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101.
Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP) 总被引:8,自引:0,他引:8
Rowe PS; Oudet CL; Francis F; Sinding C; Pannetier S; Econs MJ; Strom TM; Meitinger T; Garabedian M; David A; Macher MA; Questiaux E; Popowska E; Pronicka E; Read AP; Mokrzycki A; Glorieux FH; Drezner MK; Hanauer A; Lehrach H; Goulding JN; O'Riordan JL 《Human molecular genetics》1997,6(4):539-549
Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with
homologies to endopeptidases, on the X-chromosome), are responsible for
X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family
of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has
raised important questions regarding PEX function at the molecular level.
The aim of this study was to analyse 99 HYP families for PEX gene
mutations, and to correlate predicted changes in the protein structure with
Zn2+ metallopeptidase gene function. Primers flanking 22 characterised
exons were used to amplify DNA by PCR, and SSCP was then used to screen for
mutations. Deletions, insertions, nonsense mutations, stop codons and
splice mutations occurred in 83% of families screened for in all 22 exons,
and 51% of a separate set of families screened in 17 PEX gene exons.
Missense mutations in four regions of the gene were informative regarding
function, with one mutation in the Zn2+-binding site predicted to alter
substrate enzyme interaction and catalysis. Computer analysis of the
remaining mutations predicted changes in secondary structure,
N-glycosylation, protein phosphorylation and catalytic site molecular
structure. The wide range of mutations that align with regions required for
protease activity in NEP suggests that PEX also functions as a protease,
and may act by processing factor(s) involved in bone mineral metabolism.
相似文献
102.
Excitatory amino acids mediate responses elicited in vitro by stimulation of cortical afferents to reticularis thalami neurons of the rat 总被引:2,自引:0,他引:2
The effects of the excitatory amino acids on the nucleus reticularis thalami were examined by intracellular recordings from rat thalamic slices. Non-N-methyl-D-aspartate receptor agonists and glutamate induced a membrane depolarization and a reduction in input resistance, while N-methyl-D-aspartate and aspartate induced a prolonged discharge, which in some neurons took the form of a burst firing associated with an apparent increase in membrane input resistance. Both the N-methyl-D-aspartate and the aspartate effects were blocked by D-2-amino-5-phosphonovalerate, while the effects of glutamate, kainate and quisqualate were not. The excitatory postsynaptic potential evoked by corticothalamic fiber stimulation shows two components: an early, short-lasting, 2-amino-5-phosphonovalerate-insensitive portion, and a late, 2-amino-5-phosphonovalerate-sensitive decay phase. It is suggested that glutamate acts in nucleus reticularis thalami cells preferentially on the non-N-methyl-D-aspartate receptors, while aspartate shows an N-methyl-D-aspartate-like effect. The two excitatory amino acids glutamate and aspartate play a determinant role in the modulation of thalamic activity driven by corticothalamic projection. 相似文献
103.
Alternative splicing of exon 14 determines nuclear or cytoplasmic localisation of fmr1 protein isoforms 总被引:6,自引:9,他引:6
Impaired expression of the FMR1 gene is responsible for the fragile X
mental retardation syndrome. The FMR1 gene encodes a cytoplasmic protein
with RNA-binding properties. Its complex alternative splicing leads to
several isoforms, whose abundance and specific functions in the cell are
not known. We have cloned in expression vectors, cDNAs corresponding to
several isoforms. Western blot comparison of the pattern of endogenous FMR1
proteins with these transfected isoforms allowed the tentative
identification of the major endogenous isoform as ISO 7 and of a minor band
as an isoform lacking exon 14 sequences (ISO 6 or ISO 12), while some other
isoforms (ISO 4, ISO 5) were not expressed at detectable levels.
Surprisingly, in immunofluorescence studies, the transfected splice
variants that exclude exon 14 sequences (and have alternate C-terminal
regions) were shown to be nuclear. Such differential localisation was
however not seen in subcellular fractionation studies. Analysis of various
deletion mutants suggests the presence of a cytoplasmic retention domain
encoded in exon 14 and of a nuclear association domain encoded within the
first eight exons that appear however to lack a typical nuclear
localisation signal.
相似文献
104.
Puri Beena Nelson William Porter Kevin R. Henchal Erik A. Hayes Curtis G. 《Virus genes》1998,17(1):85-88
We have determined the complete nucleotide sequence and the deduced amino acid polypeptide sequence of the genome of a dengue-1
(DEN-1) virus strain isolated from a patient on Nauru in the Western Pacific in 1974 (West Pac 74). The complete genome is
10,735 nucleotides in length and contains a single long open reading frame of 10,176 nucleotides encoding a polyprotein of
3392 amino acids. When compared to DEN-1 Singapore S275/90, the nucleotide and amino acid sequence homology are 94% and 97.8%,
respectively.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
105.
Neil Curtis Kornelius Kupczik Paul O'higgins Mehran Moazen Michael Fagan 《Anatomical record (Hoboken, N.J. : 2007)》2008,291(5):491-501
Evaluating stress and strain fields in anatomical structures is a way to test hypotheses that relate specific features of facial and skeletal morphology to mechanical loading. Engineering techniques such as finite element analysis are now commonly used to calculate stress and strain fields, but if we are to fully accept these methods we must be confident that the applied loading regimens are reasonable. Multibody dynamics analysis (MDA) is a relatively new three dimensional computer modeling technique that can be used to apply varying muscle forces to predict joint and bite forces during static and dynamic motions. The method ensures that equilibrium of the structure is maintained at all times, even for complex statically indeterminate problems, eliminating nonphysiological constraint conditions often seen with other approaches. This study describes the novel use of MDA to investigate the influence of different muscle representations on a macaque skull model (Macaca fascicularis), where muscle groups were represented by either a single, multiple, or wrapped muscle fibers. The impact of varying muscle representation on stress fields was assessed through additional finite element simulations. The MDA models highlighted that muscle forces varied with gape and that forces within individual muscle groups also varied; for example, the anterior strands of the superficial masseter were loaded to a greater extent than the posterior strands. The direction of the muscle force was altered when temporalis muscle wrapping was modeled, and was coupled with compressive contact forces applied to the frontal, parietal and temporal bones of the cranium during biting. Anat Rec, 291:491–501, 2008. © 2008 Wiley‐Liss, Inc. 相似文献
106.
Lizard skulls vary greatly in shape and construction, and radical changes in skull form during evolution have made this an intriguing subject of research. The mechanics of feeding have surely been affected by this change in skull form, but whether this is the driving force behind the change is the underlying question that we are aiming to address in a programme of research. Here we have implemented a combined finite element analysis (FEA) and multibody dynamics analysis (MDA) to assess skull biomechanics during biting. A skull of Uromastyx hardwickii was assessed in the present study, where loading data (such as muscle force, bite force and joint reaction) for a biting cycle were obtained from an MDA and applied to load a finite element model. Fifty load steps corresponding to bilateral biting towards the front, middle and back of the dentition were implemented. Our results show the importance of performing MDA as a preliminary step to FEA, and provide an insight into the variation of stress during biting. Our findings show that higher stress occurs in regions where cranial sutures are located in functioning skulls, and as such support the hypothesis that sutures may play a pivotal role in relieving stress and producing a more uniform pattern of stress distribution across the skull. Additionally, we demonstrate how varying bite point affects stress distributions and relate stress distributions to the evolution of metakinesis in the amniote skull. 相似文献
107.
Curtis L Lee BS Cai D Morozova I Fan JL Scheff P Persky V Einoder C Diblee S 《Allergy》2002,57(7):627-631
BACKGROUND: Few studies have measured pigeon allergens in non pigeon coop environments. This study was conducted to determine approximate pigeon dropping allergen concentrations in indoor environments. METHODS: Polyclonal antibody serum was prepared by injecting a rabbit three times with crude wild pigeon dropping extract in 50 mM Tris buffer with Freund's adjuvant. One hundred and fifteen dust samples were collected in a pigeon-infested school, pigeon coops, homes and hospitals and analyzed by a direct competitive pigeon enzyme-linked immunosorbent assay (ELISA). RESULTS: The highest level of pigeon allergen inhibitory activity were recorded in four samples from pigeon coop bedding samples with a median activity of 11.2% relative to pigeon droppings. The second highest level of pigeon allergens was in a pigeon-infested high school with a median or 7.4% activity relative to pigeon droppings. At an entrance underneath pigeon roosts, one sample had a relative inhibitory activity of 62.3%. Pigeon allergen inhibitory levels were generally low in the home and hospital samples, but nevertheless 46 out of 89 of these samples were still above detection limit. CONCLUSIONS: This study suggests that large concentrations of pigeon allergens can be found in buildings without domestic pigeons such as the pigeon-infested high school. 相似文献
108.
Grebe chondrodysplasia and brachydactyly in a family 总被引:1,自引:0,他引:1
A family is reported in which various skeletal abnormalities have been segregating over three generations. The Great-grandfather (11) of the consultand had features consistent with Grebe chondrodysplasia. The other members of the family have brachydactyly, radiologically characterised by short first metacarpals and short middle phalanges of the index and little fingers. The possibility of association of familial brachydactyly and Grebe chondrodysplasia is discussed. An attempt has been made to deal with the genetic counselling problem in this particular family. 相似文献
109.
Cloning of rabies virus matrix protein mRNA and determination of its amino acid sequence 总被引:2,自引:1,他引:2
A cDNA clone of mRNA for rabies virus matrix (M) protein has been identified. The clone hybridizes to an mRNA species from rabies virus-infected cells, whose size correlates to the size of the M protein in rabies virions, and selects an mRNA that translates into a polypeptide corresponding in size to M protein. The nucleotide sequence of the cloned cDNA was determined and from this a complete amino acid sequence for M protein was deduced. The deduced sequence of 202 amino acids bears no detectable sequence homology with vesicular stomatitis virus M protein although these proteins may share functional homology. 相似文献
110.
Krokan Hans; Grafstrom Roland C.; Sundqvist Kristina; Esterbauer Hermann; Harris Curtis C. 《Carcinogenesis》1985,6(12):1755-1759
Lipid peroxidation aldehydes of the 4-hydroxy-, ß-unsaturatedtype, as well as the tobacco-smoke related , ß-unsaturatedaldehyde, acrolein, were highly cytotoxic and decreased theintracellular thiol content in cultured human bronchial fibroblastsafter treatment with micromolar concentrations. In comparison,formaldehyde and acetaldehyde were less toxic and 100- to 300-foldhigher doses were required to affect cell survival or thiollevels. The unsaturated aldehydes also markedly inhibited theDNA repair enzyme O6-methylguanine-DNA methyltransferase knownto have a cysteine residue in its active site, but had no effecton the activity of uracil-DNA glycosylase. Our results indicatethat reactive aldehydes of either exogenous or endogenous originhave direct cytotoxic effects and may also make cells more susceptibleto other toxic chemicals due to an impairment in cellular defensemechanisms, e.g., DNA repair and detoxification by systems requiringglutathione. 相似文献