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Objective:We explored circadian clock-related genes (CCRG) to establish a risk model and identify associations with the tumor immune microenvironment in cutaneous melanoma (CM).Methods:Circadian clock genes were downloaded from Circadian Gene Database. To explore CM-related circadian clock genes, we combined multivariate cox regression associated with least absolute shrinkage and selection operator (LASSO) regression in the Cancer Genome Atlas (TCGA) and validated it in the GSE65904 dataset. Time-dependent receiver operating characteristic curve (ROC) and Kaplan-Meier analysis were calculated to determine a CCRG risk score model. In addition, the overall survival nomograms of clinicopathological factors and circadian clock-related gene signatures. Additionally, we evaluated the connection between circadian clock-related genes with immune checkpoint inhibitors and immune cell infiltration.Results:Two circadian clock-related signatures were established. The risk model included SEMA4D (pConclusions:We developed and validated a circadian signature to characterize the clinical significance and tumor microenvironment of cutaneous melanoma, revealing that circadian rhythms may impact cutaneous melanoma.

Background Ultraviolet irradiation (UVR) can induce both cellular senescence and cell apoptosis, which is mainly determined by the DNA damage response. The mechanism that determines the cellular outcome after UVR has not been fully illuminated. Objective To investigate the role of ACTL6A in the response of human dermal fibroblasts to UVR. Methods Human dermal fibroblasts were used to find the function and mechanism of ACTL6A in photoaging and verified in mice. Results ACTL6A expression was significantly increased both in vitro and in vivo after UVR exposure. Interference ACTL6A expression in HDFs inhibited the UVR stress-induced premature senescence, intracellular ROS production and SASP secretion. Meanwhile, knockdown of ACTL6A promotes apoptosis of senescent cells. Conclusion ACTL6A exhibited a critical role in resolving the cell fate under UVR and maybe a potential target for the therapy of UV-induced diseases and UV-needed diseases.

Ni Zeng,1,2 Liwen Ma,3 Yuxin Cheng,1 Qingyue Xia,1 Yueyue Li,1 Yihe Chen,1 Zhiyu Lu,1 Qian Lu,1 Feng Jiang,4 Dan Luo1 1Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210000, People’s Republic of China; 2Department of Dermatology, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 3Department of Dermatology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210000, People’s Republic of China; 4Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, People’s Republic of ChinaCorrespondence: Dan LuoDepartment of Dermatology, The First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Road, Nanjing, 210000, People’s Republic of ChinaEmail daniluo2005@163.comFeng JiangDepartment of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Shanghai, 200011, People’s Republic of ChinaEmail dxyjiang@163.comObjective: In this research, we studied the genes associated with ferroptosis to develop a prognostic model and find out an association with tumor immune microenvironment in skin cutaneous melanoma (SKCM) patients.Methods: To find SKCM-related ferroptosis genes, we used Cox regression and LASSO approach on 60 genes related to ferroptosis and SKCM-related RNA-seq. Following that, a ferroptosis-related gene signature was created. Time-dependent ROC curve and Kaplan–Meier analysis were calculated to determine its capability of prediction. Besides, several assessments were used to evaluate overall survival (OS), accompanied by the creation of a nomogram for the clinicopathologic factors and the ferroptosis-related gene signature we established. We also investigated the relationship between ferroptosis-related gene signature with three immune checkpoints and immune cell infiltration.Results: Our prognostic model included two genes (ALOX5, CHAC1). In both TCGA and GEO cohorts, OS was lower in high-risk category. Using our gene signature, we can reliably predict OS. Additionally, our gene signature can predict immune cell infiltration and SKCM immunotherapy response.Conclusion: Our gene signature has shown to be a reliable predictor of OS, reflect the immune microenvironment, and predict the effectiveness of immunotherapy for SKCM patients.Keywords: skin cutaneous melanoma, SKCM, ferroptosis, immune microenvironment, immune checkpoint

Background Atopic dermatitis is the most common chronic inflammatory skin disease and presents a major public health burden worldwide. Recent observational studies revealed the potential association between atopic dermatitis with autoimmune disorders. However, there is no meta-analysis of the prevalence or incidence of autoimmune diseases in atopic dermatitis. Therefore, considering the potential clinical implications of these associations, we aimed to assess the risk of autoimmune diseases in patients with atopic dermatitis using this method. Methods PubMed, Embase, and Web of Science were searched from inception to October, 2020. Observational studies which provided estimate effects with 95% CI or raw data were included. The quality of selected studies was evaluated using the Newcastle–Ottawa Scale. Odds ratio and relative risks were pooled using a random effects model and expressed with 95% confidence intervals. Results Fourteen observational studies were included in this systematic review and meta-analysis. The random-effects meta-analysis of case–control and cross-sectional studies showed a significant association of atopic dermatitis with mutiple autoimmune diseases, including alopecia areata, celiac disease, Crohn’s disease, rheumatoid arthritis, systematic lupus erythematosus, ulcerative colitis and vitiligo. Furthermore, pooling of the results of cohort studies showed that patients with atopic dermatitis were more likely to develop these autoimmune diseases. Conclusion Our meta-analysis showed that patients with atopic dermatitis were at higher risk of multiple autoimmune diseases including alopecia areata, celiac disease, Crohn’s disease, rheumatoid arthritis, systematic lupus erythematosus, ulcerative colitis and vitiligo. It is important for early detection of the affected group so that timely management can be initiated. Dermatologists and allergists should be aware of the autoimmune diseases in patients with atopic dermatitis and develop interventions if necessary. Also, limited by the present research, we still require more large-scale studies to further establish the association between atopic dermatitis and autoimmune diseases.

Background Increasingly evidence has shown pulmonary arterial hypertension (PAH) was predisposed to occur in psoriasis, however, the common mechanism of this phenomenon is still not fully clarified. This study aims to further explore the molecular mechanisms of this complication. Methods Four datasets were downloaded from the Gene Expression Omnibus (GEO) database based on the study inclusion/exclusion criteria. After screening the communal DEGs, modules, and hub genes of psoriasis and PAH, subsequent bioinformatic analyses, consisting of function annotation analysis, co-expression analysis, drug-gene interaction prediction, and mRNA–miRNA regulation network construction were conducted. Moreover, Immune cell infiltration analysis and correlation analysis were performed to further uncover the related immune pathogenesis in psoriasis and PAH. Results 170 communal DEGs, 4 modules, and 6 hub genes were identified between GSE15197 and GSE30999, and the expression of hub genes was verified in the GSE41662 and GSE113439 respectively. The function annotation analysis of these genes mainly enriched in the Immune System and associated signal transduction, and the immune cell infiltration analysis highlighted the existence of the overlap in terms of mast cells between PAH and psoriasis. Conclusions The analysis of communal DEGs, modules, and hub genes underlined the potential role of the immune system and associated signal transduction in the common pathogenesis of psoriasis and PAH, and immune Infiltration analysis of two diseases provide us with new perspectives and exploring direction. Moreover, six hub genes (MYO5A, CDT1, ASPM, ACTR2, PTPN11, and SOST) may be used as biomarkers or therapeutic targets in psoriasis and PAH.

The novel coronavirus disease 2019 (COVID-19) vaccination is now an essential strategy for controlling the COVID-19 epidemic. This study included 132 cases of adverse skin reactions after the injection of COVID-19 vaccination from January 2021 to January 2022. The rate of adverse skin reactions after the 1st, 2nd, and 3rd doses of the COVID-19 vaccine were 52%, 40%, and 8% of total adverse skin reactions, respectively. The Urticaria-like rash was the most common manifestation of all adverse skin reactions, accounting for 40.15% of all adverse reactions. The Eczema-like rash was 27.27%. The rates of adverse skin reactions after vaccination with the COVID-19 vaccine in patients with a previous skin disease was 12.12%. Other rare skin adverse reactions after COVID-19 vaccination included herpes zoster, pityriasis rosea, erythema multiforme, chickenpox, herpes simplex, psoriasis, erythrodermatitis, arthus reaction, lichen planus recurrence, measles-like rash, frostbite rash, seborrhea, and vitiligo. There were 23 cases of adverse skin reactions in the same individual after two doses of COVID-19 vaccine. There were three cases of adverse skin reactions in the same person after three doses of the vaccine. Treatment measures are mostly mild regimens, such as oral antihistamines, compounded glycopyrrolate and topical weak to moderately potent corticosteroid creams. The total duration of these skin adverse reactions ranged from 2 weeks to 1 month.

Ultraviolet A (UVA) radiation causes skin damage. Recently, natural compounds have become an interest to protect skin from UV-induced photodamages.In this study, we investigated the protective effects of hesperetin, a citrus flavonoid, on UVA-induced oxidative stress, inflammation, apoptosis, and photoaging.Our results showed that hesperetin increased the cell viability, suppressed the intracellular ROS levels, and decreased the expression of MMPs including MMP-1 and MMP-3, pro-inflammatory cytokines including IL-6 and COX-2 in UVA-irradiated HDFs. Besides, hesperetin exerted an anti-apoptotic effect by increasing expression of anti-apoptotic protein Bcl-2 and decreasing expression of pro-apoptotic protein Bax. Moreover, these anti-photodamage effects were mediated by inhibition of ERK, p38/AP-1, and NF-κb/p65 phosphorylation.Therefore, hesperetin may be useful in the prevention of UVA-induced skin damage.

Ultraviolet A (UVA) irradiation can induce cellular senescence and cause skin photoaging, which is mainly driven by the excessive production of reactive oxygen species (ROS). Emerging studies have focused on new strategies for the prevention of skin photoaging. Ultrasmall Prussian blue nanoparticles (USPBNPs) demonstrate an intensive ability to scavenge ROS as nanozymes and exhibit great potential in the treatment of ROS-related diseases. Our goal was to investigate the anti-senescent role of USPBNPs against UVA-induced premature senescence in human dermal fibroblasts (HDFs). Our results showed that the activation of senescence-associated β-galactosidase (SA-β-gal) and the arrest of the cell cycle induced by UVA radiation in HDFs were significantly inhibited by pretreatment of USPBNPs (1 μg ml−1). Furthermore, USPBNPs downregulated the expression of DNA damage marker γH2AX and inhibited the secretion of senescence-associated secretory phenotypes (SASP) including IL-6, TNF-α and matrix metalloproteinases (MMPs). In addition, we found that the antiphotoaging effect of USPBNPs involved the scavenging of ROS as well as the inhibition of the ERK/AP-1 pathway. In conclusion, USPBNPs exhibited great potential to become novel anti-photoaging agents by alleviating UVA-induced cellular senescence and thus delaying the process of skin photoaging.

RXLR effectors, a class of secreted proteins that are transferred into host cells to manipulate host immunity, have been reported to widely exist in oomycetes, including those from genera Phytophthora, Hyaloperonospora, Albugo, and Saprolegnia. However, in Pythium species, no RXLR effector has yet been characterized, and the origin and evolution of such virulent effectors are still unknown. Here, we developed a modified regular expression method for de novo identification of RXLRs and characterized 359 putative RXLR effectors in nine Pythium species. Phylogenetic analysis revealed that all oomycetous RXLRs formed a single superfamily, suggesting that they might have a common ancestor. RXLR effectors from Pythium and Phytophthora species exhibited similar sequence features, protein structures, and genome locations. In particular, there were significantly more RXLR proteins in the mosquito biological control agent P. guiyangense than in the other eight Pythium species, and P. guiyangense RXLRs might be the result of gene duplication and genome rearrangement events, as indicated by synteny analysis. Expression pattern analysis of RXLR-encoding genes in the plant pathogen P. ultimum detected transcripts of the majority of the predicted RXLR genes, with some RXLR effectors induced in infection stages and one RXLR showing necrosis-inducing activity. Furthermore, all predicted RXLR genes were cloned from two biocontrol agents, P. oligandrum and P. periplocum, and three of the RXLR genes were found to induce a defense response in Nicotiana benthamiana. Taken together, our findings represent the first evidence of RXLR effectors in Pythium species, providing valuable information on their evolutionary patterns and the mechanisms of their interactions with diverse hosts.

Cardiomyopathies are a heterogeneous group of heart diseases that can gradually cause severe heart failure. In particular, dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are the two main types of cardiomyopathies, yet the independent and communal biological mechanisms of both remain far from elucidated. Meanwhile, ferroptosis is a non-apoptotic form of cell death that has been proven to be associated with cardiomyopathies, but the concrete nature of the interaction remains unclear. Hence, this study explored the pathogenesis and ferroptosis mechanism of HCM and DCMSix datasets were downloaded from the Gene Expression Omnibus (GEO) database based on the study inclusion/exclusion criteria. After screening the differentially expressed genes (DEGs) and hub genes of HCM and DCM, subsequent analyses, including functional annotation, co-expression, validation, and transcription factors (TF)-mRNA-microRNA (miRNA) regulatory network construction, were performed. In addition, ferroptosis-related DEGs were also identified and verified in HCM and DCM.We found 171 independent DEGs of HCM mainly enriched in the regulation of ERK1 and ERK2 cascade, while 171 independent DEGs of DCM were significantly involved in cell adhesion. Meanwhile, 32 communal DEGs (26 upregulated genes and 6 downregulated genes) and 3 hub genes [periostin (The identified independent and communal DEGs contribute to uncover a potentially distinct and common mechanism of HCM and DCM and ferroptosis-related genes could provide us with a novel direction for exploration. In addition, 3 hub genes could be potential biomarkers or therapeutic targets in patients with cardiomyopathy.

A candidate effector with glutathione peroxidase activity from the Apolygus lucorum salivary gland suppressed PAMP-triggered cell death and ROS accumulation to enhance plant susceptibility to insects and pathogens., The mirid bug Apolygus lucorum has become a major agricultural pest since the large-scale cultivation of Bt-cotton. It was assumed that A. lucorum, similarly to other phloem sap insects, could secrete saliva that contains effector proteins into plant interfaces to perturb host cellular processes during feeding. However, the secreted effectors of A. lucorum are still uncharacterized and unstudied. In this study, 1878 putative secreted proteins were identified from the transcriptome of A. lucorum, which either had homology with published aphid effectors or shared common features with plant pathogens and insect effectors. One hundred and seventy-two candidate effectors were used for cell death-inducing/suppressing assays, and a putative salivary gland effector, Apolygus lucorum cell death inhibitor 6 (Al6), was characterized. The mRNAs of Al6 were enriched at feeding stages (nymph and adult) and, in particular, in salivary glands. Moreover, we revealed that the secreted Al6 encoded an active glutathione peroxidase that reduced reactive oxygen species (ROS) accumulation induced by INF1 or Flg22. Expression of the Al6 gene in planta altered insect feeding behavior and promoted plant pathogen infections. Inhibition of cell death and enhanced plant susceptibility to insect and pathogens are dependent on glutathione peroxidase activity of Al6. Thus, this study shows that a candidate salivary gland effector, Al6, functions as a glutathione peroxidase and suppresses ROS induced by pathogen-associated molecular pattern to inhibit pattern-triggered immunity (PTI)-induced cell death. The identification and molecular mechanism analysis of the Al6 candidate effector in A. lucorum will provide new insight into the molecular mechanisms of insect–plant interactions.

The tyrosine kinase-like (TKL) gene family is widely existed in most eukaryotes and participates in many biological processes, however, has been rarely studied in oomycetes. In this study we performed bioinformatic and experimental analyses to characterize TKLs in Pythium guiyangense, a promising mosquito biological control agent. Our results revealed that TKLs were widely distributed in all the detected oomycetes, but were largely expanded in P. guiyangense in a species-specific expansion manner. The expansion was mostly driven by whole-genome duplication and tandem duplication. Domain distributions and exon-intron structures were highly conserved in the same group while diverse in different groups, suggesting of functional divergence. Transcriptional analysis revealed that over one fourth of TKLs were differentially expressed after infection of mosquito larvae, implying that these genes might participate in the infection process. Furthermore, subgroup A TKLs were functionally investigated using genetic transformation silencing method. Our findings demonstrated that subgroup A TKLs were up-regulated at the early infection stages and silencing of subgroup A TKLs led to reduced mycelia growth, zoospore production and alteration of stress responses. Pathogenicity assays also revealed that silencing of subgroup A TKLs reduced P. guiyangense virulence to mosquito larvae. Taken together, this study provides a comprehensive overview of P. guiyangense TKL family and reveals their potential roles in growth, development, stress response, and especially virulence.

Phytophthora genomes encode a myriad of Crinkler (CRN) effectors, some of which contain putative kinase domains. Little is known about the host targets of these kinase-domain-containing CRNs and their infection-promoting mechanisms. Here, we report the host target and functional mechanism of a conserved kinase CRN effector named CRN78 in a notorious oomycete pathogen, Phytophthora sojae. CRN78 promotes Phytophthora capsici infection in Nicotiana benthamiana and enhances P. sojae virulence on the host plant Glycine max by inhibiting plant H2O2 accumulation and immunity-related gene expression. Further investigation reveals that CRN78 interacts with PIP2-family aquaporin proteins including NbPIP2;2 from N. benthamiana and GmPIP2-13 from soybean on the plant plasma membrane, and membrane localization is necessary for virulence of CRN78. Next, CRN78 promotes phosphorylation of NbPIP2;2 or GmPIP2-13 using its kinase domain in vivo, leading to their subsequent protein degradation in a 26S-dependent pathway. Our data also demonstrates that NbPIP2;2 acts as a H2O2 transporter to positively regulate plant immunity and reactive oxygen species (ROS) accumulation. Phylogenetic analysis suggests that the phosphorylation sites of PIP2 proteins and the kinase domains of CRN78 homologs are highly conserved among higher plants and oomycete pathogens, respectively. Therefore, this study elucidates a conserved and novel pathway used by effector proteins to inhibit host cellular defenses by targeting and hijacking phosphorylation of plant aquaporin proteins., Author summary CRN effectors are conserved in diverse pathogens of plants, animals, and insects, and highly expanded in Phytophthora species. Nevertheless, little is known about their functions, targets, and action mechanisms. Here, we characterized a kinase-domain-containing CRN effector (CRN78) in a notorious oomycete pathogen, P. sojae. CRN78 is a virulence-essential effector of P. sojae infection, and acts via suppression of plant H2O2 accumulation and defense gene expressions. We demonstrated that CRN78 might interact with plant PIP2-family aquaporin proteins, including N. benthamiana NbPIP2;2 and soybean GmPIP2-13, and regulate their phosphorylation, resulting in subsequent 26S-dependent protein degradation. Furthermore, we revealed that NbPIP2;2 was an apoplast-to-cytoplast H2O2 transporter and positively regulated plant immunity and ROS accumulation. Importantly, this phosphorylation may be highly conserved in many plant aquaporin proteins. Thus, this study identifies a virulence-related effector from P. sojae and a novel plant immunity-related gene, and reveals a detailed mechanism of effector-mediated phosphorylation and degradation of plant aquaporin proteins.

Correction for ‘Ultrasmall Prussian blue nanoparticles attenuate UVA-induced cellular senescence in human dermal fibroblasts via inhibiting the ERK/AP-1 pathway’ by Yueyue Li et al., Nanoscale, 2021, 13, 16104–16112, https://doi.org/10.1039/D1NR04268H.

Being widely existed in oomycetes, the RXLR effector features conserved RXLR-dEER motifs in its N terminal. Every known Phytophthora or Hyaloperonospora pathogen harbors hundreds of RXLRs. In Pythium species, however, none of the RXLR effectors has been characterized yet. Here, we developed a stringent method for de novo identification of RXLRs and characterized 359 putative RXLR effectors from nine tested Pythium species. Phylogenetic analysis revealed a single superfamily formed by all oomycetous RXLRs, suggesting they descent from a common ancestor. RXLR effectors from Pythium and Phytophthora species exhibited similar sequence features, protein structures and genome locations. In particular, the mosquito biological agent P. guiyangense contains a significantly larger RXLR repertoire than the other eight Pythium species examined, which may result from gene duplication and genome rearrangement events as indicated by synteny analysis. Expression pattern analysis of RXLR-encoding genes in the plant pathogen P. ultimum detected transcripts from the vast majority of predicted RXLRs with some of them being induced at infection stages. One such RXLRs showed necrosis-inducing activity. Furthermore, all predicted RXLRs were cloned from two biocontrol agents P. oligandrum and P. periplocum. Three of them were found to encode effectors inducing defense response in Nicotiana benthamiana. Taken together, our findings represent the first complete synopsis of Pythium RXLR effectors, which provides critical clues on their evolutionary patterns as well as the mechanisms of their interactions with diverse hosts.Author summaryPathogens from the Pythium genus are widespread across multiple ecological niches. Most of them are soilborne plant pathogens whereas others cause infectious diseases in mammals. Some Pythium species can be used as biocontrol agents for plant diseases or mosquito management. Despite that phylogenetically close oomycete pathogens secrete RXLR effectors to enable infection, no RXLR protein was previously characterized in any Pythium species. Here we developed a stringent method to predict Pythium RXLR effectors and compared them with known RXLRs from other species. All oomycetous RXLRs form a huge superfamily, which indicates they may share a common ancestor. Our sequence analysis results suggest that the expansion of RXLR repertoire results from gene duplication and genome recombination events. We further demonstrated that most predicted Pythium RXLRs can be transcribed and some of them encode effectors exhibiting pathogenic or defense-inducing activities. This work expands our understanding of RXLR evolution in oomycetes in general, and provides novel insights into the molecular interactions between Pythium pathogens and their diverse hosts.

Chitinases, the enzymes responsible for the biological degradation of chitin, participate in numerous physiological processes such as nutrition, parasitism, morphogenesis and immunity in various organisms. However, the genome-wide distribution, evolution and biological functions of chitinases are rarely reported in oomycetes. This study systematically investigated the glycoside hydrolase 18 (GH18) family of chitinases from the mosquito pathogenic oomycete, Pythium guiyangense using bioinformatics and experimental assays. A total of 3 pairs of GH18 chitinase genes distributed in three distinct phylogenic clusters were identified from P. guiyangense genome, which is consistent with the ones in plant pathogenic oomycetes. Further transcriptional analysis revealed that Pgchi1/2 was highly expressed at the development stages, while Pgchi3/4 and Pgchi5/6 were up-regulated at the infection stages. The biological function analysis of chitinase genes using genetic transformation silencing method showed that silencing of Pgchi1/2 resulted in reduced zoospore production, without affecting the virulence. However, attenuation of Pgchi3/4 and Pgchi5/6 genes regulated not only oxidative stress responses, but also led to decreased infection rates to mosquito larvae. Taken together, this study provides a comprehensive overview of P. guiyangense chitinase family and reveals their diverse roles in the development, stress response, and virulence, which would elucidate insightful information on the molecular mechanism of chitinase in entomopathogenic pathogens.