350 research outputs found
Development of BromoTag:A âBump-&-Holeâ-PROTAC system to induce potent, rapid, and selective degradation of tagged target proteins
[Image: see text] Small-molecule-induced protein depletion technologies, also called inducible degrons, allow degradation of genetically engineered target proteins within cells and animals. Here, we design and develop the BromoTag, a new inducible degron system comprising a Brd4 bromodomain L387A variant as a degron tag that allows direct recruitment by heterobifunctional bumped proteolysis targeting chimeras (PROTACs) to hijack the VHL E3 ligase. We describe extensive optimization and structureâactivity relationships of our bump-and-holeâPROTACs using a CRISPR knock-in cell line expressing model target BromoTag-Brd2 at endogenous levels. Collectively, our cellular and mechanistic data qualifies bumped PROTAC AGB1 as a potent, fast, and selective degrader of BromoTagged proteins, with a favorable pharmacokinetic profile in mice. The BromoTag adds to the arsenal of chemical genetic degradation tools allowing us to manipulate protein levels to interrogate the biological function and therapeutic potential in cells and in vivo
New Hubble Space Telescope Discoveries of Type Ia Supernovae at z > 1: Narrowing Constraints on the Early Behavior of Dark Energy
We have discovered 21 new Type Ia supernovae (SNe Ia) with the Hubble Space
Telescope (HST) and have used them to trace the history of cosmic expansion
over the last 10 billion years. These objects, which include 13
spectroscopically confirmed SNe Ia at z > 1, were discovered during 14 epochs
of reimaging of the GOODS fields North and South over two years with the
Advanced Camera for Surveys on HST. Together with a recalibration of our
previous HST-discovered SNe Ia, the full sample of 23 SNe Ia at z > 1 provides
the highest-redshift sample known. Combined with previous SN Ia datasets, we
measured H(z) at discrete, uncorrelated epochs, reducing the uncertainty of
H(z>1) from 50% to under 20%, strengthening the evidence for a cosmic jerk--the
transition from deceleration in the past to acceleration in the present. The
unique leverage of the HST high-redshift SNe Ia provides the first meaningful
constraint on the dark energy equation-of-state parameter at z >1.
The result remains consistent with a cosmological constant (w(z)=-1), and
rules out rapidly evolving dark energy (dw/dz >>1). The defining property of
dark energy, its negative pressure, appears to be present at z>1, in the epoch
preceding acceleration, with ~98% confidence in our primary fit. Moreover, the
z>1 sample-averaged spectral energy distribution is consistent with that of the
typical SN Ia over the last 10 Gyr, indicating that any spectral evolution of
the properties of SNe Ia with redshift is still below our detection threshold.Comment: typos, references corrected, minor additions to exposition 82 pages,
17 figures, 6 tables. Data also available at:
http://braeburn.pha.jhu.edu/~ariess/R06. Accepted, Astrophysical Journal vol.
656 for March 10, 200
Evidence for dark energy from the cosmic microwave background alone using the Atacama Cosmology Telescope lensing measurements
For the first time, measurements of the cosmic microwave background radiation
(CMB) alone favor cosmologies with dark energy over models without dark
energy at a 3.2-sigma level. We demonstrate this by combining the CMB lensing
deflection power spectrum from the Atacama Cosmology Telescope with temperature
and polarization power spectra from the Wilkinson Microwave Anisotropy Probe.
The lensing data break the geometric degeneracy of different cosmological
models with similar CMB temperature power spectra. Our CMB-only measurement of
the dark energy density confirms other measurements from
supernovae, galaxy clusters and baryon acoustic oscillations, and demonstrates
the power of CMB lensing as a new cosmological tool.Comment: 4 pages, 3 figures; replaced with version accepted by Physical Review
Letters, added sentence on models with non-standard primordial power spectr
Mean first-passage time of surface-mediated diffusion in spherical domains
We present an exact calculation of the mean first-passage time to a target on
the surface of a 2D or 3D spherical domain, for a molecule alternating phases
of surface diffusion on the domain boundary and phases of bulk diffusion. The
presented approach is based on an integral equation which can be solved
analytically. Numerically validated approximation schemes, which provide more
tractable expressions of the mean first-passage time are also proposed. In the
framework of this minimal model of surface-mediated reactions, we show
analytically that the mean reaction time can be minimized as a function of the
desorption rate from the surface.Comment: to appear in J. Stat. Phy
Kinetics of active surface-mediated diffusion in spherically symmetric domains
We present an exact calculation of the mean first-passage time to a target on
the surface of a 2D or 3D spherical domain, for a molecule alternating phases
of surface diffusion on the domain boundary and phases of bulk diffusion. We
generalize the results of [J. Stat. Phys. {\bf 142}, 657 (2011)] and consider a
biased diffusion in a general annulus with an arbitrary number of regularly
spaced targets on a partially reflecting surface. The presented approach is
based on an integral equation which can be solved analytically. Numerically
validated approximation schemes, which provide more tractable expressions of
the mean first-passage time are also proposed. In the framework of this minimal
model of surface-mediated reactions, we show analytically that the mean
reaction time can be minimized as a function of the desorption rate from the
surface.Comment: Published online in J. Stat. Phy
The Atacama Cosmology Telescope: A Measurement of the Thermal Sunyaev-Zel'dovich Effect Using the Skewness of the CMB Temperature Distribution
We present a detection of the unnormalized skewness induced by the
thermal Sunyaev-Zel'dovich (tSZ) effect in filtered Atacama Cosmology Telescope
(ACT) 148 GHz cosmic microwave background temperature maps. Contamination due
to infrared and radio sources is minimized by template subtraction of resolved
sources and by constructing a mask using outlying values in the 218 GHz
(tSZ-null) ACT maps. We measure = -31 +- 6 \mu K^3 (measurement error
only) or +- 14 \mu K^3 (including cosmic variance error) in the filtered ACT
data, a 5-sigma detection. We show that the skewness is a sensitive probe of
sigma_8, and use analytic calculations and tSZ simulations to obtain
cosmological constraints from this measurement. From this signal alone we infer
a value of sigma_8= 0.79 +0.03 -0.03 (68 % C.L.) +0.06 -0.06 (95 % C.L.). Our
results demonstrate that measurements of non-Gaussianity can be a useful method
for characterizing the tSZ effect and extracting the underlying cosmological
information.Comment: 9 pages, 5 figures. Replaced with version accepted by Phys. Rev. D,
with improvements to the likelihood function and the IR source treatment;
only minor changes in the result
Stereoselective synthesis of allele-specific BET inhibitors
Developing stereoselective synthetic routes that are efficient and cost-effective is important to allow easy access to biologically active molecules. Our previous syntheses of allele-selective bumped inhibitors of the Bromo and Extra-Terminal (BET) bromodomain proteins, Brd2, Brd3, Brd4 and BrdT, required a wasteful, late-stage alkylation step and expensive chiral separation. To circumvent these limitations, we developed a route based on stereocontrolled alkylation of an aspartic acid derivative that was used in a divergent, racemisation-free protocol to yield structurally diverse and enantiopure triazolodiazepines. With this approach, we synthesized bumped thienodiazepine-based BET inhibitor, ET-JQ1-OMe, in five steps and 99% ee without the need for chiral chromatography. Exquisite selectivity of ET-JQ1-OMe for Leu-Ala and Leu-Val mutants over wild-type bromodomain was confirmed by isothermal titration calorimetry and X-ray crystallography. Our new approach provides unambiguous chemical evidence for the absolute stereochemistry of the active, allele-specific BET inhibitor and a viable route that will facilitate wider access to this compound class
A Rasch and factor analysis of the Functional Assessment of Cancer Therapy-General (FACT-G)
BACKGROUND: Although the Functional Assessment of Cancer Therapy â General questionnaire (FACT-G) has been validated few studies have explored the factor structure of the instrument, in particular using non-sample dependent measurement techniques, such as Rasch Models. Furthermore, few studies have explored the relationship between item fit to the Rasch Model and clinical utility. The aim of this study was to investigate the dimensionality and measurement properties of the FACT-G with Rasch Models and Factor analysis. METHODS: A factor analysis and Rasch analysis (Partial Credit Model) was carried out on the FACT-G completed by a heterogeneous sample of cancer patients (n = 465). For the Rasch analysis item fit (infit mean squares â„ 1.30), dimensionality and item invariance were assessed. The impact of removing misfitting items on the clinical utility of the subscales and FACT-G total scale was also assessed. RESULTS: The factor analysis demonstrated a four factor structure of the FACT-G which broadly corresponded to the four subscales of the instrument. Internal consistency for these four scales was very good (Cronbach's alpha 0.72 â 0.85). The Rasch analysis demonstrated that each of the subscales and the FACT-G total scale had misfitting items (infit means square â„ 1.30). All these scales with the exception of the Social & Family Well-being Scale (SFWB) were unidimensional. When misfitting items were removed, the effect sizes and the clinical utility of the instrument were maintained for the subscales and the total FACT-G scores. CONCLUSION: The results of the traditional factor analysis and Rasch analysis of the FACT-G broadly agreed. Caution should be exercised when utilising the Social & Family Well-being scale and further work is required to determine whether this scale is best represented by two factors. Additionally, removing misfitting items from scales should be performed alongside an assessment of the impact on clinical utility
The SDSS-III Baryon Oscillation Spectroscopic Survey: Quasar Target Selection for Data Release Nine
The SDSS-III Baryon Oscillation Spectroscopic Survey (BOSS), a five-year
spectroscopic survey of 10,000 deg^2, achieved first light in late 2009. One of
the key goals of BOSS is to measure the signature of baryon acoustic
oscillations in the distribution of Ly-alpha absorption from the spectra of a
sample of ~150,000 z>2.2 quasars. Along with measuring the angular diameter
distance at z\approx2.5, BOSS will provide the first direct measurement of the
expansion rate of the Universe at z > 2. One of the biggest challenges in
achieving this goal is an efficient target selection algorithm for quasars over
2.2 < z < 3.5, where their colors overlap those of stars. During the first year
of the BOSS survey, quasar target selection methods were developed and tested
to meet the requirement of delivering at least 15 quasars deg^-2 in this
redshift range, out of 40 targets deg^-2. To achieve these surface densities,
the magnitude limit of the quasar targets was set at g <= 22.0 or r<=21.85.
While detection of the BAO signature in the Ly-alpha absorption in quasar
spectra does not require a uniform target selection, many other astrophysical
studies do. We therefore defined a uniformly-selected subsample of 20 targets
deg^-2, for which the selection efficiency is just over 50%. This "CORE"
subsample will be fixed for Years Two through Five of the survey. In this paper
we describe the evolution and implementation of the BOSS quasar target
selection algorithms during the first two years of BOSS operations. We analyze
the spectra obtained during the first year. 11,263 new z>2.2 quasars were
spectroscopically confirmed by BOSS. Our current algorithms select an average
of 15 z > 2.2 quasars deg^-2 from 40 targets deg^-2 using single-epoch SDSS
imaging. Multi-epoch optical data and data at other wavelengths can further
improve the efficiency and completeness of BOSS quasar target selection.
[Abridged]Comment: 33 pages, 26 figures, 12 tables and a whole bunch of quasars.
Submitted to Ap
High-Grade B-cell Lymphoma, Not Otherwise Specified: A Multi-Institutional Retrospective Study
In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ( double hit ). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase \u3e3 Ă upper limit of normal, and a dual-expressor immunophenotype. Age \u3e60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS
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