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361.
Nidhi Arya Hadiar Rahman Andrew Rudrow Manuel Wagner Lutz Schmitt Suresh V. Ambudkar John Golin 《Molecular microbiology》2019,112(4):1131-1144
Resistance to antimicrobial and chemotherapeutic agents is a significant clinical problem. Overexpression of multidrug efflux pumps often creates broad‐spectrum resistance in cancers and pathogens. We describe a mutation, A666G, in the yeast ABC transporter Pdr5 that shows greater resistance to most of the tested compounds than does an isogenic wild‐type strain. This mutant exhibited enhanced resistance without increasing either the amount of protein in the plasma membrane or the ATPase activity. In fluorescence quenching transport assays with rhodamine 6G in purified plasma membrane vesicles, the initial rates of rhodamine 6G fluorescence quenching of both the wild type and mutant showed a strong dependence on the ATP concentration, but were about twice as high in the latter. Plots of the initial rate of fluorescence quenching versus ATP concentration exhibited strong cooperativity that was further enhanced in the A666G mutant. Resistance to imazalil sulfate was about 3–4x as great in the A666G mutant strain as in the wild type. When this transport substrate was used to inhibit the rhodamine 6G transport, the A666G mutant inhibition curves also showed greater cooperativity than the wild‐type strain. Our results suggest a novel and important mechanism: under selection, Pdr5 mutants can increase drug resistance by improving cooperative interactions between drug transport sites. 相似文献
362.
Gaurav Arya 《Molecular simulation》2016,42(13):1102-1115
Single-molecule force spectroscopy is a powerful experimental technique for probing intermolecular forces and conformational transitions of individual molecules. This technique involves measuring the mechanical response of a molecule subjected to a constant or time-varying force. Statistical mechanics has played a pivotal role in interpreting force measurements in terms of the underlying kinetics and energy landscape of the molecular transition being studied. Here, we provide a didactic review of various statistical–mechanical models used for analysing these measurements, emphasising the theoretical ideas and assumptions used in deriving these models. 相似文献
363.
3-Unsubstituted 4-hydroxyquinolin-2(1H)-one containing F and CF(3) substituent in ring is important pharmacological and synthetic target and basic synthones for a number of antibacterial fluoroquinolones and is promising potent and selective glycine site NMDA receptors. A simple facile one-step microwave enhanced multigram synthesis of such fluorinated quinolones in reasonable purity has been developed in excellent yield (85-94%) in 3-5 min, whereas conventional synthesis required the harsh conditions, long reaction period with use of environmentally unacceptable regents giving the required product in lower yield. The phototoxicity as well as the cytotoxic activities of the title compounds are evaluated against leukemia- and adenocarcinoma-derived cell lines in comparison to the normal human keratinocytes. Structure-activity relationships between the chemical structures and the antimycobacterial, antifungal activity of the evaluated compounds are also discussed. 相似文献
364.
Chakkalathara Venu Anju Neelesh Dahanukar Arya Sidharthan Kutty Ranjeet Rajeev Raghavan 《Journal of fish biology》2019,94(1):187-190
The first assessment of the demographics of Lagocephalus inermis, a species associated with pufferfish bites and fishing down the food web in the Arabian Sea, south-west coast of India, was performed based on length structured population dynamics of 1601 individuals caught in commercial fisheries. Analysis revealed that the current level of exploitation is 90% of the predicted exploitation producing maximum relative yield per recruit (Emax), suggesting high levels of exploitation with potential for significant negative consequences for trophic cascades. 相似文献
365.
Movsesyan N Ghochikyan A Mkrtichyan M Petrushina I Davtyan H Olkhanud PB Head E Biragyn A Cribbs DH Agadjanyan MG 《PloS one》2008,3(5):e2124
Background
The development of a safe and effective AD vaccine requires a delicate balance between providing an adequate anti-Aβ antibody response sufficient to provide therapeutic benefit, while eliminating an adverse T cell-mediated proinflammatory autoimmune response. To achieve this goal we have designed a prototype chemokine-based DNA epitope vaccine expressing a fusion protein that consists of 3 copies of the self-B cell epitope of Aβ42 (Aβ1–11) , a non-self T helper cell epitope (PADRE), and macrophage-derived chemokine (MDC/CCL22) as a molecular adjuvant to promote a strong anti-inflammatory Th2 phenotype.Methods and Findings
We generated pMDC-3Aβ1–11-PADRE construct and immunized 3xTg-AD mouse model starting at age of 3–4 months old. We demonstrated that prophylactic immunizations with the DNA epitope vaccine generated a robust Th2 immune response that induced high titers of anti-Aβ antibody, which in turn inhibited accumulation of Aβ pathology in the brains of older mice. Importantly, vaccination reduced glial activation and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages.Conclusions
Data from this transitional pre-clinical study suggest that our DNA epitope vaccine could be used as a safe and effective strategy for AD therapy. Future safety and immunology studies in large animals with the goal to achieve effective humoral immunity without adverse effects should help to translate this study to human clinical trials. 相似文献366.
Effects of methallibure (I.C.I. 33828) have been studied on the reproductive organs of female gerbils, Meriones hurrianae. Methallibure administration caused reduction of gonadal weight indicating suppression of pituitary gonadotrophins. In the ovaries of the treated females extensive atresia of follicles and of corpora lutea was observed. In addition methallibure interrupted the sex cycle, and a dioestrous vaginal pattern was retained throughout medication. A significant decrease in the level of RNA, protein and sialic acid in the uterus and vagina and of glycogen in the uterus was found. Histological and biochemical changes in the ovaries and uteri suggest a possible direct antioestrogenic action of the compound. 相似文献
367.
1. The effects of ligation of caput, cauda epididymides and vasectomy were studied in adult gerbils. 2. The operations were performed unilaterally, the testis and epididymides on the contralateral side serving as controls. 3. Ligation of cauda epididymides decrease testicular weight, whereas caput ligation did not change the testis weight. Accessory sex glands were reduced in size. 4. Ligation caused a drastic degeneration of the spermatogenic cells. There was a complete disruption of testicular function. Leydig cell hypertrophy was conspicuous. Caput and cauda ligation led to degenerative changes in the epididymides. Epididymal epithelium was regressed and the lumen was devoid of spermatozoa. 5. Caput and cauda ligation inhibited the synthesis of RNA, protein and sialic acid in testis and epididymides and depleted the fructose concentration in the seminal vesicle. 6. Vasectomy did not cause any alteration in sperm production during the 8 week period on the lighted side. The cytology and the biochemistry of the testis and epididymides appeared to be normal. 相似文献
368.
Nanda K Chatterjee M Arya R Mukherjee S Saini KS Dastidar S Ray A 《Biotechnology journal》2008,3(9-10):1276-1279
Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) into inactive 5' monophosphates, and exist as 11 families. Inhibitors of PDEs allow the elevation of cAMP and cGMP, which leads to a variety of cellular effects including airway smooth muscle relaxation and inhibition of cellular inflammation or of immune responses. PDE4 inhibitors specifically prevent the hydrolysis of cAMP. We have validated the manually developed reporter gene assay in a high-throughput screening format that allows for fast and cost-effective identification of potential inhibitors of PDE4 isozymes. The assay is sensitive and robust, with a Z' value of >0.5. The assay is also amenable to 384-well format. 相似文献
369.
370.
Heat shock genes — integrating cell survival and death 总被引:14,自引:0,他引:14