Aza-crown ethers with quinone side chains: Synthesis, complexation, and protonation.

The synthesis and spectroscopic investigation of aza-crown ethers with anthraquinone- and 1-aminoanthraquinone-functionalized side chains are described. Cation-induced shifts in the UV/VIS absorption spectra of the ligands dissolved in propylene carbonate are observed only for Li+ among the alkali metal ions and for Mg2+ among the alkaline earth metal ions as well as for Ag+ and Tl+. Only hypsochromic shifts of the absorption spectra of anthraquinone-bearing aza-crown ethers are observed on protonation. The variations of the extinction coefficients are discussed with respect to the sequence of protonation of the different amino groups

Cohesive and magnetic properties of grain boundaries in bcc Fe with Cr additions

Structural, cohesive, and magnetic properties of two symmetric $\Sigma3(111)$ and $\Sigma5(210)$ tilt grain boundaries (GBs) in pure bcc Fe and in dilute FeCr alloys are studied from first principles. Different concentration and position of Cr solute atoms are considered. We found that Cr atoms placed in the GB interstice enhance the cohesion by 0.5-1.2 J/m$^2$. Substitutional Cr in the layers adjacent to the boundary shows anisotropic effect on the GB cohesion: it is neutral when placed in the (111) oriented Fe grains, and enhances cohesion (by 0.5 J/m$^2$) when substituted in the boundary layer of the (210) grains. The strengthening effect of the Cr solute is dominated by the chemical component of the adhesive binding energy. Our calculations show that unlike the free iron surfaces, Cr impurities segregate to the boundaries of the Fe grains. The magnetic moments on GB atoms are substantially changed and their variation correlates with the corresponding relaxation pattern of the GB planes. The moments on Cr additions are 2-4 times enhanced in comparison with that in a Cr crystal and are antiparallel to the moments on the Fe atoms

Cysteine 893 is a target of regulatory thiol modifications of GluA1 AMPA receptors

Recent studies indicate that glutamatergic signaling involves, and is regulated by, thiol modifying and redox-active compounds. In this study, we examined the role of a reactive cysteine residue, Cys-893, in the cytosolic C-terminal tail of GluA1 AMPA receptor as a potential regulatory target. Elimination of the thiol function by substitution of serine for Cys-893 led to increased steady-state expression level and strongly reduced interaction with SAP97, a major cytosolic interaction partner of GluA1 C-terminus. Moreover, we found that of the three cysteine residues in GluA1 C-terminal tail, Cys-893 is the predominant target for Snitrosylation induced by exogenous nitric oxide donors in cultured cells and lysates. Co-precipitation experiments provided evidence for native association of SAP97 with neuronal nitric oxide synthase (nNOS) and for the potential coupling of Ca2+- permeable GluA1 receptors with nNOS via SAP97. Our results show that Cys-893 can serve as a molecular target for regulatory thiol modifications of GluA1 receptors, including the effects of nitric oxide.Peer reviewe

Biological properties of surface layers for ring of heart valve application

Oryginalna sztuczna komora wspomagania serca POLVAD opracowana w Polsce, została zastosowana dotychczas w leczeniu ponad 210 pacjentów. Najdłuższe wspomaganie serca za pomocą komory POLVAD trwało ponad rok. Dla protezy tej opracowywana jest innowacyjna zastawka dyskowa, z nisko profilowym pierścieniem wykonanym ze stopu tytanu. Dla zminimalizowania trombogenności pierścienia zastawki opracowano dyfuzyjne warstwy powierzchniowe: azotowaną typu TiN+Ti2N+αTi(N) i tlenoazotowaną typu TiO2+TiN+Ti2N+αTi(N), wytwarzane obróbką jarzeniową na potencjale plazmy. Trombogenność różnych kompozycji warstw została porównana w aspekcie aktywacji i adhezji płytek krwi do powierzchni biomateriału. Oceniono również wpływ metody sterylizacji biomateriału na intensywność adhezji trombocytów do jego powierzchni. Warstwy TiN oraz TiO2wykazały najniższą trombogenność, przy czym dla warstwy TiN korzystniejsza jest sterylizacja gazowa, podczas gdy dla warstwy TiO2- sterylizacja plazmowa.The original ventricular assist device POLVAD developed in Poland was used in over 210 patients so far. The longest POLVAD heart assistance excided one year. The innovative tilting disk valve with low profile ring made of titanium is developed for POLVAD. To minimize the valve ring thrombogenicity the diffusive surface layers were manufactured: nitriding TiN+Ti2N+αTi(N) and oxynitriding TiO2+TiN+Ti2N+αTi(N), in the glow discharge process on the plasma potential level. The thrombogenicity of different layers compositionwas compared regarding platelets activation and platelets adhesion to the material surface. The influence of material sterilization method on the platelets adhesion intensity was evaluated in addition. The nitriding TiN and oxynitriding TiO2layers have demonstrated the lowest thrombogenicity while the gas sterilization was the most profitable for nitriding layers – TiN and the plasma sterilization for oxynitriding layers – TiO2

Gene expression drives the evolution of dominance.

Dominance is a fundamental concept in molecular genetics and has implications for understanding patterns of genetic variation, evolution, and complex traits. However, despite its importance, the degree of dominance in natural populations is poorly quantified. Here, we leverage multiple mating systems in natural populations of Arabidopsis to co-estimate the distribution of fitness effects and dominance coefficients of new amino acid changing mutations. We find that more deleterious mutations are more likely to be recessive than less deleterious mutations. Further, this pattern holds across gene categories, but varies with the connectivity and expression patterns of genes. Our work argues that dominance arises as a consequence of the functional importance of genes and their optimal expression levels

Comparing Genetic Variation among Latin American Immigrants: Implications for Forensic Casework in the Arizona- and Texas-México Borderlands

The humanitarian crisis on the United States-México border is a long standing and evolving crisis in which nearly 8,000 deaths have been reported in the last two decades. These deaths are largely distributed across the Arizona-México and Texas-México border regions where demographic trends for immigrants attempting to cross into the U.S. have shifted dramatically. The demographic change and volume of immigrants seeking shelter in the U.S. presents new challenges for the forensic practitioners entrusted with the identification of individuals who lose their lives during the final segment of their journey. Within this Border context, the present study investigates how genetic variation inferred from forensically significant microsatellites can provide valuable information on regions of origin for unidentified remains on the group level. To explore how we can mobilize these genetic data to inform identification strategies, we conduct a comparative genetic analysis of identified and unidentified immigrant cases from the Arizona- and Texas-México contexts, as well as 27 other Latin American groups. Allele frequencies were utilized to calculate FST, and relationships were visually depicted in a multidimensional scaling plot. A Spearman correlation coefficient analysis assessed the strength and significance of population relationships and an agglomerative clustering analysis assessed population clusters. Results indicate that Arizona-México immigrants have the strongest relationship (\u3e80%) with groups from El Salvador, Guatemala, México, and an indigenous group from Southern México. Texas-México immigrants have the strongest relationships (\u3e80%) with groups from Belize, Colombia, Costa Rica, El Salvador, Guatemala, Honduras, and Nicaragua. These findings agree with, and are discussed in comparison to, previously reported demographic trends, population genetics research, and population history analyses. We emphasize the utility and necessity of coupling genetic variation research with a nuanced anthropological perspective for identification processes in the U.S-México border context

Epigenome-wide analysis of T-cell large granular lymphocytic leukemia identifies BCL11B as a potential biomarker

Background: The molecular pathogenesis of T-cell large granular lymphocytic leukemia (T-LGLL), a mature T-cell leukemia arising commonly from T-cell receptor alpha beta-positive CD8(+) memory cytotoxic T cells, is only partly understood. The role of deregulated methylation in T-LGLL is not well known. We analyzed the epigenetic profile of T-LGLL cells of 11 patients compared to their normal counterparts by array-based DNA methylation profiling. For identification of molecular events driving the pathogenesis of T-LGLL, we compared the differentially methylated loci between the T-LGLL cases and normal T cells with chromatin segmentation data of benign T cells from the BLUEPRINT project. Moreover, we analyzed gene expression data of T-LGLL and benign T cells and validated the results by pyrosequencing in an extended cohort of 17 patients, including five patients with sequential samples. Results: We identified dysregulation of DNA methylation associated with altered gene expression in T-LGLL. Since T-LGLL is a rare disease, the samples size is low. But as confirmed for each sample, hypermethylation of T-LGLL cells at various CpG sites located at enhancer regions is a hallmark of this disease. The interaction of BLC11B and C14orf64 as suggested by in silico data analysis could provide a novel pathogenetic mechanism that needs further experimental investigation. Conclusions: DNA methylation is altered in T-LGLL cells compared to benign T cells. In particular, BCL11B is highly significant differentially methylated in T-LGLL cells. Although our results have to be validated in a larger patient cohort, BCL11B could be considered as a potential biomarker for this leukemia. In addition, altered gene expression and hypermethylation of enhancer regions could serve as potential mechanisms for treatment of this disease. Gene interactions of dysregulated genes, like BLC11B and C14orf64, may play an important role in pathogenic mechanisms and should be further analyzed

Analysis of Marker-Defined HNSCC Subpopulations Reveals a Dynamic Regulation of Tumor Initiating Properties

Head and neck squamous carcinoma (HNSCC) tumors carry dismal long-term prognosis and the role of tumor initiating cells (TICs) in this cancer is unclear. We investigated in HNSCC xenografts whether specific tumor subpopulations contributed to tumor growth. We used a CFSE-based label retentions assay, CD49f (α6-integrin) surface levels and aldehyde dehydrogenase (ALDH) activity to profile HNSCC subpopulations. The tumorigenic potential of marker-positive and -negative subpopulations was tested in nude (Balb/c nu/nu) and NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice and chicken embryo chorioallantoic membrane (CAM) assays. Here we identified in HEp3, SQ20b and FaDu HNSCC xenografts a subpopulation of G0/G1-arrested slow-cycling CD49fhigh/ALDH1A1high/H3K4/K27me3low subpopulation (CD49f+) of tumor cells. A strikingly similar CD49fhigh/H3K27me3low subpopulation is also present in primary human HNSCC tumors and metastases. While only sorted CD49fhigh/ALDHhigh, label retaining cells (LRC) proliferated immediately in vivo, with time the CD49flow/ALDHlow, non-LRC (NLRC) tumor cell subpopulations were also able to regain tumorigenic capacity; this was linked to restoration of CD49fhigh/ALDHhigh, label retaining cells. In addition, CD49f is required for HEp3 cell tumorigenicity and to maintain low levels of H3K4/K27me3. CD49f+ cells also displayed reduced expression of the histone-lysine N-methyltransferase EZH2 and ERK1/2phosphorylation. This suggests that although transiently quiescent, their unique chromatin structure is poised for rapid transcriptional activation. CD49f− cells can “reprogram” and also achieve this state eventually. We propose that in HNSCC tumors, epigenetic mechanisms likely driven by CD49f signaling dynamically regulate HNSCC xenograft phenotypic heterogeneity. This allows multiple tumor cell subpopulations to drive tumor growth suggesting that their dynamic nature renders them a “moving target” and their eradication might require more persistent strategies

LOCAS – A Low Coverage Assembly Tool for Resequencing Projects

Motivation: Next Generation Sequencing (NGS) is a frequently applied approach to detect sequence variations between highly related genomes. Recent large-scale re-sequencing studies as the Human 1000 Genomes Project utilize NGS data of low coverage to afford sequencing of hundreds of individuals. Here, SNPs and micro-indels can be detected by applying an alignment-consensus approach. However, computational methods capable of discovering other variations such as novel insertions or highly diverged sequence from low coverage NGS data are still lacking. Results: We present LOCAS, a new NGS assembler particularly designed for low coverage assembly of eukaryotic genomes using a mismatch sensitive overlap-layout-consensus approach. LOCAS assembles homologous regions in a homologyguided manner while it performs de novo assemblies of insertions and highly polymorphic target regions subsequently to an alignment-consensus approach. LOCAS has been evaluated in homology-guided assembly scenarios with low sequence coverage of Arabidopsis thaliana strains sequenced as part of the Arabidopsis 1001 Genomes Project. While assembling the same amount of long insertions as state-of-the-art NGS assemblers, LOCAS showed best results regarding contig size, error rate and runtime. Conclusion: LOCAS produces excellent results for homology-guided assembly of eukaryotic genomes with short reads and low sequencing depth, and therefore appears to be the assembly tool of choice for the detection of novel sequenc