Browse Articles

Structure-based scaffold hopping reveals strategies to overcome oncogenic KIT and PDGFRA mutation-driven drug-resistance in GIST

Abstract Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Current tyrosine kinase inhibitors (TKIs) targeting oncogenic KIT and PDGFRA have improved patient outcomes, yet off-target toxicities and drug resistance mutations remain major clinical challenges. Many approved TKIs, often repurposed from other cancer indications, harbor diverse hinge-binding motifs that limit activity against resistance mutations clustering in the ATP-binding pocket of the kinase domain. Here, we describe a structure-based scaffold-hopping strategy to design kinase inhibitors with selectivity for mutant KIT/PDGFRA. Using structure-activity relationship (SAR) studies and 14 determined co-crystal structures, including a structure of the PDGFRA-G680R solvent-front mutation, we define key molecular interactions underlying resistance and inhibitor selectivity. Our lead 6,7-quinazoline-based inhibitors show high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling. These compounds provide selective chemical tools to interrogate resistance mechanisms, and the PDGFRA-G680R structure shows the molecular basis for targeting solvent-front mutations across oncogenic kinases.

Ribosomal architecture and rRNA modification landscape in the tick-borne parasite Babesia divergens

Abstract Babesia are tick-borne intracellular apicomplexan parasites that infect a wide range of wild and domestic animals (e.g., cattle), resulting in significant economic losses to the livestock industry. Humans are considered accidental hosts for a few Babesia species. Babesia microti and B. divergens are the most prevalent causes of human babesiosis that are showing a broadening geographic distribution. Due to the complex life cycle of Babesia species, their survival depends on the precise control of gene expression, which is primarily regulated by epigenetic, transcriptional, and post-transcriptional mechanisms. High-resolution structural information on key components of the translation machinery, such as ribosomes, could aid in the development of antiparasitic drugs. Here, we report cryogenic electron microscopy ribosome structures from B. divergens , showing associated tRNAs, an mRNA fragment, and RACK1, a signaling scaffold crucial to translation regulation. Density map analysis displays ribosome regions at high resolution, which, when combined with nanopore sequencing, enabled the comprehensive identification of rRNA modifications. The rRNA modifications localize not only to the reduced B. divergens rRNA expansion segments but also to functionally essential ribosomal sites.

α-Synuclein blocks endoplasmic reticulum co-translational protein translocation early in Parkinson’s disease

Abstract The primary mechanism and subcellular localisation of α-synuclein toxicity in Parkinson’s disease pathogenesis remain unknown. We spatially and temporally resolved proteomic and transcriptomic changes in human iPSC-derived dopaminergic neurons with increasing burden of pathological α-synuclein. We found that misfolded α-synuclein proteoforms, signified by the formation of nanoscale intraneuronal puncta, are associated with impaired translocon function at the endoplasmic reticulum (ER). We show that α-synuclein interacts with Sec61A in iPSC-derived dopaminergic neurons and in post-mortem brain tissue from patients with Parkinson’s disease. This interaction interferes with the co-translational translocation of ER-processed proteins including the vacuolar-type ATPase V0a1 subunit, glucocerebrosidase, and Cathepsin B, causing defective organelle function such as reduced lysosomal acidification, leading to increased extracellular vesicle release of α-synuclein. Defective ER-translocation was associated with increased ribosomal UFMylation and proteasomal recruitment but not activation of the unfolded protein response. Reduction of pathological α-synuclein by either CRISPRi to decrease α-synuclein expression or pharmacological activation of proteasomal degradation with repurposed drugs mitigates the ER defect. Our study offers a unifying mechanistic link between α-synuclein pathology and dysregulation of diverse organelle-associated proteins that are both Sec61A translocon substrates and genetic modifiers of Parkinson’s disease risk. Our data also provide a therapeutic rationale for proteasomal activation in early Parkinson’s disease.

Vulnerability to climate-driven pathogen-specific diarrheal diseases: secondary analysis from the Global Enteric Multicenter Study and Vaccine Impact on Diarrhea in Africa follow-up

Synergistic electronic-geometric regulation of Pt-based intermetallics resolves the activity-selectivity trade-off in borohydride oxidation

Spatially defined Rabi spectroscopy for uninterrupted optical clock interrogation

Abstract Optical lattice clocks achieve fractional frequency uncertainties of 10⁻¹⁸, yet stability is constrained by the dead time between cooling, preparation, interrogation, and detection. This sampling aliases local-oscillator noise into the clock signal (the Dick effect) and prevents continuous accumulation of oscillator phase information. We demonstrate spatially defined Rabi spectroscopy of ultracold ⁸⁸Sr atoms continuously transported in a moving optical lattice. A longitudinal excitation geometry preserves Lamb–Dicke confinement and suppresses Doppler broadening. Clock excitation is enabled only within a localised region by a transverse magnetic mixing field, defining the atom–laser interaction in space rather than in time and decoupling interrogation from preparation and detection. Transporting atoms at 16 mm s⁻¹ through a 12-mm interaction region yields a 1.2-Hz-wide spectrum close to the transit-time Fourier limit while maintaining uninterrupted atom delivery. This approach provides a practical route toward dead-time-free optical clock interrogation of continuously delivered atomic ensembles.

A critical role of the histone lysine demethylase JmjC1 in regulating severe malaria-associated virulence genes in Plasmodium falciparum

Geometric programming of asymmetric colloidal dynamics via topological defect reconfiguration

Anionic solvation reconstruction stabilizes interfacial chemistry for high-temperature and high-voltage Li metal batteries

Phosphorene dominated integrative dual-electric field guiding charge flow for vapor-fed photocatalytic hydrogen evolution

Three-site cycloadditions within one reaction intermediate with site-selectivity controlled by electronic and size bias

PPARα activation overcomes fibroinflammatory liver microenvironment-associated anti-PD-1 resistance in hepatocellular carcinoma by mediating GSDME-dependent pyroptosis

Abstract The fibroinflammatory liver microenvironment (FILM), characterized by collagen-rich stroma and immunosuppressive inflammation, is prevalent in hepatocellular carcinoma (HCC) and correlates with poor response to programmed cell death protein 1 (PD-1) blockade. Here, we show that FILM suppresses gasdermin E (GSDME)-dependent pyroptosis and promotes immune suppression and anti-PD-1 resistance. Mechanistically, FILM-associated cancer-associated fibroblasts recruit and polarize macrophages toward a nitric oxide synthase 2 (NOS2)⁺ inflammatory phenotype. NOS2+ macrophage-derived nitric oxide induces SP1 S-nitrosylation, impairs SP1 binding to the peroxisome proliferator-activated receptor alpha (PPARA) promoter and transcriptionally represses PPARA in HCC cells. PPARα downregulation reduces pyruvate dehydrogenase kinase 4 (PDK4) expression, mitochondrial reactive oxygen species production, caspase-3 activation and GSDME cleavage. Conversely, ligand activation of tumor intrinsic PPARα restores the PDK4–ROS–caspase-3–GSDME axis, enhances dendritic cell and CD8⁺ T cell activation, and sensitizes HCC to anti–PD-1 therapy. The clinically approved PPARα agonist fenofibrate enhances anti-PD-1 efficacy in HCC models in male mice and is associated with improved clinical benefit in a retrospective cohort of patients with HCC. We propose a FILM–NOS2–SP1–PPARα–PDK4 axis that controls pyroptotic immunogenicity and immunotherapy response, supporting PPARα activation as a strategy to overcome FILM-associated immune resistance in HCC.

Identifiable learning of dissipative dynamics

Stress relief principles milestoning the industrial application of lithium metal battery systems

Dynamic magnetic capture-catalytic pyrolysis for aquatic micro- and nanoplastic management

Defective indium oxide as plasmonic catalyst for efficient photo-driven methanol steam reforming

Probing the atomic dynamics of ultrafast melting with femtosecond electron diffraction

Abstract Melting is an every-day phase transition that is determined by thermodynamic parameters like temperature and pressure. In contrast, ultra-fast melting is governed by the microscopic response to a rapid energy input and, thus, can reveal the strength and dynamics of atomic bonds as well as the energy flow rate to the lattice. Accurately describing these processes remains challenging and requires detailed insights into transient states encountered. Here, we present data from femtosecond electron diffraction measurements that capture the structural evolution of copper during the ultrafast solid-to-liquid phase transformations. At absorbed energy densities 2-4 times the melting threshold, melting begins at the surface slightly below the nominal melting point followed by rapid homogeneous melting throughout the volume. Molecular dynamics simulations reproduce these observations and reveal a weak electron-lattice energy transfer rate for the given experimental conditions. Both simulations and experiments show no indications of rapid lattice collapse when its temperature surpasses proposed limits of superheating, providing evidence that the inherent dynamics limits the speed of disordering in ultrafast melting of metals.

Retraction Note: Proteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma

Cell size reduction distinctly scales spindle elongation and chromosome segregation in C. elegans

Abstract How embryos adapt their internal cellular machinery to reductions in cell size during development remains a fundamental question in cell biology. Here, we use high-resolution lattice light-sheet fluorescence microscopy and automated image analysis to quantify lineage-resolved mitotic spindle and chromosome segregation dynamics from the 2- to 64-cell stages in Caenorhabditis elegans embryos. While spindle length scales with cell size across both wild-type and size-perturbed embryos, chromosome segregation dynamics remain largely invariant, suggesting that distinct mechanisms govern these mitotic processes. Combining femtosecond laser ablation with large-scale electron tomography, we find that mid-spindle microtubules mediate chromosome segregation dynamics and remain uncoupled from cell size across all stages of early development. In contrast, spindle elongation is driven by cortically anchored motor proteins and astral microtubules, rendering it sensitive to cell size. Incorporating these experimental results into an extended stoichiometric model for both the spindle and chromosomes, we find that allowing only cell size and microtubule catastrophe rates to vary reproduces spindle pole-to-pole dynamics across development. The same model also accounts for centrosome separation and pronuclear positioning in the one-cell C. elegans embryo, spindle-length scaling across nematode species spanning ~100 million years of divergence, and spindle rotation in human cells. Thus, a unified stoichiometric framework provides a predictive, mechanistic account of spindle and nuclear dynamics across scales and species.

Exopeptidase-assisted nanopore peptide sequence identification