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Hughes, A.

Publications and source records attributed to Hughes, A..

At least 19 recordsLinked to original sources

First detected incursions of avian influenza H5N1 clade 2.3.4.4b into mainland Australia from the Southern Ocean

High pathogenicity avian influenza H5N1 clade 2.3.4.4b has caused a panzootic of devastating impact to poultry and wildlife globally. The Australian continent and broader Oceania until recently remained the last major region without confirmed detections. Here we report the first H5N1 clade 2.3.4.4b detections from two live seabirds - a brown skua and a southern giant petrel - found on the south coast of Western Australia in June 2026. Virus genome sequencing showed that both viruses were most closely related to H5N1 viruses detected recently on sub-Antarctic islands in the Southern Indian Ocean. In time-calibrated phylogeographic analyses, both viruses sampled in Western Australia clustered with viruses from Heard Island, a sub-Antarctic external territory of Australia. Ancestral location reconstruction also identified Heard Island as the most probable source location, although unsampled intermediate locations cannot be excluded. The two Western Australian detections were estimated to be independent incursions from Heard Island, rather than local transmission on mainland Australia. There was no evidence of reassortment with endemic avian influenza viruses in Australia, and both virus sequences retained key avian-like genetic markers and lacked known substitutions for reduced antiviral susceptibility. These detections revealed a Southern Ocean pathway of recurrent H5N1 incursions into Australia, highlighting the risk of potential establishment on the mainland and the need for heightened surveillance and rapid, nationally-coordinated, virus genomic characterisation.

microbiology↗

Modular Integration of Impedance Sensing for Real-Time Assessment of Barrier Integrity

Microphysiological systems (MPS) are essential for modeling tissue barriers, yet integrating electrical readouts often requires permanently sealed microfluidic architectures that limit access to open-well (direct-access) workflows used in bioscience laboratories. To resolve this issue, we present a modular approach in which functional components are added and removed from a standard MPS core using a magnetic interface. This design preserves compatibility with established open-well protocols for seeding and downstream analysis, while microfluidic perfusion or electrical sensing capabilities are added only when needed. We demonstrate this approach with an impedance-sensing module that enables continuous impedance measurements to assess barrier function. By fitting spectra to an equivalent circuit model, we quantify junctional and non-junctional electrical contributions to barrier integrity over time, alongside conventional single-frequency TEER, and complementary permeability and imaging readouts. We apply this platform across three representative use cases, including LPS-induced disruption, shear stress-mediated strengthening, and compatibility with barrier models formed above a 3D hydrogel matrix.

bioengineering↗

Plasticity Associated with Adoption of Social Roles in Clown Anemonefish

Central questions of animal behavior are how do individual phenotypes shape and how are individual phenotypes shaped by dominance hierarchies. Using clownfish (Amphiprion percula) as a model system, we investigated how individuals strategically modify their phenotype during hierarchy formation. We tested the overarching hypothesis that interactions among size- and age-matched rivals will lead to the emergence of social roles (dominant, subordinate, solitary), accompanied by divergence in four aspects of individual phenotypes: growth, feeding behavior, agonistic behaviors (aggression, submission), and gene expression. To test this, we created 30 replicates of juvenile clownfish, each comprising a size-matched pair housed together, and a solitary size-matched individual housed separately. Our results show that an individuals social context shapes its growth trajectory through coordinated changes in feeding behavior, agonistic behaviors, and gene expression. Individuals emerging as dominant within pairs grew twice as much compared to those emerging as subordinates, while subordinate and solitary individuals showed comparable growth. Initially, paired individuals consumed more food per capita than solitary individuals, but this difference declined as size hierarchies became established. Agonistic behaviors also decreased over time among paired individuals as size differences emerged. Transcriptomic analyses revealed upregulation of conserved vertebrate growth pathways and ossification related genes, and downregulation of satiety-associated genes, in dominant individuals compared to subordinates and solitaries. Here we identify associations between changes in gene expression, growth, and feeding behavior regulation that reinforce social role differentiation during dominance hierarchy formation in clownfish. Our findings lay the foundation for a broader framework to explore the mechanisms underpinning strategic growth in social vertebrates.

ecology↗

Nutrient-Responsive Formation of Mitochondrial-Derived Structures in Caenorhabditis elegans

Mitochondrial morphology is dynamically regulated through remodeling processes essential for maintaining mitochondrial function and ensuring cellular and metabolic homeostasis. While classical models of mitochondrial dynamics center on cycles of fragmentation and elongation, emerging evidence highlights additional membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and mitochondrial-derived compartments (MDCs). These mitochondrial-derived structures, however, have been predominantly characterized in cultured cells and unicellular organisms, leaving their relevance in multicellular systems largely unexplored. Here, we identify a previously uncharacterized class of mitochondrial-derived structures in Caenorhabditis elegans muscle cells that are induced in response to intermittent fasting. We show that these structures appear specifically during the refeeding phase-- coinciding with mitochondrial elongation --and are absent during fasting. Consistent with MDCs, the structures, approximately 1 {micro}m in size, are enriched in outer mitochondrial membrane markers such as TOMM-20aa1-49 and TOMM-70, but notably lack components of the inner mitochondrial membrane. Their formation requires the microtubule-associated MIRO-1/2 proteins, and their size is modulated by the mitochondrial dynamics machinery. Together, our findings reveal a nutritionally regulated mitochondrial remodeling event in C. elegans muscle that may play a role in mitochondrial quality control and adaptation to metabolic cues.

cell biology↗

Amino acids trigger MDC-dependent mitochondrial remodeling by altering mitochondrial function

Cells utilize numerous pathways to maintain mitochondrial homeostasis, including a recently identified mechanism that adjusts the content of the outer mitochondrial membrane (OMM) through formation of OMM-derived multilamellar domains called mitochondrial-derived compartments, or MDCs. MDCs are triggered by perturbations in mitochondrial lipid and protein content, as well as increases in intracellular amino acids. Here, we sought to understand how amino acids trigger MDCs. We show that amino acid-activation of MDCs is dependent on the functional state of mitochondria. While amino acid excess triggers MDC formation when cells are grown on fermentable carbon sources, stimulating mitochondrial biogenesis blocks MDC formation. Moreover, amino acid elevation depletes TCA cycle metabolites in yeast, and preventing consumption of TCA cycle intermediates for amino acid catabolism suppresses MDC formation. Finally, we show that directly impairing the TCA cycle is sufficient to trigger MDC formation in the absence of amino acid stress. These results demonstrate that amino acids stimulate MDC formation by perturbing mitochondrial metabolism. SUMMARYRaghuram and Hughes uncover a mechanism by which amino acids promote mitochondrial membrane remodeling via the Mitochondrial Derived Compartment (MDC) pathway. They show that elevated amino acids trigger MDC formation through a depletion of TCA cycle metabolites.

cell biology↗

Distinct sets of molecular characteristics define tumor-rejecting neoantigens

Challenges in identifying tumor-rejecting neoantigens limit the efficacy of neoantigen vaccines to treat cancers, including cutaneous squamous cell carcinoma (cSCC). A minority of human cSCC tumors shared neoantigens, supporting the need for personalized vaccines. Using a UV-induced mouse cSCC model which recapitulated the mutational signature and driver mutations found in human disease, we found that CD8 T cells constrain cSCC. Two MHC class I neoantigens were identified that constrained cSCC growth. Compared to the wild-type peptides, one tumor-rejecting neoantigen exhibited improved MHC binding and the other had increased solvent accessibility of the mutated residue. Across known neoantigens that do not impact MHC binding, structural modeling of the peptide/MHC complexes indicated that increased solvent accessibility, which will facilitate TCR recognition of the neoantigen, distinguished tumor-rejecting from non-immunogenic neoantigens. This work reveals characteristics of tumor-rejecting neoantigens that may be of considerable importance in identifying optimal vaccine candidates in cSCC and other cancers.

immunology↗

Mitochondrial-Derived Compartments Remove Surplus Proteins from the Outer Mitochondrial Membrane

The outer mitochondrial membrane (OMM) creates a boundary that imports most of the mitochondrial proteome while removing extraneous or damaged proteins. How the OMM senses aberrant proteins and remodels to maintain OMM integrity remains unresolved. Previously, we identified a piecemeal autophagic mechanism called the mitochondrial-derived compartment (MDC) that removes a subset of the mitochondrial proteome. Here we show that MDCs specifically sequester proteins localized only at the OMM, providing an explanation for how select mitochondrial proteins are removed by MDCs. Remarkably, selective sorting into MDCs also occurs within the OMM, as subunits of the translocase of the outer membrane (TOM) complex are excluded from MDCs unless assembly of the TOM complex is impaired. Considering that overloading the OMM with mitochondrial membrane proteins or mistargeted tail-anchored membrane proteins induces MDCs to form and sequester these proteins, we propose that one functional role of MDCs is to create an OMM-enriched trap that segregates and sequesters excess proteins from the mitochondrial surface. SUMMARYWilson and colleagues observe that mitochondrial-derived compartments (MDCs) selectively incorporate proteins from only the outer mitochondrial membrane (OMM), and robustly sequester both excess and mistargeted proteins into this OMM-enriched domain, suggesting MDCs act to remove surplus hydrophobic cargo from mitochondria.

cell biology↗

Mitochondrial-Derived Compartments are Multilamellar Domains that Encase Membrane Cargo and Cytosol

Preserving the health of the mitochondrial network is critical to cell viability and longevity. To do so, mitochondria employ several membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and compartments (MDCs) to selectively remove portions of the organelle. In contrast to well-characterized MDVs, the distinguishing features of MDC formation and composition remain unclear. Here we used electron tomography to observe that MDCs form as large, multilamellar domains that generate concentric spherical compartments emerging from mitochondrial tubules at ER-mitochondria contact sites. Time-lapse fluorescence microscopy of MDC biogenesis revealed that mitochondrial membrane extensions repeatedly elongate, coalesce, and invaginate to form these compartments that encase multiple layers of membrane. As such, MDCs strongly sequester portions of the outer mitochondrial membrane, securing membrane cargo into a protected domain, while also enclosing cytosolic material within the MDC lumen. Collectively, our results provide a model for MDC formation and describe key features that distinguish MDCs from other previously identified mitochondrial structures and cargo-sorting domains. SUMMARYWilson and colleagues use electron tomography and time-lapse fluorescence microscopy to observe that mitochondrial-derived compartments (MDCs) are generated from outer mitochondrial membrane extensions that repeatedly elongate, coalesce, and invaginate to secure membrane cargo and cytosol within a distinct, protected domain.

cell biology↗

The Norwegian Mother, Father, and Child cohort study (MoBa) genotyping data resource: MoBaPsychGen pipeline v.1

BackgroundThe Norwegian Mother, Father, and Child Cohort Study (MoBa) is a population-based pregnancy cohort, which includes approximately 114,500 children, 95,200 mothers, and 75,200 fathers. Genotyping of MoBa has been conducted through multiple research projects, spanning several years; using varying selection criteria, genotyping arrays, and genotyping centres. MoBa contains numerous interrelated families, which necessitated the implementation of a family-based quality control (QC) pipeline that verifies and accounts for diverse types of relatedness. MethodsThe MoBaPsychGen pipeline, comprising pre-imputation QC, phasing, imputation, and post-imputation QC, was developed based on current best-practice protocols and implemented to account for the complex structure of the MoBa genotype data. The pipeline includes QC on both single nucleotide polymorphism (SNP) and individual level. Phasing and imputation were performed using the publicly available Haplotype Reference Consortium release 1.1 panel as a reference. Information from the Medical Birth Registry of Norway and MoBa questionnaires were used to identify biological sex, year of birth, reported parent-offspring (PO) relationships, and multiple births (only available in the offspring generation). ResultsIn total, 207,569 unique individuals (90% of the unique individuals included in the study) and 6,981,748 autosomal SNPs passed the MoBaPsychGen pipeline. A further 174,462 chromosome X and 3,200 PAR SNPs are available in a subset of these individuals (N = 204,913 and 135,593, respectively). The relatedness checks performed throughout the pipeline allowed identification of within-generation and across-generation first-degree, second-degree, and third-degree relatives. The individuals passing post-imputation QC comprised 64,471 families ranging in size from singletons to 84 unique individuals (singletons are included as families as other family members may not have been genotyped, imputed, or passed post-imputation QC). The relationships identified include 287 monozygotic twin pairs, 22,884 full siblings, 117,004 PO pairs, 23,299 second-degree relative pairs, and 10,828 third-degree relative pairs. DiscussionMoBa contains a highly complex relatedness structure, with a variety of family structures including singletons, PO duos, full (mother, father, child) PO trios, nuclear families, blended families, and extended families. The availability of robustly quality-controlled genetic data for such a large cohort with a unique extended family structure will allow many novel research questions to be addressed. Furthermore, the MoBaPsychGen pipeline has potential utility in similar cohorts.

genetics↗

Lack of robust evidence for a Wolbachia infection in Anopheles gambiae from Burkina Faso

The endosymbiont Wolbachia can have major effects on the reproductive fitness, and vectorial capacity of host insects and may provide new avenues to control mosquito borne pathogens. Anopheles gambiae s.l is the major vector of malaria in Africa but the use of Wolbachia in this species has been limited by challenges in establishing stable transinfected lines and uncertainty around native infections. High frequencies of infection of Wolbachia have been previously reported in An. gambiae collected from the Valle du Kou region of Burkina Faso in 2011 and 2014. Here we re-evaluated the occurrence of Wolbachia in natural samples, collected from Valle du Kou over a 12-year time span, and in addition, expanded sampling to other sites in Burkina Faso. Our results showed that, in contrast to earlier reports, Wolbachia is present at an extremely low prevalence in natural population of An. gambiae. From 5,341 samples analysed only 29 were positive for Wolbachia by nested PCR representing 0.54% of prevalence. No positive samples were found with regular PCR. Phylogenetic analysis of 16S rRNA gene amplicons clustered across supergroup B, with some having similarity to sequences previously found in Anopheles from Burkina Faso. However, we cannot discount the possibility that the amplicon positive samples we detected were due to environmental contamination or were false positives. Regardless, the lack of a prominent native infection in An. gambiae s.l. is encouraging for applications utilising Wolbachia traninsfected mosquitoes for malaria control.

ecology↗

Parallel evolution of phage resistance - virulence trade - offs during in vitro and nasal Pseudomonas aeruginosa phage treatment

With rising antibiotic resistance, there has been increasing interest in treating pathogenic bacteria with bacteriophages (phage therapy). One limitation of phage therapy is the ease at which bacteria can evolve resistance. Negative effects of resistance may be mitigated when resistance results in reduced bacterial growth and virulence, or when phage coevolve to overcome resistance. Resistance evolution and its consequences are contingent on the bacteria-phage combination and their environmental context, making therapeutic outcomes hard to predict. One solution might be to conduct "in vitro evolutionary simulations" using bacteria-phage combinations from the therapeutic context. Overall, our aim was to investigate parallels between in vitro experiments and in vivo dynamics in a human participant. Evolutionary dynamics were similar, with high levels of resistance evolving quickly with limited evidence of phage evolution. Resistant bacteria - evolved in vitro and in vivo - had lower virulence. In vivo, this was linked to lower growth rates of resistant isolates, whereas in vitro phage resistant isolates evolved greater biofilm production. Population sequencing suggests resistance resulted from selection on de novo mutations rather than sorting of existing variants. These results highlight the speed at which phage resistance can evolve in vivo, and in vitro experiments may give useful insights for clinical evolutionary outcomes.

evolutionary biology↗

Within-family studies for Mendelian randomization: avoiding dynastic, assortative mating, and population stratification biases

Mendelian randomization (MR) is a widely-used method for causal inference using genetic data. Mendelian randomization studies of unrelated individuals may be susceptible to bias from family structure, for example, through dynastic effects which occur when parental genotypes directly affect offspring phenotypes. Here we describe methods for within-family Mendelian randomization and through simulations show that family-based methods can overcome bias due to dynastic effects. We illustrate these issues empirically using data from 61,008 siblings from the UK Biobank and Nord-Trondelag Health Study. Both within-family and population-based Mendelian randomization analyses reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while MR estimates from population-based samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects largely disappeared in within-family MR analyses. We found differences between population-based and within-family based estimates, indicating the importance of controlling for family effects and population structure in Mendelian randomization studies.

genetics↗

Image Quality Causes Substantial Bias in Three-Dimensional Speckle-Tracking Echocardiography Measures

BACKGROUNDThree-dimensional speckle-tracking echocardiography (3D-STE) is increasingly used to assess left ventricular (LV) mechanics but the quantitative effect of image quality on measurements is not known.\n\nOBJECTIVESTo assess the impact of image quality on 3D-STE derived LV indices.\n\nMETHODSEchocardiography was performed in two groups of 18 healthy participants. In the first study, optimal and intentionally poor-quality images were acquired. In the second study, a sheet of ultrasound-attenuating material (neoprene rubber) of three different thicknesses (2, 3 and 4 mm) was used to mimic mildly, moderately and severely impaired image quality respectively.\n\nRESULTSIn both studies sub-optimal image quality resulted in a systematic underestimation bias in all LV deformation and rotational indices. LV ejection fraction and volumes were also consistently underestimated. The extent of the bias was proportional to the impairment in image quality (i.e. the poorer the image quality the larger the bias). Reproducibility was also less good for sub-optimal images, although LV volumes and ejection fraction showed excellent reproducibility irrespective of image quality.\n\nCONCLUSIONSSub-optimal image quality introduces a substantial systematic bias and impairs the reproducibility of 3D-STE. Bias related to image quality might have important clinical implications since its magnitude is similar to that reported in association with disease and may confound associations between disease and LV mechanics.\n\nCONDENSED ABSTRACTThree-dimensional speckle-tracking echocardiography (3D-STE) is increasingly used in clinical practice. We assessed the impact of sub-optimal image quality on left ventricular (LV) deformation indices either by poor echocardiographic technique or by impairing ultrasound propagation using a neoprene sheet. Sub-optimal image quality introduces a substantial systematic bias that increases with poorer image quality. Bias due to image quality might have important clinical implications since its magnitude is similar to that reported in association with disease.

physiology↗

Biological control protects tropical forests

Biological control of invasive species can restore crop yields, and thus ease land pressure and contribute to forest conservation. In this study, we show how biological control against the mealybug Phenacoccus manihoti (Hemiptera) slowed deforestation across Southeast Asia. In Thailand, the newly-arrived mealybug caused an 18% decline in cassava yields over 2009-2010, a shortfall in national production and an escalation in the price of cassava products. This spurred an expansion of cassava cropping in neighboring countries from 713,000 ha in 2009 to >1 million ha by 2011: satellite imagery reveal 388%, 330%, 185% and 608% increases in peak deforestation rates in Cambodia, Lao PDR, Myanmar and Viet Nam focused in cassava crop expansion areas. Following release of the host-specific natural enemy Anagyrus lopezi (Hymenoptera) in 2010, mealybug outbreaks were reduced, cropping area contracted and associated deforestation slowed by 31-94% in individual countries. When used with due caution and according to current guidelines, biological control offers broad benefits for people and the environment.

ecology↗

Properties of the epigenetic clock and age acceleration

BackgroundThe methylation status of numerous CpG sites in the human genome varies with age. The Horvath epigenetic clock used a wide variety of published DNA methylation data to produce an age prediction that has been widely used to, predict age in unknown samples, and draw conclusions about speed of ageing in various tissues, environments, and diseases. Despite its utility, there are a number of assumptions in the model that require examination. We explore the characteristics of the model in whole blood and multiple brain regions from older people, who are not well represented in the original training data, and in blood from a cross-sectional population study.\n\nResultsWe find that the model systematically underestimates age in tissues from older people. A decrease in slope of the predicted ages were observed at approximately 60 years, indicating that some loci in the model may change differently with age, and that age acceleration measures will themselves be age-dependent. This is seen most strongly in the cerebellum but is also present in other examined tissues, and is consistently observed in multiple datasets. An apparent association of Alzheimers disease with age acceleration disappears when age is used as a covariate. Association tests in the literature use a variety of methods for calculating age acceleration and often do not use age as a covariate. This is a potential cause of misleading findings.\n\nConclusionsAssociations of phenotypes with age acceleration should be evaluated cautiously, and chronological age should be included as a covariate in all analyses.

genomics↗

Leveraging DNA methylation quantitative trait loci to characterize the relationship between methylomic variation, gene expression and complex traits.

Characterizing the complex relationship between genetic, epigenetic and transcriptomic variation has the potential to increase understanding about the mechanisms underpinning health and disease phenotypes. In this study, we describe the most comprehensive analysis of common genetic variation on DNA methylation (DNAm) to date, using the Illumina EPIC array to profile samples from the UK Household Longitudinal study. We identified 12,689,548 significant DNA methylation quantitative trait loci (mQTL) associations (P < 6.52x10-14) occurring between 2,907,234 genetic variants and 93,268 DNAm sites, including a large number not identified using previous DNAm-profiling methods. We demonstrate the utility of these data for interpreting the functional consequences of common genetic variation associated with > 60 human traits, using Summary data-based Mendelian Randomization (SMR) to identify 1,662 pleiotropic associations between 36 complex traits and 1,246 DNAm sites. We also use SMR to characterize the relationship between DNAm and gene expression, identifying 6,798 pleiotropic associations between 5,420 DNAm sites and the transcription of 1,702 genes. Our mQTL database and SMR results are available via a searchable online database (http://www.epigenomicslab.com/online-data-resources/) as a resource to the research community.

genetics↗

Lipoprotein Signatures of Cholesteryl Ester Transfer Protein and HMG-CoA Reductase Inhibition

BackgroundCETP inhibition reduces vascular event rates but confusion surrounds its low-density lipoprotein (LDL)-cholesterol effects. We sought to clarify associations of genetic inhibition of CETP on detailed lipoproteins.\n\nMethods and ResultsWe used variants associated with CETP (rs247617) and HMGCR (rs12916) expression in 62,400 Europeans with detailed lipoprotein profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% lower risk of coronary heart disease (CHD). Associations of lipoprotein measures with risk of incident CHD in three population-based cohorts (770 cases) were examined.\n\nCETP and HMGCR had near-identical associations with LDL-cholesterol concentration estimated by Friedewald-equation. HMGCR had a relatively consistent effect on cholesterol concentrations across all apolipoprotein B-containing lipoproteins. CETP had stronger effects on remnant and very-low-density lipoprotein cholesterol but no effect on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02SD 95%CI: -0.10, 0.05 for CETP versus -0.24SD, 95%CI -0.30, -0.18 for HMGCR). CETP had profound effects on lipid compositions of lipoproteins, with strong reductions in the triglyceride content of all highdensity lipoprotein (HDL) particles. These alterations in triglyceride composition within HDL subclasses were observationally associated with risk of CHD, independently of total cholesterol and triglycerides (strongest HR per 1-SD higher triglyceride composition in very-large HDL 1.35; 95%CI: 1.18, 1.54).\n\nConclusionCETP inhibition does not affect size-specific LDL cholesterol but may lower CHD risk by lowering cholesterol in other apolipoprotein-B containing lipoproteins and lowering triglyceride content of HDL particles. Conventional composite lipid assays may mask heterogeneous effects of lipid-altering therapies.

genetics↗

Structure of the chromatin remodelling enzyme Chd1 bound to a ubiquitinylated nucleosome

ATP-dependent chromatin remodelling proteins represent a diverse family of proteins that share ATPase domains that are adapted to regulate protein-DNA interactions. Here we present structures of the yeast Chd1 protein engaged with nucleosomes in the presence of the transition state mimic ADP-beryllium fluoride. The path of DNA strands through the ATPase domains indicates the presence of contacts conserved with single strand translocases and additional contacts with both strands that are unique to Snf2 related proteins. The structure provides connectivity between rearrangement of ATPase lobes to a closed, nucleotide bound state and the sensing of linker DNA. Two turns of linker DNA are prised off the surface of the histone octamer as a result of Chd1 binding, and both the histone H3 tail and ubiquitin conjugated to lysine 120 are re-orientated towards the unravelled DNA. This indicates how changes to nucleosome structure can alter the way in which histone epitopes are presented.

molecular biology↗