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Lymphocyte calcium signaling from
membrane to nucleus
Elena M Gallo1, Kirsten Canté-Barrett2 & Gerald R Crabtree1,2
Ca2+ signals control a variety of lymphocyte responses, ranging from short-term cytoskeletal modifications to long-
term changes in gene expression. The identification of molecules and channels that modulate Ca2+ entry into T
and B lymphocytes has both provided details of the molecular events leading to immune responses and raised
controversy. Here we review studies of the pathways that allow Ca2+ entry, the function of Ca2+ in the regulation of
cell polarity and motility and the principles by which Ca2+-dependent transcription regulates lymphocyte function.
In resting cells, the concentration of free intracellular Ca2+ ([Ca2+]i) is
kept low and constant. Ligation of lymphocyte antigen receptors initi-
ates a cascade of signaling events that eventually leads to the entry of
extracellular Ca2+ into the cell. Both resting [Ca2+]i and the entry of
extracellular Ca2+ are tightly regulated by a variety of mechanisms. These
include channels involved in control of membrane potential, the plasma
membrane Ca2+ ATPase1,2 and the sarco-endoplasmic reticulum Ca2+
ATPase pumps. Mitochondria also participate in both Ca2+ buffering
and in the maintenance of a sustained Ca2+ influx3–5. Because of space
limitations and because these mechanisms have been the topic of other
reviews6–9, we will not address them in detail here. Instead we will focus
on the signaling events connecting the lymphocyte antigen receptor to
Ca2+ entry and the transcriptional and nontranscriptional modifications
induced by Ca2+ in the cell. In the last part of the review we will also
address the issues of how signal specificity can be attained in response
to a ubiquitous second messenger such as Ca2+ and how the nucleus can
be insulated from transient increases in [Ca2+]i.
Antigen receptor signaling and the regulation of Ca2+ entry
Engagement of the T cell receptor (TCR) or B cell receptor (BCR)
results in the recruitment of adaptor molecules and kinases, ultimately
resulting in tyrosine phosphorylation of phospholipase C-γ (PLC-γ)
and an increase in [Ca2+]i (ref. 10). The key step in triggering Ca2+ flux
is the activation of PLC-γ, which hydrolyzes phosphatidylinositol-4,5-
bisphosphate to diacylglycerol and inositol-1,4,5-trisphosphate (IP3).
IP3 binds to IP3 receptors (IP3Rs) in the endoplasmic reticulum and
induces the release of Ca2+ into the cytoplasm. The depletion of Ca2+
from intracellular stores triggers entry of Ca2+ across channels in the
plasma membrane. These channels, which are responsive to depletion
of Ca2+ intracellular stores, have not been identified molecularly but
are commonly referred to as calcium release–activated Ca2+ (CRAC)
channels or store-operated channels (Fig. 1).
The pivotal function of PLC-γ in regulating Ca2+ signaling goes
beyond the generation of IP3. Mutation analysis has shown that PLC-
γ could regulate Ca2+ influx by a lipase-independent mechanism11. A
molecular description of a lipase-independent effect of PLC-γ on the
influx of Ca2+ has been provided12. PLC-γ1 regulates cell membrane
localization of the TRPC3 channel (a member of the transient receptor
potential family of channels; discussed below) in a lipase-independent
way. PLC-γ1 induces TRPC3 membrane localization by an 'intermolecu-
lar pleckstrin homology domain' wherein the PLC-γ1 C-terminal pleck-
strin homology domain interacts with a partial N-terminal pleckstrin
homology domain in TRPC3. A gain-of-function mutation in the gene
encoding PLC-γ2, which results in enhanced membrane localization of
this enzyme and increased Ca2+ influx, has also been identified13. This
mutation causes inflammation and autoimmunity in mice and attests to
the physiological relevance of Ca2+ signaling in the regulation of these
processes. The PLC-γ2 mutation does not increase the in vitro lipase
activity of PLC-γ2 or in vivo Ca2+ release from intracellular stores, but
instead causes increased entry of Ca2+ from the extracellular space. It is
possible that the mutant PLC-γ2 may promote Ca2+ entry by targeting
Ca2+-permeable channels to the cell membrane.
New participants in the regulation of Ca2+ entry in B cells
The basic steps of TCR and BCR signal transduction proceed in a fairly
parallel way. Nevertheless, these signaling pathways also involve mol-
ecules with nonhomologous functions. The linker for activation of B
cells (LAB; also known as non–T cell activation linker), the adaptor
molecule grb2 (ref. 14) and reactive oxygen species (ROS)15 have been
linked to the regulation of Ca2+ signaling in B cells.
LAB was cloned as a functional homolog of the T cell adaptor mol-
ecule LAT in myeloid lineage cell types and B cells16,17. However, data
suggest that LAB is not a functional LAT homolog18–20. Although it does
not directly bind PLC-γ or B cell linker protein (also known as SLP-
65)17,21,22, LAB positively affects Ca2+ flux. In the chicken pre–B cell line
1Program in Immunology and 2Howard Hughes Medical Institute and the
Departments of Pathology and of Developmental Biology, Stanford University,
Stanford, California 94305, USA. Correspondence should be addressed to
G.R.C. (email@example.com).
Received 16 August; accepted 14 November; published online 15 December
2005; corrected online 21 December 2005 (details online); doi:10.1038/ni1295
© 2006 Nature Publishing Group http://www.nature.com/natureimmunology
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DT40, LAB modulates Ca2+ flux by relieving an unanticipated inhibitory
activity of grb2, possibly by relocalizing grb2 to lipid rafts14. It will be
useful to determine how grb2 inhibits Ca2+ flux, how LAB prevents this
effect and how this controls B cell responses in vivo.
ROS have been linked to the regulation of Ca2+ influx in the B cell line
A20 (ref. 15). The production of ROS seems to be necessary for BCR-
dependent phosphorylation of the kinase Lyn and subsequent induction
of Ca2+ entry. In that same study15, dual oxidase 1 was newly identified
as a NADPH oxidase involved in BCR-dependent generation of ROS.
[Ca2+]i also affects ROS production in a positive feedback loop by an
unknown mechanism. It remains to be shown whether [Ca2+]i is able
to regulate dual oxidase 1 or other BCR-activated NADPH oxidases.
Thus, the molecular mechanism by which [Ca2+]i positively affects the
production of ROS after BCR activation and the biological consequences
in vivo remain unclear.
Actin cytoskeleton rearrangements and Ca2+ influx
Rearrangement of the actin cytoskeleton and formation of the 'immuno-
logical synapse' have been proposed to be involved in TCR signaling and
in the maintenance of sustained Ca2+ influx during T cell activation23–25.
However, early studies and subsequent work26 have made it clear that
TCR signaling temporally precedes the formation of the 'mature synapse'
and that prolonged signaling is required for maintenance of the synapse,
not vice versa27. In contrast to early reports28,29, subsequent studies have
suggested that rearrangement of the actin cytoskeleton (as determined
using actin polymerization inhibitors) may inhibit transcription acti-
vation by the TCR30,31. The duration- and concentration-dependent
effect of actin-polymerization inhibitors32 may explain the contradic-
tory results obtained in those studies28–30. Even so, actin rearrangements
and formation of the synapse consistently correlate with T cell activa-
tion. Moreover, patients and mice deficient in proteins such as the Rho
family guanine nucleotide–exchange factor Vav and Wiskott-Aldrich
syndrome protein, which regulate actin rearrangements and synapse
formation, have severe immune deficiencies33–39. Whether the signaling
and transcriptional effects mediated by Vav and Wiskott-Aldrich syn-
drome protein are dependent on their function in actin rearrangement
remains a matter of controversy40–43.
Vav is important in both B and T cell activation33,44. This molecule is
necessary for Ca2+ flux and activation of extracellular signal–regulated
kinase (ERK) as well as for rearrangement of the actin cytoskeleton in
response to receptor ligation33,45–48. The fact that activation of Vav is
required for synapse formation28,29 is consistent with the idea that the
synapse is a 'downstream effect' of TCR signaling.
Vav triggers actin rearrangements by activating the Rho family GTPase
Cdc42, which in turn activates its effector protein, Wiskott-Aldrich
syndrome protein49,50. This effector protein subsequently activates the
Arp2-3 complex, which initiates reorganization of the actin cytoske-
leton49,50. At present, it is not clear whether the requirement for Vav in
Ca2+ influx depends on synapse formation or requires other intermedi-
ates that are independent of the function of Vav in actin polymerization.
Early results28 indicated that Vav was not necessary for translocation
to the nucleus of the Ca2+-activated transcription factor NFATc1 (dis-
cussed below). However, work in our laboratory (unpublished results)
has indicated that Vav is essential for the translocation of both NFATc1
and NFATc2 into the nuclei of mouse T cells and for activation of NFAT-
dependent transcription.
Dynamin 2 has been proposed to be involved in cytoskeletal rear-
rangement51. Data from RNA interference experiments have indicated
that this molecule is required for efficient Ca2+ mobilization, actin polar-
ization at the T cell–antigen-presenting cell interface and activation of an
interleukin 2 (IL-2)–luciferase reporter51. Notably, dynamin 2 is neces-
sary for the phosphorylation of PLC-γ and the kinase Jnk but not for
the activation of TCR-proximal signaling. Interaction of dynamin 2 with
Vav is required for the function of dynamin 2. However, it remains to be
elucidated how exactly dynamin 2 works in concert with Vav and other
signaling molecules to regulate actin rearrangements and Ca2+ flux.
Ca2+ signaling by CRAC, L-type Ca2+ and TRP channels
The depletion of intracellular stores in response to interaction of IP3
with the IP3Rs results in Ca2+ influx across the cell membrane through
CRAC channels. The current produced by this channel is referred to as
'ICRAC'52–55. Although the mechanisms that regulate this essential event
are still poorly understood and CRAC channels remain uncharacterized
at the molecular level, data from somatic cell mutants as well as patients
have shown that ICRAC is essential for T cell activation and immune
Many different somatic Jurkat cell mutants defective in ICRAC have
been recovered from a screen for cells defective in NFAT-dependent
transcription57. Despite many attempts, it has not been possible to
complement these mutants with cDNA libraries from wild-type cells.
Although caution must be used when extrapolating results obtained in
cell lines to primary cells, that finding suggests that the channel gene
is very large, that the channel is encoded by more than one gene or
that each of the 17 mutant cell lines identified is a dominant negative
mutant or contains mutations in more than one gene. RNA interfer-
ence screens have been used to identify genes responsible for or regu-
lating ICRAC and have identified STIM1 and STIM2 (refs. 59,60). These
genes encode phosphoproteins that have a single membrane-spanning
domain and reside in the endoplasmic reticulum. The endoplasmic
reticulum side of the protein has a putative Ca2+-binding domain
and may serve as a sensor. After depletion of Ca2+ stores, STIM1
rapidly redistributes into puncta near the cytoplasmic membrane.
Suppression of STIM1 mRNA also blocks NFAT-activated transcrip-
tion in T cells59,60.
Figure 1 Regulation of Ca2+ flux in lymphocytes. Engagement of the TCR
results in recruitment of adaptor and effector molecules, eventually leading
to activation of PLC-γ. The generation of IP3 by PLC-γ leads to the opening
of IP3R channels in the endoplasmic reticulum (ER) and the release of Ca2+
into the cytoplasm. STIM1 senses the decrease in [Ca2+] in the endoplasmic
reticulum through its Ca2+-binding domain and signals this event to CRAC
channels in the plasma membrane, leading to their activation. Formation of
an 'intermolecular pleckstrin homology domain' between TRPC3 and PLC-γ
causes relocalization of TRPC3 to the cell membrane. TRPM4 depolarizes
T cells by reducing the electrochemical gradient driving Ca2+ entry into
the cell. The sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) actively
transports Ca2+ back into the endoplasmic reticulum.
© 2006 Nature Publishing Group http://www.nature.com/natureimmunology
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Those studies have provided understanding of a mechanism for sens-
ing Ca2+ store depletion and perhaps for communicating it to CRAC
channels in the cell membrane. A third study has also shown transloca-
tion and membrane insertion of endogenous STIM1 in Jurkat cells61.
The mechanism by which STIM1 and STIM2 communicate with chan-
nels carrying ICRAC is still uncertain. The use of conditional null muta-
tions, which avoids many of the drawbacks of RNA interference, will be
essential to verify the function of STIM1 and STIM2, but the fact that
two groups have isolated identical clones indicates involvement of these
proteins in regulating the channels that give rise to ICRAC.
Voltage-gated L-type Ca2+ channels
Voltage-gated Ca2+ channels are composed of a pore-forming α1 unit
and accessory subunits β, α2δ and sometimes γ. The α1 subunit confers
voltage dependence, whereas the accessory subunits modulate biophysi-
cal properties as well as expression and trafficking of the channel. The
pore-forming α1 subunit defines the nature of the four L-type Ca2+
channels: α1S, α1C, α1D and α1F, encoded by Cacna1s, Cacna1c, Cacna1d
and Cacna1f, respectively62. In excitable cells, voltage-gated Ca2+ chan-
nels open after depolarization to allow Ca2+ influx. In neurons, this
depolarization-dependent influx of Ca2+ rapidly activates NFATc4
translocation and gene expression63,64. Membrane depolarization does
not initiate lymphocyte activation and in fact seems to have a detrimen-
tal effect65,66. Consequently, the function of voltage-gated Ca2+ channels
in lymphocytes has been unclear.
Several classes of Ca2+ channel antagonists, including dihydropyridine
derivatives, have been used to indicate the existence of channels with
L-type Ca2+ channel properties in lymphocytes67. However, some of
these compounds, such as verapamil, dilitazem and nifedipine68, can
also inhibit membrane repolarization by acting on voltage-gated K+
channels and hence have an indirect detrimental effect on Ca2+ entry69.
In B cells, nicardipine and calciseptine block the Ca2+ influx induced by
antibody to immunoglobulin D (IgD) or to IgM, whereas the dihydro-
pyridine agonist Bay K 8644 prolongs the increase in [Ca2+]i induced by
antibody to immunoglobulin70,71. BCR activation induced by antibody
to IgD can cause an additional Ca2+ influx in cells whose Ca2+ intracel-
lular stores have been depleted by thapsigargin treatment70. That result
suggests that independently of CRAC channels, an additional mecha-
nism is involved in IgD-induced Ca2+ influx across the cell membrane.
However, similar experiments done with crosslinking by antibody to
IgM have not reproduced this effect71. Thus, it remains to be determined
whether CRAC channels and L-type Ca2+ channels function in the same
or in parallel pathways during physiological B cell activation. Similar
experiments with inhibitors of L-type Ca2+ channels have been done
in T cells72–74. However, in those experiments, Ca2+ influx was only
partially inhibited.
Despite partial inhibition of Ca2+ influx, the L-type Ca2+ channel
antagonist nifedipine has substantial 'downstream' effects, including
decreased phosphorylation of extracellular signal–regulated kinase,
decreased NFAT-dependent transcription and decreased IL-2 produc-
tion in human T cells72. Truncated α1C and α1D, as well as the full-length
β1 and β3 subunits, have been detected in human T cells, confirming the
existence of partial L-type Ca2+ channels in lymphocytes74. The identifi-
cation of two previously unknown α1F splice variants in human T cells
missing the voltage-sensor domain or containing an altered voltage-
sensor domain73 supports the belief that altered L-type Ca2+ channels
are expressed and possibly activated by some process independent of
membrane depolarization in nonexcitable cells. Nevertheless, the physi-
ological function of these channels in T cell and B cell activation remains
highly controversial.
Transient receptor potential channels
The 21 genes encoding the mammalian TRP family of channels (named
after the homologous drosophila transient receptor potential channel)
comprise three subfamilies based on sequence homology: TRPC, TRPV
and TRPM75. TRP channels are not ion specific and they allow the
flow of cations in general, including Ca2+. It has been suggested that
these channels might be involved in activation-induced Ca2+ influx
in lymphocytes, but it is not clear whether they respond to depletion
of stores or to other second messengers. Thus, whether TRP channels
are the molecularly unidentified CRAC channels remains controversial
(Fig. 1).
In the TRPC family, TRPC1, TRPC3 and TRPC6 are expressed and
functional in Jurkat T cells as well as in human T lymphocytes76,77.
Cyclosporine A
NFATc NFATn
Figure 2 Insulating the nucleus from transient Ca2+ fluxes. Activation-
induced Ca2+ influx occurs through CRAC channels; however, the molecular
identity of these channels is still unknown. Ca2+-bound calmodulin
(CaM) binds and activates the calcineurin phosphatase complex,
which dephosphorylates NFATc and causes its import into the nucleus.
Phosphorylation of NFATc by its nuclear kinases, such as GSK3, causes its
export from the nucleus. This strictly ties NFATc-dependent transcription
to a sustained increase in [Ca2+]i. NFATc and its nuclear partner, NFATn,
cooperatively bind to DNA. NFAT complexes (NFATc plus NFATn) act as
'coincidence detectors' and allow the integration of multiple signaling
pathways at the level of DNA binding. Inhibitors of calcineurin include
pharmacological agents such as FK506 and cyclosporine A, cellular
proteins such as Cabin (also known as Cain)163,164 and Down syndrome
critical region 1 (DSCR1)165 and pathogen-derived molecules such as
the African swine fever virus A238L protein141 and the Helicobacter
pylori vacuolating cytotoxin (VacA)142. Ca2+-bound calmodulin also
activates CaMK. Phosphorylation of CREB by CaMK allows it to bind to
its transcriptional coactivators CBP and p300. CaMK also phosphorylates
histone deacetylase 5 (HDAC), causing its export from the nucleus. Relief
of histone deacetylase inhibition activates MEF-dependent transcription.
CaMK autophosphorylation makes its activity Ca2+ independent and results
in prolonged activity even after [Ca2+]i has returned to basal concentrations.
© 2006 Nature Publishing Group http://www.nature.com/natureimmunology
Page 4
Various endogenous TRPC molecules have been shown to assemble
and form heteromultimeric channels78–80, suggesting that combinatorial
assembly of TRP proteins may give rise to channels with different pro-
perties. As TRPC channels are activated 'downstream' of PLC-γ, it was
initially thought that they also depended on intracellular store depletion,
thereby making TRP channels (part of) CRAC channels. However, these
channels may be activated by lipid products of PLC-γ such as diacyl-
glycerol76,80–83 or by direct binding to PLC-γ12.
Because TRPV6 (also known as CaT1) shares some of the biophysical
properties of CRAC channels and was found to be activated by depletion
of intracellular Ca2+ stores, it was proposed to form all or part of the
CRAC channel84. However, that idea has been challenged by other stud-
ies showing important differences between the two channels in a direct
comparison85. In that later study, TRPV6 gating was voltage dependent
and was inhibited by Ca2+ depletion from intracellular stores, in contrast
to CRAC channel gating properties85.
The human and mouse TRPM4 channels have been characterized86–88.
Unlike other TRP channels, TRPM4 is a voltage-gated and Ca2+-
activated nonselective channel that is not permeable to Ca2+ (refs. 87,89).
TRPM4 can depolarize Jurkat T cells at the peak of Ca2+ flux after acti-
vation90. This depolarization, caused by influx of Na+, reduces the elec-
trochemical gradient driving Ca2+ entry in nonexcitable cells and thus
modulates Ca2+ oscillations. Further characterization of this channel
has shown that the Ca2+ sensitivity of TRPM4 is regulated by cytosolic
ATP, protein kinase C–dependent phosphorylation and calmodulin91.
A dominant negative mutant of TRPM4, closely resembling the natu-
rally occurring splice variant TRPM4a, converts receptor-mediated Ca2+
oscillation into a long-lasting sustained increase in [Ca2+]i and results in
increased IL-2 production90. Whether regulated expression of TRPM4
isoforms is involved in the physiological regulation of Ca2+ entry in
primary T cell activation remains to be shown.
Regulation of lymphocyte responses by Ca2+ signals
Because of the plethora of Ca2+-regulated enzymes, an increase in
[Ca2+]i can lead to a variety of cellular responses. In lymphocytes, a
localized and transient increase in [Ca2+]i is not sufficient to activate
transcription56,92, which requires a more sustained Ca2+ influx across
the plasma membrane through CRAC channels (Fig. 2). Ca2+ responses
can therefore be generally subdivided into short-term, rapid responses
that do not involve transcriptional changes and long-term modifications
of cellular identity that require changes in gene transcription8. Ca2+-
regulated changes in the gene expression profile are critical in orchestrat-
ing complex cellular responses that govern lymphocyte development as
well as immune activation in the periphery.
Short-term modifications in T cell motility and polarity
The interaction between antigen-presenting cells and T cells is quickly
followed by an increase in [Ca2+]i and within minutes by a change in T
cell shape, interruption of T cell crawling and movement of the cortical
actin cytoskeleton93–95. Reorientation of the cortical actin cytoskeleton
toward the T cell–antigen-presenting cell interface involves the inter-
action of costimulatory molecules CD28-B7 and leukocyte function
antigen 1–intercellular adhesion molecule 1 and is dependent on myosin
motor proteins95. Pharmacological inhibition of the class IIA nonmuscle
myosin MyH9 interferes with T cell motility but not with synapse for-
mation96. During crawling, MyH9 is present in the uropod, but after
TCR triggering it translocates to the immune synapse96. In vitro, Ca2+
is both necessary and sufficient for MyH9 phosphorylation after TCR
engagement96. The authors of that study96 suggest that MyH9 relocation
to the immune synapse and its phosphorylation may be involved in the
abrogation of T cell movement after interaction with antigen-presenting
cells, but a direct link between these events has not been established.
Patients with mutations in MyH9 have a variety of phenotypes affecting
kidneys, platelets and leukocytes97, whereas mice deficient in MyH9 die
in utero because of severe defects in cell adhesion and tissue organiza-
tion98,99. Thus, an approach involving a conditional allele or RNA inter-
ference will be needed to assess the function of MyH9 in lymphocytes
in vivo. An increase in [Ca2+]i has also been shown to decrease mobility
of thymocytes100. In a positively selecting environment, an increase in
[Ca2+]i is both sufficient and necessary to cause thymocytes to stop
moving, possibly by enhancing the interaction with antigen-presenting
cells presenting positively selecting peptides100.
In addition to regulating cell motility, Ca2+ regulates cell polarity,
which might be required for directional cell killing. Perforin-mediated
cytotoxic lymphocyte killing by exocytosis of cytotoxic agents requires
Ca2+ (refs. 101,102). This increase in [Ca2+]i is required for the reori-
entation of the microtubule-organizing center toward the contact zone
with the target cell103–105, a process involved in the polarized secretion
of cytotoxic granules106. Although reorientation of the microtubule-
organizing center is Ca2+ dependent, it does not depend on the activity
of calcineurin or Ca2+-calmodulin–dependent kinase (CaMK)107. An
increase in [Ca2+]i to about 500 nM is both sufficient and necessary for
granule exocytosis108. That observation is consistent with the findings
that a stable immune synapse and maximal Ca2+ flux are not required for
T cell–mediated cytotoxicity and that the initial Ca2+ spike that occurs
after TCR engagement is sufficient to induce perforin and granule exo-
As has been discussed111, Ca2+ is also involved to some extent in the
migration of leukocytes to chemokines. Although Ca2+ is dispensable for
chemotaxis112 and transendothelial migration113, chemokine receptors
can activate PLC-β114, leading to an increase in [Ca2+]i. Ca2+ is necessary
for uropod retraction and detachment from fibronectin coated sub-
strates115, possibly by a mechanism involving the phosphorylation of
myosin II (ref. 116). The function of [Ca2+]i in regulating protein kinase
C and the function of these kinases in lymphocyte motility and function
have been reviewed117 and will not be addressed here.
Ca2+ signals and biological specificity
One of the mysteries that has emerged from the past 20 years of signaling
research is the observation that only about a dozen signaling pathways
connecting the membrane to the nucleus seem to be sufficient for all
of vertebrate and invertebrate development. That paradox is most clear
in Ca2+ signaling, in which ubiquitous signals produce notably specific
outcomes. 'Receptor swap' experiments, in which the TCR is replaced
by an unrelated receptor normally expressed in other cell types, have
indicated that once a cell reaches a certain point in development, the
signals necessary to progress to the next stage are fairly general. In T
cells, replacement of the T cell receptor with the acetylcholine receptor
allows activation of the gene encoding IL-2 in response to Ca2+ influx
triggered by acetylcholine118. Those types of experiments have focused
attention on the function of cellular context in determining the outcome
of signaling. Cellular context is probably defined by the transcription
factors, signaling molecules and, perhaps most importantly, by chroma-
tin accessibility of the loci encoding the molecules essential for specific
However, even in a population of cells that are apparently equivalent,
different cellular responses can be activated by the influx of Ca2+ (refs.
119,120). In that scenario, intrinsic molecular properties of a transcrip-
tional control module could determine whether it will be activated in
response to a Ca2+ flux with certain characteristics121. For example,
Ca2+ regulates activation of the transcription factors CREB and MEF
by modulating the activity of CaMK family members122,123. CaMKs
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Page 5
activate CREB by direct phosphorylation, which is necessary for its bind-
ing to 'transcriptional cointegrators' CBP and p300 (ref. 123). CaMKs
also activate MEF-dependent transcription by relieving the inhibition
of histone deacetylases124 (Fig. 2) and that of the MEF transcriptional
repressor Cabin 1 (refs. 125,126).
Because autophosphorylation renders CaMK activity independent
of Ca2+-calmodulin127,128, this enzyme is able to maintain 'molecular
memory' of a transient increase in [Ca2+]i by continuously phosphory-
lating itself. Although prolonged Ca2+-independent CaMK activity is
prevented by CaMK phosphatases129–132, transcription factors that are
activated by CaMK can be activated by CaMK even after [Ca2+]i has
returned to basal concentration. In contrast, certain signaling molecules
and transcription factor pairs, such as calcineurin-NFAT, require a sus-
tained increase in [Ca2+]i to activate transcription (discussed below).
Calcineurin and NFAT signaling
The critical function of the calcineurin phosphatase complex became
clear in the late 1980s and early 1990s, when it was discovered that the
common target of the two most effective immunosuppressants, FK506
and cyclosporine A, is calcineurin133 and calcineurin-NFAT-dependent
transcription134–136. In that pathway, an increase in [Ca2+]i results in
binding of Ca2+-calmodulin to the calcineurin complex and activation
of its phosphatase activity. Dephosphorylation of the cytoplasmatic sub-
units (NFATc) of NFAT transcription complexes by calcineurin unmasks
the nuclear localization sequence and results in their import into the
nucleus137,138. Conversely, NFATc nuclear kinases, such as glycogen
synthase kinase 3 (GSK3; ref. 139) and protein kinase A140 regulate the
export of NFATc from the nucleus by rephosphorylation. This bidirec-
tional allosteric switch, controlled by calcineurin on one hand and GSK3
and protein kinase A on the other, results in shuttling of NFATc in and
out the nucleus135,137,138. In addition to FK506 and cyclosporine A, many
pathogens produce molecules that neutralize the immune response by
targeting calcineurin or calcineurin-NFAT signaling141,142 (Fig. 2).
In contrast to the 'molecular memory' of CaMKs, the intrinsic pro-
perties of the Ca2+-calcineurin-NFAT pathway make NFAT-driven tran-
scription dependent on continuous signaling. The rapid and regulated
export of NFATc proteins from the nucleus prevents transcription in
response to transient increases in [Ca2+]i and thus enhances the speci-
ficity of gene regulation by these transcription factors. That insulator
mechanism allows separation of short-term Ca2+-dependent responses
from the activation of transcription137. In cardiac muscle, skeletal mus-
cle, neurons and other cell types that use periodic increases in Ca2+ to
regulate essential activities, the rapid export of NFATc proteins from
the nucleus is probably critical for maintaining stable patterns of gene
expression yet reserving the potential for rapid responses to specific
stimuli. We will not discuss here the many functions of calcineurin-
NFAT in regulating lymphocyte development and function as there are
reviews specifically dedicated to that topic143–146.
Specificity by integration with other pathways
Ca2+ responses are integrated in the cell with other signaling pathways,
such as the protein kinase C or mitogen-activated protein kinase path-
way, by several mechanisms. Integration can be obtained at the level
of the binding of transcription factor to DNA response elements that
receive signals from the TCR and other receptors147. NFATc alone binds
to DNA with relatively low affinity. The formation of NFAT transcrip-
tional complexes between NFATc and NFAT nuclear partners (NFATn)
increases the affinity of NFATc for DNA. Because NFATn are activated
by different signaling pathways, assembly of NFAT transcriptional
complexes functions as a molecular 'AND' gate and hence improves the
specificity of multiple pathways147 (Fig. 2).
Another mechanism of integrating Ca2+ signaling has been demon-
strated in studies of costimulation in human peripheral T cells148. In
those studies, CD28 stimulation enhances the activation of the same set
of genes activated by TCR signaling. Those data indicate that CD28 has
a quantitative function, rather than a qualitative function as previously
thought. They also indicate that CD28 is unlikely to activate a specific
signaling pathway. The finding that cyclosporine A and FK506 reverse the
effects of CD28 stimulation suggests that CD28 exerts its effects on TCR-
dependent transcription by reinforcing NFAT-dependent transcription
regulation. Substantial evidence has indicated that CD28 acts through
phosphatidylinositol-3-OH kinase and the serine-threonine kinase
Akt149–152. Activation of Akt by phosphatidylinositol-3-OH kinase results
in the phosphorylation of GSK3 on serine residues. That phosphorylation
inhibits the effect of GSK3 on NFATc proteins and prevents the export of
NFATc proteins from the nucleus. Thus, it seems that CD28 stimulation
enhances gene expression in response to the TCR by blocking the export
of NFATc proteins from the nucleus148. Those findings are consistent
with studies showing that molecules that interfere with the costimula-
tion pathway, such as cytotoxic lymphocyte antigen 4, act by preventing
accumulation of NFATc in the nucleus153,154. Additional support for the
idea that phosphatidylinositol-3-OH kinase is critical in regulating the
export of NFATc1 comes from studies of mice with mutations in the gene
encoding neurofibromatosis type 1. In the developing heart, mutations
in this gene lead to hyperactivation of the adaptor protein Ras and phos-
phatidylinositol-3-OH kinase, resulting in excessive nuclear localization
of NFATc1 and lethal heart valve defects155.
Alternative models to account for the function of costimulation in T
cell activation have also been suggested. Integration of TCR and CD28
signaling has been proposed to occur by synergistic activation of NFATc
and adaptor protein 1 (AP-1), a transcriptional complex formed by c-Jun
and c-Fos156. According to that model, TCR signaling in the absence of
costimulation leads to activation of NFATc but not AP-1. NFATc tran-
scriptional activity in the absence of its transcriptional partner AP-1
would then cause a Ca2+-induced unresponsiveness status in T cells156.
Those results are consistent with the early finding that administration of
ionomycin or activation of T cells in the absence of costimulation leads
to anergy induction, which can be prevented by the calcineurin inhibi-
tor cyclosporine A157,158. A subsequent study by that same group has
also proposed that one of the mechanisms by which calcineurin-NFATc
can induce a state of unresponsiveness in T cells is by induction of E3
ubiquitin ligases, which in turn causes selective degradation of crucial
signaling molecules such as protein kinase C-θ and PLC-γ159. Genetic
studies in mice will be needed to determine whether this mechanism is
relevant for T cell anergy in vivo.
An additional way of achieving specificity by integrating Ca2+ sig-
nals with other pathways has been suggested by studies of Notch signal-
ing160. In keratinocytes (and possibly T cells), Notch signaling is a potent
suppressor of transcription of Down syndrome critical region 1 (also
called MCIP1 or calcipressin)160. This gene was discovered originally
as being in the Down syndrome critical region on human chromosome
21 (ref. 160) and later was identified independently as a gene encoding
a calcineurin inhibitor in yeast and mammalian cells161,162. The Down
syndrome critical region 1 product blocks calcineurin activity and pre-
vents translocation of NFATc proteins into the nucleus (Fig. 2). Thus,
it could be predicted that Notch signaling should enhance calcineurin
activity, translocation of NFATc and the formation of NFAT transcrip-
tion complexes.
Conclusions and future perspectives
Ongoing studies in many laboratories have shown that Ca2+ is essential
to nearly every aspect of vertebrate organogenesis from axonal guidance
© 2006 Nature Publishing Group http://www.nature.com/natureimmunology


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JUNIORS: Academy batsman Salt wins Travel Places Player of the Month
Phil Salt of the Sussex Academy was today named as the Travel Places Player of the Month for August.
Batsman Salt, who turned 18 last week, played the innings of the year in Youth Cricket during August, to follow up his earlier 147 not out against Preston Nomads in June, for the Development XI in the Sussex Premier League.
He cracked an unbeaten 200 from only 129 balls against Horsham at Cricket Field Road, a knock that included an incredible nineteen fours and nine sixes. Later on in the month he scored 51 from 33 balls against the eventual Sussex Premier League winners Roffey in a losing cause and has also contributed for the Second Eleven during the month.
He is seen here receiving his prize of a new Travel Places branded kitbag from Katie Hanley, Marketing Executive at Travel Places who are sponsors of the of the Junior County Age Group Squads.
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|ESPN.com: Boxing
|[Print without images]
|Arthur Abraham KO'd Jermain Taylor in his first Super Six fight before things quickly went south.
|Vernon Paris, right, could make a statement and become Lamont Peterson's mandatory with a win against Zab Judah.
|Both Chris Martin and Teon Kennedy will be anxious to put their first career losses behind them when they meet Friday in Las Vegas.
• For the past few years, Golden Boy has had an exclusive hold on all of the dates for Telefutura's "Solo Boxeo Tecate" series, but that is changing this year. The series, which has moved from Friday to Saturday nights and resumed a 90-minute format that began with the Jan. 7 season premiere, will feature multiple promoters. Although Golden Boy will remain the primary dateholder, it will have far fewer cards than last year. According to Golden Boy's Richard Schaefer, his company will promote 25 of the 42 live fight cards on the Spanish-language network this year. Last year Golden Boy had all of the live cards, plus filled in other dates with fights from its extensive library. Telefutura executives are talking to a variety of promoters. The next live card is Jan. 21 -- fights to be announced -- which will be promoted by Peter and Ivan Rivera's PR Best Boxing in Puerto Rico. Golden Boy's first show of the year is Feb. 4, headlined by junior lightweight prospect Ronny Rios (16-0, 7 KOs). The next live card after that will be a Feb. 18 show promoted by Miguel Cotto's company in Puerto Rico featuring his cousin, lightweight Abner Cotto (12-0, 5 KOs), against Guillermo Sanchez (13-4-1, 5 KOs).
|Ricky Burns ran through Michael Katsidis to earn an interim lightweight belt, which he'll put on the line against Paulus Moses in March.
• Promoter Frank Warren announced Thursday that Ricky Burns will make the first defense of his interim lightweight belt against former titleholder Paulus Moses of Namibia on March 10 at the Braehead Arena in Glasgow, Scotland, Burns' home country. "I don't think Moses will be bothered about coming to Scotland," Burns said. "He won the title in Japan [in 2009], so he'll be looking to make a big upset in Scotland against me. He's a good fighter, he's a former world champion with a good record and he's lost only once in 29 fights. This is just the kind of fight I wanted to make me perform to my best." Burns (33-2, 9 KOs) vacated his junior lightweight title, moved up to 135 pounds and won a clear decision against Michael Katsidis for the vacant interim belt. Moses (28-1, 19 KOs) has won three straight since losing his belt via sixth-round knockout to Miguel Acosta in May 2010 in Namibia. "Make no mistake, I'm coming to Scotland to win the [interim] world title by knockout," Moses said. "I've beaten better fighters than Burns before. I know I can beat him easily."
• Sacramento, Calif., middleweight prospect Brandon Gonzalez (15-0, 10 KOs) was forced to withdraw from a Jan. 20 fight against Caleb Truax (18-0-1, 10 KOs) because of a slight tear in his right hamstring. The bout was supposed to be part of a "ShoBox: The New Generation" card on Showtime headlined by junior featherweight titlist Rico Ramos' mandatory defense against interim titleholder Guillermo Rigondeaux at The Palms in Las Vegas. Virgil Hunter, the 2011 ESPN.com trainer of the year, who trains Gonzalez and fighter of the year Andre Ward, told ESPN.com that Gonzalez suffered the injury doing sprints. "And it happened on the very last lap," Hunter said. "It took him to the ground. We taped it heavily and I thought we were going to make it, but he just couldn't run, couldn't do much of anything, and then the inflammation spread to his buttocks." Hunter said the doctor advised Gonzalez would need about a month of rest and that he would probably be able to resume training in about six weeks.
|Edison Miranda won't get a chance to avenge a disputed loss to Yordanis Despaigne after the latter fighter pulled out of their Feb. 3 rematch.
• Despite signing a contract, light heavyweight Yordanis Despaigne pulled out of his Feb. 3 "Friday Night Fights" rematch against Edison Miranda. Despaigne defeated Miranda on July 29 by controversial fifth-round disqualification when referee Vic Drakulich ruled Miranda had hit Despaigne with low blows. Despaigne and Miranda agreed to a rematch, but each took an interim bout and fought Dec. 17 on the Andre Ward-Carl Froch undercard. Although Miranda knocked out Kariz Kariuki in the fifth round, Despaigne was upset by Cornelius White, losing a lopsided six-round decision. ESPN and Warriors Boxing promoter Leon Margules still planned to put on the rematch until former Cuban amateur star Despaigne (9-2, 4 KOs) pulled out this week. Miranda (35-6, 30 KOs), a former middleweight and super middleweight title challenger, will now face Isaac Chilemba (18-1-1, 9 KOs) of South Africa. The fight will be Chilemba's third in the United States in his past four.
• An undisclosed medical problem has forced junior welterweight prospect Pier-Olivier Cote to withdraw from his Feb. 3 "ShoBox" main event on Showtime against Mauricio Herrera (18-1, 7 KOs). Promoter InterBox has postponed the entire show in Quebec City and Showtime has canceled that night's boxing programming, although it hopes to air the card when InterBox reschedules. According to InterBox, Cote (18-0, 12 KOs) has been informed by his doctor that he must immediately cease training for an undetermined period of time while doctors perform a battery of tests. "We are less than a month out of the most important fight in Pier-Olivier's career and he could not train adequately in the gym," trainer Francois Duguay said. "He wasn't feeling well. I really do not want to speculate what could be wrong with him until he undergoes the necessary medical tests. The first doctor he saw told him he has to stop training and rest. Until we know more, we are following his recommendations." Cote was disappointed about postponing the bout, saying, "I was really looking forward to fighting Herrera. This is the first time in my 18 fights that such a situation arises. I will follow the recommendations of the doctor and undergo every test that I have to. My goal right now is to get better and return stronger than ever."
• Middleweight titlist Daniel Geale (26-1, 15 KOs) of Australia and mandatory challenger Osumanu Adama (20-2, 15 KOs) of Ghana came to terms and avoided a purse bid. They will meet March 7 in Hobart, the capital of the Australian island of Tasmania, where Geale originally hails from. Featherweight titlist Billy Dib (33-1, 20 KOs) is also due to make a defense on the undercard. Geale will be making his second defense. Adama became the mandatory challenger in October when he knocked out former titlist Roman Karmazin in the ninth round. If Geale wins, promoter Gary Shaw hopes to bring him to the United States for a bigger fight. "After the Adama fight, I want to bring Danny to the United States and try to do a Sergio Martinez fight or a Dmitry Pirog fight or a [Gennady] Golovkin fight," Shaw said. "In a perfect world, I'd like to do a four-man tournament."
|Former junior welterweight champ Ricky Hatton will now call all the shots for his Hatton Promotions after taking over as CEO of the company.
• Former junior welterweight champ Ricky Hatton is taking over day-to-day operations of Hatton Promotions, his promotional company. Hatton has taken the title of CEO, replacing Gareth Williams, Hatton's longtime attorney, who will remain as a legal adviser. Hatton said he has recovered from the depression that hampered him following his retirement, along with a drug problem, and that he is ready for a hands-on role with the company. "This is just a structural change within the group, and Gareth will only be a phone call away for any issues we have," Hatton said in a statement. "Once I officially announced my retirement last summer, my plan was to gradually have a bigger role in our progress. My battle with depression was well-documented, and this is further evidence that I have bounced back. Gareth is a close, personal friend of mine and that will continue despite this change, and I cannot thank him enough for the job he has done apart from legal matters."
• Former junior middleweight titlist (and former undisputed welterweight champion) Cory Spinks (38-6, 11 KOs) will face Sechew Powell (26-3, 15 KOs) on Jan. 28 in Springfield, Mo., in a title eliminator that will make the winner the mandatory challenger for titlist Cornelius "K9" Bundrage (31-4, 18 KOs), who will be forced to fight one of the two opponents he defeated decisively in his past two bouts. Bundrage, who has been on the shelf for long stretches because promoter Don King hasn't lined up anything for him, easily outpointed Powell in a June title defense and blew away Spinks in five lopsided rounds in August 2010. Cruiserweight B.J. Flores (26-1-1, 16 KOs), who is from Springfield, will headline the card against an opponent to be named.
• NBC Sports Network -- formerly Versus -- announced its broadcast team for the new Main Events-promoted "Fight Night" series that debuts Jan. 21 (9 p.m. ET) in Philadelphia with former heavyweight titlist Sergei Liakhovich facing Eddie Chambers in the main event. Calling the action will be blow-by-blow man Kenny Rice, whose duties for NBC have included serving as Olympic boxing reporter and covering horse racing. Newly elected International Boxing Hall of Fame trainer Freddie Roach and cruiserweight B.J. Flores will serve as analysts, with Sports Illustrated boxing and NBA writer Chris Mannix serving as ringside reporter.
• Middleweight titlist Felix Sturm (36-2-2, 15 KOs) has retained his belt on controversial decisions in his past two fights, first a split decision against Matthew Macklin in June (in a fight widely viewed as one of the worst decisions of the year) and then in a split draw against Martin Murray in December (a fight for which many believed Sturm deserved the decision). Sturm wouldn't give Macklin a rematch -- Macklin wound up with something better, a March 17 shot against recognized champ Sergio Martinez -- and he hasn't shown interest in fighting Murray again. But England's Murray would like a rematch, and he is willing to go back to Germany to get it. Sturm is tentatively slated to fight April 13. "Felix has been a great champion, but both me and him know that night in Mannheim he did not beat me," Murray said in an open letter to Sturm. "Felix cannot beat me. He knows I am the better fighter, and so I am not expecting him to offer me a rematch. I don't think that the Sturm team [is] confident that you can win this one, and as a result they and you will avoid me. Please be fair to yourself, to me and the German people who have supported you to get this fight on. ... I won't ask for silly money, just give me a fair price. I will even come to your own city of Cologne and bring double the fans I did last time."
• Bantamweight titlist Jorge Arce (59-6-2, 45 KOs) is due to face Lorenzo Parra (31-3-1, 18 KOs) on Feb. 18 in Mexico, a rematch of their September 2010 draw in a junior featherweight title eliminator. However, the WBO may decline to sanction the fight, meaning Arce would have to look for a new opponent. ... Hot Puerto Rican prospects Thomas Dulorme (13-0, 10 KOs), a welterweight, and Jonathan Gonzalez (14-0, 13 KOs), a junior middleweight, will fight in separate bouts against opponents to be determined on the Feb. 17 edition of Showtime's "ShoBox: The New Generation" at the Chumash resort in Santa Ynez, Calif., according to Gary Shaw, who co-promotes both. ... The IBF has set a Jan. 24 deadline for a purse bid on the vacant welterweight title bout between Mike Jones and Randall Bailey, if the sides don't make a deal before then. ... Lightweight contender Kevin Mitchell of England was supposed to face Stephen Ormond on Feb. 10 in London, but Ormond withdrew. Promoter Frank Warren is looking for a replacement to face Mitchell (32-1, 24 KOs), who rebounded from a knockout loss to Michael Katsidis (and dealt with a drinking problem) to stop John Murray in the eighth round of a rousing battle in July. ... According to PR Best Boxing Promotions, former strawweight and junior flyweight champion Ivan "Iron Boy" Calderon (35-2-1, 6 KOs) of Puerto Rico will challenge strawweight titlist Moises Fuentes (14-1, 6 KOs) of Mexico for his old belt, likely in April.
"Khan blames everyone and everything but his performance and lack of ability to make adjustments in the ring for his loss. He claims that the ring announcer privately stated he won, then that the referee's discretionary actions [of two-point deductions for pushing] should be overruled, then a mystery man in a black hat with no association to the Peterson camp somehow affected the outcome of the bout, and also that the judges did not score the bout correctly. Each claim is boldly false, but because Golden Boy and Khan have the financial resources to file protests and lawyers to create questionable accusations, we are forced to address these issues. We will not let these foul tactics take away from Lamont's hard work, dedication and monumental victory."
-- Barry Hunter, manager, trainer and father figure to junior welterweight titlist Lamont Peterson, on his disgust for the ongoing complaints and protests of Amir Khan and promoter Golden Boy since Khan's Dec. 10 loss to Peterson
"As I have done throughout my entire career, I will go up a notch for this fight. Sergio is going to bring the best out of me, and I am very confident in my mind that I will be the new middleweight champion come March 17. Fighting at the Garden on St. Patty's Day, it's going to be like I'm fighting in Dublin. The Irish are coming from all over the world to see this. The atmosphere is going to be electric."
-- Middleweight contender Matthew Macklin, at a news conference this week in New York to formally announce his HBO fight against champion Sergio Martinez at the Madison Square Garden Theater
Dan Rafael is the boxing writer for ESPN.com. Follow him on Twitter at danrafaelespn.


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MaiTech Low-Power / MCU UART turn Wi-Fi / Serial to Wi-Fi Wireless Module - Black
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Funny: Cloud Atlas
- Autua ensuring Adam Ewing that he isn't going to eat him by saying that he doesn't like "white meat".
- "Cause of injury: Pussy."
- "It's people! Soylent Green is maaaaaade of peeeeplleeeee!" Later turns into Fridge Horror.
- "Are there no true Scotsmen in the house?!" and the brawl that ensues.
- Just about every scene in that segment is made of pure hilariousness.
- The Mexican woman bludgeoning the Assassin to death. "Don't call me a wetback!"
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Videos tagged "Princess Elisabeth station"
Toyota Hiluxes at Princess Elisabeth Antarctica00:36
Arrival of the Toyota Hiluxes at Utsteinen. We are so happy to have those available at Princess ELisabeth Antarctica to support scientists for the rest of the 2014-2015 season and beyond. These are true game changers. many thanks to our Mechanics Kristof Soete for customising them!+ More details
While examining satellite sea ice data, Nighat Amin of the International Polar Foundation spotted that a 70 km2 iceberg had calved off the tip of the King Baudouin Ice Shelf in late January. We interviewed glaciologists Frank Pattyn and Reinhard Drews, who have both been studying the ice shelf for some time. Ice shelves losing ice is a completely natural phenomenon, and glaciologists closely track the pace at which this happens. In the case of the King Baudouin Ice Shelf, the last major calving hasn't happened since the 1960s. What we witnessed here was a natural, albeit rare, event. Both Frank Pattyn and Reinhard Drews from the Université Libre de Bruxelles (ULB) were quite confident in saying that, according the current data they have, there is no sign of acceleration of ice discharge from this particular ice shelf, and it remains relatively stable. Whether that stability will remain true for the coming decades will largely depend on the way climate change may affect that particular part of East Antarctica.+ More details
A successful season for Jan Lenaerts04:00
Jan Lenaerts, the 2014 Inbev-Baillet Latour laureate is really happy with the work he was able to accomplish during the 2014-2015 BELARE expedition and with the support he got from the team. Jan was in Antarctica do conduct research for the BENEMELT project. BENEMELT aims at investigating how much snow melts on the ice shelves in East Antarctica, to what extent melt may increase in the future, and how this melt would impact ice shelf stability and ultimately global sea levels. His main duties this season were to: - Install an automatic weather station on the King Baudouin Ice Shelf to get continuous measurements during a one-year period - Drill several firn cores to investigate melt layers and determine snow density Jan Lenaerts will come back to Princess Elisabeth Station and camp on the ice shelf for several weeks to measure snow albedo, snow grain size, snow density, and melt layers. He also plans to investigate a large 2 km-wide scar on the ice shelf scientists form the Alfred Wegener Institute discovered in December 2014 while flying a geophysical survey.+ More details
OP0LE Princess Elisabeth Station Antarctica. From dxnews.com00:48
ON5TN and ON1EN will be active from Princess Elisabeth Station, Antarctica until end of February 2015 as OP0LE. http://dxnews.com/op0le-princess-elisabeth-station-antarctica/+ More details
A bad storm hit Utsteinen last weekend. It hit the station on Saturday: here is a quick glimpse of how it looks and feels like.+ More details
Drilling and radar measurements at the coast04:49
We followed the IceCon crew during their expedition in November and December. ULB glaciologists Jean Louis Tison and Frank Pattyn took the time to explain their research, what glaciology can teach us, and the difficulties and successes they had while in the field this season.+ More details
First drone flies over Utsteinen02:49
Our electrical engineer, Karel Moerman, brought a drone with him to Antarctica this year. We've taken aerial images of the station from an ultra light aircraft before, but this is the first time that an unmanned drone has flown over the station and shot footage. From take off to landing, this video will take you on an aerial tour of the Princess Elisabeth Antarctica station, Utsteinen Ridge, the runway where planes take off and land, and the general vicinity of the station. A fresh perspective Even for those of us who are accustomed to seeing the station on a daily basis, this footage allowed us to see the station from a fresh perspective. Thank you Karel! Music: "Uncertainty" by Ian Alex Mac+ More details
Belgian Scientists Back in Belgium02:32
After spending over a month in Antarctica, the first group of scientists and crew members left the Princess Elisabeth station and headed back to Belgium in time to spend Christmas with their families. We met with them in Zaventem Airport.+ More details
A lot of penguins and a massive leopard seal02:47
For the third year in a row, Alain Hubert visited the emperor penguin colony he confirmed the existence of two years ago. While counting the adult penguins and chicks in order to estimate the size and health of the colony, we had a startling encounter. Monitoring the penguin colony Antarctica is a protected area and wildlife should not be disturbed. Only three people approach the animals to count the chicks and adults in order to evaluate the size and health of the colony, while keeping a safe enough distance so as not to disturb the colony. Information on the estimated population of the penguins is then relayed to scientists studying emperor penguin colonies in Antarctica. Startled by a leopard seal When we moved towards the edge of the ice shelf, our cameraman Jos Van Hemelrijck spotted a leopard seal swimming nearby. As a natural predator of emperor penguins, it was likely hunting for penguins in the area. Having probably never seen any humans in its life, the seal wasn't scared. When it spotted us, it jumped up on the ice to take a closer look. Even though we were very careful to keep our distance, the speed of the animal startled us all.+ More details
First goodbyes at Princess Elisabeth Antarctica01:58
After spending nearly two months at the station, the first group of scientists and teacher Roger Radoux left for Novo. It's always an emotional moment for the team who stay and the end of a great adventure for those who leave. Everything is packed up and a big sledge hauled by a Prinoth tractor takes people and their baggage to the airstrip 2 km away from the station. After goodbyes and promises to return, our friends are boarding the Basler flight for Novo. From there, they will fly back to Cape Town. All of them will be back in Belgium in time to celebrate Christmas with friends and family!+ More details
What are Tags?
Tags are keywords that describe videos. For example, a video of your Hawaiian vacation might be tagged with "Hawaii," "beach," "surfing," and "sunburn."


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CWU Ellensburg, SURC Ballroom
The Education Career Fair is a great opportunity to meet recruiters from Eastern and Western Washington School Districts as well as other organizations.
Students: For more information and list of registered organizations visit:
To prepare for the fair, download this checklist!
Employers: Registration begins on 12/2/13, to register visit:
Questions? Contact Sandy Lindelof: firstname.lastname@example.com or 509.963.1908
CWU Ellensburg, Bouillon 206 Bring your resume and/or cover letter and have it reviewed by our trainFall Events & Workshops
Save the dates for these upcoming Fall 2015 Events! Engineering Technologies, Safety & ConsAccounting Recruiting
Are you an Accounting student looking for an internship or job? It's never too early to start famili


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The Eastland Mavericks continued their rise in Class 2A Div. I this week. They come in at number five this week after their area round victory last Thursday over Littlefield.
Cisco is once again the highest ranked team in the Big Country. The Loboes remain at number two after knocking off Spearman in Lubbock last Friday. They will take on Abernathy this Friday in Snyder.
The bulk of the Big Country teams ranked are once again in Class 1A. In division one, the Stamford Bulldogs come in at number four after pulling away for an area round win over Panhandle on Saturday night in Bowie.
Meanwhile, the Anson Tigers rise one spot to number five despite having their season ended by number two Stratford. The Tigers finish the season with a 10-2 record.
Rounding out the top ten in division one is Goldthwaite. This week the Eagles will look to pick up another playoff win over DeLeon in Brownwood.
The lone Big Country team ranked in division two is Albany. This week the Lions come in at number eight after their shutout victory over McCamey on Saturday afternoon.
Here's a complete list of all the Big Country teams that are ranked this week:
Class 2A Div. I
5) Eastland Mavericks
Class 2A Div. II
2) Cisco Loboes
Class 1A Div. I
4) Stamford Bulldogs
5) Anson Tigers
10) Goldthwaite Eagles
Class 1A Div. II
8) Albany Lions
Copyright 2015 Nexstar Broadcasting, Inc. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.


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This property allows you to book online with a credit card. After submitting a reservation request, the owner or manager has 24 hours to accept, at which time your card will be charged and you will receive an email confirmation
Recent Santa Monica reviews
"My husband and I recently stayed here and it was wonderful. Located in a quiet and attractive neighborhood and just a block from Main Street and 4 blocks from the beach. This apartment is private and clean. There is only room for 2 people. It has a small kitchenette so you could keep some food on hand. We would definitely stay here again. We did not rent a car and I'm glad we didn't. We rented bikes for $30/day to ride up and down the beach; Uber is readily available anywhere and any time of day in L.A. so we used that to get to other parts of town."Guest: McKaela B. Date of Stay: May 2015 Review Submitted: May 20, 2015View listing
"We just spent 9 nights at this lovely home! We required a wheelchair accessible living space for my daughter, and this home definelty met our needs! Ev Everything was clean, and tidy, and any questions we had, were responded to quickly. The location is more centrally located, than one would think (due to the windy roads). It just takes a moment to get one's bearings. The neighbourhood is pretty, and peaceful, and I would recommend this to anyone looking for a comfortable, yet, upscale place to stay."Guest: Catherine F. Date of Stay: June 2015 Review Submitted: July 10, 2015View listing
"Family of 4, 2 kids aged 10 & 13. We found the condo perfect for our needs. It was spotlessly clean, fresh carpets, and comfortable king size beds. It was spacious with a small outdoor balcony. Although a little far from the beach it is walkable (30 mins) or you can catch the big blue bus which will take you directly to the Promenade or Venice. Having a washer/dryer particularly at the end of our trip was great. The construction going on next door was annoying however we didn't spend much time at the condo during the day. The owners were amazing and responded to emails promptly. Overall perfect accommodation in Santa Monica."Guest: Anna P. Date of Stay: October 2014 Review Submitted: October 22, 2014View listing
"We could not have asked for anything better! Well designed, well maintained townhouse in a quiet, yet convenient neighborhood. We walked to the busy Santa Monica shopping areas and the pier many times, and then retreated to our peaceful sanctuary when done. We even got to see the 4th of July fireworks from the rooftop patio! Thank you for everything!"Guest: R and B Date of Stay: June 2015 Review Submitted: July 13, 2015View listing
Featured Destinations: Lake Almanor, Orlando Vacation Rentals, Big Bear Cabin Rentals, Anna Maria Island Rentals


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Contact Innkeeper
Nicely nestled at the foot of the medieval town of Bracciano, has two bedrooms, both served by a rooftop terrace-On the edge of the pool, you can enjoy a delicious breakfast, letting you savor the calm that provides magnificent views of the lake. The train station, a 10 minute walk, you can reach easily with its ancient Rome and St. Peter (train every 30 minutes) In the evening you'll appreciate, sensation doubt, a swim in the pool, before heading to the small local restaurants are located, all, in the vicinity of the villa
Innkeepers: chris guglielmi
Guests: 2
Visit Website
BedandBreakfast.com gift cards are the perfect gift for anyone who needs a relaxing getaway.
Score Breakdown based on1 Reviews
Write A Review
on November 22, 2012
My husband and I spent two nights at this wonderful B&B. The owners opened their house to us and were terrific hosts. We enjoyed having a private balcony and wished we had come during the summer when and we could have relaxed by the pool. They provided information about restaurants and places to visit. The train to Rome, an hour away, is within walking distance.
View More Reviews
Rome, Italy (FCO-Leonardo Da Vinci (Fiumicino)) 20 miles
Coming from Rome (Braccianese), turn on the right course towards Bracciano - passed under a railway worker and immediately left there is the barracks of the firemen, and then a gas station ...... still DUBOIS 5/600 m you see on his right panel Bracciano - at this point in front of you there are 3 roads, one who left the door to the barracks, l'autre in front of you who goes to the center) and the third, à right panel with a written PIERRE, the road and really small and salt during more or less 700m, and the way this Cupetta the slaughterhouse .... at a time on the right you see some new houses, and on the left is an old washtub. From there via Cupetta leave the slaughterhouse and take away the paintings ..... Just 30 meters and on the left a road slightly uphill which is called via the cave-continue to climb, passing through a dirt road (80metri) until you get to have shingle, The embrace of the lake and its parking lot.
Gourmet/Fine Dining,
Historical interests,
National/State parks,
Nature area,
Picnic area
Private Home Bed and Breakfast, Bed and Breakfast
infinity pool with swim against the system runs
Air conditioning, Alarm clock, Amenities Basket, Hairdryer, Internet Service, Wi-Fi
Bird watching, Boating, Canoeing, Golfing, Horseback riding, Horseshoes, Sailing, Shopping, Swimming pool, Tennis courts
chris guglielmi
English, French, Italian
EUR 80 per night
Simple! BedandBreakfast.com guarantees you're getting the best price on your bed and breakfast stay when you book your room on BedandBreakfast.com. Within 24 hours of your booking, if you find a better price for the same room on the same date(s) at the same B&B, BedandBreakfast.com will refund the difference to you!
The Best Price Guarantee covers any Bed and Breakfast booked online through BedandBreafkast.com. The Bed and Breakfast must be booked using the Book It button on BedandBreakfast.com in order to qualify.
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The BedandBreakfast.com Best Price Guarantee ensures that when you book and pay for your reservation online through the BedandBreafkast.com website, you are booking your room at the lowest available price. If you find a lower price for the same room on the same dates at the same B&B, and contact us within 24 hour of making your booking, we will refund the difference in price to you. This guarantee does not apply to bookings made over holidays and/or for special events. All requests are subject to verification by BedandBreakfast.com. BedandBreafkast.com will not accept screenshots or other purported evidence of a lower price that cannot be independently confirmed by BedandBreakfast.com personnel. Nor will BedandBreakfast.com verify any requests that it believes, in its sole discretion, is the result of a printing or other error or is made fraudulently or in bad faith.


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The Vintage Book Of Walking
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'It is good to collect things, but better to go on walks. ' Anatole France. A fundamental act, often taken for granted, yet through the centuries it has inspired a fascinating literature. This, the first comprehensive anthology on the subject, delves into why we walk and how we walk; the differences between the country hike and the city stroll; walking and wooing; walking into trouble and marching out. Then some of us will walk to meet the Maker. A mix of fiction and non-fiction, poetry and drama provides the reader with over two hundred booted authors. Xenophone and Baudelaire, Flora Thompson and Julian Barnes, Mark Twain and Roberto Calasso tramp the pages of this fascinating collection.
Random House; September 2011
Read online, or download in secure EPUB
Title: The Vintage Book Of Walking
Author: Duncan Minshull; Richard Holmes
Read online, or download in secure EPUB
Title: The Vintage Book Of Walking
Author: Duncan Minshull; Richard Holmes
Buy, download and read The Vintage Book Of Walking (eBook) by Duncan Minshull; Richard Holmes today!
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Announcements of Interest
- Call for Papers
- Grants/Fellowships/Jobs
- Conference Announcements/Reports
Call for Papers
H-Pietism promotes the academic study of Pietism, broadly defined. We welcome all interested scholars studying Pietism as an early modern religious movement in Europe (particularly Germany) and North America, as well as the many churches and religious communities, worldwide, which are descended from the Pietist and evangelical movements of the eighteenth century.
Call for Papers
The following is an announcement concerning a new fellowship program being offered by the Francke Foundations in Halle, Germany.
Dr. Liselotte Kirchner-Stipendienprogramm der Franckeschen Stiftungen
Dank einer großzügigen Stiftung von Dr. Liselotte Kirchner (Offenbach) sind die Franckeschen Stiftungen in der Lage, Forschungsstipendien zu vergeben.
Call for Papers
As found in the conference brochure:
The VII. International Moravian Conference will take place in Suchdol n. Odrou, 16 – 18 October 2015. The conference will aim to review and present new historical facts about Moravians in a set of lectures and paper presentations. Moravians were emigrants who left northern Moravia - their fatherland - in the beginning of the 18th century. They renewed the Moravian Church (Unitas Fratrum) and influenced the international mission.
Call for Papers
The Moravian Archives in Bethlehem, Pennsylvania, is offering a two-week course in early-modern German paleography to be held June 1 - 14, 2016.
Call for Papers
Christopher Gehrz, ed. The Pietist Vision of Christian Higher Education: Forming Whole and Holy Persons. Downers Grove: InterVarsity Press, 2015. 240 pp. $26.00 (paper), ISBN 978-0-8308-4071-7.
Reviewed by William Ringenberg (Taylor University, History Department)
Published on H-Pietism (October, 2015)
Commissioned by Peter James Yoder
Heart Religion No Less than Head Religion
Roland Lehmann. Die Transformation des Kirchenbegriffs in der Frühaufklärung. Tuebingen: Mohr Siebeck, 2013. xi + 428 pp. EUR 79.00 (cloth), ISBN 978-3-16-152373-1.
Reviewed by Sabine Hübner (Institut für Evangelische Theologie, Universität Oldenburg)
Published on H-Pietism (July, 2015)
Commissioned by Peter James Yoder
The Transformation of Conceptions of the Church in the Early Enlightenment
Wolfgang Breul, Jan Carsten Schnurr, eds. Geschichtsbewusstsein und Zukunftserwartung in Pietismus und Erweckungsbewegung. Göttingen: Vandehoeck & Rupprecht, 2013. 378 pages. EUR 84.99 (cloth), ISBN 978-3-525-55842-3.
Reviewed by Stephen Morgan (University of Notre Dame)
Published on H-Pietism (June, 2015)
Commissioned by Peter James Yoder
Crisis, Hope, and Eschatology in Pietism and the Awakening Movement
Roger E. Olson, Christian T. Collins Winn. Reclaiming Pietism: Retrieving an Evangelical Tradition. Grand Rapids: Wm. B. Eerdmans Publishing Company, 2015. xiii + 190 pp. $18.00 (paper), ISBN 978-0-8028-6909-8.
Reviewed by Benjamin Pietrenka (University of California, Santa Cruz (History Dept.))
Published on H-Pietism (May, 2015)
Commissioned by Peter James Yoder
Reclaiming Pietism


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UAE: Biggest climber in visa index
Click here for the top 10 rankings in the regionOctober 8, 2015 6:09
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MIDEAST STOCKS-Markets to rise on stronger global environment
Abu Dhabi's ADWEA in talks with banks for $350 mln project bond
Emirates hints at no Dubai Airshow orders, pushes decision on A350/787 to next year
UAE minister says plans to boost oil output capacity on track
MIDEAST STOCKS-Saudi, Egypt markets barely move in early trade
Qatar Q2 GDP growth accelerates to 4.8 pct year/year
UAE says reforms will better protect foreign workers
United Arab Bank secures $125 mln three-year loan
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MIDEAST STOCKS-UAE markets narrowly mixed in thin, early trade
Fourth refinery expected to cost $14.5 billion; Summer imports of LNG seen rising to 40-45 cargoes
May 9, 2012 9:16 by kippreport
Kuwait National Petroleum Company (KNPC) will launch a tender next month to build a long-delayed refinery at Al-Zour with a capacity of 615,000 barrels per day (bpd), a senior executive at KNPC said on Tuesday.
"All the contracts might be awarded by early next year and we're hoping for completion in 2017," Jamal Al-Loughani, deputy managing director of marketing at KNPC, told the MPGC conference organized by Conference Connection in Bahrain.
KNPC operates OPEC member Kuwait's three existing refineries, which together have a capacity of 930,000 bpd.
Investment in the Al-Zour refinery, estimated to cost around $14.5 billion, has been delayed for years due to political wrangling.
Loughani also said he expected Kuwait to import 40-45 cargoes of liquefied natural gas (LNG) by October 2012, more than it did during the peak summer period from March to October last year.
The Gulf Arab oil exporter needs to import gas for power generation to meet air conditioning demand in hot summer months. Loughani said he expected Kuwait to take delivery of five cargoes in May alone.
Kuwait began importing super-cooled gas in 2009 and has term deals to buy it from Royal Dutch Shelland Vitol from 2010-2013.


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It is important to stop gun control do to the clear violation of our civil liberties. It is a statistical fact gun control does not work and leads to higher rates of crime. We need to stand up as a nation and combat the cause of these atrocity's such as the Sandy Hook elementary shooting. Which are Mental illness and poverty. The causes of gun violence are not firearms. So please sing this petition to stop Obama or congress from singing any bills that will hinder our 2nd constitutional right and liberty.
Letter to
The United States Congress.
Stop gun control a clear violation of our 2nd amendment.
Trending petitions


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2010 (Jr.): Played in 35 games, starting 29... First on the team in hitting with a .338 batting average... Scored 13 runs which was a career high... Had 27 hits and 18 RBI on the season... Hit a grand slam against Nevada on April 2... Went 3-for-4 in a 10-8 win against Utah Valley on Mar. 5.
2009 (So.): Played in 15 games, starting eight... Scored a season-high two runs against Stanford on Feb. 14... Posted a .968 fielding percentage for the season... Missed part of the season due to injury.
2008 (Fr.): Played in 22 games and started 13... Recorded two multiple hit games... Recorded three RBI and a home run against San Jose State on April 5.
High School: A four-year letterwinner at Viewmont High School in Farmington, Utah... Played catcher... Hit .436 her senior year recording four home runs and 10 stolen bases... Had an .829 slugging percentage... Hit .395 as a junior with a .617 slugging percentage... Also had four triples and 27 RBI during her junior year... Earned all-state honors all four years... Was named to the all-tournament team in 2006... Earned all-Valley and first-team all-region honors as a junior... Received second-team all-league accolades as a sophomore... Helped team qualify for state all four years... Part of the team that placed third at state in 2006... Graduated with a 3.6 GPA.
Personal: Born February, 15, 1989... Daughter of Craig and Lori Tyteca... Has three sisters, Shelbi (16), Bailee (14) and Riley (9)... Full name is Shasta Nicole Tyteca... Major is psychology... Sister Shelbi has signed to play at Utah State next year... Name is pronounced Shass-ta Ted-ica.
TYTECA'S CAREER BATTING STATSYear G/GS AVG AB R H 2B 3B HR RBI BB K SAC SB 2008 22/13 .211 38 5 8 2 0 1 3 9 8 5 2-4 2009 15/8 .080 25 3 2 0 0 0 1 1 9 2 0-0 2010 35/29 .338 80 13 27 6 2 2 18 8 13 1 3-4 Totals 72/50 .259 143 21 37 8 2 3 22 18 30 8 5-8
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With a 10-run inning, Utah State softball picked up its second win over Boise State in as many...05/08/2015
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Iguana Mexican Grill is what's new under the sun
Start with a salsa sampler and the highlight, the coral salsa — a spicy and sweet combination of mango and habanero chiles. If you've got a good-sized group, the Oklahoma-sized queso is just the ticket.
The entrees range from tacos to enchiladas to burgers. Fillings are a unique take on the typical beef, pork and chicken you're used to, combining Parrott's classic training with the preparations that made them popular.
When it came to the sides, Parrott said he and his partners agreed they didn't want to become a beans-and-rice restaurant, another tribute to it's ancestry. Rice comes in either red or green, beans come in black or white, cole slaw is made with jicama — not the Tex-Mex choices you were reared on and the outcome is a triumph.
As with the old Iguana Lounge, the new Iguana Mexican Grill is bound to be a night-life destination. Take the same perfect margaritas and with a broad selection of beers, put them in an Automobile Alley location with an outdoor patio, and crowds are bound to develop.
If all that's not enough, they feature a cupcake from next door neighbor Sara Sara Cupcakes for dessert and key lime pie.
Find, rate and review more Oklahoma City restaurants on Wimgo.com
11 a.m. to 10 p.m. Monday to Saturday
10:30 a.m. to 8 p.m. Sunday


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Waterfowl Hunting
Waterfowl Hunting: your resource for Duck and Goose Hunting Supplies from Sportsman's Guide include low priced Waterfowl Blinds & Accessories for all types of Waterfowl Hunting. Browse categories that will make your hunting experience better like Duck Calls, Duck Decoys, Goose Calls, & Goose Decoys. Even throwing on new Waders or purchasing new Hand & Foot Warmers can make your outside adventures with nature an experience that is much more enjoyable!
Non-Member $19.99 Buyer's Club $17.99
Compare at $99.99 Non-Member $94.99 Buyer's Club $85.49
You Save $14.50 (15%)
Non-Member $34.99 Buyer's Club $31.49
Non-Member $4.99 Buyer's Club $4.49
Compare at $11.95 Non-Member $8.49 Buyer's Club $7.64
You Save $4.31 (36%)
Non-Member $34.99 Buyer's Club $31.49
Compare at $29.99 Non-Member $23.49 Buyer's Club $21.14
You Save $8.85 (30%)
Compare at $114.99 Non-Member $99.99 Buyer's Club $89.99
You Save $25.00 (22%)
Compare at $99.99 Non-Member $94.99 Buyer's Club $85.49
You Save $14.50 (15%)
Compare at $29.99 Non-Member $23.99 Buyer's Club $21.59
You Save $8.40 (28%)
Non-Member $124.99 Buyer's Club $112.49
Browse some of the best duck hunting and goose hunting brands available like Beavertail, Pro-Line, Tanglefree Decoys, Moss Oak Graphics, Lacrosse, Caddis, Heat Factory, Primos, Open Zone Decoys & Frogg Toggs and many more all at amazingly low prices! Don't forget to check out all Waterfowl Hunting Accessories to make the most of your hunting season.