The Perceived Impact of COVID-19 on Student Well-Being and the Mediating Role of the University Support: Evidence From France, Germany, Russia, and the UK

The rapid and unplanned change to teaching and learning in the online format brought by COVID-19 has likely impacted many, if not all, aspects of university students' lives worldwide. To contribute to the investigation of this change, this study focuses on the impact of the pandemic on student well-being, which has been found to be as important to student lifelong success as their academic achievement. Student well-being has been linked to their engagement and performance in curricular, co-curricular, and extracurricular activities, intrinsic motivation, satisfaction, meaning making, and mental health. The purpose of this study was to examine how student perceptions of their degree completion and future job prospects during the pandemic impact their well-being and what role university support plays in this relationship. We used the conservation of resources theory to frame our study and to develop five hypotheses that were later tested via structural equation modeling. Data were collected from 2,707 university students in France, Germany, Russia, and UK via an online survey. The results showed that university support provided by instructors and administration plays a mediating role in the relationship between the perceived impact of COVID-19 on degree completion and future job prospects and levels of student well-being. Student well-being is decreased by their concerns for their degree completion but not by their concerns for future job prospects. In turn, concerns for future job prospects affect student well-being over time. These results suggest that in a “new normal,” universities could increase student well-being by making support to student studies a priority, especially for undergraduates. Also, universities should be aware of the students' changing emotional responses to crisis and ensure visibility and accessibility of student support.Peer reviewe

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

Misregulation of the tumour suppressor gene CYLD drives hyperactivation of T cells leading to intestinal pathology

The tumour suppressor gene cyld is mutated in familial cylindromatosis, an autosomal-dominant condition that predisposes to multiple skin tumours. The deubiquitinase CYLD acts as a negative regulator of NF-κB signaling. To analyse the function of CYLD in vivo we used the CYLDex7/8 mice, which are characterized by loss of the full-length transcript and overexpression of a short splice variant of CYLD (sCYLD). In CYLDex7/8 mice the overexpression of sCYLD results in splenomegaly and lymphadenopathy. Additionally, the B cell population in spleen and lymph nodes is increased at the expense of T cells. Analysis of CYLDex7/8 T cells showed a significant reduction of CD4 single positive (SP) and CD8 SP T cells in the thymus and in the periphery. By investigating the impact of sCYLD in TCR signaling in thymocytes, we could demonstrate that sCYLD partially inhibited the activation of Zap70 and thereby negatively regulated TCR signaling. In vitro as well as in vivo we could show that CD4+ T cells displayed a hyperactive phenotype, proliferated to a better extent than WT cells and expressed high amounts of inflammatory cytokines such as IL-6 and IL-17A. Western Blots of steady state thymocytes and peripheral CD4+ T cells were performed, showing that the noncanonical pathway was highly upregulated visualized by the expression levels of RelB and p100 leading to a hyperactive phenotype of CD4+ T cells. In order to investigate the contribution of sCYLD in positive and negative selection in the thymus in vivo, the HY-TCR transgene (HYtg) was crossed to CYLDex7/8 mice. The analysis of CYLDex7/8 HYtg males revealed an increase in CD4+CD8+ DP as well as in CD8+ SP thymocytes, suggesting a less pronounced negative selection in CYLD mutant mice compared to HYtg control mice. Interestingly, the impaired negative selection in the thymus was accompanied by a strong colitis phenotype at early ages (4 weeks). Since medullary TECs (mTECs) play an important role in the late stage of T cell development by negatively selecting autoreactive thymocytes, the levels of mTECs in the medullary compartment was investigated. Of note, low numbers of mTECs were observed, combined with decreased expression levels of the mTEC markers UEA-1, keratin-5, claudin-3 and claudin-4. The reduction of mTECs in the medullary compartment could explain the inflammatory phenotype of CD4+ T cells in CYLDex7/8 mice leading to the severe intestinal pathology observed in these mice. Taken together, these results show an important role of sCYLD in T cell development and function as well as in NF-кB signaling of T cells.Das Tumorsuppressor Gen cyld ist mutiert in Patienten mit familiärer Zylindromatose, was zu einer autosomal-dominant vererbten Prädisposition für multiple Tumore der Haut führt. Die Deubiquitinase CYLD ist ein negativer Regulator des NF-κB Signalweges und hemmt die Aktivierung des Transkriptionsfaktors NF-κB, welcher an Entzündungsreaktion, Immunantwort, Apoptose und Onkogenese beteiligt ist. Um die in vivo Funktion von CYLD zu untersuchen, wurde der Mausstamm CYLDex7/8 analysiert, welcher ausschließlich eine natürlich vorkommende Spleißvariante des cyld Gens (sCYLD) überexprimiert. Als Kontrollen dienten CYLDko und WT Mäuse. In CYLDex7/8 Mäusen führte die Überexpression von sCYLD zu vergößerten sekundären lymphatischen Organen wie der Milz und den peripheren Lymphknoten. Dieser Phänotyp resultierte aus einer drastischen Ansammlung von B Zellen, wohingegen die Anzahl von T Zellen stark reduziert war. Des Weiteren konnte gezeigt werden, dass die Gesamtzellzahl von CD4 SP und CD8 SP T Zellen sowohl im Thymus als auch in der Milz signifikant verringert war. Um die Rolle von sCYLD im TCR Signalweg der Thymozyten zu charakterisieren wurde mittels Western Blot der Signalweg untersucht. Inter-essanterweise konnte gezeigt werden, dass sCYLD die Aktivierung und Phosphorylierung der Proteinkinase Zap70 herunterreguliert, und somit den TCR Signalweg in Thymozyten negativ reguliert. Des Weiteren konnte sowohl in vitro als auch in vivo demonstriert werden, dass sCYLD überexprimierende CD4+ T Zellen einen hyperaktiven Phänotyp besitzen, eine erhöhte Proliferationskapazität aufweisen und vermehrt inflammatorische Zytokine wie IL-6 und IL-17A produzieren. Da bekannt ist, dass CYLD ein Inhibitor des NF-κB Signalweges ist, wurde mit Hilfe von RT PCR und Western Blot die Rolle von sCYLD in diesem Signalweg untersucht. In CYLDex7/8 Thymozyten und peripheren CD4+ T Zellen konnte eine erhöhte Aktivität des alternativen NF-κB Signalweges nachgewiesen werden, wohingegen der klassische NF-κB Signalweg keine Veränderung im Vergleich zu den Kontrollen aufwies. Um den Einfluss von sCLYD auf die positive und negative Selektion in vivo im Thymus zu untersuchen, wurden CYLDex7/8 Mäuse mit HY TCR transgenen Mäusen verpaart. Die Analyse der HYtg CYLDex7/8 Männchen zeigte eine erhöhte Anzahl an CD4+CD8+ DP und CD8+ SP Thymozyten, was auf einen Defekt in der negativen Selektion von Thymozyten hinweist. Interessanterweise entwickelten HYtg CYLDex7/8 Männchen im Alter von 4 Wochen zusätzlich eine spontane Inflammation des Darmes.rnEpithelzellen der thymischen Medulla (mTECs) spielen eine essentielle Rolle in der Entwicklung zentraler Toleranz, indem sie für die Eliminierung autoreaktiver T Zellen während der späten T Zell Entwicklung im Thymus verantwortlich sind. Untersuchungen der mTECs in CYLDex7/8 Mäusen zeigten eine starke Reduktion dieser Zellpopulation im Thymus. Die Reduktion der mTECs in CYLDex7/8 Thymi könnte den inflammatorischen Phänotyp der CD4+ T Zellen erklären und somit die Entwicklung der spontanen intestinalen Pathologie. In den experimentellen Analysen der CYLDex7/8 T Zellen konnte gezeigt werden, dass die Überexpression von sCLYD in T Zellen eine wichtige Rolle in deren Entwicklung und Regulierung spielt und essentiell für die Aktivierung des alternativen NF-κB Signalweges ist

Wheat amylase-trypsin inhibitors exacerbate intestinal and airway allergic immune responses in humanized mice.

BACKGROUND Amylase-trypsin inhibitors (ATIs) in wheat and related cereals are potent activators of myeloid innate immune cells via engagement of TLR4. Furthermore, ATIs have been shown to serve as adjuvants in experimental intestinal inflammatory diseases. OBJECTIVE The aim of this study was to analyze whether ATIs are also modifiers of allergic inflammation. METHODS Therefore, CD4 T cells from donors sensitized to grass or birch pollen were stimulated with autologous allergen-pulsed dendritic cells in the presence or absence of ATIs or the control storage protein zein from corn. To analyze allergen-induced gut and lung inflammation, immunodeficient mice were engrafted with PBMCs from these allergic donors plus the respective allergen, and fed with selected diets. Three weeks later, inflammation was induced by rectal or intranasal allergen challenge and monitored by mini endoscopy or airway hyperreactivity, respectively. RESULTS Allergen-specific T-cell proliferation and cytokine production was significantly exacerbated by ATIs and not by zein. In vivo, allergen-specific human IgE level was strongly elevated in sera of mice receiving an ATI-containing diet compared with mice that were fed gluten-free and thus ATI-free diet. Importantly, allergen-induced IgE-dependent colitis and airway hyperreactivity were also enhanced in ATI-fed mice. Gut inflammation was further increased in mice receiving an additional ATI injection and even detectable in the absence of the aeroallergen, whereas zein had no such effect. Injection of anti-human TLR4 mAbs or the anti-human IgE mAb omalizumab completely abolished ATI-induced allergic inflammation. CONCLUSIONS These results underline that wheat ATIs are important nutritional activators and adjuvants of allergy, which might be exploited for nutritional therapeutic strategies

DNA repair by MGMT, but not AAG, causes a threshold in alkylation-induced colorectal carcinogenesis

© The Author 2015. Published by Oxford University Press. All rights reserved. Epidemiological studies indicate that N-nitroso compounds (NOC) are causally linked to colorectal cancer (CRC). NOC induce DNA alkylations, including O6-methylguanine (O6-MeG) and N-methylated purines, which are repaired by O6-MeGDNA methyltransferase (MGMT) and N-alkyladenine-DNA glycosylase (AAG)-initiated base excision repair, respectively. In view of recent evidence of nonlinear mutagenicity for NOC-like compounds, the question arises as to the existence of threshold doses in CRC formation. Here, we set out to determine the impact of DNA repair on the dose-response of alkylation-induced CRC. DNA repair proficient (WT) and deficient (Mgmt-/-, Aag-/- and Mgmt-/-/Aag-/-) mice were treated with azoxymethane (AOM) and dextran sodium sulfate to trigger CRC. Tumors were quantified by non-invasive mini-endoscopy. A non-linear increase in CRC formation was observed in WT and Aag-/- mice. In contrast, a linear dose-dependent increase in tumor frequency was found in Mgmt-/- and Mgmt-/-/Aag-/- mice. The data were corroborated by hockey stick modeling, yielding similar carcinogenic thresholds for WT and Aag-/- and no threshold for MGMT lacking mice. O6-MeG levels and depletion of MGMT correlated well with the observed dose-response in CRC formation. AOM induced dose-dependently DNA double-strand breaks in colon crypts including Lgr5-positive colon stem cells, which coincided with ATR-Chk1-p53 signaling. Intriguingly, Mgmt-/- mice displayed significantly enhanced levels of γ-H2AX, suggesting the usefulness of γ-H2AX as an early genotoxicity marker in the colorectum. This study demonstrates for the first time a non-linear dose-response for alkylation-induced colorectal carcinogenesis and reveals DNA repair by MGMT, but not AAG, as a key node in determining a carcinogenic threshold

EBI2 is highly expressed in multiple sclerosis lesions and promotes early CNS migration of encephalitogenic CD4 T cells

Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. EBI2 and its ligand, 7α,25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7α,25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23) and interleukin-1 beta (IL-1β), maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS) white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs

PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression

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PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression

Colorectal cancer (CRC) is one of the most common tumor entities, which is causally linked to DNA repair defects and inflammatory bowel disease (IBD). Here, we studied the role of the DNA repair protein poly(ADP-ribose) polymerase-1 (PARP-1) in CRC. Tissue microarray analysis revealed PARP-1 overexpression in human CRC, correlating with disease progression. To elucidate its function in CRC, PARP-1 deficient (PARP-1−/−) and wild-type animals (WT) were subjected to azoxymethane (AOM)/ dextran sodium sulfate (DSS)-induced colorectal carcinogenesis. Miniendoscopy showed significantly more tumors in WT than in PARP-1−/− mice. Although the lack of PARP-1 moderately increased DNA damage, both genotypes exhibited comparable levels of AOM-induced autophagy and cell death. Interestingly, miniendoscopy revealed a higher AOM/DSS-triggered intestinal inflammation in WT animals, which was associated with increased levels of innate immune cells and proinflammatory cytokines. Tumors in WT animals were more aggressive, showing higher levels of STAT3 activation and cyclin D1 up-regulation. PARP-1−/− animals were then crossed with O6-methylguanine-DNA methyltransferase (MGMT)-deficient animals hypersensitive to AOM. Intriguingly, PARP-1−/−/MGMT−/− double knockout (DKO) mice developed more, but much smaller tumors than MGMT−/− animals. In contrast to MGMT-deficient mice, DKO animals showed strongly reduced AOM-dependent colonic cell death despite similar O6-methylguanine levels. Studies with PARP-1−/− cells provided evidence for increased alkylation-induced DNA strand break formation when MGMT was inhibited, suggesting a role of PARP-1 in the response to O6-methylguanine adducts. Our findings reveal PARP-1 as a double-edged sword in colorectal carcinogenesis, which suppresses tumor initiation following DNA alkylation in a MGMT-dependent manner, but promotes inflammation-driven tumor progression

Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease

OBJECTIVE: Interleukin (IL)-17A is regarded as an important cytokine to drive psoriasis, an inflammatory skin disease marked by increased cardiovascular mortality. We aimed to test the hypothesis that overproduction of IL-17A in the skin leading to dermal inflammation may systemically cause vascular dysfunction in psoriasis-like skin disease. APPROACH AND RESULTS: Conditional overexpression of IL-17A in keratinocytes caused severe psoriasis-like skin inflammation in mice (K14-IL-17A(ind/+) mice), associated with increased reactive oxygen species formation and circulating CD11b(+) inflammatory leukocytes in blood, with endothelial dysfunction, increased systolic blood pressure, left ventricular hypertrophy, and reduced survival compared with controls. In K14-IL-17A(ind/+) mice, immunohistochemistry and flow cytometry revealed increased vascular production of the nitric oxide/superoxide reaction product peroxynitrite and infiltration of the vasculature with myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) cells accompanied by increased expression of the inducible nitric oxide synthase and the nicotinamide dinucleotide phosphate (NADPH) oxidase, nox2. Neutrophil depletion by anti-GR-1 antibody injections reduced oxidative stress in blood and vessels. Neutralization of tumor necrosis factor-alpha and IL-6 (both downstream of IL-17A) reduced skin lesions, attenuated oxidative stress in heart and blood, and partially improved endothelial dysfunction in K14-IL-17A(ind/+) mice. CONCLUSIONS: Dermal overexpression of IL-17A induces systemic endothelial dysfunction, vascular oxidative stress, arterial hypertension, and increases mortality mainly driven by myeloperoxidase(+)CD11b(+)GR1(+)F4/80(-) inflammatory cells. Depletion of the GR-1(+) immune cells or neutralization of IL-17A downstream cytokines by biologicals attenuates the vascular phenotype in K14-IL-17A(ind/+) mice