxisomal matrix proteins are synthesized on cytosolic ribosomes and transported by the shuttling receptor PEX5 to the peroxisomal membrane docking/translocation machinery, where they are translocated into the organelle matrix. Under certain experimental conditions this protein import machinery has the remarkable capacity to accept already oligomerized proteins, a property that has heavily influenced current models on the mechanism of peroxisomal protein import. However, whether or not oligomeric proteins are really the best and most frequent clients of this machinery remain unclear. In this work, we present three lines of evidence suggesting that the peroxisomal import machinery displays a preference for monomeric proteins. First, in agreement with previous findings on catalase, we show that PEX5 binds newly synthesized (monomeric) acyl-CoA oxidase 1 (ACOX1) and urate oxidase (UOX), potently inhibiting their oligomerization. Second, in vitro import experiments suggest that monomeric ACOX1 and UOX are better peroxisomal import substrates than the corresponding oligomeric forms. Finally, we provide data strongly suggesting that although ACOX1 lacking a peroxisomal targeting signal can be imported into peroxisomes when co-expressed with ACOX1 containing its targeting signal, this import pathway is inefficient

Ontogeny of the common carp (Cyprinus carpio L.) innate immune system

The ontogeny of the teleost innate immune system was studied in carp using cellular, histological and quantitative molecular techniques. Carp myeloid cells first appeared ventro-lateral of the aorta at 2 days post fertilization (the start of hatching), and subsequently around the sinuses of the vena cardinalis (or posterior blood islet), head kidney and trunk kidney. In addition, the hematopoietic tissue around the sinuses of the vena cardinalis transformed into that of the trunk kidney, which is the first description of the ontogeny of the trunk kidney hematopoietic tissue in teleosts. The mAb's used in this study reacted with carp myeloid surface molecules that are already transcribed and processed from the first appearance of myeloid cells, and thus serve a significant role in unraveling ontogenetic processes of teleost immunology. Finally, this study associated the first appearance of myeloid cells with an immune response on the molecular level: 2 days post fertilization embryos responded to LPS injection with upregulation of interleukin 1-beta, inducible nitric oxide synthase and serum amyloid A, and down-regulation of complement factor 3 and alpha2-macroglobulin, implying a functional embryonic innate defense system

Minimally important differences for the EORTC QLQ-C30 in prostate cancer clinical trials

BACKGROUND The aim of the study was to estimate the minimally important difference (MID) for interpreting group-level change over time, both within a group and between groups, for the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scores in patients with prostate cancer. METHODS We used data from two published EORTC trials. Clinical anchors were selected by strength of correlations with QLQ-C30 scales. In addition, clinicians' input was obtained with regard to plausibility of the selected anchors. The mean change method was applied for interpreting change over time within a group of patients and linear regression models were fitted to estimate MIDs for between-group differences in change over time. Distribution-based estimates were also evaluated. RESULTS Two clinical anchors were eligible for MID estimation; performance status and the CTCAE diarrhoea domain. MIDs were developed for 7 scales (physical functioning, role functioning, social functioning, pain, fatigue, global quality of life, diarrhoea) and varied by scale and direction (improvement vs deterioration). Within-group MIDs ranged from 4 to 14 points for improvement and - 13 to - 5 points for deterioration and MIDs for between-group differences in change scores ranged from 3 to 13 for improvement and - 10 to - 5 for deterioration. CONCLUSIONS Our findings aid the meaningful interpretation of changes on a set of EORTC QLQ-C30 scale scores over time, both within and between groups, and for performing more accurate sample size calculations for clinical trials in prostate cancer

Estimating the burden of disease attributable to alcohol use in South Africa in 2000

Objectives. To make quantitative estimates of the burden of disease attributable to alcohol use by sex and age group in South Africa in 2000. Design. The analysis follows the World Health Organization comparative risk assessment (CRA) methodology. Populationattributable fractions (PAFs) calculated from modelled prevalence estimates and relative risks based on the global review were applied to the burden of disease estimates from the revised South African National Burden of Disease study for 2000. The alcohol-attributable fractions for injuries were directly determined from blood alcohol concentrations (BAC > 0.05 g/100 ml) at the time of injury. Monte Carlo simulationmodelling techniques were used to quantify uncertainty in the estimates. Setting. South Africa. Subjects. Adults ≥ 15 years. Outcome measures. Deaths and disability-adjusted life years (DALYs) from ischaemic heart disease, stroke, hypertensive disease, diabetes, certain cancers, liver cirrhosis, epilepsy, alcohol use disorder, depression and intentional and unintentional injuries as well as burden from fetal alcohol syndrome (FAS) and low birth weight. Results. Alcohol harm accounted for an estimated 7.1% (95% uncertainty interval 6.6 - 7.5%) of all deaths and 7.0% (95% uncertainty interval 6.6 - 7.4%) of total DALYs in 2000. Injuries and cardiovascular incidents ranked first and second in terms of attributable deaths. Top rankings for overall attributable burden were interpersonal violence (39.0%), neuropsychiatric conditions (18.4%) and road traffic injuries (14.3%). Interpersonal violence accounted for 42.8% of the injury DALYs attributed to alcohol in males and 25.9% in females. In terms of alcohol-attributable disability, alcohol use disorders ranked first (44.6%), interpersonal violence second (23.2%), and FAS third (18.1%). Conclusions. Particular attention needs to be given to preventing and reducing the burden of alcohol-related homicide and violence, alcohol-related road traffic accidents, alcohol use disorders, and FAS. Multilevel interventions are required to target high-risk drinkers, in addition to creating awareness in the general population of the problems associated with alcohol abuse. South African Medical Journal Vol. 97 (8) Part 2 2007: pp. 664-67