Browse Articles

HER2∆16 directs luminal cell identity and estrogen receptor signaling in HER2+ breast cancer

Abstract Co-expression of the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) contributes to breast cancer heterogeneity and therapeutic resistance. However, the molecular mechanisms promoting ER positivity within HER2+ cancers remains largely unknown. Here we show, across HER2+ transgenic mouse models the oncogenic HER2 splice variant lacking exon 16 (HER2∆16) promotes the development of aggressive luminal tumors by facilitating an ER-mediated transcriptional program which is sensitive to endocrine therapies. HER2∆16 is detected across human HER2+ breast tumors and cell lines with higher levels correlating with increased expression of ER and downstream transcriptional targets. Notably, in human cell lines HER2∆16 expression is elevated upon acquired resistance to HER2-targeted therapy and can sensitize cells to the ER-antagonist tamoxifen. Overall, these findings offer valuable insights into the role of HER2∆16 in promoting luminal cell identity and estrogen receptor positivity in breast cancer, providing a useful platform to model HER2+/ER+ disease.

Deep learning completes US flood hazard maps revealing millions exposed to previously unrecognized risk

In situ iodine generation enables solution-phase polymerization of organic pollutants for continuous resource recovery from water

Systematic discovery of UFM1 receptors reveals a regulatory module in DNA repair directing non-homologous end-joining

Abstract Posttranslational modifications with ubiquitin-like modifiers (UBLs) are critical for genome maintenance, yet many remain mechanistically uncharacterised. Here, we identify UFM1 as a key regulator of non-homologous end-joining (NHEJ), a major DNA double-strand break repair pathway. Using a structure-guided chemical biology approach, we develop a photo-crosslinkable UFM1 probe and, in combination with NMR, map non-canonical UFM1-binding interfaces in core NHEJ factors, including the disordered XRCC4 tail. Mechanistically, proximity-dependent proteomics and functional assays identify Ku70 as a crucial UFMylation substrate and reveal a UFM1-dependent axis in which XRCC4 engages UFMylated Ku70 to stabilise NHEJ complex assembly on chromatin. Disruption of this molecular mechanism via UFSP2 depletion or a hypomorphic UBA5 variant in patient-derived cells impairs NHEJ function, linking UFMylation defects to compromised genome integrity processes. Our findings define a complete UFM1 signalling module in DNA repair and establish a generalisable framework for dissecting low-affinity UBL networks with broad functional and disease relevance.

Graphdiyne confined-membrane with intrinsic in-plane-pores for angstrom-scale gas sieving

Machine-learning-guided inverse design of lead-free relaxors enabled by multimodal literature mining

SMARCA4 loss reprograms p300 chromatin occupancy to subvert p53-mediated transcriptional repression in ovarian small cell carcinoma

Tumor suppressor genotype influences the extent and mode of immunosurveillance in lung cancer

Abstract The impact of cancer driving mutations on immunosurveillance throughout tumor development remains poorly understood. To better understand the contribution of tumor genotype to immunosurveillance, we generated and validated lentiviral-based vectors that create increasingly immunogenic neoantigens. This vector system is compatible with autochthonous Cre-regulated cancer models, CRISPR/Cas9-mediated somatic genome editing, and tumor barcoding. Here, we show that in the context of oncogenic KRAS-driven lung cancer and strong neoantigen expression, tumor suppressor genotype dictates the degree of immune cell recruitment, positive selection of tumors with neoantigen silencing, and tumor outgrowth. By quantifying the impact of 11 commonly inactivated tumor suppressor genes on tumor growth across neoantigenic contexts, we show that the growth-promoting effects of tumor suppressor gene inactivation correlate with increasing sensitivity to immunosurveillance. Importantly, some genotypes also dramatically changed sensitivity to immunosurveillance independently of their growth-promoting effects. We propose a model of immunoediting in which tumor suppressor gene inactivation works in tandem with neoantigen expression to shape tumor immunosurveillance and immunoediting such that the same neoantigens uniquely modulate tumor immunoediting depending on the genetic context.

A minimal chemo-mechanical Markov model for rotary catalysis of F1-ATPase

Abstract F 1 -ATPase, the catalytic domain of ATP synthase, is pivotal for mechano-chemical energy conversion in mitochondria. Aiming at a minimal yet quantitative and thermodynamically consistent model for its rotary catalysis mechanism, here we developed a chemo-mechanical Markov model incorporating essential conformational and chemical degrees of freedom. By systematically evaluating over 14,000 model variants via Bayesian inference and cross-validation, we find that a fully functional minimal model requires four functionally distinct $${\beta}$$ β -subunit conformations. Our model reconciles the decade-long bi-site versus tri-site controversy, showing that both pathways contribute depending on ATP concentration. Furthermore, our model suggests a Brownian-ratchet-like mechanism that explains the observation that one ATP hydrolysis event can trigger larger than 120º rotations, thereby explaining seemingly over 100% efficiency. Beyond this prototypic example of a complex biomolecular machine, our approach should enable one to study other enzymatic mechanisms that implement close coupling between conformational motions, substrate binding, and chemical reactions.

TASP1-mediated cleavage of REV3L enhances the activity of DNA polymerase ζ in mammalian cells

Anthraquinone‐Based Electron Reservoir‐Pump Photosensitizer Generating Radical Ion Pairs for Metabolism‐Targeted Photodynamic Therapy

ABSTRACT Type I photodynamic therapy (PDT) overcomes oxygen (O 2 ) dependence of type II PDT, but developing hypoxia‐efficient electron‐transfer photosensitizers remains challenging. Herein, we proposed an anthraquinone (AQ)‐based single‐component “electron reservoir‐pump” strategy to enhance the electron transfer ability of type I photosensitizers. In this molecular design, the AQ scaffold functioned as an intrinsic electron reservoir, while the electron‐rich tetraphenylethylene (TPE) served as an electron pump that actively donated electrons. The synergistic reservoir‐pump interaction enabled the photosensitizer AQTPE to undergo photo‐disproportionation and generate radical ion pairs: the anionic radical efficiently reduced O 2 to form superoxide (O 2 −• ), while the cationic radical oxidized key metabolic cofactor flavin adenine dinucleotide (FADH 2 ) to disrupt redox homeostasis and suppress fatty acid synthase (FASN)‐mediated metabolism. In contrast, control photosensitizers AQCN and AQNI bearing electron‐withdrawing substituents maintained singlet oxygen ( 1 O 2 ) generation. Theoretical calculations revealed that AQTPE possessed a markedly reduced singlet‐triplet energy gap (Δ E ST = 0.01 eV) and enhanced spin‐orbit coupling (7.538 cm −1 ), facilitating intersystem crossing. Notably, AQTPE nanoparticles exhibited potent type I photodynamic activity and robust tumor suppression even under hypoxic conditions. This study establishes a molecular electronegativity‐modulation framework for integrating electron reservoir‐pump systems within single‐component photosensitizers, offering a general design principle for next‐generation metabolism‐targeted and hypoxia‐tolerant photosensitizers.

‘Every box has been opened’: London botanic gardens digitizes seven million specimens

Daily briefing: Iron-Age human bones were made into tools before interment

Stereoselective Biotransformation: Transfer of Learning to Advance Drug Metabolism and Biocatalysis

ABSTRACT Chirality is an important determinant of drug action, as enantiomers can exhibit markedly different pharmacological and toxicological profiles. Although the importance of stereochemistry in drug efficacy is well established, its role in drug metabolism and disposition remains comparatively underexplored, despite the inherently stereoselective nature of drug metabolizing enzymes. Given the high prevalence of chiral drugs in clinical use and among newly approved drugs, a systematic evaluation of stereoselective drug metabolism is needed. Understanding stereoselective biotransformations has important implications for predicting drug disposition and response and may also inspire novel biocatalytic and biomimetic strategies to address challenges in enantioselective synthesis of chiral active pharmaceutical ingredients and their metabolites. In this Systematic Review, we examine current trends and practices in the investigation of stereoselectivity in drug metabolism, the key factors influencing stereoselective metabolism, and the associated challenges and opportunities. We highlight how biocatalytic approaches can improve stereoselective access to chiral metabolites, and how insights from drug metabolism and pharmacokinetics (DMPK) studies can inspire the development of novel biocatalytic and biomimetic synthesis routes. Transfer of learning and cross‑disciplinary collaboration between biocatalysis and DMPK scientists will be critical for accelerating progress in these areas and for addressing shared challenges, including stereoselectivity prediction.

Beyond the Pre‐Equilibrium Approximation: Consequences of Elementary Step (Ir)reversibility on the Mechanistic Interpretation of Tafel Slope

ABSTRACT The relationship between electrochemical potential and reaction rate—or Tafel slope—is fundamental to the study of multi‐step charge transfer reactions. However, despite its importance and ubiquitous use, Tafel slope is seldom interpreted outside of “cardinal” values. The mechanistic interpretation of cardinal Tafel slopes is predicated on the pre‐equilibrium approximation (PEA): that the path between the (catalyst) resting state and rate‐determining step is in equilibrium. This stringent approximation severely limits opportunities to elicit mechanistic information from electrochemical processes. In this Scientific Perspective, we broaden the existing framework for mechanistic interpretation of Tafel slope through a simple, universal equation that generally describes Tafel slope in terms of elementary‐step symmetry factors and approach‐to‐equilibrium (i.e., approach to PEA accuracy). The predictiveness and mechanistic utility of these theoretical developments are showcased through analysis of experimental data available in the literature for a broad range of electrochemical and thermochemical catalytic reactions, including O 2 , H 2 , Cl 2 , and CO redox. The learnings accrued in these case studies inform kinetic studies of all multi‐step charge transfer reactions and are particularly relevant for mixed‐potential‐driven mechanisms of thermochemical catalysis, which in recent years have been shown to be preponderant at metal‐liquid interfaces.

Subsurface Stabilization of Interstitial Pt Atoms on CeO ₂ (111): Rethinking Single‐Atom Catalyst Architectures

ABSTRACT Single‐atom catalysts (SACs) offer maximal efficiency by stabilizing isolated metal atoms on oxidic supports. Platinum on cerium oxide (CeO 2 ) is a key SAC system, where adsorbed CO typically exhibits red‐shifted vibrational modes due to Pt back‐donation. Using polarization‐resolved IR spectroscopy on Pt‐deposited CeO 2 (111) single‐crystal surfaces, we do not observe CO vibrational bands below 2140 cm −1 at low coverages, indicating that the surface‐bound Pt atoms are not present in detectable amounts. DFT calculations demonstrate that this unexpected observation is consistent with Pt atoms occupying buried interstitial sites. Such subsurface single‐atom sites, not considered in previous studies, are thermodynamically favored at low coverages, adopt an unusual oxidation state, and are inaccessible to direct CO binding. Our findings challenge the prevailing assumption that single atoms remain surface‐bound and highlight the critical role of subsurface interstitial species, prompting a rethinking of how active sites in single‐atom catalysts are stabilized on reducible oxides.

Automatic early detection of pathological signs following primary total hip arthroplasty using radiographs, clinical scores, and comorbidities

The growing prevalence of total hip arthroplasty (THA) revisions, along with their generally poorer outcomes compared to primary procedures, emphasizes the urgent need for early detection of primary THA failure. This study proposes a model that integrates radiographic, clinical, and comorbidity data to automatically detect pathological signs within one year after primary THA. The dataset included two independent patient cohorts: the first comprised 400 patients, leading to 801 radiographs with pathological signs and 785 without; the second included 155 patients, resulting in 417 radiographs with pathological signs and 508 without. After preprocessing, the dataset was split into training, validation, and test sets. Three models were developed, one for each data type. A deep learning framework was applied to the radiographic data, while multiple machine learning classifiers were trained on the clinical and comorbidity data. Predictive probabilities were obtained for each subset and data type, and the final combined model was generated by averaging the predicted probabilities from all individual models. The final combined model achieved an F1 score of 0.72 (95% CI: 0.65–0.79), a balanced accuracy of 0.69 (95% CI: 0.63, 0.77), and an area under the curve (AUC) of 0.72 (95% CI: 0.65, 0.79) on the internal test set. On the external validation set, it achieved an F1 score of 0.66 (95% CI: 0.62, 0.70), a balanced accuracy of 0.62 (95% CI: 0.59, 0.66), and an AUC of 0.67 (95% CI: 0.62, 0.72). The results demonstrate the potential of the developed approach to automatically detect early pathological signs of THA, enabling virtual follow-up and potentially reducing the burden on clinicians.

The time sensitivity of aspirational interventions: Evidence from a role-modeling RCT

This paper investigates the short-run effects of an aspiration-raising intervention delivered as part of a randomized controlled trial among postgraduate students at a UK university during the Covid-19 pandemic. We document suggestive evidence, that a video-based role-modeling intervention led to an immediate increase in aspirations and a delayed increase in self-reported effort. However, both effects dissipated within a few weeks. Our findings suggest that timing and reinforcement are important considerations for the sustained effectiveness of aspiration-building strategies.

Selective Hydrogenation of Formamide to Methanol Over Supported Platinum Catalysts

ABSTRACT The rising global energy demand, driven by population and economic growth, continues to be met largely by fossil fuels. Consequently, atmospheric CO 2 concentration has increased from ∼280 ppm in the pre‐industrial era to over 430 ppm today, motivating integrated capture‐and‐conversion strategies that valorize CO 2 as a feedstock. Amines are widely employed for post‐combustion CO 2 capture due to their low cost, rapid kinetics, and reversible carbamate formation. These amine–CO 2 adducts can be hydrogenated to formamides and subsequently to methanol under mild conditions (<150°C), regenerating the amine. However, selective C─N bond cleavage during the formamide hydrogenation for efficient release of methanol without sorbent deactivation remains a key challenge. Here, we demonstrate that 1 wt% Pt supported on TiO 2 (commercial P25) catalyzes the conversion of 4‐formylmorpholine to methanol with up to 62% yield and 95% selectivity at 150°C. In situ characterizations and DFT computations reveal that strong interaction between dispersed Pt and the support promotes selective C─N hydrogenolysis. The catalyst also exhibits excellent stability. These findings establish a robust heterogeneous platform for combined CO 2 capture and methanol synthesis, highlighting the critical role of support‐induced electronic effects in controlling bond scission.

Sulfur‐Directed Construction of Vinyl Cyclopropanes from 1,3‐Dienes

ABSTRACT The stereoselective cyclopropanation of 1,3‐dienes remains a long‐standing challenge in the preparation of vinyl cyclopropanes (VCPs) due to the intrinsic electronic and steric bias of the diene scaffold. We report a sulfur‐directed strategy that enables highly site‐ and diastereoselective cyclopropanation of S ‐substituted 1,3‐dienes with diazo reagents under Cu‐catalyzed reaction conditions. This unprecedented approach overrides the innate reactivity of the 1,3‐diene through a thioether‐directed reaction mode, providing rapid access to a broad library of highly functionalized S ‐VCPs obtained as single regio‐ and diastereomers. Preliminary mechanistic studies indicate a pericyclic cascade involving a 6π‐electrocyclization and a [2,3]‐sigmatropic rearrangement and postmodifications permit streamlined access to complex VCPs that remain inaccessible through conventional cyclopropanation techniques.