Biology subjects

Dodd, A.

Publications and source records attributed to Dodd, A..

15 recordsLinked to original sources

bioRxiv2026

Entrainment of the Arabidopsis circadian clock to skeleton photoperiods

Entrainment aligns the phase of the circadian clock and its outputs with 24 h fluctuations in the environmental conditions. One approach for investigating entrainment involves the application of skeleton photoperiods. In these protocols, light pulses are used to demarcate dawn and dusk, with the organism otherwise remaining under constant darkness. Historically, the consequences of skeleton photoperiod entrainment have been investigated by tracking behavioural responses in mammalian and insect models. In comparison, effects of skeleton photoperiod entrainment upon the plant circadian oscillator have received less attention. Using promoter-luciferase reporters for the Arabidopsis thaliana circadian clock, we monitored clock function during both entrainment to skeleton photoperiods, and subsequent free-running conditions. This enabled us to access molecular responses of the plant circadian oscillator to skeleton light conditions. We identified that individual circadian oscillator components in Arabidopsis can entrain to skeleton photoperiods. When these skeleton photoperiods were extended to represent long-day conditions, the oscillator underwent a phase jump relative to intact photoperiod entrainment such that it interpreted the dusk light pulse as dawn, and vice versa. This mirrors phase jumps that have been reported for rodent and insect behaviour following entrainment to long skeleton photoperiods, supporting the idea that phase jumps under skeleton photoperiod entrainment are a universal feature of circadian entrainment. Our results provide important context for the interpretation of physiological and developmental phenotypes of plants under modified light conditions.

plant biology↗

bioRxiv2026

Extra-lineage tissue programs define the transcription states of human pancreatic cancer

Cancers acquire alternate transcriptional states as they evolve, but the origins, timing and determinants of this plasticity are poorly understood in many tumours. We investigated the transcriptional states of pancreatic cancer by integrating [~]1000 tumour-enriched genomes and transcriptomes from 464 patients combined with scRNA-seq, multiome profiling, and spatial proteomics. Four epithelial states covering the spectrum of lineage plasticity were identified (Classical-1, Classical-2, Basal-1, Basal-2). Comparing these states to normal and pan-cancer human single cell atlases showed each state reflects distinct tissue programs found in other malignancies. Single cell analysis uncovered that the main transcription state of this disease (Classical-1) emerges before KRAS mutations. Spatial proteomics from patients and cancer-free donors showed that the Classical-1 program emerges during acinar-to-ductal metaplasia, and also unexpectedly, in normal ducts without disrupting their morphology. Overall, these findings link the extensive lineage plasticity potential of this organ to the origins of the transcriptional states.

cancer biology↗

bioRxiv2026

Transcriptomic, Genomic, and Clinical Characterization of Morphological Classes in Localized and Metastatic Pancreatic Cancer

BackgroundHistomorphology is a strong prognostic biomarker correlated with basal-like and classical programs in surgically resected pancreatic ductal adenocarcinoma (PDAC). However, the spectrum of morphology and its biological associations remain poorly defined in advanced disease. ObjectivesWe explored the transcriptomic and genomic underpinnings and clinical relevance of morphological classes across localized and metastatic PDAC. DesignWe unified morphological classifications into four classes: glandular, cribriform, solid, and squamous. We integrated transcriptome and whole-genome sequencing following laser-capture microdissection with morphological classifications in 348 PDAC patients, where half of the cohort included locally advance and metastatic stages to uncover molecular associations. ResultsNon-glandular morphologies comprised three distinct classes that were enriched in metastatic disease. Transcriptomic profiling exhibited that glandular tumours predominantly expressed classical epithelial programs, although a subset displayed partial or full epithelial- mesenchymal transition signatures. In contrast, non-glandular morphologies showed basal-like transcriptional programs with subtype-specific pathways, including ciliogenesis in cribriform tumours, extracellular matrix remodelling and immune evasion in solid tumours, and keratinisation programs in squamous tumours. The solid class was significantly enriched in liver metastatic lesions and was associated with increased intra-tumoural morphological heterogeneity, whole-genome doubling, KRAS major allelic imbalance, and elevated KRAS-ERK signalling. ConclusionNon-glandular morphologies identify biologically distinct PDAC tumour states that are enriched in liver metastases and associated with subtype-specific transcriptional programs and KRAS-driven genomic alterations.

cancer biology↗

bioRxiv2026

Vernalisation-induced changes to the Arabidopsis circadian clock require Polycomb Repressive Complex 2 and are FLC-independent

In many plants, prolonged winter cold and seasonal day-length changes align the transition to flowering with spring. This occurs through the vernalisation and photoperiod pathways, respectively. Despite roles for the circadian clock in regulating both pathways, their mechanisms have mainly been studied in isolation and their interactions are not fully understood. We found that vernalisation elicits changes in the circadian clock and this is linked to alterations in several clock-controlled outputs, including photoperiodic flowering. Importantly, vernalisation-induced changes in specific clock genes are stable and persist upon return to warmth, providing the circadian clock with a memory of prior long-term cold exposure. The changes are not systematic and affect specific circadian oscillator genes. This change requires the epigenetic regulator Polycomb Repressive Complex 2 (PRC2), but not the major genetic determinants of vernalisation FRIGIDA (FRI) and FLOWERING LOCUS C (FLC). In contrast to their role in FLC silencing, core PRC2 components but not accessory proteins are required for these changes in the clock post-vernalisation. Our work raises the possibility that long-term cold feeds epigenetic information into the clock as a seasonal response mechanism, potentially preparing plants for the coming season.

plant biology↗

bioRxiv2026

Circadian entrainment to environmental cues in a natural plant population

Circadian clocks coordinate physiology, development and behaviour with cycles of day and night, which contributes to organismal fitness. For this to occur, the circadian clock must be aligned with the natural daily fluctuations in the environmental conditions. Here, we investigated under natural conditions the role of environmental cues in adjusting the circadian clock, and how this affects clock outputs. By combining novel field-based experimentation in a natural plant population with genome-wide analysis and machine-learning strategies for data interpretation, we inferred that temperature cues change circadian timing under natural conditions. We inferred that low temperature cues can shift circadian phase under naturally fluctuating conditions, and that there are seasonal changes in the effects of temperature upon circadian entrainment. We also identified extensive circadian modulation of temperature responses under field conditions. Therefore, plasticity of circadian timing under natural conditions allows flexible responses of both the clock and its outputs to environmental stimuli.

plant biology↗

bioRxiv2025

Consensus molecular subtypes define distinct evolutionary trajectories of biliary tract cancers

Introduction Biliary tract cancer (BTC) comprises a family of rare malignancies subclassified by anatomy and pathology. However, this scheme may obscure shared biology and limit patient stratification. Objectives We tested whether BTC heterogeneity can be explained by coherent latent axes and evaluated the potential to unify diverse clinical and genomic factors under a tractable biological framework Methods We performed whole-genome and transcriptome sequencing of 180 tumors enriched for tumor cells by laser capture microdissection to identify shared programs in BTC. Results Network integration across transcriptomic classes identified two consensus cancer subtypes (CCS). CCS segregated with anatomical location of primary tumor and gene expression marker analyses suggest subtypes reflect tumor cell of origin differences. CCS displayed strikingly divergent molecular landscapes, explaining more variance than anatomical location of primary tumor. CCS-B tumors were mutationally loaded with clock-like and APOBEC signatures and extrachromosomal DNA, whereas CCS-A tumors were characterized by chromosome-arm deletions. Conclusion Our approach showed that harnessing the genomic and transcriptomic diversity of BTC uncovers novel biology and improves stratification.

cancer biology↗

bioRxiv2025

The subclonal footprint of pervasive early dissemination in pancreatic cancer

Early is too late describes a central problem in pancreatic cancer referring to its relentless drive to disseminate and highlights the need to understand how this disease spreads so rapidly. In this study, we profiled 1,013 samples from 277 donors, including tissue whole genome and RNA sequencing combined with plasma whole genome sequencing at [~]25x. Strikingly, local primary tumours, including some reaching 7cm, were found to shed little to no circulating tumour DNA (ctDNA). Instead, metastatic burden in the liver but not extrahepatic sites, was a main physiologic determinant of ctDNA levels. Whole-genome duplication (WGD), high cell cycle activity, and non-glandular differentiation emerged as tumour-intrinsic features related to increased ctDNA shedding. By contrast, decreased shedding was related to extrinsic features including a reactive microenvironment and unexpectedly, humoral immunity. Analysis of tumour clonal architecture showed that in patients with low ctDNA levels, the signal disproportionately originated from subclones and this signal persisted even when the primary tumour was removed. Disseminated subclones were a significant source of ctDNA in early-stage patients. Longitudinal analysis of patients revealed that subclones seeded metastases and shed ctDNA in the blood years before detection. This first report of paired tissue and plasma whole genomes in pancreatic cancer is a unique resource and has broad implications for disease surveillance, treatment monitoring, and early detection in this disease.

cancer biology↗

bioRxiv2025

Integrated spatial proteomics of human PDAC uncovers an expanded tumour-immune-stroma spectrum with genomic associations

Distinctively, pancreatic ductal adenocarcinoma (PDAC) consists of sparse tumour lesions intertwined with extensive desmoplastic stroma. The complexity of tumour-microenvironment interactions within this desmoplasia poses a challenge for accurate tumour profiling and patient stratification, and characterizes a profoundly chemoresistant tumour. Here we mapped the spatial relationships between tumour, stroma, and immune cell compartments delineating tumour and microenvironment types that expand the classical to basal spectrum of human PDAC. We used imaging mass cytometry to profile the in situ multi-cellular organization of 81 cell types in resected cases with paired whole genome sequencing. Cell types, functions, and pathway activation were distributed as highly reproducible environments in discrete locations throughout these tumours, which we deep-profiled using laser-capture mass spectrometry. We show that the connections between tumour phenotypes, vascularization, immune response, and stromal biophysical state are reinforced by genomic aberrations, altered by treatment, and associated with patient outcome. Predictive machine-learning models showed that spatial single cell data outperformed genomic or clinical features but integrated multi-omics models provide the best prediction of patient survival with compressed models requiring only 10 non-redundant robust molecular measures associated with the phenotypic spectrum of PDAC. Together, these findings define a phenotypic and molecular framework of PDAC that captures tumour-microenvironment co-dependencies and offers a refined basis for patient stratification and therapeutic targeting.

cancer biology↗

bioRxiv2025

snATAC-Express infers Gene Expression from Prioritized Chromatin Accessibility Peaks using Machine Learning

BackgroundSingle cell multi-omic investigation opens-up new opportunities to understand mechanisms of gene regulation. Existing methods for inferring transcript abundance from chromatin accessibility fail to prioritize the most relevant peaks and tend to assume positive associations between ATAC peaks and RNA counts. We hypothesize that gene regulation can be modeled as a function of combined positive and negative interactions among peaks and that causal regulatory variants are enriched in the vicinity of the most critical peaks. ResultsA machine learning pipeline leveraging single nuclear multiomic transcriptome and chromatin accessibility data is developed to model gene expression as a function of ATAC peak intensity. Multiome data was available for 18 immune cell types from 29 donors, 19 with Crohns disease. The pipeline aggregates results from three machine learning approaches (random forest regression, XGBoost, and Light GBM) as well as linear regression to identify which ATAC peaks contribute to explaining variation among donors and cell types in pseudobulk gene expression. The coefficient of determination with cross-validation was used to identify robust models which typically explain between 5% and 40% of transcript abundance, utilizing on average 47% of the ATAC peaks, representing a significant gain in predictive accuracy. The most important peaks are enriched in GWAS variants for inflammatory bowel disease and the autoimmune disease systemic lupus erythematosus, but not for rheumatoid arthritis. ConclusionAtlanta Plots visualize the proportion of ATAC peaks contributing to a predictive model of gene expression as well as the proportion of variance explained by the model. Software implementing our pipeline, "snATAC-Express", is freely available on GitHub.

bioinformatics↗

bioRxiv2022

Genome-wide circadian gating of a cold temperature response in bread wheat

Circadian rhythms coordinate the responses of organisms to their daily fluctuating environments, by establishing a temporal program of gene expression. This schedules aspects of metabolism, physiology, development and behaviour according to the time of day. Circadian regulation in plants is extremely pervasive, and is important because it underpins both productivity and seasonal reproduction. Circadian regulation extends to the control of environmental responses through a regulatory process known as circadian gating. Circadian gating is the process whereby the circadian clock regulates the response to an environmental cue, such that the magnitude of response to an identical cue varies according to the time of day of the cue. Here, we show that there is genome-wide circadian gating of responses to cold temperatures in plants. By using bread wheat as an experimental model, we establish that circadian gating is crucial to the programs of gene expression that underlie the environmental responses of a crop of major socioeconomic importance. Furthermore, we identify that circadian gating of cold temperature responses are distributed unevenly across the three wheat subgenomes, which might reflect the geographical origins of the ancestors of modern wheat. One-sentence summaryThere is genome-wide circadian gating of a response to low temperatures in a crop of major socioeconomic importance.

plant biology↗

bioRxiv2022

Graphene-based thin film microelectrode technology for in vivo high resolution neural recording and stimulation

Neuroprosthetic technology aims to restore nervous system functionality in cases of severe damage or degeneration by recording and stimulating the electrical activity of the neural tissue. One of the key factors determining the quality of the neuroprostheses is the electrode material used to establish electrical communication with the neural tissue, which is subject to strict electrical, electrochemical, and mechanical specifications as well as biological and microfabrication compatibility requirements. This work presents a nanoporous graphene-based thin film technology and its engineering to form flexible neural implants. Bench measurements show that the developed microelectrodes offer low impedance and high charge injection capacity throughout millions of pulses. In vivo electrode performance was assessed in rodents both from brain surface and intracortically showing high-fidelity recording performance, while stimulation performance was assessed with an intrafascicular implant that demonstrated low current thresholds and high selectivity for activating subsets of axons within the sciatic nerve. Furthermore, the tissue biocompatibility of the devices was validated by chronic epicortical and intraneural implantation. Overall, this works describes a novel graphene-based thin film microelectrode technology and demonstrates its potential for high-precision neural interfacing in both recording and stimulation applications.

bioengineering↗

bioRxiv2022

Circadian and environmental signal transduction in a natural population of Arabidopsis

Plants sense and respond to environmental cues during 24 h fluctuations in their environment. This requires the integration of internal cues such as circadian timing with environmental cues such as light and temperature to elicit cellular responses through signal transduction. However, the integration and transduction of circadian and environmental signals within plants growing in natural environments remains poorly understood. To gain insights into the 24 h dynamics of environmental signalling in nature, we performed a field study of signalling from the nucleus to chloroplasts in a natural population of Arabidopsis halleri. Using advanced modelling approaches to interpret the data, we identified that the circadian clock and temperature are key regulators of this pathway under natural conditions. We identified potential time-delay steps between pathway components, and diel fluctuations in the response of the pathway to temperature cues that are reminiscent of the process of circadian gating. This approach of combining studies of gene expression in the field with modelling allowed us to identify the dynamic integration and transduction of environmental cues, in plant cells, under naturally fluctuating diel cycles.

plant biology↗

bioRxiv2021

Full bandwidth electrophysiology of seizures and epileptiform activity enabled by flexible graphene micro-transistor depth neural probes

Mapping the entire frequency bandwidth of neuronal oscillations in the brain is of paramount importance for understanding physiological and pathological states. The ability to record simultaneously infraslow activity (<0.1 Hz) and higher frequencies (0.1-600 Hz) using the same recording electrode would particularly benefit epilepsy research. However, commonly used metal microelectrode technology is not well suited for recording infraslow activity. Here we use flexible graphene depth neural probes (gDNP), consisting of a linear array of graphene microtransistors, to concurrently record infraslow and high frequency neuronal activity in awake rodents. We show that gDNPs can reliably record and map with high spatial resolution seizures, post-ictal spreading depolarisation, and high frequency epileptic activity through cortical laminae to the CA1 layer of the hippocampus in a mouse model of chemically-induced seizures. We demonstrate functionality of chronically implanted devices over 10 weeks by recording with high fidelity spontaneous spike-wave discharges and associated infraslow activity in a rat model of absence epilepsy. Altogether, our work highlights the suitability of this technology for in vivo electrophysiology research, in particular, to examine the contributions of infraslow activity to seizure initiation and termination.

neuroscience↗

bioRxiv2021

Post-outbreak surveillance strategies to support proof of freedom from foot-and-mouth disease

Whilst emergency vaccination may help contain foot-and-mouth disease in a previously FMD-free country, its use complicates post-outbreak surveillance and the recovery of FMD-free status. A structured surveillance program is required that can distinguish between vaccinated and residually infected animals, and provide statistical confidence that the virus is no longer circulating in previously infected areas. Epidemiological models have been well-used to investigate the potential benefits of emergency vaccination during a control progam and when/where/whom to vaccinate in the face of finite supplies of vaccine and personnel. Less well studied are post-outbreak issues such as the management of vaccinated animals and the implications of having used vaccination during surveillance regimes to support proof-of-freedom. This paper presents enhancements to the Australian Animal Disease Model (AADIS) that allow comparisons of different post-outbreak surveillance sampling regimes for establishing proof-of-freedom from FMD. A case study is provided that compares a baseline surveillance sampling regime (derived from current OIE guidelines), with an alternative less intensive sampling regime. It was found that when vaccination was not part of the control program, a reduced sampling intensity significantly reduced the number of samples collected and the cost of the post-outbreak surveillance program, without increasing the risk of missing residual infected herds.

bioinformatics↗

bioRxiv2019

A significant role for the circadian clock in the long-term water use efficiency of Arabidopsis

In plants, water use efficiency is a complex trait derived from numerous physiological and developmental characteristics. Here, we investigated the involvement of circadian regulation in long-term water use efficiency. Circadian rhythms are generated by the circadian oscillator, which provides a cellular measure of the time of day. In plants, the circadian oscillator contributes to the regulation of many aspects of physiology, including stomatal opening, the rate of photosynthesis, carbohydrate metabolism and developmental processes. We investigated in Arabidopsis the impact of the misregulation of genes encoding a large number of components of the circadian oscillator upon whole plant, long-term water use efficiency. From this, we identified a role for the circadian oscillator in water use efficiency. This appears to be due to contributions of the circadian clock to the control of transpiration and biomass accumulation. We also identified that the circadian oscillator within guard cells can contribute to long-term water use efficiency. Our experiments indicate that knowledge of circadian regulation will be important for developing future crops that use water more efficiently. One-sentence summaryThe circadian clock in Arabidopsis makes an important contribution to long-term water use efficiency.

plant biology↗