Electron transport chain complex II sustains high mitochondrial membrane potential in hematopoietic stem and progenitor cells

The role of mitochondria in the fate determination of hematopoietic stem and progenitor cells (HSPCs) is not solely limited to the switch from glycolysis to oxidative phosphorylation, but also involves alterations in mitochondrial features and properties, including mitochondrial membrane potential (ΔΨmt). HSPCs have a high ΔΨmt even when the rates of respiration and phosphorylation are low, and we have previously shown that the minimum proton flow through ATP synthesis (or complex V) enables high ΔΨmt in HSPCs. Here we show that HSPCs sustain a unique equilibrium between electron transport chain (ETC) complexes and ATP production. HSPCs exhibit high expression of ETC complex II, which sustains complex III in proton pumping, although the expression levels of complex I or V are relatively low. Complex II inhibition by TTFA caused a substantial decrease of ΔΨmt, particularly in HSPCs, while the inhibition of complex I by Rotenone mainly affected mature populations. Functionally, pharmacological inhibition of complex II reduced in vitro colony-replating capacity but this was not observed when complex I was inhibited, which supports the distinct roles of complex I and II in HSPCs. Taken together, these data highlight complex II as a key regulator of ΔΨmt in HSPCs and open new and interesting questions regarding the precise mechanisms that regulate mitochondrial control to maintain hematopoietic stem cell self-renewal

The NJL-jet model for quark fragmentation functions

A description of fragmentation functions which satisfy the momentum and isospin sum rules is presented in an effective quark theory. Concentrating on the pion fragmentation function, we first explain why the elementary (lowest order) fragmentation process q --> q \pi is completely inadequate to describe the empirical data, although the "crossed" process \pi --> q \bar{q} describes the quark distribution functions in the pion reasonably well. Taking into account cascade-like processes in a generalized jet-model approach, we then show that the momentum and isospin sum rules can be satisfied naturally, without the introduction of ad hoc parameters. We present results for the Nambu--Jona-Lasinio (NJL) model in the invariant mass regularization scheme and compare them with the empirical parametrizations. We argue that the NJL-jet model, developed herein, provides a useful framework with which to calculate the fragmentation functions in an effective chiral quark theory.Comment: 21 pages, 7 figure

Instanton Calculus in R-R 3-form Background and Deformed N=2 Super Yang-Mills Theory

We study the ADHM construction of instantons in N=2 supersymmetric Yang-Mills theory deformed in constant Ramond-Ramond (R-R) 3-form field strength background in type IIB superstrings. We compare the deformed instanton effective action with the effective action of fractional D3/D(-1) branes at the orbifold singularity of C^2/Z_2 in the same R-R background. We find discrepancy between them at the second order in deformation parameters, which comes from the coupling of the translational zero modes of the D(-1)-branes to the R-R background. We improve the deformed action by adding a term with space-time dependent gauge coupling. Although the space-time action differs from the action in the omega-background, both actions lead to the same instanton equations of motion at the lowest order in gauge coupling.Comment: 27 pages, version to appear in JHE

Spontaneous structure formation in a network of chaotic units with variable connection strengths

As a model of temporally evolving networks, we consider a globally coupled logistic map with variable connection weights. The model exhibits self-organization of network structure, reflected by the collective behavior of units. Structural order emerges even without any inter-unit synchronization of dynamics. Within this structure, units spontaneously separate into two groups whose distinguishing feature is that the first group possesses many outwardly-directed connections to the second group, while the second group possesses only few outwardly-directed connections to the first. The relevance of the results to structure formation in neural networks is briefly discussed.Comment: 4 pages, 3 figures, REVTe

BPS Monopole Equation in Omega-background

We study deformed supersymmetries in N=2 super Yang-Mills theory in the Omega-backgrounds characterized by two complex parameters $\epsilon_1, \epsilon_2$. When one of the $\epsilon$-parameters vanishes, the theory has extended supersymmetries. We compute the central charge of the algebra and obtain the deformed BPS monopole equation. We examine supersymmetries preserved by the equation.Comment: 14 pages, typos corrected, published version in JHE

Oxidative stress dependent microRNA-34a activation via PI3Kα reduces the expression of sirtuin-1 and sirtuin-6 in epithelial cells

Sirtuin-1 (SIRT1) and SIRT6, NAD(+)-dependent Class III protein deacetylases, are putative anti-aging enzymes, down-regulated in patients with chronic obstructive pulmonary disease (COPD), which is characterized by the accelerated ageing of the lung and associated with increased oxidative stress. Here, we show that oxidative stress (hydrogen peroxide) selectively elevates microRNA-34a (miR-34a) but not the related miR-34b/c, with concomitant reduction of SIRT1/-6 in bronchial epithelial cells (BEAS2B), which was also observed in peripheral lung samples from patients with COPD. Over-expression of a miR-34a mimic caused a significant reduction in both mRNA and protein of SIRT1/-6, whereas inhibition of miR-34a (antagomir) increased these sirtuins. Induction of miR-34a expression with H2O2 was phosphoinositide-3-kinase (PI3K) dependent as it was associated with PI3Kα activation as well as phosphatase and tensin homolog (PTEN) reduction. Importantly, miR-34a antagomirs increased SIRT1/-6 mRNA levels, whilst decreasing markers of cellular senescence in airway epithelial cells from COPD patients, suggesting that this process is reversible. Other sirtuin isoforms were not affected by miR-34a. Our data indicate that miR-34a is induced by oxidative stress via PI3K signaling, and orchestrates ageing responses under oxidative stress, therefore highlighting miR-34a as a new therapeutic target and biomarker in COPD and other oxidative stress-driven aging diseases

The chemotherapeutic agent DMXAA as a unique IRF3-dependent type-2 vaccine adjuvant

5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a potent type I interferon (IFN) inducer, was evaluated as a chemotherapeutic agent in mouse cancer models and proved to be well tolerated in human cancer clinical trials. Despite its multiple biological functions, DMXAA has not been fully characterized for the potential application as a vaccine adjuvant. In this report, we show that DMXAA does act as an adjuvant due to its unique property as a soluble innate immune activator. Using OVA as a model antigen, DMXAA was demonstrated to improve on the antigen specific immune responses and induce a preferential Th2 (Type-2) response. The adjuvant effect was directly dependent on the IRF3-mediated production of type-I-interferon, but not IL-33. DMXAA could also enhance the immunogenicity of influenza split vaccine which led to significant increase in protective responses against live influenza virus challenge in mice compared to split vaccine alone. We propose that DMXAA can be used as an adjuvant that targets a specific innate immune signaling pathway via IRF3 for potential applications including vaccines against influenza which requires a high safety profile

A Note on the Picard-Fuchs Equations for N=2 Seiberg-Witten Theories

A concise presentation of the PF equations for N=2 Seiberg-Witten theories for the classical groups of rank r with N_f massless hypermultiplets in the fundamental representation is provided. For N_f=0, all r PF equations can be given in a generic form. For certain cases with N_f\neq zero, not all equations are generic. However, in all cases there are at least r-2 generic PF equations. For these cases the classical part of the equations is generic, while the quantum part can be formulated using a method described in a previous paper by the authors, which is well suited to symbolic computer calculations.Comment: 25 pages, Latex; some new references adde