全文获取类型
收费全文 | 103871篇 |
免费 | 1233篇 |
国内免费 | 821篇 |
出版年
2023年 | 47篇 |
2022年 | 92篇 |
2021年 | 186篇 |
2020年 | 123篇 |
2019年 | 121篇 |
2018年 | 11966篇 |
2017年 | 10789篇 |
2016年 | 7711篇 |
2015年 | 1060篇 |
2014年 | 806篇 |
2013年 | 977篇 |
2012年 | 5038篇 |
2011年 | 13593篇 |
2010年 | 12460篇 |
2009年 | 8674篇 |
2008年 | 10394篇 |
2007年 | 11999篇 |
2006年 | 924篇 |
2005年 | 1084篇 |
2004年 | 1543篇 |
2003年 | 1580篇 |
2002年 | 1358篇 |
2001年 | 412篇 |
2000年 | 300篇 |
1999年 | 197篇 |
1998年 | 188篇 |
1997年 | 156篇 |
1996年 | 122篇 |
1995年 | 132篇 |
1994年 | 119篇 |
1993年 | 138篇 |
1992年 | 141篇 |
1991年 | 115篇 |
1990年 | 84篇 |
1989年 | 59篇 |
1988年 | 76篇 |
1987年 | 47篇 |
1986年 | 45篇 |
1985年 | 56篇 |
1984年 | 43篇 |
1983年 | 51篇 |
1982年 | 46篇 |
1981年 | 35篇 |
1980年 | 26篇 |
1979年 | 30篇 |
1977年 | 31篇 |
1976年 | 25篇 |
1972年 | 252篇 |
1971年 | 283篇 |
1962年 | 24篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
961.
Quinn Grundy Lisa Tierney Christopher Mayes Wendy Lipworth 《Journal of bioethical inquiry》2017,14(4):541-553
Conflicts of interest, stemming from relationships between health professionals and the pharmaceutical industry, remain a highly divisive and inflammatory issue in healthcare. Given that most jurisdictions rely on industry to self-regulate with respect to its interactions with health professionals, it is surprising that little research has explored industry leaders’ understandings of conflicts of interest. Drawing from in-depth interviews with ten pharmaceutical industry leaders based in Australia, we explore the normalized and structural management of conflicts of interest within pharmaceutical companies. We contrast this with participants’ unanimous belief that the antidote to conflicts of interest with health professionals were “informed consumers.” It is, thus, unlikely that a self-regulatory approach will be successful in ensuring ethical interactions with health professionals. However, the pharmaceutical industry’s routine and accepted practices for disclosing and managing employees’ conflicts of interest could, paradoxically, serve as an excellent model for healthcare. 相似文献
962.
Graft-versus-host disease (GVHD) induced by host antigen-presenting cells (APCs) and donor-derived T cells remains the major limitation of allogeneic bone marrow transplantation (allo-BMT). Notch signaling pathway is a highly conserved cell-cell communication that is important in T cell development. Recently, Notch signaling pathway is reported to be involved in regulating GVHD. To investigate the role of Notch inhibition in modulating GVHD, we established MHC-mismatched murine allo-BMT model. We found that inhibition of Notch signaling pathway by γ-secretase inhibitor in vivo could reduce aGVHD, which was shown by the onset time of aGVHD, body weight, clinical aGVHD scores, pathology aGVHD scores, and survival. Inhibition of Notch signaling pathway by DAPT ex vivo only reduced pathology aGVHD scores in the liver and intestine and had no impact on the onset time and clinical aGVHD scores. We investigated the possible mechanism by analyzing the phenotype of host APCs and donor-derived T cells. Notch signaling pathway had a broad effect on both host APCs and donor-derived T cells. The expressions of CD11c, CD40, and CD86 as the markers of activated dendritic cells (DCs) were decreased. The proliferative response of CD8+ T cell decreased, while CD4+ Notch-deprived T cells had preserved expansion with increased expressions of CD25 and Foxp3 as markers of regulatory T cells (Tregs). In conclusion, Notch inhibition may minimize aGVHD by decreasing proliferation and activation of DCs and CD8+ T cells while preserving Tregs expansion. 相似文献
963.
Genome editing is a powerful technology that can efficiently alter the genome of organisms to achieve targeted modification of endogenous genes and targeted integration of exogenous genes. Current genome-editing tools mainly include ZFN, TALEN and CRISPR/Cas9, which have been successfully applied to all species tested including zebrafish, humans, mice, rats, monkeys, pigs, cattle, sheep, goats and others. The application of genome editing has quickly swept through the entire biomedical field, including livestock breeding. Traditional livestock breeding is associated with rate limiting issues such as long breeding cycle and limitations of genetic resources. Genome editing tools offer solutions to these problems at affordable costs. Generation of gene-edited livestock with improved traits has proven feasible and valuable. For example, the CD163 gene-edited pig is resistant to porcine reproductive and respiratory syndrome (PRRS, also referred to as “blue ear disease”), and a SP110 gene knock-in cow less susceptible to tuberculosis. Given the high efficiency and low cost of genome editing tools, particularly CRISPR/Cas9, it is foreseeable that a significant number of genome edited livestock animals will be produced in the near future; hence it is imperative to comprehensively evaluate the pros and cons they will bring to the livestock breeding industry. Only with these considerations in mind, we will be able to fully take the advantage of the genome editing era in livestock breeding. 相似文献
964.
Biswas R Yamaoka M Nakayama H Kondo T Yoshida K Bisaria VS Kondo A 《Applied microbiology and biotechnology》2012,94(3):651-658
Production of 2,3-butanediol by Bacillus subtilis takes place in late-log or stationary phase, depending on the expression of bdhA gene encoding acetoin reductase, which converts acetoin to 2,3-butanediol. The present work focuses on the development of
a strain of B. subtilis for enhanced production of 2,3-butanediol in early log phase of growth cycle. For this, the bdhA gene was expressed under the control of P
alsSD
promoter of AlsSD operon for acetoin fermentation which served the substrate for 2,3-butanediol production. Addition of acetic acid in the
medium induced the production of 2,3-butanediol by 2-fold. Two-step aerobic–anaerobic fermentation further enhanced 2,3-butanediol
production by 4-fold in comparison to the control parental strain. Thus, addition of acetic acid and low dissolved oxygen
in the medium are involved in activation of bdhA gene expression from P
alsSD
promoter in early log phase. Under the conditions tested in this work, the maximum production of 2,3-butanediol, 2.1 g/l
from 10 g/l glucose, was obtained at 24 h. Furthermore, under the optimized microaerophilic condition, the production of 2,3-butanediol
improved up to 6.1 g/l and overall productivity increased by 6.7-fold to 0.4 g/l h in the engineered strain compared to that
in the parental control. 相似文献
965.
Villalobos-Comparán M Teresa Flores-Dorantes M Teresa Villarreal-Molina M Rodríguez-Cruz M García-Ulloa AC Robles L Huertas-Vázquez A Saucedo-Villarreal N López-Alarcón M Sánchez-Muñoz F Domínguez-López A Gutiérrez-Aguilar R Menjivar M Coral-Vázquez R Hernández-Stengele G Vital-Reyes VS Acuña-Alonzo V Romero-Hidalgo S Ruiz-Gómez DG Riaño-Barros D Herrera MF Gómez-Pérez FJ Froguel P García-García E Teresa Tusié-Luna M Aguilar-Salinas CA Canizales-Quinteros S 《Obesity (Silver Spring, Md.)》2008,16(10):2296-2301
Common polymorphisms in the fat mass and obesity-associated gene (FTO) have shown strong association with obesity in several populations. In the present study, we explored the association of FTO gene polymorphisms with obesity and other biochemical parameters in the Mexican population. We also assessed FTO gene expression levels in adipose tissue of obese and nonobese individuals. The study comprised 788 unrelated Mexican-Mestizo individuals and 31 subcutaneous fat tissue biopsies from lean and obese women. FTO single-nucleotide polymorphisms (SNPs) rs9939609, rs1421085, and rs17817449 were associated with obesity, particularly with class III obesity, under both additive and dominant models (P = 0.0000004 and 0.000008, respectively). These associations remained significant after adjusting for admixture (P = 0.000003 and 0.00009, respectively). Moreover, risk alleles showed a nominal association with lower insulin levels and homeostasis model assessment of B-cell function (HOMA-B), and with higher homeostasis model assessment of insulin sensitivity (HOMA-S) only in nonobese individuals (P (dom) = 0.031, 0.023, and 0.049, respectively). FTO mRNA levels were significantly higher in subcutaneous fat tissue of class III obese individuals than in lean individuals (P = 0.043). Risk alleles were significantly associated with higher FTO expression in the class III obesity group (P = 0.047). In conclusion, FTO is a major risk factor for obesity (particularly class III) in the Mexican-Mestizo population, and is upregulated in subcutaneous fat tissue of obese individuals. 相似文献
966.
Hiroyuki Inoue Chiaki Kitao Shinichi Yano Shigeki Sawayama 《World journal of microbiology & biotechnology》2016,32(11):186
On-site cellulase and hemicellulase production is a promising way to reduce enzyme cost in the commercialization of the lignocellulose-to-ethanol process. A hemicellulase-producing fungal strain suitable for on-site enzyme production was selected from cultures prepared using wet disc-milling rice straw (WDM-RS) and identified as Trichoderma asperellum KIF125. KIF125 hemicellulase showed uniquely high abundance of β-xylosidase in the xylanolytic enzyme system compared to other fungal hemicellulase preparations. Supplementation of Talaromyces cellulolyticus cellulase with KIF125 hemicellulase was more effective than that with the hemicellulases from other fungal sources in reducing the total enzyme loading for the improvement of xylose yield in the hydrolysis of ball-milling RS, due to its high β-xylosidase dominance. β-Xylosidase in KIF125 hemicellulase was purified and classified as a glycosyl hydrolase family 3 enzyme with relatively high specificity for xylobiose. The production of KIF125 β-xylosidase in the fermentor was estimated as 118 U/g-WDM-RS (2350 U/L culture) at 48 h. These results demonstrate that KIF125 is promising as a practical hemicellulase source to combine with on-site cellulase production using T. cellulolyticus. 相似文献
967.
Haiyang Zhang Zhe Lin Daoyong Tan Chunhua Liu Yali Kuang Zhu Li 《Biotechnology letters》2017,39(1):79-84
Objectives
To develop a more effective dissolved air flotation process for harvesting microalgae biomass, a co-flocculation/air flotation (CAF) system was developed that uses an ejector followed by a helix tube flocculation reactor (HTFR) as a co-flocculation device to harvest Chlorella sp. 64.01.Results
The optimal size distribution of micro-bubbles and an air release efficiency of 96 % were obtained when the flow ratio of inlet fluid (raw water) to motive fluid (saturated water) of the ejector was 0.14. With a reaction time of 24 s in the HTFR, microalgae cells and micro-bubbles were well flocculated, and these aerated flocs caused a fast rising velocity (96 m/h) and high harvesting efficiency (94 %).Conclusions
In a CAF process, micro-bubbles can be encapsulated into microalgae flocs, which makes aerated flocs more stable. CAF is an effective approach to harvesting microalgae.968.
microRNA, a family of small non-coding RNA, plays significant roles in regulating gene expression, mainly via binding to the 3′-untranslated region of target genes. Although the role of miRNA in regulating neuroinflammation via the innate immune pathway has been studied, its role in the production of inflammatory mediators during microglial activation is poorly understood. In this study, we investigated the effect of miR-27a on lipopolysaccharide (LPS)-induced microglial inflammation. miR-27a expression was found to be rapidly decreased in microglia by real-time polymerase chain reaction (real-time PCR) after LPS stimulation. Over-expression of miR-27a significantly decreased the production of inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), whereas knockdown of miR-27a increased the expression of these inflammatory factors. We also demonstrated by loss- and gain-of-function studies that miR-27a directly suppressed the expression of toll-like receptor 4 (TLR4) and interleukin-1 receptor-associated kinase 4 (IRAK4)—a pivotal adaptor kinase in the TLR4/MyD88 signaling pathway—by directly binding their 3′-UTRs: knocking down TLR4 or IRAK4 in microglia significantly decreased TLR4 or IRAK4 expression and inhibited the downstream production of inflammatory mediators. Moreover, the inflammatory cytokines IL-6 and IL-1β were regulated by IRAK4, whereas TNF-α and NO were more dependent on TLR4 activation. Thus, miR-27a might regulate the LPS-induced production of inflammatory cytokines in microglia independently of TLR4 and IRAK4. Taken together, our results suggest that miR-27a is associated with microglial activation and the inflammatory response. 相似文献
969.
Giseli Valentini Maria Celeste Gonçalves-Vidigal Oscar P. Hurtado-Gonzales Sandra Aparecida de Lima Castro Perry B. Cregan Qijian Song Marcial A. Pastor-Corrales 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2017,130(8):1705-1722
Key message
Co-segregation analysis and high-throughput genotyping using SNP, SSR, and KASP markers demonstrated genetic linkage between Ur-14 and Co-3 4 /Phg-3 loci conferring resistance to the rust, anthracnose and angular leaf spot diseases of common bean.Abstract
Rust, anthracnose, and angular leaf spot are major diseases of common bean in the Americas and Africa. The cultivar Ouro Negro has the Ur-14 gene that confers broad spectrum resistance to rust and the gene cluster Co-3 4 /Phg-3 containing two tightly linked genes conferring resistance to anthracnose and angular leaf spot, respectively. We used co-segregation analysis and high-throughput genotyping of 179 F2:3 families from the Rudá (susceptible) × Ouro Negro (resistant) cross-phenotyped separately with races of the rust and anthracnose pathogens. The results confirmed that Ur-14 and Co-3 4 /Phg-3 cluster in Ouro Negro conferred resistance to rust and anthracnose, respectively, and that Ur-14 and the Co-3 4 /Phg-3 cluster were closely linked. Genotyping the F2:3 families, first with 5398 SNPs on the Illumina BeadChip BARCBEAN6K_3 and with 15 SSR, and eight KASP markers, specifically designed for the candidate region containing Ur-14 and Co-3 4 /Phg-3, permitted the creation of a high-resolution genetic linkage map which revealed that Ur-14 was positioned at 2.2 cM from Co-3 4 /Phg-3 on the short arm of chromosome Pv04 of the common bean genome. Five flanking SSR markers were tightly linked at 0.1 and 0.2 cM from Ur-14, and two flanking KASP markers were tightly linked at 0.1 and 0.3 cM from Co-3 4 /Phg-3. Many other SSR, SNP, and KASP markers were also linked to these genes. These markers will be useful for the development of common bean cultivars combining the important Ur-14 and Co-3 4 /Phg-3 genes conferring resistance to three of the most destructive diseases of common bean.970.
Mu Wang Ouyan Rang Fang Liu Wei Xia Yuanyuan Li Yu Zhang Songfeng Lu Shunqing Xu 《Metabolomics : Official journal of the Metabolomic Society》2018,14(4):45