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Grabow S, Delbridge ARD, Valente LJ, Strasser A. MCL-1 but not BCL-XL is critical for the development and sustained expansion of thymic lymphoma in p53-deficient mice. <i>Blood</i> . 2014;124(26):3939-3946.
Decoding MnO2 redox chemistry from mechanistic ambiguity to design principles for aqueous Zn-ion batteries
Abstract Manganese dioxide (MnO 2 ) is a leading positive electrode candidate for aqueous zinc-ion batteries, combining safety, high voltage, low cost, and sustainability for grid-scale storage. However, its practical development remains restricted by poor reversibility, rooted in an unresolved mechanistic debate spanning over a decade. Here, we combine operando characterizations, multimodal spectroscopic analyses, and theory to establish a unified picture: proton-primed MnO 2 dissolution and subsequent redeposition as nanocrystalline and disordered MnO x nanosheets, coexisting with reversible proton intercalation in parent MnO 2 and predominantly in deposited MnO x , forming a dual redox mechanism. pH-driven insulating byproduct precipitation emerges as a significant kinetic barrier that limits deep dissolution and capacity utilization. Guided by these insights, we introduce surface activation and architectural design strategies toward mitigating kinetic barriers, enabling enhanced capacity and stability in both Swagelok and pouch-type cells. By reconciling mechanistic ambiguity and translating it into actionable design principles, this work demonstrates a framework for developing durable Mn-based positive electrodes for sustainable energy storage.
Ellis L, Bots M, Lindemann RK, et al. The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy. <i>Blood</i> . 2009;114(2):380-393.
Analysis of trade-offs of post-sorting plastic packaging
Coordinatively improving polymeric phosphorescence lifetime and quantum yield via triplet exciton modulation
Abstract The advancement of polymeric materials with exceptional room temperature phosphorescence (RTP) performance is hindered by the competing relationship between long phosphorescence lifetime ( τ P ) and high absolute phosphorescence quantum yield ( Φ P ). Herein, we present an Iodine-Stretch-Boric Acid (ISB) strategy that synergistically fine-tunes the generation and quenching of triplet excitons, thus enhancing both τ P and Φ P . In this strategy, ISB harnesses the external heavy atom effects to facilitate spin-orbit coupling of phosphors, while simultaneously inducing an exceptionally dense cross-linked network within binaphthyl derivative-incorporated polyvinyl alcohol ( BINs@PVA ) films. This dual modulation engenders an optimization of the non-radiative rate constant ( $${k}_{{{{\rm{nr}}}}}^{P}$$ k nr P ) and intersystem crossing rate constant ( k ISC ) of phosphorescence emission. Notably, the RTP performance of post-ISB treated DFBN@PVA films attain a notable advancement, with long τ P of 1239.8 ms@528 nm (28.4-fold increase) and high absolute Φ P of 33.8% (24.1-fold increase). Meanwhile, ISB strategy improves the durability of the DFBN@PVA films, preserving bright RTP emission after five days of water immersion and 12 hours in acidic, alkaline and hot water, exhibiting substantial potential for multicolor secure information, antibacterial, and water resistant RTP applications.
Anti-fibrinolytic strategies improve liver regeneration in mice and reduce post-hepatectomy liver failure in patients
Pharmacological plasminogen reduction enhanced liver regeneration experimentally and clinically. siRNA-induced plasminogen deficiency promoted hepatocyte proliferation after partial hepatectomy in mice, contrasting genetic deficiency models. In the HeLiX trial, tranexamic acid reduced post-hepatectomy liver failure odds, suggesting a novel therapeutic strategy.
In-situ ceramic nanoparticle assembly within wood microstructure for strong, tough, and resilient ceramic wood
MYB builds leukemic enhancers
Threat intensity shapes cortical engram architecture supporting remote memory retrieval
Abstract The strength of persistent threat memories depends on the intensity of an aversive experience. We combined engram tagging with chemogenetics, electrophysiology and spine analyses in male mice to identify how threat intensity, following mild or strong contextual threat conditioning (CTC), shapes physiological and structural properties of prelimbic cortex (PL) pyramidal neurons. PL engram cells selectively mediate retrieval of a mild remote threat memory, and develop neuroadaptations that are time-dependent, dendritic segment-specific, and modulated by threat intensity. Specifically, increased presynaptic release probability, together with reduced postsynaptic strength and spine size, developed regardless of threat intensity. However, addition of long thin spines occurred exclusively on oblique dendrites of engram neurons after mild CTC, aligning with the PL engram contribution to mild, but not strong, threat memory. Our findings reveal how threat intensity shapes cortical engram architecture, which is pivotal for understanding the neural representation of threat memory strength and persistence.
Study of NSD2 using a dTAG system reveals its molecular mechanism and oncogenic implications in t(4;14) multiple myeloma
Abstract The histone H3 lysine 36 dimethylation (H3K36me2) methyltransferase NSD2 is deleted in Wolf-Hirschhorn syndrome and is aberrantly expressed in 10% to 15% of patients with multiple myeloma (MM) because of a t(4;14) translocation. Although NSD2 is thought to be a primary driver in MM, the exact molecular mechanisms by which it regulates transcription remain unclear. We applied the degradation tag (dTAG) system to acutely degrade NSD2 and used this, in combination with time-resolved thiol-linked alkylation for the metabolic sequencing of RNA (SLAM-seq), to identify 307 transcriptional targets of NSD2. Reconstitution with either wild-type NSD2 or a catalytically inactive mutant (NSD2Y1179A) showed that NSD2’s transcriptional effects are almost exclusively dependent on its SET domain activity. Mechanistically, H3K36me2 deposition by NSD2 antagonizes H3K27me3 levels, and treatment with 2 distinct Polycomb repressive complex 2 inhibitors demonstrated that approximately half of the NSD2 target genes are regulated in an H3K27me3-dependent manner. Cleavage under targets and tagmentation (CUT&Tag) analysis showed that upon NSD2 depletion, there was an increase in H3K27me3 that occurred at genome-wide intergenic regions rather than at the promoters or gene bodies of NSD2 target genes. These data suggest that NSD2, via H3K36me2, antagonizes H3K27me3 deposition likely at distal regulatory elements, including enhancers, creating a chromatin landscape favorable for target gene transcription. Importantly, NSD2 target genes were enriched for key oncogenic pathways, and 24 transcription factors (TFs) implicated in neurodevelopment and acute leukemia, consistent with its role in Wolf-Hirschhorn syndrome and MM. Eight of these TFs are known oncogenic drivers in acute leukemia or MM, highlighting a novel molecular mechanism for NSD2’s role in t(4;14) MM.
MYB activity drives emergent enhancer activation and enhancer-promoter interactions in acute lymphoblastic leukemia
Abstract Aberrant enhancer usage is a defining feature of oncogenic transcriptional reprogramming. Therapeutic strategies that disrupt enhancer-driven gene regulation may offer new treatment avenues. MYB is a key hematopoietic transcription factor that is frequently dysregulated in a broad range of cancers and plays a critical role in sustaining malignant cell states, including in aggressive leukemia subtypes such as KMT2A-rearranged leukemias. The molecular mechanisms by which it maintains oncogenic transcription remain incompletely understood. Here, we investigate the role of MYB in directing pathological enhancer activity to drive oncogene expression in leukemia. Using high-resolution Micro Capture-C, we show that upon MYB degradation, highly defined enhancer-promoter interactions at MYB binding sites are lost, correlating with the significant downregulation of target gene expression. When anchored to a gene desert region, the Myb transactivation domain (MybTA) is sufficient and necessary for the nucleation of an enhancer-like region. Critically, long-range chromatin interactions are established up to 400 kb away from where MybTA is anchored. This results in the activation of transcription from distal cryptic elements, which is reduced or abolished in the presence of point mutations that disrupt its interaction with the coactivators P300/CBP. All these results indicate that MYB activity alone is sufficient to generate an enhancer, inducing transcription through precise enhancer-promoter cross talk, and identify the MYB-P300/CBP axis as a therapeutically actionable vulnerability in enhancer-driven malignancies.
Remodeling of the bone marrow vasculature induced by venetoclax and azacitidine damage
Abstract The Bcl2 inhibitor venetoclax in combination with the hypomethylating agent azacitidine (ven/aza) has become increasingly used clinically for the treatment of many hematological malignancies. Although its effects on malignant cells have been extensively studied, its impact on the surrounding bone marrow (BM) microenvironment (BME) remains unexplored. In this study, we report that ven/aza therapy causes significant damage to the BME of mice. Comparatively high Bcl2 expression in the sinusoidal endothelial cell (EC; SEC) compartment among all stromal subtypes, results in high sensitivity to ven/aza treatment, causing selective depletion of SECs and breakdown in cell-cell communication pathways in the EC network, leading to vascular leakiness in the BM. Furthermore, our detailed transcriptomic and imaging studies reveals significant downregulation of essential adhesion molecules in residual SECs, leading to significant defects in human hematopoietic stem/progenitor cell (HSPC) homing and engraftment of hematopoietic stem cells (HSCs) after ven/aza treatment. To conclude, our study showcases that maintaining SEC integrity in response to ven/aza therapy may play a key factor in achieving effective engraftment of donor-derived HSCs.
Fixed-duration VenO vs FCR/BR in fit patients with untreated CLL: primary analysis of the phase 3 CRISTALLO trial
Abstract The phase 3 CRISTALLO trial compared first-line fixed-duration venetoclax-obinutuzumab (VenO) vs fludarabine, cyclophosphamide, and rituximab (FCR)/bendamustine-rituximab (BR) in patients with chronic lymphocytic leukemia (CLL), using undetectable minimal residual disease (uMRD) as the sole primary end point. Previously untreated patients with a cumulative illness rating scale score ≤6 and creatinine clearance ≥70 mL/min without del(17p)/TP53 mutations were randomized 1:1 to VenO or FCR/BR. The primary end point was uMRD (&lt;10−4) in peripheral blood (PB) using next-generation sequencing at month 15. Key secondary end points included uMRD (&lt;10−4) in PB and bone marrow (BM) at end of treatment (EOT) and progression-free survival (PFS). uMRD at deeper cutoffs were explored. At data cutoff (19 March 2024), 80 patients received VenO, and 86 received FCR/BR. Baseline characteristics were generally balanced across arms. The primary end point was met: 81.3% (VenO) and 54.7% (FCR/BR) achieved uMRD (&lt;10−4) in PB at month 15 (P = .0004). uMRD (&lt;10−4) in PB and BM at EOT was also higher with VenO vs FCR/BR. Short follow-up precluded evaluation of PFS at the first planned interim analysis; however, fewer patients progressed/died with VenO vs FCR/BR (7 vs 13). At month 15, 65.0% (VenO) and 25.6% (FCR/BR) achieved uMRD (&lt;10−6) in PB. The overall safety profile was consistent with the known safety profile of each drug. No patient in the VenO arm was deemed high risk for tumor lysis syndrome (TLS) after obinutuzumab debulking; no clinical TLS occurred. These results confirm and extend the findings from the GAIA-CLL13 trial, validating increased depth of response with VenO vs chemoimmunotherapies. This trial was registered at www.clinicaltrials.gov as NCT04285567.
Magnificent Seven? CD7 CARTs take a surprise shot at AML
Targeting ABCD1 inhibits peroxisomal fatty acid oxidation to selectively eliminate acute myeloid leukemia cells
Abstract Altered lipid metabolism enables growth of acute myeloid leukemia (AML) cells. Although mitochondrial lipid oxidation is well characterized, the contribution of peroxisomal fatty acid oxidation (pFAO) is unclear. In this study, we demonstrate that AML cells upregulate the peroxisomal very long-chain fatty acid (VLCFA) transporter ABCD1 and increase endogenous levels of pFAO relative to healthy hematopoietic cells. Genetic silencing or pharmacological inhibition of ABCD1, with eicosenol, impairs pFAO causing accumulation of VLCFAs and selective AML cell death in vitro and in vivo. Loss of ABCD1 disrupts peroxisomal fatty acid import and lipid homeostasis in AML, whereas normal progenitors remain viable by upregulating glycolysis. In murine models, ABCD1 inhibition with eicosenol reduces leukemia burden and prolongs survival without toxicity. These findings identify ABCD1 as a regulator of pFAO and a novel anti-AML therapeutic target.
High‐Accuracy Machine Learning Projections of Composition‐Dependent Thermal Stability in Halide Perovskites
ABSTRACT Halide perovskites exhibit unpredictable properties in response to environmental stressors due to several composition‐dependent degradation mechanisms. In this work, we combine high‐throughput experiments, data visualization, and machine learning (ML) techniques to quantify correlations between composition, temperature, and material properties by analyzing high‐throughput, in situ environmental photoluminescence (PL) experiments. Correlation heatmaps show the influence of Cs content on film degradation, and dimensionality reduction visualization methods uncover clear composition‐based clusters despite overlapping datasets. A robust screening of 10 ML algorithms effectively forecasts PL features with single‐composition, composition‐generalized, and composition‐generalized stacking approaches, with the highest‐performing models achieving root mean squared errors of 1.84, 10.69, and 10.28, respectively. Using a multi‐output composition‐generalized Extra‐Trees and Ridge Regression stacked model, a full PL spectrum can be predicted for any time, temperature, and composition input. Our ML‐based framework could be expanded to other perovskite families, significantly reducing the analysis time to identify stable options for photovoltaics.
Complement activation profile in adult primary immune thrombocytopenia
Abstract Complement activation has been reported in primary immune thrombocytopenia (ITP); however, its clinical relevance remains poorly understood. This study aimed to clarify the association between complement activation and various biomarkers and the clinical characteristics of patients with ITP. A total of 40 patients with ITP were enrolled in this study. Platelet-bound C1q, C3d, and C4d were elevated in a substantial population of patients with ITP compared with healthy controls with highly variable titers. Hierarchical clustering analysis showed that patients with ITP could be classified into the following 3 groups according to their levels: all negative (cluster 1), elevated C1q with negative to low C3d and C4d (cluster 2), and high C3d and C4d (cluster 3). Platelet-associated (PA) immunoglobulin M (IgM) was detected mostly in cluster 3, and PA-IgG was detected in clusters 2 and 3. The number of cases refractory to first-line therapy increased in clusters 2 and 3. Complement deposition on the platelet surface correlated with an increased percentage of immature platelets. There was no significant association between complement activation and PA glycoprotein IIb/IIIa (GPIIb/IIIa) or PA-GPIb/IX antibodies, C1s ratio in the plasma, and fatigue score. Our results suggest that PA-IgG and PA-IgM contribute differentially to the complement activation profile on the platelet surface and are associated with increase in platelet turnover, characterizing a distinct subset of patients with ITP with complement activation. Our findings also may provide a rationale for stratifying patients in future clinical trials of complement-targeted therapies.
Multi‐Metal Phenolic Network Engineered Low Density Polymeric Ablator for Thermal Protection and Insulation up to 2900K
ABSTRACT Planetary‐entry and sample‐return missions demand thermal protection materials that simultaneously minimize mass, suppress recession, and withstand prolonged exposure to ultrahigh‐temperature oxidative environments. Here, we report a metal‐phenolic‐network (MPN) engineered low‐density‐ablator that resolves this longstanding trade‐off through molecularly programmable multimetal ceramization. The material is constructed by controlled ligand exchange between a quasi‐linear Ti/Zr/Hf multimetal polymer and phenolic ligands, followed by polymerization into a nanoporous aerogel‐like‐matrix with low density, low thermal conductivity, and scalable processability. The molecular‐level dispersion of multimetal species governs the in situ evolution of hierarchical ceramic architectures during extreme heating: the surface transforms into a dense interpenetrating oxide protection layer, in which (Hf, Zr)O form a rigid skeleton while (Ti, Si)O fill the intergranular space to suppress oxygen penetration and outward mass transport; meanwhile, the interior develops a mass‐fractal carbon–ceramic network that disrupts heat‐flux propagation. The composite exhibits near‐zero recession at ultrahigh temperatures, with linear ablation rates of 0.0017 mm s −1 at 2800 K and 0.0031 mm s −1 at 2900 K, while sustaining 2500 K for 1500 s with a back‐temperature‐rise of only 369 K. This work establishes an MPN‐based materials platform for lightweight thermal protection systems that integrate ultrahigh‐temperature stability, oxidation resistance, and effective thermal insulation.
Product-Intrinsic NF-κB-Driven Transcriptional Programs Connote Durability of CAR-T Response in Multiple Myeloma
Idecabtagene vicleucel (ide-cel) induces deep responses in relapsed/refractory multiple myeloma (RRMM), yet more than half of patients relapse within one year. The intrinsic features of CAR-T products that distinguish durable from non-durable responders are poorly defined, particularly at single-cell resolution, and defining drivers of durable response is critical to guide patient counseling and to inform strategies for optimizing CAR-T manufacturing and efficacy. To address this need, 40 ide-cel infusion products (184,398 cells) were profiled using single-cell RNA sequencing. These analyses revealed that a transcriptional program in CD4 CAR-T cells that led to durable responses is characterized by NF-κB signaling, pro-survival circuits, tonic/chemokine signaling, and elevated CAR transgene expression. These features were associated with prolonged progression-free and overall survival irrespective of baseline clinical characteristics. Further, analysis of paired apheresis and tumor microenvironment samples showed that elevated NF-κB activity is an intrinsic hallmark of T-cell fitness that is characterized by a central memory phenotype and the lack of checkpoint receptorligand expression, and that these features were manifest in marrow-derived and peripheral blood T cells prior to CAR-T manufacturing. Finally, validating functional relevance, pharmacologic inhibition of NF-κB abrogated CAR-T cytotoxicity and cytokine production in vitro. Our results support that NFKB in the ide-cel product marks a signaling axis impacting CAR-T function and NFKB activity represents a global marker of T cell fitness present prior to CAR-T manufacture.