To identify genomic alterations in chronic lymphocytic leukemia (CLL), we performed single-nucleotide polymorphism–array analysis using Affymetrix Version 6.0 on 353 samples from untreated patients ...entered in the CLL8 treatment trial. Based on paired-sample analysis (n = 144), a mean of 1.8 copy number alterations per patient were identified; approximately 60% of patients carried no copy number alterations other than those detected by fluorescence in situ hybridization analysis. Copy-neutral loss-of-heterozygosity was detected in 6% of CLL patients and was found most frequently on 13q, 17p, and 11q. Minimally deleted regions were refined on 13q14 (deleted in 61% of patients) to the DLEU1 and DLEU2 genes, on 11q22.3 (27% of patients) to ATM, on 2p16.1-2p15 (gained in 7% of patients) to a 1.9-Mb fragment containing 9 genes, and on 8q24.21 (5% of patients) to a segment 486 kb proximal to the MYC locus. 13q deletions exhibited proximal and distal breakpoint cluster regions. Among the most common novel lesions were deletions at 15q15.1 (4% of patients), with the smallest deletion (70.48 kb) found in the MGA locus. Sequence analysis of MGA in 59 samples revealed a truncating mutation in one CLL patient lacking a 15q deletion. MNT at 17p13.3, which in addition to MGA and MYC encodes for the network of MAX-interacting proteins, was also deleted recurrently.
•Asteroid Bennu has a well-determined orbit due primarily to 12years of radar ranging.•The Yarkovsky effect on Bennu causes a semimajor axis drift of 284±1.5m/year.•We estimate Bennu’s bulk density ...at 1260±70kg/m3 and macroporosity 40±10%.•Bennu has a 1 in 2700 chance of an Earth impact late in the 22nd century.
The target asteroid of the OSIRIS-REx asteroid sample return mission, (101955) Bennu (formerly 1999 RQ36), is a half-kilometer near-Earth asteroid with an extraordinarily well constrained orbit. An extensive data set of optical astrometry from 1999 to 2013 and high-quality radar delay measurements to Bennu in 1999, 2005, and 2011 reveal the action of the Yarkovsky effect, with a mean semimajor axis drift rate da/dt=(-19.0±0.1)×10-4au/Myr or 284±1.5m/year. The accuracy of this result depends critically on the fidelity of the observational and dynamical model. As an example, neglecting the relativistic perturbations of the Earth during close approaches affects the orbit with 3σ significance in da/dt.
The orbital deviations from purely gravitational dynamics allow us to deduce the acceleration of the Yarkovsky effect, while the known physical characterization of Bennu allows us to independently model the force due to thermal emissions. The combination of these two analyses yields a bulk density of ρ=1260±70kg/m3, which indicates a macroporosity in the range 40±10% for the bulk densities of likely analog meteorites, suggesting a rubble-pile internal structure. The associated mass estimate is (7.8±0.9)×1010kg and GM=5.2±0.6m3/s2.
Bennu’s Earth close approaches are deterministic over the interval 1654–2135, beyond which the predictions are statistical in nature. In particular, the 2135 close approach is likely within the lunar distance and leads to strong scattering and numerous potential impacts in subsequent years, from 2175 to 2196. The highest individual impact probability is 9.5×10-5 in 2196, and the cumulative impact probability is 3.7×10-4, leading to a cumulative Palermo Scale of −1.70.
The majority of approved CAR T cell products are based on the FMC63-scFv directed against CD19. Surprisingly, although antigen binding affinity is a major determinant for CAR function, the affinity ...of the benchmark FMC63-scFv has not been unambiguously determined. That is, a wide range of affinities have been reported in literature, differing by more than 100-fold. Using a range of techniques, we demonstrate that suboptimal experimental designs can cause artefacts that lead to over- or underestimation of the affinity. To minimize these artefacts, we performed SPR with strictly monomeric and correctly folded soluble CD19, yielding an FMC63-scFv affinity of 2-6 nM. Together, apart from analyzing the FMC63-scFv affinity under optimized conditions, we also provide potential explanations for the wide range of published affinities. We expect that this study will be highly valuable for interpretations of CAR affinity-function relationships, as well as for the design of future CAR T cell generations.
To develop and externally validate models to predict the probability of postoperative naming decline in adults following temporal lobe epilepsy surgery using easily accessible preoperative clinical ...predictors.
In this retrospective, prediction model development study, multivariable models were developed in a cohort of 719 patients who underwent temporal lobe epilepsy surgery at Cleveland Clinic and externally validated in a cohort of 138 patients who underwent temporal lobe surgery at one of 3 epilepsy surgery centers in the United States (Columbia University Medical Center, Emory University School of Medicine, University of Washington School of Medicine).
The development cohort was 54% female with an average age at surgery of 36 years (SD 12). Twenty-six percent of this cohort experienced clinically relevant postoperative naming decline. The model included 5 variables: side of surgery, age at epilepsy onset, age at surgery, sex, and education. When applied to the external validation cohort, the model performed very well, with excellent calibration and a
statistic (reflecting discriminatory ability) of 0.81. A second model predicting moderate to severe postoperative naming decline included 3 variables: side of surgery, age at epilepsy onset, and preoperative naming score. This model generated a
statistic of 0.84 in the external validation cohort and showed good calibration.
Externally validated nomograms are provided in 2 easy-to-use formats (paper version and online calculator) clinicians can use to estimate the probability of naming decline in patients considering epilepsy surgery for treatment of pharmacoresistant temporal lobe epilepsy.
ABSTRACT We evaluated the planetary radar capabilities at Arecibo, the Goldstone 70 m DSS-14 and 34 m DSS-13 antennas, the 70 m DSS-43 antenna at Canberra, the Green Bank Telescope (GBT), and the ...Parkes Radio Telescope in terms of their relative sensitivities and the number of known near-Earth asteroids (NEAs) detectable per year in monostatic and bistatic configurations. In the 2015 calendar year, monostatic observations with Arecibo and DSS-14 were capable of detecting 253 and 131 NEAs respectively, with signal-to-noise ratios (SNRs) greater than 30/track. Combined, the two observatories were capable of detecting 276 NEAs. Of these, Arecibo detected 77 and Goldstone detected 32, or 30% and 24% of the numbers that were possible. The two observatories detected an additional 18 and 7 NEAs respectively, with SNRs of less than 30/track. This indicates that a substantial number of potential targets are not being observed. The bistatic configuration with DSS-14 transmitting and the GBT receiving was capable of detecting about 195 NEAs, or ∼50% more than with monostatic observations at DSS-14. Most of the detectable asteroids were targets of opportunity that were discovered less than 15 days before the end of their observing windows. About 50% of the detectable asteroids have absolute magnitudes , which corresponds to diameters m.
The 4.5 km long near-Earth asteroid 4179 Toutatis has made close Earth flybys approximately every four years between 1992 and 2012, and has been observed with high-resolution radar imaging during ...each approach. Its most recent Earth flyby in 2012 December was observed extensively at the Goldstone and Very Large Array radar telescopes. In this paper, Toutatis' spin state dynamics are estimated from observations of five flybys between 1992 and 2008. Observations were used to fit Toutatis' spin state dynamics in a least-squares sense, with the solar and terrestrial tidal torques incorporated in the dynamical model. The estimated parameters are Toutatis' Euler angles, angular velocity, moments of inertia, and the center-of-mass-center-of-figure offset. The spin state dynamics as well as the uncertainties of the Euler angles and angular velocity of the converged solution are then propagated to 2012 December in order to compare the dynamical model to the most recent Toutatis observations. The same technique of rotational dynamics estimation can be applied to any other tumbling body, given sufficiently accurate observations.
► We observed 2008 EV5 with Arecibo, Goldstone, and the VLBA in December 2008. ► EV5 rotates retrograde and its overall shape is a 400
±
50
m oblate spheroid. ► EV5 has an equatorial ridge that is ...broken by a 150-m concavity. ► The equatorial ridge is consistent with YORP spin-up reconfiguring the asteroid. ► We interpret the concavity as an impact crater.
We observed the near-Earth ASTEROID 2008 EV5 with the Arecibo and Goldstone planetary radars and the Very Long Baseline Array during December 2008. EV5 rotates retrograde and its overall shape is a 400
±
50
m oblate spheroid. The most prominent surface feature is a ridge parallel to the asteroid’s equator that is broken by a concavity about 150
m in diameter. Otherwise the asteroid’s surface is notably smooth on decameter scales. EV5’s radar and optical albedos are consistent with either rocky or stony-iron composition. The equatorial ridge is similar to structure seen on the rubble-pile near-Earth asteroid (66391) 1999 KW4 and is consistent with YORP spin-up reconfiguring the asteroid in the past. We interpret the concavity as an impact crater. Shaking during the impact and later regolith redistribution may have erased smaller features, explaining the general lack of decameter-scale surface structure.
Predicting the Earth encounters of (99942) Apophis Giorgini, Jon D.; Benner, Lance A.M.; Ostro, Steven J. ...
Icarus (New York, N.Y. 1962),
2008, 2008-1-00, 20080101, Letnik:
193, Številka:
1
Journal Article
Recenzirano
Arecibo delay–Doppler measurements of (99942) Apophis in 2005 and 2006 resulted in a five standard-deviation trajectory correction to the optically predicted close approach distance to Earth in 2029. ...The radar measurements reduced the volume of the statistical uncertainty region entering the encounter to 7.3% of the pre-radar solution, but increased the trajectory uncertainty growth rate across the encounter by 800% due to the closer predicted approach to the Earth. A small estimated Earth impact probability remained for 2036. With standard-deviation plane-of-sky position uncertainties for 2007–2010 already less than 0.2 arcsec, the best near-term ground-based optical astrometry can only weakly affect the trajectory estimate. While the potential for impact in 2036 will likely be excluded in 2013 (if not 2011) using ground-based optical measurements, approximations within the Standard Dynamical Model (SDM) used to estimate and predict the trajectory from the current era are sufficient to obscure the difference between a predicted impact and a miss in 2036 by altering the dynamics leading into the 2029 encounter. Normal impact probability assessments based on the SDM become problematic without knowledge of the object's physical properties; impact could be excluded while the actual dynamics still permit it. Calibrated position uncertainty intervals are developed to compensate for this by characterizing the minimum and maximum effect of physical parameters on the trajectory. Uncertainty in accelerations related to solar radiation can cause between 82 and 4720 Earth-radii of trajectory change relative to the SDM by 2036. If an actionable hazard exists, alteration by 2–10% of Apophis' total absorption of solar radiation in 2018 could be sufficient to produce a six standard-deviation trajectory change by 2036 given physical characterization; even a 0.5% change could produce a trajectory shift of one Earth-radius by 2036 for all possible spin-poles and likely masses. Planetary ephemeris uncertainties are the next greatest source of systematic error, causing up to 23 Earth-radii of uncertainty. The SDM Earth point-mass assumption introduces an additional 2.9 Earth-radii of prediction error by 2036. Unmodeled asteroid perturbations produce as much as 2.3 Earth-radii of error. We find no future small-body encounters likely to yield an Apophis mass determination prior to 2029. However, asteroid (144898) 2004 VD17, itself having a statistical Earth impact in 2102, will probably encounter Apophis at 6.7 lunar distances in 2034, their uncertainty regions coming as close as 1.6 lunar distances near the center of both SDM probability distributions.
Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a ...meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10
), rs10068599-T (OR = 1.09, P = 6.9 × 10
) and rs10769894-A (OR = 0.90, P = 9.4 × 10
). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed.
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