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4:30-6:30 pm: Registration: Registration Lobby
7:00 pm: Reception: West Terrace, Biddle House
8:00 pm: Dinner: Sun Porch, Biddle House
10:00 pm: Sleepy Hollow Pub
7:30 pm: Full Breakfast: Winter Palace, Biddle House
8:30 pm: Introduction: Brad Margus, Dave Frohnmayer
8:40 pm: The link between DNA damage, disease and neurodegeneration: Remarks from Session Chairs: Yossi Shiloh, Alan Lehman
8:45 pm: A-T: Yossi Shiloh
9:00 pm: A-TLD and NBS-1: Pat Conconnan
9:15 pm: Excision repair (XP/CS/TTD): Alan Lehman
9:30 pm: Helicase deficiency: Nathan Ellis
9:45 pm: Bloom syndrome: James German
10:00 pm: Fanconi anemia: Arleen Auerbach
10:15 pm: Werner syndrome: Ray Monnat
10:30 pm: Break
10:45 pm: Discussion
12:00 noon: Lunch: Biddle House
1:30 pm: Responses to DNA damage: Remarks from Session Chair: Mike Kastan
1:35 pm: General response pathways: Al Fornace
1:50 pm: DS break response pathways: Peggy Jeggo
2:05 pm: Substrates of ATM: Mike Kastan
2:20 pm: ATM function in the IR pathway: Martin Lavin
2:35 pm: ATM and ATR: Responding to damage: Kathy Brumbaugh
2:50 pm: Fanconi anemia and genomic stability: Alan D'Andrea
3:05 pm: Macromolecular response machinery: Jun Qin
3:20 pm: Break
3:35 pm: Homologous recombination repair: Larry Thompson
3:50 pm: DNA damage response in yeast: Ted Weinert
4:05 pm: BRCA1 and DNA damage: Junjie Chen
4:10 pm: Telomeres: Tej Pandita
4:15 pm: DNA damage response in Aspergillus: Steve Harris
4:20 pm: UV damage responses: Kathleen Dixon
4:30-5:30 pm: Discussion
7:00 pm: Reception: Statue Garden
8:00 pm: Dinner: Winter Palace, Biddle House
10:00 pm: Sleepy Hollow Pub
7:30 pm: Full Breakfast: Winter Palace, Biddle House
8:30 pm: Initiation of DNA damage in the nervous system: Remarks from Session Chair: Fred Alt
8:35 pm: Links between the immune and nervous system: Fred Alt
8:50 pm: DNA damage during CNS development: Peter McKinnon
9:05 pm: Endogenous DNA breaks/ V(D)J-like damage: Jerold Chun:
9:20 pm: DNA repair in neural cells: PJ Brooks
9:35 pm: Discussion
10:30 pm: Break
10:45 pm: DNA damage selectivity in the nervous system: Karl Herrup
11:00 pm: DNA damage selectivity in the nervous system: Nat Heintz
11:15 pm: Discussion
12:00 noon: Lunch: Winter Palace, Biddle House
1:30 pm: DNA damage and neural apoptosis: Remarks from Session Chair: Gene Johnson
1:35 pm: Control of neural apoptosis: Eugene Johnson
1:50 pm: Survival pathways and neural development: Michael Greenberg
2:05 pm: Mechanisms of DNA damage induced neural death: David Park
2:20 pm: Discussion
3:30 pm: Break
3:45 pm: Therapeutic approaches to CNS treatment: Xandra Breakefield
4:00 pm: Therapeutic approaches to CNS treatment: Allen Mandir, Tom Crawford
4:15 pm: Possible roles of ATM in homeostasis:: Yossi Shiloh
: Implications on treating A-T patients
4:30-5:30 pm: Discussion
7:00 pm: Reception and Barbecue: West Terrace, Biddle House
10:00 pm: Sleepy Hollow Pub
7:30 pm: Full Breakfast: Winter Palace, Biddle House
8:30 pm: Oxidative stress and neurodegeneration: Remarks from Session Chair: Mark Mattson
8:35 pm: Oxidative stress: Rod Levine
8:50 pm: Oxidative stress & neurodegeneration: Mark Mattson
9:05 pm: ATM & oxidative stress: Carrolee Barlow
9:20 pm: ATM & oxidative stress: Yossi Shiloh
9:35 pm: Discussion
10:30 pm: Break
10:45 pm: Giovanna Spinella
11:00 pm: Future Directions
Discussion Leaders: Gene Johnson, Mike Kastan
12:00 noon: Lunch: Winter Palace, Biddle House
The purpose of this meeting was to highlight past and current studies on A-T and other genetic diseases in which proteins involved in DNA damage responses are compromised, as well as research in the field of neurobiology. The meeting brought together a seemingly disparate group of researchers with the goal of delineating hypotheses and model systems that might uncover links between DNA damage response defects and neurogenetic diseases. Of course, a prime example of such a disease is ataxia telangiectasia (A-T).
A-T is a chromosomal instability syndrome that affects multiple organ systems. Patients diagnosed with A-T exhibit immunodeficiency, increased cancer susceptibility, premature aging, and neurodegeneration. It is the neurodegeneration that usually leads to the early demise of these patients, most often in the second or third decade of life. The protein product of the gene mutated in A-T, A-T-mutated (ATM), is a large protein kinase involved in cell cycle checkpoint and genotoxic stress responses. Although research has unveiled some of the signaling pathways governed by ATM in checkpoint and stress responses, little is known about the role ATM plays in surveillance of the nervous system. In part, this is due to the lack of a suitable model system. Atm -/- mice display signs that mimic the symptoms of A-T patients, but do not recapitulate all aspects of the disease, particularly the neurodegenerative syndrome.
The conference began with opening remarks from Brad Margus, President of the A-T Children's Project, and Dave Frohnmayer, co-founder of the Fanconi Anemia Research Fund, Inc. Brad Margus explained that the A-T Children' Project was organized based on the model provided by the Fanconi Anemia Research Fund. Due to the cancer-predisposition of both A-T and Fanconi Anemia patients, a meeting invitation was extended to researchers and members of the Fanconi Anemia group.
The opening session centered on a number of syndromes in which mutation of a protein involved in DNA damage responses leads to a disease phenotype. Where applicable, a link to neurodegeneration was highlighted. There are a number of syndromes whose phenotype resembles A-T. Patients with Nijmegen breakage syndrome (NBS) are immunodeficient and exhibit increased cancer incidence, but are not ataxic. The nervous system is affected in NBS, however, as these patients present with microcephaly and mental retardation. Recent studies demonstrated that the gene mutated in NBS, Nbs-1, is a downstream substrate of the ATM protein kinase, and is one member of a protein complex that binds to DNA double-strand breaks (dsb). The other two members of this Nbs-1 complex are the Rad50 and Mre11 gene products. Interestingly, another disease that bears significant similarity to A-T, the A-T-like disorder (ATLD), is characterized by Mre11 deficiency. Patients with ATLD are more A-T-like than NBS-like in that they are ataxic, but they do not present with telangiectasies. There are yet other patients who present with an NBS-like disorder (NBSLD) that is described by radiosensitivity, cancer predisposition, growth and mental retardation, with a lack of immunodeficiency and chromosomal translocations. These diseases, which highlight the importance of the ATM signaling pathway and its functional linkages to the Nbs-1/Mre11/Rad50 complex, predict that similar syndromes may arise when other genes in this pathway are mutated.
In addition to the A-T and A-T-related diseases, other cancer-prone genetic disorders were discussed. In two disorders in which patients display DNA repair-deficiencies, Xeroderma pigmentosa (XP) and Cockayne's syndrome (CS), patients are extremely sensitive to UV light and exhibit an increased incidence of skin cancer. XP patients have a defect in nucleotide excision repair (NER) but display no neurologic sequelae. CS patients show defects in transcription-coupled repair (TCR) and the repair of oxidative base damage, and intriguingly, bear neurologic pathologies, including an ataxic gait and demyelination. In the two helicase deficiencies discussed, Bloom's and Werner's syndromes, patients have an increased cancer predisposition but no neurologic disease is evident.
Fanconi anemia is grouped with these other syndromes due to the heightened cancer incidence in Fanconi patients. Although no motor defects are described for these patients, they do exhibit growth retardation, microcephaly, and learning disabilities.
Overall, the common factor in the above disorders is that the disease endows patients with a predisposition to cancer. In only some of these syndromes do patients actually exhibit neurodegenerative features, which suggests that any defect in the response to genotoxic stress does not lead to neurodegeneration. Rather, certain tissues may be more dependent on a specific type of damage response. For instance, terminally-differentiated cells are likely more dependent on genotoxic stress responses than tissues with proliferative potential. Cells that are actively proliferating, however, are usually extremely sensitive to genotoxic insults, unless the cell can repair damage prior to cell division. It is also possible that mutagenesis is an intrinsic problem in these cells or tissues rather than the result of a secondary sensitivity to radio- or chemotherapy.
One common feature of the disorders discussed at this meeting is that cells from these patients show various defects in genotoxic stress responses, and the resultant genomic instability may explain the heightened incidence of cancer. For this reason, DNA damage responses have been extensively studied. The main question discussed at this meeting was whether or not a defect in DNA damage responses also contributes to neurodegeneration.
The ATM protein kinase and other phosphoinositide 3-kinase related kinases (PIKKs) have all been molecularly cloned within the last decade. The large size of both the gene and the gene product presents a major obstacle to straightforward structure/function analysis of the individual domains of these proteins. All PIKK family members contain a highly conserved catalytic domain that bears homology to the kinase domain of PI 3-K. Outside of this region, there is very little sequence homology among family members and it is speculated that these domains may interact with other proteins to facilitate the different functions associated with individual PIKKs.
The ATM protein kinase primarily responds to (double-strand break) dsb-inducing agents, such as ionizing radiation (IR) and radiomimetic agents. The related family member, A-T- and Rad3-related (ATR), responds to IR at a later stage of the response, appears to be required for the maintenance of genome integrity during the normal cell cycle, and serves as the primary activator of the pathways triggered by cellular exposure to ultraviolet light (UV) or inhibitors of DNA replication, such as hydroxyurea (HU). A third PIKK, DNA-PKCS, is critical for the DNA repair process of non-homologous end joining (NHEJ). Cells that are deficient in any of these activities display cell cycle checkpoint defects and increased sensitivity to genotoxic agents.
Recently, the Robert T. Abraham laboratory has cloned and characterized a new PIKK family member, ATX. Kathy Brumbaugh, representing the Abraham laboratory, highlighted the main structural difference between previously identified PIKKs and ATX. Notably, there is a large insert region carboxy-terminal to the kinase domain of ATX that is not present in any of the other PIKKs. ATX is found in both the nucleus and cytoplasm, and like ATM, ATR, and DNA-PKCS, exhibits strong phosphorylating activity toward the Ser-15 site in p53. Exposure of human cells to ultraviolet (UV) light stimulates ATX kinase activity and triggers the appearance of ATX-containing nuclear foci. Cells rendered deficient for ATX function exhibit reduced basal viability and increased sensitivity to killing by UV or IR. Conversely, overexpression of ATX in ATM-deficient fibroblasts complements the radiosensitive phenotype of these cells. Thus, ATX is another PIKK that, like ATR, may signal through partially overlapping pathways with ATM. Given this potential overlap, pharmacologic or genetic strategies that increase the activity of ATR or ATX in AT cells may alleviate some of the disease phenotype.
The G2/M phase checkpoint is the critical place in the cell cycle that ensures a cell has accurately replicated its DNA prior to cell division. ATM and ATR are critical enforcers of this G2 checkpoint. However, studies done by Al Fornace and colleagues have demonstrated that the p38 mitogen-activated protein kinase (MAPK) may also play a role in mediating the G2/M checkpoint after cells are exposed to UV light. Inhibitors of the p38 kinase abrogate the G2/M checkpoint after UV treatment, which reinforces the long-known concept that UV light activates cytoplasmic signaling pathways, such as MAPKs, in addition to damaging DNA. UV light exposure is only one example of an agent that does not simply induce DNA damage; cells exposed to IR, in addition to incurring DNA damage, will generate reactive oxygen species that modify proteins and lipids within the cell. Therefore, any genotoxin or cell stress will generate more than one type of damage, as the primary lesion may be processed or trigger other secondary effects.
Kathleen Dixon presented data consistent with this idea. Current literature suggests that A-T cells have a normal response to UV. In contrast, Dixon's data suggest that UV lesions are processed to generate secondary dsbs, and thus activate ATM. While IR induces dsbs at 1 h, UV results in the appearance of dsbs at 8 h due to disruption of a replicative intermediate. The p34 subunit of replication protein A (RPA) is a critical component of several DNA repair pathways, including post-replicative repair. RPA is phosphorylated and undergoes a mobility shift after cells are exposed to UV light. This UV-induced phosphorylation first appears at 4 h, with a peak at 12 h, and is partially defective in A-T cells. The ATM-dependence of UV-induced RPA phosphorylation is restricted to the later time points. Using a comet assay to detect dsbs, Dixon demonstrated an accumulation of dsbs in normal cells at 24 h after UV light exposure, and that the number of UV-induced dsbs is higher in A-T cells. If repair does not occur, the replication fork may attempt to bypass the UV lesion and result in dsb formation, thus activating ATM.
Dixon also presented results from an in vitro assay system that measures DNA repair. This microhomology-mediated mutagenesis assay involves the addition of a restriction-digested plasmid to cell-free extracts from different cells. Extracts from cells that lack ATM are able to repair the strand break, but with reduced fidelity. This defect is rescued by restored expression of ATM, as nuclear extracts from these cells repair the break with increased fidelity.
In addition to the confusion surrounding the involvement of ATM in UV responses, a discrepancy exists in the literature regarding the role ATM plays in the G2 checkpoint. If AT cells are exposed to IR while they are in the G2- phase of the cell cycle, they do not arrest. However, AT cells that are irradiated at any other point in the cell cycle accumulate in G2, or exhibit a protracted G2 arrest. Mike Kastan presented data that may delineate the roles of ATM in these two situations. It turns out that the method used to identify the G2 phase of the cell cycle is important. Classically, a propidium iodide (PI) stain to measure DNA content is used to evaluate cell cycle distribution. In a PI-stained population, cells in G1 phase have a 2N DNA content, cells in G2/M have a 4N DNA content, and the S phase population is intermediate. Because the PI stain does not discriminate between G2 and M phases of the cell cycle, Kastan and others have used an antibody that recognizes phosphorylated histone H3 to define the G2- phase of the cell cycle. Cells that are exposed to IR and then stained with PI show a radiation dose-independent accumulation in G2; in other words, no difference is seen between exposure of cells to 1 and 10 Gy IR. G2 accumulation is due to the lack of an S phase checkpoint, as an Nbs1 mutated protein (S343A) causes similar accumulation in G2. This G2 accumulation is also ATM- and BRCA1-independent. If histone H3-phosphorylation is used as a measure of G2, higher doses of IR will result in more cells that arrest in G2. This measures the early G2 checkpoint that is ATM- and BRCA1-dependent. Thus, ATM is required to enforce the early G2 checkpoint, but the prolonged G2 arrest is not dependent on ATM. It has been proposed that this prolonged arrest is mediated by the related ATR kinase.
Over the past several years, a number of ATM, ATR, and DNA-PKCS substrates have been identified. The challenge has been to ascertain the functional relevance of phosphorylation of these proteins. A number of presentations at this session outlined either new substrates for these PIKKs, and/or elucidated the significance of phosphorylation at these sites. Kastan and coworkers analyzed two BRCA1 proteins mutated at Ser residues modified by ATM. Specifically, the phosphorylation of Ser-1387 and Ser-1423 are important for enforcing the S and G2 phase checkpoints, respectively. Because the converse is not true, it appears that these specific modifications of BRCA1 result in the activation of distinct downstream signaling pathways.
Robert T. Abraham and colleagues identified the hRad17 protein as both an ATM and ATR substrate. hRad17 bears similarity to the replication factor C group of proteins that are involved in loading the replication processivity factor PCNA onto DNA. Initial results from hRad17 studies suggest that it may load the PCNA-like checkpoint sliding clamp (CSC), composed of hRad1, hRad9, and hHus1, onto damaged DNA. ATM and ATR phosphorylate two Ser residues in hRad17, and cells that express a nonphosphorylatable mutant hRad17 (hRad17 2A) are unable to enforce the G2 checkpoint after IR and undergo increased cell death in response to multiple genotoxins. In addition, hRad17 2A is unable to associate with hRad1, a member of the CSC. Thus, the phosphorylation of these two hRad17 Ser residues is critical for the enforcement of the G2 checkpoint and association of hRad17 with the CSC.
A potential signaling link between A-T and Fanconi anemia was presented. Alan D'Andrea highlighted recent results from their studies of the Fanconi D protein. Cells that lack the FANCD2 protein exhibit radioresistant DNA synthesis (RDS), a well-known hallmark of A-T cells, and are hypersensitive to mitomycin C (MMC). The Fanconi A, C, G, F, and E proteins are in a preexisting nuclear complex, while the Fanconi D protein only associates with this complex after damage. Interestingly, this damage-inducible complex also contains BRCA1. FANCD2 is differentially modified after exposure to MMC or IR. It is mono-ubiquitinated at Lys-561 after MMC treatment but phosphorylated at Ser-222 after IR. A-T cells are competent to mediate the ubiquitination but not the phosphorylation of FANCD2. Interestingly, FANCD2-/- cells that express a S222A FANCD2 are complemented for MMC hypersensitivity, while cells that express a K561R FANCD2, which is unable to be ubiquitinated, are complemented for RDS. These results suggest that Ser-222 phosphorylation of FANCD2 is an ATM-dependent event that prevents RDS, while the ubiquitination of Lys-561 is an ATM-independent step that activates signaling pathways involved in MMC resistance.
A connection between A-T and another disease discussed at this meeting was presented by Martin Lavin. Using a yeast 2-hybrid screen to search for ATM-interacting proteins, Lavin and colleagues identified the BLM helicase. The BLM helicase copurifies and coimmunoprecipitates with ATM. This association was mapped to the helicase region of BLM and an amino-terminal fragment of ATM. They demonstrated that the Bloom's syndrome helicase (BLM) is also an ATM in vitro substrate, but the BLM protein is not reproducibly phosphorylated in response to IR. BLM is, however, phosphorylated in nocodazole-treated cells, which are arrested in mitosis. It is unknown whether this nocodazole-induced phosphorylation is dependent on ATM, and may instead reflect an ATR-dependent modification.
Another critical area of investigation in the DNA damage arena is how responses to genotoxins are initiated. Junjie Chen presented immunofluorescence evidence regarding proteins that bind to IR-induced dsbs. One of the downstream effector kinases of ATM, Chk2, exhibits a diffuse immunostaining pattern in the nucleus. In contrast, antibodies that recognize the phosphorylated form of Chk2 illuminate IR-induced foci, and colocalize with antibodies against the histone H2ax protein, Nbs1, and a p53-binding protein 53BP1. Therefore, Chen proposed a model whereby a dsb is first demarcated by histone H2ax, then recruits ATM or ATR, followed by Nbs1, Chk2, and 53BP1.
Many of the hypotheses generated for mammalian cell genotoxic stress responses are based on paradigms set forth by studies in lower eukaryotic model systems. Ted Weinert presented a model for chromosomal instability in the budding yeast, Saccharomyces cerevisiae. When a test chromosome that contained a fragile site was introduced into rad9- yeast, it was significantly less stable than in wild-type yeast. DNA breaks are induced in the fragile site by limiting replication with HU. His hypothesis is that ScRad9 is involved in the regulation of a stalled replication fork. In the presence of ScRad9, forks resume replication after repair and there is no resultant error, while in the absence of ScRad9, an alternative pathway is activated to cause breaks or chromosome loss. ScRad9 is thought to lie downstream of the ATR ortholog, ScMec1, and upstream of the human Chk2 ortholog, ScRad53 in the pathway that responds to secondary DNA damage after replication stress. Therefore, Weinert's findings are consistent with this model and suggest a specific role for ScRad9 in the regulation of stalled replication forks.
To close this session, Steve Harris described his investigation of the DNA damage response in the hyphal fungus, Aspergillus nidulans. Harris described the cloning and characterization of orthologs to the ATR, Rad26, Rad51, and RecQ helicase (similar to BLM and Werner's helicases) proteins. Thus, A. nidulans is another genetically tractable model system in which genotoxic stress responses may be studied to generate testable paradigms for mammalian cells.
This session centered on the central theme that echoed throughout the conference. The atm-/- mice display many of the signs associated with A-T, but do not develop neurodegenerative disease. Fred Alt chaired this session, which highlighted various deficient mouse model systems as well as some basic paradigms in neuronal biology.
Thanks to the gene-targeting efforts ongoing in numerous laboratories, many deficient mouse models that lack factors involved in immune receptor rearrangement and double-strand break (DSB) repair are available. All of these mice exhibit a block in lymphocyte development, also known as severe combined immunodeficiency (SCID), while only a subset show increased sensitivity to IR and/or neuronal defects. The recombinase activating gene (Rag)1 or Rag2 deficiency generates mice with a block in lymphocyte development, but they are otherwise normal. Classical SCID mice are deficient in the expression of DNA-PKCS and exhibit variable sensitivity to IR, but reveal no proliferation defects. Mice deficient in Ku70 or Ku80, which are DNA-PKCS interacting proteins, display IR sensitivity, cell proliferation defects, and neuronal apoptosis. Of all the SCID mice, the DNA ligase IV deficient animals display the most severe phenotype, as neuronal apoptosis leads to late embryonic lethality. The ligase IV lethality can be rescued by crossing the mouse with a p53- or atm-deficient strain, which suggests that an ATM-p53 checkpoint pathway is responsible for the early death of these animals. These ligase IV/p53- or ligase IV/atm-deficient mice still demonstrate a block in lymphocyte development, IR sensitivity, cell proliferation defects, and increased neuronal apoptosis compared to normal mice.
Peter McKinnon led one of the groups that generated the ligase IV-/- mice and crossed them with either atm-/- or p53-/- mice. He presented findings that the ligase IV-/-/atm-/- mice show some cerebellar abnormalities, with some regions displaying loss of Purkinje cells. In addition, the McKinnon group investigated cell death in specific neuronal tissues of atm-deficient mice. Atm-/- mice display no detectable overall neuronal apoptosis in response to IR, but the retinas of these mice reveal enhanced sensitivity to IR-induced death. Thus, it appears that ATM-dependent cell death in the nervous system is a tissue or cell-type specific process, with the retina as an example of a tissue that displays ATM-independent cell death.
These studies of retinal cell death utilized a new assay to detect apoptotic or dying cells. The assay, in situ end labeling plus (ISEL+), is a variation on the traditional TdT-mediated dUTP-X nick end labeling (TUNEL) assay that exhibits higher sensitivity. In the TUNEL assay, the enzyme terminal deoxynucleotide transferase (TdT) adds fluorescently-labelled dUTP onto broken DNA strands. ISEL involves TdT addition of digoxigenin-labelled rather than fluorescently-labelled oligonucleo-tides, which makes ISEL+ ten times more sensitive than TUNEL. Even so, the discussion that surrounded this technique questioned whether it was sensitive enough to detect early apoptotic cells or later stage death. One participant gave a reasonable estimate of how many DNA breaks are necessary to obtain an ISEL+ spot that was in the thousands. Furthermore, the question of whether normal replication-induced dsbs were detected with ISEL+ arose. Cells that incorporate BrdU, which is a measure of cells that are replicating their DNA, are not all ISEL+, so some of the dsbs generated during normal DNA replication are not detected, probably due to relatively efficient repair of these breaks. Finally, if ISEL+ is not a reliable assay for apoptosis, the discussion centered on which assay might allow early detection of apoptosis in tissues. The only other assay mentioned was detecting activated caspase 3, because this enzyme plays a critical role in developmental apoptosis of the central nervous system.
Carrolee Barlow presented evidence on the role of ATM in adult neurogenesis. The brains of A-T patients at birth display no gross abnormalities, but undergo neurodegeneration during the course of their life. Consistent with this fact, atm-/- mice are also born with brains that exhibit no major malformation. On the contrary, they do not develop the neurodegenerative sequelae seen in A-T patients. Barlow and coworkers studied adult neural progenitor cells and identified high levels of ATM protein in dividing neural progenitors. The amount of ATM protein in these progenitors decreases upon differentiation into various neural cell types. Progenitor cells from mice that lack ATM are hyperproliferative and exhibit random genomic instability. Perhaps because of this high rate of proliferation, the atm-/- progenitors do not differentiate into the many required cell types, such as neurons or oligodendrocytes. In addition, loss of ATM renders cells less responsive to stimuli that normally promote neurogenesis. Thus, ATM is required to differentiate progenitor cells into the many neural cell types required for population of the adult brain, and appears to control proliferation of these cell types.
In light of the fact that there is currently no suitable model system to study the A-T neurodegenerative phenotype, perhaps other models of neurodegeneration can provide fuel to generate testable hypotheses based on paradigms in basic neuronal biology. Karl Herrup discussed his recent findings in the field of neuronal apoptosis. As neurons leave the ventricular zone and become post-mitotic, only a low level of adult neurogenesis occurs. Once these neurons have differentiated, re-entry into the cell cycle leads to death. In Herrup's model of Alzheimer's, the neurons contain substantial cell cycle markers (cyclins, PCNA,etc), but the cell cycle cannot be completed and neurons become polyploid. The neurons remain polyploid for months before they succumb to a terminal apoptotic process, which ultimately causes the neurodegeneration in Alzheimer's disease.
Thus, neurons with an intact post-mitotic checkpoint are able to survive. This idea is consistent with data from mice that lack expression of the pRb tumor suppressor protein. Rb loss leads to continued re-entrance into the cell cycle and cell death in the central and peripheral nervous systems. Furthermore, tumors of the CNS are not neuronal in origin because expression of an oncogene in a post-mitotic neuron is lethal. Finally, the loss of contact with surrounding cells leads to cell cycle entry and death. Based on this premise, a discussant proposed that perhaps neurons in A-T patients are unable to enforce checkpoints, neurons re-enter the cell cycle, and this is the cause of the A-T neuronal cell death.
his report describes the consensus outcome of an interdisciplinary workshop held at the National Institutes of Health in April 2001. The purpose of the workshop and this document is to define the terms "spasticity", "dystonia", and "rigidity", as they are used to describe clinical features of hypertonia in children. The definitions presented here were designed to allow differentiation of clinical features even when more than one is simultaneously present. We encourage the development of clinical rating scales based on these definitions, and we encourage research to relate the degree of hypertonia to the degree of functional ability, change over time, and societal participation in children with motor disorders.
The next session explored mechanisms of neuronal apoptosis and what role DNA damage might play in effecting this response. The chair of this session, Gene Johnson, began with a brief description of the different types or stages of cell death seen in neurons. First, cells in the early stage of proliferation or immediately after they become post-mitotic are susceptible to undergoing apoptosis. Second is the classical neuronal programmed cell death that occurs during development. Third, experimentally-induced neuronal apoptosis through genetic manipulation, axotomy, or addition of stressors to mimic a disease process. Finally, the poorly defined chronic neurodegenerative disease, which is the focus of this meeting, results from irreparable cell death. Our limited understanding of the neuronal apoptosis seen in chronic neurodegenerative disease is due to the confines of current model systems as well as the lack of sensitive assays to detect low levels of apoptosis.
The two biochemically-defined pathways of apoptosis include the intrinsic pathway, which comprises factor withdrawl- and stress-induced apoptosis, and the extrinsic pathway, which is signaled through death receptors. Although these two pathways involve the activation of the apaf-1/caspase-9 and the caspase-8 signaling cascades, respectively, they ultimately converge to activate caspase-3 and cleave downstream substrates.
Johnson and colleagues studied nerve growth factor (NGF)-withdrawl-induced apoptosis of sympathetic neurons, which is one of the intrinsic pathways. The biochemical events that occur after NGF withdrawl include increased reactive oxygen species (ROS), and increased c-jun, CyclinD1, and c-myb levels. Bax and BIM, two proapoptotic bcl-2 family members are required for death, while treatment with the caspase inhibitor BAF prevents NGF-withdrawl-induced death. This apoptosis can also be prevented by pretreatment with antioxidants or expression of dominant negative c-jun.
In addition to NGF-withdrawl induced death, Johnson and coworkers investigated araC-induced death. AraC, a nucleotide chain terminator that may induce oxidative damage, is a genotoxic stress that, like NGF-withdrawl, induces apoptosis through the intrinsic pathway. The biochemical profile of araC-induced death is similar to NGF-withdrawl, and induction of the pro-apoptotic Bax is required. An interesting finding came from studies that utilized cephalon 1347 (CEP1347), an inhibitor of mixed-lineage kinase (MLK) kinases. This agent, which blocks BIM induction, is a long-term neuroprotectant in NGF-deprived neurons. However, it is ineffective at blocking araC-induced death. The dependence of both apoptosis pathways on Bax suggests that NGF-withdrawl and araC-induced death pathways converge at some point, but the results from the CEP1347 studies are consistent with a model whereby the upstream pathways are different.
Michael Greenberg studied neuronal apoptosis in a different cellular model system. His model is cerebellar granule neurons, in which brain-derived neurotrophic factor (BDNF) is required for survival. These neurons are transfectable and require the phosphoinositide 3-kinase (PI 3-K)/Akt pathway for survival. The PI 3-K/Akt pathway targets a family of Forkhead transcription factors, which include FKHRL1. Forkhead family members act to induce transcription of several proapoptotic genes. Greenberg and coworkers mapped Akt phosphorylation sites on FKHRL1 and verified the modification of these sites in intact cells. They investigated the mechanism by which Akt phosphorylation of FKHRL1 leads to cellular survival. Phosphorylation of FKHRL1 in cells exposed to BDNF causes a change in subcellular localization. The phosphorylated FKHRL1 is found in the cytoplasm, while a mutated FKHRL1 that cannot be phosphorylated remains strictly nuclear and induces apoptosis. Thus, it appears that Akt promotes cell survival by relocalization of FKHRL1 from the nucleus to the cytoplasm.
Due to the fact that FKHRL1 is a transcriptional activator, a cDNA array approach is underway to identify putative target genes. Thus far, 19 known cDNAs and 16 expressed sequence tags (ESTs) have been identified. Due to a confidentiality agreement with a private company, Greenberg could not divulge the identity of these cDNAs. However, he did report that 5 are apoptosis-related, 9 are cell cycle-related, and 5 are stress-responsive or known to be involved in G2/M arrest.
In the second half of this session, three speakers outlined current and potential future therapeutic approaches for treatment of A-T and other neurodegenerative diseases. Xandra Breakefield discussed the possibility of gene therapy for A-T. A number of factors are considered in the design of gene therapy protocols. After a vector system is identified, safety concerns need to be addressed and a suitable preclinical model established. The most challenging problems associated with ATM gene therapy are the size of the encoding cDNA and the lack of an appropriate animal model system that recapitulates the neurodegenerative phenotype. There are clear limitations on which vectors can be utilized due to the size of the ATM cDNA, and truncation or other manipulation of this cDNA is not possible if kinase activity is to be maintained. Breakefield's group is testing vectors in atm-/- mice and looking for expression in the brain. The lack of neurodegeneration in these mice makes it difficult to predict the potential advantages of restoration of ATM expression in the brain of the mouse. As an initial test of a gene therapy vector for ATM, complementation of T cell function may be a better marker for reconstitution, due to the fact that these mice do exhibit a defect in T cell function.
Allen Mandir and Tom Crawford discussed potential opportunities for developing new therapies for A-T patients. The best-case scenario would be to treat A-T patients in the asymptomatic or "presymptomatic" phase of the disease. In lieu of this early treatment, one would hope to stabilize the course of the disease or reverse the symptoms. When considering gene therapy as a treatment option, it is unclear what would be the consequence of introducing ATM into damaged neurons. In this case, one would want to introduce ATM at the earliest possible stage, prior to the accumulation of neurological damage. Another important question that would need to be addressed is how to deliver the vector for therapeutic benefit. Finally, the measure of therapeutic benefit would need to be established. These could include detection of improvement or stabilization of defined clinical signs, and activities of daily living or quality of life issues.
Yossi Shiloh completed this session with his report of a role for ATM in processes that do not involve DNA damage. Specifically, cytoskeletal abnormalities have been reported in A-T cells in culture. In recent work, Shiloh and colleagues identified highly polymerized F-actin in the perinuclear region of A-T lymphoblasts and A-T fibroblasts. The overall actin fiber organization in AT fibroblasts is also impaired, and this is complemented by ATM expression. Furthermore, A-T cells exhibit impaired cell motility and show impaired activity in a wound-healing assay, which is also corrected by ATM expression.
One additional feature of A-T cells in culture is their increased demand for certain growth factors. Two recent publications, one from Shiloh, MaCauley, and colleagues and one from Peter Glazer, demonstrate reduced insulin-like growth factor-1 receptor (IGF-1R) levels on A-T cells. Interestingly, increased IGF-1R expression on A-T cells can partially complement the poor growth of these cells in culture as well as their radiosensitivity. These findings support a role for ATM in non-genotoxin-induced responses, which could include stress that results from general cellular metabolism or cell culture.
The next session of this meeting focused on the relationship between oxidative stress and neurodegeneration. Rod Levine discussed a number of experimental methods useful in the analysis of oxidative stress effects. Levine emphasized the importance of detection of more than one marker for oxidative stress because a single marker may give misleading results. One can measure increased antioxidant proteins such as superoxide dismutase (SOD) or glutathione peroxidase, changes in low molecular weight antioxidants such as vitamin C, vitamin E, and glutathione, or assess macromolecular damage to DNA, lipid, or protein. One common oxidative modification of proteins is the addition of a carbonyl group. The amount of carbonyl-bearing proteins is elevated in many human diseases including rheumatoid arthritis, Parkinsons's disease, Alzheimer's disease, ALS, aging, diabetes, and Werner's syndrome. In healthy individuals, levels of carbonyl-bearing proteins dramatically increase during the last 1/3 of life. In contrast, Werner's syndrome patients exhibit these high levels of carbonyl-modified proteins between the ages 10 and 20.
In collaboration with Carrolee Barlow, Levine measured levels of carbonyl-bearing proteins in wild-type and atm-/- mice. Multiple tissues were examined and Levine and Barlow demonstrated no differences in the levels of carbonyl-bearing proteins between these mice. However, there is clear evidence of oxidative stress in atm-/- mice as measured by other markers. The thymus and testes exhibit increased F2 isoprotanes, the brain displays increased nitrotyrosine, and the cerebellum reveals a 6-fold increase in heme oxygenase. Levine emphasized that this was a good example of a case where the evaluation of multiple measures of oxidative stress gave a less biased result.
Levine and Barlow are currently testing a manganese-containing Eukaryon compound, which has both catalase and SOD activity and can cross the blood-brain barrier, in atm-/- mice. One of these compounds, EUK-134, can rescue the longevity defect in Caenorhabditis elegans (C.elegans) mutant mev-1 (succinate dehydrogenase). These compounds have been tested in rodents and exhibit very low levels of toxicity.
Mark Mattson, the chair for this session, next discussed his results from studies of the secondary effects of homocysteine on neurodegeneration. Homocysteine is generated from methionine, and can be converted back to methionine by vitamin B12 or to cysteine by vitamin B6. Another important nutrient, folic acid, plays a major role in keeping homocysteine levels low. Increased levels of homocysteine increase the risk for cardiovascular disease and stroke, and lead to increased DNA damage. Interestingly, a low calorie diet has been shown to decrease the risk of neurodegenerative disease in Alzheimer's and Parkinson's mouse models.
Yossi Shiloh concluded this session with work from his laboratory and others that suggest a role for ATM in the oxidative stress response. Two atm-/- mouse models have been generated that either lack SOD expression or that overexpress SOD. Both mice have a similar phenotype, which suggests that a critical level of SOD is required for a normal response to oxidative challenges. These atm-/-/SOD mice display retarded growth and increased IR sensitivity compared to atm-/- mice, but no enhancement of the neurological phenotype. Thus, it appears that even these mice are unable to recapitulate the neurodegeneration seen in A-T patients.
Future directions for the next wave of research in the crossroads of neurodegenerative disease pathologies and chromosomal instability syndromes were addressed in a closing session. First, Giovanna Spinella from the National Institute of Neurological Disorders and Stroke (NINDS) emphasized that, if the genetic syndromes discussed during this meeting indeed share commonalities, this evidence could be reported to the NINDS and possibilities for special funding would be discussed. Also, in closing remarks, Dave Frohnmayer reminded the group that the Fanconi Anemia Research Fund has funds to support post-doctoral fellows, as well as a database of available cell lines and antibodies.
Gene Johnson and Mike Kastan led the final discussion, which began with a model proposed by Kastan. Given the following evidence presented at this meeting: 1) ATM is a checkpoint protein that responds to genotoxic stress (multiple groups), 2) post-mitotic neurons that re-enter the cell cycle undergo cell death, which is an intrinsic and presumably protective response to proliferative stress in this cell type (K. Herrup), and 3) atm-/- mice exhibit increased proliferation of neural progenitors in the brain (C. Barlow), Kastan proposed that the transition from the mitotic to the post-mitotic (G0) phase in a neuron is a checkpoint. Thus, the general hypothesis proposed by Kastan is that ATM enforces this checkpoint, and neurons that lack ATM re-enter the cell cycle and die. This model predicts the neurodegeneration that occurs in A-T patients is the secondary consequence of loss of this ATM-dependent checkpoint.
Discussion of data that are consistent or at odds with this model followed. The proposed ATM checkpoint would only affect later stage neurons. If this model is true, would other post-mitotic tissues be affected? It is possible that only certain tissues or cell-types are affected, but one other example in A-T might be alpha fetoprotein (AFP) production by hepatocytes. AFP levels are only elevated in the adult human during pregnancy, in certain malignancies, and in A-T. This is an instance where a fetal protein is expressed by an adult tissue, possibly one that has re-entered the cell cycle.
Rather than a stochastic re-entry into the cell cycle, perhaps a genotoxic insult leads to cell cycle entry and the events of checkpoint loss and DNA damage are inseparable. The signal to re-enter the cell cycle in the Alzheimer's model is microglial products, and although it is unclear what this signal might be for A-T cells, genotoxic stress is a prime candidate.
In one suggestion of how to test this hypothesis, a discussant proposed that the atm-/- mouse could be crossed with Harry Orr's transgenic mouse in which SV40 T antigen (TAg) is expressed under the control of a Purkinje cell-specific promoter. When TAg is expressed in the Purkinje cells of these mice, post-mitotic neurons re-enter the cell cycle and undergo apoptosis. These TAg transgenic mice display ataxia due to an apoptotic loss of Purkinje cells. If the model proposed above is correct and TAg expression coerces the cell to resume cycling, the TAg transgenic/atm-/- mice should have an enhanced loss of Purkinje cells and subsequent cerebellar function due to the loss of the ATM-dependent checkpoint. Alternatively, if TAg-driven cell cycle entry leads to ATM-dependent apoptosis, the Purkinje cell loss would be reduced in the TAg transgenic/atm-/- mice.
Another question that arose is whether this model involves a nuclear or cytoplasmic function for ATM or both. The currently available antibodies are not specific enough to pick up nuclear ATM in Purkinje cells, but this does not necessarily mean that Purkinje cells lack nuclear ATM. Clearly, the answer to this question awaits the development of high-quality specific antibodies for ATM.
The recurring theme that sounded throughout this meeting was echoed in the final discussion. ATM is a multi-functional protein, and the model system chosen to investigate ATM functions is important. Currently, a model system to study the neurodegenerative aspects of A-T does not exist, and research in this area would benefit from the generation of such a model system. Ultimately, advances in the mechanism behind A-T neurodegeneration may lead to treatments that alleviate the neuronal pathologies that currently plague A-T patients, and could very well impact on the therapy of other neurodegenerative diseases as well.
Alt, Fred
Auerbach, Arleen
Barlow, Carrolee
Breakefield, Xandra
Brooks, PJ
Brumbaugh, Cathy
Chen, Junjie
Chun, Jerold
Concannon, Pat
Cortes, Marisa
Crawford, Thomas
D'Andrea, Alan
Dixon, Kathleen
Ellis, Nathan
Fornace, Albert
Frohnmayer, Dave
Gallo-Hendriks, Ellie
Gatti, Richard
Geller, Herbert
German, James
Harris, Steven
Heintz, Nat
Herrup, Karl
Jeggo, Penny
Johnson, Eugene
Kastan, Michael
Lavin, Martin
Lawrence, David
Lehmann, Alan
Levine, Rodney
Mandir, Allen
Margus, Brad
Mattson, Mark
McKinnon, Peter
Michael Greenberg
Monnat, Raymond J.
Pandita, Tej
Park, David
Qin, Jun
Reinhart, Peter
Shiloh, Yossi
Spinella, Giovanna
Thompson, Larry
Weinert, Ted
Last Modified April 12, 2011


text:
Let's Get the W with Kershaw on the Mound!
I hear from several fans that they will stop going to games because of status of the Dodgers concerning the ownership but for me…
I am not willing to miss seeing Kemp, Ethier, Loney, Kershaw, Billz, Broxton and Russell, my favorites! Nope, I am not going to miss hearing Vin Scully at the games.
There is no better sound than when I walk inside Dodger Stadium and I listen to Nancy Bea in the background while I walk over to the bullpen area and I hear the sound the ball is making as it hit the mitt. The boys in Blue on the field hitting BP and the pitchers in the outfield catching some baseballs.
Vin already made my day last Sunday by smiling and waiving at my friend Erik and I when we greeted him and wished him to have a happy Easter.
Nope, no matter what, I will be at the stadium, day in and day out. Is is my happy home, it is my home away from home.
There is Sandy Koufax on this picture walking to the field. He is also on the big screen.
When I am at Dodger Stadium and I look to the field and then take the rest of the view from there with the mountains in the background, all is right with the world.
Yeah, there will be some games that I will be cursing under my breath, but they will others that will be exhilarating and no better way to share those moments than with my friends at the stadium.
Let the second game begin in Pittsburgh! We got 22-year old Clayton Kershaw going this evening.
For those giving Joe Torre a hard time for starting Padilla for the Opener on the road, I say to them, did you hear what Vin Scully said ? If you did not, here it is:
"In Showbiz you would say you are opening a big musical and you would say "Padilla, you are singing the lead in Hartford, Connecticut. And you would say "Kershaw, you are singing the lead on Broadway." "
Play Ball!
I love my Dodgers!
21 Comments
You crazy girl.
So good to read you here! I am afraid our boy Kershaw did not start well. I am about to signoff work and listen to my radio on my way home on the train.
Good for you for ignoring the outside distractions and just enjoying your Dodgers. Ownership should never be allowed to ruin the game for us!
I saw a bit of that game. Kershaw pitched well, he just worked his pitch count up too quickly. If it wasn't for that homer, he would have had a solid start. Too bad you guys couldn't pull it out in extras.
I thought your guys were gonna get it last night… seems the bullpen virus hit a few teams in the 10th last night…
Phillies Outside
I admire your support of your team. However your rotation leaves a lot to be desired and I would never have started someone like Padilla who just got shot in the offseason, in such an important game. He looked horrible in his game against the Royals last week. I don't see anyone who is stepping up for you as even Kershaw who is supposedly the next ace had no control in last night's game. We are only a few games into the season but I think your starting pitching has more question marks than any team in our division. And you're right the ownership and divorce stuff should not get in the way of enjoying the team.
p.s. also you mentioned not hearing Vin Scully at the games but isn't he only on for 3 innings? So those who are staying home would actually get to hear him more. 🙂
Emma, is that shot of the field the view from your seats? What a great view of the entire field! Looks like the weather was really nice, too.
Rants, Raves, and Random Thoughts
that is right! I am not going to allow that to hinder the enjoyment of the game!
Garret Jones. I was remembering Pedro Martinez when he said "Who the h*ll is Karim Garcia" Still laugh about that one. Well, we sure know who Garrett Jones is.
Runner on third with no outs and we didn't score. Grrrr.. Hope Billinglsey get the W on this getaway day.
Here we are relying on the bullpen so early in the season. I love what Sandy Koufax said at the Safe At home Foundation event "A quality start is when you shake hands with your catcher."
I am OK with starting Padilla on the road Opener and Kershaw at home. Like Vin said, Opening at Home is like Opening on Broadway! I think the pitching ran into a snag, but they will be fine. I am not panicking with only two games played.
I always take my radio to the stadium and listen to Vin for the first three innings then I might switch to the Spanish station for Jaime, Pepe and Fernando or stay with Charlie Steiner and Rick Monday but if you are in the elevator or close to a television or the restroom, you hear Vin on tV. Yeah, that is what I miss about being at home, listening to VIn for the entire game. What is worst is when I go to San Diego, SF, AZ and I can't listen to Vin.
Yes, that is the view from my seats! A great view and great friends sitting all around me! That was Opening Day in 2008 when all the living Dodgers that play for the Dodgers were invited! It was an awesome Opening act.
Hey Emma!
Can't stay long, but unfortunately I'm not going to be able to make it on opening day. I got a job! Now now, before you go getting all excited, it's temporary. I'll be working with the Census people again and I start tomorrow. My son will be going to the game on Tuesday with my mom. I'll catch up with ya later…
Emma: What a beautiful ballpark Dodger Stadium is. And I know what you mean by cursing…only sometimes I don't do it under my breath. The season is always a crazy ride. I love it🙂
Yeah! I was getting excited that you got a job. Ok, so is only temporary. A permanent will follow or you businees will flourish. Have faith CP!
Isn't beatiful! I love it there! Hey our boy Ethier is sidelined with a sore ankle. Poor baby.
There are more ups than downs. We Live for this! I love it!
Yea, the feeling all is right in the world…That's it! I watched the Pitt/LA game today. Nice to hear Vin again.
That's a great shot of the Stadium!
bklyntrolleyblogger ,
Vin was not on the Pitt/LA game today? I thought he doesn't travel east of the Rockies. If you heard him it must have been your imagination.
@ Crzblue – what do you mean you can't hear Vin in San Diego? I hear him every time we play you guys. Would rather than listen to our guys.
Maybe you heard a promo 'cause Vin does not travel east of the Rockies.
Yeah, it could have been or just a promo. They have those. I was at work so I could no watch the game and was relying on gameday and game threads.
I can't hear KABC the Dodger Flagstation in San Diego. Maybe away from Petco Park you can hear him for the first three innings?
hahaha nice comment from Mr Scully!😀
Glad that you are sticking to your team no matter what! The team needs the fans to be loyal esp. with all the trouble going on with the ownership😦
Yay for kershaw! i'm a fan😉
Thanks Mimi! Got to stick with the young guys! I am so excited about Opening Day tomorrow! And yes, win or lose they ARE MY BUMS!
T minus 4 hours Emma. Lets Go Blue!

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"The more I know, the more nearly is my faith that of the Breton peasant."
~ Louis Pasteur, founder of physio-chemistry, father of bacteriology, inventor of bio-therapeuties, devout Catholic; offering simple, yet profound piety in a letter to his children.


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Dear prospective students and family members,
At the Office of Disability Services, we know that families of students with disabilities may have different concerns than families of typical college students. We also know that you are accustomed to playing a very active role in your student's education. The change in services and responsibility in the college environment can seem frightening, and we are aware that many high schools may not prepare students and their families for the differences they will encounter at college. We hope that the information on this page and others on our website will give you the information you need to become familiar with the post-secondary disability services world so that your student can successfully navigate this new environment.
Since your son or daughter is now an adult, both of your roles will need some adjustments. In college, students with disabilities are responsible for self-identifying to the Office of Disability Services and requesting accommodations. At this point, your role as a parent is to encourage your child to apply for necessary accommodations and empower him or her to become responsible and make his/her own decisions. We will be available to speak with you regarding your son or daughter only upon receiving a written release from him/her.
You can help your student by:
We hope that gaining familiarity with the services and procedures at Yeshiva University will reduce anxiety, help students in their decision to pursue accommodations, and assist them in gathering the necessary materials to make the process go smoothly.
Yeshiva University
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New York, NY 10033
Yeshiva University
500 West 185th Street
New York, NY 10033
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Work it outMarch 18,2014
Work it out
Being carless in Vermont is hard but possible because of the folks that drive our buses. A drivers strike will disrupt my life, and yet I support the drivers. I can sympathize with the hardship that split shifts cause to a workers life. I know firsthand, its difficult to use the time between two stints for anything productive, recreational or relaxing.
On the other hand, I see how challenging it must be to schedule hours on transit routes that are busiest on either end of the workday.
Working in a union workplace myself, I see similar scheduling challenges (and frustrations) faced by workers and management. Im sympathetic to both sides and frustrated at the attitudes of some on both sides. Workers often say things like management would love to run this place on substitute workers as if all managers are cold-hearted penny pinchers opposed to providing full-time work. I also hear managers complain about subs who arent always available when theyre needed, or seniority rules (which are in place for a good reason) that can make scheduling a sub a lengthy process. The truth is, most workers and managers are doing the best they can wanting to do the right thing, but focused on their challenges first.
I think if a problem such as split shifts can be targeted with a can-do attitude, a solution can be reached. At Chittenden County Transportation Authority, hopefully this can happen soon and we can all get back on the road.
James Sharp
MontpelierMORE IN LettersA sixth-offense DUI gets plead down to a misdemeanor. A breathalyzer is refused. Full StoryBurr Morses recollection (Whats good for the goose, Nov. Full StoryMSNBC news analyst Rachel Maddows report on the election of Republican Rutherford B. Full Story
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If you are in town… I'll be signing copies of my book on Saturday at Metropolis at 12PM.
I love the dress!
Anna of Green Gable
the first photo is ridiculously cool! as for the rest, fabulous as always!
Very nice ART looks, streetstyle is boundless I very much love it!!!)))
Love the last outfit!
It's funny how I don't usually come along such fabulous street styles while am in the CBD area. :P Only you can. :)
Am definitely coming to Saturday's event!!
that first shirt is so neat
The last photo, she looks great!
the girl's necklace is so cool! great!
the girl's necklace is so cool! great!
Each picture represents the brilliant fusion between fashion and art.
want that dress.
So the girl in the first photo is she trying to channel Lady Gaga? If so the hair needs some work, but otherwise interesting choice of fashion.
i really adore this first pic
Wow !! The dress in the first photo is original !!
Have a nice day
The girl at the third photo – super!
I love the dress with the paint that looks in 3d…
wow, i love the first dress :o
i want one :)
That first dress is great. So comical but in a good way… not sure I'd go there but I applaud her for it.
Romance was born dress is amazing…..
how cool is that violin/cello-dress?!??!
I love the jumpsuit!
juliet xxx
first pic is lovely!
Where is that first dress from?
I can't wait for more pics. Melbourne is so so great and am thinking it's going to have a bunch of fashion talent! :-)
+ + + + + + + + + + +
Intense Hardware. Also you should stop by New Zealand again!
Love the first picture sooooo much
Look at my blog
Visit http://thefashioncomesalive.blogspot.com/
The guy with sunglasses in the 2nd photo = nice xxx
Please, I need to know how can I get the dress on the first picture.
Wow a violin dress! That's better than Gaga could ever pull off!
wonderful necklace and dress
Romance Was Born… amazing dress.
really love the violin dress!
i like so much the picture with the girl that wears the dress with the bass! i think that it's great 'cause it seems that the music is always with you…everywhere!
I really love the picture with the girl that wears the violin dress! it seems that the music is always with you!!!!
the fist dres is simply wonderful :)
I think the violin print shirt/dress is from
Correct me if I'm wrong.
i LOVE the first dress! does anyone know where i could buy it?!??!


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City Council Approves Parks Master Plan
The Moore City Council approved the Parks Master Plan on February 6th. The plan gives staff a framework to work within and plans can now be made for implementation. Funding sources will have to be found for many of the projects but many items are already in the works. Citizens will see improvements in many city parks and a Championship Disc Golf Course should open in Little River Park by the end of the year. The master plan is available to view by clicking the link below.
Click Here to Review Parks Master Plan
Leisure experiences filled with healthy opportunities and fun things to do will be much easier to find in Moore as the 2022 Comprehensive P.A.T.H. (Parks, Aquatics, Trails, Health) Parks and Recreation Master Plan is implemented over the next several years. There is an air of excitement in Moore as nearly 1,000 citizens participated in the planning process to express their preferred future for the park system, recreation facilities, and recreation programs.
Citizens asked for new recreation facilities. High on the list are trails, an aquatic facility, spraygrounds, a modern recreation center, shaded playgrounds, and a permanent Farmers Market facility.
Citizens asked for opportunities to recreate in ways that embrace their desire for a healthy lifestyle and to highlight the small town environment that is one of the most cherished community values. "The master plan's highest priorities for programming include enhancing the Moore Farmer's Market and creating new and exciting recreation programs for health and wellness at the Moore Community Center" said Todd Jenson, Director of Parks and Recreation.
Citizens asked that the level of care for existing parks and facilities be increased. The master plan has identified projects to accomplish that desire. These projects will greatly improve the experience of citizens who visit a park in Moore. Included in the improvements are; permanent restrooms, drinking fountains, shade structures, additional trees, improved walking trails, better signage and upgrades to the parking and lighting. By allocating additional funds for better turf management, more maintenance equipment, and additional staffing the level of care to existing parks will be significantly increased as well.
Finally, citizens have expressed an interest in adding to the uniqueness of Moore that goes beyond its very special bond among its citizens. The Plan also recognizes Moore as the home of Toby Keith. This Master Plan has identified two transformational projects.
First, Fairmoore Park will be completely redeveloped by adding a Toby Keith Museum, a significant water feature and sprayground, a new walking trail, pavilions, and an upgraded playground.
Second, a central Moore Public Open Space project will be the home of a new aquatic facility, a modern community center, a "state of the art amphitheater", a permanent Farmer's Market, a community garden/green space, a trail lined with permanent and rotating art/sculptures, a significant water feature, and a permanent festival zone.
The master planning work is complete and work begins on implementing its vision. The citizen-driven plan provides citizens with opportunities that did not seem realistic a few short months ago; however, the time is right, elected officials and city administrators are supportive of citizen preferences and are ready to begin the hard work to turn the dream of the master plan into a reality.


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Rangers Fan "Steals" Baseball From Little Kid
I'm sure by now you've seen the video and read numerous blogs discussing the incident that took place during last night's Rangers game. If by some chance you haven't, CLICK HERE to watch the video.
After watching the video several times my first thought was: "What's the big deal?" The ball was tossed in the general direction of the kid, but there's no way to know for sure as to whether or not he was the intended target. The ball was lobbed into the air, and thus was fair game.
The guy who ended up with the ball is getting tons of critisism because he didn't give the ball to the kid. That doesn't make sense to me. The guy did nothing wrong. He didn't knock the kid down. He didn't snatch it out of his hand/glove. Heck, he didn't even reach in the kids direction. He picked the ball up off of the ground after it deflected off the hands of the 10 other guys in front of him who went for the ball. Why aren't we upset at those guys too?
I truly don't understand what makes kids so special that people seem to believe that if a ball lands within 100 feet of one, and an adult gets it, that they should immediately hand it to them. For a lot of people (adults included) they've never even come close to catching a ball. You know they have to be extremely excited when their moment of glory finally comes, and they get a ball. Why should they be required to hand over their souvenir?
Remember last season when the kid reached in front of the younger kid and snatched the baseball, only to return it back to the smaller kid moments later? Well, he was rewarded with tons of stuff. I guarantee you that the adult that came up with the ball last night would've recieved zip if he had of done the same. Why is that? What makes kids so much better than fully grown men? It baffles me.
I've never been lucky enough to get a baseball at a game. I'm sure I could easily get one if I tried hard enough, but for now I'm content with just sitting there observing. However, if that day in which I finally get a baseball comes in June, in Cincinnati, or 15 years down the road, I'm not going to hand the ball over to a kid; unless it's my own. I don't see why I should.
Now don't get me wrong. I'm not trying to sound like a kid hater. I'm not by any means. (I have 4 cousins between the ages of 6 and 12, and I love them to death.) I'm simply saying that there is something wrong if you're expected to hand over a baseball, or face being booed by thousands of people. It's just a baseball.
I'll admit, I've witnessed (in person) people tackle little kids for baseballs and keep them for themselves, but that guy last night did absolutely NOTHING wrong. Had he of tackled the kid, or snatched the ball from him I'd be bashing him like everyone else. But from my point of view, he was just doing what any person would do. He was just a fan, fulfilling the dream of any baseball fan: Catching a ball at a Major League Baseball game.
I'm aware of the more recent incident in Miami, and I still stand with my original thoughts on the matter. While it looked like the grown man took the ball from the girl, it actually appears to me that the ball would've been caught by the boy WITH THE GLOVE anyway. Whatever the case, for all we know, it might be the first ball that guy has EVER gotten. He shouldn't be critisized just because of his age and size.
Please leave a comment with your opinion of the whole situation. Whichever side you're on, I want to see what you (the reader) has to say.
16 Comments
I 100 percent agree.. I wouldn't give a ball to a kid that I caught, unless the kid was my own. Everyone thinks that adults have obligations to EVERY kid… Sorry I don't care too much about any one elses kid unless they are my own or family. But anyway great blog
I agree completely. The only kid who is getting a ball I catch is my own. There is no obligation to give it to some random kid
It's called being grown up you idiots. It's a fricken ball. Give it to the kid and get over it. Unless that's all you have in life…is a baseball.
It was meant for the kid idiots. It wasn't meant for the geezer and his girl.
Totaly agree with what you are saying. I never understood why kids get everything now a days.
Why does any adult want to take away a thrill for a small child? Take your picture with the ball them give it to the child. Lady should put herself in place of the child's parents. would you not hurt for your child.
While I can understand where you and most of the commenters are coming from, I must respectfully disagree.
The guy who got the ball appears to be in either his 40s or 50s. If, at that point in his life, getting a ball at a baseball game is as big a thrill as it seemed in the video, he may way to reevaluate his life choices.
What exactly is he going to do with the ball? It'll probably sit on a shelf for a little while, maybe get put into storage after a year or two, and then possibly one day be sold in a garage sale after he forgets how he even acquired the ball in the first place.
On the other hand, the 3 or 4 year old child would be ecstatic to have the ball and would probably play with it every day. Sure, eventually he'll probably forget how he got it and may not care about it anymore, but I personally believe that the child would appreciate the ball more and put it to good use. Baseballs are meant to be played with.
But regardless of what happened or could have happened, it is just a baseball and should not be a national story. Things like this happen all the time.
Entitlement. That's what is wrong with society today.
The bottom line, they paid just as much for their ticket for the game as the kid's parents did. They did not steal it from the kid.
It pisses me off when people boo an adult that catches a ball gets booed when they wont hand it to a kid 5 rows away yelling gimme gimme gimme.
I completely agree with you Matt. I've enjoyed reading the other comments listed here but there is one tidbit no one has commented on. The little kid burst into tears and here comes the temper tantrum. How did they get him to stop crying? Someone got him a ball. What kind of lesson does that teach the child except that if he REALLY wants something bad enough, cry and ye shall receive. Thus starts the cycle of raising a brat who will have no idea of how to behave in public or work for something he truly wants. And yes, my husband and I have caught baseballs at games, but if we were lucky enough to catch a second or third ball, it was passed on to a child close to us who had behaved him or herself during the game, didn't bang their feet on the back of our seats, didn't whine about how bored he was throughout the entire game, knew not to use other people in the seats around them as stepping stones or launching pads to get up and down every second pitch . . . . well, you get the idea. Michael Kay is a very good announcer, but as an adult, he blew that call worse than some umpires.
This is really sad that an adult gets blasted all over the internet because he got the ball off the ground and gave it to his lady over somebody else child. No one knows his situation I mean maybe he's been to 1,000 games and never got a ball. In this instance I would blame the kids dad for not getting the ball for him. Also if I was the kids parent I wouldn't let the dugout give my kid a ball just because he was crying. I mean can I take a crying kid to the concession stand and get him a free hot dog too, maybe a souvenir bat from the team store to go with the ball? That's the message you are giving to this child. I applaud the guy for not succumbing to the flawed societal view that kids are entitled to whatever they want if they throw a fit.


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Making Sense out of Static
Early in the baseball season, it's hard to separate the contenders and the pretenders. Kansas City regularly sits somewhere near the top of the AL Central after the first couple weeks and sometimes even holds on through the first couple months. Last year even the lowly Pirates looked decent for the first month or two. Unfortunately for both teams, it's a lot better to be in first place at the end of the season then at the beginning.
It's not all the much different in the political world. It's pretty safe to assume that Obama will get the Democratic nod heading into the next Presidential election but the Republican field is wide open. A prime example is Donald Trump's "candidacy." This is a man who's really only famous for being famous and who, despite his reality TV shows and real estate empire, still managed to go bankrupt. Yet somehow he and a decent number of Republicans think he can steer the country through it's current financial straits. Let's see what Donald actually looks like on the trail:
He may be on to something. I'm sure the Gettysburg Address would have been much more memorable if Lincoln could have dropped a couple F-bombs in there.
Granted, there are also serious contenders. Like him or not, Mitt Romney has the pedigree and the record to make a serious run. Jon Hunstman looks a lot like the 2010 Giants or Rangers and everybody loves a dark horse. When you figure in the Tea Party contingent and their sway in the primaries, there's just no telling where the race will end up.
What is apparent at this point, though, is that with the economy apparently picking up jobs and OBL slowly disintegrating in the Indian Ocean, Obama is enjoying a momentary upswing. If the economy continues to pick up, he might end up like the 1995-96 Chicago Bulls, an inevitability if there ever was one. After all, let's face it. The man is as cool as the day is long. This performance at the Press Corps Dinner took place hours after he made the decision to take down Bin Laden and hours before the raid happened:
Admit it, if you were in the same position you would have been sitting in an empty room, rocking back and forth and staring at a blank wall.
It's still early in the season. There's a lot of ball to be played. But despite all the speculation and analysis, no one has any idea what's going to happen. Don't worry, though. You keep coming back this way and we'll make sure you stay up to date.
3 Comments
Honestly, who in their right mind would not love to see Trump tell someone in the polkitical arena in a press conference they were "Fired".
That would get my vote just on the drama of it all possibly happening for real….but I digress.
Rays Renegade
Happy times to see Trump drop off a cliff in the polls yesterday. Bye bye. Whoever wrote those jokes for Obama at the correspondence's dinner should take over the Oscars. Good stuff.
I want to love the current administration but I would be a heck of a lot happier with them if I didn't keep hearing about how much the economy is improving when all evidence in California is to the contrary. In L.A. County, abandoned, bankrupt home construction projects sit in every city. Strip malls no longer seem to come in 100% occupancy varieties. Two to three filled store fronts in six seems about the norm. Unemployment hasn't improved, regardless of what the statistics say – statistics which do not count independent contractors, full commission employees not currently receiving a commission, people who have been unemployed too long to continue qualifying for unemployment (I count five of these folks among my close friends, a small but telling sample size), small business owners who lost their business or people who gave up the job search and went back to school. I'm not saying President Obama should have fixed all of this. I understand that wouldn't have been possible for anyone or any administration and I think he's made good progress in some cases. But he needs to stop telling me all about the emperor's great new duds when I'm looking at him with my very own eyes and can clearly see his junk.