Avaliação histopatológica, imuno-histoquímica e ultra-estrutural da resposta inflamatória crônica do robalo (Centropomus spp.) ao BCG

Objetivo do estudo foi avaliar a cinética da resposta inflamatória induzida experimentalmente com BCG em peixes modernos pertencentes ao gênero Centropomus sp. Os animais foram experimentalmente inoculados com BCG por via intramuscular na região do pedúnculo caudal sendo realizada a coleta do material nos tempos experimentais de 1, 3, 7, 14, 21 e 33 dias pós-inoculação. A fase aguda da resposta inflamatória se mostrou na forma de infiltrado composto predominantemente por células mononucleares, edema intersticial e necrose de tecido muscular. À medida que o processo se desenvolve, observa-se a organização do foco lesional na forma de um granuloma formado por células epitelióides. Essas células, ao exame imunohistoquímico apresentaram positividade a proteína S100 e citoqueratina, indicando características macrofágicas e secretória, além de apresentarem ao exame ultra-estrutural a presença de desmossomos entre as células adjacentes. Não houve participação efetiva de células gigantes e pigmentares, sugerindo ser uma característica relacionada à espécie.This study set out to evaluate inflammatory response kinetics after experimental inoculation with BCG in modern Centropomus sp. fish. BCG was applied through intramuscular injection in the caudal peduncular region, and samples were collected for analyses at days 1, 3, 7, 14, 21, and 33 post-injection. Acute phase inflammatory infiltrate was characterized by predominant mononuclear cells, intersticial edema, and muscular tissue necrosis. As the inflammatory response evolved, the lesion organized into a granuloma formed by epithelioid cells. These epithelioid cells were positive for the S100 protein and cytokeratin at histochemical analysis, which demonstrates macrophage and secretory activity, besides ultra-structural analysis showed desmosomic junctions within adjacent cells. It didn't have an expressive participation of giant cells and pigment containing cells in the inflammatory reaction, suggesting that it's a specie-specific characteristic

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

Histopathological, immunohistochemical and ultraestructural evaluation of inflammatory response in Arius genus fish under experimental inoculation of BCG

The aim of this study was to evaluate the inflammatory response kinetics after experimental inoculation with BCG in the primitive Arius sp. fish. The BCG was applied through the intramuscular injection in the caudal peduncular region, and the samples were collected for the analyses at days 1, 3, 7, 14, 21, and 33 post-injection. Acute phase inflammatory infiltrate was characterized by the predominant mononuclear cells, intersticial edema, and muscular tissue necrosis. As the inflammatory response evolved, a large number of multinuclear giant cells were formed containing the BCG. These giant cells were positive for the S100 protein at the histochemical analysis, which demonstrate the macrofage activity, confirmed by the ultra-structural analysis showing the lack of the cytoplasmic membrane enveloping the many nuclei within the giant cell. These results led to the conclusion that Arius sp. fish injected with the BCG showed a difuse inflammatory response characterized by a large number of mononuclear cells, absence of granuloma formation, and predominant giant cells.<br>Avaliou-se a cinética da resposta inflamatória induzida experimentalmente com BCG em peixes primitivos pertencentes ao gênero Arius. Os animais foram inoculados com BCG por via intramuscular na região do pedúnculo caudal, sendo realizada a coleta do material nos tempos experimentais de 1, 3, 7, 14, 21 e 33 dias pós-inoculação. A fase aguda da resposta inflamatória se mostrou na forma de infiltrado inflamatório composto predominantemente por células mononucleares, edema intersticial e necrose de tecido muscular. À medida que o processo se desenvolveu, houve formação e aumento no número de células gigantes multinucleadas envolvendo o inóculo. Essas células gigantes, ao exame imunohistoquímico, apresentaram positividade à proteína S100 indicando ação de células macrofágicas, além da ultraestrutura apontar a ausência de membrana citoplasmática entre os inúmeros núcleos presentes nas células. Em vista dos resultados obtidos podemos concluir que em peixes pertencentes ao gênero Arius sp. inoculados com BCG, verificou-se durante todo tempo experimental uma resposta inflamatória difusa composta predominantemente por células mononucleares, não havendo a formação granuloma, porém havendo o predomínio de células gigantes

17.4 Hierarchical Power Distribution and Power Management Scheme for a Single Chip Mobile Processor

A hierarchical power distribution methodology that enables more than dozen power domains in a chip and a power management scheme using 20 power domains are described. This method can achieve very low leakage current in the partial active mode of a single chip mobile processor. The single chip mobile processor embedded three CPU’s that is baseband processor, application processor, and multi-media processor. In the “waiting for calling” mode of the mobile handsets, application processor and multimedia processor part can be power-off. This chip can power off these power domains although the some of baseband parts are actively operating.. Many new techniques for multiple power domains in the chip are described