全文获取类型
收费全文 | 286篇 |
免费 | 25篇 |
出版年
2023年 | 2篇 |
2022年 | 5篇 |
2021年 | 8篇 |
2020年 | 5篇 |
2019年 | 8篇 |
2018年 | 12篇 |
2017年 | 5篇 |
2016年 | 10篇 |
2015年 | 7篇 |
2014年 | 12篇 |
2013年 | 8篇 |
2012年 | 23篇 |
2011年 | 35篇 |
2010年 | 13篇 |
2009年 | 17篇 |
2008年 | 14篇 |
2007年 | 20篇 |
2006年 | 12篇 |
2005年 | 14篇 |
2004年 | 12篇 |
2003年 | 15篇 |
2002年 | 8篇 |
2001年 | 5篇 |
2000年 | 3篇 |
1999年 | 3篇 |
1998年 | 2篇 |
1997年 | 3篇 |
1996年 | 1篇 |
1994年 | 1篇 |
1993年 | 3篇 |
1992年 | 1篇 |
1991年 | 2篇 |
1989年 | 2篇 |
1988年 | 3篇 |
1986年 | 2篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 1篇 |
1976年 | 1篇 |
1973年 | 1篇 |
1969年 | 1篇 |
1968年 | 1篇 |
排序方式: 共有311条查询结果,搜索用时 781 毫秒
71.
Barbara D'haene Catia Attanasio Diane Beysen Jose Dostie Edmond Lemire Philippe Bouchard Michael Field Kristie Jones Birgit Lorenz Bjrn Menten Karen Buysse Filip Pattyn Marc Friedli Catherine Ucla Colette Rossier Carine Wyss Frank Speleman Anne De Paepe Job Dekker Stylianos E. Antonarakis Elfride De Baere 《PLoS genetics》2009,5(6)
To date, the contribution of disrupted potentially cis-regulatory conserved non-coding sequences (CNCs) to human disease is most likely underestimated, as no systematic screens for putative deleterious variations in CNCs have been conducted. As a model for monogenic disease we studied the involvement of genetic changes of CNCs in the cis-regulatory domain of FOXL2 in blepharophimosis syndrome (BPES). Fifty-seven molecularly unsolved BPES patients underwent high-resolution copy number screening and targeted sequencing of CNCs. Apart from three larger distant deletions, a de novo deletion as small as 7.4 kb was found at 283 kb 5′ to FOXL2. The deletion appeared to be triggered by an H-DNA-induced double-stranded break (DSB). In addition, it disrupts a novel long non-coding RNA (ncRNA) PISRT1 and 8 CNCs. The regulatory potential of the deleted CNCs was substantiated by in vitro luciferase assays. Interestingly, Chromosome Conformation Capture (3C) of a 625 kb region surrounding FOXL2 in expressing cellular systems revealed physical interactions of three upstream fragments and the FOXL2 core promoter. Importantly, one of these contains the 7.4 kb deleted fragment. Overall, this study revealed the smallest distant deletion causing monogenic disease and impacts upon the concept of mutation screening in human disease and developmental disorders in particular. 相似文献
72.
Eisen JA Coyne RS Wu M Wu D Thiagarajan M Wortman JR Badger JH Ren Q Amedeo P Jones KM Tallon LJ Delcher AL Salzberg SL Silva JC Haas BJ Majoros WH Farzad M Carlton JM Smith RK Garg J Pearlman RE Karrer KM Sun L Manning G Elde NC Turkewitz AP Asai DJ Wilkes DE Wang Y Cai H Collins K Stewart BA Lee SR Wilamowska K Weinberg Z Ruzzo WL Wloga D Gaertig J Frankel J Tsao CC Gorovsky MA Keeling PJ Waller RF Patron NJ Cherry JM Stover NA Krieger CJ del Toro C Ryder HF Williamson SC Barbeau RA 《PLoS biology》2006,4(9):e286
The ciliate Tetrahymena thermophila is a model organism for molecular and cellular biology. Like other ciliates, this species has separate germline and soma functions that are embodied by distinct nuclei within a single cell. The germline-like micronucleus (MIC) has its genome held in reserve for sexual reproduction. The soma-like macronucleus (MAC), which possesses a genome processed from that of the MIC, is the center of gene expression and does not directly contribute DNA to sexual progeny. We report here the shotgun sequencing, assembly, and analysis of the MAC genome of T. thermophila, which is approximately 104 Mb in length and composed of approximately 225 chromosomes. Overall, the gene set is robust, with more than 27,000 predicted protein-coding genes, 15,000 of which have strong matches to genes in other organisms. The functional diversity encoded by these genes is substantial and reflects the complexity of processes required for a free-living, predatory, single-celled organism. This is highlighted by the abundance of lineage-specific duplications of genes with predicted roles in sensing and responding to environmental conditions (e.g., kinases), using diverse resources (e.g., proteases and transporters), and generating structural complexity (e.g., kinesins and dyneins). In contrast to the other lineages of alveolates (apicomplexans and dinoflagellates), no compelling evidence could be found for plastid-derived genes in the genome. UGA, the only T. thermophila stop codon, is used in some genes to encode selenocysteine, thus making this organism the first known with the potential to translate all 64 codons in nuclear genes into amino acids. We present genomic evidence supporting the hypothesis that the excision of DNA from the MIC to generate the MAC specifically targets foreign DNA as a form of genome self-defense. The combination of the genome sequence, the functional diversity encoded therein, and the presence of some pathways missing from other model organisms makes T. thermophila an ideal model for functional genomic studies to address biological, biomedical, and biotechnological questions of fundamental importance. 相似文献
73.
Davis AM Ellersieck MR Grimm KM Rosenfeld CS 《Molecular reproduction and development》2006,73(8):1034-1044
Since estrogens have vital functions in the uterus but might also contribute to endometrial cancer, we sought to determine the in vitro effects of methyl-piperidino-pyrazole (MPP), raloxifene, and beta-estradiol on Ishikawa and RL-95 endometrial cancer, and ovine luminal endometrial (oLE) cell lines and the in vivo effects of these compounds in the rodent uterus. MPP and raloxifene (1 nM) induced significant apoptosis in the endometrial cancer and oLE cell lines compared to beta-estradiol treated and control cells (P 相似文献
74.
75.
76.
Small, isolated populations are vulnerable to loss of genetic diversity through in-breeding and genetic drift. Sylvatic plague due to infection by the bacterium Yersinia pestis caused an epizootic in the early 1990s resullting in declines and extirpations of many black-tailed prairie dog (Cynomys ludovicianus) colonies in north-central Montana, USA. Plague-induced population bottlenecks may contribute to significant reductions in genetic variability. In contrast, gene flow maintains genetic variability within colonies. We investigated the impacts of the plague epizootic and distance to nearest colony on levels of genetic variability in six prairie dog colonies sampled between June 1999 and July 2001 using 24 variable randomly amplified polymorphic DNA (RAPD) markers. Number of effective alleles per locus (n(e)) and gene diversity (h) were significantly decreased in the three colonies affected by plague that were recovering from the resulting bottlenecks compared with the three colonies that did not experience plague. Genetic variability was not significantly affected by geographic distance between colonies. The majority of variance in gene fieqnencies was found within prairie clog colonies. Conservation of genetic variability in black-tailed prairie dogs will require the preservation of both large and small colony complexes and the gene flow amonog them. 相似文献
77.
L. D. Garaeva A. A. Bakhmedova I. V. Yartseva S. Ya. Melnik V. M. Adanin 《Russian Journal of Bioorganic Chemistry》2003,29(2):160-167
1-(2,3,5-Tri-O-acetyl)--D-ribofuranosyl indole, the key compound in the synthesis of glycosides with the bis(indole) aglycone, was obtained for the first time by the indoline–indole method. There were synthesized 3-(1-methylindol-3-yl)-4-(1-glycosylindol-3-yl)furan(or pyrrole)-2,5-diones containing the residue of -D-ribofuranose or 2-deoxy--D-ribofuranose and analogous glycosides of indolo[2,3-a]furano(or pyrrolo)[3,4-]carbazol-5,7-diones, which are structurally relative to the antitumor antibiotic rebeccamycin. Their cytotoxicities toward a number of human tumor cell lines were studied in
vitro, and the carbazole N-glycosides were shown to be more active than the bis(indole) glycosides. At the same time, the ribofuranosides were found to be less active than the corresponding ribopyranosides synthesized previously. 相似文献
78.
Zhang Z Rhinehart K Pallone TL 《American journal of physiology. Regulatory, integrative and comparative physiology》2002,283(4):R949-R957
We tested the hypothesis that constriction of descending vasa recta (DVR) is mediated by voltage-gated calcium entry. K(+) channel blockade with BaCl(2) (1 mM) or TEACl (30 mM) depolarized DVR smooth muscle/pericytes and constricted in vitro-perfused vessels. Pericyte depolarization by 100 mM extracellular KCl constricted DVR and increased pericyte intracellular Ca(2+) ([Ca(2+)](i)). The K(ATP) channel opener pinacidil (10(-7)-10(-4) M) hyperpolarized resting pericytes, repolarized pericytes previously depolarized by ANG II (10(-8) M), and vasodilated DVR. The DVR vasodilator bradykinin (10(-7) M) also reversed ANG II depolarization. The L-type Ca(2+) channel blocker diltiazem vasodilated ANG II (10(-8) M)- or KCl (100 mM)-preconstricted DVR, and the L-type agonist BayK 8644 constricted DVR. The plateau phase of the pericyte [Ca(2+)](i) response to ANG II was inhibited by diltiazem. These data support the conclusion that DVR vasoreactivity is controlled through variation of membrane potential and voltage-gated Ca(2+) entry into the pericyte cytoplasm. 相似文献
79.
80.
Elizabeth A. B. Emmert Jocelyn L. Milner Julie C. Lee Kristie L. Pulvermacher Heidi A. Olivares Jon Clardy Jo Handelsman 《Applied microbiology》1998,64(12):4683-4688
Bacillus cereus UW85 suppresses diseases of alfalfa seedlings, although alfalfa seed exudate inhibits the growth of UW85 in culture (J. L. Milner, S. J. Raffel, B. J. Lethbridge, and J. Handelsman, Appl. Microbiol. Biotechnol. 43:685–691, 1995). In this study, we determined the chemical basis for and biological role of the inhibitory activity. All of the alfalfa germ plasm tested included seeds that released inhibitory material. We purified the inhibitory material from one alfalfa cultivar and identified it as canavanine, which was present in the cultivar Iroquois seed exudate at a concentration of 2 mg/g of seeds. Multiple lines of evidence suggested that canavanine activity accounted for all of the inhibitory activity. Both canavanine and seed exudate inhibited the growth of UW85 on minimal medium; growth inhibition by either canavanine or seed exudate was prevented by arginine, histidine, or lysine; and canavanine and crude seed exudate had the same spectrum of activity against B. cereus, Bacillus thuringiensis, and Vibrio cholerae. The B. cereus UW85 populations surrounding canavanine-exuding seeds were up to 100-fold smaller than the populations surrounding non-canavanine-exuding seeds, but canavanine did not affect the growth of UW85 on seed surfaces. The spermosphere populations of canavanine-resistant mutants of UW85 were larger than the spermosphere populations of UW85, but the mutants and UW85 were similar in spermoplane colonization. These results indicate that canavanine exuded from alfalfa seeds affects the population biology of B. cereus. 相似文献