TLR4 stimulation by LPS enhances angiogenesis in a co-culture system consisting of primary human osteoblasts and outgrowth endothelial cells

The development of new approaches leading to fast and successful vascularization of tissue-engineered constructs is one of the most intensively studied subjects in tissue engineering and regenerative medicine. Recently, TLR4 activation and LPS stimulation of endothelial cells have been reported to promote angiogenesis in a variety of settings. In this study, we demonstrate that TLR4 activation by Ultrapure LPS Escherichia coli 0111:B4 (LPS-EB) significantly enhances microvessel formation in a co-culture system consisting of outgrowth endothelial cells (OECs) and primary human osteoblasts (pOBs). The precise modes of TLR4 action on the process of angiogenesis have also been investigated in this study. Using quantitative fluorescence microscopy in monocultures of OECs and pOBs, it was found that TLR4 activation through LPS-EB upregulates the expression level of TLR4/MYD88 and enhances both angiogenesis and osteogenesis. Furthermore, ELISA and qRT-PCR have shown that the level of two adhesion molecules (ICAM-1 and E-selectin), two cytokines (IL-6 and IL-8) and two growth factors (VEGF and PDGF-BB) related to angiogenesis increase significantly after LPS-EB treatment. This increased understanding of the role of TLR4 in angiogenesis could be of value in various settings related to tissue repair and tissue engineering. Moreover, since LPS and TLR4 agonists improve angiogenesis and osteogenesis, TLR4 agonists (endogenous or synthetic) could be used for angiogenesis intervention in vivo and therefore could be tested for their potential clinical applications in promoting angiogenesis in bone tissue engineering

Crowdsourcing novel childhood predictors of adult obesity

Effective and simple screening tools are needed to detect behaviors that are established early in life and have a significant influence on weight gain later in life. Crowdsourcing could be a novel and potentially useful tool to assess childhood predictors of adult obesity. This exploratory study examined whether crowdsourcing could generate well-documented predictors in obesity research and, moreover, whether new directions for future research could be uncovered. Participants were recruited through social media to a question-generation website, on which they answered questions and were able to pose new questions that they thought could predict obesity. During the two weeks of data collection, 532 participants (62% female; age = 26.5±6.7; BMI = 29.0±7.0) registered on the website and suggested a total of 56 unique questions. Nineteen of these questions correlated with body mass index (BMI) and covered several themes identified by prior research, such as parenting styles and healthy lifestyle. More importantly, participants were able to identify potential determinants that were related to a lower BMI, but have not been the subject of extensive research, such as parents packing their children\u27s lunch to school or talking to them about nutrition. The findings indicate that crowdsourcing can reproduce already existing hypotheses and also generate ideas that are less well documented. The crowdsourced predictors discovered in this study emphasize the importance of family interventions to fight obesity. The questions generated by participants also suggest new ways to express known predictors. © 2014 Bevelander et al

Meiotic arrest occurs most frequently at metaphase and is often incomplete in azoospermic men

Objective: To establish which meiotic checkpoints are activated in males with severe spermatogenic impairment to improve phenotypic characterization of meiotic defects. Design: Retrospective observational study. Setting: University medical center research laboratory and andrology clinic. Patient(s): Forty-eight patients with confirmed spermatogenic impairment (Johnsen scores 3–6) and 15 controls (Johnsen score 10). Intervention(s): None. Main Outcome Measure(s): Quantitative assessment of immunofluorescent analyses of specific markers to determine meiotic entry, chromosome pairing, progression of DNA double-strand break repair, crossover formation, formation of meiotic metaphases, metaphase arrest, and spermatid formation, resulting in a novel classification of human meiotic arrest types. Result(s): Complete metaphase arrest was observed most frequently (27%), and the patients with the highest frequency of apoptotic metaphases also displayed a reduction in crossover number. Incomplete metaphase arrest was observed in 17% of the patients. Only four patients (8%) displayed a failure to complete meiotic chromosome pairin

Unilateral aplasia of both cruciate ligaments

Aplasia of both cruciate ligaments is a rare congenital disorder. A 28-year-old male presented with pain and the feeling of instability of his right knee after trauma. The provided MRI and previous arthroscopy reports did not indicate any abnormalities except cruciate ligament tears. He was referred to us for reconstruction of both cruciate ligaments. The patient again underwent arthroscopy which revealed a hypoplasia of the medial trochlea and an extremely narrow intercondylar notch. The tibia revealed a missing anterior cruciate ligament (ACL) footprint and a single bump with a complete coverage with articular cartilage. There was no room for an ACL graft. A posterior cruciate ligament could not be identified. The procedure was ended since a ligament reconstruction did not appear reasonable. A significant notch plasty if not a partial resection of the condyles would have been necessary to implant a ligament graft. It is most likely that this would not lead to good knee stability. If the surgeon would have retrieved the contralateral hamstrings at the beginning of the planned ligament reconstruction a significant damage would have occurred to the patient. Even in seemingly clear diagnostic findings the arthroscopic surgeon should take this rare abdnormality into consideration and be familiar with the respective radiological findings. We refer the abnormal finding of only one tibial spine to as the "dromedar-sign" as opposed to the two (medial and a lateral) tibial spines in a normal knee. This may be used as a hint for aplasia of the cruciate ligaments

Nonsteroidal sulfamate derivatives as new therapeutic approaches for Neurofibromatosis 2 (NF2)

Abstract Background Neurofibromatosis 1 and 2, although involving two different tumour suppressor genes (neurofibromin and merlin, respectively), are both cancer predisposition syndromes that disproportionately affect cells of neural crest origin. New therapeutic approaches for both NF1 and NF2 are badly needed. In promising previous work we demonstrated that two non-steroidal analogues of 2-methoxy-oestradiol (2ME2), STX3451(2-(3-bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline), and STX2895 (7-Ethyl-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline) reduced tumour cell growth and induced apoptosis in malignant and benign human Neurofibromatosis 1 (NF1) tumour cells. In earlier NF1 mechanism of action studies we found that in addition to their effects on non-classical hormone-sensitive pathways, STX agents acted on the actin- and myosin-cytoskeleton, as well as PI3Kinase and MTOR signaling pathways. Tumour growth in NF2 cells is affected by different inhibitors from those affecting NF1 growth pathways: specifically, NF2 cells are affected by merlin-downstream pathway inhibitors. Because Merlin, the affected tumour suppressor gene in NF2, is also known to be involved in stabilizing membrane-cytoskeletal complexes, as well as in cell proliferation, and apoptosis, we looked for potentially common mechanisms of action in the agents’ effects on NF1 and NF2. We set out to determine whether STX agents could therefore also provide a prospective avenue for treatment of NF2. Methods STX3451 and STX2895 were tested in dose-dependent studies for their effects on growth parameters of malignant and benign NF2 human tumour cell lines in vitro. The mechanisms of action of STX3451 and STX2895 were also analysed. Results Although neither of the agents tested affected cell growth or apoptosis in the NF2 tumour cell lines tested through the same mechanisms by which they affect these parameters in NF1 tumour cell lines, both agents disrupted actin- and myosin-based cytoskeletal structures in NF2 cell lines, with subsequent effects on growth and cell death. Conclusions Both STX3451 and STX2895 provide new approaches for inducing cell death and lowering tumour burden in NF2 as well as in NF1, which both have limited treatment options.https://deepblue.lib.umich.edu/bitstream/2027.42/152170/1/40360_2019_Article_369.pd

Age profiles of sport participants.

Background: Participation in sport has many health benefits, and is popular amongst children. However participation decreases with age. While the membership records of peak sports organisations have improved markedly in recent years, there has been little research into sport participation trends across the lifespan. This study investigates age profiles of participation in sport and compares these trends between genders and residential locations. Methods: De-identified 2011 participant registration data for seven popular Australian sports (Australian Football, Basketball, Cricket, Hockey, Lawn Bowls, Netball and Tennis) were obtained and analysed according to age, gender and geographical location (metropolitan v non-metropolitan) within the state of Victoria, Australia. All data were integrated and sports were analysed collectively to produce broadly based participation profiles while maintaining confidentiality of membership data for individual sports. Results: The total number of registered participants included in the data set for 2011 was 520,102. Most participants (64.1 %) were aged less than 20 years. Nearly one third (27.6 %) of all participants were aged 10–14 years, followed by the 5–9 year age group (19.9 %). Participation declined rapidly during adolescence. A higher proportion of males than female participants were young children (4–7 years) or young adults 18–29 years; this pattern was reversed among 8–17 year-olds. A higher proportion of metropolitan participants were engaged between the ages of 4–13 and 19–29, whereas a higher proportion of non-metropolitan participants played during adolescence (14–18 years) and throughout mature adulthood (30+ years). Conclusions: Increasing participation in sport is an objective for both government and sporting organisations. In order to have both mass population-based participation, from a health policy and elite performance perspective, we need to further explore the findings arising from the analysis of this extensive data set. Such an examination will lead to better understand of the reasons for attrition during adolescence to inform program and policy developments to retain people participating in sport, for a healthy and sport performing nation

Crowdsourcing hypothesis tests: making transparent how design choices shape research results

To what extent are research results influenced by subjective decisions that scientists make as they design studies? Fifteen research teams independently designed studies to answer five original research questions related to moral judgments, negotiations, and implicit cognition. Participants from 2 separate large samples (total N > 15,000) were then randomly assigned to complete 1 version of each study. Effect sizes varied dramatically across different sets of materials designed to test the same hypothesis: Materials from different teams rendered statistically significant effects in opposite directions for 4 of 5 hypotheses, with the narrowest range in estimates being d = -0.37 to + 0.26. Meta-analysis and a Bayesian perspective on the results revealed overall support for 2 hypotheses and a lack of support for 3 hypotheses. Overall, practically none of the variability in effect sizes was attributable to the skill of the research team in designing materials, whereas considerable variability was attributable to the hypothesis being tested. In a forecasting survey, predictions of other scientists were significantly correlated with study results, both across and within hypotheses. Crowdsourced testing of research hypotheses helps reveal the true consistency of empirical support for a scientific claim.info:eu-repo/semantics/submittedVersio

Association of the MTHFR A1298C Variant with Unexplained Severe Male Infertility

The methylenetetrahydrofolate reductase (MTHFR) gene is one of the main regulatory enzymes involved in folate metabolism, DNA synthesis and remethylation reactions. The influence of MTHFR variants on male infertility is not completely understood. The objective of this study was to analyze the distribution of the MTHFR C677T and A1298C variants using PCR-Restriction Fragment Length Polymorphism (RFLP) in a case group consisting of 344 men with unexplained reduced sperm counts compared to 617 ancestry-matched fertile or normozoospermic controls. The Chi square test was used to analyze the genotype distributions of MTHFR polymorphisms. Our data indicated a lack of association of the C677T variant with infertility. However, the homozygous (C/C) A1298C polymorphism of the MTHFR gene was present at a statistically high significance in severe oligozoospermia group compared with controls (OR = 3.372, 95% confidence interval CI = 1.27–8.238; p = 0.01431). The genotype distribution of the A1298C variants showed significant deviation from the expected Hardy-Weinberg equilibrium, suggesting that purifying selection may be acting on the 1298CC genotype. Further studies are necessary to determine the influence of the environment, especially the consumption of diet folate on sperm counts of men with different MTHFR variants