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Enzymes have essential roles in catalyzing biological reactions and maintaining metabolic systems. Many in vitro enzymatic bioassays have been developed for use in industrial and research fields, such as cell biology, enzyme engineering, drug screening, and biofuel production. Of note, many of these require the use of high-throughput platforms. Although the microtiter plate remains the standard for high-throughput enzymatic bioassays, microfluidic arrays and droplet microfluidics represent emerging methods. Each has seen significant advances and offers distinct advantages; however, drawbacks in key performance metrics, including reagent consumption, reaction manipulation, reaction recovery, real-time measurement, concentration gradient range, and multiplexity, remain. Herein, we compare recent high-throughput platforms using the aforementioned metrics as criteria and provide insights into remaining challenges and future research trends.

OBJECTIVES The purpose of this study was to determine the effect of evolocumab on optical coherence tomography (OCT) measures of plaque composition. BACKGROUND The proprotein convertase subtilisin kexin type-9 inhibitor evolocumab produced coronary atheroma regression in statin-treated patients. METHODS Patients with a non-ST-segment elevation myocardial infarction were treated with monthly evolocumab 420 mg (n = 80) or placebo (n = 81) for 52 weeks. Patients underwent serial OCT and intravascular ultrasound imaging within a matched arterial segment of a nonculprit vessel. The primary analysis determined the change in the minimum fibrous cap thickness and maximum lipid arc throughout the imaged arterial segment. Additional analyses determined changes in OCT features in lipid-rich plaque regions and plaque burden. Safety and tolerability were evaluated. RESULTS Among treated patients, (age 60.5 ± 9.6 years; 28.6% women; low-density lipoprotein cholesterol [LDL-C], 141.3 ± 33.1 mg/dL), 135 had evaluable imaging at follow-up. The evolocumab group achieved lower LDL-C levels (28.1 vs 87.2 mg/dL; P < 0.001). The evolocumab group demonstrated a greater increase in minimum fibrous cap thickness (+42.7 vs +21.5 μm; P = 0.015) and decrease in maximum lipid arc (-57.5o vs. -31.4o; P = 0.04) and macrophage index (-3.17 vs -1.45 mm; P = 0.04) throughout the arterial segment. Similar benefits of evolocumab were observed in lipid-rich plaque regions. Greater regression of percent atheroma volume was observed with evolocumab compared with placebo (-2.29% ± 0.47% vs -0.61% ± 0.46%; P = 0.009). The groups did not differ regarding changes in microchannels or calcium. CONCLUSIONS The combination of statin and evolocumab after a non-ST-segment elevation myocardial infarction produces favorable changes in coronary atherosclerosis consistent with stabilization and regression. This demonstrates a potential mechanism for the improved clinical outcomes observed achieving very low LDL-C levels following an acute coronary syndrome. (Imaging of Coronary Plaques in Participants Treated With Evolocumab; NCT03570697).

LDL-C is the pivotal risk factor for atherosclerotic cardiovascular disease, and the benefit from LDL-C lowering is proportional to the magnitude of reduction. Clinical trials demonstrate that evolocumab reduces LDL-C levels by approximately 60% when measured at the trough of drug effect, which may underestimate cumulative LDL-C reduction. We obtained a time-averaged estimate of LDL-C lowering that included both peaks and troughs. Pooled analysis of 5 phase 2 trials included patients with hypercholesterolemia who received placebo or evolocumab (140 mg every 2 weeks [Q2W] or 420 mg monthly [QM]). Percent changes from baseline LDL-C and free serum PCSK9 were averaged across weeks 9-12. In 372 patients, time-averaged percent reduction from baseline in LDL-C with evolocumab vs placebo was 67.6% (95% CI: 63.9-71.3) with Q2W dosing and 65.0% (95% CI: 60.7-69.3) with QM dosing. The time-averaged measure yielded LDL-C reductions for evolocumab that exceeded measurements at the end of dosing intervals and may provide a better estimate of cardiovascular benefit during long-term therapy.

A patient with mutilated dentition was treated to an acceptable result with the help of mini-implants for anchorage, autotransplantation of 2 teeth, one dental implant, and multiple prostheses. The major problems for this mutilated dentition were multiple missing teeth, bite collapse with posterior crossbites, deepbite with a canted gummy smile, and severe skeletal discrepancy of maxillary protrusion and mandibular retrusion. Mini-implant anchorage was applied to retract and intrude the maxillary arch to reduce the protrusion and rotate the mandible counterclockwise to improve the chin projection. Two autotransplantations, one dental implant, and multiple prostheses were used to accomplish a satisfactory full mouth rehabilitation with an interdisciplinary approach, including orthodontics, periodontics, endodontics, prosthodontics, and implantology. The understanding of biological principles, improvement in surgical protocol makes it possible to preserve the periodontal ligament (PDL) cells with atraumatic extraction after loosening the donor with orthodontic force and reduce the extraoral time with the 3-dimensional print-out replica segmented from cone-beam computed tomography for trying fitness. Soft wire splinting to gain initial stabilization and root canal treatment to avoid endotoxin further reduce the risk of root resorption, loss of attachment, and ankylosis. Autotransplantation could be considered as a part of full mouth rehabilitation. Orthodontic space management is also an important procedure to confirm the site of dental implant installation in the interdisciplinary collaboration.

A 14-year 10-month-old female requested full mouth rehabilitation with protrusive lips and hopelessly decayed maxillary left first molar and mandibular right first molar. The advantages and disadvantages of various possible treatment alternatives were thoroughly discussed. The dilemma between asymmetrical orthodontic space closure and the implant-supported prosthesis was solved by the application of autotransplantation. The treatment progressed well and resulted in satisfactory occlusion and profile.

The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) trial demonstrated that evolocumab added to a background statin did not affect cognitive performance in a subset of 1,204 patients enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 inhibitors in Subjects With Elevated Risk).The authors describe patient-reported cognition in the entire FOURIER trial using a self-survey.FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dl or non-high-density cholesterol ≥100 mg/dl despite statin therapy. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition (ECog) scale. Patients compared their levels of everyday function at the end of the trial with their levels at the beginning and scored as 1 (no change or improvement), 2 (occasionally worse), 3 (consistently little worse), or 4 (consistently much worse). ECog scores were compared by the 2 randomized treatment arms and by achieved LDL-C at 4 weeks.A total of 22,655 patients completed ECog after a median duration of 2.2 years. The proportions of patients reporting cognitive decline (ECog score ≥2) at the end of the study were similar for placebo versus evolocumab, both for total score 3.6% versus 3.7% (p = 0.62) and for subdomains (memory, 5.8% vs. 6.0%; total executive, 3.6% vs. 3.7%). The proportion of patients reporting a decline in total cognitive score was similar among the 2,338 patients who achieved very low LDL-C levels (20 mg/dl) compared to the 3,613 patients with LDL-C ≥100 mg/dl (3.8% vs. 4.5%, p = 0.57).The addition of evolocumab to maximally tolerated statin therapy had no impact on patient-reported cognition after an average of 2.2 years of treatment, even among patients who achieved LDL-C 20 mg/dl.

In view of the increasing prevalence of gestational diabetes mellitus (GDM) and the increased risks of delivering a macrosomic infant, developing preeclampsia, and suffering a perinatal death due to GDM, GDM has emerged as a growing public health problem. Although the placenta was suggested to play a crucial role in the pathology of GDM, the mechanisms that induce the development of GDM are still obscure. Fibrinogen-like protein (FGL)-1 is a hepatokine that plays an important role in hepatogenesis, as well as in nonalcoholic fatty liver disease and diabetes. Although FGL-1 is also expressed by the placenta, the pathophysiological role of FGL-1 in GDM is still unknown. In this study, FGL-1 levels were evaluated in 45 subjects with (n = 16) or without (n = 29) GDM. We found that FGL-1 was mainly expressed by placental trophoblasts, and FGL-1 expression was significantly higher in subjects with GDM. FGL-1 increased trophoblast proliferation through an extracellular signal-regulated kinase 1/2-dependent pathway. In addition, plasma concentrations of FGL-1 were higher in subjects with GDM, and the increased circulating FGL-1 might contribute to systemic insulin resistance. FGL-1 disrupted the gluconeogenic action of insulin in HepG2 cells, and decreased insulin-induced glucose uptake by L6 myotubes. Taken together, placental FGL-1 possibly plays a role in the impairment of insulin function in the development of GDM, and it might be a novel biomarker for diagnosing GDM.

A nanotube assisted microwave electroporation (NAME) technique is demonstrated for delivering molecular biosensors into viable bacteria for multiplex single cell pathogen identification to advance rapid diagnostics in clinical microbiology. Due to the small volume of a bacterial cell (~femtoliter), the intracellular concentration of the target molecule is high, which results in a strong signal for single cell detection without amplification. The NAME procedure can be completed in as little as 30 minutes and can achieve over 90% transformation efficiency. We demonstrate the feasibility of NAME for identifying clinical isolates of bloodborne and uropathogenic pathogens and detecting bacterial pathogens directly from patient's samples. In conjunction with a microfluidic single cell trapping technique, NAME allows single cell pathogen identification and antimicrobial susceptibility testing concurrently. Using this approach, the time for microbiological analysis reduces from days to hours, which will have a significant impact on the clinical management of bacterial infections.

Consumers may develop different levels of expectation about a destination, depending on the source of online information that they encounter. We explored the effects of information from online advertising and electronic word-of-mouth on destination expectations and the resulting satisfaction and revisit intentions. Data from 354 first-time visitors to Japan were analyzed in a two-step approach using a confirmatory factor analysis (CFA) and structural equation modeling. Four indirect effects were examined and compared using the bootstrap method. We found that information about destinations from online advertising was negatively associated with positive disconfirmations. However, destination information acquired from electronic word-of-mouth led to an increase in the likelihood of a positive disconfirmation, and it significantly increased travel satisfaction and revisit intentions. In addition, four indirect paths through a positive disconfirmation were confirmed. However, there was no moderating effect of search effort. Based on our findings, marketers should be aware that elaborate online advertising may have factors that undermine future business. To avoid the negative disconfirmation, marketers can remind customers that the photos and videos in advertisements were taken at specific times, places, seasons, or under other conditions. Moreover, marketers should encourage their consumers to share their previous travel experiences online to offset the negative disconfirmation from destination advertising and websites.

A primary technological challenge after a disaster is rapid deployment of temporary infrastructure to provide communications for disaster management workers. 3GPP Release 12 defines proximity service (ProSe) to allow direct communications within users for Long Term Evolution-Advanced (LTE-A) public safety. To support group communications, each group members have to receive data sent from the group application server (GAS) maintained in ProSe. This paper discusses the use of vehicle-mounted mobile base station to provide group communications over a two-tier heterogeneous architecture with the aid of GAS and ProSe links. In this method, each vehicle-mounted mobile base station (BS) works in a cell breathing manner to expand or shrink the cell coverage periodically. This way can ensure GAS having the up-to-date proximity knowledge of all users while the part of high-cost group data traffic due to the users located far from the BS can be offloaded to low-cost ProSe links instead. We formulate the minimum cost problem of the ProSe-based File Distribution (PFD) in such architecture. We prove the minimum PFD problem is NP-complete and then proposes three sources selection algorithms for PFD, namely Greedy algorithm, Defer algorithm, and Recursive algorithm. Extensive simulation study is conducted to evaluate performance of the proposed algorithms.

This study proposes an efficient approach for the pricing of VIX derivatives under the affine framework and investigates the respective value of two variance components and variance jumps in the pricing of VIX derivatives. Our numerical results show that our approach significantly reduce the computational burden. Our empirical findings provide support for the use of two-variance component models as the means of capturing the fickle term structure of VIX derivatives, and the use of variance jumps is vital when included in the long-run variance component.

Metabolism studies are one of the important steps in pharmaceutical research. LC-MS combined with metabolomics data-processing approaches have been developed for rapid screening of drug metabolites. Mass defect filter (MDF) is one of the LC/MS-based metabolomics data processing approaches and has been applied to screen drug metabolites. Although MDF can remove most interference ions from an incubation sample, the true positive rate of the retaining ions is relatively low (approximately 10%). To improve the efficacy of MDF, we developed a two-stage data-processing approach by combining MDF and stable isotope tracing (SIT) for metabolite identification. Pioglitazone (PIO), which is an antidiabetic drug used to treat type 2 diabetes mellitus, was taken as an example drug. Our results demonstrated that this new approach could substantially increase the validated rate from about 10% to 74%. Most of these validated metabolite signals (13/14) could be verified as PIO structure-related metabolites. In addition, we applied this approach to identify uncommon metabolite signals (a mass change beyond the window of 50 Da around its parent drug, MDF1). SIT could remove most interference ions (approximately 98%) identified by MDF1, and four out of five validated metabolite signals could be verified as PIO structure-related metabolites. Interestingly, a lot of the verified metabolites (10/17) were novel PIO metabolites. Among these novel metabolites, nine were thiazolidinedione ring-opening signals that might be related to the toxicity of PIO. Our developed approach could significantly improve the efficacy in drug metabolite identification compared with that of MDF.

This paper studies how local shocks can have aggregate effects through the effects of social networks on expectations. First, using plausibly exogenous variation in the exposure of counties to COVID-19 shocks in their social network, we find that a 10% rise in SCI-weighted cases and deaths is associated with a 0.15% and 0.42% decline in consumption expenditures. These effects are concentrated among consumer goods & services that rely more on social-contact and are not driven by local shocks. Second, we augment a quantitative pandemic-consumption model under incomplete market with a tractable mechanism of belief formation through social communications. The model is general enough to nest a number of workhorse theories of expectation formations featuring overreaction, rational updating, or stickiness. We find that, while social communication slows the speed of aggregate belief adjustment in responses to fundamentally relevant shocks, it also moderates overreaction to local noises in aggregation. We demonstrate how the dynamic and average size of aggregate responses depend on the location of the initial shocks and the structure of the network.

Gonorrhea is an urgent global public health threat as Neisseria gonorrhoeae (Ng) has progressively developed resistance to all antibiotics commonly used for treatment. Surveillance of antimicrobial susceptibility trends is critical to monitor the emergence and spread of antimicrobial resistance. The gold standard methods for antimicrobial susceptibility testing (AST) of Ng are laborious and time-consuming. We evaluated a phenotypic molecular approach, involving a short cultivation step and quantitative PCR, with lyophilized antimicrobials to characterize antimicrobial susceptibility in Ng. There was excellent concordance between AST performed with liquid and lyophilized ciprofloxacin, penicillin, and tetracycline using the pheno-molecular assay, following a four-hour incubation step. The categorical agreement between the pheno-molecular assay and the gold standard AST results was 92.4% for characterization of antimicrobial susceptibility. Essential agreement between the two methods was 91.9%. Characterization of ceftriaxone susceptibility in Ng using the pheno-molecular assay required a six-hour incubation step.

The illiquidity risk premium hypothesis implies the existence of a positive relation between illiquidity in the option market and option returns. Based on numerous studies within the extant literature examining the roles of informed traders in the option markets, we explore how information asymmetry and short sales affect the illiquidity risk premium hypothesis. We find that the illiquidity risk premium is higher for both call and put options of those firms with higher information asymmetry, which is particularly driven by small firms. We also find that it is higher for put (call) options of those stocks with lower (higher) short-sale supply (demand).

Recently advances in miniaturization and automation have been utilized to rapidly decrease the time to result for microbiology testing in the clinic. These advances have been made due to the limitations of conventional culture-based microbiology methods, including agar plate and microbroth dilution, which have long turnaround times and require physicians to treat patients empirically with antibiotics before test results are available. Currently, there exist similar limitations in pharmaceutical sterility and bioburden testing, where the long turnaround times associated with standard microbiology testing drive costly inefficiencies in workflows. These include the time lag associated with sterility screening within drug production lines and the warehousing cost and time delays within supply chains during product testing. Herein, we demonstrate a proof-of-concept combination of a rapid microfluidic assay and an efficient cell filtration process that enables a path toward integrating rapid tests directly into pharmaceutical microbiological screening workflows. We demonstrate separation and detection of Escherichia coli directly captured and analyzed from a mammalian (i.e., CHO) cell culture with a 3.0 h incubation. The demonstration is performed using a membrane filtration module that is compatible with sampling from bioreactors, enabling in-line sampling and process monitoring.

Several process capability indices have been applied to develop variables single sampling plans (SSPs) and repetitive group sampling plans (RGSPs) for numerical measurements of quality characteristics. Both types of plans are simple to administer and easy to implement, but neither of them considers the available information of previous collected samples. In this study, we develop a modified variables repetitive group sampling plan (Modified-VRGSP) to overcome the disadvantages of the SSP and the RGSP by considering the quality history of preceding lots based on the one-sided capability index. By minimizing the average sample number while satisfying the quality levels demanded by both the producer and the consumer, the plan parameters can be obtained for product acceptance determination. The advantages of the proposed plan over existing variables sampling plans are presented.

Inflammation, oxidative stress, and formation of advanced glycated end products (AGEs) and advanced lipoxidation end products (ALEs) are important for atherosclerosis. Vascular adhesion protein-1 (VAP-1) participates in inflammation and has semicarbazide-sensitive amine oxidase (SSAO) activity, which catalyzes oxidative deamination to produce hydrogen peroxide and aldehydes, leading to generation of AGEs and ALEs. However, the effect of VAP-1/SSAO inhibition on atherosclerosis remains controversial, and no studies used coronary angiography to evaluate if plasma VAP-1/SSAO is a biomarker for coronary artery disease (CAD). Here, we examined if plasma VAP-1/SSAO is a biomarker for CAD diagnosed by coronary angiography in humans and investigated the effect of VAP-1/SSAO inhibition by a specific inhibitor PXS-4728A on atherosclerosis in cell and animal models. In the study, VAP-1/SSAO expression was increased in plaques in humans and in apolipoprotein E (ApoE)-deficient mice, and colocalized with vascular endothelial cells and smooth muscle cells (SMCs). Patients with CAD had higher plasma VAP-1/SSAO than those without CAD. Plasma VAP-1/SSAO was positively associated with the extent of CAD. In ApoE-deficient mice, VAP-1/SSAO inhibition reduced atheroma and decreased oxidative stress. VAP-1/SSAO inhibition attenuated the expression of adhesion molecules, chemoattractant proteins, and proinflammatory cytokines in the aorta, and suppressed monocyte adhesion and transmigration across human umbilical vein endothelial cells. Consequently, the expression of markers for macrophage recruitment and activation in plaques was decreased by VAP-1/SSAO inhibition. Besides, VAP-1/SSAO inhibition suppressed proliferation and migration of A7r5 SMC. Our data suggest that plasma VAP-1/SSAO is a novel biomarker for the presence and the extent of CAD in humans. VAP-1/SSAO inhibition by PXS-4728A is a potential treatment for atherosclerosis.

The South China Sea oceanic lithosphere has been subducting eastward beneath the Huatung Basin/Philippine Sea Plate since the Early Miocene (~18 Ma). The subduction is followed by the oblique collision between the Luzon arc and the subducting Eurasian plate from 6.5 Ma. The North Luzon Trough forearc strata and the Luzon arc are then obducted northwestward as the Coastal Range, eastern Taiwan, in the last 1 Ma. The collision propagates southward and is presently active in the region offshore SE Taiwan. Integrating seismic surveys offshore and a detailed forearc stratigraphy study onshore the Coastal Range, this paper overviews the characteristics of forearc deformation, dynamic sequence stratigraphy, temporal-spatial variations of forearc sedimentation and stratigraphic correlation onshore and offshore forearc sequences in response to the oblique convergent tectonics north of 20°N. Combining onshore and offshore forearc geology together allows us to reconstruct a structural evolution of the North Luzon Trough forearc basin from subduction through collision to obduction, and to discuss the mechanism and processes responsible for developments of the modern-forming forearc Lichi Melange during the active Taiwan orogeny. Seismic surveys offshore show that forearc deformation in the subduction zone is primarily caused by increase of rear prism slope and west-vergent thrusting of forearc strata along the prism top since the early forearc sedimentation. East-vergent backthrusting occurs during the late forearc sedimentation and propagates arcward when the volcanic arc collides with the accretionary prism in the collision zone. Bivergent thrusting leads to a development of the forearc Huatung Ridge popup as a bathymetric high which further controls the sedimentation of the younger forearc sequence in the collision zone. In response to the syn-sedimentation deformation, forearc depocenter shifts progressively eastward. Forearc stratigraphy thus changes from two mega-sequences bounded by an unconformity in the subduction zone to three mega-sequences juxtaposed from west to east unconformably in the collision zone. As a consequence, the forearc deformation and stratigraphy in the oblique collision zone off SE Taiwan show a characteristic temporal-spatial pattern that the lowest mega-sequence with the most intensive deformation occurs restrictedly in the west, whiles the middle and the upper mega-sequences with mild deformation crop out in the center and the eastern part of the forearc basin, respectively. Detailed biostratigraphy study using planktonic foraminifera and calcareous nannoplanktons indicates that the forearc strata onshore the Coastal Range are also composed of three sequences (lower unit S-1: 6.5–5.8 Ma; middle unit S-2: 5.8–3.0 Ma; and upper unit S-3: A structure reconstruction reveals that the North Luzon Trough forearc strata have experienced multiple stages of thrust deformation from subduction through collision to obduction. These deformations account for the mechanism and processes to develop the modern-forming highly sheared SSZ-bearing forearc Lichi Melange tectonically in the western Coastal Range during the last 1 Ma.

Introduction In high-income countries, advances in early diagnosis and treatment have improved cancer survival. However, socioeconomic inequalities in survival have persisted or increased for some adult cancers. Materials and methods We assessed net survival for the 20 most common adult cancers in Taiwan. They were stratified into six age groups and three socioeconomic groups. Results Out of 120 cancer site and age group combinations, 49 showed improvements in 5-year net survival from 2000–2004 to 2005–2010. Only cervix uteri cancer in the 35–49-year age group showed a deterioration. During 2000–2010, 13 of the 20 cancer cases experienced socioeconomic inequalities for all age groups combined, and the deprivation gaps varied with cancer site and age at diagnosis. For the five most common cancers – liver, colon and rectum, lung, breast, and oral – there were socioeconomic inequalities, and 5-year net survival improved for most or all of the six age groups from 2000–2004 to 2005–2010. Conclusion Reducing socioeconomic inequality in survival may lead to improvements in survival overall. We should focus on the age groups with large deprivation gaps. Our results are useful for prioritizing cancer sites and age groups for in-depth socioeconomic disparity studies and for proposing interventions for health disparity reductions and net cancer survival improvements.

The purpose of this research is to investigate how attitude change happens on social media and explore the factors key to persuasion. We apply social impact theory to investigate the effects of persuader immediacy or relationship closeness, message persuasiveness, and perceived supportiveness on attitude change on Facebook. Using 2016 Taiwan President election as the backdrop, 313 Taiwan President election voters were invited to participate in the survey. Results show that persuader immediacy is not significantly related to attitude change or attitude maintenance, while message persuasiveness and supportiveness are significantly related to both attitude change and maintenance, which in turn, predict one’s intentions to vote for the opposite political camp.

This research takes a different approach to examining the international risk-return tradeoff nexus from an econometrician's viewpoint. We study this tradeoff based on returns from 28 countries, covering a wide range of advanced and emerging markets. In contrast to the existing literature, we conduct panel data analysis that allows for cross-sectional dependence, along with the fixed-effects pooled OLS method that can produce consistent estimators. Empirical results show that the proposed approach could be a practical guide for investment portfolio, because of (i) the positive risk-return relation for both advanced and emerging economies, especially when it is associated with the business cycle, and (ii) the convincing out-of-sample forecasts by the fixed-effects pooled panel predictions.

Oligocene-Miocene sediments in the Taiwan region were accumulated in the NE passive-continental margin of the South China Sea. We utilized around ~200 boreholes and reflection seismic data to study the Oligo-Miocene sequence stratigraphic framework in the Taiwan region. Major sequence boundaries are used to map out various sediment isopach maps, enabling us to decipher dominant tectonic events during the course of passive-margin evolution. The Oligocene-Miocene succession is divided into 16 sequences on the basis of well-log correlation. These 16 sequences can be grouped into four (A, B, C, D) sequence sets. Isopach maps of sequence sets B and C (~21–12.5 Ma) show that they blanket the west Taiwan basins with relatively uniform thickness deposited during uniform and slow basement subsidence. Sequence sets A (~30–21 Ma) and D (~12.5–6.5 Ma), however, thickened into fault-bounded troughs, recording two extensional events that were especially active in the outer margin (i.e., the Tainan Basin). There is a general correlation between the Taiwan Miocene sequences and the glacioeustasy during the interval ~21–6.5 Ma. Therefore, eustasy is the dominant control on the Taiwan Miocene stratigraphic development. The deposition of the sequence set A during ~30–21 Ma and possibly the sequence set D in the outer margin during the late Miocene, however, appears to have been strongly modulated by extensional tectonics and local sedimentary factors (e.g., rates of basin subsidence, sediment supply and basin physiography, etc.).

Copper-ion-doped (Cu2+) PANI/WO3 films with various Cu2+ concentrations were coated onto surface acoustic wave resonators to function as room temperature nitric oxide sensors. Morphological characterization and functionalization of the sensing material were explored using scanning electron microscopy and Fourier transform infrared spectroscopy, respectively. The optimal film was discovered to be a 0.2 wt% Cu2+/PANI/WO3 film. The sensor response toward the detection of 1 ppb NO at room temperature in dry air was 165 Hz and presented a signal-to-noise ratio of approximately 37. The response and recovery times were 59 and 17 s when detecting 80 ppb NO, respectively. The frequency response was discovered to be linear in the NO concentration range 1–116 ppb. The sensor’s sensitivity, reversibility, repeatability, selectivity, and stability were studied for ppb-level NO gas sensing at room temperature in dry air.

This paper examines the impact of stock liquidity on option pricing by comparing pricing performance across two option pricing models. These two models are identical in all respects except for the presence of illiquidity in the underlying asset. Using various liquidity measures, the empirical results reveal a clear link between stock liquidity and option pricing. Specifically, adding a stock liquidity adjustment into an option pricing model produces smaller and more stable pricing errors for all comparison groups. The improvement rate is particularly high for options on stocks with lower liquidity and for out-of-the-money options. Our results are robust across liquidity measures and evaluation criteria. These findings highlight the significance of accounting for the stock liquidity when pricing options.

Digital nucleic acid amplification tests (digital NAATs) have emerged as a popular tool for nucleic acid detection due to their high sensitivity and specificity. Most current digital NAAT platforms, however, are limited to a “one-color-one-target” approach wherein each target is encoded with a specific fluorescently-labeled probe for single-plex fluorometric detection. This approach is difficult to multiplex due to spectral overlap between any additional fluorophores, and multiplexability of digital NAATs has therefore been limited. As a means to scale multiplexability, we have developed a multiplexed digital NAAT platform, termed Droplet Digital Ratiometric Fluorescence Coding (ddRFC), via a padlock probe-based nucleic acid detection assay which encodes each nucleic acid target with a unique combination of 2 fluorophores. We detect this encoded two-color fluorescence signature of each target by performing digital amplification in microfluidic droplets. To demonstrate the utility of our platform, we have synthesized 6 distinct padlock probes, each rendering a unique two-color fluorescence signature to a nucleic acid target representing a clinically important sexually transmitted infection (STI). We proceed to demonstrate broad-based, two-plex, four-plex, and six-plex detection of the STI targets with single-molecule resolution. Our design offers a cost-effective approach to scale up multiplexability by simply tuning the number of molecular beacon binding sites on the padlock probe without redesigning amplification primers or fluorescent molecular beacons. With further development, our platform has the potential to enable highly multiplexed detection of nucleic acid targets, with potentially unrestricted multiplexability, and serve as a diagnostic tool for many more diseases in the future.

In recent years, powder metallurgy has developed rapidly and has been used to produce mechanical parts with complex structures. High precision and material utilization with low production cost can be achieved through the powder metallurgy process. In order to reduce the cost of finishing processes and product scrap rate, quality management methods must be used to improve processes and increase the product yield. This study uses the Taguchi method to analyze various factors that affect parallelism in the forming stage of the powder metallurgy process and to determine the optimal parameter setting and verification. In the orthogonal array of the Taguchi method, we selected six factors with two levels as the machine setting, which would affect the product’s parallelism. The current machine setting, and possible setting were determined as the first and second levels, respectively, and several experiments were designed to ascertain the configuration of the orthogonal array. After performing the designed experiments, the signal noise ratio (S/N ratio) was calculated for estimating variability of products. New samples were manufactured based on the optimal setting and compared with the original data. The experimental result revealed that the average value of parallelism data was considerably reduced for two different products and decreased approximately 55.73% and 49.44%. Values of the S/N ratio should be in the confidence interval to verify whether the whole experiment is reproducible. Thus, the product yield and production cost were simultaneously improved for this case.

Purpose The 2015 American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG–AMP) guidelines were a major step toward establishing a common framework for variant classification. In practice, however, several aspects of the guidelines lack specificity, are subject to varied interpretations, or fail to capture relevant aspects of clinical molecular genetics. A simple implementation of the guidelines in their current form is insufficient for consistent and comprehensive variant classification. Methods We undertook an iterative process of refining the ACMG–AMP guidelines. We used the guidelines to classify more than 40,000 clinically observed variants, assessed the outcome, and refined the classification criteria to capture exceptions and edge cases. During this process, the criteria evolved through eight major and minor revisions. Results Our implementation: (i) separated ambiguous ACMG–AMP criteria into a set of discrete but related rules with refined weights; (ii) grouped certain criteria to protect against the overcounting of conceptually related evidence; and (iii) replaced the “clinical criteria” style of the guidelines with additive, semiquantitative criteria. Conclusion Sherloc builds on the strong framework of 33 rules established by the ACMG–AMP guidelines and introduces 108 detailed refinements, which support a more consistent and transparent approach to variant classification.

This paper focuses on revisiting an old issue by advanced econometrics analysis: the risks in the U.S. stock market. We analyze the firm's exposure to exchange rate, interest rate, and market shocks by the pooled regression with the error cross-section dependency. We not only examine the exchange market, and interest rate exposure to U.S. firm values in 396 samples, but we also investigate those patterns to the firms within each of the 10 specific industries by which way we may detect the direction of capital flows before and after two well-known financial crises that occurred in 2001 and 2008. All empirical results show the significant industry-specific sensitivity to these three risks which are in marked contrast to the findings that have been assessed thus far in current literature. Our results indicate: (i) in which industry the capital flows go (industry-specific effect) before and after crises; (ii) which currency, market index, and interest rate play a more important role in the sensitivity to U.S. firm stock returns before and after crises; and (iii) the prospect on hedging portfolio setting for investors before and after crises, which is consistent with the finding of Campbell {it et al.} (2010) and Lusting {it et al.} (2011).

This study investigates an AR (autoregressive)-filtered version of several conventional diagnostic tests for cross-sectional dependence in large mixed panels, including the adjusted LM test, the CD test, and the Schott test. We show that the modified tests asymptotically follow the standard normal distribution. The distinctive feature of these new tests is their simple implementation, even though the exact time series properties of each component of a mixed panel are unknown or unobservable in practice. Simulations show that the AR-filtered version of the CD test (CDAR) performs the best compared to the other testing procedures in finite sample and computation time, especially for those cases with large cross-sectional dimension. We also provide a new perspective on the role of CDAR statistic in an early warning indicator of market risk or crisis.

Background: Barrett's esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC). Current guidelines recommend endoscopic screening of patients with two or more potential BE risk factors but fail to capture two-thirds of prevalent BE cases. Given the lack of an acceptable, accurate and cost-effective tool for BE screening, new methods are needed to allow population-based screening. Here, we sought to develop a BE screening method based on methylation status in cytology samples captured by EsophaCap, a retrievable sponge sampling device, using a streamlined sensitive technique, methylation on beads (MOB). Methods: We conducted a double-blinded, prospective cohort study. 173 participants, meeting inclusion criteria, were enrolled, 80 of whom completed the study and were included in statistical analyses. We employed MOB to extract and bisulfite-convert DNA, then qMSP to assess methylation of 8 candidate genes. Lasso regression was applied to establish a prediction model for BE diagnosis. Findings: 85% (147/173) of participants were able to swallow the EsophaCap. In the training set, 5 of 8 candidate methylation biomarkers (p16, HPP1, NELL1, TAC1, and AKAP12) were significantly higher in the BE group than the control group. In a training set of EsophaCap samples, a 4-biomarker-plus-age lasso regression model showed high accuracy of BE diagnosis: AUC was 0.894, with sensitivity 94.4% (95%CI 0.71%~99%) and specificity 62.2% (95%CI 44.6%~77.3%). The lasso model also performed well in an independent test set: AUC=0.857 (p=0.001), with sensitivity=85.7% (95%CI 56.2%~97.5%) and specificity=92.8% (95%CI 64.1%~99.6%). Interpretation: EsophaCap, in combination with an epigenetic biomarker panel and MOB, is a promising, well-tolerated, low-cost esophageal sampling strategy for BE diagnosis. This approach merits further prospective studies in larger populations. Funding Statement: National Institutes of Health (Grants: CA211457, DK118250) and a Discovery Award from The Johns Hopkins University School of Medicine. Declaration of Interests: All authors state that there are no conflicts of interest. Ethics Approval Statement: This study was approved by the JHM IRB.

While numerous prior studies report that call–put implied volatility spreads positively predict future stock returns, recent literature shows that the predictive relation is negative for future call option returns. We investigate whether and, if so, how the predictive relation for options returns is influenced by various information events and conditions. In addition to confirming an opposite predictive relation for both call and put returns, we show that the predictive relation is stronger during periods of earnings announcement and/or high sentiment. In addition, we find that investors learn from informed trading and revise their predictability bias by examining the impacts of information asymmetry, stock liquidity, and options liquidity on the predictive relationships.

This paper uses a copula model to investigate the degree and determinants of European market dependence across 10 industries in 12 Euro zone and 8 non-Euro zone stock markets during the period 1992–2011. Most of the industries in Euro countries show a dependence increase with the Euro-area after the introduction of the Euro. The effects are strongest in countries with larger market capitalization and in the Financials, Industrials, Consumer Goods, Utilities, Technology and Telecommunications industries. Overall, the export intensity, interest rate sensitivity and competitiveness of an industry and the financial development and economic openness of a country are the most important determinants of changes in equity market dependence. The period around the Lehman collapse also shows higher equity market dependence between European countries, while the lower dependence increase during the period of the recent European sovereign debt crisis suggests that country-specific factors may matter more than before.

In this study, we calculated the water footprint (WF) of second-generation bioethanol and hypothesized that second-generation bioethanol feedstock in response to the gradual depletion of fossil fuels has contributed to exorbitant international oil prices. To resolve these problems, countries worldwide have actively engaged in developing alternative energy plans to reduce their dependence on petroleum. Bioethanol is a critical choose items of biofuels, and increased use of biofuels for transportation is expected to substantially raise the level of competition for freshwater resources. In this paper, Taiwan's second-generation bioethanol demonstration plant is used as an example to calculate the WF of second-generation bioethanol. Using bagasse and rice straw as raw materials, the water footprint are 268.8 L H 2 O/L EtOH and 4674.9 L H 2 O/L EtOH, respectively, which is considerably lower than that of first-generation bioethanol. In this study, we proposed two sources of feedstock that are suitable for future second-generation bioethanol: (1) nonfood crop materials; and (2) domestic waste (e.g., food waste). The results of this study can be used by countries interested in using biofuels to formulate and implement energy policies that will enable them to develop renewable energy sources and simultaneously consider the management and application of water resources.

Recent studies demonstrated impaired biological motion perception in children with autism spectrum disorder (ASD), who are characterized by deficits in social interactions and communication. Using point-light displays, the present study intended to examine the looking preferences for human and non-human biological motion paired with non-biological scrambled motion (Exp. 1) and the performance on the action identification task (Exp. 2) in typically developing (TD) children and children with ASD. Forty-two participants (21 ASD and 21 TD children) aged 3–7 years were included in this study. In Exp. 1, we found that children with ASD did not preferentially attend to biological motion as TD children did. The ASD group also exhibited shorter overall fixation time for all the point-light displays than did the TD group. In the action identification task of Exp. 2, children with ASD made more errors in naming and needed more time to respond than did TD children. Nevertheless, the actions that were likely to be correctly identified by TD children were also likely to be correctly identified by children with ASD. In conclusion, children with ASD are lacking the preference TD children have for biological motion stimuli over the scrambled motion. Moreover, such impairment might be due to an overall deficit in processing biological motion information and may explain the poor performance on action recognition in the ASD group.

We compile option-implied tail loss and gain measures based upon a deep out-of-the-money option pricing formula derived by applying ‘extreme value theory’, and then use these measures to investigate the information content of option-implied tail risk on the future returns of the underlying assets. Our empirical analysis shows that both tail measures implied by S&P 500 and VIX options can predict future changes in the corresponding underlying assets, with the tail loss (gain) measure being more informative than the tail gain (loss) measure for the S&P 500 index (VIX), and the relationships being particularly strong during periods of economic recession. Both tail measures compiled from S&P 500 and VIX options are also found to be informative on the future returns of the S&P 500 index, with the former providing the stronger contribution. Further evidence shows that these predictive relationships are driven by the tail-risk premium and quite short-lived.

The characteristics of aberrant face processing in individuals with autism spectrum disorder (ASD) have been extensively studied, but the aspect regarding sensitivity to race is relatively unexplored. The present study hypothesized that the magnitude of the otherrace effect shall be reduced in individuals with ASD owing to their inattention to faces since infancy. Using a sequential face discrimination task, we tested the other-race effect of 18 ASD (mean age = 7.5 years) and 13 age-matched typically developing (TD) children (mean age = 7.6 years). The stimuli were cropped Asian and African faces, each with four levels of difficulty: easy (change identity), medium (replaced eyes), hard-eye (widen eye spacing), and hard-mouth (moved up mouth). The TD children showed a significant ownrace advantage such that the best performance was found in the Asian easy condition. The ASD children did not exhibit such advantage at all. Moreover, ASD children showed the highest error rates in the hard-eye condition instead of the hard-mouth condition, indicating insensitivity to eyes region. In sum, our findings support the hypothesis that the other-race effect is reduced in ASD children, reflecting an incomplete development of an expert face system. 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/).

High-resolution melting (HRM) has garnered significant interest as an analytical technique for a number of applications, including DNA methylation detection, due to its inherent sensitivity and robustness. In this study, we describe a miniaturized assay platform for quantitative methylation density analysis using a microfluidic droplet array cartridge. We demonstrate that the DNA methylation level of the RASSF1A promoter can be directly analyzed using HRM. PCR products were generated by amplifying bisulfite-treated DNA with varying CpG densities using CpG island-flanking primer sets. Subsequent HRM analysis on the miniaturized droplet platform shows distinct melting curve profiles associated with methylation levels, which was verified using a conventional benchtop PCR-HRM system. The characteristic melting temperature (Tm) of the PCR products was used to directly quantify the respective levels of DNA methylation density. Our approach provides a key advantage over current gold standard methods such as methylation-specific PCR (MSP), which are incapable of providing specific information regarding the overall methylation density of the target genes. The miniaturized platform establishes a practical approach to methylation density profiling from multiple DNA samples with a potential application in point-of-care diagnostics.

Tungsten oxide, originally poor in capacitive performance, was made an excellent electrode material for supercapacitors, by dispersing it to carbon aerogels (CA), a conductive and mesoporous hosting template, that drastically improved the utilization of WO3 for capacitance generation. The WO3 was introduced to the CA, in a form of well-dispersed single crystalline nanoparticles of 15–40 nm in size, with a simple immersion-calcination process. A one order of magnitude improvement in specific capacitance was achieved with the present composition, from 54 F/g for WO3 nanoparticles to 700 F/g for WO3/CA composites (scaned at 25 mV/s in 0.5 M H2SO4 over a potential window of −0.3 to 0.5 V). The WO3/CA composites exhibited an excellent high rate capability with a 60% retention in specific capacitance at 500 mV/s, almost perfect cycle efficiency of 99%, and outstanding cycling stability of only 5% decay in specific capacitance after 4000 cycles.

This study develops a liquidity-adjusted option pricing model that demonstrates the impact of the liquidity risk on stock prices using a liquidity discount factor. The discount factor relates to both mean-reversion stochastic market liquidity and the sensitivity of stock prices to market illiquidity. Our empirical results provide strong evidence in support of incorporating liquidity risk in options pricing. In particular, our model shows marked pricing improvement for out-of-the-money or longer term options, as well as options on stocks with lower levels of liquidity.

Purpose The lungs of infants born with congenital diaphragmatic hernia suffer from immaturity as well as the short and long term consequences of ventilator-induced lung injury, including chronic lung disease. Antenatal and postnatal steroids are among current strategies promoted to treat premature lungs and limit long term morbidity. Although studied in whole-animal models, insight into ventilator-induced injury at the alveolar-capillary interface as well as the benefits of steroids, remains limited. The present study utilizes a multi-fluidic in vitro model of the alveolar-interface to analyze membrane disruption from compressive aerodynamic forces in dexamethasone-treated cultures. Methods Human alveolar epithelial cell lines, H441 and A549, were cultured in a custom-built chamber under constant aerodynamic shear followed by introduction of pressure stimuli with and without dexamethasone (0.1μM). On-chip bioelectrical measurements were noted to track changes to the cellular surface and live-dead assay to ascertain cellular viability. Results Pressure-exposed alveolar cultures demonstrated a significant drop in TEER that was less prominent with an underlying extracellular-matrix coating. Addition of dexamethasone resulted in increased alveolar layer integrity demonstrated by higher TEER values. Furthermore, dexamethasone-treated cells exhibited faster recovery, and the effects of pressure appeared to be mitigated in both cell types. Conclusion Using a novel in vitro model of the alveolus, we demonstrate a dose–response relationship between pressure application and loss of alveolar layer integrity. This effect appears to be alleviated by dexamethasone and matrix sub-coating.

Combining natural products with chemotherapy and/or radiotherapy may increase the efficacy of cancer treatment. It has been hypothesized that natural products may inhibit DNA repair and sensitize cancer cells to DNA damage-based cancer therapy. However, the molecular mechanisms underlying these activities remain unclear. In this study, we found that diallyl disulfide (DADS), an organosulfur compound, increased the sensitivity of yeast cells to DNA damage and has potential for development as an adjuvant drug for DNA damage-based cancer therapy. We induced HO endonuclease to generate a specific DNA double-strand break (DSB) by adding galactose to yeast and used this system to study how DADS affects DNA repair. In this study, we found that DADS inhibited DNA repair in single-strand annealing (SSA) system and sensitized SSA cells to a single DSB. DADS impaired DNA repair by inhibiting the protein levels of the DNA resection-related proteins Sae2 and Exo1. We also found that the recruitment of MRX and the Mec1-Ddc2 complex to a DSB was prevented by DADS. This result suggests that DADS counteracts G2/M DNA damage checkpoint activation in a Mec1 (ATR)- and Tel1 (ATM)-dependent manner. Only by elucidating the molecular mechanisms by which DADS influences DNA repair will we be able to discover new adjuvant drugs to improve chemotherapy and/or radiotherapy.

This paper presents an electromagnetically actuated platform for automated sample preparation and detection of nucleic acids. The proposed platform integrates nucleic acid extraction using silica-coated magnetic particles with real-time polymerase chain reaction (PCR) on a single cartridge. Extraction of genomic material was automated by manipulating magnetic particles in droplets using a series of planar coil electromagnets assisted by topographical features, enabling efficient fluidic processing over a variety of buffers and reagents. The functionality of the platform was demonstrated by performing nucleic acid extraction from whole blood, followed by real-time PCR detection of KRAS oncogene. Automated sample processing from whole blood to PCR-ready droplet was performed in 15 minutes. We took a modular approach of decoupling the modules of magnetic manipulation and optical detection from the device itself, enabling a low-complexity cartridge that operates in tandem with simple external instruments.