The Role of Histone Acetyltransferases in Normal and Malignant Hematopoiesis

Histone or non-histone protein acetylation plays important roles in all kinds of cellular events, including the normal and abnormal development of blood cells, through changing the epigenetic status of chromatin and regulating non-histone protein’s function. Histone acetyltransferases (HATs), which are the enzymes responsible for the histone or non-histone protein acetylation, contain p300/CBP, MYST and GNAT family etc. HATs are not only the protein modifiers and epigenetic factors, but also the critical regulators of cell development and cancerogenesis. Here we will review the function of HATs such as p300/CBP, Tip60, MOZ/MORF and GCN5/PCAF in the normal hematopoiesis and the pathogenesis of hematological malignancies. The inhibitors that have been developed to target HATs will also be reviewed here. Understanding the roles of HATs in normal/malignant hematopoiesis and the underlying mechanism will provide the potential therapeutic targets for the hematological malignancies

Influence of EOM sideband modulation noise on space-borne gravitational wave detection

Clock noise is one of the dominant noises in the space-borne gravitational wave (GW) detection. To suppress this noise, the clock noise-calibrated time-delay-interferometry (TDI) technique is proposed. In this technique, an inter-spacecraft clock tone transfer chain is necessary to obtain the comparison information of the clock noises in two spacecraft, during which an electro-optic-modulator (EOM) is critical and used to modulate the clock noise to the laser phase. Since the EOM sideband modulation process introduces modulation noise, it is significant to put forward the corresponding requirements and assess whether the commercial EOM meets. In this work, based on the typical Michelson TDI algorithm and the fundamental noise requirement of GW detectors, the analytic expression of the modulation noise requirement is strictly derived, which relax the component indicator need compared to the existing commonly used rough assessments. Furthermore, a commercial EOM (iXblue-NIR-10 GHz) is tested, and the experimental results show that it can meet the requirement of the typical GW detection mission LISA in whole scientific bandwidth by taking the optimal combination of the data stream. Even when the displacement measurement accuracy of LISA is improved to 1 pm/ $\mathrm{Hz^{1/2}}$ in the future, it still meets the demand

Experimental demonstration of picometer level signal extraction with time-delay interferometry technique

In this work, we have built an experimental setup to simulate the clock noise transmission with two spacecrafts and two optical links, and further demonstrated the extraction of picometer level signal drowned by the large laser frequency noise and clock noise with the data post-processing method. Laser frequency noise is almost eliminated by using the idea of time-delay interferometry (TDI) to construct an equal arm interferometer. Clock asynchronism and clock jitter noise are significantly suppressed by laser sideband transmitting the clock noise using an electro-optic modulator (EOM). Experimental results show a reduction in laser frequency noise by approximately 10^5 and clock noise by 10^2, recovering a weak displacement signal with an average amplitude about 60 picometer and period 1 second. This work has achieved the principle verification of the noise reduction function of TDI technique to some extent, serving the data processing research of space-borne gravitational wave detection

Discrete-time recurrent neural networks with time-varying delays: Exponential stability analysis

This is the post print version of the article. The official published version can be obtained from the link below - Copyright 2007 Elsevier LtdThis Letter is concerned with the analysis problem of exponential stability for a class of discrete-time recurrent neural networks (DRNNs) with time delays. The delay is of the time-varying nature, and the activation functions are assumed to be neither differentiable nor strict monotonic. Furthermore, the description of the activation functions is more general than the recently commonly used Lipschitz conditions. Under such mild conditions, we first prove the existence of the equilibrium point. Then, by employing a Lyapunov–Krasovskii functional, a unified linear matrix inequality (LMI) approach is developed to establish sufficient conditions for the DRNNs to be globally exponentially stable. It is shown that the delayed DRNNs are globally exponentially stable if a certain LMI is solvable, where the feasibility of such an LMI can be easily checked by using the numerically efficient Matlab LMI Toolbox. A simulation example is presented to show the usefulness of the derived LMI-based stability condition.This work was supported in part by the Engineering and Physical Sciences Research Council (EPSRC) of the UK under Grant GR/S27658/01, the Nuffield Foundation of the UK under Grant NAL/00630/G, the Alexander von Humboldt Foundation of Germany, the Natural Science Foundation of Jiangsu Education Committee of China (05KJB110154), the NSF of Jiangsu Province of China (BK2006064), and the National Natural Science Foundation of China (10471119)

Compound Bieshe Kang’ai inhibits proliferation and induces apoptosis in HCT116 human colorectal cancer cells

Purpose: To study the effect of Compound Bieshe Kang’ai (CBK) on proliferation and apoptosis in colorectal cancer cells.Methods: HCT116 colorectal cancer cells and FHs 74 Int intestinal cells were treated with CBK, followed by determination of cell proliferation with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Caspase-9 and caspase-3 activities as well as protein expressions of Bcl-2 and BAX, and mRNA levels of caspase-9, caspase-3, Bcl-2 and BAX in HCT116 cells were evaluated, followed by examination of the morphological alterations of HCT116 cells with Hoechst 33342 staining.Results: CBK suppressed proliferation of HCT116 cells in a concentration- and time-dependent pattern, without cytotoxicity to FHs 74 Int cells. CBK also elevated caspase-9 and caspase-3 activities, mitigated protein translation of Bcl-2 and augmented that of BAX. It also enhanced mRNA transcriptions of caspase-9, caspase-3 and BAX, but decreased that of Bcl-2 in HCT116 cells in a  concentrationdependent manner, as well as induced cancer cell shrinkage, nuclear fragmentation and chromatin condensation.Conclusion: The findings highlight CBK as a promising therapeutic agent for colorectal cancers, by retarding proliferation and inducing apoptosis in cancer cells.Keywords: Apoptosis, BAX, Bcl-2, Cancer, Caspase, Compound Bieshe Kang’ai, Chromatin condensation, Nuclear fragmentatio

Transferability of N-terminal mutations of pyrrolysyl-tRNA synthetase in one species to that in another species on unnatural amino acid incorporation efficiency

Genetic code expansion is a powerful technique for site-specific incorporation of an unnatural amino acid into a protein of interest. This technique relies on an orthogonal aminoacyl-tRNA synthetase/tRNA pair and has enabled incorporation of over 100 different unnatural amino acids into ribosomally synthesized proteins in cells. Pyrrolysyl-tRNA synthetase (PylRS) and its cognate tRNA from Methanosarcina species are arguably the most widely used orthogonal pair. Here, we investigated whether beneficial effect in unnatural amino acid incorporation caused by N-terminal mutations in PylRS of one species is transferable to PylRS of another species. It was shown that conserved mutations on the N-terminal domain of MmPylRS improved the unnatural amino acid incorporation efficiency up to five folds. As MbPylRS shares high sequence identity to MmPylRS, and the two homologs are often used interchangeably, we examined incorporation of five unnatural amino acids by four MbPylRS variants at two temperatures. Our results indicate that the beneficial N-terminal mutations in MmPylRS did not improve unnatural amino acid incorporation efficiency by MbPylRS. Knowledge from this work contributes to our understanding of PylRS homologs which are needed to improve the technique of genetic code expansion in the future

Inhibition of Fibroblast Growth by Notch1 Signaling Is Mediated by Induction of Wnt11-Dependent WISP-1

Fibroblasts are an integral component of stroma and important source of growth factors and extracellular matrix (ECM). They play a prominent role in maintaining tissue homeostasis and in wound healing and tumor growth. Notch signaling regulates biological function in a variety of cells. To elucidate the physiological function of Notch signaling in fibroblasts, we ablated Notch1 in mouse (Notch1Flox/Flox) embryonic fibroblasts (MEFs). Notch1-deficient (Notch1−/−) MEFs displayed faster growth and motility rate compared to Notch1Flox/Flox MEFs. Such phenotypic changes, however, were reversible by reconstitution of Notch1 activation via overexpression of the intracellular domain of Notch1 (NICD1) in Notch1-deficient MEFs. In contrast, constitutive activation of Notch1 signaling by introducing NICD1 into primary human dermal fibroblasts (FF2441), which caused pan-Notch activation, inhibited cell growth and motility, whereas cellular inhibition was relievable when the Notch activation was countered with dominant-negative mutant of Master-mind like 1 (DN-MAML-1). Functionally, “Notch-activated” stromal fibroblasts could inhibit tumor cell growth/invasion. Moreover, Notch activation induced expression of Wnt-induced secreted proteins-1 (WISP-1/CCN4) in FF2441 cells while deletion of Notch1 in MEFs resulted in an opposite effect. Notably, WISP-1 suppressed fibroblast proliferation, and was responsible for mediating Notch1's inhibitory effect since siRNA-mediated blockade of WISP-1 expression could relieve cell growth inhibition. Notch1-induced WISP-1 expression appeared to be Wnt11-dependent, but Wnt1-independent. Blockade of Wnt11 expression resulted in decreased WISP-1 expression and liberated Notch-induced cell growth inhibition. These findings indicated that inhibition of fibroblast proliferation by Notch pathway activation is mediated, at least in part, through regulating Wnt1-independent, but Wnt11-dependent WISP-1 expression