全文获取类型
收费全文 | 494250篇 |
免费 | 50337篇 |
国内免费 | 234篇 |
出版年
2018年 | 4810篇 |
2016年 | 6428篇 |
2015年 | 9160篇 |
2014年 | 10648篇 |
2013年 | 14933篇 |
2012年 | 17298篇 |
2011年 | 17689篇 |
2010年 | 11816篇 |
2009年 | 10862篇 |
2008年 | 15548篇 |
2007年 | 16184篇 |
2006年 | 15361篇 |
2005年 | 14654篇 |
2004年 | 14616篇 |
2003年 | 14165篇 |
2002年 | 13724篇 |
2001年 | 18097篇 |
2000年 | 17921篇 |
1999年 | 14778篇 |
1998年 | 5841篇 |
1997年 | 5826篇 |
1996年 | 5467篇 |
1995年 | 5291篇 |
1994年 | 5190篇 |
1993年 | 5226篇 |
1992年 | 12756篇 |
1991年 | 12541篇 |
1990年 | 12498篇 |
1989年 | 12198篇 |
1988年 | 11540篇 |
1987年 | 10809篇 |
1986年 | 10104篇 |
1985年 | 10592篇 |
1984年 | 8903篇 |
1983年 | 7641篇 |
1982年 | 6073篇 |
1981年 | 5464篇 |
1980年 | 5063篇 |
1979年 | 8353篇 |
1978年 | 6586篇 |
1977年 | 6185篇 |
1976年 | 5906篇 |
1975年 | 6313篇 |
1974年 | 6917篇 |
1973年 | 6701篇 |
1972年 | 6230篇 |
1971年 | 5625篇 |
1970年 | 4838篇 |
1969年 | 4851篇 |
1968年 | 4500篇 |
排序方式: 共有10000条查询结果,搜索用时 78 毫秒
1.
More than 50 hereditary lysosomal storage disorders (LSDs) are currently described. Most of these disorders are due to a deficiency of certain hydrolases/glycosidases and subsequent accumulation of nonhydrolyzable carbohydrate-containing compounds in lysosomes. Such accumulation causing hypertrophy of the lysosomal compartment is a characteristic feature of affected cells in LSDs. The investigation of biochemical and cellular parameters is of particular interest for understanding “life” of lysosomes in the normal state and in LSDs. This review highlights the wide spectrum of biochemical and morphological changes during developing LSDs that are extremely critical for many metabolic processes inside the various cells and tissues of affected persons. The data presented will help establish new complex strategies for metabolic correction of LSDs. 相似文献
2.
Human organ-on-a-chip systems for drug screening have evolved as feasible alternatives to animal models, which are unreliable, expensive, and at times erroneous. While chips featuring single organs can be of great use for both pharmaceutical testing and basic organ-level studies, the huge potential of the organ-on-a-chip technology is revealed by connecting multiple organs on one chip to create a single integrated system for sophisticated fundamental biological studies and devising therapies for disease. Furthermore, since most organ-on-a-chip systems require special protocols with organ-specific media for the differentiation and maturation of the tissues, multi-organ systems will need to be temporally customizable and flexible in terms of the time point of connection of the individual organ units. We present a customizable Lego®-like plug & play system, μOrgano, which enables initial individual culture of single organ-on-a-chip systems and subsequent connection to create integrated multi-organ microphysiological systems. As a proof of concept, the μOrgano system was used to connect multiple heart chips in series with excellent cell viability and spontaneously physiological beat rates. 相似文献
3.
Michael P. Gustafson Yi Lin Mary L. Maas Virginia P. Van Keulen Patrick B. Johnston Tobias Peikert Dennis A. Gastineau Allan B. Dietz 《PloS one》2015,10(3)
The development of flow cytometric biomarkers in human studies and clinical trials has been slowed by inconsistent sample processing, use of cell surface markers, and reporting of immunophenotypes. Additionally, the function(s) of distinct cell types as biomarkers cannot be accurately defined without the proper identification of homogeneous populations. As such, we developed a method for the identification and analysis of human leukocyte populations by the use of eight 10-color flow cytometric protocols in combination with novel software analyses. This method utilizes un-manipulated biological sample preparation that allows for the direct quantitation of leukocytes and non-overlapping immunophenotypes. We specifically designed myeloid protocols that enable us to define distinct phenotypes that include mature monocytes, granulocytes, circulating dendritic cells, immature myeloid cells, and myeloid derived suppressor cells (MDSCs). We also identified CD123 as an additional distinguishing marker for the phenotypic characterization of immature LIN-CD33+HLA-DR- MDSCs. Our approach permits the comprehensive analysis of all peripheral blood leukocytes and yields data that is highly amenable for standardization across inter-laboratory comparisons for human studies. 相似文献
4.
Michael Fayon Annick Andrieux Imane Bara Muriel Rebola André Labbé Roger Marthan Patrick Berger 《PloS one》2015,10(3)
We compared the proliferation of neonatal and adult airway smooth muscle cells (ASMC) with no/moderate lung disease, in glucose- (energy production by glycolysis) or glucose-free medium (ATP production from mitochondrial oxidative phosphorylations only), in response to 10% fetal calf serum (FCS) and PDGF-AA. In the presence of glucose, cell counts were significantly greater in neonatal vs. adult ASMC. Similarly, neonatal ASMC DNA synthesis in 10% FCS and PDGF-AA, and [Ca2+]i responses in the presence of histamine were significantly enhanced vs. adults. In glucose-free medium, cell proliferation was preserved in neonatal cells, unlike in adult cells, with concomitant increased porin (an indicator of mitochondrial activity) protein expression. Compared to adults, stimulated neonatal human ASMC are in a rapid and robust proliferative phase and have the capacity to respond disproportionately under abnormal environmental conditions, through increased mitochondrial biogenesis and altered calcium homeostasis. 相似文献
5.
Nóra Kutszegi ágnes F. Semsei András Gézsi Judit C. Sági Viktória Nagy Katalin Csordás Zsuzsanna Jakab Orsolya Lautner-Csorba Krisztina Míta Gábor Gábor T. Kovács Dániel J. Erdélyi Csaba Szalai 《PloS one》2015,10(10)
L-asparaginase (ASP) is a key element in the treatment of paediatric acute lymphoblastic leukaemia (ALL). However, hypersensitivity reactions (HSRs) to ASP are major challenges in paediatric patients. Our aim was to investigate genetic variants that may influence the risk to Escherichia coli-derived ASP hypersensitivity. Sample and clinical data collection was carried out from 576 paediatric ALL patients who were treated according to protocols from the Berlin—Frankfurt—Münster Study Group. A total of 20 single nucleotide polymorphisms (SNPs) in GRIA1 and GALNT10 genes were genotyped. Patients with GRIA1 rs4958351 AA/AG genotype showed significantly reduced risk to ASP hypersensitivity compared to patients with GG genotype in the T-cell ALL subgroup (OR = 0.05 (0.01–0.26); p = 4.70E-04), while no such association was found in pre-B-cell ALL. In the medium risk group two SNPs of GRIA1 (rs2055083 and rs707176) were associated significantly with the occurrence of ASP hypersensitivity (OR = 0.21 (0.09–0.53); p = 8.48E-04 and OR = 3.02 (1.36–6.73); p = 6.76E-03, respectively). Evaluating the genders separately, however, the association of rs707176 with ASP HSRs was confined only to females. Our results suggest that genetic variants of GRIA1 might influence the risk to ASP hypersensitivity, but subgroups of patients can differ significantly in this respect. 相似文献
6.
Data-Driven Method to Estimate Nonlinear Chemical Equivalence 总被引:1,自引:0,他引:1
There is great need to express the impacts of chemicals found in the environment in terms of effects from alternative chemicals of interest. Methods currently employed in fields such as life-cycle assessment, risk assessment, mixtures toxicology, and pharmacology rely mostly on heuristic arguments to justify the use of linear relationships in the construction of “equivalency factors,” which aim to model these concentration-concentration correlations. However, the use of linear models, even at low concentrations, oversimplifies the nonlinear nature of the concentration-response curve, therefore introducing error into calculations involving these factors. We address this problem by reporting a method to determine a concentration-concentration relationship between two chemicals based on the full extent of experimentally derived concentration-response curves. Although this method can be easily generalized, we develop and illustrate it from the perspective of toxicology, in which we provide equations relating the sigmoid and non-monotone, or “biphasic,” responses typical of the field. The resulting concentration-concentration relationships are manifestly nonlinear for nearly any chemical level, even at the very low concentrations common to environmental measurements. We demonstrate the method using real-world examples of toxicological data which may exhibit sigmoid and biphasic mortality curves. Finally, we use our models to calculate equivalency factors, and show that traditional results are recovered only when the concentration-response curves are “parallel,” which has been noted before, but we make formal here by providing mathematical conditions on the validity of this approach. 相似文献
7.
8.
9.
10.