Clinical trials have shown promising results for interleukin-23 inhibitors in the treatment of psoriasis. The drugs have been used in clinical practice since 2017.
To investigate the drug survival ...and effectiveness of interleukin-23 inhibitors in the treatment of psoriasis and psoriatic arthritis (PsA) in a real-world setting.
The study was a retrospective analysis of patients treated with either guselkumab, tildrakizumab, or risankizumab at the Department of Dermatology, Aarhus University Hospital, during the period from June 11 2018, to July 14 2021.
A total of 80 patients were included. During the study, 19 patients discontinued treatment with an interleukin-23 inhibitor, and mean treatment duration (SD) was 61.4 weeks (43.7). Seventy-six patients (95%) had previous use of ≥1 biologic. One-year drug survival was 81.0%. Among patients, 64.3% achieved a Psoriasis Area and Severity Index (PASI) ≤ 2 at weeks 12-17; 61.3%, at weeks 40-60. There was no statistically significant difference between the drugs regarding the chance of achieving PASI ≤ 2 (p>.05). Twenty-two patients (27.5%) had PsA. Among these, 40.9% and 36.4% achieved complete remission and partial remission, respectively.
Interleukin-23 inhibitors appear to have high and similar drug survival and effectiveness in patients with difficult-to-treat psoriasis and PsA.
Employees of the Norwegian Church Abroad (NCA) avoid discussing politics. Understanding why increases sociological understanding of how everyday and nonextreme forms of religion may contribute to ...everyday and nonextreme forms of national feeling. This article leverages insights from studying the NCA in order to contribute to the sociological literature on everyday nationalism and religion. It does this by illustrating how the microsociological strategies of silence and avoidance contribute to imagined sameness. This increases our understanding of how everyday belonging draws resources from both nation and religion. Furthermore, it highlights the interactions between religion and nation as both resources for belonging and grounds for difference. The findings are based on interviews with 32 employees in six churches in the United States, and supporting observations.
The latitudinal gradient in species richness of the European freshwater fauna is usually depicted as a contrasting pattern between lentic (standing waters) and lotic (running waters) habitats. ...Species richness decreases from south to north in lotic habitats, while lentic habitats show an intermediate richness peak in central Europe (Hof et al. 2008). In this Brevia we question the strict dichotomic split in latitudinal richness patterns between lentic and lotic habitats in Europe. We do this by demonstrating that the differences in richness patterns between headwater streams and rivers are as great as the differences between lentic and lotic habitats. We also show that species richness can be explained solely by the hypervolume defined by the variety of lotic habitats preferences in a region.
Aim
The functional trait composition of plant communities is thought to be determined largely by climate, but relationships between contemporary trait distributions and climate are often weak. ...Spatial mismatches between trait and climatic conditions are commonly thought to arise from disequilibrium responses to past environmental changes. We aimed to investigate whether current trait–climate disequilibrium is likely to emerge during plant functional responses to Holocene climate warming.
Location
North America.
Time period
14–0 ka.
Major taxa studied
Terrestrial plants.
Methods
We joined global trait data with palaeoecological time series and climate simulations on 425 sites. We estimated plant community functional composition for three leaf traits involved in resource use. We then quantified disequilibrium in plant trait temporal responses to climate change during two contrasted periods: a period of high climate variability (14–7 ka) and a period of low climate variability (7–0 ka).
Results
Functional trait composition showed consistent deviation from climatic equilibrium during both periods. The temporal dynamics of trait composition tends to be positively correlated with climate equilibrium expectations during Holocene climate warming (14–7 ka), but not during a subsequent period of low climate variability (7–0 ka).
Main conclusions
Long‐term functional responses of plants to climate change showed mixed evidence for both equilibrium and disequilibrium responses. Temporal trait dynamics were closer to the expectations of spatial dynamics under high climate variability, indicating that the relevance of space‐for‐time substitution might be dependent, in part, on climate variability. Our results also suggest that current mismatches between trait and climatic conditions might arise because of a divergence of factors influencing trait dynamics during periods of low climate variability. These findings provide a counterpoint to the common assumption that contemporary trait–climate mismatches result from lagged responses to past climate warming. Our study also demonstrates the need for a deeper investigation of the potential influence of non‐climatic factors on functional plant community dynamics.
Heat shock protein 90 (HSP90) is an important chaperone supporting the function of many proinflammatory client proteins. Recent studies indicate HSP90 inhibition may be a novel mechanism of action ...for inflammatory skin diseases; however, this has not been explored in atopic dermatitis (AD).
Our study aimed to investigate HSP90 as a novel target to treat AD.
Experimental models of AD were used including primary human keratinocytes stimulated with cytokines (TNF/IFNγ or TNF/IL-4) and a mouse model established by MC903 applications.
In primary human keratinocytes using RT-qPCR, the HSP90 inhibitor RGRN-305 strongly suppressed the gene expression of Th1- (
,
,
) and Th2-associated (
,
cytokines and chemokines related to AD. We next demonstrated that topical and oral RGRN-305 robustly suppressed MC903-induced AD-like inflammation in mice by reducing clinical signs of dermatitis (oedema and erythema) and immune cell infiltration into the skin (T cells, neutrophils, mast cells). Interestingly, topical RGRN-305 exhibited similar or slightly inferior efficacy but less weight loss compared with topical dexamethasone. Furthermore, RNA sequencing of skin biopsies revealed that RGRN-305 attenuated MC903-induced transcriptome alterations, suppressing genes implicated in inflammation including AD-associated cytokines (
), which was confirmed by RT-qPCR. Lastly, we discovered using Western blot that RGRN-305 disrupted JAK-STAT signaling by suppressing the activity of STAT3 and STAT6 in primary human keratinocytes, which was consistent with enrichment analyses from the mouse model.
HSP90 inhibition by RGRN-305 robustly suppressed inflammation in experimental models mimicking AD, proving that HSP90 inhibition may be a novel mechanism of action in treating AD.
Variation in the ability to fly or not is a key mechanism for differences in local species occurrences. It is increasingly acknowledged that physiological or behavioral mechanisms rather than ...morphological differences may drive flight abilities. However, our knowledge on the seasonal variability and stressors creating nonmorphological differences in flight abilities and how it scales to local and regional occurrences is very limited particularly for small, short‐lived species such as insects. Here, we examine how flight ability might vary across seasons and between two closely related genera of freshwater beetles with similar geographical ranges, life histories, and dispersal‐related morphology. By combining flight experiments of >1,100 specimens with colonization rates in a metacommunity of 54 ponds in northern and eastern Europe, we have analyzed the relationship between flight ability and spatio‐environmental distribution of the study genera. We find profound differences in flight ability between the two study genera across seasons. High flight ability for Acilius (97% of the tested individuals flew during the experiments) and low for Graphoderus (14%) corresponded to the different colonization rates of newly created ponds. Within a 5‐year period, 81 and 31% of the study ponds were colonized by Acilius and Graphoderus, respectively. While Acilius dispersed throughout the season, flight activity in Graphoderus was restricted to stressed situations immediately after the emergence of adults. Regional colonization ability of Acilius was independent of spatial connectivity and mass effect from propagule sources. In contrast, Graphoderus species were closely related to high connectivity between ponds in the landscape. Our data suggest that different dispersal potential can account for different local occurrences of Acilius and Graphoderus. In general, our findings provide some of the first insights into the understanding of seasonal restrictions in flight patterns of aquatic beetles and their consequences for species distributions.
This study examines how flight ability might vary across seasons and between two closely related genera of freshwater beetles. We find profound differences in flight ability between the two study genera across seasons, and the data suggest that different dispersal potential can account for different local occurrences between the study genera. Our findings provide some of the first insights into the understanding of seasonal restrictions in flight patterns of aquatic beetles and their consequences for species distributions.
The lipid-anchored small GTPase Ras is an important signaling node in mammalian cells. A number of observations suggest that Ras is laterally organized within the cell membrane, and this may play a ...regulatory role in its activation. Lipid anchors composed of palmitoyl and farnesyl moieties in H-, N-, and K-Ras are widely suspected to be responsible for guiding protein organization in membranes. Here, we report that H-Ras forms a dimer on membrane surfaces through a protein—protein binding interface. A Y64A point mutation in the switch II region, known to prevent Son of sevenless and PI3K effector interactions, abolishes dimer formation. This suggests that the switch II region, near the nucleotide binding cleft, is either part of, or allosterically coupled to, the dimer interface. By tethering H-Ras to bilayers via a membrane-miscible lipid tail, we show that dimer formation is mediated by protein interactions and does not require lipid anchor clustering. We quantitatively characterize H-Ras dimerization in supported membranes using a combination of fluorescence correlation spectroscopy, photon counting histogram analysis, time-resolved fluorescence anisotropy, single-molecule tracking, and step photobleaching analysis. The 2D dimerization Kd is measured to be ∼1 × 103 molecules/μm2, and no higher-order oligomers were observed. Dimerization only occurs on the membrane surface; H-Ras is strictly monomeric at comparable densities in solution. Analysis of a number of H-Ras constructs, including key changes to the lipidation pattern of the hypervariable region, suggest that dimerization is a general property of native H-Ras on membrane surfaces.
Psoriasis is a common chronic inflammatory skin disease accompanied by heterogenous clinical and histological features, including a characteristic keratinocyte hyperproliferation and dermal ...immunogenic profile. In addition, psoriasis is associated with widespread transcriptomic alterations including changes in microRNA (miRNA) and circular RNA (circRNA) abundance, which constitute non-coding RNA (ncRNA) classes with specific regulatory capacities in diverse physiological and pathological processes. However, the knowledge about the expression dynamics of ncRNA during psoriasis treatment is sparse. To elucidate the dynamics of miRNA and circRNA abundance during secukinumab (anti-IL-17A) treatment, we studied their expression patterns in skin biopsies from 14 patients with severe plaque-type psoriasis before and during an 84-day secukinumab therapy at day 0, 4, 14, 42, and 84 using NanoString nCounter technology. We found a comprehensive downregulation of the majority of investigated circRNAs and specific alterations in the miRNA profile, including an upregulation of miR-203a-3p, miR-93-5p, and miR-378i in lesional compared to non-lesional skin before treatment. During treatment, the circRNAs progressively returned to the expression levels observed in non-lesional skin and already four days after treatment initiation most circRNAs were significantly upregulated. In comparison, for miRNAs, the normalization to baseline during treatment was delayed and limited to a subset of miRNAs. Moreover, we observed a strong correlation between multiple circRNAs, including ciRS-7 and circPTPRA, and the psoriasis area and severity index (PASI). Similar pronounced correlations could, however, not be found for miRNAs. Finally, we did not observe any significant changes in circRNA expression in peripheral blood mononuclear cells during treatment. In conclusion, we uncovered a rapid shift in global circRNA abundance upon anti-IL-17A treatment, which predated clinical and histological improvements, and a strong correlation with PASI, indicating a biomarker potential of individual circRNAs.
Chronic inflammatory skin diseases may have a profound negative impact on the quality of life. Current treatment options may be inadequate, offering an unsatisfactory response or side effects. ...Therefore, ongoing efforts exist to identify novel effective and safe treatments. Heat shock protein (HSP) 90 is a chaperone that promotes the activity of a wide range of client proteins including key proinflammatory molecules involved in aberrant inflammation. Recently, a proof-of-concept clinical trial of 13 patients suggested that RGRN-305 (an HSP90 inhibitor) may be an oral treatment for psoriasis. However, HSP90 inhibition may be a novel therapeutic approach extending beyond psoriasis to include multiple immune-mediated inflammatory skin diseases.
This study aimed to investigate (
) the anti-inflammatory effects and mechanisms of HSP90 inhibition and (
) the feasibility of topical RGRN-305 administration (new route of administration) in models of inflammation elicited by 12-O-tetradecanoylphorbol-13-acetate (TPA) in primary human keratinocytes and mice (irritative dermatitis murine model).
In primary human keratinocytes stimulated with TPA, a Nanostring® nCounter gene expression assay demonstrated that HSP90 inhibition with RGRN-305 suppressed many proinflammatory genes. Furthermore, when measured by quantitative real-time polymerase chain reaction (RT-qPCR), RGRN-305 significantly reduced the gene expression of
and
. We next demonstrated that topical RGRN-305 application significantly ameliorated TPA-induced skin inflammation in mice. The increase in ear thickness (a marker of inflammation) was significantly reduced (up to 89% inhibition). In accordance, RT-qPCR of the ear tissue demonstrated that RGRN-305 robustly reduced the gene expression of proinflammatory markers (
and
). Moreover, RNA sequencing revealed that RGRN-305 mitigated TPA-induced alterations in gene expression and suppressed genes implicated in inflammation. Lastly, we discovered that the anti-inflammatory effects were mediated, at least partly, by suppressing the activity of NF-κB, ERK1/2, p38 MAPK and c-Jun signaling pathways, which are consistent with previous findings in other experimental models beyond skin inflammation. In summary, HSP90 inhibition robustly suppressed TPA-induced inflammation by targeting key proinflammatory cytokines and signaling pathways. Our findings suggest that HSP90 inhibition may be a novel mechanism of action for treating immune-mediated skin disease beyond psoriasis, and it may be a topical treatment option.
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