Helices on Interdomain Interface Couple Catalysis in the ATPPase Domain with Allostery in Plasmodium falciparum GMP Synthetase

GMP synthetase catalyses the conversion of XMP to GMP through a series of reactions that include hydrolysis of Gln to generate ammonia in the glutamine amidotransferase (GATase) domain, activation of XMP to adenyl-XMP intermediate in the ATP pyrophosphatase (ATPPase) domain and reaction of ammonia with the intermediate to generate GMP. The functioning of GMP synthetases entails bidirectional domain crosstalk, which leads to allosteric activation of the GATase domain, synchronization of catalytic events and tunnelling of ammonia. Herein, we have taken recourse to the analysis of structures of GMP synthetases, site-directed mutagenesis and steady-state and transient kinetics on the Plasmodium falciparum enzyme to decipher the molecular basis of catalysis in the ATPPase domain and domain crosstalk. Our results suggest an arrangement at the interdomain interface, of helices with residues that play roles in ATPPase catalysis as well as domain crosstalk enabling the coupling of ATPPase catalysis with GATase activation. Overall, the study enhances our understanding of GMP synthetases, which are drug targets in many infectious pathogens.     

As you like it: Understanding the relationship between packing design and accessibility

Accessible packaging is continually receiving greater attention as an ageing population becomes a primary driver behind inclusive design. As we age, our strength dexterity and some cognitive functions decline. For this reason, the ease of interaction with simple tasks in daily living becomes an ever increasing concern. ISO 17480 “Packaging Guidelines” consider capability issues relating to packaging and ageing to broadly come under three areas, namely, strength, dexterity, and cognition. Significant previous work has been undertaken looking at the issue of strength on packaging accessibility, with fewer studies looking at the relationship between the physical demands of dexterity and the understanding of how to open the pack. In this previous work, there has been little attempt to quantify the effect of the affordances, perceptual information and symbology, and the physical demands of the pack and how this relates to accessibility. Hence, this exploratory study seeks to use motion capture and a dexterity test, along with a cognitive demand test to study this relationship and any changes with age. This research indicates that the dexterous demands of a task are linked to the cognitive demands; and thus in reaching a level of comprehension of the pack and how to access the product a subject may interact with a pack effectively.     

A Potent N-(piperidin-4-yl)-1H-pyrrole-2-carboxamide Inhibitor of Adenylyl Cyclase of G. lamblia: Biological Evaluation and Molecular Modelling Studies

In this work, we report a derivative of N-(piperidin-4-yl)-1H-pyrrole-2-carboxamide as a new inhibitor for adenylyl cyclase of Giardia lamblia which was obtained from a study using structural data of the nucleotidyl cyclase 1 (gNC1) of this parasite. For such a study, we developed a model for this specific enzyme by using homology techniques, which is the first model reported for gNC1 of G. lamblia. Our studies show that the new inhibitor has a competitive mechanism of action against this enzyme. 2-Hydroxyestradiol was used as the reference compound for comparative studies. Results in this work are important from two points of view. on the one hand, an experimentally corroborated model for gNC1 of G. lamblia obtained by molecular modelling is presented; on the other hand, the new inhibitor obtained is an undoubtedly excellent starting structure for the development of new metabolic inhibitors for G. lamblia.     

Structural evolution at short and medium range distances during crystallization of a P2O5-Li2O-Al2O3-SiO2 glass

Li₂O-Al₂O₃-SiO₂ (LAS) glass-ceramics have important industrial applications and bulk nucleation is usually achieved by using nucleating agents. In particular, P₂O₅ is an efficient agent in glasses containing a low level of Al₂O₃ but its role in the first stages of nucleation is not well established. In this study, we combine structural investigations from local to mesoscales to describe the structural evolution during crystallization of LAS glass-ceramics. Local environment is probed using ²⁹Si and ³¹P MAS-NMR, indicating organization of P in poorly crystallized Li₃PO₄ species prior to any crystallization. To better understand the detailed nanoscale changes of the glass structure, ³¹P-³¹P DQ-DRENAR homonuclear correlation experiments have been carried out, revealing the gradual segregation of P atoms associated with the formation of disordered Li₃PO₄. Small-angle neutron scattering data also show the apparition of nanoscale heterogeneities associated with Li₃PO₄ species upon heating treatments and allow the determination of their average sizes. These new structural information enhance our understanding of the role of P in nucleation mechanisms. Nucleation is initiated by gradual change in P environment implying P segregation upon heating treatments, forming disordered Li₃PO₄ heterogeneities. The segregation of P atoms enables the precipitation of meta- and disilicate phases.     

Future Scenarios of Surface Water Resources Availability in North African Dams

Climate change may have strong impacts on water resources in developing countries. In North Africa, many dams and reservoirs have been built to secure water availability in the context of a strong inter-annual variability of precipitation. The goal of this study is to evaluate climate change impacts on surface water resources for the largest dams in Algeria, Morocco and Tunisia using high-resolution (12 km) regional climate models (RCM) simulations. To evaluate the atmospheric demand (evapotranspiration), two approaches are compared: The direct use of actual evaporation simulated by the RCMs, or estimation of reference evapotranspiration computed with the Hargreaves-Samani (HAR) equation, relying on air temperature only, and the FAO-Penman Monteith (PM) equation, computed with temperature, wind, radiation and relative humidity. Results showed a strong convergence of the RCM simulations towards increased temperature and a decrease in precipitation, in particular during spring and the western part of North Africa. A decrease in actual evapotranspiration, highly correlated to the decrease in precipitations, is observed throughout the study area. On the opposite, an increase in reference evapotranspiration is observed, with similar changes between HAR and PM equations, indicating that the main driver of change is the temperature increase. Since the catchments are rather water-limited than energy-limited, despite opposite projections for actual and reference evapotranspiration a decrease of water availability is projected for all basins under all scenarios, with a strong east-to-west gradient. The projected decrease is stronger when considering reference evapotranspiration rather than actual evaporation. These pessimistic future projections are an incentive to adapt the current management of surface water resources to future climatic conditions.     

Heat Capacity and Thermal Damping Properties of Spin-Crossover Molecules: A New Look at an Old Topic

The thermally induced spin-crossover (SCO) phenomenon in transition metal complexes is an entropy-driven process, which has been extensively studied through calorimetric methods. Yet, the excess heat capacity associated with the molecular spin-state switching has never been explored for practical applications. Herein, the thermal damping effect of an SCO film is experimentally assessed by monitoring the transient heating response of SCO-coated metallic microwires, Joule-heated by current pulses. A damping of the wire temperature, up to 10%, is evidenced on a time scale of tens of microseconds due to the spin-state switching of the molecular film. Fast heat-charging dynamics and negligible fatigability are demonstrated, which, together with the solid-solid nature of the spin transition, appear as promising features for achieving thermal energy management applications in functional devices.     

Observable Dictionary Learning for High-Dimensional Statistical Inference

This paper introduces a method for efficiently inferring a high-dimensional distributed quantity from a few observations. The quantity of interest (QoI) is approximated in a basis (dictionary) learned from a training set. The coefficients associated with the approximation of the QoI in the basis are determined by minimizing the misfit with the observations. To obtain a probabilistic estimate of the quantity of interest, a Bayesian approach is employed. The QoI is treated as a random field endowed with a hierarchical prior distribution so that closed-form expressions can be obtained for the posterior distribution. The main contribution of the present work lies in the derivation of a representation basis consistent with the observation chain used to infer the associated coefficients. The resulting dictionary is then tailored to be both observable by the sensors and accurate in approximating the posterior mean. An algorithm for deriving such an observable dictionary is presented. The method is illustrated with the estimation of the velocity field of an open cavity flow from a handful of wall-mounted point sensors. Comparison with standard estimation approaches relying on Principal Component Analysis and K-SVD dictionaries is provided and illustrates the superior performance of the present approach.     

Stack-and-Draw Applied to the Engineering of Multi-Material Fibers with Non-Cylindrical Profiles

Here, it is demonstrated that the stack-and-draw approach can be expanded to unusual materials association and profile geometries to generate fiber assemblies with unprecedented functionalities. This approach relies on the stacking of flat oxide glass slides into a preform, which is then thermally elongated into tens-of-meters-long ribbon fibers with preserved cross-section ratio. Fabrication methodology is introduced. In order to illustrate the versatility of the method, a panel of fibers with diverse geometries and functions is exposed, including glass-only exposed-core fibers for chemical sensing and, upon the insertion of metal electrodes, H-shaped multi-cavity structures and compact, glass-metal fiber optical detectors applied to a gas analysis by means of fiber-tip plasma spectroscopy. It is believed this new approach will offer an attractive, straightforward solution for designing innovative, complex multimaterial fiber platforms with enhanced functionalities.