The migrasome as a developmental learning paradigm in cell biology.

Migrasome is a newly discovered organelle composed of small vesicular structures enclosed in membrane structures. Since its discovery in 2014, migrasome has attracted increasing attention in cell biology due to its critical role in multiple disease processes. Its pivotal role in various disease processes, including cell migration, intercellular communication, removal of damaged mitochondria, embryogenesis localization, immune cell chemotaxis, and virus transmission, underscores its significance in biological systems. With research on migrasome steadily increasing, it becomes a unique resource for undergraduate cell biology education. For deeper understanding of migrasome, we applied a bibliometric approach. Here we conducted a comprehensive analysis of migrasome research by retrieving relevant literature from databases such as Web of Science, Scopus, and PubMed using the keywords "migrasome" or "migrasomes." Employing CiteSpace software and Prism, we analyzed annual publication trends, identified core authors and institutions, assessed national contributions, examined keywords, and scrutinized highly cited literature related to migrasome research. This study presents a comprehensive overview of migrasome research, elucidating its literature characteristics, key contributors, research hotspots, and emerging trends. By shedding light on the current status and future trajectories of migrasome research, we aim to provide valuable insights for teachers in cell biology education. We propose for the integration of migrasome research into undergraduate curricula to enhance the understanding of cell biology among premedical, medical, and biomedical students, thereby fostering a deeper appreciation for the intricate mechanisms governing cellular behavior and disease processes.

Compatibility of vivianite-crystallization pathway of phosphorus recovery with anaerobic digestion systems of thermally hydrolyzed sludge.

Phosphorus in sewage is mostly enriched in activated sludge in wastewater treatment plants, making excess sludge an appropriate material for phosphorus recovery. The potential of vivianite (Fe3(PO4)2·8H2O) crystallization-based phosphorus recovery during the anaerobic digestion of thermally hydrolyzed sludge was discussed with influences of organic compounds on the formation of vivianite crystals being investigated in detail. Bovine serum albumin, humic acids and alginate, as model compounds of proteins, humic acids and polysaccharides, all inhibited vivianite crystallization, with the influence of humic acids being the most significant. A sludge retention time of >12 d for effective degradation of organic compounds and a certain degree of FeII excess are suggested to decrease the organics resulting inhibition. The results demonstrate the compatibility of vivianite-crystallization pathway of phosphorus recovery with anaerobic sludge digesters, and reveal the complexity of vivianite formation in the sludge with further research warranted to minimize the inhibitory influences.

Lattice thermal conductivity of embedded nanoparticle composites: the role of particle size distribution.

Nanoparticles embedded within a crystalline solid serve as impurity phonon scattering centers that reduce lattice thermal conductivity, a desirable result for thermoelectric applications. Most studies of thermal transport in nanoparticle-laden composite materials have assumed the nanoparticles to possess a single size. If there is a distribution of nanoparticle sizes, how is thermal conductivity affected? Moreover, is there a best nanoparticle size distribution to minimize thermal conductivity? In this work, we study the thermal conductivity of nanoparticle-laden composites through a molecular dynamics approach which naturally captures phonon scattering processes more rigorously than previously used analytical theories. From thermal transport simulations of a systematic variety of nanoparticle configurations, we empirically formulate how nanoparticle size distribution, particle number density, and volume fraction affect the lattice thermal conductivity. We find at volume fractions below 10%, the particle number density is by far the most impactful factor on thermal conductivity and at fractions above 10%, the effect of the size distribution and number density is minimal compared to the volume fraction. In fact, upon comparisons of configurations with the same particle number density and volume fractions, the lattice thermal conductivity of a single nanoparticle size can be lower than that of a size distribution which contradicts intuitions that a single size would attenuate phonon transport less than a spectrum of sizes. The random alloy, which can be considered as a single size configuration of maximum particle number density where the nanoparticle size is equal to the lattice constant, is the most performant in thermal conductivity reduction at volume fractions below 10%. We conclude that nanoparticle size distribution only plays a minor role in affecting lattice thermal conductivity with the particle number density and volume fraction being the more significant factors that should be considered in fabrication of nanoparticle-laden composites for potential improved thermoelectric performance.

Temporal-spatial distributions of road silt loadings and fugitive road dust emissions in Beijing from 2019 to 2020.

Road silt loading (sL) is an important parameter in the fugitive road dust (FRD) emissions. In this study, the improved Testing Re-entrained Aerosol Kinetic Emissions from Roads (TRAKER) combined with the AP-42 method was firstly developed to quickly measure and estimate the sLs of paved roads in Beijing, China. The annual average sLs in Beijing was 0.59±0.31 g/m2 in 2020, and decreased by 22.4% compared with that in 2019. The seasonal variations of sLs followed the order of spring > winter > summer > autumn in the two years. The seasonal mean road sLs on the same type road in the four seasons presented a decline trend from 2019 to 2020, especially on the Express way, decreasing 47.4%-72.7%. The road sLs on the different type roads in the same season followed the order of Major arterial ∼ Minor arterial ∼ Branch road > Express road, and Township road ∼ Country highway > Provincial highway ∼ National highway. The emission intensities of PM10 and PM2.5 from FRD in Beijing in 2020 were lower than those in 2019. The PM10 and PM2.5 emission intensities at the four planning areas in the two years all presented the order of the capital functional core area > the urban functional expansion area > the urban development new area > the ecological conservation and development area. The annual emissions of PM10 and PM2.5 from FRD in Beijing in 2020 were 74,886 ton and 18,118 ton, respectively, decreasing by ∼33.3% compared with those in 2019.

G-quadruplex ligands inhibit chikungunya virus replication.

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus affecting human health globally. G-quadruplex secondary structures attract great attention as potential targets for antiviral strategy. In this study, we show that the CHIKV genome possesses several conserved potential G-quadruplex sequences. G-quadruplex ligands BRACO-19 and TMPyP4 could stabilize the CHIKV G-quadruplex and inhibit the transcription of constructs containing CHIKV G-quadruplex sequences. Importantly, BRACO-19 and TMPyP4 suppress CHIKV replication. Our study not only reinforces the presence of viral G-quadruplex sequences but also suggests that targeting G-quadruplex structure could represent a novel strategy to inhibit CHIKV.

Dose-Related Structural Effects of Photodynamic Therapy on Rabbit Choroidal Structure.

INTRODUCTION: Photodynamic therapy with verteporfin (vPDT) has been shown to be effective against central serous chorioretinopathy (CSC) and was the preferred therapeutic for CSC treatment. However, alterations in choroidal structure after PDT were reported, and these effects were dose-dependent. This study aimed to compare the changes in choroidal structure after PDT with different doses of verteporfin in rabbits and may provide individualized therapeutic guidance for patients who failed to respond to initial half-dose vPDT. METHODS: The full dose of verteporfin used in CSC was 6 mg/m2, which was used in patients with neovascular age-related macular degeneration. Laser fluence was 50 J/cm2 (irradiance, 600 mW/cm2, 83 s). There were 4 different dose groups in this study (100%, 70%, 50%, and 30%). The alterations were examined at 1 day, 1 week, and 1 month after vPDT using color fundus imaging, indocyanine green angiography, and histopathology analysis. RESULTS: Various degrees of choroidal alterations were demonstrated at different dose groups. Examinations on day 1 showed that gradually reduced verteporfin dose tended to decrease photochemical reactions to the choroid in terms of the number of occlusion vessels and area of the lesion. After 1 month, choroid vessel alteration persisted in high-dose groups (100% and 70%); nevertheless, alterations of low-dose groups (50% and 30%) returned to normal. CONCLUSIONS: vPDT can induce photochemical reactions of the choroid, high dose causes permanent change, and low dose causes recoverable change. The dose-dependent alterations need to be considered for the individual therapeutic plan according to the situation of a patient with CSC.

TCEA1 regulates the proliferative potential of mouse myeloid cells.

Leukemia is a malignance with complex pathogenesis and poor prognosis. Discovery of noval regulators amenable to leukemia could be of value to gain insight into the pathogenesis, diagnosis and prognosis of leukemia. Here, we conducted a large-scale shRNA library screening for functional regulators in the development of myeloid cells in primary cells. We identified eighteen candidate regulators in the primary screening. Those genes cover a wide range of cellular functions, including gene expression regulation, intracellular signaling transduction, nucleotide excision repair, cell cycle control and transcription regulation. In both primary screening and validation, shRNAs targeting Tcea1, encoding the transcription elongation factor A (SII) 1, exhibited the greatest influence on the proliferative potential of cells. Knocking down the expression of Tcea1 in the 32Dcl3 myeloid cell line led to enhanced proliferation of myeloid cells and blockage of myeloid differentiation induced by G-CSF. In addition, silence of Tcea1 inhibited apoptosis of myeloid cells. Thus, Tcea1 was identified as a gene which can influence the proliferative potential, survival and differentiation of myeloid cells. These findings have implications for how transcriptional elongation influences myeloid cell development and leukemic transformation.

Genetic-algorithm-optimized wideband on-chip polarization rotator with an ultrasmall footprint.

Polarization control of light waves is an important technique in optical communication and signal processing. On-chip polarization rotation from the fundamental transverse-electric (TE00) mode to the fundamental transverse-magnetic (TM00) mode is usually difficult because of their large effective refractive index difference. Here, we demonstrate an on-chip wideband polarization rotator designed with a genetic algorithm to convert the TE00 mode into the TM00 mode within a footprint of 0.96 µm ×4.2 µm. In simulation, the optimized structure achieves polarization rotation with a minimum conversion loss of 0.7 dB and the 1-dB bandwidth of 157 nm. Experimentally, our fabricated devices have demonstrated the expected polarization rotation with a conversion loss of ∼2.5 dB in the measured wavelength range of 1440-1580 nm, where the smallest value reaches ∼2 dB. The devices can serve as a generic approach and standard module for controlling light polarization in integrated photonic circuitry.

Genome-wide identification and characterization of the apple (Malus domestica) HECT ubiquitin-protein ligase family and expression analysis of their responsiveness to abiotic stresses.

The ubiquitin-protein ligases (E3s) directly participate in ubiquitin (Ub) transferring to the target proteins in the ubiquitination pathway. The HECT ubiquitin-protein ligase (UPL), one type of E3s, is characterized as containing a conserved HECT domain of approximately 350 amino acids in the C terminus. Some UPLs were found to be involved in trichome development and leaf senescence in Arabidopsis. However, studies on plant UPLs, such as characteristics of the protein structure, predicted functional motifs of the HECT domain, and the regulatory expression of UPLs have all been limited. Here, we present genome-wide identification of the genes encoding UPLs (HECT gene) in apple. The 13 genes (named as MdUPL1-MdUPL13) from ten different chromosomes were divided into four groups by phylogenetic analysis. Among these groups, the encoding genes in the intron-exon structure and the included additional functional domains were quite different. Notably, the F-box domain was first found in MdUPL7 in plant UPLs. The HECT domain in different MdUPL groups also presented different spatial features and three types of conservative motifs were identified. The promoters of each MdUPL member carried multiple stress-response related elements by cis-acting element analysis. Experimental results demonstrated that the expressions of several MdUPLs were quite sensitive to cold-, drought-, and salt-stresses by qRT-PCR assay. The results of this study helped to elucidate the functions of HECT proteins, especially in Rosaceae plants.

Structural requirements for the collagenase and elastase activity of cathepsin K and its selective inhibition by an exosite inhibitor.

Human cathepsin K (CatK) is a major drug target for the treatment of osteoporosis. Although its collagenase activity is unique, CatK also exerts a potent elastolytic activity that is shared with human cathepsins V and S. Other members of the cysteine cathepsin family, which are structurally similar, do not exhibit significant collagen and elastin degrading activities. This raises the question of the presence of specific structural elements, exosites, that are required for these activities. CatK has two exosites that control its collagenolytic and elastolytic activity. Modifications of exosites 1 and 2 block the elastase activity of CatK, whereas only exosite-1 alterations prevent collagenolysis. Neither exosite affects the catalytic activity, protease stability, subsite specificity of CatK or the degradation of other biological substrates by this protease. A low-molecular-mass inhibitor that docks into exosite-1 inhibits the elastase and collagenase activity of CatK without interfering with the degradation of other protein substrates. The identification of CatK exosites opens up the prospect of designing highly potent inhibitors that selectively inhibit the degradation of therapeutically relevant substrates by this multifunctional protease.

Genome-wide characterization and analysis of F-box protein-encoding genes in the Malus domestica genome.

The F-box protein family is a large family that is characterized by conserved F-box domains of approximately 40-50 amino acids in the N-terminus. F-box proteins participate in diverse cellular processes, such as development of floral organs, signal transduction and response to stress, primarily as a component of the Skp1-cullin-F-box (SCF) complex. In this study, using a global search of the apple genome, 517 F-box protein-encoding genes (F-box genes for short) were identified and further subdivided into 12 groups according to the characterization of known functional domains, which suggests the different potential functions or processes that they were involved in. Among these domains, the galactose oxidase domain was analyzed for the first time in plants, and this domain was present with or without the Kelch domain. The F-box genes were distributed in all 17 apple chromosomes with various densities and tended to form gene clusters. Spatial expression profile analysis revealed that F-box genes have organ-specific expression and are widely expressed in all organs. Proteins that contained the galactose oxidase domain were highly expressed in leaves, flowers and seeds. From a fruit ripening expression profile, 166 F-box genes were identified. The expressions of most of these genes changed little during maturation, but five of them increased significantly. Using qRT-PCR to examine the expression of F-box genes encoding proteins with domains related to stress, the results revealed that F-box proteins were up- or down-regulated, which suggests that F-box genes were involved in abiotic stress. The results of this study helped to elucidate the functions of F-box proteins, especially in Rosaceae plants.

Application of sliding mode variable structure control algorithm in PMSM vector control system in complex environment.

In order to meet the increasing demand of high-performance control in industrial production, a new sliding mode variable structure control algorithm, Asymptotic Sliding Mode Control (ASMC), is designed in this study to solve the serious chattering problem of sliding mode control. Firstly, a traditional sliding mode exponential approximation law control model and a state space and control function are constructed based on sliding mode control. Secondly, by eliminating the jitter factor, ASMC algorithm is combined with sliding mode control to achieve precise control of permanent magnet synchronous motor (PMSM) and improve its performance. The experimental results indicated that in the simulation experiment, the research system tended to stabilize within 0.2-0.3 seconds, and the system chattering was significantly suppressed. And its output was smoother, the jitter amplitude was significantly reduced by 1/3, and the output torque was more stable. In addition, when the parameter H0 changed to 2H0, the overall speed curve did not change much, with only a slight overshoot. The overshoot was only 2.8%, and the change amplitude was maintained at around 25r/min, indicating that the research system had strong self stability performance. In actual experiments, the current command oscillation of the research system was significantly reduced. The local graph showed that the output fluctuation amplitude of the asymptotic approach law actual control was significantly smaller under no-load disturbance. When the H0 changed towards 2H0, the actual adjustment time was about 0.1 seconds, which was consistent with the simulation experiment. Therefore, the contribution of the research is that the ASMC algorithm can suppress the chattering problem of the system and improve the approaching speed, thus improving the speed regulation quality of the system. This new algorithm has great theoretical and practical significance for improving the performance of PMSM, and is practical in the actual vector control system of PMSM.

Remarkable improvement of symptoms and signs of severe dry eye treated by ocular immersion hydrotherapy.

Key Clinical Message: Traditional treatment options are often insufficient in treating severe dry eyes caused by systemic diseases. This case demonstrates that ocular immersion hydrotherapy significantly alleviated symptoms and ocular surface inflammation in ocular graft-versus-host disease. Based on these findings, we propose it as a promising option for managing severe dry eye disease. Abstract: This case report investigates the efficacy of ocular immersion hydrotherapy (OIH) in treating severe dry eye secondary to ocular graft-versus-host disease (oGVHD). A 35-year-old female with a history of acute myeloid leukemia-M2 and subsequent hematopoietic stem cell transplantation (HSCT) developed high-intensity oGVHD unresponsive to conventional treatments, including topical corticosteroids and lubricants. We introduced OIH, utilizing sterilized swimming goggles filled with intraocular irrigating solutions, providing a moist microenvironment for the ocular surface. Symptoms were significantly relieved after treatment. Corneal filaments and epithelial defects were significantly reduced, and in vivo confocal microscopy (IVCM) demonstrated resolution of inflammation and reappearance of corneal nerves. This case indicates that OIH could be a promising therapeutic approach for severe dry eye conditions arising from oGVHD, particularly for patients refractory to traditional treatments. Further studies are warranted to elucidate the long-term benefits and mechanisms of OIH in oGVHD management.

Tailored chitosan/glycerol micropatterned composite dressings by 3D printing for improved wound healing.

Wound infection control is a primary clinical concern nowadays. Various innovative solutions have been developed to fabricate adaptable wound dressings with better control of infected wound healing. This work presents a facile approach by leveraging 3D printing to fabricate chitosan/glycerol into composite dressings with tailored micropatterns to improve wound healing. The bioinks of chitosan/glycerol were investigated as suitable for 3D printing. Then, three tailored micropatterns (i.e., sheet, strip, and mesh) with precise geometry control were 3D printed onto a commercial dressing to fabricate the micropatterned composite dressings. In vitro and in vivo studies indicate that these micropatterned dressings could speed up wound healing due to their increased water uptake capacity (up to ca. 16-fold@2 min), benign cytotoxicity (76.7 % to 90.4 % of cell viability), minor hemolytic activity (<1 %), faster blood coagulation effects (within 76.3 s), low blood coagulation index (14.5 % to 18.7 % @ 6 min), enhanced antibacterial properties (81.0 % to 86.1 % against S. aureus, 83.7 % to 96.5 % against E. coli), and effective inhibition of wound inflammation factors of IL-1ß and TNF-α. Such tailored micropatterned composite dressing is facile to obtain, highly reproducible, and cost-efficient, making it a promising implication for improved and personalized contaminated wound healing.

Oxidized cellulose-filled double thermo/pH-sensitive hydrogel for local chemo-photothermal therapy in breast cancer.

Lumpectomy plus radiation is a treatment option offering better survival than conventional mastectomy for patients with early-stage breast cancer. However, successive radioactive therapy remains tedious and unsafe with severe adverse reactions and secondary injury. Herein, a composite hydrogel with pH- and photothermal double-sensitive activity is developed via physical crosslinking. The composite hydrogel incorporated with tempo-oxidized cellulose nanofiber (TOCN), polyvinyl alcohol (PVA) and a polydopamine (PDA) coating for photothermal therapy (PTT) triggered in situ release of doxorubicin (DOX) drug was utilized to optimize postoperative strategies of malignant tumors inhibition. The incorporation of TOCN significantly affects the performance of composite hydrogels. The best-performing TOCN/PVA7 was selected for drug loading and polydopamine coating by rational design. In vitro studies have demonstrated that the composite hydrogel exhibited high NIR photothermal conversion efficiency, benign cytotoxicity to L929 cells, pH-dependent release profiles, and strong MCF-7 cell inhibitory effects. Then the TOCN/PVA7-PDA@DOX hydrogel is implanted into the tumor resection cavity for local in vivo chemo-photothermal synergistical therapy to ablate residue tumor tissues. Overall, this work suggests that such a chemo-photothermal hydrogel delivery system has great potential as a promising tool for the postsurgical management of breast cancer.

Motor Behavior Regulation of Rat Robots Using Integrated Electrodes Stimulated by Micro-Nervous System.

As a cutting-edge technology, animal robots based on living organisms are being extensively studied, with potential for diverse applications in the fields of neuroscience, national security, and civil rescue. However, it remains a significant challenge to reliably control the animal robots with the objective of protecting their long-term survival, and this has seriously hindered their practical implementation. To address this issue, this work explored the use of a bio-friendly neurostimulation system that includes integrated stimulation electrodes together with a remote wireless stimulation circuit to control the moving behavior of rat robots. The integrated electrodes were implanted simultaneously in four stimulation sites, including the medial forebrain bundle (MFB) and primary somatosensory cortex, barrel field (S1BF). The control system was able to provide flexibility in adjusting the following four stimulation parameters: waveform, amplitude, frequency, and duration time. The optimized parameters facilitated the successful control of the rat's locomotion, including forward movement and left and right turns. After training for a few cycles, the rat robots could be guided along a designated route to complete the given mission in a maze. Moreover, it was found that the rat robots could survive for more than 20 days with the control system implanted. These findings will ensure the sustained and reliable operation of the rat robots, laying a robust foundation for advances in animal robot regulation technology.

An optimized EEGNet decoder for decoding motor image of four class fingers flexion.

As a cutting-edge technology of connecting biological brain and external devices, brain-computer interface (BCI) exhibits promising applications on extensive fields such as medical and military. As for the disable individuals with four limbs losing the motor functions, it is a potential treatment way to drive mechanical equipments by the means of non-invasive BCI, which is badly depended on the accuracy of the decoded electroencephalogram (EEG) singles. In this study, an explanatory convolutional neural network namely EEGNet based on SimAM attention module was proposed to enhance the accuracy of decoding the EEG singles of index and thumb fingers for both left and right hand using sensory motor rhythm (SMR). An average classification accuracy of 72.91% the data of eight healthy subjects was obtained, which were captured from the one second before finger movement to two seconds after action. Furthermore, the character of event-related desynchronization (ERD) and event related synchronization (ERS) of index and thumb fingers was also studied in this study. These findings have significant importance for controlling external devices or other rehabilitation equipment using BCI in a fine way.

A chloroplast membrane protein LTO1/AtVKOR involving in redox regulation and ROS homeostasis.

KEY MESSAGE: The role of LTO1/ At VKOR-DsbA in ROS homeostasis and in redox regulation of cysteine-containing proteins in chloroplast was studied in lto1 - 2 mutant, and a potential target of LTO1 was captured. A chloroplast membrane protein LTO1/AtVKOR-DsbA encoded by the gene At4g35760 was recently found to be an oxidoreductase and involved in assembly of PSII. Here, the growth of a mutant lto1-2 line of Arabidopsis was found to be severely stunted and transgenic complementation ultimately demonstrated the phenotype changes were due to this gene. A proteomic experiment identified 23 proteins presenting a differential abundance in lto1-2 compared with wild-type plants, including components in PSII and proteins scavenging active oxygen. Three scavengers of active oxygen, L-ascorbate peroxidase 1, peroxisomal catalase 2, dehydroascorbate reductase 1, are reduced in lto1-2 plants, corresponding to high levels of accumulation of reactive oxygen species (ROS). The photosynthetic activities of PSII and the quantity of core protein D1 decreased significantly in lto1-2. Further investigation showed the synthesis of D1 was not affected in mutants both at transcription and translation levels. The soluble DsbA-like domain of LTO1 was found to have reduction, oxidation and isomerization activities, and could promote the formation of disulfide bonds in a lumenal protein, FKBP13. A potential target of LTO1 was captured which was involving in chlorophyll degradation and photooxidative stress response. Experimental results imply that LTO1 plays important roles in redox regulation, ROS homeostasis and maintenance of PSII.

Heterologous Expression and Function of Cholesterol Oxidase: A Review.

Cholesterol was first found in gallstones as an animal sterol; hence it is called cholesterol. Cholesterol oxidase is the chief enzyme in the process of cholesterol degradation. Its role is obtained by the coenzyme FAD, which catalyzes the isomerization and oxidation of cholesterol to produce cholesteric 4-ene-3-ketone and hydrogen peroxide at the same time. Recently, a great advance has been made in the discovery of the structure and function of cholesterol oxidase, and it has proven added value in clinical discovery, medical care, food and biopesticides development and other conditions. By recombinant DNA technology, we can insert the gene in the heterologous host. Heterologous expression (HE) is a successful methodology to produce enzymes for function studies and manufacturing applications, where Escherichia coli has been extensively used as a heterologous host because of its economical cultivation, rapid growth, and efficiency in offering exogenous genes. Heterologous expression of cholesterol oxidase has been considered for several microbial sources, such as Rhodococcus equi, Brevibacterium sp., Rhodococcus sp., Streptomyces coelicolor, Burkholderia cepacia ST-200, Chromobacterium, and Streptomyces spp. All related publications of numerous researchers and scholars were searched in ScienceDirect, Scopus, PubMed, and Google Scholar. In this article, the present situation and promotion of heterologous expression of cholesterol oxidase, the role of protease, and the perspective of its possible applications were reviewed.

Proteopathy Linked to Exon-Skipping Isoform of RGR-Opsin Contributes to the Pathogenesis of Age-Related Macular Degeneration.

Purpose: Proteopathy is believed to contribute to age-related macular degeneration (AMD). Much research indicates that AMD begins in the retinal pigment epithelium (RPE), which is associated with formation of extracellular drusen, a clinical hallmark of AMD. Human RPE produces a drusen-associated abnormal protein, the exon Ⅵ-skipping splice isoform of retinal G protein-coupled receptor (RGR-d). In this study, we investigate the detrimental effects of RGR-d on cultured cells and mouse retina. Methods: ARPE-19 cells were stably infected by lentivirus overexpressing RGR or RGR-d and were treated with MG132, sometimes combined with or without endoplasmic reticulum (ER) stress inducer, tunicamycin. RGR and RGR-d protein expression, degeneration pathway, and potential cytotoxicity were explored. Homozygous RGR-d mice aged 8 or 14 months were fed with a high-fat diet for 3 months and then subjected to ocular examination and histopathology experiments. Results: We confirm that RGR-d is proteotoxic under various conditions. In ARPE-19 cells, RGR-d is misfolded and almost completely degraded via the ubiquitin-proteasome system. Unlike normal RGR, RGR-d increases ER stress, triggers the unfolded protein response, and exerts potent cytotoxicity. Aged RGR-d mice manifest disrupted RPE cell integrity, apoptotic photoreceptors, choroidal deposition of complement C3, and CD86+CD32+ proinflammatory cell infiltration into retina and RPE-choroid. Furthermore, the AMD-like phenotype of RGR-d mice can be aggravated by a high-fat diet. Conclusions: Our study confirmed the pathogenicity of the RGR splice isoform and corroborated a significant role of proteopathy in AMD. These findings may contribute to greater comprehension of the multifactorial causes of AMD.