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Bortezomib (BTZ) is known to enhance the mobilization of hematopoietic stem and progenitor cells (HSPCs) induced by granulocyte colony-stimulating factor (G-CSF). However, the most effective time at which to administer BTZ to produce this enhancing effect remains debatable, and the precise mechanism underlying the effect of BTZ is poorly understood. We addressed these questions in this article by performing animal experiments. First, in agreement with previous studies, BTZ administration 12 hours before blood collection was most effective for HSPC mobilization; in contrast, BTZ administration 3 days before blood collection negatively affected HSPC harvesting. Next, in terms of the mechanism of action, G-CSF, but not BTZ, downregulated the expression of very late antigen-4 on HSPCs and vascular cell adhesion molecule-1 on bone marrow (BM) stromal cells; however, intriguingly, both G-CSF and BTZ downregulated CXCL12 chemokine expression in BM. Notably, BTZ treatment also increased BM vascular permeability. These results suggest that the pro-mobilization effect of BTZ could involve the dissociation of HSPCs from BM stromal cells triggered by G-CSF, vascular hyperpermeability elicited by BTZ, and downregulation of CXCL12 concomitantly induced by G-CSF and BTZ.

Objective Prenatal recognition of coarctation of the aorta (CoA) may improve neonatal survival and reduce morbidity. However, prenatal diagnosis of CoA remains challenging, with relatively high false–positive and false–negative rates. This study aimed to identify a novel formula based on fetal echocardiographic measures to predict prenatal identification of CoA. Methods A retrospective comparison on the echocardiographic evaluation of 30 patients with suspected CoA between May 2016 and April 2021 was performed. Fetal echocardiograms were measured for the following: Z-score of right and left ventricular diameters, tricuspid and mitral valve diameters, pulmonary artery and ascending aorta diameters, pulmonary valve and aortic valve diameters, ductus arteriosus and aortic isthmus diameters and their respective ratios, and distal aortic arch (DA) index, which is the distance between the second and third branches of the aortic arch / distal aortic arch diameter. The patients were divided into a postnatal surgical intervention group (n = 13) and a non-intervention group (n = 17). Results The measurements that showed significant differences were aortic isthmus diameter Z-score (p

Two kinds of planarized phenyldithienylboranes, which contain (CH

Isolation condensers (ICs) are important passive cooling systems in BWRs. After the Fukushima Daiichi Nuclear Power Station accident, concerns if the IC was able to restart with the inflow of hydrogen were arose. Because ICs lose heat removal ability when non-condensable gas inflow occurs, accurate evaluation of the effect is necessary. To develop analysis methods, as an initial stage, experiments and analyses considering only high-pressure steam and water were conducted. The experiment was done by an isolation condenser simulator which contains an accumulator with heaters inside, and a heat transfer tube. From the experiment, all steam was condensed at the heat transfer tube and the approximate position of complete condensation was confirmed from the temperature distribution and the observation. The experiment provided data such as temperature distribution, natural circulation flow rate, and pressure to compare with the analysis. The analyses were conducted for 4 cases of void fraction values at the heat transfer tube inlet and found that it has a high sensitivity to condensation. The reason is estimated to be the difference in inflow velocity that strongly depends on the void fraction even if the mass flow rate is constant. And the initial condition of the liquid film also affected condensation process. Heat removal at the section before the heat transfer tube should be considered to adjust void fraction at the inlet of heat transfer tube.

Perry disease (Perry syndrome) is a rare, rapidly progressive, autosomal dominant neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and respiratory symptoms including central hypoventilation. It is caused by missense mutations (e.g. p.G71A) in the DCTN1 gene. We previously generated transgenic mice that expressed human DCTN1

Isolation Condenser (IC) is one of the passive core cooling systems with natural circulation flow, which is effective for safety measures against station black out. Once core uncover occurs, hydrogen generated in the core affects operating condition of ICs. To use ICs as an important safety measure not only for transient conditions but also for accident conditions, robustness of ICs against hydrogen inflow must be understood well. In this study, experiments with high pressure steam were conducted using experimental setup simulating IC, where helium was injected to simulate hydrogen effects. When the pressure in an accumulator increased high enough, natural circulation flow generated in the experimental loop. After the long-term operation, the pressure and the natural circulation flow rate achieved nearly constant. The pressure at quasi-steady state increased with increasing the helium injection amount. The pressure difference in a section including outlet side of a vertical pipe was slightly increased when helium was injected which may have indicated that the helium accumulated in the section and caused increment of the pressure loss. The startup pressure of the IC simulator also increased when helium was injected, where the driving force by the water head difference also decreased. Though long-term operations were performed after helium injection, the effect of injected helium on operating conditions of the IC remained for quasi-steady state conditions.

The high-mobility group A protein 1a (HMGA1a) protein is known as an oncogene whose expression level in cancer tissue correlates with the malignant potential, and known as a component of senescence-related structures connecting it to tumor suppressor networks in fibroblasts. HMGA1 protein binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. Our previous studies have shown that sequence-specific RNA-binding of HMGA1a induces exon-skipping of Presenilin-2 exon 5 in sporadic Alzheimer disease. Here we show that HMGA1a induced exon-skipping of the estrogen receptor alpha (ERα) gene and increased ERα46 mRNA expression in MCF-7 breast cancer cells. An RNA-decoy of HMGA1a efficiently blocked this event and reduced ERα46 protein expression. Blockage of HMGA1a RNA-binding property consequently induced cell growth through reduced ERα46 expression in MCF-7 cells and increased sensitivity to tamoxifen in the tamoxifen-resistant cell line, MCF-7/TAMR1. Stable expression of an HMGA1a RNA-decoy in MCF-7 cells exhibited decreased ERα46 protein expression and increased estrogen-dependent tumor growth when these cells were implanted in nude mice. These results show HMGA1a is involved in alternative splicing of the ERα gene and related to estrogen-related growth as well as tamoxifen sensitivity in MCF-7 breast cancer cells.

Previous studies have indicated that sleep deprivation negatively affects hippocampal neurogenesis, which may explain the reason for the relation between sleep loss and depression. Increasing evidence indicates that the hippocampus is anatomically and functionally segregated along a dorsolateral (cognitive function)/ventromedial (control for mood and stress response) axis. Thus, the present study was conducted to elucidate regional differences in the adverse effects of sleep deprivation on hippocampal neurogenesis. Male Sprague-Dawley rats were subjected to sleep deprivation using the "platform on the water" method for 24- or 72-h. Quantification of hippocampal cell proliferation and immature newborn neurons was stereologically estimated using immunostaining with Ki-67 and doublecortin (DCX), respectively, by optical fractionator method. A consecutive three days of sleep deprivation significantly reduced the density of Ki-67- and DCX-immunopositive cells both in the dorsal and ventral hippocampal subgranular zone and the decrease in DCX-labeled cells was more pronounced in the ventral hippocampus than in dorsal region. Our results indicate that prolonged sleep deprivation decreases hippocampal cell proliferation and neurogenesis in both the dorsal and ventral dentate gyrus. Future studies will be needed to clarify the impact of sleep deprivation-induced decreases in hippocampal neurogenesis on the development of depression.

Perry disease (Perry syndrome) is a rare, rapidly progressive, autosomal dominant neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and respiratory symptoms including central hypoventilation. It is caused by missense mutations (e.g. p.G71A) in the DCTN1 gene. We previously generated transgenic mice that expressed human DCTN1G71A mutant protein under the control of Thy1 promoter. These mice exhibited apathy-like behavior and parkinsonism. However, it is possible that this phenotype was due to a gene-dosage imbalance or transgene insertion position. To circumvent these potential caveats, we have generated a knock-in mouse model carrying a p.G71A mutation in Dctn1. Heterozygous Dctn1G71A and wild-type littermates were subjected to a battery of behavioral analyses. Furthermore, immunohistochemistry for tyrosine hydroxylase (TH) was performed on brain sections of these mice, and TH signal intensity in substantia nigral neurons was quantified. Dctn1G71A mice were immobile for longer than wild-type mice of the same age and sex in the tail-suspension test, revealing depressive characteristics. In addition, the beam-walking test and pole test detected motor deficits in Dctn1G71A female mice. Finally, immunostaining revealed a decrease in TH immunoreactivity in neurons of the substantia nigra in the Dctn1G71A mice. Collectively, heterozygous Dctn1G71A mice showed depression-like behavior, motor deficits, and a functional reduction in substantia nigral neurons, as judged by TH immunostaining, thereby exhibiting multiple features of Perry disease. Hence, this mouse model will be useful in elucidating pathological mechanisms of Perry disease and for developing novel therapeutic strategies against it.

Bone morphogenetic protein (BMP) signaling in the hippocampus regulates psychiatric behaviors and hippocampal neurogenesis in non-stress conditions; however, stress-induced changes in hippocampal BMP signaling have not yet been reported. Therefore, we sought to examine whether psychosocial stress, which induces psychiatric symptoms, affects hippocampal BMP signaling. A total of 32 male Sprague-Dawley rats were exposed to a psychosocial stress using a Resident/Intruder paradigm for ten consecutive days. Subsequently, rats were subjected to a battery of behavioral tests (novelty-suppressed feeding test, sucrose preference test, and forced swimming test) for the evaluation of adult neurogenesis and activity of BMP signaling in the dorsal and ventral hippocampus. Repeated social defeat promoted anxiety-like behaviors, but neither anhedonia nor behavioral despair. Socially defeated rats exhibited an increase in the number of Ki-67-positive cells, decrease in the number of doublecortin (DCX)-positive cells, and decrease only in the dorsal hippocampus of the ratio of DCX-positive to Ki-67-positive cells, a proxy for newly-born cell maturation speed and survival. In contrast, no differences were observed in the number of 5-Bromo-2′-deoxyuridine (BrdU)-positive cells, indicating survival of newly-born cells both in the dorsal and ventral hippocampus. Furthermore, psychosocial stress significantly increased the BMP-4 and phosphorylated Smad1/5/9 expression levels specifically in the dorsal hippocampus. Our findings suggest that repeated psychosocial stress activates BMP signaling and differently affects cell proliferation and neurogenesis exclusively in the dorsal hippocampus, potentially exacerbating anxiety-related symptoms. Targeting BMP signaling is a potential therapeutic strategy for psychiatric disorders.

FF-10501 is a novel inhibitor of inosine monophosphate dehydrogenase (IMPDH). Clinical trials of FF-10501 for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are currently being conducted in the United States. Although it has been shown that FF-10501 induces apoptosis in hematological malignant cells, the intracellular mechanisms of this effect have not been characterized. We conducted an in vitro study to elucidate the mechanisms of FF-10501-induced cell death using 12 hematological malignant cell lines derived from myeloid and lymphoid malignancies. FF-10501 suppressed the growth of each cell line in a dose-dependent manner. However, the clinically relevant dose (40 μM) of FF-10501 induced cell death in three cell lines (MOLM-13, OCI-AML3, and MOLT-3). Investigation of the cell death mechanism suggested that FF-10501 induces both apoptotic and necrotic cell death. FF-10501-induced apoptosis was mediated by caspase-8 activation followed by activation of the mitochondrial pathway in MOLM-13 and MOLT-3 cells. FF-10501 induced necrotic cell death via endoplasmic reticulum stress in OCI-AML3 cells. The present study is the first to identify intracellular pathways involved in FF-10501-induced cell death.

Background Obese persons have a higher incidence of depression than healthy-weight persons. Several studies indicated that the exposure to a high fat diet (HFD) results in a decrease in hippocampal neurogenesis, which leads to higher stress response and stress-induced depression. Although stress is a risk factor for obesity and depression, no studies to date have investigated the effect of stress on the hippocampal neurogenesis of HFD-induced obese animals. The aim of this study was to elucidate whether or not obese HFD-fed mice are vulnerable to stress-induced depression by investigating hippocampal neurogenesis. Methods Sixty-four male ICR mice (four weeks of age) were fed a control (N=24) or 45%HFD (N=40) for seven weeks. Of the HFD-fed group, twenty-four mice met the criteria for “diet-induced obesity”. The animals were then exposed to three consecutive days of psychological stress using a Communication Box. Half were sacrificed to evaluate the physiological changes, and the other half were perfused to quantify hippocampal neuroblasts/immature neurons by the estimation of doublecortin-immunopositive cells. Results In the HFD-fed mice, psychological stress resulted in increases in caloric intake and visceral adipose tissue and a significant decrease in doublecortin-positive cells in the dentate gyrus; however, no such differences were found in the control diet-fed group. Limitations Further study using other neurogenic markers to assess the stage-specific changes in hippocampal neurogenesis will be required Conclusions Our findings suggest that an HFD-induced decrease in hippocampal newly-born neurons leads to stress vulnerability, which may contribute to a high risk of stress-induced depression for obese persons.

In a previous study, a phantom study of a contrast agent extraction system with computed tomography (CT) number and raw-data-based electron density (ED) was described. The current study improved this system with monochromatic CT (mCT) number and evaluated an anthropomorphic phantom for delineation of the contrast-enhanced region. Dual-energy CT images were scanned with a tissue-equivalent phantom and an anthropomorphic phantom with an iodinated contrast agent (1–130 mg/mL). The 40, 70, and 130 keV mCT images were reconstructed with 80 and 135 kV CT images. The contrast agent was separated from other materials using the gradient of the mCT number (GmCT) and the threshold mCT numbers. The system was analyzed using in-house software with Python. The evaluation of the accuracy for the contrast agent extraction was performed by measuring the ratio of the volume (ROV). The mCT number of the contrast agent and bone materials, liver, and muscle in the tissue-equivalent phantom was obviously greater than – 78 HU. The deviation of the mCT numbers between bone materials in tissue-equivalent phantom and the contrast agent were larger than 8 HU. The GmCT was within 4.0 in the tissue-equivalent phantom and more than 6.0 in the contrast agent. The ROV was 0.97–1.00 at more than 1 mg/mL contrast agent. Improved the contrast agent extraction system could be used for a patient’s CT image. It could extract the iodinated tumor or lesion automatically. The contrast agent extraction system was improved by the mCT number. It is expected to only extract the contrast-enhanced region automatically.

Objective: The aim of the current study is to evaluate the effectiveness of reduction metal artifacts using kV-CT image with the single-energy based metal artefact reduction (SEMAR) technique by single-energy reconstruction, monochromatic CT and rED reconstructed by dual-energy reconstruction. Methods: Seven different metal materials (brass, aluminum, copper, stainless, steel, lead and titanium) were placed inside the water-based PMMA phantom. After DECT-based scan, the artefact index (AI) were evaluated with the kV-CT images with and without SEMAR by single-energy reconstruction, and raw-data based electron density (rED), monochromatic CT images by dual-energy reconstruction. Moreover, the AI with evaluated with rED and the converted ED images from the kV-CT and monochromatic CT images. Results: The minimum average value of the AI with all-metal inserts was approximately 80 keV. The AI without SEMAR was larger than that with SEMAR for the 80 kV and 135 kV CT images. In the comparison of the AI for the rED and ED images that were converted from 80 kV and 135 kV CT images with and without SEMAR, the monochromatic CT images of the PMMA phantom with inserted metal materials at 80 keV revealed that the kV-CT with SEMAR reduced the metal artefact substantially. Conclusion: The converted ED from the kV-CT and monochromatic CT images could be useful for a comparison of the AI using the same contrast scale. The kV-CT image with SEMAR by single-energy reconstruction was found to substantially reduce metal artefact. Advances in knowledge: The effectiveness of reduction of metal artifacts using single-energy based metal artefact reduction (SEMAR) technique and dual-energy CT (DECT) was evaluated the electron density conversion techniques.

The hERI± gene is known for its major role in estrogen dependent growth of breast cancer. ERI± positivity is a hallmark in treating these cancers. Though there are many isoforms reported for hERI±, the splicing regulation...

Quetiapine, an atypical antipsychotic, has been used for the treatment of several neuropsychiatric disorders. However, the underlying mechanism of the broad therapeutic range of quetiapine remains unknown. We previously reported that several aversive conditions affect dorsal/ventral hippocampal neurogenesis differentially. This study was aimed to elucidate the positive effects of chronic treatment with quetiapine on regional differences in hippocampal proliferation and immature neurons and behavioral changes under psychosocial stress using the Resident-Intruder paradigm. Twenty-three male Sprague-Dawley rats were intraperitoneally administered a vehicle or quetiapine (10 mg/kg) once daily for 28 days. Two weeks after starting the injections, animals were exposed to intermittent social defeat (four times over two weeks). The behavioral effects of stress and quetiapine were evaluated by the Novelty-Suppressed Feeding (NSF) test. The stereological quantification of hippocampal neurogenesis was estimated using immunostaining with Ki-67 and doublecortin (DCX). Chronic quetiapine treatment stimulated the Ki-67- and DCX-positive cells in the dorsal hippocampus, but not in the ventral subregion. The stress-induced changes in neurogenesis and hyponeophagic behavior were not reversed by repeated administration of quetiapine. Future study with additional behavioral tests is needed to elucidate the functional significance of the quetiapine-induced increase in dorsal hippocampal neurogenesis.

Objectives: The high-mobility group A protein 1a (HMGA1a) protein is known as a transcription factor that binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. We were prompted to decipher the mechanism of HMGA1a-induced alternative splicing of the estrogen receptor alpha (ERα) that we recently reported would alter tamoxifen sensitivity in MCF-7 TAMR1 cells. Methods: Endogenous expression of full length ERα66 and its isoform ERα46 were evaluated in MCF-7 breast cancer cells by transient expression of HMGA1a and an RNA decoy (2'-O-methylated RNA of the HMGA1a RNA-binding site) that binds to HMGA1a. RNA-binding of HMGA1a was checked by RNA-EMSA. In vitro splicing assay was performed to check the direct involvement of HMGA1a in splicing regulation. RNA-EMSA assay in the presence of purified U1 snRNP was performed with psoralen UV crosslinking to check complex formation of HMGA1a-U1 snRNP at the upstream pseudo-5' splice site of exon 1. Results: HMGA1a induced exon skipping of a shortened exon 1 of ERα in in vitro splicing assays that was blocked by the HMGA1a RNA decoy and sequence-specific RNA-binding was confirmed by RNA-EMSA. RNA-EMSA combined with psoralen UV crosslinking showed that HMGA1a trapped purified U1 snRNP at the upstream pseudo-5' splice site. Conclusions: Regulation of ERα alternative splicing by an HMGA1a-trapped U1 snRNP complex at the upstream 5' splice site of exon 1 offers novel insight on 5' splice site regulation by U1 snRNP as well as a promising target in breast cancer therapy where alternative splicing of ERα is involved.

A series of 2,4,6-tri(5-aryl-2-thienyl)-1,3,5-triazines with a star-shaped π-conjugated system as a wide variety of aryl-functionalized 2,4,6-tri(2-thienyl)-1,3,5-triazines were designed and system...

Background The 5-hydroxytryptamine (5-HT) 1A receptors are considered a potential target for the treatment of mental and neuropsychiatric disorders. Several studies have indicated that 5-HT1A receptor agonists increase hippocampal neurogenesis, which is implicated in the action mechanism of antidepressants. However, these agents have not been applied to humans due to intolerable side effects. We recently showed that chronic administration of tandospirone, a clinically available 5-HT1A receptor partial agonist, increased hippocampal neurogenesis dose-dependently. The present study was done to determine if chronic tandospirone treatment has antidepressant potential from the standpoint of hippocampal neurogenesis and behavior. Methods Male Sprague-Dawley rats were intraperitoneally administered a vehicle or tandospirone (10 mg/kg) once daily for 28 days. Two weeks after starting the injections, animals were exposed to intermittent social defeat (four times over two weeks). The effects of stress and tandospirone on the rodents׳ behavior were evaluated by the Novelty-Suppressed Feeding (NSF) test. The quantification of hippocampal neurogenesis was estimated using immunostaining with Ki-67 and doublecortin (DCX). Results Chronic tandospirone treatment reversed the psychosocial stress-induced increase in the latency in the NSF test and decrease in the density of DCX-positive cells in the dentate gyrus of the dorsal and ventral hippocampus. However, no difference in the density of Ki-67-positive cells was observed between the vehicle- and tandospirone-administered groups. Limitations To clarify the antidepressant potential of TDS, the other behavioral tests for depression will be required. Conclusions Our findings suggest that tandospirone has antidepressant potential through an inhibiting effect on stress-induced changes in hippocampal neurogenesis.

Introduction A large-scale clinical trial, the Sequence Trial Alternatives to Relieve Depression (STAR*D) study, concluded that about one-third of the studied patients with major depressive disorder remitted during the initial treatment with selective serotonin reuptake inhibitors and that approximately half of the remitted subjects relapsed over a 1-year follow-up. The development of new therapeutic approaches with potent efficacy and good tolerability for the treatment of depressive disorders is of great importance. Adult hippocampal neurogenesis has been proposed to be important for understanding and treating depression and anxiety. The present study aimed to elucidate whether or not 5-hydroxytryptamine 1A (5-HT1A) receptor partial agonists have a potential therapeutic effect for the treatment of depressive and anxiety disorders, from the standpoint of neurogenesis. Methods Male Sprague–Dawley rats were subcutaneously administered a vehicle or tandospirone (TDS) (1 or 10 mg/kg) once daily for 14 days. The effects of chronic TDS treatment on neurogenesis were evaluated on the day after the last injection. The quantification of hippocampal neurogenesis was estimated using immunostaining with doublecortin (DCX), a marker protein of newborn neurons. Results Chronic TDS treatment resulted in a significant increase in the number of DCX-positive cells per volume of dentate gyrus in a dose-dependent manner. Conclusion The results strongly suggest that 5-HT1A receptor partial agonists would be useful and beneficial in the treatment of depressive and anxiety disorders through increased hippocampal neurogenesis. Electronic supplementary material The online version of this article (doi:10.1007/s40120-013-0015-0) contains supplementary material, which is available to authorized users.

Ultraviolet irradiation could be one of the alternatives to conventional treatments against algal bloom. In this study, the efficacy of UV treatment was investigated against the growth of indigenous Microcystis collected from the Terauchi reservoir, which was suffering from algal bloom on the day of sampling. Surface water from the reservoir was subjected to lab-scale UV exposure using a low-pressure UV (LP UV) lamp or a medium-pressure UV (MP UV) lamp. UV-irradiated samples were compared with non irradiated control samples to determine the growth inhibitory effect of UV irradiation. Several exposure conditions were adopted by varying UV fluence and UV fluence rate to investigate their effects on algal growth. The growth inhibition observed after MP UV irradiation was about 3-fold higher than that after LP UV irradiation, up to 50 [mJ · cm-2]. In the case of MP UV irradiation, growth inhibition was almost constant regardless of UV fluence rate at constant UV fluence. A 1.35 [mW · cm-2] UV fluence rate resulted in a growth inhibitory effect 4.6-fold higher than that of a 0.37 [mW · cm-2] UV fluence rate at constant UV fluence in the case of LP UV irradiation. The results of this study indicate that UV irradiation is effective in inhibiting the growth of indigenous Microcystis.

Lightly doped n-GaN epilayers were grown by metal-organic chemical vapor deposition (MOCVD) on sapphire substrates. The grown n-GaN epilayers were characterized using atomic force microscopy (AFM), X-ray diffraction (XRD), photoluminescence and Hall effect measurements. Enhanced PL intensity and low dark spot density (DSD) were observed on the aligned step structure n-GaN. The samples with these aligned step structure showed high electron mobilities with good structural and optical properties, while the samples with the anisotropic step structure showed broadened XRD FWHM values, low mobilities, and poor structural and optical properties. The low Hall mobility of n-GaN is due to the scattering of charged threading dislocations. A clear correlation was observed between Hall mobility and DSD by AFM. The AFM surface observation is also a better method for the evaluation of the electron mobility of lightly doped MOCVD grown n-GaN.

A trapezoidal peak shape of dissociative ions is observed in the charge inversion mass spectra. The relation between the kinetic energy release (KER) and the peak shape was simulated. Dissociation with a specific KER value having very narrow distribution for both ionic and neutral species affords the trapezoidal peak shape in a mass spectrum. The KER value was evaluated from the full width at half maximum (FWHM) of the trapezoidal peak associated with the CH3O- ions formed from CH3OH+ ions in the charge inversion mass spectrum. The KER value showed the good agreement with that evaluated from the velocity distribution of H atom formed from the photo-dissociation of neutral methanol. This agreement demonstrated that the excited neutral methanol dissociated predominantly into the methoxy radical and the hydrogen atom, and that charge inversion mass spectrometry gave the dissociation of energy-selected neutral species.