Transcriptomic-metabolomic reprogramming in EGFR-mutant NSCLC early adaptive drug escape linking TGFβ2-bioenergetics-mitochondrial priming.

The impact of EGFR-mutant NSCLC precision therapy is limited by acquired resistance despite initial excellent response. Classic studies of EGFR-mutant clinical resistance to precision therapy were based on tumor rebiopsies late during clinical tumor progression on therapy. Here, we characterized a novel non-mutational early adaptive drug-escape in EGFR-mutant lung tumor cells only days after therapy initiation, that is MET-independent. The drug-escape cell states were analyzed by integrated transcriptomic and metabolomics profiling uncovering a central role for autocrine TGFβ2 in mediating cellular plasticity through profound cellular adaptive Omics reprogramming, with common mechanistic link to prosurvival mitochondrial priming. Cells undergoing early adaptive drug escape are in proliferative-metabolic quiescent, with enhanced EMT-ness and stem cell signaling, exhibiting global bioenergetics suppression including reverse Warburg, and are susceptible to glutamine deprivation and TGFβ2 inhibition. Our study further supports a preemptive therapeutic targeting of bioenergetics and mitochondrial priming to impact early drug-escape emergence using EGFR precision inhibitor combined with broad BH3-mimetic to interrupt BCL-2/BCL-xL together, but not BCL-2 alone

Residual donors and compensation in metalorganic chemical vapor deposition as-grown n-GaN

In our recent report, [Xu et al., Appl. Phys. Lett. 76, 152 (2000)], profile distributions of five elements in the GaN/sapphire system have been obtained using secondary ion-mass spectroscopy. The results suggested that a thin degenerate n+ layer at the interface is the main source of the n-type conductivity for the whole film. The further studies in this article show that this n+ conductivity is not only from the contribution of nitride-site oxygen (ON), but also from the gallium-site silicon (SiGa) donors, with activation energies 2 meV (for ON) and 42 meV (for SiGa), respectively. On the other hand, Al incorporated on the Ga sublattice reduces the concentration of compensating Ga-vacancy acceptors. The two-donor two-layer conduction, including Hall carrier concentration and mobility, has been modeled by separating the GaN film into a thin interface layer and a main bulk layer of the GaN film. The bulk layer conductivity is to be found mainly from a near-surface thin layer and is temperature dependent. SiGa and ON should also be shallow donors and VGa-O or VGa-Al should be compensation sites in the bulk layer. The best fits for the Hall mobility and the Hall concentration in the bulk layer were obtained by taking the acceptor concentration NA=1.8×1017 cm-3, the second donor concentration ND2=1.0×1018 cm-3, and the compensation ratio C=NA/ND1=0.6, which is consistent with Rode's theory. Saturation of carriers and the low value of carrier mobility at low temperature can also be well explained. © 2001 American Institute of Physics.published_or_final_versio

Gallium/aluminum interdiffusion between n-GaN and sapphire

The distribution profiles of Ga and Al near the interface of the n-GaN/sapphire system were measured by x-ray energy dispersive spectroscopy (XEDS). The results are obtained by the corrected XED spectra. First, the gallium diffusing into the sapphire substrate obeys the law of remainder probability function. The gallium diffusion coefficient DGa=2.30×10-13 cm2s-1 was calculated by theoretical fitting. Second, the diffusion is associated with the GaN growth process at high temperature. Compared to the diffusion of Ga into the sapphire substrate, much less Al antidiffusion from the substrate to the GaN film, with diffusion coefficient DA1 approximately equal to 4.8×10-15 cm2s-1, was observed in the film. © 1998 American Institute of Physics.published_or_final_versio

Bhlhb5 Regulates the Postmitotic Acquisition of Area Identities in Layers II-V of the Developing Neocortex

While progenitor-restricted factors broadly specify area identities in developing neocortex, the downstream regulatory elements involved in acquisition of those identities in post-mitotic neurons are largely unknown. Here, we identify Bhlhb5, a transcription factor expressed in layers II–V, as a post-mitotic regulator of area identity. Bhlhb5 is initially expressed in a high caudomedial to low rostrolateral gradient that transforms into a sharp border between sensory and rostral motor cortices. Bhlhb5-null mice exhibit aberrant expression of area-specific genes and structural organization in the somatosensory and caudal motor cortices. In somatosensory cortex, Bhlhb5-null mice display post-synaptic disorganization of vibrissal barrels. In caudal motor cortex, Bhlhb5-null mice exhibit anomalous differentiation of corticospinal motor neurons, accompanied by failure of corticospinal tract formation. Together, these results demonstrate Bhlhb5’s function as an area-specific transcription factor that regulates the post-mitotic acquisition of area identities and elucidate the genetic hierarchy between progenitors and post-mitotic neurons driving neocortical arealization.Stem Cell and Regenerative Biolog

Model of defect formation in annealed undoped and Fe-doped liquid encapsulated Czochralski InP

Infrared absorption spectroscopy measurements indicate high concentration of hydrogen indium vacancy complex VInH4 in undoped and Fe-doped liquid encapsulated Czochralski (LEC) InP. Annealed undoped and Fe-doped semi-insulating (SI) InP are studied by room temperature Hall effect measurement and photocurrent spectroscopy. The results show that a mid gap donor defect and some shallow intrinsic defects are formed by high temperature annealing. This mid gap defect is shown to be phosphorus antisite related. Defect formation process and compensation mechanism in annealed SI InP are discussed.published_or_final_versio

Modeling Spatial Correlation of DNA Deformation: DNA Allostery in Protein Binding

We report a study of DNA deformations using a coarse-grained mechanical model and quantitatively interpret the allosteric effects in protein–DNA binding affinity. A recent single-molecule study (Kim et al. Science 2013, 339, 816) showed that when a DNA molecule is deformed by specific binding of a protein, the binding affinity of a second protein separated from the first protein is altered. Experimental observations together with molecular dynamics simulations suggested that the origin of the DNA allostery is related to the observed deformation of DNA’s structure, in particular, the major groove width. To unveil and quantify the underlying mechanism for the observed major groove deformation behavior related to the DNA allostery, here we provide a simple but effective analytical model where DNA deformations upon protein binding are analyzed and spatial correlations of local deformations along the DNA are examined. The deformation of the DNA base orientations, which directly affect the major groove width, is found in both an analytical derivation and coarse-grained Monte Carlo simulations. This deformation oscillates with a period of 10 base pairs with an amplitude decaying exponentially from the binding site with a decay length $l_D \approx10$ base pairs as a result of the balance between two competing terms in DNA base-stacking energy. This length scale is in agreement with that reported from the single-molecule experiment. Our model can be reduced to the worm-like chain form at length scales larger than $l_P$ but is able to explain DNA’s mechanical properties on shorter length scales, in particular, the DNA allostery of protein–DNA interactions.Chemistry and Chemical Biolog

Tunable Multifunctional Topological Insulators in Ternary Heusler Compounds

Recently the Quantum Spin Hall effect (QSH) was theoretically predicted and experimentally realized in a quantum wells based on binary semiconductor HgTe[1-3]. QSH state and topological insulators are the new states of quantum matter interesting both for fundamental condensed matter physics and material science[1-11]. Many of Heusler compounds with C1b structure are ternary semiconductors which are structurally and electronically related to the binary semiconductors. The diversity of Heusler materials opens wide possibilities for tuning the band gap and setting the desired band inversion by choosing compounds with appropriate hybridization strength (by lattice parameter) and the magnitude of spin-orbit coupling (by the atomic charge). Based on the first-principle calculations we demonstrate that around fifty Heusler compounds show the band inversion similar to HgTe. The topological state in these zero-gap semiconductors can be created by applying strain or by designing an appropriate quantum well structure, similar to the case of HgTe. Many of these ternary zero-gap semiconductors (LnAuPb, LnPdBi, LnPtSb and LnPtBi) contain the rare earth element Ln which can realize additional properties ranging from superconductivity (e. g. LaPtBi[12]) to magnetism (e. g. GdPtBi[13]) and heavy-fermion behavior (e. g. YbPtBi[14]). These properties can open new research directions in realizing the quantized anomalous Hall effect and topological superconductors.Comment: 20 pages, 5 figure

The lightest organic radical cation for charge storage in redox flow batteries

In advanced electrical grids of the future, electrochemically rechargeable fluids of high energy density will capture the power generated from intermittent sources like solar and wind. To meet this outstanding technological demand there is a need to understand the fundamental limits and interplay of electrochemical potential, stability, and solubility in low-weight redox-active molecules. By generating a combinatorial set of 1,4-dimethoxybenzene derivatives with different arrangements of substituents, we discovered a minimalistic structure that combines exceptional long-term stability in its oxidized form and a record-breaking intrinsic capacity of 161 mAh/g. The nonaqueous redox flow battery has been demonstrated that uses this molecule as a catholyte material and operated stably for 100 charge/discharge cycles. The observed stability trends are rationalized by mechanistic considerations of the reaction pathways.United States. Dept. of Energy. Office of Basic Energy Sciences. Chemical Sciences, Geosciences, & Biosciences Division (Contract DE-AC02-06CH11357