A case of fulminant amebic colitis that could be saved

An 80-year-old man was admitted to a neighboring hospital with severe diarrhea and bloody stools. He did not have a remarkable medical history, was not homosexual, and had not traveled outside the country for several years. Colonoscopy was performed on the day of admission and revealed multiple ulcerations with edematous mucosa throughout the colorectum. Histopathological findings of biopsy specimen could not identify the reason for the inflamed colon. On postadmission day 6, the patient developed severe abdominal pain and underwent an emergent surgery for pan-peritonitis due to bowel perforation. The laparotomy revealed glossy fecal pan-peritonitis with perforation of the sigmoid colon; necrosis was observed through the entire length of the colon. The colonic tissue was extremely fragile and exhibited a blotting paper-like appearance. Total colectomy, sigmoid mucous fistula, ileostomy, and intraperitoneal drainage were performed. On postadmission day 12, histopathological findings of resected specimen raised the suspicion of amebic dysentery, and we accordingly treated him with metronidazole (2,250 mg/day) administered orally. Abdominal CT images taken on days 12 and 20 postadmission showed multiple liver abscesses, which improved following metronidazole administration. Metronidazole was discontinued 14 days after initiation as the patient’s general condition improved. His condition remained stable thereafter, and he was transferred two months after admission

Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells

Foxp3+ regulatory T (Treg) cells, which suppress immune responses, are highly proliferative in vivo. However, it remains unclear how the active replication of Treg cells is maintained in vivo. Here, we show that branched-chain amino acids (BCAAs), including isoleucine, are required for maintenance of the proliferative state of Treg cells via the amino acid transporter Slc3a2-dependent metabolic reprogramming. Mice fed BCAA-reduced diets showed decreased numbers of Foxp3+ Treg cells with defective in vivo proliferative capacity. Mice lacking Slc3a2 specifically in Foxp3+ Treg cells showed impaired in vivo replication and decreased numbers of Treg cells. Slc3a2-deficient Treg cells showed impaired isoleucine-induced activation of the mTORC1 pathway and an altered metabolic state. Slc3a2 mutant mice did not show an isoleucine-induced increase of Treg cells in vivo and exhibited multi-organ inflammation. Taken together, these findings demonstrate that BCAA controls Treg cell maintenance via Slc3a2-dependent metabolic regulation

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

Studies on the DNA and Protein Synthesis in the Cell I Cell Division and its Relation to Desoxyribonucleic Acid (DNA) Synthesis and Protein Synthesis

1. By means of microsphectrophotometry the author carried out quantitative analyses of DNA and protein in an individual cell, using Euplotes woodruffi and Ehrlich ascites tumor cells as the materials through Feulgen reaction and Naphthol yellow S stain, and studied the relation between the quantities of these substances and the mitotic cycle. The results are as follows. 2. The DNA content in the macronucleus of Euplotes is increased at two ends of the nucleus, and the part where DNA is increased and that which shows no DNA increase are demarcated by the formation of a reorganization band. 3. The DNA synthesis of Euplotes is most active in the latter stage of interphase and the DNA content is completely doubled just before the cell division. 4. The protein synthesis of Euplotes cells is taking place at all phases of the mitotic cycle and there is a linear relation between the mitotic cycle and the protein contents of the cell. 5. Judging from the relationship between the DNA synthesis and the protein synthesis during the mitotic cycle of Euplotes cells, the DNA content and the protein content in an individual cell show a sigmoid curve between the two and also the similar curve can be observed in the case of Ehrlich ascites tumor cell. Therefore, it is assumed the protein synthesis is being likewise carried on all through the mitotic cycle of Ehrlich ascitess tumor cells. 6. The author discussed about the relationship between the protein synthesis and the cell division

Studies on the DNA and Protein Synthesis in the Cell I Cell Division and its Relation to Desoxyribonucleic Acid (DNA) Synthesis and Protein Synthesis

1. By means of microsphectrophotometry the author carried out quantitative analyses of DNA and protein in an individual cell, using Euplotes woodruffi and Ehrlich ascites tumor cells as the materials through Feulgen reaction and Naphthol yellow S stain, and studied the relation between the quantities of these substances and the mitotic cycle. The results are as follows. 2. The DNA content in the macronucleus of Euplotes is increased at two ends of the nucleus, and the part where DNA is increased and that which shows no DNA increase are demarcated by the formation of a reorganization band. 3. The DNA synthesis of Euplotes is most active in the latter stage of interphase and the DNA content is completely doubled just before the cell division. 4. The protein synthesis of Euplotes cells is taking place at all phases of the mitotic cycle and there is a linear relation between the mitotic cycle and the protein contents of the cell. 5. Judging from the relationship between the DNA synthesis and the protein synthesis during the mitotic cycle of Euplotes cells, the DNA content and the protein content in an individual cell show a sigmoid curve between the two and also the similar curve can be observed in the case of Ehrlich ascites tumor cell. Therefore, it is assumed the protein synthesis is being likewise carried on all through the mitotic cycle of Ehrlich ascitess tumor cells. 6. The author discussed about the relationship between the protein synthesis and the cell division

Studies on the DNA and Protein Synthesis in the Cell II. Effect of OX on the DNA and Protein Contents in the Cell

Using sea-urchin eggs, Euplotes woodruffi, HeLa cells, and Ehrlich ascites tumor cells, the author studied the action of OX substance on the DNA and protein synthesis of these cells, and obtained the following results. 1. OX substance has been found to act as to impede the incorporation of (32)P to DNA in Ehrlich ascites tumor cells. 2. OX substance leads the nuclei of Euplotes, HeLa and Ehrlich ascites tumor cells into a picnotic state. 3. OX substance is found to possess an action to diminish the DNA contents in the nuclei of HeLa and Ehrlich ascites tumor cells while it tends to increase transiently the DNA content in the nucleus of sea-urchin egg but later decreases it. 4. It has been found that OX substance brings about the disturbance on the mitotic apparatus or the functional disturbance in Ehrlich ascites tumor cells and sea-urchin eggs. 5. In addition, this substance acts as to inhibit the protein synthesis of Ehrlich ascites tumor cells. 6. From these findings, it seems that OX acts temporarily on the mitotic apparatus, thus interfering with the cell division as well as giving rise to the degeneration of the cells. accompanied by the secondary inhibition of the synthesis of DNA and RNA in the cells