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Ontario Government And Nishnawbe-Aski Nation Chiefs Create New Political Forum
Northern Table Will Help Build Prosperity For Northern First Nations
QUEEN'S PARK, April 18 – The Ontario government has taken a significant step forward in building relationships with Aboriginal communities in the North. David Ramsay, Minister Responsible for Aboriginal Affairs and Grand Chief Stan Beardy of Nishnawbe Aski Nation signed a Letter of Political Agreement between Ontario and Nishnawbe Aski First Nations this morning at Queen's Park.
"The Northern Table will create a new working relationship based on a joint commitment to positive and meaningful change among Nishnawbe-Aski First Nations, Nishnawbe-Aski Nation (NAN), and Ontario," Ramsay said. The Northern Table provides a political forum for dialogue between the Ontario government and Treaty 9 and Treaty 5 First Nations. To move forward, NAN First Nations and Ontario have agreed to work on three priorities: the development of a Memorandum of Agreement between the Ministry of Natural Resources and NAN to implement the Provincial Parks and Conservation Reserves Act in NAN territory; development of a notification protocol for Ministry of Natural Resources licences and permits for resource development activities; and to discuss land use planning, including approaches for balancing traditional and non-traditional activities for NAN First Nations both in the far north and southern parts of NAN.
The Northern Table will build on the provincial government's commitment through current initiatives, programs and services to ensure that First Nations in the North are able to successfully participate in the northern economy.
"NAN leadership has high expectations that the Northern Table will assist in developing a meaningful relationship with the Government of Ontario that is respectful of our understanding of treaties 9 and 5 signed 100 years ago," said NAN Grand Chief Stan Beardy. "Active participation by First Nation people in the economy and respect for Aboriginal and Treaty rights, will provide the basis for a better future for the people of Nishnawbe Aski."
The McGuinty government is committed to the prosperity and well being of the North. The Northern Table will help enhance First Nation participation in the benefits of resource development and advance the long-term sustainability of the northern economy.
The establishment of the Northern Table fulfills a commitment of Ontario's New Approach to Aboriginal Affairs. Launched in 2005, the New Approach to Aboriginal Affairs outlines the basis of the government's Aboriginal policy – a relationship sustained by mutual respect that will lead to improved opportunities and a better future for Aboriginal children and youth.
For further information: Anne-Marie Flanagan, Minister Ramsay's Office, (416) 327-0654; Merike Nurming, Communications Branch, (416) 326-4079; Jenna Young, Director of Communications, Nishnawbe Aski Nation, (807) 625-4952
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Marketing Executive Contracts in England |
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For the 6 months to 4 May 2015, IT contractor jobs across the England region that cited Marketing Executive in their job title mentioned the following IT skills grouped by category. The figures indicate the number of jobs and their proportion against the total number of contract IT job ads sampled with Marketing Executive in their job title. Up to 20 skills are shown per category.

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Page 1
Spleen serves as a reservoir of osteoclast precursors
through vitamin D-induced IL-34 expression in
osteopetrotic op/op mice
Yuko Nakamichia, Toshihide Mizoguchia, Atsushi Araia, Yasuhiro Kobayashia, Masahiro Satob, Josef M. Penningerc,
Hisataka Yasudad, Shigeaki Katoe, Hector F. DeLucaf,1, Tatsuo Sudag, Nobuyuki Udagawah, and Naoyuki Takahashia,1
aDivision of Hard Tissue Research, Institute for Oral Science, and Departments ofbConservative Dentistry andhBiochemistry, School of Dentistry, Matsumoto Dental
University, Nagano 399-0781, Japan;cInstitute of Molecular Biotechnology, Austrian Academy of Sciences, A-1030, Vienna, Austria;dOriental Yeast Co., Tokyo
174-8505, Japan;eLaboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan;fDepartment of
Biochemistry, University of Wisconsin, Madison, WI 53706; andgResearch Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan
Contributed by Hector F. DeLuca, May 7, 2012 (sent for review December 9, 2011)
Osteoclasts are generated from monocyte/macrophage-lineage
precursors in response to colony-stimulating factor 1 (CSF-1) and
receptor activator of nuclear factor-κB ligand (RANKL). CSF-1–mu-
tated CSF-1op/opmice as well as RANKL−/−mice exhibit osteopet-
rosis (OP) caused by osteoclast deficiency. We previously identified
RANKL receptor (RANK)/CSF-1 receptor (CSF-1R) double-positive
cells as osteoclast precursors (OCPs), which existed in bone in
RANKL−/−mice. Here we show that OCPs do not exist in bone
but in spleen in CSF-1op/opmice, and spleen acts as their reservoir.
IL-34, a newly discovered CSF-1R ligand, was highly expressed in
vascular endothelial cells in spleen in CSF-1op/opmice. Vascular en-
dothelial cells in bone also expressed IL-34, but its expression level
was much lower than in spleen, suggesting a role of IL-34 in the
splenic generation of OCPs. Splenectomy (SPX) blocked CSF-1–in-
duced osteoclastogenesis in CSF-1op/opmice. Osteoclasts appeared
in aged CSF-1op/opmice with up-regulation of IL-34 expression in
spleen and bone. Splenectomy blocked the age-associated appear-
ance of osteoclasts. The injection of 2-methylene-19-nor-(20S)-
1α,25(OH)2D3(2MD), a potent analog of 1α,25-dihidroxyvitamin
D3, into CSF-1op/opmice induced both hypercalcemia and osteoclas-
togenesis. Administration of 2MD enhanced IL-34 expression not
only in spleen but also in bone through a vitamin D receptor-medi-
ated mechanism. Either splenectomy or siRNA-mediated knock-
down of IL-34 suppressed 2MD-induced osteoclastogenesis. These
results suggest that IL-34 plays a pivotal role in maintaining the
to diverse stimuli, in CSF-1op/opmice. The present study also sug-
gests that the IL-34 gene in vascular endothelial cells is a unique
target of vitamin D.
platelet endothelial cell adhesion molecule 1-positive cells|osteoblasts|
blood stream
cyte/macrophage-lineage precursors. The differentiation of
osteoclast precursors (OCPs) into osteoclasts is regulated by
bone-forming osteoblasts. Osteoblastic cells express two cyto-
kines responsible for osteoclastogenesis: one is colony-stimulat-
ing factor 1 [CSF-1, also called macrophage colony-stimulating
factor (M-CSF)] and the other is receptor activator of nuclear
factor-κB ligand (RANKL). OCPs express CSF-1 receptor (CSF-
1R, also called c-Fms) and RANK (receptor for RANKL) and
differentiate into osteoclasts in response to CSF-1 and RANKL.
The expression of RANKL is up-regulated by osteoclast-in-
ducing factors such as parathyroid hormone (PTH) and 1α,25-
dihydroxyvitamin D3[1α,25(OH)2D3] (1, 2).
CSF-1 is the most potent growth factor for monocytes/macro-
phages (3), but its synthesis by osteoblasts occurs independently
of PTH and 1α,25(OH)2D3(2). CSF-1op/opmice cannot produce
a functionally active CSF-1 (4), and therefore, exhibit mono-
cytopenia and osteopetrosis (OP) (5, 6). However, several curious
phenomena have been observed in CSF-1op/opmice. First,
steoclasts are bone-resorbing cells generated from mono-
osteoclasts are totally absent in young CSF-1op/opmice, but appear
in aged CSF-1op/opmice (7). Second, osteopetrotic characteristics
of CSF-1R−/−mice are more severe than those of CSF-1op/opmice
(8). Third, F4/80+[F4/80(+)] macrophages exist in the splenic
red pulp in CSF-1op/opmice as well as in WT mice, and their
number is regulated by a mechanism independently of CSF-1 (9,
10). Fourth, the administration of vascular endothelial growth
factor (VEGF) rescues osteopetrosis in CSF-1op/opmice (11, 12),
but VEGF cannot substitute for CSF-1 to induce osteoclast for-
mation in vitro (13).
Recently, Lin et al. (14) discovered IL-34, as a new ligand for
CSF-1R. The amino acid sequence of IL-34 was quite different
from that of CSF-1, but IL-34 promoted macrophage colony
formation like CSF-1 did. IL-34 was specifically expressed in
splenic tissues, predominantly in the red pulp region. When IL-
34 was expressed under the control of the CSF-1 promotor in
CSF-1op/opmice, the osteopetrotic phenotype was rescued (15).
IL-34 in combination with RANKL induced osteoclastic differ-
entiation of progenitor cells in mouse (16, 17) and human (17)
cell culture systems. However, it remains unclear why IL-34
cannot substitute for CSF-1 in CSF-1op/opmice in vivo.
Using RANKL−/−mice and CSF-1op/opmice, we identified cell-
cycle–arrested RANK/CSF-1R double-positive [RANK(+)/CSF-
1R(+)] cells as the direct OCPs in vivo (18). When RANKL was
administered to RANKL−/−mice and CSF-1 to CSF-1op/opmice,
OCPs similarly differentiated into osteoclasts in bone tissue
without cell cycle progression. OCPs were detected in the vicinity
of osteoblastic cells in RANKL−/−mice, suggesting the existence
of OCPs in bone in WT mice. However, our preliminary
experiments showed that OCPs were not present in bone in CSF-
The active form of vitamin D3[1α,25(OH)2D3] regulates cal-
cium homeostasis by acting on various types of cells such as in-
testinal endothelial cells, renal tubular cells, and osteoblastic
cells (19). Shevde et al. (20) reported that 2-methylene-19-nor-
(20S)-1α,25(OH)2D3(2MD), a highly potent analog of 1α,25
(OH)2D3, strongly enhanced osteoblastic cell-mediated osteo-
clast formation and also induced bone formation in vitro and
in vivo. We have synthesized a derivative of 2MD at carbon 2
(2α-methyl-19-nor-(20S)-1α,2β,25(OH)3D3, 2-methyl-2MD), and
showed that osteoclastic bone resorption is indispensable for the
hypercalcemic action of the 2MD analog in vivo (21). Recently,
increasing evidence has been accumulating in showing that 1α,25
(OH)2D3directly regulates activities of vascular endothelial cells
Author contributions: Y.N. and N.T. designed research; Y.N., T.M., A.A., and M.S. per-
formed research; J.M.P., H.Y., and S.K. contributed new reagents/analytic tools; Y.N.,
Y.K., and N.U. analyzed data; and Y.N., H.F.D., T.S., and N.T. wrote the paper.
Conflict of interest statement: H.Y. is an employee of the Oriental Yeast Co.
Freely available online through the PNAS open access option.
1To whom correspondence may be addressed. E-mail: email@example.com or
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.
| June 19, 2012
| vol. 109
| no. 25www.pnas.org/cgi/doi/10.1073/pnas.1207361109
Page 2
through vitamin D receptors (22–24). These results suggest that
1α,25(OH)2D3plays a unique role in the vascular system beyond
the classical role in calcium homeostasis.
In the present study, we examined how osteoclasts were
formed in CSF-1op/opmice in response to various stimuli. We
found that OCPs existed in spleen but not in bone in CSF-1op/op
mice. OCPs in CSF-1op/opmice were transferred from spleen to
bone and differentiated into osteoclasts in response to CSF-1,
VEGF, and 2MD administrations, and also to aging. IL-34
appeared to play a pivotal role in the generation and storage of
OCPs in spleen and osteoclastogenesis in CSF-1op/opmice. In
addition, we have shown that the IL-34 gene in the vascular
endothelial cells is a unique target of vitamin D.
Immunohistochemical analysis showed that RANK(+) cells and
CSF-1R(+) cells were present in the proximal region of tibiae
obtained from RANKL−/−mice as well as from WT mice (Fig.
1A). Most of the RANK(+) cells expressed CSF-1R in WT mice.
Cells double positive for RANK and CSF-1R [RANK(+)/CSF-
1R(+) cells] were also detected in RANKL−/−mice and identi-
fied as the direct OCPs in vivo (18). Conversely, neither RANK
(+) cells nor CSF-1R(+) cells were detected in bone tissue in
CSF-1op/opmice (Fig. 1A, Right). In contrast, RANK(+) cells,
CSF-1R(+) cells, and RANK(+)/CSF-1R(+) cells (arrows)
were detected in spleen in CSF-1op/opmice as well as in WT mice
and RANKL−/−mice (Fig. 1B, Right). RANK(+)/CSF-1R(+)
cells were mainly observed in the red pulp region and marginal
zones. These results suggest that OCPs do not exist in bone but
do exist in spleen in CSF-1op/opmice.
We then examined the tissue distribution of IL-34 mRNA
(Fig. 2A). Consistent with the previous report (14), IL-34 was
expressed predominantly in spleen but slightly in bone (Fig. 2A).
The osteoblast level of IL-34 mRNA was much lower compared
with that of CSF-1 mRNA (Fig. 2B). Little IL-34 mRNA or CSF-
1 mRNA was expressed in bone marrow (BM) macrophages and
osteoclastic cells (Fig. 2B). IL-34(+) cells were mainly distrib-
uted in the splenic red pulp region and marginal zones (Fig. 2C),
where RANK(+)/CSF-1R(+) cells were detected (Fig. 1B). IL-
34(+) cells were similarly distributed in the spleen in WT mice
(Fig. S1 A and B). Most IL-34(+) cells expressed platelet en-
dothelial cell adhesion molecule 1 (PECAM-1), a marker of
vascular endothelial cells (Fig. 2 C–E and Fig. S1 A and B). Cells
double positive for IL-34 and PECAM-1 [IL-34(+)/PECAM-1
(+) cells] were detected as endothelial cells in blood vessels.
Most of the endothelial cells found in white pulp also expressed
IL-34 (Fig. 2 C–E). Notably, endothelial cells in central arterioles
robustly expressed IL-34 (Fig. 2D). Next, we examined the dis-
tribution of IL-34 expression in bone. PECAM-1(+) cells
expressed IL-34 but alkaline phosphatase (ALP)(+) osteoblastic
cells did not (Fig. 2F and Fig. S1C). The endothelial cell
Fig. 1.
1op/opmice. (A) Localization of RANK (red) and CSF-1R (green) in proximal
tibiae in WT, RANKL−/−, and CSF-1op/opmice. Nuclei were stained with DAPI
(blue). Lower panels show magnified views of the boxed areas in the Upper
panels. Dashed lines represent bone surface. Arrows indicate RANK(+)/CSF-
1R(+) cells. [Scale bar, 400 μm (Upper), 5 μm (Lower).] (B) Localization of
RANK (red) and CSF-1R (green) in spleen in WT, RANKL−/−, and CSF-1op/op
mice. Dashed circles represent the white pulp. Lower panels show magnified
views of the boxed areas in the Upper panels. WP; white pulp, RP; red pulp.
[Scale bar, 400 μm (Upper), 10 μm (Lower).]
Distribution of OCPs in bone and spleen in WT, RANKL−/−, and CSF-
Bone Liver Spleen
Bone Liver Spleen
Relative expression
Osteoblasts Macrophages Osteoclasts
Relative expression
Cells (Number/mm2)
: PECAM-1(+) cells
: IL-34(+) cells
White pulp
Red pulp
Fig. 2.
time RT-PCR measurements of IL-34 mRNA expression in bone, liver, and
spleen in 3-wk-old WT and CSF-1op/opmice. Data obtained from triplicate
PCRs using RNA from different mice are expressed as the mean ± SD (n = 3).
(B) Real-time RT-PCR measurements of IL-34 and CSF-1 mRNA expression in
osteoblastic cells, BM macrophages, and osteoclasts. Data obtained from
triplicate PCRs are expressed as the mean ± SD *P < 0.01. (C) Localization of
IL-34 (red) and PECAM-1 (green) in spleen in CSF-1op/opmice. Dashed circles
represent the white pulp. The outsides of the circles show the marginal
zones and red pulp. (Scale bar, 100 μm.) (D) Magnified views of the boxed
areas [(a) red pulp and (b) white pulp] in C. Nuclei were stained with DAPI
(blue). Arrows indicate IL-34(+)/PECAM-1(+) cells. (Scale bar, 20 μm.) (E)
Number of IL-34(+) cells and PECAM-1(+) cells in the red and white pulp.
Values in red bars represent percentages of IL-34(+) cells among PECAM-1(+)
cells. Data are expressed as the mean ± SD for four optical fields. (F) Lo-
calization of IL-34 (red) and PECAM-1 (green) (Left) and that of IL-34 (red)
and ALP activity (green) (Right) in the proximal tibiae in CSF-1op/opmice.
Dashed lines represent bone surface. Arrows indicate IL-34(+)/PECAM-1(+)
cells. Arrowheads indicate ALP(+) osteoblastic cells. (Scale bar, 20 μm.)
Distribution of IL-34 expression in WT and CSF-1op/opmice. (A) Real-
Nakamichi et al.PNAS
| June 19, 2012
| vol. 109
| no. 25
| 10007
Page 3
population was much lower in bone than in spleen, consistent
with the result of real-time RT-PCR (Fig. 2A). These results
suggest that IL-34 is involved in the generation of OCPs in
spleen in CSF-1op/opmice.
Then, we examined the biological activities of IL-34 in several
assays and found them to be similar to those of CSF-1 (Fig. S2).
Consistent with the previous reports (14–17), IL-34 promoted
not only the proliferation of BM macrophages (Fig. S2A), but
also the formation of osteoclasts (Fig. S2B), both of which were
similarly inhibited by adding αCSF-1R Ab. IL-34 as well as CSF-1
supported the survival of osteoclasts, which was similarly inhibi-
ted by adding αCSF-1R Ab (Fig. S2C). Thus, IL-34 is concluded
to stimulate osteoclastogenesis through CSF-1R. These results
suggest that splenic OCPs are transferred from spleen to bone in
response to CSF-1/IL-34 administration in CSF-1op/opmice.
We then examined the effect of splenectomy (SPX) on oste-
oclast formation in CSF-1op/opmice (Fig. 3A). Three-week-old
CSF-1op/opmice were subjected to SPX or a sham operation
(Sham) and injected with CSF-1 4 d after the surgery. The CSF-1
injection produced tartrate-resistant acid phosphatase (TRAP, an
osteoclast marker)(+) osteoclasts in bone in Sham CSF-1op/op
mice, but not in SPX CSF-1op/opmice. RANKL−/−mice were also
subjected to SPX or Sham and examined for osteoclastogenesis in
response to RANKL (Fig. 3B). The RANKL injection produced
osteoclasts in bone both in Sham and SPX RANKL−/−mice.
RANKL appeared to induce osteoclasts to form from RANK
(+)/CSF-1R(+) cells preexisting in bone in RANKL−/−mice.
The administration of VEGF improved the phenotype of
osteopetrosis in CSF-1op/opmice (11, 12), and a deficiency of
VEGFR1 worsened it (12). VEGF may stimulate the growth and
IL-34 synthesis of vascular endothelial cells. Consistent with the
previous reports(11, 12),the
(VEGF120) into CSF-1op/opmice increased the appearance of
TRAP(+) osteoclasts (Fig. S3A). SPX prevented VEGF-A120–
induced osteoclastogenesis in CSF-1op/opmice. However, the
VEGF120 injection did not increase the expression of IL-34
mRNA in bone, liver, or spleen in CSF-1op/opmice (Fig. S3B).
These results suggest that VEGF induces loosening of the en-
dothelial cell contacts (25), and the subsequent entry of OCPs
into the blood stream.
We next examined the possibilities of whether the spleen acts
as a reservoir of OCPs in aged CSF-1op/opmice and whether IL-34
is involved in this process as well (Fig. 4). TRAP(+) osteoclasts
were detected in bone in 10-wk-old and 10-mo-old CSF-1op/op
mice (Fig. 4A). The expression of IL-34 mRNA in bone and
spleen but not in the liver increased with aging in CSF-1op/opmice
(Fig. 4B). WT mice also exhibited an age-associated increase in
IL-34 expression in bone. CSF-1 mRNA expression showed no
correlation with aging in WT mice (Fig. 4B). Then, 5-wk-old
CSF-1op/opmice were subjected to SPX or Sham. Five weeks
later, tibiae were recovered and examined for osteoclastogenesis
(Fig. 4C). Histomorphometric analysis of tibiae showed that SPX
suppressed the age-associated appearance of osteoclasts, erosion
surface/bone surface (ES/BS), and increased bone volume/tissue
volume (BV/TV) in aged CSF-1op/opmice (Fig. 4C). These results
suggest that spleen acts as a reservoir of OCPs in the age-asso-
ciated appearance of osteoclasts in CSF-1op/opmice.
We previously reported that a large amount of a 2MD analog,
2-methyl-2MD, induced hypercalcemia in WT mice, but not in c-
Fos−/−mice (21). The potency of 2-methyl-2MD as well as 2MD
in inducing osteoclastogenesis was 100 times higher than that of
1α,25(OH)2D3(21). In the course of investigating further, we
found that administration of 2-methyl-2MD to CSF-1op/opmice
induced hypercalcemia (Fig. S4). We, then, examined whether
administration of the original 2MD induces osteoclastogenesis in
CSF-1op/opmice. CSF-1op/opmice subjected to SPX or Sham were
injected with a large amount of 2MD (Fig. 5A). The 2MD in-
jection induced the appearance of TRAP(+) osteoclasts in bone
in Sham but not in SPX CSF-1op/opmice. 2MD increased erosion
surface in parallel with the increase of osteoclast number in
Sham but not in SPX CSF-1op/opmice (Fig. 5A). 2MD is known
to induce RANKL expression in osteoblastic cells (20, 21). Then,
RANKL was injected into CSF-1op/opmice, but neither the os-
teoclast formation nor the increase in erosion surface (ES/BS)
was observed (Fig. 5A). The administration of 2MD stimulated
the expression of IL-34 mRNA in spleen and bone in CSF-1op/op
mice (Fig. 5B). The number of IL-34(+)/PECAM-1(+) cells and
that of RANK(+)/CSF-1R(+) cells were also increased in re-
sponse to 2MD administration (Fig. 5 C and D). We then per-
fluorescence-labeled control siRNA, we confirmed that the
siRNA was successfully delivered to spleen and bone (Fig. S5A).
Then IL-34 siRNA or control siRNA was injected into CSF-1op/op
mice 24 h before the administration of 2MD. The expression
of IL-34 mRNA in spleen was reduced by up to 80% by adding
IL-34 siRNA (Fig. S5B). IL-34 siRNA but not control siRNA
suppressed the 2MD-induced osteoclastogenesis in CSF-1op/op
mice (Fig. 5E). These results indicate that IL-34 is involved in
the 2MD-induced mobilization of OCPs from spleen to bone in
CSF-1op/opmice. We finally examined whether 2MD-induced up-
regulation of IL-34 expression is mediated by the vitamin D re-
ceptor (VDR) using VDR−/−mice. Although comparable levels
of IL-34 mRNA expression were detected in bone and spleen in
VDR−/−mice, the IL-34 expression was not enhanced by 2MD
administration (Fig. 5F).
of IL-34.Using
We have shown that spleen in CSF-1op/opmice acts as a reservoir
of OCPs, which are transferred to bone and differentiate into
osteoclasts in response to diverse stimuli (Fig. 6). The existence
of OCPs in spleen seems to be supported by IL-34 expressed in
vascular endothelial cells. The mysterious phenomena observed
in CSF-1op/opmice (7–12) may be explained by the transfer of
OCPs from spleen to bone.
The exclusive localization of OCPs in spleen was observed in
CSF-1op/opmice but not in RANKL−/−mice. SPX prevented
osteoclastogenesis in 2MD-induced osteoclastogenesis in CSF-
1op/opmice. However, 2MD-induced osteoclastogenesis in nor-
mal mice was not impaired by SPX (Fig. S6). Therefore, it is
unlikely that spleen acts as a reservoir of OCPs in osteoclasto-
genesis under the physiological condition in normal animals.
However, 2MD administration increased the number of OCPs as
Osteoclasts (Number/mm)
Vehicle CSF-1
Vehicle RANKL RANKL
Osteoclasts (Number/mm)
Fig. 3.
mice. Three-week-old CSF-1op/opmice (A) and 8-wk-old RANKL−/−mice (B)
were subjected to SPX or Sham. Four days later, CSF-1op/opmice and RANKL−/−
mice were administered CSF-1 (107units/kg) and RANKL (2.5 mg/kg), re-
spectively, daily for 4 d and killed 24 h after the last injection. Sections of
tibiae were double stained for TRAP and methyl green (Left), and the
number of TRAP(+) osteoclasts was counted (Right). Arrows indicate TRAP(+)
osteoclasts. Data are expressed as the mean ± SD for four optical fields from
four mice. *P < 0.01. (Scale bar, 50 μm.)
Effects of SPX on osteoclastogenesis in CSF-1op/opmice and RANKL−/−
| www.pnas.org/cgi/doi/10.1073/pnas.1207361109Nakamichi et al.
Page 4
well as the expression of IL-34 in spleen in CSF-1op/opmice. SPX
suppressed the age-associated appearance of osteoclasts in CSF-
1op/opmice. These results suggest that OCPs are generated and
maintained in spleen through IL-34 during the lifetime of CSF-
OCPs were released from spleen into the blood stream in
CSF-1op/opmice. Using an in vivo system of bone morphogenetic
protein 2 (BMP-2)–induced ectopic bone formation in RANKL−/−
mice, we demonstrated that OCPs existed in the peripheral
blood as well as in bone marrow (26). Circulating OCPs were
cell-cycle–arrested cells committed to the osteoclast lineage.
When CSF-1 was injected into CSF-1op/opmice, osteoclasts
detected in bone were generated from cell-cycle–arrested OCPs
(18). Our findings also support the notion that the lineage-
committed OCPs circulate in the blood stream and fix to the
correct site for osteoclastogenesis. Ishii et al. (27) reported that
an agonist of sphingosine 1 phosphate (S1P) increased the mi-
gration of OCPs between blood and bone. CSF-1 administration
increased the mobilization of OCPs from spleen to bone, sug-
gesting that CSF-1 as well as IL-34 plays important roles not only
in the osteoclastic differentiation of OCPs in bone but also in the
mobilization of OCPs from spleen to bone in CSF-1op/opmice.
Future studies will further clarify the mechanism by which OCPs
are transferred from spleen into blood and home to bone.
The expression level of IL-34 was much lower in bone than in
spleen. This may explain why OCPs and osteoclasts are absent in
bone in young CSF-1op/opmice. Osteoclasts appeared in aged
CSF-1op/opmice with concomitant up-regulation of IL-34 ex-
pression in bone. 2MD administration also enhanced IL-34
expression in bone. These results suggest that IL-34 generated by
vascular endothelial cells contributes to osteoclastogenesis in-
duced by aging and 2MD administration in CSF-1op/opmice.
VEGF also induced osteoclastogenesis in CSF-1op/opmice.
However, the ability of VEGF to induce osteoclastogenesis was
much weaker than that of CSF-1 and 2MD, and VEGF failed to
up-regulate IL-34 expression. These results suggest that IL-34
expressed in vascular endothelial cells in bone is essentially in-
volved in osteoclastogenesis in CSF-1op/opmice.
Administration of 2MD induced osteoclastogenesis with up-
regulation of IL-34 expression in CSF-1op/opmice. The RNA
interference experiment further supported the notion that IL-34
is involved in the 2MD-induced osteoclastogenesis in CSF-1op/op
mice. When 2MD was administered to WT mice, the expression
of IL-34 mRNA was significantly increased in WT mice (Fig. S7).
The stimulatory effect of 2MD on IL-34 expression was not
observed in VDR−/−mice. Administration of a large amount of
1α,25(OH)2D3into CSF-1op/opmice also induced osteoclasto-
genesis (Fig. S8). These findings suggest that the IL-34 gene is
a unique target of 1α,25(OH)2D3. Using the program Pattern
Search for Transcription Factor Binding Sites (PATCH 1.0), we
found five putative binding sites of VDR within the 2 kb up-
stream of the transcription start site of the mouse IL-34 gene.
The expression level of IL-34 mRNA in bone and spleen in
VDR−/−mice was comparable to that in wild-type mice. These
results suggest that VDR-mediated signals are not essential for
IL-34 expression, but are involved in the up-regulation of IL-34
expression in endothelial cells.
Relative expression
BoneLiver Spleen
Relative expression
BoneLiver Spleen
Bone Liver Spleen
Osteoclasts (Number/mm)
3-week-old 10-week-old 10-month-old
10-week-old CSF-1op/op
Sham SPX
Osteoclasts (Number/mm)
: 3-week-old : 10-week-old: 10-month-old
Sham SPX
Fig. 4.
clastogenesis in CSF-1op/opmice. (A) Appearance
of osteoclasts in CSF-1op/opmice in an age-de-
pendent manner. Sections of tibiae obtained
from CSF-1op/opmice at different ages were dou-
ble stained for TRAP and methyl green (Left), and
the number of osteoclasts was counted (Right).
Arrows indicate TRAP(+) osteoclasts. Data are
expressed as the mean ± SD for four optical fields
from four mice. (B) Expression of IL-34 and CSF-1
mRNAs in bone, liver, and spleen in CSF-1op/op
mice and WT mice at various ages. Data were
obtained from triplicate PCRs using RNA from
three mice and expressed as the mean ± SD. (C)
Effect of splenectomy on age-associated osteo-
clastogenesis. Five-week-old CSF-1op/opmice were
subjected to SPX or Sham. Five weeks later, they
were killed. Sections of tibiae were double
stained for TRAP and methyl green (Left). Osteo-
clast number (number/mm), erosion surface/bone
surface (ES/BS, %), and bone volume/tissue vol-
ume, (BV/TV, %) were measured (Right). Data are
expressed as the mean ± SD for four optical fields
from four mice. (Scale bar, 50 μm.) *P < 0.01. NS,
not significant.
Role of spleen for age-associated osteo-
Nakamichi et al.PNAS
| June 19, 2012
| vol. 109
| no. 25
| 10009
Page 5
We have not succeeded in showing the stimulation of IL-34
expression by 2MD in mouse splenic endothelial cell cultures.
Vascular microenvironment or blood vascular networks may be
required for 2MD-induced up-regulation of IL-34 expression.
Vascular endothelial cells are shown to regulate the recruitment
of monocyte/macrophage lineage cells, which play a role in an-
giogenesis (28–31). At the amino acid sequence level, IL-34 gene
is more conserved than the CSF-1 gene during evolution (32).
These results suggest that the vitamin D system and IL-34 may
fundamentally work in normal angiogenesis.
Recently, it was reported that IL-34 was expressed in synovial
tissues obtained from rheumatoid arthritis patients, and tumor
necrosis factor α (TNFα) stimulated IL-34 expression in those
synovial fibroblasts in culture (33, 34). Giant cell tumors of bone
have been shown to express IL-34 (17). Therefore, we examined
the effects of osteotropic factors such as 1α,25(OH)2D3, 2MD,
TNFα, interleukin 1β (IL-1β) and prostaglandin E2(PGE2) on
IL-34 expression in mouse osteoblastic cells in culture (Fig. S9).
Real-time RT-PCR analysis showed that TNFα, IL-1β, and
PGE2, respectively, failed to increase IL-34 mRNA expression in
osteoblastic cells in our cell culture conditions. 2MD and 1α,25
(OH)2D3significantly increased IL-34 mRNA expression in os-
teoblastic cells. However, it is unlikely that IL-34 expressed by
osteoblastic cells in response to 1α,25(OH)2D3can substitute for
CSF-1 for osteoclastogenesis, because 1α,25(OH)2D3failed to
support osteoclast formation in cocultures of hematopoietic os-
teoclast precursors and CSF-1op/opmouse-derived osteoblastic
cells (35). At present, the cause of the difference between our
result and the results reported previously is not known. Further
studies will elucidate the regulatory mechanism of IL-34 ex-
pression in fibroblastic cells as well as endothelial cells.
Both CSF-1op/opand RANKL−/−osteopetrotic mice develop
splenic extramedullary hematopoiesis due to the impaired bone
microenvironment. This suggests that spleen acts as the reservoir
of hematopoietic precursors under pathological conditions such
as osteopetrosis. Recently, Miyamoto et al. (36) reported that
the mobilization of hematopoietic stem and progenitor cells
(HSPCs) occurring after granulocyte colony-stimulating factor
(G-CSF) injection was comparable or even increased in osteo-
petrotic CSF-1op/op, RANKL−/−and c-Fos−/−mice, compared
with that in WT mice. Contrary to OCPs, the mobilization of
HSPCs was not suppressed by SPX in CSF-1op/opmice in the G-
CSF treatment (36). These results suggest that spleen cannot act
as the reservoir of HSPCs in CSF-1op/opmice, although HSPCs
exist in the enlarged spleen. Swirski et al. (37) identified unique
monocytes in spleen, which exited the spleen en masse, accu-
mulated in the injured tissue, and participated in wound healing,
in response to ischemic myocardial injury. CSF-1 has been shown
to be involved in the coordinated dynamics of the tissue distri-
bution of macrophages and dendritic cells (38). Thus, spleen
plays important roles in the maintenance and tissue distribution
of monocyte–macrophage lineage cells through IL-34 expression.
In conclusion, IL-34 plays pivotal roles in the maintenance and
mobilization of splenic OCPs in CSF-1op/opmice. IL-34 and CSF-
1 play dominant roles in determining the distribution of OCPs.
The IL-34 gene in vascular endothelial cells is a unique target of
IL-34 siRNA
Osteoclasts (Number/mm)
Control siRNA
Vehicle 2MD Vehicle 2MD
Relative expression
Bone LiverSpleen
Vehicle 2MD
Vehicle 2MD Vehicle 2MD
2MDVehicle RANKL
Osteoclasts (Number/mm)
Cells (Number/mm2)
: PECAM-1(+) cells
: IL-34(+) cells
RANK(+)/CSF-1R(+) Cells
Vehicle 2MD Vehicle
Relative expression
Vehicle RANKL
Fig. 5.
osteoclastogenesis in CSF-1op/opmice. (A) Effects of 2MD
and RANKL on osteoclastogenesis. Three-week-old CSF-
1op/opmice were subjected to SPX or Sham. Four days
later, mice were injected with 2MD (2 nmol/kg) twice
2 d apart, and killed 48 h after the second injection.
Sham mice were administered daily RANKL (2.5 mg/kg)
daily for 4 d, and killed 24 h after the last injection.
Sections of tibiae were double stained for TRAP and
methyl green (Left), and osteoclast number (Center) and
erosion surface (ES/BS) (Right) were measured. Arrows
indicate TRAP(+) osteoclasts. Data are expressed as the
mean ± SD for four optical fields from four mice. (Scale
bar, 50 μm.) (B–D) Effects of 2MD on IL-34 expression (B
and C) and RANK(+)/CSF-1R(+) cells (D). Three-week-old
CSF-1op/opmice were injected with vehicle or 2MD (2
nmol/kg) and killed 24 h after the injection. (B) Effects of
2MD on IL-34 mRNA expression. Expression of IL-34
mRNA in bone, liver, and spleen was examined by real-
time RT-PCR. Data were obtained from triplicate PCRs
using RNA from two mice and expressed as the mean ±
SD. (C) Effects of 2MD on IL-34 protein expression. Spleen
sections were stained for IL-34 (red) and PECAM-1
(green) (Left). Number of IL-34(+)/PECAM-1(+) cells in the
red pulp was counted (Right). Values in red bars repre-
sent percentages of IL-34(+) cells among PECAM-1(+)
cells. Data are expressed as the mean ± SD for four
optical fields. (D) Effects of 2MD on RANK(+)/CSF-1R(+)
cells in spleen. Spleen sections were stained for RANK
(red) and CSF-1R (green) (Left). Number of RANK
(+)/CSF-1R(+) cells in the red pulp was counted (Right).
Data are expressed as the mean ± SD for four optical
fields. (Scale bar, 10 μm.) (E) Effects of IL-34 siRNA in-
jection on osteoclastogenesis. Three-week-old CSF-1op/op
mice were i.v. injected with control siRNA or IL-34 siRNA
(10 mg/kg) or its control. One day later, they were
injected with 2MD (2 nmol/kg) twice 2 d apart and kil-
led 48 h after the second injection. Sections of tibiae
were double stained for TRAP and methyl green (Left),
and the number of osteoclasts was counted (Right).
Arrows indicate TRAP(+) osteoclasts. Data are expressed
as the mean ± SD for four optical fields from four mice.
*P < 0.01. (Scale bars, 50 μm.) (F) Effects of 2MD on IL-34 mRNA expression in VDR−/−mice. Eight-week-old VDR−/−mice were injected with vehicle or 2MD (2
nmol/kg) and killed 24 h after the injection. Data obtained from triplicate PCRs using RNA from three mice are expressed as the mean ± SD (n = 3).
Effects of SPX and IL-34 siRNA on 2MD-induced
| www.pnas.org/cgi/doi/10.1073/pnas.1207361109Nakamichi et al.
Page 6
vitamin D. Clarifying how splenic OCPs enter the blood stream
and reach bone may provide a unique strategy to control bone
Materials and Methods
Detailed protocols are given in SI Materials and Methods.
Animals. Breeding pairs of CSF-1op /+mice (B6C3Fe genetic background) were
purchased from The Jackson Laboratory and F2mice were raised in our
laboratory. Homozygous CSF-1op/opmice, identified by a lack of incisors at
postnatal day 10, and RANKL−/−mice (39) (C57BL/6 background) were fed
a softened rodent chow (Oriental Yeast) with water after weaning. VDR−/−
mice (C57BL/6 background) were generated by cross-breeding of VDR-floxed
mice with CMV-Cre mice (40). VDR−/−mice were fed a high calcium diet (CE-2
supplemented with 2% (wt/wt) calcium, 1.25% (wt/wt) phosphate, and 20%
(wt/wt) lactose; CLEA Japan) to normalize serum calcium level. Eight-week-
old male ddY mice and newborn ddY mice (Japan SLC) were used as WT mice
for preparation of BM cells and osteoblastic cells, respectively. All experi-
ments were conducted in accordance with the guidelines for studies with
laboratory animals of the Matsumoto Dental University Experimental
Animal Committee.
Splenectomy. Mice were anesthetized with isoflurane (Isoflu; Dainippon
Sumitomo Pharma) usingavaporizer(DSPharma Biomedical). The spleen was
identified after a transverse laparotomy incision just to the left of the spinal
cord and removed after appropriate blood vessel ligation. Sham-operated
animals underwent the laparotomy without a splenectomy.
Statistics. Statistical analyses were performed using the one-tailed Student
t test and Fisher's exact probability test, as appropriate. P < 0.05 was con-
sidered statistically significant.
ACKNOWLEDGMENTS. This work was supported in part by Ministry of
Education, Culture, Sports, Science, and Technology of Japan Grants-in-Aid
21791817 (to Y.N.), 22791804 (to T.M.), 21390551 (to Y.K.), and 22390351 (to
N.T.) and by a grant from the Naito Foundation for Natural Science (to T.M.).
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Endothelial cells
Circulating OCP
CSF-1, VEGF, Aging
CSF-1, VEGF, Aging
Fig. 6.
exist as RANK(+)/CSF-1R(+) cells in spleen but not in bone in CSF-1op/opmice.
IL-34 expressed by endothelial cells appears to be involved in the differen-
tiation of OCPs from hematopoietic progenitor cells. Administration of CSF-1,
2MD, or VEGF into CSF-1op/opmice produces osteoclasts in bone. Osteoclasts
also develop in bone in aged CSF-1op/opmice. OCPs in spleen are mobilized
into the circulation in response to diverse stimuli. Circulating OCPs settle
down in bone and differentiate into osteoclasts in response to RANKL and
CSF-1 or IL-34. IL-34 expression is increased in spleen and bone with aging or
2MD administration. IL-34 appears to play pivotal roles in the development
in spleen and transfer of OCPs from spleen to bone in CSF-1op/opmice.
A hypothetical model for osteoclastogenesis in CSF-1op/opmice. OCPs
Nakamichi et al.PNAS
| June 19, 2012
| vol. 109
| no. 25
| 10011


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Hmmmmm.......so I hear there is a big press release coming on April 25 as part of the 'Monstrous Summer' promotion that will introduce plans to add two MORE ships to the DCL fleet and/or major rehab on the Wonder and/or Magic. Wonder if this would affect and/or delay the likelihood of a late summer discount? Thoughts?
Thanks so much! I'm feeling better after reading all the discussion too! Just need the official word! Like everyone else here!
I don't think it should. The cruise is separate from the parks. Cruise runs deals at different times. I was on the Magic last May and the crew mentioned a major rehab after it leaves the US. As far as more ships being introduced, that would be great.
Those are incredible prices from NY. I'm paying $300 to fly out of JFK on August 24th and my friends who waited a month after me are paying $448.
I don't know how many people typically book their Disney reservations (Package or Room only) prior to Discounts being posted, but you would assume if Disney sees an uplift in reservations for a time period, they would likely reduce any Offers since the benefit becomes minimal and they run risk of existing reservations converting to plan. I also made reservations for end of October so I could book ADR fro whole trip and get room preference, but am hoping for some substantial discount to come out.
Well, I broke down and made a couple of ADRs. They WILL be cancelled if free dining isn't offered so the whole ADR experience just made me sad today. Much tougher to plan out these special meals and experiences and then cancel them than to have never made them at all. But the panic of not getting any decent bookings should we actually be so lucky as to get FD finally got to me. Sigh
Yep. Same here. Last time I wasn't able to get the room view I wanted and reservations were limited in some restaurants. As I said, my concern is that everyone is now doing this since Disney policy on cancellations is so lenient- allowing full refund up thru 45 days. That's probably a strategic move on Disneys part to get a feel for interest when evaluating offers.
You guys do not be sad.. Think positively about your trips, plan, etc! Come on people I know it's hard to wait but think optimistically..Remember, historically for Aug/Sept dates the FD offer has been offered as late as June. So don't be sad. Also, I do not believe people booking rooms will deter the FD offer to come. I also think it is better to book your ADR's now then when free dining does comes, and most desired restaurants have been booked! Things will be ok.
I keep seeing these prices whilst my husband is set on driving. I just looked at Jetblue $945 for 5 of us. Even though Islip is 10 minutes from us, the price to fly southwest, with parking for a week at Islip is more than Jetblue + LIRR + the Airtrain..
I don't think that ADRs (aka dining res.) have ANY bearing on anything. It's hotel ressies that might affect things. I always recommend making your ADRs as early as possible. They won't have anything to do with whether there is a sale or not. I think many people are confusing the terminology for the two. ADR refers to dining only.
Agreed. FD is offered and paid for by the hotels. The restaurants have no part in it except to accept the credits in exchange for a meal. When the resorts are not showing a certain occupancy, an offer is made to entice the public. FD is the most attractive since people can justify not staying on property to save on the price of a room, but everyone has to eat, so they take advantage. Sent from my iPad using DISBoards
Im not talking about Dining reservations, Im referring to the number of people that have booked Rooms/Packages with hopes of getting FD. I made my Room only reservation so I could book all Dining at $180 out for trip. As I read thru the thread on FD - it was obvious that many, many people are booking in hopes of FD - so if this is a higher volume than in past - it could impact what level of offer goes out - and more likely the number of available rooms under this offer. Im going regardless and booked my airfare - so heres to hoping for something.
We just booked JetBlue this week from LGA to MCO for $262.80 each 10/19-10/24. It actually jumped up a bit from last week when I first checked - shoulda booked then! but I still think we got a pretty good deal. We're in Manhattan and prefer a cab to/from the airport vs the subway + airtrain since we're leaving at the crack of dawn! The cab fare to LGA is metered and much lower than the set price to JFK, but either way I think the prices for both airports were close.
This has been said before and Disney knows MOST will NOT cancel . Also remember my BB back on December 6th that was cut short as I was told because of an overwhelming response ! If a lot are holding res along with BB and England there may be no reason to offer free dining. CM's do get confused. Example my BB I was told Value and Moderate both got CS which later was not true from other posts here .....
When we looked at Coronado Springs for the last week of August, we found that the latter half of the week has been completely booked by people in town for a mustang convention. Could this effect FD in any way, and ,on a side note, should we be on the lookout for a FD offer by the end of April?
I do not believe they do not offer FD because of people holding room reservations. People have been doing this every year and they still have offered FD!
I agree...I still don't think it's a good idea to book a reservation before the sale, BUT...I have been in on free dining discussions ever since 2005...and believe me when I say...EVERY year we have the EXACT same discussions. Will there be FD? When will they announce it? What dates will it cover? ETC., ETC., ETC. They WILL have a discount for September, and it will probably be announced by May 1st (my best guess). Details...who knows. But there is no need to panic...things are exactly as they have been in the rumor mill since 2005...and things always turn out ok.


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As long as the rolling blackouts continue, customers can expect some significant delays, probably over an hour, said DART spokesman Morgan Lyons. The delays are rolling and random. We didn't know when they were starting this morning and its continued to cause problems for us. As long as they're continue, it will continue to cause backup.
Passengers may have to wait on trains one hour or longer depending on the length of the blackouts. Company officials said the times are unpredictable and make it difficult to forecast how often or how long any train will take to get from one station to another.


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Researchers seek to create new 'making' discipline
Researchers from University of Wisconsin-Madison and Drexel University are pursuing the building blocks for a rich set of computational tools that would allow manufacturers to account for the material complexity of a sophisticated product within a single computer model.
Vadim Shapiro of the University of Wisconsin and William Regli of Drexel University plan to unite materials science, computing and manufacturing with an $800,000 grant from the National Science Foundation. In the process, they want to establish a new discipline they call the "informatics of making."
"We're not just talking about computing systems, but specifically computing systems in support of material activities," says Shapiro, the Bernard and Frances M. Weideman professor of mechanical engineering and computer sciences at UW-Madison. "Moving forward requires computational models that know about geometry, materials and physics."
Shapiro will contribute to this research his expertise in geometry, mathematical models and computer models. Regli will draw on his interdisciplinary experience with information systems, knowledge representation and archives.
Regli, a professor of engineering and computer science at Drexel, has long worked at the intersection of computer science and manufacturing. He says that as the 3D printing world begins to buzz about such huge possibilities as printing an entire house, it's becoming clear that computational design tools need to catch up to advances in materials science.
"If I want to design an object that has variable material properties, on a 3D printer, the tools just don't exist," says Regli, associate dean of research at Drexel's iSchool, College of Information Science & Technology. "What you're making is more than a shape; it's how the shape responds to its physical environment — for example, how it acts under certain forces."
Currently, when 3D printer users exchange data on an object they're trying to print, they use what Shapiro refers to as a "dumb" file, one that simply transmits an approximate shape of an object. Shapiro believes the next step is to create models and languages that also include information about the materials, physics and design intent.
"It's almost at the point where you can interchangeably think of materials as bits of information," Shapiro says.
Regli, whose primary background is in computer science, says the main challenge of the research is to find the right abstractions with which to unite principles of design, materials and computing. "We have to figure out how to relate the representations for material and behavior from an engineering standpoint to the computational representations," he says.
If the researchers can accomplish that, it will establish a framework in which manufacturers and engineers can build powerful new tools that harness the potential of three fast-rising scientific disciplines.
The scope of the grant is to create an abstract, foundational link between computers and materials and their behaviors, but it aims for profound impact.
"If successful," Shapiro and Regli wrote in their grant proposal, "this research should also lead to systematic re-examination of how design and manufacturing are taught and practiced at all levels."


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Posted by Daniel (Kenmare, United States) on 26 November 2006 in Plant & Nature.
vfxy Photoblogs | Cool Photoblogs | Listed on Photoblogs.org
Well done. Beautiful
26 Nov 2006 8:39pm
Fantastic, looks like a skeleton of some Alien race!! Great job. The cold black background adds to my thoughts of the ET theme.
27 Nov 2006 2:14am
great shot daniel. Great contrast.
27 Nov 2006 7:06am
Nothing short of amazing.
27 Nov 2006 8:43am
Amazing!!! No words. Perfect!
28 Nov 2006 10:20am
2 Dec 2006 10:33pm
Add your comment ...


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Redbox, the DVD rental kiosk company, today announced that it has signed two new, separate two-year distribution agreements with Summit Entertainment and NCircle Entertainment. The deals will bring hits like Twilight and New Moon from Summit as well as children's entertainment from NCircle such as Sid the Science Kid and The Cat in the Hat Knows a Lot About That!.
Normally, we wouldn't do a full-blown post about a distribution agreement, but Redbox found itself at the center of a home video maelstrom earlier this year. The company's $1-per-night movie rentals have raised a stink in Hollywood with studios polarized about Rexbox's business model. Summit and NCircle join Sony, Disney and Lionsgate on Team Redbox, but biggies like Warner Bros., Universal and Fox are embroiled in legal battles with the kiosk company. Paramount is somewhere in the middle and taking a "try before it buys" approach.
Having Summit entertainment's Twilight franchise ensures that teenage girls will swarm the machines, but fans might just burst into vampire tears when they learn that as part of the deal, Redbox will destroy Summit's product once Redbox is done with it, eliminating the possibility of those discs being sold into the aftermarket discount bins and giving Summit more control over its content.
We'll be talking with Redbox at length during a special fireside chat at our upcoming NewTeeVee Live conference on Nov. 12 to find out more about agreements like this, and more broadly how Redbox is disrupting the home video landscape. Redbox joins a packed roster of speakers including Reed Hastings, CEO of Netflix; Amy Banse, president of Comcast Interactive; Quincy Smith, president of CBS Interactive, and much more. Get your tickets today!


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NEW YORK – Toyota Motor Corp.'s Calty Design Studio and its satellite operations in Ann Arbor, MI, are investigating replacements for the Celica and MR2, Kevin Hunter, vice president-design and studio operations at Calty, says. Enthusiasts have been calling for Toyota to fill in the sports car gap in its lineup with a new entry ever since word came those cars would be phased out of the U.S. lineup. Both the Celica and MR2 ended their U.S. runs last year. Hunter doesn't detail the studies ...
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Manufacturer's Description
Mac OS X Server is a UNIX-based operating system designed for superior performance and reliability. This robust foundation provides advanced computing and networking capabilities such as preemptive multitasking, symmetric multiprocessing, and support for IPv6 and IPsec. Mac OS X Server features a server-optimized implementation of Java 2 and the latest in Web services and security standards. Cutting-edge remote-management tools allow you to securely manage and monitor your services from anywhere on the network, or even over the Internet. Built on open standards, Mac OS X Server is a model citizen in a multiplatform world. It uses native protocols to enable Mac, Windows, and UNIX clients to share files and printers. Apple's new Open Directory architecture offers centralized management of network resources using LDAPv3 directory services. Mac OS X Server also supports NFS resharing over AFP, giving Mac clients easy access to enterprise storage with improved security. Mac OS X Server 10.2 features revolutionary new tools that simplify the administration and support of Mac OS X systems. Workgroup Manager provides directory-based management of users, groups, and computers, allowing you to manage organizational resources more efficiently. You can set user and group preferences, control access to network resources, and standardize desktop environments. Workgroup Manager works with any LDAPv3 directory server, enabling you to leverage your existing network infrastructure.
The Specs
System Requirements | |
System Requirements | Xserve, Macintosh Server G4, Power Mac G4, Macintosh Server G3, Power Macintosh G3, iMac or eMac 128MB RAM; at least 256MB of RAM for high-demand servers running multiple services 4GB of available disk space Automatic hardware restart requires an Xserve, Macintosh Server G4 or Power Mac G4 released in February 2000 or later. Mac OS X Server does not support upgraded PowerPC. |
Additional Specifications | |
Brand Name | Apple |
License Pricing | Standard |
Description | 0 |
Software Name | Mac OS X Server v.10.2 |
Frequency Band | Additional Software:Open Directory AssistantNetwork Image UtilityQuickTime BroadcasterQuickTime Streaming Server AdminDirectory AccessNetInfo ManagerMySQL ManagerODBC AdministratorDisk Utility and ProcessViewer |
Language Support | English |
System Compatibility | Macintosh |
General | |
Category | Mac OS |
Class | Software-OS |
URL | http://www.apple.com |
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License Type | Complete Product |
Media Format | CD-ROM |
Software | |
Max License Size | Unlimited Client |
Related Mac OS
Mariner Software MacJournal v.6.0 - License - 1 License (Standard -...MacJournal - ( v. 6 ) - license - Mac |
$39.00 |