Chemoselective oxidation of aryl organoboron systems enabled by boronic acid-selective phase transfer

We report the direct chemoselective Brown-type oxidation of aryl organoboron systems containing two oxidizable boron groups. Basic biphasic reaction conditions enable selective formation and phase transfer of a boronic acid trihydroxyboronate in the presence of boronic acid pinacol (BPin) esters, while avoiding speciation equilibria. Spectroscopic investigations validate a base-promoted phase-selective discrimination of organoboron species. This phenomenon is general across a broad range of organoboron compounds and can also be used to invert conventional protecting group strategies, enabling chemoselective oxidation of BMIDA species over normally more reactive BPin substrates. We also demonstrate the selective oxidation of diboronic acid systems with chemoselectivity predictable a priori. The utility of this method is exemplified through the development of a chemoselective oxidative nucleophile coupling

Optical nanofibers and spectroscopy

We review our recent progress in the production and characterization of tapered optical fibers with a sub-wavelength diameter waist. Such fibers exhibit a pronounced evanescent field and are therefore a useful tool for highly sensitive evanescent wave spectroscopy of adsorbates on the fiber waist or of the medium surrounding. We use a carefully designed flame pulling process that allows us to realize preset fiber diameter profiles. In order to determine the waist diameter and to verify the fiber profile, we employ scanning electron microscope measurements and a novel accurate in situ optical method based on harmonic generation. We use our fibers for linear and non-linear absorption and fluorescence spectroscopy of surface-adsorbed organic molecules and investigate their agglomeration dynamics. Furthermore, we apply our spectroscopic method to quantum dots on the surface of the fiber waist and to caesium vapor surrounding the fiber. Finally, towards dispersive measurements, we present our first results on building and testing a single-fiber bi-modal interferometer.Comment: 13 pages, 18 figures. Accepted for publication in Applied Physics B. Changes according to referee suggestions: changed title, clarification of some points in the text, added references, replacement of Figure 13

Numerical solution of a pursuit-evasion differential game involving two spacecraft in low earth orbit

This paper considers a spacecraft pursuit-evasion problem taking place in low earth orbit. The problem is formulated as a zero-sum differential game in which there are two players, a pursuing spacecraft that attempts to minimize a payoff, and an evading spacecraft that attempts to maximize the same payoff. We introduce two associated optimal control problems and show that a saddle point for the differential game exists if and only if the two optimal control problems have the same optimal value. Then, on the basis of this result, we propose two computational methods for determining a saddle point solution: a semi-direct control parameterization method (SDCP method), which is based on a piecewise-constant control approximation scheme, and a hybrid method, which combines the new SDCP method with the multiple shooting method. Simulation results show that the proposed SDCP and hybrid methodsare superior to the semi-direct collocation nonlinear programming method (SDCNLP method), which is widely used to solve pursuit-evasion problems in the aerospace field

Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma

Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation, while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic RNAs to bind to and be stabilized by HEXIM1. HEXIM1 plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals an important role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma

The Role of Rumination and Reduced Concreteness in the Maintenance of Posttraumatic Stress Disorder and Depression Following Trauma

Rumination has been linked to posttraumatic stress disorder (PTSD) and depression following trauma. A cross-sectional (N = 101) and a prospective longitudinal study (N = 147) of road traffic accident survivors assessed rumination, PTSD and depression with self-report measures and structured interviews. We tested the hypotheses that (1) rumination predicts the maintenance of PTSD and depression and (2) reduced concreteness of ruminative thinking may be a maintaining factor. Rumination significantly predicted PTSD and depression at 6 months over and above what could be predicted from initial symptom levels. In contrast to the second hypothesis, reduced concreteness in an iterative rumination task was not significantly correlated with self-reported rumination frequency, and did not consistently correlate with symptom severity measures. However, multiple regression analyses showed that the combination of reduced concreteness and self-reported frequency of rumination predicted subsequent PTSD better than rumination frequency alone. The results support the view that rumination is an important maintaining factor of trauma-related emotional disorders

Effective Caspase Inhibition Blocks Neutrophil Apoptosis and Reveals Mcl-1 as Both a Regulator and a Target of Neutrophil Caspase Activation

Human tissue inflammation is terminated, at least in part, by the death of inflammatory neutrophils by apoptosis. The regulation of this process is therefore key to understanding and manipulating inflammation resolution. Previous data have suggested that the short-lived pro-survival Bcl-2 family protein, Mcl-1, is instrumental in determining neutrophil lifespan. However, Mcl-1 can be cleaved following caspase activity, and the possibility therefore remains that the observed fall in Mcl-1 levels is due to caspase activity downstream of caspase activation, rather than being a key event initiating apoptosis in human neutrophils

The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer

available in PMC 2011 February 3.MCL-1 has emerged as a major oncogenic and chemoresistance factor. A screen of stapled peptide helices identified the MCL-1 BH3 domain as selectively inhibiting MCL-1 among the related anti-apoptotic Bcl-2 family members, providing insights into the molecular determinants of binding specificity and a new approach for sensitizing cancer cells to apoptosis.National Institutes of Health (U.S.) (NIH award 5RO1GM084181)National Institutes of Health (U.S.) (NIH grant 5P01CA92625)National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F31CA144566)Burroughs Wellcome Fund (Career Award

Suppression of Mcl-1 via RNA interference sensitizes human hepatocellular carcinoma cells towards apoptosis induction

BACKGROUND: Hepatocelluar carcinoma (HCC) is one of the most common cancers worldwide and a major cause of cancer-related mortality. HCC is highly resistant to currently available chemotherapeutic drugs. Defects in apoptosis signaling contribute to this resistance. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 protein family which interferes with mitochondrial activation. In a previous study we have shown that Mcl-1 is highly expressed in tissues of human HCC. In this study, we manipulated expression of the Mcl-1 protein in HCC cells by RNA interference and analyzed its impact on apoptosis sensitivity of HCC cells in vitro. METHODS: RNA interference was performed by transfecting siRNA to specifically knock down Mcl-1 expression in HCC cells. Mcl-1 expression was measured by quantitative real-time PCR and Western blot. Induction of apoptosis and caspase activity after treatment with chemotherapeutic drugs and different targeted therapies were measured by flow cytometry and fluorometric analysis, respectively. RESULTS: Here we demonstrate that Mcl-1 expressing HCC cell lines show low sensitivity towards treatment with a panel of chemotherapeutic drugs. However, treatment with the anthracycline derivative epirubicin resulted in comparatively high apoptosis rates in HCC cells. Inhibition of the kinase PI3K significantly increased apoptosis induction by chemotherapy. RNA interference efficiently downregulated Mcl-1 expression in HCC cells. Mcl-1 downregulation sensitized HCC cells to different chemotherapeutic agents. Sensitization was accompanied by profound activation of caspase-3 and -9. In addition, Mcl-1 downregulation also increased apoptosis rates after treatment with PI3K inhibitors and, to a lower extent, after treatment with mTOR, Raf I and VEGF/PDGF kinase inhibitors. TRAIL-induced apoptosis did not markedly respond to Mcl-1 knockdown. Additionally, knockdown of Mcl-1 efficiently enhanced apoptosis sensitivity towards combined treatment modalities: Mcl-1 knockdown significantly augmented apoptosis sensitivity of HCC cells towards chemotherapy combined with PI3K inhibition. CONCLUSION: Our data suggest that specific downregulation of Mcl-1 by RNA interference is a promising approach to sensitize HCC cells towards chemotherapy and molecularly targeted therapies