全文获取类型
收费全文 | 5384篇 |
免费 | 387篇 |
国内免费 | 1篇 |
出版年
2023年 | 33篇 |
2022年 | 50篇 |
2021年 | 129篇 |
2020年 | 83篇 |
2019年 | 107篇 |
2018年 | 131篇 |
2017年 | 127篇 |
2016年 | 184篇 |
2015年 | 279篇 |
2014年 | 278篇 |
2013年 | 323篇 |
2012年 | 469篇 |
2011年 | 388篇 |
2010年 | 247篇 |
2009年 | 234篇 |
2008年 | 374篇 |
2007年 | 270篇 |
2006年 | 309篇 |
2005年 | 234篇 |
2004年 | 243篇 |
2003年 | 205篇 |
2002年 | 194篇 |
2001年 | 72篇 |
2000年 | 56篇 |
1999年 | 53篇 |
1998年 | 60篇 |
1997年 | 40篇 |
1996年 | 27篇 |
1995年 | 45篇 |
1994年 | 33篇 |
1993年 | 26篇 |
1992年 | 35篇 |
1991年 | 30篇 |
1990年 | 25篇 |
1989年 | 28篇 |
1988年 | 24篇 |
1987年 | 24篇 |
1986年 | 22篇 |
1985年 | 25篇 |
1984年 | 17篇 |
1983年 | 17篇 |
1982年 | 18篇 |
1981年 | 27篇 |
1980年 | 22篇 |
1979年 | 11篇 |
1978年 | 20篇 |
1977年 | 19篇 |
1976年 | 13篇 |
1974年 | 15篇 |
1973年 | 12篇 |
排序方式: 共有5772条查询结果,搜索用时 15 毫秒
161.
Several neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases as well as nonneuropathic diseases such as type II diabetes and atrial amyloidosis are associated with aggregation of amyloid polypeptides into fibrillar structures, or plaques. In this study, we use molecular dynamics simulations to test the stability and orientation of membrane-embedded aggregates of the human islet amyloid polypeptide (hIAPP) implicated in type II diabetes. We find that in both monolayers and bilayers of dipalmitoylphosphatidylglycerol (DPPG) hIAPP trimers and tetramers remain inside the membranes and preserve their β-sheet secondary structure. Lipid bilayer-inserted hIAPP trimers and tetramers orient inside DPPG at 60° relative to the membrane/water interface and lead to water permeation and Na+ intrusion, consistent with ion-toxicity in islet β-cells. In particular, hIAPP trimers form a water-filled β-sandwich that induce water permeability comparable with channel-forming proteins, such as aquaporins and gramicidin-A. The predicted disruptive orientation is consistent with the amphiphilic properties of the hIAPP aggregates and could be probed by chiral sum frequency generation (SFG) spectroscopy, as predicted by the simulated SFG spectra. 相似文献
162.
John A. Martignetti Lifeng Tian Dong Li Maria Celeste M. Ramirez Olga Camacho-Vanegas Sandra Catalina Camacho Yiran Guo Dina J. Zand Audrey M. Bernstein Sandra K. Masur Cecilia E. Kim Frederick G. Otieno Cuiping Hou Nada Abdel-Magid Ben Tweddale Denise Metry Jean-Christophe Fournet Eniko Papp Elizabeth W. McPherson Carrie Zabel Guy Vaksmann Cyril Morisot Brendan Keating Patrick M. Sleiman Jeffrey A. Cleveland David B. Everman Elaine Zackai Hakon Hakonarson 《American journal of human genetics》2013
163.
Naiara Akizu Nuri?M. Shembesh Tawfeg Ben-Omran Laila Bastaki Asma Al-Tawari Maha?S. Zaki Roshan Koul Emily Spencer Rasim?Ozgur Rosti Eric Scott Elizabeth Nickerson Stacey Gabriel Gilberto da?Gente Jiang Li Matthew?A. Deardorff Laura?K. Conlin Margaret?A. Horton Elaine?H. Zackai Elliott?H. Sherr Joseph?G. Gleeson 《American journal of human genetics》2013,92(3):392-400
The corpus callosum is the principal cerebral commissure connecting the right and left hemispheres. The development of the corpus callosum is under tight genetic control, as demonstrated by abnormalities in its development in more than 1,000 genetic syndromes. We recruited more than 25 families in which members affected with corpus callosum hypoplasia (CCH) lacked syndromic features and had consanguineous parents, suggesting recessive causes. Exome sequence analysis identified C12orf57 mutations at the initiator methionine codon in four different families. C12orf57 is ubiquitously expressed and encodes a poorly annotated 126 amino acid protein of unknown function. This protein is without significant paralogs but has been tightly conserved across evolution. Our data suggest that this conserved gene is required for development of the human corpus callosum. 相似文献
164.
Cynthia Maria De Lyra Neves Carlos Alfredo Lopes De Carvalho Cerilene Santiago Machado Fernanda Silva Das Mercês Sousa 《Grana》2013,52(4):302-308
Pollen analysis of the larval food supply is an important tool for identifying the plants that provide the floral resources used by bees. The present study documents the pollen sources consumed by larvae of the solitary bee Tetrapedia diversipes in a tropical agroecosystem. A total of 60 pollen types were recorded with three families being the most important. Euphorbiaceae (60.5%), Malpighiaceae (16.8%) and Asteraceae (12.2%) pollen had the greatest representation in the samples examined. The pollen of Dalechampia dioscoreifolia predominated in the diet of the larvae of T. diversipes (RF?=?56.35%) and indicates the importance of this plant in maintaining populations of this solitary bee. 相似文献
165.
Anita Kulukian Elaine Fuchs 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2013,368(1629)
Asymmetric cell divisions (ACDs) result in two unequal daughter cells and are a hallmark of stem cells. ACDs can be achieved either by asymmetric partitioning of proteins and organelles or by asymmetric cell fate acquisition due to the microenvironment in which the daughters are placed. Increasing evidence suggests that in the mammalian epidermis, both of these processes occur. During embryonic epidermal development, changes occur in the orientation of the mitotic spindle in relation to the underlying basement membrane. These changes are guided by conserved molecular machinery that is operative in lower eukaryotes and dictates asymmetric partitioning of proteins during cell divisions. That said, the shift in spindle alignment also determines whether a division will be parallel or perpendicular to the basement membrane, and this in turn provides a differential microenvironment for the resulting daughter cells. Here, we review how oriented divisions of progenitors contribute to the development and stratification of the epidermis. 相似文献
166.
Ligiane R. Gouvea Darliane A. Martins Denise da Gama Jean Batista Maria de Nazaré C. Soeiro Sonia R. W. Louro Paulo J. S. Barbeira Letícia R. Teixeira 《Biometals》2013,26(5):813-825
Zn(II) complexes with norfloxacin (NOR) in the absence or in the presence of 1,10-phenanthroline (phen) were obtained and characterized. In both complexes, the ligand NOR was coordinated through a keto and a carboxyl oxygen. Tetrahedral and octahedral geometries were proposed for [ZnCl2(NOR)]·H2O (1) and [ZnCl2(NOR)(phen)]·2H2O (2), respectively. Since the biological activity of the chemicals depends on the pH value, pH titrations of the Zn(II) complexes were performed. UV spectroscopic studies of the interaction of the complexes with calf-thymus DNA (CT DNA) have suggested that they can bind to CT DNA with moderate affinity in an intercalative mode. The interactions between the Zn(II) complexes and bovine serum albumin (BSA) were investigated by steady-state and time-resolved fluorescence spectroscopy at pH 7.4. The experimental data showed static quenching of BSA fluorescence, indicating that both complexes bind to BSA. A modified Stern–Volmer plot for the quenching by complex 2 demonstrated preferential binding near one of the two tryptophan residues of BSA. The binding constants obtained (K b ) showed that BSA had a two orders of magnitude higher affinity for complex 2 than for 1. The results also showed that the affinity of both complexes for BSA was much higher than for DNA. This preferential interaction with protein sites could be important to their biological mechanisms of action. The analysis in vitro of the Zn(II) complexes and corresponding ligand were assayed against Trypanosoma cruzi, the causative agent of Chagas disease and the data showed that complex 2 was the most active against bloodstream trypomastigotes. 相似文献
167.
Bridgett M. vonHoldt John P. Pollinger Dent A. Earl Heidi G. Parker Elaine A. Ostrander Robert K. Wayne 《Mammalian genome》2013,24(1-2):80-88
The ability to detect recent hybridization between dogs and wolves is important for conservation and legal actions, which often require accurate and rapid resolution of ancestry. The availability of a genetic test for dog–wolf hybrids would greatly support federal and legal enforcement efforts, particularly when the individual in question lacks prior ancestry information. We have developed a panel of 100 unlinked ancestry-informative SNP markers that can detect mixed ancestry within up to four generations of dog–wolf hybridization based on simulations of seven genealogical classes constructed following the rules of Mendelian inheritance. We establish 95 % confidence regions around the spatial clustering of each genealogical class using a tertiary plot of allele dosage and heterozygosity. The first- and second-backcrossed-generation hybrids were the most distinct from parental populations, with >90 % correctly assigned to genealogical class. In this article we provide a tool kit with population-level statistical quantification that can detect recent dog–wolf hybridization using a panel of dog–wolf ancestry-informative SNPs with divergent allele frequency distributions. 相似文献
168.
Andréa Helena Vidal André Mariano Batista Ellen Cordeiro Bento da Silva Wilton Arruda Gomes Marina Arruda Pelinca Sildivane Valcácia Silva Maria Madalena Pessoa Guerra 《Small Ruminant Research》2013,109(1):47-51
The aim of this study was to evaluate the effect of different concentrations of soybean lecithin (SL) in extenders for sperm goat cryopreservation. Sexually mature male Saanen goats (n = 4) were used, and the ejaculates were obtained using an artificial vagina method. The semen samples were pooled and diluted in a skim milk-based extender (control group; CG) or Tris extender supplemented with SL at different concentrations (G1 = 0.04%, SL G2 = 0.08% SL and G3 = 0.16%) for a final concentration of 240 × 106 spermatozoa/mL. The semen samples were packed in straws (0.25 mL), frozen using an automated system and stored in liquid nitrogen (?196 °C). After thawing (37 °C/30 s), the samples were evaluated for sperm quality parameters, including sperm motility, membrane integrity, acrosome integrity and mitochondrial activity. No significant difference was observed among the experimental and control groups for all of the parameters (P > 0.05). However, even though the control group presented a significantly lower mitochondrial membrane potential compared to fresh semen (P < 0.05), the same did not occur for the extender supplemented with soybean lecithin, that is, it did not differ from fresh sperm (P > 0.05). The extender containing soybean lecithin at different concentrations preserved the sperm quality parameters in a manner similar to the conventional skim milk-based extender. Thus, it is concluded that an extender containing soybean lecithin as the lipoprotein source can be used for freezing goat semen. 相似文献
169.
Transthyretin (TTR) is a plasma and cerebrospinal fluid (CSF)-circulating homotetrameric protein. More than 100 point mutations have been identified in the TTR gene and several are related with amyloid diseases. Here we focused our attention in the TTR L12P variant associated with severe peripheral neuropathy and leptomeningeal amyloidosis. By using different cell lines derived from tissues specialized on TTR synthesis, such as the hepatocyte and the choroid plexus expressing WT, V30M, or L12P TTR variants we analyzed secretion, intracellular aggregation and degradation patterns. Also, we used liver-specific AAV gene transfer to assess expression of the L12P variant in vivo. We found the following: (i) decreased secretion with intracellular aggregation of TTR L12P in hepatoma cells relative to WT and V30M variant; this differential property of TTR L12P variant was also observed in mice injected with L12P AAV vector; (ii) differential N-glycosylation pattern of L12P variant in hepatoma cell lysates, conditioned media and mouse sera, which might represent an escape mechanism from ERAD degradation; (iii) intracellular L12P TTR aggregates mainly localized to lysosomes in cultured cells and liver; and (iv) none of the above findings were present in choroid plexus derived cells, suggesting particular secretion/quality control mechanisms that might contribute to leptomeningeal amyloidosis associated with the L12P variant. These observations open new avenues for the treatment of TTR associated leptomeningeal amyloidosis. 相似文献
170.