全文获取类型
收费全文 | 2168篇 |
免费 | 410篇 |
国内免费 | 302篇 |
专业分类
电工技术 | 157篇 |
综合类 | 198篇 |
化学工业 | 310篇 |
金属工艺 | 26篇 |
机械仪表 | 66篇 |
建筑科学 | 71篇 |
矿业工程 | 38篇 |
能源动力 | 33篇 |
轻工业 | 453篇 |
水利工程 | 83篇 |
石油天然气 | 23篇 |
武器工业 | 32篇 |
无线电 | 160篇 |
一般工业技术 | 84篇 |
冶金工业 | 23篇 |
原子能技术 | 49篇 |
自动化技术 | 1074篇 |
出版年
2024年 | 15篇 |
2023年 | 45篇 |
2022年 | 165篇 |
2021年 | 146篇 |
2020年 | 85篇 |
2019年 | 78篇 |
2018年 | 77篇 |
2017年 | 97篇 |
2016年 | 108篇 |
2015年 | 121篇 |
2014年 | 148篇 |
2013年 | 144篇 |
2012年 | 198篇 |
2011年 | 209篇 |
2010年 | 154篇 |
2009年 | 144篇 |
2008年 | 164篇 |
2007年 | 168篇 |
2006年 | 125篇 |
2005年 | 117篇 |
2004年 | 83篇 |
2003年 | 80篇 |
2002年 | 33篇 |
2001年 | 32篇 |
2000年 | 30篇 |
1999年 | 14篇 |
1998年 | 20篇 |
1997年 | 12篇 |
1996年 | 13篇 |
1995年 | 11篇 |
1994年 | 10篇 |
1993年 | 7篇 |
1992年 | 6篇 |
1991年 | 8篇 |
1990年 | 3篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1980年 | 1篇 |
1979年 | 1篇 |
排序方式: 共有2880条查询结果,搜索用时 11 毫秒
111.
Natasha M. van Poppelen Jolique A. van Ipenburg Quincy van den Bosch Jolanda Vaarwater Tom Brands Bert Eussen Frank Magielsen Hendrikus J. Dubbink Dion Paridaens Erwin Brosens Nicole Naus Annelies de Klein Emine Kili Robert M. Verdijk 《International journal of molecular sciences》2021,22(11)
The aim of this study was exploration of the genetic background of conjunctival melanoma (CM) and correlation with recurrent and metastatic disease. Twenty-eight CM from the Rotterdam Ocular Melanoma Study group were collected and DNA was isolated from the formalin-fixed paraffin embedded tissue. Targeted next-generation sequencing was performed using a panel covering GNAQ, GNA11, EIF1AX, BAP1, BRAF, NRAS, c-KIT, PTEN, SF3B1, and TERT genes. Recurrences and metastasis were present in eight (29%) and nine (32%) CM cases, respectively. TERT promoter mutations were most common (54%), but BRAF (46%), NRAS (21%), BAP1 (18%), PTEN (14%), c-KIT (7%), and SF3B1 (4%) mutations were also observed. No mutations in GNAQ, GNA11, and EIF1AX were found. None of the mutations was significantly associated with recurrent disease. Presence of a TERT promoter mutation was associated with metastatic disease (p-value = 0.008). Based on our molecular findings, CM comprises a separate entity within melanoma, although there are overlapping molecular features with uveal melanoma, such as the presence of BAP1 and SF3B1 mutations. This warrants careful interpretation of molecular data, in the light of clinical findings. About three quarter of CM contain drug-targetable mutations, and TERT promoter mutations are correlated to metastatic disease in CM. 相似文献
112.
Bilal Ahmad Maria Batool Moon-Suk Kim Sangdun Choi 《International journal of molecular sciences》2021,22(11)
Toll-like receptor (TLR) signaling plays a critical role in the induction and progression of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematous, experimental autoimmune encephalitis, type 1 diabetes mellitus and neurodegenerative diseases. Deciphering antigen recognition by antibodies provides insights and defines the mechanism of action into the progression of immune responses. Multiple strategies, including phage display and hybridoma technologies, have been used to enhance the affinity of antibodies for their respective epitopes. Here, we investigate the TLR4 antibody-binding epitope by computational-driven approach. We demonstrate that three important residues, i.e., Y328, N329, and K349 of TLR4 antibody binding epitope identified upon in silico mutagenesis, affect not only the interaction and binding affinity of antibody but also influence the structural integrity of TLR4. Furthermore, we predict a novel epitope at the TLR4-MD2 interface which can be targeted and explored for therapeutic antibodies and small molecules. This technique provides an in-depth insight into antibody–antigen interactions at the resolution and will be beneficial for the development of new monoclonal antibodies. Computational techniques, if coupled with experimental methods, will shorten the duration of rational design and development of antibody therapeutics. 相似文献
113.
Rima Dardik Einat Avishai Shadan Lalezari Assaf A. Barg Sarina Levy-Mendelovich Ivan Budnik Ortal Barel Yulia Khavkin Gili Kenet Tami Livnat 《International journal of molecular sciences》2021,22(16)
Introduction: Hemophilia A (HA) is an X-linked bleeding disorder caused by factor VIII (FVIII) deficiency or dysfunction due to F8 gene mutations. HA carriers are usually asymptomatic because their FVIII levels correspond to approximately half of the concentration found in healthy individuals. However, in rare cases, a carrier may exhibit symptoms of moderate to severe HA primarily due to skewed inactivation of her non-hemophilic X chromosome. Aim: The aim of the study was to investigate X-chromosome inactivation (XCI) patterns in HA carriers, with special emphasis on three karyotypically normal HA carriers presenting with moderate to severe HA phenotype due to skewed XCI, in an attempt to elucidate the molecular mechanism underlying skewed XCI in these symptomatic HA carriers. The study was based on the hypothesis that the presence of a pathogenic mutation on the non-hemophilic X chromosome is the cause of extreme inactivation of that X chromosome. Methods: XCI patterns were studied by PCR analysis of the CAG repeat region in the HUMARA gene. HA carriers that demonstrated skewed XCI were further studied by whole-exome sequencing (WES) followed by X chromosome-targeted bioinformatic analysis. Results: All three HA carriers presenting with the moderate to severe HA phenotype due to skewed XCI were found to carry pathogenic mutations on their non-hemophilic X chromosomes. Patient 1 was diagnosed with a frameshift mutation in the PGK1 gene that was associated with familial XCI skewing in three generations. Patient 2 was diagnosed with a missense mutation in the SYTL4 gene that was associated with familial XCI skewing in two generations. Patient 3 was diagnosed with a nonsense mutation in the NKAP gene that was associated with familial XCI skewing in two generations. Conclusion: Our results indicate that the main reason for skewed XCI in our female HA patients was negative selection against cells with a disadvantage caused by an additional deleterious mutation on the silenced X chromosome, thus complicating the phenotype of a monogenic X-linked disease. Based on our study, we are currently offering the X inactivation test to symptomatic hemophilia carriers and plan to expand this approach to symptomatic carriers of other X-linked diseases, which can be further used in pregnancy planning. 相似文献
114.
Fabio Forghieri Giovanni Riva Ivana Lagreca Patrizia Barozzi Francesca Bettelli Ambra Paolini Vincenzo Nasillo Beatrice Lusenti Valeria Pioli Davide Giusti Andrea Gilioli Corrado Colasante Laura Galassi Hillary Catellani Francesca Donatelli Annalisa Talami Rossana Maffei Silvia Martinelli Leonardo Potenza Roberto Marasca Enrico Tagliafico Rossella Manfredini Tommaso Trenti Patrizia Comoli Mario Luppi 《International journal of molecular sciences》2021,22(17)
The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients. 相似文献
115.
Roua Hassoun Heidi Budde Hans Georg Mannherz Mria Ldi Setsuko Fujita-Becker Kai Thorsten Laser Anna Grtner Karin Klingel Desire Mhner Robert Stehle Innas Sultana Thomas Schaaf Mario Majchrzak Verena Krause Christian Herrmann Marc M. Nowaczyk Andreas Mügge Gabriele Pfitzer Rasmus R. Schrder Nazha Hamdani Hendrik Milting Kornelia Jaquet Diana Cimiotti 《International journal of molecular sciences》2021,22(17)
Rare pediatric non-compaction and restrictive cardiomyopathy are usually associated with a rapid and severe disease progression. While the non-compaction phenotype is characterized by structural defects and is correlated with systolic dysfunction, the restrictive phenotype exhibits diastolic dysfunction. The molecular mechanisms are poorly understood. Target genes encode among others, the cardiac troponin subunits forming the main regulatory protein complex of the thin filament for muscle contraction. Here, we compare the molecular effects of two infantile de novo point mutations in TNNC1 (p.cTnC-G34S) and TNNI3 (p.cTnI-D127Y) leading to severe non-compaction and restrictive phenotypes, respectively. We used skinned cardiomyocytes, skinned fibers, and reconstituted thin filaments to measure the impact of the mutations on contractile function. We investigated the interaction of these troponin variants with actin and their inter-subunit interactions, as well as the structural integrity of reconstituted thin filaments. Both mutations exhibited similar functional and structural impairments, though the patients developed different phenotypes. Furthermore, the protein quality control system was affected, as shown for TnC-G34S using patient’s myocardial tissue samples. The two troponin targeting agents levosimendan and green tea extract (-)-epigallocatechin-3-gallate (EGCg) stabilized the structural integrity of reconstituted thin filaments and ameliorated contractile function in vitro in some, but not all, aspects to a similar degree for both mutations. 相似文献
116.
Margaret Ottaviano Emilio Francesco Giunta Marianna Tortora Marcello Curvietto Laura Attademo Davide Bosso Cinzia Cardalesi Mario Rosanova Pietro De Placido Erica Pietroluongo Vittorio Riccio Brigitta Mucci Sara Parola Maria Grazia Vitale Giovannella Palmieri Bruno Daniele Ester Simeone 《International journal of molecular sciences》2021,22(7)
As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients. 相似文献
117.
梯级水库群优化调度精英集聚蛛群优化方法 总被引:1,自引:2,他引:1
将蛛群优化方法(SSO)这一新型群体智能寻优方法引入梯级水库群优化调度领域,并提出精英集聚蛛群优化方法(ESSO)进一步改善SSO的性能表现。ESSO在标准SSO方法寻优机制基础上,从精英个体动态更新策略与邻域变异搜索机制等两方面予以改进,提升蜘蛛群体的多样性与优秀个体领导能力,均衡方法的全局开采能力与局部勘探能力。澜沧江流域工程实例表明,所提ESSO方法能有效克服标准SSO的"早熟"缺陷,有效提升方法的搜索能力,可望为大规模梯级水库群优化调度提供一种新的高效求解思路。 相似文献
118.
基于新疆1960—2011年的日降水量数据,选取持续干燥指数、持续湿润指数、年总降水量、强降水天数、强降水量、1 d最大降水量、5 d最大降水量和普通日降水强度8个极端降水指标,采用线性倾向率、Mann-Kendall突变检验及主成分分析法研究新疆极端降水的时空分布特征及演变趋势。结果表明:时间变化上,新疆极端降水的持续湿润指数均呈上升趋势,持续干燥指数呈下降趋势,表明新疆降水量总体呈增加趋势;空间变化上,南疆、北疆极端降水指标的年际变化表现出明显差异,北疆湿润指数大、年际变化率大,南疆湿润指数小、年际变化率小;极端降水指标基本上在1986年、1987年发生突变,各指标突变前后的变化率存在明显差异;时间上的主成分分析表明降水量整体增加,干燥程度下降;空间上的主成分分析表明,北疆降水量多于南疆,南疆较北疆干旱。 相似文献
119.
120.
高生物量富硒酵母菌的选育 总被引:4,自引:0,他引:4
以酿酒酵母PT为出发菌株,采用梯度浓度筛选的方法对其进行驯化,得到1株生物量较高和对亚硒酸钠抗性较高的菌株GB-1。对其进行紫外诱变处理,当致死率达91.85%时,获得多株突变株。通过多次平板初筛和摇瓶复筛,得到1株高生物量富硒酵母UV-PT。采用响应面法对富硒酵母UV-PT发酵条件进行了优化。借助于SAS软件,首先利用Plackett-Burman试验设计筛选出影响富硒的3个主要因素,即转速、温度、初始pH值。在此基础上,再利用Box-Behnken试验设计及响应面分析法对发酵条件进行优化,确定最佳发酵条件:转速为203r/min,发酵温度为30.3℃,初始pH值为4.52。结果表明,优化后富硒酵母的生物量和含硒量分别为10.62g/L、1003.26μg/g,硒总含量为10654.62μg/L,为出发菌株的1.62倍。 相似文献