Synovial T cell hyporesponsiveness to myeloid dendritic cells is reversed by preventing PD-1/PD-L1 interactions

Introduction

The aim of this study was to investigate PD-1/PD-L1 involvement in the hyporesponsiveness of rheumatoid arthritis (RA) synovial fluid (SF) CD4 T cells upon stimulation by thymic stromal lymphopoietin (TSLP)–primed CD1c myeloid dendritic cells (mDCs).

Methods

Expression of PD-1 on naïve (Tn), central memory (Tcm) and effector memory (Tem) CD4 T cell subsets was assessed by flow cytometry. PD-L1 expression and its regulation upon TSLP stimulation of mDCs from peripheral blood (PB) and SF of RA patients were investigated by quantitative RT-PCR and flow cytometry. The involvement of PD-1/PD-L1 interactions in SF T cell hyporesponsiveness upon (TSLP-primed) mDC activation was determined by cell culture in the presence of PD-1 blocking antibodies, with or without interleukin 7 (IL-7) as a recognized suppressor of PD-1 expression.

Results

PD-1 expression was increased on CD4 T cells derived from SF compared with PB of RA patients. TSLP increased PD-L1 mRNA expression in both PB and SF mDCs. PD-L1 protein expression was increased on SF mDCs compared with PB mDCs and was associated with T cell hyporesponsiveness. Blockade of PD-1, as well as IL-7 stimulation, during cocultures of memory T cells and (TSLP-primed) mDCs from RA patients significantly recovered T cell proliferation.

Conclusion

SF T cell hyporesponsiveness upon (TSLP-primed) mDC stimulation in RA joints is partially dependent on PD-1/PD-L1 interactions, as PD-1 and PD-L1 are both highly expressed on SF T cells and mDCs, respectively, and inhibiting PD-1 availability restores T cell proliferation. The potential of IL-7 to robustly reverse this hyporesponsiveness suggests that such proinflammatory cytokines in RA joints strongly contribute to memory T cell activation.     

Predicting current and future global distributions of whale sharks

The Vulnerable (IUCN) whale shark spans warm and temperate waters around the globe. However, their present‐day and possible future global distribution has never been predicted. Using 30 years (1980–2010) of whale shark observations recorded by tuna purse‐seiners fishing in the Atlantic, Indian and Pacific Oceans, we applied generalized linear mixed‐effects models to test the hypothesis that similar environmental covariates predict whale shark occurrence in all major ocean basins. We derived global predictors from satellite images for chlorophyll a and sea surface temperature, and bathymetric charts for depth, bottom slope and distance to shore. We randomly generated pseudo‐absences within the area covered by the fisheries, and included fishing effort as an offset to account for potential sampling bias. We predicted sea surface temperatures for 2070 using an ensemble of five global circulation models under a no climate‐policy reference scenario, and used these to predict changes in distribution. The full model (excluding standard deviation of sea surface temperature) had the highest relative statistical support (wAIC_c = 0.99) and explained ca. 60% of the deviance. Habitat suitability was mainly driven by spatial variation in bathymetry and sea surface temperature among oceans, although these effects differed slightly among oceans. Predicted changes in sea surface temperature resulted in a slight shift of suitable habitat towards the poles in both the Atlantic and Indian Oceans (ca. 5°N and 3–8°S, respectively) accompanied by an overall range contraction (2.5–7.4% and 1.1–6.3%, respectively). Predicted changes in the Pacific Ocean were small. Assuming that whale shark environmental requirements and human disturbances (i.e. no stabilization of greenhouse gas emissions) remain similar, we show that warming sea surface temperatures might promote a net retreat from current aggregation areas and an overall redistribution of the species.     

Salarin C inhibits the maintenance of chronic myeloid leukemia progenitor cells

We previously showed that incubation of chronic myeloid leukemia (CML) cells in very low oxygen selects a cell subset where the oncogenetic BCR/Abl protein is suppressed and which is thereby refractory to tyrosine kinase inhibitors used for CML therapy. In this study, salarin C, an anticancer macrolide extracted from the Fascaplysinopsis sponge, was tested as for its activity on CML cells, especially after their incubation in atmosphere at 0.1% oxygen. Salarin C induced mitotic cycle arrest, apoptosis and DNA damage. Salarin C also concentration-dependently inhibited the maintenance of stem cell potential in cultures in low oxygen of either CML cell lines or primary cells. Surprisingly, the drug also concentration-dependently enforced the maintenance of BCR/Abl signaling in low oxygen, an effect which was paralleled by the rescue of sensitivity of stem cell potential to IM. These results suggest a potential use of salarin C for the suppression of CML cells refractory to tyrosine kinase inhibitors     

Dietary partitioning by five sympatric species of stingray (Dasyatidae) on coral reefs

Dietary characteristics and the degree of dietary partitioning by five species of sympatric stingray were assessed using stomach content and sediment analyses within a coral reef lagoon at Ningaloo Reef, Western Australia (the cowtail Pastinachus atrus, blue‐spotted fantail Taeniura lymma, blue‐spotted mask Neotrygon kuhlii, porcupine Urogymnus asperrimus rays and the reticulate whipray Himantura uarnak). A total of 2804 items were recovered from the stomachs of 170 rays and 3215 individual taxa from the environment, which were used in selectivity analyses. Twenty‐four prey taxa were identified from stomach contents and pooled into 10 taxonomic categories for analysis, of which annelids, prawns, brachyurans and bivalves were the most abundant, together accounting for 96% of the diet. Himantura uarnak had the greatest interspecific dissimilarity in diet, consuming a larger proportion of crustaceans, notably penaeids (41% of total diet) than the other four species of rays, all of which had diets dominated by annelids (71–82% of total diet). Crustacean specialization by H. uarnak may exist to maximize resources and reduce competition among sympatric species. The remaining species may partition resources on the basis of space, rather than diet.     

The protective effect of melatonin in lungs of newborn rats exposed to maternal nicotine

We investigated possible healing effects of melatonin (MEL) on biochemical and histological changes in the lungs of rat offspring caused by exposure to nicotine (NT) in utero. Pregnant rats were divided randomly into five groups. The SP group was treated with physiological saline. The EA group was treated with ethyl alcohol. The MEL group was treated with MEL. The NT group was treated with NT. The NT + MEL group was treated with NT and MEL. At the end of the study, the biochemistry and histopathology of lung tissue of the offspring were examined. Reduced alveolar development and increased numbers of alveolar macrophages and mast cells were observed in the NT group compared to the SP, EA and MEL groups. We also found increased malondialdehyde (MDA) levels and decreased total glutathione (GSH) levels in the NT group. Application of MEL ameliorated the histological and biochemical damage caused by NT. The number of alveoli was greater in the NT + MEL group than in the NT group. Also, the increased numbers of alveolar macrophages and mast cells resulting from exposure to NT were decreased following MEL treatment. We found that MEL caused a significant decrease in the level of MDA. Maternal exposure to NT caused significant structural and biochemical changes in the lungs of the offspring and administration of MEL ameliorated the changes.     

The four hexamerin genes in the honey bee: structure,molecular evolution and function deduced from expression patterns in queens,workers and drones

Background  

Hexamerins are hemocyanin-derived proteins that have lost the ability to bind copper ions and transport oxygen; instead, they became storage proteins. The current study aimed to broaden our knowledge on the hexamerin genes found in the honey bee genome by exploring their structural characteristics, expression profiles, evolution, and functions in the life cycle of workers, drones and queens.     

Vertical distributions of late stage larval fishes in the nearshore waters of the San Blas Archipelago, Caribbean Panama

Light traps were used to describe the vertical distribution of late larval stages of reef fishes in the San Blas Archipelago during three successive new moon periods. Traps were deployed in the lagoon and at an exposed site on the outer reef edge. At each site, two traps were anchored at the surface and two traps just above the bottom. Most families of reef fishes that were abundant in catches displayed clear patterns of depth preference. The larvae of gerrids, pomacentrids and lutjanids were predominantly captured in shallow traps, while gobiids, labrids, apogonids and blenniids were usually collected in deep traps. Studies that used lights to aggregate and collect larval fishes display marked differences in the composition of catches between the Great Barrier Reef (GBR) and the Caribbean. In order to determine whether such results were due to biases inherent in different sampling methods, or to locality-specific patterns of larval behaviour, we simultaneously deployed light traps and dip-netting around lights during three new moons in the San Blas Archipelago. We found that these sampling techniques collected differing components of the larval fish assemblage from the same water mass. However, there remains good evidence for the existence of locality-specific responses to light in older larval stages, suggesting that broad generalisations about patterns and causes of vertical distributions may be difficult to achieve.     

Molecular characteristics of diverse populations are consistent with the hypothesis of a recent invasion of Drosophila melanogaster by mobile P elements

Approximately 100 strains derived from natural populations of Drosophila melanogaster were tested for the presence or absence of P- element sequences by using two molecular probes derived from internal regions of a full-sized P element. Strains that had been collected from several continents at varying times during the past 60 years were examined. The oldest available strains, representing most major geographical regions of the world, exhibited no detectable hybridization to the P-element probes. In contrast, all recently collected natural populations that were tested carried P-element sequences. The earliest appearance of P elements occurred in collections made during the 1950s and early 1960s in the Americas and during the late 1960s on other continents. The youngest strains that were completely devoid of P elements originated in populations sampled during the mid-1960s in America, but as late as 1974 in populations from the USSR. There are differences in the patterns of hybridization to the two P-element probes between populations from different geographical regions. These differences are consistent with the varying P-M phenotypic properties of these populations. Taken together with the results of phenotypic tests reported in earlier studies, the available evidence is consistent with the hypothesis of a worldwide P-element invasion of D. melanogaster during the past 30 years and suggests that the putative invasion of the Americas possibly preceded by approximately a decade that in Europe, Africa, and the rest of the world.      

Spatial patterns in the distribution of damselfishes on a fringing coral reef

Damselfishes are an important element of the fauna of coral reefs. This study describes spatial patterns in the distribution of 15 species of damselfishes at Lizard Island, northern Great Barrier Reef (GBR). The aim of the work was to identify the spatial scales at which major changes in the composition and abundance of the fauna occurred. These patterns were then compared with previous studies in an attempt to determine if distributions followed general patterns at a range of localities. The assemblage found at Lizard Island was similar to that of reefs in the central GBR. The most important changes in the composition of the fauna occurred among reef zones. Shallow zones (the reef flat and crest) were dominated by herbivorous species while planktivorous and omnivorous species were most abundant in deeper zones (the reef slope). Densities of herbivorous damselfishes in shallow reef zones at Lizard Island averaged 45.5 individuals per 80 m², a value comparable to densities found in similar zones on reefs in the central and southern GBR and at one locality in the Caribbean. Comparisons of relative distributions suggested that abundant species tend to be widely distributed among zones and habitats, while rare species have restricted distributions at Lizard Island. However, computer simulation of the sampling program suggested that the ability of our study to describe the distribution patterns of rare species was limited, despite intensive sampling. Correlations between breadth of distribution and abundance may have occurred simply because rare species were less likely to be recorded within a transect. Our results suggest that it will be difficult to compare the distribution patterns of species among studies. Furthermore, the interpretation of relative patterns of distribution at a single locality in terms of ecological specialization or partitioning may first require an assessment of the ability of the sampling program to accurately record spatial patterns.     

Mitochondrial control-region sequences in two shorebird species, the turnstone and the dunlin, and their utility in population genetic studies

We determined the mitochondrial control-region sequences of five turnstones (Arenaria interpres) and three dunlins (Calidris alpina). Comparisons revealed that the central part (part II) is conserved relative to much more variable parts at the beginning (part I) and the end (part III). This pattern of sequence conservation is also found in the control regions of other vertebrates. The average sequence divergence between turnstone and dunlin was 21.8% for part I, 7.5% for part II, and 29.5% for part III. Within-species sequence divergence over the entire control region was much lower, at 0.9% for turnstones and 2.0% for dunlins. In both shorebird species, part III contains a repetitive sequence composed only of A and C nucleotides, which has not been found in the control regions of other birds. A survey of the part I sequences of 25 turnstones and 25 dunlins sampled around the world revealed that these species have very different population genetic structures. Dunlins are not only much more differentiated in their sequences but also have a strongly subdivided population genetic structure. Pleistocene vicariant events combined with strong natal philopatry and high mutation rates of the sequences are likely responsible for this population genetic subdivision. Conversely, part I sequences of turnstones are weakly differentiated and are geographically unstructured. We argue that this is not the result of global gene flow but that, instead turnstones have recently expanded from a refugial population that was bottlenecked.