全文获取类型
收费全文 | 1945篇 |
免费 | 87篇 |
国内免费 | 1篇 |
出版年
2023年 | 6篇 |
2022年 | 6篇 |
2021年 | 19篇 |
2020年 | 13篇 |
2019年 | 26篇 |
2018年 | 27篇 |
2017年 | 20篇 |
2016年 | 50篇 |
2015年 | 68篇 |
2014年 | 71篇 |
2013年 | 111篇 |
2012年 | 141篇 |
2011年 | 118篇 |
2010年 | 74篇 |
2009年 | 62篇 |
2008年 | 147篇 |
2007年 | 126篇 |
2006年 | 99篇 |
2005年 | 98篇 |
2004年 | 101篇 |
2003年 | 91篇 |
2002年 | 106篇 |
2001年 | 27篇 |
2000年 | 31篇 |
1999年 | 28篇 |
1998年 | 22篇 |
1997年 | 17篇 |
1996年 | 23篇 |
1995年 | 14篇 |
1994年 | 18篇 |
1993年 | 13篇 |
1992年 | 25篇 |
1991年 | 14篇 |
1990年 | 15篇 |
1989年 | 19篇 |
1988年 | 9篇 |
1987年 | 12篇 |
1986年 | 14篇 |
1985年 | 14篇 |
1984年 | 20篇 |
1983年 | 21篇 |
1982年 | 10篇 |
1981年 | 17篇 |
1980年 | 9篇 |
1979年 | 10篇 |
1978年 | 8篇 |
1977年 | 9篇 |
1975年 | 6篇 |
1972年 | 5篇 |
1970年 | 4篇 |
排序方式: 共有2033条查询结果,搜索用时 343 毫秒
131.
Fujito Kageyama Yoshimasa Kobayashi Gou Murohisa Erina Shimizu Fumitaka Suzuki Masataka Kikuyama Kenichi Souda Tsunehisa Kawasaki Hirotoshi Nakamura 《Biological trace element research》1998,64(1-3):185-196
Recent reports suggest the hepatic iron concentration (HIC) may influence the activity of hepatitis and the response to interferon
(IFN) therapy in patients with chronic hepatitis C (CH-C). We have evaluated iron status in 28 patients with CH-C and determined
if pretreatment iron status can predict the response to IFN-α therapy in these patients. Increased serum iron, transferrin
saturation, and ferritin levels were observed in 3 (11%), 11 (39%), and 5 (18%) patients, respectively. Hepatic iron deposits
were histologically detected in 17 (61%) patients, and 14 of them had stainable hepatocytic iron. However, all HIC values
were within the normal range (203–1279 μg/g). Seven of 17 patients treated with IFN-α for 6 mo had normalization of serum
transaminases and disappearance of serum HCV-RNA (responders). Nonresponders had a significantly higher median HIC compared
with responders (710 vs 343 μg/g, respectively;p < 0.05). There was no significant difference in other pretreatment iron parameters, serum HCV-RNA level, or HCV-genotype between
responders and nonresponders. In conclusion, mild hepatic iron accumulation occurs in patients with CH-C. Increased hepatic
iron stores are associated with poor response to IFN therapy. Pretreatment HIC may be an additional host-specific parameter
with a predictive value for responsiveness to IFN therapy, in addition to well-known predictive viral factors. 相似文献
132.
Soybean meal was fermented withAspergillus usamii to improve zinc availability through the degradation of phytic acid. Rats fed a diet containing fermented soybean meal showed
greater femoral zinc than did animals fed a diet containing regular soybean meal. Zinc solubility in the small intestine was
higher in the rats fed fermented soybean meal than in the rats fed regular soybean meal. These results suggested that fermentation
withAspergillus usamii improved zinc availability in dietary soybean meal, which was induced by the increase of zinc solubility in the small intestine.
Adding the same amount of phytate that was contained in the regular soybean mealbased diet did not affect the amount of zinc
present in rats fed a fermented soybean meal-based diet with sodium phytate. Phytase activity was found in fermented soybean
meal, and this activity may degrade added phytate in fermented soybean meal-based diet. 相似文献
133.
Takeichiro Aso Mioko Matsuo Hideyuki Kiyohara Kenichi Taguchi Fumihide Rikimaru Mototsugu Shimokawa Yuichi Segawa Yuichiro Higaki Hirohito Umeno Tadashi Nakashima Muneyuki Masuda 《PloS one》2015,10(3)
Background
At our institute, a chemoradioselection strategy has been used to select patients for organ preservation on the basis of response to an initial 30–40 Gy concurrent chemoradiotherapy (CCRT). Patients with a favorable response (i.e., chemoradioselected; CRS) have demonstrated better outcomes than those with an unfavorable response (i.e., nonchemoradioselected; N-CRS). Successful targeting of molecules that attenuate the efficacy of chmoradioselection may improve results. Thus, the aim of this study was to evaluate the association of a novel cancer stem cell (CSC) marker, CD44 variant 9 (CD44v9), with cellular refractoriness to chemoradioselection in advanced head and neck squamous cell carcinoma (HNSCC).Materials and Methods
Through a medical chart search, 102 patients with advanced HNSCC treated with chemoradioselection from 1997 to 2008 were enrolled. According to our algorithm, 30 patients were CRC following induction CCRT and 72 patients were N-CRS. Using the conventional immunohistochemical technique, biopsy specimens and surgically removed tumor specimens were immunostained with the anti-CD44v9 specific antibodies.Results
The intrinsic expression levels of CD44v9 in the biopsy specimens did not correlate with the chemoradioselection and patient survival. However, in N-CRS patients, the CD44v9-positive group demonstrated significantly (P = 0.008) worse prognosis, than the CD44v9-negative group. Multivariate analyses demonstrated that among four candidate factors (T, N, response to CCRT, and CD44v9), CD44v9 positivity (HR: 3.145, 95% CI: 1.235–8.008, P = 0.0163) was significantly correlated with the poor prognosis, along with advanced N stage (HR: 3.525, 95% CI: 1.054–9.060, P = 0.0228). Furthermore, the survival rate of the CD44v9-induced group was significantly (P = 0.04) worse than the CD44v9-non-induced group.Conclusions
CCRT-induced CD44v9-expressing CSCs appear to be a major hurdle to chemoradioselection. CD44v9-targeting seems to be a promising strategy to enhance the efficacy of chemoradioselection and consequent organ preservation and survival. 相似文献134.
Kosuke Makino Osamu Takeichi Keisuke Hatori Kenichi Imai Kuniyasu Ochiai Bunnai Ogiso 《PloS one》2015,10(4)
Periapical granulomas are lesions around the apex of a tooth caused by a polymicrobial infection. Treatment with antibacterial agents is normally performed to eliminate bacteria from root canals; however, loss of the supporting alveolar bone is typically observed, and tooth extraction is often selected if root canal treatment does not work well. Therefore, bacteria and other microorganisms could be involved in this disease. To understand the pathogenesis of periapical granulomas more precisely, we focused on the association with Epstein-Barr virus (EBV) using surgically removed periapical granulomas (n = 32). EBV DNA was detected in 25 of 32 periapical granulomas (78.1%) by real-time PCR, and the median number of EBV DNA copies was approximately 8,688.01/μg total DNA. In contrast, EBV DNA was not detected in healthy gingival tissues (n = 10); the difference was statistically significant according to the Mann-Whitney U test (p = 0.0001). Paraffin sections were also analyzed by in situ hybridization to detect EBV-encoded small RNA (EBER)-expressing cells. EBER was detected in the cytoplasm and nuclei of B cells and plasma cells in six of nine periapical granulomas, but not in healthy gingival tissues. In addition, immunohistochemical analysis for latent membrane protein 1 (LMP-1) of EBV using serial tissue sections showed that LMP-1-expressing cells were localized to the same areas as EBER-expressing cells. These data suggest that B cells and plasma cells in inflamed granulomas are a major source of EBV infection, and that EBV could play a pivotal role in controlling immune cell responses in periapical granulomas. 相似文献
135.
Vijayasree V. Giridharan Rajarajan A. Thandavarayan Somasundaram Arumugam Makoto Mizuno Hiroyuki Nawa Kenji Suzuki Kam M. Ko Prasanna Krishnamurthy Kenichi Watanabe Tetsuya Konishi 《PloS one》2015,10(11)
Amyloid β (Aβ)-induced neurotoxicity is a major pathological mechanism of Alzheimer’s disease (AD). Our previous studies have demonstrated that schisandrin B (Sch B), an antioxidant lignan from Schisandra chinensis, could protect mouse brain against scopolamine- and cisplatin-induced neuronal dysfunction. In the present study, we examined the protective effect of Sch B against intracerebroventricular (ICV)-infused Aβ-induced neuronal dysfunction in rat cortex and explored the potential mechanism of its action. Our results showed that 26 days co-administration of Sch B significantly improved the behavioral performance of Aβ (1–40)-infused rats in step-through test. At the same time, Sch B attenuated Aβ-induced increases in oxidative and nitrosative stresses, inflammatory markers such as inducible nitric oxide syntheses, cyclooxygenase-2, interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, and DNA damage. Several proteins such as receptor for advanced glycation end products (RAGE), nuclear factor-κB, mitogen-activated protein kinases, and apoptosis markers were over expressed in Aβ-infused rats but were significantly inhibited by Sch B treatment. Furthermore, Sch B negatively modulated the Aβ level with simultaneous up-regulation of HSP70 and beclin, autophagy markers in Aβ-infused rats. The aforementioned effects of Sch B suggest its protective role against Aβ-induced neurotoxicity through intervention in the negative cycle of RAGE-mediated Aβ accumulation during AD patho-physiology. 相似文献
136.
Stress induces various responses, including translational suppression and tRNA degradation in mammals. Previously, we showed that heat stress induces degradation of initiator tRNAMet (iMet) through 5′–3′ exoribonuclease Xrn1 and Xrn2, respectively. In addition, we found that rapamycin inhibits the degradation of iMet under heat stress conditions. Here, we report that the mammalian target of rapamycin (mTOR) regulates the diffusion of Xrn2 from the nucleolus to the nucleoplasm, facilitating the degradation of iMet under conditions of heat stress. Our results suggest a mechanism of translational suppression through mTOR-regulated iMet degradation in mammalian cells. 相似文献
137.
Kazuo Kusano Takashi Hirai Kenichi Shinomiya 《Biochemical and biophysical research communications》2010,393(4):812-195
Neutrotrophin-3 (NT3) plays a protective role in injured central nervous system tissues through interaction with trk receptors. To enhance the regeneration of damaged tissue, a combination therapy with cell transplantation and neurotrophins has been under development. We examined whether the transplantation of neural progenitor cells (NPCs) secreting NT3/D15A, a multi-neurotrophin with the capacity to bind both trkB and trkC, would enhance the repair of damaged tissues and the functional recovery in a chronic phase of spinal cord injury. The cultured NPCs with lentiviral vector containing either GFP or NT3/D15A were transplanted into the contused spinal cord at 6 weeks after the initial thoracic injury. Eight weeks after the transplantation, the NT3/D15A transplants displayed better survival than the GFP transplants, and they exhibited enhanced myelin formation and partial improvement of hindlimb function. Our study revealed that NT3/D15A produced positive effects in injured spinal cords even in the chronic phase. These effects suggest an enhanced neurotrophin-trk signaling by NT3/D15A. 相似文献
138.
Kitanishi K Kobayashi K Kawamura Y Ishigami I Ogura T Nakajima K Igarashi J Tanaka A Shimizu T 《Biochemistry》2010,49(49):10381-10393
YddV from Escherichia coli (Ec) is a novel globin-coupled heme-based oxygen sensor protein displaying diguanylate cyclase activity in response to oxygen availability. In this study, we quantified the turnover numbers of the active [Fe(III), 0.066 min(-1); Fe(II)-O(2) and Fe(II)-CO, 0.022 min(-1)] [Fe(III), Fe(III)-protoporphyrin IX complex; Fe(II), Fe(II)-protoporphyrin IX complex] and inactive forms [Fe(II) and Fe(II)-NO, <0.01 min(-1)] of YddV for the first time. Our data indicate that the YddV reaction is the rate-determining step for two consecutive reactions coupled with phosphodiesterase Ec DOS activity on cyclic di-GMP (c-di-GMP) [turnover number of Ec DOS-Fe(II)-O(2), 61 min(-1)]. Thus, O(2) binding and the heme redox switch of YddV appear to be critical factors in the regulation of c-di-GMP homeostasis. The redox potential and autoxidation rate of heme of the isolated heme domain of YddV (YddV-heme) were determined to be -17 mV versus the standard hydrogen electrode and 0.0076 min(-1), respectively. The Fe(II) complexes of Y43A and Y43L mutant proteins (residues at the heme distal side of the isolated heme-bound globin domain of YddV) exhibited very low O(2) affinities, and thus, their Fe(II)-O(2) complexes were not detected on the spectra. The O(2) dissociation rate constant of the Y43W protein was >150 s(-1), which is significantly larger than that of the wild-type protein (22 s(-1)). The autoxidation rate constants of the Y43F and Y43W mutant proteins were 0.069 and 0.12 min(-1), respectively, which are also markedly higher than that of the wild-type protein. The resonance Raman frequencies representing ν(Fe-O(2)) (559 cm(-1)) of the Fe(II)-O(2) complex and ν(Fe-CO) (505 cm(-1)) of the Fe(II)-CO complex of Y43F differed from those (ν(Fe-O(2)), 565 cm(-1); ν(Fe-CO), 495 cm(-1)) of the wild-type protein, suggesting that Tyr43 forms hydrogen bonds with both O(2) and CO molecules. On the basis of the results, we suggest that Tyr43 located at the heme distal side is important for the O(2) recognition and stability of the Fe(II)-O(2) complex, because the hydroxyl group of the residue appears to interact electrostatically with the O(2) molecule bound to the Fe(II) complex in YddV. Our findings clearly support a role of Tyr in oxygen sensing, and thus modulation of overall conversion from GTP to pGpG via c-di-GMP catalyzed by YddV and Ec DOS, which may be applicable to other globin-coupled oxygen sensor enzymes. 相似文献
139.
140.
In matured rat oocytes, spontaneous activation from the metaphase-II (MII) stage occurred after collection from the oviducts. It is well known that the mitogen-activated protein kinase (MAPK) pathway and p34(cdc2) kinase play an important role in the arrest at MII in other species. However, there is no information about the difference in these factors among strains of rats. In the present study, in spontaneously activated oocytes from the Wistar rat, the Mos protein level and the activity of MAPK kinase (MEK)/MAPK were decreased at 120 min (13.8, 25.7, and 19.3, respectively, P<0.05), whereas Sprague-Dawley (SD) oocytes, which were not spontaneously activated, had a high level of Mos protein and MEK/MAPK activity (75.9, 76.2, and 87.9, respectively, P<0.05). Phosphorylation of MAPK in the SD oocytes was significantly suppressed by MEK inhibitor, U0126 at 60 min; this treatment decreased p34(cdc2) kinase activity via cyclin B1 degradation in a time-dependent manner. The treatment with proteasome inhibitor, MG132 or Ca2+-chelator, BAPTA-AM, overcame the spontaneous degradation of both Mos and cyclin B1 in a dose-dependent manner in Wistar oocytes. More than 90% of Wistar oocytes treated with BAPTA-AM were arrested at MII until 120 min. In conclusion, SD oocytes carrying Mos/MEK/MAPK, maintained a high activity of p34(cdc2) kinase by stabilizing cyclin B1, thus involved in their meiotic arrest. In contrast, Wistar oocytes had a relatively low cytostatic factor activity; rapid decrease of Mos/MEK/MAPK failed to stabilize both cyclin B1 and Mos, and these oocytes were likely to spontaneously activate. 相似文献