PLoS Biology最新文献

Immunometabolism, a fundamental biogenic process that supports the function of immune cells, is often disrupted in diseases such as cancer. Tackling metabolic dysregulation at a cellular level has therefore emerged as a focus in drug development. However, as cellular metabolic rewiring takes place in response to both intrinsic factors, which can be targeted pharmacologically, and environmental changes, which cannot, fostering a homeostatic systemic metabolism through diet, exercise, and stress management is essential to support and sustain cellular fitness. This Essay conceptualizes immunometabolism as a process that can be regulated intrinsically and extrinsically and explores the potential for incorporating lifestyle changes and drug therapies that target immunometabolism into treatments for cancer.

[This corrects the article DOI: 10.1371/journal.pbio.3003569.].

Caspases, traditionally viewed as mediators of apoptosis and tumor suppressors, have also been shown to promote cell proliferation and to contribute to tumor growth. For example, the initiator caspase Dronc (the Drosophila orthologue of Caspase-9) can trigger apoptosis-induced proliferation (AiP), a process where apoptotic cells generate mitogenic signals for compensatory proliferation independently of their apoptotic function. AiP is crucial for homeostatic cell turnover, wound healing, and tissue regeneration. Previously, we established that Dronc activates the NADPH oxidase DUOX at the plasma membrane, resulting in the production of extracellular reactive oxygen species (ROS) which are required for AiP. However, the mechanism by which Dronc activates DUOX has remained elusive. Here, we identified Dronc-dependent Ca2+ entry into the cytosol as a significant factor for DUOX activation and AiP. Three cell surface Ca2+ channels of the TRP family mediate Ca2+ influx in a non-redundant fashion. Additionally, calcium-induced calcium release (CICR) from the ER was identified as another source of cytosolic Ca2+ during AiP. Notably, DUOX itself acts as a Ca2+ effector in AiP, requiring Ca2+ binding for its activation. These findings highlight the importance of Ca2+ signaling in AiP and provide insights into how similar signaling mechanisms might operate in vertebrates.

Filamentous plant pathogens secrete effectors to successfully establish host infections. In resistant crop varieties, plant immunity can be triggered by immune receptors that recognize these effectors. Resistant crop varieties are grown in large-scale monocultures imposing strong selection pressure on pathogens, driving rapid evolution of effector repertoires resulting in the frequent breakdowns of resistance within just a few growing seasons. The oomycete Peronospora effusa, responsible for downy mildew on spinach, is an example of a rapidly adapting pathogen, but it is yet unknown how P. effusa can successfully overcome resistance of spinach by genomic adaptations. To close this knowledge gap, we here generated genome assemblies and constructed a pangenome graph for 19 isolates corresponding to 19 officially denominated resistance-breaking P. effusa races, which can cause disease on a differential set of spinach cultivars. Haplotype-resolved pangenome graph analyses revealed that many isolates emerged from recent sexual recombination, yet others evolved via prolonged asexual reproduction and loss of heterozygosity. By phasing effector candidates to determine their allelic variation, we identified effector candidates associated to resistance breaking of spinach varieties and reconstructed the evolutionary events that led to their diversification. The here developed and applied computational genomics approaches offer invaluable insights into the molecular mechanisms of the rapid evolution of P. effusa, and points to potential targets for future resistance breeding.

Many organisms carry extra, non-essential chromosomes known as B chromosomes (Bs), which are selfishly transmitted at super-mendelian levels to offspring. This heightened transmission, termed drive, occurs during gametogenesis, usually in one of the two parents. In some cases, Bs can experience an opposing process, drag, which reduces their transmission. If these processes occur together in the same organism, one in each parental sex, then they may facilitate the spread of Bs while countering their accumulation in the genome to harmful levels. While previous studies have elucidated mechanistic aspects of B drive, little is known about drag or other factors that govern the inheritance of these selfish genetic elements. Here, we examined the inheritance of Paternal Sex Ratio (PSR), a single-copy B in the jewel wasp, Nasonia vitripennis, which is transmitted paternally to offspring. PSR drives by converting female-destined embryos into PSR-transmitting males. Using genetic manipulation, we produced exceptional PSR-carrying females, which were used to assess B transmission potential. We found that females transmit PSR at an unexpectedly low level compared to univalent chromosomes in other organisms. This reduced transmission stems from remarkable loss of PSR from the egg's nucleus upon entry into meiosis, an effect that may be caused by an absence of microtubule-based spindle fibers in meiosis I-arrested wasp eggs. We also found that PSR is strictly limited to a single copy per genome, likely because wasps having two PSR copies die during development. Our findings reveal the successful inheritance of this selfish B chromosome involves its restriction to a single copy and hidden female meiotic drag in addition to strong paternal drive.

Task knowledge can be encoded hierarchically such that complex tasks can be built by associating simpler tasks. This associative organization supports generalization to facilitate learning of related but novel complex tasks. To study how the brain implements generalization in hierarchical task learning, we trained human participants on two complex tasks that shared a simple task and tested them on novel complex tasks whose association could be inferred via the shared simple task. Behaviorally, we observed faster learning of the novel complex tasks than control tasks. Using electroencephalogram (EEG) data, we decoded constituent simple tasks when performing a complex task (i.e., EEG association effect). Crucially, the shared simple task, although not part of the novel complex task, could be reliably decoded from the novel complex task. This decoding strength was correlated with the EEG association effect and the behavioral generalization effect. The findings demonstrate how task learning can be accelerated by associative inference.

Bacteriophage-host interactions play a fundamental role in shaping microbial ecosystems. While extensively studied on Earth, their behavior in microgravity remains largely unexplored. Here, we report the dynamics between T7 bacteriophage and Escherichia coli in microgravity aboard the International Space Station (ISS). Phage activity was initially delayed in microgravity but ultimately successful. We identified de novo mutations in both phage and bacteria that enhanced fitness in microgravity. Deep mutational scanning of the phage receptor binding domain revealed striking differences in the number, position, and mutational preferences between terrestrial and microgravity conditions, reflecting underlying differences in bacterial adaptation. Combinatorial libraries informed by microgravity selections yielded T7 variants capable of productively infecting uropathogenic E. coli resistant to wild-type T7 under terrestrial conditions. These findings help lay the foundation for future research on the impact of microgravity on phage-host interactions and microbial communities and the terrestrial benefits of this research.

In early postnatal brain, the prefrontal cortex (PFC) remains immature and highly plastic, particularly for the intratelencephalic (IT) neurons. However, the spatiotemporal molecular and cellular dynamics of PFC during this period remain poorly characterized. Here, we performed spatiotemporal single-cell RNA analysis on mouse PFC during different postnatal time points and systematically delineated the molecular and cellular dynamics of mouse PFC during early postnatal development, among which IT neurons exhibit most dramatic alterations. Based on these comprehensive spatiotemporal atlases of PFC, we deciphered the time-specific molecular and cellular characteristics during the maturation process of IT neurons in PFC, particularly the dynamic expression programs of genes regulating axon development and synaptic formation, and the risk genes of neurological developmental diseases. Furthermore, we revealed the dynamic neuron-glia interaction patterns and the underlying signaling pathways during early postnatal period. Our study provided a comprehensive resource and important insights for PFC development and PFC-associated neurological diseases.

Brown adipose tissue (BAT) functions as a metabolic sink, efficiently processing fatty acids (FAs), glucose, and amino acids, playing a pivotal role in metabolic regulation and energy homeostasis. However, the metabolic adaptations enabling BAT to respond to fasting and refeeding cycles are not well understood. Using mass spectrometry techniques-Liquid Chromatography (LC), Capillary Electrophoresis (CE), and Spatially Resolved Imaging-we demonstrate that BAT exhibits a unique free fatty acid (FFA) and lipid-bound FA profile, with enrichment of very long-chain polyunsaturated fatty acids (VLC-PUFAs) and C13-C14 FAs compared to white adipose tissue (WAT) in male C57BL/6 mice. Alternate-day fasting (ADF) triggered a dynamic change of these FFAs in BAT, accompanied by selective alterations of upper glycolysis, glyceroneogenesis, and triglyceride synthesis, a shift less pronounced in WAT. Additionally, several BAT lipid species, including glycerolipids, glycerophospholipids, and sphingolipids, transitioned from highly unsaturated to more saturated lipids upon refeeding, alongside significant spatial and dynamic reprogramming. Mechanistically, periodic fasting and refeeding activated mTORC1, and genetic inactivation of mTORC1 in BAT diminished ADF-induced lipid saturation, storage, and redistribution in the C57BL/6 background. These findings reveal that while BAT generally prefers unsaturated fats, it undergoes substantial lipid saturation and spatially dynamic reprogramming in response to fasting and refeeding, offering new insights into BAT's adaptive role in metabolic homeostasis.

Synaptic convergence is fundamental to neuronal circuit function, underpinning computations such as coincidence detection and signal integration. Across sensory systems, convergence architecture and synaptic input strengths are key for extracting stimulus features and processing of sensory information. In the cochlear nucleus, globular bushy cells (GBCs) receive convergent inputs from multiple auditory nerve fibers via large endbulb of Held terminals. While these inputs vary considerably in size, even among those targeting the same cell, the functional consequences of this variation for sound encoding remain unclear. Here, we investigated how synaptic input variation shapes sound encoding in GBCs of Mongolian gerbils using in vitro conductance-clamp recordings and computational modeling. By simulating synaptic inputs with variable strength distributions, we found that increasing input variation enhances rate coding at the expense of temporal precision. These findings suggest that endbulb strength heterogeneity allows the GBC population to operate along a functional continuum, generating diverse information streams to downstream targets.