Stem cell factor and cKIT modulate endothelial glycolysis in hypoxia.

AIMS: In hypoxia, endothelial cells proliferate, migrate, and form new vasculature in a process called angiogenesis. Recent studies have suggested that endothelial cells rely on glycolysis to meet metabolic needs for angiogenesis in ischemic tissues and several studies have investigated the molecular mechanisms integrating angiogenesis and endothelial metabolism. Here, we investigated the role of stem cell factor (SCF) and its receptor, cKIT, in regulating endothelial glycolysis during hypoxia-driven angiogenesis. METHODS AND RESULTS: SCF and cKIT signaling increased the glucose uptake, lactate production, and glycolysis in human endothelial cells under hypoxia. Mechanistically, SCF and cKIT signaling enhanced the expression of genes encoding glucose transporter 1 (GLUT1) and glycolytic enzymes via Akt- and ERK1/2-dependent increased translation of hypoxia inducible factor 1A (HIF1A). In hypoxic conditions, reduction of glycolysis and HIF-1α expression using chemical inhibitors significantly reduced the SCF-induced in vitro angiogenesis in human endothelial cells. Compared with normal mice, mice with oxygen-induced retinopathy (OIR), characterized by ischemia-driven pathological retinal neovascularization, displayed increased levels of SCF, cKIT, HIF-1α, GLUT1, and glycolytic enzymes in the retina. Moreover, cKIT-positive neovessels in the retina of mice with OIR showed elevated expression of GLUT1 and glycolytic enzymes. Further, blocking SCF and cKIT signaling using anti-SCF neutralizing IgG and cKIT mutant mice significantly reduced the expression of HIF-1α, GLUT1, and glycolytic enzymes and decreased the pathological neovascularization in the retina of mice with OIR. CONCLUSION: We demonstrated that SCF and cKIT signaling regulates angiogenesis by controlling endothelial glycolysis in hypoxia and elucidated the SCF/cKIT/HIF-1α axis as a novel metabolic regulation pathway during hypoxia-driven pathological angiogenesis.

Ultrathin covalent organic overlayers on metal nanocrystals for highly selective plasmonic photocatalysis.

Metal nanoparticle-organic interfaces are common but remain elusive for controlling reactions due to the complex interactions of randomly formed ligand-layers. This paper presents an approach for enhancing the selectivity of catalytic reactions by constructing a skin-like few-nanometre ultrathin crystalline porous covalent organic overlayer on a plasmonic nanoparticle surface. This organic overlayer features a highly ordered layout of pore openings that facilitates molecule entry without any surface poisoning effects and simultaneously endows favourable electronic effects to control molecular adsorption-desorption. Conformal organic overlayers are synthesised through the plasmonic oxidative activation and intermolecular covalent crosslinking of molecular units. We develop a light-operated multicomponent interfaced plasmonic catalytic platform comprising Pd-modified gold nanoparticles inside hollow silica to achieve the highly efficient and selective semihydrogenation of alkynes. This approach demonstrates a way to control molecular adsorption behaviours on metal surfaces, breaking the linear scaling relationship and simultaneously enhancing activity and selectivity.

Cluster analysis driven by unsupervised latent feature learning of medications to identify novel pharmacophenotypes of critically ill patients.

Unsupervised clustering of intensive care unit (ICU) medications may identify unique medication clusters (i.e., pharmacophenotypes) in critically ill adults. We performed an unsupervised analysis with Restricted Boltzmann Machine of 991 medications profiles of patients managed in the ICU to explore pharmacophenotypes that correlated with ICU complications (e.g., mechanical ventilation) and patient-centered outcomes (e.g., length of stay, mortality). Six unique pharmacophenotypes were observed, with unique medication profiles and clinically relevant differences in ICU complications and patient-centered outcomes. While pharmacophenotypes 2 and 4 had no statistically significant difference in ICU length of stay, duration of mechanical ventilation, or duration of vasopressor use, their mortality differed significantly (9.0% vs. 21.9%, p < 0.0001). Pharmacophenotype 4 had a mortality rate of 21.9%, compared with the rest of the pharmacophenotypes ranging from 2.5 to 9%. Phenotyping approaches have shown promise in classifying the heterogenous syndromes of critical illness to predict treatment response and guide clinical decision support systems but have never included comprehensive medication information. This first-ever machine learning approach revealed differences among empirically-derived subgroups of ICU patients that are not typically revealed by traditional classifiers. Identification of pharmacophenotypes may enable enhanced decision making to optimize treatment decisions.

Regulating Electronic Structure of Iron Nitride by Tungsten Nitride Nanosheets for Accelerated Overall Water Splitting.

Two essential characteristics that are required for hybrid electrocatalysts to exhibit higher oxygen and hydrogen evolution reaction (OER and HER, respectively) activity are a favorable electronic configuration and a sufficient density of active sites at the interface between the two materials within the hybrid. In the present study, a hybrid electrocatalyst is introduced with a novel architecture consisting of coral-like iron nitride (Fe2 N) arrays and tungsten nitride (W2 N3 ) nanosheets that satisfies these requirements. The resulting W2 N3 /Fe2 N catalyst achieves high OER activity (268.5 mV at 50 mA cm-2 ) and HER activity (85.2 mV at 10 mA cm-2 ) with excellent long-term durability in an alkaline medium. In addition, density functional theory calculations reveal that the individual band centers experience an upshift in the hybrid W2 N3 /Fe2 N structure, thus improving the OER and HER activity. The strategy adopted here thus provides a valuable guide for the fabrication of cost-effective multi-metallic crystalline hybrids for use as multifunctional electrocatalysts.

Synergistic Contribution of Oligo(ethylene glycol) and Fluorine Substitution of Conjugated Polymer Photocatalysts toward Solar Driven Sacrificial Hydrogen Evolution.

To separately explore the importance of hydrophilicity and backbone planarity of polymer photocatalyst, a series of benzothiadiazole-based donor-acceptor alternating copolymers incorporating alkoxy, linear oligo(ethylene glycol) (OEG) side chain, and backbone fluorine substituents is presented. The OEG side chains in the polymer backbone increase the surface energy of the polymer nanoparticles, thereby improving the interaction with water and facilitating electron transfer to water. Moreover, the OEG-attached copolymers exhibit enhanced intermolecular packing compared to polymers with alkoxy side chains, which is possibly attributed to the self-assembly properties of the side chains. Fluorine substituents on the polymer backbone produce highly ordered lamellar stacks with distinct π-π stacking features; subsequently, the long-lived polarons toward hydrogen evolution are observed by transient absorption spectroscopy. In addition, a new nanoparticle synthesis strategy using a methanol/water mixed solvent is first adopted, thereby avoiding the screening effect of surfactants between the nanoparticles and water. Finally, hydrogen evolution rate of 26 000 µmol g-1  h-1 is obtained for the copolymer incorporated with both OEG side chains and fluorine substituents under visible-light irradiation (λ > 420 nm). This study demonstrates how the glycol side chain strategy can be further optimized for polymer photocatalysts by controlling the backbone planarity.

Pivotal challenges in artificial intelligence and machine learning applications for neonatal care.

Clinical decision support systems (CDSS) that are developed based on artificial intelligence and machine learning (AI/ML) approaches carry transformative potentials in improving the way neonatal care is practiced. From the use of the data available from electronic health records to physiological sensors and imaging modalities, CDSS can be used to predict clinical outcomes (such as mortality rate, hospital length of state, or surgical outcome) or early warning signs of diseases in neonates. However, only a limited number of clinical decision support systems for neonatal care are currently deployed in healthcare facilities or even implemented during pilot trials (or prospective studies). This is mostly due to the unresolved challenges in developing a real-time supported clinical decision support system, which mainly consists of three phases: model development, model evaluation, and real-time deployment. In this review, we introduce some of the pivotal challenges and factors we must consider during the implementation of real-time supported CDSS.

Crosstalk between BMP signaling and KCNK3 in phenotypic switching of pulmonary vascular smooth muscle cells.

Pulmonary arterial hypertension (PAH) is a progressive and devastating disease whose pathogenesis is associated with a phenotypic switch of pulmonary arterial vascular smooth muscle cells (PASMCs). Bone morphogenetic protein (BMP) signaling and potassium two pore domain channel subfamily K member 3 (KCNK3) play crucial roles in PAH pathogenesis. However, the relationship between BMP signaling and KCNK3 expression in the PASMC phenotypic switching process has not been studied. In this study, we explored the effect of BMPs on KCNK3 expression and the role of KCNK3 in the BMP-mediated PASMC phenotypic switch. Expression levels of BMP receptor 2 (BMPR2) and KCNK3 were downregulated in PASMCs of rats with PAH compared to those in normal controls, implying a possible association between BMP/BMPR2 signaling and KCNK3 expression in the pulmonary vasculature. Treatment with BMP2, BMP4, and BMP7 significantly increased KCNK3 expression in primary human PASMCs (HPASMCs). BMPR2 knockdown and treatment with Smad1/5 signaling inhibitor substantially abrogated the BMP-induced increase in KCNK3 expression, suggesting that KCNK3 expression in HPASMCs is regulated by the canonical BMP-BMPR2-Smad1/5 signaling pathway. Furthermore, KCNK3 knockdown and treatment with a KCNK3 channel blocker completely blocked BMP-mediated anti-proliferation and expression of contractile marker genes in HPAMSCs, suggesting that the expression and functional activity of KCNK3 are required for BMP-mediated acquisition of the quiescent PASMC phenotype. Overall, our findings show a crosstalk between BMP signaling and KCNK3 in regulating the PASMC phenotype, wherein BMPs upregulate KCNK3 expression and KCNK3 then mediates BMP-induced phenotypic switching of PASMCs. Our results indicate that the dysfunction and/or downregulation of BMPR2 and KCNK3 observed in PAH work together to induce aberrant changes in the PASMC phenotype, providing insights into the complex molecular pathogenesis of PAH. [BMB Reports 2022; 55(11): 565-570].

Linear and nonlinear optical properties of transfer ribonucleic acid (tRNA) thin solid films.

We successfully obtained transfer ribonucleic acid (tRNA) thin solid films (TSFs) using an aqueous solution precursor in an optimized deposition process. By varying the concentration of RNA and deposition process parameters, uniform solid layers of solid RNA with a thickness of 30 to 46 nm were fabricated consistently. Linear absorptions of RNA TSFs on quartz substrates were experimentally investigated in a wide spectral range covering UV-VIS-NIR to find high transparency for λ > 350 nm. We analyzed the linear refractive indices, n(λ) of tRNA TSFs on silicon substrates by using an ellipsometer in the 400 to 900 nm spectral range to find a linear correlation with the tRNA concentration in the aqueous solution. The thermo-optic coefficient (dn/dT) of the films was also measured to be in a range -4.21 × 10-4 to -5.81 × 10-4 °C-1 at 40 to 90 °C. We furthermore characterized nonlinear refractive index and nonlinear absorption of tRNA TSFs on quartz using a Z-scan method with a femtosecond laser at λ = 795 nm, which showed high potential as an efficient nonlinear optical material in the IR spectral range.

Sustained-Release Microspheres of Rivoceranib for the Treatment of Subfoveal Choroidal Neovascularization.

The wet type of age-related macular degeneration (AMD) accompanies the subfoveal choroidal neovascularization (CNV) caused by the abnormal extension or remodeling of blood vessels to the macula and retinal pigment epithelium (RPE). Vascular endothelial growth factor (VEGF) is known to play a crucial role in the pathogenesis of the disease. In this study, we tried to repurpose an investigational anticancer drug, rivoceranib, which is a selective inhibitor of VEGF receptor-2 (VEGFR2), and evaluate the therapeutic potential of the drug for the treatment of wet-type AMD in a laser-induced CNV mouse model using microsphere-based sustained drug release formulations. The PLGA-based rivoceranib microsphere can carry out a sustained delivery of rivoceranib for 50 days. When administered intravitreally, the sustained microsphere formulation of rivoceranib effectively inhibited the formation of subfoveal neovascular lesions in mice.

A Fully Human Monoclonal Antibody Targeting cKIT Is a Potent Inhibitor of Pathological Choroidal Neovascularization in Mice.

Stem cell factor (SCF) and its receptor, cKIT, are novel regulators of pathological neovascularization in the eye, which suggests that inhibition of SCF/cKIT signaling may be a novel pharmacological strategy for treating neovascular age-related macular degeneration (AMD). This study evaluated the therapeutic potential of a newly developed fully human monoclonal antibody targeting cKIT, NN2101, in a murine model of neovascular AMD. In hypoxic human endothelial cells, NN2101 substantially inhibited the SCF-induced increase in angiogenesis and activation of the cKIT signaling pathway. In a murine model of neovascular AMD, intravitreal injection of NN2101 substantially inhibited the SCF/cKIT-mediated choroidal neovascularization (CNV), with efficacy comparable to aflibercept, a vascular endothelial growth factor inhibitor. A combined intravitreal injection of NN2101 and aflibercept resulted in an additive therapeutic effect on CNV. NN2101 neither caused ocular toxicity nor interfered with the early retinal vascular development in mice. Ocular pharmacokinetic analysis in rabbits indicated that NN2101 demonstrated a pharmacokinetic profile suitable for intravitreal injection. These findings provide the first evidence of the potential use of the anti-cKIT blocking antibody, NN2101, as an alternative or additive therapeutic for the treatment of neovascular AMD.

Medications for Opioid Use Disorder Utilization Among Oxford House Residents.

Medications for opioid use disorder (MOUD) and recovery homes that have traditionally served those not taking medications for their recovery are important resources for treating opioid use disorder. However, little is known whether such recovery homes are a good fit for persons utilizing MOUD, and whether residents' characteristics such as drug histories and the composition of recovery homes in terms MOUD and non-MOUD residents are related to attitudes toward MOUD. The present investigation examined characteristics of persons utilizing MOUD, and attitudes regarding MOUD utilization among residents living in recovery homes (Oxford Houses, OH) in the U.S. consisting of MOUD and non-MOUD residents. Residents living with others who were utilizing MOUD reported more favorable attitudes than residents who were not living with such residents, but this was observed only among residents whose primary drug of choice involved heroin or opioids. There were no significant differences observed in terms of abstinence rates, involvement in 12-step groups, or previous MOUD treatments between residents utilizing or not utilizing MOUD. Findings suggest that persons utilizing MOUD benefit by recovery homes such as OHs whose residents have favorable attitudes toward MOUD, especially when living with fellow residents who utilize MOUD.

Uracil-doped DNA thin solid films: a new way to control optical dispersion of DNA film using a RNA constituent.

Among five nucleobases, adenine (A), guanine (G), cytosine (C), thymine (T) and uracil (U), uracil is a key distinctive constituent existing only in ribonucleic acid (RNA). RNA shares the common A, G, and C with deoxyribonucleic acid (DNA) made of A-T, G-C hydrogen bonding. We explored a new attempt to combine uracil (U) with DNA, successfully realizing U-doped DNA thin solid films for the first time. Impacts of uracil on optical properties of the films were thoroughly investigated. The method was based on optimal spin-coating of an aqueous solution of DNA and uracil over silicon or silica substrates. Optical absorption of both aqueous solution and U-doped DNA thin solid films was characterized in a wide spectral range covering UV-visible-IR. Immobilization of uracil within DNA thin solid films was experimentally confirmed by FTIR spectroscopy studies. By using an ellipsometer, we measured the refractive indices of the films and discovered that U-doping was a very effective means to control optical dispersion DNA thin solid film. We further investigated thermo-optic behavior to find impacts of U-doping in DNA films. Detailed thin film processes and optical characterizations are discussed.

Association between beverage intake and obesity in children: The Korea National Health and Nutrition Examination Survey (KNHANES) 2013-2015.

BACKGROUND/OBJECTIVES: Numerous researches have studied the association between sugar intake and obesity of children in many countries. This study was undertaken to investigate the association between beverage intake and obesity of children by reviewing a database for total sugar contents established in all foods and presented in a nutrition survey by the Korea National Health and Nutrition Examination Survey (KNHANES). SUBJECTS/METHODS: Data of 1,520 children aged 6-11 years in the 6th KNHANES (2013-2015) were analyzed for this study. A database for total sugar intake comprises the total sugar contents of all foods included in the results of a nutrition survey using the 24-hour recall method of 6th KNHANES. Beverages were categorized into carbonated beverages, fruit & vegetable drinks, other drinks, tea, and coffee. RESULTS: The average daily beverage intake of all children was 131.75 g/day, and the average daily total sugar intake in beverages was 13.76 g/day. Carbonated beverages had the highest intake rate (58.85 g/day) and also ranked highest for sugar intake (6.36 g/day). After adjusting for confounding variables, the odds ratio for obesity in children with beverage intake of ≥ 200 mL/day significantly increased by 1.83 times (95% CI, 1.11-3.00) as compared to children with beverage intake of < 200 mL/day. Also, a significant increase was observed in the odds ratio for obesity in total children (2.41 times; 95% CI, 1.35-4.33) and boys (3.15 times; 95% CI, 1.53-6.49) with carbonated beverage intake of ≥ 200 mL/day when compared with children who consumed < 200 mL/day. CONCLUSION: A positive association is observed between beverage intake and obesity in Korean children. In particular, an intake of carbonated beverages has a positive correlation with childhood obesity in boys. This study can therefore be used as scientific evidence for reducing sugar, and for the continuous management and research on beverages.

Optical dispersion control in surfactant-free DNA thin films by vitamin B2 doping.

A new route to systematically control the optical dispersion properties of surfactant-free deoxyribonucleic acid (DNA) thin solid films was developed by doping them with vitamin B2, also known as riboflavin. Surfactant-free DNA solid films of high optical quality were successfully deposited on various types of substrates by spin coating of aqueous solutions without additional chemical processes, with thicknesses ranging from 18 to 100 nm. Optical properties of the DNA films were investigated by measuring UV-visible-NIR transmission, and their refractive indices were measured using variable-angle spectroscopic ellipsometry. By doping DNA solid films with riboflavin, the refractive index was consistently increased with an index difference Δn ≥ 0.015 in the spectral range from 500 to 900 nm, which is sufficiently large to make an all-DNA optical waveguide. Detailed correlation between the optical dispersion and riboflavin concentration was experimentally investigated and thermo-optic coefficients of the DNA-riboflavin thin solid films were also experimentally measured in the temperature range from 20 to 85 °C, opening the potential to new bio-thermal sensing applications.

Changes in body weight and food security of adult North Korean refugees living in South Korea.

BACKGROUND/OBJECTIVES: Relocation to new environments can have a negative impact on health by altering body weight and dietary patterns. This study attempted to elucidate changes in body weight, food security, and their current food and nutrient consumption in adult North Korean refugees (NKR) living in South Korea (SK). SUBJECTS/METHODS: This study analyzed data on 149 adult NKR from a North Korean refugee health in SK cohort at four time points (leaving North Korea, entering SK, first examination, and second examination). Body weight was self-reported at the two earlier time points and directly measured at the two later time points. Food security, diet-related behaviors (dietary habits and food consumption), and sociodemographic information were obtained using a self-administered questionnaire. Nutrient intake information was obtained by one-day 24-hour recall. Statistical analyses were performed with SPSS ver 23.0. RESULTS: Body weight increased during relocation by an average of 4 kg, although diversified patterns were observed during the settlement period in SK. Approximately 39.6% of subjects maintained their body weight between the first and second examinations, whereas 38.6% gained and 22.1% lost at least 3% of their body weight at the first examination by the second examination. Food security status improved from 12.1% food secure proportion to 61.7%. NKR showed generally good food and nutrient consumption (index of nutrient quality: 0.77-1.93). The body weight loss group showed the most irregular meal consumption pattern (P < 0.05), and eating-out was infrequent in all three groups. Consumption frequencies of food groups did not differ by group, except in the fish group (P = 0.036). CONCLUSION: This study observed considerable body weight adjustment during the settlement period in SK after initial weight gain, whereas food security consistently improved. More detailed understanding of this process is needed to assist healthy settlement for NKR in SK.

Photosensitizer-conjugated human serum albumin nanoparticles for effective photodynamic therapy.

Photodynamic therapy (PDT) is an emerging theranostic modality for various cancers and diseases. The focus of this study was the development of tumor-targeting albumin nanoparticles containing photosensitizers for efficient PDT. To produce tumor-targeting albumin nanoparticles, the hydrophobic photosensitizer, chlorin e6 (Ce6), was chemically conjugated to human serum albumin (HSA). The conjugates formed self-assembled nanoparticle structures with an average diameter of 88 nm under aqueous conditions. As expected, the Ce6-conjugated HSA nanoparticles (Ce6-HSA-NPs) were nontoxic in their native state, but upon illumination with the appropriate wavelength of light, they produced singlet oxygen and damaged target tumor cells in a cell culture system. Importantly, when the nanoparticles were injected through the tail vein into tumor-bearing HT-29 mice, Ce6-HSA-NPs compared with free Ce6 revealed enhanced tumor-specific biodistribution and successful therapeutic results following laser irradiation. These results suggest that highly tumor-specific albumin nanoparticles have the potential to serve not only as efficient therapeutic agents, but also as photodynamic imaging (PDI) reagents in cancer treatment.

Comparative study of photosensitizer loaded and conjugated glycol chitosan nanoparticles for cancer therapy.

This study reports that tumor-targeting glycol chitosan nanoparticles with physically loaded and chemically conjugated photosensitizers can be used in photodynamic therapy (PDT). First, the hydrophobic photosensitizer, chlorin e6 (Ce6), was physically loaded onto the hydrophobically-modified glycol chitosan nanoparticles (HGC), which were prepared by self-assembling amphiphilic glycol chitosan-5ß-cholanic acid conjugates under aqueous conditions. Second, the Ce6s were chemically conjugated to the glycol chitosan polymers, resulting in amphiphilic glycol chitosan-Ce6 conjugates that formed self-assembled nanoparticles in aqueous condition. Both Ce6-loaded glycol chitosan nanoparticles (HGC-Ce6) and Ce6-conjugated chitosan nanoparticles (GC-Ce6) had similar average diameters of 300 to 350 nm, a similar in vitro singlet oxygen generation efficacy under buffer conditions, and a rapid cellular uptake profile in the cell culture system. However, compared to GC-Ce6, HGC-Ce6 showed a burst of drug release in vitro, whereby 65% of physically loaded drugs were rapidly released from the particles within 6.5h in the buffer condition. When injected through the tail vein into tumor bearing mice, HGC-Ce6 did not accumulate efficiently in tumor tissue, reflecting the burst in the release of the physically loaded drug, while GC-Ce6 showed a prolonged circulation profile and a more efficient tumor accumulation, which resulted in high therapeutic efficacy. These comparative studies with drug-loaded and drug-conjugated nanoparticles showed that the photosensitizer-conjugated glycol chitosan nanoparticles with excellent tumor targeting properties have potential for PDT in cancer treatment.