The thermal Hall conductance in the half-filled first Landau level was recently measured to take the quantized noninteger value κ_{xy}=5/2 (in units of temperature times π^{2}k_{B}^{2}/3h), which ...indicates a non-Abelian phase of matter. Such exotic states have long been predicted to arise at this filling factor, but the measured value disagrees with numerical studies, which predict κ_{xy}=3/2 or 7/2. We resolve this contradiction by invoking the disorder-induced formation of mesoscopic puddles with locally κ_{xy}=3/2 or 7/2. Interactions between these puddles generate a coherent macroscopic state that exhibits a plateau with quantized κ_{xy}=5/2. The non-Abelian quasiparticles characterizing this phase are distinct from those of the microscopic puddles and, by the same mechanism, could even emerge from a system comprised of microscopic Abelian puddles.
A promising alternative to address the problem of acquired drug resistance is to rely on combination therapies. Identification of the right combinations is often accomplished through trial and error, ...a labor and resource intensive process whose scale quickly escalates as more drugs can be combined. To address this problem, we present a broad computational approach for predicting synergistic combinations using easily obtainable single drug efficacy, no detailed mechanistic understanding of drug function, and limited drug combination testing. When applied to mutant BRAF melanoma, we found that our approach exhibited significant predictive power. Additionally, we validated previously untested synergy predictions involving anticancer molecules. As additional large combinatorial screens become available, this methodology could prove to be impactful for identification of drug synergy in context of other types of cancers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although normal tissue samples adjacent to tumors are sometimes collected from patients in cancer studies, they are often used as normal controls to identify genes differentially expressed between ...tumor and normal samples. However, it is in general more difficult to obtain and clearly define paired normal samples, and whether these samples should be treated as "normal" due to their close proximity to tumors. In this article, by analyzing the accrued data in The Cancer Genome Atlas (TCGA), we show the surprising results that the paired normal samples are in general more informative on patient survival than tumors. Different lines of evidence suggest that this is likely due to tumor micro-environment instead of tumor cell contamination or field cancerization effect. Pathway analyses suggest that tumor micro-environment may play an important role in cancer patient survival either by boosting the adjacent metabolism or the in situ immunization. Our results suggest the potential benefit of collecting and profiling matched normal tissues to gain more insights on disease etiology and patient progression.
The receptor tyrosine kinase ERBB4, a member of the epidermal growth factor receptor (EGFR) family, is unusual in that ERBB4 can undergo intramembrane proteolysis, releasing a soluble intracellular ...domain (ICD) that modulates transcription in the nucleus. We found that ERBB4 activated the transcriptional coactivator YAP, which promotes organ and tissue growth and is inhibited by the Hippo tumor-suppressor pathway. Overexpressing ERBB4 in cultured mammary epithelial cells or adding the ERBB4 ligand neuregulin 1 (NRG1) to breast cancer cell cultures promoted the expression of genes regulated by YAP, such as CTGF. Knocking down YAP or ERBB4 prevented the induction of CTGF expression by NRG1, as did treating cells with the ERBB inhibitors lapatinib or erlotinib, which reduced ERBB4 cleavage. NRG1 stimulated YAP activity to an extent comparable to that of EGF (epidermal growth factor) or LPA (lysophosphatidic acid), known activators of YAP. NRG1 stimulated YAP-dependent cell migration in breast cancer cell lines. These observations connect the unusual nuclear function of a growth factor receptor with a mechanosensory pathway and suggest that NRG1-ERBB4-YAP signaling contributes to the aggressive behavior of tumor cells.
Greatest fitness of tumor cell subclones in patients undergoing MAPK-targeting therapies requires just-right levels of MAPK pathway signaling. New therapeutic approaches induce tumor cell death by ...intensifying MAPK signaling induced by inhibitor withdrawal in combination with DNA damage, or prevent selection of resistant clones with a steep fitness barrier imposed by triple combination of BRAF, MEK, and ERK inhibitors.
.
The quest for non-Abelian quasiparticles has inspired decades of experimental and theoretical efforts, where the scarcity of direct probes poses a key challenge. Among their clearest signatures is a ...thermal Hall conductance with quantized half-integer value in units of κ_{0}=π^{2}k_{B}^{2}T/3h (T is temperature, h the Planck constant, k_{B} the Boltzmann constant). Such values were recently observed in a quantum-Hall system and a magnetic insulator. We show that nontopological "thermal metal" phases that form due to quenched disorder may disguise as non-Abelian phases by well approximating the trademark quantized thermal Hall response. Remarkably, the quantization here improves with temperature, in contrast to fully gapped systems. We provide numerical evidence for this effect and discuss its possible implications for the aforementioned experiments.
We propose an experiment to identify the topological order of the ν=5/2 state through a measurement of the electric conductance of a mesoscopic device. Our setup is based on interfacing ν=2,5/2, and ...3 in the same device. Its conductance can unambiguously establish or rule out the particle-hole symmetric Pfaffian topological order, which is supported by recent thermal measurements. Additionally, it distinguishes between the Moore-Read and anti-Pfaffian topological orders, which are favored by numerical calculations.
ERBB3/HER3 is one of the four members of the epidermal growth factor receptor (ERBB) family. It is activated by binding to ligands Neuregulin-1 and Neuregulin-2. Since ERBB3 lacks intrinsic kinase ...activity, signal transduction occurs through formation of heterodimers with EGFR, ERBB2, and ERBB4. ERBB3 is a signaling specialist since it has six binding sites for the p85 SH2 adapter subunit of phosphoinositide 3' kinases. These lipid kinases coordinate regulation of metabolism, cell size, proliferation, survival, and angiogenesis. Not surprisingly, ERBB3 signaling has been linked to cancer etiology and progression. In breast cancer, the partnership of ERBB2 and ERBB3 may be crucial for the aggressive properties of cancers with ERBB2 amplification, and may contribute to pre-existing and acquired resistance to therapy. This partnership creates opportunities for improving efficacy of ERBB-targeted pharmaceuticals, by interfering with coupling of ERBB2 to ERBB3 through dimerization inhibitors, and by use of therapeutic compounds that target AKT-dependent pathways activated through ERBB3. Additional therapeutic opportunities may be identified through better understanding of how ERBBs are regulated and deployed in normal mammary gland processes. Work using mouse models has identified the main processes regulated by each of the four ERBBs, which has practical implications in understanding breast cancer etiology, and eventual development of better prognostic, predictive, and therapeutic tools.
We present a methodology for defining and optimizing a general force field for classical molecular simulations, and we describe its use to derive the Open Force Field 1.0.0 small-molecule force ...field, codenamed Parsley. Rather than using traditional atom typing, our approach is built on the SMIRKS-native Open Force Field (SMIRNOFF) parameter assignment formalism, which handles increases in the diversity and specificity of the force field definition without needlessly increasing the complexity of the specification. Parameters are optimized with the ForceBalance tool, based on reference quantum chemical data that include torsion potential energy profiles, optimized gas-phase structures, and vibrational frequencies. These quantum reference data are computed and are maintained with QCArchive, an open-source and freely available distributed computing and database software ecosystem. In this initial application of the method, we present essentially a full optimization of all valence parameters and report tests of the resulting force field against compounds and data types outside the training set. These tests show improvements in optimized geometries and conformational energetics and demonstrate that Parsley’s accuracy for liquid properties is similar to that of other general force fields, as is accuracy on binding free energies. We find that this initial Parsley force field affords accuracy similar to that of other general force fields when used to calculate relative binding free energies spanning 199 protein–ligand systems. Additionally, the resulting infrastructure allows us to rapidly optimize an entirely new force field with minimal human intervention.
Protein phosphorylation is estimated to affect 30% of the proteome and is a major regulatory mechanism that controls many basic cellular processes. Until recently, our biochemical understanding of ...protein phosphorylation on a global scale has been extremely limited; only one half of the yeast kinases have known in vivo substrates and the phosphorylating kinase is known for less than 160 phosphoproteins. Here we describe, with the use of proteome chip technology, the in vitro substrates recognized by most yeast protein kinases: we identified over 4,000 phosphorylation events involving 1,325 different proteins. These substrates represent a broad spectrum of different biochemical functions and cellular roles. Distinct sets of substrates were recognized by each protein kinase, including closely related kinases of the protein kinase A family and four cyclin-dependent kinases that vary only in their cyclin subunits. Although many substrates reside in the same cellular compartment or belong to the same functional category as their phosphorylating kinase, many others do not, indicating possible new roles for several kinases. Furthermore, integration of the phosphorylation results with protein-protein interaction and transcription factor binding data revealed novel regulatory modules. Our phosphorylation results have been assembled into a first-generation phosphorylation map for yeast. Because many yeast proteins and pathways are conserved, these results will provide insights into the mechanisms and roles of protein phosphorylation in many eukaryotes.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
