Biology subjects

Hamilton, A.

Publications and source records attributed to Hamilton, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Prefrontal brain-to-brain synchrony during human group hunting: Evidence from fNIRS hyperscanning

Orca, wolves, chimpanzees and humans share a similarly impressive capacity for group hunting, where individuals coordinate behaviour together to capture prey. Studying hunting behaviours has important implications for understanding how behaviour in group contexts may be indicative of cognitive decline. Despite growing interest in brain circuits for prey capture, the brain regions involved in tracking prey during a hunt and the behaviours in group hunt linked to success remain unclear. Here we combined functional near infrared spectroscopy (fNIRS) and a virtual minecraft world to examine behaviour, brain dynamics and brain synchrony involved in group hunting behaviour. We focused on the prefrontal cortex (PFC) due to its known role in planning and social coordination and recorded from pairs of individuals as they either cooperated to hunt another person (prey) or simply followed another person. Hunters were more successful if they managed to keep a smaller distance to the prey and moved at speeds that were more synchronised with their co-predator. At high-range frequencies for fNIRS (0.1-0.2Hz), we found greater brain-to-brain synchrony in lateral and medial (frontopolar) PFC regions during hunting compared with chance levels. Together, these findings provide insights into what behaviours and brain dynamics associated with successful group hunting.

neuroscience↗

bioRxiv2025

Metagenomic Profiling of Bacterial (16S) and Fungal (ITS) Communities on D'Anjou Pears during Long-Term Controlled Atmosphere Storage

DAnjou pears are routinely stored for up to nine months under controlled atmosphere (CA) conditions to meet market demands. While this practice maintains fruit quality, limited information exists on pears natural microbiota throughout storage. The objective of this study was to describe fungal and bacterial composition on marketable and unmarketable conventional, whole, intact pears under two storage practices (bulk vs wrapped) at 3, 6, and 9 months in long-term CA cold storage. Storage practices had a significant effect on the composition and succession of both fungal and bacterial communities. Overall, fungal communities exhibited lower estimated Chao1 alpha diversity (mean 18.3) compared to bacterial communities (mean 166.4). No significant differences in Chao1 index were found between the bacterial and fungal communities on marketable or unmarketable pears. Trends in Chao1 indices of fungal and bacterial communities peaked at mid-storage and declined by 9 months, with wrapped pears showing parallel trends and bulk pears exhibiting a sharper late-stage reduction. No distinct clusters could be found for 3- and 6-month fungal communities, irrespective of marketability or being bulk or wrapped. The principal coordinate analysis of the bacterial communities showed tight clustering by time point for the individually wrapped pears, irrespective of their marketability. Bacterial communities included genera common in food-processing and plant environments, such as Pseudomonas and Acinetobacter. Fungal communities shifted over time, with spoilage-associated genera like Aureobasidium, Penicillium, Botrytis, and Mucor present at different storage stages. SignificanceThis study highlights the influence of storage duration and packaging on microbial succession, establishing initial benchmarks of pear surface microbiomes. The observed lack of significant differences in microbial diversity between marketable and unmarketable pears suggests that these baseline community profiles can serve as critical reference points for identifying other influential factors. Variables such as handling practices may exert a more direct effect on microbial dynamics and, consequently, product quality. Establishing these baselines is essential because they provide a foundation for detecting deviations linked to spoilage or safety risks. Moreover, understanding these patterns can guide the development of targeted microbial control strategies in postharvest systems, enabling interventions that maintain fruit quality, reduce losses, and improve food safety throughout the supply chain.

microbiology↗

bioRxiv2025

Generation of Chlorella vulgaris starch mutants and their biomass and lipid productivities under different culture media

BackgroundMicroalgae are an important feedstock for the production of a wide variety of products, including biodiesel. Biodiesel, composed of fatty acid alkyl esters, is produced through the transesterification reaction of triacylglycerol (TAG). Microalgae store their energy reserves primarily as starch and TAGs. Therefore, several studies have focused on understanding the partitioning of carbon precursors between starch and TAG biosynthetic pathways. In this study, 5 starch mutants of Chlorella vulgaris were developed and cultured on different culture media. ResultsChlorella vulgaris starch mutants were generated through UV-random mutagenesis. Five starch mutants were selected for this study: four low-starch producing mutants (st27, st29, st43 and st54) and one high-starch producing mutant (st80). The starch mutants were cultured on media with different organic carbon sources, and lipid and biomass productivity were measured. Mixotrophic growth on glucose resulted in the highest lipid productivity in all the mutants, including st80, without compromising growth, whereas photoautotrophic growth generally did not result in changes in lipid productivity of the starch mutants. The highest increase in lipid productivity was observed for st27, with a 3.8-fold higher lipid productivity than wildtype. ConclusionsAll starch mutants increased their lipid productivities when grown mixotrophically on glucose, suggesting the overflow hypothesis could explain the partitioning of carbon between starch and TAGs. Out of the mutants generated in this work, st27 resulted in the highest increases in lipid productivities, reaching an increase of 380% when grown mixotrophically on glucose, without compromising growth. The high-starch producing mutant st80 provides insight into a possibility to develop starch- and TAG-rich microalgal biomass.

bioengineering↗

bioRxiv2025

Prion protein-derived cell-penetrating peptide inhibits type II diabetes-associated islet amyloid polypeptide aggregation and cytotoxicity

Islet amyloid polypeptide (IAPP) is a 37-residue peptide hormone co-packaged and co-secreted with insulin by pancreatic {beta}-cells. A pathological hallmark of type II diabetes is the self-assembly of IAPP into {beta}-sheet rich amyloid fibers, which is associated with {beta}-cell impairment. Previously, we showed that a cell-penetrating peptide (CPP) construct, consisting of a hydrophobic signal sequence coupled to a polycationic nuclear localization signal (NLS)-like sequence, exhibited potent anti-prion activity and antagonism of Alzheimers disease-associated amyloid-{beta} (A{beta}) peptide aggregation and neurotoxicity. Here, we have extended this approach towards type II diabetes by assessing the efficacy of the CPP construct, designated as NCAM1-PrP, in inhibiting IAPP oligomerization, fiber formation and associated cytotoxicity. Using complementary in vitro and in silico experiments, we show that NCAM1-PrP effectively modulates IAPPs toxic structures into non-toxic conformations. This study underlines the potential of our designed CPP-based therapeutic approach as a versatile tool in the battle against amyloid-associated pathologies.

biochemistry↗

bioRxiv2025

STX4 is indispensable for mitochondrial homeostasis in skeletal muscle

BackgroundMitochondrial homeostasis is vital for optimal skeletal muscle integrity. Mitochondrial quality control (MQC) mechanisms that are essential for maintaining proper functions of mitochondria include mitochondrial biogenesis, dynamics and mitophagy. Previously, Syntaxin 4 (STX4) traditionally considered a cell surface protein known for glucose uptake in skeletal muscle, was also identified at the outer mitochondrial membrane. STX4 enrichment was sufficient to reverse Type 2 diabetes-associated mitochondrial damage in skeletal muscle by inactivation of mitochondrial fission. However, whether STX4 could modulate skeletal muscle mitochondrial homeostasis through MQC mechanisms involving mitochondrial biogenesis or mitophagy remains to be determined. MethodsTo determine the requirements of STX4 in mitochondrial structure, function and MQC processes of biogenesis and mitophagy, we implemented our in-house generated inducible skeletal muscle-specific STX4-knockout (skmSTX4-iKO) mice (Stx4fl/fl; Tg(HSA-rtTA/TRE-Cre)/B6) and STX4-depleted immortalized L6.GLUT4myc myotubes via siRNA knockdown (siSTX4). ResultsWe found that non-obese skmSTX4-iKO male mice (>50% reduced STX4 abundance, Soleus and Gastrocnemius ***p<0.001, Tibialis anterior (TA) ****p<0.0001) developed insulin resistance (**p<0.01), together with reduced energy expenditure (AUC *p<0.05), respiratory exchange ratio (AUC **p<0.01), and grip strength (*p<0.05). STX4 ablation in muscle also impaired mitochondrial oxygen consumption rate (****p<0.0001). Mitochondrial morphological damage was heterogenous in STX4 depleted muscle, presenting with small fragmented mitochondria (****p<0.0001) and deceased electron transport chain (ETC) abundance (CI ***p<0.001, CII *p<0.05, CIV **p<0.01) in oxidative soleus muscle, while glycolytic TA fibers display enlarged swollen mitochondria (****p<0.0001) with no change in ETC abundance. Notably, >60% reduction of STX4 in siSTX4 L6.GLUT4myc myotubes (****p<0.0001) also decreased ETC abundance (CI ****p<0.0001, CII ****p<0.0001, CIV *p<0.05) without changes in mitochondrial glucose metabolism, as shown by [U-13C] glucose isotope tracing. For MQC, both skmSTX4-iKO male mice (*p<0.05) and siSTX4 L6.GLUT4myc myotubes (*p<0.05) showed decreased mitochondrial DNA levels alongside reduced mRNA expression of mitochondrial biogenesis genes Ppargc1a (PGC1-, *p<0.05) and Tfam (*p<0.05) in skmSTX4-iKO soleus muscle and PGC1- (mRNA *p<0.05, protein ***p<0.001), NRF1 (mRNA and protein *p<0.05) and Tfam (mRNA *p<0.05) in siSTX4 L6.GLUT4myc myotubes. Furthermore, live cell imaging using mt-Keima mitophagy biosensor in siSTX4 L6.GLUT4myc cells revealed significantly impaired mitochondrial turnover by mitophagy (*p<0.05) and mitochondria-lysosome colocalization (*p<0.05). STX4 depletion also reduced canonical mitophagy markers, PINK1 and PARKIN in both skmSTX4-iKO muscle (PARKIN *p<0.05, PINK1 **p<0.01) and siSTX4 L6.GLUT4myc myotubes (PARKIN ****p<0.0001, PINK1 *p<0.05). ConclusionsOur study demonstrated STX4 as a key mitochondrial regulator required for mitochondrial homeostasis in skeletal muscle.

cell biology↗

bioRxiv2025

Oncogene Silencing via ecDNA Micronucleation

Extrachromosomal DNA (ecDNA) contributes to cancer genome instability by enabling high-copy oncogene amplification, intratumoural heterogeneity and rapid genetic change. Micronuclei (MN) are frequently observed in chromosomally unstable cancers, yet their origins and relevance in ecDNA-driven tumours remain incompletely understood. Here, we investigate the relationship between ecDNA segregation errors and MN formation. We find that ecDNA frequently localizes to MN and represents a prominent source of MN content in ecDNA-positive cancer cells. Mitotic clustering of oncogene-bearing ecDNAs is associated with asymmetric inheritance and mis-segregation into MN. Transfer of oncogenes from ecDNA into MN is accompanied by reduced transcriptional output. Single-MN sequencing shows that individual MN are enriched for ecDNA to a degree that exceeds expectations from stochastic mis-segregation and that in MN oncogenes originating from multiple distinct ecDNAs coalesce. Using live-cell imaging, we observe that cells inheriting ecDNA-positive MN show limited proliferative capacity and an increased likelihood of cell death. In neuroblastoma patients with MYCN-amplified ecDNA, higher frequencies of ecDNA-positive MN at diagnosis are associated with improved event-free and overall survival. Together, these findings link ecDNA mis-segregation to MN formation and reduced cellular fitness, suggesting that ecDNA-positive MN may reflect a state of impaired oncogenic ecDNA function with potential relevance for clinical outcome.

cancer biology↗

bioRxiv2025

Head before heart: cognitive empathy emerges before affective empathy in the developing brain

Empathy is crucial for social interactions across all cultures, and is foundational to establishing social cooperation and group ties in human societies. Challenging the current predominant view, we recently proposed that understanding others emotions (cognitive empathy) might emerge earlier than actually sharing those emotions (affective empathy) (Bulgarelli & Jones, 2023). Here we test this hypothesis by measuring which empathic component matures first during toddlerhood, a critical period for the development of broader social networks. Addressing this question is critical to understand the mechanisms through which caregivers scaffold empathy development. Traditional approaches are inadequate, as they rely on childrens verbal skills or unfamiliar scenarios that lack ecological validity. In this preregistered study, we employed a novel toddler-appropriate task to dissociate neural and physiological correlates of cognitive and affective empathy in N=90 3-to-6-year-olds using functional near-infrared spectroscopy (fNIRS) and simultaneous heart rate monitoring to identify internal markers of empathy. We found that brain regions supporting affective and cognitive empathy in young children resemble those observed in adults. Importantly, we showed an effect of age on network specialisation with brain activations of cognitive empathy stronger in younger compared to older preschoolers, and brain activations of affective empathy stronger in older compared to younger preschoolers. These results may provide the first evidence that cognitive empathy is engaged early and develops alongside or ahead of affective empathy in preschoolers, challenging existing models and suggesting a new framework for understanding the development of empathy. Significance statementEmpathy is a crucial social skill, consisting of an affective component--sharing emotion--and a cognitive component--conceptually understanding emotions. While to date it has been predominately accepted that the affective component develops earlier than the cognitive one, we recently proposed the opposite, which could have important implications for understanding the mechanisms that underpin social skills. Here we successfully developed a new task to dissociate physiological and neural markers of affective and cognitive empathy in N=90 preschoolers. We found that brain activations for cognitive empathy are stronger than for affective empathy in young children. This provide the first direct evidence for the earlier emergence of cognitive empathy, suggesting that scaffolding the understanding of others emotions may be crucial for empathy development.

neuroscience↗

bioRxiv2024

Assessing the effects of acute temperature changes of sea water temperature due to climate change on Scottish farmed Atlantic salmon and investigating genetic mitigation

Changes in growth, survival, maturation and health in Atlantic salmon post-smolts were observed under moderate and more extreme heat-wave conditions for the west coast of Scotland. A Scottish Atlantic salmon breeding programme population of 518 salmon of age 13-14 months, was observed for 4 weeks in summer, in tanks with ambient water temperature or [~] 4 degrees and [~] 8 degrees above ambient temperature. Data were recorded for the fish before and after the challenge. All fish were genotyped using a custom SNP (single nucleotide polymorphism) array (8,978 SNP genotypes after quality control). Temperature-dependant genotype-by-environment interactions and the potential for selective breeding to improve resilience were investigated. Statistical analyses revealed significant differences between thermal environments for body weight, average daily weight gain, and survival, while higher temperature induced earlier maturation, and an increase of gill health scores. QPCR (quantitative polymerase chain reaction) analyses revealed the presence of Aeromonas hydrophila, a pathogen typically more prevalent in warmer climates. Using genomic relationships and animal mixed models, body weight and average daily weight gain provided moderate heritabilities, while between-tank genetic correlations were close to 1, indicating no significant re-ranking of genotypes between the different thermal environments. These findings suggest that even short-term exposure to heat stress may be sufficient to negatively impact survival and gill health, and induce earlier maturation. However, observations took place within a commercial farm where having replicates for each thermal environment was not possible, hence further experiments with larger populations, exposed to more prolonged heat stress are needed.

genetics↗

bioRxiv2023

Chrysin directing an enhanced solubility through the formation of a supramolecular cyclodextrin-calixarene drug delivery system: a potential strategy in antifibrotic diabetes therapeutics

Calixarene 0118 (OTX008) and chrysin (CHR) are promising molecules for the treatment of fibrosis and diabetes complications but require an effective delivery system to overcome their low solubility and bioavailability. Sulfobutylated {beta}-cyclodextrin (SBECD) was evaluated for its ability to increase the solubility of CHR by forming a ternary complex with OTX008. The resulting increase in solubility and the mechanisms of complex formation were identified through phase-solubility studies, while dynamic light-scattering assessed the molecular associations within the CHR-OTX008-SBECD system. Nuclear magnetic resonance, differential scanning calorimetry, and computational studies elucidated the interactions at the molecular level, and cellular assays confirmed the systems biocompatibility. Combining SBECD with OTX008 enhances CHR solubility more than using SBECD alone, by forming water-soluble molecular associates in a ternary complex. This aids in the solubilization and delivery of CHR and OTX008. Structural investigations revealed non-covalent interactions essential to complex formation, which showed no cytotoxicity in hyperglycemic in vitro conditions. A new ternary complex has been formulated to deliver promising antifibrotic agents for diabetic complications, featuring OTX008 as a key structural and pharmacological component.

pharmacology and toxicology↗

bioRxiv2023

High performance imputation of structural and single nucleotide variants in Atlantic salmon using low-coverage whole genome sequencing

BackgroundWhole genome sequencing (WGS), despite its advantages, is yet to replace standard? methods for genotyping single nucleotide variants (SNVs) such as SNP arrays and targeted genotyping assays. Structural variants (SVs) have larger effects on traits than SNVs, but are more challenging to accurately genotype. Using low-coverage WGS with genotype imputation offers a cost-effective strategy to achieve genome-wide variant coverage, but is yet to be tested for SVs. MethodsHere, we investigate combined SNV and SV imputation with low-coverage WGS data in Atlantic salmon (Salmo salar). As the reference panel, we used genotypes for high-confidence SVs and SNVs for n=365 wild individuals sampled from diverse populations. We also generated 15x WGS data (n=20 samples) for a commercial population external to the reference panel, and called SVs and SNVs with gold-standard approaches. An imputation method selected for its established performance using low-coverage sequencing data (GLIMPSE) was tested at WGS depths of 1x, 2x, 3x, and 4x for samples within and external to the reference panel. ResultsSNVs were imputed with high accuracy and recall across all WGS depths, including for samples out-with the reference panel. For SVs, we compared imputation based purely on linkage disequilibrium (LD) with SNVs, to that supplemented with SV genotype likelihoods (GLs) from low-coverage WGS. Including SV GLs increased imputation accuracy, but as a trade-off with recall, requiring 3-4x depth for best performance. Combining strategies allowed us to capture 84% of the reference panel deletions with 87% accuracy at 1x depth. We also show that SV length affects imputation performance, with provision of SV GLs greatly enhancing accuracy for the longest SVs in the dataset. ConclusionsThis study highlights the promise of reference panel imputation using low-coverage WGS, including novel opportunities to enhance the resolution of genome-wide association studies by capturing SVs.

genetics↗

bioRxiv2022

Impact of mixing between parallel year groups on genomic prediction in Atlantic salmon breeding programmes under random selection

A commercial breeding programme in Atlantic salmon utilises a four-year generation interval with four parallel breeding populations. In this study, we develop a computer simulation of a salmon breeding programme and explore the impact of gene flow between the parallel year groups on the accuracy of genomic prediction within and between breeding lines. We simulated four parallel lines for 10 discrete generations with random selection and different mixing rates between parallel year groups. The genetic distance between fish (as a measure of diversity) and the accuracy of estimated genomic breeding values were used as criteria of comparison. With no mixing the genetic distance increased between populations, the genetic variation within populations decreased and there was no increase in accuracy when combining data across populations. Even a low percentage of mixing decreased the genetic distance between populations and increased the genetic variation within populations. The higher the percentage of mixing the faster the lines became more similar. The accuracy of prediction climbed as the percentage of mixing increased. The increase in accuracy from the combined evaluation approach compared to the within evaluation approach was greater with an increased percentage of mixing. In conclusion, if there is no gene flow between populations the lines drift apart and there is no value in combining information across populations for genomic breeding value prediction. Only a low amount of mixing between lines brings the lines closer together and facilitates the use of information across lines to improve breeding value prediction. Optimising gene flow between lines should be an integral part of salmon breeding programme design.

genetics↗

bioRxiv2022

A Synthetic ERRα Agonist Induces an Acute AerobicExercise Response and Enhances Exercise Capacity

Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Here we report the identification of a synthetic agonist for the orphan nuclear receptor ERR (estrogen receptor-related receptor ), SLU-PP-332, that activates an acute aerobic exercise genetic program in skeletal muscle in an ERR-dependent manner. SLU-PP-332 increases mitochondrial function and cellular respiration consistent with induction of this genetic program. When administered to mice, SLU-PP-332 increased the type IIa oxidative skeletal muscle fibers and enhanced exercise endurance. These data indicate the feasibility of targeting ERR for development of compounds that act as exercise mimetics that may be effective in treatment of numerous metabolic disorders and to improve muscle function in the aging.

pharmacology and toxicology↗

bioRxiv2021

The Immunomodulatory Effects of Social Isolation in Mice are Linked to Temperature Control

Living in isolation is considered an emerging societal problem that negatively affects the physical wellbeing of its sufferers in ways that we are just starting to appreciate. This study investigates the immunomodulatory effects of social isolation in mice, utilising a two-week program of sole cage occupancy followed by the testing of immune-inflammatory resilience to bacterial sepsis. Our results revealed that mice housed in social isolation showed an increased ability to clear bacterial infection compared to control socially housed animals. These effects were associated with specific changes in whole blood gene expression profile and an increased production of classical pro-inflammatory cytokines. Interestingly, equipping socially isolated mice with artificial nests as a substitute for their natural huddling behaviour reversed the increased resistance to bacterial sepsis. These results further highlight the ability of the immune system to act as a sensor of our living conditions and to respond in a compensatory fashion to external challenges that might threaten the survival of the host.

immunology↗

bioRxiv2020

DIMT1, a regulator of ribosomal biogenesis, controls beta-cell protein synthesis, mitochondrial function and insulin secretion

We previously reported that transcription factor B1 mitochondrial (TFB1M) is involved in the pathogenesis of type 2 diabetes (T2D) owing to mitochondrial dysfunction. Here, we describe that dimethyladenosine transferase 1 homolog (DIMT1), a homologue of TFB1M, is expressed and active in pancreatic {beta}-cells. Like TFB1M, it has been implicated in control of ribosomal RNA (rRNA) but its role in {beta}-cells or T2D remains to be identified. Silencing of DIMT1 impacted mitochondrial function, leading to reduced expression of mitochondrial OXPHOS proteins, reduced oxygen consumption rate (OCR), dissipated mitochondrial membrane potential ({Delta}{Psi}m) and caused a lower rate of ATP production (mATP). In addition, DIMT1 knockdown slowed the rate of protein synthesis. In accordance with these findings, DIMT1-deficiency perturbed insulin secretion in rodent and human {beta}-cell lines. These effects are likely a result of destabilization of ribosomal assembly, involving NIN1 (RPN12) binding protein 1 homolog (NOB-1) and Pescadillo ribosomal biogenesis factor 1 (PES-1). These are two critical ribosomal subunits proteins, whose interactions were perturbed upon DIMT1-deficiency, thereby disturbing protein synthesis in {beta}-cells. Thus, we have here highlighted a role of DIMT1 in ribosomal biogenesis that perturbs protein synthesis, resulting in mitochondrial dysfunction and disrupted insulin secretion, both being potential pathogenetic factors in T2D.

molecular biology↗

bioRxiv2019

Mitochondrial clearance of Ca2+ controls insulin secretion

Transport of Ca2+ from the cytosol to the mitochondrial matrix of insulin-secreting pancreatic {beta}-cells facilitates nutrient-mediated insulin secretion. However, the underlying mechanism is unclear. The establishment of the molecular identity of the mitochondrial Ca2+ uniporter (MCU) and associated proteins has allowed mitochondrial Ca2+ transport to be modified in intact cells. We examined the consequences of deficiency of the accessory protein, MICU2, in rat and human insulin-secreting cell lines as well as in mouse islets. Glucose-induced mitochondrial Ca2+ elevation and inner membrane hyperpolarization were reduced, together with cytosolic ATP/ADP-ratios and insulin secretion. Insulin secretion in Micu2 knock out mice was attenuated in vitro as well as in vivo. While KCl-evoked sub-plasmalemmal Ca2+ increases were more pronounced, the global cytosolic Ca2+ response was, surprisingly, diminished in MICU2-deficient cells. These findings were supported by selective inhibition of mitochondrial Ca2+ uptake by mitochondrial depolarization. It is concluded that mitochondrial Ca2+ transport plays an additional and hitherto unrecognized role in stimulated {beta}-cells by regulating net Ca2+ entry across the plasma membrane. This is likely accounted for by clearing of sub-plasmalemmal Ca2+ levels by mitochondria located near the plasma membrane.

molecular biology↗

bioRxiv2019

Gender-specific pathophysiological mGluR5-dependent Aβ oligomer signaling in Alzheimer mice

Sex is a key modifier of the prevalence and progression of Alzheimers disease (AD). {beta}- Amyloid (A{beta}) deposition is a pathological hallmark of AD and aberrant activation of metabotropic glutamate receptor 5 (mGluR5) by A{beta} has been linked to AD progression. We find that mGluR5 exhibits distinct sex-dependent pharmacological profiles. Specifically, endogenous mGluR5 from male mouse cortex and hippocampus binds with high-affinity to A{beta} oligomers whereas, female mGluR5 exhibits no affinity to A{beta} oligomers. The binding affinity of mGluR5 to A{beta} oligomer is dependent on its interaction with cellular prion protein (PrPC) as mGluR5 co-immunoprecipitates with PrPC from male, but not female, mouse brain. A{beta} oligomers also bind with high-affinity to human mGluR5 in male, but not female, cortex. The mGluR5/A{beta} oligomer/PrPC ternary complex is essential to elicit mGluR5-dependent pathological signaling and as a consequence mGluR5-regulated GSK3{beta}/ZBTB16 autophagic signaling is dysregulated in male, but not female, primary neuronal cultures. These sex-specific differences in mGluR5 signaling translate into in vivo differences in mGluR5-dependent pathological signaling between male and female AD mice. We show that the chronic inhibition of mGluR5 using a mGluR5-selective negative allosteric modulator reactivates GSK3{beta}/ZBTB16-regulated autophagy, mitigates A{beta} pathology and reverses cognitive decline in male, but not female, APPswe/PS1{Delta}E9 mice. Thus, it is evident that, unlike male brain, mGluR5 does not contribute to A{beta} pathology in female AD mice. This study highlights the complexity of mGluR5 pharmacology and A{beta} oligomer-activated pathological signaling and emphasizes the need for clinical trials redesign and analysis of sex-tailored treatment for AD.

neuroscience↗

bioRxiv2019

Characterising the mechanisms underlying genetic resistance to amoebic gill disease in Atlantic salmon using RNA sequencing

BackgroundGill health is one of the main concerns for Atlantic salmon aquaculture, and Amoebic Gill Disease (AGD), attributable to infection by the amoeba Neoparamoeba perurans, is a frequent cause of morbidity. In the absence of preventive measures, increasing genetic resistance of salmon to AGD via selective breeding can reduce the incidence of the disease and mitigate gill damage. Understanding the mechanisms leading to AGD resistance and the underlying causative genomic features can aid in this effort, while also providing critical information for the development of other control strategies. AGD resistance is considered to be moderately heritable, and several putative QTL have been identified. The aim of the current study was to improve understanding of the mechanisms underlying AGD resistance, and to identify putative causative genomic factors underlying the QTL. To achieve this, RNA was extracted from the gill and head kidney of AGD resistant and susceptible animals following a challenge with N. perurans, and sequenced.\n\nResultsComparison between resistant and susceptible animals pointed to differences mainly in the local immune response in the gill, involving red blood cell genes and genes related to immune function and cell adhesion. Differentially expressed immune genes highlighted differences in the Th2 and Th17 responses, which are consistent with the increased heritability observed after successive challenges with the amoeba. Five QTL-region candidate genes showed differential expression, including a gene connected to interferon responses (GVINP1), a gene involved in systemic inflammation (MAP4K4), and a positive regulator of apoptosis (TRIM39). Analyses of allele-specific expression highlighted a gene in the QTL region on chromosome 17, cellular repressor of E1A-stimulated genes 1 (CREG1), showing allelic differential expression suggestive of a cis-acting regulatory variant.\n\nConclusionsIn summary, this study provides new insights into the mechanisms of resistance to AGD in Atlantic salmon, and highlights candidate genes for further functional studies that can further elucidate the genomic mechanisms leading to resistance and contribute to enhancing salmon health via improved genomic selection.

genomics↗

bioRxiv2019

The Neural Basis of Shared Preference Learning

During our daily lives, we often learn about the similarity of the traits and preferences of others to our own and use that information during our social interactions. However, it is unclear how the brain represents similarity between the self and others. One possible mechanism is to track similarity to oneself regardless of the identity of the other (Similarity account); an alternative is to track each confederate in terms of consistency of the similarity to the self, with respect to the choices they have made before (consistency account). Our study combined fMRI and computational modelling of reinforcement learning (RL) to investigate the neural processes that underlie learning about preference similarity. Participants chose which of two pieces of artwork they preferred and saw the choices of one confederate who usually shared their preference and another who usually did not. We modelled neural activation with RL models based on the similarity and consistency accounts. Data showed more brain regions whose activity pattern fits with the consistency account, specifically, areas linked to reward and social cognition. Our findings suggest that impressions of other people can be calculated in a person-specific manner which assumes that each individual behaves consistently with their past choices.

neuroscience↗