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PPARγ regulates glucose and lipid metabolism, yet safer PPARγ-targeted insulin sensitizers are needed to treat metabolic disorders. Here, Kuang-Ting et al. elucidate structure–function relationships of non-covalent inverse agonists that enhance receptor binding and improve insulin sensitivity, providing a framework for next-generation drug design.

Lee et al. show that the development of the somatotopic map and the tonotopic map for substrate vibration is shaped by the intrinsic distribution of cutaneous end organs and selective dendritic integration within the brainstem dorsal column nuclei.

CPEB4 binds the mRNA of genes known to be associated with autism and shows an isoform imbalance in individuals with autism, and an equivalent imbalance in mice induces an autism-like phenotype.

In bacteria Zn2+-dependent deacylases are underexplored. Here, the authors identify bacterial deacylases, providing systemic structure-function analyses to reveal the basis of substrate specificity, acyl-chain preference and inhibition.

This study reveals an important chondrocytic progenitor population for maintenance of adult articular cartilage marked by Gremlin 1. Loss of these progenitors causes osteoarthritis and suggests methods to sustain them may be effective future targets for management of osteoarthritis.

Using a 3-D neural platform, the authors show that a ubiquitin variant is sufficient to induce Alzheimer’s disease-like pathology in human neurons. Suppressing expression of this variant improved pathology in neurons carrying familial mutations.

Activity recognition in live-cell imaging is laborious. Here, authors present, IVEA, a fully automated AI ImageJ plugin, that efficiently detects and classifies exocytosis events, from synaptic transmission to single-vesicle fusion, across cell types and imaging setups.

The paenilamicins are hybrid nonribosomal peptide–polyketide compounds that inhibit protein synthesis. Here the authors reveal that paenilamicins bind to a unique site on the ribosome, where they interfere with the translocation of mRNA and tRNAs during elongation.

Only praziquantel is available for treating schistosomiasis, a disease affecting >200 million people. Here, the authors identify compounds active against schistosome infections meeting the criteria for lead progression indicated by WHO with better activity against juvenile worms than praziquantel.

Adipose tissue accommodates large volume changes upon expansion, but the molecular mechanisms involved are not fully understood. Here, Aboy et al. describe CAV1 Y14 phosphorylation as required for appropriate adipocyte caveolae flattening and homeostasis.

Krastev et al. report that trapped PARP1 undergoes SUMOylation, followed by ubiquitylation, resulting in the recruitment of the p97 ATPase to remove trapped PARP1 from chromatin and prevent PARP inhibitor-induced cytotoxicity.

Reduced fitness of the tumor microenvironment is mediated by a long non-coding RNA expressed in tumors.

Chemical language models are deep learning models trained with molecules in string representation. They enable data-driven de novo design of molecules with tailored features. Here, the authors used chemical language models to design multi-target ligands.

CTCF mediates DNA–DNA interactions by forming dimers that directly bind to both sides of the DNA. Here the authors reveal that a CTCF known associated zinc finger, ZNF143, mediates gene transcription through CTCF–DNA binding to maintain murine hematopoietic stem and progenitor cell integrity.

In this work, the authors compile a chemogenomics library for NR1 nuclear hormone receptors to advance studies on unexplored therapeutic potential of these transcription factors. Its application in phenotypic settings revealed NR1 involvement in autophagy.

In this work, a nanobody based intermolecular strain sensor was used to follow the mechanical strain in the nuclear lamina. The results indicate that mechanical state of the nuclear lamina is not only affected by the cell contractility, but also chromatin packing.

OPA1 regulates the formation of the distinct mitochondrial morphology observed in T helper 17 cells, which influences cytokine expression via LKB1.

p53 regulates signalling pathways involved in metabolic homeostasis. Here the authors show that O-GlcNAcylation of p53 in the liver plays a key role in the physiological regulation of glucose homeostasis, potentially via controlling the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase.

MISCOs are spatially arranged ventral midbrain–striatum–cortical organoids that enable investigations into the human dopaminergic system.

MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.

Cox and colleagues develop PXS-5505, a first-in-class selective pan-lysyl oxidase inhibitor and show that it reduces chemotherapy-induced desmoplasia and stiffness, thereby improving chemotherapy response and survival in pancreatic cancer models.

Imaging mass cytometry is used to map the multicellular dynamics of immune checkpoint blockade-treated triple-negative breast cancer, finding that key proliferative fractions and cell–cell interactions drive response, and immunotherapy distinctively remodels tumour structure.

The ligand-activated transcription factor farnesoid X receptor (FXR) acts as a cellular sensor for bile acids and is of interest as a drug target. Here the authors employ X-ray crystallography and NMR to characterize the molecular determinants of FXR agonists, antagonists and a partial agonist that drive FXR activation and antagonism.

Male and female mice need to generate spatial maps that integrate vomeronasal signals of territory owners in the hippocampus-dependent memory. The authors show that vomeronasal information influences learning-related activity in the hippocampus via the amygdaloid PMCo, lateral entorhinal cortex, and dorsal CA1.

Study of macrophage heterogeneity in human hearts reveals a subset of inflammatory macrophages that is associated with cardiac dysfunction in patients with heart failure.

Multivesicular bodies (MVB) are endosomal compartments that can either fuse with the plasma membrane for the secretion of exosomes, or fuse with the lysosome and be degraded along with their contents. Here, the authors show that ISGylation of the MVB protein TSG101 impairs exosome secretion and acts as a regulator of MVB fate.

Human NR3 nuclear receptors translate steroid hormone signals in transcriptomic responses and serve as invaluable drug targets, however, their therapeutic potential remains underexplored. Here, the authors report a chemogenomics library of NR3 ligands to reveal elusive effects of NR3 receptor modulation in phenotypic settings, revealing potential NR3-mediated effects in endoplasmic reticulum stress and providing proof-of-concept for its suitability to correlate phenotypic outcomes with molecular targets.

The LHCb experiment at CERN has observed significant asymmetries between the decay rates of the beauty baryon and its CP-conjugated antibaryon, thus demonstrating CP violation in baryon decays.

NOT4 proteins associate with ribosomes and are required for co-translational quality control in yeast and animals. Here, Bailey et al. show that Arabidopsis NOT4A positively regulates the expression of the nuclear encoded pentatricopeptide repeat (PPR) protein PGR3 and is required for ribosome biogenesis and mRNA translation in the chloroplast.

A large-scale, five-year study in Indonesia finds that enriching oil palm-dominated landscapes with patches of trees bolsters biodiversity and ecosystem functioning without impairing oil palm yields but should not replace forest protection.

Iminophosphoranomethanide ligands have been used to stabilize metal complexes, but their application as alkyl precursors in deprotonation reactions remains unexplored. Here, the authors prepare and characterize bis- and tris- methanide alkaline and rare earth complexes through protonolysis between dibenzyl metal precursors and the CH₂(SiMe₃)P(Ph)₂ = NSiMe₃ proligand or salt elimination reactions, and show that rare earth methanides can be used as synthetic precursors for the preparation of solvent-free complexes.

The use of data-driven generative models for drug design is challenging due to the scarcity of data. Here, the authors introduce a “zero-shot" generative deep model to enable the generation of molecules by both structure- and ligand-based drug design and apply it to design PPARγ agonists with desired properties.

WISH-tags can be used in combination with quantitative polymerase chain reaction or next-generation sequencing to decipher population dynamics at the strain level within plant and mammalian microbiotas.

With the aid of deep learning, the space of chemical molecules, such as candidates for drugs, can be constrained to find new bioactive molecules. A new open source tool can generate libraries of novel molecules with user defined properties.

The factors that are associated with myeloma precursor condition progression are not well understood. Here the authors find that monoclonal gammopathies of undetermined significance and smoldering myelomas that did not progress to multiple myelomas have a distinct genomic profile and emerge later in the patient’s life.

Wherry and colleagues define the kinetics of vaccine-primed recall immune responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection, highlighting rapid activation of memory T cells and broadly enhanced immune responses in previously vaccinated individuals.

Artificial intelligence approaches can aid medicinal chemists to creatively look for new chemical entities with drug-like properties. A rule-based approach combined with a machine learning model was trained on successful synthetic routes described in chemical patent literature. This process produced computer-generated compounds that mimic known medicines.

Nuclear receptor related 1 (Nurr1) is a promising target for neuroprotection in diseases like Parkinson’s and Alzheimer’s, yet its activation mechanism by synthetic ligands remains unclear. Here, the authors elucidate Nurr1’s activation by vidofludimus, revealing its allosteric binding site and developing a more potent Nurr1 agonist, advancing rational drug design.

Simultaneous activation of Wnt and Shh pathways in murine neural precursor cells results in the formation of embryonal tumors with multilayered rosettes (ETMR) that recapitulate the histological and molecular features of human tumors. This novel mouse model represents a platform for evaluating therapeutic approaches for this rare malignant pediatric brain tumor, and provides novel insights into the cell of origin and molecular mechanisms driving the disease.