Microbiome-derived bacterial lipids regulate gene expression of proinflammatory pathway inhibitors in systemic monocytes

How the microbiome regulates responses of systemic innate immune cells is unclear. In the present study, our purpose was to document a novel mechanism by which the microbiome mediates crosstalk with the systemic innate immune system. We have identified a family of microbiome Bacteroidota-derived lipopeptides—the serine-glycine (S/G) lipids, which are TLR2 ligands, access the systemic circulation, and regulate proinflammatory responses of splenic monocytes. To document the role of these lipids in regulating systemic immunity, we used oral gavage with an antibiotic to decrease the production of these lipids and administered exogenously purified lipids to increase the systemic level of these lipids. We found that decreasing systemic S/G lipids by decreasing microbiome Bacteroidota significantly enhanced splenic monocyte proinflammatory responses. Replenishing systemic levels of S/G lipids via exogenous administration returned splenic monocyte responses to control levels. Transcriptomic analysis demonstrated that S/G lipids regulate monocyte proinflammatory responses at the level of gene expression of a small set of upstream inhibitors of TLR and NF-κB pathways that include Trem2 and Irf4. Consistent with enhancement in proinflammatory cytokine responses, decreasing S/G lipids lowered gene expression of specific pathway inhibitors. Replenishing S/G lipids normalized gene expression of these inhibitors. In conclusion, our results suggest that microbiome-derived S/G lipids normally establish a level of buffered signaling activation necessary for well-regulated innate immune responses in systemic monocytes. By regulating gene expression of inflammatory pathway inhibitors such as Trem2, S/G lipids merit broader investigation into the potential dysfunction of other innate immune cells, such as microglia, in diseases such as Alzheimer’s disease

A Roadmap for Using the UN Decade of Ocean Science for Sustainable Development in Support of Science, Policy, and Action

The health of the ocean, central to human well-being, has now reached a critical point. Most fish stocks are overexploited, climate change and increased dissolved carbon dioxide are changing ocean chemistry and disrupting species throughout food webs, and the fundamental capacity of the ocean to regulate the climate has been altered. However, key technical, organizational, and conceptual scientific barriers have prevented the identification of policy levers for sustainability and transformative action. Here, we recommend key strategies to address these challenges, including (1) stronger integration of sciences and (2) ocean-observing systems, (3) improved science-policy interfaces, (4) new partnerships supported by (5) a new ocean-climate finance system, and (6) improved ocean literacy and education to modify social norms and behaviors. Adopting these strategies could help establish ocean science as a key foundation of broader sustainability transformations

Shifting goals : effects of active and observational experience on infants' understanding of higher order goals

This study was supported by grants to the first author from NICHD (R01 HD035707 & P01 HD064653).Action-perception links have been argued to support the emergence of action understanding, but their role in infants' perception of distal goals has not been fully investigated. The current experiments address this issue. During the development of means-end actions, infants shift their focus from the means of the action to the distal goal. In Experiment One, we evaluated whether this same shift in attention (from the means to the distal goal) when learning to produce multi-step actions is reflected in infants’ perception of others’ means-end actions. Eight-month-old infants underwent active training in means-end action production and their subsequent analysis of an observed means-end action was assessed in a visual habituation paradigm. Infants' degree of success in the training paradigm was related to their subsequent interpretation of the observed action as directed at the means versus the distal goal. In Experiment Two, observational and control manipulations provided evidence that these effects depended on the infants' active engagement in the means-end actions. These results suggest that the processes that give rise to means-end structure in infants' motor behavior also support the emergence of means-end structure in their analysis of others’ goals.PostprintPeer reviewe

Capturing Value in Pharmaceutical Distribution Strategies

Market Share in the pharmaceutical industry has been dominated by manufacturers that develop the most effective Go-To-Market Strategy. New promises in Cell & Gene Therapy and Personalized Healthcare Products open a wealth of opportunities for new market share in the Asian Pacific region, if manufacturers that can position their supply chain and associated partners effectively from the start. While previous supply chain strategies for pharmaceutical distribution have relied on a single large distributor to manage affiliate level in-country logistics, administration, & payment management services, alternative distribution strategies and partnership schemes may provide greater value to the overall healthcare ecosystem for patient-centric products. To perform a proper evaluation of the potential value a novel distribution strategy could deliver to the manufacturer, patients, and healthcare system, a Multi Attribute Value Analysis (MAVA) Model was created for two use case countries. The alternatives under consideration were a traditional distributor strategy, a switch to a multiple-partner strategy to handle different components of the CGT/PHC supply chain flows, and a switch to an in-house management strategy with the manufacturer handling the majority of the distribution roles. The criteria chosen for the MAVA model evaluation included financial, logistics, and patient factors that aimed to capture a holistic view of the distributor’s performance. Value functions mapping a criteria’s rating to a normalized score were determined, and weight importance assignment was elicited from key stakeholders. Upon generating data for the initial MAVA model run, the total value a distributor could provide was determined by the model. For the new personalized healthcare product segment, it was found the multi-partnership strategy provided the best overall value in both use cases countries (with a final score of , primarily due to better performance in critical Inventory Management and Patient Engagement KPIs. From this study, it is evident that considering the market structure and pharmaceutical regulations of individual countries helps pharmaceutical companies tailor supply chain strategies to each country’s context to maximize patient satisfaction, resource mobilization and cost optimization

Shifting goals:effects of active and observational experience on infants' understanding of higher order goals

Action-perception links have been argued to support the emergence of action understanding, but their role in infants' perception of distal goals has not been fully investigated. The current experiments address this issue. During the development of means-end actions, infants shift their focus from the means of the action to the distal goal. In Experiment One, we evaluated whether this same shift in attention (from the means to the distal goal) when learning to produce multi-step actions is reflected in infants’ perception of others’ means-end actions. Eight-month-old infants underwent active training in means-end action production and their subsequent analysis of an observed means-end action was assessed in a visual habituation paradigm. Infants' degree of success in the training paradigm was related to their subsequent interpretation of the observed action as directed at the means versus the distal goal. In Experiment Two, observational and control manipulations provided evidence that these effects depended on the infants' active engagement in the means-end actions. These results suggest that the processes that give rise to means-end structure in infants' motor behavior also support the emergence of means-end structure in their analysis of others’ goals. </p

Mathematical thinking in children with developmental language disorder: The roles of pattern skills and verbal working memory

Previous research suggests that children with language disorders often have difficulties in mathematical tasks. In the current study, we investigated two relevant factors - working memory and pattern skills - that may underlie children's poor mathematics performance. Children with developmental language disorder (DLD, n = 18, ages 6-13) and age-matched typically-developing children (n = 18) completed three math tasks that tapped calculation skill and knowledge of concepts. Children also completed a visual pattern extension task and a verbal working memory task. There were four key findings: (1) children with DLD exhibited poorer mathematical knowledge than typically-developing children, both in calculation and on key math concepts, (2) children with DLD performed similarly to typically-developing children on the visual pattern extension task, (3) children with DLD had lower verbal working memory scores than typically-developing children, and these differences in working memory accounted in part for their poorer calculation performance, and (4) children's pattern extension scores predicted their arithmetic calculation scores, but not their concept scores

Millennia-old coral holobiont DNA provides insight into future adaptive trajectories

Ancient DNA (aDNA) has been applied to evolutionary questions across a wide variety of taxa. Here, for the first time, we utilized aDNA from millennia-old fossil coral fragments to gain new insights into a rapidly declining western Atlantic reef ecosystem. We sampled four Acropora palmata fragments (dated 4215 BCE to 1099 CE) obtained from two Florida Keys reef cores. From these samples, we established that it is possible both to sequence aDNA from reef cores and place the data in the context of modern-day genetic variation. We recovered varying amounts of nuclear DNA exhibiting the characteristic signatures of aDNA from the A. palmata fragments. To describe the holobiont sensu lato, which plays a crucial role in reef health, we utilized metagenome-assembled genomes as a reference to identify a large additional proportion of ancient microbial DNA from the samples. The samples shared many common microbes with modern-day coral holobionts from the same region, suggesting remarkable holobiont stability over time. Despite efforts, we were unable to recover ancient Symbiodiniaceae reads from the samples. Comparing the ancient A. palmata data to whole-genome sequencing data from living acroporids, we found that while slightly distinct, ancient samples were most closely related to individuals of their own species. Together, these results provide a proof-of-principle showing that it is possible to carry out direct analysis of coral holobiont change over time, which lays a foundation for studying the impacts of environmental stress and evolutionary constraints.publishe