ScienceBank最新文献

{"title":"Pericytes in Notch3 knockout and diabetic mice form engorged connections with vascular endothelial cells.","authors":"Timothy E Vanderleest, Harper B Gordon, Michael O'Hare, Philip Seifert, Joseph F Arboleda-Velasquez","doi":"10.61340/pn3k1dm","DOIUrl":"10.61340/pn3k1dm","url":null,"abstract":"<p><strong>Purpose: </strong>Pericytes, cells crucially important to maintain a healthy microvasculature, make direct connections with vascular endothelial cells, yet the functional significance of these contacts remains largely unexplored. This study aims to investigate the ultrastructural morphological changes that occur in the interactions between pericytes and endothelial cells in mice lacking the Notch3 receptor and in diabetic retinopathy.</p><p><strong>Methods: </strong>Serial section transmission electron microscopy (ssTEM) was used to image mouse retinal ganglion cell layer capillaries in wild type (WT; 19 vessels), Notch3 knockout (KO; 16 vessels), conditional Notch3 KO (23 vessels), and diabetic mice (18 vessels). Over 2,000 images were manually segmented to trace the boundaries of the basement membrane, endothelial cells, mural cells, and peg-and-socket connections. Automated image analysis was used to measure contact lengths between pericytes and endothelial cells and peg-and-socket features.</p><p><strong>Results: </strong>While the vessels analyzed in each group were of similar diameter and pericyte coverage, Notch3 KO vessels had deeper pegs and increased connectivity between pericytes and endothelial cells. In both Notch3 KO and diabetic conditions, there was also an increase in the size of pericyte pegs.</p><p><strong>Conclusions: </strong>As the Notch3 receptor plays an important role in cell signaling between pericytes and endothelial cells, and diabetes is also known to disrupt Notch3 signaling, our hypothesis for the enlarged peg phenotype is that the pericytes and endothelial cells actively increase their contact surface to compensate for loss of Notch3 signaling.</p>","PeriodicalId":521221,"journal":{"name":"ScienceBank","volume":"2025 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12860123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>REELIN</i>-COLBOS (H3447R) in Colombian oldest-old individuals, a case series.","authors":"Daniel Vasquez, David Aguillon, Paula Perez Corredor, Diana Paola Alzate Echeverri, Yesica Zuluaga, Ana Y Baena, Lucia Madrigal, Liliana Hincapié, Liliana Ramirez Gomez, Lusiana Martinez, Vincent Malotaux, Francisco Lopera, Yakeel T Quiroz, Joseph F Arboleda-Velasquez","doi":"10.61340/rccoop","DOIUrl":"10.61340/rccoop","url":null,"abstract":"<p><p>We previously identified <i>REELIN-</i>COLBOS (<i>RELN</i> H3447R) and <i>APOE</i> Christchurch (<i>APOE</i> R136S) as candidate gene variants associated with protection against dementia in cases at the highest risk of Alzheimer's Disease (AD) due to the <i>PSEN1</i> E280A mutation in Colombia. Here, we examined the frequency of these variants in a cohort of 135 Colombian oldest-old individuals, part of the Resist AD Project. Five carriers of the <i>REELIN</i>-COLBOS variant were identified and described here, whereas none of the cases carried <i>APOE</i> Christchurch. The first case is a 102-year-old APOE4/E3 carrier with stable performance on cognitive tests despite having suffered an episode of delirium due to pneumonia. FDG-PET revealed relatively preserved cortical glucose metabolism despite showing degenerative changes on MRI. Another case with a family history of early-onset dementia maintained independence until age 85. Despite significant comorbidities, the other three cases exhibited preserved cognition at baseline. These observations are consistent with the hypothesis that the Reelin-COLBOS variant may play a protective role against cognitive decline and support healthy aging, although further studies are needed in larger and more diverse populations to confirm this association.</p>","PeriodicalId":521221,"journal":{"name":"ScienceBank","volume":"2025 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12867035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146121705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The use of aqueous humor cfDNA for low-pass whole genome sequencing as a clinical test to identify intraocular retinoblastoma recurrence.","authors":"Douglas Chigane, Drishti Pandya, Brianne Brown, Michelle Lin, Alexander Tseng, Rachana Shah, Rima Jubran, Matthew Snider, Patrick Peng, Muskaan Singh, Venkata Yellapantula, Jaclyn A Biegel, Liya Xu, Jesse L Berry","doi":"10.61340/uahctirbr","DOIUrl":"10.61340/uahctirbr","url":null,"abstract":"<p><strong>Objective: </strong>Patients with retinoblastoma (RB) require serial examinations under anesthesia (EUA) to assess for response to treatment and disease recurrence. Monitoring for disease recurrence is complicated in patients with loss of fundoscopic view, such as with vitreous hemorrhage (VH) or cataract. Herein, we report a case of a 13-month-old male diagnosed with sporadic bilateral retinoblastoma, wherein the aqueous humor liquid biopsy was used to detect an occult tumor recurrence after 3.5 years of disease stability.</p><p><strong>Methodology: </strong>Case report.</p><p><strong>Results: </strong>A 13-month-old male diagnosed with sporadic bilateral retinoblastoma, International Intraocular Retinoblastoma Classification (IIRC) Group D1 in the right eye and Group E in the left eye, was initially treated with intravenous chemotherapy, intravitreal chemotherapy, and local consolidation. After 3.5 years of disease stability, the patient developed a massive vitreous hemorrhage in the left eye, which precluded a view of the posterior segment. EUA, B-scan ultrasonography, and magnetic resonance imaging (MRI) of the brain and bilateral orbits were inconclusive for recurrence. Aqueous humor liquid biopsy, LBSeq4Kids, is an analytically validated College of American Pathologists / Clinical Laboratory Improvement Amendments (CAP/CLIA) laboratory test available for clinical use at Children's Hospital Los Angeles. Low pass whole-genome sequencing of aqueous humor cell-free DNA (cfDNA) demonstrated the presence of circulating tumor DNA consistent with an active intraocular recurrence. Enucleation of the left eye was performed and the histopathology confirmed active RB recurrence with massive choroidal invasion.</p><p><strong>Conclusions: </strong>Aqueous humor liquid biopsy can be used to guide clinical decision-making in RB, especially when there is a loss of fundus view and intraocular recurrence is suspected.</p>","PeriodicalId":521221,"journal":{"name":"ScienceBank","volume":"2025 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12914873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146230515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retinal cell death is primarily caspase-dependent in vitro and in a mouse model of chloroquine-induced acute retinal toxicity.","authors":"Dhanesh Amarnani, Eric J Kim, Brandon V Duffy, Leslie Ramos, Leo A Kim","doi":"10.61340/rcdpcd","DOIUrl":"10.61340/rcdpcd","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the mechanism of chloroquine-induced cell death in vitro in adult human retinal pigmented epithelial (ARPE-19) cells and murine 661W photoreceptor-derived cells and to evaluate a mouse model of acute chloroquine-induced retinal toxicity.</p><p><strong>Methods: </strong>Human RPE cells and photoreceptor cells were cultured in vitro and treated with chloroquine; cell death was measured by lactate dehydrogenase release. Lysosomal-associated membrane protein-1 (LAMP-1) staining assessed lysosomal destabilization upstream of cell death initiation. The role of cathepsins, lysosomal proteases was examined by blocking their activity. Cell permeable caspase, and RIP1 kinase inhibitors were used to elucidate the role of downstream mediators of cell death signaling pathways. Adult mice were administered intravitreal injections of 50 micrograms of chloroquine. Fundus photography, optical coherence tomography, and electroretinography were used to evaluate drug-induced retinal changes after one week. Quantitative RT-PCR was used to evaluate changes in gene expression in mice retinal-pigmented epithelium and neurosensory retina.</p><p><strong>Results: </strong>ARPE-19 and 661W cells showed cell death within 24 hours of treatment. LAMP-1 staining and inhibition of cathepsins B, D, and L activity in ARPE-19 cells significantly decreased cell death, indicating that lysosomal destabilization and cathepsin release occur prior to regulated cell death. Treatment of RPE cells with caspase inhibitors and Nec-1 showed primarily caspase-dependent cell death in RPE cells whereas treatment of photoreceptor cells with caspase inhibitors and Nec-1 showed significant rescue of cell death. Chloroquine-injected animals demonstrated functional visual loss consistent with marked abnormality and disruption of the photoreceptor layer. Gene expression changes showed a significant up regulation of markers specific to caspase mediated cell death in the RPE and necrosis and oxidative stress markers in the neurosensory retina.</p><p><strong>Conclusions: </strong>ARPE-19 cells underwent both apoptotic and pyroptotic cell death while 661W cells showed activation of apoptosis and necroptosis. Chloroquine-injected mice demonstrated characteristic phenotypes also observed in human patients with chloroquine toxicity and showed activation of various cell death mediators. By elucidating the mechanism of chloroquine toxicity, we believe our findings can shed light on potential therapeutic agents.</p>","PeriodicalId":521221,"journal":{"name":"ScienceBank","volume":"2025 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12933429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147314741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}