From vocational training to education: the development of a no-frontiers education policy for Europe?

This article focuses on developments towards an EU educational policy. Education was not included as one of the Community competencies in the Treaty of Rome. The first half of the article analyses the way that the European Court of Justice and the Commission of the European Communities between them managed to develop a series of substantial Community programmes out of Article 128 on vocational training. The second half of the article discusses educational developments in the community following the Treaty on European Union and the Treaty of Amsterdam. Whilst the legal competence of the community now includes education, the author's argument is that the inclusion of an educational competence will not result in further developments to mirror those in the years before the Treaty on Europe</p

The unfavorable lipid environment reduced caveolin-1 expression in apical membranes from human preeclamptic placentas

Syncytialization process is associated with a reduction in the number of caveolas, and a decreased of caveolin-1 (Cav-1). Differentiation of syncytiotrophoblast affects the membranes phospholipid composition. Thus, disturbances in these processes are related to pathological conditions such as preeclampsia. Objective To analyse the lipid composition of the apical (MVM) and the basal (BM) membranes of syncytiotrophoblast and its relationship with Cav-1 expression in normal and preeclamptic placentas. Molecular expression of Cav-1 was determined in MVM and BM from normal and preeclamptic placentas and in detergent-resistant membranes (DRMs). Phospholipids were analyzed by thin layer chromatography. Cholesterol was also determined by enzymatic assay. Membrane fluidity was evaluated by electron paramagnetic resonance. Sphingomyelin (SM) molecular species were analyzed and quantified by gas-liquid chromatography and mass spectrometry. Cav-1 was significantly reduced in MVM from preeclamptic placentas. Regarding Cav-1 localization, it was barely detectable in syncytiotrophoblast but it was present in the endothelium. Western blots also showed a significantly decrease of Cav-1 in the apical DRMs from preeclamptic placentas. Lipid analysis showed an increase SM in MVM from preeclamptic placentas without changes in cholesterol. Preeclamptic MVM fluidity decreased significantly and we found an increase in C18:1 fatty acids of SM. We concluded that preeclamptic-MVMs are more rigid than normal ones, possible due to an increment on SM. Moreover, the increase of long and unsaturated SM molecular specie found in these vesicles may disrupt the ability of SM to assemble into lipid rafts in the luminal leaflet of the bilayer, creating an unfavorable environment for Cav-1.Instituto de Investigaciones Bioquímicas de La Plat

The Karolinska NeuroCOVID study protocol: Neurocognitive impairment, biomarkers and advanced imaging in critical care survivors

Background: This is the study plan of the Karolinska NeuroCOVID study, a study of neurocognitive impairment after severe COVID-19, relating post-intensive care unit (ICU) cognitive and neurological deficits to biofluid markers and MRI. The COVID-19 pandemic has posed enormous health challenges to individuals and health-care systems worldwide. An emerging feature of severe COVID-19 is that of temporary and extended neurocognitive impairment, exhibiting a myriad of symptoms and signs. The causes of this symptomatology have not yet been fully elucidated. Methods: In this study, we aim to investigate patients treated for severe COVID-19 in the ICU, as to describe and relate serum-, plasma- and cerebrospinal fluid-borne molecular and cellular biomarkers of immune activity, coagulopathy, cerebral damage, neuronal inflammation, and degeneration, to the temporal development of structural and functional changes within the brain as evident by serial MRI and extensive cognitive assessments at 3–12 months after ICU discharge. Results: To date, we have performed 51 3-month follow-up MRIs in the ICU survivors. Of these, two patients (~4%) have had incidental findings on brain MRI findings requiring activation of the Incidental Findings Management Plan. Furthermore, the neuropsychological and neurological examinations have so far revealed varying and mixed patterns. Several patients expressed cognitive and/or mental concerns and fatigue, complaints closely related to brain fog. Conclusion: The study goal is to gain a better understanding of the pathological mechanisms and neurological consequences of this new disease, with a special emphasis on neurodegenerative and neuroinflammatory processes, in order to identify targets of intervention and rehabilitation

The unfavorable lipid environment reduced caveolin-1 expression in apical membranes from human preeclamptic placentas

Syncytialization process is associated with a reduction in the number of caveolas, and a decreased of caveolin-1 (Cav-1). Differentiation of syncytiotrophoblast affects the membranes phospholipid composition. Thus, disturbances in these processes are related to pathological conditions such as preeclampsia. Objective To analyse the lipid composition of the apical (MVM) and the basal (BM) membranes of syncytiotrophoblast and its relationship with Cav-1 expression in normal and preeclamptic placentas. Molecular expression of Cav-1 was determined in MVM and BM from normal and preeclamptic placentas and in detergent-resistant membranes (DRMs). Phospholipids were analyzed by thin layer chromatography. Cholesterol was also determined by enzymatic assay. Membrane fluidity was evaluated by electron paramagnetic resonance. Sphingomyelin (SM) molecular species were analyzed and quantified by gas-liquid chromatography and mass spectrometry. Cav-1 was significantly reduced in MVM from preeclamptic placentas. Regarding Cav-1 localization, it was barely detectable in syncytiotrophoblast but it was present in the endothelium. Western blots also showed a significantly decrease of Cav-1 in the apical DRMs from preeclamptic placentas. Lipid analysis showed an increase SM in MVM from preeclamptic placentas without changes in cholesterol. Preeclamptic MVM fluidity decreased significantly and we found an increase in C18:1 fatty acids of SM. We concluded that preeclamptic-MVMs are more rigid than normal ones, possible due to an increment on SM. Moreover, the increase of long and unsaturated SM molecular specie found in these vesicles may disrupt the ability of SM to assemble into lipid rafts in the luminal leaflet of the bilayer, creating an unfavorable environment for Cav-1.Instituto de Investigaciones Bioquímicas de La Plat

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Interaction of microtubules and actin during the post-fusion phase of exocytosis

Exocytosis is the intracellular trafficking step where a secretory vesicle fuses with the plasma membrane to release vesicle content. Actin and microtubules both play a role in exocytosis; however, their interplay is not understood. Here we study the interaction of actin and microtubules during exocytosis in lung alveolar type II (ATII) cells that secrete surfactant from large secretory vesicles. Surfactant extrusion is facilitated by an actin coat that forms on the vesicle shortly after fusion pore opening. Actin coat compression allows hydrophobic surfactant to be released from the vesicle. We show that microtubules are localized close to actin coats and stay close to the coats during their compression. Inhibition of microtubule polymerization by colchicine and nocodazole affected the kinetics of actin coat formation and the extent of actin polymerisation on fused vesicles. In addition, microtubule and actin cross-linking protein IQGAP1 localized to fused secretory vesicles and IQGAP1 silencing influenced actin polymerisation after vesicle fusion. This study demonstrates that microtubules can influence actin coat formation and actin polymerization on secretory vesicles during exocytosis

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA-Schizophrenia consortium

Objective: Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia. Method: This prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness. Results: Positive symptom severity was negatively related to STG thickness in both hemispheres (left: βstd = −0.052; P = 0.021; right: βstd = −0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness. Conclusion: Our findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia

Polyamine Sharing between Tubulin Dimers Favours Microtubule Nucleation and Elongation via Facilitated Diffusion

We suggest for the first time that the action of multivalent cations on microtubule dynamics can result from facilitated diffusion of GTP-tubulin to the microtubule ends. Facilitated diffusion can promote microtubule assembly, because, upon encountering a growing nucleus or the microtubule wall, random GTP-tubulin sliding on their surfaces will increase the probability of association to the target sites (nucleation sites or MT ends). This is an original explanation for understanding the apparent discrepancy between the high rate of microtubule elongation and the low rate of tubulin association at the microtubule ends in the viscous cytoplasm. The mechanism of facilitated diffusion requires an attraction force between two tubulins, which can result from the sharing of multivalent counterions. Natural polyamines (putrescine, spermidine, and spermine) are present in all living cells and are potent agents to trigger tubulin self-attraction. By using an analytical model, we analyze the implication of facilitated diffusion mediated by polyamines on nucleation and elongation of microtubules. In vitro experiments using pure tubulin indicate that the promotion of microtubule assembly by polyamines is typical of facilitated diffusion. The results presented here show that polyamines can be of particular importance for the regulation of the microtubule network in vivo and provide the basis for further investigations into the effects of facilitated diffusion on cytoskeleton dynamics

Significant Effects of Antiretroviral Therapy on Global Gene Expression in Brain Tissues of Patients with HIV-1-Associated Neurocognitive Disorders

Antiretroviral therapy (ART) has reduced morbidity and mortality in HIV-1 infection; however HIV-1-associated neurocognitive disorders (HAND) persist despite treatment. The reasons for the limited efficacy of ART in the brain are unknown. Here we used functional genomics to determine ART effectiveness in the brain and to identify molecular signatures of HAND under ART. We performed genome-wide microarray analysis using Affymetrix U133 Plus 2.0 Arrays, real-time PCR, and immunohistochemistry in brain tissues from seven treated and eight untreated HAND patients and six uninfected controls. We also determined brain virus burdens by real-time PCR. Treated and untreated HAND brains had distinct gene expression profiles with ART transcriptomes clustering with HIV-1-negative controls. The molecular disease profile of untreated HAND showed dysregulated expression of 1470 genes at p<0.05, with activation of antiviral and immune responses and suppression of synaptic transmission and neurogenesis. The overall brain transcriptome changes in these patients were independent of histological manifestation of HIV-1 encephalitis and brain virus burdens. Depending on treatment compliance, brain transcriptomes from patients on ART had 83% to 93% fewer dysregulated genes and significantly lower dysregulation of biological pathways compared to untreated patients, with particular improvement indicated for nervous system functions. However a core of about 100 genes remained similarly dysregulated in both treated and untreated patient brain tissues. These genes participate in adaptive immune responses, and in interferon, cell cycle, and myelin pathways. Fluctuations of cellular gene expression in the brain correlated in Pearson's formula analysis with plasma but not brain virus burden. Our results define for the first time an aberrant genome-wide brain transcriptome of untreated HAND and they suggest that antiretroviral treatment can be broadly effective in reducing pathophysiological changes in the brain associated with HAND. Aberrantly expressed transcripts common to untreated and treated HAND may contribute to neurocognitive changes defying ART