Comprehensive behavioral phenotyping of calpastatin-knockout mice

<p>Abstract</p> <p>Background</p> <p>Calpastatin is an endogenous inhibitor of calpain, intracellular calcium-activated protease. It has been suggested to be involved in molecular mechanisms of long-term plasticity and excitotoxic pathways. However, functions of calpastatin in vivo are still largely unknown. To examine the physiological roles of calpastatin, we subjected calpastatin-knockout mice to a comprehensive behavioral test battery.</p> <p>Results</p> <p>Calpastatin-knockout mice showed decreased locomotor activity under stressful environments, and decreased acoustic startle response, but we observed no significant change in hippocampus-dependent memory function.</p> <p>Conclusion</p> <p>These results suggest that calpastatin is likely to be more closely associated with affective rather than cognitive aspects of brain function.</p

Percutaneous Transcatheter Ballon Valvuloplasty of a Stenosed Bioprosthetic Tricuspid Valve

Article信州医学雑誌 67(5): 289-292(2019)journal articl

Involvement of calpains in adult neurogenesis: implications for stroke

Calpains are ubiquitous proteases involved in cell proliferation, adhesion and motility. In the brain, calpains have been associated with neuronal damage in both acute and neurodegenerative disorders, but their physiological function in the nervous system remains elusive. During brain ischemia, there is a large increase in the levels of intracellular calcium, leading to the activation of calpains. Inhibition of these proteases has been shown to reduce neuronal death in a variety of stroke models. On the other hand, after stroke, neural stem cells (NSC) increase their proliferation and newly formed neuroblasts migrate towards the site of injury. However, the process of forming new neurons after injury is not efficient and finding ways to improve it may help with recovery after lesion. Understanding the role of calpains in the process of neurogenesis may therefore open a new window for the treatment of stroke. We investigated the involvement of calpains in NSC proliferation and neuroblast migration in two highly neurogenic regions in the mouse brain, the dentate gyrus (DG) and the subventricular zone (SVZ). We used mice that lack calpastatin, the endogenous calpain inhibitor, and calpains were also modulated directly, using calpeptin, a pharmacological calpain inhibitor. Calpastatin deletion impaired both NSC proliferation and neuroblast migration. Calpain inhibition increased NSC proliferation, migration speed and migration distance in cells from the SVZ. Overall, our work suggests that calpains are important for neurogenesis and encourages further research on their neurogenic role. Prospective therapies targeting calpain activity may improve the formation of new neurons following stroke, in addition to affording neuroprotection.Foundation for Science and Technology, (FCT, Portugal); COMPETE; FEDER [PTDC/SAU-NMC/112183/2009, PEst-C/SAU/LA0001/2013-2014, PEst-OE/EQB/LA0023/2013-2014]; NIH [GM 23244]; FCT [SFRH/BPD/78901/2011, SFRH/BD/38127/2007, SFRH/BD/78050/2011]info:eu-repo/semantics/publishedVersio

Potent amyloidogenicity and pathogenicity of Aβ43.

The amyloid-β peptide Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer\u27s disease. However, the role of Aβ43, which is found just as frequently in the brains of affected individuals, remains unresolved. We generated knock-in mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygosity was embryonic lethal, indicating that the mutation involves a loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevated Aβ43, impairment of short-term memory and acceleration of amyloid-β pathology, which accompanied pronounced accumulation of Aβ43 in plaque cores similar in biochemical composition to those observed in the brains of affected individuals. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aβ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with the age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic and abundant in vivo

Topological Effect in Ring Polymers Studied by Monte Carlo Simulation(Knots and soft-matter physics: Topology of polymers and related topics in physics, mathematics and biology)

この論文は国立情報学研究所の電子図書館事業により電子化されました。バルクにおけるリングポリマーの拡がりをモンテカルロシミュレーション法を用いて検討した。フローリの指数νとセグメントの分布を、Bond Fluctuation Model(BFM)を使って広い範囲のセグメント数(10&le;N&le;1000)で求めた。シミュレーションの結果、νはNの増加とともに減少しN=1000でν=0.365まで低下するすることがわかり、これらは理論予測であるν=2/5よりも小さい。リングポリマーのバルクにおける拡がりは、末端がないトポロジーによる自分自身による拘束と隣接するリングポリマーとの相互作用の二つによって非摂動鎖よりも小さく、かつ、分子量依存性を示すことがわかった。セグメントの分布について求めたところ、リングポリマーのセグメント数が無限大の条件では、ν→1/3を持つことが考えられることから、1/3&le;ν≪0.365が得られ、実験結果をよく説明することが分かった。理論予測は、リングポリマーのトポロジーによるエントロピー低下を充分に考慮していなかったため、本研究の結果と理論予測の結果に差が生じていると結論できる。We studied equilibrium conformations of ring polymers in the melt over the wide range of segment number, N, up to 1000 by the Monte-Carlo simulation method and the bond fluctuation model (BFM), and obtained Flory's scaling exponent ν and the radial distribution function of segments. It is clear that ν for ring polymers is decreased with N, and ν goes down to 0.365 when N reaches 1000, whose value is smaller than the theoretically-predicted one, i.e., 2/5. Ring polymer chains in the melt are squeezed both by their own topological effect and the compression effect by the neighboring ring polymer coils, and they are perturbation chains in the melt. The difference in our study and the theory is that the estimation of topological entropy loss in ring polymers was ignored in the theoretical prediction, while it has been taken into consideration in this study. If polymer coils repel each other in the melt at N→∞, they have the limiting ν value of 1/3, and we conclude that ν is in the range 1/3&le;ν≪0.365 when the molecular weight of a ring polymer is high enough

Predicting Online Item-Choice Behavior: A Shape-Restricted Regression Approach

This paper examines the relationship between user pageview (PV) histories and their itemchoice behavior on an e-commerce website. We focus on PV sequences, which represent time series of the number of PVs for each user–item pair. We propose a shape-restricted optimization model that accurately estimates item-choice probabilities for all possible PV sequences. This model imposes monotonicity constraints on item-choice probabilities by exploiting partial orders for PV sequences, according to the recency and frequency of a user’s previous PVs. To improve the computational efficiency of our optimization model, we devise efficient algorithms for eliminating all redundant constraints according to the transitivity of the partial orders. Experimental results using real-world clickstream data demonstrate that our method achieves higher prediction performance than that of a state-of-the-art optimization model and common machine learning methods

Dimension of ring polymers in bulk studied by Monte-Carlo simulation and self-consistent theory

We studied equilibrium conformations of ring polymers in melt over the wide range of segment number N of up to 4096 with Monte-Carlo simulation and obtained N dependence of radius of gyration of chains R g . The simulation model used is bond fluctuation model ͑BFM͒, where polymer segments bear excluded volume; however, the excluded volume effect vanishes at N → ϱ, and linear polymer can be regarded as an ideal chain. Simulation for ring polymers in melt was performed, and the value in the relationship R g ϰ N is decreased gradually with increasing N, and finally it reaches the limiting value, 1/3, in the range of N Ն 1536, i.e., R g ϰ N 1/3 . We confirmed that the simulation result is consistent with that of the self-consistent theory including the topological effect and the osmotic pressure of ring polymers. Moreover, the averaged chain conformation of ring polymers in equilibrium state was given in the BFM. In small N region, the segment density of each molecule near the center of mass of the molecule is decreased with increasing N. In large N region the decrease is suppressed, and the density is found to be kept constant without showing N dependence. This means that ring polymer molecules do not segregate from the other molecules even if ring polymers in melt have the relationship =1/ 3. Considerably smaller dimensions of ring polymers at high molecular weight are due to their inherent nature of having no chain ends, and hence they have less-entangled conformations

Brief internet-based cognitive behavior therapy program with a supplement drink improved anxiety and somatic symptoms in Japanese workers

Abstract Background Self-help cognitive behavior therapy (CBT) is a useful approach for the treatment of psychological problems. Recent research on the effectiveness of self-help internet-based CBT (ICBT) indicates that the paradigm moderately improves psychological problems. Furthermore, previous studies have shown that food and drinks containing supplements improve various health conditions. We investigated the effect of a brief self-help ICBT administered with a supplement drink on psychological well-being and somatic symptoms. Methods In total, 101 healthy workers were enrolled in the 4-week ICBT program, which consisted of psychoeducation on stress management, behavior activation, and cognitive restructuring. The supplement soft drink was taken every day during the program. The participants were instructed to watch on-demand video clips and read the self-help guidebook and supporting comic strip weekly on the Internet or smartphone. The Japanese version of the Profile of Mood States (POMS) was administered before and after completion of the program. Scores on the POMS tension-anxiety (POMS-TA), depression (POMS-D), and fatigue (POMS-F) subscales were used to assess the effect of the program. Somatic symptoms were assessed using the Brief Job Stress Questionnaire. Results In total, 75 participants continued the program for 4 weeks; however, of those, 27 failed to complete all weekly tasks or meet the post-assessment deadlines. Therefore, the data of 48 participants were included in the analysis. Pre-post intervention comparisons using paired t-tests revealed significant improvement on the POMS-TA, but not the POMS-D or POMS-F subscales. Moreover, participants reported a significant reduction in the severity of low back pain. Conclusion Our brief intervention moderately improved anxiety levels and the symptom of low back pain. These findings suggest that the brief ICBT program is effective in non-patient populations. Future directions for brief ICBT are discussed. Trial registration This study was registered on February 10, 2016 at UMIN. The registration number is UMIN000020962