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GLP-1 receptor stimulation preserves primary cortical
and dopaminergic neurons in cellular and rodent
models of stroke and Parkinsonism
Yazhou Lia, TracyAnn Perrya, Mark S. Kindyb,c, Brandon K. Harveyd, David Tweediea, Harold W. Hollowaya,
Kathleen Powersd, Hui Shend, Josephine M. Egane, Kumar Sambamurtib, Arnold Brossif, Debomoy K. Lahirig,
Mark P. Mattsona, Barry J. Hofferh, Yun Wangd, and Nigel H. Greiga,1
aLaboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224;bDepartment of Neuroscience, Medical
University of South Carolina, Charleston, SC 29425;cNeurological Testing Services, Mount Pleasant, SC 29466;dMolecular Neuropsychiatry Branch, Intramural
Research Program, National Institute on Drug Abuse, Baltimore, MD 21224;eLaboratory of Clinical Investigation, Intramural Research Program, National
Institute on Aging, Baltimore, MD 21224;fSchool of Pharmacy, University of North Carolina, Chapel Hill, NC 27599;gDepartment of Psychiatry, Indiana
University School of Medicine, Indianapolis, IN 46202; andhCellular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse,
Baltimore, MD 21224
Edited by Richard D. Palmiter, University of Washington School of Medicine, Seattle, WA, and approved December 5, 2008 (received for review
July 24, 2008)
Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic
intake. It enhances pancreatic islet ?-cell proliferation and glucose-
dependent insulin secretion, and lowers blood glucose and food
intake in patients with type 2 diabetes mellitus (T2DM). A long-
acting GLP-1 receptor (GLP-1R) agonist, exendin-4 (Ex-4), is the first
of this new class of antihyperglycemia drugs approved to treat
T2DM. GLP-1Rs are coupled to the cAMP second messenger path-
way and, along with pancreatic cells, are expressed within the
nervous system of rodents and humans, where receptor activation
elicits neurotrophic actions. We detected GLP-1R mRNA expression
in both cultured embryonic primary cerebral cortical and ventral
mesencephalic (dopaminergic) neurons. These cells are vulnerable
to hypoxia- and 6-hydroxydopamine–induced cell death, respec-
tively. We found that GLP-1 and Ex-4 conferred protection in these
cells, but not in cells from Glp1r knockout (-/-) mice. Administration
of Ex-4 reduced brain damage and improved functional outcome in
a transient middle cerebral artery occlusion stroke model. Ex-4
treatment also protected dopaminergic neurons against degener-
ation, preserved dopamine levels, and improved motor function in
the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse
model of Parkinson's disease (PD). Our findings demonstrate that
Ex-4 can protect neurons against metabolic and oxidative insults,
and they provide preclinical support for the therapeutic potential
for Ex-4 in the treatment of stroke and PD.
diabetes ? exendin-4 ? neurodegeneration ? neuroprotection ? stroke
adult population now affected (1). Although T2DM now occurs
more often in the young, the incidence rises dramatically with
age, along with that of many of other conditions, including acute
and chronic neurologic disorders, exemplified by stroke (2),
Parkinson's disease (PD) and Alzheimer's disease (AD) (3,4),
which, like T2DM, were once considered relatively infrequent.
Indeed, the incidence of stroke, PD, AD, and several other
suggesting that shared mechanisms, such as insulin dysregula-
tion, may underlie these conditions (5). Although associated
with different cell types in divergent areas (e.g., cortical and
striatal neurons in stroke, substantia nigral and midbrain dopa-
minergic neurons in PD, pancreatic ?-cells in T2DM), parallel
biochemical cascades are triggered by specific environmental
and genetic signals and lead to the cellular dysfunction and death
characteristic of all of these disorders. Consequently, it is
possible that an effective treatment strategy for one such disor-
der may prove beneficial in others as well.
ype 2 diabetes mellitus (T2DM) is emerging as one of the
largest health issues worldwide; with some 6% of the world's
The glucagon-like peptide-1 receptor (GLP-1R) agonist, ex-
endin-4 (Ex-4), is a long-acting analog of the endogenous
insulinotropic peptide GLP-1 (supporting information (SI) Fig.
S1). GLP-1 is derived from the posttranslational modification of
in response to food ingestion (6,7). GLP-1 and Ex-4 have potent
effects on glucose-dependent insulin secretion and insulin gene
expression through binding and activation of the G protein–
coupled GLP-1R on pancreatic ?-cells. Both peptides also have
trophic properties, inducing pancreatic ?-cell proliferation and
inhibiting apoptosis (7,8). Ex-4 has been approved for the
treatment of T2DM, in which it has been found to effectively
lower plasma glucose levels.
GLP-1R mRNA occurs widely throughout the brains of
rodents (9) and humans (6,7,10), and both GLP-1 and Ex-4 can
readily enter the brain (11) to modify feeding and satiety (12).
We have previously reported that the activation of GLP-1R by
GLP-1 and Ex-4 is neurotrophic, inducing neurite outgrowth in
PC12 cells and protecting neurons against various insults (6,13–
15) through a cascade involving the second messenger, cAMP
(13). In light of these neurotrophic actions, the long-term
efficacy of Ex-4 in treating T2DM (7), and the elevated risk of
cerebrovascular disease and PD in T2DM (1–3,5), we evaluated
GLP-1R stimulation in well-characterized cellular and animal
GLP-1R Is Expressed and Functional in Cultured Embryonic Primary
Neurons. To establish the presence of GLP-1R in primary neurons,
cultured rat embryonic cerebral cortical (CC) and ventral mesen-
cephalic (VM) cells were probed for the presence of GLP-1R
mRNA by RT-PCR. Both neuron types were found to contain
GLP-1R mRNA (Fig. 1A). Incubation of cortical neurons with the
natural agonist GLP-1 (10 nM) led to a rapid, transient elevation
of intracellular cAMP level. This level peaked within 15 min and
then returned toward baseline by 30 min (Fig. 1B), demonstrating
Author contributions: Y.L., T.P., M.S.K., B.K.H., D.T., H.W.H., K.P., H.S., D.L., and Y.W.
data; T.P., J.E., K.S., M.P.M., B.H., Y.W., and N.H.G. designed research; K.S. and A.B.
contributed new reagents/analytic tools; and M.P.M., B.H., and N.H.G. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1To whom correspondence should be addressed. E-mail: firstname.lastname@example.com.
This article contains supporting information online at www.pnas.org/cgi/content/full/
© 2009 by The National Academy of Sciences of the USA
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protein levels, along with increased intracellular cAMP levels, in
response to Ex-4 (not shown).
GLP-1R Stimulation Decreased Hypoxia- and Dopaminergic Toxin–
are vulnerable to hypoxia, resulting in a loss of viability, as
assessed by a significant elevation in lactate dehydrogenase
(LDH) level (Fig. 1C) and a decline in (3-(4,5-dimethylthiazol-
tetrazolium, inner salt) (MTS) level (not shown) compared with
cells subjected to normoxia. Incubation with a GLP-1R agonist,
GLP-1 or Ex-4 (0.01–1 ?M), afforded significant protection
against hypoxia, lowering elevated LDH levels by as much as
76%. This effect was lost in the presence of the GLP-1R
antagonist Ex-9–39, indicating that the action was mediated
through GLP-1R. To confirm this, CC neurons from Glp1r?/?
mice were similarly cultured and exposed to hypoxia/normoxia
in the presence and absence of Ex-4 and the GLP-1R antagonist.
Glp1r?/?primary CC neurons were similarly vulnerable to
hypoxia but were not protected by Ex-4 (Fig. 1D).
The viability of mesencephalic cell cultures, known to be rich
in dopaminergic neurons, was determined by quantifying ty-
the dopaminergic toxin 6-hydroxydopamine (6-OHDA). As ex-
pected, 6-OHDA decreased TH(IR) significantly, by 30% (Fig.
2A). GLP-1 and Ex-4 (0.1 ?M) fully preserved TH(IR) from
6-OHDA toxicity, and, moreover, Ex-4 elevated TH(IR) in the
absence of 6-OHDA by an additional 60%. No significant
difference in the number of DAPI-positive nuclei was found
among the treatment groups (not shown). To elucidate the
universality of these protective effects, parallel studies were
performed in SH-SY5Y cells (Fig. 2B–D). Predictably, exposure
to 6-OHDA significantly reduced cell viability (Fig. 2B), with
elevations in caspase-3 activity and Bax and declines in Bcl-2
found by Western blot analysis (Fig. 2C and D). GLP-1 and Ex-4
resulted in elevated Bcl-2 and negligible caspase-3 and Bax
levels. To define the molecular pathways responsible for the
GLP-1R–mediated protection, specific inhibitors of PKA (H89;
10 ?M) and PI3K (LY294002; 10 ?M) were investigated; these
resulted in a loss of protection (Fig. 2D).
Ex-4 Treatment Reduces Infarction Size and Improves Functional
Outcome in Stroke.Todefinethetranslationalpotentialofourcell
culture studies, the protective effect of Ex-4 was evaluated in a
Fig. 1.
cell cultures. The expected RT-PCR product size is 190 bp. GAPDH was used as
an external control and showed equal expression across lanes. Lane 1, nega-
tive control; lane 2, positive control: RNA from CHO-GLP-1R cells (CHO cells
stably transfected with rat GLP-1R); lanes 3 and 4, RNA from primary CC and
VM neurons, respectively. (B) GLP-1–stimulated release of cAMP from CC
neurons. Time-dependent cAMP levels were assayed after incubation with 10
nM GLP-1 (n ? 3). (C) Pretreatment with GLP-1/Ex-4 protects CC neurons from
hypoxia-induced loss of cell viability, as indicated by elevated levels of se-
creted LDH. Compared with normoxia (21% O2, 5% CO2), a 3-h exposure to
hypoxia (1% O2, 5% CO2) induced a significant elevation in LDH (P ? .05),
defined as a 100% response. GLP-1 and Ex-4 (0.01–1.0 ?M) protected cells,
ameliorating the hypoxia-induced elevation in LDH by up to 76%. This effect
was abolished by the GLP-1R antagonist Ex-9–39. n ? 5 for each treatment,
(D) CC neurons from Glp1?/?mice are vulnerable to hypoxia, as assessed by
.05 vs. hypoxia; 1-way ANOVA plus posthoc Dunnett's test, n ? 5).
(A) One-step RT-PCR shows rat GLP-1R mRNA expression in neuronal
Fig. 2.
neurons from 6-OHDA treatment and likewise protects SH-SY5Y cells from
6-OHDA–induced cell death. (A) TH(IR) of primary VM cells pretreated with
TH(IR) was significantly different versus PBS-treated controls (P ? .05; Dun-
with vehicle (Veh), GLP-1, or Ex-4 (0.1 u?M) for 2 h and then subjected to
6-OHDA (30 ?M) for 24 h. Subsequently, cell survival was quantified by MTS
assay. Whereas 6-OHDA reduced cell survival to 83% (*P ? .05 vs. control),
GLP-1 and Ex-4 protected against this 6-OHDA loss of cell viability (*P ? .05 vs.
markers of apoptosis were elevated by 6-OHDA (30 ?M) and lowered by Ex-4
inhibitors of PKA (H89; 10 ?M) or PI3K (LY294002; 10 ?M) and was retained
with insulin (0.01 ?M; positive control) (*P ? .05, Dunnett's t-test, n ? 5 vs.
vehicle plus 6-OHDA).
Pretreatment with GLP-1 or Ex-4 protects TH(IR) of VM primary
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well-characterized rodent model of stroke, middle cerebral
artery occlusion (MCAo), which mimics the most common type
of human stroke. A 1-h transient occlusion produced a well-
demarked area of infarction that, as assessed by triphenyltetra-
zolium chloride (TTC) staining at 48 h, spanned the right
frontal, parietal, and occipital cerebral cortices (Fig. 3A). The
infarct volume, assessed by measuring the number of 2-mm-thick
brain slices affected and the infarct area, was reduced by ? 50%
in Ex-4–pretreated rats compared with controls. Ex-4 signifi-
cantly reduced each measured parameter of infarction size (Fig.
3B–D) and was accompanied by improved functional outcome,
as assessed by locomotor activity measures at 2 days (Fig. 3E).
Because changes in body temperature, blood pressure, and
arterial blood gases may affect the outcome of stroke, these
parameters were measured in Ex-4–treated and control rats both
before and after treatment (Table S1); no significant changes
were found. Likewise, cerebral blood flow remained unchanged
before, during, and after Ex-4 administration (Fig. S2). Ex-4's
lack of effects on these parameters suggests that its beneficial
effects in stroke are due primarily to its central actions. To
confirm that these actions are mediated through GLP-1R,
parallel studies were performed in wild-type (WT) and Glp1r?/?
mice. Ex-4 was found to afford protection in the WT mice, but
not in the Glp1r?/?mice (Figs. 3F and S3).
Ex-4 Treatment Preserves Dopaminergic Cells in a MPTP-Induced PD
Model. The neuroprotective actions of Ex-4 were quantified in a
well-characterized model of PD. Exposure to 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP) induces a PD-like syndrome
in humans, monkeys, and mice. In the brain, MPTP is converted
to MPP?, which is selectively transported into dopaminergic
neuron axon terminals, causing oxidative stress, mitochondrial
dysfunction, and cell death (16). Analyses of dopaminergic
markers in mice given MPTP demonstrated a cell loss that
culminated in motor function impairment. Ex-4 afforded com-
plete protection against dopaminergic neuron damage and mo-
tor impairment. Specifically, compared with controls, MPTP
significantly reduced the number of TH-immunopositive (?)
neurons within the substantia nigra (SN) by 63%, as assessed by
immunohistochemistry (Fig. 4A and B), and depleted TH(?)
intensity by 71%, as assessed by immunoblotting (Fig. 4C). In
parallel, levels of dopamine (DA) and metabolites [dihydroxy-
reduced dramatically, and the ratio of metabolites to DA con-
centration was elevated, consequent to MPTP (Fig. 4D). In
contrast, mice given Ex-4 before MPTP showed no differences
from controls in terms of the number and intensity of SN TH(?)
At 48 h after ischemia/reperfusion, rats were killed, the brain was sliced into
2-mm sections, and stained with TTC. Marked infarction (white areas) within
the right cerebral cortex was found. The size of infarction was significantly
decreased in animals treated with Ex-4, compared to vehicle (n ? 10/group),
with regard to (B) the volume of infarction ? [sum of the infarction area in all
brain slices (mm2)] ? [slice thickness, 2 mm], (C) the area of the largest
48 h after ischemia/reperfusion in an activity chamber. Vertical activity
(VACTV) and vertical movement time (VTIME) were determined from the
number of beam interruptions that occurred in vertical sensors and the time
(s) spent in vertical movement during a 30-min test, respectively. (F) Likewise,
Ex-4 (1 ?M ? 5 ?L left lateral ventricle) decreased infarct volume in the WT
mice but was ineffective in the Glp1r?/?mice (WT control, n ? 6; WT Ex4, n ?
and Student's t-test.
Fig. 4.
were protected from MPTP-induced damage of the dopaminergic system,
quantitatively assessed by TH immunohistochemical analysis of the SN and TH
immunoblot analyses of the striatum at 7 days. (A) Representative SN sections
from control, and MPTP-treated mice with and without Ex-4. (B) Compared
with controls, TH(?) cells in SN were reduced by MPTP (*P ? .05). Those from
mice given Ex-4 and MPTP were no different from controls (P ? .05). (C)
Similarly, as assessed by immunoblotting in striatum, TH levels were signifi-
cantly reduced by MPTP (*P ? .05 vs. controls) and no different from controls
given Ex-4 were protected from MPTP-induced depletion of brain DA and
metabolites (DOPAC and HVA). DA, DOPAC, and HVA from striatum were
quantified by HPLC at 7 days in mice treated with PBS, MPTP, and MPTP plus
Ex-4. Levels of each were reduced by MPTP (P ? .05 vs. PBS) and preserved by
Ex-4 (P ? .05 vs. PBS; P ? .05 vs. MPTP) compared with controls (Dunnett's
t-test, n ? 10). The ratios of DOPAC:DA and HVA:DA were 0.08 and 0.065 in
Ex-4–treated mice.
Mice given Ex-4 (20 nM, 0.25 ?L/h in the lateral ventricle over 7 days)
Li et al.
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neurons, as assessed by immunoblotting, and DA and metabolite
levels and ratios. Motor function was quantified by several
paradigms over multiple days, including mean score of behavior,
rotarod, pole test (Fig. 5), beam walk, and open-field activity
(Fig. S4); performance in all animals was significantly impaired
by MPTP. In contrast, motor function was fully preserved after
Ex-4 treatment and for all paradigms was similar to that of
controls not treated with MPTP.
The risk of both stroke and PD is elevated in persons with T2DM
(17,18), even in newly treated patients, in whom the short-term
risk of stroke is doubled (17). Clearly, an effective neuropro-
tective strategy would be valuable for this vulnerable patient
group, as well as for the general population, given the lack of
effective treatments for stroke and PD. Increasing evidence
suggests that cortical and dopaminergic neurons die through
apoptosis after a stroke and through a related form of pro-
grammed cell death during PD (19). Evidence for classic apo-
ptosis in both conditions includes elevated levels of the apoptotic
ptotic genes and proteins (19,21,22), as was evident in our cell
culture studies. Analogous elevations in markers of apoptosis
have been described in pancreatic ?-cells during T2DM (7,23),
one of many commonalities shared by these degenerative con-
ditions. The ability to initiate a degenerative process in different
cell types by widely varying insults suggests the existence of a
common cell death network that can be entered from different
points but, once activated, follows similar interrelated biochem-
ical pathways, with little dependence on the site of entry (22). In
such a system, a strategy that effectively halts the death network
process in one disease, such as T2DM, may hold promise for
another, particularly when the molecular machineries underpin-
ning this action share commonalities.
The incretin, GLP-1, and long-acting Ex-4 induce numerous
biological actions in the pancreas, including stimulation of
glucose-dependent insulin secretion, elevated insulin synthesis,
decreased glucagon levels, and, notably, ?-cell proliferation and
inhibition of ?-cell apoptosis (7,8). These and other actions are
mediated through the G protein-coupled GLP-1R, and Ex-4 has
demonstrated therapeutic value in T2DM (7). GLP-1R is a
member of the class B family of 7-transmembrane-spanning,
heterotrimeric G protein-coupled receptors. In humans and
rodents, a single structurally identical GLP-1R has been iden-
tified that is expressed in a wide range of tissues, including the
brain. GLP-1–immunoreactive fibers and GLP-1Rs are widely
expressed throughout the brain (6,9,10). Ligand activation of the
G? subunit of GLP-1R on pancreatic ?-cells leads to activation
of adenylate cyclase activity and production of cAMP, the
primary mediator of GLP-1R activation (7).
GLP-1Rs are present in rodent cultured CC and VM primary
cells. Adding GLP-1 to primary neurons induced a time-dependent
elevation in cAMP, indicative of a functional receptor. cAMP-
mediated pathways are central to the antiapoptotic actions of
GLP-1 in ?-cells (6–8), and the neuroprotective effects of cAMP-
elevating agents are seen in many neuronal cells, including sensory
(24), dopaminergic (25), septal cholinergic (26), cerebellar granule
(27,28), and spinal cord motor neurons (29).
Our previous studies have established that a 50% GLP-1R
occupancy in primary neurons is achieved by 14 nM GLP-1 (14), a
value similar to that for ?-cells. Here we show that administration
of GLP-1 and Ex-4 to primary CC and VM neurons or SH-SY5Y
cells proved to be neuroprotective against insults that modeled
stroke and PD. Specifically, these cells were vulnerable to hypoxia
and a dopaminergic toxin, as assessed by classic markers of cell
viability and the presence of cell death markers. GLP-1 and Ex-4
concentrations as low as 10 nM conferred protection against
hypoxia. This effect was lost in the presence of the GLP-1R
antagonist Ex-9–39 and was absent in Glp1r?/?neurons, indicating
that it is GLP-1R–mediated. Interestingly, not only were VM
neurons fully protected from 6-OHDA–induced toxicity by GLP-1
and Ex-4 (100 nM), but also Ex-4 substantially elevated TH(IR)
beyond that of untreated controls (Fig. 2A), indicating both neu-
rotrophic and neuroprotective activity. TH also is expressed in
catecholamine neurons in the area postrema, and Ex-4 has been
shown to significantly elevate TH levels in these neurons by
contains a cAMP-responsive element (31), representing a further
modulatory mechanism that may account in part for the Ex-4–
induced rise in TH(IR).
These neurotrophic/protective actions are in accordance with
previous findings establishing that GLP-1R stimulation protects
hippocampal neurons from amyloid-? peptide–, Fe2?-, and
glutamate-induced toxicity (15,32,33). The pathways that under-
pin the antiapoptotic actions of many endogenous neuroprotec-
tive agents commonly converge on activation of the transcription
factor cAMP response element–binding protein by phosphory-
lation. Those mediating GLP-1's antiapoptotic actions in neu-
rons remain to be fully elucidated. Previous work has demon-
strated a clear involvement of PKA; neuroprotection by GLP-1
was abolished by Rp-cAMP, which blocks cAMP activation of
PKA (13). PI3K and MAPK are other important signaling
pathways involved in GLP-1–mediated events. A selective inhib-
itor of the former (LY294002), but not of the latter (PD98059),
has been reported to inhibit GLP-1–mediated protective effects
in neuronal cells (13). In the present study, each of these
pathways appeared to contribute to the protection afforded by
Ex-4 and GLP-1 to SH-SY5Y cells (Fig. 2D). Potential GLP-1
actions mediated through MAPK-independent signaling and
growth factor–dependent Ser/Thr kinase AktPKB have been
reviewed recently (31–33).
Administration of Ex-4 (10 ?g s.c) achieved plasma levels of
200 pg/mL (48 nM) in humans (34), which compare favorably to
the doses studied here. To evaluate the translational relevance
of the aformentioned cellular effects, the actions of centrally
administered Ex-4 were assessed in classical rodent models of
stroke and PD. Whereas Ex-4 and GLP-1 readily enter the brain
Fig. 5.
has behavioral consequences. (A) Rotarod: The ability of mice to remain on a
rotating rod at 7 days was reduced (67%; P ? .05 vs. PBS) by MPTP and
preserved by Ex-4 (P ? .05 vs. PBS; P ? .05 vs. MPTP). (B) Pole test: Assessed on
2 consecutive days, initially 3 h after MPTP. The time taken for mice to turn
around (T-Turn) and descend a pole (T-Total) was slower in the MPTP-treated
mice (P ? .05 vs. PBS and Ex-4 plus MPTP) and no different from PBS controls
(P ? .05) in the MPTP plus Ex-4 mice. (C) Mean score of behavior: A composite
of tests were rated daily. Whereas the MPTP plus Ex-4 mice were no different
than the PBS controls, the MPTP mice could be differentiated on and after 7
days (*P ? .05 vs. PBS, Dunnett's t-test, n ? 10/group).
Ex-4 protection of MPTP-induced toxicity of dopaminergic neurons
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after systemic administration (11), and Ex-4 given by this route
has proven effective in alleviating peripheral neuropathy in
rodents (35), direct administration into the brain allowed dif-
ferentiation of centrally mediated GLP-1R actions from numer-
ous systemic ones. Ischemic brain injury activates apoptotic
cascades within the ischemic core and penumbra that peak on
day 2 after MCAo. p53 mRNA and protein are up-regulated
shortly after stroke, leading to p53-dependent programmed cell
death in penumbra (36). Administration of Ex-4 substantially
decreased infarct size, as assessed by 3 related measures of TTC
staining at 48 h in rats (Fig. 3A and B). The reduced stroke
volume (?50%) was similar to that achieved by inhibition of
p53-dependent apoptosis (37), suggesting protection from apo-
ptotic rather than necrotic cell death and translating to signifi-
cant improvements in measures of motor activity. Blood flow, as
well as a wide number of physiological parameters (Table S1)
that can influence ischemic damage, remained unchanged by
Ex-4 administration, supporting a direct central GLP-1R–
mediated effect. Parallel studies in WT mice confirm that the
neuroprotective actions of Ex-4 in MCAo translate across spe-
cies, and the loss of this action in Glp1r?/?mice reaffirm that
neuroprotection is mediated through GLP-1Rs.
Administration of MPTP in mice induces a consistent dopami-
nergic cell loss that parallels many aspects of PD (16,20). In the
present study, the mice receiving MPTP demonstrated classic
reductions in both the number of TH-immunoreactive cells, a
marker of dopaminergic cells in the SN (63% loss), and of TH
intensity in immunoblot analyses of striatum (71% loss). These
animals demonstrated motor function deficits. General behavioral
assessment, combining multiple paradigms, detected differences
between the MPTP and control animals starting at 7 days after
MPTP administration and increasing with time. Specific tests of
motor function (i.e., pole test, beam traverse, open-field activity,
and rotarod) confirmed MPTP-induced impairment. To correlate
reductions in dopaminergic cells with motor function losses, con-
a 75% drop in HVA level, was evident, in line with the results of
previous MPTP studies (20). These declines resulted in a 2- to
4D). Ex-4 provided complete protection, as assessed by quantifi-
cation of TH(?) cell number, TH immunoblot analysis results, DA
and metabolite levels and ratios, and all behavioral paradigms
studied. Overall, the MPTP mice treated with Ex-4 were indistin-
guishable from controls.
Our findings indicate that the neuroprotective actions of
GLP-1R agonists appear to effectively translate across a number
of classic cellular and animal models, including stroke and PD,
as well as cholinergic ablation (14), kainic acid–induced CA3
hippocampal loss (38), and peripheral neuropathy (35). In
contrast, the Glp1r?/?mice demonstrated impaired learning, as
well as increased brain injury and associated behaviors after a
lesion (32). Together, the findings of these studies suggest a loss
of function in -/- mice and a physiological role for GLP-1R
activation in the normal brain, as in the pancreas, that can be
augmented by pharmacologic concentrations of agonists and
inhibited by antagonists. Recent studies have demonstrated that
Ex-4 can induce neurogenesis of neural stem cells both in culture
(38,39) and promote differentiation toward a neuronal pheno-
type (38), as has been reported for PC12 cells (13). Ex-4's ability
to improve dopaminergic markers and function when adminis-
tered a week or more after 6-OHDA– or cytokine-induced
apoptosis, rather than at the time of insult as in our study, is
indicative of neuroregenerative action (38,39).
In synopsis, the role of GLP-1R stimulation in balancing cell
survival versus death in pancreatic cells is well established (7)
and, together with the insulinotropic actions of Ex-4, supports its
clinical utility in T2DM. Likewise, the parallel GLP-1R–
mediated trophic and protective actions of Ex-4 in neurons may
be of clinical utility in acute and chronic neurologic disorders,
epitomized by stroke and PD. Not only are persons with T2DM
at increased risk for stroke and PD, but also several studies have
reported a high prevalence of insulin resistance in PD, vascular
dementia, and other neurodegenerative conditions (2,4,17), with
impaired glucose tolerance seen in 50%–80% of subjects (4,40).
Dopaminergic neurons and insulin receptors are both densely
localized within the SN, and dopaminergic agents used in PD
(e.g, L-DOPA) have been reported to induce hyperglycemia
(40). Together, these findings suggest that GLP-1R agonists may
exert various useful actions in persons at high risk for stroke or
with PD, a hypothesis that is amenable to clinical testing.
Materials and Methods
cells were probed for GLP-1R mRNA and stimulated with GLP-1 (10 nM) to
assess the presence and functionality of GLP-1R. CC cultures were challenged
with transient hypoxia (1% O2, 5% CO2, 37 °C, 3 h) followed by normoxia
(21%O2, 5% CO2, 37 °C, 48 h). VM cultures were exposed to 6-OHDA (30 ?M,
90 min), in the presence and absence of GLP-1 and Ex-4 (10 nM–1.0 ?M), and
studies by MTS (Promega) or LDH (Sigma) assays and in 6-OHDA studies by TH
Some studies used primary neurons from Glp1r?/?mice, and others used
assessed by Western blot analysis as described previously (20,41,42).
Animal Studies. Stroke (MCAo) Model. At 15 min after left lateral ventricle
administration of Ex-4 (1 ?M ? 20 ?L; 83 ng) or vehicle (PBS), adult male
monitored before, during, and after MCAo. Motor function, assessed in a loco-
at 48 h (SI Materials and Methods). Likewise, transient (90 min) MCAo was
performed in adult male WT and Glp1r?/?ICR mice 15 min after left lateral
size determined at 48 h (SI Materials and Methods).
PD (MPTP) Model. At 2 h after left lateral ventricle administration of Ex-4 (20
given the dopaminergic toxin MPTP (20 mg/kg in 0.1 mL of PBS i.p. at 2-h
throughout the SN were processed for immunostaining using TH antibody
(T-1299; Sigma), and TH(?) cells were quantified by image analysis. Levels of
DA, DOPAC, and HVA were measured by HPLC from striatum, and TH immu-
noblotting was performed using a TH (phospho S40) antibody (AbCam) (20).
behaviors, rotarod, pole test, beam walk, and open-field activity as described
previously (44,45) (SI Materials and Methods).
Statistics Dunnett's t-test and 1-way ANOVA with Student-Newman-Keul
(SNK) posthoc analysis were used for statistical comparison, with P ? .05
considered statistically significant. Data are presented as mean ? SEM.
ACKNOWLEDGMENTS. This work was supported in part by the Intramural
Research Programs of the National Institute on Aging and the National
Institute on Drug Abuse. Animal studies were performed in accordance with
approved protocols, in compliance with the National Institutes of Health's
Guidelines for Animal Experimentation. Daniel J. Drucker, MD, University of
Toronto, kindly provided the Glp1r?/?mice.
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Paper Plus has all your stationery needs, ranging from pencils, pens and 1B5's to printers, ink cartridges, office furniture and everything in between. Whether you are a student getting ready for your school year or a business with larger requirements, we have you covered.
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Press Releases – Ford
Press Release #195: New BDS Steering Stabilizer Kits for Super Duty
BDS Suspension is now offering redesigned single and dual steering stabilizer kits for the 1999-2004 Ford Super Duty trucks.
Press Release #194: Full Line of 2015 Ford F150 Lift Kits Now Shipping!
BDS now offers 6″ performance coilover systems designed to offer exceptional control and performance offroad with smooth, predictable handling on the highway.
Press Release #192: 2014 Ford F150 Raptor 4″ Lift Kit
4″ High Clearance Lift Systems for the 2014 Ford F150 Raptor trucks. Designed to take full advantage of the Raptor's front Fox triple internal bypass coilovers and rear 2.5″ piggyback reservoir shocks.
Press Release #190: BDS 6″ and 8″ Suspension Lifts for 2004-2008 Ford F150 4WD Trucks
6″ and 8″ replacement strut systems for the 2004-2008 Ford F150 4WD designed for smooth on road comfort and improved offroad performance with room for up to 37″ tires.
Press Release #181: 2015 Ford F150 Lift Kits Now Shipping!
BDS Suspension has been hard at work developing new products and is proud to announce now shipping FIRST TO MARKET 2.5" leveling kits and 6" suspension systems for the new aluminum-body 2015 Ford F150 4WD trucks.
Press Release #177: BDS Dual Steering Stabilizer Kit for '05-15 Ford Super Duty
New Product Release BDS177 Part# #55358 (dual mount kit) #98224019 (Fox 2.0 stabilizer ea.) Product Dual Steering Stabilizer Kit Application 2005-15 Ford F250 4wd 2005-15 Ford F350 4wd Support Files & Links View Dual Mount Kit Online Ford Dual Fox Stabilizer Kit Hi–res image: acc_55358_fox_d.jpg Ford Dual Fox Stabilizer Kit Hi–res image: acc_55358_fox_a.jpg Ford Dual Fox Stabilizer Kit Hi–res […]


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SNK? Where Are You?
This is the front of game developer SNK Playmore's Osaka headquarters. No, it was. »
This is the front of game developer SNK Playmore's Osaka headquarters. No, it was. » 6/01/10 9:00am 6/01/10 9:00am
After sitting out fighting game The King of Fighters XII, jiggly ninja Mai Shiranui is returning for KOFXIII. And she's bringing butt floss with her. » 5/28/10 8:30am 5/28/10 8:30am
Upcoming 2D arcade fighting game The King of Fighters XIII already has curvy ninja Mai Shiranui in its line-up. But just because KOFXIII has Mai, that doesn't mean the line-up is finalized. Two more fights are entering the fray. » 4/22/10 8:30am 4/22/10 8:30am
In The King of Fighters XII, character Athena Asamiya donned an impenetrable school skirt. In upcoming arcade game The King of Fighters XIII... » 4/15/10 5:00am 4/15/10 5:00am
Jiggly fighter Mai Shiranui was not in The King of Fighters XII. She is in upcoming arcade game The King of Fighters XIII. » 4/08/10 6:00am 4/08/10 6:00am
Mai Shiranui, from The King of Fighters series, wears a skimpy costume. She's a video game character. She can pull it off. But how does a real lady wear Mai's outfit? » 3/29/10 3:00am 3/29/10 3:00am
There was something missing from The King of Fighters XII. Make that, there were many things missing from KOFXII. But one of the most notable was jiggly ninja character Mai Shiranui. » 3/25/10 5:25am 3/25/10 5:25am
The latest entry in the 2D King of Fighters series has been announced by Osaka-based game developer SNK Playmore. It is The King of Fighters XIII. » 2/25/10 3:00am 2/25/10 3:00am
With at least one potential game of the year exclusively nesting on the Playstation 3 and a price drop under its belt, the PS3 has had a pretty darn good year. » 11/26/09 3:00pm 11/26/09 3:00pm
New Halo, new downloadables for Mass Effect, Fallout 3, and Grand Theft Auto, new Forza. It was a pretty good year for Xbox 360 owners. » 11/26/09 10:00am 11/26/09 10:00am
The bad news for SNK Playmore is that retailer response to The King of Fighters XII, at least at one major Japanese retailer, is that they'd like to be rid of it altogether, marking the fighting game down to $11. » 11/03/09 6:40pm 11/03/09 6:40pm
A patch, a patch, The King of Fighters XII has gotten a new online patch for the PS3 version. » 9/01/09 2:00am 9/01/09 2:00am
When you think of SNK figures, you think of curvy Mai Shiranui figures. These are not Mai Shiranui figures! » 8/28/09 3:00am 8/28/09 3:00am
This year is the 15th Anniversary of fighting game franchise The King of Fighters. To mark the occasion, developer SNK unleashes a "rebirth" for the series, The King of Fighters XII. » 8/07/09 2:40pm 8/07/09 2:40pm
One of the biggest character changes for The King of Fighters XII is schoolgirl fighter Athena. It's like she's another person altogether. » 8/07/09 7:00am 8/07/09 7:00am
SNK's 100 percent hand drawn fighter The King of Fighters XII was released with laggy online play. The game got a patch to fix that. » 7/31/09 2:00am 7/31/09 2:00am
SNK's hand-drawn 2D fighter The King of Fighters XII hasn't only suffered from lag issues, but also buggy glitch issues as well. » 7/29/09 1:00am 7/29/09 1:00am
.html Of all of the shots of the original The King of Fighters '94 to show off in this trailer for the latest version, Ignition had to go with a Mai Shiranui shot. » 7/15/09 1:20pm 7/15/09 1:20pm
No longer is The King of Fighters XII scheduled for "Summer 2009" in North America. No longer will its release date be shuffled. It will arrive on these shores July 28th. » 7/13/09 9:40pm 7/13/09 9:40pm
SNK delayed 100 percent hand-drawn fighting game The King of Fighters XII. The game was originally slated for a July 16 launch, then moved to a vague "July release". » 7/07/09 8:00am 7/07/09 8:00am


text: Manna Food Pantries Manna Food Pantries Gets $100,000 Gift From Sansing Auto Group By Bob Barrett • Dec 17, 2014 Bob Barrett / WUWF News Christmas came a week early for Manna Food Pantries this year as a well known family made a six figure gift to the non-profit. Sandy Sansing, along with members of his family and auto dealerships delivered a big end of the year gift to Manna Food Pantries Wednesday afternoon. A check for $100,000. Jay Bradshaw, the president of Manna's Board of Directors represented the board at the check presentation. He called it the largest gift to Manna since he has been on the board and "one of the largest the pantry has seen in the history of the pantry". Time To Fill The Mayflower For Manna By Bob Barrett • Nov 24, 2014 Bob Barrett / WUWF News The Annual Fill The Mayflower for Manna Food Drive is underway at the Cordova Mall in Pensacola. De De Flounlacker, the Executive Director of Manna Food Pantries says this is Manna's biggest food drive of the year, and the non-perishable food items being collected now have to last through the spring. Manna Food Pantries Gets Closer To A New Home By Bob Barrett • Oct 24, 2014 Bob Barrett / WUWF News Manna Food Pantries has taken the next step in finding a new permanent home. If you stopped by Manna's long time location in Pensacola, you'd see the non-profit operating out of a few construction trailers in front of its warehouse. But that may soon be changing. De De Flounlacker, the Executive director of Manna Food Pantries, says the food bank has closed on a 4.5 acre parcel of land at the site of the former Escambia County School District textbook depot between N. Hayne Street and N. Tarragona Street in Pensacola. Manna Food Pantries Resumes Service Next Week By Bob Barrett • Jul 22, 2014 Bob Barrett Three months after losing its building and most of its inventory to April's flood Manna Food Pantries is set to resume service later this month. Dee Dee Flounlacker, Executive Director of Manna Food Pantries announced that service will resume on Monday, July 28 just a few days short of the three month anniversary of the flood. Deal In The Works For A New Manna Food Pantry Home By Bob Barrett • Jun 19, 2014 Bob Barrett / WUWF News Manna Food Pantries and the Escambia County School District are working on a deal to move the non-profit onto the site of an abandoned school. The property is the site of the former J. Lee Pickens School on Hayne Street in Pensacola which has been vacant for 20 years. Dee Dee Flounlacker, the Executive Director of Manna Food Pantries says the deal is just for the land, not the building which was demolished last month. Big Thanks From Manna Food Pantry, But Need Persists By Bob Barrett • May 19, 2014 Bob Barrett / WUWF News Chris Rutledge, the President and CEO of Gulf Winds Federal Credit Union, stood in the sunshine at the Gonzalez Street headquarters of Manna Food Pantries Monday morning to present a check to help get the community organization back on its feet after last month's floods. The check was for over $146,000. Manna Finds Help As It Looks To Rebound By Bob Barrett • May 9, 2014 Bob Barrett / WUWF News When Governor Rick Scott came to Pensacola he spoke with many community and business leaders about recovering from last week's flood. He also spend a lot of time talking to Dee Dee Flounlacker, the Executive Director of Manna Food Pantries, the region's primary food bank. Manna Food Pantry Hopes To Come Back After The Storm By Bob Barrett • May 1, 2014 Bob Barrett / WUWF News One of the biggest losses from this week's storm was Manna Food Pantries, who's office and warehouse in Pensacola were just about a total loss. WUWF's Bob Barrett toured the damage at the Manna complex on Gonzalez Street and spoke about what it means for the future of Manna with Executive Director Dee Dee Flounlacker, who said they have lost "approximately 60 to 75 percent of our food". On Manna's food storage: The office and warehouse on Gonzalez street in Pensacola is the only place Manna stores their food. The only food still usable was stored on the higher shelves. Fill A Bowl For Manna This Weekend By Bob Barrett • Jan 13, 2014 Bob Barrett / WUWF News Manna Food Pantries will be serving up its seventh annual Fill A Bowl for Manna event this weekend. The weather will be getting chilly again towards the end of the week, which means it's a great time to think about soup. Manna Food Pantries Races to Fill Mayflower and Feed Hungry By Bob Barrett • Nov 26, 2013 Manna Food Pantry The Mayflower has landed in Pensacola as a local nonprofit looks to feed the hungry. The Mayflower in question is actually three Mayflower moving vans. They are set up in the parking lot of the Cordova Mall in Pensacola to collect food for Manna Food Pantries. It's the annual Fill The Mayflower promotion to help restock Mann's larder. Jay Bradshaw is President of Pensacola Moving and Storage and also Chairman of the Board for Manna Food Pantries. He says that they are hoping for a wide variety of food items nutritious food items like canned meats and vegetables. Pages1 2 next › last »


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A History Of The Apple Watch In Photos
Watch Eric Andre And Jimmy Kimmel Each Visit The Other's Show
The Worst Thing Eugene Cordero Has Ever Written ... Animated!
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Toys"R"Upsetting - Ninja Tortoises & The Incredible Shrek - @midnight with Chris Hardwick
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Links! 12 Celebrity Deathmatches That Defined The 90s, Kim Kardashian's Dumb New Movie, And More!
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Get A White Castle Burger Named After You with Kal Penn and John Cho


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NPS Centennial
The National Park Service turns 100 on August 25, 2016. To us, it's not about cakes and candles — it's about being an organization ready to take on the challenges of our second century. Our blueprint to get there — A Call to Action — outlines the innovative work we want to accomplish. Cape Krusenstern National Monument is a big part of this effort. Take a look at what we're doing locally and get involved!
Learning to Camp - Alongside the Arctic Ocean
Kids learn about wilderness ethics, backpacking and the National Park Service during a two-day hiking and camping trip in the Western Arctic. Read more


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Visit create.airbnb.com »
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Hospede bastante limpo e organizado. Cumpridor das regras da casa. Recomendo.
Joao and wife were fine guests. They were kind and responsible and left the apartment clean. I would welcome them back anytime.


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Celebrate your new baby girl with a baby shower, then invite all your friends with these invitations! These 8 cute invitations come with 8 envelopes, so you can send them off right away! Each one comes with spaces to write in all the information about your baby shower, such as where it will be and when your guests should arrive. They're decorated with pink stripes, a pink bow, and a pink safety pin!
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The Buford Lady Yellow Jackets have a solid cast of returnees to build their softball hopes around this spring.
The Lady Jackets, who won the preseason softball tournament, sport six returnees from the 2014 team which went 19-7.
The University of South Carolina Lancaster Lancers made the most of a rain-plagued weekend at Region X baseball foe Guilford Tech, taking two from the Titans on Sunday, March 15.
The Saturday games were rained out, and the Lancers took a pair in the scheduled Sunday afternoon doubleheader with host GTC.
The ninth annual Running for Ryan will again get legs in more ways than one.
The event, set for Saturday, April 11 at the Lancaster High School track, features the county track meet and the chance to provide a greater awareness of KLS – Klein Levin Syndrome.
Andrew Jackson made the most of one run to take a 1-0 prep baseball win over Class A's third-ranked Lewisville High at the Lions' field on Monday, March 16.
The controversy encircling former Secretary of State Hillary Clinton and her use of private email to conduct public business provides our latest example of government in the shadows, a situation we know well in South Carolina.
"Shadow government," as S.C. Press Association Executive Director Bill Rogers has labeled it, means conducting public business via private emails, texts, Twitter or other social media accounts that are not connected to government servers and thus not retrievable by government agencies and the public.
On behalf of the students and staff of Lancaster High School, we would like to express a heartfelt appreciation to the fans of the Lady Bruins basketball team. Our fans demonstrated fantastic support during the recent playoff run.
Winning a state championship is quite an accomplishment, and completing a season at 27-0 is phenomenal. This great group of young ladies handled themselves with class on and off the court. Coach Ronnie Robinson and his staff provided great direction and leadership. In short, he is the type of man you want your kids to be around.
People who commit acts of cruelty toward animals should have to face harsh consequences, said Mary Reimers, president of the Humane Society of Lancaster.
Some of the residents at Parr Place Apartments have grown tired of parking space battles they constantly fight.
Rabies is not a disease of the past. In 2014, seven laboratory cases of rabies were confirmed in Lancaster County.
A 19-year-old Rock Hill man and an acquaintance were arrested late last month after a wild incident that included a fight, shots fired, a car chase, two hit-and-runs – one involving the suspect's vehicle, another wrecked vehicle and a building – and an unsuccessful ploy to deceive police.
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The Lancaster News is your source for local news, sports, events, and information in Lancaster County and Lancaster, South Carolina, and the surrounding area..


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Potential tablet buyers are opting instead for alternative devices, and existing owners are hanging onto their tablets longer, according to research firm Gartner.
The market researcher says this poses a serious problem for businesses, where bring-your-own-device options are commonplace.
Although the popularity of 3D printing is growing in certain niches, mainstream consumer adoption is five to 10 years away, says research firm Gartner.
Chromebooks are the new netbook, but look to have a longer shelf life. Samsung has an overwhelming share of the market at 65 percent, with Acer at 21 percent.
Worldside shipments of PCs will still drop in 2014 but not as badly as they did last year. And ultramobiles will provide a bit of a boost.
The world's largest social network is creating features and tools designed to attract mobile device developers, as it works to offer all things to all people.
Curious why the One M9 looks so similar to its predecessor? HTC's Peter Chou says it's intentional.
The world's largest social network plans to allow app makers to send photos, music and other stuff through its communication service.
Shipments of PCs, tablets, and mobile phones combined will climb by 7 percent in 2014, predicts Gartner, though PCs will be on the losing end of the deal.
Researcher IDC cuts its forecast for PC shipments, saying more needs to be done to help the market stabilize.


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Father, son killed in fiery crash near Texarkana
POSTED: Friday, May 23, 2014 - 11:25am
UPDATED: Friday, May 23, 2014 - 1:21pm
Texarkana, Texas (KETK) — A father and son were killed Friday morning in a fiery crash northwest of Texarkana.
According to Department of Public Safety Trooper Sylvia Jennings, at around 4:30 a.m., a driving team out of Edison, New Jersey, was headed west on I-30 when they drove over the side and wrecked below onto County Road 2148. Authorities are unsure at this time why the 18-wheeler, which was carrying other cars, drove off the bridge.
The victims were identified as Brian Witkowski, 46, and James Witkowski, 21, said Jennings. Deputies did not say which person was driving at the time of the accident.
Traffic is flowing smoothly in both directions on I-30.
Photo Courtesy: TXKtoday.com


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Our special coverage of the closest race for years
Explore the personal stories of Syrian refugees in Lebanon
23 May 2011 21:32 GMT | Politics, Africa, France, Libya
French officials have confirmed that France and Britain will send attack helicopters to Libya in the latest effort to ramp up NATO's targeting power against Muammar Gaddafi's forces.
Alain Juppe, France's chief diplomat, affirmed on Monday the proposed use of helicopter gunships - a move Jupee says is in line with a United Nations resolution that calls for the protection of Libyan civilians and NATO's military operations.
"What we want is to better tailor our ability to strike on the ground with ways that allow more accurate hits," Juppe said.
Gerard Longuet, the French defence minister, said Britain was also sending sending helicopters while London kept mum.
"We are not in the habit of talking about any new missions we undertake until they are in operation," a British government spokesman said.
Air strikes
NATO forces have been bombing Gaddafi forces in defence of civilians since late March, but the strikes have not yet been enough to break a deadlock between rebel and government forces.
Live Box 201142012730683527
The coalition forces stepped in after a UN Security Council resolution instituted a military operation against Gaddafi forces, an arms embargo, a freeze on Libyan leaders' personal assets and travel bans on senior figures after the Libyan leader Gaddafi's violent crackdown on the popular uprising which began in February.
The French daily Le Figaro reported 12 helicopters were shipped to Libya on the French warship Tonnerre on May 17.
According to Le Figaro, French special forces, who have been in Libya to identify targets for NATO since the start of air strikes, could now be reinforced to guide helicopter attacks.
'No game changer'
Shashank Joshi, an Associate Fellow at the Royal United Services Institute thinktank, says the attack helicopters can facilitate better precision targeting at the cost of being more vulnerable to ground fire.
"Attack helicopters can fly low and slow. Fast jets can only fly high and, as the name suggests, are extremely fast. So attack helicopters allow you to hit things on the ground with precision," Joshi told Al Jazeera.
"It can be hit by small arms fire it could be hit by a shoulder-launch portable missile, and all of that means there is a risk now of NATO personnel being shot down."
The helicopters' deployment does not signal an escalation in NATO's mission in Libya, but rather an expression of increasing anxiety in London and Paris over the continuing deadlock, Joshi explained."It is an escalation in the means being used to pressure Gaddafi ... but it is not an escalation of the actual mission," he said.
"The mission is still regime change and it's just one more military instrument that reflects there is British and French anxiety that this stalemate could now harden."
While the helicopters are precise to a certain degree, they are not powerful enough to function as "a game changer," because "they can't really affect the battle deep inside Libya nor can they really attack people deep inside buildings or buried inside urban areas." Joshi added.
Explosions in Tripoli
Meanwhile, repeated NATO air strikes shook the Libyan capital Tripoli early on Tuesday, with a column of smoke rising over the neighbourhood where Gaddafi's Bab al-Aziziya residence is located.
Reports said early Tuesday seemed to be the heaviest night of bombing of Tripoli since the beginning of NATO's air campaign.
More than 20 air strikes occurred in less than 30 minutes, with explosions rattling windows and booms shaking buildings.
Witnesses said five powerful blasts were heard in the area, preceded by a whistling noise and the formation of red balls in the sky.
People's screams and shouts and crackling of anti-aircraft fire could be heard outside a hotel where journalists are staying.
Source: Al Jazeera and agencies
EU foreign policy chief Catherine Ashton becomes highest-ranking diplomat to visit Libyan rebels' stronghold.
Politics, Africa, Libya, Poland
Signs of deadly battles for Libyan rebel holdout are everywhere, from scarred buildings to roadside rockets.
Africa, Libya
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Environment, Europe, Sweden
Critics say the UK's home secretary is using Muslims as a 'political punchbag' in a bid to shore up right-wing support.
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Sunshine, Lollipops & Rainbows
Design ID: 11171280
A boy. Gleek. Starkid. Artist. Graphic Designer. Singer. Actor. Dancer. Writer. Tumblrian. Tweetling. Follow me on Twitter or Tumblr at @HaydenRodgers (probably the best way to contact me)!
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Bradford Goldendoodle Dogs and Puppies for Sale
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Mahatma Gandhi University, Kottayam, is one among the 30 universities in India selected by the Department of Science and Technology for funding under the DST-PURSE programme. Under it, the university will receive Rs.9 crore for development of research infrastructure.
The university has been placed eighth among the 30 top Indian universities selected under this programme based on its h-index (a measure to assess the quality of research in science), university authorities say.
The Promotion of University Research and Scientific Excellence (PURSE) scheme provides substantive research grants to universities based on the scientific publications in Science citation indexed journals through the SCOPUS database. The department identified universities with h-index ranging from 42-26 for R&D support during 2010-11. Mahatma Gandhi University had an h-index of 35.
The university will receive Rs.3 crore every year for three years. The grant is to be utilised by the School of Chemical Sciences, the School of Biosciences, the School of Environmental Sciences, and the School of Pure and Applied Physics, along with interdisciplinary centres such as the Centre for Nanosciences and Nanotechnology, Centre for Intensive Research in Basic Sciences, Inter-University Common Instrumentation Centre. A project implementation group (PIG) consisting of academics from all the science disciplines has been constituted by the university as per the DST guidelines.
Keywords: DST-PURSE programme


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The Holiday Event is Live!
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Career Officer
Join Date: Jun 2012
Posts: 1,933
# 22
Originally Posted by
Many more attempts and still failed every time...
I guess I just feel a bit let down as I was expecting a "gift" from Cryptic, but instead I've been given yet more grind...
Sorry you're having trouble
. Give these tips a try:
Originally Posted by
Last year this was my technique:
* The thing to remember is the NPC Racer doesn't sprint, they only ever "trot". So if you get a lead, you don't have to sprint again the whole rest of the race.
You can relax and take your time.
With that in mind:
* At the start of the Race, sprint nearly the whole opening straightaway. As you get to the first turn, reduce speed (depending on your skill you can just stop sprinting and slide, double-roll, jump, catch a corner, etc.) and make the turn.
* If you can make that first turn after sprinting, just casually trot through the rest of the course. You'll win, cuz the NPC Racer will never catch up. The end.
This is how I taught my 61-year-old (at the time) STO-playing father how to complete the race all by himself. He's a little arthritic and has bad eyesight (cataracts, well, had them, gone now, yay!), but he would win about 90% of the time using the above methods.
Other tips:
* This is not a "try it once a day"-restricted event. If you fail, don't worry/fret. Just run straight across the middle of the map, requeue with the Race Coordinator, and try again.
* Some of the turns have "snowy corners" that are still considered in-bounds, and are not slippery. Once you learn where these are they are great for stopping, taking short cuts, and making better turns.
* Those last couple of hairpin turns have major snowy corners that are still in-bounds. You can
run straight through them (that's an exaggeration, but if you spend a little times testing where the track fails, you'll see what I mean).
It is possible
to sprint the whole race. Once I got my practice up, I was doing it all the time... You don't need to, but it can be a fun challenge. I got to the point where I was regularly
overtaking the race in front of me!
In fact, if I didn't at least lap the NPC Racer in the previous race (ie the one that started before me), I considered myself a failure. LOL
This notes are all in regards to last year. I'm at work right now and haven't done the race this year, but I expect it to be the same.
Don't rush, and you'll be fine! Good Luck!
When XP earnings during a Double-XP Weekend still feel like
I'm underperforming
there's something
wrong with the reward system...
You can find/contact me in game as
RIP Terry Pratchett
Original Join Date:
Feb 2010


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Rico Love - Page 2
Cash Money Covers Billboard, Eminem Talks Dr. Dre, Tyrese Disses Usher & More
Cash Money Records founders Baby and Slim cover Billboard's first Urban Power issue, where they discuss Baby's goals; releasing 100 albums in one calender year and building the label into the industry's first billion dollar indie.
Musiq Soulchild recently stopped by Atlanta's Majic 107.5/97.5 to promote his new book 143: Love According t
Teairra Mari 'Unfinished Business' Mixtape: Tracklist Features Snoop Dogg, 2 Chainz and Rico Love
In anticipation of her long awaited sophomore album, Sex on the Radio, Teairra Mari debuts the tracklist and cover of her new mixtape, Unfinished Business, due on July 4, ThisIsRnB.com reports.
The cover of the 11-song, DJ Scream-hosted tape features the 24-year-old singer in some very business-like attire. The project itself boasts appearances by Snoop Dogg, 2 Chainz and Rico
Maybach Music Group Reveals 'Self Made, Vol. 2′ Production Credits, Listen to Album
The Maybach Music Group team will serve their sophomore compilation, Self Made, Vol. 2, to the masses on June 26, but before the effort drops, the rap stars unveil the production credits for the effort. The ful
Bobbi Kristina Walks Off Tyler Perry Set, Lil Wayne Has a Fecal Fetish & More
After filming a couple of episodes, Whitney Houston's daughter Bobbi Kristina walked off the set of her new TV show, "Tyler Perry's For Better or Worse" last week.
Diddy has anointed multi-talent DJ Khaled into his super group the Ciroc Boyz, joining Rick Ross, Fabolous an
Teairra Mari 'U Did That' Video: 2 Chainz and Singer Unite for Sexy Visuals
Teairra Mari leaves her inhibitions at the door in the visuals for "U Did That," the 2 Chainz- assisted lead single off her sophomore album, Sex on the Radio, due this summer.
"This is one on my favorite videos that I've done for a couple of reasons, starting with the mixture of grit
Ashanti Album Listening: Title Is Film-Inspired, R. Kelly Collaborates, Songs Center on Love
Ashanti's fifth album shares the same name as a popular '90s film, but that's all The BoomBox can divulge at the moment. Fans will have to wait until Thursday (March 8) to learn the name of her forthcoming opus, which will debut in the video for her Busta Rhymes-assisted single 'The Woman You Love.'
The 31-year-old chanteuse dis
Essence Black Women in Music 2012: Kelly Rowland Honored, Eve Joins
Kelly Rowland attended the 3rd annual Essence Black Women in Music event, presented by the Lincoln MKX Crossover, Wednesday night (Feb. 8) in Hollywood and was honored for her achievements in the music industry alongside record label veteran Sylvia Rhone.
Dressed in a flowing orange gown, th
Usher Gives Rico Love a Grammy for His Birthday
Grammy-winning producer-songwriter Rico Love celebrated his 29th birthday during Art Basel in Miami on Friday night (Dec. 2), partying with fellow artists Timbaland, Cee Lo Green and Yelawolf, industry legend Sylvia Rhone, and NBA
Rico Love Says He's 'the Best,' Rufus Wainwright Is 'Genius'
Rico Love is a craftsman. He doesn't hold a tool belt like Tim "the Tool Man" Taylor but his equipment of choice works with the same kind of precision. The hitmaker relies on soundboards, a recording boot


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Billy Goat Trail is comprised of three sections of trail locatednear Potomac, MD featuring beautiful wild flowers and scenic river views. The trail is used for hiking, mountain biking, trail running and walking. It is demarcated by blue blazes and is accessible year-round. Protected by NPS and TNC.
Amy A, (340)
1 month ago
One of my favorite trails to date, but heavily used. Go very early if possible. Have hiked the rocky part in both directions and in all seasons. Surprisingly pleasant in winter. Just wear lots of layers. In summer, bring PLENTY OF WATER since the rocks aren't shaded. I always bring a snack too, and now use my Camelback so my hands remain free to scramble those rocks to my heart's content. A few spots are tricky, but you can adjust the difficulty by which routes you take (some cliff edges, and almost completely vertical crevices are tucked away here and there for a challenge). Lots of spots to hang out and take in the view. One side note: if you're going from the rocky trail back toward the canal path (or vice versa) via the woods, be careful in the summer. I ran into Stinging Nettle. Ouch.
Raelynn Mayberry (78)
1 month ago
The view was beautiful! On the hike back we did have a run in with a rattle snake so watch where you step!!
David Georg (72)
1 month ago
Fun and convenient to get to. Go on a weekday if you can, when I went there was a long line to get across the river. I was standing there forever.
Katrina Gagliano (82)
2 months ago
A good, moderate hike for those who want something more challenging than the trail A (that's mostly a walking trail ), but not as difficult as something like Old Rag. I've hiked this trail multiple times now and I love it! A good way to get sweaty and do a little rock scrambling to some wonderful views.
Alexia Prochnicki (36)
2 months ago
I have been hiking the BGT since I was a little girl.... it still takes my breath away, especially in the Spring and Fall. Pluses: stunning views of the Potomac River, good wildlife especially my favorite great blue herons, some technically challenging parts but mostly up and down rocks with plenty of opportunity for rest, well marked, many hikers so you won't get lost. Minuses: no dogs : (, many hikers.
Neal Gallagher (245)
5 months ago
Moderate scrambles, great views of the Potomac.
Daphne Gassett (309)
5 months ago
Excellent trail & challenge! The earlier you go, the better.
Roberto Ricaurte (72)
5 months ago
I took my dog there for the first time and I took her on trail A which dogs aren't allowed to go on but my PitBull puppy(4monthsOld) did it like a champ she climbed up the side of the mountain and jumped over rocks I know she had a blast and will be doing it again with her
Deborah Barber (133)
6 months ago
One of my very favorite spots, I'm lucky to have had the chance to go there many, many times. Billy Goat trail section A (the most chellenging) is on Bear island, which is co-owned by the National Park Service and The Nature Conservancy (where I work). Please note that the beginning (north end) of Section A was re-routed a few years ago to enhance views and visitor safety. This end is actually more difficult now (so people know what they're getting into sooner). TNC has developed an audio tour and map that you can take with you on the trail to better understand what you are seeing--check it out! (see link)
Bryan Kluth (1558)
7 months ago
Fun. Nice views of river. Not as much rock hopping as I expected. Go on a weekday morning for almost no traffic.


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This Easter, think bunnies and bourbon.
Buffalo Trace Distillery and the City of Frankfort Department of Parks, Recreation and Historic Sites are teaming up again to host the 16th Annual Buffalo ...more
The craft beer movement in Lexington and the Bluegrass Region is alive and well! True: we are known as the birthplace of bourbon. But we are home to master brewers as well as master distillers! Craft breweries are now scattered across Kentucky, and more and more thirsty travelers are seeking out small craft brewers and locally-made beers in addition to sampling our classic bourbons. Watch a LexTreks video about the Brewgrass Trail.
The Brewgrass Trail is dedicated to showcasing the craft brewers establishing themselves in the Bluegrass. Here are the breweries you'll want to consider visiting, as well as some great Hop Spots where you are sure to find a great selection of local brews, and an energetic and friendly atmosphere.
Want to know what events are going on at the breweries including tastings, special offerings, new beers and food trucks? Go to lexbeerscene.com.
You can also stay up-to-date with Brewgrass Trail's facebook page.


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Judith Lavoie
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- Judith Lavoie is an award-winning journalist based in Victoria, British Columbia. Lavoie covered environment and First Nations stories for the Victoria Times Colonist for more than 20 years and is now working as a freelancer. She previously worked on newspapers in New Brunswick, Cyprus, England and the Middle East. Lavoie has won four Webster awards and has been nominated for a National Newspaper Award and a Michener Award.
Posts by Judith Lavoie
Alaskans Ring Alarm Bells Over Potential for More Mount Polley Disasters As B.C. Pushes Forward With New Mines2015-02-04 13:32
2014-12-10 06:18
2014-10-30 07:31
2014-05-03 11:48
U.S. Officials Search For Answers On Bitumen Spills As Canada Eyes Enbridge, Kinder Morgan Oil Pipelines2014-05-02 10:42


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Saturday 19th January's Fixtures
By Webmaster, 18th Jan 2013
2nds and 3rds OFF !!
Due to the weather, the 2nds away fixture at Lasswade and the 3rds home fixture against Bo'ness have been called off !
We're still waiting to hear word on the 1st XV fixture at Dunfermline - so far we have heard that there is no snow on the pitch, but they are waiting to inspect it at around 9.30 on Saturday morning !
We'll update the website as soon as we know !


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The rising illness
Bahrain, which is suffering from high rates of absenteeism at work, has now approved a new plan that allows civil servants in the country to take a week off to support ill family members.
October 20, 2009 2:16 by Aarti Nagraj
The Council has been debating the plan for more than a year thanks to a rise in absenteeism. According to Bahrain's Civil Service Bureau (CSB), sick leave cost the government BD4.5 million ($12 million) last year, with civil servants taking 178,000 days off – the equivalent of five years' sick leave. "The government loses BD117 ($310) per day and last year's days off were an increase from the 165,000 recorded in 2007," CSB president Ahmed al-Zayed told MPs in February.
And it's not just the public sector that is facing problems; private companies are also seeing rising numbers of absenteeism.
"It is very expensive for someone to be absent from work," Mohammed Saleh Abdullatif, the chief medical officer of Bahrain-based Gulf Petrochemical Industries told Gulf Daily News earlier this year.
"It is not only the absence of the worker – it is getting a replacement for them as well. For our company, it [sick leave] is about BD3,500 ($9,280) a month," he said.
According to him, doctors were also sometimes forced to issue medical certificates to people not genuinely ill.
"I have heard of some health centre doctors being attacked because they refused to give sick certificate. Ethically, as a doctor, I should not give sick certificate to a person that does not deserve it," he said.
In July this year, two Bahraini men assaulted a security guard at a hospital and fled after it was discovered that they were trying to get fake sick certificates.
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Museum of London
Museum of London - Has announced plans to move from its current home at the Barbican to Smithfield Market by 2021. "The museum desperately needs more space," said London Mayor Boris Johnson. "In its new home, the Museum of London will be able to unleash its full potential to attract millions of people."
Britain's hotel staff are down the bottom of the table along with their Russian colleagues when it come to friendliness and expertise, a new poll shows. London's hotels were at the foot of the UK cities in the list propped up only by Coventry's lacklustre courtesy performance.
Dr Gabriele Finaldi
It was announced today (18 March 2015) that Dr Finaldi is set to replace Nicholas Penny as Director of London's National Gallery in August. "This is a world-class collection in a world-class city and I eagerly look forward to working with the Trustees and the staff to strengthen the Gallery's bond with the public and its international standing" said Penny's successor.
Battersea Arts Centre
Twelve fire engines have been tackling a blaze at the south London cultural centre @battersea_arts. Everyone has been evacuated safely and hopefully the future of the arts mainstay will be safe.
20mph speed limits
Transport for London announces reduced speed limit of 20mph for a clutch of the capital's key highways including Commercial Street in Tower Hamlets, Westminster Bridge and Clapham High Street.
The Garden Bridge
Having pledged in public that London's new green crossing will not be maintained at public expense, Mayor Boris Johnson's office has privately re-assured the Garden Bridge Trust that the ongoing costs will in fact be 'guaranteed' by the capital's taxpayers.
Green Belt
Which amounts to 22 per cent of all Greater London's land should be opened up for more housebuilding says a report by London First. They argue new housing should be targeted toward Green Belt land that is "close to current transport links and is of poor environmental or civic value".
Stand back Hackney, move over Kensington, apparently Bexley is the capital's last remaining property hotspot. The south-east London borough was the only one to show an increase in demand for new homes over the past quarter says a new report.
Steve Strange
RIP the doyen of legendary London 80s club Blitz and early co-conspirator of the New Romantics. Born Steven John Harrington, Strange died on Thursday in Egypt aged 55. Don't Fade to Grey, Steve. Fade to Gold.
Punny Shop Names
As the UK Pun Championships take place today in Leicester here's a little inspiration for competitors from the streets of London (via Telegraph) - stay with it as they cheekily save the best to last.
Maxwell Hutchinson
Our best wishes goes out to the dapper London architect and broadcaster on @BBCLondon949 @RobertElms show who has suffered a stroke.
Mayor Boris Johnson has re-floated the prospect of a toll-tunnel to replace the Hammersmith Flyover along with other road improvement schemes for the A3 in Tolworth, A316 in Richmond, A13 in Barking and A406 at New Southgate.
Safer Lorries
Under a new scheme all lorries over 3.5 tonnes driving in London from 1 September 2015 will need to have side guards and extra mirrors to help protect cyclists.
Number 91 Bus
One of which hit trees near Kingsway, Holborn ripping its roof off. Two people were taken to hospital with facial injuries.
The Natural History Museum in South Kensington is to swap their entrance hall's Diplodocus skeleton for the bones of a blue whale. The change in Hintze Hall won't be completed until 2017 and comes as "part of a larger plan to show new specimens in the space" say the museum.


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Yet another long-awaited Malick project will finally see the light of day: in glorious IMAX!Read More »
Fox's "Maze Runner", Universal's Liam Neeson thriller, "A Walk Among The Tombstones", and Warners' family dramedy, "This Is Where I Leave You", are the three main openers this coming weekend. How will they fare? Box Office Insider takes a crack at the weekend Top 10 projections.Read More »


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Top experts from the city give a heads-up on the big fat trends that will enamour the famous five lifestyle departments this year.
Who says corporate accessories need to be dull? Give your laptop a makeover with these bags and sleeves.
Now that all the partying is behind you, it's time to hit the gym in these fashionable must-haves.
The much anticipated Renault Lodgy 7-seater MPV was unveiled by actor Anil Kapoor in India during a Hindi movie awards function
Organisations will have people with a certain set of values who are not comfortable asserting their command and authority in managerial positions.
"There will be six teams across the country and we are trying our best to make the format very attractive and popular."
Andy S Lew, managing director, Asia Pacific, Brooks Brothers on his many fashion quirks.
"Mad Men" captured the style and drive of New York's finest -- and drunkest -- 1960s ad men and their tales of creative genius and tortured infidelities.


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An incubator cultivates edible fungi that digests plastic as it grows.
The growing push to clear forests for palm oil cultivation in Africa may spell doom for that continent's great apes. Continue reading →
El Hierro is the first to secure a constant supply of electricity by combining wind and water power without reliance on any outside electricity.
The 2013 Solar Decathlon showed how beautiful and affordable solar power can be for the home. Continue reading →
The plastic backing on solar panels is made cheaply from sustainable materials. ->
Writer Alyssa Danigelis lifts the curtain on blogging for Discovery News. Get the popcorn ready.
Kiss plastic trash goodbye. British engineers have new tech to recycle it all.
For the last 56 years, the United States and Canada have failed to report Arctic fish catches to the FAO - Russia under-reported catches.
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"Agents of SHIELD's" Edward James Olmos Talks Instigating Mutiny and the Real SHIELD
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Mike Colter is reportedly Marvel's first choice for Luke Cage; a new promo shows off more of Reverse-Flash and Firestorm and more.
A Canadian teaser for "The Flash's" midseason finale features Robbie Amell declaring his new identity as Firestorm.
Oliver Queen and Barry Allen's growing friendship and professional rivalry saw a record number of viewers tune in to the two CW series.
The CW's hit superhero series go big with epic, villain-fueled promos for "The Flash" and "Arrow's" mid-season finales.
Luke Evans says "Crow" role is no longer for him; Chadwick Boseman reveals T'Challa will debut in movies and more.
Arrow and The Flash grapple with moral issues even as they team up to stop Captain Boomerang's path of death and destruction.
The next "Flash" episode is titled "The Man in the Yellow Suit," and the Reverse Flash isn't far behind -- here are images from the midseason finale.
"Arrow" heads to a midseason halt next week, but not before Stephen Amell and Matt Nable battle it out with swords in the snow.
Andrew Kreisberg and Marc Guggenehim tell CBR how this week's crossover hearkens back to their comic fan roots, and when they might do it again.
The DC supervillain film wants Winfrey to lead Leto, Smith, Hardy and the rest; Firestorm preps for a painful reunion with Snow on "Flash" and more.
A classic team-up, a superhero battle for the ages and the debut of a DC Comics character we've been waiting for all season. Plus ... the Rainbow Raider?
Manu Bennett will return as Slade Wilson for the third season of "Arrow" following the series' midseason hiatus.
Stars Stephen Amell, Grant Gustin, Emily Bett Rickards and more talk with CBR about this week's two-part "Flash" and "Arrow" crossover.
The CW has released a first look at this week's "Flash Vs. Arrow" crossover episode, combining the skills of Barry Allen and Oliver Queen.
Joseph Gordon-Levitt aims to please the "Sandman" creator with his film; the "Vampire Diaries" actress may take flight as Kara and more.
The tension between Scarlet Speedster and the Emerald Archer come to a head in a new extended trailer for The CW's "Flash Vs. Arrow" crossover.
Tom Hiddleston will reportedly be on set in January; Robbie Amell posts first photo with Firestorm partner Victor Garber and more.
Despite its home at CBS, Greg Berlanti says that "Supergirl" could still potentially cross over with The CW's "Arrow" and "The Flash."
Gwyneth Paltrow says she would play Pepper in the "Cap" sequel; Grant Gustin promises "Flash" fans have no idea what's coming and more.
More than a mundane villain of the week, the vengeful Blackout poses a threat to Barry's powers and Harrison Wells' life.
Barry Allen and Oliver Queen team-up, and square off, in the first full trailer for next week's crossover between "The Flash" and "Arrow."
"The Flash" actor Robbie Amell has divulged new information about his return to the freshman series in full Firestorm glory.
Michael Reventar discusses putting his own stamp on DC Comics' latest character to debut on television, and explains why he's not your typical villain.
Frank Grillo reveals if he's been contacted about playing the villain in "Civil War"; Peggy Carter goes undercover in new promo and more.
"Arrow" EP Marc Guggenheim told CBR that next week's crossover with "The Flash" could lead to more metahumans in Oliver Queen's world.
Emily Blunt revealed she is aware of Marvel's leading lady; new "S.H.I.E.L.D." pics show Patton Oswalt ready for action and more.
Laurel Lance's official debut as Black Canary will be part of a "trilogy" of episodes, according to "Arrow" exec producer Andrew Kreisberg.
Chadwick Boseman says now is the "right time" for Black Panther; pics from the CW superhero crossover reveal fan favorite villain and more.
Gustin and Amell get honest in behind the scenes clip; "Breaking Bad" and "Good Wife" actors in running to play Marvel heroes and more.
"Draw Back Your Bow" feels like Season 1 episode as Cupid arrives to Starling City, but a Cinderella-like subplot involving Felicity Smoak and Ray Palmer saves the day.
The CW has released photos from the "Flash Vs. Arrow" crossover episode of "The Flash," which sees Barry Allen & Oliver Queen at odds.
To help promote tonight's episode, The CW has returned to "Arrow's" roots, with a comic teasing the search for the latest threat to Starling City, Cupid.
Amy Gumenick discusses stalking Oliver Queen on "Arrow" as Cupid, the joy of taking on a physically demanding role and getting a little crazy.
The gorilla's arc will mirror that of Slade's in "Arrow"; Elle Fanning, Chloe Moretz and Hailee Steinfeld rumored for young Jean Grey and more.
Barry Allen confronts his childhood tormentor in the form of Girder in an episode that initially feels clichéd but ends with an unpredictable bang.
"The Flash" executive producer Greg Berlanti has stated that the freshman series will "directly" deal with the concept of time travel in the winter.
"Dead" beat "Sunday Night Football" in the ratings for the third consecutive week; assassins go after Bruce and Selina in a new promo and more.
Daniel Bruhl has been cast as a villain in the "Captain America" sequel; Joe and Anthony Russo may inherit "Avengers" from Whedon and more.
Batman's inciting incident may be IMAX-ready; Hayley Atwell returns to the Marvel drama in a new clip and more.
Brandon Routh gets shirtless during the Atom's workout routine in new "Arrow" photos from next week's episode, "Draw Back Your Bow."
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