The efficacy of sacubitril/valsartan in patients receiving peritoneal dialysis with diabetes and heart failure with preserved ejection fraction.

OBJECTIVE: To investigate the efficacy of sacubitril/valsartan in the treatment of peritoneal dialysis (PD) in patients with diabetes and heart failure with preserved ejection fraction (HFpEF). MATERIALS AND METHODS: Patients with diabetes who underwent PD and had HFpEF (n = 64) were divided into two groups: the experimental group (n = 31), which was administered sacubitril/valsartan, and the control group (n = 33), administered valsartan alone. Data were collected before and after treatment to compare the inter-group changes in cardiac function indexes, residual renal function (RRF), and PD adequacy indexes. RESULTS: Compared with the control group, the N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were lower in the experimental group after treatment (Wilcoxon test, p < 0.05). The descent ranges of NT-proBNP, left ventricular end-systolic dimension, and left ventricular fraction shortening, as well as increases in the amplitude of left ventricular ejection fraction after treatment were better in the experimental group than in the control group (t-test, p < 0.05). The descent ranges of residual renal glomerular filtration rate, residual renal Kt/Vurea, and residual renal creatinine clearance, as well as increases in the amplitude of ß2-microglobulin, were lower in the experimental group than in the control group (Wilcoxon test, p < 0.05). However, there were no significant differences between the two groups in the descent ranges of the PD adequacy indexes (Wilcoxon test, p > 0.05). Hyperkalemia occurred in 8 cases (25.81%) in the experimental group and 13 cases (39.39%) in the control group, while hypotension occurred in 2 cases (6.45%) and 1 case (3.03%), respectively. No other adverse effects were observed in either group. CONCLUSION: The findings suggest that sacubitril/valsartan can safely and effectively improve RRF and cardiac function in patients with diabetes combined with HFpEF receiving PD, but it has little effect on PD adequacy.

Early prediction of sepsis-induced respiratory tract infection using a biomarker-based machine-learning algorithm.

Early and differential diagnosis of sepsis is essential to avoid unnecessary antibiotic use and further reduce patient morbidity and mortality. Here, we aimed to identify predictors of sepsis and advance a machine-learning strategy to predict sepsis-induced respiratory tract infection (RTI). Patients with sepsis and RTI were selected via retrospective analysis, and essential population characteristics and laboratory parameters were recorded. To improve the performance of the primary model and avoid over-fitting, a recursive feature elimination with cross-validation (RFECV) strategy was used to screen the optimal subset of biomarkers and construct nine machine-learning models based on this subset; the average accuracy, precision, recall, and F1-score were used for evaluation of the models. We identified 430 patients with sepsis and 686 patients with RTI. A total of 39 features were collected, with 23 features identified for initial model construction. Using the RFECV algorithm, we found that the XGBoost classifier, which only needed to include seven biomarkers, demonstrated the best performance among all prediction models, with an average accuracy of 89.24 ± 2.28, while the Ridge classifier, which included 11 biomarkers, had an average accuracy of only 83.87 ± 4.69. The remaining models had prediction accuracies greater than 88%. We developed nine models for predicting sepsis using a strategy that combined RFECV with machine learning. Among these models, the XGBoost classifier, which included seven biomarkers, showed the best performance and highest accuracy for predicting sepsis and may be a promising tool for the timely identification of sepsis.

Clinical significance of glomerular IgM deposit in IgA nephropathy: a 5-year follow-up study.

The significance of glomerular IgM deposit intensity in IgA Nephropathy (IgAN) remained ambiguous and requires further research. Patients with biopsy-proven IgAN in our hospital from January 2018 to May 2023 were recruited into this retrospective single-center study. Patients who presented with positive IgM deposit were included in IgM + cohort while patients with negative IgM deposit were included in IgM- cohort. Of the IgM+, patients whose IF intensity of IgM deposits exceeded 1+ formed IgM-H cohort while patients whose IF intensity of IgM deposits was equal to 1+ consisted IgM-L cohort. Pairwise comparisons were performed among these cohorts to determine clinical disparities, following the propensity score matching process. Among 982 IgAN patients, 539 patients presented with positive IgM deposit. The Kaplan-Meier analysis showed that the IgM deposit did not contribute adversely to the outcomes (eGFR decreased from the baseline ≥ 50% continuously or reached end-stage renal disease). However, the Cox regression analysis showed that increased intensity of IgM deposit was an independent risk factor (p = 0.03) in IgM+. The IgM-H exhibited more pronounced segmental glomerulosclerosis (p = 0.02) than the IgM-L, which may also be associated more directly with higher urine protein levels (p = 0.02). Moreover, our generalized linear mixed model demonstrated a remarkably higher urine albumin/creatinine ratio (p < 0.01) and serum creatinine (p = 0.04) levels as well as lower serum albumin (p < 0.01) level in IgM-H persistently during the 5-year follow-up. This study concluded that increased intensity of glomerular IgM deposits may contribute adversely to clinicopathologic presentation and outcome in those IgM + patients.

Isocitrate dehydrogenase 3b is required for spermiogenesis but dispensable for retinal viability.

Isocitrate dehydrogenase 3 (IDH3) is a key enzyme in the mitochondrial tricarboxylic acid (TCA) cycle, which catalyzes the decarboxylation of isocitrate into α-ketoglutarate and concurrently converts NAD+ into NADH. Dysfunction of IDH3B, the ß subunit of IDH3, has been previously correlated with retinal degeneration and male infertility in humans, but tissue-specific effects of IDH3 dysfunction are unclear. Here, we generated Idh3b-KO mice and found that IDH3B is essential for IDH3 activity in multiple tissues. We determined that loss of Idh3b in mice causes substantial accumulation of isocitrate and its precursors in the TCA cycle, particularly in the testes, whereas the levels of the downstream metabolites remain unchanged or slightly increased. However, the Idh3b-KO mice did not fully recapitulate the defects observed in humans. Global deletion of Idh3b only causes male infertility but not retinal degeneration in mice. Our investigation showed that loss of Idh3b causes an energetic deficit and disrupts the biogenesis of acrosome and flagellum, resulting in spermiogenesis arrestment in sperm cells. Together, we demonstrate that IDH3B controls its substrate levels in the TCA cycle, and it is required for sperm mitochondrial metabolism and spermiogenesis, highlighting the importance of the tissue-specific function of the ubiquitous TCA cycle.

Activation of endogenous retrovirus triggers microglial immuno-inflammation and contributes to negative emotional behaviors in mice with chronic stress.

BACKGROUND: The "missing" link of complex and multifaceted interplay among endogenous retroviruses (ERVs) transcription, chronic immuno-inflammation, and the development of psychiatric disorders is still far from being completely clarified. The present study was aimed to investigate the mechanism of protective role of inhibiting ERVs on reversing microglial immuno-inflammation in basolateral amygdala (BLA) in chronic stress-induced negative emotional behaviors in mice. METHODS: Male C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for 6 w. Negative emotional behaviors were comprehensively investigated to identify the susceptible mice. Microglial morphology, ERVs transcription, intrinsic nucleic acids sensing response, and immuno-inflammation in BLA were assessed. RESULTS: Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors, and accompanied with significant microglial morphological activation, murine ERVs genes MuERV-L, MusD, and IAP transcription, cGAS-IFI16-STING pathway activation, NF-κB signaling pathway priming, as well as NLRP3 inflammasome activation in BLA. Antiretroviral therapy, pharmacological inhibition of reverse transcriptases, as well as knocking-down the ERVs transcriptional regulation gene p53 significantly inhibited microglial ERVs transcription and immuno-inflammation in BLA, as well as improved the chronic stress-induced negative emotional behaviors. CONCLUSIONS: Our results provided an innovative therapeutic approach that targeting ERVs-associated microglial immuno-inflammation may be beneficial to the patients with psychotic disorders.

Developing a machine learning prediction algorithm for early differentiation of urosepsis from urinary tract infection.

OBJECTIVES: Early recognition and timely intervention for urosepsis are key to reducing morbidity and mortality. Blood culture has low sensitivity, and a long turnaround time makes meeting the needs of clinical diagnosis difficult. This study aimed to use biomarkers to build a machine learning model for early prediction of urosepsis. METHODS: Through retrospective analysis, we screened 157 patients with urosepsis and 417 patients with urinary tract infection. Laboratory data of the study participants were collected, including data on biomarkers, such as procalcitonin, D-dimer, and C-reactive protein. We split the data into training (80%) and validation datasets (20%) and determined the average model prediction accuracy through cross-validation. RESULTS: In total, 26 variables were initially screened and 18 were statistically significant. The influence of the 18 variables was sorted using three ranking methods to further determine the best combination of variables. The Gini importance ranking method was found to be suitable for variable filtering. The accuracy rates of the six machine learning models in predicting urosepsis were all higher than 80%, and the performance of the artificial neural network (ANN) was the best among all. When the ANN included the eight biomarkers with the highest influence ranking, its model had the best prediction performance, with an accuracy rate of 92.9% and an area under the receiver operating characteristic curve of 0.946. CONCLUSIONS: Urosepsis can be predicted using only the top eight biomarkers determined by the ranking method. This data-driven predictive model will enable clinicians to make quick and accurate diagnoses.

The retina and retinal pigment epithelium differ in nitrogen metabolism and are metabolically connected.

Defects in energy metabolism in either the retina or the immediately adjacent retinal pigment epithelium (RPE) underlie retinal degeneration, but the metabolic dependence between retina and RPE remains unclear. Nitrogen-containing metabolites such as amino acids are essential for energy metabolism. Here, we found that 15N-labeled ammonium is predominantly assimilated into glutamine in both the retina and RPE/choroid ex vivo [15N]Ammonium tracing in vivo show that, like the brain, the retina can synthesize asparagine from ammonium, but RPE/choroid and the liver cannot. However, unless present at toxic concentrations, ammonium cannot be recycled into glutamate in the retina and RPE/choroid. Tracing with 15N-labeled amino acids show that the retina predominantly uses aspartate transaminase for de novo synthesis of glutamate, glutamine, and aspartate, whereas RPE uses multiple transaminases to utilize and synthesize amino acids. Retina consumes more leucine than RPE, but little leucine is catabolized. The synthesis of serine and glycine is active in RPE but limited in the retina. RPE, but not the retina, uses alanine as mitochondrial substrates through mitochondrial pyruvate carrier. However, when the mitochondrial pyruvate carrier is inhibited, alanine may directly enter the retinal mitochondria but not those of RPE. In conclusion, our results demonstrate that the retina and RPE differ in nitrogen metabolism and highlight that the RPE supports retinal metabolism through active amino acid metabolism.

Proline mediates metabolic communication between retinal pigment epithelial cells and the retina.

The retinal pigment epithelium (RPE) is a monolayer of pigmented cells between the choroid and the retina. RPE dysfunction underlies many retinal degenerative diseases, including age-related macular degeneration, the leading cause of age-related blindness. To perform its various functions in nutrient transport, phagocytosis of the outer segment, and cytokine secretion, the RPE relies on an active energy metabolism. We previously reported that human RPE cells prefer proline as a nutrient and transport proline-derived metabolites to the apical, or retinal, side. In this study, we investigated how RPE utilizes proline in vivo and why proline is a preferred substrate. By using [13C]proline labeling both ex vivo and in vivo, we found that the retina rarely uses proline directly, whereas the RPE utilizes it at a high rate, exporting proline-derived mitochondrial intermediates for use by the retina. We observed that in primary human RPE cell culture, proline is the only amino acid whose uptake increases with cellular maturity. In human RPE, proline was sufficient to stimulate de novo serine synthesis, increase reductive carboxylation, and protect against oxidative damage. Blocking proline catabolism in RPE impaired glucose metabolism and GSH production. Notably, in an acute model of RPE-induced retinal degeneration, dietary proline improved visual function. In conclusion, proline is an important nutrient that supports RPE metabolism and the metabolic demand of the retina.

Metabolic signature of eyelid basal cell carcinoma.

PURPOSE: Eyelid basal cell carcinoma (BCC) is the most common eyelid malignancy. Metabolic reprogramming is critical in tumorigenesis, but the metabolic feature of eyelid BCC remains elusive. In this study, we aim to reveal the metabolic profile in eyelid BCC using targeted metabolomics. Eyelid samples were collected from patients who had removal of BCC and from control patients who underwent blepharoplasty. Multivariate analysis of metabolomics data distinguished the two groups, indicating that eyelid BCC has significantly different metabolome than the healthy tissue. We found 16 increased and 11 decreased metabolites in the BCC tissues. These metabolites were highly enriched in the metabolism of nicotinamide adenine dinucleotide (NAD), glutathione metabolism, polyamine metabolism, and the metabolism of glycine, serine, threonine, arginine and proline. amino acid metabolism. Metabolites from NAD metabolism (Nicotinamide; Nicotinamide riboside; N1-Methylnicotinamide) had the highest sensitivity, specificity, and prediction accuracy in a prediction model for eyelid BCC. In conclusion, eyelid BCC has a signature change of cell metabolome. Metabolites in NAD metabolic pathways could potentially be biomarkers or therapeutic targets for eyelid BCC.

Differentially expressed circular RNAs in orbital adipose/connective tissue from patients with thyroid-associated ophthalmopathy.

Our study aimed to investigate the differentially expressed circRNAs and their potential roles in orbital adipose/connective tissue from patients with thyroid-associated ophthalmopathy (TAO). The orbital adipose/connective tissue samples from three TAO patients and three control individuals were collected for RNA sequencing after depletion of ribosomal RNA. Differentially expressed mRNAs and up-regulated circRNAs were used for co-expression analysis. Functional and pathway enrichment analysis were conducted for the up- and down-regulated mRNAs in the circRNA-mRNA co-expression network. Meanwhile, circRNA-miRNA interaction network was established by miRanda software. The expression levels of mRNAs and circRNAs in control and TAO samples were determined by qRT-PCR. Among all the 16,329 circRNAs predicted from RNA sequencing data, 163 circRNAs (95 down-regulated and 68 up-regulated) were differentially expressed in TAO samples. Besides, 607 differentially expressed mRNAs were identified. The co-expression analysis showed circRNA_14940 was correlated with CCND1 and TNXB, while circRNA_10135 was correlated with PTGFR, and circRNA_14936 was correlated with TNFRSF19. The up-regulated CCND1 participated in Wnt signaling pathway. The down-regulated TNXB was involved in the ECM-receptor interaction, focal adhesion, and PI3K-Akt signaling pathway. PTGFR participated in neuroactive ligand-receptor interaction and calcium signaling pathway. TNFRSF19 was involved in cytokine-cytokine receptor interaction. In the interaction network, circRNA_14936 could interact with hsa-miR-10392-3p, and circRNA_12367 could interact with hsa-miR-1228-3p. Moreover, the expression changes of MMP2, TNXB, PTGFR, CCND1, and TNFRSF19, as well as circRNA_14936, circRNA_14940, and circRNA_12367 were validated by qRT-PCR. In conclusion, the differentially expressed circRNAs might participate in pathogenesis of TAO, and we speculated that circRNA_14940-CCND1-Wnt signaling pathway might be an important regulatory axis.

LncRNA nuclear-enriched abundant transcript 1 regulates hypoxia-evoked apoptosis and autophagy via mediation of microRNA-181b.

Nuclear-enriched abundant transcript 1 (NEAT1), a vital long noncoding RNA (lncRNA), exhibits the functions in disparate cancers. Nevertheless, the influences of NEAT1 in congenital heart disease (CHD) remain unreported. The research delves into whether NEAT1 affects H9c2 cells apoptosis and autophagy under the hypoxia condition. Overexpressed NEAT1 vector was transfected into H9c2 cells; then, functions of NEAT1 in cell viability, apoptosis, autophagy, PI3K/AKT/mTOR and JAK1/STAT3 pathways were detected in H9c2 cells under hypoxia condition. Expression of NEAT1 and miR-181b in hypoxia and blood samples from CHD was evaluated. After miR-181b inhibitor transfection, functions of miR-181b repression in the above-mentioned cell behavior and PI3K/AKT/mTOR and JAK1/STAT3 pathways were reassessed. Overexpressed NEAT1 clearly allayed hypoxia-triggered H9c2 cells apoptosis and autophagy. The decreased NEAT1 and miR-181b were showcased in hypoxia and blood samples from CHD; meanwhile, elevated miR-181b evoked by overexpressed NEAT1 was observed in hypoxia-managed H9c2 cells. More importantly, miR-181b inhibition obviously overturned the influences of NEAT1 in hypoxia-affected H9c2 cells apoptosis and autophagy. Besides, overexpressed NEAT1 facilitated PI3K/AKT/mTOR and JAK1/STAT3 activations via enhancing miR-181b. The research exposed that NEAT1 eased hypoxia-triggered H9c2 cells apoptosis and autophagy by expediting PI3K/AKT/mTOR and JAK1/STAT3 pathways via elevating miR-181b.

Retracted: Emodin protects H9c2 cells against hypoxia-induced injury via regulation of miR-26a/survivin and the JAK1/STAT3 pathway.

BACKGROUND/AIM: Congenital heart disease (CHD) is a catastrophic disease. Emodin possesses biological properties in protecting against some diseases. Our study investigated to explore the effects of emodin on hypoxia-stimulated cardiomyocytes, which mimicked CHD in vitro. METHODS: H9c2 cells were stimulated with hypoxia and then the cells were treated with or without emodin, and/or transfected with miR-26a mimic, pcDNA-survivin and their corresponding negative control (NC). Cell viability and cell apoptosis were detected by Cell Counting kit-8 assay and flow cytometry, respectively. In addition, the expression of apoptotic proteins, Janus kinase 1 (JNK)/signal transducer and activator of transcription 3 (STAT3) pathway factors, and survivin were evaluated by using Western blot analysis. The expression of miR-26a was analyzed by quantitative real time polymerase chain reaction (qRT-PCR). Moreover, the target of miR-26a was verified by using a luciferase report assay. RESULTS: Hypoxia significantly decreased cell viability and increased cell apoptosis, and the accumulated levels of cleaved caspase-3 and cleaved-caspase-9 were upregulated by hypoxia compared with the control. However, emodin administration led to the opposite result. A further result showed that emodin increased the phosphorylation of JNK/STAT3 pathway-related proteins and the pathway inhibitor AG490 impaired the protective effects of emodin on hypoxia-induced injury. In addition, emodin negatively regulated the miR-26a expression, and overexpression of miR-26a enhanced cell apoptosis and upregulated the expression of cleaved-caspase-3 and cleaved-caspase-9 compared with the NC. Moreover, emodin statistically upregulated the expression of survivin, and overexpression of miR-26a decreased the expression of survivin. The luciferase of miR-26a overexpression was decreased in the wild type of the survivin group. CONCLUSION: Emodin protects hypoxia-induced cell injury as evidenced by increasing cell viability and decreasing apoptosis through downregulation of miR-26a as well as activation of the JNK/STAT3 pathway.

Iron(II)-Catalyzed Site-Selective Functionalization of Unactivated C(sp3 )-H Bonds Guided by Alkoxyl Radicals.

An alkoxyl radical guided strategy for site-selective functionalization of unactivated methylene and methine C-H bonds enabled by an FeII -catalyzed redox process is described. The mild, expeditious, and modular protocol allows efficient remote aliphatic fluorination, chlorination, amination, and alkynylation of structurally and electronically varied primary, secondary, and tertiary hydroperoxides with excellent functional-group tolerance. The application for one-pot 1,4-hydroxyl functionalization of non-oxygenated alkane substrates initiated by aerobic C-H oxygenation is also demonstrated.

Andrographolide Exerts Pro-Osteogenic Effect by Activation of Wnt/ß-Catenin Signaling Pathway in Vitro.

BACKGROUND/AIMS: Osteoporosis is a metabolic bone disorders that tortures about millions of people worldwide. Recent studies showed that Andrographolide (AP) is a promising natural compound for the treatment of osteoclast-related bone diseases. However, its potential in treatment of osteoporosis has not been fully explored. METHODS: In this study, the effect of AP on osteoblasts metabolism was investigated via the detection of cell proliferation, cell viability, ALP activity, the expression of osteogenic specific genes including runt-related transcription factor 2 (RUNX2), bone sialoprotein (BSP), osteocalcin (OCN), Bone morphogenic protein-2 (BMP2) and Alkaline phosphatase(ALP) for 3, 5 and 7 days respectively. Further exploration of the association of AP with WNT/ß-catenin signaling pathway was performed by examination of the expression of WNT related genes and proteins. RESULTS: Results showed that AP of 4.46 and 8.92 µM, especially 8.92 µM was beneficial to osteogenic differentiation by upregulating ALP activity and expression of osteogenic related genes (P<0.05). Pathway analyses identify canonical WNT/ß-catenin pathway as an important mediator in AP-induced osteogenesis. CONCLUSION: This study indicates that AP exerts its pro-osteogenic potential via activation of the WNT/ß-catenin in osteoblasts and thus may represent a candidate of therapeutic agent for osteoporosis.

Systematic review of high-dose and standard-dose chemotherapies in the treatment of primary well-differentiated osteosarcoma.

The objective of this study is to evaluate whether high-dose chemotherapy is more efficacious than standard-dose chemotherapy in the treatment of primary well-differentiated osteosarcoma. The Cochrane systematic evaluation method was adopted. A database search was conducted in MEDLINE, Embase, OVID, the Cochrane Central Register of Controlled Trials database and the Chinese Biomedical Literature CD-ROM Database. The quality of the included studies was jointly evaluated by two reviewers, and homogeneous studies were included for meta-analysis. A total of five studies were included in this meta-analysis, with 1,415 subjects with primary, nonmetastatic, well-differentiated osteosarcoma in the limbs. No statistically significant differences were found between the high-dose chemotherapy group and the low-dose group in 5-year event-free survival [RR 1.04, 95 %CI (0.95, 1.13)], 5-year overall survival [RR 1.02, 95 %CI (0.95, 1.10)], local recurrence rate [RR 0.90, 95 %CI (0.59, 1.39)], proportion of subjects with good histological response [RR 0.93, 95 %CI (0.81, 1.07)], or limb salvage rate [RR 0.97, 95 %CI (0.92, 1.02)]. A statistically significant difference was observed in the 5-year event-free survival between the subjects with good histological response to preoperative chemotherapy and the subjects with poor histological response [RR 1.55, 95 %CI (1.19, 2.00), P < 0.001]. High-dose chemotherapy did not show superior efficacy to low-dose chemotherapy in the treatment of primary well-differentiated osteosarcoma. Further high-quality randomized controlled trials are needed to provide additional reliable evidence for our observation.

Ultraconformable Integrated Wireless Charging Micro-Supercapacitor Skin.

Conformable and wireless charging energy storage devices play important roles in enabling the fast development of wearable, non-contact soft electronics. However, current wireless charging power sources are still restricted by limited flexural angles and fragile connection of components, resulting in the failure expression of performance and constraining their further applications in health monitoring wearables and moveable artificial limbs. Herein, we present an ultracompatible skin-like integrated wireless charging micro-supercapacitor, which building blocks (including electrolyte, electrode and substrate) are all evaporated by liquid precursor. Owing to the infiltration and permeation of the liquid, each part of the integrated device attached firmly with each other, forming a compact and all-in-one configuration. In addition, benefitting from the controllable volume of electrode solution precursor, the electrode thickness is easily regulated varying from 11.7 to 112.5 µm. This prepared thin IWC-MSC skin can fit well with curving human body, and could be wireless charged to store electricity into high capacitive micro-supercapacitors (11.39 F cm-3) of the integrated device. We believe this work will shed light on the construction of skin-attachable electronics and irregular sensing microrobots.

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations in conjunction with systemic lupus erythematosus: Missed diagnosis or misdiagnosis?

BACKGROUND: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare autosomal dominant systemic microvascular disorder attributed to TREX1 (three-prime repair exonuclease-1) gene mutations, often proned to misdiagnosed. METHODS: We reported a case of RVCL-S coexisting with systemic lupus erythematosus due to a mutation in the TREX1 gene. This study provided a summary and discussion of previously documented cases related to TREX1 mutations or RVCL-S. RESULTS: A 39-year-old female patient visited the clinic due to progressive memory loss and speech difficulties. Magnetic resonance imaging results showed corpus callosum atrophy and multiple subcortical calcifications in both brain hemispheres. Genetic testing revealed a TREX1 gene mutation (c.294dupA). Treatment with immunosuppressive therapy for 2 months led to improvements in communication and mobility. We also summarized previously reported cases providing an overview of TREX1 gene mutation or RCVL-S. CONCLUSION: Our case establishes a compelling foundation for future RVCL-S diagnosis and treatment paradigms. Notably, conducting systemic immunity screening in patients with RVCL-S emerges as a strategic approach to prevent potential diagnostic oversights.

Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice.

Toll-like receptor 9 (TLR9) recognizes self-DNA and plays intricate roles in systemic lupus erythematosus (SLE). However, the molecular mechanism regulating the endosomal TLR9 response is incompletely understood. Here, we report that palmitoyl-protein thioesterase 1 (PPT1) regulates systemic autoimmunity by removing S-palmitoylation from TLR9 in lysosomes. PPT1 promotes the secretion of IFNα by plasmacytoid dendritic cells (pDCs) and TNF by macrophages. Genetic deficiency in or chemical inhibition of PPT1 reduces anti-nuclear antibody levels and attenuates nephritis in B6.Sle1yaa mice. In healthy volunteers and patients with SLE, the PPT1 inhibitor, HDSF, reduces IFNα production ex vivo. Mechanistically, biochemical and mass spectrometry analyses demonstrated that TLR9 is S-palmitoylated at C258 and C265. Moreover, the protein acyltransferase, DHHC3, palmitoylates TLR9 in the Golgi, and regulates TLR9 trafficking to endosomes. Subsequent depalmitoylation by PPT1 facilitates the release of TLR9 from UNC93B1. Our results reveal a posttranslational modification cycle that controls TLR9 response and autoimmunity.

Clearance of lipid droplets by chimeric autophagy-tethering compound ameliorates the age-related macular degeneration phenotype in mice lacking APOE.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly, and there is currently no clinical treatment targeting the primary impairment of AMD. The earliest clinical hallmark of AMD is drusen, which are yellowish spots mainly composed of lipid droplets (LDs) accumulated under the retinal pigment epithelium (RPE). However, the potential pathogenic role of this excessive LD accumulation in AMD is yet to be determined, partially due to a lack of chemical tools to manipulate LDs specifically. Here, we employed our recently developed Lipid Droplets·AuTophagy Tethering Compounds (LD∙ATTECs) to degrade LDs and to evaluate its consequence on the AMD-like phenotypes in apoe-/- (apolipoprotein E; B6/JGpt-Apoeem1Cd82/Gpt) mouse model. apoe-/- mice fed with high-fat diet (apoe-/--HFD) exhibited excessive LD accumulation in the retina, particularly with AMD-like phenotypes including RPE degeneration, Bruch's membrane (BrM) thickening, drusen-like deposits, and photoreceptor dysfunction. LD·ATTEC treatment significantly cleared LDs in RPE/choroidal tissues without perturbing lipid synthesis-related proteins and rescued RPE degeneration and photoreceptor dysfunction in apoe-/--HFD mice. This observation implied a causal relationship between LD accumulation and AMD-relevant phenotypes. Mechanically, the apoe-/--HFD mice exhibited elevated oxidative stress and inflammatory signals, both of which were mitigated by the LD·ATTEC treatment. Collectively, this study demonstrated that LD accumulation was a trigger for the process of AMD and provided entry points for the treatment of the initial insult of AMD by degrading LDs.Abbreviations: AMD: age-related macular degeneration; APOE: apolipoprotein E; ATTECs: autophagy-tethering compounds; BODIPY: boron-dipyrromethene; BrM: Bruch's membrane; ERG: electroretinogram; HFD: high-fat diet; LD·ATTECs: Lipid Droplets·AuTophagy Tethering Compounds; LDs: lipid droplets; OA: oleic acid; OPL: outer plexiform layer; ROS: reactive oxygen species; RPE: retinal pigment epithelium.

Corrigendum: Integrative metabolic analysis of orbital adipose/connective tissue in patients with thyroid-associated ophthalmopathy.

[This corrects the article DOI: 10.3389/fendo.2022.1001349.].