NF-kappaB transcription factors mediate the effects of pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukin-1beta. Failure to downregulate NF-kappaB transcriptional activity results in chronic inflammation and cell death, as observed in A20-deficient mice. A20 is a potent inhibitor of NF-kappaB signalling, but its mechanism of action is unknown. Here we show that A20 downregulates NF-kappaB signalling through the cooperative activity of its two ubiquitin-editing domains. The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation. Here we define a novel ubiquitin ligase domain and identify two sequential mechanisms by which A20 downregulates NF-kappaB signalling. We also provide an example of a protein containing separate ubiquitin ligase and DUB domains, both of which participate in mediating a distinct regulatory effect.
A single–base pair resolution silkworm genetic variation map was constructed from 40 domesticated and wild silkworms, each sequenced to approximately threefold coverage, representing 99.88% of the genome. We identified ∼16 million single-nucleotide polymorphisms, many indels, and structural variations. We find that the domesticated silkworms are clearly genetically differentiated from the wild ones, but they have maintained large levels of genetic variability, suggesting a short domestication event involving a large number of individuals. We also identified signals of selection at 354 candidate genes that may have been important during domestication, some of which have enriched expression in the silk gland, midgut, and testis. These data add to our understanding of the domestication processes and may have applications in devising pest control strategies and advancing the use of silkworms as efficient bioreactors.
The water-solvable FePt nanoparticles of 3, 6, and 12 nm in diameter (3 nm-, 6 nm-, and 12 nm-FePt) were synthesized and applied as a dual modality contrast agent for CT/MRI molecular imaging. These nanoparticles present excellent biocompatibility and hemocompatibility in all test concentrations for the imaging contrast. The biodistribution analysis revealed the highest serum concentration and circulation half-life for 12 nm-FePt, followed by 6 nm-FePt then 3 nm-FePt. Thus, the 3 nm-FePt showed higher brain concentrations. Anti-Her2 antibody conjugated FePt nanoparticles demonstrated molecular expression dependent CT/MRI dual imaging contrast effect in MBT2 cell line and its Her2/neu gene knock out counterpart. Selective contrast enhancement of Her2/neu overexpression cancer lesions in both CT and MRI was found in tumor bearing animal after tail vein injection of the nanoparticles. The 12 nm-FePt outperformed 3 nm-FePt in both imaging modalities. These results indicate the potential of FePt nanoparticles to serve as novel multimodal molecular imaging contrast agents in clinical settings.
Purpose To compare the macular retinal thickness and macular volume between subjects with high myopia and non-myopia. Methods This prospective nonrandomized, comparative study recruited healthy subjects with high myopia subjects, defined as a spherical equivalence (SE) over À6 dioptres (D) or AXLX26.5 mm and the best corrected visual acuity better than 20/25, and subjects with non-myopia, defined as an with SE between 1.5D and À1.5 D and the BCVA better than 20/25. Optical coherence tomography was performed in each eye. Results Eighty high myopic eyes and 40 non-myopic eyes were included. The mean age of the high myopic group and non-myopia group was 29.6 and 27.5 years old, respectively. The mean refraction was -9.27 D in the high myopia group and -0.22 D in the non-myopia group. The high myopia group had significantly greater mean retinal thickness in the foveola and fovea 1 mm area than the non-myopia group (166 vs 149 lm, Po0.0001, 199 vs 188 lm, P ¼ 0.0063, respectively). However, the mean retinal thickness in the inner and outer macular area (superior, nasal, inferior, or temporal) of the high myopia group was significantly less than in the non-myopia group. In addition, the high myopia group had significantly smaller macular volume than the non-myopia group (Po0.0001). Conclusion This study demonstrated that the retinal thickness in individuals with high myopia is thicker in the foveola and fovea, but thinner in the inner and the outer macular region. The retina of individuals with high myopia had smaller macular volume than those with non-myopia.
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