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Retinal screening contributes to early detection of diabetic retinopathy and timely treatment. To facilitate the screening process, we develop a deep learning system, named DeepDR, that can detect early-to-late stages of diabetic retinopathy. DeepDR is trained for real-time image quality assessment, lesion detection and grading using 466,247 fundus images from 121,342 patients with diabetes. Evaluation is performed on a local dataset with 200,136 fundus images from 52,004 patients and three external datasets with a total of 209,322 images. The area under the receiver operating characteristic curves for detecting microaneurysms, cotton-wool spots, hard exudates and hemorrhages are 0.901, 0.941, 0.954 and 0.967, respectively. The grading of diabetic retinopathy as mild, moderate, severe and proliferative achieves area under the curves of 0.943, 0.955, 0.960 and 0.972, respectively. In external validations, the area under the curves for grading range from 0.916 to 0.970, which further supports the system is efficient for diabetic retinopathy grading. As the leading cause of vision loss in working-age adults, diabetic retinopathy requires routinely retinal screening. Here the authors develop a deep learning system that can facilitate the screening by providing real-time image quality assessment, lesions detection, and grades across the disease spectrum.

Diabetic retinopathy (DR) is the leading cause of preventable blindness worldwide. The risk of DR progression is highly variable among different individuals, making it difficult to predict risk and personalize screening intervals. We developed and validated a deep learning system (DeepDR Plus) to predict time to DR progression within 5 years solely from fundus images. First, we used 717,308 fundus images from 179,327 participants with diabetes to pretrain the system. Subsequently, we trained and validated the system with a multiethnic dataset comprising 118,868 images from 29,868 participants with diabetes. For predicting time to DR progression, the system achieved concordance indexes of 0.754–0.846 and integrated Brier scores of 0.153–0.241 for all times up to 5 years. Furthermore, we validated the system in real-world cohorts of participants with diabetes. The integration with clinical workflow could potentially extend the mean screening interval from 12 months to 31.97 months, and the percentage of participants recommended to be screened at 1–5 years was 30.62%, 20.00%, 19.63%, 11.85% and 17.89%, respectively, while delayed detection of progression to vision-threatening DR was 0.18%. Altogether, the DeepDR Plus system could predict individualized risk and time to DR progression over 5 years, potentially allowing personalized screening intervals. A deep learning algorithm shows promising performance in predicting progression to diabetic retinopathy in patients, up to 5 years in advance, potentially providing support for medical treatment decisions and indications for personalized screening frequency in a real-world cohort.

Although the pharmacological effects of fibroblast growth factor 21 (FGF21) are well-documented, uncertainty about its role in regulating excessive energy intake remains. Here, we show that FGF21 improves systemic insulin sensitivity by promoting the healthy expansion of subcutaneous adipose tissue (SAT). Serum FGF21 levels positively correlate with the SAT area in insulin-sensitive obese individuals. FGF21 knockout mice (FGF21KO) show less SAT mass and are more insulin-resistant when fed a high-fat diet. Replenishment of recombinant FGF21 to a level equivalent to that in obesity restores SAT mass and reverses insulin resistance in FGF21KO, but not in adipose-specific βklotho knockout mice. Moreover, transplantation of SAT from wild-type to FGF21KO mice improves insulin sensitivity in the recipients. Mechanistically, circulating FGF21 upregulates adiponectin in SAT, accompanied by an increase of M2 macrophage polarization. We propose that elevated levels of endogenous FGF21 in obesity serve as a defense mechanism to protect against systemic insulin resistance. FGF21 has a number of beneficial metabolic effects. Here, Li et al. show that FGF21 promotes the healthy expansion of subcutaneous white adipose tissue, promoting the healthy expansion of fat tissue as a regulatory mechanism to maintain systemic insulin sensitivity during nutrient excess.

Emerging evidence suggests that modulation of gut microbiota by dietary fibre may offer solutions for metabolic disorders. In a randomized placebo-controlled crossover design trial (ChiCTR-TTRCC-13003333) in 37 participants with overweight or obesity, we test whether resistant starch (RS) as a dietary supplement influences obesity-related outcomes. Here, we show that RS supplementation for 8 weeks can help to achieve weight loss (mean −2.8 kg) and improve insulin resistance in individuals with excess body weight. The benefits of RS are associated with changes in gut microbiota composition. Supplementation with Bifidobacterium   adolescentis , a species that is markedly associated with the alleviation of obesity in the study participants, protects male mice from diet-induced obesity. Mechanistically, the RS-induced changes in the gut microbiota alter the bile acid profile, reduce inflammation by restoring the intestinal barrier and inhibit lipid absorption. We demonstrate that RS can facilitate weight loss at least partially through B.   adolescentis and that the gut microbiota is essential for the action of RS. In a randomized placebo-controlled trial in 37 individuals with excess body weight, dietary supplementation with resistant starch lowers body weight and induces changes in gut microbiota composition. Mechanistic analysis in male mice shows that resistant starch at least partially facilitates weight loss through the action of Bifidobacterium   adolescentis .

The choroid layer is a vascular layer in human retina and its main function is to provide oxygen and support to the retina. Various studies have shown that the thickness of the choroid layer is correlated with the diagnosis of several ophthalmic diseases. For example, diabetic macular edema (DME) is a leading cause of vision loss in patients with diabetes. Despite contemporary advances, automatic segmentation of the choroid layer remains a challenging task due to low contrast, inhomogeneous intensity, inconsistent texture and ambiguous boundaries between the choroid and sclera in Optical Coherence Tomography (OCT) images. The majority of currently implemented methods manually or semi-automatically segment out the region of interest. While many fully automatic methods exist in the context of choroid layer segmentation, more effective and accurate automatic methods are required in order to employ these methods in the clinical sector. This paper proposed and implemented an automatic method for choroid layer segmentation in OCT images using deep learning and a series of morphological operations. The aim of this research was to segment out Bruch’s Membrane (BM) and choroid layer to calculate the thickness map. BM was segmented using a series of morphological operations, whereas the choroid layer was segmented using a deep learning approach as more image statistics were required to segment accurately. Several evaluation metrics were used to test and compare the proposed method against other existing methodologies. Experimental results showed that the proposed method greatly reduced the error rate when compared with the other state-of-the-art methods.

Fibroblast growth factor 21 (FGF21) stimulates fatty acid oxidation and ketone body production in animals. In this study, we investigated the role of FGF21 in the metabolic activity of sodium butyrate, a dietary histone deacetylase (HDAC) inhibitor. FGF21 expression was examined in serum and liver after injection of sodium butyrate into dietary obese C57BL/6J mice. The role of FGF21 was determined using antibody neutralization or knockout mice. FGF21 transcription was investigated in liver and HepG2 hepatocytes. Trichostatin A (TSA) was used in the control as an HDAC inhibitor. Butyrate was compared with bezafibrate and fenofibrate in the induction of FGF21 expression. Butyrate induced FGF21 in the serum, enhanced fatty acid oxidation in mice, and stimulated ketone body production in liver. The butyrate activity was significantly reduced by the FGF21 antibody or gene knockout. Butyrate induced FGF21 gene expression in liver and hepatocytes by inhibiting HDAC3, which suppresses peroxisome proliferator-activated receptor-α function. Butyrate enhanced bezafibrate activity in the induction of FGF21. TSA exhibited a similar set of activities to butyrate. FGF21 mediates the butyrate activity to increase fatty acid use and ketogenesis. Butyrate induces FGF21 transcription by inhibition of HDAC3.

Although obesity occurs in most of the patients with type 2 diabetes (T2D), a fraction of patients with T2D are underweight or have normal weight. Several studies have linked the gut microbiome to obesity and T2D, but the role of gut microbiota in lean individuals with T2D having unique clinical characteristics remains unclear. A metagenomic and targeted metabolomic analysis is conducted in 182 lean and abdominally obese individuals with and without newly diagnosed T2D. The abundance of Akkermansia muciniphila (A. muciniphila) significantly decreases in lean individuals with T2D than without T2D, but not in the comparison of obese individuals with and without T2D. Its abundance correlates inversely with serum 3β‐chenodeoxycholic acid (βCDCA) levels and positively with insulin secretion and fibroblast growth factor 15/19 (FGF15/19) concentrations. The supplementation with A. muciniphila is sufficient to protect mice against high sucrose‐induced impairment of glucose intolerance by decreasing βCDCA and increasing insulin secretion and FGF15/19. Furthermore, βCDCA inhibits insulin secretion and FGF15/19 expression. These findings suggest that decreased abundance of A. muciniphila is linked to the impairment of insulin secretion and glucose homeostasis in lean T2D, paving the way for new therapeutic options for the prevention or treatment of diabetes. Intestinal Akkermansia muciniphila is depleted in lean individuals with type 2 diabetes, who have increased 3β‐chenodeoxycholic acid (βCDCA), reduced insulin secretion and fibroblast growth factor 19 (FGF19) expression. A. muciniphila treatment in mice modulates βCDCA levels, stimulates insulin secretion and FGF19 expression, leading to improved glucose metabolism. The way is paved fornew therapeutic options for diabetes prevention or treatment.

Diabetic retinopathy (DR) is the main cause of vision loss or blindness in working age adults worldwide. The lack of effective diagnostic biomarkers for DR leads to unsatisfactory curative treatments. To define potential metabolite biomarkers for DR diagnosis, a multiplatform‐based metabolomics study is performed. In this study, a total of 905 subjects with diabetes without DR (NDR) and with DR at different clinical stages are recruited. Multiplatform metabolomics methods are used to characterize the serum metabolic profiles and to screen and validate the DR biomarkers. Based on the criteria p < 0.05 and false‐discovery rate < 0.05, 348 and 290 metabolites are significantly associated with the pathogenesis of DR and early‐stage DR, respectively. The biomarker panel consisting of 12‐hydroxyeicosatetraenoic acid (12‐HETE) and 2‐piperidone exhibited better diagnostic performance than hemoglobin A1c (HbA1c) in differentiating DR from diabetes, with AUCs of 0.946 versus 0.691 and 0.928 versus 0.648 in the discovery and validation sets, respectively. In addition, this panel showed higher sensitivity in early‐stage DR detection than HbA1c. In conclusion, this multiplatform‐based metabolomics study comprehensively revealed the metabolic dysregulation associated with DR onset and progression. The defined biomarker panel can be used for detection of DR and early‐stage DR. Multiplatform metabolomics methods are used to comprehensively investigate the association between the serum metabolic profiles and the onset and progression of diabetic retinopathy (DR) in a large Chinese population, and 12‐HETE and 2‐piperidone are identified as a highly effective marker panel for the detection of DR and early‐stage DR.

BackgroundNon-alcoholic fatty liver disease is an obesity-related chronic liver disorder ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis.ObjectiveTto investigate the role of Toll-like receptor (TLR) 4 in mediating the transition from steatosis to inflammation.MethodsApoE−/−/TLR4mut mice and ApoE−/−/TLR4 wild-type mice (ApoE−/−/TLR4-WT) were generated by cross-breeding an ApoE-deficient (ApoE−/−) strain with TLR4-mutant (TLR4mut) mice, which were fed with high-fat, high-cholesterol (HFHC) diet to induce obesity.ResultsApoE−/−/TLR4-WT mice fed with an HFHC diet for 12 weeks developed typical pathological features of NASH, which is associated with obesity and the metabolic syndrome. By contrast, ApoE−/−/TLR4mut mice lacking functional TLR4 were resistant to HFHC diet-induced liver inflammation and injury and were less susceptible to the diet-induced production of reactive oxygen species (ROS) and proinflammatory cytokines. In ApoE−/−/TLR4-WT mice, X-box binding protein-1 (XBP-1), a transcription factor involved in the unfolded protein responses, was activated in the liver by an HFHC diet, whereas XBP-1 activation was abrogated in ApoE−/−/TLR4mut mice. In primary rat Kupffer cells, endotoxin induced XBP-1 activation through ROS production, whereas siRNA-mediated knockdown of XBP-1 expression resulted in a marked attenuation in endotoxin-evoked NF-κB activation and cytokine production. Furthermore, adenovirus-mediated expression of dominant negative XBP-1 led to a significant attenuation in HFHC diet-induced liver inflammation and injury in mice.ConclusionsThese findings support the key role of TLR4 in Kupffer cells in mediating the progression of simple steatosis to NASH, by inducing ROS-dependent activation of XBP-1.

Background Benzo[a]pyrene (B[a]P), a carcinogen pollutant produced by combustion processes, is present in the western diet with grilled meats. Chronic exposure of B[a]P in hepatocellular carcinoma (HCC) cells promotes metastasis rather than primary proliferation, implying an unknown mechanism of B[a]P‐induced malignancy. Given that exosomes carry bioactive molecules to distant sites, we investigated whether and how exosomes mediate cancer‐stroma communications for a toxicologically associated microenvironment. Method Exosomes were isolated from B[a]P stimulated BEL7404 HCC cells (7404‐100Bap Exo) at an environmental relevant dose (100 nmol/L). Lung pre‐education animal model was prepared via injection of exosomes and cytokines. The inflammatory genes of educated lungs were evaluated using quantitative reverse transcription PCR array. HCC LM3 cells transfected with firefly luciferase were next injected to monitor tumor burdens and organotropic metastasis. Profile of B[a]P‐exposed exosomes were determined by ceRNA microarray. Interactions between circular RNA (circRNA) and microRNAs (miRNAs) were detected using RNA pull‐down in target lung fibroblasts. Fluorescence in situ hybridization and RNA immunoprecipitation assay was used to evaluate the “on‐off” interaction of circRNA‐miRNA pairs. We further developed an adeno‐associated virus inhalation model to examine mRNA expression specific in lung, thereby exploring the mRNA targets of B[a]P induced circRNA‐miRNA cascade. Results Lung fibroblasts exert activation phenotypes, including focal adhesion and motility were altered by 7404‐100Bap Exo. In the exosome‐educated in vivo model, fibrosis factors and pro‐inflammatory molecules of are up‐regulated when injected with exosomes. Compared to non‐exposed 7404 cells, circ_0011496 was up‐regulated following B[a]P treatment and was mainly packaged into 7404‐100Bap Exo. Exosomal circ_0011496 were delivered and competitively bound to miR‐486‐5p in recipient fibroblasts. The down‐regulation of miR‐486‐5p converted fibroblast to cancer‐associated fibroblast via regulating the downstream of Twinfilin‐1 (TWF1) and matrix metalloproteinase‐9 (MMP9) cascade. Additionally, increased TWF1, specifically in exosomal circ_0011496 educated lungs, could promote cancer‐stroma crosstalk via activating vascular endothelial growth factor (VEGF). These modulated fibroblasts promoted endothelial cells angiogenesis and recruited primary HCC cells invasion, as a consequence of a pre‐metastatic niche formation. Conclusion We demonstrated that B[a]P‐induced tumor exosomes can deliver circ_0011496 to activate miR‐486‐5p/TWF1/MMP9 cascade in the lung fibroblasts, generating a feedback loop that promoted HCC metastasis.