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排序方式: 共有790条查询结果,搜索用时 484 毫秒
71.
Katarina Almehed Szabolcs Hetényi Claes Ohlsson Hans Carlsten Helena Forsblad-d'Elia 《Arthritis research & therapy》2010,12(4):1-7
Introduction
The present study objective was to evaluate the incidence of methotrexate (MTX)-specific liver lesions from the analysis of a liver biopsy of inflammatory arthritis patients with elevated liver enzymes.Methods
A case-control study was performed with 1,571 arthritis patients on long-term low-dose MTX therapy. Results of liver biopsy were analyzed in 41 patients with elevated liver enzymes. The expression of autoimmune markers was also assessed. This population was compared with 41 disease control subjects obtained from the same database, also on MTX but without elevated liver enzymes, matched for age, sex and rheumatic disease.Results
Compared with the disease controls, patients with liver biopsy showed lower disease duration and lower MTX exposure, weekly and cumulative doses, reflecting shorter treatment duration due to liver abnormalities. Liver biopsies showed 17 autoimmune hepatitis-like (AIH-like) lesions, 13 nonalcoholic steatohepatitis-like lesions, seven limited liver lesions, and two primary biliary cirrhoses. However, MTX-specific lesions with dystrophic nuclei in hepatocytes were seen in only two cases. Liver biopsy lesions were associated with autoimmune markers (P = 0.007); notably, AIH-like lesions were associated with rheumatoid arthritis and with the presence of the HLA-DR shared epitope.Conclusions
MTX-specific liver lesions are rarely observed in arthritis patients under long-term MTX therapy and elevated liver enzymes. 相似文献72.
Amnon Golan Elah Pick Lyuben Tsvetkov Yasmine Nadler Harriet Kluger David F Stern 《Cell cycle (Georgetown, Tex.)》2010,9(13):2647-2656
Two major control systems regulate early stages of mitosis: activation of Cdk1 and anaphase control through assembly and disassembly of the mitotic spindle. In parallel to cell cycle progression, centrosomal duplication is regulated through proteins including Nek2. Recent studies suggest that centrosome-localized Chk1 forestalls premature activation of centrosomal Cdc25b and Cdk1 for mitotic entry, whereas Chk2 binds centrosomes and arrests mitosis only after activation by ATM and ATR in response to DNA damage. Here, we show that Chk2 centrosomal binding does not require DNA damage, but varies according to cell cycle progression. These and other data suggest a model in which binding of Chk2 to the centrosome at multiple cell cycle junctures controls co-localization of Chk2 with other cell cycle and centrosomal regulators.Key words: Chk2, centrosome, checkpoint, DNA damage, wild type, kinase-defective 相似文献
73.
Nilsson H Dragomir A Ahlander A Johannesson M Roomans GM 《Cell and tissue research》2007,330(2):257-269
Inhalation of hyperosmotic solutions (salt, mannitol) has been used in the treatment of patients with cystic fibrosis or asthma,
but the mechanism behind the effect of hyperosmotic solutions is unclear. The relation between osmolarity and permeability
changes was examined in an airway cell line by the addition of NaCl, NaBr, LiCl, mannitol, or xylitol (295–700 mOsm). Transepithelial
resistance was measured as an indicator of the tightness of the cultures. Cell-cell contacts and morphology were investigated
by immunofluorescence and by transmission electron microscopy, with lanthanum nitrate added to the luminal side of the epithelium
to investigate tight junction permeability. The electrolyte solutions caused a significant decrease in transepithelial resistance
from 450 mOsm upwards, when the hyperosmolar exposure was gradually increased from 295 to 700 mOsm; whereas the nonelectrolyte
solutions caused a decrease in transepithelial resistance from 700 mOsm upwards. Old cultures reacted in a more rigid way
compared to young cultures. Immuno-fluorescence pictures showed weaker staining for the proteins ZO-1, claudin-4, and plakoglobin
in treated samples compared to the control. The ultrastructure revealed an increased number of open tight junctions as well
as a disturbed morphology with increasing osmolarity, and electrolyte solutions opened a larger proportion of tight junctions
than nonelectrolyte solutions. This study shows that hyperosmotic solutions cause the opening of tight junctions, which may
increase the permeability of the paracellular pathway and result in increased transepithelial water transport.
This study was supported by the Swedish Asthma and Allergy Association and the Swedish Heart Lung Foundation. 相似文献
74.
Yellow fluorescent protein (YFP) is widely used as a genetically encoded fluorescent marker in biology. In the course of a comprehensive study of this protein, we observed an unusual, negative fluorescence anisotropy at pH 6.0 (McAnaney, T. B., Zeng, W., Doe, C. F. E., Bhanji, N., Wakelin, S., Pearson, D. S., Abbyad, P., Shi, X., Boxer, S. G., and Bagshaw, C. R. (2005) Biochemistry 44, 5510-5524). Here we report that the fluorescence anisotropy of YFP 10C depends on protein concentration in the low micromolar range that was not expected. We propose that the negative anisotropy is a result of unidirectional F?rster resonance energy transfer (FRET) in a dimer of YFP, with the donor chromophore in the neutral form and the acceptor chromophore in the anionic form. This unusual mechanism is supported by studies of a monomeric YFP (A206K YFP) and transient-absorption spectroscopy of YFP 10C. A detailed analysis of the chromophore transition dipole moment direction is presented. The anisotropy and rate constant of this energy transfer are consistent with values produced by an analysis of the dimer structure observed in crystals. 相似文献
75.
Harriet Davies Tom M. Brereton David B. Roy Richard Fox 《Biodiversity and Conservation》2007,16(13):3719-3736
The UK Government has set targets for biodiversity conservation in England based on several indicators, including the status
of protected areas [e.g. Sites of Special Scientific Interest (SSSIs)]. Specifically, the Government aims to achieve favourable
condition [defined by Common Standards Monitoring (CSM)] on 95% by area of SSSIs by 2010. SSSIs are important for threatened
butterflies and management to achieve favourable condition will play a key role in determining future population levels of
these high-profile insects. Because only notified features of SSSIs are considered within CSM, we investigated the level of
notification for three threatened butterflies. We found that these species were notified at only 15–33% of SSSIs where they
occurred; though most site managers did manage for them under broader site conservation objectives. We investigated the relationship
between SSSI condition status and population trend for eight butterfly species of conservation concern to assess the benefit
to butterflies of sites attaining favourable condition status. The majority (80%) of population trends on SSSIs in favourable
condition were positive, suggesting an overall beneficial impact of SSSI management. However, four of the eight species maintained
lower populations at favourable condition SSSIs than at sites in one of the unfavourable condition categories. We suggest
that current condition assessment based chiefly on notified vegetation communities lacks the sensitivity to identify the complex
habitat conditions for these (mosaic) species. As butterflies are good indictors for a wide range of invertebrates, many species
requiring fine-scale habitat heterogeneity may be at risk from the Government’s target. 相似文献
76.
Resource constraints in developing countries compel policy makers to ration the provision of healthcare services. This article examines one such set of Guidelines: A patient dialysing in the state sector in South Africa may not refuse renal transplantation when a kidney becomes available. Refusal of transplantation can lead to exclusion from the state‐funded dialysis programme. This Guideline is legally acceptable as related to Constitutional stipulations which allow for rationing healthcare resources in South Africa. Evaluating the ethical merit of the Guideline, and exploring the ethical dilemma it poses, proves a more complex task. We examine the actions of healthcare professionals as constrained by the Guideline. From a best interests framework, we argue that in these circumstances directing patient decision making (pressurising a patient to undergo renal transplantation) is not necessarily unethical or unacceptably paternalistic. We then scrutinise the guideline itself through several different ethical ‘lenses’. Here, we argue that bioethics does not provide a definitive answer as to the moral merit of rationing dialysis under these circumstances, however it can be considered just in this context. We conclude by examining a potential pitfall of the Guideline: Unwilling transplant recipients may not comply with immunosuppressive medication, which raises questions for policies based on resource management and rationing. 相似文献
77.
Ohlsson C Wallaschofski H Lunetta KL Stolk L Perry JR Koster A Petersen AK Eriksson J Lehtimäki T Huhtaniemi IT Hammond GL Maggio M Coviello AD;EMAS Study Group Ferrucci L Heier M Hofman A Holliday KL Jansson JO Kähönen M Karasik D Karlsson MK Kiel DP Liu Y Ljunggren O Lorentzon M Lyytikäinen LP Meitinger T Mellström D Melzer D Miljkovic I Nauck M Nilsson M Penninx B Pye SR Vasan RS Reincke M Rivadeneira F Tajar A Teumer A Uitterlinden AG Ulloor J Viikari J Völker U Völzke H Wichmann HE Wu TS 《PLoS genetics》2011,7(10):e1002313
Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone''s high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10−41 and rs6258, p = 2.3×10−22). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10−16). The rs6258 polymorphism in exon 4 of SHBG affected SHBG''s affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation. 相似文献
78.
79.
80.
Windahl SH Andersson N Börjesson AE Swanson C Svensson J Movérare-Skrtic S Sjögren K Shao R Lagerquist MK Ohlsson C 《PloS one》2011,6(6):e21402
Androgens are important regulators of bone mass but the relative importance of testosterone (T) versus dihydrotestosterone (DHT) for the activation of the androgen receptor (AR) in bone is unknown. 5α-reductase is responsible for the irreversible conversion of T to the more potent AR activator DHT. There are two well established isoenzymes of 5α-reductase (type 1 and type 2), encoded by separate genes (Srd5a1 and Srd5a2). 5α-reductase type 2 is predominantly expressed in male reproductive tissues whereas 5α-reductase type 1 is highly expressed in liver and moderately expressed in several other tissues including bone. The aim of the present study was to investigate the role of 5α-reductase type 1 for bone mass using Srd5a1−/− mice. Four-month-old male Srd5a1
−/− mice had reduced trabecular bone mineral density (−36%, p<0.05) and cortical bone mineral content (−15%, p<0.05) but unchanged serum androgen levels compared with wild type (WT) mice. The cortical bone dimensions were reduced in the male Srd5a1
−/− mice as a result of a reduced cortical periosteal circumference compared with WT mice. T treatment increased the cortical periosteal circumference (p<0.05) in orchidectomized WT mice but not in orchidectomized Srd5a1
−/− mice. Male Srd5a1
−/− mice demonstrated a reduced forelimb muscle grip strength compared with WT mice (p<0.05). Female Srd5a1
−/− mice had slightly increased cortical bone mass associated with elevated circulating levels of androgens. In conclusion, 5α-reductase type 1 inactivated male mice have reduced bone mass and forelimb muscle grip strength and we propose that these effects are due to lack of 5α-reductase type 1 expression in bone and muscle. In contrast, the increased cortical bone mass in female Srd5a1
−/− mice, is an indirect effect mediated by elevated circulating androgen levels. 相似文献