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991.
Dead-end elimination with backbone flexibility 总被引:1,自引:0,他引:1
MOTIVATION: Dead-End Elimination (DEE) is a powerful algorithm capable of reducing the search space for structure-based protein design by a combinatorial factor. By using a fixed backbone template, a rotamer library, and a potential energy function, DEE identifies and prunes rotamer choices that are provably not part of the Global Minimum Energy Conformation (GMEC), effectively eliminating the majority of the conformations that must be subsequently enumerated to obtain the GMEC. Since a fixed-backbone model biases the algorithm predictions against protein sequences for which even small backbone movements may result in a significantly enhanced stability, the incorporation of backbone flexibility can improve the accuracy of the design predictions. If explicit backbone flexibility is incorporated into the model, however, the traditional DEE criteria can no longer guarantee that the flexible-backbone GMEC, the lowest-energy conformation when the backbone is allowed to flex, will not be pruned. RESULTS: We derive a novel DEE pruning criterion, flexible-backbone DEE (BD), that is provably accurate with backbone flexibility, guaranteeing that no rotamers belonging to the flexible-backbone GMEC are pruned; we also present further enhancements to BD for improved pruning efficiency. The results from applying our novel algorithms to redesign the beta1 domain of protein G and to switch the substrate specificity of the NRPS enzyme GrsA-PheA are then compared against the results from previous fixed-backbone DEE algorithms. We confirm experimentally that traditional-DEE is indeed not provably-accurate with backbone flexibility and that BD is capable of generating conformations with significantly lower energies, thus confirming the feasibility of our novel algorithms. AVAILABILITY: Contact authors for source code. 相似文献
992.
Pathophysiological concentrations of branched chain keto-acids (BCKAs), such as those that occur in maple syrup urine disease,
inhibit oxygen consumption in liver homogenates and brain slices and the enzymatic activity of α-ketoglutarate- and pyruvate
dehydrogenase complexes. Consistent with previous work, studies in isolated rat liver mitochondria indicate that three BCKAs,
α-ketoisocaproate (KIC), α-keto-β-methylvalerate (KMV) and α-ketoisovalerate (KIV), preferentially inhibited State 3 respiration
supported by α-ketoglutarate relative to succinate or glutamate/malate (KIC, >100-fold; KMV, >10-fold; KIV, >4-fold). KIC
was also the most potent inhibitor (Ki,app 13 ± 2 μM). Surprisingly, sub-inhibitory concentrations of KIC and KMV can markedly stimulate State 3 respiration of mitochondria utilizing α-ketoglutarate and glutamate/malate, but not succinate. The data suggest that
physiological concentrations of the BCKAs may modulate mitochondrial respiration.
Special issue dedicated to John P. Blass. 相似文献
993.
We investigate the combination of environmental factors that influence the distribution patterns of benthic foraminiferal tests (> 63 μm) in a topographically varied region crossed by both the Subtropical and Subantarctic Fronts, south-east of New Zealand. Seafloor sample sites, extending from outer shelf (50 m) to abyssal (5000 m) depths, are bathed by five different water masses, and receive phytodetritus from Subtropical, Subantarctic and Circumpolar surface water masses. Eight mappable associations are recognised by Q-mode cluster analysis of the benthic foraminiferal census data. Similar associations are identified using cluster analysis based solely on the presence or absence of species. Canonical correspondence analysis and a correlation coefficient matrix were used to relate the faunal data to a set of environmental proxies. These show that factors related to water depth (especially decreasing food supply with increasing depth) are the most significant in determining the overall foraminiferal distribution. Other contributing factors include surface water productivity and its seasonality; bottom water ventilation; energetic state of the benthic boundary layer and resulting substrate texture; and bottom water carbonate corrosiveness. Three shallow-water associations (50–700 m), dominated by Cassidulina carinata, Trifarina angulosa, Globocassidulina canalisuturata, Gavelinopsis praegeri, and Bolivina robusta, occur in coarse substrates on the continental shelf, and on the crests and upper slopes of four seamounts under well-oxygenated, high energy regimes, and high food input. Three mid bathyal to upper abyssal associations (500–3300 m), dominated by Alabaminella weddellensis, C. carinata, and Epistominella exigua, occur in biopelagic sandy mud, beneath a region of strongly seasonal food supply, with their composition influenced by total food flux, ventilation (Oxygen Minimum Zone), and bottom current strength. An unusual lower bathyal association (1200–2100 m), dominated by T. angulosa and Ehrenbergina glabra, occurs in a belt of coarser sandy substrate that runs along the crest of the submarine plateaux slopes beneath the strongly-flowing Subantarctic Front-related currents. A deep abyssal association (3500–5000 m), dominated by Nuttallides umbonifer and Globocassidulina subglobosa, occurs on the abyssal plain beneath oligotrophic lower Circumpolar Water south-east of the Subantarctic Front and is strongly influenced by the cold, carbonate-corrosive conditions. 相似文献
994.
Stukenbrock EH Banke S Javan-Nikkhah M McDonald BA 《Molecular biology and evolution》2007,24(2):398-411
The Fertile Crescent represents the center of origin and earliest known place of domestication for many cereal crops. During the transition from wild grasses to domesticated cereals, many host-specialized pathogen species are thought to have emerged. A sister population of the wheat-adapted pathogen Mycosphaerella graminicola was identified on wild grasses collected in northwest Iran. Isolates of this wild grass pathogen from 5 locations in Iran were compared with 123 M. graminicola isolates from the Middle East, Europe, and North America. DNA sequencing revealed a close phylogenetic relationship between the pathogen populations. To reconstruct the evolutionary history of M. graminicola, we sequenced 6 nuclear loci encompassing 464 polymorphic sites. Coalescence analyses indicated a relatively recent origin of M. graminicola, coinciding with the known domestication of wheat in the Fertile Crescent around 8,000-9,000 BC. The sympatric divergence of populations was accompanied by strong genetic differentiation. At the present time, no genetic exchange occurs between pathogen populations on wheat and wild grasses although we found evidence that gene flow may have occurred since genetic differentiation of the populations. 相似文献
995.
Kindt KS Quast KB Giles AC De S Hendrey D Nicastro I Rankin CH Schafer WR 《Neuron》2007,55(4):662-676
Dopamine has been implicated in the modulation of diverse forms of behavioral plasticity, including appetitive learning and addiction. An important challenge is to understand how dopamine's effects at the cellular level alter the properties of neural circuits to modify behavior. In the nematode C. elegans, dopamine modulates habituation of an escape reflex triggered by body touch. In the absence of food, animals habituate more rapidly than in the presence of food; this contextual information about food availability is provided by dopaminergic mechanosensory neurons that sense the presence of bacteria. We find that dopamine alters habituation kinetics by selectively modulating the touch responses of the anterior-body mechanoreceptors; this modulation involves a D1-like dopamine receptor, a Gq/PLC-beta signaling pathway, and calcium release within the touch neurons. Interestingly, the body touch mechanoreceptors can themselves excite the dopamine neurons, forming a positive feedback loop capable of integrating context and experience to modulate mechanosensory attention. 相似文献
996.
We develop a kinetic model that builds on the foundation of classic Monod kinetics, but incorporates new phenomena such as substrate thresholds and survival mode observed in experiments with the H2-oxidizing methanogen Methanobacterium bryantii M.o.H. We apply our model to the experimental data presented in our companion paper on H2 thresholds. The model accurately describes H2 consumption, CH4 generation, biomass growth, substrate thresholds, and survival state during batch experiments. Methane formation stops when its Gibbs free energy is equal zero, although this does not interrupt H2 oxidation. The thermodynamic threshold for H2 oxidation occurs when the free energy for oxidizing H2 and transferring electrons to biomass is no longer negative, at approximately 0.4 nM. This threshold is not controlled by the Gibbs free energy equation of methanogenesis from H2 + HCO3- as we show in our companion paper. Beyond this threshold, the microorganisms shift to a low-maintenance metabolism called "the survival state" in response to extended H2 starvation; adding the starvation response as another new feature of the kinetic model. A kinetic threshold (or S (min)), a natural feature of the Monod kinetics, is also captured by the model at H2 concentration of around approximately 2,400 nM. S (min) is the minimum substrate concentration to maintain steady-state biomass concentration. Our model will be useful for interpreting threshold results and designing new studies to understand thresholds and their ecological implications. 相似文献
997.
We develop a comprehensive biogeochemical framework for understanding and quantitatively evaluating metals bio-protection
in sulfidic microbial systems. We implement the biogeochemical framework in CCBATCH by expanding its chemical equilibrium
and biological sub-models for surface complexation and the formation of soluble and solid products, respectively. We apply
the expanded CCBATCH to understand the relative importance of the various key ligands of sulfidic systems in Zn detoxification.
Our biogeochemical analysis emphasizes the relative importance of sulfide over other microbial products in Zn detoxification,
because the sulfide yield is an order of magnitude higher than that of other microbial products, while its reactivity toward
metals also is highest. In particular, metal-titration simulations using the expanded CCBATCH in a batch mode illustrate how
sulfide detoxifies Zn, controlling its speciation as long as total sulfide is greater than added Zn. Only in the absence of
sulfide does complexation of Zn to biogenic organic ligands play a role in detoxification. Our biogeochemical analysis conveys
fundamental insight on the potential of the key ligands of sulfidic systems to effect Zn detoxification. Sulfide stands out
for its reactivity and prevalence in sulfidic systems. 相似文献
998.
We tested the hypothesis that the H2-based membrane biofilm reactor (MBfR) is capable of reducing multiple oxidized contaminants, a common situation for groundwater
contamination. We conducted bench-scale experiments with three groundwater samples collected from California’s San Joaquin
Valley and on two synthetic groundwaters containing selenate and chromate. The actual groundwater sources had nitrate levels
exceeding 10 mg-N l−1 and different combinations of anthropogenic perchlorate + chlorate, arsenate, and dibromochloropropane (DBCP). For all actual
groundwaters, the MBfR reduced nitrate to less than 0.01 mg-N l−1. Present in two groundwaters, perchlorate + chlorate was reduced to below the California Notification Level, 6 μg-ClO4 l−1. As(V) was substantially reduced to As(III) for two groundwaters samples, which had influent As(V) concentrations from 3
to 8.8 μg-As l−1. DBCP, present in one groundwater at 1.4 μg l−1, was reduced to below its detection limit of 0.01 μg l−1, which is well below California’s 0.2 μg l−1 MCL for DBCP. For the synthetic groundwaters, two MBfRs initially reduced Se(VI) or Cr(VI) stably to Se° or Cr(III). When
we switched the influent oxidized contaminants, the new oxidized contaminant was reduced immediately, and its reduction soon
was approximately the same or greater than it had been reduced in its original MBfR. These results support that the H2-based MBfR can reduce multiple oxidized contaminants simultaneously. 相似文献
999.
Gealy EC Kerr BC Young RD Tudor D Hayes AJ Hughes CE Caterson B Quantock AJ Ralphs JR 《Histochemistry and cell biology》2007,128(6):551-555
Keratan sulphate (KS) proteoglycans (PGs) are key molecules in the connective tissue matrix of the cornea of the eye, where
they are believed to have functional roles in tissue organisation and transparency. Keratocan, is one of the three KS PGs
expressed in cornea, and is the only one that is primarily cornea-specific. Work with the developing chick has shown that
mRNA for keratocan is present in early corneal embryogenesis, but there is no evidence of protein synthesis and matrix deposition.
Here, we investigate the tissue distribution of keratocan in the developing chick cornea as it becomes compacted and transparent
in the later stages of development. Indirect immunofluorescence using a new monoclonal antibody (KER-1) which recognises a
protein epitope on the keratocan core protein demonstrated that keratocan was present at all stages investigated (E10–E18),
with distinct differences in localisation and organisation observed between early and later stages. Until E13, keratocan appeared
both cell-associated and in the stromal extracellular matrix, and was particularly concentrated in superficial tissue regions.
By E14 when the cornea begins to become transparent, keratocan was located in elongate arrays, presumably associated along
collagen fibrils in the stroma. This fibrillar label was still concentrated in the anterior stroma, and persisted through
E15–E18. Presumptive Bowman’s layer was evident as an unlabelled subepithelial zone at all stages. Thus, in embryonic chick
cornea, keratocan, in common with sulphated KS chains in the E12–E14 developmental period, exhibits a preferential distribution
in the anterior stroma. It undergoes a striking reorganisation of structure and distribution consistent with a role in relation
to stromal compaction and corneal transparency.
E. Claire Gealy and Briedgeen C. Kerr were joint first authors. 相似文献
1000.
Hair cells of the inner ear develop from an equivalence group marked by expression of the proneural gene Atoh1. In mouse, Atoh1 is necessary for hair cell differentiation, but its role in specifying the equivalence group (proneural function) has been questioned and little is known about its upstream activators. We have addressed these issues in zebrafish. Two zebrafish homologs, atoh1a and atoh1b, are together necessary for hair cell development. These genes crossregulate each other but are differentially required during distinct developmental periods, first in the preotic placode and later in the otic vesicle. Interactions with the Notch pathway confirm that atoh1 genes have early proneural function. Fgf3 and Fgf8 are upstream activators of atoh1 genes during both phases, and foxi1, pax8 and dlx genes regulate atoh1b in the preplacode. A model is presented in which zebrafish atoh1 genes operate in a complex network leading to hair cell development. 相似文献