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81.
The signal transduction initiated by the human cytokine interleukin-8 (IL-8), the main chemotactic cytokine for neutrophils, was investigated and found to encompass the stimulation of protein kinases. More specifically, IL-8 caused a transient, dose and time dependent activation of a Ser/Thr kinase activity towards myelin basic protein (MBP) and the MBP-derived peptide APRTPGGRR patterned after the specific concensus sequence in MBP for ERK enzymes. The activated MBP kinase was furthermore identified as an extracellular signal regulated kinase (ERK1) based on several criteria such as substrate specificity, molecular weight, activation-dependent mobility shift, and recognition by anti-ERK antibodies. For comparison, the chemotactic response of neutrophils to a stimulus of bacterial origin (fMet-Leu-Phe or fMLP) was also examined and found to involve the activation of a similar ERK enzyme. The present data clearly indicate that in terminally differentiated, non-proliferating human cells, the MBP kinase/ERK activity can serve other purposes than mitogenic signaling, and that processes such as chemotaxis, induced by bacterial peptides as well as by human cytokines like IL-8, involve the regulation of ERK enzyme.Abbreviations IL-8 interleukin-8 - fMLP fMet-Leu-Phe - MBP myelin basic protein - ERK extracellular signal regulated kinase - MAP2 microtubule-associated protein 2 - PK-A cAMP dependent protein kinase - PKI protein kinase inhibitor - PMSF phenyl-methanesulfonyl fluoride - PVDF poly-vinylidene difluoride - HBSF Hank's buffered salt solution - DAB 3,3-diaminobenzidine tetrahydrochloride - PNPP p-nitrophenyl-phosphate - HSA human serum albumin - EGTA [ethylenebis (oxyethylenenitrilo)]tetraacetic acid - SDS-PAGE sodium dodecyl sulfate polyacrylamide gel electrophoresis  相似文献   
82.
TM9 proteins form a family of conserved proteins with nine transmembrane domains essential for cellular adhesion in many biological systems, but their exact role in this process remains unknown. In this study, we found that genetic inactivation of the TM9 protein Phg1A dramatically decreases the surface levels of the SibA adhesion molecule in Dictyostelium amoebae. This is due to a decrease in sibA mRNA levels, in SibA protein stability, and in SibA targeting to the cell surface. A similar phenotype was observed in cells devoid of SadA, a protein that does not belong to the TM9 family but also exhibits nine transmembrane domains and is essential for cellular adhesion. A contact site A (csA)-SibA chimeric protein comprising only the transmembrane and cytosolic domains of SibA and the extracellular domain of the Dictyostelium surface protein csA also showed reduced stability and relocalization to endocytic compartments in phg1A knockout cells. These results indicate that TM9 proteins participate in cell adhesion by controlling the levels of adhesion proteins present at the cell surface.  相似文献   
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Issues of cost and genetics can result in inbreeding of canine genetic disease colonies. Beagles often are used to maintain such colonies, providing stock for outcrosses. Factor VII (FVII) deficiency is a hemostatic disorder found at increased frequency in beagles and has been characterized at the DNA level. Deficiency of FVII presents obstacles in colonies founded with beagles. An initial finding of a FVII-deficient pup from a longstanding colony prompted us to evaluate FVII deficiency fully in this colony. Current and archival records and tissues were used to reconstruct the colony pedigree, assess the contribution from beagles, and test samples to document the source and frequency of the mutant FVII allele. As part of this study we developed a PCR-based diagnostic assay that was simpler than what was previously available. Pedigree analysis revealed a founder effect implicating beagles that led to high frequency (55%) of the mutant allele. In addition, affected animals were identified. The complete picture of the clinical effect within the colony remains unclear, but unusual neonatal presentations, including hemoabdomen, have occurred in pups affected with FVII deficiency. Use of a PCR-based diagnostic assay to screen all potential beagle breeding stock will prevent similar occurrences of FVII deficiency in future canine research colonies.Abbreviations: FVII, factor VII; MPS I, mucopolysaccharidosis I; PT, prothrombin timeThe importance of developing clinically relevant large animal models for human genetic diseases is becoming increasingly evident.4 For example, preclinical assessments of gene transfer experiments require large long-lived animal models physiologically and genetically comparable to humans. Canine models are ideal because their genome has been sequenced, they are large and long-lived, and because more than 60% of inherited diseases of dogs are known to be homologs of human diseases.4The maintenance of genetic diseases in research colonies results, for all practical purposes, in a founder effect by which allelic frequencies in a research colony may be skewed upward from those in the general population, due to founding of the colony by a limited number of animals. This founder effect is due to insufficient genetic outcrosses, resulting from economic constraints and considerations such as the inbreeding needed with a recessive condition. Practically speaking, colony founders may inevitably be incompletely characterized at the genetic level, potentially leading to increased prevalence of an additional genetic disease. When available, practical screening tests (clotting times, cardiac evaluation, and so on) or breed-specific genetic tests should be conducted to reduce additional genetic diseases within a research colony.The occurrence of additional genetic diseases in research colonies can limit or confound the primary research objective and affect the number of research animals used and their health and welfare. Inherited factor VII (FVII) deficiency in beagles is such a condition.8 Although largely an asymptomatic defect, this autosomal recessive hemostatic disorder, can lead to excessive bleeding after surgery or trauma, hematoma formation, body cavity bleeding, and persistent uterine and vaginal hemorrhage.23 Factor VII deficiency also occurs in Alaskan malamutes,14 mixed breeds,13 and Alaskan klee kai dogs.11 Clinical symptoms in canines can be reduced by transfusions with fresh plasma or blood, or administration of recombinant activated human FVII.9,17 However, treatments are only a temporary solution, because the half-life of FVII protein is only 3 to 4 h and, in canines, treatment with human proteins raises concern about antibody responses to those proteins, thus potentially limiting further therapy. The FVII mutation initially described in beagles (referred to henceforth as the ‘beagle mutation’ in full recognition of its occurrence in additional breeds) is well described.1 Furthermore the beagle mutation has been documented to cause the FVII deficiency seen in the Alaskan klee kai,11 Airedale terrier, giant schnauzer, and Scottish deerhound.22 The published assay is a restriction digest to test beagles for the causative transitional missense mutation of a guanine-to-adenine located in exon 5 (leading to the G96E mutant protein).1 However, because the assay relies on an enzyme with multiple sites in the resultant amplicon, interpretation of results can be problematic, potentially requiring direct DNA sequencing for confirmation of the genotype.Herein we present data from a long-standing canine research breeding colony for mucopolysaccharidosis type I (MPS I) which indicate that FVII deficiency should be a primary concern when developing research colonies by using beagle breeding stock. We suspected factor VII deficiency in this colony after an episode of hemoabdomen in a neonate, which was noted shortly after the colony was transferred to a different institution. Using an improved PCR-based diagnostic assay for the beagle FVII mutation, we have documented the history of this mutant allele within the colony in detail and have identified the presence of this allele in other canine colonies.  相似文献   
84.
Using high resolution X chromosome array-CGH we identified an interstitial microdeletion at Xp11.23 in three brothers with moderate to severe mental retardation (MR) without dysmorphic features. The extent of the deletion was subsequently delineated to about 50 kb by regular PCR and included only the SLC38A5 and FTSJ1 genes. The loss of the FTSJ1 MR gene in males is expected to result in the observed phenotype but the contribution of the deletion of the solute carrier SLC38A5 gene is less clear. Their mother also carries the deletion and completely inactivates the aberrant X chromosome. Interestingly, the distal breakpoint is situated within a 200 kb SSX repeat region that appears to stimulate recombination since subtle copy number changes often occur at this location and it is frequently involved in translocations in tumours. Since this apparent SSX unstable structure is flanked proximally by FTSJ1 and PQBP1, subtle deletions or duplications at this location would be expected to cause MR, as in our family. So far, we have screened a cohort of 300 patients but did not find additional aberrations at the FTSJ1 locus indicating that the frequency is likely to be low.  相似文献   
85.
A series of 2-methyl-5-nitrobenzenesulfonohydrazides were prepared and evaluated as inhibitors of PI3K. An isoquinoline derivative shows good selectivity for the p110α isoform over p110β and p110δ, and also demonstrates good in vitro activity in a cell proliferation assay. Molecular modelling provides a rationalisation for the observed SAR.  相似文献   
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Scully S  Yan W  Bentley B  Cao QJ  Shao R 《PloS one》2011,6(10):e25819
We previously reported that a secreted glycoprotein YKL-40 acts as an angiogenic factor to promote breast cancer angiogenesis. However, its functional role in normal mammary gland development is poorly understood. Here we investigated its biophysiological activity in mammary epithelial development and mammary tissue morphogenesis. YKL-40 was expressed exclusively by ductal epithelial cells of parous and non-parous mammary tissue, but was dramatically up-regulated at the beginning of involution. To mimic ductal development and explore activity of elevated YKL-40 during mammary tissue regression in vivo, we grew a mammary epithelial cell line 76N MECs in a 3-D Matrigel system in the presence of lactogenic hormones including prolactin, hydrocortisone, and insulin. Treatment of 76N MECs with recombinant YKL-40 significantly inhibited acinar formation, luminal polarization, and secretion. YKL-40 also suppressed expression of E-cadherin but increased MMP-9 and cell motility, the crucial mechanisms that mediate mammary tissue remodeling during involution. In addition, engineering of 76N MECs with YKL-40 gene to express ectopic YKL-40 recapitulated the same activities as recombinant YKL-40 in the inhibition of cell differentiation. These results suggest that YKL-40-mediated inhibition of cell differentiation and polarization in the presence of lactogenic hormones may represent its important function during mammary tissue involution. Identification of this biophysiological property will enhance our understanding of its pathologic role in the later stage of breast cancer that is developed from poorly differentiated and highly invasive cells.  相似文献   
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The metabolic stability of benzoxazinone derivatives, a potent series of NPY Y5 antagonists, has been investigated. This study resulted in the identification of the structural moieties prone to metabolic transformations and which strongly influenced the in vitro half-life. This provides opportunities to optimize the structure of this new class of NPY Y5 antagonists.  相似文献   
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