The complement system in age-related macular degeneration

Age-related macular degeneration (AMD) is a chronic and progressive degenerative disease of the retina, which culminates in blindness and affects mainly the elderly population. AMD pathogenesis and pathophysiology are incredibly complex due to the structural and cellular complexity of the retina, and the variety of risk factors and molecular mechanisms that contribute to disease onset and progression. AMD is driven by a combination of genetic predisposition, natural ageing changes and lifestyle factors, such as smoking or nutritional intake. The mechanism by which these risk factors interact and converge towards AMD are not fully understood and therefore drug discovery is challenging, where no therapeutic attempt has been fully effective thus far. Genetic and molecular studies have identified the complement system as an important player in AMD. Indeed, many of the genetic risk variants cluster in genes of the alternative pathway of the complement system and complement activation products are elevated in AMD patients. Nevertheless, attempts in treating AMD via complement regulators have not yet been successful, suggesting a level of complexity that could not be predicted only from a genetic point of view. In this review, we will explore the role of complement system in AMD development and in the main molecular and cellular features of AMD, including complement activation itself, inflammation, ECM stability, energy metabolism and oxidative stress.

     

The futility of decision making research

We have each spent more than 50 years doing research that has had little impact. Even more lamentable is that our field, judgment and decision making (JDM), has on the whole had little impact during that span. We attribute that failure to the use of methodologies that emphasize testing models rather than looking for differences in behavior. The “cognitive revolution” led the field astray, toward the goal of studying model fit rather than comparing observable results. With modeling as the goal, experimentation was stultified. Simple tasks became dominant. Although a poor metaphor for real decision making, the gambling paradigm has lasted forever because the inputs to the decision are known to the researcher and thus easily modeled.     

Is the valid species Synchaeta monopus Plate, 1889 (Rotifera: Monogononta) a product of preparation artefacts?

The morphology of soft-bodied rotifers, including those of Synchaeta spp, can be strongly affected by preparation artefacts including contraction and deformation. The long-standing, valid species Synchaeta monopus is known exclusively from ethanol- or formaldehyde-preserved material and no live specimens of it have ever been described. Although this alone is cause for concern, we could also reproduce unique characteristics diagnostic for this species (e.g. the swollen body and the rudimental foot) by subjecting specimens of Synchaeta pectinata to the preservation conditions under which it was first described. This proxy experiment and comparisons to other Synchaeta species indicate that literature occurrences of S. monopus likely represent preserved and deformed specimens of Synchaeta cecilia or other marine species of Synchaeta, thereby highlighting the importance of thorough morphological investigations of the habitus using live specimens and of features that are unaffected by preservation (e.g. the trophi). We therefore recommend that S. monopus be listed as a species inquirenda until topotypes are examined. Furthermore, in ecological studies including rotifers, where the examination of preserved material is often unavoidable, we stress that light-microscopical images of the habitus and trophi of the specimens minimally be included to facilitate independent verification of the species assignments.     

Defining G protein-coupled receptor peptide ligand expressomes and signalomes in human and mouse islets

Introduction

Islets synthesise and secrete numerous peptides, some of which are known to be important regulators of islet function and glucose homeostasis. In this study, we quantified mRNAs encoding all peptide ligands of islet G protein-coupled receptors (GPCRs) in isolated human and mouse islets and carried out in vitro islet hormone secretion studies to provide functional confirmation for the species-specific role of peptide YY (PYY) in mouse islets.

Materials and methods

GPCR peptide ligand mRNAs in human and mouse islets were quantified by quantitative real-time PCR relative to the reference genes ACTB, GAPDH, PPIA, TBP and TFRC. The pathways connecting GPCR peptide ligands with their receptors were identified by manual searches in the PubMed, IUPHAR and Ingenuity databases. Distribution of PYY protein in mouse and human islets was determined by immunohistochemistry. Insulin, glucagon and somatostatin secretion from islets was measured by radioimmunoassay.

Results

We have quantified GPCR peptide ligand mRNA expression in human and mouse islets and created specific signalomes mapping the pathways by which islet peptide ligands regulate human and mouse GPCR signalling. We also identified species-specific islet expression of several GPCR ligands. In particular, PYY mRNA levels were ~ 40,000-fold higher in mouse than human islets, suggesting a more important role of locally secreted Pyy in mouse islets. This was confirmed by IHC and functional experiments measuring insulin, glucagon and somatostatin secretion.

Discussion

The detailed human and mouse islet GPCR peptide ligand atlases will allow accurate translation of mouse islet functional studies for the identification of GPCR/peptide signalling pathways relevant for human physiology, which may lead to novel treatment modalities of diabetes and metabolic disease.

     

Space use by two arboreal rodent species in a Neotropical cloud forest

Studying animal space use patterns can help increase our understating of ecological processes such as competition and community dynamics. To quantify space and habitat use in an isolated and patchy cloud forest community in Mexico, we evaluate the vertical stratification, home range and habitat selection of two arboreal rodents: Habromys schmidlyi and Reithrodontomys microdon. Using live-traps at ground level and different forest strata, we radio-equipped nine individuals of H. schmidlyi and seven of R. microdon, and evaluated fine-scale space use and broad-scale habitat selection between cloud forest and oak forest. We found an average home range of 0.24 ha for R. microdon males and 0.72 ha for females, with a preference for higher canopy in the cloud forest. For H. schmidlyi the home range was 0.83 ha for males and 0.29 ha for females, with a preference for the understory level in the cloud forest. Home range is three-dimensional for these rodents, so we estimate that on average, individuals of both species used eight trees in the time they were tracked. We characterised the vegetation at the trap sites, and used recursive partitioning to relate the presence of different plants with the probability of finding these two species and Peromyscus aztecus, a third rodent species also present in the area and considered in our analysis of habitat use. The highest probability of finding R. microdon (96%) was related to the presence of Brachythecium occidentale and Renauldia mexicana, while H. schmidlyi (95%) was found in close proximity to Fabronia ciliaris and Everniastrum. We highlight the importance of arboreal trapping in biodiversity assessments, and the role of arboreal rodents in maintaining tropical forest ecosystems. We suggest that these rodent species could avoid or reduce competition by using the vertical strata differentially, and that H. schmidlyi and R. microdon can be biological indicators for cloud forest management and conservation.     

Prion protein cleavage fragments regulate adult neural stem cell quiescence through redox modulation of mitochondrial fission and SOD2 expression

Neurogenesis continues in the post-developmental brain throughout life. The ability to stimulate the production of new neurones requires both quiescent and actively proliferating pools of neural stem cells (NSCs). Actively proliferating NSCs ensure that neurogenic demand can be met, whilst the quiescent pool makes certain NSC reserves do not become depleted. The processes preserving the NSC quiescent pool are only just beginning to be defined. Herein, we identify a switch between NSC proliferation and quiescence through changing intracellular redox signalling. We show that N-terminal post-translational cleavage products of the prion protein (PrP) induce a quiescent state, halting NSC cellular growth, migration, and neurite outgrowth. Quiescence is initiated by the PrP cleavage products through reducing intracellular levels of reactive oxygen species. First, inhibition of redox signalling results in increased mitochondrial fission, which rapidly signals quiescence. Thereafter, quiescence is maintained through downstream increases in the expression and activity of superoxide dismutase-2 that reduces mitochondrial superoxide. We further observe that PrP is predominantly cleaved in quiescent NSCs indicating a homeostatic role for this cascade. Our findings provide new insight into the regulation of NSC quiescence, which potentially could influence brain health throughout adult life.