PLoS Biology最新文献

Infantile amnesia, the inability to recall episodic memories formed during early childhood, is a hallmark of postnatal brain development. Yet the underlying mechanisms remain poorly understood. This work aimed to gain a better mechanistic understanding of infantile amnesia. Microglia, specialized macrophages of the central nervous system, are known to play an important role in synaptic refinement during postnatal development and have recently been implicated in memory-related functions. Using mouse models, we identified microglia as key regulators of memory accessibility in infancy. We profiled dynamic changes in microglial morphology across the postnatal window that paralleled the onset of infantile forgetting. We found that pharmacological inhibition of microglial activity during a specific postnatal window prevents infantile amnesia for a contextual fear memory, implicating microglia as active modulators of infant memory persistence. Using activity-dependent tagging of infant encoded engram cells, we demonstrated that microglial inhibition alters engram size and engram reactivation in the amygdala and results in changes in microglia-engram cell interactions. Furthermore, we characterized a relationship between microglial dysfunction and the lack of infantile amnesia in maternal immune activation offspring. Together, these findings reveal a novel role for microglia in regulating infant memory retrieval in mice and suggest that microglial dysfunction may contribute to altered memory trajectories in neurodevelopmental disorders.

Object recognition requires integrated processing that extends beyond the visual cortex, incorporating semantic and memory-related processes. However, it remains unclear how different attributes, such as visual, semantic, and memorability features, are encoded and interact during perception. Here, we recorded intracranial electroencephalography from 5,143 channels while participants viewed natural object images. We systematically characterized the spatiotemporal patterns of neural encoding for visual, semantic, and memorability attributes and showed that memorability was encoded in a distributed manner, which can be dissociated from visual and semantic coding. While the ventral temporal cortex (VTC) was engaged in encoding all three attributes, the representations were dissociable. Interestingly, memorability representations in the prefrontal cortex appeared to arise from integrated visual and semantic signals from the VTC; and memorability influenced early stages of visual and semantic processing. Our results were corroborated by high-resolution 7T fMRI, which revealed continuous encoding across the brain, and further validated using a separate dataset featuring within-category object variability. Lastly, single-neuron recordings confirmed semantic and memorability coding in the medial temporal lobe. Together, these findings provide a comprehensive view of how visual, semantic, and memorability attributes are dynamically encoded across the brain, highlighting the complex interplay between these attributes that collectively shape object recognition and memory formation.

Cochlear hair cells are essential for hearing, and their stereocilia bundles are critical for mechanotransduction. However, analyzing the 3D morphology of these bundles can be challenging due to their complex organization and the presence of other cellular structures in the tissue. To address this, we developed VASCilia (Vision Analysis StereoCilia), a Napari plugin suite that automates the analysis of 3D confocal microscopy datasets of phalloidin-stained cochlear hair cell bundles. VASCilia includes five deep learning-based models trained on mouse cochlear datasets that streamline the analysis process, including: (1) Z-Focus Tracker (ZFT) for selecting relevant slices in a 3D image stack; (2) PCPAlignNet (Planar Cell Polarity Alignment Network) for automated orientation of image stacks; (3) a segmentation model for identifying and delineating stereocilia bundles; (4) a tonotopic Position Prediction tool; and (5) a classification tool for identifying hair cell subtypes. In addition, VASCilia provides automated computational tools and measurement capabilities. Using VASCilia, we demonstrate its utility on challenging datasets, including neonatal wild type and Eps8 KO 5-day old mice. We further showcase its power by quantifying complex bundle disorganization in Cdh23-/- cochleae via texture analysis, which revealed systematically more heterogeneous and less regular bundles than littermate controls. These case studies demonstrate the power of VASCilia in facilitating detailed quantitative analysis of stereocilia. VASCilia also provides a user-friendly interface that allows researchers to easily navigate and use the tool, with the added capability to reload all their analyses for review or sharing purposes. We believe that VASCilia will be a valuable resource for researchers studying cochlear hair cell development and function, addressing a longstanding need in the hair cell research community for specialized deep learning-based tools capable of high-throughput image quantitation. We have released our code along with a manually annotated dataset that includes approximately 55 3D stacks featuring instance segmentation (https://github.com/ucsdmanorlab/Napari-VASCilia). This dataset comprises a total of 502 inner and 1,703 outer hair cell bundles annotated in 3D. As the first open-source dataset of its kind, we aim to establish a foundational resource for constructing a comprehensive atlas of cochlea hair cell images. Ultimately, this initiative will support the development of foundational models adaptable to various species, markers, and imaging scales to accelerate advances within the hearing research community.

Women are underrepresented in academia-especially in STEMM fields, at top institutions, and in senior positions. This is due, at least in part, to the many obstacles that they face compared to their male counterparts. There has been substantial debate as to whether the peer review system is biased against women. Some studies-mostly based on analyses of thousands of Economics research articles-have shown that manuscripts authored by women experience longer peer review times (defined as the time intervened from submission to acceptance) than comparable manuscripts authored by men. Other studies, however, have found no effect of author's gender on acceptance delays, raising questions about whether the gender gap is specific to certain fields. Biomedical and life scientists produce 36% of the research articles published annually worldwide; therefore, a comprehensive understanding of how women are treated by the peer review system requires a thorough examination of biomedicine and the life sciences. By analyzing all articles indexed in the PubMed database (>36.5 million articles published in >36,000 biomedical and life sciences journals), we show that the median amount of time spent under review is 7.4%-14.6% longer for female-authored articles than for male-authored articles, and that differences remain significant after controlling for several factors. The gender gap is pervasive, affecting most disciplines, regardless of how well women are represented in each discipline; however, the gap is absent or even reversed in some disciplines. We also show that authors based in low-income countries tend to experience longer review times. Our findings contribute to explaining the gender gap in publication rates and representation.

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.