291 research outputs found

    Tissue- specific angiogenic and invasive properties of human neonatal thymus and bone MSCs: Role of SLIT3- ROBO1

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    Although mesenchymal stem/stromal cells (MSCs) are being explored in numerous clinical trials as proangiogenic and proregenerative agents, the influence of tissue origin on the therapeutic qualities of these cells is poorly understood. Complicating the functional comparison of different types of MSCs are the confounding effects of donor age, genetic background, and health status of the donor. Leveraging a clinical setting where MSCs can be simultaneously isolated from discarded but healthy bone and thymus tissues from the same neonatal patients, thereby controlling for these confounding factors, we performed an in vitro and in vivo paired comparison of these cells. We found that both neonatal thymus (nt)MSCs and neonatal bone (nb)MSCs expressed different pericytic surface marker profiles. Further, ntMSCs were more potent in promoting angiogenesis in vitro and in vivo and they were also more motile and efficient at invading ECM in vitro. These functional differences were in part mediated by an increased ntMSC expression of SLIT3, a factor known to activate endothelial cells. Further, we discovered that SLIT3 stimulated MSC motility and fibrin gel invasion via ROBO1 in an autocrine fashion. Consistent with our findings in human MSCs, we found that SLIT3 and ROBO1 were expressed in the perivascular cells of the neonatal murine thymus gland and that global SLIT3 or ROBO1 deficiency resulted in decreased neonatal murine thymus gland vascular density. In conclusion, ntMSCs possess increased proangiogenic and invasive behaviors, which are in part mediated by the paracrine and autocrine effects of SLIT3.Comparison of mesenchymal stem/stromal cells (MSCs) from the human neonatal thymus and bone revealed that the axon guidance molecule SLIT3 is important for MSC proangiogenic effects. Not only is SLIT3 an endothelial cell stimulatory factor, but it also promotes MSC migration and invasion in an autocrine fashion via the ROBO1 receptor. Deficiency of either SLIT3 or ROBO1 can decrease the vascularization of the neonatal thymus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156475/2/sct312723_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156475/1/sct312723.pd

    GnRH-1 Neural Migration From the Nose to the Brain Is Independent From Slit2, Robo3 and NELL2 Signaling

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    Gonadotropin releasing hormone-1 (GnRH-1) neurons play a pivotal role in controlling pubertal onset and fertility once they reach their hypothalamic location. During embryonic development, GnRH-1 neurons migrate from the nasal area to the hypothalamus where they modulate gonadotropin release from the pituitary gland. Defective migration of the GnRH-1 neurons to the brain, lack of GnRH-1 secretion or signaling cause hypogonadotropic hypogonadism (HH), a pathology characterized by delayed or absence of puberty. Binding of the guidance cue Slit2 to the receptor roundabout 3 (Robo3) has been proposed to modulate GnRH-1 cell motility and basal forebrain (bFB) access during migration. However, evidence suggests that Neural EGFL Like 2 (NELL2), not Slit2, binds to Robo3. To resolve this discrepancy, we analyzed GnRH-1 neuronal migration in NELL2, Robo3, and Slit2 knock-out mouse lines. Our data do not confirm a negative effect for monogenic Robo3 and Slit2 mutations on GnRH-1 neuronal migration from the nasal area to the brain. Moreover, we found no changes in GnRH-1 neuronal migration in the brain after NELL2 loss-of-function. However, we found that Slit2 loss-of-function alters the patterning of GnRH-1 cells in the brain, suggesting that Slit2 loss-of-function affects GnRH-1 cell positioning in the brain in a Robo3 independent fashion. Our results challenge previous theories on GnRH-1 neuronal migration mechanisms and provide a new impetus to identify and understand the complex genetic mechanisms causing disorders like Kallmann syndrome (KS) and HH

    Net versus combinatory effects of firm and industry antecedents of sales growth

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    This study examines antecedents of sales growth using a two-step mixed-method approach including analyses of net effects and combinatory effects. Based on a sample of 453 respondents from manufacturing and service firms, this article shows how the combination of structural equation modeling (SEM) and fuzzy set Qualitative Comparative Analysis (fsQCA) provides more detailed insights into the causal patterns of factors to explain sales growth. This article contributes to the extant literature by highlighting fsQCA as a useful method to analyze complex causality (specifically combinatory effects of antecedent conditions) and by discussing options regarding how this approach can be used to complement findings from conventional causal data analysis procedures that analyze net effects

    Familial Occurrence of Multiple Sclerosis with Thyroid Disease and Systemic Lupus Erythematosus

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    Multiple sclerosis (MS) has some features which suggest it is an autoimmune disease. Autoimmune diseases frequently occur in families, and patients and families often have more than one type of autoimmune disease. However, there are few reports of MS occurring in patients or families with other autoimmune conditions. It is difficult to make a separate diagnosis of MS in a patient who has a systemic autoimmune disease such as systemic lupus erythematosus (SLE) or Sjogren's syndrome, because these diseases can affect the nervous system directly. However, it is possible to make independent diagnoses of MS and an autoimmune disease confined to another single organ in the same patient, or diagnoses of MS and SLE (or other autoimmune diseases) in different family members. Here we describe clinically definite MS in 2 sisters, one of whom had Graves' disease, and the other of whom had a daughter with SLE and with a high titre of anti-thyroid antibodies. Other female family members over 4 generations had histories of thyroid disease, MS and Addison's disease. Available family members were HLA typed. The MS patients were positive for HLA DR2. All but one of the affected family members were related to the proband on the maternal side, and all of these affected females shared an HLA haplotype. However, this haplotype was also present in unaffected individuals. Thus HLA type alone cannot account for the familial occurrence of these disorders. We conclude that, in this family, MS, like autoimmune thyroid disease and SLE, may be an autoimmune disease developing in genetically predisposed individuals

    Multiple Guidance Mechanisms Control Axon Growth to Generate Precise T-Shaped Bifurcation During Dorsal Funiculus Development in the Spinal Cord

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    The dorsal funiculus in the spinal cord relays somatosensory information to the brain. It is made of T-shaped bifurcation of dorsal root ganglion (DRG) sensory axons. Our previous study has shown that Slit signaling is required for proper guidance during bifurcation, but loss of Slit does not affect all DRG axons. Here, we examined the role of the extracellular molecule Netrin-1 (Ntn1). Using wholemount staining with tissue clearing, we showed that mice lacking Ntn1 had axons escaping from the dorsal funiculus at the time of bifurcation. Genetic labeling confirmed that these misprojecting axons come from DRG neurons. Single axon analysis showed that loss of Ntn1 did not affect bifurcation but rather altered turning angles. To distinguish their guidance functions, we examined mice with triple deletion of Ntn1, Slit1, and Slit2 and found a completely disorganized dorsal funiculus. Comparing mice with different genotypes using immunolabeling and single axon tracing revealed additive guidance errors, demonstrating the independent roles of Ntn1 and Slit. Moreover, the same defects were observed in embryos lacking their cognate receptors. These in vivo studies thus demonstrate the presence of multi-factorial guidance mechanisms that ensure proper formation of a common branched axonal structure during spinal cord development

    Hydrogen and Corrosion Resistance of Nickel Superalloys for Gas Turbines, Engines Cooled Blades

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    The paper presents the results of the analysis of the resistance to hydrogen and high-temperature salt corrosion of the developed alloy of the CM88Y type for the turbine blades of gas turbine engines for marine and power purposes in comparison with the industrial heat-resistant corrosion-resistant alloy CM88Y and the alloy for the protective coating of the SDP3-A blades. SDP3-A alloy was chosen as a reference sample, which has high hydrogen and corrosion resistance. The new heat-resistant alloy additionally contains such refractory metals as rhenium and tantalum, which are added to the composition of the alloy in order to increase operational characteristics while maintaining phase-structural stability. These are properties such as long-term and fatigue strength, characteristics of plasticity and strength at room and elevated temperatures. Therefore, the purpose of these studies was to determine the resistance to high-temperature salt corrosion of the developed alloy in comparison with the industrial heat-resistant nickel alloy and to evaluate the influence of alloying, hydrogen embrittlement of CM88Y and ZhS3DK alloys with different contents of chromium, boron, zirconium, hafnium, and yttrium were compared. The corrosion resistance of the materials was evaluated after crucible tests in a salt solution at a temperature of 900 °C for 30 h, according to the standard method. The corrosion resistances of alloys were determined by the mass loss, corrosion rate, and data from metallographic studies

    The Legacy of Leaded Gasoline in Bottom Sediment of Small Rural Reservoirs

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    The historical and ongoing lead (Pb) contamination caused by the 20th-century use of leaded gasoline was investigated by an analysis of bottom sediment in eight small rural reservoirs in eastern Kansas, USA. For the reservoirs that were completed before or during the period of maximum Pb emissions from vehicles (i.e., the 1940s through the early 1980s) and that had a major highway in the basin, increased Pb concentrations reflected the pattern of historical leaded gasoline use. For at least some of these reservoirs, residual Pb is still being delivered from the basins. There was no evidence of increased Pb deposition for the reservoirs completed after the period of peak Pb emissions and (or) located in relatively remote areas with little or no highway traffic. Results indicated that several factors affected the magnitude and variability of Pb concentrations in reservoir sediment including traffic volume, reservoir age, and basin size. The increased Pb concentrations at four reservoirs exceeded the U.S. Environmental Protection Agency threshold-effects level (30.2 mg kg-1) and frequently exceeded a consensus-based threshold-effects concentration (35.8 mg kg-1) for possible adverse biological effects. For two reservoirs it was estimated that it will take at least 20 to 70 yr for Pb in the newly deposited sediment to return to baseline (pre-1920s) concentrations (30 mg kg-1) following the phase out of leaded gasoline. The buried sediment with elevated Pb concentrations may pose a future environmental concern if the reservoirs are dredged, the dams are removed, or the dams fail
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