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Recently, fast Magnetic Resonance Imaging reconstruction technology has emerged as a promising way to improve the clinical diagnostic experience by significantly reducing scan times. While existing studies have used Generative Adversarial Networks to achieve impressive results in reconstructing MR images, they still suffer from challenges such as blurred zones/boundaries and abnormal spots caused by inevitable noise in the reconstruction process. To this end, we propose a novel deep framework termed Anisotropic Diffusion-Assisted Generative Adversarial Networks, which aims to maximally preserve valid high-frequency information and structural details while minimizing noises in reconstructed images by optimizing a joint loss function in a unified framework. In doing so, it enables more authentic and accurate MR image generation. To specifically handle unforeseeable noises, an Anisotropic Diffused Reconstruction Module is developed and added aside the backbone network as a denoise assistant, which improves the final image quality by minimizing reconstruction losses between targets and iteratively denoised generative outputs with no extra computational complexity during the testing phase. To make the most of valuable MRI data, we extend its application to support multi-modal learning to boost reconstructed image quality by aggregating more valid information from images of diverse modalities. Extensive experiments on public datasets show that the proposed framework can achieve superior performance in polishing up the quality of reconstructed MR images. For example, the proposed method obtains average PSNR and mSSIM values of 35.785dB and 0.9765 on the MRNet dataset, which are at least about 2.9dB and 0.07 higher than those from the baselines.
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OBJECTIVE: We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts. DESIGN: Secondary analysis of four prospective population-based studies. PARTICIPANTS: We included four European-ancestry cohorts: the United States (US) based Nurses' Health Study (NHS), NHS2, and the Health Professionals Follow-up Study, and the Rotterdam Study (RS) in the Netherlands. The US cohorts included female nurses and male health professionals aged 55+ years. The RS included residents aged 45 years or older living in Rotterdam, the Netherlands. METHODS: PRS weights were estimated by applying the Lassosum method on imputed genotype and phenotype data from the UK-Biobank. This resulted in 144,020 variants, single nucleotide polymorphism (SNPs) and indels, with non-zero betas that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C-statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits. MAIN OUTCOME MEASURES: The relative risk for POAG and Harrell's C-statistic (the equivalent of an area-under-the-curve for longitudinal models). RESULTS: Among 1,046 cases and 38,809⬠controls, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08, 5.18) in the US cohorts, and 4.89 (2.93, 8.17) in the Rotterdam Study, compared with participants with median genetic risk (3rd quintile). In restricted cubic spline analyses, the relation between continuous PRS and POAG risk increased exponentially in the US and Rotterdam cohorts (Pspline<0.05). Combining age, sex, intraocular pressure >25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (0.73, 0.75). Adding the PRS to this model improved the concordance to 0.82 (0.80, 0.84). In a meta-analysis of all cohorts, cases in the highest tertile had a larger cup-disc ratio at diagnosis, by 0.11 (0.07, 0.15), and a 2.07-fold increased risk of requiring glaucoma surgery (1.19, 3.60). CONCLUSIONS: Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies.
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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease for which there is a lack of effective pharmacological treatments. Hirudin, a natural peptide extracted from leeches, has been used for broad pharmacological purposes. In this study, we investigated the therapeutic effects of hirudin on IPF and its related mechanism of action. By constructing a mouse model of pulmonary fibrosis and treating it with hirudin in vivo, we found that hirudin exerted anti-fibrotic, anti-oxidative, and anti-fibroblast senescence effects. Moreover, using an in vitro model of stress-induced premature senescence in primary mouse lung fibroblasts and treating with hirudin, we observed inhibition of fibroblast senescence and upregulation of PGC1-alpha and Sirt3 expression. However, specific silencing of PGC1-alpha or Sirt3 suppressed the anti-fibroblast senescence effect of hirudin. Thus, the PGC1-alpha/Sirt3 pathway mediates the anti-fibroblast senescence effect of hirudin, potentially serving as a molecular mechanism underlying its anti-fibrosis and anti-oxidative stress effects exerted on the lungs.
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PURPOSE: Polygenic risk scores (PRSs) likely predict risk and prognosis of glaucoma. We compared the PRS performance for primary open-angle glaucoma (POAG), defined using International Classification of Diseases (ICD) codes vs manual medical record review. DESIGN: Retrospective cohort study. METHODS: We identified POAG cases in the Mount Sinai BioMe and Mass General Brigham (MGB) biobanks using ICD codes. We confirmed POAG based on optical coherence tomograms and visual fields. In a separate 5% sample, the absence of POAG was confirmed with intraocular pressure and cup-disc ratio criteria. We used genotype data and either self-reported glaucoma diagnoses or ICD-10 codes for glaucoma diagnoses from the UK Biobank and the lassosum method to compute a genome-wide POAG PRS. We compared the area under the curve (AUC) for POAG prediction based on ICD codes vs medical records. RESULTS: We reviewed 804 of 996 BioMe and 367 of 1006 MGB ICD-identified cases. In BioMe and MGB, respectively, positive predictive value was 53% and 55%; negative predictive value was 96% and 97%; sensitivity was 97% and 97%; and specificity was 44% and 53%. Adjusted PRS AUCs for POAG using ICD codes vs manual record review in BioMe were not statistically different (P ≥.21) by ancestry: 0.77 vs 0.75 for African, 0.80 vs 0.80 for Hispanic, and 0.81 vs 0.81 for European. Results were similar in MGB (P ≥.18): 0.72 vs 0.80 for African, 0.83 vs 0.86 for Hispanic, and 0.74 vs 0.73 for European. CONCLUSIONS: A POAG PRS performed similarly using either manual review or ICD codes in 2 electronic health record-linked biobanks; manual assessment of glaucoma status might not be necessary for some PRS studies. However, caution should be exercised when using ICD codes for glaucoma diagnosis given their low specificity (44%-53%) for manually confirmed cases of glaucoma.
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Idiopathic pulmonary fibrosis is a fatal interstitial lung disease for which effective drug therapies are lacking. Senegenin, an effective active compound from the traditional Chinese herb Polygala tenuifolia Willd, has been shown to have a wide range of pharmacological effects. In this study, we investigated the therapeutic effects of senegenin on pulmonary fibrosis and their associated mechanisms of action. We found that senegenin inhibited the senescence of epithelial cells and thus exerted anti-pulmonary-fibrosis effects by inhibiting oxidative stress. In addition, we found that senegenin promoted the expression of Sirt1 and Pgc-1α and that the antioxidative and antisenescent effects of senegenin were suppressed by specific silencing of the Sirt1 and Pgc-1α genes, respectively. Moreover, the senegenin-induced effects of antioxidation, antisenescence of epithelial cells, and antifibrosis were inhibited by treatment with Sirt1 inhibitors in vivo. Thus, the Sirt1/Pgc-1α pathway exerts its antifibrotic effect on lung fibrosis by mediating the antioxidative and antisenescent effects of senegenin.
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Central serous chorioretinopathy (CSC) is a fluid maculopathy whose etiology is not well understood. Abnormal choroidal veins in CSC patients have been shown to have similarities with varicose veins. To identify potential mechanisms, we analyzed genotype data from 1,477 CSC patients and 455,449 controls in FinnGen. We identified an association for a low-frequency (AF=0.5%) missense variant (rs113791087) in the gene encoding vascular endothelial protein tyrosine phosphatase (VE-PTP) (OR=2.85, P=4.5×10-9). This was confirmed in a meta-analysis of 2,452 CSC patients and 865,767 controls from 4 studies (OR=3.06, P=7.4×10-15). Rs113791087 was associated with a 56% higher prevalence of retinal abnormalities (35.3% vs 22.6%, P=8.0×10-4) in 708 UK Biobank participants and, surprisingly, with varicose veins (OR=1.31, P=2.3×10-11) and glaucoma (OR=0.82, P=6.9×10-9). Predicted loss-of-function variants in VEPTP, though rare in number, were associated with CSC in All of Us (OR=17.10, P=0.018). These findings highlight the significance of VE-PTP in diverse ocular and systemic vascular diseases.
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Advances in gene sequencing technologies have accelerated the identification of genetic variants, but better tools are needed to understand which are causal of disease. This would be particularly useful in fields where gene therapy is a potential therapeutic modality for a disease-causing variant such as inherited retinal disease (IRD). Here, we apply structure-based network analysis (SBNA), which has been successfully utilized to identify variant-constrained amino acid residues in viral proteins, to identify residues that may cause IRD if subject to missense mutation. SBNA is based entirely on structural first principles and is not fit to specific outcome data, which makes it distinct from other contemporary missense prediction tools. In 4 well-studied human disease-associated proteins (BRCA1, HRAS, PTEN, and ERK2) with high-quality structural data, we find that SBNA scores correlate strongly with deep mutagenesis data. When applied to 47 IRD genes with available high-quality crystal structure data, SBNA scores reliably identified disease-causing variants according to phenotype definitions from the ClinVar database. Finally, we applied this approach to 63 patients at Massachusetts Eye and Ear (MEE) with IRD but for whom no genetic cause had been identified. Untrained models built using SBNA scores and BLOSUM62 scores for IRD-associated genes successfully predicted the pathogenicity of novel variants (AUC = 0.851), allowing us to identify likely causative disease variants in 40 IRD patients. Model performance was further augmented by incorporating orthogonal data from EVE scores (AUC = 0.927), which are based on evolutionary multiple sequence alignments. In conclusion, SBNA can used to successfully identify variants as causal of disease in human proteins and may help predict variants causative of IRD in an unbiased fashion.
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BACKGROUND: Idiopathic pulmonary fibrosis is a persistent disease of the lung interstitium for which there is no efficacious pharmacological therapy. Protodioscin, a steroidal saponin, possesses diverse pharmacological properties; however, its function in pulmonary fibrosis is yet to be established. Hence, in this investigation, it was attempted to figure out the anti-pulmonary fibrosis influences of protodioscin and its pharmacological properties related to oxidative stress. METHODS: A mouse lung fibrosis model was generated using tracheal injections of bleomycin, followed by intraperitoneal injection of different concentrations of protodioscin, and the levels of oxidative stress and fibrosis were detected in the lungs. Multiple fibroblasts were treated with TGF-ß to induce their transition to myofibroblasts. It was attempted to quantify myofibroblast markers' expression levels and reactive oxygen species levels as well as Nrf2 activation after co-incubation of TGF-ß with fibroblasts and different concentrations of protodioscin. The influence of protodioscin on the expression and phosphorylation of p62, which is associated with Nrf2 activation, were detected, and p62 related genes were predicted by STRING database. The effects of Nrf2 inhibitor or silencing of the Nrf2, p62 and NBR1 genes, respectively, on the activation of Nrf2 by protodioscin were examined. The associations between p62, NBR1, and Keap1 in the activation of Nrf2 by protodioscin was demonstrated using a co-IP assay. Nrf2 inhibitor were used when protodioscin was treated in mice with pulmonary fibrosis and lung tissue fibrosis and oxidative stress levels were detected. RESULTS: In vivo, protodioscin decreased the levels of fibrosis markers and oxidative stress markers and activated Nrf2 in mice with pulmonary fibrosis, and these effects were inhibited by Nrf2 inhibitor. In vitro, protodioscin decreased the levels of myofibroblast markers and oxidative stress markers during myofibroblast transition and promoted Nrf2 downstream gene expression, with reversal of these effects after Nrf2, p62 and NBR1 genes were silenced or Nrf2 inhibitors were used, respectively. Protodioscin promoted the binding of NBR1 to p62 and Keap1, thereby reducing Keap1-Nrf2 binding. CONCLUSION: The NBR1-p62-Nrf2 axis is targeted by protodioscin to reduce oxidative stress and inhibit pulmonary fibrosis.
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Importance: Primary open-angle glaucoma (POAG) is a highly heritable disease, with 127 identified risk loci to date. Polygenic risk score (PRS) may provide a clinically useful measure of aggregate genetic burden and improve patient risk stratification. Objective: To assess whether a PRS improves prediction of POAG onset in patients with ocular hypertension. Design, Setting, and Participants: This was a post hoc analysis of the Ocular Hypertension Treatment Study. Data were collected from 22 US sites with a mean (SD) follow-up of 14.0 (6.9) years. A total of 1636 participants were followed up from February 1994 to December 2008; 1077 participants were enrolled in an ancillary genetics study, of which 1009 met criteria for this analysis. PRS was calculated using summary statistics from the largest cross-ancestry POAG meta-analysis, with weights trained using 8â¯813â¯496 variants from 449â¯186 cross-ancestry participants in the UK Biobank. Data were analyzed from July 2022 to December 2023. Exposures: From February 1994 to June 2002, participants were randomized to either topical intraocular pressure-lowering medication or close observation. After June 2002, both groups received medication. Main Outcomes and Measures: Outcome measures were hazard ratios for POAG onset. Concordance index and time-dependent areas under the receiver operating characteristic curve were used to compare the predictive performance of multivariable Cox proportional hazards models. Results: Of 1009 included participants, 562 (55.7%) were female, and the mean (SD) age was 55.9 (9.3) years. The mean (SD) PRS was significantly higher for 350 POAG converters (0.24 [0.95]) compared with 659 nonconverters (-0.12 [1.00]) (P < .001). POAG risk increased 1.36% (95% CI, 1.08-1.64) with each higher PRS decile, with conversion ranging from 9.52% (95% CI, 7.09-11.95) in the lowest PRS decile to 21.81% (95% CI, 19.37-24.25) in the highest decile. Comparison of low-risk and high-risk PRS tertiles showed a 2.0-fold increase in 20-year POAG risk for participants of European and African ancestries. In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year (95% CI, 0.01-1.03) decrease in age at diagnosis (P = .047). No significant linear association between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C index = 0.77) compared with the Ocular Hypertension Treatment Study baseline model (C index = 0.75) (P < .001). Each 1-SD higher PRS conferred a mean hazard ratio of 1.25 (95% CI, 1.13-1.44) for POAG onset. Conclusions and Relevance: Higher PRS was associated with increased risk for POAG in patients with ocular hypertension. The inclusion of a PRS improved the prediction of POAG onset. Trial Registration: ClinicalTrials.gov Identifier: NCT00000125.
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Glaucoma de Ángulo Abierto , Hipertensión Ocular , Humanos , Femenino , Persona de Mediana Edad , Masculino , Glaucoma de Ángulo Abierto/diagnóstico , Puntuación de Riesgo Genético , Factores de Riesgo , Hipertensión Ocular/diagnóstico , Presión IntraocularRESUMEN
Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq of glaucoma-relevant eye tissues reveals that the POAG and IOP colocalizing genes and genome-wide associations are enriched in specific cell types in the aqueous outflow pathways, retina, optic nerve head, peripapillary sclera, and choroid. This study nominates IOP-dependent and independent regulatory mechanisms, genes, and cell types that may contribute to POAG pathogenesis.
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Glaucoma de Ángulo Abierto , Glaucoma , Humanos , Estudio de Asociación del Genoma Completo , Glaucoma de Ángulo Abierto/genética , Regulación de la Expresión Génica , Causalidad , Glaucoma/genéticaRESUMEN
By reshaping the substrate-binding pocket of ß-amino acid dehydrogenase (ß-AADH), some variants were obtained with up to 2560-fold enhanced activity toward the model substrates (S)-ß-homophenylalanine and (R)-ß-phenylalanine. A few aromatic ß-amino acids were prepared with >99% ee and high isolated yields via either kinetic resolution of racemates or reductive amination of the corresponding ß-keto acids. This work expands the catalytic capability of ß-AADHs and highlights their practical application in the synthesis of pharmaceutically relevant ß-amino acids.
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Aminoácido Oxidorreductasas , Aminoácidos Aromáticos , Aminoácidos Aromáticos/metabolismo , Aminoácido Oxidorreductasas/química , Aminoácido Oxidorreductasas/metabolismo , Aminoácidos/metabolismo , Aminación , Cetoácidos , Especificidad por SustratoRESUMEN
BACKGROUND: Acute lung injury (ALI) is a severe disease that can lead to acute respiratory distress syndrome (ARDS), characterized by intractable hypoxemia, poor lung compliance, and respiratory failure, severely affecting patients' quality of life. The pathogenesis of ALI has not been fully elucidated yet, and sepsis is an important cause of ALI. Among the organ injuries caused by sepsis, the lungs are the earliest damaged ones. Radix cyathulae is reported to have analgesic, anti-inflammatory, and anti-aging effects. Cyasterone is extracted from Radix cyathulae. However, it is not known whether cyasterone has protective effects for ALI. This study aims to investigate the effect of cyasterone on sepsis-related ALI and its mechanism. METHODS: We used the cecal ligation peferation (CLP) method to establish a mouse sepsis model, and cyasterone was given intraperitoneally on days 1-3 to observe its preventive effect on sepsis-related acute lung injury. Primary murine peritoneal macrophages were used to investigate the molecular mechanism of cyasterone in vitro. RESULTS: Cyasterone pretreatment inhibits pro-inflammatory cytokine production, NLRP3 inflammasome activation, and oxidative stress in vivo and in vitro. In addition, cyasterone attenuates sepsis-induced ALI by activating nuclear factor erythroid2-related factor (Nrf2), which may be associated with AKT(Ser473)/GSK3ß(Ser9) pathway activation. CONCLUSIONS: Cyasterone defends against sepsis-induced ALI by inhibiting inflammatory responses and oxidative stress, which depends heavily on the upregulation of the Nrf2 pathway through phosphorylation of AKT(Ser473)/GSK3ß(Ser9). These results suggest cyasterone may be a valuable drug candidate for preventing sepsis-related ALI.
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Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that lacks effective treatment modalities. Once patients are diagnosed with IPF, their median survival is approximately 3-5 years. PPARγ is an important target for the prevention and treatment of pulmonary fibrosis. Asarinin is a lignan compound that can be extracted from food plant Asarum heterotropoides. In this study, we investigated the therapeutic effects of asarinin in a pulmonary fibrosis model constructed using bleomycin in mice and explored the underlying mechanisms. Intraperitoneal administration of asarinin to mice with pulmonary fibrosis showed that asarinin effectively attenuated pulmonary fibrosis, and this effect was significantly inhibited by the PPARγ inhibitor GW9662. Asarinin inhibited TGF-ß1-induced fibroblast-to-myofibroblast transition in vitro, while GW9662 and PPARγ gene silencing significantly inhibited this effect. In addition, asarinin inhibited not only the canonical Smad pathway of TGF-ß but also the non-canonical AKT and MAPK pathways by activating PPARγ. Our study demonstrates that asarinin can be used as a therapeutic agent for pulmonary fibrosis, and that PPARγ is its key target.
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Fibrosis Pulmonar Idiopática , Lignanos , Animales , Ratones , PPAR gamma , Lignanos/farmacología , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Bleomicina/efectos adversosRESUMEN
Importance: Better understanding of primary open-angle glaucoma (POAG) genetics could enable timely screening and promote individualized disease risk prognostication. Objective: To evaluate phenotypic features across genetic burden for POAG. Design, Setting, and Participants: This was a cross-sectional, population-based study conducted from 2006 to 2010. Included participants were individuals from the UK Biobank aged 40 to 69 years. Individuals with non-POAG forms of glaucoma were excluded from the analysis. Data were statistically analyzed from October 2022 to January 2023. Main Outcomes and Measures: POAG prevalence based on structural coding, self-reports, and glaucoma-related traits. Results: Among 407â¯667 participants (mean [SD] age, 56.3 [8.1] years; 219â¯183 majority sex [53.8%]) were 14â¯171 POAG cases. Area under receiver operating characteristic curve for POAG detection was 0.748 in a model including polygenic risk score (PRS), age, sex, and ancestry. POAG prevalence in the highest decile of PRS was 7.4% (3005 of 40â¯644) vs 1.3% (544 of 40â¯795) in lowest decile (P < .001). A 1-SD increase in PRS was associated with 1.74 times higher odds of POAG (95% CI, 1.71-1.77), a 0.61-mm Hg increase in corneal-compensated intraocular pressure (IOP; 95% CI, 0.59-0.64), a -0.09-mm Hg decrease in corneal hysteresis (95% CI, -0.10 to -0.08), a 0.08-mm Hg increase in corneal resistance factor (95% CI, 0.06-0.09), and a -0.08-diopter decrease in spherical equivalent (95% CI, -0.11 to -0.07; P < .001 for all). A 1-SD increase in PRS was associated with a thinning of the macula-region retinal nerve fiber layer (mRNFL) of 0.14 µm and macular ganglion cell complex (GCC) of 0.26 µm (P < .001 for both). In the subset of individuals with fundus photographs, a 1-SD increase in PRS was associated with 1.42 times higher odds of suspicious optic disc features (95% CI, 1.19-1.69) and a 0.013 increase in cup-disc ratio (CDR; 95% CI, 0.012-0.014; P < .001 for both). A total of 22 of 5193 fundus photographs (0.4%) in decile 10 had disc hemorrhages, and 27 of 5257 (0.5%) had suspicious optic disc features compared with 9 of 5158 (0.2%) and 10 of 5219 (0.2%), respectively, in decile 1 (P < .001 for both). CDR in decile 10 was 0.46 compared with 0.41 in decile 1 (P < .001). Conclusion and Relevance: Results suggest that PRS identified a group of individuals at substantially higher risk for POAG. Higher genetic risk was associated with more advanced disease, namely higher CDR and corneal-compensated IOP, thinner mRNFL, and thinner GCC. Associations with POAG PRS and corneal hysteresis and greater prevalence of disc hemorrhages were identified. These results suggest that genetic risk is an increasingly important parameter for risk stratification to consider in clinical practice.
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Glaucoma de Ángulo Abierto , Glaucoma , Humanos , Persona de Mediana Edad , Estudios Transversales , Glaucoma de Ángulo Abierto/diagnóstico , Glaucoma de Ángulo Abierto/epidemiología , Glaucoma de Ángulo Abierto/genética , Córnea , HemorragiaRESUMEN
Objective or Purpose: Primary open-angle glaucoma (POAG) is a highly heritable disease with 127 identified risk loci. Polygenic risks score (PRS) offers a measure of aggregate genetic burden. In this study, we assess whether PRS improves risk stratification in patients with ocular hypertension. Design: A post-hoc analysis of the Ocular Hypertension Treatment Study (OHTS) data. Setting Participants and/or Controls: 1636 participants were followed from 1994 to 2020 across 22 sites. The PRS was computed for 1009 OHTS participants using summary statistics from largest cross-ancestry POAG metanalysis with weights trained using 8,813,496 variants from 488,395 participants in the UK Biobank. Methods Interventions or Testing: Survival regression analysis, with endpoint as development of POAG, predicted disease onset from PRS incorporating baseline covariates. Main Outcomes and Measures: Outcome measures were hazard ratios for POAG onset. Concordance index and time-dependent AUC were used to compare the predictive performance of multivariable Cox-Proportional Hazards models. Results: Mean PRS was significantly higher for POAG-converters (0.24 ± 0.95) than for non-converters (-0.12 ± 1.00) (p < 0.01). POAG risk increased 1.36% with each higher PRS decile, with conversion ranging from 9.5% in the lowest PRS decile to 21.8% in the highest decile. Comparison of low- and high-risk PRS tertiles showed a 1.8-fold increase in 20-year POAG risk for participants of European and African ancestries (p<0.01). In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year decrease in age at diagnosis, (p=0.05). No significant linear relationship between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C-index = 0.77) compared to OHTS baseline model (C-index=0.75) (p<0.01). One standard deviation higher PRS conferred a mean hazard ratio of 1.25 (CI=[1.13, 1.44]) for POAG onset. Conclusions: Higher PRS is associated with increased risk for, and earlier development of POAG in patients with ocular hypertension. Early treatment may mitigate the risk from high genetic burden, delaying clinically detectable disease by up to 5.2 years. The inclusion of a PRS improves the prediction of POAG onset.
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With continued advances in gene sequencing technologies comes the need to develop better tools to understand which mutations cause disease. Here we validate structure-based network analysis (SBNA)1,2 in well-studied human proteins and report results of using SBNA to identify critical amino acids that may cause retinal disease if subject to missense mutation. We computed SBNA scores for genes with high-quality structural data, starting with validating the method using 4 well-studied human disease-associated proteins. We then analyzed 47 inherited retinal disease (IRD) genes. We compared SBNA scores to phenotype data from the ClinVar database and found a significant difference between benign and pathogenic mutations with respect to network score. Finally, we applied this approach to 65 patients at Massachusetts Eye and Ear (MEE) who were diagnosed with IRD but for whom no genetic cause was found. Multivariable logistic regression models built using SBNA scores for IRD-associated genes successfully predicted pathogenicity of novel mutations, allowing us to identify likely causative disease variants in 37 patients with IRD from our clinic. In conclusion, SBNA can be meaningfully applied to human proteins and may help predict mutations causative of IRD.
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OBJECTIVE: The m6A modification is the most common ribonucleic acid (RNA) modification, playing a role in prompting the virus's gene mutation and protein structure changes in the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Nanopore single-molecule direct RNA sequencing (DRS) provides data support for RNA modification detection, which can preserve the potential m6A signature compared to second-generation sequencing. However, due to insufficient DRS data, there is a lack of methods to find m6A RNA modifications in DRS. Our purpose is to identify m6A modifications in DRS precisely. METHODS: We present a methodology for identifying m6A modifications that incorporated mapping and extracted features from DRS data. To detect m6A modifications, we introduce an ensemble method called mixed-weight neural bagging (MWNB), trained with 5-base RNA synthetic DRS containing modified and unmodified m6A. RESULTS: Our MWNB model achieved the highest classification accuracy of 97.85% and AUC of 0.9968. Additionally, we applied the MWNB model to the COVID-19 dataset; the experiment results reveal a strong association with biomedical experiments. CONCLUSION: Our strategy enables the prediction of m6A modifications using DRS data and completes the identification of m6A modifications on the SARS-CoV-2. SIGNIFICANCE: The Corona Virus Disease 2019 (COVID-19) outbreak has significantly influence, caused by the SARS-CoV-2. An RNA modification called m6A is connected with viral infections. The appearance of m6A modifications related to several essential proteins affects proteins' structure and function. Therefore, finding the location and number of m6A RNA modifications is crucial for subsequent analysis of the protein expression profile.
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COVID-19 , SARS-CoV-2 , Humanos , ARN Viral/análisis , ARN Viral/genética , SARS-CoV-2/genética , Análisis de Secuencia de ARNRESUMEN
Traumatic brain injury is a major public health concern. A significant proportion of individuals experience post-traumatic brain injury behavioural impairments, especially in attention and inhibitory control domains. Traditional diffusion-weighted MRI techniques, such as diffusion tensor imaging, have provided tools to assess white matter structural disruptions reflecting the long-term brain tissue alterations associated with traumatic brain injury. The recently developed neurite orientation dispersion and density imaging is a more advanced diffusion MRI modality, which provides more refined characterization of brain tissue microstructures by assessing the neurite orientation dispersion and neurite density properties. In this study, neurite orientation dispersion and density imaging data from 44 young adults with chronic traumatic brain injury (who had no prior-injury diagnoses of any sub-presentation of attention deficits/hyperactivity disorder or experience of severe inattentive and/or hyperactive behaviours) and 45 group-matched normal controls were investigated, to assess the post-injury morphometrical and microstructural brain alterations and their relationships with the behavioural outcomes. Maps of fractional anisotropy, neurite orientation dispersion index and neurite density index were calculated. Vertex-wise and voxel-wise analyses were conducted for grey matter and white matter, respectively. Post hoc region-of-interest-based analyses were also performed. Compared to the controls, the group of traumatic brain injury showed significantly increased orientation dispersion index and significantly decreased neurite density index in various grey matter regions, as well as significantly decreased orientation dispersion index in several white matter regions. Brain-behavioural association analyses indicated that the reduced neurite density index of the left precentral gyrus and the reduced orientation dispersion index of the left superior longitudinal fasciculus were significantly associated with elevated hyperactive/impulsive symptoms in the patients with traumatic brain injury. These findings suggest that post-injury chronical neurite intracellular volume and angular distribution anomalies in the frontal lobe, practically the precentral area, can significantly contribute to the onset of hyperactive/impulsive behaviours in young adults with traumatic brain injury.
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Background: Traumatic brain injury (TBI)-induced attention deficits are among the most common long-term cognitive consequences in children. Most of the existing studies attempting to understand the neuropathological underpinnings of cognitive and behavioral impairments in TBI have utilized heterogeneous samples and resulted in inconsistent findings. The current research proposed to investigate topological properties of the structural brain network in children with TBI and their relationship with post-TBI attention problems in a more homogeneous subgroup of children who had severe post-TBI attention deficits (TBI-A). Materials and Methods: A total of 31 children with TBI-A and 35 group-matched controls were involved in the study. Diffusion tensor imaging-based probabilistic tractography and graph theoretical techniques were used to construct the structural brain network in each subject. Network topological properties were calculated in both global level and regional (nodal) level. Between-group comparisons among the topological network measures and analyses for searching brain-behavioral were all corrected for multiple comparisons using Bonferroni method. Results: Compared with controls, the TBI-A group showed significantly higher nodal local efficiency and nodal clustering coefficient in left inferior frontal gyrus and right transverse temporal gyrus, whereas significantly lower nodal clustering coefficient in left supramarginal gyrus and lower nodal local efficiency in left parahippocampal gyrus. The temporal lobe topological alterations were significantly associated with the post-TBI inattentive and hyperactive symptoms in the TBI-A group. Conclusion: The results suggest that TBI-related structural re-modularity in the white matter subnetworks associated with temporal lobe may play a critical role in the onset of severe post-TBI attention deficits in children. These findings provide valuable input for understanding the neurobiological substrates of post-TBI attention deficits, and have the potential to serve as quantitatively measurable criteria guiding the development of more timely and tailored strategies for diagnoses and treatments to the affected individuals. Impact statement This study provides a new insight into the neurobiological substrates associated with post-traumatic brain injury attention deficits (TBI-A) in children, by evaluating topological alterations of the structural brain network. The results demonstrated that relative to group-matched controls, the children with TBI-A had significantly altered nodal local efficiency and nodal clustering coefficient in temporal lobe, which strongly linked to elevated inattentive and hyperactive symptoms in the TBI-A group. These findings suggested that white matter structural re-modularity in subnetworks associated with temporal lobe may serve as quantitatively measurable biomarkers for early prediction and diagnosis of post-TBI attention deficits in children.
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Trastorno por Déficit de Atención con Hiperactividad , Lesiones Traumáticas del Encéfalo , Sustancia Blanca , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico por imagen , Trastorno por Déficit de Atención con Hiperactividad/etiología , Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Niño , Imagen de Difusión Tensora , HumanosRESUMEN
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