A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis

The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.     

Variation in the levels of the different xylanase inhibitors in grain and flour of 20 French wheat cultivars

A xylanase from Aspergillus aculeatus (glycoside hydrolase family 10), uninhibited by TAXI, and a xylanase from Bacillus subtilis (family 11), uninhibited by XIP-I, were selected to quantify the respective apparent levels of XIP-I and TAXI inhibitors, in flours and grains of 20 wheat varieties. The apparent TAXI amount ranged from 0.05 to 0.19 mg/g in flour (mean: 0.11 mg/g) and from 0.07 to 0.2 mg/g in grain (mean: 0.14 mg/g). The range observed for XIP-I was 0.12–0.6 mg/g in flour (mean 0.32 mg/g), and 0.21–0.56 mg/g in grain (mean: 0.41 mg/g). The inhibition profile of the xylanase from A. aculeatus by a crude inhibitor preparation suggested the presence of an additional component in wheat flour, responsible for an increase in inhibition.     

Management- and housing-related risk factors of respiratory disorders in non-weaned French Charolais calves

Our aim was to determine at calf-batch level the management- and housing-related risk factors of respiratory disorders in non-weaned Charolais calves. Farmers recorded cases according to the definition provided i.e. the association of at least one respiratory sign and, in the same calf or another calf of the same batch, at least one general sign on the same day or the day before. During farm visits, quality of farmers’ records was checked and questionnaires were applied to gather farm and herd characteristics and to describe farming practices and housing facilities. Data were suitable for analysis for 172 batches where no metaphylactic treatment was implemented. Batches had great disparity in incidence of respiratory disorders. In the 120 batches with at least one case, the quartiles of incidence rate were, respectively, 0.95, 2.15 and 3.59 cases per 1000 calf-days at-risk. For risk-factor analysis, the statistical unit was the calf-batch located in a given batch. We used a ZINB model because (i) there was significant overdispersion of incidence rates of respiratory disorders (overdispersion test statistic of O = 1049 (P < 0.001)), (ii) probability was high that a two-group modelling process existed (Vuong statistic of V = 2.44 (P = 0.0073)) and (iii) the ZINB model fit significantly better than the ZIP model (likelihood-ratio statistic of 340.14 (P < 0.001)). The risk was higher in open-fronted barns or in open barns compared to closed ones (incidence-rate ratios (IRRs): 1.9 and 1.8), in barns where no annual disinfection was implemented (IRR: 1.5) and in part slope with straw/part scraped and in part straw-bedded/part scraped barns compared to completely straw-bedded barns (IRRs: 1.9 and 1.6). Larger calf-batches were more at-risk than smaller batches (OR for the effect of an increase of 10 calves on the probability of a 0 count: 0.5).     

Individual heterogeneity in erythrocyte susceptibility to Babesia divergens is a critical factor for the outcome of experimental spleen-intact sheep infections

Susceptibility of sheep erythrocytes to Babesia divergens was investigated in vitro and a high inter-individual variability in their ability to support parasite population development was demonstrated, with some individuals having refractory red blood cells (RBC). As neither changes in growth conditions nor the use of different B. divergens strains influenced the level of susceptibility, the main factor postulated for this variability is the erythrocyte itself. Sheep therefore represent an excellent in vitro model to study the parasite-erythrocyte interaction. In addition, the existence of refractory RBC should help in the identification of the erythrocyte components required for B. divergens development. Experimental infections were carried out on spleen-intact sheep characterized by refractory or fully susceptible erythrocyte types. These differences translated into the successful infection of only those animals with susceptible erythrocytes: infected animals showed no clinical signs, but maintained an asymptomatic persistent infection, as usually observed in the natural bovine host. Sheep therefore represent model organisms that can allow us to study interactions between B. divergens and its vertebrate host at different levels of biological organisation, from the target cell to the intact animal, and represent an experimental infection model of concomitant immunity. Only a low percentage (13%) of the sheep population tested possessed susceptible erythrocytes and the potential role of sheep as a natural host or reservoir of B. divergens is discussed.     

A pilot study comparing the antispasmodic effects of inhaled salmeterol, salbutamol and ipratropium bromide using different aerosol devices on muscarinic bronchoconstriction in healthy cats

This study compared the duration and magnitude of the antispasmodic effects of salmeterol (SLM), salbutamol (SAL), ipratropium bromide (IB) and the combination of SAL and IB (SAL/IB) against carbachol-induced bronchoconstriction in healthy cats, and investigated the gain in efficacy using a two or fourfold increase in drug dosages. The drug regimens used were: (1) SLM 25 microg, SAL 100 microg, IB 20 microg and SAL/IB 100 microg/20 microg for bronchodilators delivered by a metered-dose inhaler (MDI); (2) SAL 3.75 mg and IB 62.5 microg for nebulised (NEB) medications. To monitor the bronchodilator effect, airway responsiveness was assessed at different time points using barometric whole-body plethysmography and calculation of the concentration of inhaled carbachol inducing a 300% increase of baseline Penh (enhanced pause), an estimator of airflow limitation. Maximum C-Penh300 was recorded 15 min after NEB SAL, IB MDI, NEB IB and 1h after SAL MDI and 4h after SLM MDI, respectively. C-Penh300 was significantly different from control values (without treatment) up to 24h for SLM MDI, 8h for IB MDI and 4h for other drugs. In terms of efficacy, SAL/IB MDI showed a synergistic antispasmodic effect at 15 min, 4h and 8h after administration. A fourfold increase of the initial dose of IB MDI and NEB IB significantly increased C-Penh300. Despite a fourfold dose increase, SLM displayed the weakest degree of bronchoprotection compared to other bronchodilators. The study provides evidence that inhaled bronchodilators are efficient at preventing muscarinic-induced bronchospasm in healthy cats and that SAL and IB appear to be short-acting bronchodilators in contrast to SLM.     

Simultaneous quantitative analysis of maillard reaction precursors and products by high-performance anion exchange chromatography

A new analytical setup allowing the simultaneous analysis of precursors and products of the Maillard reaction is described. It is based on high-performance anion exchange chromatography with electrochemical (ECD) and diode array detectors (DAD) coupled in series. Chromatography and detection were optimized to permit simultaneous monitoring of compounds relevant to the Maillard reaction, such as the sugar, the amino acid, and the corresponding Amadori compound as well as the cyclic intermediates 5-(hydroxymethyl)-2-furaldehyde, maltol, and 2,3-dihydro-3,5-dihydroxy-6-methyl-4(H)-pyran-4-one. Separation was achieved on a CarboPac PA-1 column using a gradient of sodium acetate in aqueous sodium hydroxide. The Amadori compound, glucose, and glycine were monitored by an ECD operating in the integrated amperometry mode. The number of analyzed compounds was further increased by coupling the ECD with a DAD for the analysis of ultraviolet-active constituents. This method was successfully applied to model Maillard reaction mixtures based on glucose and glycine.     

Cortisol and Behavioral Response to Handling (Acute) and Confinement (Chronic) Stressors in Juvenile Spotted Wolffish,Anarhichas minor

The purpose of this study was to determine the cortisol response of spotted wolffish (Anarhichas minor) after exposure to air immersion and netting (acute stress) under a range of increasing densities (chronic stressor). In addition, the presence of a cumulative negative impact from chronic stress was assessed by the application of an additional acute stressor following rearing at various densities, and proxies of behavior were evaluated (feeding and aggression data). The stress response to air immersion and netting led to increasing plasma cortisol values at 0.5, 13, and 37 h post-stress, with the highest value achieved after 13 h. At 168 h, cortisol concentrations returned to similar pre-stress value. Changes in cortisol concentrations were relatively low after acute stress (five to six fold increases) and recovery time long lasting (>37 h). Prolonged rearing at 20, 30, and 40 kg m^?2 showed a non-significant trend of increasing cortisol values with increasing density, and the cortisol response after the application of an additional acute stressor was significantly altered, i.e., higher cortisol levels were measured in unstressed (chronic stress only) compared to stressed fish (chronic stress + acute stress). Our results suggest that (1) spotted wolffish is a low responder that additionally displays a long-lasting cortisol elevation following an acute stressor; (2) fixed densities did not lead to significant differences of plasma cortisol concentration or aggression levels, although involved marked changes in daily feed intake and food conversion efficiency were observed; and (3) cortisol levels reached acute stress values after prolonged chronic stress. Although this species displays indications of being relatively resistant to handling disturbances during aquaculture practices, it is nevertheless responsive to chronic stress factors that could alter the physiological response to subsequent acute stressor.     

Criteria for selecting productive and stable pea cultivars

The beginning and duration of the seed set in the growth cycle determine the level and stability of the yield of a pea (Pisum sativum L.) genotype. The objective of the present study was to identify criteria for selecting genotypes, both in terms of timing of seed set and productivity. Genotypes were initially compared in field experiments for two different levels of inter-plant competition, but using the same photo-thermal conditions. These experiments showed that the initiation and, particularly, the duration of seed set were affected by plant growth rates, indicating that selection on these variables must be done by comparing genotypes under regular cropping conditions. When measuring seed production of the whole plant, we found that mean dry seed weight per podded node all over the plant and the number of podded nodes on any fertile stem were similar to those on the main stem. These results confirmed that branches and main stems have a similar reproductive pattern, and thus that any podded stem of the canopy is representative of every stem of the plant. Lastly, we showed that, when associated, the number of podded nodes, the mean dry seed weight per podded node on the main stem (or on any reproductive stem of the canopy), and the number of basal branches per plant are suitable criteria for selecting for productivity among genotypes with a similar duration of seed set. This revised version was published online in August 2006 with corrections to the Cover Date.     

Ecological classification of white lupin landrace genetic resources

Information on the adaptation of germplasm pools to specific agroclimatic conditions is essential for ensuring high genetic progress while broadening the genetic base of breeding programmes. This study aimed to provide an ecological classification of global white lupin (Lupinus albus L.) landrace genetic resources on the basis of their adaptation pattern, verifying whether region of origin could conveniently contribute to such a classification. Some 113 landraces representing 11 regional pools were evaluated in three major agroclimatic conditions, i.e., Mediterranean and subcontinental climate in Italy under autumn sowing, and suboceanic climate in France under spring sowing. The classification of regional pools by pattern analysis suggested the presence of five major ecological groups composed as follows: A = Azores, Greece and Italy; B = Madeira and Canaries; C = Maghreb, Portugal and Spain; D = East Africa, Egypt and West Asia; and E = Turkey. This classification implied specific adaptation ranging from the cold-prone, autumn-sown environment (group A) to the spring-sown environment (groups D and E). Ecological grouping accounted for about half of the overall genotypic variation and genotype × environment interaction variation in just 3.6% of its degrees of freedom in an analysis of variance. It reflected largely the entry groups issued by pattern analysis classification of the individual accessions. Our classification of ecological groups can drive the incorporation of exotic genetic resources in European breeding programmes as a function of the targeted agroclimatic conditions. In addition, it can contribute to the definition of global or user-specific core collections.     

Spatial variability of the functional stability of microbial respiration process: a microcosm study using tropical forest soil

Purpose

Understanding the ability of ecosystem processes to resist to and to recover from disturbances is critical to sustainable land use. However, the spatial variability of the stability has rarely been addressed. Here, we investigated the functional stability of a soil microbial process for 24 soils collected from adjacent locations from a 0.3?ha tropical rainforest plot in Paracou, French Guiana.

Materials and methods

The 24 locations were characterized regarding soil chemical and biological (microbial diversity) parameters and forest structure. The corresponding soils were submitted to an experimental transient heat disturbance during a microcosm experiment. The response of the respiration process was followed using substrate-induced respiration (SIR).

Results and discussion

The response of soil SIR to heat disturbance varied widely between samples. The variability of the SIR response increased just after the disturbance, and a global rather homogeneous decrease in SIR rates was observed 15 and 30?days after. The stability of SIR in response to heat disturbance could not be related to either the genetic or the metabolic diversity of the microbial community. The initial level of SIR before the disturbance was the soil variable that best correlated with the impact of the disturbance: the soil locations with the highest initial SIR rates were the most affected 15 and 30?days after the heat disturbance.

Conclusions

Such a heterogeneous response suggests that the response of soil processes to a disturbance will be difficult to assess from only local-scale analyses and highlights the need for spatial explicitness in understanding biogeochemical processes.