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991.
992.
Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2. 总被引:19,自引:5,他引:14 下载免费PDF全文
A J Capobianco P Zagouras C M Blaumueller S Artavanis-Tsakonas J M Bishop 《Molecular and cellular biology》1997,17(11):6265-6273
The Notch genes of Drosophila melanogaster and vertebrates encode transmembrane receptors that help determine cell fate during development. Although ligands for Notch proteins have been identified, the signaling cascade downstream of the receptors remains poorly understood. In human acute lymphoblastic T-cell leukemia, a chromosomal translocation damages the NOTCH1 gene. The damage apparently gives rise to a constitutively activated version of NOTCH protein. Here we show that a truncated version of NOTCH1 protein resembling that found in the leukemic cells can transform rat kidney cells in vitro. The transformation required cooperation with the E1A oncogene of adenovirus. The transforming version of NOTCH protein was located in the nucleus. In contrast, neither wild-type NOTCH protein nor a form of the truncated protein permanently anchored to the plasma membrane produced transformation in vitro. We conclude that constitutive activation of NOTCH similar to that found in human leukemia can contribute to neoplastic transformation. Transformation may require that the NOTCH protein be translocated to the nucleus. These results sustain a current view of how Notch transduces a signal from the surface of the cell to the nucleus. 相似文献
993.
Identification of a modifier gene locus on chromosome 1p35-36 in familial adenomatous polyposis 总被引:5,自引:0,他引:5
Zuzana Dobbie Karl Heinimann D. Tim Bishop Hansjakob Müller R. J. Scott 《Human genetics》1997,99(5):653-657
Phenotypic variability based on nonallelic heterogeneity is a characteristic feature of the dominantly inherited disease,
familial adenomatous polyposis (FAP). A modifying locus, called Mom-1, which strongly influences disease expression has been mapped in the mouse model of FAP to the region of murine chromosome
4, which has synteny to human chromosome 1p35-36. In the present study, this chromosomal region was investigated by using
14 microsatellite markers within a large FAP kindred in which patients harbor the same germ-line mutation but show markedly
different disease characteristics. The linkage program MLINK was used to determine whether any correlation exists between
these markers and the development of extracolonic symptoms in polyposis coli patients. Depending on the mode of inheritance
of the affected locus, a maximum lod score was observed for markers D1S211 and D1S197, reaching 2.08 and 1.77, respectively.
The observed values obtained within one large FAP family are supportive of a phenotype-modifying locus within this chromosomal
region.
Received: 6 December 1996 / Revised: 23 December 1996 相似文献
994.
Naturally occurring baculoviruses can be used to control a wide range of insect pests. Most baculoviruses are used as biopesticides,
that is, they are sprayed onto high-density pest populations in a manner akin to the use of synthetic chemical pesticides.
However, other strategies that use the biological features of the viruses are also possible and should increase as we expand
our knowledge of baculovirus ecology. In order to develop a baculovirus control program, several areas need to be studied
before progressing to large scale field studies and commercialization. These range from laboratory efficacy testing and the
development of production systems to detailed study of pest behavior and the development of appropriate application strategies. 相似文献
995.
Binding of the estrogen receptor to DNA. The role of waters. 总被引:2,自引:0,他引:2
Molecular dynamics simulations are carried out to investigate the binding of the estrogen receptor, a member of the nuclear hormone receptor family, to specific and non-specific DNA. Two systems have been simulated, each based on the crystallographic structure of a complex of a dimer of the estrogen receptor DNA binding domain with DNA. One structure includes the dimer and a consensus segment of DNA, ds(CCAGGTCACAGTGACCTGG); the other structure includes the dimer and a nonconsensus segment of DNA, ds(CCAGAACACAGTGACCTGG). The simulations involve an atomic model of the protein-DNA complex, counterions, and a sphere of explicit water with a radius of 45 A. The molecular dynamics package NAMD was used to obtain 100 ps of dynamics for each system with complete long-range electrostatic interactions. Analysis of the simulations revealed differences in the protein-DNA interactions for consensus and nonconsensus sequences, a bending and unwinding of the DNA, a slight rearrangement of several amino acid side chains, and inclusion of water molecules at the protein-DNA interface region. Our results indicate that binding specificity and stability is conferred by a network of direct and water mediated protein-DNA hydrogen bonds. For the consensus sequence, the network involves three water molecules, residues Glu-25, Lys-28, Lys-32, Arg-33, and bases of the DNA. The binding differs for the nonconsensus DNA sequence in which case the fluctuating network of hydrogen bonds allows water molecules to enter the protein-DNA interface. We conclude that water plays a role in furnishing DNA binding specificity to nuclear hormone receptors. 相似文献
996.
A. I. Agulnik C. E. Bishop J. L. Lerner S. I. Agulnik V. V. Solovyev 《Mammalian genome》1997,8(2):134-138
Mammalian evolution is believed to be male driven because the greater number of germ cell divisions per generation in males
increases the opportunity for errors in DNA replication. Since the Y Chromosome (Chr) replicates exclusively in males, its
genes should also evolve faster than X or autosomal genes. In addition, estimating the overall male-to-female mutation ratio
(αm) is of great importance as a large αm implies that replication-independent mutagenic events play a relatively small role in evolution. A small αm suggests that the impact of these factors may, in fact, be significant. In order to address this problem, we have analyzed
the rates of evolution in the homologous X-Y common SMCX/SMCY genes from three different species—mouse, human, and horse. The SMC genes were chosen because the X and Y copies are highly homologous, well conserved in evolution, and in all probability functionally
interchangeable. Sequence comparisons and analysis of synonymous substitutions in approximately 1kb of the 5′ coding region
of the SMC genes reveal that the Y-linked copies are evolving approximately 1.8 times faster than their X homologs. The male-to-female
mutation ratio αm was estimated to be 3. These data support the hypothesis that mammalian evolution is male driven. However, the ratio value
is far smaller than suggested in earlier works, implying significance of replication-independent mutagenic events in evolution.
Received: 18 April 1996 / Accepted: 4 October 1996 相似文献
997.
CO2 transport in normovolemic anemia: complete compensation and stability of blood CO2 tensions 总被引:1,自引:0,他引:1
Deem Steven; Alberts Michael K.; Bishop Michael J.; Bidani Akhil; Swenson Erik R. 《Journal of applied physiology》1997,83(1):240-246
Deem, Steven A., Michael K. Alberts, Michael J. Bishop,Akhil Bidani, and Erik R. Swenson.CO2 transport in normovolemic anemia: complete compensation and stability of bloodCO2 tensions. J. Appl. Physiol. 83(1): 240-246, 1997.Isovolemichemodilution does not appear to impairCO2 elimination nor causeCO2 retention despite theimportant role of red blood cells in bloodCO2 transport. We studied thisphenomenon and its physiological basis in eight New Zealand Whiterabbits that were anesthetized, paralyzed, and mechanically ventilatedat a fixed minute ventilation. Isovolemic anemia was induced bysimultaneous blood withdrawal and infusion of 6% hetastarch insequential stages; exchange transfusions ranged from 15-30 ml involume. Variables measured after each hemodilution included hematocrit(Hct), arterial and venous blood gases, mixed expiredPCO2 andPO2, and blood pressure; also, O2 consumption,CO2 production, cardiac output(), and physiological dead space were calculated.Data were analyzed by comparison of changes in variables with changesin Hct and by using the model of capillary gas exchange described byBidani (J. Appl. Physiol. 70:1686-1699, 1991). There was complete compensation for anemia withstability of venous and arterial PCO2between Hct values of 36 ± 3 and 12 ± 1%, which was predictedby the mathematical model. Over this range of hemodilution, rose 50%, and theO2 extraction ratio increased 61%without a decline in CO2production or a rise in alveolar ventilation. The dominantcompensations maintaining CO2transport in normovolemic anemia include an increased and an augmented Haldane effect arising from theaccompanying greater O2extraction. 相似文献
998.
Ryan, Kathy L., W. Fred Taylor, and Vernon S. Bishop.Arterial baroreflex modulation of heat-induced vasodilation in therabbit ear. J. Appl. Physiol. 83(6):2091-2097, 1997.The purpose of this study was to determinewhether nonthermal baroreflexes arising from cardiopulmonaryand/or arterial baroreceptors modulate rabbit ear blood flow(EBF) during hyperthermia. Intact and sinoaortic-denervated (SAD)rabbits were chronically instrumented with a Doppler ultrasonic flowprobe for measurement of EBF velocity (kHz). During whole body heatingin conscious rabbits, EBF and ear vascular conductance (EVC) increasedas core temperature increased until maximal plateau levels of EBF andEVC were reached. The maximal plateau level of EVC attained during heatstress was lower in SAD than in intact rabbits. Subsequentintrapericardial administration of procaine at maximal EBF blockedcardiac afferents but did not alter EVC in either animal group. In asecond experiment, ramp decreases in mean arterial pressure wereproduced by vena caval occlusion at maximal EBF. In intact rabbits, EBFand EVC decreased linearly as mean arterial pressure fell, but EBF andEVC did not decrease during vena caval occlusion in SAD rabbits. Thusneither pharmacological nor mechanical unloading of cardiacbaroreceptors results in reflex vasoconstriction in the heat-stressedrabbit ear. However, baroreflexes arising from arterial baroreceptorsmay modulate EBF in heat-stressed rabbits. 相似文献
999.
When employed as a transgene reporter, the herpes simplex type 1 virus (HSV1) thymidine kinase gene (tk) is ectopically expressed in mouse testis. The principal testicular mRNA lacks the 5'-end of the tk reading frame. As a result the principal translation products, P2 and P3, are N-terminally truncated. These co-migrate in SDS-PAGE with polypeptides synthesised during HSV1 infection that were previously thought to be initiated at methionine codons ATG46 and ATG60. Prompted by these observations we generated modified tk genes each carrying only one of the first three ATG codons. Transfected cells expressed both full-length enzyme (P1) and P2 when only ATG1 was unmodified, P2 and P3 when only ATG46 was unmodified or P2 and a fourth polypeptide (P4) when only ATG60 was unmodified. Our observations indicate that P3 is initiated at ATG46 rather than ATG60, while P2 is initiated at a non-ATG codon rather than ATG46 and P4 is initiated at ATG60. When either of two putative non-ATG initiation codons was modified P2 was no longer produced. Cells mainly expressing either P1 or P3 exhibited the same sensitivity to Ganciclovir as cells transfected with the unaltered tk gene. P1 and P3 both have TK activity while P4 probably has none. 相似文献
1000.