全文获取类型
收费全文 | 610篇 |
免费 | 28篇 |
国内免费 | 1篇 |
出版年
2024年 | 2篇 |
2023年 | 6篇 |
2022年 | 21篇 |
2021年 | 31篇 |
2020年 | 13篇 |
2019年 | 23篇 |
2018年 | 36篇 |
2017年 | 21篇 |
2016年 | 28篇 |
2015年 | 38篇 |
2014年 | 41篇 |
2013年 | 45篇 |
2012年 | 45篇 |
2011年 | 38篇 |
2010年 | 22篇 |
2009年 | 20篇 |
2008年 | 24篇 |
2007年 | 19篇 |
2006年 | 29篇 |
2005年 | 19篇 |
2004年 | 15篇 |
2003年 | 15篇 |
2002年 | 8篇 |
2001年 | 4篇 |
2000年 | 6篇 |
1999年 | 4篇 |
1998年 | 5篇 |
1997年 | 6篇 |
1996年 | 3篇 |
1995年 | 4篇 |
1994年 | 4篇 |
1993年 | 1篇 |
1992年 | 5篇 |
1991年 | 2篇 |
1990年 | 3篇 |
1989年 | 5篇 |
1988年 | 4篇 |
1987年 | 4篇 |
1986年 | 1篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1980年 | 1篇 |
1978年 | 3篇 |
1971年 | 1篇 |
1965年 | 1篇 |
1938年 | 1篇 |
排序方式: 共有639条查询结果,搜索用时 31 毫秒
151.
Qosay Al-Balas Nahoum G. Anthony Bilal Al-Jaidi Amani Alnimr Grainne Abbott Alistair K. Brown Rebecca C. Taylor Gurdyal S. Besra Timothy D. McHugh Stephen H. Gillespie Blair F. Johnston Simon P. Mackay Geoffrey D. Coxon 《PloS one》2009,4(5)
Background
Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world''s population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration.Methodology/Principal Findings
Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM''s novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the β-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)thiazole-4-carboxylate inhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism.Conclusions/Significance
These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents. 相似文献152.
Fabiano Oliveira Seydou Doumbia Jennifer M. Anderson Ousmane Faye Souleymane S. Diarra Pierre Traoré Moumine Cisse Guimba Camara Koureissi Tall Cheick A. Coulibaly Sibiry Samake Ibrahim Sissoko Bourama Traoré Daouda Diallo Somita Keita Rick M. Fairhurst Jesus G. Valenzuela Shaden Kamhawi 《PLoS neglected tropical diseases》2009,3(12)
Apart from a single report, the last publication of cutaneous leishmaniasis (CL) in Mali dates back more than 20 years. The absence of information on the current status of CL in Mali led us to conduct a cohort study in Kemena and Sougoula, two villages in Central Mali from which cases of CL have been recently diagnosed by Mali''s reference dermatology center in Bamako. In May 2006, we determined the baseline prevalence of Leishmania infection in the two villages using the leishmanin skin test (LST). LST-negative individuals were then re-tested over two consecutive years to estimate the annual incidence of Leishmania infection. The prevalence of Leishmania infection was significantly higher in Kemena than in Sougoula (45.4% vs. 19.9%; OR: 3.36, CI: 2.66–4.18). The annual incidence of Leishmania infection was also significantly higher in Kemena (18.5% and 17% for 2007 and 2008, respectively) than in Sougoula (5.7% for both years). These data demonstrate that the risk of Leishmania infection was stable in both villages and confirm the initial observation of a significantly higher risk of infection in Kemena (OR: 3.78; CI: 2.45–6.18 in 2007; and OR: 3.36; CI: 1.95–5.8 in 2008; P<0.005). The absence of spatial clustering of LST-positive individuals in both villages indicated that transmission may be occurring anywhere within the villages. Although Kemena and Sougoula are only 5 km apart and share epidemiologic characteristics such as stable transmission and random distribution of LST-positive individuals, they differ markedly in the prevalence and annual incidence of Leishmania infection. Here we establish ongoing transmission of Leishmania in Kemena and Sougoula, Central Mali, and are currently investigating the underlying factors that may be responsible for the discrepant infection rates we observed between them.
Trial Registration
ClinicalTrials.gov NCT00344084相似文献153.
Samhita S Rhodes Kristina M Ropella Amadou K S Camara Qun Chen Matthias L Riess Paul S Pagel David F Stowe 《Journal of applied physiology》2006,100(3):940-950
Positive inotropic drugs may attenuate or exacerbate the deleterious effects of ischemia and reperfusion (IR) injury on excitation-contraction coupling in hearts. We 1) quantified the phase-space relationship between simultaneously measured myoplasmic Ca2+ concentration ([Ca2+]) and isovolumetric left ventricular pressure (LVP) using indexes of loop area, orientation, and position; and 2) quantified cooperativity by linearly modeling the phase-space relationship between [Ca2+] and rate of LVP development in intact hearts during administration of positive inotropic drugs before and after global IR injury. Unpaced, isolated guinea pig hearts were perfused at a constant pressure with Krebs-Ringer solution (37 degrees C, 1.25 mM CaCl2). [Ca2+] was measured ratiometrically by indo 1 fluorescence by using a fiber-optic probe placed at the left ventricular free wall. LVP was measured by using a saline-filled latex balloon and transducer. Drugs were infused for 2 min, 30 min before, and for 2 min, 30 min after 30-min global ischemia. IR injury worsened Ca2+-contraction coupling, as seen from decreased orientation and repositioning of the loop rightward and downward and reduced cooperativity of contraction and relaxation with or without drugs. Dobutamine (4 microM) worsened, whereas dopamine (8 microM) improved Ca2+-contraction coupling before and after IR injury. Dobutamine and dopamine improved cooperativity of contraction and relaxation after IR injury, whereas only dopamine increased cooperativity of relaxation before IR injury. Digoxin (1 microM) improved Ca2+-contraction coupling and cooperativity of contraction after but not before ischemia. Levosimendan (1 microM) did not alter Ca2+-contraction coupling or cooperativity, despite producing concomitant increases in contractility, relaxation, and Ca2+ flux before and after ischemia. Dynamic indexes based on LVP-[Ca2+] diagrams (area, shape, position) can be used to identify and measure alterations in Ca2+-contraction coupling during administration of positive inotropic drugs in isolated hearts before and after IR injury. 相似文献
154.
Johan Haumann David F. Stowe Age D. Boelens Amadou K.S. Camara 《Biophysical journal》2010,99(4):997-1006
ADP influx and ADP phosphorylation may alter mitochondrial free [Ca2+] ([Ca2+]m) and consequently mitochondrial bioenergetics by several postulated mechanisms. We tested how [Ca2+]m is affected by H2PO4− (Pi), Mg2+, calcium uniporter activity, matrix volume changes, and the bioenergetic state. We measured [Ca2+]m, membrane potential, redox state, matrix volume, pHm, and O2 consumption in guinea pig heart mitochondria with or without ruthenium red, carboxyatractyloside, or oligomycin, and at several levels of Mg2+ and Pi. Energized mitochondria showed a dose-dependent increase in [Ca2+]m after adding CaCl2 equivalent to 20, 114, and 485 nM extramatrix free [Ca2+] ([Ca2+]e); this uptake was attenuated at higher buffer Mg2+. Adding ADP transiently increased [Ca2+]m up to twofold. The ADP effect on increasing [Ca2+]m could be partially attributed to matrix contraction, but was little affected by ruthenium red or changes in Mg2+ or Pi. Oligomycin largely reduced the increase in [Ca2+]m by ADP compared to control, and [Ca2+]m did not return to baseline. Carboxyatractyloside prevented the ADP-induced [Ca2+]m increase. Adding CaCl2 had no effect on bioenergetics, except for a small increase in state 2 and state 4 respiration at 485 nM [Ca2+]e. These data suggest that matrix ADP influx and subsequent phosphorylation increase [Ca2+]m largely due to the interaction of matrix Ca2+ with ATP, ADP, Pi, and cation buffering proteins in the matrix. 相似文献
155.
Florent K. N’Guessan Dénis Y. N’Dri Fatoumata Camara Marcellin K. Djè 《World journal of microbiology & biotechnology》2010,26(4):693-699
Starter cultures of Candida tropicalis and Saccharomyces cerevisiae isolated from tchapalo were tested in pure culture and co-culture of four ratios [2:1, 25:4, 1:4, 2:3 (cells/cells)] for their ability to ferment sorghum wort to produce tchapalo. All the starters showed means growth rate between 0.043 and 0.101 h?1. Only C. tropicalis in pure culture showed growth rate lower than that of S. cerevisiae in single culture. During fermentation, according to total soluble solids depletion, yeast starters could be grouped in four different profiles. But in the beer produced, total soluble solids contents were statistically identical. The lowest values were obtained with co-culture C. tropicalis + S. cerevisiae in the ratios of 2:1 and 2:3. Starter cultures with large ratio of C. tropicalis produced a higher organic acids and 2-butanone than S. cerevisiae in pure culture. However, co-culture C. tropicalis + S. cerevisiae (2:1) was the alone starter which produced higher ethanol than S. cerevisiae in pure culture. The beers produced with C. tropicalis + S. cerevisiae (25:4), C. tropicalis + S. cerevisiae (1:4) and C. tropicalis were widely different from those produced with the others starter cultures. 相似文献
156.
157.
Matthew P. Hare Standish K. Allen Jr. Paulette Bloomer Mark D. Camara Ryan B. Carnegie Jenna Murfree Mark Luckenbach Donald Meritt Cheryl Morrison Kennedy Paynter Kimberly S. Reece Colin G. Rose 《Conservation Genetics》2006,7(5):717-734
Many of the methods currently employed to restore Chesapeake Bay populations of the eastern oyster, Crassostrea virginica, assume closed recruitment in certain sub-estuaries despite planktonic larval durations of 2–3 weeks. In addition, to combat parasitic disease, artificially selected disease tolerant oyster strains are being used for population supplementation. It has been impossible to fully evaluate these unconventional tactics because offspring from wild and selected broodstock are phenotypically indistinguishable. This study provides the first direct measurement of oyster recruitment enhancement by using genetic assignment tests to discriminate locally produced progeny of a selected oyster strain from progeny of wild parents. Artificially selected oysters (DEBY strain) were planted on a single reef in each of two Chesapeake Bay tributaries in 2002, but only in the Great Wicomico River (GWR) were they large enough to potentially reproduce the same year. Assignment tests based on eight microsatellite loci and mitochondrial DNA markers were applied to 1579 juvenile oysters collected throughout the GWR during the summer of 2002. Only one juvenile oyster was positively identified as an offspring of the 0.75 million DEBY oysters that were planted in the GWR, but 153 individuals (9.7%) had DEBY ×wild F1 multilocus genotypes. Because oyster recruitment was high across the region in 2002, the proportionately low enhancement measured in the GWR would not otherwise have been recognized. Possible causes for low enhancement success are discussed, each bearing on untested assumptions underlying the restoration methods, and all arguing for more intensive evaluation of each component of the restoration strategy. 相似文献
158.
Khan WN Lodhi MA Ali I Azhar-Ul-Haq Malik A Bilal S Gul R Choudhary MI 《Journal of enzyme inhibition and medicinal chemistry》2006,21(1):17-19
Phytochemical investigations on the chloroform and ethyl acetate soluble fractions of the roots of Ranunculus repens led to the isolation of methyl 3,4,5-trihydroxybenzoate 1, R(+)- 4-methoxydalbergione 2 and R(+)-dalbergiophenol 3. The structures of these compounds were established through spectral studies including 1D and 2D NMR experiments and by comparison with literature data. These compounds showed potent inhibitory activity against urease. 相似文献
159.
Alpha-amylase was produced from Penicillium griseofulvum by an SSF technique. Alpha-amylase was immobilized on Celite by an adsorption method. Various parameters, such as effect of pH and temperature, substrate concentration, operational and storage stability, ability to hydrolyze starch and products of hydrolysis were investigated; these findings were compared with the free enzyme. The activity yield of immobilization was 87.6%. The optimum pH and temperature for both enzymes were 5.5 degrees C and 40 degrees C, respectively. The thermal, and the operational and storage stabilities of immobilized enzyme were better than that of the free enzyme. Km and Vmax were calculated from Lineweaver-Burk plots for both enzymes. Km values were 9.1 mg mL(-1) for free enzyme, and 7.1 mg mL(-1) for immobilized enzyme. The Vmax of the immobilized enzyme was approximately 40% smaller than that of the free enzyme. The hydrolysis ability of the free and immobilized enzyme were determined as 99.3% and 97.9%, respectively. Hydrolysis products of the a-amylase from P. griseofulvum were maltose, unidentified oligosaccharides, and glucose. 相似文献
160.
Controlled initiation of chromosomal replication in Escherichia coli requires functional Hda protein
下载免费PDF全文
![点击此处可从《Journal of bacteriology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Regulatory inactivation of DnaA helps ensure that the Escherichia coli chromosome is replicated only once per cell cycle, through accelerated hydrolysis of active replication initiator ATP-DnaA to inactive ADP-DnaA. Analysis of deltahda strains revealed that the regulatory inactivation of DnaA component Hda is necessary for maintaining controlled initiation but not for cell growth or viability. 相似文献