CD26/DPP-4 inhibition recruits regenerative stem cells via stromal cell-derived factor-1 and beneficially influences ischaemia-reperfusion injury in mouse lung transplantation†

OBJECTIVES The CD26 antigen is a transmembrane glycoprotein that is constitutively expressed on activated lymphocytes and in pulmonary parenchyma. This molecule is also identified as dipeptidyl peptidase-4 (DPP-4) that cleaves a host of biologically active peptides. Here, we aimed to identify an important substrate of CD26/DPP-4—stromal cell-derived factor-1 (SDF-1/CXCL12)—as a key modulator for stem-cell homing together with its receptor CXCR4 in response to ischaemic injury of the lung. METHODS Orthotopic single lung transplantation (Tx) was performed between syngeneic C57BL/6 mice. Inhibition of CD26/DPP-4 activity in recipients was achieved using vildagliptin (10mg/kg, every 12h) subcutaneously, and 6h ischaemia time was applied prior to implantation. Forty-eight hours after Tx, lung histology, SDF-1 levels (enzyme-linked immunosorbent assay) in lung, spleen and plasma, and expression of the SDF-1 receptor CXCR4 in blood and lung were assessed. Homing of regenerative progenitor cells to the transplanted lung was evaluated using fluorescent-activated cell sorting. RESULTS Compared with untreated lung transplanted mice, systemic DPP-4 inhibition of Tx recipients resulted in an increase in protein concentration of SDF-1 in plasma, spleen and lung. Concordantly, the frequency of cells bearing the SDF-1 receptor CXCR4 rose significantly in the circulation and also in the lungs of DPP-4-inhibited recipients. We found co-expression of CXCR4/CD34 in the grafts of animals treated with vildagliptin, and the stem-cell markers Flt-3 and c-kit were present on a significantly increased number of cells. The morphology of grafts from DPP-4 inhibitor-treated recipients revealed less alveolar oedema when compared with untreated recipients. CONCLUSIONS Targeting the SDF-1-CXCR4 axis through CD26/DPP-4 inhibition increased the intragraft number of progenitor cells contributing to the recovery from ischaemia-reperfusion lung injury. Stabilization of endogenous SDF-1 is achievable and may be a promising strategy to intensify sequestration of regenerative stem cells and thus emerges as a novel therapeutic concep

Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling

The Gram-negative anaerobe Porphyromonas gingivalis is associated with chronic periodontitis. Clinical isolates of P. gingivalis strains with high dipeptidyl peptidase 4 (DPP4) expression also had a high capacity for biofilm formation and were more infective. The X-ray crystal structure of P. gingivalis DPP4 was solved at 2.2 Å resolution. Despite a sequence identity of 32%, the overall structure of the dimer was conserved between P. gingivalis DPP4 and mammalian orthologues. The structures of the substrate binding sites were also conserved, except for the region called S2-extensive, which is exploited by specific human DPP4 inhibitors currently used as antidiabetic drugs. Screening of a collection of 450 compounds as inhibitors revealed a structure-activity relationship that mimics in part that of mammalian DPP9. The functional similarity between human and bacterial DPP4 was confirmed using 124 potential peptide substrates

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

RAAB - Rapid Assessment of Avoidable Blindness

RAAB is a free software package for data entry and analysis of rapid assessment of avoidable blindness surveys

Differential heavy-metal sensitivity in two cryptic species of the marine nematode Litoditis marina as revealed by developmental and behavioural assays

Monteiro LC, Van Butsel J, De Meester N, Traunspurger W, Derycke S, Moens T. Differential heavy-metal sensitivity in two cryptic species of the marine nematode Litoditis marina as revealed by developmental and behavioural assays. Journal of Experimental Marine Biology and Ecology. 2018;502:203-210

Management of acute heart failure in adult patients with congenital heart disease

Heart failure is an increasing reason for hospitalization and the leading cause of death in patients with adult congenital heart disease (ACHD). Recently, the European Society of Cardiology and the American Heart Association published consensus documents on the management of chronic heart failure in ACHD patients. However, little data and/or guidelines are available for the management of (sub)acute heart failure. The ACHD population is heterogeneous by definition and often has complex underlying anatomy, which could pose a challenge to the physician confronted with the ACHD patient in (sub)acute heart failure. Recognizing the underlying anatomy and awareness of the possible complications related would result in better treatment, avoid unnecessary delays, and improve outcomes of the ACHD patient with (sub)acute heart failure. This review focuses on the management of (sub)acute heart failure in ACHD with specific attention to lesion-specific issues