Phosphatase-regulated recruitment of the spindle- and kinetochore-associated (Ska) complex to kinetochores

Kinetochores move chromosomes on dynamic spindle microtubules and regulate signaling of the spindle checkpoint. The spindle- and kinetochore-associated (Ska) complex, a hexamer composed of two copies of Ska1, Ska2 and Ska3, has been implicated in both roles. Phosphorylation of kinetochore components by the well-studied mitotic kinases Cdk1, Aurora B, Plk1, Mps1, and Bub1 regulate chromosome movement and checkpoint signaling. Roles for the opposing phosphatases are more poorly defined. Recently, we showed that the C terminus of Ska1 recruits protein phosphatase 1 (PP1) to kinetochores. Here we show that PP1 and protein phosphatase 2A (PP2A) both promote accumulation of Ska at kinetochores. Depletion of PP1 or PP2A by siRNA reduces Ska binding at kinetochores, impairs alignment of chromosomes to the spindle midplane, and causes metaphase delay or arrest, phenotypes that are also seen after depletion of Ska. Artificial tethering of PP1 to the outer kinetochore protein Nuf2 promotes Ska recruitment to kinetochores, and it reduces but does not fully rescue chromosome alignment and metaphase arrest defects seen after Ska depletion. We propose that Ska has multiple functions in promoting mitotic progression and that kinetochore-associated phosphatases function in a positive feedback cycle to reinforce Ska complex accumulation at kinetochores

Singular M-matrices which may not have a nonnegative generalized inverse

A matrix A ∈ ℝn×n is a GM-matrix if A = sI − B, where 0 < ρ(B) ≤ s and B ∈WPFn i.e., both B and Bthave ρ(B) as their eigenvalues and their corresponding eigenvector is entry wise nonnegative. In this article,we consider a generalization of a subclass of GM-matrices having a nonnegative core nilpotent decompositionand prove a characterization result for such matrices. Also, we study various notions of splitting of matricesfrom this new class and obtain sufficient conditions for their convergence

Sivakumar, Weak monotonicity of matrices and sub classes of proper splitting

Abstract. This article concerns weak monotonicity of matrices, with specific emphasis on its relationship with a certain class of proper splittings. The matrix A ∈ Rm×n is weak monotone provided Ax ≥ 0 = ⇒ x ∈ Rn ++N(A), where N(A) is the nullspace of A. In particular, the following extension of wellknown characterizations forM-matricesisobtained. Suppose that int(Rm +)∩R(A) = φ. Then the statements (a) A is weak-monotone. (b) R m + ∩R(A) ⊆ ARn +. (c) There exists x 0 ≥ 0 such that Ax 0&gt; 0. satisfy (a) ⇔ (b) ⇒ (c). Suppose further that A can be written as A = U −V, where A and U have the same range space and null space, U and V are nonnegative, VU † ≥ 0 (where U † denotes the Moore-Penrose inverse of U), and Ax ≥ 0, Ux ≥ 0 = ⇒ x ∈ Rn + + N(A). Then each of the above statements is equivalent to the statement (d) ρ(VU † ) &lt; 1. Key words. Proper splittings; Weak monotonicity; Nonnegativity; Moore-Penrose inverse

WEAK MONOTONICITY OF INTERVAL MATRICES ∗

Abstract. This article concerns weak monotonicity of interval matrices, with specific emphasis on its relationship with a certain class of proper splittings. Key words. Weak monotonicity; Moore-Penrose inverse; Interval matrix; range kernal regularity; proper splitting AMS subject classifications. 15A09, 15B48. 1. Introduction and Preliminaries. A real n × n matrix A is monotone if Ax ≥ 0 implies x ≥ 0, where by x ≥ 0 we mean that all the components of x are nonnegative. It can be easily shown that A is monotone if and only if A is nonsingular and A −1 ≥ 0, where for a matrix B, we denote B ≥ 0, if all the entries of B are nonnegative. Due to this fact, monotone matrices are also referred to as inverse positiv

CHD-associated enhancers shape human cardiomyocyte lineage commitment

Enhancers orchestrate gene expression programs that drive multicellular development and lineage commitment. Thus, genetic variants at enhancers are thought to contribute to developmental diseases by altering cell fate commitment. However, while many variant-containing enhancers have been identified, studies to endogenously test the impact of these enhancers on lineage commitment have been lacking. We perform a single-cell CRISPRi screen to assess the endogenous roles of 25 enhancers and putative cardiac target genes implicated in genetic studies of congenital heart defects (CHDs). We identify 16 enhancers whose repression leads to deficient differentiation of human cardiomyocytes (CMs). A focused CRISPRi validation screen shows that repression of TBX5 enhancers delays the transcriptional switch from mid- to late-stage CM states. Endogenous genetic deletions of two TBX5 enhancers phenocopy epigenetic perturbations. Together, these results identify critical enhancers of cardiac development and suggest that misregulation of these enhancers could contribute to cardiac defects in human patients

Caffeic acid protects rat heart mitochondria against isoproterenol-induced oxidative damage

Cardiac mitochondrial dysfunction plays an important role in the pathology of myocardial infarction. The protective effects of caffeic acid on mitochondrial dysfunction in isoproterenol-induced myocardial infarction were studied in Wistar rats. Rats were pretreated with caffeic acid (15 mg/kg) for 10 days. After the pretreatment period, isoproterenol (100 mg/kg) was subcutaneously injected to rats at an interval of 24 h for 2 days to induce myocardial infarction. Isoproterenol-induced rats showed considerable increased levels of serum troponins and heart mitochondrial lipid peroxidation products and considerable decreased glutathione peroxidase and reduced glutathione. Also, considerably decreased activities of isocitrate, succinate, malate, α-ketoglutarate, and NADH dehydrogenases and cytochrome-C-oxidase were observed in the mitochondria of myocardial-infarcted rats. The mitochondrial calcium, cholesterol, free fatty acids, and triglycerides were considerably increased and adenosine triphosphate and phospholipids were considerably decreased in isoproterenol-induced rats. Caffeic acid pretreatment showed considerable protective effects on all the biochemical parameters studied. Myocardial infarct size was much reduced in caffeic acid pretreated isoproterenol-induced rats. Transmission electron microscopic findings also confirmed the protective effects of caffeic acid. The possible mechanisms of caffeic acid on cardiac mitochondria protection might be due to decreasing free radicals, increasing multienzyme activities, reduced glutathione, and adenosine triphosphate levels and maintaining lipids and calcium. In vitro studies also confirmed the free-radical-scavenging activity of caffeic acid. Thus, caffeic acid protected rat’s heart mitochondria against isoproterenol-induced damage. This study may have a significant impact on myocardial-infarcted patients