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141.
142.
A combination of inter- and intra-species genome comparisons is required to identify and classify the full spectrum of genetic changes, both subtle and gross, that have accompanied the evolutionary divergence of humans and other primates. In this study, gene order comparisons of 11,518 human and chimpanzee orthologous gene pairs were performed to detect regions of inverted gene order that are potentially indicative of small-scale rearrangements such as inversions. By these means, a total of 71 potential micro-rearrangements were detected, nine of which were considered to represent micro-inversions encompassing more than three genes. These putative inversions were then investigated by FISH and/or PCR analyses and the authenticity of five of the nine inversions, ranging in size from approximately 800 kb to approximately 4.4 Mb, was confirmed. These inversions mapped to 1p13.2-13.3, 7p22.1, 7p13-14.1, 18p11.21-11.22 and 19q13.12 and encompass 50, 14, 16, 7 and 16 known genes, respectively. Intriguingly, four of the confirmed inversions turned out to be polymorphic: three were polymorphic in the chimpanzee and one in humans. It is concluded that micro-inversions make a significant contribution to genomic variability in both humans and chimpanzees and inversion polymorphisms may be more frequent than previously realized.  相似文献   
143.
BACKGROUND: Viruses are being exploited as vectors to deliver therapeutic genetic information into target cells. The success of this approach will depend on the ability to overcome current limitations, especially in terms of safety and efficiency, through molecular engineering of the viral particles. METHODS: Here we show that in vitro directed evolution can be successfully performed to randomize the viral capsid by error prone PCR and to obtain mutants with improved phenotype. RESULTS: To demonstrate the potential of this technology we selected several adeno-associated virus (AAV) capsid variants that are less efficiently neutralized by human antibodies. These mutations can be used to generate novel vectors for the treatment of patients with pre-existing immunity to AAV. CONCLUSIONS: Our results demonstrate that combinatorial engineering overcomes the limitations of rational design approaches posed by incomplete understanding of the infectious process and at the same time offers a powerful tool to dissect basic viral biology by reverse genetics.  相似文献   
144.
Abundant calcispheres occur in Upper Carnian and Norian hemipelagic limestone successions of the Southern Apennines and Sicily. They exhibit a variety of morphologies that were investigated with optical and scanning electron microscopy (SEM). The most common morphology is that of a full solid sphere of radiaxial calcite crystals, 20–22 μm in diameter on average, with or without a minor hollow in the center. Smaller forms may be clusters of sub-micron crystals, only rarely disposed as to form a spherical test with a diameter of 10 μm or less. Larger forms are similar to small forms (clusters or spheres of sub-micron crystals) with an epitaxial calcite overgrowth. The taxonomic attribution of these calcispheres is uncertain, mostly because of their poor preservation, but a comparison is possible with some Mesozoic calcispheres attributed to calcareous dinocysts. The amount of epitaxial overgrowth is variable, but in most cases much larger than the original sphere. This prevents a significant evaluation of the contribution of calcispheres to carbonate pelagic sedimentation by point counting in thin-section. However, it can be shown that calcispheres become abundant only after a major climatic perturbation dated at the end of the Early Carnian, known as the Carnian Pluvial Event (CPE). This event involved a strong and prolonged enhancement of the hydrological cycle, with consequent supply of excess hydrogen carbonate to the oceans and increased seawater alkalinity. Although calcispheres of this type are known at least from the Middle Triassic, it is only shortly after the CPE that they become abundant, and the first common occurrence of calcareous nannoplankton in the western Tethys is thus Late Carnian in age.  相似文献   
145.
Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as ‘reduced (or incomplete) penetrance’. Reduced penetrance is not uncommon; indeed, there are many known examples of ‘disease-causing mutations’ that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease.  相似文献   
146.
Uecker H  Hermisson J 《Genetics》2011,188(4):915-930
A population that adapts to gradual environmental change will typically experience temporal variation in its population size and the selection pressure. On the basis of the mathematical theory of inhomogeneous branching processes, we present a framework to describe the fixation process of a single beneficial allele under these conditions. The approach allows for arbitrary time-dependence of the selection coefficient s(t) and the population size N(t), as may result from an underlying ecological model. We derive compact analytical approximations for the fixation probability and the distribution of passage times for the beneficial allele to reach a given intermediate frequency. We apply the formalism to several biologically relevant scenarios, such as linear or cyclic changes in the selection coefficient, and logistic population growth. Comparison with computer simulations shows that the analytical results are accurate for a large parameter range, as long as selection is not very weak.  相似文献   
147.
Under normal growth conditions the mammalian target of rapamycin complex 1 (mTORC1) negatively regulates the central autophagy regulator complex consisting of Unc-51-like kinases 1/2 (Ulk1/2), focal adhesion kinase family-interacting protein of 200 kDa (FIP200) and Atg13. Upon starvation, mTORC1-mediated repression of this complex is released, which then leads to Ulk1/2 activation. In this scenario, Atg13 has been proposed as an adaptor mediating the interaction between Ulk1/2 and FIP200 and enhancing Ulk1/2 kinase activity. Using Atg13-deficient cells, we demonstrate that Atg13 is indispensable for autophagy induction. We further show that Atg13 function strictly depends on FIP200 binding. In contrast, the simultaneous knockout of Ulk1 and Ulk2 did not have a similar effect on autophagy induction. Accordingly, the Ulk1-dependent phosphorylation sites we identified in Atg13 are expendable for this process. This suggests that Atg13 has an additional function independent of Ulk1/2 and that Atg13 and FIP200 act in concert during autophagy induction.  相似文献   
148.
Zusammenfassung Die spektrale Empfindlichkeitskurve des Auges von Calliphora erythrocephala wird zwischen 400 und 690 m gemessen (Abb. 5). Sie hat zwei deutliche Maxima, und zwar bei 540 und 630 m. Das sichtbare Spektrum reicht bis etwa 730 m. Bei 400 m beträgt die Empfindlichkeit noch 30% der maximalen bei 540 m (gegenüber 5% bei den Wirbeltieren).Das Farbensehen wird mit einer neuen elektrophysiologischen Methode untersucht: Es werden die Belichtungspotentiale bei heterochromatischem Flimmern wirksamkeitsgleicher monochromatischer Lichter beobachtet (Abb. 9, 10).Glühlicht, das dem menschlichen Auge unbunt erscheint, kann von fast allen Farben des Spektrums unterschieden werden; eine Ausnahme macht nur gelbes Licht von 580 m, das mit Unbunt vertauschbar ist (Graustelle).Innerhalb des roten Bereiches (690–630 m) ist die Farbenunterscheidung nur gering. Jedoch wird dieser Bereich von allen anderen als eigene Qualität unterschieden. Von 630 m bis zur Graustelle liegt ein Bereich eigener Qualität. Die verschiedenen Wellenlängen dieses Bereiches werden sehr gut unterschieden. Von 580 m (Graustelle) bis 480 m nimmt die Farbigkeit wieder zu und erreicht bei 480 m ein Maximum; die Farbenunterscheidung in diesem Bereich ist geringer als zwischen 630 und 580 m (Orange), aber besser als im roten Gebiet. Der Bereich um 480–500 m hebt sich von der spektralen Umgebung als ein Gebiet starker Farbigkeit ab, von hier nimmt nach beiden Seiten die WeißVerhüllung zu. Beiderseits dieses Bereiches gibt es Wellenlängen, die miteinander verwechselt werden (Abb. 13).In vielen Eigenschaften ist das Farbensehen von Calliphora der tritanopen Farbenfehlsichtigkeit des Menschen ähnlich.Es wurden Individuen gefunden, die Anomalitäten des Farbensehens und zugleich Abweichungen in der spektralen Empfindlichkeit aufwiesen. Eines dieser Tiere war total farbenblind; ihm fehlte gleichzeitig die Rotempfindlichkeit.Das normale Auge von Calliphora besitzt im Bereich von 400 bis 700 m wahrscheinlich nur zwei farbenspezifische Rezeptorensysteme. Das Maximum dieser Systeme liegt bei 630 bzw. 520 m. Für beide wird der ungefähre Verlauf der spektralen Empfindlichkeit angegeben.Die Untersuchungen wurden mit Unterstützung der Deutschen Forschungsgemeinschaft durchgeführt.  相似文献   
149.
Summary Isolated gastrula ectoderm has no neural-inducing activity and does not differentiate into neural tissues. It has, however, a high neural-inducing capacity, but the inducing factors are present in a masked, inactive form. The inducing factors are partially activated by homogenization and by freezing of the homogenate and are fully activated by treatment with ethanol. The relative distribution of inducing factors in different subcellular fractions changes after treatment with demecolcine and cytochalasin B or after autolytic incubation of the homogenate. The inducing activity of the high-speed supernatant is enhanced under these conditions. The experiments suggest that the activation of neuralizing factor(s) depends on the release from complex structures. Cytoskeletal elements seem to be involved. When early neural plate homogenate was fractionated, the high-speed supernatant showed neural-inducing activity. This is in contrast to the high-speed supernatant from the ectoderm homogenate, which shows no such activity.  相似文献   
150.
Rat brain microsomes have the capacity to liberate radioactive free aldehydes from 1-[1-14C]alk-1'-enyl-sn-glycero-3-phosphoethanolamine (lysoplasmalogen). Glycerophosphoethanolamine was found using 1-alk-1'-enyl-sn-glycero-3-phospho-[3H]ethanolamine. The ratio of both products released by lysoplasmalogenase action was 1:1. Another enzymic activity could be demonstrated, which hydrolyzes lysoplasmalogen at the hydrophilic part of the molecule, a lysophospholipid phosphodiesterase. Thus, 1-[1-14C]alk-1'-enylglycerol was detected as well as [3H]ethanolamine, again in a molar ratio, from the respective labeled substrates. This enzyme possesses nearly the same affinity toward the substrate as lysoplasmalogenase. Whereas the lysophospholipid phosphodiesterase is totally inhibited in the presence of NaF or EDTA, lysoplasmalogenase activity is not affected by these reagents. 1-[1-14C]Alk-1'-enylglycerol acts also as substrate for lysoplasmalogenase, which liberates radioactive aldehydes at the same rate as from lysoplasmalogen. Because the apparent Km and Vmax values are nearly identical for both substrates, the enzyme activities are inhibited in the same way, and the pH optimum is about 7.2 in both cases, it is concluded that both substrates were attacked by the same enzyme. The enzyme does not differentiate between a substrate substituted at the sn-3 position of glycerol and one that is not. It requires only a free OH group at the sn-2 position. Phosphoethanolamine phosphatase activity was also determined under our experimental conditions.  相似文献   
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