Biology subjects

Miller, K.

Publications and source records attributed to Miller, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Tetrahydrobiopterin restores oligodendrocyte maturation after hypoxic white matter injury by reprogramming translational output

Complex congenital heart defects (CHDs) are frequently associated with chronic cerebral hypoxemia, leading to impaired white matter maturation. One proposed mechanism involves hypoxia-induced disruption of the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), resulting in oxidative stress and impaired oligodendrocyte (OL) development. While our previous studies found BH4 supplementation improves hypoxia-induced white matter dysmaturation, the molecular mechanisms remain incompletely understood. Because OL maturation requires coordinated translational control, we hypothesized that BH4 promotes white matter maturation by restoring translation programs disrupted by hypoxia.Translating Ribosome Affinity Purification sequencing (TRAP-seq) was performed on OL lineage cells isolated from transgenic ribosomal reporter mice exposed to chronic hypoxia with or without daily BH4 treatment. Differential translation, weighted gene co-expression network analysis, pathway enrichment, RNAscope, and immunohistochemistry identified translational programs associated with hypoxia and BH4-mediated rescue. Developmental hypoxia extensively altered the OL translatome, suppressing transcripts associated with OL maturation while enriching pathways related to translational regulation and cellular stress. Network analyses identified BH4-responsive gene modules enriched for OL maturation, protein metabolism, and translation-related processes. BH4 partially reversed hypoxia-induced translational changes, restored OL maturation gene expression, and normalized nuclear localization of the lineage regulator OLIG1, consistent with recovery of maturation-associated regulatory programs. Developmental hypoxia disrupts OL maturation through coordinated alterations in ribosome-associated gene expression and post-transcriptional regulatory pathways. BH4 promotes recovery of OL maturation programs, including restoration of translation-related networks and OLIG1 nuclear localization, providing mechanistic insight into BH4-supported white matter maturation under chronic hypoxic conditions.

neuroscience↗

bioRxiv2026

Limb-localized induction of regeneration reshapes brain and amputation-site transcriptional states in adult Xenopus laevis

Limb regeneration requires coordinated tissue reconstruction and nervous system reintegration, yet whether regenerative induction alters brain responses to limb loss remains unclear. We analyzed transcriptomics from the paired brains and amputation sites of adult Xenopus laevis after hindlimb amputation with or without a 24 hour exposure to localized, pro-regenerative multi-drug treatment (MDT) delivered through a wearable bioreactor device. At 24 hours post treatment (24 HPT), MDT brains showed increased vascular and basement membrane transcripts and enrichment of oxidative phosphorylation and mTORC1 programs. In the limb, an exploratory integrated stress response (ISR) score increased at 11 and 24 HPT and returned to control levels by 7 days post-treatment (7 DPT), coinciding with induction of growth differentiation factor 15 (GDF15), a cytokine responsive to mitochondrial stress. We detected no corresponding increase in brain ISR score. At 7 DPT, MDT brains showed enrichment of immune, heme metabolism and biosynthetic programs, reduced synaptic transmission gene expression, and increased gdf15.L. Relative to an external uninjured reference, MDT and amputation only brains showed concordant changes, with treatment modifying selected programs. Cross-species comparative analyses identified partial overlap with an axolotl regenerative glutamatergic signature and separation from selected mammalian injury profiles. These findings reveal cross-tissue responses to regenerative induction and identify candidate mechanisms of brain body communication in biomedically engineered vertebrate limb regeneration.

neuroscience↗

bioRxiv2026

(E,E)-bisantrene suppresses MYC expression and displays anti-leukemic activity in acute myeloid leukemia

Background: Acute myeloid leukemia (AML) is genetically diverse with a high unmet clinical need for improved treatment options. Dysregulation of the transcription factor MYC plays a central role in AML progression and therapeutic resistance. (E,E)-bisantrene was recently found to inhibit MYC transcription and downstream activity via G-quadruplex DNA stabilization. This study aimed to evaluate the mechanism of action and preclinical activity of (E,E)-bisantrene in AML. Methods: The in vitro and in vivo activity of (E,E)-bisantrene was determined in a variety of AML models (cell lines, xenograft mouse models, and ex vivo human AML mononuclear cells). Transcriptomic, proteomic and phosphoproteomic analyses were performed after treatment with (E,E)-bisantrene. Analyses of -omics data to identify enriched pathways and upstream regulators were performed. Results: (E,E)-bisantrene demonstrated potent anti-proliferative activity across a panel of AML cell lines, inducing apoptosis and reducing S phase proportions. (E,E)-bisantrene significantly prolonged survival in cell- and patient-derived xenograft models of AML. Mechanistically, RNA-seq and proteomic analysis of MOLM13 and MV4-11 cells treated with (E,E)-bisantrene showed significant reductions in the activity of MYC and E2F, together with the cell cycle regulators CDK1/2/4/5. Transcript and protein levels of MYC were reduced in a dose- and time-dependent manner. TP53 and inflammation-associated transcript signatures were also observed. Conclusion: Anti-proliferative activity of (E,E)-bisantrene in preclinical AML models was associated with a downregulation of MYC, CDK1/2/4/5 and E2F. This study supports the ongoing clinical evaluation of (E,E)-bisantrene in AML where MYC is a clinically relevant driver of disease aggressiveness and therapy resistance.

cancer biology↗

bioRxiv2026

Backbone Thioamide Substitution Enhances the Activity of Short Peptides in Modulating the Aggregation of α-Synuclein

The non-amyloid-{beta} component (NAC) region of the Parkinson's-associated protein -synuclein plays a key role in its pathogenic aggregation, motivating the development of molecules that target this critical region. Here, we show that a minimal NAC-derived motif, 66VGGAVVT72, can be reprogrammed through backbone engineering to modulate -synuclein aggregation. Backbone thioamide substitution of this peptide enhances its interactions with -synuclein fibrils and accelerates aggregation, whereas N-methylation disrupts {beta}-sheet hydrogen bonding and inhibits fibrillization. Strikingly, combining these modifications yields hybrid peptides that inhibit the fibrillization of full-length -synuclein at sub-stoichiometric concentrations. Consistent with in vitro results, these backbone-modified peptides can also reduce seeded -synuclein aggregation in cells. These results establish that minimal amyloidogenic sequences can be systematically tuned from aggregation promoters to inhibitors through backbone-level perturbations, particularly thioamide incorporation.

biochemistry↗

bioRxiv2026

NAMPT activation uncovers a senescence-specific vulnerability and promotes healthy aging in combination with NAM

Aging is driven by multiple interacting processes, suggesting that effective strategies to promote healthy aging may require simultaneous targeting of more than one underlying mechanism. Here we identify a strategy that couples restoration of nicotinamide adenine dinucleotide (NAD+) homeostasis with selective targeting of senescent cells, two mechanistically linked features of aging. Senescent cells express elevated intracellular levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the nicotinamide (NAM) salvage pathway for NAD+ biosynthesis. Despite increased NAMPT abundance, isotope-tracing studies revealed decreased NAD+ biosynthesis and consumption, indicating that elevated NAMPT abundance was not accompanied by a corresponding increase in NAD+ metabolic flux. Treatment with the NAMPT activator SBI-0802162 engaged the spare enzymatic capacity of NAMPT in senescent cells and produced a marked rise in intracellular NAD+ that, when sustained, disrupted their transcriptional program and selectively reduced the viability of senescent cells but not proliferating cells. In mice, SBI-0802162 reduced circulating NAM levels, suggesting that sustained NAMPT activation may be limited by substrate availability. This observation prompted the development of a combination approach using SBI-0802162 together with dietary NAM supplementation. Co-administration of SBI-0802162 and NAM robustly increased tissue NAD+, suppressed select age-associated inflammatory signatures and markers of cellular senescence in a tissue-specific manner. These molecular effects occurred alongside preserved physical performance in aged mice and reductions in food intake and body weight, which were observed whether SBI-0802162 was present in the chow or administered by oral gavage. Together, these findings establish a mechanistically integrated approach to target two convergent features of aging, NAD+ dysregulation and senescent cell accumulation, and support combined NAMPT activation and NAM supplementation as a strategy to promote healthy aging.

molecular biology↗

bioRxiv2026

Decoding human sperm signalling: Phosphoproteomic discovery of kinases governing fertilization competency

Capacitation, the process whereby sperm gain the functional competence to fertilize an egg in the absence of de novo transcription and translation, is orchestrated by a hierarchy of kinases driving the phosphorylation of sperm proteins. While increased phosphorylation, in particular tyrosine phosphorylation, is a revered hallmark of fertilization competency in our species, only a limited repository of phosphorylated substrates and kinases have ever been reported from human sperm. To broaden therapeutic targets for sperm targeted contraceptives and infertility therapies, we adapted a contemporary phosphoproteomic technique termed EasyPhos to generate bespoke methodology for the investigation of human sperm signalling. This approach yielded high depth phosphoproteomes of non-capacitated and capacitated human spermatozoa with in silico investigation of the phosphosites revealing 52 kinases with previously uncharacterized roles in sperm capacitation. Investigating the function of the putative sperm capacitation kinases identified yielded several kinases with novel roles in the regulation of sperm function. Of particular interest, polo like kinase 1 (PLK1) inhibition significantly reduced progressive sperm motility, attenuated capacitation-associated tyrosine phosphorylation and reduced the sperm acrosome reaction, an essential step to achieve fertilization. These findings reveal extensive phosphoproteome remodelling during human sperm capacitation, expanding the landscape of molecular targets for fertility control.

Cell Biology↗

bioRxiv2026

Microscopy-informed structural connectivity mapping in the in vivohuman brain via domain adaptation

Characterising human brain connectivity remains a major challenge in neuroscience. Multimodal datasets combining diffusion MRI with high-resolution microscopy in the same brain offer a unique link between macroscopic imaging and microstructural detail, but we lack tools to leverage these data to improve connectivity estimates for in vivo human imaging. We present a deep learning model that predicts high-resolution microscopy-informed fibre orientations from diffusion MRI. The model uses microscopy-derived three-dimensional fibre orientation maps as biologically grounded training targets. It is trained on a bespoke macaque dataset integrating in vivo MRI, postmortem MRI, and whole-brain microscopy, and then translated to in vivo human imaging. We use domain adaptation to predict fibre orientations from diverse MRI datasets: first to bridge differences in tissue state in the macaque (postmortem to in vivo), and then to generalise across species (macaque to human). Our method derives microscale-informed fibre architecture from diffusion MRI without requiring microscopy at inference. It leverages data that can easily be acquired only in animal models whilst generalising to in vivo human diffusion MRI with minimal acquisition requirements. The microscopy-informed fibre orientation distributions support biologically meaningful tractography, enhancing superficial white matter and cortical-subcortical pathway delineation for in vivo human data. More broadly, this work establishes a general framework for transferring microstructural information from microscopy to non-invasive imaging, enabling biologically informed mapping of brain connectivity.

neuroscience↗

bioRxiv2026

Clinical and primary cell evidence reveals complex CFTR function-phenotype relationships

RationaleThe CFTR function-phenotype relationship remains incompletely understood, with prior work yielding heterogeneous findings suggesting linear and nonlinear associations. ObjectiveDefine the genotype-function-phenotype relationship using data from the Clinical and Functional TRanslation of CFTR (CFTR2) and human nasal epithelial (HNE) studies. MethodsClinical data (sweat chloride, lung function, pancreatic status) from 84,418 individuals in CFTR2 were linked to CFTR functional measures derived from 289 CFTR genotypes. Total genotype function was calculated as the average percent wild-type chloride conductance of both variants in heterologous cell lines. This framework was applied to an HNE cohort including people with CF, CF heterozygotes, and controls. CFTR function was derived from short circuit measurements in HNEs from 153 individuals and correlated with phenotype for 415 individuals. Weighted linear and logarithmic regressions were applied to evaluate the function-phenotype relationship. Measurements and Main ResultsSimple linear regression obscured marked heterogeneity across datasets. Piecewise linear regressions revealed marked attenuation of slope magnitude with increasing function across phenotypes. This pattern was well-described by a logarithmic function, such that modeling function on a log scale rendered the relationship approximately linear. HNE data demonstrated similar attenuation, corroborating this pattern. ConclusionsLarge-scale natural history data integrated with primary cell findings show that the function-phenotype relationship is not sufficiently described by a single linear effect but is a proportional relationship, in which equivalent changes in CFTR function yield different phenotypic outcomes depending on baseline function. This framework provides precision in predicting clinical benefits from CFTR-directed therapies and identifying meaningful thresholds of CFTR rescue. Impact StatementThis work integrates registry and primary cell data to define the relationship amongst CFTR genotype, CFTR protein function, and clinical phenotype. These findings establish reference points for evaluating the degree of phenotypic improvement anticipated from functional restoration from CFTR-targeted treatments. More broadly, this study advances the understanding of CF disease mechanisms by linking molecular function to real-world clinical outcomes across data sources. At a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSThe relationship between CFTR function and clinical phenotype remains incompletely understood. Prior studies have suggested both linear and nonlinear associations between CFTR activity and disease manifestations. Defining this relationship is increasingly important for interpreting functional data and predicting clinical benefit from CFTR-directed therapies. What This Study Adds to the FieldUsing clinical and functional data from more than 84,000 individuals in CFTR2 together with primary human nasal epithelial cell measurements spanning people with cystic fibrosis, carriers, and unaffected controls, we demonstrate that the CFTR function-phenotype relationship is not adequately described by a single linear model. Instead, the relationship is best fitted by piecewise linear regressions of varying slope conforming to a logarithmic pattern, with the greatest phenotypic gains occurring at the lowest levels of baseline CFTR function. These findings provide a quantitative framework for interpreting functional rescue and predicting therapeutic benefit across the CFTR functional spectrum.

genetics↗

bioRxiv2026

Transcription Factor Subtype Governs Response and Resistance to DLL3-Directed T-Cell Engagement in Small Cell Lung Cancer

Although small cell lung cancer (SCLC) comprises transcription factor (TF)-defined molecular subtypes (ASCL1, NEUROD1, POU2F3), the extent to which these subtypes predict response to clinically effective therapy in patients--and whether therapy can select for subtype switching--remains unknown. The recent approval of the DLL3xCD3 bispecific T-cell engager tarlatamab represents one of the first meaningful advances in relapsed small cell lung cancer (SCLC) in decades, yet responses remain heterogeneous and resistance is inevitable. Here, we inferred SCLC gene expression from circulating chromatin in prospectively collected patient plasma (46 patients; 167 samples), enabling interrogation of response and acquired resistance to tarlatamab. Parallel development of the first immunocompetent syngeneic mouse model to study tarlatamab response and resistance enabled functional validation. Across species, findings converged on a central principle: TF subtype governs both initial response and acquired resistance. Therapeutic response was significantly associated with ASCL1-subtype tumors, whereas NEUROD1-subtype tumors exhibited inferior responses and POU2F3-subtype tumors were uniformly resistant, consistent with DLL3 being a direct ASCL1 transcriptional target and most highly expressed in ASCL1-positive tumors. Strikingly, one mode of acquired resistance revealed therapeutic selection for a NEUROD1-high state with concomitant DLL3 downregulation. Other resistant tumors exhibited enrichment of regulatory and exhausted T-cell programs, highlighting tarlatamabs dual-targeting mechanism of action. Together, these results reveal that tarlatamab exerts selective pressure against ASCL1-driven lineages, facilitating resistance through loss of an antigen intrinsically linked to that state. These findings underscore the clinical relevance of TF-defined molecular subtypes in human SCLC. More broadly, they highlight the power of integrating longitudinal in vivo plasma transcriptional profiling from patient plasma with functional mouse modeling to uncover clinical and biological mechanisms of response and resistance to cell-surface-targeted therapies.

cancer biology↗

bioRxiv2026

Somatic variants activating the RAS-MAPK pathway confer susceptibility to hippocampal sclerosis in drug-resistant epilepsy

Hippocampal sclerosis is a frequent finding in pediatric epilepsy surgery and has traditionally been regarded as an acquired lesion. It commonly co-occurs with focal cortical dysplasia (FCD IIIa), yet whether hippocampal injury is secondary to seizures or reflects a shared underlying etiology remains unresolved. Here we identified somatic variants activating the RAS-MAPK pathway in 40% of patients with hippocampal sclerosis, but in none with non-sclerotic hippocampus. Gain-of-function variants in PTPN11 were the most common finding, with mutations present in both cortex and hippocampus and enriched in hippocampal neurons, consistent with a shared developmental origin. In mice, Ptpn11D61Y mutants developed profound hippocampal degeneration and gliosis following subthreshold kainic acid exposure, whereas wild-type controls were unaffected. p38-dependent stress pathways were upregulated in patients and mice, suggesting a mechanism through which ERK-p38 crosstalk lowers the threshold for seizure-induced injury. These results provide a genetic explanation for FCD IIIa, elucidate the role of somatic mutations within the RAS-MAPK pathway in driving hippocampal sclerosis, and provide a target for pathway-specific interventions for intractable seizures.

neuroscience↗

bioRxiv2026

The fidelity of mRNA translation as a novel regulatory layer for brain development

Although the fidelity of mRNA translation is essential for maintaining proteome integrity, whether translation error rates vary across cell types and developmental stages in vivo remains largely unexplored. Here, we generate a gain-of-activity dual-luciferase knock-in reporter mouse that enables quantitative monitoring of translation errors in vivo. Using this system, we systematically characterize the spatiotemporal dynamics of translation fidelity across mammalian development. Mature organs exhibit lower error rates than pluripotent embryonic stem cells. Translation fidelity diverges sharply among organs, becoming progressively established during embryonic development, with brain and muscle displaying the highest accuracy. To determine functional significance, we experimentally increased translation errors during cerebral organoid formation and in vitro neuronal differentiation. Elevated error rates reduced neuronal output by impairing neuronal maturation without altering neural progenitor populations. Consistently, differentiated neurons display uniformly elevated fidelity across multiple classes of translation errors, including stop codon readthrough, amino acid misincorporation, and ribosomal frameshifting. These findings demonstrate that translation fidelity is not a fixed intrinsic property of the translation machinery but is developmentally regulated and required for efficient neuronal differentiation. Together, our results identify translation fidelity as a developmentally tuned, tissue-specific dimension of gene expression in vivo.

developmental biology↗

bioRxiv2026

Histone variant H2A.Z mutant suppresses the senescence-associated secretory phenotype

Cellular senescence features a durable cell-cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP) driven in part by chromatin remodeling. The histone variant H2A.Z plays an essential role in regulating gene expression through modulating nucleosome dynamics and is known to regulate the expression of cell cycle genes during the early stages of cellular senescence. However, how the intrinsic stability of H2A.Z-containing nucleosomes plays a role in the establishment of the senescent phenotype remains unexplored. To investigate this, we employed H2A.Z R80C, a H2A.Z mutant that destabilizes nucleosomes by disrupting histone-DNA interactions. We observed that expression of H2A.Z R80C causes suppression of SASP in senescent primary human fibroblasts, without affecting expression of cell cycle genes. H2A.Z knockdown did not suppress the SASP, demonstrating that SASP suppression is likely due to altered stability of H2A.Z-containing nucleosomes rather than loss of H2A.Z function. Mechanistically, SASP suppression is linked to decreased H3K27ac at SASP gene loci. These findings offer a novel avenue for understanding and manipulating the SASP during aging and other senescence-related pathologies.

molecular biology↗

bioRxiv2025

Viral evolution of T1L mammalian orthoreovirus enhances breast cancer stem-like cell killing

BackgroundBreast cancer is the second leading cause of death in women in the US. Among the different subtypes of breast cancer, estrogen receptor positive (ER+) has a more favorable prognosis; however, patients can experience cancer recurrence 10 years or more after initial diagnosis. Breast cancer stem-like cells (BCSCs) are slowly proliferating cells that drive metastasis and resistance to therapies that target rapidly proliferating tumor cells. BCSC self-renewal and survival pathways make them difficult to eliminate; no selective therapeutics currently exist to target them. Our research aims to use mammalian orthoreovirus (MRV) as an oncolytic agent to eliminate BCSCs. MethodsWe evaluated the effects of three different MRV strains (T3D, T1L and R2) under both 2D and 3D culture conditions (which enrich for BCSCs) in parental and paclitaxel resistant (TaxR) MCF7 cells using cell viability assays, flow cytometry, western blotting, and tumorsphere assays. We identified differentially expressed genes in response to T1L by RNA sequencing. Novel MRV strains were developed by serial passaging of the parental T1L strain in TaxR BCSCs, leading to the isolation and sequencing of three distinct MRV clones. The novel MRV clones were assessed for their oncolytic effects using the aforementioned techniques alongside inhibitor-based studies targeting cell death pathways. ResultsNotably, at least two clones (T1L SP B and T1L SP C) demonstrated enhanced oncolytic potency compared to the parent T1L strain against MCF7 TaxR BCSCs, even though their infectivity and viral protein synthesis was reduced. Whole genome sequencing of the viral clones identified changes in viral protein sequences that correlate with enhanced potency against BCSCs. T1L, T1L SP B and T1L SP C induced apoptosis; however, T1L SP B may induce a more immunogenic form of cell death in the TaxR cells, as indicated by the increased release of extracellular ATP (eATP), a damage-associated molecular pattern (DAMP), which is associated with immunogenic cell death. ConclusionsIn summary, we developed novel oncolytic viruses promote oncolysis in therapy-resistant BCSCs. We found that T1L SP B induces apoptosis in a more immunogenic manner, highlighting the potential of these viruses to eliminate BCSCs and stimulate the immune system.

cancer biology↗

bioRxiv2025

Computational Modeling of Motor-Driven Extension of Microtubule Bundles in Axons

In addition to actin assembly at the growth cone, neuronal axons elongate via interactions between microtubules and microtubule-associated proteins including dynein motor proteins and cross-linking proteins. Dynein translocates microtubules toward the growth cone to exert extensile forces for axonal outgrowth. During this process, microtubules are most likely to experience compressive loads, which can result in bending deformation on microtubules called buckling. Such buckled microtubules are impaired in their ability to bear compressive forces and may not contribute significantly to axonal outgrowth. If microtubules are interconnected by cross-linking proteins, they are less likely to be buckled and thus able to resist larger compressive loads. Despite the importance of the buckling and connectivity of microtubules, their effects on the axonal outgrowth have not been investigated to date. In this study, using an agent-based computational model, we created a microtubule bundle to simulate the microtubule system in axons. This bundle increased its length by interactions between dynein-like motors and microtubules against a mechanical load. We found that intermediate cross-linking density resulted in maximal elongation of the bundle, because microtubules were easily buckled at low cross-linking density, whereas the displacement of microtubules was inhibited at high cross-linking density. When individual microtubules were much stiffer, the bundle showed higher elongation even with lower cross-linking density, since stiff microtubules were less likely to be buckled by compressive loads. Our study provides new insights into the mechanisms driving axonal outgrowth.

biophysics↗

bioRxiv2025

Generalized brain-state modeling with KenazLBM

The large-scale functional state of a human brain remains difficult to characterize, much less predict. Regardless, techniques have been engineered to electrically neuromodulate the brain to treat a subset of neurologic and psychiatric disorders with moderate efficacy. Accurate characterization of a brains instantaneous functional state has stymied the development of more effective neuromodulation paradigms. Advanced computational methods are required to address this gap and enable large-scale neuroscience. Here we define the concept of generalized brain-state modeling across humans as Large Brain-State Modeling (LBM) and present KenazLBM as the worlds first example. KenazLBM can instantaneously characterize the functional state of a persons brain with raw iEEG data, and predict future brain-states. KenazLBM was trained on over 17.9 billion unique multichannel tokens from people undergoing intracranial electroencephalography (iEEG) recordings, and has learned to interrelate brain-states between people into a common interpretable topology. Most importantly, the model generalizes to unseen subject data with significant recording channel heterogeneity from the training set. We offer KenazLBM as a first generalized brain-state model to serve as a new paradigm of basic neuroscience inquiry and potential translation into neuromodulation therapeutics.

neuroscience↗

bioRxiv2025

Multi-modal Monte Carlo MRI simulator of tissue microstructure

Monte Carlo simulation of MRI signals is a powerful tool for modelling and quantifying tissue microstructure. While these methods have been used in MRI for decades, they typically focus on one aspect of microstructure and one type of MRI contrast at a time. In this paper, we present a new Monte Carlo MRI (MCMR) simulator for investigating the impact of tissue microstructure on arbitrary MRI sequences. A key feature of the proposed simulator is that substrates can incorporate multiple microstructural features (diffusion, T1/T2 relaxation, membrane permeability, local off-resonance fields, surface relaxation and magnetisation transfer) simultaneously. This provides a single forward model from tissue microstructure to MRI signals that captures a broad range of contrasts typically considered to be of different MRI "modalities". We validate the results of the simulator by reproducing previous findings in well-established sequences, namely diffusion-weighted MRI, magnetisation transfer imaging, and gradient and spin echo sequences. The simulator is fully open source and packaged along with detailed documentation and tutorials.

neuroscience↗

bioRxiv2025

Interferon signaling underlies radiotherapy responses in malignant peripheral nerve sheath tumors (MPNSTs)

Malignant peripheral nerve sheath tumors (MPNSTs) have poor outcomes despite multimodal treatment with surgery, radiation, and systemic therapy. Here, we combine bulk and single cell transcriptomics, genome wide CRISPRi screens, and multiplatform molecular analysis across MPNST cells, mouse allograft models, and human patient samples to understand the mediators of radiation response. Our data reveal MPNSTs induce a type I interferon signature that functionally underlies radiation response. Moreover, irradiation of immunocompetent mouse MPNST allografts leads to interferon mediated T-cell recruitment and activation. Analysis of human MPNST resection specimens demonstrates increased microenvironmental and CD8+ T-cell infiltration are associated with improved local control following radiotherapy while chromosome 9p loss, which harbors an interferon gene cluster, is associated with poor radiotherapy response and decreased CD8+ T-cell infiltration. Taken together, these results provide preclinical rationale for combining immunomodulatory agents targeting interferon signaling to improve radiation responses in MPNSTs, which may be broadly applicable to other soft tissue sarcomas.

cancer biology↗

bioRxiv2025

Approximating Signal Sources in Stereo-EEG Single Pulse Electrical Stimulation using Re-referencing and Spectral Analysis

Stereoelectroencephalography (sEEG) is a method of epilepsy monitoring that uses stereotactically placed depth electrodes. Connectivity between brain regions may be assessed by delivering a current pulse from sEEG electrode(s) and monitoring all other electrodes for Brain Stimulation-Evoked Potentials (BSEPs). However, the shape, magnitude, and spectral content of BSEPs are sensitive to the analysis approaches used to study them. In order to understand the nuance between analysis and interpretation of BSEP data, we carefully apply and contrast modified common average & bipolar re-referencing techniques, combined with wavelet-based spectral analysis on measured data from 4 human subjects. Comparison between analysis approaches allows us to identify recording sites within, near, or far from the tissue source of the BSEPs they record. We further explore the interaction between re-referencing techniques and dipole source orientation, providing methods to estimate source location and upper bound of far field recordings. This systematic application and comparison of different analysis tools can enable those who study BSEPs to localize potential sources within, near, or far from measurement sites, and more accurately constrain how brain connectivity is understood from stimulation experiments.

neuroscience↗