全文获取类型
收费全文 | 1205篇 |
免费 | 97篇 |
出版年
2023年 | 6篇 |
2022年 | 15篇 |
2021年 | 35篇 |
2020年 | 18篇 |
2019年 | 25篇 |
2018年 | 21篇 |
2017年 | 20篇 |
2016年 | 41篇 |
2015年 | 58篇 |
2014年 | 74篇 |
2013年 | 73篇 |
2012年 | 81篇 |
2011年 | 101篇 |
2010年 | 54篇 |
2009年 | 43篇 |
2008年 | 61篇 |
2007年 | 44篇 |
2006年 | 35篇 |
2005年 | 37篇 |
2004年 | 32篇 |
2003年 | 27篇 |
2002年 | 21篇 |
2001年 | 26篇 |
2000年 | 25篇 |
1999年 | 18篇 |
1998年 | 9篇 |
1996年 | 7篇 |
1995年 | 9篇 |
1994年 | 13篇 |
1993年 | 8篇 |
1992年 | 17篇 |
1991年 | 16篇 |
1990年 | 21篇 |
1989年 | 18篇 |
1988年 | 14篇 |
1987年 | 15篇 |
1986年 | 14篇 |
1985年 | 18篇 |
1984年 | 12篇 |
1983年 | 7篇 |
1982年 | 8篇 |
1979年 | 10篇 |
1978年 | 9篇 |
1977年 | 6篇 |
1976年 | 9篇 |
1975年 | 6篇 |
1973年 | 11篇 |
1971年 | 6篇 |
1970年 | 6篇 |
1969年 | 8篇 |
排序方式: 共有1302条查询结果,搜索用时 218 毫秒
151.
Shakhawat Chowdhury 《人类与生态风险评估》2012,18(5):1051-1068
Dermal exposure to volatile compounds (VC) in municipal water while showering is typically estimated using a steady-state condition between VC in water impacting on skin and skin exposed to water. The lag times to achieve steady-state between VC and skin can vary in the range of 7.5–218.3 min, while shower duration is often less than these values. Estimates of dermal exposure to VC using steady-state while showering may misinterpret exposure. This study developed models and estimated exposure to some disinfection byproducts (DBPs) through dermal pathway by considering lag times while showering. Dermal uptakes of VC were compared using different approaches. In the proposed approach, uptakes of trihalomethanes were estimated between 9.55 × 10?10–1.43 × 10?8 mg/cm2 of skin during the lag times from exposure to water with trihalomethanes of 50 μg/L. These values were higher than the steady-state estimates (1.37 × 10?10–4.34 × 10?9 mg/cm2), and lower than the average exposure analysis (4.12 × 10-8–1.93 × 10?6 mg/cm2). Using the Drinking Water Surveillance Program data in Ontario, chronic daily intakes of trihalomethanes were estimated to be 9.40 × 10?7 (1.85 × 10?7–1.65 × 10?6), 3.89 × 10?6 (7.11 × 10?7–2.33 × 10?5), and 1.40 × 10?6 (4.0 × 10?7–1.77 × 10?6) mg/kg/day in Toronto, Ottawa, and Hamilton, respectively. The findings can be useful in understanding THMs exposure and risk through dermal pathway. 相似文献
152.
The visceral form of leishmaniasis is the most severe form of the disease and of particular concern due to the emerging problem of HIV/visceral leishmaniasis (VL) co-infection in the tropics. Till date miltefosine, amphotericin B and pentavalent antimony compounds remain the main treatment regimens for leishmaniasis. However, because of severe side effects, there is an urgent need for alternative improved therapies to combat this dreaded disease. In the present study, we have used the murine model of leishmaniasis to evaluate the potential role played by soluble leishmanial antigen (SLA) pulsed-CpG-ODN stimulated dendritic cells (SLA-CpG-DCs) in restricting the intracellular leishmanial growth. We found that mice vaccinated with a single dose of SLA-pulsed DC stimulated by CpG-ODN were protected against a subsequent leishmanial challenge and had a dramatic reduction in parasite burden along with the generation of parasite specific cytotoxic T lymphocytes. Moreover, we demonstrate that the induction of protective immunity conferred by SLA-CpG-DCs depends entirely on the CXC chemokine IFN-γ-inducible protein 10 (CXCL10; IP-10). CXCL10 is directly involved in the generation of a parasite specific CD8+ T cell-mediated immune response. We observed significant reduction of CD8+ T cells in mice depleted of CXCL10 suggesting a direct role of CXCL10 in the generation of CD8+ T cells in SLA-CpG-DCs vaccinated mice. CXCL10 also contributed towards the generation of perforin and granzyme B, two important cytolytic mediators of CD8+ T cells, following SLA-CpG-DCs vaccination. Together, these findings strongly demonstrate that CXCL10 is critical for rendering a protective cellular immunity during SLA-CpG-DC vaccination that confers protection against Leishmania donovani infection. 相似文献
153.
154.
Abhishek Chowdhury Shantanu Sen Pradip Dey Pankaj Chetia Anupam Das Talukdar Amitabha Bhattacharjee Manabendra Dutta Choudhury 《Bioinformation》2012,8(18):875-880
The advent of Multi Drug Resistant (MDR) strain of Mycobacterium tuberculosis (TB) necessitated search for new drug targets for the
bacterium. It is reported that 3.3% of all new tuberculosis cases had multidrug resistance (MDR-TB) in 2009 and each year, about
0.44 million MDR-TB cases are estimated to emerge and 0.15 million people with MDR-TB die. Keeping such an alarming situation
under consideration we wanted to design suitable anti tubercular molecules for new target using computational tools. In the work
Methionine aminopeptidase (MetAP) of Mycobacterium tuberculosis was considered as target and three non-toxic phenolic=ketonic
compounds were considered as ligands. Docking was done with Flex X and AutoDock 4.2 separately. Ten proven inhibitors of
MetAP were collected from literature with their IC50 and were correlated using EasyQSAR to generate QSAR model. Activity of
ligands in question was predicted from QSAR. Pharmacophore for each docking was generated using Ligandscout 3.0. Toxicity of
the ligands in question was predicted on Mobyle@rpbs portal and Actelion property explorer. Molecular docking with target
showed that of all three ligands, 3-ammonio-3-(4-oxido-1H-imidazol-1-ium-5-yl) propane-1, 1-bis (olate) has highest affinity (-
37.5096) and lowest IC50 (4.46 µM). We therefore, propose that -3-ammonio-3-(4-oxido-1H-imidazol-1-ium-5-yl) propane-1,1-
bis(olate) as a potent MetAP inhibitor may be a new anti-tubercular drug particularly in the context of Multi Drug Resistant
Tuberculosis (MDR-TB). 相似文献
155.
Céline Serbielle Shafinaz Chowdhury Samuel Pichon Stéphane Dupas Jérôme Lesobre Enrico O Purisima Jean-Michel Drezen Elisabeth Huguet 《BMC biology》2008,6(1):38
Background
In pathogens, certain genes encoding proteins that directly interact with host defences coevolve with their host and are subject to positive selection. In the lepidopteran host-wasp parasitoid system, one of the most original strategies developed by the wasps to defeat host defences is the injection of a symbiotic polydnavirus at the same time as the wasp eggs. The virus is essential for wasp parasitism success since viral gene expression alters the immune system and development of the host. As a wasp mutualist symbiont, the virus is expected to exhibit a reduction in genome complexity and evolve under wasp phyletic constraints. However, as a lepidopteran host pathogenic symbiont, the virus is likely undergoing strong selective pressures for the acquisition of new functions by gene acquisition or duplication. To understand the constraints imposed by this particular system on virus evolution, we studied a polydnavirus gene family encoding cyteine protease inhibitors of the cystatin superfamily. 相似文献156.
Das R Mazhab-Jafari MT Chowdhury S SilDas S Selvaratnam R Melacini G 《The Journal of biological chemistry》2008,283(28):19691-19703
Exchange proteins directly activated by cAMP (EPACs) are guanine nucleotide-exchange factors for the small GTPases Rap1 and Rap2 and represent a key receptor for the ubiquitous cAMP second messenger in eukaryotes. The cAMP-dependent activation of apoEPAC is typically rationalized in terms of a preexisting equilibrium between inactive and active states. Structural and mutagenesis analyses have shown that one of the critical determinants of the EPAC activation equilibrium is a cluster of salt bridges formed between the catalytic core and helices alpha1 and alpha2 at the N terminus of the cAMP binding domain and commonly referred to as ionic latch (IL). The IL stabilizes the inactive states in a closed topology in which access to the catalytic domain is sterically occluded by the regulatory moiety. However, it is currently not fully understood how the IL is allosterically controlled by cAMP. Chemical shift mapping studies consistently indicate that cAMP does not significantly perturb the structure of the IL spanning sites within the regulatory region, pointing to cAMP-dependent dynamic modulations as a key allosteric carrier of the cAMP-signal to the IL sites. Here, we have therefore investigated the dynamic profiles of the EPAC1 cAMP binding domain in its apo, cAMP-bound, and Rp-cAMPS phosphorothioate antagonist-bound forms using several 15N relaxation experiments. Based on the comparative analysis of dynamics in these three states, we have proposed a model of EPAC activation that incorporates the dynamic features allosterically modulated by cAMP and shows that cAMP binding weakens the IL by increasing its entropic penalty due to dynamic enhancements. 相似文献
157.
Southwell J Chowdhury SF Gottlieb B Beitel LK Lumbroso R Purisima EO Trifiro M 《The Journal of steroid biochemistry and molecular biology》2008,111(1-2):138-146
Prostate cancer may progress by circumventing ablation therapy due to mutations in the androgen receptor (AR) gene. The most intensively studied is the T877A mutation in the ligand binding domain (LBD), which causes the AR to become promiscuous, i.e., respond to a number of different ligands. Our investigations have shown that the T877A mutation alters the inverse relationship between CAG repeat length and transactivation in a noticeable albeit minor manner, while increasing N/C terminal interactions. In the presence of beta-catenin, a coactivator over-expressed in prostate cancer, the inverse relationship between CAG repeat length and transactivation is reversed for the wild type (wt) AR as well. We have also used molecular modeling with the AR and FXXLF and LXXLL peptides to investigate N/C terminal and coactivator interactions. In T877A, this approach revealed an increase in the flexibility of amino acid residues in the activation function 2 (AF-2) domain in the LBD, and a larger solvent accessible surface in T877A compared to the wt AR AF-2 domain. Thus, the improved induced fit of the AR N-terminal domain FXXLF-containing peptide into the T877A LBD could be due to the increased flexibility and solvent accessibility of the AF-2 domain. These new observations suggest that the AR CAG effect can be overridden by prostate cancer mutations, and also further our understanding of hormone-refractory prostate cancer by helping to explain the promiscuity of the T877A mutation. 相似文献
158.
This paper analyzes data on approximately 30,000 women from a survey in Uttar Pradesh in 1995 together with the data from surveys of public and private providers of healthcare and family planning services. A framework was developed for analyzing the effects of quality of services on utilization, and for understanding the gradual evolution of the healthcare infrastructure. The empirical results from logistic regressions for use of female sterilization and IUD showed significant effects of quality of services in government and private hospitals, and of socioeconomic variables such as education, caste, and an index of household possessions. Secondly, models for infant mortality of children born in the preceding 3-year period showed significant effects of socioeconomic variables, quality of healthcare services and birth spacing. Lastly, analysis of data at a more aggregated (Primary Sampling Unit) level indicated differential effects of economic development on the quality of services available in the public and private facilities. 相似文献
159.
Putative Virulence Traits and Pathogenicity of Vibrio cholerae Non-O1, Non-O139 Isolates from Surface Waters in Kolkata, India
下载免费PDF全文
![点击此处可从《Applied microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Prasanta K. Bag Poulami Bhowmik Tapas K. Hajra T. Ramamurthy Pradipta Sarkar Mrinmoyee Majumder Goutam Chowdhury Suresh C. Das 《Applied microbiology》2008,74(18):5635-5644
Vibrio cholerae non-O1, non-O139 was isolated from natural surface waters from different sites sampled in diarrhea endemic zones in Kolkata, India. Twenty-one of these isolates were randomly selected and included in the characterization. The multiserogroup isolates were compared by their virulence traits with a group of clinical non-O1, non-O139 isolates from the same geographic area. Of the 21 environmental isolates, 6 and 14 strains belonged to Heiberg groups I and II, respectively. Three of the environmental isolates showed resistance to 2,2-diamine-6,7-diisopropylpteridine phosphate. All of the non-O1, non-O139 strains were positive for toxR, and except for one environmental isolate, none of them were positive for tcpA in the PCR assay. None of the isolates were positive for genes encoding cholera toxin (ctxA), heat-stable toxin (est), heat-labile toxin (elt), and Shiga toxin variants (stx) of Escherichia coli. Additionally, except for one environmental isolate (PC32), all were positive for the gene encoding El Tor hemolysin (hly). The culture supernatants of 86% (18 of 21) of the environmental isolates showed a distinct cytotoxic effect on HeLa cells, and some of these strains also produced cell-rounding factor. The lipase, protease, and cell-associated hemagglutination activities and serum resistance properties of the environmental and clinical isolates did not differ much. However, seven environmental isolates exhibited very high hemolytic activities (80 to 100%), while none of the clinical strains belonged to this group. The environmental isolates manifested three adherence patterns, namely, carpet-like, diffuse, and aggregative adherence, and the clinical isolates showed diffuse adherence on HeLa cells. Of the 11 environmental isolates tested for enteropathogenic potential, 8 (73%) induced positive fluid accumulation (≥100) in a mouse model, and the reactivities of these isolates were comparable to those of clinical strains of non-O1, non-O139 and toxigenic O139 V. cholerae. Comparison of the counts of the colonized environmental and clinical strains in the mouse intestine showed that the organisms of both groups had similar colonizing efficiencies. These findings indicate the presence of potentially pathogenic V. cholerae non-O1, non-O139 strains in surface waters of the studied sites in Kolkata. 相似文献
160.
Effect of osmolytes and chaperone-like action of P-protein on folding of nucleocapsid protein of Chandipura virus. 总被引:10,自引:0,他引:10
A Majumder S Basak T Raha S P Chowdhury D Chattopadhyay S Roy 《The Journal of biological chemistry》2001,276(33):30948-30955
Amino acid sequences of nucleocapsid proteins are mostly conserved among different rhabdoviruses. The protein plays a common functional role in different RNA viruses by enwrapping the viral genomic RNA in an RNase-resistant form. Upon expression of the nucleocapsid protein alone in COS cells and in bacteria, it forms large insoluble aggregates. In this work, we have reported for the first time the full-length cloning of the N gene of Chandipura virus and its expression in Escherichia coli in a soluble monomeric form and purification using nonionic detergents. The biological activity of the soluble recombinant protein has been tested, and it was found to possess efficient RNA-binding ability. The state of aggregation of the recombinant protein was monitored using light scattering. In the absence of nonionic detergents, it formed large aggregates. Aggregation was significantly reduced in the presence of osmolytes such as d-sorbitol. Aggregate formation was suppressed in the presence of another viral product, phosphoprotein P, in a chaperone-like manner. Both the osmolyte and phosphoprotein P also suppressed aggregation to a great extent during refolding from a guanidine hydrochloride-denatured form. The function of the phosphoprotein and osmolyte appears to be synergistic to keep the N-protein in a soluble biologically competent form in virus-infected cells. 相似文献