Vascular endothelium forms a continuous, semipermeable barrier that regulates the transvascular movement of hormones, macromolecules, and other solutes. Here, we describe a novel immediate early gene that is expressed selectively in vascular endothelial cells, verge (vascular early response gene). Verge protein includes an N-terminal region of ∼70 amino acids with modest homology (∼30% identity) to Apolipoprotein L but is otherwise unique. Verge mRNA and protein are induced selectively in the endothelium of adult vasculature by electrical or chemical seizures. Verge expression appears to be responsive to local tissue conditions, because it is induced in the hemisphere ipsilateral to transient focal cerebral ischemia. In contrast to the transient expression in adult, Verge mRNA and protein are constitutively expressed at high levels in the endothelium of developing tissues (particularly heart) in association with angiogenesis. Verge mRNA is induced in cultured endothelial cells by defined growth factors and hypoxia. Verge protein is dramatically increased by cysteine proteinase inhibitors, suggesting rapid turnover, and is localized to focal regions near the periphery of the cells. Endothelial cell lines that stably express Verge form monolayers that show enhanced permeability in response to activation of protein kinase C by phorbol esters. This response is accompanied by reorganization of the actin cytoskeleton and the formation of paracellular gaps. These studies suggest that Verge functions as a dynamic regulator of endothelial cell signaling and vascular function.
The authors describe a project that has gone further than most in developing the new knowledge, habits of mind, and individual and social resources that will be needed for reform to persist and prosper. It has been neither easy nor fast - but significant learning rarely is. Few professional development projects would commit themselves to such an ambitious agenda as reforming mathematics education, promoting equity, and developing teacher leadership, for any one of these objectives alone presents a daunting challenge. Learning mathematics is threatening to most teachers, especially elementary teachers whose limited experiences with mathematics have often been anxiety-provoking and uninspiring. Creating new understandings of equity brings out deep affective responses as participants attempt to make sense of emotionally charged issues. Developing leadership requires teachers to learn new skills and abilities while taking on unfamiliar roles and responsibilities. It can also provoke feelings of uncertainty and ambivalence. Almost four years ago a far-sighted mathematics professor whom we will call Charles(1) started the Mathematics Education, Equity, and Leadership (MEEL) project with the intention of meeting all three of these goals simultaneously. But he had not fully envisioned the complexities and challenges inherent in such an effort. This article is about those challenges, about the project that took them on, and about some of the people who faced them together. The Project and Its Leaders Charles has been working for many years to develop a cadre of knowledgeable teacher leaders who will foster change in their schools through their own teaching and through their interaction with others. He grew up in New York City as a Jew attending a school that enrolled mostly Christians. There he experienced firsthand the oppressive effects of inequitable treatment by a majority group. His thinking has been greatly influenced by learning about the Holocaust and by the civil rights movement of the 1960s. In the summer of 1992 Charles started MEEL, which was designed to develop teacher leaders who would work particularly on developing equity in mathematics education. Building on his many years as a director of and participant in a local mathematics project, Charles launched MEEL with nine elementary teachers. By drawing on networks of bilingual teachers, the project has grown from nine teachers to more than 30.(2) Every summer the project holds a two-week institute that includes sessions on mathematics, equity, and leadership. Throughout the academic year, participants convene in two-day retreats and monthly meetings, and ongoing networking and support groups are provided by project leaders. Charles believes that significant educational change entails learning on the part of everyone involved in reform, including himself. Maria, the Latina teacher whom he chose to lead the project with him, has greatly influenced his learning. Maria's knowledge and understanding were partially forged from her everyday experiences as a minority female in a white, male-dominated world and from her extensive classroom experiences working with students of color, who often came from economically disadvantaged situations and spoke little English. In addition, Maria gained understanding from previous experience as a leader. Maria grew up in a Mexican American community in California that consisted of two distinct cultures: Mexican American and white. She learned English because her parents didn't want her to struggle against the sometimes oppressive language barriers in school; she learned Spanish because it was the language of her community. Maria married a man who was half Native American and half Mexican American, and she lived with him on his reservation in Montana. There she worked as a teacher's aide while pursuing a teaching degree, and later she taught first grade. Maria's adopted son is American Indian and has sometimes struggled with mathematics in school. …
For most of U.S. history, local communities were the primary arbiters of school quality. Beginning in the mid-twentieth century, states began assuming more and more control over school standards and outcomes. The question we seek to answer is whether and the extent to which a particular kind of local voice—the voice of education practitioners—is represented in states' current, significant initiatives to improve low-performing schools. In the article, we focus on the role that practitioner knowledge played in the development of school improvement policies across three state education agencies. We draw on interviews, surveys, and document analyses collected for a larger exploratory study of knowledge utilization. Contrary to earlier research showing weak or uneven connections between state agencies and practitioners, we found that practitioner advice networks were generally stronger than states' research advice networks. We found ample illustration of staff using this advice to make sense of research for their own contexts, and for their own approaches to school improvement. Agencies formed ties to practitioners in districts and schools, in professional membership associations, within their own agencies, or in other agencies wrestling with similar problems. Who they turned to differed depending on earlier improvement policies and institutional histories.
Neuroinflammation is associated with a variety of neurological diseases, such as Alzheimer disease (AD), and is reliably detected by the presence of activated microglia. In early AD, high numbers of activated microglia are observed, particularly in brain regions involved in memory (e.g. hippocampus, entorhinal cortex). The ability of neurons to alter their transcriptional programs in response to synaptic input, also known as synaptic plasticity, is of fundamental importance to the mechanisms underlying learning and memory. Previously, we showed that neuroinflammation, induced by chronic lipopolysaccaride-infusion in young rats, led to a significant increase in the number of neurons expressing the behaviorally-induced immediate early gene Arc in hippocampal regions that showed activated microglia. Arc is transcribed in neurons that are part of stable neural networks activated during spatial exploratory behaviors. Given the role of Arc regulation in synaptic plasticity and memory, we hypothesized that neuroinflammation alters synaptic activity associated with spatial learning and memory. To test this hypothesis, we exposed rodents to 2 distinct learning experiences separated by a rest interval. Using a novel and sensitive technique, cellular compartmental analysis of temporal activity by fluorescence in situ hybridization (catFISH), we could assess the activity history of neurons in the CA1 area and entorhinal cortex. Here we found that Arc mRNA expression was induced in the same group neurons after exploration of the same novel environment while two different populations of neurons responded to two different environments in animals with experimental induced inflammation, similar to the control animals. Our data suggest that the CA1 area of the hippocampus is able to compensate for the neuroinflammation-induced alteration of activity in the DG and CA3 areas, perhaps through the direct projection from the layer III entorhinal cortical input to CA1. We are currently identifying the temporal dynamics of Arc transcription and Arc protein translation in the different layers of the entorhinal cortex and as it relates to the extent of microglial activation. Understanding how the presence of activated microglia affects synaptic plasticity is of critical importance for the development of strategies to prevent cognitive dysfunctions associated with initial stages of AD.
Chronic treatment of adult male F-344 rats (9-12 months old) with therapeutically relevant doses of memantine (30 mg/kg/day in chow for > 8 weeks) increased the maintenance of long-term potentiation of field excitatory postsynaptic potentials from perforant path-granule cell hippocampal synapses recorded in the fascia dentata in vivo. In contrast, there was no effect of memantine on baseline synaptic responses or population spikes. Likewise, short-term exploratory modulation of these hippocampal evoked responses was not different between memantine-treated and control rats. Both groups of rats were able to learn the spatial version of the Morris water task equally well, but the memantine-treated group showed a strong tendency to show more selective spatial search patterns in the training quadrant of the water pool during a final probe trial. As such, these studies provide the first electrophysiological evidence that memantine can increase the durability of synaptic plasticity and provide preclinical confirmation of the cognitive improvement seen with memantine in the treatment of demented patients.
As the human life span increases, the number of people suffering from cognitive decline is rising dramatically. The mechanisms underlying age-associated memory impairment are, however, not understood. Here we show that memory disturbances in the aging brain of the mouse are associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation and fail to initiate a hippocampal gene expression program associated with memory consolidation. Restoration of physiological H4K12 acetylation reinstates the expression of learning-induced genes and leads to the recovery of cognitive abilities. Our data suggest that deregulated H4K12 acetylation may represent an early biomarker of an impaired genome-environment interaction in the aging mouse brain. PMID: 20448184 Funding information This work was supported by: Howard Hughes Medical Institute, United States
