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Research policy observers are increasingly concerned about the potential impact of current academic working conditions on mental health, particularly in PhD students. The aim of the current study is threefold. First, we assess the prevalence of mental health problems in a representative sample of PhD students in Flanders, Belgium (N=3659). Second, we compare PhD students to three other samples: (1) highly educated in the general population (N=769); (2) highly educated employees (N=592); and (3) higher education students (N=333). Third, we assess those organizational factors relating to the role of PhD students that predict mental health status. Results based on 12 mental health symptoms (GHQ-12) showed that 32% of PhD students are at risk of having or developing a common psychiatric disorder, especially depression. This estimate was significantly higher than those obtained in the comparison groups. Organizational policies were significantly associated with the prevalence of mental health problems. Especially work-family interface, job demands and job control, the supervisor’s leadership style, team decision-making culture, and perception of a career outside academia are linked to mental health problems.

Agonists of Toll-like receptors (TLRs) are potent activators of the innate immune system and hold promise as vaccine adjuvant and for anticancer immunotherapy. Unfortunately, in soluble form they readily enter systemic circulation and cause systemic inflammatory toxicity. Here we demonstrate that by covalent ligation of a smallmolecule imidazoquinoline-based TLR7/8 agonist to 50-nm-sized degradable polymeric nanogels the potency of the agonist to activate TLR7/8 in in vitro cultured dendritic cells is largely retained. Importantly, imidazoquinoline-ligated nanogels focused the in vivo immune activation on the draining lymph nodes while dramatically reducing systemic inflammation. Mechanistic studies revealed a prevalent passive diffusion of the nanogels to the draining lymph node. Moreover, immunization studies in mice have shown that relative to soluble TLR7/8 agonist, imidazoquinoline-ligated nanogels induce superior antibody and T-cell responses against a tuberculosis antigen. This approach opens possibilities to enhance the therapeutic benefit of small-molecule TLR agonist for a variety of applications.nanotechnology | Toll-like receptor | dendritic cells | lymph node | vaccine A ctivation of the innate immune system crucially depends on the recognition of evolutionary conserved microbe-associated molecular patterns by host pattern recognition receptors (PRRs). Triggering of PRRs not only elicits a direct antimicrobial and inflammatory cascade but also activates the necessary antigen-presenting cells to subsequently prime antigen-specific T-and B-cell immune responses (1). Agonists of Toll-like receptors (TLRs) are among the most potent activators of the innate immune response identified to date and, thus, are under intensive investigation as adjuvants for vaccination (2) or as agents for anticancer immunotherapy (3). Especially promising in this context are agonists of the endosomal TLR7 and TLR8, which typically recognize singlestranded RNAs generated during viral infection (4) but can also be activated by synthetic small-molecule agonists (5). Molecular adjuvants (6, 7) that are agonists of TLR7/8 indeed activate a broad spectrum of antigen-presenting cells, both in mice (only TLR7) and humans, and typically induce high levels of type I IFN and IL-12, the most vital cytokines to drive the Th1 and cytotoxic T-cell responses required to combat intracellular infections and cancer (7,8).Due to their pharmacokinetic profile, most molecular adjuvants rapidly diffuse after administration and evoke systemic inflammatory responses that cause dose-limiting toxicity (9, 10). In the context of intratumoral administration, these dose-limiting toxicities prevent these compounds from reaching the necessary intratumoral concentration to yield real therapeutic benefit. In the context of vaccination, the rapid diffusion of molecular adjuvants dramatically lowers the ability of antigen and TLR agonist to reach the same antigen-presenting cells in the draining lymph node (DLN), which results in suboptimal immunity to the del...

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This study examines how and why entrepreneurial passion for founding changes over time. In particular, we propose that in the founding phase of a venture's lifecycle entrepreneurs' founding identity centrality will remain stable over time. We also propose, however, that in our sample and time period studied, entrepreneurs' intense positive feelings for founding will decrease over time. On the basis of theories of positive illusion, selfregulation and role theory, we further hypothesize that venture idea change, change in role ambiguity and entrepreneurs' feedback-seeking behaviour are factors that help explain the rate of change in entrepreneurs' intense positive feelings for founding. Using a three-wave longitudinal research design, we find that among a sample of 112 entrepreneurs' identity centrality does not change over time, whereas intense positive feelings for founding decrease over time. Moreover, the more entrepreneurs change their venture ideas, the weaker their decrease in intense positive feelings. Further, we show that entrepreneurs who frequently seek feedback suffer less from reduced positive feelings in response to higher increases in role ambiguity as compared to entrepreneurs who seek less feedback.

Although the Alternative Uses divergent thinking task has been widely used in psychometric and experimental studies of creativity, the cognitive processes underlying this task have not been examined in detail before the two studies are reported here. In Experiment 1, a verbal protocol analysis study of the Alternative Uses task was carried out with a Think aloud group (N=40) and a Silent control group (N=64). The groups did not differ in fluency or novelty of idea production indicating no verbal overshadowing. Analysis of protocols from the Think aloud group suggested that initial responses were based on a strategy of Retrieval from long-term memory of pre-known uses. Later responses tended to be based on a small number of other strategies: property-use generation, imagined Disassembly of the target object into components and scanning of Broad Use categories for possible uses of the target item. Novelty of uses was particularly associated with the Disassembly strategy. Experiment 2 (N=103) addressed the role of executive processes in generating new and previously known uses by examining individual differences in category fluency, letter fluency and divergent task performance. After completing the task, participants were asked to indicate which of their responses were new for them. It was predicted and found in regression analyses that letter fluency (an executively loading task) was related to production of 'new' uses and category fluency was related to production of 'old' uses but not vice versa.

To date, the mRNA delivery field has been heavily dominated by lipid-based systems. Reports on the use of nonlipid carriers for mRNA delivery in contrast are rare in the context of mRNA vaccination. This paper describes the potential of a cell-penetrating peptide containing the amphipathic RALA motif to deliver antigen-encoding mRNA to the immune system. RALA condenses mRNA into nanocomplexes that display acidic pH-dependent membrane disruptive properties. RALA mRNA nanocomplexes enable mRNA escape from endosomes and thereby allow expression of mRNA inside the dendritic cell cytosol. Strikingly, RALA mRNA nanocomplexes containing pseudouridine and 5-methylcytidine modified mRNA elicit potent cytolytic T cell responses against the antigenic mRNA cargo and show superior efficacy in doing so when compared to RALA mRNA nanocomplexes containing unmodified mRNA. RALA's unique sequence and structural organization are vital to act as mRNA vaccine vehicle, as arginine-rich peptide variants that lack the RALA motif show reduced mRNA complexation, impaired cellular uptake and lose the ability to transfect dendritic cells in vitro and to evoke T cell immunity in vivo.

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