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801.
802.
803.
Subtype-selective antagonism of N-methyl-D-aspartate receptor ion channels by synthetic conantokin peptides 总被引:1,自引:0,他引:1
Conantokin-G (con-G), conantokin-T (con-T), a truncated conantokin-R (con-R[1-17]), that functions the same as wild-type con-R, and variant sequences of con-T, were chemically synthesized and employed to investigate their selectivities as antagonists of glutamate/glycine-evoked ion currents in human embryonic kidney-293 cells expressing various combinations of NMDA receptor (NMDAR) subunits (NR), viz., NR1a/2A, NR1a/2B, NR1b/2A and NR1b/2B. Con-G did not substantially affect ion flow into NR1a,b/NR2A-transfected cells, but potently inhibited cells expressing NR1a,b/NR2B, showing high NR2B selectivity. Con-T and con-R served as non-selective antagonists of all of four NMDAR subunit combinations. C-terminal truncation variants of the 21-residue con-T were synthesized and examined in this regard. While NMDAR ion channel antagonist activity, and the ability to adopt the Ca(2+)-induced alpha-helical conformation, diminished as a function of shortening the COOH-terminus of con-T, NMDAR subtype selectivity was enhanced in the con-T[1-11], con-T[1-9], and con-T[1-8] variants toward NR2A, NR1b, and NR1b/2A, respectively. Receptor subtype selectivity was also obtained with Met-8 sequence variants of con-T. Con-T[M8A] and con-T[M8Q] displayed selectivity with NR2B-containing subunits, while con-T[M8E] showed enhanced activity toward NR1b-containing NMDAR subtypes. Of those studied, the most highly selective variant was con-T[M8I], which showed maximal NMDAR ion channel antagonism activity toward the NR1a/2A subtype. These studies demonstrate that it is possible to engineer NMDAR subtype antagonist specificity into con-T. Since the subunit composition of the NMDAR varies temporally and spatially in developing brain and in various disease states, conantokins with high subtype selectivities are potentially valuable drugs that may be used at specific stages of disease and in selected regions of the brain. 相似文献
804.
Veld PA; Weber RF; Los FJ; den Hollander N; Dhont M; Pieters MH; Van Hemel JO 《Human reproduction (Oxford, England)》1997,12(8):1642-1644
Two case histories are presented documenting structural chromosome
abnormalities in infertile males. The abnormalities were detected only
after application of intracytoplasmic sperm injection (ICSI) was repeatedly
unsuccessful or resulted in an abnormal pregnancy. A mosaic Robertsonian
translocation 45,XY,der(13;13)(q10; q10)/46,XY,t(13;13)(p10;p10),
der(13p;13p) incompatible with normal offspring was found in a male with
extreme oligozoospermia after three subsequent ICSI treatments were
unsuccessful and one had resulted in a spontaneous abortion. A second case
involved a Robertsonian translocation 45,XY,der(13;14)(q10;q10) which was
detected in a male with extreme oligozoospermia after ultrasound
abnormalities were found in an ICSI-induced twin pregnancy. Amniocentesis
showed an unbalanced 46,XY,+13,der(13;14)(q10;q10) karyotype in one twin
and a Robertsonian 45,XX,der(13;14)(q10;q10) karyotype in the other twin.
Chromosome analysis of males with abnormal sperm characteristics is advised
prior to ICSI.
相似文献
805.
Treatment of the male with follicle-stimulating hormone in intrauterine insemination with husband's spermatozoa: a randomized study 总被引:1,自引:1,他引:1
Matorras R; Perez C; Corcostegui B; Pijoan JI; Ramon O; Delgado P; Rodriguez- Escudero FJ 《Human reproduction (Oxford, England)》1997,12(1):24-28
We have examined the potential of follicle-stimulating hormone (FSH)
therapy for the male to improve pregnancy rates in intrauterine
insemination (IUI) with husband's spermatozoa. A prospective randomized
trial was performed in 148 couples undergoing IUI because of male
subfertility. In the treatment group, 150 IU FSH were administered to the
husbands, either i.m. or s.c., three times a week, starting 3 months before
the beginning of IUI cycles and maintained until the fifth IUI cycle. In
the control group no treatment was given. FSH therapy did not change semen
parameters. The pregnancy rate per cycle was 13.47% in the FSH group versus
10.07% in the non-FSH group; the pregnancy rate per woman was 44.38% in the
FSH group versus 37.18% in the non-FSH group. Although the pregnancy rate
increase was > 30% per cycle and > 20% per woman, statistical
significance was not achieved. The cumulative pregnancy rate was 59.20% in
the FSH group versus 42.91% in the non-FSH group. The pregnancy rate
outside the IUI cycle was 14.70% (10/68) in the FSH group versus 2.5%
(2/80) in the non-FSH group, the difference being statistically
significant. In conclusion, a non-significant trend towards higher
pregnancy rates in IUI was observed in the FSH group.
相似文献
806.
Invariant chain (Ii) association with MHC class II molecules is strongly dependent upon interaction of CLIP (Ii exon 3, residues 81 - 104) with the peptide binding groove of the class II dimer. This dominant interaction does not adequately explain, however, the efficient association of Ii with class II molecules of diverse allelic and isotypic origin, which have markedly different affinities for synthetic peptides corresponding to CLIP. In agreement with other recent observations, we demonstrate here that class II molecules with occupied binding sites unable to engage CLIP maintain association with Ii in mild detergent. The association is direct and not mediated through unoccupied class II chains bound to properly assembled and loaded class II dimers, nor is it mediated through chaperones. The site of this CLIP-independent binding has been mapped using truncation mutants and an Ii-human transferrin receptor chimeric protein to the transmembrane segment of Ii. The existence of multiple low-affinity sites of interaction between MHC class II and Ii helps explain how effective occupancy of all newly synthesized class II molecules can occur despite substantial variations in the strength of CLIP-dependent association that arise from class II binding domain polymorphism. These data establishing a site of Ii-MHC class II association N-terminal to CLIP also provide new insight into the possible functional relationship between the sequential endocytic proteolysis of Ii from its C terminus and a series of contact sites with MHC class II molecules spread from the transmembrane region through to the tip of the lumenal segment of Ii. 相似文献
807.
Background
The majority of childhood acute myeloid leukemia (AML) patients lack a matched‐related bone marrow transplant (BMT) donor in first remission.Procedure
Disease‐free survival (DFS), overall survival (OS), relapse‐free survival (RFS), and post‐relapse outcome were evaluated for children with de novo AML on CCG 213 and the standard timing (ST) and intensive timing (IT) induction arms of CCG 2891 who were randomized to (intent‐to‐treat, ITT) or who received (as‐treated, AT) only chemotherapy intensification.Results
Outcomes at 8 years post‐induction in ITT analysis of chemotherapy intensification were as follows: 31% DFS, 43% OS on CCG 213; 34% DFS, 51% OS on CCG 2891 ST; 48% DFS, 56% OS on CCG 2891 IT. All toxic deaths during and following Capizzi II chemotherapy intensification on both protocols were in patients >3 years of age (P ≤ 0.001). Black race was a significant poor prognostic factor for OS (P = 0.008, hazard ratio: 1.74, 95% CI: 1.15–2.61). Overall 48% of patients on both trials relapsed and 19.1% of patients who relapsed on these trials survived. CR1 >12 months portends a much better OS for patients who relapse. Post‐relapse treatment included BMT in 47% of patients.Conclusions
OS on CCG 2891 was superior to CCG 213 but equivalent between ST and IT arms due to better salvage rates post‐relapse in ST patients. Overall survival for childhood AML in the absence of BMT in CR1 is influenced by duration of CR1 and by race. Pediatr Blood Cancer 2008;50:9–16. © 2007 Wiley‐Liss, Inc. 相似文献808.
809.