U-Shape Pillar Strip for 3D Cell-Lumped Organoid Model (3D-COM) Mimicking Lung Cancer Hypoxia Conditions in High-Throughput Screening (HTS).

Hypoxia is a representative tumor characteristic associated with malignant progression in clinical patients. Engineered in vitro models have led to significant advances in cancer research, allowing for the investigation of cells in physiological environments and the study of disease mechanisms and processes with enhanced relevance. In this study, we propose a U-shape pillar strip for a 3D cell-lumped organoid model (3D-COM) to study the effects of hypoxia on lung cancer in a high-throughput manner. We developed a U-pillar strip that facilitates the aggregation of PDCs mixed with an extracellular matrix to make the 3D-COM in 384-plate array form. The response to three hypoxia-activated prodrugs was higher in the 3D-COM than in the 2D culture model. The protein expression of hypoxia-inducible factor 1 alpha (HIF-1α) and HIF-2α, which are markers of hypoxia, was also higher in the 3D-COM than in the 2D culture. The results show that 3D-COM better recapitulated the hypoxic conditions of lung cancer tumors than the 2D culture. Therefore, the U-shape pillar strip for 3D-COM is a good tool to study the effects of hypoxia on lung cancer in a high-throughput manner, which can efficiently develop new drugs targeting hypoxic tumors.

E proteins control the development of NKγδT cells through their invariant T cell receptor.

T cell receptor (TCR) signaling regulates important developmental transitions, partly through induction of the E protein antagonist, Id3. Although normal γδ T cell development depends on Id3, Id3 deficiency produces different phenotypes in distinct γδ T cell subsets. Here, we show that Id3 deficiency impairs development of the Vγ3+ subset, while markedly enhancing development of NKγδT cells expressing the invariant Vγ1Vδ6.3 TCR. These effects result from Id3 regulating both the generation of the Vγ1Vδ6.3 TCR and its capacity to support development. Indeed, the Trav15 segment, which encodes the Vδ6.3 TCR subunit, is directly bound by E proteins that control its expression. Once expressed, the Vγ1Vδ6.3 TCR specifies the innate-like NKγδT cell fate, even in progenitors beyond the normally permissive perinatal window, and this is enhanced by Id3-deficiency. These data indicate that the paradoxical behavior of NKγδT cells in Id3-deficient mice is determined by its stereotypic Vγ1Vδ6.3 TCR complex.

A Method to Reduce Tension Differences in Pull/Push Manipulation for a Robot in Fluorescence Emission-Guided Surgical Microscopy.

MOTIVATION: A fluorescence emission-guided microscope used to monitor the outcome of cancer removal surgery is highly effective when employing a manipulator to motorize and switch the observation direction. It is necessary to minimize the alignment of looper tension between the stands for pull/push to change the direction of the manipulator and reduce the error rate caused by tension differences. This paper presents a method to minimize the error rate of looper tension between the stands. METHODS: \The looper is inserted between the stands of the manipulator to minimize the difference in tension and make the stress on the pull and push of the looper constant. The constant stress allows the manipulator to move stably in left/right, up/down, and left/right movements, which will be effective for full-camera observation and close-up shots of the end effector. RESULTS: Reducing the tolerance for differences in the manipulator's looper tension (angle and tension) is crucial. When the input value of the looper tension angle is 50°, the output should closely match 50°. Consequently, the measured response has a tolerance of ±49.98%, resulting in an error rate of .02% (1/50th level). CONCLUSION: A method is proposed to minimize the error rate of the manipulator's looper tension in a robot-based fluorescence emission-guided microscope used to observe the status of cancer surgery. As a result, a stable manipulator with a minimal error rate can achieve a 3.986x magnification for close-up observation by switching between high and low orientations.

The long-term effects of the fenestration in patients with extracardiac Fontan circulation-a multicenter Korean cohort study based on national Fontan registry.

Introduction: The long-term effects of fenestration in patients with Fontan circulation remain unclear. We aim to evaluate the fenestration impact on early and late outcomes in patients with extracardiac Fontan (ECF) using a propensity score matching analysis. Methods: We performed an extensive retrospective multicenter clinical data review of the Korean Fontan registry and included 1,233 patients with surgical ECF (779 fenestrated, 454 non-fenestrated). Demographics, baseline, and follow-up data were collected and comprehensively analyzed. Patients were divided into two groups according to the baseline presence or absence of surgical fenestration. Subsequently, patients were sub-divided according to the fenestration status at the last follow-up. Propensity-score matching was performed to account for collected data between the 2 groups using a multistep approach. The primary outcomes were survival and freedom from Fontan failure (FFF). We also looked at postoperative hemodynamics, cardiopulmonary exercise test results, oxygen saturations, and functional status. Results: After propensity-score matching (454 matched pairs), there was no difference in survival or FFF between the 2 groups. However, ECF patients with baseline fenestration had significantly lower oxygen saturation (p = 0.001) and lower functional status (p < 0.001). Patients with fenestration had significantly longer bypass times, higher postoperative central venous pressure, higher postoperative left atrial pressure, and less prolonged pleural effusion in the early postoperative period. The propensity score matching according to the fenestration status at the last follow-up (148 matched pairs) showed that patients with a persistent fenestration had significantly lower oxygen saturation levels (p < 0.001). However there were no intergroup differences in the functional status, survival and FFF. Conclusions: Our results showed no long-term benefits of the Fenestration in terms of survival and FFF. Patients with persistent fenestration showed oxygen desaturation but no difference in exercise intolerance was shown between the 2 groups.

Estimating entanglement entropy via variational quantum circuits with classical neural networks.

Entropy plays a crucial role in both physics and information science, encompassing classical and quantum domains. In this paper, we present the quantum neural entropy estimator (QNEE), an approach that combines classical neural network (NN) with variational quantum circuits to estimate the von Neumann and Rényi entropies of a quantum state. QNEE provides accurate estimates of entropy while also yielding the eigenvalues and eigenstates of the input density matrix. Leveraging the capabilities of classical NN, QNEE can classify different phases of quantum systems that accompany the changes of entanglement entropy. Our numerical simulation demonstrates the effectiveness of QNEE by applying it to the 1D XXZ Heisenberg model. In particular, QNEE exhibits high sensitivity in estimating entanglement entropy near the phase transition point. We expect that QNEE will serve as a valuable tool for quantum entropy estimation and phase classification.

Decreased incidence of Kawasaki disease in South Korea during the SARS-CoV-2 pandemic.

Purpose: Analyzing Kawasaki disease epidemiology during the SARS-CoV-2 pandemic in South Korea using 2012-2020 National Health Insurance Service data. Methods: The incidence of Kawasaki disease for 2012-2020 was investigated to identify changes in incidence after the start of the pandemic. National Health Insurance Service data from the Republic of Korea were used. Kawasaki disease was defined based on the International Statistical Classification of Diseases and Related Health Problems, the Tenth Revision diagnostic code (M30.3), and the intravenous immunoglobulin prescription code. Prescription history was collected for the following medications: intravenous immunoglobulin, aspirin, corticosteroids, tumor necrosis factor-α antagonist, clopidogrel, and anticoagulation drugs. Results: The Kawasaki disease incidence per 100,000 individuals younger than 5 years was 238.9, 230.0, and 141.2 in 2018, 2019, and 2020, respectively. Regarding the incidence from 2012 to 2020, it was the highest in 2018 and decreased to 141.2 (p < 0.001) in 2020, after the start of the pandemic. In 2020, 28.3% of all patients with KD were infants, a percentage significantly higher than that of the previous year (p < 0.001). There was biphasic seasonality in the monthly Kawasaki disease incidence. The Kawasaki disease incidence was the highest in winter followed by that in early summer. Conclusion: After the start of the pandemic, the Kawasaki disease incidence decreased, and the percentage of patients with Kawasaki disease aged <1 year increased. These findings provide support for the hypothesis suggesting an infectious trigger in Kawasaki disease.

Gadolinium-Based Magnetic Resonance Theranostic Agent with Gallic Acid as an Anti-Neuroinflammatory and Antioxidant Agent.

Studies in the field have actively pursued the incorporation of diverse biological functionalities into gadolinium-based contrast agents, aiming at the amalgamation of MRI imaging and therapeutic capabilities. In this research, we present the development of Gd-Ga, an anti-neuroinflammatory MR contrast agent strategically designed to target inflammatory mediators for comprehensive imaging diagnosis and targeted lesion treatment. Gd-Ga is a gadolinium complex composed of 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetylamide (DO3A) conjugated with gallic acid (3,4,5-trihydroxybenzoic acid). Upon intravenous administration in LPS-induced mouse models, Gd-Ga demonstrated a remarkable three-fold increase in signal-to-noise (SNR) variation compared to Gd-DOTA, particularly evident in both the cortex and hippocampus 30 min post-MR monitoring. In-depth investigations, both in vitro and in vivo, into the anti-neuroinflammatory properties of Gd-Ga revealed significantly reduced protein expression levels of pro-inflammatory mediators compared to the LPS group. The alignment between in silico predictions and phantom studies indicates that Gd-Ga acts as an anti-neuroinflammatory agent by directly binding to MD2. Additionally, the robust antioxidant activity of Gd-Ga was confirmed by its effective scavenging of NO and ROS. Our collective findings emphasize the immense potential of this theranostic complex, where a polyphenol serves as an anti-inflammatory drug, presenting an exceptionally efficient platform for the diagnosis and treatment of neuroinflammation.

Development of an Artificial Soft Solid Gel Using Gelatin Material for High-Quality Ultrasound Diagnosis.

For ultrasound diagnosis, a gel is applied to the skin. Ultrasound gel serves to block air exposure and match impedance between the skin and the probe, enhancing imaging efficiency. However, if use of the ultrasound gel exceeds a certain period of time, it may dry out and be exposed to air, causing impedance mismatch and reducing imaging resolution. In such cases, the use of a soft, solid gel proves advantageous, as it can be employed for an extended period without succumbing to the drying phenomenon and can be reused after disinfection. Its soft consistency ensures excellent skin adhesion. Our soft solid gel demonstrated approximately 1.2 times better performance than water, silicone, and traditional ultrasound gels. When comparing the dimensions of grayscale, dead zone, vertical, and horizontal regions, the measurements for the traditional ultrasound gel were 93.79 mm, 45.32 mm, 103.13 mm, 83.86 mm, and 83.86 mm, respectively. In contrast, the proposed soft solid gel exhibited dimensions of 105.64 mm, 34.48 mm, 141.1 mm, and 102.8 mm.

Ideal chest compression site for cardiopulmonary resuscitation in fontan circulation patients with dextrocardia.

BACKGROUND: We aimed to identify the ideal chest compression site for cardiopulmonary resuscitation (CPR) in patients with a single ventricle with dextrocardia corrected by Fontan surgery. METHODS: The most recent stored chest computed tomography images of all patients with a single ventricle who underwent Fontan surgery were retrospectively analysed. We reported that the ideal chest compression site is the largest part of the compressed single ventricle. To identify the ideal chest compression site, we measured the distance from the midline of the sternum to the point of the maximum sagittal area of the single ventricle as a deviation and calculated the area fraction of the compressed structures. RESULTS: 58 patients (67.2% male) were analysed. The mean right deviation from the midline of the sternum to the ideal compression site was similar to the mean sternum width (32.85 ± 15.61 vs. 31.05 ± 6.75 mm). When chest compression was performed at the ideal site, the area fraction of the single ventricle significantly increased by 7%, which was greater than that of conventional compression (0.15 ± 0.10 vs. 0.22 ± 0.11, P < 0.05). CONCLUSIONS: When performing CPR on a patient with Fontan circulation with dextrocardia, right-sided chest compression may be better than the conventional location.

Comparative Sensing and Judgment Control System for Temperature Maintenance for Optimal Treatment in Hyperthermic Intraperitoneal Chemotherapy Surgery.

For tumors wherein cancer cells remain in the tissue after colorectal cancer surgery, a hyperthermic anticancer agent is injected into the abdominal cavity to necrotize the remaining cancer cells with heat using a hyperthermic intraperitoneal chemotherapy system. However, during circulation, the processing temperature is out of range and the processing result is deteriorated. This paper proposes a look-up table (LUT) module design method that can stably maintain the processing temperature range during circulation via feedback. If the temperature decreases or increases, the LUT transmits a command signal to the heat exchanger to reduce or increase heat input, thereby maintaining the treatment temperature range. The command signal for increasing and decreasing heat input is Tp and Ta, respectively. The command signal for the treatment temperature range is Ts. If drug temperatures below 41 and above 43 °C are input to the LUT, it sends a Tp or Ta signal to the heat exchanger to increase or decrease the input heat, respectively. If the drug's temperature is 41-43 °C, the LUT generates a Ts signal and proceeds with the treatment. The proposed system can automatically control drug temperature using temperature feedback to ensure rapid, accurate, and safe treatment.

Effects of Fermented Polygonum cuspidatum on the Skeletal Muscle Functions.

Plant extract fermentation is widely employed to enhance the nutritional and pharmaceutical value of functional foods. Polygonum cuspidatum (Pc) contains flavonoids, anthraquinones, and stilbenes, imparting protective effects against inflammatory diseases, cancer, diabetes, and cardiovascular diseases. However, the effects of fermented Pc on skeletal muscle strength remain unexplored. In this study, we generated fermented Pc using a complex of microorganisms containing Lactobacillus spp. (McPc) and assessed its effects on muscle strength and motor function in mice. Compared to unfermented Pc water extract, elevated levels of emodin and resveratrol were noted in McPc. This was identified and quantified using UPLC-QTOF/MS and HPLC techniques. Gene expression profiling through RNA-seq and quantitative RT-PCR revealed that McPc administration upregulated the expression of genes associated with antioxidants, glycolysis, oxidative phosphorylation, fatty acid oxidation, and mitochondrial biogenesis in cultured C2C12 myotubes and the gastrocnemius muscle in mice. McPc significantly improved skeletal muscle strength, motor coordination, and traction force in mice subjected to sciatic neurectomy and high-fat diet (HFD). McPc administration exhibited more pronounced improvement of obesity, hyperglycemia, fatty liver, and hyperlipidemia in HFD mice compared to control group. These findings support the notion that emodin and resveratrol-enriched McPc may offer health benefits for addressing skeletal muscle weakness.

Structural basis of pH-dependent activation in a CLC transporter.

CLCs are dimeric chloride channels and anion/proton exchangers that regulate processes such as muscle contraction and endo-lysosome acidification. Common gating controls their activity; its closure simultaneously silences both protomers, and its opening allows them to independently transport ions. Mutations affecting common gating in human CLCs cause dominant genetic disorders. The structural rearrangements underlying common gating are unknown. Here, using single-particle cryo-electron microscopy, we show that the prototypical Escherichia coli CLC-ec1 undergoes large-scale rearrangements in activating conditions. The slow, pH-dependent remodeling of the dimer interface leads to the concerted opening of the intracellular H+ pathways and is required for transport. The more frequent formation of short water wires in the open H+ pathway enables Cl- pore openings. Mutations at disease-causing sites favor CLC-ec1 activation and accelerate common gate opening in the human CLC-7 exchanger. We suggest that the pH activation mechanism of CLC-ec1 is related to the common gating of CLC-7.

A Quenched Disorder in the Quantum-Critical Superconductor CeCoIn5.

Emergent inhomogeneous electronic phases in metallic quantum systems are crucial for understanding high-Tc superconductivity and other novel quantum states. In particular, spin droplets introduced by nonmagnetic dopants in quantum-critical superconductors (QCSs) can lead to a novel magnetic state in superconducting phases. However, the role of disorders caused by nonmagnetic dopants in quantum-critical regimes and their precise relation with superconductivity remain unclear. Here, the systematic evolution of a strong correlation between superconductive intertwined electronic phases and antiferromagnetism in Cd-doped CeCoIn5 is presented by measuring current-voltage characteristics under an external pressure. In the low-pressure coexisting regime where antiferromagnetic (AFM) and superconducting (SC) orders coexist, the critical current (Ic ) is gradually suppressed by the increasing magnetic field, as in conventional type-II superconductors. At pressures higher than the critical pressure where the AFM order disappears, Ic remarkably shows a sudden spike near the irreversible magnetic field. In addition, at high pressures far from the critical pressure point, the peak effect is not suppressed, but remains robust over the whole superconducting region. These results indicate that magnetic islands are protected around dopant sites despite being suppressed by the increasingly correlated effects under pressure, providing a new perspective on the role of quenched disorders in QCSs.

Adjustment of the Length Variation With Wire-driven Using the Stand Looper Tension Technique for Surgical Robot Applications.

MOTIVATION: The wire-driven method used in the field of surgical robots has the advantage of light weight. However, in the process of pull and push for the operation of forceps, the length of the wire is not match, causing malfunction. To solve this problem, the application of looper-tension technology would be suitable. This paper contributes to adjusting the length of the wire by inserting a stand between the wire-driven joints and adding a looper-tension between the stands to adjust the rotation radius of the roll. METHODS: The method consisting of three rolls and loopers for connection between the stands minimizes errors by adjusting the length of the loop in a balanced state due to the rotation change of the roll during the pull and push of the robot arm. The angle and tension applied to the looper are 25° and 8.6 MPa, respectively. RESULTS: An output response can be obtained when the reference operating point fluctuates by ± 50% of the input angle and tension, and if the reference operating point fluctuates by ± 30% while the input angle and tension are fixed, the output response occurs oppositely. When a .15 kg object is loaded up/down with 1.5 newton using forceps, the change in length of pull and push coincides. CONCLUSION: The advantage is that the error of wire pull, and push operation can be reduced, and accurate operation can be expected. Since the proposed technology is applied between joints, the integration process is not complicated, and the weight is light.

Correction: High-dose drug heat map analysis for drug safety and efficacy in multi-spheroid brain normal cells and GBM patient-derived cells.

[This corrects the article DOI: 10.1371/journal.pone.0251998.].

Multi-Asymmetric Irradiation Method Using a Ring Array to Obtain an Emission-Capable LED Beam Power Effect to Observe Cancer Removal Status in a Surgical Microscope.

The light emitting diodes (LEDs) used in surgical fluorescence microscopes have weak power, to induce fluorescence emission. The LED induces fluorescence emission throughout a lesion due to its large beam width; however, the beam irradiation intensity is not uniform within the beam width, resulting in a fluorescence emission induction difference. To overcome this problem, this study proposes an asymmetric irradiation array for supplying power uniformly throughout the beam width of the LED and increasing the intensity of the LED. To increase the irradiation power of the LEDs, a multi-asymmetric irradiation method with a ring-type array structure was used. The LED consisted of eight rings, and the space between the LEDs, the placement position, and the placement angle were analyzed to devise an experimental method using 3D printing technology. To test the irradiation power of the LED, the working distance (WD) between the LED and target was 30 cm. The bias voltage of the LED for irradiating the light source was 5.0 V and the measured power was 4.63 mW. The brightness (lux) was 1153 lx. Consequently, the LED satisfied the fluorescence emission induction conditions. The diameter of the LED-irradiated area was 9.5 cm. Therefore, this LED could be used to observe fluorescent emission-guided lesions. This study maximized the advantages of LEDs with optimal conditions for fluorescence emission by increasing the beam width, irradiation area, and energy efficiency, using a small number of LEDs at the maximum WD. The proposed method, optimized for fluorescence expression-induced surgery, can be made available at clinical sites by mass producing them through semiconductor processes.

Design of a Compact Hologram System Capable of 3D Lesion Diagnosis in Clinic.

MOTIVATION: This paper proposes a small-sized hologram system for the 3D imaging of lesions in a clinical environment. In a general hologram system, the distance between the beam-generating device and the screen (400 mm) and the size of the screen must be increased proportionally to obtain excellent image quality. However, in a clinical environment, the beam spread distance and screen size must be reduced. This paper proposes a method for reducing the beam divergence distance and screen size for clinical applications. METHODS: To reduce the beam spread distance and screen size, a beam prism with a 45° refractive index is used to reduce the beam spread distance by 1/3. The direction of the bent light must be adjusted such that it can reach the screen accurately. However, because the reflected light may be refracted owing to the material properties of the mirror and cause loss, this problem can be solved by using a full reflection mirror. RESULTS: The beam spread distance of the designed hologram system is 200 mm. The types of lesions obtained from the 3D images of the hologram include the lung, liver, and colon. The image resolution is 300 × 145. CONCLUSION: If the proposed method is used in a clinical environment, doctors can improve their understanding of the patient quickly and efficiently; thereby, shortening the treatment time. The proposed hologram system is expected to be useful in treatment rooms, operating rooms, and educational programs in medical schools.