PLoS Biology最新文献

Parkinson's disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils. Intracerebral injection of 24-OHC enhances the spread of α-Syn pathology and dopaminergic neurodegeneration via elevated X-box binding protein 1 (XBP1) and lymphocyte-activation gene 3 (LAG3) levels. Thus, elevated CYP46A1 and 24-OHC promote neurotoxicity and the spread of α-Syn via the XBP1-LAG3 axis. Strategies aimed at inhibiting the CYP46A1-24-OHC axis and LAG3 could hold promise as disease-modifying therapies for PD.

Gap junctions allow the exchange of small molecules between cells. How this function could be used to promote cell growth is not yet fully understood. During Drosophila ovarian follicle development, germ cells, which are surrounded by epithelial somatic cells, undergo massive growth. We found that this growth depends on gap junctions between these cell populations, with a requirement for Innexin4 and Innexin2, in the germ cells and the somatic cells, respectively. Translatomic analyses revealed that somatic cells express enzymes and transporters involved in amino acid metabolism that are absent in germ cells. Among them, we identified a putative amino acid transporter required for germline growth. Its ectopic expression in the germline can partially compensate for its absence or the one of Innexin2 in somatic cells. Moreover, affecting either gap junctions or the import of some amino acids in somatic cells induces P-bodies in the germ cells, a feature usually associated with an arrest of translation. Finally, in somatic cells, innexin2 expression and gap junction assembly are regulated by the insulin receptor/PI3K kinase pathway, linking the growth of the two tissues. Overall, these results support the view that metabolic transfer through gap junction promotes cell growth and illustrate how such a mechanism can be integrated into a developmental program, coupling growth control by extrinsic systemic signals with the intrinsic coordination between cell populations.

GitHub, a platform widely used in software development, offers a robust framework for documenting all activities of laboratory research projects. This Community Page highlights the benefits of, and provides guidance for, incorporating the GitHub ecosystem into "wet" lab workflows.

Fungi can intervene in hosts' brain function. In humans, they can drive neuroinflammation, neurodegenerative diseases and psychiatric disorders. However, how fungi alter the host brain is unknown. The mechanism underlying innate immunity to fungi is well-known and universally conserved downstream of shared Toll/TLR receptors, which via the adaptor MyD88 and the transcription factor Dif/NFκB, induce the expression of antimicrobial peptides (AMPs). However, in the brain, Toll-1 could also drive an alternative pathway via Sarm, which causes cell death instead. Sarm is the universal inhibitor of MyD88 and could drive immune evasion. Here, we show that exposure to the fungus Beauveria bassiana reduced fly life span, impaired locomotion and caused neurodegeneration. Beauveria bassiana entered the Drosophila brain and induced the up-regulation of AMPs, and the Toll adaptors wek and sarm, within the brain. RNAi knockdown of Toll-1, wek or sarm concomitantly with infection prevented B. bassiana-induced cell loss. By contrast, over-expression of wek or sarm was sufficient to cause neuronal loss in the absence of infection. Thus, B. bassiana caused cell loss in the host brain via Toll-1/Wek/Sarm signalling driving immune evasion. A similar activation of Sarm downstream of TLRs upon fungal infections could underlie psychiatric and neurodegenerative diseases in humans.

Tropical forests hold most of Earth's biodiversity and a higher concentration of threatened mammals than other biomes. As a result, some mammal species persist almost exclusively in protected areas, often within extensively transformed and heavily populated landscapes. Other species depend on remaining remote forested areas with sparse human populations. However, it remains unclear how mammalian communities in tropical forests respond to anthropogenic pressures in the broader landscape in which they are embedded. As governments commit to increasing the extent of global protected areas to prevent further biodiversity loss, identifying the landscape-level conditions supporting wildlife has become essential. Here, we assessed the relationship between mammal communities and anthropogenic threats in the broader landscape. We simultaneously modeled species richness and community occupancy as complementary metrics of community structure, using a state-of-the-art community model parameterized with a standardized pan-tropical data set of 239 mammal species from 37 forests across 3 continents. Forest loss and fragmentation within a 50-km buffer were associated with reduced occupancy in monitored communities, while species richness was unaffected by them. In contrast, landscape-scale human density was associated with reduced mammal richness but not occupancy, suggesting that sensitive species have been extirpated, while remaining taxa are relatively unaffected. Taken together, these results provide evidence of extinction filtering within tropical forests triggered by anthropogenic pressure occurring in the broader landscape. Therefore, existing and new reserves may not achieve the desired biodiversity outcomes without concurrent investment in addressing landscape-scale threats.

[This corrects the article DOI: 10.1371/journal.pbio.3002339.].

Repetitive stress, a common feature of modern life, is a major risk factor for psychiatric and sensory disorders. Despite the prevalence of perceptual abnormalities in these disorders, little is known about how repetitive stress affects sensory processing and perception. Here, we combine repetitive stress in mice, longitudinal measurement of cortical activity, and auditory-guided behaviors to test if sound processing and perception of neutral sounds in adults are modulated by repetitive stress. We found that repetitive stress alters sound processing, increasing spontaneous cortical activity while dampening sound-evoked responses in pyramidal and PV cells and heightening sound-evoked responses in SST cells. These alterations in auditory processing culminated in perceptual shifts, particularly a reduction in loudness perception. Additionally, our work reveals that the impact of stress on perception evolves gradually as the stressor persists over time, emphasizing the dynamic and evolving nature of this mechanism. Our findings provide insight into a possible mechanism by which repetitive stress alters sensory processing and behavior, challenging the idea that stress primarily modulates emotionally charged stimuli.

Rodent and human data implicate the hippocampus in the arbitration of approach-avoidance conflict (AAC), which arises when an organism is confronted with a stimulus associated simultaneously with reward and punishment. Yet, the precise contributions of this structure are underexplored, particularly with respect to the decision-making processes involved. We assessed humans with hippocampal damage and matched neurologically healthy controls on a computerized AAC paradigm in which participants first learned whether individual visual images were associated with the reward or loss of game points and were then asked to approach or avoid pairs of stimuli with non-conflicting or conflicting valences. To assess hippocampal involvement more broadly in response conflict, we also administered a Stroop and a Go/No-go task. On the AAC paradigm, following similar learning outcomes in individuals with hippocampal damage and matched controls, both participant groups approached positive and negative image pairs at the same rate but critically, those with hippocampal damage approached conflict pairs more often than controls. Choice and response AAC data were interrogated using the hierarchical drift diffusion model, which revealed that, compared to controls, individuals with hippocampal damage were more biased towards approach, required less evidence to make a decision during conflict trials, and were slower to accumulate evidence towards avoidance when confronted with conflicting image pairs. No significant differences were found between groups in performance accuracy or response time on the response conflict tasks. Taken together, these findings demonstrate the importance of the hippocampus to the evidence accumulation processes supporting value-based decision-making under motivational conflict.

In multi-animal tracking, addressing occlusion and crowding is crucial for accurate behavioral analysis. However, in situations where occlusion and crowding generate complex interactions, achieving accurate pose tracking remains challenging. Therefore, we introduced virtual marker tracking (vmTracking), which uses virtual markers for individual identification. Virtual markers are labels derived from conventional markerless multi-animal tracking tools, such as multi-animal DeepLabCut (maDLC) and Social LEAP Estimates Animal Poses (SLEAP). Unlike physical markers, virtual markers exist only within the video and attribute features to individuals, enabling consistent identification throughout the entire video while keeping the animals markerless in reality. Using these markers as cues, annotations were applied to multi-animal videos, and tracking was conducted with single-animal DeepLabCut (saDLC) and SLEAP's single-animal method. vmTracking minimized manual corrections and annotation frames needed for training, efficiently tackling occlusion and crowding. Experiments tracking multiple mice, fish, and human dancers confirmed vmTracking's variability and applicability. These findings could enhance the precision and reliability of tracking methods used in the analysis of complex naturalistic and social behaviors in animals, providing a simpler yet more effective solution.

Every mammal studied to date has been found to have a male mutation bias: male parents transmit more de novo mutations to offspring than female parents, contributing increasingly more mutations with age. Although male-biased mutation has been studied for more than 75 years, its causes are still debated. One obstacle to understanding this pattern is its near universality-without variation in mutation bias, it is difficult to find an underlying cause. Here, we present new data on multiple pedigrees from two primate species: aye-ayes (Daubentonia madagascariensis), a member of the strepsirrhine primates, and olive baboons (Papio anubis). In stark contrast to the pattern found across mammals, we find a much larger effect of maternal age than paternal age on mutation rates in the aye-aye. In addition, older aye-aye mothers transmit substantially more mutations than older fathers. We carry out both computational and experimental validation of our results, contrasting them with results from baboons and other primates using the same methodologies. Further, we analyze a set of DNA repair and replication genes to identify candidate mutations that may be responsible for the change in mutation bias observed in aye-ayes. Our results demonstrate that mutation bias is not an immutable trait, but rather one that can evolve between closely related species. Further work on aye-ayes (and possibly other lemuriform primates) should help to explain the molecular basis for sex-biased mutation.