Lipid Binding Defects and Perturbed Synaptogenic Activity of a Collybistin R290H Mutant That Causes Epilepsy and Intellectual Disability

Signaling at nerve cell synapses is a key determinant of proper brain function, and synaptic defects—or synaptopathies—are at the basis of many neurological and psychiatric disorders. In key areas of the mammalian brain, such as the hippocampus or the basolateral amygdala, the clustering of the scaffolding protein Gephyrin and of γ-aminobutyric acid type A receptors at inhibitory neuronal synapses is critically dependent upon the brain-specific guanine nucleotide exchange factor Collybistin (Cb). Accordingly, it was discovered recently that an R290H missense mutation in the diffuse B-cell lymphoma homology domain of Cb, which carries the guanine nucleotide exchange factor activity, leads to epilepsy and intellectual disability in human patients. In the present study, we determined the mechanism by which the Cb^R290H mutation perturbs inhibitory synapse formation and causes brain dysfunction. Based on a combination of biochemical, cell biological, and molecular dynamics simulation approaches, we demonstrate that the R290H mutation alters the strength of intramolecular interactions between the diffuse B-cell lymphoma homology domain and the pleckstrin homology domain of Cb. This defect reduces the phosphatidylinositol 3-phosphate binding affinity of Cb, which limits its normal synaptogenic activity. Our data indicate that impairment of the membrane lipid binding activity of Cb and a consequent defect in inhibitory synapse maturation represent a likely molecular pathomechanism of epilepsy and mental retardation in humans.     

Ecological patterns strongly impact the biogeography of western Palaearctic longhorn beetles (Coleoptera: Cerambycoidea)

We aim to unravel the biogeographic structuring of western Palaearctic longhorn beetles with focus on the location of different refugia, barriers to dispersal and postglacial range expansions with their particular filters. The interaction of different ecological features with these structures is analysed. The western Palaearctic was divided into 95 geographic entities. We produced presence-only matrices for all 955 Cerambycoidea species autochthonous to this area and derived species richness distributions and extracted faunal regions and faunal elements by cluster analyses and principal component analyses. Similar analyses were performed for sub-families and ecological groups. Longhorn beetles show a strong biogeographic structuring in the western Palaearctic. Species numbers strongly decrease to the north and west. Less mobile species and root feeders mostly contribute to the fauna of the Mediterranean region, whilst mobile species are more widespread. Feeders on broad-leaved trees dominate in western Europe, whilst feeders on coniferous trees are most important in northern Europe. Our results support multiple refugia in the Mediterranean region and underline the importance of Provence, Crimea and Crete as such refugia. Crete even might be an area of old endemism. The Atlanto- and the Ponto-Mediterranean regions are more strongly structured than assumed in classical biogeography. Mediterranean assemblages are mostly composed of non-flying species, root feeders and species with small distributions not found outside their glacial refugia. Tree feeders left their glacial retreats with their host plants. These range dynamics result in biogeographic structures with several dispersal barriers and filters composed of mountains, sea straits and climatic conditions.     

Comparison of different culture conditions for smooth muscle cell differentiation of human umbilical cord vein CD146+ perivascular cells

Pericytes are CD146+ perivascular cells (PCs) that have multipotential differentiation capacity as mesenchymal stem cells. Beside their crucial roles in vascular development and blood flow regulation, they have ability to differentiate into vascular cell types in vivo. These properties make pericytes preferred cells in the field of vascular tissue engineering. Culture medium for in vitro differentiation of pericytes to vascular smooth muscle cells (SMCs) has not been defined yet. The aim of this study is to try different culture media for SMC differentiation of CD146+ PCs. For this purpose, CD146+ PCs were isolated from human umbilical cord vein. Then they were characterized by immunofluorescence staining and flow cytometric analysis. Three different culture media including; (1) Transforming growth factor beta 1 (TGF-β1)+ bone morphogenic protein 4, (2) TGF-β1+ l-ascorbic acid (l-AA) and (3) Horse serum, were compared for differentiation of CD146+ PCs to SMCs by IFS and real time polymerase chain reaction. As a result, in the case of SMC differentiation of CD146+ PCs, second culture medium including TGF-β1 and l-AA was found to be more effective than other two media. These results are important for establishing proper culture conditions for in vitro SMC differentiation of CD146+ PCs.     

Endemic diversification in the mountains: genetic,morphological, and geographical differentiation of the <Emphasis Type="Italic">Hemidactylus</Emphasis> geckos in southwestern Arabia

In this study, we provide genetic, morphological, and geographical comparisons for 11 species of the southwestern Arabian radiation of Hemidactylus geckos, nine of which are endemic to the region. By using a coalescence-based species-tree reconstruction in combination with divergence time estimations and speciation probability testing, we show that most of the speciation events occurred in the Pliocene, which is more recent than previously thought based on calibrations of concatenated data sets. The current dating indicates that the changing climate at the beginning of the Pliocene, from hot and dry to cold and wet, is likely responsible for increased speciation in Hemidactylus. Analyses of geographic and altitudinal overlap of the species and their morphological differentiation show that most species do not occur in sympatry. Those that overlap geographically are usually differentiated by their altitudinal preference, head shape, body size, or their combination. Our results indicate that the topographically complex mountains of southwestern Arabia support a significant radiation of Hemidactylus geckos by allowing multiple allopatric speciation events to occur in a relatively small area. Consequently, we describe two new species endemic to the Asir Mountains of Saudi Arabia, H. alfarraji sp. n. and H. asirensis sp. n., and elevate two former subspecies of H. yerburii to a species level, H. montanus and H. pauciporosus.     

The evolution of intermediate castration virulence and ant coexistence in a spatially structured environment

Theory suggests that spatial structuring should select for intermediate levels of virulence in parasites, but empirical tests are rare and have never been conducted with castration (sterilizing) parasites. To test this theory in a natural landscape, we construct a spatially explicit model of the symbiosis between the ant-plant Cordia nodosa and its two, protecting ant symbionts, Allomerus and Azteca . Allomerus is also a castration parasite, preventing fruiting to increase colony fecundity. Limiting the dispersal of Allomerus and host plant selects for intermediate castration virulence. Increasing the frequency of the mutualist, Azteca , selects for higher castration virulence in Allomerus , because seeds from Azteca -inhabited plants are a public good that Allomerus exploits. These results are consistent with field observations and, to our knowledge, provide the first empirical evidence supporting the hypothesis that spatial structure can reduce castration virulence and the first such evidence in a natural landscape for either mortality or castration virulence.     

Burrow Dusting or Oral Vaccination Prevents Plague-Associated Prairie Dog Colony Collapse

Plague impacts prairie dogs (Cynomys spp.), the endangered black-footed ferret (Mustela nigripes) and other sensitive wildlife species. We compared efficacy of prophylactic treatments (burrow dusting with deltamethrin or oral vaccination with recombinant “sylvatic plague vaccine” [RCN-F1/V307]) to placebo treatment in black-tailed prairie dog (C. ludovicianus) colonies. Between 2013 and 2015, we measured prairie dog apparent survival, burrow activity and flea abundance on triplicate plots (“blocks”) receiving dust, vaccine or placebo treatment. Epizootic plague affected all three blocks but emerged asynchronously. Dust plots had fewer fleas per burrow (P < 0.0001), and prairie dogs captured on dust plots had fewer fleas (P < 0.0001) than those on vaccine or placebo plots. Burrow activity and prairie dog density declined sharply in placebo plots when epizootic plague emerged. Patterns in corresponding dust and vaccine plots were less consistent and appeared strongly influenced by timing of treatment applications relative to plague emergence. Deltamethrin or oral vaccination enhanced apparent survival within two blocks. Applying insecticide or vaccine prior to epizootic emergence blunted effects of plague on prairie dog survival and abundance, thereby preventing colony collapse. Successful plague mitigation will likely entail strategic combined uses of burrow dusting and oral vaccination within large colonies or colony complexes.