Construction of the safe neutralizing assay system using pseudotyped Nipah virus and G protein-specific monoclonal antibody.

Nipah virus (NiV) is a recently emerged paramyxovirus that causes acute respiratory illness and fatal encephalitis in a broad spectrum of vertebrates, including humans. Due to its high pathogenicity and mortality rates, NiV requires handling in biosafety level-4 (BSL-4) containment facilities and no effective vaccines or therapeutic agents are currently available. Since current diagnostic tests for detecting serum neutralizing antibodies against NiV mainly employ live viruses, establishment of more safe and robust alternative diagnostic methods is an essential medical requirement. Here, we have developed a pseudotyped NiV and closely related Hendra virus (HeV) expressing envelope attachment (G) and fusion (F) glycoproteins using the Moloney murine leukemia virus (MuLV) packaging system. We additionally generated polyclonal antibodies (pAbs) against NiV-G and HeV-G and assessed their neutralizing activities for potential utilization in the pseudovirus-based neutralization assay and further application in the serum diagnostic test. To enhance the specificity of neutralizing antibody and sensitivity of the serological diagnostic test, monoclonal antibodies (mAbs) against NiV-G were generated, and among which four out of six mAb clones showed significant reactivity. Specifically, the 7G9 clone displayed the highest sensitivity. The selected mAb clones showed no cross-reactivity with HeV-G and efficient neutralizing activities against pseudotyped NiV. These results validate the safety and specificity of neutralization assays against NiV and HeV and present a useful tool to design effective vaccines and serological diagnosis.

From Woohwang Cheongsimwon* to Ginseng - The History of Medicine Use in the Joseon Era -*.

In Korean traditional medicine, though herbal decoction, acupuncture, and moxibustion are all used to treat diseases, restorative medicines are the most widely preferred treatment method. This paper explores the historical background of restorative herbal medicines and ginseng among the Korean public and Korean traditional medicine practice. It also seeks to clarify how social and cultural perspectives on drug use have changed since restorative medicine became mainstream during the Joseon era. Drug use tendencies were affected by the medical system of the Joseon Dynasty, patients' desires for reliable treatment, and perceptions of the human body and the causes of disease. In the late Joseon Dynasty, medicine, an industry originally monopolized by the government, began to be manufactured and traded on the free market, and medical personnel began to participate in medical activities on a large scale. As the health preserving theory became more popular and medical personnel became more accessible, medicinal preferences also changed. Specifically, whereas preference was first given to common medicines, such as Cheongsimwon, which are effective for various symptoms, restorative medicines, such as ginseng, gradually became more popular. These restorative medicines were faithful to the basic tenet of East Asian traditional medicine: to avoid disease by making the body healthy before the onset of illness. Patients' desires for safe treatment and growing competition among commercial doctors who wanted stable profits further increased the popularity of milder medicines. Ultimately, as ginseng cultivation was realized, its use expanded even further in a wave of commercialization.

Therapeutic dosage assessment based on population pharmacokinetics of a novel single-dose transdermal donepezil patch in healthy volunteers.

PURPOSE: We performed population pharmacokinetic (PK) analysis of a novel transdermal donepezil patch in healthy subjects who participated in a phase I trial. We also studied the optimal dosage regimen with repeated patch application for achieving a therapeutic range using a PK simulation model. METHODS: This study used data from a randomized, single-dose escalation phase I clinical trial conducted in Korea. The population PK analysis was performed using NONMEM software, version 7.3. From the final PK model, we simulated repeat patch application results assuming various transdermal absorption rates. RESULTS: Based on the clinical trial data, novel donepezil patches with doses of 43.75 mg/12.5 cm(2), 87.5 mg/25 cm(2), and 175 mg/50 cm(2) were placed on each subject. A linear one-compartment, first-order elimination with sequential zero- and first-order absorption model best described the donepezil plasma concentrations after patch application. Simulated results on the basis of the PK model showed that repeat application of the patches of 87.5 mg/25 cm(2) and 175 mg/50 cm(2) every 72 h would cover the therapeutic range of donepezil and reach steady-state faster with fewer fluctuations in concentration compared to typical oral administrations. CONCLUSION: A linear one-compartment with sequential zero- and first-order absorption model was effective for describing the PKs of donepezil after application of patch. Based on this analysis, 87.5 mg/25 cm(2) or 175 mg/50 cm(2) patch application every 72 h is expected to achieve the desired plasma concentration of donepezil.

Binary mask designs with single- and double-layer absorber stacks for extreme ultraviolet lithography and actinic inspection.

In this study, we propose binary mask (BIM) designs with single- and double-layer absorber stacks with high optical contrast at a wavelength of 13.5 nm for use in extreme ultraviolet lithography (EUVL) and actinic defect inspection. The optimum thickness of the absorber stack was estimated using a method based on the transfer matrix. In the double-layer designs, [Ag/SnTe] has a minimum thickness of ∼32 nm with almost 100% optical contrast compared to the TaN layer. In addition, a SnTe absorber layer was deposited using radio frequency magnetron sputtering. The optical constant of the SnTe layer at 13.5 nm wavelength was determined using the density of the layer, which was obtained from x-ray reflectivity measurements. The reflectance of the SnTe single-layer absorber stack was measured in the EUV region and compared with the simulated reflectance by using the calculated optical constants. The results show that the new BIM designs for EUVL and actinic inspection can be helpful in reducing the geometric shadow effect compared to the TaN absorber layer with a thickness of ∼70 nm.

Machine Learning-Driven Design Optimization of Buckling-Induced Quasi-Zero Stiffness Metastructures for Low-Frequency Vibration Isolation.

Metastructures, artificial arrangements of micro/macrostructures, possess unique properties and are of significant interest in aerospace, stealth technology, and various other applications. Recent studies have focused on quasi-zero stiffness metastructures, providing an outstanding vibration isolation capability. However, existing methods are constrained to low preloads and lack the consideration of structural analysis, despite their intended use in practical structures. This study introduces metastructures with quasi-zero stiffness characteristics under high preloads by inducing local buckling. An optimization framework combining deep reinforcement learning and finite-element analysis is employed to derive an optimal model that considers both structural safety and quasi-zero stiffness characteristics. To validate the optimization results, quasi-zero stiffness metastructures are fabricated via 3D printing, and compression and vibration experiments are conducted. The fabricated metastructures exhibit quasi-zero stiffness characteristics under a high target preload along with outstanding vibration reduction performance, even in the low-frequency range.

Effect of ¹8F-FDG administration on measurements of bone mineral density and body composition by dual-energy X-ray absorptiometry.

The purpose of this study was to determine whether antecedent administration of ¹8F-fluorodeoxyglucose (FDG) used in positron emission tomography (PET) scanning results in corruption of bone mineral density (BMD) and body composition measured by dual-energy X-ray absorptiometry (DXA) system. DXA measurements of BMD and body composition had been performed twice, before and after ¹8F-FDG PET scan in 30 patients. The comparison of pre-values and post-values of all BMD values showed a decrease after the injection. However, only the decrease of whole-body BMD (WB-BMD) was statistically significant (p < 0.05). Whole-body fat mass had increased and whole-body lean body mass had decreased after the injection of ¹8F-FDG, and these were statistically significant (p < 0.05). There is statistically significant correlation between the injected ¹8F-FDG dose and a decrease of WB-BMD (r = -0.405; p < 0.05). The findings of this study suggest that when both ¹8F-FDG PET and DXA measurements for whole-body composition are performed in close-time proximity, ¹8F-FDG PET scans should follow the DXA measurement. Otherwise, BMD measurements of total femur or lumbar spine could be followed by ¹8F-FDG PET in close-time proximity.

Improving the Deformability and Recovery Moment of Shape Memory Polymer Composites for Bending Actuators: Multiple Neutral Axis Skins and Deployable Core.

Shape memory polymer composite (SMPC) actuators have received significant attention for applications in space deployable structures because of their light weight and simple actuating process without any additional components. However, conventional SMPC actuators exhibit limited deformation owing to damages caused by the slight elongation of fibers and microbuckling. In this study, we designed a sandwich-structured SMPC bending actuator to increase deformability and the recovery moment with two novel features: multiple neutral axis (MNA) skins and a deployable core. The MNA skins were fabricated as layered structures of a soft layer (the polydimethylsiloxane/ethoxylated polyethylenimine layer) and hard layers (the SMPC layer) based on the MNA effect derived from the large modulus difference between the soft and hard layers. Under the bending deformation, the large shear strain in the soft layer significantly decreases the axial strain in SMPC layers and increases deformability. Applying the deployable core on the sandwich-structured SMPC bending actuator increases the recovery moment owing to the deploying force of the core. To the best of our knowledge, the sandwich-structured SMPC bending actuator composed of two MNA skins and a deployable core yielded the world's largest width-normalized recovery moment of 51.2 N·m/m with the smallest bending radius of 15 mm.

Electronic Packaging Enhancement Engineered by Reducing the Bonding Temperature via Modified Cure Cycles.

Semiconductor packaging continues to reduce in thickness following the overall thinning of electronic devices such as smartphones and tablets. As the package becomes thinner, the warpage of the semiconductor package becomes more important due to the reduced bending stiffness and driven by thermal residual stresses and thermal expansion mismatch during the epoxy molding compound (EMC) curing to create the package. To address this packaging reliability issue, in this study, we developed a modified cure cycle that adds a rapid cooling step to the conventional cure cycle (CCC) to enhance the reliability of the EMC molded to a copper substrate (EMC/Cu bi-layer package) by lowering the bonding temperature of the EMC/Cu bi-layer package. Modeling of the package via Timoshenko theory including effective cure shrinkage allowed the rapid cooling step to be quantified and confirmed via experiments. The modified cure cycle resulted in a 26% reduction in residual strain, a 27% reduction in curvature, and a 40% increase in peel strength compared to the CCC, suggesting that this is an effective new method for managing warping effects in such packaged structures.

Pediatricians' perception of factors concerning the clinical application of blockchain technology to pediatric health care: a questionnaire survey.

BACKGROUND: Interest in digital medical information has increased because it allows doctors to easily access a patient's medical records and provide appropriate medical care. Blockchain technology ensures data safety, reliability, integrity, and transparency by distributing medical data to all users over a peer-to-peer network. This study attempted to assess pediatricians' thoughts and attitudes toward introducing blockchain technology into the medical field. METHODS: This study used a questionnaire survey to examine the thoughts and attitudes of 30- to 60-year-old pediatricians regarding the introduction of blockchain technology into the medical field. Responses to each item were recorded on a scale ranging from 1 (never agree) to 7 (completely agree). RESULTS: The scores for the intentions and expectations of using blockchain technology were 4.0 to 4.6. Pediatricians from tertiary hospitals responded more positively (4.5-4.9) to the idea of using blockchain technology for hospital work relative to the general population (4.3-4.7). However, pediatricians working in primary and secondary hospitals had a slightly negative view of the application of blockchain technology to hospital work (p=0.018). CONCLUSION: When introducing the medical records of related pediatric and adolescent patients using blockchain technology in the future, it would be better to conduct a pilot project that prioritizes pediatricians in tertiary hospitals. The cost, policy, and market participants' perceptions are essential factors to consider when introducing technology in the medical field.

Reducing Bonding Temperature and Energy Consumption in Electronic Packaging Using Flash Electro-Thermal Carbon Fiber Heating Elements.

Semiconductor packaging based on an epoxy molding compound (EMC) currently has several disadvantages including warpage, limited processing area, and variability that all negatively affect cost and production yield. We propose a facile EMC molding process method using a flash electro-thermal carbon fiber heating (FE-CH) device based on carbon fiber-based papers to manufacture an EMC molded to a copper substrate (EMC/Cu bi-layer package) via Joule heating, and using this device, a modified cure cycle that combines the conventional cure cycle (CCC) with rapid cooling was performed using FE-CH to reduce the curvature of the EMC/Cu bi-layer package. Compared to the conventional hot press process, which uses 3.17 MW of power, the FE-CH process only uses 32.87 kW, resulting in a power consumption reduction of over 100 times when following the CCC. Furthermore, the FE-CH-cured EMC/Cu bi-layer package exhibits mechanical properties equivalent to those of a hot press-cured specimen, including the degree of cure, elastic modulus, curvature, bonding temperature, residual strain, and peel strength. The modified cure cycle using the FE-CH results in a 31% reduction in residual strain, a 32% reduction in curvature, and a 47% increase in peel strength compared to the CCC, indicating that this new process method is very promising for reducing a semiconductor package's price by reducing the process cost and warpage.

Optical performance of extreme ultraviolet lithography mask with an indium tin oxide absorber.

In this study, we propose a new extreme ultraviolet (EUV) binary mask with an indium tin oxide (ITO) absorber. The optical constant of ITO film at 13.5 nm wavelength in the EUV regime was determined by means of X-ray reflectivity measurements and the chemical composition was determined using Rutherford backscattering spectrometry. The reflectance of a binary mask with an ITO absorber layer at various thicknesses was also measured to investigate the optical performance in the EUV regime. It was found that the extinction coefficient of ITO film is higher than that of a typical absorber layer, TaN, and that the reflectance of the ITO absorber in the binary mask at a wavelength of 13.5 nm is reduced to 0.62% at a thickness of 45 nm. Therefore, it is expected that the ITO film can be employed as a thin absorber of a binary mask to reduce the geometrical shadow effect in extreme ultraviolet lithography.

[Development of anatomy in the edo period: on the publication of the zoshi].

Chinese medicine that saw rapid development since the writing of Yellow Emperor's Canon of Internal Medicine (Hunagti Neiching) greatly influenced Korea and then Japan, firmly establishing its dominant position in the East Asian world. However, as sciences of the west were gradually imparted to East Asia, medical topography was changing little by little as well. It was Japan that actively accommodated Western medicine. During Edo Japan, many interpretation officers played an active part for exchanges with influential merchants from the Netherlands and the resultant compilation of Kaitai Shinsho in 1774 made anatomy of the West introduced to the nation in earnest. Thereafter, starting with anatomy, westernization of Japanese medicine rapidly unfolded in the nation. Accommodation of Western anatomy was enabled by the development of empirical medicine and resulting practice of dissection. Two decades before the compilation of Kaitai Shinsho, the first dissection was made in Japan and five years later, Zoshi was published by Yamawaki Toyo, triggering great controversy over dissection in the nation's medical world. It was very meaningful in that it raised a question about positivity of traditional medicine, namely, the Theory of Visceras and Bowels, and made a verification of it. Dissection of the human body that started with Yamawaki Toyo's book was faced with criticisms from Sano Yassada and through his publication of Hi Zoshi and others on one hand but it led to practice of dissection itself on the other hand. Sixteen years later a second dissection was performed by Kawaguchi Shinnin and Kaishihen was complied by him. Thereafter, western medicine was rapidly accommodated by the nation through successive dissections, publications of anatomy books, and translations of western anatomy books, and through the Meiji Restoration the medical world was reorganized into one centered on western medicine. Modern anatomy of the West was widely introduced to East Asia and at the same time Japan led a cultural attitude to massively accept Western sciences through translations. Such academic climate, which was literally called Dutch learning(Ran Gaku), made Japan reflect itself from Western perspectives and transformed East Asia's medieval world view, knowledge system, and medical thoughts.

Unilateral Internuclear Ophthalmoplegia Following Minor Head Injury.

A lesion in the medial longitudinal fasciculus (MLF) causes internuclear ophthalmoplegia (INO). Many intracranial lesions, such as multiple sclerosis or vascular disorders may be associated with INO; however, INO is a rare complication of minor head injury. The mechanism underlying injury to the MLF may be shear force on the brain stem during head trauma. The shear force can tear or stretch the fibers of the MLF and can also lead to compromise or rupture of the perforating branches of the basilar artery. We present an unusual case of unilateral INO after minor head injury in a patient with a small site of hemorrhage in the midline of the pontomesencephalic junction, confirmed by brain magnetic resonance imaging using susceptibility-weighted imaging.

Customizable, conformal, and stretchable 3D electronics via predistorted pattern generation and thermoforming.

Recently, three-dimensional electronics (3DE) is attracting huge interest owing to the increasing demands for seamless integration of electronic systems on 3D curvilinear surfaces. However, it is still challenging to fabricate 3DE with high customizability, conformability, and stretchability. Here, we present a fabrication method of 3DE based on predistorted pattern generation and thermoforming. Through this method, custom-designed 3DE is fabricated through the thermoforming process. The fabricated 3DE has high 3D conformability because the thermoforming process enables the complete replication of both the overall shape and the surface texture of the 3D mold. Furthermore, the usage of thermoplastic elastomer and a liquid metal­based conductive electrode allows for high thermoformability during the device fabrication as well as high stretchability during the device operation. We believe that this technology can enable a wide range of new functionalities and multiscale 3D morphologies in wearable electronics.

RNA interference-mediated suppression of TNF-α converting enzyme as an alternative anti-TNF-α therapy for rheumatoid arthritis.

Excessive tumor necrosis factor-α (TNF-α) is associated with the pathogenesis of rheumatoid arthritis (RA). Approximately 90% of patients with RA, who have inadequate response to methotrexate, follow anti-TNF-α therapy as the first-line immuno-treatment. However, ineffective long-term anti-TNF-α antibody cycling for 40% of non-responders to anti-TNF-α antibodies is costly and associated with various side effects, which needs alternative mechanism of action therapies. In the present study, a novel strategy to down-regulate TNF-α level was developed by using an alternative method of suppressing TNF-α converting enzyme (TACE), a transmembrane enzyme involved in cleaving and releasing bioactive soluble TNF-α. TACE suppression can be an effective remedy to block the production of soluble TNF-α, leading to an increased sensitivity to anti-TNF-α non-responders. A disease site-targeted RNA interference system was developed by forming non-viral complex between shRNA against TACE (shTACE) and bone resorption site-specific peptide carrier composed of aspartate repeating and arginine repeating sequences. The shTACE/peptide carrier complex alleviated arthritic symptoms in collagen induced arthritis (CIA) models by demonstrating enhanced anti-inflammatory and anti-osteoclastogenic effects. Similar results were obtained with human primary synovial cells and osteoclast precursor isolated from tissues and synovial fluids of RA patients. Taken together, the shTACE/targeting peptide complex provides a strong potential as an alternative anti-TNF-α therapeutic for RA treatment.

N2O dynamics in the western Arctic Ocean during the summer of 2017.

The western Arctic Ocean (WAO) has experienced increased heat transport into the region, sea-ice reduction, and changes to the WAO nitrous oxide (N2O) cycles from greenhouse gases. We investigated WAO N2O dynamics through an intensive and precise N2O survey during the open-water season of summer 2017. The effects of physical processes (i.e., solubility and advection) were dominant in both the surface (0-50 m) and deep layers (200-2200 m) of the northern Chukchi Sea with an under-saturation of N2O. By contrast, both the surface layer (0-50 m) of the southern Chukchi Sea and the intermediate (50-200 m) layer of the northern Chukchi Sea were significantly influenced by biogeochemically derived N2O production (i.e., through nitrification), with N2O over-saturation. During summer 2017, the southern region acted as a source of atmospheric N2O (mean: + 2.3 ± 2.7 µmol N2O m-2 day-1), whereas the northern region acted as a sink (mean - 1.3 ± 1.5 µmol N2O m-2 day-1). If Arctic environmental changes continue to accelerate and consequently drive the productivity of the Arctic Ocean, the WAO may become a N2O "hot spot", and therefore, a key region requiring continued observations to both understand N2O dynamics and possibly predict their future changes.

Studies on Pre-Modern Medical History in Korea, 2010-2019: Increased Study Areas and Diversified Approaches.

The goal of this article is to summarize the current status of medical history research conducted from 2010 to 2019, following Shin Dongwon's research covering 2000-2010 regarding the current status of Korean pre-modern medical history. The list of references is organized according to several principles. The representative subjects of the Korean Society for the History of Medicine and the Korean Society of Medical history are Korean Journal of Medical History and The Journal of Korean Medical History, and Yonsei Journal of Medical History of the Yonsei University Medical History Institute. Subsequently, "Reviews and Prospects" of the History Journal and "Korean History Research Report" of the National History Compilation Committee are also summarized, and "Medical History Company Research," which was recently published by the Medical History Research Society, is also included. Unlike previous periods, many studies have been conducted on the topic, and the characteristics of the system are largely classified. Most notably, the medical data related to carriers that were concentrated in the early 2010s. It is also worth noting that the research on the agenda, including Lee Soo-gi's newly discovered agenda, is also increasing. In addition, studies that combine the history of medicine with women's history and intellectual history as interdisciplinary studies have been increasing. As such, this is an opportunity for future medical history research to expand the horizon.

CD64-targeted HO-1 RNA interference enhances chemosensitivity in orthotopic model of acute myeloid leukemia and patient-derived bone marrow cells.

Acute myeloid leukemia is the most frequent and life-threatening blood cancer. The main treatment is chemotherapy, sometimes followed by stem cell transplant. Resistance to chemotherapy and hepatotoxicity of the CD33-targeted therapy require an alternative therapeutic strategy. Here, we report CD64-targeted RNA interference as a novel AML therapy, which was delivered by a recombinant fusion protein of CD64-binding antibody and nona-arginine (sR9). The sR9-mediated heme oxygenase-1 siRNA (siHO-1) delivery efficiently enhanced apoptotic response to daunorubicin of AML cells and AML-targeted HO-1 silencing improved chemotherapy and prolonged survival in orthotopic myeloid leukemia model. CD64 expression was verified and HO-1-silencing-mediated chemo-sensitization was also validated in leukemic blast cells originated from AML M4/M5 patient's bone marrow. Collectively, CD64-targeted RNA interference could be a promising strategy for AML therapy and AML-targeted HO-1 suppression is expected to improve the chemotherapeutic effect in future clinical trials.

Pharmacokinetic Evaluation by Modeling and Simulation Analysis of a Donepezil Patch Formulation in Healthy Male Volunteers.

INTRODUCTION: This study characterized the pharmacokinetics (PKs) of a donepezil patch formulation currently under development, using mixed effect modeling analysis, and explored optimal patch dosing regimens in comparison with the donepezil oral formulation. METHODS: PK data used in this analysis were from 60 healthy Korean male subjects participating in two Phase I studies, where subjects received single or multiple doses of donepezil of 43.75, 87.5, and 175 mg via patches, and 12 of them received a single oral dose of 10 mg of donepezil, followed by a single dose of donepezil via a patch. Donepezil PKs were analyzed by nonlinear mixed effect modeling using NONMEM software. RESULTS: A well-stirred model with two-compartment distribution and delayed absorption was chosen as the best model for the oral formulation. The PKs of donepezil after the patch applications were best described by a two-compartment linear model with zero-order absorption (D2) and absorption delay. The relative bioavailability (BA) of donepezil after the patch application compared with oral dosing was described to be affected by the duration of patch application. CONCLUSION: PK simulations based on the chosen PK models suggested that, overall, donepezil exposure in plasma is similar whether with 10 mg of oral donepezil every 24 h or a 175 mg patch every 72 h, and likewise with 5 mg of oral donepezil every 24 h or an 87.5 mg patch every 72 h.

Heme Oxygenase 1-Targeted Hybrid Nanoparticle for Chemo- and Immuno-Combination Therapy in Acute Myelogenous Leukemia.

Acute myelogenous leukemia (AML) is a fatal blood cancer with high patient mortality. Daunorubicin and cytarabine are first-line chemotherapy for AML, with bone marrow transplantation in most cases. Recently, cancer immunotherapy has been challenged in AML and leukemia-niche myeloid cells are promising targets for the AML immunotherapy. Heme oxygenase 1 (HO1) is an antioxidative and cytoprotective enzyme inducing chemo-resistant AML and has been focused as an immune checkpoint molecule in tumor microenvironments. Herein, lipid-polymer hybrid nanoparticle (hNP) is loaded with tin mesoporphyrin (SnMP), a HO1-inhibitor, and non-covalently modified with an engineered antibody for leukemic cell-targeted delivery. HO1-inhibiting T-hNP (T-hNP/SnMP) enhances chemo-sensitivity in human leukemia cells. In a human AML-bearing orthotopic mouse model, intravenously injected T-hNP not only actively targets to human leukemia cells but passively targets to CD11b+ myeloid cells in a bone marrow niche. The T-hNP/SnMP enhances the chemo-therapeutic effect of daunorubicin and boosts immune response by reprogramming bone marrow myeloid cells resulting from the recruitment of the monocyte-lineage and induction of inflammatory genes. The ex vivo study demonstrates an enhanced immune response of HO1-inhibited bone marrow CD11b+ myeloid cells against apoptotic leukemia cells. Collectively, HO1-inhibiting dual cell-targeted T-hNP/SnMP has a strong potential as a novel therapeutic in AML.