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991.
992.
993.
Fazhao Li Han Xiao Zhiping Hu Fangfang Zhou Binbin Yang 《European journal of cell biology》2018,97(3):216-229
HSPB8 is a member of ubiquitous small heat shock protein (sHSP) family, whose expression is induced in response to a wide variety of unfavorable physiological and environmental conditions. Investigation of HSPB8 structure indicated that HSPB8 belongs to the group of so-called intrinsically disordered proteins and possesses a highly flexible structure. Unlike most other sHSPs, HSPB8 tends to form small-molecular-mass oligomers and exhibits substrate-dependent chaperone activity. In cooperation with BAG3, the chaperone activity of HSPB8 was reported to be involved in the delivery of misfolded proteins to the autophagy machinery. Through this way, HSPB8 interferes with pathological processes leading to neurodegenerative diseases. Accordingly, published studies have identified genetic links between mutations of HSPB8 and some kind of neuromuscular diseases, further supporting its important role in neurodegenerative disorders. In addition to their anti-aggregation properties, HSPB8 is indicated to interact with a wide range of client proteins, modulating their maturations and activities, and therefore, regulates a large repertoire of cellular functions, including apoptosis, proliferation, inflammation and etc. As a result, HSPB8 has key roles in cancer biology, autoimmune diseases, cardiac diseases and cerebral vascular diseases. 相似文献
994.
Mechanistic studies of sesquiterpene cyclases based on their carbon isotope ratios at natural abundance
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During the process of terpene biosynthesis, C–C bond breaking and forming steps are subjected to kinetic carbon isotope effects, leading to distinct carbon isotopic signatures of the products. Accordingly, carbon isotopic signatures could be used to reveal the ‘biosynthetic history’ of the produced terpenoids. Five known sesquiterpene cyclases, regulating three different pathways, representing simple to complex biosynthetic sequences, were heterologously expressed and used for in vitro assays with farnesyl diphosphate as substrate. Compound specific isotope ratio mass spectrometry measurements of the enzyme substrate farnesyl diphosphate (FDP) and the products of all the five cyclases were performed. The calculated δ13C value for FDP, based on δ13C values and relative amounts of the products, was identical with its measured δ13C value, confirming the reliability of the approach and the precision of measurements. The different carbon isotope ratios of the products reflect the complexity of their structure and are correlated with the frequency of carbon–carbon bond forming and breaking steps on their individual biosynthetic pathways. Thus, the analysis of carbon isotopic signatures of terpenes at natural abundance can be used as a powerful tool in elucidation of associated biosynthetic mechanisms of terpene synthases and in future in vivo studies even without ‘touching’ the plant. 相似文献
995.
Donghui Zhou Khuchtumur Bum-Erdene David Xu Degang Liu Doug Tompkins Rania S. Sulaiman Timothy W. Corson John M. Chirgwin Samy O. Meroueh 《Bioorganic & medicinal chemistry》2018,26(23-24):6128-6134
Bone is a common site of metastasis for breast, prostate, lung, kidney and other cancers. Bone metastases are incurable, and substantially reduce patient quality of life. To date, there exists no small-molecule therapeutic agent that can reduce tumor burden in bone. This is partly attributed to the lack of suitable in vitro assays that are good models of tumor growth in bone. Here, we take advantage of a novel ex vivo model of bone colonization to report a series of pyrrolopyrazolone small molecules that inhibit cancer cell invasion and ex vivo tumor growth in bone at single-digit micromolar concentration. We find that the compounds modulated the expression levels of genes associated with bone-forming osteoblasts, bone-destroying osteoclasts, cancer cell viability and metastasis. Our compounds provide chemical tools to uncover novel targets and pathways associated with bone metastasis, as well as for the development of compounds to prevent and reverse bone tumor growth in vivo. 相似文献
996.
Meng Lei Huayun Feng Enhe Bai Hui Zhou Jia Wang Jingmiao Shi Xueyuan Wang Shihe Hu Zhaogang Liu Yongqiang Zhu 《Bioorganic & medicinal chemistry》2018,26(14):3975-3981
A series of novel dipeptidyl boronic acid inhibitors of 20S proteasome were designed and synthesized. Aliphatic groups at R1 position were designed for the first time to fully understand the SAR (structure–activity relationship). Among the screened compounds, novel inhibitor 5c inhibited the CT-L (chymotrypsin-like) activity with IC50 of 8.21?nM and the MM (multiple myeloma) cells RPMI8226, U266B and ARH77 proliferations with the IC50 of 8.99, 6.75 and 9.10?nM, respectively, which showed similar in vitro activities compared with the compound MLN2238 (biologically active form of marketed MLN9708). To investigate the oral availability, compound 5c was esterified to its prodrug 6a with the enzymatic IC50 of 6.74?nM and RPMI8226, U266B and ARH77 cell proliferations IC50 of 2.59, 4.32 and 3.68?nM, respectively. Furthermore, prodrug 6a exhibited good pharmacokinetic properties with oral bioavailability of 24.9%, similar with MLN9708 (27.8%). Moreover, compound 6a showed good microsomal stabilities and displayed stronger in vivo anticancer efficacy than MLN9708 in the human ARH77 xenograft mouse model. Finally, cell cycle results showed that compound 6a had a significant inhibitory effect on CT-L and inhibited cell cycle progression at the G2M stage. 相似文献
997.
神经肽在参与调控人体各种生理功能上发挥着重要的作用,如痛觉、睡眠、情绪、学习与记忆等生理活动都受到神经肽的影响。神经肽主要存在于机体的神经组织内,其他体液和器官中也有少量的分布。目前对全脑组织神经肽高通量鉴定的研究仍不足,高通量检测这些神经肽对了解神经肽的组成和功能具有重要的意义。本研究通过对小鼠全脑组织内源性肽段的萃取,运用液相串联质谱(LC-MS/MS)技术对全脑组织的神经肽进行检测,共鉴定到1 830条内源性肽段和99条预测神经肽肽段。这些内源性肽段的鉴定在疾病的治疗和机制研究以及药物的研发方面提供了参考价值,也为研究新的神经肽及其功能奠定了基础。 相似文献
998.
Jingjie Mo Renzhe Jin Qingrong Yan Izabela Sokolowska Michael J. Lewis 《MABS-AUSTIN》2018,10(3):406-415
Glycation has been observed in antibody therapeutics manufactured by the fed-batch fermentation process. It not only increases the heterogeneity of antibodies, but also potentially affects product safety and efficacy. In this study, non-glycated and glycated fractions enriched from a monoclonal antibody (mAb1) as well as glucose-stressed mAb1 were characterized using a variety of biochemical, biophysical and biological assays to determine the effects of glycation on the structure and function of mAb1. Glycation was detected at multiple lysine residues and reduced the antigen binding activity of mAb1. Heavy chain Lys100, which is located in the complementary-determining region of mAb1, had the highest levels of glycation in both stressed and unstressed samples, and glycation of this residue was likely responsible for the loss of antigen binding based on hydrogen/deuterium exchange mass spectrometry analysis. Peptide mapping and intact liquid chromatography-mass spectrometry (LC-MS) can both be used to monitor the glycation levels. Peptide mapping provides site specific glycation results, while intact LC-MS is a quicker and simpler method to quantitate the total glycation levels and is more useful for routine testing. Capillary isoelectric focusing (cIEF) can also be used to monitor glycation because glycation induces an acidic shift in the cIEF profile. As expected, total glycation measured by intact LC-MS correlated very well with the percentage of total acidic peaks or main peak measured by cIEF. In summary, we demonstrated that glycation can affect the function of a representative IgG1 mAb. The analytical characterization, as described here, should be generally applicable for other therapeutic mAbs. 相似文献
999.
Qian Dong Yuxue Liang Xinjian Yan Sanford P. Markey Yuri A. Mirokhin Dmitrii V. Tchekhovskoi 《MABS-AUSTIN》2018,10(3):354-369
We describe the creation of a mass spectral library composed of all identifiable spectra derived from the tryptic digest of the NISTmAb IgG1κ. The library is a unique reference spectral collection developed from over six million peptide-spectrum matches acquired by liquid chromatography-mass spectrometry (LC-MS) over a wide range of collision energy. Conventional one-dimensional (1D) LC-MS was used for various digestion conditions and 20- and 24-fraction two-dimensional (2D) LC-MS studies permitted in-depth analyses of single digests. Computer methods were developed for automated analysis of LC-MS isotopic clusters to determine the attributes for all ions detected in the 1D and 2D studies. The library contains a selection of over 12,600 high-quality tandem spectra of more than 3,300 peptide ions identified and validated by accurate mass, differential elution pattern, and expected peptide classes in peptide map experiments. These include a variety of biologically modified peptide spectra involving glycosylated, oxidized, deamidated, glycated, and N/C-terminal modified peptides, as well as artifacts. A complete glycation profile was obtained for the NISTmAb with spectra for 58% and 100% of all possible glycation sites in the heavy and light chains, respectively. The site-specific quantification of methionine oxidation in the protein is described. The utility of this reference library is demonstrated by the analysis of a commercial monoclonal antibody (adalimumab, Humira®), where 691 peptide ion spectra are identifiable in the constant regions, accounting for 60% coverage for both heavy and light chains. The NIST reference library platform may be used as a tool for facile identification of the primary sequence and post-translational modifications, as well as the recognition of LC-MS method-induced artifacts for human and recombinant IgG antibodies. Its development also provides a general method for creating comprehensive peptide libraries of individual proteins. 相似文献
1000.
A detailed analytical study using combined normal phase high pressure liquid chromatography (HPLC), gas chromatography (GC)
and gas chromatography/mass spectrometry (GC/MS) of Polynuclear Aromatic Hydrocarbons (PAHs) in fish from the Red Sea was
undertaken. This investigation involves a preliminary assessment of the sixteen parent compounds issued by the U.S. Environmental
Protection Agency(EPA).
The study revealed measurable levels of Σ PAHs (the sum of three to five or six ring parent compounds) (49.2 ng g−1 dry weight) and total PAHs (all PAH detected) (422.1 ng g−1 dry weight) in edible muscle of fishes collected from the Red Sea. These concentrations are within the range of values reported
for other comparable regions of the world. Mean concentrations for individual parent PAH in fish muscles were; naphthalene
19.5, biphenyl 4.6, acenaphthylene 1.0, acenaphthene 1.2, fluorene 5.5, phenanthrene 14.0, anthracene 0.8, fluoranthene 1.5,
pyrene 1.8, benz(a)anthracene 0.4, chrysene 1.9, benzo(b)fluoranthene 0.5, benzo(k)fluoranthene 0.5, benzo(e)pyrene 0.9, benzo(a)pyrene
0.5, perylene 0.2, and indeno(1,2,3-cd)pyrene 0.1 ng g−1 dry weight respectively. The Red Sea fish extracts exhibit the low molecular weight aromatics as well as the discernible
alkyl-substituted species of naphthalene, fluorene, phenanthrene and dibenzothiophene. Thus, it was suggested that the most
probable source of PAHs is oil contamination originating from spillages and/or heavy ship traffic.
It was concluded that the presence of PAHs in the fish muscles is not responsible for the reported fish kill phenomenon. However,
the high concentrations of carcinogenic chrysene encountered in these fishes should be considered seriously as it is hazardous
to human health. Based on fish consumption by Yemeni‘s population it was calculated that the daily intake of total carcinogens
were 0.15 μg/person/day.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献