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1.
The prediction of a protein's tertiary structure is still a considerable problem because the huge amount of possible conformational space1 makes it computationally difficult. With regard to side-chain modelling, a solution has been attempted by the grouping of side-chain conformations into representative sets of rotamers2??. Nonetheless, an exhaustive combinatorial search is still limited to carefully indentified packing units?? containing a limited number of residues. For larger systems other strategies had to be developed, such as the Monte Carlo Procedure?? and the genetic algorithm and clustering approach?. Here we present a theorem, referred to as the 'dead-end elimination' theorem, which imposes a suitable condition to identify rotamers that cannot be members of the global minimum energy conformation. Application of this theorem effectively controls the computational explosion of the rotamer combinatorial problem, thereby allowing the determination of the global minimum energy conformation of a large collection of side chains. 相似文献
2.
Holst F Stahl PR Ruiz C Hellwinkel O Jehan Z Wendland M Lebeau A Terracciano L Al-Kuraya K Jänicke F Sauter G Simon R 《Nature genetics》2007,39(5):655-660
Using an Affymetrix 10K SNP array to screen for gene copy number changes in breast cancer, we detected a single-gene amplification of the ESR1 gene, which encodes estrogen receptor alpha, at 6q25. A subsequent tissue microarray analysis of more than 2,000 clinical breast cancer samples showed ESR1 amplification in 20.6% of breast cancers. Ninety-nine percent of tumors with ESR1 amplification showed estrogen receptor protein overexpression, compared with 66.6% cancers without ESR1 amplification (P < 0.0001). In 175 women who had received adjuvant tamoxifen monotherapy, survival was significantly longer for women with cancer with ESR1 amplification than for women with estrogen receptor-expressing cancers without ESR1 amplification (P = 0.023). Notably, we also found ESR1 amplification in benign and precancerous breast diseases, suggesting that ESR1 amplification may be a common mechanism in proliferative breast disease and a very early genetic alteration in a large subset of breast cancers. 相似文献
3.
In this article we consider the growing interest in recent years in the use of documentary strategies in the wold of contemporary art, film and performing arts and explore some of the central epistemological assumptions underpinning the persistent idea that the documentary should be equated with ‘non-fiction’. Following Stella Bruzzi we argue that if documentary theory maintains objectivity as the primary measure of value, it will inevitably and continuously arrive at the conclusion that the documentary genre is fundamentally flawed. Instead, we propose to move beyond the ‘realist epistemology’ of documentary theory and focus on the ‘documentary real’, i.e. the specific performativity of the reality constructed in and by the documentary genre. In the last paragraphs, we introduce the various articles that address the “documentary real” in this special issue. 相似文献
4.
Yvonne G. J. van Helden Roger W. L. Godschalk Hans J. M. Swarts Peter C. H. Hollman Frederik J. van Schooten Jaap Keijer 《Cellular and molecular life sciences : CMLS》2011,68(3):489-504
Molecular mechanisms triggered by high dietary beta-carotene (BC) intake in lung are largely unknown. We performed microarray
gene expression analysis on lung tissue of BC supplemented beta-carotene 15,15′-monooxygenase 1 knockout (Bcmo1
−/−) mice, which are—like humans—able to accumulate BC. Our main observation was that the genes were regulated in an opposite direction in male and female Bcmo1
−/− mice by BC. The steroid biosynthetic pathway was overrepresented in BC-supplemented male Bcmo1
−/− mice. Testosterone levels were higher after BC supplementation only in Bcmo1
−/− mice, which had, unlike wild-type (Bcmo1
+/+) mice, large variations. We hypothesize that BC possibly affects hormone synthesis or metabolism. Since sex hormones influence
lung cancer risk, these data might contribute to an explanation for the previously found increased lung cancer risk after
BC supplementation (ATBC and CARET studies). Moreover, effects of BC may depend on the presence of frequent human BCMO1 polymorphisms, since these effects were not found in wild-type mice. 相似文献
5.
Increasing evidence implies altered signaling through the neurotrophic receptor tyrosine kinase TrkB in promoting tumor formation
and metastasis. TrkB, sometimes in conjunction with its primary ligand BDNF, is often overexpressed in a variety of human
cancers, ranging from neuroblastomas to pancreatic ductal adenocarcinomas, in which it may allow tumor expansion and contribute
to resistance to anti-tumor agents. In vitro, TrkB acts as a potent suppressor of anoikis (detachment-induced apoptosis), which is associated with the acquisition of
an aggressive tumorigenic and metastatic phenotype in vivo. In view of its predicted contribution to tumorigenicity and metastasis in humans, TrkB corresponds to a potential drug target,
and preclinical models have already been established. The encouraging results of pharmacological Trk inhibitors in tumor xenograft
models suggest that TrkB inhibition may represent a promising novel anti-tumor therapeutic strategy. This hypothesis is currently
being evaluated in clinical trials. Here, we will discuss the latest developments on TrkB in these contexts as well as highlight
some critical questions that remain to be addressed for evaluating TrkB as a therapeutic target in cancer.
Received 12 October 2005; received after revision 19 December 2005; accepted 11 January 2006 相似文献
6.
In this paper we argue that an existing theory of concepts called dynamic frame theory, although not developed with that purpose in mind, allows for the precise formulation of a number of problems associated with induction from a single instance. A key role is played by the distinction we introduce between complete and incomplete dynamic frames, for incomplete frames seem to be very elegant candidates for the format of the background knowledge used in induction from a single instance. Furthermore, we show how dynamic frame theory provides the terminology to discuss the justification and the fallibility of incomplete frames. In the Appendix, we give a formal account of incomplete frames and the way these lead to induction from a single instance. 相似文献
7.
Résumé La capacité de transport de la bilirubine dans le foie de rat a été mesurée par différents auteurs. Dans nos expériments leT
m
était variable selon les conditions expérimentales. En stabilisant la température à 38 C pendant les 10 h qui suivent l'opération, le Tm s'avère 50% plus élevé que les valeurs données dans la littérature. En plus la valeur du Tm était étroitement correlée au débit biliaire. 相似文献
8.
Frederik Kunze 《Journal of forecasting》2020,39(2):313-333
By linking measures of forecast accuracy as well as testing procedures with regard to forecast rationality this paper investigates aggregated survey forecasts with forecast horizons of 3, 12, and 24 months for the exchange rates of the Chinese yuan, the Hong Kong dollar, the Japanese yen, and the Singapore dollar vis-à-vis the US dollar and, hence, for four different currency regimes. The rationality of the exchange rate predictions is initially assessed utilizing tests for unbiasedness and efficiency which indicate that the investigated forecasts are irrational in the sense that the predictions are biased. As one major contribution of this paper, it is subsequently shown that these results are not consistent with an alternative, less restrictive, measure of rationality. Investigating the order of integration of the time series as well as cointegrating relationships, this empirical evidence supports the conclusion that the majority of forecasts are in fact rational. Regarding forerunning properties of the predictions, the results are rather mediocre, with shorter term forecasts for the tightly managed USD/CNY FX regime being one exception. As one additional important and novel evaluation result, it can be concluded, that the currency regime matters for the quality of exchange rate forecasts. 相似文献
9.
Long-period astronomical forcing of mammal turnover 总被引:1,自引:0,他引:1
van Dam JA Abdul Aziz H Alvarez Sierra MA Hilgen FJ van den Hoek Ostende LW Lourens LJ Mein P van der Meulen AJ Pelaez-Campomanes P 《Nature》2006,443(7112):687-691
Mammals are among the fastest-radiating groups, being characterized by a mean species lifespan of the order of 2.5 million years (Myr). The basis for this characteristic timescale of origination, extinction and turnover is not well understood. Various studies have invoked climate change to explain mammalian species turnover, but other studies have either challenged or only partly confirmed the climate-turnover hypothesis. Here we use an exceptionally long (24.5-2.5 Myr ago), dense, and well-dated terrestrial record of rodent lineages from central Spain, and show the existence of turnover cycles with periods of 2.4-2.5 and 1.0 Myr. We link these cycles to low-frequency modulations of Milankovitch oscillations, and show that pulses of turnover occur at minima of the 2.37-Myr eccentricity cycle and nodes of the 1.2-Myr obliquity cycle. Because obliquity nodes and eccentricity minima are associated with ice sheet expansion and cooling and affect regional precipitation, we infer that long-period astronomical climate forcing is a major determinant of species turnover in small mammals and probably other groups as well. 相似文献
10.
Kimberly Vanhees Indira G. C. Vonhögen Frederik J. van Schooten Roger W. L. Godschalk 《Cellular and molecular life sciences : CMLS》2014,71(2):271-285
The research field of fetal programming has developed tremendously over the years and increasing knowledge suggests that both maternal and paternal unbalanced diet can have long-lasting effects on the health of offspring. Studies implicate that macronutrients play an important role in fetal programming, although the importance of micronutrients is also becoming increasingly apparent. Folic acid and vitamins B2, B6 and B12 are essential for one-carbon metabolism and are involved in DNA methylation. They can therefore influence the programming of the offspring’s epigenome. Also, other micronutrients such as vitamins A and C, iron, chromium, zinc and flavonoids play a role in fetal programming. Since it is estimated that approximately 78 % of pregnant women in the US take vitamin supplements during pregnancy, more attention should be given to the long-term effects of these supplements on offspring. In this review we address several different studies which illustrate that an unbalanced diet prior and during pregnancy, regarding the intake of micronutrients of both mother and father, can have long-lasting effects on the health of adult offspring. 相似文献