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991.
Iero M Squarcina P Romero P Guillaume P Scarselli E Cerino R Carrabba M Toutirais O Parmiani G Rivoltini L 《Cancer immunology, immunotherapy : CII》2007,56(12):1979-1991
The use of “altered peptide ligands” (APL), epitopes designed for exerting increased immunogenicity as compared with native
determinants, represents nowadays one of the most utilized strategies for overcoming immune tolerance to self-antigens and
boosting anti-tumor T cell-mediated immune responses. However, the actual ability of APL-primed T cells to cross-recognize
natural epitopes expressed by tumor cells remains a crucial concern. In the present study, we show that CAP1-6D, a superagonist
analogue of a carcinoembriyonic antigen (CEA)-derived HLA-A*0201-restricted epitope widely used in clinical setting, reproducibly
promotes the generation of low-affinity CD8+ T cells lacking the ability to recognized CEA-expressing colorectal carcinoma (CRC) cells. Short-term T cell cultures, obtained
by priming peripheral blood mononuclear cells from HLA-A*0201+ healthy donors or CRC patients with CAP1-6D, were indeed found to heterogeneously cross-react with saturating concentrations
of the native peptide CAP1, but to fail constantly lysing or recognizing through IFN- γ release CEA+CRC cells. Characterization of anti-CAP1-6D T cell avidity, gained through peptide titration, CD8-dependency assay, and staining
with mutated tetramers (D227K/T228A), revealed that anti-CAP1-6D T cells exerted a differential interaction with the two CEA
epitopes, i.e., displaying high affinity/CD8-independency toward the APL and low affinity/CD8-dependency toward the native
CAP1 peptide. Our data demonstrate that the efficient detection of self-antigen expressed by tumors could be a feature of
high avidity CD8-independent T cells, and underline the need for extensive analysis of tumor cross-recognition prior to any
clinical usage of APL as anti-cancer vaccines. 相似文献
992.
A novel regulatory mechanism of the bone morphogenetic protein (BMP) signaling pathway involving the carboxyl-terminal tail domain of BMP type II receptor 总被引:1,自引:0,他引:1 下载免费PDF全文
Chan MC Nguyen PH Davis BN Ohoka N Hayashi H Du K Lagna G Hata A 《Molecular and cellular biology》2007,27(16):5776-5789
Bone morphogenetic protein (BMP) signaling regulates many different biological processes, including cell growth, differentiation, and embryogenesis. BMPs bind to heterogeneous complexes of transmembrane serine/threonine (Ser/Thr) kinase receptors known as the BMP type I and II receptors (BMPRI and BMPRII). BMPRII phosphorylates and activates the BMPRI kinase, which in turn activates the Smad proteins. The cytoplasmic region of BMPRII contains a "tail" domain (BMPRII-TD) with no enzymatic activity or known regulatory function. The discovery of mutations associated with idiopathic pulmonary artery hypertension mapping to BMPRII-TD underscores its importance. Here, we report that Tribbles-like protein 3 (Trb3) is a novel BMPRII-TD-interacting protein. Upon BMP stimulation, Trb3 dissociates from BMPRII-TD and triggers degradation of Smad ubiquitin regulatory factor 1 (Smurf1), which results in the stabilization of BMP receptor-regulated Smads and potentiation of the Smad pathway. Downregulation of Trb3 inhibits BMP-mediated cellular responses, including osteoblast differentiation of C2C12 cells and maintenance of the smooth muscle phenotype of pulmonary artery smooth muscle cells. Thus, Trb3 is a critical component of a novel mechanism for regulation of the BMP pathway by BMPRII. 相似文献
993.
In Prader-Willi syndrome (PWS) growth hormone therapy (GHT) improves height, body composition, agility and muscular strength. In such patients it is necessary to consider the potential diabetogenic effect of GHT, since they tend to develop type 2 diabetes, particularly after the pubertal age. The aim of our study was to investigate the effects of GHT on glucose and insulin homeostasis in PWS children. An oral glucose tolerance test (OGTT) was performed in 24 prepubertal PWS children (15 male, 9 female, age: 5.8 +/- 2.8 years), 16 were obese (group A) and 8 had normal weight (group B), before and after 2.7 +/- 1.3 years GHT (0.22 +/- 0.03 mg/kg/week) and, only at baseline, in 35 prepubertal children with simple obesity (19 male, 16 female) (group C). Fasting glucose and insulin, glucose tolerance, insulin sensitivity index (ISI), homeostasis model assessment of insulin resistance (HOMA-IR), quick insulin check index (QUICKI), area under the curves (AUC) of glucose and insulin were estimated. At the start of GHT, all PWS children were normoglycaemic and normotolerant but two developed impaired glucose tolerance after 2.2 and 1.9 years of therapy, respectively. At baseline, group A showed lower fasting insulin levels, HOMA-IR and AUC of insulin, higher ISI, QUICKI and AUC of glucose than group C. Comparing groups A and B, AUC of insulin was higher and ISI lower in group A. During GHT, a significant increase of fasting insulin and glucose, a worsening of insulin resistance (HOMA-IR) and insulin sensitivity (QUICKI) was found only in group A while ISI did not change. The AUC of glucose decreased in both groups instead AUC of insulin did not change. BMI-SDS decreased in group A and increased in group B. The increased insulin resistance and decreased insulin sensitivity in obese PWS patients, as well as the occurrence of impaired glucose tolerance during GHT, suggest that a close monitoring of glucose and insulin homeostasis is mandatory, especially in treated obese PWS children. 相似文献
994.
995.
PE is a functional domain responsible for protein translocation and localization on mycobacterial cell wall 总被引:4,自引:1,他引:3
Cascioferro A Delogu G Colone M Sali M Stringaro A Arancia G Fadda G Palù G Manganelli R 《Molecular microbiology》2007,66(6):1536-1547
The PE family of Mycobacterium tuberculosis includes 98 proteins which share a highly homologous N-terminus sequence of about 110 amino acids (PE domain). Depending on the C-terminal domain, the PE family can be divided in three subfamilies, the largest of which is the PE_PGRS with 61 members. In this study, we determined the cellular localization of three PE proteins by cell fractionation and immunoelectron microscopy by expressing chimeric epitope-tagged recombinant proteins in Mycobacterium smegmatis. We demonstrate that the PE domain of PE_PGRS33 and PE11 (a protein constituted by the only PE domain) contains the information necessary for cell wall localization, and that they can be used as N-terminal fusion partners to deliver a sufficiently long C-terminus-linked protein domain on the mycobacterial cell surface. Indeed, we demonstrate that PE_PGRS33 and Rv3097c (a lipase belonging to the PE family) are surface exposed and localize in the mycobacterial cell wall. Moreover, we found that PE_PGRS33 is easily extractable by detergents suggesting its localization in the mycobacterial outer membrane. Beyond defining the cellular localization of these proteins, and a function for their PE domains, these data open the interesting possibility to construct recombinant mycobacteria expressing heterologous antigens on their surface for vaccine purposes. 相似文献
996.
Ricci F Caprio F Poscia A Valgimigli F Messeri D Lepori E Dall'Oglio G Palleschi G Moscone D 《Biosensors & bioelectronics》2007,22(9-10):2032-2039
Glucose biosensors based on the use of planar screen-printed electrodes modified with an electrochemical mediator and with glucose oxidase have been optimised for their application in the continuous glucose monitoring in diabetic patients. A full study of their operative stability and temperature dependence has been accomplished, thus giving useful information for in vivo applications. The effect of dissolved oxygen concentration in the working solution was also studied in order to evaluate its effect on the linearity of the sensors. Glucose monitoring performed with serum samples was performed to evaluate the effect of matrix components on operative stability and demonstrated an efficient behaviour for 72 h of continuous monitoring. Finally, these studies led to a sensor capable of detecting glucose at concentrations as low as 0.04 mM and with a good linearity up to 2.0 mM (at 37 degrees C) with an operative stability of ca. 72 h, thus demonstrating the possible application of these sensors for continuous glucose monitoring in conjunction with a microdialysis probe. Moreover, preliminary in vivo experiments for ca. 20 h have demonstrated the feasibility of this system. 相似文献
997.
Lagerstedt JO Cavigiolio G Roberts LM Hong HS Jin LW Fitzgerald PG Oda MN Voss JC 《Biochemistry》2007,46(34):9693-9699
The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIOWA) leads to the formation of beta-secondary structure rich amyloid fibrils in vivo. Here we show that full-length apoA-IIOWA has a decreased lipid-binding capability, an increased amino-terminal sensitivity to protease, and a propensity to form annular protofibrils visible by electron microscopy. The molecular basis for the conversion of apolipoprotein A-I to a proamyloidogenic form was examined by electron paramagnetic resonance spectroscopy. Our recent findings [Lagerstedt, J. O., Budamagunta, M. S., Oda, M. N., and Voss, J. C. (2007) J. Biol. Chem. 282, 9143-9149] indicate that Gly26 in the native apoprotein separates a preceding beta-strand structure (residues 20-25) from a downstream largely alpha-helical region. The current study demonstrates that the G26R variant promotes a structural transition of positions 27-56 to a mixture of coil and beta-strand secondary structure. Microscopy and staining by amyloidophilic dyes suggest that this alteration extends throughout the protein within 1 week of incubation in vitro, leading to insoluble aggregates of distinct morphology. The severe consequences of the Iowa mutation likely arise from the combination of losing the contribution of the native Gly residue in terminating beta-strand propagation and the promotion of beta-structure when an Arg is introduced adjacent to the succeeding residue of identical charge and size, Arg27. 相似文献
998.
The Ceprano calvarium represents one of the most important sources of information about both the dynamics of the earliest hominid dispersal toward Europe and the evolution of the genus Homo in the early-to-middle Pleistocene. In this paper, the midsagittal vault profile and the 3D frontal bone morphology of Ceprano are investigated comparatively, using landmark coordinates and Procrustes superimposition. In fact, despite the fact that the skull appears partially distorted by diagenetic pressures (thus precluding a comprehensive landmark-based analysis), some aspects of the overall morphology are suitable for consideration in terms of geometric morphometrics. The midsagittal profile shows an archaic shape, comparable with the H. ergaster/erectus range of variation because of the fronto-parietal flattening, the development of the supraorbital and nuchal structures, and the occurrence of a slightly larger occipital bone. By contrast, the frontal bone displays a derived 3D shape that, mostly because of the widening of the frontal squama, appears comparable with the Afro-European variation of the Middle Pleistocene (i.e., H. heidelbergensis/rhodesiensis). Taking into account the unique morphological pattern displayed by Ceprano, its role as a link between early Homo and the Middle Pleistocene populations of Europe and Africa is not falsified. Thus, when aspects of the Ceprano's morphology are described within the analytical framework provided by geometric morphometrics, the relationships between Ceprano and the subsequent Afro-European fossil record are emphasized, suggesting the occurrence of an ancestral stock of H. heidelbergensis/rhodesiensis that is properly represented by the Italian specimen. 相似文献
999.
Camilla Bernasconi Giorgio Volponi Claudia Picozzi Roberto Foschino 《Applied microbiology》2007,73(19):6321-6325
A quantitative real-time PCR targeting the tnaA gene was studied to detect Escherichia coli and distinguish E. coli from Shigella spp. These microorganisms revealed high similarity in the molecular organization of the tna operon. 相似文献
1000.
In Drosophila melanogaster, the two chromosomal proteins HP1 and HP2 colocalize on heterochromatic and euchromatic sites in polytene chromosomes. Mutations
in the HP2 gene act as dominant suppressors of position effect variegation, demonstrating a role for HP2 in the formation
or maintenance of heterochromatin. In this paper, we investigated whether a putative homolog of the D. melanogaster HP2 is involved in the facultative heterochromatinization process in mealybugs. Using an antibody raised against the Drosophila HP2, we identified in the mealybug Planococcus citri a cross-reactive epitope, which we refer to as HP2-like. We investigated the HP2-like pattern during the male embryo development
where the entire paternal haploid chromosome set becomes heterochromatic. The HP2 antibody heavily decorates the chromocenters,
where it localizes with HP1, and marks the chromatin before it acquires the full cytological characteristics of the male-specific
heterochromatin. In euchromatic chromosomes, HP2-like is mainly concentrated at telomeric sites. The interplay between HP2-like
and HP1-like was studied by dsRNA interference experiments. Extinguishing HP1-like expression by RNAi does not prevent the
association of HP2-like with facultative heterochromatin, implying that HP2-like binds to chromatin in a HP1-independent manner.
Our results confirm and extend the structural and functional conservation of proteins involved in heterochromatin assembly.
Silvia Volpi and Silvia Bongiorni contributed equally to the work. 相似文献