Biology subjects

Palmer, S.

Publications and source records attributed to Palmer, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Goal directed closed-loop training of network bursts in cortical cultures produces improved performance and error correction over days

Dissociated neural cultures are living systems with no evolutionary history in their current form, which makes them a testbed for asking what goals neural tissue can learn to pursue once it is removed from its evolved body. It remains unclear which features of network activity such a culture can be trained to control, and whether that training is retained from one day to the next. We built an open-source closed-loop platform, the Holistic Agential Learning platform (HAL), that detects a network burst on a high-density microelectrode array, estimates its spatial origin in real time, and applies a minimal reinforcement rule. Here, a burst that originates off the goal side triggers global random stimulation that persists until the next burst. Over days of training, rat cortical cultures (n=10) increased the fraction of bursts that initiated on the goal side. This gain accrued between sessions, with little change within a session, a consolidation-like pattern that we interpret as a statement about timescale while the mechanism remains untested. The burst origin moved toward the goal side, while the burst peak and the repertoire of propagation directions were preserved. Trained cultures also recovered from incorrect states more reliably over days, while the rate at which they entered those states was unchanged, and this recovery effect was the most robust difference from unstimulated controls (n=6). Cultures that began on either side of chance converged to a similar level of performance. Damaged cultures (n=6) with comparable burst statistics showed neither the across-day gain nor the consolidation-like pattern. Training reweighted the activity patterns each culture already had, and we saw no new ones, which we read as a simple form of niche construction in which the tissue keeps a trace of its history that biases what it does next. These results identify burst initiation and error recovery as trainable variables in a novel living system, and they support training the tissue rather than engineering the machine.

bioengineering↗

bioRxiv2026

Bio-inspired chromatophore network model generates dynamic skin patterns akin to those observed in cephalopods

Cephalopod skin exhibits a wide range of dynamic visual displays, including traveling waves, light/dark flashes, and flickering, all generated by muscle-regulated expansion and retraction of pigment-filled elastic sacs known as chromatophores. While central neural control is essential for high-level body-wide pattern coordination, experimental evidence from excised and denervated skin reveals that intricate spatiotemporal patterns can also emerge spontaneously in the skin. This raises questions about the respective roles of central versus peripheral control. To determine the simplest control necessary to generate such patterns, we developed ChromatoNet, a biophysical model of chromatophore arrays that includes mechanical interactions on 1- and 2-dimensional lattices with the excitability properties of radial muscles. With minimal external input, our modified Morris--Lecar model reproduces a rich repertoire of skin dynamics, including spontaneous flickering as well as traveling and spiral waves. Both spontaneous and stimulus-evoked waves emerge at an intrinsic resonant frequency, determined by model parameters. Propagation speeds remain stable across conditions and are consistent with the range observed in denervated skin preparations. The model generates diverse output states in response to local couplings and the time-dependence and shape of the input stimulation, with little top-down direction. The results provide a proof-of-principle that chromatophore/muscle dynamics with minimal central neural driving can produce rich dynamic patterns.

neuroscience↗

bioRxiv2026

Large deletion variants in a Plasmodium falciparum ookinete protein gene and associations with different endemic populations and mosquito vectors

The Plasmodium falciparum PIMMS43 gene encodes an ookinete protein that is important for mosquito infection. Here, large indel variants within the coding sequence are identified, and frequencies in natural infections of humans and mosquitoes investigated. Comparing long-read genome sequences in a small panel of P. falciparum strains and related species revealed a 150 bp deletion in the central part of the gene in several strains including the standard 3D7 reference genome. Mapping of short-read genome sequence data from 524 P. falciparum infections from nine different countries to full-length PIMMS43 showed the 150 bp deletion and an alternative 90 bp deletion to be common structural variants. Across African populations, the 150 bp deletion had a mean allele frequency of 32%, and the 90 bp deletion a mean frequency of 12%, with significant geographical variation. Targeted genotyping of 30 oocysts from naturally infected mosquitoes in Tanzania by nested PCR showed overall deletion variant frequencies similar to those seen in human infections in the same country. Although sample size was limited, a difference in the variant frequencies in oocysts from Anopheles gambiae and Anopheles funestus suggests potential vector-specific selection. The findings highlight the importance of surveying structural genomic variation and its potential role in parasite adaptation. Data summaryThe long-read genome sequence data sources are listed in the Supplementary Information (Supplementary Table 1). The short-read genome sequence data from human infections were extracted as a selected subset of those in the Pf7 release of global data from the MalariaGEN Consortium as described in the Methods. The SNP and indel genotypes derived from each sample of parasites cultured in the laboratory and from natural mosquito infections are given in the Supplementary Information (Supplementary Tables 1 and 3, Supplementary Figure 1). Impact statementThis study identifies large indel polymorphisms in the malaria parasite transmission-stage gene PIMMS43, reflecting substantial structural variation previously overlooked by genome-wide SNP-focused analyses. Using long- and short-read genomic data across diverse samples followed by targeted genotyping, we show that deletion variants are frequent and geographically structured, with initial evidence consistent with potential vector-specific selection. This highlights the importance of incorporating structural variation into population genomic surveillance and studies of parasite adaptation.

genomics↗

bioRxiv2026

Optimality with room to vary: stiff and sloppy modes in a sensory population

Populations of sensory neurons are thought to be shaped by selective pressures for optimal information transmission, yet real neural circuits display substantial variability across stimulus repeats, across time, and between individuals. Reconciling this variability with normative theories requires understanding not only the optimal code, but also how performance changes under perturbations of that code. Here we analyze large-scale recordings from retinal ganglion cells responding to diverse naturalistic movies and spatial noise. We fit low-rank Ising models, recast as interpretable latent variable models, revealing that retinal population activity is well described by a small number of collective modes tightly coupled to the visual stimulus. The spatial receptive fields of the leading latent variables closely align with the principal components of masked natural images, consistent with efficient coding. Perturbation analyses based on the Hessian of the efficient coding objective show that this agreement is concentrated along stiff directions, where small deviations strongly degrade performance, whereas sloppy directions tolerate large variability. Across stimulus ensembles, the same stiff latent modes form a stable backbone of population interactions that generalizes between scenes and supports both efficient stimulus reconstruction and predictive coding of future inputs. These results show how sensitivity to perturbations structures sensory population codes, allowing normative optimality to coexist with rich variability.

neuroscience↗

bioRxiv2026

Phase-variable restriction modification systems dynamically regulate plasmid transmission in Neisseria gonorrhoeae

Horizontal gene transfer (HGT) in bacteria is shaped by restriction-modification systems (RMSs) that define genetic barriers between species and lineages. Neisseria gonorrhoeae harbours numerous RMS, most of which are part of its core genome. Here, we show that phase variation in these RMSs can limit interspecies and intraspecies plasmid exchange. While NlaIV likely influenced the acquisition of pConj from the meningococcus, phase variation of the NgoAV RMS produces epigenetically heterogeneous populations that present variable bottlenecks to within-species plasmid transmission, influencing the spread of anti-microbial-resistance plasmids, pConj and pbla. A LEAT sequence extends or retracts a molecular ruler within the HsdS specificity subunit, altering spacing of recognition motifs, while truncation of the protein leads to a switch from non-palindromic to palindromic recognition motifs. Thus, while the repertoire of gonococcal RMSs is largely conserved, phase-variation dynamically modulates gene flow, shaping plasmid transmission, and the evolution and spread of antimicrobial resistance.

microbiology↗

bioRxiv2025

The tuberculosis-associated microenvironment promotes HIV-1 persistence by impairing CD8+ T cell-mediated viral control

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the most common coinfection in people living with HIV-1 (PLWH). This coinfection is associated with accelerated HIV-1 disease progression and reduced survival. However, the immunological and virological mechanisms driving this progression are incompletely understood. To address this knowledge gap, using pleural effusion samples from PLWH and TB, we investigated the HIV-1 genetic landscape and the anti-HIV-1 immune response impacted by a TB-associated microenvironment. Our results revealed an enrichment of genetically intact HIV-1 and impaired CD8+ T cell-mediated antiviral response at the site of HIV-1/Mtb coinfection. These findings indicate that the TB-associated microenvironment promotes the persistence of cells infected with replication-competent HIV-1 by creating a niche of reduced antiviral immune pressure, potentially contributing to the worsened clinical outcomes observed in PLWH and TB.

immunology↗

bioRxiv2025

Discovering flexible codes for prediction across timescales in the retina

The retina must encode visual information in a way that supports fast, predictive behavior despite significant processing delays. How this encoding adapts in an ever-changing world, when the temporal statistics of visual input shift, remains an open question. Here we record from populations of retinal ganglion cells in the axolotl as they respond to a stochastic moving bar stimulus across five different temporal correlation scales. Using the information bottleneck (IB) framework, and treating the prediction horizon as a free parameter inferred from the data, we ask what timescale of future motion the retina is optimized to predict under each stimulus condition. We find that the retina adapts its predictive encoding to the changing stimulus statistics: as the time constant of the stimulus dynamics increases, the inferred prediction horizon lengthens. The population shifts toward encoding more velocity information, and motion anticipation grows, all the while maintaining near-optimal prediction efficiency. Population surprise, quantified through a Boltzmann machine model of the retinal response distribution, tracks stimulus surprise under the inferred optimal compression. This connects the retinas reversal response to efficient predictive encoding. These results show that retinal population codes flexibly adjust their predictive timescale to the temporal structure of their inputs. More broadly, they demonstrate that the IB framework can be used to discover, not just test for, computational objectives in sensory populations.

neuroscience↗

bioRxiv2025

The terrestrial-aquatic transition impacts endocranial shape in caniform carnivorans

Mammals exhibit remarkable diversity in brain size and morphology, shaped by numerous ecological radiations throughout the Cenozoic. Although previous studies have demonstrated the influence of phylogeny, allometry, and various ecological variables on endocranial morphology in certain mammalian lineages, the extent to which locomotor behaviour influences brain shape evolution remains unclear. The suborder Caniformia, or 'dog-like' carnivorans, is an ecologically diverse clade, containing terrestrial, arboreal, fossorial, and semiaquatic species, each facing a unique set of sensory and motor challenges. Here, we evaluate the impact of phylogeny, allometry, and locomotor mode on brain shape evolution in caniforms. We examine endocranial morphology in 73 species using high-density 3D geometric morphometrics, principal component analysis and phylogenetic comparative methods. Our findings indicate that the terrestrial-to-aquatic transition significantly impacts endocranial shape across caniforms, which is associated with maximum dive duration. This effect is more pronounced in pinnipeds than in other semiaquatic fissipeds, such as mustelids and ursids, likely due to their more derived ecology and greater commitment to aquatic life. Aquatic caniforms tend to exhibit expanded neocortices alongside reduced paleocortices and olfactory bulbs. These morphological changes likely reflect selection pressures acting on both the brain and the surrounding cranial architecture in aquatic environments.

evolutionary biology↗

bioRxiv2024

Watch-breaker: establishment of a microwell array-based miniaturized thymic organoid model suitable for high throughput applications.

T-cell development depends critically on the thymic stroma, in particular the diverse array of functionally distinct thymic epithelial cell (TEC) types. However, a robust in vitro thymus model mimicking the native thymus and compatible with medium/high-throughput analyses is currently lacking. Here, we demonstrate a novel high-density microwell array-based miniaturized thymus organoid (mTO) model, that supports T-cell commitment and development, possesses key organizational characteristics of the native thymus and is compatible with live-imaging and medium/high-throughput applications. We establish the minimum cellular input required for functional mTO and show that mTO TEC phenotype and complexity closely mirrors the native thymus. Finally, we use mTO to probe the role of fetal thymic mesenchyme, revealing a requirement beyond maintenance of Foxn1 in differentiation/maintenance of mature TEC subpopulations. Collectively, mTO present a new in vitro model of the native thymus adaptable to medium/high-throughput applications and validated for exploration of thymus- and thymus organoid-biology.

immunology↗

bioRxiv2023

The immunosuppressive Tuberculosis-associated microenvironment inhibits viral replication and promotes HIV-1 latency in CD4+ T cells

Author SummaryMycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the most common coinfection among people living with HIV-1. This coinfection alters the efficacy of the immune response against both HIV-1 and Mtb, and is associated with accelerated HIV-1 disease progression and reduced survival. Enhanced HIV-1 replication in macrophages induced by Mtb coinfection may contribute to the worsened clinical outcomes observed in HIV-1/TB coinfected individuals. However, the impact of the HIV-1/TB coinfection on HIV-1 replication and latency in CD4+ T cells remains poorly studied. In this study, we used the acellular fraction of tuberculous pleural effusion (TB-PE) as a proxy for the microenvironment generated by Mtb infection. Using this physiologically relevant fluid, we investigated whether viral replication and HIV-1 latency in CD4+ T cells are affected by a TB-associated microenvironment. Interestingly, our results revealed that TB-PE shaped the transcriptional profile of CD4+ T cells impairing T cell receptor-dependent cell activation and decreased HIV-1 replication. Moreover, this immunosuppressive TB microenvironment promoted viral latency and inhibited HIV-1 reactivation in CD4+ T cells from people living with HIV-1. This study indicates that the immune response induced by TB may contribute to the persistence of the viral reservoir by silencing HIV-1 expression in individuals coinfected with both pathogens, allowing the virus to persist undetected by the immune system and increasing the size of the HIV-1 latent reservoir in cells at the site of the coinfection.

pathology↗

bioRxiv2023

Stimulus invariant aspects of the retinal code drive discriminability of natural scenes

Everything that the brain sees must first be encoded by the retina, which maintains a reliable representation of the visual world in many different, complex natural scenes while also adapting to stimulus changes. This study quantifies whether and how the brain selectively encodes stimulus features about scene identity in complex naturalistic environments. While a wealth of previous work has dug into the static and dynamic features of the population code in retinal ganglion cells, less is known about how populations form both flexible and reliable encoding in natural moving scenes. We record from the larval salamander retina responding to five different natural movies, over many repeats, and use these data to characterize the population code in terms of single-cell fluctuations in rate and pairwise couplings between cells. Decomposing the population code into independent and cell-cell interactions reveals how broad scene structure is encoded in the retinal output. while the single-cell activity adapts to different stimuli, the population structure captured in the sparse, strong couplings is consistent across natural movies as well as synthetic stimuli. We show that these interactions contribute to encoding scene identity. We also demonstrate that this structure likely arises in part from shared bipolar cell input as well as from gap junctions between retinal ganglion cells and amacrine cells.

neuroscience↗

bioRxiv2023

ScopeViewer: A Browser-Based Solution for Visualizing Spatial Transcriptomics Data

MotivationSpatial transcriptomics (ST) enables a high-resolution interrogation of molecular characteristics within specific spatial contexts and tissue morphology. Despite its potential, visualization of ST data is a challenging task due to the complexities in handling, sharing and visualizing large image datasets together with molecular information. ResultsWe introduce ScopeViewer, a browser-based software designed to overcome these challenges. ScopeViewer offers the following functionalities: (1) It visualizes large image data and associated annotations at various zoom levels, allowing for intricate exploration of the data; (2) It enables dual interactive viewing of the original images along with their annotations, providing a comprehensive understanding of the context; (3) It displays spatial molecular features with optimized bandwidth, ensuring a smooth user experience; and (4) It bolsters data security by circumventing data transfers. AvailabilityScopeViewer is available at: https://datacommons.swmed.edu/scopeviewer ContactXiaowei.Zhan@UTSouthwestern.edu, Guanghua.Xiao@UTSouthwestern.edu Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2023

Thymic epithelial cell fate and potency in early organogenesis assessed by single cell transcriptional and functional analysis.

During development, cortical (c) and medullary (m) thymic epithelial cells (TEC) arise from the third pharyngeal pouch endoderm. Current models suggest that within the thymic primordium most TEC exist in a bipotent/common thymic epithelial progenitor cell (TEPC) state able to generate both cTEC and mTEC, at least until embryonic day 12.5 (E12.5) in the mouse. This view, however, is challenged by recent transcriptomics and genetic evidence. We therefore set out to investigate the fate and potency of TEC in the early thymus. Here using single cell (sc) RNAseq we identify a candidate mTEC progenitor population at E12.5, consistent with recent reports. Via lineage-tracing we demonstrate this population as mTEC fate-restricted, validating our bioinformatics prediction. Using potency analyses we also establish that most E11.5 and E12.5 progenitor TEC are cTEC- fated. Finally we show that overnight culture causes most if not all E12.5 cTEC-fated TEPC to acquire functional bipotency, and provide a likely molecular mechanism for this changed differentiation potential. Collectively, our data overturn the widely held view that a common TEPC predominates in the E12.5 thymus, showing instead that sublineage-primed progenitors are present from the earliest stages of thymus organogenesis but that these early fetal TEPC exhibit cell-fate plasticity in response to extrinsic factors. Our data provide a significant advance in the understanding of fetal thymic epithelial development and thus have implications for thymus-related clinical research, in particular research focussed on generating TEC from pluripotent stem cells.

developmental biology↗

bioRxiv2023

IsoAnalytics: A Single-cell Proteomics Web Server

MotivationSingle-cell proteomics provide unprecedented resolution to examine biological processes. Customized data analysis and facile data visualization are crucial for scientific discovery. Further, userfriendly data analysis and visualization software that is easily accessible for the general scientific community is essential. ResultsWe have created a web server, IsoAnalytics, that gives users without computational or bioinformatics background the ability to directly analyze and interactively visualize data obtained from the Isoplexis single cell technology platform. We envision this open-sourced web server will increase research productivity and serve as a free, competitive alternative for single-cell proteomics research. ContactAndrew.Koh@utsouthwestern.edu and Xiaowei.Zhan@utsouthwestern.edu AvailabilityIsoAnalytics is free and available at: https://cdc.biohpc.swmed.edu/isoplexis/ and is implemented in Python, with all major browsers supported. Code for IsoAnalytics is free and available at: https://github.com/zhanxw/Isoplexis_Data_Analysis. Supplementary InformationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2022

Learning low-dimensional generalizable naturalfeatures from retina using a U-net

Much of sensory neuroscience focuses on presenting stimuli that are chosen by the experimenter because they are parametric and easy to sample and are thought to be behaviorally relevant to the organism. However, it is not generally known what these relevant features are in complex, natural scenes. This work focuses on using the retinal encoding of natural movies to determine the presumably behaviorally-relevant features that the brain represents. It is prohibitive to parameterize a natural movie and its respective retinal encoding fully. We use time within a natural movie as a proxy for the whole suite of features evolving across the scene. We then use a task-agnostic deep architecture, an encoder-decoder, to model the retinal encoding process and characterize its representation of "time in the natural scene" in a compressed latent space. In our end-to-end training, an encoder learns a compressed latent representation from a large population of salamander retinal ganglion cells responding to natural movies, while a decoder samples from this compressed latent space to generate the appropriate future movie frame. By comparing latent representations of retinal activity from three movies, we find that the retina has a generalizable encoding for time in the natural scene: the precise, low-dimensional representation of time learned from one movie can be used to represent time in a different movie, with up to 17 ms resolution. We then show that static textures and velocity features of a natural movie are synergistic. The retina simultaneously encodes both to establishes a generalizable, low-dimensional representation of time in the natural scene.

neuroscience↗

bioRxiv2022

Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells

The network of thymic stromal cells provides essential niches with unique molecular cues controlling T-cell development and selection. Recent single-cell RNA-sequencing studies uncovered a large transcriptional heterogeneity among thymic epithelial cells (TEC) demonstrating a previously unappreciated complexity. However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here we deconvoluted by massively parallel flow cytometry and machine learning known and novel TEC phenotypes into novel subpopulations and related these by CITEseq to the corresponding TEC subtypes defined by the cells individual RNA profiles. This approach phenotypically identified perinatal cTEC, physically located these cells within the cortical stromal scaffold, displayed their dynamic change during the life course and revealed their exceptional efficiency in positively selecting immature thymocytes. Collectively, we have identified novel markers that allow for an unprecedented dissection of the thymus stromal complexity, the cells physical isolation and assignment of specific functions to individual TEC subpopulations.

immunology↗

bioRxiv2021

Dynamic evolution of MLKL in primate and poxvirus genomes indicates necroptosis is a critical, not auxiliary, countermeasure during infection

Pathogen infection triggers host innate defenses which can lead to the activation of regulated cell death (RCD) pathways such as apoptosis. Given a key role in immunity, apoptotic effectors are often counteracted by pathogen-encoded antagonists. Mounting evidence indicates that programmed necrosis, which is mediated by the RIPK3/MLKL axis and termed necroptosis, evolved as a countermeasure to pathogen-mediated inhibition of apoptotic signaling. However, whether this emerging inflammatory RCD pathway functions primarily as a "back-up" or fundamental response remains inconclusive. We hypothesized that if necroptosis is an instrumental defense, then its effectors should display specific signatures associated with pathogen conflict that are rare in combination: rapid evolution, viral homolog hereafter virolog, and induction by cytokines (e.g. interferons). Our rapid evolution analysis across the necroptosis pathway revealed: 1) strong signatures of positive selection for RIPK3 and MLKL in primate genomes and to a lesser extent DAI/ZBP1, 2) elevated rates of amino acid substitution on multiple surfaces including the RIPK3/MLKL binding interface and 3) evidence supporting a means of activating RIPK3 independent of homotypic RHIM domain interactions. Interestingly, a poxvirus MLKL homolog has recently been identified that acts as a RIPK3 pseudosubstrate. Our findings indicate that poxvirus MLKLs are also subject to similar but distinct volatile patterns of evolution comparable to host necroptotic factors. Specifically, viral MLKLs have undergone numerous gains and losses in poxvirus evolution with some species harboring three distinct copies. Furthermore, we confirm that MLKL can be induced by cytokines like interferon gamma. In summary, MLKL displays all three hallmarks of pivotal immune factors of which only OAS1, but not other factors like cGAS, APOBEC3G, or PKR, exhibits. These data support the hypothesis that over evolutionary time, necroptosis has served as a key battleground during infection and is therefore, not an auxiliary response. SummaryRegulated cell death (RCD), such as apoptosis, is a common host defense against invading pathogens. Necroptosis, an inflammatory RCD pathway, is thought to have emerged as an auxiliary response when other cell death pathways are suppressed by pathogens during infection. In our analyses, we have identified genetic changes in host and viral factors associated with necroptosis that display signatures of adaptation and may have served as evolutionary countermeasures to shape infection outcomes. Consistent with repeated targeting by pathogen-encoded inhibitors, we found robust signatures of rapid evolution for the essential catalysts of necroptosis, RIPK3 and MLKL. Notably, an evolutionary signature specific to RIPK3 for a domain shared with other necroptotic factors suggests an undefined means to trigger this host defense pathway. In contrast, poxviruses appear to circumvent this pathway by constantly altering the number and nature of factors they deploy to suppress necroptosis including a mimic of MLKL, which was stolen from infected cells. Collectively, our findings provide new insights into host and viral genetics that may influence infection outcomes and the factors shaping the ability of pathogens to infect and spread to new species. Furthermore, these data support the notion that necroptosis is a fundamental, not auxiliary, host response during infection.

evolutionary biology↗

bioRxiv2021

In-depth single-cell analysis of translation-competent HIV-1 reservoirs identifies cellular sources of plasma viremia

Clonal expansion of HIV-infected cells contributes to the long-term persistence of the HIV reservoir in ART-suppressed individuals. However, the contribution to plasma viremia from cell clones that harbor inducible proviruses is poorly understood. Here, we describe a single-cell approach to simultaneously sequence the TCR, integration sites and proviral genomes from translation-competent reservoir cells, called STIP-Seq. By applying this approach to blood samples from eight participants, we showed that the translation-competent reservoir mainly consists of proviruses with short deletions at the 5-end of the genome, often involving the major splice donor site. TCR and integration site sequencing revealed that antigen-responsive cells can harbor inducible proviruses integrated into cancer-related genes. Furthermore, we found several matches between proviruses retrieved with STIP-Seq and plasma viruses obtained during ART and upon treatment interruption, showing that STIP-Seq can capture clones that are responsible for low-level viremia or viral rebound.

microbiology↗