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791.
Maria J. Mokrosz Beata Duszyska Stanisaw Misztal Aleksandra Kodziska Ewa Tatarczyska Ewa Chojnacka-Wjcik Marta Dziedzicka-Wasylewska 《Archiv der Pharmazie》1998,331(10):325-330
A series of 1-[ω-(4-aryl-1-piperazinyl)alkyl]indolin-2(1H)-one derivatives 2–14 was synthesized in order to obtain ligands with a dual 5-HT1A/5-HT2A activity. The majority of those compounds ( 2–5, 7, 10–13 ) exhibited a high 5-HT1A (Ki = 2 – 44 nM) and/or 5-HT2A affinity (Ki = 51 and 39 for 5 and 7 , respectively). Induction of lower lip retraction (LLR) and behavioral syndrome and inhibition of these efects evoked by 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) were used for determination the agonistic and antagonistic activity, respectively, at 5-HT1A receptors. The 5-HT2A antagonistic activity was assessed by the blocking effect on the head twitches induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice. Two of the tested compounds, 1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-6-fluoroindolin-2(1H)-one ( 5 ) and 1-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}indolin-2(1H)-one ( 7 ), demonstrated a high 5-HT1A/5-HT2A affinity and an in vivo antagonistic activity towards both receptor subtypes. 相似文献
792.
《Clinical Lymphoma, Myeloma & Leukemia》2023,23(6):438-445
IntroductionNon-Hodgkin lymphoma (NHL) is a heterogeneous disease, with each subtype associated with different risk factors. Within this group, diffuse large B-cell lymphoma (DLBCL) can be highlighted, the most common type of NHL.NK cells are key components of the innate immune response and may play an important antitumor role.ObjectiveThe objective of the present work was to determine the polymorphism of KIR genes in Brazilian patients with DLBCL.Materials and MethodsFurthermore, we evaluated the association between the polymorphism of these genes and their ligands with the clinical course of the disease. For the study, 112 patients with DLBCL and 222 voluntary blood and bone marrow donors. The genetic material of these samples were extracted for KIR and HLA typing, determination of HLA ligands, determination of the KIR haplotype and search for the deletion of 22 bp in the KIR2DS4 gene. KIR genotype distributions were made by direct counting using 2 × 2 contingency tables using Fisher's exact test. The magnitude of the association was measured by odds ratio (OR) and 95% confidence interval. P values <.05 were considered significant. Overall survival and progression-free survival were assessed with a Kaplan-Meier estimator.ResultsIn the present study, an association of HLA-Bw4 and HLA-Bw480I ligand was found with more advanced stages of the disease. Also, an association of the KIR2DL3 gene with a better response to treatment was found.ConclusionWith this, we can conclude that the polymorphism of KIR genes and the association with HLA ligands can influence the prognosis of DLBCL, as well as the response to treatment was found. With this, we can conclude that the polymorphism of KIR genes and the association with HLA ligands can influence the prognosis of DLBCL, as well as the response to treatment.Non-Hodgkin lymphoma (NHL) is a heterogeneous disease, with each subtype associated with different risk factors. Within this group, diffuse large B-cell lymphoma (DLBCL) can be highlighted, the most common type of NHL.NK cells are key components of the innate immune response and may play an important antitumor role. The objective of the present work was to determine the polymorphism of KIR genes in Brazilian patients with DLBCL. Furthermore, we evaluated the association between the polymorphism of these genes and their ligands with the clinical course of the disease. For the study, 112 patients with DLBCL and 222 voluntary blood and bone marrow donors. The genetic material of these samples were extracted for KIR and HLA typing, determination of HLA ligands, determination of the KIR haplotype and search for the deletion of 22 bp in the KIR2DS4 gene. KIR genotype distributions were made by direct counting using 2 × 2 contingency tables using Fisher's exact test. The magnitude of the association was measured by odds ratio (OR) and 95% confidence interval. P values <.05 were considered significant. Overall survival and progression-free survival were assessed with a Kaplan-Meier estimator. In the present study, an association of HLA-Bw4 and HLA-Bw480I ligand was found with more advanced stages of the disease. Also, an association of the KIR2DL3 gene with a better response to treatment was found. With this, we can conclude that the polymorphism of KIR genes and the association with HLA ligands can influence the prognosis of DLBCL, as well as the response to treatment was found. With this, we can conclude that the polymorphism of KIR genes and the association with HLA ligands can influence the prognosis of DLBCL, as well as the response to treatment. 相似文献
793.
目的 基于SHAP法观察以临床、病理、MRI特征及体素内不相干运动(IVIM)成像定量参数联合模型预测宫颈癌细胞程序性死亡蛋白1(PD-1)及其配体(PD-L1)表达的价值。方法 采集63例治疗前初诊宫颈癌盆腔MRI,并对病理标本行PD-1/PD-L1免疫组织化学染色;比较PD-1表达阳性与阴性组、PD-L1表达阳性与阴性组临床、病理、MRI表现及IVIM参数(真实弥散系数D、灌注相关弥散系数D*及灌注分数f)的差异,并以logistic回归分析筛选宫颈癌PD-1及PD-L1表达阳性的独立影响因素,建立预测宫颈癌PD-1及PD-L1表达阳性联合模型;以受试者工作特征(ROC)曲线评估模型诊断效能,以SHAP法解释其中各变量的贡献价值。结果 PD-1阳性组与阴性组、PD-L1阳性组与阴性组之间肿瘤病理分级、宫旁浸润、淋巴结转移及D值差异均有统计学意义(P均<0.05)。FIGO分期、肿瘤病理分级、宫旁浸润、淋巴结转移和D值均为宫颈癌PD-1/PD-L1表达阳性的独立影响因素(P均<0.05);以之建立的联合模型的曲线下面积分别为0.85及0.89。根据SHAP值,联合模型中FIGO分期和肿瘤病理分级的贡献最大。结论 以宫颈癌临床、病理、MRI特征及IVIM参数D值构建的联合模型可有效预测其PD-1/PD-L1表达。 相似文献
794.
795.
《药学学报(英文版)》2023,13(5):2152-2175
We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase–hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC50 = 1.06 ± 0.31 nmol/L) and hMAO-B (IC50 = 4.46 ± 0.18 μmol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood–brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19. 相似文献
796.
Gisela Andrea Camacho-Hernandez Khorshada Jahan Amy Hauck Newman 《Basic & clinical pharmacology & toxicology》2023,133(5):473-484
Fluorescence microscopy has revolutionized the visualization of physiological processes in live-cell systems. With the recent innovations in super resolution microscopy, these events can be examined with high precision and accuracy. The development of fluorescently labelled small molecules has provided a significant advance in understanding the physiological relevance of targeted proteins that can now be visualized at the cellular level. One set of physiologically important target proteins are the monoamine transporters (MATs) that play an instrumental role in maintaining monoamine signalling homeostasis. Understanding the mechanisms underlying their regulation and dysregulation is fundamental to treating several neuropsychiatric conditions such as attention deficit hyperactivity disorder (ADHD), anxiety, depression and substance use disorders. Herein, we describe the rationale behind the small molecule design of fluorescently labelled ligands (FLL) either as MAT substrates or inhibitors as well as their applications to advance our understanding of this class of transporters in health and disease. 相似文献
797.
目的:利用噬菌体7肽库进行体外快速差减筛选(biopanning and rapid analysis of selective interactive ligands,BRASIL),从而获得卵巢癌细胞株HO-8910细胞表面特异性结合肽。方法:以中国仓鼠卵巢细胞株CHO为吸附细胞,卵巢癌细胞株HO-8910为靶细胞,利用噬菌体展示技术联合差减筛选策略,经过连续5轮生物淘洗,随机挑选13个噬菌体单克隆进行DNA测序,利用噬菌体竞争结合实验、ELISA实验、细胞免疫染色、细胞免疫荧光、合成多肽的竞争抑制实验鉴定阳性噬菌体的亲和性及特异性。结果:筛选出的噬菌体NPMIRRQ与卵巢癌细胞株HO-8910有较高的亲和性及特异性。结论:阳性噬菌体表面展示的多肽NPMIRRQ可能为卵巢癌的早期诊断和转移复发监测提供新思路。 相似文献
798.
799.