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91.
Yi Zhu Julius Bogomolovas Siegfried Labeit Henk Granzier 《The Journal of biological chemistry》2009,284(20):13914-13923
The small heat shock protein αB-crystallin interacts with N2B-Us, a
large unique sequence found in the N2B element of cardiac titin. Using single
molecule force spectroscopy, we studied the effect of αB-crystallin on
the N2B-Us and its flanking Ig-like domains. Ig domains from the proximal
tandem Ig segment of titin were also studied. The effect of wild type
αB-crystallin on the single molecule force-extension curve was
determined as well as that of mutant αB-crystallins harboring the
dilated cardiomyopathy missense mutation, R157H, or the desmin-related
myopathy mutation, R120G. Results revealed that wild type αB-crystallin
decreased the persistence length of the N2B-Us (from ∼0.7 to ∼0.2 nm)
but did not alter its contour length. αB-crystallin also increased the
unfolding force of the Ig domains that flank the N2B-Us (by 51 ± 3
piconewtons); the rate constant of unfolding at zero force was estimated to be
∼17-fold lower in the presence of αB-crystallin (1.4 ×
10-4 s-1 versus 2.4 × 10-3
s-1). We also found that αB-crystallin increased the
unfolding force of Ig domains from the proximal tandem Ig segment by 28
± 6 piconewtons. The effects of αB-crystallin were attenuated by
the R157H mutation (but were still significant) and were absent when using the
R120G mutant. We conclude that αB-crystallin protects titin from damage
by lowering the persistence length of the N2B-Us and reducing the Ig domain
unfolding probability. Our finding that this effect is either attenuated
(R157H) or lost (R120G) in disease causing αB-crystallin mutations
suggests that the interaction between αB-crystallin and titin is
important for normal heart function.αB-crystallin is a member of the small heat shock protein family that
by inhibiting denaturation and aggregation of proteins functions as a
molecular chaperone (1).
Although αB-crystallin has been most intensively studied in the
vertebrate eye lens, it is also found in many other tissues
(2) with cardiac muscle
expressing αB-crystallin at 3-5% of the total soluble protein
(3). Up-regulation of
αB-crystallin occurs in a number of cardiac disorders, including
familial cardiac hypertrophy, and overexpression appears to protect the
cardiac cell from ischemia reperfusion injury (for a review see Ref.
4). An important binding
partner of αB-crystallin in cardiac muscle is titin
(5,
6). Titin is a large
filamentous protein that forms a continuous filament along the myofibril, with
single titin molecules spanning from the edge to the middle of the sarcomere,
a distance of ∼1 μm (7).
The I-band region of titin is extensible and functions as a molecular spring
that, when extended, develops force
(8,
9). This force is an important
determinant of the passive stiffness of the heart that determines the filling
characteristics during the diastolic part of the heart cycle
(10). The interaction between
αB-crystallin and titin could be important for maintaining heart
function, especially when stressed, such as during ischemia
(5), warranting studies of the
effect of αB-crystallin on the biomechanical properties of titin.The molecular spring region of titin contains three distinct spring
elements (7). The first element
is the tandem Ig segment, consisting of serially linked Ig domains that form
the so-called proximal tandem Ig segment (15 Ig domains) near the Z-disk of
the sarcomere and a distal segment (22 Ig domains) near the A-band
(11). The second spring
element is the PEVK, a unique sequence that contains largely prolines,
glutamates, valines, and lysines
(11). The third element
consists of a large unique sequence (in human 572 residues in size) named the
N2B-Us; it is heart-specific and dominates the extension of titin near the
upper limit of the physiological sarcomere length range
(12). αB-crystallin
appears to preferentially bind to the N2B-Us, although weak binding to Ig
domains has also been detected
(6). Previous studies have
shown that αB-crystallin increases the unfolding force of Ig 91-98, a
fragment that contains eight Ig domains from the distal tandem Ig segment of
titin (6). However, the
mechanical effect of αB-crystallin on the N2B-Us (its main binding
partner in titin) has not been investigated.The association between αB-crystallin and titin has prompted a search
for disease causing mutations in αB-crystallin. This revealed in
patients with dilated cardiomyopathy
(DCM),2 a missense
mutation, R157H, that affects an evolutionarily conserved amino acid residue;
the mutation decreases the binding to the N2B domain without affecting
distribution of the mutant crystallin protein in cardiomyocytes
(13). In another disease, the
desmin-related myopathy mutation R120G
(14) decreases the binding of
αB-crystallin to the N2B element and causes intracellular aggregates of
the mutant protein (13).In the present study, we used single molecule force spectroscopy and
determined the contour length (CL; end-to-end length when stretched with
infinite force) and persistence length (PL; a measure of the bending rigidity)
of the N2B-Us. We also studied the unfolding force of Ig domains, those that
flank the N2B-Us and those that make up the proximal tandem Ig segment. In
addition, we investigated the effect of wild type and R157H and R120G
αB-crystallin on the molecular mechanics of the N2B-Us, its flanking Ig
domains, and the Ig domains in the proximal tandem Ig segment. Findings
support that αB-crystallin functions as a chaperone that lowers the
probability of Ig domain unfolding and the persistence length of the titin
N2B-Us spring region. Importantly, this chaperone function is significantly
reduced by the R157H mutation and abolished by the R120G mutation. 相似文献
92.
93.
E. DILLANE P. MCGINNITY J. P. COUGHLAN M. C. CROSS E. DE EYTO E. KENCHINGTON P. PRODÖHL T. F. CROSS 《Molecular ecology》2008,17(22):4786-4800
Contemporary genetic structure of Atlantic salmon (Salmo salar L.) in the River Moy in Ireland is shown here to be strongly related to landscape features and population demographics, with populations being defined largely by their degree of physical isolation and their size. Samples of juvenile salmon were collected from the 17 major spawning areas on the river Moy and from one spawning area in each of five smaller nearby rivers. No temporal allele frequency differences were observed within locations for 12 microsatellite loci, whereas nearly all spatial samples differed significantly, suggesting that each was a separate population. Bayesian clustering and landscape genetic analyses suggest that these populations can be combined hierarchically into five genetically informative larger groupings. Lakes were found to be the single most important determinant of the observed population structure. Spawning area size was also an important factor. The salmon population of the closest nearby river resembled genetically the largest Moy population grouping. In addition, we showed that anthropogenic influences on spawning habitats, in this case arterial drainage, can affect relationships between populations. Our results show that Atlantic salmon biodiversity can be largely defined by geography, and thus, knowledge of landscape features (for example, as characterized within Geographical Information Systems) has the potential to predict population structure in other rivers without an intensive genetic survey, or at least to help direct sampling. This approach of combining genetics and geography, for sampling and in subsequent statistical analyses, has wider application to the investigation of population structure in other freshwater/anadromous fish species and possibly in marine fish and other organisms. 相似文献
94.
Brian R. Anderson Julius Bogomolovas Siegfried Labeit Henk Granzier 《The Journal of biological chemistry》2013,288(8):5303-5315
Titin plays crucial roles in sarcomere organization and cardiac elasticity by acting as an intrasarcomeric molecular spring. A mutation in the tenth Ig-like domain of titin''s spring region is associated with arrhythmogenic cardiomyopathy, a disease characterized by ventricular arrhythmias leading to cardiac arrest and sudden death. Titin is the first sarcomeric protein linked to arrhythmogenic cardiomyopathy. To characterize the disease mechanism, we have used atomic force microscopy to directly measure the effects that the disease-linked point mutation (T16I) has on the mechanical and kinetic stability of Ig10 at the single molecule level. The mutation decreases the force needed to unfold Ig10 and increases its rate of unfolding 4-fold. We also found that T16I Ig10 is more prone to degradation, presumably due to compromised local protein structure. Overall, the disease-linked mutation weakens the structural integrity of titin''s Ig10 domain and suggests an Ig domain disease mechanism. 相似文献
95.
The growth of two strains of Myxococcus virescens exhibiting dispersed growth was followed in casamino acids (N III-C) media and casitone media. The changes in optical density, pH, pigmentation as well as the secretion of bacteriolytic and proteolytic enzymes, DNA and polysaccharides during growth were recorded. In both media the bacteria grew exponentially with a generation time of 4 (casitone) and 20 hours (N III-C) respectively. The maximal cell mass was about 4 times higher in casitone than in casamino acids media. The amounts of bacteriolytic enzymes produced by the two strains in N III-C medium were different but in casitone medium they were about equal and considerably higher. The maximal values of proteolytic enzymes were about the same in both media and always occurred later than the bacteriolytic maxima. Both activity peaks appeared before the phase of decline. The polysaccharide production reached a maximum during the stationary growth phase in both media. A higher value was reached during growth in casitone medium than in N III-C medium. During the phase of decline a second increase of polysaccharide in the medium appeared. No DNA could be detected in the cell-free solutions until the beginning of the phase of decline. 相似文献
96.
97.
98.
99.
Jochen Gohlke Paola Tonino Johan Lindqvist John E. Smith III Henk Granzier 《The Journal of general physiology》2021,153(3)
Nebulin is a skeletal muscle protein that associates with the sarcomeric thin filaments and has functions in regulating the length of the thin filament and the structure of the Z-disk. Here we investigated the nebulin gene in 53 species of birds, fish, amphibians, reptiles, and mammals. In all species, nebulin has a similar domain composition that mostly consists of ∼30-residue modules (or simple repeats), each containing an actin-binding site. All species have a large region where simple repeats are organized into seven-module super-repeats, each containing a tropomyosin binding site. The number of super-repeats shows high interspecies variation, ranging from 21 (zebrafish, hummingbird) to 31 (camel, chimpanzee), and, importantly, scales with body size. The higher number of super-repeats in large animals was shown to increase thin filament length, which is expected to increase the sarcomere length for optimal force production, increase the energy efficiency of isometric force production, and lower the shortening velocity of muscle. It has been known since the work of A.V. Hill in 1950 that as species increase in size, the shortening velocity of their muscle is reduced, and the present work shows that nebulin contributes to the mechanistic basis. Finally, we analyzed the differentially spliced simple repeats in nebulin''s C terminus, whose inclusion correlates with the width of the Z-disk. The number of Z-repeats greatly varies (from 5 to 18) and correlates with the number of super-repeats. We propose that the resulting increase in the width of the Z-disk in large animals increases the number of contacts between nebulin and structural Z-disk proteins when the Z-disk is stressed for long durations. 相似文献