全文获取类型
收费全文 | 1748篇 |
免费 | 94篇 |
出版年
2023年 | 4篇 |
2022年 | 16篇 |
2021年 | 23篇 |
2020年 | 19篇 |
2019年 | 20篇 |
2018年 | 37篇 |
2017年 | 23篇 |
2016年 | 45篇 |
2015年 | 84篇 |
2014年 | 77篇 |
2013年 | 143篇 |
2012年 | 124篇 |
2011年 | 152篇 |
2010年 | 79篇 |
2009年 | 61篇 |
2008年 | 132篇 |
2007年 | 128篇 |
2006年 | 124篇 |
2005年 | 114篇 |
2004年 | 99篇 |
2003年 | 100篇 |
2002年 | 65篇 |
2001年 | 12篇 |
2000年 | 13篇 |
1999年 | 17篇 |
1998年 | 15篇 |
1997年 | 7篇 |
1996年 | 6篇 |
1995年 | 6篇 |
1994年 | 5篇 |
1993年 | 9篇 |
1992年 | 6篇 |
1991年 | 7篇 |
1990年 | 6篇 |
1989年 | 5篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1986年 | 3篇 |
1985年 | 10篇 |
1984年 | 4篇 |
1983年 | 3篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1978年 | 3篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1974年 | 4篇 |
1972年 | 2篇 |
1967年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有1842条查询结果,搜索用时 46 毫秒
41.
Wei Su Sergey V. Slepenkov Michael K. Slevin Shawn M. Lyons Marcin Ziemniak Joanna Kowalska Edward Darzynkiewicz Jacek Jemielity William F. Marzluff Robert E. Rhoads 《RNA (New York, N.Y.)》2013,19(1):1-16
Metazoan replication-dependent histone mRNAs are only present in S-phase, due partly to changes in their stability. These mRNAs end in a unique stem–loop (SL) that is required for both translation and cell-cycle regulation. Previous studies showed that histone mRNA degradation occurs through both 5′→3′ and 3′→5′ processes, but the relative contributions are not known. The 3′ end of histone mRNA is oligouridylated during its degradation, although it is not known whether this is an essential step. We introduced firefly luciferase reporter mRNAs containing the histone 3′ UTR SL (Luc-SL) and either a normal or hDcp2-resistant cap into S-phase HeLa cells. Both mRNAs were translated, and translation initially protected the mRNAs from degradation, but there was a lag of ∼40 min with the uncleavable cap compared to ∼8 min for the normal cap before rapid decay. Knockdown of hDcp2 resulted in a similar longer lag for Luc-SL containing a normal cap, indicating that 5′→3′ decay is important in this system. Inhibition of DNA replication with hydroxyurea accelerated the degradation of Luc-SL. Knockdown of terminal uridyltransferase (TUTase) 4 but not TUTase 3 slowed the decay process, but TUTase 4 knockdown had no effect on destabilization of the mRNA by hydroxyurea. Both Luc-SL and its 5′ decay intermediates were oligouridylated. Preventing oligouridylation by 3′-deoxyadenosine (cordycepin) addition to the mRNA slowed degradation, in the presence or absence of hydroxyurea, suggesting oligouridylation initiates degradation. The spectrum of oligouridylated fragments suggests the 3′→5′ degradation machinery stalls during initial degradation, whereupon reuridylation occurs. 相似文献
42.
Aleksandra Markiewicz Marzena We?nicka-Ja?kiewicz Jaros?aw Skokowski Janusz Ja?kiewicz Jolanta Szade Jacek Jassem Anna J. ?aczek 《PloS one》2013,8(8)
Introduction
Amplification of the ESR1 gene, coding for estrogen receptor alpha, was shown to predict responsiveness to tamoxifen, however its prognostic impact in breast cancer patients has not been thoroughly investigated. Other factors that could contribute to responsiveness to tamoxifen treatment are polymorphisms in ESR1 gene and genes involved in tamoxifen metabolism.The aim of this study was to assess the prognostic role of ESR1 gene dosage in a consecutive group of breast cancer patients and to correlate this feature with clinico-pathological factors. Additionally, ESR1 PvuII, CYP2C19*2 and UGT2B15*2 polymorphisms were analyzed in the tamoxifen-treated subgroup of patients.Materials and Methods
Primary tumor samples from 281 stage I-III consecutive breast cancer patients were analyzed for ESR1 gene dosage using real-time PCR with locked nucleic acids hydrolysis probes. In the tamoxifen-treated subgroup of patients, ESR1 PvuII, CYP2C19*2 and UGT2B15*2 polymorphism in leukocytes genomic DNA were analyzed. Results were correlated with clinico-pathological factors and with disease-free survival (DFS) and overall survival (OS).Results
ESR1 amplification (with a cut-off level of 2.0) was found in 12% of the entire group of breast cancer patients, and in 18% of the ER-negative subgroup. This feature was associated with decreased DFS both in the entire group (P=0.007) and in the ER-negative subgroup (P=0.03), but not in the tamoxifen-treated patients.Patients with ESR1 PvuII wt/wt genotype and at least one UGT2B15 wt allele had a worse DFS (P=0.03) and showed a trend towards decreased Os (P=0.08) in comparison to patients with ESR1 PvuII wt/vt or vt/vt genotype and UGT2B15 *2/*2 genotype.Conclusions
ESR1 amplification can occur in ER-negative tumors and may carry poor prognosis. In the tamoxifen-treated subgroup, poor prognosis was related to the combined presence of ESR1 PvuII wt/wt and UGT2B15wt/wt or wt/*2 genotype. 相似文献43.
Mucha Joanna Zadworny Marcin Helmisaari Heljä-Sisko Nihlgård Bengt Repo Tapani Żytkowiak Maciej Małek Stanisław Reich Peter B. Oleksyn Jacek 《Plant and Soil》2020,455(1-2):507-518
Plant and Soil - Any grouping of tree species concerned with SOC sequestration should include trees that are as homogeneous as possible in their carbon sequestration. We propose a classification of... 相似文献
44.
Aleksandra Łukasiewicz Małgorzata Niśkiewicz Jacek Radwan 《Evolution; international journal of organic evolution》2020,74(8):1851-1855
Elaborate sexually selected ornaments and armaments are costly but increase the reproductive success of their bearers (usually males). It has been postulated that high-quality males can invest disproportionately more in such traits, making those traits honest signals of genetic quality. However, genes associated with such traits may have sexually antagonistic effects on fitness. Here, using a bulb mite Rhizoglyphus robini, a species in which a distinct dimorphism exists between males in the expression of a sexually selected weapon, we compare inbreeding and gender load between lines derived from armed fighters and unarmed scramblers. After four generations of sib-mating, inbreeding depression for female fitness was significantly lower in fighter-derived lines compared to scrambler-derived lines, suggesting that fighter males had significantly higher genetic quality. However, outbred females from fighter-derived lines had significantly lower fitness compared to outbred females from scrambler-derived lines, demonstrating significant gender load associated with the presence of a sexually selected male weapon. Our results imply that under outbreeding, genetic benefits of mating with bearers of elaborate sexually selected traits might be swamped by the costs of decreased fitness of female progeny due to sexually antagonistic effects. 相似文献
45.
Helena Rudnicka Tadeusz Debniak Cezary Cybulski Tomasz Huzarski Jacek Gronwald Jan Lubinski Bohdan Gorski 《Molecular biology reports》2013,40(12):6619-6623
BRCA1 and BRCA2 are two major genes associated with familial breast and ovarian cancer susceptibility. In Poland standard BRCA gene test is usually limited to Polish founder BRCA1 mutations: 5382insC, C61G and 4153delA. To date, just a few single large genomic rearrangements (LGRs) of BRCA1 gene have been reported in Poland. Here we report the first comprehensive analysis of large mutations in BRCA1 and BRCA2 genes in this country. We screened LGRs in BRCA1 and BRCA2 genes by multiplex ligation-dependent probe amplification in 200 unrelated patients with strong family history of breast/ovarian cancers and negative for BRCA1 Polish founder mutations. We identified three different LGRs in BRCA1 gene: exons 13-19 deletion, exon 17 deletion and exon 22 deletion. No LGR was detected in BRCA2 genes. Overall, large rearrangements accounted for 3.7 % of all BRCA1 mutation positive families in our population and 1.5 % in high-risk families negative for Polish founder mutation. 相似文献
46.
Krzysztof Mędrek Piotr Magnowski Bartłomiej Masojć Anita Chudecka-Głaz Bogdan Torbe Janusz Menkiszak Marek Spaczyński Jacek Gronwald Jan Lubiński Bohdan Górski 《Molecular biology reports》2013,40(3):2145-2147
Among many alterations within the TP53 gene the rs1042522 (C72G, p.Pro72Arg) has been associated with numerous cancers , however the results differ between populations for opposite Pro or Arg alleles. Similar thus inconclusive results are observed in ovarian cancer, which may suggest that the rs1042522 does not influence ovarian carcinogensis directly, but might be linked to another pathogenic alteration. WRAP53 which overlaps the TP53 is required to maintain normal levels of p53 upon DNA damage, but also when altered may independently increase the risk of cancer. To evaluate the association between three SNPs located in WRAP53–TP53 region: rs1042522, rs2287497, rs2287498 and ovarian cancer risk in Polish population we genotyped 626 cases and 1,045 healthy controls. Our results provide the evidence for an association between studied SNPs and a risk of invasive ovarian cancer in Poland. We found that CC homozygotes in rs1042522 were more frequent in cancers when compared to controls (OR = 1.46, p = 0.03). Similarly in WRAP53 both TT homozygotes in rs2287497 (OR = 1.95, p = 0.03) and AA homozygotes in rs2287498 (OR = 2.65, p = 0,01) were more frequent among cases than healthy individuals. There is also a suggestive evidence that specific homozygosity of studied SNPs in TP53–WRAP53 region is significantly overrepresented in ovarian cancer patients. In conclusion SNPs in WRAP53 (rs2287497 and rs2287498) have stronger association with an ovarian cancer risk than rs1042522 in TP53. 相似文献
47.
This research explores the distributions and community composition of pelagic species in the sub-Arctic and Arctic waters of the northern Bering and central and southern Chukchi seas during September 2007 by linking pelagic zooplankton and fish assemblages to water masses. Juvenile saffron cod (Eleginus gracilis), polar cod (Boreogadus saida), and shorthorn sculpin (Myoxocephalus scorpius) were most abundant in warm, low salinity Alaska Coastal Water (ACW) of the central Chukchi Sea, characterized by low chlorophyll, low nutrients, and small zooplankton taxa. Adult Pacific herring (Clupea pallasii) were more abundant in the less stratified Bering Strait waters and in the colder, saltier Bering Shelf Water of the northern Bering and southern Chukchi seas, characterized by high chlorophyll, high nutrients, and larger zooplankton taxa. Juvenile pink (Oncorhynchus gorbuscha) and chum (O. keta) salmon were most abundant in the less stratified ACW in the central Chukchi Sea and Bering Strait. Abundances of large zooplankton were dominated by copepods (Eucalanus bungii, Calanus glacialis/marshallae, Metridia pacifica) followed by euphausiids (juvenile Thysanoessa raschii and unidentified taxa), whereas small zooplankton were dominated by bivalve larvae and copepods (Centropages abdominalis, Oithona similis, Pseudocalanus sp.). Pelagic community composition was related to environmental factors, with highest correlations between bottom salinity and large zooplankton taxa, and latitude and fish species. These data were collected in a year with strong northward retreat of summer sea ice and therefore provide a baseline for assessing the effects of future climate warming on pelagic ecosystems in sub-Arctic and Arctic regions. 相似文献
48.
This investigation was designed to explore the relationships between lichen symbionts (phycobiont and mycobiont) and the substrate on which they grow by examining the chemical and ultrastructural features of the lichen-soil interface. These lichens form an integral part of microbiotic soil crusts. Fragments of three different lichen biotypes growing over gypsum crystals and marls were fixed and embedded in resin. The lichen-substratum interface was then examined by scanning electron microscopy with backscattered electron imaging. In situ observation, microanalytical (EDS), and FT-Raman plus infrared spectroscopy of the lichen-substratum interface indicated that different ultrastructural features of the mycobiont were related to biogeochemical processes and Ca 2+ distribution in the soil crust. Phycobionts were observed to make direct contact with the substratum and to be surrounded by a nondifferentiated thallus structure. These observations suggest that they can grow outside the thallus in the early stages of lichen development in the semi-arid conditions of their habitat. The particular ultrastructural features of the lichen thallus and of the lichen-substratum interface appear to have marked effects on runoff phenomena and ponding generation of the surface. 相似文献
49.
50.
Robert J. Duszynski Jacek Topczewski Elizabeth E. LeClair 《Development, growth & differentiation》2013,55(2):282-300
The zebrafish maxillary barbel is an integumentary organ containing skin, glands, pigment cells, taste buds, nerves, and endothelial vessels. The maxillary barbel can regenerate (LeClair & Topczewski 2010); however, little is known about its molecular regulation. We have studied fibroblast growth factor (FGF) pathway molecules during barbel regeneration, comparing this system to a well‐known regenerating appendage, the zebrafish caudal fin. Multiple FGF ligands (fgf20a, fgf24), receptors (fgfr1‐4) and downstream targets (pea3, il17d) are expressed in normal and regenerating barbel tissue, confirming FGF activation. To test if specific FGF pathways were required for barbel regeneration, we performed simultaneous barbel and caudal fin amputations in two temperature‐dependent zebrafish lines. Zebrafish homozygous for a point mutation in fgf20a, a factor essential for caudal fin blastema formation, regrew maxillary barbels normally, indicating that the requirement for this ligand is appendage‐specific. Global overexpression of a dominant negative FGF receptor, Tg(hsp70l:dn‐fgfr1:EGFP)pd1 completely blocked fin outgrowth but only partially inhibited barbel outgrowth, suggesting reduced requirements for FGFs in barbel tissue. Maxillary barbels expressing dn‐fgfr1 regenerated peripheral nerves, dermal connective tissue, endothelial tubes, and a glandular epithelium; in contrast to a recent report in which dn‐fgfr1 overexpression blocks pharyngeal taste bud formation in zebrafish larvae (Kapsimali et al. 2011), we observed robust formation of calretinin‐positive tastebuds. These are the first experiments to explore the molecular mechanisms of maxillary barbel regeneration. Our results suggest heterogeneous requirements for FGF signaling in the regeneration of different zebrafish appendages (caudal fin versus maxillary barbel) and taste buds of different embryonic origin (pharyngeal endoderm versus barbel ectoderm). 相似文献