Neuroprotection by the selective iNOS inhibitor GW274150 in a model of Parkinson disease

Neuroinflammation and the activation of inducible nitric oxide synthase (iNOS) have been proposed to play a role in the pathogenesis of Parkinson disease (PD). In this study we investigated the effects of the selective iNOS inhibitor GW274150 in the 6-OHDA model of PD. 6-OHDA administration was associated with increased numbers of cells expressing iNOS. Administration of the iNOS inhibitor twice daily for 7 days, beginning 2 days after the 6-OHDA lesioning, led to a significant neuroprotection as shown by assessment of the integrity of the nigrostriatal system by tyrosine hydroxylase immunocytochemistry and HPLC assessment of striatal dopamine content. However, GW274150 displayed a bell-shaped neuroprotective profile, being ineffective at high doses. 6-OHDA lesioning was associated with an increase in microglial activation as assessed by the MHC II antigen OX-6 and the number of matrix metalloproteinase 9 (MMP-9)-immunopositive cells. NO is a known modulator of MMP-9, and iNOS inhibition was associated with decreased numbers of MMP-9-immunopositive cells, culminating in a reduction in the numbers of reactive microglia. Withdrawal of GW274150 for a further 7 days negated any neuroprotective effects of iNOS inhibition, suggesting that the damaging effects of inflammation last beyond 7 days in this model and the continued administration of the drug may be required.     

Pulmonary Oil Deposition in Patients Subjected to Lymphography: Detection by Thoracic Photoscan and Sputum Examination

During clinical trials of intralymphatic therapy with radioiodinated ethiodized oil (Lipiodol Ultra-Fluid; Ethiodol) [LUF-I¹³¹] for malignant disease involving lymph nodes, significant pulmonary deposition of radioactive material was demonstrated by thoracic scan in each of five cases treated. Radioactivity was detected in sputum obtained from two cases. Induced sputum specimens were subsequently obtained from patients undergoing lymphography. Fat demonstrated in sputum was confirmed as Lipiodol in one of six patients tested. Sputum examination and use of tracer doses of LUF-I¹³¹ plus photoscanning are suggested as sensitive methods of assessing the incidence of oil deposition in the lungs of patients undergoing lymphography. Despite limitation of the volume of oil injected, monitoring of the infusion, and absence of radiographic evidence of contrast medium in the lungs, some degree of pulmonary oil deposition appears to be an inevitable result of lymphography. Further study of lung dosimetry is being undertaken by the authors before clinical usage of endolymphatic radioisotope therapy is expanded.     

Quality determination and the repair of poor quality spots in array experiments

Background  

A common feature of microarray experiments is the occurence of missing gene expression data. These missing values occur for a variety of reasons, in particular, because of the filtering of poor quality spots and the removal of undefined values when a logarithmic transformation is applied to negative background-corrected intensities. The efficiency and power of an analysis performed can be substantially reduced by having an incomplete matrix of gene intensities. Additionally, most statistical methods require a complete intensity matrix. Furthermore, biases may be introduced into analyses through missing information on some genes. Thus methods for appropriately replacing (imputing) missing data and/or weighting poor quality spots are required.     

An atlas of human kinase regulation

The coordinated regulation of protein kinases is a rapid mechanism that integrates diverse cues and swiftly determines appropriate cellular responses. However, our understanding of cellular decision‐making has been limited by the small number of simultaneously monitored phospho‐regulatory events. Here, we have estimated changes in activity in 215 human kinases in 399 conditions derived from a large compilation of phosphopeptide quantifications. This atlas identifies commonly regulated kinases as those that are central in the signaling network and defines the logic relationships between kinase pairs. Co‐regulation along the conditions predicts kinase–complex and kinase–substrate associations. Additionally, the kinase regulation profile acts as a molecular fingerprint to identify related and opposing signaling states. Using this atlas, we identified essential mediators of stem cell differentiation, modulators of Salmonella infection, and new targets of AKT1. This provides a global view of human phosphorylation‐based signaling and the necessary context to better understand kinase‐driven decision‐making.     

Differential responses of marine communities to natural and anthropogenic changes

Responses of ecosystems to environmental changes vary greatly across habitats, organisms and observational scales. The Quaternary fossil record of the Po Basin demonstrates that marine communities of the northern Adriatic re-emerged unchanged following the most recent glaciation, which lasted approximately 100 000 years. The Late Pleistocene and Holocene interglacial ecosystems were both dominated by the same species, species turnover rates approximated predictions of resampling models of a homogeneous system, and comparable bathymetric gradients in species composition, sample-level diversity, dominance and specimen abundance were observed in both time intervals. The interglacial Adriatic ecosystems appear to have been impervious to natural climate change either owing to their persistence during those long-term perturbations or their resilient recovery during interglacial phases of climate oscillations. By contrast, present-day communities of the northern Adriatic differ notably from their Holocene counterparts. The recent ecosystem shift stands in contrast to the long-term endurance of interglacial communities in face of climate-driven environmental changes.     

Developmentally-related changes in surface membrane glycopeptides of murine haemopoietic cells.

We have carried out a comparative study of mature murine granulocytes with two immature haemopoietic cell lines (multipotential cells, FDCP-Mix, and granulocyte progenitor cells, FDCP-2) with respect to the structure and composition of their surface membrane glycopeptides. The glycopeptides were labelled biosynthetically by incubation of the cells for 1-3 days with [3H]glucosamine. Cell-associated glycopeptides were released by treatment with trypsin and the trypsin extract was exhaustively digested with Pronase to remove most residual peptide. Radiolabelled materials were fractionated by chromatography on lectin affinity columns connected in the series: lentil lectin (LCA), concanavalin A (Con A) and wheat germ agglutinin (WGA). Lectin-binding glycopeptides were eluted with appropriate competing sugars and further analysed by gel filtration, base/borohydride elimination and susceptibility to degradation by glycosidases including endo-beta-galactosidase. Abundant quantities of N-linked polylactosamine-type glycopeptides, which bound only to the WGA columns, were identified on mature granulocytes but the molecules were highly-branched (i.e. resistant to endo-beta-galactosidase). In contrast, there seemed to be very little branching in the polylactosamine chains from FDCP-2 cells, whilst corresponding carbohydrates from multipotential FDCP-Mix cells gave evidence for both linear and branched domains in the same, large complex glycans. O-Linked tetrasaccharides of general structure: NeuAc-Gal-(NeuAc)-GalNAc were found in clusters on WGA-binding glycopeptides from all cell types, these components being especially prominent on mature granulocytes. FDCP-2 cells were distinguished by the presence of monosialylated and non-sialylated counterparts of the foregoing tetrasaccharides. The relative amount of LCA-binding glycopeptides was low on FDCP-Mix cells by comparison with FDCP-2 cells and mature granulocytes. Our findings therefore demonstrate that notable differences in gross composition and molecular fine structure of surface membrane glycopeptides are detectable in haemopoietic cells at different stages of development. The relationship of these differences to the biological properties of cell surfaces remains to be established.     

Aboveground Carbon Storage and Its Links to Stand Structure,Tree Diversity and Floristic Composition in South-Eastern Tanzania

African savannas and dry forests represent a large, but poorly quantified store of biomass carbon and biodiversity. Improving this information is hindered by a lack of recent forest inventories, which are necessary for calibrating earth observation data and for evaluating the relationship between carbon stocks and tree diversity in the context of forest conservation (for example, REDD+). Here, we present new inventory data from south-eastern Tanzania, comprising more than 15,000 trees at 25 locations located across a gradient of aboveground woody carbon (AGC) stocks. We find that larger trees disproportionately contribute to AGC, with the largest 3.7% of individuals containing half the carbon. Tree species diversity and carbon stocks were positively related, implying a potential functional relationship between the two, and a ‘win–win’ scenario for conservation; however, lower biomass areas also contain diverse species assemblages meaning that carbon-oriented conservation may miss important areas of biodiversity. Despite these variations, we find that total tree abundance and biomass is skewed towards a few locally dominant species, with eight and nine species (5.7% of the total) accounting for over half the total measured trees and carbon, respectively. This finding implies that carbon production in these areas is channelled through a small number of relatively abundant species. Our results provide key insights into the structure and functioning of these heterogeneous ecosystems and indicate the need for novel strategies for future measurement and monitoring of carbon stocks and biodiversity, including the use for larger plots to capture spatial variations in large tree density and AGC stocks, and to allow the calibration of earth observation data.     

Directed attention eliminates 'change deafness' in complex auditory scenes

In natural environments that contain multiple sound sources, acoustic energy arising from the different sources sums to produce a single complex waveform at each of the listener's ears. The auditory system must segregate this waveform into distinct streams to permit identification of the objects from which the signals emanate [1]. Although the processes involved in stream segregation are now reasonably well understood [1, 2 and 3], little is known about the nature of our perception of complex auditory scenes. Here, we examined complex scene perception by having listeners detect a discrete change to an auditory scene comprising multiple concurrent naturalistic sounds. We found that listeners were remarkably poor at detecting the disappearance of an individual auditory object when listening to scenes containing more than four objects, but they performed near perfectly when their attention was directed to the identity of a potential change. In the absence of directed attention, this "change deafness" [4] was greater for objects arising from a common location in space than for objects separated in azimuth. Change deafness was also observed for changes in object location, suggesting that it may reflect a general effect of the dependence of human auditory perception on attention.