Tackling MARCKS-PIP3 circuit attenuates fibroblast activation and fibrosis progression.

Targeting activated fibroblasts, including myofibroblast differentiation, has emerged as a key therapeutic strategy in patients with idiopathic pulmonary fibrosis (IPF). However, there is no available therapy capable of selectively eradicating myofibroblasts or limiting their genesis. Through an integrative analysis of the regulator genes that are responsible for the activation of IPF fibroblasts, we noticed the phosphatidylinositol 4,5-bisphosphate (PIP2)-binding protein, myristoylated alanine-rich C-kinase substrate (MARCKS), as a potential target molecule for IPF. Herein, we have employed a 25-mer novel peptide, MARCKS phosphorylation site domain sequence (MPS), to determine if MARCKS inhibition reduces pulmonary fibrosis through the inactivation of PI3K/protein kinase B (AKT) signaling in fibroblast cells. We first observed that higher levels of MARCKS phosphorylation and the myofibroblast marker α-smooth muscle actin (α-SMA) were notably overexpressed in all tested IPF lung tissues and fibroblast cells. Treatment with the MPS peptide suppressed levels of MARCKS phosphorylation in primary IPF fibroblasts. A kinetic assay confirmed that this peptide binds to phospholipids, particularly PIP2, with a dissociation constant of 17.64 nM. As expected, a decrease of phosphatidylinositol (3,4,5)-trisphosphate pools and AKT activity occurred in MPS-treated IPF fibroblast cells. MPS peptide was demonstrated to impair cell proliferation, invasion, and migration in multiple IPF fibroblast cells in vitro as well as to reduce pulmonary fibrosis in bleomycin-treated mice in vivo. Surprisingly, we found that MPS peptide decreases α-SMA expression and synergistically interacts with nintedanib treatment in IPF fibroblasts. Our data suggest MARCKS as a druggable target in pulmonary fibrosis and also provide a promising antifibrotic agent that may lead to effective IPF treatments.-Yang, D. C., Li, J.-M., Xu, J., Oldham, J., Phan, S. H., Last, J. A., Wu, R., Chen, C.-H. Tackling MARCKS-PIP3 circuit attenuates fibroblast activation and fibrosis progression

Almost Sure Frequency Independence of the Dimension of the Spectrum of Sturmian Hamiltonians

We consider the spectrum of discrete Schr\"odinger operators with Sturmian potentials and show that for sufficiently large coupling, its Hausdorff dimension and its upper box counting dimension are the same for Lebesgue almost every value of the frequency.Comment: 12 pages, to appear in Commun. Math. Phy

The impact of a single round of community mass treatment with azithromycin on disease severity and ocular Chlamydia trachomatis load in treatment-naïve trachoma-endemic island communities in West Africa.

BACKGROUND: Trachoma, a neglected tropical disease, is caused by ocular infection with Chlamydia trachomatis (Ct). The World Health Organization (WHO) recommends three annual rounds of community mass drug treatment with azithromycin (MDA) if the prevalence of follicular trachoma in 1-9 year olds (TF1-9) exceeds 10% at district level to achieve an elimination target of district-level TF1-9 below 5% after. To evaluate this strategy in treatment-naïve trachoma-endemic island communities in Guinea Bissau, we conducted a cross-sectional population-based trachoma survey on four islands. The upper tarsal conjunctivae of each participant were clinically assessed for trachoma and conjunctival swabs were obtained (n = 1507). We used a droplet digital PCR assay to detect Ct infection and estimate bacterial load. We visited the same households during a second cross-sectional survey and repeated the ocular examination and obtained conjunctival swabs from these households one year after MDA (n = 1029). RESULTS: Pre-MDA TF1-9 was 22.0% (136/618). Overall Ct infection prevalence (CtI) was 18.6% (25.4% in 1-9 year olds). Post-MDA (estimated coverage 70%), TF1-9 and CtI were significantly reduced (7.4% (29/394, P < 0.001) and 3.3% (34/1029, P < 0.001) (6.6% in 1-9 year olds, P < 0.001), respectively. Median ocular Ct load was reduced from 2038 to 384 copies/swab (P < 0.001). Following MDA cases of Ct infection were highly clustered (Moran's I 0.27, P < 0.001), with fewer clusters of Ct infection overall, fewer clusters of cases with high load infections and less severe disease. CONCLUSIONS: Despite a significant reduction in the number of clusters of Ct infection, mean Ct load, disease severity and presence of clusters of cases of high load Ct infection suggesting the beginning of trachoma control in isolated island communities, following a single round of MDA we demonstrate that transmission is still ongoing. These detailed data are useful in understanding the epidemiology of ocular Ct infection in the context of MDA and the tools employed may have utility in determining trachoma elimination and surveillance activities in similar settings

SECURITY EDUCATION IN AFRICA: PATTERNS AND PROSPECTS

This article is part of a larger study exploring global patterns of security education, in order to enhance the collaborative pursuit of security by the majority of the world’s countries. We draw on interviews at multinational training events, site visits and open sources. Here we describe general patterns of police, gendarme and military education in Africa, with particular attention to university-like institutions. This leads us to focus on mid-career military staff colleges as the most likely venues for building communities of educated professionals to enhance security. We identify states in each region with the greatest potential to play a leading role in the development of knowledge addressing new security challenges. South Africa, Nigeria and Kenya have obvious educational potential. Good governance and national policies are more important than size and wealth, and this suggests that smaller states like Senegal and Botswana could make important contributions. Mechanisms contributing to regional security communities include the African Peace and Security Architecture, career incentives, innovation, and regional training centres. Understanding the patterns of security education lays the groundwork to understand innovation, diffusion and the influence of the content of security of education

Generic Continuous Spectrum for Ergodic Schr"odinger Operators

We consider discrete Schr"odinger operators on the line with potentials generated by a minimal homeomorphism on a compact metric space and a continuous sampling function. We introduce the concepts of topological and metric repetition property. Assuming that the underlying dynamical system satisfies one of these repetition properties, we show using Gordon's Lemma that for a generic continuous sampling function, the associated Schr"odinger operators have no eigenvalues in a topological or metric sense, respectively. We present a number of applications, particularly to shifts and skew-shifts on the torus.Comment: 14 page

Loss of buoyancy control in the copepod Calanus finmarchicus

A mechanism is demonstrated that could explain large-scale aggregations of lipid-rich copepods in the surface waters of marine environments. Laboratory experiments establish that changes in salinity and temperature induce lipid-mediated buoyancy instability that entrains copepods in surface waters. Reduced hydrostatic pressure associated with forced ascent of copepods at fjordic sills, shelf breaks and seamounts would also reduce the density of the lipid reserves, forcing copepods and particularly those in diapause to the surface. We propose that salinity, temperature and hydrodynamics of the physical environment, in conjunction with the biophysical properties of lipids, explain periodic high abundances of lipid-rich copepods in surface waters