全文获取类型
收费全文 | 2318篇 |
免费 | 268篇 |
专业分类
2586篇 |
出版年
2021年 | 16篇 |
2019年 | 18篇 |
2018年 | 24篇 |
2016年 | 39篇 |
2015年 | 73篇 |
2014年 | 67篇 |
2013年 | 91篇 |
2012年 | 103篇 |
2011年 | 99篇 |
2010年 | 52篇 |
2009年 | 53篇 |
2008年 | 102篇 |
2007年 | 103篇 |
2006年 | 93篇 |
2005年 | 87篇 |
2004年 | 99篇 |
2003年 | 69篇 |
2002年 | 75篇 |
2001年 | 88篇 |
2000年 | 64篇 |
1999年 | 57篇 |
1998年 | 36篇 |
1997年 | 39篇 |
1996年 | 27篇 |
1995年 | 27篇 |
1994年 | 24篇 |
1993年 | 25篇 |
1992年 | 40篇 |
1991年 | 33篇 |
1990年 | 54篇 |
1989年 | 49篇 |
1988年 | 39篇 |
1987年 | 33篇 |
1986年 | 39篇 |
1985年 | 36篇 |
1984年 | 29篇 |
1983年 | 29篇 |
1982年 | 19篇 |
1981年 | 19篇 |
1980年 | 16篇 |
1979年 | 29篇 |
1978年 | 30篇 |
1977年 | 20篇 |
1976年 | 33篇 |
1975年 | 23篇 |
1974年 | 23篇 |
1973年 | 26篇 |
1972年 | 24篇 |
1971年 | 17篇 |
1970年 | 21篇 |
排序方式: 共有2586条查询结果,搜索用时 0 毫秒
101.
A retrospective study of 20 patients who underwent vena caval fenestration showed that in 50% of the patients the procedure was done for prophylaxis and in 50% it was done for therapeutic reasons. After this procedure five patients had persistent leg swelling, two had deep venous thrombosis, two had pulmonary emboli and one died of a respiratory arrest. We recommend limiting the use of vena caval fenestration to those patients who have verified pulmonary embolism while adequately anticoagulated or patients who have pulmonary embolism and a major contraindication to anticoagulation. 相似文献
102.
MF Perutz 《Current opinion in structural biology》1996,6(6):848-858
Several dominantly inherited, late onset, neurodegenerative diseases are due to expansion of CAG repeats, leading to expansion of glutamine repeats in the affected proteins. These proteins are of very different sizes and, with one exception, show no sequence homology to known proteins or to each other; their functions are unknown. In some, the glutamine repeat starts near the N-terminus, in another near the middle and in another near the C-terminus, but regardless of these differences, no disease has been observed in individuals with fewer than 37 repeats, and absence of disease has never been found in those with more than 41 repeats. Protein constructs with more than 41 repeats are toxic to E. coli and to CHO cells in culture, and they elicit ataxia in transgenic mice. These observations argue in favour of a distinct change of structure associated with elongation beyond 37–41 glutamine repeats. The review describes experiments designed to find out what these structures might be and how they could influence the properties of the proteins of which they form part. Poly-
-glutamines form pleated sheets of β-strands held together by hydrogen bonds between their amides. Incorporation of glutamine repeats into a small protein of known structure made it associate irreversibly into oligomers. That association took place during the folding of the protein molecules and led to their becoming firmly interlocked by either strand- or domain-swapping. Thermodynamic considerations suggest that elongation of glutamine repeats beyond a certain length may lead to a phase change from random coils to hydrogen-bonded hairpins. Possible mechanisms of expansion of CAG repeats are discussed in the light of looped DNA model structures. 相似文献
103.
Elizabeth Fullam Akane Kawamura Helen Wilkinson Areej Abuhammad Isaac Westwood Edith Sim 《The protein journal》2009,28(6):281-293
Arylamine N-acetyltansferase (NAT) from Mycobacterium tuberculosis (TBNAT) is a potential drug target for anti-tubercular therapy. Recombinant TBNAT is much less soluble and is produced in
lower yields than the closely related NAT from Mycobacterium marinum (MMNAT). In order to explore MMNAT as a model for TBNAT in drug discovery, we compare the two mycobacterial NAT enzymes.
Two site-directed mutants of MMNAT have been prepared and characterised: MMNAT71, Tyr → Phe and MMNAT209, Met → Thr, in which
residues within 6 Å of the active-site cysteine have been replaced with the corresponding residue from TBNAT. Two chimeric
proteins have also been produced in which the third domain of MMNAT has been replaced by the third domain of TBNAT and vice
versa. The activity profile of the chimeric proteins suggests a role for the third domain in the evolutionary divergence of
NAT between these closely related mycobacterial species. 相似文献
104.
Ryan P. Topping John C. Wilkinson Karin Drotschmann Scarpinato 《The Journal of biological chemistry》2009,284(21):14029-14039
Mismatch repair (MMR) proteins participate in cytotoxicity induced by
certain DNA damage-inducing agents, including cisplatin
(cis-diamminedichloroplatinum(II), CDDP), a cancer chemotherapeutic
drug utilized clinically to treat a variety of malignancies. MMR proteins have
been demonstrated to bind to CDDP-DNA adducts and initiate MMR
protein-dependent cell death in cells treated with CDDP; however, the
molecular events underlying this death remain unclear. As MMR proteins have
been suggested to be important in clinical responses to CDDP, a clear
understanding of MMR protein-dependent, CDDP-induced cell death is critical.
In this report, we demonstrate MMR protein-dependent relocalization of
cytochrome c to the cytoplasm and cleavage of caspase-9, caspase-3,
and poly(ADP-ribose) polymerase upon treatment of cells with CDDP. Chemical
inhibition of caspases specifically attenuates CDDP/MMR protein-dependent
cytotoxicity, suggesting that a caspase-dependent signaling mechanism is
required for the execution of this cell death. p53 protein levels were
up-regulated independently of MMR protein status, suggesting that p53 is not a
mediator of MMR-dependent, CDDP-induced death. This work is the first
indication of a required signaling mechanism in CDDP-induced, MMR
protein-dependent cytotoxicity, which can be uncoupled from other CDDP
response pathways, and defines a critical contribution of MMR proteins to the
control of cell death.The MMR2 system of
proteins plays roles in diverse cellular processes, perhaps most notably in
preserving genomic integrity by recognizing and facilitating the repair of
post-DNA replication base pairing errors. Recognition of these errors and
recruitment of repair machinery is performed by the MutSα complex
(consisting of the MMR proteins MSH2 and MSH6) or MutSβ complex
(consisting of MSH2 and MSH3). Defects in MMR proteins render cells
hypermutable and promote microsatellite instability, a hallmark of MMR
defects. MMR protein defects are found in a wide variety of sporadic cancers,
as well as in hereditary non-polyposis colorectal cancer
(1).In addition to their role in DNA repair, MMR proteins also play a role in
cytotoxicity induced by specific types of DNA-damaging chemotherapeutic drugs,
such as CDDP, which is utilized clinically to treat a number of different
cancer types. MutSα recognizes multiple types of DNA damage, including
1,2-intrastrand CDDP adducts and O6-methylguanine lesions
(2). Treatment of cells with
compounds that induce these types of lesions, including CDDP and methylating
agents such as
N-methyl-N′-nitro-N-nitrosoguanidine (MNNG),
results in MMR protein-dependent cell cycle arrest and cell death
(3–7).
This suggests that MMR proteins, in addition to their role in DNA repair, are
also capable of initiating cell death in response to certain types of DNA
damage.Cells treated with DNA-damaging agents frequently activate an apoptotic
cell death pathway mediated by the mitochondria. This intrinsic death
signaling pathway predominantly involves the coordinated activity of two
groups of proteins: pro-death members of the Bcl-2 family that control the
integrity of mitochondrial membranes, and members of the caspase family of
cysteinyl proteases that proteolytically cleave intracellular substrates,
giving rise to apoptotic morphology and destruction of the cell
(8,
9). Pro-death Bcl-2 family
members, such as Bax and Bak, target the outer mitochondrial membrane and
cause the cytosolic release of pro-death factors residing within the
mitochondria of unstressed cells
(8). Predominant among these
factors is cytochrome c, whose cytoplasmic localization results in
the formation of a caspase-activating platform known as the apoptosome
(10). This complex includes
the adaptor protein Apaf-1, and when formed the apoptosome promotes the
cleavage and activation of caspase-9
(11,
12). Once activated, this
apical caspase proceeds to cleave and activate caspase-3, the predominant
effector protease of apoptosis.A significant amount of evidence has been gathered illustrating MMR
protein-dependent pro-death signaling in response to methylating agents
(13–16,
3). In contrast, the MMR
protein-dependent cytotoxic response to CDDP is largely unknown, with only the
p53-related transactivator protein p73 and the c-Abl kinase clearly implicated
as potential mediators of CDDP/MMR protein-dependent cell death in human cells
(17,
18). Interestingly, ATM, Chk1,
Chk2, and p53, which are activated in an MMR protein-dependent manner after
treatment of cells with MNNG
(3,
13), are not involved in the
MMR-dependent response to CDDP
(7,
17). In addition, the
magnitude of MMR protein-dependent cell death induced by methylating agents
and CDDP differs (4). These
findings suggest that unique signaling pathways may be engaged by MMR proteins
depending upon the type of recognized lesion. As such, there is a requirement
for further study of the molecular events underlying MMR protein-dependent
cell death and cell cycle arrest for each type of recognized DNA lesion. This
is particularly relevant in the case of CDDP, as evidence from a limited
number of retrospective clinical studies suggests that MMR proteins play an
important role in patient response to CDDP. Several studies examining
immunohistochemical staining against MSH2 or MLH1 have demonstrated that
levels of these proteins are reduced in ovarian and esophageal tumor samples
following CDDP-based chemotherapy
(19,
20). Low levels of MMR protein
post-chemotherapy seem to be predictive of lower overall survival in a certain
subset of tumors (esophageal cancer), but not others (ovarian and non-small
cell lung cancer)
(19–21).
Two recent studies examining MMR protein levels and microsatellite instability
in germ cell tumors from patients receiving platinum-based chemotherapy have
suggested a prognostic value for pre-chemotherapy MMR protein status in these
tumors (22,
23). This potential clinical
relevance underscores the need for a greater understanding of MMR
protein-dependent mechanisms of CDDP-induced cell death.In this study, we report that CDDP induces an MMR protein-dependent
decrease in cell viability and MMR protein-dependent signaling in the form of
cytochrome c release to the cytoplasm and cleavage of caspase-9,
caspase-3, and PARP. Chemical inhibition of caspases specifically attenuates
CDDP/MMR protein-dependent loss of cell viability, indicating a requirement
for caspase activation in this process and uncoupling MMR protein-dependent
cytotoxic signaling from other CDDP response pathways. Additionally, the
CDDP-induced, MMR protein-dependent cytotoxic response is independent of p53
signaling. Our results demonstrate for the first time an MMR protein-dependent
pro-death signaling pathway in cells treated with CDDP. 相似文献
105.
Westerhoff HV Kolodkin A Conradie R Wilkinson SJ Bruggeman FJ Krab K van Schuppen JH Hardin H Bakker BM Moné MJ Rybakova KN Eijken M van Leeuwen HJ Snoep JL 《Journal of mathematical biology》2009,58(1-2):7-34
Systems Biology is the science that aims to understand how biological function absent from macromolecules in isolation, arises when they are components of their system. Dedicated to the memory of Reinhart Heinrich, this paper discusses the origin and evolution of the new part of systems biology that relates to metabolic and signal-transduction pathways and extends mathematical biology so as to address postgenomic experimental reality. Various approaches to modeling the dynamics generated by metabolic and signal-transduction pathways are compared. The silicon cell approach aims to describe the intracellular network of interest precisely, by numerically integrating the precise rate equations that characterize the ways macromolecules’ interact with each other. The non-equilibrium thermodynamic or ‘lin–log’ approach approximates the enzyme rate equations in terms of linear functions of the logarithms of the concentrations. Biochemical Systems Analysis approximates in terms of power laws. Importantly all these approaches link system behavior to molecular interaction properties. The latter two do this less precisely but enable analytical solutions. By limiting the questions asked, to optimal flux patterns, or to control of fluxes and concentrations around the (patho)physiological state, Flux Balance Analysis and Metabolic/Hierarchical Control Analysis again enable analytical solutions. Both the silicon cell approach and Metabolic/Hierarchical Control Analysis are able to highlight where and how system function derives from molecular interactions. The latter approach has also discovered a set of fundamental principles underlying the control of biological systems. The new law that relates concentration control to control by time is illustrated for an important signal transduction pathway, i.e. nuclear hormone receptor signaling such as relevant to bone formation. It is envisaged that there is much more Mathematical Biology to be discovered in the area between molecules and Life. 相似文献
106.
Echolocating bats are auditory specialists, with exquisite hearing that spans several octaves. In the ultrasonic range, bat audiograms typically show highest sensitivity in the spectral region of their species-specific echolocation calls. Well-developed hearing in the audible range has been commonly attributed to a need to detect sounds produced by prey. However, bat pups often emit isolation calls with low-frequency components that facilitate mother-young reunions. In this study, we examine whether low-frequency hearing in bats exhibits correlated evolution with (i) body size; (ii) high-frequency hearing sensitivity or (iii) pup isolation call frequency. Using published audiograms, we found that low-frequency hearing sensitivity is not dependent on body size but is related to high-frequency hearing. After controlling for high-frequency hearing, we found that low-frequency hearing exhibits correlated evolution with isolation call frequency. We infer that detection and discrimination of isolation calls have favoured enhanced low-frequency hearing because accurate parental investment is critical: bats have low reproductive rates, non-volant altricial young and must often identify their pups within large crèches. 相似文献
107.
Contrasting patterns of X‐chromosome divergence underlie multiple sex‐ratio polymorphisms in stalk‐eyed flies 下载免费PDF全文
Sex‐linked segregation distorters cause offspring sex ratios to differ from equality. Theory predicts that such selfish alleles may either go to fixation and cause extinction, reach a stable polymorphism or initiate an evolutionary arms race with genetic modifiers. The extent to which a sex ratio distorter follows any of these trajectories in nature is poorly known. Here, we used X‐linked sequence and simple tandem repeat data for three sympatric species of stalk‐eyed flies (Teleopsis whitei and two cryptic species of T. dalmanni) to infer the evolution of distorting X chromosomes. By screening large numbers of field and recently laboratory‐bred flies, we found no evidence of males with strongly female‐biased sex ratio phenotypes (SR) in one species but high frequencies of SR males in the other two species. In the two species with SR males, we find contrasting patterns of X‐chromosome evolution. T. dalmanni‐1 shows chromosome‐wide differences between sex‐ratio (XSR) and standard (XST) X chromosomes consistent with a relatively old sex‐ratio haplotype based on evidence including genetic divergence, an inversion polymorphism and reduced recombination among XSR chromosomes relative to XST chromosomes. In contrast, we found no evidence of genetic divergence on the X between males with female‐biased and nonbiased sex ratios in T. whitei. Taken with previous studies that found evidence of genetic suppression of sex ratio distortion in this clade, our results illustrate that sex ratio modification in these flies is undergoing recurrent evolution with diverse genomic consequences. 相似文献
108.
Increased cell size and shortened peptidoglycan interpeptide bridge of NaCl-stressed Staphylococcus aureus and their reversal by glycine betaine. 总被引:3,自引:0,他引:3 下载免费PDF全文
U Vijaranakul M J Nadakavukaren B L de Jonge B J Wilkinson R K Jayaswal 《Journal of bacteriology》1995,177(17):5116-5121
Staphylococcus aureus cells grown in a defined medium under conditions of high ionic stress (2.5 M NaCl) were significantly larger than cells grown under unstressed conditions, even though the cells grew much more slowly under stressed conditions. Analysis of the structure of peptidoglycan from stressed cells showed a shorter interpeptide bridge than in peptidoglycan from unstressed cells. Glycine betaine inclusion in the high-NaCl medium resulted in cells with sizes and interpeptide bridges similar to those of cells grown under unstressed conditions. 相似文献
109.
Monteiro R van Dinther M Bakkers J Wilkinson R Patient R ten Dijke P Mummery C 《Developmental biology》2008,315(1):55-71
Ligands of the transforming growth factor β (TGFβ) superfamily, like Nodal and bone morphogenetic protein (BMP), are pivotal to establish left-right (LR) asymmetry in vertebrates. However, the receptors mediating this process are unknown. Here we identified two new type II receptors for BMPs in zebrafish termed bmpr2a and bmpr2b that induce a classical Smad1/5/8 response to BMP binding. Morpholino-mediated knockdown of bmpr2a and bmpr2b showed that they are required for the establishment of concomitant cardiac and visceral LR asymmetry. Expression of early laterality markers in morphants indicated that bmpr2a and bmpr2b act upstream of pitx2 and the nodal-related southpaw (spaw), which are expressed asymmetrically in the lateral plate mesoderm (LPM), and subsequently regulate lefty2 and bmp4 in the left heart field. We demonstrated that bmpr2a is required for lefty1 expression in the midline at early segmentation while bmpr2a/bmpr2b heteromers mediate left-sided spaw expression in the LPM. We propose a mechanism whereby this differential interpretation of BMP signalling through bmpr2a and bmpr2b is essential for the establishment of LR asymmetry in the zebrafish embryo. 相似文献
110.
Helen van der Plas Graeme Meintjes Charlotte Schutz Rene Goliath Landon Myer Dorothea Baatjie Robert J. Wilkinson Gary Maartens Marc Mendelson 《PloS one》2013,8(2)