“Hot” executive functions are comparable across monolingual and bilingual elementary school children: Results from a study with the Iowa Gambling Task

Past research found performance differences between monolingual and bilingual children in the domain of executive functions (EF). Furthermore, recent studies have reported advantages in processing efficiency or mental effort in bilingual adults and children. These studies mostly focused on the investigation of “cold” EF tasks. Studies including measures of “hot” EF, i.e., tasks operating in an emotionally significant setting, are limited and hence results are inconclusive. In the present study, we extend previous research by investigating performance in a task of the “hot” EF domain by both behavioral data and mental effort via pupillary changes during task performance. Seventy-three monolingual and bilingual school children (mean age = 107.23 months, SD = 10.26) solved the Iowa Gambling Task in two different conditions. In the standard task, characterized by constant gains and occasional losses, children did not learn to improve their decision-making behavior. In a reversed task version, characterized by constant losses and occasional gains, both monolinguals and bilinguals learned to improve their decision-making behavior over the course of the task. In both versions of the task, children switched choices more often after losses than after gains. Bilinguals switched their choices less often than monolinguals in the reversed task, indicating a slightly more mature decision-making strategy. Mental effort did not differ between monolinguals and bilinguals. Conclusions of these findings for the bilingual advantage assumption will be discussed

Reactive oxygen species produced by myeloid cells in psoriasis as a potential biofactor contributing to the development of vascular inflammation.

Psoriasis is an immune-mediated inflammatory skin disease driven by interleukin-17A (IL-17A) and associated with cardiovascular dysfunction. We used a severe psoriasis mouse model of keratinocyte IL-17A overexpression (K14-IL-17Aind/+ , IL-17Aind/+ control mice) to investigate the activity of neutrophils and a potential cellular interconnection between skin and vasculature. Levels of dermal reactive oxygen species (ROS) and their release by neutrophils were measured by lucigenin-/luminol-based assays, respectively. Quantitative RT-PCR determined neutrophilic activity and inflammation-related markers in skin and aorta. To track skin-derived immune cells, we used PhAM-K14-IL-17Aind/+ mice allowing us to mark all cells in the skin by photoconversion of a fluorescent protein to analyze their migration into spleen, aorta, and lymph nodes by flow cytometry. Compared to controls, K14-IL-17Aind/+ mice exhibited elevated ROS levels in the skin and a higher neutrophilic oxidative burst accompanied by the upregulation of several activation markers. In line with these results psoriatic mice displayed elevated expression of genes involved in neutrophil migration (e.g., Cxcl2 and S100a9) in skin and aorta. However, no direct immune cell migration from the psoriatic skin into the aortic vessel wall was observed. Neutrophils of psoriatic mice showed an activated phenotype, but no direct cellular migration from the skin to the vasculature was observed. This suggests that highly active vasculature-invading neutrophils must originate directly from the bone marrow. Hence, the skin-vasculature crosstalk in psoriasis is most likely based on the systemic effects of the autoimmune skin disease, emphasizing the importance of a systemic therapeutic approach for psoriasis patients

An Alternative Pathway of Imiquimod-Induced Psoriasis-Like Skin Inflammation in the Absence of Interleukin-17 Receptor A Signaling

Topical application of imiquimod (IMQ) on the skin of mice induces inflammation with common features found in psoriatic skin. Recently, it was postulated that IL-17 has an important role both in psoriasis and in the IMQ model. To further investigate the impact of IL-17RA signaling in psoriasis, we generated IL-17 receptor A (IL-17RA)–deficient mice (IL-17RAdel) and challenged these mice with IMQ. Interestingly, the disease was only partially reduced and delayed but not abolished when compared with controls. In the absence of IL-17RA, we found persisting signs of inflammation such as neutrophil and macrophage infiltration within the skin. Surprisingly, already in the naive state, the skin of IL-17RAdel mice contained significantly elevated numbers of Th17- and IL-17-producing γδ T cells, assuming that IL-17RA signaling regulates the population size of Th17 and γδ T cells. Upon IMQ treatment of IL-17RAdel mice, these cells secreted elevated amounts of tumor necrosis factor-α, IL-6, and IL-22, accompanied by increased levels of the chemokine CXCL2, suggesting an alternative pathway of neutrophil and macrophage skin infiltration. Hence, our findings have major implications in the potential long-term treatment of psoriasis by IL-17-targeting drugs

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors

Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. Methods: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. Findings: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. Conclusions: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. Funding: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.

BACKGROUND Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. METHODS In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. FINDINGS When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. CONCLUSIONS We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. FUNDING This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen

Decoding the substrate supply to human neuronal nitric oxide synthase

Nitric oxide, produced by the neuronal nitric oxide synthase (nNOS) from L-arginine is an important second messenger molecule in the central nervous system: It influences the synthesis and release of neurotransmitters and plays an important role in long-term potentiation, long-term depression and neuroendocrine secretion. However, under certain pathological conditions such as Alzheimer's or Parkinson's disease, stroke and multiple sclerosis, excessive NO production can lead to tissue damage. It is thus desirable to control NO production in these situations. So far, little is known about the substrate supply to human nNOS as a determinant of its activity. Measuring bioactive NO via cGMP formation in reporter cells, we demonstrate here that nNOS in both, human A673 neuroepithelioma and TGW-nu-I neuroblastoma cells can be fast and efficiently nourished by extracellular arginine that enters the cells via membrane transporters (pool I that is freely exchangeable with the extracellular space). When this pool was depleted, NO synthesis was partially sustained by intracellular arginine sources not freely exchangeable with the extracellular space (pool II). Protein breakdown made up by far the largest part of pool II in both cell types. In contrast, citrulline to arginine conversion maintained NO synthesis only in TGW-nu-I neuroblastoma, but not A673 neuroepithelioma cells. Histidine mimicked the effect of protease inhibitors causing an almost complete nNOS inhibition in cells incubated additionally in lysine that depletes the exchangeable arginine pool. Our results identify new ways to modulate nNOS activity by modifying its substrate supply

“Hot” executive functions are comparable across monolingual and bilingual elementary school children: Results from a study with the Iowa Gambling Task

Past research found performance differences between monolingual and bilingual children in the domain of executive functions (EF). Furthermore, recent studies have reported advantages in processing efficiency or mental effort in bilingual adults and children. These studies mostly focused on the investigation of “cold” EF tasks. Studies including measures of “hot” EF, i.e., tasks operating in an emotionally significant setting, are limited and hence results are inconclusive. In the present study, we extend previous research by investigating performance in a task of the “hot” EF domain by both behavioral data and mental effort via pupillary changes during task performance. Seventy-three monolingual and bilingual school children (mean age = 107.23 months, SD = 10.26) solved the Iowa Gambling Task in two different conditions. In the standard task, characterized by constant gains and occasional losses, children did not learn to improve their decision-making behavior. In a reversed task version, characterized by constant losses and occasional gains, both monolinguals and bilinguals learned to improve their decision-making behavior over the course of the task. In both versions of the task, children switched choices more often after losses than after gains. Bilinguals switched their choices less often than monolinguals in the reversed task, indicating a slightly more mature decision-making strategy. Mental effort did not differ between monolinguals and bilinguals. Conclusions of these findings for the bilingual advantage assumption will be discussed

“Hot” executive functions are comparable across monolingual and bilingual elementary school children: Results from a study with the Iowa Gambling Task

Past research found performance differences between monolingual and bilingual children in the domain of executive functions (EF). Furthermore, recent studies have reported advantages in processing efficiency or mental effort in bilingual adults and children. These studies mostly focused on the investigation of “cold” EF tasks. Studies including measures of “hot” EF, i.e., tasks operating in an emotionally significant setting, are limited and hence results are inconclusive. In the present study, we extend previous research by investigating performance in a task of the “hot” EF domain by both behavioral data and mental effort via pupillary changes during task performance. Seventy-three monolingual and bilingual school children (mean age = 107.23 months, SD = 10.26) solved the Iowa Gambling Task in two different conditions. In the standard task, characterized by constant gains and occasional losses, children did not learn to improve their decision-making behavior. In a reversed task version, characterized by constant losses and occasional gains, both monolinguals and bilinguals learned to improve their decision-making behavior over the course of the task. In both versions of the task, children switched choices more often after losses than after gains. Bilinguals switched their choices less often than monolinguals in the reversed task, indicating a slightly more mature decision-making strategy. Mental effort did not differ between monolinguals and bilinguals. Conclusions of these findings for the bilingual advantage assumption will be discussed

Case-Fatality and Temporal Trends in Patients with Psoriasis and End-Stage Renal Disease

Background and Objectives: During the last decades, growing evidence corroborates that chronic inflammatory disease impairs the body beyond the cutaneous barrier. Linkage between psoriasis and kidney disease, and in particular between psoriasis and end-stage renal disease (ESRD), have not yet been elucidated. We sought to analyze the impact of concomitant psoriasis on the in-hospital outcomes of patients hospitalized with ESRD. Patients and Methods: We analyzed data on characteristics, comorbidities, and in-hospital outcomes of all hospitalized patients with ESRD stratified for concomitant psoriasis in the German nationwide in-patient sample between 2010 and 2020. Results: Overall, 360,980 hospitalizations of patients treated for ESRD in German hospitals were identified from 2010 to 2020 and among these 1063 patients (0.3%) additionally suffered from psoriasis. While the annual number of all ESRD patients increased within this time, the number of patients with ESRD and the additional psoriasis diagnosis decreased slightly. Patients with ESRD and psoriasis were five years younger (66 [IQR, 56–75] vs. 71 [59–79] years, p < 0.001), were more often obese (17.5% vs. 8.2%, p < 0.001) and more frequently had cancer (4.9% vs. 3.3%, p < 0.001), diabetes mellitus (42.7% vs. 38.5%, p = 0.005) and coronary artery disease (31.1% vs. 28.0%, p = 0.026). Multivariate regression models demonstrated that psoriasis was not associated with in-hospital case-fatality in patients with ESRD (OR 1.02 (95%CI 0.78–1.33), p = 0.915). Conclusions: ESRD patients with the concomitant psoriasis diagnosis were hospitalized on average 5 years earlier than patients without psoriasis. A higher prevalence of severe life-shortening comorbidities including coronary artery disease and cancer was detected in ESRD patients with psoriasis despite their younger age. Our findings support the understanding of psoriasis as an autoimmune skin disease crossing the boundary between dermatology and internal medicine