Citation: Chen Q, Ma Q, Wu C, et al. Macular vascular fractal dimension in the deep capillary layer as an early indicator of microvascular loss for retinopathy in type 2 diabetic patients. Invest Ophthalmol Vis Sci. 2017;58:3785-3794. DOI:10.1167/ iovs.17-21461 PURPOSE. To determine the ability of fractal dimension to detect early changes in the retinal microvascular network imaged by optical coherence tomography angiography (OCT-A) in type 2 diabetic patients. METHODS.Sixty-seven patients with type 2 diabetic mellitus (DM) (48 with no diabetic retinopathy [DR], 19 with minimal DR) and 40 control subjects. Macular OCT-A images of the superficial and deep retinal capillary layers in a 2.5-mm diameter concentric annular zone (excluding the foveal avascular zone) were subdivided into six annular rings and four quadrants. A custom automated algorithm was developed to quantify the complexity and density of the two retinal capillary layers by fractal analysis.RESULTS. Compared to controls, the fractal dimensional parameter (D box ) of the two retinal capillary layers in most regions was significantly lower in diabetic patients with minimal DR (P < 0.05). The D box of the diabetic patients with no DR was also decreased in most regions of the deep retinal capillary layer (P < 0.05), but not in the superficial retinal capillary layer (P > 0.05). Based on the receiver operating characteristic curve analysis, the D box values for the deep retinal capillary layer had the highest index to discriminate diabetic patients with and without minimal DR from controls. CONCLUSIONS.Fractal dimension based on OCT-A has the potential to quantitatively characterize retinal microvascular changes in the early stage of DM. Changes in the fractal dimension in the deep retinal capillary layer could be an early indicator of microvasculature changes associated with retinopathy in type 2 diabetic patients.
Transient receptor potential vanilloid 4 (TRPV4) is widely expressed in the central nervous system and can be activated by multiple stimuli during cerebral ischemia. Recently, we reported that intracerebroventricular (icv.) injection of HC-067047, a specific TRPV4 antagonist, reduced brain infarction following 60-min of middle cerebral artery occlusion (MCAO). This study was undertaken to investigate the molecular mechanisms underlying TRPV4-mediated neuronal injury in cerebral ischemia. We demonstrated that TRPV4 expression was upregulated in the ipsilateral hippocampus at 4 to 48 h post-MCAO, peaking at 18 h post-MCAO. Treatment with TRPV4 antagonists (HC-067047 and ruthenium red) dose-dependently reduced brain infarction at 24 h post-MCAO. Phosphorylation of protein kinase B (p-Akt) was downregulated and that of extracellular signal-related kinase (p-ERK) was upregulated at 8 to 24 h post-MCAO, which was markedly blocked by treatment with HC-067047. Icv. injection of GSK1016790A (a TRPV4 agonist), dose-dependently induced hippocampal neuronal death, accompanied by an increase in phosphorylation of the NR2B subunit of the N-methyl-D-aspartate receptor (NMDAR). In addition, the level of p-Akt was decreased and that of p-ERK was increased by GSK1016790A-injection, which was sensitive to an NR2B antagonist. The neuronal toxicity of GSK1016790A was blocked by treatment with an NR2B antagonist and a phosphatidylinositol-3-kinase (PI3K) agonist but not by administration of a MAPK/ERK kinase antagonist. We conclude that the activation of TRPV4 is upregulated and involved in neuronal injury during cerebral ischemia and that the neurotoxicity associated with TRPV4-activation is mediated through NR2B-NMDAR and the related downregulation of the Akt signaling pathway.
Transgenic pigs play an important role in producing higher quality food in agriculture and improving human health when used as animal models for various human diseases in biomedicine. Production of transgenic pigs, however, is a lengthy and inefficient process that hinders research using pig models. Recent applications of the CRISPR/Cas9 system for generating site-specific gene knockout/knockin models, including a knockout pig model, have significantly accelerated the animal model field. However, a knockin pig model containing a site-specific transgene insertion that can be passed on to its offspring remains lacking. Here, we describe for the first time the generation of a site-specific knockin pig model using a combination of CRISPR/Cas9 and somatic cell nuclear transfer. We also report a new genomic “safe harbor” locus, named pH11, which enables stable and robust transgene expression. Our results indicate that our CRISPR/Cas9 knockin system allows highly efficient gene insertion at the pH11 locus of up to 54% using drug selection and 6% without drug selection. We successfully inserted a gene fragment larger than 9 kb at the pH11 locus using the CRISPR/Cas9 system. Our data also confirm that the gene inserted into the pH11 locus is highly expressed in cells, embryos and animals.
BackgroundSoybean is a valuable crop that provides protein and oil. Soybean requires a large amount of nitrogen (N) to accumulate high levels of N in the seed. The yield and protein content of soybean seeds are directly affected by the N-use efficiency (NUE) of the plant, and improvements in NUE will improve yields and quality of soybean products. Genetic engineering is one of the approaches to improve NUE, but at present, it is hampered by the lack of information on genes associated with NUE. Solexa sequencing is a new method for estimating gene expression in the transcription level. Here, the expression profiles were analyzed between two soybean varieties in N-limited conditions to identify genes related to NUE.ResultsTwo soybean genotypes were grown under N-limited conditions; a low-N-tolerant variety (No.116) and a low-N-sensitive variety (No.84-70). The shoots and roots of soybeans were used for sequencing. Eight libraries were generated for analysis: 2 genotypes × 2 tissues (roots and shoots) × 2 time periods [short-term (0.5 to 12 h) and long-term (3 to 12 d) responses] and compared the transcriptomes by high-throughput tag-sequencing analysis. 5,739,999, 5,846,807, 5,731,901, 5,970,775, 5,476,878, 5,900,343, 5,930,716, and 5,862,642 clean tags were obtained for the eight libraries: L1, 116-shoot short-term; L2 84-70-shoot short-term; L3 116-shoot long-term; L4 84-70-shoot long-term; L5 116-root short-term; L6 84-70-root short-term; L7 116-root long-term;L8 84-70-root long-term; these corresponded to 224,154, 162,415, 191,994, 181,792, 204,639, 206,998, 233,839 and 257,077 distinct tags, respectively. The clean tags were mapped to the reference sequences for annotation of expressed genes. Many genes showed substantial differences in expression among the libraries. In total, 3,231genes involved in twenty-two metabolic and signal transduction pathways were up- or down-regulated. Twenty-four genes were randomly selected and confirmed their expression patterns by quantitative RT-PCR; Twenty-one of the twenty-four genes showed expression patterns consistent with the Digital Gene Expression (DGE) data.ConclusionsA number of soybean genes were differentially expressed between the low-N-tolerant and low-N-sensitive varieties under N-limited conditions. Some of these genes may be candidates for improving NUE. These findings will help to provide a detailed understanding of NUE mechanisms, and also provide a basis for breeding soybean varieties that are tolerant to low-N conditions.
Although there has been significant progress in the development of transition-metal-catalyzed hydrosilylations of alkenes over the past several decades, metal-free hydrosilylation is still rare and highly desirable. Herein, we report a convenient visible-light-driven metal-free hydrosilylation of both electron-deficient and electron-rich alkenes that proceeds through selective hydrogen atom transfer for Si-H activation. The synergistic combination of the organophotoredox catalyst 4CzIPN with quinuclidin-3-yl acetate enabled the hydrosilylation of electron-deficient alkenes by selective Si-H activation while the hydrosilylation of electron-rich alkenes was achieved by merging photoredox and polarity-reversal catalysis.
Since the seminal work of Zhang in 2016, donor–acceptor cyanoarene-based fluorophores, such as 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN), have been widely applied in photoredox catalysis and used as excellent metal-free alternatives to noble metal Ir- and Ru-based photocatalysts. However, all the reported photoredox reactions involving this chromophore family are based on harnessing the energy from a single visible light photon, with a limited range of redox potentials from −1.92 to +1.79 V vs SCE. Here, we document the unprecedented discovery that this family of fluorophores can undergo consecutive photoinduced electron transfer (ConPET) to achieve very high reduction potentials. One of the newly synthesized catalysts, 2,4,5-tri(9H-carbazol-9-yl)-6-(ethyl(phenyl)amino)isophthalonitrile (3CzEPAIPN), possesses a long-lived (12.95 ns) excited radical anion form, 3CzEPAIPN•–*, which can be used to activate reductively recalcitrant aryl chlorides (E red ≈ −1.9 to −2.9 V vs SCE) under mild conditions. The resultant aryl radicals can be engaged in synthetically valuable aromatic C–B, C–P, and C–C bond formation to furnish arylboronates, arylphosphonium salts, arylphosphonates, and spirocyclic cyclohexadienes.
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