Biology subjects

Nicholls, M.

Publications and source records attributed to Nicholls, M..

5 recordsLinked to original sources

bioRxiv2025

Substantial cold tolerance in all life stages of the biting midge Culicoides nubeculosus (Diptera: Ceratopogonidae)

In temperate regions, vector-borne disease risk is mediated by cold winter conditions, however, the cold tolerance of key vector taxa remains poorly understood. Culicoides biting midges are the primary vectors of several pathogens of medical and veterinary importance including bluetongue virus, where seasonal cold weather in temperate regions limits midge activity and pathogen transmission. Here, we provide the first comprehensive assessment of cold tolerance across all developmental stages of Culicoides nubeculosus, a widely used laboratory species that is endemic to northern Europe. Eggs, first-instar larvae, fourth-instar larvae, pupae, and adults were exposed to acute (1 h) and extended (6 and 24 h) cold treatments spanning -1 to -18 {degrees}C, with survival, development, emergence, and adult wing size quantified. Culicoides nubeculosus showed substantial but stage-specific cold tolerance, with survival limits of [≤] -18 {degrees}C for eggs, -14 {degrees}C for pupae, -10 {degrees}C for L1 larvae and adults, and -7 {degrees}C for L4 larvae. While the effect of cold exposure duration varied across temperatures and life stages, extended exposure generally reduced survival at lower temperatures. Cold stress caused sublethal effects, including reduced adult emergence when eggs or larvae were exposed and reductions in adult wing size of up to [~]10%, depending on the life stage. These results reveal substantial cold tolerance across the full life history of C. nubeculosus, suggesting that factors beyond temperature influence population phenology. Our findings provide new insights into Culicoides ecology, with implications for seasonal vector population dynamics and arbovirus transmission risk in temperate regions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/692099v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@199de25org.highwire.dtl.DTLVardef@c75202org.highwire.dtl.DTLVardef@1d91e6dorg.highwire.dtl.DTLVardef@15c9984_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗

bioRxiv2025

TRANCERs: Engineering enhancers into autonomous tissue-specific expression cassettes

Due to the scarcity of autonomous cell-specific promoters, control of transgene expression remains a major challenge, particularly for therapeutic applications where specificity and compactness are critical. We developed TRANCERs (TRanscriptionally Autonomous enhaNCERs), a modular system that converts gene regulatory elements (enhancers) into cell-specific standalone promoters by coupling enhancer activity with known and novel principles of transcript stability and nuclear export. This vastly increases the current repertoire of highly specific promoters available to science. We show TRANCERs drive lineage-restricted expression of genes both in vitro and in vivo, and that this expression pattern faithfully mirrors the activity of the enhancer element used. Their compact footprint and resistance to epigenetic silencing makes them ideally suited for payload-limited delivery systems such as viral vectors. TRANCERs provide a broadly applicable strategy for precise and programmable control of gene expression, enabling highly specific and customisable expression patterns for both basic research and gene-based therapies.

synthetic biology↗

bioRxiv2024

Hemogenic endothelium of the vitelline and umbilical arteries is the major contributor to mouse fetal lympho-myelopoiesis

Embryonic hematopoiesis consists of distinct waves originating in rapid succession from different anatomical locations. Hematopoietic progenitors appearing earlier than definitive hematopoietic stem cells (HSCs) play key roles in fetal and postnatal life. However, their precise origin, identity and the extent of their contribution need further clarification. To this aim, we took advantage of a genetic fate-mapping strategy in mice that allows labeling and tracking of distinct subsets of hemogenic endothelium (HE). Time-course labeling of hematopoietic progenitors emerging from HE between E8.5 and E9.5, before intra-embryonic definitive HSC generation, revealed a major fetal lympho-myeloid contribution which declined in the adult. Lineage tracing coupled with whole-mount imaging and single-cell RNA sequencing located its source within hematopoietic clusters of vitelline and umbilical arteries. Functional assays confirmed the transient nature of these progenitors. We therefore unveiled a hitherto unidentified early wave of fetal-restricted hematopoietic stem/progenitor cells poised for differentiation that provide a major contribution to pre-natal hematopoiesis.

developmental biology↗

bioRxiv2023

Optimizing CRE and PhiC31 mediated recombination in Aedes aegypti

Genetic manipulation of Aedes aegypti is key to developing a deeper understanding of this insects biology, vector-virus interactions and makes future genetic control strategies possible. Despite some advances, this process remains laborious and requires highly skilled researchers and specialist equipment. Here we present two improved methods for genetic manipulation in this species. Use of transgenic lines which express Cre recombinase allowed, by simple crossing schemes, germline or somatic recombination of transgenes, which could be utilized for numerous genetic manipulations. PhiC31 integrase based methods for site-specific integration of genetic elements was also improved, by developing a plasmid which expresses PhiC31 when injected into early embryos, eliminating the need to use costly and unstable mRNA as is the current standard.

bioengineering↗

bioRxiv2021

Progesterone receptor-A isoform interaction with RUNX transcription factors controls chromatin remodelling at promoters during ovulation

Progesterone receptor (PGR) plays diverse roles in reproductive tissues and thus coordinates mammalian fertility. In the ovary, acutely induced PGR is the key determinant of ovulation through transcriptional control of a unique set of genes that culminates in follicle rupture. However, the molecular mechanisms for PGRs specialised function in ovulation is poorly understood. To address this, we assembled a detailed genomic profile of PGR action through combined ATAC-seq, RNA-seq and ChIP-seq analysis in wildtype and isoform-specific PGR null mice. We demonstrated the unique action of PGR-A isoform in the ovary through a transcriptional complex involving physical interaction with RUNX and JUN/FOS transcription factors. The assembly of this unique complex directs targeting of PGR binding to proximal promoter regions and enables chromatin accessibility, leading to ovulatory gene induction. This PGR signalling mechanism is specific to ovulation and provides potential targets for infertility treatments as well as new contraceptives that block ovulation.

molecular biology↗