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Purpose: The aims of this study were to verify proximal phalangeal head normalization after a stretching exercise in patients with infantile-type camptodactyly and to propose radiographic indices for quantifying bony deformities., Methods: Forty-eight fingers of 20 patients with camptodactyly were enrolled in this study. All patients and their parents received instruction on how to perform the stretching exercise. The qualitative assessments of proximal phalangeal head remodeling were conducted by consensus of 2 hand surgeons. Two radiographic parameters, head triangle ratio (HTR) and head angle (HA), were measured on finger lateral radiographs taken at the initial visit and at 12-month follow-up. The intra- and interobserver reliability of both parameters was assessed. Those parameters of the patients were compared with those of 177 fingers of 80 children without camptodactyly. The extent of proximal interphalangeal (PIP) joint flexion contracture was used to evaluate clinical outcomes resulting from nonsurgical treatment., Results: Qualitative assessments of proximal phalangeal head remodeling exhibited meaningful improvements. Both radiographic parameters showed significant change between their status before and after intervention and had excellent intra- and interobserver reliability. Average PIP joint flexion contracture significantly improved. In the noncamptodactyly group, neither parameter showed significant differences in accordance with finger types and age ranges., Conclusions: Stretching improved movement within the proximal phalangeal joint and helped to restore proximal phalangeal head roundness and concentricity in patients with infantile-type camptodactyly. The HTR and HA would be useful indices for objectively assessing the degree of bony deformity in patients with camptodactyly., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2020 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Introduction: High dietary sodium is a leading contributor to hypertension, and hypertension is the leading underlying cause of death globally. There is a robust body of evidence supporting the health benefits of sodium reduction. Sodium intake in South Korea is high, with about half the population consuming > 4000 mg/day, twice the recommended upper limit., Methods: In 2012, South Korea implemented its National Plan to Reduce Sodium Intake, with a goal of reducing population sodium consumption by 20%, to 3900 mg/day, by 2020. The plan included five key components: (1) a consumer awareness campaign designed to change food consumption behaviours; (2) increased availability of low-sodium foods at schools and worksites; (3) increased availability of low-sodium meals in restaurants; (4) voluntary reformulation of processed foods to lower sodium content; and (5) development of low-sodium recipes for food prepared at home. Monitoring and evaluation included tracking sodium intake and sources of dietary sodium using the Korea National Health and Nutrition Examination Survey., Results: By 2014, South Korea had reduced dietary sodium consumption among adults by 23.7% compared to a survey conducted in 2010 prior to implementation of a nationwide salt reduction campaign that used this comprehensive, multipronged approach. The reductions in sodium intake were accompanied by reductions in population blood pressure and hypertension prevalence. Although causal associations between the sodium reduction programme and reduced sodium intake cannot be made, the declines occurred with the introduction of the programme., Conclusion: Multicomponent interventions have great potential to reduce population sodium intake. Lessons learnt from South Korea could be applied to other countries and are likely very relevant to other Asian countries with similar food sources and consumption profiles., Competing Interests: Competing interests: NRCC is a member of World Action on Salt and Health (WASH)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Stress biomarkers such as hormones and neurotransmitters in bodily fluids can indicate an individual's physical and mental state, as well as influence their quality of life and health. Thus, sensitive and rapid detection of stress biomarkers (e.g., cortisol) is important for management of various diseases with harmful symptoms, including post-traumatic stress disorder and depression. Here, we describe rapid and sensitive cortisol detection based on a conducting polymer (CP) nanotube (NT) field-effect transistor (FET) platform. The synthesized polypyrrole (PPy) NT was functionalized with the cortisol antibody immunoglobulin G (IgG) for the sensitive and specific detection of cortisol hormone. The anti-cortisol IgG was covalently attached to a basal plane of PPy NT through an amide bond between the carboxyl group of PPy NT and the amino group of anti-cortisol IgG. The resulting field-effect transistor-type biosensor was utilized to evaluate various cortisol concentrations. Cortisol was sensitively measured to a detection limit of 2.7 × 10 -10 M (100 pg/mL), with a dynamic range of 2.7 × 10 -10 to 10 -7 M; it exhibited rapid responses (<5 s). We believe that our approach can serve as an alternative to time-consuming and labor-intensive health questionnaires; it can also be used for diagnosis of underlying stress-related disorders.

Though epigallocatechin-3-gallate (EGCG), a major compound of green tea, has anti-diabetes, anti-obesity, anti-inflammatory, and antitumor effects, the underlying antitumor molecular mechanism of EGCG was not fully understood so far. Here the sensitizing effect of EGCG to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) was examined in colorectal cancers. Cotreatment of EGCG and TRAIL synergistically enhanced cytotoxicity and sub G1 accumulation, increased the number of terminal deoxynucleotidyl transferase-dT-mediated dUTP nick end labelling (TUNEL)-positive cells in SW480 and HCT116 cells. Furthermore, this cotreatment promoted the cleavages of poly (adenosine diphosphate-ribose) polymerase (PARP) and induced caspase 8 activation compared to TRAIL or EGCG alone in SW480 and HCT116 cells. Of note, cotreatment of EGCG and TRAIL increased the expression of death receptor 5 (DR5) at protein and mRNA levels and also DR5 cell surface level in colon cancer cells. Conversely, depletion of DR5 reduced the apoptotic activity of cotreatment of EGCG and TRAIL to increase cytotoxicity, sub-G1 population and PARP cleavages in colon cancer cells. Overall, our findings provide evidence that EGCG can be a sensitizer of TRAIL via DR5 and caspase 8 mediated apoptosis in colorectal cancer cells., Competing Interests: The authors declare no conflict of interest.

The role of Situin 1 (SIRT1) in tumorigenesis is still controversial due to its wide range of substrates, including both oncoproteins and tumor suppressors. A recent study has demonstrated that SIRT1 interferes in the Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven activation of the Raf-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway, thereby inhibiting tumorigenesis. However, the molecular mechanism of SIRT1 as a tumor suppressor in RAS-driven tumorigenesis has been less clearly determined. This study presents evidence that the ectopic expression of SIRT1 attenuates RAS- or MEK-driven ERK activation and reduces cellular proliferation and transformation in vitro. The attenuation of ERK activation by SIRT1 results from prompt dephosphorylation of ERK, while MEK activity remains unchanged. We identified that MKP1, a dual specific phosphatase for MAPK, was deacetylated by SIRT1. Deacetylation of MKP1 by direct interaction with SIRT1 increased the binding affinity to ERK which in turn facilitated inactivation of ERK. Taken together, these results suggest that SIRT1 would act as a tumor suppressor by modulating RAS-driven ERK activity through MKP1 deacetylation.

Recognizing the age-related decline in skeletal muscle feed artery (SMFA) vasodilatory function, this study examined the link between vasodilatory and mitochondrial respiratory function in the human vasculature. Twenty-four SMFAs were harvested from young (35 ± 6 yr, n = 9) and old (71 ± 9 yr, n = 15) subjects. Vasodilation in SMFAs was assessed, by pressure myography, in response to flow-induced shear stress, acetylcholine (ACh), and sodium nitroprusside (SNP) while mitochondrial respiration was measured, by respirometry, in permeabilized SMFAs. Endothelium-dependent vasodilation was significantly attenuated in the old, induced by both flow (young: 92 ± 3, old: 45 ± 4%) and ACh (young: 92 ± 3, old: 54 ± 5%), with no significant difference in endothelium-independent vasodilation. Complex I and I + II state 3 respiration was significantly lower in the old (CI young: 10.1 ± 0.8, old: 7.0 ± 0.4 pmol·s -1 ·mg -1 ; CI + II young: 12.3 ± 0.6, old: 7.6 ± 0.4 pmol·s -1 ·mg -1 ). The respiratory control ratio (RCR) was also significantly attenuated in the old (young: 2.2 ± 0.1, old: 1.1 ± 0.1). Furthermore, state 3 (CI + II) and 4 respiration, as well as RCR, were significantly correlated ( r  = 0.49-0.86) with endothelium-dependent, but not endothelium-independent, function. Finally, the direct intervention with mitochondrial-targeted antioxidant (MitoQ) significantly improved endothelium-dependent vasodilation in the old but not in the young. Thus, the age-related decline in vasodilatory function is linked to attenuated vascular mitochondrial respiratory function, likely by augmented free radicals. NEW & NOTEWORTHY In human skeletal muscle feed arteries, the well-recognized age-related fall in endothelium-dependent vasodilatory function is strongly linked to a concomitant fall in vascular mitochondrial respiratory function. The direct intervention with the mitochondrial-targeted antioxidant restored vasodilatory function in the old but not in the young, supporting the concept that exacerbated mitochondrial-derived free radical production is linked to age-related vasodilatory dysfunction. Age-related vasodilatory dysfunction in humans is linked to attenuated vascular mitochondrial respiratory function, likely a consequence of augmented free radical production.

Clinical use of the chemotherapeutic doxorubicin (DOX) promotes skeletal muscle atrophy and weakness, adversely affecting patient mobility and strength. Although the mechanisms responsible for DOX-induced skeletal muscle dysfunction remain unclear, studies implicate the significant production of reactive oxygen species (ROS) in this pathology. Supraphysiological ROS levels can enhance protein degradation via autophagy, and it is established that DOX upregulates autophagic signaling in skeletal muscle. To determine the precise contribution of accelerated autophagy to DOX-induced skeletal muscle dysfunction, we inhibited autophagy in the soleus via transduction of a dominant negative mutation of the autophagy related 5 (ATG5) protein. Targeted inhibition of autophagy prevented soleus muscle atrophy and contractile dysfunction acutely following DOX administration, which was associated with a reduction in mitochondrial ROS and maintenance of mitochondrial respiratory capacity. These beneficial modifications were potentially the result of enhanced transcription of antioxidant response element-related genes and increased antioxidant capacity. Specifically, our results showed significant upregulation of peroxisome proliferator-activated receptor gamma co-activator 1-alpha, nuclear respiratory factor-1, nuclear factor erythroid-2-related factor-2, nicotinamide-adenine dinucleotide phosphate quinone dehydrogenase-1, and catalase in the soleus with DOX treatment when autophagy was inhibited. These findings establish a significant role of autophagy in the development of oxidative stress and skeletal muscle weakness following DOX administration., Competing Interests: The authors declare no conflict of interest.

Quantum dots (QDs) have been widely studied as promising materials for various applications because of their outstanding photoluminescence (PL). Although ligand exchange methods for QDs have been developed over two decades, the PL quantum yield (QY) of aqueous phase QDs is still lower than that of their organic phase and the mechanism of quenching has not been clearly understood. In this study, we demonstrate for the first time that 3-mercaptopropionic-capped CdZnSeS/ZnS core/shell QDs obtained via ligand exchange in a ternary solvent system containing chloroform/water/dimethyl sulfoxide can enable the fast phase transfer and zero reduction of PL under ambient condition. The new solvent system allows the ligand-exchanged QDs to exhibit enhanced QYs up to 8.1% of that of the organic-phase QDs. Based on both theoretical calculation and experiment, it was found that control over the physical/chemical perturbation between the organic/aqueous phases by choosing appropriate solvents for the ligand exchange process is very important to preserve the optical properties of QDs. We believe that our new technologies and theoretical knowledge offer opportunities for the future design and optimization of highly stable and highly luminescent aqueous-phase QDs for various applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In this study, ultrasensitive and precise detection of a representative brain hormone, dopamine (DA), was demonstrated using functional conducting polymer nanotubes modified with aptamers. A high-performance aptasensor was composed of interdigitated microelectrodes (IMEs), carboxylated polypyrrole nanotubes (CPNTs) and DA-specific aptamers. The biosensors were constructed by sequential conjugation of CPNTs and aptamer molecules on the IMEs, and the substrate was integrated into a liquid-ion gating system surrounded by pH 7.4 buffer as an electrolyte. To confirm DA exocytosis based on aptasensors, DA sensitivity and selectivity were monitored using liquid-ion gated field-effect transistors (FETs). The minimum detection level (MDL; 100 pM) of the aptasensors was determined, and their MDL was optimized by controlling the diameter of the CPNTs owing to their different capacities for aptamer introduction. The MDL of CPNT aptasensors is sufficient for discriminating between healthy and unhealthy individuals because the total DA concentration in the blood of normal person is generally determined to be ca. 0.5 to 6.2 ng/mL (3.9 to 40.5 nM) by high-performance liquid chromatography (HPLC) (this information was obtained from a guidebook "Evidence-Based Medicine 2018 SCL " which was published by Seoul Clinical Laboratory). The CPNTs with the smaller diameters (CPNT2: ca. 120 nm) showed 100 times higher sensitivity and selectivity than the wider CPNTs (CPNT1: ca. 200 nm). Moreover, the aptasensors based on CPNTs had excellent DA discrimination in the presence of various neurotransmitters. Based on the excellent sensing properties of these aptasensors, the DA levels of exogeneous DA samples that were prepared from PC12 cells by a DA release assay were successfully measured by DA kits, and the aptasensor sensing properties were compared to those of standard DA reagents. Finally, the real-time response values to the various exogeneous DA release levels were similar to those of a standard DA aptasensor. Therefore, CPNT-based aptasensors provide efficient and rapid DA screening for neuron-mediated genetic diseases such as Parkinson's disease.

A novel platform of microfluidic paper-based analytical devices (μPADs) for dual detection of bisphenol A (BPA), a model analyte, was fabricated using an electronic digital plotter to create the stacked layer of μPADs and generate the lateral-flow channel without using an external pump. Two detection techniques, including electrochemical detection and laser desorption ionization mass spectrometric detection (LDI-MS), were used complementarily to improve the precision in the detection of BPA. The fluid sample was delivered to both detection zones by the capillary action, automatically generated from the fabricated microfluidic device. For an electrochemical sensor, two ballpoint pens filled with silver nanoparticles (AgNPs) and multiwall carbon nanotube (MWCNT) ink were used to print onto the paper with a contact printing method using a digital plotter. To further improve the sensitivity, zinc oxide (ZnO) was used to modify both electrochemical and LDI-MS detection zones. For BPA detection, high electrocatalytic properties and strong UV absorption of ZnO promote the electron transfer in the electrochemical sensor and ionization efficiency in LDI-MS with low interferences compared with a conventional organic matrix. Under optimal conditions, this platform showed a dual detection capability for BPA with a detection limit of 0.35 μM for electrochemical detection and with an ultralow detection limit of 0.01 pM for LDI-MS. This novel platform might be very useful for trace analyses requiring high precision detection of various analytes.

Dietary salt restriction is a well-established approach to lower blood pressure and reduce cardiovascular disease risk in hypertensive individuals. However, little is currently known regarding the effects of salt restriction on central and peripheral hemodynamic responses to exercise in those with hypertension. Therefore, this study sought to determine the impact of salt restriction on the central and peripheral hemodynamic responses to static-intermittent handgrip (HG) and dynamic single-leg knee extension (KE) exercise in individuals with hypertension. Twenty-two subjects (14 men and 8 women, 51 ± 10 yr, 173 ± 11 cm, 99 ± 23 kg) forewent their antihypertensive medication use for at least 2 wk before embarking on a 5-day liberal salt (LS: 200 mmol/day) diet followed by a 5-day restricted salt (RS: 10 mmol/day) diet. Subjects were studied at rest and during static intermittent HG exercise at 15, 30, and 45% of maximal voluntary contraction and KE exercise at 40, 60, and 80% of maximum KE work rate. Salt restriction lowered resting systolic blood pressure (supine: -12 ± 12 mmHg, seated: -17 ± 12 mmHg) and diastolic blood pressure (supine: -3 ± 9 mmHg, seated: -5 ± 7 mmHg, P < 0.05). Despite an ~8 mmHg lower mean arterial blood pressure during both HG and KE exercise following salt restriction, neither central nor peripheral hemodynamics were altered. Therefore, salt restriction can lower blood pressure during exercise in subjects with hypertension, reducing the risk of cardiovascular events, without impacting central and peripheral hemodynamics during either arm or leg exercise. NEW & NOTEWORTHY This is the first study to examine the potential blood pressure-lowering benefit of a salt-restrictive diet in individuals with hypertension without any deleterious effects of exercising blood flow. While mean arterial pressure decreased by ~8 mmHg following salt restriction, these findings provide evidence for salt restriction to provide protective effects of reducing blood pressure without inhibiting central or peripheral hemodynamics required to sustain arm or leg exercise in subjects with hypertension.

Cell migration, an essential process for normal cell development and cancer metastasis, differs from a simple random walk: the mean-square displacement (〈(Δr) 2 (t)〉) of cells sometimes shows non-Fickian behavior, and the spatiotemporal correlation function (G(r, t)) of cells is often non-Gaussian. We find that this intriguing cell migration should be attributed to heterogeneity in a cell population, even one with a homogeneous genetic background. There are two limiting types of heterogeneity in a cell population: cellular heterogeneity and temporal heterogeneity. Cellular heterogeneity accounts for the cell-to-cell variation in migration capacity, while temporal heterogeneity arises from the temporal noise in the migration capacity of single cells. We illustrate that both cellular and temporal heterogeneity need to be taken into account simultaneously to elucidate cell migration. We investigate the two-dimensional migration of A549 lung cancer cells using time-lapse microscopy and find that the migration of A549 cells is Fickian but has a non-Gaussian spatiotemporal correlation. We find that when a theoretical model considers both cellular and temporal heterogeneity, the model reproduces all of the anomalous behaviors of cancer cell migration.

The cause of progression to non-alcoholic fatty liver disease (NAFLD) is not fully understood. In the present study, we aimed to investigate how curcumin, a natural phytopolyphenol pigment, ameliorates NAFLD. Initially, we demonstrated that curcumin dramatically suppresses fat accumulation and hepatic injury induced in methionine and choline-deficient (MCD) diet mice. The severity of hepatic inflammation was alleviated by curcumin treatment. To identify the proteins involved in the pathogenesis of NAFLD, we also characterized the hepatic proteome in MCD diet mice. As a result of two-dimensional proteomic analysis, it was confirmed that thirteen proteins including antioxidant protein were differentially expressed in hepatic steatosis. However, the difference in expression was markedly improved by curcumin treatment. Interestingly, eight of the identified proteins are known to undergo O -GlcNAcylation modification. Thus, we further focused on elucidating how the regulation of O -linked β- N -acetylglucosamine ( O -GlcNAc) modification is associated with the progression of hepatic steatosis leading to hepatitis in MCD diet mice. In parallel with lipid accumulation and inflammation, the MCD diet significantly up-regulated hexosamine biosynthetic pathway (HBP) and O -GlcNAc transferase (OGT) via ER stress. Curcumin treatment alleviates the severity of hepatic steatosis by relieving the dependence of O -GlcNAcylation on nuclear factor-κB (NF-κB) in inflammation signaling. Conversely, the expressions of superoxide dismutase 1 (SOD1) and SIRT1 were significantly upregulated by curcumin treatment. In conclusion, curcumin inhibits O -GlcNAcylation pathway, leading to antioxidant responses in non-alcoholic steatohepatitis (NASH) mice. Therefore, curcumin will be a promising therapeutic agent for diseases involving hyper- O -GlcNAcylation, including cancer.

Lateral flow assay (LFA) technology has recently received interest in the biochemical field since it is simple, low-cost, and rapid, while conventional laboratory test procedures are complicated, expensive, and time-consuming. In this paper, we propose a robust smartphone-based analyte detection method that estimates the amount of analyte on an LFA strip using a smartphone camera. The proposed method can maintain high estimation accuracy under various illumination conditions without additional devices, unlike conventional methods. The robustness and simplicity of the proposed method are enabled by novel image processing and machine learning techniques. For the performance analysis, we applied the proposed method to LFA strips where the target analyte is albumin protein of human serum. We use two sets of training LFA strips and one set of testing LFA strips. Here, each set consists of five strips having different quantities of albumin-10 femtograms, 100 femtograms, 1 picogram, 10 picograms, and 100 picograms. A linear regression analysis approximates the analyte quantity, and then machine learning classifier, support vector machine (SVM), which is trained by the regression results, classifies the analyte quantity on the LFA strip in an optimal way. Experimental results show that the proposed smartphone application can detect the quantity of albumin protein on a test LFA set with 98% accuracy, on average, in real time.

Background: Electroacupuncture (EA) is often used in clinical settings due to its analgesic effect, but its safety has not been verified due to the lack of clear criteria. This study examined the critical range of the corrosion of stainless steel types STS304 and STS316, which have been used clinically, and the relationship between needle corrosion and cell necrosis., Method: The critical point of corrosion for STS304 and STS316 was identified by varying the time, frequency, and stimulation intensity. In a tissue necrosis experiment, EA stimulation was applied to rats using STS316 needles with different thicknesses at maximum intensity for 60 min, and the presence of corrosion and tissue necrosis was determined. A cytotoxicity experiment was also conducted and assessed the needles and tissue necrosis., Results: The results showed that STS316 was more stable than STS304 and that only coated needles corroded. Furthermore, tissue necrosis was observed regardless of corrosion, and slight cell necrosis was associated with needles with corrosion., Conclusions: This study demonstrated that non-coated STS316 was the most stable for EA stimulation and that corrosion byproducts and cell necrosis were not directly related.

Sortase A (SrtA), a type of transpeptidase responsible for anchoring surface proteins to the peptidoglycan cell wall, is important in the virulence of gram-positive bacteria. Three compounds were isolated from marine-derived Streptomyces sp. MBTH32 using various chromatography techniques. The structures of these compounds were determined based on spectroscopic data and comparisons with previously reported data. Among the metabolites tested, lumichrome showed strong inhibitory activity against Staphylococcus aureus SrtA without affecting cell viability. The results of cell clumping activity assessment suggest the potential for using this compound to treat S. aureus infection by inhibiting SrtA activity.

Background: The long-term data with direct acting antiviral agents were rare. This study investigated the durability of a sustained virologic response (SVR) and the improvement of fibrosis after daclatasvir and asunaprevir (DCV/ASV) treatment in genotype 1b (GT1b) hepatitis C virus (HCV)-infected patients., Methods: A total of 288 HCV GT1b patients without baseline non-structural 5A (NS5A) resistance-associated substitution (RAS) treated with DCV/ASV were enrolled. Virologic response was measured at 12 weeks and 1 year after treatment completion. In cirrhotic patients, liver function, aspartate transaminase to platelet ratio index (APRI), FIB-4 index, fibrosis index (FI), and liver stiffness measurement (LSM) at baseline and 1 year after treatment completion were evaluated., Results: SVR12 was obtained in 278 patients (96.5%). Six patients who checked NS5A RAS after treatment failure were RAS positive. Only one patient showed no durability of SVR. In cirrhotic patients who achieved SVR12 (n = 59), the changes of albumin (3.8 [2.2-4.7] to 4.3 [2.4-4.9] g/dL; P < 0.001), platelet count (99 [40-329] to 118 [40-399] × 10³/mm³; P < 0.001), APRI (1.8 [0.1-14.8] to 0.6 [0.1-4.8]; P < 0.001), FIB-4 index (5.45 [0.6-32.8] to 3.3 [0.4-12.2]; P < 0.001), FI (5.5 [0.6-32.8] to 3.3 [0.4-12.2]; P < 0.001), and LSM (17.2 [5.3-48.0] to 11.2 [3.7-28.1] kPa; P = 0.001) between baseline and 1 year after treatment completion were observed., Conclusion: DCV/ASV treatment for HCV GT1b infected patients without RAS achieved high SVR rates and showed durable SVR. Cirrhotic patients who achieved SVR12 showed the improvement of liver function and fibrosis markers., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2019 The Korean Academy of Medical Sciences.)

Drug repositioning is an attractive alternative to conventional drug development when new beneficial effects of old drugs are clinically validated because pharmacokinetic and safety profiles are generally already available. Since ~ 30% of drugs newly approved by the US food and drug administration (FDA) are developed through drug repositioning, identifying novel usage for existing drugs is an emerging strategy for developing disease treatments. With advances in next-generation sequencing technologies, available transcriptome data related to diseases have expanded rapidly. Harnessing these resources enables a better understanding of disease mechanisms and drug mode of action (MOA), and moves toward personalized pharmacotherapy. In this review, we briefly outline publicly available large-scale transcriptome databases and tools for drug repositioning. We also highlight recent approaches leading to the discovery of novel drug targets, drug response biomarkers, drug indications, and drug MOA.

Field-effect transistor (FET) devices based on conductive nanomaterials have been used to develop biosensors. However, development of FET-based biosensors that allow efficient stability, especially in the gas phase, for obtaining reliable and reproducible responses remains a challenge. In this study, we developed a nanodisc (ND)-functionalized bioelectronic nose (NBN) based on a nickel (Ni)-decorated carboxylated polypyrrole nanoparticle (cPPyNP)-FET that offers the detection of liquid and gaseous cadaverine (CV). The TAAR13c, specifically binding to CV, which is an indicator of food spoilage, was successfully constructed in NDs. The NBN was fabricated by the oriented assembly of TAAR13c-embedded NDs (T13NDs) onto the transistor with Ni/cPPyNPs. The NBN showed high performance in selectivity and sensitivity for the detection of CV, with excellent stability in both aqueous and gas phases. Moreover, the NBN allowed efficient measurement of corrupted real-food samples. It demonstrates the ND-based device can allow the practical biosensor that provides high stability in the gas phase.

The precise mechanism of hepatic cirrhosis remains largely unclear. In particular, a potential regulatory mechanism by which protein kinase C-delta (PKCδ ) affects profibrogenic gene expression involved in hepatic cirrhosis has never been explored. In the present study, we investigated whether PKCδ activation is involved in liver inflammatory fibrosis in both lipopolysaccharide (LPS)-treated RAW 264.7 and CCl 4 -treated mice. PKCδ was strongly activated by LPS or CCl 4 treatment and consequently stimulated nuclear factor (NF)-κB inflammatory response. Interestingly, the activation of PKCδ negatively regulated sirtuin-1 (SIRT1) expression, whereas PKCδ suppression by PKCδ peptide inhibitor V1-1 or siRNA dramatically increased SIRT1 expression. Furthermore, we showed that the negative regulation of PKCδ leads to a decrease in SIRT1 expression. To our knowledge, these results are the first demonstration of the involvement of PKCδ in modulating NF-κB through SIRT1 signaling in fibrosis in mice, suggesting a novel role of PKCδ in inflammatory fibrosis. The level of NF-κB p65 in the nucleus was also negatively regulated by SIRT1 activity. We showed that the inhibition of PKCδ promoted SIRT1 expression and decreased p65 levels in the nucleus through deacetylation. Moreover, the inactivation of PKCδ with V1-1 dramatically suppressed the inflammatory fibrosis, indicating that PKCδ represents a promising target for treating fibrotic diseases like hepatic cirrhosis., Competing Interests: The authors declare no conflict of interest.

Multiple sclerosis (MS) is a demyelination disease that causes gradual damage to neurons. Despite the necessity of appropriate treatments at each disease stage to prevent the worsening of the damage, it is still difficult to cure MS. In this study, metabolomics and lipidomics studies were performed with time-course plasma samples (early, peak, chronic phase for MS) to elucidate the mechanism during MS progression after induction of experimental autoimmune encephalomyelitis (EAE), which is the animal model for multiple sclerosis (MS). Plasma samples were analyzed using ultra-high performance liquid chromatography-orbitrap-mass spectrometry (UHPLC-Orbitrap-MS) and metabolic changes were observed using multivariate analysis. We also measured the activity of NADPH and MMP-9 to evaluate the degree of the inflammation during the disease progression. As a result, 49 metabolites, which had significant differences either at each time point or with time-course changes between control (CTL) and EAE groups, were identified. Among them, glycerophospholipids and fatty acyls were downregulated during disease progression compared with the CTL group. However, glycerolipids, taurine-conjugated bile acids (BAs), and sphingolipids exhibited the reverse pattern. These metabolic changes were accompanied by increases in oxidative stress and immune response upon observing the changes in the activities of NADPH oxidase and MMP-9. In particular, 26 metabolites showed significant differences at specific stages. The metabolite level of the plasma was significantly altered in response to the EAE pathogenesis, and these changes were related to inflammation status at each disease stage. This study can provide crucial information for reducing damage by differentiating treatment strategies according to disease progression., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Over the last decade, nucleic acid amplification tests (NAATs) including polymerase chain reaction (PCR) were an indispensable methodology for diagnosing cancers, viral and bacterial infections owing to their high sensitivity and specificity. Because the NAATs can recognize and discriminate even a few copies of nucleic acid (NA) and species-specific NA sequences, NAATs have become the gold standard in a wide range of applications. However, limitations of NAAT approaches have recently become more apparent by reason of their lengthy run time, large reaction volume, and complex protocol. To meet the current demands of clinicians and biomedical researchers, new NAATs have developed to achieve ultrafast sample-to-answer protocols for the point-of-care testing (POCT). In this review, ultrafast NA-POCT platforms are discussed, outlining their NA amplification principles as well as delineating recent advances in ultrafast NAAT applications. The main focus is to provide an overview of NA-POCT platforms in regard to sample preparation of NA, NA amplification, NA detection process, interpretation of the analysis, and evaluation of the platform design. Increasing importance will be given to innovative, ultrafast amplification methods and tools which incorporate artificial intelligence (AI)-associated data analysis processes and mobile-healthcare networks. The future prospects of NA POCT platforms are promising as they allow absolute quantitation of NA in individuals which is essential to precision medicine., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Acupuncture has become a common complementary and alternative treatment approach for anxiety and depression. However, there is little research on the detailed mechanism of acupuncture therapy relieving depression. Previously, 17β-estradiol (E2) was shown to prevent oxidative stress and endoplasmic reticulum (ER) stress in ovariectomized (OVX) rats. This study investigated whether stimulation of Sanyinjiao (SP6) using a mechanical acupuncture instrument can alleviate depression-like behavior caused by estrogen deficiency in OVX rats. Furthermore, we found that acupuncture reduced ER stress and oxidative stress-related proteins expression., Methods: The OVX operation was performed on female SD rats that were separated into four groups: The E2 (2.5 μg/kg, i.p.) injection group (OVX + E2), the OVX group (OVX), and the OVX with acupuncture stimulation group (OVX + SP6). Non-acupoint stimulation group (OVX + NonAcu). The acupuncture point stimulation began three weeks after surgery. The depressive behavior was analyzed by the forced swim test and open field test. The 8-OHDG, BiP, Sigma receptor 1, pJNK, PDI, Ero1-Iα and Calnexin protein levels were evaluated by immunoreactivity in the amygdala., Results: Acupuncture stimulation reduced depressive behavior and altered depression-related proteins. Stimulation of SP6 decreased the immobility time of the FST and altered the ER stress and oxidative stress marker proteins, such as 8-OHDG, BiP, pJNK, PDI, Ero1-Ia and Calnexin., Conclusion: Our results indicated that acupuncture at SP6 showed a significant antidepressant-like effect on an OVX-induced depression rat model by mitigation of ER stress and oxidative stress in amygdala.

Objective: The objective of this study was to analyze uptake patterns and intensity of 18 F-fluorodeoxyglucose (FDG) and 18 F-sodium fluoride (NaF) radioligands in carotid atheroma among stroke patients according to carotid atheroma characteristics., Methods: Between September 2015 and January 2017, consecutive acute stroke or transient ischemic attack patients with 50% or more proximal internal carotid artery stenosis on brain computed tomography angiography were prospectively enrolled. All patients received FDG and NaF positron emission tomography (PET) evaluation when their neurological status was stabilized. Uptake values of FDG and NaF were compared by target to blood ratio (TBR) according to the calcification burden, atheroma volume and the presence of a necrotic core of carotid atheroma., Results: A total of 18 patients with 36 carotid arteries were finally enrolled, with 10 patients diagnosed as acute cerebral infarction due to symptomatic carotid stenosis. FDG uptake at symptomatic carotid arteries was significantly more increased than that at asymptomatic arteries (TBR: 1.17±0.23 vs. 1.01±0.15, Mann-Whitney U -test, p =0.02), but NaF uptake was not different (TBR: 1.38±0.49 vs. 1.51±0.40, p =0.40). In terms of calcification degree, NaF uptake increased as calcification burden increased (none, 1.28±0.36; spotty, 1.29±0.29; linear, 1.74±0.44; analysis of variance, p =0.02)., Conclusion: Carotid evaluation by FDG is superior to NaF PET in the detection of symptomatic carotid atherosclerosis among stroke patients. NaF PET uptake reflects the overall calcification burden., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (Copyright © 2019 The Korean Society of Lipid and Atherosclerosis.)

Recent advanced paper-based microfluidic devices provide an alternative technology for the detection of biomarkers by using affordable and portable devices for point-of-care testing (POCT). Programmable paper-based microfluidic devices enable a wide range of biomarker detection with high sensitivity and automation for single- and multi-step assays because they provide better control for manipulating fluid samples. In this review, we examine the advances in programmable microfluidics, i.e., paper-based continuous-flow microfluidic (p-CMF) devices and paper-based digital microfluidic (p-DMF) devices, for biomarker detection. First, we discuss the methods used to fabricate these two types of paper-based microfluidic devices and the strategies for programming fluid delivery and for droplet manipulation. Next, we discuss the use of these programmable paper-based devices for the single- and multi-step detection of biomarkers. Finally, we present the current limitations of paper-based microfluidics for biomarker detection and the outlook for their development.

The erythrocyte membrane is composed of a phospholipid bilayer, which is known to undergo physicochemical changes during storage at low temperatures. This study was conducted to identify marker phospholipids that indicate alteration during deep-frozen storage and to determine the amount of marker phospholipids. Our research suggested a method to detect phospholipids by profiling analysis of thermally injured red blood cells (RBCs) without protecting agents. Human blood was stored at -80°C for 72 days. The RBC membrane phospholipids were extracted through a modified Bligh and Dyer method. Six selected phospholipids were analyzed and quantified using liquid chromatography-tandem mass spectrometry, and an in vitro model system was developed. The intracellular level of N-nervonoyl-D-erythro-sphingosylphosphorylcholine significantly increased in the thermally injured RBCs, and multiple biomarker candidates were evaluated by profiling analysis and mass spectrometry technology for targeted metabolomics., (© 2019 John Wiley & Sons, Ltd.)

Background: Mechanical ventilation (MV) is a life-saving measure for patients in respiratory failure. However, prolonged MV results in significant diaphragm atrophy and contractile dysfunction, a condition referred to as ventilator-induced diaphragm dysfunction (VIDD). While there are currently no clinically approved countermeasures to prevent VIDD, increased expression of heat shock protein 72 (HSP72) has been demonstrated to attenuate inactivity-induced muscle wasting. HSP72 elicits cytoprotection via inhibition of NF-κB and FoxO transcriptional activity, which contribute to VIDD. In addition, exercise-induced prevention of VIDD is characterized by an increase in the concentration of HSP72 in the diaphragm. Therefore, we tested the hypothesis that increased HSP72 expression is required for the exercise-induced prevention of VIDD. We also determined whether increasing the abundance of HSP72 in the diaphragm, independent of exercise, is sufficient to prevent VIDD., Methods: Cause and effect was determined by inhibiting the endurance exercise-induced increase in HSP72 in the diaphragm of exercise trained animals exposed to prolonged MV via administration of an antisense oligonucleotide targeting HSP72. Additional experiments were performed to determine if increasing HSP72 in the diaphragm via genetic (rAAV-HSP72) or pharmacological (BGP-15) overexpression is sufficient to prevent VIDD., Results: Our results demonstrate that the exercise-induced increase in HSP72 protein abundance is required for the protective effects of exercise against VIDD. Moreover, both rAAV-HSP72 and BGP-15-induced overexpression of HSP72 were sufficient to prevent VIDD. In addition, modification of HSP72 in the diaphragm is inversely related to the expression of NF-κB and FoxO target genes., Conclusions: HSP72 overexpression in the diaphragm is an effective intervention to prevent MV-induced oxidative stress and the transcriptional activity of NF-κB and FoxO. Therefore, overexpression of HSP72 in the diaphragm is a potential therapeutic target to protect against VIDD., (© 2019 The Authors Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Microbial electrochemical technology (MET) that can harvest electricity/valuable materials and enhance the efficiency of conventional biological processes through the redox reaction of organic/inorganic compounds has attracted considerable attention. MET-based anaerobic digestion (AD) systems treating swine manure were operated at different applied voltages (0.1, 0.3, 0.5, 0.7, and 0.9 V) and temperatures (25, 35, and 45 °C). Among the MET-based AD systems with different applied voltages at 35 °C, M4 at 0.7 V showed the highest methane production (2.96 m 3 -CH 4 /m 3 ) and methane yield (0.64 m 3 -CH 4 /kg-VS). The methane production and yield increased with increasing temperature at an applied voltage of 0.7 V. Nevertheless, the MET-based AD systems (LM at 25 °C and 0.7V) showed competitive AD performance (2.33 m 3 -CH 4 /m 3 and 0.53 m 3 -CH 4 /VS) compared with the conventional AD system (35 °C). The microbial community was affected by the applied voltage and temperature, and hydrogenotrophic methanogens such as M. flavescens, M. hungatei, and M. thermautotrophicus were mainly responsible for methane production in MET-based AD systems. Therefore, the methane production can be enhanced by an applied voltage or by direct interspecies electron transfer because M. flavescens and M. thermautotrophicus were especially predominant in cathode of MET-based AD systems. The MET-based AD systems can help enhance biogas production from swine manure with no significant change in methane content. Furthermore, MET-based AD systems will be a promising AD system through low material development and the optimal operation.

There have been reports linking nonalcoholic fatty liver disease (NAFLD) with gallstone disease (GD) owing to shared risk factors. However, there are no reported associations between the different NAFLD grades and GD. This study aimed to determine whether NAFLD grade is an independent risk factor for GD in a Korean population.This study enrolled 7886 participants who completed a questionnaire and underwent medical examination and ultrasound scanning at the Health Promotion Center of Jeju National University Hospital in Korea, from January 2009 to December 2017. Fatty liver grading and presence of gallstones were investigated using abdominal ultrasound. Body mass index and biochemical parameters were measured, and age, sex, and metabolic syndrome status were collected from medical records. Univariate and multivariate analyses were performed to identify risk factors for GD.The estimated prevalences of NAFLD and GD were 40.6% and 4.5%, respectively. In the univariate analysis, factors associated with GD were age; NAFLD; presence of metabolic syndrome; and levels of fasting blood glucose, high-density lipoproteins, aspartate aminotransferase, and alanine aminotransferase. Multivariate logistic regression analysis revealed older age and higher NAFLD grade as independent risk factors for GD.Older age and higher grade of NAFLD were independent risk factors for GD in our cohort. There was a strong correlation between grade of NAFLD on abdominal ultrasonography and GD.

Early detection of coronary artery dysfunction is of paramount cardiovascular clinical importance, but a noninvasive assessment is lacking. Indeed, the brachial artery flow-mediated dilation test only weakly correlated with acetylcholine-induced coronary artery function ( r=0.36). However, brachial artery flow-mediated dilation methodologies have, over time, substantially improved. This study sought to determine if updates to this technique have improved the relationship with coronary artery function and the noninvasive indication of coronary artery dysfunction. Coronary artery and brachial artery function were assessed in 28 patients referred for cardiac catheterization (61±11 years). Coronary artery function was determined by the change in artery diameter with a 1.82 μg/min intracoronary acetylcholine infusion. Based on the change in vessel diameter, patients were characterized as having dysfunctional coronary arteries (>5% vasoconstriction) or relatively functional coronary arteries (<5% vasoconstriction). Brachial artery function was determined by flow-mediated dilation, adhering to current guidelines. The acetylcholine-induced change in vessel diameter was smaller in patients with dysfunctional compared with relatively functional coronary arteries (-11.8±4.6% versus 5.8±9.8%, P<0.001). Consistent with this, brachial artery flow-mediated dilation was attenuated in patients with dysfunctional compared with relatively functional coronaries (2.9±1.9% versus 6.2±4.2%, P=0.007). Brachial artery flow-mediated dilation was strongly correlated with the acetylcholine-induced change in coronary artery diameter ( r=0.77, P<0.0001) and was a strong indicator of coronary artery dysfunction (receiver operator characteristic=78%). The current data support that updates to the brachial artery flow-mediated dilation technique have strengthened the relationship with coronary artery function, which may now provide a clinically meaningful indication of coronary artery dysfunction.

Human pyridoxal 5'-phosphate phosphatase (PLPP), also known as a chronophin, is a phosphatase belonging to subfamily II of the HAD phosphatases, characterized by a large cap domain. As a member of the subfamily, its cap-open conformation is expected for substrate binding. We determined apo and PLP-bound PLPP/chronophin structures showing a cap-closed conformation. The active site, in which a PLP molecule was found, is too small to accommodate a phospho-cofilin peptide, the substrate of chronophin. A conformational change to a cap-open conformation may be required for substrate binding. The core and cap domains are joined through linker peptide hinges that change conformation to open the active site. The crystal structures reveal that a disulphide bond between the cap and core domains restricts the hinge motion. The enzyme displays PLP dephosphorylation activity in the cap-closed conformation with the disulphide bond and even in the crystal state, in which repositioning of the cap and core domains is restricted. Structural analysis suggests that a small substrate such as PLP can bind to the active site through a small movement of a local motif. However, a change to the cap-open conformation is required for binding of larger substrates such as phosphopeptides to the active site., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Continuous passive leg movement (PLM) is a promising clinical assessment of the age-related decline in peripheral vascular function. To further refine PLM, this study evaluated the efficacy of a single PLM (sPLM), a simplified variant of the more established continuous movement approach, to delineate between healthy young and old men based on vascular function. Twelve young (26 ± 5 yr) and 12 old (70 ± 7 yr) subjects underwent sPLM (a single passive flexion and extension of the knee joint through 90°), with leg blood flow (LBF, common femoral artery with Doppler ultrasound), blood pressure (finger photoplethysmography), and leg vascular conductance (LVC) assessed. A receiver operator characteristic curve analysis was used to determine an age-specific cut score, and a factor analysis was performed to assess covariance. Baseline LBF and LVC were not different between groups ( P = 0.6). The high level of covariance and similar predictive value for all PLM-induced LBF and LVC responses indicates LBF, alone, can act as a surrogate variable in this paradigm. The peak sPLM-induced increase in LBF from baseline was attenuated in the old (Young: 717 ± 227, Old: 260 ± 97 ml/min, P < 0.001; cut score: 372 ml/min), as was the total LBF response (Young: 155 ± 67, Old: 26 ± 17 ml, P < 0.001; cut score: 58 ml). sPLM, a simplified version of PLM, exhibits the prerequisite qualities of a valid screening test for peripheral vascular dysfunction, as evidenced by an age-related attenuation in the peripheral hyperemic response and a clearly delineated age-specific cut score. NEW & NOTEWORTHY Single passive leg movement (sPLM) exhibits the prerequisite qualities of a valid screening test for peripheral vascular dysfunction. sPLM displayed an age-related reduction in the peripheral hemodynamic response for amplitude, duration, initial rate of change, and total change with clearly delineated age-specific cut scores. sPLM has a strong candidate variable that is a simple single numeric value, for which to appraise peripheral vascular function, the 45-s hyperemic response (leg blood flow area under the curve: 45 s).

A spoof fingerprint was fabricated on paper and applied for a spoofing attack to unlock a smartphone on which a capacitive array of sensors had been embedded with a fingerprint recognition algorithm. Using an inkjet printer with an ink made of carbon nanotubes (CNTs), we printed a spoof fingerprint having an electrical and geometric pattern of ridges and furrows comparable to that of the real fingerprint. With this printed spoof fingerprint, we were able to unlock a smartphone successfully; this was due to the good quality of the printed CNT material, which provided electrical conductivities and structural patterns similar to those of the real fingerprint. This result confirms that inkjet-printing CNTs to fabricate a spoof fingerprint on paper is an easy, simple spoofing route from the real fingerprint and suggests a new method for outputting the physical ridges and furrows on a two-dimensional plane., Competing Interests: The authors declare no competing financial interest.

Despite great potential for regenerative medicine, the high tumorigenic potential of human pluripotent stem cells (hPSCs) to form undesirable teratoma is an important technical hurdle preventing safe cell therapy. Various small molecules that induce the complete elimination of undifferentiated hPSCs, referred to as "stemotoxics," have been developed to facilitate tumor-free cell therapy, including the Survivin inhibitor YM155. In the present work, based on the chemical structure of YM155, total 26 analogs were synthesized and tested for stemotoxic activity toward human embryonic stem cells (hESCs) and induced PSCs (iPSCs). We found that a hydrogen bond acceptor in the pyrazine ring of YM155 derivatives is critical for stemotoxic activity, which is completely lost in hESCs lacking SLC35F2 , which encodes a solute carrier protein. These results suggest that hydrogen bonding interactions between the nitrogens of the pyrazine ring and the SLC35F2 protein are critical for entry of YM155 into hPSCs, and hence stemotoxic activity.

Aims: Peroxiredoxin5 (Prdx5), a thioredoxin peroxidase, is an antioxidant enzyme that is widely studied for its antioxidant properties and protective roles in neurological and cardiovascular disorders. This study is aimed at investigating the functional significance of Prdx5 in mitochondria and at analyzing its roles in ciliogenesis during the process of vertebrate development., Results: We found that several Prdx genes were strongly expressed in multiciliated cells in developing Xenopus embryos, and their peroxidatic functions were crucial for normal cilia development. Depletion of Prdx5 increased levels of cellular reactive oxygen species (ROS), consequently leading to mitochondrial dysfunction and abnormal cilia formation. Proteomic and transcriptomic approaches revealed that excessive ROS accumulation on Prdx5 depletion subsequently reduced the expression level of pyruvate kinase (PK), a key metabolic enzyme in energy production. We further confirmed that the promotor activity of PK was significantly reduced on Prdx5 depletion and that the reduction in PK expression and its promoter activity led to ciliary defects observed in Prdx5-depleted cells., Innovation: Our data revealed the novel relationship between ROS and Prdx5 and the consequent effects of this interaction on vertebrate ciliogenesis. The normal process of ciliogenesis is interrupted by the Prdx5 depletion, resulting in excessive ROS levels and suggesting cilia as vulnerable targets of ROS., Conclusion: Prdx5 plays protective roles in mitochondria and is critical for normal cilia development by regulating the levels of ROS. The loss of Prdx5 is associated with excessive production of ROS, resulting in mitochondrial dysfunction and aberrant ciliogenesis.

In this study, we use density functional theory (DFT) calculations to investigate the effect of moisture on the performance of three types of nanofiber (NF)-based air-filter media prepared by electrospinning polyvinyl alcohol, polyvinylidene fluoride, and polyacrylonitrile (PAN). Based on the DFT calculations of the intermolecular interactions between the NF-based filter media and water molecules, the PAN-NF filter is expected to exhibit the best performance in the wet state. Experiment studies also successfully demonstrate that the PAN-NF filter medium has better performance in the filtration of particulate matter (PM) than a commercial semi-high efficiency particulate air filter under wet conditions, and these results are in good agreement with the DFT calculation. The PAN-NF filter shows better performance because of its hydrophilic nature and the relatively low thickness the filter medium that allowed fast recovery of its PM-filtration performance.

Key Points: The present study aimed to determine the impact of ageing on endogenous adropin levels in human skeletal muscle feed arteries (SMFAs) and the role of adropin in age-related vascular dysfunction. Adropin protein expression falls progressively with advancing age in the human peripheral vasculature. Endothelial-dependent vasodilatation, typically attenuated with age, was strongly correlated with SMFA adropin protein levels. Adropin incubation restored age-related endothelial-dependent vasodilatory dysfunction and increased the phosphorylated endothelial nitric oxide synthase (eNOS)/eNOS ratio in an age-dependent manner in the SMFAs. The role of nitric oxide bioavailability was additionally indicated by NOS blockade ablating both the positive vascular effects of adropin incubation and the relationship between endothelial function and adropin protein expression. Additional evidence of a mechanistic link between declining adropin and age-related endothelial dysfunction was documented by a progressively increasing magnitude of effect of adropin-induced eNOS-mediated vasodilatation with ageing. Adropin appears to be a novel therapeutic target for facilitating the restoration of endothelial function with ageing., Abstract: The present study aimed to determine the impact of advancing age on endogenous adropin levels in human skeletal muscle feed arteries (SMFAs) and the role of adropin in age-related vascular dysfunction. Adropin protein expression and vasodilatory capacity was assesed in SMFAs from Young (27 ± 2 years, n = 10), Middle Aged (54 ± 2 years, n = 10) and Old (75 ± 2 years, n = 16) subjects. Endothelial-dependent vasodilatation, with and without adropin incubation, was assessed in response to flow-induced shear stress and ACh. Both SMFA adropin protein expression and endothelial-dependent vasodilatory function exhibited a progressive, age-related, reduction (Flow: Y: 65 ± 3%; Middle Aged: 36 ± 3%; Old: 15 ± 2%; ACh: Young: 63 ± 2%, Middle Aged: 34 ± 3%; Old: 23 ± 3%, P < 0.05). There was a strong positive correlation between SMFA adropin protein expression and both flow (r = 0.81, P < 0.05) and ACh (r = 0.78, P < 0.05). Adropin incubation in the Middle Aged and Old SMFAs restored the vasodilatory response to flow (Middle Aged + Adropin: 59 ± 3%; Old + Adropin: 47 ± 3%, P < 0.05) and ACh (Middle Aged + Adropin: 59 ± 3%; Old + Adropin: 49 ± 2%, P < 0.05). A mechanistic link between adropin and nitric oxide (NO) biovavailabilty was supported by (i) increased phosphorylated endothelial NO synthase (eNOS)/eNOS protein expression with adropin incubation only in the Middle Aged and Old SMFAs; (ii) eNOS blockade ablating both the positive vascular effects of adropin incubation and the relationship between endothelial function and adropin protein expression and (iii) a progressive increase in the magnitude of effect of adropin-induced eNOS-mediated vasodilatation with advancing age. Adropin could be a novel therapeutic target for facilitating the restoration of endothelial function via increased NO bioavailability, with advancing age., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Background & Aims: Sorafenib is first-line standard of care for patients with advanced hepatocellular carcinoma (HCC), yet it confers limited survival benefit. Therefore, we aimed to compare clinical outcomes of sorafenib combined with concurrent conventional transarterial chemoembolization (cTACE) vs. sorafenib alone in patients with advanced HCC., Methods: In this investigator-initiated, multicenter, phase III trial, patients were randomized to receive sorafenib alone (Arm S, n = 169) or in combination with cTACE on demand (Arm C, n = 170). Sorafenib was started within 3 days and cTACE within 7-21 days of randomization. The primary endpoint was overall survival (OS)., Results: For Arms C and S, the median OS was 12.8 vs. 10.8 months (hazard ratio [HR] 0.91; 90% CI 0.69-1.21; p = 0.290); median time to progression, 5.3 vs. 3.5 months (HR 0.67; 90% CI 0.53-0.85; p = 0.003); median progression-free survival, 5.2 vs. 3.6 months (HR 0.73; 90% CI 0.59-0.91; p = 0.01); and tumor response rate, 60.6% vs. 47.3% (p = 0.005). For Arms C and S, serious (grade ≥3) adverse events occurred in 33.3% vs. 19.8% (p = 0.006) of patients and included increased alanine aminotransferase levels (20.3% vs. 3.6%), hyperbilirubinemia (11.8% vs. 3.0%), ascites (11.8% vs. 4.2%), thrombocytopenia (7.2% vs. 1.2%), anorexia (7.2% vs. 1.2%), and hand-foot skin reaction (10.5% vs. 11.4%). A post hoc subgroup analysis compared OS in Arm C patients (46.4%) receiving ≥2 cTACE sessions to Arm S patients (18.6 vs. 10.8 months; HR 0.58; 95% CI 0.40-0.82; p = 0.006)., Conclusion: Compared with sorafenib alone, sorafenib combined with cTACE did not improve OS in patients with advanced HCC. However, sorafenib combined with cTACE significantly improved time to progression, progression-free survival, and tumor response rate. Sorafenib alone remains the first-line standard of care for patients with advanced HCC., Lay Summary: For patients with advanced hepatocellular carcinoma requiring sorafenib therapy, co-administration with conventional transarterial chemoembolization did not improve overall survival compared to sorafenib alone. Therefore, sorafenib alone remains the first-line standard of care for patients with advanced hepatocellular carcinoma. Clinical Trial Number: NCT01829035., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

We often temporally prepare our attention for an upcoming event such as a starter pistol. In such cases, our attention should be properly allocated around the expected moment of the event to process relevant sensory input efficiently. In this study, we examined the dynamic changes of attention levels near the expected moment by measuring contrast sensitivity to a target that was temporally cued by a five-second countdown. We found that the overall attention level decreased rapidly after the expected moment, while it stayed relatively constant before it. Results were not consistent with the predictions of existing explanations of temporal attention such as the hazard rate or the stimulus-driven oscillations. A control experiment ruled out the possibility that the observed pattern was due to biased time perception. In a further experiment with a wider range of cue-stimulus-intervals, we observed that attention level increased until the last 500 ms of the interval range, and thereafter, started to decrease. Based on the performances of a generative computational model, we suggest that our results reflect the nature of temporal attention that takes into account the subjectively estimated hazard rate and the probability of relevant events occurring in the near future.

Nonlinear hysteretic systems are common in many engineering problems. The maximum response estimation of a nonlinear hysteretic system under stochastic excitations is an important task for designing and maintaining such systems. Although a nonlinear time history analysis is the most rigorous method to accurately estimate the responses in many situations, high computational costs and modelingtime hamper adoption of the approach in a routine engineering practice. Thus, various simplified regression equations are often introduced to replace a nonlinear time history analysis in engineering practices, but the accuracy of the estimated responses is limited. This paper proposes a deep neural network trained by the results of the nonlinear time history analyses as an alternative of such simplified regression equations. To this end, a convolutional neural network (CNN) which is usually applied to abstract features from visual imagery is introduced to analyze the information of the hysteretic behavior of the system, then, merged with neural networks representing the stochastic random excitation to predict the responses of a nonlinear hysteretic system. For verification, the proposed deep neural network is applied to the earthquake engineering area to predict the structural responses under earthquake excitations. The results confirm that the proposed deep neural network provides a superior performance compared to the simplified regression equations which are developed based on a limited dataset. Moreover, to give an insight of the proposed deep neural network, the extracted features from the deep neural network are investigated with various numerical examples. The method is expected to enable engineers to effectively predict the response of the hysteretic system without performing nonlinear time history analyses, and provide a new prospect in the relevant engineering fields. The supporting source code and data are available for download at https://github.com/TyongKim/ERD2., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS); its cause is unknown. To understand the pathogenesis of MS, researchers often use the experimental autoimmune encephalomyelitis (EAE) mouse model. Here, the aim is to build a proteome map of the biological changes that occur during MS at the major onset sites-the brain and the spinal cord. Quantitative proteome profiling is performed in five specific brain regions and the spinal cord of EAE and healthy mice with high-resolution mass spectrometry based on tandem mass tags. On average, 7400 proteins per region are quantified, with the most differentially expressed proteins in the spinal cord (1691), hippocampus (104), frontal cortex (83), cerebellum (63), brainstem (50), and caudate nucleus (41). Moreover, region-specific and commonly expressed proteins in each region are identified and bioinformatics analysis is performed. Pathway analysis reveals that protein clusters resemble their functions in disease pathogenesis (i.e., by inducing inflammatory responses, immune activation, and cell-cell adhesion). In conclusion, the study provides an understanding of the pathogenesis of MS in the EAE animal model. It is expected that the comprehensive proteome map of the brain and spinal cord can be used to identify biomarkers for the pathogenesis of MS., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The potent cytotoxicity of reactive oxygen species (ROS) can cause various diseases, however, it may also serve as a powerful chemotherapeutic strategy capable of killing cancer cells. Oxalomalate (OMA, α-hydroxy-β-oxalosuccinic acid), a tricarboxylic acid intermediate, is a well-known competitive inhibitor of two classes of NADP + -dependent isocitrate dehydrogenase (IDH) isoenzymes, which serve as the major antioxidants and redox regulators in the mitochondria and cytosol. In this study, we investigated the therapeutic effects of OMA in melanoma and elucidated the associated underlying mechanisms of action using in vitro and in vivo models. OMA targeting IDH enzymes suppressed melanoma growth through activation of apoptosis and inhibition of angiogenesis. Mechanistically, our findings showed that OMA activated p53-mediated apoptosis through ROS-dependent ATM-Chk2 signaling and reduced the expression of vascular endothelial growth factor through ROS-dependent E2F1-mediated hypoxia inducible factor-1α degradation. In particular, OMA-induced suppression of IDH activity resulted in induction of ROS stress response, ultimately leading to apoptotic cell death and antiangiogenic effects in melanoma cells. Thus, OMA might be a potential candidate drug for melanoma skin cancer therapy., (Copyright © 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Acupuncture has been used to treat a variety of diseases and symptoms for more than 2,500 years. While a number of studies have shown that nerves are responsible for initiating the effects of acupuncture, several lines of study have emphasized the role of connective tissue in the initiation of acupuncture signals. To determine whether nerves or connective tissue mediate the action of acupuncture, we constructed a robotic acupuncture needle twister that mimicked the twisting of the needle by an acupuncturist, and we examined the role of nerves and connective tissues in the generation of acupuncture effects in rat cocaine-induced locomotion, stress-induced hypertension, and mustard oil-induced visceral pain models. Robotic or manual twisting of acupuncture needles effectively suppressed cocaine-induced hyperactivity, elevated systemic blood pressure or mustard oil-induced visceral pain in rats. These acupuncture effects were completely abolished by injecting bupivacaine, a local anesthetic, into acupoints. However, disruption of connective tissue by injecting type I collagenase into acupoints did not affect these acupuncture effects. Our findings suggest that nerve tissue, but not connective tissue, is responsible for generating the effects of acupuncture.

In order to fabricate a digital microfluidic (DMF) chip, which requires a patterned array of electrodes coated with a dielectric film, we explored two simple methods: Ballpoint pen printing to generate the electrodes, and wrapping of a dielectric plastic film to coat the electrodes. For precise and programmable printing of the patterned electrodes, we used a digital plotter with a ballpoint pen filled with a silver nanoparticle (AgNP) ink. Instead of using conventional material deposition methods, such as chemical vapor deposition, printing, and spin coating, for fabricating the thin dielectric layer, we used a simple method in which we prepared a thin dielectric layer using pre-made linear, low-density polyethylene (LLDPE) plastic (17-μm thick) by simple wrapping. We then sealed it tightly with thin silicone oil layers so that it could be used as a DMF chip. Such a treated dielectric layer showed good electrowetting performance for a sessile drop without contact angle hysteresis under an applied voltage of less than 170 V. By using this straightforward fabrication method, we quickly and affordably fabricated a paper-based DMF chip and demonstrated the digital electrofluidic actuation and manipulation of drops.

Epigenetic modifier lysine demethylase 3a (Kdm3a) specifically demethylates mono‑ and di‑methylated ninth lysine of histone 3 and belongs to the Jumonji domain‑containing group of demethylases. Kdm3a serves roles during various biological and pathophysiological processes, including spermatogenesis and metabolism, determination of sex, androgen receptor‑mediated transcription and embryonic carcinoma cell differentiation. In the present study, physiological functions of Kdm3a were evaluated during embryogenesis of Xenopus laevis. Spatiotemporal expression pattern indicated that kdm3a exhibited its expression from early embryonic stages until tadpole stage, however considerable increase of kdm3a expression was observed during the neurula stage of Xenopus development. Depleting kdm3a using kdm3a antisense morpholino oligonucleotides induced anomalies, including head deformities, small‑sized eyes and abnormal pigmentation. Whole‑mount in situ hybridization results demonstrated that kdm3a knockdown was associated with defects in neural crest migration. Further, quantitative polymerase chain reaction revealed abnormal expression of neural markers in kdm3a morphants. RNA sequencing of kdm3a morphants indicated that kdm3a was implicated in mesoderm formation, cell adhesion and metabolic processes of embryonic development. In conclusion, the results of the present study indicated that Kdm3a may serve a role in neural development during Xenopus embryogenesis and may be targeted for treatment of developmental disorders. Further investigation is required to elucidate the molecular mechanism underlying the regulation of neural development by Kdm3a.

One of the recently emerging topics in biotechnology is natural receptors including G protein-coupled receptors, ligand-gated ion channels, enzyme-linked receptors, and intracellular receptors, due to their molecular specificity. These receptors, other than intracellular receptors, which are membrane proteins expressed on the cell membrane, can detect extracellular stimuli. Many researchers have utilized cells with natural receptors embedded in the cellular membrane for human sense-mimicking platforms based on electrochemical impedance spectroscopy, quartz crystal microbalances, surface plasmon resonance, and surface acoustic waves. In addition, integration of conducting nanomaterials and natural receptors allows highly sensitive and selective responses toward target molecules, enabling, for example, nanobioelectronic noses for odorants, nanobioelectronic tongues for tastants, and G-protein-coupled receptor sensors for hormones, dopamine, cadaverine, geosmin, trimethylamine, etc. Moreover, as a part of nanobioelectronic sensors, natural receptors can be produced in various forms, such as peptides, proteins, nanovesicles, and nanodiscs, and each sensor can provide an ultralow limit of detection. In this Review, we discuss biosensors with natural receptors and then especially focus on natural receptor-conjugated conducting nanomaterial sensors. To provide a fundamental understanding, the sections encompass (1) the fabrication of conducting nanomaterials, (2) the production of natural receptors, (3) the characteristics of natural receptors, (4) the technology for immobilizing both components, and (5) their sensing applications. Finally, perspective is given on a new development in the use of natural receptors in a wide range of industries, such as food, cosmetics, and healthcare. In addition, artificial olfactory codes will be characterized by signal processing in the near future, leading to human olfactory standardization.

Parkinson's disease (PD), a neurodegenerative disorder, is characterized by a loss of dopaminergic neurons in the substantia nigra (SN) of the brain and it is well known that the pathogenesis of PD is related to a number of risk factors including oxidative stress. Antioxidant 1 (ATOX1) protein plays a crucial role in various diseases as an antioxidant and chaperone. In this study, we determined whether Tat-ATOX1 could protect against 1-methyl-4-phenylpyridinium ion (MPP + )-induced SH-SY5Y cell death and in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of PD. In the MPP + exposed SH-SY5Y cells, Tat-ATOX1 markedly inhibited cell death and toxicities. In addition, Tat-ATOX1 markedly suppressed the activation of Akt and mitogen activated protein kinases (MAPKs) as well as cleavage of caspase-3 and Bax expression levels. In a MPTP-induced animal model, Tat-ATOX1 transduced into brain and protected dopaminergic neuronal cell loss. Taken together, Tat-ATOX1 inhibits dopaminergic neuronal death through the suppression of MAPKs and apoptotic signal pathways. Thus, Tat-ATOX1 represents a potential therapeutic protein drug candidate for PD., (Copyright © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)