Drosophila Strip serves as a platform for early endosome organization during axon elongation

Early endosomes are essential for regulating cell signalling and controlling the amount of cell surface molecules during neuronal morphogenesis. Early endosomes undergo retrograde transport (clustering) before their homotypic fusion. Small GTPase Rab5 is known to promote early endosomal fusion, but the mechanism linking the transport/clustering with Rab5 activity is unclear. Here we show that Drosophila Strip is a key regulator for neuronal morphogenesis. Strip knockdown disturbs the early endosome clustering, and Rab5-positive early endosomes become smaller and scattered. Strip genetically and biochemically interacts with both Glued (the regulator of dynein-dependent transport) and Sprint (the guanine nucleotide exchange factor for Rab5), suggesting that Strip is a molecular linker between retrograde transport and Rab5 activation. Overexpression of an active form of Rab5 in strip-mutant neurons suppresses the axon elongation defects. Thus, Strip acts as a molecular platform for the early endosome organization that has important roles in neuronal morphogenesis.This work was supported by grants from the National Institute of General Medical Science of the National Institutes of Health (R01-GM085232 to V.I.G.), the National Institutes of Health (R01-DC005982 to L.L.), the Japanese Ministry of Education, Science, Sports, Culture, and Technology (MEXT), the Japan Society for the Promotion of Science, and the Japan Science and Technology Agency (to C.S., K.T., Y.Y., M.M., and T.C.)

Silent Intravascular Lymphoma Initially Manifesting as a Unilateral Adrenal Incidentaloma

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of malignant lymphoma. Although the involvement of adrenal glands in IVLBCL is often observed, primary adrenal IVLBCL is rare. Most reported cases of adrenal IVLBCL showed bilateral lesions resulting in rapidly progressive adrenal failure and poor prognosis. Here, we report a case of slowly progressive primary adrenal IVLBCL manifesting initially with unilateral adrenal incidentaloma. This case is a silent IVLBCL and shows that the enlargement of both adrenal glands can be followed

The impact of laparoscopic gynecological surgery training on the technicity index of a developing country center

ABSTRACT Purpose: To compare laparoscopic gynecological surgery training between a developed country’s reference center (host center) and a public reference service in a developing country (home center), and use the technicity index (TI) to compare outcomes and to determine the impact of laparoscopic gynecological surgery fellowship training on the home center’s TI. Methods: The impact of training on the home center was assessed by comparing surgical performance before and after training. TI was assessed in 2017 in the host center, and before and after training in the home center. Epidemiological and clinical data, and information on reason for surgery, preoperative images, estimated intraoperative bleeding, operative time, surgical specimen weight, hospital stay length, complication and reintervention rates were collected from both institutions. Home center pre-training data were retrospectively collected between 2010 and 2013, while post-training data were prospectively collected between 2015 and 2017. A two-tail Z-score was used for TI comparison. Results: The analysis included 366 hysterectomies performed at the host center in 2017, and 663 hysterectomies performed at the home center between 2015 and 2017. TI in the host center was 82.5%, while in the home center it was 6% before training and 22% after training. There were no statistical differences in length of hospital stay, preoperative uterine volume, surgical specimen weight and complication rate between centers. However, significantly shorter mean operative time and lower blood loss during surgery were observed in the host center. Conclusions: High-quality laparoscopic training in a world-renowned specialized center allowed standardizing laparoscopic hysterectomy procedures and helped to significantly improve TI in the recipient’s center with comparable surgical outcomes

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

Avoiding the incompatibility of peripheral parenteral nutrition solution and midazolam injection for intravenous sedation

OBJECTIVES: We have observed white turbidity when a midazolam injection is administered from a lateral tube during the administration of a peripheral parenteral nutrition (PPN) solution. The aim of the current study was to determine how to avoid compound changes when co-administering a midazolam injection and a PPN solution. METHODS: Midazolam solutions were prepared by diluting a midazolam injection with a 5% glucose intravenous infusion. We examined the formulation of the midazolam injection and a PPN solution at the concentrations used in a clinical setting for changes in appearance, pH, and midazolam content in test tubes and during administration conditions. RESULTS: With a 1/4.8 dilution of midazolam in undiluted solution, clouding occurred. A strong correlation was revealed between the midazolam content as measured through high-performance liquid chromatography and the mixture’s midazolam concentration (R(2)=0.9918). The capture rate of midazolam infused with PPN solution was 91.0% at a 1/6 dilution, whereas it decreased to <90% at a 1/4.8 dilution. CONCLUSIONS: Our results suggest that the administration of a midazolam injection solution diluted by ≥6-fold with glucose solution or saline from a side tube during the administration of a PPN solution did not cause changes in composition