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111.
Thomas P. Matthews Tatiana McHardy Suki Klair Kathy Boxall Martin Fisher Michael Cherry Charlotte E. Allen Glynn J. Addison John Ellard G. Wynne Aherne Isaac M. Westwood Rob van Montfort Michelle D. Garrett John C. Reader Ian Collins 《Bioorganic & medicinal chemistry letters》2010,20(14):4045-4049
A range of 3,6-di(hetero)arylimidazo[1,2-a]pyrazine ATP-competitive inhibitors of CHK1 were developed by scaffold hopping from a weakly active screening hit. Efficient synthetic routes for parallel synthesis were developed to prepare analogues with improved potency and ligand efficiency against CHK1. Kinase profiling showed that the imidazo[1,2-a]pyrazines could inhibit other kinases, including CHK2 and ABL, with equivalent or better potency depending on the pendant substitution. These 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines appear to represent a general kinase inhibitor scaffold. 相似文献
112.
Isaac Wirgin Cheryl Grunwald Joseph Stabile John R. Waldman 《Conservation Genetics》2010,11(3):689-708
Shortnose sturgeon Acipenser brevirostrum is federally listed as ‘‘an endangered species threatened with extinction’’ in the U.S. but its listing status is currently
under review. As part of this process, the U.S. National Marine Fisheries Service will determine if shortnose sturgeon are
divided into Distinct Population Segments (DPS) across its distribution. In this regard, we sought to determine if shortnose
sturgeon occur in genetically “discrete population segments,” and if so, the boundaries of each. We used mitochondrial DNA
(mtDNA) control region sequence analysis to assess the genetic discreteness of 14 of 19 river populations that were recommended
as DPS in the 1998 Final Recovery Plan for Shortnose Sturgeon. Nine of the 14 proposed DPS proved significantly discrete (P < 0.05 after Bonferoni correction) from both of their bracketing populations, the exceptions being those in the Penobscot
River, Chesapeake Bay, Cooper River, and Ogeechee River (our sample from the Cape Fear River was insufficient to statistically
analyze). Haplotype frequencies in the newly “rediscovered” Penobscot River collection were almost identical to those in the
proximal Kennebec River system. Genetic data in combination with tagging results suggest that shortnose sturgeon in the Penobscot
River are probably migrants from the Kennebec. Likewise, shortnose sturgeon found today within the Chesapeake Bay appear to
be migrants from the Delaware River. While haplotype frequencies in the remnant Santee River population in Lake Marion differed
significantly from those in nearby Winyah Bay, they did not differ significantly from those in the Cooper River. This suggests
that the Cooper River harbors descendants of the Santee River population that are unable to access their historical spawning
locales. The Ogeechee River collection was not genetically distinct from that in the nearby Savannah River, suggesting that
it may host descendants of hatchery-reared individuals of Savannah River ancestry. Our genetic results indicate that most,
but not all, rivers with shortnose sturgeon host genetically discrete populations, constituting important information in the
consideration of DPS designations. However, shortnose sturgeon migrations through coastal waters to proximal rivers and release
of hatchery-reared fish may confound results from genetic studies such as ours and lead to the possible misidentification
of discrete population segments. 相似文献
113.
Activation-induced cytidine deaminase targets DNA at sites of RNA polymerase II stalling by interaction with Spt5 总被引:1,自引:0,他引:1
Pavri R Gazumyan A Jankovic M Di Virgilio M Klein I Ansarah-Sobrinho C Resch W Yamane A Reina San-Martin B Barreto V Nieland TJ Root DE Casellas R Nussenzweig MC 《Cell》2010,143(1):122-133
Activation-induced cytidine deaminase (AID) initiates antibody gene diversification by creating U:G mismatches. However, AID is not specific for antibody genes; Off-target lesions can activate oncogenes or cause chromosome translocations. Despite its importance in these transactions little is known about how AID finds its targets. We performed an shRNA screen to identify factors required for class switch recombination (CSR) of antibody loci. We found that Spt5, a factor associated with stalled RNA polymerase II (Pol II) and single stranded DNA (ssDNA), is required for CSR. Spt5 interacts with AID, it facilitates association between AID and Pol II, and AID recruitment to its Ig and non-Ig targets. ChIP-seq experiments reveal that Spt5 colocalizes with AID and stalled Pol II. Further, Spt5 accumulation at sites of Pol II stalling is predictive of AID-induced mutation. We propose that AID is targeted to sites of Pol II stalling in part via its association with Spt5. 相似文献
114.
David M. Alba Salvador Moyà‐Solà Assumpció Malgosa Isaac Casanovas‐Vilar Josep M. Robles Sergio Almécija Jordi Galindo Cheyenn Rotgers Juan Vicente Bertó Mengual 《American journal of physical anthropology》2010,141(1):52-75
Pliopithecus (Pliopithecus) canmatensis sp. nov. is described from several Late Aragonian localities from Abocador de Can Mata (ACM) in els Hostalets de Pierola (Vallès‐Penedès Basin, Catalonia, Spain), spanning from ~11.7 to 11.6 Ma (C5r.3r subchron), and being correlated to the MN8 (reference locality La Grive L3). The ACM remains display a pliopithecine dental morphology with well‐developed pliopithecine triangles on M/2 and M/3. This, together with other occlusal details, negates an attribution to the subgenus Epipliopithecus. Although slightly smaller, the ACM remains are most similar in size to comparable elements of P. piveteaui and P. antiquus. Several occlusal details (such as the greater development of the buccal cingulid in lower molars) and dental proportions (M/3 much longer than M/2), however, indicate greater similarities with P. antiquus from Sansan and La Grive. The ACM remains, however, differ from P. antiquus in dental proportions as well as occlusal morphology of the lower molars (including the less peripheral position of the protoconid and more medial position of the hypoconulid, the more mesial position of the buccal cuspids as compared to the lingual ones, the narrower but distinct mesial fovea, the higher trigonid, and the more extensive buccal cingulid, among others). These differences justify a taxonomic distinction at the species level of the ACM pliopithecid remains with respect to P. antiquus. Previous pliopithecid findings from the Vallès‐Penedès Basin, previously attributed to P. antiquus, are neither attributable to the latter species nor to the newly erected one. Am J Phys Anthropol, 2010. © 2009 Wiley‐Liss, Inc. 相似文献
115.
Vicenç Méndez Isaac Llopis Daniel Campos Werner Horsthemke 《Theoretical population biology》2010,77(4):250-256
We determine the critical patch size below which extinction occurs for populations living in one-dimensional habitats surrounded by completely hostile environments in the presence of environmental fluctuations. The population dynamics is reformulated in terms of a stochastic reaction–diffusion equation and is reduced to a deterministic equation that incorporates the systematic contributions of the noise. We obtain bifurcation diagrams and relations for the mean population density at the stationary state, the critical patch size, and the mean number of individuals in the habitat. The effect of the noise differs, depending on whether it affects the net growth rate or the intraspecific competition term. Fluctuations in the net growth rate decrease the critical patch size, whereas fluctuations in the competition term do not change the critical patch size. We compare our analytical results with numerical solutions of the stochastic partial differential equations and show that our procedure proves useful in dealing with reaction–diffusion equations with multiplicative noise. 相似文献
116.
Diap Graciela Amuasi John Boakye Isaac Sevcsik Ann-Marie Pecoul Bernard 《Malaria journal》2010,9(1):1-11
Background
Malaria microscopy and rapid diagnostic tests are insensitive for very low-density parasitaemia. This insensitivity may lead to missed asymptomatic sub-microscopic parasitaemia, a potential reservoir for infection. Similarly, mixed infections and interactions between Plasmodium species may be missed. The objectives were first to develop a rapid and sensitive PCR-based diagnostic method to detect low parasitaemia and mixed infections, and then to investigate the epidemiological importance of sub-microscopic and mixed infections in Rattanakiri Province, Cambodia.Methods
A new malaria diagnostic method, using restriction fragment length polymorphism analysis of the cytochrome b genes of the four human Plasmodium species and denaturing high performance liquid chromatography, has been developed. The results of this RFLP-dHPLC method have been compared to 1) traditional nested PCR amplification of the 18S rRNA gene, 2) sequencing of the amplified fragments of the cytochrome b gene and 3) microscopy. Blood spots on filter paper and Giemsa-stained blood thick smears collected in 2001 from 1,356 inhabitants of eight villages of Rattanakiri Province have been analysed by the RFLP-dHPLC method and microscopy to assess the prevalence of sub-microscopic and mixed infections.Results
The sensitivity and specificity of the new RFLP-dHPLC was similar to that of the other molecular methods. The RFLP-dHPLC method was more sensitive and specific than microscopy, particularly for detecting low-level parasitaemia and mixed infections. In Rattanakiri Province, the prevalences of Plasmodium falciparum and Plasmodium vivax were approximately two-fold and three-fold higher, respectively, by RFLP-dHPLC (59% and 15%, respectively) than by microscopy (28% and 5%, respectively). In addition, Plasmodium ovale and Plasmodium malariae were never detected by microscopy, while they were detected by RFLP-dHPLC, in 11.2% and 1.3% of the blood samples, respectively. Moreover, the proportion of mixed infections detected by RFLP-dHPLC was higher (23%) than with microscopy (8%).Conclusions
The rapid and sensitive molecular diagnosis method developed here could be considered for mass screening and ACT treatment of inhabitants of low-endemicity areas of Southeast Asia. 相似文献117.
Novel Rumen Bacterial Diversity in Two Geographically Separated Sub-Species of Reindeer 总被引:2,自引:0,他引:2
Svalbard reindeer (Rangifer tarandus platyrhynchus) live under austere nutritional conditions on the high-arctic archipelago of Svalbard, while semi-domesticated Norwegian
reindeer (R. tarandus tarandus) migrate between lush coastal summer pastures and inland winter pastures with lichens on mainland Norway. Svalbard reindeer
are known to have high rumen concentrations of cellulolytic bacteria, ranging from 15% of the viable population in summer
to 35% in winter, compared to only 2.5% in Norwegian reindeer. Their rumen bacterial diversity was investigated through comparative
analyses of 16S rRNA gene sequences (∼1.5 kb in length) generated from clone libraries (n = 121) and bacterial isolates (n = 51). LIBSHUFF comparisons of the composition of the two 16S rRNA libraries from Norwegian reindeer showed a significant
effect of artificial feeding compared to natural pasture, but failed to yield significant differences between libraries from
Norwegian reindeer and Svalbard reindeer. The combined sequences from reindeer were not significantly different from those
reported in wild Thompson’s gazelle in Kenya but did differ from those reported in domestic cattle in Japan. A total of 90
distinct operational taxonomic units (OTUs) were identified by employing a criterion of 97% similarity, while the Chao1 index
estimated the reindeer bacterial rumen population richness at 698 OTUs. The majority of the clone library sequences (92.5%)
represented novel strains with <97% identity to any known sequence in the public database, most of them affiliated with the
bacterial phylum Firmicutes (low G+C Gram-positives) related to the order Clostridiales (76.7%), while Gram-negative bacteria in the Bacteriodales (Prevotella–Bacteroides group) contributed to 22.5%. Also, six of the isolates were putatively novel strains, possibly representing new species in
the Clostridium subphylum (cluster XIVa), Actinomyces and Butyrivibrio. 相似文献
118.
Bacterial Diversity and Distribution in the Holocene Sediments of a Northern Temperate Lake 总被引:1,自引:0,他引:1
Sediments contain an abundance of microorganisms. However, the diversity and distribution of microorganisms associated with
sediments are poorly understood, particularly in lacustrine environments. We used banding patterns from denaturing gradient
gel electrophoresis (DGGE) and 16S rDNA sequences to assess the structure of bacterial communities in the Holocene sediments
of a meromictic lake in Minnesota. Cluster analysis of the DGGE banding patterns indicates that the early- and middle-Holocene
samples group separately from the late-Holocene samples. About 79% of the recovered bacterial sequences cluster with the α-,
β-, δ-, ɛ-, and γ- Proteobacteriaceae and Firmicutes. The remaining ∼21% lack cultured representatives. The taxonomic lineages
of bacteria differ statistically among the early-, middle-, and late-Holocene samples, although the difference is smallest
between early- and middle-Holocene samples. Early- and middle-Holocene samples are dominated by ɛ-Proteobacteriaceae, and
late-Holocene samples are dominated by sequences from uncultured subphyla. We only recovered δ-Proteobacteriaceae in late-Holocene
sediments and α- and γ- Proteobacteriaceae in late- and middle-Holocene sediments. Diversity estimates derived from early-,
middle-, and late-Holocene clone libraries indicate that the youngest (late-Holocene) samples had significantly greater bacterial
diversity than the oldest (early-Holocene) samples, and the middle-Holocene samples contained intermediate levels of diversity.
The observed patterns of diversity may be caused by increased bacterial niche-partitioning in younger sediments that contain
a greater abundance of labile organic matter than older sediments.
D. M. Nelson and S. Ohene-Adjei contributed equally to this work 相似文献
119.
Peled IJ 《Plastic and reconstructive surgery》2007,120(5):1433; author reply 1433
120.
Kelly BN Kyere S Kinde I Tang C Howard BR Robinson H Sundquist WI Summers MF Hill CP 《Journal of molecular biology》2007,373(2):355-366
The CA domain of the human immunodeficiency virus type 1 (HIV-1) Gag polyprotein plays critical roles in both the early and late phases of viral replication and is therefore an attractive antiviral target. Compounds with antiviral activity were recently identified that bind to the N-terminal domain of CA (CAN) and inhibit capsid assembly during viral maturation. We have determined the structure of the complex between CAN and the antiviral assembly inhibitor N-(3-chloro-4-methylphenyl)-N′-{2-[({5-[(dimethylamino)-methyl]-2-furyl}-methyl)-sulfanyl]ethyl}-urea) (CAP-1) using a combination of NMR spectroscopy and X-ray crystallography. The protein undergoes a remarkable conformational change upon CAP-1 binding, in which Phe32 is displaced from its buried position in the protein core to open a deep hydrophobic cavity that serves as the ligand binding site. The aromatic ring of CAP-1 inserts into the cavity, with the urea NH groups forming hydrogen bonds with the backbone oxygen of Val59 and the dimethylamonium group interacting with the side-chains of Glu28 and Glu29. Elements that could be exploited to improve binding affinity are apparent in the structure. The displacement of Phe32 by CAP-1 appears to be facilitated by a strained main-chain conformation, which suggests a potential role for a Phe32 conformational switch during normal capsid assembly. 相似文献