Systematic Detection of Short‐Term Slow Slip Events in Southcentral Alaska

Slow slip events (SSEs) are important for the slip budget along a megathrust fault. Although the recurrence of weeks-long short-term SSEs (S-SSEs) in southcentral Alaska has been suggested, a large amount of noise prevented us from detecting discrete events. We applied a systematic detection method to Global Navigation Satellite System data and detected 31 S-SSEs during the 14-year analysis period. The events mainly occurred at a depth from 35 to 45 km at a down-dip extension of the 1964 Alaska earthquake, and the active clusters correlated with the region of the subducting Yakutat microplate. A large cumulative slip of S-SSEs indicated a significant contribution to stress transfer along the plate interface, and its source area spatially coincided with that of the long-term SSEs and the afterslip of the 1964 earthquake. Large and recurrent S-SSEs are key phenomena for understanding interplate slip kinematics in this region

Earthquake Swarm Detection Along the Hikurangi Trench, New Zealand: Insights Into the Relationship Between Seismicity and Slow Slip Events

Earthquake swarms, which are anomalous increases in the seismicity rate without a distinguishable mainshock, often accompany transient aseismic processes, such as fluid migration and episodic aseismic slip along faults. Investigations of earthquake swarm activity can provide insights into the causal relationship between aseismic processes and seismicity. Slow slip events (SSEs) along the plate interface in the Hikurangi Trench, New Zealand, are often accompanied by intensive earthquake swarms. However, the detailed spatiotemporal distribution of these earthquake swarms is still unclear. Here, we use the epidemic-type aftershock-sequence (ETAS) model to detect earthquake swarms (M ≥ 3) and create a new earthquake swarm catalog (1997–2015) along the Hikurangi Trench. We compare the earthquake swarm catalog with Global Navigation Satellite System (GNSS) time series data, and existing SSE and tectonic tremor catalogs. Most of the detected (119) earthquake swarm sequences were intraplate events, and their epicenters were mainly concentrated along the east coast of the North Island, whereas many tectonic tremors were located inland. Twenty-five of the detected earthquake swarms occurred within 25 days before and after transient eastward GNSS displacements due to known or newly detected SSEs. We find that the earthquake swarms sometimes preceded the GNSS displacements by more than several days. SSE-induced stress loading is therefore not a plausible triggering mechanism for these pre-SSE earthquake swarms. We propose that high fluid pressure within the slab, which accumulated before the SSEs, may have caused intraplate fluid migration, which in turn triggered the pre-SSE earthquake swarms

Double-Stranded RNA of Intestinal Commensal but Not Pathogenic Bacteria Triggers Production of Protective Interferon-β

SummaryThe small intestine harbors a substantial number of commensal bacteria and is sporadically invaded by pathogens, but the response to these microorganisms is fundamentally different. We identified a discriminatory sensor by using Toll-like receptor 3 (TLR3). Double-stranded RNA (dsRNA) of one major commensal species, lactic acid bacteria (LAB), triggered interferon-β (IFN-β) production, which protected mice from experimental colitis. The LAB-induced IFN-β response was diminished by dsRNA digestion and treatment with endosomal inhibitors. Pathogenic bacteria contained less dsRNA and induced much less IFN-β than LAB, and dsRNA was not involved in pathogen-induced IFN-β induction. These results identify TLR3 as a sensor to small intestinal commensal bacteria and suggest that dsRNA in commensal bacteria contributes to anti-inflammatory and protective immune responses

FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters

乳がんの再発を起こす原因細胞を解明. 京都大学プレスリリース. 2023-11-16.The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain–containing ion transport regulator 3 (FXYD3), a component of the Na⁺/K⁺ pump. Accordingly, FXYD3⁺ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3⁺ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3⁺ CSCs were sensitive to senolytic Na⁺/K⁺ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3⁺ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na⁺/K⁺ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Development of a detection method for short-term slow slip events using GNSS data and its application to the Nankai subduction zone

Using global navigation satellite system (GNSS) data to detect millimeter-order signals of short-term slow slip events (S-SSEs) and to estimate their source parameters, especially duration, is challenging because of low signal-to-noise ratio. Although the duration of S-SSEs in the Nankai subduction zone has been estimated using tiltmeters, its regional variation has never been quantitatively studied. We developed an S-SSE detection method to estimate both the fault model and duration with their errors based on the detection methods developed by previous studies and applied it to a 23-year period of GNSS data in the Nankai subduction zone. We extracted S-SSE signals by calculating correlation coefficients between the GNSS time series and a synthetic template representing the time evolution of an S-SSE and by computing the average of correlation coefficients weighted by the predicted S-SSE signals. We enhanced the signals for duration estimation by stacking GNSS time series weighted by displacements calculated from the estimated fault model. By applying the developed method, we detected 284 S-SSEs from 1997 to 2020 in the Nankai subduction zone from Tokai to Kyushu and discussed their regional characteristics. The results include some newly detected S-SSEs, including events accompanying very low-frequency earthquakes and repeating earthquakes in offshore Kyushu. Our study provides the first geodetic evidence for synchronization of S-SSEs and other seismic phenomena in offshore Kyushu. We estimated the cumulative slip and duration, and their error carefully. We also estimated the average slip rate by dividing the cumulative slip by the cumulative duration. This study clarified that the average slip rate in western Shikoku was approximately twice as that in eastern Shikoku and Kyushu. These regional differences were statistically significant at the 95% confidence interval. Multiple factors can influence the regional characteristics of S-SSEs, and we speculate that the subducting plate interface geometry is one of the dominant factors

Architecture compliance checking at runtime: An industry experience report

In this paper, we report on our experiences we made with architecture compliance checking at run-time. To that end, we constructed hierarchical colored Petri nets (CP-nets), using existing general purpose functional programming languages, for bridging the abstraction gap between architectural views and run-time traces. In an industry example, we were able to extract views that helped us to identify a number of architecturally relevant issues (e.g., style constraint violations) that would not have been detected otherwise. Finally, we demonstrate how to systematically design reusable hierarchical CP-nets, and package valuable experiences and lessons learned from the example application