Cell Reports

Epicutaneous Staphylococcus aureus initiates cross-tissue IL-36R signaling for neutrophilic lung inflammation in a model of the atopic march Kline et al. report that in a preclinical model of the atopic march, Staphylococcus aureus skin exposure initiates neutrophilic lung inflammation that requires skin and lung epithelial IL-36R signaling. Neutrophil-derived serine proteases and IL-36R-dependent NETosis exacerbate lung pathogenesis, which can be ameliorated with protease inhibitors and IL-36R blockade.

Epicutaneous Staphylococcus aureus initiates cross-tissue IL-36R signaling for neutrophilic lung inflammation in a model of the atopic march

Cell-of-origin-specific behavioral deficits in oligodendrocyte-derived glioblastoma In this study, Sher et al. use preclinical mouse models to explore how glioblastoma, a highly aggressive brain tumor, can arise from oligodendrocytes. They find that these tumors cause early motor dysfunction and show a distinct myelin-related gene-expression pattern, indicating that gliomas may disrupt neural function in a lineage-specific manner.

Cell-of-origin-specific behavioral deficits in oligodendrocyte-derived glioblastoma

19S proteasome loss regulates mitotic spindle assembly through a ubiquitin-independent degradation mechanism Marescal and Cheeseman show that depletion of proteasome 19S lid subunits, but not that of other proteasome components, uniquely leads to the formation of monopolar spindles during mitosis. This phenotype arises from the aberrant ubiquitin-independent degradation of the motor protein KIF11 by the 20S proteasome core upon 19S loss.

19S proteasome loss regulates mitotic spindle assembly through a ubiquitin-independent degradation mechanism

FGF-induced phospholipase Cγ signaling regulates lacrimal gland branching by competing with PI3K in phosphoinositide metabolism Wang et al. demonstrate that PLCγ1 negatively regulates FGF signaling through both of its SH2 domains. Deletion of PLCγ1 results in increased PIP3 levels and enhanced AKT activation without impacting MAPK signaling. This reveals a novel mechanism by which PLCγ1 controls branching through the modulation of phosphoinositide metabolism.

FGF-induced phospholipase Cγ signaling regulates lacrimal gland branching by competing with PI3K in phosphoinositide metabolism

Piezo mediates oviposition in shielding gaps to protect moth eggs from parasitoid wasp Ma et al. show that Mythimna separata prefer to lay eggs in narrow slits shielding eggs from Trichogramma dendrolimi. The Piezo receptor in ovipositor bristles mediates the narrow-slit detection.

Piezo mediates oviposition in shielding gaps to protect moth eggs from parasitoid wasp

The mitotic ATR-Chk1 pathway promotes CDK1 activity for faithful chromosome segregation Joo et al. demonstrate that constitutive mitotic ATR and Chk1 activity ensures faithful chromosome segregation. In mitosis, Chk1 phosphorylates and inhibits Myt1, a kinase that deactivates CDK1, a necessary step in sustaining proper CDK1 activity. Inhibition of mitotic Chk1 leads to defective Aurora B signaling pathway through CDK1 phosphorylation of INCENP.

The mitotic ATR-Chk1 pathway promotes CDK1 activity for faithful chromosome segregation

Human intelligence relates to neural measures of cognitive map formation Tenderra et al. show that human intelligence is linked to interindividual differences in relational integration in hippocampal cognitive maps. Map-like representations of information learned piecemeal scaled with fluid intelligence, and this relationship specifically reflected relational integration rather than general mnemonic processing. These findings highlight a neural mechanism underlying general cognitive ability.

Human intelligence relates to neural measures of cognitive map formation

Striatal modulation supports context-specific reinforcement and not action selection Hodge et al. used closed-loop optogenetic stimulation and naturalistic behaviors to determine that striatal activity does not select the action to perform but rather biases performance through reinforcement. The striatal projection neuron (SPN) manipulations that more closely approximate endogenous temporal dynamics demonstrate that SPNs shape future performance based on behavioral history.

Striatal modulation supports context-specific reinforcement and not action selection

Cancer-associated fibroblast-derived fibulin-5 promotes radioresistance in non-small-cell lung cancer Zhang et al. revealed that cancer-associated fibroblast (CAF)-derived Fibulin-5 promotes radioresistance in non-small-cell lung cancer (NSCLC). FBLN5 knockdown in CAFs could enhance radiosensitivity by inducing ferroptosis via decreased ACSL4 expression. Their work identified FBLN5 as a biomarker and a therapeutic target for NSCLC radiotherapy.

Cancer-associated fibroblast-derived fibulin-5 promotes radioresistance in non-small-cell lung cancer

IGSF10 is a RET antagonist regulating Ewing sarcoma growth and GnRH neuron migration While IGSF10 mutations are associated with hereditary delayed puberty, the mechanism of action of IGSF10 has been an enigma. Jayabal et al. report that IGSF10 functions as a RET antagonist and that RET inactivation by IGSF10 plays important roles in Ewing sarcoma growth and GnRH neuron migration.

IGSF10 is a RET antagonist regulating Ewing sarcoma growth and GnRH neuron migration

Ancient genomes from the Yellow River Bend reveal long-distance population interactions between the Central Plains, Steppe, and southern China Zou et al. report genome-wide data of 23 individuals dating to the 4th–2nd millennia BP in the Yellow River Bend. We find a significant prevalence of Yangshao-related genetic ancestry in this region and reveal an unexpected long-distance contact with the Mongolian Steppe and southern China, highlighting significant prehistoric population dynamics.

Ancient genomes from the Yellow River Bend reveal long-distance population interactions between the Central Plains, Steppe, and southern China

RNA-programmable cell-type monitoring and manipulation in the human cortex with CellREADR The study of human neural circuits has been limited by a lack of experimental tools for targeting cellular populations. Matthews et al. demonstrate the utility of CellREADR, an RNA sense-editing technology, for accessing RNA-defined cell populations and probing their microcircuit functions in ex vivo human brain tissues.

RNA-programmable cell-type monitoring and manipulation in the human cortex with CellREADR

Dual targeting of transferrin receptor and CD98hc enhances brain exposure of large molecules Wells et al. developed a dual-targeting transport vehicle binding both transferrin receptor and CD98hc, two proteins highly expressed at the blood-brain barrier. Through affinity tuning, the authors demonstrated that brain concentration, kinetics, and cellular distribution can be modulated, offering a versatile platform for CNS delivery of biotherapeutics.

Dual targeting of transferrin receptor and CD98hc enhances brain exposure of large molecules

Structure of a SARS-CoV-2 spike S2 subunit in a pre-fusion, open conformation Olmedillas, Rajamanickam et al. stabilize a SARS-CoV-2 spike S2 subunit to remain pre-fusion in the absence of S1. Antibodies from survivors and vaccinees recognize stabilized S2 and full spike alike and yielded a high-resolution cryo-EM structure of pre-fusion S2 in an “open” conformation reminiscent of previously proposed “breathing” adjustments.

Structure of a SARS-CoV-2 spike S2 subunit in a pre-fusion, open conformation

Synaptic and intrinsic plasticity mediated by CCK-type signaling coordinates behavioral changes during motivational state shifts Zhang et al. employed multidisciplinary approaches to comprehensively characterize cholecystokinin (CCK)-type signaling in the nervous system and gut of the mollusk Aplysia californica, revealing that CCK functions as a brain-gut peptide regulating satiety, analogous to its role in mammals. Tellingly, these effects are mediated through both synaptic and intrinsic plasticity mechanisms.

Synaptic and intrinsic plasticity mediated by CCK-type signaling coordinates behavioral changes during motivational state shifts

Members of the MYB68 subclade orchestrate cork differentiation by regulating stem cell proliferation and suberin deposition Molina et al. show that transcription factors of the MYB68 subclade promote cork differentiation in the Arabidopsis root. On the one hand, they activate suberin biosynthesis and polymerizing enzymes; on the other hand, they repress cork cambium proliferation by interfering with the function of WOX4 and BP.

Members of the MYB68 subclade orchestrate cork differentiation by regulating stem cell proliferation and suberin deposition

The void and the brain Blackburne et al. track the electroencephalogram activity of volunteers inhaling a high dose of the powerful psychedelic 5-methoxy-N,N-dimethyltryptamine, revealing profoundly slowed-down brain activity but no significant reduction of alpha band power that is typical of other psychedelics.

The void and the brain

Opsin 5 mediates violet light-accelerated wound healing in mammalian corneas Díaz et al. demonstrate that mechanical injury to the surface of the cornea induces temporary expression of an opsin photoreceptor, Opn5, in mice and primates. The induction of this photoreceptor is associated with accelerated healing in the presence of violet light.

Opsin 5 mediates violet light-accelerated wound healing in mammalian corneas

Complex slow waves in the human brain under 5-MeO-DMT Blackburne et al. show how the psychedelic drug 5-MeO-DMT affects the human brain. The authors report changes in the spatiotemporal organization of slow waves and find that 5-MeO-DMT pushes human brain dynamics toward a low-dimensional steady state on a steepened energy landscape.

Complex slow waves in the human brain under 5-MeO-DMT

Immune signaling mediates stromal changes to support epithelial reprogramming in celiac duodenum Richards et al. provide a comprehensive scRNA-seq characterization of the celiac duodenum, highlighting a role for T-myeloid-stromal-epithelial cell communication in response to gluten ingestion.

Immune signaling mediates stromal changes to support epithelial reprogramming in celiac duodenum

Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis Nuyttens et al. demonstrate that sepsis-associated hyperlactatemia results from impaired mitochondrial pyruvate metabolism. While MPC and PCX remain functional, thiamine deficiency suppresses PDC activity. Septic mitochondria do enhance GPT2 activity to consume some pyruvate and to induce glutamate-mediated TCA anaplerosis. Thiamine pyrophosphate (TPP) restores pyruvate oxidation, allowing a synergistic TPP-plus-glucose therapy.

Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis

Antibiotic perturbation of the human gut phageome preserves its individuality and promotes blooms of virulent phages Antibiotic-induced disruption of the gut microbiome leads to a transient loss of microbiome diversity (bacterial and viral) and causes blooms of bacteria and their viruses. Our analysis suggests that these viruses (phages) prey on bacteria that become dominant, thereby preventing their dominance and contributing to the recovery of microbiome balance.

Antibiotic perturbation of the human gut phageome preserves its individuality and promotes blooms of virulent phages

Effective cerebellar neuroprosthetic control after stroke Rangwani et al. show that rats can control an external device using cerebellar activity, even after stroke. The team found that stroke-affected rats learned this cerebellum driven brain-machine interface task as efficiently as healthy animals using motor cortex or cerebellum neural activity.

Effective cerebellar neuroprosthetic control after stroke

PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson’s disease Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking; LRRK2-activating mutations are linked to Parkinson’s disease. Chiang et al. reveal that PPM1M reverses Rab phosphorylation in vitro and in vivo, and a rare inactivating mutation is ∼6-fold enriched in people with Parkinson’s disease.

PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson’s disease

The antigen presentation landscape of cytokine-stressed human pancreatic islets Nanaware et al. characterize peptides presented by MHC proteins in inflamed human pancreatic islets and test them for reactivity with CD4 and CD8 T cells from patients with T1D. These results identify naturally processed islet peptides targeted by autoimmune T cells and highlight pathways that generate immune epitopes in disease.

The antigen presentation landscape of cytokine-stressed human pancreatic islets

Coordinated expression of retained introns and poison exons in renal cell carcinoma Martínez et al. identify a set of ccRCC tumors with high levels of intron retention (IR) and poison exon (PE) inclusion, producing transcripts normally targeted by the NMD pathway. These tumors have altered mTOR signaling, are associated with poor prognosis, and have unique signatures of immune cell infiltration.

Coordinated expression of retained introns and poison exons in renal cell carcinoma

An SRRM3-regulated neural alternative splicing program is subverted to promote tumor progression in pancreatic neuroendocrine cells Potiri et al. uncover how the splicing factor SRRM3 drives tumor progression in pancreatic neuroendocrine tumors (PanNETs) via neural microexon inclusion. Aberrant splicing disrupts insulin secretion and calcium signaling, revealing a novel link between neuroendocrine dysfunction and cancer. Therapeutic redirection using splice-switching ASOs can effectively impair tumor growth in preclinical models.

An SRRM3-regulated neural alternative splicing program is subverted to promote tumor progression in pancreatic neuroendocrine cells

Single-nucleus neuronal transcriptional profiling of male C. elegans uncovers regulators of sex-specific and sex-shared behaviors Morillo et al. generated a single-nucleus RNA sequencing atlas of adult Caenorhabditis elegans male neurons. Compared with hermaphrodite neurons, they identified neuronal markers, sex-biased features, and regulators of male-specific behavior. These data expand the transcriptional landscape of the C. elegans nervous system, providing a foundation for studies on sex differences.

Single-nucleus neuronal transcriptional profiling of male C. elegans uncovers regulators of sex-specific and sex-shared behaviors

Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence Wei et al. demonstrate that a ketogenic diet induces oxidative stress and cellular senescence in an estrogen-dependent manner, with effects seen in male, but not female, mice. A similar response was observed with a high-fat diet, suggesting that elevated fatty acid oxidation may contribute to senescence under specific metabolic conditions.

Divergent sex-specific effects on a ketogenic diet: Male, but not female, mice exhibit oxidative stress and cellular senescence

Epistasis in the receptor-binding domain of contemporary H3N2 viruses that reverted to bind sialylated di-LacNAc repeats Liang et al. shows how contemporary H3N2 viruses reverted to bind sialylated di-LacNAc at the molecular level. Using complex symmetrical and asymmetric N-glycans, major epistatic interactions were revealed.

Epistasis in the receptor-binding domain of contemporary H3N2 viruses that reverted to bind sialylated di-LacNAc repeats