Biology subjects

Berry, K.

Publications and source records attributed to Berry, K..

14 recordsLinked to original sources

bioRxiv2026

Blood-brain barrier dysfunction predicts cognitive trajectory after ischemic stroke

Ischemic stroke doubles the risk of dementia.1-4 Stroke severity and location affect cognition early,5,6 but late dementia risk is not related to infarct characteristics, nor is it reduced by preventing additional strokes,3,6,7 and its mechanism is unknown. We identified a plasma proteomic signature of chronic stroke that was consistent with blood-brain barrier (BBB) dysfunction, including a 58% decrease in plasma levels of platelet-derived growth factor B and downregulation of its pathway compared to healthy controls. During 2 years of follow-up, the stroke-specific proteome was accentuated in stroke survivors who subsequently declined in the processing speed/executive function cognitive domain. To test BBB function, we performed dynamic contrast-enhanced MRI 6-9 months after stroke in an additional cohort and found 1.7-fold higher whole brain BBB leakage compared to controls. Finally, we compared autopsy tissue from people with infarcts and dementia at death to those with infarcts and no dementia. Those who died with dementia had dramatic loss of vascular mural cell coverage compared to those without dementia (median 0.7% vs. 27%). Thus, our proteomic, functional, and structural data implicate chronic BBB dysfunction in cognitive decline late after stroke, revealing potential proteomic and imaging biomarkers and, importantly, a novel target for intervention.

neuroscience↗

bioRxiv2026

Morphoelectric Diversity and Specialization of Neuronal Cell Types in the Primate Striatum

The basal ganglia are evolutionary ancient subcortical nuclei that form interconnected loops with the neocortex and limbic system to regulate movement, learning, habit formation, emotion, and motivation. Their dysfunction contributes to major neurological and psychiatric disorders, yet most cellular-level insights derive from rodent studies, leaving knowledge gaps in humans and translationally relevant primate species. To address this, we generated multi-modal Patch-seq data linking transcriptomic identity with morphological and electrophysiological properties in macaque striatum, the input nucleus of the basal ganglia. We found underappreciated diversity among medium spiny neurons, including non-canonical types, and variation aligned with functional gradients. Interneurons also exhibited spatial variation and even greater morphoelectric diversity, highlighting their functional modularity. Despite broad evolutionary conservation, we identified primate-specific features and key differences from rodent striatal neurons. By integrating molecular classification with cellular properties that shape network function, our findings provide insights into the functional organization of the primate striatum.

neuroscience↗

bioRxiv2026

Latent cytomegalovirus disrupts NK cell responses to P. falciparum and impairs parasite control

BackgroundNK cells are major innate and adaptive responders to malaria, with multiple roles in protection. Function of NK cells is heterogeneous, underpinned by expression of a diversity of receptors. One driver of NK cell heterogeneity is latent CMV infection, which drives the expansion of memory-like NK cells. We have recently reported that latent CMV infection can negatively impact the adaptive immune response to malaria, but whether CMV-mediated changes to the NK cell compartment also impact innate responses to malaria is unknown. MethodsWe investigated the impact of latent CMV infection on NK cell response to the malaria parasite Plasmodium falciparum in vitro, and in CMV seronegative and seropositive individuals during controlled human malaria infection. We analysed NK cell activation, cytotoxicity and NK cell receptor expression. Additionally, we investigated the impact of CMV serostatus on cytokine production in response to TLR stimulation in the myeloid cell compartment. The impact of CMV and NK cell responses on parasite control and malaria symptoms was investigated. ResultsNK cells from CMV seropositive individuals had reduced responsiveness to P. falciparum parasites in vitro and had reduced activation during controlled human infection. Reduced activation was not restricted to NK subsets modulated by CMV but occurred across the entire NK cell compartment. Consistent with global NK cell attenuation, IL-12 production from myeloid cells, a response that supports NK cell activation on exposure to P. falciparum parasites, was lower in CMV infected individuals. Linking NK cell activation to clinical outcomes, NK cells expressing perforin were associated with parasite control in CMV seronegative individuals. ConclusionCMV infection modulates NK cell responses during malaria by disruption of IL-12, leading to reduced parasite control.

immunology↗

bioRxiv2026

Human Neocortical Glutamatergic Neurons Revealed Through Multimodal Profiling

The human neocortex underlies higher cognition and is the engine of complex thought. Yet our understanding of its neuronal diversity is limited by sparse access to tissue, inconsistent sampling across studies, and a lack of multiple modality data. Although single-cell transcriptomic taxonomies are an important framework for characterizing cell type diversity, transcriptomic information alone cannot reveal the cellular properties that define neuronal computations. To address this, we performed Patch-seq, a method for collecting Morphology, Electrophysiology, and Transcriptomic data from a single neuron. We focused on glutamatergic, neocortical, excitatory neurons, the principal long-range projecting neurons of the cortex, and systematically integrated their morphoelectric features with transcriptomic identity. In combination with spatial transcriptomic data, we interrogated 39 of 42 transcriptomically-defined neuron types with a layer-centric perspective. Morphoelectric properties, such as cortical depth, apical dendrite structure, and excitability clearly distinguish transcriptomic subclasses and support many finer transcriptomic types. Morphoelectric properties are influenced by spatial location in supragranular layers, while deeper layers exhibit greater heterogeneity. Cross-species comparisons reveal conserved subclass organization but pronounced differences in apical dendrite arborization between mouse and human, and surprising similarities between human and macaque. Together, these datasets provide a unified multimodal reference that advances our understanding of human cortical circuitry and establishes a foundation for experimental and computational studies of human brain function and disease.

neuroscience↗

bioRxiv2025

Specialization and adaptation in pollen sterol use by wild bees

O_LISterols are essential metabolites in eukaryots, acting as stabilizing components of membranes and steroid hormone precursors. Unlike other animals, insects cannot biosynthesise sterols de novo so must acquire them from diet. Honeybees selectively uptake a subset of pollen sterols for use in their own tissues, rather than converting b-sitosterol or stigmasterol to cholesterol, as occurs in most insect herbivores because they do not have the chemical architecture to modify sterols like other insects. We do not know if this strategy is also employed by other bee species. C_LIO_LIHere, we measured the sterol profiles of 56 species representing all families of UK bees to identify whether the same pollen sterols are used by solitary and eusocial bee species. C_LIO_LIThe {Delta}5 sterols 24-methylenecholesterol, isofucosterol and {beta}-sitosterol which are common components of pollen sterolomes were also the main sterols found in all bee species. Campesterol and cholesterol were recorded almost universally in bees but in proportionately small amounts, despite their low abundance in pollen. C_LIO_LIOur data suggest an ecological rather than phylogenetic driver of bee sterols because related species differed as a function of pollen diet. Generalist species contained more 24-methlyenecholesterol than their specialist congeners suggesting a trade-off between competition for food and desirable sterols. Asteraceae specialists have adapted to use pollen sterols that are not used by generalists, potentially gaining an advantage over these species. Despite the uptake of less common sterols by specialists, they still relied on similar sterols to other bee species. The dietary requirements of specialists could be fulfilled by pollen from non-host species, suggesting that while essential, sterols are not the primary driving force of pollen foraging choices. C_LI

biochemistry↗

bioRxiv2025

Multimodal Validation of the Existence of Transitional Cerebellar Progenitors in the Human Fetal Cerebellum

The developing human cerebellum comprises a series of transient progenitor states that are essential for generating diverse neural subtypes, yet the identity and validation of intermediate cell populations bridging stem-like and lineage-committed neuronal precursors remain limited. In our previous single-cell transcriptomic study, we identified a distinct transitional cerebellar progenitor (TCP) population enriched in specific progenitor zones such as the rhombic lip during human fetal cerebellar development. To address the concerns raised in the Matters Arising regarding the existence of the TCP cells, we provide additional multimodal validations of this population. Rigorous reanalysis of our single-cell transcriptomic data, applying stringent quality control measures, validated the quality of TCP cells and their classification as a transcriptionally distinct population. Multiple orthogonal validations of TCP signature genes (SOX11 and HNRNPH1) using RNAscope in situ hybridization, Xenium-based spatial transcriptomics, and immunohistochemistry on additional fetal cerebellar samples across different stages demonstrated the consistent presence of TCPs in the rhombic lip, transitioning from PRTG+ stem-like zones in the ventricular zone at early developmental stages to the subventricular zone overlapping with EOMES+ unipolar brush cell precursors at later stages. TCP-like populations were also independently identified in two fetal cerebellar single-nucleus transcriptomic atlases, and their gene signature was enriched in a cell population associated with aggressive medulloblastomas. Collectively, these multimodal validations confirm the existence of a transitional progenitor population in the human fetal cerebellum, with implications for cerebellar lineage progression and medulloblastoma origin.

developmental biology↗

bioRxiv2022

Malaria drives unique regulatory responses across multiple immune cell subsets

Plasmodium falciparum malaria results in immunoregulatory responses across multiple cell subsets, which protects the individual from inflammatory mediated immunopathogenesis. However, these anti-inflammatory responses also hamper the development of effective anti-parasitic immunity. Understanding malaria induced tolerogenic responses in specific cell subsets may inform the development of strategies to boost protective immunity during drug treatment and vaccination. Here, we analysed the immune landscape with single cell RNA sequencing of peripheral blood mononuclear cells during falciparum malaria and at convalescence in children and adults from a low malaria transmission area in Malaysia. To understand malaria driven changes specific to each immune cell subset, we interrogated transcriptional changes in sub-clustered major immune cell types during infection. We found that malaria drove development of immunosuppressive monocytes, alongside NK and {gamma}{delta} T cells which regulated inflammatory function but maintained cytolytic capacity. IL10-producing CD4 T cells and IL10-producing regulatory B cells were also induced. Type I interferon responses were identified across all cell types, linking Type I interferon signalling with the induction of immunoregulatory networks during malaria. Together, these findings provide insights into cell-specific and shared immunoregulatory changes induced during malaria, and provides a data set resource for additional analysis of anti-parasitic immunity and disease pathogenesis.

immunology↗

bioRxiv2022

Single-cell Atlas of Human Fetal Cerebellum Decoding Medulloblastoma Origin and Oncogenesis

Medulloblastoma (MB) is the most common malignant childhood brain tumor1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3,4 or human counterparts from frozen tissue nuclei5 have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group-3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin-loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs reveal potential cell populations predisposed to transformation and regulatory circuitries underlying tumor cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.

cancer biology↗

bioRxiv2021

Characterization of a fiber-coupled EvenField illumination system for fluorescence microscopy

Fluorescence microscopy benefits from spatially and temporally homogeneous illumination with illumination area matched to the shape and size of the camera sensor. Fiber-coupled illumination schemes have the added benefit of straightforward and robust alignment and ease of installation compared to free-space coupled illumination. Commercial and open-source fiber-coupled, homogenized illumination schemes have recently become available to the public; however, there have been no published comparisons of speckle reduction schemes to date. We characterize three different multimode fibers in combination with two laser speckle reduction devices and compare spatial and temporal profiles to a commercial unit. This work yields a new design, the EvenField Illuminator, which is freely available along for researchers to integrate into their own imaging systems.

neuroscience↗

bioRxiv2021

Connectivity and Synaptic Physiology in the Mouse and Human Cortex

To elucidate cortical microcircuit structure and synaptic properties we present a unique, extensive, and public synaptic physiology dataset and analysis platform. Through its application, we reveal principles that relate cell type to synapse properties and intralaminar circuit organization in the mouse and human cortex. The dynamics of excitatory synapses align with the postsynaptic cell subclass, whereas inhibitory synapse dynamics partly align with presynaptic cell subclass but with considerable overlap. Despite these associations, synaptic properties are heterogeneous in most subclass to subclass connections. The two main axes of heterogeneity are strength and variability. Cell subclasses divide along the variability axis, while the strength axis accounts for significant heterogeneity within the subclass. In human cortex, excitatory to excitatory synapse dynamics are distinct from those in mouse and short-term plasticity varies with depth across layers 2 and 3. With a novel connectivity analysis that enables fair comparisons between circuit elements, we find that intralaminar connection probability among cell subclasses exhibits a strong layer dependence.These and other findings combined with the analysis platform create new opportunities for the neuroscience community to advance our understanding of cortical microcircuits.

neuroscience↗

bioRxiv2020

Computational model of neurodegenerative damage in the olfactory bulb: role of bulb and damage geometry, damage site, and identification of a potential non-invasive marker of early Parkinson's disease onset

Several neurodegenerative diseases impact the olfactory system, and in particular the olfactory bulb, early in disease progression. One mechanism by which damage occurs is via synaptic dysfunction. Here, we implement a computational model of the olfactory bulb and investigate the effect of weakened connection weights on network oscillatory behavior. Olfactory bulb network activity can be modeled by a system of equations that describes a set of coupled nonlinear oscillators. In this modeling framework, we propagate damage to synaptic weights using several strategies, varying from localized to global. Damage propagated in a dispersed or spreading manner leads to greater oscillatory power at moderate levels of damage. This increase arises from a higher average level of mitral cell activity due to a shift in the balance between excitation and inhibition. That this shift leads to greater oscillations critically depends on the nonlinearity of the activation function. Linearized analysis of the network dynamics predicts when this shift leads to loss of oscillatory activity. We thus demonstrate one potential mechanism involved in the increased gamma oscillations seen in some animal models of Alzheimers disease and highlight the potential that pathological olfactory bulb behavior presents as an early biomarker of disease.

neuroscience↗

bioRxiv2020

Human cortical expansion involves diversification and specialization of supragranular intratelencephalic-projecting neurons

The neocortex is disproportionately expanded in human compared to mouse, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers that selectively make connections within the cortex and other telencephalic structures. Single-cell transcriptomic analyses of human and mouse cortex show an increased diversity of glutamatergic neuron types in supragranular cortex in human and pronounced gradients as a function of cortical depth. To probe the functional and anatomical correlates of this transcriptomic diversity, we describe a robust Patch-seq platform using neurosurgically-resected human tissues. We characterize the morphological and physiological properties of five transcriptomically defined human glutamatergic supragranular neuron types. Three of these types have properties that are specialized compared to the more homogeneous properties of transcriptomically defined homologous mouse neuron types. The two remaining supragranular neuron types, located exclusively in deep layer 3, do not have clear mouse homologues in supragranular cortex but are transcriptionally most similar to deep layer mouse intratelencephalic-projecting neuron types. Furthermore, we reveal the transcriptomic types in deep layer 3 that express high levels of non-phosphorylated heavy chain neurofilament protein that label long-range neurons known to be selectively depleted in Alzheimers disease. Together, these results demonstrate the power of transcriptomic cell type classification, provide a mechanistic underpinning for increased complexity of cortical function in human cortical evolution, and implicate discrete transcriptomic cell types as selectively vulnerable in disease.

neuroscience↗

bioRxiv2020

Toward an integrated classification of neuronal cell types: morphoelectric and transcriptomic characterization of individual GABAergic cortical neurons

Neurons are frequently classified into distinct groups or cell types on the basis of structural, physiological, or genetic attributes. To better constrain the definition of neuronal cell types, we characterized the transcriptomes and intrinsic physiological properties of over 3,700 GABAergic mouse visual cortical neurons and reconstructed the local morphologies of 350 of those neurons. We found that most transcriptomic types (t-types) occupy specific laminar positions within mouse visual cortex, and many of those t-types exhibit consistent electrophysiological and morphological features. We observed that these properties could vary continuously between t-types, which limited the ability to predict specific t-types from other data modalities. Despite that, the data support the presence of at least 20 interneuron met-types that have congruent morphological, electrophysiological, and transcriptomic properties. HighlightsO_LIPatch-seq data obtained from >3,700 GABAergic cortical interneurons C_LIO_LIComprehensive characterization of morpho-electric features of transcriptomic types C_LIO_LI20 interneuron met-types that have congruent properties across data modalities C_LIO_LIDifferent Sst met-types preferentially innervate different cortical layers C_LI

neuroscience↗

bioRxiv2019

TET1-mediated Oligodendrocyte Homeostasis Regulates Myelination and Synaptic Functions

Ten-eleven translocation (TET) proteins, the dioxygenase for DNA hydroxymethylation, are important players in nervous system development and diseases. However, their role in myelination and remyelination after injury remains elusive. Here, we identify a genome-wide and locus-specific DNA hydroxymethylation landscape shift during differentiation of oligodendrocyte-progenitor cells (OPC). Ablation of Tet1 results in stage-dependent defects in oligodendrocyte (OL) development and myelination in the mouse brain. The mice lacking Tet1 in the oligodendrocyte lineage develop behavioral deficiency. We also show that TET1 is required for remyelination in adulthood. Transcriptomic, genomic occupancy, and DNA hydroxymethylation profiling reveal a critical TET1-regulated epigenetic program for oligodendrocyte differentiation that includes genes associated with myelination, cell division, and calcium transport. Tet1-deficient OPCs exhibit reduced calcium activity, increasing calcium activity rescues the differentiation defects in vitro. Deletion of a TET1-5hmC target gene, Itpr2 impairs the onset of OPC differentiation. Together, our results suggest that stage-specific TET1-mediated epigenetic programming and intracellular signaling are important for proper myelination and remyelination in mice.

neuroscience↗