Regional projections of extreme apparent temperature days in Africa and the related potential risk to human health

Regional climate modelling was used to produce high resolution climate projections for Africa, under a “business as usual scenario”, that were translated into potential health impacts utilizing a heat index that relates apparent temperature to health impacts. The continent is projected to see increases in the number of days when health may be adversely affected by increasing maximum apparent temperatures (AT) due to climate change. Additionally, climate projections indicate that the increases in AT results in a moving of days from the less severe to the more severe Symptom Bands. The analysis of the rate of increasing temperatures assisted in identifying areas, such as the East African highlands, where health may be at increasing risk due to both large increases in the absolute number of hot days, and due to the high rate of increase. The projections described here can be used by health stakeholders in Africa to assist in the development of appropriate public health interventions to mitigate the potential health impacts from climate change.

Annular modes and apparent eddy feedbacks in the Southern Hemisphere

Lagged correlation analysis is often used to infer intraseasonal dynamical effects but is known to be affected by non-stationarity. We highlight a pronounced quasi-two-year peak in the anomalous zonal wind and eddy momentum flux convergence power spectra in the Southern Hemisphere, which is prima facie evidence for non-stationarity. We then investigate the consequences of this non-stationarity for the Southern Annular Mode and for eddy momentum flux convergence. We argue that positive lagged correlations previously attributed to the existence of an eddy feedback are more plausibly attributed to non-stationary interannual variability external to any potential feedback process in the mid-latitude troposphere. The findings have implications for the diagnosis of feedbacks in both models and re-analysis data as well as for understanding the mechanisms underlying variations in the zonal wind.

Study of the pozzolanic reaction kinetics in sugar cane bagasse-clay ash/calcium hydroxide system: kinetic parameters and pozzolanic activity

This paper presents a study of the pozzolanic reaction kinetics between calcium hydroxide and a mixture of sugar cane bagasse with 20 and 30% of clay, burned at 800 and 1000 degrees C (SCBCA) by electrical conductivity measurements. A kinetic-diffusive model produced in previous studies by some of the authors was used. The model was fitted to the experimental data, which allowed the computation of the kinetic parameters of the pozzolanic reaction (reaction rate constant and free energy of activation) that rigorously characterised the pozzolanic activity of the materials. The results show that SCBCA demonstrated reactivity and good pozzolanic qualities in the range 800-1000 degrees C.

Effect of somatic cell counts on lipolysis, proteolysis and apparent viscosity of UHT milk during storage

In this work, lipolysis, proteolysis and viscosity of ultra-high temperature (UHT) milk containing different somatic cell counts (SCC) were investigated. UHT milks were analysed on days 8, 30, 60, 90 and 120 of storage. Lipolysis as measured by free fatty acids increase, casein degradation and viscosity of UHT milk were not affected by SCC but increased during storage. A negative relationship was observed between SCC and casein as a percentage of true protein on the 120th day of storage, hence indicating that high SCC increases the proteolysis of UHT milk by the end of its shelf life.

Paleomagnetism of the Santa Fe Group, central Brazil: Implications for the late Paleozoic apparent polar wander path for South America

Paleomagnetic and rockmagnetic data are reported for the Floresta Formation (Santa Fe Group) of the Sanfranciscana Basin, central Brazil. This formation represents the Permo-Carboniferous glacial record of the basin and comprises the Brocoto (diamictites and flow diamictites), Brejo do Arroz (red sandstones and shales with dropstones and invertebrate trails), and Lavado (red sandstones) members, which crop out near the cities of Santa Fe de Minas and Canabrava, Minas Gerais State. Both Brejo do Arroz and Lavado members were sampled in the vicinities of the two localities. Alternating field and thermal demagnetizations of 268 samples from 76 sites revealed reversed components of magnetization in all samples in accordance with the Permo-Carboniferous Reversed Superchron. The magnetic carriers are magnetite and hematite with both minerals exhibiting the same magnetization component, suggesting a primary origin for the remanence. We use the high-quality paleomagnetic pole for the Santa Fe Group (330.9 degrees E 65.7 degrees S; N = 60; alpha(95) = 4.1 degrees; k = 21) in a revised late Carboniferous to early Triassic apparent polar wander path for South America. On the basis of this result it is shown that an early Permian Pangea A-type fit is possible if better determined paleomagnetic poles become available.

NMR Chemical Shielding and Spin-Spin Coupling Constants of Liquid NH(3): A Systematic Investigation using the Sequential QM/MM Method

The NMR spin coupling parameters, (1)J(N,H) and (2)J(H,H), and the chemical shielding, sigma((15)N), of liquid ammonia are studied from a combined and sequential QM/MM methodology. Monte Carlo simulations are performed to generate statistically uncorrelated configurations that are submitted to density functional theory calculations. Two different Lennard-Jones potentials are used in the liquid simulations. Electronic polarization is included in these two potentials via an iterative procedure with and without geometry relaxation, and the influence on the calculated properties are analyzed. B3LYP/aug-cc-pVTZ-J calculations were used to compute the V(N,H) constants in the interval of -67.8 to -63.9 Hz, depending on the theoretical model used. These can be compared with the experimental results of -61.6 Hz. For the (2)J(H,H) coupling the theoretical results vary between -10.6 to -13.01 Hz. The indirect experimental result derived from partially deuterated liquid is -11.1 Hz. Inclusion of explicit hydrogen bonded molecules gives a small but important contribution. The vapor-to-liquid shifts are also considered. This shift is calculated to be negligible for (1)J(N,H) in agreement with experiment. This is rationalized as a cancellation of the geometry relaxation and pure solvent effects. For the chemical shielding, U(15 N) Calculations at the B3LYP/aug-pcS-3 show that the vapor-to-liquid chemical shift requires the explicit use of solvent molecules. Considering only one ammonia molecule in an electrostatic embedding gives a wrong sign for the chemical shift that is corrected only with the use of explicit additional molecules. The best result calculated for the vapor to liquid chemical shift Delta sigma((15)N) is -25.2 ppm, in good agreement with the experimental value of -22.6 ppm.

Kinetic and Crystallographic Studies on Glyceraldehyde-3-Phosphate Dehydrogenase from Trypanosoma cruzi in Complex with Iodoacetate

Kinetic and crystallographic studies on the formation of the complex between iodoacetate and the enzyme glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma cruzi were conducted in order to investigate the mechanistic and structural basis underlying enzyme inactivation. The crystallographic complex reveal important structural features useful for the design of novel inhibitors.

Ligand induced interaction of thyroid hormone receptor beta with its coregulators

Thyroid hormones exert most of their physiological effects through two thyroid hormone receptor (TR) subtypes, TR alpha and TR beta, which associate with many transcriptional coregulators to mediate activation or repression of target genes. The search for selective TR beta ligands has been stimulated by the finding that several pharmacological actions mediated by TR beta might be beneficial in medical conditions such as obesity, hypercholesterolemia and diabetes. Here, we present a new methodology which employs surface plasmon resonance to investigate the interactions between TR beta ligand binding domain (LBD) complexes and peptides derived from the nuclear receptor interaction motifs of two of its coregulators, SRC2 and DAX1. The effect of several TR beta ligands, including the TR beta selective agonist GC-I and the TR beta selective antagonist NH-3, were investigated. We also determined the kinetic rate constants for the interaction of TR beta-T3 with both coregulators, and accessed the thermodynamic parameters for the interaction with DAX1. Our findings Suggest that flexibility plays an important role in the interaction between the receptor and its coregulators. and point out important aspects of experimental design that should be addressed when using TR beta LBD and its agonists. Furthermore, the methodology described here may be useful for the identification of new TR beta ligands. (C) 2008 Elsevier Ltd. All rights reserved.

The binding of synthetic triiodo L-thyronine analogs to human transthyretin: Molecular basis of cooperative and non-cooperative ligand recognition

Transthyretin (TTR) is a tetrameric beta-sheet-rich transporter protein directly involved in human amyloid diseases. Several classes of small molecules can bind to TTR delaying its amyloid fibril formation, thus being promising drug candidates to treat TTR amyloidoses. In the present study, we characterized the interactions of the synthetic triiodo L-thyronine analogs and thyroid hormone nuclear receptor TR beta-selecfive agonists GC-1 and GC-24 with the wild type and V30M variant of human transthyretin (TTR). To achieve this aim, we conducted in vitro TTR acid-mediated aggregation and isothermal titration calorimetry experiments and determined the TTR:GC-1 and TTR:GC-24 crystal structures. Our data indicate that both GC-1 and GC-24 bind to TTR in a non-cooperative manner and are good inhibitors of TTR aggregation, with dissociation constants for both hormone binding sites (HBS) in the low micromolar range. Analysis of the crystal structures of TTRwt:GC-1(24) complexes and their comparison with the TTRwt X-ray structure bound to its natural ligand thyroxine (T4) suggests, at the molecular level, the basis for the cooperative process displayed by T4 and the non-cooperative process provoked by both GC-1 and GC-24 during binding to TTR. (C) 2010 Elsevier Inc. All rights reserved.

Structural basis for selective inhibition of purine nucleoside phosphorylase from Schistosoma mansoni: Kinetic and structural studies

Selectivity plays a crucial role in the design of enzyme inhibitors as novel antiparasitic agents, particularly in cases where the target enzyme is also present in the human host. Purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) is an attractive target for the discovery of potential antischistosomal agents. In the present work, kinetic studies were carried out in order to determine the inhibitory potency, mode of action and enzyme selectivity of a series of inhibitors of SmPNP. In addition, crystallographic studies provided important structural insights for rational inhibitor design, revealing consistent structural differences in the binding mode of the inhibitors in the active sites of the SmPNP and human PNP (HsPNP) structures. The molecular information gathered in this work should be useful for future medicinal chemistry efforts in the design of new inhibitors of SmPNP having increased affinity and selectivity. (C) 2010 Elsevier Ltd. All rights reserved.

The effect of carbonyl group in the asymmetry Of (3,4)J(CH) coupling constants in norbornanones

A rationalization of the known difference between the (3,4)J(C4H1) and (3,4)J(C1H4) couplings transmitted mainly through the 7-bridge in norbornanone is presented in terms of the effects of hyperconjugative interactions involving the carbonyl group. Theoretical and experimental studies Of (3,4)J(CH) couplings were carried out in 3-endo- and 3-exo-X-2-norbornanone derivatives (X = Cl, Br) and in exo- and endo-2-noborneol compounds. Hyperconjugative interactions were studied with the natural bond orbital (NBO) method. Hyperconjugative interactions involving the carbonyl pi*c(2) =o and sigma*c(2) =o antibonding orbitals produce a decrease of three-bond contribution to both (3,4) J(C4H1) and (3,4)J(C1H4) couplings. However, the latter antibonding orbital also undergoes a strong sigma c(3)-c(4) ->sigma*c(2) =o interaction, which defines an additional coupling pathway for (3,4)J(C4H1) but not for (3,4)J(C1H4). This pathway is similar to that known for homoallylic couplings, the only difference being the nature of the intermediate antibonding orbital; i.e. for (3,4)J(C4H1) it is of sigma*-type, while in homoallylic couplings it is of pi*-type. Copyright (c) 2007 John Wiley & Sons, Ltd.

INSECT CHYMOTRYPSINS: CHLOROMETHYL KETONE INACTIVATION AND SUBSTRATE SPECIFICITY RELATIVE TO POSSIBLE COEVOLUTIONAL ADAPTATION OF INSECTS AND PLANTS

Insect digestive chymotrypsins are present in a large variety of insect orders but their substrate specificity still remains unclear. Ewer insect chymotrypsins from 3 different insect orders (Dictyoptera, Coleoptera and two Lepidoptera) were isolated using affinity chromatography. Enzymes presented molecular masses in the range of 20 to 31 kDa and pH optima in the range of 7.5 to 10.0. Kinetic characterization. using different, colorimetric and fluorescent substrates indicated that insect chymotrypsins differ from, bovine chymotrypsin in their primary specificity toward small substrates (like N-benzoyl-L-Tyr p-nitroanilide) rather than on their preference for large substrates (exemplified by Succynil-Ala-Ala-Pro-Phe P-nitroanilide). Chloromethyl ketones (TPCK, N-alpha-tosyl-L-Phe chloromethyl ketone and Z-GGF-CK, N-carbobenzoxy-Gly-Gly-phe-CK) inactivated all chymotrypsins legated. Inactivation rates follow apparent first-order kinetics with variable second order rates (TPCK, 42 to 130 M(-1)s(-1); Z-GGF-CK, 150 to 450 M(-1)s(-1) that may be remarkably low for S. frugiperda chymotrypsin (TPCK, 6 M(-1)s(-1); Z-GGF-CK, 6.1 M(-1) s(-1)). Homology modelling and sequence alignment showed that. in lepidopteran chymotrypsins, differences in the amino acid residues in the neighborhood of the catalytic His 57 may affect its pKa, value. This is Proposed as the cause of the decrease in His 57 reactivity toward chloromethyl ketones. Such amino acid replacement in the active site is proposed. to be an adaptation to the presence of dietary ketones. (C) 2009 Wiley Periodicals, Inc.

Inhibition of myeloperoxidase-mediated protein nitration by tempol: Kinetics, mechanism, and implications

Despite the therapeutic potential of tempol (4-hydroxy-2,2,6,6-tetra-methyl-1-piperidinyloxy) and related nitroxides as antioxidants, their effects on peroxidase-mediated protein tyrosine nitration remain unexplored. This posttranslational protein modification is a biomarker of nitric oxide-derived oxidants, and, relevantly, it parallels tissue injury in animal models of inflammation and is attenuated by tempol treatment. Here, we examine tempol effects on ribonuclease (RNase) nitration mediated by myeloperoxidase (MPO), a mammalian enzyme that plays a central role in various inflammatory processes.. Some experiments were also performed with horseradish peroxidase (HRP). We show that tempol efficiently inhibits peroxidase-mediated RNase nitration. For instance, 10 mu M tempol was able to inhibit by 90% the yield of 290 mu M 3-nitrotyrosine produced from 370 mu M RNase. The effect of tempol was not completely catalytic because part of it was consumed by recombination with RNase-tyrosyl radicals. The second-order rate constant of the reaction of tempol with MPO compound I and 11 were determined by stopped-flow kinetics as 3.3 x 10(6) and 2.6 x 10(4) M-1 s(-1), respectively (pH 7.4, 25 degrees C); the corresponding HRP constants were orders of magnitude smaller. Time-dependent hydrogen peroxide and nitrite consumption and oxygen production in the incubations were quantified experimentally and modeled by kinetic simulations. The results indicate that tempol inhibits peroxidase-mediated RNase nitration mainly because of its reaction with nitrogen dioxide to produce the oxammonium cation, which, in turn, recycles back to tempol by reacting with hydrogen peroxide and superoxide radical to produce oxygen and regenerate nitrite. The implications for nitroxide antioxidant mechanisms are discussed.

Inhibition Mechanism of Rat alpha(3)beta(4) Nicotinic Acetylcholine Receptor by the Alzheimer Therapeutic Tacrine

Nicotinic acetylcholine receptors (nAChRs) were studied in detail in the past regarding their interaction with therapeutic and drug addiction related compounds. Using fast kinetic whole-cell recording, we have now studied effects of tacrine, an agent used clinically to treat Alzheimer`s disease, on currents elicited by activation of rat alpha(3)beta(4) nAChR heterologously expressed in KX alpha(3)beta(4)R2 cells. Characterization of receptor activation by nicotine used as agonist revealed a K(d) of 23 +/- 0.2 mu M and 4.3 +/- 1.3 for the channel opening equilibrium constant, Phi(-1). Experiments were performed to investigate whether tacrine is able to activate the alpha(3)beta(4) nAChR. Tacrine did not activate whole-cell currents in KX alpha(3)beta(4)R2 cells but inhibited receptor activity at submicromolar concentration. Dose response curves obtained with increasing agonist or inhibitor concentration revealed competitive inhibition of nAChRs by tacrine, with an apparent inhibition constant, K(I), of 0.8 mu M. The increase of Phi(-1) in the presence of tacrine suggests that the drug stabilizes a nonconducting open channel form of the receptor. Binding studies with TCP and MK-801 ruled out tacrine binding to common allosteric sites of the receptor. Our study suggests a novel mechanism for action of tacrine on nAChRs besides inhibition of acetylcholine esterase.