全文获取类型
收费全文 | 474篇 |
免费 | 39篇 |
国内免费 | 1篇 |
出版年
2023年 | 2篇 |
2022年 | 9篇 |
2021年 | 15篇 |
2020年 | 11篇 |
2019年 | 4篇 |
2018年 | 11篇 |
2017年 | 9篇 |
2016年 | 17篇 |
2015年 | 27篇 |
2014年 | 40篇 |
2013年 | 34篇 |
2012年 | 42篇 |
2011年 | 42篇 |
2010年 | 30篇 |
2009年 | 17篇 |
2008年 | 19篇 |
2007年 | 17篇 |
2006年 | 17篇 |
2005年 | 15篇 |
2004年 | 13篇 |
2003年 | 11篇 |
2002年 | 17篇 |
2001年 | 10篇 |
2000年 | 5篇 |
1999年 | 10篇 |
1998年 | 8篇 |
1997年 | 2篇 |
1996年 | 5篇 |
1995年 | 3篇 |
1993年 | 6篇 |
1992年 | 4篇 |
1991年 | 4篇 |
1990年 | 5篇 |
1989年 | 5篇 |
1988年 | 3篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1983年 | 4篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1979年 | 3篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1975年 | 3篇 |
1973年 | 1篇 |
1971年 | 2篇 |
1969年 | 1篇 |
1966年 | 1篇 |
排序方式: 共有514条查询结果,搜索用时 390 毫秒
91.
92.
93.
Tran Tinh Hien Nguyen Thi Dung Nguyen Thanh Truong Ninh Thi Thanh Van Tran Nguyen Bich Chau Nguyen Van Minh Hoang Tran Thi Thu Nga Cao Thu Thuy Pham Van Minh Nguyen Thi Cam Binh Tran Thi Diem Ha Pham Van Toi To Song Diep James I. Campbell Elaine Stockwell Constance Schultsz Cameron P. Simmons Clare Glover Winnie Lam Filipe Marques James P. May Anthony Upton Ronald Budhram Gordon Dougan Jeremy Farrar Nguyen Van Vinh Chau Christiane Dolecek 《PloS one》2010,5(7)
Background
The emergence of drug resistant typhoid fever is a major public health problem, especially in Asia. An oral single dose typhoid vaccine would have major advantages. M01ZH09 is a live oral single dose candidate typhoid vaccine containing Salmonella enterica serovar Typhi (Ty2 aroC − ssaV −) ZH9 with two independently attenuating deletions. Studies in healthy adults demonstrated immunogenicity and an acceptable safety profile.Objectives
We conducted a randomised placebo controlled, single-blind trial to evaluate the safety and immunogenicity of M01ZH09 in healthy Vietnamese children aged 5 to 14 years.Methods
Subjects were randomly assigned to receive either a nominal dose of 5×109 CFU of M01ZH09 or placebo and were followed up for 28 days. The primary safety outcome was the proportion of subjects with any adverse event attributed to M01ZH09. The primary immunogenicity endpoint was the proportion of subjects who showed a positive immune response to M01ZH09 in the Salmonella Typhi lipopolysaccharide (LPS) specific serum IgA and IgG ELISA.Principal Findings
One hundred and fifty-one children were enrolled, 101 subjects received M01ZH09 and 50 subjects received placebo. An intention to treat analysis was conducted. There were no serious adverse events and no bacteraemias. In the M01ZH09 group, 26 (26%; 95% CI, 18–5%) of 101 subjects experienced adverse events compared to 11 (22%; 95% CI, 12–36%) of 50 subjects in the placebo group (odds ratio (OR) [95%CI] = 1.23 [0.550–2.747]; p = 0.691). Faecal shedding of S. Typhi (Ty2 aroC − ssaV −) ZH9 was detected in 51 (51%; 95% CI, 41–61%) of 100 M01ZH09 subjects. No shedding was detected beyond day 3. A positive immune response, defined as 70% increase (1.7 fold change) in LPS specific serum IgG (day 14 or 28) and/or 50% increase (1.5 fold change) in LPS specific serum IgA (day 7 or 14) from baseline was detected in 98 (97%; 95% CI, 92–99%) of 101 M01ZH09 recipients and 8 (16%; 95% CI, 7–29%) of 50 placebo recipients. Twenty-eight (100%; 95% CI, 88–100%) of 28 vaccine recipients who were evaluated in the LPS specific IgA ELISPOT assay showed a positive response compared to none of the 14 placebo recipients tested.Conclusions
This was the first phase II trial of a novel oral candidate typhoid vaccine in children in an endemic country. M01ZH09 had an appropriate safety profile and was immunogenic in children.Trial Registration
Controlled-trials.comISRCTN91111837 相似文献94.
To TK Nakaminami K Kim JM Morosawa T Ishida J Tanaka M Yokoyama S Shinozaki K Seki M 《Biochemical and biophysical research communications》2011,(3):414-419
The control of energy homeostasis within the hypothalamus is under the regulated control of homeostatic hormones, nutrients and the expression of neuropeptides that alter feeding behavior. Elevated levels of palmitate, a predominant saturated fatty acid in diet and fatty acid biosynthesis, alter cellular function. For instance, a key mechanism involved in the development of insulin resistance is lipotoxicity, through increased circulating saturated fatty acids. Although many studies have begun to determine the underlying mechanisms of lipotoxicity in peripheral tissues, little is known about the effects of excess lipids in the brain. To determine these mechanisms we used an immortalized, clonal, hypothalamic cell line, mHypoE-44, to demonstrate that palmitate directly alters the expression of molecular clock components, by increasing Bmal1 and Clock, or by decreasing Per2, and Rev-erbα, their mRNA levels and altering their rhythmic period within individual neurons. We found that these neurons endogenously express the orexigenic neuropeptides NPY and AgRP, thus we determined that palmitate administration alters the mRNA expression of these neuropeptides as well. Palmitate treatment causes a significant increase in NPY mRNA levels and significantly alters the phase of rhythmic expression. We explored the link between AMPK and the expression of neuropeptide Y using the AMPK inhibitor compound C and the AMP analog AICAR. AMPK inhibition decreased NPY mRNA. AICAR also elevated basal NPY, but prevented the palmitate-mediated increase in NPY mRNA levels. We postulate that this palmitate-mediated increase in NPY and AgRP synthesis may initiate a detrimental positive feedback loop leading to increased energy consumption. 相似文献
95.
Huchen Hucho hucho from the Drina River (Serbia) revealed recently the decrease in breakpoint values for both standard length (Sl) and weight (w) in relation to the values recorded in 1999 from 110 cm to 98.4 cm and from 16.5 kg to 10.5 kg, respectively. That might
indicate to the change in certain population parameters that could have an influence to the growth in the adult period of
life. 相似文献
96.
97.
Christos G. Savva Jill S. Dewey Samir H. Moussa Kam H. To Andreas Holzenburg Ry Young 《Molecular microbiology》2014,91(1):57-65
At a programmed time in phage infection cycles, canonical holins suddenly trigger to cause lethal damage to the cytoplasmic membrane, resulting in the cessation of respiration and the non‐specific release of pre‐folded, fully active endolysins to the periplasm. For the paradigm holin S105 of lambda, triggering is correlated with the formation of micron‐scale membrane holes, visible as interruptions in the bilayer in cryo‐electron microscopic images and tomographic reconstructions. Here we report that the size distribution of the holes is stable for long periods after triggering. Moreover, early triggering caused by an early lysis allele of S105 formed approximately the same number of holes, but the lesions were significantly smaller. In contrast, early triggering prematurely induced by energy poisons resulted in many fewer visible holes, consistent with previous sizing studies. Importantly, the unrelated canonical holins P2 Y and T4 T were found to cause the formation of holes of approximately the same size and number as for lambda. In contrast, no such lesions were visible after triggering of the pinholin S2168. These results generalize the hole formation phenomenon for canonical holins. A model is presented suggesting the unprecedentedly large size of these holes is related to the timing mechanism. 相似文献
98.
Tan To Cheung Ronnie T. P. Poon Kenneth S. H. Chok Albert C. Y. Chan Simon H. Y. Tsang Wing Chiu Dai Thomas C. C. Yau See Ching Chan Sheung Tat Fan Chung Mau Lo 《PloS one》2014,9(4)
Background and aim
Spontaneous rupture of hepatocellular carcinoma (HCC) carries a high mortality. The use of radiofrequency ablation (RFA) in recent years has enriched the armamentarium for hemostasis of spontaneously ruptured HCCs but its results have not been documented. This study investigated the prognosis and outcome of spontaneous rupture of HCC as well as the results of using RFA for hemostasis.Patients and method
From January 1991 to December 2010, 5283 patients were diagnosed with HCC at our hospital, and 189 of them had spontaneous rupture of HCCs. They were grouped under two periods: period 1, 1991–2000, n = 70; period 2, 2001–2010, n = 119. RFA was available in period 2 only.Results
Hepatitis B virus infection was predominant in both periods. Surgical hemostasis was mainly achieved by hepatic artery ligation in period 1 and by RFA in period 2. The 30-day hospital mortality after surgical treatment was 55.6% (n = 18) in period 1 and 19.2% (n = 26) in period 2 (p = 0.012). Multivariate analysis identified 4 independent factors for better overall survival, namely, hemostasis by transarterial chemoembolization (hazard ratio 0.516, 95% confidence interval 0.354–0.751), hemostasis by RFA (hazard ratio 0.431, 95% confidence interval 0.236–0.790), having surgery as a subsequent treatment (hazard ratio 0.305, 95% confidence interval 0.186–0.498), and a serum total bilirubin level <19 umol/L (hazard ratio 1.596, 95% confidence interval 1.137–2.241).Conclusion
The use of RFA for hemostasis during laparotomy greatly reduced the hospital mortality rate when compared with conventional hepatic artery ligation. 相似文献99.
Yan Han Man To Ling Huawei Mao Jian Zheng Ming Liu Kwok Tai Lam Yuan Liu Wenwei Tu Yu-Lung Lau 《PloS one》2014,9(1)
Although smokers have increased susceptibility and severity of seasonal influenza virus infection, there is no report about the risk of 2009 pandemic H1N1 (pdmH1N1) or avian H9N2 (H9N2/G1) virus infection in smokers. In our study, we used mouse model to investigate the effect of cigarette smoke on pdmH1N1 or H9N2 virus infection. Mice were exposed to cigarette smoke for 21 days and then infected with pdmH1N1 or H9N2 virus. Control mice were exposed to air in parallel. We found that cigarette smoke exposure alone significantly upregulated the lung inflammation. Such prior cigarette smoke exposure significantly reduced the disease severity of subsequent pdmH1N1 or H9N2 virus infection. For pdmH1N1 infection, cigarette smoke exposed mice had significantly lower mortality than the control mice, possibly due to the significantly decreased production of inflammatory cytokines and chemokines. Similarly, after H9N2 infection, cigarette smoke exposed mice displayed significantly less weight loss, which might be attributed to lower cytokines and chemokines production, less macrophages, neutrophils, CD4+ and CD8+ T cells infiltration and reduced lung damage compared to the control mice. To further investigate the underlying mechanism, we used nicotine to mimic the effect of cigarette smoke both in vitro and in vivo. Pre-treating the primary human macrophages with nicotine for 72 h significantly decreased their expression of cytokines and chemokines after pdmH1N1 or H9N2 infection. The mice subcutaneously and continuously treated with nicotine displayed significantly less weight loss and lower inflammatory response than the control mice upon pdmH1N1 or H9N2 infection. Moreover, α7 nicotinic acetylcholine receptor knockout mice had more body weight loss than wild-type mice after cigarette smoke exposure and H9N2 infection. Our study provided the first evidence that the pathogenicity of both pdmH1N1 and H9N2 viruses was alleviated in cigarette smoke exposed mice, which might partially be attributed to the immunosuppressive effect of nicotine. 相似文献
100.
Roch K. Dabiré Moussa Namountougou Abdoulaye Diabaté Dieudonné D. Soma Joseph Bado Hyacinthe K. Toé Chris Bass Patrice Combary 《PloS one》2014,9(7)
An entomological survey was carried out at 15 sites dispersed throughout the three eco-climatic regions of Burkina Faso (West Africa) in order to assess the current distribution and frequency of mutations that confer resistance to insecticides in An. gambiae s.l. populations in the country. Both knockdown (kdr) resistance mutation variants (L1014F and L1014S), that confer resistance to pyrethroid insecticides, were identified concomitant with the ace-1 G119S mutation confirming the presence of multiple resistance mechanisms in the An. gambiae complex in Burkina Faso. Compared to the last survey, the frequency of the L1014F kdr mutation appears to have remained largely stable and relatively high in all species. In contrast, the distribution and frequency of the L1014S mutation has increased significantly in An. gambiae s.l. across much of the country. Furthermore we report, for the first time, the identification of the ace.1 G116S mutation in An. arabiensis populations collected at 8 sites. This mutation, which confers resistance to organophosphate and carbamate insecticides, has been reported previously only in the An. gambiae S and M molecular forms. This finding is significant as organophosphates and carbamates are used in indoor residual sprays (IRS) to control malaria vectors as complementary strategies to the use of pyrethroid impregnated bednets. The occurrence of the three target-site resistance mutations in both An. gambiae molecular forms and now An. arabiensis has significant implications for the control of malaria vector populations in Burkina Faso and for resistance management strategies based on the rotation of insecticides with different modes of action. 相似文献