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Cell Metabolism
Short Article
Autophagy Is Important in Islet Homeostasis
and Compensatory Increase of Beta Cell Mass
in Response to High-Fat Diet
Chie Ebato,1,6Toyoyoshi Uchida,1,6Masayuki Arakawa,1Masaaki Komatsu,3,4,5Takashi Ueno,3Koji Komiya,1
Kosuke Azuma,1Takahisa Hirose,1,2Keiji Tanaka,4Eiki Kominami,3Ryuzo Kawamori,1,2Yoshio Fujitani,1,2,*
and Hirotaka Watada1,*
1Department of Medicine, Endocrinology, and Metabolism
2Center for Therapeutic Innovations in Diabetes
3Department of Biochemistry
Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
4Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan
5PRESTO, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan
6These authors contributed equally to this work
*Correspondence: email@example.com (Y.F.), email@example.com (H.W.)
DOI 10.1016/j.cmet.2008.08.009
Autophagy is an evolutionarily conserved machinery
for bulk degradation of cytoplasmic components.
Here, we report upregulation of autophagosome
formation in pancreatic beta cells in diabetic db/db
and in nondiabetic high-fat-fed C57BL/6 mice. Free
fatty acids (FFAs), which can cause peripheral insulin
resistance associated with diabetes, induced au-
tophagy in b cells. Genetic ablation of atg7 in b cells
resulted in degeneration of islets and impaired glu-
cose tolerance with reduced insulin secretion. While
high-fat diet stimulated b cell autophagy in control
mice, it induced profound deterioration of glucose
tolerance in autophagy-deficient mutants, partly be-
cause of the lack of compensatory increase in b cell
mass. These findings suggest that basal autophagy
is important for maintenance of normal islet architec-
ture and function. The results also identified a unique
role for inductiveautophagy as an adaptive response
of b cells in the presence of insulin resistance
induced by high-fat diet.
Recent studies have shown that progressively decreased pan-
creatic b cell function and b cell mass are common features of
subjects with type 2 diabetes mellitus (Butler et al., 2003; Rho-
des, 2005). Early in the disease, pancreatic b cells overproduce
insulin to compensate for insulin resistance but eventually fail to
do so, and this may result in cell death, with clinical manifesta-
tions of diabetes. Because of the high secretory activity, b cells
are constantly exposed to various kinds of stresses, such as glu-
colipotoxicity and oxidative stress (DeFronzo, 2004; Unger and
Zhou, 2001). However, little is known so far about the molecular
lular damage associated with the high capability of insulin secre-
tion, which may be accelerated by increased insulin resistance.
Autophagy is a catabolic process that involves the degrada-
tion of cellular components through the lysosomal machinery.
It is a tightly regulated process and plays an important role in
cell growth, development, and homeostasis, where it helps to
maintain a balance between the synthesis, degradation, and
subsequent recycling of cellular components (Levine and Klion-
sky, 2004). The principal role of autophagy is to reallocate nutri-
ents from unnecessary processes to more pivotal processes
required for survival (Kuma et al., 2004). In addition, a low level
of constitutive autophagy is also important for maintaining the
quality of proteins and organelles, in order to maintain cell func-
tions, as recently reported in various organs, including the liver
(Komatsu et al., 2005), brain (Hara et al., 2006; Komatsu et al.,
2006), and heart (Nakai et al., 2007). Thus, autophagy functions
as a cell-protective mechanism. Autophagy is upregulated when
cells are preparing to rid themselves of damaging cytoplasmic
components, for instance, during infection or protein aggregate
accumulation (Levine and Kroemer, 2008). While it has been re-
ported that significant number of autophagic vacuoles are found
in b cells of ZDF rats, a rodent model of type 2 diabetes (Li et al.,
autophagy in b cells, and no causal link has been reported
between autophagy and pathogenesis of diabetes. In the pres-
ent study, we describe the generation of a conditional knockout
mouse of Atg7. We then used these mice to examine the role of
autophagy in adult pancreatic b cells. The results suggest that
autophagy is important for maintaining normal islet homeostasis
and compensatory b cell hyperplasia in response to high-fat (HF)
diet intake.
Induction of Autophagy in Pancreatic b Cells
We first examined whether autophagic vacuoles are present in
mouse pancreatic b cells under various pathophysiological
conditions. Electron microscopic (EM) analysis indicated that
Cell Metabolism 8, 325–332, October 8, 2008 ª2008 Elsevier Inc. 325
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autophagosomes were hardly observed in b cells of C57BL/6
mice and in db/misty mice, and those identified were of relatively
small size (?0.5 mm) (Figure 1A, b and f, arrows). In contrast,
analysis of b cells in db/db and in C57BL/6 mice that had been
fed HF diet for 12 weeks showed active formation of large auto-
phagosomes (0.5–2 mm in diameter), which were recognized as
double-membrane structures containing multilamellar struc-
tures, mitochondria, and insulin granules (Figure 1A, c, d, g,
and h). Different from what is seen in most other organs (Kuma
et al., 2004), overnight starvation of C57BL/6 mice did not result
in any increase in autophagic vacuole formation in b cells (data
not shown). On the other hand, ex vivo starvation of islets iso-
autophagic vacuoles, similar to those observed in C57BL/6 mice
fed standard chow diet (data not shown).
In the next step, we investigated the signals that stimulate au-
tophagy in b cells. Marked induction of autophagy, comparable
to the levels induced by amino acid deprivation, was observed in
for 24 hr, assessed by conversion of microtubule-associated
bottom) suggested increase in autophagic flux by FFA stimula-
human islets exposed to FFAs showed autophagic vacuole
formation (Lupi et al., 2002), although they did not observe
increased autophagic flux. FFA exposure for more than 12 hr
induced autophagy in INS-1 cells, whereas FFA exposure for
a shorter time had no significant effects (Figure 1C). The FFA-re-
lated autophagosome induction was further confirmed by the
tures, representing autophagosomes, in INS-1 cells exposed to
FFA (data not shown). In contrast, exposure of these cells to high
glucose (from 2.8 to 30 mM) or to tolbutamide did not induce
autophagy (Figure 1B, top and third panel). In addition, high
glucose did not augment autophagy levels induced by FFA
Figure 1. Upregulation of Autophagosome Formation in HF-Fed and in Diabetic Mice
(A) Electron microscopic (EM)analysisrevealedautophagosomeformationinbcells of 20-week-oldmicefed standard (STD) diet(aand b)or HFdietfor 12weeks
(from 8 to 20 week of age) (c and d). Beta cells in 10-week-old db/misty (db/m) (e and f) and db/db (g and h) mice were examined. Scale bars represent 1 mm.
Density of autophagosomes was calculated, and data are presented as mean ± SEM of three mice for each group. **p < 0.01 versus controls.
(B) FFA but not high glucose can induce autophagy in INS-1 cells. For ''control,''cells were incubated in RPMI1640 supplementedwithFCS and amino acids. For
''starvation,'' cells were incubated for 2 hr in Hank's buffer free of serum and amino acids.
(C) Time course of FFA-induced autophagy. So that accumulation of LC3-II could be visualized, the lysosome inhibitors pepstatin-A (10 mg/ml) and E-64-d
(10mg/ml)wereadded totheculturemedium for thelast2hrperiod unlessotherwiseindicated (Band C).Datafor western blots arepresentedasarepresentative
from more than five independent experiments.
Cell Metabolism
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326 Cell Metabolism 8, 325–332, October 8, 2008 ª2008 Elsevier Inc.
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(Figure1B, second panel). Since FFAisa key mediator of periph-
eral insulin resistance in diabetes (DeFronzo, 2004; Unger and
Zhou, 2001), upregulation of b cell autophagy by FFA suggests
its potential role in the regulation of b cell function in diabetes
or obesity-associated conditions.
Basal Autophagy Is Indispensable for the Maintenance
of Normal Islet Architecture
To determine the physiological role of autophagy in pancreatic
b cells, we generated mice deficient for Atg7, an essential
gene for autophagosome formation, specifically in pancreatic
b cells. We crossed mice carrying an Atg7floxallele (Figure S1
available online) with transgenic mice that expressed the Cre re-
combinase in a b cell-specific manner (Rip-Cre) (Gannon et al.,
2000). The resulting Atg7flox/flox:Rip-Cre mice (referred hereafter
to as Atg7f/f:Cre) were indistinguishable in body weight and food
intake (Figure S2) from age-matched control Atg7f/flittermates
(from newborn until at least 16 weeks of age). In Atg7f/f:Cre
mice, we observed approximately 70% reduction in Atg7 protein
level in isolated islet preparation (Figure 2A). Reduction of
autophagy in Atg7f/f:Cre mice was confirmed by suppression
of Atg7-dependent conversion of LC3-I to LC3-II (a phosphati-
dylethanolamine conjugate) and accumulation of p62 and polyu-
biquitin. These changes were also confirmed by immunohisto-
chemical staining of pancreata of 20-week-old Atg7f/f:Cre mice
for polyubiquitin, insulin, and p62 (Figures 2B and 2C).
Atg7f/fand Atg7f/f:Cre mice revealed degenerative changes in
islets. The mutant islets contained multiple cyst-like structures,
measuring15–20mmindiameter,whichweredetectable asearly
as 4 weeks of age and increased in number in an age-dependent
like structures, occasionally associated with caspase-3-positive
apoptotic cells (Figure 2D, c), were not fat-laden adipocytes,
judged by oil red O staining (data not shown). Toluidine-blue
staining of thin-sliced sections showed that mutant islets, but
Figure 2. Beta Cell-Specific Inactivation of Atg7 and Islet Morphological Abnormalities in Mutant Mice
(A) Pancreatic islets were isolated from 16-week-old Atg7f/f, Atg7f/+:RIP-Cre, and Atg7f/f:RIP-Cre (Atg7f/f:Cre) mice. Cell lysates were subjected to immunoblot
analysis of Atg7, poly-ubiquitin, p62, and LC3.
(B) Representative images of H&E staining and immunostaining with ubiquitin antibodies of 20-week-old Atg7f/fand Atg7f/f:Cre islets. Arrowheads in d indicate
ubiquitin-positive aggregates. Scale bars represent 100 mm (a and b) and 50 mm (c and d).
(C) Double staining for insulin (red) and p62 (green) of 20-week-old islets. Nuclei were labeled by DAPI (blue). Colocalization of p62 and insulin-depleted b cells is
indicated by arrowheads and arrows. Scale bars represent 100 mm.
(D) Magnified images of degenerative lesions in Atg7f/f:Cre islets. H&E staining (a), insulin (green) and DAPI (blue) staining (b), caspase-3 staining (c), Toluidine-
blue staining of Atg7f/f:Cre (d), and Atg7f/f(e) islets. Scale bars represent 5 mm (a–c) and 50 mm (d and e). Electron microscopic analysis of a degenerative b cells
indicated by the small square in d is shown (f, g). Note the presence of inclusion bodies (arrows in f and g) and concentric membranous structures in b cells of
Atg7f/f:Cre (arrowhead in g). Scale bars represent 5 mm.
(E) Electron micrographs of b cells. Deformed mitochondria were noted in Atg7-deficient b cells (small inset). Scale bars represent 5 mm.
Cell Metabolism
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Cell Metabolism 8, 325–332, October 8, 2008 ª2008 Elsevier Inc. 327
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not control islets, contained enlarged ''balloon-like'' cells with
H&E sections. EM analysis indicated that the ''balloon-like'' cells
were most likely degenerating b cells, on the basis of the obser-
vation that they were relatively rich in mitochondria and always
associated with a small number of insulin vesicles (Figure 2D,
f and g). These cells frequently contained inclusion bodies (Fig-
ure 2D, arrow in f) and aberrant concentric membranous struc-
tures (Figure 2D, arrowhead in g), similar to those observed in
Atg7-deficient livers (Komatsu et al., 2005). The accumulation
of inclusion bodies increased in an age-dependent manner
(data not shown). Despite the presence of highly degenerated
insulin-positive cells were also found in the mutant islets. Double
like structure of adult islets in Atg7f/f:Cre mice was generally
maintained (data not shown).
Autophagy is responsible for constitutive protein turnover in
quiescent hepatocytes even under nutrient-rich conditions, and
defective autophagy is associated with accumulation of large,
ubiquitin-containing inclusion bodies with overexpression of
LC3-binding protein p62 in liver and brain (Komatsu et al., 2005,
2006, 2007). The present data suggest that ubiquitin and p62
are also involved in the formation of protein aggregates in b cells.
Insulin and p62 double staining showed colocalization of insulin-
depleted ballooning b cells with p62 (Figure 2C, arrows and
arrowheads), suggesting that the expression of p62 reflects
damaged b cells. The mutant b cells contained deformed and
tochondria was reported in Atg7-deficient hepatocytes and neu-
Nakai et al., 2007). These results suggest that the turnover of mi-
Impaired Insulin Secretion in Atg7-Deficient Mice
Next, we evaluated whether the changes in islet morphology
were associated with changes in b cell function. The nonfasting
blood glucose level of Atg7f/f:Cre mice was significantly higher
than that of control mice throughout the study (Figure 3A). Intra-
peritoneal glucose tolerance tests (IPGTT) showed glucose
intolerance with reduced insulin secretion in Atg7f/f:Cre mice
(Figure 3B). Insulin tolerance test (ITT) revealed that insulin
sensitivity of Atg7f/f:Cre mice was comparable with that of the
control group (Figure S4A). These results suggest that the
impaired glucose tolerance in Atg7f/f:Cre mice is primarily
caused by insufficient glucose-stimulated insulin secretion. Glu-
cose-stimulatedinsulin release in isolated islets was significantly
reduced in Atg7f/f:Cre mice compared to control mice (Fig-
secretion between the two groups, the deficiency of signaling
events upstream of KATPchannel closure appears to be respon-
sible for the defects in glucose-stimulated insulin secretion.
Since the mitochondrion is a key machinery involved in the reg-
ulation of glucose-induced insulin secretion in b cells (Silva et al.,
2000), the defective insulin secretory capacity of mutant b cells
could be due to accumulation of dysfunctional mitochondria
in Atg7f/f:Cre islets. To test this possibility, we measured glu-
cose-stimulated ATP production in isolated islets with the ATP
assay (Fujimoto et al., 2002). The significantly lower ATP produc-
lated islets) relative to control islets (1.60-fold increase, p < 0.05)
suggested a defective mitochondrial function under standard
(STD) diet conditions (Figure 3D).
Inductive Beta Cell Autophagy as an Adaptive Response
against Increased Insulin Resistance
Next, we investigated the physiopathological effect of induced
Eight-week-old Atg7f/f:Cre and Atg7f/fmice were fed HF diet for
12 weeks. During the period, both mice groups consumed the
same amount of food and displayed similar weight gain (Figures
S5A and S5B). HF-fed Atg7f/f:Cre mice had significantly higher
nonfasting glucose levels and severely impaired glucose toler-
ance compared with HF-fed Atg7f/fmice (Figures 4A and 4B).
These results indicate that under HF diet, the difference in
glucose tolerance between Atg7f/f:Cre and Atg7f/fmice seems
to become larger than under STD diet (Figures 3A and 3B versus
Figures 4A and 4B).
Morphometric analysis showed that the islet cell area during
the 12 week HF diet increased by 2-fold in Atg7f/fmice but not
in Atg7f/f:Cre mice, indicating failure of compensatory hyperpla-
3+apoptotic cells were noted in the islets of HF-laden Atg7f/f:Cre
mice, compared with Atg7f/fmice. These findings may account
for the lack of b cell hyperplasia (Figures 4D and 4E). However,
the concentration of immunoreactive insulin (IRI) was higher in
Atg7f/f:Cre mice despite the lower b cell mass (Figure 4B). Since
the insulin ELISA used in this study does not discriminate
between insulin and proinsulin, it is possible that a significant
amount of the detected IRI is secreted as biologically inactive
proinsulin, as reported in subjects with type 2 diabetes (Roder
et al., 1999).
In agreement with the increased apoptosis described above,
degeneration of islets in Atg7f/f:Cre mice became more pro-
nounced when these mice were fed HF diet; the number of
degenerative vacuoles and p62 immunoreactivity were in-
creased (Figure 2C versus Figure 4G). These degenerative
changes were associated with upregulation of polyubiquitinated
proteins and p62, compared with STD-diet-fed mice (Figure S6).
Recently, we reported that liver injury caused by autophagy
deficiency is highly dependent on accumulation of p62 and
that this accumulation is associated with the activation of detox-
ifying enzymes, including glutathione 300 S-transferase (GST)
families, cytochrome P450 families, and NAD(P)H dehydroge-
nase quinone 1 (Nqo1) (Komatsu et al., 2007). In the next step,
we quantitated the expression levels of downstream targets for
p62 accumulation, including Nqo1, GST-mu, and GST-theta in
Atg7f/f:Cre and Atg7f/fmice and found that two of them were
moderately increased (Figure 4H). These results suggest the
possible involvement of p62 in b cell injury caused by autophagy
deficiency, but this needs further investigation in future studies.
Our study showed that autophagic vacuole formation is mark-
edlyupregulated in the presenceof insulinresistance associated
Cell Metabolism
Roles for Autophagy in Pancreatic Islet Homeostasis
328 Cell Metabolism 8, 325–332, October 8, 2008 ª2008 Elsevier Inc.
Page 5
autophagy in b cells, we inactivated Atg7 selectively in b cells.
Loss of autophagy in b cells resulted in age-dependent accumu-
lation of ubiquitinated proteins and damaged organelles, which
may cause dysfunction and degeneration of b cells. The results
suggest that ubiquitinated proteins, which otherwise form toxic
aggregates, are constantly cleared by autophagy, and that au-
tophagy can act as a defense mechanism against various types
cent study showing that diabetes-induced oxidative stress can
induce ubiquitination and storage of proteins into cytoplasmic
aggregates of pancreatic b cells (Kaniuk et al., 2007). Recently,
Marsh et al. reported that autophagy is markedly upregulated
in secretory-deficient Rab3?/?b cells (Marsh et al., 2007). In
this case, autophagy appears to be involved in maintaining intra-
cellular insulin content by accelerating insulin degradation rate in
b cells. Our in vivo study provides genetic evidence that autoph-
stasis by constantly degrading potentially toxic cytoplasmic
components, such as damaged organelles and p62, which is
commonly observed in other pivotal organs such as liver and
heart (Komatsu et al., 2005; Nakai et al., 2007). Hepatic injury
in liver-specific Atg7-deficient mice largely depends on the intra-
hepatic accumulation of p62 (Komatsu et al., 2007). Similar
mechanisms could account for the b cell failure in b cell-specific
Atg7-deficient mice. This needs to be thoroughly investigated by
the generation of b cell-specific Atg7 and p62 double-deficient
Autophagy has long been characterized as a key strategy for
maintaining energy homeostasis under nutrient-poor conditions.
Indeed, autophagy is necessary for survival in the early neonatal
starvation period in mice (Kuma et al., 2004). Interestingly, our
study revealed that b cell-autophagy is markedly upregulated
by high calorie intake, a common state in many developed
Figure 3. Impaired Glucose Tolerance and Defective Insulin Secretion in Atg7f/f:Cre Mice
(A) Nonfasting glucose levels of STD-diet-fed Atg7f/f(n = 10), Atg7f/+:Cre (n = 9), and Atg7f/f:Cre (n = 10) mice.
(B) Blood glucose concentrations and serum insulin levels measured during IPGTT at the age of 16 weeks. Open circles, Atg7f/fmice (n = 9); solid triangles,
Atg7f/+:Cre mice (n = 9); solid circles, Atg7f/f:Cre mice (n = 9). Data are mean ± SEM. *p < 0.05, **p < 0.01 (Atg7f/fversus Atg7f/f:Cre);#p < 0.05,##p < 0.01
(Atg7f/+:Cre versus Atg7f/f:Cre).
(C) Insulin secretion induced by insulinotropic agents in batch-incubated pancreatic islets isolated from STD-diet-fed Atg7f/f(open bars) and Atg7f/f:Cre (solid
bars) mice at 16 weeks of age. Data are mean ± SEM. **p < 0.01 (Atg7f/fversus Atg7f/f:Cre). Data were obtained from at least eight replicates for each group.
(D)Glucose-stimulatedATPproductionfromisolatedisletsofSTD-diet-fedAtg7f/fandAtg7f/f:Cremice.Dataarepresentedasfoldincrease ofATPlevelsinduced
by glucose stimulation (16.7 mM glucose) relative to the levels before stimulation (2.8 mM glucose). *p < 0.05 (Atg7f/fversus Atg7f/f:Cre). Data were obtained from
at least eight replicates for each group.
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Roles for Autophagy in Pancreatic Islet Homeostasis
Cell Metabolism 8, 325–332, October 8, 2008 ª2008 Elsevier Inc. 329
Page 6
countries, in contrast to energy starvation. This inductive au-
tophagy appears to be triggered by increased insulin resistance
caused by high calorie intake or obesity. A candidate mediator is
high serum FFA concentrations result in increased production of
reactive oxygen species, b cell dysfunction, and apoptosis of
b cells, a state termed ''b cell lipotoxicity''(DeFronzo, 2004;
Unger and Zhou, 2001). As shown in our study (Figure 4D), loss
of autophagy resulted in substantial cell death of b cells when
animals were fed HF diet. Thus, the concept of FFA-induced
activation of autophagy in b cells is conceivable as an adaptive
response, providing cells with a safety mechanism to eliminate
Figure 4. Deterioration of Glucose Tolerance in HF-Fed Atg7f/f:Cre Mice
(A) Nonfasting glucose levels of Atg7f/f(n = 9), Atg7f/+:Cre (n = 8), and Atg7f/f:Cre (n = 8) mice during HF-diet periods.
(B) Blood glucose concentrations and serum insulin levels measured during IPGTT at the age of 20 weeks after 12 weeks of HF diet. Open circles, Atg7f/fmice
(n = 10); closed triangles, Atg7f/+:Cre mice (n = 9); closed circles, Atg7f/f:Cre mice (n = 9). Data are mean ± SEM. *p < 0.05, **p < 0.01 (Atg7f/fversus Atg7f/f:Cre);
#p < 0.05,##p < 0.01 (Atg7f/+:Cre versus Atg7f/f:Cre).
(C) Percent islet area of Atg7f/fand Atg7f/f:Cre mice fed STD and HF diet.
(D and E) Number of cleaved caspase-3- and Ki-67-positive intraislet cells in Atgf/fand Atg7f/f:Cre mice fed STD and HF diet. Data are mean ± SEM.yp < 0.05,
yyp < 0.01 (Atg7f/fwith STD versus Atg7f/fwith HF);{p < 0.05,{{p < 0.01 (Atg7f/fwith HF versus Atg7f/f:Cre with STD);zp < 0.05,zzp < 0.01 (Atg7f/fwith HF versus
Atg7f/f:Cre with HF);!!p < 0.01 (Atg7f/fwith STD versus Atg7f/f:Cre with HF);xp < 0.05 (Atg7f/f:Cre with STD versus Atg7f/f:Cre with HF). For morphometric analysis,
four mice were examined for each genotype (C–E).
(F) Representative images of H&E staining, immunostaining with ubiquitin antibody of HF-fed Atg7f/fand Atg7f/f:Cre islets (at 20 weeks of age). Arrowheads in
d indicate ubiquitin-positive aggregates. Scale bars represent 100 mm (a and b) and 50 mm (c and d).
(G) Double staining for insulin (red) and p62 (green) of 20-week-old islets. Nuclei were labeled by DAPI (blue). Scale bars represent 100 mm.
(H) The mRNA expression levels of various genes in Atg7-deficient islets. The mRNA levels of the indicated genes were determined by real-time RT-PCR analysis
with total islet RNA extracted from Atg7f/f(open bars) and Atg7f/f:Cre (black bars) mice fed STD diet. Values for Atg7f/f:Cre islets were expressed relative to the
mRNA level of each gene in Atg7f/fislets. Data are mean ± SEM. *p < 0.05 (Atg7f/fversus Atg7f/f:Cre).
Cell Metabolism
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330 Cell Metabolism 8, 325–332, October 8, 2008 ª2008 Elsevier Inc.
Page 7
damaged mitochondria and/or other cell structures and to avoid
tions (Meijer and Codogno, 2007). Autophagy induction by FFA
was not inhibited by Etomoxir, a CPT-1 inhibitor (K.K., unpub-
lished data), suggesting that FFA influx into mitochondria is not
essential for this process. Elucidation of molecular mechanisms
underlying the FFA-induced autophagy awaits further investiga-
tion. Based on the possible implication of autophagy in the path-
ogenesis of diabetes, manipulation of autophagic activity in
b cells could be useful therapeutically by preventing disease
progression, particularly under insulin-resistant states, such as
obesity and metabolic syndrome.
Animal Experiments
The study protocol was reviewed and approved by the Animal Care and Use
Committee of Juntendo University. All mice were housed in specific patho-
gen-free barrier facilities, maintained under 12 hr light/dark cycle, and fed
a standard rodent food (Oriental Yeast) for the STD study or rodent food con-
taining 60% fat (Research Diet) for the 12 week HF study and provided with
water ad libitum. We used the Rat Insulin Promotor-driven Cre recombinase
(RIP-Cre)-Flox strategy todeleteATG geneinapancreaticbcell-specific man-
ner. Generation of Atg7flox/+mice was described previously (Komatsu et al.,
2005). We crossed RIP-Cre+/?:Atg7flox/+mice with Atg7flox/+mice to generate
Atg7flox/flox(Atg7f/f), RIP-Cre+/?:Atg7+/+, RIP-Cre+/?:Atg7flox/+(Atg7f/+:Cre),
and RIP-Cre+/?:Atg7flox/flox(Atg7f/f:Cre) mice. We used 6- to 16-week-old
male mice for the STD study and 8- to 20-week-old mice for the HF study.
Then, these mice were used for further analyses. PCR analysis for determina-
tion of genotype was performed as described previously (Komatsu et al.,
Cell Culture and Immunoblot Analysis
INS-1 cells were cultured as previously described (Asfari et al., 1992). Oleic
acid (100 mM, Sigma) was dissolved in 0.1N NaOH, then adjusted to 1 mM
oleic acid and 1% bovine serum albumin solution in RPMI 1640. Immunoblot
analysis was performed as described previously (Uchida et al., 2007). Anti-
LC3 and anti-ubiquitin antibodies (Abs) were described previously (Komatsu
et al., 2005). Anti-p62 Ab (1:1,000) and anti-GAPDH Ab (1:1,000) were
purchased from Progen and Cell Signaling, respectively. Immunoreactivity
was visualized and quantitated with Fuji LAS 3000 (Fuji Film).
Assay of Insulin Secretion from Isolated Islets
Pancreatic islets were obtained from five to six mice at 16 weeks of age by
collagenase digestion, as described previously (Uchida et al., 2007). In brief,
five size-matched islets were incubated in 400 ml Krebs-Ringer solutions
containing glucoseor KCl for 60 min or 10min,respectively.Insulin concentra-
sorbent assay (ELISA).
Data Analysis
concentration, body weight, food intake, glucose concentrations, and insulin
levels during IPGTT and ITT were examined for statistical significance by the
nonrepeated ANOVA, followed by post hoc analysis (Bonferroni's test). Statis-
tical differences between two groups were calculated by the unpaired
Student's t test. A p value less than 0.05 denoted the presence of a statistically
significant difference.
Supplemental Data include Supplemental Experimental Procedures and
six figures and can be found with this article online at http://www.
We thank Dr. C.B. Wollheim (Geneva) for the gift of INS-1 cells, Dr. K. Otsu
(Osaka University) for the valuable suggestions, and Ms. N. Daimaru, Ms.
E. Magoshi, and Mr. M. Kamimura for the excellent technical assistance.
This work was supported by grants from the Ministry of Education, Sports
and Culture of Japan (to R.K. [19659236], Y.F. [19591067], and H.Y.
[19044039]) and by the Takeda Science Foundation, Astellas Foundation,
and Suzuken Memorial Foundation (to Y.F.).
Received: March 30, 2008
Revised: June 28, 2008
Accepted: August 12, 2008
Published: October 7, 2008
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telaar, M.K., and Burant, C.F. (2006). Islet microvasculature in islet hyperplasia
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text:
Meet the characters of Beatrix Potter's magical, timeless world that's been reimagined for a whole new generation. Let's meet Peter, his friends and foes.
Go on a magical mermaid adventure with Dora and rescue the stolen treasure!
The race is on to stop Crusher from taking Gaby's tools
Create and color your own Peppa pictures online
Help Tissue Girl Molly & Soaper Boy Gil catch the germy nose and save the town
The race is on! Help Nick Jr. pals collect party favors in time for the fiesta
Help Marshall save the turtles and fly with Skye to Chickaletta's rescue!
Get groovy with colors & glitter to create unique designs
The Team needs your help! Round up the bad guys and get your own UmiCops badge
Get great ideas on hosting a Nick Jr. themed birthday bash!

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Macbeth Act IV and Imagery By Julia M., Joon-Ha, and Anastasia, and Marina Agenda 1. Quiz 2. Characters in Act IV 3. Summary of Act IV 4. Enactment 5. Imagery throughout the play 6. Discussion Quiz 1. Which was not a prophecy in Act IV? a. Birnam Wood must rise for Macbeth to be defeated b. Beware of Macduff c. Macbeth will fight Macduff heroically d. Nobody born from woman may hurt Macbeth 2. Macbeth was freaked out by Banquo in scene I because… a. He was trying to kill Macbeth b. He was dead and came back as a ghost c. He and Macbeth had the same outfit 3. Who are Lady Macduff and her son discussing? a. Banquo b. Fleance c. Donalbain d. Macduff 4. Which character believes that Scotland is suffering and will later succeed Macbeth? a. Ross b. Hecate c. Macduff d. Malcom 5. What does Ross report to Macduff about his family? Quiz Answers 1. C 2. B 3. D 4. D 5. C Characters 1. The Witches: conjure the three apparitions that predict Macbeth's future 2. Macbeth - the Thane of Glamis. Made Thane of Cawdor after prophecy. At beginning-noble, brave and loyal, but as his temptation leads him to murder. Turns selfish. 3. Lady Macbeth - Macbeth's wife, ambitious, strong, ruthless, urges her husband to kill Duncan and seize the crown. Is eventually guilty. Very strong and independent. Characters 4. Macduff - A Scottish nobleman. Leads against Macbeth. wants Malcolm to be king; wants to kill Macbeth as revenge for murdering his family. 5. Malcolm - The son of Duncan, whose restoration to the throne signals Scotland's return to order, flees Scotland when his father, King Duncan, is killed, but later takes over and "fixes" his country. Characters 6. Lady Macduff - Macduff's wife. Loving mother and wife -very different from Lady Macbeth. She is sweeter, kinder and not as independent and strong as Macbeth's wife. 7. Lennox and Ross - Scottish noblemen- act as messengers Scene I Macbeth comes to the witches and demands to know the truth about his prophecy. 1. They call upon the 4 apparitions 1. Beware of Macduff 2. He will not be killed by a man born from a woman 3. He is safe until the Birnam Wood moves to Dunsinane Hill. 4. 8 kings appear and Banquo"s ghost walks at the end of the line carrying a mirror. Scene I cont"d 2. Lennox tells Macbeth that Macduff has fled to England. 3. Macbeth decides to send murderers to kill Macduff"s wife and children. "Eye of newt and toe of frog, wool of bat and tongue of dog" (IV.i). Scene II 1. Lady Macduff is angry that her husband fled and left her and her children defenseless, but does not flee when told to because she argues that she is innocent. 2. Lady Macduff tells her son that his father is dead, but he doesn"t agree. 3. Murderers come and kill Lady Macduff and her children Scene III 1.Malcom tests Macduff"s loyalty to Scotland by falsely telling him that Malcom will be a horrible king because he is lustful, greedy, and violent. Macduff, after disagreeing at first, is scared for Scotland, and therefore passed the test. 2. Doctor enters and tells Macduff that King Edward has the power to cure anyone just by touching him or her. 3. Ross comes from Scotland and informs the men the horrors of Scotland . At first hesitant , he later confesses to Macduff that his wife and children are dead. 4. Crushed by the news, Macduff announces that he will use his anger to get revenge and kill Macbeth . Enactment Blood Imagery 1. "What bloody man is that? He can report, As seemeth by his plight, of the revolt the newest state" (I.ii.1) 2. "Which smok'd with bloody execution"(I.ii.20) 3. "Will all great Neptune"s ocean wash this blood Clean from my hand? No; this hand will rather the multitudinous seas incarnadine, making the green one red." (II. ii. 78-81) 4. "And on thy blade and dudgeon gouts of blood, Which was not so before. There"s no such thing: It is the bloody business which informs thus to mine eyes." (II.i.58) 5. "What, will these hands ne"er be clean?…Here"s the smell of the blood still: all the perfumes of Arabia will not sweeten this little hand." (V. i.45,53-55) 6. "I am in blood stepped in so far, that, should I wade no more, returning were as tedious go o'er." (III. iv. 168-170) Dagger Imagery 1. "There"s daggers in men"s smiles. The near in blood, the nearer bloody." (II.iii.165-166) 2."Stepped in the colors of their trade, their daggers unmannerly breeched with gore." (II.iii.134) 3."That my keen knife see not the wound it makes, nor heaven peep through the blanket of the dark to cry "Hold, hold!"" (I.v.59) 4."Is this a dagger which I see before me, the handle toward my hand?" (II.i.44) 5."This is the air-drawn dagger which you said led you to Duncan." (III.iv.75) 6."Be this the whetstone of your sword. Let grief convert to anger. Blunt not the heart; enrage it." (IV.iii.268) Baby Imagery 1. "And pity, like a newborn babe striding the blast, or heaven"s cherubin horsed Upon the sightless couriers of the air, shall blow the horrid deed in every eye,that tears shall drown the wind" (I.vii.21) 2. "Each new morn / New windows howl, new orphans cry, new sorrows / Strike heaven on the face..." (IV.iii.5-8). 3.. "I have given suck, and know how tender "tis to love the babe that milks me. I would, while it was smiling in my face, have plucked my nipple from his boneless gums and dashed the brains out…" (I.vii.62) 4."O treachery! Fly, good Fleance, fly, fly, fly! Thou mayst revenge--O slave!" (III.iii.25-26). 5."Murderer: He's a traitor. Son: Thou liest, thou shag-eared villain! Murderer: What, you egg? Stabbing him. Young fry of treachery! Son: He has killed me mother. Run away, I pray you" (IV.ii.92-98) 6.Thunder. 2nd Apparition, a Bloody Child. "Be bloody, bold, and resolute. Laugh to scorn The power of man, for none of woman born Shall harm Macbeth" (IV.i.90-92) Nature Imagery 1. "Bear welcome in your eye, your hand, your tongue; look like the innocent flower, but be the serpent under 't" (I.v.63-65) 2. "As hounds and greyhounds, mongrels, spaniels, and curs, shoughs, water-rugs, and demi-wolves are clept"(III.i.103) 3. "A falcon, tow"ring in her pride of place, was by a mousing owl hawked at and killed." (II.iv.15) 4. "There the grown serpent lies. The worm that"s fled hath nature that in time will venom breed." (III.iv.32) Nature Imagery cont'd 5. "Scale of dragon, tooth of wolf, witch"s mummy, maw and gulf of the ravined salt-sea shark,…gall of goat and slips of yew slivered in the moon"s eclipse, Nose of Turk and Tartar"s lips, finger of birth-strangled babe"(IV.i.22) 6. "Now God help thee, poor monkey!" (IV.ii.65) 7. "And Duncan"s horses…turned wild in nature, broke their stalls, flung out, contending "gainst obedience…" (II.iv.17) Other Imagery 1. "When shall we three meet again? In thunder, lightning, or in rain?"(I.i.1) 2. "By the clock `tis day, and yet dark night strangles the traveling lamp" (II. iv.6-7) 3. "New honors come upon him like strange garments, cleave not to their mould but with the aid of use." (I. iii. 144-145) 4. "The Thane of Cawdor lives: why do you dress me in borrow'd robes?" (I.iii.114) Discussion Questions 1. In Act IV, Scene i, in which the Three Witches show the three apparitions, Shakespeare has them speak an almost riddle-like prophecy. Why do you think Shakespeare intended to do this? 2. If you were writing a scene in which a character's critical future was to be said, how would you word it? Would you just blurt it out, or also try to riddle it up? 3. In Act IV, Scene iii, Malcolm tests Macduff by saying he will be an even worse king than Macbeth. What characteristics make Duncan and Malcolm good kings, and what traits make Macbeth a tyrant?
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Here's a great project for different ages to do together
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There was a posting on one of the genealogical mailing lists that I belong to on making rugs. It set me thinking about the rugs that my great grandmother, Annie Prudence Butcher, nee Harris who lived in Surrey, used to make.
She used to use string instead of knitting wool then somehow used carpet wool cut in lengths which then allowed the string to be able to be attached to the hesian back using a sacking needle. Looking front to back there was the wool at the front, string in the middle then the hesian back.
I might try and make a very small one as a sample, so that I can see the process that was used in making a rug in this tradtional way.
The ramblings & obsessions of a fisherman's wife! ~ a potpourri of history, genealogy and books. Also some general ramblings if they take my fancy!
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Saturday, 28 January 2006
Making Rugs
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I'm using dwr to handle ajax calls to a java backend, I'm returning a Map in java, and I need to know its size in javascript when it returns in a callback function. Is there a way to do that?
Take the 2-minute tour ×
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You basically need to know how to determine the size of a javascript associative array, because this is what dwr returns in this case. This is explained, of course, on Stack Overflow: http://stackoverflow.com/questions/5223/length-of-javascript-associative-array


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Covers national and Maryland state tort and workers compensation legislation. Also focuses on boating, car, motorcycle, pedestrian and truck accidents, as well as medical malpractice and wrongful death. By Lebowitz & Mzhen.
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Haad Salad Villa
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... at approximately 1 o clock. However, nobody actually told us the plan, so we turned up at a bar, sat and waited, but we ended up waiting for about an hour and a half until the next bus came to take us to the pier. It was so long and boring, but we did end up meeting a couple of cool people. We met a sound guy called Leo, who was from Italy, and seemed to know everything! Seeing as we ended up coming to Koh Phangnan a day early, we didn't have ...
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... hammock and did Ashtanga yoga and meditated (tried to meditate) each day.
We had a special surprise one morning and hiked to the other side of hill/mountain where we got on a wooden raft with motor and took a drive around the lake. It was so peaceful and beautiful. We stopped at a cave and got a lighted tour of it from the man who discovered it. Such a treat.
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... we never got his name) what Lynne wanted with respect to shading and colouring because it didn't seem to us like he understood. But in the end it was all figured out and Lynne had been "bambooed". Needing to decompress and celebrate we ended back at the Happy Hippo for a G&T, which turned into two because of the massive downpour that started not long after we arrived and of course we were not prepared with umbrellas or jackets. ...


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"Damn you, Tore," I grumbled to myself as I staggered out of bed at midnight, after only two hours of fitful sleep, in order to make the excruciatingly early call time of 1:30 a.m. at the TV stage set up in
's display at the Los Angeles Auto Show. This seemingly ridiculous call time for "talent" (supposedly, that's me) was ordered by Tore Dietrich, the president of High Impact Television, an independent news production company that specializes in live TV news reports from major trade shows. Well, I really couldn't get too upset, because the "crew" call time was nonexistent: Tore and his 30-person crew had been working around the clock from the day previous. And by 3 a.m. or so, we'd be linking up to a satellite to transmit our first live, behind-the-scenes report from the show floor to a series of major eastern-time-zone cities like Boston, Detroit, Pittsburgh, and New York. Pretty cool stuff.
Okay, so it's cool for the first half-dozen TV reports, when you'll still have your wits about you, but stand under the lights for six to eight hours on end, batting back answers to off-the-wall questions from some faraway news anchor, and your brain will seriously begin to fry. My little task was to do live news broadcasts to virtually every major metropolitan city in the country, as well as Canada. That totals four days, two airplane flights, and way too much sleep deprivation necessary to produce back-to-back-to-back live "stand ups" of yours truly, jabbering on about what's hot at not only the L.A Auto Show, but also a sneak peek, before-it-opens, expos of the North American International Auto Show in Detroit.
In case you've never seen it in person, Detroit is truly the granddaddy of all auto shows, with over 6000 journalists from around the world in attendance on press days and more than a million people barging through the doors during the nine days it's open to the public. With the staggering number of outrageous concept cars to ogle, world premieres to report on, bigwig execs to interview, and mega-dollar displays to peruse, the Detroit Show is considered big news virtually everywhere cars exist.
And that's where Motor Trend and High Impact TV come in. Although I'm the face on your TV, it's really Tore's crew that makes it all happen. Believe me, the stress level of producing not just one, but 70, live TV reports is enough to give aneurisms to everyone in the immediate vicinity.
Wanna be a TV news god for a day? Here's what to expect: You try to go to sleep at 6 p.m. the night before, but find you can't overrule your internal clock, so you toss and turn until about 10:30. The alarm rings 90 minutes later. Once on the set, and after too many chocolate crullers, you're made up, wired up, and propped up into position in front of the camera. It's now 2:45 a.m., and there's no sign of life except for your production crew scrambling around like mad, ironically juxtaposed to a triumvirate of bored security guards playing Hackey Sack with stale blueberry muffins. Way out in the parking lot, inside the $1 million satellite truck, is your tech crew: They're your human link to the outside world, so treat them nicely, even though you'll probably never see them face-to-face. In your ear is Kirby, your audio technician, Leslie, your technical director (controls the video switching and reminds you of stuff, if you forget), George, the master satellite technician (beams you up to the "bird"), and several other hardworking pros who keep it all together even when something unforeseen happens during a broadcast (like when you hear your own voice in your earpiece with a two-second delay, or the time you suddenly get 150 decibels of white noise in your ear as the Dallas news anchor is posing his most poignant query). Without these folks, you'd be left to fry.
Then there's your floor crew: Diane, your producer, Edgar and Dan, the camera operators, Melissa, the make-up artist, numerous grips, gaffers, and production assistants, as well as Lisa, the director who gives you broadcast data (duration of your segment, the news anchor's name, and the city you're broadcasting to), as well as the five-four-three-two-finger countdown to "on the air" that makes you feel like a big shot.
I'm telling you all this mostly because I can't believe it myself. Our brain-draining total: 70 live broadcasts covering 38 new cars from 15 manufacturers. Whew.
So, the next time you see me on some early morning news broadcast (we'll be at the New York Auto Show on April 19-20), cut me some slack if I look a little bit tired, okay?
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Music / K / Kathryn Scott / Lyrics / When I Survey The Wondrous Cross / Lyrics
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My mother's physican claims that Coreg (part of beta blocker family) in the low dosage 3.1 mg can be stopped without titration (gradually withdrawal over 1-2 weeks). Is there any literature that suggests this can be done? JP
Can Coreg be stopped without titration?
- Posted:
- 5 Nov 2004 by jonpaulsen
- Topics:
- coreg
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5 Nov 2004
Info from the Coreg website at http://www.coreg.com/index.htm
Patients taking Coreg should avoid stopping therapy abruptly. With certain beta-blocking agents, stopping therapy abruptly has led to chest pain, and in some cases heart attack. The dosage of Coreg should be reduced gradually over a 1- to 2-week period, and the patient should be carefully monitored.
Further Information
- Coreg Information for Consumers
- Coreg Information for Healthcare Professionals (includes dosage details)
- Side Effects of Coreg (detailed)
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What ! A tomato! could it be?
Came back from meandering around Oklahoma, had a great time saw a lot of country and found this golf ball size. ME! really growing tomatoes...A couple hundred more and I will firing up the canners.
also the peppers are coming on pretty fast.
my first one this year.
Last year I had 22 plants big huge beautiful plants and no tomatoes until September, and then we only got 2. Most people in this area said it was a bad tomato year so I didn't feel too bad.
Year before, my first real garden and first year here, I lost everything to the hot wind. Again the locals assured me it wasn't me just the challenges we face here in the panhandle.
Well a couple weeks ago I was getting worried. On here everyone talking about tomatoes and I had plenty blooms no fruit yet. I fertilized and it seems to have helped, plus rain couldn't hurt, right...
Kim glad you have tomatoes setting. I picked my first one last week. It will be another 7-10 days before I pick another one. They will be few for a while. But at least can have a BMP once in a while.
Have your sweet potato slips arrived. I put two potatoes in container to grow slips from. One has produced 7 so far and has more breaking through. The other hasn't produced any. I did take a few off of some potatoes I didn't cover and have them rooting in water now. I started planting slips the night before the heat hit. So far have kept all alive. I have developed a system that works for me after losing several nice ones the first year. I water them in well after planting. Then I put straw around them and sparsely cover the top of them also. Then cover this with a piece of shade cloth. I water them again the second night and after that look at them when I get home around 4 and only water if I see some wilting. I give them at least 7 days to root some and then start removing the shade cloth of an evening and putting it back before I leave for work. Then over a weekend I will remove it of a morning and gradually after 2-3 weeks will have it removed and they do fine. After I have the shade cloth removed I then remove the straw I had over them. I still lose one once in a while but not as often. There maybe be better methods but this one works well for me. Otherwise the heat kills them faster than I can set them out. Jay
Jay thanks for the tips on the sweet potatoes. I was worried about how to keep them going in this heat. I haven't received them yet I am going to keep 20 and give my FIL 80. He has more room and is ready to go. If it threatens frost before they are done I have a few cattle panels ready to makeshift a tunnel in my fall area.
I have quite a few tomatoes coming now. I am really starting to get excited that some may actually make it into jars this year. I have had cases of jars waiting patiently to be filled for 3 years.
Kim I'm sure there are many other ways and maybe some better. It is the way that I found that has worked for me. Even if the ground is wet and they are wilting severely I water them. My garden is in deep sand also. Without an established root system it is hard for them to uptake enough water in the extreme heat and especially with the winds we've had. Shading them helps reduce their water requirements.
I've got a few tomatoes set. Some of my earlier plants are just now really loaded with blooms. And now we have the high heat. It hit 94 today but has been cloudy and is 88 now. So maybe I will get a little fruit set. They are saying possibly cooler down the road 7-10 days. Also the winds are supposed to be milder than they have been that should help also. My later plants aren't ready for heavy fruit set yet. Jay


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I found this Hotel excellent value, the staff were really lovely and very helpful. I felt really at home. We will certainly stay again the next time we are in London.I can highly recommend this Hotel. - Heather
Lots of gadgets, no hidden extras for room service, which can be ordered by the in-room iPad... Library of 3D films available for 46" 3D television. Very high tech hotel. Breakfast was amazing. - Anonymous
Excellent conditions, nice and quiet, great rooms - not very spacey butone has to keep in mind it's Europe and the hotel is the formerresidence of a former British Lord! Great location: close to Victoriasubway and also within walking distance from both tourist attractions(ex. Buckingham Palace and Westminster) and stylish shopping area(Brompton and Kensington). Very friendly and obliging staff. - Mihaela
It is very bad,noisy and old hotel it was same 2 star or BandB - Fayz
The hotel was spotless, staff very attentive and polite. Food was also of a high standard in the blue boar restaurant. We went for my 50th birthday and they upgraded the room and also laid on complimentary fruit, chocolates and a bottle of champagne. Much appreciated and went down well. This hotel is perfect for the sightseeing tourist as 5 minute walk from westminister or Buckingham palace with easy access to tube and shopping. Loved it and will go back. - Anonymous


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Judge Dredd doesn't tolerate street art - - part of a series by RYCA Art.
*Previously: Judge Dredd Lego CubeDude.
*Buy Judge Dredd toys at eBay.
Monday, March 22, 2010
Judge Dredd vs. Shepard Fairey
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Its fun to stay at the Y.M.C.A!!
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Anybody have a family membership to the Y? I'm thinking of getting one for the whole family.Do you like it?
Posted by Anonymous on Jan. 18, 2013 at 2:20 PM
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Yes I love it.
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Latest Lagotto Romagnolo Stories
2011-07-29 13:06:51
A new epilepsy gene, LGI2, has been found in the Lagotto Romagnolo dogs, known from their gift for truffle hunting.
2011-07-29 06:27:37
Truffle hunting dogs may be the answer in treating benign childhood epilepsies.
Latest Lagotto Romagnolo Reference Libraries
2008-05-27 16:37:00
The Lagotto Romagnolo is a gun dog from Italy traditionally used as a water retriever. The breed originated in the lowlands of the Romagna sub-region of Italy and has a natural instinct for working and hunting. The Lagotto generally stands 16 to 19 inches tall and weighs 24 to 35 pounds. It has a thick, curly wooly coat which is usually white, cream, or brown, but can be brown with orange patches or roan. It has large, round, dark eyes. The breed is primarily bred as a retriever and...
Word of the Day
- To play, gamble.
- To impose upon; delude; trick; humbug; also, to joke; chaff.
- A deceitful game or trick; trickery; humbug; nonsense.
The word 'gammon' in the sense of 'joke, trick' may come from 'backgammon'.


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So who are we going to draft...
with our top 5 pick?
I can't believe we've taken such a freaking downward spiral. I really feel that with the talent on this team, there is no way they should be so freaking awful and inconsistent on a nightly basis. If it wasn't for Manny playing like Jesus for the first half of the season, we'd likely be battling Toronto for Steven Stamkos.
Our 1st, the 1st for Jackman, Stempniak + some more things
If Toronto gets the 1st overall, they would riot if they traded their Stamkos for darn near anything. If anyone else gets the pick, we could use another top tier prospect. Stamkos and Berglund as our top centers for the next decade makes me happy
If the Blues continue to play the way they have over the last twenty games (6-9-5 : only slightly better than their last ten 3-5-2), they'll finish with right around 80 points, pretty much the same as last season.
As it is right now, without too much deviation in the way the teams have played over the past, say, twenty games, here are the teams with a good chance to finish with fewer points than the Blues:
Los Angeles
Tampa Bay
Washington is also possible, but the way they're racking up points over the past twenty games, I seriously doubt it (but it would be really twisted for the Blues to have a better record than the team that wins the Southeast). Sadly, only three of those teams are in the Western Conference - it's pretty much the same standings as right now.
Last season, the fewest points needed to make the playoffs were 92 (in the East, 96 in the West), and it's going to be very close to that this year. If the Blues right the ship and continue on with something resembling their overall record this season, they'll get about 87-88 points. In order to hit 92 points, in their remaining 34 games, they'd have to have a record of 19-11-3. And that is just to hit the theoretical floor, which multiple other teams may hit or raise. So the playoffs are not entirely out of the question, but you really must assume they are from a management standpoint, considering they'll need at least 20 wins out of the remaining 34 games.
At this point, I think it's a lot more likely that the Blues will end up with a top-ten pick than it is they'll make the playoffs. However, I have serious doubts that they'll get a top-five pick. 8-10 is most likely. The draft is so-so on forwards and deep in defense - unless there's somebody in the 3-7 range who is just THAT much better than 8-10, I don't see the Blues going out of their way to shuffle picks.
They can get an outstanding player in that range.
As a side-note, I don't think the Blues will move Stempniak for any purpose, regardless of some struggles this season. With more and more vets leaving the team over the next couple of seasons, I think they'll likely look to Stempniak to step into a more prominent leadership position.
If your scenario holds, two words...
Kyle Beach.
Beach Eller Oshie would be a talented line that would piss off fans of every other team in the league. Beach is borderline nuts. Oshie hits everything and gets under your skin. Eller apparently has a rather spirited side from his WJCs
There are always players who rise and fall nearer to draft time, but it seems like Beach will go before the 8-10 range. He's kind of a questionable pick. Some dispute the extent of his skills, but he's obviously talented. The question is how that talent will develop. But most of all, the Blues have clearly said they'll only draft coachable players. They're doing their research and scouting now and will have plenty of time to interview guys when that time comes. But there's a decent possibility that Beach will not even appear on their list of desirable draftees. We'll see if and when that time comes.
Either way, I completely trust Jarmo and his staff to get the job done, whether it's a safe pick, a risky pick, something off the map, doesn't matter. Defenseman, sniper, playmaker, goaltender. Just get somebody good.
I'm hoping Beach is the kind of player with red flags that scare off certain other teams in need of a safe pick that can't afford to roll the dice. There are some question marks with Beach, but I'm not concerned with what I read about his attitude or rumors. There were questions about David Perron's attitude by reports and rumors as well. The Blues scouts did their own investigation and selected him. If Beach's problems are deemed overblown, minor, temporary, or correctable I'd love to have him here. If not Colin Wilson would be high on my list.
BTW: If we get a late first for Jackman, I'm keeping my eye on David Toews. I have a feeling he'll be climbing the charts in the 2nd half.
My hope in the late first or early second (using a possible pick for Jackman this year or the 2nd for KT last year):
Chet Pickard -- Tri-City (WHL)
Position: G Height: 6.02 Weight: 206
Is a big, strong, athletic goalie who competes hard. Has had the opportunity over the past few years to back up possibly the best junior in the world Carey Price. This year as the No. 1 Pickard has shaken off a slow start to bring the supposedly rebuilding Tri-City Americans to a top ten national ranking and be a legitimate title contender. He is good technically but it needs maturing. Excellent fitness level. Will turn heads if invited to the combine. Can play the puck well. Has great composure. Is in definite vein of Price. Is a big part of Americans success and is playing virtually every night and showing no fatigue.
Manny is not getting any younger nor his knee any healthier, and unless Bishop is the answer, I don't see a #1 goaltender currently in the system that can take the rest of this soon-to-be elite talent base to the promised land.
I'd be very happy to get someone who is compared to Carey Price. :yo:
Here is an interesting site for updated mock drafts. As is, it has us picking 10th taking Zac Boychuk, a 5'9" 176 lb. center (which I don't necessarily agree with, we need to get bigger at center). 1-7 are pretty much locks. Stamkos through Schenn are all solid picks. I don't see any of those teams trading down. If the Blues can pick up another pick in the 11-20 range, we could be able to pick up a guy like Boedker at 10 and a "blue chip" D-man with 11-20 such as Teubert. With our 2nd rounders take another forward and maybe a goalie. In a D-rich draft we should be able to find some more D in the later rounds.
I and others have serious doubts about the accuracy of that site.
FWIW, I ran the model I have that projects results for the remainder of the season. According to it, we made the playoffs 16% of the time and our average finish was 3rd to last ..... in the league. It's sensitive to results from the last 10 games so if we reel off a 10-game winning streak we suddenly look much better, but the results that fell out didn't appear to be too out of whack.
We're quickly turning into sellers at this point - if we do become sellers, a top-5 pick this year may not be out of the question unless some players not named Brad Boyes start scoring at a 25-30 goal pace.
If that holds true, Kyle Beach or Luke Schenn could very well be ours. As much as I think it is great for this organization to make the playoffs this year, another great draft from a deeeeep class may be even more beneficial. As it stands we have 3 of the first 50 picks. I'd love to see us pick up another first or second rounder and overhaul the D and go after that franchise forward we've been lacking since Hull or Shanny.
IMO it will cost too much for us to move up into the #1 slot to be a realistic option.
If the Blues do end up with a top 5 pick; Alex Pietrangelo is the guy I'd be targetting. IMO Pietrangelo will be the best D man in this years draft and he and EJ would give us a Pronger/Mac type combo. Cup winning teams are typically built from the net out and Alex and EJ would give us the foundation for a truely dominant defensive corps(and, unlike a lot of other "dominant defensive units" they'd be together for a very long time).
1) There is a slight bit of difference between our defensive situation and our offensive situation.
What the Blues lack on defense is that Take-Charge player who can legitamately affect the flow of the game. Brewer and Jackman should be doing that but aren't, and EJ isn't ready for that yet.
The difference is that we already have that guy up front in TJ Oshie. Oshie may not be a 100 point player, but he will be a "spark plug" type player that will jumpstart our offense. When you put a guy like Oshie into the mix with Berglund, Eller, Perron, Stempniak, Boyes, etc... the need for a "franchise forward" decreases radically.
2) I also disagree that we don't have a 'potential 100 point player" among our forwards. IMO Perron and Berglund have the skill to put up those types of numbers. Whether they hit that number is a seperate issue entirely as there are a lot of things that have to go right for a player to get to the century mark(coaching system, chemistry with linemates, health, etc...); but I definately think they have the skill to get to that mark.
3) Last thing I'm going to disagree on is the need for a " top 10-15" scorer period. Those kinds of players may be fun to watch but it is incredibly debateable on whether they actually "help" a team win a Cup, which is the actual goal of this organization. IMO the key to winning the Cup is to have incredible depth up front coupled with a very strong back-end(both in terms of goal tending and defensive play). Guys like Crosby and Stamkos are fun to watch, but they can be shut down come PO time just like any other player.
I know you're going to claim that we already have depth and that Stamkos wouldn't change that; but I still don't agree with your position. Getting Stamkos would be fun to watch, but building a truely dominant defensive unit would get us closer to reaching our ultimate objective of winning the Cup.
That's exactly what I'm looking for at this point in time. Beach is tailor-made for this franchise, IMO, and that line would do exactly as Checker says -- score lots and irritate the dog **** out of teams and fans all over the league (especially, I hope, Detroit).
I also like Czech prospect Tomas Kubalik at center.
Why all the love for Beach? I am not opposed to having him.
Also, I haven't been looking at the draft too much, but I am overdue to start. So I will get on that ;)
Speaking of the WHL, anyone know if someone holds the rights to Tyson Sexsmith? This guy is a beast. 31 wins last year, 30 this year to go along with a 1.97 GAA and 6 SO.
Edit: Property of the Sharks, boo
We definatly need a top flight Power Forward, the one we have isnt doing his job. I aint talking about Backes.
That could be a good thing, When you are a physical and or adgitiating player you are suppost to be a pain in the ass like Avery is.
As far as the high PIM's go it depends on how much of that is stupid IE ill timed penalties. Others will have to answer that.
AS far as being cheap, A lot of that sometimes depends on who the guy plays for. A lot of people hate Steve Downie because he is cheap at times but he can also play a bit and I think if he was wearing the Bluenote he would be a fan favorite. Myself if he would have threw the hit he threw on McAmmond earlier this year on Maltby while playing for the Blues, I think he would be a bit of a folk hero here.
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Visit our Facebook page at https://www.facebook.com/eveshamparish
All Saints Book Club
This new book club will have its first meeting on Thursday 9th April at 7.30pm at Noelle Beaumont's house. Our first read will be Karen Joy Fowler's novel We Are All Completely Beside Ourselves. Each month we'll meet in a host's home and discuss the book for an hour then over a dish of delicious pudding we'll choose next month's book and share any recommendations of books we've enjoyed. If you love reading then do come along for some stimulating discussion, yummy puddings and fun! If you'd like more information contact Noelle via church house on 01386 442213
All Saints Saturday Sizzle and Share
On Saturday 4th April I will be hosting the first All Saints Saturday Sizzle and Share for men. It will be at my house and a cooked breakfast will start sizzling at 8.00am but if you are not an early riser feel free to come a bit later, anytime before 9.30.
It will be an opportunity to get to know each other a bit better sharing a meal and fellowship. I will be looking for volunteers to host future Saturday Sizzle and Share breakfasts on the first Saturday of each month so if you are interested let me know.
If you would like to come contact me via church house on 01386 442213 so I know how many to cater for.
Fred Beaumont
All Saints' PCC Evesham PCC Treasurer
SoulFood Sunday Evening Service Every Sunday 6pm All Saints - meal and reflection, free entry, all welcome. Run by Churches Together in Evesham and District
News to share?
Please contact Chris Sheehan on 01386 442213, 07977 072105 or on email@example.com
All Saints' Church welcomes you!
All Saints' Church is open usually from 9am to 5pm and all are welcome to visit or seek a quiet place for reflection
The Church and Meeting Rooms are available to hire for one-off or regular events - please see our contact page to enquire.
Five Marks of a Healthy Church
have adopted the Five marks of a healthy church. These marks, were formulated by the Anglican Consultative Council and have been endorsed by General Synod and are:
1.to proclaim the good news of the kingdom;
2.to teach, baptize and nurture new believers;
3.to respond to human need by loving service;
4.to seek to transform the unjust structures of society;
5.to strive to safeguard the integrity of creation, and sustain and renew the life of the earth
We now have the facility to accept charitable donations online. Please go to Services, Worship and Giving and then Giving for Life
Or click here.
All Saints' Church Contact Details (see also separate contacts page)
Our postal address is:
Church House Market Place, Evesham,
Worcestershire WR11 4RW
Church Office is in Church House
Phone 01386 442213 between 9.30 am and 1.30 pm on the above
All Saints' Church is
open usually from 9am to 5pm and all are welcome to visit or seek a quiet place for reflection


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Sons and daughters of any future UK monarch will have equal right to the throne, after Commonwealth leaders agreed to change succession laws. The ban on the monarch being married to a Roman Catholic was also lifted. Read the full BBC report
UK ratifies change in monarchy
Date: October 28, 2011
Posted In: News from Europe


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A short motion clip that explores and displays the various uses of the typeface 'Univers' designed by the great Adrian Frutiger. Through the info graphic style, this clip shows various companies and real life situations where this wonderful typeface has been used. Enjoy!
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Whilst sorting through my Lego today, I found some endor troopers that I made a while ago.
I used the hasbro helmet and the torso from endor luke, as well as some of Jeffs blasters.
Its neat finding stuff you forgot you had.. maybe tomorrow I will find something else, like a tie fighter! ;)
Endor Rebel Troopers
Started by jonfett , Dec 20 2004 03:54 PM
4 replies to this topic
Posted 20 December 2004 - 03:54 PM
#Exam-Mode Activated!
Posted 04 January 2005 - 05:32 PM
jonfett, on Dec 20 2004, 02:54 PM, said:
I wish I couls stop finding these :P
maybe tomorrow I will find something else, like a tie fighter! ;)
Yeah they are pretty cool tho, I might make some *satis* .
O and, my 100th post.
Lets party :-D ;) :oo :D :') :') :') :')
Posted 04 January 2005 - 05:58 PM
Hehe, I am getting closer to the 2000 ;)
Posted 04 January 2005 - 06:14 PM
Lets have a joined party. :')
*satis* :-D :D
Lets have a joined party. :')
*satis* :-D :D
Posted 16 January 2005 - 11:25 PM
nicely done
I dare you to find someone with an earlier joining date! Jipay! -SIEG
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Safety and Efficacy of T-2345 Compared to Xalatan in Subjects With Primary Open Angle Glaucoma or Ocular Hypertension
This study is ongoing, but not recruiting participants.
Nephron Pharmaceuticals Corporation
Information provided by (Responsible Party):
Nephron Pharmaceuticals Corporation
ClinicalTrials.gov Identifier:
First received: February 7, 2014
Last updated: September 29, 2014
Last verified: September 2014
- Full Text View
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- Disclaimer
- How to Read a Study Record
No Study Results Posted on ClinicalTrials.gov for this Study
|Study Status:
|This study is ongoing, but not recruiting participants.
|Estimated Study Completion Date:
|December 2014
|Estimated Primary Completion Date:
|December 2014 (Final data collection date for primary outcome measure)


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NORTON - The 2nd Annual Veterans Family Day will be held Saturday, Aug. 9, noon-4 p.m., at the VFW - Fillmore-Nason Post 8049, 38 Summer St., Norton.
There will be music, dancing, meat raffle, 50/50 raffle, food, kids' activities and more.
There is no charge and all veterans, service members and their families are invited.
For more information, call 508-285-3845.
Location, ST | website.com


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lol bs. Get any windows PC honestly that has a decent processor/500gb+ HD. Most have like 1+ year warranties I think.
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lol bs. Get any windows PC honestly that has a decent processor/500gb+ HD. Most have like 1+ year warranties I think.
lmao. my boy got a samsung laptop from best buy freshman year and now going into our junior year it's shit and he uses a white MacBook now. And he knows what he's doing. He's a network admin/ tech support at my school making close to $20 an hour 40 hours a week.


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