コンバラトキシンによる凝固亢進における単球由来組織因子陽性細胞外小胞の関与

Objectives: Convallatoxin (CNT) is a natural cardiac glycoside extracted from lily of the valley (Convallaria majalis). Although it is empirically known to cause blood coagulation disorders, the underlying mechanism remains unclear. CNT exerts cytotoxicity and increases tissue factor (TF) expression in endothelial cells. However, the direct action of CNT on blood coagulation remains unclear. Therefore, herein, we investigated the effects of CNT on whole blood coagulation system and TF expression in monocytes. Methods: Blood samples were collected from healthy volunteers to measure plasma thrombin–antithrombin complex (TAT) concentration using ELISA and to perform rotational thromboelastometry (ROTEM) and whole-blood extracellular vesicle (EV)-associated TF (EV-TF) analysis. The effects of CNT were also investigated using the monocytic human cell line THP-1. Quantitative real-time PCR and western blotting were performed, and PD98059, a mitogen-activated protein kinase (MAPK) inhibitor, was used to elucidate the action mechanism of CNT-mediated TF production. Results: CNT treatment increased EV-TF activity, shortened the whole blood clotting time in rotational thromboelastometry analysis, and increased TAT levels, which is an index of thrombin generation. Furthermore, CNT increased TF mRNA expression in THP-1 cells and EV-TF activity in the cell culture supernatant. Therefore, CNT may induce a hypercoagulable state with thrombin generation, in which elevated EV-TF activity derived from monocytes might be involved. These procoagulant effects of CNT were reversed by PD98059, suggesting that CNT-induced TF production in monocytes might be mediated by the MAPK pathway. Conclusions: The findings of the present study have further clarified the procoagulant properties of CNT.本文は発行元が定める公開猶予期間終了後に公開

Development of split-force-controlled body weight support (SF-BWS) robot for gait rehabilitation

This study introduces a body-weight-support (BWS) robot actuated by two pneumatic artificial muscles (PAMs). Conventional BWS devices typically use springs or a single actuator, whereas our robot has a split force-controlled BWS (SF-BWS), in which two force-controlled actuators independently support the left and right sides of the user’s body. To reduce the experience of weight, vertical unweighting support forces are transferred directly to the user’s left and right hips through a newly designed harness with an open space around the shoulder and upper chest area to allow freedom of movement. A motion capture evaluation with three healthy participants confirmed that the proposed harness does not impede upper-body motion during laterally identical force-controlled partial BWS walking, which is quantitatively similar to natural walking. To evaluate our SF-BWS robot, we performed a force-tracking and split-force control task using different simulated load weight setups (40, 50, and 60 kg masses). The split-force control task, providing independent force references to each PAM and conducted with a 60 kg mass and a test bench, demonstrates that our SF-BWS robot is capable of shifting human body weight in the mediolateral direction. The SF-BWS robot successfully controlled the two PAMs to generate the desired vertical support forces

Structural insights into the G protein selectivity revealed by the human EP3-Gi signaling complex

熱、炎症などに関与するプロスタグランジン受容体EP3シグナリング複合体の可視化 --緑内障、高眼圧症治療薬の合理的設計に貢献--. 京都大学プレスリリース. 2022-09-15.Prostaglandin receptors have been implicated in a wide range of functions, including inflammation, immune response, reproduction, and cancer. Our group has previously determined the crystal structure of the active-like EP3 bound to its endogenous agonist, prostaglandin E₂. Here, we present the single-particle cryoelectron microscopy (cryo-EM) structure of the human EP3-Gi signaling complex at a resolution of 3.4 Å. The structure reveals the binding mode of Gi to EP3 and the structural changes induced in EP3 by Gi binding. In addition, we compare the structure of the EP3-Gi complex with other subtypes of prostaglandin receptors (EP2 and EP4) bound to Gs that have been previously reported and examine the differences in amino acid composition at the receptor-G protein interface. Mutational analysis reveals that the selectivity of the G protein depends on specific amino acid residues in the second intracellular loop and TM5

Associations between Chest CT Abnormalities and Clinical Features in Patients with the Severe Fever with Thrombocytopenia Syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus. It involves multiple organ systems, including the lungs. However, the significance of the lung involvement in SFTS remains unclear. In the present study, we aimed to investigate the relationship between the clinical findings and abnormalities noted in the chest computed tomography (CT) of patients with SFTS. The medical records of 22 confirmed SFTS patients hospitalized in five hospitals in Nagasaki, Japan, between April 2013 and September 2019, were reviewed retrospectively. Interstitial septal thickening and ground-glass opacity (GGO) were the most common findings in 15 (68.1%) and 12 (54.5%) patients, respectively, and lung GGOs were associated with fatalities. The SFTS patients with a GGO pattern were elderly, had a disturbance of the conscious and tachycardia, and had higher c-reactive protein levels at admission (p = 0.009, 0.006, 0.002, and 0.038, respectively). These results suggested that the GGO pattern in patients with SFTS displayed disseminated inflammation in multiple organs and that cardiac stress was linked to higher mortality. Chest CT evaluations may be useful for hospitalized patients with SFTS to predict their severity and as early triage for the need of intensive care

Prognostic impact of clinical factors for immune checkpoint inhibitor with or without chemotherapy in older patients with non-small cell lung cancer and PD-L1 TPS ≥ 50%

IntroductionThe proportion of older patients diagnosed with advanced-stage non-small cell lung cancer (NSCLC) has been increasing. Immune checkpoint inhibitor (ICI) monotherapy (MONO) and combination therapy of ICI and chemotherapy (COMBO) are standard treatments for patients with NSCLC and programmed cell death ligand-1 (PD-L1) tumor proportion scores (TPS) ≥ 50%. However, evidence from the clinical trials specifically for older patients is limited. Thus, it is unclear which older patients benefit more from COMBO than MONO.MethodsWe retrospectively analyzed 199 older NSCLC patients of Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and PD-L1 TPS ≥ 50% who were treated with MONO or COMBO. We analyzed the association between treatment outcomes and baseline patient characteristics in each group, using propensity score matching.ResultsOf the 199 patients, 131 received MONO, and 68 received COMBO. The median overall survival (OS; MONO: 25.2 vs. COMBO: 42.2 months, P = 0.116) and median progression-free survival (PFS; 10.9 vs. 11.8 months, P = 0.231) did not significantly differ between MONO and COMBO group. In the MONO group, OS was significantly shorter in patients without smoking history compared to those with smoking history [HR for smoking history against non-smoking history: 0.36 (95% CI: 0.16-0.78), P = 0.010]. In the COMBO group, OS was significantly shorter in patients with PS 1 than those with PS 0 [HR for PS 0 against PS 1: 3.84 (95% CI: 1.44-10.20), P = 0.007] and for patients with squamous cell carcinoma (SQ) compared to non-squamous cell carcinoma (non-SQ) [HR for SQ against non-SQ: 0.17 (95% CI: 0.06-0.44), P < 0.001]. For patients with ECOG PS 0 (OS: 26.1 months vs. not reached, P = 0.0031, PFS: 6.5 vs. 21.7 months, P = 0.0436) or non-SQ (OS: 23.8 months vs. not reached, P = 0.0038, PFS: 10.9 vs. 17.3 months, P = 0.0383), PFS and OS were significantly longer in the COMBO group.ConclusionsECOG PS and histological type should be considered when choosing MONO or COMBO treatment in older patients with NSCLC and PD-L1 TPS ≥ 50%

Clinical Differentiation of Severe Fever with Thrombocytopenia Syndrome from Japanese Spotted Fever

Severe fever with thrombocytopenia syndrome (SFTS) and Japanese spotted fever (JSF; a spotted fever group rickettsiosis) are tick-borne zoonoses that are becoming a significant public health threat in Japan and East Asia. Strategies for treatment and infection control differ between the two; therefore, initial differential diagnosis is important. We aimed to compare the clinical characteristics of SFTS and JSF based on symptomology, physical examination, laboratory data, and radiography findings at admission. This retrospective study included patients with SFTS and JSF treated at five hospitals in Nagasaki Prefecture, western Japan, between 2013 and 2020. Data from 23 patients with SFTS and 38 patients with JSF were examined for differentiating factors and were divided by 7:3 into a training cohort and a validation cohort. Decision tree analysis revealed leukopenia (white blood cell [WBC] < 4000/µL) and altered mental status as the best differentiating factors (AUC 1.000) with 100% sensitivity and 100% specificity. Using only physical examination factors, absence of skin rash and altered mental status resulted in the best differentiating factors with AUC 0.871, 71.4% sensitivity, and 90.0% specificity. When treating patients with suspected tick-borne infection, WBC < 4000/µL, absence of skin rash, and altered mental status are very useful to differentiate SFTS from JSF

若年女性の生活習慣と脂質代謝の関連に関する検討

The purpose of this study is to review the factors influencing lipid metabolism of young women in terms of both exercise and nutrition. From the side of nutrition，we reviewed how lipid metabolism is influenced by taking a commercial fish oil supplement（LIQUAMEN）. Total cholesterol deteriorated significantly by taking LIQUAMEN. Improvement of lipid metabolism by LIQUAMEN was suggested. The value of HDL-cholesterol，adiponectin，and leptin were significantly lower in the group of living activity strength Ⅱ while the values of TG and TNF-α increased significantly. This result suggested the possibility that lipid metabolism deteriorated in subjects whose activity was below a certain amount. It also suggested the possibility that lipid metabolism improved in those whose activity was above a certain amount. In the body fat-to-weight ratio， the living activity strengthⅢ・ Ⅳ group showed a significantly lower tendency compared to the group of living activity strength Ⅱ and the group of living activity strengthⅢ・ Ⅳ . This finding suggested that if activity was greater than a certain amount，the body fat-to-weight ratio tended to be comparatively low

Markov Switching Model for Quick Detection of Event Related Desynchronization in EEG

Quick detection of motor intentions is critical in order to minimize the time required to activate a neuroprosthesis. We propose a Markov Switching Model (MSM) to achieve quick detection of an event related desynchronization (ERD) elicited by motor imagery (MI) and recorded by electroencephalography (EEG). Conventional brain computer interfaces (BCI) rely on sliding window classifiers in order to perform online continuous classification of the rest vs. MI classes. Based on this approach, the detection of abrupt changes in the sensorimotor power suffers from an intrinsic delay caused by the necessity of computing an estimate of variance across several tenths of a second. Here we propose to avoid explicitly computing the EEG signal variance, and estimate the ERD state directly from the voltage information, in order to reduce the detection latency. This is achieved by using a model suitable in situations characterized by abrupt changes of state, the MSM. In our implementation, the model takes the form of a Gaussian observation model whose variance is governed by two latent discrete states with Markovian dynamics. Its objective is to estimate the brain state (i.e., rest vs. ERD) given the EEG voltage, spatially filtered by common spatial pattern (CSP), as observation. The two variances associated with the two latent states are calibrated using the variance of the CSP projection during rest and MI, respectively. The transition matrix of the latent states is optimized by the “quickest detection” strategy that minimizes a cost function of detection latency and false positive rate. Data collected by a dry EEG system from 50 healthy subjects, was used to assess performance and compare the MSM with several logistic regression classifiers of different sliding window lengths. As a result, the MSM achieves a significantly better tradeoff between latency, false positive and true positive rates. The proposed model could be used to achieve a more reactive and stable control of a neuroprosthesis. This is a desirable property in BCI-based neurorehabilitation, where proprioceptive feedback is provided based on the patient's brain signal. Indeed, it is hypothesized that simultaneous contingent association between brain signals and proprioceptive feedback induces superior associative learning