Biology subjects

Simpson, S.

Publications and source records attributed to Simpson, S..

At least 19 recordsLinked to original sources

bioRxiv2026

High frame rate in vivo two-photon microscopy to quantify murine cerebrospinal fluid flow heterogeneity

Cerebrospinal fluid (CSF) flows through perivascular spaces (PVSs) surrounding brain vasculature, and impaired flow has been linked to neurodegenerative diseases such as Alzheimer's. However, the mechanisms driving CSF flow and its oscillatory dynamics remain poorly understood. Using high frame rate two-photon imaging (up to 113 Hz), we show that CSF flow is spatially heterogeneous and highly pulsatile, quantified using a regional CSF pulsatility index (PI). Reduced-order simulations with realistic domain length and Windkessel boundary conditions show that arterial pulsations generate peak CSF velocities but contribute negligibly to net transport. PI varies non-monotonically in space and substantially with downstream hydraulic resistance and compliance, indicating that CSF pulsatility is an emergent property of the hydraulic network rather than simply a consequence of local arterial wall motion. Measurements and simulations of the phase between arterial wall motion and CSF velocity further constrain proposed CSF driving mechanisms. Finally, we perform mouse-specific simulations to estimate average and peak wall shear stresses which support the potential role of pulsatile CSF flow in perivascular mechanotransduction. Together, these results establish CSF pulsatility as a measurable signature of network-scale CSF dynamics.

neuroscience↗

bioRxiv2026

Epistatic evolution drives HLA-dependent CD8+ T Cell escape risk in diverse populations

Understanding how viral evolution shapes HLA-dependent T cell escape is crucial to identify individuals at risk of reduced cellular immunity to emerging variants. Nevertheless, we lack frameworks to model HLA diversity and the evolutionary feasibility of T cell-evading mutations. Here, we construct an HLA map capturing variation in epitope specificity across HLA-typed cohorts. Enhancing this framework with SARS-CoV-2 CD8 T cell escape reveals heterogeneous escape across HLA-defined groups, with clusters enriched for HLA-B*07:02, HLA-A*03:01 and HLA-A*02:01 showing higher epitope loss. To assess the evolutionary plausibility of escape, we model viral sequence fitness using an epistasis-aware protein language approach trained on coronaviruses to systematically score mutations across viral lineages. We find that the fitness effect of mutations dynamically changes with evolving sequence context, and that T cell-evading mutations become fitter with additional escape mutations. This study links host HLA diversity to viral fitness landscapes for surveillance and vaccine design.

genomics↗

bioRxiv2026

Curcumin Alleviates Systemic Inflammation and Gut Dysbiosis Induced by Circadian Rhythm Disruption in a Rodent Model of Jet Lag

Circadian rhythm disruption is increasingly recognized as a systemic stressor that promotes immune dysregulation and gut microbial imbalance, processes implicated in a wide range of inflammatory and neurodegenerative diseases. However, therapeutic strategies targeting the gut-immune interface under conditions of circadian misalignment remain limited. Here, we investigated whether curcumin, a plant-derived polyphenol with known anti-inflammatory properties, mitigates inflammation and gut dysbiosis induced by severe circadian disruption in a rodent model of chronic jet lag Rats were subjected to repeated 12-hour inversions of the light-dark cycle and treated daily with curcumin (40 mg/kg/day) or vehicle delivered orally in almond butter. Circadian disruption significantly increased circulating proinflammatory cytokines and altered gut microbial composition. Curcumin treatment markedly reduced plasma levels of IFN-{gamma}, TNF-, IL-6, and CXCL1, decreased Peyers patch size, and partially restored circadian-regulated activity patterns. Shotgun metagenomic analysis revealed that curcumin shifted the gut microbiome toward a more eubiotic profile, characterized by increased species richness, reduced dominance of inflammatory taxa, decreased relative abundance of Proteobacteria, and increased Firmicutes, with a trend toward enrichment of Actinobacteria. Collectively, these findings demonstrate that curcumin attenuates systemic and intestinal inflammation associated with circadian rhythm disruption, likely through combined suppression of proinflammatory signaling and modulation of the gut microbiome. Despite its limited systemic bioavailability, curcumin exerted robust effects at the gut-immune interface, highlighting the microbiome as a critical therapeutic target for chronobiology-associated inflammatory disorders. These results support curcumin as a potentially promising chronoprotective intervention for conditions characterized by circadian misalignment, including shift work and jet lag.

animal behavior and cognition↗

bioRxiv2025

Detection of Japanese Encephalitis (JE) Virus in Piggery effluent from an Australian Farm Prior to Outbreaks of JE

Japanese encephalitis virus (JEV), a mosquito-borne orthoflavivirus, raises concerns about its seasonal re-emergence. Pigs are a major amplifying host and JEV infection can manifest as significant reproductive disease and losses, necessitating robust surveillance. This study evaluated effluent surveillance for early JEV detection in piggery effluent from a Victorian farm between December 2024 and March 2025. Effluent samples were tested using JEV-specific real-time reverse transcription (RT)-PCR, with positive detections found on four separate sampling days, despite an absence of clinical signs in livestock through the testing period. Subsequent veterinary investigations for JEV in litters born on 17/05/2025 (suspect cases only) aligned with a positive effluent sample collected during the estimated JEV infection exposure periods of the sows. With the single clinically confirmed JEV case (which farrowed on 1/06/2025) collection of the same positive effluent sample fell just outside, but near, the estimated exposure period for the affected sow. These findings highlight ability of effluent monitoring to detect JEV infection 2 to 4 months before clinical manifestations present, offering potential for a non-invasive, herd-level early warning system. Intermittent detections may suggest limitations in grab sampling and low viral loads in effluent samples. Integrating effluent surveillance with veterinary clinical testing of litters suspected of being exposed to JEV or during high-risk periods could enhance JEV management in Australias enzootic regions, supporting One Health strategies.

molecular biology↗

bioRxiv2025

Angulin-1/LSR inhibition transiently disrupts the blood-tumor barrier to enhance doxil permeability and impair malignant glioma progression

The blood-tumor barrier (BTB) prevents effective central nervous system (CNS) drug delivery, especially in malignant gliomas. Brain endothelium predominates the BTB and connects through bicellular and tricellular tight junctions (TJ). Angulin-1/LSR, is a highly expressed endothelial tricellular TJ. Our studies explore the role of Angubindin-1, an Angulin-1/LSR binder, to disrupt tricellular TJ integrity, increase drug entry and hamper glioma progression. Using rat brain endothelial cells (RBMVEC) we tracked Angulin-1/LSR localization and expression to the membrane; binding tightest to Angubindin-1 2-8 hours post-treatment (p < 0.05). Angubindin-1 dose-dependently reduced bicellular and tricellular TJs 1-4 hours post treatment (p < 0.05), returning to baseline by 24 hours (p < 0.05). In human and rat-derived glioma cells, Angubindin-1 transiently reduced Angulin-1/LSR expression between 2-8 hours (p < 0.05), with return to baseline by 24 hours (p < 0.001). Silenced Angulin-1/LSR expression on endothelium resulted in decreased mRNA levels of bicellular (occludin, claudin-5, ZO-1) and tricellular (tricellulin/MARVELD2, angulin-1/LSR) TJs compared to control (p < 0.01). Angubindin-1 treatment also inhibited efflux transporter P-gp in both RBMVECs and glioma cells with high P-gp expression only. Orthotopic rat glioma models were treated with Doxil (3 mg/kg), Angubindin-1 (10 mg/kg), or combination to evaluate BTB permeability/drug accumulation, and overall survival. Combination therapy enhanced Doxil tumor accumulation by 20% (p < 0.001), reduced tumor volume by day 14 (77.5% vs. 81.6%, p < 0.05), and significantly extended survival compared to Doxil alone (24 days vs. 18 days, p < 0.0001). These findings demonstrate the effects of tricellular tight junction inhibition on disrupting the BTB, enhancing CNS drug delivery, and improving rodent glioma survival. SignificanceThis study demonstrates that Angubindin-1, a targeted modulator of tricellular tight junction protein Angulin-1/LSR, transiently disrupts BTB integrity to enhance chemotherapy delivery and prolong survival in glioma-bearing rats. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/667901v1_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@b1b46corg.highwire.dtl.DTLVardef@bc552dorg.highwire.dtl.DTLVardef@7c1a74org.highwire.dtl.DTLVardef@1ace101_HPS_FORMAT_FIGEXP M_FIG C_FIG Angubindin-1 targets both bicellular tight junctions and the tricellular tight junction protein, Angulin-1/LSR, in brain endothelial and glioma cells leading to transient disruption of the blood-tumor barrier (BTB) and inhibition of P-glycoprotein towards enhanced Doxil penetration and reduced tumor burden.

cell biology↗

bioRxiv2025

Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats

BackgroundCocaine use disorder (CUD) is a major public health crisis with detrimental individual and societal effects. The specific genes mediating CUD remain largely unknown. MethodsWe conducted a genome-wide association study (GWAS) using outbred N/NIH Heterogeneous Stock (HS; n = 836, female = 415, male = 421) rats. We examined multiple CUD-related phenotypes that captured acquisition of self-administration, escalation of intake, and compulsive-like responding. ResultsConsistent with the existing literature, these traits were phenotypically and genetically correlated and exhibited modest heritability (h2 = 0.07 - 0.16). We identified six genome-wide significant associations. One locus on chromosome 19 was associated with the variable time between cocaine infusions (post infusion interval) and contains several carboxylesterase genes that are orthologous to the human CES1 gene; notably, carboxylesterases metabolize cocaine. Three non-synonymous coding variants in the genes Ces1c and Ces1d were in perfect linkage disequilibrium with this locus, suggesting that one or more of them might be the causal SNP. The other 5 loci also contained promising coding and expression variants, including Trak2, a gene previously associated with CUD in human GWAS and Slc10a7, Plcl1, and Satb2 which have been associated with alcohol and tobacco use disorder. ConclusionsThis is the largest genetic study of cocaine self-administration ever conducted in any species. Our results replicate previous loci associated with CUD in humans and provide several novel biological insights including the potential of pharmacological strategies targeting carboxylesterases for the treatment of CUD.

genetics↗

bioRxiv2025

In-situ calibration of passive samplers for monitoring host-associated fecal markers in an urban river

Passive sampling in aquatic environments has shown promise as a time- and cost-efficient method with improved sensitivity for detecting microbial pollution in dynamic and variable conditions. However, quantitative descriptions of its field performance have been scarce, impeding its broader application in environmental settings. The performance of two membrane-based passive samplers (Torpedo and MSTFlow) in quantifying human (Carjivirus, Pepper Mild Mottle Virus [PMMoV], Tomato Brown Rugose Fruit Virus [ToBRFV]) and avian (Helicobacter spp. GFD marker) fecal pollution markers in an urban riverine environment over a 72-h deployment was evaluated using a first-order kinetic model to characterize their microbial adsorption characteristics. Results were compared with those from parallel composite and time-weighted auto-sampling. Accumulation in passive samplers exhibited an initial lag phase (0 to 8 h for viruses) and reached equilibrium within 16 h of initial deployment, except for GFD. Sampling rates were highest for PMMoV (6.29 and 5.11 mL/h) for MSTFlow and Torpedo samplers respectively, followed by Carjivirus (4.63 and 3.63 mL/h), ToBRFV (2.17 and 1.22 mL/h) and GFD (0.68 mL/h in Torpedo sampler). At equilibrium, both sampler configurations accumulated more than 22-170 times the amount of target gene copies in each mL of grab water samples depending on sampler and virus. These findings highlight passive sampling as a promising, sensitive, cost-effective, and low-maintenance alternative for continuous microbial water quality monitoring in aquatic environments. Overall, this study advances the understanding of passive sampling kinetics and supports broader adoption of passive samplers for tracking fecal pollution in environmental waters.

microbiology↗

bioRxiv2025

Hyper-Glycosylation as a Central Metabolic Driver of Alzheimers Disease

Alzheimers disease (AD) is a neurodegenerative disorder characterized by devastating degenerative decline. Metabolic disruptions are widely observed, yet their involvement in the molecular etiology of AD remains underexplored. Utilizing spatial metabolomics, lipidomics, and glycomics in both mouse models and human post-mortem samples, we identified a hyper-glycosylation phenotype as a hallmark of AD. To investigate the underlying mechanisms and whether the observed effect was a driver of the observed decline, we developed an advanced spatial isotopic tracing pulse-chase method to study the dynamics of N-linked glycans. Our analysis revealed enhanced glycan biosynthesis in AD mouse models. Based on these findings, we performed genetic and dietary interventions to modulate glycan biosynthesis. Genetic knockdown of glycan biosynthetic enzymes ameliorated the hyper-glycosylation and improved cognitive and behavioral outcomes in AD mice. In contrast, oral glucosamine supplementation drove hyper-glycosylation and exacerbated cognitive and behavioral deficits. To assess the clinical relevance of these findings, we conducted a retrospective analysis of a large population of patients with mild cognitive impairment (MCI), AD, and Alzheimers Disease Related Dementias (ADRD) stratified by glucosamine use, leveraging electronic health records. Consistently, glucosamine supplementation was associated with increased mortality in AD and ADRD patient cohorts, and significantly elevated progression from MCI to AD compared to age-matched controls. Collectively, our findings establish hyper-glycosylation as a pathological driver of AD and highlight glycan metabolism as an actional target in the fight against AD.

neuroscience↗

bioRxiv2025

Surveillance of Japanese Encephalitis Virus in Piggery Effluent and Environmental Samples: A Complementary Tool for Outbreak Detection

Japanese encephalitis virus (JEV) is an emerging public health and biosecurity concern in Australia, with recent human cases and detections in mosquitoes and pigs across multiple states highlight the risk to susceptible human and animal populations. While traditional surveillance methods such as mosquito trapping, sentinel chicken programs and direct testing of pig specimens remain essential, monitoring effluent offers a valuable complementary approach for detecting infections within animal populations. This study presents the first evidence of JEV in Australian piggery effluents/environmental waters, demonstrating the feasibility of effluent and environmental water surveillance for JEV monitoring. Effluent/environmental samples from multiple piggery sites were analyzed using real-time reverse transcription polymerase chain reaction (RT-PCR), revealing the presence of JEV genetic fragments in solid and liquid fractions of effluents at three farms, with corresponding veterinary cases in some herds. Viral RNA was detected more frequently in solid fraction of effluent samples, aligning with previous findings on the partitioning behaviour of mosquito-borne viruses. The detection of JEV in the borrow pit (i.e., a man-made excavation that holds water) water sample highlights potential transmission pathways via mosquito vectors. These findings demonstrate the value of effluent monitoring as an additional tool for JEV surveillance in piggery settings, supporting potential early warning systems and mitigation strategies. Integrating effluent-based monitoring with traditional surveillance approaches could improve livestock industry related disease detection, risk assessments, and response efforts for human and animal health in endemic and emerging regions. Wastewater/effluent surveillance may have important applications for the management of a wide range of emerging animal diseases. IMPORTANCEThis study presents the first evidence of Japanese encephalitis virus (JEV) detection in Australian piggery effluents, establishing effluent surveillance as a valuable complementary tool for monitoring viral pathogens in animal populations. Our findings support the integration of effluent monitoring with traditional surveillance systems to improve early warning capabilities, enhance biosecurity, and mitigate risks to both animal and human health.

molecular biology↗

bioRxiv2025

A preclinical pig model of Angelman syndrome mirrors the early developmental trajectory of the human condition

Angelman syndrome is a neurodevelopmental disorder characterized by severe motor and cognitive deficits. It is caused by the loss of the maternally inherited allele of the imprinted ubiquitin-protein ligase E3A (UBE3A) gene. Rodent models of Angelman syndrome do not fully recapitulate all the symptoms associated with the condition and are limited as a preclinical model for therapeutic development. Here, we show that pigs (Sus scrofa) with a maternally inherited deletion of UBE3A (UBE3A-/+) have altered postnatal behaviors, impaired vocalizations, reduced brain growth, motor incoordination, and ataxia. Neonatal UBE3A-/+ pigs exhibited several symptoms observed in infants with Angelman syndrome, including hypotonia, suckling deficits, and failure to thrive. Collectively, these findings are consistent with the pathophysiology and developmental trajectory observed in individuals with Angelman syndrome. We anticipate that this pig model will advance our understanding of the pathophysiology of Angelman syndrome and be used as a preclinical large animal model for therapeutic development.

genetics↗

bioRxiv2025

High Incidence of Estrous Cycle Irregularities in Heterogeneous Stock (HS) Rats is Associated with Severe Cocaine Addiction-like Behaviors

Hormonal fluctuations throughout the estrous cycle have been hypothesized to influence drug-related behaviors. Preclinical models show that some cocaine-related behaviors are influenced by the estrous cycle. However, the extent to which the estrous cycle modulates cocaine self-administration in outbred heterogeneous stock (HS) rats, a population that captures human genetic diversity, is unknown. This study aimed to examine the relationship between estrous phases and cocaine self-administration behavior in HS rats using a model of extended access to cocaine self-administration. We focused on the escalation of intake, breaking point, and resistance to foot shock. Using vaginal swabbing and lavage techniques, we first characterized the relationship between estrous phase and cocaine intake. We then comprehensively evaluated estrous cycling patterns in young adult and adult HS rats, comparing them with Wistar rats. Contrary to our hypothesis, estrous phase showed no association with cocaine self-administration in HS rats. HS rats exhibited irregular estrous cycling with variability to the phase length, even in the absence of drug exposure, a phenomenon not observed in the Wistar strain. Irregular estrous cycle was associated with high cocaine-related behaviors. This study provides the first evidence that some female HS rats exhibit irregular estrous cycling. Moreover, rats with severe addiction-like behaviors had more instances of irregular cycling. These results demonstrate that, in HS rats, the estrous phase per se has no major influence on cocaine self-administration, but that the severity of addiction-like behaviors are associated with more irregularity of the estrus cycle. As HS rats gain popularity in behavioral and genome-wide studies, understanding these cycle disruptions is crucial as they may reveal genetic links into female vulnerability to drugs.

neuroscience↗

bioRxiv2024

High fat low carbohydrate diet is linked to protection against CNS autoimmunity

Multiple sclerosis (MS) is a common central nervous system (CNS) autoimmune disease, and diets and nutrients are emerging as critical contributing factors. However, a comprehensive understanding of their impacts and the underlying mechanisms involved is lacking. Harnessing state-of-the-art nutritional geometry analytical methods, we first revealed that globally, increased carbohydrate supply was associated with increased MS disease burden, while fat supply had an opposite effect. Furthermore, in a preclinical MS mouse model, experimental autoimmune encephalomyelitis (EAE), we found that an isocaloric diet high in carbohydrate aggravated EAE, while a diet enriched in fat was fully protective. This was reflected by reduced neuroinflammation and skewing towards anti-inflammatory phenotypes, which involved transcriptomic, epigenetic and immunometabolic changes. We showcased that manipulating diets is a potentially efficient and cost-effective approach to prevent and/or ameliorate EAE. This exhibits translational potentials for intervention/prevention of MS and possibly other autoimmune diseases.

immunology↗

bioRxiv2024

A fully phased, chromosome-scale genome of sugar beet line FC309 enables the discovery of Fusarium Yellows resistance QTL

Sugar beet (Beta vulgaris L.) is a global source for table sugar and animal fodder. Here we report a highly contiguous and haplotype phased genome assembly and annotation for sugar beet line FC309. Both assembled haplomes for FC309 represent the largest and most contiguous assembled beet genomes reported to date, as well as gene annotations sets that capture over 1500 additional protein-coding loci compared to prior beet genome annotations. These new genomic resources were used to identify novel quantitative trait loci (QTL) for Fusarium Yellows resistance from the FC309 genetic background using an F2 mapping-by-sequencing approach. The highest QTL signals were detected on Chromosome 3, spanning approximately 10 Mbp in both haplomes. A parallel transcriptome profiling experiment identified candidate genes within the Chromosome 3 QTL with plausible roles in disease response, including NBS-LRR genes with expression trends suggestive of their role as causal resistance genes. Collectively, the genomic resources for FC309 presented here be foundational tool for comparative genomics, mapping other traits in the FC309 background, and as a reference genome for other beet studies due to its contiguity, completeness, and high-quality gene annotations.

plant biology↗

bioRxiv2024

Nutribloods: novel synthetic lepidopteran haemolymphs for understanding insect-microbe interactions in vitro

Understanding the role of nutrients in microbial population dynamics relies on a sound appreciation of their nutritional environment and how this may vary in different habitats. For microbial pathogens and commensals, this can be especially challenging because the microbe may share nutritional resources with its host. Here we design a series of 20 synthetic haemolymphs (nutribloods) that mimic haemolymph nutrient profiles of caterpillars fed on one of 20 chemically-defined diets, that vary in their protein:carbohydrate (P:C) ratio and caloric density. Using these, we are able to simulate the range of nutritional conditions that insect blood pathogens might face, providing a model system for understanding the role of nutrition in microbial growth. We tested this using the entomopathogen, Xenorhabdus nematophila, a gram-positive extracellular bacterium of insect hosts. This revealed that whilst bacterial fitness peaked in nutriblood nutrient space that was high in carbohydrates and low in proteins, levels of amino acids in the nutribloods also appear to be an important driving force for bacterial growth. Using synthetic haemolymphs that had average levels of all nutrients other than carbohydrate, protein or amino acids, we also established that bacterial growth is generally enhanced by carbohydrate and amino acids but reduced by proteins. Here, we have established a tractable model system for examining the role that nutrition plays in the growth of an entomopathogenic bacterium. In future work, this model host-pathogen system can be used to test a range of nutritionally-driven processes, including competition during co-infection and interactions with the host microbiome, as well as comparative studies of other entomopathogens.

physiology↗

bioRxiv2024

Sleep selectively and durably enhances real-world sequence memory

Sleep is thought to play a critical role in the retention of episodic memories. Yet it remains unclear whether and how sleep actively transforms memory for specific experiences. More generally, little is known about sleeps effects on memory for multidimensional real-world experiences, both overnight and in the days to months that follow. In an exception to the law of forgetting, we showed that sleep actively and selectively improves retrieval of a one-time real-world experience (a controlled but immersive art tour) - specifically boosting memory for the order of tour items (sequential associations), but not perceptual details from the tour (featural associations). This above-baseline increase in sequence memory was not evident after a matched period of wakefulness. Moreover, the sleep-induced advantage of sequence over featural memory grew over time up to one-year post-encoding. Finally, overnight polysomnography showed that sleep-related memory enhancement was associated with the duration and neurophysiological hallmarks of slow-wave sleep previously linked to neural replay, particularly spindle-slow wave coupling. These results suggest that sleep serves a crucial and selective role in enhancing sequential organization in episodic memory at the expense of specific details, linking sleep-related neural mechanisms to the transformation and enhancement of memory for complex real-life experiences. Significance StatementSleep affects the retention of episodic memories. Yet, it remains unclear whether sleep active transforms how we remember past experiences, overnight and beyond. We investigated memory for different dimensions underlying a dynamic real-world event - sequential associations versus atemporal featural associations - before and after sleep or wakefulness, and serially up to a year later. Sleep actively and selectively enhanced sequence memory, with this preferential sequence retention growing with time. Overnight memory enhancement is associated with the duration and neurophysiological hallmarks of slow-wave sleep previously linked to sequential neural replay, particularly spindle-slow wave coupling. Our findings support an active role for sleep in transforming different aspects of real-world memory, with sequence structure coming to dominate long-term memory for dynamic real-world experiences.

neuroscience↗

bioRxiv2023

Fungal infection alters collective nutritional intake of ant colonies

In many animals, parasitic infections impose significant fitness costs [1-6]. Animals are known to alter their feeding behavior when infected to help combat various parasites [7-12]. For instance, they can adjust nutrient intake to support their immune system [13,14]. However, parasites can also manipulate host foraging behavior to increase their own development, survival and transmission [15-18]. The mechanisms by which nutrition influences host-parasite interactions are still not well understood. Until now, studies that examine the impact of diet on infection have mainly focused on the host, and less on the parasite [12,13, 19-25]. Using Nutritional Geometry [26], we investigated the role of key nutrients: amino acids and carbohydrates, in a host-parasite system: the Argentine ant, Linepithema humile, and the entomopathogenic fungus, Metarhizium brunneum. We first established that the fungus grew and reproduced better on diets comprising four times less amino acids than carbohydrates (1:4 AA:C ratio). Second, when facing food combinations, the fungus exploited the two complementary food resources to reach the same performance as on this optimal diet, revealing the ability of fungal pathogens to solve complex nutritional challenges. Third, when ants were fed on this optimal fungal diet, their lifespan decreased when healthy, yet not when Metarhizium-infected, compared to their favored carbohydrate-rich diet. Interestingly, when the ants were given a binary choice between different diets, the foragers of uninfected colonies avoided intake of the fungal optimum diet, whilst choosing it when infected. Experimental disentanglement of full pathogenic infection and pure immune response to fungal cell wall material, combined with immune measurements, allowed us to conclude that this change of nutritional choice in infected ants did not result from pathogen manipulation but likely represents a compensation of the host to counterbalance the cost of using amino acids during the immune response. The observed change in foraging behavior in infected colonies towards an otherwise harmful diet (self-medication), suggests a collective compensatory mechanism for the individual cost of immunity. In short, we demonstrated that infected ants converge on a diet that is proven to be costly for survival in the long term but that could help them fight infection in the short term. HighlightsO_LIThe insect-pathogenic fungus Metarhizium brunneum performs best on protein-rich diets and is able to solve complex nutritional challenges C_LIO_LIWhile harmful to healthy ants, protein-rich diets did not shorten infected ants lifespan C_LIO_LIContrary to healthy ants, when given a choice, infected and immune-stimulated ants choose a protein-rich diet C_LI

animal behavior and cognition↗

bioRxiv2023

Transcript errors generate a continuous stream of amyloid and prion-like proteins in human cells

Aging is characterized by the accumulation of amyloid and prion-like proteins. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that transcript errors generate amyloid and prion-like proteins in a wide variety of human cell types, including stem cells, brain organoids, and fully differentiated neurons. Intriguingly, some of these proteins are identical to proteins previously implicated in familial cases of amyloid diseases, raising the possibility that both familial and non-familial cases are caused by identical mutant proteins. However, transcript errors also generate amyloid proteins that have not been observed before, suggesting that aging cells are exposed to a second class of pathogenic proteins we are currently unaware of. Finally, we show that transcript errors are readily generated by DNA damage, a hallmark of human aging and a staple of multiple proteotoxic diseases, including Alzheimers disease. Together, these observations greatly expand our understanding of mutagenesis in human aging and disease and suggest a new mechanism by which amyloid diseases can develop.

molecular biology↗

bioRxiv2023

Microbial short-chain fatty acids regulate drug seeking and transcriptional control in a model of cocaine seeking

Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an FR1 schedule. However, microbiome-depleted subjects exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.

neuroscience↗