Leukemia inhibitory factor regulates glucocorticoid receptor expression in the hypothalamic-pituitary-adrenal axis

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine belonging to the gp130 family. LIF is induced peripherally and within the brain during inflammatory or chronic autoimmune diseases and is a potent stimulator of the hypothalamic-pituitary-adrenal (HPA) axis. Here we investigated the role of LIF in mediating glucocorticoid receptor (GR) expression in the HPA axis. LIF treatment (3 microg/mouse, i.p.) markedly decreased GR mRNA levels in murine hypothalamus (5-fold, P < 0.01) and pituitary (1.7-fold, P < 0.01) and downregulated GR protein levels. LIF decreased GR expression in murine corticotroph cell line AtT20 within 2 h, and this effect was sustained for 8 h after treatment. LIF-induced GR mRNA reduction was abrogated in AtT20 cells overexpressing dominant-negative mutants of STAT3, indicating that intact JAK-STAT signaling is required to mediate LIF effects on GR expression. Conversely, mice with LIF deficiency exhibited increased GR mRNA levels in the hypothalamus and pituitary (3.5- and 3.5-fold, respectively; P < 0.01 for both) and increased GR protein expression when compared with wild-type littermates. The suppressive effects of dexamethasone on GR were more pronounced in LIF-null animals. These data suggest that LIF maintains the HPA axis activation by decreasing GR expression and raise the possibility that LIF might contribute to the development of central glucocorticoid resistance during inflammation.     

Differential cadmium and zinc distribution in relation to their physiological impact in the leaves of the accumulating Zygophyllum fabago L.

Cadmium and zinc share many similar physiochemical properties, but their compartmentation, complexation and impact on other mineral element distribution in plant tissues may drastically differ. In this study, we address the impact of 10 μm Cd or 50 μm Zn treatments on ion distribution in leaves of a metallicolous population of the non‐hyperaccumulating species Zygophyllum fabago at tissue and cell level, and the consequences on the plant response through a combined physiological, proteomic and metabolite approach. Micro‐proton‐induced X‐ray emission and laser ablation inductively coupled mass spectrometry analyses indicated hot spots of Cd concentrations in the vicinity of vascular bundles in response to Cd treatment, essentially bound to S‐containing compounds as revealed by extended X‐ray absorption fine structure and non‐protein thiol compounds analyses. A preferential accumulation of Zn occurred in vascular bundle and spongy mesophyll in response to Zn treatment, and was mainly bound to O/N‐ligands. Leaf proteomics and physiological status evidenced a protection of photosynthetically active tissues and the maintenance of cell turgor through specific distribution and complexation of toxic ions, reallocation of some essential elements, synthesis of proteins involved in photosynthetic apparatus or C‐metabolism, and metabolite synthesis with some specificities regarding the considered heavy metal treatment.     

Switches, catapults, and chaperones: steady-state kinetic analysis of Hsp70-substrate interactions

Hsp70 chaperones are heterotropic allosteric systems in which ATP and misfolded or aggregated polypeptides are the activating ligands. To gain insight into the mechanism by which ATP and polypeptides regulate Hsp70 chaperone activity, the effect of a short peptide on the K(M) for ATP was analyzed using the Escherichia coli Hsp70 called DnaK. In the absence of peptide, the K(-P)(M) for ATP is 52 +/- 11 nM, whereas this value jumps to 14.6 +/- 1.6 microM in the presence of saturating peptide. This finding supports a mechanism in which ATP binding drives the chaperone in one direction and peptide binding pushes the chaperone back in the opposite direction (and thus increases K(M)), according to ATP + DnaK.P <==> ATP.DnaK.P <==> ATP.DnaK* + P, where ATP.DnaK.P is an intermediate from which competing ATP hydrolysis occurs (ATP.DnaK.P --> ADP.DnaK.P). We show that this branched mechanism can even explain how DnaK hydrolyzes ATP in the absence of peptide and that the true rate constant for DnaK-mediated ATP hydrolysis (k(hy)) in the absence of peptide may be as high as 0.5 s(-)(1) (rather than 5 x 10(-)(4) s(-)(1) as often stated in the literature). What happens is that a conformational equilibrium outcompetes ATP hydrolysis and effectively reduces the concentration of the intermediate by a factor of a thousand, resulting in the following relation: k(cat) = k(hy)/1000 = 5 x 10(-)(4) s(-)(1). How polypeptide substrates and the co-chaperone DnaJ modulate DnaK to achieve its theoretical maximal rate of ATP hydrolysis, which we suggest is 0.5 s(-)(1), is discussed.     

International guide to prescribing psychotropic medication for the management of problem behaviours in adults with intellectual disabilities

Psychotropic medications are used regularly to manage problem behaviours among people with intellectual disabilities. This causes concern because often these medications are used out of their licensed indications in this context. The WPA Section on Psychiatry of Intellectual Disability has recently developed an evidence and consensus-based international guide for practitioners for the use of psychotropic medications for problem behaviours among adults with intellectual disabilities. This guide advises on assessment of behaviours, producing a formulation, initiation of treatment, assessment of out-come and adverse effects, follow-up arrangements, and possibility of discontinuation of treatment.     

Ants of Central Altai: Spatial-typological structure and classification of communities

The basic features of spatial differentiation of ant communities were studied based on quantitative counts in all the landscapes of Central Altai. Gradual changes in the structure of ant communities on altitudinal belts were observed, as well as the mosaic patterns of the complexes determined by the variations in meso- and microclimatic conditions within the belt. The main trends in the correlated changes of ant communities and environmental factors were revealed. Classification of ant communities which may form the basis for the legend of a medium-scale map was made using multidimensional factor analysis. The specific features of the spatial differentiation of ant communities in Central Altai, as well as those in Northeast Altai studied earlier, are largely determined by fluctuations in the hydrothermal conditions of these regions. Among the anthropogenic factors, the most significant one in both provinces is transformation of habitats caused by plowing, stocking, annual mowing, and construction.