Increased neutrophil-derived IL-17A identified in generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) is considered to be a distinct clinical entity from psoriasis vulgaris (PV), with different clinical and histological manifestations. The pathogenesis of GPP has not been thoroughly elucidated, especially in those patients lacking interleukin (IL)36RN. In present study, we performed RNA sequence analysis on skin lesions from 10 GPP patients (4 with and 6 without IL36RN mutation) and 10 PV patients without IL36RN mutation. Compared with PV, significantly overexpressed genes in GPP patients were enriched in IL-17 signalling pathway (MMP1, MMP3, DEFB4A and DEFB4B, etc.) and associated with neutrophil infiltration (MMP1, MMP3, ANXA and SERPINB, etc.). GPP with IL36RN mutations evidenced WNT11 upregulation and IL36RN downregulation in comparison to those GPP without IL36RN mutations. The expression of IL-17A/IL-36 in skin or serum and the origin of IL-17A in skin were also investigated. IL-17A expression in skin was significantly higher in GPP than PV patients, whereas, there were no differences in skin IL-36α/IL-36γ/IL-36RA or serum IL-17A/IL-36α/IL-36γ between GPP than PV. Besides, double immunofluorescence staining of MPO/IL-17A or CD3/IL-17A further confirmed that the majority of IL-17A in GPP skin was derived from neutrophils, but not T cells. These data emphasized the role of neutrophil-derived IL-17A in the pathogenesis of GPP with or without IL36RN mutations. Targeting neutrophil-derived IL-17A might be a promising treatment for GPP.

Increased soluble endoglin levels in newly-diagnosed type 2 diabetic patients are associated with endothelial dysfunction.

Endothelial dysfunction (ED) contributes to the pathologic process underlying macrovascular complications, a common complication of type 2 diabetes mellitus (T2DM). Soluble endoglin (sEng) shed from the extracellular domain of the entire endoglin molecule blocks endothelial protection mediated by transforming growth factor-beta 1 (TGF-ß1). The reactive hyperemia index (RHI), which is determined by reactive hyperemia peripheral arterial tonometry (RH-PAT), is a new index with which to evaluate ED. This study determined the changes in serum sEng levels in newly-diagnosed (untreated) T2DM patients and the correlation with the RHI. The T2DM group included 34 newly-diagnosed T2DM patients, while the control group included 53 healthy adults. The clinical data from the two groups were evaluated retrospectively. The intima-media thickness (IMT) of the common carotid artery (CCA) and the ankle-brachial index (ABI) of both legs were used to assess structural vascular changes. The serum sEng level was determined using an ELISA kit. Endothelial function was assessed using RH-PAT and the RHI was computed. The serum sEng level in the T2DM group was significantly greater than the control group, although the RHI was significantly lower in the T2DM group (p < 0.05). The serum sEng level was negatively correlated with the RHI in T2DM patents (r = 0.354, p = 0.041). The serum sEng level, CCA-IMT, and ABI were not significantly correlated with T2DM (p > 0.05). In summary, among newly-diagnosed T2DM patients, the serum sEng levels were inversely correlated with the RHI, and an elevated sEng level may be associated with ED.

RNA-Seq Transcriptomic Analysis of Green Tea Polyphenols Modulation of Differently Expressed Genes in Enterococcus faecalis Under Bile Salt Stress.

Enterococcus faecalis (E. faecalis) belongs to lactic acid bacteria which can be used as a probiotic additive and feed, bringing practical value to the health of humans and animals. The prebiotic function of tea polyphenols lays a foundation for green tea polyphenols (GTP) to repair the adverse changes of E. faecalis under stress conditions. In this study, RNA-sequence analysis was used to explore the protective effect of GTP on E. faecalis under bile salt stress. A total of 50 genes were found to respond to GTP under bile salts stress, containing 18 up-regulated and 32 down-regulated genes. The results showed that multiple genes associated with cell wall and membrane, transmembrane transport, nucleotide transport and metabolism were significantly differentially expressed (P < 0.05), while GTP intervention can partly alleviate the detrimental effects of bile salt on amino acid metabolism and transport. The present study provides the whole genome transcriptomics of E. faecalis under bile salt stress and GTP intervention which help us understand the growth and mechanism of continuous adaptation of E. faecalis under stress conditions.

Candicidin Isomer Production Is Essential for Biocontrol of Cucumber Rhizoctonia Rot by Streptomyces albidoflavus W68.

Diseases caused by soilborne fungal pathogens result in significant crop yield losses and quality reduction. Streptomyces albidoflavus strain W68 is effective in controlling several soilborne fungal diseases. To identify antifungal substances critical for biocontrol activity of W68, the genome of W68 was sequenced and a linear chromosome of 6.80 Mb was assembled. A total of 21 secondary metabolite biosynthesis gene clusters (BGCs), accounting for 12.27% of the genome, were identified. Core gene deletion mutants for each of all 8 BGCs for nonribosomal peptide synthetases and polyketide synthases were created. Among them, only the mutant lacking ctg1-5755 (the gene was renamed as fscDW68) in BGC 19, which shares 100% sequence similarity with the BGC for candicidin synthesis, showed obvious reduction in antifungal activity. A pot experiment revealed that biocontrol effects of the ΔfscDW68 mutant in Rhizoctonia rot of cucumber were also significantly compromised relative to W68. Liquid chromatography-mass spectrometry (LC-MS) analysis revealed that W68 but not the ΔfscDW68 mutant can produce candicidin isomers, indicating that the production of candicidin isomers is key for antifungal activity and biocontrol activity of S. albidoflavus W68.IMPORTANCE This study reports that candicidin-like secondary metabolites produced by microbial cells in natural soil environments can effectively control soilborne fungal diseases, revealing a novel mechanism of microbial biocontrol agents. We demonstrated that the main antifungal activity and biocontrol activity of Streptomyces albidoflavus strain W68 are attributable to the production of candicidin isomers, suggesting that gene clusters for candicidin-like compound biosynthesis might be used as molecular markers to screen and breed microbial strains for biocontrol agent development.

Homologous recombination as a mechanism to recognize repetitive DNA sequences in an RNAi pathway.

Quelling is an RNAi-related phenomenon that post-transcriptionally silences repetitive DNA and transposons in Neurospora. We previously identified a type of DNA damage-induced small RNA called qiRNA that originates from ribosomal DNA. To understand how small RNAs are generated from repetitive DNA, we carried out a genetic screen to identify genes required for qiRNA biogenesis. Factors directly involved in homologous recombination (HR) and chromatin remodeling factors required for HR are essential for qiRNA production. HR is also required for quelling, and quelling is also the result of DNA damage, indicating that quelling and qiRNA production share a common mechanism. Together, our results suggest that DNA damage-triggered HR-based recombination allows the RNAi pathway to recognize repetitive DNA to produce small RNA.

A putative transcription factor LFC1 negatively regulates development and yield of winter mushroom.

Basidioma is the fruiting body of mushroom species. The deep understanding on the mechanism of basidioma development is valuable for mushroom breeding and cultivation. From winter mushroom (Flammulina velutipes), one of the top five industrially cultivated mushrooms, a novel putative Zn(II)2Cys6 transcription factor LFC1 with negative regulatory function in basidioma development was identified. The transcript level of lfc1 was dramatically decreased during basidioma development. Neither overexpression nor knockdown of lfc1 affected hyphal vegetative growth. However, knockdown of lfc1 could promote basidioma development and shorten cultivation time by 2 days, while overexpression of lfc1 delayed the optimal harvest time by 3 days. In the lfc1 knockdown strain, in which the lfc1 expression was reduced by 72%, mushroom yield and biological efficiency could be increased at least by 24%. Knockdown of lfc1 did not affect the shape of caps but significantly increased basidioma length and number, while its overexpression did not affect basidioma length but dramatically reduced basidioma number. In addition, rather than producing basidiomata with round caps as in wild type, the caps of basidiomata in the lfc1 overexpression mutants were significantly larger and the cap edge was wrinkled. RNA-seq analysis revealed that 455 genes had opposite transcriptional responses to lfc1 overexpression and knockdown. Some of them were previously reported as genes involved in basidioma development, including 3 hydrophobin encoding genes, 2 lectin encoding genes, FVFD16, an Eln2 ortholog encoding gene, and 3 genes encoding membrane components. As LFC1 homologs are widely present in mushroom species, lfc1 can be useful in mushroom breeding.Key Points• A novel transcription factor LFC1 negatively regulates fruiting in winter mushroom• LFC1 regulated transcription of more than 400 genes.• Reduction of LFC1 expression could shorten cultivation time and increase yield.• lfc1 could be a potentially useful reference gene for mushroom breeding.

Global study on slope instability modes based on 62 municipal solid waste landfills.

This study summarized global examples of landfill slope instability over the past 40 years, then selected 62 cases from 22 different counties to analyse the primary factors causing landfill instability. Three slope instability modes in landfill were categorized according to the position of the slip surface: (1) slip surfaces generated inside the waste pile; (2) slip surfaces that pass through the foundation soil; and (3) slip surfaces that occur along the interface between the bottom liner and the municipal solid waste (MSW) pile. These three types of slope instability modes account for 69.4%, 19.32% and 11.28% of all slope instability, respectively. Moreover, five primary causes of landfill instability were identified. A high landfill leachate level was the dominant cause, accounting for 40.32% of cases. This was followed by inadequate compaction of MSW, which accounted for 22.58% of cases, and insufficiently bearing capacity of the foundation, which accounted for 19.35% of cases. Moreover, low shear strength of the liner-MSW interface and rapid release or deflagration of landfill gas were critical factors affecting landfill stability. Factors of safety were calculated using GeoStudio software for selected landfills in China (Maoershan and Xiaping) and Sri Lanka (Meethotamulla). Results from this study are expected to contribute to the prevention and control of landfill failure.

Hybrid model for the prediction of municipal solid waste generation in Hangzhou, China.

Accurate prediction of municipal solid waste (MSW) generation is necessary for choosing appropriate waste treatment methods and for planning the distribution of disposal facilities. In this study, a hybrid model was established to forecast MSW generation through the combination of the ridge regression and GM(1,N) models. The hybrid model is multivariate and involves total urban population, total retail sales of social consumer goods, per capita consumption expenditure of urban areas, tourism, and college graduation. Compared with the constituent models alone, the hybrid model yields higher accuracy, with a mean absolute percentage error (MAPE) of only 2.59%. Through weight allocation and optimal treatment of residuals, the hybrid model also balances the growth trends of the individual models, making the prediction curve smoother. The model coefficients and correlation analysis show that population, economics, and educational factors are influential for waste generation. MSW output in Hangzhou will gradually increase in the future, and is expected to reach 5.12 million tons in 2021. Results can help decision makers to develop the measures and policies of waste management in the future.

Influence of effective stress and dry density on the permeability of municipal solid waste.

A landfill is one of the main sites for disposal of municipal solid waste and the current landfill disposal system faces several problems. For instance, excessive leachate water is an important factor leading to landfill instability. Understanding the permeability characteristics of municipal solid waste is a relevant topic in the field of environmental geotechnical engineering. In this paper, the current research progress on permeability characteristics of municipal solid waste is discussed. A review of recent studies indicates that the research in this field is divided into two categories based on the experimental method employed: field tests and laboratory tests. This paper summarizes test methods, landfill locations, waste ages, dry densities and permeability coefficients across different studies that focus on permeability characteristics. Additionally, an experimental study on compressibility and permeability characteristics of fresh municipal solid waste under different effective stresses and compression times was carried out. Moreover, the relationships between the permeability coefficient and effective stress as well as dry density were obtained and a permeability prediction model was established. Finally, the experimental results from the existing literature and this paper were compared and the effects of effective stress and dry density on the permeability characteristics of municipal solid waste were summarized. This study provides the basis for analysis of leachate production in a landfill.

Transcription factor ADS-4 regulates adaptive responses and resistance to antifungal azole stress.

Azoles are commonly used as antifungal drugs or pesticides to control fungal infections in medicine and agriculture. Fungi adapt to azole stress by rapidly activating the transcription of a number of genes, and transcriptional increases in some azole-responsive genes can elevate azole resistance. The regulatory mechanisms that control transcriptional responses to azole stress in filamentous fungi are not well understood. This study identified a bZIP transcription factor, ADS-4 (antifungal drug sensitive-4), as a new regulator of adaptive responses and resistance to antifungal azoles. Transcription of ads-4 in Neurospora crassa cells increased when they were subjected to ketoconazole treatment, whereas the deletion of ads-4 resulted in hypersensitivity to ketoconazole and fluconazole. In contrast, the overexpression of ads-4 increased resistance to fluconazole and ketoconazole in N. crassa. Transcriptome sequencing (RNA-seq) analysis, followed by quantitative reverse transcription (qRT)-PCR confirmation, showed that ADS-4 positively regulated the transcriptional responses of at least six genes to ketoconazole stress in N. crassa. The gene products of four ADS-4-regulated genes are known contributors to azole resistance, including the major efflux pump CDR4 (Pdr5p ortholog), an ABC multidrug transporter (NcAbcB), sterol C-22 desaturase (ERG5), and a lipid transporter (NcRTA2) that is involved in calcineurin-mediated azole resistance. Deletion of the ads-4-homologous gene Afads-4 in Aspergillus fumigatus caused hypersensitivity to itraconazole and ketoconazole, which suggested that ADS-4 is a functionally conserved regulator of adaptive responses to azoles. This study provides important information on a new azole resistance factor that could be targeted by a new range of antifungal pesticides and drugs.

An increased proportion of circulating Th22 and Tc22 cells in psoriasis.

Psoriasis is a common dermatosis mediated by T cells. This study investigated the correlation of Th22 cells and Tc22 cells with psoriasis. A total of 30 psoriasis patients and 11 age- and sex-matched healthy controls were recruited for this study. The proportions of circulating Th22 and Tc22 cells, expression of aryl hydrocarbon receptor, and IL-22 levels in the psoriasis patients were significantly higher than those in the control subjects (p<0.05). There was a positive correlation between the proportion of circulating Th22 cells, IL-22 levels, and PASI score. The IL-22 levels and PASI score were also positively correlated. There was no correlation between the proportion of circulating Tc22 cells and IL-22 level or PASI score. These data are consistent with Th22 cells involvement in the pathogenesis of psoriasis.

Personal treatment experience for severe generalized pustular psoriasis of pregnancy: two case reports.

Generalized pustular psoriasis of pregnancy (GPPP) is a rare and severe variant of pustular psoriasis. It has been called the most dangerous and life-threatening dermatosis in pregnant woman. To explore the treatment of GPPP, we conducted a retrospective study of two cases of GPPP in our clinic and other related reported cases and manuscripts. In 1992, a GPPP patient came to our clinic. We prescribed her antibiotics and dexamethasone. The pregnancy was artificially terminated. After delivery, she took a retinoid and a topical steroid and recovered progressively. In 2012, we treated another GPPP patient. Methylprednisolone and cyclosporine were administered. Maternal and fetal statuses were monitored closely. The treatment was effective and a healthy baby was delivered. We compared our two GPPP cases and found that cyclosporine and a sufficient dosage of steroid were an effective treatment. Antibiotics could be tried in mild cases or the initial stages before excluding sepsis. Based on other reported GPPP cases, TNF-α antagonists are used as rescue therapy in GPPP refractory to steroid and cyclosporine therapy, but careful consideration of the advantages and disadvantages is warranted before using them. Supportive measures are necessary to maintain pregnancy and prevent complications in cases of GPPP.

Compressibility characteristics of municipal solid waste considering multiple factors.

Borehole samples were collected from a municipal solid waste (MSW) landfill in Xi'an, China, and subjected to a series of basic geotechnical and compression tests. This study aims to investigate the influence of composition, dry unit weight, moisture content, organic content, and landfill age on the compressibility of MSW. The results show that with increasing landfill age, the compressible components and organic content exhibit a decreasing trend while the dry unit weight increases. The moisture content does not vary significantly. There is also a linear trend between the logarithm of the primary compression strain and vertical stress. In addition, with an increase in compressible components content, moisture content, and organic content, the modified primary compression index (Cc') shows an increasing trend, whereas with an increase in dry unit weight and landfill age, Cc' shows a decreasing trend. Furthermore, regarding the 34 sets of data, authors only selected five data points for a detailed comparative analysis, this decision was made on the basis that these data points are representative. A modified primary compression index prediction model that considers the dry unit weight, moisture content, and landfill age of the MSW as influencing factors results in a fitting coefficient of 0.797. The Cc' values in this study are within the range of 0.12 to 0.36. These findings provide a reference for the vertical expansion design of existing landfills.

Increased S. aureus colonization and reduced antimicrobial peptide expression in erythrodermic psoriasis.

BACKGROUND: Erythrodermic psoriasis (EP) is a severe and rare condition characterized by prominent erythema and scaling over 75 % of the body surface area. Unlike psoriasis vulgaris (PV), EP carries high risk of systemic involvement, including superficial skin infections and sepsis, particularly those caused by Staphylococcus aureus. OBJECTIVE: To explore the microecological characteristics of EP and detect the levels of antimicrobial peptides (AMPs) in both skin and serum of EP patients. METHODS: In this study, skin microbiomes of 10 EP patients were analyzed through 16S rRNA gene sequencing. The expressions of AMPs, Interleukin-4/13 (IL-4/13), Interleukin-17 (IL-17) and Interferon-γ (IFN-γ) in skin were detected via immunohistochemical staining and serum levels of AMP were evaluated by ELISA. We also enrolled 10 AD and 10 PV patients as controls. RESULTS: EP patients retained rich microbial diversity, dominated by S. aureus. The AMPs of hBD2, LL-37, and RNase7 in EP keratinocytes were significantly lower than those in PV, but higher than those in AD. The expression levels of IL-4, IL-13 and IFN-γ in lesions are similar between EP and AD, but quite different from PV. What's more, the serum AMP levels in EP were similar to those in PV while significantly lower than in AD. CONCLUSION: We found EP patients have a rich microbial diversity dominated by S. aureus in lesions, while lower serum and skin AMPs expressions, which may account for the increased incidence of S. aureus cutaneous infections and sepsis in EP patients.

Efficacy and safety of a noninvasive, home-based radiofrequency device for facial rejuvenation: An open-label, intraindividual controlled trial.

BACKGROUND: Wrinkle formation is the most visible characteristic of facial aging. Radiofrequency (RF) technology is currently utilized to reduce facial wrinkles and contribute to skin rejuvenation. OBJECTIVE: To analyze the efficacy and safety of a noninvasive, home-based RF device applied for facial rejuvenation in Chinese people. METHODS: A single-center, open-label, intraindividual controlled trial was performed on subjects who received an 8-week treatment of the RF device. A total of 22 female individuals aged 25-60 years with Fitzpatrick skin type III-IV were enrolled. Efficacy of treatment was subjectively evaluated using the Fitzpatrick Wrinkle Classification Scale (FWCS) assessed by physician or overall satisfaction of subject with a 10-point VAS, and objectively using the skin ultrasound examination as well as the 3D skin analysis system. Adverse event was recorded at each visit. RESULTS: In comparison with the baseline, evaluator-assessed FWCS scores showed significant improvement at 4 weeks (p < 0.005) and 8 weeks (p < 0.005) after treatment. All subjects reported different degrees of improvement in facial wrinkles after 8 weeks of treatment. The results of skin ultrasound examination revealed significant increase of the dermal thickness at week 8 (p < 0.05) as compared to the baseline. In addition, a significant decrease in the proportion and density of perioral wrinkles evaluated by the 3D skin analysis system was observed from baseline to week 4. The treatment was well-tolerated, and no serious adverse event was observed. CONCLUSION: This noninvasive, home-based RF device was effective in improving skin texture and elasticity with a safe and well-tolerated treating procedure.

Unmet Needs and Treatment Preference of Systemic Treatments for Moderate-to-Severe Psoriasis from the Perspectives of Patients and Dermatologists in China.

INTRODUCTION: The treatment options for moderate to severe psoriasis (msPsO) in China have been greatly increased with the approvals of biologics. However, the unmet needs and treatment preferences of systemic treatments for msPsO in China remain unclarified. METHODS: Fifty dermatologists and 300 patients with msPsO (41% with severe psoriasis) were surveyed for effectiveness, safety, treatment convenience, and treatment preferences (using a choice-based conjoint questionnaire). Descriptive statistics and conjoint simulation analyses were employed to summarize survey information and assess treatment preferences. RESULTS: Both patients and dermatologists reported shorter treatment duration for oral drugs (2.7-6.2 months) than that for biologics (9.5-17.0 months). The most frequently reported treatment discontinuation reasons by the surveyed patients and dermatologists were unsatisfactory effectiveness (average 84.5%) for oral drugs and loss of efficacy over time (average 68.5%) for biologics. Commonly reported treatment inconveniences included regular lab tests for traditional oral drugs (average 71.5%) and administration assistance for biologics (average 58.0%). Injection site reactions (average 51.5%) and needle fear (average 35.5%) were frequently reported for biologics among the surveyed patients and dermatologists. Once-daily oral treatment was preferred over biweekly subcutaneous injection treatment when the two had comparable attributes (average in patients 87.1% vs. 12.9%; average in dermatologists 93.4% vs. 6.6%). CONCLUSIONS: Unmet needs of systemic treatments remain for msPsO in China. Once-daily oral treatment is preferred over biweekly subcutaneous injections to treat msPsO when other treatment attributes are comparable.