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151.
Grün R Stringer C McDermott F Nathan R Porat N Robertson S Taylor L Mortimer G Eggins S McCulloch M 《Journal of human evolution》2005,49(3):316-334
In order to resolve long-standing issues surrounding the age of the Skhul early modern humans, new analyses have been conducted, including the dating of four well-provenanced fossils by ESR and U-series. If the Skhul burials took place within a relatively short time span, then the best age estimate lies between 100 and 135 ka. This result agrees very well with TL ages obtained from burnt flint of 119+/-18 ka (Mercier et al., 1993). However, we cannot exclude the possibility that the material associated with the Skhul IX burial is older than those of Skhul II and Skhul V. These and other recent age estimates suggest that the three burial sites, Skhul, Qafzeh and Tabun are broadly contemporaneous, falling within the time range of 100 to 130 ka. The presence of early representatives of both early modern humans and Neanderthals in the Levant during Marine Isotope Stage 5 inevitably complicates attempts at segregating these populations by date or archaeological association. Nevertheless, it does appear that the oldest known symbolic burials are those of early modern humans at Skhul and Qafzeh. This supports the view that, despite the associated Middle Palaeolithic technology, elements of modern human behaviour were represented at Skhul and Qafzeh prior to 100 ka. 相似文献
152.
Ferrarini L Bertelli L Feala J McCulloch AD Paternostro G 《Bioinformatics (Oxford, England)》2005,21(3):338-348
MOTIVATION: Many aging genes have been found from unbiased screens in model organisms. Genetic interventions promoting longevity are usually quantitative, while in many other biological fields (e.g. development) null mutations alone have been very informative. Therefore, in the case of aging the task is larger and the need for a more efficient genetic search strategy is especially strong. RESULTS: The topology of genetic and metabolic networks is organized according to a scale-free distribution, in which hubs with large numbers of links are present. We have developed a computational model of aging genes as the hubs of biological networks. The computational model shows that, after generalized damage, the function of a network with scale-free topology can be significantly restored by a limited intervention on the hubs. Analyses of data on aging genes and biological networks support the applicability of the model to biological aging. The model also might explain several of the properties of aging genes, including the high degree of conservation across different species. The model suggests that aging genes tend to have a higher number of connections and therefore supports a strategy, based on connectivity, for prioritizing what might otherwise be a random search for aging genes. 相似文献
153.
Worldwide, and particularly in Europe, Japan and the USA, cardiovascular disease is a major killer. It can be treated using tissue or organ transplant surgery, but donor organs may be scarce. Tissue engineering is the integration of engineering principles and biology to produce satisfactory synthetic replacement body parts, using viable cells in a suitable matrix, for regenerative medicine. The aim of this study was to measure and compare cell proliferation kinetics after different time intervals of myofibroblasts in a synthetic matrix, thus to be able to deduce the period that a transplanted-cell population can be expected to survive in a tissue-engineered environment. Porcine aortic wall cells were grown in a porous sponge scaffold, that later could be fashioned into aortic or heart valve substitutes. Freshly acquired cells were seeded on identical sponges and were grown under normal culture conditions for a period of 4 weeks. Seeding concentration was a million cells per sponge. Cells progressively populated the sponges, both covering the surface and infiltrating the depth of the matrix, via sponge pores. Samples were taken at 1 week and at 4 weeks, and the rate of cell proliferation was determined by the metaphase arrest technique. Specimens were also taken for light and electron microscopy to determine whether these transplanted cells were capable of synthesizing their own extracellular matrix. 相似文献
154.
SHP-2 modulates interleukin-1-induced Ca2+ flux and ERK activation via phosphorylation of phospholipase Cgamma1 总被引:2,自引:0,他引:2
Wang Q Downey GP Herrera-Abreu MT Kapus A McCulloch CA 《The Journal of biological chemistry》2005,280(9):8397-8406
Interleukin-1 (IL-1) signaling is dependent on focal adhesions, structures that are enriched with tyrosine kinases and phosphatases. Because the non-receptor tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) is enriched in focal adhesions and IL-1-induced ERK activation requires increased Ca(2+), we determined whether SHP-2 modulates IL-1-induced Ca(2+) signaling. In SHP-2-deficient fibroblasts, IL-1-induced Ca(2+) signaling and ERK activation were markedly diminished compared with cells expressing SHP-2. IL-1-induced Ca(2+) release from the endoplasmic reticulum occurred in the vicinity of focal adhesions and was strongly inhibited by the blockage of phospholipase C (PLC) catalytic activity. Immunoprecipitation and immunostaining showed that SHP-2, the endoplasmic reticulum-specific protein calnexin, and PLCgamma1 were associated with focal adhesions; however, these associations and IL-1-induced ERK activation dissipated after cells were plated on non-integrin substrates. IL-1 promoted phosphorylation of SHP-2 and PLCgamma1. IL-1-induced phosphorylation of PLCgamma1 was diminished in SHP-2-deficient cells but was restored by stable transfection with SHP-2. BAPTA/AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester)) blocked IL-1-induced phosphorylation of SHP-2 and PLCgamma1, indicating mutually dependent interactive roles for Ca(2+), SHP-2, and PLCgamma1 in IL-1 signaling. We conclude that SHP-2 is critical for IL-1-induced phosphorylation of PLCgamma1 and thereby enhances IL-1-induced Ca(2+) release and ERK activation. Focal adhesions co-localizing with the endoplasmic reticulum may provide molecular staging sites required for ERK activation. 相似文献
155.
Roach GD Burgess H Lamond N Dorrian J Holmes A Fletcher A McCulloch K Dawson D 《Journal of human ergology》2001,30(1-2):255-260
In most studies, the magnitude and rate of adaptation to various night work schedules is assessed using core body temperature as the marker of circadian phase. The aim of the current study was to assess adaptation to a simulated night work schedule using salivary dim light melatonin onset (DLMO) as an alternative circadian phase marker. It was hypothesised that the night work schedule would result in a phase delay, manifest in relatively later DLMO, but that this delay would be somewhat inhibited by exposure to natural light. Participants worked seven consecutive simulated 8-hour night shifts (23:00-07:00 h). By night 7, there was a mean cumulative phase delay of 5.5 hours, equivalent to an average delay of 0.8 hours per day. This indicates that partial circadian adaptation occurred in response to the simulated night work schedule. The radioimmunoassay used in the current study provides a sensitive assessment of melatonin concentration in saliva that can be used to determine DLMO, and thus provides an alternative phase marker to core body temperature, at least in laboratory studies. 相似文献
156.
Lamond N Dorrian J Roach GD Burgess HJ Holmes AL McCulloch K Fletcher A Dawson D 《Journal of human ergology》2001,30(1-2):137-142
The current study investigated changes in night-time performance, daytime sleep, and circadian phase during a week of simulated shift work. Fifteen young subjects participated in an adaptation and baseline night sleep, directly followed by seven night shifts. Subjects slept from approximately 0800 hr until they naturally awoke. Polysomnographic data was collected for each sleep period. Saliva samples were collected at half hourly intervals, from 2000 hr to bedtime. Each night, performance was tested at hourly intervals. Analysis indicated that there was a significant increase in mean performance across the week. In general, sleep was not negatively affected. Rather, sleep quality appeared to improve across the week. However, total sleep time (TST) for each day sleep was slightly reduced from baseline, resulting in a small cumulative sleep debt of 3.53 (SD = 5.62) hours. Finally, the melatonin profile shifted across the week, resulting in a mean phase delay of 5.5 hours. These findings indicate that when sleep loss is minimized and a circadian phase shift occurs, adaptation of performance can occur during several consecutive night shifts. 相似文献
157.
Ramakrishna R Edwards JS McCulloch A Palsson BO 《American journal of physiology. Regulatory, integrative and comparative physiology》2001,280(3):R695-R704
Mitochondrial metabolism is a critical component in the functioning and maintenance of cellular organs. The stoichiometry of biochemical reaction networks imposes constraints on mitochondrial function. A modeling framework, flux-balance analysis (FBA), was used to characterize the optimal flux distributions for maximal ATP production in the mitochondrion. The model predicted the expected ATP yields for glucose, lactate, and palmitate. Genetic defects that affect mitochondrial functions have been implicated in several human diseases. FBA can characterize the metabolic behavior due to genetic deletions at the metabolic level, and the effect of mutations in the tricarboxylic acid (TCA) cycle on mitochondrial ATP production was simulated. The mitochondrial ATP production is severely affected by TCA-cycle mutations. In addition, the model predicts the secretion of TCA-cycle intermediates, which is observed in clinical studies of mitochondriopathies such as those associated with fumarase deficiency. The model provides a systemic perspective to characterize the effect of stoichiometric constraints and specific metabolic fluxes on mitochondrial function. 相似文献
158.
Intercellular mechanotransduction: cellular circuits that coordinate tissue responses to mechanical loading 总被引:4,自引:0,他引:4
Physical forces play an important role in modulating cell function and shaping tissue structure. Mechanotransduction, the process by which cells transduce physical force-induced signals into biochemical responses, is critical for mediating adaptations to mechanical loading in connective tissues. While much is known about mechanotransduction in cells involving forces delivered through extracellular matrix proteins and integrins, there is limited understanding of how mechanical signals are propagated through the interconnected cellular networks found in tissues and organs. We propose that intercellular mechanotransduction is a critical component for achieving coordinated remodeling responses to force application in connective tissues. We examine here recent evidence on different pathways of intercellular mechanotransduction and suggest a general model for how multicellular structures respond to mechanical loading as an integrated unit. 相似文献
159.
Wang Q Ko KS Kapus A McCulloch CA Ellen RP 《The Journal of biological chemistry》2001,276(25):23056-23064
The cytotoxicity of infectious agents can be mediated by disruption of calcium signaling in target cells. Outer membrane proteins of the spirochete Treponema denticola, a periodontal pathogen, inhibit agonist-induced Ca(2+) release from internal stores in gingival fibroblasts, but the mechanism is not defined. We determined here that the major surface protein (Msp) of T. denticola perturbs calcium signaling in human fibroblasts by uncoupling store-operated channels. Msp localized in complexes on the cell surface. Ratio fluorimetry showed that in cells loaded with fura-2 or fura-C18, Msp induced cytoplasmic and near-plasma membrane Ca(2+) transients, respectively. Increased conductance was confirmed by fluorescence quenching of fura-2-loaded cells with Mn(2+) after Msp treatment. Calcium entry was blocked with anti-Msp antibodies and inhibited by chelating external Ca(2+) with EGTA. Msp pretreatment reduced the amplitude of [Ca(2+)](i) transients upon challenge with ATP or thapsigargin. In experiments using cells loaded with mag-fura-2 to report endoplasmic reticulum Ca(2+), Msp reduced Ca(2+) efflux from endoplasmic reticulum stores when ATP was used as an agonist. Msp alone did not induce Ca(2+) release from these stores. Msp inhibited store-operated influx of extracellular calcium following intracellular Ca(2+) depletion by thapsigargin and also promoted the assembly of subcortical actin filaments. This actin assembly was blocked by chelating intracellular Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester. The reduced amplitude of agonist-induced transients and inhibition of store-operated Ca(2+) entry due to Msp were reversed by latrunculin B, an inhibitor of actin filament assembly. Thus, Msp retards Ca(2+) release from endoplasmic reticulum stores, and it inhibits subsequent Ca(2+) influx by uncoupling store-operated channels. Actin filament rearrangement coincident with conformational uncoupling of store-operated calcium fluxes is a novel mechanism by which surface proteins and toxins of pathogenic microorganisms may damage host cells. 相似文献
160.