From fossils to mind

Fossil endocasts record features of brains from the past: size, shape, vasculature, and gyrification. These data, alongside experimental and comparative evidence, are needed to resolve questions about brain energetics, cognitive specializations, and developmental plasticity. Through the application of interdisciplinary techniques to the fossil record, paleoneurology has been leading major innovations. Neuroimaging is shedding light on fossil brain organization and behaviors. Inferences about the development and physiology of the brains of extinct species can be experimentally investigated through brain organoids and transgenic models based on ancient DNA. Phylogenetic comparative methods integrate data across species and associate genotypes to phenotypes, and brains to behaviors. Meanwhile, fossil and archeological discoveries continuously contribute new knowledge. Through cooperation, the scientific community can accelerate knowledge acquisition. Sharing digitized museum collections improves the availability of rare fossils and artifacts. Comparative neuroanatomical data are available through online databases, along with tools for their measurement and analysis. In the context of these advances, the paleoneurological record provides ample opportunity for future research. Biomedical and ecological sciences can benefit from paleoneurology's approach to understanding the mind as well as its novel research pipelines that establish connections between neuroanatomy, genes and behavior

Beta2-Microglobulin Amyloid Fibrils Are Nanoparticles That Disrupt Lysosomal Membrane Protein Trafficking and Inhibit Protein Degradation by Lysosomes.

Fragmentation of amyloid fibrils produces fibrils that are reduced in length but have an otherwise unchanged molecular architecture. The resultant nanoscale fibril particles inhibit the cellular reduction of the tetrazolium dye 3-(4,5-dimethylthi-azol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), a substrate commonly used to measure cell viability, to a greater extent than unfragmented fibrils. Here we show that the internalization of β2-microglobulin (β2m) amyloid fibrils is dependent on fibril length, with fragmented fibrils being more efficiently internalized by cells. Correspondingly, inhibiting the internalization of fragmented β2m fibrils rescued cellular MTT reduction. Incubation of cells with fragmented β2m fibrils did not, however, cause cell death. Instead, fragmented β2m fibrils accumulate in lysosomes, alter the trafficking of lysosomal membrane proteins, and inhibit the degradation of a model protein substrate by lysosomes. These findings suggest that nanoscale fibrils formed early during amyloid assembly reactions or by the fragmentation of longer fibrils could play a role in amyloid disease by disrupting protein degradation by lysosomes and trafficking in the endolysosomal pathway

Early Presymptomatic and Long-Term Changes of Rest Activity Cycles and Cognitive Behavior in a MPTP-Monkey Model of Parkinson's Disease

It is increasingly recognized that non-motor symptoms are a prominent feature of Parkinson's disease and in the case of cognitive deficits can precede onset of the characteristic motor symptoms. Here, we examine in 4 monkeys chronically treated with low doses of the neurotoxin MPTP the early and long-term alterations of rest-activity rhythms in relationship to the appearance of motor and cognitive symptoms.Behavioral activity recordings as well as motor and cognitive assessments were carried out continuously and in parallel before, during and for several months following MPTP-treatment (12–56 weeks). Cognitive abilities were assessed using a task that is dependent on the functional integrity of the fronto-striatal axis. Rest-activity cycles were monitored continuously using infrared movement detectors of locomotor activity. Motor impairment was evaluated using standardized scales for primates. Results show that MPTP treatment led to an immediate alteration (within one week) of rest-activity cycles and cognitive deficits. Parkinsonian motor deficits only became apparent 3 to 5 weeks after initiating chronic MPTP administration. In three of the four animals studied, clinical scores returned to control levels 5–7 weeks following cessation of MPTP treatment. In contrast, both cognitive deficits and chronobiological alterations persisted for many months. Levodopa treatment led to an improvement of cognitive performance but did not affect rest-activity rhythms in the two cases tested.Present results show that i) changes in the rest activity cycles constituted early detectable consequences of MPTP treatment and, along with cognitive alterations, characterize the presymptomatic stage; ii) following motor recovery there is a long-term persistence of non-motor symptoms that could reflect differential underlying compensatory mechanisms in these domains; iii) the progressive MPTP-monkey model of presymptomatic ongoing parkinsonism offers possibilities for in-depth studies of early non-motor symptoms including sleep alterations and cognitive deficits

Transplantation rénale dans le cadre de la sclérodermie systémique : étude française multicentrique

La transplantation rénale chez les patients sclérodermiques est peu étudiée dans la littérature. Le risque de récidive de crise rénale sclérodermique après greffe et le potentiel sevrage de la dialyse font surseoir à une inscription précoce sur liste d'attente. La transplantation peut-elle être considérée comme une alternative thérapeutique pour les patients sclérodermiques insuffisants rénaux chroniques terminaux en termes de mortalité ? Matériels et méthodes : L'étude menée est observationnelle rétrospective multicentrique sur les centres hospitaliers universitaires français. Les patients greffés entre le 1er janvier 2001 et le 31 décembre 2012 ont été répertoriés. Un questionnaire a été envoyé à tous les centres et recense les évènements intercurrents survenant pendant et après la greffe, la stratégie d'immunosuppression et les récidives rénales. Cette population est comparée à la population dialysée et atteinte de sclérodermie systémique sur la même période, issue du registre REIN. Résultats : Vingt-six patients ont été transplantés sur cette période. Les taux de survie retrouvés pour 22 d'entre eux après 40 mois d'exposition moyenne sont de 100%, 88% et 82% à 1, 3, 5 ans respectivement. Le décès survient en moyenne après 23.3+/-24.6mois (5-77) et touche 4 patients. L'analyse des patients dialysés de la même période retrouve des survies de 76%, 51% et 32% aux mêmes délais. Le décès survient en moyenne à 20.2+/-17.5mois (0.4-70). Après comparaison statistique, il existe un bénéfice significatif en termes de pronostic pour la transplantation, p=0.0006. Conclusion : La survie après greffe rénale des patients atteints de sclérodermie systémique insuffisants rénaux terminaux est acceptable et doit être envisagée dans cette population. La survie est meilleure qu'en dialyse pour la même période en France sans morbidité liée à la greffe trop importante. D'autres études de plus larges effectifs sont nécessaires afin d'étayer cette thèse

Transplantation rénale dans le cadre de la sclérodermie systémique (étude française multicentrique)

La transplantation rénale chez les patients sclérodermiques est peu étudiée dans la littérature. Le risque de récidive de crise rénale sclérodermique après greffe et le potentiel sevrage de la dialyse font surseoir à une inscription précoce sur liste d attente. La transplantation peut-elle être considérée comme une alternative thérapeutique pour les patients sclérodermiques insuffisants rénaux chroniques terminaux en termes de mortalité ? Matériels et méthodes : L étude menée est observationnelle rétrospective multicentrique sur les centres hospitaliers universitaires français. Les patients greffés entre le 1er janvier 2001 et le 31 décembre 2012 ont été répertoriés. Un questionnaire a été envoyé à tous les centres et recense les évènements intercurrents survenant pendant et après la greffe, la stratégie d immunosuppression et les récidives rénales. Cette population est comparée à la population dialysée et atteinte de sclérodermie systémique sur la même période, issue du registre REIN.Résultats : Vingt-six patients ont été transplantés sur cette période. Les taux de survie retrouvés pour 22 d entre eux après 40 mois d exposition moyenne sont de 100%, 88% et 82% à 1, 3, 5 ans respectivement. Le décès survient en moyenne après 23.3+/-24.6mois (5-77) et touche 4 patients. L analyse des patients dialysés de la même période retrouve des survies de 76%, 51% et 32% aux mêmes délais. Le décès survient en moyenne à 20.2+/-17.5mois (0.4-70). Après comparaison statistique, il existe un bénéfice significatif en termes de pronostic pour la transplantation, p=0.0006. Conclusion : La survie après greffe rénale des patients atteints de sclérodermie systémique insuffisants rénaux terminaux est acceptable et doit être envisagée dans cette population. La survie est meilleure qu en dialyse pour la même période en France sans morbidité liée à la greffe trop importante D autres études de plus large effectifs sont nécessaires afin d étayer cette thèse.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

Trehalose-Based Nucleolipids as Nanocarriers for Autophagy Modulation: An In Vitro Study

International audienceThe Autophagy Lysosomal Pathway is one of the most important mechanisms for removing dysfunctional cellular components. Increasing evidence suggests that alterations in this pathway play a pathogenic role in Parkinson’s disease, making it a point of particular vulnerability. Numerous studies have proposed nanotechnologies as a promising approach for delivering active substances within the central nervous system to treat and diagnose neurodegenerative diseases. In this context, the aim was to propose the development of a new pharmaceutical technology for the treatment of neurodegenerative diseases. We designed a trehalose-based nanosystem by combining both a small natural autophagy enhancer molecule named trehalose and an amphiphilic nucleolipid conjugate. To improve nucleolipid protection and cellular uptake, these conjugates were formulated by rapid mixing in either solid lipid nanoparticles (Ø = 120.4 ± 1.4 nm) or incorporated into poly(lactic-co-glycolic acid) nanoparticles (Ø = 167.2 ± 2.4 nm). In vitro biological assays demonstrated a safe and an efficient cellular uptake associated with autophagy induction. Overall, these nucleolipid-based formulations represent a promising new pharmaceutical tool to deliver trehalose and restore the autophagy impaired function

The Use of Ferritin to Identify Critically Ill Patients With Secondary Hemophagocytic Lymphohistiocytosis*

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Kidney transplantation in patients with systemic sclerosis: a nationwide multicentre study

International audienceKidney transplantation is one of the therapeutic options for end-stage renal disease (ESRD) in systemic sclerosis (SS). Current evidence demonstrates poorer patient and graft survival after transplantation in SS than in other primary kidney diseases. All the patients presenting ESRD associated with SS who had received a kidney allograft between 1987 and 2013 were systematically included from 20 French kidney transplantation centres. Thirty-four patients received 36 kidney transplants during the study period. Initial kidney disease was scleroderma renal crisis in 76.4%. Extrarenal involvement of SS was generally stable, except cardiac and gastrointestinal involvements, which worsened after kidney transplantation in 45% and 26% of cases, respectively. Patient survival was 100%, 90.3% and 82.5% at 1, 3 and 5 years post-transplant, respectively. Pulmonary involvement of SS was an independent risk factor of death after transplantation. Death-censored graft survival was 97.2% after 1 and 3 years, and 92.8% after 5 years. Recurrence of scleroderma renal crisis was diagnosed in three cases. In our study, patient and graft survivals after kidney transplantation can be considered as excellent. On this basis, we propose that in the absence of extrarenal contraindication, SS patients presenting with ESRD should be considered for kidney transplantation

Induced Cognitive Impairments Reversed by Grafts of Neural Precursors: A Longitudinal Study in a Macaque Model of Parkinson's Disease

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Principles of inter-areal connections of the macaque cortex

The operation of real world networks is largely determined by their weighted and spatial characteristics. Surprisingly little is known about these features in cortex. We generated in macaque, a consistent database of inter-areal connections comprising projection densities (link weights) and physical lengths. Contrary to previous assumptions, the cortical connection matrix is dense (66%) and therefore, not a small-world graph. Link weights are both highly specific and heterogeneous and we show that it is these properties that characterize the network. The embedding of this weighted network is governed by a distance rule that predicts both its binary features as well as the global and local communication efficiencies. Analysis of the efficiency of this weighted network suggests that small changes in global communication efficiency are offset by large changes in local efficiency. These findings indicate a weight-based hierarchical layering in cortical architecture and processing