全文获取类型
收费全文 | 2383篇 |
免费 | 215篇 |
国内免费 | 1篇 |
专业分类
2599篇 |
出版年
2023年 | 10篇 |
2022年 | 24篇 |
2021年 | 35篇 |
2020年 | 25篇 |
2019年 | 42篇 |
2018年 | 33篇 |
2017年 | 36篇 |
2016年 | 83篇 |
2015年 | 127篇 |
2014年 | 137篇 |
2013年 | 152篇 |
2012年 | 213篇 |
2011年 | 158篇 |
2010年 | 115篇 |
2009年 | 84篇 |
2008年 | 128篇 |
2007年 | 135篇 |
2006年 | 139篇 |
2005年 | 126篇 |
2004年 | 112篇 |
2003年 | 115篇 |
2002年 | 127篇 |
2001年 | 27篇 |
2000年 | 17篇 |
1999年 | 25篇 |
1998年 | 34篇 |
1997年 | 19篇 |
1996年 | 21篇 |
1995年 | 19篇 |
1994年 | 21篇 |
1993年 | 24篇 |
1992年 | 23篇 |
1991年 | 17篇 |
1990年 | 9篇 |
1989年 | 9篇 |
1988年 | 12篇 |
1987年 | 9篇 |
1986年 | 15篇 |
1985年 | 7篇 |
1984年 | 12篇 |
1982年 | 9篇 |
1981年 | 7篇 |
1980年 | 11篇 |
1979年 | 8篇 |
1978年 | 7篇 |
1977年 | 8篇 |
1976年 | 17篇 |
1974年 | 5篇 |
1973年 | 8篇 |
1967年 | 5篇 |
排序方式: 共有2599条查询结果,搜索用时 15 毫秒
61.
62.
63.
Kalscheuer VM FitzPatrick D Tommerup N Bugge M Niebuhr E Neumann LM Tzschach A Shoichet SA Menzel C Erdogan F Arkesteijn G Ropers HH Ullmann R 《Human genetics》2007,121(3-4):501-509
We report on three unrelated mentally disabled patients, each carrying a de novo balanced translocation that truncates the
autism susceptibility candidate 2 (AUTS2) gene at 7q11.2. One of our patients shows relatively mild mental retardation; the other two display more profound disorders.
One patient is also physically disabled, exhibiting urogenital and limb malformations in addition to severe mental retardation.
The function of AUTS2 is presently unknown, but it has been shown to be disrupted in monozygotic twins with autism and mental retardation, both
carrying a translocation t(7;20)(q11.2;p11.2) (de la Barra et al. in Rev Chil Pediatr 57:549–554, 1986; Sultana et al. in Genomics 80:129–134, 2002). Given the overlap of this autism/mental retardation (MR) phenotype and the MR-associated disorders in our patients, together
with the fact that mapping of the additional autosomal breakpoints involved did not disclose obvious candidate disease genes,
we ascertain with this study that AUTS2 mutations are clearly linked to autosomal dominant mental retardation. 相似文献
64.
Madsen PP Kibaek M Roca X Sachidanandam R Krainer AR Christensen E Steiner RD Gibson KM Corydon TJ Knudsen I Wanders RJ Ruiter JP Gregersen N Andresen BS 《Human genetics》2006,118(6):680-690
Short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) is an autosomal recessive disorder of l-isoleucine catabolism. Little is known about the clinical presentation associated with this enzyme defect, as it has been
reported in only a limited number of patients. Because the presence of C5-carnitine in blood may indicate SBCADD, the disorder
may be detected by MS/MS-based routine newborn screening. It is, therefore, important to gain more knowledge about the clinical
presentation and the mutational spectrum of SBCADD. In the present study, we have studied two unrelated families with SBCADD,
both with seizures and psychomotor delay as the main clinical features. One family illustrates the fact that affected individuals
may also remain asymptomatic. In addition, the normal level of newborn blood spot C5-acylcarnitine in one patient underscores
the fact that newborn screening by MS/MS currently lacks sensitivity in detecting SBCADD. Until now, seven mutations in the SBCAD gene have been reported, but only three have been tested experimentally. Here, we identify and characterize an IVS3+3A>G
mutation (c.303+3A>G) in the SBCAD gene, and provide evidence that this mutation is disease-causing in both families. Using a minigene approach, we show that
the IVS3+3A>G mutation causes exon 3 skipping, despite the fact that it does not appear to disrupt the consensus sequence
of the 5′ splice site. Based on these results and numerous literature examples, we suggest that this type of mutation (IVS+3A>G)
induces missplicing only when in the context of non-consensus (weak) 5′ splice sites. Statistical analysis of the sequences
shows that the wild-type versions of 5′ splice sites in which +3A>G mutations cause exon skipping and disease are weaker on
average than a random set of 5′ splice sites. This finding is relevant to the interpretation of the functional consequences
of this type of mutation in other disease genes. 相似文献
65.
Blomqvist ME Reynolds C Katzov H Feuk L Andreasen N Bogdanovic N Blennow K Brookes AJ Prince JA 《Human genetics》2006,119(1-2):29-37
Most genetic sequence variants that contribute to variability in complex human traits will have small effects that are not
readily detectable with population samples typically used in genetic association studies. A potentially valuable tool in the
gene discovery process is meta-analysis of the accumulated published data, but in order to be valid these require a sample
of studies representative of the true genetic effect and thus hypothetically should include some positive and an abundance
of negative reports. A survey of the literature on association studies for Alzheimer disease (AD) from January 2004–April
2005, identified 138 studies, 86 of which reported positive findings other than for apolipoprotein E (APOE), strongly indicative of publication bias. We report here an analysis of 62 genetic markers, tested for association with
AD risk as well as for possible effects upon quantitative indices of AD severity (mini-mental state examination scores, age-at-onset,
and cerebrospinal fluid (CSF) β-amyloid (Aβ) and CSF tau proteins). Within this set, only modest signals were present that,
with the exception of APOE are easily lost when corrections for multiple hypotheses are applied. In isolation, results are thus broadly negative. Genes
studied encompass both novel candidates as well as several recently claimed to be associated with AD (e.g. urokinase plasminogen
activator (PLAU) and acetyl-coenzyme A acetyltransferase 1 (ACAT1)). By reporting these data we hope to encourage the publication of gene compendia to guide further studies and aid future
meta-analyses aimed at resolving the involvement of genes in complex human traits. 相似文献
66.
Piscirickettsia salmonis induces apoptosis in macrophages and monocyte‐like cells from rainbow trout
Verónica Rojas Norbel Galanti Niels C. Bols Verónica Jiménez Rodolfo Paredes Sergio H. Marshall 《Journal of cellular biochemistry》2010,110(2):468-476
Piscirickettsia salmonis is the etiologic agent of the salmonid rickettsial septicemia (SRS) which causes significant losses in salmon production in Chile and other and in other regions in the southern hemisphere. As the killing of phagocytes is an important pathogenic mechanism for other bacteria to establish infections in vertebrates, we investigated whether P. salmonis kills trout macrophages by apoptosis. Apoptosis in infected macrophages was demonstrated by techniques based on morphological changes and host cell DNA fragmentation. Transmission electron microcopy showed classic apoptotic characteristics and terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling showed fragmented DNA. Programmed cell death type I was further confirmed by increased binding of annexin V to externalized phosphatidylserine in infected macrophages. Moreover, significant increases of caspase 3 activation were detected in infected cells and treatment with caspase inhibitor caused a decrease in levels of apoptosis. This is the first evidence that P. salmonis induces cell death in trout macrophages. This could lead to bacterial survival and evasion of the host immune response and play an important role in the establishment of infection in the host. J. Cell. Biochem. 110: 468–476, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
67.
Microtubule plus-end conformations and dynamics in the periphery of interphase mouse fibroblasts 下载免费PDF全文
Zovko S Abrahams JP Koster AJ Galjart N Mommaas AM 《Molecular biology of the cell》2008,19(7):3138-3146
The plus ends of microtubules (MTs) alternate between phases of growth, pause, and shrinkage, a process called "dynamic instability." Cryo-EM of in vitro-assembled MTs indicates that the dynamic state of the plus end corresponds with a particular MT plus-end conformation. Frayed ("ram's horn like"), blunt, and sheet conformations are associated with shrinking, pausing, and elongating plus ends, respectively. A number of new conformations have recently been found in situ but their dynamic states remained to be confirmed. Here, we investigated the dynamics of MT plus ends in the peripheral area of interphase mouse fibroblasts (3T3s) using electron microscopical and tomographical analysis of cryo-fixed, freeze-substituted, and flat-embedded sections. We identified nine morphologically distinct plus-end conformations. The frequency of these conformations correlates with their proximity to the cell border, indicating that the dynamic status of a plus end is influenced by features present in the periphery. Shifting dynamic instability toward depolymerization with nocodazole enabled us to address the dynamic status of these conformations. We suggest a new transition path from growth to shrinkage via the so-called sheet-frayed and flared ends, and we present a kinetic model that describes the chronology of events taking place in nocodazole-induced MT depolymerization. 相似文献
68.
Niels Andreasen Monica Simeoni Henrik Ostlund Pia I. Lisjo Tormod Fladby Amy E. Loercher Gerard J. Byrne Frances Murray Paul T. Scott-Stevens Anders Wallin Yinghua Y. Zhang Lena H. Bronge Henrik Zetterberg Agneta K. Nordberg Astrid J. Yeo Shahid A. Khan Jan Hilpert Prafull C. Mistry 《PloS one》2015,10(3)
Objective
To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the Fc-inactivated anti-β amyloid (Aβ) monoclonal antibody (mAb) GSK933776 in patients with mild Alzheimer’s disease (AD) or mild cognitive impairment (MCI).Methods
This was a two-part, single blind, placebo-controlled, first-time-in-human (FTIH) study of single (n = 18) and repeat dose (n = 32) intravenous GSK933776 0.001–6 mg/kg (ClinicalTrials.gov: NCT00459550). Additional safety data from an open-label, uncontrolled, single dose study of intravenous GSK933776 1–6 mg/kg (n = 18) are included (ClinicalTrials.gov: NCT01424436).Results
There were no cases of amyloid-related imaging abnormalities-edema (ARIA-E) or –hemorrhage (ARIA-H) after GSK933776 administration in both studies. Three patients across the two studies developed anti-GSK933776 antibodies. Plasma GSK933776 half-life (t1/2) was 10–15 days after repeat dosing. After each of three administrations of GSK933776, plasma levels of total Aβ42 and Aβ increased whereas plasma levels of free Aβ decreased dose dependently; no changes were observed for placebo. For total Aβ42 the peak:trough ratio was ≤2 at doses ≥3 mg/kg; for total Aβ the ratio was ≤2 at 6 mg/kg. CSF concentrations of Aβ showed increases from baseline to week 12 for Aβ X–38 (week 12:baseline ratio: 1.65; 95%CI: 1.38, 1.93) and Aβ X–42 (week 12:baseline ratio: 1.18; 95%CI: 1.06, 1.30) for values pooled across doses.Conclusion
In this FTIH study the Fc-inactivated anti-Aβ mAb GSK933776 engaged its target in plasma and CSF without causing brain ARIA-E/H in patients with mild AD or MCI.Trial Registration
ClinicalTrials.gov NCT00459550 相似文献69.
Sofia J. van Moorsel Marc W. Schmid Niels C. A. M. Wagemaker Thomas van Gurp Bernhard Schmid Philippine Vergeer 《Molecular ecology》2019,28(17):4097-4117
In long‐term grassland experiments, positive biodiversity effects on plant productivity commonly increase with time. Subsequent glasshouse experiments showed that these strengthened positive biodiversity effects persist not only in the local environment but also when plants are transferred into a common environment. Thus, we hypothesized that community diversity had acted as a selective agent, resulting in the emergence of plant monoculture and mixture types with differing genetic composition. To test our hypothesis, we grew offspring from plants that were grown for eleven years in monoculture or mixture environments in a biodiversity experiment (Jena Experiment) under controlled glasshouse conditions in monocultures or two‐species mixtures. We used epiGBS, a genotyping‐by‐sequencing approach combined with bisulphite conversion, to provide integrative genetic and epigenetic (i.e., DNA methylation) data. We observed significant divergence in genetic and DNA methylation data according to selection history in three out of five perennial grassland species, namely Galium mollugo, Prunella vulgaris and Veronica chamaedrys, with DNA methylation differences mostly reflecting the genetic differences. In addition, current diversity levels in the glasshouse had weak effects on epigenetic variation. However, given the limited genome coverage of the reference‐free bisulphite method epiGBS, it remains unclear how much of the differences in DNA methylation was independent of underlying genetic differences. Our results thus suggest that selection of genetic variants, and possibly epigenetic variants, caused the rapid emergence of monoculture and mixture types within plant species in the Jena Experiment. 相似文献
70.
Kassack MU Höfgen B Lehmann J Eckstein N Quillan JM Sadée W 《Journal of biomolecular screening》2002,7(3):233-246
Ligand binding studies reveal information about affinity to G protein-coupled receptors (GPCRs) rather than functional properties. Increase in intracellular Ca(2+) appears to represent a universal second messenger signal for a majority of recombinant GPCRs. Here, we exploit Ca(2+) signaling as a fast and sensitive functional screening method for a number of GPCRs coupled to different G proteins. Ca(2+) fluorescence measurements are performed using Oregon Green 488 BAPTA-1/AM and a microplate reader equipped with an injector. Buffer alone or test compounds dissolved in buffer are injected into a cell suspension, and fluorescence intensity is recorded for 30 s. Each of the GPCRs tested--G(q)-coupled P2Y(2), G(s)-coupled dopamine D1 and D5, G(i)-coupled dopamine D2L, and G(q/11)-coupled muscarinic acetylcholine M1--yielded a significant rise in intracellular free [Ca(2+)] on agonist stimulation. Agonist stimulation was dose dependent, as shown for ATP or UTP stimulation of P2Y(2) receptors (EC(50) = 1 microM), SKF38393 stimulation of hD1 and hD5 (EC(50) = 18.1 nM and 2.7 nM), and quinpirole at hD2L (EC(50) = 6.5 nM). SCH23390 (at hD1 and hD5) and spiperone, haloperidol, and clozapine (at hD2L) competitively antagonized the Ca(2+) response. Furthermore, the Ca(2+) assay served to screen suramin analogs for antagonistic activity at P2Y(2) receptors. Screening at dopamine receptors revealed LE300, a new lead for a dopamine receptor antagonist. Advantages of the assay include fast and simple 96- or 384-well plate format (high-throughput screening), use of a visible light-excitable fluorescent dye, applicability to a majority of GPCRs, and simultaneous analysis of distinct Ca(2+) fluxes. 相似文献