| 1. |
- Yu, Wenjin, et al.
(författare)
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Deep Learning-Based Classification of Cancer Cell in Leptomeningeal Metastasis on Cytomorphologic Features of Cerebrospinal Fluid
- 2022
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 12, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is a critical challenge to diagnose leptomeningeal metastasis (LM), given its technical difficulty and the lack of typical symptoms. The existing gold standard of diagnosing LM is to use positive cerebrospinal fluid (CSF) cytology, which consumes significantly more time to classify cells under a microscope.Objective: This study aims to establish a deep learning model to classify cancer cells in CSF, thus facilitating doctors to achieve an accurate and fast diagnosis of LM in an early stage.Method: The cerebrospinal fluid laboratory of Xijing Hospital provides 53,255 cells from 90 LM patients in the research. We used two deep convolutional neural networks (CNN) models to classify cells in the CSF. A five-way cell classification model (CNN1) consists of lymphocytes, monocytes, neutrophils, erythrocytes, and cancer cells. A four-way cancer cell classification model (CNN2) consists of lung cancer cells, gastric cancer cells, breast cancer cells, and pancreatic cancer cells. Here, the CNN models were constructed by Resnet-inception-V2. We evaluated the performance of the proposed models on two external datasets and compared them with the results from 42 doctors of various levels of experience in the human-machine tests. Furthermore, we develop a computer-aided diagnosis (CAD) software to generate cytology diagnosis reports in the research rapidly.Results: With respect to the validation set, the mean average precision (mAP) of CNN1 is over 95% and that of CNN2 is close to 80%. Hence, the proposed deep learning model effectively classifies cells in CSF to facilitate the screening of cancer cells. In the human-machine tests, the accuracy of CNN1 is similar to the results from experts, with higher accuracy than doctors in other levels. Moreover, the overall accuracy of CNN2 is 10% higher than that of experts, with a time consumption of only one-third of that consumed by an expert. Using the CAD software saves 90% working time of cytologists.Conclusion: A deep learning method has been developed to assist the LM diagnosis with high accuracy and low time consumption effectively. Thanks to labeled data and step-by-step training, our proposed method can successfully classify cancer cells in the CSF to assist LM diagnosis early. In addition, this unique research can predict cancer’s primary source of LM, which relies on cytomorphologic features without immunohistochemistry. Our results show that deep learning can be widely used in medical images to classify cerebrospinal fluid cells. For complex cancer classification tasks, the accuracy of the proposed method is significantly higher than that of specialist doctors, and its performance is better than that of junior doctors and interns. The application of CNNs and CAD software may ultimately aid in expediting the diagnosis and overcoming the shortage of experienced cytologists, thereby facilitating earlier treatment and improving the prognosis of LM.
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| 2. |
- Hao, Jiaming, et al.
(författare)
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High performance optical absorber based on a plasmonic metamaterial
- 2010
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 96:25, s. 251104-
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Tidskriftsartikel (refereegranskat)abstract
- High absorption efficiency is particularly desirable at present for various microtechnological applications including microbolometers, photodectors, coherent thermal emitters, and solar cells. Here we report the design, characterization, and experimental demonstration of an ultrathin, wide-angle, subwavelength high performance metamaterial absorber for optical frequencies. Experimental results show that an absorption peak of 88% is achieved at the wavelength of similar to 1.58 mu m, though theoretical results give near perfect absorption. (C) 2010 American Institute of Physics. [doi: 10.1063/1.3442904]
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| 3. |
- Hao, Jiaming, et al.
(författare)
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Manipulate light polarizations by metamaterials : From microwave to optics
- 2008
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Ingår i: PROCEEDINGS OF THE 2008 INTERNATIONAL WORKSHOP ON METAMATERIALS. - NEW YORK : IEEE. ; , s. 89-89
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Konferensbidrag (refereegranskat)abstract
- Recently, artificially designed metamaterials have become of considerable interests, because they exhibit extraordinary optical characteristics that do not exist in nature and promise many potential applications, such as negative refraction, subwavelength imaging, and electromagnetic invisibility cloaking. Although creating metamaterials at the optical frequency range faces numerous technological challenges, such materials with particular properties have been realized gradually based on new device concepts. In this talk, we present our efforts to employ specific metamaterials to manipulate the polarization states of incident lights, in both microwave [1, 2] and optical frequency regimes [3]. Experimental results reveal that the maximum polarization conversion ratio (PGR) value can reach 100% in microwave regime (see left figure below) and 92% in optical frequency (see right figure blow) under certain conditions. Theoretical studies combined with numerical simulations show that the governing physics is dominated by the unique reflection properties of the metamaterials
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| 4. |
- Hao, Jiaming, et al.
(författare)
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Manipulate light polarizations with metamaterials : From microwave to visible
- 2010
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Ingår i: Frontiers of Physics in China. - : Springer Science and Business Media LLC. - 1673-3487 .- 1673-3606. ; 5:3, s. 291-307
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Tidskriftsartikel (refereegranskat)abstract
- Polarization is an important characteristic of electromagnetic (EM) waves, and efficient manipulations over EM wave polarizations are always desirable in practical applications. Here, we review the recent efforts in controlling light polarizations with metamaterials, at frequencies ranged from microwave to visible. We first presented a 4 x 4 version transfer matrix method (TMM) to study the scatterings by an anisotropic metamaterial of EM waves with arbitrary propagating directions and polarizations. With the 4 x 4 TMM, we discovered several amazing polarization manipulation phenomena based on the reflection geometry and proposed corresponding model metamaterial systems to realize such effects. Metamaterial samples were fabricated with the help of finite-difference-time-domain (FDTD) simulations, and experiments were performed to successfully realize these ideas at both microwave and visible frequencies. Efforts in employing metamaterials to manipulate light polarizations based on the transmission geometry are also reviewed.
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| 5. |
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| 6. |
- Hao, Jiaming, et al.
(författare)
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Nearly total absorption of light and heat generation by plasmonic metamaterials
- 2011
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 83:16, s. 165107-
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Tidskriftsartikel (refereegranskat)abstract
- We theoretically and numerically study the absorption effect and the heat generation in plasmonic metamaterials under light radiation at their plasmonic resonance. Three different types of structures, all possessing high-performance absorption for visible lights, are investigated. The main aim of this work is to present an intuitive and original understanding of the high-performance absorption effects. From the macroscopic electromagnetic point of view, the effective-medium approach is used to describe the absorption effects of the plasmonic metamaterials. On the other hand, the field distributions and heat generation effects in such plasmonic nanostructures are investigated, which also provides a satisfactory qualitative description of such absorption behavior based upon the microscopic perspective.
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| 7. |
- Hao, Jiaming, et al.
(författare)
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Optical metamaterial for polarization control
- 2009
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Ingår i: Physical Review A. Atomic, Molecular, and Optical Physics. - 1050-2947 .- 1094-1622. ; 80:2
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Tidskriftsartikel (refereegranskat)abstract
- We present the design, characterization, and modeling of a specific optical metamaterial, and employ it to manipulate the light polarizations at optical frequencies. Experimental results reveal that the maximum polarization conversion efficiency, i.e., the energy portion converted from s to p polarization after reflection, can be as high as 96% at the wavelength of similar to 685 nm. Simulations and analytical results, which are in reasonable agreements with the experimental results, reveal that the underlying physics are governed by the particular electric and magnetic resonances in the optical metamaterial.
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| 8. |
- Jiang, Jiwan, et al.
(författare)
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A Personalized Human Drivers' Risk Sensitive Characteristics Depicting Stochastic Optimal Control Algorithm for Adaptive Cruise Control
- 2020
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Ingår i: IEEE Access. - 2169-3536 .- 2169-3536. ; 8, s. 145056-145066
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents a personalized stochastic optimal adaptive cruise control (ACC) algorithm for automated vehicles (AVs) incorporating human drivers' risk-sensitivity under system and measurement uncertainties. The proposed controller is designed as a linear exponential-of-quadratic Gaussian (LEQG) problem, which utilizes the stochastic optimal control mechanism to feedback the deviation from the design car-following target. With the risk-sensitive parameter embedded in LEQG, the proposed method has the capability to characterize risk preference heterogeneity of each AV against uncertainties according to each human drivers' preference. Further, the established control theory can achieve both expensive control mode and non-expensive control mode via changing the weighting matrix of the cost function in LEQG to reveal different treatments on input. Simulation tests validate the proposed approach can characterize different driving behaviors and its effectiveness in terms of reducing the deviation from equilibrium state. The ability to produce different trajectories and generate smooth control of the proposed algorithm is also verified.
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| 9. |
- Li, Meng, et al.
(författare)
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A cooperative energy efficient truck platoon lane-changing model preventing platoon decoupling in a mixed traffic environment
- 2024
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Ingår i: Journal of Intelligent Transportation Systems. - : Informa UK Limited. - 1547-2442 .- 1547-2450. ; 28:2, s. 174-188
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Tidskriftsartikel (refereegranskat)abstract
- Truck platooning has gained increasing attention due to the benefits in energy and operation efficiency in freight transportation. One significant challenge for deploying truck platoons is the safe and efficient interaction with surrounding traffic, especially at freeway discontinuities where mandatory lane changes usually lead to the decoupling of truck platoons. This study proposes a cooperative truck platoon lane-changing model (CTPLC) to prevent the decoupling of truck platoons in a mixed traffic environment. Specifically, a two-step control strategy is presented, where vehicles in the target lane firstly cooperatively adjust speeds to create an appropriate gap for a truck platoon, and then trucks within the truck platoon conduct lane change sequentially. The cooperative speed profiles are generated by solving an optimization problem considering the lane-changing influence and energy consumption. Based on that, a two-dimensional nonlinear model predictive control (MPC) algorithm is employed to generate vehicular acceleration and steering angle for each truck. A series of numerical simulation experiments were conducted to validate the proposed strategy. As shown by the results, our proposed method truck platoon could conduct a lane change in a traffic-efficient and safe manner, and meanwhile, our method was more energy-efficient than a benchmark strategy.
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| 10. |
- Rasmussen, Michel, et al.
(författare)
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Enhanced cGMP Interactor Rap Guanine Exchange Factor 4 (EPAC2) Expression and Activity in Degenerating Photoreceptors: : A Neuroprotective Response?
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 23:9
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Tidskriftsartikel (refereegranskat)abstract
- The disease retinitis pigmentosa (RP) leads to photoreceptor degeneration by a yet undefined mechanism(s). In several RP mouse models (i.e., rd mice), a high cyclic GMP (cGMP) level within photoreceptors is detected, suggesting that cGMP plays a role in degeneration. The rap guanine exchange factor 4 (EPAC2) is activated by cyclic AMP (cAMP) and is an accepted cGMP-interacting protein. It is unclear whether and how cGMP interacts with EPAC2 in degenerating photoreceptors; we therefore investigated EPAC2 expression and interactions with cGMP and cAMP in retinas of the rd1 and rd10 models for retinal degeneration. EPAC2 expression in the photoreceptor layer increased significantly during rd1 and rd10 degeneration, and an increase in EPAC2 interactions with cGMP but not cAMP in the rd1 was also seen via a proximity ligation assay on histological sections. Retinal explant cultures revealed that pharmacological inhibition of the EPAC2 activity reduced the photoreceptor layer thickness in the rd10 retina, suggesting that EPAC2 inhibition promotes degeneration. Taken together, our results support the hypothesis that high degeneration-related cGMP leads to increased EPAC2 and cGMP interactions, inhibiting EPAC2. By inference, EPAC2 could have neuroprotective capacities that may be exploited in the future.
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| 11. |
- Roy, Akanksha, et al.
(författare)
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Integrative Kinase Activity Profiling and Phosphoproteomics of rd10 Mouse Retina during cGMP-Dependent Retinal Degeneration
- 2024
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Ingår i: International Journal of Molecular Sciences. - 1661-6596. ; 25:6
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Tidskriftsartikel (refereegranskat)abstract
- Inherited retinal degenerative diseases (IRDs) are a group of rare diseases that lead to a progressive loss of photoreceptor cells and, ultimately, blindness. The overactivation of cGMP-dependent protein kinase G (PKG), one of the key effectors of cGMP-signaling, was previously found to be involved in photoreceptor cell death and was studied in murine IRD models to elucidate the pathophysiology of retinal degeneration. However, PKG is a serine/threonine kinase (STK) with several hundred potential phosphorylation targets and, so far, little is known about the specificity of the target interaction and downstream effects of PKG activation. Here, we carried out both the kinome activity and phosphoproteomic profiling of organotypic retinal explant cultures derived from the rd10 mouse model for IRD. After treating the explants with the PKG inhibitor CN03, an overall decrease in peptide phosphorylation was observed, with the most significant decrease occurring in seven peptides, including those from the known PKG substrate cyclic-AMP-response-element-binding CREB, but also Ca2+/calmodulin-dependent kinase (CaMK) peptides and TOP2A. The phosphoproteomic data, in turn, revealed proteins with decreased phosphorylation, as well as proteins with increased phosphorylation. The integration of both datasets identified common biological networks altered by PKG inhibition, which included kinases predominantly from the so-called AGC and CaMK families of kinases (e.g., PKG1, PKG2, PKA, CaMKs, RSKs, and AKTs). A pathway analysis confirmed the role of CREB, Calmodulin, mitogen-activated protein kinase (MAPK) and CREB modulation. Among the peptides and pathways that showed reduced phosphorylation activity, the substrates CREB, CaMK2, and CaMK4 were validated for their retinal localization and activity, using immunostaining and immunoblotting in the rd10 retina. In summary, the integrative analysis of the kinome activity and phosphoproteomic data revealed both known and novel PKG substrates in a murine IRD model. This data establishes a basis for an improved understanding of the biological pathways involved in cGMP-mediated photoreceptor degeneration. Moreover, validated PKG targets like CREB and CaMKs merit exploration as novel (surrogate) biomarkers to determine the effects of a clinical PKG-targeted treatment for IRDs.
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| 12. |
- Wu, Jiaming, 1989, et al.
(författare)
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Stationary Condition Based Performance Analysis of the Contraflow Left-Turn Lane Design Considering the Influence of the Upstream Intersection
- 2021
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Ingår i: Transportation Research, Part C: Emerging Technologies. - : Elsevier BV. - 0968-090X. ; 122
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Tidskriftsartikel (refereegranskat)abstract
- The present study conducted an operational performance analysis of the contraflow left-turn lane (CLL) design considering the influence of the upstream signalized intersection. The arrival distribution was generated using a platoon dispersion model. A stationary condition was defined, in which the performance of the CLL design remained stable in any stationary cycle. It has proved that the CLL system always converges to the stationary condition after a few cycles if the arrival distribution is fixed. In stationary cycles, the CLL design generates either recurrent and constant residual queues or no queues, depending on the arrival distributions of left-turning vehicles. Based on the stationary condition, analytical models were developed to estimate the operational performance for left-turns at signalized intersections with the CLL design. The results show that both the arrival pattern and the length of the contraflow lane can significantly influence the operational performance of the CLL design. The residual queues in the stationary condition could increase control delay significantly, leading to an overlong delay of the left-turning vehicles if the contraflow lane was not carefully designed. To this end, an empirical optimization method was proposed to minimize the control delay by optimizing the length of contraflow lanes and the offset between adjacent intersections. The research results can be directly employed by traffic engineers to optimize the CLL design and to estimate the operational performance of the signalized intersections with the CLL design.
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| 13. |
- Wu, Jiaming, 1989, et al.
(författare)
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The cooperative sorting strategy for connected and automated vehicle platoons
- 2021
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Ingår i: Transportation Research, Part C: Emerging Technologies. - : Elsevier BV. - 0968-090X. ; 123
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents a "cooperative vehicle sorting" strategy that seeks to optimally sort connected and automated vehicles (CAVs) in a multi-lane platoon to reach an ideally organized platoon. In the proposed method, a CAV platoon is firstly discretized into a grid system, where a CAV moves from one cell to another in discrete time-space domain. Then, the cooperative sorting problem is modeled as a path-finding problem in the graphic domain. The problem is solved by the deterministic A* algorithm with a stepwise strategy, where only one vehicle can move within a movement step. The resultant shortest path is further optimized with an integer linear programming algorithm to minimize the sorting time by allowing multiple movements within a step. To improve the algorithm running time and address multiple shortest paths, a distributed stochastic A* algorithm (DSA*) is developed by introducing random disturbances to the edge costs to break uniform paths (with equal path cost). Numerical experiments are conducted to demonstrate the effectiveness of the proposed DSA* method. The results report shorter sorting time and significantly improved algorithm running time due to the use of DSA*. In addition, we find that the optimization performance can be further improved by increasing the number of processes in the distributed computing system.
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| 14. |
- Zhou, Fangting, 1993, et al.
(författare)
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Collaborative electric vehicle routing with meet points
- 2024
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Ingår i: Communications in Transportation Research. - 2772-4247.
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, we develop a profit-sharing-based optimal routing mechanism to incentivize horizontal collaboration among urban goods distributors. The core of this mechanism is based on exchanging goods at meet points, which is optimally planned en route. We propose a Collaborative Electric Vehicle Routing Problem with Meet Points (CoEVRPMP) considering constraints such as time windows, opportunity charging, and meet-point synchronization. The proposed CoEVRPMP is formulated as a mixed-integer nonlinear programming model. We present an exact method via branching and a matheuristic that combines adaptive large neighborhood search with linear programming. The viability and scalability of the collaborative method are demonstrated through numerical case studies, including a real-world case and a large-scale experiment with up to 500 customers. The findings underscore the significance of horizontal collaboration among delivery companies in attaining both higher individual profits and lower total costs. Moreover, collaboration helps to reduce the environmental footprint by decreasing travel distance.
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| 15. |
- Zhou, Jiaming, et al.
(författare)
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A Potential Neuroprotective Role for Pyruvate Kinase 2 in Retinal Degeneration
- 2023
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Ingår i: Retinal Degenerative Diseases XIX : Mechanisms and Experimental Therapy - Mechanisms and Experimental Therapy. - 9783031276804 - 9783031276811 ; 1415, s. 479-483
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Bokkapitel (refereegranskat)abstract
- Retinitis pigmentosa (RP) is an inherited disorder that results in vision impairment that specific therapeutic strategies are not available. However, it is widely regarded that the cGMP system, including cGMP and its interactor cGMP-dependent protein kinase (PKG), acts as a crucial effector during retinal degeneration. We have previously identified a list of cGMP-PKG-dependent genes in the context of RP, and in this study, we further validated one of the targets, namely, pyruvate kinase 2 (PKM2), and investigated the potential role of PKM2 for the photoreceptors’ well-being during RP. With the aid of organotypic retinal explant cultures, we pharmacologically manipulated the PKM2 activities in different RP mouse models via the addition of TEPP-46 (a PKM2 activator) and found that activation of PKM2 alleviates the progress of photoreceptor death in the rd10 mouse model. This observation provides supportive evidence that PKM2 may serve as a novel potential molecular target in RP.
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| 16. |
- Zhou, Jiaming, et al.
(författare)
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A Potential Role of Cyclic Dependent Kinase 1 (CDK1) in Late Stage of Retinal Degeneration
- 2022
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 11:14
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Tidskriftsartikel (refereegranskat)abstract
- Cyclin dependent kinase 1 (CDK1) has long been known to drive the cell cycle and to regulate the division and differentiation of cells. Apart from its role in mitosis regulation, it also exerts multiple functions as a protein kinase, including engagement in cell death, possibly via a cell cycle-independent mechanism. The latter is suggested, since CDK1 re-expression can be found in non-dividing and terminally differentiated neurons in several neurodegeneration models. However, the details of if and how CDK1 might be involved in the neurodegenerative condition, retinitis pigmentosa (RP), which displays progressive vision loss, are unclear. In the present study, we investigated CDK1 in degenerating RP photoreceptors of the rd1 RP model, including whether there is a link between this kinase and the cGMP-PKG system, which is regarded as a disease driver. With experiments performed using either in vivo retinal tissue or in vitro material, via organotypic retinal explants, our results showed that CDK1 appears in the photoreceptors at a late stage of their degeneration, and in such a position, it may be associated with the cGMP-PKG network.
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| 17. |
- Zhou, Jiaming, et al.
(författare)
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cGMP-PKG dependent transcriptome in normal and degenerating retinas: Novel insights into the retinitis pigmentosa pathology
- 2021
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Ingår i: Experimental Eye Research. - : Elsevier BV. - 0014-4835. ; 212
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Tidskriftsartikel (refereegranskat)abstract
- Retinitis Pigmentosa represents a group of genetic disorders that cause progressive vision loss via degeneration of pho8toreceptors, but there is in principle no treatment available. For any therapy development, a deeper comprehension of the dis9ease-leading mechanism(s) at the molecular level is needed. Here we focused on the cGMP-PKG system, which has been suggested10 to be a driver in several models of the disease. To gain insights in its downstream signaling we manipulated the cGMP-PKG system11 with the aid of organotypic retinal explant cultures from either a mouse-based disease model, i.e. the rd1 mouse, or its healthy12 wild-type counterpart (wt), by adding different types of cGMP analogues to either inhibit or activate PKG in retinal explants from13 rd1 and wt, respectively. An RNA sequencing was then performed to study the cGMP-PKG dependent transcriptome. Expression14 changes of gene sets related to specific pathways or functions, that fulfilled criteria involving that the changes should match PKG15 activation and inhibition, were determined via bioinformatics. The analyses highlighted that several gene sets linked to oxidative16 phosphorylation and mitochondrial pathways were regulated by this enzyme system. Specifically, the expression of such pathway17 components was upregulated in the rd1 treated with PKG inhibitor and downregulated in the wt with PKG activator treatment,18 suggesting that cGMP-PKG act as a negative regulator in this context. Downregulation of energy production pathways may thus19 play an integral part in the mechanism behind the degeneration for at least several RP mutations.
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| 18. |
- Zhou, Jiaming
(författare)
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Genes and proteins controlled by cGMP-PKG during retinal degeneration
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- prevalence was reported as 1:3000-4000 worldwide, making it the main reason for blindness in the working population in industrial countries. The mutations of over 70 genes have been related to this genetic disorder, and there is generally no effective treatment, except for gene therapy for the RPE65 mutations. Hence, new molecular targets are required for novel treatment development. The signaling molecule cGMP and its dependent protein kinase G (cGMP-PKG) have been regarded as one of theprime effectors to drive the disease. However, the insights into the downstream signaling of the system, are still unclear. This thesis aimed to explore the cGMP-PKG-dependent transcriptome and proteome.The Paper I showed the cGMP-PKG-dependent transcriptome in this study. Applying RNA sequencing to study the retinal explants from the diseased rd1 models and WT with cGMP-PKG manipulation, I identified the cGMP-PKG-dependent genes and proposed that this system may negatively regulate oxidative phosphorylation and mitochondrial pathways, which may affect retinal degeneration.The paper II investigated the cGMP-PKG phosphoproteome. The phosphorylated peptide enrichment and mass-spectrometry were applied to explore the cGMP-PKG-dependent phosphoproteome within rd1 retinal explants with PKG inhibition or not. I identified a list of cGMP-PKG-dominated phosphorylations and picked up RAF1 proto-oncogene, serine/threonine kinase (RAF1) for further validation. This suggested that RAF1 may be involved in retinal degeneration, although in an as yet unclear mechanism.The Paper III investigated cGMP-PKG-dependent kinase activity profiling and the phosphoproteome with a microarray-based technique and mass-spectrometry, respectively. The rd10 model, with a different mutation in the gene for PDE6 was used. This yielded the lists of cGMP-PKG-dependent kinase and phosphorylations, which were partially compatible with Paper II. Also, this showed that Ca2+/calmodulindependent protein kinase II and IV (CaMK2, CaMK4) may play a role during retinal degeneration.Paper IV focused on cyclin-dependent kinase 1 (CDK1), which was identified from Paper II, namely, and investigated if it has effects on retinal degeneration. The data showed that CDK1 participates in the late stage of retinal degeneration, and also provided a link between this enzyme and the cGMP-PKG system.The Paper V validated another target, pyruvate kinase isozyme M2 (PKM2) identified in the previous transcriptome study. The PKM2 within retinas was activated from two disease models, namely rd2 and rd10 in a pharmacological manner during explant culture. I observed that PKM2 activation in rd10 alleviated the photoreceptor degeneration while no difference was noticed in rd2 under treatment.All in all, this thesis provides novel insights about cGMP-PKG-dependent targets, which may have a role during photoreceptor degeneration and cast light on the therapeutic development of this retinal disease.
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| 19. |
- Zhou, Jiaming, et al.
(författare)
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Pyruvate Kinase 2, an Energy Metabolism Related Enzyme, May Have a Neuroprotective Function in Retinal Degeneration
- 2023
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Ingår i: ASN Neuro. - : SAGE Publications. - 1759-0914. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Retinitis pigmentosa (RP) is an inherited disorder that results in vision impairment but general and mutation-independent therapeutic strategies are not available. However, it is widely regarded that the cGMP system, including cGMP and its interactor cGMP-dependent protein kinase (PKG), acts as a crucial effector during retinal degeneration. We have previously identified a list of cGMP-PKG-dependent genes in the context of RP, and in this study, we further validated one of these, namely pyruvate kinase 2 (PKM2), and investigated the potential role of PKM2 for the photoreceptors’ well-being during RP. With the aid of organotypic retinal explant cultures, we pharmacologically manipulated the PKM2 activities in two different RP mouse models (rd2 and rd10) via the addition of TEPP-46 (a PKM2 activator) and found that activation of PKM2 alleviates the progress of photoreceptor death in the rd10 mouse model. We also noted that the expression of both PKM2 and one of its targets, glucose transporter-1 (Glut1), showed alterations depending on the degeneration state. The observations provide supportive evidence that PKM2 may serve as a novel potential molecular target in RP.
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| 20. |
- Zhou, Jiaming, et al.
(författare)
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The Phosphoproteome of the Rd1 Mouse Retina, a Model of Inherited Photoreceptor Degeneration, Changes after Protein Kinase G Inhibition
- 2023
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Ingår i: International Journal of Molecular Sciences. - 1661-6596. ; 24:12
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Tidskriftsartikel (refereegranskat)abstract
- Retinitis pigmentosa (RP) is a frequent cause of blindness among the working population in industrial countries due to the inheritable death of photoreceptors. Though gene therapy was recently approved for mutations in the RPE65 gene, there is in general no effective treatment presently. Previously, abnormally high levels of cGMP and overactivation of its dependent protein kinase (PKG) have been suggested as causative for the fatal effects on photoreceptors, making it meaningful to explore the cGMP-PKG downstream signaling for more pathological insights and novel therapeutic target development purposes. Here, we manipulated the cGMP-PKG system in degenerating retinas from the rd1 mouse model pharmacologically via adding a PKG inhibitory cGMP-analogue to organotypic retinal explant cultures. A combination of phosphorylated peptide enrichment and mass spectrometry was then applied to study the cGMP-PKG-dependent phosphoproteome. We identified a host of novel potential cGMP-PKG downstream substrates and related kinases using this approach and selected the RAF1 protein, which may act as both a substrate and a kinase, for further validation. This showed that the RAS/RAF1/MAPK/ERK pathway may be involved in retinal degeneration in a yet unclarified mechanism, thus deserving further investigation in the future.
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