Human iPS cell (iPSC)-derived cardiomyocytes (CMs) hold promise for drug discovery for heart diseases and cardiac toxicity tests. To utilize human iPSC-derived CMs, the establishment of ...three-dimensional (3D) heart tissues from iPSC-derived CMs and other heart cells, and a sensitive bioassay system to depict physiological heart function are anticipated. We have developed a heart-on-a-chip microdevice (HMD) as a novel system consisting of dynamic culture-based 3D cardiac microtissues derived from human iPSCs and microelectromechanical system (MEMS)-based microfluidic chips. The HMDs could visualize the kinetics of cardiac microtissue pulsations by monitoring particle displacement, which enabled us to quantify the physiological parameters, including fluidic output, pressure, and force. The HMDs demonstrated a strong correlation between particle displacement and the frequency of external electrical stimulation. The transition patterns were validated by a previously reported versatile video-based system to evaluate contractile function. The patterns are also consistent with oscillations of intracellular calcium ion concentration of CMs, which is a fundamental biological component of CM contraction. The HMDs showed a pharmacological response to isoproterenol, a β-adrenoceptor agonist, that resulted in a strong correlation between beating rate and particle displacement. Thus, we have validated the basic performance of HMDs as a resource for human iPSC-based pharmacological investigations.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Contactless particle manipulation based on a thermal field has shown great potential for biological, medical, and materials science applications. However, thermal diffusion from a high-temperature ...area causes thermal damage to bio-samples. Besides, the permanent bonding of a sample chamber onto microheater substrates requires that the thermal field devices be non-disposable. These limitations impede use of the thermal manipulation approach. Here, a novel manipulation platform is proposed that combines microheaters and an area cooling system to produce enough force to steer sedimentary particles or cells and to limit the thermal diffusion. It uses the one-time fabricated motherboard and an exchangeable sample chamber that provides disposable use. Sedimentary objects can be steered to the bottom center of the thermal field by combined thermal convection and thermophoresis. Single particle or cell manipulation is realized by applying multiple microheaters in the platform. Results of a cell viability test confirmed the method's compatibility in biology fields. With its advantages of biocompatibility for live cells, operability for different sizes of particles and flexibility of platform fabrication, this novel manipulation platform has a high potential to become a powerful tool for biology research.
A flexible manipulation platform combines microheaters and an area cooling system to position and manipulate single particles and cells.
BACKGROUNDIn two phase 3, global clinical trials (COUGH-1 and COUGH-2), the P2X3-receptor antagonist gefapixant significantly reduced objective 24-h cough frequency in participants with refractory or ...unexplained chronic cough (RCC or UCC) at a dosage of 45 mg twice daily (BID), with an acceptable safety profile. The primary objective of this phase 3, randomized, double-blind, parallel-group study was to assess the safety and tolerability of gefapixant in Japanese participants with RCC or UCC (ClinicalTrials.gov, NCT03696108; JAPIC-CTI, 184154). METHODSParticipants aged ≥20 years with chronic cough lasting ≥4 months and a diagnosis of RCC or UCC despite treatment in accordance with Japanese Respiratory Society guidelines were randomized 1:1 to receive gefapixant 15 or 45 mg BID for 52 weeks. The primary objective was to evaluate the safety and tolerability of gefapixant, including adverse events (AEs) and discontinuations due to AEs. Cough-specific quality of life was assessed using the Leicester Cough Questionnaire as a secondary objective. RESULTSOf 169 randomized and treated participants, 63% were female and mean age was 58 years. Adverse events were reported by 79 (94%) and 82 (96%) participants in the 15- and 45-mg BID groups, respectively. Most treatment-related AEs were taste related. Discontinuations due to AEs occurred in 6 (7%) and 17 (20%) participants receiving gefapixant 15 or 45 mg BID, respectively. There were no serious treatment-related AEs or deaths. Leicester Cough Questionnaire total scores improved from baseline through Week 52. CONCLUSIONSGefapixant had an acceptable safety profile, with no serious treatment-related AEs in Japanese participants.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
We present the detection of a secondary outflow associated with a Class I source, Ser-emb 15, in the Serpens Molecular Cloud. We reveal two pairs of molecular outflows consisting of three ...lobes, that is, primary and secondary outflows, using Atacama Large Millimeter/submillimeter Array
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CO and SiO line observations at a resolution of ∼318 au. The secondary outflow is elongated approximately perpendicular to the axis of the primary outflow in the plane of the sky. We also identify two compact structures, Sources A and B, within an extended structure associated with Ser-emb 15 in the 1.3 mm continuum emission at a resolution of ∼40 au. The projected sizes of Sources A and B are 137 au and 60 au, respectively. Assuming a dust temperature of 20 K, we estimate the dust mass to be 2.4 × 10
−3
M
⊙
for Source A and 3.3 × 10
−4
M
⊙
for Source B. C
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O line data imply rotational motion around the extended structure, but we cannot resolve rotational motion in Source A and/or B because the angular and frequency resolutions are insufficient. Therefore, we cannot conclude whether Ser-emb 15 is a single or binary system. Thus, either Source A or Source B could drive the secondary outflow. We discuss two scenarios that might explain the driving mechanism of the primary and secondary outflows: the Ser-emb 15 system is (1) a binary system composed of Sources A and B, or (2) a single-star system composed of Source A alone. In either case, the system could be a suitable target for investigating the disk and/or binary formation processes in complicated environments. Detecting these outflows should contribute to understanding complex star-forming environments, which may be common in the star formation processes.
Abstract
We report on an Atacama Large Millimeter/submillimeter Array study of the Class I or II intermediate-mass protostar DK Cha in the Chamaeleon II region. The
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CO(
J
= 2–1) images have an ...angular resolution of ∼1″ (∼250 au) and show high-velocity blueshifted (≳70 km s
−1
) and redshifted (≳50 km s
−1
) emissions, which have 3000 au scale crescent-shaped structures around the protostellar disk traced in the 1.3 mm continuum. Because the high-velocity components of the CO emission are associated with the protostar, we concluded that the emission traces the pole-on outflow. The blueshifted outflow lobe has a clear layered velocity gradient with a higher-velocity component located on the inner side of the crescent shape, which can be explained by a model of an outflow with a higher velocity in the inner radii. Based on the directly driven outflow scenario, we estimated the driving radii from the observed outflow velocities and found that the driving region extends over 2 orders of magnitude. The
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CO emission traces a complex envelope structure with arc-like substructures with lengths of ∼1000 au. We identified the arc-like structures as streamers because they appear to be connected to a rotating infalling envelope. DK Cha is useful for understanding characteristics that are visible by looking at nearly face-on configurations of young protostellar systems, providing an alternative perspective for studying the star formation process.
Background: Aortic valve calcification (AVC) has a strong association with cardiovascular outcomes in patients with type 2 diabetics (T2D). The objective of this study was to determine the prevalence ...and risk factors for AVC in Japanese T2D.Methods: We conducted a cross-sectional study of 193 consecutive T2D with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 and without overt heart disease (110 men, mean age 61 years). AVC was determined as bright echoes > 1 mm on at least one cusp of the aortic valve by echocardiography.Results: Eighty-two (42%) diabetic patients had AVC, 9 patients had aortic valve stenosis, and 25 had regurgitation. Patients with AVC were older (67 vs. 55 years), with longer diabetic duration (15 vs. 11 years), lower HbA1c (9.1 vs. 10.0%), higher presence of diabetic retinopathy (66 vs. 47%), lower BMI (24 vs. 26 kg/m2), and lower eGFR (82.1 vs. 90.4 mL/min/1.73 m2) (p < 0.01) than patients without AVC. By logistic regression analysis, older age (p < 0.001) and presence of diabetic retinopathy (p < 0.05) were independent risk factors for AVC in T2D.Conclusions: The prevalence of AVC was 42% in Japanese T2D. Diabetic retinopathy associates with presence of AVC.
Sophisticated functions of biological tissues are supported by small biological units of cells that are localized within a region of 100 μm scale. The cells in these units secrete molecules to form ...their microenvironment to play a vital role in biological functions. Various microfluidic devices have been developed to analyze the microenvironment but were not designed for cells in a culture dish in a confluent condition, a typical setup for cell and tissue cultivation. This study presents a novel glass capillary-based microfluidic device for studying confluent cells in a culture dish. The multiple capillaries allow the device to confine the local flow in 100 μm or smaller scale to form two adjacent regions with different chemical properties; it can simultaneously perform local cell stimulation and collect secreted molecules from the stimulated cells. Cell removal was achieved upon trypsin stimulation from a limited area (3.8 × 10–3 ± 1.0 × 10–3 mm2), which corresponded to 7.6 ± 2.0 cells, using the mouse skeletal myoblast cell line (C2C12 cells) in a confluent condition. Microenvironmental analysis was demonstrated by measuring the secreted tumor necrosis factor alpha (TNF-α) collected from the microenvironment of the stimulated and unstimulated mouse leukemic monocyte cell line (RAW264 cells) to track temporal changes in the TNF-α production. The TNF-α secreted from stimulated cells was approximately four-fold higher than that from unstimulated cells in 90 min. This device enables local cell stimulation and the collection of secreted molecules for cells under confluent conditions, which contributes to the analysis of the cellular microenvironment.
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IJS, KILJ, NUK, PNG, UL, UM
Bio-actuators and sensors are increasingly employed in microscale devices for numerous applications. Unlike other artificial devices actuated by living cells or tissues, here we introduce a ...microvalve system actuated by the stimuli-responsive action plant, Mimosa pudica (sleepy plant). This system realizes the control of the valve to open and close by dropping and recovering responses of Mimosa pudica branch upon external physical stimulations. The results showed that one matured single uncut Mimosa pudica branch produced average force of 15.82 ± 0.7 mN. This force was sufficient for actuating and keeping the valve open for 8.46 ± 1.33 min in a stimulation-recovering cycle of 30 min. Additionally, two separately cut Mimosa pudica branches were able to keep the valve open for 2.28 ± 0.63 min in a stimulating-recovering cycle of 20min. The pressure resistance and the response time of the valve were 4.2 kPa and 1.4 s, respectively. This demonstration of plant-microfluidics integration encourages exploiting more applications of microfluidic platforms that involve plant science and plant energy harvesting.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aim: We aimed to compare the low-density lipoprotein cholesterol (LDL-c) values obtained by direct measurement (D) and by the Friedewald equation (F), and examine the validity of the LDL-c + 30 mg/dL ...value as a non-high-density lipoprotein cholesterol (non-HDL-c) reference value. Additionally, we evaluated the association between the discrepancies between D and F and the clinical background.Methods: We collected 2,237 samples from patients ≥ 20 year-old, in either fasting or non-fasting state.Results: The Spearman's correlation coefficient between D and F was 0.964 and there was a correlation between LogD and LogF (R2 = 0.9259). The average of % Bias was -4.94% in TG < 400 mg/dL. A weak correlation between non-HDL-c and D + 30 was observed in TG ≥ 400 mg/dL (R2 = 61%). In the most cases with D lower than F, end-stage liver disease was observed. In the cases with D higher than F, no particular diseases were observed.Conclusion: In conclusion, a significant correlation was found between D and F. Both D and F could be continuously compared and examined as follow-up data in TG < 400 mg/dL. We proposed to reconsider LDL-c + 30 mg/dL as a reference value of non-HDL-c in TG ≥ 400 mg/dL.
The geometrical confinement of small cell colonies gives differential cues to cells sitting at the periphery versus the core. To utilize this effect, for example to create spatially graded ...differentiation patterns of human mesenchymal stem cells (hMSCs) in vitro or to investigate underpinning mechanisms, the confinement needs to be robust for extended time periods. To create highly repeatable micro-fabricated structures for cellular patterning and high-throughput data mining, we employed here a simple casting method to fabricate more than 800 adhesive patches confined by agarose micro-walls. In addition, a machine learning based image processing software was developed (open code) to detect the differentiation patterns of the population of hMSCs automatically. Utilizing the agarose walls, the circular patterns of hMSCs were successfully maintained throughout 15 days of cell culture. After staining lipid droplets and alkaline phosphatase as the markers of adipogenic and osteogenic differentiation, respectively, the mega-pixels of RGB color images of hMSCs were processed by the software on a laptop PC within several minutes. The image analysis successfully showed that hMSCs sitting on the more central versus peripheral sections of the adhesive circles showed adipogenic versus osteogenic differentiation as reported previously, indicating the compatibility of patterned agarose walls to conventional microcontact printing. In addition, we found a considerable fraction of undifferentiated cells which are preferentially located at the peripheral part of the adhesive circles, even in differentiation-inducing culture media. In this study, we thus successfully demonstrated a simple framework for analyzing the patterned differentiation of hMSCs in confined microenvironments, which has a range of applications in biology, including stem cell biology.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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