CENP-C recruits M18BP1 to centromeres to promote CENP-A chromatin assembly

CENP-C provides a link between existing CENP-A chromatin and the proteins required for new CENP-A nucleosome assembly

Dual recognition of CENP-A nucleosomes is required for centromere assembly

CENP-C and CENP-N recognize distinct structural elements of CENP-A nucleosomes, providing a foundation for the assembly of other centromere and kinetochore components

Alveolar Epithelial Type II Cells Activate Alveolar Macrophages and Mitigate P. Aeruginosa Infection

Although alveolar epithelial type II cells (AECII) perform substantial roles in the maintenance of alveolar integrity, the extent of their contributions to immune defense is poorly understood. Here, we demonstrate that AECII activates alveolar macrophages (AM) functions, such as phagocytosis using a conditioned medium from AECII infected by P. aeruginosa. AECII-derived chemokine MCP-1, a monocyte chemoattractant protein, was identified as a main factor in enhancing AM function. We proposed that the enhanced immune potency of AECII may play a critical role in alleviation of bacterial propagation and pneumonia. The ability of phagocytosis and superoxide release by AM was reduced by MCP-1 neutralizing antibodies. Furthermore, MCP-1−/− mice showed an increased bacterial burden under PAO1 and PAK infection vs. wt littermates. AM from MCP-1−/− mice also demonstrated less superoxide and impaired phagocytosis over the controls. In addition, AECII conditioned medium increased the host defense of airway in MCP-1−/− mice through the activation of AM function. Mechanistically, we found that Lyn mediated NFκB activation led to increased gene expression and secretion of MCP-1. Consequently Lyn−/− mice had reduced MCP-1 secretion and resulted in a decrease in superoxide and phagocytosis by AM. Collectively, our data indicate that AECII may serve as an immune booster for fighting bacterial infections, particularly in severe immunocompromised conditions

ICAR: endoscopic skull‐base surgery

n/

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Dynamics of the interaction of human IgG subtype immune complexes with cells expressing R and H allelic forms of a low-affinity Fcγ receptor CD32A

CD32A, the major phagocytic FcγR in humans, exhibits a polymorphism in the ligand binding domain. Individuals homozygous for the R allelic form of CD32A (CD32AR allele) are more susceptible to bacterial infections and autoimmune diseases as compared with H allelic CD32A (CD32AH) homozygous and CD32AR/H heterozygous individuals. To understand the mechanisms behind this differential susceptibility, we have investigated the dynamics of the interaction of these allelic forms of CD32A when they are simultaneously exposed to immune complexes (IC). Binding studies using Ig fusion proteins of CD32A alleles showed that the R allele has significantly lower binding not only to human IgG2, but also to IgG1 and IgG3 subtypes. Competition assays using purified molecules demonstrated that CD32AH-Ig outcompetes CD32AR-Ig for IC binding when both alleles simultaneously compete for the same ligand. CD32AH-Ig blocked the IC binding mediated by both the allelic forms of cell surface CD32A, whereas CD32A R-Ig blocked only CD32AR and was unable to cross-block IC binding mediated by CD32AH. Two-dimensional affinity measurements also demonstrated that CD32AR has significantly lower affinity toward all three subtypes as compared with CD32AH. Our data suggest that the lower binding of CD32AR not only to IgG2 but also to IgG1 and IgG3 might be responsible for the lack of clearance of IC leading to increased susceptibility to bacterial infections and autoimmune diseases. Our data further suggests that in humans, inflammatory cells from CD32AR/H heterozygous individuals may predominantly use the H allele to mediate Ab-coated target cell binding during phagocytosis and Ab-dependent cellular cytotoxicity, resulting in a phenotype similar to CD32AH homozygous individuals. Copyright © 2009 by The American Association of Immunologists, Inc

Electron-Ion Temperature Ratio in Astrophysical Shocks

Collisionless shock waves in supernova remnants and the solar wind heat electrons less effectively than they heat ions, as is predicted by kinetic simulations. However, the values of T ( e )/T ( p ) inferred from the H alpha profiles of supernova remnant shocks behave differently as a function of Mach number or Alfven Mach number than what is measured in the solar wind or predicted by simulations. Here we determine T ( e )/T ( p ) for supernova remnant shocks using H alpha profiles, shock speeds from proper motions, and electron temperatures from X-ray spectra. We also improve the estimates of sound speed and Alfven speed used to determine Mach numbers. We find that the H alpha determinations are robust and that the discrepancies among supernova remnant shocks, solar wind shocks, and computer-simulated shocks remain. We discuss some possible contributing factors, including shock precursors, turbulence, and varying preshock conditions

Electron–Ion Temperature Ratio in Astrophysical Shocks

Collisionless shock waves in supernova remnants and the solar wind heat electrons less effectively than they heat ions, as is predicted by kinetic simulations. However, the values of T$_e$/T$_p$ inferred from the H alpha profiles of supernova remnant shocks behave differently as a function of Mach number or Alfv\'{e}n Mach number than what is measured in the solar wind or predicted by simulations. Here we determine T$_e$/T$_p$ for supernova remnant shocks using H alpha profiles, shock speeds from proper motions, and electron temperatures from X-ray spectra. We also improve the estimates of sound speed and Alfv\'{e}n speed used to determine Mach numbers. We find that the H alpha determinations are robust and that the discrepancies among supernova remnant shocks, solar wind shocks and computer-simulated shocks remain. We discuss some possible contributing factors, including shock precursors, turbulence and varying preshock conditions