Reciprocal regulation of IL-33 receptor-mediated inflammatory response and pulmonary fibrosis by TRAF6 and USP38.

The warning cytokine interleukin-33 receptor (IL-33R) mediates local inflammatory responses and plays crucial roles in the pathogenesis of immune diseases such as pulmonary fibrosis and rheumatoid arthritis. Whether and how IL-33R is regulated remain enigmatic. Here, we identified ubiquitin-specific protease 38 (USP38) as a negative regulator of IL-33R­mediated signaling. USP38 deficiency promotes interleukin-33 (IL-33)­induced downstream proinflammatory responses in vitro and in vivo. Usp38−/− mice are more susceptible to inflammatory damage and death and developed more serious pulmonary fibrosis after bleomycin treatment. USP38 is constitutively associated with IL-33R and deconjugates its K27-linked polyubiquitination at K511, resulting in its autophagic degradation. We further show that the E3 ubiquitin ligase tumor necrosis factor receptor­associated factor 6 (TRAF6) catalyzes K27-linked polyubiquitination of IL-33R at K511, and that deficiency of TRAF6 inhibits IL-33­mediated signaling. Our findings suggest that K27-linked polyubiquitination and deubiquitination of IL-33R by TRAF6 and USP38 reciprocally regulate IL-33R level and signaling, which represents a critical mechanism in the regulation of IL-33­triggered lung inflammatory response and pulmonary fibrosis.

KAT5 acetylates cGAS to promote innate immune response to DNA virus.

The DNA sensor cGMP-AMP synthase (cGAS) senses cytosolic microbial or self DNA to initiate a MITA/STING-dependent innate immune response. cGAS is regulated by various posttranslational modifications at its C-terminal catalytic domain. Whether and how its N-terminal unstructured domain is regulated by posttranslational modifications remain unknown. We identified the acetyltransferase KAT5 as a positive regulator of cGAS-mediated innate immune signaling. Overexpression of KAT5 potentiated viral-DNA-triggered transcription of downstream antiviral genes, whereas a KAT5 deficiency had the opposite effects. Mice with inactivated Kat5 exhibited lower levels of serum cytokines in response to DNA virus infection, higher viral titers in the brains, and more susceptibility to DNA-virus-induced death. Mechanistically, KAT5 catalyzed acetylation of cGAS at multiple lysine residues in its N-terminal domain, which promoted its DNA-binding ability. Our findings suggest that KAT5-mediated cGAS acetylation at its N terminus is important for efficient innate immune response to DNA virus.

The efficacy and safety of dupilumab for the treatment of atopic dermatitis among Chinese patients in clinical practice: A single-center retrospective study.

Little real-work data regarding the efficacy and safety of dupilumab in the treatment of atopic dermatitis (AD) is available at present. To assess the efficacy and safety of dupilumab at 12 weeks in the treatment of AD in clinical routine clinical practice. A retrospective, single-centre study of adult patients with moderate to severe AD treated with dupilumab for 12 weeks in China. In total, 60 patients (48 male, 12 female; mean age: 53.2 ± 15.6) were enrolled in this retrospective study. These patients exhibited a mean AD disease course of 10.6 years (6.0), 30% exhibited a family history of allergies, and 31 (51.7%) had one or more allergic comorbidities. Following dupilumab treatment for 12 weeks, 83.3% and 42% of patients had achieved EASI-50 and EASI-75, respectively. Overall, adverse events (AEs) were reported by 15% of patients, with the most common being conjunctivitis, injection site reactions, and herpes simplex virus infections. Laboratory testing after 12 weeks revealed pronounced decreases in both circulating eosinophil counts (from 0.6 (0.1-2.8) to 0.3 (0.1-9.7) 109 /L) and total IgE concentrations (from 327 (2.46-2500) to 230 (47.6-2200) U/ml) in these patients. These real-world data reaffirm the safety and efficacy of dupilumab as a treatment for moderate-to-severe AD among Chinese patients in clinical practice.

PTPN1/2-mediated dephosphorylation of MITA/STING promotes its 20S proteasomal degradation and attenuates innate antiviral response.

Upon cytosolic viral DNA stimulation, cGMP-AMP synthase (cGAS) catalyzes synthesis of 2'3'cGMP-AMP (cGAMP), which binds to the adaptor protein MITA (mediator of IRF3 activation, also called STING, stimulator of IFN genes) and induces innate antiviral response. How the activity of MITA/STING is regulated to avoid excessive innate immune response is not fully understood. Here we identified the tyrosine-protein phosphatase nonreceptor type (PTPN) 1 and 2 as MITA/STING-associated proteins. PTPN1 and PTPN2 are associated with MITA/STING following viral infection and dephosphorylate MITA/STING at Y245. Dephosphorylation of MITA/STING leads to its degradation via the ubiquitin-independent 20S proteasomal pathway, which is dependent on the intrinsically disordered region (IDR) of MITA/STING. Deficiencies of PTPN1 and PTPN2 enhance viral DNA-induced transcription of downstream antiviral genes and innate antiviral response. Our findings reveal that PTPN1/2-mediated dephosphorylation of MITA/STING and its degradation by the 20S proteasomal pathway is an important regulatory mechanism of innate immune response to DNA virus.

Development of herpes zoster during infliximab treatment for pediatric generalized pustular psoriasis: A case report.

The present authors report a 12-year-old Chinese child with generalized pustular psoriasis who was responded well to infliximab, but an adverse effect of herpes zoster occurred after the first infusion soon. The antiviral treatment was effective and no recurrence or flaring was observed after half-year of follow-up. This case reminds us to highlight the risk of viral infection during biological treatment on patients with psoriasis or autoimmune disease.

Miliaria crystallina secondary to herbal remedies-induced toxic epidermal necrolysis: A case report.

Miliaria crystallina is a skin disorder that often erupts in the process of febrile diseases or under hot and humid climatic conditions. Toxic epidermal necrolysis (TEN) is a rare, acute, and life-threatening mucocutaneous disease with a mortality rate of 25-35%. There has been no inevitable connection between the two diseases among previously reported cases, but we observed a case of secondary miliaria crystallina a woman with herbal remedies-induced TEN during the therapeutic process.

Efficacy assessment of UVA1 and narrowband UVB for treatment of scalp psoriasis.

To compare the efficacy and safety of UVA1 and narrowband UVB (NB-UVB) therapy in the treatment of scalp psoriasis. Patients with scalp psoriasis were randomly assigned to either UVA1 or NB-UVB therapy. Both treatments were performed three times weekly for 6 weeks. Clinical efficacy was evaluated by using Psoriasis Scalp Severity Index (PSSI), and patient-reported quality of life (QoL) was assessed by Dermatology Life Quality Index (DLQI). Totally 68 patients completed the study. Both UVA1 and NB-UVB phototherapy achieved a statistically significant reduction of PSSI and DLQI scores at the end of the treatment period. Compared with the NB-UVB group, the significantly greater improvements occurred in UVA1 treatment group at week 3, although differences declined thereafter through week 10. Both UVA1 and NB-UVB therapy were well-tolerated in this study, and the occurrence of adverse events (AEs) was uncommon. Both UVA1 and NB-UVB phototherapy could offer relief of scalp symptoms in patients with scalp involvement. Furthermore, UVA1 treatment could improve the clinical manifestations and QoL more quickly than NB-UVB therapy.

Ginsenoside Rh2 Suppresses Neovascularization in Xenograft Psoriasis Model.

BACKGROUND/AIMS: Psoriasis is a common inflammatory skin disease of undetermined etiology and poor prognosis. The current therapies have focused on direct inhibition of local inflammation, e.g. through hormone treatments. However, neovascularization plays a critical role in the development of psoriasis but so far no therapies have been developed to suppress psoriasis-associated neovascularization. METHODS: We treated AGR129 mice that had received human PN skin grafts with different doses of Ginsenoside Rh2 (GRh2). The acanthosis and papillomatosis index were evaluated. The percentage of T lymphocytes in the grafts was quantified by flow cytometry. The levels of vascularization in the grafts were quantified based on CD31-positive area. We examined the levels of VEGF-A in the skin treated with GRh2. We treated AGR129 mice that had received human PN skin grafts with different doses of soluble Flt-1 (sFlt1) and then evaluated the effects on the acanthosis and papillomatosis index, T lymphocyte percentage and vessel density. RESULTS: GRh2 dose-dependently decreased the acanthosis and papillomatosis index, T lymphocyte percentage and vessel density in PN skin grafts in mice. GRh2 inhibited VEGF-A levels in the PN skin grafts. Treatment with sFlt1 mimicked the effects of GRh2 on the acanthosis and papillomatosis index, T lymphocyte percentage and vessel density in PN skin grafts in mice. CONCLUSIONS: GRh2 may have an anti-psoriasis effect through neovascularization suppression.

Disease Burden and Coping Strategies of Spouses of Patients with Psoriasis: A Qualitative Study.

Background: Psoriasis is a chronic autoimmune inflammatory skin condition characterized by erythema, papules, and scales. It imposes a heavy psychological and social strain on both patients and their families. Surprisingly, there's limited research delving into the disease burden and coping strategies of spouses contending with psoriasis. Objective: The objective is to explore the disease burden faced and coping strategies utilized by spouses of individuals living with psoriasis. This exploration aims to offer insights crucial for devising mental health support and intervention strategies. Methods: The research methodology employed in this study was phenomenological, a qualitative approach. A total of fifteen spouses of patients with psoriasis were selected using an objective sampling method for in-depth, semi-structured interviews. Thematic analysis was then applied to the recorded interview data to derive meaningful themes. Results: This study has identified and analyzed three core themes concerning the disease burden and coping strategies of spouses of patients with psoriasis: Overwhelming disease burden; Lack of support system; Coping strategies (Problem - centered coping strategies: Proactive acquisition of disease knowledge; Active confrontation of illness - related issues; Behavioral habit alteration; and Emotional - centered coping strategies: Active acceptance and normalization; Passive acceptance and internalized stigma; Avoidance of disease - related problems). Conclusion: This study adds valuable insights into comprehending the disease burden encountered by spouses of patients with psoriasis and sheds light on the coping strategies they employ. Healthcare providers should proactively recognize and address the burden experienced by spouses early on. Establishing a robust support network is crucial, and promoting adaptive coping strategies can significantly aid spouses in effectively navigating and managing the complexities associated with psoriasis.

Effects of simulated microgravity on current generation of electrochemically active bacteria: Insights from case-control study using random positioning machine.

Electrochemically active bacteria (EAB) exhibit promising prospects for space exploration and life support systems. However, the effects of the space environment on EAB are unclear. In this study, the effects of simulated microgravity on the current generation of mixed-culture EAB were illustrated, and the underlying mechanism was elucidated. The results demonstrated that the electrochemical activity of mixed-culture EAB was enhanced, which was mainly due to the enrichment of Geobacter and the increase in EAB biomass. Additionally, the genes and proteins of the biofilm changed obviously under simulated microgravity conditions, including: I) genes related to signal transfer, II) genes related to cell wall synthesis, and III) genes related to riboflavin synthesis. This study first revealed the enrichment in EAB abundance, the increase in EAB biomass, and the promotion of current generation under simulated microgravity.

Stochastic processes drive the soil fungal communities in a developing mid-channel bar.

Intricate associations between rhizosphere microbial communities and plants play a critical role in developing and maintaining of soil ecological functioning. Therefore, understanding the assembly patterns of rhizosphere microbes in different plants and their responses to environmental changes is of great ecological implications for dynamic habitats. In this study, a developing mid-channel bar was employed in the Yangtze River to explore the assembly processes of rhizosphere fungal communities among various plant species using high-throughput sequencing-based null model analysis. The results showed a rare significant variation in the composition and alpha diversity of the rhizosphere fungal community among various plant species. Additionally, the soil properties were found to be the primary drivers instead of plant species types. The null model analysis revealed that the rhizosphere fungal communities were primarily driven by stochastic processes (i.e., undominated processes of ecological drift), and the predominance varied with various plant species. Moreover, the assembly processes of rhizosphere fungal communities were significantly related to the changes in soil properties (i.e., soil total carbon, total nitrogen, organic matter, and pH). The co-occurrence network analysis revealed that many keystone species belonged to unclassified fungi. Notably, five network hubs were almost unaffected by the measured soil properties and aboveground plant traits, indicating the effect of stochastic processes on the rhizosphere fungal community assembly. Overall, these results will provide insights into the underlying mechanisms of fungal community assembly in the rhizosphere soils, which are significant for maintaining the functional stability of a developing ecosystem.

Long-term efficacy and safety of guselkumab in Chinese patients with moderate-to-severe plaque psoriasis.

Background: Randomized controlled trials indicated guselkumab, the first anti-interleukin-23 monoclonal antibody, is efficacious in plaque psoriasis. However, guselkumab's performance in real life is scarcely examined, especially in China. Objectives: This work aimed to assess the long-term effectiveness of guselkumab in actual clinical practice in China. Methods: A retrospective study was performed for plaque psoriasis cases administered guselkumab in Shanghai Skin Disease Hospital between January 2020 and September 2022. Results: A total of 37 patients were included (29 men, 78.4%), with a mean follow-up period of 72.3 ± 26.7 weeks (range of 12-108 weeks). At baseline, clinical examination revealed a mean PASI of 12.3 ± 7.1, a mean BSA of 17.1 ± 18.1, and a mean DLQI of 7.7 ± 4.3. Twenty-two (62.9%) and 17 (48.6%) cases achieved PASI 90 and PASI 100 responses at week 28. From weeks 60 to 92, >80% of cases achieved PASI 90 and PASI 100 responses. Regarding safety, no cases of serious AEs were recorded. A total of nine cases (24.3%) had different abnormal results in HBV markers, and two were T-SPOT positive. There was no hepatitis B virus or tuberculosis outbreak in these patients. Conclusion: This real-life study confirmed the long-term efficacy and safety of guselkumab in daily clinical practice.

Development of bullous pemphigoid during treatment of psoriasis with ustekinumab: a case report and literature review.

Ustekinumab is a biological therapy that has been approved for treating moderate-to-severe psoriasis. Although injection site reactions, nasopharyngitis, headaches, and infections are the common adverse events associated with ustekinumab, the development of bullous pemphigoid (BP) is also thought to be related to ustekinumab. Given that psoriasis itself can be complicated by BP, it is worthwhile to investigate the relationship between ustekinumab, psoriasis, and BP. Here we report a case of a male patient who developed BP twice after psoriasis treatment with ustekinumab. The patient's psoriasis and BP were brought under control by discontinuing ustekinumab and administering methotrexate, minocycline, and topical corticosteroids. Because of the increasing use of biologics in patients with psoriasis, BP should be considered a potential adverse event associated with ustekinumab.

Signaling and functions of interleukin-33 in immune regulation and diseases.

Interleukin-33 (IL-33) which belongs to the interleukin-1 (IL-1) family is an alarmin cytokine with critical roles in tissue homeostasis, pathogenic infection, inflammation, allergy and type 2 immunity. IL-33 transmits signals through its receptor IL-33R (also called ST2) which is expressed on the surface of T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s), thus inducing transcription of Th2-associated cytokine genes and host defense against pathogens. Moreover, the IL-33/IL-33R axis is also involved in development of multiple types of immune-related diseases. In this review, we focus on current progress on IL-33-trigggered signaling events, the important functions of IL-33/IL-33R axis in health and diseases as well as the promising therapeutic implications of these findings.

Shift from soil chemical to physical filters in assembling riparian floristic communities along a flooding stress gradient.

Understanding community assembly is a key issue in recognizing community succession and guiding the restoration of degraded ecosystems. Based on the stress-dominance hypothesis (SDH), along a gradient of increasing environmental stress, the relative importance of environmental filtering is supposed to be dominant but species interaction could be a minor process in assembling communities. However, this hypothesized model of the assembly-rule shift was equivocally supported by various studies. In this study, by examining riparian plant communities with the zonation distribution of species composition along a markedly contrast flooding-stress gradient, a general aim was to clarify whether assembly rules of the communities would be also sorted into the zonation pattern as expected by the SDH. Another aim was to identify how edaphic factors associate with the assembly processes. Firstly, we found that even under the distinct stress gradient, community assembly was not stratified into different rules as the SDH expected, but environmental filtering appeared as a dominant assembly process across the stress gradient. Secondly, although filtering holds as a dominant assembly rule, environmental filters were found different along the gradient. By disentangling the filters of edaphic attributes, we found that the filters significantly shifted from soil physical properties to chemical nutrients governing the filtering process along the gradient. This result revealed that, across the contrast gradient, the environmental deterministic process on assembly is so strong that the other assembly processes became weaker. By synthesizing our results, the SDH may not be applied even under the context of a contrast stress gradient, which suggests that environmental context may be a key in testing and applying the SDH. Finally, in guiding riparian restoration under strong stress, we suggest that soil physical structure rather than chemical nutrients shall be given a priority for consideration in rebuilding the degraded riparian communities.

Ixekizumab four-week dosing is comparable to two-week dosing in psoriasis patients and reduces treatment costs: experience in a real-world setting over a 12-week period

Background: Little is known about different Ixekizumab (IXE) dosing regimens during routine clinical practice. Objectives: To evaluate the real-world effectiveness and safety of different IXE dosing regimens in patients with psoriasis. Materials & Methods: This study retrospectively compared patients who were dosed with IXE every two or four weeks (80 mg/week following a starting dose of 160 mg at Week 0). At Weeks 0, 4, and 12, the Psoriasis Area and Severity Index (PASI) and the Dermatology Life Quality Index (DLQI) were recorded, with adverse events also documented. Results: In total, 66 patients were analysed, of whom 30 (45.5%) and 36 (54.5%) were included in the two-week and four-week IXE dosing groups, respectively. In the overall patient cohort, 86.3%, 60.6%, and 31.8% exhibited PASI 75, PASI, 90, and PASI 100 responses at Week 12, respectively. The mean baseline PASI score was 12.4±7.6 and the mean baseline DLQI score was 11.3±6.9, with these values declining rapidly following IXE administration to 1.6±2.4, and 2.6±4.0 at Week 12, respectively. Response rates were elevated in the two-week group as compared to the four-week group at Weeks 4 and 12 of treatment, but these differences were not significant. Adverse events were reported in 25 patients (37.9%), with injection site reactions being most common, followed by infections. Conclusion: IXE is effective and safe in a real-world setting for the treatment of plaque psoriasis. Moreover, patients can reduce their medical expenses by choosing a four-week dosing regimen while still attaining therapeutic benefits.

[Relationship between alien plant invasion and landscape matrix in the water-level fluctuating zone of the Three Gorges Reservoir, China.] / ä¸‰å³¡åº“åŒºæ¶ˆè½å¸¦å¤–æ¥æ¤ç‰©å ¥ä¾µä¸Žæ™¯è§‚åŸºè´¨ç»„æˆç»“æž„çš„å ³è”æ€§.

Invasive process of alien species is affected by not only the invaded habitats, but also the surrounding landscape matrix. Understanding the effects of landscape matrix on alien species is of great significance for controlling invasive alien species. We surveyed plant communities along the water-level fluctuating zone (WLFZ) of the Three Gorges Reservoir. Invasive status of alien plant species was evaluated. Totally 10 spatial scales of the surrounding landscape matrix in the scope of 2000 m (including WLFZ) were classified, and 14 landscape indices were applied to analyze the landscape matrix composition and configuration. Using the principal component analysis and correlation analysis, the effects of landscape matrix on the alien invasive plant species and associated scale effect were tested. Results showed that a total of 42 alien invasive plant species were found in the WLFZ, belonging to 17 families and 36 genera. Fuling was a dividing place to differentiate invasive species distribution. The number of the alien invasive species between Fuling and the Three Gorges Dam was found more than that between Fuling and Jiangjin. For the all scales (within 2000 m). The higher the landscape matrix fragmentation was, the more difficult the alien species invading. The higher landscape connectivity was, the easier the alien species invading. The effects of landscape matrix composition and configuration on the invasive plant diversity at large scales (1200-2000 m) was more significant than those at small scales (200-1000 m), in which landscape matrix composition and configuration at 1200-1400 m showed the strongest effect, demonstrating a significant spatial scale effect. Different invasive plant species showed the scale effects of landscape matrix composition and configuration. At all scales, Xanthium strumarium and Bidens frondosa showed weak correlations with landscape indices, but Bidens tripartita and Erigeron canadensis showed strong correlations. Landscape matrix was closely related to invasive plant species, and demonstrated a significant scale effect. The alien invasive plant species could be traced to the landscape matrix at large scales. Grassland and forest patches at the small scales could be used as the 'stepping stone' for the alien species transiting before they arrived at the WLFZ. In order to control alien plants in the WLFZ, land-use management and optimization should be strengthened at different scales of landscape matrix on the basis of enhancement of habitat management. A diversified comprehensive control for alien species should thus be taken into account.