17 research outputs found

    TNF receptor agonists induce distinct receptor clusters to mediate differential agonistic activity

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    Monoclonal antibodies (mAb) and natural ligands targeting costimulatory tumor necrosis factor receptors (TNFR) exhibit a wide range of agonistic activities and antitumor responses. The mechanisms underlying these differential agonistic activities remain poorly understood. Here, we employ a panel of experimental and clinically-relevant molecules targeting human CD40, 4-1BB and OX40 to examine this issue. Confocal and STORM microscopy reveal that strongly agonistic reagents induce clusters characterized by small area and high receptor density. Using antibody pairs differing only in isotype we show that hIgG2 confers significantly more receptor clustering than hIgG1 across all three receptors, explaining its greater agonistic activity, with receptor clustering shielding the receptor-agonist complex from further molecular access. Nevertheless, discrete receptor clustering patterns are observed with different hIgG2 mAb, with a unique rod-shaped assembly observed with the most agonistic mAb. These findings dispel the notion that larger receptor clusters elicit greater agonism, and instead point to receptor density and subsequent super-structure as key determinants.</p

    Measuring Cognitive Abilities in the Wild: Validating a Population-Scale Game-Based Cognitive Assessment

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    Rapid individual cognitive phenotyping holds the potential to revolutionize domains as wide-ranging as personalized learning, employment practices, and precision psychiatry. Going beyond limitations imposed by traditional lab-based experiments, new efforts have been underway towards greater ecological validity and participant diversity to capture the full range of individual differences in cognitive abilities and behaviors across the general population. Building on this, we developed Skill Lab, a novel game-based tool that simultaneously assesses a broad suite of cognitive abilities while providing an engaging narrative. Skill Lab consists of six mini-games as well as 14 established cognitive ability tasks. Using a popular citizen science platform (N = 10725), we conducted a comprehensive validation in the wild of a game-based cognitive assessment suite. Based on the game and validation task data, we constructed reliable models to simultaneously predict eight cognitive abilities based on the users’ in-game behavior. Follow-up validation tests revealed that the models can discriminate nuances contained within each separate cognitive ability as well as capture a shared main factor of generalized cognitive ability. Our game-based measures are five times faster to complete than the equivalent task-based measures and replicate previous findings on the decline of certain cognitive abilities with age in our large cross-sectional population sample (N = 6369). Taken together, our results demonstrate the feasibility of rapid in-the-wild systematic assessment of cognitive abilities as a promising first step towards population-scale benchmarking and individualized mental health diagnostics

    Criticism of the paper “The association between early career informal mentorship in academic collaborations and junior author performance”

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    The authors of this letter represent a large student body who have generally had especially positive experiences with female mentors’ advice and mentorships and do not support the conclusions of the article “The association between early career informal mentorship in academic collaborations and junior author performance” because its conclusions regarding gender reach beyond the article’s scope and because the quality of mentorships cannot be analysed only through citation counts. Publications are not equivalent to learning outcomes or professional advancement. After careful review of the aforementioned article, we see numerous scientific flaws. The causal inferences that can be drawn from the observed effects of gender on the mentor-protégé relationship are insubstantial and other aspects of the paper are limited in the reductionist design of their mentor-protégé relationship assessment, which is based on the scientific impact of future papers

    A highly virulent variant of HIV-1 circulating in the Netherlands

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    We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV-CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences-is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence
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