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881.
882.
Zou J Hofer AM Lurtz MM Gadda G Ellis AL Chen N Huang Y Holder A Ye Y Louis CF Welshhans K Rehder V Yang JJ 《Biochemistry》2007,46(43):12275-12288
Ca2+ regulates numerous biological processes through spatiotemporal changes in the cytosolic Ca2+ concentration and subsequent interactions with Ca2+ binding proteins. The endoplasmic reticulum (ER) serves as an intracellular Ca2+ store and plays an essential role in cytosolic Ca2+ homeostasis. There is a strong need to develop Ca2+ sensors capable of real-time quantitative Ca2+ concentration measurements in specific subcellular environments without using natural Ca2+ binding proteins such as calmodulin, which themselves participate as signaling molecules in cells. In this report, a strategy for creating such sensors by grafting a Ca2+-binding motif into chromophore sensitive locations in green fluorescence protein is described. The engineered Ca2+ sensors exhibit large ratiometric fluorescence and absorbance changes upon Ca2+ binding with affinities corresponding to the Ca2+ concentrations found in the ER (Kd values range from 0.4 to 2 mM). In addition to characterizing the optical and metal binding properties of the newly developed Ca2+ sensors with various spectroscopic methods, we also examined the kinetic properties using stopped-flow spectrofluorimetry to ensure accurate monitoring of dynamic Ca2+ changes. The developed Ca2+ sensor was successfully targeted to the ER of mammalian cell lines to monitor Ca2+ changes occurring in this compartment in response to stimulation with agonists. We envision that this class of Ca2+ sensors can be modified further to measure the Ca2+ concentration in other cellular compartments, providing tools for studying the contribution of these compartments to cellular Ca2+ signaling. 相似文献
883.
Guyon JR Steffen LS Howell MH Pusack TJ Lawrence C Kunkel LM 《Biochimica et biophysica acta》2007,1772(2):205-215
Zebrafish reproduce in large quantities, grow rapidly, and are transparent early in development. For these reasons, zebrafish have been used extensively to model vertebrate development and disease. Like mammals, zebrafish express dystrophin and many of its associated proteins early in development and these proteins have been shown to be vital for zebrafish muscle stability. In dystrophin-null zebrafish, muscle degeneration becomes apparent as early as 3 days post-fertilization (dpf) making the zebrafish an excellent organism for large-scale screens to identify other genes involved in the disease process or drugs capable of correcting the disease phenotype. Being transparent, developing zebrafish are also an ideal experimental model for monitoring the fate of labeled transplanted cells. Although zebrafish dystrophy models are not meant to replace existing mammalian models of disease, experiments requiring large numbers of animals may be best performed in zebrafish. Results garnered from using this model could lead to a better understanding of the pathogenesis of the muscular dystrophies and the development of future therapies. 相似文献
884.
This study examined the role of maternal provisioning in controlling interpopulation variation in hatching size in nine isolated populations of the intertidal gastropod Nucella ostrina, in which development to the early juvenile stage takes place within an egg capsule. Variation among populations was almost entirely due to the ratio of nurse eggs to embryo, which explained 65% of the variation in hatching size. Egg size was not a significant predictor of hatching size. Differences among seven of these populations in the nurse egg/embryo ratio were entirely due to the number of nurse eggs allocated per capsule; these populations allocated different numbers of nurse eggs per capsule but allocated the same number of embryos. Intriguingly, the two most wave-sheltered populations allocated significantly more nurse eggs and more embryos to each capsule than did the seven other populations, but they maintained nurse egg/embryo ratios consistent with patterns observed in the other populations. Inter- and intrapopulation variation in hatching size appears to be controlled largely by different mechanisms: within-population variation being controlled mainly by differences in allocation of embryos per capsule, whereas most among-population variation being due to differences in allocation of nurse eggs per capsule. 相似文献
885.
The luminal environment along the epididymal duct is important for spermatozoal maturation. This environment is unique and created by the blood-epididymal barrier, which is formed by tight and adhering junctions. For the human epididymis, little information exists on the proteins that comprise these junctions. Our objectives were to assess the gene expression profiles in the different segments of the human epididymis and to identify the proteins that make up the blood-epididymal barrier. Using microarrays, we identified 2980 genes that were differentially expressed by at least 2-fold between the various segments. Of the many genes involved in diverse functions, were those that encoded adhesion proteins (cadherins and catenins) and tight junctional proteins (claudins [CLDN] and others). PCR analyses confirmed the microarray data. Immunolocalization of CLDNs 1, 3, 4, 8, and 10 revealed that the localization of CLDNs differed along the epididymis. In all three segments, CLDNs 1, 3, and 4 were localized to tight junctions, along the lateral margins of adjacent principal cells, and at the interface between basal and principal cells. CLDN8 was localized to tight junctions in all three segments, in addition to being localized in the caput along the lateral margins of principal cells, and in the corpus, at the interface between principal and basal cells. CLDN10, tight junction protein 1, and occludin were localized exclusively to tight junctions in all three epididymal segments. These data indicate that the epididymis displays a complex pattern of gene expression, which includes genes that are implicated in the formation of the blood-epididymal barrier, which suggests complex regulation of this barrier. 相似文献
886.
The fossil vertebrate locality of Laugnac is the type locality of the Neogene mammalian zone MN2b. It has yielded many remains of Suoidea belonging to two different genera.Xenohyus venitor is characterized by its large size and especially its large central upper incisors, I1/ and I2/. It is quite difficult to know its phyletic relationships because the material is not abundant.Hyotherium cf.meisneri is more abundant with a quite good skull, pieces of skull, jaws and isolated teeth. It belongs to a peculiar lineage different from that ofH. major from Saint Gérand-le-Puy, France. It has some similarities withAureliachoerus aurelianensis from later geological levels (MN3-MN5). 相似文献
887.
B Mahalingam J M Louis C C Reed J M Adomat J Krouse Y F Wang R W Harrison I T Weber 《European journal of biochemistry》1999,263(1):238-245
Mutants of HIV-1 protease that are commonly selected on exposure to different drugs, V82S, G48V, N88D and L90M, showed reduced catalytic activity compared to the wild-type protease on cleavage site peptides, CA-p2, p6pol-PR and PR-RT, critical for viral maturation. Mutant V82S is the least active (2-20% of wild-type protease), mutants N88D, R8Q, and L90M exhibit activities ranging from 20 to 40% and G48V from 50 to 80% of the wild-type activity. In contrast, D30N is variable in its activity on different substrates (10-110% of wild-type), with the PR-RT site being the most affected. Mutants K45I and M46L, usually selected in combination with other mutations, showed activities that are similar to (60-110%) or greater than (110-530%) wild-type, respectively. No direct relationship was observed between catalytic activity, inhibition, and structural stability. The mutants D30N and V82S were similar to wild-type protease in their stability toward urea denaturation, while R8Q, G48V, and L90M showed 1.5 to 2.7-fold decreased stability, and N88D and K45I showed 1.6 to 1.7-fold increased stability. The crystal structures of R8Q, K45I and L90M mutants complexed with a CA-p2 analog inhibitor were determined at 2.0, 1.55 and 1.88 A resolution, respectively, and compared to the wild-type structure. The intersubunit hydrophobic contacts observed in the crystal structures are in good agreement with the relative structural stability of the mutant proteases. All these results suggest that viral resistance does not arise by a single mechanism. 相似文献
888.
Analytica is an easy-to-learn, easy-to-use modeling tool that allows modelers to represent what they know through influence diagrams. These diagrams show which model quantities are derived from which others and indicate by shape and color the roles that different nodes play in the model, e.g., decision variables, chance variables, outcome variables, deterministic functions, or abstractions of sub-models. A wide variety of built-in probability distributions allow uncertainties about input values to be painlessly specified and propagated through the model via a fast, professional Monte-Carlo simulation engine. Resulting uncertainties and sensitivities about any quantity in the model can be viewed with admirable ease and flexibility by selecting among probability density, cumulative distribution, confidence band, sensitivity analysis, and other displays. Analytica features clever hierarchical model management and navigation features that serious model-builders will appreciate and that novice modelers will learn from as they are led to develop well-structured, well-documented models. Simple continuous (compartmental-flow) and Markov chain dynamic simulation models can be built by paying some detailed attention to arrays and indices, although Analytica does not support true discrete-event simulation. Within its chosen domain—uncertainty propagation through influence diagram models—Analytica is by far the easiest and best tool that we have seen. 相似文献
889.
The first experimental evidence for the development of polarized CD4+ Th1 and Th2 responses in vivo has been obtained using the murine model of infection with Leishmania major, an intracellular parasite of macrophages in their vertebrate host. Genetically determined resistance and susceptibility to infection with this parasite have been clearly demonstrated to result from the development of polarized Th1 and Th2 responses, respectively. Using this model system, the dominant role of cytokines in the induction of polarized CD4+ responses has been validated in vivo. The requisite role of IL-4 in mediating both Th2 differentiation and susceptibility to infection in BALB/c mice has directed interest towards the search for evidence of IL-4 production early after infection and identification of its cellular source. We have been able to demonstrate a burst of IL-4 production in susceptible BALB/c mice within the first day of infection with L. major and could establish that this rapidly produced IL-4 instructed Th2 lineage commitment of subsequently activated CD4+ T cells and stabilized this commitment by downregulating IL-12 Rbeta2 chain expression, resulting in susceptibility to infection. Strikingly, this early IL-4 response to infection resulted from the cognate recognition of a single epitope in a distinctive antigen, LACK, from this complex microorganism by a restricted population of CD4+ T cells that express Vbeta4-Valpha8 T cell receptors. 相似文献
890.
Tuomo Rankinen Jacques Gagnon Louis Prusse Treva Rice Arthur S. Leon James S. Skinner Jack H. Wilmore D. C. Rao Claude Bouchard 《Obesity (Silver Spring, Md.)》1999,7(5):423-430
RANKINEN, T., JACQUES GAGNON, LOUIS PÉRUSSE, TREVA RICE, ARTHUR s. LEON, JAMES s. SKINNER, JACK H. WILMORE, D. C. RAO, AND CLAUDE BOUCHARD. Body fat, resting and exercise blood pressure and the angiotensinogen M235T polymorphism: the Heritage family study. Obes Res. Objective: The association of resting and exercise blood pressure (BP) and fat mass with the angiotensinogen (AGT) M235T polymorphism was investigated in 522 sedentary Caucasian subjects from 99 families. Research Methods and Procedures: Resting BP was measured on two separate days, three times each day, and the mean of six valid measurements was used. Exercise BP was measured during a cycle ergometer test at a constant power output (50 W). Body composition was derived from underwater weighing and the AGT M235T polymorphism was typed with a polymerase chain reaction-based method. Results: Neither resting nor exercise BP was associated with the AGT genotypes. In mothers, the homozygotes for the T allele showed 8. 8 kg and 7. 1 kg greater (p = 0. 017) age-adjusted body fat mass (FM) than the MM homozygotes and heterozygotes, respectively. Sixty-nine percent of all TT homozygotes were found in the highest FM tertile, whereas only 16% of the MM homozygotes fell in the same tertile (p = 0. 008). Moreover, a significant interaction was seen between FM and T-allele carrier status in women with regard to resting diastolic BP (p = 0. 002). Among women with a FM≥24 kg, carriers of the T allele showed a 6. 3 mmHg higher diastolic blood pressure (DBP) than non-carriers whereas no difference was found in women with a FM less than 24 kg. A similar trend toward an interaction term was evident with resting systolic blood pressure (p = 0. 011) and exercise DBP (p = 0. 012). Body fat was not associated with the AGT polymorphism in fathers or in offspring. Discussion: These data suggest that the AGT M235T polymorphism is associated with body fatness in women, and that the relationship between DBP and AGT M235T polymorphism is dependent on FM in middle-aged sedentary normotensive women. 相似文献