Publications in Nature Communications

Neurodegenerative disorders display brain region tropism accompanied by the emergence of distinct cellular states that contribute to disease pathogenesis, with molecular alterations occurring predominantly in glial cells. Here we show the emergence of a microglial state with distinct spatial distribution in the brains of terminally sick prion-infected mice characterized by high expression of Gpnmb (glycoprotein non-metastatic melanoma protein B), transcriptional signatures consistent with phagocytic activity, and increased expression of lysosomal genes in regions undergoing pronounced cell death. We find that this cellular state is not induced by pathological protein aggregates but by soluble factors released by dying cells regardless of the initiating insult. This work defines Gpnmb⁺ microglia as a distinct phagocytic state that links cell death to microglial activation and reveals a generalizable mechanism by which microglia respond to cell loss.

Contractile injection systems (CISs) mediate cell-cell interactions and are widespread among bacteria and archaea. These phage tail-like macromolecular machines puncture their target by a tube that is propelled by a contractile sheath. The mechanism underlying CIS firing, which starts with target binding and ends with sheath contraction, remains unclear. Here, we investigate the extracellular CIS from Algoriphagus machipongonensis (AlgoCIS) by a multimodal cryo-electron microscopy approach and structure-guided engineering, which allowed us to arrest AlgoCIS in multiple intermediate states of firing. Together with the post-firing structure, our data suggest a stepwise firing mechanism involving all structural modules: signal propagation starts with the binding of the tail-fibers, followed by opening of the cage, an expansion of the baseplate iris, and resulting in sheath contraction and the release of cap adaptor. Our study will serve as a framework for understanding the firing mechanism of diverse CISs and will facilitate the engineering of CISs for biomedical applications.

Hippocampal CA3 pyramidal neurons (PNs) form the largest autoassociative network in the mammalian brain. Whether CA3–CA3 recurrent connectivity is genetically preconfigured or environmentally shaped during ongoing memory storage is currently unknown. To address this question, we performed multicellular patch-clamp-based circuit mapping of up to eight CA3 PNs in the mouse hippocampus at multiple postnatal time points (P7–8, P18–25, and P45–50). Here, we show that the hippocampal CA3 network undergoes a developmental transformation from local, dense, and random connectivity to a distributed, sparse, and structured configuration. Thus, sparse and structured connectivity may emerge via experience-dependent mechanisms. In parallel, the strength of single synapses is downregulated; single synaptic events are sufficient to trigger postsynaptic spiking early in development, whereas spatial summation of several inputs is required at later time points. Biologically inspired models of memory storage by Hebbian synaptic plasticity and retrieval via pattern completion suggest that developmental changes improve specific aspects of memory storage and retrieval. Our results imply a developmental transformation of the neuronal code and the memory functions in the hippocampal CA3 network.

Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) represents a global health crisis associated with dysregulated hepatic triglyceride (TG) synthesis, oxidation and secretion. Despite progress in targeting hepatic lipid synthesis/oxidation for MASLD treatment and a well-documented relationship between circadian rhythms and lipid metabolism, the adaptive mechanisms coordinating TG secretion with circadian timing remain incompletely understood. Here we identify an autocrine regulatory pathway where circadian hepatic Fibroblast Growth Factor 1 (Fgf1) expression synchronizes diurnal TG secretion with the active phase. FGF1 activation of FGFR4 induces an mTORC1-IRE1-XBP1 signaling cascade involving atypical IRE1 activation that promotes TG secretion. Consistently, dietary-driven MASLD is exacerbated in liver-specific FGF1 knockout mice, while exogenous FGF1 halts disease progression in a Metabolic dysfunction-Associated Steatohepatitis (MASH) mouse model. This study causally associates FGF1 circadian rhythmicity with TG secretion to establish FGF1 as a crucial pacemaker in hepatic lipid homeostasis.

Multiplex social networks capture multiple types of relations among the same people. Their structure reflects how exchanges arise from individual attributes related to independence, the status or resources of others related to dependence, and mutual influence related to interdependence. Understanding these systems is challenging because layers can play distinct yet complementary roles. We introduce the Multiplex Latent Trade-off Model, MLT, a framework for identifying roles in multiplex networks that incorporates independence, dependence, and interdependence. MLT represents roles as trade-offs, requiring each node to distribute source and target roles across layers while allocating community memberships within hierarchical structures. Applying MLT to 176 multiplex networks, including social, health, and economic layers from villages in western Honduras, we identify core principles of social exchange and reveal multi-scale communities. Link-prediction analyses show that modeling interdependence most improves predictions for social ties, whereas health and economic ties are shaped more strongly by individual status and behavior.

Inhibitors of the protein kinase WEE1 have emerged as promising agents for cancer therapy. In this study, we uncover synergistic interactions between WEE1 small-molecule inhibitors and defects in mRNA translation, mediated by activation of the integrated stress response (ISR) through the kinase GCN2. Using a pooled CRISPRi screen, we identify GSPT1 and ALKBH8 as factors whose depletion confer hypersensitivity to the WEE1 inhibitor, AZD1775. We demonstrate that this synergy depends on ISR activation, which is induced by the off-target activity of WEE1 inhibitors. Furthermore, PROTAC-based WEE1 inhibitors and molecular glues show reduced or no ISR activation, suggesting potential strategies to minimise off-target toxicity. Our findings reveal that certain WEE1 inhibitors elicit dual toxicity via ISR activation and genotoxic stress, with ISR activation being independent of WEE1 itself or cell-cycle status. This dual mechanism highlights opportunities for combination therapies, such as pairing WEE1 inhibitors with agents targeting the mRNA translation machinery. This study also underscores the need for more precise WEE1 targeting strategies to mitigate off-target effects, with implications for optimising the therapeutic potential of WEE1 inhibitors.

The enzyme AMPD1 is expressed in skeletal muscle and is involved in ATP production. All available Neandertal genomes carry a lysine-to-isoleucine substitution at position 287 in AMPD1. This variant, which occurs at an allele frequency of 0–8% outside Africa, was introduced to modern humans by gene flow from Neandertals. Here, we show that the catalytic activity of the purified Neandertal AMPD1 is ~25% lower than the ancestral enzyme, and when introduced in mice, it reduces AMPD activity in muscle extracts by ~80%. Among present-day Europeans, another AMPD1 variant encoding a stop codon occurs at an allele frequency of 9–14%. Individuals heterozygous for this variant are less likely to be top-performing athletes in various sports, but otherwise reduced AMPD1 activity is well tolerated in present-day humans. While being conserved among vertebrates, AMPD1 seems to have become less functionally important among Neandertals and modern humans.

The ability to robustly predict guide RNA (gRNA) activity is a long-standing goal for CRISPR applications, as it would reduce the need to pre-screen gRNAs. Quantification of formation of short insertions and deletions (indels) after DNA cleavage by transcribed gRNAs has been typically used to measure and predict gRNA activity. We evaluate the effect of chemically synthesized Cas9 gRNAs on different cellular DNA cleavage outcomes and find that the activity of different gRNAs is largely similar and often underestimated when only indels are scored. We provide a simple linear model that reliably predicts synthetic gRNA activity across cell lines, robustly identifies inefficient gRNAs across different published datasets, and is easily accessible via online genome browser tracks. In addition, we develop a homology-directed repair efficiency prediction tool and show that unintended large-scale repair events are common for Cas9 but not for Cas12a, which may be relevant for safety in gene therapy applications.