Pcdhβ deficiency affects hippocampal CA1 ensemble activity and contextual fear discrimination

Clustered protocadherins (Pcdhs), a large group of adhesion molecules, are important for axonal projections and dendritic spread, but little is known about how they influence neuronal activity. The Pcdhβ cluster is strongly expressed in the hippocampus, and in vivo Ca2+ imaging in Pcdhβ-deficient mice revealed altered activity of neuronal ensembles but not of individual cells in this region in freely moving animals. Specifically, Pcdhβ deficiency increased the number of large-size neuronal ensembles and the proportion of cells shared between ensembles. Furthermore, Pcdhβ-deficient mice exhibited reduced repetitive neuronal population activity during exploration of a novel context and were less able to discriminate contexts in a contextual fear conditioning paradigm. These results suggest that one function of Pcdhβs is to modulate neural ensemble activity in the hippocampus to promote context discrimination

IL-6, IL-8, and IL-10 Are Associated with Hyperferritinemia in Rapidly Progressive Interstitial Lung Disease with Polymyositis/Dermatomyositis

Objective. Hyperferritinemia is frequently accompanied by rapidly progressive (RP) interstitial lung disease (ILD) with polymyositis (PM)/dermatomyositis (DM). To clarify the mechanism of RP-ILD with hyperferritinemia, we investigated the associations between serum ferritin levels and various cytokines in patients with PM/DM. Methods. This retrospective study included 38 patients admitted to our hospital with PM/DM. Levels of serum ferritin and cytokines (IL-1 , IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-18, TNF-, IFN-, IFN-, and IP-10) were measured. Disease activity was evaluated using the tool proposed by the International Myositis Assessment and Clinical Studies Group. We analyzed the associations between disease activity and levels of serum ferritin and cytokines. Results. The levels of serum ferritin, IL-8, IL-10, IL-18, and TNF-, were significantly correlated with disease activity. In a multivariate analysis, IL-6 ( = 3.6, = 0.0010), IL-8 ( = 4.8, < 0.0001), and IL-10 ( = 5.7, < 0.0001) significantly contributed to serum ferritin levels. The levels of serum ferritin, IL-6, IL-8, and IL-10, were higher in the RP-ILD subset than in the non-ILD subset or the chronic ILD subset. Conclusion. IL-6, IL-8, and IL-10 are significant contributors to hyperferritinemia in PM/DM. The regulation of these cytokines might offer a possible treatment strategy for RP-ILD with PM/DM

Syntheses and Characterization of New Nickel Coordination Polymers with 4,4′-Dipyridylsulfide. Dynamic Rearrangements of One-Dimensional Chains Responding to External Stimuli: Temperature Variation and Guest Releases/Re-Inclusions

Crystal structures and dynamic rearrangements of one-dimensional coordination polymers with 4,4′-dipyridylsulfide (dps) have been studied. Reaction of Ni(NO3)2·6H2O with dps in EtOH yielded [Ni(dps)2(NO3)2] ·EtOH (1), which had channels filled with guest EtOH molecules among the four Ni(dps)2 chains. This coordination polymer reversibly transformed the channel structure responding to temperature variations. Immersion of 1 in m-xylene released guest EtOH molecules to yield a guest-free coordination polymer [Ni(dps)2(NO3)2] (2a), which was also obtained by treatment of Ni(NO3)2·6H2O with dps in MeOH. On the other hand, removal of the guest molecules from 1 upon heating at 130 °C under reduced pressure produced a guest-free coordination polymer [Ni(dps)2(NO3)2] (2b). Although the 2a and 2b guest-free coordination polymers have the same formula, they showed differences in the assembled structures of the one-dimensional chains. Exposure of 2b to EtOH vapor reproduced 1, while 2a did not convert to 1 in a similar reaction. Reaction of Ni(NO3)2·6H2O with dps in acetone provided [Ni(dps)(NO3)2(H2O)] ·Me2CO (4) with no channel structure. When MeOH or acetone was used as a reaction solvent, the [Ni(dps)2(NO3)2] · (guest molecule) type coordination polymer, which was observed in 1, was not formed. Nevertheless, the reaction of Ni(NO3)2·6H2O with dps in MeOH/acetone mixed solution produced [Ni(dps)2(NO3)2]·0.5(MeOH·acetone) (5), which has an isostructural Ni-dps framework to 1

Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis

Xenobiotic transporters play key roles in disposition of certain therapeutic agents, although limited information is available on their roles other than pharmacokinetic issues. Here, suppressive effect of multispecific organic cation transporter OCTN1/SLC22A4 on liver fibrosis was proposed in liver injury models. After injection of hepatotoxins such as dimethylnitrosamine (DMN) or concanavalin A, hepatic fibrosis, and oxidative stress, evaluated in terms of Sirius red and 4-hydroxy-2-nonenal staining, respectively, were more severe in liver of octn1/slc22a4 gene knockout (octn1-/-) mice than that in wild-type mice. DMN treatment markedly increased α-smooth muscle actin and F4/80, markers of activated stellate and Kupffer cells, respectively, in liver of octn1-/-, but had less effect in wild-type mice. Thus, octn1/slc22a4 gene deletion results in more severe hepatic fibrosis, oxidative stress, and inflammation. DMN-treated wild-type mice showed increased Octn1 staining and hepatic concentration of its food-derived antioxidant ergothioneine (ERGO). The upregulated Octn1 was co-localized with α-smooth muscle actin. Functional expression of Octn1 was demonstrated in activated human hepatic stellate cell lines, LI90 and LX-2. Provision of ERGO-rich feed ameliorated DMN-induced liver fibrosis and oxidative stress. Overall, Octn1 is upregulated in activated stellate cells, resulting in increased delivery of its substrate antioxidant ERGO and a protective effect against liver fibrosis. © 2016 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.Embargo Period 12 month

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

On-Chip Method to Measure Mechanical Characteristics of a Single Cell by Using Moiré Fringe

We propose a method to characterize the mechanical properties of cells using a robot-integrated microfluidic chip (robochip) and microscopy. The microfluidic chip is designed to apply the specified deformations to a single detached cell using an on-chip actuator probe. The reaction force is simultaneously measured using an on-chip force sensor composed of a hollow folded beam and probe structure. In order to measure the cellular characteristics in further detail, a sub-pixel level of resolution of probe position is required. Therefore, we utilize the phase detection of moiré fringe. Using this method, the experimental resolution of the probe position reaches 42 nm. This is approximately ten times smaller than the optical wavelength, which is the limit of sharp imaging with a microscope. Calibration of the force sensor is also important in accurately measuring cellular reaction forces. We calibrated the spring constant from the frequency response, by the proposed sensing method of the probe position. As a representative of mechanical characteristics, we measured the elastic modulus of Madin-Darby Cannie Kidney (MDCK) cells. In spite of the rigid spring constant, the resolution and sensitivity were twice that achieved in our previous study. Unique cellular characteristics can be elucidated by the improvements in sensing resolution and accuracy

A case of popliteal pseudoaneurysm following vessel injury and subintimal application of paclitaxel-coated balloon

Paclitaxel-coated balloon (PCB) is a commonly used endovascular device for symptomatic patients with a femoropopliteal lesion. However, pseudoaneurysm is a rarely encountered complication after PCB treatment. PCB treatment for right popliteal arterial occlusion was performed on a 67-year-old female. Three months later, a right popliteal pseudoaneurysm was detected and a covered stent was implanted. The mechanism of pseudoaneurysm, indicated by the serial assessment of angiography and intravascular ultrasound during these endovascular treatments, was arterial wall injury, subintimal passage of wires, subintimal PCB attachment, and arterial dilation after PCB treatment. Our case suggested that the subintimal PCB application after arterial wall injury may have a risk of pseudoaneurysm after the PCB treatment