Disruption in murine Eml1 perturbs retinal lamination during early development.

During mammalian development, establishing functional neural networks in stratified tissues of the mammalian central nervous system depends upon the proper migration and positioning of neurons, a process known as lamination. In particular, the pseudostratified neuroepithelia of the retina and cerebrocortical ventricular zones provide a platform for progenitor cell proliferation and migration. Lamination defects in these tissues lead to mispositioned neurons, disrupted neuronal connections, and abnormal function. The molecular mechanisms necessary for proper lamination in these tissues are incompletely understood. Here, we identified a nonsense mutation in the Eml1 gene in a novel murine model, tvrm360, displaying subcortical heterotopia, hydrocephalus and disorganization of retinal architecture. In the retina, Eml1 disruption caused abnormal positioning of photoreceptor cell nuclei early in development. Upon maturation, these ectopic photoreceptors possessed cilia and formed synapses but failed to produce robust outer segments, implying a late defect in photoreceptor differentiation secondary to mislocalization. In addition, abnormal positioning of Müller cell bodies and bipolar cells was evident throughout the inner neuroblastic layer. Basal displacement of mitotic nuclei in the retinal neuroepithelium was observed in tvrm360 mice at postnatal day 0. The abnormal positioning of retinal progenitor cells at birth and ectopic presence of photoreceptors and secondary neurons upon maturation suggest that EML1 functions early in eye development and is crucial for proper retinal lamination during cellular proliferation and development

Decomposing uncertainties in the future terrestrial carbon budget associated with emission scenarios, climate projections, and ecosystem simulations using the ISI-MIP results

We examined the changes to global net primary production (NPP), vegetation biomass carbon (VegC), and soil organic carbon (SOC) estimated by six global vegetation models (GVMs) obtained from the Inter-Sectoral Impact Model Intercomparison Project. Simulation results were obtained using five global climate models (GCMs) forced with four representative concentration pathway (RCP) scenarios. To clarify which component (i.e., emission scenarios, climate projections, or global vegetation models) contributes the most to uncertainties in projected global terrestrial C cycling by 2100, analysis of variance (ANOVA) and wavelet clustering were applied to 70 projected simulation sets. At the end of the simulation period, changes from the year 2000 in all three variables varied considerably from net negative to positive values. ANOVA revealed that the main sources of uncertainty are different among variables and depend on the projection period. We determined that in the global VegC and SOC projections, GVMs are the main influence on uncertainties (60 % and 90 %, respectively) rather than climate-driving scenarios (RCPs and GCMs). Moreover, the divergence of changes in vegetation carbon residence times is dominated by GVM uncertainty, particularly in the latter half of the 21st century. In addition, we found that the contribution of each uncertainty source is spatiotemporally heterogeneous and it differs among the GVM variables. The dominant uncertainty source for changes in NPP and VegC varies along the climatic gradient. The contribution of GVM to the uncertainty decreases as the climate division becomes cooler (from ca. 80 % in the equatorial division to 40 % in the snow division). Our results suggest that to assess climate change impacts on global ecosystem C cycling among each RCP scenario, the long-term C dynamics within the ecosystems (i.e., vegetation turnover and soil decomposition) are more critical factors than photosynthetic processes. The different trends in the contribution of uncertainty sources in each variable among climate divisions indicate that improvement of GVMs based on climate division or biome type will be effective. On the other hand, in dry regions, GCMs are the dominant uncertainty source in climate impact assessments of vegetation and soil C dynamics

Muon Physics: A Pillar of the Standard Model

Since its discovery in the 1930s, the muon has played an important role in our quest to understand the sub-atomic theory of matter. The muon was the first second-generation standard-model particle to be discovered, and its decay has provided information on the (Vector -Axial Vector) structure of the weak interaction, the strength of the weak interaction, G_F, and the conservation of lepton number (flavor) in muon decay. The muon's anomalous magnetic moment has played an important role in restricting theories of physics beyond the standard standard model, where at present there is a 3.4 standard-deviation difference between the experiment and standard-model theory. Its capture on the atomic nucleus has provided valuable information on the modification of the weak current by the strong interaction which is complementary to that obtained from nuclear beta decay.Comment: 8 pages, 9 figures. Invited paper for the Journal of Physical Society in Japan (JPSJ), Special Topics Issue "Frontiers of Elementary Particle Physics, The Standard Model and beyond

A Splicing Mutation in Slc4a5 Results in Retinal Detachment and Retinal Pigment Epithelium Dysfunction

Fluid and solute transporters of the retinal pigment epithelium (RPE) are core components of the outer blood-retinal barrier. Characterizing these transporters and their role in retinal homeostasis may provide insights into ocular function and disease. Here, we describe RPE defects in tvrm77 mice, which exhibit hypopigmented patches in the central retina. Mapping and nucleotide sequencing of tvrm77 mice revealed a disrupted 5\u27 splice donor sequence in Slc4a5, a sodium bicarbonate cotransporter gene. Slc4a5 expression was reduced 19.7-fold in tvrm77 RPE relative to controls, and alternative splice variants were detected. SLC4A5 was localized to the Golgi apparatus of cultured human RPE cells and in apical and basal membranes. Fundus imaging, optical coherence tomography, microscopy, and electroretinography (ERG) of tvrm77 mice revealed retinal detachment, hypopigmented patches corresponding to neovascular lesions, and retinal folds. Detachment worsened and outer nuclear layer thickness decreased with age. ERG a- and b-wave response amplitudes were initially normal but declined in older mice. The direct current ERG fast oscillation and light peak were reduced in amplitude at all ages, whereas other RPE-associated responses were unaffected. These results link a new Slc4a5 mutation to subretinal fluid accumulation and altered light-evoked RPE electrophysiological responses, suggesting that SLC4A5 functions at the outer blood-retinal barrier

Identification of Arhgef12 and Prkci as genetic modifiers of retinal dysplasia in the Crb1rd8 mouse model.

Mutations in the apicobasal polarity gene CRB1 lead to diverse retinal diseases, such as Leber congenital amaurosis, cone-rod dystrophy, retinitis pigmentosa (with and without Coats-like vasculopathy), foveal retinoschisis, macular dystrophy, and pigmented paravenous chorioretinal atrophy. Limited correlation between disease phenotypes and CRB1 alleles, and evidence that patients sharing the same alleles often present with different disease features, suggest that genetic modifiers contribute to clinical variation. Similarly, the retinal phenotype of mice bearing the Crb1 retinal degeneration 8 (rd8) allele varies with genetic background. Here, we initiated a sensitized chemical mutagenesis screen in B6.Cg-Crb1rd8/Pjn, a strain with a mild clinical presentation, to identify genetic modifiers that cause a more severe disease phenotype. Two models from this screen, Tvrm266 and Tvrm323, exhibited increased retinal dysplasia. Genetic mapping with high-throughput exome and candidate-gene sequencing identified causative mutations in Arhgef12 and Prkci, respectively. Epistasis analysis of both strains indicated that the increased dysplastic phenotype required homozygosity of the Crb1rd8 allele. Retinal dysplastic lesions in Tvrm266 mice were smaller and caused less photoreceptor degeneration than those in Tvrm323 mice, which developed an early, large diffuse lesion phenotype. At one month of age, Müller glia and microglia mislocalization at dysplastic lesions in both modifier strains was similar to that in B6.Cg-Crb1rd8/Pjn mice but photoreceptor cell mislocalization was more extensive. External limiting membrane disruption was comparable in Tvrm266 and B6.Cg-Crb1rd8/Pjn mice but milder in Tvrm323 mice. Immunohistological analysis of mice at postnatal day 0 indicated a normal distribution of mitotic cells in Tvrm266 and Tvrm323 mice, suggesting normal early development. Aberrant electroretinography responses were observed in both models but functional decline was significant only in Tvrm323 mice. These results identify Arhgef12 and Prkci as modifier genes that differentially shape Crb1-associated retinal disease, which may be relevant to understanding clinical variability and underlying disease mechanisms in humans

Quantifying uncertainties in soil carbon responses to changes in global mean temperature and precipitation

Soil organic carbon (SOC) is the largest carbon pool in terrestrial ecosystems and may play a key role in biospheric feedbacks with elevated atmospheric carbon dioxide (CO2) in a warmer future world. We examined the simulation results of seven terrestrial biome models when forced with climate projections from four representative-concentration-pathways (RCPs)-based atmospheric concentration scenarios. The goal was to specify calculated uncertainty in global SOC stock projections from global and regional perspectives and give insight to the improvement of SOC-relevant processes in biome models. SOC stocks among the biome models varied from 1090 to 2650 Pg C even in historical periods (ca. 2000). In a higher forcing scenario (i.e., RCP8.5), inconsistent estimates of impact on the total SOC (2099–2000) were obtained from different biome model simulations, ranging from a net sink of 347 Pg C to a net source of 122 Pg C. In all models, the increasing atmospheric CO2 concentration in the RCP8.5 scenario considerably contributed to carbon accumulation in SOC. However, magnitudes varied from 93 to 264 Pg C by the end of the 21st century across biome models. Using the time-series data of total global SOC simulated by each biome model, we analyzed the sensitivity of the global SOC stock to global mean temperature and global precipitation anomalies (ΔT and ΔP respectively) in each biome model using a state-space model. This analysis suggests that ΔT explained global SOC stock changes in most models with a resolution of 1–2 °C, and the magnitude of global SOC decomposition from a 2 °C rise ranged from almost 0 to 3.53 Pg C yr−1 among the biome models. However, ΔP had a negligible impact on change in the global SOC changes. Spatial heterogeneity was evident and inconsistent among the biome models, especially in boreal to arctic regions. Our study reveals considerable climate uncertainty in SOC decomposition responses to climate and CO2 change among biome models. Further research is required to improve our ability to estimate biospheric feedbacks through both SOC-relevant and vegetation-relevant processes

Anti-prion drug mPPIg5 inhibits PrP(C) conversion to PrP(Sc).

Prion diseases, also known as transmissible spongiform encephalopathies, are a group of fatal neurodegenerative diseases that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans. The 'protein only hypothesis' advocates that PrP(Sc), an abnormal isoform of the cellular protein PrP(C), is the main and possibly sole component of prion infectious agents. Currently, no effective therapy exists for these diseases at the symptomatic phase for either humans or animals, though a number of compounds have demonstrated the ability to eliminate PrPSc in cell culture models. Of particular interest are synthetic polymers known as dendrimers which possess the unique ability to eliminate PrP(Sc) in both an intracellular and in vitro setting. The efficacy and mode of action of the novel anti-prion dendrimer mPPIg5 was investigated through the creation of a number of innovative bio-assays based upon the scrapie cell assay. These assays were used to demonstrate that mPPIg5 is a highly effective anti-prion drug which acts, at least in part, through the inhibition of PrP(C) to PrP(Sc) conversion. Understanding how a drug works is a vital component in maximising its performance. By establishing the efficacy and method of action of mPPIg5, this study will help determine which drugs are most likely to enhance this effect and also aid the design of dendrimers with anti-prion capabilities for the future

Erratum: Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts.

[This corrects the article DOI: 10.1038/s42003-018-0226-0.]

A stochastic model of Echinococcus multilocularis transmission in Hokkaido, Japan, focusing on the infection process

Echinococcus multilocularis causes human alveolar echinococcus. In Japan, high prevalence of E. multilocularis among the fox population has been reported throughout Hokkaido. Accordingly, control measures, such as fox hunting and the distribution of bait containing Praziquantel, have been conducted. This study developed a transmission model for individuals in the fox population and included a stochastic infection process to assess the prevalence of E. multilocularis. To make our model realistic, we used the worm burden for each individual in the fox population. We assumed that the worm burden depends on the number of protoscoleces in a predated vole and the number of infection experiences. We carried out stochastic simulations with 1,000 trials for the situations of Koshimizu and Sapporo, Hokkaido, Japan. The distribution of the worm burden among foxes obtained using the model agreed with dissection data. The simulation indicates that a careful choice of season is necessary for an effective distribution of Praziquantel-containing bait. A stochastic model for E. multilocularis, which can assess the range of the prevalence in the fox population, would be helpful in analyzing their complex life-cycle and also in designing control strategies.</p