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121.
Olga Kononova Joost Snijder Melanie Brasch Jeroen Cornelissen Ruxandra?I. Dima Kenneth?A. Marx Gijs?J.L. Wuite Wouter?H. Roos Valeri Barsegov 《Biophysical journal》2013,105(8):1893-1903
Physical properties of capsids of plant and animal viruses are important factors in capsid self-assembly, survival of viruses in the extracellular environment, and their cell infectivity. Combined AFM experiments and computational modeling on subsecond timescales of the indentation nanomechanics of Cowpea Chlorotic Mottle Virus capsid show that the capsid’s physical properties are dynamic and local characteristics of the structure, which change with the depth of indentation and depend on the magnitude and geometry of mechanical input. Under large deformations, the Cowpea Chlorotic Mottle Virus capsid transitions to the collapsed state without substantial local structural alterations. The enthalpy change in this deformation state ΔHind = 11.5–12.8 MJ/mol is mostly due to large-amplitude out-of-plane excitations, which contribute to the capsid bending; the entropy change TΔSind = 5.1–5.8 MJ/mol is due to coherent in-plane rearrangements of protein chains, which mediate the capsid stiffening. Direct coupling of these modes defines the extent of (ir)reversibility of capsid indentation dynamics correlated with its (in)elastic mechanical response to the compressive force. This emerging picture illuminates how unique physico-chemical properties of protein nanoshells help define their structure and morphology, and determine their viruses’ biological function. 相似文献
122.
Olga Kononova Joost Snijder Melanie Brasch Jeroen Cornelissen Ruxandra I. Dima Kenneth A. Marx Gijs J.L. Wuite Wouter H. Roos Valeri Barsegov 《Biophysical journal》2013
Physical properties of capsids of plant and animal viruses are important factors in capsid self-assembly, survival of viruses in the extracellular environment, and their cell infectivity. Combined AFM experiments and computational modeling on subsecond timescales of the indentation nanomechanics of Cowpea Chlorotic Mottle Virus capsid show that the capsid’s physical properties are dynamic and local characteristics of the structure, which change with the depth of indentation and depend on the magnitude and geometry of mechanical input. Under large deformations, the Cowpea Chlorotic Mottle Virus capsid transitions to the collapsed state without substantial local structural alterations. The enthalpy change in this deformation state ΔHind = 11.5–12.8 MJ/mol is mostly due to large-amplitude out-of-plane excitations, which contribute to the capsid bending; the entropy change TΔSind = 5.1–5.8 MJ/mol is due to coherent in-plane rearrangements of protein chains, which mediate the capsid stiffening. Direct coupling of these modes defines the extent of (ir)reversibility of capsid indentation dynamics correlated with its (in)elastic mechanical response to the compressive force. This emerging picture illuminates how unique physico-chemical properties of protein nanoshells help define their structure and morphology, and determine their viruses’ biological function. 相似文献
123.
124.
Babu V. Sajesh Melanie Bailey Zelda Lichtensztejn Philip Hieter Kirk J. McManus 《Genetics》2013,195(3):757-767
Synthetic lethality is a rational approach to identify candidate drug targets for selective killing of cancer cells harboring somatic mutations that cause chromosome instability (CIN). To identify a set of the most highly connected synthetic lethal partner genes in yeast for subsequent testing in mammalian cells, we used the entire set of 692 yeast CIN genes to query the genome-wide synthetic lethal datasets. Hierarchical clustering revealed a highly connected set of synthetic lethal partners of yeast genes whose human orthologs are somatically mutated in colorectal cancer. Testing of a small matrix of synthetic lethal gene pairs in mammalian cells suggested that members of a pathway that remove reactive oxygen species that cause DNA damage would be excellent candidates for further testing. We show that the synthetic lethal interaction between budding yeast rad54 and sod1 is conserved within a human colorectal cancer context. Specifically, we demonstrate RAD54B-deficient cells are selectively killed relative to controls via siRNA-based silencing and chemical inhibition and further demonstrate that this interaction is conserved in an unrelated cell type. We further show that the DNA double strand breaks, resulting from increased reactive oxygen species following SOD1 inhibition, persist within the RAD54B-deficient cells and result in apoptosis. Collectively, these data identify SOD1 as a novel candidate cancer drug target and suggest that SOD1 inhibition may have broad-spectrum applicability in a variety of tumor types exhibiting RAD54B deficiencies. 相似文献
125.
Max Keller Melanie Kaske Tobias Holzammer Günther Bernhardt Armin Buschauer 《Bioorganic & medicinal chemistry》2013,21(21):6303-6322
The structurally related peptides neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) are endogenous agonists of the NPY receptor (YR) family, which in humans comprises four functionally expressed subtypes, designated Y1R, Y2R, Y4R and Y5R. Nonpeptide antagonists with high affinity and selectivity have been described for the Y1R, Y2R and Y5R, but such compounds are still lacking for the Y4R. In this work, the structures of the high affinity selective (R)-argininamide-type Y1R antagonists BIBP3226 and BIBO3304 were linked via the guanidine or urea moieties to give homo-dimeric argininamides with linker lengths ranging from 31 to 41 atoms. Interestingly, the twin compounds proved to be by far less selective for the Y1R than the R-configured monovalent parent compounds. The decrease in selectivity ratio was most pronounced for Y1R versus Y4R subtype, resulting in comparable affinities of bivalent ligands for Y1R and Y4R (e.g. UR-MK177 ((R,R)-49): Ki = 230 nM (Y1R) and 290 nM (Y4R)). With a Ki value of 130 nM and a Kb value of 20 nM, UR-MK188 ((R,R)-51) was superior to all Y4R antagonists known to date. The S,S-configured optical antipodes of UR-MK177 and UR-MK188 (UR-MEK381 ((S,S)-49) and UR-MEK388 ((S,S)-51)) were synthesized to investigate the stereochemical discrimination by the different receptor subtypes. Whereas preference for R,R-configured argininamides was characteristic of the Y1R, stereochemical discrimination by the Y4R was not observed. This may pave the way to selective Y4R antagonists. 相似文献
126.
127.
Many aquatic ecosystems are sustained by detrital subsidies of leaf litter derived from exogenous sources. Although numerous studies have examined the effects of litter species richness and identity on decomposition processes, it remains unclear how these effects extend to associated invertebrate communities or how these effects vary spatially according to local environmental context. Using field enrichment experiments, we assessed how the species richness, assemblage composition, and supply of detrital litter resources interact to affect benthic communities of three temperate Australian estuarine mudflats. Our experiments utilized eight litter sources that are presently experiencing human‐mediated changes in their supply to estuarine mudflats. Contrary to predictions, we did not detect effects of the species richness of detrital mixtures on benthic communities. Macroinvertebrate community structure and, in particular, abundance were, instead, influenced by the assemblage composition of detrital mixtures. At two of the three sites, plots receiving the most labile detrital mix, containing the ephemeral algae Chaetomorpha and Ulva, supported the fewest macroinvertebrates of all the experimental enrichments. The large effect of detrital mix identity on macroinvertebrate communities is of concern given present trends of proliferation of macroalgae at the expense of more refractory seagrasses and marsh grasses. As such environmental degradation continues, it will be important to more fully understand under what environmental contexts such compositional changes in detrital resources will have the most detrimental effects on important prey resources for commercially important fish and wading shorebirds. 相似文献
128.
Hiroshi Shinozuka Melanie L. Hand Noel O. I. Cogan German C. Spangenberg John W. Forster 《Ecology and evolution》2013,3(13):4415-4426
In plant species, control of flowering time is an important factor for adaptation to local natural environments. The Vrn1, CO, FT1 and CK2α genes are key components in the flowering‐specific signaling pathway of grass species. Meadow fescue is an agronomically important forage grass species, which is naturally distributed across Europe and Western Asia. In this study, meadow fescue flowering‐time‐related genes were resequenced to assess nucleotide diversity in European and Western Asian subpopulations. Identified sequence polymorphisms were then converted into PCR‐based molecular genetic markers, and a meadow fescue germplasm collection was genotyped to investigate global allelic variation. Lower nucleotide diversities were observed for the Vrn1 and CO orthologs, while relatively higher values were observed for the FT1 and casein kinase II α‐subunit (CK2α) orthologs. The nucleotide diversity for FT1 orthologs in the Western Asian subpopulation was significantly higher than those of the European subpopulation. Similarly, significant differences in nucleotide diversity for the remaining genes were observed between several combinations of subpopulation. The global allele distribution pattern was consistent with observed level of nucleotide diversity. These results suggested that the degree of purifying selection acting on the genes differs according to geographical location. As previously shown for model plant species, functional specificities of flowering‐time‐related genes may also vary according to environmental conditions. 相似文献
129.
Nikolai M. Veter Larisa R. G. DeSantis Lindsey T. Yann Shelly L. Donohue Ryan J. Haupt Sarah E. Corapi Siobhan L. Fathel Emily K. Gootee Lucas F. Loffredo Jennifer L. Romer Stoycho M. Velkovsky 《Biology letters》2013,9(5)
Macroecology strives to identify ecological patterns on broad spatial and temporal scales. One such pattern, Rapoport''s rule, describes the tendency of species'' latitudinal ranges to increase with increasing latitude. Several mechanisms have been proposed to explain this rule. Some invoke climate, either through glaciation driving differential extinction of northern species or through increased seasonal variability at higher latitudes causing higher thermal tolerances and subsequently larger ranges. Alternatively, continental tapering or higher interspecific competition at lower latitudes may be responsible. Assessing the incidence of Rapoport''s rule through deep time can help to distinguish between competing explanations. Using fossil occurrence data from the Palaeobiology Database, we test these hypotheses by evaluating mammalian compliance with the rule throughout the Caenozoic of North America. Adherence to Rapoport''s rule primarily coincides with periods of intense cooling and increased seasonality, suggesting that extinctions caused by changing climate may have played an important role in erecting the latitudinal gradients in range sizes seen today. 相似文献
130.
Yan Hu Brian L. Ellis Ying Y. Yiu Melanie M. Miller Joseph F. Urban Linda Z. Shi Raffi V. Aroian 《PloS one》2013,8(7)
Soil-transmitted helminths are parasitic nematodes that inhabit the human intestine. These parasites, which include two hookworm species,
Ancylostoma
duodenale
and Necator americanus, the whipworm
Trichuris
trichiura
, and the large roundworm
Ascaris
lumbricoides
, infect upwards of two billion people and are a major cause of disease burden in children and pregnant women. The challenge with treating these diseases is that poverty, safety, and inefficient public health policy have marginalized drug development and distribution to control infection in humans. Anthelmintics (anti-worm drugs) have historically been developed and tested for treatment of non-human parasitic nematodes that infect livestock and companion animals. Here we systematically compare the in vitro efficacy of all major anthelmintic classes currently used in human therapy (benzimidazoles, nicotinic acetylcholine receptor agonists, macrocyclic lactones, nitazoxanide) against species closely related to human parasitic nematodes-Ancylostoma ceylanicum,
Trichuris
muris
, and
Ascaris
suum
--- as well as a rodent parasitic nematode used in veterinary drug discovery,
Heligmosomoides
bakeri
, and the free-living nematode Caenorhabditis elegans. Extensive in vitro data is complemented with single-dose in vivo data in three rodent models of parasitic diseases. We find that the effects of the drugs in vitro and in vivo can vary greatly among these nematode species, e.g., the efficacy of albendazole is strong on A. ceylanicum but weak on
H
. bakeri
. Nonetheless, certain commonalities of the in vitro effects of the drugs can be seen, e.g., nitazoxanide consistently shows an all-or-nothing response. Our in vitro data suggest that further optimization of the clinical efficacy of some of these anthelmintics could be achieved by altering the treatment routine and/or dosing. Most importantly, our in vitro and in vivo data indicate that the hookworm A. ceylanicum is a particularly sensitive and useful model for anthelmintic studies and should be incorporated early on in drug screens for broad-spectrum human soil-transmitted helminth therapies. 相似文献