Macroglial diversity:white and grey areas and relevance to remyelination

Macroglia, comprising astrocytes and oligodendroglial lineage cells, have long been regarded as uniform cell types of the central nervous system (CNS). Although regional morphological differences between these cell types were initially described after their identification a century ago, these differences were largely ignored. Recently, accumulating evidence suggests that macroglial cells form distinct populations throughout the CNS, based on both functional and morphological features. Moreover, with the use of refined techniques including single-cell and single-nucleus RNA sequencing, additional evidence is emerging for regional macroglial heterogeneity at the transcriptional level. In parallel, several studies revealed the existence of regional differences in remyelination capacity between CNS grey and white matter areas, both in experimental models for successful remyelination as well as in the chronic demyelinating disease multiple sclerosis (MS). In this review, we provide an overview of the diversity in oligodendroglial lineage cells and astrocytes from the grey and white matter, as well as their interplay in health and upon demyelination and successful remyelination. In addition, we discuss the implications of regional macroglial diversity for remyelination in light of its failure in MS. Since the etiology of MS remains unknown and only disease-modifying treatments altering the immune response are available for MS, the elucidation of macroglial diversity in grey and white matter and its putative contribution to the observed difference in remyelination efficiency between these regions may open therapeutic avenues aimed at enhancing endogenous remyelination in either area

EFFECTS OF LAND COVER, WATER REDISTRIBUTION, AND TEMPERATURE ON ECOSYSTEM PROCESSES IN THE SOUTH PLATTE BASIN

Over one‐third of the land area in the South Platte Basin of Colorado, Nebraska, and Wyoming, has been converted to croplands. Irrigated cropland now comprises 8% of the basin, while dry croplands make up 31%. We used the RHESSys model to compare the changes in plant productivity and vegetation‐related hydrological processes that occurred as a result of either land cover alteration or directional temperature changes (−2°C, +4°C). Land cover change exerted more control over annual plant productivity and water fluxes for converted grasslands, while the effect of temperature changes on productivity and water fluxes was stronger in the mountain vegetation. Throughout the basin, land cover change increased the annual loss of water to the atmosphere by 114 mm via evaporation and transpiration, an increase of 37%. Both irrigated and nonirrigated grains became active earlier in the year than shortgrass steppe, leading to a seasonal shift in water losses to the atmosphere. Basin‐wide photosynthesis increased by 80% due to grain production. In contrast, a 4°C warming scenario caused annual transpiration to increase by only 3% and annual evaporation to increase by 28%, for a total increase of 71 mm. Warming decreased basin‐wide photosynthesis by 16%. There is a large elevational range from east to west in the South Platte Basin, which encompasses the western edge of the Great Plains and the eastern front of the Rocky Mountains. This elevational gain is accompanied by great changes in topographic complexity, vegetation type, and climate. Shortgrass steppe and crops found at elevations between 850 and 1800 m give way to coniferous forests and tundra between 1800 and 4000 m. Climate is increasingly dominated by winter snow precipitation with increasing elevation, and the timing of snowmelt influences tundra and forest ecosystem productivity, soil moisture, and downstream discharge. Mean annual precipitation of \u3c500 mm on the plains below 1800 m is far less than potential evapotranspiration of 1000–1500 mm and is insufficient for optimum plant productivity. The changes in water flux and photosynthesis from conversion of steppe to cropland are the result of redistribution of snowmelt water from the mountains and groundwater pumping through irrigation projects

A fluorophore attached to nicotinic acetylcholine receptor beta M2 detects productive binding of agonist to the alpha delta site

To study conformational transitions at the muscle nicotinic acetylcholine (ACh) receptor (nAChR), a rhodamine fluorophore was tethered to a Cys side chain introduced at the beta-19' position in the M2 region of the nAChR expressed in Xenopus oocytes. This procedure led to only minor changes in receptor function. During agonist application, fluorescence increased by (Delta-F/F) approximate to 10%, and the emission peak shifted to lower wavelengths, indicating a more hydrophobic environment for the fluorophore. The dose-response relations for Delta-F agreed well with those for epibatidine-induced currents, but were shifted approximate to 100-fold to the left of those for ACh-induced currents. Because (i) epibatidine binds more tightly to the alpha-gamma-binding site than to the alpha-delta site and (ii) ACh binds with reverse-site selectivity, these data suggest that Delta-F monitors an event linked to binding specifically at the alpha-delta-subunit interface. In experiments with flash-applied agonists, the earliest detectable Delta-F occurs within milliseconds, i.e., during activation. At low [ACh] (less than or equal to 10 muM), a phase of Delta-F occurs with the same time constant as desensitization, presumably monitoring an increased population of agonist-bound receptors. However, recovery from Delta-F is complete before the slowest phase of recovery from desensitization (time constant approximate to 250 s), showing that one or more desensitized states have fluorescence like that of the resting channel. That conformational transitions at the alpha-delta-binding site are not tightly coupled to channel activation suggests that sequential rather than fully concerted transitions occur during receptor gating. Thus, time-resolved fluorescence changes provide a powerful probe of nAChR conformational changes

Revisiting the Strange Stories: Revealing Mentalizing Impairments in Autism

A test of advanced theory of mind (ToM), first introduced by F. Happé (1994), was adapted for children (mental, human, animal, and nature stories plus unlinked sentences). These materials were closely matched for difficulty and were presented to forty-five 7- to 12-year-olds with autism and 27 control children. Children with autism who showed ToM impairment on independent tests performed significantly more poorly than controls solely on the mental, human, and animal stories with greatest impairment on the former and least on the latter. Thus, a mentalizing deficit may affect understanding of biologic agents even when this does not explicitly require understanding others' mental states

Hydrophobic and Charged Residues in the C-Terminal Arm of Hepatitis C Virus RNA-Dependent RNA Polymerase Regulate Initiation and Elongation.

The RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV) is essential for viral genome replication. Crystal structures of the HCV RdRp reveal two C-terminal features, a β-loop and a C-terminal arm, suitably located for involvement in positioning components of the initiation complex. Here we show that these two elements intimately regulate template and nucleotide binding, initiation, and elongation. We constructed a series of β-loop and C-terminal arm mutants, which were used for in vitro analysis of RdRp de novo initiation and primer extension activities. All mutants showed a substantial decrease in initiation activities but a marked increase in primer extension activities, indicating an ability to form more stable elongation complexes with long primer-template RNAs. Structural studies of the mutants indicated that these enzyme properties might be attributed to an increased flexibility in the C-terminal features resulting in a more open polymerase cleft, which likely favors the elongation process but hampers the initiation steps. A UTP cocrystal structure of one mutant shows, in contrast to the wild-type protein, several alternate conformations of the substrate, confirming that even subtle changes in the C-terminal arm result in a more loosely organized active site and flexible binding modes of the nucleotide. We used a subgenomic replicon system to assess the effects of the same mutations on viral replication in cells. Even the subtlest mutations either severely impaired or completely abolished the ability of the replicon to replicate, further supporting the concept that the correct positioning of both the β-loop and C-terminal arm plays an essential role during initiation and in HCV replication in general. IMPORTANCE: HCV RNA polymerase is a key target for the development of directly acting agents to cure HCV infections, which necessitates a thorough understanding of the functional roles of the various structural features of the RdRp. Here we show that even highly conservative changes, e.g., Tyr→Phe or Asp→Glu, in these seemingly peripheral structural features have profound effects on the initiation and elongation properties of the HCV polymerase

Agent familiarity and emotional context influence the everyday empathic responding of young children with autism

Whereas research addressing empathy in ASD tends to employ pencil-and-paper and lab-based behavioural methods, the current study is novel in eliciting parent-report data regarding everyday empathy, sampling various emotional situations regularly encountered by children. Parents of typically-developing children and children diagnosed with ASD and DS completed the newly-developed Day-to-Day Child Empathy Questionnaire. Analysis of descriptions of their children’s responses to the various empathy-inducing situations supports the notion of an empathy deficit in ASD, confirming previous laboratory-based findings. However, important moderation effects were also demonstrated, for both control and clinical groups. In particular, parents reported children in all groups to be more likely to respond empathically to a familiar agent. The nature of children’s responses also according to the specific emotional context

Grey matter OPCs are less mature and less sensitive to IFN gamma than white matter OPCs:consequences for remyelination

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by the formation of demyelinated lesions in the central nervous system. At later stages of the disease repair in the form of remyelination often fails, which leads to axonal degeneration and neurological disability. For the regeneration of myelin, oligodendrocyte progenitor cells (OPCs) have to migrate, proliferate and differentiate into remyelinating oligodendrocytes. Remyelination occurs faster and is more extensive in grey matter (GM) lesions than in white matter (WM) lesions. Here, we examined differences in neonatal OPCs from GM (gmOPCs) and WM (wmOPCs), both intrinsically and in response to environmental (injury) signals. We show that gmOPCs are less mature than wmOPCs, both on morphological and on gene-expression level. Additionally, gmOPCs proliferate more and differentiate slower than wmOPCs. When exposed to astrocyte-secreted signals wmOPC, but not gmOPC, migration decreases. In addition, wmOPCs are more sensitive to the detrimental effects of IFNγ treatment on proliferation, differentiation, and process arborisation, which is potentiated by TNFα. Our results demonstrate that OPCs from GM and WM differ both intrinsically and in response to their environment, which may contribute to the difference in remyelination efficiency between GM and WM MS lesions

Multi-Gap Superconductivity in MgB2: Magneto-Raman Spectroscopy

Electronic Raman scattering studies on MgB2 single crystals as a function of excitation and polarization have revealed three distinct superconducting features: a clean gap below 37 cm-1 and two coherence peaks at 109 cm-1 and 78 cm-1 which we identify as the superconducting gaps in \pi- and \sigma-bands and as the Leggett's collective mode arising from the fluctuation in the relative phase between two superconducting condensates residing on corresponding bands. The temperature and field dependencies of the superconducting features have been established. A phononic Raman scattering study of the E2g boron stretching mode anharmonicity and of superconductivity induced self-energy effects is presented. We show that anharmonic two phonon decay is mainly responsible for the unusually large linewidth of the E2g mode. We observe ~2.5% hardening of the E2g phonon frequency upon cooling into the superconducting state and estimate the electron-phonon coupling strength associated with this renormalization.Comment: Invited review in a special issue "Superconductivity in MgB_2: Physics and Applications

Variants Downstream of the Ornithine Decarboxylase Gene Influence Risk of Colorectal Adenoma and Aspirin Chemoprevention

Increased mucosal polyamine levels and ornithine decarboxylase (ODC) activity are associated with an increased risk of colorectal neoplasia, and aspirin treatment reduces risk. Previous studies suggest that a single nucleotide polymorphism (SNP) in the promoter of the ODC gene (rs2302615) may be associated with adenoma risk and/or response to aspirin chemoprevention. However, a comprehensive investigation of common genetic variation in the region of ODC gene is lacking. Using a tag SNP approach, we investigated associations between genotype or haplotype and adenoma risk among a cohort of 792 white non-Hispanic participants in a randomized trial of aspirin. Generalized linear regression was used to compute relative risks (RRs) and 95% confidence intervals (95% CIs) adjusted for age and sex. The false discovery rate was used to account for multiple testing. Interactions terms were used to assess whether genotype modified the effect of aspirin treatment. Of 15 SNPs analyzed, 7 were statistically significantly associated with adenoma risk. However, in multiple SNP regression models, only 2 of these, located downstream of the gene, were independently associated with risk: rs11694911 (1.29 RR, 1.08–1.53 95% CI, P=0.005) and rs2430420 (1.20 RR, 1.03–1.40 95% CI, P=0.022). In addition, there was evidence that rs2430420 and rs28362380 modified the effect of aspirin treatment, whereas the previously investigated SNP, rs2302615, had no statistically significant main effect or interaction with aspirin treatment. Our findings suggest that common genetic variants located downstream (3’) of the ODC gene influence risk of colorectal adenoma and may also impact the efficacy of aspirin chemoprevention