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Dysfunctions of the mitochondrial energy-generating machinery cause a series of progressive, untreatable and usually fatal diseases collectively known as mitochondrial disease. High energy-requiring organs such as the brain are especially affected, leading to developmental delay, ataxia, respiratory failure, hypotonia, seizures and premature death. While neural affectation is a critical component of the pathology, only discrete neuronal populations are susceptible. However, their molecular identity and their contribution to the disease remain unknown. Mice lacking the mitochondrial Complex I subunit NDUFS4 (Ndufs4KO mice) recapitulate the classical signs of Leigh Syndrome (LS), the most common presentation of mitochondrial disease with predominant CNS affectation. Here, we identify the critical role of two genetically-defined neuronal populations driving the fatal phenotype in Ndufs4KO mice. Selective inactivation of Ndufs4 in Vglut2-expressing glutamatergic neurons causes brainstem inflammation, motor and respiratory deficits, and early death. On the other hand, Ndufs4 deletion in GABAergic neurons leads to basal ganglia inflammation without motor or respiratory involvement, but accompanied by severe refractory epileptic seizures preceding premature death. These results provide novel insight in the cell type-specific contribution to LS pathology and open new avenues to understand the underlying cellular mechanisms of mitochondrial disease.

Based on the monoamine oxidase (MAO) inhibition properties of aminoheterocycles with a carbonitrile group we have carried out a systematic exploration to discover new classes of carbonitriles endowed with dual MAO and AChE inhibitory activities, and Aβ anti-aggregating properties. Eighty-three nitrile-containing compounds, 13 of which are new, were synthesized and evaluated. in vitro screening revealed that 31, a new compound, presented the best lead for trifunctional inhibition against MAO A (0.34 μM), MAO B (0.26 μM), and AChE (52 μM), while 32 exhibited a lead for selective MAO A (0.12 μM) inhibition coupled to AChE (48 μM) inhibition. Computational analysis revealed that the malononitrile group can find an advantageous position with the aromatic cleft and FAD of MAO A or MAO B. However, the total binding energy can be handicapped by an internal penalty caused by twisting of the ligand molecule and subsequent disruption of the conjugation (32 in MAO B compared to the conjugated 31). Conjugation is also important for AChE as well as the hydrophilic character of malononitrile that allows this group to be in close contact with the aqueous environment as seen for 83. Although the effect of 31 and 32 against Aβ, was very weak, the effect of 63 and 65, and of the new compound 75, indicated that these compounds were able to disaggregate Aβ fibrils. The most effective was 63, a (phenylhydrazinylidene)propanedinitrile derivative that also inhibited MAO A (1.65 μM), making it a potential lead for Alzheimer's disease application., European Cooperation in Science and Technology, Grant/Award Numbers: STSM CM1103-29512, STSM D34-05989, STSMCM1103- 29510; Portuguese Foundation for Science and Technology, Grant/Award Number: FCT -Project PTDC/SAUNEU/ 64151/2006 (MCC); Slovak Research and Development Agency (MM); Slovak Research and Development Agency; Foundation for Science and Technology

A comprehensive experimental characterization of Spanish anthracite oxy-combustion has been conducted, and the results are discussed in this paper, encompassing combustion efficiency, heat transfer, and pollutant emissions. The experimental work has been carried out in a 90 kW th bubbling fluidized reactor under a variety of O 2 /CO 2 atmospheres and operating conditions (fluidization velocity, Ca:S ratio, and secondary oxidant supply). Combustion efficiency is improved under oxy-firing compared to air-firing, mainly due to the multiple-bubble regime and the lower fluidization velocities. The share of radiative heat transfer also rises, since O 2 /CO 2 operation leads to an increase of the temperature in the dense zone of the reactor. Concerning SO 2 emissions, the minimum values are found under the richest O 2 atmosphere, yielding maximum values of sulfur capture efficiency in the temperature range of 880–890 °C. A decrease of NO x emissions is also observed under oxy-firing conditions, while the benefit of secondary oxidant supply has to be optimized for every specific O 2 concentration.

The external heat exchanger (EHE) plays an essential role in the adequate control of the heat balance in large-scale oxy-fuel circulating fluidized bed (CFB) boilers. However, the EHE of an oxy-fuel CFB presents two particularities compared to the known air-combustion case: the composition of the fluidizing gas and the higher flow of recycled solids. Both these issues are addressed in this paper: Firstly, heat transfer coefficients are measured in a 90 kW bubbling fluidized bed, operated at different temperatures, with air and with a wide range of O-2/CO2 mixtures. Thereafter, experiments are also carried out in a cold scaled-down EHE in order to assess the influence of an increment in the solids flow across the EHE on heat transfer. Based on the results of these experiments, an expression for the heat transfer coefficient is proposed which accounts for gas composition and solids flow rate. Finally, a model for the EHE is integrated into a large oxy-fuel CFB model in order to quantify the influence of oxy-fuel operation mode on the heat transfer surfaces required in the EHE.

The design, synthesis, and pharmacological evaluation of donepezil-indolyl based amines 7-10, amides 12-16, and carboxylic acid derivatives 5 and 11, as multipotent ASS234 analogs, able to inhibit simultaneously cholinesterase (ChE) and monoamine oxidase (MAO) enzymes for the potential treatment of Alzheimer's disease (AD), is reported. Theoretical studies using 3D-Quantitative Structure-Activity Relationship (3D-QSAR) was used to define 3D-pharmacophores for inhibition of MAO A/B, AChE, and BuChE enzymes. We found that, in general, and for the same substituent, amines are more potent ChE inhibitors (see compounds 12, 13versus7 and 8) or equipotent (see compounds 14, 15versus9 and 10) than the corresponding amides, showing a clear EeAChE inhibition selectivity. For the MAO inhibition, amides were not active, and among the amines, compound 14 was totally MAO A selective, while amines 15 and 16 were quite MAO A selective. Carboxylic acid derivatives 5 and 11 showed a multipotent moderate selective profile as EeACE and MAO A inhibitors. Propargylamine 15 [N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl) prop-2-yn-1-amine] resulted in the most potent hMAO A (IC50 = 5.5 ± 1.4 nM) and moderately potent hMAO B (IC50 = 150 ± 31 nM), EeAChE (IC50 = 190 ± 10 nM), and eqBuChE (IC 50 = 830 ± 160 nM) inhibitor. However, the analogous N-allyl and the N-morpholine derivatives 16 and 14 deserve also attention as they show an attractive multipotent profile. To sum up, donepezil-indolyl hybrid 15 is a promising drug for further development for the potential prevention and treatment of AD. © 2014 Elsevier B.V.

Amyloid beta (Aβ ) aggregation and deposition is a key pathological hallmark of AD. Growing evidence suggests that neurotoxicity of this peptide is related to the formation of toxic oligomeric aggregates. Therefore, a deeply investigated therapeutic strategy comes at present from blocking the formation of these species to non-toxic aggregates. Among other considered strategies, the multi-target approach has been proposed as a more suitable potential therapy, precisely due to the multifactorial nature of AD. In this context, we recently identified ASS234, a novel compound that possesses a significant multipotent profile since it is able to inhibit cholinesterase and monoamine oxidase enzymes as well as to interfere in Aβ aggregation process. In this work, we investigated more in detail the effects of ASS234 on Aβ aggregation and toxicity in vitro as well as we explored its ability to penetrate to the CNS. We report that ASS234 inhibited Aβ 1-42 self-aggregation more efficiently than that of Aβ 1-40 , limiting the formation of fibrillar and oligomeric species. Additionally, ASS234 completely blocked the aggregation mediated by AChE of both Aβ 1-42 and Aβ 1-40 , showing a dual binding site to AChE. Interestingly, ASS234 significantly reduced A β 1-42 -mediated toxicity in SH-SY5Y human neuroblastoma cells through the prevention of the mitochondrial apoptosis pathway activation. Also importantly, we observed a significant ability of ASS234 to capture free-radical species in vitro as well as a potent effect in preventing the Aβ 1-42 -induced depletion of antioxidant enzymes (catalase and SOD-1). Finally, we report the capability of ASS234 to cross the bloodbrain barrier. Overall, our in vitro results show that ASS234 may have an impact on different processes involved in AD pathogenesis and provide evidences that it has encouraging attributes as a therapeutic lead compound.

This paper studies the SO 2 and NO x emissions from coal oxy-firing in bubbling fluidized bed combustors. The influence of bed temperature and excess oxygen is measured and discussed. The results are also compared with conventional air combustion, in order to determine whether oxy-firing contributes to increase emission levels. Two completely different coals, Central Europe bituminous and domestic Spanish high-sulfur lignite, have been tested in the CIRCE 90 kW fluidized bed combustor. Although literature data are scarce, a comparison with the findings of the research is fair. Good SO 2 capture efficiencies have been reached, even for the lignite tests, pointing towards the direct sulphation of added sorbent-limestone as the dominant mechanism. As for the NO x emissions, significant coupled influences of oxygen and carbon monoxide concentrations are reported. Notwithstanding this, no relevant differences are observed between air- and oxy-firing if NO x emissions are normalized by energy unit. The paper provides clear insights into the effect of operating conditions of oxy-fuel fluidized beds upon SO 2 and NO x emissions.

Alzheimer's disease (AD) is a complex neuro- degenerative disorder with a multifaceted pathogenesis. There are at present three Food and Drug Administration- approved drugs based on the ''one drug, one target'' para- digm (donepezil, galantamine and rivastigmine) that improve symptoms by inhibiting acetylcholinesterase. However, apart from the beneficial palliative properties, cholinergic drugs have shown little efficacy to prevent the progression of the disease evidencing the unsuitability of this strategy for the complex nature of AD. By contrast, the multifactorial nature of this neurodegenerative disorder supports the most current innovative therapeutic approach based on the ''one drug, multiple targets'' paradigm, which suggests the use of compounds with multiple activities at different target sites. Accordingly, the also called multitar- get-directed ligand (MTDL) approach has been the subject of increasing attention by many research groups, which have developed a variety of hybrid compounds acting on very diverse targets. The therapeutic potential of monoamine oxidase inhibitors (MAOI) in AD has been suggested due to their demonstrated neuroprotective properties besides their enhancing effect on monoaminergic transmission. Espe- cially, those containing a propargylamine moiety are of particular interest due to their reported beneficial actions. Therefore, targeting MAO enzymes should be considered in therapeutic interventions. This review makes a special emphasis on MTDLs that commonly target MAO enzymes. There is at present an urgent need for real disease-modifying therapies for AD and the MTDL approach makes a break- through for the development of new drugs capable of addressing the biological complexity of this disorder.

The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review., peer-reviewed

Highlights:ASS2324 is a hybrid compound resulting from the juxtaposition of donepezil and the propargylamine PF9601NASS2324 is a multi-target directed propargylamine able to bind to all the AChE/BuChE and MAO A/B enzymesASS2324 shows antioxidant, neuroprotective and suitable permeability propertiesASS2324 restores the scopolamine-induced cognitive impairment to the same extent as donepezil, and is less toxicASS2324 prevents β-amyloid induced aggregation in the cortex of double transgenic miceASS2324 is the most advanced anti-Alzheimer agent for pre-clinical studies that we have identified in our laboratoriesThe complex nature of Alzheimer's disease (AD) has prompted the design of Multi-Target-Directed Ligands (MTDL) able to bind to diverse biochemical targets involved in the progress and development of the disease. In this context, we have designed a number of MTD propargylamines (MTDP) showing antioxidant, anti-beta-amyloid, anti-inflammatory, as well as cholinesterase and monoamine oxidase (MAO) inhibition capacities. Here, we describe these properties in the MTDL ASS234, our lead-compound ready to enter in pre-clinical studies for AD, as a new multipotent, permeable cholinesterase/monoamine oxidase inhibitor, able to inhibit Aβ-aggregation, and possessing antioxidant and neuroprotective properties., MU and JM thank MINECO (Spain) for support (Grant SAF2012-33304; SAF2015-65586-R). RR, MU, GE, and JM thank EU (COST Action 1103) for support.

Recently, oxy-fuel combustion has received increasing attention as one of the short-term solutions for capturing CO2 from power plants. Despite their quick development, there are several issues that need further research. Combustion characteristics, heat transfer, emissions levels, optimum oxygen concentration and flue gas recycle are the main concern of the literature. All these issues may introduce several changes in power plant and boiler configuration that causes uncertainty in the final design of future installations. In this respect, oxy-fuel combustion in fluidized bed seems to present advantages in terms of flexibility, operational adaptability and simplicity of design modifications respect to air combustion. These issues have been though scarcely analysed in open literature. Oxy-fuel combustion in fluidized beds would require the use of additional heat transfer surfaces in order to control the bed temperature and the pollutant formation, minimising the CO emission and taking advantage of the fuel energy in the steam cycle. Moreover, the adaptability to different operational conditions (flue gas recycle, oxygen concentration, boiler load, etc.) inherent to fluidized bed characteristic would require an accurate location of heat transfer surfaces. To achieve this aim, this paper describes and compares the simulation results of a circulating fluidized bed boiler with an external heat exchanger, working under air and oxy-firing conditions. Calculation of fluidization conditions and comparison with different oxy-fuel combustion characteristics are presented. Results show the suitable location of heat transfer equipment in circulating fluidized bed to obtain similar temperature profiles along the boiler. A broad range of conditions have been run for different boiler designs, and several operational limitations have been set for selected boiler geometries.

The fate of trace elements and the properties of oxy-combustion residues were evaluated in a 90 kWth bubbling fluidized bed (BFB) oxy-combustion pilot plant fed with coal and limestone (bed material). Sampling of solid streams (coal, limestone, bottom ash, cyclone fly ash, and bag-filter fly ash) and exhaust gas (SOx, NOx, CO2, CO, and Hg) was undertaken through 4 h operating at 70% load, 70:30 CO2/O2 ratio of raw gas and 800–820 °C in a single (without re-circulation) oxy-combustion test run. The retention of SO2 (98.2 %), NOx (99.9%), and Hg (92.5%) and remaining elements (99.9%) attained high efficiencies while low retention for Cl is achieved (19%). Speciation of gaseous Hg revealed that most of the gaseous Hg occurs in the exhaust gas as Hg0. The proportions of Cl and Hg in the exhaust gas may be considered of concern with respect to subsequent CO2-rich gas treatment and oxy-combustion cycles by partial re-circulation of exhaust gas. The high abatement capacity for most of elements (Hg, S, NH 4 + , F, Se, As, B, Se, Cd, and Sn) is mostly due to condensation in bag filters. The low gas temperature (45 °C), and high-Ca content promotes condensation on fly ash collected in the bag filters. The Hg gaseous speciation and the enrichment in bag filters is indicative that most of the Hg retained is Hg2+, most probably as Hg-sulphate species. Calcite and lime are the main crystalline phases in bottom ash, quartz, illite, and calcite in cyclone fly ash and gypsum–bassanite in bag-filter fly ash. The dissolution of these species produces a moderate alkalinity (pH = 10.7–11.1) in bottom ash and cyclone fly ash leachates and slight (pH = 8) in bag-filter fly ash leachates. The leaching potential of most of elements in oxy-combustion residues is relatively low, falling in the range of non-hazardous materials according to Decision 2003/33/EC. Nevertheless, the high condensation of elements of environmental concern coupled with the use of a fuel rich in the aforementioned elements would increase the leachable potential, and consequently, may affect the disposal of this type of fly ash.

Oxyfuel combustion is a promising alternative for CO 2 capture. While this has been proven in pulverized fuel (PF) burners, research in fluidized bed (FB) reactors is still scarce. Our work aims to increase the knowledge about this technology. To this purpose, a 95 kW th FB oxyfuel combustion test rig has been erected. Its main characteristics are described in this paper, giving detailed information on the subsystems: the FB reactor, the fuel and oxidant supplies, and ancillaries. Plant flexibility is emphasized. It allows to operate under different CO 2 /O 2 ratios, and to recycle CO 2 from the flue gases. Both the processes design and monitoring are supported by simulations that have been validated against experimental data, regarding fluid dynamics, combustion, and heat transfer. Finally, the performance of the facility has been tested both with coal alone and blended with biomass. CO 2 concentrations over 90% (dry basis) in the flue gases have been obtained. Comparison of air and oxygen combustion tests and operational recommendations are discussed, confirming the feasibility of the FB oxyfuel technology for CO 2 capture purposes.

In oxy-fuel combustion it is generally accepted that fed O2 into the boiler diluted together with CO2 is advantageous when similar combustion conditions as in air-firing case want to be reached. In experimental oxy-fuel combustion plants, auxiliary CO2 from commercial tanks is often used for carrying out experimental tests. However, this fact entails high operational costs in addition to scale prices are not applied in experimental size plants. A reduction of these costs could be achieved by supplying the required CO2 through flue gas recirculation, as it would happen in an industrial oxy-fuel plant. However, transition from air-firing to oxy-firing, and changes in the flue gas composition during operation can vary conditions inside the boiler. This issue becomes particularly important when oxy-fuel combustion takes place inside a fluidized bed boiler, where fluidization conditions must be kept inside a narrow optimum range, i.e. fluidization velocity or oxygen content at inlet, although changes in recirculation rates or flue gas composition could disturb it. With this aim, an efficient recycled flue gas control strategy has been modeled and validated through experiments in a test rig. This system could be easily adapted to any experimental oxy-fuel pilot plant, since it has been designed for controlling conventional instrumentation, valves and drives.

Post-combustion CO 2 capture and storage (CCS) presents a promising strategy to capture, compress, transport and store CO 2 from a high volume–low pressure flue gas stream emitted from a fossil fuel-fired power plant. This work undertakes the simulation of CO 2 capture and compression integration into an 800 MW e supercritical coal-fired power plant using chemical process simulators. The focus is not only on the simulation of full load of flue gas stream into the CO 2 capture and compression, but also, on the impact of a partial load. The result reveals that the energy penalty of a low capture efficiency, for example, at 50% capture efficiency with 10% flue gas load is higher than for 90% flue gas load at the equivalent capture efficiency by about 440 kWh e /tonne CO 2 . The study also addresses the effect of CO 2 capture performance by different coal ranks. It is found that lignite pulverized coal (PC)-fired power plant has a higher energy requirement than subbituminous and bituminous PC-fired power plants by 40.1 and 98.6 MW e , respectively. In addition to the investigation of energy requirement, other significant parameters including energy penalty, plant efficiency, amine flow rate and extracted steam flow rate, are also presented. The study reveals that operating at partial load, for example at half load with 90% CO 2 capture efficiency, as compared with full load, reduces the energy penalty, plant efficiency drop, amine flow rate and extracted steam flow rate by 9.9%, 24.4%, 50.0% and 49.9%, respectively. In addition, the effect of steam extracted from different locations from a series of steam turbine with the objective to achieve the lowest possible energy penalty is evaluated. The simulation shows that a low extracted steam pressure from a series of steam turbines, for example at 300 kPa, minimizes the energy penalty by up to 25.3%.

The improvement of specific energy consumption and the reduction of steam temperature to drive the system are two of the main challenges to improve the performance of distillation processes in desalination plants, especially for multi-effect distillation technique. The low temperature requirement is a suitable characteristic to integrate multi-effect distillation units as bottom system. Obviously, one of the best options is to use low-grade heat from power plants or gas turbines as a cogeneration system. Mitigation of CO2 emissions from power plants will be a priority for most of power companies in a near future, one of the most promising techniques is carbon capture and storage. Nevertheless, energy requirements and efficiency penalties in the overall system are some of their disadvantages. They are largely caused by CO2 compression above both its critical temperature and pressure prior storage. There are a huge low-grade heat coming from condensing water in the CO2 stream and from compressors intercooli...

Compression of CO 2 is an essential process in the development of carbon capture and storage (CCS) technologies. In spite of power requirements for CO 2 compression could be as much as 100 kWe per tonne CO 2 , the minimization of energy requirements has received little attention in the literature. Although intercooling compression reduces power requirements, it introduces important cooling necessities that could be minimized. The aim of this paper is the integration of intercooling compression into the low-pressure part of a steam cycle to take advantage of the intercooling heat and analyse the energetic and economical results under different assumptions. Simulation and optimization have been performed in order to evaluate the intercooling configuration, energy requirements and the most cost-effective integration. Results have shown reduction in compression power requirement around 40% and reduction of the incremental COE around 23%. Proposed integration could be used to increase the efficiency of CO 2 capture processes and, therefore, to reduce the CO 2 capture cost.

Due to security, sustainability of supply, strategic and energetic dependence reasons, it is well accepted the necessity to continue using coal as main fuel for producing electricity from power plants. In order to reduce CO2 concentrations in the atmosphere, it is essential to develop carbon capture and storage technologies that lead to zero emissions fossil fuels power plants. Absorption by chemical solvents combined with CO2 long-term storage appears to offer interesting and commercial applicable CO2 capture technology. However, the high regeneration energy requirements make necessary a process optimization in large-scale power plants. Although actual CO2 capture cost remains around 55 €/ton CO2, the target is to maintain this cost below 25 €/ton CO2. This paper proposes different possibilities to overcome the energy requirements by means of amine scrubbing integration into a commercial power plant, and presents a technical and economical analysis of the performance of these approaches. Although some schemes show small efficiency penalties, it becomes essential to calculate specific cost per ton CO2, the main aim is to chose the proper configuration to implement large-scale cost-effective schemes that leads to CO2 capture demonstration projects.

Laura Fernández-Fernández et al., © 2015 The Royal Society of Chemistry. The possible modulatory effect of the functional LMN diet, rich in theobromine, polyphenols and polyunsaturated fatty acids, on the catecholaminergic and cholinergic neurotransmission, affecting cognition decline during aging has been studied. 129S1/SvlmJ mice were fed for 10, 20, 30 and 40 days with either LMN or control diets. The enzymes involved in catecholaminergic and cholinergic metabolism were determined by both immunohistological and western blot analyses. Noradrenalin, dopamine and other metabolites were quantified by HPLC analysis. Theobromine, present in cocoa, the main LMN diet component, was analysed in parallel using SH-SY5Y and PC12 cell lines. An enhanced modulatory effect on both cholinergic and catecholaminergic transmissions was observed on 20 day fed mice. Similar effect was observed with theobromine, besides its antioxidant capacity inducing SOD-1 and GPx expression. The enhancing effect of the LMN diet and theobromine on the levels of acetylcholine-related enzymes, dopamine and specially noradrenalin confirms the beneficial role of this diet on the >cognitive reserve> and hence a possible reducing effect on cognitive decline underlying aging and Alzheimer's disease., The present study was supported by the Spanish Ministry of Industry (CDTI) through the following projects: Project CENIT (MET-DEV-FUN); Programa Ingenio 2010, Programa INCOMES and a grant from the Chinese Scholarship Council (P. S.)

Alzheimer’s disease (AD) is a multifactorial neurological disorder in which oxidative stress plays an important role. Diet is closely related to cognition, and at present, there is mounting evidence that certain antioxidant components of diet intake could be beneficial for preventing AD. LMN diet, based on cocoa, nuts, polyphenols, and polyunsaturated fatty acids (patent WO2007063158) has been previously reported to reduce the cardiovascular risk factors common to AD pathology. Herein we report the antioxidant behavior of LMN using SH-SY5Y cell line lesioned with hydrogen peroxide and measuring the expression of the antioxidant enzymes superoxide dismutase-1 and glutathione peroxidase. The signaling pathways involved were also assessed. The antioxidant effect was also demonstrated in hippocampus and plasma of 4-month-old 129S1/SvImJ male mice fed with LMN diet. Integrated metabolome analyses of these tissues and plasma from human subjects after acute consumption of LMN reinforced the importance of oxidative stress, acting possibly through poly (ADP-ribose) polymerase-1 modulation and linoleic acid metabolism.

Appropriate distribution and supply of mitochondria to critical neuronal sites are thought to be necessary for the normal maintenance of neuronal architecture and activity, including synaptic plasticity and function. Imaging of neurons in vitro has provided understanding of the basic mechanisms of mitochondrial transport and the regulation of mitochondrial dynamics. However, in vivo imaging studies of neurons are preferable to in vitro approaches because of the advantage of being performed in their natural environment. Here, we present useful protocols to image and study axonal transport of mitochondria in vivo, in the peripheral nerves of mice. Imaging in motor and sensory axons of living mice allows researchers to analyze mitochondrial dynamics in two distinct neuronal populations that are often affected in peripheral neuropathies.

Appropriate distribution and supply of mitochondria to critical neuronal sites are thought to be necessary for the normal maintenance of neuronal architecture and activity, including synaptic plasticity and function. Imaging of neurons in vitro has provided understanding of the basic mechanisms of mitochondrial transport and the regulation of mitochondrial dynamics. However, in vivo imaging studies of neurons are preferable to in vitro approaches because of the advantage of being performed in their natural environment. Here, we present useful protocols to image and study axonal transport of mitochondria in vivo, in the peripheral nerves of mice. Imaging in motor and sensory axons of living mice allows researchers to analyze mitochondrial dynamics in two distinct neuronal populations that are often affected in peripheral neuropathies.

Background: PF9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] is an inhibitor of monoamine oxidase B (MAO-B), which has shown to possess neuroprotective properties in several in vitro and in vivo models of Parkinson's disease (PD). As there is evidence that excitotoxicity may be implicated in the pathophysiology of several neurodegenerative diseases, the aim of the present work was to investigate the effects of PF9601N in an acute in vivo model of excitotoxicity induced by the local administration of kainic acid during striatal microdialysis in adult rats. Methods: The basal and evoked release of neurotransmitters was monitored by HPLC analysis of microdialysate samples and tissue damage was evaluated histologically >ex vivo.> Results: PF9601N (40 mg/kg, single i.p. administration) reduced the kainate-evoked release of glutamate and aspartate and increased taurine release, but it had no effect on the release of dopamine, DOPAC, and HVA. PF9601N pretreatment also resulted in a significant reduction in the kainate-induced astrocytosis, microgliosis, and apoptosis. Conclusions: The results suggest PF9601N to be a good candidate for the treatment of neurodegenerative diseases mediated by excitotoxicity.

Progress in combustion technologies with fossil fuel made possible use of oxygen for combustion in industrial processes, reducing drastically CO 2 and NO x emissions as well as allowing for higher ...

Amyloid beta (Aβ) aggregation and deposition is a key pathological hallmark of AD. Growing evidence suggests that neurotoxicity of this peptide is related to the formation of toxic oligomeric aggregates. Therefore, a deeply investigated therapeutic strategy comes at present from blocking the formation of these species to non-toxic aggregates. Among other considered strategies, the multi-target approach has been proposed as a more suitable potential therapy, precisely due to the multifactorial nature of AD. In this context, we recently identified ASS234, a novel compound that possesses a significant multipotent profile since it is able to inhibit cholinesterase and monoamine oxidase enzymes as well as to interfere in Aβ aggregation process. In this work, we investigated more in detail the effects of ASS234 on Aβ aggregation and toxicity in vitro as well as we explored its ability to penetrate to the CNS. We report that ASS234 inhibited Aβ1-42 self-aggregation more efficiently than that of Aβ1-40, limiting the formation of fibrillar and oligomeric species. Additionally, ASS234 completely blocked the aggregation mediated by AChE of both Aβ1-42 and Aβ1-40, showing a dual binding site to AChE. Interestingly, ASS234 significantly reduced Aβ1-42-mediated toxicity in SH-SY5Y human neuroblastoma cells through the prevention of the mitochondrial apoptosis pathway activation. Also importantly, we observed a significant ability of ASS234 to capture free-radical species in vitro as well as a potent effect in preventing the Aβ1-42-induced depletion of antioxidant enzymes (catalase and SOD-1). Finally, we report the capability of ASS234 to cross the bloodbrain barrier. Overall, our in vitro results show that ASS234 may have an impact on different processes involved in AD pathogenesis and provide evidences that it has encouraging attributes as a therapeutic lead compound.

Herein, we report the biological evaluation of a series of indole substituted hydrazides and hydrazines throughout the assessment of their multipotent inhibitory potency towards monoamine oxidase (MAO) A and B, semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), and the cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Hydrazine JL72 (3-(3-hydrazinylpropyl)-1H-indole) showed a potent, reversible and non-time-dependent inhibition of MAO-A, which suggests its capacity in restoring serotoninergic neurotransmission being devoid of the side effects observed for classic MAO-A inhibitors. In addition, JL72 behaved as a moderate BuChE inhibitor. Finally, both hydrazines and hydrazides derivatives showed high affinity towards SSAO/VAP-1. Among them, JL72 behaved as a noncompetitive and the most potent inhibitor (IC50 = 0.19 ± 0.04 μM), possessing also a significant anti-inflammatory activity. The combined inhibition of SSAO/VAP-1, MAO (A and B), AChE and BuChE appear as an important therapeutic target to be considered in the treatment of cerebrovascular and neurological disorders such as Alzheimer's disease. © 2012 Springer-Verlag Wien.

Semicarbazide-sensitive amine oxidase (SSAO) metabolizes the oxidative deamination of primary aromatic and aliphatic amines. The final cytotoxic products of its catalysis contribute to diseases involving vascular degeneration. The increasing interest in measuring SSAO activity has led to the development of several different methods. Herein, we compare SSAO activity results obtained with radiometric and fluorimetric methods in 49 plasma samples. Although not interchangeable, a significant correlation was obtained between methods. Considering these limitations, the fluorimetric method might replace the radioisotopic one.

The synthesis, pharmacological evaluation and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amines 1 – 7 of type I , and 9 – 12 of type II , designed as multipotent inhibitors able to simultaneously inhibit monoamine oxidases (MAO-A/B) as well as cholinesterase (AChE/BuChE) enzymes, as potential drugs for the treatment of Alzheimer's disease, are described. Indole derivatives 1 – 7 of type I are well known MAO inhibitors whose capacity to inhibit AChE and BuChE was here investigated for the first time. As a result, compound 7 was identified as a MAO-B inhibitor (IC 50 = 31 ± 2 nM) and a moderately selective eqBuChE inhibitor (IC 50 = 4.7 ± 0.2 μM). Conversely, the new and readily available 5-amino-7-(prop-2-yn-1-yl)-6,7,8,9-tetrahydropyrido[2,3- b ][1,6]naphthyridine derivatives 9 – 13 of type II are poor MAO inhibitors, but showed AChE selective inhibition, compound 12 being the most attractive as it acts as a non-competitive inhibitor on Ee AChE (IC 50 = 25 ± 3 nM, K i = 65 nM). The ability of this compound to interact with the AChE peripheral binding site was confirmed by kinetic studies and by molecular modeling investigation. Studies on human ChEs confirmed that 12 is a selective AChE inhibitor with inhibitory potency in the submicromolar range. Moreover, in agreement with its mode of action, 12 was shown to be able to inhibit A β aggregation induced by hAChE by 30.6%.

Summary The majority of the technology development for CO2 capture and storage (CCS) is driven by the electric-utility industry, in which the emphasis is on large centralized units for electric-power generation with coal as the primary fuel. The implementation of CCS in oil-sands operations has significant potential to provide meaningful carbon-emissions reductions. This paper presents various concepts for integrating leading CO2-capture techniques to bitumen-extraction and -upgrading processes. The main carbon-capture technologies are reviewed, and their relative advantages and disadvantages for implementation in bitumen mining, thermal bitumen extraction, and bitumen upgrading are discussed, leading to a qualitative assessment of their suitability for each oil-sands process.

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50=5.2±1.1 nM) and MAO-B (IC50=43±8.0 nM) and is a moderately potent inhibitor of AChE (IC50=0.35±0.01 μM) and BuChE (IC50=0.46±0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly with profound medical and social consequences. The pathogenesis of AD is a complex and heterogeneous process which classical neuropathological hallmarks found in the brain are extracellular deposits of beta-amyloid (A)-containing plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. Mutation of presenilin-1 (PS-1), presenilin-2 (PS-2), and altered amyloid precursor protein (APP) genes has been reported to cause inherited AD. In addition, other genes such as apolipoprotein E-4 (APOE), endothelial nitric oxide synthase-3, and alpha-2-macroglubulin have also been associated with AD. A further number of hypothesis have been proposed for AD mechanism, which include: the amyloid cascade, vascular damage, excitotoxicity, deficiency of neurotrophic factors, mitochondrial dysfunction, trace element neurotoxicity, inflammation and oxidative stress hypothesis. The oxidative stress (OS) hypothesis of aging postulated by Dr. Denham Harman in 1956 proposed that brain aging is associated to a progressive imbalance between the anti-oxidant defenses and the pro-oxidant species that can occur as a result of either an increase in free radical production or a decrease in antioxidant defence. The fact that age is the main risk factor for AD development provides considerable support to the OS hypothesis since the effects produced by reactive oxygen species (ROS) can accumulate over the years (Nunomura et al., 2001). The link between AD and OS is additionally supported by the finding of decreased levels of antioxidant enzymes, increased protein, lipid and DNA oxidation and advanced glycation end products (AGEs) and ROS formation in neurons of AD patients (Perry et al., 2000; Barnham et al., 2004). It has been reported that the accumulation of the oligomeric form of A, the most toxic form of the peptide, induces OS in neurons (Butterfield, 2002), supporting the hypothesis and suggesting that OS plays a causative role in the development of AD. Then, a large amount of literature has demonstrated that OS is an important feature in AD pathogenesis that deserves to be deeply studied (Perry et al, 2002: Markesbery et al, 1999). In this Chapter, we address the main factors involved in the generation of oxidative stress and provide an overview of the oxidative stress biomarkers status in Alzheimer’s disease. The Chapter concludes with a revision of the controversial efficacy of antioxidants as potential treatment in AD therapy as well as an update of the main antioxidant compounds found to have a beneficial effect in AD.

We examined whether LMN diet, reported to induce neurogenesis in adult mice, was able to antagonize the age-related behavioural impairment and neuropathology in wild type (WT) mice and Tg2576 mice, a mouse model of Alzheimer's disease (AD). Thirteen-month-old mice (once the amyloid (Aβ) plaques were formed) were fed with the LMN diet for 5 months, and in the last 2 months of the regimen they received a battery of behavioural tests. In general, both aging and (to a higher extent) Tg2576 genotype deteriorated sensorimotor reflexes, exploratory behaviour in the hole board, activity (but not anxiety) in the elevated plus-maze, ambulation in the home cage during the dark phase, and spatial learning in the Morris water maze. LMN diet did not affect the detrimental effects observed in sensorimotor reflexes, but clearly reversed the effects of both aging and Tg2576 genotype. This behavioural amelioration was correlated with a 70% increase in cellular proliferation in subventricular zone (SVZ) of the brain, but did not correlate with a decrease of amyloid plaques. In contrast, administration of LMN diet to 10 months old mice (before the plaques are formed) strongly suggested a putative delay in the formation of plaques, as indicated by a decreasing tendency of soluble and fibrillar Aβ levels in hippocampus which correlated with a decrease in Aβ (1-40, 1-42) plasma content. Herein we describe for the first time that LMN diet rich in polyphenols, dry fruits and cocoa, was able to decrease behavioural deterioration caused by aging and Tg2576 genotype and to delay the Aβ plaque formation. These results corroborate the increasing importance of polyphenols as human dietary supplements in amelioration of the cognitive impairment during aging and neurological disorders such as AD.

The synthesis, biological evaluation and molecular modeling of new multipotent inhibitors of type I and type II , able to simultaneously inhibit monoamine oxidases (MAO) as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), is described. Compounds of type I were prepared by sequential reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile ( 14 ) [or 2,6-dichloropyridine-3,5-dicarbonitrile ( 15 )] with prop-2-yn-1-amine (or N -methylprop-2-yn-1-amine) and 2-(1-benzyl-piperidin-4-yl)alkylamines 22–25 . Compounds of type II were prepared by Friedlander type reaction of 6-amino-5-formyl-2-(methyl(prop-2-yn-1-yl)amino)nicotinonitriles 32 and 33 with 4-(1-benzylpiperidin-4-yl)butan-2-one ( 31 ). The biological evaluation of molecules 1–11 showed that most of these compounds are potent, in the nanomolar range, and selective AChEI, with moderate and equipotent selectivity for MAO-A and MAO-B inhibition. Kinetic studies of compound 8 proved that this is a Ee AChE mixed type inhibitor (IC 50 = 16 ± 2; Ki = 12 ± 3 nM). Molecular modeling investigation on compound 8 confirmed its dual AChE inhibitory profile, binding simultaneously at the catalytic active site (CAS) and at the peripheric anionic site (PAS). In overall, compound 11 , as a potent and selective dual AChEI, showing a moderate and selective MAO-A inhibitory profile, can be considered as an attractive multipotent drug for further development on two key pharmacological targets playing key roles in the therapy of Alzheimer’s disease.

The majority of the technology development for CO2 Capture and Storage (CCS) is driven by the electric utility industry, where the emphasis is on large centralized units for electric power generation with coal as the primary fuel. The implementation of CCS in oil sands operations has significant potential to provide meaningful carbon emissions reductions. This paper presents various concepts for integrating leading CO2 capture techniques to bitumen extraction and upgrading processes. The main carbon capture technologies are reviewed and their relative advantages and disadvantages for implementation in bitumen mining, thermal bitumen extraction, and upgrading are discussed, leading to a qualitative assessment of their suitability for each oil sands process.

At present it is widely accepted that there are at least two neurogenic sites in the adult mammalian brain: the subventricular zone (SVZ) of lateral ventricles and the subgranular zone (SGZ) of the hippocampus dentate gyrus. The adult proliferation rate declines with aging and is altered in several neurodegenerative pathologies including Alzheimer's disease. The aim of this work was to study whether a natural diet rich in polyphenols and polyunsaturated fatty acids (LMN diet) can modulate neurogenesis in adult mice and give insight into putative mechanisms. Results with BrdU and PCNA demonstrated that the LMN fed mice had more newly generated cells in the SVZ and SGZ, and those with DCX (undifferentiated neurons) and tyrosine hydroxylase, calretinin, and calbindin (differentiated neurons) immunostainings and western blots demonstrated a significant effect on neuronal populations, strongly supporting a positive role of the LMN diet on adult neurogenesis. In primary rat neuron cultures, the LMN cream dramatically protected against damage caused by both hydrogen peroxide and Abeta(1-42), demonstrating a potent antioxidant effect that could play a major role in the normal adult neurogenesis and, moreover, the LMN diet could have a significant effect combating the cognitive function decline during both aging and neurodegenerative diseases such as Alzheimer's disease.

Canada's oil industry is a growing energy source, with proven reserves exceeding 174 billion barrels. The majority of the production is attributable to oil sands. Thermal bitumen extraction is the predominant production method, and is poised to grow at an annual rate of 23% to 2025. This has important long-term GHG emissions implications. To date, CO 2 emissions mitigation efforts have overwhelmingly focused on implementing CCS in bitumen upgrading operations, rather than in thermal bitumen extraction processes. The paper covers the application of CO 2 capture to the main thermal bitumen extraction process: SAGD (Steam-assisted gravity drainage). The paper presents four SAGD-oxy-fuel integration configurations and compares their techno-economics to a SAGD process featuring natural gas-fired co-generation without CO 2 capture (reference case). Configuration one is a natural-gas fired co-generation boiler retrofitted for oxy-fuel operation. Configuration two is an oxy-fuel fluidized boiler using bitumen as fuel. The third configuration features a natural gas oxy-fuel boiler integrated with a cryogenic Air Separation Unit (ASU). The pressurized “waste” N2 is expanded in a turbine with additional heat integration. The fourth configuration features natural gas oxy-combustion with O2 from an Oxygen Transport Membrane (OTM) unit. Other integration concepts, including Chemical Looping combustion (CLC) are introduced. Because these concepts are in an earlier stage of development, the discussion covers their qualitative aspects and potential benefits over the previously mentioned cases.

Among the main challenges of Carbon Capture and Storage (CCS) technologies, the reduction of energy penalties associated with the capture process and the integration of the new process in the design of a complex system - original power plant and capture facility - are major issues. Traditionally, the Second Law of Thermodynamics is an essential tool for process optimization through the application of exergy and exergy destruction (irreversibility) concepts. An exergy analysis provides a guide for identifying those systems and equipments with larger irreversibility. Modifications in the design of these systems may lead to reduction of thermodynamic inefficiencies in CO 2 capture facilities, improving their performance and reducing costs. In this work, some examples of the application of the Second Law of Thermodynamics are presented for postcombustion, oxyfuel combustion and precombustion CO 2 capture technologies. The main target is to identify the equipment with larger irreversibilities and to propose items for future optimization.