Establishment of canine mammary gland tumor cell lines harboring PI3K/Akt activation as a therapeutic target.

Canine mammary gland tumors (MGT) have a poor prognosis in intact female canines, posing a clinical challenge. This study aimed to establish novel canine mammary cancer cell lines from primary tumors and characterize their cellular and molecular features to find potential therapeutic drugs. The MGT cell lines demonstrated rapid cell proliferation and colony formation in an anchorage-independent manner. Vimentin and α-SMA levels were significantly elevated in MGT cell lines compared to normal canine kidney (MDCK) cells, while CDH1 expression was either significantly lower or not detected at all, based on quantitative real-time PCR (qRT-PCR) analysis. Functional annotation and enrichment analysis revealed that epithelial-mesenchymal transition (EMT) phenotypes and tumor-associated pathways, particularly the PI3K/Akt signaling pathway, were upregulated in MGT cells. BYL719 (Alpelisib), a PI3K inhibitor, was also examined for cytotoxicity on the MGT cell lines. The results show that BYL719 can significantly inhibit the proliferation of MGT cell lines in vitro. Overall, our findings suggest that the MGT cell lines may be valuable for future studies on the development, progression, metastasis, and management of tumors.

Repositioning of ezetimibe for the treatment of idiopathic pulmonary fibrosis.

BACKGROUND: We previously identified ezetimibe, an inhibitor of Niemann-Pick C1-like intracellular cholesterol transporter 1 and European Medicines Agency-approved lipid-lowering agent, as a potent autophagy activator. However, its efficacy against pulmonary fibrosis has not yet been evaluated. This study aimed to determine whether ezetimibe has therapeutic potential against idiopathic pulmonary fibrosis. METHODS: Primary lung fibroblasts isolated from both humans and mice were employed for mechanistic in vitro experiments. mRNA sequencing of human lung fibroblasts and gene set enrichment analysis were performed to explore the therapeutic mechanism of ezetimibe. A bleomycin-induced pulmonary fibrosis mouse model was used to examine in vivo efficacy of the drug. Tandem fluorescent-tagged microtubule-associated protein 1 light chain 3 transgenic mice were used to measure autophagic flux. Finally, the medical records of patients with idiopathic pulmonary fibrosis from three different hospitals were reviewed retrospectively, and analyses on survival and lung function were conducted to determine the benefits of ezetimibe. RESULTS: Ezetimibe inhibited myofibroblast differentiation by restoring the mechanistic target of rapamycin complex 1-autophagy axis with fine control of intracellular cholesterol distribution. Serum response factor, a potential autophagic substrate, was identified as a primary downstream effector in this process. Similarly, ezetimibe ameliorated bleomycin-induced pulmonary fibrosis in mice by inhibiting mechanistic target of rapamycin complex 1 activity and increasing autophagic flux, as observed in mouse lung samples. Patients with idiopathic pulmonary fibrosis who regularly used ezetimibe showed decreased rates of all-cause mortality and lung function decline. CONCLUSION: Our study presents ezetimibe as a potential novel therapeutic for idiopathic pulmonary fibrosis.

Effect of α″-Ti Martensitic Phase Formation on Plasticity in Ti-Fe-Sn Ultrafine Eutectic Composites.

Extensive research has been conducted on Ti-Fe-Sn ultrafine eutectic composites due to their high yield strength, compared to conventional microcrystalline alloys. The unique microstructure of ultrafine eutectic composites, which consists of the ultrafine-grained lamella matrix with the formation of primary dendrites, leads to high strength and desirable plasticity. A lamellar structure is known for its high strength with limited plasticity, owing to its interface-strengthening effect. Thus, extensive efforts have been conducted to induce the lamellar structure and control the volume fraction of primary dendrites to enhance plasticity by tailoring the compositions. In this study, however, it was found that not only the volume fraction of primary dendrites but also the morphology of dendrites constitute key factors in inducing excellent ductility. We selected three compositions of Ti-Fe-Sn ultrafine eutectic composites, considering the distinct volume fractions and morphologies of ß-Ti dendrites based on the Ti-Fe-Sn ternary phase diagram. As these compositions approach quasi-peritectic reaction points, the α″-Ti martensitic phase forms within the primary ß-Ti dendrites due to under-cooling effects. This pre-formation of the α″-Ti martensitic phase effectively governs the growth direction of ß-Ti dendrites, resulting in the development of round-shaped primary dendrites during the quenching process. These microstructural evolutions of ß-Ti dendrites, in turn, lead to an improvement in ductility without a significant compromise in strength. Hence, we propose that fine-tuning the composition to control the primary dendrite morphology can be a highly effective alloy design strategy, enabling the attainment of greater macroscopic plasticity without the typical ductility and strength trade-off.

Association between serum high-density lipoprotein cholesterol and lung function in adults: three cross-sectional studies from US and Korea National Health and Nutrition Examination Survey.

INTRODUCTION: Cholesterol is an irreplaceable nutrient in pulmonary metabolism; however, studies on high-density lipoprotein cholesterol (HDL-C) levels have shown conflicting results regarding lung function. Therefore, we investigated the association between lung function and HDL-C levels in three cross-sectional studies conducted in the USA and South Korea. METHODS: US National Health and Nutrition Examination Survey (NHANES) III, US NHANES 2007-2012, and Korea National Health and Nutrition Examination Survey (KNHANES) IV-VII performed spirometry and met the American Thoracic Society recommendations. Multiple linear regression models were used to determine the relationship between serum lipid levels and lung function. The models were adjusted for age, sex, household income, body mass index, smoking pack year, use of lipid-lowering medication and race. Serum HDL-C levels were classified into three groups to assess the dose-response relationship according to the guideline from the National Cholesterol Education Program-Adult Treatment Panel III. RESULTS: The adult participants of the KNHANES (n=31 288), NHANES III (n=12 182) and NHANES 2007-2012 (n=9122) were analysed. Multivariate linear regression analysis of the serum cholesterol profiles revealed that only serum HDL-C was associated with forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) in all three studies. A 1 SD increase in the HDL-C level increased the percent predicted FVC by 0.5%-1.5% p, and the per cent predicted FEV1 by 0.5%-1.7% p. In terms of HDL-C levels, correlations between the HDL-C groups and the per cent predicted FVC and FEV1 showed dose-response relationships. Compared with the normal group, high HDL-C levels increased FVC by 0.75%-1.79% p and FEV1 by 0.55%-1.90% p, while low levels led to 0.74%-2.19% p and 0.86%-2.68% p reductions in FVC and FEV1, respectively. Subgroup analyses revealed weaker associations in females from KNHANES and NHANES III. CONCLUSION: In the three nationwide cross-sectional studies, high HDL-C levels were associated with improved FVC and FEV1. However, future studies are needed to confirm this correlation and elucidate the underlying mechanisms.

Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) occurs due to the accumulation of fat in the liver, leading to fatal liver diseases such as nonalcoholic steatohepatitis (NASH) and cirrhosis. Elucidation of the molecular mechanisms underlying NAFLD is critical for its prevention and therapy. Here, we observed that deubiquitinase USP15 expression was upregulated in the livers of mice fed a high-fat diet (HFD) and liver biopsies of patients with NAFLD or NASH. USP15 interacts with lipid-accumulating proteins such as FABPs and perilipins to reduce ubiquitination and increase their protein stability. Furthermore, the severity of NAFLD induced by an HFD and NASH induced by a fructose/palmitate/cholesterol/trans-fat (FPC) diet was significantly ameliorated in hepatocyte-specific USP15 knockout mice. Thus, our findings reveal an unrecognized function of USP15 in the lipid accumulation of livers, which exacerbates NAFLD to NASH by overriding nutrients and inducing inflammation. Therefore, targeting USP15 can be used in the prevention and treatment of NAFLD and NASH.

A Coiled Carbon Nanotube Yarn-Integrated Surface Electromyography System To Monitor Isotonic and Isometric Movements.

A surface electromyogram (sEMG) electrode collects electrical currents generated by neuromuscular activity by a noninvasive technique on the skin. It is particularly attractive for wearable systems for various human activities and health care monitoring. However, it remains challenging to discriminate EMG signals from isotonic (concentric/eccentric) and isometric movements. By applying nanotechnology, we provide a coiled carbon nanotube (CNT) yarn-integrated sEMG device to overcome sEMG-based motion recognition. When the arm was contracted at different angles, the sEMG-derived root mean square amplitude signals were constant regardless of the angle of the moving arm. However, the coiled CNT yarn-derived open circuit voltage (OCV) signals proportionally increased when the arm's angle increased, and presented negative and positive values depending on the moving direction of the arm. Moreover, isometric contraction is characterized by the onset of EMG signals without an OCV signal, and isotonic contraction is determined by both EMG signals and OCV signals. Taken together, the integration of EMG and coiled CNT yarn electrodes provides complementary information, including the strength, direction, and degree of muscle movement. Therefore, we suggest that our system has high potential as a wearable system to monitor human motions in industrial and human system applications.

A Novel Approach on Deep Learning-Based Decision Support System Applying Multiple Output LSTM-Autoencoder: Focusing on Identifying Variations by PHSMs' Effect over COVID-19 Pandemic.

Following the outbreak of the COVID-19 pandemic, the continued emergence of major variant viruses has caused enormous damage worldwide by generating social and economic ripple effects, and the importance of PHSMs (Public Health and Social Measures) is being highlighted to cope with this severe situation. Accordingly, there has also been an increase in research related to a decision support system based on simulation approaches used as a basis for PHSMs. However, previous studies showed limitations impeding utilization as a decision support system for policy establishment and implementation, such as the failure to reflect changes in the effectiveness of PHSMs and the restriction to short-term forecasts. Therefore, this study proposes an LSTM-Autoencoder-based decision support system for establishing and implementing PHSMs. To overcome the limitations of existing studies, the proposed decision support system used a methodology for predicting the number of daily confirmed cases over multiple periods based on multiple output strategies and a methodology for rapidly identifying varies in policy effects based on anomaly detection. It was confirmed that the proposed decision support system demonstrated excellent performance compared to models used for time series analysis such as statistical models and deep learning models. In addition, we endeavored to increase the usability of the proposed decision support system by suggesting a transfer learning-based methodology that can efficiently reflect variations in policy effects. Finally, the decision support system proposed in this study provides a methodology that provides multi-period forecasts, identifying variations in policy effects, and efficiently reflects the effects of variation policies. It was intended to provide reasonable and realistic information for the establishment and implementation of PHSMs and, through this, to yield information expected to be highly useful, which had not been provided in the decision support systems presented in previous studies.

Implementation of a Collaborated Antimicrobial Stewardship Program and Outpatient Parenteral Antimicrobial Therapy (OPAT) Unit-driven Monoclonal Antibody Therapy Program for COVID-19 at an NYC Hospital.

OBJECTIVES: This study aimed to assess the processes and clinical outcomes of a joint collaboration between Antimicrobial Stewardship Program (ASP) and the outpatient parenteral antimicrobial therapy (OPAT) unit for delivery of monoclonal antibody therapy for mild-to-moderate COVID-19. METHODS: We carried out a retrospective, interim analysis of our COVID-19 monoclonal antibody therapy program. Outcomes included clinical response, incidence of hospitalization, and adverse events. RESULTS: A total of 175 patients (casirivimab-imdevimab, n = 130; bamlanivimab, n = 45) were treated between December 2020 and March 1, 2021. The median time from symptom onset was 6 (IQR 4, 8) days at time of treatment. Of 135 patients available for follow-up, 71.9% and 85.9% of patients reported symptom improvement within 3 and 7 days of treatment, respectively. A total of 9 (6.7%) patients required COVID-19-related hospitalization for progression of symptoms, all within 14 days of treatment. A total of 7 (4%) patients experienced an infusion-related reaction. CONCLUSIONS: ASP-OPAT collaboration is a novel approach to implement an efficient and safe monoclonal antibody therapy program for the treatment of mild-to-moderate COVID-19.

Digital Healthcare for Airway Diseases from Personal Environmental Exposure.

Digital technologies have emerged in various dimensions of human life, ranging from education to professional services to well-being. In particular, health products and services have expanded by the use and development of artificial intelligence, mobile health applications, and wearable electronic devices. Such advancements have enabled accurate and updated tracking and modeling of health conditions. For instance, digital health technologies are capable of measuring environmental pollution and predicting its adverse health effects. Several health conditions, including chronic airway diseases such as asthma and chronic obstructive pulmonary disease, can be exacerbated by pollution. These diseases impose substantial health burdens with high morbidity and mortality. Recently, efforts have been made to develop digital technologies to alleviate such conditions. Moreover, the COVID-19 pandemic has facilitated the application of telemedicine and telemonitoring for patients with chronic airway diseases. This article reviews current trends and studies in digital technology utilization for investigating and managing environmental exposure and chronic airway diseases. First, we discussed the recent progression of digital technologies in general environmental healthcare. Then, we summarized the capacity of digital technologies in predicting exacerbation and self-management of airway diseases. Concluding these reviews, we provided suggestions to improve digital health technologies' abilities to reduce the adverse effects of environmental exposure in chronic airway diseases, based on personal exposure-response modeling.

Biocompatibility of NbTaTiVZr with Surface Modifications for Osteoblasts.

We report a potential biomedical material, NbTaTiVZr, and the impact of surface roughness on the osteoblast culture and later behavior based on in vitro tests of preosteoblasts. Cell activities such as adhesion, viability, and typical protein activity on NbTaTiVZr showed comparable results with that of commercially pure Ti (CP-Ti). In addition, NbTaTiVZr with a smooth surface exhibits better cell adhesion, viability, and typical protein activity which shows that surface modification can improve the biocompatibility of NbTaTiVZr. This supports the biological evidence and shows that NbTaTiVZr can potentially be evaluated as a biomedical material for clinical use.

Hemicellulose-based hydrogels for advanced applications.

Hemicellulose-based hydrogels are three-dimensional networked hydrophilic polymer with high water retention, good biocompatibility, and mechanical properties, which have attracted much attention in the field of soft materials. Herein, recent advances and developments in hemicellulose-based hydrogels were reviewed. The preparation method, formation mechanism and properties of hemicellulose-based hydrogels were introduced from the aspects of chemical cross-linking and physical cross-linking. The differences of different initiation systems such as light, enzymes, microwave radiation, and glow discharge electrolytic plasma were summarized. The advanced applications and developments of hemicellulose-based hydrogels in the fields of controlled drug release, wound dressings, high-efficiency adsorption, and sensors were summarized. Finally, the challenges faced in the field of hemicellulose-based hydrogels were summarized and prospected.

Visible and infrared dual-band imaging via Ge/MoS2 van der Waals heterostructure.

Multispectral photodetectors are emerging devices capable of detecting photons in multiple wavelength ranges, such as visible (VIS), near infrared (NIR), etc. Image data acquired with these photodetectors can be used for effective object identification and navigations owing to additional information beyond human vision, including thermal image and night vision. However, these capabilities are hindered by the structural complexity arising from the integration of multiple heterojunctions and selective absorbers. In this paper, we demonstrate a Ge/MoS2 van der Waals heterojunction photodetector for VIS- and IR-selective detection capability under near-photovoltaic and photoconductive modes. The simplified single-polarity bias operation using single pixel could considerably reduce structural complexity and minimize peripheral circuitry for multispectral selective detection. The proposed multispectral photodetector provides a potential pathway for the integration of VIS/NIR vision for application in self-driving, surveillance, computer vision, and biomedical imaging.

Strength can be controlled by edge dislocations in refractory high-entropy alloys.

Energy efficiency is motivating the search for new high-temperature (high-T) metals. Some new body-centered-cubic (BCC) random multicomponent "high-entropy alloys (HEAs)" based on refractory elements (Cr-Mo-Nb-Ta-V-W-Hf-Ti-Zr) possess exceptional strengths at high temperatures but the physical origins of this outstanding behavior are not known. Here we show, using integrated in-situ neutron-diffraction (ND), high-resolution transmission electron microscopy (HRTEM), and recent theory, that the high strength and strength retention of a NbTaTiV alloy and a high-strength/low-density CrMoNbV alloy are attributable to edge dislocations. This finding is surprising because plastic flows in BCC elemental metals and dilute alloys are generally controlled by screw dislocations. We use the insight and theory to perform a computationally-guided search over 107 BCC HEAs and identify over 106 possible ultra-strong high-T alloy compositions for future exploration.

Deep Dichromatic Model Estimation Under AC Light Sources.

The dichromatic reflection model has been popularly exploited for computer vison tasks, such as color constancy and highlight removal. However, dichromatic model estimation is an severely ill-posed problem. Thus, several assumptions have been commonly made to estimate the dichromatic model, such as white-light (highlight removal) and the existence of highlight regions (color constancy). In this paper, we propose a spatio-temporal deep network to estimate the dichromatic parameters under AC light sources. The minute illumination variations can be captured with high-speed camera. The proposed network is composed of two sub-network branches. From high-speed video frames, each branch generates chromaticity and coefficient matrices, which correspond to the dichromatic image model. These two separate branches are jointly learned by spatio-temporal regularization. As far as we know, this is the first work that aims to estimate all dichromatic parameters in computer vision. To validate the model estimation accuracy, it is applied to color constancy and highlight removal. Both experimental results show that the dichromatic model can be estimated accurately via the proposed deep network.

Development of Precipitation-Strengthened Al0.8NbTiVM (M = Co, Ni) Light-Weight Refractory High-Entropy Alloys.

Single-phase solid-solution refractory high-entropy alloys (RHEAs) have been receiving significant attention due to their excellent mechanical properties and phase stability at elevated temperatures. Recently, many studies have been reported regarding the precipitation-enhanced alloy design strategy to further improve the mechanical properties of RHEAs at elevated temperatures. In this study, we attempted to develop precipitation-hardened light-weight RHEAs via addition of Ni or Co into Al0.8NbTiV HEA. The added elements were selected due to their smaller atomic radius and larger mixing enthalpy, which is known to stimulate the formation of precipitates. The addition of the Ni or Co leads to the formation of the sigma precipitates with homogeneous distribution. The formation and homogeneous distribution of sigma particles plays a critical role in improvement of yield strength. Furthermore, the Al0.8NbTiVM0.2 (M = Co, Ni) HEAs show excellent specific yield strength compared to single-phase AlNbTiV and NbTiVZr RHEA alloys and conventional Ni-based superalloy (Inconel 718) at elevated temperatures.

Lattice-Distortion-Enhanced Yield Strength in a Refractory High-Entropy Alloy.

Severe distortion is one of the four core effects in single-phase high-entropy alloys (HEAs) and contributes significantly to the yield strength. However, the connection between the atomic-scale lattice distortion and macro-scale mechanical properties through experimental verification has yet to be fully achieved, owing to two critical challenges: 1) the difficulty in the development of homogeneous single-phase solid-solution HEAs and 2) the ambiguity in describing the lattice distortion and related measurements and calculations. A single-phase body-centered-cubic (BCC) refractory HEA, NbTaTiVZr, using thermodynamic modeling coupled with experimental verifications, is developed. Compared to the previously developed single-phase NbTaTiV HEA, the NbTaTiVZr HEA shows a higher yield strength and comparable plasticity. The increase in yield strength is systematically and quantitatively studied in terms of lattice distortion using a theoretical model, first-principles calculations, synchrotron X-ray/neutron diffraction, atom-probe tomography, and scanning transmission electron microscopy techniques. These results demonstrate that severe lattice distortion is a core factor for developing high strengths in refractory HEAs.

Temperature dependence of elastic and plastic deformation behavior of a refractory high-entropy alloy.

Single-phase solid-solution refractory high-entropy alloys (HEAs) show remarkable mechanical properties, such as their high yield strength and substantial softening resistance at elevated temperatures. Hence, the in-depth study of the deformation behavior for body-centered cubic (BCC) refractory HEAs is a critical issue to explore the uncovered/unique deformation mechanisms. We have investigated the elastic and plastic deformation behaviors of a single BCC NbTaTiV refractory HEA at elevated temperatures using integrated experimental efforts and theoretical calculations. The in situ neutron diffraction results reveal a temperature-dependent elastic anisotropic deformation behavior. The single-crystal elastic moduli and macroscopic Young's, shear, and bulk moduli were determined from the in situ neutron diffraction, showing great agreement with first-principles calculations, machine learning, and resonant ultrasound spectroscopy results. Furthermore, the edge dislocation-dominant plastic deformation behaviors, which are different from conventional BCC alloys, were quantitatively described by the Williamson-Hall plot profile modeling and high-angle annular dark-field scanning transmission electron microscopy.

Snake fang-inspired stamping patch for transdermal delivery of liquid formulations.

A flexible microneedle patch that can transdermally deliver liquid-phase therapeutics would enable direct use of existing, approved drugs and vaccines, which are mostly in liquid form, without the need for additional drug solidification, efficacy verification, and subsequent approval. Specialized dissolving or coated microneedle patches that deliver reformulated, solidified therapeutics have made considerable advances; however, microneedles that can deliver liquid drugs and vaccines still remain elusive because of technical limitations. Here, we present a snake fang-inspired microneedle patch that can administer existing liquid formulations to patients in an ultrafast manner (<15 s). Rear-fanged snakes have an intriguing molar with a groove on the surface, which enables rapid and efficient infusion of venom or saliva into prey. Liquid delivery is based on surface tension and capillary action. The microneedle patch uses multiple open groove architectures that emulate the grooved fangs of rear-fanged snakes: Similar to snake fangs, the microneedles can rapidly and efficiently deliver diverse liquid-phase drugs and vaccines in seconds under capillary action with only gentle thumb pressure, without requiring a complex pumping system. Hydrodynamic simulations show that the snake fang-inspired open groove architectures enable rapid capillary force-driven delivery of liquid formulations with varied surface tensions and viscosities. We demonstrate that administration of ovalbumin and influenza virus with the snake fang-inspired microneedle patch induces robust antibody production and protective immune response in guinea pigs and mice.

Common features of atopic dermatitis with hypoproteinemia.

PURPOSE: The purpose of this study was to identify the causes, symptoms, and complications of hypoproteinemia to prevent hypoproteinemia and provide appropriate treatment to children with atopic dermatitis. METHODS: Children diagnosed with atopic dermatitis with hypoproteinemia and/or hypoalbuminemia were retrospectively reviewed. The patients' medical records, including family history, weight, symptoms, treatment, complications, and laboratory test results for allergies and skin cultures, were examined. RESULTS: Twenty-six patients (24 boys) were enrolled. Seven cases had growth retardation; 7, keratoconjunctivitis; 6, aural discharges; 5, eczema herpeticum; 4, gastrointestinal tract symptoms; and 2, developmental delays. In 21 cases, topical steroids were not used. According to the blood test results, the median values of each parameter were elevated: total IgE, 1,864 U/mL; egg white-specific IgE, 76.5 kUA/L; milk IgE, 20.5 kUA/L; peanut IgE, 30 kUA/L; eosinophil count, 5,810/µL; eosinophil cationic protein, 93.45 µg/L; and platelet count, 666.5×103/µL. Serum albumin and total protein levels decreased to 2.7 g/dL and 4.25 g/dL, respectively. Regarding electrolyte abnormality, 10 patients had hyponatremia, and 12, hyperkalemia. Systemic antibiotics were used to treat all cases, and an antiviral agent was used in 12 patients. Electrolyte correction was performed in 8 patients. CONCLUSION: Hypoproteinemia accompanying atopic dermatitis is common in infants younger than 1 year and may occur because of topical steroid treatment continuously being declined or because of eczema herpeticum. It may be accompanied by growth retardation, keratoconjunctivitis, aural discharge, and eczema herpeticum and can be managed through skin care and topical steroid application without intravenous albumin infusion.

Hierarchically Nanostructured CuO⁻Cu Current Collector Fabricated by Hybrid Methods for Developed Li-Ion Batteries.

We present a simple method of fabricating a hierarchically nanostructured CuO⁻Cu current collector by using laser ablation and metal mold imprinting to maximize the surface area. The laser ablation of the Cu current collector created the CuO nanostructure on the Cu-collector surface. The microstructure was transferred by subsequent imprinting of the microstructure metal mold on the Cu collector. Then, the laser-ablation nanostructure was formed. Consequently, a hierarchical structure is generated. The laser-ablated hierarchical CuO⁻Cu current collector exhibited an improved capacity while maintaining a cyclability that is similar to those of conventional graphite batteries.