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21.
An Activated Protein Kinase C α Gives a Differentiation Signal for Hematopoietic Progenitor Cells and Mimicks Macrophage Colony-stimulating Factor–stimulated Signaling Events
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Andrew Pierce Clare M. Heyworth Sian E. Nicholls Elaine Spooncer T. Michael Dexter Janet M. Lord P. Jane Owen-Lynch Gwen Wark Anthony D. Whetton 《The Journal of cell biology》1998,140(6):1511-1518
Highly enriched, bipotent, hematopoietic granulocyte macrophage colony-forming cells (GM-CFC) require cytokines for their survival, proliferation, and development. GM-CFC will form neutrophils in the presence of the cytokines stem cell factor and granulocyte colony-stimulating factor, whereas macrophage colony-stimulating factor leads to macrophage formation. Previously, we have shown that the commitment to the macrophage lineage is associated with lipid hydrolysis and translocation of protein kinase C α (PKCα) to the nucleus. Here we have transfected freshly prepared GM-CFC with a constitutively activated form of PKCα, namely PKAC, in which the regulatory domain has been truncated. Greater than 95% of the transfected cells showed over a twofold increase in PKCα expression with the protein being located primarily within the nucleus. The expression of PKAC caused macrophage development even in the presence of stimuli that normally promote only neutrophilic development. Thus, M-CSF–stimulated translocation of PKCα to the nucleus is a signal associated with macrophage development in primary mammalian hematopoietic progenitor cells, and this signal can be mimicked by ectopic PKAC, which is also expressed in the nucleus. 相似文献
22.
Tang X Downes CP Whetton AD Owen-Lynch PJ 《The Journal of biological chemistry》2000,275(17):13142-13148
Leukemogenic oncogenes, such as the Abelson protein-tyrosine kinases (PTK), disrupt the normal regulation of survival, proliferation, and differentiation in hemopoietic progenitor cells. In the absence of cytokines, hemopoietic progenitor cells die by apoptosis. Abl PTKs mediate suppression of this apoptotic response leading to aberrant survival. To investigate the mechanism of Abl PTK action, we have used an interleukin-3-dependent murine mast cell line that expresses a temperature-sensitive form of the v-ABL PTK, which is active at the permissive temperature of 32 degrees C and inactive at 39 degrees C. At the permissive temperature, these cells are resistant to apoptosis induced both by the withdrawal of the hemopoietic growth factor (interleukin-3) and the addition of cytotoxic drugs. We demonstrate that v-Abl associates with and stimulates activation of phosphatidylinositol 3-kinase (PI3K) and, crucially, that this activation results in enhanced cellular levels of the mass of the second messenger phosphatidylinositol-3,4,5-trisphosphate. Activation of PI3K leads to enhanced activity of PKB and increased levels of the anti-apoptotic protein Bcl-X(L). Transfection of cells with a dominant negative PKB reduces both the Abl-stimulated PKB activity and the survival effect conferred by activation of this oncogene. Thus, PI3K and PKB are required for the anti-apoptotic effects of Abl PTK. 相似文献
23.
Duijnisveld BJ Bigot A Beenakker KG Portilho DM Raz V van der Heide HJ Visser CP Chaouch S Mamchaoui K Westendorp RG Mouly V Butler-Browne GS Nelissen RG Maier AB 《Arthritis research & therapy》2011,13(6):R207-10
Introduction
Chronic inflammation is a profound systemic modification of the cellular microenvironment which could affect survival, repair and maintenance of muscle stem cells. The aim of this study was to define the role of chronic inflammation on the regenerative potential of satellite cells in human muscle.Methods
As a model for chronic inflammation, 11 patients suffering from rheumatoid arthritis (RA) were included together with 16 patients with osteoarthritis (OA) as controls. The mean age of both groups was 64 years, with more females in the RA group compared to the OA group. During elective knee replacement surgery, a muscle biopsy was taken from the distal musculus vastus medialis. Cell populations from four RA and eight OA patients were used for extensive phenotyping because these cell populations showed no spontaneous differentiation and myogenic purity greater than 75% after explantation.Results
After mononuclear cell explantation, myogenic purity, viability, proliferation index, number of colonies, myogenic colonies, growth speed, maximum number of population doublings and fusion index were not different between RA and OA patients. Furthermore, the expression of proteins involved in replicative and stress-induced premature senescence and apoptosis, including p16, p21, p53, hTERT and cleaved caspase-3, was not different between RA and OA patients. Mean telomere length was shorter in the RA group compared to the OA group.Conclusions
In the present study we found evidence that chronic inflammation in RA does not affect the in vitro regenerative potential of human satellite cells. Identification of mechanisms influencing muscle regeneration by modulation of its microenvironment may, therefore, be more appropriate. 相似文献24.
Jeroen Slikkerveer Pieter A Dijkmans Gertjan T Sieswerda Pieter AFM Doevendans Arie PJ van Dijk Freek WA Verheugt Thomas R Porter Otto Kamp 《Trials》2008,9(1):1-7
Background
The CONSORT Statement provides recommendations for reporting randomized controlled trials. We assessed the extent to which leading medical journals that publish reports of randomized trials incorporate the CONSORT recommendations into their journal and editorial processes.Methods
This article reports on two observational studies. Study 1: We examined the online version of 'Instructions to Authors' for 165 high impact factor medical journals and extracted all text mentioning the CONSORT Statement or CONSORT extension papers. Any mention of the International Committee of Medical Journal Editors (ICMJE) or clinical trial registration were also sought and extracted. Study 2: We surveyed the editor-in-chief, or editorial office, for each of the 165 journals about their journal's endorsement of CONSORT recommendations and its incorporation into their editorial and peer-review processes.Results
Study 1: Thirty-eight percent (62/165) of journals mentioned the CONSORT Statement in their online 'Instructions to Authors'; of these 37% (23/62) stated this was a requirement, 63% (39/62) were less clear in their recommendations. Very few journals mentioned the CONSORT extension papers. Journals that referred to CONSORT were more likely to refer to ICMJE guidelines (RR 2.16; 95% CI 1.51 to 3.08) and clinical trial registration (RR 3.67; 95% CI 2.36 to 5.71) than those journals which did not. Study 2: Thirty-nine percent (64/165) of journals responded to the on-line survey, the majority were journal editors. Eighty-eight percent (50/57) of journals recommended authors comply with the CONSORT Statement; 62% (35/56) said they would require this. Forty-one percent (22/53) reported incorporating CONSORT into their peer-review process and 47% (25/53) into their editorial process. Eighty-one percent (47/58) reported including CONSORT in their 'Instructions to Authors' although there was some inconsistency when cross checking information on the journal's website. Sixty-nine percent (31/45) of journals recommended authors comply with the CONSORT extension for cluster trials, 60% (27/45) for harms and 42% (19/45) for non-inferiority and equivalence trials. Few journals mentioned these extensions in their 'Instructions to Authors'.Conclusion
Journals should be more explicit in their recommendations and expectations of authors regarding the CONSORT Statement and related CONSORT extensions papers. 相似文献25.
A three-year survey (1997–99) was carried out on organically reared sheep flocks throughout Sweden. The aim was to determine the prevalence and intensity of nematode infections and to establish relationships between sheep management practices and parasite infections. Faecal samples from ewes and lambs were collected from 152 organic flocks around lambing-time and during the grazing-period for analysis. Results were compared with the different management practices that farmers use to prevent parasitism in their flocks. A high proportion of the flocks was infected with nematodes. The most prevalent species were Haemonchus contortus, Teladorsagia circumeincta, Trichostrongylus axei, T. colubriformis and Chabertia ovina and infections progressively increased during summer in lambs grazing on permanent pastures. Severity of parasitic infection in lambs was highly dependent on egg output from the ewes. H. contortus was found in 37% of the flocks, even at latitudes approximating the Polar Circle. Nematodirus battus was recorded for the first time in Sweden during the course of this study. Lambs turned out onto permanent pasture showed higher nematode faecal egg counts (epg) than lambs that had grazed on pastures, which had not carried sheep the previous year. This beneficial effect of lambs grazing non-infected pastures persisted if the ewes were treated with an anthelmintic before turn-out and if the lambs were kept on pastures of low infectivity after weaning. In lambs, the prevalence and the magnitude of their egg counts were higher during autumn in flocks where lambs were slaughtered after 8 months of age, compared with flocks where all lambs were slaughtered before this age. These results will be used in providing advice to farmers of ways to modify their flock management in order to minimise the use of anthelmintics, but at the same time efficiently produce prime lambs. 相似文献
26.
C Monde S Syampungani A Rico PJ van den Brink 《African Journal of Aquatic Science》2017,42(3):235-243
The potential of red claw crayfish and hybrid African catfish (Clarias gariepinus and Clarias ngamensis) as predators for Schistosoma host snails was evaluated in 2014 by monitoring the consumption of snails by crayfish and catfish in experimental tanks over time under laboratory conditions. After 15 days, both crayfish and catfish had significantly reduced the populations of Bulinus globosus. Crayfish consumed 6.9 snails d?1, whereas catfish consumed 5.9 snails d?1. However, when supplied with an alternative prey, Melanoides tuberculata (100 individuals per tank), crayfish clearly preferred M. tuberculata (100% consumed over seven days) to B. globosus (100 individuals per tank) (54% consumed over the same period). Catfish, conversely, did not have a clear preference for either prey species, consuming 77% and 88% of M. tuberculata and B. globosus, respectively. It was also observed that young catfish were more efficient predators than older ones, because of ontogenetic shifts in their diet with age. Hybrid catfish retain the molluscivorous characteristics of their parent stock and red claw crayfish also preys on Schistosoma host snails. However, the effectiveness of both predators is affected by the presence of an alternative prey. Therefore, under suitable conditions, these species can be considered for biological control of schistosomiasis transmission. 相似文献
27.
J Steinbuch AC van Dijk FHBM Schreuder MTB Truijman J Hendrikse PJ Nederkoorn A van der Lugt E Hermeling APG Hoeks WH Mess 《Cardiovascular ultrasound》2017,15(1):9
Background
Mean or maximal intima-media thickness (IMT) is commonly used as surrogate endpoint in intervention studies. However, the effect of normalization by surrounding or median IMT or by diameter is unknown. In addition, it is unclear whether IMT inhomogeneity is a useful predictor beyond common wall parameters like maximal wall thickness, either absolute or normalized to IMT or lumen size. We investigated the interrelationship of common carotid artery (CCA) thickness parameters and their association with the ipsilateral internal carotid artery (ICA) stenosis degree.Methods
CCA thickness parameters were extracted by edge detection applied to ultrasound B-mode recordings of 240 patients. Degree of ICA stenosis was determined from CT angiography.Results
Normalization of maximal CCA wall thickness to median IMT leads to large variations. Higher CCA thickness parameter values are associated with a higher degree of ipsilateral ICA stenosis (p?<?0.001), though IMT inhomogeneity does not provide extra information. When the ratio of wall thickness and diameter instead of absolute maximal wall thickness is used as risk marker for having moderate ipsilateral ICA stenosis (>50%), 55 arteries (15%) are reclassified to another risk category.Conclusions
It is more reasonable to normalize maximal wall thickness to end-diastolic diameter rather than to IMT, affecting risk classification and suggesting modification of the Mannheim criteria.Trial registration
Clinical trials.gov NCT01208025.28.
Cecilia Wieder Clment Frainay Nathalie Poupin Pablo Rodríguez-Mier Florence Vinson Juliette Cooke Rachel PJ Lai Jacob G. Bundy Fabien Jourdan Timothy Ebbels 《PLoS computational biology》2021,17(9)
Over-representation analysis (ORA) is one of the commonest pathway analysis approaches used for the functional interpretation of metabolomics datasets. Despite the widespread use of ORA in metabolomics, the community lacks guidelines detailing its best-practice use. Many factors have a pronounced impact on the results, but to date their effects have received little systematic attention. Using five publicly available datasets, we demonstrated that changes in parameters such as the background set, differential metabolite selection methods, and pathway database used can result in profoundly different ORA results. The use of a non-assay-specific background set, for example, resulted in large numbers of false-positive pathways. Pathway database choice, evaluated using three of the most popular metabolic pathway databases (KEGG, Reactome, and BioCyc), led to vastly different results in both the number and function of significantly enriched pathways. Factors that are specific to metabolomics data, such as the reliability of compound identification and the chemical bias of different analytical platforms also impacted ORA results. Simulated metabolite misidentification rates as low as 4% resulted in both gain of false-positive pathways and loss of truly significant pathways across all datasets. Our results have several practical implications for ORA users, as well as those using alternative pathway analysis methods. We offer a set of recommendations for the use of ORA in metabolomics, alongside a set of minimal reporting guidelines, as a first step towards the standardisation of pathway analysis in metabolomics. 相似文献
29.
BackgroundPeople with severe mental illness (SMI) have higher rates of a range of physical health conditions, yet little is known regarding the clustering of physical health conditions in this population. We aimed to investigate the prevalence and clustering of chronic physical health conditions in people with SMI, compared to people without SMI.Methods and findingsWe performed a cohort-nested accumulated prevalence study, using primary care data from the Clinical Practice Research Datalink (CPRD), which holds details of 39 million patients in the United Kingdom. We identified 68,783 adults with a primary care diagnosis of SMI (schizophrenia, bipolar disorder, or other psychoses) from 2000 to 2018, matched up to 1:4 to 274,684 patients without an SMI diagnosis, on age, sex, primary care practice, and year of registration at the practice. Patients had a median of 28.85 (IQR: 19.10 to 41.37) years of primary care observations. Patients with SMI had higher prevalence of smoking (27.65% versus 46.08%), obesity (24.91% versus 38.09%), alcohol misuse (3.66% versus 13.47%), and drug misuse (2.08% versus 12.84%) than comparators. We defined 24 physical health conditions derived from the Elixhauser and Charlson comorbidity indices and used logistic regression to investigate individual conditions and multimorbidity. We controlled for age, sex, region, and ethnicity and then additionally for health risk factors: smoking status, alcohol misuse, drug misuse, and body mass index (BMI). We defined multimorbidity clusters using multiple correspondence analysis (MCA) and K-means cluster analysis and described them based on the observed/expected ratio. Patients with SMI had higher odds of 19 of 24 conditions and a higher prevalence of multimorbidity (odds ratio (OR): 1.84; 95% confidence interval [CI]: 1.80 to 1.88, p < 0.001) compared to those without SMI, particularly in younger age groups (males aged 30 to 39: OR: 2.49; 95% CI: 2.27 to 2.73; p < 0.001; females aged 18 to 30: OR: 2.69; 95% CI: 2.36 to 3.07; p < 0.001). Adjusting for health risk factors reduced the OR of all conditions. We identified 7 multimorbidity clusters in those with SMI and 7 in those without SMI. A total of 4 clusters were common to those with and without SMI; while 1, heart disease, appeared as one cluster in those with SMI and 3 distinct clusters in comparators; and 2 small clusters were unique to the SMI cohort. Limitations to this study include missing data, which may have led to residual confounding, and an inability to investigate the temporal associations between SMI and physical health conditions.ConclusionsIn this study, we observed that physical health conditions cluster similarly in people with and without SMI, although patients with SMI had higher burden of multimorbidity, particularly in younger age groups. While interventions aimed at the general population may also be appropriate for those with SMI, there is a need for interventions aimed at better management of younger-age multimorbidity, and preventative measures focusing on diseases of younger age, and reduction of health risk factors.In an observational analysis of primary care data from the UK, Naomi Launders and colleagues study the prevalence and clustering of physical health conditions and multimorbidity in individuals with severe mental illnesses. 相似文献
30.
Improved analyses of human mtDNA sequences support a recent African origin for Homo sapiens 总被引:3,自引:1,他引:2
New quantitative methods are applied to the 135 human mitochondrial
sequences from the Vigilant et al. data set. General problems in analyzing
large numbers of short sequences are discussed, and an improved strategy is
suggested. A key feature is to focus not on individual trees but on the
general "landscape" of trees. Over 1,000 searches were made from random
starting trees with only one tree (a local optimum) being retained each
time, thereby ensuring optima were found independently. A new tree
comparison metric was developed that is unaffected by rearrangements of
trees around many very short internal edges. Use of this metric showed that
downweighting hypervariable sites revealed more evolutionary structure than
studies that weighted all sites equally. Our results are consistent with
convergence toward a global optimum. Crucial features are that the best
optima show very strong regional differentiation, a common group of 49
African sequences is found in all the best optima, and the best optima
contain the 16 !Kung sequences in a separate group of San people. The other
86 sequences form a heterogeneous mixture of Africans, Europeans,
Australopapuans, and Asians. Thus all major human lineages occur in Africa,
but only a subset occurs in the rest of the world. The existence of these
African-only groups strongly contradicts multiregional theories for the
origin of Homo sapiens that require widespread migration and interbreeding
over the entire range of H. erectus. Only when the multiregional model is
rejected is it appropriate to consider the root, based on a single locus,
to be the center of origin of a population (otherwise different loci could
give alternative geographic positions for the root). For this data, several
methods locate the root within the group of 49 African sequences and are
thus consistent with the recent African origin of H. sapiens. We
demonstrate that the time of the last common ancestor cannot be the time of
major expansion in human numbers, and our results are thus also consistent
with recent models that differentiate between the last common ancestor,
expansion out of Africa, and the major expansion in human populations. Such
a two-phase model is consistent with a wide range of molecular and
archeological evidence.
相似文献