247 research outputs found
Species-Specific and Inhibitor-Dependent Conformations of LpxC: Implications for Antibiotic Design
LpxC is an essential enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria. Several promising antimicrobial lead compounds targeting LpxC have been reported, though they typically display a large variation in potency against different Gram-negative pathogens. We report that inhibitors with a diacetylene scaffold effectively overcome the resistance caused by sequence variation in the LpxC substrate-binding passage. Compound binding is captured in complex with representative LpxC orthologs, and structural analysis reveals large conformational differences that mostly reflect inherent molecular features of distinct LpxC orthologs, whereas ligand-induced structural adaptations occur at a smaller scale. These observations highlight the need for a molecular understanding of inherent structural features and conformational plasticity of LpxC enzymes for optimizing LpxC inhibitors as broad-spectrum antibiotics against Gram-negative infections
Heavy quarkonium: progress, puzzles, and opportunities
A golden age for heavy quarkonium physics dawned a decade ago, initiated by
the confluence of exciting advances in quantum chromodynamics (QCD) and an
explosion of related experimental activity. The early years of this period were
chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in
2004, which presented a comprehensive review of the status of the field at that
time and provided specific recommendations for further progress. However, the
broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles
could only be partially anticipated. Since the release of the YR, the BESII
program concluded only to give birth to BESIII; the -factories and CLEO-c
flourished; quarkonium production and polarization measurements at HERA and the
Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the
deconfinement regime. All these experiments leave legacies of quality,
precision, and unsolved mysteries for quarkonium physics, and therefore beg for
continuing investigations. The plethora of newly-found quarkonium-like states
unleashed a flood of theoretical investigations into new forms of matter such
as quark-gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the
spectroscopy, decays, production, and in-medium behavior of c\bar{c}, b\bar{b},
and b\bar{c} bound states have been shown to validate some theoretical
approaches to QCD and highlight lack of quantitative success for others. The
intriguing details of quarkonium suppression in heavy-ion collisions that have
emerged from RHIC have elevated the importance of separating hot- and
cold-nuclear-matter effects in quark-gluon plasma studies. This review
systematically addresses all these matters and concludes by prioritizing
directions for ongoing and future efforts.Comment: 182 pages, 112 figures. Editors: N. Brambilla, S. Eidelman, B. K.
Heltsley, R. Vogt. Section Coordinators: G. T. Bodwin, E. Eichten, A. D.
Frawley, A. B. Meyer, R. E. Mitchell, V. Papadimitriou, P. Petreczky, A. A.
Petrov, P. Robbe, A. Vair
An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics
For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types
DES13S2cmm: the first superluminous supernova from the Dark Energy Survey
We present DES13S2cmm, the first spectroscopically-confirmed superluminous
supernova (SLSN) from the Dark Energy Survey (DES). We briefly discuss the data
and search algorithm used to find this event in the first year of DES
operations, and outline the spectroscopic data obtained from the European
Southern Observatory (ESO) Very Large Telescope to confirm its redshift (z =
0.663 +/- 0.001 based on the host-galaxy emission lines) and likely spectral
type (type I). Using this redshift, we find M_U_peak = -21.05 +0.10 -0.09 for
the peak, rest-frame U-band absolute magnitude, and find DES13S2cmm to be
located in a faint, low metallicity (sub-solar), low stellar-mass host galaxy
(log(M/M_sun) = 9.3 +/- 0.3); consistent with what is seen for other SLSNe-I.
We compare the bolometric light curve of DES13S2cmm to fourteen similarly
well-observed SLSNe-I in the literature and find it possesses one of the
slowest declining tails (beyond +30 days rest frame past peak), and is the
faintest at peak. Moreover, we find the bolometric light curves of all SLSNe-I
studied herein possess a dispersion of only 0.2-0.3 magnitudes between +25 and
+30 days after peak (rest frame) depending on redshift range studied; this
could be important for 'standardising' such supernovae, as is done with the
more common type Ia. We fit the bolometric light curve of DES13S2cmm with two
competing models for SLSNe-I - the radioactive decay of 56Ni, and a magnetar -
and find that while the magnetar is formally a better fit, neither model
provides a compelling match to the data. Although we are unable to conclusively
differentiate between these two physical models for this particular SLSN-I,
further DES observations of more SLSNe-I should break this degeneracy,
especially if the light curves of SLSNe-I can be observed beyond 100 days in
the rest frame of the supernova.Comment: Accepted by MNRAS (2015 January 23), 13 pages, 6 figures, 2 table
Measurement of the splashback feature around SZ-selected Galaxy clusters with DES, SPT, and ACT
We present a detection of the splashback feature around galaxy clusters selected using the SunyaevâZelâdovich (SZ) signal. Recent measurements of the splashback feature around optically selected galaxy clusters have found that the splashback radius, rsp, is smaller than predicted by N-body simulations. A possible explanation for this discrepancy is that rsp inferred from the observed radial distribution of galaxies is affected by selection effects related to the optical cluster-finding algorithms. We test this possibility by measuring the splashback feature in clusters selected via the SZ effect in data from the South Pole Telescope SZ survey and the Atacama Cosmology Telescope Polarimeter survey. The measurement is accomplished by correlating these cluster samples with galaxies detected in the Dark Energy Survey Year 3 data. The SZ observable used to select clusters in this analysis is expected to have a tighter correlation with halo mass and to be more immune to projection effects and aperture-induced biases, potentially ameliorating causes of systematic error for optically selected clusters. We find that the measured rsp for SZ-selected clusters is consistent with the expectations from simulations, although the small number of SZ-selected clusters makes a precise comparison difficult. In agreement with previous work, when using optically selected redMaPPer clusters with similar mass and redshift distributions, rsp is âŒ2Ï smaller than in the simulations. These results motivate detailed investigations of selection biases in optically selected cluster catalogues and exploration of the splashback feature around larger samples of SZ-selected clusters. Additionally, we investigate trends in the galaxy profile and splashback feature as a function of galaxy colour, finding that blue galaxies have profiles close to a power law with no discernible splashback feature, which is consistent with them being on their first infall into the cluster
DES Y3 + KiDS-1000: Consistent cosmology combining cosmic shear surveys
We present a joint cosmic shear analysis of the Dark Energy Survey (DES Y3)
and the Kilo-Degree Survey (KiDS-1000) in a collaborative effort between the
two survey teams. We find consistent cosmological parameter constraints between
DES Y3 and KiDS-1000 which, when combined in a joint-survey analysis, constrain
the parameter with a mean value of
. The mean marginal is lower than the maximum a
posteriori estimate, , owing to skewness in the marginal
distribution and projection effects in the multi-dimensional parameter space.
Our results are consistent with constraints from observations of the
cosmic microwave background by Planck, with agreement at the level.
We use a Hybrid analysis pipeline, defined from a mock survey study quantifying
the impact of the different analysis choices originally adopted by each survey
team. We review intrinsic alignment models, baryon feedback mitigation
strategies, priors, samplers and models of the non-linear matter power
spectrum.Comment: 38 pages, 21 figures, 15 tables, submitted to the Open Journal of
Astrophysics. Watch the core team discuss this analysis at
https://cosmologytalks.com/2023/05/26/des-kid
Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.
Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy
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