Epstein-Barr virus gp350 mediates viral attachment and is a leading vaccine target, yet its protective epitopes remain incompletely defined. Zhao et al. identify three distinct antibody-binding sites, including a neutralizing epitope outside the receptor-binding site, and show in vivo protection conferred by a fully human anti-gp350 monoclonal antibody.

Ye et al. describe a synthetic-lethality-analogous killing model. Shared peptide-MHC-II co-activation enables Treg perforin-granzyme B cytotoxicity; responder Bim confers susceptibility in vitro and in mouse airway inflammation.

(Cell Reports 40, 111195; August 16, 2022)

Yang et al. show that inhibiting methyl-donor metabolism enhances totipotent reprogramming by relaxing three-dimensional genome architecture. This process is accompanied by DNA hypomethylation and reduced chromatin binding of methylation-associated proteins, revealing a potential CTCF-independent mechanism linking cellular metabolism, genome organization, and cell fate.

Zhao et al. show histone lactylation drives FTO-mediated Arg1 mRNA stabilization. Lactylation controls macrophage metabolism via HIF1α/YY1 LLPS; IL-10 shapes its dual functions in hypoxic lung injury.

Lee et al. identify two functionally distinct lateral hypothalamic GABAergic ensembles. One encodes motivationally salient stimuli across appetitive and aversive contexts, while the other generalizes across feeding and drinking; the consumption-related responses scale with food value and pharmacological satiety.

Zhang et al. reveal that GC-rich α-herpesvirus genomes generate G4 structures that threaten genome stability. The study shows that viruses overcome this challenge by exploiting host ssDNA gap prevention pathways, uncovering a conserved vulnerability for antiviral intervention.

Antonini et al. show that p63 and p73 act together in cutaneous squamous cell carcinoma, co-occupying enhancers to drive a shared oncogenic program. The two factors converge on EGFR-ligand genes, with amphiregulin as a dominant mediator whose depletion impairs proliferation and tumor growth.

Zhang et al. identify transcriptional and epigenomic differences between adipocytes isolated from subjects who are insulin sensitive and insulin resistant. At one specific locus encoding an important GWAS gene for type 2 diabetes, they show that cis-regulatory regions identified in human subjects are important for gene expression.

Patai, E.Z. et al. show via analyzing spontaneous navigation behavior that humans are idiosyncratic, flexibly adapt strategies to variable degrees to achieve learning, and that strategies do not reflect trait-level characteristics. The relationship between hippocampal activity and strategy use is not linear and changes depending on Alzheimer’s disease risk.

Venegas-Molina et al. demonstrate the utility of limited proteolysis-coupled mass spectrometry (LiP-MS) for the discovery of plant metabolite-binding proteins by identifying enzymes that glycosylate the plant hormone jasmonic acid in tomato. Glycosylation leads to partial attenuation of hormone activity, indicating that these enzymes participate in jasmonic acid catabolism.

Anti-myeloperoxidase (MPO) IgG drives ANCA-associated vasculitis by activating neutrophils. Krollmann et al. demonstrate that, beyond neutrophil activation, anti-MPO IgG facilitates TLR9-dependent DNA sensing in murine GM-CSF-derived bone marrow myeloid cells and human pDCs, establishing a role for ANCAs in inducing pathogenic nucleic acid immunity.

Jain et al. demonstrate that RNA helicase DDX39A regulates α-Synuclein amyloidogenesis by unwinding RNA G-quadruplexes (rG4s) and that viral rG4s accelerate this aggregation by perturbing α-Synuclein-DDX39A interaction equilibrium. They further show that α-Synuclein reciprocally enhances DDX39A helicase activity through co-condensation, proposing a mechanistic link between viral infections and Parkinson’s disease.

Kohli et al. apply enzyme- and nutrient-constrained genome-scale modeling to more than 10,000 tumors across 28 cancer types, defining a pan-cancer metabolic-flux landscape. This analysis reveals tissue-specific metabolic adaptations and vulnerabilities, including bile acid-linked redox and lipid rewiring, renal-specific purine dependence, and flux-based survival predictors, such as biotin uptake.

Zhang et al. demonstrate that increased extracellular fluid viscosity promotes immunosuppressive M2-like macrophage polarization through integrin/FAK-STAT3 signaling and cytoskeletal remodeling. This viscosity-driven macrophage state accelerates breast cancer progression and reduces the response to anti-PD-1 immunotherapy, linking a physical property of the tumor microenvironment to immune evasion.

Mahale et al. identify MSEP, a protein encoded within the ARHGEF17-AS1 antisense locus, and show that it localizes to the mitotic spindle and supports spindle organization through a TPX2-associated pathway. The work reveals distinct RNA- and protein-associated outputs from a single bifunctional genomic locus.

Chan et al. show that individual Kenyon cell types in the Drosophila associative learning center, the mushroom body, encode odors according to different principles. Biased projection-neuron input yields food-related odor representations by αβ Kenyon cells that support the categorization of food odors in addition to their discrimination.

Lee et al. describe a condensate-based signaling mechanism regulating cell volume homeostasis. TSC22D, WNK, and NRBP proteins form dynamic condensates that modulate WNK-SPAK/OSR1 signaling. WNK-dependent phosphorylation of NRBP1 and TSC22D2 promotes pathway activation and condensate dissolution. These findings support a model where TWN bodies behave as signaling assemblies for osmo-regulation.

Sun et al. find that hypoxia-induced MCUB promotes a restricted mitochondrial Ca2+ flux state that supports metabolic adaptation and mitochondrial homeostasis in glioblastoma. Targeting MCUB-dependent calcium gating exerts antitumor effects and enhances radiosensitivity, revealing this mechanism as a potential therapeutic vulnerability.

Matrix viscoelasticity governs cardiac fibroblast-macrophage crosstalk, with soft, viscous environments amplifying profibrotic signaling through dynamic paracrine feedback. Atcha et al. examine how mechanical cues and sequential immune activation synergize to recapitulate post-infarction fibrosis, identifying cytokine networks that may serve as therapeutic targets in cardiac remodeling.

McColl et al. demonstrate that SARS-CoV-2 impairs placental iron efflux, leading to persistent iron accumulation and impaired maternal-fetal iron transfer, and activates ferroptosis signaling, which may limit viral replication. This uncovers both a novel antiviral role of ferroptosis in the placenta and a new mechanism for adverse pregnancy outcomes associated with COVID-19.

Camptothecin and its analog Topotecan drive human microglia toward a CD74high/MHChigh state with enhanced amyloid-β phagocytosis and altered inflammatory signaling. Using cell, organoid, and zebrafish models, Haage et al. link a transcriptomic microglial subtype to distinct functional properties, uncovering a pharmacological route to model microglial states implicated in neurodegeneration.

Using simultaneously recorded population spiking activity in the macaque pulvinar and early visual cortical areas V1 and V2, Xu et al. evaluate signaling motifs among these three structures. They find evidence for a relaying of signals from V1 to the pulvinar and on to V2.

Shiromoto et al. show that PIWI-interacting RNAs and TRP53 protect mouse spermatogonial stem cells from exogenous retroviral infection. Disruption of this pathway enhances viral expression and germline transmission following testicular infection, revealing a mechanism that preserves genome integrity across generations.

Alcaraz Jr. et al. show that dietary supplementation with calcium-αKG modulates lung cancer epigenetics and transcriptional programs in a sex-dependent way, resulting in reduced tumor growth in females but increased tumor growth in males.