Inorganic Pyrophosphate at Serum Concentration May Not Be Able to Inhibit Mineralization: A Study in Aqueous Solutions and Serum.

The constituent ions of calcium phosphate in body fluids are in the supersaturated state and tend to form minerals physiologically or pathologically. Inorganic pyrophosphate (PPi) has been considered as one of the most important inhibitors against the formation of calcium phosphate minerals. However, serum PPi concentrations in humans are maintained at a level of several µmol/L, and its effectiveness and mechanism for mineralization inhibition remain ambiguous. Therefore, this work studied the mineralization process in an aqueous solution, explored the effective inhibitory concentration of PPi by titration, and characterized the species during the reactions. We find that PPi at a normal serum concentration does not inhibit mineralization significantly. Such a conclusion was further confirmed in the PPi-added serum. This work indicates that PPi may not be a major direct inhibitor of mineralization in serum and possibly functions via alternative mechanisms.

Rediscovering AMD with Swept-Source OCT Imaging: The 2022 Charles L. Schepens, MD, Lecture.

PURPOSE: Swept-source optical coherence tomography angiography (SS-OCTA) scans of eyes with age-related macular degeneration (AMD) were used to replace color, autofluorescence, infrared reflectance, and dye-based fundus angiographic imaging for the diagnosis and staging of AMD. Through the use of different algorithms with the SS-OCTA scans, both structural and angiographic information can be viewed and assessed using both cross-sectional and en face imaging strategies. DESIGN: Presented at the 2022 Charles L. Schepens, MD, Lecture at the American Academy of Ophthalmology Retina Subspecialty Day, Chicago, Illinois, on September 30, 2022 PARTICIPANTS: Patients with AMD METHODS: Review of published literature and ongoing clinical research using SS-OCTA imaging in AMD. MAIN OUTCOME MEASURES: SS-OCTA imaging of AMD at different stages of disease progression. RESULTS: Volumetric SS-OCTA dense raster scans were used to diagnose and stage both exudative and nonexudative AMD. In eyes with nonexudative AMD, a single SS-OCTA scan was used to detect and measure structural features in the macula such as the area and volume of both typical soft drusen and calcified drusen, the presence and location of hyperreflective foci, the presence of reticular pseudodrusen, also known as subretinal drusenoid deposits, the thickness of the outer retinal layer, the presence and thickness of basal laminar deposits, the presence and area of persistent choroidal hypertransmission defects, and the presence of treatment-naïve nonexudative macular neovascularization. In eyes with exudative AMD, the same SS-OCTA scan pattern was used to detect and measure the presence of macular fluid, the presence and type of macular neovascularization, and the response of exudation to treatment with vascular endothelial growth factor inhibitors. In addition, the same scan pattern was used to quantitate choriocapillaris (CC) perfusion, CC thickness, choroidal thickness, and the vascularity of the choroid. CONCLUSIONS: Compared with using several different instruments to perform multimodal imaging, a single SS-OCTA scan provides a convenient, comfortable, and comprehensive approach for obtaining qualitative and quantitative anatomic and angiographic information to monitor the onset, progression, and response to therapies in both nonexudative and exudative AMD.

AbDPP: Target-oriented antibody design with pretraining and prior biological structure knowledge.

Antibodies represent a crucial class of complex protein therapeutics and are essential in the treatment of a wide range of human diseases. Traditional antibody discovery methods, such as hybridoma and phage display technologies, suffer from limitations including inefficiency and a restricted exploration of the immense space of potential antibodies. To overcome these limitations, we propose a novel method for generating antibody sequences using deep learning algorithms called AbDPP (target-oriented antibody design with pretraining and prior biological knowledge). AbDPP integrates a pretrained model for antibodies with biological region information, enabling the effective use of vast antibody sequence data and intricate biological system understanding to generate sequences. To target specific antigens, AbDPP incorporates an antibody property evaluation model, which is further optimized based on evaluation results to generate more focused sequences. The efficacy of AbDPP was assessed through multiple experiments, evaluating its ability to generate amino acids, improve neutralization and binding, maintain sequence consistency, and improve sequence diversity. Results demonstrated that AbDPP outperformed other methods in terms of the performance and quality of generated sequences, showcasing its potential to enhance antibody design and screening efficiency. In summary, this study contributes to the field by offering an innovative deep learning-based method for antibody generation, addressing some limitations of traditional approaches, and underscoring the importance of integrating a specific antibody pretrained model and the biological properties of antibodies in generating novel sequences. The code and documentation underlying this article are freely available at https://github.com/zlfyj/AbDPP.

Deep-learning-based automated measurement of outer retinal layer thickness for use in the assessment of age-related macular degeneration, applicable to both swept-source and spectral-domain OCT imaging.

Effective biomarkers are required for assessing the progression of age-related macular degeneration (AMD), a prevalent and progressive eye disease. This paper presents a deep learning-based automated algorithm, applicable to both swept-source OCT (SS-OCT) and spectral-domain OCT (SD-OCT) scans, for measuring outer retinal layer (ORL) thickness as a surrogate biomarker for outer retinal degeneration, e.g., photoreceptor disruption, to assess AMD progression. The algorithm was developed based on a modified TransUNet model with clinically annotated retinal features manifested in the progression of AMD. The algorithm demonstrates a high accuracy with an intersection of union (IoU) of 0.9698 in the testing dataset for segmenting ORL using both SS-OCT and SD-OCT datasets. The robustness and applicability of the algorithm are indicated by strong correlation (r = 0.9551, P < 0.0001 in the central-fovea 3 mm-circle, and r = 0.9442, P < 0.0001 in the 5 mm-circle) and agreement (the mean bias = 0.5440 um in the 3-mm circle, and 1.392 um in the 5-mm circle) of the ORL thickness measurements between SS-OCT and SD-OCT scans. Comparative analysis reveals significant differences (P < 0.0001) in ORL thickness among 80 normal eyes, 30 intermediate AMD eyes with reticular pseudodrusen, 49 intermediate AMD eyes with drusen, and 40 late AMD eyes with geographic atrophy, highlighting its potential as an independent biomarker for predicting AMD progression. The findings provide valuable insights into the ORL alterations associated with different stages of AMD and emphasize the potential of ORL thickness as a sensitive indicator of AMD severity and progression.

Unleashing the power of optical attenuation coefficients to facilitate segmentation strategies in OCT imaging of age-related macular degeneration: perspective.

The use of optical attenuation coefficients (OAC) in optical coherence tomography (OCT) imaging of the retina has improved the segmentation of anatomic layers compared with traditional intensity-based algorithms. Optical attenuation correction has improved our ability to measure the choroidal thickness and choroidal vascularity index using dense volume scans. Algorithms that combine conventional intensity-based segmentation with depth-resolved OAC OCT imaging have been used to detect elevations of the retinal pigment epithelium (RPE) due to drusen and basal laminar deposits, the location of hyperpigmentation within the retina and along the RPE, the identification of macular atrophy, the thickness of the outer retinal (photoreceptor) layer, and the presence of calcified drusen. OAC OCT algorithms can identify the risk-factors that predict disease progression in age-related macular degeneration.

The Impact of Cataracts on the Measurement of Macular Choriocapillaris Flow Deficits Using Swept-Source OCT Angiography.

Purpose: The impact of cataracts on the measurement of macular choriocapillaris flow deficits (CC FDs) was assessed by comparing the quantitative results before and after cataract surgery using an image quality algorithm developed for swept-source optical coherence tomography angiography (SS-OCTA) scans and a validated strategy for quantifying the CC FDs. Methods: SS-OCTA image quality scores and CC FDs measurements within the fovea-centered 1-mm, 3-mm, and 5-mm diameter circles were compared before and after cataract surgery. CC FDs changes in a modified Early Treatment Diabetic Retinopathy Study (ETDRS) grid were further investigated. Results: Twenty-four eyes were studied. Overall image quality in all three circles was observed to improve significantly following the removal of cataracts (all P < 0.05). Although there was good repeatability in the measurements of CC FDs at both visits (intraclass correlation coefficients were over 0.95), significant decreases in CC FD measurements were observed after surgery within the 1-mm circle (P < 0.001) and the 3-mm circle (P = 0.011), but no changes were observed within the 5-mm circle (P = 0.509) or any of the quadrant sectors of the modified ETDRS grid (all P > 0.05). Conclusions: The presence of cataracts resulted in worse image quality and increased CC FD measurements within the fovea-centered 1-mm and 3-mm circles, with the 1-mm circle being impacted the most. Translational Relevance: The impaired detection of CC perfusion deficits within the central macula of cataract eyes needs to be appreciated when imaging the CC in phakic eyes, especially in clinical trials.

Decreased Central Macular Choriocapillaris Perfusion Correlates With Increased Low Luminance Visual Acuity Deficits.

PURPOSE: Correlations between low luminance visual acuity deficits (LLVADs) and central choriocapillaris perfusion deficits were investigated to help explain how increases in LLVAD scores at baseline predict annual growth rates of geographic atrophy (GA). DESIGN: Prospective cross-sectional study. METHODS: Photopic luminance best-corrected visual acuity (PL-BCVA) and low luminance BCVA (LL-BCVA) were measured using the Early Treatment Diabetic Retinopathy Study chart. LL-BCVA was measured using a 2.0-log unit neutral density filter. LLVADs were calculated as the difference between PL-BCVA and LL-BCVA. Within a fovea-centered 1-mm circle, the percentage of choriocapillaris flow deficits (CC FD%), drusen volume, optical attenuation coefficient (OAC) elevation volume, and outer retinal layer (ORL) thickness were assessed. RESULTS: In all 90 eyes (30 normal eyes; 31 drusen-only eyes; 29 non-foveal GA eyes), significant correlations were found between the central CC FD% and PL-BCVA (r = -0.393, P < .001), LL-BCVA (r = -0.534, P < .001), and the LLVAD (r = 0.439, P < .001). Central cube root (cubrt) drusen volume, cubrt OAC elevation volume, and ORL thickness were correlated with PL-BCVA, LL-BCVA, and LLVADs (all P < .05). Stepwise regression models showed that central cubrt OAC elevation volume and ORL thickness were associated with PL-BCVA (R2 = 0.24, P < .05); central CC FD%, cubrt OAC elevation volume, and ORL thickness were associated with LL-BCVA (R2 = 0.44, P < .01); and central CC FD% and ORL thickness were associated with LLVAD (R2 = 0.24, P < .01). CONCLUSIONS: The significant correlations between central CC FD% and LLVAD support the hypothesis that the ability of LLVAD to predict the growth of GA is mediated through a decrease in macular choriocapillaris perfusion.

Decreased Macular Choriocapillaris Perfusion in Eyes With Macular Reticular Pseudodrusen Imaged With Swept-Source OCT Angiography.

Purpose: To determine if macular reticular pseudodrusen (RPD) were associated with markers of impaired macular choroidal perfusion, we investigated measurements of macular choriocapillaris (CC) flow deficits (FDs), CC thickness, and mean choroidal thickness (MCT) in eyes with macular RPD compared with normal eyes and eyes with soft drusen. Methods: Eyes with intermediate age-related macular degeneration (iAMD) and normal eyes underwent 6 × 6 mm swept-source optical coherence tomography angiography (SS-OCTA) imaging to diagnose macular RPD, occupying over 25% of the fovea-centered 5 mm diameter circle, and measure outer retinal layer (ORL) thickness, CC FDs, CC thickness, MCT, and choroidal vascularity index (CVI) using previously published strategies within the same fovea-centered 5 mm circle. Results: Ninety eyes were included; 30 normal eyes, 30 eyes with soft drusen, and 30 eyes with macular RPD. The RPD eyes showed higher macular CC FDs than normal eyes (P < 0.001) and soft drusen eyes (P = 0.019). Macular CC thickness was decreased in RPD eyes compared with normal eyes (P < 0.001) and soft drusen eyes (P = 0.016). Macular MCT in RPD eyes was thinner than normal eyes (P = 0.005) and soft drusen eyes (P < 0.001). No statistically and clinically significant differences were found in the ORL thickness and CVI measurements between RPD eyes and the other two groups (all P > 0.05). Conclusions: Eyes with macular RPD had decreased macular CC perfusion, decreased CC thickness, and decreased MCT measurements compared with normal and soft drusen eyes, suggesting that RPD may result from impaired choroidal perfusion.

Longitudinal quantification of choriocapillaris flow deficits in persistent placoid maculopathy: a case report.

BACKGROUND: Persistent placoid maculopathy (PPM) is a rare idiopathic chorioretinopathy characterized by choriocapillaris (CC) hypoperfusion. In a case of PPM, we quantified CC flow deficits (FDs) over time and observed an increase in CC perfusion as the visual acuity and outer photoreceptor anatomy improved. CASE PRESENTATION: A 58-year-old man was diagnosed with PPM in both eyes based on the patient's clinical presentation and imaging. He presented with sudden-onset central scotomas in both eyes for about two months. On referral, the best corrected visual acuity (BCVA) was 20/20 in the right eye and 20/100 in the left eye. Plaque-like yellowish macular lesions were observed bilaterally and autofluorescence imaging showed bilateral hyperautofluorescent lesions. Fluorescein angiography (FA) revealed early-phase hyper-fluorescent staining that intensified in the late phases, while indocyanine green angiography (ICGA) displayed persistent hypofluorescence in both eyes. Foveal centered swept source optical coherence tomography (SS-OCT) B-scans showed bilateral focal deposits on the level of retinal pigment epithelium (RPE) and disruption of outer photoreceptor bands. The CC FDs were quantified on SS-OCT angiography (SS-OCTA) images using a previously published algorithm that was validated. The CC FD% was 12.52% in the right eye and 14.64% in the left eye within a 5 mm circle centered on the fovea. After 5 months of steroid treatment, BCVA remained 20/20 in the right eye and improved to 20/25 in the left eye. On OCT imaging, the outer photoreceptor bands fully recovered in both eyes, while some focal deposits remained along the RPE in the left eye. The CC perfusion in both eyes improved, with CC FD% decreasing from 12.52% to 9.16% in the right eye and from 14.64% to 9.34% in the left eye. CONCLUSIONS: Significant impairment of macular CC perfusion was detected after the onset of PPM. Improvement in central macular CC perfusion corresponded with improvements in BCVA and outer retinal anatomy. Our findings suggest that imaging and quantification of CC FDs could serve as a valuable imaging strategy for diagnosing PPM and for following disease progression.

Automated segmentation and quantification of calcified drusen in 3D swept source OCT imaging.

Qualitative and quantitative assessments of calcified drusen are clinically important for determining the risk of disease progression in age-related macular degeneration (AMD). This paper reports the development of an automated algorithm to segment and quantify calcified drusen on swept-source optical coherence tomography (SS-OCT) images. The algorithm leverages the higher scattering property of calcified drusen compared with soft drusen. Calcified drusen have a higher optical attenuation coefficient (OAC), which results in a choroidal hypotransmission defect (hypoTD) below the calcified drusen. We show that it is possible to automatically segment calcified drusen from 3D SS-OCT scans by combining the OAC within drusen and the hypoTDs under drusen. We also propose a correction method for the segmentation of the retina pigment epithelium (RPE) overlying calcified drusen by automatically correcting the RPE by an amount of the OAC peak width along each A-line, leading to more accurate segmentation and quantification of drusen in general, and the calcified drusen in particular. A total of 29 eyes with nonexudative AMD and calcified drusen imaged with SS-OCT using the 6 × 6 mm2 scanning pattern were used in this study to test the performance of the proposed automated method. We demonstrated that the method achieved good agreement with the human expert graders in identifying the area of calcified drusen (Dice similarity coefficient: 68.27 ± 11.09%, correlation coefficient of the area measurements: r = 0.9422, the mean bias of the area measurements = 0.04781 mm2).

Biochar and nano-ferric oxide synergistically alleviate cadmium toxicity of muskmelon.

Cadmium is toxic to plants. The accumulation of cadmium in edible plants such as muskmelon may affect the safe production of crops and result in human health problem. Thus effective measures are urgently needed for soil remediation. This work aims to investigate the effects of nano-ferric oxide and biochar alone or mixture on muskmelon under cadmium stress. The results of growth and physiological indexes showed that compared with the application of cadmium alone, the composite treatment (biochar and nano-ferric oxide) decreased malondialdehyde content by 59.12% and ascorbate peroxidase activity increased by 276.6%. Their addition can increase the stress resistance of plants. The results of soil analysis and cadmium content determination in plants showed that the composite treatment was beneficial to reduce the cadmium content in various parts of muskmelon. In the presence of high concentration of cadmium, the Target Hazard Quotient value of peel and flesh of muskmelon in the composite treatment was less than 1, which means the edible risk was greatly reduced. Furthermore, the addition of composite treatment increased the content of effective components; the contents of polyphenols, flavonoids, and saponins in the flesh of the compound treatment were increased by 99.73%, 143.07%, and 18.78% compared with the cadmium treatment. The results provide a technical reference for the further application of biochar combined with nano-ferric oxide in the field of soil heavy metal remediation, and provide a theoretical basis for further research on reducing the toxicity of cadmium to plants and improving the edible quality of crops.

Transcriptome studies on cadmium tolerance and biochar mitigating cadmium stress in muskmelon.

Cadmium pollution in agricultural soil is a great threat to crop growth and human health. In this research, with 1%, 3% and 5% biochar applied to control soil cadmium pollution, melon was selected to be the experimental object for physiological detection and transcriptome analysis, through which we explored the mechanism of cadmium tolerance and biochar mitigating cadmium stress in muskmelon. Three set concentrations of biochar have a mitigative effect on muskmelon cadmium stress, and 5% biochar and 3% biochar respectively have the best and the worst alleviative effect. The alleviation of biochar to cadmium stress on muskmelon is primarily in the manner of inhibiting cadmium transfer, while the resistance of muskmelon to cadmium stress is through activating phenylpropanoid pathway and overexpressing stress related genes. Under cadmium treatment, 11 genes of the phenylpropane pathway and 19 stress-related genes including cytochrome P450 family protein genes and WRKY transcription factor genes were up-regulated, while 1%, 3%, 5% biochar addition significantly downregulated 3, 0, 7 phenylpropane pathway genes and 17, 5, 16 stress-related genes, respectively. Genes such as cytochrome P450 protein family genes, WRKY transcription factor genes, and annexin genes may play a key role in muskmelon's resistance to cadmium stress. The results show the key pathways and genes of cadmium stress resistance and the effect of different concentrations of biochar in alleviating cadmium stress, which provide a reference for the research of cadmium stress resistance in crops and the application of biochar in cadmium pollution in agricultural soil.

Hopper flows of deformable particles.

Numerous experimental and computational studies show that continuous hopper flows of granular materials obey the Beverloo equation that relates the volume flow rate Q and the orifice width w: Q ∼ (w/σavg - k)ß, where σavg is the average particle diameter, kσavg is an offset where Q ∼ 0, the power-law scaling exponent ß = d - 1/2, and d is the spatial dimension. Recent studies of hopper flows of deformable particles in different background fluids suggest that the particle stiffness and dissipation mechanism can also strongly affect the power-law scaling exponent ß. We carry out computational studies of hopper flows of deformable particles with both kinetic friction and background fluid dissipation in two and three dimensions. We show that the exponent ß varies continuously with the ratio of the viscous drag to the kinetic friction coefficient, λ = ζ/µ. ß = d - 1/2 in the λ → 0 limit and d - 3/2 in the λ → ∞ limit, with a midpoint λc that depends on the hopper opening angle θw. We also characterize the spatial structure of the flows and associate changes in spatial structure of the hopper flows to changes in the exponent ß. The offset k increases with particle stiffness until k ∼ kmax in the hard-particle limit, where kmax ∼ 3.5 is larger for λ → ∞ compared to that for λ → 0. Finally, we show that the simulations of hopper flows of deformable particles in the λ → ∞ limit recapitulate the experimental results for quasi-2D hopper flows of oil droplets in water.

A preliminary investigation of amino acid and acylcarnitine levels in neonates from the Tibet autonomous.

Background: The purpose of the study was to investigate the levels of amino acids and acylcarnitines in newborns of the Tibet Autonomous Region for the first time and to provide an experimental basis for the diagnosis of genetic metabolic diseases. Methods: We detected concentrations of 43 kinds of amino acids, acylcarnitines and succinylacetone in the dried blood spots of 18482 newborns using liquid chromatography tandem mass spectrometry and diagnose the case by gene sequencing. We compared the indexes between Tibet and our lab, where most data come from an inland area and Han Chinese people. Then we compared amino acid and acylcarnitine levels of seven regions in Tibet and explored their impact factors. Results: We described the levels of amino acids and acylcarnitines in Tibet newborns using 95% confidence intervals. The distribution of amino acid and acylcarnitines were different in Tibet. Conclusion: This study has contributed to filling in the blanks of Tibet newborn screening, which should be considered in the newborn metabolic disease screening in this area.

Does the Outer Retinal Thickness Around Geographic Atrophy Represent Another Clinical Biomarker for Predicting Growth?

PURPOSE: To determine whether the outer retinal layer (ORL) thickness around geographic atrophy (GA) could serve as a clinical biomarker to predict the annual enlargement rate (ER) of GA. DESIGN: Retrospective analysis of a prospective, observational case series. METHODS: Eyes with GA were imaged with a swept-source OCT 6 × 6 mm scan pattern. GA lesions were measured from customized en face OCT images and the annual ERs were calculated. The ORL was defined and segmented from the inner boundary of outer plexiform layer (OPL) to the inner boundary of retinal pigment epithelium (RPE) layer. The ORL thickness was measured at different subregions around GA. RESULTS: A total of 38 eyes from 27 participants were included. The same eyes were used for the choriocapillaris (CC) flow deficit (FD) analysis and the RPE to the Bruch membrane (RPE-BM) distance measurements. A negative correlation was observed between the ORL thickness and the GA growth. The ORL thickness in a 300-µm rim around GA showed the strongest correlation with the GA growth (r = -0.457, P = .004). No correlations were found between the ORL thickness and the CC FDs; however, a significant correlation was found between the ORL thickness and the RPE-BM distances around GA (r = -0.398, P = .013). CONCLUSIONS: ORL thickness showed a significant negative correlation with annual GA growth, but also showed a significant correlation with the RPE-BM distances, suggesting that they were dependently correlated with GA growth. This finding suggests that the loss of photoreceptors was associated with the formation of basal laminar deposits around GA.

Depth-resolved visualization and automated quantification of hyperreflective foci on OCT scans using optical attenuation coefficients.

An automated depth-resolved algorithm using optical attenuation coefficients (OACs) was developed to visualize, localize, and quantify hyperreflective foci (HRF) seen on OCT imaging that are associated with macular hyperpigmentation and represent an increased risk of disease progression in age related macular degeneration. To achieve this, we first transformed the OCT scans to linear representation, which were then contrasted by OACs. HRF were visualized and localized within the entire scan by differentiating HRF within the retina from HRF along the retinal pigment epithelium (RPE). The total pigment burden was quantified using the en face sum projection of an OAC slab between the inner limiting membrane (ILM) to Bruch's membrane (BM). The manual total pigment burden measurements were also obtained by combining manual outlines of HRF in the B-scans with the total area of hypotransmission defects outlined on sub-RPE slabs, which was used as the reference to compare with those obtained from the automated algorithm. 6×6 mm swept-source OCT scans were collected from a total of 49 eyes from 42 patients with macular HRF. We demonstrate that the algorithm was able to automatically distinguish between HRF within the retina and HRF along the RPE. In 24 test eyes, the total pigment burden measurements by the automated algorithm were compared with measurements obtained from manual segmentations. A significant correlation was found between the total pigment area measurements from the automated and manual segmentations (P < 0.001). The proposed automated algorithm based on OACs should be useful in studying eye diseases involving HRF.

Investigating the AC079305/DUSP1 Axis as Oxidative Stress-Related Signatures and Immune Infiltration Characteristics in Ischemic Stroke.

Background: Oxidative stress (OS) and immune inflammation play complex intersections in the pathophysiology of ischemic stroke (IS). However, a competing endogenous RNA- (ceRNA-) based mechanism linked to the intersections in IS has not been explored. We aimed to identify potential OS-related signatures and analyze immune infiltration characteristics in IS. Methods: Three datasets (GSE22255, GSE110993, and GSE140275) from the GEO database were extracted. Differentially expressed long noncoding RNAs, microRNAs, and messenger RNAs (DElncRNAs, DEmiRNAs, and DEmRNAs) between IS patients and controls were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were explored. Moreover, a triple ceRNA network was constructed to reveal transcriptional regulation mechanisms. A comprehensive strategy among least absolute shrinkage and selection operator (LASSO) regression, DEmRNAs, uprelated DEmRNAs, and OS-related genes was adopted to select the best signature. Then, we evaluated and verified the discriminant ability of the signature via receiver operating characteristic (ROC) analysis. Immune infiltration characteristics were explored via the CIBERSORT algorithm. Moreover, the best signature was verified via qPCR and western blot methods in rat brain tissues and PC12 cells. Results: 11 DEmRNAs were identified totally. Enrichment analysis showed that the DEmRNAs were primarily concentrated in MAPK-associated biological processes and immune or inflammation-involved pathways. DUSP1 was identified as the best signature with an area under the ROC curve of 73.5% (95%CI = 57.02-89.98, sensitivity = 95%, and specificity = 60%) in GSE22255 and 100.0% (95%CI = 100.00-100.00, sensitivity = 100%, and specificity = 100%) in GSE140275. Importantly, we also identified the AC079305/DUSP1 axis in the ceRNA network. Immune infiltration showed that resting mast cells infiltrate less in IS patients compared with controls. And DUSP1 was negatively correlated with resting mast cells (r = -0.703, P < 0.01), whereas it was positively correlated with neutrophils (r = 0.339, P < 0.05). Both in vivo and in vitro models confirmed the upregulated expression of DUSP1 and the downregulated expression of miR-429. Conclusion: This study identified the ceRNA-based AC079305/DUSP1 axis as a promising OS-related signature for IS. Immune infiltrating cells, especially mast cells, may exert a pivotal role in IS progression. Pharmacological agents targeting signatures, their receptors, or mast cells may shed a novel light on therapeutic targets for IS.

Correlation between microalbuminuria and atherosclerotic intracranial and extracranial arterial stenosis in patients with cerebral infarction.

BACKGROUND AND AIMS: Microalbuminuria (MAU) reflects the generalized vascular endothelial dysfunction. Whether MAU has correlation with atherosclerotic intracranial and extracranial arterial stenosis in cerebral infarction patients is not known and is explored in the present investigation. METHODS: We enrolled 255 cerebral infarction patients hospitalized at the department of neurology. All patients underwent digital subtraction angiography (DSA) to evaluate the severity and distribution of intracranial and extracranial arterial stenosis. MAU was expressed as the urine albumin-to-creatinine ratio (UACR). We collected basic information, medical history reviews and laboratory results of each participant. The multivariate logistic regression analysis was utilized to analyze the risk factors for severity and distribution of cerebral arterial stenosis. RESULTS: The prevalence of MAU in patients with cerebral infarction was 39.2%, patients with MAU had older age, lower blood uric acid, higher systolic blood pressure (SBP), higher prevalence of hypertension and diabetes (p < 0.05) and higher incidence of atherosclerotic intracranial and extracranial arterial stenosis (χ2 = 5.900, p = 0.015). In multiple logistic regression analysis for intracranial and extracranial arterial stenosis more than 50% or occlusion groups, UACR (OR 1.088 95%CI 1.012-1.170p = 0.022), male (OR 2.196 95%CI 1.085-4.442p = 0.029) as well as SBP (OR 5.870 95%CI 1.026-1.048p = 0.015) showed statistical significance. But UACR had no correlation with the distribution of intracranial and extracranial artery stenosis after adjusting for all potential confounders. CONCLUSIONS: Microalbuminuria was an independent risk factor for intracranial and extracranial arterial stenosis more than 50% or occlusion.

Identification of novel variations in SLC6A8 and GAMT genes causing cerebral creatine deficiency syndrome.

Cerebral creatine deficiency syndromes (CCDSs) are a group of rare mendelian disorders mainly characterized by intellectual disability, movement anomaly, behavior disorder and seizures. SLC6A8, GAMT, and GATM are known genes responsible for CCDS. In this study, seven pediatric patients with developmental delay were recruited and submitted to a series of clinical evaluation, laboratory testing, and genetic analysis. The clinical manifestations and core biochemical indications of each child were basically consistent with the diagnosis of CCDS. Genetic diagnosis determined that all patients were positive for SLC6A8 or GAMT variation. A total of 12 variants were identified in this cohort, including six novel ones. The frequency of these variants, the Revel scores and the conservatism of the affected amino acids support their pathogenicity. Our findings expanded the mutation spectrum of CCDS disorders, and provided solid evidence for the counseling to affected families.

Automatic geographic atrophy segmentation using optical attenuation in OCT scans with deep learning.

A deep learning algorithm was developed to automatically identify, segment, and quantify geographic atrophy (GA) based on optical attenuation coefficients (OACs) calculated from optical coherence tomography (OCT) datasets. Normal eyes and eyes with GA secondary to age-related macular degeneration were imaged with swept-source OCT using 6 × 6 mm scanning patterns. OACs calculated from OCT scans were used to generate customized composite en face OAC images. GA lesions were identified and measured using customized en face sub-retinal pigment epithelium (subRPE) OCT images. Two deep learning models with the same U-Net architecture were trained using OAC images and subRPE OCT images. Model performance was evaluated using DICE similarity coefficients (DSCs). The GA areas were calculated and compared with manual segmentations using Pearson's correlation and Bland-Altman plots. In total, 80 GA eyes and 60 normal eyes were included in this study, out of which, 16 GA eyes and 12 normal eyes were used to test the models. Both models identified GA with 100% sensitivity and specificity on the subject level. With the GA eyes, the model trained with OAC images achieved significantly higher DSCs, stronger correlation to manual results and smaller mean bias than the model trained with subRPE OCT images (0.940 ± 0.032 vs 0.889 ± 0.056, p = 0.03, paired t-test, r = 0.995 vs r = 0.959, mean bias = 0.011 mm vs mean bias = 0.117 mm). In summary, the proposed deep learning model using composite OAC images effectively and accurately identified, segmented, and quantified GA using OCT scans.