Light is necessary for asexual sporulation in Aspergillus nidulans but will elicit conidiation only if irradiation occurs during a critical period of development. We show that conidiation is induced by red light and suppressed by an immediate shift to far red light. Conidiation-specific gene functions switch from light-independent to light-dependent activities coincident with the expression of brlA, a regulator of conidiophore development. We also show that light dependence is abolished by a mutation in the velvet gene, which allows conidiation to occur in the absence of light. We propose that the initiation of late gene expression is regulated by velvet and controlled by a red light photoreceptor, whose properties are reminiscent of phytochrome-mediated responses observed in higher plants.
Neuromedins are a family of peptides best known for their contractile activity on smooth muscle preparations. The biological mechanism of action of neuromedin U remains unknown, despite the fact that the peptide was first isolated in 1985. Here we show that neuromedin U potently activates the orphan G proteincoupled receptor FM3, with subnanomolar potency, when FM3 is transiently expressed in human HEK-293 cells. Neuromedins B, C, K, and N are all inactive at this receptor. Quantitative reverse transcriptase-polymerase chain reaction analysis of neuromedin U expression in a range of human tissues showed that the peptide is highly expressed in the intestine, pituitary, and bone marrow, with lower levels of expression seen in stomach, adipose tissue, lymphocytes, spleen, and the cortex. Similar analysis of FM3 expression showed that the receptor is widely expressed in human tissue with highest levels seen in adipose tissue, intestine, spleen, and lymphocytes, suggesting that neuromedin U may have a wide range of presently undetermined physiological effects. The discovery that neuromedin U is an endogenous agonist for FM3 will significantly aid the study of the full physiological role of this peptide. G protein-coupled receptors (GPCRs)1 represent one of the largest gene superfamilies identified to date, with more than 1000 members cloned from a wide range of species. The current explosion in the availability of human genomic sequence data is allowing many more members of this family to be identified in man. Most if not all of these newly identified GPCRs fall into the category of orphan receptors, for which the endogenous ligand(s) remain to be identified. Typically these orphan receptors show only low levels of similarity (less than 35% identity) with known GPCRs, too low to classify them with any confidence into a specific receptor subfamily, although one can often predict the likely class of ligand for these receptors, e.g. peptide, nucleotide, lipid, etc., by using phylogenetic analysis.Recently, naturally occurring ligands have been identified for a number of these orphan GPCRs using a "reverse-pharmacological" approach (1), that is using the recombinant orphan receptor as a specific sensor component of a bioassay. Tissue extracts have often been the source of these natural ligands (2, 3), although more recently the ligands for several orphans have been identified as a result of screening large libraries of known or putative GPCR ligands (4 -6). Here, we describe how this latter approach has been used to identify neuromedin U (NmU) as a naturally occurring ligand for the orphan receptor FM3.Neuromedin U was first isolated over 15 years ago from extracts of porcine spinal cord, using a uterine smooth muscle contraction bioassay to monitor purification (7). Two molecular forms were isolated; neuromedin U-8 (NmU-8) and neuromedin U-25 (NmU-25). NmU-like immunoreactivity has since been detected in neurones in the mammalian brain and gastrointestinal tracts of various species (8 -10) and in the thyroid and endocri...
The induction of clusterin has been associated with a variety of disease states where it appears to provide a cytoprotective effect. The increased expression of clusterin mRNA in the early stages of osteoarthritis (OA) may reflect an attempt by the chondrocytes to protect and repair the tissue. In contrast, the decrease in clusterin mRNA in the advanced osteoarthritic cartilage accompanies the final degenerative stages of the disease. An understanding of the expression of clusterin in osteoarthritis may allow consideration of this protein as a marker for cartilage changes in this chronic degenerative condition.
Treatment with partial (p)MHC class II-β1α1 constructs (also referred to as recombinant T-cell receptor ligands – RTL) linked to antigenic peptides can induce T-cell tolerance, inhibit recruitment of inflammatory cells and reverse autoimmune diseases. Here we demonstrate a novel regulatory pathway that involves RTL binding to CD11b+ mononuclear cells through a receptor comprised of MHC class II invariant chain (CD74), cell-surface histones and MHC class II itself for treatment of experimental autoimmune encephalomyelitis (EAE). Binding of RTL constructs with CD74 involved a previously unrecognized MHC class II-α1/CD74 interaction that inhibited CD74 expression, blocked activity of its ligand, macrophage migration inhibitory factor, and reduced EAE severity. These findings implicate binding of RTL constructs to CD74 as a key step in both antigen-driven and bystander T-cell tolerance important in treatment of inflammatory diseases.
CD74, the cell surface form of the MHC class II invariant chain, is a key inflammatory factor that is involved in various immune mediated diseases as part of the Macrophage Migration Inhibitory Factor (MIF) binding complex. However, little is known about the natural regulators of CD74 in this context. In order to study the role of the HLA-DR molecule in regulating CD74, we utilized the HLA-DRα1 domain, which was shown to bind to and downregulate CD74 on CD11b+ monocytes. We found that DRα1 directly inhibited binding of MIF to CD74 and blocked its downstream inflammatory effects in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE). Potency of the DRα1 domain could be destroyed by trypsin digestion but enhanced by addition of a peptide extension (MOG-35–55 peptide) that provided secondary structure not present in DRα1. These data suggest a conformationally-sensitive determinant on DRα1-MOG that is responsible for optimal binding to CD74 and antagonism of MIF effects, resulting in reduced axonal damage and reversal of ongoing clinical and histological signs of EAE. These results demonstrate natural antagonist activity of DRα1 for MIF that was strongly potentiated by the MOG peptide extension, resulting in a novel therapeutic, DRα1-MOG-35–55,that within the limitations of the EAE model may have the potential to treat autoimmune diseases such as multiple sclerosis.
Recombinant TCR ligands (RTLs) consisting of covalently linked α1 and β1 domains of MHC class II molecules tethered to specific antigenic peptides represent minimal TCR ligands. In a previous study we reported that the rat RTL201 construct, containing RT1.B MHC class II domains covalently coupled to the encephalitogenic guinea pig myelin basic protein (Gp-MBP72–89) peptide, could prevent and treat actively and passively induced experimental autoimmune encephalomyelitis in vivo by selectively inhibiting Gp-MBP72–89 peptide-specific CD4+ T cells. To evaluate the inhibitory signaling pathway, we tested the effects of immobilized RTL201 on T cell activation of the Gp-MBP72–89-specific A1 T cell hybridoma. Activation was exquisitely Ag-specific and could not be induced by RTL200 containing the rat MBP72–89 peptide that differed by a threonine for serine substitution at position 80. Partial activation by RTL201 included a CD3ζ p23/p21 ratio shift, ZAP-70 phosphorylation, calcium mobilization, NFAT activation, and transient IL-2 production. In comparison, anti-CD3ε treatment produced stronger activation of these cellular events with additional activation of NF-κB and extracellular signal-regulated kinases as well as long term increased IL-2 production. These results demonstrate that RTLs can bind directly to the TCR and modify T cell behavior through a partial activation mechanism, triggering specific downstream signaling events that deplete intracellular calcium stores without fully activating T cells. The resulting Ag-specific activation of the transcription factor NFAT uncoupled from the activation of NF-κB or extracellular signal-regulated kinases constitutes a unique downstream activation pattern that accounts for the inhibitory effects of RTL on encephalitogenic CD4+ T cells.
OBJECTIVE In the last several decades, there has been much debate regarding the ideal treatment for sagittal synostosis. The purpose of this study was to compare perioperative, anthropometric, and subjective assessments of cosmetic outcomes between open and endoscopic management of isolated sagittal synostosis. METHODS At their routine postoperative follow-up, pediatric patients with sagittal craniosynostosis were recruited to undergo digital cranial measurement and standardized photography for objective and subjective assessments of perioperative outcomes. Age-normalized z-scores for cephalic index, head circumference, euryon-euryon diameter (Eu-Eu), and glabella-opisthocranion diameter (G-Op) were calculated for each patient. Faculty surgeons, surgical trainees, nurses, and laypersons were asked to rate the normalcy of craniofacial appearances using a 5-point Likert scale. Outcomes were compared between patients treated with endoscopic correction and those treated with open repair. RESULTS A total of 50 patients were included in the study. Thirty-one had undergone open surgical correction, and 19 had undergone endoscopic treatment. Endoscopic repair involved significantly lower operative time, blood loss, transfusion rate, and hospital length of stay than those with open repair (p < 0.001). There was no significant difference between groups in terms of z-scores for head circumference (p = 0.22), cephalic index (p = 0.25), or Eu-Eu (p = 0.38). Endoscopic treatment was associated with a significantly lower G-Op (p = 0.009). Additionally, the average subjective rating of head shape was higher for endoscopic treatment when corrected for age, gender, and ethnicity (p = 0.02). CONCLUSIONS The study findings suggest that patients who are treated endoscopically may have an overall more normal appearance in skull morphology and cosmesis, although these results are limited by poor reliability.
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