Zinc opposes genotoxicity of cadmium and vanadium but not of lead

Protection by essential metals against the genotoxic effects of toxic elements is an open question. Here, human Hs27 dermal fibroblasts and B-mel melanoblasts were exposed for 10 days to (1 μM) zinc (Zn) or copper (Cu) or selenium (+ 4, Sei; + 6, Sea). Afterwards, cells were exposed for 3 days to subtoxic concentrations of lead (Pb, 100 μM) or vanadium (+ 5, V, 2 μM) or cadmium (Cd, 3 μM), slightly reducing, by themselves, cell proliferation and unaffecting cell viability and apoptosis. Genotoxic damage was evaluated by cytokinesis-block micronucleus assay (CBMN) and single cell gel electrophoresis (Comet assay, CA). CBMN and CA were preliminarly assessed following 3, 10 and 30 days of exposure to the above concentrations of Pb, V and Cd: Pb induced micronuclei (MN) formation in both Hs27 and B-mel cells, without determining direct DNA damage (as shown by CA); V did not reveal genotoxic effects on fibroblasts (as shown by CBMN and CA) but increased the frequency of MN and comets in melanoblasts; Cd induced a great number of MN and comets in fibroblasts but not in melanoblasts; all these effects did not differ after 3, 10 or 30 days of exposure to such elements so that Hs27 and B-mel cells were exposed to Pb,V and Cd for 3 days following pretreatment with (1 μM) Zn, Cu, Sei or Sea. By itself, the 10 day-exposure to (1 μM) Zn, Cu, Sei or Sea did not affect cell proliferation, viability, apoptosis and formation of MN or comets in either Hs27 or B-mel cells. Only Zn significantly reduced the Cd- and V-induced MN and comet formation in fibroblasts and melanoblasts, respectively; in these cells, however, Zn did not affect the Pb-induced MN formation. These results emphasize the role of Zn, in respect to other essential metals, in opposing the genotoxic effects of cancerogenic (Cd) or potentially cancerogenic elements (V).     

When correlation implies causation in multisensory integration

Inferring which signals have a common underlying cause, and hence should be integrated, represents a primary challenge for a perceptual system dealing with multiple sensory inputs [1-3]. This challenge is often referred to as the correspondence problem or causal inference. Previous research has demonstrated that spatiotemporal cues, along with prior knowledge, are exploited by the human brain to solve this problem [4-9]. Here we explore the role of correlation between the fine temporal structure of auditory and visual signals in causal inference. Specifically, we investigated whether correlated signals are inferred to originate from the same distal event and hence are integrated optimally [10]. In a localization task with visual, auditory, and combined audiovisual targets, the improvement in precision for combined relative to unimodal targets was statistically optimal only when audiovisual signals were correlated. This result demonstrates that humans use the similarity in the temporal structure of multisensory signals to solve the correspondence problem, hence inferring causation from correlation.     

Thrombopoietin complements G(i)- but not G(q)-dependent pathways for integrin {alpha}(IIb){beta}(3) activation and platelet aggregation

Binding of thrombopoietin (TPO) to the cMpl receptor on human platelets potentiates aggregation induced by a number of agonists, including ADP. In this work, we found that TPO was able to restore ADP-induced platelet aggregation upon blockade of the G(q)-coupled P2Y1 purinergic receptor but not upon inhibition of the G(i)-coupled P2Y12 receptor. Moreover, TPO triggered platelet aggregation upon co-stimulation of G(z) by epinephrine but not upon co-stimulation of G(q) by the thromboxane analogue U46619. Platelet aggregation induced by TPO and G(i) stimulation was biphasic, and cyclooxygenase inhibitors prevented the second but not the first phase. In contrast to ADP, TPO was unable to induce integrin alpha(IIb)beta(3) activation, as evaluated by binding of both fibrinogen and PAC-1 monoclonal antibody. However, ADP-induced activation of integrin alpha(IIb)beta(3) was blocked by antagonists of the G(q)-coupled P2Y1 receptor but was completely restored by the simultaneous co-stimulation of cMpl receptor by TPO. Inside-out activation of integrin alpha(IIb)beta(3) induced by TPO and G(i) stimulation occurred independently of thromboxane A(2) production and was not mediated by protein kinase C, MAP kinases, or Rho-dependent kinase. Importantly, TPO and G(i) activation of integrin alpha(IIb)beta(3) was suppressed by wortmannin and Ly294002, suggesting a critical regulation by phosphatidylinositol 3-kinase. We found that TPO did not activate phospholipase C in human platelets and was unable to restore ADP-induced phospholipase C activation upon blockade of the G(q)-coupled P2Y1 receptor. TPO induced a rapid and sustained activation of the small GTPase Rap1B through a pathway dependent on phosphatidylinositol 3-kinase. In ADP-stimulated platelets, Rap1B activation was reduced, although not abolished, upon blockade of the P2Y1 receptor. However, accumulation of GTP-bound Rap1B in platelets activated by co-stimulation of cMpl and P2Y12 receptor was identical to that induced by the simultaneous ligation of P2Y1 and P2Y12 receptor by ADP. These results indicate that TPO can integrate G(i), but not G(q), stimulation and can efficiently support integrin alpha(IIb)beta(3) activation platelet aggregation by an alternative signaling pathway independent of phospholipase C but involving the phosphatidylinositol 3-kinase and the small GTPase Rap1B.     

A class of pyrrole derivatives endowed with analgesic/anti-inflammatory activity

We report the synthesis and bio-pharmacological evaluation of a class of pyrrole derivatives featuring a small appendage fragment (carbaldehyde, oxime, nitrile) on the central core. Compound 1c proved to be extremely effective in vivo, showing an interesting anti-nociceptic profile that is comparable to reference compounds already marketed, hence representing a great stimulus for a further improvement of this class of molecules.     

Quantitative evaluation of rigid and elastic registrations for abdominal perfusion imaging with X-ray computed tomography

ObjectivesDynamic X-ray computed tomography with contrast agent injection allows quantifying the tumor response to an antiangiogenic treatment. For hepatic tumors, it is crucial to correct for respiratory movements to ensure a good quantification of perfusion parameters.Material and MethodsTwo registration models were tested on eight dynamic exams: 1) rigid model and 2) elastic model based on Free Form Deformation. Each exam included about 50 volumes acquired under free-breathing conditions. The registration methods were quantitatively and automatically evaluated by defining a global score. This score was based on a Dice index and measured the superimposition rate between corresponding bony structures of different frames of the temporal exam.ResultsBefore registration, the mean value of the score was 0.78. After rigid registration, these values were globally lower with an average of 0.73. After elastic registration, a mean score of 0.90 was reached which was much higher than before registration.ConclusionThis automatic evaluation showed its interest for controlling the quality of dynamic CT registrations. It also helped proving that elastic methods are much more efficient than rigid methods for registering abdominal dynamic volumes, when considering the whole field of view.     

A re-evaluation of the mesangial cells of the renal glomerulus

Summary The topographical localization of the mesangial cells in renal glomeruli of rats, and their relationships with the structures at the hilus of the glomerulus were studied in this investigation. It was observed that the mesangial cells occupy a parietal position in the wall of the glomerular capillaries, and that they are anatomically continuous with the smooth muscle cells of the tunica media of the glomerular arterioles.This study was supported by a United States Public Health Service Grant AM 08628 (Institute of Arthritis and Metabolic Diseases).     

Can we optimise the exercise training prescription to maximise improvements in mitochondria function and content?

Background

While there is agreement that exercise is a powerful stimulus to increase both mitochondrial function and content, we do not know the optimal training stimulus to maximise improvements in mitochondrial biogenesis.

Scope of review

This review will focus predominantly on the effects of exercise on mitochondrial function and content, as there is a greater volume of published research on these adaptations and stronger conclusions can be made.

Major conclusions

The results of cross-sectional studies, as well as training studies involving rats and humans, suggest that training intensity may be an important determinant of improvements in mitochondrial function (as determined by mitochondrial respiration), but not mitochondrial content (as assessed by citrate synthase activity). In contrast, it appears that training volume, rather than training intensity, may be an important determinant of exercise-induced improvements in mitochondrial content. Exercise-induced mitochondrial adaptations are quickly reversed following a reduction or cessation of physical activity, highlighting that skeletal muscle is a remarkably plastic tissue. Due to the small number of studies, more research is required to verify the trends highlighted in this review, and further studies are required to investigate the effects of different types of training on the mitochondrial sub-populations and also mitochondrial adaptations in different fibre types. Further research is also required to better understand how genetic variants influence the large individual variability for exercise-induced changes in mitochondrial biogenesis.

General significance

The importance of mitochondria for both athletic performance and health underlines the importance of better understanding the factors that regulate exercise-induced changes in mitochondrial biogenesis. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.     

Interaction of mildronate with the mitochondrial carnitine/acylcarnitine transport protein

The interaction of mildronate [3-(2,2,2-trimethylhydrazine) propionate] with the purified mitochondrial carnitine/acylcarnitine transporter reconstituted in liposomes has been studied. Mildronate, externally added to the proteoliposomes, strongly inhibited the carnitine/carnitine antiport catalyzed by the reconstituted transporter with an IC(50) of 560 muM. A kinetic analysis revealed that the inhibition is completely competitive, that is, mildronate interacts with the substrate-binding site. The half-saturation constant of the transporter for external mildronate (K(i)) is 530 muM. Carnitine/mildronate antiport has been measured as [(3)H]carnitine uptake into proteoliposomes containing internal mildronate or as [(3)H]carnitine efflux from proteoliposomes in the presence of external mildronate, indicating that mildronate is transported by the carnitine/acylcarnitine transporter and that the inhibition observed was due to the transport of mildronate in the place of carnitine. The intraliposomal half-saturation constant for mildronate transport (K(m)) has been determined. Its value, 18 mM, is much higher than the external half-saturation constant (K(i)) in agreement with the asymmetric properties of the transporter. In vivo, the antiport reaction between cytosolic (administered) mildronate and matrix carnitine may cause intramitochondrial carnitine depletion. This effect, together with the inhibition of the physiological transport, will lead to impairment of fatty acid utilization.     

Moderate Warming in Microcosm Experiment Does Not Affect Microbial Communities in Temperate Vineyard Soils

Changes in the soil microbial community structure can lead to dramatic changes in the soil ecosystem. Temperature, which is projected to increase with climate change, is commonly assumed to affect microbial communities, but its effects on agricultural soils are not fully understood. We collected soil samples from six vineyards characterised by a difference of about 2 °C in daily soil temperature over the year and simulated in a microcosm experiment different temperature regimes over a period of 1 year: seasonal fluctuations in soil temperature based on the average daily soil temperature measured in the field; soil temperature warming (2 °C above the normal seasonal temperatures); and constant temperatures normally registered in these temperate soils in winter (3 °C) and in summer (20 °C). Changes in the soil bacterial and fungal community structures were analysed by automated ribosomal intergenic spacer analysis (ARISA). We did not find any effect of warming on soil bacterial and fungal communities, while stable temperatures affected the fungal more than the bacterial communities, although this effect was soil dependent. The soil bacterial community exhibited soil-dependent seasonal fluctuations, while the fungal community was mainly stable. Each soil harbours different microbial communities that respond differently to seasonal temperature fluctuations; therefore, any generalization regarding the effect of climate change on soil communities should be made carefully.