Considering the occurrence of serious heart failure in a gene knockout mouse of PIP5Kγ and in congenital abnormal cases in humans in which the gene was defective as reported by others, the present ...study attempted to localize PIP5Kγ in the heart during prenatal stages. It was done on the basis of the supposition that phenotypes caused by gene mutation of a given molecule are owed to the functional deterioration of selective cellular sites normally expressing it at significantly higher levels in wild mice. PIP5Kγ-immunoreactivity was the highest in the heart at E10 in contrast to almost non-significant levels of the immunoreactivity in surrounding organs and tissues such as liver. The immunoreactivity gradually weakened in the heart with the prenatal age, and it was at non-significant levels at newborn and postnatal stages. Six patterns in localization of distinct immunoreactivity for PIP5Kγ were recognized in cardiomyocytes: (1) its localization on the plasma membranes and subjacent cytoplasm without association with short myofibrils and (2) its localization on them as well as short myofibrils in association with them in cardiomyocytes of early differentiation at E10; (3) its spot-like localization along long myofibrils in cardiomyocytes of advanced differentiation at E10; (4) rare occurrences of such spot-like localization along long myofibrils in cardiomyocytes of advanced differentiation at E14; (5) its localization at Z-bands of long myofibrils; and (6) its localization at intercellular junctions including the intercalated discs in cardiomyocytes of advanced differentiation at E10 and E14, especially dominant at the latter stage. No distinct localization of PIP5Kγ-immunoreactivity of any patterns was seen in the heart at E18 and P1D. The present finding suggests that sites of PIP5Kγ-appearance and probably of its high activity in cardiomyocytes are shifted from the plasma membranes through short myofibrils subjacent to the plasma membranes and long myofibrils, to Z-bands as well as to the intercalated discs during the mid-term gestation. It is further suggested that PIP5Kγ is involved in the differentiation of myofibrils as well as intercellular junctions including the intercalated discs at later stages of the mid-term gestation. Failures in its involvement in the differentiation of these structural components are thus likely to cause the mid-term gestation lethality of the mutant mice for PIP5Kγ.
Aims/hypothesis
Incretins stimulate insulin secretion in a glucose-dependent manner but also promote pancreatic beta cell protection. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new ...glucose-lowering treatment that blocks incretin degradation by DPP-4. We assessed whether DPP-4 inhibition suppresses the progression to hyperglycaemia in a low-dose streptozotocin (STZ)-induced diabetic mouse model, and then investigated how DPP-4 inhibition affects islet function and morphology.
Methods
The DPP-4 inhibitor, des-fluoro-sitagliptin (SITA), was administered to mice during and after STZ injections, and in some mice also before STZ.
Results
In control mice, STZ resulted in hyperglycaemia associated with impaired insulin secretion and excess glucagon secretion. In SITA-treated STZ mice, these metabolic abnormalities were improved, particularly when SITA administration was initiated before STZ injections. We observed beta cell loss and dramatic alpha cell expansion associated with decreased insulin content and increased glucagon content after STZ administration. In SITA-treated mice, islet architecture and insulin content were preserved, and no significant increase in glucagon content was observed. After STZ exposure, beta cell apoptosis increased before hyperglycaemia, and SITA treatment reduced the number of apoptotic beta cells. Interestingly, alpha cell proliferation was observed in non-treated mice after STZ injection, but the proliferation was not observed in SITA-treated mice.
Conclusions/interpretation
Our results suggest that the ability of DPP-4 inhibition to suppress the progression to STZ-induced hyperglycaemia involves both alleviation of beta cell death and alpha cell proliferation.
High energy density physics is the field of physics dedicated to the study of matter and plasmas in extreme conditions of temperature, densities and pressures. It encompasses multiple disciplines ...such as material science, planetary science, laboratory and astrophysical plasma science. For the latter, high energy density states can be accompanied by extreme radiation environments and super-strong magnetic fields. The creation of high energy density states in the laboratory consists in concentrating/depositing large amounts of energy in a reduced mass, typically solid material sample or dense plasma, over a time shorter than the typical timescales of heat conduction and hydrodynamic expansion. Laser-generated, high current-density ion beams constitute an important tool for the creation of high energy density states in the laboratory. Focusing plasma devices, such as cone-targets are necessary in order to focus and direct these intense beams towards the heating sample or dense plasma, while protecting the proton generation foil from the harsh environments typical of an integrated high-power laser experiment. A full understanding of the ion beam dynamics in focusing devices is therefore necessary in order to properly design and interpret the numerous experiments in the field. In this work, we report a detailed investigation of large-scale, kilojoule-class laser-generated ion beam dynamics in focusing devices and we demonstrate that high-brilliance ion beams compress magnetic fields to amplitudes exceeding tens of kilo-Tesla, which in turn play a dominant role in the focusing process, resulting either in a worsening or enhancement of focusing capabilities depending on the target geometry.
Using one of the world most powerful laser facility, we demonstrate for the first time that high-contrast multi-picosecond pulses are advantageous for proton acceleration. By extending the pulse ...duration from 1.5 to 6 ps with fixed laser intensity of 10
W cm
, the maximum proton energy is improved more than twice (from 13 to 33 MeV). At the same time, laser-energy conversion efficiency into the MeV protons is enhanced with an order of magnitude, achieving 5% for protons above 6 MeV with the 6 ps pulse duration. The proton energies observed are discussed using a plasma expansion model newly developed that takes the electron temperature evolution beyond the ponderomotive energy in the over picoseconds interaction into account. The present results are quite encouraging for realizing ion-driven fast ignition and novel ion beamlines.
To enhance the core heating efficiency in electron-driven fast ignition, we propose fast-electron beam guiding using externally applied longitudinal magnetic fields. Based on particle-in-cell ...simulations for FIREX-class experiments, we demonstrate sufficient beam guiding performance in collisional dense plasma by kilotesla-class external magnetic fields for the case with moderate mirror ratio ( 10). Boring of the mirror field was found through the formation of magnetic pipe structure due to the resistive effects, which indicates a possibility of beam guiding in high mirror field for higher laser intensity and/or longer pulse duration.
Abstract Inhibitory neurons play important roles in a number of brain functions. They are composed of GABAergic neurons and glycinergic neurons, and vesicular GABA transporter (VGAT) is specifically ...expressed in these neurons. Since the inhibitory neurons are scattered around in the CNS, it is difficult to identify these cells in living brain preparations. The glutamate decarboxylase (GAD) 67–GFP knock-in mouse has been widely used for the identification of GABAergic neurons, but their GAD67 expression was decreased compared to the wild-type mice. To overcome such a problem and to highlight the function and morphology of inhibitory neurons, we generated four lines of VGAT–Venus transgenic mice (lines #04, #29, #39 and #49) expressing Venus fluorescent protein under the control of mouse VGAT promoter. We found higher expression level of Venus transcripts and proteins as well as brighter fluorescent signal in line #39 mouse brains, compared to brains of other lines examined. By Western blots and spectrofluorometric measurements of forebrain, the line #39 mouse showed stronger GFP immunoreactivity and brighter fluorescent intensity than the GAD67–GFP knock-in mouse. In addition, Venus was present not only in somata, but also in neurites in the line #39 mouse by histological studies. In situ hybridization analysis showed that the expression pattern of Venus in the line #39 mouse was similar to that of endogenous VGAT. Double immunostaining analysis in line #39 mouse showed that Venus-expressing cells are primarily immunoreactive for GABA in cerebral cortex, hippocampus and cerebellar cortex and for GABA or glycine in dorsal cochlear nucleus. These results demonstrate that the VGAT–Venus line #39 mouse should be useful for studies on function and morphology of inhibitory neurons in the CNS.
Here, we report a novel target of the drug memantine, ATP-sensitive K
(K
) channels, potentially relevant to memory improvement. We confirmed that memantine antagonizes memory impairment in ...Alzheimer's model APP23 mice. Memantine increased CaMKII activity in the APP23 mouse hippocampus, and memantine-induced enhancement of hippocampal long-term potentiation (LTP) and CaMKII activity was totally abolished by treatment with pinacidil, a specific opener of K
channels. Memantine also inhibited Kir6.1 and Kir6.2 K
channels and elevated intracellular Ca
concentrations in neuro2A cells overexpressing Kir6.1 or Kir6.2. Kir6.2 was preferentially expressed at postsynaptic regions of hippocampal neurons, whereas Kir6.1 was predominant in dendrites and cell bodies of pyramidal neurons. Finally, we confirmed that Kir6.2 mutant mice exhibit severe memory deficits and impaired hippocampal LTP, impairments that cannot be rescued by memantine administration. Altogether, our studies show that memantine modulates Kir6.2 activity, and that the Kir6.2 channel is a novel target for therapeutics to improve memory impairment in Alzheimer disease patients.
To enhance the core heating efficiency in fast ignition laser fusion, the concept of relativistic electron beam guiding by external magnetic fields was evaluated by integrated simulations for FIREX ...class targets. For the cone-attached shell target case, the core heating performance deteriorates by applying magnetic fields since the core is considerably deformed and most of the fast electrons are reflected due to the magnetic mirror formed through the implosion. On the other hand, in the case of a cone-attached solid ball target, the implosion is more stable under the kilo-tesla-class magnetic field. In addition, feasible magnetic field configuration is formed through the implosion. As a result, the core heating efficiency doubles by magnetic guiding. The dependence of core heating properties on the heating pulse shot timing was also investigated for the solid ball target.
Abstract
A laser inertial fusion energy (IFE) reactor requires repetitive injection of fuel pellets and laser engagement to fuse fusion fuel beyond a few Hz. We demonstrate 10 Hz free-fall bead ...pellet injection and laser engagement with γ-ray generation. Deuterated polystyrene beads with a diameter of 1 mm were engaged by counter illuminating ultra-intense laser pulses with an intensity of 5 × 10
17
W cm
−2
at 10 Hz. The spatial distribution of free-fall beads was 0.86 mm in the horizontal direction and 0.18 mm in the vertical direction. The system operated for more than 5 min and 3500 beads were supplied with achieved frequencies of 2.1 Hz for illumination on the beads and 0.7 Hz for γ-ray generation; these frequencies were three times greater than with the previous 1 Hz injection system. The duration of operation was limited by the pellet supply. This injection and engagement system could be used for laser IFE research platforms.
N,N
'
-bis(1-aryl-3-heteroaryl)propylidenehydrazine dihydrochlorides,
P1, P4 – P8,
and
R1 – R7,
were assayed against human oral squamous cell carcinoma (HSC-2, HSC-3, HSC-4), human promyelocytic ...leukemia cell line (HL-60), and human normal oral cells (HGF, HPC, and HPLF) as non-tumor cells to evaluate their cytotoxic properties. Peplomycin was used as a reference compound. It was found that
P-
and
R-
series hydrazone compounds exhibited cytotoxicity in a range of 11 ± 0.68 – 300 ± 1.0 ± M. Compound
P1
which is a non-substituted hydrazone containing piperidine ring and compound
R2
which is a 4-methyl hydrazone derivative containing pyrrolidine ring showed the most potent cytotoxic activity. These hydrazone compounds may serve as promising candidates for further studies.
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