Regulation of Pancreatic β Cell Mass by Cross-Interaction between CCAAT Enhancer Binding Protein β Induced by Endoplasmic Reticulum Stress and AMP-Activated Protein Kinase Activity

During the development of type 2 diabetes, endoplasmic reticulum (ER) stress leads to not only insulin resistance but also to pancreatic beta cell failure. Conversely, cell function under various stressed conditions can be restored by reducing ER stress by activating AMP-activated protein kinase (AMPK). However, the details of this mechanism are still obscure. Therefore, the current study aims to elucidate the role of AMPK activity during ER stress-associated pancreatic beta cell failure. MIN6 cells were loaded with 5-amino-1-ϐ-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) and metformin to assess the relationship between AMPK activity and CCAAT enhancer binding protein ϐ (C/EBPϐ) expression levels. The effect of C/EBPϐ phosphorylation on expression levels was also investigated. Vildagliptin and metformin were administered to pancreatic beta cell-specific C/EBPϐ transgenic mice to investigate the relationship between C/EBPϐ expression levels and AMPK activity in the pancreatic islets. When pancreatic beta cells are exposed to ER stress, the accumulation of the transcription factor C/EBPϐ lowers the AMP/ATP ratio, thereby decreasing AMPK activity. In an opposite manner, incubation of MIN6 cells with AICAR or metformin activated AMPK, which suppressed C/EBPϐ expression. In addition, administration of the dipeptidyl peptidase-4 inhibitor vildagliptin and metformin to pancreatic beta cell-specific C/EBPϐ transgenic mice decreased C/EBPϐ expression levels and enhanced pancreatic beta cell mass in proportion to the recovery of AMPK activity. Enhanced C/EBPϐ expression and decreased AMPK activity act synergistically to induce ER stress-associated pancreatic beta cell failure

Single Event Tolerance of X-ray SOI Pixel Sensors

We evaluate the single event tolerance of the X-ray silicon-on-insulator (SOI) pixel sensor named XRPIX, developed for the future X-ray astronomical satellite FORCE. In this work, we measure the cross-section of single event upset (SEU) of the shift register on XRPIX by irradiating heavy ion beams with linear energy transfer (LET) ranging from 0.022 MeV/(mg/cm2) to 68 MeV/(mg/cm2). From the SEU cross-section curve, the saturation cross-section and threshold LET are successfully obtained to be $3.4^{+2.9}_{-0.9}\times 10^{-10}~{\rm cm^2/bit}$ and $7.3^{+1.9}_{-3.5}~{\rm MeV/(mg/cm^2)}$, respectively. Using these values, the SEU rate in orbit is estimated to be $\lesssim$ 0.1 event/year primarily due to the secondary particles induced by cosmic-ray protons. This SEU rate of the shift register on XRPIX is negligible in the FORCE orbit.Comment: 9 pages, 5 figures, accepted for publication in JATI

X-ray Radiation Damage Effects on Double-SOI Pixel Detectors for the Future Astronomical Satellite "FORCE"

We have been developing the monolithic active pixel detector "XRPIX" onboard the future X-ray astronomical satellite "FORCE". XRPIX is composed of CMOS pixel circuits, SiO2 insulator, and Si sensor by utilizing the silicon-on-insulator (SOI) technology. When the semiconductor detector is operated in orbit, it suffers from radiation damage due to X-rays emitted from the celestial objects as well as cosmic rays. From previous studies, positive charges trapped in the SiO2 insulator are known to cause the degradation of the detector performance. To improve the radiation hardness, we developed XRPIX equipped with Double-SOI (D-SOI) structure, introducing an additional silicon layer in the SiO2 insulator. This structure is aimed at compensating for the effect of the trapped positive charges. Although the radiation hardness to cosmic rays of the D-SOI detectors has been evaluated, the radiation effect due to the X-ray irradiation has not been evaluated. Then, we conduct an X-ray irradiation experiment using an X-ray generator with a total dose of 10 krad at the SiO2 insulator, equivalent to 7 years in orbit. As a result of this experiment, the energy resolution in full-width half maximum for the 5.9 keV X-ray degrades by 17.8 $\pm$ 2.8% and the dark current increases by 89 $\pm$ 13%. We also investigate the physical mechanism of the increase in the dark current due to X-ray irradiation using TCAD simulation. It is found that the increase in the dark current can be explained by the increase in the interface state density at the Si/SiO2 interface.Comment: 15 pages, 12 figures, accepted for publication in Journal of Astronomical Telescopes, Instruments, and System

Education program for prevention of outdoor accidents in middle-high aged trekkers: Monitoring of change in blood pressure and heart rate during exercise

This is an observational study to evaluate cardiovascular parameters during an educational trekking program. The number of alpine accidents involving elderly trekkers has been increasing in developed countries in recent years. Many middle-high aged trekkers have potential cardiovascular risks of which they are unaware. More than 77% of trekkers involved in alpine accidents in Japan were aged >40 years. The most common cardiovascular conditions were stroke or heart attack while trekking at altitude. An alpine club conducted an 8-month education program with participants aged >40 years in the setting of a mountain-side town. Blood pressure and heart rate during outdoor exercise were monitored, and any other adverse effects were recorded. As a result, the cardiovascular parameters evaluated during the first and final trek presented a physiological and similar behavior, however, lower heart rate values were registered at the highest point of the route in the final trek (p < 0.05). The trend of these parameters was similar in males and females, and there was little correlation between the cardiovascular parameters and age. In conclusion, the lower heart rate values may indicate the higher risk awareness of trekkers while self-pacing the physical activity outdoors, which may indicate the positive effect of the education program in increasing the safety of such unsupervised activities

In vivo recording of the circadian calcium rhythm in Prokineticin 2 neurons of the suprachiasmatic nucleus

Abstract Prokineticin 2 (Prok2) is a small protein expressed in a subpopulation of neurons in the suprachiasmatic nucleus (SCN), the primary circadian pacemaker in mammals. Prok2 has been implicated as a candidate output molecule from the SCN to control multiple circadian rhythms. Genetic manipulation specific to Prok2-producing neurons would be a powerful approach to understanding their function. Here, we report the generation of Prok2-tTA knock-in mice expressing the tetracycline transactivator (tTA) specifically in Prok2 neurons and an application of these mice to in vivo recording of Ca2+ rhythms in these neurons. First, the specific and efficient expression of tTA in Prok2 neurons was verified by crossing the mice with EGFP reporter mice. Prok2-tTA mice were then used to express a fluorescent Ca2+ sensor protein to record the circadian Ca2+ rhythm in SCN Prok2 neurons in vivo. Ca2+ in these cells showed clear circadian rhythms in both light–dark and constant dark conditions, with their peaks around midday. Notably, the hours of high Ca2+ nearly coincided with the rest period of the behavioral rhythm. These observations fit well with the predicted function of Prok2 neurons as a candidate output pathway of the SCN by suppressing locomotor activity during both daytime and subjective daytime

Angiomatous Meningioma in the Craniocervical Junction

Introduction. Spinal angiomatous meningioma arising in the craniocervical junction has not been reported. Case Presentation. A 68-year-old man presented to our hospital with pain in the back and left leg. He showed slight motor weakness in his upper extremities. Magnetic resonance imaging revealed a mass with marked enhancement in the craniocervical junction. Computed tomography angiography showed feeding vessels arising from the right vertebral artery. Preoperative embolization of the feeding vessels was performed to reduce intraoperative bleeding. Gross total resection of the tumor was achieved by debulking and piecemeal resection. The tumor attachment to the dura mater was also resected (Simpson grade 1 resection). A histopathological examination confirmed the diagnosis of an angiomatous meningioma. The patient’s symptoms improved shortly after surgery. Conclusions. We achieved gross total resection of spinal angiomatous meningioma arising in the craniocervical junction. A preoperative evaluation and embolization of the feeding arteries may help prevent massive intraoperative bleeding

In vivo recording of suprachiasmatic nucleus dynamics reveals a dominant role of arginine vasopressin neurons in circadian pacesetting.

The central circadian clock of the suprachiasmatic nucleus (SCN) is a network consisting of various types of neurons and glial cells. Individual cells have the autonomous molecular machinery of a cellular clock, but their intrinsic periods vary considerably. Here, we show that arginine vasopressin (AVP) neurons set the ensemble period of the SCN network in vivo to control the circadian behavior rhythm. Artificial lengthening of cellular periods by deleting casein kinase 1 delta (CK1δ) in the whole SCN lengthened the free-running period of behavior rhythm to an extent similar to CK1δ deletion specific to AVP neurons. However, in SCN slices, PER2::LUC reporter rhythms of these mice only partially and transiently recapitulated the period lengthening, showing a dissociation between the SCN shell and core with a period instability in the shell. In contrast, in vivo calcium rhythms of both AVP and vasoactive intestinal peptide (VIP) neurons in the SCN of freely moving mice demonstrated stably lengthened periods similar to the behavioral rhythm upon AVP neuron-specific CK1δ deletion, without changing the phase relationships between each other. Furthermore, optogenetic activation of AVP neurons acutely induced calcium increase in VIP neurons in vivo. These results indicate that AVP neurons regulate other SCN neurons, such as VIP neurons, in vivo and thus act as a primary determinant of the SCN ensemble period

Development of Novel Decarboxylation-Urea Method toward Interlayer-Anion-Controlled Layered Double Hydroxides

Layered double hydroxides (LDHs) are representative of a 2D anionic clay. Simple and homogeneous synthesis of interlayer-anion-controlled LDH is essential for studies and industrial production. In this study, we report the one-pot synthesis of an LDH that is selective for interlayer anions, which was labeled as “decarboxylation-urea method”. We obtained LDHs intercalated with NO3–, Cl–, and SO42– by removing CO2 in this method. The ionic conductivities of the prepared LDHs were investigated for their applicability to electrolytes, and it was found that Zn–Al LDH intercalated with NO3– showed the highest ionic conductivity (18 mS cm–1). Therefore, the LDH intercalated with NO3– synthesized using the decarboxylation-urea method is promising as an alkaline solid electrolyte

Docosahexaenoic Acid Reduces Palmitic Acid-Induced Endoplasmic Reticulum Stress in Pancreatic Β Cells

Abstract: Endoplasmic reticulum (ER) stress leads to peripheral insulin resistance and the progression of pancreatic beta cell failure in type 2 diabetes. Although ER stress plays an important role in the pathogenesis of diabetes, it is indispensable for cellular activity. Therefore, when assessing the pathological significance of ER stress, it is important to monitor and quantify ER stress levels. Here, we have established a novel system to monitor ER stress levels quickly and sensitively, and using this method, we have clarified the effect of differences in glucose concentration and various fatty acids on the ER of pancreatic β cells. First, we developed a cell system that secretes Gaussia luciferase in culture medium depending on the activation of the GRP78 promoter. This system could sensitively monitor ER stress levels that could not be detected with real-time RT-PCR and immunoblotting. This system revealed that hyperglycemia does not induce unfolded protein response (UPR) in a short period of time in MIN6 cells, a mouse pancreatic β cell line. Physiological concentrations of palmitic acid, a saturated fatty acid, induced ER stress quickly, while physiological concentrations of oleic acid, an unsaturated fatty acid, did not. Docosahexaenoic acid, an n-3 unsaturated fatty acid, inhibited palmitic acid-induced ER stress. In this study, we have established a system that can sensitively detect ER stress levels of living cells in a short period of time. This system can be used to monitor the state of the ER in living cells and lead to the investigation of the significance of physiological or pathological ER stress levels