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1.
The apparent concentration-effect relationship is the ensemble of many effector units (such as individual cells or channels)
that do not always exhibit a uniform stimulus-effect relationship. This concept is substantiated by many observations of heterogeneity
in receptor-effector populations including hormone secreting cells, response to hormonal stimuli, activity pattern of second
messengers, stimulus-evoked synaptic currents, and single ion channels. The relationship between drug concentration and magnitude
of pharmacologic response is commonly described by the sigmoidalE
max model which was derived from the Hill equation. The sigmoidicity factor (N) in this model is assumed to be a pure mathematical parameter without physiological connotations. This work demonstrates
that the numerical value ofN (measured empirically) is the product of two factors: (i) the degree of heterogeneity of the effector subunits, i.e., the
elemental component that upon drug stimulus contributes its pharmacological effect independently and does not interact with
other subunits (it could range from a single receptor up to a whole tissue), and (ii) value ofN
*—the shape factor of the subunits' concentration-effect relationship. A special case of this approach occurs whenN
*>5, which is an on-off case. HereN is determined by the distribution (density equation) of the subunit values. In case of heterogeneity of the microparameters
of the effector subunits the apparentN will always have a lower value thanN
*. According to this theory it can be concluded that without knowledge of the distribution of the microparameters no mechanistic
interpretation can be deduced from the apparentN value. If in the futureN
* can be determined by theoretical or experimental methods, the distribution function relatingN
* toN can be calculated. The relevance of this theory is increased in view of the progress being made in advanced research techniques
which may enable us to determine the concentration-effect relationship at the level of the individual effector unit. 相似文献
2.
A Nussler S Pied J Goma L Rénia F Miltgen G E Grau D Mazier 《International immunology》1991,3(4):317-321
We examined the capacity of murine recombinant tumor necrosis factor (rmTNF) to induce an inhibitory effect at the hepatic stage on malaria induced by Plasmodium yoelii sporozoites. When injected three times, 1.0 micrograms of rmTNF was found to protect 78% of mice against a sporozoite challenge. In contrast, whatever the dose and the schedule of administration, no inhibition was observed when purified hepatocyte cultures were infected with P. yoelii. The addition of non-parenchymal hepatic cells to hepatocyte cultures restored the capacity of TNF to modulate hepatic stage development, leading to up to 44% inhibition. Antibodies to interleukin 6 reversed the anti-parasite activity in the co-culture system. 相似文献
3.
Association between HLA and Japanese patients with rheumatoid arthritis 总被引:12,自引:0,他引:12
N Ohta Y K Nishimura K Tanimoto Y Horiuchi C Abe Y Shiokawa T Abe M Katagiri T Yoshiki T Sasazuki 《Human immunology》1982,5(2):123-132
Japanese patients with rheumatoid arthritis (RA) were observed to have a statistical association with HLA-DR4, MT3. Strong association between the clinical severity of RA and HLA was also observed. Male patients had a stronger association with HLA than female patients. Males are more resistant to RA than females. This suggested that the threshold of liability for RA is higher in males than in females. Japanese patients with RA with systemic vasculitis were negative for HLA-Bw44 and had antilymphocytotoxic autoantibody, indicating that RA with systemic vasculitis is different in etiology from RA without systemic vasculitis. 相似文献
4.
Sushmita Chakraborty Jakob Schneider Dipendra Kumar Mitra Katharina F. Kubatzky 《Immunology》2023,169(3):309-322
Interleukin (IL)-9 is an emerging player in the pathogenesis of various chronic inflammatory diseases including bone disorders like rheumatoid arthritis (RA) and psoriatic arthritis. Recently, IL-9 was shown to enhance the osteoclast formation and their function in RA. However, the mechanisms by which IL-9 influences osteoclastogenesis are not known. Therefore, in this study we aimed to unravel the direct and indirect ways by which IL-9 can influence osteoclast formation. We used mouse bone marrow precursor cells for checking the effect of IL-9 on osteoclast differentiation and its function. Next, IL-9 induced signalling pathway were checked in the process of osteoclastogenesis. T cells play an important role in enhancing osteoclastogenesis in inflammatory conditions. We used splenic T cells to understand the impact of IL-9 on the functions of T effector (Teff) and regulatory T (Treg) cells. Furthermore, the effect of IL-9 mediated modulation of the T cell response on osteoclasts was checked using a coculture model of T cells with osteoclast precursors. We showed that IL-9 enhanced osteoclast formation and its function. We found that IL-9 activates STAT3, P38 MAPK, ERK1/2, NFκB and we hypothesize that it mediates the effect on osteoclastogenesis by accelerating mitochondrial biogenesis. Additionally, IL-9 was observed to facilitate the functions of pro-osteoclastogenic IL-17 producing T cells, but inhibits the function of anti-osteoclastogenic Treg cells. Our observations suggest that IL-9 can influence osteoclastogenesis directly by modulating the signalling cascade in the precursor cells; indirectly by enhancing IL-17 producing T cells and by reducing the functions of Treg cells. 相似文献
5.
Guillaume Beaudoin-Bussires Ariana Arduini Catherine Bourassa Halima Medjahed Gabrielle Gendron-Lepage Jonathan Richard Qinghua Pan Zhen Wang Chen Liang Andrs Finzi 《Viruses》2022,14(6)
Viruses use many different strategies to evade host immune responses. In the case of SARS-CoV-2, its Spike mutates rapidly to escape from neutralizing antibodies. In addition to this strategy, ORF8, a small accessory protein encoded by SARS-CoV-2, helps immune evasion by reducing the susceptibility of SARS-CoV-2-infected cells to the cytotoxic CD8+ T cell response. Interestingly, among all accessory proteins, ORF8 is rapidly evolving and a deletion in this protein has been linked to milder disease. Here, we studied the effect of ORF8 on peripheral blood mononuclear cells (PBMC). Specifically, we found that ORF8 can bind monocytes as well as NK cells. Strikingly, ORF8 binds CD16a (FcγRIIIA) with nanomolar affinity and decreases the overall level of CD16 at the surface of monocytes and, to a lesser extent, NK cells. This decrease significantly reduces the capacity of PBMCs and particularly monocytes to mediate antibody-dependent cellular cytotoxicity (ADCC). Overall, our data identifies a new immune-evasion activity used by SARS-CoV-2 to escape humoral responses. 相似文献
6.
近年来,随着锌指核酸酶、转录激活子样效应因子核酸酶和成簇可调控间隔短回文重复RNA引导核酸酶的出现,“基因组编辑”技术得到广泛应用。由于此类技术具有高效和可定制的特点,在基因治疗、细胞模型、糖基化工程、细胞工程等方面许多新策略、新方法不断涌现,产生了十分重要的影响。本文就近年来基因组编辑技术的发展及其在基因治疗和生物制药领域的应用进行综述。 相似文献
7.
《Expert Review of Clinical Immunology》2013,9(2):267-276
This review summarizes the present understanding of the biology of CD4 T cells during both the acute and memory phases of the response to nonpersisting viral infection. Elucidating the precise role of CD4 T cells in viral infections has been a challenge due to characteristics intrinsic to the CD4 response and the slow development of tools that allow accurate identification of the virus-specific cells in vitro and in vivo. This is especially apparent in comparison with antiviral CD8 T cells, for which immunologists possess many tools for tracking the cells throughout a response. However, recent developments in technology to follow antigen-specific CD4 T cells in virus infections have improved our understanding greatly. Ex vivo technologies such as the enzyme-linked spot forming assays and more recently the FluoroSPOT assays, cytokine capture and the advent of class II major histocompatibility complex multimers have improved our ability to accurately enumerate the virus-specific CD4 T-cell response. The development of virus-primed T-cell receptor transgenic CD4 T cells and imaging technologies that take advantage of allotype marking and luciferase or fluorescent transgenes now allow for high-resolution tracking of virus-specific CD4 T cells in many tissues. Inspite of these new technologies, many questions remain regarding the dynamics of CD4 memory T-cell populations and their contribution to immune protection against viral infections. 相似文献
8.
9.
Takashi Inozume Ken‐ichi Hanada Kazuyo Takeda Tatsuo Maeda Kazutoshi Harada Tatsuyoshi Kawamura 《The Journal of dermatology》2019,46(1):52-56
Cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) is one of the important molecules that regulate the anti‐melanoma T‐cell response. Currently, there are some reports showing that CTLA‐4 is expressed not only by T cells but also by various kinds of tumor cells, including melanoma cells. However, there is no report that shows the role of CTLA‐4 expressed by melanoma cells in melanoma‐specific cytotoxic T‐lymphocyte (CTL) response. In this report, we confirmed substantial CTLA‐4 expression and the localization of CTLA‐4 in melanoma cell lines and tissues. Also, we examined its impact on melanoma‐specific CTL in vitro, and found that CTLA‐4 expressed by melanoma cells does not affect melanoma‐specific CTL in the effector phase. Our findings suggest the importance of elucidating the role of CTLA‐4 expressed by melanoma cells, particularly in anti‐CTLA‐4 antibody therapy. 相似文献
10.