Comment on the calculation of forces for multibody interatomic potentials

The system of particles interacting via multibody interatomic potential of general form is considered. Possible variants of partition of the total force acting on a single particle into pair contributions are discussed. Two definitions for the force acting between a pair of particles are compared. The forces coincide only if the particles interact via pair or embedded-atom potentials. However in literature both definitions are used in order to determine Cauchy stress tensor. A simplest example of the linear pure shear of perfect square lattice is analyzed. It is shown that, Hardy's definition for the stress tensor gives different results depending on the radius of localization function. The differences strongly depend on the way of the force definition.Comment: 9 pages, 2 figure

Particular features of interrelation of motivation, values and sense of life’s meaning as subjective factors of individualizing trajectory in the system of continuous education

The relevance of the problem under study is based on the fact that, as regards methodological and theoretical aspects, the problem of value and motivational sphere is poorly elaborated regarding the interrelation between professional education and professional activity and on the empirical level there is no clear understanding of how the sense of purpose of life and own professional values is related to the professional motivation. The aim of the article is to identify the specific features of the interrelation and effects of meaning of life to the professional values and motivation. The leading method of research is questionnaire method which makes it possible to identify the following: level of sense of life’s purpose – method of life-meaning orientations, specific features of professional motivation – method “Motivation of professional activity” and method “Level of correlation between value and availability of value”. The article presents and discusses the results of empirical study of the interrelation between professional values, professional motivation and life-meaning orientations, as well as the effects of the level of life’s meaning on professional motivation. The practical value is the possibility to use the results of the research in developing programs for correcting and increasing professional motivation, as well as for developing technologies of psychology-pedagogical assistance to sense-making and professional self-identification in projecting and implementing individual educational trajectories in the continuous vocational education system. The article can be useful for specialists in professiology, teachers of technical subjects and professional consultants for forecasting professional development of a person. © 2016 Zavodchikov et al

Managing change in the holding company as a factor in solving strategic problems of the Region

The relevance of the investigated problem is caused by the necessity of changes in holding company’s management systems to address the strategic problems of the region. The purpose of the study is to develop a method of forming teams at the corporate level for the coordination and implementation of programs for the implementation of reforms and their subsequent impact on the institutional environment of the region. The leading approach to the study of the problem is systemic and situational approach in the framework of the theory and methodology of innovation management that allow to analyze the change management features in the company. The following results were obtained from the study: analyzed regionally significant holding companies which have a significant impact on the socio-economic indicators. Article Submissions may be useful for organizations engaged in development, as well as consultants and experts on issues of innovation and production management. with the proposed mechanism can plan and implement economic development, in which the organization will be ensured current stability, long-term sustainability, the pace of development of the relevant market situation. © 2016 Krivtsov, Polinova and Chupina

NF-Y Recruits Ash2L to Impart H3K4 Trimethylation on CCAAT Promoters

BACKGROUND: Different histone post-translational modifications (PTMs) are crucial in the regulation of chromatin, including methylations of H3 at Lysine 4 by the MLL complex. A relevant issue is how this is causally correlated to the binding of specific transcription factors (TFs) in regulatory regions. NF-Y is a TF that regulates 30% of mammalian promoters containing the widespread CCAAT element. We and others established that the presence of H3K4me3 is dependent upon the binding of NF-Y. Here, we investigate the mechanisms of H3K4me3 deposition by NF-Y. METHODS: We employed Chromatin Immunoprecipitation in cells in which Ash2L and NF-Y subunits were knocked down by RNAi, to monitor the presence of histones PTMs and components of the MLL complex. We performed gene expression profiling of Ash2L-knocked down cells and analyzed the regulated genes. We performed ChIPs in leukemic cells in which MLL1 is devoid of the methyltransferase domain and fused to the AF4 gene. RESULTS: Knock down of the Ash2L subunit of MLL leads to a decrease in global H3K4me3 with a concomitant increase in H3K79me2. Knock down of NF-Y subunits prevents promoter association of Ash2L, but not MLL1, nor WDR5, and H3K4me3 drops dramatically. Endogenous NF-Y and Ash2L specifically interact in vivo. Analysis of the promoters of Ash2L regulated genes, identified by transcriptional profiling, suggests that a handful TF binding sites are moderately enriched, among which the CCAAT box. Finally, leukemic cells carrying the MLL-AF4 translocation show a decrease of H3K4me3, absence of Ash2L and increase in H3K79me2, while NF-Y binding was not significantly affected. CONCLUSIONS: Three types of conclusions are reached: (i) H3K4 methylation is not absolutely required for NF-Y promoter association. (ii) NF-Y acts upstream of H3K4me3 deposition by recruiting Ash2L. (iii) There is a general cross-talk between H3K4me3 and H3K79me2 which is independent from the presence of MLL oncogenic fusions

ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

Additional sex combs-like (ASXL) proteins are mammalian homologues of additional sex combs (Asx), a regulator of trithorax and polycomb function in Drosophila. While there has been great interest in ASXL1 due to its frequent mutation in leukemia, little is known about its paralog ASXL2, which is frequently mutated in acute myeloid leukemia patients bearing the RUNX1-RUNX1T1 (AML1-ETO) fusion. Here we report that ASXL2 is required for normal haematopoiesis with distinct, non-overlapping effects from ASXL1 and acts as a haploinsufficient tumour suppressor. While Asxl2 was required for normal haematopoietic stem cell self-renewal, Asxl2 loss promoted AML1-ETO leukemogenesis. Moreover, ASXL2 target genes strongly overlapped with those of RUNX1 and AML1-ETO and ASXL2 loss was associated with increased chromatin accessibility at putative enhancers of key leukemogenic loci. These data reveal that Asxl2 is a critical regulator of haematopoiesis and mediates transcriptional effects that promote leukemogenesis driven by AML1-ETO

Structural Biology of Human H3K9 Methyltransferases

SET domain methyltransferases deposit methyl marks on specific histone tail lysine residues and play a major role in epigenetic regulation of gene transcription. We solved the structures of the catalytic domains of GLP, G9a, Suv39H2 and PRDM2, four of the eight known human H3K9 methyltransferases in their apo conformation or in complex with the methyl donating cofactor, and peptide substrates. We analyzed the structural determinants for methylation state specificity, and designed a G9a mutant able to tri-methylate H3K9. We show that the I-SET domain acts as a rigid docking platform, while induced-fit of the Post-SET domain is necessary to achieve a catalytically competent conformation. We also propose a model where long-range electrostatics bring enzyme and histone substrate together, while the presence of an arginine upstream of the target lysine is critical for binding and specificity. Enhanced version: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available i

Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia

Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML

Differential regulation of myeloid leukemias by the bone marrow microenvironment

Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSC) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM)1, and may be the cause of relapse following chemotherapy.2 Targeting the niche is a novel strategy to eliminate persistent and drug-resistant LSC. CD443,4 and IL-65 have been implicated previously in the LSC niche. Transforming growth factor (TGF)-β1 is released during bone remodeling6 and plays a role in maintenance of CML LSCs7, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor8,9 attenuates BCR-ABL1-induced CML-like myeloproliferative neoplasia (MPN)10 but enhances MLL-AF9-induced AML11 in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSC. PTH treatment caused a 15-fold decrease in LSCs in wildtype mice with CML-like MPN, and reduced engraftment of immune deficient mice with primary human CML cells. These results demonstrate that LSC niches in chronic and acute myeloid leukemias are distinct, and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSC, a prerequisite for the cure of CML

Misguided Transcriptional Elongation Causes Mixed Lineage Leukemia

Investigation of the activity of a family of fusion proteins that cause aggressive leukemia suggests transcriptional elongation as a new mechanism for oncogenic transformation

In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

We used an in vivo small hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase Syk. In contrast, loss of Itgb3 in normal hematopoietic stem and progenitor cells did not affect engraftment, reconstitution, or differentiation. Finally, using an Itgb3 knockout mouse model, we confirmed that Itgb3 is dispensable for normal hematopoiesis but is required for leukemogenesis. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML.National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant P01 CA108631)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant RC1 CA145229)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant R01 CA140292)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant CA148180