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151.
Karlsson EK Baranowska I Wade CM Salmon Hillbertz NH Zody MC Anderson N Biagi TM Patterson N Pielberg GR Kulbokas EJ Comstock KE Keller ET Mesirov JP von Euler H Kämpe O Hedhammar A Lander ES Andersson G Andersson L Lindblad-Toh K 《Nature genetics》2007,39(11):1321-1328
With several hundred genetic diseases and an advantageous genome structure, dogs are ideal for mapping genes that cause disease. Here we report the development of a genotyping array with approximately 27,000 SNPs and show that genome-wide association mapping of mendelian traits in dog breeds can be achieved with only approximately 20 dogs. Specifically, we map two traits with mendelian inheritance: the major white spotting (S) locus and the hair ridge in Rhodesian ridgebacks. For both traits, we map the loci to discrete regions of <1 Mb. Fine-mapping of the S locus in two breeds refines the localization to a region of approximately 100 kb contained within the pigmentation-related gene MITF. Complete sequencing of the white and solid haplotypes identifies candidate regulatory mutations in the melanocyte-specific promoter of MITF. Our results show that genome-wide association mapping within dog breeds, followed by fine-mapping across multiple breeds, will be highly efficient and generally applicable to trait mapping, providing insights into canine and human health. 相似文献
152.
Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes 总被引:3,自引:0,他引:3
Kantarci S Al-Gazali L Hill RS Donnai D Black GC Bieth E Chassaing N Lacombe D Devriendt K Teebi A Loscertales M Robson C Liu T MacLaughlin DT Noonan KM Russell MK Walsh CA Donahoe PK Pober BR 《Nature genetics》2007,39(8):957-959
Donnai-Barrow syndrome is associated with agenesis of the corpus callosum, congenital diaphragmatic hernia, facial dysmorphology, ocular anomalies, sensorineural hearing loss and developmental delay. By studying multiplex families, we mapped this disorder to chromosome 2q23.3-31.1 and identified LRP2 mutations in six families with Donnai-Barrow syndrome and one family with facio-oculo-acoustico-renal syndrome. LRP2 encodes megalin, a multiligand uptake receptor that regulates levels of diverse circulating compounds. This work implicates a pathway with potential pharmacological therapeutic targets. 相似文献
153.
Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death 总被引:1,自引:0,他引:1
Baines CP Kaiser RA Purcell NH Blair NS Osinska H Hambleton MA Brunskill EW Sayen MR Gottlieb RA Dorn GW Robbins J Molkentin JD 《Nature》2005,434(7033):658-662
Mitochondria play a critical role in mediating both apoptotic and necrotic cell death. The mitochondrial permeability transition (mPT) leads to mitochondrial swelling, outer membrane rupture and the release of apoptotic mediators. The mPT pore is thought to consist of the adenine nucleotide translocator, a voltage-dependent anion channel, and cyclophilin D (the Ppif gene product), a prolyl isomerase located within the mitochondrial matrix. Here we generated mice lacking Ppif and mice overexpressing cyclophilin D in the heart. Ppif null mice are protected from ischaemia/reperfusion-induced cell death in vivo, whereas cyclophilin D-overexpressing mice show mitochondrial swelling and spontaneous cell death. Mitochondria isolated from the livers, hearts and brains of Ppif null mice are resistant to mitochondrial swelling and permeability transition in vitro. Moreover, primary hepatocytes and fibroblasts isolated from Ppif null mice are largely protected from Ca2+-overload and oxidative stress-induced cell death. However, Bcl-2 family member-induced cell death does not depend on cyclophilin D, and Ppif null fibroblasts are not protected from staurosporine or tumour-necrosis factor-alpha-induced death. Thus, cyclophilin D and the mitochondrial permeability transition are required for mediating Ca2+- and oxidative damage-induced cell death, but not Bcl-2 family member-regulated death. 相似文献
154.
Until now, the analysis of burrowing mechanics has neglected the mechanical properties of impeding, muddy, cohesive sediments, which behave like elastic solids. Here we show that burrowers can progress through such sediments by using a mechanically efficient, previously unsuspected mechanism--crack propagation--in which an alternating 'anchor' system of burrowing serves as a wedge to extend the crack-shaped burrow. The force required to propagate cracks through sediment in this way is relatively small: we find that the force exerted by the annelid worm Nereis virens in making and moving into such a burrow amounts to less than one-tenth of the force it needs to use against rigid aquarium walls. 相似文献
155.
156.
Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters 总被引:1,自引:0,他引:1
Na+/Cl--dependent transporters terminate synaptic transmission by using electrochemical gradients to drive the uptake of neurotransmitters, including the biogenic amines, from the synapse to the cytoplasm of neurons and glia. These transporters are the targets of therapeutic and illicit compounds, and their dysfunction has been implicated in multiple diseases of the nervous system. Here we present the crystal structure of a bacterial homologue of these transporters from Aquifex aeolicus, in complex with its substrate, leucine, and two sodium ions. The protein core consists of the first ten of twelve transmembrane segments, with segments 1-5 related to 6-10 by a pseudo-two-fold axis in the membrane plane. Leucine and the sodium ions are bound within the protein core, halfway across the membrane bilayer, in an occluded site devoid of water. The leucine and ion binding sites are defined by partially unwound transmembrane helices, with main-chain atoms and helix dipoles having key roles in substrate and ion binding. The structure reveals the architecture of this important class of transporter, illuminates the determinants of substrate binding and ion selectivity, and defines the external and internal gates. 相似文献
157.
Doppler spectroscopy has detected 152 planets around nearby stars. A major puzzle is why many of their orbits are highly eccentric; all planets in our Solar System are on nearly circular orbits, as is expected if they formed by accretion processes in a protostellar disk. Several mechanisms have been proposed to generate large eccentricities after planet formation, but so far there has been little observational evidence to support any particular model. Here we report that the current orbital configuration of the three giant planets around upsilon Andromedae (upsilon And) probably results from a close dynamical interaction with another planet, now lost from the system. The planets started on nearly circular orbits, but chaotic evolution caused the outer planet (upsilon And d) to be perturbed suddenly into a higher-eccentricity orbit. The coupled evolution of the system then causes slow periodic variations in the eccentricity of the middle planet (upsilon And c). Indeed, we show that upsilon And c periodically returns to a very nearly circular state every 6,700 years. 相似文献
158.
Tuzun E Sharp AJ Bailey JA Kaul R Morrison VA Pertz LM Haugen E Hayden H Albertson D Pinkel D Olson MV Eichler EE 《Nature genetics》2005,37(7):727-732
Inversions, deletions and insertions are important mediators of disease and disease susceptibility. We systematically compared the human genome reference sequence with a second genome (represented by fosmid paired-end sequences) to detect intermediate-sized structural variants >8 kb in length. We identified 297 sites of structural variation: 139 insertions, 102 deletions and 56 inversion breakpoints. Using combined literature, sequence and experimental analyses, we validated 112 of the structural variants, including several that are of biomedical relevance. These data provide a fine-scale structural variation map of the human genome and the requisite sequence precision for subsequent genetic studies of human disease. 相似文献
159.
Gribouval O Gonzales M Neuhaus T Aziza J Bieth E Laurent N Bouton JM Feuillet F Makni S Ben Amar H Laube G Delezoide AL Bouvier R Dijoud F Ollagnon-Roman E Roume J Joubert M Antignac C Gubler MC 《Nature genetics》2005,37(9):964-968
Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (Potter phenotype). Absence or paucity of differentiated proximal tubules is the histopathological hallmark of the disease and may be associated with skull ossification defects. We studied 11 individuals with renal tubular dysgenesis, belonging to nine families, and found that they had homozygous or compound heterozygous mutations in the genes encoding renin, angiotensinogen, angiotensin converting enzyme or angiotensin II receptor type 1. We propose that renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity. This is the first identification to our knowledge of a renal mendelian disorder linked to genetic defects in the renin-angiotensin system, highlighting the crucial role of the renin-angiotensin system in human kidney development. 相似文献
160.
MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. 总被引:31,自引:0,他引:31
Scott A Armstrong Jane E Staunton Lewis B Silverman Rob Pieters Monique L den Boer Mark D Minden Stephen E Sallan Eric S Lander Todd R Golub Stanley J Korsmeyer 《Nature genetics》2002,30(1):41-47
Acute lymphoblastic leukemias carrying a chromosomal translocation involving the mixed-lineage leukemia gene (MLL, ALL1, HRX) have a particularly poor prognosis. Here we show that they have a characteristic, highly distinct gene expression profile that is consistent with an early hematopoietic progenitor expressing select multilineage markers and individual HOX genes. Clustering algorithms reveal that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. We propose that they constitute a distinct disease, denoted here as MLL, and show that the differences in gene expression are robust enough to classify leukemias correctly as MLL, acute lymphoblastic leukemia or acute myelogenous leukemia. Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets. 相似文献