Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation

CDC42-C末端異常症に於ける炎症病態を解明 --ゴルジ体への異常蓄積がパイリンインフラマソーム形成を過剰促進--. 京都大学プレスリリース. 2022-05-02.Mutations in the C-terminal region of the CDC42 gene cause severe neonatal-onset autoinflammation. Effectiveness of IL-1β–blocking therapy indicates that the pathology involves abnormal inflammasome activation; however, the mechanism underlying autoinflammation remains to be elucidated. Using induced-pluripotent stem cells established from patients carrying CDC42[R186C], we found that patient-derived cells secreted larger amounts of IL-1β in response to pyrin-activating stimuli. Aberrant palmitoylation and localization of CDC42[R186C] protein to the Golgi apparatus promoted pyrin inflammasome assembly downstream of pyrin dephosphorylation. Aberrant subcellular localization was the common pathological feature shared by CDC42 C-terminal variants with inflammatory phenotypes, including CDC42[*192C*24] that also localizes to the Golgi apparatus. Furthermore, the level of pyrin inflammasome overactivation paralleled that of mutant protein accumulation in the Golgi apparatus, but not that of the mutant GTPase activity. These results reveal an unexpected association between CDC42 subcellular localization and pyrin inflammasome activation that could pave the way for elucidating the mechanism of pyrin inflammasome formation

Understanding Planetesimal Evolution: Bulk Chemistry, Petrology, and O-Isotope Studies of the Rumuruti Chondrite Group.

This thesis presents cosmochemical discoveries coupled with improvements of analytical techniques focused on deepening our understanding of the formation of rocky planetary bodies during the early evolution of the solar system. Chondrite meteorites and their components have been utilized to study the early stages of planetary body formation since they are thought to be samples of these bodies. Previous attempts to construct a comprehensive model for planetesimal evolution that explains cosmochemical signatures have relied on the well-known chondrite groups, such as ordinary and carbonaceous chondrites, that had been studied for over a hundred years. In this thesis, I primarily focused on studies of a relatively new and unstudied meteorite group, the Rumuruti (R) chondrites. The bulk chemistry, petrology and O-isotope studies presented in this thesis have revealed evidence that the chondrite parent object(s) are formed through chaotic accretionary processes. In addition to the studies of R chondrites detailed here, another study designed to further our understanding of the petrology of iron meteorite inclusions is presented. The main thesis findings include the following:The quantification of oxygen isotope SIMS matrix effects in olivine samples (from Mg-rich to Fe-rich) were investigated by using the UCLA CAMECA ims 1270 and 1290 instruments in order to improve the accuracy of in situ O-isotope measurements in geochemical/cosmochemical olivine samples. One of the main findings was that oxygen isotope SIMS matrix effects are reproducible. With this knowledge in hand, a model curve was developed that can be used for correcting observations of instrumental mass fractionation in olivine samples of intermediate chemical composition. The model curve was calibrated by utilizing data from SIMS analysis on a San Carlos olivine, which was chosen to be the primary standard in O-isotope studies in the R chondrite chondrules.R chondrite parent body evolutionary processes were explored by analyzing the bulk chemistry and petrology of R chondrites from petrologic types 3 to 6. I confirmed that R chondrites have a monolithic bulk composition and that R chondrites are closely related in terms of composition to ordinary chondrites. However, R-chondrite volatile abundances are much higher in comparison to those found in ordinary chondrites. And, it was found that metamorphosed R chondrites recorded different degrees of oxidation within their olivine and spinel components. These results suggest that local environment conditions on the parent asteroid were not uniform but instead were diverse. The oxygen isotope composition of different chondrite components in one of the least equilibrated R chondrites, PRE 95404, was examined in order to investigate the apparent heterogeneity, as evidenced just above, in the parent body formation conditions. The results show that the different chondrite components present in PRE95404 experienced a variety of metamorphic processes suggesting that material from different proto bodies were incorporated into the fine grain matrix before they were finally lithified in the R parent bodies. These results conflict with the conventional ordinary chondrite accretionary model, which starts from chondrule formations followed by immediate accretion yielding the chondritic asteroids that subsequently underwent in situ metamorphism. Instead, the thesis results support a model that the R chondrite parent body formed by accretion of pre-existing planetesimal materials. The studies presented in the thesis also clarify the relationships between the R chondrites and other chondrite groups.Lastly, a new a mineral, MnCr2S4, was discovered during an investigation of Cr-bearing inclusions found in iron meteorites. The new mineral has been given the name Joegoldsteinite

Psychometric Properties of the Japanese Version of the Parental Acceptance and Action Questionnaire in Parents with Infants and Toddlers

We aimed to examine the reliability and validity of the Parental Acceptance and Action Questionnaire-Japanese version (PAAQ-J). We considered a total of 2000 mothers with infants and toddlers aged 0–3 years and evaluated their scores on the PAAQ-J Acceptance and Action Questionnaire-II (AAQ-II) and Hospital Anxiety and Depression Scale (HADS). We conducted an exploratory factor analysis, creating a PAAQ-J with 12 items and three factors (α = 0.80): Inaction-Behavior, Inaction-Cognition, and Unwillingness, with α of 0.84, 0.72 and 0.68, respectively. The test-retest reliability examination results showed that the interclass correlation coefficient was 0.49, with 95% CI between 0.44 and 0.54. The correlation coefficient of PAAQ-J was 0.57, 0.32, and 0.33 with AAQ-II, and HADS-depression and HADS-anxiety, respectively. PAAQ-J’s validity to adequately evaluate an individual’s avoidance of experiences regarding childcare and their psychological flexibility was proven. Since the original PAAQ was for 6–18-year-old children with anxiety symptoms, it is necessary to examine its reliability and validity not only for infants and toddlers, but also for parents of older children and adolescents in the future

Joegoldsteinite: A new sulfide mineral (MnCr_2S_4) from the Social Circle IVA iron meteorite

Joegoldsteinite, a new sulfide mineral of end-member formula MnCr_2S_4, was discovered in the Social Circle IVA iron meteorite. It is a thiospinel, the Mn analog of daubréelite (Fe^(2+)Cr_2S_4), and a new member of the linnaeite group. Tiny grains of joegoldsteinite were also identified in the Indarch EH4 enstatite chondrite. The chemical composition of the Social Circle sample determined by electron microprobe is (wt%) S 44.3, Cr 36.2, Mn 15.8, Fe 4.5, Ni 0.09, Cu 0.08, total 101.0, giving rise to an empirical formula of (Mn_(0.82)Fe_(0.23))Cr_(1.99)S_(3.95). The crystal structure, determined by electron backscattered diffraction, is a Fd3m spinel-type structure with a = 10.11 Å, V = 1033.4 Å^3, and Z = 8

Joegoldsteinite: A new sulfide mineral (MnCr_2S_4) from the Social Circle IVA iron meteorite

Joegoldsteinite, a new sulfide mineral of end-member formula MnCr_2S_4, was discovered in the Social Circle IVA iron meteorite. It is a thiospinel, the Mn analog of daubréelite (Fe^(2+)Cr_2S_4), and a new member of the linnaeite group. Tiny grains of joegoldsteinite were also identified in the Indarch EH4 enstatite chondrite. The chemical composition of the Social Circle sample determined by electron microprobe is (wt%) S 44.3, Cr 36.2, Mn 15.8, Fe 4.5, Ni 0.09, Cu 0.08, total 101.0, giving rise to an empirical formula of (Mn_(0.82)Fe_(0.23))Cr_(1.99)S_(3.95). The crystal structure, determined by electron backscattered diffraction, is a Fd3m spinel-type structure with a = 10.11 Å, V = 1033.4 Å^3, and Z = 8

AQUEOUS ALTERATION ON ASTEROIDS SIMPLIFIES SOLUBLE ORGANIC MATTER MIXTURES

International audienceBiologically relevant abiotic extraterrestrial soluble organic matter (SOM) has been widely investigated to study the origin of life and the chemical evolution of protoplanetary disks. Synthesis of biologically relevant organics, in particular, seems to require aqueous environments in the early solar system. However, SOM in primitive meteorites includes numerous chemical species besides the biologically relevant ones and the reaction mechanisms that comprehensively explain the complex nature of SOM are unknown. Besides, the initial reactants, which formed before asteroid accretion, were uncharacterized. We examined the mass-distribution of SOM extracted from three distinct Tagish Lake meteorite fragments, which exhibit different degrees of aqueous alteration though they originated from a single asteroid. We report that mass-distributions of SOM in the primordial fragments are well fit by the Schulz-Zimm (SZ) model for the molecular weight distribution patterns found in chain-growth polymerization experiments. Also, the distribution patterns diverge further from SZ with increasing degrees of aqueous alteration. These observations imply that the complex nature of the primordial SOM 1) was established before severe alteration on the asteroid, 2) possibly existed before parent body accretion, and 3) later became simplified on the asteroid. Therefore, aqueous reactions on asteroids are not required conditions for cultivating complex SOM. Furthermore, we found that overall H/C ratios of SOM decrease with increasing of aqueous alteration, and the estimate of H loss from the SOM is 10-30%. Organics seem to be a significant H2 source that may have caused subsequent chemical reactions in the Tagish Lake meteorite parent body

Molecular growth pattern of soluble CHN compounds from Ryugu

Written with the The Hayabusa2-initial-analysis SOM team and the Hayabusa2-initial-analysis core.International audienceAn polymerization pattern has been found in the soluble organic matter of Ryugu's regolith and compared to other carbonaceous chondrites and analogues

Molecular growth pattern of soluble CHN compounds from Ryugu

Written with the The Hayabusa2-initial-analysis SOM team and the Hayabusa2-initial-analysis core.International audienceAn polymerization pattern has been found in the soluble organic matter of Ryugu's regolith and compared to other carbonaceous chondrites and analogues

Molecular growth pattern of soluble CHN compounds from Ryugu

Written with the The Hayabusa2-initial-analysis SOM team and the Hayabusa2-initial-analysis core.International audienceAn polymerization pattern has been found in the soluble organic matter of Ryugu's regolith and compared to other carbonaceous chondrites and analogues

Enhancing data acquisition for the analysis of complex organic matter in direct‐infusion Orbitrap mass spectrometry using micro-scans

International audienceRationaleAcquisition quality in analytical science is key to obtaining optimal data from a sample. In very high‐resolution mass spectrometry, quality is driven by the optimization of multiple parameters, including the use of scans and micro‐scans (or transients) for performing a Fourier transformation.MethodsThirty‐nine mass spectra of a single synthesized complex sample were acquired using various numbers of scans and micro‐scans determined through a simple experimental design. An electrospray ionization source coupled with an LTQ Orbitrap XL™ mass spectrometer was used, and acquisition was performed using a single mass range. All the resulting spectra were treated in the same way to enable comparisons of assigned stoichiometric formulae between acquisitions.ResultsConverting the number of scans into micro‐scans enhances signal quality by lowering noise and reducing artifacts. This modification also increases the number of attributed stoichiometric formulae for an equivalent acquisition time, giving access to a larger molecular diversity for the analyzed complex sample.ConclusionsFor complex samples, the use of long acquisition times leads to optimal data quality, and the use of micro‐scans instead of scans‐only maximizes the number of attributed stoichiometric formulae