Foetal alcohol spectrum disorders (FASDs) refer to a range of adverse physical, behavioural and cognitive effects caused by perinatal alcohol exposure. While cognitive impairments are well documented, FASD has also been associated with sleep disturbances and circadian rhythm disruptions. This study aimed to examine the effects of perinatal alcohol exposure on circadian rhythms at behavioural and gene expression levels across two developmental stages (adolescence and adulthood) in both male and female mice. Using a validated prenatal and lactation alcohol exposure (PLAE) protocol, we assessed circadian patterns of locomotor activity under free-running conditions and spatial memory performance during adolescence and adulthood. Additionally, we evaluated the impact of PLAE on circadian expression of clock and non-circadian genes involved in neurotransmission across key brain regions, including the medial prefrontal cortex and hippocampus. PLAE altered circadian rhythmicity and impaired spatial memory. Gene expression analyses revealed disrupted oscillatory patterns in clock genes and in genes related to plasticity and cognition, including those from the expanded endocannabinoid system (e.g. Cnr1, Dagla, Faah) and other neurotransmitter systems (e.g. Oprm1, Slc17a8, Drd1, Gabra1). These findings underscore the impact of early alcohol exposure on biological rhythms and neurobehavioural function, highlighting circadian dysregulation as a contributing factor to FASD.

Fetal skin has an intrinsic regenerative capability to restore an injured site's architecture and functionality. This is preserved until the third trimester, when wound healing transitions to a scarring reparative response. This change coincides with the dynamic remodelling of dermal extracellular matrix (ECM). Here, we used primary human fetal or adult dermal fibroblast (fHDF and aHDF)-derived ECMs to demonstrate that different extrinsic signals from these ECMs dramatically altered gene expression in a primary human keratinocyte population grown on these matrices. Gene array data revealed keratinocytes grown on fHDF ECM markedly upregulated expression of cell-cycle genes, whereas on aHDF ECM expression of differentiation genes was favoured. Detailed proteomic analyses indicated compositionally distinct ECMs were deposited by aHDFs and fHDFs. Moreover, aHDFs and fHDFs contained subpopulation(s) that differentially expressed CD90, CD146 and CD26. On fHDFs the extracellular domain of CD26 was shed whereas on aHDFs full-length CD26 dominated. The proteomic and gene array data supported the fine-tuning of BMP/TGFβ/SMAD signalling pathways being a mechanism by which fetal matrices promote keratinocyte self-renewal. Collectively, these findings revealed that a fundamental aspect of skin development is dictated by the ECM of the dermis, specifically extrinsic signals from dermal fibroblast ECM direct keratinocyte self-renewal or differentiation.

Ageing is an intricate and progressive decline across all biological systems, marked by various molecular and cellular processes termed as the hallmarks of ageing. One of the hallmarks is mitochondrial dysfunction, which is brought about through several pathways: mutations in mitochondrial DNA, elevated reactive oxygen species production, disrupted mitochondrial dynamics and impaired mitophagy. Here, we explore the role of high mobility group box 1 (HMGB1) as a potential contributor to mitochondrial dysfunction, examining how it may influence these pathways through its dual roles as both a protector of mitochondrial integrity and a promoter of inflammatory damage. Furthermore, we consider how mitochondrial dysfunction, possibly mediated by HMGB1, could link to other hallmarks of ageing, positioning HMGB1 as a possible central regulator in the ageing process.

Metamonada is a eukaryotic supergroup of free-living and parasitic anaerobic protists. Their characteristic feature is the presence of highly reduced mitochondria that have lost the ability to produce ATP by oxidative phosphorylation and in some cases even by substrate phosphorylation, with all ATP being imported from the cytosol. Given this striking difference in cellular ATP metabolism when compared to aerobic mitochondria, we studied the presence of mitochondrial carrier proteins (MCPs) mediating the transport of ATP across the inner mitochondrial membrane. Our bioinformatic analyses revealed remarkable reduction of MCP repertoire in Metamonada with striking loss of the major ADP/ATP carrier (AAC). Instead, nearly all species retained carriers orthologous to human SLC25A43 protein, a little-characterized MCP. Heterologous expression of metamonad SLC25A43 carriers confirmed their mitochondrial localization, and functional analysis revealed that SLC25A43 orthologues represent a distinct group of ATP transporters, which we designate as ATP-importing carriers (AIC). Together, our findings suggest that AIC facilitate the ATP import into highly reduced anaerobic mitochondria, compensating for their diminished or absent energy metabolism.

The retinal determination genetic network controls the development of the visual system in all seeing animals through the molecular regulation of cells to adopt an eye tissue fate. The compound eye of the fruit fly, Drosophila melanogaster, is an excellent model system to study the complex mechanisms within the network that regulate specification of cellular identity during embryogenesis. In Drosophila, the two Pax6 paralogues, eyeless and twin of eyeless, sit at the very pinnacle of the network and their expression early in development activates critical downstream components of the retinal determination pathway. In this study, we investigate the expression of 21 known components of the network in two established embryonic cell lines, Kc167 and S2 cells, that show reciprocal expression patterns for the two Pax6 paralogues. Network mapping reveals that many of the components of the network demonstrate extensive interactions with additional factors. Integrating the transcriptional profile of the cell lines, interaction maps and embryonic expression patterns enables us to identify 16 potential novel components of the genetic network, 11 of which are transcription factors. We confirm the regulatory potential for a subset of the novel transcription factors through the identification of predicted binding sites in previously characterized enhancers for the core genes in the network.

The type III secretion system (T3SS) has traditionally been studied for its role in bacterial virulence. However, recent research emphasizes its dual role in beneficial interactions between bacteria and plants. This review examines the immunomodulatory functions of T3SS beyond pathogenicity and focuses on how T3SS effectors manipulate plant immune responses to promote symbioses. By comparing T3SS mechanisms in pathogenic and non-pathogenic bacteria, we aim to understand how this system enables beneficial microbes to colonize plants and improve plant growth and stress resilience. We also investigate the potential of T3SS to trigger induced systemic resistance in plants, a mechanism that could be utilized in agriculture to improve crop resistance to pathogens. The review concludes with an outlook on future research and emphasizes the need for comprehensive studies on T3SS effectors in non-pathogenic bacteria and their interactions with plant hosts.

Pigment-dispersing factors (PDFs) are neuropeptides that play key roles in controlling the circadian rhythms in various insects, whereas their function remains elusive in other protostomes including tardigrades (water bears). Here we show that the three PDFs of the tardigrade Hypsibius exemplaris are co-localized in two pairs of inner lobe cells in the brain, whereas only one PDF occurs in four additional cerebral and two extracerebral cells. The axons of the inner lobe cells pass through the contralateral brain hemisphere, descend to the ventral nerve cord and terminate in two pairs of potential release sites in the posteriormost trunk ganglion. Using in vitro assays, we demonstrate that all three PDFs and their deorphanized receptor (PDFR) are functional. Widespread localization of PDFR suggests that tardigrade PDFs may act as multifunctional hormones and neuromodulators that control major functions including light detection, neural processing, locomotion, feeding, digestion, osmoregulation, growth, embryonic development and oogenesis/reproduction.

Trace elements are often omitted from chemically defined growth media. From established properties of trace elements, we deduce that this omission makes experiments unnecessarily sensitive to unavoidable contamination with trace elements. We confirm this experimentally by growing 11 bacterial strains in high replicate with and without supplementing trace elements, keeping all other conditions as fixed as possible to isolate the effect of trace elements. We find that supplementing trace elements considerably reduces variability of growth even in this benign scenario, and we argue that typical experimental set-ups exacerbate this. We discuss implications for the design and use of trace-element supplements and in particular argue that their use should be standard practice, as they can reduce variability of almost all experiments using chemically defined media, taking a step towards greater precision and replicability in microbiology.

Essential to much medical progress (for example, preventing AIDS, tuberculosis and cancer) is understanding how the class of immunity is controlled. Most envisage that pathogen- or danger-associated signals are critical. Many classical observations, particularly on the variables of immunization affecting the class of immunity generated, are paradoxical under this dominant view, and are therefore neglected. Among these is the role of antigen dose. Plausible strategies to prevent and treat AIDS, cancer and tuberculosis are based on such neglected observations. Many suggest that the information overload stultifies the canon, inhibiting progress. I illustrate here that seeking and resolving paradoxes can provide a different perspective from that of the dominant canon, opening vistas that address major issues pertinent to world health.

In the Drosophila wing epithelium, canonical Wnt signalling is activated by the gradient of secreted Wingless protein (Wnt1 homolog), which interacts redundantly with the Frizzled1 and Frizzled2 receptors. While sharing overlapping functions, these receptors also have distinct non-canonical roles and exhibit differential expression patterns along the Wingless gradient. Moreover, Frizzled2, unlike Frizzled1, is thought to be essential for sustaining low-level Wingless signalling and promoting cell survival in the absence of the ligand. This raises the possibility of the two receptors acting differently along the Wingless gradient. In this study, we investigated the role of these receptors in cell survival across varying Wingless levels. We find that the loss of Frizzled2 in cells at a distance from the Wingless-producing cells-where Wingless levels are low-leads to competitive elimination of cells. In contrast, Frizzled1 is dispensable for cell survival, regardless of distance from the Wingless source. Our findings show that Frizzled2 is essential for competitive cell survival under low-Wingless conditions, and the two receptors are not equally redundant across the Wingless concentration gradient, providing insight into a mechanism for spatial and temporal precision in developmental signalling.