全文获取类型
收费全文 | 701篇 |
免费 | 78篇 |
出版年
2021年 | 8篇 |
2019年 | 9篇 |
2018年 | 13篇 |
2017年 | 6篇 |
2016年 | 11篇 |
2015年 | 22篇 |
2014年 | 26篇 |
2013年 | 30篇 |
2012年 | 34篇 |
2011年 | 30篇 |
2010年 | 40篇 |
2009年 | 33篇 |
2008年 | 29篇 |
2007年 | 28篇 |
2006年 | 31篇 |
2005年 | 33篇 |
2004年 | 23篇 |
2003年 | 23篇 |
2002年 | 20篇 |
2001年 | 21篇 |
2000年 | 23篇 |
1999年 | 14篇 |
1998年 | 12篇 |
1997年 | 12篇 |
1996年 | 9篇 |
1995年 | 11篇 |
1994年 | 6篇 |
1993年 | 9篇 |
1992年 | 8篇 |
1991年 | 14篇 |
1990年 | 6篇 |
1989年 | 10篇 |
1988年 | 13篇 |
1987年 | 6篇 |
1986年 | 6篇 |
1985年 | 7篇 |
1984年 | 7篇 |
1983年 | 8篇 |
1982年 | 23篇 |
1981年 | 8篇 |
1980年 | 7篇 |
1979年 | 11篇 |
1978年 | 9篇 |
1977年 | 14篇 |
1976年 | 12篇 |
1975年 | 7篇 |
1974年 | 4篇 |
1972年 | 7篇 |
1971年 | 7篇 |
1970年 | 3篇 |
排序方式: 共有779条查询结果,搜索用时 3 毫秒
81.
Haringman JJ Vinkenoog M Gerlag DM Smeets TJ Zwinderman AH Tak PP 《Arthritis research & therapy》2005,7(4):R862-R867
Analysis of biomarkers in synovial tissue is increasingly used in the evaluation of new targeted therapies for patients with
rheumatoid arthritis (RA). This study determined the intrarater and inter-rater reliability of digital image analysis (DIA)
of synovial biopsies from RA patients participating in clinical trials. Arthroscopic synovial biopsies were obtained before
and after treatment from 19 RA patients participating in a randomized controlled trial with prednisolone. Immunohistochemistry
was used to detect CD3+ T cells, CD38+ plasma cells and CD68+ macrophages. The mean change in positive cells per square millimetre for each marker was determined by different operators
and at different times using DIA. Nonparametric tests were used to determine differences between observers and assessments,
and to determine changes after treatment. The intraclass correlations (ICCs) were calculated to determine the intrarater and
inter-rater reliability. Intrarater ICCs showed good reliability for measuring changes in T lymphocytes (R = 0.87), plasma
cells (R = 0.62) and macrophages (R = 0.73). Analysis by Bland–Altman plots showed no systemic differences between measurements.
The smallest detectable changes were calculated and their discriminatory power revealed good response in the prednisolone
group compared with the placebo group. Similarly, inter-rater ICCs also revealed good reliability for measuring T lymphocytes
(R = 0.68), plasma cells (R = 0.69) and macrophages (R = 0.72). All measurements identified the same cell types as changing
significantly in the treated patients compared with the placebo group. The measurement of change in total positive cell numbers
in synovial tissue can be determined reproducibly for various cell types by DIA in RA clinical trials. 相似文献
82.
83.
Direct inoculation of simian immunodeficiency virus from sooty mangabeys in black mangabeys (Lophocebus aterrimus): first evidence of AIDS in a heterologous African species and different pathologic outcomes of experimental infection
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Apetrei C Gormus B Pandrea I Metzger M ten Haaft P Martin LN Bohm R Alvarez X Koopman G Murphey-Corb M Veazey RS Lackner AA Baskin G Heeney J Marx PA 《Journal of virology》2004,78(21):11506-11518
A unique opportunity for the study of the role of serial passage and cross-species transmission was offered by a series of experiments carried out at the Tulane National Primate Research Center in 1990. To develop an animal model for leprosy, three black mangabeys (BkMs) (Lophocebus aterrimus) were inoculated with lepromatous tissue that had been serially passaged in four sooty mangabeys (SMs) (Cercocebus atys). All three BkMs became infected with simian immunodeficiency virus from SMs (SIVsm) by day 30 postinoculation (p.i.) with lepromatous tissue. One (BkMG140) died 2 years p.i. from causes unrelated to SIV, one (BkMG139) survived for 10 years, whereas the third (BkMG138) was euthanized with AIDS after 5 years. Histopathology revealed a high number of giant cells in tissues from BkMG138, but no SIV-related lesions were found in the remaining two BkMs. Four-color immunofluorescence revealed high levels of SIVsm associated with both giant cells and T lymphocytes in BkMG138 and no detectable SIV in the remaining two. Serum viral load (VL) showed a significant increase (>1 log) during the late stage of the disease in BkMG138, as opposed to a continuous decline in VL in the remaining two BkMs. With the progression to AIDS, neopterin levels increased in BkMG138. This study took on new significance when phylogenetic analysis unexpectedly showed that all four serially inoculated SMs were infected with different SIVsm lineages prior to the beginning of the experiment. Furthermore, the strain infecting the BkMs originated from the last SM in the series. Therefore, the virus infecting BkMs has not been serially passaged. In conclusion, we present the first compelling evidence that direct cross-species transmission of SIV may induce AIDS in heterologous African nonhuman primate (NHP) species. The results showed that cross-species-transmitted SIVsm was well controlled in two of three BkMs for 2 and 10 years, respectively. Finally, this case of AIDS in an African monkey suggests that the dogma of SIV nonpathogenicity in African NHP hosts should be reconsidered. 相似文献
84.
Bollen AM Baskin CR Treuting PM 《Comparative medicine》2006,56(4):245; author reply 245-245; author reply 246
85.
Identification and characterization of the water gap in physically dormant seeds of Geraniaceae, with special reference to Geranium carolinianum 总被引:1,自引:0,他引:1
Background and Aims
Physical dormancy in seeds of species of Geraniaceae is caused by a water-impermeable palisade layer in the outer integument of the seed coat and a closed chalaza. The chalazal cleft has been reported to be the water gap (i.e. location of initial water entry) in innately permeable seeds of Geraniaceae. The primary aim of this study was to re-evaluate the location of the water gap and to characterize its morphology and anatomy in physically dormant seeds of Geraniaceae, with particular reference to G. carolinianum.Methods
Length, width, mass, anatomy and germination of two seed types (light brown and dark brown) of G. carolinianum were compared. Location, anatomy and morphology of the water gap were characterized using free-hand and microtome tissue sectioning, light microscopy, scanning electron microscopy, dye tracking, blocking and seed-burial experiments.Key Results
Treatment with dry heat caused a colour change in the palisade cells adjacent to the micropyle. When placed in water, the ‘hinged valve’ (blister) erupted at the site of the colour change, exposing the water gap. The morphology and anatomy in the water-gap region differs from those of the rest of the seed coat. The morphology of the seed coat of the water-gap region is similar in G. carolinianum, G. columbinum, G. molle and G. pusillum and differs from that of the closely related species Erodium cicutarium.Conclusions
Dislodgment of swollen ‘hinged valve’ palisade cells adjacent to the micropyle caused the water gap to open in physically dormant seeds of G. carolinianum, and it was clear that initial water uptake takes place through this gap and not via the chalazal opening as previously reported. This water gap (‘hinged valve gap’) differs from water gaps previously described for other families in morphology, anatomy and location in the seed coat. 相似文献86.
Anurima Majumder Lakshmanan Govindasamy Andrew Magis Róbert Kiss Tímea Polgár Rebekah Baskin Robert W. Allan Mavis Agbandje-McKenna Gary W. Reuther Gy?rgy M. Keser? Kirpal S. Bisht Peter P. Sayeski 《The Journal of biological chemistry》2010,285(41):31399-31407
Somatic mutations in the Jak2 protein, such as V617F, cause aberrant Jak/STAT signaling and can lead to the development of myeloproliferative neoplasms. This discovery has led to the search for small molecule inhibitors that target Jak2. Using structure-based virtual screening, our group recently identified a novel small molecule inhibitor of Jak2 named G6. Here, we identified a structure-function correlation of this compound. Specifically, five derivative compounds of G6 having structural similarity to the original lead compound were obtained and analyzed for their ability to (i) inhibit Jak2-V617F-mediated cell growth, (ii) inhibit the levels of phospho-Jak2, phospho-STAT3, and phospho-STAT5; (iii) induce apoptosis in human erythroleukemia cells; and (iv) suppress pathologic cell growth of Jak2-V617F-expressing human bone marrow cells ex vivo. Additionally, we computationally examined the interactions of these compounds with the ATP-binding pocket of the Jak2 kinase domain. We found that the stilbenoid core-containing derivatives of G6 significantly inhibited Jak2-V617F-mediated cell proliferation in a time- and dose-dependent manner. They also inhibited phosphorylation of Jak2, STAT3, and STAT5 proteins within cells, resulting in higher levels of apoptosis via the intrinsic apoptotic pathway. Finally, the stilbenoid derivatives inhibited the pathologic growth of Jak2-V617F-expressing human bone marrow cells ex vivo. Collectively, our data demonstrate that G6 has a stilbenoid core that is indispensable for maintaining its Jak2 inhibitory potential. 相似文献
87.
Xeric limestone prairies (XLPs) are open, nonforested areas in which herbaceous plant communities occur on shallow, rocky
soils derived from calcareous substrates. These grasslands are characterized by dominance of C4 perennial grasses (particularlySchizachyrium scoparium) and are distributed in eastern United States from Missouri and Pennsylvania south to Arkansas and Georgia. XLPs occur in
the Ozark Plateaus, Central Lowland, Interior Low Plateaus, Appalachian Plateaus, Ridge and Valley, and Coastal Plain physiographic
provinces, and they are developed on Alfisols, Ultisols, Mollisols, Inceptisols, and Vertisols derived from Paleozoic limestones
(also Eocene), dolomites, and calcareous shales. The C4 perennial prairie grassS. scoparium is the characteristic dominant taxon in XLPs of eastern United States. However, C3 perennial forbs are dominant in some sites, and C4 annual grasses (Sporobolus spp.) may be locally dominant in shallow-soil-zone microsites. Thirteen taxa apparently are endemic, or nearly so, to this
vegetation type, including eight in the Ridge and Valley in Alabama (Cahaba River valley), four in the Ozark Plateaus in Missouri
and Arkansas, and one in the Ridge and Valley of West Virginia and Virginia. Various types of information are used to construct
a conceptual model of the origin, maintenance, and successional dynamics of XLPs. Affinities of XLPs in eastern United States
to other herbaceous vegetation types in eastern and western North America are discussed, and directions for future research
are suggested. 相似文献
88.
Skirgello OE Balyasnikova IV Binevski PV Sun ZL Baskin II Palyulin VA Nesterovitch AB Albrecht RF Kost OA Danilov SM 《Biochemistry》2006,45(15):4831-4847
Angiotensin I-converting enzyme (ACE), a key enzyme in cardiovascular pathophysiology, consists of two homologous domains (N and C), each bearing a Zn-dependent active site. We modeled the 3D-structure of the ACE N-domain using known structures of the C-domain of human ACE and the ACE homologue, ACE2, as templates. Two monoclonal antibodies (mAb), 3A5 and i2H5, developed against the human N-domain of ACE, demonstrated anticatalytic activity. N-domain modeling and mutagenesis of 21 amino acid residues allowed us to define the epitopes for these mAbs. Their epitopes partially overlap: amino acid residues K407, E403, Y521, E522, G523, P524, D529 are present in both epitopes. Mutation of 4 amino acid residues within the 3A5 epitope, N203E, R550A, D558L, and K557Q, increased the apparent binding of mAb 3A5 with the mutated N-domain 3-fold in plate precipitation assay, but abolished the inhibitory potency of this mAb. Moreover, mutation D558L dramatically decreased 3A5-induced ACE shedding from the surface of CHO cells expressing human somatic ACE. The inhibition of N-domain activity by mAbs 3A5 and i2H5 obeys similar kinetics. Both mAbs can bind to the free enzyme and enzyme-substrate complex, forming E.mAb and E.S.mAb complexes, respectively; however, only complex E.S can form a product. Kinetic analysis indicates that both mAbs bind better with the ACE N-domain in the presence of a substrate, which, in turn, implies that binding of a substrate causes conformational adjustments in the N-domain structure. Independent experiments with ELISA demonstrated better binding of mAbs 3A5 and i2H5 in the presence of the inhibitor lisinopril as well. This effect can be attributed to better binding of both mAbs with the "closed" conformation of ACE, therefore, disturbing the hinge-bending movement of the enzyme, which is necessary for catalysis. 相似文献
89.
Czerwinski SE Skvorak JP Maxwell DM Lenz DE Baskin SI 《Journal of biochemical and molecular toxicology》2006,20(5):241-246
Knowledge of partition coefficient (log P) data can play a critical role in understanding the pharmacokinetic and pharmacodistributive properties of toxic organophosphorus (OP) compounds. Using a recently published gas chromatographic method, the octanol:water log P values for the compounds tabun (GA), sarin (GB), cyclosarin (GF), and O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX) were determined to be 0.384 +/- 0.033, 0.299 +/- 0.016, 1.038 +/- 0.055, and 0.675 +/- 0.070, respectively. Based on these data, the log P value of the fluorophosphonate fragment, common to GB, soman (GD), and GF, was determined to be -2.256 +/- 0.273. The predictive value for absorption and distribution of the determined log P values was compared to measured values. The time to onset of local fasciculations (47.3, 29.0, 8.8, 8.5, and 6.3 min, respectively) in guinea pigs exposed percutaneously to equilethal doses of GA, VX, GF, GB, or GD was used as an indicator of dermal penetration. There was a good correlation (r = 0.95) between the measured log P value and the rate of onset of local fasciculations. Assuming a direct correspondence, equilibrium tissue:blood log P may be estimated from octanol:water log P. Comparison of the estimated and directly measured tissue:blood log P revealed a correlation of 0.8 for GD in liver, muscle, and adipose tissue. Our results demonstrate the use of log P data to both predict absorption and determine the distribution of OP compounds in tissues. This facilitates further estimates of in vivo OP effects from in vitro experiments. 相似文献
90.