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91.
J. M. Lawson J. Tremble C. Dayan H. Beyan R. D. G. Leslie M. Peakman T. I. M. Tree 《Clinical and experimental immunology》2008,154(3):353-359
Type I diabetes (T1D) is a T cell‐mediated autoimmune disease characterized by loss of tolerance to islet autoantigens, leading to the destruction of insulin‐producing beta cells. Peripheral tolerance to self is maintained in health through several regulatory mechanisms, including a population of CD4+CD25hi naturally occurring regulatory T cells (Tregs), defects in which could contribute to loss of self‐tolerance in patients with T1D. We have reported previously that near to T1D onset, patients demonstrate a reduced level of suppression by CD4+CD25hi Tregs of autologous CD4+CD25‐ responder cells. Here we demonstrate that this defective regulation is also present in subjects with long‐standing T1D (> 3 years duration; P = 0·009). No difference was observed in forkhead box P3 or CD127 expression on CD4+CD25hi T cells in patients with T1D that could account for this loss of suppression. Cross‐over co‐culture assays demonstrate a relative resistance to CD4+CD25hi Treg‐mediated suppression within the CD4+CD25‐ T cells in all patients tested (P = 0·002), while there appears to be heterogeneity in the functional ability of CD4+CD25hi Tregs from patients. In conclusion, this work demonstrates that defective regulation is a feature of T1D regardless of disease duration and that an impaired ability of responder T cells to be suppressed contributes to this defect. 相似文献
92.
Yoshitaka Saito Terutaka Ozawa Akinori Nishiyama 《Pflügers Archiv : European journal of physiology》1990,417(4):382-390
Kinetic properties of the Na+-H+ antiport in the acinar cells of the isolated, superfused mouse lacrimal gland were studied by measuring intracellular pH (pHi) and Na+ activity (aNai) with the aid of double-barreled H+- and Na+-selective microelectrodes, respectively. Bicarbonate-free solutions were used throughout. Under untreated control conditions, pHi was 7.12±0.01 and aNai was 6.7±0.6 mmol/l. The cells were acid-loaded by exposure to an NH
4
+
solution followed by an Na+-free N-methyl-d-glucamine (NMDG+) solution. Intracellular Na+ and H+ concentrations were manipulated by changing the duration of exposure to the above solutions. Subsequent addition of the standard Na+ solution rapidly increased pHi. This Na+-induced increase in pHi was almost completely inhibited by 0.5 mmol/l amiloride and was associated with a rapid, amiloride-sensitive increase in aNai. The rate of pHi recovery induced by the standard Na+ solution increased in a saturable manner as pHi decreased, and was negligible at pHi 7.2–7.3, indicating an inactivation of the Na+-H+ antiport. The apparent K
m for intracellular H+ concentration was 105 nmol/l (pH 6.98). The rate of acid extrusion from the acid-loaded cells increased proportionally to the increase in extracellular pH. Depletion of aNai to less than 1 mmol/l by prolonged exposure to NMDG+ solution significantly increased the rate of Na+-dependent acid extrusion. The rate of acid extrusion increased as the extracellular Na+ concentration increased following Michaelis-Menten kinetics (V
max was 0.55 pH/min and the apparent K
m was 75 mmol/l at pHi 6.88). The results clearly showed that the Na+-H+ antiport activity is dependent on the chemical potential gradient of both Na+ and H+ ions across the basolateral membrane, and that the antiporter is asymmetric with respect to the substrate affinity of the transport site. The data agree with the current model of activation and inactivation of the antiporter by an intracellular site through changes in the intracellular Na+ and H+ concentrations. 相似文献
93.
In the filamentous fungus Neurospora crassa during conditions of sulfur limitation, CYS3, a major positive-acting regulatory protein, turns on the expression of an entire set of genes which encode permeases and
enzymes involved in the acquisition of sulfur from environmental sources. CYS3 functions as a homodimeric protein and possesses
a b-Zip domain that confers sequence-specific DNA binding. Expression of various hybrid GAL4-CYS3 fusion proteins in yeast
was used to detect regions involved in gene activation. An amino-terminal serine/threonine-rich domain of CYS3 alone strongly
activated expression of β-galactosidase, the yeast reporter. Moreover, mutant CYS3 proteins with amino-acid substitutions in this region that showed
increased expression in Neurospora also displayed an enhanced activation potential in yeast. The cys-3 gene of the exotic N. crassa Mauriceville strain and of N. intermedia were cloned and demonstrated to be functional for gene activation and for sulfur-mediated regulation by complementation of
a loss-of-function cys-3 mutation. The amino-terminal serine/threonine-rich region is highly conserved in these two CYS3 proteins, in agreement with
the possibility that it serves as the activation domain. Surprisingly, an extended promoter region of the cys-3 gene in the Mauriceville strain and in N. intermedia was very well conserved with that of the standard N. crassa gene, including the presence of three CYS3-binding sites possibly involved in autogenous control. Results are presented which
indicate that synthesis of the CYS3 regulatory protein is highly regulated and can be detected in the nucleus of cells subjected
to sulfur de-repression, but is not found in the nucleus or the cytoplasm of S-repressed cells. The amino-acid substitutions
of the CYS3 protein present in a temperature-sensitive cys-3 mutant and in a second-site revertant of a cys-3 null mutation are presented and are shown to affect their DNA-binding activities.
Received: 9 January / 5 March 1998 相似文献
94.
95.
Natural killer (NK) cells play an important role in host defense mechanisms against infection and neoplasia. Interferon- (IFN-) has been shown to activate NK cells and to augment their cytotoxic activity, albeit its role in the maturation pathway of NK cells has not been elucidated. The present study examined whether IFN- activates the immature NK subset (Free cells) to become cytotoxic and also ascertained whether IFN- uses the same pathway of activation as that mediated by interleukin-2 (IL-2). Incubation of sorted Free cells overnight with IFN- resulted in augmentation of their cytotoxic function against NK sensitive target cells. The enhanced cytotoxic activity was not accompanied by a new recruitment of NK-target binder cells but by an increase in the frequency of killer cells in the conjugate fraction. Activation of the Free subset by IFN- resulted in upregulation of CD69, CD11b, and CD2 surface expression and stimulated secretion of IFN-. Unlike IL-2, IFN- did not stimulate the Free cells to proliferate or secrete TNF- and activation of cytotoxicity and modulation of surface antigens by IFN- were independent of TNF-. The failure of IFN- to stimulate secretion and proliferation by Free cells appeared to be mediated by negative signals. This was corroborated in experiments demonstrating that when Free cells were cultured with both IFN- and IL-2, a significant inhibition was observed for both the IL-2 dependent secretion of TNF- and proliferation. These results demonstrate that IFN- serves as both an activator and a regulator of NK function. Further, activation of the immature Free NK cells by IL-2 and IFN- proceeds by TNF--dependent and independent pathways, respectively. The findings also support our contention that the mechanism of activation of the cytotoxic machinery of NK cells is not linked to the mechanism of activation of cytokine secretion and/or proliferation.Abbreviations used IFN
interferon
- IL
interleukin
- PBL
peripheral blood leukocytes
- PE
phycoerythrin
- PE-GAM
PE-conjugated Fab2 goat anti-mouse IgG
- NK
natural killer
- NRS
normal rabbit serum
- TNF
tumor necrosis factor
- FCS
fetal calf serum
- FITC
fluorescein isothiocyanate
- PBS
phosphate-buffered saline
- MACS
magnetic cell sorting
- ELISA
enzyme-linked immunosorbent assay
- BSA
bovine serum albumin
- PKC
protein kinase C
- mAb
monoclonal antibody
- PBMC
peripheral blood mononuclear cells
- BCLL
B-chronic lymphocytic leukemia
- E
effector
- T
target 相似文献
96.
A group of six rabbits reared at +20°C ambient temperature was adapted to moderate cold by housing for seven weeks at +10°C. Rectal and skin temperatures, metabolic heat production and respiratory evaporative heat loss were recorded continuously over 1 h for each animal on 3 days per week in the climatic chamber.There was no significant change either of rectal or of ear skin temperature during the acclimatisation process. On the other hand, metabolic heat production was progressively reduced (20% in the 7th week). Slight changes of mean skin temperature and respiratory evaporative heat loss could not account for compensation. Therefore it must be concluded that both adaptive improvement of peripheral insulation and reduction of heat production were achieved during the acclimatisation process. Both processes together ensure that deviations of core temperature are minimal. The possible origin of the functional adaptive effects is discussed. The results are in full agreement both with former neurophysiological results and with system-theoretical considerations of adaptive processes.Dedicated to the 60th birthday of Professor Dr. Kurt Brück 相似文献
97.
I. S. Breslav B. N. Volkov E. L. Kalacheva M. A. Pogodin S. M. Sidikov V. P. Frolova A. M. Shmeleva 《Bulletin of experimental biology and medicine》1980,89(1):5-6
A method of assessing the respiratory response to a hypercapnic stimulus after an increase in alveolar pCO2 in accordance with an assigned program is suggested. The results are independent of the metabolic level, resistance to respiration, and other factors. Unlike the widely used rebreathing method, this new method enables the ventilatory sensitivity to CO2 to be compared at rest, during muscular work, when the resistance to respiration is changed, and so on. It can also be used for both clinical and experimental investigations.Respiratory Physiology Group, I. P. Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. (Presented by Academician of the Academy of Medical Sciences of the USSR V. N. Chernigovskii.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 89, No. 1, pp. 6–7, January, 1980. 相似文献
98.
Lactating female rats failed to display sexual receptivity after receiving 50 μg of estradiol benzoate followed by 1 mg of progesterone. Lactating rats appear to be insensitive to progesterone, based on several experiments. In ovariectomized control rats receiving moderate estrogen priming (1 μg EB for 3 days), progesterone greatly facilitated sexual receptivity; similarly estrogen-primed lactating females showed no responsiveness to progesterone injections, even at a high dose of progesterone (10 mg). Consistent with this reduced behavioral responsiveness to progesterone, lactating females had significantly reduced nuclear progestin receptor levels after an injection of 1 mg progesterone compared to ovariectomized controls. On the other hand, both ovariectomized controls and lactating rats responded with high levels of receptivity to 3 days of priming with 10 μg of estradiol benzoate (without progesterone). Lactating females treated for 3 days with a moderate dose (1 μg) of estradiol benzoate showed slightly reduced receptivity compared to ovariectomized controls; this result could reflect a reduced sensitivity to estrogen but is more likely related to the somewhat lower serum levels of estradiol and consequently lower nuclear estrogen receptors in lactating females compared to ovariectomized controls. The possibility of reduced sensitivity to estrogen leading to a reduced sensitivity to progesterone cannot be eliminated (since animals respond to progesterone only after estrogen priming); however, the reported results favor the idea that lactating females are primarily refractory to progesterone and do not have a generalized insensitivity to estrogen. 相似文献
99.
100.
Effects of Beta-Adrenergic Activity on T-Wave Amplitude 总被引:1,自引:0,他引:1
Richard J. Contrada David S. Krantz Lynn A. Durel Linda Levy Patrick J. LaRiccia Judith R. Anderson Theodore Weiss 《Psychophysiology》1989,26(4):488-492
This study addresses the hypothesis that electrocardiographic T-wave amplitude is influenced by beta-adrenergic stimulation of the heart. Beta-adrenergic activity was manipulated both pharmacologically and through behavioral challenge. Under resting conditions, 12 healthy men underwent infusion of placebo and then the beta-agonist, isoproterenol, and the beta-blocker, propranolol, in a counterbalanced, crossover design. During infusion of placebo, subjects also underwent two behavioral challenges, a structured interview and mental arithmetic. Analysis of the resting data indicated that propranolol produced a significant increase in T-wave amplitude, and isoproterenol produced significant T-wave amplitude attenuation. As previously reported, drug effects were also in evidence for heart rate. Behaviorally-induced reduction of T-wave amplitude was observed for mental arithmetic but not structured interview, which again paralleled heart rate data. Both pharmacological and behavioral data reported in this study support the hypothesis that the T-wave is significantly affected by beta-sympathetic influence on the heart. However, a nonspecific effect of heart rate change on T-wave amplitude would also account for these results. The findings are discussed in terms of their implications for the utility of T-wave amplitude in psychophysiological research. 相似文献