全文获取类型
收费全文 | 1115篇 |
免费 | 154篇 |
国内免费 | 3篇 |
出版年
2023年 | 9篇 |
2022年 | 11篇 |
2021年 | 23篇 |
2020年 | 15篇 |
2019年 | 13篇 |
2018年 | 25篇 |
2017年 | 10篇 |
2016年 | 25篇 |
2015年 | 49篇 |
2014年 | 39篇 |
2013年 | 61篇 |
2012年 | 73篇 |
2011年 | 75篇 |
2010年 | 48篇 |
2009年 | 35篇 |
2008年 | 69篇 |
2007年 | 62篇 |
2006年 | 53篇 |
2005年 | 47篇 |
2004年 | 52篇 |
2003年 | 40篇 |
2002年 | 38篇 |
2001年 | 10篇 |
2000年 | 17篇 |
1999年 | 17篇 |
1998年 | 10篇 |
1997年 | 10篇 |
1996年 | 10篇 |
1995年 | 12篇 |
1994年 | 13篇 |
1993年 | 11篇 |
1992年 | 10篇 |
1991年 | 11篇 |
1990年 | 13篇 |
1989年 | 21篇 |
1988年 | 16篇 |
1987年 | 13篇 |
1986年 | 19篇 |
1985年 | 19篇 |
1984年 | 19篇 |
1983年 | 11篇 |
1982年 | 12篇 |
1981年 | 8篇 |
1980年 | 16篇 |
1979年 | 9篇 |
1977年 | 10篇 |
1976年 | 9篇 |
1975年 | 9篇 |
1973年 | 11篇 |
1967年 | 7篇 |
排序方式: 共有1272条查询结果,搜索用时 406 毫秒
971.
972.
973.
Hoi Y. Tong Cristina Lucía Dávila-Fajardo Alberto M. Borobia Luis Javier Martínez-González Rubin Lubomirov Laura María Perea León María J. Blanco Ba?ares Xando Díaz-Villamarín Carmen Fernández-Capitán José Cabeza Barrera Antonio J. Carcas PGX-ACE Investigators Group 《PloS one》2016,11(3)
There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (<11 mg/week, 11–21 mg/week, >21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in extreme-dosage patients. The predictability of the pharmacogenetic algorithm did not vary significantly between diseases. 相似文献
974.
Alwine Gassen Doris Brechtefeld Niklas Schandry J. Manuel Arteaga-Salas Lars Israel Axel Imhof Christian J. Janzen 《Nucleic acids research》2012,40(20):10302-10311
Cell-cycle progression requires careful regulation to ensure accurate propagation of genetic material to the daughter cells. Although many cell-cycle regulators are evolutionarily conserved in the protozoan parasite Trypanosoma brucei, novel regulatory mechanisms seem to have evolved. Here, we analyse the function of the histone methyltransferase DOT1A during cell-cycle progression. Over-expression of DOT1A generates a population of cells with aneuploid nuclei as well as enucleated cells. Detailed analysis shows that DOT1A over-expression causes continuous replication of the nuclear DNA. In contrast, depletion of DOT1A by RNAi abolishes replication but does not prevent karyokinesis. As histone H3K76 methylation has never been associated with replication control in eukaryotes before, we have discovered a novel function of DOT1 enzymes, which might not be unique to trypanosomes. 相似文献
975.
Background
Hair cells in the auditory, vestibular, and lateral-line systems respond to mechanical stimulation and transmit information to afferent nerve fibers. The sensitivity of mechanoelectrical transduction is modulated by the efferent pathway, whose activity usually reduces the responsiveness of hair cells. The basis of this effect remains unknown.Methodology and Principal Findings
We employed immunocytological, electrophysiological, and micromechanical approaches to characterize the anatomy of efferent innervation and the effect of efferent activity on the electrical and mechanical properties of hair cells in the bullfrog''s sacculus. We found that efferent fibers form extensive synaptic terminals on all macular and extramacular hair cells. Macular hair cells expressing the Ca2+-buffering protein calretinin contain half as many synaptic ribbons and are innervated by twice as many efferent terminals as calretinin-negative hair cells. Efferent activity elicits inhibitory postsynaptic potentials in hair cells and thus inhibits their electrical resonance. In hair cells that exhibit spiking activity, efferent stimulation suppresses the generation of action potentials. Finally, efferent activity triggers a displacement of the hair bundle''s resting position.Conclusions and Significance
The hair cells of the bullfrog''s sacculus receive a rich efferent innervation with the heaviest projection to calretinin-containing cells. Stimulation of efferent axons desensitizes the hair cells and suppresses their spiking activity. Although efferent activation influences mechanoelectrical transduction, the mechanical effects on hair bundles are inconsistent. 相似文献976.
Bratoeff E Segura T Recillas S Carrizales E Palacios A Heuze I Cabeza M 《Journal of enzyme inhibition and medicinal chemistry》2009,24(3):655-662
The aim of this study was to determine the biological activity of 4 steroidal derivatives (9a, 9b and 10a, 10b) prepared from the commercially available 17alpha acetoxyprogesterone, where 9a, 9b, have the Delta(4)-3-oxo structure and 10a and 10b an epoxy group at C-4 and C-5. These steroids were tested as inhibitors of 5alpha-reductase enzyme, which is present in androgen-dependent tissues and converts testosterone to its more active reduced metabolite dihydrotestosterone. The pharmacological effect of these steroids was demonstrated by the significant decrease of the weight of the prostate gland of gonadectomized hamsters treated with testosterone plus finasteride or with steroids 10a and 10b. For the studies in vitro the IC(50) values were determined by measuring the steroid concentration that inhibits 50% of the activity of-5alpha-reductase. In this study we also determined the capacity of these steroids to bind to the androgen receptor present in the rat prostate cytosol. The results from this work indicated that compounds 9a, 9b, 10a, and 10b inhibited the 5alpha reductase activity with IC(50) values of 360, 370, 13 and 4.9 nM respectively. However these steroids did not bind to the androgen receptors since none competed with labeled mibolerone. Steroid 10b, an epoxy steroidal derivative containing bromine atom in the ester moiety, was the most active inhibitor of 5alpha-reductase enzyme, present in human prostate homogenates with an IC(50) value of 4.9 nM and also showed in vivo pharmacological activity since it decreased the weight of the prostate from hamsters treated with testosterone in a similar way as finasteride. 相似文献
977.
978.
Recent functional neuroimaging evidence suggests a bottleneck between learning new information and remembering old information. In two behavioral experiments and one functional MRI (fMRI) experiment, we tested the hypothesis that learning and remembering compete when both processes happen within a brief period of time. In the first behavioral experiment, participants intentionally remembered old words displayed in the foreground, while incidentally learning new scenes displayed in the background. In line with a memory competition, we found that remembering old information was associated with impaired learning of new information. We replicated this finding in a subsequent fMRI experiment, which showed that this behavioral effect was coupled with a suppression of learning-related activity in visual and medial temporal areas. Moreover, the fMRI experiment provided evidence that left mid-ventrolateral prefrontal cortex is involved in resolving the memory competition, possibly by facilitating rapid switching between learning and remembering. Critically, a follow-up behavioral experiment in which the background scenes were replaced with a visual target detection task provided indications that the competition between learning and remembering was not merely due to attention. This study not only provides novel insight into our capacity to learn and remember, but also clarifies the neural mechanisms underlying flexible behavior. 相似文献
979.
Differences in patterns of diet and subsistence through the analysis of dental pathology and tooth wear were studied in skeletal populations of Natufian hunter-gatherers (10,500-8300 BC) and Neolithic populations (8300-5500 BC, noncalibrated) from the southern Levant. 1,160 Natufians and 804 Neolithic teeth were examined for rate of attrition, caries, antemortem tooth loss, calculus, periapical lesions, and periodontal processes. While the Natufian people manifest a higher rate of dental attrition and periodontal disease (36.4% vs. 19%), Neolithic people show a higher rate of calculus. Both populations manifested low and similar rates of caries (6.4% in the Natufian vs. 6.7% in the Neolithic), periapical lesions (not over 1.5%), and antemortem tooth loss (3.7% vs. 4.5%, respectively). Molar wear pattern in the Neolithic is different than in the Natufian. The current study shows that the dental picture obtained from the two populations is multifactorial in nature, and not exclusively of dietary origin, i.e., the higher rate and unique pattern of attrition seen in the Natufian could result from a greater consumption of fibrous plants, the use of pestles and mortars (which introduce large quantities of stone-dust to the food), and/or the use of teeth as a "third hand." The two major conclusions of this study are: 1) The transition from hunting and gathering to a food-producing economy in the Levant did not promote changes in dental health, as previously believed. This generally indicates that the Natufians and Neolithic people of the Levant may have differed in their ecosystem management (i.e., gathering vs. growing grains), but not in the type of food consumed. 2) Changes in food-preparation techniques and nondietary usage of the teeth explain much of the variation in tooth condition in populations before and after the agricultural revolution. 相似文献
980.
Natalya Karol Claude Brodski Yuval Bibi Tehila Kaisman Michal Forberg Michal Hershfinkel Israel Sekler William F. Silverman 《Journal of cellular physiology》2010,224(3):567-574
Release of Zn2+ from presynaptic glutamatergic terminals has long been considered the principle challenge necessitating the existence of zinc homeostatic proteins (ZHP) in the mammalian nervous system. It is now known that neural cells also possess an intracellular zinc pool, termed here [Zn2+]i, which functions in a cell signaling context. A major challenge is characterizing the interaction of these two populations of zinc ions. To assess the relationship of this Zn2+ pool to cellular ZHP production, we employed immunofluorescence and immunoblot analysis to compare the expression of ZHP's ZnT‐1 and MT‐I/II in olfactory bulb and hippocampus of wild‐type and ZnT‐3 KO mice, which lack synaptic Zn2+. In both areas, the respective distribution and concentration of ZnT‐1 and MT‐I/II were identical in ZnT‐3 KO and control animals. We subsequently examined ZHP content in ZnT‐3 KO and WT mice treated with a membrane‐permeable Zn2+ chelator. In both olfactory bulb and hippocampus of the KO mice, the ZHP content was significantly reduced 15 h after chelation of [Zn2+]i compared to WT controls. Our findings support the conclusion that ZHP expression is regulated by crosstalk between synaptic and intracellular pools of Zn2+. J. Cell. Physiol. 224: 567–574, 2010. © 2010 Wiley‐Liss, Inc. 相似文献