全文获取类型
收费全文 | 1358篇 |
免费 | 106篇 |
国内免费 | 7篇 |
专业分类
耳鼻咽喉 | 13篇 |
儿科学 | 29篇 |
妇产科学 | 29篇 |
基础医学 | 192篇 |
口腔科学 | 17篇 |
临床医学 | 73篇 |
内科学 | 270篇 |
皮肤病学 | 153篇 |
神经病学 | 129篇 |
特种医学 | 56篇 |
外科学 | 76篇 |
综合类 | 4篇 |
预防医学 | 47篇 |
眼科学 | 88篇 |
药学 | 96篇 |
中国医学 | 3篇 |
肿瘤学 | 196篇 |
出版年
2023年 | 9篇 |
2022年 | 19篇 |
2021年 | 27篇 |
2020年 | 19篇 |
2019年 | 29篇 |
2018年 | 57篇 |
2017年 | 32篇 |
2016年 | 44篇 |
2015年 | 39篇 |
2014年 | 48篇 |
2013年 | 72篇 |
2012年 | 87篇 |
2011年 | 117篇 |
2010年 | 54篇 |
2009年 | 57篇 |
2008年 | 87篇 |
2007年 | 111篇 |
2006年 | 85篇 |
2005年 | 85篇 |
2004年 | 93篇 |
2003年 | 79篇 |
2002年 | 77篇 |
2001年 | 5篇 |
2000年 | 12篇 |
1999年 | 14篇 |
1998年 | 24篇 |
1997年 | 13篇 |
1996年 | 9篇 |
1995年 | 2篇 |
1994年 | 5篇 |
1993年 | 4篇 |
1992年 | 5篇 |
1990年 | 6篇 |
1989年 | 6篇 |
1988年 | 2篇 |
1987年 | 4篇 |
1986年 | 5篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 5篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1978年 | 1篇 |
1977年 | 2篇 |
1976年 | 1篇 |
1974年 | 1篇 |
1972年 | 1篇 |
1932年 | 1篇 |
1931年 | 1篇 |
1930年 | 2篇 |
排序方式: 共有1471条查询结果,搜索用时 15 毫秒
31.
32.
Xiaoli Guo Atsuko Kimura Kazuhiko Namekata Chikako Harada Nobutaka Arai Kohsuke Takeda Hidenori Ichijo Takayuki Harada 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(6)
Neuroinflammation is well known to be associated with neurodegenerative diseases. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that has been implicated in neuroinflammation, but its precise cellular and molecular mechanisms remain unknown. In this study, we generated conditional knockout (CKO) mice that lack ASK1 in T cells, dendritic cells, microglia/macrophages, microglia, or astrocytes, to assess the roles of ASK1 during experimental autoimmune encephalomyelitis (EAE). We found that neuroinflammation was reduced in both the early and later stages of EAE in microglia/macrophage-specific ASK1 knockout mice, whereas only the later-stage neuroinflammation was ameliorated in astrocyte-specific ASK1 knockout mice. ASK1 deficiency in T cells and dendritic cells had no significant effects on EAE severity. Further, we found that ASK1 in microglia/macrophages induces a proinflammatory environment, which subsequently activates astrocytes to exacerbate neuroinflammation. Microglia-specific ASK1 deletion was achieved using a CX3CR1CreER system, and we found that ASK1 signaling in microglia played a major role in generating and maintaining disease. Activated astrocytes produce key inflammatory mediators, including CCL2, that further activated and recruited microglia/macrophages, in an astrocytic ASK1-dependent manner. Astrocyte-specific analysis revealed CCL2 expression was higher in the later stage compared with the early stage, suggesting a greater proinflammatory role of astrocytes in the later stage. Our findings demonstrate cell-type–specific roles of ASK1 and suggest phase-specific ASK1-dependent glial cell interactions in EAE pathophysiology. We propose glial ASK1 as a promising therapeutic target for reducing neuroinflammation.Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK) kinase kinase that stimulates the c-Jun N-terminal kinase (JNK) and p38 MAPK pathways, and it mediates diverse biological signals leading to cell death, differentiation, and senescence (1, 2). Deletion of ASK1 in mice suppresses neuronal cell death from injury (3, 4), and recent studies indicate that ASK1 is involved in various neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis (MS) (5–8). MS is an inflammatory disease of the central nervous system (CNS) characterized by localized areas of demyelination. Experimental autoimmune encephalomyelitis (EAE) is a classic model widely used to explore pathogenic mechanisms of MS, generated by administering a myelin basic protein peptide that induces an autoimmune response directed to myelin (9). During MS/EAE, activated microglia/macrophages are the first cells to respond to inflammatory insults within the CNS. Microglia/macrophages may be polarized into proinflammatory or antiinflammatory states, with each state having a distinct molecular phenotype and effector function, and targeting microglia/macrophages may have therapeutic benefits in MS/EAE treatment (10–12). Astrocytes, another subset of glia, are the most abundant cell population within the CNS. Astrocytes are involved in the regulation of synaptic function, plasticity, and maintaining brain homeostasis, and they are thought to contribute to the pathogenesis of MS/EAE by producing proinflammatory cytokine/chemokines such as CCL2 (13–16). In recent years, astrocytes have also been shown to polarize into different subtypes: A1 astrocytes are neurotoxic, and blocking the conversion of astrocytes into the A1 phenotype is neuroprotective (17, 18); although, nowadays, the activation state is described to be more diverse than the simple A1/A2 nomenclature (19, 20). Studies of intrinsic and external factors involved in astrocyte activation or polarization may provide information regarding how astrocytic function changes during disease, which may lead to the development of novel therapies.We previously reported that ASK1 deficiency ameliorated the severity of EAE, using conventional ASK1 knockout (ASK1 KO) mice (21). In this study, we selectively deleted ASK1 from five types of cells: T cells, dendritic cells, microglia/macrophages, microglia, and astrocytes, to dissect out the roles of ASK1 in different cell types during neuroinflammation. Our study revealed pathogenic roles of ASK1 signaling in innate immune cells and how they interact with each other in the progression of MS/EAE. 相似文献
33.
Case of Mycobacterium haemophilum misdiagnosed as Mycobacterium intracellulare due to one base insertion in the bacterial genome 下载免费PDF全文
Rika Nishikawa Yozo Yamada Haruhisa Kanki Hiroshi Matsuoka Tatsuya Nakamura Takumi Jikimoto Mari Kusuki Norihisa Ishii Kenichiro Ohnuma Kazue Nakanaga Chikako Nishigori 《The Journal of dermatology》2018,45(1):64-66
Mycobacterium haemophilum is a slow‐growing, non‐tuberculous mycobacteria that causes cutaneous infection. We describe a case of cutaneous infection in a 68‐year‐old Japanese man with polymyositis. This was caused by M. haemophilum harboring one base insertion in gene sequence. At first, the causal microorganism was misidentified as M. intracellulare by COBAS® TaqMan® MAI test. However, poor growth on Ogawa media and growth enhancement on 7H11C agar around a hemin‐containing disk prompted us to reinvestigate the causal microorganisms, which were revealed to be M. haemophilum. Amplified polymerase chain reaction products were sequenced, and the 16S rRNA gene, rpoB, hsp65 and internal transcribed spacer region sequences showed a 100%, 100%, 99.66% and 99.7% match, respectively, with the corresponding regions of M. haemophilum, but it harbored a novel gene sequence in hsp65. The sequences determined by gene analysis of the M. haemophilum strain were deposited into the International Nucleotide Sequence Database. Although numerous cases of M. haemophilum infection have been reported in other countries, only six cases have been reported in Japan to date. It could be possible that this novel mutation lead to misdiagnosis. As M. haemophilum prefers a lower growth temperature (30–32°C) and it requires iron in the culture medium, M. haemophilum could be misidentified or overlooked. Accordingly, a M. haemophilum infection should be considered in cases of cutaneous infection of the body sites, of which surface temperature is low. 相似文献
34.
Cutaneous squamous cell carcinoma,thyroid cancer and Langerhans cell histiocytosis in a patient with X‐linked recessive Mendelian susceptibility to mycobacterial diseases with a nuclear factor‐κB essential modifier mutation 下载免费PDF全文
Yuta Inoue Akira Shimizu Mariko Suto Chikako Kishi Ayumi Takahashi Masahito Yasuda Mayuko Iijima Hirokazu Arakawa Osamu Ishikawa 《The Journal of dermatology》2018,45(8):1017-1019
Nuclear factor (NF)‐κB essential modifier (NEMO), also known as IκB kinase subunit‐γ (IKKγ), is a pivotal molecule in the NF‐κB signaling pathway. Mutations of NEMO cause incontinentia pigmenti and X‐linked ectodermal dysplasia with immunodeficiency. Mendelian susceptibility to mycobacterial diseases (MSMD), which confers an almost selective predisposition to mycobacterial infection, is also caused by NEMO mutations. We herein report the first case of a patient with X‐linked recessive (XR) MSMD who developed cutaneous squamous cell carcinoma, thyroid cancer and Langerhans cell histiocytosis. The relationship between NEMO mutation and oncogenesis is discussed. 相似文献
35.
Noriko Goto Mariko Tsujimoto Hiroshi Nagai Taro Masaki Shosuke Ito Kazumasa Wakamatsu Chikako Nishigori 《Experimental dermatology》2018,27(7):754-762
4‐(4‐Hydroxyphenyl)‐2‐butanol (rhododendrol, RD), a skin‐whitening agent, was reported to cause skin depigmentation in some users, which is attributed to its cytotoxicity to melanocyte. It was reported that cytotoxicity to melanocyte is possibly mediated by oxidative stress in a tyrosinase activity‐dependent manner. We examined the effect of UV radiation (UVR) on RD‐induced melanocyte cytotoxicity as an additional aggravating factor. UVR enhanced RD‐induced cytotoxicity in normal human epidermal melanocytes (NHEMs) via the induction of endoplasmic reticulum (ER) stress. Increased generation of intracellular reactive oxygen species (ROS) was detected. Pretreatment with N‐acetyl cysteine (NAC), antioxidant and precursor of glutathione significantly attenuated ER stress‐induced cytotoxicity in NHEMs treated with RD and UVR. Increase in cysteinyl‐RD‐catechol and RD‐pheomelanin in NHEMs treated with RD and UVR suggested that, after UVR excitation, RD or RD metabolites are potent ROS‐generating substances and that the tendency to produce RD‐pheomelanin during melanogenesis amplifies ROS generation in melanocytes. Our results help to elucidate the development mechanisms of RD‐induced leukoderma and provide information for innovation of safe skin‐whitening compounds. 相似文献
36.
Sachiko Kawasaki-Yatsugi Shin-ichi Yatsugi Masayasu Takahashi Takashi Toya Chikako Ichiki Masao Shimizu-Sasamata Tokio Yamaguchi Kazuo Minematsu 《Brain research》1998,793(1-2)
The neuroprotective effect of YM872 ([2.3-dioxo-7-(1H-imidazol-1-yl) 6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]acetic acid monohydrate), a novel α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist with improved water solubility, was examined in a rat focal cerebral ischemia model. Rats were subjected to permanent middle cerebral artery (MCA) occlusion using the intraluminal suture occlusion method for 24 h. YM872 was intravenously infused for 4 h (20 and 40 mg/kg/h) or 24 h (10 and 20 mg/kg/h), starting 5 min after the MCA occlusion, to investigate the effect of prolonged duration of the treatment on infarct volume. In the 4 h infusion study, YM872 reduced the cortical infarct volume by 48% at a dose of 40 mg/kg/h. YM872 did not significantly reduce the infarct at 20 mg/kg/h for 4 h. In the 24 h infusion study, however, YM872 markedly reduced the cortical infarct volume by 62%, even at 20 mg/kg/h. The present study indicates that the neuroprotective effect of YM872 is enhanced by extending the duration of treatment, and demonstrates the benefit of the prolonged treatment with AMPA antagonists following focal cerebral ischemia. YM872, a highly water soluble compound, is applicable to investigate the role of AMPA receptors in ischemic models without concern about nephrotoxicity and could be useful in the treatment of human stroke. 相似文献
37.
Habuchi C Iritani S Sekiguchi H Torii Y Ishihara R Arai T Hasegawa M Tsuchiya K Akiyama H Shibayama H Ozaki N 《Journal of the neurological sciences》2011,301(1-2):77-85
Diffuse neurofibrillary tangles with calcification (DNTC) is a relatively rare presenile dementia that clinically shows overlapping symptoms of Alzheimer's disease and frontotemporal lobar degeneration (FTLD). DNTC is pathologically characterized by localized temporal or frontotemporal atrophy with massive neurofibrillary tangles, neuropil threads and Fahr's-type calcification without senile plaques. We tried to clarify the molecular basis of DNTC by immunohistochemically examining the appearance and distribution of accumulated alpha-synuclein (aSyn) and TAR DNA-binding protein of 43kDa (TDP-43) in the brains of 10 Japanese autopsy cases. We also investigated the clinically characteristic symptoms from the clinical charts and previous reports, and the correlations with neuropathological findings. The characteristic symptoms were evaluated using the Neuropsychiatric Inventory Questionnaire (NPI-Q). As a result, we confirmed the high frequency of neuronal cytoplasmic accumulation of aSyn (80%) and phosphorylated TDP-43 (90%) in DNTC cases. There was a significant correlation between some selected items of NPI-Q scores and the severity of the limbic TDP-43 pathology. The pathology of DNTC included TDP-43 and aSyn pathology with high frequency. These abnormal accumulations of TDP-43 might be involved in the pathological process of DNTC, having a close relationship to the FTLD-like psychiatric symptoms during the clinical course. 相似文献
38.
Clearance of apoptotic photoreceptors: elimination of apoptotic debris into the subretinal space and macrophage-mediated phagocytosis via phosphatidylserine receptor and integrin alphavbeta3 总被引:1,自引:0,他引:1 下载免费PDF全文
Hisatomi T Sakamoto T Sonoda KH Tsutsumi C Qiao H Enaida H Yamanaka I Kubota T Ishibashi T Kura S Susin SA Kroemer G 《The American journal of pathology》2003,162(6):1869-1879
The effective phagocytotic clearance of apoptotic debris is fundamental to the maintenance of neural tissues during apoptosis. Retinal photoreceptors undergo apoptosis after retinal detachment. Although their induction phase of apoptosis has been well discussed, their phagocytotic process remains quite unclear. We herein demonstrate that apoptotic photoreceptors are selectively eliminated from their physiological localization, the outer nuclear layer, to the subretinal space, and then phagocytosed by monocyte-derived macrophages. This could be shown by an ultrastructural and immunophenotypic analysis. Moreover, in chimera mice expressing transgenic green fluorescent protein in bone marrow-derived cells, the local infiltration of macrophages could be detected after retinal detachment-induced photoreceptor apoptosis. The local injection of an antibody blocking the phosphatidylserine receptor (PSR) or a peptide (GRGDSP)-blocking integrin alphavbeta3 revealed that phagocytotic clearance involves the PSR as well as integrin alphavbeta3 in vivo. Importantly, the level of blockade obtained with these reagents was different. Although anti-PSR increased the frequency of apoptotic cells that fail to bind to macrophages, GRGDSP prevented the engulfment (but not the recognition) of apoptotic photoreceptor cells by macrophages. To our knowledge, this is the first report describing the mechanisms through which apoptotic photoreceptors are selectively eliminated via a directional process in the subretinal space. 相似文献
39.
Preoperative diagnosis of clear cell sarcoma of the kidney by detection of BCOR internal tandem duplication in circulating tumor DNA 下载免费PDF全文
Hitomi Ueno‐Yokohata Hajime Okita Keiko Nakasato Tomoro Hishiki Ryota Shirai Shinichi Tsujimoto Tomoo Osumi Satoshi Yoshimura Yuji Yamada Yoko Shioda Chikako Kiyotani Keita Terashima Osamu Miyazaki Kimikazu Matsumoto Nobutaka Kiyokawa Takako Yoshioka Motohiro Kato 《Genes, chromosomes & cancer》2018,57(10):525-529
Clear cell sarcoma of the kidney (CCSK) is the second most common renal malignancy in children. The prognosis is poorer in CCSK than in Wilms’ tumor, and multimodal treatment including surgery, intensive chemotherapy, and radiation is required to improve the outcome for children with CCSK. Histological evaluation is required for the diagnosis. However, biopsies of tumors to obtain diagnostic specimens are not routinely performed because of the risk of spreading tumor cells during the procedure. Recently, internal tandem duplication (ITD) of BCOR has been recognized as a genetic hallmark of CCSK. We herein established a novel BCOR‐ITD‐specific polymerase chain reaction method with well‐designed primers, and then performed a liquid biopsy for cell‐free DNA (cfDNA) obtained from plasma of three children with nonmetastatic renal tumors (stage II) and from one control. BCOR‐ITD was positively detected in the cfDNA of two cases, both of which were later diagnosed as CCSK based on histological feature of the resected tumor specimen, while it was not detected for a normal control and a patient diagnosed with Wilms’ tumor. Our study is the first one of preoperative circulating tumor DNA assay in pediatric renal tumors. The liquid biopsy method enables less invasive, preoperative diagnosis of CCSK with no risk of tumor spillage, which can avoid iatrogenic upstaging. 相似文献
40.
Chikako Kamae Kohsuke Imai Tamaki Kato Tsubasa Okano Kenichi Honma Noriko Nakagawa Tzu-Wen Yeh Emiko Noguchi Akira Ohara Tomonari Shigemura Hiroshi Takahashi Shunichi Takakura Masatoshi Hayashi Aoi Honma Seiichi Watanabe Tomoko Shigemori Osamu Ohara Hiroyuki Sasaki Takeo Kubota Tomohiro Morio Hirokazu Kanegane Shigeaki Nonoyama 《Journal of clinical immunology》2018,38(8):927-937