Phospholipase D Family Member 4, a Transmembrane Glycoprotein with No Phospholipase D Activity, Expression in Spleen and Early Postnatal Microglia

BACKGROUND: Phospholipase D (PLD) catalyzes conversion of phosphatidylcholine into choline and phosphatidic acid, leading to a variety of intracellular signal transduction events. Two classical PLDs, PLD1 and PLD2, contain phosphatidylinositide-binding PX and PH domains and two conserved His-x-Lys-(x)(4)-Asp (HKD) motifs, which are critical for PLD activity. PLD4 officially belongs to the PLD family, because it possesses two HKD motifs. However, it lacks PX and PH domains and has a putative transmembrane domain instead. Nevertheless, little is known regarding expression, structure, and function of PLD4. METHODOLOGY/PRINCIPAL FINDINGS: PLD4 was analyzed in terms of expression, structure, and function. Expression was analyzed in developing mouse brains and non-neuronal tissues using microarray, in situ hybridization, immunohistochemistry, and immunocytochemistry. Structure was evaluated using bioinformatics analysis of protein domains, biochemical analyses of transmembrane property, and enzymatic deglycosylation. PLD activity was examined by choline release and transphosphatidylation assays. Results demonstrated low to modest, but characteristic, PLD4 mRNA expression in a subset of cells preferentially localized around white matter regions, including the corpus callosum and cerebellar white matter, during the first postnatal week. These PLD4 mRNA-expressing cells were identified as Iba1-positive microglia. In non-neuronal tissues, PLD4 mRNA expression was widespread, but predominantly distributed in the spleen. Intense PLD4 expression was detected around the marginal zone of the splenic red pulp, and splenic PLD4 protein recovered from subcellular membrane fractions was highly N-glycosylated. PLD4 was heterologously expressed in cell lines and localized in the endoplasmic reticulum and Golgi apparatus. Moreover, heterologously expressed PLD4 proteins did not exhibit PLD enzymatic activity. CONCLUSIONS/SIGNIFICANCE: Results showed that PLD4 is a non-PLD, HKD motif-carrying, transmembrane glycoprotein localized in the endoplasmic reticulum and Golgi apparatus. The spatiotemporally restricted expression patterns suggested that PLD4 might play a role in common function(s) among microglia during early postnatal brain development and splenic marginal zone cells

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 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

Amorphous Mineral Colloids of Soils of the Pacific Region and Adjacent Areas

Volume: 15Start Page: 477End Page: 48

Status and availability of zinc in Hawaiian soils

Typescript.Thesis--University of Hawaii, 1964.Bibliography: leaves 105-113.xi, 113 leaves mounted ill. (part col.) tablesThe study of micro-nutrients in tropical soils has been receiving increasing attention in the past decade. There is an awareness that a great shortage of information exists today regarding the status and availability of micro-nutrients. Zinc is one of these trace elements that has been established as being in critical supply in many tropical countries. Because of the rapid disappearance of new lands, the heretofore common cropping practice of "shifting agriculture" will become a thing of the past in many tropical areas. It is expected that as land is intensively farmed year after year, the depletion of zinc, as well as other trace elements, will continue to grow. The very process of soil weathering in the tropics is a process of attrition of this element from the soil. It can also be expected that the use of modern concentrated, purified, inorganic fertilizers with resultant heavy crop removal from the soil will further contribute toward a shortage of this element. In Hawaii the problem of zinc deficiency was recognized in certain soils shortly before World War II. Lyman and Dean (45) reported zinc deficiency in pineapples and described symptoms which consisted of blistering and mottling of leaves and of curvature of the "heart" leaves. This "crookneck" symptom in pineapple has subsequently been recognized in Queensland, Australia (2). The Hawaiian pineapple industry has recognized the existence of zinc deficiency and has included zinc in their foliage spray program in many of their fields. Zinc deficiency in coffee has been recognized as being a widespread problem. Some of Hawaii's problems are akin to those of Brazil's in that zinc-deficient plants are in both cases usually located on hilly lands at high altitudes and with moderately high to high rainfall conditions. Zinc, when applied as a foliar spray, has been reported by Shoji and Ota (63) to be more successful in correcting zinc-deficiency in coffee than when added to the soil. Younge and Plucknett (85) have associated zinc-deficiency with coral limed-areas. The pH was found to have become excessively high in such areas. Observations and yield data were taken on corn and alfalfa. In his fertility study of humid Hawaiian pastures, Younge (84) showed that Kaimi clover-paspalum forage responded to zinc application. Clements (23) reported that neither phosphate nor coral stone significantly affected the zinc-index readings for sugar cane grown in a hydrol humic latosol, but a highly significant interaction between them was shown. The writer is not aware of any widespread zinc deficiency problem in the sugar cane industry in Hawaii today. Although much progress has been made in the recognition of zinc-deficiency, there yet remains to be found satisfactory explanations of the mechanisms and conditions that affect the availability of zinc in soils. As a result, whereas foliage spray of zinc has been generally effective in correcting zinc deficiency, soil applications of this trace element have often given erratic responses, giving good results in some instances and poor results in other cases. There is a need for a better fundamental understanding of the status and availability of soil-applied zinc, as well as that of the indigenous zinc. This need is especially critical in Hawaii and other tropical areas where quantitative data from basic micro-nutrient studies are meager and where results obtained with temperate region soils often do not apply. Thus, the objectives of this study were: 1. To determine the total and extractable zinc content of the major Hawaiian great soil groups. 2. To relate the growth of plants to the availability of zinc in Hawaiian soils. 3. To study the effect of lime on the availability of zinc. 4. To study the effect of phosphorus on the availability of zinc. S. To study the sorption of zinc in Hawaiian soils

The Role of Dehydration in the Development of Laterite

Volume: 7Start Page: 438End Page: 44