Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine.

Thrombocytopenia, prevalent in the majority of patients with myeloid malignancies, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), is an independent adverse prognostic factor. Azacitidine (AZA), a mainstay therapeutic agent for stem cell transplant-ineligible patients with MDS/AML, often transiently induces or further aggravates disease-associated thrombocytopenia by an unknown mechanism. Here, we uncover the critical role of an acute type-I interferon (IFN-I) signaling activation in suppressing megakaryopoiesis in AZA-mediated thrombocytopenia. We demonstrate that megakaryocytic lineage-primed progenitors present IFN-I receptors and, upon AZA exposure, engage STAT1/SOCS1-dependent downstream signaling prematurely attenuating thrombopoietin receptor (TPO-R) signaling and constraining megakaryocytic progenitor cell growth and differentiation following TPO-R stimulation. Our findings directly implicate RNA demethylation and IFN-I signal activation as a root cause for AZA-mediated thrombocytopenia and suggest mitigation of TPO-R inhibitory innate immune signaling as a suitable therapeutic strategy to support platelet production, particularly during the early phases of AZA therapy.

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche.

Hematopoietic stem cells (HSCs) sustain the lifelong production of all blood cell lineages. The functioning of aged HSCs is impaired, including a declined repopulation capacity and myeloid and platelet-restricted differentiation. Both cell-intrinsic and microenvironmental extrinsic factors contribute to HSC aging. Recent studies highlight the emerging role of inflammation in contributing to HSC aging. In this review, we summarize the recent finding of age-associated changes of HSCs and the bone marrow niche in which they lodge, and discuss how inflammation may drive HSC aging.

A comprehensive transcriptome signature of murine hematopoietic stem cell aging.

We surveyed 16 published and unpublished data sets to determine whether a consistent pattern of transcriptional deregulation in aging murine hematopoietic stem cells (HSC) exists. Despite substantial heterogeneity between individual studies, we uncovered a core and robust HSC aging signature. We detected increased transcriptional activation in aged HSCs, further confirmed by chromatin accessibility analysis. Unexpectedly, using 2 independent computational approaches, we established that deregulated aging genes consist largely of membrane-associated transcripts, including many cell surface molecules previously not associated with HSC biology. We show that Selp (P-selectin), the most consistent deregulated gene, is not merely a marker for aged HSCs but is associated with HSC functional decline. Additionally, single-cell transcriptomics analysis revealed increased heterogeneity of the aged HSC pool. We identify the presence of transcriptionally "young-like" HSCs in aged bone marrow. We share our results as an online resource and demonstrate its utility by confirming that exposure to sympathomimetics or deletion of Dnmt3a/b molecularly resembles HSC rejuvenation or aging, respectively.

Flexible Transparent Polypyrrole-Decorated MXene-Based Film with Excellent Photothermal Energy Conversion Performance.

Flexible transparent heaters based on photothermal energy conversion are highly desired for next-generation electronic devices. However, how to balance the photothermal conversion efficiency and transparency is still a huge challenge. In this work, we demonstrate a flexible polycarbonate (PC) film with balanced photothermal energy conversion performance and transparency obtained from the spraying polypyrrole (PPy)-modified Ti3C2Tx MXene (MXene@PPy) layer. Due to the synergistic light-to-heat effects of MXene and the attached PPy nanoparticles, the resulted transparent film heater (MP-PC) can obtain a satisfying photothermal conversion performance (47.5 °C at 100 mW/cm2) at a low spraying density of MXene and thus show an effective transmittance of 51.61%, simultaneously. Moreover, the photothermal conversion performance reveals an outstanding stability without significant deterioration after exposing to an outdoor environment for seven months. Besides, arising from the excellent surface electrical resistance (413 Ω/sq), the MP-PC film also exhibits an effective Joule heating capacity with a high heating temperature of 108 °C at 24 V input voltage. As one of the promising applications, the MP-PC film exhibits the effectiveness and feasibility as a light-triggered thermal therapy film for human skin in cold environments.

Flexible MXene/Silver Nanowire-Based Transparent Conductive Film with Electromagnetic Interference Shielding and Electro-Photo-Thermal Performance.

Transparent conductive film (TCF) is promising for optoelectronic instrument applications. However, designing a robust, stable, and flexible TCF that can shield electromagnetic waves and work in harsh conditions remains a challenge. Herein, a multifunctional and flexible TCF with effective electromagnetic interference shielding (EMI) performance and outstanding electro-photo-thermal effect is proposed by orderly coating Ti3C2Tx MXene and a silver nanowire (AgNW) hybrid conductive network using a simple and scalable solution-processed method. Typically, the air-plasma-treated polycarbonate (PC) film was sequentially spray-coated with MXene and AgNW to construct a highly conductive network, which was transferred and partly embedded into an ultrathin poly(vinyl alcohol) (PVA) film using spin coating coupled with hot pressing to enhance the interfacial adhesion. The peeled MXene/AgNW-PVA TCF exhibits an optimal optical and electrical performance of sheet resistance 18.3 Ω/sq and transmittance 52.3%. As a consequence, the TCF reveals an effective EMI shielding efficiency of 32 dB in X-band with strong interfacial adhesion and satisfactory flexibility. Moreover, the high electrical conductivity and localized surface plasmon resonance (LSPR) effect of hybrid conductive network endow the TCF with low-voltage-driven Joule heating performance and excellent photothermal effect, respectively, which can ensure the normal functioning under extreme cold condition. In view of the comprehensive performance, this work offers new solutions for next-generation transparent EMI shielding challenges.

Characterisation of low molecular weight glutenin subunit genes from Pseudoroegneria spicata and Pd. strigosa.

We report the characterisation of nine novel low molecular weight glutenin subunit (LMW-GS) genes from two Pseudoroegneria species, Pd. spicata and Pd. strigosa. We found that all nine LMW-GS genes possess the same primary structure shared by other published LMW-GS. Five genes encode LMW-i type subunits, three encode LMW-m type subunits and one encodes a peptide similar to B-3 hordeins of Hordeum chilense. No LMW-s type subunit genes were found in Pseudoroegneria. One subunit, PSt24-LMW-2, contains six conserved cysteine residues, and the other eight subunits all contain eight cysteine residues. We show that one cysteine residue is located in the signal peptide of PSt24-LMW-1, suggesting a mature peptide containing only seven cysteine residues. Phylogenetic analysis indicates that the LMW-GS genes from the St genome cluster together and suggests a distant relationship with LMW-GS of the A and B genomes of wheat. Slippage/unequal crossing over and illegitimate recombination are effective mechanisms for enriching variations of seed storage proteins.

Novel LMW glutenin subunit genes from wild emmer wheat (Triticum turgidum ssp. dicoccoides) in relation to Glu-3 evolution.

Four low-molecular-weight-isoleucine (LMW-i)-type and one novel chimeric (between LMW-i and LMW-methionine (m) types) low-molecular-weight glutenin subunit (LMW-GS) genes were characterized from wild emmer wheat (Triticum dicoccoides), designated as emmer-1 to emmer-5. All five LMW-GS genes possessed the same primary structure shared by other published LMW-GSs. The three genes emmer-1, emmer-3, and emmer-5 are similar, with the exception that emmer-3 and emmer-5 lost a few repeat motifs compared to emmer-1. Gene duplication and insertions/deletions of repeat motifs mediated through unequal crossing over may be responsible for the generation of these three Glu-3 alleles. Although the first residue of mature peptide of emmer-4 is isoleucine, it is not typical LMW-i-type LMW-GS. Phylogenetic analysis indicated that emmer-4 is located in the LMW-m subgroup, suggesting a closer relationship with LMW-m-type gene Y14104 of T. durum. Sequence alignment indicated that the emmer-4 is likely a chimeric gene generated by illegitimate recombination between LMW-i and LMW-m type. Unequal crossing over and illegitimate recombination are effective mechanisms for enriching both copy numbers and variations of LMW-GSs.