Metal-Oxide Nanomaterials Synthesis and Applications in Flexible and Wearable Sensors.

Metal-oxide nanomaterials (MONs) have gained considerable interest in the construction of flexible/wearable sensors due to their tunable band gap, low cost, large specific area, and ease of manufacturing. Furthermore, MONs are in high demand for applications, such as gas leakage alarms, environmental protection, health tracking, and smart devices integrated with another system. In this Review, we introduce a comprehensive investigation of factors to boost the sensitivity of MON-based sensors in environmental indicators and health monitoring. Finally, the challenges and perspectives of MON-based flexible/wearable sensors are considered.

Transparent Air Filters with Active Thermal Sterilization.

The worldwide proliferation of COVID-19 poses the urgent need for sterilizable and transparent air filters to inhibit virus transmission while retaining ease of communication. Here, we introduce copper nanowires to fabricate transparent and self-sterilizable air filters. Copper nanowire air filter (CNAF) allowed visible light penetration, thereby can exhibit facial expressions, helpful for better communication. CNAF effectively captured particulate matter (PM) by mechanical and electrostatic filtration mechanisms. The temperature of CNAF could be controlled by Joule-heating up to 100 °C with thermal stability. CNAF successfully inhibited the growth of E. coli because of the oligodynamic effect of copper. With heat sterilization, the antibacterial efficiency against G. anodireducens was greatly improved up to 99.3% within 10 min. CNAF showed high reusability with stable filtration efficiency and thermal antibacterial efficacy after five repeated uses. Our result suggests an alternative form of active antimicrobial air filter in preparation for the current and future pandemic situations.

Toxicological Evaluation of a Probiotic-Based Delivery System for P8 Protein as an Anti-Colorectal Cancer Drug.

PURPOSE: This study aimed to toxicological evaluate a probiotics-based delivery system for p8 protein as an anti-colorectal cancer drug. INTRODUCTION: Lactic acid bacteria (LAB) have been widely ingested for many years and are regarded as very safe. Recently, a Pediococcus pentosaceus SL4 (PP) strain that secretes the probiotic-derived anti-cancer protein P8 (PP-P8) has been developed as an anti-colorectal cancer (CRC) biologic by Cell Biotech. We initially identified a Lactobacillus rhamnosus (LR)-derived anti-cancer protein, P8, that suppresses CRC growth. We also showed that P8 penetrates specifically into CRC cells (DLD-1 cells) through endocytosis. We then confirmed the efficacy of PP-P8, showing that oral administration of this agent significantly decreased tumor mass (~42%) relative to controls in a mouse CRC xenograft model. In terms of molecular mechanism, PP-P8 induces cell-cycle arrest in G2 phase through down-regulation of Cyclin B1 and Cdk1. In this study, we performed in vivo toxicology profiling to obtain evidence that PP-P8 is safe, with the goal of receiving approval for an investigational new drug application (IND). METHODS: Based on gene therapy guidelines of the Ministry of Food and Drug Safety (MFDS) of Korea, the potential undesirable effects of PP-P8 had to be investigated in intact small rodent or marmoset models prior to first-in-human (FIH) administration. The estimated doses of PP-P8 for FIH are 1.0×1010 - 1.0×1011 CFU/person (60 kg). Therefore, to perform toxicological investigations in non-clinical animal models, we orally administered PP-P8 at doses of 3.375 × 1011, 6.75 × 1011, and 13.5×1011 CFU/kg/day; thus the maximum dose was 800-8000-fold higher than the estimated dose for FIH. RESULTS: In our animal models, we observed no adverse effects of PP-P8 on clinicopathologic findings, relative organ weight, or tissue pathology. In addition, we observed no inflammation or ulceration during pathological necropsy. CONCLUSION: These non-clinical toxicology studies could be used to furnish valuable data for the safety certification of PP-P8.

Reversible, Selective, Ultrawide-Range Variable Stiffness Control by Spatial Micro-Water Molecule Manipulation.

Evolution has decided to gift an articular structure to vertebrates, but not to invertebrates, owing to their distinct survival strategies. An articular structure permits kinematic motion in creatures. However, it is inappropriate for creatures whose survival strategy depends on the high deformability of their body. Accordingly, a material in which the presence of the articular structure can be altered, allowing the use of two contradictory strategies, will be advantageous in diverse dynamic applications. Herein, spatial micro-water molecule manipulation, termed engineering on variable occupation of water (EVO), that is used to realize a material with dual mechanical modes that exhibit extreme differences in stiffness is introduced. A transparent and homogeneous soft material (110 kPa) reversibly converts to an opaque material embodying a mechanical gradient (ranging from 1 GPa to 1 MPa) by on-demand switching. Intensive theoretical analysis of EVO yields the design of spatial transformation scheme. The EVO gel accomplishes kinematic motion planning and shows great promise for multimodal kinematics. This approach paves the way for the development and application of smart functional materials.

A synthetic probiotic engineered for colorectal cancer therapy modulates gut microbiota.

BACKGROUND: Successful chemoprevention or chemotherapy is achieved through targeted delivery of prophylactic agents during initial phases of carcinogenesis or therapeutic agents to malignant tumors. Bacteria can be used as anticancer agents, but efforts to utilize attenuated pathogenic bacteria suffer from the risk of toxicity or infection. Lactic acid bacteria are safe to eat and often confer health benefits, making them ideal candidates for live vehicles engineered to deliver anticancer drugs. RESULTS: In this study, we developed an effective bacterial drug delivery system for colorectal cancer (CRC) therapy using the lactic acid bacterium Pediococcus pentosaceus. It is equipped with dual gene cassettes driven by a strong inducible promoter that encode the therapeutic protein P8 fused to a secretion signal peptide and a complementation system. In an inducible CRC cell-derived xenograft mouse model, our synthetic probiotic significantly reduced tumor volume and inhibited tumor growth relative to the control. Mice with colitis-associated CRC induced by azoxymethane and dextran sodium sulfate exhibited polyp regression and recovered taxonomic diversity when the engineered bacterium was orally administered. Further, the synthetic probiotic modulated gut microbiota and alleviated the chemically induced dysbiosis. Correlation analysis demonstrated that specific bacterial taxa potentially associated with eubiosis or dysbiosis, such as Akkermansia or Turicibacter, have positive or negative relationships with other microbial members. CONCLUSIONS: Taken together, our work illustrates that an effective and stable synthetic probiotic composed of P. pentosaceus and the P8 therapeutic protein can reduce CRC and contribute to rebiosis, and the validity and feasibility of cell-based designer biopharmaceuticals for both treating CRC and ameliorating impaired microbiota. Video abstract.

Probiotic-derived p8 protein induce apoptosis via regulation of RNF152 in colorectal cancer cells.

Worldwide, colorectal cancer (CRC) is one of the most common cancers and is a leading cause of cancer-related deaths. Accumulating evidence suggests that probiotics suppress the development of various cancers including CRC. Recently, we reported a Lactobacillus rhamnosus (LR)-derived 8 kDa protein (p8) that displayed anti-cancer properties in CRC cells. However, the precise anti-cancer mechanism of p8 and its target genes has not been fully examined. In the present study, we reveal that p8 leads to apoptotic cells and cleaved PARP1 expression in a mouse xenograft model of CRC. Additionally, we identified Ring finger protein 152 (RNF152) as a putative target of p8 using RNA-sequencing. Furthermore, the expression levels of RNF152 were increased following in vivo and in vitro treatment with p8. We also found that p8 leads to the accumulation of cleaved PARP1 in CRC cells. These results suggest that p8 induces apoptosis via regulation of RNF152, thus inhibiting the development of CRC.

Sensitive Wearable Temperature Sensor with Seamless Monolithic Integration.

Accurate temperature field measurement provides critical information in many scientific problems. Herein, a new paradigm for highly sensitive, flexible, negative temperature coefficient (NTC) thermistor-based artificial skin is reported, with the highest temperature sensing ability reported to date among previously reported NTC thermistors. This artificial skin is achieved through the development of a novel monolithic laser-induced reductive sintering scheme and unique monolithic structures. The unique seamless monolithic structure simultaneously integrates two different components (a metal electrode and metal oxide sensing channel) from the same material at ambient pressure, which cannot be achieved by conventional heterogeneous integration through multiple, complex steps of photolithography or vacuum deposition. In addition to superior performance, electronic skin with high temperature sensitivity can be fabricated on heat-sensitive polymer substrates due to the low-temperature requirements of the process. As a proof of concept, temperature-sensitive artificial skin is tested with conformally attachable physiological temperature sensor arrays in the measurement of the temperatures of exhaled breath for the early detection of pathogenic progression in the respiratory system. The proposed highly sensitive flexible temperature sensor and monolithic selective laser reductive sintering are expected to greatly contribute to the development of essential components in various emerging research fields, including soft robotics and healthcare systems.

Colorectal Cancer Therapy Using a Pediococcus pentosaceus SL4 Drug Delivery System Secreting Lactic Acid Bacteria-Derived Protein p8.

Despite decades of research into colorectal cancer (CRC), there is an ongoing need for treatments that are more effective and safer than those currently available. Lactic acid bacteria (LAB) show beneficial effects in the context of several diseases, including CRC, and are generally regarded as safe. Here, we isolated a Lactobacillus rhamnosus (LR)-derived therapeutic protein, p8, which suppressed CRC proliferation. We found that p8 translocated specifically to the cytosol of DLD-1 cells. Moreover, p8 down-regulated expression of Cyclin B1 and Cdk1, both of which are required for cell cycle progression. We confirmed that p8 exerted strong anti-proliferative activity in a mouse CRC xenograft model. Intraperitoneal injection of recombinant p8 (r-p8) led to a significant reduction (up to 59%) in tumor mass when compared with controls. In recent years, bacterial drug delivery systems (DDSs) have proven to be effective therapeutic agents for acute colitis. Therefore, we aimed to use such systems, particularly LAB, to generate the valuable therapeutic proteins to treat CRC. To this end, we developed a gene expression cassette capable of inducing secretion of large amounts of p8 protein from Pediococcus pentosaceus SL4 (PP). We then confirmed that this protein (PP-p8) exerted anti-proliferative activity in a mouse CRC xenograft model. Oral administration of PP-p8 DDS led to a marked reduction in tumor mass (up to 64%) compared with controls. The PP-p8 DDS using LAB described herein has advantages over other therapeutics; these advantages include improved safety (the protein is a probiotic), cost-free purification, and specific targeting of CRC cells.

Moiré-Free Imperceptible and Flexible Random Metal Grid Electrodes with Large Figure-of-Merit by Photonic Sintering Control of Copper Nanoparticles.

Flexible micro/nano metal grid transparent conductors emerged as an alternative to the fragile/rigid indium tin oxide electrode. They are usually fabricated by the combination of the conventional photolithography and the vacuum deposition of regular metal grid patterns, however, seriously suffer from moiré and starburst problems induced by periodic regular pattern structures. In this paper, we demonstrated flexible and imperceptible random copper microconductors with an extremely high figure-of-merit (∼2000) by the thermal conduction layer-assisted photonic sintering of copper nanoparticles without damages in the plastic substrate. This process can be easily applied to complicated structures and surfaces including a random pattern which is imperceptible and free of interferences. As a proof-of-concept, a transparent windshield defogger in a car was demonstrated with a Cu transparent random conductor at an extreme and reversible fogging state.

Assimilation of Satellite-Based Snow Cover and Freeze/Thaw Observations Over High Mountain Asia.

Toward qualifying hydrologic changes in the High Mountain Asia (HMA) region, this study explores the use of a hyper-resolution (1 km) land data assimilation (DA) framework developed within the NASA Land Information System using the Noah Multi-parameterization Land Surface Model (Noah-MP) forced by the meteorological boundary conditions from Modern-Era Retrospective analysis for Research and Applications, Version 2 data. Two different sets of DA experiments are conducted: (1) the assimilation of a satellite-derived snow cover map (MOD10A1) and (2) the assimilation of the NASA MEaSUREs landscape freeze/thaw product from 2007 to 2008. The performance of the snow cover assimilation is evaluated via comparisons with available remote sensing-based snow water equivalent product and ground-based snow depth measurements. For example, in the comparison against ground-based snow depth measurements, the majority of the stations (13 of 14) show slightly improved goodness-of-fit statistics as a result of the snow DA, but only four are statistically significant. In addition, comparisons to the satellite-based land surface temperature products (MOD11A1 and MYD11A1) show that freeze/thaw DA yields improvements (at certain grid cells) of up to 0.58 K in the root-mean-square error (RMSE) and 0.77 K in the absolute bias (relative to model-only simulations). In the comparison against three ground-based soil temperature measurements along the Himalayas, the bias and the RMSE in the 0-10 cm soil temperature are reduced (on average) by 10 and 7%, respectively. The improvements in the top layer of soil estimates also propagate through the deeper soil layers, where the bias and the RMSE in the 10-40 cm soil temperature are reduced (on average) by 9 and 6%, respectively. However, no statistically significant skill differences are observed for the freeze/thaw DA system in the comparisons against ground-based surface temperature measurements at mid-to-low altitude. Therefore, the two proposed DA schemes show the potential of improving the predictability of snow mass, surface temperature, and soil temperature states across HMA, but more ground-based measurements are still required, especially at high-altitudes, in order to document a more statistically significant improvement as a result of the two DA schemes.

Evaluating the uncertainty of terrestrial water budget components over High Mountain Asia.

This study explores the uncertainties in terrestrial water budget estimation over High Mountain Asia (HMA) using a suite of uncoupled land surface model (LSM) simulations. The uncertainty in the water balance components of precipitation (P), evapotranspiration (ET), runoff(R), and terrestrial water storage (TWS) is significantly impacted by the uncertainty in the driving meteorology, with precipitation being the most important boundary condition. Ten gridded precipitation datasets along with a mix of model-, satellite-, and gauge-based products, are evaluated first to assess their suitability for LSM simulations over HMA. The datasets are evaluated by quantifying the systematic and random errors of these products as well as the temporal consistency of their trends. Though the broader spatial patterns of precipitation are generally well captured by the datasets, they differ significantly in their means and trends. In general, precipitation datasets that incorporate information from gauges are found to have higher accuracy with low Root Mean Square Errors and high correlation coefficient values. An ensemble of LSM simulations with selected subset of precipitation products is then used to produce the mean annual fluxes and their uncertainty over HMA in P, ET, and R to be 2.11±0.45, 1.26±0.11, and 0.85±0.36 mm per day, respectively. The mean annual estimates of the surface mass (water) balance components from this model ensemble are comparable to global estimates from prior studies. However, the uncertainty/spread of P, ET, and R is significantly larger than the corresponding estimates from global studies. A comparison of ET, snow cover fraction, and changes in TWS estimates against remote sensing-based references confirms the significant role of the input meteorology in influencing the water budget characterization over HMA and points to the need for improving meteorological inputs.

Shear-Assisted Laser Transfer of Metal Nanoparticle Ink to an Elastomer Substrate.

Selective laser sintering of metal nanoparticle ink is an attractive technology for the creation of metal layers at the microscale without any vacuum deposition process, yet its application to elastomer substrates has remained a highly challenging task. To address this issue, we introduced the shear-assisted laser transfer of metal nanoparticle ink by utilizing the difference in thermal expansion coefficients between the elastomer and the target metal electrode. The laser was focused and scanned across the absorbing metal nanoparticle ink layer that was in conformal contact with the elastomer with a high thermal expansion coefficient. The resultant shear stress at the interface assists the selective transfer of the sintered metal nanoparticle layer. We expect that the proposed method can be a competent fabrication route for a transparent conductor on elastomer substrates.

Highly Controlled Nanoporous Ag Electrode by Vaporization Control of 2-Ethoxyethanol for a Flexible Supercapacitor Application.

Controlling the surface morphology of the electrode on the nanoscale has been studied extensively because the surface morphology of a material directly leads to the functionalization in various fields of studies. In this study, we designed a simple and cost-effective method to fine-tune the surface morphology and create controlled nanopores on the silver electrode by utilizing 2-ethoxyethanol and two successive heat treatments. High electrical conductivity and mechanical robustness of nanoporous silver corroborate its prospect to be employed in various applications requiring a certain degree of flexibility. As a proof-of-concept, a high-performance supercapacitor was fabricated by electrodepositing MnO2. This method is expected to be useful in various electronic applications as well as energy storage devices.

A Probiotic Preparation Alleviates Atopic Dermatitis-Like Skin Lesions in Murine Models.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a complex etiology that encompasses immunologic responses. AD is frequently associated with elevated immunoglobulin (Ig) E levels, and common environmental factors contribute to its pathogenesis. Several recent studies have documented the role of specific lactic acid bacteria in the treatment and prevention of AD in humans and mice. In this study, the efficacy of Duolac ATP, a probiotic preparation, was determined in a mouse model with AD-like skin lesions. Alterations in the cytokine levels and histological staining suggested the alleviation of AD. The in vivo test showed that T helper (Th)2 cytokines, IgE, interleukin (IL)-4, and IL-5, were significantly downregulated, whereas Th1 cytokines, IL-12p40 and interferon (IFN)-γ, were upregulated in all groups of mice treated with Duolac ATP compared to that observed in the group of mice treated with 1-chloro-2,4-dinitrobenzene (DNCB) alone. Moreover, the scratch score decreased in all mice treated with Duolac ATP. Staining of the dorsal area of the mice in each group with hematoxylin and eosin and toluidine blue further confirmed the alleviation of AD in mice orally treated with Duolac ATP. These results suggest that Duolac ATP inhibits the development of AD-like skin lesions in NC/Nga mice by suppressing the Th2 cell response and increasing the Th1 cell response. Thus, Duolac ATP is beneficial and effective for the treatment of AD-like skin lesions.

Improvement of atopic dermatitis-like skin lesions by IL-4 inhibition of P14 protein isolated from Lactobacillus casei in NC/Nga mice.

Atopic dermatitis (AD) is a chronic inflammatory skin disease, with a complex etiology encompassing immunologic responses. AD is frequently associated with elevated serum immunoglobulin (Ig) E levels and is exacerbated by a variety of environmental factors, which contribute to its pathogenesis. However, the etiology of AD remains unknown. Recently, reports have documented the role of lactic acid bacteria (LAB) in the treatment and prevention of AD in humans and mice. The LAB, Lactobacillus casei (LC), is frequently used in the treatment of AD. To identify the active component of LC, we screened fractions obtained from the ion exchange chromatography of LC extracts. Using this approach, we identified the candidate protein, P14. We examined whether the P14 protein has anti-atopic properties, using both in vitro and in vivo models. Our results showed that the P14 protein selectively downregulated serum IgE and interleukin-4 cytokine levels, as well as the AD index and scratching score in AD-like NC/Nga mice. In addition, histological examination was also effective in mice. These results suggest that the P14 protein has potential therapeutic effects and that it may also serve as an effective immunomodulatory agent for treating patients with AD.

Use of selected lactic acid bacteria in the eradication of Helicobacter pylori infection.

Helicobacter pylori is among the major pathogenic bacteria that cause chronic gastritis and peptic ulcer disease and is related to the development of gastric cancer. Several chemicals, including antibiotics, have been used to eradicate H. pylori; however, they do not always curb the infection. Ten representative type strains of lactic acid bacteria (LAB) were screened for antagonism toward H. pylori via inhibition of urease activity. Strains inhibiting the binding of H. pylori to human gastric cell line cells and suppressing H. pylori-induced interleukin-8 (IL-8) production were also screened. Of these, Pediococcus pentosaseus (SL4), which inhibited the adhesion of H. pylori to MKN-45 gastric cancer cells, Bifidobacterium longum (BG7), with urease inhibiting activity, and Lactococcus lactis (SL3), and Enterococcus faecalis (SL5), which suppressed H. pylori-induced IL-8 production within MKN-45 and AGS cells, were selected. In mouse model, these LAB stains in combination significantly suppressed IL-8 levels in serum. Gastric pH also recovered to normal values after the administration of these LAB. These stains effectively suppressed H. pylori viability, although not to the extent of antibiotic treatment. When used as probiotics, LAB may help decrease the occurrence of gastritis and reduce the risk of H. pylori infection without, inducing side effects.

A Probiotic Preparation Duolac-Gold Ameliorates Dextran Sulphate Sodium-induced Mouse Colitis by Downregulating the Expression of IL-6.

Probiotics are live microorganisms that confer a health benefit on the host. Duolac-Gold is a mixture of six probiotic bacteria containing three species of Bifidobacteria, two species of Lactobacillus, and Streptococcus thermophilus [corrected]. The aim of this study was to assess the anti-inflammatory effects of Duolac-Gold in an inflammatory bowel disease (IBD) mouse model. IBD was induced by administering 1.5% dextran sulfate sodium (DSS) for 10 days. After induction of DSS-induced colitis, Duolac-Gold was orally administered at three different concentrations. Interestingly, Duolac-Gold treatment accelerated IBD healing, and anti-inflammatory activity was assessed by weight loss, length of the colon, and a microscopic damage score by histology. The expression of inflammatory related cytokines was measured in colon tissues and serum. Of these cytokines, the expression of interleukin-6 decreased remarkably after Duolac-Gold treatment. Taken together, these results suggest that Duolac-Gold treatment is effective in IBD healing by regulating IL-6.

A study on the prevention of salmonella infection by using the aggregation characteristics of lactic Acid bacteria.

Salmonella is one of the major pathogenic bacteria that cause food poisoning. This study investigated whether heat-killed as well as live Lactobacillus protects host animal against Salmonella infection. Live and heat-killed Lactobacillusacidophilus was administered orally to Sprague-Dawley rats for 2 weeks before the rats were inoculated with Salmonella. Rise in body temperature was moderate in the group that was treated with heat-killed bacteria as compared to the Salmonella control group. The mean amount of feed intake and water consumption of each rat in the heat-killed bacteria group were nearly normal. The number of fecal Salmonellae was comparable between the live and the heat-killed L. acidophilus groups. This finding shows that L. acidophilus facilitates the excretion of Salmonella. Moreover, the levels of pro inflammatory cytokines, including tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta, in the heat-killed L. acidophilus group were significantly lower when compared to the levels in the Salmonella control group. These results indicate that nonviable lactic acid bacteria also could play an important role in preventing infections by enteric pathogens such as Salmonella.