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Siglec-glycolipid interactions are often studied outside the context of a lipid bilayer. Here, the authors combine a variety of chemical biology techniques to demonstrate a unique and physiologically relevant ability of Siglec-6 to recognize glycolipids in a membrane.

The RANK–RANKL pathway drives intestinal epithelial expansion in pregnancy and lactation.

Quantifying ecosystem dynamics is critical in the face of rapid environmental change. This study uses airborne eDNA to quantify changes in organism abundances across the tree of life and reveal a regional decline in biodiversity over three decades.

Two side-by-side papers report that H3K27me3 deposited by polycomb repressive complex 2 represents an epigenetic barrier that restricts naive human pluripotent cell differentiation into alternative lineages including trophoblasts.

Lee, Barone et al. engineered a mutant form of LSD1, Y391K, which renders the nucleosome demethylase activity of LSD1 insensitive to Lys14 acetylation of histone H3, providing a useful tool to illuminate the functional consequences of disconnecting histone modification crosstalk.

Drug resistance remains a major challenge in cancer treatment. Here, the authors identify Connexin43 as target that enhances BRAF/MEKi efficacy by interfering with DNA repair pathways, overcoming drug resistance. They develop an mRNA therapy that improves efficacy and sensitizes resistant cells.

During wound induced hair follicle neogenesis (WIHN), stem cells regenerate hair follicles but how this arises is unclear. Here, the authors show that self-noncoding dsRNA activates the antiviral receptor TLR3 to induce intrinsic retinoic acid, which stimulates WIHN in mice, and in isolated human keratinocyte cells.

Cyclin B1 is a mitotic co-factor of CDK5.

ENTRAP-seq systematically links protein sequence to transcriptional output in a native plant context.

A multimodal analysis of patients with 22 different immune-mediated monogenic diseases versus matched healthy controls leads to the development of the immune health metric, which could be implemented broadly to predict responses to aging, vaccination and other immune perturbations.

CD4⁺ T cells promote immunity to tuberculosis infection via macrophages. Here the authors show upregulation of SLAMF1/CD150 on infected macrophages after interaction with CD4⁺ T cells and that the presence of SLAMF1 promotes ROS production by macrophages and the absence of Slamf1 in macrophages results in higher mycobacterial loads in infected mice.

A pangenome of oat, assembled from 33 wild and domesticated oat lines, sheds light on the evolution and genetic diversity of this cereal crop and will aid genomics-assisted breeding to improve productivity and sustainability.

Mulholland et al. identify progenitor exhausted T cells, expressing intermediate levels of PD-1 (PD-1^int), as a prominent source of pro-inflammatory cytokines in the murine atherosclerotic aorta and potential cellular targets driving checkpoint inhibition-elicited pro-atherosclerotic immune responses. They further demonstrate elevated levels of circulating PD-1-expressing T cells in individuals with subclinical cardiovascular disease.

RNA-binding protein TDP-43 contains a region forming a dynamic α-helical multimer that accounts for its functional role, evolutionary conservation, and disruption in amyotrophic lateral sclerosis, making for a possible therapeutic target.

Studying the role of protein ubiquitination requires well-characterized ubiquitinated protein derivatives. This protocol describes a semisynthetic approach that can be used to make probes for reader proteins, deubiquitinases and ubiquitin carriers.

Cancer associated fibroblasts can shape the tumor microenvironment (TME) and modulate immune infiltration. Here the authors characterize the TME in preclinical models of softtissue sarcomas, identifying a subset of “glycolytic” cancer-associated fibroblasts that inhibit cytotoxic T cell infiltration into the tumor parenchyma.

Enzymes in the cytidine diphosphate–ethanolamine metabolic pathway, which promotes de novo synthesis of phosphatidylethanolamine, are shown to act as post-transcriptional mediators of the differentiation of T follicular helper (T_FH) cells, by regulating the chemokine receptor CXCR5.

Next generation precision lysine-specific histone demethylase 1A (LSD1) covalent inhibitors which selectively block LSD1 enzyme activity by forming a compact N-formyl-FAD adduct have been developed, but the mechanism of adduct formation was unclear. Here, the authors show that the covalent inhibitor-FAD adduct undergoes a Grob fragmentation and elucidate the structure-activity relationships that promote this transformation.

Transcriptomic analysis of BCR-ABL1 lymphoblastic leukemia identifies three subgroups, each associated with a maturation arrest at a specific stage of B-cell progenitor differentiation and distinct genetic and clinical features.

The molecular basis for the enrollment of X family DNA polymerases in non-homologous end joining (NHEJ) is unclear. Here the authors elucidate the structure of Pol λ within the DNA-PK long-range complex and Pol μ in association with Ku70/80 and characterize the interaction between the BRCT domains of Pol λ and μ with Ku70/80.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.

Defining the composition of the secretome of pyroptotic macrophages reveals the involvement of the component factors in wound healing.

Stem-like CD8⁺ T cells specific for lymphocytic choriomeningitis virus are generated early during chronic infection, suggesting that this crucial fate commitment occurs irrespective of the infection outcome.

Chromosomes are coated in proteins and RNA called the mitotic chromosome periphery. Here, broadband microrheology analysis has shown that this coat has dynamic, liquid-like properties and provides an external structural constraint.

Identification and characterization of cytoplasmic STAR protein-RNA interactions in D. melanogaster testis germ stem cells and functional impact of binding, providing new insights into the importance of RNA-protein networks during spermatogenesis.

Haploinsufficiency in three genes associated with risk of autism spectrum disorder—KMT5B, ARID1B and CHD8—in cell lines from multiple donors results in cell-type-specific asynchronous development of GABAergic neurons and cortical deep-layer excitatory projection neurons.

The control of flagellar synthesis and function in the Lyme spirochete Borrelia burgdorferi is poorly understood, as this pathogen lacks the typical flagellar sigma factor and transcriptional regulators. Here, the authors identify a broadly conserved structural flagellar component that modulates flagellar assembly and is important for cell division, motility and virulence.

The developing heart integrates several progenitor cell types. Here they show that the pericardium enveloping the heart develops among cells that form the mesothelium around inner organs and body cavities, distinct from the classic heart field.

To date, covariance of carbonate and organic carbon isotope records has been assumed to denote fidelity of the original signal. This study shows that post-depositional alteration can create strong correlations, raising doubts about the use of correlated records to imply important changes in past global carbon cycling.

PBK is a mitotic kinase implicated in cancer. This study reveals how PBK evicts key C2H2-zinc finger transcription factors such as Ikaros, Aiolos and CTCF from DNA as cells divide, regulating mitotic chromatin accessibility and chromosome compaction.

Bellaart et al. address how the ubiquitin ligase tripartite motif-containing protein 37, the gene for which is mutated in Mulibrey nanism, uses peptide motif recognition and substrate-directed oligomerization to prevent the formation of ectopic spindle poles that cause chromosome missegregation.

Polθ has been recently identified as a therapeutic target in cancer but specific inhibitors are currently unavailable. Here, the authors identify small molecule inhibitors of Polθ’s polymerase activity which elicit BRCA1/2 synthetic lethality, enhance the effect of PARP inhibitors and target PARP inhibitor resistance caused by 53BP1/Shieldin pathway defects.

The cell of origin for high-grade serous carcinoma (HGSC) remains to be determined. Here, the authors characterize the different cell types and states of the mouse uterine tube and identify transitional pre-ciliated cells as a cancer-prone cell state, which could be targeted therapeutically.

The efficacy of CAR-T cells against solid tumors is still limited by immunosuppressive factors. Here, the authors show that engineering of CAR T cells with A1R enhances their efficacy against solid tumors in vitro and in vivo.

Chan and colleagues report that tumor ecosystem and microbiome features are associated with response to anti-PD-L1 avelumab plus chemoradiotherapy in patients with locally advanced head and neck cancer.

TIRTL-seq is a high-throughput method for paired T cell receptor sequencing at the cohort scale.

This paper highlights the far-red chemigenetic H₂O₂ reporter oROS-HT₆₃₅, which enables detailed insights into intricate intracellular and intercellular H₂O₂ dynamics, along with their environmental interactants, through spatially resolved, multiplexed real-time H₂O₂ imaging.

In cancer, the impact on cellular fitness of copy-number gains affecting collaterally-amplified genes remains poorly understood compared to oncogenes. Here, the authors integrate genomic data from tumours and cell lines and identify a class of ‘Amplification-Related Gain Of Sensitivity’ (ARGOS) genes, with potential therapeutic applications.

MYCN-amplified neuroblastoma remains an aggressive childhood cancer with its core regulatory circuits less understood. Here, the authors identify that the transcriptional corepressor Runx1t1 is indispensable for MYCN-driven neuroblastoma tumorigenesis.

Around half of the heritability underpinning familial high-grade serous ovarian carcinoma remains unidentified. Here, the authors show that extremely rare protein encoding loss-of-function variants, with a high degree of genetic heterogeneity, may account for some of this missing heritability.

Mouse models of lung and colorectal cancer with sporadic DNA mismatch repair deficiency clarify that the intratumor heterogeneity and clonal architecture rather than tumor mutational burden are powerful determinants of immunotherapy response.

Serological analysis and infection outcomes of participants in the multi-center, prospectively enrolled OCTAVE cohort, comprising 2,686 participants with immune-suppressive diseases who recieved two COVID-19 vaccines, reveals specific clinical phenotypes that might benefit from specific COVID-19 therapeutic strategies.

Nociceptin is an opioid peptide regulating important brain functions, including motivation and 2stress responses. Here, the authors develop and validate a genetically encoded sensor as a tool for high-resolution detection of endogenous nociceptin in living animals.

Air surveillance offers a potential means of monitoring airborne pathogens without the need for individual sampling. Here, the authors perform continuous air sampling in 15 community settings in the US for 29 weeks and demonstrate its feasibility for routine detection of SARS-CoV-2 and other respiratory pathogens.

ABD957 is a potent and selective inhibitor of the ABHD17 family of depalmitoylases that disrupts N-Ras signaling in human acute myeloid leukemia cells and can synergize with MEK inhibition.

Khetarpal et al. show that the metabolic regulator PGC-1α is essential in heart muscle cells for exercise-driven cardiac growth, and that suppression of the stress-induced myokine GDF15 is required to enable cardiomyocyte adaptations to training.

Application of human induced pluripotent stem cells (hiPSCs) for tissue regeneration is hindered by off-target cell differentiation. Here, the authors use bulk and single cell RNA-sequencing to identify WNT and MITF as off-target hubs during chondrogenic differentiation; inhibiting these pathways enhanced homogeneity and yield.

RMC-7977, a multi-selective RAS(ON) inhibitor, exhibits potent tumour-selective activity in multiple pre-clinical models of pancreatic ductal adenocarcinoma through a combination of pharmacology and oncogene dependence.