Changes in the gene expression profiles of the brains of male European eels (Anguilla anguilla) during sexual maturation

Background: The vertebrate brain plays a critical role in the regulation of sexual maturation and reproduction by integrating environmental information with developmental and endocrine status. The European eel Anguilla anguilla is an important species in which to better understand the neuroendocrine factors that control reproduction because it is an endangered species, has a complex life cycle that includes two extreme long distance migrations with both freshwater and seawater stages and because it occupies a key position within the teleost phylogeny. At present, mature eels have never been caught in the wild and little is known about most aspects of reproduction in A. anguilla. The goal of this study was to identify genes that may be involved in sexual maturation in experimentally matured eels. For this, we used microarrays to compare the gene expression profiles of sexually mature to immature males. Results: Using a false discovery rate of 0.05, a total of 1,497 differentially expressed genes were identified. Of this set, 991 were expressed at higher levels in brains (forebrain and midbrain) of mature males while 506 were expressed at lower levels relative to brains of immature males. The set of up-regulated genes includes genes involved in neuroendocrine processes, cell-cell signaling, neurogenesis and development. Interestingly, while genes involved in immune system function were down-regulated in the brains of mature males, changes in the expression levels of several receptors and channels were observed suggesting that some rewiring is occurring in the brain at sexual maturity. Conclusions: This study shows that the brains of eels undergo major changes at the molecular level at sexual maturity that may include re-organization at the cellular level. Here, we have defined a set of genes that help to understand the molecular mechanisms controlling reproduction in eels. Some of these genes have previously described functions while many others have roles that have yet to be characterized in a reproductive context. Since most of the genes examined here have orthologs in other vertebrates, the results of this study will contribute to the body of knowledge concerning reproduction in vertebrates as well as to an improved understanding of eel biology.Peer Reviewe

Delayed crystallization of ultrathin Gd2O3 layers on Si(111) observed by in situ X-ray diffraction

We studied the early stages of Gd2O3 epitaxy on Si(111) in real time by synchrotron-based, high-resolution X-ray diffraction and by reflection high-energy electron diffraction. A comparison between model calculations and the measured X-ray scattering, and the change of reflection high-energy electron diffraction patterns both indicate that the growth begins without forming a three-dimensional crystalline film. The cubic bixbyite structure of Gd2O3 appears only after a few monolayers of deposition

A randomised controlled trial to determine the effect on response of including a lottery incentive in health surveys [ISRCTN32203485]

BACKGROUND: Postal questionnaires are an economical and simple method of data collection for research purposes but are subject to non-response bias. Several studies have explored the effect of monetary and non-monetary incentives on response. Recent meta-analyses conclude that financial incentives are an effective way of increasing response rates. However, large surveys rarely have the resources to reward individual participants. Three previous papers report on the effectiveness of lottery incentives with contradictory results. This study aimed to determine the effect of including a lottery-style incentive on response rates to a postal health survey. METHODS: Randomised controlled trial. Setting: North and West Birmingham. 8,645 patients aged 18 or over randomly selected from registers of eight general practices (family physician practices). Intervention: Inclusion of a flyer and letter with a health questionnaire informing patients that returned questionnaires would be entered into a lottery-style draw for £100 of gift vouchers. Control: Health questionnaire accompanied only by standard letter of explanation. Main outcome measures: Response rate and completion rate to questionnaire. RESULTS: 5,209 individuals responded with identical rates in both groups (62.1%). Practice, patient age, sex and Townsend score (a postcode based deprivation measure) were identified as predictive of response, with higher response related to older age, being female and living in an area with a lower Townsend score (less deprived). CONCLUSION: This RCT, using a large community based sample, found that the offer of entry into a lottery style draw for £100 of High Street vouchers has no effect on response rates to a postal health questionnaire

Discrepancy between prevalence and perceived effectiveness of treatment methods in myofascial pain syndrome: Results of a cross-sectional, nationwide survey

Background: Myofascial pain is a common dysfunction with a lifetime prevalence affecting up to 85% of the general population. Current guidelines for the management of myofascial pain are not available. In this study we investigated how physicians on the basis of prescription behaviour evaluate the effectiveness of treatment options in their management of myofascial pain. Methods: We conducted a cross-sectional, nationwide survey with a standardized questionnaire among 332 physicians (79.8% male, 25.6% female, 47.5 +/- 9.6 years) experienced in treating patients with myofascial pain. Recruitment of physicians took place at three German meetings of pain therapists, rheumatologists and orthopaedists, respectively. Physicians estimated the prevalence of myofascial pain amongst patients in their practices, stated what treatments they used routinely and then rated the perceived treatment effectiveness on a six-point scale (with 1 being excellent). Data are expressed as mean +/- standard deviation. Results: The estimated overall prevalence of active myofascial trigger points is 46.1 +/- 27.4%. Frequently prescribed treatments are analgesics, mainly metamizol/paracetamol (91.6%), non-steroidal anti-inflammatory drugs/coxibs (87.0%) or weak opioids (81.8%), and physical therapies, mainly manual therapy (81.1%), TENS (72.9%) or acupuncture (60.2%). Overall effectiveness ratings for analgesics (2.9 +/- 0.7) and physical therapies were moderate (2.5 +/- 0.8). Effectiveness ratings of the various treatment options between specialities were widely variant. 54.3% of all physicians characterized the available treatment options as insufficient. Conclusions: Myofascial pain was estimated a prevalent condition. Despite a variety of commonly prescribed treatments, the moderate effectiveness ratings and the frequent characterizations of the available treatments as insufficient suggest an urgent need for clinical research to establish evidence-based guidelines for the treatment of myofascial pain syndrome

Crystal Structures of the FAK Kinase in Complex with TAE226 and Related Bis-Anilino Pyrimidine Inhibitors Reveal a Helical DFG Conformation

Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase required for cell migration, proliferation and survival. FAK overexpression has been documented in diverse human cancers and is associated with a poor clinical outcome. Recently, a novel bis-anilino pyrimidine inhibitor, TAE226, was reported to efficiently inhibit FAK signaling, arrest tumor growth and invasion and prolong the life of mice with glioma or ovarian tumor implants. Here we describe the crystal structures of the FAK kinase bound to TAE226 and three related bis-anilino pyrimidine compounds. TAE226 induces a conformation of the N-terminal portion of the kinase activation loop that is only observed in FAK, but is distinct from the conformation in both the active and inactive states of the kinase. This conformation appears to require a glycine immediately N-terminal to the “DFG motif”, which adopts a helical conformation stabilized by interactions with TAE226. The presence of a glycine residue in this position contributes to the specificity of TAE226 and related compounds for FAK. Our work highlights the fact that kinases can access conformational space that is not necessarily utilized for their native catalytic regulation, and that such conformations can explain and be exploited for inhibitor specificity

Systemic Inhibition of NF-κB Activation Protects from Silicosis

Background: Silicosis is a complex lung disease for which no successful treatment is available and therefore lung transplantation is a potential alternative. Tumor necrosis factor alpha (TNFα) plays a central role in the pathogenesis of silicosis. TNFα signaling is mediated by the transcription factor, Nuclear Factor (NF)-κB, which regulates genes controlling several physiological processes including the innate immune responses, cell death, and inflammation. Therefore, inhibition of NF-κB activation represents a potential therapeutic strategy for silicosis. Methods/Findings: In the present work we evaluated the lung transplant database (May 1986-July 2007) at the University of Pittsburgh to study the efficacy of lung transplantation in patients with silicosis (n = 11). We contrasted the overall survival and rate of graft rejection in these patients to that of patients with idiopathic pulmonary fibrosis (IPF, n = 79) that was selected as a control group because survival benefit of lung transplantation has been identified for these patients. At the time of lung transplantation, we found the lungs of silica-exposed subjects to contain multiple foci of inflammatory cells and silicotic nodules with proximal TNFα expressing macrophage and NF-κB activation in epithelial cells. Patients with silicosis had poor survival (median survival 2.4 yr; confidence interval (CI): 0.16-7.88 yr) compared to IPF patients (5.3 yr; CI: 2.8-15 yr; p = 0.07), and experienced early rejection of their lung grafts (0.9 yr; CI: 0.22-0.9 yr) following lung transplantation (2.4 yr; CI:1.5-3.6 yr; p<0.05). Using a mouse experimental model in which the endotracheal instillation of silica reproduces the silica-induced lung injury observed in humans we found that systemic inhibition of NF-κB activation with a pharmacologic inhibitor (BAY 11-7085) of IκBα phosphorylation decreased silica-induced inflammation and collagen deposition. In contrast, transgenic mice expressing a dominant negative IκBα mutant protein under the control of epithelial cell specific promoters demonstrate enhanced apoptosis and collagen deposition in their lungs in response to silica. Conclusions: Although limited by its size, our data support that patients with silicosis appear to have poor outcome following lung transplantation. Experimental data indicate that while the systemic inhibition of NF-κB protects from silica-induced lung injury, epithelial cell specific NF-κB inhibition appears to aggravate the outcome of experimental silicosis. © 2009 Di Giuseppe et al

Male urine signals social rank in the Mozambique tilapia (Oreochromis mossambicus)

<p>Abstract</p> <p>Background</p> <p>The urine of freshwater fish species investigated so far acts as a vehicle for reproductive pheromones affecting the behaviour and physiology of the opposite sex. However, the role of urinary pheromones in intra-sexual competition has received less attention. This is particularly relevant in lek-breeding species, such as the Mozambique tilapia (<it>Oreochromis mossambicus</it>), where males establish dominance hierarchies and there is the possibility for chemical communication in the modulation of aggression among males. To investigate whether males use urine during aggressive interactions, we measured urination frequency of dye-injected males during paired interactions between size-matched males. Furthermore, we assessed urinary volume stored in the bladder of males in a stable social hierarchy and the olfactory potency of their urine by recording of the electro-olfactogram.</p> <p>Results</p> <p>Males released urine in pulses of short duration (about one second) and markedly increased urination frequency during aggressive behaviour, but did not release urine whilst submissive. In the stable hierarchy, subordinate males stored less urine than males of higher social rank; the olfactory potency of the urine was positively correlated with the rank of the male donor.</p> <p>Conclusion</p> <p>Dominant males store urine and use it as a vehicle for odorants actively released during aggressive disputes. The olfactory potency of the urine is positively correlated with the social status of the male. We suggest that males actively advertise their dominant status through urinary odorants which may act as a 'dominance' pheromone to modulate aggression in rivals, thereby contributing to social stability within the lek.</p

Ceacam1 separates graft-versus-host-disease from graft-versus-tumor activity after experimental allogeneic bone marrow transplantation.

BACKGROUND: Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models. METHODS: We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In vivo, Ceacam1(-/-) T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi), CD62L(lo)). Additionally, Ceacam1(-/-) CD8 T cells had greater expression of the gut-trafficking integrin α(4)β(7), though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/-) recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/-) mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+) lymphoma model was improved in animals receiving Ceacam1(-/-) vs. control T cells. CONCLUSIONS: We conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the donor graft and host tissues, this suggests that targeting Ceacam1 may represent a potent strategy for the regulation of GVHD and GVT after allogeneic transplantation

Community-based knowledge transfer and exchange: Helping community-based organizations link research to action

<p>Abstract</p> <p>Background</p> <p>Community-based organizations (CBOs) are important stakeholders in health systems and are increasingly called upon to use research evidence to inform their advocacy, program planning, and service delivery efforts. CBOs increasingly turn to community-based research (CBR) given its participatory focus and emphasis on linking research to action. In order to further facilitate the use of research evidence by CBOs, we have developed a strategy for community-based knowledge transfer and exchange (KTE) that helps CBOs more effectively link research evidence to action. We developed the strategy by: outlining the primary characteristics of CBOs and why they are important stakeholders in health systems; describing the concepts and methods for CBR and for KTE; comparing the efforts of CBR to link research evidence to action to those discussed in the KTE literature; and using the comparison to develop a framework for community-based KTE that builds on both the strengths of CBR and existing KTE frameworks.</p> <p>Discussion</p> <p>We find that CBR is particularly effective at fostering a climate for using research evidence and producing research evidence relevant to CBOs through community participation. However, CBOs are not always as engaged in activities to link research evidence to action on a larger scale or to evaluate these efforts. Therefore, our strategy for community-based KTE focuses on: an expanded model of 'linkage and exchange' (<it>i.e</it>., producers and users of researchers engaging in a process of asking and answering questions together); a greater emphasis on both producing and disseminating systematic reviews that address topics of interest to CBOs; developing a large-scale evidence service consisting of both 'push' efforts and efforts to facilitate 'pull' that highlight actionable messages from community relevant systematic reviews in a user-friendly way; and rigorous evaluations of efforts for linking research evidence to action.</p> <p>Summary</p> <p>Through this type of strategy, use of research evidence for CBO advocacy, program planning, and service delivery efforts can be better facilitated and continually refined through ongoing evaluations of its impact.</p