CD134 as target for specific drug delivery to auto-aggressive CD4<Superscript>+</Superscript>T cells in adjuvant arthritis

T cells have an important role during the development of autoimmune diseases. In adjuvant arthritis, a model for rheumatoid arthritis, we found that the percentage of CD4⁺ T cells expressing the activation marker CD134 (OX40 antigen) was elevated before disease onset. Moreover, these CD134⁺ T cells showed a specific proliferative response to the disease-associated epitope of mycobacterial heat shock protein 60, indicating that this subset contains auto-aggressive T cells. We studied the usefulness of CD134 as a molecular target for immune intervention in arthritis by using liposomes coated with a CD134-directed monoclonal antibody as a drug targeting system. Injection of anti-CD134 liposomes subcutaneously in the hind paws of pre-arthritic rats resulted in targeting of the majority of CD4⁺CD134⁺ T cells in the popliteal lymph nodes. Furthermore, we showed that anti-CD134 liposomes bound to activated T cells were not internalized. However, drug delivery by these liposomes could be established by loading anti-CD134 liposomes with the dipalmitate-derivatized cytostatic agent 5'-fluorodeoxyuridine. These liposomes specifically inhibited the proliferation of activated CD134⁺ T cells in vitro, and treatment with anti-CD134 liposomes containing 5'-fluorodeoxyuridine resulted in the amelioration of adjuvant arthritis. Thus, CD134 can be used as a marker for auto-aggressive CD4⁺ T cells early in arthritis, and specific liposomal targeting of drugs to these cells via CD134 can be employed to downregulate disease development.     

An Overexpression Screen of Toxoplasma gondii Rab-GTPases Reveals Distinct Transport Routes to the Micronemes

The basic organisation of the endomembrane system is conserved in all eukaryotes and comparative genome analyses provides compelling evidence that the endomembrane system of the last common eukaryotic ancestor (LCEA) is complex with many genes required for regulated traffic being present. Although apicomplexan parasites, causative agents of severe human and animal diseases, appear to have only a basic set of trafficking factors such as Rab-GTPases, they evolved unique secretory organelles (micronemes, rhoptries and dense granules) that are sequentially secreted during invasion of the host cell. In order to define the secretory pathway of apicomplexans, we performed an overexpression screen of Rabs in Toxoplasma gondii and identified Rab5A and Rab5C as important regulators of traffic to micronemes and rhoptries. Intriguingly, we found that not all microneme proteins traffic depends on functional Rab5A and Rab5C, indicating the existence of redundant microneme targeting pathways. Using two-colour super-resolution stimulated emission depletion (STED) we verified distinct localisations of independent microneme proteins and demonstrate that micronemal organelles are organised in distinct subsets or subcompartments. Our results suggest that apicomplexan parasites modify classical regulators of the endocytic system to carryout essential parasite-specific roles in the biogenesis of their unique secretory organelles.     

Sacred natural sites and biodiversity conservation: a systematic review

Biodiversity and Conservation - Sacred natural sites (SNS) have gained recognition from conservationists, and are regarded as the oldest form of habitat protection in human history. Many case...     

ProADD: A database on Protein Aggregation Diseases

ProADD, a database for protein aggregation diseases, is developed to organize the data under a single platform to facilitate easy access for researchers. Diseases caused due to protein aggregation and the proteins involved in each of these diseases are integrated. The database helps in classification of proteins involved in the protein aggregation diseases based on sequence and structural analysis. Analysis of proteins can be done to mine patterns prevailing among the aggregating proteins.

Availability

http://bicmku.in/ProADD     

The Conceptualisation and Measurement of DSM-5 Internet Gaming Disorder: The Development of the IGD-20 Test

Background

Over the last decade, there has been growing concern about ‘gaming addiction’ and its widely documented detrimental impacts on a minority of individuals that play excessively. The latest (fifth) edition of the American Psychiatric Association''s Diagnostic and Statistical Manual of Mental Disorders (DSM-5) included nine criteria for the potential diagnosis of Internet Gaming Disorder (IGD) and noted that it was a condition that warranted further empirical study. Aim: The main aim of this study was to develop a valid and reliable standardised psychometrically robust tool in addition to providing empirically supported cut-off points.

Methods

A sample of 1003 gamers (85.2% males; mean age 26 years) from 57 different countries were recruited via online gaming forums. Validity was assessed by confirmatory factor analysis (CFA), criterion-related validity, and concurrent validity. Latent profile analysis was also carried to distinguish disordered gamers from non-disordered gamers. Sensitivity and specificity analyses were performed to determine an empirical cut-off for the test.

Results

The CFA confirmed the viability of IGD-20 Test with a six-factor structure (salience, mood modification, tolerance, withdrawal, conflict and relapse) for the assessment of IGD according to the nine criteria from DSM-5. The IGD-20 Test proved to be valid and reliable. According to the latent profile analysis, 5.3% of the total participants were classed as disordered gamers. Additionally, an optimal empirical cut-off of 71 points (out of 100) seemed to be adequate according to the sensitivity and specificity analyses carried.

Conclusions

The present findings support the viability of the IGD-20 Test as an adequate standardised psychometrically robust tool for assessing internet gaming disorder. Consequently, the new instrument represents the first step towards unification and consensus in the field of gaming studies.     

Protection of HepG2 cells against acrolein toxicity by 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide via glutathione-mediated mechanism

Acrolein is an environmental toxicant, mainly found in smoke released from incomplete combustion of organic matter. Several studies showed that exposure to acrolein can lead to liver damage. The mechanisms involved in acrolein-induced hepatocellular toxicity, however, are not completely understood. This study examined the cytotoxic mechanisms of acrolein on HepG2 cells. Acrolein at pathophysiological concentrations was shown to cause apoptotic cell death and an increase in levels of protein carbonyl and thiobarbituric acid reactive acid substances. Acrolein also rapidly depleted intracellular glutathione (GSH), GSH-linked glutathione-S-transferases, and aldose reductase, three critical cellular defenses that detoxify reactive aldehydes. Results further showed that depletion of cellular GSH by acrolein preceded the loss of cell viability. To further determine the role of cellular GSH in acrolein-mediated cytotoxicity, buthionine sulfoximine (BSO) was used to inhibit cellular GSH biosynthesis. It was observed that depletion of cellular GSH by BSO led to a marked potentiation of acrolein-mediated cytotoxicity in HepG2 cells. To further assess the contribution of these events to acrolein-induced cytotoxicity, triterpenoid compound 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) was used for induction of GSH. Induction of GSH by CDDO-Im afforded cytoprotection against acrolein toxicity in HepG2 cells. Furthermore, BSO significantly inhibited CDDO-Im-mediated induction in cellular GSH levels and also reversed cytoprotective effects of CDDO-Im in HepG2 cells. These results suggest that GSH is a predominant mechanism underlying acrolein-induced cytotoxicity as well as CDDO-Im-mediated cytoprotection. This study may provide understanding on the molecular action of acrolein which may be important to develop novel strategies for the prevention of acrolein-mediated toxicity.     

The enzymatic hydrolysis of starch-based PVOH and polyol plasticised blends

Thermoplastic starch (TPS) materials present several advantages to the plastic industry and when blended with other materials they can exhibit improved mechanical and moisture sensitivity properties compared to pure TPS materials. However, the biodegradability of these blends, through such processes as enzymatic degradation, needs to be characterised to ensure the beneficial properties of TPS are not compromised. The aims of the study were to investigate the effect of varying polyvinyl alcohol (PVOH) content and polyol type within the TPS blends on the rate and extent of starch enzymatic hydrolysis using enzymes α-amylase and amyloglucosidase. The results of this study have revealed that TPS:PVOH blends with a PVOH content at 50 wt% exhibited a significantly reduced rate and extent of starch hydrolysis. The results suggest that this may have been attributed to interactions between starch and PVOH that further prevented enzymatic attack on the remaining starch phases within the blend. The extent of starch hydrolysis was not significantly affected by polyol type, however, the rate of starch hydrolysis from the maltitol blend was significantly reduced compared to sorbitol and glycerol substrates.     

Plant traits link hypothesis about resource-use and response to herbivory

Grazing by large herbivores, in interplay with environmental productivity, is a key driver of the composition of the vegetation with important consequences on the ecosystem and, consequently, for land management. We tested the predictions of the resource availability – resource–acquisition theory by assessing the extent to which community averages of plant traits, known to be related to plant growth, competitive ability and response to grazing were correlated with resource gradients within local (200 km²) geographical ranges. Second, we assessed the applicability of the same set of plant traits to make inferences on ecological effects of grazing by sheep in alpine ecosystems in Norway, using a data set consisting of 16 sites in central Norway. We estimated grazing intensity by free-ranging sheep based on GPS telemetry, soil properties, plant species composition and species traits i.e. specific leaf area (SLA), leaf dry matter content (LDMC), leaf size and plant height. Soil fertility and the interaction between soil fertility and grazing, but not grazing intensity alone, were significantly related to plant species and traits composition. Generally, average SLA showed lower correspondence with soil fertility and grazing than the other traits. Leaf size and plant height were lowest at sites with high grazing intensity and in sites with low fertility, and increased with soil fertility in little and moderately grazed sites, but declined at high fertility sites when grazing was intense. LDMC showed the opposite trend. Grazing intensity was more related to the variability in plant composition and average plant traits when environmental productivity was high. Our results therefore are indicative of a convergence of responses to grazing and nutrient limitation.     

Host-selective toxins produced by <Emphasis Type="Italic">Stagonospora nodorum</Emphasis> confer disease susceptibility in adult wheat plants under field conditions

Stagonospora nodorum, causal agent of Stagonospora nodorum blotch (SNB), is a destructive pathogen of wheat worldwide. As is true for many necrotrophic host–pathogen systems, the wheat-S. nodorum system is complex and resistance to SNB is usually quantitatively inherited. We recently showed that S. nodorum produces at least four proteinaceous host-selective toxins that interact with dominant host sensitivity/susceptibility gene products to induce SNB in seedlings. Here, we evaluated a population of wheat recombinant inbred lines that segregates for Tsn1, Snn2, and Snn3, which confer sensitivity to the toxins SnToxA, SnTox2, and SnTox3, respectively, to determine if compatible host–toxin interactions are associated with adult plant susceptibility to SNB foliar disease under field conditions. Artificial inoculation of the population in 2 years and two locations with a fungal isolate known to produce SnToxA and SnTox2 indicated that compatible SnToxA–Tsn1 and SnTox2–Snn2 interactions accounted for as much as 18 and 15% of the variation in disease severity on the flag leaf, respectively. As previously reported for seedlings, the effects of these two interactions in conferring adult plant susceptibility were largely additive. Additional adult plant resistance QTLs were identified on chromosomes 1B, 4B, and 5A, of which, the 1B and 5A QTLs were previously reported to be associated with seedling resistance to SNB. Therefore, in this population, some of the same QTLs are responsible for seedling and adult plant resistance/susceptibility. This is the first report showing that host-selective toxins confer susceptibility of adult plants to SNB, further substantiating the importance of compatible toxin–host interactions in the wheat-S. nodorum pathosystem. Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture.