Regulation of glycine receptor diffusion properties and gephyrin interactions by protein kinase C

Glycine receptors (GlyRs) can dynamically exchange between synaptic and extrasynaptic locations through lateral diffusion within the plasma membrane. Their accumulation at inhibitory synapses depends on the interaction of the β-subunit of the GlyR with the synaptic scaffold protein gephyrin. An alteration of receptor-gephyrin binding could thus shift the equilibrium between synaptic and extrasynaptic GlyRs and modulate the strength of inhibitory neurotransmission. Using a combination of dynamic imaging and biochemical approaches, we have characterised the molecular mechanism that links the GlyR-gephyrin interaction with GlyR diffusion and synaptic localisation. We have identified a protein kinase C (PKC) phosphorylation site within the cytoplasmic domain of the β-subunit of the GlyR (residue S403) that causes a reduction of the binding affinity between the receptor and gephyrin. In consequence, the receptor's diffusion in the plasma membrane is accelerated and GlyRs accumulate less strongly at synapses. We propose that the regulation of GlyR dynamics by PKC thus contributes to the plasticity of inhibitory synapses and may be involved in maladaptive forms of synaptic plasticity.     

Leptotene/zygotene chromosome movement via the SUN/KASH protein bridge in Caenorhabditis elegans

The Caenorhabditis elegans inner nuclear envelope protein matefin/SUN-1 plays a conserved, pivotal role in the process of genome haploidization. CHK-2-dependent phosphorylation of SUN-1 regulates homologous chromosome pairing and interhomolog recombination in Caenorhabditis elegans. Using time-lapse microscopy, we characterized the movement of matefin/SUN-1::GFP aggregates (the equivalent of chromosomal attachment plaques) and showed that the dynamics of matefin/SUN-1 aggregates remained unchanged throughout leptonene/zygotene, despite the progression of pairing. Movement of SUN-1 aggregates correlated with chromatin polarization. We also analyzed the requirements for the formation of movement-competent matefin/SUN-1 aggregates in the context of chromosome structure and found that chromosome axes were required to produce wild-type numbers of attachment plaques. Abrogation of synapsis led to a deceleration of SUN-1 aggregate movement. Analysis of matefin/SUN-1 in a double-strand break deficient mutant revealed that repair intermediates influenced matefin/SUN-1 aggregate dynamics. Investigation of movement in meiotic regulator mutants substantiated that proper orchestration of the meiotic program and effective repair of DNA double-strand breaks were necessary for the wild-type behavior of matefin/SUN-1 aggregates.     

French Experience of 2009 A/H1N1v Influenza in Pregnant Women

Background

The first reports on the pandemic influenza 2009 A/H1N1v from the USA, Mexico, and Australia indicated that this disease was associated with a high mortality in pregnant women. The aim of this study was to describe and compare the characteristics of severe critically ill and non-severe pregnant women with 2009 A/H1N1v-related illness in France.

Methodology/Principal Findings

A national registry was created to screen pregnant women with laboratory-confirmed 2009 A/H1N1v influenza. Three hundred and fifteen patients from 46 French hospitals were included: 40 patients were admitted to intensive care units (severe outcomes), 111 were hospitalized in obstetric or medical wards (moderate outcomes), and 164 were outpatients (mild outcomes). The 2009 A/H1N1v influenza illness occurred during all pregnancy trimesters, but most women (54%), notably the severe patients (70%), were in the third trimester. Among the severe patients, twenty (50%) underwent mechanical ventilation, and eleven (28%) were treated with extracorporeal membrane oxygenation. Three women died from A/H1N1v influenza. We found a strong association between the development of a severe outcome and both co-existing illnesses (adjusted odds ratio [OR], 5.1; 95% confidence interval [CI], 2.2–11.8) and a delay in oseltamivir treatment after the onset of symptoms (>3 or 5 days) (adjusted OR, 4.8; 95% CI, 1.9–12.1 and 61.2, 95% CI; 14.4–261.3, respectively). Among the 140 deliveries after 22 weeks of gestation known to date, 19 neonates (14%) were admitted to a neonatal intensive care unit, mainly for preterm delivery, and two neonates died. None of these neonates developed 2009 A/H1N1v infection.

Conclusions

This series confirms the high incidence of complications in pregnant women infected with pandemic A/H1N1v observed in other countries but depicts a lower overall maternal and neonatal mortality and morbidity than indicated in the USA or Australia. Moreover, our data demonstrate the benefit of early oseltamivir treatment in this specific population.     

Regulation of NADPH Oxidase Activity in Phagocytes: RELATIONSHIP BETWEEN FAD/NADPH BINDING AND OXIDASE COMPLEX ASSEMBLY*

The X⁺-linked chronic granulomatous disease (X⁺-CGD) variants are natural mutants characterized by defective NADPH oxidase activity but with normal Nox2 expression. According to the three-dimensional model of the cytosolic Nox2 domain, most of the X⁺-CGD mutations are located in/or close to the FAD/NADPH binding regions. A structure/function study of this domain was conducted in X⁺-CGD PLB-985 cells exactly mimicking 10 human variants: T341K, C369R, G408E, G408R, P415H, P415L, Δ507QKT509-HIWAinsert, C537R, L546P, and E568K. Diaphorase activity is defective in all these mutants. NADPH oxidase assembly is normal for P415H/P415L and T341K mutants where mutation occurs in the consensus sequences of NADPH- and FAD-binding sites, respectively. This is in accordance with their buried position in the three-dimensional model of the cytosolic Nox2 domain. FAD incorporation is abolished only in the T341K mutant explaining its absence of diaphorase activity. This demonstrates that NADPH oxidase assembly can occur without FAD incorporation. In addition, a defect of NADPH binding is a plausible explanation for the diaphorase activity inhibition in the P415H, P415L, and C537R mutants. In contrast, Cys-369, Gly-408, Leu-546, and Glu-568 are essential for NADPH oxidase complex assembly. However, according to their position in the three-dimensional model of the cytosolic domain of Nox2, only Cys-369 could be in direct contact with cytosolic factors during oxidase assembly. In addition, the defect in oxidase assembly observed in the C369R, G408E, G408R, and E568K mutants correlates with the lack of FAD incorporation. Thus, the NADPH oxidase assembly process and FAD incorporation are closely related events essential for the diaphorase activity of Nox2.     

An invasive species may be better than none: invasive signal and native noble crayfish have similar community effects

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MHC class I A loci polymorphism and diversity in three Southeast Asian populations of cynomolgus macaque

Cynomolgus macaques (Macaca fascicularis, Mafa) have emerged as important animal models for biomedical research, necessitating a more extensive characterization of their major histocompatibility complex polymorphic regions. The current information on the polymorphism or diversity of the polygenetic Mafa class I A loci is limited in comparison to the more commonly studied rhesus macaque Mafa class I A loci. Therefore, in this paper, to better elucidate the degree and types of polymorphisms and genetic differences of Mafa-A1 among three native Southeast Asian populations (Indonesian, Vietnamese, and Filipino) and to investigate how the allele differences between macaques and humans might have evolved to affect their respective immune responses, we identified 83 Mafa-A loci-derived alleles by DNA sequencing of which 66 are newly described. Most alleles are unique to each population, but seven of the most frequent alleles were identical in sequence to some alleles in other macaque species. We also revealed (1) the large and dynamic genetic and structural differences and similarities in allelic variation by analyzing the population allele frequencies, Hardy-Weinberg’s equilibrium, heterozygosity, nucleotide diversity profiles, and phylogeny, (2) the difference in genetic structure of populations by Wright’s FST statistic and hierarchical analysis of molecular variance, and (3) the different demographic and selection pressures on the three populations by performing Tajima’s D test of neutrality. The large level of diversity and polymorphism at the Mafa-A1 was less evident in the Filipino than in the Vietnam or the Indonesian populations, which may have important implications in animal capture, selection, and breeding for medical research.     

Angiosperm flora and biogeography of the páramo region of Colombia,Northern Andes

Páramo is the neotropical high elevation ecosystem in the northern Andes and Central America consisting of multiple dissected open areas above 3000 m a.s.l. Complex evolutionary processes that occurred within these ecosystems gave rise to a unique tropical Andean flora. Previous phytogeographical classifications for Colombian páramos have been based on subjective assessments of species distributions. However, a detailed floristic analysis highlighting affinities between páramo regions in Colombia has not yet been proposed. The aim of this study is to provide an analytical scenario for the patterns of regional plant diversity in a hierarchical framework based on the biogeographical history of the páramos, based on 30 localities of the Colombian páramos. Parsimony analysis of endemicity (PAE) and Jaccard similarity indices were applied to a presence/absence data matrix of páramo angiosperm species. Altitudinal distribution of species was used to determine the percentage of the páramo flora endemic to this ecosystem. Genera are shared among páramos, whereas species composition is highly endemic. 86% of the páramo angiosperm plant species is endemic to this ecosystem. The Colombian Páramo areas can be grouped using PAE into five biogeographical units, based on angiosperm species composition. These are: (1) Páramos de la Cordillera Oriental; (2) Páramos de la Cordillera Central and Macizo Colombiano; (3) Páramos de Antioquia; (4) Páramos del Norte; (5) Páramos de la Cordillera Occidental.     

Heterogeneity and Convergence of Olfactory First-Order Neurons Account for the High Speed and Sensitivity of Second-Order Neurons

In the olfactory system of male moths, a specialized subset of neurons detects and processes the main component of the sex pheromone emitted by females. It is composed of several thousand first-order olfactory receptor neurons (ORNs), all expressing the same pheromone receptor, that contact synaptically a few tens of second-order projection neurons (PNs) within a single restricted brain area. The functional simplicity of this system makes it a favorable model for studying the factors that contribute to its exquisite sensitivity and speed. Sensory information—primarily the identity and intensity of the stimulus—is encoded as the firing rate of the action potentials, and possibly as the latency of the neuron response. We found that over all their dynamic range, PNs respond with a shorter latency and a higher firing rate than most ORNs. Modelling showed that the increased sensitivity of PNs can be explained by the ORN-to-PN convergent architecture alone, whereas their faster response also requires cell-to-cell heterogeneity of the ORN population. So, far from being detrimental to signal detection, the ORN heterogeneity is exploited by PNs, and results in two different schemes of population coding based either on the response of a few extreme neurons (latency) or on the average response of many (firing rate). Moreover, ORN-to-PN transformations are linear for latency and nonlinear for firing rate, suggesting that latency could be involved in concentration-invariant coding of the pheromone blend and that sensitivity at low concentrations is achieved at the expense of precise encoding at high concentrations.