Sulfonamido-derivatives of unsubstituted carbazoles as BACE1 inhibitors

A novel series of variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylsulfonamides has been synthesized and assayed for β-Secretase (BACE1) inhibitory activity. BACE1 is a widely recognized drug target for the prevention and treatment of Alzheimer's Disease (AD). The introduction of benzyl substituents on the nitrogen atom of the arylsulfonamide moiety has so far led to the best results, with three derivatives showing IC₅₀ values ranging from 1.6 to 1.9?μM. Therefore, a significant improvement over the previously reported series of N-carboxamides (displaying IC₅₀’s?≥?2.5?μM) has been achieved, thus suggesting an active role of the sulfonamido-portion in the inhibition process. Preliminary molecular modeling studies have been carried out to rationalize the observed structure-activity relationships.     

Comparative life cycle assessment and life cycle costing of lodging in the Himalaya

Purpose

The main aim of the study is to assess the environmental and economic impacts of the lodging sector located in the Himalayan region of Nepal, from a life cycle perspective. The assessment should support decision making in technology and material selection for minimal environmental and economic burden in future construction projects.

Methods

The study consists of the life cycle assessment and life cycle costing of lodging in three building types: traditional, semi-modern and modern. The life cycle stages under analysis include raw material acquisition, manufacturing, construction, use, maintenance and material replacement. The study includes a sensitivity analysis focusing on the lifespan of buildings, occupancy rate and discount and inflation rates. The functional unit was formulated as the ‘Lodging of one additional guest per night’, and the time horizon is 50 years of building lifespan. Both primary and secondary data were used in the life cycle inventory.

Results and discussion

The modern building has the highest global warming potential (kg CO_2-eq) as well as higher costs over 50 years of building lifespan. The results show that the use stage is responsible for the largest share of environmental impacts and costs, which are related to energy use for different household activities. The use of commercial materials in the modern building, which have to be transported mostly from the capital in the buildings, makes the higher GWP in the construction and replacement stages. Furthermore, a breakdown of the building components shows that the roof and wall of the building are the largest contributors to the production-related environmental impact.

Conclusions

The findings suggest that the main improvement opportunities in the lodging sector lie in the reduction of impacts on the use stage and in the choice of materials for wall and roof.

     

Effects of Hydraulic Soil Properties on Vegetation Pattern Formation in Sloping Landscapes

Current models of vegetation pattern formation rely on a system of weakly nonlinear reaction–diffusion equations that are coupled by their source terms. While these equations, which are used to describe a spatiotemporal planar evolution of biomass and soil water, qualitatively capture the emergence of various types of vegetation patterns in arid environments, they are phenomenological and have a limited predictive power. We ameliorate these limitations by deriving the vertically averaged Richards’ equation to describe flow (as opposed to “diffusion”) of water in partially saturated soils. This establishes conditions under which this nonlinear equation reduces to its weakly nonlinear reaction–diffusion counterpart used in the previous models, thus relating their unphysical parameters (e.g., diffusion coefficient) to the measurable soil properties (e.g., hydraulic conductivity) used to parameterize the Richards equation. Our model is valid for both flat and sloping landscapes and can handle arbitrary topography and boundary conditions. The result is a model that relates the environmental conditions (e.g., precipitation rate, runoff and soil properties) to formation of multiple patterns observed in nature (such as stripes, labyrinth and spots).     

Data distribution in public veterinary service: health and safety challenges push for context-aware systems

Background

Today’s globalised and interconnected world is characterized by intertwined and quickly evolving relationships between animals, humans and their environment and by an escalating number of accessible data for public health. The public veterinary services must exploit new modeling and decision strategies to face these changes. The organization and control of data flows have become crucial to effectively evaluate the evolution and safety concerns of a given situation in the territory. This paper discusses what is needed to develop modern strategies to optimize data distribution to the stakeholders.

Main text

If traditionally the system manager and knowledge engineer have been concerned with the increase of speed of data flow and the improvement of data quality, nowadays they need to worry about data overflow as well. To avoid this risk an information system should be capable of selecting the data which need to be shown to the human operator. In this perspective, two aspects need to be distinguished: data classification vs data distribution. Data classification is the problem of organizing data depending on what they refer to and on the way they are obtained; data distribution is the problem of selecting which data is accessible to which stakeholder. Data classification can be established and implemented via ontological analysis and formal logic but we claim that a context-based selection of data should be integrated in the data distribution application. Data distribution should provide these new features: (a) the organization of situation types distinguishing at least ordinary vs extraordinary scenarios (contextualization of scenarios); (b) the possibility to focus on the data that are really important in a given scenario (data contextualization by scenarios); and (c) the classification of which data is relevant to which stakeholder (data contextualization by users).

Short conclusion

Public veterinary services, to efficaciously and efficiently manage the information needed for today’s health and safety challenges, should contextualize and filter the continuous and growing flow of data by setting suitable frameworks to classify data, users’ roles and possible situations.

     

N$_{3}^{-}$ azide anion confined inside finite-size carbon nanotubes

In this work, the confinement of an N\(_{3}^{-}\) azide anion inside finite-size single-wall zigzag and armchair carbon nanotubes of different diameters has been studied by wave function and density functional theory. Unrelaxed and relaxed interaction energies have been computed, resulting in a favorable interaction between the guest and host system. In particular, the largest interaction has been observed for the confinement in an armchair (5,5) carbon nanotube, for which a natural population analysis as well as an investigation based on the molecular electrostatic potential has been carried out. The nature of the interaction between the two fragments appears to be mainly electrostatic, favored by the enhanced polarizability of the nanotube wall treated as a finite system and passivated by hydrogen atoms. The results obtained are promising for possible applications of this complex as a starting point for the stabilization of larger polynitrogen compounds, suitable as a high-energy density material.     

Mass loss and macroinvertebrate colonisation of fish carcasses in riffles and pools of a NW Italian stream

In this study, we analysed the decomposition of trout carcasses in a low-order Apennine stream, with the aim to investigate the mass loss rate in a Mediterranean lotic system, and to examine the influence of microhabitats on the invertebrates colonising fish carcasses. In May 2003, we put 56 dead rainbow trout (Oncorhynchus mykiss) in the stream, placing seven sets (four trout each) in both riffle and pool habitats. At four dates, we removed one trout per set to measure its dry mass and determine the associated macroinvertebrate assemblage. Fifty-eight macroinvertebrate taxa colonised the carcasses, with significant differences between the erosive and depositional microhabitats. Riffle trouts hosted richer and denser colonist communities than pool trouts. Chironomidae, Serratella ignita, Habrophlebia sp., Dugesia sp. and Protonemura sp. were the five most abundant taxa. Decomposition was initially very rapid in both environments and then tapered off over time. The mass loss rate was higher (k= –0.057 day^–1) than that found in other studies. Higher Mediterranean temperatures probably increase the process. Although we found no significant difference between riffles and pools, mass loss was more regular in erosive habitats, underlining the importance of local, small-scale conditions. In small, low-order, heterotrophic streams, fish carcasses represent an important resource and shelter for rich and diversified invertebrate assemblages.     

Effect of recovery mode on repeated sprint ability in young basketball players

The aim of this study was to examine the effect of recovery mode on repeated sprint ability in young basketball players. Sixteen basketball players (age, 16.8 +/- 1.2 years; height, 181.3 +/- 5.7 cm; body mass, 73 +/- 10 kg; VO2max, 59.5 +/- 7.9 mL x kg(-1) x min(-1)) performed in random order over 2 separate occasions 2 repeated sprint ability protocols consisting of 10 x 30-m shuttle run sprints with 30 seconds of passive or active (running at 50% of maximal aerobic speed) recovery. Results showed that fatigue index (FI) during the active protocol was significantly greater than in the passive condition (5.05 +/- 2.4, and 3.39 +/- 2.3, respectively, p < 0.001). No significant association was found between VO2peak and FI and sprint total time (TT) in either repeated sprint protocols. Blood lactate concentration at 3 minutes post exercise was not significantly different between the 2 recovery conditions. The results of this study show that during repeated sprinting, passive recovery enabled better performance, reducing fatigue. Consequently, the use of passive recovery is advisable during competition in order to limit fatigue as a consequence of repeated high intensity exercise.     

Intracellular bacteriolysis triggers a massive apoptotic cell death in Shigella-infected epithelial cells

Infected epithelial cells, which act as a first barrier against pathogens, seldom undergo apoptosis. Rather, infected epithelial cells undergo a slow cell death that displays hallmarks of necrosis. Here, we demonstrate that rapid intracellular lysis of Shigella flexneri, provoked by either the use of a diaminopimelic acid auxotroph mutant or treatment of infected cells with antibiotics of the beta-lactam family, resulted in a massive and rapid induction of apoptotic cell death. This intracellular bacteriolysis-mediated apoptotic death (IBAD) was characterized by the specific involvement of the mitochondrial-dependent cytochrome c/Apaf-1 axis that resulted in the activation of caspases-3, -6 and -9. Importantly, Bcl-2 family members and the NF-kappaB pathway seemed to be critical modulators of IBAD. Finally, we identified that IBAD was also triggered by Salmonella enterica serovar Typhimurium but not by the Gram-positive bacteria, Listeria monocytogenes. Together, our results demonstrate that, contrary to previous findings, epithelial cells are intrinsically able to mount an efficient apoptotic cell death response following infection. Indeed, apoptosis in normal circumstances is masked by powerful anti-apoptotic mechanisms, which are overcome in IBAD. Our results also uncover an unexpected consequence of the treatment of infected cells with certain classes of antibiotics.