2-Bromo-4-chloro-6-{(E)-[4-(diethyl­amino)­phen­yl]imino­meth­yl}phenol

In the title compound, C17H18BrClN2O, the dihedral angle between the aromatic rings is 3.0 (1)°. The methyl­ethanamine group assumes an extended conformation. An intra­molecular O—H⋯N hydrogen bond generates an S(6) ring motif. The crystal packing is stabilized by C—H⋯π and π–π [centroid–centroid distances = 3.691 (1) and 3.632 (1) Å] inter­actions

Delayed spinal extradural hematoma following thoracic spine surgery and resulting in paraplegia: a case report

<p>Abstract</p> <p>Introduction</p> <p>Postoperative spinal extradural hematomas are rare. Most of the cases that have been reported occured within 3 days of surgery. Their occurrence in a delayed form, that is, more than 72 hours after surgery, is very rare. This case is being reported to enhance awareness of delayed postoperative spinal extradural hematomas.</p> <p>Case presentation</p> <p>We report a case of acute onset dorsal spinal extradural hematoma from a paraspinal muscular arterial bleed, producing paraplegia 72 hours following surgery for excision of a spinal cord tumor at T8 level. The triggering mechanism was an episode of violent twisting movement by the patient. Fresh blood in the postoperative drain tube provided suspicion of this complication. Emergency evacuation of the clot helped in regaining normal motor and sensory function. The need to avoid straining of the paraspinal muscles in the postoperative period is emphasized.</p> <p>Conclusion</p> <p>Most cases of postoperative spinal extradural hematomas occur as a result of venous bleeding. However, an arterial source of bleeding from paraspinal muscular branches causing extradural hematoma and subsequent neurological deficit is underreported. Undue straining of paraspinal muscles in the postoperative period after major spinal surgery should be avoided for at least a few days.</p

Global hybrids from the semiclassical atom theory satisfying the local density linear response

We propose global hybrid approximations of the exchange-correlation (XC) energy functional which reproduce well the modified fourth-order gradient expansion of the exchange energy in the semiclassical limit of many-electron neutral atoms and recover the full local density approximation (LDA) linear response. These XC functionals represent the hybrid versions of the APBE functional [Phys. Rev. Lett. 106, 186406, (2011)] yet employing an additional correlation functional which uses the localization concept of the correlation energy density to improve the compatibility with the Hartree-Fock exchange as well as the coupling-constant-resolved XC potential energy. Broad energetical and structural testings, including thermochemistry and geometry, transition metal complexes, non-covalent interactions, gold clusters and small gold-molecule interfaces, as well as an analysis of the hybrid parameters, show that our construction is quite robust. In particular, our testing shows that the resulting hybrid, including 20\% of Hartree-Fock exchange and named hAPBE, performs remarkably well for a broad palette of systems and properties, being generally better than popular hybrids (PBE0 and B3LYP). Semi-empirical dispersion corrections are also provided.Comment: 12 pages, 4 figure

Double-diffusive convection in an inclined porous layer with a concentration-based internal heat source

© 2017, The Author(s). The thermosolutal instability of double-diffusive convection in an inclined fluid-saturated porous layer with a concentration-based internal heat source is investigated. The linear instability of small-amplitude perturbations to the system is analyzed with respect to transverse and longitudinal rolls. The resultant eigenvalue problem is solved numerically utilizing the Chebyshev tau method. It is shown that an increasing inclination angle causes a strong stabilization in the transverse rolls irrespective of the internal heat source or vertical solutal Rayleigh number. Furthermore, substantial qualitative changes are demonstrated in the linear instability thresholds with variations in the inclination angle and concentration-based heat source

Inferring stabilizing mutations from protein phylogenies : application to influenza hemagglutinin

One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution

Breast cancer-specific mutations in CK1ε inhibit Wnt/β-catenin and activate the Wnt/Rac1/JNK and NFAT pathways to decrease cell adhesion and promote cell migration

Introduction Breast cancer is one of the most common types of cancer in women. One of the genes that were found mutated in breast cancer is casein kinase 1 epsilon (CK1ε). Because CK1ε is a crucial regulator of the Wnt signaling cascades, we determined how these CK1ε mutations interfere with the Wnt pathway and affect the behavior of epithelial breast cancer cell lines. Methods We performed in silico modeling of various mutations and analyzed the kinase activity of the CK1ε mutants both in vitro and in vivo. Furthermore, we used reporter and small GTPase assays to identify how mutation of CK1ε affects different branches of the Wnt signaling pathway. Based on these results, we employed cell adhesion and cell migration assays in MCF7 cells to demonstrate a crucial role for CK1ε in these processes. Results In silico modeling and in vivo data showed that autophosphorylation at Thr 44, a site adjacent to the breast cancer point mutations in the N-terminal lobe of human CK1ε, is involved in positive regulation of the CK1ε activity. Our data further demonstrate that, in mammalian cells, mutated forms of CK1ε failed to affect the intracellular localization and phosphorylation of Dvl2; we were able to demonstrate that CK1ε mutants were unable to enhance Dvl-induced TCF/LEF-mediated transcription, that CK1ε mutants acted as loss-of-function in the Wnt/β-catenin pathway, and that CK1ε mutants activated the noncanonical Wnt/Rac-1 and NFAT pathways, similar to pharmacological inhibitors of CK1. In line with these findings, inhibition of CK1 promoted cell migration as well as decreased cell adhesion and E-cadherin expression in the breast cancer-derived cell line MCF7. Conclusions In summary, these data suggest that the mutations of CK1ε found in breast cancer can suppress Wnt/β-catenin as well as promote the Wnt/Rac-1/JNK and Wnt/NFAT pathways, thus contributing to breast cancer development via effects on cell adhesion and migration. In terms of molecular mechanism, our data indicate that the breast cancer point mutations in the N-terminal lobe of CK1ε, which are correlated with decreased phosphorylation activities of mutated forms of CK1ε both in vitro and in vivo, interfere with positive autophosphorylation at Thr 4

Sequence and Structure Signatures of Cancer Mutation Hotspots in Protein Kinases

Protein kinases are the most common protein domains implicated in cancer, where somatically acquired mutations are known to be functionally linked to a variety of cancers. Resequencing studies of protein kinase coding regions have emphasized the importance of sequence and structure determinants of cancer-causing kinase mutations in understanding of the mutation-dependent activation process. We have developed an integrated bioinformatics resource, which consolidated and mapped all currently available information on genetic modifications in protein kinase genes with sequence, structure and functional data. The integration of diverse data types provided a convenient framework for kinome-wide study of sequence-based and structure-based signatures of cancer mutations. The database-driven analysis has revealed a differential enrichment of SNPs categories in functional regions of the kinase domain, demonstrating that a significant number of cancer mutations could fall at structurally equivalent positions (mutational hotspots) within the catalytic core. We have also found that structurally conserved mutational hotspots can be shared by multiple kinase genes and are often enriched by cancer driver mutations with high oncogenic activity. Structural modeling and energetic analysis of the mutational hotspots have suggested a common molecular mechanism of kinase activation by cancer mutations, and have allowed to reconcile the experimental data. According to a proposed mechanism, structural effect of kinase mutations with a high oncogenic potential may manifest in a significant destabilization of the autoinhibited kinase form, which is likely to drive tumorigenesis at some level. Structure-based functional annotation and prediction of cancer mutation effects in protein kinases can facilitate an understanding of the mutation-dependent activation process and inform experimental studies exploring molecular pathology of tumorigenesis

Rubisco evolution in C₄ eudicots: an analysis of Amaranthaceae sensu lato.

BACKGROUND: Rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase) catalyses the key reaction in the photosynthetic assimilation of CO₂. In C₄ plants CO₂ is supplied to Rubisco by an auxiliary CO₂-concentrating pathway that helps to maximize the carboxylase activity of the enzyme while suppressing its oxygenase activity. As a consequence, C₄ Rubisco exhibits a higher maximum velocity but lower substrate specificity compared with the C₃ enzyme. Specific amino-acids in Rubisco are associated with C₄ photosynthesis in monocots, but it is not known whether selection has acted on Rubisco in a similar way in eudicots. METHODOLOGY/PRINCIPAL FINDINGS: We investigated Rubisco evolution in Amaranthaceae sensu lato (including Chenopodiaceae), the third-largest family of C₄ plants, using phylogeny-based maximum likelihood and Bayesian methods to detect Darwinian selection on the chloroplast rbcL gene in a sample of 179 species. Two Rubisco residues, 281 and 309, were found to be under positive selection in C₄ Amaranthaceae with multiple parallel replacements of alanine by serine at position 281 and methionine by isoleucine at position 309. Remarkably, both amino-acids have been detected in other C₄ plant groups, such as C₄ monocots, illustrating a striking parallelism in molecular evolution. CONCLUSIONS/SIGNIFICANCE: Our findings illustrate how simple genetic changes can contribute to the evolution of photosynthesis and strengthen the hypothesis that parallel amino-acid replacements are associated with adaptive changes in Rubisco

Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands