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Keller, R.

Publications and source records attributed to Keller, R..

11 recordsLinked to original sources

Intrinsic Goals for Autonomous Agents: Hierarchical Exploration Captures Future Volitional Action in Drosophila

Animals have a remarkable ability to act autonomously---driven by intrinsic motivation---without external sensory cues or extrinsic objectives, yet the computational mechanisms behind this ability largely remain a mystery. To understand how biological autonomy may emerge from optimizing intrinsic goals, we use recent whole-brain recordings in the fruit fly (\textit{Drosophila melanogaster}) that identify neural representations of spontaneous exploratory decisions more than $10$ seconds in advance. Combined with a neuromechanical digital twin of \textit{Drosophila}, these recordings allow us to test whether intrinsically motivated artificial agents with realistic embodiments quantitatively match fly behavior and internal representations of future volitional action during exploration. We implement a hierarchical, intrinsically motivated agent whose policy operates over a discrete library of motor primitives---fixed low-level controllers that actuate joint dynamics---closely matching ethological theories of behavioral syllables. We train agents with no external reward using $20$ intrinsic motivation algorithms spanning curiosity, entropy, and competency methods. We evaluate frozen policies in a virtual tethered-ball assay modeled after the fruit-fly experiment, allowing us to compare spontaneous locomotor statistics and internal representations and decode future turn direction from both kinematics and neural activations on the same timescales observed in flies. We find that DIAYN---a hierarchical competency algorithm that learns a discrete set of policies maximizing behavioral entropy and the separability of their induced sensory observations---achieves the strongest joint behavioral and neural prospective coding performance with the fruit fly. Surprisingly, DIAYN's learned policies closely capture individual variability in fly exploration strategies, suggesting that this behavioral diversity optimizes a concrete computational goal of maximizing state-space coverage at the \emph{population} level. Furthermore, DIAYN agents' latent activity closely captures the specific sum-difference rule in interhemispheric encoding of future kinematics in biological flies. Together, these results establish hierarchical, intrinsically motivated agents as a powerful framework for reverse-engineering animal autonomy.

neuroscience↗

Visual uncertainty and task demands shape active sensing strategies in mice

In natural environments, animals actively sample visual information to guide behavior. Sensory feedback is dynamic and often requires active movements, whether saccading across the lines of this page or walking through a park. From high-acuity vision in hawks to low-acuity mice, many animals actively navigate to seek information, which can be called infotaxis. Although mice have relatively low-acuity vision, they still rely on sight for critical behaviors including navigation and prey capture. Yet, how sensitive they are to visual information and performing infotaxis has not been established. Here, we develop a virtual reality object discrimination task to investigate visual decision-making under naturalistic conditions. We show that mice perform infotaxis by actively seeking out informative views to guide their choices. Stimulus manipulations confirm that this strategy is modulated by the amount of available visual information. These results reveal that mice use principled active strategies to resolve visual uncertainty, highlighting a key role for information-seeking in natural vision. HighlightsO_LIMice perform active visual sensing in a free-range VR object discrimination task. C_LIO_LIThey perform infotaxis and select the correct object under variable visibility. C_LIO_LIDecisions decoded from head-body movements and speed reflect occlusion sensitivity. C_LI

neuroscience↗

US6 hijacks the peptide-loading complex by trapping transporter-chaperone dynamics

Adaptive immune responses are initiated by major histocompatibility class I (MHC I) presentation of antigenic peptides on the cell surface. This process relies on the peptide-loading complex (PLC), a dynamic transporter-multichaperone assembly in the endoplasmic reticulum (ER), to ensure high-fidelity selection, editing, and loading of peptides onto MHC I heterodimers1. The PLC is the primary target for viral immune evasion2, elicited in particular by human cytomegalovirus (HCMV)3, causing lifelong infections with severe risks for immunocompromised individuals. While the overall architecture of the PLC is known4, how its activity is jeopardized by viral immune evasins remains unclear. Here, we present the 2.59-2.88 [A] cryogenic electron microscopy structure of native human PLC associated with the HCMV immune evasin US6. US6 inhibits the heterodimeric transporter associated with antigen processing (TAP1/2) by latching its transmembrane helix laterally onto TAP2 and using its central disulfide-rich domain to mimic a translocating peptide. This effectively plugs the ER-lumenal exit and locks TAP in an outward-facing open conformation with closed nucleotide-binding domains and asymmetrically occluded ATP and ADP. The structure also highlights the role of the unique N-terminal transmembrane domains of TAP as dynamic scaffolds that recruit the MHC I-specific chaperone tapasin by clamping its transmembrane helix to the core transmembrane domain of each transporter subunit. Our findings uncover the molecular mechanism of US6-mediated viral immune evasion and reveal potential targets for therapeutic modulation of antigen presentation in cancer and infectious diseases.

immunology↗

Plant host identity drives Andropogon gerardii rhizobiome assembly strategies under increasing abiotic stress

Predicted changes in precipitation threaten tallgrass prairies by altering the soil microbial communities that are essential for plant resilience. Andropogon gerardii, a dominant grass in tallgrass prairies, spans the contiguous North American precipitation gradient. However, it remains unclear to what extent the rhizosphere microbiomes (rhizobiomes) are influenced by the plant-host environmental interaction. To assess how environmental and host factors shape the rhizobiome, we surveyed A. gerardii populations across 25 remnant prairie sites (June-August 2023) within its native range in the United States, characterizing the microbiomes in the rhizosphere and soils using 16S amplicon sequencing. We demonstrated that while geographic location largely structured both rhizosphere and soil communities, regional precipitation (60-day rainfall) emerged as a primary driver of the microbial community assembly. We observed distinct microbial divides across the dry and wet regions of the North American "arid-humid divide." Importantly, we found the first compelling large-scale evidence that regional precipitation has a profound influence on rhizobiome assembly. In the most arid regions, rhizosphere microbial communities exhibited significantly more predicted stochasticity than those in the local soil and contained taxa related to host-benefiting functions. Our study suggests that intensified host-driven selection for specific microbial variants occurs under heightened abiotic stress, highlighting the hosts pivotal role in shaping its rhizobiome composition in challenging environments.

microbiology↗

Flagellin in the human gut microbiome is a diet-adjustable adjuvant for vaccination

The intestinal microbiota is thought to modulate immune responsiveness to vaccines. Human studies on this topic, however, have yielded inconsistent results1,2. We hypothesized that the microbiome would influence innate immune responses, and thus vaccine reactogenicity, more directly than vaccine immunogenicity. To test this, we established the {micro}HEAT (Microbial-Human Ecology And Temperature) study, which longitudinally profiled the fecal microbiota, oral body temperature and serum antibody responses of 171 healthy adults (18-40 years old) before and after vaccination for SARS-CoV-2. Increased temperature after vaccination ({Delta}T) was associated with habitual diet and with baseline metabolic and immune markers. The microbiomes of {Delta}T-high ({Delta}Thi) participants were characterized by high expression of flagellin and an overabundance of the flagellated bacterium Waltera. Fecal samples from {Delta}Thi participants induced more inflammation in human cells and stronger post-vaccine temperature responses in mice compared to {Delta}Tlo samples, suggesting a causal role for the microbiome. Moreover, Waltera flagellin replicated the inflammatory phenotypes in vitro and was modulable via a dietary additive. Overall, these data suggest that flagellin from the gut microbiome stimulates innate immunity and vaccine reactogenicity, and that this axis can be manipulated via diet. These findings have implications for improving human vaccine tolerance and immunogenicity.

microbiology↗

Childhood cancer mutagenesis caused by a domesticated DNA transposase

Genomic rearrangements are a hallmark of most solid tumors, including medulloblastoma, one of the most common brain tumors in children. Childhood cancers involve dysregulated cell development, but their mutational causes remain largely unknown. One of the most common forms of medulloblastoma is caused by ectopic activation of Sonic Hedgehog (SHH) signaling in cerebellar granule cell progenitors, associated with genetic deletions, amplifications, and other oncogenic chromosomal rearrangements. Here, we show that PiggyBac Transposable Element Derived 5 (Pgbd5) promotes tumor development in multiple developmentally-accurate mouse models of SHH medulloblastoma. Most mice with Pgbd5 deficiency do not develop tumors, while Pgbd5-deficient mice maintain largely normal cerebellar development. Mouse medulloblastomas expressing Pgbd5 exhibit significantly increased numbers of somatic structural DNA rearrangements, with PGBD5-specific transposon sequences at their breakpoints. Similar sequence breakpoints recurrently affect somatic DNA rearrangements of known tumor suppressors and oncogenes in medulloblastomas in 329 children. Therefore, this study identifies PGBD5 as a primary medulloblastoma mutator and provides a genetic mechanism responsible for the generation of somatic oncogenic DNA rearrangements in childhood cancer. One-Sentence SummaryInduction of somatic oncogenic mutations by the DNA transposase PGBD5 in cerebellar progenitor cells promotes medulloblastoma development.

cancer biology↗

Drosophila functional screening of de novo variants in autism uncovers deleterious variants and facilitates discovery of rare neurodevelopmental diseases

Individuals with autism spectrum disorders (ASD) exhibit an increased burden of de novo variants in a broadening range of genes. We functionally tested the effects of ASD missense variants using Drosophila through humanization rescue and overexpression-based strategies. We studied 79 ASD variants in 74 genes identified in the Simons Simplex Collection and found 38% of them caused functional alterations. Moreover, we identified GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in eight previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes point to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.

genetics↗

Scribble mutation disrupts convergent extension and apical constriction during mammalian neural tube closure

Morphogenesis of the vertebrate neural tube occurs by elongation and bending of the neural plate, tissue shape changes that are driven at the cellular level by polarized cell intercalation and cell shape changes, notably apical constriction and cell wedging. Coordinated cell intercalation, apical constriction, and wedging undoubtedly require complex underlying cytoskeletal dynamics and remodeling of adhesions. Mutations of the gene encoding Scribble result in neural tube defects in mice, however the cellular and molecular mechanisms by which Scrib regulates neural cell behavior remain unknown. Analysis of Scribble mutants revealed defects in neural tissue shape changes, and live cell imaging of mouse embryos showed that the Scrib mutation results in defects in polarized cell intercalation, particularly in rosette resolution, and failure of both cell apical constriction and cell wedging. Scrib mutant embryos displayed aberrant expression of the junctional proteins ZO-1, Par3, Par6, E- and N-cadherins, and the cytoskeletal proteins actin and myosin. These findings show that Scribble has a central role in organizing the molecular complexes regulating the morphomechanical neural cell behaviors underlying vertebrate neurulation, and they advance our understanding of the molecular mechanisms involved in mammalian neural tube closure. HighlightsO_LIPolarized cell intercalation is lost in Scrib mutant embryos C_LIO_LIScrib mutation has specific effects on rosette formation and resolution C_LIO_LIScrib mutation disrupts apical constriction and cell shape changes necessary for neural tube closure C_LIO_LIAdherens and tight junction composition is altered in the neural epithelial cells of Scrib mutants C_LI

developmental biology↗

Evaluation of the Escherichia coli population in the intestinal microbiota of rattus wistar submitted to secondhand smoke and supplemented with prebiotics

Many chronic conditions, including smoking, have been shown to be associated with modifications in the gut microbiota and to remedy the effects of these changes, functional foods such as prebiotics have shown beneficial effects. The aim of this work was to evaluate changes in the bacterial population of Escherichia coli in the intestinal microbiota of rats submitted to passive smoke and to the supplementation of prebiotics incorporated into the basal diet. The animals were divided into: Control Group (CG) = basal diet; Smoking Control Group (GCT) = basal diet with exposure to smoking; Prebiotic Group (GP) = basal diet incorporated with 1g of Immunowall(R) per kg of diet; Prebiotic Tobacco Group (GPT) = basal diet incorporated with 1g of ImmunowallTM per kg of diet with exposure to smoking. The animals were exposed to the smoke twice a day for 180 days. The obtained data were analyzed through the nonparametric Kruklla-Wallis test. Bacterial populations were amplified by real-time PCR. The results of this study revealed a significant decrease (p = 0.04 and p = 0.01) in Escherichia coli population in the group of animals supplemented with prebiotics in the intestinal microbiota of rats exposed and not exposed to cigarette smoke reinforcing the modulating effect of potential pathogens on the intestinal microbiota by functional foods.

microbiology↗

Characterization of convergent thickening, a major convergence force producing morphogenic movement in amphibians

We characterize the morphogenic process of convergent thickening (CT), which occurs in the involuting marginal zone (IMZ) during gastrulation of Xenopus, the African clawed frog. CT was described previously as the tendency of explants of the ventral IMZ of Xenopus to converge their circumblastoporal dimension and thicken their radial dimension (Keller and Danilchik 1988). Here we show that CT occurs from the onset of gastrulation, initially throughout the pre-involution IMZ. We suggest that CT is driven by an increase in the interfacial tension between the deep IMZ and its epithelium, resulting in cells of the deep IMZ tending to minimize their surface area. In explants, this results in a progressive shortening (convergence) of the IMZ along its longer mediolateral axis and thickening in the orthogonal planes, and can generate tensile force (Shook et al. 2018). In vivo, convergence of the annular IMZ generates circumferential tension, closing the blastopore. These results provide the first clear example of a tensile morphogenic force from a Holtfreterian/Steinbergian change in tissue affinity.

developmental biology↗

Large, long range tensile forces drive convergence during Xenopus blastopore closure and body axis elongation

Indirect evidence suggests that blastopore closure during gastrulation of anamniotes, including amphibians such as Xenopus laevis, depends on circumblastoporal convergence forces generated by the marginal zone (MZ), but direct evidence is lacking. We show that explanted MZs generate tensile convergence forces up to 1.5 N during gastrulation and over 4 N thereafter. These forces are generated by convergent thickening (CT) until the midgastrula and increasingly by convergent extension (CE) thereafter. Explants from ventralized embryos, which lack tissues expressing CE but close their blastopores, produce up to 2 N of tensile force, showing that CT alone generates forces sufficient to close the blastopore. Uniaxial tensile stress relaxation assays show stiffening of mesodermal and ectodermal tissues around the onset of neurulation, potentially enhancing long-range transmission of convergence forces. These results illuminate the mechanobiology of early vertebrate morphogenic mechanisms, aid interpretation of phenotypes, and give insight into the evolution of blastopore closure mechanisms.

biophysics↗