How Cholesterol Constrains Glycolipid Conformation for Optimal Recognition of Alzheimer's β Amyloid Peptide (Aβ1-40)

Membrane lipids play a pivotal role in the pathogenesis of Alzheimer's disease, which is associated with conformational changes, oligomerization and/or aggregation of Alzheimer's β-amyloid (Aβ) peptides. Yet conflicting data have been reported on the respective effect of cholesterol and glycosphingolipids (GSLs) on the supramolecular assembly of Aβ peptides. The aim of the present study was to unravel the molecular mechanisms by which cholesterol modulates the interaction between Aβ1–40 and chemically defined GSLs (GalCer, LacCer, GM1, GM3). Using the Langmuir monolayer technique, we show that Aβ1–40 selectively binds to GSLs containing a 2-OH group in the acyl chain of the ceramide backbone (HFA-GSLs). In contrast, Aβ1–40 did not interact with GSLs containing a nonhydroxylated fatty acid (NFA-GSLs). Cholesterol inhibited the interaction of Aβ1–40 with HFA-GSLs, through dilution of the GSL in the monolayer, but rendered the initially inactive NFA-GSLs competent for Aβ1–40 binding. Both crystallographic data and molecular dynamics simulations suggested that the active conformation of HFA-GSL involves a H-bond network that restricts the orientation of the sugar group of GSLs in a parallel orientation with respect to the membrane. This particular conformation is stabilized by the 2-OH group of the GSL. Correspondingly, the interaction of Aβ1–40 with HFA-GSLs is strongly inhibited by NaF, an efficient competitor of H-bond formation. For NFA-GSLs, this is the OH group of cholesterol that constrains the glycolipid to adopt the active L-shape conformation compatible with sugar-aromatic CH-π stacking interactions involving residue Y10 of Aβ1–40. We conclude that cholesterol can either inhibit or facilitate membrane-Aβ interactions through fine tuning of glycosphingolipid conformation. These data shed some light on the complex molecular interplay between cell surface GSLs, cholesterol and Aβ peptides, and on the influence of this molecular ballet on Aβ-membrane interactions

TDP-43 régule la dynamique et la fonction des Granules de Stress via G3BP1

Les Granule de Stress (GS) sont des inclusions cytoplasmiques contenant des protéines et des ARNm qui s’assemblent en réponse à l’exposition à un stress. Leur formation fait partie intégrante de la réponse cellulaire au stress et est considérée comme une étape déterminante pour la résistance au stress et la survie cellulaire. Actuellement, les GS sont reliés à divers pathologies allant des infections virales aux maladies neurovégétatives. L’une d’entre elle, la Sclérose Latérale Amyotrophique (SLA) est particulièrement agressive, caractérisée par une perte des neurones moteurs aboutissant à la paralysie et à la mort du patient en cinq ans en moyenne. Les mécanismes de déclenchement de la pathologie restent encore à déterminer. TDP-43 (TAR DNA binding protein 43) et FUS (Fused in liposarcoma) sont deux protéines reliées à la pathologie qui présentent des similarités de structure et de fonction, suggérant un mécanisme commun de toxicité. TDP-43 et FUS sont toutes les deux recrutées au niveau des GS en condition de stress. Nous avons démontré pour la première fois que la fonction des GS est de protéger les ARNm de la dégradation induite par l’exposition au stress. Cette fonction n’était que suspectée jusqu’alors. De plus nous avons mis en évidence que G3BP1 (Ras GTPase-activating protein-binding protein 1) est l’effectrice de cette fonction via son implication dans la dynamique de formation des GS. TDP-43 étant un régulateur de G3BP1, nous prouvons ainsi que la perte de fonction de TDP-43/G3BP1 aboutit à un défaut de réponse au stress aboutissant à une vulnérabilisation cellulaire. Le mécanisme de toxicité emprunter par FUS diffère de celui de TDP-43 et ne semble pas passer par une perte de fonction dans le cadre de la réponse au stress.Stress Granule (SGs) are cytoplasmic inclusions sequestering proteins and mRNAs following a stress exposure. Their assembly is part of the cell stress response and is considered an important step for stress resistance and cell survival. SG are currently linked to different pathogenesis from viral infection to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).ALS is an aggressive disease, characterized by neuronal death leading to paralysis and death within five years. Pathogenesis mechanisms are still not fully understood. TDP-43 (TAR DNA binding protein 43) and FUS (Fused in liposarcoma) are two proteins linked to the disease that share many structural features and functions suggesting a common toxicity mechanism. TDP-43 and FUS are both recruited to SGs in stress conditions. We demonstrate for the first time that SGs function to protect mRNA from degradation induced after stress exposure, a function that was only suspected until now. We also prove that G3BP1 (Ras GTPase-activating protein-binding protein 1) is the effector of this function via it’s implication in the dynamics of SG formation. As TDP-43 is a regulator of G3BP1, we prove that loss of TDP-43/G3BP1 function leads to a stress response defect yielding increased cellular vulnerability. Furthermore, we have discovered that the mechanism of toxicity for FUS is different from TDP-43, and does not implicate a loss of function mechanism during the cell stress response

Eheä identiteetti - avain johdonmukaiseen yrityskuvaan : case: TS-Yhtymä Oy

Siirretty Doriast

Louis Aimé Augustin Leprince, inventeur et artiste, précurseur du cinéma

« Beim dem Apparat von Leprince finden wir zum ersten Male das Element bei dem Reihenbilderapparat, das kurze Zeit später dem Kinematographen seinen Siegeszug ermöglichte… Der Schritt zum Einfachen wurde noch nicht gewagt ; trotzdem aber läßt sich nicht verkennen, daß von diesem Apparat zum Urtyp des modernen Kinematographen mit einem Objektiv und absatzweise geschalteten Film ein heute scheinbar ausserordentlich leicht zu fassender Gedanke hinüberleitet. » (« Dans l’appareil de Leprince nous..

Muséographier le sport ou l’exposition comme terrain de jeu

Comment mettre en scène les collections et les pratiques sportives ? Des muséographes confrontés à ce challenge livrent, à travers deux de leurs réalisations, les démarches qu’ils ont adoptées pour que les histoires et les émotions spécifiques à ce domaine puissent être traduites, au-delà de la simple relation de l’événement sportif, à travers des dispositifs interactifs ludiques et pédagogiques

Sistema de Evaluación Integral para la Calidad Educativa : Colegio Aulas Colombianas San Luis (IED) Localidad de Santa Fe

Este documento tiene como finalidad presentar y promover la construcción de estrategias para que el colegio pueda implementar la evaluación como una práctica para aprender y mejorar

G3BP1 promotes stress-induced RNA granule interactions to preserve polyadenylated mRNA

G3BP1, a target of TDP-43, is required for normal stress granule (SG) assembly, but the functional consequences of failed SG assembly remain unknown. Here, using both transformed cell lines and primary neurons, we investigated the functional impact of this disruption in SG dynamics. While stress-induced translational repression and recruitment of key SG proteins was undisturbed, depletion of G3BP1 or its upstream regulator TDP-43 disturbed normal interactions between SGs and processing bodies (PBs). This was concomitant with decreased SG size, reduced SG–PB docking, and impaired preservation of polyadenylated mRNA. Reintroduction of G3BP1 alone was sufficient to rescue all of these phenotypes, indicating that G3BP1 is essential for normal SG–PB interactions and SG function

TDP-43 induces p53-mediated cell death of cortical progenitors and immature neurons

TAR DNA-binding protein 43 (TDP-43) is a key player in neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Accumulation of TDP-43 is associated with neuronal death in the brain. How increased and disease-causing mutant forms of TDP-43 induce cell death remains unclear. Here we addressed the role of TDP-43 during neural development and show that reduced TDP-43 causes defects in neural stem/progenitor cell proliferation but not cell death. However, overexpression of wild type and TDP-43A315T proteins induce p53-dependent apoptosis of neural stem/progenitors and human induced pluripotent cell (iPS)-derived immature cortical neurons. We show that TDP-43 induces expression of the proapoptotic BH3-only genes Bbc3 and Bax, and that p53 inhibition rescues TDP-43 induced cell death of embryonic mouse, and human cortical neurons, including those derived from TDP-43G298S ALS patient iPS cells. Hence, an increase in wild type and mutant TDP-43 induces p53-dependent cell death in neural progenitors developing neurons and this can be rescued. These findings may have important implications for accumulated or mutant TDP-43 induced neurodegenerative diseases

Application of dye leak test for gastrointestinal tract tightness control in bariatric surgery

Проблема ожирения широко распространена как в Республике Беларусь, так и в мировом масштабе. Так по данным ВОЗ ожирением страдают 640 млн человек в мире. В Республике Беларусь в 2015–2016 г. распространенность ожирения среди взрослого населения составляла 24,5 % . Морбидное ожирение при ИМТ >40 кг/м2, или >35 кг/м2 при наличии сопутствующей патологии, часто оказывается рефрактерным к консервативным методам лечения и наиболее эффективным способом устойчивого снижения массы тела пациентов является именно хирургическое вмешательство. Среди выполняемых бариатрических операций преобладают вмешательства, предусматривающие резекцию или шунтирование желудка. Так в мире доля гастрошунтирования на петле по Ру составляет 41,9 %, рукавной резекция желудка – 32,6 %, а на долю минигастрошунтирования приходится 5,0 %. Одним из наиболее частых осложнений после перечисленных бариатрических вмешательств является несостоятельность линии швов желудка или анастомозов. После рукавной резекции желудка частота этого осложнения достигает 3,9 %, а после гастрошунтирования на петле по Ру – до 8 %. The problem of obesity is widespread both in the Republic of Belarus and on a global scale. So, according to the WHO, 640 million people in the world suffer from obesity [6]. In the Republic of Belarus in 2015–2016.rasprostranennost' ozhireniya sredi vzroslogo naseleniya sostavlyala 24,5 %. Morbidnoye ozhireniye pri IMT >40 kg/m 2 , ili >35 kg/m 2 pri nalichii soputstvuyushchey patologii, chasto okazyvayetsya refrakternym k konservativnym the prevalence of obesity among the adult population was 24.5 %. Morbid obesity with a BMI >40 kg/m 2 , or >35 kg/m 2 in the presence of concomitant pathology, is often weight loss in patients is precisely surgical intervention. Among the performed bariatric operations, interventions involving gastric resection or bypass surgery prevail. Thus, in the world, the share of gastric bypass surgery on a Roux-type loop is 41.9 %, sleeve gastrectomy is 32.6 %, and the share of mini-gastric bypass is 5.0 %. One of the most common complications after the listed bariatric procedures is the failure of the gastric suture line or anastomoses. After gastric sleeve gastrectomy, the incidence of this complication reaches 3.9 %, and after Roux-en-Y loop gastric bypass surgery – up to 8 %