Organoid technology provides a revolutionary paradigm toward therapy but has yet to be applied in humans, mainly because of reproducibility and scalability challenges. Here, we overcome these ...limitations by evolving a scalable organ bud production platform entirely from human induced pluripotent stem cells (iPSC). By conducting massive “reverse” screen experiments, we identified three progenitor populations that can effectively generate liver buds in a highly reproducible manner: hepatic endoderm, endothelium, and septum mesenchyme. Furthermore, we achieved human scalability by developing an omni-well-array culture platform for mass producing homogeneous and miniaturized liver buds on a clinically relevant large scale (>108). Vascularized and functional liver tissues generated entirely from iPSCs significantly improved subsequent hepatic functionalization potentiated by stage-matched developmental progenitor interactions, enabling functional rescue against acute liver failure via transplantation. Overall, our study provides a stringent manufacturing platform for multicellular organoid supply, thus facilitating clinical and pharmaceutical applications especially for the treatment of liver diseases through multi-industrial collaborations.
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•Development of a clinical-scale production platform for human liver bud organoids•Efficient differentiation into liver-bud-forming triple progenitors from human iPSCs•Self-organization into liver buds entirely from iPSCs, including HLA homozygous clones•Reproducible hepatic functionality and therapeutic effects for animal liver failure
With the goal of clinical translation of liver bud transplant therapy, Takebe et al. established a massive organoid production platform from endoderm, endothelial, and mesenchymal progenitor populations specified entirely from human iPSCs, reproducibly demonstrating functionality both in vitro and in vivo.
Status of the AMS system at Yamagata University Moriya, Toru; Takeyama, Mirei; Sakurai, Hirohisa ...
Nuclear instruments & methods in physics research. Section B, Beam interactions with materials and atoms,
01/2019, Letnik:
439
Journal Article
Recenzirano
An accelerator mass spectrometry (AMS) system and an automated graphitization line were installed at Yamagata University (YU) in 2009. Approximately 2000 samples are measured per year using the ...YU-AMS system. The long-term stability of the system was assessed by measuring the standard sample IAEA-C7 graphitized by the automated graphitization line. In March 2014, a second automated graphitization line and an additional ion source for the YU-AMS system were installed to meet the requirement of 14C measurement for pharmacological and medical applications. A phosphoric acid treatment system was also developed for the radiocarbon dating of calcium carbonate (CaCO3) in shell and coral samples. Performance tests on the new YU-AMS system were carried out by measuring the C-series standard samples (C1-C9) and oxalic acid II (HOxII) obtained from IAEA and NIST, respectively. The results of the 14C concentration pMC are in good agreement with the consensus values. Performance tests for medical applications were also carried out by measuring the 14C concentration of 14C-glucose in human plasma.
Hardware Trojans (HTs) have become a serious problem, and extermination of them is strongly required for enhancing the security and safety of integrated circuits. An effective solution is to identify ...HTs at the gate level via machine learning techniques. However, machine learning has specific vulnerabilities, such as adversarial examples . In reality, it has been reported that adversarial modified HTs greatly degrade the performance of a machine learning-based HT detection method. Therefore, we propose a robust HT detection method using adversarial training ( R-HTDetector ). We formally describe the robustness of R-HTDetector in modifying HTs. Our work gives the world-first adversarial training for HT detection with theoretical backgrounds. We show through experiments with Trust-HUB benchmarks that R-HTDetector overcomes adversarial examples while maintaining its original accuracy.
The absolute configurations at five chiral centers, except for C-32(
S) reported previously, in iejimalides A, C, and D, potent cytotoxic 24-membered macrolides isolated from a tunicate
Eudistoma cf.
...rigida, were assigned as 4
R, 9
S, 17
S, 22
S, and 23
S on the basis of detailed analysis of NMR data and chemical means. Furthermore, the structures proposed for iejimalides A, C, and D were revised to their 13
Z-isomers. Iejimalides A–D (
1–
4) exhibited antitumor activity in vivo.
Guanfacine is used for the treatment of attention‐deficit/hyperactivity disorder (ADHD). Using liquid chromatography–tandem mass spectrometry (LC–MS/MS), metabolite profiling of guanfacine was ...performed in plasma and urine collected from healthy Japanese adults following repeated oral administration of guanfacine extended‐release formulation. Unchanged guanfacine was the most abundant component in both plasma and urine (from the MS signal intensity). In plasma, the M3 metabolite (a sulfate of hydroxy‐guanfacine) was the prominent metabolite; the M2 metabolite (a glucuronide of a metabolite formed by monooxidation of guanfacine), 3‐hydroxyguanfacine and several types of glucuronide at different positions on guanfacine were also detected. In urine, the M2 metabolite and 3‐hydroxyguanfacine were the principal metabolites. From metabolite analysis, the proposed main metabolic pathway of guanfacine is monooxidation on the dichlorobenzyl moiety, followed by glucuronidation or sulfation. A minor pathway is glucuronidation at different positions on guanfacine. As the prominent metabolites in plasma were glucuronide and sulfate of hydroxyguanfacine, which have no associated toxicity concerns, further toxicity studies of the metabolites, for example in animals, were not deemed necessary.
An offset-free, wavelength-tunable, and midinfrared frequency comb working at 184 MHz based on difference frequency generation (DFG) in a PPMgSLT crystal was demonstrated. A coherent Raman soliton ...pulse and Yb-fiber laser output were used as the seed pulses of DFG, and wavelength tunability in the range 3.1-5.2 μm was realized. A quantum cascade laser stabilized by the absorption line of N 2 O was used to measure the beat signal with an MIR comb. The MIR comb had a good spatial beam profile, and a high signal-to-noise ratio (SNR) of 70 dB at a wavelength of 4.52 μm was confirmed. A stable and sharp beat signal was observed in the MIR region with a linewidth of 160 kHz, and the SNR was larger than 20 dB.
3'-Hydroxy-4'-methoxydiclofenac (VI) is a human-specific metabolite known to accumulate in the plasma of patients after repeated administration of diclofenac sodium. Diclofenac also produces ...glutathione-conjugated metabolites, some of which are human-specific. In the present study, we investigated whether these metabolites could be generated in humanized chimeric mice produced from TK-NOG mice. After a single oral administration of diclofenac to humanized mice, the unchanged drug in plasma peaked at 0.25 hour and then declined with a half-life (t1/2) of 2.4 hours. 4'-Hydroxydiclofenac (II) and 3'-hydroxydiclofenac also peaked at 0.25 hour and were undetectable within 24 hours. However, VI peaked at 8 hours and declined with a t1/2 of 13 hours. When diclofenac was given once per day, peak and trough levels of VI reached plateau within 3 days. Studies with administration of II suggested VI was generated via II as an intermediate. Among six reported glutathione-conjugated metabolites of diclofenac, M1 (5-hydroxy-4-(glutathion-S-yl)diclofenac) to M6 (2'-(glutathion-S-yl)monoclofenac), we found three dichlorinated conjugates M1, M2 (4'-hydroxy-3'-(glutathion-S-yl)diclofenac), and M3 (5-hydroxy-6-(glutathion-S-yl)diclofenac), and a single monochlorinated conjugate M4 (2'-hydroxy-3'-(glutathion-S-yl)monoclofenac) or M5 (4'-hydroxy-2'-(glutathion-S-yl)monoclofenac), in the bile of humanized chimeric mice. M4 and M5 are positional isomers and have been previously reported as human-specific in vitro metabolites likely generated via arene oxide and quinone imine-type intermediates, respectively. The biliary monochlorinated metabolite exhibited the same mass spectrum as those of M4 and M5, and we discuss whether this conjugate corresponded to M4 or M5. Overall, humanized TK-NOG chimeric mice were considered to be a functional tool for the study of drug metabolism of diclofenac in humans.
Recently, the great demand for integrated circuits (ICs) drives third parties to be involved in IC design and manufacturing steps. At the same time, the threat of injecting a malicious circuit, ...called a hardware Trojan, by third parties has been increasing. Machine learning is one of the powerful solutions for detecting hardware Trojans. However, a weakness of such a machine-learning-based classification method against adversarial examples (AEs) has been reported, which causes misclassification by adding perturbation in input samples. This paper firstly proposes a framework generating adversarial examples for hardware-Trojan detection at gate-level netlists utilizing neural networks. The proposed framework replaces hardware Trojan circuits with logically equivalent ones, and makes it difficult to detect them. Secondly, we propose a Trojan-net concealment degree (TCD) and a modification evaluating value (MEV) as measures of the amount of modifications. Finally, based on the MEV, we pick up adversarial modification patterns to apply to the circuits against hardware-Trojan detection. The experimental results using benchmarks demonstrate that the proposed framework successfully decreases the true positive rate (TPR) by a maximum of 30.15 points.
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