Biology subjects

Cooper, B.

Publications and source records attributed to Cooper, B..

14 recordsLinked to original sources

bioRxiv2026

Inflections in adolescent cortical maturation signal psychopathology risk

Cerebral cortical maturation supports emotional, social, and cognitive development during adolescence1. Neurodevelopmental theories of psychiatric illnesses, which peak in onset around age 182, implicate subtle alterations in adolescent cortical development3. However, mechanistic links between cortical maturation and emergent psychopathology have remained elusive. This gap likely reflects a need for more nuanced understanding of cortical development4, larger, longitudinal samples powered to detect small effects,5 and more uniform image quality control.6 Using 29,482 structural MRI scans from 11,720 adolescents in the Adolescent Brain Cognitive Development (ABCD) study, we demonstrate reproducible differences in the contour and tempo of maturation across the cortical surface. Regional trajectories are robust to image quality variance and align with increasing functional specialization over time. Thicker cortex in early-maturing sensory regions predicts psychiatric symptoms as early as four years prior to their emergence, a pattern that subsequently spreads to association cortex. Overlap with spatially and temporally organized gene co-expression networks implicates prenatal programming of this sequence of maturation and its links to psychopathology. These findings present a novel, versatile neurodevelopmental framework for cortical maturation during adolescence that sequentially implicates sensory and association cortex in risk for emergent psychiatric symptoms.

neuroscience↗

bioRxiv2026

Lipid-associated architecture and divergent ammonium transport distinguish a bacterial Rhesus protein

Nitrification is a major process in the global nitrogen cycle, initiated by the oxidation of ammonia to nitrite. The ammonia-oxidising bacterium Nitrosomonas europaea catalyses this first and rate-limiting step and depends on ammonium both as an energy substrate and as a nitrogen source, making ammonium acquisition central to its physiology. Cellular ammonium transport is mediated by the Amt/Mep/Rh superfamily, whose members share a conserved fold despite divergent physiological roles. Remarkably, N. europaea lacks a canonical prokaryotic Amt transporter and instead expresses NeRh50, a Rh-family protein proposed to have been acquired from a eukaryotic lineage. Here, we determine a cryo-EM structure of NeRh50 that reveals tightly associated lipids at the monomer-monomer interfaces, including density consistent with an unusual inverted lipid orientation. Native mass spectrometry and molecular dynamics simulations further support persistent lipid association at these interfaces. NeRh50 also differs functionally from canonical AmtB, selectively mediating electrogenic ammonium transport with ~70-fold lower apparent affinity. Transport is enhanced under alkaline conditions but not by an imposed proton gradient, suggesting membrane-potential dependence. Together, these findings reveal divergence from canonical Amt proteins in both membrane-associated architecture and transport properties, providing insight into the functional and evolutionary diversification of the Amt/Mep/Rh superfamily.

biochemistry↗

bioRxiv2026

STING agonists in combination with epigenetic drugs potentiate ZNFX1-driven inflammatory necroptosis in TP53-mutated AML

TP53-mutated acute myeloid leukemia (AML) has dismal outcomes with current treatments and represents a critical unmet need. TP53-mutated AML is proposed to be susceptible to immunotherapeutic approaches but, to date, there is no established immunotherapy for this sub-group. Expression of stimulator of interferon genes (STING), a key innate immune driver that activates interferon (IFN) signaling, is decreased by epigenetic silencing or mutation in many cancers, including those with TP53 mutations. Here, we report that response to the next-generation synthetic STING agonist C92 is potentiated in AML cell lines and primary cells with TP53-mutated versus wild-type (WT) cells, representing a previously undescribed vulnerability of these leukemia cells to STING small molecule therapies. Moreover, combining treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC), significantly increases STING activation, with marked transcriptome-wide increase in repetitive elements (REs) and upregulation of a critical set of interferon-related genes. Cell death in TP53 KO versus WT AML is specifically dependent on innate immune zinc finger NFX1-type containing 1 (ZNFX1) and Z-DNA-binding protein 1 (ZBP1) driving increased cleavage and activation of Receptor-Interacting-Serine/Threonine-Protein Kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL), suggesting mechanisms of necroptosis. Finally, C92 and DAC combination significantly reduces leukemia burden in humanized AML mouse models, accompanied by increased immune responses, including cytokines and cytotoxic T lymphocytes in the leukemia microenvironment. These results support development of clinical trial strategies combining STING agonists with DNMTis for patients with TP53-mutated AML. SummaryO_LITP53-mutated AML potentiates effects of novel next-generation STING agonist C92, with unique allosteric and non-cyclic dinucleotide (non-CD) mechanism of action, inducing increased STING activation and cytokine release C_LIO_LISTING agonists and DNMTis, synergistically increase STING activation with marked transcriptome-wide increase in repetitive elements (REs) and upregulation of a critical set of interferon-related genes in TP53-mutated AML C_LIO_LISTING agonists induce necroptosis via a STING-ZNFX1-ZBP1-necroptosis axis in TP53-mutated AML. C_LIO_LIThis drug combination reduces leukemia burden, activates immune responses in AML models and supports translation for high-risk AML patients. C_LI Statement of Translational RelevanceThis pre-clinical study identifies a novel therapeutic vulnerability in (TP53)-mutated acute myeloid leukemia (AML), a poor prognosis subtype with a critical unmet need. Novel next-generation STING agonist C92, with unique allosteric and non-cyclic dinucleotide (non-CD) mechanism of action, induces increased STING activation and cytokine release, compared with WT TP53 in AML cell lines and primary cells, and has superior STING activity with respect to several STING agonists currently in clinical studies. Combining C92 treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC) synergistically increases STING activation, with marked transcriptome-wide increase in repetitive elements (REs) and upregulation of a critical set of interferon-related genes, driving ZNFX1-driven inflammatory necroptotic cell death. Utilizing humanized mouse models, C92 in combination with DAC significantly reduces leukemia burden and enhances cytotoxic T-cell responses in the tumor microenvironment, supporting clinical translation for high-risk AML patients.

cancer biology↗

bioRxiv2025

OpenStride: an inexpensive, open-source force plate actometry system for quantification of rodent motor activity and behaviour

IntroductionForce plate actometry (FPA) enables quantitative assessment of rodent motor and behavioural activity. Through tracking centre of mass at high temporal and spatial resolution, FPA can directly quantifying motor performance and various behaviours in the context of operator-independent, naturalistic movement. Previously designed systems have been expensive and non-customisable, and they are no longer commercially available. MethodsWe designed OpenStride, an open-source FPA system consisting of both hardware and software. Our system was designed to be able to be constructed with standard tools worldwide at a cost of [~]$550 USD, with modifiable hardware files, modular software, and support for both Mac and Windows operating systems. Required tools include 3D printing and acrylic laser cutting. ResultsOpenStride reliably tracks position within a 30 x 30 cm2 environment. Based on these positional data, OpenStride currently quantifies tremor, ataxia, distance, velocity, low-mobility bouts, and centre-vs-margin time, with potential to expand to additional analyses. ConclusionsOpenStride is intended to provide a valuable tool for high-throughput, inexpensive study of motor and behavioural function and dysfunction. Software and hardware files will be freely disseminated online via GitHub at the time of final publication to enable others to construct and utilise the OpenStride system.

neuroscience↗

bioRxiv2025

Antioxidant role of the GABA shunt in regulating redox balance in blood progenitors during Drosophila hematopoiesis

Redox balance is crucial for normal development of stem and progenitor cells that reside in oxidative environments. This study explores the mechanisms of redox homeostasis in such niches and investigates myeloid-like blood progenitor cells that generate reactive oxygen species (ROS) and moderate it developmentally. Our findings reveal that during lymph gland development, as the blood-progenitor cells oxidize pyruvate via the TCA cycle leading to the generation of ROS, these cell also de novo synthesize GSH to counter excessive ROS and ensure redox balance. GABA metabolism, through GABA-shunt, restricts pyruvate dehydrogenase (PDH) activity and consequently TCA rate. This allows a metabolic route to sustain serine levels in these cells which is the rate limiting precursor controlling de novo GSH production. Disruption of GABA metabolism leads to a metabolic imbalance, characterized by excessive PDH activity, heightened TCA rate leading to impaired serine/GSH production and overall ROS dysregulation. Overall, the study presents a unique metabolic state whereby, in the blood-progenitor cells, by keeping PDH and TCA activity in check and promoting serine/GSH generation, GABA metabolism establishes a metabolic framework that optimises the use of ROS in blood-progenitors, while ensuring redox homeostasis.

developmental biology↗

bioRxiv2025

Fexinidazole and Corallopyronin A target Wolbachia-infected sheath cells present in filarial nematodes

The discovery of the endosymbiotic bacteria Wolbachia as an obligate symbiont of filarial nematodes has led to antibiotic-based treatments for filarial diseases. While lab and clinical studies have yielded promising results, recent animal studies reveal that Wolbachia levels may rebound following treatment with suboptimal doses of the antibiotic rifampicin. Previous work showed that a likely source of the bacterial rebound in females were dense clusters of Wolbachia in ovarian tissue. The number, size, and density of these Wolbachia clusters were not diminished despite antibiotic treatment. Here we define the cellular characteristics of the Wolbachia clusters in Brugia pahangi (wBp) and identify drugs that also target them. We have evidence that the Wolbachia clusters originate from newly formed sheath cells adjacent to the ovarian Distal Tip Cells. The dramatically enlarged volume of an infected sheath cell is strikingly similar to endosymbiont-induced bacteriocytes found in many insect species. Ultrastructural analysis reveals that the clustered Wolbachia present within the sheath cells exhibit a distinct morphology and form direct connections with the oocyte membrane and possibly the cytoplasm. This includes membrane-based channels providing a connection between Wolbachia-infected sheath cells and oocytes. We also determined that the Wolbachia within the sheath cells are either quiescent or replicating at a very low rate. Screens of known antibiotics and other drugs revealed that two drugs, Fexinidazole and Corallopyronin A, significantly reduced the number of clustered Wolbachia located within the sheath cells.

pathology↗

bioRxiv2024

Physiological correlates of a simple saccadic-decision task in superior colliculus

Our vision is best only in the center of our gaze, and we use saccadic eye movements to direct gaze to objects and features of interest. We make more than 180,000 saccades per day, and accurate and efficient saccades are crucial for most visuo-motor tasks. Saccades are typically studied using small point stimuli, despite the fact that most real-world visual scenes are composed of extended objects. Recent studies in humans have shown that the initiation latency of saccades is strongly dependent on the size of the target (the "size-latency effect"), perhaps reflecting a tradeoff between the cost of making a saccade to a target and the expected information gain that would result. Here, we investigate the neuronal correlates of the size-latency effect in the macaque superior colliculus. We analyzed the latency variations of saccades to different size targets within a stochastic accumulator model framework. The model predicted a steeper increase in activity for smaller targets compared to larger ones. Surprisingly, the model also predicted an increase in saccade initiation threshold for larger targets. We found that the activity of intermediate-layer SC visuomotor neurons is in close agreement with the model predictions. We also found evidence that these effects may be a consequence of the visual responses of SC neurons to targets of different sizes. These results shed new light on the sources of delay within the saccadic system, a system that we heavily depend upon in the performance of most visuo-motor tasks.

neuroscience↗

bioRxiv2021

Defining dysfunction due to loss of MECP2 in Rett Patient Brain

Rett Syndrome is characterized by a postnatal loss of neurophysiological function and regression of childhood development. Because the syndrome is X-linked and males with MECP2 mutations generally do not survive birth, the study of this syndrome has been complicated by the fact that in female brain, a portion of neurons express wild type MECP2, and another portion express a non-functional allele of MECP2. Therefore, bulk-RNA-sequencing of Rett brain is confounded by the presence of chimerism of neurons for functional MECP2 in neurons. We developed an approach that allows for single-nuclei transcriptional profiling of individual neurons and a direct comparison between neurons that express functional MECP2 with those that express the disease-causing allele. We found that mutant neurons from Rett brain show patterns of aberrant expression of synaptic and metabolic genes, both of which can be detected in in vitro models of Rett Syndrome. We used these resources to identify a role for POU2F1/OCT1 transcription factor in mediating the response to stress due to loss of MECP2, highlighting a potential key molecular regulator of stress in Rett neurons. Together, our new sorting approach enables us to highlight defective molecular and metabolic pathways in Rett brain neurons and suggests that in vitro models could serve as valuable tools to further study this syndrome and potentially for development of novel therapeutics.

molecular biology↗

bioRxiv2021

Bisphenol S and bisphenol F are less disruptive to cardiac electrophysiology and potentially safer for use in medical products, as compared to bisphenol A

BackgroundBisphenol A (BPA) is a high-production volume chemical that is commonly used to manufacture consumer and medical-grade plastic products. Due to its ubiquity, the general population can incur daily environmental exposure to BPA, while heightened BPA exposure has been reported in intensive care patients and industrial workers. Due to health concerns, structural analogues are being explored as replacements for BPA. ObjectiveThis study aimed to examine the direct nongenomic effects of BPA on cardiac electrophysiology and compare its safety profile to recently developed alternatives, including BPS (bisphenol S) and BPF (bisphenol F). MethodsWhole-cell voltage-clamp recordings were performed on cell lines transfected with Nav1.5, hERG, or Cav1.2. Results of single channel experiments were validated by conducting electrophysiology studies on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and intact, whole heart preparations. ResultsOf the chemicals tested, BPA was the most potent inhibitor of both fast (INa-P) and late (INa-L) sodium channel (IC50 = 55.3 and 23.6 M, respectively), L-type calcium channel (IC50 = 30.8 M) and hERG channel current (IC50 = 127 M). The inhibitory effects of BPA and BPF on L-type calcium channels were supported by microelectrode array recordings, which revealed shortening of the extracellular field potential (akin to QT interval). Further, BPA and BPF exposure impaired atrioventricular conduction in intact, whole heart experiments. BPS did not alter any of the cardiac electrophysiology parameters tested. DiscussionResults of this study demonstrate that BPA and BPF exert an immediate inhibitory effect on cardiac ion channels, and that BPS may be a safer alternative. Intracellular signaling or genomic effects of bisphenol analogues were not investigated; therefore, additional mechanistic studies are necessary to fully elucidate the safety profile of bisphenol analogues on the heart.

pharmacology and toxicology↗

bioRxiv2021

Targeting of TP53-independent cell cycle checkpoints overcomes FOLFOX resistance in Metastatic Colorectal Cancer

Patients with colorectal cancer (CRC) frequently develop liver metastases during the course of their disease. A substantial proportion of them receive neoadjuvant FOLFOX (5-Fluorouracil, Oxaliplatin, Leucovorin) prior to surgery in an attempt to enable successful surgical removal of their metastases and to reduce the risk of recurrence. Yet, the majority of patients progress during treatment or recur following surgery, and molecular mechanisms that contribute to FOLFOX resistance remain poorly understood. Here, using a combination of phenotypic, transcriptomic and genomic analyses of both tumor samples derived from patients with metastatic CRC and matching patient-derived tumor organoids (PDTOs), we characterize a novel FOLFOX resistance mechanism and identify inhibitors that target this mechanism to resensitize metastatic organoids to FOLFOX. Resistant PDTOs, identified after in vitro exposure to FOLFOX, exhibited elevated expression of E2F pathway, S phase, G2/M and spindle assembly checkpoints (SAC) genes. Similar molecular features were detected in CRLM from patients with progressive disease while under neoadjuvant FOLFOX treatment, highlighting the relevance of this finding. FOLFOX resistant PDTOs displayed inactivating mutations of TP53 and exhibited transcriptional features of P53 pathway downregulation. We found that they accumulated in early S-phase and underwent significant DNA damage during FOLFOX exposure, thereafter arresting in G2/M while they repaired their DNA after FOLFOX withdrawal. In parallel, results of a large kinase inhibitor screen indicated that drugs targeting regulators of the DNA damage response, G2M checkpoint and SAC had cytotoxic effects on PDTOs generated from patients whose disease progressed during treatment with FOLFOX. Corroborating this finding, CHK1 and WEE1 inhibitors were found to synergize with FOLFOX and sensitize previously resistant PDTOs. Additionally, targeting the SAC master regulator MPS1 using empesertib after exposure to FOLFOX, when cells accumulate in G2M, was also very effective to kill FOLFOX-resistant PDTOs. Our results indicate that targeted and timely inhibition of specific cell cycle checkpoints shows great potential to improve response rates to FOLFOX in patients with metastatic CRC, for whom therapeutic alternatives remain extremely limited.

cancer biology↗

bioRxiv2020

Plasticity of behavioural variability reflects conflicting selection in group-living and solitary desert locusts

Animals living in groups tend to express less variable behaviour than animals living alone. It is widely assumed that this difference reflects, at least in part, an adaptive response to contrasting selection pressures: group-living should favour the evolution of more uniform behaviour whereas lone-living should favour behaviour that is less predictable. Empirical evidence linking these contrasting selection pressures to intrinsic differences in behavioural variability is, however, largely lacking. The desert locust, Schistocerca gregaria, manifests in two very distinct eco-phenotypes, a lone-living cryptic "solitarious phase" and a swarming "gregarious phase" that aggregates into very large and dense groups. This "phase polyphenism" has evolved in response to contrasting selection pressures that change rapidly and unpredictably. Phase differences in mean behaviour are well-characterised, but no previous study has considered differences in variability. Here we used locust phase polyphenism to test the hypothesis that group living leads to the evolution of reduced intrinsic variability in behaviour. We measured two behaviours in both phenotypes: locomotor activity in the presence of conspecifics, and locomotor hesitation in approaching food when alone. We assayed each individual repeatedly and estimated variability relative to the mean in log-normal mixed-effects models that explicitly account for the means-variance dependency in the behavioural measures. Our results demonstrate that relative behavioural variability differs between the two phases in line with predictions from ecological theory: both within-individual and between-individual variability were lower in the group-living gregarious phenotype. This contrasts with previous studies on social niche construction in spiders and crickets, and highlights the importance of social ecology: in animals that form non-social collectives, such as locusts, reduced individual behavioural variability is key for coherent collective behaviour. The differences in variability persisted when gregarious locusts were tested in isolation and solitarious locusts were tested in groups, indicating that they arise not simply as flexible reactions to different social contexts, but are intrinsic to the individual animals of each phase. This "variance polyphenism" in locusts provides empirical evidence that evolutionary adaptation for group living has driven a reduction in within- and between-individual behavioural variability.

ecology↗

bioRxiv2019

Marketplace Shrimp Mislabeling in North Carolina

Seafood mislabeling occurs in a wide range of seafood products worldwide, resulting in public distrust, economic fraud, and health risks for consumers. We quantified the extent of shrimp mislabeling in coastal and inland North Carolina. We used standard DNA barcoding procedures to determine the species identity of 106 shrimp sold by 60 vendors across North Carolina as \"local\" shrimp. Thirty-four percent of the purchased shrimp was mislabeled, and surprisingly the percentage did not differ significantly between coastal and inland counties. Roughly one third of product incorrectly marketed as \"local\" was in fact whiteleg shrimp: an imported, and very likely farmed, species from the eastern Pacific (and not found in North Carolina waters). In addition to the negative ecosystem consequences of shrimp farming (e.g., the loss of mangroves forests and the coastal buffering they provide) and seafood importation, North Carolina fishers--as with local fishers elsewhere--are negatively impacted when vendors label farmed, frozen, and imported shrimp as local, fresh, and wild-caught.

ecology↗

bioRxiv2017

Simulations for Designing and Interpreting Intervention Trials in Infectious Diseases

Here we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly in emerging infectious disease, that more accurately reflects the dynamics of the transmission process. Interventions in infectious diseases can have indirect effects on those not receiving the intervention as well as direct effects on those receiving the intervention. Combinations of interventions can have complex interactions at the population level. These often cannot be adequately addressed with standard study designs and analytic methods. Simulations can help to accurately represent transmission dynamics in an increasingly complex world which is critical for proper trial design and interpretation. Some ethical aspects of a trial can also be quantified using simulations. After a trial has been conducted, simulations can be used to explore possible explanations for the observed effects. A great deal is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods and the conduct of clinical trials.

epidemiology↗

bioRxiv2017

Tolerance of chronic HDACi-administration used for treatment of neurological and visceral disease including lung pathogenesis.

Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use in neurological disorders has raised concern because HDACs are required for brain function. We have previously shown that a triple combination formulation (TCF) of the pan HDACi vorinostat (Vo) improves pharmacokinetic exposure and entry of Vo into the brain. TCF treatment significantly delayed both neurodegeneration and death in the Npc1nmf164 murine model of Niemann Pick Type C (NPC) disease. The TCF induces no metabolic toxicity, but its risk to normal brain functions and potential utility in treating lung disease, a major NPC clinical complication, remain unknown. Here we report that TCF administered for 8-10 months was not detrimental to brain or neuromuscular functions of healthy mice, based on quantitative analyses of major Purkinje neurons in the cerebellum, inflammation in the hippocampus and symptoms of progressive neurocognitive/muscular disease. The TCF was also not injurious to lung tissue but rather improved delivery of Vo to lungs and reduced accumulation of foamy macrophages in Npc1nmf164 mice. Together these data support feasibility of tolerable, chronic administration of an HDACi formulation to treat brain and systemic disease including lung pathology, a frequent cause of death in NPC and possibly other neurological diseases.

neuroscience↗