Armeniaspiroles, a new class of antibacterials: antibacterial activities and total synthesis of 5-chloro-Armeniaspirole A

Armeniaspiroles, a novel class of natural products isolated from Streptomyces armeniacus, are characterized by a novel spiro[4.4]non-8-ene scaffold. Various derivatives of Armeniaspiroles could be obtained by halogenation, alkylation, addition/elimination or reductions. A total synthesis of the 5-chloro analog of Armeniaspirole A has been accomplished in a linear six-step sequence. 5-Chloro-Armeniaspirole A exhibits good activity against a range of multidrug-resistant, Gram-positive bacterial pathogens.     

The Shc protein Rai enhances T-cell survival under hypoxia

Hypoxia occurs in physiological and pathological conditions. T cells experience hypoxia in pathological and physiological conditions as well as in lymphoid organs. Indeed, hypoxia-inducible factor 1α (HIF-1α) affects T cell survival and functions. Rai, an Shc family protein member, exerts pro-survival effects in hypoxic neuroblastoma cells. Since Rai is also expressed in T cells, we here investigated its role in hypoxic T cells. In this work, hypoxia differently affected cell survival, proapoptotic, and metabolic programs in T cells, depending upon Rai expression. By using Jurkat cells stably expressing Rai and splenocytes from Rai^−/−mice, we demonstrated that Rai promotes T cell survival and affects cell metabolism under hypoxia. Upon exposure to hypoxia, Jurkat T cells expressing Rai show (a) higher HIF-1α protein levels; (b) a decreased cell death and increased Akt/extracellular-signal-regulated kinase phosphorylation; (c) a decreased expression of proapoptotic markers, including caspase activities and poly(ADP-ribose) polymerase cleavage; (d) an increased glucose and lactate metabolism; (e) an increased activation of nuclear factor-kB pathway. The opposite effects were observed in hypoxic splenocytes from Rai^−/−mice. Thus, Rai plays an important role in hypoxic signaling and may be relevant in the protection of T cells against hypoxia.     

Irp9, encoded by the high-pathogenicity island of Yersinia enterocolitica,is able to convert chorismate into salicylate,the precursor of the siderophore yersiniabactin

The Irp9 protein of Yersinia enterocolitica participates in the synthesis of salicylate, the precursor of the siderophore yersiniabactin. In Pseudomonas species, salicylate synthesis is mediated by two enzymes: isochorismate synthase and isochorismate pyruvate-lyase. Both enzymes are required for complementation of a Yersinia irp9 mutant. However, irp9 is not able to complement Escherichia coli entC for the production of enterobactin, which requires isochorismate as a precursor. These results suggest that Irp9 directly converts chorismate into salicylate.     

Ocean acidification alters foraging behaviour in Dungeness crab through impairment of the olfactory pathway

Crustacean olfaction is fundamental to most aspects of living and communicating in aquatic environments and more broadly, for individual- and population-level success. Accelerated ocean acidification from elevated CO₂ threatens the ability of crabs to detect and respond to important olfactory-related cues. Here, we demonstrate that the ecologically and economically important Dungeness crab (Metacarcinus magister) exhibits reduced olfactory-related antennular flicking responses to a food cue when exposed to near-future CO₂ levels, adding to the growing body of evidence of impaired crab behaviour. Underlying this altered behaviour, we find that crabs have lower olfactory nerve sensitivities (twofold reduction in antennular nerve activity) in response to a food cue when exposed to elevated CO₂. This suggests that near-future CO₂ levels will impact the threshold of detection of food by crabs. We also show that lower olfactory nerve sensitivity in elevated CO₂ is accompanied by a decrease in the olfactory sensory neuron (OSN) expression of a principal chemosensory receptor protein, ionotropic receptor 25a (IR25a) which is fundamental for odorant coding and olfactory signalling cascades. The OSNs also exhibit morphological changes in the form of decreased surface areas of their somata. This study provides the first evidence of the effects of high CO₂ levels at multiple levels of biological organization in marine crabs, linking physiological and cellular changes with whole animal behavioural responses.     

Relationship between optimal lactate removal power output and Olympic triathlon performance

To investigate the relationships between race performance and parameters at the optimal power output for lactate removal, 10 male triathletes were examined. Exercise intensities for lactate removal were defined by calculating 50% of difference (DeltaT) between running velocity (V(r)) at individual anaerobic threshold (IAT) and at individual ventilatory threshold (IVT), then choosing 3 V(r): at IVT plus 50% DeltaT (IVT(+50%DeltaT)), at IVT, and at IVT minus 50% DeltaT (IVT(-50%DeltaT)). After a 6-minute treadmill run at 75% of difference between IAT and V(.-)O2max, all triathletes performed a 30-minute active recovery run at IVT(+50%DeltaT), IVT, and IVT(-50%DeltaT). Capillary blood lactate was determined at 1, 3, 6, 9, 12, 15, 20, 25, and 30 minutes of recovery. The IVT(-50%DeltaT) recovery was the most efficient V(r) for lactate removal. Running velocities at IVT and IVT(-50%DeltaT) were highly (p < 0.01) related to cycle, run, and overall race time. V(.-)O2max values at IAT, IVT(+50%DeltaT), and IVT were less (p < 0.05) related to split and overall race time. The variable most related to overall race time, as determined by stepwise multiple linear regression analysis, was the V(r) at IVT(-50%DeltaT) (r = 0.87, p = 0.001). The R(2) value of 0.76 indicated that V(r) at IVT(-50%DeltaT) could account for 76% of the variance in triathlon race time. This study shows that the race performances of triathletes are highly related to the V(r) at which the most efficient lactate removal (IVT(-50%DeltaT)) occurs. These findings suggest that the assessment of V(r) at IVT and IAT (from which V(r) at IVT(-50%DeltaT) are calculated) may be a useful method for monitoring training-induced adaptations and performance improvements in athletes who participate in Olympic triathlons.     

Glycerophosphoinositol-4-phosphate enhances SDF-1alpha-stimulated T-cell chemotaxis through PTK-dependent activation of Vav

Glycerophosphoinositols (GPIs) are water-soluble phosphoinosite metabolites produced by all cell types, whose levels increase in response to a variety of extracellular stimuli, and are particularly high in Ras-transformed cells. GPIs are released to the extracellular space, wherefrom they can be taken up by other cells through a specific transporter. Exogenous GPIs affect a plethora of cellular functions. Among these compounds the most active is GroPIns4P, which affects cAMP levels and PKA-dependent functions through the inhibition of heterotrimeric Gs proteins. GroPIns4P has also recently been found to promote actin cytoskeleton reorganization by inducing Rho and Rac activation through an as yet unidentified mechanism. Here we have assessed the potential effects of GroPIns4P on T-cells. We found that GroPIns4P enhances CXCR4-dependent chemotaxis. This activity results from the capacity of GroPIns4P to activate the Rho GTPase exchange factor, Vav, through an Lck-dependent pathway which also results in activation of the stress kinases JNK and p38. GroPIns4P was also found to activate with a delayed kinetics the Lck-dependent activation of ZAP-70, Shc and Erk1/2. The activities of GroPIns4P were found to be dependent on its capacity to inhibit cAMP production and PKA activation. Collectively, the data provide the first evidence of a role of glycerophosphoinositols as modulators of T-cell signaling and establish a mechanistic basis for the effects of this phosphoinositide derivative on F-actin dynamics.     

High variation reduces the value of feather stable isotope ratios in identifying new wintering areas for aquatic warblers Acrocephalus paludicola in West Africa

Stable isotope analysis of feathers can be useful in the study of seasonal interactions and migratory connectivity in birds. For the Palaearctic–African migration system, however, the lack of isotope data from feathers of known origin in Africa renders the geographic assignment of birds captured on European breeding grounds to potential wintering areas problematic. Rectrices of the threatened aquatic warbler Acrocephalus paludicola grown in Africa were sampled across six European countries to assess whether birds in different breeding populations shared similar isotopic signatures and so were likely to have wintered in the same region in Africa. Freshly grown feathers of aquatic warblers collected at the only known wintering site in Senegal showed high variation in carbon, nitrogen, and hydrogen isotope ratios. Due to similarly high variation in isotope ratios of African‐grown feathers within all breeding populations, it was not possible to determine whether different populations wintered in different regions. However, isotope signatures of 20% of birds captured on European breeding grounds fell outside the range of those captured in Senegal, suggesting a wider wintering distribution than is currently known. We therefore assessed whether the origin of these feathers could be estimated by trying to establish isotopic gradients across sub‐Saharan West Africa. Feathers of three ecologically similar surrogate species were sampled from wetlands across a 3000 km east‐west and a 2000 km north–south transect. Within‐site variation in feather isotope ratios was frequently larger than the difference predicted by gradients across West Africa. Thus, predicting the origin of individual feathers using single‐isotope gradients was not reliable. The large within‐site variability of feather isotope ratios of a habitat specialist species like the aquatic warbler indicates that using feather isotope ratios will require large sample sizes from many locations, and may thus not be an efficient tool in identifying wintering areas of Palaearctic–African migrants.     

A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria

Human genetics and immune responses are considered to critically influence the outcome of malaria infections including life-threatening syndromes caused by Plasmodium falciparum. An important role in immune regulation is assigned to the apoptosis-signaling cell surface receptor CD95 (Fas, APO-1), encoded by the gene FAS. Here, a candidate-gene association study including variant discovery at the FAS gene locus was carried out in a case-control group comprising 1,195 pediatric cases of severe falciparum malaria and 769 unaffected controls from a region highly endemic for malaria in Ghana, West Africa. We found the A allele of c.−436C>A (rs9658676) located in the promoter region of FAS to be significantly associated with protection from severe childhood malaria (odds ratio 0.71, 95% confidence interval 0.58–0.88, p_empirical = 0.02) and confirmed this finding in a replication group of 1,412 additional severe malaria cases and 2,659 community controls from the same geographic area. The combined analysis resulted in an odds ratio of 0.71 (95% confidence interval 0.62–0.80, p = 1.8×10⁻⁷, n = 6035). The association applied to c.−436AA homozygotes (odds ratio 0.47, 95% confidence interval 0.36–0.60) and to a lesser extent to c.−436AC heterozygotes (odds ratio 0.73, 95% confidence interval 0.63–0.84), and also to all phenotypic subgroups studied, including severe malaria anemia, cerebral malaria, and other malaria complications. Quantitative FACS analyses assessing CD95 surface expression of peripheral blood mononuclear cells of naïve donors showed a significantly higher proportion of CD69⁺CD95⁺ cells among persons homozygous for the protective A allele compared to AC heterozygotes and CC homozygotes, indicating a functional role of the associated CD95 variant, possibly in supporting lymphocyte apoptosis.