TRPM2-dependent autophagy inhibition exacerbates oxidative stress-induced CXCL16 secretion by keratinocytes in vitiligo.

Vitiligo is a depigmented skin disease due to the destruction of melanocytes. Under oxidative stress, keratinocyte-derived chemokine C-X-C motif ligand 16 (CXCL16) plays a critical role in recruiting CD8+ T cells, which kill melanocytes. Autophagy serves as a protective cell survival mechanism and impairment of autophagy has been linked to increased secretion of the proinflammatory cytokines. However, the role of autophagy in the secretion of CXCL16 under oxidative stress has not been investigated. Herein, we initially found that autophagy was suppressed in both keratinocytes of vitiligo lesions and keratinocytes exposed to oxidative stress in vitro. Autophagy inhibition also promoted CXCL16 secretion. Furthermore, upregulated transient receptor potential cation channel subfamily M member 2 (TRPM2) functioned as an upstream oxidative stress sensor to inhibit autophagy. Moreover, TRPM2-mediated Ca2+ influx activated calpain to shear autophagy related 5 (Atg5) and Atg12-Atg5 conjugate formation was blocked to inhibit autophagy under oxidative stress. More importantly, Atg5 downregulation enhanced the binding of interferon regulatory factor 3 (IRF3) to the CXCL16 promoter region by activating Tank-binding kinase 1 (TBK1), thus promoting CXCL16 secretion. These findings suggested that TRPM2-restrained autophagy promotes CXCL16 secretion via the Atg5-TBK1-IRF3 signaling pathway under oxidative stress. Inhibition of TRPM2 may serve as a potential target for the treatment of vitiligo. © 2024 The Pathological Society of Great Britain and Ireland.

Synaptotagmin-7-mediated activation of spontaneous NMDAR currents is disrupted in bipolar disorder susceptibility variants.

Synaptotagmin-7 (Syt7) plays direct or redundant Ca2+ sensor roles in multiple forms of vesicle exocytosis in synapses. Here, we show that Syt7 is a redundant Ca2+ sensor with Syt1/Doc2 to drive spontaneous glutamate release, which functions uniquely to activate the postsynaptic GluN2B-containing NMDARs that significantly contribute to mental illness. In mouse hippocampal neurons lacking Syt1/Doc2, Syt7 inactivation largely diminishes spontaneous release. Using 2 approaches, including measuring Ca2+ dose response and substituting extracellular Ca2+ with Sr2+, we detect that Syt7 directly triggers spontaneous release via its Ca2+ binding motif to activate GluN2B-NMDARs. Furthermore, modifying the localization of Syt7 in the active zone still allows Syt7 to drive spontaneous release, but the GluN2B-NMDAR activity is abolished. Finally, Syt7 SNPs identified in bipolar disorder patients destroy the function of Syt7 in spontaneous release in patient iPSC-derived and mouse hippocampal neurons. Therefore, Syt7 could contribute to neuropsychiatric disorders through driving spontaneous glutamate release.

MIF inhibition alleviates vitiligo progression by suppressing CD8+ T cell activation and proliferation.

In vitiligo, autoreactive CD8+ T cells have been established as the main culprit considering its pathogenic role in mediating epidermal melanocyte-specific destruction. Macrophage migration inhibitory factor (MIF) is a pleiotropic molecule that plays a central role in various immune processes including the activation and proliferation of T cells; but whether MIF is intertwined in vitiligo development and progression and its involvement in aberrantly activated CD8+ T cells remains ill-defined. In this study, we found that MIF was overabundant in vitiligo patients and a mouse model for human vitiligo. Additionally, inhibiting MIF ameliorated the disease progression in vitiligo mice, which manifested as less infiltration of CD8+ T cells and more retention of epidermal melanocytes in the tail skin. More importantly, in vitro experiments indicated that MIF-inhibition suppressed the activation and proliferation of CD8+ T cells from the lymph nodes of vitiligo mice, and the effect extended to CD8+ T cells in peripheral blood mononuclear cells of vitiligo patients. Finally, CD8+ T cells derived from MIF-inhibited vitiligo mice also exhibited an impaired capacity for activation and proliferation. Taken together, our results show that MIF might be clinically targetable in vitiligo treatment, and its inhibition might ameliorate vitiligo progression by suppressing autoreactive CD8+ T cell activation and proliferation. © 2023 The Pathological Society of Great Britain and Ireland.

Semi-transparent organic photovoltaics.

As an economical solar energy conversion technology, organic photovoltaics (OPVs) are regarded as a promising solution to environmental problems and energy challenges. With the highest efficiency of OPVs exceeding 20%, the research focus will shift from efficiency-oriented aspects to commercialization-oriented aspects in the near future. Semi-transparent OPVs (STOPVs) are one of the most possible commercialized forms of OPVs, and have achieved power conversion efficiency over 14% with average visible light transmittance over 20% so far. In this tutorial review, we first systematically summarize the device structures, operating principles and evaluation parameters of STOPVs, and compare them with those of opaque OPVs. Then, strategies to construct high-performance STOPVs by cooperatively optimizing materials and devices are proposed. Methods to realize the scale-up of STOPVs in terms of minimization of electrode and interconnect resistance are summarized. The potential applications of STOPVs in multifunctional windows, agrivoltaics and floating photovoltaics are also discussed. Finally, this review highlights major challenges and research directions that need to be addressed prior to the future commercialization of STOPVs.

New framework for recombination and adaptive evolution analysis with application to the novel coronavirus SARS-CoV-2.

The 2019 novel coronavirus (SARS-CoV-2) has spread rapidly worldwide and was declared a pandemic by the WHO in March 2020. The evolution of SARS-CoV-2, either in its natural reservoir or in the human population, is still unclear, but this knowledge is essential for effective prevention and control. We propose a new framework to systematically identify recombination events, excluding those due to noise and convergent evolution. We found that several recombination events occurred for SARS-CoV-2 before its transfer to humans, including a more recent recombination event in the receptor-binding domain. We also constructed a probabilistic mutation network to explore the diversity and evolution of SARS-CoV-2 after human infection. Clustering results show that the novel coronavirus has diverged into several clusters that cocirculate over time in various regions and that several mutations across the genome are fixed during transmission throughout the human population, including D614G in the S gene and two accompanied mutations in ORF1ab. Together, these findings suggest that SARS-CoV-2 experienced a complicated evolution process in the natural environment and point to its continuous adaptation to humans. The new framework proposed in this study can help our understanding of and response to other emerging pathogens.

Fatty acids metabolism affects the therapeutic effect of anti-PD-1/PD-L1 in tumor immune microenvironment in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a highly invasive and metastatic subtype of kidney malignancy and is correlated with metabolic reprogramming for adaptation to the tumor microenvironment comprising infiltrated immune cells and immunomodulatory molecules. The role of immune cells in the tumor microenvironment (TME) and their association with abnormal fatty acids metabolism in ccRCC remains poorly understood. METHOD: RNA-seq and clinical data of KIRC from The Cancer Genome Atlas (TCGA) and E-MTAB-1980 from the ArrayExpress dataset. The Nivolumab group and Everolimus group of the CheckMate 025 study, the Atezolizumab arm of IMmotion150 and the Atezolizumab plus Bevacizumab group of IMmotion151 cohort were obtained for subsequent analysis. After differential expression genes identification, the signature was constructed through univariate Cox proportional hazard regression and simultaneously the least absolute shrinkage and selection operator (Lasso) analysis and the predictive performance of our signature was assessed by using receiver operating characteristic (ROC), Kaplan-Meier (KM) survival analysis, nomogram, drug sensitivity analysis, immunotherapeutic effect analysis and enrichment analysis. Immunohistochemistry (IHC), qPCR and western blot were performed to measure related mRNA or protein expression. Biological features were evaluated by wound healing, cell migration and invasion assays and colony formation test and analyzed using coculture assay and flow cytometry. RESULTS: Twenty fatty acids metabolism-related mRNA signatures were constructed in TCGA and possessed a strong predictive performance demonstrated through time-dependent ROC and KM survival analysis. Notably, the high-risk group exhibited an impaired response to anti-PD-1/PD-L1 (Programmed death-1 receptor/Programmed death-1 receptor-ligand) therapy compared to the low-risk group. The overall levels of the immune score were higher in the high-risk group. Additionally, drug sensitivity analysis observed that the model could effectively predict efficacy and sensitivity to chemotherapy. Enrichment analysis revealed that the IL6-JAK-STAT3 signaling pathway was a major pathway. IL4I1 could promote ccRCC cells' malignant features through JAK1/STAT3 signaling pathway and M2-like macrophage polarization. CONCLUSION: The study elucidates that targeting fatty acids metabolism can affect the therapeutic effect of PD-1/PD-L1 in TME and related signal pathways. The model can effectively predict the response to several treatment options, underscoring its potential clinical utility.

Synaptotagmin-7 deficiency induces mania-like behavioral abnormalities through attenuating GluN2B activity.

Synaptotagmin-7 (Syt7) probably plays an important role in bipolar-like behavioral abnormalities in mice; however, the underlying mechanisms for this have remained elusive. Unlike antidepressants that cause mood overcorrection in bipolar depression, N-methyl-d-aspartate receptor (NMDAR)-targeted drugs show moderate clinical efficacy, for unexplained reasons. Here we identified Syt7 single nucleotide polymorphisms (SNPs) in patients with bipolar disorder and demonstrated that mice lacking Syt7 or expressing the SNPs showed GluN2B-NMDAR dysfunction, leading to antidepressant behavioral consequences and avoidance of overcorrection by NMDAR antagonists. In human induced pluripotent stem cell (iPSC)-derived and mouse hippocampal neurons, Syt7 and GluN2B-NMDARs were localized to the peripheral synaptic region, and Syt7 triggered multiple forms of glutamate release to efficiently activate the juxtaposed GluN2B-NMDARs. Thus, while Syt7 deficiency and SNPs induced GluN2B-NMDAR dysfunction in mice, patient iPSC-derived neurons showed Syt7 deficit-induced GluN2B-NMDAR hypoactivity that was rescued by Syt7 overexpression. Therefore, Syt7 deficits induced mania-like behaviors in mice by attenuating GluN2B activity, which enabled NMDAR antagonists to avoid mood overcorrection.

Comparison of visual quality after SMILE correction of low-to-moderate myopia in different optical zones.

OBJECTIVE: To compare the effects of different optical zones for small-incision lenticule extraction (SMILE) on postoperative visual quality in low-to-moderate myopia. METHODS: This retrospective case-control study involved patients who underwent SMILE using two optical-zone diameters: 6.5 mm (50 patients, 100 eyes) and 6.8 mm (50 patients, 100 eyes). Uncorrected visual acuity (UCVA), best corrected visual acuity, spherical equivalent (SE), corneal higher-order aberrations (HOAs), and subjective visual-quality questionnaire scores were assessed. RESULTS: Postoperatively, UCVA and SE did not differ between the two groups (P > 0.05). In both groups, corneal HOAs, spherical aberration, and coma significantly increased at 1 and 3 months postoperatively (P < 0.05), while trefoil was unchanged after surgery (P > 0.05). Corneal HOAs, spherical aberration, and coma significantly differed between the groups at 1 and 3 months (P < 0.05), while trefoil did not (P > 0.05). Visual-quality scores were higher in the 6.8 mm group than in the 6.5 mm group at 1 month (P = 0.058), but not at 3 months (P > 0.05). In both groups, subjective scores significantly decreased at 1 month (P < 0.05) and gradually returned to the preoperative level at 3 months (P > 0.05). The subjective visual-quality scores were negatively and positively correlated with pupillary and optical-zone diameter, respectively (P < 0.05 for both). Objective visual-quality indicators (HOAs, spherical aberration, and coma) were negatively correlated with optical-zone diameter (P < 0.05) but not pupillary diameter (P > 0.05). CONCLUSION: SMILE in different optical zones effectively corrected low-to-moderate myopia. The larger the optical-zone diameter, the better the early postoperative visual quality.

Recent Advances in ZIF-Derived Atomic Metal-N-C Electrocatalysts for Oxygen Reduction Reaction: Synthetic Strategies, Active Centers, and Stabilities.

Exploring highly active, stable electrocatalysts with earth-abundant metal centers for the oxygen reduction reaction (ORR) is essential for sustainable energy conversion. Due to the high cost and scarcity of platinum, it is a general trend to develop metal-N-C (M-N-C) electrocatalysts, especially those prepared from the zeolite imidazolate framework (ZIF) to replace/minimize usage of noble metals in ORR electrocatalysis for their amazingly high catalytic efficiency, great stability, and readily-tuned electronic structure. In this review, the most pivotal advances in mechanisms leading to declined catalytic performance, synthetic strategies, and design principles in engineering ZIF-derived M-N-C for efficient ORR catalysis, are presented. Notably, this review focuses on how to improve intrinsic ORR activity, such as M-Nx -Cy coordination structures, doping metal-free heteroatoms in M-N-C, dual/multi-metal sites, hydrogen passivation, and edge-hosted M-Nx . Meanwhile, how to increase active sites density, including formation of M-N complex, spatial confinement effects, and porous structure design, are discussed. Thereafter, challenges and future perspectives of M-N-C are also proposed. The authors believe this instructive review will provide experimental and theoretical guidance for designing future, highly active ORR electrocatalysts, and facilitate their applications in diverse ORR-related energy technologies.

Th1-like Treg in vitiligo: An incompetent regulator in immune tolerance.

Vitiligo is an autoimmune skin disease resulting from epidermal melanocyte destruction mediated by CD8+T cells that breach the self-tolerance. Regulatory T cells (Tregs) are critical for keeping the CD8+T cells in check, but the deficiency of Tregs leading to the immune disequilibrium in vitiligo remains undefined. In the present study, we used RNA-sequencing (RNA-seq) to acquire the transcriptome data of Tregs from vitiligo patients and healthy controls, respectively. Further flow cytometry analysis and immunofluorescence assays substantiated the phenotype of Th1-like Tregs in vitiligo. CD8+T cell-/vitiligo serum-Treg co-culture assays and chemotaxis assays were used to functionally examine this subset of Tregs. As a result, RNA-seq, flow cytometry, and immunofluorescence all indicated the transition of bona fide Treg to the Th1-like T-bet+IFN-γ+Treg in vitiligo patients. Besides, these Th1-like Tregs exhibited significantly dampened suppression on the proliferation and activation of CD8+T cells and a markedly higher tendency to be chemoattracted by CXCL10 and CXCL16. More interestingly, vitiligo serum could even elicit bona fide Tregs of healthy controls to adopt the Th1-like phenotype and manifest impaired suppression. To conclude, Tregs from vitiligo patients are functionally disturbed and the Th1-skewed inflammatory microenvironment in the serum of vitiligo patients is responsible for the generation of Th1-like Tregs. We provide a clinical exploitable strategy that in addition to simply replenishing the bona fide Treg or promoting the homing of Treg to the skin, the normalization of the Th1-skewed inflammatory environment in vitiligo patients and targeting the incompetent Th1-like Tregs might be critical in the future treatment of vitiligo.

Perspectives of New Advances in the Pathogenesis of Vitiligo: From Oxidative Stress to Autoimmunity.

Vitiligo is an autoimmune cutaneous disease in which melanocytes are destroyed by CD8⁺ T cells resulting in disfiguring white spots. From the very beginning of the disease, oxidative stress plays a significant role in promoting the onset of vitiligo, as noted by many studies. Multiple factors lead to the overproduction of reactive oxygen species (ROS), and collaboratively cause ROS accumulation in vulnerable melanocytes. However, ROS are responsible for melanocyte damage manifested by the level of molecules, organelles, and cells, and the generation of autoantigens, through different pathways related to the dysregulation of melanocytes. Recent studies have shown that presentation of autoantigens is mediated by innate immunity, which bridges the gap between oxidative stress and adaptive immunity. The recruitment of CD8⁺ T cells induced by cytokines and chemokines guarantees the final destruction of epidermal melanocytes. Moreover, emerging concerns regarding regulatory T cells and resident memory T cells help explain the reinstatement and relapse of vitiligo. Here, we provide new perspectives in the advances in understanding of this disease pathogenesis and we attempt to find more interrelationships between oxidative stress and autoimmunity.

Tail regeneration after autotomy revives survival: a case from a long-term monitored lizard population under avian predation.

Caudal autotomy in lizards has intrigued scientists for more than 100 years. Because of the relative lack of literature under natural conditions, the complicated association among field autotomy rate, real predation pressure, the long-term cost of tail loss, and the benefit of regeneration remains equivocal. In this study, we conducted a 7-year capture-mark-recapture (CMR) programme with a wild population of a sexually dichromatic lizard, Takydromus viridipunctatus We used autotomy indexes and a contemporary bird census mega-dataset of four predatory birds as predictors to examine the association between tail loss and predation pressure. We further estimated the survival cost of tail loss and alleviation by regeneration under natural conditions through CMR modelling. We found that large and small avian predators affect lizard survival through the following two routes: the larger-sized cattle egret causes direct mortality while the smaller shrikes and kestrels are the major causes of autotomy. Following autotomy, the survival rate of tailless individuals over the next month was significantly lower than that of tailed individuals, especially males during the breeding season, which showed a decline of greater than 30%. This sex-related difference further demonstrated the importance of reproductive costs for males in this sexually dichromatic species. However, the risk of mortality returned to baseline after the tails were fully grown. This study indicates the benefit of tail regeneration under natural conditions, which increases our understanding of the cost-benefit dynamics of caudal autotomy and further explains the maintenance of this trait as an evolutionarily beneficial adaption to long-term predator-prey interactions.

The effect of junction modes between backbones and side chains of polyimides on the stability of liquid crystal vertical alignment.

Polyimides (PI-N9 and PI-N12) were synthesized from two kinds of functional diamines, whose junction modes between backbones and side chains were different. Side chains of PI-N9 were linked to the backbones with an ether bond spacer; and side chains of PI-N12 were directly linked to the backbones without any spacer. The PI alignment layer surfaces were investigated by atomic force microscopy, surface free energy measurements, X-ray photo-electron spectroscopy and polarized attenuated total reflection Fourier transformed infrared spectroscopy. It was found that PI-N9 lost the vertical alignment capability after high-strength rubbing, while PI-N12 could still induce liquid crystals (LCs) to align vertically under the same condition. The mechanism of the macroscopic molecular orientation of the PI surface is proposed. During the high-strength rubbing process, the side chain could rotate around the flexible ether bond which existed between the side chain and the main chain of PI-N9 and then fell over. Therefore, PI-N9 could not induce the vertical alignment of LCs anymore. But PI-N12 could keep LCs aligning vertically all the time, which proved that the stability of LC alignment induced by PI-N12 was better.

Pharmacokinetic comparison of berberine in rat plasma after oral administration of berberine hydrochloride in normal and post inflammation irritable bowel syndrome rats.

In the present study, post inflammation irritable bowel syndrome (PI-IBS) rats were firstly established by intracolonic instillation of acetic acid with restraint stress. Then the pharmacokinetics of berberine in the rat plasma were compared after oral administration of berberine hydrochloride (25 mg/kg) to normal rats and PI-IBS rats. Quantification of berberine in the rat plasma was achieved by using a sensitive and rapid UPLC-MS/MS method. Plasma samples were collected at 15 different points in time and the pharmacokinetic parameters were analyzed by WinNonlin software. Compared with the normal group, area under the plasma concentration vs. time curve from zero to last sampling time (AUC0-t) and total body clearance (CL/F) in the model group significantly increased or decreased, (2039.49 ± 492.24 vs. 2763.43 ± 203.14; 4999.34 ± 1198.79 vs. 3270.57 ± 58.32) respectively. The results indicated that the pharmacokinetic process of berberine could be altered in PI-IBS pathological conditions.

Intervaginal space injection of photothermal chemotherapy nanoparticles for facilitating tumor targeting and improving outcomes in mice.

Although numerous photothermal nanoparticles have been designed to improve the enhanced and permeability and retention (EPR) effect, the delivery of nanoparticles to the tumor site remains a major obstacle in cancer treatment. The interstital structure and its internal fluid that play an important role in material transmission, intercellular signal transduction, tissue morphology, immunity, tumor development, and disease diagnosis and treatment may be considered as a new route for drug delivery. Here, we prepared a nanoplatform composed of polydopamine (PDA), indocyanine green (ICG) as a photothermal agent, and paclitaxel (PTX) as a chemotherapeutic drug. The designed PDA-ICG nanoparticles displayed excellent photothermal conversion ability, with the synergistic effect of PTX, the growth of MDA-MB-231 cells was significantly suppressed with the cell viability of 6.19% in vitro. Taking advantage of bioimaging ability of ICG, tumor-targeting of the nanoparticles injected into the interstitial space was study, Compared with intravenous injection, nanoparticles better targeted the tumor based on the interstitial fluid flow in MBA-MD-231 bearing mice. Furthermore, the antitumor efficacy was studied in vivo. With the improved accumulation of PDA-ICG-PTX nanoparticles injected into the interstitial space and the synergistic effect of photothermal therapy and chemotherapy, tumor growth was inhibited without obvious side effects. These results demonstrated that interstitial space injection may be a superior administration route for tumor-targeting nanoparticles. The PDA-ICG-PTX nanoparticles delivered via the interstitial space exhibit great potential in the photothermal chemotherapy of cancers.

Freeze-Thaw Damage Characterization of Cement-Stabilized Crushed Stone Base with Skeleton Dense Gradation.

The skeleton dense graded cement-stabilized crushed stone base is a widely used material for road construction. However, this material is susceptible to freeze-thaw damage, which can lead to degradation and failure, for which there is still a lack of an in-depth understanding of the freeze-thaw damage characteristics. This study aims to assess the mechanical performance and the freeze-thaw damage characteristics of the cement-stabilized crushed stone base with skeleton dense gradation based on a mechanical test and acoustic technology in a laboratory. There is a gradually increasing trend in the mass loss rate of the base material with an increase in freeze-thaw cycles. The curve steepens significantly after 15 cycles, following a parabola-fitting pattern relationship. The compressive strength of the cement-stabilized crushed stone base also decreased with a parabola-fitting pattern, and the decrease rate may accelerate as the freeze-thaw cycles increase. The resilience modulus of the base material decreased with increasing freeze-thaw cycles, following a parabolic trend. This suggests that the material's resistance to freeze-thaw damage decreases with increasing cycles. The ultrasonic wave velocity decreased with increasing freeze-thaw cycles, exhibiting a parabolic trend. This decline can be attributed to microcracks and defects developing within the material, offering insights for monitoring and predicting its service life. The damage progression of the cement-stabilized crushed stone base was found to occur in three stages: initial, stationary, and failure. The duration of stage I increased with freeze-thaw cycles, while the duration of stage III decreased. The findings provide valuable insights into the mechanisms and processes of freeze-thaw damage in a cement-stabilized crushed stone base with skeleton dense gradation.

Confinement of Oligopeptides by Terminally Functionalized Polyisoprene to Improve Their Mechanical Strength, Creep Resistance, and Antifatigue Properties.

A small amount of terminal polar phase endows natural rubber (NR) with excellent comprehensive properties superior to those of synthetic isoprene rubber. In this work, the comprehensive properties of synthetic rubber were remarkably improved by introducing a stable terminal nanoconfinement structure by combining terminal hydroxyl groups and pentapeptide molecules noncovalently into the same phases. The results show that the stable terminal phases hardly affect the free chain motion but enhance the entanglement. Under cyclic loading, the terminal polar phases undergo hierarchically structural changes such as reversible dissociation of the weak bonds, phase deformation, and crystalline reorganization, all of which dissipate the stress and are beneficial for high strength and extensibility. At the same time, synthetic rubbers demonstrate much superior fatigue resistance and lower hysteresis relative to NR and maintain comparable dimensional stability. This strategy suggests that the comprehensive properties of elastomers can be regulated and upgraded by facile terminal noncovalent interactions.

Oxidative stress-induced hypermethylation and low expression of ANXA2R: Novel insights into the dysfunction of melanocytes in vitiligo.

BACKGROUND: Vitiligo is a skin disorder with melanocyte destruction caused by complex interplay between multiple genetic and environmental factors. Recent studies have suggested DNA methylation is involved in the melanocyte damage, but the underlying mechanism remains unknown. OBJECTIVE: To explore the abnormal DNA methylation patterns in vitiligo lesional and nonlesional skin, and the mechanism of DNA methylation involved in vitiligo pathogenesis. METHODS: Initially, the genome-wide aberrant DNA methylation profiles in lesional and nonlesional skin of vitiligo were detect via Illumina methylation EPIC 850k Beadchip. Subsequently, a comprehensive analysis was conduct to investigate the genomic characteristics of differentially methylated regions (DMRs). Furthermore, the effects of key aberrant methylated genes on cell apoptosis and function of both melanocytes and keratinocytes were further identified and validated by western bloting, ELISA, and immunofluorescence. RESULTS: Compared with nonlesional skins, we discovered 79 significantly differentially methylated CpG sites in vitiligo lesions. These DMRs were mainly located in the gene body and the TS1500 region. Annexin A2 receptor (ANXA2R), a crucial gene in cell apoptosis, was hypermethylated in vitiligo lesions. Furthermore, we showed that ANXA2R displayed hypermethylation and low expression levels in both keratinocytes and melanocytes of vitiligo patients, and the hypermethylated-triggered downregulation of ANXA2R under oxidative stress induced melanocyte apoptosis, and inhibited the secretion of stem cell factor (SCF) from keratinocytes thus impaired the survival of melanocytes. CONCLUSIONS: Our study illustrates the DNA methylation modification in vitiligo, and further demonstrates the molecular mechanism of hypermethylated ANXA2R in the dysfunction of melanocytes under oxidative stress.

A nomogram based on TFE3 IHC results and clinical factors as a preliminary screening scheme for TFE3-rearranged renal cell carcinoma.

BACKGROUND: TFE3 immunohistochemistry (TFE3-IHC) is controversial in the diagnosis of TFE3-rearranged renal cell carcinoma (TFE3-rearranged RCC). This study is to investigate the accuracy and sensitivity of IHC and establish a predictive model to diagnose TFE3-rearranged RCC. METHODS: Retrospective analysis was performed by collecting IHC and fluorescence in situ hybridization (FISH) results from 228 patients. IHC results were evaluated using three scoring systems. Scoring system 1 is graded based on nuclear staining intensity, scoring system 2 is graded based on the percentage of stained tumor cell nuclei, and scoring system 3 is graded based on both the nuclear staining intensity and the percentage. We collected patients' IHC results and clinical information. Important variables were screened based on univariate logistic regression analysis. Then, independent risk factors were established through multivariate logistic regression, and a nomogram model was constructed. The model was validated in internal test set and external validation set. The receiver operating characteristic curve (ROC curve), calibration curve, and decision curve analysis (DCA) were generated to assess discriminative ability of the model. RESULTS: The accuracy of IHC based on three scoring systems were 0.829, 0.772, and 0.807, respectively. The model included four factors including age, gender, lymph node metastasis and IHC results. Area under the curve (AUC) values were 0.935 for the training set, 0.934 for the internal test set, 0.933 for all 228 patients, and 0.916 for the external validation set. CONCLUSIONS: TFE3 IHC has high accuracy in the diagnosis of TFE3-rearranged RCC. Clinical information such as age and lymph node metastasis are independent risk factors, which can be used as a supplement to the results of TFE3 IHC. This study confirms the value of IHC in the diagnosis of TFE3-rearranged RCC. The accuracy of the diagnosis can be improved by incorporating IHC with other clinical risk factors.