Biology subjects

Marshall, K.

Publications and source records attributed to Marshall, K..

11 recordsLinked to original sources

bioRxiv2026

Increased replication-associated single-stranded DNA promotes formaldehyde-induced mutagenesis.

Formaldehyde (FA) is an environmentally abundant and endogenously produced aldehyde that has been shown to cause DNA damage, mutagenesis, and carcinogenesis. Several studies have demonstrated that FA induces guanine mutations resulting in a mutation signature like SBS40. In this work, we demonstrate that replication defects generating single-stranded DNA (ssDNA) caused by the downregulation of the major replicative polymerases results in elevated FA mutagenesis. We found that loss of Mrc1 (CLASPIN) resulted in a high accumulation of ssDNA and FA mutagenesis, and that these phenotypes were not dependent on Mrc1s checkpoint activity. Loss of DNA-protein crosslink repair results in elevated FA sensitivity with no alteration to mutagenesis, likely due to the inability of the fork to bypass unprocessed protein adducts. Finally, we show that FA-induced mutagenesis is dependent on Pol {zeta}-mediated translesion synthesis, while deficiencies in the template switching pathway do not alter error-free bypass of FA adducts. Overall, our work points towards replication-associated ssDNA as a major substrate for FA-induced damage and elucidates the pathways that function to prevent FA mutagenesis at replication forks.

genetics↗

bioRxiv2026

The curse of dimensionality in motor cortex

Understanding how motor cortex generates movement is a foundational challenge in neuroscience. Unsupervised dimensionality reduction techniques, such as principal component analysis (PCA), are widely used to transform high-dimensional neural recordings into a compact, low-dimensional space. The dimensionality of this space--that is, the number of principal components needed to explain a fixed fraction of variance--is broadly assumed to be an intrinsic property of the underlying neural dynamics, potentially modulated by task complexity. Here, by comparing con-strained reaching and unconstrained naturalistic behaviors recorded from the same animal on the same day, we show that this assumption breaks down in two distinct ways. First, across four non-human primates, the dominant axes of low-dimensional neural activity separate behavioral contexts rather than movement kinematics, with neural activity shifting rapidly between task-specific regions of state space at task transitions. Notably, traditional dimensionality metrics are insensitive to movement complexity across tasks. Instead, unsupervised dimensionality scales with the number of recorded neurons, exhibiting non-saturating growth up to 1000 simultaneously recorded electrodes, a pattern that holds across PCA, factor analysis, shared variance component analysis, and nonlinear autoencoders. This scaling has direct consequences for decoding: while decoders trained on unsupervised subspaces improve only modestly with electrode count, super-vised methods leverage additional electrodes to separate neural states from a vanishingly small fraction of total variance (<10% at 1000 electrodes). Together, these results challenge current views on cortical dimensionality, reveal a greater-than-appreciated role for behavioral context in shaping motor cortical activity, and motivate careful consideration of computational methods as experimental data volumes scale.

neuroscience↗

bioRxiv2025

Signatures of covert neuron loss in the local field potential of motor cortex

BackgroundCovert stroke is understudied despite occurring ten times for every symptomatic stroke and contributing to strokes enormous global disease burden. For instance, it is unknown whether covert stroke replicates the peri-infarct neuroelectrophysiological frequency spectrum impact of symptomatic stroke. This motivated the use of our novel electrolytic lesioning platform to explore the spectral consequences of covert neuron loss. MethodsDuring a multi-month period of participation in an arm reaching task, neuron loss was induced via electrolytic lesions to the motor cortex of two large animals (U: n = 4; H: n = 7). Behavioral metrics were paired with spectrum estimates from local field potential recordings. These spectra were represented as bandpowers, aperiodic/periodic parameters, and decomposed time-frequency tensors. Lesion impact was assessed using nonparametric permutation tests of next-day effects and state space model parameters. ResultsTask success rate was unaffected by lesions, but shifts in aperiodic structure reduced next-day{gamma} bandpower (30 - 100 Hz; U: -1.38{micro}V2, p < 1 x 10-3; H: -1.66{micro}V2, p = 0.001) while sensorimotor rhythms spanning 8 - 45 Hz ({Sigma}SMR) were amplified (Monkey U: 8.68{micro}V2, p < 1 x 10-3; Monkey H: 2.40{micro}V2, p = 0.004). Additionally, state space modeling showed that spectral perturbations to{gamma} and {Sigma}SMR outlasted any behavioral impact of the lesions (Monkey U: Behavior=1 d,{gamma} =2 d, {Sigma}SMR =2 d; Monkey H: Behavior=0 d,{gamma} =3 d, {Sigma}SMR =1 d). Finally, tensor decomposition revealed interpretable, animal-specific perturbations to time-frequency dynamics. ConclusionCovert neuron loss induced multi-day spectral perturbations similar to those observed after symptomatic stroke. The neural spectrum is thus more sensitive to neuron loss than previously understood and could be responsive to neuron loss caused by covert stroke. This work also motivates the use of electrolytic lesions to bridge covert and symptomatic regimes of neuron loss, advancing our causal understanding of post-stroke interactions between spectrum and behavior.

neuroscience↗

bioRxiv2025

Virus infection of honey bee queens alters lipid profiles and indirectly suppresses a retinue pheromone component via reducing ovary mass

Virus infections reduce honey bee (Apis mellifera) ovary mass (in part due to resource-allocation trade-offs with immunity) and are linked to the presence of supersedure cells in colonies, indicating that workers are attempting to replace their queen. Pheromones, lipids, and lipid transport proteins could mediate relationships among virus infection, ovary mass, and supersedure. When we infected honey bee queens in the laboratory and profiled their queen retinue pheromone (QRP) components from head extracts, we found that virus infections specifically reduced the QRP component methyl oleate. Data from an observational field study were consistent with this pattern. Lipidomics analysis of the same extracts suggests that virus infection decreases triacylglycerol abundances (major sources of stored energy). Reducing ovary mass via laying restriction was sufficient to lower methyl oleate abundance [-] suggesting that virus infection reduces methyl oleate indirectly via ovary effects [-] but was insufficient to reduce abundance of most triacylglycerols or stimulate immune effector expression. Abundance of circulating apolipophorin-III, a lipid transporter and putative potentiator of immune effectors, was lower in queens with restricted laying, suggesting that its expression may be controlled by nutrient availability while its immune-stimulating capacity is governed by other mechanisms. Prior research has shown that queen pheromone blends lacking methyl oleate are less attractive to workers; therefore, diminishing methyl oleate could result in a less desirable pheromone bouquet and possibly stimulate supersedure. The mechanism of methyl oleate reduction is yet to be determined, but is clearly tied to ovary size and possibly resource availability or mobilization.

physiology↗

bioRxiv2024

Enhancing Radiation-induced Reactive Oxygen Species Generation Through Mitochondrial Transplantation in Human Glioblastoma

Glioblastoma (GBM) is the most aggressive primary brain malignancy in adults, with high recurrence rates and resistance to standard therapies. This study explores mitochondrial transplantation as a novel method to enhance the radiobiological effect (RBE) of ionizing radiation (IR) by increasing mitochondrial density in GBM cells, potentially boosting reactive oxygen species (ROS) production and promoting radiation-induced cell death. Using cell-penetrating peptides (CPPs), mitochondria were transplanted into GBM cell lines U3020 and U3035. Transplanted mitochondria were successfully incorporated into recipient cells, increasing mitochondrial density significantly. Mitochondrial chimeric cells demonstrated enhanced ROS generation post-irradiation, as evidenced by increased electron paramagnetic resonance (EPR) signal intensity and fluorescent ROS assays. The transplanted mitochondria retained functionality and viability for up to 14 days, with mitochondrial DNA (mtDNA) sequencing confirming high transfection and retention rates. Notably, mitochondrial transplantation was feasible in radiation-resistant GBM cells, suggesting potential clinical applicability. These findings support mitochondrial transplantation as a promising strategy to overcome therapeutic resistance in GBM by amplifying ROS-mediated cytotoxicity, warranting further investigation into its efficacy and mechanisms in vivo.

cancer biology↗

bioRxiv2023

conn2res: A toolbox for connectome-based reservoir computing

The connection patterns of neural circuits form a complex network. How signaling in these circuits manifests as complex cognition and adaptive behaviour remains the central question in neuroscience. Concomitant advances in connectomics and artificial intelligence open fundamentally new opportunities to understand how connection patterns shape computational capacity in biological brain networks. Reservoir computing is a versatile paradigm that uses nonlinear dynamics of high-dimensional dynamical systems to perform computations and approximate cognitive functions. Here we present conn2res: an open-source Python toolbox for implementing biological neural networks as artificial neural networks. conn2res is modular, allowing arbitrary architectures and arbitrary dynamics to be imposed. The toolbox allows researchers to input connectomes reconstructed using multiple techniques, from tract tracing to noninvasive diffusion imaging, and to impose multiple dynamical systems, from simple spiking neurons to memristive dynamics. The versatility of the conn2res toolbox allows us to ask new questions at the confluence of neuroscience and artificial intelligence. By reconceptualizing function as computation, conn2res sets the stage for a more mechanistic understanding of structure-function relationships in brain networks.

neuroscience↗

bioRxiv2021

Genomic signatures of desert adaptation at gene-rich regions in zebu cattle from the African drylands

Sudan, the largest country in Africa, acts as a corridor between North and sub-Saharan Africa along the river Niles. It comprises warm arid and semi-arid grazing lands, and it is home to the second-largest African population of indigenous livestock. Indigenous Sudanese cattle are mainly indicine/zebu (humped) type. They thrive in the harshest dryland environments characterised by high temperatures, long seasonal dry periods, nutritional shortages, and vector diseases challenges. We investigated genome diversity in six indigenous African zebu breeds sampled in Sudan (Aryashai, Baggara, Butana, Fulani, Gash, and Kenana). We adopted three genomic scan approaches to identify candidate selective sweeps regions (ZHp, FST, XP-EHH). We identified a set of gene-rich selective sweep regions shared across African and Asian zebu or unique to Sudanese zebu. In particular, African and Asian zebu candidate gene-rich regions are detected on chromosomes 2, 5 and 7. They include genes involved in immune response, body size and conformation, and stress response to heat. In addition, a 250 kb selective sweep on chromosome 16 was detected exclusively in five Sudanese zebu populations. This region spans seven genes, including PLCH2, PEX10, PRKCZ and SKI, which are involved in alternative adaptive metabolic strategies of insulin signalling, glucose homeostasis, and fat metabolism. Together, these genes may contribute to the zebu cattle resilience to heat, nutritional and water shortages. Our results highlight the putative importance of selection at gene-rich genome regions, which might be under a common regulatory genetic control, as an evolutionary mechanism for rapid adaptation to the complexity of environmental challenges.

evolutionary biology↗

bioRxiv2021

A locus conferring tolerance to Theileria infection in African cattle

East Coast fever, a tick-borne cattle disease caused by the Theileria parva parasite, is among the biggest natural killers of cattle in East Africa, leading to over 1 million deaths annually. Here we report on the genetic analysis of a cohort of Boran cattle demonstrating heritable tolerance to infection by T. parva (h2 = 0.65, s.e. 0.57). Through a linkage analysis we identify a 6 Mb genomic region on Bos taurus chromosome 15 that is significantly associated with survival outcome following T. parva exposure. Testing this locus in an independent cohort of animals replicates this association with survival following T. parva infection. A stop gained polymorphism in this region was found to be highly associated with survival across both related and unrelated animals, with only one of the 20 homozygote carriers (T/T) of this change succumbing to the disease in contrast to 44 out of 97 animals homozygote for the reference allele (C/C). Consequently, we present a genetic locus linked to tolerance of one of Africas most important cattle diseases, raising the promise of marker-assisted selection for cattle that are less susceptible to infection by T. parva. Author SummaryMore than a million cattle die of East Coast fever in Africa each year, the impact of which disproportionately falls onto low-income, smallholder farmers. The lack of a widely accessible vaccine, heavy reliance on chemicals to control the tick vector and inadequate drug treatments means that new approaches for controlling the disease are urgently required. Through a genetic study of an extended pedigree of Boran cattle that are more than three times less likely to succumb to the disease than matched controls, we identify a region on chromosome 15 of the cattle genome associated with a high level of tolerance to the disease. We show that a variant in this region is also associated with survival in an independent cohort, and is linked to rates of cell expansion during infection. This genetic variant can therefore support marker-assisted selection, allowing farmers to breed tolerant cattle and offers a route to introduce this beneficial DNA to non-native breeds, enabling reduced disease incidence and increased productivity, which would be of benefit to millions of rural smallholder farmers across Africa.

genetics↗

bioRxiv2021

The disease associated Tau35 fragment has an increased propensity to aggregate compared to full-length tau

Tau35 is a truncated form of tau found in human brain in a subset of tauopathies. Tau35 expression in mice recapitulates key features of human disease, including progressive increase in tau phosphorylation, along with cognitive and motor dysfunction. The appearance of aggregated tau suggests that Tau35 may have structural properties distinct from those of other tau species that could account for its pathological role in disease. To address this hypothesis, we performed a structural characterization of monomeric and aggregated Tau35 and compared the results to those of two longer isoforms, 2N3R and 2N4R tau. We used small angle X-ray scattering to show that Tau35, 2N3R and 2N4R tau all behave as disordered monomeric species but Tau35 exhibits higher rigidity. In the presence of the poly-anion heparin, Tau35 increases thioflavin T fluorescence significantly faster and to a greater extent than full-length tau, demonstrating a higher propensity to aggregate. We used atomic force microscopy, transmission electron microscopy and X-ray fiber diffraction to demonstrate that Tau35 aggregates are morphologically similar to previously reported tau fibrils but they are more densely packed. These data increase our understanding of the aggregation inducing properties of clinically relevant tau fragments and their potentially damaging role in the pathogenesis of human tauopathies.

biophysics↗

bioRxiv2021

A cattle graph genome incorporating global breed diversity

Despite only 8% of cattle being found in Europe, European breeds dominate current genetic resources. This adversely impacts cattle research in other important global cattle breeds. To mitigate this issue, we have generated the first assemblies of African breeds, which have been integrated with genomic data for 294 diverse cattle into the first graph genome that incorporates global cattle diversity. We illustrate how this more representative reference assembly contains an extra 116.1Mb (4.2%) of sequence absent from the current Hereford sequence and consequently inaccessible to current studies. We further demonstrate how using this graph genome increases read mapping rates, reduces allelic biases and improves the agreement of structural variant calling with independent optical mapping data. Consequently, we present an improved, more representative, reference assembly that will improve global cattle research.

genomics↗

bioRxiv2019

Misfolded Amyloid β-42 induced impairment of the endo-lysosomal pathway revealed by real-time optical monitoring

Misfolding and aggregation of proteins is strongly linked to several neurodegenerative diseases but how such species bring about their cytotoxic actions remains poorly understood. Here we used specifically-designed optical reporter probes and live fluorescence imaging in primary hippocampal neurons to characterise the mechanism by which prefibrillar, oligomeric forms of the Alzheimers-associated peptide, A{beta}42, exert their detrimental effects. We used a pH-sensitive reporter, A{beta}42-CypHer, to track A{beta} internalisation in real time, demonstrating that oligomers are rapidly taken up into cells in a dynamin-dependent manner, and trafficked via the endo-lysosomal pathway resulting in accumulation in lysosomes. In contrast, a non-assembling variant of A{beta}42 (vA{beta}42) assayed in the same way is not internalised. Tracking ovalbumin uptake into cells using CypHer or Alexa Fluor tags shows that preincubation with A{beta}42 significantly disrupts protein uptake. Our results identify a potential mechanism by which amyloidogenic aggregates directly impair cellular function through disruption of the endosomal-lysosomal pathway.

neuroscience↗