Functional Analysis of Free Fatty Acid Receptor GPR120 in Human Eosinophils: Implications in Metabolic Homeostasis

Recent evidence has shown that eosinophils play an important role in metabolic homeostasis through Th2 cytokine production. GPR120 (FFA4) is a G protein-coupled receptor (GPCR) for long-chain fatty acids that functions as a regulator of physiological energy metabolism. In the present study, we aimed to investigate whether human eosinophils express GPR120 and, if present, whether it possesses a functional capacity on eosinophils. Eosinophils isolated from peripheral venous blood expressed GPR120 at both the mRNA and protein levels. Stimulation with a synthetic GPR120 agonist, GW9508, induced rapid down-regulation of cell surface expression of GPR120, suggesting ligand-dependent receptor internalization. Although GPR120 activation did not induce eosinophil chemotactic response and degranulation, we found that GW9508 inhibited eosinophil spontaneous apoptosis and Fas receptor expression. The anti-apoptotic effect was attenuated by phosphoinositide 3-kinase (PI3K) inhibitors and was associated with inhibition of caspase-3 activity. Eosinophil response investigated using ELISpot assay indicated that stimulation with a GPR120 agonist induced IL-4 secretion. These findings demonstrate the novel functional properties of fatty acid sensor GPR120 on human eosinophils and indicate the previously unrecognized link between nutrient metabolism and the immune system

Towards regulation of Endocrine Disrupting chemicals (EDCs) in water resources using bioassays - A guide to developing a testing strategy

Endocrine disrupting chemicals (EDCs) are found in every environmental medium and are chemically diverse. Their presence in water resources can negatively impact the health of both human and wildlife. Currently, there are no mandatory screening mandates or regulations for EDC levels in complex water samples globally. Bioassays, which allow quantifying in vivo or in vitro biological effects of chemicals are used commonly to assess acute toxicity in water. The existing OECD framework to identify single-compound EDCs offers a set of bioassays that are validated for the Estrogen-, Androgen-, and Thyroid hormones, and for Steroidogenesis pathways (EATS). In this review, we discussed bioassays that could be potentially used to screen EDCs in water resources, including in vivo and in vitro bioassays using invertebrates, fish, amphibians, and/or mammalians species. Strengths and weaknesses of samples preparation for complex water samples are discussed. We also review how to calculate the Effect-Based Trigger values, which could serve as thresholds to determine if a given water sample poses a risk based on existing quality standards. This work aims to assist governments and regulatory agencies in developing a testing strategy towards regulation of EDCs in water resources worldwide. The main recommendations include 1) opting for internationally validated cell reporter in vitro bioassays to reduce animal use & cost; 2) testing for cell viability (a critical parameter) when using in vitro bioassays; and 3) evaluating the recovery of the water sample preparation method selected. This review also highlights future research avenues for the EDC screening revolution (e.g., 3D tissue culture, transgenic animals, OMICs, and Adverse Outcome Pathways (AOPs)).This work was supported by the Fonds de recherche du Québec - Nature et technologies (FRQNT-290501) to JR, Natural Sciences and Engineering Research Council (NSERC) of Canada (NSERC-DG-2020-06475), and Canada Research Chairs to VSL (CRC-950-232235). LNM was supported by a H2020-Marie Skłodowska-Curie Action MSCA-IF-RI- 2017 awarded by the European Commission (ref. 797725-EpiSTOX). The authors are grateful to the Intersectorial Centre for Endocrine Disruptor Analysis (ICEDA)'s researcher network that facilitated this Special Issue. We thank Peta Neale that compiled references from the literature for EBT value that can be found in Table 3.Peer reviewe

Degenerative changes in the appendicular joints of ancient human populations from the Japan Islands

Degenerative changes in six major limb joints were investigated to compare their prevalence among five ancient skeletal populations from the Japan Islands. The populations assessed in this study consisted of the farmers in the northern Kyushu/Yamaguchi area and the foragers from the northwestern Kyushu area from the Yayoi period (5th century BC to 3rd century AD); the Okhotsk (5th to 12th centuries AD) foragers from Hokkaido and Sakhalin; the common people from medieval Kamakura (12th to 14th centuries AD) in Kanto, central Japan; and the early-modern farmers (17th to 19th centuries AD) from Kumejima, in the southernmost island chain (Ryukyu Islands). Crude prevalence comparisons showed that the shoulder and hip joints were principally affected in early-modern Kumejima and medieval Kamakura, which contrasted with the high prevalence of elbow and knee joint changes in the Okhotsk people. The heavy dependence on marine mammals and fish for dietary protein intake probably required flexion and extension movements of the most severely degenerated joints in the Okhotsk people. The northern Kyushu/Yamaguchi and northwestern Kyushu Yayoi peoples were more affected by degeneration in the wrist joints than others, possibly due to their use of innovative tools such as stone or shell knives and harpoons. A multivariate logistic regression analysis, adjusted for age, region, and sex as the predictor variables for degenerative changes in joints, was applied to only the two samples from Kumejima and Kamakura (including previously reported spine data) because of their better preservation. This revealed differences in the prevalence of changes in some joints; for example, age-related changes were recognized. The Kumejima people were more commonly affected by hip and knee joint changes, whereas the Kamakura people were more commonly affected by changes to apophyseal joints. Because a stable isotope analysis indicated that the trophic levels of the two populations were almost the same, the pattern of degenerative changes would have reflected differences in their specific workloads, such as wet rice cultivation using a peculiar hoe by the Kumejima people. This study, combining multivariate logistic regression analysis of degenerative joint changes and stable isotope analyses, uses large skeletal populations to add clarity to the actual rigors of ancient life. © 2015 Elsevier Ltd and INQUA

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

アリリックー臭素化大豆油の加熱脱臭素反応の分光光度計による研究

　前報において，N-ブロムコハク酸イミド(NBS)によって臭素化した大豆油の加熱脱臭素反応につき述べ，脱臭素油の特性や乾燥性に影響する諸因子につきやや詳細に論じた。　　本報は，主に加熱脱臭素反応中の共役酸の挙動を分光光度計により検討したものである。すなわち，NBSによって臭素化した大豆油(臭素含量，16.7%，17.4%，および28.3%)を120゜，150゜，200゜，および250゜の各温度において加熱脱臭素を行い，時間による共役酸生成量の変化を分光光度計により測定した。その結果，温度の上昇とともに脱臭素率は増加するが，共役酸生成は，これに伴わずにかえって減少することを認めた。120゜の比較的低温，6時問で全共役酸33%を含む油が得られた。250゜の比較的高温では，15分の短時間で全共役酸21%の油が得られたが，加熱時間の延長とともにかえってその含有量は減少した。勿論この減少は生成共役酸の重合に基くものと思われる。臭素含量は，前者の場合には28%より15%に，後者の場合には15分間で10%まで減少した。　なお個々の共役酸の熱に対する安定度は，温度および共役の程度に支配される。ジエンは高温においても比較的安定であるが，トリエンおよびテトラエンは温度によって著しく影響され，特に高温においては重合し易く，時間とともにその含有量は減少し，ついには全く消失した。　　加熱脱臭素油を亜鉛と処理すると，さらに脱臭素が起ることから，加熱脱臭素油は，正常の臭化アリル型より脱臭素され難いvic-二臭化物型のものを若干含有するものと推定した。反応後期において起る脱臭素の困難性は，この存在に基くものと考えられる

大豆油のアリリック－臭素化及び脱臭化水素

　本研究は半乾性油の乾燥性を改善する目的で行ったものである。　N-ブロモ琥珀酸イミドによって大豆油を臭素化した。適当な条件に於ては，殆んど定量的に，アリルの位置に臭素が導入されることがわかった。　　かくして得られた臭素化大豆油を各種条件の下で加熱脱臭化水素を行った。脱臭化水素油の特数及び乾燥性は反応条件により著しく影響されるが，特に脱臭化水素温度が生成油の乾燥性を決定する重要な因子であって，比較的低温(150℃.)が最も適当であることを明かにした。例えば，臭素化油(Br，16.9%)を真空，150℃，1時間で脱臭化水素すると，15.1%の共役ヂエン，3.6%の共役トリエン及び4.7%の共役テトラエンを含む油が得られた。この油は極めて速かに乾燥し，その指触乾燥時間は，乾燥剤なしで，40～50分であった。なお脱臭素率は約86%であった。もっと高い温度(250℃.)では，脱臭素率は91%まで向上したが，生成油の共役成分含量は却って減少し，乾燥性は良くなかっ

Efectos genotóxicos y citotóxicos de soja (variedad Nueva Andrea 66RR) en médula ósea de ratones Swiss albinos

El presente trabajo estudia los posibles efectos tóxicos a nivel genético y citológico que podría ocasionar el consumo de soja transgénica producida en el Paraguay. Se planteó como objetivo dilucidar los potenciales efectos genotóxicos y citotóxicos de soja transgénica Nueva Andrea 66RRN obtenidas en un campo experimental particular con diferentes dosis del herbicida Glifosato. Como modelo experimental biológico se utilizó ratones Mus musculus de la cepa Swiss albinos adquiridos del bioterio del Instituto de Investigaciones en Ciencias de la Salud de la UNA. Como controles se utilizó soja convencional de la variedad BRS 282 para el control negativo y el químico Ciclofosfamida como control positivo. Los tratamientos consistieron en la administración mediante ingesta de las sojas, en forma de pellets elaborados en el laboratorio haciendo una mezcla de proporción 1:1:3 siendo estos: soja, almidón de mandioca y balanceado comercial, respectivamente. El periodo de tratamiento fue de 14 días. Los parámetros evaluados fueron presencia de Micronúcleos en Eritrocitos policromáticos y porcentaje de Eritrocitos policromáticos en extendido de médula ósea; para el ensayo de genotoxicidad y citotoxicidad, respectivamente. Para descartar alguna diferencia en la calidad nutricional que pudiese interferir en los ensayos, también se ha realizado ensayos de composición nutricional de las sojas transgénicas. No se ha observado un incremento en la proporción de Eritrocitos policromáticos micronucleados en ningún tratamiento con las sojas transgénicas ni convencional; si en el control positivo y tampoco diferencias en el porcentaje de eritrocitos policromáticos sobre los normocromáticos. Los conteos fueron testeados mediante análisis estadísticos descriptivos y contrastes de hipótesis tanto paramétricos como no paramétricos.CONACYT - Consejo Nacional de Ciencia y TecnologíaPROCIENCI