Inhibition of TGF beta 1 and TGF beta 3 promotes hematopoiesis in Fanconi anemia

Fanconi anemia (FA) is a chromosome instability syndrome with congenital abnormalities, cancer predisposition and bone marrow failure (BMF). Although hematopoietic stem and progenitor cell (HSPC) transplantation is the recommended therapy, new therapies are needed for FA patients without suitable donors. BMF in FA is caused, at least in part, by a hyperactive growth-suppressive transforming growth factor beta (TGF beta) pathway, regulated by the TGF beta 1, TGF beta 2, and TGF beta 3 ligands. Accordingly, the TGF beta pathway is an attractive therapeutic target for FA. While inhibition of TGF beta 1 and TGF beta 3 promotes blood cell expansion, inhibition of TGF beta 2 is known to suppress hematopoiesis. Here, we report the effects of AVID200, a potent TGF beta 1- and TGF beta 3-specific inhibitor, on FA hematopoiesis. AVID200 promoted the survival of murine FA HSPCs in vitro. AVID200 also promoted in vitro the survival of human HSPCs from patients with FA, with the strongest effect in patients progressing to severe aplastic anemia or myelodysplastic syndrome (MDS). Previous studies have indicated that the toxic upregulation of the nonhomologous end-joining (NHEJ) pathway accounts, at least in part, for the poor growth of FA HSPCs. AVID200 downregulated the expression of NHEJ-related genes and reduced DNA damage in primary FA HSPC in vitro and in in vivo models. Collectively, AVID200 exhibits activity in FA mouse and human preclinical models. AVID200 may therefore provide a therapeutic approach to improving BMF in FA. (c) 2020 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.Peer reviewe

RNA-seq Analysis Reveals That an ECF σ Factor, AcsS, Regulates Achromobactin Biosynthesis in Pseudomonas syringae pv. syringae B728a

Iron is an essential micronutrient for Pseudomonas syringae pv. syringae strain B728a and many other microorganisms; therefore, B728a has evolved methods of iron acquirement including the use of iron-chelating siderophores. In this study an extracytoplasmic function (ECF) sigma factor, AcsS, encoded within the achromobactin gene cluster is shown to be a major regulator of genes involved in the biosynthesis and secretion of this siderophore. However, production of achromobactin was not completely abrogated in the deletion mutant, implying that other regulators may be involved such as PvdS, the sigma factor that regulates pyoverdine biosynthesis. RNA-seq analysis identified 287 genes that are differentially expressed between the AcsS deletion mutant and the wild type strain. These genes are involved in iron response, secretion, extracellular polysaccharide production, and cell motility. Thus, the transcriptome analysis supports a role for AcsS in the regulation of achromobactin production and the potential activity of both AcsS and achromobactin in the plant-associated lifestyle of strain B728a

MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia

Bone marrow failure (BMF) in Fanconi anemia (FA) patients results from dysfunctional hematopoietic stem and progenitor cells (HSPCs). To identify determinants of BMF, we performed single-cell transcriptome profiling of primary HSPCs from FA patients. In addition to overexpression of p53 and TGF-beta pathway genes, we identified high levels of MYC expression. We correspondingly observed coexistence of distinct HSPC subpopulations expressing high levels of TP53 or MYC in FA bone marrow (BM). Inhibiting MYC expression with the BET bromodomain inhibitor (+)-JQ1 reduced the clonogenic potential of FA patient HSPCs but rescued physiological and genotoxic stress in HSPCs from FA mice, showing that MYC promotes proliferation while increasing DNA damage. MYC-high HSPCs showed significant downregulation of cell adhesion genes, consistent with enhanced egress of FA HSPCs from bone marrow to peripheral blood. We speculate that MYC overexpression impairs HSPC function in FA patients and contributes to exhaustion in FA bone marrow.Peer reviewe

TGFβ pathway is required for viable gestation of Fanconi anemia embryos.

Overexpression of the TGFβ pathway impairs the proliferation of the hematopoietic stem and progenitor cells (HSPCs) pool in Fanconi anemia (FA). TGFβ promotes the expression of NHEJ genes, known to function in a low-fidelity DNA repair pathway, and pharmacological inhibition of TGFβ signaling rescues FA HSPCs. Here, we demonstrate that genetic disruption of Smad3, a transducer of the canonical TGFβ pathway, modifies the phenotype of FA mouse models deficient for Fancd2. We observed that the TGFβ and NHEJ pathway genes are overexpressed during the embryogenesis of Fancd2-/- mice and that the Fancd2-/-Smad3-/- double knockout (DKO) mice undergo high levels of embryonic lethality due to loss of the TGFβ-NHEJ axis. Fancd2-deficient embryos acquire extensive genomic instability during gestation which is not reversed by Smad3 inactivation. Strikingly, the few DKO survivors have activated the non-canonical TGFβ-ERK pathway, ensuring expression of NHEJ genes during embryogenesis and improved survival. Activation of the TGFβ-NHEJ axis was critical for the survival of the few Fancd2-/-Smad3-/- DKO newborn mice but had detrimental consequences for these surviving mice, such as enhanced genomic instability and ineffective hematopoiesis

Balance Confidence and Fear of Falling Avoidance Behavior Are Most Predictive of Falling in Older Adults: Prospective Analysis

Evidence suggests that there are several fall predictors in the elderly population, including previous fall history and balance impairment. To date, however, the role of psychological factors has not yet been thoroughly vetted in conjunction with physical factors as predictors of future falls

Silver Nanowire/Optical Adhesive Coatings as Transparent Electrodes for Flexible Electronics

We present new flexible, transparent, and conductive coatings composed of an annealed silver nanowire network embedded in a polyurethane optical adhesive. These coatings can be applied to rigid glass substrates as well as to flexible polyethylene terephthalate (PET) plastic and elastomeric polydimethylsiloxane (PDMS) substrates to produce highly flexible transparent conductive electrodes. The coatings are as conductive and transparent as indium tin oxide (ITO) films on glass, but they remain conductive at high bending strains and are more durable to marring and scratching than ITO. Coatings on PDMS withstand up to 76% tensile strain and 250 bending cycles of 15% strain with a negligible increase in electrical resistance. Since the silver nanowire network is embedded at the surface of the optical adhesive, these coatings also provide a smooth surface (root mean squared surface roughness \u3c10 nm), making them suitable as transparent conducting electrodes in flexible light-emitting electrochemical cells. These devices continue to emit light even while being bent to radii as low as 1.5 mm and perform as well as unstrained devices after 20 bending cycles of 25% tensile strain. © 2013 American Chemical Society