Biology subjects

Cooper, R.

Publications and source records attributed to Cooper, R..

16 recordsLinked to original sources

bioRxiv2026

A platform for deep topographic multiomic mapping of the bone marrow environment in multiple myeloma

Multiple myeloma is a genetically complex plasma cell malignancy in which profound intratumoral heterogeneity shapes disease progression and therapeutic resistance. Genomic subclones dynamically emerge and evolve under treatment pressure, yet their spatial organization within intact bone marrow remains poorly defined. We hypothesized that genetically distinct myeloma subclones occupy spatially discrete ecological niches associated with unique molecular and microenvironmental states. To test this, we here demonstrate a proof-of-concept spatial tri-omics workflow combining laser capture microdissection-based genomics and deep LC-MS/MS proteomics with single-cell spatial transcriptomics, integrated by digital co-registration of adjacent tissue sections. Applied to a myeloma bone marrow trephine, this approach enabled coordinated profiling of matched anatomical regions demonstrating that genomic, transcriptomic and proteomic profiles converged to define clone-specific microenvironmental programmes. We show that genetically distinct myeloma subclones occupy mutually exclusive regions of the same bone marrow biopsy. Remarkably, an aggressive del(17p) clone and a gain(12q) clone occupied defined anatomical territories within the same trephine-biopsied section, each clone exhibiting distinct genomic, transcriptomic, proteomic and cellular ecosystems. The del(17p) clone localized to a fibrotic, osteolytic and angiogenic niche enriched for activated stromal cells, osteoblasts, osteoclasts and immunoregulatory myeloid populations, whereas the gain(12q) clone occupied a comparatively quiescent marrow niche with limited stromal remodelling. Together, these findings demonstrate that genetically distinct myeloma subclones establish spatially and biologically discrete ecological niches through coordinated remodelling of stromal, immune and bone compartments, providing a framework for understanding clonal evolution within the bone marrow microenvironment.

cancer biology↗

bioRxiv2026

Processing strategies for improving cortical thickness correspondence between low-field and high-field MRI in young people

Portable low-field MRI systems are a promising complement to conventional high-field systems, enabling broader access to MRI. However, correspondence in cortical thickness estimates between low- and high-field MRI in young people remains limited despite its importance for neurodevelopment and psychopathology. To evaluate how multiple low-field image processing approaches improve cortical thickness correspondence with high-field MRI in a large sample of young individuals, we collected T1-weighted (T1w) and T2-weighted (T2w) data using both low-field (64mT) and high-field (3T) MRI within one week of each other from a community sample of young people. We applied deep learning-based super-resolution methods (SynthSR v1 and SynthSR v2) followed by recon-all, or other reconstruction methods (recon-all-clinical and recon-any), to low-field data acquired across multiple sequences (T1w and T2w) and orientations (axial, coronal, sagittal, and multi-orientation average), with and without resampling and/or co-registration. We assessed global, lobar, and regional cortical thickness correspondence with 3T MRI measures based on the Desikan-Killiany atlas using Pearson and intraclass correlations. We compared pipelines using Steiger's Z-tests and Fisher's Z-tests. A total of 150 individuals (mean age, 18.63+/-5.07; 80 female) were included. We observed the highest global correspondence with recon-all-clinical applied to coronal T1w images (r=0.40, pFDR=3.02e-05), which significantly exceeded the best global correspondence in our previous study (Fisher's Z=1.99, p=0.047). At the lobar and regional levels, multi-orientation T2w images processed with recon-all-clinical showed the highest correspondence across the greatest number of regions (4/12 lobes; 13/68 regions). This pipeline showed the highest correspondence and largest improvements relative to recon-all alone in frontal, cingulate, and temporal regions, including the right pars triangularis (r=0.52, pFDR=4.78e-11; Steiger's Z=4.78, pFDR=4.25e-06), right caudal anterior cingulate (r=0.47, pFDR=3.83e-09; Steiger's Z=5.46, pFDR=1.32e-07), and left parahippocampal regions (r=0.58, pFDR=2.98e-14; Steiger's Z=5.17, pFDR=6.01e-07). We observed significantly improved cortical thickness correspondence in low-field MRI in young people relative to recon-all alone and our prior work. The recon-all-clinical pipeline yielded moderate correspondence, particularly in frontal, cingulate, and temporal regions. Our results demonstrate a methodological improvement in the use of low-field MRI for assessing cortical thickness in young people, providing a quantitative benchmark for current tools in this area.

neuroscience↗

bioRxiv2026

Transforming avian to mammalian modes of digit patterning

How a conserved embryonic organiser--the Sonic hedgehog (Shh)-expressing Zone of Polarising Activity (ZPA)--generates diverse limb architectures in amniotes remains a central problem in evolutionary and developmental biology. The principal difference across species lies in the number of digits produced from ZPA tissue: two in mammals1, one in the chick leg2 and none in the chick wing2. Here we show that this divergence is governed by a Shh-p27Kip1 pathway operating in avian, but not mammalian ZPAs. In chick wing ZPA explants, attenuation of this pathway reveals an intrinsic digit-forming programme, enabling cells to self-organise signalling networks and generate digits after grafting into a host wing bud. Guided by these findings, we redirected the chick leg, which retains stem amniote digit identities, to follow a mammalian-like developmental trajectory. Precise temporal restriction of Shh signalling transforms chick legs into pentadactyl limbs with digit identities characteristic of mammals and their therapsid ancestors, with two digits arising from the ZPA. These findings establish a unifying framework for how Shh controls both digit number and identity across amniotes.

developmental biology↗

bioRxiv2026

Robust evidence for modest diversity loss across the K/Pg in neoselachians: Response to Guinot et al.

We reconstructed the neoselachian diversity over the past 145 million years using new occurrence dataset and DeepDive1-3. We recovered a small decline through the K/Pg following a steady increase during the Cretaceous, and a prolonged, substantial decline towards the present following a mid-Eocene peak2. Guinot et al. argue that our conclusions are compromised by problems in the underlying data and by the way extinction magnitude across the K/Pg was quantified. They cast doubt particularly on the pattern across the K/Pg, which they consider to be at odds with all previous analyses. They raise no issue with the Cretaceous trend, even though it was recovered with the same dataset and methods. We audited the alleged data issues reported in Guinot et al. and found that they mostly reflect operational choices (see Supplementary Information). However, we applied their data treatment and ran sensitivity tests to evaluate how this approach affects our results, specifically around the K/Pg. None of our tests recovered a diversity collapse for neoselachians during this interval. As such, we demonstrate that our findings are robust and consistent across different data treatments.

paleontology↗

bioRxiv2026

Evaluation of an Oxford Nanopore sequencing workflow for mycobacteria from primary MGIT culture

Illumina sequencing of primary MGIT cultures is an established workflow in several reference mycobacteriology laboratories. Oxford Nanopore Technologies (ONT) provides real-time genetic sequencing yielding long reads which help resolve repetitive genomes and is being explored for in-house implementation within diagnostic laboratories. However, low DNA yields from primary MGIT cultures frequently limit the application of ONT workflows, due to high minimum DNA input requirements for library preparation. We validated a modified ONT workflow combining rapid, semi-automated DNA extraction from MGIT cultures with Rapid PCR-Barcoding for whole-genome amplification, and compared its performance with Illumina sequencing for species identification and Mycobacterium tuberculosis complex (MTBC) single-nucleotide polymorphism (SNP) detection. A platform-agnostic analysis pipeline enabled consistent human read removal, taxonomic assignment, and MTBC genomic characterisation. ONT sequencing data was subsampled at 1, 6, and 72 hours to determine the earliest time point for reliable species identification. The concordance between sequencing platforms on species classification was 98.3% (95.8-99.5%) with all differences arising from potential mixed infections. SNP agreement was high, with a mean of 0.3 and a median of 0 SNP differences between sequencing platforms after masking. These findings demonstrate the feasibility of PCR-amplified ONT sequencing as a reliable alternative for routine genomic characterisation of MGIT cultures. IMPORTANCERapid identification of mycobacterial infections is essential for timely patient care and infection control. Many clinical laboratories currently rely on outsourcing sequencing to external reference centres, which adds time and delays the return of clinically actionable results. These services commonly use Illumina sequencing, which, while highly accurate, involves complex workflows and longer turnaround times. Newer technologies offer the potential to generate results in real time, but their use has been limited by the low amount of DNA available from routine culture samples. In this study, we developed an improved workflow that increases the amount of usable DNA and enables reliable, rapid sequencing directly from these samples. This approach allows multiple samples to be processed together and reduces the time needed to obtain results. Importantly, it could enable clinical laboratories to perform sequencing in-house, reducing reliance on external services and improving turnaround times.

molecular biology↗

bioRxiv2025

Redefining the topology of the human bone marrow using augmented spatial transcriptomic analysis

The bone marrow (BM) is the main site of haematopoiesis in adult life. Our understanding of the pathogenesis of BM-derived blood cancers is limited by lack of spatial contextualisation. While emerging spatial transcriptomic (ST) platforms offer unprecedented opportunities for spatially-resolved cellular phenotyping, we recognise and incorporate the power of AI-based tissue feature detection to enhance ST workflows. We perform ST analysis to define the topology of the normal bone marrow (BM) and BM in myeloproliferative neoplasms (MPNs), profiling 5,104,452 cells across 30 human BM samples. Following rigorous histology-based QC, we identify spatially-restricted trajectories of haematopoiesis and extend our understanding of the haematopoietic stem cell (HSC) niche. We find that BM fibrosis in MPN is associated with expansion of distinct immune and stromal co-enriched cell neighbourhoods. We then present a machine learning (ML)-based model trained on ST data that quantifies BM microenvironmental deviation, identifying heretofore unrecognised inter- and intra-individual sample heterogeneity in MPN. Our study demonstrates the potential for AI-based augmented ST analysis, and redefines our understanding of human BM topology.

cancer biology↗

bioRxiv2025

Neural signatures of recollection are sensitive to memory quality and specific event features

Episodic memories reflect a bound representation of multimodal features that can be recollected with varying levels of precision. Recent fMRI investigations have demonstrated that the precision and content of information retrieved from memory engage a network of posterior medial temporal and parietal regions co-activated with the hippocampus. Yet, comparatively little is known about how memory content and precision affect common neural signatures of memory captured by electroencephalography (EEG), where recollection has been associated with changes in event-related potential (ERP) and oscillatory measures of neural activity. Here, we used a multi-feature paradigm previously reported in Cooper & Ritchey (2019) with continuous measures of memory, in conjunction with scalp EEG, to characterize the content and quality of information that drives ERP and oscillatory markers of episodic memory. A common signature of memory retrieval in left posterior regions, called the late positive component (LPC), was sensitive to overall memory quality and also to precision of recollection for spatial features. Analysis of oscillatory markers during recollection revealed that alpha/beta desynchronization was modulated by overall memory quality and also by individual features in memory. Importantly, we found evidence of a relationship between these two neural markers of memory retrieval, suggesting that they may represent complementary aspects of the recollection experience. These findings demonstrate how time-sensitive and dynamic processes identified with EEG correspond to overall episodic recollection, and also to the retrieval of precise features in memory.

neuroscience↗

bioRxiv2025

Co-Activation Patterns in Neonates using High-Density Diffuse Optical Tomography: Insights into Early Dynamic Functional Connectivity

SignificanceDynamic functional connectivity (FC) in neonates is a growing area of interest due to the developmental significance of early functional networks. There are several emerging techniques to measure dynamic FC, adding new perspectives to well-studied static FC networks. Recent dynamic FC studies suggest that adult resting-state networks are driven by key moments of dynamic activity rather than sustained correlations. Co-activation pattern (CAP) analysis leverages this theory, clustering high-activity frames to identify recurring configurations of significant activity. High-density diffuse optical tomography (HD-DOT) is an infant-friendly modality that measures hemodynamic changes in the cortex and has been used to investigate static FC in term-aged infants. CAP analysis has not yet been applied to neonatal HD-DOT and may reveal temporal features of early functional networks that are not apparent from static methods. AimThis study applies CAP analysis to neonatal HD-DOT to characterize transient co-activation states and provide new insight into early functional brain networks beyond what is known from static FC methods alone. ApproachTask-free HD-DOT data were acquired from a cohort of sleeping term newborns at the Rosie Hospital, Cambridge UK (n = 44, postmenstrual age = 40+3 (range: 38+2-42+6) weeks). In each recording, the top 15% of seed-selected frames were clustered using the K-means algorithm for three regions of interest (ROIs: frontal, central, and parietal) to identify significant seed-associated patterns of co-activation or co-deactivation. These co-activation patterns (CAPs) were characterized for each infant using four metrics: consistency, fractional occupancy, dwell time, and transition likelihood. ResultsDistinct CAPs, reflecting the dynamic organization of neonatal cortical networks, were identified for frontal, central, and parietal regions. These CAPs showed high consistency scores, reflecting high intra-cluster spatial correlation and validating the efficacy of CAP analysis for newborn HD-DOT data. The CAP decomposition revealed significant patterns not observed in conventional static functional connectivity analyses. Several neonatal CAPs exhibited frontoparietal co-activation, potentially reflecting early default mode network activity, which is immature and modular for the first year after birth. ConclusionsThis work demonstrates the utility of CAP analysis with newborn HD-DOT and provides new insight into the dynamics of neonatal functional connectivity.

neuroscience↗

bioRxiv2023

Ramped V1 transcranial ultrasonic stimulation modulates but does not evoke visual evoked potentials

Transcranial ultrasonic stimulation (TUS), has been shown to evoke visual evoked potential (VEP)-like potentials on EEG recordings, and also to modulate sensory evoked potentials. However, pulsed TUS is accompanied by an auditory confound, and it is possible that any observed effects were, in-part, evoked by this confound. Therefore, we used ramped TUS pulses, which are not as easily audible, to examine whether primary visual cortex (V1) TUS evokes VEP-like potentials, and modulates VEPs elicited using a checkerboard stimulus. MethodsWe tested 14 healthy participants (31 {+/-} 4.3 yrs, 4 F and 10 M). TUS was applied to the left V1 using a 270 kHz transducer (H115-2AA, Sonic Concepts). Ramped pulses (1 ms ramp, 3.25 ms total pulse duration) were repeated at 250 Hz, with a pulse train duration of 300 ms, an effective duty cycle of 50%, and Isppa without ramping of 16 W/cm2 in water. EEG was recorded from 16 channels using the g.USBamp amplifier (g.tec medical engineering GmbH). In two blocks (TUS-only), real and sham (100 each) TUS trials were repeated every 2 s. In another two blocks (TUS+checkerboard), a checkerboard stimulus was flipped every 0.5 s, and every fourth stimulus was associated with either a real or sham (100 each) TUS trial. The TUS trial started approx. 130 ms (0-5 ms jitter) before the checkerboard flip. All EEG data were analysed using Fieldtrip, and cluster-based permutation tests were used to test for differences between conditions. Results and discussionIn the TUS-only condition, in contrast to a previous study, we found no evoked potentials using ramped pulses which minimised the auditory artifact. In the TUS+checkerboard condition, we observed a modulation of the early-component of the VEP in real TUS, relative to no TUS trials. This suggests that, in line with in-vitro and animal data, there is a direct neuromodulatory effect of ultrasound, in addition to any confounding effects. Moving forward, ramping offers a relatively easy approach to minimise the auditory confound.

neuroscience↗

bioRxiv2022

Integrating region- and network-level contributions to episodic recollection using multilevel structural equation modeling

The brain is composed of networks of interacting brain regions that support higher order cognition. For instance, a posterior medial (PM) network appears to support recollection and other forms of episodic construction. Past research has focused largely on the roles of individual brain regions in recollection or on their mutual engagement as part of an integrated network. Yet the relationship between these region- and network-level contributions remains poorly understood. Here we applied multilevel structural equation modeling (SEM) to examine the functional organization of the PM network and its relationship to episodic memory outcomes. We evaluated two aspects of functional heterogeneity in the PM network: first, the organization of individual regions into subnetworks, and second, the presence of regionally-specific contributions while accounting for network-level effects. The results suggest that the PM network is composed of ventral and dorsal subnetworks, with the ventral subnetwork making a unique contribution to recollection, and that memory-related activity in individual regions is well accounted for by these network-level effects. These findings highlight the importance of considering both region and network levels of analysis when studying brain-behavior relationships.

neuroscience↗

bioRxiv2021

Daily feeding rhythm linked to microbiome composition in two zooplankton species

Host-associated microbial communities are impacted by external and within-host factors, i.e., diet and feeding behavior. For organisms known to have a circadian rhythm in feeding behavior, microbiome composition is likely impacted by the different rates of microbe introduction and removal across a daily cycle, in addition to any diet-induced changes in microbial interactions. Here, we measured feeding behavior and used 16S rRNA sequencing to compare the microbial community across a diel cycle in two distantly related species of Daphnia, that differ in their life history traits, to assess how daily feeding patterns impact microbiome composition. We find that Daphnia species reared under similar laboratory conditions have significantly different microbial communities. Additionally, we reveal that Daphnia have daily differences in their microbial composition that correspond with feeding behavior, such that there is greater microbiome diversity at night during the host's active feeding phase. These results highlight that zooplankton microbiomes are relatively distinct and are likely influenced by host phylogeny.

microbiology↗

bioRxiv2021

Widespread nociceptive maps in the human neonatal somatosensory cortex

Topographic cortical maps are essential for spatial localisation of sensory stimulation and generation of appropriate task-related motor responses. Somatosensation and nociception are finely mapped and aligned in the adult somatosensory (S1) cortex, but in infancy, when pain behaviour is disorganised and poorly directed, nociceptive maps may be less refined. We compared the topographic pattern of S1 activation following noxious (clinically required heel lance) and innocuous (touch) mechanical stimulation of the same skin region in newborn infants (n=32) using multi-optode functional near-infrared spectroscopy (fNIRS). Signal to noise ratio and overall activation area did not differ with stimulus modality. Within S1 cortex, touch and lance of the heel elicit localised, partially overlapping increases in oxygenated haemoglobin (HbO), but while touch activation was restricted to the heel area, lance activation extended into cortical hand regions. The data reveals a widespread cortical nociceptive map in infant S1, consistent with their poorly directed pain behaviour.

neuroscience↗

bioRxiv2020

Mapping the organization and dynamics of the posterior medial network during movie watching

Brain regions within a posterior medial network (PMN) are characterized by sensitivity to episodic tasks, and they also demonstrate strong functional connectivity as part of the default network. Despite its cohesive structure, delineating the intranetwork organization and functional diversity of the PMN is crucial for understanding its contributions to multidimensional event cognition. Here, we probed functional connectivity of the PMN during movie watching to identify its pattern of connections and subnetwork functions in a split-sample replication of 136 participants. Consistent with prior findings of default network fractionation, we identified distinct PMN subsystems: a Ventral PM subsystem (retrosplenial cortex, parahippocampal cortex, posterior angular gyrus) and a Dorsal PM subsystem (medial prefrontal cortex, hippocampus, precuneus, posterior cingulate cortex, anterior angular gyrus). Ventral and Dorsal PM subsystems were differentiated by functional connectivity with parahippocampal cortex and precuneus and integrated by retrosplenial cortex and posterior cingulate cortex, respectively. Finally, the distinction between PMN subsystems is functionally relevant: whereas both Dorsal and Ventral PM connectivity tracked the movie content, only Ventral PM connections increased in strength at event transitions and appeared sensitive to episodic memory. Overall, these findings reveal PMN functional pathways and the distinct functional roles of intranetwork subsystems during event cognition.

neuroscience↗

bioRxiv2019

Progression from feature-specific brain activity to hippocampal spatial binding during episodic encoding

The hallmark of episodic memory is recollecting multiple perceptual details tied to a specific spatial-temporal context. To remember an event, it is therefore necessary to integrate such details into a coherent representation during initial encoding. Here we tested how the brain encodes and binds multiple, distinct kinds of features in parallel, and how this process evolves over time during the event itself. We analyzed data from 27 human subjects (16 females, 11 males) who learned a series of objects uniquely associated with a color, a panoramic scene location, and an emotional sound while functional magnetic resonance imaging data were collected. By modeling how brain activity relates to memory for upcoming or just-viewed information, we were able to test how the neural signatures of individual features as well as the integrated event changed over the course of encoding. We observed a striking dissociation between early and late encoding processes: left inferior frontal and visuo-perceptual signals at the onset of an event tracked the amount of detail subsequently recalled and were dissociable based on distinct remembered features. In contrast, memory-related brain activity shifted to the left hippocampus toward the end of an event, which was particularly sensitive to binding item color and sound associations with spatial information. These results provide evidence of early, simultaneous feature-specific neural responses during episodic encoding that predict later remembering and suggest that the hippocampus integrates these features into a coherent experience at an event transition. SIGNIFICANCE STATEMENTUnderstanding and remembering complex experiences is crucial for many socio-cognitive abilities, including being able to navigate our environment, predict the future, and share experiences with others. Probing the neural mechanisms by which features become bound into meaningful episodes is a vital part of understanding how we view and reconstruct the rich detail of our environment. By testing memory for multimodal events, our findings show a functional dissociation between early encoding processes that engage lateral frontal and sensory regions to successfully encode event features, and later encoding processes that recruit hippocampus to bind these features together. These results highlight the importance of considering the temporal dynamics of encoding processes supporting multimodal event representations.

neuroscience↗

bioRxiv2019

Flower-like patterns in multi-species biofilms

Diverse interactions among species within bacterial biofilms often lead to intricate spatiotemporal dynamics. The spatial structure of biofilms can determine growth and survival of different species, but the mechanisms driving formation of this structure are not fully understood. Here, we describe the emergence of complex structures in a biofilm grown from mixtures of motile and non-motile bacterial species on a soft agar surface. Time-lapse imaging shows that non-motile bacteria "hitchhike" on the motile bacteria as the latter migrate outward. The non-motile bacteria accumulate at the boundary of the colony and trigger an instability that leaves behind striking flower-like patterns. The mechanism of the front instability governing this pattern formation is elucidated by a mathematical model for the frictional motion of the colony interface, with friction depending on the local concentration of the nonmotile species along the interface. A more elaborate two-dimensional phase-field model that explicitly accounts for the interplay between growth, mechanical stress from the motile species, and friction provided by the non-motile species, fully reproduces the observed flower-like patterns.

microbiology↗

bioRxiv2018

Developmental factors associated with decline in grip strength from midlife to old age: a British birth cohort study

Maintenance of muscle strength is important for healthy ageing, protecting against chronic disease and enabling independent living. We tested whether developmental factors were associated with grip strength trajectories between 53 and 69 years, and operated independently or on the same pathway/s as adult factors, in 3058 participants from a British birth cohort. Grip strength (kg) at ages 53, 60-64 and 69, was analysed using multilevel models, testing for age and sex interactions, to estimate associations with developmental factors (birthweight, growth parameters, motor and cognitive development) and childhood socioeconomic position (SEP) and investigate potential adult mediators. Heavier birthweight, beginning to walk on time, later puberty and greater weight 0-26 years in men, and earlier age at first standing in women, were associated with stronger grip but not with its decline; these associations were independent of adult factors. The slower decline in grip strength (by 0.068kg/year, 95% confidence interval (CI) 0.024,0.11 per 1SD, p=.003) in men with higher childhood cognition was attenuated by adult verbal memory which became increasingly positively associated with grip strength at older ages. Thus grip strength may increasingly reflect neural ageing processes. Targeting developmental factors to promote muscle development should increase the chance of independence in old age.

epidemiology↗