Abstract
Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the
RB1
gene. Children with germline mutations in
RB1
have a high likelihood of ...developing retinoblastoma and other malignancies later in life. Genetically engineered mouse models of retinoblastoma share some similarities with human retinoblastoma but there are differences in their cellular differentiation. To develop a laboratory model of human retinoblastoma formation, we make induced pluripotent stem cells (iPSCs) from 15 participants with germline
RB1
mutations. Each of the stem cell lines is validated, characterized and then differentiated into retina using a 3-dimensional organoid culture system. After 45 days in culture, the retinal organoids are dissociated and injected into the vitreous of eyes of immunocompromised mice to support retinoblastoma tumor growth. Retinoblastomas formed from retinal organoids made from patient-derived iPSCs have molecular, cellular and genomic features indistinguishable from human retinoblastomas. This model of human cancer based on patient-derived iPSCs with germline cancer predisposing mutations provides valuable insights into the cellular origins of this debilitating childhood disease as well as the mechanism of tumorigenesis following
RB1
gene inactivation.
Super-enhancers are expansive regions of genomic DNA comprised of multiple putative enhancers that contribute to the dynamic gene expression patterns during development. This is particularly ...important in neurogenesis because many essential transcription factors have complex developmental stage- and cell-type specific expression patterns across the central nervous system. In the developing retina, Vsx2 is expressed in retinal progenitor cells and is maintained in differentiated bipolar neurons and Müller glia. A single super-enhancer controls this complex and dynamic pattern of expression. Here we show that deletion of one region disrupts retinal progenitor cell proliferation but does not affect cell fate specification. The deletion of another region has no effect on retinal progenitor cell proliferation but instead leads to a complete loss of bipolar neurons. This prototypical super-enhancer may serve as a model for dissecting the complex gene expression patterns for neurogenic transcription factors during development. Moreover, it provides a unique opportunity to alter expression of individual transcription factors in particular cell types at specific stages of development. This provides a deeper understanding of function that cannot be achieved with traditional knockout mouse approaches.
In the developing retina, multipotent neural progenitors undergo unidirectional differentiation in a precise spatiotemporal order. Here we profile the epigenetic and transcriptional changes that ...occur during retinogenesis in mice and humans. Although some progenitor genes and cell cycle genes were epigenetically silenced during retinogenesis, the most dramatic change was derepression of cell-type-specific differentiation programs. We identified developmental-stage-specific super-enhancers and showed that most epigenetic changes are conserved in humans and mice. To determine how the epigenome changes during tumorigenesis and reprogramming, we performed integrated epigenetic analysis of murine and human retinoblastomas and induced pluripotent stem cells (iPSCs) derived from murine rod photoreceptors. The retinoblastoma epigenome mapped to the developmental stage when retinal progenitors switch from neurogenic to terminal patterns of cell division. The epigenome of retinoblastomas was more similar to that of the normal retina than that of retina-derived iPSCs, and we identified retina-specific epigenetic memory.
•Changes in histone modifications were more prominent than those in DNA methylation•Epigenetic changes were more prevalent at differentiation genes than progenitors•The retinoblastoma epigenome resembles the retina at a developmental transition•Histone modifications are important for neuronal epigenetic memory in iPSCs
Aldiri, Xu, and colleagues show in this article how the epigenome of the mouse and human retina changes during development in coordination with transcriptional programs. They also relate those developmental changes to retinoblastoma and epigenetic memory in retina-derived iPSCs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Currently, the engineering of miniature spectrometers mainly faces three problems: the mismatch between the number of filters at the front end of the detector and the spectral reconstruction ...accuracy; the lack of a stable spectral reconstruction algorithm; and the lack of a spectral reconstruction evaluation method suitable for engineering. Therefore, based on 20 sets of filters, this paper classifies and optimizes the filter array by the K-means algorithm and particle swarm algorithm, and obtains the optimal filter combination under different matrix dimensions. Then, the truncated singular value decomposition-convex optimization algorithm is used for high-precision spectral reconstruction, and the detailed spectral reconstruction process of two typical target spectra is described. In terms of spectral evaluation, due to the strong randomness of the target detected during the working process of the spectrometer, the standard value of the target spectrum cannot be obtained. Therefore, we adopt the method of joint cross-validation of multiple sets of data for spectral evaluation. The results show that when the random error of +/− 2 code values is applied multiple times for reconstruction, the spectral angle cosine value between the reconstructed curves becomes more than 0.995, which proves that the spectral reconstruction under this algorithm has high stability. At the same time, the spectral angle cosine value of the spectral reconstruction curve and the standard curve can reach above 0.99, meaning that it realizes a high-precision spectral reconstruction effect. A high-precision spectral reconstruction algorithm based on truncated singular value-convex optimization, which is suitable for engineering applications, is established in this paper, providing important scientific research value for the engineering application of micro-spectrometers.
Wave glider is an unmanned surface vehicle that can directly convert wave energy into forward propulsion and fulfill long-term marine monitoring. A previous study suggested that the wave motion and ...stiffness of restoring springs mounted on the hydrofoil are the main factors affecting the propulsion performance of the wave glider. In this paper, the dynamic responses and nonlinear characteristics of the underwater propulsion mechanism considering the nonlinear stiffness of restoring springs are investigated based on a fluid–rigid body coupled model. Firstly, models of propulsion mechanism with different kinds of restoring springs are proposed, and the linear and nonlinear characteristics of the restoring spring are considered. Then, a fluid–rigid body coupled model of a wave glider is developed by coupling the rigid body dynamics model and hydrodynamic model. Dynamic responses are simulated by the numerical analysis method, and the nonlinear characteristics with different restoring springs are illustrated by the time/frequency domain motion response and phase diagram analysis. The effects of the wave excitation frequency, wave heights and the location of the connection point of springs on the propulsion performance of the wave glider are analyzed. The results show that multi-frequency responses occurred in the propulsion system, and the nonlinear restoring spring on the hydrofoil can provide a larger restoring moment to avoid excessive pitch angle and is more suitable for different sea conditions, which provides a reference for developing propulsion mechanisms with high performance in complex marine environments.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•The K-means algorithm is combined with the PSO algorithm to reduce the data dimension, and the number of filter arrays is reduced to 20.•The IReg-Cvx algorithm is suitable for high-precision ...spectral reconstruction of typical ground objects with slopes below 0.4.•Compared with the traditional Standard Regularization, the spectral reconstruction accuracy is improved by an order of magnitude in the large disturbance environment.
Recently, micro-spectrometer based on filter array has received extensive attention in terms of cost and size. Yet, the spectrometer will produce large noise in the work, which has a great impact on the spectral reconstruction. In this paper, a low-dimensional filter array is selected based on the K-means-PSO（Particle Swarm Optimization） method to achieve the purpose of data dimensionality reduction, which further reduces the cost and processing difficulty of the micro-spectrometer. To address the redundancy and poor accuracy of spectral reconstruction data obtained by micro-spectrometers, a convex optimization algorithm constrained by three-segment regularization of a low-rank-matrix (IReg-Cvx algorithm) was proposed for spectral reconstruction in this study. In order to test algorithm universality and stability better, we selected 120 kinds of ground spectral curves, and the low-dimensional filter array is fused with the IReg-Cvx algorithm. Apply the corresponding constraints according to the different slopes of the curve, and the high-quality spectral reconstruction of the ground object target spectrum can be stably realized under the noise environment of 30, 25, and 20 dB.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nanotechnology-based pesticide formulations would ensure effective utilization of agricultural inputs. In the present work, mesoporous silica nanoparticles (MSNs) with particle diameters of ~110 nm ...and pore sizes of ~3.7 nm were synthesized via a liquid crystal templating mechanism. A water-soluble chitosan (CS) derivative (
-(2-hydroxyl)propyl-3-trimethyl ammonium CS chloride, HTCC) was successfully capped on the surface of pyraclostrobin-loaded MSNs. The physicochemical and structural analyses showed that the electrostatic interactions and hydrogen bonding were the major forces responsible for the formation of HTCC-capped MSNs. HTCC coating greatly improved the loading efficiency (LC) (to 40.3%) compared to using bare MSNs as a single encapsulant (26.7%). The microstructure of the nanoparticles was revealed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The pyraclostrobin-loaded nanoparticles showed an initial burst and subsequent sustained release behavior. HTCC-capped MSNs released faster than bare MSNs in the initial stage. Pyraclostrobin-loaded HTCC-capped MSNs with half doses of pyraclostrobin technical demonstrated almost the same fungicidal activity against
(Sacc.), which obviously reduced the applied pesticide and enhanced the utilization efficiency. Therefore, HTCC-decorated MSNs demonstrated great potential as nanocarriers in agrochemical applications.
•The filter has the advantages of polarization insensitivity, ultrawide angle, high manufacturability, and easy integration.•For infrared spectrum reconstruction, the use of filters as spectral ...sampling channels can eliminate the influence of slits or complex optical splitting elements in spectral imaging technology.•IReg improves spectral reconstruction accuracy in largely disturbed environments.•Reduced data dimensionality, design flexibility, and lower difficulty and cost.
In this study, a broadband mid-infrared photonic filter is designed. It has the advantages of polarization insensitivity, ultrawide angle, high manufacturability, and easy integration. For infrared spectrum reconstruction, the use of filters as spectral sampling channels can eliminate the influence of slits or complex optical splitting elements in spectral imaging technology. Further, we propose a low-rank matrix logarithm regularization algorithm based on a three-segment filter function (IReg algorithm) combined with the designed filter for a variety of mid-infrared detector front ends, which can significantly suppress noise interference. Here, we demonstrate that the stability of the spectral reconstruction accuracy under the large disturbance environment obtained by the IReg algorithm is much higher than those of the L2 and L1 algorithms. In the low-dimensional matrix state, the accuracy and stability of the ill-conditioned linear equations are guaranteed, the anti-noise ability is enhanced, the effect of data dimensionality reduction is realized, and the accuracy of mid-infrared spectral reconstruction is improved.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
The resistance of Helicobacter pylori (H. pylori) to antibiotics is increasing worldwide, lowering its efficacy in current eradication therapies. This study evaluated H. pylori resistance ...to antibiotics in the southeast coastal region of China and suggests appropriate alternatives.
Materials and Methods
Seventeen thousand seven hundred and thirty one H. pylori strains were collected from eight areas of two provinces in coastal southeast China from 2010 to 2012. The resistance of these strains to six antibiotics was tested using the agar dilution method.
Results
The resistance rates to clarithromycin, metronidazole, levofloxacin, amoxicillin, gentamicin and furazolidone were 21.5, 95.4, 20.6, 0.1, 0.1 and 0.1%, respectively. Double, triple and quadruple antibacterial resistant percentages were 25.5, 7.5 and 0.1%, respectively. A positive association between the resistance to levofloxacin and to clarithromycin was found, but there was a negative correlation in the resistances to levofloxacin and to metronidazole.
Conclusions
The prevalence of H. pylori resistance to clarithromycin, metronidazole, levofloxacin and multiple antibiotics in coastal southeast China is high. Choice of therapy should be individualized based on a susceptibility test in this region of the country.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Cell-based therapies to treat retinal degeneration are now being tested in clinical trials. However, it is not known whether the source of stem cells is important for the production of differentiated ...cells suitable for transplantation. To test this, we generated induced pluripotent stem cells (iPSCs) from murine rod photoreceptors (r-iPSCs) and scored their ability to make retinae by using a standardized quantitative protocol called STEM-RET. We discovered that r-iPSCs more efficiently produced differentiated retinae than did embryonic stem cells (ESCs) or fibroblast-derived iPSCs (f-iPSCs). Retinae derived from f-iPSCs had fewer amacrine cells and other inner nuclear layer cells. Integrated epigenetic analysis showed that DNA methylation contributes to the defects in f-iPSC retinogenesis and that rod-specific CTCF insulator protein-binding sites may promote r-iPSC retinogenesis. Together, our data suggest that the source of stem cells is important for producing retinal neurons in three-dimensional (3D) organ cultures.
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•iPSCs can be produced from differentiated murine rod photoreceptors•Rod-derived iPSCs are more efficient at producing retina than fibroblast iPSCs•Retinae derived from murine fibroblast iPSCs have reduced INL cell populations•CTCF may contribute to epigenetic memory of rod-derived iPSCs
Cellular therapies to treat retinal degeneration are in clinical trials, but it is unclear how the stem cell source impacts the production of differentiated cells for transplantation. Hiler et al. show that iPSCs derived from retinal photoreceptors retain retinal epigenetic memory and make retina more efficiently than fibroblast iPSCs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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