Biology subjects

Rowe, J.

Publications and source records attributed to Rowe, J..

At least 19 recordsLinked to original sources

bioRxiv2026

From group-level neurophysiological biomarkers to individual-level phenotyping to identify mechanisms of neurodegenerative disease

Precision medicine approaches require physiological effects to be informative when translated to the individual. Reliable group differences may have limited individual value when distributions overlap, mechanisms are heterogeneous, or patients differ in phenotype. A feature can differ between group means and still overlap heavily across individuals Moreover, combinations of physiological abnormalities may reveal subject-level structure that is not captured by any single marker at the group level. We evaluate the translation between group- and individual-level features derived from resting-state magnetoencephalography (MEG) using behavioural-variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy (PSP) as demonstrator conditions. These illnesses have distinct molecular pathology but share the pressing need for therapeutic development and have partially overlapping clinical and physiological features. We combine clinical phenotype, power spectral density (PSD), and latent network mechanisms inferred by dynamic causal modelling (DCM) to compare groups and to access their individuals mapping translations. We used classification as an exploratory probe of how group-defined physiological features from 74 healthy controls, 45 participants with bvFTD and 55 participants with PSP support individual assignment. Clinical scores showed strong individual-level translation, consistent with clinical diagnostic definitions (e.g, controls-vs-PSP accuracy 0.94; bvFTD-vs-PSP accuracy 0.83). MEG spectra feature classified individuals weakly (accuracy ~0.6), despite group level re-organization (e.g., reduced beta-band and increased fronto-insular alpha-phase/beta-amplitude coupling in bvFTD). Inferred biophysical parameters gave intermediate performance (e.g. PSP-vs-control accuracy 0.70; bvFTD-vs-PSP accuracy 0.74) while retaining mechanistic interpretability. Using this approach, experimental medicine studies of neurological disease can formally trade between mechanistic insight and classification performance, in using biomarkers that can account for individual heterogeneity within and between diagnostic groups.

bioengineering↗

bioRxiv2026

A Bayesian approach to volumetric analysis in rare neurodegenerative disorders

Identifying regional brain atrophy is critical for understanding neurodegenerative disorders. Traditionally, group comparisons rely on frequentist statistics, utilising $p$-values and point estimates that offer limited characterization of uncertainty. Bayesian methods provide an alternative by estimating effect sizes and credible intervals while incorporating prior knowledge and uncertainty. This study evaluated the feasibility of Bayesian hierarchical modelling to assess regional brain atrophy in Progressive Supranuclear Palsy (PSP) and Corticobasal Syndrome (CBS) compared to healthy controls. Participants meeting diagnostic criteria for CBS or PSP, together with healthy controls, were recruited from the Cambridge Centre for Parkinson-plus. Grey matter volume, cortical thickness, and subcortical volumes were derived using FreeSurfer for 210 cortical and 36 subcortical regions defined by the Human Brainnetome Atlas. Participants with PSP were classified into Richardson syndrome (PSP-RS), corticobasal syndrome variant (PSP-CBS), frontal variant (PSP-F), and other presentations (PSP-Other). Bayesian hierarchical ANOVA models with appropriate priors were used to estimate group differences. Regions of practical equivalence (ROPE) were calculated to assess evidence of meaningful group effects. A total of 428 people were included (113 PSP-RS, 30 PSP-CBS, 23 PSP-Other, 19 PSP-F, 81 CBS, and 162 healthy controls). For grey matter volume, there was evidence of whole brain volume loss compared to controls for all disease groups except PSP-Other, which showed evidence of no difference. For cortical thickness, there was evidence of global cortical thinning in CBS compared to controls, but for no other group. For subcortical volume all groups showed evidence of volume loss compared to controls. Patterns of regional atrophy were identified in keeping with previous literature, with the largest effect observed in the left pre-motor thalamus (30\% reduction in CBS). There was greater loss of subcortical volume in PSP-RS compared to other PSP subgroups. Bayesian hierarchical modelling provides a feasible framework for quantifying regional brain atrophy, with interpretable effect size estimates and uncertainty measures. This approach complements conventional statistical methods, particularly in the assessment of rare neurodegenerative and neuropsychiatric disorders.

neuroscience↗

bioRxiv2026

Serial Thermal Ablation Induces Abscopal Antitumor Immunity and Reveals Targetable CSF1R-Dependent Resistance in Pancreatic Cancer

Thermal ablation is increasingly used for local control of pancreatic ductal adenocarcinoma (PDAC), but its capacity to induce systemic antitumor immunity and the mechanisms limiting this response remain incompletely defined. Using a bilateral LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) flank tumor model, we show serial radiofrequency ablation (RFA) enhances local tumor control and induces a robust abscopal response. This effect was associated with increased activation of CD8 T cells and natural killer cells, and was abrogated by CD8 T cell depletion. Single-cell RNA sequencing revealed expansion of cytotoxic immune programs alongside induction of a CSF1R-driven myeloid response consistent with adaptive immune resistance. Although combinatorial blockade of PD-L1 and CD73 augmented systemic antitumor responses, and the addition of CSF1R inhibition in this context further enhanced both local and distant tumor control. These findings identify a CSF1R-dependent myeloid resistance program which constrains ablation-induced systemic immunity and demonstrate that rational combination immunotherapy can potentiate the systemic efficacy of tumor ablation in PDAC. STATEMENT OF TRANSLATIONAL RELEVANCERadiofrequency ablation is a local thermal therapy that induces tumor destruction and modulation of the tumor microenvironment used for treatment of many solid tumors, including pancreatic cancer. Serial thermal ablations induce a CD8+ T cells and NK cell antitumor immunological response; however, Nt5e (CD73) is increased in tumor cells, PD-1 is increased in CD8+ T cells, and serial ablations increase a CSF1R+ macrophage cluster in ablated tumors. Combinational targeting of CD73, PD-L1, and CSF1R alleviates CSF1R-dependent therapeutic resistance and enhances local and systemic tumor control. This study identifies targetable countervailing mechanisms to local ablation therapy and provides a rationale for combinatorial strategies integrating serial tumor ablation with systemic immunomodulatory agents. Future prospective studies should evaluate the influence of timing, dosage, and sequence of ablation on immune priming to improve clinical interventions in pancreatic cancer.

cancer biology↗

bioRxiv2025

Apathy as a Loss of Prior Precision on Action Outcomes

Apathy is common in neurological disease, associated with poor prognosis and limited treatments. Current models posit that goal-directed actions are reduced because costs or effort outweigh the expected reward. We highlight an alternative account of apathy, based on the reduction in precision of prior beliefs about action outcomes. In this preregistered study, we test the hypothesis that precision is encoded in the GABAergic gain of prefrontal superficial pyramidal neurons. Fifty healthy adults undertook a goal-directed task during magnetoencephalography. Estimates of synaptic efficacy or gain were obtained by dynamic causal modelling of induced responses. There was strong evidence of a negative correlation between prior precision and apathy (Bayes Factor=12, p<0.01), and that prior precision was associated with gain in prefrontal and premotor neuronal populations (Posterior probability>0.99). The importance of prior precision and GABAergic gain for goal-directed actions opens new avenues to advance the understanding and treatment of apathy.

neuroscience↗

bioRxiv2025

Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis

Amino acids play critical roles in the activation and function of lymphocytes. Here we show that the non-essential amino acid, asparagine, is essential for optimal activation and proliferation of CD4+ T cells. We demonstrate that asparagine depletion at different time points after CD4+ T cell activation reduces mitochondrial membrane potential and function. Furthermore, asparagine depletion at specific time points during CD4+ T cell differentiation reduces cytokine production in multiple CD4+ T cell subsets. In an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE), myelin oligodendrocyte-specific pathogenic T helper 17 cells differentiated under Asn-deficient conditions exhibited reduced encephalitogenic potential and attenuated EAE severity. In a model of EAE induced by active immunization, therapeutic depletion of extracellular Asn significantly reduced disease severity. These results identify asparagine as a key metabolic regulator of the pathogenicity of autoreactive CD4+ T cells and suggest that targeting asparagine metabolism may be a novel therapeutic strategy for autoimmunity.

immunology↗

bioRxiv2025

Small tau aggregates exhibit disease-specific molecular profiles across tauopathies

Tauopathies are neurodegenerative diseases marked by pathological tau aggregation. While disease-specific folds of insoluble tau filaments have been established, it remains unclear whether the smaller, earlier species also differ across tauopathies. Here, we characterise these small tau aggregates from post-mortem brain of individuals with Alzheimers disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration, Picks disease, and healthy controls. Using two complementary single-molecule assays, we confirm that small tau aggregates vary in abundance, morphology, and post-translational modifications. AD features specific long, fibrillar-shaped aggregates enriched in phospho-epitopes, while PSP aggregates are shorter, round, and selectively phosphorylated at serine-356, a site we identify as correlating with markers of inflammation and apoptosis. Aggregate properties co-vary with cellular stress signatures and align with disease-specific seeding profiles, suggesting distinct pathological mechanisms. These findings suggest that small tau aggregates are not a shared intermediate, but instead encode disease-specific mechanisms, with potential as both biomarkers and therapeutic targets. Key pointsSmall tau aggregates show disease-specific signatures across tauopathies, differing in abundance, morphology, and post-translational modifications. Tau aggregates in AD show enhanced phosphorylation density and structural heterogeneity, including a distinct population of long fibrillar species detectable in the soluble fraction. Alzheimers disease is characterised by specific long, fibrillar-shaped tau aggregates enriched in disease-relevant phospho-epitopes. PSP features round pSer356-positive aggregates that correlate with apoptotic and inflammatory markers, suggesting a distinct mechanism of toxicity. Isoform-specific biosensor assays reveal divergent seeding behaviour: CBD shows strong 4R seeding, while PSP lacks seeding activity. Features of small aggregates co-vary with distinct patterns of gliosis and cell stress, suggesting disease-specific mechanisms of tau-mediated toxicity.

neuroscience↗

bioRxiv2023

Reliability of dynamic causal modelling of resting state magnetoencephalography

This study assesses the reliability of resting-state dynamic causal modelling (DCM) of magneto-electroencephalography under conductance-based canonical microcircuit models, in terms of both posterior parameter estimates and model evidence. We use resting state magneto-electroencephalography (MEG) data from two sessions, acquired two weeks apart, from a cohort with high between-subject variance arising from Alzheimers disease. Our focus is not on the effect of disease, but on the predictive validity of the methods implicit in their reliability, which is crucial for future studies of disease progression and drug intervention. To assess the predictive validity of first-level DCMs, we compare model evidence associated with the covariance among subject-specific free energies (i.e., the quality of the models) with vs. without interclass correlations. We then used parametric empirical Bayes (PEB) to investigate the predictive validity of DCM parameters at the between subject level. Specifically, we examined the evidence for or against parameter differences (i) within-subject, within-session, between-epochs; (ii) within-subject between-session and (iii) within-site between-subjects, accommodating the conditional dependency among parameter estimates. We show that for data acquired close in time, and under similar circumstances, more than 95% of inferred DCM parameters are unlikely to differ, speaking to mutual predictability over sessions. Using PEB, we show a reciprocal relationship between a conventional definition of reliability and the conditional dependency among inferred model parameters. Our analyses confirm the predictive validity and reliability of the conductance-based DCMs for resting-state neurophysiological data. In this respect, the implicit generative modelling is suitable for interventional and longitudinal studies of neurological and psychiatric disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/562379v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@135c964org.highwire.dtl.DTLVardef@38e4a7org.highwire.dtl.DTLVardef@12bc358org.highwire.dtl.DTLVardef@25f110_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Combined studies of N170/M170 responses to single letters and pseudoletters

To read efficiently, individuals must be able to rapidly identify letters within their visual networks, which occurs through forming line segments into letters and then letters into words. The temporal processes and utilized brain areas that engage in this process are widely thought to be left-lateralized within the brain. However, a range of studies demonstrate that the processing of unfamiliar stimuli, such as pseudoletters, is temporally delayed and bilaterally processed when compared to letters. The present study investigated the contributions of both hemispheres and how these interactions impact the temporal dynamics of implicit visual processing of single-letters as compared to unfamiliar pseudoletters (false fonts). The results of 5 "in-house" studies are presented within a meta-analysis (synthesis analysis), 3 High-density EEG studies and 2 MEG studies. Of the 3 EEG studies, 2 focused on measuring event related potentials (ERPs) while the participants performed an orthographic discrimination task (letters vs pseudoletters) and the other was a target detection task in which the participants detected infrequent, simple perceptual targets within a series of pseudoletter and letter strings. Of the 2 MEG studies, one was a discrimination task and the other a target detection task. Delayed N170 waveforms to pseudoletters as compared to letters were exhibited across all studies. Lateralization of the ERP differences between letter-evoked and pseudoletter-evoked responses were bilaterally distributed, whereas lateralization measure separately for letters and pseudoletters were primarily left-lateralized. As a whole, these in-house studies indicate that ERPs to letters occur earlier than to pseudoletters, and that interpretation of hemispheric laterality depends on whether the researcher is assessing ERP differences between letters and pseudoletters or the ERP waveforms of the separate letter and pseudoletter conditions.

neuroscience↗

bioRxiv2023

Biodistribution Analysis of Peptide-Coated Magnetic Iron Nanoparticles: A Simple and Quantitative Method

Biodistribution is the tracking of compounds or molecules of interest in the subject which is integral to understanding their anticipated efficacy and safety. Nanoparticles are highly desirable delivery systems which have the ability to deliver higher nucleic acid and drug payloads and they have enhanced tumor permeability due to their unique properties such as high surface area to volume ratio. Studying the biodistribution of nanoparticles is crucial to understand their effectiveness and safety in vivo, facilitate a more application driven approach for nanoparticle development which will lead to their successful translation into clinical use. In this study, we present a relatively simple method to determine the biodistribution of magnetic iron nanoparticles in mice. Branched Amphiphilic Peptide coated Magnetic Nanobeads BAPc-MNBs like their counterpart i.e., Branched Amphiphilic Peptide capsules (BAPCs) with a hollow water-filled core, are readily taken up by cells in vitro and have widespread application as a nanodelivery systems. We evaluated the BAPc-MNBs tissue distribution in wildtype mice injected intravenously (i.v.), intraperitoneally (i.p.) or orally gavaged to understand the biological interactions of the peptide nanoparticles and to further the development of branched amphiphilic peptides-based nanoparticles. BAPc-MNBs were distributed widely to various organs when injected i.v. and were eliminated from the system via the intestines in feces. The spleen was found to accumulate the highest amount of BAPc-MNBs in mice administered the NPs i.v. and i.p. while they were not absorbed into the system via oral gavage. This study not only presents a relatively simple quantification method to determine in vivo biodistribution of magnetic iron nanoparticles that can be widely applied but also demonstrates the potential of Branched Amphiphilic Peptides in the form of BAPCs or BAPc-MNBs as a delivery system.

biochemistry↗

bioRxiv2023

Stomata, a vulnerability in the plant defence against phytophagous mites that ABA can overcome

Arthropod herbivory possess a significant threat to crop yield, prompting plants to employ intricate defense mechanisms against pest feeding. The generalist pest, Tetranychus urticae, inflicts rapid damage and remains a challenge due to its broad target range. In this study, we explored Arabidopsis thalianas response to T. urticae infestation, revealing the induction of abscisic acid (ABA), a hormone typically associated with abiotic stress adaptation, including stomatal closure during water stress. Leveraging a FRET-based ABA biosensor (nlsABACUS2-400n), we observed elevated ABA levels in various leaf cell types post-mite feeding. While ABAs role in pest resistance or susceptibility has been debated, an ABA-deficient mutant exhibited increased mite infestation, alongside intact canonical biotic stress signalling, indicating an independent function of ABA in mite defense. Through genetic and pharmacological interventions targeting ABA levels, ABA signalling, stomatal aperture, and density, we established that ABA-triggered stomatal closure effectively hinders mite feeding and minimizes leaf cell damage. This study underscores the critical interplay between biotic and abiotic stresses in plants, highlighting how the vulnerability to mite infestation arising from open stomata, crucial for transpiration and photosynthesis, underscores the intricate relationship between these two stress types.

plant biology↗

bioRxiv2023

Characterization and super-resolution imaging of small tau aggregates in human samples.

Hyperphosphorylation and aggregation of the microtubule binding protein tau plays a key role in the development of Alzheimers disease. While the structure of the filamentous aggregates formed in humans has recently been determined to atomic resolution, there is far less information available about the smaller aggregate precursors, thought to be the most neurotoxic. To address this gap, we have developed a single molecule pull-down (SiMPull) able to detect tau aggregates in clinically relevant human samples. This method enables the detection and characterisation of individual tau aggregates, as opposed to averaged features obtained from traditional bulk techniques. We report the number, size and shape of individual aggregates measured via super-resolution microscopy, revealing disease-specific differences in tau aggregate morphology. By adapting the assay to simultaneously detect multiple phosphorylation sites in individual aggregates, we were also able to derive compositional profiles for pathological modifications present in individual aggregates. We demonstrate that tau aggregates in Alzheimers disease are significantly more likely to contain both the AT8 and T181 pathological phosphorylation markers, rather than only one. Together, tau SiMPull identified distinct subpopulations of large, modified tau aggregates that were invisible to traditional methodologies. These morphological and compositional differences distinguish samples taken from disease cohorts, offering to illuminate underlying disease mechanisms, and providing a foundation for novel diagnostic strategies.

biochemistry↗

bioRxiv2023

Compartment-Specific Activation of the Proton-Sensor GPR65 is Uncoupled from Receptor Trafficking

The canonical view of G protein-coupled receptor (GPCR) function is that receptor trafficking is tightly coupled to signaling. GPCRs remain on the plasma membrane (PM) at the cell surface until they are activated, after which they are desensitized and internalized into endosomal compartments. This canonical view presents an interesting context for proton-sensing GPCRs because they are more likely to be activated in acidic endosomal compartments than at the PM. Here we show that the trafficking of the prototypical proton-sensor GPR65 is fully uncoupled from signaling, unlike that of other known mammalian GPCRs. GPR65 internalized and localized to early and late endosomes, from where they signal at steady state, irrespective of extracellular pH. Acidic extracellular environments stimulated receptor signaling at the PM in a dose-dependent manner, although endosomal GPR65 was still required for a full signaling response. Receptor mutants that were incapable of activating cAMP trafficked normally, internalized, and localized to endosomal compartments. Our results show that GPR65 is constitutively active in endosomes, and suggest a model where changes in extracellular pH reprograms the spatial pattern of receptor signaling and biases the location of signaling to the cell surface.

pharmacology and toxicology↗

bioRxiv2023

Cognition's dependence on functional network integrity with age is conditional on structural network integrity

Maintaining good cognitive function is crucial for well-being across the lifespan. We proposed that the degree of cognitive maintenance is determined by the functional interactions within and between large-scale brain networks. Such connectivity can be represented by the white matter architecture of structural brain networks that shape intrinsic neuronal activity into integrated and distributed functional networks. We explored how the function-structure connectivity convergence, and the divergence of functional connectivity from structural connectivity, contribute to the maintenance of cognitive function across the adult lifespan. Multivariate analyses were used to investigate the relationship between function-structure connectivity convergence and divergence with multivariate cognitive profiles, respectively. Cognitive function was increasingly dependent on function-structure connectivity convergence as age increased. The dependency of cognitive function on connectivity was particularly strong for high-order cortical networks and subcortical networks. The results suggest that brain functional network integrity sustains cognitive functions in old age, as a function of the integrity of the brains structural connectivity.

neuroscience↗

bioRxiv2022

Next-generation ABACUS biosensors reveal cellular ABA dynamics driving root growth at low aerial humidity

The plant hormone abscisic acid (ABA) accumulates under abiotic stress to recast water relations and development. To overcome a lack of high-resolution, sensitive reporters, we developed ABACUS2s, next-generation FRET biosensors for ABA with high affinity, signal-to-noise ratio and orthogonality, that reveal endogenous ABA patterns in Arabidopsis thaliana. We mapped stress-induced ABA dynamics in high-resolution to reveal the cellular basis for local and systemic ABA functions. At reduced foliar humidity, roots cells accumulated ABA in the elongation zone, the site of phloem transported ABA unloading. Phloem ABA and root ABA signalling were both essential to maintain root growth at low humidity. ABA coordinates a robust system to maintain root growth in response to foliar stresses, enabling plants to maintain foraging of deeper soil for water uptake

plant biology↗

bioRxiv2022

Chemical bonds in collagen rupture selectivelyunder tensile stress

Collagen fibres are the main constituent of the extracellular matrix, and fulfil an important role in the structural stability of living multicellular organisms. An open question is how collagen absorbs pulling forces, and if the applied forces are strong enough to break bonds, what mechanisms underlie this process. As experimental studies on this topic are challenging, simulations are an important tool to further our understanding of these mechanisms. Here, we present pulling simulations of collagen triple helices, revealing the molecular mechanisms induced by tensile stress. At lower forces, pulling alters the configuration of proline residues leading to an effective absorption of applied stress. When forces are strong enough to introduce bond ruptures, these are located preferentially in X-position residues. Reduced backbone flexibility, for example through mutations or cross linking, weakens tensile resistance, leading to localised ruptures around these perturbations. In fibre-like segments, a significant overrepresentation of ruptures in proline residues compared to amino acid contents is observed. This study confirms the important role of proline in the structural stability of collagen, and adds detailed insight into the molecular mechanisms underlying this observation.

molecular biology↗

bioRxiv2022

Neurochemistry-enriched dynamic causal models of magnetoencephalography, using magnetic resonance spectroscopy

We present a hierarchical and empirical Bayesian framework for testing hypotheses about synaptic neurotransmission, based on the integration of ultra-high field magnetic resonance spectroscopy (7T-MRS) and magnetoencephalography data (MEG). A first level dynamic causal modelling of cortical microcircuits is used to infer the connectivity parameters of a generative model of individuals neurophysiological observations. At the second level, individuals 7T-MRS estimates of regional neurotransmitter concentration supply empirical priors on synaptic connectivity. We compare the group-wise evidence for alternative empirical priors, defined by monotonic functions of spectroscopic estimates, on subsets of synaptic connections. For efficiency and reproducibility, we used Bayesian model reduction (BMR), parametric empirical Bayes and variational Bayesian inversion. In particular, we used Bayesian model reduction to compare models of how spectroscopic neurotransmitter measures inform estimates of synaptic connectivity. This identifies the subset of synaptic connections that are influenced by neurotransmitter levels, as measured by 7T-MRS. We demonstrate the method using resting-state MEG (i.e., task-free recording) and 7T-MRS data from healthy adults. We perform cross-validation using split-sampling of the MEG dataset. Our results confirm the hypotheses that GABA concentration influences local recurrent inhibitory intrinsic connectivity in deep and superficial cortical layers, while glutamate influences the excitatory connections between superficial and deep layers and connections from superficial to inhibitory interneurons. The method is suitable for applications with magnetoencephalography or electroencephalography, and is well-suited to reveal the mechanisms of neurological and psychiatric disorders, including responses to psychopharmacological interventions.

neuroscience↗

bioRxiv2022

ABA signaling prevents phosphodegradation of the Arabidopsis SR45 splicing factor to negatively autoregulate inhibition of early seedling development

Alternative splicing is a key posttranscriptional mechanism to expand the coding capacity of eukaryotic genomes. Although the functional relevance of this process remains poorly understood in plant systems, major modulators of alternative splicing called serine/arginine-rich (SR) proteins have been implicated in plant stress responses mediated by the abscisic acid (ABA) hormone. Loss of function of the Arabidopsis thaliana SR-like protein SR45, a bona fide splicing factor, has been shown to cause plant hypersensitivity to environmental cues and activation of the ABA pathway. Also, consistent with both animal and plant SR proteins being extensively and reversibly phosphorylated at their C-termini, ABA-induced changes in the phosphorylation status of SR45 have been reported. Here, we show that SR45 overexpression reduces Arabidopsis sensitivity to ABA during early seedling development. Moreover, exposure to ABA dephosphorylates SR45 at multiple amino acid residues and leads to accumulation of the protein via reduction of SR45 ubiquitination and proteasomal degradation. Using phosphomutant and phosphomimetic transgenic Arabidopsis lines, we demonstrate the functional relevance of ABA-mediated dephosphorylation of a single SR45 residue, T264, in antagonizing SR45 ubiquitination and degradation to promote its function as a repressor of seedling ABA sensitivity. Taken together, our results reveal a mechanism in which ABA signaling negatively autoregulates during early plant development via posttranslational control of the SR45 splicing factor.

plant biology↗

bioRxiv2022

Radiofrequency ablation remodels the tumor microenvironment and promotes systemic immunomodulation in pancreatic cancer

Background and AimsPancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to therapy. A major contributing factor to therapeutic failure is profound desmoplasia and a well-documented hypoxic tumor microenvironment (TME). In PDAC, several therapeutic approaches, including chemotherapy and radiation alone or combined with immune checkpoint inhibitors, have shown minimal therapeutic success, placing an imperative need for the discovery and application of innovative treatments. Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) is a promising immunomodulator therapy for PDAC. In this work, we hypothesized RFA promotes local and systemic stromal and immunomodulating effects that can be identified for new combination therapeutic strategies. MethodsTo test our hypothesis, a syngeneic PDAC mouse model was performed by symmetrically injecting 100k murine KPC cells in bilateral flanks of C57BL/6 female mice. RFA treatment initiated when tumors reached 200-500 mm3 and was performed only in the right flank. The left flank tumor (non-RFA contralateral side) was used as a paired control for further analysis. ResultsRFA promoted a significant reduction in tumor growth rate 4 days after treatment in RFA treated and non-RFA side contralateral tumors from treated mice when compared to controls. Histological analysis revealed a significant increase in expression of cleaved Caspase3 in RFA treated tumors. In addition, collagen deposition and CD31+ cells were significantly elevated in RFA side and non-RFA contralateral tumors from RFA treated mice. Proteome profiling showed changes in C5a and IL-23 in RFA responsive tumors, indicating a role of RFA in modulating intratumoral inflammatory responses. ConclusionsThese data indicate RFA promotes local and systemic anti-tumor responses in a syngeneic mouse model of PDAC implicating RFA treatment for local tumors as well as metastatic disease. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

cancer biology↗