全文获取类型
收费全文 | 5833篇 |
免费 | 300篇 |
国内免费 | 8篇 |
出版年
2024年 | 13篇 |
2023年 | 86篇 |
2022年 | 143篇 |
2021年 | 312篇 |
2020年 | 146篇 |
2019年 | 166篇 |
2018年 | 180篇 |
2017年 | 153篇 |
2016年 | 270篇 |
2015年 | 294篇 |
2014年 | 310篇 |
2013年 | 470篇 |
2012年 | 424篇 |
2011年 | 460篇 |
2010年 | 263篇 |
2009年 | 236篇 |
2008年 | 318篇 |
2007年 | 287篇 |
2006年 | 260篇 |
2005年 | 216篇 |
2004年 | 200篇 |
2003年 | 169篇 |
2002年 | 168篇 |
2001年 | 47篇 |
2000年 | 41篇 |
1999年 | 40篇 |
1998年 | 30篇 |
1997年 | 32篇 |
1996年 | 18篇 |
1995年 | 27篇 |
1994年 | 28篇 |
1993年 | 22篇 |
1992年 | 18篇 |
1991年 | 16篇 |
1990年 | 15篇 |
1989年 | 17篇 |
1988年 | 17篇 |
1987年 | 18篇 |
1986年 | 7篇 |
1985年 | 23篇 |
1984年 | 21篇 |
1983年 | 16篇 |
1982年 | 25篇 |
1981年 | 13篇 |
1980年 | 16篇 |
1979年 | 9篇 |
1978年 | 13篇 |
1977年 | 10篇 |
1974年 | 6篇 |
1966年 | 7篇 |
排序方式: 共有6141条查询结果,搜索用时 109 毫秒
981.
Eddy Karnabi Yongxia Qu Salvatore Mancarella Raj Wadgaonkar Mohamed Boutjdir 《Biochemical and biophysical research communications》2009,384(4):409-414
Cav1.2 (α1C) and Cav1.3 (α1D) L-type Ca channels are co-expressed in the heart. To date, there are no pharmacological or biophysical tools to separate α1D from α1C Ca currents (ICa-L) in cardiomyocytes. Here, we established a physiological model to study α1D ICa-L in native myocytes using RNA interference. Transfection of rat neonatal cardiomyocytes (RNC) with α1C specific siRNA resulted in low silencing efficiency (50-60%) at the mRNA and protein levels. The use of lentivirus shRNA resulted in 100% transfection efficiency and 92% silencing of the α1C gene by real-time PCR and Western blot. Electrophysiological experiments showed that the total ICa-L was similarly reduced by 80% in lentivirus transfected cells. Both biochemical and functional data demonstrated high transfection and silencing efficiency in the cardiomyocytes using lentiviral shRNA. This novel approach allows for the assessments of the roles of α1C and α1D Ca channels in native myocytes and could be used to examine their roles in physiological and pathological settings. 相似文献
982.
Mohamed Ali Borgi Moez Rhimi Nushin Aghajari Mamdouh Ben Ali Michel Juy Richard Haser Samir Bejar 《Biologia》2009,64(5):845-851
The implication of the original alanine 63 (Ala63) and the unique cysteine 306 (Cys306) residues in the thermostability of
the Streptomyces sp. SK glucose isomerase (SKGI) were investigated by site-directed mutagenesis and homology modelling. The Cys306 to Ala
mutation within SKGI dramatically affected its thermal stability by decreasing the half-life from 80 to 15 min at 90°C while
the Ala63 to Ser replacement shifted this half-life to 65 min. The electrophoretic analysis proves that the residue Cys306
participates in oligomerization of the SKGI. Its stabilizing role is materialized by hydrogen bonds established with arginines
at positions 284 and 259, as deduced from the constructed three-dimensional model. We have also shown that the presence of
an Ala63 instead of Ser63 seems to be more suitable for enzyme thermostability by maintaining hydrophobic pocket that contributes
to the protection of the enzyme active site. 相似文献
983.
Food partitioning and spatial subsidy in shelter‐limited fishes inhabiting patchy reefs of Patagonia
D. E. Galvn F. Botto A. M. Parma L. Bandieri N. Mohamed O. O. Iribarne 《Journal of fish biology》2009,75(10):2585-2605
The diets of the most conspicuous reef‐fish species from northern Patagonia, the carnivorous species Pseudopercis semifasciata, Acanthistius patachonicus, Pinguipes brasilianus and Sebastes oculatus were studied. Pinguipes brasilianus had the narrowest diet and most specialized feeding strategy, preying mostly on reef‐dwelling organisms such as sea urchins, limpets, bivalves, crabs and polychaetes. The diet of A. patachonicus was characterized by the presence of reef and soft‐bottom benthic organisms, mainly polychaetes, crabs and fishes. Pseudopercis semifasciata showed the broadest spectrum of prey items, preying upon reef, soft‐bottom and transient organism (mainly fishes, cephalopods and crabs). All S. oculatus guts were empty, but stable‐isotope analyses suggested that this species consumed small fishes and crabs. In general, P. brasilianus depended on local prey populations and ate different reef‐dwelling prey than the other species. Pseudopercis semifasciata, A. patachonicus and probably S. oculatus, however, had overlapping trophic niches and consumed resources from adjacent environments. The latter probably reduces the importance of food as a limiting resource for these reef‐fish populations, facilitating their coexistence in spite of their high trophic overlap. 相似文献
984.
985.
Tumor necrosis factor (TNF) and members of the interferon (IFN) family have been shown to independently inhibit the replication of a variety of viruses. In addition, previous reports have shown that treatment with various combinations of these antiviral cytokines induces a synergistic antiviral state that can be significantly more potent than addition of any of these cytokines alone. The mechanism of this cytokine synergy and its effects on global gene expression, however, are not well characterized. Here, we use DNA microarray analysis to demonstrate that treatment of uninfected primary human fibroblasts with TNF plus IFN-β induces a distinct synergistic state characterized by significant perturbations of several hundred genes which are coinduced by the individual cytokines alone, as well as the induction of more than 850 novel host cell genes. This synergy is mediated directly by the two ligands, not by intermediate secreted factors, and is necessary and sufficient to completely block the productive replication and spread of myxoma virus in human fibroblasts. In contrast, the replication of two other poxviruses, vaccinia virus and tanapox virus, are only partially inhibited in these cells by the synergistic antiviral state, whereas the spread of both of these viruses to neighboring cells was efficiently blocked. Taken together, our data indicate that the combination of TNF and IFN-β induces a novel synergistic antiviral state that is highly distinct from that induced by either cytokine alone. 相似文献
986.
Tamer M. A. Mohamed Delvac Oceandy Sukhpal Prehar Nasser Alatwi Zeinab Hegab Florence M. Baudoin Adam Pickard Aly O. Zaki Raja Nadif Elizabeth J. Cartwright Ludwig Neyses 《The Journal of biological chemistry》2009,284(18):12091-12098
The cardiac neuronal nitric-oxide synthase (nNOS) has been described as a
modulator of cardiac contractility. We have demonstrated previously that
isoform 4b of the sarcolemmal calcium pump (PMCA4b) binds to nNOS in the heart
and that this complex regulates β-adrenergic signal transmission in
vivo. Here, we investigated whether the nNOS-PMCA4b complex serves as a
specific signaling modulator in the heart. PMCA4b transgenic mice (PMCA4b-TG)
showed a significant reduction in nNOS and total NOS activities as well as in
cGMP levels in the heart compared with their wild type (WT) littermates. In
contrast, PMCA4b-TG hearts showed an elevation in cAMP levels compared with
the WT. Adult cardiomyocytes isolated from PMCA4b-TG mice demonstrated a
3-fold increase in Ser16 phospholamban (PLB) phosphorylation as
well as Ser22 and Ser23 cardiac troponin I (cTnI)
phosphorylation at base line compared with the WT. In addition, the relative
induction of PLB phosphorylation and cTnI phosphorylation following
isoproterenol treatment was severely reduced in PMCA4b-TG myocytes, explaining
the blunted physiological response to the β-adrenergic stimulation. In
keeping with the data from the transgenic animals, neonatal rat cardiomyocytes
overexpressing PMCA4b showed a significant reduction in nitric oxide and cGMP
levels. This was accompanied by an increase in cAMP levels, which led to an
increase in both PLB and cTnI phosphorylation at base line. Elevated cAMP
levels were likely due to the modulation of cardiac phosphodiesterase, which
determined the balance between cGMP and cAMP following PMCA4b overexpression.
In conclusion, these results showed that the nNOS-PMCA4b complex regulates
contractility via cAMP and phosphorylation of both PLB and cTnI.Neuronal nitric-oxide synthase
(nNOS)5 is involved in
a number of key processes in cardiomyocytes including calcium cycling
(1), the β-adrenergic
contractile response (2,
3), post-infarct left
ventricular remodeling (4), and
the regulation of redox equilibrium
(5). Moreover, a polymorphism
in an nNOS-interacting protein, CAPON, has been found to form a quantitative
trait for the determination of the QT interval in humans
(6), whereas a mutation in
α1-syntrophin (SNTA1), another interacting partner of nNOS, has been
associated with long QT syndrome
(7). The signaling events
downstream of the nNOS-CAPON
(8) and nNOS-SNTA1
(7) complexes, which are
responsible for mediating cardiac repolarization and sodium current
respectively, have been elucidated. The nNOS-containing protein complex is
therefore of immediate relevance to human pathology.In recent years, we have shown that the sarcolemmal calcium pump, which
ejects calcium to the extracellular compartment (reviewed in Refs.
9 and
10), is an important molecule
involved in signal regulation and transmission in the heart
(11). We have demonstrated
that isoform 4b of the sarcolemmal calcium pump (also known as PMCA4b for
plasma membrane calcium/calmodulin-dependent
ATPase 4b) modulates signaling through a tight molecular
interaction with nNOS, leading to the modulation of β-adrenergic
responsiveness in the heart
(12). However, the events
following signaling through the PMCA4b-nNOS complex remain unknown.In myocardial cells, nNOS has been localized to the sarcolemma
(13), sarcoplasmic reticulum
(2), and mitochondria
(14), and translocation
between compartments has been demonstrated
(15). It has been speculated
that these various localizations provide specificity to NO signaling, but the
exact mechanisms have yet to be elucidated. In this study, we show a mechanism
by which one fraction of nNOS serves highly specific functions through binding
to PMCA4b. As PMCA4b is confined to the sarcolemma and is a calcium pump, it
is the first identified protein to fulfill these aggregate functions. 1) It
acts as an anchoring protein; 2) it regulates nNOS activity; and 3) it
modulates a process at the plasma membrane, i.e. β-adrenergic
signaling. 相似文献
987.
Hanene Medini Ameur Elaissi Farhat Farhat Mohamed Larbi Khouja Rachid Chemli Fathia Harzallah‐Skhiri 《化学与生物多样性》2009,6(9):1378-1387
The essential‐oil composition of 60 individual trees of Juniperus phoenicea L. from four Tunisian populations in three different periods were investigated by GC and GC/MS analyses. 59 Compounds were identified in the oils, and a relatively high variation in their contents was found. All the oils were dominated by the terpenic hydrocarbon fraction, and the main component was α‐pinene (20.28–40.86%). The results of the oil compositions were processed by hierarchical clustering and principal component analysis (PCA) allowing establishing four groups of essential‐oils differentiated by one compound or more. Pattern of geographic variation in essential‐oil composition indicated that individuals from the continental site (Makthar) were clearly distinguished from those from littoral localities (Tabarka, Hawaria, and Rimel). 相似文献
988.
Histopathological effects of cisplatin,doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats
下载免费PDF全文
![点击此处可从《International journal of biological sciences》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Hassan I El-Sayyad Mohamed F Ismail F M Shalaby RF Abou-El-Magd Rajiv L Gaur Augusta Fernando Madhwa HG Raj Allal Ouhtit 《International journal of biological sciences》2009,5(5):466-473
Cisplatin, doxorubicin and fluorouracil (5-FU), drugs belonging to different chemical classes, have been extensively used for chemotherapy of various cancers. Despite extensive investigations into their hepatotoxicity, there is very limited information on their effects on the structure and ultra-structure of liver cells in vivo. Here, we demonstrate for the first time, the effects of these three anticancer drugs on rat liver toxicity using both light and electron microscopy. Light microscopic observations revealed that higher doses of cisplatin and doxorubicin caused massive hepatotoxicity compared to 5-FU treatment, including dissolution of hepatic cords, focal inflammation and necrotic tissues. Interestingly, low doses also exhibited abnormal changes, including periportal fibrosis, degeneration of hepatic cords and increased apoptosis. These changes were confirmed at ultrastructural level, including vesiculated rough endoplasmic reticulum and atrophied mitochondria with ill-differentiated cisternae, dense collection of macrophages and lymphocytes as well as fibrocytes with collagenous fibrils manifesting early sign of fibrosis, especially in response to cisplatin and doxorubicin -treatment. Our results provide in vivo evidence, at ultrastructural level, of direct hepatotoxicity caused by cisplatin, doxorubicin and 5-FU at both light and electron microscopi. These results can guide the design of appropriate treatment regimen to reduce the hepatotoxic effects of these anticancer drugs. 相似文献
989.
990.
Sylvanne M Daniels Carlos E Melendez-Peña Robert J Scarborough Aïcha Daher Helen S Christensen Mohamed El Far Damian FJ Purcell Sébastien Lainé Anne Gatignol 《BMC molecular biology》2009,10(1):38-13