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8. Diminished Neuronal ESCRT-0 Function Exacerbates AMPA Receptor Derangement and Accelerates Prion-Induced Neurodegeneration

Author

Lawrence, Jessica A, Aguilar-Calvo, Patricia, Ojeda-Juárez, Daniel, Khuu, Helen, Soldau, Katrin, Pizzo, Donald P, Wang, Jin, Malik, Adela, Shay, Timothy F, Sullivan, Erin E, Aulston, Brent, Song, Seung Min, Callender, Julia A, Sanchez, Henry, Geschwind, Michael D, Roy, Subhojit, Rissman, Robert A, Trejo, JoAnn, Tanaka, Nobuyuki, Wu, Chengbiao, Chen, Xu, Patrick, Gentry N, and Sigurdson, Christina J

Subjects
Biomedical and Clinical Sciences, Neurosciences, Acquired Cognitive Impairment, Dementia, Emerging Infectious Diseases, Neurodegenerative, Rare Diseases, Transmissible Spongiform Encephalopathy (TSE), Infectious Diseases, Aging, Brain Disorders, 2.1 Biological and endogenous factors, Neurological, Male, Female, Mice, Humans, Animals, Prions, Prion Proteins, Receptors, AMPA, Neurons, Prion Diseases, Neurodegenerative Diseases, Endosomal Sorting Complexes Required for Transport, amyloid, ESCRT, neurodegeneration, proteostasis, synapse, ubiquitin, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicity in vivo, we prion-challenged conditional knockout mice (male and female) having Hrs deleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrPC, which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prion-affected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration.SIGNIFICANCE STATEMENT Prion diseases are rapidly progressive neurodegenerative disorders characterized by prion aggregate spread through the central nervous system. Early disease features include ubiquitinated protein accumulation and synapse loss. Here, we investigate how prion aggregates alter ubiquitinated protein clearance pathways (ESCRT) in mouse and human prion-infected brain, discovering a marked reduction in Hrs. Using a prion-infection mouse model with neuronal Hrs (nHrs) depleted, we show that low neuronal Hrs is detrimental and markedly shortens survival time while accelerating synaptic derangements, including ubiquitinated protein accumulation, indicating that Hrs loss exacerbates prion disease progression. Additionally, Hrs depletion increases the surface distribution of prion protein (PrPC), linked to aggregate-induced neurotoxic signaling, suggesting that Hrs loss in prion disease accelerates disease through enhancing PrPC-mediated neurotoxic signaling.

Published
2023

10. Integrating a Manual Pipette into a Collaborative Robot Manipulator for Flexible Liquid Dispensing

Author

Zhang, Junbo, Wan, Weiwei, Tanaka, Nobuyuki, Fujita, Miki, and Harada, Kensuke

Subjects
Computer Science - Robotics
Abstract

This paper presents a system integration approach for a 6-DoF (Degree of Freedom) collaborative robot to operate a pipette for liquid dispensing. Its technical development is threefold. First, we designed an end-effector for holding and triggering manual pipettes. Second, we took advantage of a collaborative robot to recognize labware poses and planned robotic motion based on the recognized poses. Third, we developed vision-based classifiers to predict and correct positioning errors and thus precisely attached pipettes to disposable tips. Through experiments and analysis, we confirmed that the developed system, especially the planning and visual recognition methods, could help secure high-precision and flexible liquid dispensing. The developed system is suitable for low-frequency, high-repetition biochemical liquid dispensing tasks. We expect it to promote the deployment of collaborative robots for laboratory automation and thus improve the experimental efficiency without significantly customizing a laboratory environment.

Published
2022

11. What's Next? Lessons on Education Recovery: Findings from a Survey of Ministries of Education amid the COVID-19 Pandemic

Author

United Nations Educational, Scientific, and Cultural Organization (UNESCO), Institute for Statistics (UIS) (Canada), UNICEF Office of Research – Innocenti (Italy), United Nations Children's Fund (UNICEF), World Bank, Organisation for Economic Cooperation and Development (OECD) (France), Chang, Gwang-Chol, Eck, Matthias, McOmish, Elspeth, Sass, Justine, Vargas Tamez, Carlos, Wallet, Peter, Imhof, Adolfo Gustavo, Montoya, Silvia, Li, Yifan, Antoninis, Manos, Murakami, Yuki, Zekrya, Lema, Dewan, Pragya, Mishra, Sakshi, Mizunoya, Suguru, Onam, Oscar, Reuge, Nicolas, Yao, Haogen, Yameogo, Jean Luc, Brossard, Matt, Dreesen, Thomas, Dsouza, Andrea, Jeon, Youngkwang, Kamei, Akito, Nagesh, Radhika, Nugroho, Anindita, Pontuschka, Rafael, Akmal, Maryam, Azevedo, João Pedro, Azzi-Huck, Kaliope, Cobo, Cristobal, Gilberto, Alison, Holla, Alaka, Shmis, Tigran, Tanaka, Nobuyuki, Wong, Yi Ning, Carvalho, António, Charbonnier, Eric, Doumet, Marie-Hélène, and Heckmann, Corinne

Abstract

United Nations Educational, Scientific and Cultural Organization (UNESCO), the United Nations Children's Fund (UNICEF), the World Bank and the Organisation for Economic Co-operation and Development (OECD) have collaborated in the third round of the Survey on National Education Responses to COVID-19 School Closures, administered by the UNESCO Institute for Statistics (UIS) and OECD to Ministry of Education officials. The questions covered four levels of education: preprimary, primary, lower secondary and upper secondary. While the first two rounds of the survey were implemented during the periods May-June and July-October 2020, respectively, the third round was implemented during the period February-June 2021. In total, 143 countries responded to the questionnaire. Thirty-one countries submitted responses to the OECD ("OECD survey") and 112 countries responded to the UIS ("UIS survey"). Seven countries responded to both surveys. In these instances, the more complete set responses were used in analysis.

Published
2021

26. Call for emergency action to restore dietary diversity and protect global food systems in times of COVID-19 and beyond: Results from a cross-sectional study in 38 countries

Author

Bergheim, Ina, Staltner, Raphaela, Devine, Amanda, Sambell, Ros, Wallace, Ruth, Allehdan, Sabika Salem, Alalwan, Tariq Abdulkarim, Al-Mannai, Mariam Ahamad, Ouvrein, Gaëlle, Poels, Karolien, Vandebosch, Heidi, Maldoy, Katrien, Matthys, Christophe, Smits, Tim, Vrinten, Jules, DeSmet, Ann, Teughels, Nelleke, Geuens, Maggie, Vermeir, Iris, Proesmans, Viktor, Hudders, Liselot, De Barcellos, Marcia Dutra, Ostermann, Cristina, Brock, Ana Luiza, Favieiro, Cynthia, Trizotto, Rafaela, Stangherlin, Isadora, Mafra, Anthonieta Looman, Correa Varella, Marco Antônio, Valentova, Jaroslava Varella, Fisher, Maryanne L., MacEacheron, Melanie, White, Katherine, Habib, Rishad, Dobson, David S., Schnettler, Berta, Orellana, Ligia, Miranda-Zapata, Edgardo, Wen-Yu Chang, Angela, Jiao, Wen, Liu, Matthew Tingchi, Grunert, Klaus G., Christensen, Rikke Nyland, Reisch, Lucia, Janssen, Meike, Abril-Ulloa, Victoria, Encalada, Lorena, Kamel, Iman, Vainio, Annukka, Niva, Mari, Salmivaara, Laura, Mäkelä, Johanna, Torkkeli, Kaisa, Mai, Robert, Risch, Pamela Kerschke, Altsitsiadis, Efthymios, Stamos, Angelos, Antronikidis, Andreas, Henchion, Maeve, McCarthy, Sinead, McCarthy, Mary, Micalizzi, Alessandra, Schulz, Peter J., Farinosi, Manuela, Komatsu, Hidenori, Tanaka, Nobuyuki, Kubota, Hiromi, Tayyem, Reema, Al-Awwad, Narmeen J., Al-Bayyari, Nahla, Ibrahim, Mohammed O., Hammouh, Fadwa, Dashti, Somaia, Dashti, Basma, Alkharaif, Dhuha, Alshatti, Amani, Al Mazedi, Maryam, Mansour, Rania, Naim, Elissa, Mortada, Hussein, Gutierrez Gomez, Yareni Yunuen, Geyskens, Kelly, Goukens, Caroline, Roy, Rajshri, Egli, Victoria, Morenga, Lisa Te, Waly, Mostafa, Qasrawi, Radwan, Hamdan, Motasem, Sier, Rania Abu, Al Halawa, Diala Abu, Agha, Hazem, Liria Domínguez, María Reyna, Palomares, Lita, Wasowicz, Grazyna, Bawadi, Hiba, Othman, Manal, Pakari, Jaafar, Farha, Allam Abu, Abu-El-Ruz, Rasha, Petrescu, Dacinia Crina, Petrescu Mag, Ruxandra Malina, Arion, Felix, Vesa, Stefan Cristian, Alkhalaf, Majid M., Bookari, Khlood, Arrish, Jamila, Rahim, Zackaria, Kheng, Roy, Ngqangashe, Yandisa, June-Rose Mchiza, Zandile, Gonzalez-Gross, Marcela, Pantoja-Arévalo, Lisset, Gesteiro, Eva, Ríos, Yolanda, Yiga, Peter, Ogwok, Patrick, Ocen, Denis, Bamuwamye, Michael, Al Sabbah, Haleama, Taha, Zainab, Ismail, Leila Cheikh, Aldhaheri, Ayesha, Pineda, Elisa, Miraldo, Marisa, Holford, Dawn Liu, Van den Bulck, Hilde, Hoteit, Maha, Hoteit, Reem, Aljawaldeh, Ayoub, Van Royen, Kathleen, Pabian, Sara, Decorte, Paulien, Cuykx, Isabelle, Teunissen, Lauranna, and De Backer, Charlotte

Published
2023
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38. Tumor immune microenvironment dynamics and outcomes of prognosis in non‐muscle‐invasive bladder cancer.

Author

Kamitani, Rei, Tanaka, Nobuyuki, Anno, Tadatsugu, Murakami, Tetsushi, Masuda, Tsukasa, Yasumizu, Yota, Takeda, Toshikazu, Morita, Shinya, Kosaka, Takeo, Mikami, Shuji, Matsumoto, Kazuhiro, and Oya, Mototsugu

Abstract

Agents that target PD‐1 and PD‐L1 have been developed in the treatment of bladder cancer (BC). However, the diversity of immune cell infiltration in non‐muscle‐invasive BC (NMIBC) and the dynamics of the microenvironment as it progresses to muscle‐invasive/metastatic disease remains unknown. To assess tumor immune activity, hierarchical clustering was applied to 159 BC samples based on cellular positivity for the defined immune cellular markers (CD3/CD4/CD8/FOXP3/CD20/PD‐1/PD‐L1/LAG3/TIGIT), divided into two clusters. There was a "hot cluster" (25%) consisting of patients with a high expression of these markers and a "cold cluster" (75%) comprising those without. The expression of CD39, CD44, CD68, CD163, IDO1, and Ki67 was significantly higher in tumors in the hot cluster. Immunologically, high‐grade T1 tumors were significantly hotter, whereas tumors that had progressed to muscle invasion turned cold. However, a certain number of high‐grade NMIBC patients were in the cold cluster, and these patients had a significantly higher risk of disease progression. Using an externally available TCGA dataset, RB1 and TP53 alterations were more frequently observed in TCGA hot cluster; rather FGFR3, KDM6A, and KMT2A alterations were common in TCGA cold/intermediate cluster. Analyses of recurrent tumors after BCG therapy revealed that tumor immune activity was widely maintained before and after treatment, and high FGFR3 expression was detected after recurrence in tumors initially classified into the cold cluster. Collectively, we revealed the dynamics of the tumor microenvironment in BC as a whole and identified candidate molecules as therapeutic targets for recurrent NMIBC, e.g., after BCG therapy. [ABSTRACT FROM AUTHOR]

Published
2024
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40. IMAGENE trial: multicenter, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy of niraparib with PD-1 inhibitor in solid cancer patients with homologous recombination repair genes mutation

Author

Kato, Taigo, Matsubara, Nobuaki, Shiota, Masaki, Eto, Masatoshi, Osawa, Takahiro, Abe, Takashige, Shinohara, Nobuo, Yasumizu, Yota, Tanaka, Nobuyuki, Oya, Mototsugu, Nishimoto, Koshiro, Hayashi, Takuji, Nakayama, Masashi, Kojima, Takahiro, Namikawa, Kenjiro, Fujisawa, Takao, Okano, Susumu, Hida, Eisuke, Nakamura, Yoshiaki, Bando, Hideaki, Yoshino, Takayuki, and Nonomura, Norio

Published
2022
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44. PD36-08 ARTIFICIAL INTELLIGENCE-BASED SURGICAL PHASE RECOGNITION IN ROBOT-ASSISTED RADICAL PROSTATECTOMY AND CROSS-SURGEON EXTERNAL VALIDITY VERIFICATION

Author

Konnai, Yuichiro, primary, Fukumoto, Keishiro, additional, Takeuchi, Masashi, additional, Tanigawa, Mio, additional, Takeuchi, Rei, additional, Yasumizu, Yota, additional, Tanaka, Nobuyuki, additional, Takeda, Toshikazu, additional, Matsumoto, Kazuhiro, additional, Morita, Shinya, additional, Kosaka, Takeo, additional, Mizuno, Ryuichi, additional, Asanuma, Hiroshi, additional, and Oya, Mototsugu, additional

Published
2024
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45. PD20-09 THREE-DIMENSIONAL IMAGING AND SPATIAL ANALYSIS OF INTACT TISSUE IMPROVE DIAGNOSTIC YIELD AND ACCURACY IN UPPER TRACT UROTHELIAL CARCINOMA DIAGNOSIS

Author

Fukumoto, Keishiro, primary, Yasumizu, Yota, additional, Tanaka, Nobuyuki, additional, Takeda, Toshikazu, additional, Matsumoto, Kazuhiro, additional, Morita, Shinya, additional, Kosaka, Takeo, additional, Mizuno, Ryuichi, additional, Asanuma, Hiroshi, additional, Uhlén, Per, additional, and Oya, Mototsugu, additional

Published
2024
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