Biology subjects

Phillips, B.

Publications and source records attributed to Phillips, B..

16 recordsLinked to original sources

bioRxiv2026

The NORAD-pumilio regulatory axis links lncRNA dysregulation to tau propagation-associated phenotypes

Long non-coding RNAs (lncRNAs) are increasingly implicated in neurodegenerative disease, yet their roles in tauopathy remain poorly understood. Here, we defined the lncRNA landscape across iPSC-derived neurons, astrocytes, and microglia harboring the frontotemporal dementia-associated MAPT IVS10+16 mutation and investigated how lncRNA dysregulation interfaces with tau pathology. Transcriptomic analyses revealed extensive cell-type specific lncRNA expression changes, with neurons exhibiting the greatest degree of mutation-associated remodeling. Comparative analyses with MAPT IVS10+16 patient brain tissue identified NORAD and MIR22HG as lncRNAs significantly dysregulated across all three cell types and human brains. NORAD was also altered in Alzheimers disease and Parkinsons disease brains, suggesting a broader role in neurodegenerative disease. Mechanistically, NORAD-associated protein networks converged on pathways related to RNA regulation, cytoskeletal organization, proteostasis, and tau interaction networks. Given the established role of NORAD in regulating PUM1 and PUM2 RNA-binding (pumilio) proteins, we examined the NORAD-pumilio axis and identified enrichment of pumilio-associated pathways linked to autophagy, endocytosis, proteostasis, and cytoskeletal regulation. NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation. Together, these findings identify widespread lncRNA dysregulation across neural cell types in the setting of a MAPT mutation and nominate the NORAD-pumilio axis as a regulatory pathway linking RNA homeostasis and tau propagation biology.

neuroscience↗

bioRxiv2025

Addressing cultural and knowledge barriers to enable preclinical sex inclusive research

For over thirty years, research has highlighted a sex bias in early research, risking the validity of biological knowledge. The first step towards change is effectively challenging misconceptions allowing researchers to perceive sex inclusive research as do-able. Utilising the theory of planned behaviour, we quantified researchers intention as a proxy measure for conducting sex inclusive research and explored attitude (value of the behaviour), subjective norm (perceived social pressure) and behavioural control (ability to conduct the behaviour). Additionally, we quantified the knowledge gap, prevalence of misconceptions, and assessed perceived benefits and barriers. We tested a workshop intervention that directly challenges the cultural embedded barriers. The data shows researchers intentions were high, but they had weak statistical knowledge and misunderstandings leading to a perception that inclusive research is prohibitive due to cost and animal use. We demonstrate that participation in the training intervention improved knowledge, altered the perceived barriers and cultural expectations.

scientific communication and education↗

bioRxiv2023

5-HT 2A and 5-HT 2C receptor antagonism differentially modulates reinforcement learning and cognitive flexibility: behavioral and computational evidence

Cognitive flexibility, the ability to adapt behavior in response to a changing environment, is disrupted in several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Evidence suggests that flexibility, which can be operationalized using reversal learning tasks, is modulated by serotonergic transmission. However, how exactly flexible behavior and associated reinforcement learning (RL) processes are modulated by 5-HT action on specific receptors is unknown. We investigated the effects of 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) antagonism on cognitive flexibility and underlying RL mechanisms. Thirty-six male Lister hooded rats were trained on a touchscreen visual discrimination and reversal task. We evaluated the effects of systemic treatments with the 5-HT2AR and 5-HT2CR antagonists M100907 and SB-242084, respectively, on reversal learning performance and performance on probe trials where correct and incorrect stimuli were presented with a third, probabilistically rewarded, stimulus. Computational models were fitted to task choice data to extract RL parameters, including a novel model designed specifically for this task. 5-HT2AR antagonism impaired reversal learning during certain phases. 5-HT2CR antagonism, on the other hand, impaired learning from positive feedback. RL models further differentiated these effects. 5-HT2AR antagonism decreased punishment learning rate at high and low doses. The low dose also increased exploration (beta) and increased stimulus and side stickiness (kappa). 5-HT2CR antagonism also increased beta, but reduced side stickiness. These data indicate that 5-HT2A and 5-HT2CRs both modulate different aspects of flexibility, with 5-HT2ARs modulating learning from negative feedback and 5-HT2cRs for learning from positive feedback.

animal behavior and cognition↗

bioRxiv2023

Region-specific reversal of epidermal planar polarity in the fancy rosette mouse

The planar cell polarity (PCP) pathway collectively orients thousands of cells with respect to a body axis to direct cellular behaviors that are essential for embryonic morphogenesis. Hair follicles of the murine epidermis provide a striking readout of PCP activity in their uniform alignment along the entire skin surface. Here, we characterize, from the molecular to tissue-scale, PCP establishment in the rosette fancy mouse, a natural variant with posterior-specific whorls in its fur, to understand how epidermal polarity is coordinated across the tissue. We find that embryonic hair follicles of rosette mutants emerge with reversed orientations specifically in the posterior region, creating a mirror image of epidermal polarity. The rosette trait is associated with a missense mutation in the core PCP gene Fzd6, which alters a consensus site for N-linked glycosylation and inhibits its membrane localization. Unexpectedly, this defect in Fzd6 trafficking, observed across the entire dorsal epidermis, does not interfere with the ability of other core PCP proteins to localize asymmetrically. Rather, the normally uniform axis of PCP asymmetry is disrupted and rotated in the posterior region such that polarity is reflected on either side of a transition zone. The result is a reversal of polarized cell movements that orient nascent follicles, specifically in the posterior of the embryo. Collectively, our multiscale analysis of epidermal polarity reveals PCP patterning can be regionally decoupled to produce the unique posterior whorls of the fancy rosette mouse. SummaryRegion-specific rotation of the Planar Cell Polarity axis reverses posterior hair follicles in the fancy rosette mouse.

developmental biology↗

bioRxiv2023

An allelic series at the EDNRB2 locus controls diverse piebalding patterns in the domestic pigeon

Variation in pigment patterns within and among vertebrate species reflects underlying changes in cell migration and function that can impact health, reproductive success, and survival. The domestic pigeon (Columba livia) is an exceptional model for understanding the genetic changes that give rise to diverse pigment patterns, as selective breeding has given rise to hundreds of breeds with extensive variation in plumage color and pattern. Here, we map the genetic architecture of a suite of pigmentation phenotypes known as piebalding. Piebalding is characterized by patches of pigmented and non-pigmented feathers, and these plumage patterns are often breed-specific and stable across generations. Using a combination of quantitative trait locus mapping in F2 laboratory crosses and genome-wide association analysis, we identify a locus associated with piebalding across many pigeon breeds. This shared locus harbors a candidate gene, EDNRB2, that is a known regulator of pigment cell migration, proliferation, and survival. We discover multiple distinct haplotypes at the EDNRB2 locus in piebald pigeons, which include a mix of protein-coding, noncoding, and structural variants that are associated with depigmentation in specific plumage regions. These results identify a role for EDNRB2 in pigment patterning in the domestic pigeon, and highlight how repeated selection at a single locus can generate a diverse array of stable and heritable pigment patterns. AUTHOR SUMMARYBoth wild and domestic birds show striking variation in pigment patterning, and these pigment patterns can play critical roles in mate choice, communication, and camouflage. Despite the importance of pigment patterning for survival and reproductive success, the mechanisms that control pigment patterning remain incompletely understood. In domestic pigeons, artificial selection has given rise to a wide array of pigmentation patterns within a single species, including a suite of phenotypes called "piebalding" that is characterized by regional loss of feather pigment. Here, we took advantage of the wide array of distinct piebalding phenotypes in domestic pigeons to map the genetic basis of region-specific loss of plumage pigment. Rather than focusing on a single piebalding pattern, we sought to broadly understand genetic control of regional pigment loss by examining several breeds with different piebalding patterns. We compared the genomes of piebald and non-piebald pigeons using both genetic crosses and genome-wide association studies, and identified several genetic changes affecting the endothelin receptor gene EDNRB2. Our findings highlight how independent mutations at a single locus can drive diversification of plumage pigment patterning within a species.

genetics↗

bioRxiv2023

Sex disparities in age-related neuromuscular decline: unveiling female susceptibility from early to late elderly

BackgroundFemales typically have a longer lifespan than males which is not matched by an improved healthspan, with older females having higher rates of frailty, characteristic of a sex specific degradation of the neuromuscular system. Several motor unit (MU) characteristics show sex-specific behaviour during mid-level contractions in healthy younger people, highlighting a potential influence of hormonal differences that may be augmented in older age. The purpose of this study was to investigate sex differences in physical performance and MU features of the aged human vastus lateralis (VL) from early to late elderly. MethodsThis study included 21 healthy older males (mean {+/-} SD, range: 67.2 {+/-} 7.6, 56 - 81 yrs) and 17 healthy older females (69.5 {+/-} 5.2, 60 - 78 yrs). Intramuscular electromyography data were collected from VL during standardised submaximal sustained contractions. Muscle size and physical performance characteristics were also measured. Multiple mixed-effects linear regression models with age considered were conducted and statistical significance was accepted when p<0.05. ResultsWhen compared to males, early to late elderly females had smaller cross-sectional area of VL (p<0.001), lower knee extensor torque (p<0.001) and poorer force steadiness (p=0.036), as well as higher MU firing rate (FR) (p=0.025) and greater MU FR variability (p=0.031). With progression from early to late elderly, both sexes showed decreased functional capacity at a similar rate. ConclusionFunctional deterioration occurs to a similar extent in both sexes from early to late elderly. However, throughout the majority of the elderly period males demonstrate a greater muscle size, strength, and functional performance. Older females have greater MUFR variability and worse force steadiness than older males. These findings help to address the lack of MU data in older females, and suggest earlier interventions are needed in older females to prevent functional deterioration and reduce the health-sex paradox within ageing humans.

physiology↗

bioRxiv2022

Including both sexes in in vivo research does not necessitate an increase in sample size: a key role for factorial analysis methods

In recent years, there has been a strong drive to improve the inclusion of animals of both sex during in vivo research, driven by a need to improve sex representation in fundamental biology and drug development. This has resulted in inclusion mandates by funding bodies and journals, alongside numerous published manuscripts highlighting the issue and providing guidance to scientists. However, progress is slow and blockers to the routine use of both sexes remain. From a statistical and experimental design perspective, concerns include difficulty selecting and conducting an appropriate analysis and the perceived need for a higher sample size to achieve an equivalent level of statistical power. When both sexes are included, analysis errors are frequent, including inappropriate pooling or sex-disaggregation of the data. These mistakes result in a failure to properly account for the variation in the data that arises from sex, and subsequently lead to poor inference regarding the biological impact of sex. The purpose of this manuscript is to address frequently cited blockers and analysis errors, thus providing a practical guide to support scientists in the design of in vivo studies which include both sexes. Primarily, we demonstrate that there is no loss of power to detect treatment effects when splitting the sample size across sexes in most common biological scenarios, providing that the data are analysed appropriately. In the rare situations where power is lost, the benefit of understanding the role of sex outweighs the power considerations. When estimating a generalisable translatable effect, where exploring sex differences are not the primary scientific objective, we recommend splitting the sample size across male and female mice as a standard strategy. We also demonstrate an optimal analysis pipeline for analysing data gathered using both sexes which is designed to help address common analysis errors.

genetics↗

bioRxiv2022

Store-Operated Ca2+ Channels Mediate Microdomain Ca2+ Signals and Amplify Gq-Coupled Ca2+ Elevations in Capillary Pericytes

Pericytes are multifunctional cells of the vasculature that are vital to brain homeostasis, yet many of their fundamental physiological properties remain unexplored. Ca2+ is a ubiquitous second messenger across cell-types, where it mediates diverse functions such as contractility and gene transcription. It is therefore important to understand the cellular mechanisms underlying Ca2+ signalling in capillary pericytes. Here, we performed pharmacological and ion substitution experiments to investigate the mechanisms underlying pericyte Ca2+ signaling in acute cortical brain slices of PDGFR{beta}-GCaMP6f mice. We report that in mid-capillary bed pericytes ([≥] 4th branch order), spontaneous microdomain Ca2+ signals are dependent on extracellular Ca2+, but largely independent of depolarization, L- and T-type voltage-gated calcium channels (VGCCs), and TRPC3/6 channels. In contrast, these microdomain signals were inhibited by multiple Orai channel blockers, including the specific antagonist GSK-7975A. Furthermore, capillary pericytes exhibited classical store operated calcium entry (SOCE) following store depletion that was sensitive to GSK-7975A and required for amplification of intracellular Ca2+ increases evoked by the vasoconstrictor endothelin-1. These results suggest that Orai SOCE mediates microdomain Ca2+ signals at rest and amplifies Gq-GPCR coupled Ca2+ elevations in capillary pericytes. Thus, SOCE is a major regulator of pericyte Ca2+ and a target for manipulating their function in health and disease.

neuroscience↗

bioRxiv2021

Different adjuvanted pediatric HIV envelope vaccines induced distinct plasma antibody responses despite similar B cell receptor repertoires in infant rhesus macaques.

Different HIV vaccine regimens elicit distinct plasma antibody responses in both human and nonhuman primate models. Previous studies in human and non-human primate infants showed that adjuvants influenced the quality of plasma antibody responses induced by pediatric HIV envelope vaccine regimens. We recently reported that use of the 3M052-SE adjuvant and longer intervals between vaccinations are associated with higher magnitude of antibody responses in infant rhesus macaques. However, the impact of different adjuvants in HIV vaccine regimens on the developing infant B cell receptor (BCR) repertoire has not been studied. This study evaluated whether pediatric HIV envelope vaccine regimens with different adjuvants induced distinct antigen-specific memory B cell repertoires and whether specific immunoglobulin (Ig) immunogenetic characteristics are associated with higher magnitude of plasma antibody responses in vaccinated infant rhesus macaques. We utilized archived preclinical pediatric HIV vaccine studies PBMCs and tissue samples from 19 infant rhesus macaques immunized either with (i) HIV Env protein with a squalene adjuvant, (ii) MVA-HIV and Env protein coadministered using a 3-week interval, (iii) MVA-HIV prime/ protein boost with an extended 6-week interval between immunizations, or (iv) with HIV Env administered with 3M-052-SE adjuvant. Frequencies of vaccine-elicited HIV Env-specific memory B cells from PBMCs and tissues were similar across vaccination groups (frequency range of 0.06-1.72%). There was no association between vaccine-elicited antigen-specific memory B cell frequencies and plasma antibody titer or avidity. Moreover, the epitope specificity and Ig immunogenetic features of vaccine-elicited monoclonal antibodies did not differ between the different vaccine regimens. These data suggest that pediatric HIV envelope vaccine candidates with different adjuvants that previously induced higher magnitude and quality of plasma antibody responses in infant rhesus macaques were not driven by distinct antigen-specific memory BCR repertoires.

immunology↗

bioRxiv2021

Two Genomic Loci Control Three Eye Colors in the Domestic Pigeon (Columba livia)

The iris of the eye shows striking color variation across vertebrate species, and may play important roles in crypsis and communication. The domestic pigeon (Columba livia) has three common iris colors, orange, pearl (white), and bull (dark brown), segregating in a single species, thereby providing a unique opportunity to identify the genetic basis of iris coloration. We used comparative genomics and genetic mapping in laboratory crosses to identify two candidate genes that control variation in iris color in domestic pigeons. We identified a nonsense mutation in the solute carrier SLC2A11B that is shared among all pigeons with pearl eye color, and a locus associated with bull eye color that includes EDNRB2, a gene involved in neural crest migration and pigment development. However, bull eye is likely controlled by a heterogeneous collection of alleles across pigeon breeds. We also found that the EDNRB2 region is associated with regionalized plumage depigmentation (piebalding). Our results establish a genetic link between iris and plumage color, two traits that were long known by pigeon breeders to co-occur, and demonstrate the importance of gene duplicates in establishing possibilities and constraints in the evolution of color and color pattern among vertebrates.

genetics↗

bioRxiv2019

European common frog (Rana temporaria) recolonised Switzerland from multiple glacial refugia in northern Italy via trans- and circum-Alpine routes

The high mountain ranges of western Europe have had a profound effect on the recolonisation of Europe from glacial refugia. The Alps present a particularly interesting case, because they present an absolute barrier to dispersal to most lineages, obstructing recolonisation from multiple refugia in the Italian Alps. Here we investigate the effect of the European Alps on the the phylogeographic history of Rana temporaria across its range in Switzerland. Based on partial cytochrome b and COX1 sequences we find two mitochondrial lineages that occur roughly north and south of the alpine ridge bisecting Switzerland, with contact zones between them in the east and west. The northern haplogroup falls within the previously identified common western European haplogroup, while the southern haplogroup is unique to Switzerland. We find that the lineages diverged ~110 kya, approximately the onset of the last glacial maximum, indicative of origins in separate refugia. Phylogenetic analyses suggest that the lineages originate from two refugia in northern Italy, and colonised Switzerland via trans- and curcum-alpine routes. Our results show that the European Alps is a semi-permeable barrier to dispersal for R. temporaria, and have contributed to the complex recolonisation history of Switzerland.

evolutionary biology↗

bioRxiv2018

Bangers and cash: Baiting efficiency in a heterogeneous population.

O_LIContext: The uptake of baits is a key variable in management actions aimed at the vaccination, training, or control of many vertebrate species. Increasingly, however, it is appreciated that individuals of the target species vary in their likelihood of taking baits. To optimise a baiting program, then, we require knowledge, not only on the rate of bait uptake, and how this changes with bait availability, but also knowledge on the proportion of the target population that will take a bait.\nC_LIO_LIThe invasive cane toad (Rhinella marina) is a major threat to northern quolls (Dasyurus hallucatus), which are poisoned when they attack this novel toxic prey item. Conditioned taste aversion baits (cane toad sausages) can be delivered in the field to train individual northern quolls to avoid toads.\nC_LIO_LIMethods: Here we report on a large-scale field trial across eleven sites across one large property in Western Australia. Camera trapping and statistical modelling was used to estimate the proportion of baitable animals in the population, and the proportion of these that were baited at varying bait availabilities.\nC_LIO_LIResults: Population estimates varied at each site from 3.5 ({+/-}0.76 SD) to 18 ({+/-} 1.58 SD) individual quolls per site, resulting in a range across sites of 0.6-4 baits available per individual. Bait uptake increased with increasing bait availability.\nC_LIO_LIWe also estimate that only 62% of individual quolls are baitable, and that a baiting rate of 3 baits per individual (rather than per area) will result in almost all of these baitable individuals being treated.\nC_LIO_LIWe compared our statistical method with prior data informing the probability of being baitable; and with probability of being baitable set to 1; this resulted in largely differing estimates in relation to an appropriate baiting rate.\nC_LIO_LISynthesis and applications: Data and models such as ours provide wildlife managers with information critical to informed decision making and are fundamental to estimate the cost-efficiency of any baiting campaign.\nC_LI

ecology↗

bioRxiv2018

How many, and when? Optimising targeted gene flow for a step change in the environment

Targeted gene flow is an emerging conservation strategy that involves translocating individuals with particular traits to places where they are of benefit, thereby increasing a populations evolutionary resilience. While the idea can work in theory, questions remain as to how best to implement it. Here, we vary timing of introduction and size of the introduced cohort to maximise our objective - survival of the recipient populations genome. We demonstrate our approach using the northern quoll, an Australian marsupial predator threatened by the toxic cane toad. We highlight a general trade-off between maintaining a local genome and reducing population extinction risk, but show that key management levers can optimise this so that 100% of the populations genome is preserved. In our case, any action was better than not acting at all (even with strong outbreeding depression), but the size of the benefit was sensitive to timing and size of the introduction.

ecology↗

bioRxiv2017

The population genetics of spatial sorting

In most systems, dispersal occurs despite clear fitness costs to dispersing individuals. Theory posits that spatial heterogeneity in habitat quality pushes dispersal rates to evolve towards zero, while temporal heterogeneity in habitat quality favours non-zero dispersal rates. One aspect of dispersal evolution that has received a great deal of recent attention is a process known as spatial sorting, which has been referred to as a \"shy younger sibling\" of natural selection. More precisely, spatial sorting is the process whereby variation in dispersal ability is sorted along density clines and will, in nature, often be a transient phenomenon. Despite this transience, spatial sorting is likely a general mechanism behind non-zero dispersal in spatiotemporally varying environments. While generally transient, spatial sorting is persistent on invasion fronts, where its effect cannot be ignored, causing rapid evolution of traits related to dispersal. Spatial sorting is described in several elegant models, yet these models require a high level of mathematical sophistication and are not accessible to most evolutionary biologists or their students. Here, we frame spatial sorting in terms of the classic haploid and diploid models of natural selection. We show that, on an invasion front, spatial sorting can be conceptualized precisely as selection operating through space rather than (as with natural selection) time, and that genotypes can be viewed as having both spatial and temporal aspects of fitness. The resultant model is strikingly similar to classic models of natural selection. This similarity renders the model easy to understand (and to teach), but also suggests that many established theoretical results around natural selection could apply equally to spatial sorting.

evolutionary biology↗

bioRxiv2017

Not such silly sausages: Northern quolls exhibit aversion to toads after training with toad sausages.

The invasion of toxic cane toads (Rhinella marina) is a major threat to northern quolls (Dasyurus hallucatus) which are poisoned when they attack this novel prey item. Quolls are now endangered as a consequence of the toad invasion. Conditioned taste aversion can be used to train individual quolls to avoid toads, but we currently lack a training technique that can be used at a landscape scale to buffer entire populations from toad impact. Broad scale deployment requires a bait that can be used for training, but there is no guarantee that such a bait will ultimately elicit aversion to toads. Here we test a manufactured bait--a toad sausage--for its ability to elicit aversion to toads in northern quolls. To do this, we exposed one group of quolls to a toad sausage and another to a control sausage and compared the quolls predatory responses when presented with a dead adult toad. Captive quolls that consumed a single toad sausage showed substantially reduced interest in cane toads, interacting with them for less than half the time of their untrained counterparts and showing substantially reduced attack behaviour. We also quantified bait uptake in the field, by both quolls and non-target species. These field trials showed that wild quolls were the most frequent species attracted to the baits, and that approximately 61% of quolls consumed toad-aversion baits when first encountered. Between 40-68% of these animals developed aversion to further bait consumption. Our results suggest that toad-aversion sausages can be used to train wild quolls to avoid cane toads. This opens the possibility for broad-scale quoll training with toad aversion sausages: a technique that may allow wildlife managers to prevent quoll extinctions at a landscape scale.

ecology↗

bioRxiv2017

Using Connectivity To Identify Climatic Drivers Of Local Adaptation

This preprint has been reviewed and recommended by Peer Community In Evolutionary Biology (http://dx.doi.org/10.24072/pci.evolbiol.100034). Despite being able to conclusively demonstrate local adaptation, we are still often unable to objectively determine the climatic drivers of local adaptation. Given the rapid rate of global change, understanding the climatic drivers of local adaptation is vital. Not only will this tell us which climate axes matter most to population fitness, but such knowledge is critical to inform management strategies such as translocation and targeted gene flow. While simple assessments of geographic trait variation are useful, geographic variation (and its associations with environment) may represent plastic, rather than evolved, differences. Additionally, the vast number of trait-environment combinations makes it difficult to determine which aspects of the environment populations adapt to. Here we argue that by incorporating a measure of landscape connectivity as a proxy for gene flow, we can differentiate between trait-environment relationships underpinned by genetic differences versus those that reflect phenotypic plasticity. By doing so, we can rapidly shorten the list of trait-environment combinations that may be of adaptive significance. We demonstrate how this reasoning can be applied using data on geographic trait variation in a lizard species from Australia's Wet Tropics rainforest. Our analysis reveals an overwhelming signal of local adaptation for the traits and environmental variables we investigated. Our analysis also allows us to rank environmental variables by the degree to which they appear to be driving local adaptation. Although encouraging, methodological issues remain: we point to these issue in the hope that the community can rapidly hone the methods we sketch here. The promise is a rapid and general approach to identifying the environmental drivers of local adaptation.

evolutionary biology↗