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Recyclable thermoplastic silicone elastomers from non-carbon heteroatomic polymer backbones
Single-cell profiling of ANKRD26 thrombocytopenia reveals progenitor expansion and polyploid apoptosis via JUNB-p21
Abstract ANKRD26-related thrombocytopenia 2 (THC2) is a rare inherited platelet disorder caused by germ line variants in the 5′ untranslated region (UTR) of ANKRD26. Although prior studies using in vitro models or isolated case reports have suggested impaired megakaryopoiesis as a central mechanism, detailed insights have remained elusive, primarily due to the rarity, fragility, and heterogeneity of megakaryocytes (MKs). Here, we present a comprehensive, crossvalidated analysis of bone marrow samples from 4 independent patients with THC2, integrating single-cell transcriptomics and ex vivo functional profiling. Across all patients, we analyzed CD34+ hematopoietic stem and progenitor cells (HSPCs; 47 281 THC2 HSPCs vs 51 907 control cells) and primary MKs (pMKs; 7309 THC2 pMKs vs 5077 control cells), uncovering a consistent pattern of MK progenitors (MkP) expansion and a marked reduction in polyploid MKs, indicating a conserved pathophysiologic phenotype. In our index patient, we identified the 5′ UTR single-nucleotide variant in ANKRD26 that led to significantly elevated expression across 4 MK lineage subsets, spanning multipotent progenitors, common myeloid progenitors, MK-erythroid progenitors, and MkP as well as in terminally enriched pMKs. Confocal imaging localized ANKRD26 to the centrosome, implicating it in mitotic regulation during MK maturation. Mechanistically, we discovered that elevated ANKRD26 induces apoptosis in polyploid MKs via JUNB-mediated transcriptional activation of CDKN1A (p21), operating independently of the canonical p53-PIDDosome axis. This multipatient study provided the most comprehensive cellular and molecular portrait of ANKRD26-driven thrombocytopenia to date, offering novel insights into defective megakaryopoiesis and identifying candidate therapeutic targets to restore platelet production.
Ultra-narrow donor-acceptor nanoribbons
Abstract Donor–acceptor (D–A) architectures underpin many high-performance conjugated polymers but remain largely unexplored in atomically precise nanoribbons. Here, we report the on-surface synthesis of ultra-narrow D–A nanoribbons using two complementary brominated precursors based on the electron donor peri-xanthenoxanthene and the acceptor anthanthrone. High-resolution scanning tunnelling microscopy, non-contact atomic force microscopy and scanning tunnelling spectroscopy reveal submolecular structural and electronic features of the resulting nanoribbons. Homopolymerisation of each precursor yields structurally well-defined donor-only and acceptor-only nanoribbons, whose electronic character strengthens with length. Co-deposition of both precursors produces mixed D–A nanoribbons with tuneable electronic structures governed by monomer sequence. The spatial character and energetic alignment of their frontier orbitals match gas-phase density functional theory calculations, while a simplified linear combination of molecular orbitals model captures dominant trends. This bottom-up synthetic strategy enables precise control over nanoribbon composition and functionality, offering a versatile platform for engineering π-conjugated nanostructures with tailored optoelectronic properties.
Selective depletion of ABO-responsive B cells by T-cell–engaging bispecific antibody conjugates for ABOi transplantation
Abstract Organ transplantation is a pivotal treatment for patients with organ failure. ABO-incompatible (ABOi) transplantation, developed to expand the donor pool, presents significant clinical challenges due to preexisting antibodies targeting ABO antigens on donor organs. Current therapies using broad B-cell depletion, such as rituximab, effectively reduce antibody-mediated rejection but increase infection risks. Therefore, there is a critical need for targeted methods to specifically eliminate ABO-responsive B cells. Here, we developed a novel bispecific antibody-ligand conjugate (BiALC) platform designed to selectively target ABO-responsive B cells. Using synthetic trisaccharide A antigens conjugated to T-cell–recruiting Fab fragments, our optimized hexameric construct, (A3-peg)2-αCD3, demonstrated enhanced affinity and potent cytotoxicity specifically against type A antigen–responsive B cells. Notably, BiALC maintained robust efficacy even in the presence of circulating anti-A antibodies. In murine models, (A3-peg)2-αCD3 selectively depleted A-responsive B cells without broadly affecting total immunoglobulin M–positive (IgM+) and IgG+ B-cell populations, preserving overall immune competence. Similarly, the human-compatible BiALC, (A3-peg)2-αhCD3, effectively and selectively depleted type A–responsive B cells from human peripheral blood mononuclear cells, with potency comparable with that of rituximab, while sparing total antibody-secreting cells. Overall, the BiALC strategy offers a promising antigen-specific approach to reduce rejection risks in ABOi transplantation without inducing broad immunosuppression through nonspecific pan–B-cell depletion, supporting its potential for clinical translation.
NSF awards record number of coveted PhD fellowships in surprise move
Predicting individual differences of fear and cognitive learning and extinction
Abstract The ability to acquire new information and to modify previously learned knowledge are critical in an ever-changing world. However, the efficacy of learning is notably variable among individuals, with extinction learning being the epitome of such variability. Abundant studies have identified a core network of brain regions including the amygdala, hippocampus, dorsal anterior cingulate cortex (ACC), ventromedial prefrontal cortex (PFC) and, more recently, the cerebellum, as key players in learning and extinction. Yet, the precise interactions within this network and their relationship to individual learning abilities and extinction have remained largely unexplored. In the present study, we examined how functional (FC), effective (EC), and structural (SC) connectivity patterns in the core learning network allow the prediction of individual differences in the efficacy of learning, extinction, and renewal. Analysing a large dataset of over 500 participants across a multitude of paradigms, our results revealed that FC predicted better acquisition, with a central role of ACC and hippocampus, whereas SC, involving ACC and amygdala, predicted higher levels of extinction learning. EC results suggested a predominantly inhibitory coupling among core learning network nodes, with paradigm-specific EC connectivity patterns predicting learning. Our predictions not only generalised between fear and cognitive predictive learning paradigms but were also successful in predicting learning from task-related FC and simulated data. Together, these results describe the multimodal neural determinants of learning, extinction, and renewal, and may inform individualised interventions for affective disorders based on neural connectivity patterns.
Common variants, rare disease: new insights into AML risk
Horizontal gene transfer and diploidy illuminate evolution and stress adaptation in oleaginous Scenedesmaceae (Chlorophyta)
A phase 1/2 study of donor-derived anti-CD33 CAR T-cell therapy (VCAR33) for relapsed/refractory AML after allogeneic HCT
Abstract VCAR33, a donor-derived CD33-directed chimeric antigen receptor T-cell (CAR T) product, was developed to decrease relapse of high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (alloHCT). We describe preclinical characterization of the VCAR33 construct, which was optimized for long-term antitumor surveillance based on killing and persistence assays. Prior to its use in post-alloHCT maintenance, we evaluated safety and efficacy of VCAR33 in a phase 1/2 clinical study for adults with relapsed or measurable residual disease (MRD)–positive CD33+ AML/MDS after alloHCT. Fifteen patients received VCAR33 across 2 arms stratified by disease burden: 7 patients in arm A (bone marrow blasts ≥5%) at dose level 1 (DL1; 1 × 106 CAR+ Ts per kg) and 8 patients in arm B (bone marrow blasts <5%) at DL1 (n = 5) and DL2 (3 × 106 CAR+ Ts per kg; n = 3). The study ended for nonsafety reasons before escalation to DL3 (1 × 107 CAR+ Ts per kg) and maximum tolerated dose was not determined. The most common treatment-related adverse event was cytokine release syndrome (93.3%; all <grade 3). Four patients (26.7%) experienced immune cell–associated neurotoxicity syndrome (1 ≥grade 3) and 1 patient (6.7%) had grade 3 acute graft-versus-host disease within 28 days of VCAR33 infusion. Fourteen patients (93.3%) had transient VCAR33 expansion. Overall response rate was 20%: 2 patients had complete remission with incomplete count recovery in arm A and 1 arm B patient achieved MRD clearance. This allogeneic CAR T product demonstrated acceptable safety and preliminary antileukemic activity. This trial was registered at www.clinicaltrials.gov as #NCT05984199.
What Orbán’s fall from power means for research
HCN1 is a primary HCN Pacemaker Channel in Neurons
Abstract Rhythmic activity of specialized pacemaker neurons in the brain is necessary to control alertness and circadian timing. Four HCN channels have been identified to generate the pacemaker current I h or I q , differing in activation speed, voltage dependence, single-channel conductance, and cAMP sensitivity. Here we show the time-resolved operation of single HCN1, HCN2 and HCN4 channels during the pacemaker depolarization using a dynamic neuronal action potential clamp at femtosiemens resolution. All channels produce a relevant open probability during pacemaker depolarization. However, only mHCN1 channels are significantly activated and deactivated in action potential cycles whereas the gating in mHCN2 and mHCN4 channels is at best barely resolvable and too slow. Simulations suggest that the role of HCN1 channels is to trigger the initial neuronal pacemaker depolarization before other depolarizing conductances take over this role. In conclusion, mHCN1 channels are the primary HCN pacemaker channels that operate as trigger channels for pacemaking.
Beyond the code: noncoding splicing rewires mutant SF3B1
Genetically encoded assembly recorder temporally resolves cellular history
Abstract Cells constantly change their molecular state in response to internal and external cues 1 . Mapping cellular activity in tissues with spatiotemporal precision is essential for understanding organ physiology, pathology and regenerative processes. Current cell-sensing modalities primarily rely on either end point analysis that takes static snapshots 2 or real-time sensing that monitors a small subset of cells 3,4 . Here we introduce granularly expanding memory for intracellular narrative integration (GEMINI), an in cellulo recording platform that leverages a computationally designed protein assembly as an intracellular memory device to record the history of individual cells. GEMINI grows predictably within live cells, capturing cellular events as tree-ring-like fluorescent patterns for imaging-based retrospective readout. Absolute chronological information of activity histories is attainable with hour-level accuracy. GEMINI effectively maps differential NF-κB-mediated transcriptional changes, resolving fast dynamics of 15 min and providing quantifiable signal amplitudes. In a xenograft model, GEMINI records inflammation-induced signalling dynamics across tissue, revealing spatial heterogeneity linked to vascular density. When expressed in the mouse brain, GEMINI minimally impacts neuronal functions and can resolve both transcriptional changes and activity patterns of neurons. Together, GEMINI provides a robust and generalizable means for spatiotemporal mapping of cell dynamics underlying physiological and pathological processes in both culture and intact tissues.
Blinatumomab nonresponse correlates with poor survival after brexucabtagene autoleucel in B-cell ALL
Abstract In a real-world analysis of brexucabtagene autoleucel recipients with relapsed/refractory B-cell acute lymphoblastic leukemia (N = 278), lack of response to prior blinatumomab correlates with significantly worse following chimeric antigen receptor T-cell therapy outcomes.
Donor T cells on double duty: VCAR33 for AML after transplant
Oncogenic <i>SF3B1</i> mutations alter the splicing of mRNA noncoding regions to induce a novel therapeutic vulnerability
Abstract Oncogenic mutations of SF3B1 are common in myeloid cancers, chronic lymphocytic leukemia (CLL), and select solid tumors. Their mechanistic basis for promoting oncogenesis has been investigated in detail, with the stereotyped missplicing of messenger RNA (mRNA) protein coding sequences most intensively studied. These changes, in genes such as MAP3K7, BRD9, and ABCB7, typically lead to loss of function, thus contributing to cancer pathogenesis. Here, we systematically analyzed the impact of mutant SF3B1 on noncoding regions of mRNA transcripts across disease types, in both cell lines and primary patient specimens. This identified numerous novel and highly reproducible splicing alterations in such regions. Studies of a target gene, DCAF16, revealed multiple complex mutation-induced alterations in its 5′ and 3′ untranslated regions (UTRs). Remarkably, these were mechanistically associated with increased DCAF16 protein levels in SF3B1-mutant cells, representing, to our knowledge, the first time that oncogenic SF3B1 has been found to increase levels of a target protein in a gain-of-function manner. DCAF16 is a substrate recognition adapter for the DDB1/CUL4 E3 ubiquitin ligase complex. Novel protein degrader small molecules that coopt DCAF16 to degrade BRD4 as a neosubstrate demonstrated preferential selectivity for SF3B1-mutant cancers and CLL primary patient specimens due to increased DCAF16 protein levels. In turn, this reveals the therapeutic relevance of mutant SF3B1 dysregulation of transcript UTRs and uncovers a novel strategy for the treatment of these important neoplasms.