Moral decision-making at night and the impact of night work with blue-enriched white light or warm white light: a counterbalanced crossover study.

BACKGROUND: Cognitive function, including moral decision-making abilities, can be impaired by sleep loss. Blue-enriched light interventions have been shown to ameliorate cognitive impairment during night work. This study investigated whether the quality of moral decision-making during simulated night work differed for night work in blue-enriched white light, compared to warm white light. METHODS: Using a counterbalanced crossover design, three consecutive night shifts were performed in blue-enriched white light (7000 K) and warm white light (2500 K) provided by ceiling-mounted LED luminaires (photopic illuminance: ∼200 lx). At 03:30 h on the second shift (i.e. twice) and at daytime (rested), the Defining Issues Test-2, assessing the activation of cognitive schemas depicting different levels of cognitive moral development, was administered. Data from 30 (10 males, average age 23.3 ± 2.9 years) participants were analysed using linear mixed-effects models. RESULTS: Activation of the post-conventional schema (P-score), that is, the most mature moral level, was significantly lower for night work in warm white light (EMM; estimated marginal mean = 44.3, 95% CI = 38.9-49.6; pholm=.007), but not blue-enriched white light (EMM = 47.5, 95% CI = 42.2-52.8), compared to daytime (EMM = 51.2, 95% CI = 45.9-56.5). Also, the P-score was reduced for night work overall (EMM = 45.9, 95% CI = 41.1-50.8; p=.008), that is, irrespective of light condition, compared to daytime. Neither activation of the maintaining norms schema (MN-score), that is, moderately developed moral level, nor activation of the personal interest schema (i.e. the lowest moral level) differed significantly between light conditions. The MN-score was however increased for night work overall (EMM = 26.8, 95% CI = 23.1-30.5; p=.033) compared to daytime (EMM = 23.1, 95% CI = 18.9-27.2). CONCLUSION: The results indicate that moral decisions during simulated night work in warm white light, but not blue-enriched white light, become less mature and principle-oriented, and more rule-based compared to daytime, hence blue-enriched white light may function as a moderator. Further studies are needed, and the findings should be tentatively considered.Trial registration: ClinicalTrials.gov (ID: NCT03203538) Registered: 26/06/2017; https://clinicaltrials.gov/study/NCT03203538.

The quality of moral decision-making, seen as the activation of cognitive schemas depicting different levels of moral development, was reduced during simulated night work in warm white light, but not blue-enriched light, compared to daytime.The quality of moral decision-making sems to be reduced during simulated night work, compared to daytime.More studies assessing the impact of night work and light interventions on the quality of moral decision-making are needed to validate these tentative findings.

Daily interpersonal conflicts and daily negative and positive affect: exploring the moderating role of neuroticism.

BACKGROUND AND OBJECTIVES: Drawing on affective events theory, the present study investigates relationships between daily interpersonal conflicts and negative and positive affective reactions, and tested whether trait neuroticism moderates immediate (same day) and persisting (next-day) affective reactions. DESIGN AND METHODS: A sample of 53 Norwegian naval cadets completed a diary questionnaire for 30 consecutive days (total N = 1590). RESULTS: As predicted, the findings showed that cadets reported more negative affect (but not less positive affect) on days they were confronted with affective events that were of a conflicting nature. In addition, the proposed interaction effects between daily conflict and neuroticism were significant for both negative and positive affect. Specifically, the immediate and persistent effects of daily conflicts on negative affect were strongest for individuals high (vs. low) in neuroticism. Moreover, individuals high in neuroticism reported less positive affect on days with conflicts, whereas individuals low in neuroticism reported more positive affect the two days following interpersonal conflicts. CONCLUSIONS: The findings contribute to affective events theory with important knowledge about the role of trait neuroticism in dealing with interpersonal conflicts in a natural work setting.

Virtual team-cooperation from home-office: a quantitative diary study of the impact of daily transformational- and passive-avoidant leadership - and the moderating role of task interdependence.

During the Covid-19 pandemic, most of the workforce moved from office setting to home-office and virtual teamwork. Whereas the relationship between leadership and team cooperation in physical settings is well documented - less is known about how daily virtual team cooperation is influenced by daily constructive as well as destructive leadership, and how intervening mechanisms influence this relationship. In the present study, we test the direct effect of daily transformational- and passive avoidant leadership, respectively, on the daily quality of virtual team cooperation - and the moderating effect of task interdependence. Using virtual team cooperation as outcome, we hypothesized that (a) transformational leadership relates positively to virtual team cooperation, (b) passive-avoidant leadership relates negatively, and (c) moderated by task interdependence. Our hypotheses were tested in a 5-day quantitative diary study with 58 convenience sampled employees working from home in virtual teams. The results show that virtual team cooperation is a partially malleable process - with 28% variation in daily virtual team cooperation resulting from within team variation from day to day. Surprisingly, the results of multilevel modeling lend support only to the first hypothesis (a). Taken together, our findings suggest that in virtual settings, inspirational and development-oriented transformational leadership plays a key role in daily team cooperation, while passive-avoidance has little impact - independently of task interdependence. Hence, in virtual team settings, the study shows that "good is stronger than bad" - when comparing the negative effects of destructive leadership to the positive effect of constructive and inspirational leadership. We discuss the implications of these findings for further research and practice.

Proteogenomic identification of Hepatitis B virus (HBV) genotype-specific HLA-I restricted peptides from HBV-positive patient liver tissues.

The presentation of virus-derived peptides by HLA class I molecules on the surface of an infected cell and the recognition of these HLA-peptide complexes by, and subsequent activation of, CD8+ cytotoxic T cells provides an important mechanism for immune protection against viruses. Recent advances in proteogenomics have allowed researchers to discover a growing number of unique HLA-restricted viral peptides, resulting in a rapidly expanding repertoire of targets for immunotherapeutics (i.e. bispecific antibodies, engineered T-cell receptors (TCRs), chimeric antigen receptor T-cells (CAR-Ts)) to infected tissues. However, genomic variability between viral strains, such as Hepatitis-B virus (HBV), in combination with differences in patient HLA alleles, make it difficult to develop therapeutics against these targets. To address this challenge, we developed a novel proteogenomics approach for generating patient-specific databases that enable the identification of viral peptides based on the viral transcriptomes sequenced from individual patient liver samples. We also utilized DNA sequencing of patient samples to identify HLA genotypes and assist in target selection. Liver samples from 48 HBV infected patients, primarily from Asia, were examined to reconstruct patient-specific HBV genomes, identify regions within the human chromosomes targeted by HBV integrations and obtain a comprehensive view of HBV peptide epitopes using our HLA class-I (HLA-I) immunopeptidomics discovery platform. Two previously reported HLA associated HBV-derived peptides, HLA-A02 binder FLLTRILTI (S194-202) from the large surface antigen and HLA-A11 binder STLPETTVVRR (C141-151) from the capsid protein were validated by our discovery platform, but both were detected at very low frequencies. In addition, we identified and validated, using heavy peptide analogues, novel strain-specific HBV-HLA associated peptides, such as GSLPQEHIVQK (P606-616) and variants. Overall, our novel approach can guide the development of bispecific antibody, TCR-T, or CAR-T based therapeutics for the treatment of HBV-related HCC and inform vaccine development.

Daily work pressure and task performance: The moderating role of recovery and sleep.

Whereas previous research has focused on the link between (mental and physical) workload and task performance, less is known about the intervening mechanisms influencing this relationship. In the present study, we test the moderating roles of daily recovery and total sleep time in the relationship between work pressure and daily task performance. Using performance and recovery theories, we hypothesized that (a) work pressure relates positively to daily task performance, and that both (b) daily recovery in the form of psychological detachment and relaxation, and (c) total sleep time independently enhance this relationship. Our hypotheses were tested in a 30-day diary study with 110 officer cadets on a cross-Atlantic voyage on a Naval sail ship. The results of multilevel modeling lend support to all three hypotheses. Taken together, our findings suggest that recovery and sleep duration between shifts play a key role in the relationship between daily work pressure and task performance. We discuss the implications of these findings for the stressor-detachment model.

High affinity human Fc specific monoclonal antibodies for capture kinetic analyses of antibody-antigen interactions.

We recently demonstrated that capturing human monoclonal antibodies (hmAbs) using high affinity anti-human Fc (AHC) antibodies allows reliable characterization of antibody-antigen interactions. Here, we characterized six human Fc specific mouse monoclonal antibodies (mAbs) and compared their binding profiles with three previously characterized goat AHC polyclonal antibodies (pAbs), exhibiting properties of a good capture reagent. All six mouse AHC mAbs specifically bound with high affinity to the Fc region of hIgG1, hIgG2, hIgG4 and to 43 different hIgG variants, containing substitutions and/or mutations in the hinge and/or Fc region, that have been reported to exhibit modified antibody effector function and/or pharmacokinetics. Biacore sensor surfaces individually derivatized with mouse AHC mAbs exhibited >2.5-fold higher hIgG binding capacity compared to the three goat AHC pAb surfaces and reproducibly captured hIgG over 300 capture-regeneration cycles. The results of the capture kinetic analyses performed on 31 antibody-antigen interactions using surfaces derivatized with either of the two highest affinity AHC mAbs (REGN7942 or REGN7943) were in concordance with those performed using goat AHC pAb surfaces. Our data demonstrate that AHC mAbs such as REGN7942 and REGN7943 that have properties superior than the three goat AHC pAbs are highly valuable research reagents, especially to perform capture kinetic analyses of antibody-antigen interactions on optical biosensors.

Teamwork on Patrol: Investigating Teamwork Processes and Underlaying Coordinating Mechanisms in a Police Training Program.

The Big Five theory suggests that five components in teamwork are essential for team effectiveness in stressful environments. Furthermore, three coordinating mechanisms are claimed to be decisive to upholding and informing vital teamwork processes. Although much research has been conducted into the Big Five theory and its components, to the best of our knowledge, no study has yet been made of the relative importance of the three mechanisms and their impact on team effectiveness. Also, only a few studies have tried to investigate whether the components and the coordinating mechanisms are trainable. This study aims to make a theoretical contribution to the part of the theory focusing on the coordinating mechanisms. Secondly, it investigates whether training can improve team performance. Working in teams of two, 166 police officers participated in a simulated operational scenario. Correlational analyses indicated that all Big Five teamwork behaviors and coordinating mechanisms relate to external ratings of team performance. Only the mechanisms of Closed Loop Communication (CLC) and Shared Mental Model (SMM) predicted performance indicators, with SMM predicting above and beyond the effect of CLC. No effect of the training program was found. The study provides new evidence in a police situation that the most important coordinating mechanism of the Big Five theory is that of shared mental models, which in turn has consequences for the type of training needed.

Development of Novel Glucocorticoids for Use in Antibody-Drug Conjugates for the Treatment of Inflammatory Diseases.

Glucocorticoids (GCs) are widely used to treat a variety of autoimmune and inflammatory diseases; however, systemic delivery of GCs is associated with side effects that affect essentially every organ system, reflecting the nearly ubiquitous expression of the glucocorticoid receptor (GR). Targeted delivery of GCs to diseased tissues using antibody-glucocorticoid conjugates (GC-ADCs) offers a therapeutic alternative to overcome these adverse effects. Herein, we describe novel classes of GCs that exhibited greater potency than dexamethasone and budesonide, a 100-fold selectivity toward the GR over other nuclear receptors, and no in vitro safety liability in pharmacology assays (hERG, AMES) and that demonstrated a substantial reduction in tumor necrosis factor-α (TNF-α) release in mice challenged with lipopolysaccharide (LPS). The site-specific conjugated GC-ADCs via cathepsin-cleavable linkers were highly stable in plasma and specifically released GCs in antigen-positive cells, suggesting that these novel GCs can serve as ADC payloads to treat autoimmune and inflammatory diseases.

Gaming in the Military: A Longitudinal Study of Changes in Gaming Behavior Among Conscripts During Military Service and Associated Risk Factors.

A central task in military leadership is to take care of one's followers, which presupposes knowledge about relevant risk factors. Very little research has focused on the risks of developing problematic gaming behavior during military service. The present study tries to bridge this gap by assessing prevalence rates and associated risk factors of problem gaming in a sample of Norwegian conscripts across two time-points: at the beginning and end of duty. The sample comprised 2,555 individuals aged 18-24 years. A total of 1,017 (39.8%) completed the questionnaire at Time 1, ~1 month after starting the military service. Respondents who completed the first wave, at enrollment, were invited to participate in wave two, after completing their service. At Time 2, 259 (25.5%) participants responded. The prevalence rates of gaming addiction were 0.5% at Time 1 and 4.6% at Time 2, while problem gaming use was reported by 4.8% of the sample at Time 1 and 8.1% of the sample at Time 2. Paired sample t-tests revealed an overall significant increase in the mean scores on the Gaming Addiction Scale from T1 (M = 0.86, SD = 1.35) to T2 (M = 1.31, SD = 2.14), t = -2.40, p < 0.05. According to the reliable change index, 17.1% of the sample showed a reliable negative change, whereas 8.3% exhibited a reliable positive change in gaming addiction scores. However, no psychological variables measured at T1 (loneliness, boredom proneness-Internal, boredom proneness-External, anxiety, depression, game addiction, and time spent gaming) were related to attrition (from T1 to T2), or worsening of game addiction, while a positive relationship was observed between boredom proneness-External and reduced gaming addiction from T1 to T2. In sum, we observed a tendency toward a negative change in gaming behaviors during military service which may complicate the soldiers' reintegration into civilian life after their service. More research is needed to assess potential gaming problems in the Military.

Tumoural activation of TLR3-SLIT2 axis in endothelium drives metastasis.

Blood vessels support tumours by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer1. Here we use mouse models of breast and lung cancer to investigate whether endothelial cells also have active 'instructive' roles in the dissemination of cancer. We purified genetically tagged endothelial ribosomes and their associated transcripts from highly and poorly metastatic tumours. Deep sequencing revealed that metastatic tumours induced expression of the axon-guidance gene Slit2 in endothelium, establishing differential expression between the endothelial (high Slit2 expression) and tumoural (low Slit2 expression) compartments. Endothelial-derived SLIT2 protein and its receptor ROBO1 promoted the migration of cancer cells towards endothelial cells and intravasation. Deleting endothelial Slit2 suppressed metastatic dissemination in mouse models of breast and lung cancer. Conversely, deletion of tumoural Slit2 enhanced metastatic progression. We identified double-stranded RNA derived from tumour cells as an upstream signal that induces expression of endothelial SLIT2 by acting on the RNA-sensing receptor TLR3. Accordingly, a set of endogenous retroviral element RNAs were upregulated in metastatic cells and detected extracellularly. Thus, cancer cells co-opt innate RNA sensing to induce a chemotactic signalling pathway in endothelium that drives intravasation and metastasis. These findings reveal that endothelial cells have a direct instructive role in driving metastatic dissemination, and demonstrate that a single gene (Slit2) can promote or suppress cancer progression depending on its cellular source.

Outcomes of a Proximal Workplace Intervention Against Workplace Bullying and Harassment: A Protocol for a Cluster Randomized Controlled Trial Among Norwegian Industrial Workers.

Background: Workplace bullying is an important and prevalent risk factors for health impairment, reduced workability and lowered efficiency among both targets and observers. Development and tests of effective organizational intervention strategies are therefore highly important. The present study describes the background, design, and protocol of a cluster randomized controlled trial evaluating the effectiveness of an organization-wide intervention on preventing workplace bullying with a focus on promoting active and constructive bystander behavior. The main overarching goal is to develop an easy to use and standardized organizational intervention based on theory and research in the role of bystanders in bullying situations with the potential of reducing the prevalence of workplace bullying. The theoretical framework of the study is theory of planned behavior (TPB; Ajzen, 1991).Methods/Design: Using a full randomized control trial (RCT) design, this project will empirically test the outcomes of an intervention program targeting bullying and harassment as the main distal outcomes and perceived behavioral control and helping behavior among bystanders as the main proximal outcome. A 1-year cluster randomized controlled design will be utilized, in which controls will also receive the intervention. About 1,500 workers from two different locations of a Norwegian industrial company will be randomized into one intervention group and two control groups with at least 400 workers in each group. A survey will be conducted electronically. With a total of three assessments over 10­12 months, the time interval between the measurement times will be 4 months. Thus, the data collection will take place at baseline, completion of the intervention and at 4 months follow-up.Discussion: This study primarily aims to develop, implement, and evaluate an intervention based on the abovementioned features with the ultimate aim of reducing the prevalence of workplace bullying, by awareness raising and training of bystanders. Manager involvement and involvement of the union representative and the elected health and safety representatives is an important feature of the program. Results of the intervention study will provide important information regarding the effectiveness of preventive interventions against workplace bullying when focusing on bystanders, particularly so regarding the role of bystander awareness, bystander self-efficacy, and bystander behavioral control on the one hand and the prevalence of bullying and harassment on the other.

Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5.

Complement is a key component of the innate immune system. Inappropriate complement activation underlies the pathophysiology of a variety of diseases. Complement component 5 (C5) is a validated therapeutic target for complement-mediated diseases, but the development of new therapeutics has been limited by a paucity of preclinical models to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of candidate therapies. The present report describes a novel humanized C5 mouse and its utility in evaluating a panel of fully human anti-C5 antibodies. Surprisingly, humanized C5 mice revealed marked differences in clearance rates amongst a panel of anti-C5 antibodies. One antibody, pozelimab (REGN3918), bound C5 and C5 variants with high affinity and potently blocked complement-mediated hemolysis in vitro. In studies conducted in both humanized C5 mice and cynomolgus monkeys, pozelimab demonstrated prolonged PK and durable suppression of hemolytic activity ex vivo. In humanized C5 mice, a switch in dosing from in-house eculizumab to pozelimab was associated with normalization of serum C5 concentrations, sustained suppression of hemolytic activity ex vivo, and no overt toxicity. Our findings demonstrate the value of humanized C5 mice in identifying new therapeutic candidates and treatment options for complement-mediated diseases.

The impact of different human IgG capture molecules on the kinetics analysis of antibody-antigen interaction.

Surface plasmon resonance (SPR) is a well-established method to characterize biomolecular interactions and is widely used in drug discovery and development. Here, we demonstrate that capture surfaces profoundly impact the binding kinetics parameters that are measured for antibody-antigen interactions. Six unique antibody-antigen interactions were characterized using eight different anti-human IgG capture surfaces. The antigen binding affinities for six different human monoclonal antibodies (hmAbs) captured using three different goat anti-human Fc (AHC) polyclonal antibody (pAb) surfaces were in reasonable agreement (3-7-fold weaker) with those measured by kinetic exclusion assay (KinExA). In contrast, up to 81, 32, 489, 2826, and 219-fold weaker antigen binding affinities were measured using mouse AHC mAb, Protein G, Protein A, Protein A/G, and Protein L surfaces, respectively. Protein A, Protein A/G and Protein G interacted with the Fab of hmAbs, possibly affecting antigen binding to hmAbs captured over these surfaces. Additional studies revealed that mouse AHC mAb binds hmAbs with a weak affinity (5.5-36.3 nM) and t½ values of 1.4-3.3min, compared to the sub-nanomolar affinities of the goat AHC pAbs. These results emphasize the value of measuring binding kinetics of the capture molecule before immobilizing them onto the sensor surface to perform capture kinetics assays on label-free biosensors.

A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP ß-CTFs, Not Aß.

Familial Alzheimer's disease (fAD) results from mutations in the amyloid precursor protein (APP) and presenilin (PSEN1 and PSEN2) genes. Here we leveraged recent advances in induced pluripotent stem cell (iPSC) and CRISPR/Cas9 genome editing technologies to generate a panel of isogenic knockin human iPSC lines carrying APP and/or PSEN1 mutations. Global transcriptomic and translatomic profiling revealed that fAD mutations have overlapping effects on the expression of AD-related and endocytosis-associated genes. Mutant neurons also increased Rab5+ early endosome size. APP and PSEN1 mutations had discordant effects on Aß production but similar effects on APP ß C-terminal fragments (ß-CTFs), which accumulate in all mutant neurons. Importantly, endosomal dysfunction correlated with accumulation of ß-CTFs, not Aß, and could be rescued by pharmacological modulation of ß-secretase (BACE). These data display the utility of our mutant iPSCs in studying AD-related phenotypes in a non-overexpression human-based system and support mounting evidence that ß-CTF may be critical in AD pathogenesis.

Neuronally Enriched RUFY3 Is Required for Caspase-Mediated Axon Degeneration.

Selective synaptic and axonal degeneration are critical aspects of both brain development and neurodegenerative disease. Inhibition of caspase signaling in neurons is a potential therapeutic strategy for neurodegenerative disease, but no neuron-specific modulators of caspase signaling have been described. Using a mass spectrometry approach, we discovered that RUFY3, a neuronally enriched protein, is essential for caspase-mediated degeneration of TRKA+ sensory axons in vitro and in vivo. Deletion of Rufy3 protects axons from degeneration, even in the presence of activated CASP3 that is competent to cleave endogenous substrates. Dephosphorylation of RUFY3 at residue S34 appears required for axon degeneration, providing a potential mechanism for neurons to locally control caspase-driven degeneration. Neuronally enriched RUFY3 thus provides an entry point for understanding non-apoptotic functions of CASP3 and a potential target to modulate caspase signaling specifically in neurons for neurodegenerative disease.

Long-Range Guidance of Spinal Commissural Axons by Netrin1 and Sonic Hedgehog from Midline Floor Plate Cells.

An important model for axon pathfinding is provided by guidance of embryonic commissural axons from dorsal spinal cord to ventral midline floor plate (FP). FP cells produce a chemoattractive activity, comprised largely of netrin1 (FP-netrin1) and Sonic hedgehog (Shh), that can attract the axons at a distance in vitro. netrin1 is also produced by ventricular zone (VZ) progenitors along the axons' route (VZ-netrin1). Recent studies using region-specific netrin1 deletion suggested that FP-netrin1 is dispensable and VZ-netrin1 sufficient for netrin guidance activity in vivo. We show that removing FP-netrin1 actually causes guidance defects in spinal cord consistent with long-range action (i.e., over hundreds of micrometers), and double mutant analysis supports that FP-netrin1 and Shh collaborate to attract at long range. We further provide evidence that netrin1 may guide via chemotaxis or haptotaxis. These results support the model that netrin1 signals at both short and long range to guide commissural axons in spinal cord.

Daily sleep quality and naval work performance: the role of leadership.

BACKGROUND: Poor sleep is a growing concern in naval settings. Previous research has demonstrated that both civilian and military naval work strains sleep quality as well as a negative relationship between sleep quality and crew work performance. Variables moderating this relationship, such as leadership are of interest. MATERIALS AND METHODS: The present paper investigates how sailors' daily variations in sleep quality influence self-rated naval work-performance and interacts with perceived daily transformational leadership during a 30-day naval training mission. RESULTS: Using multi-level analysis, we found significant positive main effects of sleep quality and transformational leadership on naval work performance. Transformational leadership moderated the sleep quality-work performance link. Individuals who experienced higher levels of leadership were less prone to reductions in performance after poor sleep. CONCLUSIONS: Overall, the results suggest that leadership can partly negate some of the reduction in performance that often accompanies poor sleep, and that leadership becomes more important as the crew becomes sleepier.

Trust After Just 45 Seconds? An Experimental Vignette Study of How Leader Behavior and Emotional States Influence Immediate Trust in Strangers.

Many critical and unexpected situations are handled by people that have never met. In the literature, development of immediate trust has been identified as a prerequisite for such temporary groups and leadership to function well. Limited experimental research has studied what leadership stimulates immediate trust between strangers. The present study investigate how four leadership styles, combining autocratic or democratic leadership behavior with low or high emotional stability, is related to immediate trust in a leader displayed through a 45-s video vignette of a car accident. A sample of 280 adults, randomly assigned to one of four conditions (1, autocratic/stable; 2, autocratic/unstable; 3, democratic/stable; 4, democratic/unstable) rated immediate trust after watching the vignette. The results show that autocratic and emotionally stable leaders were on average rated higher on immediate trust than all other leadership styles, after controlling for generalized trust.