87 research outputs found
Transcriptome Analysis of Targeted Mouse Mutations Reveals the Topography of Local Changes in Gene Expression.
The unintended consequences of gene targeting in mouse models have not been thoroughly studied and a more systematic analysis is needed to understand the frequency and characteristics of off-target effects. Using RNA-seq, we evaluated targeted and neighboring gene expression in tissues from 44 homozygous mutants compared with C57BL/6N control mice. Two allele types were evaluated: 15 targeted trap mutations (TRAP); and 29 deletion alleles (DEL), usually a deletion between the translational start and the 3' UTR. Both targeting strategies insert a bacterial beta-galactosidase reporter (LacZ) and a neomycin resistance selection cassette. Evaluating transcription of genes in +/- 500 kb of flanking DNA around the targeted gene, we found up-regulated genes more frequently around DEL compared with TRAP alleles, however the frequency of alleles with local down-regulated genes flanking DEL and TRAP targets was similar. Down-regulated genes around both DEL and TRAP targets were found at a higher frequency than expected from a genome-wide survey. However, only around DEL targets were up-regulated genes found with a significantly higher frequency compared with genome-wide sampling. Transcriptome analysis confirms targeting in 97% of DEL alleles, but in only 47% of TRAP alleles probably due to non-functional splice variants, and some splicing around the gene trap. Local effects on gene expression are likely due to a number of factors including compensatory regulation, loss or disruption of intragenic regulatory elements, the exogenous promoter in the neo selection cassette, removal of insulating DNA in the DEL mutants, and local silencing due to disruption of normal chromatin organization or presence of exogenous DNA. An understanding of local position effects is important for understanding and interpreting any phenotype attributed to targeted gene mutations, or to spontaneous indels
Long-term Evolution of Protostellar and Protoplanetary Disks. I. Outbursts
As an initial investigation into the long-term evolution of protostellar
disks, we explore the conditions required to explain the large outbursts of
disk accretion seen in some young stellar objects. We use one-dimensional
time-dependent disk models with a phenomenological treatment of the
magnetorotational instability (MRI) and gravitational torques to follow disk
evolution over long timescales. Comparison with our previous two-dimensional
disk model calculations (Zhu et al. 2009b, Z2009b) indicates that the neglect
of radial effects and two-dimensional disk structure in the one-dimensional
case makes only modest differences in the results; this allows us to use the
simpler models to explore parameter space efficiently. We find that the mass
infall rates typically estimated for low-mass protostars generally result in
AU-scale disk accretion outbursts, as predicted by our previous analysis (Zhu
et al. 2009a,Z2009a). We also confirm quasi-steady accretion behavior for high
mass infall rates if the values of -parameter for the magnetorotational
instability is small, while at this high accretion rate convection from the
thermal instability may lead to some variations. We further constrain the
combinations of the -parameter and the MRI critical temperature, which
can reproduce observed outburst behavior. Our results suggest that dust
sublimation may be connected with full activation of the MRI. This is
consistent with the idea that small dust captures ions and electrons to
suppress the MRI. In a later paper we will explore both long-term outburst and
disk evolution with this model, allowing for infall from protostellar envelopes
with differing angular momenta.Comment: Accepted to publish in Ap
Response Assessment of NovoTTF-100A Versus Best Physician\u27s Choice Chemotherapy in Recurrent Glioblastoma
The NovoTTF-100A device emits frequency-tuned alternating electric fields that interfere with tumor cell mitosis. In phase III trial for recurrent glioblastomas, NovoTTF-100A was shown to have equivalent efficacy and less toxicity when compared to Best Physician\u27s Choice (BPC) chemotherapy. We analyzed the characteristics of responders and nonresponders in both cohorts to determine the characteristics of response and potential predictive factors. Tumor response and progression were determined by Macdonald criteria. Time to response, response duration, progression-free survival (PFS) ± Simon-Makuch correction, overall survival (OS), prognostic factors, and relative hazard rates were compared between responders and nonresponders. Median response duration was 7.3 versus 5.6 months for NovoTTF-100A and BPC chemotherapy, respectively (P = 0.0009). Five of 14 NovoTTF-100A responders but none of seven BPC responders had prior low-grade histology. Mean cumulative dexamethasone dose was 35.9 mg for responders versus 485.6 mg for nonresponders in the NovoTTF-100A cohort (P \u3c 0.0001). Hazard analysis showed delayed tumor progression in responders compared to nonresponders. Simon-Makuch-adjusted PFS was longer in responders than in nonresponders treated with NovoTTF-100A (P = 0.0007) or BPC chemotherapy (P = 0.0222). Median OS was longer for responders than nonresponders treated with NovoTTF-100A (P \u3c 0.0001) and BPC chemotherapy (P = 0.0235). Pearson analysis showed strong correlation between response and OS in NovoTTF-100A (P = 0.0002) but not in BPC cohort (P = 0.2900). Our results indicate that the response characteristics favor NovoTTF-100A and data on prior low-grade histology and dexamethasone suggest potential genetic and epigenetic determinants of NovoTTF-100A response
Binary-induced collapse of a compact, collisionless cluster
We improve and extend Shapiro's model of a relativistic, compact object which
is stable in isolation but is driven dynamically unstable by the tidal field of
a binary companion. Our compact object consists of a dense swarm of test
particles moving in randomly-oriented, initially circular, relativistic orbits
about a nonrotating black hole. The binary companion is a distant, slowly
inspiraling point mass. The tidal field of the companion is treated as a small
perturbation on the background Schwarzschild geometry near the hole; the
resulting metric is determined by solving the perturbation equations of Regge
and Wheeler and Zerilli in the quasi-static limit. The perturbed spacetime
supports Bekenstein's conjecture that the horizon area of a near-equilibrium
black hole is an adiabatic invariant. We follow the evolution of the system and
confirm that gravitational collapse can be induced in a compact collisionless
cluster by the tidal field of a binary companion.Comment: 9 Latex pages, 14 postscript figure
Energy-Economical Heuristically Based Control of Compass Gait Walking on Stochastically Varying Terrain
Investigation uses simulation to explore the inherent tradeoffs ofcontrolling high-speed and highly robust walking robots while minimizing energy consumption. Using a novel controller which optimizes robustness, energy economy, and speed of a simulated robot on rough terrain, the user can adjust their priorities between these three outcome measures and systematically generate a performance curveassessing the tradeoffs associated with these metrics
Type D Personality, Temperament, and Mental Health in Military Personnel Awaiting Deployment
Type D personality, temperament, and mental health in military personnel awaitin
Class II MHC Self-Antigen Presentation in Human B and T Lymphocytes
Human CD4[superscript +] T cells process and present functional class II MHC-peptide complexes, but the endogenous peptide repertoire of these non-classical antigen presenting cells remains unknown. We eluted and sequenced HLA-DR-bound self-peptides presented by CD4[superscript +] T cells in order to compare the T cell-derived peptide repertoire to sequences derived from genetically identical B cells. We identified several novel epitopes derived from the T cell-specific proteome, including fragments of CD4 and IL-2. While these data confirm that T cells can present peptides derived from the T-cell specific proteome, the vast majority of peptides sequenced after elution from MHC were derived from the common proteome. From this pool, we identified several identical peptide epitopes in the T and B cell repertoire derived from common endogenous proteins as well as novel endogenous epitopes with promiscuous binding. These findings indicate that the endogenous HLA-DR-bound peptide repertoire, regardless of APC type and across MHC isotype, is largely derived from the same pool of self-protein.National Institutes of Health (U.S.) (grant P01AI039671)National Institutes of Health (U.S.) (P01AI045757
Addressing climate change with behavioral science: a global intervention tournament in 63 countries
Effectively reducing climate change requires marked, global behavior change. However, it is unclear which strategies are most likely to motivate people to change their climate beliefs and behaviors. Here, we tested 11 expert-crowdsourced interventions on four climate mitigation outcomes: beliefs, policy support, information sharing intention, and an effortful tree-planting behavioral task. Across 59,440 participants from 63 countries, the interventionsâ effectiveness was small, largely limited to nonclimate skeptics, and differed across outcomes: Beliefs were strengthened mostly by decreasing psychological distance (by 2.3%), policy support by writing a letter to a future-generation member (2.6%), information sharing by negative emotion induction (12.1%), and no intervention increased the more effortful behaviorâseveral interventions even reduced tree planting. Last, the effects of each intervention differed depending on peopleâs initial climate beliefs. These findings suggest that the impact of behavioral climate interventions varies across audiences and target behaviors
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