Functional involvement of γ-secretase in signaling of the triggering receptor expressed on myeloid cells-2 (TREM2).

BACKGROUND: Triggering receptor expressed on myeloid cells-2 (TREM2) exerts important functions in the regulation of monocytes, like dendritic cells, osteoclasts, tissue macrophages, and microglia. Mutations in TREM2 are associated with several diseases, including Nasu-Hakola disease, frontotemporal dementia, and Alzheimer's disease (AD). TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis. FINDINGS: We show that inhibition of γ-secretase-dependent cleavage of the TREM2 C-terminal fragment in cellular membranes interferes with TREM2-dependent signaling and cellular function. Inhibition of γ-secretase decreases membrane-proximal signaling and intracellular Ca(2+) response. Decreased signaling alters morphological changes and phagocytic activity of cells upon selective stimulation of TREM2. CONCLUSIONS: The data demonstrate the importance of γ-secretase-dependent intramembrane processing in TREM2-mediated signaling and, thus, a functional relation of two AD-associated proteins

Mechanisms underlying dual effects of serotonin during development of Helisoma trivolvis (Mollusca).

BACKGROUND: Serotonin (5-HT) is well known as widely distributed modulator of developmental processes in both vertebrates and invertebrates. It is also the earliest neurotransmitter to appear during neuronal development. In aquatic invertebrates, which have larvae in their life cycle, 5-HT is involved in regulation of stages transition including larval metamorphosis and settlement. However, molecular and cellular mechanisms underlying developmental transition in aquatic invertebrate species are yet poorly understood. Earlier we demonstrated that in larvae of freshwater molluscs and marine polychaetes, endogenous 5-HT released from the neurons of the apical sensory organ (ASO) in response to external stimuli retarded larval development at premetamorphic stages, and accelerated it at metamorphic stages. Here we used a freshwater snail Helisoma trivolvis to study molecular mechanisms underlying these dual developmental effects of 5-HT. RESULTS: Larval development of H. trivolvis includes transition from premetamorphic to metamorphic stages and shares the main features of metamorphosis with free-swimming aquatic larvae. Three types of 5-HT receptors (5-HT1-, 5-HT4- and 5-HT7-like) are functionally active at premetamorphic (trochophore, veliger) and metamorphic (veliconcha) stages, and expression patterns of these receptors and respective G proteins undergo coordinated changes during development. Stimulation of these receptors modulated cAMP-dependent regulation of cell divisions. Expression of 5-HT4- and 5-HT7-like receptors and their downstream Gs protein was down-regulated during the transition of pre- to metamorphic stage, while expression of 5-HT1 -like receptor and its downstream Gi protein was upregulated. In accordance with relative amount of these receptors, stimulation of 5-HTRs at premetamorphic stages induces developmental retardation, while their stimulation at metamorphic stages induces developmental acceleration. CONCLUSIONS: We present a novel molecular mechanism that underlies stage-specific changes in developmental tempo of H. trivolvis larvae in response to endogenous 5-HT produced by the neurons of the ASO. We suggest that consecutive changes in expression patterns of different receptors and their downstream partners in the course of larval development represent the molecular base of larval transition from premetamorphic (non-competent) to metamorphic (competent) state

Assessment of ion kinetic effects in shock-driven inertial confinement fusion implosions using fusion burn imaging

The significance and nature of ion kinetic effects in D3He-filled, shock-driven inertial confinement fusion implosions are assessed through measurements of fusion burn profiles. Over this series of experiments, the ratio of ion-ion mean free path to minimum shell radius (the Knudsen number, NK) was varied from 0.3 to 9 in order to probe hydrodynamic-like to strongly kinetic plasma conditions; as the Knudsen number increased, hydrodynamic models increasingly failed to match measured yields, while an empirically-tuned, first-step model of ion kinetic effects better captured the observed yield trends [Rosenberg et al., Phys. Rev. Lett. 112, 185001 (2014)]. Here, spatially resolved measurements of the fusion burn are used to examine kinetic ion transport effects in greater detail, adding an additional dimension of understanding that goes beyond zero-dimensional integrated quantities to one-dimensional profiles. In agreement with the previous findings, a comparison of measured and simulated burn profiles shows that models including ion transport effects are able to better match the experimental results. In implosions characterized by large Knudsen numbers (NK3), the fusion burn profiles predicted by hydrodynamics simulations that exclude ion mean free path effects are peaked far from the origin, in stark disagreement with the experimentally observed profiles, which are centrally peaked. In contrast, a hydrodynamics simulation that includes a model of ion diffusion is able to qualitatively match the measured profile shapes. Therefore, ion diffusion or diffusion-like processes are identified as a plausible explanation of the observed trends, though further refinement of the models is needed for a more complete and quantitative understanding of ion kinetic effects

Statins in unconventional secretion of insulin-degrading enzyme and degradation of the amyloid-β peptide.

Population-based studies demonstrated that statins might decrease the risk of developing Alzheimer's disease (AD). Statins inhibit the 3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase and thereby de novo synthesis of cholesterol. Cell culture and animal studies indicated that cholesterol affects the proteolytic processing of the amyloid precursor protein and the generation of amyloid-β (Aβ). Recently, we have demonstrated that statins can also stimulate the degradation of Aβ. The statin-induced clearance of Aβ could be attributed to increased release of the insulin-degrading enzyme (IDE) via an exosome-related unconventional secretory pathway. Interestingly, this statin-induced secretion of exosome-associated IDE was independent of cellular cholesterol concentrations, but rather caused by impairment of isoprenoid biosynthesis and protein prenylation. We further identified a new hexapeptide sequence in the C-terminal region of IDE, named the SlyX motif that is critically involved in IDE secretion. Taken these findings together, the increased clearance of Aβ by stimulated secretion of IDE might contribute to the protective effects of statins against AD

Two-Stage Rotational Disordering of a Molecular Crystal Surface: C60

We propose a two-stage mechanism for the rotational surface disordering phase transition of a molecular crystal, as realized in C$_{60}$ fullerite. Our study, based on Monte Carlo simulations, uncovers the existence of a new intermediate regime, between a low temperature ordered $(2 \times 2)$ state, and a high temperature $(1 \times 1)$ disordered phase. In the intermediate regime there is partial disorder, strongest for a subset of particularly frustrated surface molecules. These concepts and calculations provide a coherent understanding of experimental observations, with possible extension to other molecular crystal surfaces.Comment: 4 pages, 2 figure

РИСК-АНАЛИЗ УСЛОВИЙ КОНТРОЛЯ ЯДЕРНЫХ МАТЕРИАЛОВ ДЛЯ ИСКЛЮЧЕНИЯ НЕРЕГЛАМЕНТИРОВАННОЙ ЯДЕРНОЙ ДЕЯТЕЛЬНОСТИ

The paper examines the conditions of nuclear materials (NM) security management at the sites of nuclear fuel cycle (NFC) from non-proliferation point of view. Applied to the non-proliferation the conditions for acceptable risk were defined. The basic levels of NM control have been set. On the base of acceptable risk concept the issues of risk management were considered. The task of unacceptable risk area suppression was formulated. Requirements to the NM control effectiveness were evaluated for various scenarios of undeclared activity (inside and outside of NFC). The role of the out-of-site control in creating NM protection in-depth was demonstrated.В работе анализируются условия безопасного обращения с ядерными материалами на объектах ядерного топливного цикла (ЯТЦ) с точки зрения проблемы ядерного нераспространения. Применительно к этой области сформулированы условия приемлемого риска и определены основные уровни контроля ядерных материалов. На основе понятия приемлемого риска рассмотрены задачи управления риском. Сформулирована задача подавления области неприемлемого риска. Для различных сценариев нерегламентированной деятельности получены  требования к эффективности контрольной деятельности внутри и вне объектов ЯТЦ.  Продемонстрирована роль внеобъектового контроля в создании эшелонированной защиты ядерных материалов

РИСК-АНАЛИЗ УСЛОВИЙ КОНТРОЛЯ ЯДЕРНЫХ МАТЕРИАЛОВ ДЛЯ ИСКЛЮЧЕНИЯ НЕРЕГЛАМЕНТИРОВАННОЙ ЯДЕРНОЙ ДЕЯТЕЛЬНОСТИ

The paper examines the conditions of nuclear materials (NM) security management at the sites of nuclear fuel cycle (NFC) from non-proliferation point of view. Applied to the non-proliferation the conditions for acceptable risk were defined. The basic levels of NM control have been set. On the base of acceptable risk concept the issues of risk management were considered. The task of unacceptable risk area suppression was formulated. Requirements to the NM control effectiveness were evaluated for various scenarios of undeclared activity (inside and outside of NFC). The role of the out-of-site control in creating NM protection in-depth was demonstrated.В работе анализируются условия безопасного обращения с ядерными материалами на объектах ядерного топливного цикла (ЯТЦ) с точки зрения проблемы ядерного нераспространения. Применительно к этой области сформулированы условия приемлемого риска и определены основные уровни контроля ядерных материалов. На основе понятия приемлемого риска рассмотрены задачи управления риском. Сформулирована задача подавления области неприемлемого риска. Для различных сценариев нерегламентированной деятельности получены  требования к эффективности контрольной деятельности внутри и вне объектов ЯТЦ.  Продемонстрирована роль внеобъектового контроля в создании эшелонированной защиты ядерных материалов

Morphology of supported polymer electrolyte ultra-thin films: a numerical study

Morphology of polymer electrolytes membranes (PEM), e.g., Nafion, inside PEM fuel cell catalyst layers has significant impact on the electrochemical activity and transport phenomena that determine cell performance. In those regions, Nafion can be found as an ultra-thin film, coating the catalyst and the catalyst support surfaces. The impact of the hydrophilic/hydrophobic character of these surfaces on the structural formation of the films has not been sufficiently explored yet. Here, we report about Molecular Dynamics simulation investigation of the substrate effects on the ionomer ultra-thin film morphology at different hydration levels. We use a mean-field-like model we introduced in previous publications for the interaction of the hydrated Nafion ionomer with a substrate, characterized by a tunable degree of hydrophilicity. We show that the affinity of the substrate with water plays a crucial role in the molecular rearrangement of the ionomer film, resulting in completely different morphologies. Detailed structural description in different regions of the film shows evidences of strongly heterogeneous behavior. A qualitative discussion of the implications of our observations on the PEMFC catalyst layer performance is finally proposed

Performance and Mix Measurements of Indirect Drive Cu-Doped Be Implosions

The ablator couples energy between the driver and fusion fuel in inertial confinement fusion (ICF). Because of its low opacity, high solid density, and material properties, beryllium has long been considered an ideal ablator for ICF ignition experiments at the National Ignition Facility. We report here the first indirect drive Be implosions driven with shaped laser pulses and diagnosed with fusion yield at the OMEGA laser. The results show good performance with an average DD neutron yield of ~2 × 10[superscript 9] at a convergence ratio of R[subscript 0]/R ~ 10 and little impact due to the growth of hydrodynamic instabilities and mix. In addition, the effect of adding an inner liner of W between the Be and DD is demonstrated.United States. Dept. of Energy (Lawrence Livermore National Laboratory Contract DE-AC52-07NA27344