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Regulatory T cells (Tregs) play a crucial and complex role in balancing the immune response to viral infection. Primarily, they serve to regulate the immune response by limiting the expression of proinflammatory cytokines, reducing inflammation in infected tissue, and limiting virus-specific T cell responses. But excessive activity of Tregs can also be detrimental and hinder the ability to effectively clear viral infection, leading to prolonged disease and potential worsening of disease severity. Not much is known about the impact of Tregs during severe influenza. In the present study, we show that CD4+/CD25+FoxP3+ Tregs are strongly involved in disease progression during influenza A virus (IAV) infection in mice. By comparing sublethal with lethal dose infection in vivo, we found that not the viral load but an increased number of CD4+/CD25+FoxP3+ Tregs may impair the immune response by suppressing virus specific CD8+ T cells and favors disease progression. Moreover, the transfer of induced Tregs into mice with mild disease symptoms had a negative and prolonged effect on disease outcome, emphasizing their importance for pathogenesis. Furthermore, treatment with MEK-inhibitors resulted in a significant reduction of induced Tregs in vitro and in vivo and positively influenced the progression of the disease. Our results demonstrate that CD4+/CD25+FoxP3+ Tregs are involved in the pathogenesis of severe influenza and indicate the potential of the MEK-inhibitor zapnometinib to modulate CD4+/CD25+FoxP3+ Tregs. Thus, making MEK-inhibitors even more promising for the treatment of severe influenza virus infections.

Abstract Siblings strongly influence each other in their social development and are a major source of support and conflict. Yet, studies are mostly observational, and little is known about how adult sibling relationships influence social behavior. Previous tasks exploring dynamically adjusting social interactions have limitations in the level of interactivity and naturalism of the interaction. To address these limitations, we created a cooperative tetris puzzle-solving task and an interactive version of the chicken game task. We validated these two tasks to study cooperative and competitive behavior in real-time interactions (N = 56). Based on a dominance questionnaire (DoPL), sibling pairs were clustered into pairs that were both low in dominance (n = 7), both high in dominance (n = 8), or one low and one high in dominance (n = 13). Consistent with our hypothesis, there were significantly more mutual defections, less use of turn-taking strategies, and a non-significant trend for reduced success in solving tetris puzzles together among high dominance pairs compared to both other pair types. High dominant pairs also had higher Machiavellian and hypercompetitiveness traits and more apathetic sibling relationships. Both tasks constitute powerful and reliable tools to study personality and relationship influences on real and natural social interactions by demonstrating the different cooperative and competitive dynamics between siblings.

IntroductionThe Taylor Aggression Paradigm (TAP) is a well-established tool for assessing provocation-induced reactive aggression. We introduce an interactive version, the iTAP, with real-time opponents across 60 trials, including five simulated provocation trials in the middle. In this quasi-experimental study, we evaluate the effectiveness of the paradigm to investigate reactive aggression in interacting participants. The design allows us to employ the TAP in settings of high familiarity dyads, addressing an existing gap.MethodTwenty-eight healthy same-sex adult sibling pairs (N = 56) competed against each other in the iTAP, exemplifying high familiarity through their social and emotional co-development, and mutual knowledge. Additionally, we explore naturally arising aggression types in terms of sibling pairs’ reciprocal aggression trajectories across trials. Lastly, we investigate situational and personal variables influencing reactive aggression on the iTAP within high familiarity dyads.ResultsIn line with non-interactive TAP versions, siblings employed a global “tit-for-tat” strategy in response to heightened provocation: Aggression increased during manipulated trials of increasing provocation, persisted during real interaction and declined in the final block, suggesting sibling co-regulation which was underscored by the convergence in within-pair aggression level. We found no gender differences in these dynamics but a trend for higher initial aggression levels within brother pairs and higher responsiveness to increased provocation in sister pairs. Overall aggression levels were related to situational variables including trial outcome (lost, won, and tie), Further, siblings’ state anger correlated positively with aggression scores on the iTAP. Aggression was not reliably related to personal variables predicting aggression. We identified subgroups of sibling pairs with distinct provocation-aggression patterns related to differences in reported behavioral motivations and emotional states. The results highlight situational over personal variables in determining aggressive behavior on the task in this sample of healthy adults. While no direct link between sibling relationship quality and aggression was found, the overall behavior was likely influenced by the familiarity between siblings and the specific context of their relationship.ConclusionThe iTAP demonstrates promise as a tool for studying reciprocal aggressive behavior. The emergence of different interaction patterns underscores the ecological validity introduced by the interactive context, which complements the standard versions of the TAP.

The recent COVID-19 pandemic again highlighted the urgent need for broad-spectrum antivirals, both for therapeutic use in acute viral infection and for pandemic preparedness in general. The targeting of host cell factors hijacked by viruses during their replication cycle presents one possible strategy for development of broad-spectrum antivirals. By inhibiting the Raf/MEK/ERK signaling pathway, a central kinase cascade of eukaryotic cells, which is being exploited by numerous viruses of different virus phyla, the small-molecule MEK inhibitor zapnometinib has the potential to address this need. We here performed a side-by-side comparison of the antiviral efficacy of zapnometinib against IAV and SARS-CoV-2 to determine the concentration leading to 50% of its effect on the virus (EC50) and the concentration leading to 50% reduction of ERK phosphorylation (IC50) in a comparable manner, using the same experimental conditions. Our results show that the EC50 value and IC50 value of zapnometinib are indeed lower for IAV compared to SARS-CoV-2 using one representative strain for each. The results suggest that IAV’s replication has a stronger dependency on an active Raf/MEK/ERK pathway and, thus, that IAV is more susceptible to treatment with zapnometinib than SARS-CoV-2. With zapnometinib’s favorable outcome in a recent phase II clinical trial in hospitalized COVID-19 patients, the present results are even more promising for an upcoming phase II clinical trial in severe influenza virus infection.

The environmental gains of dietary change are often assessed in relation to average national diets, overlooking differences in individual consumption habits and people’s willingness to change. This study combines microdata on food intake and consumer behaviour to elicit the likely environmental gains of dietary shifts. We focus on the Netherlands owing to the country’s ambition to halve its dietary footprint by 2050. Linking food recall survey data from a cross-section of the population ( n = 4313), life cycle inventory analysis for 220 food products, and behavioural survey data ( n = 1233), we estimate the dietary footprints of consumer groups across water, land, biodiversity and greenhouse gas (GHG). We find that meat and dairy significantly contribute to the dietary GHG footprint (59%), land footprint (54%), and biodiversity footprint (59%) of all consumer groups and that male consumers impose a 30%–32% greater burden than women across these impact areas. Our scenario analysis reveals that simply replacing cow milk with soy milk could reduce the GHG, land and biodiversity footprints by ≈8% if widely adopted by the Dutch adult population. These footprints could be further reduced to ≈20% with full adoption of the EAT-Lancet diet but with a significantly increased blue water footprint. However, when incorporating gender- and age-specific willingness to reduce meat and dairy consumption, the environmental gains resulting from partial adoption of the No-Milk diet and EAT diet diminish to a mere ≈0.8% and ≈4.5%, respectively. Consequently, consumer motivation alone is insufficient to realise the significant environmental gains often promised by dietary change. Yet, substituting high-impact food products offers a near-term opportunity to accelerate a rapid sustainable dietary transition. Future studies on sustainable dietary transition must incorporate consumer behaviour to fully comprehend the lock-in of food consumption patterns and targeted policy action required to secure a sustainable food future.

Cardiovascular diseases (CVD) are the leading cause of death worldwide, causing approximately 17.9 deaths annually. Their risk factors are mainly related to an inappropriate lifestyle and include, among others, low physical activity, obesity, hypertension or type 2 diabetes. Nowadays, there is an increase in the incidence of CVD as well as sleeping disorders, so many studies have focused on finding the connection between these phenomena. The impact of sleep duration on the occurrence of cardiovascular diseases and their risk factors was analyzed based on a systematic analysis of the literature. The review was carried out using keywords, based on data contained in the Google Scholar search engine database, in the PubMed scientific database and medical electronic journals. The analyzed studies indicate that sleep duration, its both excessive shortening and lengthening, as well as poor quality, may be associated with CVD, their risk factors and increased overall mortality. Researchers point to the connection between sleep duration and development of hypertension, obesity and type 2 diabetes, with short sleep identified as a stronger risk factor. In addition long sleep was associated with poor health and overall worse results of the subjects more often than short sleep. This suggests that long sleep may not be the cause, but a consequence of yet undiagnosed, coexisting chronic diseases. The results indicate the need to assess sleep disorders as a goal for primary and secondary prevention of CVD and reduction of their risk factors. The importance of long sleep remains ambiguous, whether it is the reason for health deterioration or results from it and requires further research. Large intervention studies are also still needed to assess whether improvements in sleep duration and its quality can reduce cardiovascular risk and improve long-term health outcomes.

The Raf/MEK/ERK signaling pathway plays a key role in regulating cellular proliferation, differentiation, apoptosis, cytokine production, and immune responses. However, it is also involved in diseases such as cancer, and numerous viruses rely on an active Raf/MEK/ERK pathway for propagation. This pathway, and particularly MEK1/2, are therefore promising therapeutic targets. Assessment of target engagement is crucial to determine pharmacodynamics or the efficacy of a MEK1/2 inhibitor. In the field of infectious diseases, this is usually first determined in clinical trials with healthy volunteers. One method to detect MEK1/2 inhibitor target engagement is to assess the degree of ERK1/2 phosphorylation, as ERK1/2 is the only known substrate of MEK1/2. As healthy subjects, however, only feature a low baseline MEK1/2 activation and therefore low ERK1/2 phosphorylation in most tissues, assessing target engagement is challenging, and robust methods are urgently needed. We hence developed a method using PBMCs isolated from whole blood of healthy blood donors, followed by ex vivo treatment with the MEK1/2 inhibitor zapnometinib and stimulation with PMA to first inhibit and then induce MEK1/2 activation. As PMA cannot activate MEK1/2 upon MEK1/2 inhibition, MEK1/2 inhibition results in impaired MEK1/2 activation. In contrast, PMA stimulation without MEK1/2 inhibition results in high MEK1/2 activation. We demonstrated that, without MEK1/2 inhibitor treatment, MEK1/2 stimulation with PMA induces high MEK1/2 activation, which is clearly distinguishable from baseline MEK1/2 activation in human PBMCs. Furthermore, we showed that treatment with the MEK1/2 inhibitor zapnometinib maintains the MEK1/2 activation at approximately baseline level despite subsequent stimulation with PMA. As our protocol is easy to follow and preserves the cells in an in vivo-like condition throughout the whole handling process, this approach can be a major advance for the easy assessment of MEK1/2 inhibitor target engagement in healthy probands for clinical drug development.

The mitogen-activated protein kinase (MEK) inhibitor zapnometinib is in development to treat acute viral infections like COVID-19 and influenza. While the antiviral efficacy of zapnometinib is well documented, further data on target engagement/pharmacodynamics (PD) and pharmacokinetics (PK) are needed. Here, we report zapnometinib PK and PD parameters in mice, hamsters, dogs, and healthy human volunteers. Mice received 25 mg/kg/day zapnometinib (12.5 mg/kg p. o. twice daily, 8 h interval). Syrian hamsters received 30 mg/kg (15 mg/kg twice daily) or 60 mg/kg/day once daily. Beagle dogs were administered 300 mg/kg/day, and healthy human volunteers were administered 100, 300, 600 and 900 mg zapnometinib (once daily p. o.). Regardless of species or formulation, zapnometinib maximum plasma concentration (Cmax) was reached between 2–4 h after administration with an elimination half-life of 4–5 h in dogs, 8 h in mice or hamsters and 19 h in human subjects. Doses were sufficient to cause up to 80% MEK inhibition. Across all species approximately 10 μg/ml zapnometinib was appropriate to inhibit 50% of peripheral blood mononuclear cells (PBMC) MEK activity. In mice, a 50%–80% reduction of MEK activity was sufficient to reduce influenza virus titer in the lungs by more than 90%. In general, while >50% MEK inhibition was reached in vivo at most doses, 80% inhibition in PBMCs required significantly higher doses and appeared to be the practical maximal level obtained in vivo. However, the period of reduced phosphorylated extracellular-signal regulated kinase (pERK), a measure of MEK inhibition, was maintained even after elimination of zapnometinib from plasma, suggesting a sustained effect on MEK consistent with regulatory effects or a slow off-rate. These data suggest a target plasma Cmax of at least 10 μg/ml zapnometinib in further clinical studies.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic effects daily dental work. Therefore, infection control measures are necessary to prevent infection of dental personnel during dental treatments. The use of a preprocedural mouth rinse with chlorhexidine (CHX), cetylpyridinium chloride (CPC), or hydrogen peroxide (H2O2) solution for 30–60 s may reduce the viral load and may protect the personnel in a dental practice. In the present study the virucidal effect of the mouth rinsing solutions ViruProX® with 0.05% CPC and 1.5% H2O2 and BacterX® pro containing 0.1% CHX, 0.05% CPC, and 0.005% sodium fluoride (F-) was investigated in vitro. The mouth rinsing solutions successfully inactivated infectious SARS-CoV-2 particles, the causative agent of coronavirus disease 2019 (COVID-19), within 30 s. To determine the effective components, CHX, CPC, H2O2, and a combination of CHX and CPC, were tested against SARS-CoV-2 in addition. While a combination of CPC and CHX as well as CPC alone led to a significant reduction of infectious viral particles, H2O2 and CHX alone had no virucidal effect against SARS-CoV-2. It can be assumed that preprocedural rinsing of the mouth with ViruProX® or BacterX® pro will reduce the viral load in the oral cavity and could thus lower the transmission of SARS-CoV-2 in dental practice.

Researchers are increasingly being asked to ensure that all products of research activity – not just traditional publications – are preserved and made widely available for study and reuse as a precondition for publication or grant funding, or to conform to disciplinary best practices. In order to conform to these requirements, scholars need effective, easy-to-use tools and services for the long-term curation of their research data. The DataShare service, developed at the University of California, is being used by researchers to: (1) prepare for curation by reviewing best practice recommendations for the acquisition or creation of digital research data; (2) select datasets using intuitive file browsing and drag-and-drop interfaces; (3) describe their data for enhanced discoverability in terms of the DataCite metadata schema; (4) preserve their data by uploading to a public access collection in the UC3 Merritt curation repository; (5) cite their data in terms of persistent and globally-resolvable DOI identifiers; (6) expose their data through registration with well-known abstracting and indexing services and major internet search engines; (7) control the dissemination of their data through enforceable data use agreements; and (8) discover and retrieve datasets of interest through a faceted search and browse environment. Since the widespread adoption of effective data management practices is highly dependent on ease of use and integration into existing individual, institutional, and disciplinary workflows, the emphasis throughout the design and implementation of DataShare is to provide the highest level of curation service with the lowest possible technical barriers to entry by individual researchers. By enabling intuitive, self-service access to data curation functions, DataShare helps to contribute to more widespread adoption of good data curation practices that are critical to open scientific inquiry, discourse, and advancement.