Hybrid dynamic/static method for large-scale simulation of metabolism

BACKGROUND: Many computer studies have employed either dynamic simulation or metabolic flux analysis (MFA) to predict the behaviour of biochemical pathways. Dynamic simulation determines the time evolution of pathway properties in response to environmental changes, whereas MFA provides only a snapshot of pathway properties within a particular set of environmental conditions. However, owing to the large amount of kinetic data required for dynamic simulation, MFA, which requires less information, has been used to manipulate large-scale pathways to determine metabolic outcomes. RESULTS: Here we describe a simulation method based on cooperation between kinetics-based dynamic models and MFA-based static models. This hybrid method enables quasi-dynamic simulations of large-scale metabolic pathways, while drastically reducing the number of kinetics assays needed for dynamic simulations. The dynamic behaviour of metabolic pathways predicted by our method is almost identical to that determined by dynamic kinetic simulation. CONCLUSION: The discrepancies between the dynamic and the hybrid models were sufficiently small to prove that an MFA-based static module is capable of performing dynamic simulations as accurately as kinetic models. Our hybrid method reduces the number of biochemical experiments required for dynamic models of large-scale metabolic pathways by replacing suitable enzyme reactions with a static module

A simplified method for power-law modelling of metabolic pathways from time-course data and steady-state flux profiles

BACKGROUND: In order to improve understanding of metabolic systems there have been attempts to construct S-system models from time courses. Conventionally, non-linear curve-fitting algorithms have been used for modelling, because of the non-linear properties of parameter estimation from time series. However, the huge iterative calculations required have hindered the development of large-scale metabolic pathway models. To solve this problem we propose a novel method involving power-law modelling of metabolic pathways from the Jacobian of the targeted system and the steady-state flux profiles by linearization of S-systems. RESULTS: The results of two case studies modelling a straight and a branched pathway, respectively, showed that our method reduced the number of unknown parameters needing to be estimated. The time-courses simulated by conventional kinetic models and those described by our method behaved similarly under a wide range of perturbations of metabolite concentrations. CONCLUSION: The proposed method reduces calculation complexity and facilitates the construction of large-scale S-system models of metabolic pathways, realizing a practical application of reverse engineering of dynamic simulation models from the Jacobian of the targeted system and steady-state flux profiles

Stable Iodine Distribution among Children after the 2011 Fukushima Nuclear Disaster in Japan: An Observational Study

福島第一原発事故後の安定ヨウ素剤配布後の実態調査を実施 --安定ヨウ素剤の情報提供・内服指示に関する課題が浮き彫りに--. 京都大学プレスリリース. 2019-01-10.Context: Intake of stable iodine helps prevent childhood thyroid cancer in nuclear emergencies but there is limited case information. Objective: We identified the intake rate and the factors associated with no intake among children who did not take stable iodine after the Fukushima disaster. Design: Retrospective observational study. Setting: Data were obtained from thyroid cancer screening performed in August–November 2017. Participants: Children in Miharu Town, Fukushima, Japan. Intervention: No intervention. Main Outcome Measures: We performed multilevel logistic regression analysis at the regional and individual levels. We qualitatively examined the reasons for no intake of stable iodine based on closed- and open-ended questions. Results: The rate of distribution was 94.9%, but the intake rate was only 63.5%. Intake was lower in those aged 0–2 years compared with those aged ≥3 years: odds ratio (OR), 0.21 [95% confidence interval (CI), 0.11–0.36]. Parents’ intake was positively associated with their children’s intake [OR, 61.0 (95% CI, 37.9–102.9)]. The variance partition coefficient for regions was 0.021, suggesting that the intake of stable iodine was more likely affected by individual than by regional factors. The main reasons for avoiding intake were concern about safety, issues related to distribution, drug information sharing, and instructions for intake. There were no claimed adverse effects. Conclusions: The distribution and consumption of stable iodine occurred without claims of adverse effects after the Fukushima disaster. To prepare for future nuclear emergencies, it is important to explain to both children and parents the need for intake of stable iodine, particularly among young children

Subjective intelligibility of speech sounds enhanced by ideal ratio mask via crowdsourced remote experiments with effective data screening

It is essential to perform speech intelligibility (SI) experiments with human listeners to evaluate the effectiveness of objective intelligibility measures. Recently crowdsourced remote testing has become popular to collect a massive amount and variety of data with relatively small cost and in short time. However, careful data screening is essential for attaining reliable SI data. We compared the results of laboratory and crowdsourced remote experiments to establish an effective data screening technique. We evaluated the SI of noisy speech sounds enhanced by a single-channel ideal ratio mask (IRM) and multi-channel mask-based beamformers. The results demonstrated that the SI scores were improved by these enhancement methods. In particular, the IRM-enhanced sounds were much better than the unprocessed and other enhanced sounds, indicating IRM enhancement may give the upper limit of speech enhancement performance. Moreover, tone pip tests, for which participants were asked to report the number of audible tone pips, reduced the variability of crowdsourced remote results so that the laboratory results became similar. Tone pip tests could be useful for future crowdsourced experiments because of their simplicity and effectiveness for data screening.Comment: This paper was submitted to Interspeech 2022 (http://www.interspeech2022.org

Hypotaurine is an Energy-Saving Hepatoprotective Compound against Ischemia-Reperfusion Injury of the Rat Liver

Metabolome analyses assisted by capillary electrophoresis-mass spectrometry (CE-MS) have allowed us to systematically grasp changes in small molecular metabolites under disease conditions. We applied CE-MS to mine out biomarkers in hepatic ischemia-reperfusion. Rat livers were exposed to ischemia by clamping of the portal inlet followed by reperfusion. Metabolomic profiling revealed that l contents of taurine in liver and plasma were significantly increased. Of interest is an elevation of hypotaurine, collectively suggesting significance of hypotaurine/taurine in post-ischemic responses. Considering the anti-oxidative capacity of hypotaurine, we examined if supplementation of the compound or its precursor amino acids could affect hepatocellular viability and contents of taurine in liver and plasma. Administration of hypotaurine, N-acetylcysteine or methionine upon reperfusion comparablly attenuated the post-ischemic hepatocellular injury but with different metabolomic profiling among groups: rats treated with methionine or N-acetylcysteine but not those treated with hypotaurine, exhibited significant elevation of hepatic lactate generation without notable recovery of the energy charge. Furthermore, the group treated with hypotaurine exhibited elevation of the plasma taurine, suggesting that the exogenously administered compound was utilized as an antioxidant. These results suggest that taurine serves as a surrogate marker for ischemia-reperfusion indicating effectiveness of hypotaurine as an energy-saving hepatoprotective amino acid

青年の選択的道徳不活性化の研究

本研究では，選択的道徳不活性化尺度を翻訳し，定時制高校で質問紙調査を行うことで，その信頼性と妥当性を検討することを目的とした。調査は，定時制高校の1～4年生12クラス260名の生徒を対象とした。選択的道徳不活性化尺度は探索的因子分析の結果，1因子25項目から構成された。また，選択的道徳不活性化尺度の25項目について十分な内的一貫性(α =.88)が認められた。さらに，同時に測定したいじめの態度尺度と学校での4つの攻撃経験との間に関連が示されたことから，本研究で一定の信頼性と妥当性が認められたと考えられる

N -Ethyl- N -Nitrosourea Induces Retinal Photoreceptor Damage in Adult Rats

Seven-week-old male Lewis rats received a single intraperitoneal injection of N-ethyl-N-nitrosourea (ENU) (100, 200, 400 or 600 mg/kg), and retinal damage was evaluated 7 days after the treatment. Sequential morphological features of the retina and retinal DNA damage, as determined by a TUNEL assay and phospho-histone H2A.X (γ-H2AX), were analyzed 3, 6, 12, 24 and 72 hr, 7 days, and/or 30 days after 400 mg/kg ENU treatment. Activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) was analyzed immunohistochemically by poly (ADP-ribose) (PAR) expression in response to DNA damage of the retina. All rats that received ≥ 400 mg/kg of ENU developed retinal degeneration characterized by the loss of photoreceptor cells in both the central and peripheral retina within 7 days. In the 400 mg/kg ENU-treated rats, TUNEL-positive signals were only located in the photoreceptor cells and peaked 24 hr after ENU treatment. The γ-H2AX signals in inner retinal cells appeared at 24 hr and peaked at 72 hr after ENU treatment, and the PAR signals selectively located in the photoreceptor cell nuclei appeared at 12 hr and peaked at 24 hr after ENU treatment. However, degeneration was restricted to photoreceptor cells, and no degenerative changes in inner retinal cells were seen at any time points. Retinal thickness and the photoreceptor cell ratio in the central and peripheral retina were significantly decreased, and the retinal damage ratio was significantly increased 7 days after ENU treatment. In conclusion, ENU induced retinal degeneration in adult rats that was characterized by photoreceptor cell apoptosis through PARP activity

Delayed Follow-up Visits and Thyrotropin Among Patients With Levothyroxine During the COVID-19 Pandemic

Context: The indirect effects of the COVID-19 pandemic on clinical practice have received great attention, but evidence regarding thyroid disease management is lacking. Objective: We aimed to investigate the association between delayed follow-up visits during the pandemic and their serum thyrotropin (TSH) levels among patients being treated with levothyroxine. Methods: This study included 25 361 patients who made a follow-up visit as scheduled (n = 9063) or a delayed follow-up visit ( 4.5 mIU/L, aRR [95% CI] = 1.72 [1.60-1.85]; and TSH > 10 mIU/L, aRR [95% CI] = 2.38 [2.16-2.62]). Conclusion: A delayed follow-up visit during the COVID-19 pandemic was associated with less well-controlled TSH among patients with levothyroxine