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Abstract The cancer stem cell (CSC) hypothesis postulates that cancer originates from the malignant transformation of stem/progenitor cells and is considered to apply to many cancers, including liver cancer. Identification that CSCs are responsible for drug resistance, metastasis, and secondary tumor appearance suggests that these populations are novel obligatory targets for the treatment of cancer. Here, we describe our new method for identifying potential CSC candidates. The reprogramming of cancer cells via induced pluripotent stem cell (iPSC) technology is a novel therapy for the treatment and for the study of CSC-related genes. This technology has advantages for studying the interactions between CSC-related genes and the cancer niche microenvironment. This technology may also provide a useful platform for studying the genes involved in the generation of CSCs before and after reprogramming, and for elucidating the mechanisms underlying cancer initiation and progression. The present review summarizes the current understanding of transcription factors involved in the generation of liver CSCs from liver cancer cell-derived iPSCs and how these contribute to oncogenesis, and discusses the modeling of liver cancer development.

Abstract Background Physical scaffolds are useful for supporting cells to form three-dimensional (3D) tissue. However, it is non-trivial to develop a scheme that can robustly guide cells to self-organize into a tissue with the desired 3D spatial structures. To achieve this goal, the rational regulation of cellular self-organization in 3D extracellular matrix (ECM) such as hydrogel is needed. Results In this study, we integrated the Turing reaction–diffusion mechanism with the self-organization process of cells and produced multicellular 3D structures with the desired configurations in a rational manner. By optimizing the components of the hydrogel and applying exogenous morphogens, a variety of multicellular 3D architectures composed of multipotent vascular mesenchymal cells (VMCs) were formed inside hyaluronic acid (HA) hydrogels. These 3D architectures could mimic the features of trabecular bones and multicellular nodules. Based on the Turing reaction–diffusion instability of morphogens and cells, a theoretical model was proposed to predict the variations observed in 3D multicellular structures in response to exogenous factors. It enabled the feasibility to obtain diverse types of 3D multicellular structures by addition of Noggin and/or BMP2. Conclusions The morphological consistency between the simulation prediction and experimental results probably revealed a Turing-type mechanism underlying the 3D self-organization of VMCs in HA hydrogels. Our study has provided new ways to create a variety of self-organized 3D multicellular architectures for regenerating biomaterial and tissues in a Turing mechanism-based approach.

Abstract Background Conventional approaches for benzodiazepine tapering have their limitations. Anecdotal studies have shown that acupuncture is a potential treatment for facilitating successful benzodiazepine tapering. As of today, there was no randomized controlled trial examining its efficacy and safety. The purpose of the study is to evaluate the efficacy of using electroacupuncture as an adjunct treatment to gradual tapering of benzodiazepine doses in complete benzodiazepine cessation in long-term benzodiazepine users. Methods/Design The study protocol of a randomized, assessor- and subject-blinded, controlled trial is presented. One hundred and forty-four patients with histories of using benzodiazepines in ≥50% of days for more than 3 months will be randomly assigned in a 1:1 ratio to receive either electroacupuncture or placebo electroacupuncture combined with gradual benzodiazepine tapering schedule. Both experimental and placebo treatments will be delivered twice per week for 4 weeks. Major assessments will be conducted at baseline, week 6 and week 16 post-randomization. Primary outcome is the cessation rate of benzodiazepine use. Secondary outcomes include the percentage change in the doses of benzodiazepine usage and the severity of withdrawal symptoms experienced based on the Benzodiazepine Withdrawal Symptom Questionnaire, insomnia as measured by the Insomnia Severity Index, and anxiety and depressive symptoms as evaluated by the Hospital Anxiety and Depression Scale. Adverse events will also be measured at each study visit. Discussion Results of this study will provide high quality evidence of the efficacy and safety of electroacupuncture as an adjunct treatment for benzodiazepine tapering in long-term users. Trial registration ClinicalTrials.gov NCT02475538 .

A 103.12-Gb/s wavelength-division-multiplexing (WDM) four-level pulse amplitude modulation (PAM4) transmission based on 850-nm and 880-nm vertical-cavity surface-emitting lasers (VCSELs) with light injection and optoelectronic feedback techniques is proposed and experimentally demonstrated. Results show that two such 7.5-GHz VCSELs with light injection and optoelectronic feedback techniques are potent for 103.12-Gb/s WDM PAM4 transmissions. To the authors' knowledge, it is the first one to successfully adopt two VCSEL transmitters with light injection and optoelectronic feedback techniques in a WDM PAM4 transmission. A total transmission rate of 103.12 Gb/s (51.56 Gb/s/λ × 2 λs) is achieved in the proposed WDM PAM4 transmissions. The link performances of the proposed WDM PAM4 transmissions have been evaluated in real time. Good real-time bit error rate performance and three independent clear eye diagrams are obtained at a 180-m OM4 multimode fiber operation. Such a proposed 103.12-Gb/s WDM PAM4 VCSEL-based transmission has great potential for providing efficient bandwidth in short-reach optical communications.

A 56 Gb/s four-level pulse amplitude modulation (PAM4) light-based WiFi (LiFi) transmission based on a 680-nm/5.4-GHz vertical-cavity surface-emitting laser (VCSEL) with a two-stage injection-locked technique is proposed and demonstrated. Experimentally results show that a 5.4-GHz VCSEL with a two-stage injection-locked technique is effective for 56 Gb/s PAM4 LiFi transmissions. To the authors' knowledge, it is the first one to adopt a 680-nm VCSEL transmitter with two-stage injection-locked technique in a 56 Gb/s PAM4 LiFi transmission. A pair of doublet lenses is employed in the proposed PAM4 VCSEL-based LiFi transmissions to enhance the free-space link. The link performances of the proposed PAM4 LiFi transmissions have been analyzed in real time. Good bit error rate performance and three independent clear eye diagrams are obtained over a 20-m free-space link. Such a proposed 56 Gb/s PAM4 VCSEL-based LiFi transmission with two-stage injection-locked technique has the potential to play a significant role in future wireless infrastructure for providing high transmission rate and long free-space transmission distance effectively.

This paper seeks to optimize customer attraction for mobile apps in m-commerce. We model this problem as a mobile-oriented catalog (MOC) segmentation problem. We use query-based learning (QBL) to develop MOCs and aim to attract most number of customers through minimal number of MOCs. This paper illustrates how to design attractive MOCs to recommend items by using QBL genetic algorithm (QBLGA). We propose preference modeling, Product2Vec, Transaction2Vec, and their variations as our oracles of QBLGA. These oracles can aggregate similar purchasing experiences to optimize combination of products for MOC construction. We divide these oracles into major oracle and minor oracles, and then, QBLGA uses these two types of oracles to produce high-attractive products. Experiments show that QBLGA outperforms the state-of-the-art algorithm to attract the greatest number of customers.

In recent years, many researchers have examined dynamic optimization problems (DOPs). The key challenge lies in the fact that the optimal solution of a DOP typically changes over time. This paper focuses on using query-based learning dynamic particle swarm optimization (QBLDPSO) to solve DOPs. QBLDPSO is mainly used for improving multi-population-based PSO; our QBL mechanism includes two learning strategies that integrate the concepts of diversity and memory into PSO. The first learning strategy, QBL quantum parameter adaptation (QBLQPA), is used to apply the concept of diversity to the multi-population based algorithm. This is different from typical diversity-based PSO approaches, which passively maintain the diversity of particles in the solution space. We actively adapt the ratio of quantum particles and neutral particles to achieve diversity without analyzing the distribution of optima in the solution space. The second learning strategy is query-based learning optima prediction (QBLOP). Although QBLOP exploits the concept of memory, we do not need to analyze the history of all particles. We select the k nearest particles to the current best solution and use a minimum encompassing circle as the possible prediction region. Our experimental results are based on the generalized dynamic benchmark generator (GDBG), which is adopted as a benchmark for the DOP. The proposed method outperforms two state-of-the-art multi-population-based PSO methods with the average improvements of 11.37% and 8% using QBLQPA. In particular, for the recurrent problems in GDBG, our method improves performance by 35.06%.

Current antibiotic therapies for tuberculosis are lengthy and onerous. Here, the authors use an output-driven approach to optimize drug doses for two experimental drug regimens in a mouse model of tuberculosis, leading to improved regimens that reduce treatment time by 75%.

Background Rheumatic diseases are related to both abnormal bone turnover and atherogenesis, but a mechanistic link was missing. Methods and Results We investigated the effect of cumulative rheumatic inflammation (CRI) on risk of coronary calcification in a retrospective cohort of 145 rheumatoid arthritis patients. A time‐adjusted aggregate CRI score was derived by conglomerating all quarterly biomarker encounters of serum C‐reactive protein over 60 months immediately preceding computed tomography coronary angiography. Flow cytometry was performed to measure the osteocalcin‐positive (OCN+) CD34+KDR+ and OCN+CD34+ circulating endothelial progenitor cells (EPCs). Conventional early circulating EPCs CD34+CD133+KDR+ was determined. Coronary calcification was defined as any Agatston score >0. 50% of patients (n=72/145) had coronary calcification. CRI score was associated with presence of coronary calcification (P=0.004) (multivariable‐adjusted: highest versus lowest quartile: odds ratio=5.6 [95% CI 1.1–28.9], P=0.041). Receiver operating characteristics curve revealed divergent behavior of OCN‐expressing circulating EPCs (OCN+CD34+ EPCs: area under the curve=0.60, P=0.034; OCN+CD34+KDR+ EPCs: area under the curve=0.59, P=0.053, positive predictors) versus conventional early EPCs (CD34+CD133+KDR+: area under the curve=0.60, P=0.034, negative predictor) for coronary calcification, which persisted after multivariable adjustments (OCN+CD34+KDR+ [>75th percentile]: odds ratio=7.2 [95% CI 1.8–27.9], P=0.005; OCN+CD34+ EPCs [>75th percentile]: odds ratio=6.0 [95% CI 1.5–23.3], P=0.010; CD34+CD133+KDR+ [>75th percentile: odds ratio=0.3 [95% CI 0.1–1.0], P=0.053). Intriguingly, the CRI score was associated with increased OCN+CD34+ EPCs (highest versus lowest quartile: B=+25.6 [95% CI 0.8–50.5] [×103/mL peripheral blood], P=0.043), but reduced CD34+CD133+KDR+ EPCs (highest versus lowest quartile: B=−16.2 [95% CI −31.5 to −0.9], P=0.038). Conclusions Preceding 60 months of CRI is associated with increased risk of coronary calcification and altered OCN expression in circulating EPCs.

It is known that Metric Temporal Logic (MTL) is strictly less expressive than the Monadic First-Order Logic of Order and Metric (FO[

Background: Breast reconstruction plays a vital role in the restoration of form post-mastectomy. Autologous breast reconstructions using both free as well as pedicled flaps form the bulk of the breast reconstruction in our centre. Objective: This study seeks to evaluate the muscle-sparing modification of the pedicled transverse rectus abdominis myocutaneous (MS-TRAM) flaps against conventional transverse rectus abdominis myocutaneous (TRAM) flaps, in an attempt to marry the benefits of both and minimise the drawbacks of each technique. Patients and methods: A retrospective analysis of 20 women, 10 of whom had undergone unilateral immediate breast reconstruction with pedicled MS-TRAM flaps after skin-sparing mastectomy (MS group), and 10 who had undergone the conventional pedicled TRAM flap (control group) by the same surgeon (S. Ho) over a two-year period from 2013 to 2015 was performed. Patients’ records were reviewed, assessing patient demographics including age, smoking status and evaluating the operative time, time to ambulation, length of hospital stay, pain scores and abdominal bulge rates. Results: Mean operative time was not significantly longer in the MS group. Pain scores were lower in the MS group. The length of hospital stay was not significantly different between the two groups. Abdominal bulge rates at 24 months postoperatively were 0% in the MS group patients and 10% in the control group. Conclusion The pedicled MS-TRAM flap is an excellent breast reconstruction option that is comparable to the conventional TRAM flap. It preserves innervated muscle in the donor site that reduces time to ambulation and postoperative pain. It does not add significantly to surgical time and does not require microvascular anastomosis.

Ultrafast laser-induced transparency is demonstrated using femtosecond (fs) pump-probe experiments in the organic P3HT:PCBM (donor:acceptor) blend structure. For above band gap pumping, ultrafast transient signals strongly depend on the probe photon energy. Most intriguingly, for below band gap pumping at 0.95 eV, or 1.3 µm at a telecom wavelength, a huge transmission increase up to 30% only during the laser pulse ∼100 fs is observed as a pump-driven, quasi-instantaneous suppression of absorption for the high photon-energy energy probe beam. We attribute the observed laser-driven transparency to dynamic Franz-Keldysh effect, at least one order of magnitude stronger compared to the multiphoton nonlinearities. Our results may be used for development of low-cost, beyond 100 Gbit/s optical switching devices.

BackgroundShorter, more effective treatments for tuberculosis (TB) are urgently needed. While many TB drugs are available, identification of the best regimens is challenging because of the large number of possible drug-dose combinations. We have found consistently that responses of cells or whole animals to drug-dose stimulations fit a parabolic response surface (PRS), allowing us to identify and optimize the best drug combinations by testing only a small fraction of the total search space. Previously, we used PRS methodology to identify three regimens (PRS Regimens I-III) that in murine models are much more effective than the standard regimen used to treat TB. However, PRS Regimens I and II are unsuitable for treating drug-resistant TB and PRS Regimen III includes an experimental drug. Here, we use PRS methodology to identify from an expanded pool of drugs new highly effective near-universal drug regimens comprising only approved drugs.Methods and findingsWe evaluated combinations of 15 different drugs in a human macrophage TB model and identified the most promising 4-drug combinations. We then tested 14 of these combinations in Mycobacterium tuberculosis-infected BALB/c mice and chose for PRS dose optimization and further study the two most potent regimens, designated PRS Regimens IV and V, consisting of clofazimine (CFZ), bedaquiline (BDQ), pyrazinamide (PZA), and either amoxicillin/clavulanate (AC) or delamanid (DLM), respectively. We then evaluated the efficacy in mice of optimized PRS Regimens IV and V, as well as a 3-drug regimen, PRS Regimen VI (CFZ, BDQ, and PZA), and compared their efficacy to PRS Regimen III (CFZ, BDQ, PZA, and SQ109), previously shown to reduce the time to achieve relapse-free cure in mice by 80% compared with the Standard Regimen (isoniazid, rifampicin, PZA, and ethambutol). Efficacy measurements included early bactericidal activity, time to lung sterilization, and time to relapse-free cure. PRS Regimens III-VI all rapidly sterilized the lungs and achieved relapse-free cure in 3 weeks (PRS Regimens III, V, and VI) or 5 weeks (PRS Regimen IV). In contrast, mice treated with the Standard Regimen still had high numbers of bacteria in their lungs after 6-weeks treatment and none achieved relapse-free cure in this time-period.ConclusionsWe have identified three new regimens that rapidly sterilize the lungs of mice and dramatically shorten the time required to achieve relapse-free cure. All mouse drug doses in these regimens extrapolate to doses that are readily achievable in humans. Because PRS Regimens IV and V contain only one first line drug (PZA) and exclude fluoroquinolones and aminoglycosides, they should be effective against most TB cases that are multidrug resistant (MDR-TB) and many that are extensively drug-resistant (XDR-TB). Hence, these regimens have potential to shorten dramatically the time required for treatment of both drug-sensitive and drug-resistant TB. If clinical trials confirm that these regimens dramatically shorten the time required to achieve relapse-free cure in humans, then this radically shortened treatment has the potential to improve treatment compliance, decrease the emergence of drug resistance, and decrease the healthcare burden of treating both drug-sensitive and drug-resistant TB.

A well-established financial trading system should well perform in resource allocation, risk management, and sustainability. In this paper, we propose a self-management portfolio system with adaptive association mining for practical applications. The system allocates funds into independent units for risk management, and utilizes association mining and adaptive closing mechanism for resource allocation and sustainability, and adopts a self-management module for monitoring positions. The proposed system boosts the annual return and Sharpe ratio to 9.1% and 0.578 (increased to 2.28 and 2.48 times), and reduces the drawdown risk to 34.6% (decreased to almost half). Furthermore, the system rapidly closes the stock positions to avoid drawdown risk in the bear markets, and gradually increases the stock positions when the market turns into bull. Compared with benchmarks, proposed system outperforms all benchmarks in all measurements and on randomly sampled dataset.

Fe, Mg, and O are among the most abundant elements in terrestrial planets. While the behavior of the Fe–O, Mg–O, and Fe–Mg binary systems under pressure have been investigated, there are still very few studies of the Fe–Mg–O ternary system at relevant Earth’s core and super-Earth’s mantle pressures. Here, we use the adaptive genetic algorithm (AGA) to study ternary Fe _x Mg _y O _z phases in a wide range of stoichiometries at 200 GPa and 350 GPa. We discovered three dynamically stable phases with stoichiometries FeMg _2 O _4 , Fe _2 MgO _4, and FeMg _3 O _4 with lower enthalpy than any known combination of Fe–Mg–O high-pressure compounds at 350 GPa. With the discovery of these phases, we construct the Fe–Mg–O ternary convex hull. We further clarify the composition- and pressure-dependence of structural motifs with the analysis of the AGA-found stable and metastable structures. Analysis of binary and ternary stable phases suggest that O, Mg, or both could stabilize a BCC iron alloy at inner core pressures.

Previous studies suggested that perceived social support (PSS) significantly contributes to psychological wellbeing (PWB), partially explained by the sense of mattering. Nevertheless, individuals with different personality might perceive social support in different ways from the other. The interaction of PSS with trait narcissism, one of the dark triad personality traits was investigated by collecting data from 141 college students who were recruited purposively and instructed to respond to the scales of PWB, PSS, mattering, and narcissism. Bootstrap analysis with 5,000 samples in 95% confidence interval was utilized to test the moderated mediation hypothesis. The results suggested that individuals with moderate-to-high narcissism levels tend to perceive social support as decreasing their sense of mattering to other people, and as they do not feel they matter, their PWB was negatively affected. Limitations, implications, and suggestions are discussed. [ABSTRACT FROM AUTHOR]

Environmental concern is a subjective state of society and researchers have typically relied on survey data to measure it. However, survey-based methods only capture a snapshot of it at the time and place the surveys were conducted. To overcome these problems, we develop an observable indicator that allows us to study environmental concern over time and across territories based on big data. The indicator composes of keyword groups that fit with the environmental concern measures revealed by a large-scale survey. We find that keywords associated with climate change, water pollution and waste management are the strongest predictors of environmental concern. To the best of our knowledge, our paper is the first to use online search data to capture subjective environmental concern. [ABSTRACT FROM AUTHOR]