全文获取类型
收费全文 | 69篇 |
免费 | 16篇 |
专业分类
85篇 |
出版年
2022年 | 1篇 |
2021年 | 1篇 |
2016年 | 4篇 |
2015年 | 2篇 |
2014年 | 2篇 |
2013年 | 6篇 |
2012年 | 3篇 |
2011年 | 3篇 |
2010年 | 2篇 |
2009年 | 3篇 |
2008年 | 5篇 |
2007年 | 8篇 |
2006年 | 5篇 |
2005年 | 1篇 |
2004年 | 5篇 |
2003年 | 5篇 |
2002年 | 3篇 |
2001年 | 4篇 |
2000年 | 1篇 |
1999年 | 2篇 |
1997年 | 1篇 |
1995年 | 1篇 |
1992年 | 1篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1984年 | 1篇 |
1975年 | 3篇 |
1973年 | 1篇 |
1972年 | 1篇 |
排序方式: 共有85条查询结果,搜索用时 0 毫秒
51.
A membrane-destabilizing peptide in capsid protein L2 is required for egress of papillomavirus genomes from endosomes 下载免费PDF全文
Kämper N Day PM Nowak T Selinka HC Florin L Bolscher J Hilbig L Schiller JT Sapp M 《Journal of virology》2006,80(2):759-768
Papillomaviruses are internalized via clathrin-dependent endocytosis. However, the mechanism by which viral genomes pass endosomal membranes has not been elucidated. In this report we show that the minor capsid protein L2 is required for egress of viral genomes from endosomes but not for initial uptake and uncoating and that a 23-amino-acid peptide at the C terminus of L2 is necessary for this function. Pseudogenomes encapsidated by L1 and L2 lacking this peptide accumulated in vesicular compartments similar to that observed with L1-only viral particles, and these mutant pseudoviruses were noninfectious. This L2 peptide displayed strong membrane-disrupting activity, induced cytolysis of bacteria and eukaryotic cells in a pH-dependent manner, and permeabilized cells after exogenous addition. Fusions between green fluorescent protein and the L2 peptide integrated into cellular membranes like the wild type but not like C-terminal mutants of L2. Our data indicate that the L2 C terminus facilitates escape of viral genomes from the endocytic compartment and that this feature is conserved among papillomaviruses. Furthermore, the characteristic of this peptide differs from the classical virus-encoded membrane-penetrating peptides. 相似文献
52.
Justin B. Callaway Scott A. Smith Douglas G. Widman Karen P. McKinnon Frank Scholle Gregory D. Sempowski Dirk P. Dittmer James E. Crowe Jr. Aravinda M. de Silva Jenny P.-Y. Ting 《PloS one》2015,10(8)
Dengue virus is a major global health threat and can lead to life-threatening hemorrhagic complications due to immune activation and cytokine production. Cross-reactive antibodies to an earlier dengue virus infection are a recognized risk factor for severe disease. These antibodies bind heterologous dengue serotypes and enhance infection into Fc-receptor-bearing cells, a process known as antibody-dependent enhancement of infection. One crucial cytokine seen elevated in severe dengue patients is IL-1β, a potent inflammatory cytokine matured by the inflammasome. We used a highly-physiologic system by studying antibody-dependent enhancement of IL-1β in primary human monocytes with anti-dengue human monoclonal antibodies isolated from patients. Antibody-enhancement increased viral replication in primary human monocytes inoculated with supernatant harvested from Vero cells infected with dengue virus serotype 2 (DENV-2) 16681. Surprisingly, IL-1β secretion induced by infectious supernatant harvested from two independent Vero cell lines was not enhanced by antibody. Secretion of multiple other inflammatory cytokines was also independent of antibody signaling. However, IL-1β secretion did require NLRP3 and caspase-1 activity. Immunodepletion of dengue virions from the infectious supernatant confirmed that virus was not the main IL-1β-inducing agent, suggesting that a supernatant component(s) not associated with the virion induced IL-1β production. We excluded RNA, DNA, contaminating LPS, viral NS1 protein, complement, and cytokines. In contrast, purified Vero-derived DENV-2 16681 exhibited antibody-enhancement of both infection and IL-1β induction. Furthermore, C6/36 mosquito cells did not produce such an inflammatory component, as crude supernatant harvested from insect cells infected with DENV-2 16681 induced antibody-dependent IL-1β secretion. This study indicates that Vero cells infected with DENV-2 16681 may produce inflammatory components during dengue virus propagation that mask the virus-specific immune response. Thus, the choice of host cell and viral purity should be carefully considered, while insect-derived virus represents a system that elicits antibody-dependent cytokine responses to dengue virus with fewer confounding issues. 相似文献
53.
54.
N Garcia Segarra L Mittaz AB Campos-Xavier CF Bartels B Tuysuz Y Alanay R Cimaz V Cormier-Daire M Di Rocco HC Duba NH Elcioglu F Forzano T Hospach E Kilic JB Kuemmerle-Deschner G Mortier S Mrusek S Nampoothiri E Obersztyn RM Pauli A Selicorni R Tenconi S Unger GE Utine M Wright B Zabel ML Warman A Superti-Furga L Bonafé 《American journal of medical genetics. Part C, Seminars in medical genetics》2012,(3):217-229
Progressive pseudorheumatoid dysplasia (PPRD) is a genetic, non-inflammatory arthropathy caused by recessive loss of function mutations in WISP3 (Wnt1-inducible signaling pathway protein 3; MIM 603400), encoding for a signaling protein. The disease is clinically silent at birth and in infancy. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness. Affected children are referred to pediatric rheumatologists and orthopedic surgeons; however, signs of inflammation are absent and anti-inflammatory treatment is of little help. Bony enlargement at the interphalangeal joints progresses leading to camptodactyly. Spine involvement develops in late childhood and adolescence leading to short trunk with thoracolumbar kyphosis. Adult height is usually below the 3rd percentile. Radiographic signs are relatively mild. Platyspondyly develops in late childhood and can be the first clue to the diagnosis. Enlargement of the phalangeal metaphyses develops subtly and is usually recognizable by 10 years. The femoral heads are large and the acetabulum forms a distinct "lip" overriding the femoral head. There is a progressive narrowing of all articular spaces as articular cartilage is lost. Medical management of PPRD remains symptomatic and relies on pain medication. Hip joint replacement surgery in early adulthood is effective in reducing pain and maintaining mobility and can be recommended. Subsequent knee joint replacement is a further option. Mutation analysis of WISP3 allowed the confirmation of the diagnosis in 63 out of 64 typical cases in our series. Intronic mutations in WISP3 leading to splicing aberrations can be detected only in cDNA from fibroblasts and therefore a skin biopsy is indicated when genomic analysis fails to reveal mutations in individuals with otherwise typical signs and symptoms. In spite of the first symptoms appearing in early childhood, the diagnosis of PPRD is most often made only in the second decade and affected children often receive unnecessary anti-inflammatory and immunosuppressive treatments. Increasing awareness of PPRD appears to be essential to allow for a timely diagnosis. 相似文献
55.
56.
Evidence for beneficial effect of intravenous glucose on the hemodynamic response to acute asphyxia.
S F Scholle D M Griggs 《Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)》1975,148(3):743-747
Anesthetized rabbits were subjected to two 4-min periods of asphyxia with a 15-min recovery period intervening. During the recovery period animals received an iv infusion of either isotonic glucose or mannitol. Results indicated that glucose had a beneficial effect on systolic blood pressure during the second period of asphyxia. A direct metabolic action of glucose on the myocardium is favored as the explanation, but other possibilities include peripheral or neurohumoral effects. 相似文献
57.
58.
From genetic footprinting to antimicrobial drug targets: examples in cofactor biosynthetic pathways 总被引:9,自引:0,他引:9 下载免费PDF全文
Gerdes SY Scholle MD D'Souza M Bernal A Baev MV Farrell M Kurnasov OV Daugherty MD Mseeh F Polanuyer BM Campbell JW Anantha S Shatalin KY Chowdhury SA Fonstein MY Osterman AL 《Journal of bacteriology》2002,184(16):4555-4572
Novel drug targets are required in order to design new defenses against antibiotic-resistant pathogens. Comparative genomics provides new opportunities for finding optimal targets among previously unexplored cellular functions, based on an understanding of related biological processes in bacterial pathogens and their hosts. We describe an integrated approach to identification and prioritization of broad-spectrum drug targets. Our strategy is based on genetic footprinting in Escherichia coli followed by metabolic context analysis of essential gene orthologs in various species. Genes required for viability of E. coli in rich medium were identified on a whole-genome scale using the genetic footprinting technique. Potential target pathways were deduced from these data and compared with a panel of representative bacterial pathogens by using metabolic reconstructions from genomic data. Conserved and indispensable functions revealed by this analysis potentially represent broad-spectrum antibacterial targets. Further target prioritization involves comparison of the corresponding pathways and individual functions between pathogens and the human host. The most promising targets are validated by direct knockouts in model pathogens. The efficacy of this approach is illustrated using examples from metabolism of adenylate cofactors NAD(P), coenzyme A, and flavin adenine dinucleotide. Several drug targets within these pathways, including three distantly related adenylyltransferases (orthologs of the E. coli genes nadD, coaD, and ribF), are discussed in detail. 相似文献
59.
Genetic modulation of the serotonergic pathway: influence on weight reduction and weight maintenance
Dirk Wallmeier Julia K. Winkler Thomas Fleming Annika Woehning Katharina Huennemeyer Eva Roeder Peter P. Nawroth Hans-Christoph Friederich Christian Wolfrum Jobst-Hendrik Schultz Gottfried Rudofsky 《Genes & nutrition》2013,8(6):601-610
The serotonergic pathway plays a major role in the development of obesity. Its activity can be modulated by the 5-HT transporter–linked polymorphic region in the SLC6A4 gene and the upstream variable number of tandem repeats polymorphism in the MAOA gene. We studied whether these genetic modulations have an influence on weight reduction and weight maintenance in a one-year weight reduction program (OPTIFAST®52). The polymorphisms were genotyped by PCR in a sample of 135 female and 67 male subjects with severe obesity (44 ± 13 years, 122.3 ± 22.2 kg, BMI: 41.7 ± 6.7 kg/m2). The program leads to a total weight loss of 19.9 ± 9.8 kg (16.9 ± 8.3 %) in women and 27.4 ± 13.6 kg (20.4 ± 9.9 %) in men. Anthropometric measurements and blood levels were determined at the start of the program (T0), after the weight reduction phase (T1) and after the subsequent weight maintenance phase at the end of the program (T2). Each polymorphism alone did not significantly influence weight loss or weight maintenance neither in men nor in women. However, women carrying both risk genotypes (SS and 3/3) displayed a lower total weight loss during the program (p = 0.05). This effect derived mainly from difficulties in the weight maintenance phase (p = 0.11), while the weight reduction phase was not affected (p = 0.61). No influence was found in men (p = 0.93). Modulation of the serotonergic pathway by carrying both risk alleles seems to influence success of weight loss programs in women with severe obesity due to problems in stabilizing body weight after weight reduction. 相似文献
60.
M. Erdel Hans-Christoph Duba Irmgard Verdorfer Arno Lingenhel Ralf Geiger Karl-Heinz Gutenberger Edgar Ludescher Barbara Utermann Gerd Utermann 《Human genetics》1997,99(5):596-601
We report the use of comparative genomic hybridization (CGH) to define the origin of a small extra segment (unidentifiable
by classical cytogenetics) present in a de novo add(13)q34 chromosome that we found in the karyotype of a newly born boy with
congenital heart defects, brain anomalies and dysmorphic signs. Initial investigation with fluorescence in situ hybridization
(FISH) and a chromosome-13-specific library revealed that the excess material was not derived from chromosome 13. To uncover
the origin of the unknown chromosome material, CGH was carried out on DNA isolated from blood lymphocytes of the patient.
By using a conventional fluorescence microscope with no digital imaging devices, a single distinct region with gain of fluorescent
intensity was observed on distal chromosome 6q. Confirmation of this finding by FISH with a chromosome-6-specific paint and
a subtelomeric yeast artificial chromosome clone from 6q26-q27, in combination with the band morphology of the small extra
chromosomal segment, allowed us to diagnose the additional material as being derived from chromosome 6q23-qter. FISH with
a telomere 13q probe detected a terminal deletion of 13q34-qter on the derivative chromosome 13, indicating that the der(13)
was a result of a translocation event. Genotyping of the hypervariable apolipoprotein (a) gene, which lies within 6q26-q27,
showed that the additional chromosome 6 material was inherited from the mother. The karyotype of the proposita is therefore:
46,XY,-13,+der(13)t(6;13)(q23;q34) de novo (mat). Our results confirm the usefulness of CGH as an attractive alternative method
for the characterization of constitutional small genetic imbalances and contribute to the delineation of the trisomy 6q23-qter
phenotype.
Received: 26 November 1996 / Revised: 2 January 1997 相似文献