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The molecular chaperone sigma 1 receptor mediates rescue of retinal cone photoreceptor cells via modulation of NRF2
摘要： Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic target for retinal degenerative disease. Earlier studies showed that activation of Sig1R via the high-affinity ligand (+)-pentazocine ((+)-PTZ) induced profound rescue of cone photoreceptor cells in the rd10 mouse model of retinitis pigmentosa; however the mechanism of rescue is unknown. Improved cone function in (+)-PTZ-treated mice was accompanied by reduced oxidative stress and normalization of levels of NRF2, a transcription factor that activates antioxidant response elements (AREs) of hundreds of cytoprotective genes. Here, we tested the hypothesis that modulation of NRF2 is central to Sig1R-mediated cone rescue. Activation of Sig1R in 661W cone cells using (+)-PTZ induced dose-dependent increases in NRF2-ARE binding activity and NRF2 gene/protein expression, whereas silencing Sig1R significantly decreased NRF2 protein levels and increased oxidative stress, although (+)-PTZ did not disrupt NRF2-KEAP1 binding. In vivo studies were conducted to investigate whether, in the absence of NRF2, activation of Sig1R rescues cones. (+)-PTZ was administered systemically for several weeks to rd10/nrf2+/+ and rd10/nrf2-/- mice. Through post-natal day 42, cone function was significant in rd10/nrf2+/+, but minimal in rd10/nrf2-/- mice as indicated by electroretinographic recordings using natural noise stimuli, optical coherence tomography and retinal histological analyses. Immunodetection of cones was limited in (+)-PTZ-treated rd10/nrf2-/-, though considerable in (+)-PTZ-treated rd10/nrf2+/+mice. The data suggest that Sig1R-mediated cone rescue requires NRF2 and provide evidence for a previously-unrecognized relationship between these proteins.
关键词： retinitis pigmentosa,NRF2-KEAP1,retinal neuroprotection,retina,rd10 mouse,NRF2-Neh luciferase assay,oxidative stress
更新于2025-11-21 11:08:12
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Utilization of Multiphoton Imaging For Real-Time Fate Determination of Mesenchymal Stem Cells in an Immunocompetent Mouse Model
摘要： The clinical application of Mesenchymal Stem Cells (MSCs) for the treatment of a variety of diseases is the focus of intense research. Despite large research efforts many questions regarding MSC biology in vivo remain unanswered. For instance, we do not know for certain whether MSCs exert their therapeutic effects directly within the target tissue or indirectly by influencing the polarization of other cell types, such as macrophages, which can then home to the target tissue microenvironment. To help address this issue, the application of intravital multiphoton microscopy allows for the determination of the dynamic action of intact MSCs versus endogenous host cells at the target tissue site in real time.
关键词： Mesenchymal Stem Cell,Granulocyte,MSC,Intravital,Mouse Model,Multiphoton
更新于2025-09-23 15:23:52
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Pre-conditioning with Remote Photobiomodulation Modulates the Brain Transcriptome and Protects Against MPTP Insult in Mice
摘要： Transcranial photobiomodulation (PBM), which involves the application of low-intensity red to near-infrared light (600-1100nm) to the head, provides neuroprotection in animal models of various neurodegenerative diseases. However, the absorption of light energy by the human scalp and skull may limit the utility of transcranial PBM in clinical contexts. We have previously shown that targeting light at peripheral tissues (i.e. “remote PBM”) also provides protection of the brain in an MPTP mouse model of Parkinson’s disease, suggesting remote PBM might be a viable alternative strategy for overcoming penetration issues associated with transcranial PBM. This present study aimed to determine an effective pre-conditioning regimen of remote PBM for inducing neuroprotection and elucidate the molecular mechanisms by which remote PBM enhances the resilience of brain tissue. Balb/c mice were irradiated with 670nm light (4J/cm2 per day) targeting dorsum and hindlimbs for 2, 5 or 10 days, followed by injection of the parkinsonian neurotoxin MPTP (50mg/kg) over two consecutive days. Despite no direct irradiation of the head, 10 days of pre-conditioning with remote PBM significantly attenuated MPTP-induced loss of midbrain tyrosine hydroxylase-positive dopaminergic cells and mitigated the increase in FOS-positive neurons in the caudate-putamen complex. Interrogation of the midbrain transcriptome by RNA microarray and pathway enrichment analysis suggested upregulation of cell signaling and migration (including CXCR4+ stem cell and adipocytokine signaling), oxidative stress response pathways and modulation of the blood-brain barrier following remote PBM. These findings establish remote PBM preconditioning as a viable neuroprotective intervention and provide insights into the mechanisms underlying this phenomenon.
关键词： MPTP,microarray,Parkinson’s disease,mouse model,neuroprotection,photobiomodulation
更新于2025-09-23 15:23:52
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Early Onset Ultrastructural and Functional Defects in RPE and Photoreceptors of a Stargardt-Like Macular Dystrophy (STGD3) Transgenic Mouse Model
摘要： PURPOSE. We investigated the interplay between photoreceptors expressing mutant ELOVL4 (responsible for Stargardt-like disease, STGD3) and RPE in the initial stages of retinal degeneration. METHODS. Using electron microscopy and electroretinogram (ERG), we assessed RPE and photoreceptor ultrastructure and function in transgenic ELOVL4 (TG1-2 line; TG) and wild-type (WT) littermates. Experiments were done at P30, 1 month before photoreceptor loss in TG and at P90, a time point with approximately 30% rod loss. To further elucidate the mechanism underlying our ultrastructural and functional results, we undertook Western blotting and immunohistochemistry of key proteins involved in phagocytosis of outer segments by RPE cells. RESULTS. Firstly, we showed that in TG mouse photoreceptors, endogenous ELOVL4 protein is not mislocalized in the presence of the mutated ELOVL4 protein. Secondly, we found evidence of RPE toxicity at P30, preceding any photoreceptor loss. Pathology in RPE cells was exacerbated at P90. Furthermore, higher proportions of phagosomes remained at the apical side of RPE cells. Subretinal lysosomal deposits were immunopositive for phagocytic proteins. Ultrastructural analysis of photoreceptor (rod) outer segments showed disrupted surface morphology consisting of disc spacing irregularities. Finally, rods and RPE exhibited signs of dysfunction as measured by the ERG a-wave leading edge (P30) and c-wave (P90), respectively. CONCLUSIONS. The presence of human mutant ELOVL4 in transgenic mouse photoreceptors leads to early outer segment disc pathology and RPE cytotoxicity. Defective processing of these abnormal discs by RPE cells ultimately may be responsible for outer segment truncation, photoreceptor death, and vision loss.
关键词： mouse,outer segment,Stargardt-like dystrophy,photoreceptor,STGD3,phagocytosis,ELOVL4,RPE
更新于2025-09-23 15:23:52
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Mouse optical imaging for understanding resting-state functional connectivity in human fMRI
摘要： Resting-state functional connectivity (FC), which measures the temporal correlation of spontaneous hemodynamic activity between distant brain areas, is a widely accepted method in functional magnetic resonance imaging (fMRI) to assess the connectome of healthy and diseased human brains. A common assumption underlying FC is that it reflects the temporal structure of large-scale neuronal activity that is converted into large-scale hemodynamic activity. However, direct observation of such relationship has been difficult. In this commentary, we describe our recent progress regarding this topic. Recently, transgenic mice that express a genetically encoded calcium indicator (GCaMP) in neocortical neurons are enabling the optical recording of neuronal activity in large-scale with high spatiotemporal resolution. Using these mice, we devised a method to simultaneously monitor neuronal and hemodynamic activity and addressed some key issues related to the neuronal basis of FC. We propose that many important questions about human resting-state fMRI can be answered using GCaMP expressing transgenic mice as a model system.
关键词： mouse,calcium imaging,functional connectivity,fMRI,resting-state
更新于2025-09-23 15:23:52
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Lack of cone mediated retinal function increases susceptibility to form-deprivation myopia in mice
摘要： Retinal photoreceptors are important in visual signaling for normal eye growth in animals. We used Gnat2 cplf3/cplf3 (Gnat2-/-) mice, a genetic mouse model of cone dysfunction to investigate the influence of cone signaling in ocular refractive development and myopia susceptibility in mice. Refractive development under normal visual conditions was measured for Gnat2-/- and age-matched Gnat2+/+ mice, every 2 weeks from 4 to 14 weeks of age. Weekly measurements were performed on a separate cohort of mice that underwent monocular form-deprivation (FD) in the right eye from 4 weeks of age using head-mounted diffusers. Refraction, corneal curvature, and ocular biometrics were obtained using photorefraction, keratometry and optical coherence tomography, respectively. Retinas from FD mice were harvested, and analyzed for dopamine (DA) and 3,4-dihydroxyphenylacetate (DOPAC) using high-performance liquid chromatography. Under normal visual conditions, Gnat2+/+ and Gnat2-/- mice showed similar refractive error, axial length, and corneal radii across development (p>0.05), indicating no significant effects of the Gnat2 mutation on normal ocular refractive development in mice. Three weeks of FD produced a significantly greater myopic shift in Gnat2-/- mice compared to Gnat2+/+ controls (-5.40 ± 1.33 D vs -2.28 ± 0.28 D, p=0.042). Neither the Gnat2 mutation nor FD altered retinal levels of DA or DOPAC. Our results indicate that cone pathways needed for high acuity vision in primates are not as critical for normal refractive development in mice, and that both rods and cones contribute to visual signalling pathways needed to respond to FD in mammalian eyes.
关键词： mouse,form-deprivation,dopamine,Gnat2,Refractive error,cone photoreceptors
更新于2025-09-23 15:23:52
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Raman spectroscopic analysis of testicular lamina propria predicts spermatogenesis in a mouse infertility model
摘要： The status of the testicular lamina propria (LP) is associated with spermatogenesis. The aim of this study was to determine whether Raman spectroscopy (RS) could detect material components within the LP and predict spermatogenesis. Twenty adult male mice were divided into a busulfan-treated group (n ? 16 mice receiving a single injection of 50 mg kg(cid:2)1, i.p., busulfan) and a control group (n ? 4 mice receiving an equivalent volume of 0.9% saline solution injected i.p.). Mice were killed 2, 4, 6 and 8 weeks after injection of busulfan or saline solution (n ? 1 control and 4 busulfan-treated mice at each time point). The testicular tubules were assessed by RS and compared with histopathological observations. Control tubules had raw spectral intensities below 2000 arbitrary units, whereas busulfan tubules had strengthened intensities that peaked at Week 4 (absent spermatogenesis) and returned to normal levels at Week 8 (restored spermatogenesis). The change in the LP revealed by RS occurred before the change in spermatogenesis detected by histopathology. Correspondingly, the sensitivity/specificity of RS for distinguishing busulfan-treated and control tubules at 2, 4, 6 and 8 weeks were 65.00%/70.00%, 95.00%/100.00%, 40.00%/100.00% and 25.00%/95.00% respectively. Collectively, RS could be used to evaluate the status of the LP and as a complement to histopathological evaluation to predict tubules with the potential to develop spermatogenesis for infertile patients.
关键词： spermatogenesis,busulfan,mouse infertility model,testicular lamina propria,Raman spectroscopy
更新于2025-09-23 15:22:29
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[Institution of Engineering and Technology 7th International Conference on Imaging for Crime Detection and Prevention (ICDP 2016) - Madrid, Spain (23-25 Nov. 2016)] 7th International Conference on Imaging for Crime Detection and Prevention (ICDP 2016) - Using keystroke and mouse dynamics for user identification in the online collaborative game League of Legends
摘要： The popularity of computer games has grown exponentially in the last few years. It is not uncommon to find players of online games who can dedicate their whole lives in order to became the best in their favourite game. The best players normally become celebrities and can even get sponsored to compete in game tourneys. It is accepted that each player should follow the his/her own path to increase level, so the experience reflected in the gamer's level is how proficient he/she is in the game. However, this increased popularity has also created a desire on some players to cheat (by paying others more experienced players to play for them) for the progress in the game and thus to improve their status. The companies that develop such games have very strict punishment for such breaking of the rules, but, it can be very difficult to identify when this 'account sharing' happens. This paper focus on the collection and analysis of a new online game database for continuous mouse dynamics and keystroke dynamics authentication in order to identify whether who is playing is really the account holder. Our very first results point to very interesting possibilities for security biometric-based applications in this new game analysis area.
关键词： Mouse dynamics,League of Legends,User identification,Online game,Keystroke dynamics
更新于2025-09-23 15:22:29
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Longitudinal analysis of molecular alteration in serum samples of dextran sodium sulfate-induced colitis mice by using infrared spectroscopy
摘要： Established diagnostic regimens for in?ammatory bowel diseases, such as colonoscopy, sigmoidoscopy, and small bowel follow-through have high sensitivity, but adherence rates of the eligible population for the disease screening is poor due to associated expenses, the risk of complications, time, and comfort issues. Thus, it is critical to develop an A?ordable, Sensitive, Speci?c, User-friendly, Rapid, Equipment-free, and Deliverable (ASSURED) screening test that could increase the participation rate of the eligible group. In this study, we present infrared spectroscopy of serum accompanied with data analysis to monitor longitudinal analysis of molecular alteration in colitis mouse samples. Dextran Sodium Sulfate-induced colitis mouse model sera were used to understand the disease aggravation by testing of the alteration of carbohydrates and the protein secondary structures re?ected in the spectra. Samples derived from mouse models at days 0, 3, and 7 of chemical administration were used for spectral measurements. Spectral data at Biomarker peaks show there is not any speci?c alteration of serum sample composition at day 3 of the chemical feeding, but a signi?cant alteration on the marker can be seen at day 7. The results of this study will thus pave the way for the development of an ASSURED prototype that can have clinical application.
关键词： Colitis,Longitudinal analysis,Serum,Infrared ATR spectroscopy,Mouse models
更新于2025-09-23 15:22:29
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Real-time motorized electrical hospital bed control with eye-gaze tracking
摘要： Patients with motor neuron disease and most terminal patients cannot use their hands or arms, and so they need another person for their all needs. However, the mental functions and memories of such patients are generally sound, and they can control their eyes. Using an eye-gaze tracking technique, we have realized a real-time system for such patients. The system controls a motorized electrical hospital bed (EHB) by eye gaze with 4 degrees of freedom, using a low-cost webcam. Contactless systems that require calibration cannot be used for EHB control. The system developed in this work does not require any calibration process and it is contactless. These properties are the most innovative part of the proposed approach. To begin, the system detects the eye region and computes the iris centers. It then tracks the centers and moves a mouse pointer on a screen with the eye gaze. The speci(cid:12)c movements of the mouse pointer are evaluated as position changing requests and the completed movements of the mouse pointer change the EHB position electrically. The communication between the computer and the EHB is provided by a relay control card driven by Arduino Mega. The system works under day/arti(cid:12)cial lighting conditions successfully with or without eyeglasses. The system was tested with 30 volunteers on the EHB safely and was completed with 90% success (the exceptions being people with slanted eyes).
关键词： electrical hospital bed,Calibration-free eye tracking,real-time eye-gaze tracking,eye-based mouse control
更新于2025-09-23 15:21:21