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A natural solution from caterpillar cuticles for flexible impact-resistant materials

Reply to: “Is Dual-Checkpoint Blockade Beneficial Beyond Prolonging Chemoradiotherapy-to-Surgery Interval in Rectal Cancer?” and “Dual Immunotherapy in the Neoadjuvant Interval for Locally Advanced Rectal Cancer: A New Hope?”

Cost-effective abatement of industrial sources of nitrous oxide with methane for urgent climate mitigation

AAML1831: A Phase III Trial Comparing Standard Induction Therapy With CPX-351 in De Novo Pediatric AML: A Report From the Children's Oncology Group

PURPOSE The Children's Oncology Group phase III clinical trial AAML1831 (ClinicalTrials.gov identifier: NCT04293562 ) evaluated liposomal daunorubicin and cytarabine (CPX-351) versus standard daunorubicin/cytarabine (DA) induction therapy in children and young adults with newly diagnosed AML. We hypothesized that CPX-351 given during induction 1 and 2 would improve outcomes compared with DA. PATIENTS AND METHODS Patients (21 years and younger) were randomly assigned to two cycles of DA induction (arm A = DA) or CPX-351 (arm B = CPX-351). All patients also received gemtuzumab ozogamicin in induction 1. Postinduction chemotherapy was according to risk assignment made at the end of induction 1 (EOI1). Those with high-risk (HR) AML received consolidation with allogeneic hematopoietic stem-cell transplantation (HSCT), whereas low-risk (LR) patients received chemotherapy alone. Protocol-specified interim analysis monitored efficacy and futility of CPX-351 induction with respect to the primary end point, event-free survival (EFS) from study entry. Disease-free survival (DFS) was calculated to determine the impact of EOI1 risk assignment. RESULTS Seven hundred twenty-one eligible patients with FLT3 wild-type AML were randomly assigned to DA (n = 358) or CPX-351 (n = 363). Interim analysis determined that the futility monitoring rule was crossed because of inferior EFS in the CPX-351 arm and the random assignment was stopped. The two-year EFS from study entry was 62.2% for DA versus 51.2% for CPX-351 ( P = .011). DFS for patients with HR AML was comparable for both arms. However, DFS was significantly lower and cumulative incidence of relapse (CIR) was higher for LR patients assigned to CPX-351 versus DA (2-year DFS from EOI1: DA: 73.8% v CPX-351 57.5% [ P = .001]; 2-year CIR Arm DA: 23.6% v CPX-351: 39.9% [ P = .001]). CONCLUSION CPX-351 was inferior to DA induction in the AAML1831 trial with differential EFS largely driven by events in LR patients.

Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis

Abstract Autoimmune thyroiditis arises from disrupted homeostasis of thyroid follicular epithelial cells and coordinated immune cell activation within the microenvironment. However, its pathogenesis is not fully understood. Here, we identify a mitochondrial (mt) DNA-cGAS-STING inflammatory axis as a driver of autoimmune thyroiditis in mice. By contrast, ubiquitin-dependent mitophagy mediated by PINK1 and Parkin was found to protect mice from disease. Mechanistically, mitochondrial dysfunction elevates mitochondrial reactive oxygen species levels, activating the ATM-CHK2 DNA damage response pathway, which in turn phosphorylates the autophagy adapter TAX1BP1 at Ser722. This modification promotes the recruitment of mitochondria to autophagosomes, thereby facilitating mitophagy. Impairing the ATM-CHK2-TAX1BP1 mitophagy pathway causes mtDNA leakage into the cytosol and triggers cGAS-STING-dependent inflammation. Notably, pharmacological inhibition of STING with C176 effectively slows autoimmune thyroiditis progression. Together, these findings define an mtDNA-driven pathogenic mechanism in autoimmune thyroiditis and identify STING as a potential therapeutic target.

Dielectric stacking-engineered scalable reconfigurable transistor platform for adaptive logic circuits

Abstract Although reconfigurable van der Waals devices featuring flexible logic transformation offer a promising strategy toward adaptable architectures to accommodate diverse computational demands, reliable polarity control and scalable integration remain challenging. Here, we demonstrate a reconfigurable field-effect transistor based on the scalable dielectric oxide-van der Waals quasi-floating-gate configuration, enabling nonvolatile polarity switching and multi-state programmability. Charge trapping engineering in an atomic-layer Al 2 O 3 /HfO 2 /Al 2 O 3 dielectric stack achieves performance with nonvolatile conductance update (>6-bits for 1000 s), robust endurance (>3 × 10 5 cycles), and well-balanced electron/hole transport (current mismatch ratio ~ 1%). TCAD simulation and surface potential analysis reveal oxygen vacancies-dominated polarity switching dynamics. Using a silicon-compatible top-gate dielectric process and complementary design, diverse logic gates—including eight Boolean operations and seamless AND-OR-Invert/OR-AND-Invert transformations—are accommodated into compact reconfigurable logic-in-memory circuits. These transistors also simplify ternary content-addressable memory design, underscoring their potential for efficient logic-in-memory computing.

Nickel catalysis enables chemoselectivity in radiation chemistry

A benchmark study of vision and pathology foundation models for computational pathology

JN.1-adapted vaccination is associated with readjustment of ancestral memory B cells toward neutralization within the JN.1 antigenic space

Abstract The antigenic drift of SARS-CoV-2 toward the JN.1 lineage has prompted the development of variant-adapted COVID-19 booster vaccines. However, these boosters are thought to primarily recall pre-existing memory B cells (MBC), raising concerns about their ability to realign the immune response in highly pre-exposed populations. Here we analyze antibody and B cell responses in pre-exposed individuals ( n  = 42; median 4.5 prior COVID-19 vaccinations; 90% with at least one prior SARS-CoV-2 infection) following vaccination with a JN.1-adapted mRNA vaccine. Vaccination is associated with increased IgG binding and enhanced neutralization of JN.1 and related descendant variants. Longitudinal profiling of antigen-specific MBC shows that Wu01-only and Wu01/JN.1 cross-reactive cells remain dominant, while JN.1-only cells modestly increase by day 21. Single-cell RNA-sequencing of antigen-specific MBC in a representative sub-cohort ( n  =  7 ), combined with functional monoclonal antibody analyses, demonstrates that somatic hypermutation (SHM) drives intra-clonotype specialization toward improved JN.1 binding and neutralization. These findings indicate maturation of pre-existing, class-switched MBC rather than substantial de novo recruitment of naïve B cells. In conclusion, JN.1-adapted booster vaccination is associated with refinement of pre-existing MBC repertoires toward the JN.1 antigenic space and with enhanced neutralization of contemporary and antigenically proximate variants.

The BRCT domain enhances DNA binding and catalytic efficiency of fungal PARPs

Abstract Aspergillus fumigatus infections are a major yet often neglected global health challenge magnified by a growing at-risk population, limited treatment options, and the emergence of drug-resistant strains. Regulation of the DNA damage response (DDR) by ADP-ribosylation signalling has recently emerged as an important feature of fungal pathogenesis, but the underlying mechanisms remain largely elusive. Here we present a comprehensive phylogenetic and functional characterisation of Af -PARP1, the A. fumigatus PARP homologue. Our data reveal Af -PARP1 as a DNA-dependent poly(ADP-ribosyl)transferase with unique domain architecture, DNA damage selectivity, and activation dynamics distinct from its mammalian and plant homologues. We show that the fungal specific BRCT domain plays a crucial role in both damage recognition and ADP-ribosylation signal establishment. Collectively, our findings reveal a divergence in DDR-associated ADP-ribosylation specific to fungi, highlighting the potential of this signalling pathway as target for antifungal therapy.

CDC7 and APC/CCdh1 gate distinct routes to initiate DNA replication

Structural insights into ligand recognition and activation of the human oxoglutarate receptor OXGR1

Transcript-aware rare genetic variant association analyses of cardiopulmonary traits in participants from the All of Us Research Program

IFI208, an interferon-stimulated gene, promotes host antiviral responses through liquid-liquid phase separation of MDA5

Cryo-EM structures of biopsy-derived TTR fibrils in hereditary transthyretin amyloidosis

Abstract Hereditary transthyretin amyloidosis (ATTRv) is a fatal autosomal dominant disease characterized by systemic deposition of transthyretin (TTR) amyloid fibrils, leading to progressive neuropathy and cardiomyopathy. More than 130 pathogenic mutations in the TTR gene have been identified, but their roles in TTR fibril formation and disease pathogenesis remain unclear. Here, using cryo-electron microscopy (cryo-EM), we present nineteen high-resolution TTR fibril structures (1.9-3.4 Å) from gastrocnemius muscle biopsies and vitreous humor of ten living ATTRv patients carrying nine distinct heterozygous mutations. Deep-learning-based analysis of cryo-EM densities enables semi-quantitative assessment of mutant or wild-type dominance within fibrils. These compositional profiles, combined with their structures, suggest an association between disease onset and the TTR species (wild-type or mutant) that primarily initiates amyloid formation. This biopsy-based workflow broadens access to patient tissue for amyloid structural studies, enabling systematic investigation of heterogeneous hereditary amyloidoses and the role of mutations in amyloid formation.

Leiomodin2 is a polymerase at the pointed ends of actin filaments

RETROFIT: Reference-free deconvolution of cell-type mixtures in spatial transcriptomics

MRD dynamics predicts progression and reveals a vulnerable state for immunotherapy interception in multiple myeloma

The clinical significance of one or two measurable residual disease (MRD) assessments is established in multiple myeloma (MM). However, how to stratify patients according to ≥3 MRD assessments remains unknown. The traits of MRD resistance and if treatment of persistent MRD vs relapse could improve outcomes also remains unknown. MRD dynamics were computed using next-generation flow cytometry and Connector in 539 newly-diagnosed MM patients with ≥3 assessments in the GEM2012MENOS65/GEM2014MAIN and GEM2017FIT trials. Molecular and immune profiling were performed in matched diagnostic and MRD samples. The survival impact of treating persistent MRD vs relapse was investigated with anti-BCMA CAR T cells in MIcγ1huCRBN mice. Computed MRD dynamics based on 3,610 MRD assessments identified five subgroups with different survival. Patients with late-sustained MRD response had excellent outcomes, similar to those with early-sustained MRD response. Patients with volatile results and those with primarily and resurgent MRD resistance had dismal survival. MRD dynamics outperformed transplant-eligibility and the R-ISS. These results were validated in 249 MM patients treated in routine practice. Multiomics characterization of MRD dynamics in patients and mouse models of MRD resistance revealed genomic evolution, transcriptional adaption and a pro-inflammatory tumor-immune microenvironment. Increasing clonality and exhaustion of endogenous T cells throughout disease progression urged investigating if MRD interception with anti-BCMA CAR-T cells could improve outcomes. Infusion at MRD resistance prolonged mouse survival compared to identical treatment at relapse. Altogether, MRD dynamics is the strongest predictor of progression and may help tailoring treatment to prevent additional tumor and immune alterations prior to relapse.

Loss of Nemp1 disrupts female meiosis and activates a conserved ATM-CHK2 checkpoint

Factor V is an anticoagulant of the extrinsic pathway of coagulation and modifier of thrombin generation in hemophilia A

Factor V (FV) links procoagulant amplification to anticoagulant feedback, but how FV limits tissue factor-initiated coagulation are not fully defined. We hypothesized that procofactor FV downregulates factor X (FX) activation by tissue factor:factor VIIa (TF:FVIIa), independently of tissue factor pathway inhibitor α (TFPIα), and that this mechanism is especially important in hemophilia. Thrombin generation was measured in FV/FVIII‑immunodepleted plasma and synthetic plasma while titrating FV, with TFPIα removed, blocked, or re-added. TF:FVIIa activation of FX was measured on phosphatidylserine‑containing or phosphatidylserine‑free liposomes with antibodies against the FV light chain and C2 domain. FV and TFPIα levels modulated thrombin generation in plasma from people with hemophilia A. In TF‑initiated coagulation lacking TFPIα, thrombin generation peaked at 2 nM FV and decreased as FV increased; at 20 nM FV (normal concentration), peak thrombin and thrombin generation rate were reduced by up to 50-80%, with larger effects at low FVIII. In purified TF:FVIIa assays, FV reduced FX activation by ~80% at physiologic concentration and inhibited FX activation on TF-expressing fibroblasts. Increasing PS content enhanced FX activation and increased the FV-sensitive component, while blocking the FV light chain or C2 domain partially relieved inhibition. In hemophilia A plasma, higher FV was associated with longer lag time and time-to-peak, and lower peak thrombin independent of TFPIα. Thus, FV is an endogenous anticoagulant that inhibits TF-initiated coagulation by limiting FX activation by TF:FVIIa through a membrane-dependent mechanism. This mechanism refines models of coagulation initiation and may help explain how FV variation contributes to bleeding and thrombosis.