Effects of adiponectin on the renal sympathetic nerve activity and blood pressure in rats

Adiponectin is an adipocytokine that modulates energy homeostasis and glucose metabolism. Here, we examined the effects of acute intravenous (iv) and lateral cerebral ventricular (LCV) injections of adiponectin on the renal sympathetic nerve activity (RSNA) and blood pressure (b/p) in urethane-anesthetized rats. Both iv and LCV injections of adiponectin induced dose-dependent suppressions of RSNA and b/p. Moreover, we found that bilateral lesions of the hypothalamic suprachiasmatic nucleus (SCN) abolished the effects of iv injection of adiponectin on RSNA and b/p. These findings suggest that adiponectin decreases the RSNA and b/p in a dose-dependent manner and that the SCN is implicated in mechanism of adiponectin actions on RSNA and b/p. These findings also suggest that the hypotensive-action activity of adiponectin is realized, at least partially, via changes in activities of autonomic nerves activity.     

Association of Dishevelled with the clathrin AP-2 adaptor is required for Frizzled endocytosis and planar cell polarity signaling

Upon activation by Wnt, the Frizzled receptor is internalized in a process that requires the recruitment of Dishevelled. We describe a novel interaction between Dishevelled2 (Dvl2) and micro2-adaptin, a subunit of the clathrin adaptor AP-2; this interaction is required to engage activated Frizzled4 with the endocytic machinery and for its internalization. The interaction of Dvl2 with AP-2 requires simultaneous association of the DEP domain and a peptide YHEL motif within Dvl2 with the C terminus of micro2. Dvl2 mutants in the YHEL motif fail to associate with micro2 and AP-2, and prevent Frizzled4 internalization. Corresponding Xenopus Dishevelled mutants show compromised ability to interfere with gastrulation mediated by the planar cell polarity (PCP) pathway. Conversely, a Dvl2 mutant in its DEP domain impaired in PCP signaling exhibits defective AP-2 interaction and prevents the internalization of Frizzled4. We suggest that the direct interaction of Dvl2 with AP-2 is important for Frizzled internalization and Frizzled/PCP signaling.     

On-chip identification and interaction analysis of gel-resolved proteins using a diamond-like carbon-coated plate

We developed a novel protein chip made of a diamond-like, carbon-coated stainless steel plate (DLC plate), the surface of which is chemically modified with N-hydroxysuccinimide ester. To produce a high-density protein chip using the DLC plate, proteins separated by SDS gel electrophoresis or two-dimensional electrophoresis were electroblotted onto the DLC plate and immobilized covalently. A high blotting efficiency (25-70%) for transferring proteins from the gels onto the DLC plates was achieved by improvement of the electrophoresis device and electroblotting techniques. With the use of the DLC plate, we developed novel techniques to identify proteins immobilized on the chip and to detect protein-protein interactions on the chip by mass spectrometric analysis. We also developed a technique to identify post-translationally modified proteins, such as glycoproteins, on the protein chip.     

Searching for the origins of musicality across species

In the introduction to this theme issue, Honing et al. suggest that the origins of musicality—the capacity that makes it possible for us to perceive, appreciate and produce music—can be pursued productively by searching for components of musicality in other species. Recent studies have highlighted that the behavioural relevance of stimuli to animals and the relation of experimental procedures to their natural behaviour can have a large impact on the type of results that can be obtained for a given species. Through reviewing laboratory findings on animal auditory perception and behaviour, as well as relevant findings on natural behaviour, we provide evidence that both traditional laboratory studies and studies relating to natural behaviour are needed to answer the problem of musicality. Traditional laboratory studies use synthetic stimuli that provide more control than more naturalistic studies, and are in many ways suitable to test the perceptual abilities of animals. However, naturalistic studies are essential to inform us as to what might constitute relevant stimuli and parameters to test with laboratory studies, or why we may or may not expect certain stimulus manipulations to be relevant. These two approaches are both vital in the comparative study of musicality.     

Mast cells and dendritic cells form synapses that facilitate antigen transfer for T cell activation

Mast cells (MCs) produce soluble mediators such as histamine and prostaglandins that are known to influence dendritic cell (DC) function by stimulating maturation and antigen processing. Whether direct cell–cell interactions are important in modulating MC/DC function is unclear. In this paper, we show that direct contact between MCs and DCs occurs and plays an important role in modulating the immune response. Activation of MCs through FcεRI cross-linking triggers the formation of stable cell–cell interactions with immature DCs that are reminiscent of the immunological synapse. Direct cellular contact differentially regulates the secreted cytokine profile, indicating that MC modulation of DC populations is influenced by the nature of their interaction. Synapse formation requires integrin engagement and facilitates the transfer of internalized MC-specific antigen from MCs to DCs. The transferred material is ultimately processed and presented by DCs and can activate T cells. The physiological outcomes of the MC–DC synapse suggest a new role for intercellular crosstalk in defining the immune response.     

Peripheral blood CD4+CD25+CD127low regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response

IntroductionTocilizumab (TCZ), an anti-interleukin-6 receptor antibody, is clinically effective against rheumatoid arthritis (RA), and several reports have indicated how TCZ influences a number of mechanisms underlying RA pathogenesis. However, it is still unclear whether TCZ affects inflammatory cells in peripheral blood and whether any such changes are associated with clinical response. We evaluated associations between proportions of subsets of peripheral immune cells and clinical response in patients with RA treated with TCZ.MethodsThirty-nine consecutive patients with RA who started to receive TCZ as their first biologic between March 2010 and April 2012 were enrolled. The proportions of several subsets of peripheral cells with their levels of expression of differentiation markers, activation markers and costimulatory molecules were measured sequentially from baseline to week 52 by flow cytometry analysis.ResultsClinical Disease Activity Index (CDAI) remission was achieved in 53.8% of patients at week 52 of TCZ therapy. The proportions of CD4⁺CD25⁺CD127^low regulatory T cells (T_reg) and HLA-DR⁺ activated T_reg cells significantly increased with TCZ therapy (P < 0.001 and P < 0.001, respectively), whereas proportions of CD3⁺CD4⁺CXCR3⁻CCR6⁺CD161⁺ T helper 17 cells did not change over the 52 weeks. The proportions of CD20⁺CD27⁺ memory B cells, HLA-DR⁺CD14⁺ and CD69⁺CD14⁺ activated monocytes, and CD16⁺CD14⁺ monocytes significantly decreased (P < 0.001, P < 0.001, P < 0.001 and P < 0.001, respectively). Among them, only the change in T_reg cells was inversely correlated with the change in CDAI score (ρ = −0.40, P = 0.011). The most dynamic increase in T_reg cells was observed in the CDAI remission group (P < 0.001).ConclusionThis study demonstrates that TCZ affected proportions of circulating immune cells in patients with RA. The proportion of T_reg cells among CD4⁺ cells correlated well with clinical response.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0526-4) contains supplementary material, which is available to authorized users.     

Hesr1 and Hesr3 are essential to generate undifferentiated quiescent satellite cells and to maintain satellite cell numbers

Satellite cells, which are skeletal muscle stem cells, divide to provide new myonuclei to growing muscle fibers during postnatal development, and then are maintained in an undifferentiated quiescent state in adult skeletal muscle. This state is considered to be essential for the maintenance of satellite cells, but their molecular regulation is unknown. We show that Hesr1 (Hey1) and Hesr3 (Heyl) (which are known Notch target genes) are expressed simultaneously in skeletal muscle only in satellite cells. In Hesr1 and Hesr3 single-knockout mice, no obvious abnormalities of satellite cells or muscle regenerative potentials are observed. However, the generation of undifferentiated quiescent satellite cells is impaired during postnatal development in Hesr1/3 double-knockout mice. As a result, myogenic (MyoD and myogenin) and proliferative (Ki67) proteins are expressed in adult satellite cells. Consistent with the in vivo results, Hesr1/3-null myoblasts generate very few Pax7(+) MyoD(-) undifferentiated cells in vitro. Furthermore, the satellite cell number gradually decreases in Hesr1/3 double-knockout mice even after it has stabilized in control mice, and an age-dependent regeneration defect is observed. In vivo results suggest that premature differentiation, but not cell death, is the reason for the reduced number of satellite cells in Hesr1/3 double-knockout mice. These results indicate that Hesr1 and Hesr3 are essential for the generation of adult satellite cells and for the maintenance of skeletal muscle homeostasis.