Maturation of the lymphoid system. III. Induction of selective unresponsiveness by injection of a haptenated carbohydrate into neonatal mice.

Neonatal treatment of A/J mice with DNP-Ficoll reduced or eliminated indirect anti-DNP PFC normally produced in response to adult challenge with DNP-keyhole limpet hemocyanin. The remaining direct anti-DNP PFC response was of low avidity. Spleen cells from neonatal A/J mice inhibited the in vitro but not the in vivo response of adult spleen cells to DNP-Ficoll.

Cognition and brain function in schizotypy : a selective review

Schizotypy refers to a set of personality traits thought to reflect the subclinical expression of the signs and symptoms of schizophrenia. Here, we review the cognitive and brain functional profile associated with high questionnaire scores in schizotypy. We discuss empirical evidence from the domains of perception, attention, memory, imagery and representation, language, and motor control. Perceptual deficits occur early and across various modalities. Whilst the neural mechanisms underlying visual impairments may be linked to magnocellular dysfunction, further effects may be seen downstream in higher cognitive functions. Cognitive deficits are observed in inhibitory control, selective and sustained attention, incidental learning and memory. In concordance with the cognitive nature of many of the aberrations of schizotypy, higher levels of schizotypy are associated with enhanced vividness and better performance on tasks of mental rotation. Language deficits seem most pronounced in higher-level processes. Finally, higher levels of schizotypy are associated with reduced performance on oculomotor tasks, resembling the impairments seen in schizophrenia. Some of these deficits are accompanied by reduced brain activation, akin to the pattern of hypoactivations in schizophrenia spectrum individuals. We conclude that schizotypy is a construct with apparent phenomenological overlap with schizophrenia and stable inter-individual differences that covary with performance on a wide range of perceptual, cognitive and motor tasks known to be impaired in schizophrenia. The importance of these findings lies not only in providing a fine-grained neurocognitive characterisation of a personality constellation known to be associated with real-life impairments, but also in generating hypotheses concerning the aetiology of schizophrenia.

Assessment of the soil compaction of two ultisols caused by logging operations

The impact of wood loads on bulk density and preconsolidation pressure and of harvester and forwarder traffic on rut depth, bulk density and preconsolidation pressure of two Ultisols were examined in this study. Our objective was to quantify the threshold beyond which significant soil compaction and rutting would occur. This study was carried out in the county of Eunápolis, state of Bahia, Brazil, (16 º 23 ' 17 '' S and 39 º 10 ' 06 '' W; altitude 80 m asl) in two Ultisols (PAd2 and PAd3) with different texture classes, in experimental areas with eucalypt plantation. The study involved measurements at the wood load site and machine driving at specific locations in the forest during logging operations. The treatments consisted of one harvester pass and, 8, 16 and 40 passes of a fully loaded forwarder. Thresholds were established based on the rut depth and percentage of preconsolidation pressure values in the region of additional soil compaction defined in the bearing capacity model. The percentage of soil samples with values of preconsolidation pressure in the region of additional soil compaction indicated a greater susceptibility of PAd3 than of PAd2 to soil compaction. The threshold levels established here based on preconsolidation pressure and rut depth indicated that no more than eight forwarder passes should be allowed in loading operations in order to minimize soil compaction.

A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity.

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) plays a key role in adipocyte differentiation and insulin sensitivity. Its synthetic ligands, the thiazolidinediones (TZD), are used as insulin sensitizers in the treatment of type 2 diabetes. These compounds induce both adipocyte differentiation in cell culture models and promote weight gain in rodents and humans. Here, we report on the identification of a new synthetic PPARgamma antagonist, the phosphonophosphate SR-202, which inhibits both TZD-stimulated recruitment of the coactivator steroid receptor coactivator-1 and TZD-induced transcriptional activity of the receptor. In cell culture, SR-202 efficiently antagonizes hormone- and TZD-induced adipocyte differentiation. In vivo, decreasing PPARgamma activity, either by treatment with SR-202 or by invalidation of one allele of the PPARgamma gene, leads to a reduction of both high fat diet-induced adipocyte hypertrophy and insulin resistance. These effects are accompanied by a smaller size of the adipocytes and a reduction of TNFalpha and leptin secretion. Treatment with SR-202 also dramatically improves insulin sensitivity in the diabetic ob/ob mice. Thus, although we cannot exclude that its actions involve additional signaling mechanisms, SR-202 represents a new selective PPARgamma antagonist that is effective both in vitro and in vivo. Because it yields both antiobesity and antidiabetic effects, SR-202 may be a lead for new compounds to be used in the treatment of obesity and type 2 diabetes.

Molecular basis of selective PPARgamma modulation for the treatment of Type 2 diabetes.

Peroxisome proliferator-activated receptors (PPARs) (alpha, beta/delta and gamma) are lipid sensors capable of adapting gene expression to integrate various lipid signals. As such, PPARs are also very important pharmaceutical targets, and specific synthetic ligands exist for the different isotypes and are either currently used or hold promises in the treatment of major metabolic disorders. In particular, compounds of the class of the thiazolinediones (TZDs) are PPARgamma agonists and potent insulin-sensitizers. The specific but still broad expression patterns of PPARgamma, as well as its implication in numerous pathways, constitutes also a disadvantage regarding drug administration, since this potentially increases the chance to generate side-effects through the activation of the receptor in tissues or cells not affected by the disease. Actually, numerous side effects associated with the administration of TZDs have been reported. Today, a new generation of PPARgamma modulators is being actively developed to activate the receptor more specifically, in a cell and time-dependent manner, in order to induce a specific subset of target genes only and modulate a restricted number of metabolic pathways. We will discuss here why and how the development of such selective PPARgamma modulators is possible, and summarize the results obtained with the published molecules.

Tc-99m-MAA SPECT-derived tumor-to-normal liver ratios for partition model dosimetry in selective internal radiation therapy (SIRT)

Aim: When planning SIRT using 90Y microspheres, the partition model is used to refine the activity calculated by the body surface area (BSA) method to potentially improve the safety and efficacy of treatment. For this partition model dosimetry, accurate determination of mean tumor-to-normal liver ratio (TNR) is critical since it directly impacts absorbed dose estimates. This work aimed at developing and assessing a reliable methodology for the calculation of 99mTc-MAA SPECT/CT-derived TNR ratios based on phantom studies. Materials and methods: IQ NEMA (6 hot spheres) and Kyoto liver phantoms with different hot/background activity concentration ratios were imaged on a SPECT/CT (GE Infinia Hawkeye 4). For each reconstruction with the IQ phantom, TNR quantification was assessed in terms of relative recovery coefficients (RC) and image noise was evaluated in terms of coefficient of variation (COV) in the filled background. RCs were compared using OSEM with Hann, Butterworth and Gaussian filters, as well as FBP reconstruction algorithms. Regarding OSEM, RCs were assessed by varying different parameters independently, such as the number of iterations (i) and subsets (s) and the cut-off frequency of the filter (fc). The influence of the attenuation and diffusion corrections was also investigated. Furthermore, both 2D-ROIs and 3D-VOIs contouring were compared. For this purpose, dedicated Matlab© routines were developed in-house for automatic 2D-ROI/3D-VOI determination to reduce intra-user and intra-slice variability. Best reconstruction parameters and RCs obtained with the IQ phantom were used to recover corrected TNR in case of the Kyoto phantom for arbitrary hot-lesion size. In addition, we computed TNR volume histograms to better assess uptake heterogeneityResults: The highest RCs were obtained with OSEM (i=2, s=10) coupled with the Butterworth filter (fc=0.8). Indeed, we observed a global 20% RC improvement over other OSEM settings and a 50% increase as compared to the best FBP reconstruction. In any case, both attenuation and diffusion corrections must be applied, thus improving RC while preserving good image noise (COV<10%). Both 2D-ROI and 3D-VOI analysis lead to similar results. Nevertheless, we recommend using 3D-VOI since tumor uptake regions are intrinsically 3D. RC-corrected TNR values lie within 17% around the true value, substantially improving the evaluation of small volume (<15 mL) regions. Conclusions: This study reports the multi-parameter optimization of 99mTc MAA SPECT/CT images reconstruction in planning 90Y dosimetry for SIRT. In phantoms, accurate quantification of TNR was obtained using OSEM coupled with Butterworth and RC correction.

Backhoe loaders as base machines in logging operations

Summary

Selective requirement for c-Myc at an early stage of V(alpha)14i NKT cell development.

Valpha14 invariant (Valpha14i) NKT cells are a subset of regulatory T cells that utilize a semi-invariant TCR to recognize glycolipids associated with monomorphic CD1d molecules. During development in the thymus, CD4(+)CD8(+) Valpha14i NKT precursors recognizing endogenous CD1d-associated glycolipids on other CD4(+)CD8(+) thymocytes are selected to undergo a maturation program involving sequential expression of CD44 and NK-related markers such as NK1.1. The molecular requirements for Valpha14i NKT cell maturation, particularly at early developmental stages, remain poorly understood. In this study, we show that CD4-Cre-mediated T cell-specific inactivation of c-Myc, a broadly expressed transcription factor with a wide range of biological activities, selectively impairs Valpha14i NKT cell development without perturbing the development of conventional T cells. In the absence of c-Myc, Valpha14i NKT cell precursors are blocked at an immature CD44(low)NK1.1(-) stage in a cell autonomous fashion. Residual c-Myc-deficient immature Valpha14i NKT cells appear to proliferate normally, cannot be rescued by transgenic expression of BCL-2, and exhibit characteristic features of immature Valpha14i NKT cells such as high levels of preformed IL-4 mRNA and the transcription factor promyelocytic leukemia zinc finger. Collectively our data identify c-Myc as a critical transcription factor that selectively acts early in Valpha14i NKT cell development to promote progression beyond the CD44(low)NK1.1(-) precursor stage.

Simultaneous quantification of selective serotonin reuptake inhibitors and metabolites in human plasma by liquid chromatography-electrospray mass spectrometry for therapeutic drug monitoring.

A simple and sensitive liquid chromatography-electrospray ionization mass spectrometry method was developed for the simultaneous quantification in human plasma of all selective serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) and their main active metabolites (desmethyl-citalopram and norfluoxetine). A stable isotope-labeled internal standard was used for each analyte to compensate for the global method variability, including extraction and ionization variations. After sample (250μl) pre-treatment with acetonitrile (500μl) to precipitate proteins, a fast solid-phase extraction procedure was performed using mixed mode Oasis MCX 96-well plate. Chromatographic separation was achieved in less than 9.0min on a XBridge C18 column (2.1×100mm; 3.5μm) using a gradient of ammonium acetate (pH 8.1; 50mM) and acetonitrile as mobile phase at a flow rate of 0.3ml/min. The method was fully validated according to Société Française des Sciences et Techniques Pharmaceutiques protocols and the latest Food and Drug Administration guidelines. Six point calibration curves were used to cover a large concentration range of 1-500ng/ml for citalopram, desmethyl-citalopram, paroxetine and sertraline, 1-1000ng/ml for fluoxetine and fluvoxamine, and 2-1000ng/ml for norfluoxetine. Good quantitative performances were achieved in terms of trueness (84.2-109.6%), repeatability (0.9-14.6%) and intermediate precision (1.8-18.0%) in the entire assay range including the lower limit of quantification. Internal standard-normalized matrix effects were lower than 13%. The accuracy profiles (total error) were mainly included in the acceptance limits of ±30% for biological samples. The method was successfully applied for routine therapeutic drug monitoring of more than 1600 patient plasma samples over 9 months. The β-expectation tolerance intervals determined during the validation phase were coherent with the results of quality control samples analyzed during routine use. This method is therefore precise and suitable both for therapeutic drug monitoring and pharmacokinetic studies in most clinical laboratories.

Comparative genomics of the vertebrate insulin/TOR signal transduction pathway: A network-level analysis of selective pressures

Complexity of biological function relies on large networks of interacting molecules. However, the evolutionary properties of these networks are not fully understood. It has been shown that selective pressures depend on the position of genes in the network. We have previously shown that in the Drosophila insulin/target of rapamycin (TOR) signal transduction pathway there is a correlation between the pathway position and the strength of purifying selection, with the downstream genes being most constrained. In this study, we investigated the evolutionary dynamics of this well-characterized pathway in vertebrates. More specifically, we determined the impact of natural selection on the evolution of 72 genes of this pathway. We found that in vertebrates there is a similar gradient of selective constraint in the insulin/TOR pathway to that found in Drosophila. This feature is neither the result of a polarity in the impact of positive selection nor of a series of factors affecting selective constraint levels (gene expression level and breadth, codon bias, protein length, and connectivity). We also found that pathway genes encoding physically interacting proteins tend to evolve under similar selective constraints. The results indicate that the architecture of the vertebrate insulin/TOR pathway constrains the molecular evolution of its components. Therefore, the polarity detected in Drosophila is neither specific nor incidental of this genus. Hence, although the underlying biological mechanisms remain unclear, these may be similar in both vertebrates and Drosophila.

Interplanetary transfer of photosynthesis: an experimental demonstration of a selective dispersal filter in planetary island biogeography.

We launched a cryptoendolithic habitat, made of a gneissic impactite inoculated with Chroococcidiopsis sp., into Earth orbit. After orbiting the Earth for 16 days, the rock entered the Earth's atmosphere and was recovered in Kazakhstan. The heat of entry ablated and heated the rock to a temperature well above the upper temperature limit for life to below the depth at which light levels are insufficient for photosynthetic organisms ( approximately 5 mm), thus killing all of its photosynthetic inhabitants. This experiment shows that atmospheric transit acts as a strong biogeographical dispersal filter to the interplanetary transfer of photosynthesis. Following atmospheric entry we found that a transparent, glassy fusion crust had formed on the outside of the rock. Re-inoculated Chroococcidiopsis grew preferentially under the fusion crust in the relatively unaltered gneiss beneath. Organisms under the fusion grew approximately twice as fast as the organisms on the control rock. Thus, the biologically destructive effects of atmospheric transit can generate entirely novel and improved endolithic habitats for organisms on the destination planetary body that survive the dispersal filter. The experiment advances our understanding of how island biogeography works on the interplanetary scale.