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871.
Population-level analyses often use average quantities to describe heterogeneous systems, particularly when variation does not arise from identifiable groups. A prominent example, central to our current understanding of epidemic spread, is the basic reproductive number, R(0), which is defined as the mean number of infections caused by an infected individual in a susceptible population. Population estimates of R(0) can obscure considerable individual variation in infectiousness, as highlighted during the global emergence of severe acute respiratory syndrome (SARS) by numerous 'superspreading events' in which certain individuals infected unusually large numbers of secondary cases. For diseases transmitted by non-sexual direct contacts, such as SARS or smallpox, individual variation is difficult to measure empirically, and thus its importance for outbreak dynamics has been unclear. Here we present an integrated theoretical and statistical analysis of the influence of individual variation in infectiousness on disease emergence. Using contact tracing data from eight directly transmitted diseases, we show that the distribution of individual infectiousness around R(0) is often highly skewed. Model predictions accounting for this variation differ sharply from average-based approaches, with disease extinction more likely and outbreaks rarer but more explosive. Using these models, we explore implications for outbreak control, showing that individual-specific control measures outperform population-wide measures. Moreover, the dramatic improvements achieved through targeted control policies emphasize the need to identify predictive correlates of higher infectiousness. Our findings indicate that superspreading is a normal feature of disease spread, and to frame ongoing discussion we propose a rigorous definition for superspreading events and a method to predict their frequency. 相似文献
872.
873.
Microsomal glutathione S-transferases: selective up-regulation of leukotriene C4 synthase during lipopolysaccharide-induced pyresis 总被引:4,自引:0,他引:4
Schröder O Sjöström M Qiu H Jakobsson PJ Haeggström JZ 《Cellular and molecular life sciences : CMLS》2005,62(1):87-94
Cysteinyl-leukotrienes (cys-LTs) are potent smooth muscle contracting agents, which play key roles in inflammatory and allergic diseases. The committed step in cys-LT biosynthesis is catalyzed by leukotriene C4 synthase (LTC4S) as well as microsomal glutathione S-transferase type 2 (MGST2) and type 3 (MGST3). Here we report that intraperitoneal injections of lipopolysaccharide in rats lead to a strong increase of LTC4S messenger RNA (mRNA) levels after approximately 1 h, particularly in the heart, brain, adrenal glands and liver, without any significant effect on MGST2 and MGST3 mRNA levels. After 6 h, LTC4S mRNA returns to basal levels, concomitant with a 4.9-, 4.0-, 2.9- and 2.3-fold induction of LTC4S protein in brain, heart, liver and adrenal gland, respectively. Hence, challenge with lipopolysaccharide in vivo causes an organ-selective, local priming for leukotriene C4 synthesis. Moreover, these data suggest that LTC4S and cys-LTs may be involved in acute systemic inflammatory responses such as fever and tachycardia.Received 12 August 2004; received after revision 27 October 2004; accepted 1 November 2004 相似文献
874.
Lactoferrin (LF) is a member of the transferrin family that is expressed and secreted by glandular epithelial cells and is found in the secondary granules of neutrophils. Originally viewed as an iron-binding protein in milk, with bacteriostatic properties, it is becoming increasingly evident that LF is a multifunctional protein to which several physiological roles have been attributed. These include regulation of iron homeostasis, host defense against a broad range of microbial infections, anti-inflammatory activity, regulation of cellular growth and differentiation and protection against cancer development and metastasis. While iron binding is likely central to some of the biological roles of LF, other activities, including specific interactions with mammalian receptors and microbial components, also contribute to the pleoitropic functional nature of this protein. In this article, recent advances in the understanding of these functions at the cellular and molecular level are discussed. 相似文献
875.
Ko MA Rosario CO Hudson JW Kulkarni S Pollett A Dennis JW Swallow CJ 《Nature genetics》2005,37(8):883-888
The polo-like kinase Plk4 (also called Sak) is required for late mitotic progression, cell survival and postgastrulation embryonic development. Here we identified a phenotype resulting from Plk4 haploinsufficiency in Plk4 heterozygous cells and mice. Plk4+/- embryonic fibroblasts had increased centrosomal amplification, multipolar spindle formation and aneuploidy compared with wild-type cells. The incidence of spontaneous liver and lung cancers was approximately 15 times high in elderly Plk4+/- mice than in Plk4+/+ littermates. Using the in vivo model of partial hepatectomy to induce synchronous cell cycle entry, we determined that the precise regulation of cyclins D1, E and B1 and of Cdk1 was impaired in Plk4+/- regenerating liver, and p53 activation and p21 and BubR1 expression were suppressed. These defects were associated with progressive cell cycle delays, increased spindle irregularities and accelerated hepatocellular carcinogenesis in Plk4+/- mice. Loss of heterozygosity occurs frequently (approximately 60%) at polymorphic markers adjacent to the PLK4 locus in human hepatoma. Reduced Plk4 gene dosage increases the probability of mitotic errors and cancer development. 相似文献
876.
Jacquet S Malaval C Martinez LO Sak K Rolland C Perez C Nauze M Champagne E Tercé F Gachet C Perret B Collet X Boeynaems JM Barbaras R 《Cellular and molecular life sciences : CMLS》2005,62(21):2508-2515
Cell surface receptors for high-density lipoprotein (HDL) on hepatocytes are major partners in the regulation of cholesterol
homeostasis. We recently identified a cell surface ATP synthase as a high-affinity receptor for HDL apolipoprotein A-I (apoA-I)
on human hepatocytes. Stimulation of this ectopic ATP synthase by apoA-I triggered a low-affinity-receptor-dependent HDL endocytosis
by a mechanism strictly related to the generation of ADP. This suggests that nucleotide G-protein- coupled receptors of the
P2Y family are molecular components in this pathway. Only P2Y1 and P2Y13 are present on the membrane of hepatocytes. Using both a pharmacological approach and small interference RNA, we identified
P2Y13 as the main partner in hepatic HDL endocytosis, in cultured cells as well as in situ in perfused mouse livers. We also found
a new important action of the antithrombotic agent AR-C69931MX as a strong activator of P2Y13-mediated HDL endocytosis.
Received 9 May 2005; received after revision 24 June 2005; accepted 1 September 2005 相似文献
877.
Cruz FW Burns SJ Karmann I Sharp WD Vuille M Cardoso AO Ferrari JA Dias PL Viana O 《Nature》2005,434(7029):63-66
During the last glacial period, large millennial-scale temperature oscillations--the 'Dansgaard/Oeschger' cycles--were the primary climate signal in Northern Hemisphere climate archives from the high latitudes to the tropics. But whether the influence of these abrupt climate changes extended to the tropical and subtropical Southern Hemisphere, where changes in insolation are thought to be the main direct forcing of climate, has remained unclear. Here we present a high-resolution oxygen isotope record of a U/Th-dated stalagmite from subtropical southern Brazil, covering the past 116,200 years. The oxygen isotope signature varies with shifts in the source region and amount of rainfall in the area, and hence records changes in atmospheric circulation and convective intensity over South America. We find that these variations in rainfall source and amount are primarily driven by summer solar radiation, which is controlled by the Earth's precessional cycle. The Dansgaard/Oeschger cycles can be detected in our record and therefore we confirm that they also affect the tropical hydrological cycle, but that in southern subtropical Brazil, millennial-scale climate changes are not as dominant as they are in the Northern Hemisphere. 相似文献
878.
Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen 总被引:45,自引:0,他引:45
Stover CK Pham XQ Erwin AL Mizoguchi SD Warrener P Hickey MJ Brinkman FS Hufnagle WO Kowalik DJ Lagrou M Garber RL Goltry L Tolentino E Westbrock-Wadman S Yuan Y Brody LL Coulter SN Folger KR Kas A Larbig K Lim R Smith K Spencer D Wong GK Wu Z Paulsen IT Reizer J Saier MH Hancock RE Lory S Olson MV 《Nature》2000,406(6799):959-964
Pseudomonas aeruginosa is a ubiquitous environmental bacterium that is one of the top three causes of opportunistic human infections. A major factor in its prominence as a pathogen is its intrinsic resistance to antibiotics and disinfectants. Here we report the complete sequence of P. aeruginosa strain PAO1. At 6.3 million base pairs, this is the largest bacterial genome sequenced, and the sequence provides insights into the basis of the versatility and intrinsic drug resistance of P. aeruginosa. Consistent with its larger genome size and environmental adaptability, P. aeruginosa contains the highest proportion of regulatory genes observed for a bacterial genome and a large number of genes involved in the catabolism, transport and efflux of organic compounds as well as four potential chemotaxis systems. We propose that the size and complexity of the P. aeruginosa genome reflect an evolutionary adaptation permitting it to thrive in diverse environments and resist the effects of a variety of antimicrobial substances. 相似文献
879.
Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1 总被引:46,自引:0,他引:46
880.
Geometry-dominated fluid adsorption on sculpted solid substrates 总被引:1,自引:0,他引:1
The shape and chemical composition of solid surfaces can be controlled at a mesoscopic scale. Exposing such structured substrates to a gas that is close to coexistence with its liquid phase can produce quite distinct adsorption characteristics compared to those of planar systems, which may be important for technologies such as super-repellent surfaces or micro-fluidics. Recent studies have concentrated on the adsorption of liquids on rough and heterogeneous substrates, and the characterization of nanoscopic liquid films. But the fundamental effect of geometry on the adsorption of a fluid from the gas phase has hardly been addressed. Here we present a simple theoretical model which shows that varying the shape of the substrate can exert a profound influence on the adsorption isotherms of liquids. The model smoothly connects wetting and capillary condensation through a number of examples of fluid interfacial phenomena, and opens the possibility of tailoring the adsorption properties of solid substrates by sculpting their surface shape. 相似文献