Targeting the Ets Binding Site of the HER2/neu Promoter with Pyrrole-Imidazole Polyamides

Three DNA binding polyamides (1-3) were synthesized that bind with high affinity (Ka = 8.7·10^9 M^-1 to 1.4·10^10 M^-1) to two 7-base pair sequences overlapping the Ets DNA binding site (EBS; GAGGAA) within the regulatory region of the HER2/neu proximal promoter. As measured by electrophoretic mobility shift assay, polyamides binding to flanking elements upstream (1) or downstream (2 and 3) of the EBS were one to two orders of magnitude more effective than the natural product distamycin at inhibiting formation of complexes between the purified EBS protein, epithelial restricted with serine box (ESX), and the HER2/neu promoter probe. One polyamide, 2, completely blocked Ets-DNA complex formation at 10 nM ligand concentration, whereas formation of activator protein-2-DNA complexes was unaffected at the activator protein-2 binding site immediately upstream of the HER2/neu EBS, even at 100 nM ligand concentration. At equilibrium, polyamide 1 was equally effective at inhibiting Ets/DNA binding when added before or after in vitro formation of protein-promoter complexes, demonstrating its utility to disrupt endogenous Ets-mediated HER2/neu preinitiation complexes. Polyamide 2, the most potent inhibitor of Ets-DNA complex formation by electrophoretic mobility shift assay, was also the most effective inhibitor of HER2/neu promoter-driven transcription measured in a cell-free system using nuclear extract from an ESX- and HER2/neu-overexpressing human breast cancer cell line, SKBR-3

Physiologic adaptations of the tubuloglomerular feedback system

The maintenance of volume homeostasis is sufficiently important to mammalian terrestrial life that a large amount of evolutionary energy has been expended in the development of multiple control systems, each involved in regulating the volume and composition of internal body fluids. The kidney, which participates in most of these systems, has evolved physiologic attributes which enhance the efficiency of volume regulation. Perhaps the most fundamental of these attributes is a close coordination between the processes of glomerular filtration and tubular reabsorption. Such coordination is required to prevent the amplification of small fluctuations in glomerular filtration rate into large fluctuations in total body salt and water content.It was first suggested by Homer Smith that reabsorption of fluid from the nephron should increase as the delivery of tubular fluid into that segment increases [1]. When applied to the proximal tubule, this principle of flow-dependent transport has come to be referred to as “glomerulotubular balance” [2, 3]. Glomerulotubular balance depends upon intrinsic properties of the proximal nephron including the affinities and densities of various solute transporters and the differential permeabilities of the nephron to various solutes and water, and upon the trans-epithelial concentration gradients of these solutes [4–6]. By definition, glomerulotubular balance describes the functional dependence of tubular reabsorption on glomerular filtration rate independently of other neuro-humoral effectors of tubular transport. However, since glomerulotubular balance is a substrate-driven process, it cannot accomplish an increment in proximal tubular reabsorption which exceeds an increment in delivered load. Therefore, in the absence of effectors other than glomerulotubular balance the volume of fluid entering the distal nephron must be a monotonically increasing function of GFR [7].How then, may the kidney avert an unintentional diuresis should the hemodynamic forces favoring glomerular filtration combine to overwhelm the reabsorptive capacity of the nephron? In 1937 Goormaghtigh suggested that the juxtaglomerular apparatus might participate in the maintenance of volume homeostasis by generating some sort of signal in response to changes in the composition of distal tubular fluid [8]. The peculiar anatomic arrangement of the nephron would facilitate transmission of this signal to the upstream glomerulus and lead to alterations in the physiologic determinants of glomerular filtration. This hypothesis has been refined over the past three decades as substantial experimental data have accrued to support the existence of an operational system of tubuloglomerular feedback (TGF) [9]. Contemporary models of the TGF system, by analogy to negative feedback-driven control systems in engineering control theory, divide the system into three component processes [10]. The first of these components is a parameter which the system is designed to regulate, in this case, the rate at which tubular fluid transits the late proximal nephron or VLP. The second component includes the macula densa and surrounding interstitium which serve to detect differences between the current value of VLP and some internal set-point, and translate this information into an output command. The third component, or effector limb, of the TGF system is constituted by the contractile glomerular mesangium and glomerular arterioles which respond to the aforementioned output command by altering nephron filtration rate (SNGFR) to keep VLP in line with the system's internal set-point. When TGF is allowed to function as a closed-loop system [7], as is the case in vivo, its presence is, by nature, undetectable. However, when late proximal flow is uncoupled from nephron filtration by artificial microperfusion of the late proximal tubule, a dependence of SNGFR on VLP can be defined [11]. This relationship is referred to as the “TGF function”, or “gain” of the TGF system [7, 10]. This TGF function specifies a continuum of points in the VLP-SNGFR plane at which the nephron may operate. The actual operating point of the system exists at the point in this plane where the TGF and glomerulotubular balance functions intersect (Fig. 1).The TGF function may vary in response to the changing needs of the organism, both with regard to volume homeostasis and renal function. The altering of TGF under conditions of pregnancy, loss of renal mass, and a variety of other pathophysiologic conditions suggests that the juxtaglomerular apparatus is involved in events pertinent not merely to volume regulation but to overall renal growth and function

Addition of tabulated equation of state and neutrino leakage support to IllinoisGRMHD

We have added support for realistic, microphysical, finite-temperature equations of state (EOS) and neutrino physics via a leakage scheme to IllinoisGRMHD, an open-source GRMHD code for dynamical spacetimes in the Einstein Toolkit. These new features are provided by two new, NRPy+-based codes: NRPyEOS, which performs highly efficient EOS table lookups and interpolations, and NRPyLeakage, which implements a new, AMR-capable neutrino leakage scheme in the Einstein Toolkit. We have performed a series of strenuous validation tests that demonstrate the robustness of these new codes, particularly on the Cartesian AMR grids provided by Carpet. Furthermore, we show results from fully dynamical GRMHD simulations of single unmagnetized neutron stars, and magnetized binary neutron star mergers. This new version of IllinoisGRMHD, as well as NRPyEOS and NRPyLeakage, is pedagogically documented in Jupyter notebooks and fully open source. The codes will be proposed for inclusion in an upcoming version of the Einstein Toolkit.Comment: 20 pages, 9 figures. v2 matches PRD versio

The Revised TESS Input Catalog and Candidate Target List

We describe the catalogs assembled and the algorithms used to populate the revised TESS Input Catalog (TIC), based on the incorporation of the Gaia second data release. We also describe a revised ranking system for prioritizing stars for 2-minute cadence observations, and assemble a revised Candidate Target List (CTL) using that ranking. The TIC is available on the Mikulski Archive for Space Telescopes (MAST) server, and an enhanced CTL is available through the Filtergraph data visualization portal system at the URL http://filtergraph.vanderbilt.edu/tess_ctl.Comment: 30 pages, 16 figures, submitted to AAS Journals; provided to the community in advance of publication in conjunction with public release of the TIC/CTL on 28 May 201

Gravity-darkening Analysis of the Misaligned Hot Jupiter MASCARA-4 b

MASCARA-4 b is a hot Jupiter in a highly misaligned orbit around a rapidly rotating A3V star that was observed for 54 days by the Transiting Exoplanet Survey Satellite (TESS). We perform two analyses of MASCARA-4 b using a stellar gravity-darkened model. First, we measure MASCARA-4 b's misaligned orbital configuration by modeling its TESS photometric light curve. We take advantage of the asymmetry in MASCARA-4 b's transit due to its host star's gravity-darkened surface to measure MASCARA-4 b's true spin–orbit angle to be 104°+7°-13°. We also detect a ~4σ secondary eclipse at 0.491 ± 0.007 orbital phase, proving that the orbit is slightly eccentric. Second, we model MASCARA-4 b's insolation including gravity darkening and find that the planet's received X-ray and ultraviolet flux varies by 4% throughout its orbit. MASCARA-4 b's short-period, polar orbit suggests that the planet likely underwent dramatic orbital evolution to end up in its present-day configuration and that it receives a varying stellar irradiance that perpetually forces the planet out of thermal equilibrium. These findings make MASCARA-4 b an excellent target for follow-up characterization to better understand the orbital evolution and present-day environment of planets around high-mass stars

Does a local financial incentive scheme reduce inequalities in the delivery of clinical care in a socially deprived community? A longitudinal data analysis.

BACKGROUND: Socioeconomic deprivation is associated with inequalities in health care and outcomes. Despite concerns that the Quality and Outcomes Framework pay-for-performance scheme in the UK would exacerbate inequalities in primary care delivery, gaps closed over time. Local schemes were promoted as a means of improving clinical engagement by addressing local health priorities. We evaluated equity in achievement of target indicators and practice income for one local scheme. METHODS: We undertook a longitudinal survey over four years of routinely recorded clinical data for all 83 primary care practices. Sixteen indicators were developed that covered five local clinical and public health priorities: weight management; alcohol consumption; learning disabilities; osteoporosis; and chlamydia screening. Clinical indicators were logit transformed from a percentage achievement scale and modelled allowing for clustering of repeated measures within practices. This enabled our study of target achievements over time with respect to deprivation. Practice income was also explored. RESULTS: Higher practice deprivation was associated with poorer performance for five indicators: alcohol use registration (OR 0.97; 95 % confidence interval 0.96,0.99); recorded chlamydia test result (OR 0.97; 0.94,0.99); osteoporosis registration (OR 0.98; 0.97,0.99); registration of repeat prednisolone prescription (OR 0.98; 0.96,0.99); and prednisolone registration with record of dual energy X-ray absorptiometry (DEXA) scan/referral (OR 0.92; 0.86,0.97); practices in deprived areas performed better for one indicator (registration of osteoporotic fragility fracture (OR 1.26; 1.04,1.51). The deprivation-achievement gap widened for one indicator (registered females aged 65-74 with a fracture referred for a DEXA scan; OR 0.97; 0.95,0.99). Two other indicators indicated a similar trend over two years before being withdrawn (registration of fragility fracture and over-75 s with a fragility fracture assessed and treated for osteoporosis risk). For one indicator the deprivation-achievement gap reduced over time (repeat prednisolone prescription (OR 1.01; 1.01,1.01). Larger practices and those serving more affluent areas earned more income per patient than smaller practices and those serving more deprived areas (t = -3.99; p =0.0001). CONCLUSIONS: Any gaps in achievement between practices were modest but mostly sustained or widened over the duration of the scheme. Given that financial rewards may not reflect the amount of work undertaken by practices serving more deprived patients, future pay-for-performance schemes also need to address fairness of rewards in relation to workload

A new cross term in the two-particle Hanbury-Brown-Twiss correlation function

Using two specific models and a model-independent formalism, we show that in addition to the usual quadratic ``side'', ``out'' and ``longitudinal'' terms, a previously neglected ``out-longitudinal'' cross term arises naturally in the exponent of the two-particle correlator. Since its effects can be easily observed, such a term should be included in any experimental fits to correlation data. We also suggest a method of organizing correlation data using rapidity rather than longitudinal momentum differences since in the former every relevant quantity is longitudinally boost invariant.Comment: 11 pages, RevTeX 3.0 and 2 postscript figure

Science Impacts of the SPHEREx All-Sky Optical to Near-Infrared Spectral Survey: Report of a Community Workshop Examining Extragalactic, Galactic, Stellar and Planetary Science

SPHEREx is a proposed SMEX mission selected for Phase A. SPHEREx will carry out the first all-sky spectral survey and provide for every 6.2" pixel a spectra between 0.75 and 4.18 $\mu$m [with R$\sim$41.4] and 4.18 and 5.00 $\mu$m [with R$\sim$135]. The SPHEREx team has proposed three specific science investigations to be carried out with this unique data set: cosmic inflation, interstellar and circumstellar ices, and the extra-galactic background light. It is readily apparent, however, that many other questions in astrophysics and planetary sciences could be addressed with the SPHEREx data. The SPHEREx team convened a community workshop in February 2016, with the intent of enlisting the aid of a larger group of scientists in defining these questions. This paper summarizes the rich and varied menu of investigations that was laid out. It includes studies of the composition of main belt and Trojan/Greek asteroids; mapping the zodiacal light with unprecedented spatial and spectral resolution; identifying and studying very low-metallicity stars; improving stellar parameters in order to better characterize transiting exoplanets; studying aliphatic and aromatic carbon-bearing molecules in the interstellar medium; mapping star formation rates in nearby galaxies; determining the redshift of clusters of galaxies; identifying high redshift quasars over the full sky; and providing a NIR spectrum for most eROSITA X-ray sources. All of these investigations, and others not listed here, can be carried out with the nominal all-sky spectra to be produced by SPHEREx. In addition, the workshop defined enhanced data products and user tools which would facilitate some of these scientific studies. Finally, the workshop noted the high degrees of synergy between SPHEREx and a number of other current or forthcoming programs, including JWST, WFIRST, Euclid, GAIA, K2/Kepler, TESS, eROSITA and LSST.Comment: Report of the First SPHEREx Community Workshop, http://spherex.caltech.edu/Workshop.html , 84 pages, 28 figure