Histone-Binding of DPF2 Mediates Its Repressive Role in Myeloid Differentiation

Double plant homeodomain finger 2 (DPF2) is a highly evolutionarily conserved member of the d4 protein family that is ubiquitously expressed in human tissues and was recently shown to inhibit the myeloid differentiation of hematopoietic stem/progenitor and acute myelogenous leukemia cells. Here, we present the crystal structure of the tandem plant homeodomain finger domain of human DPF2 at 1.6-Å resolution. We show that DPF2 interacts with the acetylated tails of both histones 3 and 4 via bipartite binding pockets on the DPF2 surface. Blocking these interactions through targeted mutagenesis of DPF2 abolishes its recruitment to target chromatin regions as well as its ability to prevent myeloid differentiation in vivo. Our findings suggest that the histone binding of DPF2 plays an important regulatory role in the transcriptional program that drives myeloid differentiation

Nano-assemblies of cationic mPEG brush block copolymers with gadolinium polyoxotungstate [Gd(W5O18)2]9− form stable, high relaxivity MRI contrast agents

Polyoxometalates (POMs) incorporating paramagnetic ions, such as gadolinium, show promise as contrast agents for application in magnetic resonance imaging (MRI). Specifically, [Gd(W5O18)2]9− (denoted as GdWO) has been reported to have a higher relaxivity than commercially available contrast agents, but it's clinical utility has been limited by the intrinsic instability of POMs at physiological pH (7.4). In the current report we present a stability study on neat GdWO and nano-assemblies of block copolymers with GdWO in the pH range 5.0–7.4 to assess their suitability as MRI contrast agents. Neat GdWO only maintained structural stability between pH 5.4 and 6.4, and demonstrated poor MRI contrast at pH 7.4. To address this pH instability, GdWO was self-assembled with cationic mPEG brush block copolymers containing 20 or 40 units derived from the cationic monomer, 2-dimethylaminoethyl methacrylate (DMAEMA). Nano-assemblies with different charge ratios were synthesised and characterised according to their size, stability, contrasting properties and toxicity. The longitudinal relaxivity (r1) of the nano-assemblies was found to be dependent on the charge ratio, but not on the length of the cationic polymer block. Further investigation of PDMAEMA20 nano-assemblies demonstrated that they were stable over the pH range 5.0–7.4, exhibiting a higher r1 than either neat GdWO (2.77 s−1 mM−1) or clinical MRI contrast agent Gd-DTPA (4.1 s−1 mM−1) at pH 7.4. Importantly, the nano-assembly with the lowest charge ratio (0.2), showed the highest r1 (12.1 s−1 mM−1) whilst, stabilising GdWO over the pH range studied, eliciting low toxicity with MDA-MB231 cells

The Polycomb Group Protein L3MBTL1 Represses a SMAD5-Mediated Hematopoietic Transcriptional Program in Human Pluripotent Stem Cells

SummaryEpigenetic regulation of key transcriptional programs is a critical mechanism that controls hematopoietic development, and, thus, aberrant expression patterns or mutations in epigenetic regulators occur frequently in hematologic malignancies. We demonstrate that the Polycomb protein L3MBTL1, which is monoallelically deleted in 20q- myeloid malignancies, represses the ability of stem cells to drive hematopoietic-specific transcriptional programs by regulating the expression of SMAD5 and impairing its recruitment to target regulatory regions. Indeed, knockdown of L3MBTL1 promotes the development of hematopoiesis and impairs neural cell fate in human pluripotent stem cells. We also found a role for L3MBTL1 in regulating SMAD5 target gene expression in mature hematopoietic cell populations, thereby affecting erythroid differentiation. Taken together, we have identified epigenetic priming of hematopoietic-specific transcriptional networks, which may assist in the development of therapeutic approaches for patients with anemia

Patterns of protein carbonylation during Medicago truncatula seed maturation

Seeds mainly acquire their physiological quality during maturation, whereas oxidative conditions reign within cells triggering protein carbonylation. To better understand the role of this protein modification in legume seeds, we compared by proteomics patterns of carbonylated proteins in maturing seeds of Medicago truncatula naturally desiccated or prematurely dried, a treatment known to impair seed quality acquisition. In both cases, protein carbonylation increased in these seeds, accompanying water removal. We identified several proteins whose extent of carbonylation varied when comparing natural desiccation and premature drying and that could therefore be responsible for the impairment of seed quality acquisition or expression. In particular, we focused on PM34, a protein specific to seeds exhibiting a high sensitivity to carbonylation and of which function in dicotyledons was not known before. PM34 proved to have a cellulase activity presumably associated with cell elongation, a process required for germination and subsequent seedling growth. We discuss the possibility that PM34 (abundance or redox state) could be used to assess crop seed quality

Culturally adaptive storytelling intervention versus didactic intervention to improve hypertension control in Vietnam- 12 month follow up results: A cluster randomized controlled feasibility trial

INTRODUCTION: Vietnam is experiencing an epidemiologic transition with an increased prevalence of non-communicable diseases. The country needs novel, large-scale, and sustainable interventions to improve hypertension control. We report the 12 month follow-up results of a cluster randomized feasibility trial in Hung Yen province, Vietnam, which evaluated the feasibility and acceptability of two community-based interventions to improve hypertension control: a storytelling and a didactic intervention. METHODS: The storytelling intervention included stories in the patients\u27 own words about coping with hypertension and didactic content about the importance of healthy lifestyle behaviors in controlling elevated blood pressure levels. The didactic intervention included only didactic content, which were general recommendations for managing several important risk factors for hypertension and other non-communicable diseases. The storytelling intervention was delivered by two DVDs three months apart; the didactic intervention included only one DVD. The trial was conducted in patients with poorly controlled hypertension from 4 communes (communities), which were equally randomized to the two interventions. RESULTS: The mean age of the 160 patients was 66 years and 54% were men. Between baseline enrollment and the 12 month follow-up, mean systolic blood pressure declined by 10.8 mmHg (95% CI: 6.5-14.9) in the storytelling group and by 5.8 mmHg (95% CI: 1.6-10.0) in the didactic content group. The storytelling group also experienced more improvement in several health behaviors, including increased levels of physical activity and reduced consumption of salt and alcohol. CONCLUSIONS: We observed considerable long-term beneficial effects of both interventions, especially of our storytelling intervention, among patients with inadequately controlled hypertension. A large scale randomized trial should more systematically compare the short and long-term effectiveness of the two interventions in controlling hypertension. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02483780

Roc632: An overview

The present paper aims to analyze and explore the ROC632 package, specifying its main characteristics and functions. More specifically, the goal of this study is the evaluation of the effectiveness of the package and its strengths and weaknesses. This package was created in order to overcome the lack of information concerning incomplete time-to-event data, adapting the 0.632+ bootstrap estimator for the evaluation of time dependent ROC curves. By applying this package to a specific dataset (DLBCLpatients), it becomes possible to assess tangible data, determining if it is able to analyze complete and incomplete data efficiently and without bias.(undefined)info:eu-repo/semantics/publishedVersio

Culturally adaptive storytelling intervention versus didactic intervention to improve hypertension control in Vietnam: a cluster-randomized controlled feasibility trial

BACKGROUND: Vietnam is experiencing an epidemiologic transition with an increased prevalence of non-communicable diseases. Novel, large-scale, effective, and sustainable interventions to control hypertension in Vietnam are needed. We report the results of a cluster-randomized feasibility trial at 3 months follow-up conducted in Hung Yen province, Vietnam, designed to evaluate the feasibility and acceptability of two community-based interventions to improve hypertension control: a storytelling intervention, We Talk about Our Hypertension, and a didactic intervention. METHODS: The storytelling intervention included stories about strategies for coping with hypertension, with patients speaking in their own words, and didactic content about the importance of healthy lifestyle behaviors including salt reduction and exercise. The didactic intervention included only didactic content. The storytelling intervention was delivered by two DVDs at 3-month intervals; the didactic intervention included only one installment. The trial was conducted in four communes, equally randomized to the two interventions. RESULTS: The mean age of the 160 study patients was 66 years, and 54% were men. Most participants described both interventions as understandable, informative, and motivational. Between baseline and 3 months, mean systolic blood pressure declined by 8.2 mmHg (95% CI 4.1-12.2) in the storytelling group and by 5.5 mmHg (95% CI 1.4-9.5) in the didactic group. The storytelling group also reported a significant increase in hypertension medication adherence. CONCLUSIONS: Both interventions were well accepted in several rural communities and were shown to be potentially effective in lowering blood pressure. A large-scale randomized trial is needed to compare the effectiveness of the two interventions in controlling hypertension. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02483780

A regulatory network-based approach dissects late maturation processes related to the acquisition of desiccation tolerance and longevity of Medicago truncatula seeds

In seeds, desiccation tolerance (DT) and the ability to survive the dry state for prolonged periods of time (longevity) are two essential traits for seed quality that are consecutively acquired during maturation. Using transcriptomic and metabolomic profiling together with a conditional-dependent network of global transcription interactions, we dissected the maturation events from the end of seed filling to final maturation drying during the last 3 weeks of seed development in Medicago truncatula. The network revealed distinct coexpression modules related to the acquisition of DT, longevity, and pod abscission. The acquisition of DT and dormancy module was associated with abiotic stress response genes, including late embryogenesis abundant (LEA) genes. The longevity module was enriched in genes involved in RNA processing and translation. Concomitantly, LEA polypeptides accumulated, displaying an 18-d delayed accumulation compared with transcripts. During maturation, gulose and stachyose levels increased and correlated with longevity. A seed-specific network identified known and putative transcriptional regulators of DT, including ABSCISIC ACID-INSENSITIVE3 (MtABI3), MtABI4, MtABI5, and APETALA2/ ETHYLENE RESPONSE ELEMENT BINDING PROTEIN (AtAP2/EREBP) transcription factor as major hubs. These transcriptional activators were highly connected to LEA genes. Longevity genes were highly connected to two MtAP2/EREBP and two basic leucine zipper transcription factors. A heat shock factor was found at the transition of DT and longevity modules, connecting to both gene sets. Gain- and loss-of-function approaches of MtABI3 confirmed 80% of its predicted targets, thereby experimentally validating the network. This study captures the coordinated regulation of seed maturation and identifies distinct regulatory networks underlying the preparation for the dry and quiescent states

Quantitative trait loci analysis reveals a correlation between the ratio of sucrose/raffinose family oligosaccharides and seed vigour in Medicago truncatula

Seed vigour is important for successful establishment and high yield, especially under suboptimal environmental conditions. In legumes, raffinose oligosaccharide family (RFO) sugars have been proposed as an easily available energy reserve for seedling establishment. In this study, we investigated whether the composition or amount of soluble sugars (sucrose and RFO) is part of the genetic determinants of seed vigour of Medicago truncatula using two recombinant inbred line (RIL) populations. Quantitative trait loci (QTL) mapping for germination rate, hypocotyl and radicle growth under water deficit and nutritional stress, seed weight and soluble sugar content was performed using RIL populations LR1 and LR4. Seven of the 12 chromosomal regions containing QTL for germination rate or post-germinative radicle growth under optimal or stress conditions co-located with Suc/RFO QTL. A significant negative correlation was also found between seed vigour traits and Suc/RFO. In addition, one QTL that explained 80% of the variation in the ratio stachyose/verbascose co-located with a stachyose synthase gene whose expression profile in the parental lines could explain the variation in oligosaccharide composition. The correlation and co-location of Suc/RFO ratio with germination and radicle growth QTL suggest that an increased Suc/RFO ratio in seeds of M. truncatula might negatively affect seed vigour

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT