全文获取类型
收费全文 | 2834篇 |
免费 | 233篇 |
国内免费 | 1篇 |
出版年
2023年 | 14篇 |
2022年 | 48篇 |
2021年 | 94篇 |
2020年 | 49篇 |
2019年 | 55篇 |
2018年 | 67篇 |
2017年 | 68篇 |
2016年 | 144篇 |
2015年 | 228篇 |
2014年 | 213篇 |
2013年 | 224篇 |
2012年 | 334篇 |
2011年 | 211篇 |
2010年 | 132篇 |
2009年 | 115篇 |
2008年 | 136篇 |
2007年 | 136篇 |
2006年 | 125篇 |
2005年 | 104篇 |
2004年 | 87篇 |
2003年 | 79篇 |
2002年 | 58篇 |
2001年 | 33篇 |
2000年 | 23篇 |
1999年 | 39篇 |
1998年 | 26篇 |
1997年 | 12篇 |
1996年 | 17篇 |
1995年 | 22篇 |
1994年 | 9篇 |
1993年 | 10篇 |
1992年 | 20篇 |
1991年 | 14篇 |
1990年 | 4篇 |
1989年 | 4篇 |
1988年 | 5篇 |
1987年 | 7篇 |
1986年 | 9篇 |
1985年 | 10篇 |
1984年 | 7篇 |
1983年 | 10篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1979年 | 5篇 |
1978年 | 4篇 |
1977年 | 9篇 |
1976年 | 5篇 |
1971年 | 3篇 |
1968年 | 3篇 |
1960年 | 3篇 |
排序方式: 共有3068条查询结果,搜索用时 15 毫秒
121.
Le Zhang Sun-Ok Fernandez-Kim Tina L. Beckett Dana M. Niedowicz Katharina Kohler Kalavathi Dasuri Annadora J. Bruce-Keller M. Paul Murphy Jeffrey N. Keller 《生物化学与生物物理学报:疾病的分子基础》2019,1865(9):2157-2167
Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, while obesity is a major global public health problem associated with the metabolic disorder type 2 diabetes mellitus (T2DM). Chronic obesity and T2DM have been identified as invariant risk factors for dementia and late-onset AD, while their impacts on the occurrence and development of AD remain unclear. As shown in our previous study, the diabetic mutation (db, Leprdb/db) induces mixed or vascular dementia in mature to middle-aged APPΔNL/ΔNL x PS1P264L/P264L knock-in mice (db/AD). In the present study, the impacts of the db mutation on young AD mice at 10 weeks of age were evaluated. The db mutation not only conferred young AD mice with severe obesity, impaired glucose regulation and activated mammalian target of rapamycin (mTOR) signaling pathway in the mouse cortex, but lead to a surprising improvement in memory. At this young age, mice also had decreased cerebral Aβ content, which we have not observed at older ages. This was unlikely to be related to altered Aβ synthesis, as both β- and γ-secretase were unchanged. The db mutation also reduced the cortical IL-1β mRNA level and IBA1 protein level in young AD mice, with no significant effect on the activation of microglia and astrocytes. We conclude that the db mutation could transitorily improve the memory of young AD mice, a finding that may be partially explained by the relatively improved glucose homeostasis in the brains of db/AD mice compared to their counterpart AD mice, suggesting that glucose regulation could be a strategy for prevention and treatment of neurodegenerative diseases like AD. 相似文献
122.
Andreas Kahrer Anna Moyses Lisa Hochfellner Wolfgang Tiefenbrunner Alois Egartner Teresa Miglbauer Katharina Müllner Lara Reinbacher Christina Pilz Julia Votzi Helfried Scheifinger 《Journal of Applied Entomology》2019,143(10):1143-1153
In a series of laboratory experiments, acclimated pupae of Tuta absoluta were exposed to various constant low temperatures in order to estimate their maximum survival times (Kaplan–Meier, Lt99.99). A Weibull function was fitted to the data points, describing maximum survival time as a function of temperature. In another experiment at ?6°C, the progress of mortality increasing with exposure time was identified. These values were fitted by a sigmoidal function converging asymptotically to 100% mortality for very long exposure times. Analysing mortality data from the maximum survival experiment by a generalized linear model showed a significant common slope parameter (p < .001) that reveals parallelism of the survival curves at each temperature if a log time axis is used. These curves appear stretched (time scaled) if plotted with a nonlogarithmic time axis. By combining these mathematical relations, it was possible to calculate a species‐specific ‘mortality surface’ which exhibits mortalities, depending on temperature and duration of exposure. In order to accumulate hourly mortalities for courses of varying temperatures, an algorithm was developed which yields mortality values from that surface taking into account the attained mortality level. In validation experiments, recorded mortalities were compared against modelled mortalities. Prediction of mortality was partially supported by the model, but pupae experiencing intensely fluctuating temperatures showed decreased mortality, probably caused by rapid cold hardening during exposure. Despite this observation, mortality data converged to distinct levels very close to 100% depending on the intensity of temperature fluctuations that were characteristic for different types of experiments. The highest mortality limit occurred at intensely fluctuating temperatures in laboratory experiments. This constituted a benchmark that was not reached under various field conditions. Thus, it was possible to identify temperature limits for the extinction of field populations of Tuta absoluta pupae. 相似文献
123.
124.
Soumyaparna Das Valerie Popp Michael Power Kathrin Groeneveld Jie Yan Christian Melle Luke Rogerson Marlly Achury Frank Schwede Torsten Strasser Thomas Euler Franois Paquet-Durand Vasilica Nache 《Cell death & disease》2022,13(1)
Hereditary degeneration of photoreceptors has been linked to over-activation of Ca2+-permeable channels, excessive Ca2+-influx, and downstream activation of Ca2+-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca2+-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca2+-influx, most probably by blocking the pore of Ca2+-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca2+ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca2+-independent degenerative mechanisms.Subject terms: Cell death in the nervous system, Ion channels in the nervous system, Molecular neuroscience 相似文献
125.
126.
Markus Albert Anna K. Jehle Martin Lipschis Katharina Mueller Yi Zeng Georg Felix 《European journal of cell biology》2010,89(2-3):200-207
In this review we focus on pattern recognition receptors in plants that detect extracellular signals indicative for pathogen attack and injury. We start out with a discussion on FLS2, which binds and responds to bacterial flagellin, and then concentrate on ligand–receptor interactions as initial steps in the molecular receptor activation process. Comparison with other receptor kinases, whether involved in plant immunity or regulation of other cellular programs, might indicate common principles of receptor activation. 相似文献
127.
Heterotetrameric (alphabetagammadelta) sarcosine oxidase from Corynebacterium sp. P-1 (cTSOX) contains noncovalently bound FAD and NAD(+) and covalently bound FMN, attached to beta(His173). The beta(His173Asn) mutant is expressed as a catalytically inactive, labile heterotetramer. The beta and delta subunits are lost during mutant enzyme purification, which yields a stable alphagamma complex. Addition of stabilizing agents prevents loss of the delta but not the beta subunit. The covalent flavin link is clearly a critical structural element and essential for TSOX activity or preventing FMN loss. The alpha subunit was expressed by itself and purified by affinity chromatography. The alpha and beta subunits each contain an NH(2)-terminal ADP-binding motif that could serve as part of the binding site for NAD(+) or FAD. The alpha subunit and the alphagamma complex were each found to contain 1 mol of NAD(+) but no FAD. Since NAD(+) binds to alpha, FAD probably binds to beta. The latter could not be directly demonstrated since it was not possible to express beta by itself. However, FAD in TSOX from Pseudomonas maltophilia (pTSOX) exhibits properties similar to those observed for the covalently bound FAD in monomeric sarcosine oxidase and N-methyltryptophan oxidase, enzymes that exhibit sequence homology with beta. A highly conserved glycine in the ADP-binding motif of the alpha(Gly139) or beta(Gly30) subunit was mutated in an attempt to generate NAD(+)- or FAD-free cTSOX, respectively. The alpha(Gly139Ala) mutant is expressed only at low temperature (t(optimum) = 15 degrees C), but the purified enzyme exhibited properties indistinguishable from the wild-type enzyme. The much larger barrier to NAD(+) binding in the case of the alpha(Gly139Val) mutant could not be overcome even by growth at 3 degrees C, suggesting that NAD(+) binding is required for TSOX expression. The beta(Gly30Ala) mutant exhibited subunit expression levels similar to those of the wild-type enzyme, but the mutation blocked subunit assembly and covalent attachment of FMN, suggesting that both processes require a conformational change in beta that is induced upon FAD binding. About half of the covalent FMN in recombinant preparations of cTSOX or pTSOX is present as a reversible covalent 4a-adduct with a cysteine residue. Adduct formation is not prevented by mutating any of the three cysteine residues in the beta subunit of cTSOX to Ser or Ala. Since FMN is attached via its 8-methyl group to the beta subunit, the FMN ring must be located at the interface between beta and another subunit that contains the reactive cysteine residue. 相似文献
128.
Strasser V Fasching D Hauser C Mayer H Bock HH Hiesberger T Herz J Weeber EJ Sweatt JD Pramatarova A Howell B Schneider WJ Nimpf J 《Molecular and cellular biology》2004,24(3):1378-1386
The Reelin signaling cascade plays a crucial role in the correct positioning of neurons during embryonic brain development. Reelin binding to apolipoprotein E receptor 2 (ApoER2) and very-low-density-lipoprotein receptor (VLDLR) leads to phosphorylation of disabled 1 (Dab1), an adaptor protein which associates with the intracellular domains of both receptors. Coreceptors for Reelin have been postulated to be necessary for Dab1 phosphorylation. We show that bivalent agents specifically binding to ApoER2 or VLDLR are sufficient to mimic the Reelin signal. These agents induce Dab1 phosphorylation, activate members of the Src family of nonreceptor tyrosine kinases, modulate protein kinase B/Akt phosphorylation, and increase long-term potentiation in hippocampal slices. Induced dimerization of Dab1 in HEK293 cells leads to its phosphorylation even in the absence of Reelin receptors. The mechanism for and the sites of these phosphorylations are identical to those effected by Reelin in primary neurons. These results suggest that binding of Reelin, which exists as a homodimer in vivo, to ApoER2 and VLDLR induces clustering of ApoER2 and VLDLR. As a consequence, Dab1 becomes dimerized or oligomerized on the cytosolic side of the plasma membrane, constituting the active substrate for the kinase; this process seems to be sufficient to transmit the signal and does not appear to require any coreceptor. 相似文献
129.
Proapoptotic BH3-only Bcl-2 family member Bik/Blk/Nbk is expressed in hemopoietic and endothelial cells but is redundant for their programmed death
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Coultas L Bouillet P Stanley EG Brodnicki TC Adams JM Strasser A 《Molecular and cellular biology》2004,24(4):1570-1581
The BH3-only members of the Bcl-2 protein family are essential for initiation of programmed cell death and stress-induced apoptosis. We have determined the expression pattern in mice of the BH3-only protein Bik, also called Blk or Nbk, and examined its physiological function by gene targeting. We found that Bik is expressed widely in the hematopoietic compartment and in endothelial cells of the venous but not arterial lineages. Nevertheless, its loss did not increase the numbers of such cells in mice or protect hematopoietic cells in vitro from apoptosis induced by cytokine withdrawal or diverse other cytotoxic stimuli. Moreover, whereas loss of the BH3-only protein Bim rescued mice lacking the prosurvival protein Bcl-2 from fatal polycystic kidney disease and lymphopenia, loss of Bik did not. These results indicate that any function of Bik in programmed cell death and stress-induced apoptosis must overlap that of other BH3-only proteins. 相似文献
130.
Conserved tertiary base pairing ensures proper RNA folding and efficient assembly of the signal recognition particle Alu domain 总被引:1,自引:1,他引:0
下载免费PDF全文
![点击此处可从《Nucleic acids research》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Huck L Scherrer A Terzi L Johnson AE Bernstein HD Cusack S Weichenrieder O Strub K 《Nucleic acids research》2004,32(16):4915-4924
Proper folding of the RNA is an essential step in the assembly of functional ribonucleoprotein complexes. We examined the role of conserved base pairs formed between two distant loops in the Alu portion of the mammalian signal recognition particle RNA (SRP RNA) in SRP assembly and functions. Mutations disrupting base pairing interfere with folding of the Alu portion of the SRP RNA as monitored by probing the RNA structure and the binding of the protein SRP9/14. Complementary mutations rescue the defect establishing a role of the tertiary loop–loop interaction in RNA folding. The same mutations in the Alu domain have no major effect on binding of proteins to the S domain suggesting that the S domain can fold independently. Once assembled into a complete SRP, even particles that contain mutant RNA are active in arresting nascent chain elongation and translocation into microsomes, and, therefore, tertiary base pairing does not appear to be essential for these activities. Our results suggest a model in which the loop–loop interaction and binding of the protein SRP9/14 play an important role in the early steps of SRP RNA folding and assembly. 相似文献