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When cancers progress to metastasis, disseminated cancer cells frequently lodge near vasculature in secondary organs. However, our understanding of the cellular crosstalk evoked at perivascular sites is still rudimentary. In this study, we identify intercellular machinery governing formation of a pro-metastatic vascular niche during breast cancer colonization in lungs. We show that four secreted factors, INHBB, SCGB3A1, OPG and LAMA1, induced in metastasis-associated endothelial cells (ECs), are essential components of the vascular niche and promote metastasis in mice by enhancing stem cell properties and survival ability of cancer cells. Notably, blocking VEGF, a key regulator of EC behavior, dramatically suppressed EC proliferation, whereas no impact was observed on the expression of the four vascular niche factors in lung ECs. However, perivascular macrophages, activated via the TNC-TLR4 axis, were shown to be crucial for EC-mediated production of niche components. Together, our findings provide mechanistic insights into the formation of vascular niches in metastasis.

This paper proposes a network of neural oscillators having lateral inhibition structures. Our previous research suggested a new control system for active mass dampers (AMDs) consisting of a neural oscillator network and a position controller. However, the proposed system required a large number of neural oscillators for robust operation, which made the implementation more difficult in microcomputers. Thus, there was a need to limit the number of oscillators for application. This research addressed this need by changing the internal structure of the network. This paper provides new structures that reduce the number of neural oscillators. The introduced lateral inhibition structures used in this work should be useful for the implementation of the network into the microcomputers.

In contextul actualei pandemii de COVID-19 care a afectat și România, populația s-a confruntat cu o serie de probleme de ordin conomic și social determinate de reducerea activitații agenților economici și a instituțiilor publice, reorganizare aactivitații serviciilor de sanatate, de asistența sociala și a celor de educație. Viaţa pentru copiii din mediul rural s-a inrautaţit considerabil in perioada pandemiei, arata o cercetare realizata de World Vision România in perioada 10 mai – 27 iunie 2020. Cei mai mulţi parinţi din mediul rural nu au lucrat in aceasta perioada, iar aproape jumatate dintre ei, nu au reusit sa asigure deloc sau au asigurat parţial accesul la educaţie, alimente, medicamente si produse de igiena. Inchiderea școlilor cauzata de COVID-19 nu a afectat doar invațarea, ci și alte aspecte sociale precum sanatatea mintala, violența sau inegalitațile sociale pronunțate. O categorie afectata de catre pandemia COVID-19 este reprezentata de copiii din mediul rural, unde accesul la internet și, in special, accesul la conexiunea pe banda larga este mai limitat decât in mediul urban.

Acidic pH levels are often observed in growing tumors, with profound effects on cancer cells and surrounding microenvironment. In this issue of Developmental Cell, Funato et al. (2020) show that expression of oncogenic phosphatase of regenerating liver 3 (PRL3) shifts cellular preference for environmental pH, leading to acid addiction.

OBJECTIVES To compare conventional procedures with the half-turned truncal switch operation (HTTSO) for the management of complete transposition of the great arteries with left ventricular outflow tract (LVOT) obstruction using time-resolved 3-dimensional magnetic resonance phase-contrast imaging. METHODS We identified 2 cases that underwent the Rastelli procedure and one case that underwent the Réparation a l'étage ventriculaire before 2002 [conventional procedures group (group C)], and 16 cases of HTTSO that were performed between 2002 and 2020 [HTTSO group (group H)]. Postoperative haemodynamics were assessed using time-resolved 3-dimensional magnetic resonance phase-contrast imaging in cases in both groups. RESULTS The median follow-up period was 20.4 years in group C, and 6.1 years in group H. In group C, all 3 patients underwent reoperation because of postoperative right ventricular outflow tract obstruction and/or insufficiency. In addition, permanent pacemaker implantation was needed in 1 patient because of complete atrioventricular block complicated by ventricular septal defect enlargement. In group H, reoperation for LVOT/right ventricular outflow tract obstruction was not needed. A time-resolved 3-dimensional magnetic resonance phase-contrast imaging examination revealed high energy loss and wall shear stress in the winding LVOT in the group C. In contrast, low energy loss and wall shear stress, with straight and smooth LVOT, were identified in group H. CONCLUSIONS HTTSO was shown to be superior to conventional procedures because a straight and wide LVOT could be obtained. Therefore, HTTSO should be the first choice for complete transposition of the great arteries with LVOT obstruction.

OBJECTIVES Late complications of arterial switch operations (ASO) for transposition of the great arteries, such as neo-pulmonary artery (PA) stenosis and/or neoaortic regurgitation, have been reported. We developed an alternative reconstruction method called the longitudinal extension (LE) method to prevent PA bifurcation stenosis (PABS). METHODS We identified 48 patients diagnosed with transposition of the great arteries and performed ASO using the Lecompte manoeuvre for neo-PA reconstruction. In 9 consecutive patients (from 2014), the LE method was performed (LE). Before 2014, conventional techniques were performed in 39 patients (C). The median body weight and age in the LE and C groups were 3.0 and 3.1 kg and 12 and 26 days, respectively. In the LE group, 1 patient underwent bilateral PA banding before ASO. In C, PA banding and arch repair were performed in 1 patient each. Patients who received concomitant procedures were included. RESULTS The median follow-up in LE and C groups was 1.9 and 10.1 years, respectively. Early mortality/late death was not found in group LE and in 1 patient in group C. Only 1 case required ascending aorta sliding plasty in LE, and 8 patients needed PA augmentation for PABS in C. The median velocity of right/left PA was measured as 1.6/1.9 m/s in LE and 2.1/2.3 m/s in C, so it showed a lower value in LE. CONCLUSIONS Excellent mid-term results were obtained with the LE method. It was considered a useful procedure in preventing PABS, which is a primary late complication of ASO. Further follow-up and investigations are needed.

OBJECTIVES In Japan, homograft and bovine jugular vein are available in very limited institutions for the reconstruction of the right ventricular outflow tract, and handmade expanded polytetrafluoroethylene (ePTFE)-valved conduits have been widely used instead. This study aimed to clarify the long-term outcomes and the durability of the ePTFE-valved conduits purely by narrowing down to those with large sizes to eliminate the influence of the body growth. METHODS Between January 2002 and December 2015, patients who underwent right ventricular outflow tract reconstruction in 34 Japanese institutions using ePTFE-valved conduits with a diameter of ≥18 mm were included. All the valved conduits were made in the authors’ institution and delivered to each participating institution. RESULTS Overall, 502 patients were included. Early mortality was 1.4% and not related to conduit failure. The overall survival rate was 98.2% at 5 years and 96.6% at 10 years. Freedom from conduit explantation was 99.5% at 5 years and 89.0% at 10 years. Three patients (0.13 per 100 patient-years) developed infective endocarditis of the conduit, and only 1 patient required conduit removal. Pulmonary insufficiency was mild or less in 480 (96%) patients, and conduit stenosis was mild or less in 436 (88%) patients at the latest follow-up. CONCLUSIONS By narrowing the analyses down to only ePTFE conduits with a large size, satisfactory long-term outcomes of these conduits with a fan-shaped valve and bulging sinuses were shown. These conduits would be among the optimal choices for right ventricular outflow tract reconstruction.

The purpose of this formative, cross-sectional study was to describe independent eating occasions (iEOs) among a convenience sample of low-income early adolescents (10&ndash, 13 years, n = 46) in 10 U.S. states, including environmental context, foods selected and reasons for selection, and parental rules about foods consumed. Participants took pictures of all foods consumed over 24 h and participated in semi-structured interviews to describe the context of each eating occasion using the pictures as a guide. Responses based on a total of 304 eating occasions were coded to classify foods based on United States Department of Agriculture (USDA) MyPlate food groups and to characterize parental rules and reasons for food selection. Average age was 10.9 &plusmn, 1.1 years and 60% were female. Approximately 58% of eating occasions were classified as iEOs with approximately 65% as snacks. Most iEOs took place at home. Foods frequently consumed during iEOs were from the sweets, total fruit, dairy, and whole fruit food categories. Primary parental rules for iEOs focused on avoiding certain foods and not eating too much. Early adolescents selected foods for convenience, taste preferences, and availability. Foods selected during iEOs were based on parent, household and early adolescent factors, which could be addressed to influence overall diet quality.

Background Echocardiography vector flow mapping can assess dynamic flow to treat congenital heart diseases. We evaluated intracardiac flow, energy loss, left ventricular output kinetic energy, and energetic performance index using vector flow mapping during Glenn and Damus-Kaye-Stansel procedures in order to assess the efficacy of the surgery. Case presentation A 9-month-old boy underwent Glenn and Damus-Kaye-Stansel procedures. The energy loss depends on the left ventricular preload; therefore, energy loss decreased after the Glenn procedure. After the Damus-Kaye-Stansel procedure, the kinetic energy would increase owing to the integrated systemic outflow; however, in our case, kinetic energy decreased, which was potentially explained by the fact that kinetic energy also depends on the left ventricular preload. After the Glenn and Damus-Kaye-Stansel procedures, we detected an improvement in energetic performance index, indicating that the cardiac workload improved as well. Conclusion We revealed the efficiency of the Glenn and Damus-Kaye-Stansel procedures using vector flow mapping.

Gellular automata are cellular automata with the properties of asynchrony, Boolean totality, and non-camouflage. In distributed computing, it is essential to determine whether problems can be solved by self-stable gellular automata. From any initial configuration, self-stable gellular automata converge to desired configurations, as self-stability implies the ability to recover from temporary malfunctions in transitions or states. In this paper, we show that three typical problems in distributed computing, namely, solving a maze, distance-2 coloring, and spanning tree construction, can be solved with self-stable gellular automata.

Chemoattractant sensing, adhesiveness, and migration are critical events underlying the recruitment of neutrophils (PMNs) to sites of inflammation or infection. Defects in leukocyte adhesion or migration result in immunodeficiency disorders characterized by recurrent infections. In this study, we evaluated the role of Arf6 on PMN adhesion in vitro and on migration to inflammatory sites using PMN-Arf6 conditional knockout (cKO) mice. In PMN-like PLB-985 silenced for Arf6 fMLP-mediated adhesion to the β2 integrin ligands, ICAM-1 and fibrinogen or the β1/β2 integrin ligand fibronectin was significantly reduced. Furthermore, overexpression of wild-type Arf6 promoted basal and fMLP-induced adhesion to immobilized integrin ligands, while overexpression of the dominant-negative Arf6 has the opposite effects. Using the Elane-Cre deleting mouse strains, we report that the level of Arf6 deletion in inflammatory PMNs isolated from the dorsal air pouches was stronger when compared to naïve cells isolated from the bone marrow. In PMN-Arf6 cKO mice, the recruitment of PMNs into the dorsal air pouch injected with LPS or the chemoattractant fMLP was significantly diminished. Impaired cell migration correlated with reduced cell surface expression of CD11a and CD11b in Arf6 cKO PMNs. Our results highlight that Arf6 regulates the activity and possibly the recycling of PMN integrins, and this compromises PMN migration to inflammatory sites.

2018年度からは教育・人間科学講座発行

Two major phospholipase D (PLD) isozymes in mammals, PLD1 and PLD2, hydrolyze the membrane phospholipid phosphatidylcholine to choline and the lipid messenger phosphatidic acid. Although their roles in cancer cells have been well studied, their functions in tumor microenvironment have not yet been clarified. Here, we demonstrate that PLD2 in cytotoxic CD8+ T cells plays a crucial role in anti-tumor immunity by regulating their cell proliferation. We found that growth of tumors formed by subcutaneously transplanted cancer cells is enhanced in Pld2-knockout mice. Interestingly, this phenotype was found to be at least in part attributable to the ablation of Pld2 from bone marrow cells. The number of CD8+ T cells, which induce cancer cell death, significantly decreased in the tumor produced in Pld2-knockout mice. In addition, CD3/CD28-stimulated proliferation of primary cultured splenic CD8+ T cells is markedly suppressed by Pld2 ablation. Finally, CD3/CD28-dependent activation of Erk1/2 and Ras is inhibited in Pld2-deleted CD8+ T cells. Collectively, these results indicate that PLD2 in CD8+ T cells plays a key role in their proliferation through activation of the Ras/Erk signaling pathway, thereby regulating anti-tumor immunity.

Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.

Gears used in actuators for robot articulations are showing a trend toward having smaller modules. Thus, profile measurements of small module gears are strongly desired. Our aim was to develop a probe artifact that enables ultra-fine-pitch cylindrical gears to be measured, by minimizing the size of the probe head. The configurations of the contact-type probe and holder were designed under consideration of interference with an adjacent tooth during profile measurements of an objective tooth. After manufacturing the artifact, a 0.1-module spur gear was measured as a trial, and reasonable results were obtained. In addition, a calibration plate for roughness was measured using the developed probe artifact. The evaluated roughness showed a strong correlation with the “true roughness”. Therefore, the developed probe can be expected to enable “pseudo” roughness to be evaluated.

研究グループは、パラアスリートの栄養に関する知識や理想とする食事の実現ができているか等の食行動上の課題を明らかにするため、国際大会および国体出場レベルかつ肢体不自由を伴うパラアスリート32名に、栄養知識や食行動、ボディイメージ(自分自身が無意識に持っている「自分の身体」についてのイメージ)等をアンケート形式で調査しました。その結果、対象の約4割が食材の調達や調理に介助を必要としており、自力ではパラアスリート自身が理想としている食事の実現が難しいことがわかりました。また、良いボディイメージを持っているパラアスリートほど自身の食習慣を健康的であると評価していましたが、実際には栄養知識について問う設問の正答率は低く、「体調が良い」「身体に異常がない」といった主観的感覚をもとに自分の食事量を「適切」と判断していることがわかりました。さらに、パラアスリートが栄養に関する知識を得る手段として、栄養士を挙げた例は極めて少なく、スポーツ栄養の正しい知識を持っている栄養士との接点がほとんどないのが実態であると思われました。本研究によってパラアスリートに対する栄養知識の教育や、食行動におけるサポート体制の必要性が明らかになりました。今後、このような対処に関わる研究の蓄積によって、より効果的な栄養サポート方法の開発に貢献することが期待されます。, Limited information exists on dietary practices in para-athletes. The aim of this study was to clarify the actual situation of para-athletes' dietary practice and to sort out the factors (i.e., eating perception, nutrition knowledge, and body image), that may hinder their dietary practices, and explored the practical challenges in nutritional support and improving nutrition knowledge for para-athletes. Thirty-two Japanese para-athletes (22 men) and 45 collegiate student athletes without disabilities (27 men) participated in the online survey. The questionnaire included demographic characteristics, eating perception, dietary practices, and nutrition knowledge. The Japanese version of the body appreciation scale was used to determine their body image. Para-athletes who answered that they knew their ideal amount and way of eating showed significantly higher body image scores (r = 0.604, p < 0.001). However, mean score for nutrition knowledge of para-athletes were significantly lower than collegiate student athletes (19.4 ± 6.8 vs. 24.2 ± 6.1 points, p = 0.001). Both groups did not identify a dietitian as the source of nutrition information or receiving their nutrition advice. The results indicate para-athletes have unique eating perceptions and inadequate nutrition knowledge. Future interventions are needed to examine nutritional supports and education in relation to the role of dietitians.