Magnetic Dirac semimetal state of (Mn,Ge)Bi2_2Te4_4

For quantum electronics, the possibility to finely tune the properties of magnetic topological insulators (TIs) is a key issue. We studied solid solutions between two isostructural Z$_2$ TIs, magnetic MnBi$_2$Te$_4$ and nonmagnetic GeBi$_2$Te$_4$, with Z$_2$ invariants of 1;000 and 1;001, respectively. For high-quality, large mixed crystals of Ge$_x$Mn$_{1-x}$Bi$_2$Te$_4$, we observed linear x-dependent magnetic properties, composition-independent pairwise exchange interactions along with an easy magnetization axis. The bulk band gap gradually decreases to zero for $x$ from 0 to 0.4, before reopening for $x>0.6$, evidencing topological phase transitions (TPTs) between topologically nontrivial phases and the semimetal state. The TPTs are driven purely by the variation of orbital contributions. By tracing the x-dependent $6p$ contribution to the states near the fundamental gap, the effective spin-orbit coupling variation is extracted. As $x$ varies, the maximum of this contribution switches from the valence to the conduction band, thereby driving two TPTs. The gapless state observed at $x=0.42$ closely resembles a Dirac semimetal above the Neel temperature and shows a magnetic gap below, which is clearly visible in raw photoemission data. The observed behavior of the Ge$_x$Mn$_{1-x}$Bi$_2$Te$_4$ system thereby demonstrates an ability to precisely control topological and magnetic properties of TIs

Site- and spin-dependent coupling at the highly ordered h-BN/Co(0001) interface

Using photoelectron diffraction and spectroscopy, we explore the structural and electronic properties of the hexagonal boron nitride (h-BN) monolayer epitaxially grown on the Co(0001) surface. Perfect matching of the lattice parameters allows formation of a well-defined interface where the B atoms occupy the hollow sites while the N atoms are located above the Co atoms. The corrugation of the h-BN monolayer and its distance from the substrate were determined by means of R-factor analysis. The obtained results are in perfect agreement with the density functional theory (DFT) predictions. The electronic structure of the interface is characterized by a significant mixing of the h-BN and Co states. Such hybridized states appear in the h-BN band gap. This allows to obtain atomically resolved scanning tunneling microscopy (STM) images from the formally insulating 2D material being in contact with ferromagnetic metal. The STM images reveal mainly the nitrogen sublattice due to a dominating contribution of nitrogen orbitals to the electronic states at the Fermi level. We believe that the high quality, well-defined structure and interesting electronic properties make the h-BN/Co(0001) interface suitable for spintronic applications.L.V.Ya. acknowledges the RSF (Grant No. 16-42-01093). A.V.T., V.O.S., K.A.B., O.Yu.V., and D.Yu.U. acknowledge St. Petersburg State University for research Grant No. 11.65.42.2017. M.V.K. and I.I.O. acknowledge the RFBR (Grant No. 16-29-06410). C.L. acknowledges the DFG (Grant Nos. LA655-17/1 and LA655-19/1).Peer reviewe

Lipidomics: A Tool for Studies of Atherosclerosis

Lipids, abundant constituents of both the vascular plaque and lipoproteins, play a pivotal role in atherosclerosis. Mass spectrometry-based analysis of lipids, called lipidomics, presents a number of opportunities not only for understanding the cellular processes in health and disease but also in enabling personalized medicine. Lipidomics in its most advanced form is able to quantify hundreds of different molecular lipid species with various structural and functional roles. Unraveling this complexity will improve our understanding of diseases such as atherosclerosis at a level of detail not attainable with classical analytical methods. Improved patient selection, biomarkers for gauging treatment efficacy and safety, and translational models will be facilitated by the lipidomic deliverables. Importantly, lipid-based biomarkers and targets should lead the way as we progress toward more specialized therapeutics

B-MYB Is Essential for Normal Cell Cycle Progression and Chromosomal Stability of Embryonic Stem Cells

Background: The transcription factor B-Myb is present in all proliferating cells, and in mice engineered to remove this gene, embryos die in utero just after implantation due to inner cell mass defects. This lethal phenotype has generally been attributed to a proliferation defect in the cell cycle phase of G1. Methodology/Principal Findings: In the present study, we show that the major cell cycle defect in murine embryonic stem (mES) cells occurs in G2/M. Specifically, knockdown of B-Myb by short-hairpin RNAs results in delayed transit through G2/M, severe mitotic spindle and centrosome defects, and in polyploidy. Moreover, many euploid mES cells that are transiently deficient in B-Myb become aneuploid and can no longer be considered viable. Knockdown of B-Myb in mES cells also decreases Oct4 RNA and protein abundance, while over-expression of B-MYB modestly up-regulates pou5f1 gene expression. The coordinated changes in B-Myb and Oct4 expression are due, at least partly, to the ability of B-Myb to directly modulate pou5f1 gene promoter activity in vitro. Ultimately, the loss of B-Myb and associated loss of Oct4 lead to an increase in early markers of differentiation prior to the activation of caspase-mediated programmed cell death. Conclusions/Significance: Appropriate B-Myb expression is critical to the maintenance of chromosomally stable and pluripotent ES cells, but its absence promotes chromosomal instability that results in either aneuploidy or differentiation-associated cell death

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

52 Genetic Loci Influencing Myocardial Mass.

BACKGROUND: Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES: This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS: We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS: We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10(-8). These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS: Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (&gt;250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation