全文获取类型
收费全文 | 4959篇 |
免费 | 245篇 |
国内免费 | 3篇 |
出版年
2022年 | 28篇 |
2021年 | 61篇 |
2020年 | 28篇 |
2019年 | 51篇 |
2018年 | 72篇 |
2017年 | 53篇 |
2016年 | 91篇 |
2015年 | 145篇 |
2014年 | 178篇 |
2013年 | 329篇 |
2012年 | 333篇 |
2011年 | 302篇 |
2010年 | 199篇 |
2009年 | 195篇 |
2008年 | 316篇 |
2007年 | 308篇 |
2006年 | 318篇 |
2005年 | 314篇 |
2004年 | 314篇 |
2003年 | 297篇 |
2002年 | 273篇 |
2001年 | 55篇 |
2000年 | 67篇 |
1999年 | 60篇 |
1998年 | 64篇 |
1997年 | 53篇 |
1996年 | 46篇 |
1995年 | 39篇 |
1994年 | 37篇 |
1993年 | 36篇 |
1992年 | 45篇 |
1991年 | 43篇 |
1990年 | 41篇 |
1989年 | 65篇 |
1988年 | 40篇 |
1987年 | 26篇 |
1986年 | 35篇 |
1985年 | 25篇 |
1984年 | 30篇 |
1983年 | 25篇 |
1982年 | 23篇 |
1981年 | 17篇 |
1980年 | 15篇 |
1979年 | 16篇 |
1978年 | 15篇 |
1977年 | 11篇 |
1976年 | 17篇 |
1975年 | 14篇 |
1974年 | 8篇 |
1973年 | 12篇 |
排序方式: 共有5207条查询结果,搜索用时 437 毫秒
931.
Michio Hashimoto Hossain Md Shahdat Masanori Katakura Yoko Tanabe Shuji Gamoh Koji Miwa Toshio Shimada Osamu Shido 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2009,1791(4):289-296
Amyloid β peptide25–35 (Aβ25–35) encompasses one of the neurotoxic domains of full length Aβ1–40/42, the major proteinaceous component of amyloid deposits in Alzheimer's disease (AD). We investigated the effect of docosahexaenoic acid (DHA, 22:6, n-3), an essential brain polyunsaturated fatty acid, on the in vitro fibrillation of Aβ25–35 and found that it significantly reduced the degree of fibrillation, as shown by a decrease in the intensity of both the thioflavin T and green fluorescence in confocal microscopy. Transmission electron microscopy revealed that DHA-incubated samples were virtually devoid of structured fibrils but had an amorphous-like consistency, whereas the controls contained structured fibers of various widths and lengths. The in vitro fibrillation of Aβ25–35 appeared to be pH-dependent, with the strongest effect seen at pH 5.0. DHA inhibited fibrillation at all pHs, with the strongest effect at pH 7.4. It also significantly decreased the levels of Aβ25–35 oligomers. Nonreductive gradient gel electrophoresis revealed that the molecular size of the oligomers of Aβ25–35 was 10 kDa (equivalent to decamers of Aβ25–35) and that DHA dose-dependently reduced these decamers. These results suggest that DHA decreases the in vitro fibrillation of Aβ25–35 by inhibiting the oligomeric amyloid species and, therefore, Aβ25–35-related neurotoxicity or behavioral impairment could be restrained by DHA. 相似文献
932.
933.
We develop discrete-time models for analyzing the long-run equilibrium outcomes on invasive species management in two-patch
environments with migration. In particular, the focus is on a situation where removal operations for invasive species are
implemented only in one patch (controlled patch). The new features of the model are that (1) asymmetry in density-dependent
migration is considered, which may originate from impact of harvesting as well as heterogeneous habitat conditions, and (2)
the effect of density-dependent catchability accounts for the fact that the required effort level to remove one individual
may rise as the existing population decreases. The model is applied to agricultural damage control in the raccoon (Procyon lotor) problem that has occurred in Hokkaido, Japan. Numerical illustrations demonstrate that the long-run equilibrium outcomes
largely depend on the degree of asymmetry in migration as well as the sensitivity of catchability in response to a change
in the population size of the invasive species. Furthermore, we characterize the conditions under which the economically optimal
effort levels are qualitatively affected by the above two factors, and conclude that aiming at local extermination of invasive
species in the controlled patch is justified.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
934.
Gregory D. Fairn Koji Ogata Roberto J. Botelho Philip D. Stahl Richard A. Anderson Pietro De Camilli Tobias Meyer Shoshana Wodak Sergio Grinstein 《The Journal of cell biology》2009,187(5):701-714
Plasmalemmal phosphatidylinositol (PI) 4,5-bisphosphate (PI4,5P2) synthesized by PI 4-phosphate (PI4P) 5-kinase (PIP5K) is key to the polymerization of actin that drives chemotaxis and phagocytosis. We investigated the means whereby PIP5K is targeted to the membrane and its fate during phagosome formation. Homology modeling revealed that all PIP5K isoforms feature a positively charged face. Together with the substrate-binding loop, this polycationic surface is proposed to constitute a coincidence detector that targets PIP5Ks to the plasmalemma. Accordingly, manipulation of the surface charge displaced PIP5Ks from the plasma membrane. During particle engulfment, PIP5Ks detached from forming phagosomes as the surface charge at these sites decreased. Precluding the change in surface charge caused the PIP5Ks to remain associated with the phagosomal cup. Chemically induced retention of PIP5K-γ prevented the disappearance of PI4,5P2 and aborted phagosome formation. We conclude that a bistable electrostatic switch mechanism regulates the association/dissociation of PIP5Ks from the membrane during phagocytosis and likely other processes. 相似文献
935.
Stavros Garantziotis Zhuowei Li Erin N. Potts Koji Kimata Lisheng Zhuo Daniel L. Morgan Rashmin C. Savani Paul W. Noble W. Michael Foster David A. Schwartz John W. Hollingsworth 《The Journal of biological chemistry》2009,284(17):11309-11317
Ozone is a common urban environmental air pollutant and significantly
contributes to hospitalizations for respiratory illness. The mechanisms, which
regulate ozone-induced bronchoconstriction, remain poorly understood.
Hyaluronan was recently shown to play a central role in the response to
noninfectious lung injury. Therefore, we hypothesized that hyaluronan
contributes to airway hyperreactivity (AHR) after exposure to ambient ozone.
Using an established model of ozone-induced airways disease, we characterized
the role of hyaluronan in airway hyperresponsiveness. The role of hyaluronan
in response to ozone was determined by using therapeutic blockade, genetically
modified animals, and direct challenge to hyaluronan. Ozone-exposed mice
demonstrate enhanced AHR associated with elevated hyaluronan levels in the
lavage fluid. Mice deficient in either CD44 (the major receptor for
hyaluronan) or inter-α-trypsin inhibitor (molecule that facilitates
hyaluronan binding) show similar elevations in hyaluronan but are protected
from ozone-induced AHR. Mice pretreated with hyaluronan-binding peptide are
protected from the development of ozone-induced AHR. Overexpression of
hyaluronan enhances the airway response to ozone. Intratracheal instillation
of endotoxin-free low molecular weight hyaluronan induces AHR dependent on
CD44, whereas instillation of high molecular weight hyaluronan protects
against ozone-induced AHR. In conclusion, we demonstrate that hyaluronan
mediates ozone-induced AHR, which is dependent on the fragment size and both
CD44 and inter-α-trypsin inhibitor. These data support the conclusion
that pulmonary matrix can contribute to the development of airway
hyperresponsiveness.Ozone is a commonly encountered urban air pollutant that significantly
contributes to increased morbidity
(1–4)
and can lead to a significant economic burden. It has been estimated that each
year inhalation of ambient ozone contributes to 800 premature deaths, 4,500
hospital admissions, 900,000 school absences, and more than 1 million
restricted activity days with an estimated $5 billion annual economic burden
(5). Population-based studies
suggest that for each 10 ppb increase in 1-h daily maximum level of ozone
there is an increase in mortality risk of 0.39–0.87%, especially in
individuals with pre-existing respiratory disease
(2,
3,
6,
7). However, the biological
mechanisms, which regulate the response to ambient ozone exposure, remain
poorly understood.Hyaluronan is an abundant extracellular matrix component, which has been
recently shown to play a significant role in the response to noninfectious
lung injury. Short fragment hyaluronan
(sHA)2 is released in
the lung after sterile injury such as bleomycin instillation
(8) or high tidal volume
ventilation (9) and can modify
the tissue response to injury. Furthermore, hyaluronan has been identified in
airway secretions from asthmatics
(10), and high molecular
weight hyaluronan can attenuate the bronchoconstrictive response in
exercise-induced asthma (11).
We therefore hypothesized that hyaluronan may contribute to the biological
response to airway injury after exposure to ozone.In this study, we provide evidence that hyaluronan mediates ozone-induced
AHR. Mice exposed to ozone demonstrate elevated lung lavage fluid levels of
hyaluronan, which is of low molecular weight. We observed that animals
deficient in either CD44 (a hyaluronan surface receptor) or
inter-α-trypsin inhibitor (IaI, which facilitates hyaluronan binding)
are protected from ozone-induced AHR. Overexpression of hyaluronan by airway
epithelia enhances ozone-induced AHR. Furthermore, pretreatment of mice with
hyaluronan-binding peptide or high molecular weight hyaluronan protects
animals from the development of ozone-induced AHR. Direct instillation of low
molecular weight, but not high molecular weight, hyaluronan alone induces AHR.
Our observations support a critical role for short fragment hyaluronan in the
development of airway hyperresponsiveness after exposure to ozone. 相似文献
936.
937.
938.
We surveyed plant community development at the abandoned Ogushi sulfur mine. We found seven communities dominated by the following
respective species: Deschampsia flexuosa, Miscanthus sinensis, shrub willow, Gaultheria miqueliana–Betula ermanii, Sasa senanensis–Betula ermanii, willow–Betula ermanii, and Sasa kurilensis–Abies veitchii. We examined the succession of these communities, in which younger communities of low height and ground cover contained seedlings
of the successive communities that were taller and had higher ground cover. To understand the development of these different
communities, we surveyed damage from mining pollution and effects of immature soils formed by landslides. The average pH (H2O) was 4.12, and aluminum concentrations were not sufficiently high to damage plant growth, except in areas where sulfur had
been mined. The organic carbon and nitrogen content in soil samples were very low because of a delay in soil development caused
by a large landslide in 1937. Hence, succession was positively correlated with the soil development stage. The delay in soil
development after a large landslide influenced the seven successional steps of the plant communities, but mineral poisons
at the abandoned Ogushi sulfur mine had no effect on succession. 相似文献
939.
Buxiang Sun Koji Wakame Eri Sato Hiroshi Nishioka Okezie I. Aruoma Hajime Fujii 《Cancer epidemiology》2009,33(3-4):293-299
Background: Active hexose correlated compound (AHCC) (a mixture of polysaccharides, amino acids, lipids and minerals derived from cultured mycelia of a Basidiomycete mushroom, Lentinula edodes) was used to assess amelioration of alopecia (hair loss) caused by cytosine arabinoside (Ara-C) and modulation of liver injury caused by single doses 6-mercaptopurine (6-MP) plus methotrexate (MTX). Methods: Follicular integrity and hair growth was assessed in male and female SD neonatal rats (8 days old) treated with a single dose of Ara-C (30 mg/kg/day, i.p.) and AHCC (500 mg/kg/day, p.o.) for 7 consecutive days. The side effects of a single oral dose of 6-MP (2.5 mg/kg body weight) plus MTX (30 mg/kg body weight) and their amelioration by treatment with AHCC (1000 mg/kg body weight) for 28 days were assessed in male ddY mice (8 weeks old). Results: Of the Ara-C treated rats 71.4% showed severe alopecia and 28.6% showed moderate alopecia. However, the AHCC (p.o.)-treated Ara-C group was significantly protected from alopecia. Ara-C treated rats had profound loss of hair follicles but the Ara-C plus AHCC-treated group had mild losses of follicles. AHCC supplementation to the 6-MP- and MTX-treated mice significantly increased body weight, erythrocytes, leukocytes and serum albumin, improved liver hypertrophy and degeneration, normalized the activities of serum glutamic oxaloacetic transaminase (sGOT) and serum glutamic pyruvic transaminase (sGPT), and enhanced liver drug-metabolizing enzymes. Conclusion: Co-administration of AHCC significantly reduced the side effects associated with Ara-C, 6-MP and MTX. However, the molecular mechanism for AHCC activity and its clinical integrity for use needs defining. 相似文献
940.
Yukio Hirayama Mamiko Yoshimura Yuriko Ozeki Isamu Sugawara Tadashi Udagawa Satoru Mizuno Naoki Itano Koji Kimata Aki Tamaru Hisashi Ogura Kazuo Kobayashi Sohkichi Matsumoto 《PLoS pathogens》2009,5(10)
In spite of the importance of hyaluronan in host protection against infectious organisms in the alveolar spaces, its role in mycobacterial infection is unknown. In a previous study, we found that mycobacteria interact with hyaluronan on lung epithelial cells. Here, we have analyzed the role of hyaluronan after mycobacterial infection was established and found that pathogenic mycobacteria can grow by utilizing hyaluronan as a carbon source. Both mouse and human possess 3 kinds of hyaluronan synthases (HAS), designated HAS1, HAS2, and HAS3. Utilizing individual HAS-transfected cells, we show that HAS1 and HAS3 but not HAS2 support growth of mycobacteria. We found that the major hyaluronan synthase expressed in the lung is HAS1, and that its expression was increased after infection with Mycobacterium tuberculosis. Histochemical analysis demonstrated that hyaluronan profoundly accumulated in the granulomatous legion of the lungs in M. tuberculosis-infected mice and rhesus monkeys that died from tuberculosis. We detected hyaluronidase activity in the lysate of mycobacteria and showed that it was critical for hyaluronan-dependent extracellular growth. Finally, we showed that L-Ascorbic acid 6-hexadecanoate, a hyaluronidase inhibitor, suppressed growth of mycobacteria in vivo. Taken together, our data show that pathogenic mycobacteria exploit an intrinsic host-protective molecule, hyaluronan, to grow in the respiratory tract and demonstrate the potential usefulness of hyaluronidase inhibitors against mycobacterial diseases. 相似文献