551 resultados para patella groove
Resumo:
Hairpin pyrrole-imdazole polyamides are cell-permeable, sequence-programmable oligomers that bind in the minor groove of DNA. This thesis describes studies of Py-Im polyamides targeted to biologically important DNA repeat sequences for the purpose of modulating disease states. Design of a hairpin polyamide that binds the CG dyad, a site of DNA methylation that can become dysregulated in cancer, is described. We report the synthesis of a DNA methylation antagonist, its sequence specificity and affinity informed by Bind-n-Seq and iteratively designed, which improves inhibitory activity in a cell-free assay by 1000-fold to low nanomolar IC50. Additionally, a hairpin polyamide targeted to the telomeric sequence is found to trigger a slow necrotic-type cell death with the release of inflammatory molecules in a model of B cell lymphoma. The effects of the polyamide are unique in this class of oligomers; its effects are characterized and a functional assay of phagocytosis by macrophages is described. Additionally, hairpin polyamides targeted to pathologically expanded CTG•CAG triplet repeat DNA sequences, the molecular cause of myotonic dystrophy type 1, are synthesized and assessed for toxicity. Lastly, ChIP-seq of Hypoxia-Inducible Factor is performed under hypoxia-induced conditions. The study results show that ChIP-seq can be employed to understand the genome-wide perturbation of Hypoxia-Inducible Factor occupancy by a Py-Im polyamide.
Resumo:
报道了一种具有高分辨率和高效且价廉的解调系统的光纤布拉格光栅(FBG)温度传感器。提出了光纤光栅的金属槽封装技术,以提高传感光栅的温度灵敏性。研究了金属槽封装光栅的温度灵敏性,理论分析和实验结果表明,封装光栅的温度灵敏系数比普通裸光栅提高了3.6倍。系统利用一长周期光栅(LPG)作为线性滤波器,宽带光源经此长周期光栅调制后入射到传感光栅,可解调布拉格传感光栅的波长位移。理论分析与实验结果一致,系统可达到的温度分辨率为0.02℃。
Resumo:
The Barton laboratory has established that octahedral rhodium complexes bearing the sterically expansive 5,6-chrysene diimine ligand can target thermodynamically destabilized sites, such as base pair mismatches, in DNA with high affinity and selectivity. These complexes approach DNA from the minor groove, ejecting the mismatched base pairs from the duplex in a binding mode termed metalloinsertion. In recent years, we have shown that these metalloinsertor complexes also exhibit cytotoxicity preferentially in cancer cells that are deficient in the mismatch repair (MMR) machinery.
Here, we establish that a sensitive structure-activity relationship exists for rhodium metalloinsertors. We studied the relationship between the chemical structures of metalloinsertors and their effect on biological activity for ten complexes with similar DNA binding affinities, but wide variation in their lipophilicity. Drastic differences were observed in the selectivities of the complexes for MMR-deficient cells. Compounds with hydrophilic ligands were highly selective, exhibiting preferential cytotoxicity in MMR-deficient cells at low concentrations and short incubation periods, whereas complexes with lipophilic ligands displayed poor cell-selectivity. It was discovered that all of the complexes localized to the nucleus in concentrations sufficient for mismatch binding; however, highly lipophilic complexes also exhibited high mitochondrial uptake. Significantly, these results support the notion that mitochondrial DNA is not the desired target for our metalloinsertor complexes; instead, selectivity stems from targeting mismatches in genomic DNA.
We have also explored the potential for metalloinsertors to be developed into more complex structures with multiple functionalities that could either enhance their overall potency or impart mismatch selectivity onto other therapeutic cargo. We have constructed a family of bifunctional metalloinsertor conjugates incorporating cis-platinum, each unique in its chemical structure, DNA binding interactions, and biological activity. The study of these complexes in MMR-deficient cells has established that the cell-selective biological activity of rhodium metalloinsertors proceeds through a critical cellular pathway leading to necrosis.
We further explored the underlying mechanisms surrounding the biological response to mismatch recognition by metalloinsertors in the genome. Immunofluorescence assays of MMR-deficient and MMR-proficient cells revealed that a critical biomarker for DNA damage, phosphorylation of histone H2AX (γH2AX) rapidly accumulates in response to metalloinsertor treatment, signifying the induction of double strand breaks in the genome. Significantly, we have discovered that our metalloinsertor complexes selectively inhibit transcription in MMR-deficient cells, which may be a crucial checkpoint in the eventual breakdown of the cell via necrosis. Additionally, preliminary in vivo studies have revealed the capability of these compounds to traverse the complex environments of multicellular organisms and accumulate in MMR-deficient tumors. Our ever-increasing understanding of metalloinsertors, as well as the development of new generations of complexes both monofunctional and bifunctional, enables their continued progress into the clinic as promising new chemotherapeutic agents.
Resumo:
Pyrrole–Imidazole polyamides are programmable, cell-permeable small molecules that bind in the minor groove of double-stranded DNA sequence-specifically. Polyamide binding has been shown to alter the local helical structure of DNA, disrupt protein-DNA interactions, and modulate endogenous gene expression. Py–Im polyamides targeted to the androgen receptor-DNA interface have been observed to decrease expression of androgen-regulated genes, upregulate p53, and induce apoptosis in a hormone-sensitive prostate cancer cell line. Here we report that androgen response element (ARE)-targeted polyamides induced DNA replication stress in a hormone-insensitive prostate cancer cell line. The ATR checkpoint kinase was activated in response to this stress, causing phosphorylation of MCM2, and FANCD2 was monoubiquitinated. Surprisingly, little single-stranded DNA was exhibited, and the ATR targets RPA2 and Chk1 were not phosphorylated. We conclude that polyamide induces relatively low level replication stress, and suggest inhibition of the replicative helicase as a putative mechanism based on in vitro assays. We also demonstrate polyamide-induced inhibition of DNA replication in cell free extracts from X. laevis oocytes. In this system, inhibition of chromatin decondensation is observed, preventing DNA replication initiation. Finally, we show that Py-Im polyamides targeted to the ARE and ETS binding sequence downregulate AR- and ERG-driven signaling in a prostate cancer cell line harboring the TMPRSS2-ERG fusion. In a mouse xenograft model, ARE-targeted polyamide treatment reduced growth of the tumor.
Resumo:
We describe high-efficiency diffraction gratings fabricated in fused silica at the wavelength of 632.8 nm by rigorous coupled-wave analysis (RCWA). High-density holographic gratings, if the groove density falls within the range of 1575-1630 lines/mm and the groove depth within the range of 1.1-1.3 microns, can realize high diffraction efficiencies at the wavelength of 632.8 nm, e.g., the first Bragg diffraction efficiency can theoretically achieve more than 93% both in TE- and TM-polarized incidences, which greatly reduces the polarization-dependent losses. Note that with different groove profiles further optimized, the maximum efficiency of more than 99.69% can be achieved for TM-polarized incidence, or 97.81% for TE-polarized incidence.
Resumo:
We propose a miniature pulse compressor that can be used to compensate the group velocity dispersion that is produced by a commercial femtosecond laser cavity. The compressor is composed of two identical highly efficient deep-etched transmissive gratings. Compared with prism pairs, highly efficient deep-etched transmissive grating pairs are lightweight and small. With an optimized groove depth and a duty cycle, 98% diffraction efficiency of the -1 transmissive order can be achieved at a wavelength of 800 nm under Littrow conditions. The deep-etched gratings are fabricated in fused silica by inductively coupled plasma etching. With a pair of the fabricated gratings, the input positively chirped 73.9 fs pulses are neatly compressed into the nearly Fourier transform-limited 43.2 fs pulses. The miniature deep-etched grating-based pulse compressor should be of interest for practical applications. (c) 2008 Optical Society of America
Resumo:
This review examines water quality and stress indicators at levels of organisation from the individual to the community and beyond by means of three case studies concentrating on rocky shores within the north-east Atlantic. Responses of dogwhelks (Nucella) to tributyltin pollution from antifouling paints is examined as the main case study. There are effects at the individual level (development of male sexual characteristics in the female leading to effective sterility) and population level (reduction in juveniles, few females and eventual population disappearance of dogwhelks in badly contaminated areas) but information on community level effects of dogwhelk demise is sparse. Such effects were simulated by dogwhelk removal experiments on well studied, moderately exposed ledges on shores on the Isle of Man. The removal of dogwhelks reduced the size and longevity of newly established Fucus clumps that had escaped grazing. Removal of dogwhelks also increased the likelihood of algal escapes. In a factorial experiment dogwhelks were shown to be less important than limpets \{Patella) in structuring communities but still had a significant modifying effect by increasing the probability of algal escapes. Community level responses to stress on rocky shores are then explored by reference to catastrophic impacts such as oil spills, using the Torrey Canyon as a case study. Recovery of the system in response to this major perturbation took between 10-15 years through a series of damped oscillations. The final case study is that of indicators of ecosystem level change in response to climate fluctuations, using ratios of northern \{Semibalanus balanoides) and southern (Chthamalus spp.) barnacles. Indices derived from counts on the shore show good correlations with inshore sea-water temperatures after a 2-year lag phase. The use of barnacles to measure offshore changes is reviewed. The discussion considers the use of bioindicators at various levels of organisation.
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A deep binary silicon grating as high-extinction-ratio reflective polarizing beam splitter (PBS) at the wavelength of 1550 nm is presented. The design is based on the phenomenon of total internal reflection (TIR) by using the rigorous coupled wave analysis (RCWA). The extinction ratio of the rectangular PBS grating can reach 2.5×105 with the optimum grating period of 397 nm and groove depth of 1.092 μm. The effciencies of TM-polarized wave in the 0th order and TE-polarized wave in the −1st order can both reach unity at the Littrow angle. Holographic recording technology and inductively coupled plasma (ICP) etching could be used to fabricate the silicon PBS grating.
Resumo:
为了充分利用放大介质的增益带宽,获得脉宽更短,功率更高的输出脉冲,需要将输入到主放大链的种子脉冲进行光谱整形来补偿放大过程中的增益窄化效应。提出了利用变栅距反射光栅实现中心波长1053nm,谱宽6nm啁啾脉冲的光谱整形。运用严格的光栅衍射耦合波理论分析光栅的衍射特性,发现该方案不会引入相位畸变。分别计算和分析了刻槽深度、入射角大小、光栅周期以及入射光波长的变化对衍射效率的影响,通过选取适当的光栅参量可获得0.5%~84%的光谱调制深度。
Resumo:
在拼接光栅和拼接光栅压缩器的设计中,子光栅调节偏差不可避免,各维偏差与拼接光栅的时间特性之间的关系很关键。通过脉冲压缩理论分析得到各维偏差和聚焦脉冲时间宽度展宽之间的解析关系,从数值计算结果分析,面平行左右偏差对脉冲的时间宽度影响较大,必须控制在21.08 μrad内;条纹密度差异对脉冲宽度的影响很显著,相对条纹密度的比值应控制在10-5以内;从消除角色散的角度分析,面平行俯仰偏差和条纹平行度偏差可以相互补偿,条纹密度差异和面平行左右偏差也可以相互补偿。
Resumo:
The antireflection properties of triangular shaped gratings are studied by a combination of the effective medium theory and the anisotropic thin-film theory. The triangular shaped structures are analyzed as a function of grating period, filling factor, and groove depth, and the antireflective characteristics are also studied when visible-infrared light is incident upon them. Numerical examples are given for gratings on glass substrate with refractive index of 1.5. The results show that this kind of grating is capable of reducing reflections, and could achieve very low reflectivity over a wide field of view and a wide waveband by choosing appropriate parameters.
Resumo:
以薄膜光学的干涉理论和衍射光学的傅里叶模式理论为基础,给出了0.8μm飞秒激光器用多层介质膜脉宽压缩光栅的理论设计;设计采用H3L(HL)^9H0.5L2.4H的多层介质膜为基底,当刻蚀后表面浮雕结构的占宽比为0.35,线密度为1480线/mm,槽深为0.2μm,顶层HfO2的剩余厚度为0.15μm时,对于Littrow角度(36.7°)和TE波模式入射的衍射光栅其-1级衍射效率达到95%以上.
Resumo:
设计了在0°和90°方位角下都具有低旁带的鉴别用导模共振滤光片。利用严格的耦合波理论,分析了这种器件在不同入射角、不同光栅槽深和覆盖不同厚度SiO2层情况下的衍射特性。得到了满足鉴别要求的导模共振滤光片结构。在30°入射角情况下,对于TE模式偏振光,设计的滤光片在0°和90°方位角下都有形状对称的反射光谱、低的旁带、两个位置分开的共振峰和适当的半宽度。
Resumo:
基于严格耦合波理论建立了梯形介质膜光栅的衍射机理模型,利用该模型讨论了底角为70°的梯形介质膜光栅-1级的衍射行为。通过对梯形介质膜光栅的占空比、槽深和剩余厚度的优化,设计了应用于1053 nm和51.2°角度入射的梯形介质膜光栅。对于顶层为HfO2的介质膜光栅,当槽深为200 nm,剩余厚度为100 nm,占空比为0.35时,其衍射效率优于99.5%,而对于顶层为SiO2的梯形光栅,为获得99.5%的衍射效率,其槽深为800 nm,剩余厚度为320 nm。而且,获得同样的衍射效率,顶层为HfO2的梯形光栅具有更宽的光谱特性。数值计算表明,严格耦合波理论模型对梯形介质膜光栅衍射效率的计算具有很好的收敛性和稳定性。
Resumo:
It is demonstrated with powerful evidence that the extraordinary transmission of a metallic grating is undoubtedly due to the excitation of standing surface plasma waves in the Fabry-Perot like resonator. This is the first time that the strong standing waves set up in the groove of a sub-wavelength double-layer grating (SWDG) for the surface plasma waves have been reported. Moreover, about 90% transmission is gained with an SWDG, more easily fabricated than ordinary metallic gratings, in the first peak of transmission spectrum.