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101.
Ubiquitin conjugation during endoplasmic-reticulum-associated degradation (ERAD) depends on the activity of Ubc7. Here we show that Ubc1 acts as a further ubiquitin-conjugating enzyme in this pathway. Absence of both enzymes results in marked stabilization of an ERAD substrate and induction of the unfolded-protein response (UPR). Furthermore, basic ERAD activity is sufficient to eliminate unfolded proteins under normal conditions. However, when stress is applied, the UPR is required to increase ERAD activity. We thus demonstrate, for the first time, a regulatory loop between ERAD and the UPR, which is essential for normal growth of yeast cells. 相似文献
102.
Differential role of neurokinin receptors in human lymphocyte and monocyte chemotaxis 总被引:4,自引:0,他引:4
The precise nature of neurokin receptor involvement in human immune cell chemotaxis is unclear. This study therefore sought to directly compare the chemotactic effects of neurokinins on human T lymphocytes and monocytes. Substance P was found to have a similar dose-dependent chemotactic action on T lymphocyte and monocyte populations. In contrast, T lymphocytes were found to be more responsive than monocytes both to the highly selective NK-1 agonist, [Sar(9)Met O(2)(11)]-substance P, and also to the NK-2 selective agonist, beta-alanine neurokinin A((4-10)). Consistent with these findings, substance P-induced chemotaxis of both T lymphocyte and monocytes was attenuated by the selective NK-1 antagonist LY303870. However, the selective NK-2 antagonist MEN 10,376 was only effective in inhibiting the T lymphocyte response. The study confirms that neurokinins have chemotactic actions on immune cells and indicates important functional differences between human T lymphocyte and monocyte responses. This provides a potential mechanism by which the nervous system can selectively influence cellular recruitment in inflammatory disease. 相似文献
103.
High rate of DNA loss in the Drosophila melanogaster and Drosophila virilis species groups 总被引:6,自引:3,他引:3
We recently proposed that patterns of evolution of non-LTR
retrotransposable elements can be used to study patterns of spontaneous
mutation. Transposition of non-LTR retrotransposable elements commonly
results in creation of 5' truncated, "dead-on-arrival" copies. These
inactive copies are effectively pseudogenes and, according to the neutral
theory, their molecular evolution ought to reflect rates and patterns of
spontaneous mutation. Maximum parsimony can be used to separate the
evolution of active lineages of a non-LTR element from the fate of the
"dead-on-arrival" insertions and to directly assess the relative
frequencies of different types of spontaneous mutations. We applied this
approach using a non-LTR element, Helena, in the Drosophila virilis group
and have demonstrated a surprisingly high incidence of large deletions and
the virtual absence of insertions. Based on these results, we suggested
that Drosophila in general may exhibit a high rate of spontaneous large
deletions and have hypothesized that such a high rate of DNA loss may help
to explain the puzzling dearth of bona fide pseudogenes in Drosophila. We
also speculated that variation in the rate of spontaneous deletion may
contribute to the divergence of genome size in different taxa by affecting
the amount of superfluous "junk" DNA such as, for example, pseudogenes or
long introns. In this paper, we extend our analysis to the D. melanogaster
subgroup, which last shared a common ancestor with the D. virilis group
approximately 40 MYA. In a different region of the same transposable
element, Helena, we demonstrate that inactive copies accumulate deletions
in species of the D. melanogaster subgroup at a rate very similar to that
of the D. virilis group. These results strongly suggest that the high rate
of DNA loss is a general feature of Drosophila and not a peculiar property
of a particular stretch of DNA in a particular species group.
相似文献
104.
105.
The X chromosome constitutes a unique genomic environment because it is present in one copy in males, but two copies in females. This simple fact has motivated several theoretical predictions with respect to how standing genetic variation on the X chromosome should differ from the autosomes. Unmasked expression of deleterious mutations in males and a lower census size are expected to reduce variation, while allelic variants with sexually antagonistic effects, and potentially those with a sex-specific effect, could accumulate on the X chromosome and contribute to increased genetic variation. In addition, incomplete dosage compensation of the X chromosome could potentially dampen the male-specific effects of random mutations, and promote the accumulation of X-linked alleles with sexually dimorphic phenotypic effects. Here we test both the amount and the type of genetic variation on the X chromosome within a population of Drosophila melanogaster, by comparing the proportion of X linked and autosomal trans-regulatory SNPs with a sexually concordant and discordant effect on gene expression. We find that the X chromosome is depleted for SNPs with a sexually concordant effect, but hosts comparatively more SNPs with a sexually discordant effect. Interestingly, the contrasting results for SNPs with sexually concordant and discordant effects are driven by SNPs with a larger influence on expression in females than expression in males. Furthermore, the distribution of these SNPs is shifted towards regions where dosage compensation is predicted to be less complete. These results suggest that intrinsic properties of dosage compensation influence either the accumulation of different types of trans-factors and/or their propensity to accumulate mutations. Our findings document a potential mechanistic basis for sex-specific genetic variation, and identify the X as a reservoir for sexually dimorphic phenotypic variation. These results have general implications for X chromosome evolution, as well as the genetic basis of sex-specific evolutionary change. 相似文献
106.
107.
Background
Selenium and coenzyme Q10 are important antioxidants in the body. As the intake of selenium is low in Europe, and the endogenous production of coenzyme Q10 decreases as age increases, an intervention trial using selenium and coenzyme Q10 for four years was performed. As previously reported, the intervention was accompanied by reduced cardiovascular mortality. The objective of the present study was to analyze cardiovascular mortality for up to 10 years after intervention, to evaluate if mortality differed in subgroups differentiated by gender, diabetes, ischemic heart disease (IHD), and functional class.Methods
Four-hundred forty-three healthy elderly individuals were included from a rural municipality in Sweden. All cardiovascular mortality was registered, and no participant was lost to the follow-up. Based on death certificates and autopsy results mortality was registered.Findings
Significantly reduced cardiovascular mortality could be seen in those on selenium and coenzyme Q10 intervention. A multivariate Cox regression analysis demonstrated a reduced cardiovascular mortality risk in the active treatment group (HR: 0.51; 95%CI 0.36–0.74; P = 0.0003). The reduced mortality could be seen to persist during the 10-year period. Subgroup analysis showed positive effects in both genders. An equally positive risk reduction could be seen in those with ischemic heart disease (HR: 0.51; 95%CI 0.27–0.97; P = 0.04), but also in the different functional classes.Conclusions
In a 10-year follow-up of a group of healthy elderly participants given four years of intervention with selenium and coenzyme Q10, significantly reduced cardiovascular mortality was observed. The protective action was not confined to the intervention period, but persisted during the follow-up period. The mechanism explaining the persistency remains to be elucidated. Since this was a small study, the observations should be regarded as hypothesis-generating. 相似文献108.
Sisters and brothers are completely unrelated with respect to the sex chromosomes they inherit from their heterogametic parent. This has the potential to result in a previously unappreciated form of genetic conflict between the sex chromosomes, called sexually antagonistic zygotic drive (SA-ZD). SA-ZD can arise whenever brothers and sisters compete over limited resources or there is brother–sister mating coupled with inbreeding depression. Although theory predicts that SA-ZD should be common and influence important evolutionary processes, there is little empirical evidence for its existence. Here we discuss the current understanding of SA-ZD, why it would be expected to elude empirical detection when present, and how it relates to other forms of genetic conflict.When a diploid individual reproduces sexually, the two alleles at heterozygous loci are necessarily in competition because reproduction by one allele must be at the expense of the other. Such competition is an inescapable component of the organismal level of evolution that was originally advanced by Darwin and later integrated with the field of genetics during the modern synthesis of the early 20th century (Huxley 1942). If the competition is mediated by Mendelian segregation followed by (1) differences in the Darwinian fitness (i.e., survival and fecundity) that each allele produces in offspring, (2) random sampling (genetic drift), and/or (3) differences in the alleles’ mutation or migration rates, then no genetic conflict exists and only canonical evolution at the organismal level occurs. But alleles can also compete outside the context of organismal evolution via diverse mechanisms of selection at the level of the gene that are collectively called genomic conflict (or selfish, ultraselfish, and parasitic DNA). These mechanisms can be divided into three general classes (Burt and Trivers 2006): (1) gonotaxis (in which the selfish elements bias Mendelian segregation by moving away from dead-end polar bodies and into the functional egg during oogenesis, i.e., meiotic or centromeric drive), (2) interference (in which the selfish element kills or debilitates noncarrier gametes or offspring, i.e., segregation distortion and zygotic drive), and (3) overreplication (in which the selfish element increases its copy number in the genome, e.g., biased gene conversion, transposable elements, and homing endonucleases). De novo mutations can also gain a transmission advantage by increasing the rate of stem cell division in the germ line (germline drive) (e.g., Yoon et al. 2013). All of these genomic conflict mechanisms have been described in detail in Burt and Trivers (2006).Genomic conflict frequently leads to reduced fitness at the organismal level. Meiotic drive can harm the organism as a whole because the attributes that provide a segregation advantage in oogenesis (e.g., the structure of the centromere and neighboring heterochromatin) can be maladaptive during spermatogenesis and contribute to male sterility (see, for review, Elde et al. 2011). Segregation distorters and zygotic drivers can substantially reduce a carrier male’s fitness because they kill up to half of his sperm (leading to reduced fertility) and offspring, respectively. Sex-linked, meiotic drivers in WZ females (like birds) and segregation distorters and zygotic drivers in XY males (like insects and mammals) cause biased sex ratios that reduce fitness with respect to Fisherian sex ratio selection and can also reduce population growth and potentially drive species to extinction. Biased gene conversion and germline drive (Yoon et al. 2013) reduce organismal fitness when harmful mutations accumulate to elevated levels (i.e., beyond the conventional values predicted by mutation-selection balance) because they have a molecular drive advantage over an allele that is more beneficial at the organismal level. Transposable elements insert at new places in the genome where they can disrupt gene function and thereby reduce their carrier’s fitness.Zygotic drive is an unusual form of genetic conflict because it directly reduces Darwinian fitness by killing or debilitating offspring. It is favored by gene-level selection when there is competition among siblings for limiting resources. By killing or weakening noncarrier competitor siblings, the gene(s) coding for zygotic drive gain a selective advantage because their survival is increased at the expense of siblings carrying alleles that are not identical by descent—despite any fitness loss to the parents, siblings, or other parts of the genome.Zygotic drive of the autosomes has been observed in a wide diversity of model organisms (e.g., worms, beetles, and mice) (reviewed in Burt and Trivers 2006) in which it can be efficiently detected because of the availability of numerous genetic markers. In general, an autosomal zygotic driver must have both a driver allele at one locus and a protective allele at a responder locus. In worms (Caenorhabditis elegans), a molecular mechanism leading to zygotic drive was recently discovered. Here a zygotic driver is coded by a pair of tightly linked genes, in which an allele at one gene (peel-1) produces a toxin, the driver locus, which is packaged in the sperm and transmitted to the zygote, whereas an allele at another gene (zeel-1) produces an antidote (the protective allele, which is expressed very early in development) that rescues only those embryos that inherit zeel-1 (and usually also the tightly linked driver, peel-1) (Seidel et al. 2011). Zygotic drive on the autosomes is expected to be difficult to evolve—and therefore to be relatively rare in genomes—because it requires an improbable phenotype (i.e., a functionally coupled driver gene product and a responder gene sequence or product) and genotype (i.e., very close linkage between the loci coding for the driver and responder). 相似文献
109.
Roman Gebauer Daniel Volaík Josef Urban Isabella Brja Nina Elisabeth Nagy Toril Drabls Eldhuset Paal Krokene 《Ecology and evolution》2015,5(21):4989-4998
Predicted increases in the frequency and duration of drought are expected to negatively affect tree vitality, but we know little about how water shortage will influence needle anatomy and thereby the trees’ photosynthetic and hydraulic capacity. In this study, we evaluated anatomical changes in sun and shade needles of 20‐year‐old Norway spruce trees exposed to artificial drought stress. Canopy position was found to be important for needle structure, as sun needles had significantly higher values than shade needles for all anatomical traits (i.e., cross‐sectional needle area, number of tracheids in needle, needle hydraulic conductivity, and tracheid lumen area), except proportion of xylem area per cross‐sectional needle area. In sun needles, drought reduced all trait values by 10–40%, whereas in shade needles, only tracheid maximum diameter was reduced by drought. Due to the relatively weaker response of shade needles than sun needles in drought‐stressed trees, the difference between the two needle types was reduced by 25% in the drought‐stressed trees compared to the control trees. The observed changes in needle anatomy provide new understanding of how Norway spruce adapts to drought stress and may improve predictions of how forests will respond to global climate change. 相似文献
110.