Multifunctional Wearable System for Mapping Body Temperature and Analyzing Sweat.

Integrated wearable bioelectronic health monitoring systems have revealed new possibilities for collecting personalized physiological information. Wearable sweat sensors have the potential to noninvasively measure valuable biomarkers. Mapping sweat and skin-temperature throughout the body can provide detailed information on the human body. However, existing wearable systems cannot evaluate such data. Here, we report a multifunctional wearable platform that can wirelessly measure local sweat loss, sweat chloride concentration, and skin temperature. The approach combines a reusable electronics module to monitor skin temperature and a microfluidic module for monitoring sweat loss and sweat chloride concentration. The miniaturized electronic system takes temperature measurements from the skin and wirelessly transmits the obtained data to a user device using Bluetooth technology. In contrast, the microfluidic system provides accurate colorimetric analysis of the chloride concentration and sweat loss. Thus, this integrated wearable system has great application potential in individualized health management systems for sports researchers and competitors and can also be applied in clinical settings.

Melatonin protects against cadmium-induced oxidative stress via mitochondrial STAT3 signaling in human prostate stromal cells.

Melatonin protects against Cadmium (Cd)-induced toxicity, a ubiquitous environmental toxicant that causes adverse health effects by increasing reactive oxygen species (ROS) production and mitochondrial dysfunction. However, the underlying mechanism remains unclear. Here, we demonstrate that Cd exposure reduces the levels of mitochondrially-localized signal transducer and activator of transcription 3 (mitoSTAT3) using human prostate stromal cells and mouse embryonic fibroblasts. Melatonin enhances mitoSTAT3 abundance following Cd exposure, which is required to attenuate ROS damage, mitochondrial dysfunction, and cell death caused by Cd exposure. Moreover, melatonin increases mitochondrial levels of GRIM-19, an electron transport chain component that mediates STAT3 import into mitochondria, which are downregulated by Cd. In vivo, melatonin reverses the reduced size of mouse prostate tissue and levels of mitoSTAT3 and GRIM-19 induced by Cd exposure. Together, these data suggest that melatonin regulates mitoSTAT3 function to prevent Cd-induced cytotoxicity and could preserve mitochondrial function during Cd-induced stress.

Rapid antimicrobial susceptibility testing for low bacterial concentrations integrating a centrifuge based bacterial cell concentrator.

Antibiotic resistance threatens human health worldwide. Patients infected with antibiotic-resistant bacteria require appropriate antibiotic prescriptions based on a rapid antibiotic susceptibility test (AST). Various rapid AST methods have been developed to replace the conventional AST method, which requires a long testing time. However, in most cases, these methods require a high density of bacterial samples, which leads to an additional incubation or concentration process. In this study, we introduce a rapid AST platform that allows the use of low-density bacterial samples by concentrating bacterial cells and performing AST on a single microfluidic chip. In addition, the outlet-free loading process enables the platform to load the sample and concentrate bacteria into a small field of view for single-cell detection. Using this method, rapid AST determined antibiotic resistance in three hours from a standard strain of 103 colony-forming unit (CFU) per ml bacterial concentration. This technique can be used for the cell-based drug testing of various low-concentration bacterial samples.

Recent Developments in Electrochemical Sensors for the Detection of Antibiotic-Resistant Bacteria.

The development of efficient point-of-care (POC) diagnostic tools for detecting infectious diseases caused by destructive pathogens plays an important role in clinical and environmental monitoring. Nevertheless, evolving complex and inconsistent antibiotic-resistant species mire their drug efficacy. In this regard, substantial effort has been expended to develop electrochemical sensors, which have gained significant interest for advancing POC testing with rapid and accurate detection of resistant bacteria at a low cost compared to conventional phenotype methods. This review concentrates on the recent developments in electrochemical sensing techniques that have been applied to assess the diverse latent antibiotic resistances of pathogenic bacteria. It deliberates the prominence of biorecognition probes and tailor-made nanomaterials used in electrochemical antibiotic susceptibility testing (AST). In addition, the bimodal functional efficacy of nanomaterials that can serve as potential transducer electrodes and the antimicrobial agent was investigated to meet the current requirements in designing sensor module development. In the final section, we discuss the challenges with contemporary AST sensor techniques and extend the key ideas to meet the demands of the next POC electrochemical sensors and antibiotic design modules in the healthcare sector.

Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression.

Preproenkephalin (PPE) is a precursor molecule for multiple endogenous opioid peptides Leu-enkephalin (ENK) and Met-ENK, which are involved in a wide variety of modulatory functions in the nervous system. Despite the functional importance of ENK in the brain, the effect of brain-derived factor(s) on PPE expression is unknown. We report the dual effect of neural epidermal growth factor (EGF)-likelike 2 (NELL2) on PPE gene expression. In cultured NIH3T3 cells, transfection of NELL2 expression vectors induced an inhibition of PPE transcription intracellularly, in parallel with downregulation of protein kinase C signaling pathways and extracellular signal-regulated kinase. Interestingly, these phenomena were reversed when synthetic NELL2 was administered extracellularly. The in vivo disruption of NELL2 synthesis resulted in an increase in PPE mRNA level in the rat brain, suggesting that the inhibitory action of intracellular NELL2 predominates the activation effect of extracellular NELL2 on PPE gene expression in the brain. Biochemical and molecular studies with mutant NELL2 structures further demonstrated the critical role of EGF-like repeat domains in NELL2 for regulation of PPE transcription. These are the first results to reveal the spatio-specific role of NELL2 in the homeostatic regulation of PPE gene expression.

Diindolylmethane Inhibits Cadmium-Induced Autophagic Cell Death via Regulation of Oxidative Stress in HEL299 Human Lung Fibroblasts.

Cadmium (Cd), a harmful heavy metal, can lead to various pulmonary diseases, including chronic obstructive pulmonary disease (COPD), by inducing cytotoxicity and disturbing redox homeostasis. The aim of the present study was to investigate Cd-mediated cytotoxicity using human lung fibroblasts and the therapeutic potential of 3,3'-diindolylmethane (DIM). Cadmium significantly reduced the cell viability of human embryonic lung (HEL299) cells accompanied by enhanced oxidative stress as evidenced by the increased expression of autophagy-related proteins such as LC3B and p62. However, treatment with DIM significantly suppressed autophagic cell death in Cd-induced HEL299 fibroblasts. In addition, DIM induced antioxidant enzyme activity and decreased intracellular reactive oxygen species (ROS) levels in Cd-damaged HEL299 cells. This study suggests that DIM effectively suppressed Cd-induced lung fibroblast cell death through the upregulation of antioxidant systems and represents a potential agent for the prevention of various diseases related to Cd exposure.

Characterization of KRC-108 as a TrkA Kinase Inhibitor with Anti-Tumor Effects.

Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion. KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. Furthermore, KRC-108 exhibited anti-tumor activity in vivo in a KM12C cell xenograft model. These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers.

Effects of Bisphenol A and Its Alternatives, Bisphenol F and Tetramethyl Bisphenol F on Osteoclast Differentiation.

Bisphenol A (BPA) is a typical environmental endocrine disruptor that exhibits estrogen-mimicking, hormone-like properties and can cause the collapse of bone homeostasis by an imbalance between osteoblasts and osteoclasts. Various BPA substitutes, structurally similar to BPA, have been used to manufacture 'BPA-free' products; however, the regulatory role of BPA alternatives in osteoclast differentiation still remains unelucidated. This study aimed to investigate the effects of these chemicals on osteoclast differentiation using the mouse osteoclast precursor cell line RAW 264.7. Results confirmed that both BPA and its alternatives, bisphenol F and tetramethyl bisphenol F (TMBPF), were nontoxic to RAW 264.7 cells. In particular, tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cell staining and activity calculation assays revealed that TMBPF enhanced osteoclast differentiation upon stimulation of the receptor activator of nuclear factor-kappa B ligand (RANKL). Additionally, TMBPF activated the mRNA expression of osteoclast-related target genes, such as the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), tartrate-resistant acid phosphatase (TRAP), and cathepsin K (CtsK). Western blotting analysis indicated activation of the mitogen-activated protein kinase signaling pathway, including phosphorylation of c-Jun N-terminal kinase and p38. Together, the results suggest that TMBPF enhances osteoclast differentiation, and it is critical for bone homeostasis and skeletal health.

Battery-free, wireless soft sensors for continuous multi-site measurements of pressure and temperature from patients at risk for pressure injuries.

Capabilities for continuous monitoring of pressures and temperatures at critical skin interfaces can help to guide care strategies that minimize the potential for pressure injuries in hospitalized patients or in individuals confined to the bed. This paper introduces a soft, skin-mountable class of sensor system for this purpose. The design includes a pressure-responsive element based on membrane deflection and a battery-free, wireless mode of operation capable of multi-site measurements at strategic locations across the body. Such devices yield continuous, simultaneous readings of pressure and temperature in a sequential readout scheme from a pair of primary antennas mounted under the bedding and connected to a wireless reader and a multiplexer located at the bedside. Experimental evaluation of the sensor and the complete system includes benchtop measurements and numerical simulations of the key features. Clinical trials involving two hemiplegic patients and a tetraplegic patient demonstrate the feasibility, functionality and long-term stability of this technology in operating hospital settings.

Color-Coded Droplets and Microscopic Image Analysis for Multiplexed Antibiotic Susceptibility Testing.

Since the discovery of antibiotics, the emergence of antibiotic resistance has become a global issue that is threatening society. In the era of antibiotic resistance, finding the proper antibiotics through antibiotic susceptibility testing (AST) is crucial in clinical settings. However, the current clinical process of AST based on the broth microdilution test has limitations on scalability to expand the number of antibiotics that are tested with various concentrations. Here, we used color-coded droplets to expand the multiplexing of AST regarding the kind and concentration of antibiotics. Color type and density differentiate the kind of antibiotics and concentration, respectively. Microscopic images of a large view field contain numbers of droplets with different testing conditions. Image processing analysis detects each droplet, decodes color codes, and measures the bacterial growth in the droplet. Testing E. coli ATCC 25922 with ampicillin, gentamicin, and tetracycline shows that the system can provide a robust and scalable platform for multiplexed AST. Furthermore, the system can be applied to various drug testing systems, which require several different testing conditions.

Microscopic Analysis of Bacterial Inoculum Effect Using Micropatterned Biochip.

Antimicrobial resistance has become a major problem in public health and clinical environments. Against this background, antibiotic susceptibility testing (AST) has become necessary to cure diseases in an appropriate and timely manner as it indicates the necessary concentration of antibiotics. Recently, microfluidic based rapid AST methods using microscopic analysis have been shown to reduce the time needed for the determination of the proper antibiotics. However, owing to the inoculum effect, the accurate measurement of the minimal inhibitory concentration (MIC) is difficult. We tested four standard bacteria: Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Enterococcus faecalis, against five different antibiotics: piperacillin, cefotaxime, amikacin, levofloxacin, and ampicillin. The results showed that overall, the microfluidic system has a similar inoculum effect compared to the conventional AST method. However, due to the different testing conditions and determination protocols of the growth of the microfluidic based rapid AST, a few results are not identical to the conventional methods using optical density. This result suggests that microfluidic based rapid AST methods require further research on the inoculum effect for practical use in hospitals and can then be used for effective antibiotic prescriptions.

Soft, skin-interfaced sweat stickers for cystic fibrosis diagnosis and management.

The concentration of chloride in sweat remains the most robust biomarker for confirmatory diagnosis of cystic fibrosis (CF), a common life-shortening genetic disorder. Early diagnosis via quantitative assessment of sweat chloride allows prompt initiation of care and is critically important to extend life expectancy and improve quality of life. The collection and analysis of sweat using conventional wrist-strapped devices and iontophoresis can be cumbersome, particularly for infants with fragile skin, who often have insufficient sweat production. Here, we introduce a soft, epidermal microfluidic device ("sweat sticker") designed for the simple and rapid collection and analysis of sweat. Intimate, conformal coupling with the skin supports nearly perfect efficiency in sweat collection without leakage. Real-time image analysis of chloride reagents allows for quantitative assessment of chloride concentrations using a smartphone camera, without requiring extraction of sweat or external analysis. Clinical validation studies involving patients with CF and healthy subjects, across a spectrum of age groups, support clinical equivalence compared to existing device platforms in terms of accuracy and demonstrate meaningful reductions in rates of leakage. The wearable microfluidic technologies and smartphone-based analytics reported here establish the foundation for diagnosis of CF outside of clinical settings.

Visualization of superficial vein dynamics in dorsal hand by near-infrared imaging in response to elevated local temperature.

SIGNIFICANCE: Dry or moist skin-contact thermal stimulation for vein puncture (VP) and vein cannulation (VC) may not be feasible for sensitive skin. For a damaged, burned, or dark skin, near-infrared (NIR) imaging is preferred to visualize a vein. Postprocessing of NIR images is always required because the skin is a reflective material and veins need segmentation for quantitative analysis. AIM: Our pilot study aims to observe the effect of noncontact local heating on the superficial metacarpal veins in the dorsal surface of the hand and to visualize vein dynamics using an NIR imaging system. APPROACH: Our experiment consists of studies A and B at two ambient temperatures, 19°C and 25°C. A simple reflection-based NIR imaging system was installed to acquire sequential vein images for 5 min before and after applying 10 min of radiant thermal stimulation. To measure the vein diameter (VD), we trained a convolutional neural network (CNN) on sequential raw images to predict vein-segmentation masks as output images. Later these masked images were postprocessed for the VD measurements. RESULTS: The average VD was significantly increased after thermal stimulation in study A. The maximum increments in VD were 39.3% and 9.19%, 1 min after thermal stimulation in studies A and B, respectively. Both the VD and skin temperature (Tskin) follow negative exponentials in time, and the VD is proportional to Tskin. A multiple linear-regression model was made to predict the final VD. A significant difference was observed in the change of the VD. CONCLUSIONS: NIR imaging with CNN can be used for quantitative analyses of vein dynamics. This finding can be further extended to develop real-time, image-guided medical devices by integrating them with a radiant heater and to assist medical practitioners in achieving high success rates for VP or VC.

Characterization of LDD-2633 as a Novel RET Kinase Inhibitor with Anti-Tumor Effects in Thyroid Cancer.

Rearranged during transfection (RET), a receptor tyrosine kinase, is activated by glial cell line-derived neurotrophic factor family ligands. Chromosomal rearrangement or point mutations in RET are observed in patients with papillary thyroid and medullary thyroid carcinomas. Oncogenic alteration of RET results in constitutive activation of RET activity. Therefore, inhibiting RET activity has become a target in thyroid cancer therapy. Here, the anti-tumor activity of a novel RET inhibitor was characterized in medullary thyroid carcinoma cells. The indirubin derivative LDD-2633 was tested for RET kinase inhibitory activity. In vitro, LDD-2633 showed potent inhibition of RET kinase activity, with an IC50 of 4.42 nM. The growth of TT thyroid carcinoma cells harboring an RET mutation was suppressed by LDD-2633 treatment via the proliferation suppression and the induction of apoptosis. The effects of LDD-2633 on the RET signaling pathway were examined; LDD-2633 inhibited the phosphorylation of the RET protein and the downstream molecules Shc and ERK1/2. Oral administration of 20 or 40 mg/kg of LDD-2633 induced dose-dependent suppression of TT cell xenograft tumor growth. The in vivo and in vitro experimental results supported the potential use of LDD-2633 as an anticancer drug for thyroid cancers.

Skin-Interfaced Microfluidic Systems that Combine Hard and Soft Materials for Demanding Applications in Sweat Capture and Analysis.

Eccrine sweat contains a rich blend of electrolytes, metabolites, proteins, metal ions, and other biomarkers. Changes in the concentrations of these chemical species can indicate alterations in hydration status and they can also reflect health conditions such as cystic fibrosis, schizophrenia, and depression. Recent advances in soft, skin-interfaced microfluidic systems enable real-time measurement of local sweat loss and sweat biomarker concentrations, with a wide range of applications in healthcare. Uses in certain contexts involve, however, physical impacts on the body that can dynamically deform these platforms, with adverse effects on measurement reliability. The work presented here overcomes this limitation through the use of microfluidic structures constructed in relatively high modulus polymers, and designed in geometries that offer soft, system level mechanics when embedded low modulus elastomers. Analytical models and finite element analysis quantitatively define the relevant mechanics of these systems, and serve as the basis for layouts optimized to allow robust operation in demanding, rugged scenarios such as those encountered in football, while preserving mechanical stretchability for comfortable, water-tight bonding to the skin. Benchtop testing and on-body field studies of measurements of sweat loss and chloride concentration under imposed mechanical stresses and impacts demonstrate the key features of these platforms.

Apigenin enhances apoptosis induction by 5-fluorouracil through regulation of thymidylate synthase in colorectal cancer cells.

Although effective drugs have been developed, including 5-fluorouracil (5-FU), advanced colorectal cancer (CRC) shows low therapeutic sensitivity resulting from the development of 5-FU resistance. Thymidylate synthase (TS) is a target protein of 5-FU, and elevated TS lowers the 5-FU sensitivity of CRC cells. Here, we tested the efficacy of several candidate phytochemicals against human CRC-derived HCT116 cells expressing wild-type tumor suppressor protein P53 and HT29 cells expressing mutant P53. Among them, we found that apigenin enhanced the inhibitory effect of 5-FU on cell viability. In addition, apigenin inhibited the upregulation of TS induced by 5-FU. Apigenin also potentiated 5-FU-induced apoptosis of HCT116 cells and enhanced cell cycle disruption. Furthermore, apigenin increased reactive oxygen species production, intracellular and intramitochondrial Ca2+ concentrations, and mitochondrial membrane potential upon cotreatment with 5-FU. Knockdown of forkhead box protein M, a transcription factor modulating 5-FU sensitivity, enhanced the potentiation of apoptosis by apigenin in HCT116 cells. Moreover, apigenin suppressed TS expression and inhibited the viability of 5-FU-resistant HCT116 cells. Therefore, apigenin may improve the therapeutic efficacy of 5-FU against CRC by suppressing TS, but apoptosis induction is mainly dependent on functional P53.

Dynamic Pore Modulation of Stretchable Electrospun Nanofiber Filter for Adaptive Machine Learned Respiratory Protection.

The recent emergence of highly contagious respiratory disease and the underlying issues of worldwide air pollution jointly heighten the importance of the personal respirator. However, the incongruence between the dynamic environment and nonadaptive respirators imposes physiological and psychological adverse effects, which hinder the public dissemination of respirators. To address this issue, we introduce adaptive respiratory protection based on a dynamic air filter (DAF) driven by machine learning (ML) algorithms. The stretchable elastomer fiber membrane of the DAF affords immediate adjustment of filtration characteristics through active rescaling of the micropores by simple pneumatic control, enabling seamless and constructive transition of filtration characteristics. The resultant DAF-respirator (DAF-R), made possible by ML algorithms, successfully demonstrates real-time predictive adapting maneuvers, enabling personalizable and continuously optimized respiratory protection under changing circumstances.

Binary genetic algorithm for optimal joinpoint detection: Application to cancer trend analysis.

The joinpoint regression model (JRM) is used to describe trend changes in many applications and relies on the detection of joinpoints (changepoints). However, the existing joinpoint detection methods, namely, the grid search (GS)-based methods, are computationally demanding, and hence, the maximum number of computable joinpoints is limited. Herein, we developed a genetic algorithm-based joinpoint (GAJP) model in which an explicitly decoupled computing procedure for optimization and regression is used to embed a binary genetic algorithm into the JRM for optimal joinpoint detection. The combinations of joinpoints were represented as binary chromosomes, and genetic operations were performed to determine the optimum solution by minimizing the fitness function, the Bayesian information criterion (BIC) and BIC3 . The accuracy and computational performance of the GAJP model were evaluated via intensive simulation studies and compared with those of the GS-based methods using BIC, BIC3 , and permutation test. The proposed method showed an outstanding computational efficiency in detecting multiple joinpoints. Finally, the suitability of the GAJP model for the analysis of cancer incidence trends was demonstrated by applying this model to data on the incidence of colorectal cancer in the United States from 1975 to 2016 from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Thus, the GAJP model was concluded to be practically feasible to detect multiple joinpoints up to the number of grids without requirement to preassign the number of joinpoints and be easily extendable to cancer trend analysis utilizing large datasets.