Neutral sphingomyelinase (nSMase) activation in response to environmental stress or inflammatory cytokine stimuli generates the second messenger ceramide, which mediates the stress-induced apoptosis. ...However, the signaling pathways and activation mechanism underlying this process have yet to be elucidated. Here we show that the phosphorylation of nSMase1 (sphingomyelin phosphodiesterase 2, SMPD2) by c-Jun N-terminal kinase (JNK) signaling stimulates ceramide generation and apoptosis and provide evidence for a signaling mechanism that integrates stress- and cytokine-activated apoptosis in vertebrate cells. An nSMase1 was identified as a JNK substrate, and the phosphorylation site responsible for its effects on stress and cytokine induction was Ser-270. In zebrafish cells, the substitution of Ser-270 for alanine blocked the phosphorylation and activation of nSMase1, whereas the substitution of Ser-270 for negatively charged glutamic acid mimicked the effect of phosphorylation. The JNK inhibitor SP600125 blocked the phosphorylation and activation of nSMase1, which in turn blocked ceramide signaling and apoptosis. A variety of stress conditions, including heat shock, UV exposure, hydrogen peroxide treatment, and anti-Fas antibody stimulation, led to the phosphorylation of nSMase1, activated nSMase1, and induced ceramide generation and apoptosis in zebrafish embryonic ZE and human Jurkat T cells. In addition, the depletion of MAPK8/9 or SMPD2 by RNAi knockdown decreased ceramide generation and stress- and cytokine-induced apoptosis in Jurkat cells. Therefore the phosphorylation of nSMase1 is a pivotal step in JNK signaling, which leads to ceramide generation and apoptosis under stress conditions and in response to cytokine stimulation. nSMase1 has a common central role in ceramide signaling during the stress and cytokine responses and apoptosis.
A series of poly(guanamine) (
c
-PG)s containing tetraazacalix2arene2-triazine (
m
PDA
2
CyC
2
) were successfully prepared by solution polycondensation of
m
PDA
2
CyC
2
with various aromatic ...diamines in an aprotic organic solvent with a lithium chloride additive (5 wt%) at 150 °C for 6 hours. The number-average molecular weights (
M
n
)s of these
c
-PG polymers reached up to 31 500, with a relatively broad molecular weight distribution (
M
w
/
M
n
) of 5.3. They showed good solubility in aprotic organic solvents, such as
N
-methylpyrrolidone and
N
,
N
-dimethylacetamide at a concentration of 2 mg mL
−1
. The glass transition temperatures (
T
g
) of the
c
-PG polymers were in the range 359 °C-392 °C, approximately 160 °C higher than those of counterpart polymers (
i.e.
, with no aza-calixarene-based PG (
l
-PG)). The coefficients of thermal expansion (CTEs) of the
c
-PG polymers were 29.7-48.1 ppm K
−1
(at 100 °C-150 °C), much lower than those of
l
-PG samples,
i.e.
, 59.1-85.1 ppm K
−1
. Transparent and almost colorless
c
-PG films were successfully prepared by a solution casting method, showing maximum tensile strength (
σ
S
), modulus (
E
γ
), and elongation at break (
E
b
) values of 151 MPa, 6.3 GPa, and 4.4%, respectively, for the
c
-PG polymer from
m
PDA
2
CyC
2
and 4,4′-oxydianiline monomers. The corresponding
l
-PG film exhibited
σ
S
,
E
γ
, and
E
b
values of just 76 MPa, 5.4 GPa, and 1.6%, respectively. These outstanding thermal and mechanical properties of the
c
-PG polymers can be attributed to their multiple hydrogen bonding interaction between
m
PDA
2
CyC
2
residues in the polymer backbone. This interaction was identified by infrared spectroscopy measurements at the broad absorption band around 3000-3400 cm
−1
.
Poly(guanamine)s containing tetraazacalix2arene2triazine ring within the polymer main-chain show outstanding thermal and mechanical properties arisen from the multiple-hydrogen bond.
While chemotherapy is a major mode of cancer therapeutics, its efficacy is limited by systemic toxicities and drug resistance. Recent advances in nanomedicine provide the opportunity to reduce ...systemic toxicities. However, drug resistance remains a major challenge in cancer treatment research. Here we developed a nanomedicine composed of a phase-change nano-droplet (PCND) and an anti-cancer antibody (9E5), proposing the concept of ultrasound cancer therapy with intracellular vaporisation. PCND is a liquid perfluorocarbon nanoparticle with a liquid-gas phase that is transformable upon exposure to ultrasound. 9E5 is a monoclonal antibody targeting epiregulin (EREG). We found that 9E5-conjugated PCNDs are selectively internalised into targeted cancer cells and kill the cells dynamically by ultrasound-induced intracellular vaporisation. In vitro experiments show that 9E5-conjugated PCND targets 97.8% of high-EREG-expressing cancer cells and kills 57% of those targeted upon exposure to ultrasound. Furthermore, direct observation of the intracellular vaporisation process revealed the significant morphological alterations of cells and the release of intracellular contents.
Highlights • ATX significantly alleviated ADHD-related behavioral abnormalities of PACAP−/− mice. • ATX significantly alleviated impaired prepulse inhibition in PACAP−/− mice. • The ATX-induced ...increase in extracellular DA and NA levels were higher in PACAP−/− mice compared to wild-type mice. • PACAP−/− mice are an ideal rodent model for the study of ADHD etiology and drug development.
A fast beam-profile monitor has been developed for high-energy photon beamlines at the Research Center for Electron Photon Science, Tohoku University. The position of the photon converted into an ...electron–positron pair in a 0.5mm-thick aluminum plate is measured with two hodoscopes made of scintillating fibers with cross-sections of 3×3mm2. Events in which charged particles are produced upstream are rejected with a charge veto plastic scintillator placed in front of the plate, and pair-production events are identified with a trigger plastic scintillator placed behind the plate. The position is determined by a developed logic module with a field-programmable gate array. The dead time for processing an event is 35ns, and a high data acquisition efficiency (~100%) can be achieved with this monitor for high-intensity photon beams corresponding to 20MHz tagging signals.
Origins of low resistivity in H-ion implanted KNbO3 bulk single crystals are studied by elastic recoil detection analysis (ERDA) and Van der Pauw methods. The H-ion implantation (peak ion fluence: ...5.0×1015cm−2) into KNbO3 is performed using a 500keV implanter. The sheet resistance decreases from ∼108Ω/□ for an un-implanted KNbO3 sample to 2.33×105Ω/□ for as-implanted, 2.29×105Ω/□ for 100°C annealed, and 4.25×105Ω/□ for 150°C annealed samples, respectively. The ERDA experiment using the 1.5MeV-4He+ beam can evaluate hydrogen from the surface to around 60nm. The hydrogen concentration near the surface estimated using the 1.5MeV helium beam is 5.1×1014cm−2 for un-implanted KNbO3 sample, 5.6×1014cm−2 for as-implanted, 3.4×1014cm−2 for 150°C annealed samples, respectively, indicating that a part of hydrogen is diffused out by annealing. The low resistive layer induced in H-ion implanted KNbO3 suggests the existence of a shallow energy level related to the complex defect consisting of hydrogen interstitial and the proton induced defect such as oxygen vacancy.
Monodisperse aromatic N -methyl benzamide-based molecules (repeat number: x = 5–10, molar mass distribution M w / M n = 1.02–1.04) connected with terephthalic acid at both sides (MAB x–x ) were ...rapidly prepared by a step-wise condensation reaction using the reported one-pot dendrimer synthetic method. These were copolymerized with NH 2 -terminated poly(propylene oxide) (PPO y ) using a condensation reagent at ambient temperature, and the relationship between the structure and the properties was evaluated. The copolymers, poly(MAB x–x - b -PPO y ), had M n values up to 12 500 g mol −1 ( M w / M n = 1.6), with only a single T g at −70 °C by DSC, assignable to the pure PPO domain. Only for the copolymer films consisting of a monodisperse MAB x–x segment, did the dynamic mechanical analysis (DMA) show two T g values at −70 and above 50 °C, indicating the clear phase segregation of the copolymers. The mechanical properties of the copolymer films were mostly dependent on the fraction of the monodisperse hard segment, and the tensile modulus and elongation at break varied from 3.3 to 32.5 MPa and 150 to 540%, respectively.
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