A Phytophthora sojae CRN effector mediates phosphorylation and degradation of plant aquaporin proteins to suppress host immune signaling.

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.

Clinical observation and analysis of skin reactions caused by COVID-19 vaccination.

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.

Prediction and Characterization of RXLR Effectors in Pythium Species.

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.

The glycoside hydrolase 18 family chitinases are associated with development and virulence in the mosquito pathogen Pythium guiyangense.

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.

The mirid bug Apolygus lucorum deploys a glutathione peroxidase as a candidate effector to enhance plant susceptibility.

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.

Genome-wide and functional analyses of tyrosine kinase-like family genes reveal potential roles in development and virulence in mosquito pathogen Pythium guiyangense.

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.

Exploring the influencing factors on acne, melasma, and rosacea: A case-control study in China.

BACKGROUND: The severity and treatment response of acne, melasma, and rosacea may be influenced by various currently unclear internal and external factors. This study aimed to provide evidence to the influencing factors for the mentioned conditions through a real-world case-control study. METHODS: An online survey consisting of 60 questions was implemented, collecting information on demographics, socioeconomics, genetic factors, lifestyle habits, environmental exposures, and skin care behaviors. Then we constructed univariate and multivariate logistic regressions. Furthermore, we analyzed the dose-response relationship between exposure and outcome. RESULTS: A total of 399 individuals, including 94 acne patients, 107 melasma patients, and 91 rosacea patients were included. Acne and melasma were positively correlated with screen time (acne: odds ratio [OR]: 2.24, 95% confidence interval [CI]: 1.25-4.02; melasma: OR: 1.59, 95% CI: 1.09-2.31), while exercise exerted a protective effect on both acne (OR: 0.31, 95% CI: 0.13-0.77) and melasma (OR: 0.42, 95% CI: 0.22-0.80) in a dose-response relationship. In addition, males were associated with an elevated risk of acne (OR: 6.62, 95% CI: 1.01-43.26). Aging (OR: 1.15, 95% CI: 1.07-1.24) and irregular bowel movements (OR: 2.99, 95% CI: 1.11-8.08) were independent risk factors for melasma. Rosacea was positively associated with BMI (OR: 1.17, 95% CI: 1.01-1.35). CONCLUSION: In our study, we highlighted exercise as an independent protective factor for both acne and melasma in a dose-response trend. Inversely, extended use of electronic equipment was independently associated with higher risks of acne and melasma. Rosacea, however, was more likely to be related with BMI.

Maslinic acid attenuates UVB-induced oxidative damage in HFF-1 cells.

BACKGROUND: Oxidative damage is one of the major mechanisms of ultraviolet B (UVB)-induced damage to the skin. Maslinic acid (MA) is a natural compound of pentacyclic triterpene acids. It has been proved to have anti-inflammatory and antioxidant properties. OBJECTIVE: This study aimed to explore the effects of MA on oxidative damage in human foreskin fibroblast cells (HFF-1) and the potential molecular mechanisms. METHODS: A specific dose of UVB radiation was used to induce oxidative damage in HFF-1. Based on this, we performed measurements of cell proliferation, reactive oxygen species (ROS) levels, antioxidant enzyme activity, inflammation-related mediators, and NF-κB nuclear localization with or without the addition of MA. RESULTS: MA significantly promoted cell proliferation viability at 10 and 20 µM. The addition of MA 24 h before UVB irradiation was more effective at enhancing cell proliferation and also produced lower ROS levels compared to co-cultured fibroblasts and MA for 24 h after irradiation. However, there was no statistically significant difference between groups at concentrations of 10 and 20 µM. The pretreatment group with MA had elevated superoxide dismutase and catalase activities, decreased IL-6 generation, and lowered mRNA levels of IL-6, TNF-α and MMP3 in comparison with the UVB-irradiated group without additional MA. Meanwhile, the nuclear translocation of NF-κB and the degradation of IκB were inhibited by MA pretreatment. CONCLUSION: Taken together, these findings suggest that MA may alleviate UVB-induced oxidative damage in HFF-1 by inhibiting the nuclear translocation of NF-κB.

The commonness in immune infiltration of rheumatoid arthritis and atherosclerosis: Screening for central targets via microarray data analysis.

Background: Although increasing evidence has reported an increased risk of atherosclerosis (AS) in rheumatoid arthritis (RA), the communal molecular mechanism of this phenomenon is still far from being fully elucidated. Hence, this article aimed to explore the pathogenesis of RA complicated with AS. Methods: Based on the strict inclusion/exclusion criteria, four gene datasets were downloaded from the Gene Expression Omnibus (GEO) database. After identifying the communal differentially expressed genes (DEGs) and hub genes, comprehensive bioinformatics analysis, including functional annotation, co-expression analysis, expression validation, drug-gene prediction, and TF-mRNA-miRNA regulatory network construction, was conducted. Moreover, the immune infiltration of RA and AS was analyzed and compared based on the CIBERSORT algorithm, and the correlation between hub genes and infiltrating immune cells was evaluated in RA and AS respectively. Results: A total of 54 upregulated and 12 downregulated communal DEGs were screened between GSE100927 and GSE55457, and functional analysis of these genes indicated that the potential pathogenesis lies in immune terms. After the protein-protein interaction (PPI) network construction, a total of six hub genes (CCR5, CCR7, IL7R, PTPRC, CD2, and CD3D) were determined as hub genes, and the subsequent comprehensive bioinformatics analysis of the hub genes re-emphasized the importance of the immune system in RA and AS. Additionally, three overlapping infiltrating immune cells were found between RA and AS based on the CIBERSORT algorithm, including upregulated memory B cells, follicular helper T cells and γδT cells. Conclusions: Our study uncover the communal central genes and commonness in immune infiltration between RA and AS, and the analysis of six hub genes and three immune cells profile might provide new insights into potential pathogenesis therapeutic direction of RA complicated with AS.

Exploring the Communal Pathogenesis, Ferroptosis Mechanism, and Potential Therapeutic Targets of Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy via a Microarray Data Analysis.

Background: 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 DCM via a bioinformatics analysis. Methods: Six 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. Results: 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 (POSTN), insulin-like growth factor-binding protein-5 (IGFBP5), and fibromodulin (FMOD)] were determined to be shared between HCM and DCM and the functional annotation of these genes highlighted the important position of growth hormone in HCM and DCM. Moreover, we identified activating transcription factor 3 (ATF3), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and solute carrier family 1 member 5 (SLC1A5) as ferroptosis-related genes in HCM and STAT3 as a ferroptosis-related gene in DCM. Conclusion: 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.

Construction of Circadian Clock Signature for Tumor Microenvironment in Predicting Survival for Cutaneous Melanoma.

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 (p<0.001, HR: 0.709, 95% CI: 0.581 to 0.867) and SOD-2 (p=0.009, HR: 0.790, 95% CI: 0.663 to 0.944) in patients with TCGA melanoma. The risk model was based on two CCRGs enriched in base excision repair, glycosylphosphatidyl (GPI), and one carbon of the folate pathway. The overall survival was lower in the high-risk group. In addition, the circadian-clock signature may be able to evaluate the immunotherapy response. CONCLUSIONS: 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.

Hesperetin attenuates UVA-induced photodamage in human dermal fibroblast cells.

BACKGROUND: Ultraviolet A (UVA) radiation causes skin damage. Recently, natural compounds have become an interest to protect skin from UV-induced photodamages. METHODS: In this study, we investigated the protective effects of hesperetin, a citrus flavonoid, on UVA-induced oxidative stress, inflammation, apoptosis, and photoaging. RESULTS: 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. CONCLUSION: Therefore, hesperetin may be useful in the prevention of UVA-induced skin damage.

Correction: Ultrasmall Prussian blue nanoparticles attenuate UVA-induced cellular senescence in human dermal fibroblasts via inhibiting the ERK/AP-1 pathway.

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.

Construction of a Ferroptosis-Related Gene Signature for Predicting Survival and Immune Microenvironment in Melanoma Patients.

OBJECTIVE: 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.

Atopic dermatitis and risk of autoimmune diseases: a systematic review and meta-analysis.

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.

Ultrasmall Prussian blue nanoparticles attenuate UVA-induced cellular senescence in human dermal fibroblasts via inhibiting the ERK/AP-1 pathway.

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 ß-galactosidase (SA-ß-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.