A Neurophysiological Study on the Sympathetic Premotor Nuclei in the Pons and Medulla Oblongata

The aim of this study was to neurophysiologically demonstrate the activities of the premotor nuclei of sympathetic  vasomotion, by capturing the diachronic changes in the action potentials which are generated in  the pons and medulla oblongata. To do so, ten male Wistar rats weighing 300g were used as subjects.  Microelectrodes were inserted in the muscular branch of the sciatic nerve and the ventral side of the pons  and medulla oblongata, and the muscle sympathetic nerve activity (MSA) was induced. The regular spontaneous  action potentials, which synchronize with muscle sympathetic nerve activity, were observed in the  rostral ventrolateral medulla oblongata (RVLM), and the differences among the action potentials of individual  cells of the RVLM region noted. Autonomic postganglionic nerves are controlled in turn by preganglionic  nerves that originate from specific nuclei in the medulla. These nerves directly influence cardiovascular  function by regulating the rate and force of contraction of the heart and the diameter of blood  vessels. RVLM cells in fact exert a widespread control over the sympathetic outflow. We conclude from the  experiment that premotor nuclei of sympathetic vasomotion exist in the RVLM.

An Electrophysiological Experimental Study on the Spontaneous Sympathetic Nerve Activity in the Rostral Ventrolateral Medulla Oblongata

The sympathetic postganglionic nerve fibers, which are controlled by preganglionic fibers originating from  specific nuclei in the medulla oblongata, and the thoracic and upper lumbar segments of the spinal cord,  together with the local autoregulatory mechanisms and circulating hormones, directly influence the cardiovascular  function. Recently, the studies on the sympathetic preganglionic fibers have remarkably progressed,  and the anatomical (Strack et al., 1988), functional (Janig, 1985), and chemical (Krukoff, 1985)  characteristics of the synaptic input have been clarified. However, the peripheral sympathetic nerve activities  vary depending on the organs concerned (including the skin, muscle, or internal organs) as they have  their own physiological characteristics (Janig and McLachlan, 1986) including the response pattern to the  peripheral receptor stimulation. Many areas, including the histological and functional roles of the peripheral  part, nerve centers, and central pathway of the circulatory system, are still unknown. The peripheral sympathetic nerve activities in humans consist of the skin sympathetic activity (SSA) that  controls the sweat glands / skin vasomotion, and the muscle sympathetic activity (MSA) that controls the  vascular smooth muscles in the skeletal muscles, and each activity has different characteristics. SSA  involving regulation of the body temperature and MSA involving regulation of the blood pressure can be  separately recorded (Burke et al., 1977; Hagbarth et al., 1975; Vallbo et al., 1979; Wallin and Eckberg,  1982; Yatomi et al., 1989) from the sympathetic postganglionic efferent fibers by microneurography  (Hagbarth et al., 1972). By recording and comparing the action patterns and responses to stimulations of the premotor nuclei, along  with other vital rhythms, we hoped to clarify the complex mechanism of the sympathetic nerve activities  and to contribute in the treatment of disorders resulting from sympathetic dysfunction. We also report our  findings on the premotor nuclei that produce sympathetic preganglionic fiber activities by using topographic  mapping analysis of the changes in the central action potentials in the rostral ventrolateral medulla  oblongata (RVLM) region to visually capture the complicated action patterns to compare the cross correlations  with MSA and SSA using microneurography and ECG.

An experimental study on the peripheral autonomic nerve potential in the spinal cord injury model by microneurography

The purpose of the present investigation was to analyze the effects of spinal cord injury (SCI) on the  peripheral sympathetic nerve, skin sympathetic activity (SSA), and muscle sympathetic activity (MSA). To  do this sixteen male Japanese white rabbits weighing 1.0 kg-1.5 kg were used. The exposed spinal cord was  transected at various levels. Microelectrodes were placed on the muscular branch and on the cutaneous  branch, and they were separately induced using a 0.5 -5 kHz amplifier. The data were calculated with the  time reset integration value at 60 seconds. Results: It is usually satisfactory to considered that the peripheral sympathetic fibers from T1-3 generally  pass up through the sympathetic chain to the upper extremities, and that fibers from T9-11 pass up through  the sympathetic chain to the lower limbs. In the electrophysiological properties studied, the SSA could not  be recognized as a spontaneous activity. On the other hand, the MSA could be recognized as a spontaneous  regular activity which synchronizes with the R wave of the electrocardiogram. Conclusions: The MSA potentials synchronized with the heart rate, and they seem to correlate with the  body homeostasis. The existence of a central regulatory mechanism is suggested from those findings not  only in vital rhythms, such as the heart rate variability but also in the MSA.

Distribution of Stable DnaA-Binding Sites on the Bacillus Subtilis Genome Detected using a Modified ChIP-chip Method

We developed a modified ChIP-chip method, designated ChAP-chip (Chromatin Affinity Precipitation coupled with tiling chip). The binding sites of Bacillus subtilis Spo0J determined using this technique were consistent with previous findings. A DNA replication initiator protein, DnaA, formed stable complexes at eight intergenic regions on the B. subtilis genome. Characterization of the binding sequences suggested that two factors—the local density of DnaA boxes and their affinities for DnaA—are critical for stable binding. We further showed that in addition to autoregulation, DnaA directly modulate the expression of sda in a positive, and ywlC and yydA in a negative manner. Examination of possible stable DnaA-binding sequences in other Bacillus species suggested that DnaA-dependent regulation of those genes is maintained in most bacteria examined, supporting their biological significance. In addition, a possible stable DnaA-binding site downstream of gcp is also suggested to be conserved. Furthermore, potential DnaA-binding sequences specific for each bacterium have been identified, generally in close proximity to oriC. These findings suggest that DnaA plays several additional roles, such as control of the level of effective initiator, ATP-DnaA, and/or stabilization of the domain structure of the genome around oriC for the proper initiation of chromosome replication

Effectiveness of prehospital Magill forceps use for out-of-hospital cardiac arrest due to foreign body airway obstruction in Osaka City

Background: Although foreign body airway obstruction (FBAO) accounts for many preventable unintentional accidents, little is known about the epidemiology of FBAO patients and the effect of forceps use on those patients. This study aimed to assess characteristics of FBAO patients transported to hospitals by emergency medical service (EMS) personnel, and to verify the relationship between prehospital Magill forceps use and outcomes among out-of-hospital cardiac arrests (OHCA) patients with FBAO. Methods: We retrospectively reviewed ambulance records of all patients who suffered FBAO, and were treated by EMS in Osaka City from 2000 through 2007, and assessed the characteristics of those patients. We also performed a multivariate logistic-regression analysis to assess factors associated with neurologically favorable survival among bystander-witnessed OHCA patients with FBAO in larynx or pharynx. Results: A total of 2,354 patients suffered from FBAO during the study period. There was a bimodal distribution by age among infants and old adults. Among them, 466 (19.8%) had an OHCA when EMS arrived at the scene, and 344 were witnessed by bystanders. In the multivariate analysis, Magill forceps use for OHCA with FBAO in larynx or pharynx was an independent predictor of neurologically favorable survival (16.4% [24/146] in the Magill forceps use group versus 4.3% [4/94] in the non-use group; adjusted odds ratio, 3.96 [95% confidence interval, 1.21-13.00], p = 0.023).Conclusions: From this large registry in Osaka, we revealed that prehospital Magill forceps use was associated with the improved outcome of bystander-witnessed OHCA patients with FBAO

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