全文获取类型
收费全文 | 696篇 |
免费 | 59篇 |
国内免费 | 4篇 |
出版年
2024年 | 2篇 |
2023年 | 5篇 |
2022年 | 12篇 |
2021年 | 16篇 |
2020年 | 20篇 |
2019年 | 20篇 |
2018年 | 28篇 |
2017年 | 26篇 |
2016年 | 37篇 |
2015年 | 42篇 |
2014年 | 55篇 |
2013年 | 53篇 |
2012年 | 55篇 |
2011年 | 44篇 |
2010年 | 33篇 |
2009年 | 33篇 |
2008年 | 27篇 |
2007年 | 31篇 |
2006年 | 27篇 |
2005年 | 25篇 |
2004年 | 20篇 |
2003年 | 13篇 |
2002年 | 19篇 |
2001年 | 13篇 |
2000年 | 15篇 |
1999年 | 8篇 |
1998年 | 9篇 |
1997年 | 2篇 |
1996年 | 4篇 |
1995年 | 3篇 |
1993年 | 3篇 |
1992年 | 5篇 |
1991年 | 2篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 4篇 |
1985年 | 6篇 |
1984年 | 2篇 |
1983年 | 6篇 |
1982年 | 2篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1978年 | 6篇 |
1977年 | 3篇 |
1976年 | 5篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1973年 | 4篇 |
1972年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有759条查询结果,搜索用时 312 毫秒
1.
Abstract: The relationship between elevations in intracellular free Ca2+ concentration ([Ca2+]i) by different mechanisms and tyrosine hydroxylase (TH) gene expression was examined. Depolarization by an elevated K+ concentration triggered rapid and sustained increases in [Ca2+]i from a basal level of ~50 to 110–150 nM and three- to fourfold elevations in TH mRNA levels, requiring extracellular calcium but not inositol 1,4,5-trisphosphate (IP3). On the other hand, bradykinin or thapsigargin, both of which induce release of intracellular calcium stores via IP3 or inhibition of Ca2+-ATPase, rapidly elevated [Ca2+]i to >200 nM and increased TH gene expression (three-to fivefold). Confocal imaging showed that the elevations in [Ca2+]i in each case occurred throughout the cyto- and nucleoplasm. The initial rise in [Ca2+]i due to either bradykinin or thapsigargin, which did not require extracellular calcium, was sufficient to initiate the events leading to increased TH expression. Consistent with this, the effects of bradykinin on TH expression were inhibited by 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid or 3,4,5-trimethoxybenzoic acid 8-(diethylamino)-octyl ester which chelates or inhibits the release of intracellular calcium, respectively. Bradykinin required a rise in [Ca2+]i for <10 min, as opposed to 10–30 min for depolarization to increase TH mRNA levels. These results demonstrate that although each of these treatments increased TH gene expression by raising [Ca2+]i, there are important differences among them in terms of the magnitude of elevated [Ca2+]i, requirements for extracellular calcium or release of intracellular calcium stores, and duration of elevated [Ca2+]i, indicating the involvement of different calcium signaling pathways leading to regulation of TH gene expression. 相似文献
2.
Nielsen J; Peixoto AA; Piccin A; Costa R; Kyriacou CP; Chalmers D 《Molecular biology and evolution》1994,11(6):839-853
The region of the clock gene period (per) that encodes a repetitive tract
of threonine-glycine (Thr-Gly) pairs has been compared between Dipteran
species both within and outside the Drosophilidae. All the non-
Drosophilidae sequences in this region are short and present a remarkably
stable picture compared to the Drosophilidae, in which the region is much
larger and extremely variable, both in size and composition. The
accelerated evolution in the repetitive region of the Drosophilidae appears
to be mainly due to an expansion of two ancestral repeats, one encoding a
Thr-Gly dipeptide and the other a pentapeptide rich in serine, glycine, and
asparagine or threonine. In some drosophilids the expansion involves a
duplication of the pentapeptide sequence, but in Drosophila pseudoobscura
both the dipeptide and the pentapeptide repeats are present in larger
numbers. In the nondrosophilids, however, the pentapeptide sequence is
represented by one copy and the dipeptide by two copies. These observations
fulfill some of the predictions of recent theoretical models that have
simulated the evolution of repetitive sequences.
相似文献
3.
Valentina Sora Adrian Otamendi Laspiur Kristine Degn Matteo Arnaudi Mattia Utichi Ludovica Beltrame Dayana De Menezes Matteo Orlandi Ulrik Kristoffer Stoltze Olga Rigina Peter Wad Sackett Karin Wadt Kjeld Schmiegelow Matteo Tiberti Elena Papaleo 《Protein science : a publication of the Protein Society》2023,32(1):e4527
Reliable prediction of free energy changes upon amino acid substitutions (ΔΔGs) is crucial to investigate their impact on protein stability and protein–protein interaction. Advances in experimental mutational scans allow high-throughput studies thanks to multiplex techniques. On the other hand, genomics initiatives provide a large amount of data on disease-related variants that can benefit from analyses with structure-based methods. Therefore, the computational field should keep the same pace and provide new tools for fast and accurate high-throughput ΔΔG calculations. In this context, the Rosetta modeling suite implements effective approaches to predict folding/unfolding ΔΔGs in a protein monomer upon amino acid substitutions and calculate the changes in binding free energy in protein complexes. However, their application can be challenging to users without extensive experience with Rosetta. Furthermore, Rosetta protocols for ΔΔG prediction are designed considering one variant at a time, making the setup of high-throughput screenings cumbersome. For these reasons, we devised RosettaDDGPrediction, a customizable Python wrapper designed to run free energy calculations on a set of amino acid substitutions using Rosetta protocols with little intervention from the user. Moreover, RosettaDDGPrediction assists with checking completed runs and aggregates raw data for multiple variants, as well as generates publication-ready graphics. We showed the potential of the tool in four case studies, including variants of uncertain significance in childhood cancer, proteins with known experimental unfolding ΔΔGs values, interactions between target proteins and disordered motifs, and phosphomimetics. RosettaDDGPrediction is available, free of charge and under GNU General Public License v3.0, at https://github.com/ELELAB/RosettaDDGPrediction . 相似文献
4.
Evolutionary origin of human and primate malarias: evidence from the circumsporozoite protein gene 总被引:8,自引:1,他引:7
We have analyzed the conserved regions of the gene coding for the
circumsporozoite protein (CSP) in 12 species of Plasmodium, the malaria
parasite. The closest evolutionary relative of P. falciparum, the agent of
malignant human malaria, is P. reichenowi, a chimpanzee parasite. This is
consistent with the hypothesis that P. falciparum is an ancient human
parasite, associated with humans since the divergence of the hominids from
their closest hominoid relatives. Three other human Plasmodium species are
each genetically indistinguishable from species parasitic to nonhuman
primates; that is, for the DNA sequences included in our analysis, the
differences between species are not greater than the differences between
strains of the human species. The human P. malariae is indistinguishable
from P. brasilianum, and P. vivax is indistinguishable from P. simium; P.
brasilianum and P. simium are parasitic to New World monkeys. The human P.
vivax-like is indistinguishable from P. simiovale, a parasite of Old World
macaques. We conjecture that P. malariae, P. vivax, and P. vivax-like are
evolutionarily recent human parasites, the first two at least acquired only
within the last several thousand years, and perhaps within the last few
hundred years, after the expansion of human populations in South America
following the European colonizations. We estimate the rate of evolution of
the conserved regions of the CSP gene as 2.46 x 10(-9) per site per year.
The divergence between the P. falciparum and P. reichenowi lineages is
accordingly dated 8.9 Myr ago. The divergence between the three lineages
leading to the human parasites is very ancient, about 100 Myr old between
P. malariae and P. vivax (and P. vivax-like) and about 165 Myr old between
P. falciparum and the other two.
相似文献
5.
Presence of Epstein-Barr virus receptors, but absence of virus penetration, in cells of an Epstein-Barr virus genome-negative human lymphoblastoid T line (Molt 4). 总被引:5,自引:0,他引:5 下载免费PDF全文
This paper reports a unique type of interaction of Epstein-Barr virus (EBV) with an EBV receptor-positive, genome-negative human lymphoid T cell line (Molt 4), which can be summarized as follows. Although Molt 4 cells express receptors for EBV, they appear to block the penetration of this virus. These observations are derived from combined studies with immunofluorescence and electron microscopy. It is possible that T cell lines bearing receptors for EBV may express such a control on virus penetration. 相似文献
6.
Photosynthetic enhancement studies performed at 619 nm (excitation of Systems I and II) and at 446 nm (mainly excitation of System I) revealed an 18% photosynthetic enhancement simultaneously with a 31% reduction in glycolate excretion. This observation supports the hypothesis that some glycolate may be consumed in an oxidation process associated with System I when System II is poorly excited and the supply of electrons from the water splitting process of photosynthesis is low. 相似文献
7.
Yeast hexokinase A(ATP:D-hexose 6-phosphotransferase) is inactivated when incubated in the presence of xylose and ATPMg, or in the presence of D-lyxose in a reaction medium in which ATPMg is being continuously regenerated (phosphoenolpyruvate and pyruvate kinase). The inactivation is due to the phorphorylation of the protein. A linear relationship was observed between the inactivation and the incorporation of 32P from [gamma-32P] ATP. All hexokinase and ATPase activity of the enzyme is lost when one phosphoryl group is incorporated per enzyme subunit (molecular weight 51,000). The phosphoryl group is covalently bound by a ester linkage with a serine residue of the protein. 相似文献
8.
Fred Bernardes Filho Jaci Maria Santana Regina Coeli Palma de Almeida Glauber Voltan Natlia Aparecida de Paula Marcel Nani Leite Claudia Maria Lincoln Silva Camila Tormena Lean Basoli Joelma Menezes Moises Batista da Silva John Stewart Spencer Wilson Marques Jr Norma Tiraboschi Foss Marco Andrey Cipriani Frade 《PLoS neglected tropical diseases》2020,14(12)
BackgroundThis study evaluates an active search strategy for leprosy diagnosis based on responses to a Leprosy Suspicion Questionnaire (LSQ), and analyzing the clinical, immunoepidemiological and follow-up aspects for individuals living in a prison population.MethodsA cross-sectional study based on a questionnaire posing 14 questions about leprosy symptoms and signs that was distributed to 1,400 prisoners. This was followed by dermatoneurological examination, anti-PGL-I serology and RLEP-PCR. Those without leprosy were placed in the Non-leprosy Group (NLG, n = 1,216) and those diagnosed with clinical symptoms of leprosy were placed in the Leprosy Group (LG, n = 34).FindingsIn total, 896 LSQ were returned (64%), and 187 (20.9%) of the responses were deemed as positive for signs/symptoms, answering 2.7 questions on average. Clinically, 1,250 (89.3%) of the prisoners were evaluated resulting in the diagnosis of 34 new cases (LG), based on well-accepted clinical signs and symptoms, a new case detection rate of 2.7% within this population, while the NLG were comprised of 1,216 individuals. The confinement time medians were 39 months in the LG while it was 36 months in the NLG (p>0.05). The 31 leprosy cases who responded to the questionnaire (LSQ+) had an average of 1.5 responses. The symptoms “anesthetized skin area” and “pain in nerves” were most commonly mentioned in the LG while “tingling, numbness in the hands/feet”, “sensation of pricks and needles”, “pain in nerves” and “spots on the skin” responses were found in more than 30% of questionnaires in the NLG. Clinically, 88.2% had dysesthetic macular skin lesions and 97.1% presented some peripheral nerve impairment, 71.9% with some degree of disability. All cases were multibacillary, confirming a late diagnosis. Anti-PGL-I results in the LG were higher than in the NLG (p<0.0001), while the RLEP-PCR was positive in 11.8% of the patients.InterpretationOur findings within the penitentiary demonstrated a hidden prevalence of leprosy, although the individuals diagnosed were likely infected while living in their former communities and not as a result of exposure in the prison. The LSQ proved to be an important screening tool to help identify leprosy cases in prisons. 相似文献
9.
dos Santos Fernanda Marcelia Pflüger Pricila Fernandes Lazzarotto Leticia Uczay Mariana de Aguida Wesley Roberto da Silva Lisiane Santos Boaretto Fernanda Brião Menezes de Sousa Jayne Torres Picada Jaqueline Nascimento da Silva Torres Iraci Lucena Pereira Patrícia 《Neurochemical research》2021,46(8):2066-2078
Neurochemical Research - Gamma-decanolactone (GD) has been shown to reduce epileptic behavior in different models, inflammatory decreasing, oxidative stress, and genotoxic parameters. This study... 相似文献
10.
Fabrícia F. Nascimento Ana Lazar Albert N. Menezes Andressa da Matta Durans Janio C. Moreira Jorge Salazar-Bravo Paulo S. D′Andrea Cibele R. Bonvicino 《PloS one》2013,8(4)
The Neotropics harbors a high diversity of species and several hypotheses have been proposed to account for this pattern. However, while species of forested domains are frequently studied, less is known of species from open vegetation formations occupying, altogether, a larger area than the Amazon Forest. Here we evaluate the role of historical barriers and the riverine hypothesis in the speciation patterns of small mammals by analyzing an ancient rodent lineage (Thrichomys, Hystricomorpha). Phylogenetic and biogeographic analyses were carried out with mitochondrial and nuclear DNA markers to analyze the evolutionary relationships between Thrichomys lineages occurring in dry domains along both banks of the Rio São Francisco. This river is one of the longest of South America whose course and water flow have been modified by inland tectonic activities and climate changes. Molecular data showed a higher number of lineages than previously described. The T. inermis species complex with 2n = 26, FN = 48 was observed in both banks of the river showing a paraphyletic arrangement, suggesting that river crossing had occurred, from east to west. A similar pattern was also observed for the T. apereoides complex. Thrichomys speciation occurred in Late Miocene when the river followed a different course. The current geographic distribution of Thrichomys species and their phylogenetic relationships suggested the existence of frequent past connections between both banks in the middle section of the Rio São Francisco. The extensive palaeodune region found in this area has been identified as a centre of endemism of several vertebrate species and is likely to be a center of Thrichomys diversification. 相似文献