全文获取类型
收费全文 | 8806篇 |
免费 | 933篇 |
国内免费 | 409篇 |
专业分类
电工技术 | 278篇 |
综合类 | 468篇 |
化学工业 | 2166篇 |
金属工艺 | 466篇 |
机械仪表 | 517篇 |
建筑科学 | 709篇 |
矿业工程 | 262篇 |
能源动力 | 93篇 |
轻工业 | 2081篇 |
水利工程 | 173篇 |
石油天然气 | 239篇 |
武器工业 | 79篇 |
无线电 | 390篇 |
一般工业技术 | 824篇 |
冶金工业 | 324篇 |
原子能技术 | 94篇 |
自动化技术 | 985篇 |
出版年
2024年 | 40篇 |
2023年 | 156篇 |
2022年 | 242篇 |
2021年 | 834篇 |
2020年 | 320篇 |
2019年 | 262篇 |
2018年 | 268篇 |
2017年 | 289篇 |
2016年 | 337篇 |
2015年 | 423篇 |
2014年 | 634篇 |
2013年 | 642篇 |
2012年 | 665篇 |
2011年 | 645篇 |
2010年 | 469篇 |
2009年 | 504篇 |
2008年 | 450篇 |
2007年 | 478篇 |
2006年 | 408篇 |
2005年 | 404篇 |
2004年 | 305篇 |
2003年 | 283篇 |
2002年 | 203篇 |
2001年 | 173篇 |
2000年 | 128篇 |
1999年 | 121篇 |
1998年 | 82篇 |
1997年 | 72篇 |
1996年 | 42篇 |
1995年 | 54篇 |
1994年 | 39篇 |
1993年 | 26篇 |
1992年 | 31篇 |
1991年 | 27篇 |
1990年 | 21篇 |
1989年 | 21篇 |
1988年 | 6篇 |
1987年 | 18篇 |
1986年 | 5篇 |
1985年 | 11篇 |
1984年 | 2篇 |
1981年 | 1篇 |
1980年 | 3篇 |
1978年 | 1篇 |
1966年 | 1篇 |
1960年 | 1篇 |
1951年 | 1篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
1.
Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS. 相似文献
2.
3.
Milena Jankovic Ivana Novakovic Dejan Nikolic Jasmina Mitrovic Maksic Slavko Brankovic Ivana Petronic Dragana Cirovic Sinisa Ducic Mirko Grajic Dragana Bogicevic 《International journal of molecular sciences》2021,22(9)
Diabetic neuropathy (DN), the most common chronic and progressive complication of diabetes mellitus (DM), strongly affects patients’ quality of life. DN could be present as peripheral, autonomous or, clinically also relevant, uremic neuropathy. The etiopathogenesis of DN is multifactorial, and genetic components play a role both in its occurrence and clinical course. A number of gene polymorphisms in candidate genes have been assessed as susceptibility factors for DN, and most of them are linked to mechanisms such as reactive oxygen species production, neurovascular impairments and modified protein glycosylation, as well as immunomodulation and inflammation. Different epigenomic mechanisms such as DNA methylation, histone modifications and non-coding RNA action have been studied in DN, which also underline the importance of “metabolic memory” in DN appearance and progression. In this review, we summarize most of the relevant data in the field of genetics and epigenomics of DN, hoping they will become significant for diagnosis, therapy and prevention of DN. 相似文献
4.
5.
6.
Cho-Yi Chen Masaoki Kawasumi Tien-Yun Lan Chi-Lam Poon Yi-Sian Lin Pin-Jou Wu Yao-Chung Chen Bing-Hong Chen Cheng-Hsien Wu Jeng-Fan Lo Rueyhung Roc Weng Yi-Chen Sun Kai-Feng Hung 《International journal of molecular sciences》2021,22(1)
Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal–epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics. 相似文献
7.
Margarita A. Sazonova Vasily V. Sinyov Anastasia I. Ryzhkova Marina D. Sazonova Tatiana V. Kirichenko Victoria A. Khotina Zukhra B. Khasanova Natalya A. Doroschuk Vasily P. Karagodin Alexander N. Orekhov Igor A. Sobenin 《International journal of molecular sciences》2021,22(2)
Chronic stress is a combination of nonspecific adaptive reactions of the body to the influence of various adverse stress factors which disrupt its homeostasis, and it is also a corresponding state of the organism’s nervous system (or the body in general). We hypothesized that chronic stress may be one of the causes occurence of several molecular and cellular types of stress. We analyzed literary sources and considered most of these types of stress in our review article. We examined genes and mutations of nuclear and mitochondrial genomes and also molecular variants which lead to various types of stress. The end result of chronic stress can be metabolic disturbance in humans and animals, leading to accumulation of reactive oxygen species (ROS), oxidative stress, energy deficiency in cells (due to a decrease in ATP synthesis) and mitochondrial dysfunction. These changes can last for the lifetime and lead to severe pathologies, including neurodegenerative diseases and atherosclerosis. The analysis of literature allowed us to conclude that under the influence of chronic stress, metabolism in the human body can be disrupted, mutations of the mitochondrial and nuclear genome and dysfunction of cells and their compartments can occur. As a result of these processes, oxidative, genotoxic, and cellular stress can occur. Therefore, chronic stress can be one of the causes forthe occurrence and development of neurodegenerative diseases and atherosclerosis. In particular, chronic stress can play a large role in the occurrence and development of oxidative, genotoxic, and cellular types of stress. 相似文献
8.
Nitsa Buaron Antonella Mangraviti Francesco Volpin Ann Liu Mariangela Pedone Eric Sankey Dina Aranovich Itay Adar Fausto J. Rodriguez Abraham Nyska Riki Goldbart Tamar Traitel Henry Brem Betty Tyler Joseph Kost 《Advanced functional materials》2021,31(44):2100643
Treating neuroinflammation-related injuries and disorders through manipulation of neuroinflammation functions is being heralded as a new therapeutic strategy. In this study, a novel pectic galactan (PG) polysaccharide based gene therapy approach is developed for targeting reactive gliosis in neuroinflammation. Galectin-3 (Gal-3) is a cell protein with a high affinity to β-galactoside sugars and is highly expressed in reactive gliosis. Since PG carries galactans, it can target reactive gliosis via specific carbohydrate interaction between galactan and Gal-3 on the cell membrane, and therefore can be utilized as a carrier for delivering genes to these cells. The carrier is synthesized by modifying quaternary ammonium groups on the PG. The resulting quaternized PG (QPG) is found to form complexes with plasmid DNA with a mean diameter of 100 nm and have the characteristics required for targeted gene therapy. The complexes efficiently condense large amounts of plasmid per particle and successfully bind to Gal-3. The in vivo study shows that the complexes are biocompatible and safe for administration and can selectively transfect reactive glial cells of an induced cortical lesion. The results confirm that this PG-based delivery system is a promising platform for targeting Gal-3 overexpressing neuroinflammation cells for treating neuroinflammation-related injuries and neurodegenerative diseases. 相似文献
9.
Jakub Drzmisek Daniel Stipl Denisa Petrackova Branislav Vecerek Ana Dienstbier 《International journal of molecular sciences》2021,22(2)
Bacterial pathogens sense specific cues associated with different host niches and integrate these signals to appropriately adjust the global gene expression. Bordetella pertussis is a Gram-negative, strictly human pathogen of the respiratory tract and the etiological agent of whooping cough (pertussis). Though B. pertussis does not cause invasive infections, previous results indicated that this reemerging pathogen responds to blood exposure. Here, omics RNA-seq and LC–MS/MS techniques were applied to determine the blood-responsive regulon of B. pertussis. These analyses revealed that direct contact with blood rewired global gene expression profiles in B. pertussis as the expression of almost 20% of all genes was significantly modulated. However, upon loss of contact with blood, the majority of blood-specific effects vanished, with the exception of several genes encoding the T3SS-secreted substrates. For the first time, the T3SS regulator BtrA was identified in culture supernatants of B. pertussis. Furthermore, proteomic analysis identified BP2259 protein as a novel secreted T3SS substrate, which is required for T3SS functionality. Collectively, presented data indicate that contact with blood represents an important cue for B. pertussis cells. 相似文献
10.
Marta Gabasa Marselina Arshakyan Alejandro Llorente Lourdes Chuli-Peris Irina Pavelescu Antoni Xaubet Javier Pereda Jordi Alcaraz 《International journal of molecular sciences》2020,21(22)
Pro-inflammatory cytokines like interleukin-1β (IL-1β) are upregulated during early responses to tissue damage and are expected to transiently compromise the mechanical microenvironment. Fibroblasts are key regulators of tissue mechanics in the lungs and other organs. However, the effects of IL-1β on fibroblast mechanics and functions remain unclear. Here we treated human pulmonary fibroblasts from control donors with IL-1β and used Atomic Force Microscopy to unveil that IL-1β significantly reduces the stiffness of fibroblasts concomitantly with a downregulation of filamentous actin (F-actin) and alpha-smooth muscle (α-SMA). Likewise, COL1A1 mRNA was reduced, whereas that of collagenases MMP1 and MMP2 were upregulated, favoring a reduction of type-I collagen. These mechanobiology changes were functionally associated with reduced proliferation and enhanced migration upon IL-1β stimulation, which could facilitate lung repair by drawing fibroblasts to sites of tissue damage. Our observations reveal that IL-1β may reduce local tissue rigidity by acting both intracellularly and extracellularly through the downregulation of fibroblast contractility and type I collagen deposition, respectively. These IL-1β-dependent mechanical effects may enhance lung repair further by locally increasing pulmonary tissue compliance to preserve normal lung distension and function. Moreover, our results support that IL-1β provides innate anti-fibrotic protection that may be relevant during the early stages of lung repair. 相似文献