RESUMO
Rhodopsin mutations are associated with the autosomal-dominant form of retinitis pigmentosa (RP). Here we report simultaneous occurrence of RP associated with bilateral nanophthalmos and acute angle-closure glaucoma in patient with a new mutation in rhodopsin (R135W). ARPE-19 cells were transfected with myc-tagged wild-type (WT) and R135W rhodopsin constructs. The half-life of WT and R135W rhodopsin was analyzed via cycloheximide chase analysis. We found that R135W rhodopsin was accumulated in the endoplasmic reticulum (ER) and induced unfolded protein response (UPR) and apoptosis. Moreover, chaperone HSP70 alleviated ER stress and prevented apoptosis induced by R135W rhodopsin by attenuating UPR signaling. These findings reveal the novel pathogenic mechanism of RP and suggest that chaperone HSP70 has potential therapeutic significance for RP.
Assuntos
Glaucoma de Ângulo Fechado/genética , Hiperopia/genética , Microftalmia/genética , Retinose Pigmentar/genética , Rodopsina/genética , Adulto , Apoptose/genética , Linhagem Celular , Criança , Pré-Escolar , Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Glaucoma de Ângulo Fechado/complicações , Glaucoma de Ângulo Fechado/patologia , Proteínas de Choque Térmico HSP72/genética , Humanos , Hiperopia/complicações , Hiperopia/patologia , Masculino , Microftalmia/complicações , Microftalmia/patologia , Pessoa de Meia-Idade , Chaperonas Moleculares/genética , Mutação/genética , Linhagem , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Retinose Pigmentar/complicações , Retinose Pigmentar/patologia , Transdução de Sinais/genética , Resposta a Proteínas não Dobradas , Sequenciamento do ExomaRESUMO
BACKGROUND: Non-proliferative diabetic retinopathy (NPDR) poses a significant challenge in diabetes management due to its microvascular changes in the retina. Laser photocoagulation, a conventional therapy, aims to mitigate the risk of progressing to proliferative diabetic retinopathy (PDR). AIM: To compare the efficacy and safety of multi-spot vs single-spot scanning panretinal laser photocoagulation in NPDR patients. METHODS: Forty-nine NPDR patients (86 eyes) treated between September 2020 and July 2022 were included. They were randomly allocated into single-spot (n = 23, 40 eyes) and multi-spot (n = 26, 46 eyes) groups. Treatment outcomes, including best-corrected visual acuity (BCVA), central macular thickness (CMT), and mean threshold sensitivity, were assessed at predetermined intervals over 12 months. Adverse reactions were also recorded. RESULTS: Energy levels did not significantly differ between groups (P > 0.05), but the multi-spot group exhibited lower energy density (P < 0.05). BCVA and CMT improvements were noted in the multi-spot group at one-month post-treatment (P < 0.05). Adverse reaction incidence was similar between groups (P > 0.05). CONCLUSION: While energy intensity and safety were comparable between modalities, multi-spot scanning demonstrated lower energy density and showed superior short-term improvements in BCVA and CMT for NPDR patients, with reduced laser-induced damage.
RESUMO
OBJECTIVE: Sepsis is a life-threatening condition in the ICU and requires treatment in time. Despite the accuracy of existing sepsis prediction models, insufficient focus on reducing alarms could worsen alarm fatigue and desensitisation in ICUs, potentially compromising patient safety. In this retrospective study, we aim to develop an accurate, robust, and readily deployable method in ICUs, only based on the vital signs and laboratory tests. METHODS: Our method consists of a customised down-sampling process and a specific dynamic sliding window and XGBoost to offer sepsis prediction. The down-sampling process was applied to the retrospective data for training the XGBoost model. During the testing stage, the dynamic sliding window and the trained XGBoost were used to predict sepsis on the retrospective datasets, PhysioNet and FHC. RESULTS: With the filtered data from PhysioNet, our method achieved 80.74% accuracy (77.90% sensitivity and 84.42% specificity) and 83.95% (84.82% sensitivity and 82.00% specificity) on the test set of PhysioNet-A and PhysioNet-B, respectively. The AUC score was 0.89 for both datasets. On the FHC dataset, our method achieved 92.38% accuracy (88.37% sensitivity and 95.16% specificity) and 0.98 AUC score on the test set of FHC. CONCLUSION: Our results indicate that the down-sampling process and the dynamic sliding window with XGBoost brought robust and accurate performance to give sepsis prediction under various hospital settings. The localisation and robustness of our method can assist in sepsis diagnosis in different ICU settings.
Assuntos
Sepse , Humanos , Estudos Retrospectivos , Sepse/diagnóstico , Aprendizado de Máquina , Sinais Vitais , Unidades de Terapia IntensivaRESUMO
Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function. Synaptic abnormalities, such as defects in the density and morphology of postsynaptic dendritic spines, underlie the pathology of various neuropsychiatric disorders. Protocadherin 17 (PCDH17) is associated with major mood disorders, including bipolar disorder and depression. However, the molecular mechanisms by which PCDH17 regulates spine number, morphology, and behavior remain elusive. In this study, we found that PCDH17 functions at postsynaptic sites, restricting the number and size of dendritic spines in excitatory neurons. Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety- and depression-like behaviors in mice. Mechanistically, PCDH17 interacts with actin-relevant proteins and regulates actin filament (F-actin) organization. Specifically, PCDH17 binds to ROCK2, increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3 (Ser3). Inhibition of ROCK2 activity with belumosudil (KD025) ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression, suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development. Hence, these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior, providing pathological insights into the neurobiological basis of mood disorders.