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61.
One of the most difficult and time-consuming aspects of building compartmental models of single neurons is assigning values to free parameters to make models match experimental data. Automated parameter-search methods potentially represent a more rapid and less labor-intensive alternative to choosing parameters manually. Here we compare the performance of four different parameter-search methods on several single-neuron models. The methods compared are conjugate-gradient descent, genetic algorithms, simulated annealing, and stochastic search. Each method has been tested on five different neuronal models ranging from simple models with between 3 and 15 parameters to a realistic pyramidal cell model with 23 parameters. The results demonstrate that genetic algorithms and simulated annealing are generally the most effective methods. Simulated annealing was overwhelmingly the most effective method for simple models with small numbers of parameters, but the genetic algorithm method was equally effective for more complex models with larger numbers of parameters. The discussion considers possible explanations for these results and makes several specific recommendations for the use of parameter searches on neuronal models. 相似文献
62.
Douty B Wayland B Ala PJ Bower MJ Pruitt J Bostrom L Wei M Klabe R Gonneville L Wynn R Burn TC Liu PC Combs AP Yue EW 《Bioorganic & medicinal chemistry letters》2008,18(1):66-71
The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I complexed with PTP1B were solved and revealed the inhibitors are interacting extensively with the B site of the enzyme. 相似文献
63.
ObjectivesTo examine patients'' views on access and continuity in general practice to derive quality standards.DesignSecondary analysis of data from general practice research studies and routine quality assessment activities undertaken by practices and primary care trusts.SettingGeneral practice.ParticipantsGeneral practice patients.ResultsSatisfactory standards of access were next day appointments with general practitioners and a 6-10 minute wait for consultations to begin. A satisfactory level of continuity was seeing the same general practitioner “a lot of the time.” Standards varied with the analytic method used and by sociodemographic group.ConclusionsStandards expected by patients in primary care can be derived from linked report-assessment pairs. Patients may have expectations of access that are in excess of government targets. Patients also have high expectations of continuity of care. It is unclear the degree to which such standards are reliable or valid, how conflicts between access and continuity should be resolved, or how these standards relate to other priorities of patients such as high quality interpersonal care.
What is already known on this topic
Standards are increasingly being set for the provision of health servicesSurveys and consultation exercises before the NHS plan helped set the standard for a maximum waiting time of 48 hours for appointments to see general practitionersThe optimal methods by which patients should be involved in setting standards and the utility of such standards are unclearWhat this study adds
Satisfactory standards of access were next day appointments, a 6-10 minute wait for consultations to begin, and seeing the same general practitioner a lot of the timePatients may have expectations for access to primary care in excess of current government targets 相似文献64.
Molly A. Bower Mare Cudic William Campbell John D. Wade Laszlo Otvos 《International journal of peptide research and therapeutics》2003,10(5-6):463-473
Analogs of pyrrhocoricin, a proline-rich antibacterial peptide with a potential therapeutic use, show multiple actions on
bacterial cells. We used a dual-fluorochrome membrane viability assay to provide evidence that the lead drug candidate, Pip-pyrr-MeArg
dimer derivative, kills bacteria better than the native peptide due to an improved activity on bacterial membranes. This assay
was also instrumental in documenting that activity on bacterial membranes and toxicity to human cells can be correlated, and
the predominant mode of action can be changed from intracellular DnaK inhibition to membrane disintegration. Similar analyses
with an alanine-scan on pyrrhocoricin identified Lys3 as a crucial player to interaction with bacterial membranes, three prolines
in mid-chain position as being responsible for maintaining structural integrity and Asp2, Tyr6, Leu7, and Arg9 as putative
contact points to the D-E helix of the bacterial target protein DnaK. 相似文献
65.
Taylor RM Lee JP Palacino JJ Bower KA Li J Vanier MT Wenger DA Sidman RL Snyder EY 《Journal of neurochemistry》2006,97(6):1585-1599
While transplanted neural stem cells (NSCs) have been shown to hold promise for cell replacement in models of a number of neurological disorders, these examples have typically been under conditions where the host cells become dysfunctional due to a cell autonomous etiology, i.e. a 'sick' cell within a relatively supportive environment. It has long been held that cell replacement in a toxic milieu would not likely be possible; donor cells would succumb in much the same way as endogenous cells had. Many metabolic diseases are characterized by this situation, suggesting that they would be poor targets for cell replacement therapies. On the other hand, models of such diseases could prove ideal for testing the capacity for cell replacement under such challenging conditions. In the twitcher (twi ) mouse -- as in patients with Krabbe or globoid cell leukodystrophy (GLD), for which it serves as an authentic model -- loss of galactocerebrosidase (GalC) activity results in the accumulation of psychosine, a toxic glycolipid. Twi mice, like children with GLD, exhibit inexorable neurological deterioration presumably as a result of dysfunctional and ultimately degenerated oligodendrocytes with loss of myelin. It is believed that GLD pathophysiology is related to a psychosine-filled environment that kills not only host oligodendrocytes but theoretically any new cells placed into that milieu. Through the implantation of NSCs into the brains of both neonatal and juvenile/young adult twi mice, we have determined that widespread oligodendrocyte replacement and remyelination is feasible. NSCs appear to be intrinsically resistant to psychosine -- more so in their undifferentiated state than when directed ex vivo to become oligodendrocytes. This resistance can be enhanced by engineering the NSCs to over-express GalC. Some twi mice grafted with such engineered NSCs had thicker white tracts and lived 2-3 times longer than expected. While their brains had detectable levels of GalC, it was probably more significant that their psychosine levels were lower than in twi mice that died at a younger age. This concept of resistance based on differentiation state extended to human NSCs which could similarly survive within the twi brain. Taken together, these results suggest a number of points regarding cellular therapies against degenerative diseases with a prominent cell non-autonomous component: Cell replacement is possible if cells resistant to the toxic environment are employed. Furthermore, an important aspect of successful treatment will likely be not only cell replacement but also cross-correction of host cells to provide them with enzyme activity and hence resistance. While oligodendrocyte replacement alone was not a sufficient treatment for GLD (even when extensive), the replacement of both cells and molecules -- e.g. with NSCs that could both become oligodendrocytes and 'pumps' for GalC -- emerges as a promising basis for a multidisciplinary strategy. Most neurological disease are complex in this way and will likely require multifaceted approaches, perhaps with NSCs serving as the 'glue'. 相似文献
66.
Sarah E. Knowles Gill Toms Caroline Sanders Penny Bee Karina Lovell Stefan Rennick-Egglestone David Coyle Catriona M. Kennedy Elizabeth Littlewood David Kessler Simon Gilbody Peter Bower 《PloS one》2014,9(1)
Objective
Computerised therapies play an integral role in efforts to improve access to psychological treatment for patients with depression and anxiety. However, despite recognised problems with uptake, there has been a lack of investigation into the barriers and facilitators of engagement. We aimed to systematically review and synthesise findings from qualitative studies of computerised therapies, in order to identify factors impacting on engagement.Method
Systematic review and meta-synthesis of qualitative studies of user experiences of computer delivered therapy for depression and/or anxiety.Results
8 studies were included in the review. All except one were of desktop based cognitive behavioural treatments. Black and minority ethnic and older participants were underrepresented, and only one study addressed users with a co-morbid physical health problem. Through synthesis, we identified two key overarching concepts, regarding the need for treatments to be sensitive to the individual, and the dialectal nature of user experience, with different degrees of support and anonymity experienced as both positive and negative. We propose that these factors can be conceptually understood as the ‘non-specific’ or ‘common’ factors of computerised therapy, analogous to but distinct from the common factors of traditional face-to-face therapies.Conclusion
Experience of computerised therapy could be improved through personalisation and sensitisation of content to individual users, recognising the need for users to experience a sense of ‘self’ in the treatment which is currently absent. Exploiting the common factors of computerised therapy, through enhancing perceived connection and collaboration, could offer a way of reconciling tensions due to the dialectal nature of user experience. Future research should explore whether the findings are generalisable to other patient groups, to other delivery formats (such as mobile technology) and other treatment modalities beyond cognitive behaviour therapy. The proposed model could aid the development of enhancements to current packages to improve uptake and support engagement. 相似文献67.
Colin Green David A. Richards Jacqueline J. Hill Linda Gask Karina Lovell Carolyn Chew-Graham Peter Bower John Cape Stephen Pilling Ricardo Araya David Kessler J. Martin Bland Simon Gilbody Glyn Lewis Chris Manning Adwoa Hughes-Morley Michael Barkham 《PloS one》2014,9(8)
Background
Collaborative care is an effective treatment for the management of depression but evidence on its cost-effectiveness in the UK is lacking.Aims
To assess the cost-effectiveness of collaborative care in a UK primary care setting.Methods
An economic evaluation alongside a multi-centre cluster randomised controlled trial comparing collaborative care with usual primary care for adults with depression (n = 581). Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICER) were calculated over a 12-month follow-up, from the perspective of the UK National Health Service and Personal Social Services (i.e. Third Party Payer). Sensitivity analyses are reported, and uncertainty is presented using the cost-effectiveness acceptability curve (CEAC) and the cost-effectiveness plane.Results
The collaborative care intervention had a mean cost of £272.50 per participant. Health and social care service use, excluding collaborative care, indicated a similar profile of resource use between collaborative care and usual care participants. Collaborative care offered a mean incremental gain of 0.02 (95% CI: –0.02, 0.06) quality-adjusted life-years over 12 months, at a mean incremental cost of £270.72 (95% CI: –202.98, 886.04), and resulted in an estimated mean cost per QALY of £14,248. Where costs associated with informal care are considered in sensitivity analyses collaborative care is expected to be less costly and more effective, thereby dominating treatment as usual.Conclusion
Collaborative care offers health gains at a relatively low cost, and is cost-effective compared with usual care against a decision-maker willingness to pay threshold of £20,000 per QALY gained. Results here support the commissioning of collaborative care in a UK primary care setting. 相似文献68.
Cloning, sequencing, and characterization of the Bacillus subtilis biotin biosynthetic operon. 总被引:4,自引:0,他引:4
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S Bower J B Perkins R R Yocum C L Howitt P Rahaim J Pero 《Journal of bacteriology》1996,178(14):4122-4130
A 10-kb region of the Bacillus subtilis genome that contains genes involved in biotin-biosynthesis was cloned and sequenced. DNA sequence analysis indicated that B. subtilis contains homologs of the Escherichia coli and Bacillus sphaericus bioA, bioB, bioD, and bioF genes. These four genes and a homolog of the B. sphaericus bioW gene are arranged in a single operon in the order bioWAFDR and are followed by two additional genes, bioI and orf2. bioI and orf2 show no similarity to any other known biotin biosynthetic genes. The bioI gene encodes a protein with similarity to cytochrome P-450s and was able to complement mutations in either bioC or bioH of E. coli. Mutations in bioI caused B. subtilis to grow poorly in the absence of biotin. The bradytroph phenotype of bioI mutants was overcome by pimelic acid, suggesting that the product of bioI functions at a step prior to pimelic acid synthesis. The B. subtilis bio operon is preceded by a putative vegetative promoter sequence and contains just downstream a region of dyad symmetry with homology to the bio regulatory region of B. sphaericus. Analysis of a bioW-lacZ translational fusion indicated that expression of the biotin operon is regulated by biotin and the B. subtilis birA gene. 相似文献
69.
Arora K Gwinn WM Bower MA Watson A Okwumabua I MacDonald HR Bukrinsky MI Constant SL 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(1):517-522
The main regulators of leukocyte trafficking during inflammatory responses are chemokines. However, another class of recently identified chemotactic agents is extracellular cyclophilins, the proteins mostly known as receptors for the immunosuppressive drug, cyclosporine A. Cyclophilins can induce leukocyte chemotaxis in vitro and have been detected at elevated levels in inflamed tissues, suggesting that they might contribute to inflammatory responses. We recently identified CD147 as the main signaling receptor for cyclophilin A. In the current study we examined the contribution of cyclophilin-CD147 interactions to inflammatory responses in vivo using a mouse model of acute lung injury. Blocking cyclophilin-CD147 interactions by targeting CD147 (using anti-CD147 Ab) or cyclophilin (using nonimmunosuppressive cyclosporine A analog) reduced tissue neutrophilia by up to 50%, with a concurrent decrease in tissue pathology. These findings are the first to demonstrate the significant contribution of cyclophilins to inflammatory responses and provide a potentially novel approach for reducing inflammation-mediated diseases. 相似文献
70.