全文获取类型
收费全文 | 1226篇 |
免费 | 55篇 |
国内免费 | 5篇 |
专业分类
1286篇 |
出版年
2024年 | 4篇 |
2023年 | 23篇 |
2022年 | 48篇 |
2021年 | 103篇 |
2020年 | 48篇 |
2019年 | 47篇 |
2018年 | 72篇 |
2017年 | 47篇 |
2016年 | 56篇 |
2015年 | 78篇 |
2014年 | 80篇 |
2013年 | 89篇 |
2012年 | 99篇 |
2011年 | 89篇 |
2010年 | 44篇 |
2009年 | 45篇 |
2008年 | 43篇 |
2007年 | 41篇 |
2006年 | 21篇 |
2005年 | 32篇 |
2004年 | 25篇 |
2003年 | 27篇 |
2002年 | 18篇 |
2000年 | 8篇 |
1999年 | 3篇 |
1998年 | 6篇 |
1997年 | 7篇 |
1996年 | 4篇 |
1995年 | 7篇 |
1994年 | 3篇 |
1993年 | 3篇 |
1992年 | 6篇 |
1991年 | 9篇 |
1990年 | 4篇 |
1989年 | 6篇 |
1988年 | 3篇 |
1985年 | 4篇 |
1984年 | 6篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1976年 | 1篇 |
1974年 | 1篇 |
1972年 | 2篇 |
1970年 | 1篇 |
1966年 | 1篇 |
1965年 | 2篇 |
1964年 | 1篇 |
1962年 | 1篇 |
排序方式: 共有1286条查询结果,搜索用时 15 毫秒
101.
Mohammad Islamuddin Garima Chouhan Abdullah Farooque Bilikere S. Dwarakanath Dinkar Sahal Farhat Afrin 《PLoS neglected tropical diseases》2015,9(1)
Background
In the absence of vaccines and limitations of currently available chemotherapy, development of safe and efficacious drugs is urgently needed for visceral leishmaniasis (VL) that is fatal, if left untreated. Earlier we reported in vitro apoptotic antileishmanial activity of n-hexane fractions of Artemisia annua leaves (AAL) and seeds (AAS) against Leishmania donovani. In the present study, we investigated the immunostimulatory and therapeutic efficacy of AAL and AAS.Methodology/Principal Findings
Ten-weeks post infection, BALB/c mice were orally administered AAL and AAS for ten consecutive days. Significant reduction in hepatic (86.67% and 89.12%) and splenic (95.45% and 95.84%) parasite burden with decrease in spleen weight was observed. AAL and AAS treated mice induced the strongest DTH response, as well as three-fold decrease in IgG1 and two-fold increase in IgG2a levels, as compared to infected controls. Cytometric bead array further affirmed the elicitation of Th1 immune response as indicated by increased levels of IFN-γ, and low levels of Th2 cytokines (IL-4 and IL-10) in serum as well as in culture supernatant of lymphocytes from treated mice. Lymphoproliferative response, IFN-γ producing CD4+ and CD8+ T lymphocytes and nitrite levels were significantly enhanced upon antigen recall in vitro. The co-expression of CD80 and CD86 on macrophages was significantly augmented. CD8+ T cells exhibited CD62Llow and CD44hi phenotype, signifying induction of immunological memory in AAL and AAS treated groups. Serum enzyme markers were in the normal range indicating inertness against nephro- and hepato-toxicity.Conclusions/Significance
Our results establish the two-prong antileishmanial efficacy of AAL and AAS for cure against L. donovani that is dependent on both the direct leishmanicidal action as well as switching-on of Th1-biased protective cell-mediated immunity with generation of memory. AAL and AAS could represent adjunct therapies for the treatment of leishmaniasis, either alone or in combination with other antileishmanial agents. 相似文献102.
Maternal hypoxia is associated with a decrease in left ventricular capillary density while cardiac performance is preserved, implying a mismatch between metabolism and diffusive exchange. We hypothesised this requires a switch in substrate metabolism to maximise efficiency of ATP production from limited oxygen availability. Rat pups from pregnant females exposed to hypoxia (FIO2=0.12) at days 10-20 of pregnancy were grown to adulthood and working hearts perfused ex vivo. 14C-labelled glucose and 3H-palmitate were provided as substrates and metabolism quantified from recovery of 14CO2 and 3H2O, respectively. Hearts of male offspring subjected to Maternal Hypoxia showed a 20% decrease in cardiac output (P<0.05), despite recording a 2-fold increase in glucose oxidation (P<0.01) and 2.5-fold increase (P<0.01) in palmitate oxidation. Addition of insulin to Maternal Hypoxic hearts, further increased glucose oxidation (P<0.01) and suppressed palmitate oxidation (P<0.05), suggesting preservation in insulin signalling in the heart. In vitro enzyme activity measurements showed that Maternal Hypoxia increased both total and the active component of cardiac pyruvate dehydrogenase (both P<0.01), although pyruvate dehydrogenase sensitivity to insulin was lost (NS), while citrate synthase activity declined by 30% (P<0.001) and acetyl-CoA carboxylase activity was unchanged by Maternal Hypoxia, indicating realignment of the metabolic machinery to optimise oxygen utilisation. Capillary density was quantified and oxygen diffusion characteristics examined, with calculated capillary domain area increased by 30% (P<0.001). Calculated metabolic efficiency decreased 4-fold (P<0.01) for Maternal Hypoxia hearts. Paradoxically, the decline in citrate synthase activity and increased metabolism suggest that the scope of individual mitochondria had declined, rendering the myocardium potentially more sensitive to metabolic stress. However, decreasing citrate synthase may be essential to preserve local PO2, minimising regions of hypoxia and hence maximising the area of myocardium able to preserve cardiac output following maternal hypoxia. 相似文献
103.
104.
Rick?K. Huang Ulrich Baxa Gudrun Aldrian Abdullah?B. Ahmed Joseph?S. Wall Naoko Mizuno Oleg Antzutkin Alasdair?C. Steven Andrey?V. Kajava 《Biophysical journal》2014,106(10):2134-2142
The established correlation between neurodegenerative disorders and intracerebral deposition of polyglutamine aggregates motivates attempts to better understand their fibrillar structure. We designed polyglutamines with a few lysines inserted to overcome the hindrance of extreme insolubility and two D-lysines to limit the lengths of β-strands. One is 33 amino acids long (PolyQKd-33) and the other has one fewer glutamine (PolyQKd-32). Both form well-dispersed fibrils suitable for analysis by electron microscopy. Electron diffraction confirmed cross-β structures in both fibrils. Remarkably, the deletion of just one glutamine residue from the middle of the peptide leads to substantially different amyloid structures. PolyQKd-32 fibrils are consistently 10–20% wider than PolyQKd-33, as measured by negative staining, cryo-electron microscopy, and scanning transmission electron microscopy. Scanning transmission electron microscopy analysis revealed that the PolyQKd-32 fibrils have 50% higher mass-per-length than PolyQKd-33. This distinction can be explained by a superpleated β-structure model for PolyQKd-33 and a model with two β-solenoid protofibrils for PolyQKd-32. These data provide evidence for β-arch-containing structures in polyglutamine fibrils and open future possibilities for structure-based drug design. 相似文献
105.
Sinan Ince Ismail Kucukkurt Ibrahim Hakki Cigerci A. Fatih Fidan Abdullah Eryavuz 《Journal of trace elements in medicine and biology》2010,24(3):161-164
The aims of this study were to clarify the effects of high dietary supplementation with boric acid and borax, called boron (B) compounds, on lipid peroxidation (LPO), antioxidant activity, some vitamin levels, and DNA damage in rats. Thirty Sprague Dawley male rats were divided into three equal groups: the animals in the first group (control) were fed with a standard rodent diet containing 6.4 mg B/kg, and the animals in the experimental group were fed with a standard rodent diet added with a supra-nutritional amount of boric acid and borax (100 mg B/kg) throughout the experimental period of 28 days. The B compounds decreased malondialdehyde (MDA), DNA damage, the protein carbonyl content (PCO) level in blood, and glutathione (GSH) concentration in the liver, Cu–Zn superoxide dismutase (SOD), and catalase (CAT) activity in the kidney. The B compounds increased GSH concentration in blood and the vitamin C level in plasma. Consequently, our results demonstrate that B supplementation (100 mg/kg) in diet decreases LPO, and enhances the antioxidant defense mechanism and vitamin status. There are no differences in oxidant/antioxidant balance and biochemical parameters except for serum vitamin A and liver GSH concentration, between the boron compounds used in this study. 相似文献
106.
Vessela D. Kancheva Luciano Saso Petya V. Boranova Abdullah Khan Manju K. Saroj Mukesh K. Pandey Shashwat Malhotra Jordan Z. Nechev Sunil K. Sharma Ashok K. Prasad Maya B. Georgieva Carleta Joseph Anthony L. DePass Ramesh C. Rastogi Virinder S. Parmar 《Biochimie》2010
The chain-breaking antioxidant activities of eight coumarins [7-hydroxy-4-methylcoumarin (1), 5,7-dihydroxy-4-methylcoumarin (2), 6,7-dihydroxy-4-methylcoumarin (3), 6,7-dihydroxycoumarin (4), 7,8-dihydroxy-4-methylcoumarin (5), ethyl 2-(7,8-dihydroxy-4-methylcoumar-3-yl)-acetate (6), 7,8-diacetoxy-4-methylcoumarin (7) and ethyl 2-(7,8-diacetoxy-4-methylcoumar-3-yl)-acetate (8)] during bulk lipid autoxidation at 37 °C and 80 °C in concentrations of 0.01–1.0 mM and their radical scavenging activities at 25 °C using TLC–DPPH test have been studied and compared. It has been found that the o-dihydroxycoumarins 3–6 demonstrated excellent activity as antioxidants and radical scavengers, much better than the m-dihydroxy analogue 2 and the monohydroxycoumarin 1. The substitution at the C-3 position did not have any effect either on the chain-breaking antioxidant activity or on the radical scavenging activity of the 7,8-dihydroxy- and 7,8-diacetoxy-4-methylcoumarins 6 and 8. The comparison with DL-α-tocopherol (TOH), caffeic acid (CA) and p-coumaric acid (p-CumA) showed that antioxidant efficiency decreases in the following sequence: 相似文献
107.
Abdullah Farooque Niharika Singh Jawahar Singh Adhikari Farhat Afrin Bilikere Srinivasa Rao Dwarakanath 《PloS one》2014,9(9)
Two-deoxy-D-glucose (2-DG), an inhibitor of glycolysis differentially enhances the radiation and chemotherapeutic drug induced cell death in cancer cells in vitro, while the local tumor control (tumor regression) following systemic administration of 2-DG and focal irradiation of the tumor results in both complete (cure) and partial response in a fraction of the tumor bearing mice. In the present studies, we investigated the effects of systemically administered 2-DG and focal irradiation of the tumor on the immune system in Ehrlich ascites tumor (EAT) bearing Strain “A” mice. Markers of different immune cells were analyzed by immune-flow cytometry and secretary cytokines by ELISA, besides monitoring tumor growth. Increase in the expression of innate (NK and monocytes) and adaptive CD4+cells, and a decrease in B cells (CD19) have been observed after the combined treatment, suggestive of activation of anti-tumor immune response. Interestingly, immature dendritic cells were found to be down regulated, while their functional markers CD86 and MHC II were up regulated in the remaining dendritic cells following the combination treatment. Similarly, decrease in the CD4+ naïve cells with concomitant increase in activated CD4+ cells corroborated the immune activation. Further, a shift from Th2 and Th17 to Th1 besides a decrease in inflammatory cytokines was also observed in the animals showing complete response (cure; tumor free survival). This shift was also complimented by respective antibody class switching followed by the combined treatment. The immune activation or alteration in the homeostasis favoring antitumor immune response may be due to depletion in T regulatory cells (CD4+CD25+FoxP3+). Altogether, these results suggest that early differential immune activation is responsible for the heterogenous response to the combined treatment. Taken together, these studies for the first time provided insight into the additional mechanisms underlying radio-sensitization by 2-DG in vivo by unraveling its potential as an immune-modulator besides direct effects on the tumor. 相似文献
108.
Willy J. Malaisse Abdullah Sener Francine Malaisse-Lagae 《Molecular and cellular biochemistry》1981,37(3):157-165
Summary Nutrients which stimulate insulin secretion are currently thought to initiate the series of cellular events eventually leading
to insulin release either by interacting with a stereospecific receptor system (the regulatory site hypothesis) or by acting
as a fuel (the substrate site hypothesis) in the pancreaticB-cell. The latter hypothesis is supported by a number of observations indicating that the capacity of nutrients to stimulate
insulin release is indeed highly dependent on their capacity to increase catabolic fluxes in isolated pancreatic islets. However,
these observations do not rule out the existence of nutrient receptors in islet cells. For instance, a nonmetabolized analog
of L-leucine stimulates insulin release by causing allosteric activation of glutamate dehydrogenase, which should be considered,
therefore, as a receptor for certain amino acids. Likewise, the increase in glycolytic flux, which is associated with the
process of glucose-stimulated insulin release, is attributable not solely to a mass action phenomenon but also to the activation
of phosphofructokinase by fructose 2.6-bisphosphate. The biosynthesis of this activator may involve a glucose receptor system.
The fact that certain nutrient secretagogues (e.g D-glucose and L-leucine) act in the B-cell both as substrates and enzyme
activators permits reconciliation of the substrate site and regulatory site hypotheses for insulin release. 相似文献
109.
Phosphate starvation response controls genes required to synthesize the phosphate analog arsenate 下载免费PDF全文
Qian Wang Yoon‐Suk Kang Abdullah Alowaifeer Kaixiang Shi Xia Fan Lu Wang Jonathan Jetter Brian Bothner Gejiao Wang Timothy R. McDermott 《Environmental microbiology》2018,20(5):1782-1793
Environmental arsenic poisoning affects roughly 200 million people worldwide. The toxicity and mobility of arsenic in the environment is significantly influenced by microbial redox reactions, with arsenite (AsIII) being more toxic than arsenate (AsV). Microbial oxidation of AsIII to AsV is known to be regulated by the AioXSR signal transduction system and viewed to function for detoxification or energy generation. Here, we show that AsIII oxidation is ultimately regulated by the phosphate starvation response (PSR), requiring the sensor kinase PhoR for expression of the AsIII oxidase structural genes aioBA. The PhoRB and AioSR signal transduction systems are capable of transphosphorylation cross‐talk, closely integrating AsIII oxidation with the PSR. Further, under PSR conditions, AsV significantly extends bacterial growth and accumulates in the lipid fraction to the apparent exclusion of phosphorus. This could spare phosphorus for nucleic acid synthesis or triphosphate metabolism wherein unstable arsenic esters are not tolerated, thereby enhancing cell survival potential. We conclude that AsIII oxidation is logically part of the bacterial PSR, enabling the synthesis of the phosphate analog AsV to replace phosphorus in specific biomolecules or to synthesize other molecules capable of a similar function, although not for total replacement of cellular phosphate. 相似文献
110.
Shatoor Abdullah S. Al Humayed Suliman Almohiy Hussain M. 《Journal of physiology and biochemistry》2022,78(1):151-168
Journal of Physiology and Biochemistry - This study examined whether astaxanthin (ASX) could alleviate hepatic steatosis in rats fed a high-fat diet (HFD) by modulating the nuclear factor erythroid... 相似文献