全文获取类型
收费全文 | 879篇 |
免费 | 124篇 |
出版年
2022年 | 12篇 |
2021年 | 24篇 |
2020年 | 5篇 |
2019年 | 10篇 |
2018年 | 22篇 |
2017年 | 16篇 |
2016年 | 34篇 |
2015年 | 42篇 |
2014年 | 36篇 |
2013年 | 47篇 |
2012年 | 71篇 |
2011年 | 73篇 |
2010年 | 47篇 |
2009年 | 35篇 |
2008年 | 43篇 |
2007年 | 39篇 |
2006年 | 44篇 |
2005年 | 35篇 |
2004年 | 27篇 |
2003年 | 27篇 |
2002年 | 23篇 |
2001年 | 13篇 |
2000年 | 23篇 |
1999年 | 15篇 |
1998年 | 7篇 |
1997年 | 7篇 |
1996年 | 8篇 |
1995年 | 7篇 |
1994年 | 9篇 |
1993年 | 5篇 |
1992年 | 11篇 |
1991年 | 14篇 |
1990年 | 15篇 |
1989年 | 11篇 |
1988年 | 13篇 |
1987年 | 11篇 |
1986年 | 16篇 |
1985年 | 10篇 |
1984年 | 14篇 |
1983年 | 5篇 |
1982年 | 6篇 |
1981年 | 6篇 |
1979年 | 5篇 |
1977年 | 4篇 |
1976年 | 4篇 |
1971年 | 5篇 |
1969年 | 4篇 |
1968年 | 7篇 |
1967年 | 4篇 |
1937年 | 5篇 |
排序方式: 共有1003条查询结果,搜索用时 390 毫秒
41.
Masato Ohtani Toshiaki Kondo Naoki Tani Saneyoshi Ueno Leong S. Lee Kevin K. S. Ng Norwati Muhammad Reiner Finkeldey Mohamad Na'iem Sapto Indrioko Koichi Kamiya Ko Harada Bibian Diway Eyen Khoo Kensuke Kawamura Yoshihiko Tsumura 《Molecular ecology》2013,22(8):2264-2279
Tropical rainforests in South‐East Asia have been affected by climatic fluctuations during past glacial eras. To examine how the accompanying changes in land areas and temperature have affected the genetic properties of rainforest trees in the region, we investigated the phylogeographic patterns of a widespread dipterocarp species, Shorea leprosula. Two types of DNA markers were used: expressed sequence tag‐based simple sequence repeats and chloroplast DNA (cpDNA) sequence variations. Both sets of markers revealed clear genetic differentiation between populations in Borneo and those in the Malay Peninsula and Sumatra (Malay/Sumatra). However, in the south‐western part of Borneo, genetic admixture of the lineages was observed in the two marker types. Coalescent simulation based on cpDNA sequence variation suggested that the two lineages arose 0.28–0.09 million years before present and that following their divergence migration from Malay/Sumatra to Borneo strongly exceeded migration in the opposite direction. We conclude that the genetic structure of S. leprosula was largely formed during the middle Pleistocene and was subsequently modified by eastward migration across the subaerially exposed Sunda Shelf. 相似文献
42.
V KW Wong T Li B YK Law E DL Ma N C Yip F Michelangeli C KM Law M M Zhang K YC Lam P L Chan L Liu 《Cell death & disease》2013,4(7):e720
Autophagy is an important cellular process that controls cells in a normal homeostatic state by recycling nutrients to maintain cellular energy levels for cell survival via the turnover of proteins and damaged organelles. However, persistent activation of autophagy can lead to excessive depletion of cellular organelles and essential proteins, leading to caspase-independent autophagic cell death. As such, inducing cell death through this autophagic mechanism could be an alternative approach to the treatment of cancers. Recently, we have identified a novel autophagic inducer, saikosaponin-d (Ssd), from a medicinal plant that induces autophagy in various types of cancer cells through the formation of autophagosomes as measured by GFP-LC3 puncta formation. By computational virtual docking analysis, biochemical assays and advanced live-cell imaging techniques, Ssd was shown to increase cytosolic calcium level via direct inhibition of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump, leading to autophagy induction through the activation of the Ca2+/calmodulin-dependent kinase kinase–AMP-activated protein kinase–mammalian target of rapamycin pathway. In addition, Ssd treatment causes the disruption of calcium homeostasis, which induces endoplasmic reticulum stress as well as the unfolded protein responses pathway. Ssd also proved to be a potent cytotoxic agent in apoptosis-defective or apoptosis-resistant mouse embryonic fibroblast cells, which either lack caspases 3, 7 or 8 or had the Bax-Bak double knockout. These results provide a detailed understanding of the mechanism of action of Ssd, as a novel autophagic inducer, which has the potential of being developed into an anti-cancer agent for targeting apoptosis-resistant cancer cells. 相似文献
43.
44.
Karin Lundeng?rd Gunnar Cedersund Sebastian Sten Felix Leong Alexander Smedberg Fredrik Elinder Maria Engstr?m 《PLoS computational biology》2016,12(6)
Functional magnetic resonance imaging (fMRI) measures brain activity by detecting the blood-oxygen-level dependent (BOLD) response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new, independent validation data. These results open the door to a new type of fMRI analysis that more accurately reflects the true neuronal activity. 相似文献
45.
Cryptococcus neoformans is an encapsulated basidiomycetous yeast commonly associated with pigeon droppings and soil. The opportunistic pathogen infects humans through the respiratory system and the metabolic implications of C. neoformans infection have yet to be explored. Studying the metabolic profile associated with the infection could lead to the identification of important metabolites associated with pulmonary infection. Therefore, the aim of the study was to simulate cryptococcal infection at the primary site of infection, the lungs, and to identify the metabolic profile and important metabolites associated with the infection at low and high multiplicity of infections (MOI). The culture supernatant of lung epithelial cells infected with C. neoformans at MOI of 10 and 100 over a period of 18 hours were analysed using gas chromatography mass spectrometry. The metabolic profiles obtained were further analysed using multivariate analysis and the pathway analysis tool, MetaboAnalyst 2.0. Based on the results from the multivariate analyses, ten metabolites were selected as the discriminatory metabolites that were important in both the infection conditions. The pathways affected during early C. neoformans infection of lung epithelial cells were mainly the central carbon metabolism and biosynthesis of amino acids. Infection at a higher MOI led to a perturbance in the β-alanine metabolism and an increase in the secretion of pantothenic acid into the growth media. Pantothenic acid production during yeast infection has not been documented and the β-alanine metabolism as well as the pantothenate and CoA biosynthesis pathways may represent underlying metabolic pathways associated with disease progression. Our study suggested that β-alanine metabolism and the pantothenate and CoA biosynthesis pathways might be the important pathways associated with cryptococcal infection. 相似文献
46.
47.
Shuqiang Huang Anna Jisu Lee Ryan Tsoi Feilun Wu Ying Zhang Kam W Leong Lingchong You 《Molecular systems biology》2016,12(2)
Engineered bacteria have great potential for medical and environmental applications. Fulfilling this potential requires controllability over engineered behaviors and scalability of the engineered systems. Here, we present a platform technology, microbial swarmbot, which employs spatial arrangement to control the growth dynamics of engineered bacteria. As a proof of principle, we demonstrated a safeguard strategy to prevent unintended bacterial proliferation. In particular, we adopted several synthetic gene circuits to program collective survival in Escherichia coli: the engineered bacteria could only survive when present at sufficiently high population densities. When encapsulated by permeable membranes, these bacteria can sense the local environment and respond accordingly. The cells inside the microbial swarmbot capsules will survive due to their high densities. Those escaping from a capsule, however, will be killed due to a decrease in their densities. We demonstrate that this design concept is modular and readily generalizable. Our work lays the foundation for engineering integrated and programmable control of hybrid biological–material systems for diverse applications. 相似文献
48.
Jorge D García-García Kristen Van Gelder Jaya Joshi Ulschan Bathe Bryan J Leong Steven D Bruner Chang C Liu Andrew D Hanson 《Plant physiology》2022,188(2):971
Continuous directed evolution of enzymes and other proteins in microbial hosts is capable of outperforming classical directed evolution by executing hypermutation and selection concurrently in vivo, at scale, with minimal manual input. Provided that a target enzyme’s activity can be coupled to growth of the host cells, the activity can be improved simply by selecting for growth. Like all directed evolution, the continuous version requires no prior mechanistic knowledge of the target. Continuous directed evolution is thus a powerful way to modify plant or non-plant enzymes for use in plant metabolic research and engineering. Here, we first describe the basic features of the yeast (Saccharomyces cerevisiae) OrthoRep system for continuous directed evolution and compare it briefly with other systems. We then give a step-by-step account of three ways in which OrthoRep can be deployed to evolve primary metabolic enzymes, using a THI4 thiazole synthase as an example and illustrating the mutational outcomes obtained. We close by outlining applications of OrthoRep that serve growing demands (i) to change the characteristics of plant enzymes destined for return to plants, and (ii) to adapt (“plantize”) enzymes from prokaryotes—especially exotic prokaryotes—to function well in mild, plant-like conditions.Continuous directed evolution using the yeast OrthoRep system is a powerful way to improve enzymes for use in plant engineering as illustrated by “plantizing” a bacterial thiamin synthesis enzyme. 相似文献
49.
50.
Homeotic mutations in flowers lead to the development of floral organs in abnormal locations. In most laboratory-induced examples of this type of mutation, two adjacent whorls of organs are affected, resulting in two whorls of abnormal organ formation. However, the crinkled petal mutant of Clarkia tembloriensis is interesting because it is a naturally occurring mutation and it affects only the second whorl of organs, producing sepaloid petals. In this study one wild-type population (Cantua Creek-2) and one crinkled petal mutant population (Red Rocks) were compared using 181 different primers in random amplified polymorphic DNA (RAPD) analysis. Bulk DNA from each parent population and their subsequent crosses were used to compare the genetic differences between the two populations and to search for molecular markers linked with the CRINKLED PETAL locus. A linkage map was developed for the CRINKLED PETAL gene, and markers were discovered which flanked both sides of the locus. 相似文献