Biology subjects

Herbert, J.

Publications and source records attributed to Herbert, J..

11 recordsLinked to original sources

bioRxiv2026

Tandem repeats in methanogenic archaea and their viruses reveal a shared potential for rapid genomic diversification

Methanogenic archaea drive global methane emissions, yet the molecular basis of their physiological flexibility is unclear. Archaeal adaptation is typically attributed to horizontal gene transfer, which is episodic and cannot explain rapid, reversible change. Here we show that direct tandem repeats (TRs) offer an intrinsic alternative. By screening 50,567 prokaryotic genomes, we find TR densities in Methanosarcina more than 30-fold above the prokaryotic average, paralleling Borg extrachromosomal elements. These TRs recur at conserved loci while sharing almost no sequence identity between strains, indicating independent origin, and evolve during routine cultivation. Methanogen TRs are transcribed, show ribosome occupancy, and lie near regulatory and cofactor-related genes, whilst being depleted around core energy-conserving and translational machinery. Genic TRs generate intrinsically disordered regions in proteins carrying nucleotide-binding, protein-protein interaction and cell-surface domains, and occur in structural and surface proteins of methanogen-infecting viruses. TRs are therefore an overlooked source of variability and adaptation potential in methanogens and their viruses.

microbiology↗

bioRxiv2026

Virus {Psi}M2 enters a non-lytic lifecycle alternative to lysogeny during infection of Methanothermobacter marburgensis

Methanogens, a diverse group of archaea that produce methane during energy metabolism, are prevalent in anoxic habitats where they are exposed to viral infections. The head-tailed virus {Psi}M2 is one of few virus isolates that infect a methanogen host and was described as a lytic virus that lyses its host, Methanothermobacter marburgensis. Here, we present evidence that {Psi}M2 does not exclusively follow the classic lytic lifecycle but can also enter an alternative, chronic infection-like state. Growth experiments showed that infected cultures in minimal medium, optimized for the methanogen host (MS medium) did not exhibit complete lysis but continuously released infective virions. In contrast, in a suboptimal complex medium (SAB medium), the {Psi}M2-infected culture released virions in the exponential growth phase and eventually lysed after 14 hours post infection. Although the genome of {Psi}M2 encodes a putative integrase, a prerequisite for lysogeny, whole genome sequencing of {Psi}M2-infected M. marburgensis cultures revealed that the viral DNA remained extrachromosomal rather than integrating into the host genome, likely due to a mutation in the integrase gene. These findings suggest that {Psi}M2 enters a non-lytic lifecycle alternative to lysogeny under suboptimal host growth conditions. Sequencing further identified a heterogeneous viral population including previously undescribed variants. A high density of non-synonymous mutations and frameshift-inducing insertions was observed within ORFs predicted to encode a capsid protein and a major spike protein, suggesting these viral variants to differ in host recognition and infectivity. Overall, our results show more complex viral behavior and greater genetic variability than previously described.

microbiology↗

bioRxiv2026

Therapeutic targeting of fibrin-microglia interactions ameliorates Alzheimer disease-related hyperexcitability and brain network dysfunction

Brain network dysfunction--including hyperexcitability, altered oscillations, and sleep disruption--is prominent in Alzheimers disease (AD), but the contribution of vascular-neuroimmune processes to these alterations remains unclear. Here, we blocked the pro-inflammatory interaction of the blood protein fibrin with microglia using genetic (Fgg{gamma}390-396A mice) and antibody-based (5B8 and THN392) strategies to test its role in AD-related network dysfunction. The 5xFAD model of AD exhibited network hyperexcitability associated with oscillatory slowing, sleep states, and disrupted sleep-circadian rhythms. These deficits were largely attenuated by blocking fibrin-microglia interactions in 5xFAD;Fgg{gamma}390-396A mice. Notably, pharmacological interventions after disease onset with both anti-fibrin antibodies similarly attenuated these AD-related network deficits and behavioral abnormalities. We conclude that vascular-neuroimmune processes driven by fibrin-microglia interactions promote AD-related network dysfunction and that targeting the fibrin-microglia axis--currently under clinical evaluation with the humanized antibody THN391-- represents a promising therapeutic strategy for AD. There is a companion manuscript submitted to bioRxiv (Yan et al., 2026).110 HIGHLIGHTSO_LIFibrin promotes AD-related network hyperexcitability and oscillatory slowing in 5xFAD mice C_LIO_LIFibrin promotes AD-related disruption of sleep and circadian rhythms in 5xFAD mice C_LIO_LIGenetic blocking of fibrin-microglia interactions rescues AD-related brain network dysfunction C_LIO_LIAnti-fibrin antibodies (5B8 and THN392) show acute and chronic therapeutic benefit C_LI

neuroscience↗

bioRxiv2025

APOE4-Aβ synergy drives brain network dysfunction and neuronal lysosomal-ER proteostasis dysregulation in preclinical Alzheimer's disease

Amyloid-{beta} (A{beta}) and APOE4 represent two of the strongest pathological and genetic risk factors for Alzheimers disease (AD), but how these co-pathogens interact during preclinical stages remains undefined. We addressed this question by developing a humanized knock-in model expressing physiological, endogenously regulated human A{beta} and APOE4. Aged AppNLF:APOE4 mice displayed incipient amyloidosis with subtle memory-related changes, consistent with preclinical AD. We found largely distinct, non-overlapping APOE4- and A{beta}-driven functional synaptic, sleep, and behavioral alterations. However, at the transcriptomic level, APOE4xA{beta} had a pronounced detrimental interaction in neuronal populations, whereas glial populations were primarily affected by either genotype. We found APOE4xA{beta} molecular interactions in neuronal populations, including excitatory and inhibitory cells, converged on a core lysosomal-ER proteostasis axis. We propose that APOE4xA{beta} interaction produces an early neuronal pathogenic signature, involving the lysosomal-ER proteostasis axis, preceding functional decline and driving disease progression. APOE4xA{beta}-KI models provide a physiologically relevant platform to study early pathogenesis. HighlightsO_LIEarly synergistic APOE4xA{beta} interaction emerges predominantly at the transcriptomic level in neurons, but not in glial cells. C_LIO_LIAPOE4 and A{beta} drive largely non-overlapping physiological changes in preclinical stages of disease, but converge at the level of network hyperexcitability. C_LIO_LIAPOE4xA{beta} neuronal synergy converges on a conserved lysosomal-ER proteostasis axis. C_LIO_LIHumanized APOE4xA{beta} KI mice provide a physiologically relevant model to dissect early AD pathogenesis in preclinical stages C_LI

neuroscience↗

bioRxiv2024

Prosocial reward relates to speech reception thresholds and age relates to subjective ratings of speech perception in noise

I.Motivation plays an important role in a listeners effort when in noisy environments. However, there remain gaps in the previous literature pertaining to the social psychological factors underlying motivation and listening effort. To fill these gaps, this study explored how prosociality and social reward relate to speech perception in noise (SPiN) in a group of normal hearing English speakers (n = 136; mean age: 29.6, age range: 18-68). We investigated SPiN performance and subjective listening experiences across different speech masking conditions: 1-speaker, 2-speaker, and speech-spectrum shaped noise (SSN), along with a working memory task, and questionnaires pertaining to social orientation. Results indicated a robust effect of different maskers, and that individuals who rated themselves higher in prosocial traits performed better in the masker that yielded the highest threshold out of the three conditions, the 2-speaker condition. Additionally, subjective ratings of listening effort particularly in the 1-speaker condition related to age, where older participants reported greater effort. These findings highlight prosociality and age as important social psychological factors influencing SPiN performance and listening effort, respectively, particularly in complex listening scenarios.

neuroscience↗

bioRxiv2023

Widefield in vivo imaging system with two fluorescence and two reflectance channels, a single sCMOS detector, and shielded illumination

SignificanceWidefield microscopy of the entire dorsal part of mouse cerebral cortex enables large-scale ("mesoscopic") imaging of different aspects of neuronal activity with spectrally compatible fluorescent indicators as well as hemodynamics via oxy- and deoxyhemoglobin absorption. Versatile and cost-effective imaging systems are needed for large-scale, color-multiplexed imaging of multiple fluorescent and intrinsic contrasts. AimDevelop a system for mesoscopic imaging of two fluorescent and two reflectance channels. ApproachExcitation of red and green fluorescence is achieved through epi-illumination. Hemoglobin absorption imaging is achieved using 525- and 625-nm LEDs positioned around the objective lens. An aluminum hemisphere placed between objective and cranial window provides diffuse illumination of the brain. Signals are recorded sequentially by a single sCMOS detector. ResultsWe demonstrate performance of our imaging system by recording large-scale spontaneous and stimulus-evoked neuronal, cholinergic, and hemodynamic activity in awake head-fixed mice with a curved "crystal skull" window expressing the red calcium indicator jRGECO1a and the green acetylcholine sensor GRABACh3.0. Shielding of illumination light through the aluminum hemisphere enables concurrent recording of pupil diameter changes. ConclusionsOur widefield microscope design with single camera can be used to acquire multiple aspects of brain physiology and is compatible with behavioral readouts of pupil diameter.

neuroscience↗

bioRxiv2023

The emergence and diversification of a zoonotic pathogen from within the microbiota of intensively farmed pigs

The expansion and intensification of livestock production is predicted to promote the emergence of pathogens. As pathogens sometimes jump between species this can affect the health of humans as well as livestock. Here we investigate how livestock microbiota can act as a source of these emerging pathogens through analysis of Streptococcus suis, a ubiquitous component of the respiratory microbiota of pigs that is also a major cause of disease on pig farms and an important zoonotic pathogen. Combining molecular dating, phylogeography and comparative genomic analyses of a large collection of isolates, we find that several pathogenic lineages of S. suis emerged in the 19th and 20th centuries, during an early period of growth in pig farming. These lineages have since spread between countries and continents, mirroring trade in live pigs. They are distinguished by the presence of three genomic islands with putative roles in metabolism and cell adhesion, and an ongoing reduction in genome size, which may reflect their recent shift to a more pathogenic ecology. Reconstructions of the evolutionary histories of these islands reveal constraints on pathogen emergence that could inform control strategies, with pathogenic lineages consistently emerging from one subpopulation of S. suis and acquiring genes through horizontal transfer from other pathogenic lineages. These results shed light on the capacity of the microbiota to rapidly evolve to exploit changes in their host population and suggest that the impact of changes in farming on the pathogenicity and zoonotic potential of S. suis is yet to be fully realised.

evolutionary biology↗

bioRxiv2021

Predicting Bird Distributions Under Global Change

An introduction to predictive distribution modelling for conservation to encourage novel perspectives. The rapid pace and potentially irreversible consequences of global change create an urgent need to predict the spatial responses of biota for conservation to better inform the prioritization and management of terrestrial habitats and prevent future extinctions. Here, we provide an accessible entry point to the field to guide near-future work building predictive species distribution models (SDMs) by synthesizing a technical framework for the proactive conservation of avian biodiversity. Our framework offers a useful approach to navigate the challenges surrounding the large spatio-temporal resolution of datasets and datasets that favor hypothesis testing at broad spatio-temporal scales and coarse resolutions, which can affect our ability to assess the validity of current predicted distributions. We explain how to improve the accuracy of predictive models by determining the extent to which: 1) dispersal limitation impacts the rate of range shifts, 2) taxa are rare at their range limits, and 3) land use and climate change interact. Finally, we offer approaches to filling knowledge gaps by creatively leveraging existing methods and data sources. RESUMENUna introduccion a la modelizacion predictiva de la distribucion para la conservacion con el fin de fomentar nuevas perspectivas. El rapido ritmo y las consecuencias potencialmente irreversibles del cambio global crean una necesidad urgente de predecir las respuestas espaciales de la biota para la conservacion, con el fin de informar mejor la priorizacion y gestion de los habitats terrestres y prevenir futuras extinciones. Aqui proporcionamos un punto de entrada accesible al campo para guiar el trabajo del futuro proximo en la construccion de modelos predictivos de distribucion de especies (SDM), sintetizando un marco tecnico para la conservacion proactiva de la biodiversidad aviar. Nuestro marco ofrece un enfoque util para navegar por los retos que rodean a la gran resolucion espacio-temporal de los conjuntos de datos y a los conjuntos de datos que favorecen la comprobacion de hipotesis a escalas espacio-temporales amplias y resoluciones gruesas, lo que puede afectar a nuestra capacidad para evaluar la validez de las distribuciones predichas actuales. Explicamos como mejorar la precision de los modelos predictivos determinando hasta que punto 1) la limitacion de la dispersion influye en el ritmo de los cambios de area de distribucion, 2) los taxones son raros en los limites de su area de distribucion, y 3) el uso del suelo y el cambio climatico interactuan. Por ultimo, proponemos enfoques para colmar las lagunas de conocimiento aprovechando de forma creativa los metodos y fuentes de datos existentes.

ecology↗

bioRxiv2021

Mutation rate dynamics reflect ecological changes in an emerging zoonotic pathogen

While mutation is often deleterious, it can also be adaptive. Mutation rates vary both within and between bacterial species, and understanding what drives this variation is essential for understanding the evolutionary dynamics of bacterial populations. In this study we investigate two factors that are predicted to influence the trade-off between the costs and benefits of mutation: ecology and genome size. To investigate the relationship between these factors and mutation rate we conducted mutation accumulation experiments on eight strains of the emerging zoonotic pathogen Streptococcus suis. Natural variation within this species allows us to compare tonsil carriage and invasive disease isolates, from both more and less pathogenic populations, with a wide range of genome sizes. We find that invasive disease isolates have repeatedly evolved mutation rates that are higher than those of closely related carriage isolates, regardless of variation in genome size. Independent of this variation in overall rate, we also observe a stronger bias towards G/C to A/T mutations in isolates from more pathogenic populations, whose genomes tend to be smaller and more AT-rich. Our results suggest that ecology is a stronger correlate of mutation rate than genome size over these timescales, and that transitions to invasive disease are consistently accompanied by rapid increases in mutation rate. These results shed light on the impact ecology can have on the adaptive potential of bacterial pathogens.

evolutionary biology↗

bioRxiv2019

Neutrophil: Airway Epithelial Interactions Result in Increased Epithelial Damage and Viral Clearance during RSV Infection

Respiratory syncytial virus (RSV) is a major cause of paediatric respiratory disease. Large numbers of neutrophils are recruited into the airways of children with severe RSV disease. It is not clear whether or how neutrophils enhance recovery from disease or contribute to its pathology. Using an in vitro model of the differentiated airway epithelium, we found that addition of physiological concentrations of neutrophils to RSV infected nasal cultures was associated with greater epithelial damage with lower ciliary activity, cilia loss, less tight junction expression (ZO-1) and more detachment of epithelial cells than seen with RSV infection alone. This was also associated with a decrease in infectious virus and fewer RSV positive cells in cultures after neutrophil exposure compared to pre-exposure. Epithelial damage in response to RSV infection was associated with neutrophil activation (within 1h), and neutrophil degranulation with significantly greater cellular expression of CD11b, MPO and higher neutrophil elastase and myeloperoxidase activity in apical surface medias compared to that from mock-infected AECs. We also recovered more apoptotic neutrophils from RSV infected cultures (>40%), compared to <5% in mock infected cultures after 4h. The results of this study could provide important insights into the role of neutrophils in host response in the airway.

immunology↗

bioRxiv2019

CRISPR/Cas9-based mutagenesis frequently provokes on-target mRNA misregulation

The introduction of insertion-deletions (INDELs) by activation of the error-prone non-homologous end-joining (NHEJ) pathway underlies the mechanistic basis of CRISPR/Cas9-directed genome editing. The ability of CRISPR/Cas9 to achieve gene elimination (knockouts) is largely attributed to the emergence of a pre-mature termination codon (PTC) from a frameshift-inducing INDEL that elicits non-sense mediated decay (NMD) of the mutant mRNA. Yet, the impact on gene expression as a consequence of CRISPR/Cas9-introduced INDELs into RNA regulatory sequences has been largely left uninvestigated. By tracking DNA-mRNA-protein relationships in a collection of CRISPR/Cas9-edited cell lines that harbor frameshift-inducing INDELs in various targeted genes, we detected the production of foreign mRNAs or proteins in [~]50% of the cell lines. We demonstrate that these aberrant protein products are derived from the introduction of INDELs that promote internal ribosomal entry, convert pseudo-mRNAs into protein encoding molecules, or induce exon skipping by disruption of exon splicing enhancers (ESEs). Our results using CRISPR/Cas9-introduced INDELs reveal facets of an epigenetic genome buffering apparatus that likely evolved to mitigate the impact of such mutations introduced by pathogens and aberrant DNA damage repair, and that more recently pose challenges to manipulating gene expression outcomes using INDEL-based mutagenesis.

molecular biology↗