Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Multi-purpose infrastructure for delivering and supporting mobile context-aware applications

The use of contextual information in mobile devices is receiving increasing attention in mobile and ubiquitous computing research. An important requirement for mobile development today is that devices should be able to interact with the context. In this paper we present a series of contributions regarding previous work on context-awareness. In the first place, we describe a client-server architecture that provides a mechanism for preparing target non context-aware applications in order to be delivered as context-aware applications in a semi-automatic way. Secondly, the framework used in the server to instantiate specific components for context-awareness, the Implicit Plasticity Framework, provides independence from the underlying mobile technology used in client device, as it is shown in the case studies presented. Finally, proposed infrastructure deals with the interaction among different context constraints provided by diverse sensors. All of these contributions are extensions to the infrastructure based on the Dichotomic View of plasticity, which now offers multi-purpose support.

Multi-scale effects of nestling diet on breeding performance in a terrestrial top predator inferred from stable isotope analysis

Inter-individual diet variation within populations is likely to have important ecological and evolutionary implications. The diet-fitness relationships at the individual level and the emerging population processes are, however, poorly understood for most avian predators inhabiting complex terrestrial ecosystems. In this study, we use an isotopic approach to assess the trophic ecology of nestlings in a long-lived raptor, the Bonelli"s eagle Aquila fasciata, and investigate whether nestling dietary breath and main prey consumption can affect the species" reproductive performance at two spatial scales: territories within populations and populations over a large geographic area. At the territory level, those breeding pairs whose nestlings consumed similar diets to the overall population (i.e. moderate consumption of preferred prey, but complemented by alternative prey categories) or those disproportionally consuming preferred prey were more likely to fledge two chicks. An increase in the diet diversity, however, related negatively with productivity. The age and replacements of breeding pair members had also an influence on productivity, with more fledglings associated to adult pairs with few replacements, as expected in long-lived species. At the population level, mean productivity was higher in those population-years with lower dietary breadth and higher diet similarity among territories, which was related to an overall higher consumption of preferred prey. Thus, we revealed a correspondence in diet-fitness relationships at two spatial scales: territories and populations. We suggest that stable isotope analyses may be a powerful tool to monitor the diet of terrestrial avian predators on large spatio-temporal scales, which could serve to detect potential changes in the availability of those prey on which predators depend for breeding. We encourage ecologists and evolutionary and conservation biologists concerned with the multi-scale fitness consequences of inter-individual variation in resource use to employ similar stable isotope-based approaches, which can be successfully applied to complex ecosystems such as the Mediterranean.

Contribution of femoral and proximal sciatic nerve branches to the sensory innervation of hindlimb digits in the rat

The present study was performed to investigate the possibility of 'aberrant' innervation of the tips of the hindlimb digits in the rat, i.e., from other sources than the femoral and the main sciatic branches (tibial, peroneal, sural). Cutaneous injections of fluorescent tracers in the digits were combined with either selective nerve transections to restrict afferent routes followed by detection of labeled neurons in dorsal root ganglia (DRGs), or by a delayed application of a second tracer to afferent nerves under study to detect double labeled neurons in DRGs. The results show that the tips of the digits were represented in DRGs L3-6. The femoral nerve afferents from digits 1 and 2 projected primarily to DRG L3 and to a smaller extent to DRG L4. A small number of neurons from primarily medial digits 1 and 2, but also from lateral digits 3-5, were found to project to DRGs L4 and L5 via a proximal branch that leaves the sciatic nerve near the sciatic notch and runs distally in the posterior part of the thigh, here called the musculocutaneous nerve of the hindlimb. We also have some evidence indicating innervation of the tips of the digits from the posterior cutaneous nerve of the thigh. Aberrant innervation such as that described here might contribute to remaining and perhaps abnormal sensibility after nerve injury and is of interest for the interpretation of results in experimental studies of collateral and regenerative sprouting after such injury

Sciatic and femoral nerve sensory neurones occupy different regions of the L4 dorsal root ganglion in the adult rat.

The topographical distribution of sciatic and femoral nerve sensory neuronal somata in the L4 dorsal root ganglion of the adult rat was mapped after retrograde tracing with one or two of the dyes Fast Blue, Fluoro-Gold, or Diamidino Yellow. The tracers were applied to the proximal transected end of either nerve alone, or from both nerves in the same animal using separate tracers. Three-dimensional reconstructions of the distribution of labelled neurones were made from serial sections of the L4 dorsal root ganglion which is the only ganglion that these two nerves share. The results showed that with little overlap, femoral nerve neurones distribute dorsally and rostrally whereas sciatic nerve neurones distribute medially and ventrally. This finding indicates the existence of a somatotopical organisation for the representation of different peripheral nerves in dorsal root ganglia of adult animals.

Multi-sided Böhm-Bawerk assignment markets: the core

[cat] En aquest treball introduïm la classe de "multi-sided Böhm-Bawerk assignment games", que generalitza la coneguda classe de jocs d’assignació de Böhm-Bawerk bilaterals a situacions amb un nombre arbitrari de sectors. Trobem els extrems del core de qualsevol multi-sided Böhm-Bawerk assignment game a partir d’un joc convex definit en el conjunt de sectors enlloc del conjunt de venedors i compradors. Addicionalment estudiem quan el core d’aquests jocs d’assignació és estable en el sentit de von Neumann-Morgenstern.

Consistency and the core of multi-sided assignment markets

[cat] En aquest treball es demostra que en el domini dels jocs d’assignació equilibrats multisectorials (Quint, 1991), el core és l’única solució no buida que satisfà derived consistency i projection consistency. També es caracteritza el core en tota la classe dels jocs d’assignació multisectorials amb els axiomes de singleness best, individual antimonotonicity i derived consistency. Com a casos particulars, s’obtenen dues noves axiomàtiques del core per als jocs d’assignació bilaterals (Shapley and Shubik, 1972).

Multi-sided Böhm-Bawerk assignment markets: the core

[cat] En aquest treball introduïm la classe de "multi-sided Böhm-Bawerk assignment games", que generalitza la coneguda classe de jocs d’assignació de Böhm-Bawerk bilaterals a situacions amb un nombre arbitrari de sectors. Trobem els extrems del core de qualsevol multi-sided Böhm-Bawerk assignment game a partir d’un joc convex definit en el conjunt de sectors enlloc del conjunt de venedors i compradors. Addicionalment estudiem quan el core d’aquests jocs d’assignació és estable en el sentit de von Neumann-Morgenstern.

Consistency and the core of multi-sided assignment markets

[cat] En aquest treball es demostra que en el domini dels jocs d’assignació equilibrats multisectorials (Quint, 1991), el core és l’única solució no buida que satisfà derived consistency i projection consistency. També es caracteritza el core en tota la classe dels jocs d’assignació multisectorials amb els axiomes de singleness best, individual antimonotonicity i derived consistency. Com a casos particulars, s’obtenen dues noves axiomàtiques del core per als jocs d’assignació bilaterals (Shapley and Shubik, 1972).

Climate change impacts on lakes: an integrated ecological perspective based on a multi-faceted approach, with special focus on shallow lakes

Freshwater ecosystems and their biodiversity are presently seriously threatened by global development and population growth, leading to increases in nutrient inputs and intensification of eutrophication-induced problems in receiving fresh waters, particularly in lakes. Climate change constitutes another threat exacerbating the symptoms of eutrophication and species migration and loss. Unequivocal evidence of climate change impacts is still highly fragmented despite the intensive research, in part due to the variety and uncertainty of climate models and underlying emission scenarios but also due to the different approaches applied to study its effects. We first describe the strengths and weaknesses of the multi-faceted approaches that are presently available for elucidating the effects of climate change in lakes, including space-for-time substitution, time series, experiments, palaeoecology and modelling. Reviewing combined results from studies based on the various approaches, we describe the likely effects of climate changes on biological communities, trophic dynamics and the ecological state of lakes. We further discuss potential mitigation and adaptation measures to counteract the effects of climate change on lakes and, finally, we highlight some of the future challenges that we face to improve our capacity for successful prediction.

A Gradient based algorithm for blind inversion of Wiener System using multi-variate score functions

A Wiener system is a linear time-invariant filter, followed by an invertible nonlinear distortion. Assuming that the input signal is an independent and identically distributed (iid) sequence, we propose an algorithm for estimating the input signal only by observing the output of the Wiener system. The algorithm is based on minimizing the mutual information of the output samples, by means of a steepest descent gradient approach.

Studying the non-thermal lobes of IRAS 16547-4247 through a multi-wavelength approach

In recent years, massive protostars have turned out to be a possible population of high-energy emitters. Among the best candidates is IRAS 16547-4247, a protostar that presents a powerful outflow with clear signatures of interaction with its environment. This source has been revealed to be a potential high-energy source because it displays non-thermal radio emission of synchrotron origin, which is evidence of relativistic particles. To improve our understanding of IRAS 16547-4247 as a high-energy source, we analyzed XMM-Newton archival data and found that IRAS 16547-4247 is a hard X-ray source. We discuss these results in the context of a refined one-zone model and previous radio observations. From our study we find that it may be difficult to explain the X-ray emission as non-thermal radiation coming from the interaction region, but it might be produced by thermal Bremsstrahlung (plus photo-electric absorption) by a fast shock at the jet end. In the high-energy range, the source might be detectable by the present generation of Cherenkov telescopes, and may eventually be detected by Fermi in the GeV range.

Deep GMRT radio observations and a multi-wavelength study of the region around HESS J1858+020

Context. There are a number of very high energy sources in the Galaxy that remain unidentified. Multi-wavelength and variability studies, and catalogue searches, are powerful tools to identify the physical counterpart, given the uncertainty in the source location and extension. Aims. This work carries out a thorough multi-wavelength study of the unidentified, very high energy source HESS J1858+020 and its environs. Methods. We have performed Giant Metrewave Radio Telescope observations at 610 MHz and 1.4 GHz to obtain a deep, low-frequency radio image of the region surrounding HESS J1858+020. We analysed archival radio, infrared, and X-ray data as well. This observational information, combined with molecular data, catalogue sources, and a nearby Fermi gamma-ray detection of unidentified origin, are combined to explore possible counterparts to the very high energy source. Results. We provide with a deep radio image of a supernova remnant that might be related to the GeV and TeV emission in the region. We confirm the presence of an H ii region next to the supernova remnant and coincident with molecular emission. A potential region of star formation is also identified. We identify several radio and X-ray sources in the surroundings. Some of these sources are known planetary nebulae, whereas others may be non-thermal extended emitters and embedded young stellar objects. Three old, background Galactic pulsars also neighbour HESS J1858+020 along the line of sight. Conclusions. The region surrounding HESS J1858+020 is rich in molecular structures and non-thermal objects that may potentially be linked to this unidentified very high energy source. In particular, a supernova remnant interacting with nearby molecular clouds may be a good candidate, but a star forming region, or a non-thermal radio source of yet unclear nature, may also be behind the gamma-ray source. The neighbouring pulsars, despite being old and distant, cannot be discarded as candidates. Further observational studies are needed, however, to narrow the search for a counterpart to the HESS source.

Control of hair cell excitability by vestibular primary sensory neurons.

In the rat utricle, synaptic contacts between hair cells and the nerve fibers arising from the vestibular primary neurons form during the first week after birth. During that period, the sodium-based excitability that characterizes neonate utricle sensory cells is switched off. To investigate whether the establishment of synaptic contacts was responsible for the modulation of the hair cell excitability, we used an organotypic culture of rat utricle in which the setting of synapses was prevented. Under this condition, the voltage-gated sodium current and the underlying action potentials persisted in a large proportion of nonafferented hair cells. We then studied whether impairment of nerve terminals in the utricle of adult rats may also affect hair cell excitability. We induced selective and transient damages of afferent terminals using glutamate excitotoxicity in vivo. The efficiency of the excitotoxic injury was attested by selective swellings of the terminals and underlying altered vestibular behavior. Under this condition, the sodium-based excitability transiently recovered in hair cells. These results indicate that the modulation of hair cell excitability depends on the state of the afferent terminals. In adult utricle hair cells, this property may be essential to set the conditions required for restoration of the sensory network after damage. This is achieved via re-expression of a biological process that occurs during synaptogenesis.