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171.
Katherine J. Kayser-Bricker Matthew P. Glenn Sang Hoon Lee Said M. Sebti Jin Q. Cheng Andrew D. Hamilton 《Bioorganic & medicinal chemistry》2009,17(4):1764-1771
Akt has emerged as a critical target for the development of anti-cancer therapies. It has been found to be amplified, overexpressed, or constitutively activated in numerous human malignancies with oncogenesis derived from the simultaneous promotion of cell survival and suppression of apoptosis. A valuable alternative to the more common ATP-mimetic based chemotherapies is a substrate-mimetic approach, which has the potential advantage of inherent specificity of the substrate-binding pocket. In this paper we present the development of high affinity non-peptidic, substrate-mimetic inhibitors based on the minimum GSK3β substrate sequence. Optimization of initial peptidic leads resulted in the development of several classes of small molecule inhibitors, which have comparable potency to the initial peptidomimetics, while eliminating the remaining amino acid residues. We have identified the first non-peptidic substrate-mimetic lead inhibitors of Akt 29a–b, which have affinities of 17 and 12 μM, respectively. This strategy has potential to provide a useful set of molecular probes to assist in the validation of Akt as a potential target for anti-cancer drug design. 相似文献
172.
Abdallah Said Essa Jennifer Rosenthal Kramer David Y. Graham Gerhard Treiber 《Helicobacter》2009,14(2):109-118
Background: Low success rates with triple therapy for Helicobacter pylori infections have prompted search for alternatives. In one, a proton-pump inhibitor (PPI) and amoxicillin was followed by the PPI plus clarithromycin and a nitroimidazole (sequential therapy); in another, these four drugs were given concomitantly (concomitant therapy).
Aim: To compare concomitant therapy with standard triple therapy for H. pylori infection.
Methods: By searching PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and abstracts of major gastrointestinal meeting, two independent reviewers systemically identified randomized controlled trials (RCT) comparing concomitant quadruple to standard triple therapies as well as studies reporting eradication rates of concomitant quadruple therapy in treatment of H. pylori . Pooled eradication rates and odds ratios (OR) with 95% confidence intervals (CI) were calculated, and univariable metaregression analysis for all extracted variables was conducted.
Results: We identified nine studies (10 treatment arms) including five qualifying RCTs (576 subjects) comparing concomitant (293 subjects, duration 3 to 5 days) and triple therapy (283 subjects, duration 5 to 10 days) and four other studies evaluating concomitant therapy (478 subjects, duration 3 to 7 days). Pooled estimates of the five RCTs showed superiority of concomitant therapy over triple therapy; with intention-to-treat) pooled OR of 2.86 (95% CI: 1.73–4.73) and per-protocol (PP) pooled OR of 3.52 (95% CI: 1.95–6.38). Considering all 10 treatment arms, the ITT eradication rate was 89.7% (95% CI: 86.8–92.1%) and PP was 92.9% (95% CI: 90.2–94.8%).
Conclusion: Concomitant therapy appears to be an effective alternative to triple therapy and is less complex than sequential therapy. 相似文献
Aim: To compare concomitant therapy with standard triple therapy for H. pylori infection.
Methods: By searching PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and abstracts of major gastrointestinal meeting, two independent reviewers systemically identified randomized controlled trials (RCT) comparing concomitant quadruple to standard triple therapies as well as studies reporting eradication rates of concomitant quadruple therapy in treatment of H. pylori . Pooled eradication rates and odds ratios (OR) with 95% confidence intervals (CI) were calculated, and univariable metaregression analysis for all extracted variables was conducted.
Results: We identified nine studies (10 treatment arms) including five qualifying RCTs (576 subjects) comparing concomitant (293 subjects, duration 3 to 5 days) and triple therapy (283 subjects, duration 5 to 10 days) and four other studies evaluating concomitant therapy (478 subjects, duration 3 to 7 days). Pooled estimates of the five RCTs showed superiority of concomitant therapy over triple therapy; with intention-to-treat) pooled OR of 2.86 (95% CI: 1.73–4.73) and per-protocol (PP) pooled OR of 3.52 (95% CI: 1.95–6.38). Considering all 10 treatment arms, the ITT eradication rate was 89.7% (95% CI: 86.8–92.1%) and PP was 92.9% (95% CI: 90.2–94.8%).
Conclusion: Concomitant therapy appears to be an effective alternative to triple therapy and is less complex than sequential therapy. 相似文献
173.
Said I. Ismail Ismail S. Mahmoud Mahmoud Al-Ardah Amid Abdelnour Nidal A. Younes 《Journal of genetics》2009,88(2):233-238
Five patients, four brothers and their paternal aunt, presented with a history of overt hyperthyroidism and goiter. Hyperthyroidism
in this family was remarkable for its poor response to carbimazole (30–50 mg/d). The thyroid ultrasound showed a diffusely
enlarged gland in all the affected members, and thyroid stimulating antibodies (TSAB) were negative. Screening for germline
mutations in thyroid stimulating hormone (TSH) receptor (TSHR) gene was performed by direct sequencing of genomic DNA extracted from peripheral blood leukocytes of all family members.
The sequence analysis of all TSHR gene exons and intron borders revealed two genomic variants. The first was a single nucleotide polymorphism (SNP) within
exon seven (Asn187Asn), whereas the other was located in intron seven (IVS7+68T>G). All affected members, two asymptomatic
brothers with sub-clinical hyperthyroidism, and their father were heterozygous for those two genomic variants. Anti-thyroid
drug treatment for several months successfully relieved symptoms in one subject, whereas the remaining patients required total
thyroidectomy to control their disease. This is the first Jordanian family with familial non-autoimmune hyperthyroidism, with
mutations affecting the TSHR gene. 相似文献
174.
Rym Zitari-Chatti Noureddine Chatti Domenico Fulgione Immacolata Caiazza Gennaro Aprea Ali Elouaer Khaled Said Teresa Capriglione 《Genetica》2009,136(3):439-447
In this study we analysed mitochondrial DNA variation in Penaeus kerathurus prawns collected from seven locations along a transect across the Siculo–Tunisian region in order to verify if any population
structuring exists over a limited geographical scale and to delineate the putative transition zone with sufficient accuracy.
Partial DNA sequences of COI and 16S genes were analysed. In contrast to the highly conservative 16S gene, the COI sequences
exhibited sufficient diversity for population analysis. The COI gene revealed low levels of haplotype and nucleotide diversities.
The size of the annual landings of this commercial species suggests large population sizes. Hence, the low genetic diversity
detected in this study could indicate a possible reduction in effective population sizes in the past. We detected significant
genetic differentiation between eastern and western populations likely due to restricted gene flow across the Siculo–Tunisian
boundary. We discuss the different evolutionary forces that may have shaped the genetic variation and suggest that the genetic
divide is probably maintained by present-day dispersal limitation.
R. Zitari-Chatti and N. Chatti are contributed equally to the work. 相似文献
175.
Driss Mountassif ;Tarik Baibai ;Latifa Fourrat ;Adnane Moutaouakkil ;Abdelghani Iddar ;M'Hammed Said El Kebbaj ;Abdelaziz S oukri 《Acta biochimica et biophysica Sinica》2009,(5):399-406
A new procedure utilizing immunoaffinity column chromatography has been used for the purification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 1.2.1.12) from human erythrocytes. The comparison between this rapid method (one step) and the tra- ditional procedure including ammonium sulfate fractionation followed by Blue Sepharose CL-6B chromatography shows that the new method gives a highest specific activity with a highest yield in a short time. The characterization of the purified GAPDH reveals that the native enzyme is a homotetramer of -150 kDa with an absolute specificity for the oxidized form of nicotinamide adenine dinucleotide (NAD+). Western blot analysis using purified monospecific polyclonal antibodies raised against the purified GAPDH showed a single 36 kDa band corresponding to the enzyme subunit. Studies on the effect of temperature and pH on enzyme activity revealed optimal values of about 43℃ and 8.5, respectively. The kinetic parameters were also calculated: the Vmax was 4.3 U/mg and the Km values against G3P and NAD+ were 20.7 and 17.8 μM, respectively. The new protocol described represents a simple, economic, and reproducible tool for the purification of GAPDH and can be used for other proteins. 相似文献
176.
Staphylococcus epidermidis polysaccharide intercellular adhesin induces IL-8 expression in human astrocytes via a mechanism involving TLR2 总被引:1,自引:0,他引:1
Niall T. Stevens Irina Sadovskaya Said Jabbouri Tafiq Sattar James P. O'Gara Hilary Humphreys Catherine M. Greene 《Cellular microbiology》2009,11(3):421-432
Staphylococcus epidermidis is an opportunistic biofilm-forming pathogen associated with neurosurgical device-related meningitis. Expression of the polysaccharide intercellular adhesin (PIA) on its surface promotes S. epidermidis biofilm formation. Here we investigated the pro-inflammatory properties of PIA against primary and transformed human astrocytes. PIA induced IL-8 expression in a dose- and/or time-dependent manner from U373 MG cells and primary normal human astrocytes. This effect was inhibited by depletion of N -acetyl-β- d -glucosamine polymer from the PIA preparation with Lycopersicon esculentum lectin or sodium meta -periodate. Expression of dominant-negative versions of the TLR2 and TLR4 adaptor proteins MyD88 and Mal in U373 MG cells inhibited PIA-induced IL-8 production. Blocking IL-1 had no effect. PIA failed to induce IL-8 production from HEK293 cells stably expressing TLR4. However, in U373 MG cells which express TLR2, neutralization of TLR2 impaired PIA-induced IL-8 production. In addition to IL-8, PIA also induced expression of other cytokines from U373 MG cells including IL-6 and MCP-1. These data implicate PIA as an important immunogenic component of the S. epidermidis biofilm that can regulate pro-inflammatory cytokine production from human astrocytes, in part, via TLR2. 相似文献
177.
Background
Radiation is a primary or secondary therapeutic modality for treatment of head and neck cancer. A common side effect of irradiation to the neck and neck region is xerostomia caused by salivary gland dysfunction. Approximately 40,000 new cases of xerostomia result from radiation treatment in the United States each year. The ensuing salivary gland hypofunction results in significant morbidity and diminishes the effectiveness of anti-cancer therapies as well as the quality of life for these patients. Previous studies in a rat model have shown no correlation between induction of apoptosis in the salivary gland and either the immediate or chronic decrease in salivary function following γ-radiation treatment.Methodology/Principal Finding
A significant level of apoptosis can be detected in the salivary glands of FVB mice following γ-radiation treatment of the head and neck and this apoptosis is suppressed in transgenic mice expressing an activated mutant of Akt (myr-Akt1). Importantly, this suppression of apoptosis in myr-Akt1 mice preserves salivary function, as measured by saliva output, three and thirty days after γ-radiation treatment. In order to translate these studies into a preclinal model we found that intravenous injection of IGF1 stimulated activation of endogenous Akt in the salivary glands in vivo. A single injection of IGF1 prior to exposure to γ-radiation diminishes salivary acinar cell apoptosis and completely preserves salivary gland function three and thirty days following irradiation.Conclusions/Significance
These studies suggest that apoptosis of salivary acinar cells underlies salivary gland hypofunction occurring secondary to radiation of the head and neck region. Targeted delivery of IGF1 to the salivary gland of patients receiving head and neck irradiation may be useful in reducing or eliminating xerostomia and restoring quality of life to these patients. 相似文献178.
Zhao TY Zou SP Alimova YV Wang G Hauser KF Ghandour MS Knapp PE 《Journal of neurochemistry》2006,98(5):1541-1550
Although short interfering RNA (siRNA)-induced gene silencing can be transmitted between cells in plants and in Caenorhabditis elegans, this phenomenon has been barely studied in mammalian cells. Both immortalized oligodendrocytes and SNB19 glioblastoma cells were transfected with siRNA constructs for phosphatase and tensin homolog deleted on chromosome 10 (PTEN) or Akt/protein kinase B (Akt). Co-cultures were established between silenced cells and non-silenced cells which were hygromycin resistant and/or expressed green fluorescent protein. After fluorescence sorting or hygromycin selection to remove the silenced cells, the expression of PTEN or Akt genes in the originally unsilenced cells was in all cases significantly decreased. Importantly, silencing did not occur in transwell culture studies, suggesting that transmission of the silencing signal requires a close association between cells. These results provide the first direct demonstration that an siRNA-induced silencing signal can be transmitted between mammalian CNS cells. 相似文献
179.
Hu B Gilkes DM Farooqi B Sebti SM Chen J 《The Journal of biological chemistry》2006,281(44):33030-33035
The p53 tumor suppressor plays a key role in maintaining genomic stability and protection against malignant transformation. MDM2 and MDMX are both p53-binding proteins that regulate p53 stability and activity. Recent development of the MDM2 inhibitor Nutlin 3 has greatly facilitated functional analysis of MDM2-p53 binding. We found that although MDMX is homologous to MDM2 and binds to the same region on p53 N terminus, Nutlin does not disrupt p53-MDMX interaction. The ability of Nutlin to activate p53 is compromised in tumor cells overexpressing MDMX. Combination of Nutlin with MDMX siRNA resulted in synergistic activation of p53 and growth arrest. These results suggest that MDMX is also a valid target for p53 activation in tumor cells. Development of novel compounds that are MDMX-specific or optimized for dual-inhibition of MDM2 and MDMX are necessary to achieve full activation of p53 in tumor cells. 相似文献
180.
Kiran Mahajan Domenico Coppola Sridevi Challa Bin Fang Y. Ann Chen Weiwei Zhu Alexis S. Lopez John Koomen Robert W. Engelman Charlene Rivera Rebecca S. Muraoka-Cook Jin Q. Cheng Ernst Sch?nbrunn Said M. Sebti H. Shelton Earp Nupam P. Mahajan 《PloS one》2010,5(3)
The AKT/PKB kinase is a key signaling component of one of the most frequently activated pathways in cancer and is a major target of cancer drug development. Most studies have focused on its activation by Receptor Tyrosine Kinase (RTK) mediated Phosphatidylinositol-3-OH kinase (PI3K) activation or loss of Phosphatase and Tensin homolog (PTEN). We have uncovered that growth factors binding to RTKs lead to activation of a non-receptor tyrosine kinase, Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation. Mice expressing activated Ack1 specifically in the prostate exhibit AKT Tyr176-phosphorylation and develop murine prostatic intraepithelial neoplasia (mPINs). Further, expression levels of Tyr176-phosphorylated-AKT and Tyr284-phosphorylated-Ack1 were positively correlated with the severity of disease progression, and inversely correlated with the survival of breast cancer patients. Thus, RTK/Ack1/AKT pathway provides a novel target for drug discovery. 相似文献