Synthetic and biochemical studies on the effect of persulfidation on disulfide dimer models of amyloid β42 at position 35 in Alzheimer's etiology

Protein persulfidation plays a role in redox signaling as an anti-oxidant. Dimers of amyloid β42 (Aβ42), which induces oxidative stress-associated neurotoxicity as a causative agent of Alzheimer's disease (AD), are minimum units of oligomers in AD pathology. Met35 can be susceptible to persulfidation through its substitution to homoCys residue under the condition of oxidative stress. In order to verify whether persulfidation has an effect in AD, herein we report a chemical approach by synthesizing disulfide dimers of Aβ42 and their evaluation of biochemical properties. A homoCys-disulfide dimer model at position 35 of Aβ42 formed a partial β-sheet structure, but its neurotoxicity was much weaker than that of the corresponding monomer. In contrast, the congener with an alkyl linker generated β-sheet-rich 8–16-mer oligomers with potent neurotoxicity. The length of protofibrils generated from the homoCys-disulfide dimer model was shorter than that of its congener with an alkyl linker. Therefore, the current data do not support the involvement of Aβ42 persulfidation in Alzheimer's disease

Development of pericardial fat count images using a combination of three different deep-learning models

Rationale and Objectives: Pericardial fat (PF), the thoracic visceral fat surrounding the heart, promotes the development of coronary artery disease by inducing inflammation of the coronary arteries. For evaluating PF, this study aimed to generate pericardial fat count images (PFCIs) from chest radiographs (CXRs) using a dedicated deep-learning model. Materials and Methods: The data of 269 consecutive patients who underwent coronary computed tomography (CT) were reviewed. Patients with metal implants, pleural effusion, history of thoracic surgery, or that of malignancy were excluded. Thus, the data of 191 patients were used. PFCIs were generated from the projection of three-dimensional CT images, where fat accumulation was represented by a high pixel value. Three different deep-learning models, including CycleGAN, were combined in the proposed method to generate PFCIs from CXRs. A single CycleGAN-based model was used to generate PFCIs from CXRs for comparison with the proposed method. To evaluate the image quality of the generated PFCIs, structural similarity index measure (SSIM), mean squared error (MSE), and mean absolute error (MAE) of (i) the PFCI generated using the proposed method and (ii) the PFCI generated using the single model were compared. Results: The mean SSIM, MSE, and MAE were as follows: 0.856, 0.0128, and 0.0357, respectively, for the proposed model; and 0.762, 0.0198, and 0.0504, respectively, for the single CycleGAN-based model. Conclusion: PFCIs generated from CXRs with the proposed model showed better performance than those with the single model. PFCI evaluation without CT may be possible with the proposed method

Evaluation of oral immunotherapy efficacy and safety by maintenance dose dependency: A multicenter randomized study

Background Generally, oral immunotherapy (OIT) aims for daily administration. Recently, the efficacy of treatment with OIT at a low dose has been reported. However, the optimal dose and the evaluation of dose-dependent OIT outcome have not been described. Methods A multicenter, parallel, open-labeled, prospective, non-placebo controlled, randomized study enrolled 101 Japanese patients for treatment with OIT. We hypothesized that target dose OIT would induce short-term unresponsiveness (StU) earlier than reduced dose OIT. StU was defined as no response to 6200 mg whole egg, 3400 mg milk, and 2600 mg wheat protein, as evaluated by oral food challenge after 2-week ingestion cessation. To compare the two doses of OIT efficacy, the maximum ingestion doses during the maintenance phase of OIT were divided into 100%-dose or 25%-dose groups against their target StU dose, respectively. A total of 51 patients were assigned to the 100%-dose group [hen's egg (HE) = 26, cow's milk (CM) = 13, wheat = 12] and 50 to the 25%-dose group (HE = 25, CM = 13, wheat = 12). Primary outcome was established by comparing StU at 1 year. Secondary outcome was StU at 2 years and established by comparing allergic symptoms and immunological changes. Results The year 1 StU rates (%) for the 100%- and 25%-dose groups were 26.9 vs. 20.0 (HE), 7.7 vs. 15.4 (CM), and 50.0 vs. 16.7 (wheat), respectively. The year 2 StU rates were 30.8 vs. 36.0 (HE), 7.7 vs. 23.1 (CM), and 58.3 vs. 58.3 (wheat), respectively. There were no statistically significant differences in StU between years 1 and 2. The total allergic symptom rate in the 25%-dose group was lower than that in the 100%-dose group for egg, milk, and wheat. Antigen-specific IgE levels for egg-white, milk, and wheat decreased at 12 months. Conclusions Reduced maintenance dose of egg OIT showed similar therapeutic efficacy to the target dose. However, we were not able to clearly demonstrate the efficacy, particularly for milk and wheat. Reducing the maintenance dose for eggs, milk, and wheat may effectively lower the symptoms associated with their consumption compared to the target OIT dose. Furthermore, aggressive reduction of the maintenance dose might be important for milk and wheat, compared to the 25%-dose OIT

Stat3 is indispensable for damage-induced crypt regeneration but not for Wnt-driven intestinal tumorigenesis.

金沢大学ナノ生命科学研究所Signal transducer and activator of transcription 3 (Stat3) has been shown to play a role in intestinal regeneration and colitis-associated colon carcinogenesis. However, the role of Stat3 in the Wnt-driven sporadic intestinal tumorigenesis remains poorly understood. We examined the roles of Stat3 in intestinal regeneration and tumorigenesis by organoid culture experiments using Stat3∆IEC mouse-derived intestinal epithelial cells in which Stat3 was disrupted. The regeneration of intestinal mucosa and organoid formation were significantly suppressed by Stat3 disruption, which was compensated by Wnt activation. Furthermore, once organoids were recovered, Stat3 was no longer required for organoid growth. These results indicate that Stat3 and Wnt signaling cooperatively protect epithelial cells at the early phase of intestinal regeneration. In contrast, intestinal tumorigenesis was not suppressed by Stat3 disruption in adenomatous polyposis coli ( Apc) Δ716 and Apc∆716 Tgfbr2∆IEC mice, thus indicating that Stat3 is not required for Wnt activation-driven intestinal tumorigenesis. Mechanistically, Itga5 and Itga6 were down-regulated by Stat3 disruption, and focal adhesion kinase (FAK) activation was also suppressed. Notably, FAK inhibitor suppressed the organoid formation of wild-type epithelial cells. These results indicate that Stat3 is indispensable for the survival of epithelial cells through the activation of integrin signaling and the downstream FAK pathway; however, it is not required for the Wnt signaling-activated normal or tumor epithelial cells.-Oshima, H., Kok, S.-Y., Nakayama, M., Murakami, K., Voon, D. C.-C., Kimura, T., Oshima, M. Stat3 is indispensable for damage-induced crypt regeneration but not for Wnt-driven intestinal tumorigenesis

Diminished Medial Prefrontal Activity behind Autistic Social Judgments of Incongruent Information

Individuals with autism spectrum disorders (ASD) tend to make inadequate social judgments, particularly when the nonverbal and verbal emotional expressions of other people are incongruent. Although previous behavioral studies have suggested that ASD individuals have difficulty in using nonverbal cues when presented with incongruent verbal-nonverbal information, the neural mechanisms underlying this symptom of ASD remain unclear. In the present functional magnetic resonance imaging study, we compared brain activity in 15 non-medicated adult males with high-functioning ASD to that of 17 age-, parental-background-, socioeconomic-, and intelligence-quotient-matched typically-developed (TD) male participants. Brain activity was measured while each participant made friend or foe judgments of realistic movies in which professional actors spoke with conflicting nonverbal facial expressions and voice prosody. We found that the ASD group made significantly less judgments primarily based on the nonverbal information than the TD group, and they exhibited significantly less brain activity in the right inferior frontal gyrus, bilateral anterior insula, anterior cingulate cortex/ventral medial prefrontal cortex (ACC/vmPFC), and dorsal medial prefrontal cortex (dmPFC) than the TD group. Among these five regions, the ACC/vmPFC and dmPFC were most involved in nonverbal-information-biased judgments in the TD group. Furthermore, the degree of decrease of the brain activity in these two brain regions predicted the severity of autistic communication deficits. The findings indicate that diminished activity in the ACC/vmPFC and dmPFC underlies the impaired abilities of individuals with ASD to use nonverbal content when making judgments regarding other people based on incongruent social information

Automatic classification between COVID-19 pneumonia, non-COVID-19 pneumonia, and the healthy on chest X-ray image: combination of data augmentation methods

This study aimed to develop and validate computer-aided diagnosis (CXDx) system for classification between COVID-19 pneumonia, non-COVID-19 pneumonia, and the healthy on chest X-ray (CXR) images. From two public datasets, 1248 CXR images were obtained, which included 215, 533, and 500 CXR images of COVID-19 pneumonia patients, non-COVID-19 pneumonia patients, and the healthy samples, respectively. The proposed CADx system utilized VGG16 as a pre-trained model and combination of conventional method and mixup as data augmentation methods. Other types of pre-trained models were compared with the VGG16-based model. Single type or no data augmentation methods were also evaluated. Splitting of training/validation/test sets was used when building and evaluating the CADx system. Three-category accuracy was evaluated for test set with 125 CXR images. The three-category accuracy of the CAD system was 83.6% between COVID-19 pneumonia, non-COVID-19 pneumonia, and the healthy. Sensitivity for COVID-19 pneumonia was more than 90%. The combination of conventional method and mixup was more useful than single type or no data augmentation method. In conclusion, this study was able to create an accurate CADx system for the 3-category classification. Source code of our CADx system is available as open source for COVID-19 research

A Research about Education Technique for a Learning of Coordinates in Junior High School Home Economics Field : Through the Evaluation Activities for Analyzing the Clothing life by self and the other person

中学校「技術・家庭」家庭分野における着装学習に関する効果的な指導方法について, 授業での学習内容を生かして着装できるようになることを目的に, 検討を行った。まず自己の衣生活を見つめ, 日常の着装行動を自己と他者から評価することを長期休暇の課題とした。また本時では, 色彩に着目しパーソナルカラーを探る活動を行い, 着装学習とその評価活動に関する指導方法に検討を加え, 実践し, その効果を検証した。さらにこれらの評価活動の有用性についても検討した。実践は, 広島大学附属三原中学校の3年生を対象に, 2009年12月に行った。 日常生活の着装行動について評価活動を取り入れた結果, 生徒自身が個々の衣生活を多面的にとらえ, 衣服や着装に対する関心が高まった。デザイン, 色彩, 素材を, TPOに応じて適性を考慮しながら衣服選択していることを, 自己評価を通じて認識するなかで, 生活知と学校知の結びつきが行われていることが明らかとなった。これより, 色のみでなく複合的な着装のあり方を学習できる実践方法として, 自己と他者による評価活動が有効であることが示唆された。今後は被服製作活動への展開を試み, 評価活動との関係性を検討することが課題である