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Suppression of astrocyte BMP signaling improves molecular signatures and functional deficits in a fragile X syndrome mouse model
B-lymphoblastic leukemia with synchronous <i>KMT2A</i> :: <i>TXNRD1</i> and <i>IGH</i> :: <i>CEBPD</i> rearrangements
Allogeneic hematopoietic cell transplantation in mature T- or NK-lymphomas: a phase II clinical trial
Abstract Allogeneic hematopoietic cell transplantation (HCT) is a potential cure for patients with peripheral T-/NK-cell lymphomas (PTCL), but its application is understudied. This prospective trial evaluates a unique reduced-intensity (RIC) transplantation platform in 31 patients with PTCL (NCT03922724). One-year progression-free survival, the primary endpoint, is 53% (95% CI 29-72%) on the RIC arm and 60% (95% CI 25-83%) on the modified-RIC arm. The 3-year overall survival is 61% (95% CI 42-76%), with relapse estimated at 18% (95% CI 6-34%) at 3 years. Transplant-related mortality was 24% (95% CI 10-41%) at 1-year, low at 11% (95% CI 2-29%) for patients ≤60 years but 56% (95% CI 17-82%) for patients >60 years, p = 0.01. There was no grade III-IV acute graft-versus-host disease, while chronic graft-versus-host disease was estimated at 23% (95 CI 10-38%) at 2 years. This study demonstrates a benefit regardless of pre-transplantation disease status, challenging the requirement of remission for HCT.
Novel phosphatase-based regulatory loop for HbF expression
Regulating adsorption selectivity by charge-polarized Auδ−-Cuδ+ site for stable glucose electrooxidation
Abstract Electro-reforming of biomass into value-added chemicals offers a sustainable approach for future energy developments. However, noble metal catalysts toward glucose electrooxidation suffer from deactivation, poor selectivity, and limited power density. Here, we present Au δ− -Cu δ+ sites in AuCu alloy that serve as stable and efficient catalyst for selective glucose electrooxidation to potassium gluconate at high current density. AuCu alloy ensures the co-adsorption of OH − on electron-deficient Cu δ+ sites and glucose on electron-rich Au δ− sites, stimulating the formation of oxidative *OH and intermediates. Selective adsorption of OH species on Cu δ+ sites also restrains the Au-OH formation and its subsequent oxidation to AuO x , thereby preventing catalyst deactivation. Especially, for glucose electrooxidation, Au 4 Cu 2 alloy delivers a high selectivity toward potassium gluconate (97.15%), along with a low potential of 0.74 V (versus reversible hydrogen electrode) to achieve industrial current density of 500 mA cm −2 . Furthermore, Au 4 Cu 2 alloy realizes a stable electrolysis with a potassium gluconate productivity of 9.46 mmol cm –2 h –1 and Faraday efficiency of 93.60% in the membrane-free flow electrolyzer.
Expression of cFLIP in B cells is essential for diffuse large B-cell lymphoma pathogenesis
Diffuse large B cell lymphoma (DLBCL) is a highly heterogenous malignant disease that remains a major clinical challenge as relapsed and refractory disease is difficult to treat. Apoptosis evasion is a major feature of DLBCL. However, while the suppression of intrinsic apoptosis has long been recognized as a lymphoma-promoting event, the role of extrinsic apoptosis has remained poorly defined. Here, we demonstrated at the genetic level that expression of cFLIP, the most crucial, non-redundant inhibitor of extrinsic apoptosis, in B cells is necessary for the development of diffuse large B cell lymphoma (DLBCL) in an autochthonous murine model. Indeed, B cell-specific deletion of Cflar, the gene encoding for cFLIP, prevented lymphomagenesis mediated by oncogenic Myd88 and overexpression of BCL2. In human lymphoma cells, we showed that the absence of cFLIP sensitizes ABC- but not GCB DLBCL subtype cells to TRAIL- or LPS-induced, Caspase-8-mediated apoptosis. Furthermore, we unveiled a cell death-independent role of cFLIP in the suppression of pro-inflammatory cytokines at the transcriptional level, selectively in the ABC subtype.These results indicate that the suppression of intrinsic apoptosis can support lymphomagenesis only if extrinsic apoptosis is properly controlled. Moreover, licensing extrinsic apoptosis via cFLIP deletion can efficiently promote the death of DLBCL cells despite the suppression of the intrinsic pathway. Overall, these data provide the rationale for the development of cFLIP inhibitors for the treatment of ABC DLBCL and possibly other haematological cancers.
Centralized brain networks controlling antennal grooming coordination
An optimized CRISPR-Cas12a genome-wide screen reveals PTPA phosphatase pathway in fetal hemoglobin silencing
Abstract Reactivating the fetal globin genes HBG1 and HBG2 in adult erythroid cells represents a validated therapeutic approach for hemoglobinopathies. Central mediators of the fetal-to-adult hemoglobin transition include the direct transcriptional HBG1/2 repressors BCL11A, LRF, and NFIA/X. Limited-scale screens have expanded the regulatory circuity surrounding fetal globin silencing, but systematic genome-wide dissection of such pathways is lacking. We used a 2-tiered genetic screening strategy, a novel CRISPR-Cas12a–based screening platform followed by a domain-focused CRISPR-Cas9 screen, to interrogate all known human protein-coding genes for their impact on HBG1/2 regulation and erythroid cellular fitness, generating a comprehensive resource for the field. Among the top new hits was protein phosphatase 2A (PP2A) phosphatase activator (PTPA), an activator of the serine-threonine phosphatase PP2A whose loss elevates HBG1/2 levels while preserving erythroid differentiation. Phenotypic rescue experiments revealed that PTPA silences HBG1/2 expression primarily by regulating BCL11A expression. To our knowledge, this study represents the most comprehensive CRISPR dissection of HBG regulation to date, highlighting the power of Cas12a-based genome-scale screening for uncovering disease-relevant pathways.
Reactive formation of magnesiowüstite at the lunar core-mantle boundary
How I select hematopoietic cell donors in the era of posttransplant cyclophosphamide
Abstract Selection of a hematopoietic progenitor cell donor for allogeneic hematopoietic cell transplantation (HCT) is essential for treatment planning; however, the parameters that define an “optimal” donor in the modern era are not well defined. Historically, donor-recipient HLA mismatching correlated strongly with risk for graft-versus-host disease (GVHD) and reduced survival. For this reason, donor selection was typically hierarchical: HLA-matched related and unrelated donors were evaluated first, followed by HLA-mismatched donors (or deferral of HCT altogether) in patients lacking an HLA-matched donor. The advent of posttransplant cyclophosphamide (PTCy)-based GVHD prevention has changed this paradigm. Survival outcomes after HLA-mismatched donor HCT with PTCy, including from related haploidentical or HLA-mismatched unrelated donors, approach those in HLA-matched donor recipients in recent clinical trials and retrospective studies. These encouraging results present a new challenge: In the PTCy era, how should donors be prioritized among the many potential sources available? Herein, we review HLA and non-HLA parameters that inform adult donor selection, address disease-specific considerations, and discuss approaches to increase donor availability, including use of match probability-based donor search. Case vignettes focusing on concepts that may be adapted to heterogeneous clinical scenarios are presented.
Marine heatwaves can supercharge cyclones
Scalable and multiplexed recorders of gene regulation dynamics across weeks
Abstract Gene expression is dynamically controlled by gene regulatory networks comprising multiple regulatory components to mediate cellular functions 1 . An ideal tool for analysing these processes would track multi-component dynamics with both spatiotemporal resolution and scalability within the same cells, a capability not yet achieved. Here we present CytoTape, a genetically encoded, physiologically compatible, modular protein tape recorder for multiplexed and spatiotemporally scalable recording of gene regulation dynamics continuously for up to 3 weeks, with single-cell, up to minutes-scale resolution. CytoTape uses a flexible, thread-like, elongating intracellular protein self-assembly engineered via computationally assisted rational design, built on our earlier XRI technology 2 . We demonstrate its utility across multiple mammalian cell types, achieving simultaneous recording of five transcription factor activities and gene transcriptional activities. CytoTape reveals that divergent transcriptional trajectories correlate with transcriptional history and signal integration, and that distinct immediate early genes (IEGs) exhibit complex temporal correlations within single cells. We further extended CytoTape into CytoTape-vivo for scalable, spatiotemporally resolved single-cell recording in the living brain, enabling simultaneous weeks-long recording of doxycycline-dependent and IEG promoter-dependent gene expression histories across up to 14,123 neurons spanning multiple brain regions per mouse. Together, the CytoTape toolkit establishes a versatile platform for scalable and multiplexed analysis of cell physiological processes in vitro and in vivo.
Investigating the structural evolution of lithium zirconium nitrochloride solid electrolytes for all-solid-state batteries
<i>NPM1</i> -mutated acute myeloid leukemia with a hybrid granulocytic and monocytic phenotype
Spatiotemporal asymmetries on brain energy landscape uncover system entrapment related to depression severity
Common variation at 1q23.3, 2p23.3, 2q33.3, and 2p21 influences the risk of acute myeloid leukemia
Abstract Acute myeloid leukemia (AML) is a complex hematologic malignancy with multiple disease subgroups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here, we perform a meta-analysis of 4 published GWAS plus 2 new GWAS, totaling 4710 AML cases and 12 938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P = 1.35 × 10−8; EFR3B, POMC, DNMT3A, and DNAJC27), which also significantly associates with patient survival (P = 6.09 × 10−3). Our analysis also identifies 3 new genome-wide significant risk loci for disease subgroups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P = 7.0 × 10−10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P = 3.28 × 10−8; PARD3B) and 2p21 (rs79918355; P = 1.60 × 10−9; EPCAM). We also investigated loci previously associated with the risk of clonal hematopoiesis (CH) or CH of indeterminate potential and identified several variants associated with the risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease subgroup specific risk loci.