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Henderson, K.

Publications and source records attributed to Henderson, K..

12 recordsLinked to original sources

Dissociable effects of curiosity and hedonic valence on reinforcement learning

Curiosity and exploration support learning and adaptive decision-making in uncertain environments. While these processes are sensitive to motivational context, it remains unclear how outcome valence shapes exploration across species. Human studies suggest that aversive contexts increase exploration, but these effects often rely on verbal framing and explicit instructions. To gain deeper insight into how exploration strategies emerge from experience alone, this study investigated the influence of hedonic valence on novelty seeking, exploration, and reinforcement learning in rhesus macaques. Using visual tokens as secondary reinforcers, we found that monkeys explored novel, uncertain options more frequently when exploitation would lead to losses rather than gains. However, our analyses clarified that this heightened novelty seeking was primarily a consequence of the monkeys employing an optimistic prior belief about the value of novelty, rather than a categorical, valence-dependent shift in their underlying curiosity or the information bonus associated with exploration. Approach and avoidance motivation did influence other aspects of reinforcement learning. Monkeys demonstrated faster learning from losses than from gains, indicating that they were averse to losing tokens. They also frequently chose an option and then quickly aborted their choice. These choice balks were strategic responses to approach-avoidance conflicts and uncertainty, and represented self-generated bouts of exploratory behavior that led to valence-dependent use of directed and random exploration. These findings suggest that different strategies are used to manage explore-exploit tradeoffs induced by novelty or internal motivational conflicts, revealing dissociable effects of curiosity and hedonic valence on reinforcement learning.

animal behavior and cognition↗

KDM5 demethylases suppress R-loop-mediated viral mimicry and DNA damage in breast cancer cells

Tumors with low expression of Interferon-Stimulated Genes (ISG) and Antigen Presentation (AP) genes respond relatively poorly to current immunotherapies. One of the early hallmarks of cancer is DNA hypomethylation in genomic repeat regions, resulting in the expression of normally silenced endogenous "viral" elements. Such epigenetic changes have the potential to augment anti-tumor immune responses as well as reduce tumor cell fitness through the generation of aberrant nucleic acid species (NAS) and consequent activation of NAS-sensing pathways. Therefore, tumor evolution should favor additional selective events that suppress NAS generation, possibly yielding specific therapeutic vulnerabilities. Here, we show that the Lysine Demethylase 5 (KDM5) family of epigenetic regulatory enzymes suppress R-loop formation in genomic repeat regions in cancer cells. We find that KDM5 inhibition in luminal breast cancer cells results in R-loop-mediated DNA damage, reduced cell fitness and an increase in ISG and AP signatures as well as cell surface Major Histocompatibility Complex (MHC) class I, mediated by RNA:DNA hybrid activation of the CGAS/STING pathway. KDM5 inhibition does not result in DNA damage or activation of the CGAS/STING pathway in normal breast epithelial cells, suggesting that KDM5 inhibitors may enable a wide therapeutic window in this setting, as compared to STING agonists or Type I Interferons. These findings provide new insights into the interplay between epigenetic regulation of genomic repeats, R-loop formation, innate immunity, and cell fitness in the context of cancer evolution and therapeutic vulnerability.

cancer biology↗

Assessing the Biosecurity Risk of Footwear as a Fomite for Transmission of Adventitious Infectious Agents to Mice

The soles of staff shoes accessing vivaria can become contaminated on urban streets, potentially serving as a source of fomite-mediated transmission of adventitious agents to laboratory rodents. While shoe covers may mitigate this risk, donning them can lead to hand contamination. Staff accessing our vivaria use motor-driven shoe cleaners hundreds of times daily to remove and collect particulates via a vacuum collection system from the top, sole, and sides of shoes instead of shoe covers. Shoe cleaner debris (SCD) and contact media (CM) exposed to SCD from shoe cleaners in 5 vivaria were assessed by PCR for 84 adventitious agents. SCD and CM samples tested positive for 33 and 37 agents, respectively, and a combined 39 agents total. To assess SCD infectivity, NSG and Swiss outbred mice were housed for 7 days in direct contact with SCD and oronasally inoculated with a suspension created from SCD collected from each of the 5 vivaria. Mice were tested by PCR and serology 3-, 7-, 14- and 63-days post-inoculation. All mice remained healthy until the studys end and tested negative for all agents found in SCD/CM except murine astrovirus 1, Staphyloccocus xylosus and Candidatus Savagella, agents known to be enzootic in the experimental mouse source colony. In a follow-up study, the soles of 27 staff street shoes were directly sampled using CM. Half of CM was used for PCR, while the other half was added as bedding material to a cage containing NSG and Swiss outbred mice. While CM tested positive for 11 agents, all mice were healthy 63 days post-exposure and again positive for only enzootic agents. These results suggest that shoe debris might not be a significant biosecurity risk to laboratory mice, questioning the need for shoe covers or cleaners when entering experimental barrier vivaria.

microbiology↗

Transcriptomic diversity of amygdalar subdivisions across humans and nonhuman primates

The amygdaloid complex mediates learning, memory, and emotions. Understanding the cellular and anatomical features that are specialized in the amygdala of primates versus other vertebrates requires a systematic, anatomically-resolved molecular analysis of constituent cell populations. We analyzed five nuclear subdivisions of the primate amygdala with single-nucleus RNA sequencing in macaques, baboons, and humans to examine gene expression profiles for excitatory and inhibitory neurons and confirmed our results with single-molecule FISH analysis. We identified distinct subtypes of FOXP2+ interneurons in the intercalated cell masses and protein-kinase C-{delta} interneurons in the central nucleus. We also establish that glutamatergic, pyramidal-like neurons are transcriptionally specialized within the basal, lateral, or accessory basal nuclei. Understanding the molecular heterogeneity of anatomically-resolved amygdalar neuron types provides a cellular framework for improving existing models of how amygdalar neural circuits contribute to cognition and mental health in humans by using nonhuman primates as a translational bridge.

neuroscience↗

A split-GAL4 driver line resource for Drosophila CNS cell types

Techniques that enable precise manipulations of subsets of neurons in the fly central nervous system have greatly facilitated our understanding of the neural basis of behavior. Split-GAL4 driver lines allow specific targeting of cell types in Drosophila melanogaster and other species. We describe here a collection of 3060 lines targeting a range of cell types in the adult Drosophila central nervous system and 1373 lines characterized in third-instar larvae. These tools enable functional, transcriptomic, and proteomic studies based on precise anatomical targeting. NeuronBridge and other search tools relate light microscopy images of these split-GAL4 lines to connectomes reconstructed from electron microscopy images. The collections are the result of screening over 77,000 split hemidriver combinations. Previously published and new lines are included, all validated for driver expression and curated for optimal cell type specificity across diverse cell types. In addition to images and fly stocks for these well-characterized lines, we make available 300,000 new 3D images of other split-GAL4 lines.

neuroscience↗

Distinct Heterogeneity in the Naive T cell Compartments of Children and Adults

AbstractThe naive T cell compartment undergoes multiple changes across age that associate with altered susceptibility to infection and autoimmunity. In addition to the acquisition of naive-like memory T cell subsets, mouse studies describe substantial molecular reprogramming of the naive compartment in adults compared with adolescents. However, these alterations are not well delineated in human aging. Using a new trimodal single cell technology (TEA-seq), we discovered that the composition and transcriptional and epigenetic programming of the naive T cell compartment in children (11-13 yrs) is distinct from that of older adults (55-65 yrs). Naive CD4 T cells, previously considered relatively resistant to aging, exhibited far more pronounced molecular reprogramming than naive CD8 T cells, in which alterations are preferentially driven by shifts in naive-like memory subsets. These data reveal the complex nature of the naive T cell compartment that may contribute to differential immune responses across the spectrum of human age. One Sentence SummaryThe naive CD8 and CD4 T cell compartments in humans are heterogeneous and impacted differently with age, in which naive CD8 T cell subsets dramatically shift in composition and true naive CD4 T cells display significant molecular re-programming.

immunology↗

Habitat percolation transition undermines sustainability in social-ecological agricultural systems

Steady increases in human population size and resource consumption are driving rampant agricultural expansion and intensification. Habitat loss caused by agriculture puts the integrity of ecosystems at risk, and threatens the persistence of human societies that rely on ecosystem services. We develop a spatially explicit model describing the coupled dynamics of an agricultural landscape and human population size to study the effect of different land-use management strategies, defined by agricultural clustering and intensification, on the sustainability of the social-ecological system. We show how agricultural expansion can cause natural habitat to undergo a percolation transition leading to abrupt habitat fragmentation that feedbacks on humans decision making, aggravating landscape degradation. We found that agricultural intensification to spare land from conversion is a successful strategy only in highly natural landscapes, and that clustering agricultural land is the most effective measure to preserve large connected natural fragments, avoid severe fragmentation, and thus, enhance sustainability.

ecology↗

Multi-omic Single-cell Atlas Reveals Broad Ex Vivo Effects on Human Immunobiology

Multi-omic profiling of human peripheral blood is increasingly utilized to identify biomarkers and pathophysiologic mechanisms of disease. The importance of these platforms in clinical and translational studies led us to investigate the impact of delayed blood processing on the numbers and state of peripheral blood mononuclear cells (PBMC) and on the plasma proteome. Similar to previous studies, we show minimal effects of delayed processing on the numbers and general phenotype of PBMCs up to 18 hours. In contrast, profound changes in the single-cell transcriptome and composition of the plasma proteome become evident as early as 6 hours after blood draw. These reflect patterns of cellular activation across diverse cell types that lead to progressive distancing of the gene expression state and plasma proteome from native in vivo biology. Differences accumulating during an overnight rest (18 hours) could confound relevant biologic variance related to many underlying disease states.

immunology↗

Kinetic-Mechanistic Evidence for Which E. coli RNA Polymerase-{lambda}PR Open Promoter Complex Initiates and for Stepwise Disruption of Contacts in Bubble Collapse

In transcription initiation, specific contacts between RNA polymerase (RNAP) and promoter DNA are disrupted as the RNA-DNA hybrid advances into the cleft, resulting in escape of RNAP. From the pattern of large and small rate constants for steps of initiation at {lambda}PR promoter at 19{degrees}C, we proposed that in-cleft interactions are disrupted in extending 3-mer to 5-mer RNA, -10 interactions are disrupted in extending 6-mer to 9-mer, and -35 interactions are disrupted in extending 10-mer to 11-mer, allowing RNAP to escape. Here we test this mechanism and determine enthalpic and entropic activation barriers of all steps from kinetic measurements at 25{degrees}C and 37{degrees}C. Initiation at 37{degrees}C differs significantly from expectations based on lower-temperature results. At low concentration of the second iNTP (UTP), synthesis of full-length RNA at 37{degrees}C is slower than at 25{degrees}C and no transient short RNA intermediates are observed, indicating a UTP-dependent bottleneck step early in the 37{degrees}C mechanism. Analysis reveals that the 37{degrees}C {lambda}PR OC (RPO) cannot initiate and must change conformation to a less-stable initiation complex (IC) capable of binding the iNTP. We find that IC is the primary {lambda}PR OC species below 25{degrees}C, and therefore conclude that IC must be the I3 intermediate in RPO formation. Surprisingly, Arrhenius activation energy barriers to five steps where RNAP-promoter in-cleft and -10 contacts are disrupted are much smaller than for other steps, including a negative barrier for the last of these steps. We interpret these striking effects as enthalpically-favorable, entropically-unfavorable, stepwise bubble collapse accompanying disruption of RNAP contacts. SignificanceTranscription initiation is highly regulated. To understand regulation, mechanisms of initiation and escape of RNA polymerase (RNAP) from the promoter must be understood. RNAP forms a highly-stable open complex (RPO) with {lambda}PR promoter at 37{degrees}C. From experiments determining effects of temperature on rate constants for each step of RNA synthesis, we find that RPO cannot bind the initiating nucleotides, that the I3 intermediate and not RPO is the initiation complex, and that contacts of RNAP with single-stranded DNA of the discriminator and -10 region and with -35 duplex DNA are disrupted stepwise as the RNA-DNA hybrid moves into the cleft. Evidence is obtained for stepwise bubble collapse and base stacking accompanying disruption of interactions of the single-stranded discriminator and -10 regions with RNAP.

biochemistry↗

Unequal access to resources undermines global sustainability

We are a global society with various land use patterns, inequality, and the movement of people and goods. The various practices and behaviours associated with our current society raise questions about the future sustainability of the human population and the natural environment. We derive a model of a global socio-ecological system to explore the connections between human well-being and land resources, specifically looking at resource accessibility, conservation initiatives and human migration between two economically diverse regions. We find that the spatial aspect of a global system with two distinct regions, allows for faster development of technology, higher peaks in population size, greater natural land degradation, and generally speaking lower population well-being in the long-term. The unequal access to resources and differences in technological progress, alter the outcome of land management (i.e., conservation) and social behaviours (i.e., migration). We conclude that any socio-ecological management practices should be conscientious of the diversity in land access, population size, population well-being and development within the global society, as the potential for unintended consequences is high. Inequality needs to be addressed to promote sustainability.

ecology↗

Agricultural land use and the sustainability of social-ecological systems

Agricultural land expansion and intensification, driven by human consumption of agricultural goods, are among the major threats to environmental degradation and biodiversity conservation. Land degradation can ultimately hamper agricultural production through a decrease in ecosystem services. Thus, designing viable land use strategies is a key sustainability challenge. We develop a model describing the coupled dynamics of human demography and landscape composition, while imposing a trade-off between agricultural expansion and intensification. We model land use strategies spanning from low-intensity agriculture and high land conversion rates per person to high-intensity agriculture and low land conversion rates per person; and explore their consequences on the long-term dynamics of the coupled human-land system. We seek to characterise the strategies viability in the long run; and understand the mechanisms that potentially lead to large-scale land degradation and population collapse due to resource scarcity. We show that the viability of land use strategies strongly depends on the lands intrinsic recovery rate. We also find that socio-ecological collapses occur when agricultural intensification is not accompanied by a sufficient decrease in land conversion. Based on these findings we stress the dangers of naive land use planning and the importance of precautionary behaviour for land use management.

ecology↗

Mechanobiological Conditioning of Mesenchymal Stem Cells Enhances Therapeutic Angiogenesis by Inducing a Hybrid Pericyte-Endothelial Phenotype

Stem cell therapies have great promise for revolutionizing treatments for cardiovascular disease and other disorders but have not yet achieved their potential due to poor efficacy and heterogeneity in patient response. Here, we used a novel high throughput screening system to optimize the conditioning of mesenchymal stem cells using a combinatorial set of biochemical factors, pharmacological inhibitors and biomechanical forces. Our studies revealed that a combination of specific kinase inhibitors and a complex mechanical strain waveform dramatically increased the population of mesenchymal stem cells that express markers for both pericytes and endothelial cells. These mechanically and pharmacologically conditioned mesenchymal stem cells had superior properties in enhancing endothelial tube formation, production of angiogenic growth factors and induction of angiogenesis following implantation. Overall, our work supports that combinatorial optimization of mechanical conditioning and pharmacological treatments can significantly enhance the regenerative properties of mesenchymal stem cells.

bioengineering↗