Effects of MASP-1 of the Complement System on Activation of Coagulation Factors and Plasma Clot Formation

BACKGROUND: Numerous interactions between the coagulation and complement systems have been shown. Recently, links between coagulation and mannan-binding lectin-associated serine protease-1 (MASP-1) of the complement lectin pathway have been proposed. Our aim was to investigate MASP-1 activation of factor XIII (FXIII), fibrinogen, prothrombin, and thrombin-activatable fibrinolysis inhibitor (TAFI) in plasma-based systems, and to analyse effects of MASP-1 on plasma clot formation, structure and lysis. METHODOLOGY/PRINCIPAL FINDINGS: We used a FXIII incorporation assay and specific assays to measure the activation products prothrombin fragment F1+2, fibrinopeptide A (FPA), and activated TAFI (TAFIa). Clot formation and lysis were assessed by turbidimetric assay. Clot structure was studied by scanning electron microscopy. MASP-1 activated FXIII and, contrary to thrombin, induced FXIII activity faster in the Val34 than the Leu34 variant. MASP-1-dependent generation of F1+2, FPA and TAFIa showed a dose-dependent response in normal citrated plasma (NCP), albeit MASP-1 was much less efficient than FXa or thrombin. MASP-1 activation of prothrombin and TAFI cleavage were confirmed in purified systems. No FPA generation was observed in prothrombin-depleted plasma. MASP-1 induced clot formation in NCP, affected clot structure, and prolonged clot lysis. CONCLUSIONS/SIGNIFICANCE: We show that MASP-1 interacts with plasma clot formation on different levels and influences fibrin structure. Although MASP-1-induced fibrin formation is thrombin-dependent, MASP-1 directly activates prothrombin, FXIII and TAFI. We suggest that MASP-1, in concerted action with other complement and coagulation proteins, may play a role in fibrin clot formation

MASP-1 Induces a Unique Cytokine Pattern in Endothelial Cells: A Novel Link between Complement System and Neutrophil Granulocytes

Microbial infection urges prompt intervention by the immune system. The complement cascade and neutrophil granulocytes are the predominant contributors to this immediate anti-microbial action. We have previously shown that mannan-binding lectin-associated serine protease-1 (MASP-1), the most abundant enzyme of the complement lectin pathway, can induce p38-MAPK activation, NFkappaB signaling, and Ca(2+)-mobilization in endothelial cells. Since neutrophil chemotaxis and transmigration depends on endothelial cell activation, we aimed to explore whether recombinant MASP-1 (rMASP-1) is able to induce cytokine production and subsequent neutrophil chemotaxis in human umbilical vein endothelial cells (HUVEC). We found that HUVECs activated by rMASP-1 secreted IL-6 and IL-8, but not IL-1alpha, IL-1ra, TNFalpha and MCP-1. rMASP-1 induced dose-dependent IL-6 and IL-8 production with different kinetics. rMASP-1 triggered IL-6 and IL-8 production was regulated predominantly by the p38-MAPK pathway. Moreover, the supernatant of rMASP-1-stimulated HUVECs activated the chemotaxis of neutrophil granulocytes as an integrated effect of cytokine production. Our results implicate that besides initializing the complement lectin pathway, MASP-1 may activate neutrophils indirectly, via the endothelial cells, which link these effective antimicrobial host defense mechanisms

Charting Evolution’s Trajectory: Using Molluscan Eye Diversity to Understand Parallel and Convergent Evolution

For over 100 years, molluscan eyes have been used as an example of convergent evolution and, more recently, as a textbook example of stepwise evolution of a complex lens eye via natural selection. Yet, little is known about the underlying mechanisms that create the eye and generate different morphologies. Assessing molluscan eye diversity and understanding how this diversity came about will be important to developing meaningful interpretations of evolutionary processes. This paper provides an introduction to the myriad of eye types found in molluscs, focusing on some of the more unusual structures. We discuss how molluscan eyes can be applied to the study of evolution by examining patterns of convergent and parallel evolution and provide several examples, including the putative convergence of the camera-type eyes of cephalopods and vertebrates

Regional differentiation of felid vertebral column evolution: a study of 3D shape trajectories

Recent advances in geometric morphometrics provide improved techniques for extraction of biological information from shape and have greatly contributed to the study of ecomorphology and morphological evolution. However, the vertebral column remains an under-studied structure due in part to a concentration on skull and limb research, but most importantly because of the difficulties in analysing the shape of a structure composed of multiple articulating discrete units (i.e. vertebrae). Here, we have applied a variety of geometric morphometric analyses to three-dimensional landmarks collected on 19 presacral vertebrae to investigate the influence of potential ecological and functional drivers, such as size, locomotion and prey size specialisation, on regional morphology of the vertebral column in the mammalian family Felidae. In particular, we have here provided a novel application of a method—phenotypic trajectory analysis (PTA)—that allows for shape analysis of a contiguous sequence of vertebrae as functionally linked osteological structures. Our results showed that ecological factors influence the shape of the vertebral column heterogeneously and that distinct vertebral sections may be under different selection pressures. While anterior presacral vertebrae may either have evolved under stronger phylogenetic constraints or are ecologically conservative, posterior presacral vertebrae, specifically in the post-T10 region, show significant differentiation among ecomorphs. Additionally, our PTA results demonstrated that functional vertebral regions differ among felid ecomorphs mainly in the relative covariation of vertebral shape variables (i.e. direction of trajectories, rather than in trajectory size) and, therefore, that ecological divergence among felid species is reflected by morphological changes in vertebral column shape

Complement lectin pathway activation is associated with COVID-19 disease severity, independent of MBL2 genotype subgroups

Peer reviewed: TrueIntroductionWhile complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood.MethodsWe therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome.ResultsWe show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p&amp;lt;0.0001) and COVID-19 severity. Despite this, genetic variations in MBL2 are not associated with susceptibility to SARS-CoV-2 infection or disease outcomes such as mortality and the development of Long COVID.ConclusionIn conclusion, activation of the MBL-LP only plays a minor role in COVID-19 pathogenesis, since no clinically meaningful, consistent associations with disease outcomes were noted.</jats:sec

Transpulmonary thermodilution in neonates undergoing arterial switch surgery

Measurement of the global end-diastolic volume index (GEDI) by transpulmonary thermodilution (TPTD) has become a useful technique for measuring preload in adults. This study aimed to investigate the hemodynamic changes in neonates during the postoperative period after arterial switch surgery. Over a 13-month period, the postoperative data of 12 neonates with transposition of the great arteries were retrospectively investigated. Arterial and central venous blood pressures were monitored, Cardiac index (CI), stroke volume index (SVI), systemic vascular resistance index (SVRI), GEDI, and extravascular lung water index (ELWI) were measured by thermodilution. The CI was significantly correlated with the SVRI only in the closed chest condition (r = -0.92; P < 0.001). The CI and SVI values were significantly lower and the ELWI and SVRI values significantly higher in both the open and closed chest conditions than the postextubation values. The relationship between change in GEDI and change in CI was stronger in the open chest condition (r = 0.93; P < 0.006) than in the closed chest condition (r = 0.75; P = 0.055). However, the latter just missed statistical significance. According to the findings, TPTD seems to be a useful tool for assessing cardiac function after neonatal arterial switch surgery. Establishment of normal values will be essential for proper guidance of therapy for this population using volumetric parameters

Retrospective assessment of the most common mitochondrial DNA mutations in a large Hungarian cohort of suspect mitochondrial cases

Abstract Prevalence estimations for mitochondrial disorders still vary widely and only few epidemiologic studies have been carried out so far. With the present work we aim to give a comprehensive overview about frequencies of the most common mitochondrial mutations in Hungarian patients. A total of 1328 patients were tested between 1999 and 2012. Among them, 882 were screened for the m.3243A > G, m.8344A > G, m.8993T > C/G mutations and deletions, 446 for LHON primary mutations. The mutation frequency in our cohort was 2.61% for the m.3243A > G, 1.47% for the m.8344A > G, 17.94% for Leber's Hereditary Optic Neuropathy (m.3460G > A, m.11778G > A, m.14484T > C) and 0.45% for the m.8993T > C/G substitutions. Single mtDNA deletions were detected in 14.97%, while multiple deletions in 6.01% of the cases. The mutation frequency in Hungarian patients suggestive of mitochondrial disease was similar to other Caucasian populations. Further retrospective studies of different populations are needed in order to accurately assess the importance of mitochondrial diseases and manage these patients