Biology subjects

Palmer, J.

Publications and source records attributed to Palmer, J..

14 recordsLinked to original sources

bioRxiv2026

Molecular Origins of pH Gradients in Charge-Regulated Biomolecular Condensates

Biomolecular condensates exhibit spontaneous electrochemical microenvironments characterized by asymmetric ion distributions and pH gradients that emerge from protein-sequence-dependent charge regulation. Despite their biological importance, mechanistic understanding of these microenvironments has been constrained by the absence of computationally tractable frameworks capable of treating proton exchange, counterion partitioning, and buffer equilibria on consistent thermodynamic footing. Here, we introduce the buffered Charge-Regulation Monte Carlo (b-CR-MC) framework, which couples grand-canonical exchange of ions and buffer species with explicit charge regulation of titratable residues. By extending the CR-MC ion-merging strategy to multicomponent reservoirs and employing the Restricted Primitive Model, b-CR-MC achieves computational efficiency while maintaining thermodynamic rigor, with quantitative agreement to the more expensive generalized G-RxMC approach. Applied to full-length FUS (net positive) and PGL-3 (net negative) under physiological conditions, the framework reveals sequence-dependent pH gradients: the dense phase of FUS exhibits an alkaline shift, while PGL-3 exhibits an acidic shift, in both cases driving the condensate interior toward the proteins isoelectric point. Slab-geometry simulations further resolve the Donnan potential and continuous ion profiles across the condensate interface, confirming the direction and magnitude of these electrochemical shifts. Additionally, we identify spatially resolved buffer depletion within dense phases, establishing that dynamic charge regulation is a primary determinant rather than a secondary correction to condensate electrochemistry. By establishing a sequence-resolved, thermodynamically consistent computational platform, b-CR-MC enables quantitative prediction of how mutations and post-translational modifications reprogram condensate microenvironments across biological and pathophysiological contexts.

biophysics↗

bioRxiv2026

Multimodal Hypersampling of the adult human heart resolves tissue-specific cell states and disease-associated variants

Cardiovascular diseases often arise in anatomically specialised regions of the heart that remain poorly represented in existing single-cell and spatial atlas references. Here we profiled 28 regions of the adult human heart from 36 donors, combining paired single-nucleus RNA and chromatin accessibility assays with spatial transcriptomics. The resulting atlas integrates 1,059,175 expression profiles and 452,614 chromatin accessibility profiles, and defines spatial niches across the heart. In cardiac valves, we identify a valve fibroblast-macrophage niche that is polarised to the non-fibrosa surface and expands with age. Aortic stenosis genetic risk was enriched in inflammatory regulatory programmes of the Valve Fibroblast Immune cell state. In pulmonary veins, we define PITX2+ Myocardial Sleeve Cells, a region-restricted cardiomyocyte population in which a fine-mapped 4q25 atrial fibrillation variant intersects a cell type-specific open chromatin region. In coronary arteries, we resolve a RUNX1-marked synthetic smooth muscle layer in the subintima that provides a molecular identity for diffuse intimal thickening, a constitutive feature of the healthy vessel wall and a substrate for atherosclerosis, and show by perturbation in human smooth muscle cells that RUNX1 promotes cell-cycle entry while restraining inflammatory cytokine gene expression. Finally, allele-specific accessibility together with deep learning models fine-tuned to predict regulatory activity from DNA sequence identify cell type-specific regulatory effects at GWAS loci for atrial fibrillation, coronary artery disease and calcific aortic valve stenosis, including a variant whose Valve Fibroblast-specific effect on the polyamine transporter ATP13A3 is opposite in direction to the effect seen in bulk-tissue eQTL references that lack valve cells. Together with these cardiac sequence models and CardioSleuth, an AI-powered exploration engine for cardiac regulatory effects, this atlas links cardiac anatomy, gene regulation and disease genetics at single-cell resolution. By placing genetic risk in its precise cellular and anatomical context, it provides a foundation for mechanistic disease understanding, cell-state-specific therapeutic target nomination, and improved interpretation of inherited cardiovascular risk to inform future therapy and management.

Cell Biology↗

bioRxiv2025

An Interactive Brain Atlas of Knowledge

Biomedical knowledge about the brain increases every day, with a rapidly growing number of scientific publications, datasets, and software tools. While this informational plethora is not merely comprehensible by human beings, recent developments in information science and computational linguistics aim to make this knowledge programmatically accessible by literature mining. However, integrating these semantic methods into neuroimaging standards remains insufficient, hindering researchers from unraveling their full potential. Therefore, we developed the semantic meta-analysis platform The Virtual Brain adapter of semantics (TVBase) that projects biomedical knowledge preserved in over 36 million scientific articles onto a 3D standardized brain. The literature-mining platform SCAIView was used to extract ontologically defined biomedical entities and their associations with brain anatomy from the PubMed database. By querying a specific concept, the association strength with each anatomical term was calculated using entropy. To project the data onto a standardized brain, we created a unique transformation matrix that links over 800 anatomical terms to voxel coordinates of a parcellated standard brain. This novel method of knowledge projection extracts region-specific information about biomedical concepts from the literature to support translational multi-scale approaches to computational neuroscience. The multi-purpose software framework TVBase is openly available as a Python library. It aims for hypothesis-free neuroimaging pattern interpretation, hypothesis generation, and applications in personalized medicine.

neuroscience↗

bioRxiv2024

Brain Structural Organization Revealed by Unbiased Cell-Type Distribution Clustering

Cell-type composition across brain regions is a critical structural factor shaping both local and long-range brain circuits. Here, we employed single-cell resolution imaging of the mouse brain, combined with computational analyses, to map the distribution of 30 cell classes and types defined by gene marker expression in Cre recombinase-based genetic mouse models. This approach generated a comprehensive atlas of cell type-specific densities across the male and female brain, revealing (1) surprisingly broad sex differences in cells tagged by developmental cell-type markers, (2) shared cell type composition signatures among functionally related brain structures, and (3) close associations not only between specific cell types but also discrete cell type densities and anatomical regions and subregions. In summary, despite the relatively broad cell type classification enabled by the Cre mouse models, our findings highlight intricate relationships between brain cell type distribution and anatomical organization, associating distinct local cell densities with region-specific brain functions.

neuroscience↗

bioRxiv2024

Multiomic analysis reveals developmental dynamics of the human heart in health and disease

Developmental dynamics involve the specification of diverse cell types and their spatial organization into multicellular niches. Here, we combine single-cell and spatial multiomics to define 19 distinct tissue niches in the developing heart, leading to the development of a context-aware, resolution-agnostic niche classification tool (TissueTypist). Applying high-resolution spatial profiling to the developing sinoatrial node, we resolve three pacemaker cell subtypes arrayed along a linear axis. First trimester subpopulations, such as the pacemaker cells in the sinus horn and sinoatrial node head region, display neuro-attractant programmes and interact with parasympathetic neurons via interactions including Semaphorin-Plexin signalling. Temporal trajectories map maturation of atrial and ventricular cardiomyocytes, uncovering a lipid-metabolic switch and potential key regulators of cell type identity. In the ventricle, we identify cellular and transcriptional gradients along both pseudotime and transmural axes, offering new molecular insights into myocardial compaction and maturation. Comparative profiling of euploid and trisomy 21 hearts shows a depletion of compact cardiomyocytes and heightened apoptosis, validated in isogenic-matched trisomy 21 and euploid iPSC-derived cardiomyocytes. This implicates disrupted myocardial growth may be a mechanism for Downs syndrome-associated congenital heart disease. Overall, we deliver a spatially resolved framework of human cardiac development, enabling systematic exploration of developmental niches in health and disease.

developmental biology↗

bioRxiv2023

Within-host rates of insertion and deletion in the HIV-1 surface envelope glycoprotein

Under selection by neutralizing antibodies, the HIV-1 envelope glycoprotein gp120 undergoes rapid evolution within hosts, particularly in regions encoding the five variable loops (V1-V5). Indel polymorphisms are abundant in these loops, where they can facilitate immune escape by modifying the length, composition and glycosylation profile of these structures. Here, we present a comparative analysis of within-host indel rates and characteristics within the variable regions of gp120. We analyzed a total of 3,437 HIV-1 gp120 sequences sampled longitudinally from 29 different individuals using coalescent models in BEAST. Next, we used Historian to reconstruct ancestral sequences from the resulting tree samples, and fit a Poisson generalized linear model to the distribution of indel events to estimate their rates in the five variable loops. Overall, the mean insertion and deletion rates were 1.6 x 10-3 and 2.5 x 10-3/ nt / year, respectively, with significant variation among loops. Insertions and deletions also followed similar length distributions, except for significantly longer indels in V1 and V4 and shorter indels in V5. Insertions in V1, V2, and V4 tended to create new N-linked glycosylation sites significantly more often than expected by chance, which is consistent with positive selection to alter glycosylation patterns.

evolutionary biology↗

bioRxiv2023

High-throughput confocal airy beam oblique light-sheet tomography of brain-wide imaging at single-cell resolution

Brain research is an area of research characterized by its cutting-edge nature, with brain mapping constituting a crucial aspect of this field. As sequencing tools have played a crucial role in gene sequencing, brain mapping largely depends on automated, high-throughput and high-resolution imaging techniques. Over the years, the demand for high-throughput imaging has scaled exponentially with the rapid development of microscopic brain mapping. In this paper, we introduce the novel concept of confocal Airy beam into oblique light-sheet tomography named CAB-OLST. We demonstrate that this technique enables the high throughput of brain-wide imaging of long-distance axon projection for the entire mouse brain at a resolution of 0.26 m x 0.26 m x 1.06 m in 58 hours. This technique represents an innovative contribution to the field of brain research by setting a new standard for high-throughput imaging techniques.

neuroscience↗

bioRxiv2022

Honeybees vary collective decision making across landscapes

Honeybee (Apis mellifera) colony foraging decisions arise from the waggle dances of individual foragers, processed and filtered through a series of feedback loops that produce emergent collective behaviour. This process is an example of animal communication at the height of eusociality, yet a growing body of evidence suggests that its value for colony foraging success is heavily dependent on local ecology. Although colonies are thought to vary their use of the waggle dance in response to local ecological conditions, this is yet to be empirically established. Here, we quantify waggle dance use based on colony level dance-decoding and show that the impact of dance use on collective foraging is clear in some colonies but nearly negligible in others. We outline how these estimates of dance use can be combined with land-use data to explore the landscape characteristics that drive collective foraging. Our methodology provides a means to quantify the real-world importance of a celebrated example of animal communication and opens the door to the exploration of the selection pressures that may have driven the evolution of this remarkable collective behaviour.

animal behavior and cognition↗

bioRxiv2021

Cerebrovascular response to exercise interacts with individual genotype and amyloid-beta deposition to influence response inhibition with aging

The etiology of cognitive dysfunction associated with Alzheimers disease (AD) and dementia is multifactorial. Yet, mechanistic interactions among key neurobiological factors linked to AD pathology are unclear. This study tested the effect of interactions between cerebrovascular function, individual genotype, and structural brain pathology on response inhibition performance, an early and sensitive indicator of cognitive executive dysfunction with aging. We quantified cerebrovascular response (CVR) to moderate-intensity aerobic exercise using transcranial doppler ultrasound and global amyloid-beta (A{beta}) deposition using positron emission tomography in a group of cognitively normal older adults genotyped as APOE4 carriers and noncarriers. We quantified response inhibition during a cognitive Stroop test. Individuals with blunted CVR possessed greater A{beta} deposition. There was CVR-by-carrier status-by-A{beta} interaction on response inhibition. Blunted CVR was associated with impaired response inhibition specifically in carriers. Despite having greater A{beta} deposition, carriers with higher CVR demonstrated better response inhibition. Cerebrovascular interactions with individual genotype and structural brain pathology may provide a physiologically-informed target for precision-medicine approaches for early treatment and prevention of cognitive dysfunction with aging. HighlightsO_LINeurobiological interactions between CVR, APOE genotype, and A{beta} are behaviorally significant. C_LIO_LIBlunted CVR to exercise is associated with impaired response inhibition specifically in APOE4 carriers. C_LIO_LIAPOE4 carriers with more robust CVR have higher response inhibition performance, despite having greater A{beta} deposition. C_LIO_LIAssessment of multifactorial neurobiological variables offers an early and sensitive biomarker of cognitive behavioral dysfunction with aging. C_LI

physiology↗

bioRxiv2021

Prefrontal-motor and somatosensory-motor cortical network interactions during reactive balance are associated with distinct aspects of balance behavior in older adults

Heightened reliance on the cerebral cortex for postural stability with aging is well-known, yet the cortical dynamics of balance control, particularly in relationship to balance function, is unclear. Here we aimed to investigate motor cortical activity in relationship to the level of balance challenge presented during reactive balance recovery, and identify circuit-specific interactions between motor cortex and prefrontal or somatosensory regions to metrics of balance function that predict fall risk. Using electroencephalography, we assessed motor cortical beta power, and beta coherence during balance reactions to perturbations in older adults. We found that individuals with greater somatosensory-motor beta coherence at baseline and lower beta power evoked over motor regions following perturbations demonstrated higher general clinical balance function. At the group-level, beta coherence between prefrontal-motor regions reduced during balance reactions. Older adults with the highest post-perturbation prefrontal-motor coherence showed greater cognitive dual-task interference and elicited stepping reactions at lower perturbation magnitudes. Our results support motor cortical beta activity as a potential biomarker for individual level of balance challenge and implicate prefrontal-and somatosensory-motor cortical networks in different aspects of balance control in older adults. Cortical network activity during balance may provide a neural target for precision-medicine efforts aimed at fall-prevention with aging.

neuroscience↗

bioRxiv2020

Divided Attention in Perception:A Unified Analysis of Dual-Task Deficits and Congruency Effects

How well can one perceive simultaneous stimuli at two widely spaced visual locations? Are the stimuli processed independently? If not, does the dependency affect perception, disrupt signals in later stages, or both? To address these questions, we measured effects of divided attention using a dual-task paradigm with stimuli presented in noise on either side of fixation. This paradigm was applied to detecting Gabor patches and to the semantic categorization of words. We measured dual-task deficits which are a decline in mean performance for a dual task compared to a single task. There was such a deficit for categorizing two words but relatively little deficit for detecting two Gabors. We also measured congruency effects which are when performance at one location depends on whether the stimulus at the other location requires the same response. There was such a congruency effect for detecting two Gabors but relatively little congruency effect for categorizing two words. Further experiments were consistent with the dual-task deficit in word categorization being perceptual, but the congruency effect in Gabor detection being due to later processes. Results of additional experiments showed that the congruency effect was consistent with either graded selection errors or with all-or-none selection followed by graded interactive processing. To answer our opening question: for Gabor detection, perceptual processes were largely independent but later processes caused congruency effects; for word categorization, perceptual processes had capacity limits but even in combination with later processes caused relatively little congruency effects. In summary, there was evidence for two different kinds of dependency. Such complementary dependencies are inconsistent with theories of divided attention that depend on a single dependency such as a single resource or single source of interactive processing.

neuroscience↗

bioRxiv2020

Set-size effects in change detection depend on failures of retrieval and/or comparison and not on perception, encoding or storage

Set-size effects in change detection is often used to investigate the capacity limits of dividing attention. Such capacity limits have been attributed to a variety of processes including perception, memory encoding, memory storage, memory retrieval, comparison and decision. In this study, we investigated the locus of the effect of increasing set size from 1 to 2. To measure purely attentional effects and not other phenomena such as crowding, a precue was used to manipulate relevant set size and keep the display constant across conditions. The task was to detect a change in the orientation of 1 or 2 Gabor patterns. The locus of the capacity limits was determined by varying when observers were cued to the only stimulus that was relevant. We began by measuring the baseline set-size effect in an initial experiment. In the next experiment, a 100% valid postcue was added to test for an effect of decision. This postcue did not change the set-size effects. In the critical experiments, a 100% valid cue was provided during the retention interval between displays, or only one stimulus was presented in the second display (local recognition). For both of these conditions, there was little or no set-size effect. This pattern of results was found for both hard-to-discriminate stimuli typical of perception experiments and easy-to-discriminate stimuli typical of memory experiments. These results are consistent with capacity limits in memory retrieval, and/or comparison. For these set sizes, the results are not consistent with capacity limits in perception, memory encoding or memory storage. Significance SectionThe change detection paradigm is often used to demonstrate effects of divided attention. But it is not clear whether these effects are due to perception, memory, or judgment and decision. In this article, we present new evidence that the divided attention effect in change detection is due to limits in memory retrieval or comparison processes. These results are not consistent with limits in perception, memory encoding or memory storage.

animal behavior and cognition↗

bioRxiv2018

Parallel spatial channels converge at a bottleneck in anterior word-selective cortex

In most environments, the visual system is confronted with many relevant objects simultaneously. That is especially true during reading. However, behavioral data demonstrate that a serial bottleneck prevents recognition of more than one word at a time. We used functional magnetic resonance imaging (fMRI) to investigate how parallel spatial channels of visual processing converge into a serial bottleneck for word recognition. Observers viewed pairs of words presented simultaneously. We found that retinotopic cortex processed the two words in parallel spatial channels, one in each contralateral hemisphere. Responses were higher for attended words than ignored words, but were not reduced when attention was divided, even though behavioral performance suffered greatly. We then analyzed two word-selective regions along the occipito-temporal sulcus (OTS) of both hemispheres (i.e., sub-regions of visual word form area, VWFA). Unlike retinotopic cortex, each word-selective region responded to words on both sides of fixation. Nonetheless, a single region in the left hemisphere (VWFA-1 in posterior OTS) contained spatial channels for both hemifields that were independently modulated by selective attention. Thus, the left posterior VWFA supports parallel processing of multiple words. In contrast, a more anterior word-selective region in the left hemisphere (VWFA-2 in mid-OTS) showed limited spatial and attentional selectivity, consistent with activity of a single channel. Therefore, the visual system can process two words in parallel up to a late stage in the ventral stream. The transition from two parallel channels to a single channel in more anterior regions is consistent with the observed bottleneck in behavior.

neuroscience↗

bioRxiv2018

Phylogenetic measures of indel rate variation among the HIV-1 group M subtypes

The transmission and pathogenesis of human immunodeficiency virus type 1 (HIV-1) is disproportionately influenced by evolution in the five variable regions of the virus surface envelope glycoprotein (gp120). Insertions and deletions (indels) are a significant source of evolutionary change in these regions. However, the influx of indels relative to nucleotide substitutions has not yet been quantified through a comparative analysis of HIV-1 sequence data. Here we develop and report results from a phylogenetic method to estimate indel rates for the gp120 variable regions across five major subtypes and two circulating recombinant forms (CRFs) of HIV-1 group M. We processed over 26,000 published HIV-1 gp120 sequences, from which we extracted 6,605 sequences for phylogenetic analysis. In brief, our method employs maximum likelihood to reconstruct phy-logenies scaled in time and fits a Poisson model to the observed distribution of indels between closely related pairs of sequences in the tree (cherries). The rate estimates ranged from 3.0 x 10-5 to 1.5 x 10-3 indels/nt/year and varied significantly among variable regions and subtypes. Indel rates were significantly lower in the region encoding variable loop V3, and also lower for HIV-1 subtype B relative to other subtypes. We also found that variable loops V1, V2 and V4 tended to accumulate significantly longer indels. Further, we observed that the nucleotide composition of indel sequences was significantly distinct from that of the flanking sequence in HIV-1 gp120. Indels affected potential N-linked glycosylation sites substantially more often in V1 and V2 than expected by chance, which is consistent with positive selection on glycosylation patterns within these regions of gp120. These results represent the first comprehensive measures of indel rates in HIV-1 gp120 across multiple subtypes and CRFs, and identifies novel and unexpected patterns for further research in the molecular evolution of HIV-1.

microbiology↗