IL-4Rα Blockade by Dupilumab Decreases Staphylococcus aureus Colonization and Increases Microbial Diversity in Atopic Dermatitis.

Dupilumab is a fully human antibody to interleukin-4 receptor α that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor α inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus

IL-4R alpha blockade by dupilumab decreases Staphylococcus aureus colonization and increases microbial diversity in atopic dermatitis

Dupilumab is a fully human antibody to interleukin-4 receptor alpha that improves the signs and symptoms of moderate to severe atopic dermatitis (AD). To determine the effects of dupilumab on Staphylococcus aureus colonization and microbial diversity on the skin, bacterial DNA was analyzed from swabs collected from lesional and nonlesional skin in a double-blind, placebo-controlled study of 54 patients with moderate to severe AD randomized (1:1) and treated with either dupilumab (200 mg weekly) or placebo for 16 weeks. Microbial diversity and relative abundance of Staphylococcus were assessed by DNA sequencing of 16S ribosomal RNA, and absolute S. aureus abundance was measured by quantitative PCR. Before treatment, lesional skin had lower microbial diversity and higher overall abundance of S. aureus than nonlesional skin. During dupilumab treatment, microbial diversity increased and the abundance of S. aureus decreased. Pronounced changes were seen in nonlesional and lesional skin. Decreased S. aureus abundance during dupilumab treatment correlated with clinical improvement of AD and biomarkers of type 2 immunity. We conclude that clinical improvement of AD that is mediated by interleukin-4 receptor alpha inhibition and the subsequent suppression of type 2 inflammation is correlated with increased microbial diversity and reduced abundance of S. aureus

The best time to acquire new skills: age-related differences in implicit sequence learning across the human lifespan

Implicit skill learning underlies obtaining not only motor, but also cognitive and social skills through the life of an individual. Yet, the ontogenetic changes in humans’ implicit learning abilities have not yet been characterized, and, thus, their role in acquiring new knowledge efficiently during development is unknown. We investigated such learning across the life span, between 4-85 years of age with an implicit probabilistic sequence learning task, and we found that the difference in implicitly learning high vs. low probability events - measured by raw reaction time (RT) - exhibited a rapid decrement around age of 12. Accuracy and z-transformed data showed partially different developmental curves suggesting a re-evaluation of analysis methods in developmental research. The decrement in raw RT differences supports an extension of the traditional 2-stage lifespan skill acquisition model: in addition to a decline above the age 60 reported in earlier studies, sensitivity to raw probabilities and, therefore, acquiring new skills is significantly more effective until early adolescence than later in life. These results suggest that due to developmental changes in early adolescence, implicit skill learning processes undergo a marked shift in weighting raw probabilities vs. more complex interpretations of events, which, with appropriate timing, prove to be an optimal strategy for human skill learning

Model averaging, optimal inference, and habit formation

Postulating that the brain performs approximate Bayesian inference generates principled and empirically testable models of neuronal function-the subject of much current interest in neuroscience and related disciplines. Current formulations address inference and learning under some assumed and particular model. In reality, organisms are often faced with an additional challenge-that of determining which model or models of their environment are the best for guiding behavior. Bayesian model averaging-which says that an agent should weight the predictions of different models according to their evidence-provides a principled way to solve this problem. Importantly, because model evidence is determined by both the accuracy and complexity of the model, optimal inference requires that these be traded off against one another. This means an agent's behavior should show an equivalent balance. We hypothesize that Bayesian model averaging plays an important role in cognition, given that it is both optimal and realizable within a plausible neuronal architecture. We outline model averaging and how it might be implemented, and then explore a number of implications for brain and behavior. In particular, we propose that model averaging can explain a number of apparently suboptimal phenomena within the framework of approximate (bounded) Bayesian inference, focusing particularly upon the relationship between goal-directed and habitual behavior

The role of complex cues in social and reproductive plasticity

Phenotypic plasticity can be a key determinant of fitness. The degree to which the expression of plasticity is adaptive relies upon the accuracy with which information about the state of the environment is integrated. This step might be particularly beneficial when environments, e.g. the social and sexual context, change rapidly. Fluctuating temporal dynamics could increase the difficulty of determining the appropriate level of expression of a plastic response. In this review, we suggest that new insights into plastic responses to the social and sexual environment (social and reproductive plasticity) may be gained by examining the role of complex cues (those comprising multiple, distinct sensory components). Such cues can enable individuals to more accurately monitor their environment in order to respond adaptively to it across the whole life course. We briefly review the hypotheses for the evolution of complex cues and then adapt these ideas to the context of social and sexual plasticity. We propose that the ability to perceive complex cues can facilitate plasticity, increase the associated fitness benefits and decrease the risk of costly ‘mismatches’ between phenotype and environment by (i) increasing the robustness of information gained from highly variable environments, (ii) fine-tuning responses by using multiple strands of information and (iii) reducing time lags in adaptive responses. We conclude by outlining areas for future research that will help to determine the interplay between complex cues and plasticity

From Craft to Nature: The Emergence of Natural Teleology

A teleological explanation is an explanation in terms of an end or a purpose. So saying that ‘X came about for the sake of Y’ is a teleological account of X. It is a striking feature of ancient Greek philosophy that many thinkers accepted that the world should be explained in this way. However, before Aristotle, teleological explanations of the cosmos were generally based on the idea that it had been created by a divine intelligence. If an intelligent power made the world, then it makes sense that it did so with a purpose in mind, so grasping this purpose will help us understand the world. This is the pattern of teleological explanation that we find in the Presocratics and in Plato. However, with Aristotle teleology underwent a change: instead of thinking that the ends were explanatory because a mind had sought to bring them about, Aristotle took the ends to operate in natural beings independently of the efforts of any creative intelligence. Indeed, he thought that his predecessors had failed to understand what was distinctive of nature, namely, that its ends work from the inside of natural beings themselves

Aristotle on the Matter for Birth, Life, and the Elements

This essay considers three case studies of Aristotle’s use of matter, drawn from three different scientific contexts: menstrual fluid as the matter of animal generation in the Generation of Animals, the living body as matter of an organism in Aristotle’s On the Soul (De Anima), and the matter of elemental transformation in Generation and Corruption. I argue that Aristotle conceives of matter differently in these treatises (1) because of the different sorts of changes under consideration, and (2) because sometimes he is considering the matter for one specific change, and sometimes the matter for all of a thing’s natural changes. My account allows me to explain some of the strange features that Aristotle ascribes to the matter for elemental transformation in Generation and Corruption II. These features were interpreted by later commentators as general features of all matter. I argue that they are a result of the specific way that Aristotle thinks about the transmutation of the elements