The neuropeptide neuromedin U promotes autoantibody-mediated arthritis

Introduction: Neuromedin U (NMU) is a neuropeptide with pro-inflammatory activity. The primary goal of this study was to determine if NMU promotes autoantibody-induced arthritis. Additional studies addressed the cellular source of NMU and sought to define the NMU receptor responsible for its pro-inflammatory effects. Methods: Serum containing arthritogenic autoantibodies from K/BxN mice was used to induce arthritis in mice genetically lacking NMU. Parallel experiments examined whether NMU deficiency impacted the early mast-cell-dependent vascular leak response induced by these autoantibodies. Bone-marrow chimeric mice were generated to determine whether pro-inflammatory NMU is derived from hematopoietic cells or stromal cells. Mice lacking the known NMU receptors singly and in combination were used to determine susceptibility to serum-transferred arthritis and in vitro cellular responses to NMU. Results: NMU-deficient mice developed less severe arthritis than control mice. Vascular leak was not affected by NMU deficiency. NMU expression by bone-marrow-derived cells mediated the pro-arthritogenic effect. Deficiency of all of the known NMU receptors, however, had no impact on arthritis severity and did not affect the ability of NMU to stimulate intracellular calcium flux. Conclusions: NMU-deficient mice are protected from developing autoantibody-induced inflammatory arthritis. NMU derived from hematopoietic cells, not neurons, promotes the development of autoantibody-induced inflammatory arthritis. This effect is mediated by a receptor other than the currently known NMU receptors

高齢者による地区活動を活性化する要因の検討

本研究の目的は、65歳以上の要介護状態にない高齢者を対象とした質問紙調査から、地区活動の支援経験が、身体的健康状態、 自己効力感などの心理的健康状態とどのように関連しているかを明らかにし、地区活動の活性化のための要因を考察することである。調査の結果、地区活動の支援を「現在している」と回答した人や友人・隣人との交流が頻回にある人は自己効力感が高く、活動能力にも影響していることが明らかになり、 自己効力感を高く維持していくことは、地区活動の支援を積極的に行えることにつながると考えられた。今後は地区活動の支援のあり方や参加の仕方の工夫と意味づけをしていくことで、 自己効力感の維持につながり、地区活動の活性化につながると思われた

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

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

ショクジ セッシュ キジュン 2010ネンバン ニ ヨル カンリ エイヨウシ ヨウセイ カテイ ノ ジョシ ガクセイ ノ エイヨウ シンタイ カツドウ ヒョウカ

The purpose of this study was to assess the nutritional status of women university students in the third-grade of a registered dietitian training course, based on the Dietary Reference Intakes for Japanese(2010). We initially selected 46 students, and obtained valid responses from 41 students(89.1%). We performed body measurements, blood tests, a dietary weighing method for 3 days, and the measurement of physical activity by the accelerometer. In regard to the physique and blood test of the subjects, 24.4% were underweight, 4.9% were obese and 20.0% were anemic. The dietary weighing method showed that the rate of women who took vitamin C below the estimated average requirement was 90.0%, that of folic acid, iron and calcium were 41.0%, 83.0%, and 68.0% respectively. While the rate of salt intake greater than the dietary goal (7.5g/day)was 36.5%, the rate of fat energy ratio greater than the dietary goal(30%)was 31.7%. The average number of steps per day was 8,907 ± 2,293. These results showed that there was an overall insufficient intake of total energy, vitamins, and minerals, indicating that further nutritional management for the women students is required

Gastrin-releasing peptide mediates photic entrainable signals to dorsal subsets of suprachiasmatic nucleus via induction of Period gene in mice. Mol Pharmacol

ABSTRACT The suprachiasmatic nucleus (SCN), locus of the central circadian clock, consists of two neuronal populations (i.e., a lightrecipient ventral SCN subpopulation directly entrained by light and a dorsal SCN subpopulation with an autonomous oscillatory function possessing an indirect or weak light response). However, the mechanism underlying the transmission of photic signals from the ventral to dorsal SCN remains unclear. Because gastrin-releasing peptide (GRP), expressed mainly in the ventral SCN, exerts phase-shifting actions, loss of the GRP receptor intuitively implies a reduction of photic information from the ventral to dorsal SCN. Therefore, using GRP receptordeficient mice, we examined the involvement of GRP and the GRP receptor in light-and GRP-induced entrainment by the assessment of behavioral rhythm and induction of mousePeriod (mPer) gene in the SCN, which is believed to be a critical for photic entrainment. Administration of GRP during nighttime dose dependently produced a phase delay of behavior in wildtype but not GRP receptor-deficient mice. This phase-shift by GRP was closely associated with induction of mPer1 and mPer2 mRNA as well as c-Fos protein in the dorsal portion of the SCN, where the GRP receptor was also expressed abundantly. Both the light-induced phase shift in behavior and the induction of mPer mRNA and c-Fos protein in the dorsal SCN were attenuated in GRP receptor-deficient mice. Our present studies suggest that GRP neurons in the retinorecipient ventral area of the SCN convey the photic entrainable signals from the ventral SCN to the dorsal SCN via induction of the mPer gene. Daily behavioral and physiological rhythms persist under conditions absent of environmental time cues, suggesting the existence of endogenous time-keeping systems and daily light/dark cycle entrains the self-oscillating circadian rhythms to the environmental 24-h period. The suprachiasmatic nucleus (SCN) was found to harbor the central circadian pacemaker in mammals (for review, see Gastrin-releasing peptide (GRP) may be a possible candidate for neurotransmitters involved in transmission to the dorsal SCN based on the following reports. First, the cell somata of GRP neurons were restricted to the ventral SCN, whereas the fibers extended into the dorsal portion (Gun

Bombesin Inhibits Alveolarization and Promotes Pulmonary Fibrosis in Newborn Mice

Rationale: Bombesin-like peptides promote fetal lung development. Normally, levels of mammalian bombesin (gastrin-releasing peptide [GRP]) drop postnatally, but these levels are elevated in newborns that develop bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by arrested alveolarization. In premature baboons with BPD, antibombesin antibodies reduce lung injury and promote alveolarization