Open Biology最新文献

The unfolded protein response (UPR) is an ancient, highly conserved homeostatic cellular stress response pathway with diverse functions that include, but are not limited to, alleviating stress resulting from the presence of unfolded proteins in the endoplasmic reticulum of cells. Maintaining homeostasis and managing stress are critical to infection tolerance (i.e. host ability to mitigate infection-induced disease independently of strategies involving pathogen elimination). Stress responses such as the UPR are general mediators of tolerance, and the UPR may be activated during infections to promote host health. Understanding tolerance is an emerging priority in animal immunity, and there is unique motivation to understand how disease vectors tolerate infections because tolerance has implications for the efficiency of human pathogen transmission. However, stress responses are scarcely studied in arthropods, and the UPR has not been investigated in the context of a systemic mosquito infection. Herein, we characterize the trajectories of mortality and UPR transcript abundance in Aedes aegypti in response to infection with the opportunistic bacterial pathogen Serratia marcescens. We reveal that, with the exception of atf6, which displayed comparatively delayed activation, transcript levels of all UPR genes we measured harmoniously activate, peak, then diminish prior to the advent of appreciable infection-induced mortality.

Excitatory amino acid transporters not only mediate high-affinity glutamate uptake but also conduct an uncoupled chloride current. In zebrafish, a whole-genome duplication gave rise to two eaat2 paralogues with distinct roles. Excitatory amino acid transporter 2a (SLC1A2b, GLT-1) functions primarily in Müller glia as a glutamate transporter, whereas excitatory amino acid transporter 2b is expressed in cone photoreceptors and exhibits a prominent glutamate-independent chloride current. We hypothesized that this leak current stabilizes the cone resting membrane potential, thereby supporting rapid visual signalling. In order to test this hypothesis, we generated eaat2b knockout zebrafish using CRISPR-Cas9-mediated genome editing. While eaat2b mutants showed no gross morphological abnormalities, they exhibited reduced electroretinogram b-wave amplitudes. Consistent with our hypothesis, eaat2b-deficient larvae displayed a significant reduction in flicker fusion electroretinogram power at each stimulus frequency, indicating impaired temporal processing likely due to delayed repolarization of cone photoreceptors. Our findings reveal a critical role for an excitatory amino acid transporter 2b-mediated chloride anion leak current in regulating the kinetics of photoreceptor responses. This functional innovation, enabled by a whole-genome duplication in the teleost lineage, highlights how gene duplications can lead to the acquisition of physiologically relevant new functions.

The endosteum is a thin layer of connective tissue lining the inner surfaces of bones adjoining the medullary cavity. The endosteum houses a variety of cells crucial for bone growth, repair and remodelling, including bone-forming osteoblasts, bone-resorbing osteoclasts and their precursor cells. Historically, the endosteum has been extensively studied as a key site for haematopoiesis by which blood cells are incessantly produced. However, recent studies have defined the endosteum as a niche for skeletal stem cells, underscoring the importance of the harmony between the inner endosteum and the outer periosteum in maintaining bone homeostasis. The endosteum also plays a significant role in pathological conditions, as it is recognized as a preferential site for bone metastasis of several common carcinomas, including breast and prostate cancers. The uniquely complex microenvironment of the endosteum favours the survival of cancer cells, contributing to dormancy, resistance to therapies and eventually, reemergence and progression. In this review, we discuss the multifaceted functions of the bone marrow endosteum, focusing on its dual roles in normal bone haematopoiesis and tumour metastasis.

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.

Dictyostelium discoideum is a social amoeba that transitions from unicellular to multicellular forms in response to environmental signals, making it an intriguing model for studying cell aggregation and differentiation. Although previous studies have demonstrated that Dictyostelium slugs exhibit phototaxis, the mechanisms behind light-induced developmental changes remain unclear. In this study, we investigated how light triggers the transition to multicellularity and its associated metabolites and genes. Our findings revealed that spore yield depends on light exposure, with slower multicellular development under dark incubation. Transcriptomics analysis on QS9 amoebae identified upregulation of small GTPases such as rasD and racL in response to light, which likely promote cell movement, phagocytosis and actin protrusions. Light also enhanced cAMP production, driving the aggregation, post-aggregation and development of single cells. Additionally, c-di-GMP was essential for cell differentiation during multicellular growth and was upregulated by light. Metabolomic analysis on QS9 amoebae revealed that the downregulation of LPC (lysophosphatidylcholine) was detected under both unicellular and multicellular phases. Moreover, reduced levels of GSH (glutathione) in dark may impede multicellular structures of D. discoideum. These findings provide insights into light-triggered cell differentiation and pattern formation, offering a better understanding of molecular mechanisms underlying the transition to multicellularity in Dictyostelium cells.

Histone deacetylase four (HDAC4) undergoes dynamic nucleocytoplasmic shuttling, a process critical for regulating its activity. However, aberrant nuclear accumulation of HDAC4 is associated with both neurodevelopmental and neurodegenerative disease, and in our Drosophila model, impairs normal neuronal development. Upon nuclear accumulation, HDAC4 forms biomolecular condensates, previously termed aggregates, that correlate with the severity of defects in development of the Drosophila mushroom body and adult eye. Here we determined that nuclear condensation of HDAC4 is dependent on self-oligomerization, and that impairing oligomerization reduces condensation and the severity of neurodevelopmental phenotypes in Drosophila. HDAC4 condensates are highly dynamic and are stabilized by the presence of MEF2, which promotes their formation, ultimately exacerbating phenotypic severity. These data provide insight into the role of HDAC4 condensates in normal neuronal function and suggest that their dysregulation may contribute to neurodevelopmental disorders. Consequently, targeting oligomerization of HDAC4 and its interaction with MEF2 present potential therapeutic strategies for diseases associated with HDAC4 nuclear accumulation.

Transfer RNAs (tRNAs) and their modifications are central to bacterial translation and physiology, yet their roles in stress adaptation remain underexplored. While extensively studied in eukaryotes, and linked to diseases, bacterial tRNA modifications are only recently gaining attention. This review highlights emerging insights into how tRNA modifications and associated enzymes contribute to bacterial survival under oxidative and antibiotic stresses, both disrupting proteostasis. We examine the environmental and physiological stresses bacteria encounter, focussing on reactive oxygen species and sub-lethal antibiotic exposure. These stresses challenge proteome integrity and trigger adaptive responses involving key stress regulators. We explore the expanding field of bacterial epitranscriptomics, detailing the diversity, dynamics and structural impact of tRNA modifications, and how they influence selective translation. Central to this is the concept of modification tunable transcripts, linking specific codon usage patterns to stress-responsive translation reprogramming. Beyond their catalytic roles, tRNA-modifying enzymes also have additional functions. We discuss this dual functionality and its broader implications for bacterial adaptability. By integrating recent technological advances and conceptual models, this review underscores the potential of targeting tRNA modifications as a novel strategy to combat bacterial pathogenicity and antibiotic resistance. With many aspects still unresolved, the study of bacterial tRNA modifications promises rich opportunities for discovery and therapeutic innovation.

Sequences called flipons can adopt discrete, alternative nucleic acid conformations, such as the left-handed Z-DNA and Z-RNA double helices (referred to collectively as ZNA), and the four-stranded RNA and DNA G-quadruplexes. Each flipon conformation encodes different information. For example, the base-specific interactions of proteins with B-DNA enable sequence-specific recognition. In contrast, the higher energy Z-DNA and G-quadruplexes facilitate the speedy scanning of chromosomes to locate active regions of the genome. Results synthesized from small-scale benchside and large-scale computational experimental approaches provide compelling evidence that zinc-finger protein domains (ZFDs) not only engage in base-specific recognition of B-DNA, but also bind directly to Z-DNA and G-quadruplexes. The findings address the long-standing speed-stability paradox of how high-affinity ZFPs with multiple zinc fingers can rapidly localize to a specific binding site. The energy gap between different DNA interaction modes enables fast off-rates during the scanning of Z-DNA for cognate binding sites, and a slow off-rate following engagement of the B-DNA conformer. ZFPs represent the most prominent human transcription factor family with 804 annotated members. The coevolution of flipons and ZFP enhances suppression of retroelements and enables rapid, context-specific responses. ZNA and GQ binding proteins are consequently more frequent in the proteome than currently conceded.

Typically, unchecked pancreatic cell proliferation results in the development of pancreatic cancer, which has the potential to spread to other bodily organs. About 90% of instances of pancreatic cancer are pancreatic adenocarcinomas. About 10-20% of pancreatic carcinomas are resectable and potentially curable, and the 5-year survival rate is only 4%; as a result, the majority of pancreatic cancer treatments are palliative in nature. Surgical resection is the only curative treatment; however, because of late diagnosis, the majority of patients appear at an advanced stage, and only a small percentage (10-20%) of them are candidates for surgery. Due to pancreatic cancer's strong resistance to practically all chemotherapeutic drugs and conventional radiotherapies, conventional radiation and chemotherapies have little effectiveness in extending patients' overall life. A lot of scientific studies, however, frequently use the metaphorical term 'double-edged sword' to indicate how autophagy plays a different function in cancer. The use of autophagy inhibitors is thought to be advantageous in combining antineoplastic drugs to improve the sensitivity of cancer cells to therapeutic compounds that activate autophagy. In this review, we aim to look into autophagy along with searching for the most effective strategy in order to treat pancreatic adenocarcinoma with the least drug resistance.

Many marine invertebrates have a biphasic life cycle with a free-swimming larva and a bottom-dwelling adult. The transition from a planktonic to a benthic lifestyle is a significant step in the animal's life history, highly regulated and influenced by external and internal factors. Since the readiness to settle and the presence of a suitable seafloor habitat do not always coincide, larvae sometimes need to extend their planktonic phase. Little is currently known regarding how larvae partition their energy for coordinating development and growth according to food type and availability in their settlement habitat. Here, I investigate the effect of food availability and type on development in Platynereis dumerilii larvae. I assessed cell proliferation, growth and feeding onset over six days using two different food sources. The results indicate that food availability and type affect larval growth, with starved larvae slowing development and conserving resources, whereas fed larvae allocate resources to brain development and posterior growth. Overall, this work contributes to our understanding of how competent marine larvae regulate the duration of their planktonic phase and how nutritional status affects development.