Phosphorylation but Not Oligomerization Drives the Accumulation of Tau with Nucleoporin Nup98

Tau is a neuronal protein that stabilizes axonal microtubules (MTs) in the central nervous system. In Alzheimer’s disease (AD) and other tauopathies, phosphorylated Tau accumulates in intracellular aggregates, a pathological hallmark of these diseases. However, the chronological order of pathological changes in Tau prior to its cytosolic aggregation remains unresolved. These include its phosphorylation and detachment from MTs, mislocalization into the somatodendritic compartment, and oligomerization in the cytosol. Recently, we showed that Tau can interact with phenylalanine-glycine (FG)-rich nucleoporins (Nups), including Nup98, that form a diffusion barrier inside nuclear pore complexes (NPCs), leading to defects in nucleocytoplasmic transport. Here, we used surface plasmon resonance (SPR) and bio-layer interferometry (BLI) to investigate the molecular details of Tau:Nup98 interactions and determined how Tau phosphorylation and oligomerization impact the interactions. Importantly, phosphorylation, but not acetylation, strongly facilitates the accumulation of Tau with Nup98. Oligomerization, however, seems to inhibit Tau:Nup98 interactions, suggesting that Tau-FG Nup interactions occur prior to oligomerization. Overall, these results provide fundamental insights into the molecular mechanisms of Tau-FG Nup interactions within NPCs, which might explain how stress-and disease-associated posttranslational modifications (PTMs) may lead to Tau-induced nucleocytoplasmic transport (NCT) failure. Intervention strategies that could rescue Tau-induced NCT failure in AD and tauopathies will be further discussed

Deep lithospheric structures along the southern central Chile Margin from wide-angle P-wave modellilng

Crustal- and upper-mantle structures of the subduction zone in south central Chile, between 42 degrees S and 46 degrees S, are determined from seismic wide-angle reflection and refraction data, using the seismic ray tracing method to calculate minimum parameter models. Three profiles along differently aged segments of the subducting Nazca Plate were analysed in order to study subduction zone structure dependencies related to the age, that is, thermal state, of the incoming plate. The age of the oceanic crust at the trench ranges from 3 Ma on the southernmost profile, immediately north of the Chile triple junction, to 6.5 Ma old about 100 km to the north, and to 14.5 Ma old another 200 km further north, off the Island of Chiloe. Remarkable similarities appear in the structures of both the incoming as well as the overriding plate. The oceanic Nazca Plate is around 5 km thick, with a slightly increasing thickness northward, reflecting temperature changes at the time of crustal generation. The trench basin is about 2 km thick except in the south where the Chile Ridge is close to the deformation front and only a small, 800-m-thick trench infill could develop. In south central Chile, typically three quarters (1.5 km) of the trench sediments subduct below the decollement in the subduction channel. To the north and south of the study area, only about one quarter to one third of the sediments subducts, the rest is accreted above. Similarities in the overriding plate are the width of the active accretionary prism, 35-50 km, and a strong lateral crustal velocity gradient zone about 75-80 km landward from the deformation front, where landward upper-crustal velocities of over 5.0-5.4 km s<SU-1</SU decrease seaward to around 4.5 km s<SU-1</SU within about 10 km, which possibly represents a palaeo-backstop. This zone is also accompanied by strong intraplate seismicity. Differences in the subduction zone structures exist in the outer rise region, where the northern profile exhibits a clear bulge of uplifted oceanic lithosphere prior to subduction whereas the younger structures have a less developed outer rise. This plate bending is accompanied by strongly reduced rock velocities on the northern profile due to fracturing and possible hydration of the crust and upper mantle. The southern profiles do not exhibit such a strong alteration of the lithosphere, although this effect may be counteracted by plate cooling effects, which are reflected in increasing rock velocities away from the spreading centre. Overall there appears little influence of incoming plate age on the subduction zone structure which may explain why the M-w = 9.5 great Chile earthquake from 1960 ruptured through all these differing age segments. The rupture area, however, appears to coincide with a relatively thick subduction channel

Farnesylated Nuclear Proteins Kugelkern and Lamin Dm0 Affect Nuclear Morphology by Directly Interacting with the Nuclear Membrane

Nuclear shape changes are observed during a variety of developmental processes, pathological conditions and ageing. Here, the molecular mechanism is analyzed how the farnesylated nuclear proteins interact with the nuclear envelope and deform the phospholipid bilayer

Classification of the nucleolytic ribozymes based upon catalytic mechanism

The nucleolytic ribozymes carry out site-specific RNA cleavage reactions by nucleophilic attack of the 2’-oxygen atom on the adjacent phosphorus with an acceleration of a million-fold or greater. A major part of this arises from concerted general acid-base catalysis. Recent identification of new ribozymes has expanded the group to a total of nine and this provides a new opportunity to identify sub-groupings according to the nature of the general base and acid. These include nucleobases, hydrated metal ions, and 2’-hydroxyl groups. Evolution has selected a number of different combinations of these elements that lead to efficient catalysis. These differences provide a new mechanistic basis for classifying these ribozymes

Выбор метода периоперационного обезболивания при тотальном эндопротезировании тазобедренного сустава

Objective: to evaluate the efficiency and safety of various perioperative analgesia modes during total hip joint replacement (THR). Subjects and methods. A randomized controlled trial enrolled 90 patients who were divided into 3 groups according to the choice of a perioperative analgesia mode on day 1: general sevofluorane anesthesia, by switching to intravenous patient-controlled analgesia with fentanyl (PCA, GA group), a combination of general and spinal bupiva-caine anesthesia, by switching to PCA with fentanyl (SA group), a combination of general and epidural ropivacaine anesthesia with continuous postoperative epidural ropivacaine infusion (EA group). All the patients received non-opi-oid analgesics after surgery. Results. Prolonged epidural block ensures better postoperative analgesia at rest and during mobilization and a less need for opioids than other analgesia modes (p<0.05). With neuroaxial block, the preoperative need for sympatomimetics is much higher than that in the GA group (p<0.05). There is also a trend toward a higher incidence of cardiac arrhythmias and postoperative nausea and vomiting in the SA and EA groups. There are no differences in the frequency of hemotransfusion and postoperative complications and the length of hospital stay. Conclusion. Prolonged epidural block provides excellent perioperative analgesia during THR, but the risk-benefit ratio needs to be carefully assessed when an analgesia mode is chosen.Цель исследования . Оценить эффективность и безопасность различных методов периоперационного обезболивания при тотальном эндопротезировании тазобедренного сустава (ТЭТС). Материал и методы. В рандомизированное контролируемое исследование вошло 90 пациентов, которые были разделены на 3 группы в зависимости от выбора метода периоперационного обезболивания в 1-е сутки: общая анестезия севофлураном с переходом на внутривенную контролируемую пациентом анальгезию фентанилом (КПА, группа ОА), комбинация общей и спинномозговой анестезии бупивакаином с переходом на КПА фентанилом (группа СА), комбинация общей и эпиду-ральной анестезии ропивакаином с постоянной послеоперационной эпидуральной инфузией ропивакаина (группа ЭА). Все пациенты после операции получали неопиоидные анальгетики. Результаты. Продленная эпидуральная блокада обеспечивает лучшее послеоперационное обезболивание в покое и при движении, а также меньшую потребность в опиоидах в сравнении с другими группами (р<0,05). При нейроаксиальной блокаде периоперационная потребность в симпатомиметиках значительно выше, чем в группе ОА (р<0,05). Также отмечена тенденция к большей частоте возникновения нарушений ритма сердца и послеоперационной тошноты и рвоты в группах СА и ЭА. Различий в частоте проведения гемотрансфузии, послеоперационных осложнений и длительности госпитализации выявлено не было. Заключение. Продленная эпидуральная блокада обеспечивает отличную периоперационную анальгезию при ТЭТС, но при выборе метода обезболивания необходимо тщательно оценивать соотношение риск-польза

Mycobacterium tuberculosis releases an antacid that remodels phagosomes

International audienc

Search for neutral charmless B decays at LEP

A search for rare charmless decays of \Bd and \Bs mesons has been performed in the exclusive channels \Bd_{(\mathrm s)}\ra\eta\eta, \Bd_{(\mathrm s)}\ra\eta\pio and \Bd_{(\mathrm s)}\ra\pio\pio. The data sample consisted of three million hadronic \Zo decays collected by the L3 experiment at LEP from 1991 through 1994. No candidate event has been observed and the following upper limits at 90\% confidence level on the branching ratios have been set \begin{displaymath} \mathrm{Br}(\Bd\ra\eta\eta)<4.1\times 10^{-4},\,\, \mathrm{Br}(\Bs\ra\eta\eta)<1.5\times 10^{-3},\,\, \end{displaymath} \begin{displaymath} \mathrm{Br}(\Bd\ra\eta\pio)<2.5\times 10^{-4},\,\, \mathrm{Br}(\Bs\ra\eta\pio)<1.0\times 10^{-3},\,\, \end{displaymath} \begin{displaymath} \mathrm{Br}(\Bd\ra\pio\pio)<6.0\times 10^{-5},\,\, \mathrm{Br}(\Bs\ra\pio\pio)<2.1\times 10^{-4}. \end{displaymath} These are the first experimental limits on \Bd\ra\eta\eta and on the \Bs neutral charmless modes