Author Correction: Climatic controls of decomposition drive the global biogeography of forest-tree symbioses.

In this Letter, a middle initial and additional affiliation have been added for author G. J. Nabuurs; two statements have been added to the Supplementary Acknowledgements; and a citation to the French National Institute has been added to the Methods; see accompanying Author Correction for further details.

Climatic controls of decomposition drive the global biogeography of forest-tree symbioses.

The identity of the dominant root-associated microbial symbionts in a forest determines the ability of trees to access limiting nutrients from atmospheric or soil pools1,2, sequester carbon3,4 and withstand the effects of climate change5,6. Characterizing the global distribution of these symbioses and identifying the factors that control this distribution are thus integral to understanding the present and future functioning of forest ecosystems. Here we generate a spatially explicit global map of the symbiotic status of forests, using a database of over 1.1 million forest inventory plots that collectively contain over 28,000 tree species. Our analyses indicate that climate variables-in particular, climatically controlled variation in the rate of decomposition-are the primary drivers of the global distribution of major symbioses. We estimate that ectomycorrhizal trees, which represent only 2% of all plant species7, constitute approximately 60% of tree stems on Earth. Ectomycorrhizal symbiosis dominates forests in which seasonally cold and dry climates inhibit decomposition, and is the predominant form of symbiosis at high latitudes and elevation. By contrast, arbuscular mycorrhizal trees dominate in aseasonal, warm tropical forests, and occur with ectomycorrhizal trees in temperate biomes in which seasonally warm-and-wet climates enhance decomposition. Continental transitions between forests dominated by ectomycorrhizal or arbuscular mycorrhizal trees occur relatively abruptly along climate-driven decomposition gradients; these transitions are probably caused by positive feedback effects between plants and microorganisms. Symbiotic nitrogen fixers-which are insensitive to climatic controls on decomposition (compared with mycorrhizal fungi)-are most abundant in arid biomes with alkaline soils and high maximum temperatures. The climatically driven global symbiosis gradient that we document provides a spatially explicit quantitative understanding of microbial symbioses at the global scale, and demonstrates the critical role of microbial mutualisms in shaping the distribution of plant species.

Structural patterns of the human ABCC4/MRP4 exporter in lipid bilayers rationalize clinically observed polymorphisms.

The ABCC4/MRP4 exporter has a clinical impact on membrane transport of a broad range of xenobiotics. It is expressed at key locations for drug disposition or effects such as in the liver, the kidney and blood cells. Several polymorphisms and mutations (e.g., p.Gly187Trp) leading to MRP4 dysfunction are associated with an increased risk of toxicity of some drugs. So far, no human MRP4 structure has been elucidated, precluding rationalization of these dysfunctions at a molecular level. We constructed an atomistic model of the wild type (WT) MRP4 and the p.Gly187Trp mutant embedded in different lipid bilayers and relaxed them for hundreds of nanoseconds by molecular dynamics simulations. The WT MRP4 molecular structure confirmed and ameliorated the general knowledge about the transmembrane helices and the two nucleotide binding domains. Moreover, our model elucidated positions of three generally unresolved domains: L1 (linker between the two halves of the exporter); L0 (N-terminal domain); and the zipper helices (between the two NBDs). Each domain was thoroughly described in view of its function. The p.Gly187Trp mutation induced a huge structural impact on MRP4, mainly affecting NBD 1 structure and flexibility. The structure of transporter enabled rationalization of known dysfunctions associated with polymorphism of MRP4. This model is available to the pharmacology community to decipher the impact of any other clinically observed polymorphism and mutation on drug transport, giving rise to in silico predictive pharmacogenetics.

Short implants compared to implants in vertically augmented bone: a systematic review.

OBJECTIVES: To assess relevant data comparing short implants or implants associated with vertical ridge augmentation derived from RCT's and CCT's. MATERIAL AND METHODS: A PubMed and hand search was performed to identify all RCT's and CCT's published in English language comparing short implants to implants associated with vertical ridge augmentation. RESULTS: The initial search resulted in 3387 articles. A total of 17 articles were eligible for full-text analysis and four were finally included. This review tends to demonstrate similar implant survival rates between implants placed in vertically augmented bone and short implants (95.09% vs. 96.24%, respectively) with a follow-up ranging from 1 to 5 years. In terms of prosthetic survival rates, there were no differences between the treatments. More surgical complications were reported when using implants placed in vertically augmented bone compared to short implants (56 patients with surgical complications compared to 18 patients, respectively). CONCLUSIONS: This evidence should, however, be interpreted with caution as it is derived from four RCT's with limited sample size (ranging from 15 to 30 per group), limited follow-up and performed by the same research group.

Spatio-temporal variation of biting flies, Stomoxys spp. (Diptera: Muscidae), along a man-made disturbance gradient, from primary forest to the city of Makokou (North-East, Gabon).

Understanding the pattern of abundance of vector populations is important to control the potential of transmission of associated pathogens. The pattern of abundance of Stomoxys Geoffroy, an ubiquitous blood-sucking fly, is poorly known in tropical Africa. In this study, we investigated the spatio-temporal pattern of abundance of the Stomoxys genus along a gradient of man-made disturbance in north-eastern Gabon. Three sites (one in primary forest, one in secondary forest and one in a man-made environment) were monitored during 13 months using Vavoua traps. Seven species and subspecies were found to live in sympatry, but with distinct patterns of abundance with respect to space and time. The most abundant species was Stomoxys transvittatus Villeneuve, whereas the rarest species was S. xanthomelas Roubaud. Stomoxys calcitrans Linné was preferentially found in man-made environments, whereas S. xanthomelas was preferentially found in primary forest. Stomoxys abundance was the greatest in secondary forest, then in man-made environments and finally in primary forest. A seasonal variation in Stomoxys abundance was also found. In conclusion, forest degradation and deforestation are likely both to favour the concentration of populations of Stomoxys, and to change the specific composition of the Stomoxys community.

Novel retinoid-related molecules as apoptosis inducers and effective inhibitors of human lung cancer cells in vivo.

Lung cancer causes more than 140,000 deaths annually in the United States alone, and the prognosis for non-small cell lung cancer (NSCLC) is particularly poor. Therapies using small molecules that preferentially kill lung tumor cells by inducing cellular suicide (apoptosis) would therefore be highly desirable. Retinoids have shown promise as cancer preventive and cancer therapeutic agents. Retinoid signals are mediated by two classes of nuclear receptors: the retinoic acid receptors (RAR alpha, beta, and gamma) and the retinoid X receptors (RXR alpha, beta and gamma). These receptors usually bind as heterodimers to specific DNA sequences and/or interact with other transcriptional regulators, such as AP-1 (ref. 10) to regulate gene transcription. Synthetic retinoids can be made that activate only specific portions of the complex retinoid response network and activate selective biological programs. To identify retinoids with novel biological activities, we used a high-throughput "biological activity fingerprint" screen on a large library of retinoids and retinoid-related molecules (RRMs). We identified new structures that are highly effective against lung cancer cells in vitro, inducing apoptosis. We show here for one of these compounds that it is very effective against a human NSCLC in vivo in an animal model. These new molecules show a distinct pattern of receptor signaling.

Pitfalls and challenges associated with phenoconversion in forensic toxcicology.

PURPOSE: In recent years, several publications have demonstrated the interest and the usefulness of pharmacogenetics in forensic toxicology. However, this approach remains namely focused on DNA-based phenotype, which may potentially lead to misinterpretation. Other determinants such as co-medication or physiological parameters may also impact the phenotype. This article aims to highlight the importance of considering such determinants in forensic toxicology, through the original case of a heroin-related fatality. METHOD: Ethanol concentration determination and toxicological screening were performed using gas chromatography with flame ionization detection, liquid chromatography with diode array detection and gas chromatography with mass spectrometry detection. CYP2C19 and CYP2D6 genotypes were determined by Taqman® real-time PCR analyses. RESULTS: Femoral blood analyses revealed the presence of ethanol, morphine, codeine, venlafaxine (VEN), O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV), paroxetine, and risperidone. 6-acetylmorphine was also identified in urine. VEN, paroxetine and risperidone were quantified at supra-therapeutic or toxic blood concentrations. NDV was not quantified. The metabolic ratio of VEN (ODV to VEN) was exceptionally low (about 0.7). Pharmacogenetics testing showed that the patient was heterozygous for the CYP2C19*2 loss-of-function allele, which predict an intermediate metabolism for CYP2C19. None of the deficient CYP2D6 alleles investigated were identified. Those results suggest an extensive CYP2D6-metabolism phenotype. CONCLUSION: A discrepancy was seen between the results of the genomic evaluation and the observed metabolic ratio of VEN. This tends to exclude a genetic origin and lead us to formulate other hypotheses, such as phenoconversion that may have been induced by drug interaction involving patients' regular medications. Phenoconversion is as a complex phenomenon that leads to genotype-phenotype mismatch without any genetic abnormality particularly described for cytochromes P450 2D6 and 2C19. Although transient, phenoconversion can have a significant impact on the analysis and interpretation of genotype-focused clinical outcomes correlation and in forensic toxicology conclusions.

Maternal caffeine ingestion during gestation and lactation influences respiratory adaptation to acute alveolar hypoxia in newborn rats and adenosine A2A and GABA A receptor mRNA transcription.

Caffeine is a widely used psychostimulant freely crossing the placental barrier. At the doses usually absorbed, it acts as an antagonist of both A1 and A2A adenosine receptors. Pregnant women are generally not advised to limit their caffeine consumption and thus expose their progeny to the drug during the whole of gestation and lactation. The possibility that such caffeine exposure may have long-term consequences on brain development has led to several behavioral investigations on animal models. Despite the crucial role played by adenosine receptor systems in neonatal breathing control, few studies in vitro have been concerned with the consequences of maternal caffeine absorption on breathing, and none in the unrestrained intact animal. The present investigation analyzed the influence of caffeine exposure via placental and milk transfer on resting ventilation and on the response to moderate alveolar hypoxia of 0 to 2-day-old newborn rat (P0-P2) together with the possible underlying mechanisms. Dams absorbed caffeine (46+/-3 mg/kg/day) via drinking fluid (0.2 g/L) throughout gestation, in conditions mimicking moderate human consumption. Caffeine exposure did not significantly affect basal respiratory parameters. In contrast, it attenuated both the early increase and the secondary decrease in ventilation triggered by moderate alveolar hypoxia (11% O2 inhaled). The abolition of Fos protein expression evoked by hypoxia suggested that caffeine exposure may decrease the activity of O2-sensing peripheral chemoreceptor pathway. From real-time PCR data, those functional alterations were associated to increases in A2A adenosine receptor and alpha2 GABA(A) receptor subunit mRNAs in the medulla. This indicates that, even at moderate doses, maternal caffeine consumption may induce a series of subtle developmental alterations that may affect modulation of breathing control in the neonate in pathological situations such hypoxia.

The receptor-DNA complex determines the retinoid response: a mechanism for the diversification of the ligand signal.

To obtain insights into the principles governing the complex biological responses to retinoids, we have analyzed the ligand sensitivities of various retinoid receptor-DNA complexes. We find that different retinoid receptor heterodimers show distinct activation patterns with various response elements while a given heterodimer can be activated at different retinoic acid concentrations on different response elements. In vitro binding experiments suggest that the same retinoic acid receptor-retinoid X receptor (RAR-RXR) heterodimer can have different ligand affinities, depending on the response element it is bound to. The differential responses of a particular receptor heterodimer with various retinoic acid responsive elements can be enhanced through the use of conformationally restricted retinoids. RAR- and RXR-selective retinoids can also synergistically activate the receptor heterodimers, indicating that both partners in the heterodimer can contribute to ligand-induced transcriptional activation. However, the relative influence of the RAR or RXR partner is specific for each response element. Together, our data demonstrate that it is the receptor-DNA complex and not the receptor alone that determines the ligand response. This flexibility allows for a highly pleiotropic retinoid response. Furthermore, conformationally restricted retinoids can accentuate the differential responses and exhibit a certain degree of gene selectivity by differentially activating the RAR or RXR component in the context of a given response element.

[Pharmacogenetics and immunosuppressor drugs: impact and clinical interest in transplantation]. / Pharmacogénétique des médicaments immunosuppresseurs. Impact et intérêt clinique en transplantation.

The domain of solid organ transplantation is characterized by the use of variable drug combinations with drug-drug interactions, and the presence of two genomes, that of the transplanted organ and that of the receiver, which can be involved in the pharmacogenetics of these drugs. This paper is a literature review of the impact of the genetic polymorphisms of the metabolic enzymes, efflux transporters and therapeutic targets of the main immunosuppressive drugs (cyclosporine, tacrolimus, sirolimus and mycophenolate) on the dose-concentration and concentration-effect relationships of these drugs. The polymorphisms of metabolic enzymes have significant effects on the pharmacokinetics of all these drugs, but the clinical trials for validating treatment individualization based on these genetic differences are still lacking. It should be noted that the influence of the donor's genome has seldom been studied and has been found to be significant in liver transplant recipients. The influence of efflux transporter genes polymorphisms, in particular of P-glycoprotein and MPR2, is controversial. As for the polymorphisms of the drug targets genes, either they have not been reported (calcineurin, mTOR), or their influence has only been the subject of a few preliminary studies (IMPDH2). The pharmacogenetics of immunosuppressants is thus still an open field for investigations and potential therapeutic progress.

[Molecular pharmacogenetics in hospital laboratories in France: current data and future prospects]. / La pharmacogénétique moléculaire hospitalière en France: données actuelles et perspectives.

Molecular pharmacogenetic units have recently been established in several hospital laboratories in France. The clinical impact of these units is still limited and numerous problems of organizational, ethical, legal, technical, social and economical nature remain to be resolved. However, an increasing number of these units, a rise in their activities and an enlargement of their scope of application are foreseeable in the future. Ultimately, these units would significantly contribute to limit the public health problem caused by interindividual variabilities in drug effects. In view of these prospects, it seems essential that such hospital activity should be quickly recognised by the authorities and the various health sectors in France. It is also essential that the problems that arise from such pharmacogenetic activities should be considered by the authorities and would profit from the organization of a national network and from financial guarantees.

Response to Comment on "The extent of forest in dryland biomes".

Schepaschenko et al question our findings, claiming that we did not refer to all existing maps and that we did not account for all sources of uncertainty. In our response, we detail our selection criteria for reference maps, which clarify why the work of Schepaschenko et al was not used, and we explain why our uncertainty assessment is complete and how it was misunderstood by Schepaschenko et al.

Response to Comment on "The extent of forest in dryland biomes".

De la Cruz et al question the reliability of our results, claiming that we do not refer to the most appropriate spatial extent of drylands. In our response, we explain why we chose an existing and internationally recognized delineation of drylands among several options, and why our findings are due to a difference of remote sensing technique and not to the definition of drylands we have selected.

Response to Comment on "The extent of forest in dryland biomes".

Griffith et al do not question the quality of our analysis, but they question our results with respect to the definition of forest we employed. In our response, we explain why the differences we report result from a difference of technique and not of definition, and how anyone can adapt-as we did-our data set to any forest definition and tree cover threshold of interest.

Imaging the premotor areas.

Recent imaging studies of motor function provide new insights into the organization of the premotor areas of the frontal lobe. The pre-supplementary motor area and the rostral portion of the dorsal premotor cortex, the 'pre-PMd', are, in many respects, more like prefrontal areas than motor areas. Recent data also suggest the existence of separate functional divisions in the rostral cingulate zone.

Asymptotic distribution of stage-grouped population models.

Matrix models are often used to predict the dynamics of size-structured or age-structured populations. The asymptotic behaviour of such models is defined by their malthusian growth rate lambda, and by their stationary distribution w that gives the asymptotic proportion of individuals in each stage. As the coefficients of the transition matrix are estimated from a sample of observations, lambda and w can be considered as random variables whose law depends on the distribution of the observations. The goal of this study is to specify the asymptotic law of lambda and w when using the maximum likelihood estimators of the coefficients of the transition matrix. We prove that lambda and w are asymptotically normal, and the expressions of the asymptotic variance of lambda and of the asymptotic covariance matrix of w are given. The convergence speed of lambda and w towards their asymptotic law is studied using simulations. The results are applied to a real case study that consists of a Usher model for a tropical rain forest in French Guiana. They permit to assess the number of trees to measure to get a given precision on the estimated asymptotic diameter distribution, which is an important information on tropical forest management.

Motor areas on the medial wall of the hemisphere.

The primary motor cortex (M1) receives input from four premotor areas on the medial wall of the hemisphere: the supplementary motor area (SMA) and three cingulate motor areas located on the banks of the cingulate sulcus (CMAr, CMAd and CMAv). All four premotor areas have maps of the body containing distinct proximal and distal representations of the arm. Surprisingly, the size of the distal representation is comparable to or larger than the size of the proximal representation in each area. Thus, contrary to some previous hypotheses, the anatomical substrate exists for the premotor areas on the medial wall to be involved in the control of distal, as well as proximal arm movements. Each of the premotor areas on the medial wall also has substantial direct projections to the spinal cord. Corticospinal axons from these premotor areas terminate in the intermediate zone of the spinal cord. Some corticospinal axons from SMA, CMAd, and CMAv terminate around motoneurons. In this respect, these motor areas are like M1 and appear to have direct connections with spinal motoneurons, particularly those innervating muscles of the fingers and wrist. These results suggest that the premotor areas on the medial wall are an important source of descending commands for the generation and control of movement. In recent experiments we examined the pattern of functional activation in the premotor areas on the medial wall during the performance of sequences of pointing movements. The patterns of activation were then compared with the body maps revealed by our anatomical studies. Overall, our initial results indicate that the attributes of motor control are unequally represented across the premotor areas. For example, one of the areas on the medial wall, the CMAd, was strongly and selectively activated during the performance of highly practised, remembered sequences of movement. Further insights into the function of the premotor areas are likely to come from examining their participation in a broad range of behavioural paradigms. These initial results support our hypothesis that each premotor area makes some unique contribution to the planning, initiation and/or execution of movement.

Bilateral interaction in the second somatosensory area (SII) of the cat and contribution of the corpus callosum.

There are indications in the literature that convergent ipsilateral and contralateral input to the second somatosensory area (SII) may interact. Single unit activity of SII bilateral cells was studied to evaluate the impact of simultaneous bilateral stimulation of the receptive fields (RF) on neural discharge. The cellular responses to unilateral ipsilateral and contralateral, as well as to bilateral stimulation were compared. 22% of bilateral cells showed interaction, usually facilitation. Bilaterally evoked responses were found to be as great as 250% of the strongest unilateral response. Only bilateral responses stronger or weaker than the dominant unilateral response by at least 50% were considered as interactive. The great majority of interactive cells had their RF on the forelimb and were responsive to deep stimulation. The corpus callosum appears to be responsible for part of the observed interaction since in callosotomized cats only 5% of bilateral cells were interactive. A non-callosal ipsilateral pathway must be postulated because both bilaterality and bilateral interaction persist to some degree after callosotomy. A putative role for bilateral interaction in sensory-motor integration is discussed.

Cutaneous afferent activity in the median nerve during grasping in the primate.

Neural activity was recorded from the median nerve of a monkey during grasping and lifting, using a chronically implanted cuff electrode. At the onset of lifting, there was an initial dynamic response during which the intensity of the neural signal increased rapidly. This neural response attained its peak value well before the displacement, the load force or the grip force. The time course and peak of the rectified, integrated neurogram were best correlated with the rate of change of grip force. The neural activity declined exponentially to a steady value following the initial peak. During steady holding the mean amplitude of the neurogram was best correlated with the mean grip force. At the end of the holding phase there was a short burst of neural activity as the monkey relaxed the grip force and released the object. During some blocks of trials pulse perturbations were applied to the object. When the monkey did not increase the grip force in advance of the perturbation, the perturbation produced a relatively large displacement of the object and a burst of neural activity whose onset coincided with the onset of displacement. When the monkey anticipated the perturbation by increasing the grip force during the holding period preceding the perturbation, the perturbation produced a relatively small displacement and relatively little increase in neural activity.

Effects of the atrial antiarrhythmic drug AVE0118 on cardiac ion channels.

Previous studies in pigs and goats have demonstrated that AVE0118 prolongs atrial refractoriness without any effect on the QT-interval. The purpose of the present study was to investigate the effect of the compound on various cardiac ion channels. AVE0118 blocked the pig Kv1.5 and the human Kv1.5 expressed in Xenopus oocytes with IC(50) values of 5.4+/-0.7 microM and 6.2+/-0.4 microM respectively. In Chinese hamster ovary (CHO) cells, AVE0118 decreased the steady-state hKv1.5 current with an IC(50) of 1.1+/-0.2 microM. The hKv4.3/KChIP2.2 current in CHO cells was blocked by AVE0118 by accelerating the apparent time-constant of inactivation ( tau(inact)), and the integral current was inhibited with an IC(50) of 3.4+/-0.5 microM. At 10 microM AVE0118 tau(inact) decreased from 9.3+/-0.6 ms ( n=8, control) to 3.0+/-0.3 ms ( n=8). The K(ACh) current was investigated in isolated pig atrial myocytes by application of 10 microM carbachol. At a clamp potential of -100 mV the I(KACh) was half-maximally blocked by 4.5+/-1.6 microM AVE0118. In the absence of carbachol, AVE0118 had no effect on the inward current recorded at -100 mV. Effects on the I(Kr) current were investigated on HERG channels expressed in CHO cells. AVE0118 blocked this current half-maximally at approximately 10 microM. Comparable results were obtained in isolated guinea pig ventricular myocytes, where half-maximal inhibition of the I(Kr) tail current occurred at a similar concentration of AVE0118. Other ionic currents, like the I(Ks), I(KATP) (recorded in guinea pig ventricular myocytes), and L-type Ca(2+) (recorded in pig atrial myocytes) were blocked by 10 microM AVE0118 by 10+/-3% ( n=6), 28+/-7% ( n=4), and 22+/-13% ( n=5) respectively. In summary, AVE0118 preferentially inhibits the atrial K(+) channels I(Kur), I(to) and I(KACH). This profile may explain the selective prolongation of atrial refractoriness described previously in pigs and goats.