Physics

Next-generation selective estrogen receptor-α (ERα) antagonist/degraders (SERDs) are being developed for ER-positive breast cancer (ER⁺ BC), with intentions of improving outcomes for patients. In recent clinical trials of metastatic ER⁺ BC, next-generation SERDs demonstrated clinical activity, and elacestrant received an approval for advanced ESR1-mutant disease. However, responses to these drugs were highly heterogeneous: across trials and independent of ESR1 status, 30-50% of patients progressed by their first follow-up scan while other patients sustained benefit for 2 years or more. Here, we interrogate the basis for heterogeneous responses by comparing biopsies from non-responding patients (NR; progression-free survival <2 months) and responding patients (Resp; PFS ≥ 2 months) who received the next-generation SERD giredestrant. While Resp tumors maintain high dependency on ERα signaling, NR tumors exhibit loss of luminal lineage identity and by extension, ERα dependence. NR tumors instead up-regulate multiple ERα-independent proliferative pathways, such as EGFR/MAPK and Hippo/TEAD, which may represent targetable dependencies in NR disease. Modeling resistance and lineage plasticity in vitro, we find that giredestrant-resistant ER⁺ BC cell lines exhibit profound shifts in chromatin accessibility, with the transcription factors, FOXA1 and FOXM1, implicated in gene expression of NR-upregulated proliferative pathways.

BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), residual disease after primary surgery has limited prognostic effect in gBRCApv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival ( ≤ 3 years, n = 42). Patients with BRCA2-deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA, RAD21 and MYC amplification define BRCA2-deficient HGSC with exceptionally short survival. Patients with BRCA1-deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1-deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.

Platelets play a pivotal role in haemostasis during both external trauma and spontaneous vascular injury. Thrombocytopenia, an abnormally low platelet count caused by conditions such as autoimmune disease or chemotherapy, can lead to excessive bleeding and potentially serious medical complications. Although platelet transfusion remains the most direct and conventional treatment for thrombocytopenia, its clinical use is limited by donor scarcity and safety concerns. In this study, we developed a recombinant Fc-fusion protein composed of fibrinogen-, thrombin-, and collagen-binding modules-representing a tripartite haemostatic mechanism-derived from endogenous proteins or single-chain variable fragments. Intravenous administration of this recombinant protein significantly reduced bleeding in thrombocytopenic male mice subjected to liver laceration by targeting the injury site and promoting fibrin network formation. Importantly, the protein did not induce detectable pulmonary microthrombi and suppressed spontaneous intestinal bleeding in a chemotherapy-induced thrombocytopenic male mouse model. Taken together, these findings suggest that the recombinant protein can recruit fibrinogen and thrombin to collagen-exposed wound sites, facilitating fibrin gel formation even in the absence of platelets. Thus, it may serve as a promising alternative to conventional platelet transfusion therapy in thrombocytopenic conditions.

Superconductivity, characterized by dissipationless current flow with flux expulsion or quantization, is usually suppressed when the magnetic field or the temperature is sufficiently high. However, in rare instances, superconductivity can reappear upon increasing the temperature or magnetic field, a phenomenon known as reentrant superconductivity. It usually emerges from competing orders in strongly correlated materials. Here we demonstrate reentrant superconductivity as a function of both temperature and magnetic field, tuned by radio-frequency power in a relatively simple system: granular aluminum, which exhibits the properties of a naturally occurring Josephson junction array. At low temperatures, giant Shapiro steps emerge, exhibiting characteristics of a single Josephson junction. Coherent phase locking across the array's multiple junctions amplifies the quantized voltage, enabling tunability at radio frequencies, as observed in artificially designed Josephson arrays. We show that our system can be tuned from a coherent superconducting (stiff-phase) to an insulating (phase-fluctuating) state using radio-frequency power. We propose that radio-frequency power modulates the Josephson coupling energy, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msub><mml:mrow><mml:mi>E</mml:mi></mml:mrow><mml:mrow><mml:mi>J</mml:mi></mml:mrow></mml:msub></mml:math>. Remarkably, at elevated temperatures, the screening of the electron charge suppresses the charging energy, causing superconductivity to reappear. This many-body effect cannot be described within a single junction framework and involves many-body correlations. Our system can therefore be tuned to observe both the single-junction regime and many-body correlation effects, serving as a quantum simulator for complex phenomena in condensed matter physics.

Sleep is essential for health and regulated by genetic and environmental factors. We perform genome-wide association studies of device-measured sleep duration, efficiency, and accelerometer-derived rapid eye movement (REM) and non-rapid eye movement (NREM) sleep in 80,013 UK Biobank participants. We identify 20 autosomal loci, 12 of which have not been previously reported, including genome-wide significant associations for REM and NREM sleep duration. MEIS1 shows strong opposing effects on REM and NREM durations and is intolerant to loss-of-function mutations, suggesting an essential role in the regulation of REM/NREM sleep balance. Functional enrichment analysis identifies statistically significant pathways related to chromatin remodelling, lipid metabolism, and metal ion homeostasis while tissue enrichment analysis highlights significant signals in the hypothalamus and frontal cortex. Sex-stratified analyses identify distinct loci, including FOXP2 and NRXN3 in females and LRP1B, NPBWR2, and PABPC4 in males. Mendelian randomization supports associations between shorter sleep duration and higher cardiometabolic risk. These findings highlight sex- and phase-specific regulators of human sleep architecture, providing biological insights and potential therapeutic targets.

Understanding how urban systems and traffic dynamics co-evolve is crucial for advancing sustainable and resilient cities. However, their bidirectional causal relationships remain underexplored due to challenges of simultaneously inferring spatial heterogeneity, temporal variation, and feedback mechanisms. Here we present a spatio-temporal causality framework that bridges correlation and causation by integrating spatio-temporal weighted regression with spatio-temporal convergent cross-mapping. Characterizing cities through urban structure, form, and function, the framework uncovers bidirectional causal patterns between urban systems and traffic dynamics across 30 cities on six continents. Our findings reveal asymmetric bidirectional causality, with urban systems exerting stronger influences on traffic dynamics than the reverse in most cities. Urban form and function shape mobility more profoundly than structure, even though structure often exhibits higher correlations. This does not preclude the reversed causal direction, whereby long-established mobility patterns can also reshape the built environment over time. Finally, we identify three causal archetypes: tightly coupled, pattern-heterogeneous, and workday-attenuated, which support city-to-city learning and inform context-sensitive strategies in sustainable urban and transport planning.

Chemosynthetic symbioses enable many deep-sea animals to flourish, yet the genomic basis of ectosymbiosis in deep-sea bivalves is poorly understood. We present a chromosome-level genome for the glass scallop Catillopecten margaritatus, the only scallop known to host sulphur-oxidising bacteria on its gills. The genome comprises a conserved set of 19 chromosomes shared with common scallops, and evolutionary analyses place the lineage split in the Early Devonian, predating the establishment of ectosymbiosis. Integrating genome, gene-expression, and shell chemistry data, we identify adaptations to deep-sea life and symbiosis: loss of vision, enhanced mantle sensing, reduced shell calcification, immune mechanisms that recognise and accommodate symbionts, robust sulphide detoxification, and host provisioning of metabolites to the bacteria. The species also retains predatory feeding, indicating mixotrophy. These results clarify how this species colonised chemosynthetic habitats, broaden the spectrum of symbiotic strategies in bivalves, and provide a genomic framework for testing transitions from asymbiosis to symbiosis.

Epitaxial thin films of the lamellar transition metal dichalcogenide ${\mathrm{NiTe}}_{2}$ have been grown by molecular beam epitaxy on GaAs(111)B substrates. Using in-plane grazing-incidence x-ray diffraction measurements, we show that two distinct epilayers form during growth: (1) an epitaxial interface contact layer, with a 2D hexagonal lattice structure with in-plane lattice parameter matching the GaAs(111)B surface, and (2) the epitaxial ${\mathrm{NiTe}}_{2}$ thin film. The in-plane lattice constant of the ${\mathrm{NiTe}}_{2}$ film is observed to increase while the out-of-plane parameter decreases, both approaching their bulk values, as the film thickness increases. The interfacial contact layer is ascribed to Te atoms substituting for the upper As atoms of the GaAs(111)B (2x2) surface on exposure to Te at the onset of growth, forming a (1x1) Ga--Te hexagonal contact layer with no dangling bonds, which acts as a quasi-van der Waals substrate. We show that a similar contact layer is seen also in the growth of other Te and Se compounds. The presence of this interfacial contact layer, which seems universal for chalcogenide growth on GaAs(111)B, may have significance for understanding the electronic and optical properties of epitaxial layered materials in contact with the substrate.