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Degeneration of the hippocampus is associated with Alzheimer's disease, and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apopotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive towards increases in activity and regions subject to modification. We have discovered compounds that are orally available, non-toxic, stable in mice, rats and cell culture, and capable of penetrating the blood-brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photocrosslinking.
Alzheimer's disease (AD) accounts for about 80% of all cases of dementia, and is the fifth leading cause of death in individuals aged 65 or older. AD is the most prevalent and devastating neurodegenerative disorder today. The greatest risk factor for developing this disease is advancing age. By 2025, the majority of baby boomers will have reached age 65 and the number of people in this age group with AD is predicted to expand by about 50% to nearly 8 million. By 2050, the number of afflicted individuals in the US is expected to have risen to between 11 and 16 million. People with AD are high users of health care, long-term care, and hospice services, and total payments for these types of care from all sources currently exceed $177 billion per year in the US.1
Pathologic changes in the brains of patients with AD include the accumulation of extracellular neuritic plaques between neurons, and neurofibrillary tangles within neurons.2 Numerous clinical trials aimed at reducing these plaques in Alzheimer's patients have failed to elicit cognitive improvement, even when the brain tissue of patients has been cleared of plaques. Disappointingly, the most recent data from late-stage trials of a γ-secretase inhibitor, Eli Lilly's semagacestat, were sufficiently discouraging to halt the trial.3 Currently, several biological and small molecule drug candidates that target the production or accumulation of Aβ42 plaques are in late-stage clinical trials. Other therapies for AD include acetylcholinesterase inhibitors (Aricept, Exelon, Razadyne and Cognex) and an NMDA antagonist (Namenda). These treatments offer some symptomatic relief, but no lasting benefit as they fail to address the underlying biology of AD.
An alternative approach to treating AD focuses on promoting hippocampal neurogenesis. AD is characterized by neurodegeneration in the cerebral cortex, hippocampus and other subcortical structures.4 Accordingly, we hypothesized that small molecules that retard neuronal death or increase neurogenesis may represent novel therapeutic agents. Currently no drugs operate through this mechanism. Nonetheless, groundbreaking studies starting in the 1960's demonstrated that neurogenesis in adult mammals occurs in two regions of the brain, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus within the hippocampus.5,6,7 This process is important for maintenance of the normal structure and function of the hippocampus, and thus essential to hippocampal-dependent memory and learning.8 In particular, neurogenesis in the dentate gyrus serves to produce neurons that integrate locally in the granular layer of the dentate gyrus, which displays lifelong structural and functional plasticity. This process appears to be active within all mammalian species, including humans.9 In adult mice, neurogenesis is a month-long process involving proliferation of neuronal precursor cells and subsequent maturation. During this process the vast majority of the newly formed hippocampal neural precursor cells undergo apoptosis prior to maturation whereas the surviving cells mostly become incorporated as fully functional neurons.
The process of neurogenesis in adult mice can be affected by both environmental and chemical stimuli. Neurogenesis increases in adult mice when they are housed in an enriched environment containing toys, nesting materials and exercise equipment.10,11 Similarly, neurogenesis is enhanced when mice are free to exercise voluntarily.12,13 Provocatively, engagement in enriching educational activities and exercise also delays the onset and progression of AD.14 Antidepressants enhance neurogenesis in adult mice and humans,15 and allopregnanolone, a metabolite of progesterone that is synthesized in the CNS, promotes neurogenesis and learning in a mouse model of AD.16 In the latter instance, enhancement of neurogenesis was associated with amelioration of cognitive deficits.17 Finally, deficits in neurogenesis precede the formation of plaques and tangles associated with AD in mouse models of that disease.18 Taken together, the evidence suggests that drugs that promote hippocampal neurogenesis might provide effective treatment strategies for patients with Alzheimer's disease.
To identify small molecules capable of promoting neurogenesis, we screened a collection of 2000 structurally unrelated small molecules assembled from an in-house compound library (Fig 1).19 Initially, molecules were screened by directly injecting mixtures of 10 compounds intracerebroventricularly (ICV) into the left lateral ventricle of living mice. Compounds were introduced over 7 days at a concentration of 10 μM each (12 μL/day at a constant rate). With this dosing, we estimated that compounds would attain intracerebroventricular concentrations in the low-micromolar to mid-nanomolar concentration range. During compound infusion, the thymidine analog bromodeoxyuridine (BrdU, 50 mg/kg) was administered daily to mark newly born hippocampal neural precursor cells. After 1 week of compound administration, the animals were sacrificed, 40 μm brain slices were prepared, and tissue was processed for immunohistochemical staining with an antibody to BrdU to identify newborn cells. Neurogenesis was quantified by counting BrdU+ cells in the hippocampal dentate gyrus in the brain hemisphere opposite to the side of compound infusion. The number of positive cells was normalized against the volume of the dentate gyrus.
One of the molecules that we discovered with this approach was named P7C3, as it was identified as Compound 3 (C3) from Pool 7 (P7). Mice treated with P7C3 had approximately twice the number of BrdU+ cells as mice treated with vehicle alone (artificial cerebral spinal fluid, CSF), and a similar number as mice treated with a positive control, fibroblast growth factor 2 (FGF-2). Unlike some antidepressant drugs that have been reported to enhance neurogenesis after two to three weeks of treatment,20 P7C3 affects neurogenesis within days of administration. Additional studies have revealed that P7C3 maintains activity when a 1 μM solution was infused ICV (12 μL/day for 7 days); it displays maximal neurogenesis activity with an oral dose of 5 mg/kg and measurable activity at 1 mg/kg. The molecular target of P7C3 is not known. However, time-course experiments revealed that P7C3 does not stimulate proliferation of neural precursor cells. Rather, P7C3 increases the number of newborn neurons that survive the month-long maturation process. The mature neurons express neuron-specific proteins and appear fully functional.19 Accordingly, P7C3 enhances neurogenesis – i.e. is proneurogenic – by virtue of its neuroprotective activity. P7C3 was found to repair the structure and function of the dentate gyrus in mice deficient in the npas3 gene, a genotype characterized by an absence of hippocampal neurogenesis.21 Furthermore, it also enhanced neurogenesis in the dentate gyrus, impeded neuron cell death, and preserved cognitive capacity as a function of terminal aging in rats. In contrast, no effect was observed on neurogenesis in middle-aged rats, which do not display impaired neurogenesis.22 Finally, P7C3 is not toxic to embryonic, weaning or adult mice.
Here we describe efforts to understand the structural requirements for activity and to improve P7C3's potency, stability and toxicity profile. To the best of our knowledge, this is the first class of small molecules designed to promote neurogenesis, and as such may represent lead compounds for the treatment of debilitating neurodegenerative diseases.
P7C3 contains a dibromocarbazole connected to an aniline with a 2-hydroxypropyl linker. We set out to determine which positions of P7C3 would tolerate modification, systematically optimize each subsection of P7C3, and identify derivatives that could be used for affinity chromatography. Several commercially available analogs of P7C3 provided early indications of the structure/activity relationship. The bromines on the carbazole appear particularly important, as the derivatives with dichloro (1) and parent (2) carbazole did not appear active at the concentrations tested (Scheme 1, Fig 1). We tested derivatives possessing methyl or methoxy substitution on the aniline ring, and discovered that methyl (3–5) or ortho-methoxy substitutions appeared to decrease activity in our assay. In contrast, a methoxy group was well tolerated in the meta or para position (7, 8). A long-term objective is to identify the molecular target of P7C3, and to this end we planned to synthesize active derivatives that could be used as reagents for affinity chromatography. In that context, the observation that an O-alkyl group did not compromise activity was encouraging. Indeed, many of the synthetic analogs (see below) were prepared from m-anisidine with this consideration in mind. We tested two commercially available analogs possessing saturated heterocyclic rings rather than an aniline (9, 10). Previous work from a group at Serono Pharmaceuticals revealed that several carbazoles inhibited Bid-mediated release of cytochrome c, and, as a consequence, were anti-apoptotic.23 The most active compound from the Serono study (9) proved moderately active in our assay while a less active Serono compound (10) was also less active in our experiments.19 Finally, we evaluated the activity of dimebon (11), a γ-tetrahydrocarboline originally used as an antihistamine in Russia. This drug has recently been reported to block apoptosis of cortical neurons exposed to amyloid-beta peptide.24
Anecdotal evidence of its efficacy against AD and age related cognitive decline25 prompted Medivation and Pfizer to conduct clinical trials in the U.S. to determine dimebon's efficacy in treating several forms of neurodegenerative disease. While phase II data appeared exceptionally encouraging,26 unpublished results from a phase III study showed that dimebon offered no benefit for patients suffering from AD.27 Provocatively, dimebon is active in our neurogenesis assay, but substantially less so than P7C3.
Synthetically, P7C3 can emerge from a union of a carbazole, an aniline and an epoxide (Scheme 2). This convergent synthetic approach allows the independent variation of the two rings. Furthermore, additional processing of P7C3 and its derivatives provided access to a range of derivatives. Throughout the manuscript, compounds with numbers highlighted in green showed activity as good as or better than our positive control, FGF-2 (see below). As shown in Scheme 2, a wide range of analogs was prepared by first condensing 2- or 3-ring heterocycles with epibromohydrin.28 The resulting epoxides 13 were then opened with various anilines, thiols or heterocycles. We found that ring-opening with anilines generally required Lewis acid activation of the epoxides (BiCl329 or LiBr30) whereas alcohols, indole and carbazoles required deprotonation of the nucleophile with NaH. Stronger nucleophiles such as sodium azide, hydrazine, ammonia, thiophenol or aminopyridines reacted with the terminal epoxides upon simple heating. In a slight modification of this sequence, dibromocarbazole was allowed to react with arylglycidyl ethers to provide aryl ethers 42 and 43 directly. Similarly, m-anisidine was first condensed with epoxy-2-methyl-propyl chloride and then exposed to the carbazole to yield the tertiary alcohol 46.31 This synthetic approach provided access to a wide range of structural diversity, although the overall yields ranged from rather abysmal to nearly quantitative. However, none of the syntheses has been optimized. Complete experimental details are provided as supporting information.
Several of the analogs prepared according to Scheme 2 were subject to additional transformations. For instance, the thioethers 24 and 44 were oxidized with either NaIO4 or m-CPBA to provide either a diastereomeric mixture of sulfoxides (25) or the sulfones (26, 45), respectively. Phthalimide 39 was deprotected and acylated to provide derivative 41. Similarly, P7C3 analog 7 was subject to further processing (Scheme 3). For example, methylation was O-selective at low conversion, yielding ether 47. Urea formation and acylation were facile, providing 48 and 49 in quantitative yield. Oxidation with SO3·Py produced ketone 50 and, unexpectedly, thioether 51. A potential mechanism for this unusual and, to our knowledge, unprecedented, oxidation is provided in the supporting information. In brief, an α-ketoimine may be trapped by methanethiol released from DMSO.
Fluorination appeared to improve activity (see below), so a series of fluorinated analogs were prepared, as shown in Table 1. We used either DAST (Et2NSF3) or its morpholino analog. Reactions were generally cleaner using the latter reagent. For aniline-containing starting materials, the NH proved problematic. In these cases, protection of the nitrogen with a 4-nitrobenzene sulfonyl (4-Ns) group32 greatly improved the fluorination. Similarly, the difluorides 61 and 62 were prepared from the corresponding ketones (eq 1).
To explore the SAR on the right hand fragment, we replaced the N-phenyl ring with heterocyclic rings as shown in eq 2. The primary amine 28 condensed with 2-chloropyrimidine to provide analog 63. Introduction of pyridine rings required initial conversion to a urea. Subsequent Cu-catalyzed cross coupling with iodo-pyridines33 and hydrolysis of the cyclic urea yielded aminopyridines 64–66. Five-membered heterocyclic rings were incorporated as shown in Scheme 4. Thus, hydrazine 30 was condensed with a diketone to yield pyrazole 67 while azide 31 underwent Cu-catalyzed cycloaddition to yield the corresponding triazole (68).34
Several analogs were prepared with modified linking groups between the carbazole and aniline. As shown in Scheme 5, epoxide openings and alkylations provided derivatives without the aniline NH (69), without the central OH (70) or with additional methylenes in the linker (71, 72). Similarly, the secondary aniline was replaced with a secondary amide (73) through the following sequence: ring opening of methyl glycidate with dibromocarbazole, hydrolysis of the ester, and coupling to aniline by way of the acid chloride (eq 3).
Ester 73 was originally conceived as a precursor to optically active derivatives of P7C3. Our plan was to perform the ring opening with enantioenriched methyl glycidate, and, following amidation, reduce scalemic 73 to yield optically active 7. In the event, however, we found that the ester generated in this manner was racemic, with the optical purity presumably being a casualty of the basic reaction conditions. Similarly, ring-opening of optically active epichlorohydrin yielded racemic epoxide 13 (heterocycle = Br2-carbazole). In this case, epichlorohydrin was likely racemized by adventitious chloride ion.35 Ultimately, using the known Mitsunobu reaction of dibromocarbazole with optically active glycidol,23 we were able to prepare both enantiomers of epoxide 13 in >99% ee, and from them access the single enantiomers of both 7 and the sulfone 26.36 Likewise, both enantiomers of the aryl ether 42 were prepared from optically active phenyl glycidyl ether. Interestingly, when these alcohols were subjected to the fluorination reaction conditions shown in Table 1, the resulting fluorides were found to have <20% ee. Partial reaction flux through an aziridinium ion likely provides a mechanism for retention of configuration that competes with the usual invertive pathway.
Finally, to provide a reagent for mechanism-of-action studies, the coumarin-tagged37 derivative 76 was prepared from anisidine derivative 7. Thus, cleavage of the methyl ether (→ 74), alkylation (→ 75) and conjugation to a coumarin derivative provided the desired reagent in acceptable yield (Scheme 6).
All of the analogs were tested in live mice for their proneurogenic effect. Following the procedure described above, 10 μM solutions were administered continuously for 7 days (12 μL/day) by means of subcutaneous osmotic minipumps that delivered compound through a canula implanted into the left lateral ventricle. We estimate that the in vivo concentrations were in the low micromolar to mid-nanomolar range.19 The results are shown in Figure 3 grouped by the region of P7C3 that each analog modifies. Thus, derivatives of the carbazole, the propyl linker, the heteroatom or the aromatic ring were tested (Scheme 7). Some compounds represent multiple changes from P7C3.
The bromines on P7C3 are particularly important: the dimethyl (14), dichloro (17) and diiodo (20) versions appear to have little activity, and the mono-bromo derivative (16) appears substantially less active in our assays. Nonetheless, dibromination is not required as the bromo-methyl-substituted compound (15) is highly active. Likewise, in a promising result for the synthesis of photocrosslinking agents, the azido-bromo-carbazole (18) retains significant activity. The substantial activity of the bis-nitrile (19) indicates that the bromines can be replaced entirely, and provides a lead compound with substantially reduced lipophilicity.
The carbazole ring system does not appear to be strictly required. For example, the β-carboline (38) is as active as P7C3. The tetrahydro-γ-carboline 33, a structural hybrid between dimebon and P7C3, shows intermediated activity, as does the dimethyl indole 27.
In the linker region, several compounds were improved by replacing the hydroxyl with a fluorine. Indeed, the most active compound prepared (53), is the fluorinated anisidine derivative. Similar trends were observed with the N-methyl derivative (35 vs. 56) and the sulfoxide-containing analogs (26 vs. 58). However, the effect of fluorines appears dependent on context. For example, while the activities of the m- and p-anisidine-containing analogs are improved by fluorination (7 vs. 53; 8 vs. 54), the parent compound with an aniline ring gains little from fluorination (P7C3 vs 52). Similarly, the derivative featuring a phenol is highly active with a 2-hydroxypropyl linker, but less active with a 2-fluoropropyl linker (42 vs. 57).
Two additional changes to the linker region were well tolerated. First, conversion to a tertiary alcohol (46) improved activity. Second, extending to a hydroxy butyl linker maintained high activity, so long as the extra methylene was inserted between the hydroxy group and the aniline (72). In contrast, inclusion of an additional methylene between the hydroxyl and the carbazole (71) essentially abrogated activity. Intermediate activity was observed for analogs possessing O- or N-methyl groups (35, 47), a ketone (50), an α-thioketone (51), an N-acyl group (49), a cyclic urea (48), an amide (73), or an unsubstituted propyl chain (70).
P7C3 features a nitrogen linking the propyl chain to the right-hand aromatic ring. We synthesized several congeners to explore the effectiveness of alternative heteroatoms. Encouragingly, the aniline could be replaced with an aryl ether (42, 43), an aryl thioether (24) or an aryl sulfone (26) and retain superior activity. Interestingly, while both the thioether and sulfone were highly active, the mixture of diastereomeric sulfoxides was equivalent to vehicle. Because C-S bonds are longer than C-N bonds, we speculated that smaller groups than Br might be tolerated on the carbazole. While not confirming our reasoning, it was heartening to observe substantial neuroprotective activity from a dichlorocarbazole possessing a sulfone linker (45). While several heteroatoms appear acceptable at this position, an analog with only a hydrocarbon linker (69) did not appear neuroprotective at the concentration tested.
The right-hand aromatic fragment tolerates substantial variation, although some surprising observations were made. Modest activity is retained even with simple NH2- or O-alkyl-terminated compounds (28, 29), i.e. compounds lacking a right-hand aromatic ring. As described above, a piperazine group effectively replaces the aniline. Heteroaromatic rings have proved less effective with two notable exceptions. The 2-aminopyridine (64) displays activity nearly as high as P7C3 itself, and the azapyridone (32) maintains robust activity. In contrast, the other pyridines, pyrazines, indoles, carbazoles, pyrazoles and triazoles were substantially less active in our assays. Substitution around the aniline ring of P7C3 was somewhat enigmatic. For instance, a 3-OMe (7) group had little effect on activity, but a minor extension to an OEt (21) group23 essentially abrogated activity. Likewise, a 3-N3 group (22) substantially decreased activity. Nonetheless, substantial activity was observed for a derivative designed to facilitate affinity chromatography and localization studies, the coumrain-linked analog (76),38 Meanwhile, the 4-OMe (8), 4-OEt39 and 4-N3 (23) derivatives were all highly active.
Finally, several enantiomeric pairs were tested. Specifically, we tested the anisidine analog of P7C3 (7), the aryl ether 42, and the sulfoxide 26. In all three cases evaluated, a significant difference in activity was noted between the two enantiomers. The same enantiomer displayed higher activity in all three cases, although the R/S designation varies due to differences in priority among the substituents.
Tertiary alcohol 46, fluoro-aniline 53 and fluoro-sulfone 58 were evaluated at a range of doses. In each instance, 10 – 0.01 μM solutions were infused over a 7 day period at a constant rate (12 μL/day) concurrent with IV administration of BrdU. The tertiary alcohol (46) roughly paralleled P7C3, showing substantial activity when a 1 μM solution was infused, but showing little effect from a 0.1 μM solution. In contrast, both fluorides maintained activity at 0.1 μM. Indeed, our most potent analog (53) remained active when 0.01 μM solution was infused, which corresponds to a total of 0.43 mg added over one week's time.
Several of our most potent compounds were analyzed for pharmacokinetic properties and hallmarks of toxicity (Table 2). A competition assay was performed to determine if P7C3 or its derivatives bound to the hERG channel, as interference with hERG function can cause cardiac toxicity.40 Specifically, we measured what percentage of [3H]astemizole (Kd = 6.8 nM) was displaced with a 10 μM concentration of drug.41 P7C3 and (R)-7 showed significant displacement of the radioligand, and (S)-42 showed modest binding. Encouragingly, the other analogs tested appear to bind hERG only weakly.
The tetrahydrocarboline dimebon (11) had been used in Russia as an antihistamine prior to engendering enthusiasm regarding its potential as a treatment for Alzheimer's disease. Accordingly, we performed a competition assay using [125I]aminopotentidine, a potent (Kd = 0.1 nM) ligand for the histamine H2 receptor.41 Using this assay, dimebon displaced 99% of the aminopotentidine at 10 μM. P7C3 and (R)-7 also display modest binding to this receptor. However, histamine binding and neuroprotection activity are clearly unrelated because several of our most potent analogs display weak or no binding. No analog showed significant binding to the histamine H1, H3 or H4 receptor.
To determine metabolic stability, compounds were incubated with either mouse or human hepatocytes at 2 μM. HPLC/MS/MS analysis of the culture media at several time points provided measurements of half-life. Gratifyingly, of the analogs tested, most were extremely stable. Compound 58, a fluorosulfone, had a half-life of 2–3 h. Compound 26, a β-hydroxy sulfoxide, was quite stable towards mouse hepatocytes, but was processed by human hepatocytes with a t1/2 < 1 h. All other analogs displaying high activity showed only marginal levels of metabolism after 4 h. While we did not determine the metabolites of the two sulfoxides, it is interesting to note that during their syntheses these compounds displayed a tendency to undergo β-elimination to yield vinyl sulfones. We conjecture that this reactivity profile in the flask is mirrored by their reactivity in cell culture.
As previously reported, P7C3 is orally available and displays favorable distribution into the brain (AUC brain: AUC plasma ratio of 3.7 for oral delivery). For comparison, brain exposure to 53 was determined after intraperitoneal (IP) and oral gavage (PO) administration. It was found to have good penetration, with a AUC brain:AUC plasma of 0.61 and 0.82 by IP and oral gavage administration, respectively. Treating at 20 mg/kg PO with fluoride 53 resulted in approximately 0.9 μM concentration in the brain (450 ng/g brain tissue) 4 hr after dosing.
Neurodegenerative diseases remain an area of unmet medical need. The poignancy of medicine's deficiency in this arena will only become more evident in the near future. Aging populations in most industrialized countries, and many developing ones, will confront an increasing incidence of neurodegenerative disorders.1 In that context, small molecules capable of fostering the growth of new neurons could facilitate the development of novel molecular therapeutics. P7C3 possesses this ability, and has been found to repair damaged neural circuitry in mice and improve cognition in aged rats. Accordingly, we became interested in improving the activity of P7C3 in terms of potency and toxicity as well as identifying reagents to aid studies of its mode of action.
We modified nearly every atom of P7C3 during this study. Our investigation has revealed several important characteristics of P7C3 and has led to the discovery of improved analogs. First, we found that P7C3 displays an encouraging combination of sensitivity and flexibility. That is, while effects are evident from modification to all sections of the molecule - the carbazole, the linker region, the aryl ring - none of these subunits is sacrosanct. For instance, highly active analogs were identified in which the carbazole had been replaced with a carboline, the hydroxy-propyl linker had been replaced either a fluoropropyl linker or a hydroxybutyl linker, or the aniline had been replaced with an aminopyridine, a phenol, a thiophenol or an aryl sulfone. This SAR should allow the identification of safe, effective and bioavailable analogs for further development.
Second, we have shown that the neuoroprotective activity of P7C3 and its analogs is unrelated to histamine receptor binding. No mechanism of action has been suggested for dimebon's putative anti-AD activity, but a) it is active in our assay and b) it is a potent antagonist of the histamine receptor. We cannot claim with certainty that dimebon and the P7C3 class of molecules work by the same mechanism, but we can exclude the possibility that binding to the histamine receptor is required for proneuorogenic activity.
Third, we have prepared analogs of P7C3 that we anticipate will facilitate mechanism-of-action studies. Specifically, we have prepared two aryl azides (18, 23) that could be used for photoaffinity studies. Likewise, we have prepared an active derivative containing a coumarin moiety for use in pull-down and localization experiments. More broadly, we have revealed which sections of P7C3 accommodate alteration; this knowledge is expected to aid the preparation of other derivatives that will be useful in mode-of-action studies.
Finally, we have identified analogs displaying no observed toxicity, no binding of the hERG channel, good blood/brain distribution, oral availability and excellent metabolic stability. We are optimistic that this information will enable the discovery of the molecular target of P7C3, and will continue to facilitate the identification of compounds suitable for further development.
P7C3 was discovered using an unusual approach. Modern drug discovery relies on high-throughput screening against defined receptors or enzymes using in vitro or cell-based assays. In connection with neurodegenerative diseases, however, little consensus exists regarding which receptors or enzymes represent ideal targets. Furthermore, these diseases likely involve pathologies of multiple cell types in the complex setting of the central nervous system. Accordingly, devising simple, predictive assays has proven difficult, a challenge which manifests itself in the paucity of available therapeutics. We opted for an alternative strategy wherein we identified and optimized molecules capable of affecting a desired function, neurogenesis, within a living mammal. The risks of this approach were clear, among which were low throughput, an inability to separate binding to a target from pharmacokinetic effects, and ignorance of the molecular target. Nonetheless, the benefits of this experimental design appear to outweigh these limitations as we were able to simultaneously select for molecules that possessed activity within live mice and rats, desirable toxicity profiles and acceptable physical characteristics. It may be that this atavistic approach to drug discovery deserves consideration for other complex diseases.
Test compounds were evaluated as described previously.19 Compounds were infused intracerebroventricularly (i.c.v.) into the left lateral ventricle of four adult (12 week old) wild-type C57BL/J6 mice by means of surgically implanted Alzet osmotic minipumps that delivered solution into animals at a constant rate of 0.5 μl/hour for 7 days. Bromodeoxyuridine (BrdU) was injected intraperitoneally at 50 mg/kg/day for six days during pump infusion. Twenty-four hours after the final BrdU administration, mice were sacrificed by transcardial perfusion with 4% paraformaldehyde at pH 7.4, and their brains were processed for immunohistochemical detection of incorporated BrdU in the SGZ. Dissected brains were immersed in 4% paraformaldehyde overnight at 4 °C, then cryoprotected in sucrose before being sectioned into 40 μm thick free-floating sections. Unmasking of BrdU antigen was achieved through incubating tissue sections for two hours in 50% formamide/2X SSC at 65 °C, followed by a five minute wash in 2X SSC and subsequent incubation for thirty minutes in 2M HCl at 37 °C. Sections were processed for immunohistochemical staining with mouse monoclonal anti-BrdU (1:100). The number of BrdU+ cells in the entire dentate gyrus SGZ in the contralateral hemisphere (opposite side of surgically implanted pump) was quantified by counting BrdU+ cells within the SGZ and dentate gyrus in every fifth section throughout the entire hippocampus and then normalizing for dentate gyrus volume.
Binding to hERG and histamine receptors was performed by MDS Pharma Services, now Ricera. Briefly, a competition binding assay was performed in which the level of specific binding of a radioligand, used at a low concentration (≤Kd), was determined in the presence of 10 μM test compound. Specific radioligands, the concentration utilized, and historical Kd values as measured by Ricera for each receptor and radioligand are as follows: HERG: 1.5 nM [3H]Astemizole (Kd 6.8 nM); Histamine H1: 1.2 nM [3H]Pyrilamine (Kd 1.1 nm); Histamine H2: 0.1 nM [125I]Aminopotentidine (Kd 0.45 nM); Histamine H3: 3 nM [3H] (R)-(−)-α-Methylhistamine (Kd 2.4 nM); Histamine H4: 8.2 nM [3H]histamine (Kd 5.7 nM).
HeLa cells were plated at optimally determined densities for either 96 or 384 well plates and compounds were added in serial five-fold dilutions the following day. Forty-eight hours later, cell viability was assessed by addition of CellTiter-Glo Reagent (Promega, Madison, WI). Growth Inhibitory 50 (GI50) values were calculated according to the formula 100 × (T−T0)/(C−T0) = 50, where T = optical density of test well after 48 hr exposure to compound; T0 = optical density at time zero; and C = control optical density. The LC50 (concentration of drug resulting in a 50% reduction in the measured protein/ATP at the end of the drug treatment as compared to that at the beginning) indicating a net loss of cells following treatment is calculated from [(T−T0)/T0] × 100 = −50.
Male ICR/CD-1 mouse hepatocytes, InVitroGRO HI and HT Medium, and Celsis Torpedo Antibiotic Mix were purchased from Celsis/In Vitro Technologies (Baltimore, MD). Cryopreserved hepatocytes were thawed in HT Media containing antibiotics, resuspended in HI media at 2 ×106/ml and plated in 96 well plates at 0.05 ml (105 cells)/well. Compounds to be tested were dissolved in DMSO at 2 mM, further diluted to 4 μM in HI media, and added to the cells in 50 μl so that the final compound concentration was 2 μM. Two additional wells containing compound and no cells were plated to serve as time 0 (C0) and endpoint solvent control (Cep). The cells were then placed in a 37 °C, 5% CO2 incubator. At the timepoints indicated, the well contents were harvested and a 2-fold volume of methanol added to lyse the cells and precipitate proteins. The samples were incubated 10 min at RT and then spun at 15,000 × g for 5 min in a microcentrifuge. The supernatant was analyzed by LC/MS/MS. Metabolism of 7-ethoxycoumarin was used to monitor hepatocyte performance.
P7C3 was prepared for dosing by dissolving the compound in DMSO at 50 mg/ml. The compound was diluted to a final formulation of 3% DMSO/10% cremophor EL (Sigma, St. Louis, MO)/87.5% D5W (5% dextrose in water, pH 7.2). Adult mice were dosed IV, IP or via oral gavage (PO) in a total volume of 0.2 ml. Compound 53 was prepared in a similar fashion in 5% DMSO/10% cremophor EL/85% D5W and dosed either IP or PO. Animals were sacrificed at varying times after dosing by inhalation overdose of CO2. Whole blood was collected with an ACD solution (sodium citrate) coated syringe and needle. The blood was subsequently centrifuged at 9300 × g for 10 min to isolate plasma. Plasma was stored at −80 °C until analysis. Brains were isolated from mice immediately after sacrifice, rinsed extensively with PBS, blotted dry, weighed, and snap frozen in liquid nitrogen. Lysates were prepared by homogenizing the brain tissue in a 3-fold volume of PBS (weight of brain in g × 3 = volume of PBS in ml added). Total lysate volume was estimated as volume of PBS added + volume of brain in ml. One hundred μl of either plasma or brain was processed by addition of 200 μl of acetonitrile to precipitate plasma or tissue protein and release bound drug. In some experiments, this mixture was centrifuged at 16,100 × g for 5 min and the supernatant analyzed directly by HPLC/MS/MS while in other experiments the sample was additionally processed by passage over a solid phase extraction column. An additional 700 μl of PBS was added to the plasma or lysate acetonitrile mixture and the sample centrifuged at 16,100 × g for 5 min. Nine hundred μl of supernatant was mixed with 1 ml of PBS and passed over a Waters (Milford, MA) OASIS HLB solid phase extraction column primed by addition of 2 ml acetonitrile followed by 2 ml of water. The column was washed twice with 2 ml of 5% acetonitrile in H20 and compound was eluted by addition of 2 ml of acetonitrile. 500 μl of the eluant was added to 500 μl of H20 containing 0.2% formic acid (final formic acid 0.1%) and analyzed by HPLC/MS/MS as described above. Standard curves were prepared by addition of P7C3 to blank plasma or blank brain lysate. A value of 3-fold above the signal obtained from blank plasma or brain lysate was designated the limit of detection (LOD). The limit of quantitation (LOQ) was defined as the lowest concentration at which back calculation yielded a concentration within 20% of theoretical. The LOQ for both plasma and brain was 5 ng/ml. In general back calculation of points on both curves yielded values within 25% of theoretical over 4 orders of magnitude (10000 to 5 ng/ml). Pharmacokinetic parameters were calculated using the noncompartmental analysis tool of WinNonLin (Pharsight). Bioavailability was calculated as AUCoral/AUCiv × Doseiv/Doseoral × 100 (AUC is area under the concentration time curve). The Brain:Blood ratio was calculated using AUC values.
Funding provided by The Hartwell Foundation, Staglin Family fund, UT Southwestern High Risk/High impact research fund, National Alliance for Research on Schizophrenia and Depression, Morton H. Meyerson Family Tzedakah fund (A.A.P), NIH (1R01 MH087986, 5DP1OD000276, RO1MN59388, 5PO1CA95471), a Simons Foundation Autism Research Initiative grant, the Welch foundation (I-1612, I-1422). JMR is a fellow of the Alfred P. Sloan Foundation.
SUPPORTING INFORMATION Complete experimental details and characterization data for new compounds; full citations for abbreviated references.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Drs. Myrow and Bundy-Myrow
participate in most Western New York insurance plans and serve
on many provider panels. Prospective clients should
consult their employers or health insurance companies to determine
their mental health benefit. Co-pays with many plans are higher
for mental health services than for medical appointments.
For clients and professionals who pay on their own, there
are standard fees, which can sometimes be negotiated, depending
on circumstances. Paying privately has the advantage of greater
privacy. Please make it a point to discuss these
issues with us as needed.
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Available in several distributions ranging from 70% up/30% down to 100% down, Bruno LED Softshine is specifiable with high and low lumen packages that make the luminaire well-suited for a variety of applications.
Bruno LED can be specified as nLight®-enabled to provide network controls connectivity, energy-saving digital lumen management or both. It is also available with an integrated sensor for daylight dimming and/or occupancy detection control. Plus, Bruno LED can be configured with X, T, L or straight connectors to form creative suspension arrangements.
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Why we did it – WordPress plugin to Import Facebook Events
As developers we get a lot of client requests for social network integration. Unfortunately, we are seeing a trend emerge where clients ask to have their entire site simply output a giant feed from all of their social networks. Sure this would save time from having to update content across platforms but at what cost? This approach is useless to search engines partially due to duplicate content but mainly because the content doesn't originate from their domain.
In one recent case my agency Volk, was contracted to generate a feed from my clients Facebook events. We looked at many event plugins and we were disappointed with the monthly or yearly costs of each. We could obviously bill our clients for the additional cost year after year but that becomes a hassle for everyone and we run the risk of clients looking at competitors for cheaper rates.
We decided to develop WordPress Facebook Events Importer to use over and over again. Facebook Events Importer retrieves all event data and stores it into virtual any WordPress install. We are excited to share our solution for Importing Facebook Events with the WP community and like WordPress… for free. We have plenty of code examples to help you integrate this solution into your project.
We will continue supporting this plugin for a long time to come. We will be enhancing current features and enhancing it with new ones. Stop back frequently to find out what we've added and as always keep your plugins up to date!
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- Built for WordPress – Import Facebook Events


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SA Mines and Energy Journal : June-July 2010
JUNE/JULY 2010 SA MINES & ENERGY JOURNAL 26 FEATURE When more than 400 people -- half Orroroo's population -- turned up to hear the presenta- tion from mining company Linc Energy, it was all good news. A slice of South Australia's agricultural heritage mixed with the new world of emerging energy technologies is being hailed by locals as a recipe for economic and social success. Orroroo -- a farming community of 850 people 52km north of Jamestown -- is being talked up as Australia's "epicentre for renewable technology" . Linc Energy, a multinational mining company at the forefront of underground coal gasification, is gearing up to start a commercial operation at Orroroo. It's a regional jump-start heading to many parts of South Australia as new technology opens up opportunities for businesses that have struggled for years. "It's exciting in lots of ways and people shouldn't underestimate the impact, " said Orroroo Council CEO Iian Wilson. About 30 drilling crew and engineers have been creating the first buzz of activity over the last five months. In Adelaide's CBD, around 120 Linc Energy employees are getting ready to move into new corporate offices in the ANZ building on King William Street. All this activity is related to the emergence of two new energy technologies that are moving from the experimental phase into commercialisation. Ministers have been briefed on-site, approvals granted and shareholders updated. Linc Energy announced in November last year it had identified a coal mineralisation target of between 1.0 and 1.3 billion tonnes. The coal deposit is heralded by Linc as "the best UCG location and coal deposit that it has drilled or examined to date" . That's a big call from a company with sites in Queensland and Wyoming, Montana and North Dakota in the US as well as Uzbekistan and Vietnam. The coal has been there for millions of years. It sits "stranded" so far under the surface that it's not feasible to mine it in the traditional sense of coal mining. But the two new technologies of Underground Coal Gasification (UCG) and Gas to Liquids (GTL) can realise the resource. Put in its simplest form, UCG pushes air down an injection well to the coal seam which is ignited, producing gas which flows up another well to power generating plant, or to plant that liquefies the gas for transport elsewhere. Linc Energy currently operates three pilot UCG plants in Queensland. The biggest of these, the Chinchilla Demonstration Facility, was commissioned in October 2008 and is successfully producing liquid hydrocarbons. The next stage for Linc is a commercial operation and that's where Orroroo comes into play. Linc chief executive officer Peter Bond: "Linc Energy's entry into the South Australian market was prompted by a number of factors, and our work at our Chinchilla Demonstration facility north of Brisbane and the Queensland government's delays in coming to a commercial decision on the UCG technology were instrumental in turning our attention to South Australia. " "Linc Energy's acquisition of South Australian petroleum and gas explorer SAPEX Limited in October 2008 also provided us with access to Petroleum Exploration Licences (PELs) and Exploration Licences (ELs) in the Arckaringa and Walloway Basins, " he said. "Underground Coal Gasification (UCG) is an evolving technology and has required significant research and development by Linc Energy to convert UCG synthesis gas (syngas) into liquid fuels. "Our Chinchilla plant is the only one of its kind in the world and includes new generation UCG trial generators, a fully operational GTL pilot plant and a specialised laboratory to analyse and monitor the gas to liquid technology around the clock. " The company's plan is to fast track the commissioning of a modest sized UCG commercial facility at Orroroo to confirm the suitability of the resources for low cost synthesis gas production that can be used for power generation. Locals have been told the plan is for a 20-30mW plant with a long term plan for a 500mW power station. The site is ideally located just 40km from 275kV transmission lines and 75 minutes by road from Port Augusta. When Mr Bond made the announcement at the end of 2009 he commented that "these initial drilling results are fantastic and confirm my belief that the coal in this area has all the attributes we are looking for in our first commercial USG site. " "By that I mean great coal, at ideal depth, excellent coal seam thickness, good geology and flat terrain. "This deposit can support significant production of low- cost synthesis gas for power generation and synthetic fuels GTL production for a generation or more. " The synthesised fuels he refers to include diesel and jet fuels. Mineral Resources Development Minister Paul Holloway confirmed he has travelled to Chinchilla to inspect first-hand the company's progress in developing its projects in Queensland's Surat Basin. "The next stage of the process is for Linc Energy to consult with relevant government agencies, " Mr Holloway said. "The decision by Linc Energy to develop its first commercial underground coal gasification in South Australia's Walloway Basin is great news for the State's economy. "Linc Energy's investment confirms South Australia's supportive policies can not only lure explorers, but can also ensure the crucial follow- up investment into mine construction, support services and technological development, " he said. Mr Bond said his company has been able to meet government requirements: "A range of mining and exploration licences, government, environmental and regulatory approvals were required to get us to this point and more will be required as we move towards commercialisation especially in areas such as generating power and connection to the transmission system. "We currently have two rigs in the Walloway Basin. One is focused on appraising and defining the coal resource and further assessing the overburden and the second is focussed on drilling piezometer wells to gather baseline hydro-geological information for the UCG team to prepare for the environmental submissions for our first UCG trial operation. " Mr Bond also outlined the projects timetable. A pre-production stage referred to as UCG Generator 5 is targeted to commence operations by the end of 2010, " he said. "This will involve the construction and operation of one UCG gas generator designed to provide us with site- Orroroo throbs with a new energy The South Australian mid-north town of Orroroo is on the verge of boom times as Linc Energy prepares to tap into a major coal seam near the town writes Kevin Naughton. Linc Energy's demonstration plant at Chinchilla in Queensland -- a commercial operation is planned for Orroroo
April-May 2010
August-Sept 2010
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SO I look around.
There's a lil one travelling in the company of her folks. They're a family of 4 - on a scooter and she's in front - standing it out! Head is covered and frilly frock is on. It's still a lil chilly dilli morning.
ooooohhhh - whatttt a a wooonnndderrfffuulll daayyyy... NO SCHOOL.
I'm going to have a lot of fun with my cousins... dat's where we're headed!!
I want to sing (actually started singing)
(traffic moves suddenly - father is jolted out of inertia)
Dad - drive carefully!! (looks up at him)
Can't you see i'm standing here in the cold - while you sit comfortably!!
At least I'm not sandwiched like my brother between you and ma. Yes - i like the fresh air!
Whay can't we buy a car? Look at all those big cars... the people seem to be so comfortable.
I also want that new frock and colorful cap that girl is wearing.... it's so nice!!!
(Traffic starts again - this time it moves for a bit and stops
The music in my vehicle gets louder - disturbs the train of thought.)


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There are total 9 letters in Jacquards, Starting with J and ending with S.
Total 68 words created by multiple letters combination of Jacquards in English Dictionary.
Jacquards is a scrabble word? Yes (28 Points)
Jacquards has worth 28 Scrabble points. Each letter point as below.
Words that starting with Jacquards
Words that containing Jacquards
Words that ending with Jacquards


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Impressart Metal Stamps - Deco Alphabet Stamp Lowercase Set 1.5mm
$ 70.00
Deco Alphabet Set, all lowercase letters in the small 1.5mm size. This size metal stamp is ideal for stamping rings.
There are 26 letters, plus seven punctuation marks included in this set.
SIZE: 1.5mm
This punch set is suitable on softer metals, such as nickel silver, copper, brass, aluminum, and pewter, as well as leather, polymer clay and epoxy clay.


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Channel your inner grasshopper and focus on the improvement of the coordination of the body and mind; valid for all ages and skill levels


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Image by Brian, Creative Commons
No two people have identical time-use issues. Some of us tend to overcommit, others are prone to procrastination, and still others suffer from excessive perfectionism. In each case, the end result may be high stress and long hours as a deadline approaches, but those are just the symptoms. To solve the problem, you need to look at the root cause, and then tailor the solution to your specific issue.
Too often, we think of "getting organized" as a one-approach-fits-all endeavor, which leads people to accumulate calendars, planners, and journals. In a burst of determination, we use them for a short period of time and then set them aside when it turns out that they don't actually help.
So instead of going shopping for the latest planning tool, take the time to identify your biggest time-use issue.
As a first step, I recommend time tracking to gather data on how you are spending your days. However, many people seem to have an aversion to time tracking and never make it past that step. If you're one of those people, you can also start by simply thinking about how you feel about your time. Do you feel overworked but essentially in control? Or is the feeling more of being overwhelmed by the work you need to do? Do you feel like you can't catch up on your to-do list? Or do you have all the necessary balls in the air, but feel worried that you're going to drop a few?
Once you've teased out the type of time-use stress you're feeling, think about how you might solve the problem.
- If you are worried about dropping a ball or two: Maybe you need to make sure that you've truly captured everything you need to do in your planning. Update your to-do lists and calendars. Sketch out when you need to do each task — and in what order — to make sure you keep all those balls in the air. Also ask yourself if you're trying to juggle too many balls at once. Maybe you would benefit from limiting the number of tasks you have under way. Look into the idea of limiting your work in progress, borrowed from the Kanban management process, and give it a try.
- If you are feeling like you can't catch up: Ask yourself why. Are you procrastinating and creating extra deadline stress for yourself? One technique that might help you is the Pomodoro method of working in short sprints. Another technique for procrastinators: Take the work you're avoiding and break it down into small tasks. Keep breaking those tasks into smaller and smaller jobs until you have something that you feel like you can do right now. If you are not procrastinating, are you instead being pulled in too many directions and therefore not making progress on any one thing? Here again, limiting work in progress might be a good technique to try.
- If you are feeling overwhelmed: The most likely problem is an underlying weakness in your planning system. If you use a to-do list, perhaps it needs more structure. Some people get overwhelmed if their list is too long. Instead, try breaking your to-do list into multiple levels. I use a three-part system: (1) a long-term to-do list in Trello that can grow as long as it needs to, in order to capture all of my ideas; (2) a mid-range list on a physical kanban board; and (3) a daily list of specific tasks I intend to complete in any given day. If you're more of a calendar person, you might also try separating levels of planning between different systems. For instance, you could use a physical calendar for sketching out your long-term plans, thereby reserving your electronic calendar for firm deadlines. Or perhaps you can take advantage of the ability of electronic systems like Google calendar to toggle the display of multiple calendars, and put your different layers of planning into different electronic calendars.
- If you're feeling overworked: That may be the most difficult time-management issue to solve, because to solve it, you have to find a way to take a break, despite the long to-do list that drove you to overwork in the first place. If you are feeling overworked, you probably are overworked. Our culture encourages people to work long hours, and it is common for people to routinely work more than a standard 40-hour week. I believe, based on research and on my own experience, that dialing back your work hours to a more reasonable number will actually allow you — in the long run — to get just as much (if not more) done, without the exhaustion. However, getting to that point can be tough. You may have to slog through the long hours a little longer to reach a place where your deadlines allow you a break.
My approach when I find myself feeling overworked — and yes, it still happens to me on occasion, usually caused by my tendency to overcommit — is to take a hard look at my upcoming deadlines. If I can find one that can be delayed without causing large problems, I delay it. Years as a project manager have taught me that it is far better to tell someone that the thing I promised in a month will actually be delivered in six weeks, than to allow the pressure to build and risk a meltdown that leads to missed deadlines without warning.
I also invest a little more time in planning. When I'm worn out, my efficiency suffers, so I rely on my kanban board and my daily to-do list to help keep me focused and making progress. I also use the procrastination-busting techniques I mentioned earlier, even if I'm not truly procrastinating. When I'm already overworked, I can't afford to waste even small amounts of time.
Using those techniques, I clear some space for a real break — ideally, a full weekend. If I can't manage that, then I take as much time off as I can. Back when my children were younger, child-care duties and household chores could make my weekends feel less restful than my weekdays. I usually couldn't get a full day's break from both work and home duties, but I could schedule a half-day off on a weekday. Leaving my kids at daycare, I would slip out to a nearby mall with a good book, have a leisurely lunch, and then find a comfortable spot to spend an hour or two reading. I offer these details merely as an example. The point is: Find a way to take a real break from all of the things on your to-do list, and take it, guilt free. You'll return to work after that break refreshed and much more productive.
Whatever motivated you to try to "get organized," once you've resolved that problem, stop and reflect on why it happened. Does this sort of problem happen often? If so, it is probably the weakest point in how you approach time.
So shore it up. Think about what systems you could put it place to keep the problem from happening again. That could be the technique you just used, or it could be a different approach you identify to head off the problem before it has a chance to recur. Pick one or two things to try to improve, and then consciously practice them until the new system becomes habit.
Unfortunately, you will not then be in time-use nirvana. Instead, you will probably now recognize a new problem, which is the next weakest point in your approach to time. There is no such thing as perfect time-use system. It is a never-ending process, but the rewards are great: less stress, more meaningful work completed, and more time for the other things you enjoy in life. And fewer barely used planners cluttering up your office.


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5/8" X 98" Heavy Duty Kevlar/Aramid Cord Belt
Part #: 12-7643
List Price: $41.18Our Price: $30.99
5/8" X 98" Heavy Duty Kevlar/Aramid Cord Belt
|OEM Replacement This part is aftermarket equipment designed to replace the original manufacturer's part numbers specified here. It is manufactured using high-quality materials, to the same specifications as the original part.
|OEM 5L-980, OEM B095, OEM B95, Gravely 23640, Oregon 75-598


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Our new Remora superfamily boasts 2 variants & 7 weights across 5 widths. Bonus: italics bundled free!» Read More
G-Type is a digital type foundry.
And an established custom font studio.
Featured News
A custom version of our Houschka typeface has been produced for a global solutions provider.» Read More
Three old G-Type favourites have been spruced up and re-released in desktop and web formats.» Read More
G-Type webfonts can now be licensed and downloaded directly from our shop.» Read More


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This is epic - and you only need to let them dry for about five minutes before they are ready to use DIY Glitter-Dipped Cups
Lower ab workouts! Challenge friends by tagging them! #female6packguide
Ab workout! For more fitness advise motivation and exercises, follow my "Sweat is Fat Craying" board.
Try this quick and focused workout to tone the lower part of your abs and work off the pooch. We concentrate on the abs for five minutes and guarantee you feel the burn. You don't need any equipment, but don't forget to breathe! #abworkout #fitness
30 Cute and Different Ear Piercings... Time for some new piercings.
10 Hilarious Things To Do In Public funny jokes story lol funny quote funny quotes funny sayings joke humor stories funny jokes
Tone up in 5 minutes with this quick and efficient ab workout! - Flat Abs in 5!
Flat Abs in 20! – Kayla Itsines. Her program's ridic tough but a totally doable commitment. Love BBG


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BLOOMFIELD, NJ — "The Oval" in Essex County Brookdale Park has been dedicated as the "Tom Fleming Athletic Complex" in honor of the late Tom Fleming, a professional runner, coach and elementary school teacher. A native of Bloomfield, Fleming helped make running a popular sport in the 1970s after he won the New York City Marathon twice and finished second in the Boston Marathon twice.
"Tom was recognized throughout the world as one of the greatest long distance runners from America," said Essex County Executive Joseph DiVincenzo. "But in Essex County, he was a beloved coach and elementary school teacher who unselfishly gave his time to help others on the track or in the classroom. His legacy will be the many lives he touched and people – adult runners, high school athletes and elementary school students – who he inspired."
The complex being named in Fleming's honor includes a state-of-the-art, quarter mile, rubberized running track and a multi-purpose football and soccer field with a synthetic grass surface. The rubber surface was installed on the running track and the synthetic grass surface was installed on the soccer/football field in 2004; both were updated again in 2014. The complex currently hosts the Essex County Special Olympics' Spring Games and area high school athletic competitions, and provides recreational and professional runners and walkers with a place to safely train.
Elected officials from Bloomfield, Glen Ridge and Montclair remembered their most famous resident and commented that the complex dedication was a fitting way to remember Fleming.
"Seldom do we go through life and meet a person like Tom. This dedication will ensure that the children who run here know who Tom Fleming was," Bloomfield Mayor Michael Venezia said.
"Because of all the time he spent here running, training and coaching, Brookdale Park truly became Tom's office. This dedication will ensure his legacy lives on," Glen Ridge Councilman Dan Murphy said.
Fleming's name was placed at the top of the scoreboard. A bronze plaque outlining his career, accomplishments and contributions is located in a raised flower bed at the base of the scoreboard.
The plaque begins with Fleming's famous quote: "Somewhere, someone in the world is training when you are not. When you race him, he will win." It continues: "Most elite runners train twice a day – it was not unusual, however, for local track icon Tom Fleming to train three times – covering 150 miles a week. He began running at Bloomfield High School and then at William Paterson College, becoming a four-time NCAA All-American and Conference Champion. At the height of his career, Fleming won the New York City Marathon twice, in 1973 and 1975. He placed second in the Boston Marathon, in 1973 and 1975, when he achieved a 2:12:05 PR.
"Tom opened one of the first running stores in 1978 where, true to his love of the sport, he would mentor anyone seeking running advice. For the past 18 years, he taught fourth grade and coached boys and girls track at Montclair Kimberly Academy, passionate about passing on his skills, encouraging each student to strive for their personal best. A charismatic storyteller, generous with his time and talent, he taught everyone that the only way to succeed was to work hard."
Fleming died suddenly on Wednesday, April 19 while coaching the Montclair Kimberley Academy's track and field team at a meet in Verona. He had been working at MKA as a fourth-grade teacher and varsity track and field and cross country coach since 2000.
Fleming was born in Long Branch, raised in Bloomfield and attended Bloomfield High School, where he began his career as a competitive runner.


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136 Hawkes Point Drive
Troutman, NC 28166
$799,000 (Active)
Beds: 4
Baths: 5
Sq. Ft.: 3,562
Type: Single Family Home
Listing # 3227833
WATERFRONT living all on one level! This custom built home is situated perfectly on Lake Norman across from Lake Norman State Park giving it lovely views! Your Owner's Suite includes 2 master baths. 2 addl bedrooms with private baths. All lakeside rooms have doors leading out to the covered veranda for easy access to Lake Life. Dock your boat at your private pier, enjoy a swim in your pool or relax in the hot tub. Store all your pool & lake toys in the extended garage underneath the veranda.
Property Features
Location Information
County: Iredell
Subdivision: Hawkes Bay
Interior Features
Master on Main: yes
Rooms: Main Floor Bathroom(s), Bedroom(s), Dining Rm, Foyer, Great Rm, Kitchen, Laundry, Living Rm, Master BR, Office, Pantry, Upper Floor Bonus Rm
Interior: Attic Other, Breakfast Bar, Built-Ins, Cable Available, Garage Shop, Kitchen Island, Open Floorplan, Pantry, Skylight(s), Split BR Plan, Vaulted Ceiling, Walk-In Closet(s), Whirlpool
Has Fireplace: yes
Fireplace Description: Great Room, Wood Burning, Other
Floors: Tile, Carpet
Laundry: 1st Floor, Laundry Room
Water Heater: Electric
Additional Equipment: Cable Prewire, Ceiling Fan(s), Convection Oven, Dishwasher, Disposal, Double Oven, Ice Maker Connection, Microwave, Wall Oven, Warming Drawer
Sq. Ft. Basement: 0
Exterior Features
Stories: 1 Story/F.R.O.G.
Is New Construction: No
Exterior: Boat Lift, Boat Slip, Floating Dock, Hot Tub, In-Ground Irrigation, Outdoor Fireplace, Personal Watercraft Lift, Pier, Pool-In-Ground
Siding: Brick Veneer Full
Foundation: Crawl Space
Water: Well
Parking Description: Attached Garage, Garage - 1 Car, Garage - 2 Car, Garage Door Opener, Keypad Entry
Has Garage: yes
Driveway: Concrete
Has a Pool: yes
Has Golf Course: No
Lot Description: Cul-de-sac Lot, Lake Access, Trees, Views, Waterfront, Water view
Lot Size in Acres: 0.88
Zoning: Residential
Has Waterfront: yes
View Description: Cul-de-sac Lot, Lake Access, Trees, Views, Waterfront, Water view
Elementary School: Troutman
Jr. High School: Troutman
High School: South Iredell
Additional Information
Property Type: SFR
Property SubType: 1 Story/F.R.O.G.
Year Built: 2002
Status: Active
Association Fee: 685
Community Features: Lake
Listing Courtesy of:
Keller Williams Mooresville
Keller Williams Mooresville
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CarolinaMLS data last updated at August 21, 2017 5:13 PM ET
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- Alexander Kain, John-Paul Hosom, Xiaochuan Niu, Jan P. H. van Santen, Melanie Fried-Oken, Janice Staehely
- Speech Communication
- 2007
In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: Abstract Dysarthria is a speech motor disorder usually resulting in a substantive… (More)
Dysarthria is a motor speech disorder that is often associated with irregular phonation (e.g. vocal fry) and amplitude, incoordination of articulators, and restricted movement of articulators, among other problems. The present study is part of a project on voice transformation systems for dysarthria, with the goal of producing intelligibility-enhanced… (More)
Linguistic control factors such as word stress and phrase-finality affect not only duration and pitch, but also spectral structure and spectral dynamics. We propose methods for predicting and synthesizing prosodic effects on spectral balance: (i) A new multi-dimensional measure of spectral balance, in which energy is measured in five " formant frequency… (More)
- Jan P. H. van Santen, Lois M. Black, +5 authors Xiaochuan Niu
- 2003
This paper focuses on generation of expressive speech, specifically speech displaying vocal affect. Generating speech with vocal affect is important for diagnosis, research, and remedia-tion for children with autism and developmental language disorders. However, because vocal affect involves many acoustic factors working together in complex ways, it is… (More)
- Xiaochuan Niu, Jan P. H. van Santen
- 2003
In natural speech, prosodic factors such as accent, stress, phrasal position and speaking style play important roles in controlling several acoustic features, including segmental duration, pitch, and spectral balance, i.e., the amplitude pattern across different frequency ranges of the power spectrum. To synthesize speech that sounds natural, these effects… (More)
- Xiaochuan Niu, Alexander Kain, Jan P. H. van Santen
- 2006
- Xiaochuan NIU, Liqin SHEN, Weibin ZHU, Qin SHI
- 2000
In this paper, a method of pitch contour modelling based on the hidden Markov model (HMM) states of an acoustic unit is presented. A pair of vectors is computed from the alignment of the speech data with the acoustic unit's HMM states. The pitch contour feature of the acoustic unit is represented by the vector pair so that the variants of the acoustic… (More)
- Xiaochuan Niu, Alexander Kain, Jan P. H. van Santen
- 2005
Accurate estimation of velar movements is useful for automatic speech recognition, speech enhancement, and diagnosis of certain speech disorders. This paper reports on initial results of a project on estimation of velar movements, for two-microphone setups where the microphones are differentially positioned to pick up nasal and oral speech output. Toward… (More)
- Xiaochuan Niu, Jan P. H. van Santen
- 2007
Automatic detection of different oral-nasal configurations during speech is useful for understanding normal nasalization and assessing certain speech disorders. We propose an algorithm to extract nasalization features from dual-channel acoustic signals that are acquired by a simple two-microphone setup. The feature is based on a dual-channel acoustic model… (More)


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text:
International Journal of Tourism Research
© John Wiley & Sons Ltd
Edited By: John Fletcher
Impact Factor: 1.857
ISI Journal Citation Reports © Ranking: 2016: 16/45 (HOSPITALITY LEISURE SPORT & TOURISM)
Online ISSN: 1522-1970
Associated Title(s): Progress in Tourism & Hospitality Research
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Fawcett, T. (2006). An introduction to ROC analysis. Pattern Recognition Letters, 27, 861–874. DOI: 10.1016/j.patrec.2005.10.010.
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Daley, C. E., & Nagle, R. J. (1996). Relevance of WISC-III Indicators for assessment of learning disabilities. Journal of Psychoeducational Assessment, 14, 320–333.
Ramus, F., Rosen, S., Dakin, S. C., Day, B. L., Castellote, J. M., White, S., & Frith, U. (2003). Theories of developmental dyslexia: Insights from a multiple case study of dyslexic adults. Brain, 126, 841–865. DOI: 10.1093/brain/awg076
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Rutter, M., Caspi, A., Fergusson, D., Horwood, L. J., Goodman, R., Maughan, B., … Carroll, J. (2004). Sex differences in developmental reading disability: New findings from 4 epidemiological studies. Journal of the American Medical Association, 291, 2007–2012. DOI: 10.1001/jama.291.16.2007
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van Bergen, E., de Jong, P. F., Maassen, B., Krikhaar, E., Plakas, A., & van der Leij, A. (in press). IQ of four-year-olds who go on to develop dyslexia. Journal of Learning Disabilities. DOI: 10.1177/0022219413479673
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Beck, I. (1989). Reading today and tomorrow: Teacher's edition for grades 1 and 2. Austin, TX: Holt.
Bradley, L., & Bryant, P. (1985). Rhyme and reason in reading and spelling. Ann Arbor, MI: University of Michigan Press.
Howell, K. W., Fox, S. L., & Morehead, K. W. (1993). Curriculum–based evaluation: Teaching and decision making (2nd ed.). Pacific Grove, CA: Brooks/Cole.
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Borstrøm, I., & Elbro, C. (1997). Prevention of dyslexia in kindergarten: Effects of phoneme awareness training with children of dyslexic parents. In C. Hulme & M. Snowling (Eds.), Dyslexia: Biology, cognition and intervention (pp. 235–253). London: Whurr.
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Provenzano, D., & Baggio, R. (2017). The contribution of human migration to tourism: The VFR travel between the EU28 member states. International Journal of Tourism Research, 19, 412-420. DOI:10.1002/jtr.2127
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text: Butt buddies! Fluttershy is a VERY SHY character that should be NEVER messed with because then she'll turn into Doahkiin (because fans say so) and rage saying "YOUR GOING TO LOVE ME". Retrieved from "http://callofduty4s.wikia.com/wiki/Fluttershy?oldid=5770" Ad blocker interference detected! Wikia is a free-to-use site that makes money from advertising. We have a modified experience for viewers using ad blockers Wikia is not accessible if you've made further modifications. Remove the custom ad blocker rule(s) and the page will load as expected. Categories: Add category Cancel Save


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Russ Feingold
- Obama-Trump Voters Exist. Here's What They Think.The New York Times
- PSen. Ron Johnson: McCain's Cancer Might Have Caused Health Care 'No' Votephoenixnewtimes.com
- Fake News Isn't Going Anywhere: It's Hugely Profitable—and Right-Wingers Love Italternet.orgNetherlands , France , Hermann Park , Houston , Washington
- 5 Things Americans Love About John McCain That Critics Hateobserver.com
- Five Stories That Show Why People Love John McCainPOLITICOGreece , China , Delaware , New Hampshire , Phoenix
- If You Give A Damn About John McCain, Support What He Stands Forhuffingtonpost.comDelaware , Wall Street , Wisconsin , Georgia , Arizona
- America steals votes from felons. Until it stops, our democracy will be weakenedThe Guardian
- ABaldwin raises $4.7 million, has $3.9 million cash on handapnewsarchive.com
- Trump's next attack on democracy: mass voter suppression | Russ FeingoldThe GuardianMaine , New Hampshire , North Carolina , Oklahoma , Kentucky
- How to Invent the Career You WantForbes
- The surprising GOP holdout on the Senate's health billPOLITICO
- America risks one-party rule if gerrymandering isn't stoppedThe Guardian
- U.S. Supreme Court leaves key campaign finance restriction in placeReuters
- Wisconsin ID law repels many votersThe Toledo BladeMadison , Milwaukee , Cannon Park , Wisconsin
- Donald Trump acts like an illegitimate president for a reasonThe Guardian
- NVeteran Capitol Hill staffer named director of federal relationsnews.uic.edu
- Former Sen. Feingold launches new advocacy groupsanluisobispo.com
- If Gorsuch is confirmed, the legitimacy of the US supreme court won't recoverThe Guardian
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El Espejo, Volume 3, 2013 Page: 25
This periodical is part of the collection entitled: General Collection and was provided to Digital Library by the UNT College of Arts and Sciences.
Extracted Text
The following text was automatically extracted from the image on this page using optical character recognition software:
El Espejo Literario
Aguilar, Candida
Cervantes, Rafael
Derms, Brittney
Garrido, Jair
G6mez-Divalos, Ricardo
Heleodoro Nfiez, Juan
Hidalgo, Luis
Richardson-Davis Shantelle
Sanchez, Antonio S.
"Pensar y sentir"
"Quisiera que el amor por
Mexico y su oficio fuera lo mismo"
"En silencio"
"El Inmigrante"
"Ella", "Miedo"
"La burla del mundo"
"Espero que"
"Amor extranjero"
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Reference the current page of this Periodical.
University of North Texas. El Espejo, Volume 3, 2013, periodical, January 2013; Denton, Texas. (digital.library.unt.edu/ark:/67531/metadc146583/m1/28/: accessed August 16, 2017), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT College of Arts and Sciences.


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You probably know Bono as the lead singer of U2. You might even know he attended Mount Temple Comprehensive School where he met his future wife, Alison Stewart, and the future members of U2. You might also have known he co-founded the charities DATA, EDUN, the ONE Campaign and Product Red, nominated for the Nobel Peace Prize, was granted a knighthood by Queen Elizabeth II of the United Kingdom. You probably knew that, with Bill and Melinda Gates, he was named Time Person of the Year in 2005, and made a Commandeur of the French Ordre des Arts et des Lettres (Order of Arts and Letters).
But what you didn't know is that Bono also does a mean Bill Clinton impression.


text:
|Reviews for My Little Brother
| Koganei Kaoru chapter 2 . 7/23/2005
I love the last three lines of the story! It just suddenly stops! Hehee...I would love to be Kaoru and Tokiya's brother that would be so fun! Me and Kaoru are like twins! Same everything! Well, I'll stop rambling about my major Koganei Kaoru obsession! Excellent job!
| Koganei Kaoru chapter 1 . 7/23/2005
The first Chapter was great! I was literally rolling on the floor! You discribe Kaoru so well! I can't wait to read the next chapter!
| Rayestar Ikina chapter 2 . 4/5/2004
You gonna finish? *sniff* Me likes Kaoru getting along with Tokiya, do you? Continue please! Or at least start another story with both of them, please?
| Whispering Hope chapter 2 . 8/27/2003
This is the first fanfic with a Koganei and Mikagami "brother" relationship! Thank you for writing it! *starts to cry* It was the only one I found so far...
| loneranger chapter 1 . 5/9/2003
Good one... I don't like it... I LOVE it ! Who would have thought? ... Mi-chan & Kogane...
| Hume chapter 2 . 4/27/2003
Nice... but Miichan and Koganei? OK, that's good. But what I'm thinking of is like... Koganei with his rivals. Like Joker and Tsukishiro. Yeah, I know it's cheesy *grin grin*. But it's not all that bad _;;.


text:
The Decline of the Qing Dynasty 19 th century. Chapter 22.1. Causes of Decline. Internal. External. Land used to grow opium. British Opium Trade. Peasant Unrest, corruption . high population, Food Shortages . The Decline of the Qing Dynasty. The Opium Wars. Tai Ping Rebellion.
Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.
Chapter 22.1
Land used to grow opium
British Opium Trade
Peasant Unrest, corruption
high population,
Food ShortagesThe Decline of the Qing Dynasty
The Opium Wars
Tai Ping Rebellion
Growing Influence of Imperialists
Opposition of conservatives to One Hundred Days of Rebellion
War with Japan
Boxer Rebellion
drug – Opium.
asked England to quit based
on morale issues –
but Britain refused
1850 – 1864 rights and use of ports but do not have administrative control. By the end of the 19
The economic problems within China leads to a Peasant revolt
Hong Xiuquan leads the revolt
Hong believes God gave him the mission to destroy Qing dynasty
Hong captures town Yongan and proclaims a new dynastyThe Tai Ping Rebellion
launches massive reforms


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