| 1. |
- Birney, Ewan, et al.
(author)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Journal article (peer-reviewed)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Tomlins, Scott A., et al.
(author)
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The role of SPINK1 in ETS rearrangement-negative prostate cancers
- 2008
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In: Cancer Cell. - Amsterdam : Elsevier. - 1535-6108 .- 1878-3686. ; 13:6, s. 519-28
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Journal article (peer-reviewed)abstract
- ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers ( approximately 10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.
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| 3. |
- Cao, Xianhua, et al.
(author)
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Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model
- 2006
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In: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 23:8, s. 1675-1686
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Journal article (peer-reviewed)abstract
- Purpose. To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug intestinal absorption and the differences in oral bioavailability between human and rat. Materials and Methods. The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situ intestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis. Results. No correlation (r(2) = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r(2) = 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r(2) > 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns. Conclusions. The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.
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| 4. |
- Cao, Yu, 1969
(author)
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Contacts on Silicon Carbide by Use of Nickel and Tantalum ---Preparation and Characterisation
- 2007
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Doctoral thesis (other academic/artistic)abstract
- Silicon carbide (SiC) is one of the attractive semiconductors due to its good electrical, thermal and mechanical properties. It is a promising material for high temperature, high power and high frequency application. Reliable electrodes are always necessary to utilise SiC for electronic devices. Nickel (Ni) and tantalum (Ta) can be used for both ohmic and Schottky contact on n-type SiC. Since metallisation represents one of the most important steps in the fabrication of electronic devices, the knowledge of the interaction between Ni, Ta and SiC, as well as electrical behaviour, is of primary importance for understanding and optimising the device performance. After annealing Ni/SiC samples at 800 and 950oC in vacuum for 20 min, Ni reacts with SiC to form textured Ni2Si and C. Its formation may consist of two stages: initial reaction rate and subsequent diffusion controlled stage. For ultra thin initial Ni layer (3 6 nm), islands formation of Ni2Si is observed after heat treatment. Increasing the Ni film thickness prevents this phenomenon. The C released owing to the reaction forms a thin graphite layer on the top of the surface and also tends to form cluster inside the reaction layer. The overall degree of graphitisation increases with increasing temperature from 800oC to 950oC. This work also deals with the impact of pre-treatment prior the metal deposition on the distribution of reaction product in Ni/SiC system. Argon ion etching before the Ni deposition helps the formation of multi-layer structure during annealing. For the samples without pre-treatment or with chemical cleaning procedure, there is more C agglomerated at the surface and no multi-layer structure. The possible reason is given. The silicides formed at the interface are dependent on the Ni layer thickness and substrate surface condition. This thesis reports a systematic in-situ XPS study on Ni silicides focusing on both the core level and Auger peaks. The peak position, shape, as well as satellite are compared in different silicides. The effect of argon ion sputtering on surface composition and chemical states has also been investigated. It has been found that low energy argon ions reduce the atomic mixing of the silicide, but increase preferential sputtering. After correcting the influence of the electron attenuation length, the measured depth profile is successfully reconstructed. In Ta/SiC system, no evident interface reaction occurs at 650°C. However, with the inco-operation of Ni, the formation temperature of Ta carbide and silicide is lowered due to the mediating effect of Ni. With the annealing temperature increasing to 950C, the dominant carbide changes from Ta2C in Ta/SiC to TaC in Ni/Ta/SiC. A layer structure is developed in both Ni/SiC and Ni/Ta/SiC system. A number of C vacancies are preferentially produced in the near interface region of the underlying SiC. Electrical measurements show that ohmic contact is formed after annealing at or above 800C in Ta/SiC and Ni/Ta/SiC. The alteration of the SiC subsurface by the reaction is important to the formation of the ohmic contact. High enough temperature is important to provide for sufficient interface change to obtain ohmic behaviour.
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| 5. |
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| 6. |
- Cao, Yu, 1969, et al.
(author)
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Interface Reactions and Electrical Properties of Ta/4H-SiC Contacts
- 2007
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In: Materials Science Forum. - Stafa : Trans Tech Publications Ltd.. - 1662-9752 .- 0255-5476. - 0878494421 ; 556-557, s. 713-716
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Journal article (peer-reviewed)abstract
- This study deals with the interfacial reactions and electrical properties of Ta/4H-SiCcontacts. Tantalum thin films (~100 nm) were deposited onto SiC wafer at room temperature byargon ion beam sputtering. The samples were then heated in high vacuum at 650°C, 800°C or950°C for 30 min. X-ray photoelectron spectroscopy (XPS), glancing angle X-ray diffraction(XRD), Auger electron spectroscopy (AES) and current-voltage (I-V) technique were used forcharacterising the samples. Ohmic contact is formed in the studied samples after annealing at orabove 800°C even though considerable amount of metallic Ta still exists. The reaction zonepossesses a layered structure of Ta2C/Ta2C+Ta5Si3/SiC. High enough temperature is needed toprovide for sufficient interface change to tailor the contact properties.
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| 7. |
- Cao, Yu, 1969, et al.
(author)
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Investigation of Ni/Ta contacts on 4H silicon carbide
- 2007
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In: Applied Surface Science. - : Elsevier BV. - 0169-4332. ; 254:1 SPEC. ISS., s. 139-142
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Journal article (peer-reviewed)abstract
- Nickel and Tantalum thin films with 3:5 thickness ratios were deposited in succession onto 4H–SiC substrate at room temperature. The sampleswere then heated in situ in vacuum at 650, 800 or 950 8C for 30 min. Glancing angle X-ray diffraction (XRD), Auger electron spectroscopy (AES)and current–voltage (I–V) technique were used for characterising the interfacial reactions and electrical properties. Amorphous Ni–Ta can beformed by solid-state reaction at 650 8C. The minor dissolved Ni in the Ta metal promotes the reaction between Ta and SiC. With increasingannealing temperature up to 950 8C, the dominant carbide changes from Ta2C to TaC and a layer structure is developed. Electrical measurementsshow that ohmic contact is formed after annealing at or above 800 8C.
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| 10. |
- Cao, Yong-Xiao, et al.
(author)
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Ligustilide induces vasodilatation via inhibiting voltage dependent calcium channel and receptor-mediated Ca(2+) influx and release.
- 2006
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In: Vascular Pharmacology. - : Elsevier BV. - 1537-1891. ; 45:3, s. 171-176
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Journal article (peer-reviewed)abstract
- The purpose of the present study was to investigate the effect of ligustilide on vasodilatation in rat mesenteric artery and the mechanisms responsible for it. Isometric tension of rat mesenteric artery rings was recorded by a sensitive myograph system in vitro. The results showed that ligustilide at concentrations more than 10 mu M relaxed potassium chloride (KCl)-preconstricted rat mesenteric artery in a con centration-dependent manner. The vasodilatation effect of ligustilide was not dependent on endothelium. Ligustilide rightwards shifted concentration-response curves induced by KCl, calcium chloride (CaCl2), noradrenaline (NA) or 5-hydroxytryptamine (5-HT) in a non-parallel manner. This suggests that the vasodilatation effects were most likely via voltage-dependent calcium channel (VDCC) and receptor-operated calcium channel (ROCC). Propranolol, glibenclamide, tetraethylammonium and barium chloride did not affect the vasodilation induced by ligustilide, showing that beta-adrenoceptor, ATP sensitive potassium channel, calcium-activated potassium channel and inwardly rectifying potassium channel were not involved in the vasodilatation. Ligustilide concentration-dependently inhibited the vasoconstriction induced by NA or CaCl2 in Ca2+-free medium, indicating that the vasodilatation relates to inhibition of extracellular Ca2+ influx through VDCC and ROCC, and intracellular Ca2+ release from Ca2+ store. Since caffeine-induced contraction was inhibited by ligustilide, inhibition of intracellular Ca2+ released by ligustilide occurred via the ryanodine receptors. Our results suggest that ligustilide induces vasodilatation in rat mesenteric artery by inhibiting the VDCC and ROCC, and receptor-mediated Ca2+ influx and release. (c) 2006 Elsevier Inc. All rights reserved.
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