全文获取类型
收费全文 | 422篇 |
免费 | 81篇 |
国内免费 | 9篇 |
专业分类
耳鼻咽喉 | 4篇 |
儿科学 | 12篇 |
妇产科学 | 4篇 |
基础医学 | 42篇 |
口腔科学 | 6篇 |
临床医学 | 77篇 |
内科学 | 88篇 |
皮肤病学 | 18篇 |
神经病学 | 26篇 |
特种医学 | 84篇 |
外科学 | 36篇 |
综合类 | 6篇 |
现状与发展 | 1篇 |
预防医学 | 21篇 |
眼科学 | 2篇 |
药学 | 25篇 |
肿瘤学 | 60篇 |
出版年
2024年 | 4篇 |
2023年 | 24篇 |
2022年 | 5篇 |
2021年 | 5篇 |
2020年 | 16篇 |
2019年 | 6篇 |
2018年 | 16篇 |
2017年 | 21篇 |
2016年 | 20篇 |
2015年 | 11篇 |
2014年 | 23篇 |
2013年 | 17篇 |
2012年 | 11篇 |
2011年 | 8篇 |
2010年 | 12篇 |
2009年 | 13篇 |
2008年 | 5篇 |
2007年 | 12篇 |
2006年 | 4篇 |
2005年 | 11篇 |
2004年 | 6篇 |
2003年 | 6篇 |
2002年 | 4篇 |
2001年 | 9篇 |
2000年 | 5篇 |
1999年 | 8篇 |
1998年 | 18篇 |
1997年 | 7篇 |
1996年 | 5篇 |
1995年 | 9篇 |
1994年 | 20篇 |
1993年 | 12篇 |
1992年 | 11篇 |
1991年 | 6篇 |
1990年 | 6篇 |
1989年 | 15篇 |
1988年 | 12篇 |
1987年 | 13篇 |
1986年 | 11篇 |
1985年 | 10篇 |
1984年 | 12篇 |
1983年 | 10篇 |
1982年 | 7篇 |
1981年 | 8篇 |
1980年 | 9篇 |
1979年 | 3篇 |
1978年 | 3篇 |
1977年 | 3篇 |
1976年 | 3篇 |
1975年 | 4篇 |
排序方式: 共有512条查询结果,搜索用时 31 毫秒
21.
Andrea Saponaro Sofia R. Pauleta Francesca Cantini Manolis Matzapetakis Christian Hammann Chiara Donadoni Lei Hu Gerhard Thiel Lucia Banci Bina Santoro Anna Moroni 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(40):14577-14582
cAMP signaling in the brain mediates several higher order neural processes. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels directly bind cAMP through their cytoplasmic cyclic nucleotide binding domain (CNBD), thus playing a unique role in brain function. Neuronal HCN channels are also regulated by tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), an auxiliary subunit that antagonizes the effects of cAMP by interacting with the channel CNBD. To unravel the molecular mechanisms underlying the dual regulation of HCN channel activity by cAMP/TRIP8b, we determined the NMR solution structure of the HCN2 channel CNBD in the cAMP-free form and mapped on it the TRIP8b interaction site. We reconstruct here the full conformational changes induced by cAMP binding to the HCN channel CNBD. Our results show that TRIP8b does not compete with cAMP for the same binding region; rather, it exerts its inhibitory action through an allosteric mechanism, preventing the cAMP-induced conformational changes in the HCN channel CNBD.Hyperpolarization-activated cyclic nucleotide-gated (HCN1–4) channels are the molecular determinants of the h-current (Ih), which regulates critical neuronal properties, including membrane resting potential, dendritic excitability, and intrinsic rhythmicity (1). HCN channels are dually regulated by voltage and by binding of cAMP to the cyclic nucleotide binding domain (CNBD), which is found on the cytoplasmic C-terminal tail of the channel. The CNBD exerts a tonic inhibition on the channel pore, with the opening transition of the channel being allosterically coupled to the conformational changes in the CNBD induced by cAMP binding (2). Thus, the closed-to-open transition of the channel is thought to reflect the transition from the cAMP-free conformation to the cAMP-bound conformation of the CNBD, which stabilize, respectively, the closed and open states of the channel (2, 3). The C-linker, an α-helical folded domain that connects the CNBD to the pore region, conveys the regulation of channel gating from the CNBD to the pore (4–6). As a result of this allosteric mechanism, the binding of cAMP shifts the voltage dependence of the HCN channel opening to more positive potentials and increases maximal Ih at extreme negative voltages, where voltage gating is complete.In addition to cAMP, HCN channels in the brain are regulated by auxiliary proteins, such as TRIP8b, a cytosolic β-subunit of neuronal HCN channels, which inhibits channel activation by antagonizing the effects of cAMP (7–9). We have previously shown that TRIP8bcore, an 80-aa sequence located in the TRIP8b protein core that directly interacts with the C-linker/CNBD region of HCN channels, is necessary and sufficient to prevent all of the effects of cAMP on the channel (10, 11). TRIP8bcore decreases both the sensitivity of the channel to cAMP [half maximal concentration (k1/2)] and the efficacy of cAMP in inducing channel opening [half activation voltage (V1/2)]; conversely, cAMP binding inhibits these actions of TRIP8b. These mutually antagonistic effects are well described by a cyclic allosteric model in which TRIP8b binding reduces the affinity of the channel for cAMP, with the affinity of the open state for cAMP being reduced to a greater extent than the cAMP affinity of the closed state (11).A second important action of TRIP8b is to reduce maximal current through HCN channels in the absence of cAMP (11). As a consequence, application of cAMP produces a larger increase in maximal Ih in the presence of TRIP8b than in its absence. The observation that TRIP8b exerts opposing influences on the two major actions of cAMP on HCN channel function, namely, reduces the effect of cAMP to shift the voltage dependence of channel gating but enhances the effect of cAMP to increase maximal current, has important implications for the ability of cAMP to modulate neuronal excitability in vivo. Thus, the relative extent by which neuromodulatory transmitters alter maximal Ih or shift the voltage dependence of HCN channel gating can vary widely among distinct classes of neurons (12–14). The differential expression of TRIP8b may provide a mechanistic explanation for this finding, because in neurons with high levels of TRIP8b expression, cAMP will exert a larger action to enhance maximal current, and a smaller action to alter the voltage dependence of channel gating, compared with neurons in which TRIP8b expression is low. Such fine-tuning broadens the range of physiological actions that cAMP can exert to modulate neuronal firing.In the present study, we address the structural basis for the mutually antagonistic effects of cAMP and TRIP8b on HCN channel function. Although our previous biochemical and electrophysiological data strongly support the hypothesis that TRIP8b and cAMP binding sites do not overlap, direct structural information on the TRIP8b–CNBD complex is required to validate the allosteric antagonism model of interaction between the two ligands. A plausible hypothesis for the antagonistic effect of TRIP8b and cAMP is that each of the two ligands stabilizes the CNBD in a conformation that decreases the affinity for the other. To test this hypothesis, we first generated the 3D structure of the cAMP-free HCN2 channel CNBD using solution NMR spectroscopy and then characterized its interaction with the TRIP8bcore fragment. By comparing the cAMP-free with the available cAMP-bound HCN2 channel CNBD structure (15, 16), we reconstruct the full conformational changes induced by cAMP binding, revealing critical transitions occurring in the P- and C-helices of the CNBD, and further highlighting the role of the N-terminal helical bundle in transducing the movements of the CNBD to the channel pore. We next identify, through NMR titration, site-directed mutagenesis, and biochemical interaction assays, the binding site of TRIP8bcore on the cAMP-free form of the HCN2 channel CNBD. Our results demonstrate that cAMP and TRIP8b do not directly compete for the same binding region and support a model of mutual allosteric inhibition between cAMP and TRIP8b. Finally, our results clarify the mechanism by which TRIP8b antagonizes the effect of cAMP on channel gating: TRIP8b directly interacts with two mobile elements that drive the ligand-induced conformational changes in the CNBD. TRIP8b binding to the CNBD therefore prevents the cAMP-induced transition and stabilizes the channel in the cAMP-free conformation. 相似文献
22.
Drug‐induced liver injury (DILI) is the most common cause of acute liver failure and often responsible for drug withdrawals from the market. Clinical manifestations vary, and toxicity may or may not appear dose‐dependent. We present several machine‐learning models (decision tree induction, k‐nearest neighbor, support vector machines, artificial neural networks) for the prediction of clinically relevant DILI based solely on drug structure, with data taken from published DILI cases. Our models achieved corrected classification rates of up to 89%. We also studied the association of a drug's interaction with carriers, enzymes and transporters, and the relationship of defined daily doses with hepatotoxicity. The results presented here are useful as a screening tool both in a clinical setting in the assessment of DILI as well as in the early stages of drug development to rule out potentially hepatotoxic candidates. 相似文献
23.
24.
25.
26.
Miao Huang RN MSN Ruiqi Yang RN MSN Chuanlai Zhang RN BD Xiuni Gan RN MSN 《Nursing in critical care》2023,28(6):931-939
Background
Hyperglycaemia is common in critically ill adult patients. Many studies have identified the content, methods, and effects of glycaemic control but have not explored the effects of knowledge, attitudes, and practices (KAP) on glycaemic control in critically ill adults. Various factors also influence the KAP of intensive care unit (ICU) staff.Aims
To assess KAP regarding glucose management for critically ill adults among nurses and medical professionals and identify the factors that influence their KAP in ICUs.Methods
A multicentre cross-sectional survey.Results
In total, 403/459 (response rate: 87.8%) participants from ICUs in nine tertiary hospitals in China participated in this study, 82.4% of whom were female and 93.4% of whom were nurses. The mean work experience was 8.88 years, and the mean critical care experience was 6.59 years. The scoring rate for the three dimensions of knowledge, attitudes, and practices were 82.35%, 87.69%, and 76%, respectively. We did not find any other factors affecting the KAP scores except for the level of knowledge awareness (p < 0.001), awareness of the importance (p < 0.001), and training for glucose control (p = 0.004).Conclusion
ICU staff KAP regarding glycaemic control in critically ill adults among ICU professionals were acceptable in China. However, ICU professionals' current knowledge regarding nutrition, glucose variability, and skills related to glucose management could be improved.Relevance to Clinical Practice
ICU educators should provide more skills-related training for healthcare professionals in the glycaemic management of critically ill adults. Moreover, the process of managing blood glucose in adult ICU patients is a collaborative, multidisciplinary team effort, with monitoring and feedback required during implementation. 相似文献27.
Hua Zhang PhD Shaodong Qiu BD Fei Chen PhD Zhimin Zhu MD 《Journal of clinical ultrasound : JCU》2019,47(7):412-418
Because of better awareness and understanding of its pathophysiology, the cardiorenal syndrome (CRS) is more often diagnosed and better managed. The echocardiographic evaluation of CRS now benefits from three-dimensional speckle tracking echocardiography (3D-STE), which allows multidimensional and real-time evaluation of regional myocardial and overall cardiac function, and helps assessing the degree of myocardial damage. This article describes the application of 3D-STE in evaluating the myocardial motion in patients with CRS. 相似文献
28.
Shimazaki C; Wisniewski D; Scheinberg DA; Atzpodien J; Strife A; Gulati S; Fried J; Wisniewolski R; Wang CY; Clarkson BD 《Blood》1988,72(4):1248-1254
The efficacy of immunomagnetic beads to purge human myeloma cells from bone marrow ex vivo was evaluated. The optimal conditions for purging were studied first by using three myeloma cell lines: RPMI-8226, SKO- 007, and SKMM-2. Myeloma cells labeled with the vital fluorescent dye Hoechst 33342 were admixed with normal bone marrow cells, and two monoclonal antibodies reactive with the myeloma cells (PCA-1 and BL-3) were added alone or in combination with the cells. Magnetic beads coated with goat antimouse immunoglobulin G were then added, and the tumor cells to which beads were attached were separated from the mixture with a magnet. The efficacy of tumor cell removal was dependent on the bead-to-tumor ratio; a ratio of more than 500 was optimal in the presence of excess normal marrow cells. The combination of monoclonal antibodies PCA-1 and BL-3 increased the tumor cell removal as compared with either antibody alone. Two cycles of treatment were more effective than one cycle was. Under optimal conditions, 2.3 to 4 logs of tumor cells could be removed from the mixture containing 10% myeloma cells without a significant loss of normal hematopoietic progenitors as measured by CFU-GM, CFU-GEM, and BFU-E. When the efficacy of this procedure was tested on fresh bone marrow from patients with multiple myeloma (MM) by using the combination of PCA-1, BL-3, and J-5, 1.6 to 2.5 logs of tumor cells could be removed by one cycle of treatment, even from marrows containing less than 10% myeloma cells. These observations support the use of monoclonal antibody combinations and immunobeads as a reliable and nontoxic method to eliminate contaminating myeloma cells ex vivo in preparation for autologous bone marrow transplantation in patients with MM. 相似文献
29.
Zhuravleva J Paggetti J Martin L Hammann A Solary E Bastie JN Delva L 《British journal of haematology》2008,143(3):378-382
The inv(8)(p11q13) chromosomal abnormality, described in acute myeloid leukaemias (AML), fuses the histone acetyl-transferase (HAT) MYST3 (MOZ) gene with another HAT gene, NCOA2 (TIF2). We generated a transgenic zebrafish in which the MYST3/NCOA2 fusion gene was expressed under control of the spi1 promoter. An AML developed in 2 of 180 MYST3/NCOA2-EGFP-expressing embryos, 14 and 26 months after injection of the fusion gene in a one-cell embryo, respectively. This leukaemia was characterised by an extensive invasion of kidneys by myeloid blast cells. This model, which is the first zebrafish model of AML, demonstrates the oncogenic potency of MYST3/NCOA2 fusion gene. 相似文献
30.
Four patients with Philadelphia (Ph') positive chronic myeloid leukemia (CML) were studied before, after, and on relapse following allogeneic bone marrow transplantation (BMT). Southern analysis of DNA from cells collected before and at relapse after BMT was performed in order to investigate the origin of the leukemia at relapse. Using minisatellite probes we showed that the relapse occurred in cells of host origin in all four patients and this was confirmed with a Y chromosome specific probe in two male patients who had a female donor. Furthermore, using two probes for the breakpoint cluster region (bcr) on chromosome 22, we showed that leukemic cells at relapse bore identical rearrangements to those in the disease at time of presentation of each patient. We conclude that relapse in all four patients is due to re-emergence of the original leukemic clone. 相似文献