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Abstract Tactile function is essential for human life as it enables us to recognize texture and respond to external stimuli, including potential threats with sharp objects that may result in punctures or lacerations. Severe skin damage caused by severe burns, skin cancer, chemical accidents, and industrial accidents damage the structure of the skin tissue as well as the nerve system, resulting in permanent tactile sensory dysfunction, which significantly impacts an individual’s daily life. Here, we introduce a fully-implantable wireless powered tactile sensory system embedded artificial skin (WTSA), with stable operation, to restore permanently damaged tactile function and promote wound healing for regenerating severely damaged skin. The fabricated WTSA facilitates (i) replacement of severely damaged tactile sensory with broad biocompatibility, (ii) promoting of skin wound healing and regeneration through collagen and fibrin-based artificial skin (CFAS), and (iii) minimization of foreign body reaction via hydrogel coating on neural interface electrodes. Furthermore, the WTSA shows a stable operation as a sensory system as evidenced by the quantitative analysis of leg movement angle and electromyogram (EMG) signals in response to varying intensities of applied pressures.

Background/Objectives: In this study, HECP2k polymer, polyethylenimine2k (PEI2k)-modified hydroxyethyl cellulose (HEC) was utilized to form the nanocomplexes with receptor activator of nuclear factor k-B (RANK) siRNA and zoledronate (Zol) for osteoclast inhibition. HECP2k/(RANK siRNA + Zol) nanocomplexes prepared by simple mixing were anticipated to overcome the low transfection efficiency of siRNA and the low bioavailability of Zol. Methods: The characterization of both HECP2k/(pDNA + Zol) nanocomplexes and HECP2k/(RANK siRNA + Zol) nanocomplexes was performed. Results: The nanocomplexes were successfully formed even in the presence of Zol, showing about 200 nm sizes and about 20 mV of positive zeta potential values suitable for efficient cellular uptake. They also possessed high endosome buffering ability by PEI and Zol, suggesting the potential for efficient endosomal escape. It was found that the low cytotoxic nanocomplexes (>90% cell viability) displayed greater transfection efficiency than PEI25k and even HECP2k polyplexes. Finally, it was found by tartrate-resistant acid phosphatase (TRAP) assay and qPCR analysis that HECP2k/(RANK siRNA + Zol) nanocomplexes could inhibit the TRAP to about 50% value and another characteristic osteoclastic gene expression, increasing FAS gene expression to about 16 times higher than control and more efficiently (about 3 times and 5 times higher, respectively) than HECP2k/siRNA polyplexes and Zol only. Conclusions: HECP2k/(RANK siRNA + Zol) nanocomplexes formed by simple mixing showed great potential for inhibiting osteoclast differentiation and osteoclast activity, inducing the apoptosis via combinatorial effects of RANK siRNA and Zol.

Abstract Background Nano-sized drug delivery system has been widely studied as a potential technique to promote tumor-specific delivery of anticancer drugs due to its passive targeting property, but resulting in very restricted improvements in its systemic administration so far. There is a requirement for a different approach that dramatically increases the targeting efficiency of therapeutic agents at targeted tumor tissues. Methods To improve the tumor-specific accumulation of anticancer drugs and minimize their undesirable toxicity to normal tissues, a tumor-implantable micro-syringe chip (MSC) with a drug reservoir is fabricated. As a clinically established delivery system, six liposome nanoparticles (LNPs) with different compositions and surface chemistry are prepared and their physicochemical properties and cellular uptake are examined in vitro. Subsequently, MSC-guided intratumoral administration is studied to identify the most appropriate for the higher tumor targeting efficacy with a uniform intratumoral distribution. For efficient cancer treatment, pro-apoptotic anticancer prodrugs (SMAC-P-FRRG-DOX) are encapsulated to the optimal LNPs (SMAC-P-FRRG-DOX encapsulating LNPs; ApoLNPs), then the ApoLNPs are loaded into the 1 μL-volume drug reservoir of MSC to be delivered intratumorally for 9 h. The tumor accumulation and therapeutic effect of ApoLNPs administered via MSC guidance are evaluated and compared to those of intravenous and intratumoral administration of ApoLNP in 4T1 tumor-bearing mice. Results MSC is precisely fabricated to have a 0.5 × 4.5 mm needle and 1 μL-volume drug reservoir to achieve the uniform intratumoral distribution of LNPs in targeted tumor tissues. Six liposome nanoparticles with different compositions of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (PC), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (PS), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)2000] (PEG2000-DSPE) are prepared with average sizes of 100–120 nm and loaded into the 1 μL-volume drug reservoir in MSC. Importantly negatively charged 10 mol% of PS-containing LNPs are very slowly infused into the tumor tissue through the micro-syringe of the MSC over 6 h. The intratumoral targeting efficiency of MSC guidance is 93.5%, effectively assisting the homogeneous diffusion of LNPs throughout the tumor tissue at 3.8- and 2.7-fold higher concentrations compared to the intravenous and intratumoral administrations of LNPs, respectively. Among the six LNP candidates 10 mol% of PS-containing LNPs are finally selected for preparing pro-apoptotic SMAC-P-FRRG-DOX anticancer prodrug-encapsulated LNPs (ApoLNPs) due to their moderate endocytosis rate high tumor accumulation and homogenous intratumoral distribution. The ApoLNPs show a high therapeutic effect specifically to cathepsin B-overexpressing cancer cells with 6.6 μM of IC50 value while its IC50 against normal cells is 230.7 μM. The MSC-guided administration of ApoLNPs efficiently inhibits tumor growth wherein the size of the tumor is 4.7- and 2.2-fold smaller than those treated with saline and intratumoral ApoLNP without MSC, respectively. Moreover, the ApoLNPs remarkably reduce the inhibitor of apoptosis proteins (IAPs) level in tumor tissues confirming their efficacy even in cancers with high drug resistance. Conclusion The MSC-guided administration of LNPs greatly enhances the therapeutic efficiency of anticancer drugs via the slow diffusion mechanism through micro-syringe to tumor tissues for 6 h, whereas they bypass most hurdles of systemic delivery including hepatic metabolism, rapid renal clearance, and interaction with blood components or other normal tissues, resulting in the minimum toxicity to normal tissues. The negatively charged ApoLNPs with cancer cell-specific pro-apoptotic prodrug (SMAC-P-FRRG-DOX) show the highest tumor-targeting efficacy when they are treated with the MSC guidance, compared to their intravenous or intratumoral administration in 4T1 tumor-bearing mice. The MSC-guided administration of anticancer drug-encapsulated LNPs is expected to be a potent platform system that facilitates overcoming the limitations of systemic drug administration with low delivery efficiency and serious side effects. Graphical Abstract

Abstract To evaluate the associations of periodontal disease (PD) with systemic diseases, including diabetes mellitus (DM) and cardiovascular disease (CVD), as well as the reciprocal association. The CVD included the cases of coronary heart disease and heart failure. A prospective study was conducted from 2007 to 2019 using linked data from three databases in Korea. Three separate study groups were formed to individually determine the risks of PD (n = 10,533), DM (n = 14,523) and CVD (n = 14,315). All diseases were confirmed based on physicians’ diagnoses using medical records and self-reports. Cox proportional hazard regression was applied with 95% confidence intervals (CIs) to obtain hazard ratios (HRs). PD was significantly associated with an elevated risk of DM (HR [95% CI]: 1.22 [1.07–1.39]) after full adjustment for age, sex, lifestyle factors, body mass index, dental behaviour and CVD. PD was also found to increase the risk of CVD (1.27 [1.03–1.57]), whereas CVD increased the risk of PD (1.20 [1.09–1.32]) after full adjustment for other covariates including DM. This study found a bidirectional association between PD and CVD, as well as a positive association of PD with DM.

Abstract The objective of this study was to automatically classify surgical plans for maxillary sinus floor augmentation in implant placement at the maxillary posterior edentulous region using a 3D distance-guided network on CBCT images. We applied a modified ABC classification method consisting of five surgical approaches for the deep learning model. The proposed deep learning model (SinusC-Net) consisted of two stages of detection and classification according to the modified classification method. In detection, five landmarks on CBCT images were automatically detected using a volumetric regression network; in classification, the CBCT images were automatically classified as to the five surgical approaches using a 3D distance-guided network. The mean MRE for landmark detection was 0.87 mm, and SDR for 2 mm or lower, 95.47%. The mean accuracy, sensitivity, specificity, and AUC for classification by the SinusC-Net were 0.97, 0.92, 0.98, and 0.95, respectively. The deep learning model using 3D distance-guidance demonstrated accurate detection of 3D anatomical landmarks, and automatic and accurate classification of surgical approaches for sinus floor augmentation in implant placement at the maxillary posterior edentulous region.

Abstract Background Photodynamic therapy (PDT) is a promising strategy to promote antitumor immunity by inducing immunogenic cell death (ICD) in tumor cells. However, practical PDT uses an intense visible light owing to the shallow penetration depth of the light, resulting in immunosuppression at the tumor tissues. Methods Herein, we propose an implantable micro-scale light-emitting diode device (micro-LED) guided PDT that enables the on-demand light activation of photosensitizers deep in the body to potentiate antitumor immunity with mild visible light. Results The micro-LED is prepared by stacking one to four micro-scale LEDs (100 μm) on a needle-shape photonic device, which can be directly implanted into the core part of the tumor tissue. The photonic device with four LEDs efficiently elicits sufficient light output powers without thermal degradation and promotes reactive oxygen species (ROS) from a photosensitizer (verteporfin; VPF). After the intravenous injection of VPF in colon tumor-bearing mice, the tumor tissues are irradiated with optimal light intensity using an implanted micro-LED. While tumor tissues under intense visible light causes immunosuppression by severe inflammatory responses and regulatory T cell activation, mild visible light elicits potent ICD in tumor cells, which promotes dendritic cell (DC) maturation and T cell activation. The enhanced therapeutic efficacy and antitumor immunity by micro-LED guided PDT with mild visible light are assessed in colon tumor models. Finally, micro-LED guided PDT in combination with immune checkpoint blockade leads to 100% complete tumor regression and also establishes systemic immunological memory to prevent the recurrence of tumors. Conclusion Collectively, this study demonstrates that micro-LED guided PDT with mild visible light is a promising strategy for cancer immunotherapy.

Abstract The purpose of this study was to propose a continuity-aware contextual network (Canal-Net) for the automatic and robust 3D segmentation of the mandibular canal (MC) with high consistent accuracy throughout the entire MC volume in cone-beam CT (CBCT) images. The Canal-Net was designed based on a 3D U-Net with bidirectional convolutional long short-term memory (ConvLSTM) under a multi-task learning framework. Specifically, the Canal-Net learned the 3D anatomical context information of the MC by incorporating spatio-temporal features from ConvLSTM, and also the structural continuity of the overall MC volume under a multi-task learning framework using multi-planar projection losses complementally. The Canal-Net showed higher segmentation accuracies in 2D and 3D performance metrics (p

Abstract Continued research on the epidermal electronic sensor aims to develop sophisticated platforms that reproduce key multimodal responses in human skin, with the ability to sense various external stimuli, such as pressure, shear, torsion, and touch. The development of such applications utilizes algorithmic interpretations to analyze the complex stimulus shape, magnitude, and various moduli of the epidermis, requiring multiple complex equations for the attached sensor. In this experiment, we integrate silicon piezoresistors with a customized deep learning data process to facilitate in the precise evaluation and assessment of various stimuli without the need for such complexities. With the ability to surpass conventional vanilla deep regression models, the customized regression and classification model is capable of predicting the magnitude of the external force, epidermal hardness and object shape with an average mean absolute percentage error and accuracy of

Abstract Human nonverbal communication tools are very ambiguous and difficult to transfer to machines or artificial intelligence (AI). If the AI understands the mental state behind a user’s decision, it can learn more appropriate decisions even in unclear situations. We introduce the Brain–AI Closed-Loop System (BACLoS), a wireless interaction platform that enables human brain wave analysis and transfers results to AI to verify and enhance AI decision-making. We developed a wireless earbud-like electroencephalography (EEG) measurement device, combined with tattoo-like electrodes and connectors, which enables continuous recording of high-quality EEG signals, especially the error-related potential (ErrP). The sensor measures the ErrP signals, which reflects the human cognitive consequences of an unpredicted machine response. The AI corrects or reinforces decisions depending on the presence or absence of the ErrP signals, which is determined by deep learning classification of the received EEG data. We demonstrate the BACLoS for AI-based machines, including autonomous driving vehicles, maze solvers, and assistant interfaces.

Abstract As one of conducting polymers, PEDOT:PSS, is commonly used in organic electronics, especially for bioelectronics due to its advantages such as high electrical and ionic conductivity, solution-processability and biocompatibility. Creating bioelectronics with the PEDOT:PSS requires advanced techniques to obtain physical/chemical modification of the PEDOT:PSS for improved performance and various applications. To satisfy these demands, fibrillary gelation of PEDOT:PSS by injection to choline acetate, an ionic liquid, with a constant flow rate was used in this study to make a conductive fiber and improve characteristics of PEDOT:PSS. Conductive fibers by fibrillary gelation showed enhanced electrical conductivity of about 400 S cm−1 and volumetric capacitance of about 154 F cm−3 which would be strongly beneficial to be utilized for organic electrochemical transistors (OECTs), resulting in a high transconductance of 19 mS in a depletion-mode. Moreover, dedoping of the conductive fibers by PEI (polyethyleneimine) enabled the creation of enhancement-mode OECTs. Interdigitated inverters were then fabricated by connecting depletion and enhancement-mode OECTs. These results demonstrate that these conductive fibers and electronic-textiles are suitable candidates for applications in bio-integrated electronics.

In this study, Saccharomyces cerevisiae culture fluid (SCCF) has been added to a diet of lactating dairy cows to attempt to improve the ruminal fermentation and potentially increase the dry matter intake (DMI) and milk yield. This study was conducted to investigate the effects of SCCF on the milk yield and blood biochemistry in lactating cows during the summer. Twenty-four Holstein dairy cows were randomly assigned to one of four treatments: (1) total mixed ration (TMR-1) (Control); (2) TMR-1 supplemented with SCCF (T1); (3) TMR-2 (containing alfalfa hay) (T2); and (4) TMR-2 supplemented with SCCF (T3). SCCF (5 ml/head, 2.0×107 CFU/mL) was mixed with TMRs daily before feeding to dairy cows. The mean daily temperature-humidity index (THI) during this trial was 76.92 ± 0.51 on average and ranged from 73.04 to 81.19. For particle size distribution, TMR-2 had a lower >19 mm fraction and a higher 8–19 mm fraction than TMR-1 (p < 0.05). The type of TMR did not influence the DMI, body weight (BW), milk yield and composition, or blood metabolites. The milk yield and composition were not affected by the SCCF supplementation, but somatic cell counts were reduced by feeding SCCF (p < 0.05). Feeding SCCF significantly increased the DMI but did not affect the milk yield of dairy cows. The NEFA concentration was slightly decreased compared to that in the control and T2 groups without SCCF. Feeding a yeast culture of S. cerevisiae may improve the feed intake, milk quality and energy balance of dairy cows under heat stress.

We evaluated the effects of heat stress on physiological responses and milk production in Holstein and Jersey cows reared in Korea. The mean average temperature-humidity index (THI) increased significantly from May to August and then decreased until October. The mean average rectal temperature (RT) was increased in Holstein cows compared with Jersey cows, as the THI values increased from 61 to 85. The average respiratory rate (RR) was increased in Jersey cows compared with Holstein cows when the THI value increased from 61 to 85. The average surface temperature of the rumen and udder was higher in Jersey cows than in Holstein cows when the THI value increased from 61 to 85. No significant difference was noted with respect to relative serum volumes between the breeds and THI ranges, but we measured significant changes in serum pH in Holstein and Jersey cows when the THI value increased from 61 to 85. Milk production was not significantly changed in Holstein cows when the THI increased from 61 to 85, but milk production and milk protein content were significantly altered in Jersey cows when the THI increased from 61 to 85. Current study suggests that Holstein cows still have an advantage in terms of the economic returns of dairy farms in Korea. Therefore, further research is required regarding the heat tolerance of Jersey cows in Korean climatic conditions.

The purpose of this study was to determine the effects of photoperiod and light intensity on milk production, milk composition, hormones levels and blood metabolites indices of Korean Holstein dairy cows in automatic milking system (AMS). A total of 24 Holstein dairy cows were selected and used to four subsequent treatments for the experimental periods of 60 days. The light programs consisted of (1) Control: the natural photoperiod with 14.2 h of the light period and 9.4 h of the dark period (below 10 Lux); (2) T1: 16 h of the long day photoperiod (LDPP) with 50 Lux of light; (3) T2: 16 h of LDPP with 100 Lux of light; and (4) T3: 16 h of LDPP with 200 Lux of light, respectively. Importantly, there was a significant difference in the thurl activity of dairy cows between the different light intensity programs (p < 0.05). Milk yield was higher in T1 and T2 (40.80 ± 1.71 and 39.90 ± 2.02 kg/d, respectively) than those of Control and T3 (32.18 ± 1.51 and 35.76 ± 2.80 kg/d, respectively) (p < 0.05), but DMI was lower in T1, T2, and T3 compared to Control (p < 0.05). Also, milk fat percentage, the contents of milk fat and total solids were higher in T2 than those in the others (p < 0.05). The average daily melatonin level in milk was high to T3 (28.20 ± 0.43 pg/mL), T2 (24.62 ± 0.32 pg/mL), T1 (19.78 ± 0.35 pg/mL), and Control (19.36 ± 0.45 pg/mL) in order (p < 0.05). Also, the cortisol levels in milk and blood were lower in treatment groups than in Control (p < 0.05). The results of this study showed that it will be effective to improve the milk yield and milk composition, and to reduce the stress of dairy cows when the light conditions regulate to extend the photoperiod to 16 h at a light emitting diode (LED) intensity of 100 Lux under the AMS in dairy farm.

Objective In this study we investigated the effect of seasonal thermal stress on milk production and milk compositions between Holstein and Jersey dairy cows under the temperate-climate in Korea. Methods A total of 9 Holstein lactating dairy cows (2.0±0.11 parity) which had a daily milk yield of 29.77±0.45 kg, and days in milk of 111.2±10.29 were selected similarly at the beginning of the experiments in each season. Also, a total of 9 Jersey lactating dairy cows (1.7±0.12 parity) which had a daily milk yield of 20.01±0.43 kg, and days in milk of 114.0± 9.74 were selected similarly at the beginning of the experiments. Results Results showed that the average ambient temperature (°C) and temperature-humidity index (THI) were higher in summer, and were lower in winter (p

Recently, Jersey cattle was introduced and produced by embryo transfer to Korea. This study was conducted to investigate the differences of milk compositions between Jersey and Holstein cows and the relationship between days in milk (DIM) and milk compositions during early lactation. Data were collected from twelve lactating cows from Department of Animal Resources Development at National Institute of Animal Science. Cows in parity 1 were used, and calved at spring from April to March of 2017. All cows were housed in two sections within a free-stall barn, which divided into six from each breed, and received a basal total mixed ration. Milk samples of each cow were collected at 3 DIM and 30 DIM for analyzing the milk compositions, including fatty acids (FA), amino acids and minerals. Total solids, citrate, and milk urea nitrogen level were differed between the breeds (p < 0.05). As DIM went from 3 to 30, milk protein, total solids, and somatic cell count decreased (p < 0.05), but lactose increased in all breed milk (p < 0.05). Citrate and free fatty acid (FFA) elevated in Jersey milk (p < 0.05), whereas reduced in Holstein milk (p < 0.05). Proportions of some individual FA varied from the breeds. Myristic (C14:0), palmitic (C16:0), and arachidonic acid (C20:4) in milk from all cows were higher at 3 DIM than at 30 DIM (p < 0.05). Also, stearic (C18:0) and oleic acid (C18:1) were lower at 3 DIM than at 30 DIM (p < 0.05), and the C18:1 to C18:0 ratio was significantly differed in DIM × breed interactions (p < 0.05). The contents of the individual amino acids did not differ from the breeds. Calcium, phosphorous, magnesium, and zinc (Zn) contents was significantly increased in Holstein milk than Jersey milk at 3 DIM. Also, K and Zn concentrations were higher in Holstein milk than in Jersey milk at 30 DIM (p < 0.05). It was concluded that Jersey cows would produce more effective milk in processing dairy products and more proper energy status compared with Holstein cows in early lactation under the same environmental and nutritional conditions.

Hydroxyethyl cellulose (HEC), widely known for its biocompatibility and water solubility, is a polysaccharide with potential for pharmaceutical applications. Here, we synthesized polyethylenimine2k (PEI2k)-conjugated hydroxyethyl cellulose (HECP2k) for doxorubicin/Bcl-2 siRNA co-delivery systems. HECP2ks were synthesized by reductive amination of PEI2k with periodate-oxidized HEC. The synthesis of the polymers was characterized using 1H NMR, 13C NMR, primary amine quantification, FT-IR, and GPC. Via agarose gel electrophoresis and Zeta-sizer measurement, it was found that HECP2ks condensed pDNA to positively charged and nano-sized complexes (100–300 nm, ~30 mV). The cytotoxicity of HECP2ks was low and HECP2k 10X exhibited higher transfection efficiency than PEI25k even in serum condition, showing its high serum stability from ethylene oxide side chains. Flow cytometry analysis and confocal laser microscopy observation verified the superior cellular uptake and efficient endosome escape of HECP2k 10X. HECP2k 10X also could load Dox and Bcl-2 siRNA, forming nano-particles (HECP2k 10X@Dox/siRNA). By median effect analysis and annexin V staining analysis, it was found that HECP2k 10X@Dox/siRNA complexes could cause synergistically enhanced anti-cancer effects to cancer cells via induction of apoptosis. Consequently, it was concluded that HECP2k possesses great potential as a promising Dox/Bcl-2 siRNA co-delivery carrier.

This review focuses on surface modifications to gallium‐based liquid metals (LMs), which are stretchable conductors with metallic conductivity and nearly unlimited extensibility due to their liquid nature. Despite the enormous surface tension of LM, it can be patterned into nonspherical shapes, such as wires, due to the presence of a native oxide shell. Incorporating inherently soft LM into elastomeric devices offers comfort, mechanical compliance, and stretchability. The thin oxide layer also enables the formation of stable liquid colloids and LM micro/nanosized droplets that do not coalesce easily. The oxide layer can also be exfoliated and chemically modified into semiconductor 2D materials to create and deposit atomically thin materials at room temperature. Thus, the interface and its manipulation are important. This review summarizes physical and chemical methods of modifying the surface of LM to tune its properties. The surface modification of LM provides unique applications, including use in soft biomedical sensors and actuators with mechanical properties similar to human tissue.

The effect of severely compromised teeth on masticatory function has not been properly evaluated in previous studies, as they were often considered equivalent to the healthy tooth or excluded as if absent in the dentition. Hopeless teeth, which refer to non-salvageable teeth that require extraction, can interfere with masticatory function. As posterior occlusion is directly related to the masticatory function, we evaluated pairs opposing posterior teeth (POPs) that reflect the arrangement as well as the number of remaining posterior teeth. This study investigated the relationship of a hopeless tooth to handgrip strength according to POPs in the elderly. This cross-sectional study used data from the Korea National Health and Nutrition Examination Survey (KNHANES). Among the data of 23,466 participants from 2015 to 2018, participants aged 60 years or older (n = 4,729) were included. In males with POPs scores of 0-7, considered poor posterior occlusion, the association with low handgrip strength persisted in the multivariate logistic regression model adjusted for all confounding variables. The odds ratio (OR) in the absence of hopeless teeth (OR = 1.91, 95% CI: 1.02-3.59) increased in the presence of a hopeless tooth (OR = 2.78, 95% CI: 1.42-5.47). Even with POPs scores of 8-11, considered good posterior occlusion, the association was significantly high in the presence of a hopeless tooth (OR = 2.82, 95% CI: 1.06-7.52). In females, the association disappeared in adjusted models. The fewer pairs of natural posterior teeth with occlusion, the greater the risk of low handgrip strength. Dentition containing hopeless teeth increases the risk of low handgrip strength, even in dentition with sufficient posterior occlusion. Preserving the posterior teeth in a healthy condition through personal oral hygiene and regular dental management is essential for maintaining components of physical function such as handgrip strength.

Objective Dairy cattle nutrient requirement systems acknowledge amino acid (AAs) requirements in aggregate as metabolizable protein (MP) and assume fixed efficiencies of MP used for milk protein. Regulation of mammary protein synthesis may be associated with AA input and milk protein output. The aim of this study was to evaluate the effect of nanoemulsified methionine and cysteine on the in-vitro expression of milk protein (casein) in bovine mammary epithelial cells (MAC-T cells). Methods Methionine and cysteine were nonionized using Lipoid S 75 by high-speed homogenizer. The nanoemulsified AA particle size and polydispersity index were determined by dynamic light scattering correlation spectroscopy using a high-performance particle sizer instrument. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to determine the cytotoxicity effect of AAs with and without nanoionization at various concentrations (100 to 500 μg/mL) in mammary epithelial cells. MAC-T cells were subjected to 100% of free AA and nanoemulsified AA concentration in Dulbecco’s modified Eagle medium/nutrient mixture F-12 (DMEM/F12) for the analysis of milk protein (casein) expression by the quantitative reverse transcription polymerase chain reaction method. Results The AA-treated cells showed that cell viability tended to decrease (80%) in proportion to the concentration before nanogenesis, but cell viability increased as much as 90% after nanogenesis. The analysis of the expression of genetic markers related to milk protein indicated that; αs2-casein increased 2-fold, κ-casein increased 5-fold, and the amount of unchanged β-casein expression was nearly doubled in the nanoemulsified methionine-treated group when compared with the free-nanoemulsified methionine-supplemented group. On the contrary, the non-emulsified cysteine-administered group showed higher expression of genetic markers related to milk protein αs2-casein, κ-casein, and β-casein, but all the genetic markers related to milk protein decreased significantly after nanoemulsification. Conclusion Detailed knowledge of factors, such nanogenesis of methionine, associated with increasing cysteine and decreasing production of genetic markers related to milk protein (casein) will help guide future recommendations to producers for maximizing milk yield with a high level of milk protein casein.

Introduction: The impact of device-assisted enteroscopy (DAE) on long-term rebleeding in patients with obscure gastrointestinal bleeding (OGIB) exhibiting detectable small-bowel lesions remains unclear. We investigated the long-term rebleeding rate and predictive factors for DAE in patients with OGIB. Method: Patients with OGIB with small bowel lesions detected through DAE were enrolled at three Korean tertiary hospitals. Predictive risk factors associated with rebleeding were analyzed using the Cox regression analysis. Results: From April 2008 to April 2021, 141 patients were enrolled, including 38 patients (27.0%) with rebleeding. The rebleeding rates at 1, 2, and 3 years were 25.0%, 29.6%, and 31.1%, respectively. The Cox regression analysis revealed that multiple small-bowel lesions (hazard ratio [HR]: 2.551, 95% confidence interval [CI]: 1.157–5.627, p = 0.020), the need for more than five packed red blood cells (RBC) transfusions (HR: 2.704, 95% CI: 1.412–5.181, p = 0.003), and ulcerative lesions (HR: 1.992, 95% CI: 1.037–3.826, p = 0.039) were positively associated with rebleeding. Therapeutic interventions for patients with detectable lesions, overt bleeding (vs. occult bleeding), comorbidities, and medications were not associated with rebleeding. Conclusion: More than 25% of patients with OGIB having detectable small-bowel lesions had rebleeding. Patients with multiple lesions, a requirement of more than five packed RBC transfusions, and ulcerative lesions were associated with a higher risk of rebleeding.

Regulatory T cells (Tregs) promote immune suppression in the tumour. Here, the authors show that Tregs suppress cytotoxic T lymphocyte (CTL) activity by impairing Ca2+ signalling and that adoptive transfer of CTLs engineered with an optogenetic control of Ca2+overcome the immune suppression at the tumour site.

In this work, highly osmotic oxidized sucrose-crosslinked polyethylenimine (SP2K) polymers were developed for gene delivery systems, and the transfection mechanism is examined. First, periodate-oxidized sucrose and polyethylenimine 2K (PEI2K) were crosslinked with various feed ratios via reductive amination. The synthesis was confirmed by 1H NMR and FTIR. The synthesized SP2K polymers could form positively charged (~40 mV zeta-potential) and nano-sized (150–200 nm) spherical polyplexes with plasmid DNA (pDNA). They showed lower cytotoxicity than PEI25K but concentration-dependent cytotoxicity. Among them, SP2K7 and SP2K10 showed higher transfection efficiency than PEI25K in both serum and serum-free conditions, revealing the good serum stability. It was found that SP2K polymers possessed high osmolality and endosome buffering capacity. The transfection experiments with cellular uptake inhibitors suggest that the transfection of SP2K polymers would progress by multiple pathways, including caveolae-mediated endocytosis. It was also thought that caveolae-mediated endocytosis of SP2K polyplexes would be facilitated through cyclooxygenase-2 (COX-2) expression induced by high osmotic pressure of SP2K polymers. Confocal microscopy results also supported that SP2K polyplexes would be internalized into cells via multiple pathways and escape endosomes efficiently via high osmolality and endosome buffering capacity. These results demonstrate the potential of SP2K polymers for gene delivery systems.

Brassica oleracea var. capitata L. (cabbage) is a popular vegetable with a wide range of pharmacological activities that help to promote human health. The present study investigated the beneficial effects of B. oleracea var. capitata L. extract (BOE) on HCl/ethanol (H/E)-induced gastric damages in mice. Pre-administration of BOE (25–100 mg/kg) for 7 consecutive days significantly decreased macroscopically visible lesion on the gastric mucosa induced by H/E. In addition, results from hematoxylin and eosin-stained gastric tissue showed that BOE inhibited invaded percentage of lesion and prevented the reduction in mucosal thickness in peri-ulcerative region. BOE significantly alleviated the H/E-mediated decreases in Alcian blue binding, total hexose, sialic acid, and collagen in the gastric tissue, suggesting BOE attenuates the gastric damage via preserving the integrity of gastric mucus. Moreover, BOE significantly decreased histamine level in the plasma and reduced mRNA levels associated with secreting gastric acid. Furthermore, BOE inhibited myeloperoxidase activity and suppressed nuclear factor-κB mRNA and its dependent inflammatory genes expression induced by H/E. BOE also strengthened antioxidant enzyme activity, with a mitigating H/E-mediated increase in malondialdehyde level of the gastric tissue. Thus, these results suggest that BOE has the potential to protect the gastric tissue via inhibiting gastric acid secretion, inflammation, and oxidative stress.

This study aimed to determine the effects of replacing corn with hydroponically sprouted barley (HSB) in Holstein heifer feed on growth performance and blood metabolites. For this purpose, the barley was prepared with hydroponic sprouting under optimized conditions, and its chemical composition was analyzed on a dry matter (DM) basis. A total of 30 Holstein heifers that were 7 months old with an average body weight of 212.60 ± 55.00 kg were used in a completely randomized design comprising 10 repetitions and three groups over a period of 11 months. Dietary treatments included control (CON), basal diet (corn meal-based diets), and trail diets, in which 10% and 30% HSB gradually replaced corn meal. The growth performance and biochemical indices were analyzed every month. Results showed that the HSB diet increased chemical compositions compared with the control diets on a DM basis. In addition, diets with up to 30% HSB did not show any negative effects on the growth performance (body weight, height at withers, and height at rump) or selected blood metabolites of heifers compared with the CON diet. In conclusion, the use of HSB instead of corn meal did not lead to any adverse effects on growth performance or biochemical indices; therefore, HSB can be used as an alternative dietary source for raising Holstein heifers.

Streptococcus parauberis is utilized as an oral vaccine by first inactivating the cells with formalin to produce formalin- killed cells (FKC) and then encapsulating them with polymer beads consisting of a cross-linked alginate-Ca2+ network. The encapsulation efficiency and media-dependent release are controlled by pre-treating the FKC with two types of clay nanoparticles: kaolinite (KA) and layered double hydroxide (LDH). The addition of LDH induced large agglomerates of FKC, and the KA enhanced the dispersion of FKC. The differences in the dispersibility of the FKC upon the use of clay nanoparticles was determined to strongly affect the encapsulation efficiency and release properties. The FKC + LDH mixture exhibited a slightly reduced encapsulation efficiency compared to the FKC alone. However, FKC + KA exhibited a dramatically improved encapsulation efficiency. In terms of the media-dependent release, the alginate beads were found to be fairly stable under gastric conditions and in deionized water with or without clay nanoparticles, preserving most of the encapsulated FKC. The intestine was the final target organ for FKC vaccination, and release at the site varied according to the use of clay nanoparticles. Both clays seemed to enhance the release of FKC, the cumulative amount being 3.6 times and 1.3 times larger for LDH and KA, respectively, than was shown with only FKC encapsulated beads.

We prepared hybrids consisting of Angelica gigas Nakai (AGN) root or flower extract and layered double hydroxide (LDH) for potential anticancer nanomedicine, as decursin species (DS) in AGN are known to have anticancer activity. Dimethylsulfoxide solvent was determined hybridization reaction media, as it has affinity to both AGN and LDH moiety. In order to develop inter-particle spaces in LDH, a reversible dehydration-rehydration, so-called reconstruction route, was applied in AGN-LDH hybridization. Quantitative analyses on AGN-LDH hybrids indicated that the content of DS was two times more concentrated in the hybrids than in extract itself. Using X-ray diffraction, FT-IR spectroscopy, scanning electron microscopy, and zeta-potential measurement, we found that AGN extract moiety was incorporated into inter-particle spaces of LDH nanoparticles during the reconstruction reaction. Time-dependent DS release from hybrids at pH 7.4 (physiological condition) and pH 4.5 (lysosomal condition) exhibited a pH-dependent release of extract-incorporated LDH hybrids. An anticancer activity test using HeLa, A549, and HEK293T cells showed that the AGN-LDH hybrid, regardless of extract type, showed enhanced anticancer activity compared with extract alone at an equivalent amount of DS, suggesting a nanomedicine effect of AGN-LDH hybrids.

The study aimed to determine the physical characteristics of estrus mucus and conception rates in dairy cattle. Samples of estrus mucus from the cervix were collected from 108 dairy cattle during heat and were examined for color and consistency. Samples were taken from bred animals at starting from day of breeding to the completion of one estrus cycle. The color of the cervical mucus was studied based on its transparency while the consistency was based on the thinness and thickness of the cervical mucus. The dairy cattle were bred and the pregnancy diagnosis was performed at the 60th day post breeding. Findings showed that the estrus mucus of the dairy cattle was transparent in 58.3%, turbid in 31.5% and dirty in 10.2%. It was further observed that the mucus consistency of the dairy cattle was thin in 74.1% and thick in 25.9%. In the pregnant group, 67.3% mucus samples were found transparent, turbid in 23.6% and dirty in 9.1%. However, the corresponding figures for the non-pregnant group had 49.1%, 39.6% and 11.3%. The consistency of cervical mucus was found to be thin in 74.1% and thick in 25.9% of dairy cattle. The conception rates of dairy cattle with thin and thick consistency of cervical mucus were 81.8% and 18.2%, respectively. Pregnant was associated with consistency of cervical mucus (p

Tumor tissue represents a slightly acidic pH condition compared to normal tissue due to the accumulation of lactic acids via anaerobic metabolism. In this work, pH-responsive charge-conversional polymer (poly(ethylene imine)-poly(l-lysine)-poly(l-glutamic acid), PKE polymer) was employed for endowing charge-conversional property and serum stability to poly(ethylene imine) conjugated reduced graphene oxide-based drug delivery system (PEI-rGO). Zeta-potential value of PEI-rGO coated with PK5E7 polymer (PK5E7(PEI-rGO)) was −10.9 mV at pH 7.4 and converted to 29.2 mV at pH 6.0, showing pH-responsive charge-conversional property. Sharp-edged plate morphology of PEI-rGO was transformed to spherical nanostructures with vague edges by PK5E7 coating. Size of PK5E7(PEI-rGO) was found to be smaller than that of PEI-rGO in the serum condition, showing its increased serum stability. Loaded doxorubicin (DOX) in PK5E7(PEI-rGO) could be released rapidly in lysosomal condition (pH 5.0, 5 mM glutathione). Furthermore, DOX-loaded PK5E7(PEI-rGO) showed enhanced anticancer activity in HeLa and A549 cells in the tumor microenvironment-mimicking condition (pH 6.0, serum), which would be mediated by non-specific cellular interaction with decorated serum proteins. These results indicate that the pH-responsive charge-conversional PKE polymer coating strategy of cationic rGO nanostructures possesses a potential for acidic tumor microenvironment-targeted drug delivery systems.

In this study, we prepared stabilized vitamin A and C nanoemulsions, and investigated their efficacy on milk-specific proteins in bovine mammary epithelial cells (MAC-T). Emulsions of vitamin A (vit-A) and C (vit-C) were prepared using Lipoid S 75 and microfluidization. The particle size and polydispersity index (PDI) of nanoemulsified vit-A and vit-C were studied. The cytotoxic effect of nanoemulsion-free and nanoemulsified vit-A and vit-C was determined by an MTT assay. In addition, the efficacy of nanoemulsified vit-A and vit-C on the in vitro expression pattern of milk-specific proteins in MAC-T cells was investigated by quantitative RT-PCR. The results showed that the efficacies of stabilized nanoemulsions of vit-A and vit-C were 100% and 92.7%, respectively. The particle sizes were around 475.7 and 225.4 nm, and the zeta potentials were around −33.5 and −21.3 mV, respectively. The expression changes of αs2-, β- and κ-casein were higher in the presence of a stabilized nanoemulsion of vit-A, compared with nanoemulsion-free vit-A. Furthermore, the expression changes of αs2- and β-casein were lower and that of κ-casein was higher in the presence of a stabilized nanoemulsion of vit-C, compared with nanoemulsion-free vit-C. Thus, our findings demonstrate the efficacy of nanoemulsified vit-A and vit-C in changing the expression of milk-specific proteins in MAC-T cells.

i-motif is cytosine (C)-rich oligonucleotide (ODN) which shows pH-responsive structure change in acidic condition. Therefore, it has been utilized for the trigger of intercalated drug release, responding to environmental pH change. In this study, 2.76 molecules of i-motif binding ODNs (IBOs) were conjugated to each hyaluronic acid (HA) via amide bond linkages. Synthesis of HA-IBO conjugate (HB) was confirmed by FT-IR and agarose gel electrophoresis with Stains-All staining. After hybridization of HB with i-motif ODN (IMO), it was confirmed that doxorubicin (DOX) could be loaded in HB-IMO hybrid structure (HBIM) with 65.6% of drug loading efficiency (DLE) and 25.0% of drug loading content (DLC). At pH 5.5, prompt and significant DOX release from HBIM was observed due to the disruption of HBIM hybrid structure via i-motif formation of IMO, contrary to pH 7.4 condition. Then, HBIM was complexed with low molecular weight polyethylenimine (PEI1.8k), forming positively charged nanostructures (Z-average size: 126.0 ± 0.4 nm, zeta-potential: 16.1 ± 0.3 mV). DOX-loaded HBIM/PEI complexes displayed higher anticancer efficacy than free DOX in A549 cells, showing the potential for pH-responsive anticancer drug delivery systems.

Recent work involving microscale inorganic light-emitting diodes on flexible and stretchable substrates is reviewed. Techniques for materials growth, device fabrication, and assembly are summarized, along with highlights of optical, electrical, and mechanical properties that can be achieved. Some examples of emerging applications in biomedical devices illustrate the value of these methods in areas where conventional approaches are unsuitable.

Cholic acid-conjugated methylcellulose-polyethylenimines (MCPEI-CAs) were synthesized and characterized for drug delivery systems. Their synthesis was confirmed by 1H NMR and FT-IR analysis. Induced circular dichroism result with Congo red showed that methylcellulose (MC) and polyethylenimine-grafted cationic derivative (MC-PEI) would have helical conformation and random coil structure, respectively. It was found that MCPEI-CAs could form positively charged (>30 mV Zeta-potential) and spherical nano-aggregates (~250 nm Z-average size) by hydrophobic interaction of CA moieties. Critical aggregation concentration of MCPEI-CA10 was measured as 7.2 × 10−3 mg/mL. MCPEI-CA10 could encapsulate the anticancer drug doxorubicin (Dox) with 58.0% of drug loading content and 23.2% of drug loading efficiency and its release was facilitated in acidic condition. Cytotoxicity of MCPEI-CAs was increased with the increase of cholic acid (CA) graft degrees, probably due to the cellular membrane disruption by interaction with specific molecular structure of amphiphilic MCPEI-CA nano-aggregates. MCPEI-CA10/Dox nano-aggregates showed concentration-dependent anticancer activity, which could overcome the multidrug resistance of cancer cells. In this work, molecular conformation change of MC derivatives by chemical modification and a potential of MCPEI-CA10/Dox nano-aggregates for drug delivery systems were revealed.

Self-assembling multifunctional peptide was designed for gene delivery systems. The multifunctional peptide (MP) consists of cellular penetrating peptide moiety (R8), matrix metalloproteinase-2 (MMP-2) specific sequence (GPLGV), pH-responsive moiety (H5), and hydrophobic moiety (palmitic acid) (CR8GPLGVH5-Pal). MP was oxidized to form multifunctional peptide dimer (MPD) by DMSO oxidation of thiols in terminal cysteine residues. MPD could condense pDNA successfully at a weight ratio of 5. MPD itself could self-assemble into submicron micelle particles via hydrophobic interaction, of which critical micelle concentration is about 0.01 mM. MPD showed concentration-dependent but low cytotoxicity in comparison with PEI25k. MPD polyplexes showed low transfection efficiency in HEK293 cells expressing low level of MMP-2 but high transfection efficiency in A549 and C2C12 cells expressing high level of MMP-2, meaning the enhanced transfection efficiency probably due to MMP-induced structural change of polyplexes. Bafilomycin A1-treated transfection results suggest that the transfection of MPD is mediated via endosomal escape by endosome buffering ability. These results show the potential of MPD for MMP-2 targeted gene delivery systems due to its multifunctionality.

We have successfully prepared nanohybrids of biofunctional ferulic acid and layered double hydroxide nanomaterials through reconstruction and exfoliation-reassembly routes. From X-ray diffraction and infrared spectroscopy, both nanohybrids were determined to incorporate ferulic acid molecules in anionic form. Micrsocopic results showed that the nanohybrids had average particle size of 150 nm with plate-like morphology. As the two nanohybridization routes involved crystal disorder and random stacking of layers, the nanohybrids showed slight alteration in z-axis crystallinity and particle size. The zeta potential values of pristine and nanohybrids in deionized water were determined to be positive, while those in cell culture media shifted to negative values. According to the in vitro anticancer activity test on human cervical cancer HeLa cells, it was revealed that nanohybrids showed twice anticancer activity compared with ferulic acid itself. Therefore we could conclude that the nanohybrids of ferulic acid and layered double hydroxide had cellular delivery property of intercalated molecules on cancer cell lines.

Background/Aims: Increased prevalence of nonalcoholic fatty liver disease (NAFLD) and inflammatory bowel disease (IBD) has been reported. However, the effects of NAFLD on the outcome of IBD remains unclear. We investigated whether the presence of NAFLD could influence the outcomes of patients with IBD. Methods: We recruited 3,356 eligible patients with IBD into our study between November 2005 and November 2020. Hepatic steatosis and fibrosis were diagnosed using hepatic steatosis index of ≥30 and fibrosis-4 of ≥1.45, respectively. The primary outcome was clinical relapse, defined based on the following: IBD-related admission, surgery, or first use of corticosteroids, immunomodulators, or biologic agents for IBD. Results: The prevalence of NAFLD in patients with IBD was 16.7%. Patients with hepatic steatosis and advanced fibrosis were older, had a higher body mass index, and were more likely to have diabetes (all p<0.05). Conclusions: Hepatic steatosis was independently associated with increased risks of clinical relapse in patients with ulcerative colitis and Crohn’s disease, whereas fibrotic burden in the liver was not. Future studies should investigate whether assessment and therapeutic intervention for NAFLD will improve the clinical outcomes of patients with IBD. [ABSTRACT FROM AUTHOR]