Induction of Amyloid-beta(42) Production by Fipronil and Other Pyrazole Insecticides

Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer’s disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the ‘human chemical exposome’ contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products, we screened a library of 3500 + compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental “Alzheimerogens” which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD

Next generation emergency services based on the Pan-European Mobile Emergency Application (PEMEA) protocol: Leveraging mobile positioning and context information

In this paper, we analyze requirements of next generation 112 emergency services in the era of ubiquitous mobile devices and sensors and present the design, implementation, and piloting results of our testbed, which was developed within the H2020 project NEXES. The system leverages a multihop location-aware PEMEA routing network that finds the geographically closest responsible public service answering point (PSAP) and supports cross-border application roaming. Our reference mobile implementation utilizes multiple device and network-based positioning technologies, which, combined, both outperform traditional cell-tower based positioning and provide a means for detecting fraudulent calls. The system is extensible and can establish a variety of communication channels after the initial emergency session is set up; we demonstrate this with an interoperable WebRTC-based video call. The obtained results demonstrate the viability and flexibility of PEMEA-based over-the-top emergency services, show high user acceptance when comparing them with existing solutions, and thus pave the road for further rollout of such systems

Relationship between affective temperaments and aggression in euthymic patients with bipolar mood disorder and major depressive disorder

So far there is a scarce of studies dealing with the relationship between different aspects of aggressive behaviour and affective temperaments among various mood disorders. The aim of the present study was to explore in a group of patients with affective mood disorders the relationship between affective temperaments and aggression.100 consecutive outpatients in euthymic phase of mood disorders (46 with bipolar disorder-type I, 18 with bipolar disorder-type II and 36 with major depressive disorder) were self-assessed with the Aggression Questionnaire and the short version of Slovenian Temperament Evaluation of Memphis, Pisa, Paris and San Diego - Autoquestionnaire (TEMPS-A).The factorial analysis of the TEMPS-A subscales revealed 2 main factors: Factor 1 (prominent cyclothymic profile) consisted of cyclothymic, depressive, irritable, and anxious temperaments and Factor 2 (prominent hyperthymic profile) which was represented by the hyperthymic temperament, and by depressive and anxious temperaments as negative components. Patients with prominent cyclothymic profile got their diagnosis later in their life and had significantly higher mean scores on anger and hostility (non-motor aggressive behaviour) compared with patients with prominent hyperthymic profile.We included patients with different mood disorders, therefore the sample selection may influence temperamental and aggression profiles. We used self-report questionnaires which can elicit sociable desirable answers.Anger and hostility could represent stable personality characteristics of prominent cyclothymic profile that endure even in remission. It seems that distinct temperamental profile could serve as a good diagnostic and prognostic value for non-motor aspects of aggressive behaviour

39K NMR and EPR study of multiferroic K3Fe5F15

39K NMR spectra and relaxation times of polycrystalline K3Fe5F15 have been used as a microscopic detector of the local magnetic fields at the magnetic transition at TN = 123 K. The NMR lineshape widens abruptly upon crossing TN due to the onset of internal magnetic fields, while we find no significant lineshift. The paraelectric to ferroelectric transition at Tc = 490 K and the magnetic transition at TN have also been studied using X-band EPR (electron paramagnetic resonance). An increase and subsequent decrease in the EPR susceptibilities is observed on approaching TN from above. There is also a significant increase in the linewidth. At the same time the g-factor first decreases and then increases with decreasing temperature. The local magnetic field is different at different K sites and is much smaller than the magnetic field around the Fe sites. This seems to be consistent with the behaviour of a weak ferrimagnet. The ferrimagnetism does not seem to be due to spin canting as the lattice is disordered, but may arise from thermal blocking of superparamagnetic percolation clusters. The ferroelectric transition at Tc shows no electronic anomaly, demonstrating that we are dealing with a classical phonon anomaly as found in conventional oxides rather than an electronic transition

Slovenia and the European Union: Macroeconomic Development Scenarios.

Consistent projections are presented for Slovenia's economic development in the form of two scenarios: one assuming accession to the European Union in 2005, and another assuming that no accession takes place before 2010. If accession does not take place, the growth of GDP will fluctuate between 3 and 4 percent, while in the accession scenario it achieves 5-6% in the years before and after accession. In both scenarios some reorientation of trade to former Yugoslav regions is expected, but in case of accession the high share of trade with the EU is maintained. Budgetary policy and agreement with social parters are expected to take care of moderate wage developments, which are even more crucial in case of accession due to the increased competitive pressures. The forecasts assume not only that external conditions will be favorable, or at least not adverse, but that internal structural reforms and economic policy making will fulfill all the ambitious targets that the official national and international documents prescribe.

Using the physical properties of artefacts to manage through‐life knowledge flows in the built environment: an initial exploration

Effective through‐life management of built facilities requires effective through‐life knowledge management to support it. The KIM (Immortal Information and Through‐Life Knowledge Management) project attempted to develop such an approach, based on a dichotomy of knowledge and information. Knowledge is conceived in terms of communities of practice. An initial philosophical analysis demonstrates deficiencies in this conception. Drawing inspiration from production theory, a tripartite analysis is offered, suggesting that knowledge flows consist of: social practices, information and physical properties. Literature on physical properties from design studies, production management and ethnomethodology is briefly reviewed to demonstrate the information bearing functions of physical properties. Fieldwork conforming to the unique adequacy requirement of methods was carried out on construction sites, in hotel and hospital facilities during the use stage of their life cycles. Safety barriers on construction sites were found to have informational properties beyond their function as a physical barrier. The quality of information delivered by wayfinding signs was found to depend upon both the physical placement of the signs in relation to the surrounding environment and the physical layout of the sign itself. It was found that social practices are institutionalized to repair the knowledge flow when the physically instantiated wayfinding system breaks down. Finally, through the investigation of practices surrounding emergency resuscitation equipment, it was found that if the physical properties of information are not designed to mesh with the work practices of the setting, this will lead to a breakdown in the knowledge flow. It is suggested that elements of knowledge management, ethnomethodology, production management and design studies might be integrated to form the basis of a hybrid discipline

Slovenia and the European Union: Macroeconomic Development Scenarios

Consistent projections are presented for Slovenia's economic development in the form of two scenarios: one assuming accession to the European Union in 2005, and another assuming that no accession takes place before 2010. If accession does not take place, the growth of GDP will fluctuate between 3 and 4 percent, while in the accession scenario it achieves 5-6% in the years before and after accession. In both scenarios some reorientation of trade to former Yugoslav regions is expected, but in case of accession the high share of trade with the EU is maintained. Budgetary policy and agreement with social partners are expected to take care of moderate wage developments, which are even more crucial in case of accession due to the increased competitive pressures. The forecasts assume not only that external conditions will be favorable, or at least not adverse, but that internal structural reforms and economic policy making will fulfill all the ambitious targets that the official national and ..