全文获取类型
收费全文 | 267篇 |
免费 | 32篇 |
出版年
2022年 | 7篇 |
2021年 | 6篇 |
2020年 | 5篇 |
2019年 | 2篇 |
2018年 | 5篇 |
2017年 | 3篇 |
2016年 | 4篇 |
2015年 | 10篇 |
2014年 | 8篇 |
2013年 | 17篇 |
2012年 | 15篇 |
2011年 | 13篇 |
2010年 | 18篇 |
2009年 | 8篇 |
2008年 | 10篇 |
2007年 | 9篇 |
2006年 | 5篇 |
2005年 | 7篇 |
2004年 | 9篇 |
2003年 | 9篇 |
2002年 | 3篇 |
2001年 | 8篇 |
2000年 | 11篇 |
1999年 | 10篇 |
1998年 | 4篇 |
1997年 | 5篇 |
1996年 | 4篇 |
1995年 | 3篇 |
1993年 | 3篇 |
1992年 | 7篇 |
1991年 | 6篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 6篇 |
1987年 | 3篇 |
1985年 | 4篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1968年 | 2篇 |
1958年 | 5篇 |
1956年 | 2篇 |
1955年 | 2篇 |
1954年 | 2篇 |
1953年 | 4篇 |
1952年 | 4篇 |
1951年 | 2篇 |
排序方式: 共有299条查询结果,搜索用时 15 毫秒
21.
Huang Xudong Atwood Craig S. Moir Robert D. Hartshorn Mariana A. Tanzi Rudolph E. Bush Ashley I. 《Journal of biological inorganic chemistry》2004,9(8):954-960
Nucleation-dependent protein aggregation (seeding) and amyloid fibril-free formation of soluble SDS-resistant oligomers (oligomerization) by hydrophobic interaction is an in vitro model thought to propagate -amyloid (A) deposition, accumulation, and incur neurotoxicity and synaptotoxicity in Alzheimers disease (AD), and other amyloid-associated neurodegenerative diseases. However, A is a high-affinity metalloprotein that aggregates in the presence of biometals (zinc, copper, and iron), and neocortical A deposition is abolished by genetic ablation of synaptic zinc in transgenic mice. We now present in vitro evidence that trace (0.8 µM) levels of zinc, copper, and iron, present as common contaminants of laboratory buffers and culture media, are the actual initiators of the classic A1–42-mediated seeding process and A oligomerization. Replicating the experimental conditions of earlier workers, we found that the in vitro precipitation and amyloidosis of A1–40 (20 µM) initiated by A1–42 (2 µM) were abolished by chelation of trace metal contaminants. Further, metal chelation attenuated formation of soluble A oligomers from a cell-free culture medium. These data suggest that protein self-assembly and oligomerization are not spontaneous in this system as previously thought, and that there may be an obligatory role for metal ions in initiating A amyloidosis and oligomerization. 相似文献
22.
23.
April M. Weissmiller Orlangie Natera-Naranjo Sol M. Reyna Matthew L. Pearn Xiaobei Zhao Phuong Nguyen Soan Cheng Lawrence S. B. Goldstein Rudolph E. Tanzi Steven L. Wagner William C. Mobley Chengbiao Wu 《PloS one》2015,10(2)
Clues to Alzheimer disease (AD) pathogenesis come from a variety of different sources including studies of clinical and neuropathological features, biomarkers, genomics and animal and cellular models. An important role for amyloid precursor protein (APP) and its processing has emerged and considerable interest has been directed at the hypothesis that Aβ peptides induce changes central to pathogenesis. Accordingly, molecules that reduce the levels of Aβ peptides have been discovered such as γ-secretase inhibitors (GSIs) and modulators (GSMs). GSIs and GSMs reduce Aβ levels through very different mechanisms. However, GSIs, but not GSMs, markedly increase the levels of APP CTFs that are increasingly viewed as disrupting neuronal function. Here, we evaluated the effects of GSIs and GSMs on a number of neuronal phenotypes possibly relevant to their use in treatment of AD. We report that GSI disrupted retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF), suppressed BDNF-induced downstream signaling pathways and induced changes in the distribution within neuronal processes of mitochondria and synaptic vesicles. In contrast, treatment with a novel class of GSMs had no significant effect on these measures. Since knockdown of APP by specific siRNA prevented GSI-induced changes in BDNF axonal trafficking and signaling, we concluded that GSI effects on APP processing were responsible, at least in part, for BDNF trafficking and signaling deficits. Our findings argue that with respect to anti-amyloid treatments, even an APP-specific GSI may have deleterious effects and GSMs may serve as a better alternative. 相似文献
24.
Derivative emission spectrofluorimetry: Application to the analysis of newly approved FDA combination of ibuprofen and famotidine in tablets
下载免费PDF全文
![点击此处可从《Luminescence》网站下载免费的PDF全文](/ch/ext_images/free.gif)
A new combination of ibuprofen (NSAID) and famotidine (H2 receptor antagonist) was recently approved by the FDA. It was formulated to relief pain while decreasing the risk of ulceration, which is a common problem for patients receiving NSAID. A rapid and simple derivative emission spectrofluorimetric method is proposed for the simultaneous analysis of this combination in their pharmaceutical preparation. The method is based upon measurement of the native fluorescence intensity of the two drugs at λex = 233 nm in acetonitrile. The emission data were differentiated using the first (D1) derivative technique. The plots of derivative fluorescence intensity versus concentration were rectilinear over a range of 2–35 and 0.4–8 µg/mL for both ibuprofen (IBU) and famotidine (FAM), respectively. The method was sensitive as the limits of detection were 0.51 and 0.12 µg/mL and limits of quantitation were 1.70 and 0.39 µg/mL, for IBU and FAM respectively. The proposed derivative emission spectrofluorimetric method was successfully applied for the determination of the two drugs in their synthetic mixtures and tablets with good accuracy and precision. The proposed method was validated as per ICH guidelines. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献
25.
Ahmed Fahal EL Sheikh Mahgoub Ahmed M. EL Hassan Manar Elsheikh Abdel-Rahman 《PLoS neglected tropical diseases》2015,9(3)
This communication reports on the Mycetoma Research Centre of the University of Khartoum, Sudan experience on 6,792 patients seen during the period 1991–2014.The patients were predominately young (64% under 30 years old) males (76%). The majority (68%) were from the Sudan mycetoma belt and 28% were students. Madurella mycetomatis eumycetoma was the most common type (70%). In 66% of the patients the duration of the disease was less than five years, and 81% gave a history of sinuses discharging mostly black grains (78%). History of trauma at the mycetoma site was reported in 20%. Local pain was reported in 27% of the patients, and only 12% had a family history of mycetoma. The study showed that 57% of the patients had previous surgical excisions and recurrence, and only 4% received previous medical treatment for mycetoma. Other concomitant medical diseases were reported in 4% of the patients. The foot (76%) and hand (8%) were the most commonly affected sites. Less frequently affected sites were the leg and knee (7%), thigh (2%), buttock (2%) and arm and forearm (1%). Rare sites included the chest wall, head and neck, back, abdominal wall, perineum, oral cavity, tongue and eye. Multiple sites mycetoma was recorded in 135 (2%) of cases. At presentation, 37% of patients had massive lesions, 79% had sinuses, 8% had local hyper-hydrosis at the mycetoma lesion, 11% had regional lymphadenopathy, while 6% had dilated tortuous veins proximal to the mycetoma lesions. The diagnosis of mycetoma was established by combined imaging techniques and cytological, histopathological, serological tests and grain culture. Patients with actinomycetoma received a combination of antimicrobial agents, while eumycetoma patients received antifungal agents combined with various surgical excisions. Surgical excisions in the form of wide local excision, debridement or amputation were done in 807 patients, and of them 248 patients (30.7%) had postoperative recurrence. Different types of amputations were done in 120 patients (1.7%). 相似文献
26.
Ahmed Fahal EL Sheikh Mahgoub Ahmed Mohamed EL Hassan Angom Osman Jacoub Doaa Hassan 《PLoS neglected tropical diseases》2015,9(3)
Mycetoma is a unique neglected tropical disease which is endemic in what is known as the “mycetoma belt”. The disease has many devastating impacts on patients and communities in endemic area and is characterised by massive deformity, destruction and disability. Mycetoma is commonly seen in the foot and hand and less frequent in other parts of the body. Mycetoma of the head and neck is a rarity and is associated with high morbidity and even mortality if not treated early. In this communication we report on 49 patients with head and neck mycetoma followed up at the Mycetoma Research Centre in Khartoum. Most of the reported patients had actinomycetoma and the majority were young adult males from mycetoma endemic areas in the Sudan. Most of them were students, farmers and workers. Prior to presentation the majority had long disease duration and the cause was multifactorial. Advanced disease with massive lesion, deformity and disability was the common presentation. There was no obvious history of local trauma, familial tendency or other predisposing factor identified in this group of patients. MRI and CT scan were the most accurate diagnostic tools to determine the disease extent. The treatment outcome was rather poor and characterised by low cure rate, poor outcome and high follows-up dropout. Such a gloomy outcome calls for structured and objective health education programs. 相似文献
27.
Imre Mäger Emelía Eiríksdóttir Samir EL Andaloussi Ülo Langel 《生物化学与生物物理学报:生物膜》2010,1798(3):338-1672
Cell-penetrating peptides (CPPs) have shown great potency for cargo delivery both in vitro and in vivo. Different biologically relevant molecules need to be delivered into appropriate cellular compartments in order to be active, for instance certain drugs/molecules, e.g. antisense oligonucleotides, peptides, and cytotoxic agents require delivery into the cytoplasm. Assessing uptake mechanisms of CPPs can help to develop novel and more potent cellular delivery vectors, especially in cases when reaching a specific intracellular target requires involvement of a specific internalization pathway. Here we measure the overall uptake kinetics, with emphasis on cytoplasmic delivery, of three cell-penetrating peptides M918, TP10 and pVec using a quenched fluorescence assay. We show that both the uptake levels and kinetic constants depend on the endocytosis inhibitors used in the experiments. In addition, in some cases only the internalization rate is affected by the endocytosis inhibitors while the total uptake level is not and vice versa, which emphasizes importance of kinetic studies when assessing the uptake mechanisms of CPPs. Also, there seems to be a correlation between lower total cellular uptake and higher first-order rate constants. Furthermore, this may indicate simultaneous involvement of different endocytic pathways with different efficacies in the internalization process, as hypothesized but not shown earlier in an uptake kinetics assay. 相似文献
28.
CLAUDIA HEMP KJETIL LYSNE VOJE KLAUS‐GERHARD HELLER ELŻBIETA WARCHAŁOWSKA‐ŚLIWA ANDREAS HEMP 《Zoological Journal of the Linnean Society》2010,158(1):66-82
A new genus, Altihoratosphaga, is erected for species formerly assigned to Horatosphaga Schaum, 1853, and a new species is described. Four species are included in Altihoratosphaga: Altihoratosphaga nomima (Karsch, 1896), Altihoratosphaga montivaga ( Sjöstedt, 1909 ), Altihoratosphaga nou (Hemp, 2007) and Altihoratosphaga hanangensis sp. nov. All four species are restricted to Tanzanian localities, and, except for A. nomima, for which no ecological data are available, are confined to montane forest habitats. Data on ecology, acoustics, chromosomes, and molecular relationships are provided, as well as a key to Altihoratosphaga species. The present‐day distribution of Altihoratosphaga species suggests former migration events at times when wetter and colder climatic fluctuations favoured connections between montane forest communities, which today are isolated, enabling flightless taxa such as Altihoratosphaga and Monticolaria to spread. © 2010 The Linnean Society of London, Zoological Journal of the Linnean Society, 2010, 158 , 66–82. 相似文献
29.
Tauqeer Ahmad Yasir Sobia Aslam Muhammad Shahid Rizwan Allah Wasaya Muhammad Ateeq Muhammad Naeem Khan Sikander Khan Tanveer Walid Soufan Basharat Ali Allah Ditta Arpna Kumari Ayman EL Sabagh 《Phyton》2022,91(11):2491-2504
In soil biota, higher and enduring concentration of heavy metals like cadmium (Cd) is hazardous and associated
with great loss in growth, yield, and quality parameters of most of the crop plants. Recently, in-situ applications of
eco-friendly stabilizing agents in the form of organic modifications have been utilized to mitigate the adverse
effects of Cd-toxicity. This controlled experiment was laid down to appraise the imprints of various applied
organic amendments namely poultry manure (PM), farmyard manure (FYM), and sugarcane press mud (PS)
to immobilize Cd in polluted soil. Moreover, phytoavailability of Cd in wheat was also accessed under an alkaline
environment. Results revealed that the addition of FYM (5–10 ton ha-1
) in Cd-contaminated soil significantly
increased germination rate, leaf chlorophyll content, plant height, spike length, biological and grain yield amongst
all applied organic amendments. Moreover, the addition of FYM (5–10 ton ha-1
) also reduced the phytoavailability of Cd by 73–85% in the roots, 57–83% in the shoots, and 81–90% in grains of wheat crop. Thus, it is affirmed
that incorporation of FYM (5–10 ton ha-1
) performed better to enhance wheat growth and yield by remediating
Cd. Thus, the application of FYM (5–10 ton ha-1
) reduced the toxicity induced by Cd to plants by declining its
uptake and translocation as compared to all other applied organic amendments to immobilize Cd under sandy
alkaline polluted soil. 相似文献
30.
Quantitative trait loci and candidate genes underlying genotype by environment interaction in the response of Arabidopsis thaliana to drought
下载免费PDF全文
![点击此处可从《Plant, cell & environment》网站下载免费的PDF全文](/ch/ext_images/free.gif)
MOHAMED EL‐SODA WILLEM KRUIJER MARCOS MALOSETTI MAARTEN KOORNNEEF MARK G. M. AARTS 《Plant, cell & environment》2015,38(3):585-599
Drought stress was imposed on two sets of Arabidopsis thaliana genotypes grown in sand under short‐day conditions and analysed for several shoot and root growth traits. The response to drought was assessed for quantitative trait locus (QTL) mapping in a genetically diverse set of Arabidopsis accessions using genome‐wide association (GWA) mapping, and conventional linkage analysis of a recombinant inbred line (RIL) population. Results showed significant genotype by environment interaction (G×E) for all traits in response to different watering regimes. For the RIL population, the observed G×E was reflected in 17 QTL by environment interactions (Q×E), while 17 additional QTLs were mapped not showing Q×E. GWA mapping identified 58 single nucleotide polymorphism (SNPs) associated with loci displaying Q×E and an additional 16 SNPs associated with loci not showing Q×E. Many candidate genes potentially underlying these loci were suggested. The genes for RPS3C and YLS7 were found to contain conserved amino acid differences when comparing Arabidopsis accessions with strongly contrasting drought response phenotypes, further supporting their candidacy. One of these candidate genes co‐located with a QTL mapped in the RIL population. 相似文献