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191.
Jianzhong Liu Shunqing Wang Ping Zhang Nasser Said-Al-Naief Suzanne M. Michalek Xu Feng 《The Journal of biological chemistry》2009,284(18):12512-12523
Lipopolysaccharide (LPS), a common bacteria-derived product, has long been
recognized as a key factor implicated in periodontal bone loss. However, the
precise cellular and molecular mechanisms by which LPS induces bone loss still
remains controversial. Here, we show that LPS inhibited osteoclastogenesis
from freshly isolated osteoclast precursors but stimulated osteoclast
formation from those pretreated with RANKL in vitro in tissue culture
dishes, bone slices, and a co-culture system containing osteoblasts,
indicating that RANKL-mediated lineage commitment is a prerequisite for
LPS-induced osteoclastogenesis. Moreover, the RANKL-mediated lineage
commitment is long term, irreversible, and TLR4-dependent. LPS exerts the dual
function primarily by modulating the expression of NFATc1, a master regulator
of osteoclastogenesis, in that it abolished RANKL-induced NFATc1 expression in
freshly isolated osteoclast precursors but stimulated its expression in
RANKL-pretreated cells. In addition, LPS prolonged osteoclast survival by
activating the Akt, NF-κB, and ERK pathways. Our current work has not
only unambiguously defined the role of LPS in osteoclastogenesis but also has
elucidated the molecular mechanism underlying its complex functions in
osteoclast formation and survival, thus laying a foundation for future
delineation of the precise mechanism of periodontal bone loss.LPS,2 a
common bacteria-derived product, has long been recognized as a key factor
implicated in the development of chronic periodontitis. LPS plays an important
role in periodontitis by initiating a local host response in gingival tissues
that involves recruitment of inflammatory cells, production of prostanoids and
cytokines, elaboration of lytic enzymes and activation of osteoclast formation
and function to induce bone loss
(1-3).Osteoclasts, the body''s sole bone-resorbing cells, are multinucleated giant
cells that differentiate from cells of hematopoietic lineage upon stimulation
by two critical factors: the macrophage/monocyte colony-forming factor (M-CSF)
and the receptor activator of NF-κB ligand (RANKL)
(4-6).
RANKL exerts its effects on osteoclast formation and function by binding to
its receptor, RANK (receptor activator of NF-κB) expressed on osteoclast
precursors and mature osteoclasts
(7-9).
RANKL also has a decoy receptor, osteoprotegerin, which inhibits RANKL action
by competing with RANK for binding RANKL
(10,
11).RANK is a member of the tumor necrosis factor receptor (TNFR) family
(12). Members of the TNFR
family lack intrinsic enzymatic activity, and hence they transduce
intracellular signals by recruiting various adaptor proteins including TNF
receptor-associated factors (TRAFs) through specific motifs in the cytoplasmic
domain (13,
14). It has been established
that RANK contains three functional TRAF-binding sites
(369PFQEP373, 559PVQEET564, and
604PVQEQG609) that, redundantly, play a role in
osteoclast formation and function
(15,
16). Collectively, through
these functional TRAF-binding motifs, RANK activates six major signaling
pathways, NF-κB, JNK, ERK, p38, NFATc1, and Akt, which play important
roles in osteoclast formation, function, and/or survival
(15,
17-19).
In particular, NFATc1 has been established as a master regulator of osteoclast
differentiation
(20-22).The involvement of osteoclasts in the pathogenesis of periodontal bone loss
is supported by observations that osteoclasts are physically present and
functionally involved in bone resorption in periodontal tissues
(23-27).
RANKL and RANK knockout mice develop osteopetrosis and show failure in tooth
eruption due to a lack of osteoclasts
(24,
25,
28). Moreover,
op/op mice, in which a mutation in the coding region of the
M-CSF gene generates a stop codon that leads to premature termination of
translation of M-CSF mRNA, also show osteopetrosis and failure in tooth
eruption due to a defect in osteoclast development
(26,
27).Whereas the role of osteoclasts in periodontal disease associated alveolar
bone destruction has been well established, the precise role of LPS in
osteoclastogenesis still remains controversial. The vast majority of the
previous studies demonstrated that LPS stimulates osteoclastogenesis. This is
consistent with the role that LPS, a well recognized pathogenic factor in
periodontitis, presumably plays in periodontal bone loss
(29-33).
However, two previous studies demonstrated, surprisingly, that LPS plays
bifunctional roles in osteoclastogenesis in that although it inhibits
osteoclast formation from normal osteoclast precursors, it reverses to promote
osteoclastogenesis from osteoclast precursors pretreated with RANKL
(34,
35). Given that this finding
is inconsistent with the presumed role of LPS as a pathogenic factor in
periodontal bone loss and lacks careful and further validation, the prevalent
view is still that LPS stimulates osteoclastogenesis
(1-3).
Importantly, if LPS indeed has a dual function in osteoclastogenesis, the
molecular mechanism by which LPS exerts a dual effect on osteoclastogenesis
need to be further elucidated.In the present work, using various in vitro assays, we have
demonstrated independently that LPS inhibits osteoclastogenesis from normal
osteoclast precursors but promotes the development of osteoclasts from
RANKL-pretreated cells in tissue culture dishes and bone slices in single-cell
and co-culture settings, confirming the two previous observations that LPS
play a bifunctional role in osteoclastogenesis
(34,
35). Moreover, we have further
shown that the RANKL-mediated lineage commitment is long term and irreversible
in LPS-mediated osteoclastogenesis. More importantly, we have revealed that
LPS inhibits osteoclastogenesis by suppressing NFATc1 expression and JNK
activation while it prolongs osteoclast survival by activating the Akt,
NF-κB, and ERK pathways. These studies have not only unambiguously and
precisely defined the role of LPS in osteoclastogenesis but, more importantly,
may also lead to a paradigm shift in future investigation of the molecular
mechanism of periodontal bone loss. 相似文献
192.
Nasser H. Zawia Debomoy K. Lahiri Fernando Cardozo-Pelaez 《Free radical biology & medicine》2009,46(9):1241-1249
Alzheimer disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The sporadic nature of 90% of AD cases, the differential susceptibility to and course of the illness, as well as the late age onset of the disease suggest that epigenetic and environmental components play a role in the etiology of late-onset AD. Animal exposure studies demonstrated that AD may begin early in life and may involve an interplay between the environment, epigenetics, and oxidative stress. Early life exposure of rodents and primates to the xenobiotic metal lead (Pb) enhanced the expression of genes associated with AD, repressed the expression of others, and increased the burden of oxidative DNA damage in the aged brain. Epigenetic mechanisms that control gene expression and promote the accumulation of oxidative DNA damage are mediated through alterations in the methylation or oxidation of CpG dinucleotides. We found that environmental influences occurring during brain development inhibit DNA-methyltransferases, thus hypomethylating promoters of genes associated with AD such as the β-amyloid precursor protein (APP). This early life imprint was sustained and triggered later in life to increase the levels of APP and amyloid-β (Aβ). Increased Aβ levels promoted the production of reactive oxygen species, which damage DNA and accelerate neurodegenerative events. Whereas AD-associated genes were overexpressed late in life, others were repressed, suggesting that these early life perturbations result in hypomethylation as well as hypermethylation of genes. The hypermethylated genes are rendered susceptible to Aβ-enhanced oxidative DNA damage because methylcytosines restrict repair of adjacent hydroxyguanosines. Although the conditions leading to early life hypo- or hypermethylation of specific genes are not known, these changes can have an impact on gene expression and imprint susceptibility to oxidative DNA damage in the aged brain. 相似文献
193.
We determined host plant effect on susceptibility of whitefly Bemisia tabaci to the entomopathogenic fungus Beauveria bassiana under controlled conditions. Insects were reared on cucumber, eggplant, tomato or cabbage. Fungal suspensions of 1×104, 105, 106, 107 and 108 conidia/mL were applied on second-instar nymphs. Nymphal survival significantly differed among different host plant species on which the nymphs were reared. Ten days after inoculation with 1×108 conidia/mL, percent survival was 4.2±0.7, 9.6±0.4, 13.4±0.8, and 24.3±0.9% on cucumber, eggplant, tomato and cabbage, respectively. Average survival times of nymphs were also significantly influenced by host plant species. After inoculation with 1×108 conidia/mL, survival times were 4.8±0.15, 6.0±0.11, 5.7±0.13, and 6.2±0.08 days for nymphs reared on cucumber, eggplant, tomato, and cabbage, respectively. Virulence also differed depending on host plant species; 10 days after inoculation, LC50 values were 4.6×104, 1.6×105, 4.2×105 and 2.1×106 conidia/mL on cucumber, eggplant, tomato and cabbage, respectively. Nymphs on cucumber showed highest susceptibility. 相似文献
194.
Synthesis of some novel 4-arylhydrazono-5-trifluoromethyl-2,4-dihydropyrazol-3-ones, their N- and N,O-bis- β-d-glucosides is described. Antimicrobial evaluation of eight selected compounds against Aspergillus fumigatus RCMB 002008 (1), Penicillium italicum RCMB 001018 (1), Syncephalastrum racemosum RCMB 016001, Candida albicans RCMB 005003, Staphylococcus aureus RCMB 106-001 (1), Pseudomonas aeruginosa RCMB 102-002, Bacillus subtilis RCMB 101-001, and Escherichia coli RCMB 103-001 has been achieved. The screening results indicated that all the tested compounds exhibited different inhibitory effects against five to seven different organisms of the eight test organisms. 相似文献
195.
MicroRNA-122 Inhibits Tumorigenic Properties of Hepatocellular Carcinoma Cells and Sensitizes These Cells to Sorafenib 总被引:1,自引:0,他引:1
Shoumei Bai Mohd W. Nasser Bo Wang Shu-Hao Hsu Jharna Datta Huban Kutay Arti Yadav Gerard Nuovo Pawan Kumar Kalpana Ghoshal 《The Journal of biological chemistry》2009,284(46):32015-32027
MicroRNAs are negative regulators of protein coding genes. The liver-specific microRNA-122 (miR-122) is frequently suppressed in primary hepatocellular carcinomas (HCCs). In situ hybridization demonstrated that miR-122 is abundantly expressed in hepatocytes but barely detectable in primary human HCCs. Ectopic expression of miR-122 in nonexpressing HepG2, Hep3B, and SK-Hep-1 cells reversed their tumorigenic properties such as growth, replication potential, clonogenic survival, anchorage-independent growth, migration, invasion, and tumor formation in nude mice. Further, miR-122-expressing HCC cells retained an epithelial phenotype that correlated with reduced Vimentin expression. ADAM10 (a distintegrin and metalloprotease family 10), serum response factor (SRF), and insulin-like growth factor 1 receptor (Igf1R) that promote tumorigenesis were validated as targets of miR-122 and were repressed by the microRNA. Conversely, depletion of the endogenous miR-122 in Huh-7 cells facilitated their tumorigenic properties with concomitant up-regulation of these targets. Expression of SRF or Igf1R partially reversed tumor suppressor function of miR-122. Further, miR-122 impeded angiogenic properties of endothelial cells in vitro. Notably, ADAM10, SRF, and Igf1R were up-regulated in primary human HCCs compared with the matching liver tissue. Co-labeling studies demonstrated exclusive localization of miR-122 in the benign livers, whereas SRF predominantly expressed in HCC. More importantly, growth and clonogenic survival of miR-122-expressing HCC cells were significantly reduced upon treatment with sorafenib, a multi-kinase inhibitor clinically effective against HCC. Collectively, these results suggest that the loss of multifunctional miR-122 contributes to the malignant phenotype of HCC cells, and miR-122 mimetic alone or in combination with anticancer drugs can be a promising therapeutic regimen against liver cancer. 相似文献
196.
Alessandra Nasser Caiafa Fernando Roberto Martins 《Biodiversity and Conservation》2010,19(9):2597-2618
The assessment of species rarity considers local abundance (scarce or abundant population), habitat affinity (stenoecious
or euryecious species), and geographic distribution (stenotopic or eurytopic species). When analyzed together these variables
classify species into eight categories, from common species to those having small populations, unique habitats, and restricted
geographic distribution (form 7), as proposed by Rabinowitz in 1981. Based on these categories, it is possible to calculate
the frequency of the different forms of rarity of the species present in a given site. The Brazilian Atlantic rainforest is
considered a hotspot of the world biodiversity harboring many endemic species, which have restricted geographic distribution.
Our objective was to identify the forms of rarity of tree species and their proportions in the southern portion of the Brazilian
Atlantic rainforest using Rabinowitz’s forms of rarity. All the seven forms of rarity are present in the 846 tree species
we analyzed: 46% eurytopic and 54% stenotopic, 73% euryecious and 27% stenoecious, 76% locally abundant and 24% locally scarce
species. Eurytopic, euryecious locally abundant species accounted for 41.1%, whereas 58.9% were somehow rare: 4.5% eurytopic,
euryecious locally scarce, 0.2% eurytopic, stenoecious locally abundant, 0.1% eurytopic, stenoecious locally scarce, 19.5%
stenotopic, euryecious locally abundant, 8.0% stenotopic, euryecious locally scarce, 15.6% stenotopic, stenoecious locally
abundant, and 11.0% stenotopic, stenoecious locally scarce. Considering that the most restrictive forms of rarity precedes
extinction, the application of Rabinowitz’s system demonstrated that most tree species of the southern Brazilian Atlantic
rainforest are threatened due to their restricted geographic distribution, restriction to a single habitat, reduced local
abundance, or even to a combination of these variables. 相似文献
197.
A 28-year-old woman was admitted to our institution, reporting progressive dyspnea, cough, and weight loss of 14 kg. Two-dimensional echocardiography revealed a left atrial mass, and cardiac magnetic resonance imaging showed localized involvement of the mass with adjacent structures. These clinical signs and radiographic images were highly suggestive of cardiac sarcoma. The patient underwent emergent mediastinal exploration, and an incisional biopsy of the mass showed high-grade sarcoma. Removing the tumor required radical en bloc resection of the left atrium, including the mitral valve, the left pulmonary vein, and the left lower lobe of the lung. Autotransplantation was necessary for the resection and reconstruction. We report a unique method of handling the right atrium to avoid the potential complications associated with bicaval anastomoses after autotransplantation. 相似文献
198.
Background
The validity of Doppler echocardiographic (DE) measurement of systolic pulmonary artery pressure (sPAP) has been questioned. Recent studies suggest that mean pulmonary artery pressure (mPAP) might reflect more accurately the invasive pressures.Methodology/Principal Findings
241 patients were prospectively studied to evaluate the diagnostic accuracy of mPAP for the diagnosis of PH. Right heart catheterization (RHC) and DE were performed in 164 patients mainly for preoperative evaluation of heart valve dysfunction. The correlation between DE and RHC was better when mPAP (r = 0.93) and not sPAP (r = 0.81) was assessed. Bland-Altman analysis revealed a smaller variation of mPAP than sPAP. The following ROC analysis identified that a mPAP≥25.5 mmHg is useful for the diagnosis of PH. This value was validated in an independent cohort of patients (n = 50) with the suspicion of chronic-thromboembolic pulmonary hypertension. The calculated diagnostic accuracy was 98%, based on excellent sensitivity of 98% and specificity of 100%. The corresponding positive and negative predictive values were 100%, respectively 88%.Conclusion
mPAP has been found to be highly accurate for the initial diagnosis of PH. A cut-off value of 25.5 mmHg might be helpful to avoid unnecessary RHC and select patients in whom RHC might be beneficial. 相似文献199.
Nonenveloped viruses such as Simian Virus 40 (SV40) exploit established cellular pathways for internalization and transport to their site of penetration. By analyzing mutant SV40 genomes that do not express VP2 or VP3, we found that these structural proteins perform essential functions that are regulated by VP1. VP2 significantly enhanced SV40 particle association with the host cell, while VP3 functioned downstream. VP2 and VP3 both integrated posttranslationally into the endoplasmic reticulum (ER) membrane. Association with VP1 pentamers prevented their ER membrane integration, indicating that VP1 controls the function of VP2 and VP3 by directing their localization between the particle and the ER membrane. These findings suggest a model in which VP2 aids in cell binding. After capsid disassembly within the ER lumen, VP3, and perhaps VP2, oligomerizes and integrates into the ER membrane, potentially creating a viroporin that aids in viral DNA transport out of the ER. 相似文献
200.