The Turkey Ig-like receptor family: identification, expression and function.

The chicken leukocyte receptor complex located on microchromosome 31 encodes the chicken Ig-like receptors (CHIR), a vastly expanded gene family which can be further divided into three subgroups: activating CHIR-A, bifunctional CHIR-AB and inhibitory CHIR-B. Here, we investigated the presence of CHIR homologues in other bird species. The available genome databases of turkey, duck and zebra finch were screened with different strategies including BLAST searches employing various CHIR sequences, and keyword searches. We could not identify CHIR homologues in the distantly related zebra finch and duck, however, several partial and complete sequences of CHIR homologues were identified on chromosome 3 of the turkey genome. They were designated as turkey Ig-like receptors (TILR). Using cDNA derived from turkey blood and spleen RNA, six full length TILR could be amplified and further divided according to the typical sequence features into one activating TILR-A, one inhibitory TILR-B and four bifunctional TILR-AB. Since the TILR-AB sequences all displayed the critical residues shown to be involved in binding to IgY, we next confirmed the IgY binding using a soluble TILR-AB1-huIg fusion protein. This fusion protein reacted with IgY derived from various gallinaceous birds, but not with IgY from other bird species. Finally, we tested various mab directed against CHIR for their crossreactivity with either turkey or duck leukocytes. Whereas no staining was detectable with duck cells, the CHIR-AB1 specific mab 8D12 and the CHIR-A2 specific mab 13E2 both reacted with a leukocyte subpopulation that was further identified as thrombocytes by double immunofluorescence employing B-cell, T-cell and thrombocyte specific reagents. In summary, although the turkey harbors similar LRC genes as the chicken, their distribution seems to be distinct with predominance on thrombocytes rather than lymphocytes

Discovery of Diverse Small Molecule Chemotypes with Cell-Based PKD1 Inhibitory Activity

Protein kinase D (PKD) is a novel family of serine/threonine kinases regulated by diacylglycerol, which is involved in multiple cellular processes and various pathological conditions. The limited number of cell-active, selective inhibitors has historically restricted biochemical and pharmacological studies of PKD. We now markedly expand the PKD1 inhibitory chemotype inventory with eleven additional novel small molecule PKD1 inhibitors derived from our high throughput screening campaigns. The in vitro IC50s for these eleven compounds ranged in potency from 0.4 to 6.1 µM with all of the evaluated compounds being competitive with ATP. Three of the inhibitors (CID 1893668, (1Z)-1-(3-ethyl-5-methoxy-1,3-benzothiazol-2-ylidene)propan-2-one; CID 2011756, 5-(3-chlorophenyl)-N-[4-(morpholin-4-ylmethyl)phenyl]furan-2-carboxamide; CID 5389142, (6Z)-6-[4-(3-aminopropylamino)-6-methyl-1H-pyrimidin-2-ylidene]cyclohexa-2,4-dien-1-one) inhibited phorbol ester-induced endogenous PKD1 activation in LNCaP prostate cancer cells in a concentration-dependent manner. The specificity of these compounds for PKD1 inhibitory activity was supported by kinase assay counter screens as well as by bioinformatics searches. Moreover, computational analyses of these novel cell-active PKD1 inhibitors indicated that they were structurally distinct from the previously described cell-active PKD1 inhibitors while computational docking of the new cell-active compounds in a highly conserved ATP-binding cleft suggests opportunities for structural modification. In summary, we have discovered novel PKD1 inhibitors with in vitro and cell-based inhibitory activity, thus successfully expanding the structural diversity of small molecule inhibitors available for this important pharmacological target

High spatial resolution analysis of ferromanganese concretions by LA-ICP-MS†

A procedure was developed for the determination of element distributions in cross-sections of ferromanganese concretions using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The effects of carrier flow rates, rf forward power, ablation energy, ablation spot size, repetition rate and number of shots per point on analyte intensity were studied. It is shown that different carrier gas flow rates are required in order to obtain maximum sensitivities for different groups of elements, thus complicating the optimisation of ICP parameters. On the contrary, LA parameters have very similar effects on almost all elements studied, thus providing a common optimum parameter set for the entire mass range. However, for selected LA parameters, the use of compromise conditions was necessary in order to compensate for relatively slow data acquisition by ICP-MS and maintain high spatial resolution without sacrificing the multielemental capabilities of the technique. Possible variations in ablation efficiency were corrected for mathematically using the sum of Fe and Mn intensities. Quantification by external calibration against matrix-matched standards was successfully used for more than 50 elements. These standards, in the form of pressed pellets (no binder), were prepared in-house using ferromanganese concentrates from a deep-sea nodule reference material as well as from shallow-marine concretions varying in size and having different proportions of three major phases: aluminosilicates, Fe- and Mn-oxyhydroxides. Element concentrations in each standard were determined by means of conventional solution nebulisation ICP-MS following acid digestion. Examples of selected inter-element correlations in distribution patterns along the cross-section of a concretion are given

Cardiovascular inflammation in healthy women: multilevel associations with state-level prosperity, productivity and income inequality

<p>Abstract</p> <p>Background</p> <p>Cardiovascular inflammation is a key contributor to the development of atherosclerosis and the prediction of cardiovascular events among healthy women. An emerging literature suggests biomarkers of inflammation vary by geography of residence at the state-level, and are associated with individual-level socioeconomic status. Associations between cardiovascular inflammation and state-level socioeconomic conditions have not been evaluated. The study objective is to estimate whether there are independent associations between state-level socioeconomic conditions and individual-level biomarkers of inflammation, in excess of individual-level income and clinical covariates among healthy women.</p> <p>Methods</p> <p>The authors examined cross-sectional multilevel associations among state-level socioeconomic conditions, individual-level income, and biomarkers of inflammation among women (n = 26,029) in the Women's Health Study, a nation-wide cohort of healthy women free of cardiovascular diseases at enrollment. High sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1) and fibrinogen were measured between 1993 and 1996. Biomarker levels were examined among women within quartiles of state-level socioeconomic conditions and within categories of individual-level income.</p> <p>Results</p> <p>The authors found that favorable state-level socioeconomic conditions were correlated with lower hsCRP, in excess of individual-level income (e.g. state-level real per capital gross domestic product fixed effect standardized Βeta coefficient [Std B] -0.03, 95% CI -0.05, -0.004). Individual-level income was more closely associated with sICAM-1 (Std B -0.04, 95% CI -0.06, -0.03) and fibrinogen (Std B -0.05, 95% CI -0.06, -0.03) than state-level conditions.</p> <p>Conclusions</p> <p>We found associations between state-level socioeconomic conditions and hsCRP among healthy women. Personal household income was more closely associated with sICAM-1 and fibrinogen than state-level socioeconomic conditions. Additional research should examine these associations in other cohorts, and investigate what more-advantaged states do differently than less-advantaged states that may influence levels of cardiovascular inflammation among healthy women.</p

More stories on Th17 cells

For more than two decades, immunologists have been using the so-called Th1/Th2 paradigm to explain most of the phenomena related to adaptive immunity. the Th1/Th2 paradigm implied the existence of two different, mutually regulated, CD4(+) T helper subsets: Th1 cells, driving cell-mediated immune responses involved in tissue damage and fighting infection against intracellular parasites; and Th2 cells that mediate IgE production and are particularly involved in eosinophilic inflammation, allergy and clearance of helminthic infections. A third member of the T helper set, IL-17-producing CD4(+) T cells, now called Th17 cells, was recently described as a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells. the Th17 subset has been linked to autoimmune disorders, being able to produce IL-17, IL-17F and IL-21 among other inflammatory cytokines. Interestingly, it has been reported that there is not only a cross-regulation among Th1, Th2 and Th17 effector cells but there is also a dichotomy in the generation of Th17 and T regulatory cells. Therefore, Treg and Th17 effector cells arise in a mutually exclusive fashion, depending on whether they are activated in the presence of TGF-beta or TGF-beta plus inflammatory cytokines such as IL-6. This review will address the discovery of the Th17 cells, and recent progress on their development and regulation.Crohn's and Colitis Foundation of AmericaNIHLa Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USAUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, São Paulo, BrazilNIH: RO1 AI050265-06Web of Scienc

Inequitable walking conditions among older people: examining the interrelationship of neighbourhood socio-economic status and urban form using a comparative case study

<p>Abstract</p> <p>Background</p> <p>Supportive neighbourhood walking conditions are particularly important for older people as they age and who, as a group, prefer walking as a form of physical activity. Urban form and socio-economic status (SES) can influence neighbourhood walking behaviour. The objectives of this study were: a) to examine how urban form and neighbourhood SES inter-relate to affect the experiences of older people who walk in their neighbourhoods; b) to examine differences among neighbourhood stakeholder key informant perspectives on socio-political processes that shape the walkability of neighbourhood environments.</p> <p>Methods</p> <p>An embedded comparative case study examined differences among four Ottawa neighbourhoods that were purposefully selected to provide contrasts on urban form (inner-urban versus suburban) and SES (higher versus lower). Qualitative data collected from 75 older walkers and 19 neighbourhood key informants, as well as quantitative indicators were compared on the two axes of urban form and SES among the four neighbourhoods.</p> <p>Results and discussion</p> <p>Examining the inter-relationship of neighbourhood SES and urban form characteristics on older people's walking experiences indicated that urban form differences were accentuated positively in higher SES neighbourhoods and negatively in lower SES neighbourhoods. Older people in lower SES neighbourhoods were more affected by traffic hazards and more reliant on public transit compared to their higher SES counterparts. In higher SES neighbourhoods the disadvantages of traffic in the inner-urban neighbourhood and lack of commercial destinations in the suburban neighbourhood were partially offset by other factors including neighbourhood aesthetics. Key informant descriptions of the socio-political process highlighted how lower SES neighbourhoods may face greater challenges in creating walkable places. These differences pertained to the size of neighbourhood associations, relationships with political representatives, accessing information and salient neighbourhood association issues. Findings provide evidence of inequitable walking environments.</p> <p>Conclusion</p> <p>Future research on walking must consider urban form-SES inter-relationships and further examine the equitable distribution of walking conditions as well as the socio-political processes driving these conditions. There is a need for municipal governments to monitor differences in walking conditions among higher and lower SES neighbourhoods, to be receptive to the needs of lower SES neighbourhood and to ensure that policy decisions are taken to address inequitable walking conditions.</p

IL-1β Processing in Host Defense: Beyond the Inflammasomes

Stimulation and release of proinflammatory cytokines is an essential step for the activation of an effective innate host defense, and subsequently for the modulation of adaptive immune responses. Interleukin-1β (IL-1β) and IL-18 are important proinflammatory cytokines that on the one hand activate monocytes, macropages, and neutrophils, and on the other hand induce Th1 and Th17 adaptive cellular responses. They are secreted as inactive precursors, and the processing of pro-IL-1β and pro-IL-18 depends on cleavage by proteases. One of the most important of these enzymes is caspase-1, which in turn is activated by several protein platforms called the inflammasomes. Inflammasome activation differs in various cell types, and knock-out mice defective in either caspase-1 or inflammasome components have an increased susceptibility to several types of infections. However, in other infections and in models of sterile inflammation, caspase-1 seems to be less important, and alternative mechanisms such as neutrophil-derived serine proteases or proteases released from microbial pathogens can process and activate IL-1β. In conclusion, IL-1β/IL-18 processing during infection is a complex process in which the inflammasomes are only one of several activation mechanisms

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Psychopharmacological treatment of trichotillomania in an adolescent case: Significant improvement with aripiprazole augmentation [Bir ergen olguda trikotilomaninin psikofarmakolojik tedavisi: Aripiprazol augmentasyonu ile belirgin iyileşme]

Trichotillomania (TTM) is a chronic impulse control disorder characterized by pulling out one’s own hair, resulting in noticeable hair loss. The emergence of TTM is generally in adolescence. A number of pharmacological agents and psychotherapy (especially cognitive-behavioral therapy) have been used in the treatment of TTM but in the literature, no consensus has yet been established. Here, we report the case of a 15-year-old adolescent with trichotillomania who responded to aripiprazole treatment. © 2014, Cukurova Univ Tip Fakultesi Psikiyatri Anabilim Dali. All rights reserved