Lithium Decreases Glial Fibrillary Acidic Protein in a Mouse Model of Alexander Disease.

Alexander disease is a fatal neurodegenerative disease caused by mutations in the astrocyte intermediate filament glial fibrillary acidic protein (GFAP). The disease is characterized by elevated levels of GFAP and the formation of protein aggregates, known as Rosenthal fibers, within astrocytes. Lithium has previously been shown to decrease protein aggregates by increasing the autophagy pathway for protein degradation. In addition, lithium has also been reported to decrease activation of the transcription factor STAT3, which is a regulator of GFAP transcription and astrogliogenesis. Here we tested whether lithium treatment would decrease levels of GFAP in a mouse model of Alexander disease. Mice with the Gfap-R236H point mutation were fed lithium food pellets for 4 to 8 weeks. Four weeks of treatment with LiCl at 0.5% in food pellets decreased GFAP protein and transcripts in several brain regions, although with mild side effects and some mortality. Extending the duration of treatment to 8 weeks resulted in higher mortality, and again with a decrease in GFAP in the surviving animals. Indicators of autophagy, such as LC3, were not increased, suggesting that lithium may decrease levels of GFAP through other pathways. Lithium reduced the levels of phosphorylated STAT3, suggesting this as one pathway mediating the effects on GFAP. In conclusion, lithium has the potential to decrease GFAP levels in Alexander disease, but with a narrow therapeutic window separating efficacy and toxicity

Changes in Global Gene Expression in Response to Chemical and Genetic Perturbation of Chromatin Structure

DNA methylation is important for controlling gene expression in all eukaryotes. Microarray analysis of mutant and chemically-treated Arabidopsis thaliana seedlings with reduced DNA methylation revealed an altered gene expression profile after treatment with the DNA methylation inhibitor 5-aza-2′ deoxycytidine (5-AC), which included the upregulation of expression of many transposable elements. DNA damage-response genes were also coordinately upregulated by 5-AC treatment. In the ddm1 mutant, more specific changes in gene expression were observed, in particular for genes predicted to encode transposable elements in centromeric and pericentromeric locations. These results confirm that DDM1 has a very specific role in maintaining transcriptional silence of transposable elements, while chemical inhibitors of DNA methylation can affect gene expression at a global level

Connectivity of Default-Mode Network Is Associated with Cerebral Edema in Hepatic Encephalopathy

Cerebral edema, a well-known feature of acute liver disease, can occur in cirrhotic patients regardless of hepatic encephalopathy (HE) and adversely affect prognosis. This study characterized and correlated functional HE abnormalities in the brain to cerebral edema using resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI). Forty-one cirrhotic patients (16 without HE, 14 minimal HE, 11 overt HE) and 32 healthy controls were assessed. The HE grade in cirrhotic patients was evaluated by the West Haven criteria and neuro-psychological examinations. Functional connectivity correlation coefficient (fc-CC) of the default mode network (DMN) was determined by rs-fMRI, while the corresponding mean diffusivity (MD) was obtained from DTI. Correlations among inter-cortical fc-CC, DTI indices, Cognitive Ability Screening Instrument scores, and laboratory tests were also analyzed. Results showed that gradual reductions of HE-related consciousness levels, from “without HE” or “minimal HE” to “overt HE”, correlated with decreased anterior-posterior fc-CC in DMN [F(4.415), p = 0.000)]. The MD values from regions with anterior-posterior fc-CC differences in DMN revealed significant differences between the overt HE group and other groups. Increased MD in this network was inversely associated with decreased fc-CC in DMN and linearly correlated with poor cognitive performance. In conclusion, cerebral edema can be linked to altered cerebral temporal architecture that modifies both within- and between-network connectivity in HE. Reduced fc-CC in DMN is associated with behavior and consciousness deterioration. Through appropriate targets, rs-fMRI technology may provide relevant supplemental information for monitoring HE and serve as a new biomarker for clinical diagnosis

Specific Marking of hESCs-Derived Hematopoietic Lineage by WAS-Promoter Driven Lentiviral Vectors

Genetic manipulation of human embryonic stem cells (hESCs) is instrumental for tracing lineage commitment and to studying human development. Here we used hematopoietic-specific Wiskott-Aldrich syndrome gene (WAS)-promoter driven lentiviral vectors (LVs) to achieve highly specific gene expression in hESCs-derived hematopoietic cells. We first demonstrated that endogenous WAS gene was not expressed in undifferentiated hESCs but was evident in hemogenic progenitors (CD45−CD31+CD34+) and hematopoietic cells (CD45+). Accordingly, WAS-promoter driven LVs were unable to express the eGFP transgene in undifferentiated hESCs. eGFP+ cells only appeared after embryoid body (EB) hematopoietic differentiation. The phenotypic analysis of the eGFP+ cells showed marking of different subpopulations at different days of differentiation. At days 10–15, AWE LVs tag hemogenic and hematopoietic progenitors cells (CD45−CD31+CD34dim and CD45+CD31+CD34dim) emerging from hESCs and at day 22 its expression became restricted to mature hematopoietic cells (CD45+CD33+). Surprisingly, at day 10 of differentiation, the AWE vector also marked CD45−CD31low/−CD34− cells, a population that disappeared at later stages of differentiation. We showed that the eGFP+CD45−CD31+ population generate 5 times more CD45+ cells than the eGFP−CD45−CD31+ indicating that the AWE vector was identifying a subpopulation inside the CD45−CD31+ cells with higher hemogenic capacity. We also showed generation of CD45+ cells from the eGFP+CD45−CD31low/−CD34− population but not from the eGFP−CD45−CD31low/−CD34− cells. This is, to our knowledge, the first report of a gene transfer vector which specifically labels hemogenic progenitors and hematopoietic cells emerging from hESCs. We propose the use of WAS-promoter driven LVs as a novel tool to studying human hematopoietic development

Effects of maternal immune activation on gene expression patterns in the fetal brain

We are exploring the mechanisms underlying how maternal infection increases the risk for schizophrenia and autism in the offspring. Several mouse models of maternal immune activation (MIA) were used to examine the immediate effects of MIA induced by influenza virus, poly(I:C) and interleukin IL-6 on the fetal brain transcriptome. Our results indicate that all three MIA treatments lead to strong and common gene expression changes in the embryonic brain. Most notably, there is an acute and transient upregulation of the α, β and γ crystallin gene family. Furthermore, levels of crystallin gene expression are correlated with the severity of MIA as assessed by placental weight. The overall gene expression changes suggest that the response to MIA is a neuroprotective attempt by the developing brain to counteract environmental stress, but at a cost of disrupting typical neuronal differentiation and axonal growth. We propose that this cascade of events might parallel the mechanisms by which environmental insults contribute to the risk of neurodevelopmental disorders such as schizophrenia and autism

The role of horizontal resolution in simulating drivers of the global hydrological cycle

The role of atmospheric general circulation model (AGCM) horizontal resolution in representing the global energy budget and hydrological cycle is assessed, with the aim of improving the understanding of model uncertainties in simulating the hydrological cycle. We use two AGCMs from the UK Met Office Hadley Centre: HadGEM1-A at resolutions ranging from 270 to 60 km, and HadGEM3-A ranging from 135 to 25 km. The models exhibit a stable hydrological cycle, although too intense compared to reanalyses and observations. This over-intensity is explained by excess surface shortwave radiation, a common error in general circulation models (GCMs). This result is insensitive to resolution. However, as resolution is increased, precipitation decreases over the ocean and increases over the land. This is associated with an increase in atmospheric moisture transport from ocean to land, which changes the partitioning of moisture fluxes that contribute to precipitation over land from less local to more non-local moisture sources. The results start to converge at 60-km resolution, which underlines the excessive reliance of the mean hydrological cycle on physical parametrization (local unresolved processes) versus model dynamics (large-scale resolved processes) in coarser HadGEM1 and HadGEM3 GCMs. This finding may be valid for other GCMs, showing the necessity to analyze other chains of GCMs that may become available in the future with such a range of horizontal resolutions. Our finding supports the hypothesis that heterogeneity in model parametrization is one of the underlying causes of model disagreement in the Coupled Model Intercomparison Project (CMIP) exercises

Macrophages in Breast Cancer: Do Involution Macrophages Account for the Poor Prognosis of Pregnancy-Associated Breast Cancer?

Macrophage influx is associated with negative outcomes for women with breast cancer and has been demonstrated to be required for metastasis of mammary tumors in mouse models. Pregnancy-associated breast cancer is characterized by particularly poor outcomes, however the reasons remain obscure. Recently, post-pregnancy mammary involution has been characterized as having a wound healing signature. We have proposed the involution-hypothesis, which states that the wound healing microenvironment of the involuting gland is tumor promotional. Macrophage influx is one of the prominent features of the involuting gland, identifying the macrophage a potential instigator of tumor progression and a novel target for breast cancer treatment and prevention