Long-term dynamics of aberrant neuronal activity in awake Alzheimer's disease transgenic mice

Alzheimer's disease (AD) is associated with aberrant neuronal activity, which is believed to critically determine disease symptoms. How these activity alterations emerge, how stable they are over time, and whether cellular activity dynamics are affected by the amyloid plaque pathology remains incompletely understood. We here repeatedly recorded the activity from identified neurons in cortex of awake APPPS1 transgenic mice over four weeks during the early phase of plaque deposition using in vivo two-photon calcium imaging. We found that aberrant activity during this stage largely persisted over the observation time. Novel highly active neurons slowly emerged from former intermediately active neurons. Furthermore, activity fluctuations were independent of plaque proximity, but aberrant activity was more likely to persist close to plaques. These results support the notion that neuronal network pathology observed in models of cerebral amyloidosis is the consequence of persistent single cell aberrant neuronal activity, a finding of potential diagnostic and therapeutic relevance for AD

Quantum Tests of the Foundations of General Relativity

The role of the equivalence principle in the context of non-relativistic quantum mechanics and matter wave interferometry, especially atom beam interferometry, will be discussed. A generalised form of the weak equivalence principle which is capable of covering quantum phenomena too, will be proposed. It is shown that this generalised equivalence principle is valid for matter wave interferometry and for the dynamics of expectation values. In addition, the use of this equivalence principle makes it possible to determine the structure of the interaction of quantum systems with gravitational and inertial fields. It is also shown that the path of the mean value of the position operator in the case of gravitational interaction does fulfill this generalised equivalence principle.Comment: Classical and Quantum Gravity 15, 13 (1998

Novel multicomponent B2-ordered aluminides: Compositional design, synthesis, characterization, and thermal stability

For the first time, multicomponent alloys belonging to a B2-ordered single phase were designed and fabricated by melting route. The design concept of high entropy alloys is applied to engineering the transition metal sublattice of binary B2 aluminide. The equiatomic substitution of transition metal elements in the Ni sublattice of binary AlNi followed to produce Al(CoNi), Al(FeNi), Al(CoFe), Al(CoFeNi), Al(CoFeMnNi), and Al(CoCuFeMnNi) multicomponent alloys. CALculation of PHAse Diagrams (CALPHAD) approach was used to predict the phases in these alloys. X-ray diffraction and transmission electron microscopy were used to confirm the B2 ordering in the alloys. Thermal stability of the B2 phase in these alloys was demonstrated by prolonged heat treatments at 1373 K and 1073 K up to 200 h. © 2020 by the author. Licensee MDPI, Basel, Switzerland

Publisher correction: unveiling the Re effect in Ni-based single crystal superalloys

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Clinical decision-making on spinal cord injury-associated pneumonia: a nationwide survey in Germany

Study design: Survey study. Objectives: Spinal cord injury (SCI)-associated pneumonia (SCI-AP) is associated with poor functional recovery and a major cause of death after SCI. Better tackling SCI-AP requires a common understanding on how SCI-AP is defined. This survey examines clinical algorithms relevant for diagnosis and treatment of SCI-AP. Setting: All departments for SCI-care in Germany. Methods: The clinical decision-making on SCI-AP and the utility of the Centers for Disease Control and Prevention (CDC) criteria for diagnosis of ‘clinically defined pneumonia’ were assessed by means of a standardized questionnaire including eight case vignettes of suspected SCI-AP. The diagnostic decisions based on the case information were analysed using classification and regression trees (CART). Results: The majority of responding departments were aware of the CDC-criteria (88%). In the clinical vignettes, 38–81% of the departments diagnosed SCI-AP in accordance with the CDC-criteria and 7–41% diagnosed SCI-AP in deviation from the CDC-criteria. The diagnostic agreement was not associated with the availability of standard operating procedures for SCI-AP management in the departments. CART analysis identified radiological findings, fever, and worsened gas exchange as most important for the decision on SCI-AP. Frequently requested supplementary diagnostics were microbiological analyses, C-reactive protein, and procalcitonin. For empirical antibiotic therapy, the departments used (acyl-)aminopenicillins/β-lactamase inhibitors, cephalosporins, or combinations of (acyl-)aminopenicillins/β-lactamase inhibitors with fluoroquinolones or carbapenems. Conclusions: This survey reveals a diagnostic ambiguity regarding SCI-AP despite the awareness of CDC-criteria and established SOPs. Heterogeneous clinical practice is encouraging the development of disease-specific guidelines for diagnosis and management of SCI-AP

Анализ условий труда и разработка мероприятий по их усовершенствованию на предприятии ООО

В данной выпускной квалификационной работе проводиться анализ условий труда и травматизма на Юргинском машиностроительном заводе. На основании этих исследований выявляются опасные и вредные производственные факторы, а так же разрабатываются мероприятия по усовершенствованию условий труда.In this graduation qualification work, an analysis of working conditions and injuries at the Yurga machine-building plant is carried out. Based on these studies, hazardous and harmful production factors are identified, as well as measures are being developed to improve working conditions

Product release is rate-limiting for catalytic processing by the Dengue virus protease

Dengue Virus (DENV) is the most prevalent global arbovirus, yet despite an increasing burden to health care there are currently no therapeutics available to treat infection. A potential target for antiviral drugs is the two-component viral protease NS2B-NS3pro, which is essential for viral replication. Interactions between the two components have been investigated here by probing the effect on the rate of enzyme catalysis of key mutations in a mobile loop within NS2B that is located at the interface of the two components. Steady-state kinetic assays indicated that the mutations greatly affect catalytic turnover. However, single turnover and fluorescence experiments have revealed that the mutations predominantly affect product release rather than substrate binding. Fluorescence analysis also indicated that the addition of substrate triggers a near-irreversible change in the enzyme conformation that activates the catalytic centre. Based on this mechanistic insight, we propose that residues within the mobile loop of NS2B control product release and present a new target for design of potent Dengue NS2B-NS3 protease inhibitors

Current Challenges and Opportunities in Microstructure-Related Properties of Advanced High-Strength Steels

This is a viewpoint paper on recent progress in the understanding of the microstructure–property relations of advanced high-strength steels (AHSS). These alloys constitute a class of high-strength, formable steels that are designed mainly as sheet products for the transportation sector. AHSS have often very complex and hierarchical microstructures consisting of ferrite, austenite, bainite, or martensite matrix or of duplex or even multiphase mixtures of these constituents, sometimes enriched with precipitates. This complexity makes it challenging to establish reliable and mechanism-based microstructure–property relationships. A number of excellent studies already exist about the different types of AHSS (such as dual-phase steels, complex phase steels, transformation-induced plasticity steels, twinning-induced plasticity steels, bainitic steels, quenching and partitioning steels, press hardening steels, etc.) and several overviews appeared in which their engineering features related to mechanical properties and forming were discussed. This article reviews recent progress in the understanding of microstructures and alloy design in this field, placing particular attention on the deformation and strain hardening mechanisms of Mn-containing steels that utilize complex dislocation substructures, nanoscale precipitation patterns, deformation-driven transformation, and twinning effects. Recent developments on microalloyed nanoprecipitation hardened and press hardening steels are also reviewed. Besides providing a critical discussion of their microstructures and properties, vital features such as their resistance to hydrogen embrittlement and damage formation are also evaluated. We also present latest progress in advanced characterization and modeling techniques applied to AHSS. Finally, emerging topics such as machine learning, through-process simulation, and additive manufacturing of AHSS are discussed. The aim of this viewpoint is to identify similarities in the deformation and damage mechanisms among these various types of advanced steels and to use these observations for their further development and maturation.</p

The SZT2 Interactome Unravels New Functions of the KICSTOR Complex

Seizure threshold 2 (SZT2) is a component of the KICSTOR complex which, under catabolic conditions, functions as a negative regulator in the amino acid-sensing branch of mTORC1. Mutations in this gene cause a severe neurodevelopmental and epileptic encephalopathy whose main symptoms include epilepsy, intellectual disability, and macrocephaly. As SZT2 remains one of the least characterized regulators of mTORC1, in this work we performed a systematic interactome analysis under catabolic and anabolic conditions. Besides numerous mTORC1 and AMPK signaling components, we identified clusters of proteins related to autophagy, ciliogenesis regulation, neurogenesis, and neurodegenerative processes. Moreover, analysis of SZT2 ablated cells revealed increased mTORC1 signaling activation that could be reversed by Rapamycin or Torin treatments. Strikingly, SZT2 KO cells also exhibited higher levels of autophagic components, independent of the physiological conditions tested. These results are consistent with our interactome data, in which we detected an enriched pool of selective autophagy receptors/regulators. Moreover, preliminary analyses indicated that SZT2 alters ciliogenesis. Overall, the data presented form the basis to comprehensively investigate the physiological functions of SZT2 that could explain major molecular events in the pathophysiology of developmental and epileptic encephalopathy in patients with SZT2 mutations

Experimental and computational study of trace element distribution between orthopyroxene and anhydrous silicate melts: substitution mechanisms and the effect of iron

Although orthopyroxene (Opx) is present during a wide range of magmatic differentiation processes in the terrestrial and lunar mantle, its effect on melt trace element contents is not well quantified. We present results of a combined experimental and computational study of trace element partitioning between Opx and anhydrous silicate melts. Experiments were performed in air at atmospheric pressure and temperatures ranging from 1,326 to 1,420°C in the system CaO-MgO-A