Runx1 deficiency permits granulocyte lineage commitment but impairs subsequent maturation

First-hits in the multi-hit process of leukemogenesis originate in germline or hematopoietic stem cells (HSCs), yet leukemia-initiating cells (LICs) usually have a lineage-committed phenotype. The molecular mechanisms underlying this compartment shift during leukemia evolution have not been a major focus of investigation and remain poorly understood. Here a mechanism underlying this shift was examined in the context of Runx1 deficiency, a frequent leukemia-initiating event. Lineage-negative cells isolated from the bone marrow of Runx1-haploinsufficient and wild-type control mice were cultured in granulocyte-colony-stimulating factor to force lineage commitment. Runx1-haploinsufficient cells demonstrated significantly greater and persistent exponential cell growth than wild-type controls. Not surprisingly, the Runx1-haploinsufficient cells were differentiation-impaired, by morphology and by flow-cytometric evaluation for granulocyte differentiation markers. Interestingly, however, this impaired differentiation was not because of decreased granulocyte lineage commitment, as RNA and protein upregulation of the master granulocyte lineage-commitment transcription factor Cebpa, and Hoxb4 repression, was similar in wild-type and Runx1-haploinsufficient cells. Instead, RNA and protein expression of Cebpe, a key driver of progressive maturation after lineage commitment, were significantly decreased in Runx1-haploinsufficient cells. Primary acute myeloid leukemia cells with normal cytogenetics and RUNX1 mutation also demonstrated this phenotype of very high CEBPA mRNA expression but paradoxically low expression of CEBPE, a CEBPA target gene. Chromatin-immunoprecipitation analyses suggested a molecular mechanism for this phenotype: in wild-type cells, Runx1 binding was substantially greater at the Cebpe than at the Cebpa enhancer. Furthermore, Runx1 deficiency substantially diminished high-level Runx1 binding at the Cebpe enhancer, but lower-level binding at the Cebpa enhancer was relatively preserved. Thus, Runx1-deficiency permits Cebpa upregulation and the exponential cell growth that accompanies lineage commitment, but by impairing activation of Cebpe, a key proliferation-terminating maturation gene, extends this exponential growth. These mechanisms facilitate germline cell or HSC of origin, yet evolution into LIC with lineage-committed phenotype.Fil: Ng, K. P.. Cleveland Clinic. Translational Hematology and Oncology Research; Estados UnidosFil: Hu, Z.. Cleveland Clinic. Translational Hematology and Oncology Research; Estados UnidosFil: Ebrahem, Q.. Cleveland Clinic. Translational Hematology and Oncology Research; Estados UnidosFil: Negrotto, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Cleveland Clinic. Translational Hematology and Oncology Research; Estados UnidosFil: Lausen, J.. Georg-Speyer-Haus, Institute for Biomedical Research; AlemaniaFil: Saunthararajah, Y.. Cleveland Clinic; Estados Unido

Committee machines -- a universal method to deal with non-idealities in memristor-based neural networks

Artificial neural networks are notoriously power- and time-consuming when implemented on conventional von Neumann computing systems. Consequently, recent years have seen an emergence of research in machine learning hardware that strives to bring memory and computing closer together. A popular approach is to realise artificial neural networks in hardware by implementing their synaptic weights using memristive devices. However, various device- and system-level non-idealities usually prevent these physical implementations from achieving high inference accuracy. We suggest applying a well-known concept in computer science -- committee machines -- in the context of memristor-based neural networks. Using simulations and experimental data from three different types of memristive devices, we show that committee machines employing ensemble averaging can successfully increase inference accuracy in physically implemented neural networks that suffer from faulty devices, device-to-device variability, random telegraph noise and line resistance. Importantly, we demonstrate that the accuracy can be improved even without increasing the total number of memristors.Comment: 22 pages, 18 figures, 4 table

In2O3 based perovskite solar cells

Session PWed: Posters-Wednesday: Paper 9749-47Hybrid organic-inorganic perovskite solar cells have attracted lots of attention in recent years. Growth and properties of perovskite layer and its relationship to photovoltaic performance have been extensively studied. Comparably less attention was devoted to the research of the influence of electron transporting layer (ETL). Conventionally, TiO2 is selected as ETL. However, photocatalytic property of this transparent conductive metal oxide reduces the stability of perovskite solar cells under illumination. To realize the commercialization, the stability of perovskite solar cell must be improved. In this study, we replace TiO2 by In2O3, which is not only transparent and conductive, but also has little photocatalytic effect and it has higher electron mobility than TiO2. Investigation on different solution process methods of In2O3 as ETL is demonstrated. © 2016 SPIE.Link_to_subscribed_fulltex

Thermal Assisted Oxygen Annealing for High Efficiency Planar CH3NH3PbI3 Perovskite Solar Cells

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From error bounds to the complexity of first-order descent methods for convex functions

This paper shows that error bounds can be used as effective tools for deriving complexity results for first-order descent methods in convex minimization. In a first stage, this objective led us to revisit the interplay between error bounds and the Kurdyka-\L ojasiewicz (KL) inequality. One can show the equivalence between the two concepts for convex functions having a moderately flat profile near the set of minimizers (as those of functions with H\"olderian growth). A counterexample shows that the equivalence is no longer true for extremely flat functions. This fact reveals the relevance of an approach based on KL inequality. In a second stage, we show how KL inequalities can in turn be employed to compute new complexity bounds for a wealth of descent methods for convex problems. Our approach is completely original and makes use of a one-dimensional worst-case proximal sequence in the spirit of the famous majorant method of Kantorovich. Our result applies to a very simple abstract scheme that covers a wide class of descent methods. As a byproduct of our study, we also provide new results for the globalization of KL inequalities in the convex framework. Our main results inaugurate a simple methodology: derive an error bound, compute the desingularizing function whenever possible, identify essential constants in the descent method and finally compute the complexity using the one-dimensional worst case proximal sequence. Our method is illustrated through projection methods for feasibility problems, and through the famous iterative shrinkage thresholding algorithm (ISTA), for which we show that the complexity bound is of the form $O(q^{k})$ where the constituents of the bound only depend on error bound constants obtained for an arbitrary least squares objective with $\ell^1$ regularization

3D simulations of multipacting in the 56 MHz SRF cavity

The 56 MHz SRF Quarter-Wave Resonator (QWR) is designed for RHIC as a storage cavity to improve the collider performance. 2D multipacting simulation has been done for the cavity alone. Ripples were added to the outer body of the cavity for multipacting suppression based on the simulation findings. During operation, there will be four higher order mode (HOM) couplers. All of these components will be exposed to high RF fields. In this paper we compare 2D and 3D codes simulation results for multipacting in the cavity. We also report 3D simulation results for multipacting simulation at the couplers

The disability rate of 5-year post-stroke and its correlation factors: A national survey in China

Few studies on long-term functional outcome have been conducted in post-stroke patients in China. The objective of this study was to conduct a nationwide survey in China to investigate the 5-year prevalence of post-stroke disability and its correlation factors. A total of 893 patients with ischemic stroke were included. Demographic, clinical and neuro-imaging information were collected with standardized instruments that assessed stroke severity, depression, cognitive impairment, stroke recurrence and physical disability. Disability was assessed with the modified Ranking Score (mRS), of which a cutoff score _2 indicates disability. Statistical analysis included chi-square tests, two independent samples t-tests, Mann-Whitney U test and multiple logistic regression analysis. The frequency of disability in this study population was 45%. Multivariate analyses revealed that older age, lower education level, previous history of stroke, stroke severity at admission, depression, cognitive impairment at 3 months, and stroke recurrence within 5 years follow up were all significantly associated with post-stroke disability. The disability rate in 5-year post-stroke was high in Chinese patients. Treatment of depression, s

Numerical Renormalization Group Approach to a Quantum Dot Coupled to Normal and Superconducting Leads

We study transport through a quantum dot coupled to normal and superconducting leads using the numerical renormalization group method. We show that the low-energy properties of the system are described by the local Fermi liquid theory despite of the superconducting correlations penetrated into the dot due to a proximity effect. We calculate the linear conductance due to the Andreev reflection in the presence of the Coulomb interaction. It is demonstrated that the maximum structure appearing in the conductance clearly characterizes a crossover between two distinct spin-singlet ground states, i.e. the superconducting singlet state and the Kondo singlet state. It is further elucidated that the gate-voltage dependence of the conductance shows different behavior in the superconducting singlet region from that in the Kondo singlet region.Comment: 10 pages, 6 figures; a typo in eq. (B.5) corrected, which does not affect any other results of the pape

Flavon exchange effects in models with abelian flavor symmetry

In models with abelian flavor symmetry the small mixing angles and mass ratios of quarks and leptons are typically given by powers of small parameters characterizing the spontaneous breaking of flavor symmetry by "flavon" fields. If the scale of the breaking of flavor symmetry is near the weak scale, flavon exchange can lead to interesting flavor-violating and CP violating effects. These are studied. It is found that d_e, mu -> e + gamma, and mu-e conversion on nuclei can be near present limits. For significant range of parameters mu-e conversion can be the most sensitive way to look for such effects.Comment: 19 pages, 5 Postscript figures, LATE