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101.
Shroff R Vergara F Muck A Svatos A Gershenzon J 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(16):6196-6201
The spatial distribution of plant defenses within a leaf may be critical in explaining patterns of herbivory. The generalist lepidopteran larvae, Helicoverpa armigera (the cotton bollworm), avoided the midvein and periphery of Arabidopsis thaliana rosette leaves and fed almost exclusively on the inner lamina. This feeding pattern was attributed to glucosinolates because it was not evident in a myrosinase mutant that lacks the ability to activate glucosinolate defenses by hydrolysis. To measure the spatial distribution of glucosinolates in A. thaliana leaves at a fine scale, we constructed ion intensity maps from MALDI-TOF (matrix assisted laser desorption/ionization-time of flight) mass spectra. The major glucosinolates were found to be more abundant in tissues of the midvein and the periphery of the leaf than the inner lamina, patterns that were validated by HPLC analyses of dissected leaves. In addition, there were differences in the proportions of the three major glucosinolates in different leaf regions. Hence, the distribution of glucosinolates within the leaf appears to control the feeding preference of H. armigera larvae. The preferential allocation of glucosinolates to the periphery may play a key role in the defense of leaves by creating a barrier to the feeding of chewing herbivores that frequently approach leaves from the edge. 相似文献
102.
Goldbach-Mansky R Shroff SD Wilson M Snyder C Plehn S Barham B Pham TH Pucino F Wesley RA Papadopoulos JH Weinstein SP Mellis SJ Kastner DL 《Arthritis and rheumatism》2008,58(8):2432-2442
OBJECTIVE: Familial cold autoinflammatory syndrome (FCAS) is caused by mutations in the CIAS1 gene, leading to excessive secretion of interleukin-1beta (IL-1beta), which is associated with cold-induced fevers, joint pain, and systemic inflammation. This pilot study was conducted to assess the safety and efficacy of rilonacept (IL-1 Trap), a long-acting IL-1 receptor fusion protein, in patients with FCAS. METHODS: Five patients with FCAS were studied in an open-label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injection, were evaluated 6 and 10 days later for clinical efficacy, and remained off treatment until a clinical flare occurred. At the time of flare, patients were again treated with 300 mg of rilonacept and then given maintenance doses of 100 mg/week. Patients whose FCAS was not completely controlled were allowed a dosage increase to 160 mg/week and then further to 320 mg/week during an intrapatient dosage-escalation phase. Safety, disease activity measures (daily diary reports of rash, joint pain and/or swelling, and fevers), health quality measures (Short Form 36 health survey questionnaire), and serum markers of inflammation (erythrocyte sedimentation rate [ESR], high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA], and IL-6) were determined at 3, 6, 9, 12, and 24 months after initiation of rilonacept and were compared with baseline values. RESULTS: In all patients, clinical symptoms typically induced by cold (rash, fever, and joint pain/swelling) improved within days of rilonacept administration. Markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (P < 0.01, P < 0.001, and P < 0.001, respectively) at doses of 100 mg. Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain. Furthermore, levels of the acute-phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR. All patients continued taking the study drug. The drug was well-tolerated. Weight gain in 2 patients was noted. No study drug-related serious adverse events were seen. CONCLUSION: In this study, we present 2-year safety and efficacy data on rilonacept treatment in 5 patients with FCAS. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the good tolerability suggest that this drug may be a promising therapeutic option in patients with FCAS, and the data led to the design of a phase III study in this patient population. 相似文献
103.
Carissa van den Berk-Clark Sundari Balan Manan V. Shroff Greg Widner 《Substance use & misuse》2016,51(5):625-636
Background: Prior research suggests that both posttraumatic stress disorder (PTSD) and alcohol abuse affect behavioral healthcare utilization among combat-exposed military populations. However, their interactive effect is not well documented, especially after experiencing psychological trauma. Objective: This study examined the role of hazardous alcohol use (i.e. repeated patterns of drinking which lead to harmful consequences) on behavioral healthcare utilization among service members stratified by past-year combat exposure. Method: This study utilized a sample of National Guard service members who participated in an in-depth survey 2–4 months after returning from Operation Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn deployments (2011–2013) (n = 467). We examine the marginal effect (the change in the probability) of hazardous alcohol use on utilization while controlling for trauma exposure, PTSD and other potential covariates. Results: In the unadjusted logistic model, hazardous alcohol use reduced the probability of behavioral healthcare utilization by 77% among service members who had been exposed to combat within the past year. In the adjusted model, which controlled for socio-demographics (age, gender, and race), health status (PTSD symptoms, depression and physical health), and measures of stigma (perception of services as embarrassing or harmful to one's career or social networks), hazardous alcohol use further reduced the utilization probability by 302%. Conclusion/Importance: Although these findings require replication, they appear to demonstrate that when combat-exposed service members engaged in hazardous alcohol use at postdeployment, they were much less likely to utilize behavioral healthcare to manage their posttraumatic stress symptoms during this period. 相似文献
104.
105.
106.
Govardhan KS Ramyasri K Kethora D Ravishekar Y Prasenjit M 《Anti-cancer agents in medicinal chemistry》2011,11(3):272-279
Altered cellular metabolism is a hallmark of tumorigenesis. Described first in 1924 by Otto Warburg, a cancer cell undergoes complete metabolic reprogramming to attain nutrient self-sufficiency for proliferation and survival. Interplay between diverse signalling cascades confers this metabolic advantage. In this review we focus on signalling molecules that regulate this altered metabolic paradigm in a cancer cell with emphasis on small molecule mediated intervention for attenuation of growth and progression of tumor. 相似文献
107.
Cockayne syndrome is a rare multi-systemic autosomal recessive condition characterized by variable post natal growth failure, neurological impairment, feeding difficulty, and progressive skin, ophthalmological, auditory and dental abnormalities. Life-span is usually shortened and death occurs in childhood or adolescence in the majority of cases. Only 3 cases of chromosomal aberrations as a cause of CS have been previously reported. We report a patient with a clinical phenotype of severe infantile CS who has a paternally inherited 5 Mb deletion of 10q11.2 resulting in loss of one allele and a previously unreported frameshift mutation of ERCC6 on the maternal allele. 相似文献
108.
109.
Administering relaxin to conscious rats and humans elicits systemic and renal vasodilation. The molecular mechanisms vary
according to the duration of relaxin exposure—so-called “rapid” (within minutes) or “sustained” (hours to days) vasodilatory
responses—both being endothelium-dependent. Rapid responses are mediated by Gαi/o protein coupling to phosphoinositol-3 kinase/Akt (protein kinase B)–dependent phosphorylation and activation of nitric oxide
synthase. Sustained responses are mediated by vascular endothelial and placental growth factors, as well as increases in arterial
gelatinase activity. Thus, after hours or days of relaxin treatment, respectively, arterial MMP-9 or MMP-2 hydrolyze “big”
endothelin (ET) at a gly-leu bond to form ET1-32, which in turn activates the endothelial ETB receptor/nitric oxide vasodilatory pathway. Administration of relaxin to conscious rats also increases global systemic arterial
compliance and passive compliance of select isolated blood vessels such as small renal arteries (SRA). The increase in SRA
passive compliance is mediated by both geometric remodeling (outward) and compositional remodeling (decreased collagen). Relaxin-induced
geometric remodeling has also been observed in brain parenchymal arteries, and this remodeling appears to be via the activation
of peroxisome proliferator–activated receptor-γ. Given the vasodilatory and arterial remodeling properties of relaxin, the
hormone may have therapeutic potential in the settings of abnormal pregnancies, heart failure, and pathologies associated
with stiffening of arteries. 相似文献
110.
Fluorescent dextran tracers of varying sizes have been used to assess paranodal permeability in myelinated sciatic nerve fibers from control and three "myelin mutant" mice, Caspr-null, cst-null, and shaking. We demonstrate that in all of these the paranode is permeable to small tracers (3 kDa and 10 kDa), which penetrate most fibers, and to larger tracers (40 kDa and 70 kDa), which penetrate far fewer fibers and move shorter distances over longer periods of time. Despite gross diminution in transverse bands (TBs) in the Caspr-null and cst-null mice, the permeability of their paranodal junctions is equivalent to that in controls. Thus, deficiency of TBs in these mutants does not increase the permeability of their paranodal junctions to the dextrans we used, moving from the perinodal space through the paranode to the internodal periaxonal space. In addition, we show that the shaking mice, which have thinner myelin and shorter paranodes, show increased permeability to the same tracers despite the presence of TBs. We conclude that the extent of penetration of these tracers does not depend on the presence or absence of TBs but does depend on the length of the paranode and, in turn, on the length of "pathway 3," the helical extracellular pathway that passes through the paranode parallel to the lateral edge of the myelin sheath. 相似文献