Cell-surface expressed contactin 1 and neurofascin 155 control wiring of the nervous system and interact across cells to form and maintain paranodal myelin-axon junctions. The molecular mechanism of ...contactin 1 - neurofascin 155 adhesion complex formation is unresolved. Crystallographic structures of complexed and individual contactin 1 and neurofascin 155 binding regions presented here, provide a rich picture of how competing and complementary interfaces, post-translational glycosylation, splice differences and structural plasticity enable formation of diverse adhesion sites. Structural, biophysical, and cell-clustering analysis reveal how conserved Ig1-2 interfaces form competing heterophilic contactin 1 - neurofascin 155 and homophilic neurofascin 155 complexes whereas contactin 1 forms low-affinity clusters through interfaces on Ig3-6. The structures explain how the heterophilic Ig1-Ig4 horseshoe's in the contactin 1 - neurofascin 155 complex define the 7.4 nm paranodal spacing and how the remaining six domains enable bridging of distinct intercellular distances.
Signaling of SorCS receptors by proneurotrophin ligands regulates neuronal plasticity, induces apoptosis and is associated with mental disorders. The detailed structure of SorCS2 and its ...extracellular specificity are unresolved. Here we report crystal structures of the SorCS2-NGF complex and unliganded SorCS2 ectodomain, revealing cross-braced SorCS2 homodimers with two NGF dimers bound in a 2:4 stoichiometry. Five out of six SorCS2 domains directly contribute to dimer formation and a C-terminal membrane proximal unreported domain, with an RNA recognition motif fold, locks the dimer in an intermolecular head-to-tail interaction. The complex structure shows an altered SorCS2 conformation indicating substantial structural plasticity. Both NGF dimer chains interact exclusively with the top face of a SorCS2 β-propeller. Biophysical experiments reveal that NGF, proNGF, and proBDNF bind at this site on SorCS2. Taken together, our data reveal a structurally flexible SorCS2 receptor that employs the large β-propeller as a ligand binding platform.
•Fish hydrolysate contains n-3 LC-PUFAs and low molecular weight peptides.•Fish hydrolysate prevents age-related short-term memory deficits.•Fish hydrolysate affects navigation strategies during ...spatial learning.•Fish hydrolysate possesses immunomodulatory and anxiolytic properties.•Fish hydrolysate is promising for the prevention of age-related cognitive decline.
Brain aging is characterized by a decline in cognitive functions, which can lead to the development of neurodegenerative pathologies. Age-related spatial learning and memory deficits are associated with a chronic low-grade inflammation. Anxiety disorders and stress response alterations, occurring for a part of the elderly, have also been linked to an increased neuroinflammation and thus, an accelerated cognitive decline. Nutrition is an innovative strategy to prevent age-related cognitive impairments. Among the nutrients, n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides from proteins, especially those from marine resources, are good candidates for their immunomodulatory, anxiolytic and neuroprotective properties. The aim of this study is to determine the combined effect of n-3 LC-PUFAs and low molecular weight peptides on cognitive functions, and their mechanism of action. We are the first to show that a dietary supplementation with a fish hydrolysate containing n-3 LC-PUFAs and low molecular weight peptides prevented the age-related spatial short-term memory deficits and modulated navigation strategies adopted during spatial learning. In addition, the fish hydrolysate displayed anxiolytic activities with the reduction of anxiety-like behaviour in aged mice, restored the plasmatic corticosterone levels similar to adult animals following an acute stress and modulated the hypothalamic stress response. These effects on behaviour can be explained by the immunomodulatory and neuroprotective properties of the fish hydrolysate that limited microgliosis in vivo, decreased LPS-induced expression of pro-inflammatory cytokines and increased the expression of growth factors such as BDNF and NGF in vitro. Thus, n-3 LC-PUFAs and low molecular weight peptides contained in the fish hydrolysate can play an important role in the limitation of neuroinflammation and stress response alterations during aging and represent a potential strategy for the prevention of age-related cognitive decline.
Type-I transmembrane proteins represent a large group of 1,412 proteins in humans with a multitude of functions in cells and tissues. They are characterized by an extracellular, or luminal, ...N-terminus followed by a single transmembrane helix and a cytosolic C-terminus. The domain composition and structures of the extracellular and intercellular segments differ substantially amongst its members. Most of the type-I transmembrane proteins have roles in cell signaling processes, as ligands or receptors, and in cellular adhesion. The extracellular segment often determines specificity and can control signaling and adhesion. Here we focus on recent structural understanding on how the extracellular segments of several diverse type-I transmembrane proteins engage in interactions and can undergo conformational changes for their function. Interactions at the extracellular side by proteins on the same cell or between cells are enhanced by the transmembrane setting. Extracellular conformational domain rearrangement and structural changes within domains alter the properties of the proteins and are used to regulate signaling events. The combination of structural properties and interactions can support the formation of larger-order assemblies on the membrane surface that are important for cellular adhesion and intercellular signaling.
La neuroinflammation représente un mécanisme de défense crucial du système nerveux central contre les agents pathogènes afin d’assurer un retour à l’homéostasie dans le cerveau. Cette réponse ...immunitaire physiologique est orchestrée par les cellules microgliales, les cellules du système immunitaire cérébral. Cependant, une production soutenue et incontrôlée des facteurs pro-inflammatoires associée à une activation microgliale ainsi qu’une dérégulation de la résolution de l’inflammation contribuent à l’apparition d’une inflammation chronique à bas bruit, comme observé au cours du vieillissement et dans les maladies neurodégénératives, pouvant entraîner des lésions neuronales responsables, en partie, des troubles cognitifs. La nutrition apparaît comme une stratégie innovante pour prévenir les altérations liées à la neuroinflammation. Les acides gras polyinsaturés n-3 (AGPI n-3) à longue chaîne et les peptides de petits poids moléculaires sont de bons candidats en raison de leurs propriétés immunomodulatrices et pro-résolutives via la production d’oxylipines. L’objectif de cette étude est d’évaluer le potentiel anti-inflammatoire du Mnemosyss®, un hydrolysat de coproduits marins combinant ces composés, sur l’inflammation aiguë et de comparer cet effet à une supplémentation en DHA seul.
Des souris âgées de 7 semaines ont été supplémentées pendant 18jours avec du Mnemosyss®, du DHA ou une solution contrôle. L’inflammation aiguë a été induite par une injection intrapéritonéale de lipopolysaccharide (LPS) et les souris ont été euthanasiées 2h après. Les analyses ont été effectuées dans l’hippocampe. L’expression des marqueurs inflammatoires, des marqueurs d’activation microgliale a été mesurée par RT-qPCR. L’expression protéique de IκB et de NF-κB a été quantifiée par Western-Blot. Enfin, la composition en oxylipines a été évaluée par chromatographie liquide couplée à la spectrométrie de masse.
En réponse au LPS, la supplémentation en Mnemosyss® diminue l’expression des cytokines pro-inflammatoires IL-6 (p<0,001), IL-1β (p<0,001) et TNF-α (p<0,01) alors que le DHA réduit uniquement l’expression de l’IL-6 (p<0,01). Cette baisse de l’expression des cytokines pro-inflammatoires est associée à une augmentation de l’expression protéique de IκB (p<0,05 et p<0,01 vs. DHA et contrôle, respectivement) et à une modulation des marqueurs d’activation microgliale dans l’hippocampe. Les effets du Mnemosyss® pourraient être dus, en partie, au changement du profil en oxylipines vers un profil plus anti-inflammatoire par rapport à la supplémentation en DHA.
Cette étude démontre le pouvoir anti-inflammatoire et pro-résolutif du Mnemosyss®. Celui-ci est même plus efficace que le DHA seul pourtant apporté en plus grande quantité suggérant un effet des peptides seuls ou une potentialisation du DHA par les peptides. Il pourrait donc être proposé pour freiner l’inflammation au cours du vieillissement ou lors de pathologies inflammatoires aiguës ou chroniques.
The cell-surface attached glycoprotein contactin 2 is ubiquitously expressed in the nervous system and mediates homotypic cell-cell interactions to organize cell guidance, differentiation, and ...adhesion. Contactin 2 consists of six Ig and four fibronectin type III domains (FnIII) of which the first four Ig domains form a horseshoe structure important for homodimerization and oligomerization. Here we report the crystal structure of the six-domain contactin 2
and show that the Ig5-Ig6 combination is oriented away from the horseshoe with flexion in interdomain connections. Two distinct dimer states, through Ig1-Ig2 and Ig3-Ig6 interactions, together allow formation of larger oligomers. Combined size exclusion chromatography with multiangle light scattering (SEC-MALS), small-angle X-ray scattering (SAXS) and native MS analysis indicates contactin 2
oligomerizes in a glycan dependent manner. SAXS and negative-stain electron microscopy reveals inherent plasticity of the contactin 2 full-ectodomain. The combination of intermolecular binding sites and ectodomain plasticity explains how contactin 2 can function as a homotypic adhesion molecule in diverse intercellular environments.
Objective Pulmonary inflammatory pseudotumor is an uncommon disease, often with a benign presentation. However, invasion of adjacent thoracic organs, local recurrence, and distant metastases have ...been described, and the best management strategy remains unclear. We present a single large institutional experience in patients with pulmonary inflammatory pseudotumor and propose guidelines for treatment of this patient population. Methods A retrospective study was performed to review all patients who underwent resection for pulmonary inflammatory pseudotumor between 1974 and 2007. Results A total of 25 patients were treated with pulmonary inflammatory pseudotumor at the Marie Lannelongue Hospital. The mean age was 33 years. Two patients were referred after an incomplete resection. One patient presented with cerebral metastasis. We performed a complete resection in all patients: wedge resection (n = 7), lobectomy (n = 6), sleeve arterial lobectomy (n = 1), lobectomy with thoracic inlet exenteration (n = 2), bilobectomy (n = 2), pneumonectomy with brain metastasectomy (n = 1), sleeve pneumonectomy (n = 2), sleeve main bronchus or tracheal resection (n = 2), wedge with sleeve main pulmonary artery resections (n = 1), and sleeve pneumonectomy with esophageal, aortic arch, and right pulmonary artery resection (n = 1). No adjuvant therapy was given to any patients. Postoperative 30-day mortality and morbidity rates were 4% and 8%, respectively. With a mean follow-up of 80 months (range 4–369 months, 100% follow-up), actuarial 10-year survival was 89%. One patient died of an extensive sarcomatous recurrence 2 years after surgery. Conclusion Pulmonary inflammatory pseudotumor is a malignant disease affecting young patients with local invasion, distant metastasis, local recurrence, and sarcomatous degeneration. A complete resection should always be performed at initial presentation because of its high likelihood of cure with aggressive management.
Objective Airway replacement after long-segment tracheal resection for benign and malignant disease remains a challenging problem because of the lack of a substitute conduit. Ideally, an airway ...substitute should be well vascularized, rigid, and autologous to avoid infections, airway stenosis, and the need for immunosuppression. We report the development of an autologous tracheal substitute for long-segment tracheal resection that satisfies these criteria and demonstrates excellent short-term functional results in a large-animal study. Methods Twelve adult pigs underwent long-segment (6 cm, 60% of total length) tracheal resection. Autologous costal cartilage strips measuring 6 cm × 2 mm were harvested from the chest wall and inserted at regular 0.5-cm intervals between dermal layers of a cervical skin flap. The neotrachea was then scaffolded by rotating the composite cartilage skin flap around a silicone stent measuring 6 cm in length and 1.4 cm in diameter. The neotrachea replaced the long segment of tracheal resection, and the donor flap site was closed with a double-Z plasty. Animals were killed at 1 week (group I, n = 4), 2 weeks (group II, n = 4), and 5 weeks (group III, n = 4). In group III the stent was removed 1 week before death. Viability of the neotrachea was monitored by means of daily flexible bronchoscopy and histologic examination at autopsy. Long-term morbidity and mortality were determined by monitoring weight gain, respiratory distress, and survival. Results There was no mortality during the study period. Weight gain was appropriate in all animals. Daily bronchoscopy and postmortem histologic evaluation confirmed excellent viability of the neotrachea. There was no evidence of suture-line dehiscence. Five animals had distal granulomas that were removed by using rigid bronchoscopy. In group III 1 animal had tracheomalacia, which was successfully managed by means of insertion of a silicon stent. Conclusion Airway reconstruction with autologous cervical skin flaps scaffolded with costal cartilages is a novel approach to replace long segments of resected trachea. This preliminary study demonstrates excellent respiratory function and survival in large animals undergoing resection of more than 50% of their native trachea. Use of cervical skin flaps buttressed with costal cartilage is a promising solution for long-segment tracheal replacement.
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