Time-delayed collective flow diffusion models for inferring latent people flow from aggregated data at limited locations

The rapid adoption of wireless sensor devices has made it easier to record location information of people in a variety of spaces (e.g., exhibition halls). Location information is often aggregated due to privacy and/or cost concerns. The aggregated data we use as input consist of the numbers of incoming and outgoing people at each location and at each time step. Since the aggregated data lack tracking information of individuals, determining the flow of people between locations is not straightforward. In this article, we address the problem of inferring latent people flows, that is, transition populations between locations, from just aggregated population data gathered from observed locations. Existing models assume that everyone is always in one of the observed locations at every time step; this, however, is an unrealistic assumption, because we do not always have a large enough number of sensor devices to cover the large-scale spaces targeted. To overcome this drawback, we propose a probabilistic model with flow conservation constraints that incorporate travel duration distributions between observed locations. To handle noisy settings, we adopt noisy observation models for the numbers of incoming and outgoing people, where the noise is regarded as a factor that may disturb flow conservation, e.g., people may appear in or disappear from the predefined space of interest. We develop an approximate expectation-maximization (EM) algorithm that simultaneously estimates transition populations and model parameters. Our experiments demonstrate the effectiveness of the proposed model on real-world datasets of pedestrian data in exhibition halls, bike trip data and taxi trip data in New York City

Pathophysiological relevance of sputum MUC5AC and MUC5B levels in patients with mild asthma

[Background] Airway mucus hypersecretion is an important pathophysiological feature of asthma. MUC5AC and MUC5B are the major secreted polymeric mucins in airways, and their compositions affect mucus properties. Despite the increasing appreciation of MUC5AC and MUC5B compositions in asthmatic airways, their pathophysiological relevance remains to be fully understood in humans. [Methods] In this cross-sectional study, we prospectively enrolled newly referred steroid-untreated patients with mild asthma and healthy controls. We compared induced sputum MUC5AC and MUC5B levels between patients and controls. Subsequently, we assessed the correlation between MUC5AC and MUC5B levels and clinical indices in patients. Sputum MUC5AC and MUC5B levels were measured using enzyme-linked immunosorbent assays. [Results] Sputum MUC5AC and MUC5B levels were significantly higher in patients (n = 87) than in controls (n = 22) (p = 0.0002 and p = 0.006, respectively). The ratio of sputum MUC5AC to MUC5B tended to be higher in patients than in controls (p = 0.07). Sputum MUC5AC levels significantly and positively correlated with fractional exhaled nitric oxide at expiratory flow of 50 mL/s (Spearman's rho = 0.29, p = 0.006), sputum eosinophil proportion (rho = 0.34, p = 0.0013), and airway sensitivity (rho = 0.39, p = 0.0005). By contrast, sputum MUC5B levels significantly and positively correlated with airway sensitivity (rho = 0.35, p = 0.002) and negatively correlated with airway reactivity (rho = −0.33, p = 0.004). [Conclusions] Sputum MUC5AC is increased by protein levels and involved in airway type 2/eosinophilic inflammation and airway hyperresponsiveness in steroid-untreated patients with mild asthma

Liquid Biopsy Targeting Monocarboxylate Transporter 1 on the Surface Membrane of Tumor-Derived Extracellular Vesicles from Synovial Sarcoma

Simple Summary Synovial sarcoma (SS) is associated with a high risk of recurrence and poor prognosis, and no biomarker useful in monitoring tumor burden exists. We identified monocarboxylate transporter 1 (MCT1) expressed in extracellular vesicles (EVs) derived from synovial sarcoma as a potential such marker. Circulating levels of MCT1(+)CD9(+) EVs were significantly correlated with tumor volume in a SS mouse model. Serum levels of MCT1(+)CD9(+) EVs reflected tumor burden and treatment response in SS patients. Patients with MCT1 expression on the plasma membrane have significantly worse overall survival than those with nuclear expression. Silencing of MCT1 reduced the malignant phenotype including cellular viability, migration, and invasion of SS cells. MCT1 may thus be a promising novel target for liquid biopsies and a novel therapeutic target. The lack of noninvasive biomarkers that can be used for tumor monitoring is a major problem for soft-tissue sarcomas. Here we describe a sensitive analytical technique for tumor monitoring by detecting circulating extracellular vesicles (EVs) of patients with synovial sarcoma (SS). The proteomic analysis of purified EVs from SYO-1, HS-SY-II, and YaFuSS identified 199 common proteins. DAVID GO analysis identified monocarboxylate transporter 1 (MCT1) as a surface marker of SS-derived EVs, which was also highly expressed in SS patient-derived EVs compared with healthy individuals. MCT1(+)CD9(+) EVs were also detected from SS-bearing mice and their expression levels were significantly correlated with tumor volume (p = 0.003). Furthermore, serum levels of MCT1(+)CD9(+) EVs reflected tumor burden in SS patients. Immunohistochemistry revealed that MCT1 was positive in 96.7% of SS specimens and its expression on the cytoplasm/plasma membrane was significantly associated with worse overall survival (p = 0.002). Silencing of MCT1 reduced the cellular viability, and migration and invasion capability of SS cells. This work describes a new liquid biopsy technique to sensitively monitor SS using circulating MCT1(+)CD9(+) EVs and indicates the therapeutic potential of MCT1 in SS

Structure of SARS-CoV-2 membrane protein essential for virus assembly

新型コロナウイルスのウイルス形成に必須の膜タンパク質の構造を解明. 京都大学プレスリリース. 2022-08-08.The coronavirus membrane protein (M) is the most abundant viral structural protein and plays a central role in virus assembly and morphogenesis. However, the process of M protein-driven virus assembly are largely unknown. Here, we report the cryo-electron microscopy structure of the SARS-CoV-2 M protein in two different conformations. M protein forms a mushroom-shaped dimer, composed of two transmembrane domain-swapped three-helix bundles and two intravirion domains. M protein further assembles into higher-order oligomers. A highly conserved hinge region is key for conformational changes. The M protein dimer is unexpectedly similar to SARS-CoV-2 ORF3a, a viral ion channel. Moreover, the interaction analyses of M protein with nucleocapsid protein (N) and RNA suggest that the M protein mediates the concerted recruitment of these components through the positively charged intravirion domain. Our data shed light on the M protein-driven virus assembly mechanism and provide a structural basis for therapeutic intervention targeting M protein

Gene Knockout and Metabolome Analysis of Carnitine/Organic Cation Transporter OCTN1

金沢大学医薬保健研究域薬学系Purpose: Solute carrier OCTN1 (SLC22A4) is an orphan transporter, the physiologically important substrate of which is still unidentified. The aim of the present study was to examine physiological roles of OCTN1. Methods: We first constructed octn1 gene knockout (octn1-/-) mice. Metabolome analysis was then performed to identify substrates in vivo. The possible association of the substrate identified with diseased conditions was further examined. Results: The metabolome analysis of blood and several organs indicated complete deficiency of a naturally occurring potent antioxidant ergothioneine in octn1-/- mice among 112 metabolites examined. Pharmacokinetic analyses after oral administration revealed the highest distribution to small intestines and extensive renal reabsorption of [3H]ergothioneine, both of which were much reduced in octn1-/- mice. The octn1-/- mice exhibited greater susceptibility to intestinal inflammation under the ischemia and reperfusion model. The blood ergothioneine concentration was also much reduced in Japanese patients with Crohn\u27s disease, compared with healthy volunteers and patients with another inflammatory bowel disease, ulcerative colitis. Conclusions: These results indicate that OCTN1 plays a pivotal role for maintenance of systemic and intestinal exposure of ergothioneine, which could be important for protective effects against intestinal tissue injuries, providing a possible diagnostic tool to distinguish the inflammatory bowel diseases. © 2010 Springer Science+Business Media, LLC

Endothelial cells enhance the in vivo bone-forming ability of osteogenic cell sheets

Addressing the problem of vascularization is of vital importance when engineering three-dimensional (3D) tissues. Endothelial cells are increasingly used in tissue-engineered constructs to obtain prevascularization and to enhance in vivo neovascularization. Rat bone marrow stromal cells were cultured in thermoresponsive dishes under osteogenic conditions with human umbilical vein endothelial cells (HUVECs) to obtain homotypic or heterotypic cell sheets (CSs). Cells were retrieved as sheets from the dishes after incubation at 20 °C. Monoculture osteogenic CSs were stacked on top of homotypic or heterotypic CSs, and subcutaneously implanted in the dorsal flap of nude mice for 7 days. The implants showed mineralized tissue formation under both conditions. Transplanted osteogenic cells were found at the new tissue site, demonstrating CS bone-inductive effect. Perfused vessels, positive for human CD31, confirmed the contribution of HUVECs for the neovascularization of coculture CS constructs. Furthermore, calcium quantification and expression of osteocalcin and osterix genes were higher for the CS constructs, with HUVECs demonstrating the more robust osteogenic potential of these constructs. This work demonstrates the potential of using endothelial cells, combined with osteogenic CSs, to increase the in vivo vascularization of CS-based 3D constructs for bone tissue engineering purposes.We would like to acknowledge Mariana T Cerqueira for the illustration in Figure 1. This study was supported by Formation of Innovation Center for Fusion of Advanced Technologies in the Special Coordination Funds for Promoting Science and Technology 'Cell Sheet Tissue Engineering Center (CSTEC)' and the Global CUE program, the Multidisciplinary Education and Research Center for Regenerative Medicine (MERCREM), from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. Financial support to RP Pirraco by the Portuguese Foundation for Science and Technology (FCT) through the PhD Grant SFRH/BD/44893/2008 is also acknowledged