The Possible Role of TASK Channels in Rank-Ordered Recruitment of Motoneurons in the Dorsolateral Part of the Trigeminal Motor Nucleus.

Because a rank-ordered recruitment of motor units occurs during isometric contraction of jaw-closing muscles, jaw-closing motoneurons (MNs) may be recruited in a manner dependent on their soma sizes or input resistances (IRs). In the dorsolateral part of the trigeminal motor nucleus (dl-TMN) in rats, MNs abundantly express TWIK (two-pore domain weak inwardly rectifying K channel)-related acid-sensitive-K(+) channel (TASK)-1 and TASK3 channels, which determine the IR and resting membrane potential. Here we examined how TASK channels are involved in IR-dependent activation/recruitment of MNs in the rat dl-TMN by using multiple methods. The real-time PCR study revealed that single large MNs (>35 μm) expressed TASK1 and TASK3 mRNAs more abundantly compared with single small MNs (15-20 μm). The immunohistochemistry revealed that TASK1 and TASK3 channels were complementarily distributed in somata and dendrites of MNs, respectively. The density of TASK1 channels seemed to increase with a decrease in soma diameter while there were inverse relationships between the soma size of MNs and IR, resting membrane potential, or spike threshold. Dual whole-cell recordings obtained from smaller and larger MNs revealed that the recruitment of MNs depends on their IRs in response to repetitive stimulation of the presumed Ia afferents. 8-Bromoguanosine-cGMP decreased IRs in small MNs, while it hardly changed those in large MNs, and subsequently decreased the difference in spike-onset latency between the smaller and larger MNs, causing a synchronous activation of MNs. These results suggest that TASK channels play critical roles in rank-ordered recruitment of MNs in the dl-TMN

Adjuvant concurrent chemoradiation therapy (CCRT) alone versus CCRT followed by adjuvant chemotherapy: Which is better in patients with radically resected extrahepatic biliary tract cancer?: a non-randomized, single center study

<p>Abstract</p> <p>Background</p> <p>There is currently no standard adjuvant therapy for patients with curatively resected extrahepatic biliary tract cancer (EHBTC). The aim of this study was to analyze the clinical features and outcomes between patients undergoing adjuvant concurrent chemoradiation therapy (CCRT) alone and those undergoing CCRT followed by adjuvant chemotherapy after curative resection.</p> <p>Methods</p> <p>We included 120 patients with EHBTC who underwent radical resection and then received adjuvant CCRT with or without further adjuvant chemotherapy between 2000 and 2006 at Seoul National University Hospital.</p> <p>Results</p> <p>Out of 120 patients, 30 received CCRT alone, and 90 received CCRT followed by adjuvant chemotherapy. Baseline characteristics were comparable between the two groups. Three-year disease-free survival (DFS) rates for CCRT alone and CCRT followed by adjuvant chemotherapy were 26.6% and 45.2% (p = 0.04), respectively, and 3-year overall survival (OS) rates were 30.8% and 62.6% (p < 0.01), respectively. CCRT followed by adjuvant chemotherapy showed longer survival than did CCRT alone, especially in R1 resection (microscopically positive margins) or negative lymph node.</p> <p>Conclusion</p> <p>Adjuvant CCRT followed by adjuvant chemotherapy prolonged DFS and OS, compared with CCRT alone in patients with curatively resected EHBTC. Adjuvant chemotherapy deserves to consider after adjuvant CCRT. In the future, a randomized prospective study will be needed, with the objective of investigating the role of adjuvant chemotherapy.</p

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

The Transition of Sleep Behaviors in Twin Infants and Their Mothers in Early Infancy

Background: The mothers of twins often suffer from sleeplessness. However, little is known about the relation of sleep behaviors between these mothers and their infants. The change of this relation with age has not been reported. The aims of this study are firstly to clarify the sleep behaviors of twin infants and their mothers by using actigraphy (four measurement periods at approximately 4- to 6-week intervals) and secondary to evaluate the relations of sleep behaviors between twin infants and their mothers. Methods: Five twin pairs and their mothers (first-time mother) were participated in this prospective longitudinal study. Their sleep behaviors were recorded for 7 consecutive days by using an actigraph, when the infants reached a corrected age (CA) of 3–6 weeks, 8–11 weeks, 13–15 weeks, and 17–20 weeks. Sleep status was classified into 3 states: both infants sleeping, only one infant sleeping, and both infants awake. Results: All infants were cobedded. The time awake during the nocturnal period decreased by almost 90 minutes from CA 3–6 weeks to CA 8–11 weeks. Sleep duration in the nocturnal period increased by almost 85 minutes, and the proportion of time with both infants sleeping rapidly increased in the same period. Maternal sleep duration during the period of both infants sleeping was positively correlated with CA. Conclusion: This research revealed the transition of sleep behaviors in twin infants and their mothers in early infancy. Cobedding may facilitate more synchronized sleep states of twin infants

Whole-body counting of Fukushima residents after the TEPCO Fukushima Daiichi Nuclear Power Station accident

At the request of Fukushima Prefecture, the Japan Atomic Energy Agency (JAEA) started whole-body counting of residents on July 11, 2011 to assess radiation exposure after the TEPCO Fukushima Daiichi Nuclear Power Station accident. The JAEA has examined residents in Iitate, Kawamata, Namie, and 8 other local communities. The measurement capacity of the whole-body counting device is approximately 100 persons per day and the total number of people to measure reached 9,927 by the end of January 2012. Two types of whole body counters equipped with large-size NaI(Tl) detectors were used to perform the measurements. Routinely used phantoms (Canberra RMC-II transfer phantom or water-filled block phantom developed by JAEA) were used to perform peak efficiency calibration of the counters and the results of peak efficiency calibration were verified with different-sized bottle mannequin absorber (BOMAB) phantoms imitating an adult male, a 10-year-old and a 4-year-old. As the measurement started at 4 month after the accident, short half-life radionuclides such as 131I originating from the accident were not detected in this work. Approximately 80% of the residents had levels below the minimum detectable amount (MDA). No artificial nuclides other than 134Cs and 137Cs were found in the present whole-body counting. The maximum whole-body content of radiocesium (134Cs and 137Cs together) was 2.7 kBq for children 1 mSv, and the maximum CED was 3 mSv. The extrapolated 50th percentiles (medians) of the CED for 13-17 years old and those >17 years old were 0.02 mSv and 0.025 mSv, respectively. These values represent the basic knowledge for the reconstruction of internal exposure of the entire resident population

Direct measurements of employees involved in the Fukushima Daiichi nuclear power station accident for internal dose estimates: JAEA\u27s experiences

Japan Atomic Energy Agency (JAEA) performed internal dose measurements of employees involved in the Fukushima Daiichi nuclear power station accident. Nuclear Fuel Cycle Engineering Laboratories (NFCEL), one of the JAEA\u27s core centers, examined 560 of these employees by direct (in vivo) measurements during the period from April 20 to August 5 in 2011. These measurements consisted of whole-body counting for radiocesium and thyroid counting for radioiodine. The whole-body counting was conducted with two types of whole-body counters (WBCs): a standing-type WBC with two large NaI(Tl) detectors (FastscanTM, Canberra Inc.) and a chair-type WBC with HPGe detectors (GC5021, Canberra Inc.) installed in a shielded chamber made of 20-cm-thick steel. The thyroid counting was mainly performed using one of the two HPGe detectors equipped with the chair-type WBC. The subjects examined in this work were divided into two groups: Group 1 was the first 39 subjects who were measured up to June 17, 2011 and Group 2 was the remaining 521 subjects who were measured on and after June 18, 2011. We validated the performance of our direct measurements by comparing measurement results of the Group 1 subjects using two different methods (e.g., the standing-type WBC vs. the chair-type WBC). Tentative internal dose estimates of the subjects of Group 1 were also performed based on the assumption of a single intake scenario on either March 12, when the first hydrogen explosion occurred at the station or the first day of work after the accident. It was found that the contribution of 131I to the total internal dose greatly exceeded those of 134Cs and 137Cs, the other major nuclides detected in the measurements. The maximum committed effective dose (CED) was found in a male subject whose thyroid content of 131I was 9760 Bq on May 23, 2011; the CED of this subject was estimated to be 600 mSv including a small contribution of 134Cs and 137Cs. The typical minimum detectable activity for 131I in the present thyroid counting was 10 Bq for a counting time of 10 min, making it difficult to identify a residual thyroid content corresponding to a CED of 20 mSv for the subjects of Group 2

Results of whole body counting for JAEA staff members engaged in the emergency radiological monitoring for the Fukushima nuclear disaster

A massive earthquake and tsunami on March 11, 2011, resulted in the release of an enormous amount of radioactive materials into the environment. On the day after the earthquake the Japan Atomic Energy Agency (JAEA) began emergency radiological monitoring. Measurements with a whole body counter (WBC) for the staff members who had returned from Fukushima began at the end of March because a power blackout for several days and lingering increased ambient radiation levels had rendered the WBCs inoperable. The measured activity level for I-131 due to inhalation for emergency staff varied from below detection limit to 7 kBq, which corresponds to an estimated initial intake range of <1 to 60 kBq when extrapolated back to the date the staff began the monitoring in Fukushima. The measured activity levels for Cs-134 and Cs-137 were both in the ranges from below detection limit to 3 kBq. When using the median values for each set of measurements, the ratio of the initial intake of I-131 to Cs-137 was 11. The maximum committed effective dose of 0.8 mSv was recorded for a member of the 4th monitoring team dispatched from March 15 to 20