STAT3 Dysregulation of XRCC1 Results on Altered Base Excision Repair

Base Excision Repair (BER) is a critical DNA repair pathway, repairing base damage, the spontaneous decay of bases, abasic sites, and single-strand DNA breaks. BER requires the sequential action of multiple proteins, including poly(ADP ribose) polymerase 1 (PARP1), X-ray cross complementing group 1 (XRCC1), and DNA polymerase beta (POL ). Expression changes and polymorphisms in BER proteins alter the response of cancer cells to multiple DNA damaging chemotherapeutics, with overexpression of XRCC1 increasing chemoresistance in gastric, gallbladder, and ovarian cancer. However, the transcriptional regulation of XRCC1 remains largely understudied. Here, we identify the signal transducer and activator of transcription 3 (STAT3) as a novel regulator of XRCC1 in TNBC cell line models, the osteosarcoma cell line U2OS, and the human embryonic kidney cell line HEK293T. Glucose, epidermal growth factor (EGF) and interleukin 6 (IL-6) are all known to activate STAT3 and promote transcription We have found that this constitutive activation results in persistent occupancy of STAT3 at the XRCC1 promoter in TNBC cell lines, inducing overexpression of XRCC1 protein. However, the non-tumorigenic HEK293T cell line and osteosarcoma U2OS cell line do not have constitutively activated STAT3 but demonstrate an inducible response to the activation of STAT3 from exogenous stimuli. Using acute exposures to EGF, IL-6, and glucose, we observed increased activated STAT3 and subsequent increases in XRCC1 expression in HEK293T and xvii U2OS cells. Critically, the increased XRCC1 expression induced by high glucose exposure resulted in increased DNA repair, measured through alkaline comet assay, and increased survival following methyl methanesulfonate (MMS) challenge in both HEK293T and U2OS cells. Furthermore, continued exposure to elevated glucose concentrations resulted in persistent STAT3 occupancy at the XRCC1 promoter and elevated XRCC1 expression in both HEK293T and U2OS cells, similar to what is seen in constitutively active TNBC cell lines. Low glucose adaption reversed these effects by reducing STAT3 activation and occupancy at the XRCC1 promoter in the HEK293T U2OS cells. However, low glucose adaptation in the MDA-MB-231, which have constitutively active STAT3, only slightly reduced STAT3 activation. Upstream regulators of STAT3 revealed a correlation between IL-6R expression and the inducibility of STAT3 activation and subsequent XRCC1 expression. High EGFR expression and low IL-6R expression resulted in minimal inducibility of MDA-231. In addition to these findings, we also identified POLB as a target for STAT3 regulation and mapped the STAT3 binding site within the POLB promoter. These results demonstrate that activation of STAT3 regulates XRCC1 expression and altered BER functions across various cell line models. More importantly, it links constitutive activation of STAT3 with dysregulation of XRCC1 and BER in TNBC cells and undercovers a critical mechanism by which XRCC1 can become dysregulated in cancer and promote chemoresistance

Astrometric orbits of SB9 stars

Hipparcos Intermediate Astrometric Data (IAD) have been used to derive astrometric orbital elements for spectroscopic binaries from the newly released Ninth Catalogue of Spectroscopic Binary Orbits (SB9). Among the 1374 binaries from SB9 which have an HIP entry, 282 have detectable orbital astrometric motion (at the 5% significance level). Among those, only 70 have astrometric orbital elements that are reliably determined (according to specific statistical tests discussed in the paper), and for the first time for 20 systems, representing a 10% increase relative to the 235 DMSA/O systems already present in the Hipparcos Double and Multiple Systems Annex. The detection of the astrometric orbital motion when the Hipparcos IAD are supplemented by the spectroscopic orbital elements is close to 100% for binaries with only one visible component, provided that the period is in the 50 - 1000 d range and the parallax is larger than 5 mas. This result is an interesting testbed to guide the choice of algorithms and statistical tests to be used in the search for astrometric binaries during the forthcoming ESA Gaia mission. Finally, orbital inclinations provided by the present analysis have been used to derive several astrophysical quantities. For instance, 29 among the 70 systems with reliable astrometric orbital elements involve main sequence stars for which the companion mass could be derived. Some interesting conclusions may be drawn from this new set of stellar masses, like the enigmatic nature of the companion to the Hyades F dwarf HIP 20935. This system has a mass ratio of 0.98 but the companion remains elusive.Comment: Astronomy & Astrophysics, in press (16 pages, 12 figures); also available at http://www.astro.ulb.ac.be/Html/ps.html#Astrometr

Do Childhood Vaccines Have Non-Specific Effects on Mortality

A recent article by Kristensen et al. suggested that measles vaccine and bacille Calmette–Guérin (BCG) vaccine might\ud reduce mortality beyond what is expected simply from protection against measles and tuberculosis. Previous reviews of the potential effects of childhood vaccines on mortality have not considered methodological features of reviewed studies. Methodological considerations play an especially important role in observational assessments, in which selection factors for vaccination may be difficult to ascertain. We reviewed 782 English language articles on vaccines and childhood mortality and found only a few whose design met the criteria for methodological rigor. The data reviewed suggest that measles vaccine delivers its promised reduction in mortality, but there is insufficient evidence to suggest a mortality benefit above that caused by its effect on measles disease and its sequelae. Our review of the available data in the literature reinforces how difficult answering these considerations has been and how important study design will be in determining the effect of specific vaccines on all-cause mortality.\u

Obsidian Samples from Archaeological Sites in Northwestern Alaska: A Preliminary Report

Reports the Na and Mn contents and Na/Mn ratios, determined by neutron activation analyses of 103 obsidian samples from the Onion Portage and nine related archeological sites. The occurrence and stratigraphic distribution are noted of four groups of obsidian distinguished by Mn content and Na/Mn ratio. Group B, the largest, appears in a complex with an age of 4000-3900 BC and in another of 1000-1700 AD, group A in complexes dating at 2600-2200 and 1500-500 BC, group C occurs 2200-1800 BC; and group D 400-1700 AD. There are at least four obsidian sources represented whose geographic locations are unknown

Modern Analysis Techniques for Spectroscopic Binaries

Techniques to extract information from spectra of unresolved multi-component systems are revised, with emphasis on recent developments and practical aspects. We review the cross-correlation techniques developed to deal with such spectra, discuss the determination of the broadening function and compare techniques to reconstruct component spectra. The recent results obtained by separating or disentangling the component spectra is summarized. An evaluation is made of possible indeterminacies and random and systematic errors in the component spectra.Comment: 12 pages, 3 figures, Invited talk to appear in the proceedings of IAU Symp. No. 240 'Binary Stars as Critical Tools and Tests in Contemporary Astrophysics' (Prague, 22-25 August 2006), Eds. W. Hartkopf, E. Guinan & P. Harmanec (Cambridge Univ. Press

The Highly Miniaturised Radiation Monitor

We present the design and preliminary calibration results of a novel highly miniaturised particle radiation monitor (HMRM) for spacecraft use. The HMRM device comprises a telescopic configuration of active pixel sensors enclosed in a titanium shield, with an estimated total mass of 52 g and volume of 15 cm$^3$. The monitor is intended to provide real-time dosimetry and identification of energetic charged particles in fluxes of up to 10$^8$ cm$^{-2}$ s$^{-1}$ (omnidirectional). Achieving this capability with such a small instrument could open new prospects for radiation detection in space.Comment: 17 pages, 15 figure

Sparse Estimation using Bayesian Hierarchical Prior Modeling for Real and Complex Linear Models

In sparse Bayesian learning (SBL), Gaussian scale mixtures (GSMs) have been used to model sparsity-inducing priors that realize a class of concave penalty functions for the regression task in real-valued signal models. Motivated by the relative scarcity of formal tools for SBL in complex-valued models, this paper proposes a GSM model - the Bessel K model - that induces concave penalty functions for the estimation of complex sparse signals. The properties of the Bessel K model are analyzed when it is applied to Type I and Type II estimation. This analysis reveals that, by tuning the parameters of the mixing pdf different penalty functions are invoked depending on the estimation type used, the value of the noise variance, and whether real or complex signals are estimated. Using the Bessel K model, we derive a sparse estimator based on a modification of the expectation-maximization algorithm formulated for Type II estimation. The estimator includes as a special instance the algorithms proposed by Tipping and Faul [1] and by Babacan et al. [2]. Numerical results show the superiority of the proposed estimator over these state-of-the-art estimators in terms of convergence speed, sparseness, reconstruction error, and robustness in low and medium signal-to-noise ratio regimes.Comment: The paper provides a new comprehensive analysis of the theoretical foundations of the proposed estimators. Minor modification of the titl

Rotation, activity, and lithium abundance in cool binary stars

We have used two robotic telescopes to obtain time-series high-resolution spectroscopy and V I and/or by photometry for a sample of 60 active stars. Orbital solutions are presented for 26 SB2 and 19 SB1 systems with unprecedented phase coverage and accuracy. The total of 6,609 R=55,000 echelle spectra are also used to systematically determine effective temperatures, gravities, metallicities, rotational velocities, lithium abundances and absolute H{\alpha}-core fluxes as a function of time. The photometry is used to infer unspotted brightness, V - I and/or b - y colors, spot-induced brightness amplitudes and precise rotation periods. Our data are complemented by literature data and are used to determine rotation-temperature-activity relations for active binary components. We also relate lithium abundance to rotation and surface temperature. We find that 74% of all known rapidly-rotating active binary stars are synchronized and in circular orbits but 26% are rotating asynchronously of which half have Prot > Porb and e > 0. Because rotational synchronization is predicted to occur before orbital circularization active binaries should undergo an extra spin-down besides tidal dissipation. We suspect this to be due to a magnetically channeled wind with its subsequent braking torque. We find a steep increase of rotation period with decreasing effective temperature for active stars. For inactive, single giants with Prot > 100 d, the relation is much weaker. Our data also indicate a period-activity relation for H{\alpha} of the form RH{\alpha} \propto P - 0.24 for binaries and RH{\alpha} \propto P -0.14 for singles. Lithium abundances in our sample increase with effective temperature. On average, binaries of comparable effective temperature appear to exhibit 0.25 dex less surface lithium than singles. We also find a trend of increased Li abundance with rotational period of form log n(Li) \propto - 0.6 log Prot

Cutoff in the Bernoulli-Laplace Model With Unequal Colors and Urn Sizes

We consider a generalization of the Bernoulli-Laplace model in which there are two urns and $n$ total balls, of which $r$ are red and $n - r$ white, and where the left urn holds $m$ balls. At each time increment, $k$ balls are chosen uniformly at random from each urn and then swapped. This system can be used to model phenomena such as gas particle interchange between containers or card shuffling. Under a reasonable set of assumptions, we bound the mixing time of the resulting Markov chain asymptotically in $n$ with cutoff at $\log{n}$ and constant window. Among other techniques, we employ the spectral analysis of arXiv:0906.4242 on the Markov transition kernel and the chain coupling tools of arXiv:2203.08647 and arXiv:1606.01437

Helix 11 Dynamics Is Critical for Constitutive Androstane Receptor Activity

SummaryThe constitutive androstane receptor (CAR) transactivation can occur in the absence of exogenous ligand and this activity is enhanced by agonists TCPOBOP and meclizine. We use biophysical and cell-based assays to show that increased activity of CAR(TCPOBOP) relative to CAR(meclizine) corresponds to a higher affinity of CAR(TCPOBOP) for the steroid receptor coactivator-1. Additionally, steady-state fluorescence spectra suggest conformational differences between CAR(TCPOBOP):RXR and CAR(meclizine):RXR. Hydrogen/deuterium exchange (HDX) data indicate that the CAR activation function 2 (AF-2) is more stable in CAR(TCPOBOP):RXR and CAR(meclizine):RXR than in CAR:RXR. HDX kinetics also show significant differences between CAR(TCPOBOP):RXR and CAR(meclizine):RXR. Unlike CAR(meclizine):RXR, CAR(TCPOBOP):RXR shows a higher overall stabilization that extends into RXR. We identify residues 339–345 in CAR as an allosteric regulatory site with a greater magnitude reduction in exchange kinetics in CAR(TCPOBOP):RXR than CAR(meclizine):RXR. Accordingly, assays with mutations on CAR at leucine-340 and leucine-343 confirm this region as an important determinant of CAR activity