Brightness versus apparent contrast. 2: Large-field asymmetry.

Experiments were performed on the quasi-static perception of brightness and of apparent contrast of a foveal 1-deg disk, presented either as a luminance increment or decrement against a 300 cd.m-2 background. Results suggest that the perceptual attributes of brightness and apparent (or subjective) contrast should be distinguished. For an equal brightness difference with respect to the background, luminance increments are more effective than decrements. For an equal apparent contrast it is found that increments and decrements, up to 100 cd.m-2, are about equally effective; for higher values luminance decrements are more effective. Brightness increments and decrements can both be described by a Stevens power function of the respective luminance increments and decrements. Apparent contrast can, apart from applying a usual luminance contrast formula, also be described as a power function of the luminance difference with the background.     

Topical Delivery of 5-Fluorouracil from Pheroid™ Formulations and the In Vitro Efficacy Against Human Melanoma

Drug delivery vehicles can influence the topical delivery and the efficacy of an active pharmaceutical ingredient (API). In this study, the influence of Pheroid™ technology, which is a unique colloidal drug delivery system, on the skin permeation and antimelanoma efficacy of 5-fluorouracil were investigated. Lotions containing Pheroid™ with different concentrations of 5-fluorouracil were formulated then used in Franz cell skin diffusion studies and tape stripping. The in vitro efficacy of 5-fluorouracil against human melanoma cells (A375) was investigated using a flow cytometric apoptosis assay. Statistically significant concentrations of 5-fluorouracil diffused into and through the skin with Pheroid™ formulations resulting in an enhanced in vitro skin permeation from the 4.0% 5-fluorouracil lotion (p < 0.05). The stratum corneum-epidermis and epidermis-dermis retained 5-fluorouracil concentrations of 2.31 and 6.69 μg/ml, respectively, after a diffusion study with the 4.0% Pheroid™ lotion. Subsequent to the apoptosis assay, significant differences were observed between the effect of 13.33 μg/ml 5-fluorouracil in Pheroid™ lotion and the effects of the controls. The results obtained suggest that the Pheroid™ drug delivery system possibly enhances the flux and delivery of 5-fluorouracil into the skin. Therefore, using Pheroid™ could possibly be advantageous with respect to topical delivery of 5-fluorouracil.KEY WORDS: A375 cells, cell culture, flow cytometry, melanoma, permeation enhancer     

Enhanced B-Cell Receptor Recognition of the Autoantigen Transglutaminase 2 by Efficient Catalytic Self-Multimerization

A hallmark of the gluten-driven enteropathy celiac disease is autoantibody production towards the enzyme transglutaminase 2 (TG2) that catalyzes the formation of covalent protein-protein cross-links. Activation of TG2-specific B cells likely involves gluten-specific CD4 T cells as production of the antibodies is dependent on disease-associated HLA-DQ allotypes and dietary intake of gluten. IgA plasma cells producing TG2 antibodies with few mutations are abundant in the celiac gut lesion. These plasma cells and serum antibodies to TG2 drop rapidly after initiation of a gluten-free diet, suggestive of extrafollicular responses or germinal center reactions of short duration. High antigen avidity is known to promote such responses, and is also important for breakage of self-tolerance. We here inquired whether TG2 avidity could be a feature relevant to celiac disease. Using recombinant enzyme we show by dynamic light scattering and gel electrophoresis that TG2 efficiently utilizes itself as a substrate due to conformation-dependent homotypic association, which involves the C-terminal domains of the enzyme. This leads to the formation of covalently linked TG2 multimers. The presence of exogenous substrate such as gluten peptide does not inhibit TG2 self-cross-linking, but rather results in formation of TG2-TG2-gluten complexes. The celiac disease autoantibody epitopes, clustered in the N-terminal part of TG2, are conserved in the TG2-multimers as determined by mass spectrometry and immunoprecipitation analysis. TG2 multimers are superior to TG2 monomer in activating A20 B cells transduced with TG2-specific B-cell receptor, and uptake of TG2-TG2-gluten multimers leads to efficient activation of gluten-specific T cells. Efficient catalytic self-multimerization of TG2 and generation of multivalent TG2 antigen decorated with gluten peptides suggest a mechanism by which self-reactive B cells are activated to give abundant numbers of plasma cells in celiac disease. Importantly, high avidity of the antigen could explain why TG2-specific plasma cells show signs of an extrafollicular generation pathway.     

Significant effects of season and bird age on use of coppice woodland by songbirds

Woodland birds have experienced widespread population declines across Europe, resulting partly from a decrease in management practices such as coppicing. Increasing fuelwood demand may reverse the decline of coppicing, making it timely to attempt a fuller understanding of its effects. Here, the impact of coppicing on year‐round habitat use by adults and juveniles of 16 songbird species was quantified from a quasi‐experimental study over 32 years (1978–2009) in Treswell Wood, Nottinghamshire, UK. Habitat use was inferred using capture rates from more than 10 000 h of mist‐netting (> 25 000 captures) and detailed information on coppicing. Capture rates varied with coppice age in different ways: (1) increases as coppice aged (e.g. Marsh Tit Poecile palustris, juvenile Eurasian Treecreepers Certhia familiaris); (2) declines as coppice aged (e.g. Eurasian Blue Tit Cyanistes caeruleus, Great Tit Parus major); (3) peaks in capture rates at intermediate coppice age (i.e. 5–15 years) (e.g. Garden Warbler Sylvia borin, Willow Warbler Phylloscopus trochilus, adult Treecreepers); and (4) a peak at intermediate ages, followed by a decline, before an increase in use again at the oldest coppice ages (i.e. > 20 years) (e.g. Common Blackbird Turdus merula, Eurasian Blackcap Sylvia atricapilla, Eurasian Bullfinch Pyrrhula pyrrhula). Responses to coppice age were similar in different seasons, although Willow Tits Poecile montana showed little preference during breeding but avoided older coppice at other times. Juveniles and adults often differed in their responses to coppice age. The analyses reveal patterns in habitat use that are relevant to woodland management and conservation policy. They suggest that a mosaic of age structures in woodland is beneficial to a wide range of woodland species, and that management should consider the requirements of all age‐classes of birds at different times of year.     

Bidirectional plasticity gated by hyperpolarization controls the gain of postsynaptic firing responses at central vestibular nerve synapses

Linking synaptic plasticity with behavioral learning requires understanding how synaptic efficacy influences postsynaptic firing in neurons whose role in behavior is understood. Here, we examine plasticity at a candidate site of motor learning: vestibular nerve synapses onto neurons that mediate reflexive movements. Pairing nerve activity with changes in postsynaptic voltage induced bidirectional synaptic plasticity in vestibular nucleus projection neurons: long-term potentiation relied on calcium-permeable AMPA receptors and postsynaptic hyperpolarization, whereas long-term depression relied on NMDA receptors and postsynaptic depolarization. Remarkably, both forms of plasticity uniformly scaled synaptic currents evoked by pulse trains, and these changes in synaptic efficacy were translated into linear increases or decreases in postsynaptic firing responses. Synapses onto local inhibitory neurons were also plastic but expressed only long-term depression. Bidirectional, linear gain control of vestibular nerve synapses onto projection neurons provides a plausible mechanism for motor learning underlying adaptation of vestibular reflexes.     

Analyses archéométriques dans la grotte ornée Mayenne-Sciences (Thorigné-en-Charnie, Mayenne)

Since 1998, a multidisciplinary team works on the study of the representations in the cave Mayenne-Sciences (Thorigné-en-Charnie, Mayenne). Particularly, there are trials for U-TH (TIMH) datations of the speleothems recovering the drawings and fossils of the bats; this would help to know at what date the decorated cave was closed. The studies already allowed to know better the black drawings, executed with a wooden charcoal crayon. Thus, it was possible to make removals which gave two dates from the Gravettian phase; this feeds again the discussion about the chronocultural position of this cave, on of the most septentrional caves we know.     

Microbial responses to P addition in six South African forest soils

Forests growing on highly weathered soils are often phosphorus (P) limited and competition between geochemical and biological sinks affects their soil P dynamics. In an attempt to elucidate the factors controlling the relative importance of these two sinks, we investigated the relationship of between soil microbial growth kinetics and soil chemical properties following amendments with C, N and P in six South African forest soils. Microbial growth kinetics were determined from respiration curves derived from measurements of CO₂ effluxes from soil samples in laboratory incubations. We found that microbial growth rates after C + N additions were positively related to NaOH-extractable P and decreased with soil depth, whereas the lag time (the time between substrate addition and exponential growth) was negatively related to extractable P. However, the growth rate and lag time were unrelated to the soil’s sorption properties or Al and Fe contents. Our results indicate that at least some of the NaOH-extractable inorganic P may be biologically available within a relatively short time (days to weeks) and might be more labile than previously thought. Our results also show that microbial utilization of C + N only seemed to be constrained by P in the deeper part of the soil profiles.     

<Emphasis Type="Italic">TRAF1/C5</Emphasis>polymorphism is not associated with increased mortality in rheumatoid arthritis: two large longitudinal studies

Introduction  

Recently an association between a genetic variation in TRAF1/C5 and mortality from sepsis or cancer was found in rheumatoid arthritis (RA). The most prevalent cause of death, cardiovascular disease, may have been missed in that study, since patients were enrolled at an advanced disease stage. Therefore, we used an inception cohort of RA patients to investigate the association between TRAF1/C5 and cardiovascular mortality, and replicate the findings on all-cause mortality. As TRAF1/C5 associated mortality may not be restricted to RA, we also studied a large cohort of non-RA patients.     

Mesenchymal stem cells in autoimmune diseases: hype or hope?

Intervention with mesenchymal stem cells (MSCs) represents a promising therapeutic tool in treatment-refractory autoimmune diseases. A new report by Schurgers and colleagues in a previous issue of Arthritis Research & Therapy sheds novel mechanistic insight into the pathways employed by MSCs to suppress T-cell proliferation in vitro, but, at the same time, indicates that MSCs do not influence T-cell reactivity and the disease course in an in vivo arthritis model. Such discrepancies between the in vitro and in vivo effects of potent cellular immune modulators should spark further research and should be interpreted as a sign of caution for the in vitro design of MSC-derived interventions in the setting of human autoimmune diseases.