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[Display omitted] • A novel social defeat stress paradigm was conducted to develop a perinatal depression-like model in mice. • Chronic ND-SDS efficiently reduced exploratory behavior and social interaction in perinatal mice. • Stress-susceptible perinatal female mice subjected to a chronic ND-SDS also exhibited an anhedonic phenotype. Depression is more prevalent in women than in men. Perinatal stress is one of the main risk factors for depression in women. However, there is no suitable female model for perinatal depression that uses the social defeat stress (SDS) paradigm. The standard chronic SDS protocol, which is the most useful method for developing a depression-like model, is effective only in male mice. Thus, this study aimed to characterize a novel SDS method for producing a perinatal depression-like model mouse. We induced chronic SDS in perinatal female mice, wherein chronic non-discriminatory SDS (ND-SDS) was used to induce substantial stress in female mice. The female mice were placed in aggressive ICR mouse cages with sentinel male mice under ND-SDS conditions. Stressed female mice subjected to ND-SDS during the perinatal period efficiently exhibited stress-susceptible phenotypes, such as a social avoidance phenotype and anhedonic behavior, whereas stressed female mice subjected to SDS did not show depressive-like behaviors. These results indicate that chronic ND-SDS in perinatal females could be used to develop a female perinatal depression-like model that can be used to study women's health. [ABSTRACT FROM AUTHOR]

ABSTRACT ( tBuC5H4)TiCl2(N=C tBu2) ( 1) exhibited remarkable catalytic activities (12,000-43,700 kg-polymer/mol-Ti·h) and efficient comonomer incorporation in ethylene copolymerization with tetracyclododecene (TCD) in the presence of methylaluminoxane, and the catalytic activity by 1 increased even at 60 °C. The resultant polymers are high molecular weight amorphous poly(ethylene- co-TCD)s ( Mn = 5.88-7.03 × 105) with uniform compositions (with high Tg values, 108-203 °C); a linear relationship between Tg values and the TCD contents was observed. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 2662-2667 [ABSTRACT FROM AUTHOR]

Kaempferol (KMP) is an important flavonoid in many fruits and vegetables. Preclinical studies on KMP have reported its pharmacological effects, including antimicrobial, antioxidant, anti‐inflammatory, antitumor, antidiabetic, myocardial protective, and neuroprotective effects. Additionally, some epidemiological studies have revealed a negative association between the consumption of KMP‐containing foods and the risk of developing several disorders, such as cancer and cardiovascular diseases. Thus, although a large body of literature has demonstrated the benefits of KMP supplementation, there are no reports of clinical trials evaluating the safety of KMP aglycone administration or KMP aglycone‐rich food consumption. The purpose of this study was to evaluate the safety of a high dose of KMP aglycone by administrating KMP aglycone‐containing supplements to healthy adults. This study had a randomized, double‐blind, placebo‐controlled design and a 4‐week duration. Participants were randomly allocated to the KMP (n = 24) or placebo (n = 24) group. For 4 weeks, the KMP group received a capsule containing 50‐mg KMP daily, a dose approximately five times higher than the estimated human dietary intake. The placebo group received a capsule containing cornstarch‐based powder daily. The general toxicity parameters were evaluated by examining the characteristics of the participants, hematological and blood biochemical parameters, general urinalysis, qualitative urine tests, and adverse events. No clinical changes were observed in anthropometric and blood pressure measurements or blood and urine parameters in the KMP group compared to those in the placebo group. Furthermore, no adverse events owing to KMP aglycone administration occurred. The study results revealed that the consumption of 50‐mg KMP aglycone daily for 4 weeks is safe in healthy adults. [ABSTRACT FROM AUTHOR]

• Effect of short-term temperature stress was evaluated during 5 days before anthesis. • Auxin-related factors were investigated using Micro-Tom as a model system. • DR5::GUS expression under high temperature was inhibited with the fruit development. • Fruit set and DR5::GUS expression were not inhibited under low-temperature stress. • The expression of ToFZY for auxin synthesis were affected by high-temperature stress. Poor fruit set and growth are known to be caused by temperature stress in tomato cultivation. We focused on the effect of short-term temperature stress on each day during the five days before anthesis. The relationship between temperature stress and auxin-related factors was investigated using an experimental tomato cultivar, Micro-Tom expressing the auxin reporter DR5::GUS as a model system. While DR5::GUS expression in the control plants increased in ovaries and transferred to peduncles during the later developmental stages, that under high-temperature stress was not detected or very low. Some smaller fruit grew even under high-temperature stress probably due to the low level of DR5::GUS expression. Therefore, it was suggested that temporary high-temperature stress at any stage in this study affected the localization of auxin to ovaries and peduncles, and further affected fruit set and growth. By contrast, no decreased fruit set was observed with some delay and recovery of fruit growth under low-temperature stress, and this corresponded to the levels of DR5::GUS expression. The expression of GUS with the promoter of the tomato PIN gene, which is involved in the auxin transport, was not affected by high-temperature stress. On the other hand, the expression of ToFZY genes involved in auxin synthesis were affected by temperature stress, suggesting a part of the mechanism of the decrease in DR5::GUS expression under high-temperature stress. [ABSTRACT FROM AUTHOR]

This paper discusses the instability of suction bucket foundations that are growing in importance for bottom-mounted offshore wind turbines in association with wave-induced liquefaction of sand beds. The instability of suction bucket foundations should be understood in light of fluid–soil–structure interactions. In this study, we investigated the instability using centrifuge wave testing in a drum channel with viscous scaling to match the time-scaling laws for fluid wave propagation and consolidation of the soil. This paper highlights the effects of loosening and heaving of the sand inside the bucket during the installation process, which is one of the onsite problems, on the overall stability and clarifies the stability of the whole system in light of wave–soil–structure interactions. The experimental results showed that the instability of the suction bucket is ascribed to the occurrence and progress of liquefaction of the sand bed around the bucket. The experimental results further demonstrated the effect of embedment of the bucket in a dense layer. An embedded depth of the bucket tip equal to one-third of the bucket skirt length prevented instability of the foundation, despite the spread of liquefaction in the loose sand bed. Even when the dense sand inside and underneath the bucket was loosened during the installation process, the foundation bucket remained stable against severe wave actions. The present study examined and summarized the overall stability of suction bucket foundations in sand beds under severe wave loading and clarified the importance of the progress of liquefaction around the foundations. [ABSTRACT FROM AUTHOR]

PQBP1 is a nuclear-cytoplasmic shuttling protein that is engaged in RNA metabolism and transcription. In mouse embryonic brain, our previous in situ hybridization study revealed that PQBP1 mRNA was dominantly expressed in the periventricular zone region where neural stem progenitor cells (NSPCs) are located. Because the expression patterns in NSPCs are related to the symptoms of intellectual disability and microcephaly in PQBP1 gene-mutated patients, we investigated the transcriptional regulation of PQBP1 by NSPC-specific transcription factors. We selected 132 genome sequences that matched the consensus sequence for the binding of Sox2 and POU transcription factors upstream and downstream of the mouse PQBP1 gene. We then screened the binding affinity of these sequences to Sox2-Pax6 or Sox2-Brn2 with gel mobility shift assays and found 18 genome sequences that interacted with the NSPC-specific transcription factors. Some of these sequences had cis-regulatory activities in Luciferase assays and in utero electroporation into NSPCs. Furthermore we found decreased levels of expression of PQBP1 protein in NSPCs of heterozygous Sox2-knockout mice in vivo by immunohistochemistry and western blot analysis. Collectively, these results indicated that Sox2 regulated the transcription of PQBP1 in NSPCs. [ABSTRACT FROM AUTHOR]

In preclinical models, it has been reported that social defeat stress activates microglial cells in the CNS. Translocator protein 18 kDa (TSPO) is a mitochondrial protein expressed on microglia in the CNS that has been proposed to be a useful biomarker for brain injury and inflammation. We hypothesized that a TSPO antagonist, ONO-2952, would inhibit the neuroinflammation induced by microglial hyperactivation and associated depressive-like behaviors. An in vitro analysis showed that ONO-2952 suppressed the release of pro-inflammatory cytokines and mitochondrial reactive oxygen species in cultured microglia stimulated by lipopolysaccharide. In mice submitted to chronic social defeat stress, microglia predominantly expressed TSPO in limbic areas implicated in depressive-like behaviors, including the amygdala, ventral hippocampus and nucleus accumbens, in which an increase in the production of pro-inflammatory cytokines in vivo were associated. Treating animals with ONO-2952 during chronic social defeat stress ameliorated impairments in social avoidance and anxiety-like behaviors and suppressed pro-inflammatory cytokine production, suggesting that ONO-2952 exerted an anti-stress effect in this animal model of depression. Thus, targeting TSPO as a candidate for the development of antidepressants that reduce susceptibility to chronic stress could pave the way toward therapeutic interventions for relapse prophylaxis in depression. Image 1 • Chronic stress induces TSPO expression in the limbic areas implicated in depression. • ONO-2952 suppresses cytokine expression induced in the limbic areas by chronic stress. • ONO-2952 inhibits cytokines and reactive oxygen species production in the cultured microglia. • ONO-2952 displays anti-anxiety and antidepressant effects. [ABSTRACT FROM AUTHOR]

Protein phosphorylation is deeply involved in the pathological mechanism of various neurodegenerative disorders. However, in human pathological samples, phosphorylation can be modified during preservation by postmortem factors such as time and temperature. Postmortem changes may also differ among proteins. Unfortunately, there is no comprehensive database that could support the analysis of protein phosphorylation in human brain samples from the standpoint of postmortem changes. As a first step toward addressing the issue, we performed phosphoproteome analysis with brain tissue dissected from mouse bodies preserved under different conditions. Quantitative whole proteome mass analysis showed surprisingly diverse postmortem changes in phosphoproteins that were dependent on temperature, time and protein species. Twelve hrs postmortem was a critical time point for preservation at room temperature. At 4°C, after the body was cooled down, most phosphoproteins were stable for 72 hrs. At either temperature, increase greater than 2-fold was exceptional during this interval. We found several standard proteins by which we can calculate the postmortem time at room temperature. The information obtained in this study will be indispensable for evaluating experimental data with human as well as mouse brain samples. [ABSTRACT FROM AUTHOR]

DNA repair defends against naturally occurring or disease-associated DNA damage during the long lifespan of neurons and is implicated in polyglutamine disease pathology. In this study, we report that mutant huntingtin (Htt) expression in neurons causes double-strand breaks (DSBs) of genomic DNA, and Htt further promotes DSBs by impairing DNA repair. We identify Ku70, a component of the DNA damage repair complex, as a mediator of the DNA repair dysfunction in mutant Htt-expressing neurons. Mutant Htt interacts with Ku70, impairs DNA-dependent protein kinase function in nonhomologous end joining, and consequently increases DSB accumulation. Expression of exogenous Ku70 rescues abnormal behavior and pathological phenotypes in the R6/2 mouse model of Huntington's disease (HD). These results collectively suggest that Ku70 is a critical regulator of DNA damage in HD pathology. [ABSTRACT FROM AUTHOR]

Abstract: HMGB1 is an evolutionarily conserved non-histone chromatin-associated protein with key roles in maintenance of nuclear homeostasis; however, the function of HMGB1 in the brain remains largely unknown. Recently, we found that the reduction of nuclear HMGB1 protein level in the nucleus associates with DNA double-strand break (DDSB)-mediated neuronal damage in Huntington’s disease [M.L. Qi, K. Tagawa, Y. Enokido, N. Yoshimura, Y. Wada, K. Watase, S. Ishiura, I. Kanazawa, J. Botas, M. Saitoe, E.E. Wanker, H. Okazawa, Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases, Nat. Cell Biol. 9 (2007) 402–414]. In this study, we analyze the region- and cell type-specific changes of HMGB1 and DDSB accumulation during the aging of mouse brain. HMGB1 is localized in the nuclei of neurons and astrocytes, and the protein level changes in various brain regions age-dependently. HMGB1 reduces in neurons, whereas it increases in astrocytes during aging. In contrast, DDSB remarkably accumulates in neurons, but it does not change significantly in astrocytes during aging. These results indicate that HMGB1 expression during aging is differentially regulated between neurons and astrocytes, and suggest that the reduction of nuclear HMGB1 might be causative for DDSB in neurons of the aged brain. [Copyright &y& Elsevier]

During reward-based learning tasks, animals make orofacial movements that globally influence brain activity at the timings of reward expectation and acquisition. These orofacial movements are not explicitly instructed and typically appear along with goal-directed behaviors. Here, we show that reinforcing optogenetic stimulation of dopamine neurons in the ventral tegmental area (oDAS) in mice is sufficient to induce orofacial movements in the whiskers and nose without accompanying goal-directed behaviors. Pavlovian conditioning with a sensory cue and oDAS elicited cue-locked and oDAS-aligned orofacial movements, which were distinguishable by a machine-learning model. Inhibition or knockout of dopamine D1 receptors in the nucleus accumbens inhibited oDAS-induced motion but spared cue-locked motion, suggesting differential regulation of these two types of orofacial motions. In contrast, inactivation of the whisker primary motor cortex (wM1) abolished both types of orofacial movements. We found specific neuronal populations in wM1 representing either oDAS-aligned or cue-locked whisker movements. Notably, optogenetic stimulation of wM1 neurons successfully replicated these two types of movements. Our results thus suggest that accumbal D1-receptor-dependent and -independent neuronal signals converge in the wM1 for facilitating distinct uninstructed orofacial movements during a reward-based learning task. [Display omitted] • Optogenetic stimulation of VTA-DA neurons (oDAS) elicits orofacial movement • Cue-oDAS association induces distinct cue-locked and oDAS-aligned orofacial actions • Accumbal D1Rs mediate oDAS-aligned, but not cue-locked, motion • Different neuronal signals converge in wM1, triggering unique orofacial movements Investigating how mice display differential orofacial movements during reward anticipation and acquisition, Li and Nakano et al. highlight the pivotal role of the whisker primary motor cortex. It channels distinct neuronal signals—some via the mesolimbic dopamine pathway, others bypassing it—to facilitate unique orofacial actions. [ABSTRACT FROM AUTHOR]

Patients with major depressive disorder have elevated peripheral inflammation; the degree of this increase correlates with the severity of the disorder. Chronic psychological stress increases pro-inflammatory cytokines and promotes microglial activation, leading to stress vulnerability. Epigenetics, including DNA methylation and histone modification, are also related to the pathophysiology of major depressive disorder. Sodium butyrate (SB), a histone deacetylase inhibitor, exerts an antidepressant effect by altering gene expression in the hippocampus. In this study, we investigated whether lipopolysaccharide (LPS)-induced depressive-like behaviors in mice are affected by the repeated treatment with SB. Intraperitoneal injection of LPS (5 mg/kg) induced cytokines and ionized calcium-binding adaptor molecule 1(Iba1), a marker of microglial activation, in the hippocampus. It also increased the immobility time in a forced swim test, without changing locomotion. Repeated treatment with SB reduced LPS-induced alterations. These findings suggested that epigenetic regulation exist in hippocampal microglial activation, and is involved in depressive-like behaviors associated with neuro-inflammation. Further, using cDNA microarray analyses, we examined whether LPS and SB treatment affected the microglial gene profiles. Our results indicated 64 overlapping genes, between LPS-increased genes and SB-decreased genes. Among these genes, EF hand calcium binding domain 1 was a particularly distinct candidate gene. Altogether, our findings indicated that microglial activation mediated through epigenetic regulation may be involved in depressive-like behaviors. In addition, we demonstrated the effect of SB on gene information in hippocampal microglia under neuroinflammatory conditions. [ABSTRACT FROM AUTHOR]

Abstract: The modifying potential of Agaricus blazei Murrill fruit-body extract (ABFE) on tumor development was investigated in a medium-term multi-organ carcinogenesis bioassay. Male 6-week-old F344 rats were treated with N-nitrosodiethylamine (DEN), N-methyl-N-nitrosourea (MNU), 1,2-dimethylhydrazine dihydrochloride (DMH), N-butyl-N-(hydroxybutyl)-nitrosamine (BBN), and diisopropanolnitrosamine (DHPN) for initiation (DMBDD treatment). After a 1-week withdrawal period, the animals received distilled water (vehicle control) or ABFE A, gamma-amino butyric acid (GABA) at 0.8mg/kg, ABFE B (GABA level of 3.0mg/kg) or ABFE C (GABA level of 12.0mg/kg) by gavage for 24weeks. There were no effects of ABFE on survival rate, general condition, body weight, food and water consumption, and organ weights. The multiplicity of large intestinal nodules, smaller than 2mm was significantly increased in the ABFE C group with DMBDD treatment. However, there were no significantly inter-group differences in incidences of hyperplastic or neoplastic lesions in colon or other organs, or in immunohistochemically identified preneoplastic lesions in the liver. In conclusion, A. blazei Murrill fruit-body extract, even at a GABA level up to 12mg/kg, did not exert modifying potential in the present medium-term multi-organ carcinogenesis bioassay in male F344 rats (DMBDD method). [Copyright &y& Elsevier]

Selective vulnerability of neurons is a critical feature of neurodegenerative diseases, but the underlying molecular mechanisms remain largely unknown. We here report that Omi/HtrA2, a mitochondrial protein regulating survival and apoptosis of cells, decreases selectively in striatal neurons that are most vulnerable to the Huntington’s disease (HD) pathology. In microarray analysis, Omi/HtrA2 was decreased under the expression of mutant huntingtin (htt) in striatal neurons but not in cortical or cerebellar neurons. Mutant ataxin-1 (Atx-1) did not affect Omi/HtrA2 in any type of neuron. Western blot analysis of primary neurons expressing mutant htt also confirmed the selective reduction of the Omi/HtrA2 protein. Immunohistochemistry with a mutant htt-transgenic mouse line and human HD brains confirmed reduction of Omi/HtrA2 in striatal neurons. Overexpression of Omi/HtrA2 by adenovirus vector reverted mutant htt-induced cell death in primary neurons. These results collectively suggest that the homeostatic but not proapoptotic function of Omi/HtrA2 is linked to selective vulnerability of striatal neurons in HD pathology. [ABSTRACT FROM AUTHOR]

Peripheral lipopolysaccharide (LPS) injection induces systemic inflammation through the activation of the inhibitor of nuclear factor kappa B (NF-κB) kinase (IKK)/NF-κB signaling pathway, which promotes brain dysfunction resulting in conditions including anorexia. LPS-mediated reduction of food intake is associated with activation of NF-κB signaling and phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the hypothalamus. We recently reported phospholipase C-related catalytically inactive protein (PRIP) as a new negative regulator of phosphatidylinositol 3-kinase/AKT signaling. AKT regulates the IKK/NF-κB signaling pathway; therefore, this study aimed to investigate the role of PRIP/AKT signaling in LPS-mediated neuroinflammation-induced anorexia. PRIP gene (Prip1 and Prip2) knockout (Prip -KO) mice intraperitoneally (ip) administered with LPS exhibited increased anorexia responses compared with wild-type (WT) controls. Although few differences were observed between WT and Prip -KO mice in LPS-elicited plasma pro-inflammatory cytokine elevation, hypothalamic pro-inflammatory cytokines were significantly upregulated in Prip -KO rather than WT mice. Hypothalamic AKT and IKK phosphorylation and IκB degradation were significantly increased in Prip -KO rather than WT mice, indicating further promotion of AKT-mediated NF-κB signaling. Consistently, hypothalamic STAT3 was further phosphorylated in Prip -KO rather than WT mice. Furthermore, suppressor of cytokine signaling 3 (Socs3), a negative feedback regulator for STAT3 signaling, and cyclooxogenase-2 (Cox2), a candidate molecule in LPS-induced anorexigenic responses, were upregulated in the hypothalamus in Prip -KO rather than WT mice. Pro-inflammatory cytokines were upregulated in hypothalamic microglia isolated from Prip -KO rather than WT mice. Together, these findings indicate that PRIP negatively regulates LPS-induced anorexia caused by pro-inflammatory cytokine expression in the hypothalamus, which is mediated by AKT-activated NF-κB signaling. Importantly, hypothalamic microglia participate in this PRIP-mediated process. Elucidation of PRIP-mediated neuroinflammatory responses may provide novel insights into the pathophysiology of many brain dysfunctions. • Prip -KO mice show susceptibility to LPS-induced anorexia. • PRIP deficiency enhances LPS-induced hypothalamic inflammatory cytokine expression. • PRIP deficiency enhances hypothalamic AKT/NF-κB/STAT3 signaling after LPS treatment. • PRIP deficiency enhances inflammatory responses in hypothalamic microglia. • PRIP negatively regulates the progression of LPS-induced anorexia. [ABSTRACT FROM AUTHOR]