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International Journal of Medical... 2024Synuclein family members (Snca, Sncb, and Scng) are expressed in the retina, but their precise locations and roles are poorly understood. We performed an extensive...
Synuclein family members (Snca, Sncb, and Scng) are expressed in the retina, but their precise locations and roles are poorly understood. We performed an extensive analysis of the single-cell transcriptome in healthy and injured retinas to investigate their expression patterns and roles. We observed the expression of all synuclein family members in retinal ganglion cells (RGCs), which remained consistent across species (human, mouse, and chicken). We unveiled differential expression of Snca across distinct clusters (highly expressed in most), while Sncb and Sncg displayed uniform expression across all clusters. Further, we observed a decreased expression in RGCs following traumatic axonal injury. However, the proportion of α-Syn-positive RGCs in all RGCs and α-Syn-positive intrinsically photosensitive retinal ganglion cells (ipRGCs) in all ipRGCs remained unaltered. Lastly, we identified changes in communication patterns preceding cell death, with particular significance in the pleiotrophin-nucleolin (Ptn-Ncl) and neural cell adhesion molecule signaling pathways, where communication differences were pronounced between cells with varying expression levels of Snca. Our study employs an innovative approach using scRNA-seq to characterize synuclein expression in health retinal cells, specifically focusing on RGC subtypes, advances our knowledge of retinal physiology and pathology.
Topics: Animals; Retinal Ganglion Cells; Humans; Mice; alpha-Synuclein; gamma-Synuclein; beta-Synuclein; Chickens; Transcriptome; Single-Cell Analysis; Retina; Neoplasm Proteins
PubMed: 38903914
DOI: 10.7150/ijms.95598 -
ELife Jun 2024Brain structural circuitry shapes a richly patterned functional synchronization, supporting for complex cognitive and behavioural abilities. However, how coupling of...
Brain structural circuitry shapes a richly patterned functional synchronization, supporting for complex cognitive and behavioural abilities. However, how coupling of structural connectome (SC) and functional connectome (FC) develops and its relationships with cognitive functions and transcriptomic architecture remain unclear. We used multimodal magnetic resonance imaging data from 439 participants aged 5.7-21.9 years to predict functional connectivity by incorporating intracortical and extracortical structural connectivity, characterizing SC-FC coupling. Our findings revealed that SC-FC coupling was strongest in the visual and somatomotor networks, consistent with evolutionary expansion, myelin content, and functional principal gradient. As development progressed, SC-FC coupling exhibited heterogeneous alterations dominated by an increase in cortical regions, broadly distributed across the somatomotor, frontoparietal, dorsal attention, and default mode networks. Moreover, we discovered that SC-FC coupling significantly predicted individual variability in general intelligence, mainly influencing frontoparietal and default mode networks. Finally, our results demonstrated that the heterogeneous development of SC-FC coupling is positively associated with genes in oligodendrocyte-related pathways and negatively associated with astrocyte-related genes. This study offers insight into the maturational principles of SC-FC coupling in typical development.
Topics: Humans; Connectome; Young Adult; Male; Adolescent; Female; Brain; Magnetic Resonance Imaging; Child; Child, Preschool; Adult; Nerve Net
PubMed: 38900563
DOI: 10.7554/eLife.93325 -
BMC Ophthalmology Jun 2024Dry eye is a chronic and multifactorial ocular surface disease caused by tear film instability or imbalance in the microenvironment of the ocular surface. It can lead to... (Review)
Review
BACKGROUND
Dry eye is a chronic and multifactorial ocular surface disease caused by tear film instability or imbalance in the microenvironment of the ocular surface. It can lead to various discomforts such as inflammation of the ocular surface and visual issues. However, the mechanism of dry eye is not clear, which results in dry eye being only relieved but not cured in clinical practice. Finding multiple environmental pathways for dry eye and exploring the pathogenesis of dry eye have become the focus of research. Studies have found that changes in microbiota may be related to the occurrence and development of dry eye disease.
METHODS
Entered the keywords "Dry eye", "Microbiota", "Bacteria" through PUBMED, summarised the articles that meet the inclusion criteria and then filtered them while the publication time range of the literature was defined in the past 5 years, with a deadline of 2023.A total of 13 clinical and 1 animal-related research articles were screened out and included in the summary.
RESULTS
Study found that different components of bacteria can induce ocular immune responses through different receptors present on the ocular surface, thereby leading to an imbalance in the ocular surface microenvironment. Changes in the ocular surface microbiota and gut microbiota were also found when dry eye syndrome occurs, including changes in diversity, an increase in pro-inflammatory bacteria, and a decrease in short-chain fatty acid-related bacterial genera that produce anti-inflammatory effects. Fecal microbiota transplantation or probiotic intervention can alleviate signs of inflammation on the ocular surface of dry eye animal models.
CONCLUSIONS
By summarizing the changes in the ocular surface and intestinal microbiota when dry eye occurs, it is speculated and concluded that the intestine may affect the occurrence of eye diseases such as dry eye through several pathways and mechanisms, such as the occurrence of abnormal immune responses, microbiota metabolites- intervention of short-chain fatty acids, imbalance of pro-inflammatory and anti-inflammatory factors, and release of neurotransmitters, etc. Analyzing the correlation between the intestinal tract and the eyes from the perspective of microbiota can provide a theoretical basis and a new idea for relieving dry eyes in multiple ways in the future.
Topics: Dry Eye Syndromes; Humans; Gastrointestinal Microbiome; Animals; Tears
PubMed: 38898418
DOI: 10.1186/s12886-024-03526-2 -
Brain and Behavior Jun 2024Major depressive disorder (MDD) is associated with dysfunctional reward processing, which involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc)....
INTRODUCTION
Major depressive disorder (MDD) is associated with dysfunctional reward processing, which involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc). Since ketamine elicits rapid antidepressant and antianhedonic effects in MDD, this study sought to investigate how serial ketamine infusion (SKI) treatment modulates static and dynamic functional connectivity (FC) in Hb and NAc functional networks.
METHODS
MDD participants (n = 58, mean age = 40.7 years, female = 28) received four ketamine infusions (0.5 mg/kg) 2-3 times weekly. Resting-state functional magnetic resonance imaging (fMRI) scans and clinical assessments were collected at baseline and 24 h post-SKI. Static FC (sFC) and dynamic FC variability (dFCv) were calculated from left and right Hb and NAc seeds to all other brain regions. Changes in FC pre-to-post SKI, and correlations with changes with mood and anhedonia were examined. Comparisons of FC between patients and healthy controls (HC) at baseline (n = 55, mean age = 32.6, female = 31), and between HC assessed twice (n = 16) were conducted as follow-up analyses.
RESULTS
Following SKI, significant increases in left Hb-bilateral visual cortex FC, decreases in left Hb-left inferior parietal cortex FC, and decreases in left NAc-right cerebellum FC occurred. Decreased dFCv between left Hb and right precuneus and visual cortex, and decreased dFCv between right NAc and right visual cortex both significantly correlated with improvements in mood ratings. Decreased FC between left Hb and bilateral visual/parietal cortices as well as increased FC between left NAc and right visual/parietal cortices both significantly correlated with improvements in anhedonia. No differences were observed between HC at baseline or over time.
CONCLUSION
Subanesthetic ketamine modulates functional pathways linking the Hb and NAc with visual, parietal, and cerebellar regions in MDD. Overlapping effects between Hb and NAc functional systems were associated with ketamine's therapeutic response.
Topics: Humans; Ketamine; Male; Depressive Disorder, Major; Nucleus Accumbens; Adult; Female; Habenula; Magnetic Resonance Imaging; Middle Aged; Antidepressive Agents; Anhedonia
PubMed: 38894648
DOI: 10.1002/brb3.3511 -
Sensors (Basel, Switzerland) May 2024Trunk compensatory movements frequently manifest during robotic-assisted arm reaching exercises for upper limb rehabilitation following a stroke, potentially impeding...
Trunk compensatory movements frequently manifest during robotic-assisted arm reaching exercises for upper limb rehabilitation following a stroke, potentially impeding functional recovery. These aberrant movements are prevalent among stroke survivors and can hinder their progress in rehabilitation, making it crucial to address this issue. This study evaluated the efficacy of visual feedback, facilitated by an RGB-D camera, in reducing trunk compensation. In total, 17 able-bodied individuals and 18 stroke survivors performed reaching tasks under unrestricted trunk conditions and visual feedback conditions. In the visual feedback modalities, the target position was synchronized with trunk movement at ratios where the target moved at the same speed, double, and triple the trunk's motion speed, providing real-time feedback to the participants. Notably, trunk compensatory movements were significantly diminished when the target moved at the same speed and double the trunk's motion speed. Furthermore, these conditions exhibited an increase in the task completion time and perceived exertion among stroke survivors. This outcome suggests that visual feedback effectively heightened the task difficulty, thereby discouraging unnecessary trunk motion. The findings underscore the pivotal role of customized visual feedback in correcting aberrant upper limb movements among stroke survivors, potentially contributing to the advancement of robotic-assisted rehabilitation strategies. These insights advocate for the integration of visual feedback into rehabilitation exercises, highlighting its potential to foster more effective recovery pathways for post-stroke individuals by minimizing undesired compensatory motions.
Topics: Humans; Stroke Rehabilitation; Male; Feedback, Sensory; Robotics; Female; Middle Aged; Arm; Stroke; Movement; Adult; Exercise Therapy; Torso; Aged; Survivors; Upper Extremity
PubMed: 38894119
DOI: 10.3390/s24113331 -
International Journal of Molecular... Jun 2024The first member of the arrestin family, visual arrestin-1, was discovered in the late 1970s. Later, the other three mammalian subtypes were identified and cloned. The... (Review)
Review
The first member of the arrestin family, visual arrestin-1, was discovered in the late 1970s. Later, the other three mammalian subtypes were identified and cloned. The first described function was regulation of G protein-coupled receptor (GPCR) signaling: arrestins bind active phosphorylated GPCRs, blocking their coupling to G proteins. It was later discovered that receptor-bound and free arrestins interact with numerous proteins, regulating GPCR trafficking and various signaling pathways, including those that determine cell fate. Arrestins have no enzymatic activity; they function by organizing multi-protein complexes and localizing their interaction partners to particular cellular compartments. Today we understand the molecular mechanism of arrestin interactions with GPCRs better than the mechanisms underlying other functions. However, even limited knowledge enabled the construction of signaling-biased arrestin mutants and extraction of biologically active monofunctional peptides from these multifunctional proteins. Manipulation of cellular signaling with arrestin-based tools has research and likely therapeutic potential: re-engineered proteins and their parts can produce effects that conventional small-molecule drugs cannot.
Topics: Humans; Animals; Arrestins; Signal Transduction; Receptors, G-Protein-Coupled; Protein Binding; Phosphorylation
PubMed: 38892473
DOI: 10.3390/ijms25116284 -
International Journal of Molecular... May 2024Wet age-related macular degeneration (wet AMD) is a primary contributor to visual impairment and severe vision loss globally, but the prevailing treatments are often... (Review)
Review
Wet age-related macular degeneration (wet AMD) is a primary contributor to visual impairment and severe vision loss globally, but the prevailing treatments are often unsatisfactory. The development of conventional treatment strategies has largely been based on the understanding that the angiogenic switch of endothelial cells (ECs) is mainly dictated by angiogenic growth factors. Even though treatments targeting vascular endothelial growth factor (VEGF), like ranibizumab, are widely administered, more than half of patients still exhibit inadequate or null responses, suggesting the involvement of other pathogenic mechanisms. With advances in research in recent years, it has become well recognized that EC metabolic regulation plays an active rather than merely passive responsive role in angiogenesis. Disturbances of these metabolic pathways may lead to excessive neovascularization in angiogenic diseases such as wet AMD, therefore targeted modulation of EC metabolism represents a promising therapeutic strategy for wet AMD. In this review, we comprehensively discuss the potential applications of EC metabolic regulation in wet AMD treatment from multiple perspectives, including the involvement of ECs in wet AMD pathogenesis, the major endothelial metabolic pathways, and novel therapeutic approaches targeting metabolism for wet AMD.
Topics: Humans; Endothelial Cells; Wet Macular Degeneration; Animals; Vascular Endothelial Growth Factor A; Ranibizumab; Angiogenesis Inhibitors; Metabolic Networks and Pathways; Neovascularization, Pathologic
PubMed: 38892113
DOI: 10.3390/ijms25115926 -
Neural Development Jun 2024The thalamic reticular nucleus (TRN) serves as an important node between the thalamus and neocortex, regulating thalamocortical rhythms and sensory processing in a state...
The thalamic reticular nucleus (TRN) serves as an important node between the thalamus and neocortex, regulating thalamocortical rhythms and sensory processing in a state dependent manner. Disruptions in TRN circuitry also figures prominently in several neurodevelopmental disorders including epilepsy, autism, and attentional defects. An understanding of how and when connections between TRN and 1st order thalamic nuclei, such as the dorsal lateral geniculate nucleus (dLGN), develop is lacking. We used the mouse visual thalamus as a model system to study the organization, pattern of innervation and functional responses between TRN and the dLGN. Genetically modified mouse lines were used to visualize and target the feedforward and feedback components of these intra-thalamic circuits and to understand how peripheral input from the retina impacts their development.Retrograde tracing of thalamocortical (TC) afferents through TRN revealed that the modality-specific organization seen in the adult, is present at perinatal ages and seems impervious to the loss of peripheral input. To examine the formation and functional maturation of intrathalamic circuits between the visual sector of TRN and dLGN, we examined when projections from each nuclei arrive, and used an acute thalamic slice preparation along with optogenetic stimulation to assess the maturation of functional synaptic responses. Although thalamocortical projections passed through TRN at birth, feedforward axon collaterals determined by vGluT2 labeling, emerged during the second postnatal week, increasing in density through the third week. Optogenetic stimulation of TC axon collaterals in TRN showed infrequent, weak excitatory responses near the end of week 1. During weeks 2-4, responses became more prevalent, grew larger in amplitude and exhibited synaptic depression during repetitive stimulation. Feedback projections from visual TRN to dLGN began to innervate dLGN as early as postnatal day 2 with weak inhibitory responses emerging during week 1. During week 2-4, inhibitory responses continued to grow larger, showing synaptic depression during repetitive stimulation. During this time TRN inhibition started to suppress TC spiking, having its greatest impact by week 4-6. Using a mutant mouse that lacks retinofugal projections revealed that the absence of retinal input led to an acceleration of TRN innervation of dLGN but had little impact on the development of feedforward projections from dLGN to TRN. Together, these experiments reveal how and when intrathalamic connections emerge during early postnatal ages and provide foundational knowledge to understand the development of thalamocortical network dynamics as well as neurodevelopmental diseases that involve TRN circuitry.
Topics: Animals; Geniculate Bodies; Mice; Thalamic Nuclei; Visual Pathways; Mice, Inbred C57BL; Mice, Transgenic; Neural Pathways
PubMed: 38890758
DOI: 10.1186/s13064-024-00183-5 -
Investigative Ophthalmology & Visual... Jun 2024Ubiquitination serves as a fundamental post-translational modification in numerous cellular events. Yet, its role in regulating corneal epithelial wound healing (CEWH)...
PURPOSE
Ubiquitination serves as a fundamental post-translational modification in numerous cellular events. Yet, its role in regulating corneal epithelial wound healing (CEWH) remains elusive. This study endeavored to determine the function and mechanism of ubiquitination in CEWH.
METHODS
Western blot and immunoprecipitation were used to discern ubiquitination alterations during CEWH in mice. Interventions, including neuronally expressed developmentally downregulated 4 (Nedd4) siRNA and proteasome/lysosome inhibitor, assessed their impact on CEWH. In vitro analyses, such as the scratch wound assay, MTS assay, and EdU staining, were conducted to gauge cell migration and proliferation in human corneal epithelial cells (HCECs). Moreover, transfection of miR-30/200 coupled with a luciferase activity assay ascertained their regulatory mechanism on Nedd4.
RESULTS
Global ubiquitination levels were markedly increased during the mouse CEWH. Importantly, the application of either proteasomal or lysosomal inhibitors notably impeded the healing process both in vivo and in vitro. Furthermore, Nedd4 was identified as an essential E3 ligase for CEWH. Nedd4 expression was significantly upregulated during CEWH. In vivo studies revealed that downregulation of Nedd4 substantially delayed CEWH, whereas further investigations underscored its role in regulating cell proliferation and migration, through the Stat3 pathway by targeting phosphatase and tensin homolog (PTEN). Notably, our findings pinpointed miR-30/200 family members as direct regulators of Nedd4.
CONCLUSIONS
Ubiquitination holds pivotal significance in orchestrating CEWH. The critical E3 ligase Nedd4, under the regulatory purview of miR-30 and miR-200, facilitates CEWH through PTEN-mediated Stat3 signaling. This revelation sheds light on a prospective therapeutic target within the realm of CEWH.
Topics: Nedd4 Ubiquitin Protein Ligases; Animals; Ubiquitination; Mice; Cell Movement; Cell Proliferation; Wound Healing; PTEN Phosphohydrolase; Epithelium, Corneal; Ubiquitin-Protein Ligases; Humans; Mice, Inbred C57BL; Endosomal Sorting Complexes Required for Transport; Blotting, Western; STAT3 Transcription Factor; Cells, Cultured; Disease Models, Animal; MicroRNAs; Immunoprecipitation; Male; Gene Expression Regulation
PubMed: 38888282
DOI: 10.1167/iovs.65.6.29 -
Radiation Oncology (London, England) Jun 2024Rare but severe toxicities of the optic apparatus have been observed after treatment of intracranial tumours with proton therapy. Some adverse events have occurred at...
BACKGROUND AND PURPOSE
Rare but severe toxicities of the optic apparatus have been observed after treatment of intracranial tumours with proton therapy. Some adverse events have occurred at unusually low dose levels and are thus difficult to understand considering dose metrics only. When transitioning from double scattering to pencil beam scanning, little consideration was given to increased dose rates observed with the latter delivery paradigm. We explored if dose rate related metrics could provide additional predicting factors for the development of late visual toxicities.
MATERIALS AND METHODS
Radiation-induced intracranial visual pathway lesions were delineated on MRI for all index cases. Voxel-wise maximum dose rate (MDR) was calculated for 2 patients with observed optic nerve toxicities (CTCAE grade 3 and 4), and 6 similar control cases. Additionally, linear energy transfer (LET) related dose enhancing metrics were investigated.
RESULTS
For the index cases, which developed toxicities at low dose levels (mean, 50 Gy), some dose was delivered at higher instantaneous dose rates. While optic structures of non-toxicity cases were exposed to dose rates of up to 1 to 3.2 Gy/s, the pre-chiasmatic optic nerves of the 2 toxicity cases were exposed to dose rates above 3.7 Gy/s. LET-related metrics were not substantially different between the index and non-toxicity cases.
CONCLUSIONS
Our observations reveal large variations in instantaneous dose rates experienced by different volumes within our patient cohort, even when considering the same indications and beam arrangement. High dose rate regions are spatially overlapping with the radiation induced toxicity areas in the follow up images. At this point, it is not feasible to establish causality between exposure to high dose rates and the development of late optic apparatus toxicities due to the low incidence of injury.
Topics: Humans; Proton Therapy; Brain Neoplasms; Radiotherapy Dosage; Female; Male; Middle Aged; Adult; Radiation Injuries; Aged; Optic Nerve; Organs at Risk; Radiotherapy Planning, Computer-Assisted; Dose-Response Relationship, Radiation
PubMed: 38886727
DOI: 10.1186/s13014-024-02464-z