全文获取类型
收费全文 | 1494篇 |
免费 | 131篇 |
国内免费 | 27篇 |
出版年
2023年 | 15篇 |
2022年 | 12篇 |
2021年 | 26篇 |
2020年 | 26篇 |
2019年 | 30篇 |
2018年 | 62篇 |
2017年 | 42篇 |
2016年 | 46篇 |
2015年 | 44篇 |
2014年 | 87篇 |
2013年 | 138篇 |
2012年 | 59篇 |
2011年 | 75篇 |
2010年 | 55篇 |
2009年 | 73篇 |
2008年 | 74篇 |
2007年 | 86篇 |
2006年 | 57篇 |
2005年 | 84篇 |
2004年 | 69篇 |
2003年 | 65篇 |
2002年 | 54篇 |
2001年 | 42篇 |
2000年 | 35篇 |
1999年 | 32篇 |
1998年 | 35篇 |
1997年 | 20篇 |
1996年 | 33篇 |
1995年 | 30篇 |
1994年 | 18篇 |
1993年 | 15篇 |
1992年 | 14篇 |
1991年 | 15篇 |
1990年 | 10篇 |
1989年 | 6篇 |
1988年 | 5篇 |
1987年 | 4篇 |
1986年 | 5篇 |
1985年 | 5篇 |
1984年 | 13篇 |
1983年 | 7篇 |
1982年 | 4篇 |
1981年 | 5篇 |
1980年 | 4篇 |
1979年 | 7篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1975年 | 1篇 |
1973年 | 1篇 |
排序方式: 共有1652条查询结果,搜索用时 31 毫秒
61.
Inesse Ben-Abdallah-Bouhjar Soumya Mougou-Zerelli Hanene Hannachi Hela Ben-Khelifa Najla Soyah Audrey Labalme Damien Sanlaville Hatem Elghezal Ali Saad 《Gene》2013
Partial duplication of 11q is related to several malformations like growth retardation, intellectual disability, hypoplasia of corpus callosum, short nose, palate defects, cardiac, urinary tract abnormalities and neural tube defects. We have studied the clinical and molecular characteristics of a patient with severe intellectual disabilities, dysmorphic features, congenital inguinal hernia and congenital cerebral malformation which is referred to as cytogenetic exploration. We have used FISH and array CGH analysis for a better understanding of the double chromosomic aberration involving a 7p microdeletion along with a partial duplication of 11q due to adjacent segregation of a paternal reciprocal translocation t(7;11)(p22;q21) revealed after banding analysis. The patient's karyotype formula was: 46,XY,der(7)t(7;11)(p22;q21)pat. FISH study confirmed these rearrangement and array CGH technique showed precisely the loss of at least 140 Kb on chromosome7p22.3pter and 33.4 Mb on chromosome11q22.1q25. Dysmorphic features, severe intellectual disability and brain malformations could result from the 11q22.1q25 trisomy. Our study provides an additional case for better understanding and delineating the partial duplication 11q. 相似文献
62.
The cysteine and glycine-rich protein 1 and 2 genes (CSRP1 and CSRP2) are an effective growth factor in promoting skeletal muscle growth in vitro and vivo. However, in cattle, the information on the CSRP1 and CSRP2 genes is very limited. The aim of this study was to examine the association of the CSRP1 and CSRP2 variants with growth and carcass traits in cattle breeds. Three single nucleotide variants (SNVs) were identified within the bovine CSRP1 gene, whereas CSRP2 gene has not detected any SNVs, using DNA pooled sequencing, PCR-RFLP, and forced PCR-RFLP methods. These SNVs include g. 801T>C (Intron 2), g. 46T>C (Exon 3) and g. 99C>G (Intron 3). Besides, we also investigated haplotype frequencies and linkage disequilibrium (LD) coefficients for three SNVs in all study populations. LD and haplotype structure of CSRP1 were different between breeds. The result of haplotype analysis demonstrated eight haplotype present in QC (Qinchuan) and one haplotype in CH (Chinese Holstein). Only haplotype 1 (TTC), shared by all two populations, comprised 10.74% and 100.00%, of all haplotypes observed in QC and CH, respectively. Haplotype 5 (CTC) had the highest haplotype frequencies in QC (30.98%) and haplotype 1 had the highest haplotype frequencies in CH (100.00%). The statistical analyses indicated that one single SNV and 19 combined haplotypes were significantly or highly significantly associated with growth and carcass traits in the QC cattle population (P < 0.05 or P < 0.01). Quantitative real-time PCR (qRT-PCR) analyses showed that the bovine CSRP1 and CSRP2 genes were widely expressed in many tissues. The results of this study suggest that the CSRP1 gene possibly is a strong candidate gene that affects growth and carcass traits in the Chinese beef cattle breeding. 相似文献
63.
64.
Luz Ma. González-Huerta Olga Messina-Baas Héctor Urueta Jaime Toral-López Sergio A. Cuevas-Covarrubias 《Gene》2013
Purpose
To describe at molecular level a family with pulverulent congenital cataract associated with a CRYGC gene mutation.Methods
One family with several affected members with pulverulent congenital cataract and 230 healthy controls were examined. Genomic DNA from leukocytes was isolated to analyze the CRYGA-D cluster, CX46, CX50 and MIP genes through high-resolution melting curve and DNA sequencing.Results
DNA sequencing in the affected members revealed the c.143G>A mutation (p.R48H) in exon 2 of the CRYGC gene; 230 healthy controls and ten healthy relatives were also analyzed and none of them showed the c.143G>A mutation. No other polymorphisms or mutations were found to be present.Conclusion
In the present study, we described a family with pulverulent congenital cataract that segregated the c.143G>A mutation (p.R48H) in the CRYGC gene. A few mutations have been described in the CRYGC gene in autosomal dominant cataract, none of them with pulverulent cataract making clear the clinical heterogeneity of congenital cataract. This mutation has been associated with the phenotype of congenital cataract but also is considered an SNP in the NCBI data base. Our data and previous report suggest that p.R48H could be a disease-causing mutation and not an SNP. 相似文献65.
Cystatins are extensively studied cysteine protease inhibitors, found in wide range of organisms with highly conserved structural folds. S-type of cystatins is well known for their abundance in saliva, high selectivity and poorer activity towards host cysteine proteases in comparison to their immediate ancestor cystatin C. Despite more than 90% sequence similarity, the members of this group show highly dissimilar binding affinity towards papain. Cystatin M/E is a potent inhibitor of legumain and papain like cysteine proteases and recognized for its involvement in skin barrier formation and potential role as a tumor suppressor gene. However, the structures of these proteins and their complexes with papain or legumain are still unknown. In the present study, we have employed computational methods to get insight into the interactions between papain and cystatins. Three-dimensional structures of the cystatins are generated by homology modelling, refined with molecular dynamics simulation, validated through numerous web servers and finally complexed with papain using ZDOCK algorithm in Discovery Studio. A high degree of shape complementarity is observed within the complexes, stabilized by numerous hydrogen bonds (HB) and hydrophobic interactions. Using interaction energy, HB and solvent accessible surface area analyses, we have identified a series of key residues that may be involved in papain–cystatin interaction. Differential approaches of cystatins towards papain are also noticed which are possibly responsible for diverse inhibitory activity within the group. These findings will improve our understanding of fundamental inhibitory mechanisms of cystatin and provide clues for further research. 相似文献
66.
An extracellular low temperature-active alkaline stable peptidase from Acinetobacter sp. MN 12 was purified to homogeneity with a purification fold of 9.8. The enzyme exhibited specific activity of 6,540 U/mg protein, with an apparent molecular weight of 35 kDa. The purified enzyme was active over broad range of temperature from 4 to 60 °C with optimum activity at 40 °C. The enzyme retained more than 75 % of activity over a broad range of pH (7.0–11.0) with optimum activity at pH 9.0. The purified peptidase was strongly inhibited by phenylmethylsulfonyl fluoride, giving an indication of serine type. The K m and V max for casein and gelatin were 0.3529, 2.03 mg/ml and 294.11, 384.61 μg/ml/min respectively. The peptidase was compatible with surfactants, oxidizing agents and commercial detergents, and effectively removed dried blood stains on cotton fabrics at low temperature ranging from 15 to 35 °C. 相似文献
67.
Alleviation of chromium toxicity in rice seedlings by applying exogenous glutathione 总被引:1,自引:0,他引:1
Boyin Qiu Fanrong Zeng Shengguan Cai Xiaojian Wu Shamsi Imran Haider Feibo Wu Guoping Zhang 《Journal of plant physiology》2013
The effect of exogenous reduced glutathione (GSH) on alleviation of hexavalent chromium (Cr6+) toxicity to rice seedlings and its physiological mechanisms were comprehensively investigated in a series of experiments. Our results showed that growth and nutrient uptake of rice seedlings were dramatically reduced under 100 μM Cr6+ stress, and the reduction was significantly alleviated by exogenous GSH. Cr6+ stress also reduced cell viability in root tips and damaged ultrastructure of both chloroplasts and root cells, while the addition of GSH alleviates those negative effects. Cr-induced toxicity and GSH-caused Cr alleviation differed significantly between Cr-tolerant Line 117 (L117) and Cr-sensitive Line 41 (L41). Under Cr6+ stress, cystine content was increased and GSH content was decreased in rice plants, exogenous GSH, however, mitigated the Cr-toxicity by reversing the Cr-induced changes of the two compounds. The types of Cr-induced secretion of organic acids varied between the genotypes, where reduction in the contents of acetic and lactic acids and tartaric and malic acids were observed in L117 and L41, respectively. The addition of GSH alleviated the reduction of secretion of these organic acids. Exogenous GSH also altered the forms of Cr ions in the rhizosphere and the fraction of distribution at subcellular level in both shoots and roots. It may be concluded that the alleviation of Cr6+ toxicity by exogenous GSH is directly attributed to its regulation on forms of Cr ions in rhizosphere and their distribution at subcellular levels. 相似文献
68.
Svetlana Sharoyan Alvard Antonyan Sona Mardanyan Hayk Harutyunyan Naira Movsisyan Narek Hovnanyan Karlen Hovnanyan 《Neurochemistry international》2013
The aggregates of amyloid beta peptides (Aβs) are regarded as one of the main pathological hallmarks of Alzheimer’s disease (AD). An imbalance between the rates of synthesis and clearance of Aβs is considered to be a possible cause for the onset of AD. Dipeptidyl peptidases II and IV (DPPII and DPPIV) are serine proteases removing N-terminal dipeptides from polypeptides and proteins with proline or alanine on the penultimate position. Alanine is an N-terminal penultimate residue in Аβs, and we presumed that DPPII and DPPIV could cleave them. The results of present in vitro research demonstrate for the first time the ability of DPPIV to truncate the commercial Aβ40 and Aβ42 peptides, to hinder the fibril formation by them and to participate in the disaggregation of preformed fibrils of these peptides. The increase of absorbance at 334 nm due to complex formation between primary amines with o-phtalaldehyde was used to show cleaving of Aβ40 and Aβ42. The time-dependent increase of the quantity of primary amines during incubation of peptides in the presence of DPPIV suggested their truncation by DPPIV, but not by DPPII. The parameters of the enzymatic breakdown by DPPIV were determined for Aβ40 (Km = 37.5 μM, kcat/Km = 1.7 × 103 M−1sec−1) and Aβ42 (Km = 138.4 μM, kcat/Km = 1.90 × 102 M−1sec−1). The aggregation-disaggregation of peptides was controlled by visualization on transmission electron microscope and by Thioflavin-T fluorescence on spectrofluorimeter and fluorescent microscope. DPPIV hindered the peptide aggregation/fibrillation during 3-4 days incubation in 20 mM phosphate buffer, pH 7.4, 37 °C by 50–80%. Ovalbumin, BSA and DPPII did not show this effect. In the presence of DPPIV, the preformed fibrils were disaggregated by 30–40%. Conclusion: for the first time it was shown that the Aβ40 and Aβ42 are substrates of DPPIV. DPPIV prohibits the fibrillation of peptides and promotes disaggregation of their preformed aggregates. 相似文献
69.
Presenilin is the catalytic component of the γ-secretase complex, a membrane-embedded aspartyl protease that plays a central role in biology and in the pathogenesis of Alzheimer’s disease. Upon assembly with its three protein cofactors (nicastrin, Aph-1 and Pen-2), presenilin undergoes autoproteolysis into two subunits, each of which contributes one of the catalytic aspartates to the active site. A family of presenilin homologs, including signal peptide peptidase, possess proteolytic activity without the need for other protein factors, and these simpler intramembane aspartyl proteases have given insight into the action of presenilin within the γ-secretase complex. Cellular and molecular studies support a nine-transmembrane topology for presenilins and their homologs, and small-molecule inhibitors and cysteine scanning with crosslinking have suggested certain presenilin residues and regions that contribute to substrate recognition and handling. Identification of partial complexes has also offered clues to protein–protein interactions within the γ-secretase complex. Biophysical methods have allowed 3D views of the γ-secretase complex and presenilins. Most recently, the crystal structure of a microbial presenilin homolog has confirmed a nine-transmembrane topology and intramembranous location and proximity of the two conserved and essential aspartates. The crystal structure also provides a platform for the formulation of specific hypotheses regarding substrate interaction and catalysis as well as the pathogenic mechanism of Alzheimer-causing presenilin mutations. This article is part of a Special Issue entitled: Intramembrane Proteases. 相似文献
70.
Intramembrane proteolysis is widely conserved throughout different forms of life, with three major types of proteases being known for their ability to cleave peptide bonds directly within the transmembrane domains of their substrates. Although intramembrane proteases have been extensively studied in humans and model organisms, they have only more recently been investigated in protozoan parasites, where they turn out to play important and sometimes unexpected roles. Signal peptide peptidases are involved in endoplasmic reticulum (ER) quality control and signal peptide degradation from exported proteins. Recent studies suggest that repurposing inhibitors developed for blocking presenilins may be useful for inhibiting the growth of Plasmodium, and possibly other protozoan parasites, by blocking signal peptide peptidases. Rhomboid proteases, originally described in the fly, are also widespread in parasites, and are especially expanded in apicomplexans. Their study in parasites has revealed novel roles that expand our understanding of how these proteases function. Within this diverse group of parasites, rhomboid proteases contribute to processing of adhesins involved in attachment, invasion, intracellular replication, phagocytosis, and immune evasion, placing them at the vertex of host–parasite interactions. This article is part of a Special Issue entitled: Intramembrane Proteases. 相似文献