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排序方式: 共有98条查询结果,搜索用时 15 毫秒
61.
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63.
Frank Rutsch Mary MacDougall Changming Lu Insa Buers Olga Mamaeva Yvonne Nitschke Gillian?I. Rice Heidi Erlandsen Hans?Gerd Kehl Holger Thiele Peter Nürnberg Wolfgang H?hne Yanick?J. Crow Annette Feigenbaum Raoul?C. Hennekam 《American journal of human genetics》2015,96(2):275-282
Singleton-Merten syndrome (SMS) is an infrequently described autosomal-dominant disorder characterized by early and extreme aortic and valvular calcification, dental anomalies (early-onset periodontitis and root resorption), osteopenia, and acro-osteolysis. To determine the molecular etiology of this disease, we performed whole-exome sequencing and targeted Sanger sequencing. We identified a common missense mutation, c.2465G>A (p.Arg822Gln), in interferon induced with helicase C domain 1 (IFIH1, encoding melanoma differentiation-associated protein 5 [MDA5]) in four SMS subjects from two families and a simplex case. IFIH1 has been linked to a number of autoimmune disorders, including Aicardi-Goutières syndrome. Immunohistochemistry demonstrated the localization of MDA5 in all affected target tissues. In vitro functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in interferon beta induction. Interferon signature genes were upregulated in SMS individuals’ blood and dental cells. Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arterial calcification and dental inflammation and resorption. 相似文献
64.
André B. P. van Kuilenburg Judith Meijer Adri N. P. M. Mul Raoul C. M. Hennekam Jan M. N. Hoovers Christine E. M. de Die-Smulders Peter Weber Andrea Capone Mori Jörgen Bierau Brian Fowler Klaus Macke Jörn Oliver Sass Rutger Meinsma Julia B. Hennermann Peter Miny Lida Zoetekouw Raymon Vijzelaar Joost Nicolai Bauke Ylstra M. Estela Rubio-Gozalbo 《Human genetics》2009,125(5-6):581-590
Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently described autosomal recessive disorder of the pyrimidine degradation pathway and can lead to mental and motor retardation and convulsions. DPD deficiency is also known to cause a potentially lethal toxicity following administration of the antineoplastic agent 5-fluorouracil. In an ongoing study of 72 DPD deficient patients, we analysed the molecular background of 5 patients in more detail in whom initial sequence analysis did not reveal pathogenic mutations. In three patients, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb deletion of exon 14–16 of DPYD. In the fifth patient, a c.299_302delTCAT mutation in exon 4 was found and also loss of heterozygosity of the entire DPD gene. Further analysis demonstrated a de novo deletion of approximately 14 Mb of chromosome 1p13.3–1p21.3, which includes DPYD. Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have contributed to the severe psychomotor retardation and unusual craniofacial features in this patient. Our study showed for the first time the presence of genomic deletions affecting DPYD in 7% (5/72) of all DPD deficient patients. Therefore, screening of DPD deficient patients for genomic deletions should be considered. 相似文献
65.
Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations 总被引:2,自引:0,他引:2 下载免费PDF全文
Johnston JJ Olivos-Glander I Killoran C Elson E Turner JT Peters KF Abbott MH Aughton DJ Aylsworth AS Bamshad MJ Booth C Curry CJ David A Dinulos MB Flannery DB Fox MA Graham JM Grange DK Guttmacher AE Hannibal MC Henn W Hennekam RC Holmes LB Hoyme HE Leppig KA Lin AE Macleod P Manchester DK Marcelis C Mazzanti L McCann E McDonald MT Mendelsohn NJ Moeschler JB Moghaddam B Neri G Newbury-Ecob R Pagon RA Phillips JA Sadler LS Stoler JM Tilstra D Walsh Vockley CM Zackai EH Zadeh TM Brueton L 《American journal of human genetics》2005,76(4):609-622
66.
The estimation of the amount of evolutionary divergence that has taken
place between two DNA coding sequences depends strongly on the degree of
constraint on amino acid replacements. If amino acid replacements are
relatively unconstrained, the individual nucleotide is the appropriate unit
of analysis and the method of Tajima and Nei can be used. If amino acid
replacements are constrained, however, this method is shown to be
inapplicable. For sequences with strong amino acid constraints, a method is
outlined analogous to the Tajima and Nei method using codons as the unit of
analysis. Only synonymous substitutions are used. Codon usage data can be
employed to estimate the necessary parameters of the calculation, or a
priori models of substitution may be employed. Sequences with significant
but intermediate constraints on amino acid replacements are, in principle,
unanalyzable.
相似文献
67.
Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation 下载免费PDF全文
Pasutto F Sticht H Hammersen G Gillessen-Kaesbach G Fitzpatrick DR Nürnberg G Brasch F Schirmer-Zimmermann H Tolmie JL Chitayat D Houge G Fernández-Martínez L Keating S Mortier G Hennekam RC von der Wense A Slavotinek A Meinecke P Bitoun P Becker C Nürnberg P Reis A Rauch A 《American journal of human genetics》2007,80(3):550-560
68.
Marka van Blitterswijk Lotte Vlam Michael A. van Es W-Ludo van der Pol Eric A. M. Hennekam Dennis Dooijes Helenius J. Schelhaas Anneke J. van der Kooi Marianne de Visser Jan H. Veldink Leonard H. van den Berg 《PloS one》2012,7(11)
Progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) are devastating motor neuron diseases (MNDs), which result in muscle weakness and/or spasticity. We compared mutation frequencies in genes known to be associated with MNDs between patients with apparently sporadic PMA and ALS. A total of 261 patients with adult-onset sporadic PMA, patients with sporadic ALS, and control subjects of Dutch descent were obtained at national referral centers for neuromuscular diseases in The Netherlands. Sanger sequencing was used to screen these subjects for mutations in the coding regions of superoxide dismutase-1 (SOD1), angiogenin (ANG), fused in sarcoma/translated in liposarcoma (FUS/TLS), TAR DNA-binding protein 43 (TARDBP), and multivesicular body protein 2B (CHMP2B). In our cohort of PMA patients we identified two SOD1 mutations (p.D90A, p.I113T), one ANG mutation (p.K17I), one FUS/TLS mutation (p.R521H), one TARDBP mutation (p.N352S), and one novel CHMP2B mutation (p.R69Q). The mutation frequency of these genes was similar in sporadic PMA (2.7%) and ALS (2.0%) patients, and therefore, our findings demonstrate a genetic overlap between apparently sporadic PMA and ALS. 相似文献
69.
André B. P. van Kuilenburg Judith Meijer Adri N. P. M. Mul Rutger Meinsma Veronika Schmid Doreen Dobritzsch Raoul C. M. Hennekam Marcel M. A. M. Mannens Marion Kiechle Marie-Christine Etienne-Grimaldi Heinz-Josef Klümpen Jan Gerard Maring Veerle A. Derleyn Ed Maartense Gérard Milano Raymon Vijzelaar Eva Gross 《Human genetics》2010,128(5):529-538
Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme acting in the catabolism of the widely used antineoplastic agent 5-fluorouracil (5FU). DPD deficiency is known to cause a potentially lethal toxicity following administration of 5FU. Here, we report novel genetic mechanisms underlying DPD deficiency in patients presenting with grade III/IV 5FU-associated toxicity. In one patient a genomic DPYD deletion of exons 21–23 was observed. In five patients a deep intronic mutation c.1129–5923C>G was identified creating a cryptic splice donor site. As a consequence, a 44 bp fragment corresponding to nucleotides c.1129–5967 to c.1129–5924 of intron 10 was inserted in the mature DPD mRNA. The deleterious c.1129–5923C>G mutation proved to be in cis with three intronic polymorphisms (c.483 + 18G>A, c.959–51T>G, c.680 + 139G>A) and the synonymous mutation c.1236G>A of a previously identified haplotype. Retrospective analysis of 203 cancer patients showed that the c.1129–5923C>G mutation was significantly enriched in patients with severe 5FU-associated toxicity (9.1%) compared to patients without toxicity (2.2%). In addition, a high prevalence was observed for the c.1129–5923C>G mutation in the normal Dutch (2.6%) and German (3.3%) population. Our study demonstrates that a genomic deletion affecting DPYD and a deep intronic mutation affecting pre-mRNA splicing can cause severe 5FU-associated toxicity. We conclude that screening for DPD deficiency should include a search for genomic rearrangements and aberrant splicing. 相似文献
70.
A Pseudomonas aeruginosa TIR effector mediates immune evasion by targeting UBAP1 and TLR adaptors 下载免费PDF全文
Paul RC Imbert Arthur Louche Jean‐Baptiste Luizet Teddy Grandjean Sarah Bigot Thomas E Wood Stéphanie Gagné Amandine Blanco Lydia Wunderley Laurent Terradot Philip Woodman Steve Garvis Alain Filloux Benoit Guery Suzana P Salcedo 《The EMBO journal》2017,36(13):1869-1887
Bacterial pathogens often subvert the innate immune system to establish a successful infection. The direct inhibition of downstream components of innate immune pathways is particularly well documented but how bacteria interfere with receptor proximal events is far less well understood. Here, we describe a Toll/interleukin 1 receptor (TIR) domain‐containing protein (PumA) of the multi‐drug resistant Pseudomonas aeruginosa PA7 strain. We found that PumA is essential for virulence and inhibits NF‐κB, a property transferable to non‐PumA strain PA14, suggesting no additional factors are needed for PumA function. The TIR domain is able to interact with the Toll‐like receptor (TLR) adaptors TIRAP and MyD88, as well as the ubiquitin‐associated protein 1 (UBAP1), a component of the endosomal‐sorting complex required for transport I (ESCRT‐I). These interactions are not spatially exclusive as we show UBAP1 can associate with MyD88, enhancing its plasma membrane localization. Combined targeting of UBAP1 and TLR adaptors by PumA impedes both cytokine and TLR receptor signalling, highlighting a novel strategy for innate immune evasion. 相似文献