Biology subjects

Gibbs, M.

Publications and source records attributed to Gibbs, M..

9 recordsLinked to original sources

bioRxiv2025

Brown Adipose Tissue Dysfunction Links Obesogen Exposure to Reduced Energy Expenditure and Transgenerational Obesity

Obesity has become a global health challenge, and increasing evidence suggests that environmental obesogens contribute to its prevalence. Tributyltin (TBT) is a model obesogen known to activate PPAR{gamma} and RXR and to promote transgenerational obesity in mice, but the mechanisms linking TBT exposure to impaired energy balance remain poorly defined. Brown adipose tissue (BAT) is a central regulator of energy expenditure (EE) and basal metabolic rate (BMR) through both UCP1-dependent and UCP1-independent pathways. Here, we tested whether ancestral TBT exposure disrupts BAT function across generations. To assess whether TBT alters body composition and thermogenic capacity, we measured fat and lean mass, BAT gene expression, mitochondrial abundance, and core body temperature in F1 and F3 offspring. TBT-group males accumulated more fat mass without changes in lean mass or food intake scaled to metabolic size, indicating reduced EE/BMR. Expression of BAT lineage and oxidative genes (Zic1, Ebf2, Pgc1a, Pdk4) was suppressed in TBT-group males across generations. Ucp1 expression was unchanged at baseline but decreased after high-fat diet (HFD) challenge, whereas Ucp2 and Ucp4 were reduced even at baseline. In addition, key UCP1-independent thermogenic genes involved in creatine (Slc6a8, Ckb) and calcium (Atp2a2, Itpr) futile cycles were significantly decreased, while lipid-cycle genes (Pnpla2, Abhd5) were unaffected. Mitochondrial DNA content was largely unchanged, but core body temperature was reduced in TBT-group males prior to diet challenge, confirming impaired basal thermogenesis. These findings demonstrate that ancestral TBT exposure produces male-specific and heritable defects in BAT identity and thermogenic capacity. By suppressing both UCP1-dependent and UCP1-independent pathways without altering mitochondrial abundance, TBT-group males exhibit reduced energy expenditure and basal metabolic rate. These results identify BAT dysfunction as a mechanistic link between environmental obesogen exposure and transgenerational susceptibility to obesity.

pharmacology and toxicology↗

bioRxiv2025

Stochastic gates for covariate selection in population pharmacokinetics modelling

Covariate selection in population pharmacokinetics modelling is essential for understanding interindividual variability in drug response and optimizing dosing. Traditional stepwise covariate modelling is often time-consuming, compared to the new machine learning alternatives. This study investigates the use of Neural Networks with Stochastic Gates for automated covariate selection, aiming to efficiently identify relevant covariates while penalizing excessive covariate inclusion. On various synthetic datasets the approach demonstrated robustness in detecting important covariates, overcoming challenges such as high correlations, low covariate frequencies, high interindividual variability and complex covariate dependencies. In real clinical data from a monalizumab study, the method successfully identified covariates that matched those found by experts. However, for tixagevimab/cilgavimab, it identified a superset of covariates, indicating a potential need for further pruning. This machine learning-based method enhances the covariate pre-selection process in population pharmacokinetics model development, offering significant time savings and improving efficiency even under challenging scenarios. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/656586v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1f5180borg.highwire.dtl.DTLVardef@1fd97e7org.highwire.dtl.DTLVardef@1ffc3d0org.highwire.dtl.DTLVardef@90c207_HPS_FORMAT_FIGEXP M_FIG C_FIG Study HighlightsO_ST_ABSWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?C_ST_ABSCovariate selection in population pharmacokinetics modelling is a crucial step in drug development and dosing determination. Traditionally, this process is conducted in a stepwise manner, which can be very time-consuming. Recently, fast machine learning (ML)-based methods for covariate selection have emerged in the literature, offering more efficient alternatives. WHAT QUESTION DID THIS STUDY ADDRESS?Can we use Neural Networks with Stochastic Gates, incorporating explicit penalization on the number of covariates, to select superior set of covariates compared to prior ML-based methods? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?Neural Networks with Stochastic Gates provide a reliable approach in accurately detecting covariates because they can effectively eliminate irrelevant covariates even in cases with high inter-covariates correlation. HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?This approach accelerates pharmacokinetic model development by significantly reducing the time required for covariate evaluation. Additionally, it allows for the screening of a wider set of covariates, potentially leading to fewer falsely missed covariates and better-quality models, a task that would be infeasible with traditional stepwise covariate modelling.

pharmacology and toxicology↗

bioRxiv2024

Glia-derived secretory fatty acid binding protein Obp44a regulates lipid storage and efflux in the developing Drosophila brain

Glia derived secretory factors play diverse roles in supporting the development, physiology, and stress responses of the central nervous system (CNS). Through transcriptomics and imaging analyses, we have identified Obp44a as one of the most abundantly produced secretory proteins from Drosophila CNS glia. Protein structure homology modeling and Nuclear Magnetic Resonance (NMR) experiments reveal Obp44a as a fatty acid binding protein (FABP) with a high affinity towards long-chain fatty acids in both native and oxidized forms. Further analyses demonstrate that Obp44a effectively infiltrates the neuropil, traffics between neuron and glia, and is secreted into hemolymph, acting as a lipid chaperone and scavenger to regulate lipid and redox homeostasis in the developing brain. In agreement with this essential role, deficiency of Obp44a leads to anatomical and behavioral deficits in adult animals and elevated oxidized lipid levels. Collectively, our findings unveil the crucial involvement of a noncanonical lipid chaperone to shuttle fatty acids within and outside the brain, as needed to maintain a healthy brain lipid environment. These findings could inspire the design of novel approaches to restore lipid homeostasis that is dysregulated in CNS diseases.

developmental biology↗

bioRxiv2022

Splicing inactivation generates hybrid mRNA-snoRNA transcripts targeted by cytoplasmic RNA decay

Many small nucleolar RNAs (snoRNA)s are processed from introns of host genes, but the importance of splicing for proper biogenesis and the fate of the snoRNAs is not well understood. Here we show that inactivation of splicing factors or mutation of splicing signals leads to the accumulation of partially processed hybrid mRNA-snoRNA transcripts (hmsnoRNA). HmsnoRNAs are processed to the mature 3'-ends of the snoRNAs by the nuclear exosome and bound by snoRNP proteins. HmsnoRNAs are unaffected by translation-coupled RNA quality control pathways, but they are degraded by the major cytoplasmic exonuclease Xrn1p due to their mRNA-like 5'-extensions. These results show that completion of splicing is required to promote complete and accurate processing of intron-encoded snoRNAs and that splicing defects lead to degradation of hybrid mRNA-snoRNA species by cytoplasmic decay, underscoring the importance of splicing for the biogenesis of intron encoded snoRNAs. Significance StatementSmall nucleolar RNAs mediate modifications of nucleosides within ribosomal RNAs, which are necessary for proper ribosomal function and translation. Many snoRNAs are encoded within introns of host genes and accurate biogenesis of these small RNAs is required to produce functional snoRNAs. The work presented here shows that when the splicing reactions are inactivated, snoRNAs undergo a distinct biogenesis pathway which leads to the production of aberrant hybrid RNAs that contain both mRNAs and small RNAs components of the host genes. While snoRNAs are primarily found in the nucleolus, these hybrid RNAs are degraded by the cytoplasmic mRNA degradation pathway. These results demonstrate the importance of splicing to promote accurate snoRNA processing and prevent the production of aberrant mRNA-snoRNA hybrids.

molecular biology↗

bioRxiv2021

Modelling effects of water regulation on the population viability of threatened amphibians

The regulation of river systems alters hydrodynamics and often reduces lateral connectivity between river channels and floodplains. For taxa such as frogs that rely on floodplain wetlands to complete their lifecycle, decreasing inundation frequency can reduce recruitment and increase the probability of local extinction. We virtually reconstructed the inundation patterns of wetlands under natural and regulated flow conditions and built stochastic population models to quantify the probability of local extinction under different inundation scenarios. Specifically, we explored the interplay of habitat size, inundation frequency, and successive dry years on the local extinction probability of the threatened southern bell frog Litoria raniformis in the Murray River floodplains of South Australia. We hypothesised that the changes to wetland inundation resulting from river regulation are a principal driver of L. raniformis declines in this semi-arid system. Regulation has reduced the inundation frequency of essential habitats below critical thresholds for the persistence of many fresh water-dependent species. Successive dry years raise the probability of local extinction, and these effects are strongest in smaller wetlands. Larger wetlands and those with more frequent average inundation are less susceptible to these effects. Elucidating these trends informs the prioritisation of treatment sites and the frequency of conservation interventions. Environmental water provision (through pumping or the operation of flow-regulating structures) is a promising tool to reduce the probability of breeding failure and local extinction. Our modelling approach can be used to prioritise the delivery of environmental water to L. raniformis and potentially many other frog species.

ecology↗

bioRxiv2020

Can early exposure to stress enhance resilience to ocean warming in two oyster species?

Securing economically and ecologically significant molluscs, as our oceans warm and acidify due to climate change, is a global priority. South eastern Australia receives warm water in a strengthening East Australia Current and so resident species are vulnerable to elevated temperature and marine heat waves. This study tested whether oysters pre exposed to elevated temperature or heat stress enhances resilience to ocean warming later in life. Two Australian species, the flat oyster, Ostrea angasi, and the Sydney rock oyster, Saccostrea glomerata, were given a mild dose of warm water or "heat shock" stress in the laboratory and then transferred to elevated temperature conditions where we used the thermal outfall from power generation as a proxy to investigate the impacts of ocean warming. Shell growth, condition index, lipid content and profile and survival of oysters was impacted by elevated temperature in the field, with flat oysters being more impacted than Sydney rock oysters. Flat oysters grew faster than Sydney rock oysters at ambient temperature, but were more sensitive to elevated temperature. Early exposure to heat stress did little to ameliorate the negative effects of increased temperature, although the survival of heat shocked flat oysters was greater than non-heat shocked oysters. Further investigations are required to determine if early exposure to heat stress can act to inoculate oysters to future stress and overall enhance resilience of oysters to ocean warming.

ecology↗

bioRxiv2019

A transcriptomic atlas of mammalian olfactory mucosae reveals an evolutionary influence on food odor detection in humans

The mammalian olfactory system displays species-specific adaptations to different ecological niches. To investigate the evolutionary dynamics of olfactory sensory neuron (OSN) sub-types across 95 million years of mammalian evolution, we applied RNA-sequencing of whole olfactory mucosa samples from mouse, rat, dog, marmoset, macaque and human. We find that OSN subtypes representative of all known mouse chemosensory receptor gene families are present in all analyzed species. Further, we show that OSN subtypes expressing canonical olfactory receptors (ORs) are distributed across a large dynamic range and that homologous subtypes can be either highly abundant across all species or species/order-specific. Interestingly, highly abundant mouse and human OSN subtypes detect odorants with similar sensory profiles, and sense ecologically relevant odorants, such as mouse semiochemicals or human key food odorants. Taken together, our results allow for a better understanding of the evolution of mammalian olfaction in mammals and provide insights into the possible functions of highly abundant OSN subtypes in mouse and human.

neuroscience↗

bioRxiv2018

Highly efficient CRISPR/Cas9-mediated tissue specific mutagenesis in Drosophila

Tissue-specific loss-of-function (LOF) analysis is an essential approach for characterizing gene function. Here we describe an efficient CRISPR-mediated tissue-restricted mutagenesis (CRISPR-TRiM) method for ablating gene function in Drosophila. This binary system consists of a tissue-specific Cas9 and a ubiquitously expressed multi-guide RNA (gRNA) transgene. To facilitate the construction of these components, we developed convenient tools for generating and evaluating enhancer-driven Cas9 lines, identified a multi-gRNA design that is highly efficient in mutagenizing somatic cells, and established an assay for testing the efficiency of multi-gRNAs in creating double-stranded breaks. We found that excision of genomic DNA induced by two gRNAs is infrequent in somatic cells, while indels more reliably cause tissue-specific LOF. Furthermore, we show that enhancer-driven Cas9 is less cytotoxic yet results in more complete gene removal than Gal4-driven Cas9 in larval neurons. Finally, we demonstrate that CRISPR-TRiM efficiently unmasks redundant gene functions in neuronal morphogenesis. Importantly, two Cas9 transgenes that turn on with different timings in the neuronal lineage revealed the extent to which gene products persist in cells after tissue-specific gene knockout. These CRISRPR tools can be applied to analyze tissue-specific gene function in many biological processes.

developmental biology↗

bioRxiv2016

Vertically transmitted rhabdoviruses are found across three insect families and have dynamic interactions with their hosts

A small number of free-living viruses have been found to be obligately vertically transmitted, but it remains uncertain how widespread vertically transmitted viruses are and how quickly they can spread through host populations. Recent metagenomic studies have found several insects to be infected with sigma viruses (Rhabdoviridae). Here, we report that sigma viruses that infect Mediterranean fruit flies (Ceratitis capitata), Drosophila immigrans, and speckled wood butterflies (Pararge aegeria) are all vertically transmitted. We find patterns of vertical transmission that are consistent with those seen in Drosophila sigma viruses, with high rates of maternal transmission, and lower rates of paternal transmission. This mode of transmission allows them to spread rapidly in populations, and using viral sequence data we found the viruses in D. immigrans and C. capitata had both recently swept through host populations. The viruses were common in nature, with mean prevalences of 12% in C. capitata, 38% in D. immigrans and 74% in P. aegeria. We conclude that vertically transmitted rhabdoviruses may be widespread in insects, and that these viruses can have dynamic interactions with their hosts.

evolutionary biology↗