Biology subjects

Campbell, A. J.

Publications and source records attributed to Campbell, A. J..

11 recordsLinked to original sources

bioRxiv2026

Discovery of GluA3 preferring AMPA receptor positive allosteric modulator BRD3290

Schizophrenia is a debilitating neuropsychiatric disease that lacks effective treatments for many symptom domains including negative, cognitive and sleep disturbances. Lack of clear disease etiology has hampered the development of new, effective treatments for the unmet needs of people with schizophrenia. Large scale human genetics have identified rare loss of function mutations that substantially increase risk of developing schizophrenia, including in GRIA3, the gene that encodes the GluA3 receptor subunit of the AMPA receptor (AMPAR). Several drug discovery programs have been aimed at developing AMPAR positive allosteric modulators (PAMs) as a novel treatment for schizophrenia. Despite intense drug discovery efforts, there are no FDA approved AMPAR PAMs. We therefore hypothesized that selectively targeting GluA3, the AMPAR subunit implicated by human genetics, could yield a safer and more effective AMPAR PAM for the potential treatment of schizophrenia. Using a combination of medicinal chemistry, in vitro, and in vivo studies, we discovered BRD3290, a GluA3-preferring AMPAR PAM with reasonable potency in heterologous cells, as well as favorable tolerability and brain exposure. Peripheral administration of BRD3290 engaged an established AMPAR PAM target engagement biomarker but did not improve performance of wildtype mice in the novel object recognition task (NOR), in contrast to the nonselective AMPAR PAM PF-4778574, which improved mouse NOR. These findings suggest that the GluA3 selectivity profile of BRD3290 was insufficient to enhance cognitive function in this mouse NOR paradigm. This work highlights the challenges of AMPAR subtype-selective modulation and provides molecular insights into the ability to develop subtype-selective AMPAR PAMs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/740780v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1577f62org.highwire.dtl.DTLVardef@16c1750org.highwire.dtl.DTLVardef@16eaef3org.highwire.dtl.DTLVardef@19fdb6f_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

Surveillance on California dairy farms reveals multiple sources of H5N1 transmission

Transmission routes of highly pathogenic H5N1 between cows or to humans remain unclear due to limited data from affected dairy farms. We performed air, farm wastewater, and milk sampling on 14 H5N1 positive dairy farms across two different California regions. Infectious virus was detected in the air in milking parlors and in wastewater streams, while viral RNA was found in exhaled breath of cows. Sequence analysis of infectious H5N1 virus from air and wastewater samples on one farm revealed viral variants relevant for potential human susceptibility. Longitudinal analysis of milk from the individual quarters of cows revealed a high prevalence of subclinical H5N1 positive cows. Additionally, a heterogeneous distribution of infected quarters that maintained a consistent pattern over time was observed, inconsistent with shared milking equipment serving as the sole transmission mode. The presence of subclinically infected cows was further supported by detection of antibodies in the milk of animals that exhibited no clinical signs during the H5N1 outbreak on one farm. Our data highlight additional sources and potential modes of H5N1 transmission on dairy farms.

microbiology↗

bioRxiv2025

Resting-State EEG Aperiodic Exponent Moderates the Association Between Age and Memory Performance in Older Adults

Memory functions are susceptible to age-related cognitive decline, making it essential to explore the underlying neurophysiological mechanisms that contribute to memory function during healthy ageing. Resting-state EEG (rsEEG) parameters, particularly the aperiodic exponent, a marker of cortical excitation-inhibition balance, and individual alpha peak frequency, a correlate of neural processing efficiency, have demonstrated associations with ageing and cognitive functions. This study investigated associations between these rsEEG markers and performance across multiple memory systems in healthy older adults (n = 99) aged 50-84 years, specifically the direct associations of these markers on memory across episodic, working, and visual short-term memory systems, assessed via computerised tasks, as well as their moderating effects on age-memory relationships. While no direct associations were seen between rsEEG markers and memory performance across tasks beyond the contribution of age, gender and education, results revealed significant moderating effects of the aperiodic exponent on age-related performance in episodic and visual short-term memory. Notably, for individuals with a higher exponent, age was not significantly associated with episodic or visual short-term memory performance, whereas those with average and lower exponent values showed poorer performance with older age. These findings suggest that average and lower aperiodic exponents may reflect a marker of decrement in age-related memory performance and higher exponents may index an underlying protective mechanism against age-related memory decline. This investigation extends the current understanding of cognitive ageing mechanisms by identifying the aperiodic exponent as a potential biomarker explaining individual differences in cognitive ageing trajectories in older adult populations, particularly in episodic and visual short-term memory systems, and establishes a framework for studying neuroprotective mechanisms and developing interventions to preserve cognitive function in older adults.

neuroscience↗

bioRxiv2024

A sustainable and bee-pollinated coffee to start your day

The integration of managed pollinators into agricultural systems represents a practical strategy for boosting crop production, optimising sustainable farming practices, and improving rural livelihoods. However, the use of managed bees to supplement the contribution of wild pollinators still faces challenges, such as over-reliance on pesticides in intensively managed agroecosystems. Here, we placed managed bee colonies on conventional farms to assess their impact on arabica coffee yield, quality and market value, while also to evaluate colony health in coffee fields treated with field rates of thiamethoxam-based products. We show that supplementing farms with managed bees increased farmer income by enhancing coffee yield and beverage quality, which is rewarded by specialty coffee markets. Moreover, our field-based study reveals that, even when exposed to field-realistic levels of the neonicotinoid thiamethoxam, managed bee colonies exhibited no significant adverse effects on their health within coffee fields. Our results underline that pollination is a key input on intensively managed coffee farms, and that agricultural production and environmental conservation interact synergically to maximize profitability, which is fundamental to encourage farmers to be good stewards of their croplands by adopting nature-positive practices.

ecology↗

bioRxiv2024

Genomics 2 Proteins portal: A resource and discovery tool for linking genetic screening outputs to protein sequences and structures

Recent advances in AI-based methods have revolutionized the field of structural biology. Concomitantly, high-throughput sequencing and functional genomics technologies have enabled the detection and generation of variants at an unprecedented scale. However, efficient tools and resources are needed to link these two disparate data types - to "map" variants onto protein structures, to better understand how the variation causes disease and thereby design therapeutics. Here we present the Genomics 2 Proteins Portal (G2P; g2p.broadinstitute.org/): a human proteome-wide resource that maps 19,996,443 genetic variants onto 42,413 protein sequences and 77,923 structures, with a comprehensive set of structural and functional features. Additionally, the G2P portal generalizes the capability of linking genomics to proteins beyond databases by allowing users to interactively upload protein residue-wise annotations (variants, scores, etc.) as well as the protein structure to establish the connection. The portal serves as an easy-to-use discovery tool for researchers and scientists to hypothesize the structure-function relationship between natural or synthetic variations and their molecular phenotype.

bioinformatics↗

bioRxiv2023

Functional Analysis of Human GRIN2A Mutations Associated with Schizophrenia and Neurodevelopmental Disorders Reveals Distinct Pathological Mechanism

Human genetic studies have revealed rare missense and protein-truncating variants in GRIN2A, encoding for the GluN2A subunit of the NMDA receptors, that confer significant risk for schizophrenia (SCZ). Mutations in GRIN2A are also associated with epilepsy and developmental delay/intellectual disability (DD/ID). However, it remains enigmatic how alterations to the same protein can result in diverse clinical phenotypes. Here, we performed functional characterization of human GluN1/GluN2A heteromeric NMDA receptors that contain SCZ-linked GluN2A variants, and compared them to NMDA receptors with GluN2A variants associated with epilepsy or DD/ID. Our findings demonstrate that SCZ-associated GRIN2A variants were predominantly loss-of-function (LoF), whereas epilepsy and DD/ID-associated variants resulted in both gain- and loss-of-function phenotypes. We additionally show that M653I and S809R, LoF GRIN2A variants associated with DD/ID, exert a dominant-negative effect when co-expressed with a wild-type GluN2A, whereas E58Ter and Y698C, SCZ-linked LoF variants, and A727T, an epilepsy-linked LoF variant, do not. These data offer a potential mechanism by which SCZ/epilepsy and DD/ID-linked variants can cause different effects on receptor function and therefore result in divergent pathological outcomes.

neuroscience↗

bioRxiv2022

Influenza A virus reassortment is strain dependent

RNA viruses can exchange genetic material during coinfection, an interaction that creates novel strains with implications for viral evolution and public health. Influenza A viral genetic exchange occurs when genome segments from distinct strains reassort in coinfection. Predicting potential reassortment between influenza strains is a longstanding goal. Experimental coinfection studies have shed light on factors that limit or promote reassortment. However, determining the reassortment potential between diverse Influenza A strains has remained an elusive goal. To fill this gap, we developed a high throughput genotyping approach to quantify reassortment among a diverse panel of human influenza virus strains, encompassing 41 years of epidemics, multiple geographic locations, and both circulating human subtypes A/H1N1 and A/H3N2. We found that the reassortment rate (proportion of reassortants) is an emergent property of a pair of strains where strain identity is a predictor of the reassortment rate. We show little evidence that antigenic subtype drives reassortment as intersubtype (H1N1xH3N2) and intrasubtype reassortment rates were, on average, similar. Instead, our data suggest that certain strains bias the reassortment rate up or down, independently of the coinfecting partner. We also observe that viral productivity is an emergent property of coinfections and that it is not correlated to reassortment rate, thus affecting the total number of reassortant progeny produced. Assortment of individual segments among progeny, and pairwise segment combinations within progeny, were not random and generally favored homologous combinations. This outcome was not related to strain similarity or shared subtype. Reassortment rate was closely correlated to both the proportion of unique genotypes and the proportion of progeny with heterologous pairwise segment combinations. We provide experimental evidence that viral genetic exchange is potentially an individual social trait subject to natural selection, which implies the propensity for reassortment is not evenly shared among strains. This study highlights the need for research incorporating diverse strains to discover the traits that shift the reassortment potential as we work towards the goal of predicting influenza virus evolution resulting from segment exchange.

microbiology↗

bioRxiv2021

Differential effects of soil-based agricultural diversification on arthropods and crop yield

Many agricultural management tactics, such as reduced tillage, aim to promote biodiversity and ecosystem services. Responses to such tactics can be context dependent, however, and differentially impact (i) functional groups of service-providing organisms and (ii) crop yields. In canola (Brassica napus L., B. rapa L.) crop fields we assessed how soil tillage and landscape context (amount of semi-natural habitat within 1 km of each field) affected arthropod biodiversity and crop yield. We assessed effects of full (multiple tillage passes that leave soil surface bare), intermediate (tilled once and some stubble remains), or no (seed planted directly into last years stubble) tillage on functional groups with unique diets and reproductive strategies: (i) herbivores, (ii) kleptoparasites, (iii) parasitoids, (iv) pollinators, and (v) predators. Effects of tillage and landscape context on arthropod abundance and diversity varied across functional groups. Pollinators responded strongest to tillage, benefitting from intermediate tillage. Predators and herbivores responded strongly to landscape context, as both were more abundant in landscapes with more semi-natural habitat. Our results suggest natural history differences among functional groups mediate effects of landscape context on biodiversity. However, variation in arthropod communities had little effect on canola crop yield. The effects of soil management practices on aboveground arthropods are complex, and practices thought to increase some aspects of agricultural sustainability may not be beneficial in other contexts. Identifying practices such as intermediate tillage that may increase soil quality and arthropod diversity is a key to designing agricultural ecosystems that will effectively benefit both biodiversity and human well-being.

ecology↗

bioRxiv2020

DNA methylation proxies for 16 plasma proteins predict the incidence of 7 leading causes of morbidity

Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNAm signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample, (Generation Scotland; n=9,537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore - disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.

genomics↗

bioRxiv2020

Multimodal small-molecule screening for human prion protein binders

Prion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), and there are currently no therapeutic options. PrP ligands could theoretically antagonize prion formation by protecting the native protein from misfolding or by targeting it for degradation, but no validated small-molecule binders have been discovered to date. We deployed a variety of screening methods in an effort to discover binders of PrP, including 19F-observed and saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, differential scanning fluorimetry (DSF), DNA-encoded library selection, and in silico screening. A single benzimidazole compound was confirmed in concentration-response, but affinity was very weak (Kd > 1 mM), and it could not be advanced further. The exceptionally low hit rate observed here suggests that PrP is a difficult target for small-molecule binders. While orthogonal binder discovery methods could yield high affinity compounds, non-small-molecule modalities may offer independent paths forward against prion disease.

biochemistry↗

bioRxiv2019

Insights into protein structural, physicochemical, and functional consequences of missense variants in 1,330 disease-associated human genes

Interpretation of the colossal number of genetic variants identified from sequencing applications is one of the major bottlenecks in clinical genetics, with the inference of the effect of amino acid-substituting missense variants on protein structure and function being especially challenging. Here we evaluated the burden of amino acids affected in pathogenic variants (n=32,923) compared to the variants (n=164,915) from the general population in 1,330 disease-associated genes on forty protein features using over 14,000 experimentally-solved 3D structures. By analyzing the whole gene/variant set jointly, we identified 18 features associated with 3D mutational hotspots that are generally important for protein fitness and stability. Individual analyses performed for twenty-four protein functional classes further revealed 240 characteristics of mutational hotspots in total, including new associations recapitulating the sheer diversity across proteins essential structural regions. We demonstrated that the function-specific features of variants correspond to the readouts of mutagenesis experiments and positively correlate with clinically-interpreted pathogenic and benign missense variants. Finally, we made our results available through a web server to foster accessibility and downstream research. Our findings represent a crucial step towards translational genetics, from highlighting the impact of mutations on protein structure to rationalizing the pathogenicity of variants in terms of the perturbed molecular mechanisms.

genetics↗