PSD-95 protects synapses from β-amyloid

Beta-amyloid (Aβ) depresses excitatory synapses by a poorly understood mechanism requiring NMDA receptor (NMDAR) function. Here, we show that increased PSD-95, a major synaptic scaffolding molecule, blocks the effects of Aβ on synapses. The protective effect persists in tissue lacking the AMPA receptor subunit GluA1, which prevents the confounding synaptic potentiation by increased PSD-95. Aβ modifies the conformation of the NMDAR C-terminal domain (CTD) and its interaction with protein phosphatase 1 (PP1), producing synaptic weakening. Higher endogenous levels or overexpression of PSD-95 block Aβ-induced effects on the NMDAR CTD conformation, its interaction with PP1, and synaptic weakening. Our results indicate that increased PSD-95 protects synapses from Aβ toxicity, suggesting that low levels of synaptic PSD-95 may be a molecular sign indicating synapse vulnerability to Aβ. Importantly, pharmacological inhibition of its depalmitoylation increases PSD-95 at synapses and rescues deficits caused by Aβ, possibly opening a therapeutic avenue against Alzheimer’s disease

On-Line Monitoring for Temporal Logic Robustness

In this paper, we provide a Dynamic Programming algorithm for on-line monitoring of the state robustness of Metric Temporal Logic specifications with past time operators. We compute the robustness of MTL with unbounded past and bounded future temporal operators MTL over sampled traces of Cyber-Physical Systems. We implemented our tool in Matlab as a Simulink block that can be used in any Simulink model. We experimentally demonstrate that the overhead of the MTL robustness monitoring is acceptable for certain classes of practical specifications

A Theory of Sampling for Continuous-time Metric Temporal Logic

This paper revisits the classical notion of sampling in the setting of real-time temporal logics for the modeling and analysis of systems. The relationship between the satisfiability of Metric Temporal Logic (MTL) formulas over continuous-time models and over discrete-time models is studied. It is shown to what extent discrete-time sequences obtained by sampling continuous-time signals capture the semantics of MTL formulas over the two time domains. The main results apply to "flat" formulas that do not nest temporal operators and can be applied to the problem of reducing the verification problem for MTL over continuous-time models to the same problem over discrete-time, resulting in an automated partial practically-efficient discretization technique.Comment: Revised version, 43 pages

Labour Market and Social Policy in Italy: Challenges and Changes. Bertelsmann Policy Brief #2016/02

vEight years after the outbreak of the financial crisis, Italy has still to cope with and overcome a plethora of economic and social challenges. On top of this, it faces an unfavourable demographic structure and severe disparities between its northern and southern regions. Some promising reforms have recently been enacted, specifically targeting poverty and social exclusion. However, much more remains to be done on the way towards greater economic stability and widely shared prosperity

Влияние фенилгидразина и алкилсульфатов на осмотическую чувствительность эритроцитов млекопитающих

Показано, что чувствительность эритроцитов млекопитающих к гипертоническому стрессу при 37 °С после обработки фенилгидразином зависит от видовой принадлежности клеток. Установлено, что модификация фенилгидразином эритроцитов млекопитающих приводит к снижению антигемолитической активности алкилкилсульфатов в условиях гипертонического стресса.Показано, що чутливість еритроцитів ссавців до гіпертонічного стресу при 37 °С після обробки фенілгідразином залежить від видової приналежності клітин. Встановлено, що модифікація фенілгідразином еритроцитів ссавців призводить до зниження антигемолітичної активності алкілсульфатів в умовах гіпертонічного стресу.It is shown that the sensitivity of mammalian erythrocytes to hypertonic stress at 37 °C after the treatment with phenylhydrazine depends on the species of a cell. We have established that the modification with phenylhydrazine of mammalian erythrocytes leads to a decrease of the alkyl sulfates antihemolytic activity under hypertonic stress

Robust Model-Checking of Linear-Time Properties in Timed Automata

International audienceFormal verification of timed systems is well understood, but their \emphimplementation is still challenging. Recent works by Raskin \emphet al. have brought out a model of parameterized timed automata that can be used to prove \emphimplementability of timed systems for safety properties. We define here a more general notion of robust model-checking for linear-time properties, which consists in verifying whether a property still holds even if the transitions are slightly delayed or expedited. We provide PSPACE algorithms for the robust model-checking of Büchi-like and LTL properties. We also verify bounded-response-time properties

Model Checking Classes of Metric LTL Properties of Object-Oriented Real-Time Maude Specifications

This paper presents a transformational approach for model checking two important classes of metric temporal logic (MTL) properties, namely, bounded response and minimum separation, for nonhierarchical object-oriented Real-Time Maude specifications. We prove the correctness of our model checking algorithms, which terminate under reasonable non-Zeno-ness assumptions when the reachable state space is finite. These new model checking features have been integrated into Real-Time Maude, and are used to analyze a network of medical devices and a 4-way traffic intersection system.Comment: In Proceedings RTRTS 2010, arXiv:1009.398

Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R 95845 at 2.8 å resolution

AbstractBackground: HIV-1 reverse transcriptase (RT) is a multifunctional enzyme that copies the RNA genome of HIV-1 into DNA. It is a heterodimer composed of a 66 kDa (p66) and a 51 kDa (p51) subunit. HIV-1 RT is a crucial target for structure-based drug design, and potent inhibitors have been identified, whose efficacy, however, is limited by drug resistance.Results The crystal structure of HIV-1 RT in complex with the non-nucleoside inhibitor α-anilinophenylacetamide (α-APA) R 95845 has been determined at 2.8 å resolution. The inhibitor binds in a hydrophobic pocket near the polymerase active site. The pocket contains five aromatic amino acid residues and the interactions of the side chains of these residues with the aromatic rings of non-nucleoside inhibitors appear to be important for inhibitor binding. Most of the amino acid residues where mutations have been correlated with high levels of resistance to non-nucleoside inhibitors of HIV-1 RT are located close to α-APA. The overall fold of HIV-1 RT in complex with α-APA is similar to that found when in complex with nevirapine, another non-nucleoside inhibitor, but there are significant conformational changes relative to an HIV-1 RT/DNA/Fab complex.Conclusion The non-nucleoside inhibitor-binding pocket has a flexible structure whose mobility may be required for effective polymerization, and may be part of a hinge that permits relative movements of two subdomains of the p66 subunit denoted the ‘palm’ and ‘thumb’. An understanding of the structure of the inhibitor-binding pocket, of the interactions between HIV-1 RT and α-APA, and of the locations of mutations that confer resistance to inhibitors provides a basis for structure-based design of chemotherapeutic agents for the treatment of AIDS

LNCS

We solve the offline monitoring problem for timed propositional temporal logic (TPTL), interpreted over dense-time Boolean signals. The variant of TPTL we consider extends linear temporal logic (LTL) with clock variables and reset quantifiers, providing a mechanism to specify real-time constraints. We first describe a general monitoring algorithm based on an exhaustive computation of the set of satisfying clock assignments as a finite union of zones. We then propose a specialized monitoring algorithm for the one-variable case using a partition of the time domain based on the notion of region equivalence, whose complexity is linear in the length of the signal, thereby generalizing a known result regarding the monitoring of metric temporal logic (MTL). The region and zone representations of time constraints are known from timed automata verification and can also be used in the discrete-time case. Our prototype implementation appears to outperform previous discrete-time implementations of TPTL monitoring