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There exists significant hype regarding how much machine learning and incorporating social media data can improve forecast accuracy in commercial applications. To assess if the hype is warranted, we use data from the film industry in simulation experiments that contrast econometric approaches with tools from the predictive analytics literature. Further, we propose new strategies that combine elements from each literature in a bid to capture richer patterns of heterogeneity in the underlying relationship governing revenue. Our results demonstrate the importance of social media data and value from hybrid strategies that combine econometrics and machine learning when conducting forecasts with new big data sources. Specifically, although both least squares support vector regression and recursive partitioning strategies greatly outperform dimension reduction strategies and traditional econometrics approaches in forecast accuracy, there are further significant gains from using hybrid approaches. Further, Monte Carlo experiments demonstrate that these benefits arise from the significant heterogeneity in how social media measures and other film characteristics influence box office outcomes. This paper was accepted by J. George Shanthikumar, big data analytics.

The performance-driven design of SDN architectures leaves many security vulnerabilities, a notable one being the communication bottleneck between the controller and the switches. Functioning as a cache between the controller and the switches, the flow table mitigates this bottleneck by caching flow rules received from the controller at each switch, but is very limited in size due to the high cost and power consumption of the underlying storage medium. It thus presents an easy target for attacks. Observing that many existing defenses are based on simplistic attack models, we develop a model of intelligent attacks that exploit specific cache-like behaviors of the flow table to infer its internal configuration and state, and then design attack parameters accordingly. Our evaluations show that such attacks can accurately expose the internal parameters of the target flow table and cause measurable damage with the minimum effort.

Since 2016, all of four major U.S. operators have rolled out Wi-Fi calling services. They enable mobile users to place cellular calls over Wi-Fi networks based on the 3GPP IMS technology. Compared with conventional cellular voice solutions, the major difference lies in that their traffic traverses untrusted Wi-Fi networks and the Internet. This exposure to insecure networks can cause the Wi-Fi calling users to suffer from security threats. Its security mechanisms are similar to the VoLTE, because both of them are supported by the IMS. They include SIM-based security, 3GPP AKA, IPSec, etc. However, are they sufficient to secure Wi-Fi calling services? Unfortunately, our study yields a negative answer. We conduct the first security study on the operational Wi-Fi calling services in three major U.S. operators networks using commodity devices. We disclose that current Wi-Fi calling security is not bullet-proof and uncover three vulnerabilities. By exploiting the vulnerabilities, we devise two proof-of-concept attacks: telephony harassment or denial of voice service and user privacy leakage; both of them can bypass the existing security defenses. We have confirmed their feasibility using real-world experiments, as well as assessed their potential damages and proposed a solution to address all identified vulnerabilities.

Background and aims Few studies have examined and compared spousal concordance in different populations. This study aimed to quantify and compare spousal similarities in cardiometabolic risk factors and diseases between Dutch and Japanese populations. Methods This cross-sectional study included 28,265 Dutch Lifelines Cohort Study spouse pairs (2006–2013) and 5,391 Japanese Tohoku Medical Megabank Organization (ToMMo) Cohort Study pairs (2013–2016). Spousal similarities in cardiometabolic risk factors were evaluated using Pearson's correlation or logistic regression analyses adjusted for spousal age. Results The husbands' and wives’ average ages in the Lifelines and ToMMo cohorts were 50.0 and 47.7 years and 63.2 and 60.4 years, respectively. Significant spousal similarities occurred with all cardiometabolic risk factors and diseases of interest in both cohorts. The age-adjusted correlation coefficients ranged from 0.032 to 0.263, with the strongest correlations observed in anthropometric traits. Spousal odds ratios [95% confidence interval] for the Lifelines vs. ToMMo cohort ranged from 1.45 (1.36–1.55) vs. 1.20 (1.05–1.38) for hypertension to 6.86 (6.30–7.48) vs. 4.60 (3.52–6.02) for current smoking. An increasing trend in spousal concordance with age was observed for sufficient physical activity in both cohorts. For current smoking, those aged 20–39 years showed the strongest concordance between pairs in both cohorts. The Dutch pairs showed stronger similarities in anthropometric traits and lifestyle habits (smoking and drinking) than their Japanese counterparts. Conclusions Spouses showed similarities in several cardiometabolic risk factors among Dutch and Japanese populations, with regional and cultural influences on spousal similarities.

Background To assess the efficacy and safety of corticosteroids in COVID-19 patients compared with standard care or placebo. Methods Electronic databases were searched to identify relevant studies. The mortality, adverse events, and other data from studies were pooled for statistical analysis. Results Ten randomized clinical trials were eligible for inclusion. Corticosteroid treatment in COVID-19 patients did not significantly reduce the risk of death (RR: 0.93; CI: 0.82, 1.05) and the need for mechanical ventilation (RR: 0.82; CI: 0.62, 1.08). No mortality reduction was also observed in the subgroup of patients requiring mechanical ventilation (RR: 0.90; CI: 0.79–1.03). The use of corticosteroids increased mortality in the subgroup of patients not requiring oxygen support (RR: 1.24; CI: 1.00–1.55). The survival benefit was observed in a low dosage of corticosteroids (RR: 0.90; CI: 0.84–0.97) and dexamethasone (RR: 0.90; 95% CI: 0.79–1.04). There was no difference in the rates of adverse events (RR: 1.13; CI: 0.58, 2.20) and secondary infections (RR: 0.87; CI: 0.66, 1.15). Conclusion Corticosteroid treatment did not convincingly improve survival in severe COVID-19 patients. Low-dose dexamethasone could be considered as a drug for the treatment of COVID-19 patients. More high-quality trials are needed to further verify this conclusion. Expert Opinion: The effect of corticosteroids on patient survival highly depended on the selection of the right dosage and type and in a specific subgroup of patients. This meta-analysis, which included more RCTs, evaluated the safety and efficacy in severe COVID-19 patients and analyzed the effects of different types of corticosteroid treatments. Corticosteroid treatment did not convincingly improve survival in severe COVID-19 patients. But the low dose dexamethasone appear to have a role in the management of severe COVID-19 patients.

The thirty years of Kazakhstan’s independence have been characterized by rapid growth of trade and economic cooperation with China, one of the world’s largest economies, which has steadily increased its presence in the region. Based on statistics published by the General Administration of Customs of the People’s Republic of China and the National Bank of Kazakhstan, legal and regulatory documents of the two countries and reports by international organizations, this article examines the specific features and further prospects of bilateral cooperation between China and Kazakhstan in the field of trade, investment, and energy, as well as in implementing integration projects. The authors have identified the main stages of interaction between the two countries, the problems they encounter, and the opportunities for trade and economic cooperation, which has developed rapidly since the turn of the century. Objectively, this process is mutually beneficial for both sides, especially in the sphere of energy, promotion of infrastructure projects, establishment of joint ventures, and other long-term plans. However, despite the positive dynamics of this process, the article identifies a number of negative phenomena in trade and economic relations. Overall, trade declined because of the drop in oil prices and the resultant weakening of Kazakhstan’s national currency tenge, since oil is the basis of the country’s exports. At the same time, when trade indicators began to improve after 2017, some negative phenomena were still in evidence. They were primarily due to the consequences of the pandemic, an increase in Sinophobia, and Kazakhstan’s participation in new regional projects, such as the Eurasian Economic Union (EAEU). In the authors’ opinion, investment specifics and trade asymmetry are the main areas where both parties should adjust their approaches in order to tap the full potential of cooperation in these sectors.

Carriers are rolling out Internet of Things (IoT) services including various IoT devices and use scenarios. Compared with conventional non-IoT devices such as smartphones and tablets, IoT devices have limited network capabilities (e.g., low rates) and specific use scenarios (e.g., inside vehicles only). These specialized use scenarios lead to carries often offering cheaper device access fees for IoT devices. However, the aforementioned disparity of service charging between IoT and non-IoT devices may lead to security issues. In this work, we conduct the first empirical security study on cellular IoT service charging over two major US carriers and make three major contributions. First, we discover four security vulnerabilities and analyze their root causes, which help us identify two significant security threats, IoT masquerading and IoT use scenario abuse. Second, we devise three proof-of-concept attacks and assess their real-world impact. We determine that they can be exploited to allow adversaries to pay 43.75-80.00 percent less for cellular data services. Third, we analyze the challenges in addressing these vulnerabilities and develop an anti-abuse solution to mitigate attack incentives. The solution is standard-compliant and can be used immediately in practice. Our prototype and evaluation confirm its effectiveness.

Purpose Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease of unknown cause with a variable course. Acute exacerbations of IPF (AE-IPF) is sudden accelerations of the disease or a superimposed idiopathic acute injury significantly reducing lung function. To examine the serum concentrations of Progranulin (PGRN) and activin A in patients with AE-IPF in a pilot study. Methods Twenty-one patients with AE-IPF were compared with 23 patients with stable IPF as a control group. Serum PGRN and activin A levels, arterial blood gas measurements, and lung function were determined in these two groups. Results Peripheral blood PGRN and activin A levels in patients with AE-IPF were 83.7 + 10.0 and 14.2 ± 1.7 ng/ml (mean + SD), respectively; higher than those in the control group 61.0 + 5.8 and 5.8 + 1.0 (p r = − 0.857 (p r = − 0.757 (p Conclusion Progranulin (PGRN) and activin A may be involved in the pathogenesis of AE-IPF. They may be possible markers of disease activity in AE-IPF.

Medication adherence to antiretroviral therapy (ART) among elderly people living with HIV (PLWH) is of serious concern. Our study aimed to understand the medication adherence of elderly PLWH under ART based on the health belief model (HBM). A baseline survey with a total of 529 elderly PLWH was conducted in Sichuan. Logistic and linear regression analysis, mediation analysis, and path analysis based on prior evidence were used. Only self-efficacy showed direct associations with medication adherence in the last four days (ORm = 1.37, 95%CI: 1.11, 1.70) and the last month (ORm = 1.39, 95%CI: 1.18, 1.63) in the multivariate analysis. Self-efficacy mediated the relations between perceived benefits, perceived barriers, cues to action and medication adherence. Inner relations existed within the HBM. In addition to the direct effects, perceived benefits (β = 0.149, p = 0.031; β = 0.093, p = 0.005), perceived barriers (β = -0.070, p = 0.008; β = -0.062, p = 0.012), and cues to action (β = 0.184, p = 0.013; β = 0.135, p = 0.014) showed indirect effects on medication adherence in the last four days and the last month, respectively. HBM may be effective in predicting medication adherence of elderly PLWH, and self-efficacy may be a crucial predictor and mediator. Efforts should be focused on how to enhance elderly PLWH's self-efficacy without neglect of other medication beliefs.

Supplemental digital content is available in the text., Purpose Lifelong exercise is known to attenuate sarcopenia (age-associated reduction in muscle mass and function); however, the underlying molecular mechanisms remain unclear. As microRNAs are widely involved in the regulation of skeletal muscle growth and development, we aimed to evaluate the effects of lifelong regular exercise on age-related alterations in muscle microRNA expression profiles as well as on skeletal muscle atrophy, apoptosis, and mitochondria and autophagy dysfunction. Methods Female 8-month-old Sprague-Dawley rats were divided into four groups; 1) 18 months of moderate-intensity continuous training (MICT) initiated at 8 months (adult-MICT, n = 12), 2) 8 months of MICT initiated at 18 months (presarcopenia-MICT, n = 12), 3) 8-month-old adult sedentary controls (adult-SED), and 4) 26-month-old aging sedentary controls (old-SED). Age skeletal muscles were then subjected to quantitative reverse transcription–polymerase chain reaction, Kyoto Encyclopedia of Genes and Genomes, immunoblotting, and miR-486 3′ untranslated region luciferase reporter gene analyses. Results Age-related loss of miR-486 expression was improved, skeletal muscle atrophy and apoptosis were downregulated, and mitochondrial activity and autophagy were upregulated in the adult-MICT group. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the PI3K/Akt pathway was upregulated in adult-MICT rats compared with that in old-SED. In vitro analyses in rat skeletal muscle L6 cells further confirmed that miR-486 targets PTEN, not SAV1, thereby activating the PI3K/Akt pathway and indirectly inhibiting HIPPO signaling. Conclusions Compared with presarcopenia-MICT rats, adult-MICT rats experienced greater beneficial effects regarding ameliorated age-related alterations in muscle miRNA expression profile, skeletal muscle atrophy, apoptosis, and mitochondria and autophagy dysfunction, which is potentially associated with the increased miR-486 expression and concomitant targeting of the PTEN/Akt signaling pathway.

Energy efficiency (EE) has been regarded as an essential design metric in 5G mobile communications. However, the massive antenna numbers, larger bandwidths, and higher density of base stations have been severely deteriorating the power consumption of 5G networks. In this article, the fundamental EE-spectrum efficiency (SE) joint design issues are thoughtfully considered. The relationships between EE and SE in single-input single-output (SISO), multiple-input multiple-output, and hybrid beamforming structures are first reviewed, where the increase of SE (EE) will unfortunately bring a reduction of EE (SE). To resolve this contradiction, a non-orthogonal multiple access (NOMA) scheme with energy-efficient user scheduling and resource allocation is investigated, which promises a simultaneous increase of EE and SE. Furthermore, a precoded waveform overlapping multiplexing scheme is presented, with significant improvements in EE and SE over the traditional Nyquist-criterion-based SISO systems. The waveform overlapping multiple access scheme is further proposed, which promises large performance improvements over the NOMA schemes discussed in 5G New Radio. The application of the waveform overlapping scheme in multiple-antenna systems is also investigated. Finally, the challenges of the waveform overlapping scheme and several other research topics are discussed. For sustainable development of the wireless communications industry, greener design in physical layer technologies should be second to none in the future 6G networks and beyond.

Background Previous studies have suggested that sensory loss is linked to depression. However, most of these studies have been conducted in developed countries and the results are mixed. Objectives The current study aims to examine the longitudinal relationship between hearing loss, vision loss, dual sensory loss, and depression among Chinese older adults over four years. Methods The data were obtained from the China Health and Retirement Longitudinal Survey (CHARLS). In total, 6353 Chinese older adults aged 60 years and over were included at baseline in this study. Self-reported hearing and vision status was used, and dual sensory loss was a combined variable of hearing loss and vision loss. Depressive symptoms were assessed by The Center for Epidemiologic Studies Depression Scale (CESD-10). The baseline relationship between sensory loss and depression was explored by logistic regression analyses. A logistic mixed model was used to assess whether baseline sensory loss was associated with incident depression for older adults with no depressive symptoms at baseline over four years. Results At baseline, vision loss (OR=1.46, 95%CI: 1.19-1.79) and dual sensory loss (OR=2.14, 95%CI: 1.77-2.58) were associated with depression, while hearing loss was not. After four years, vision loss (OR=1.60, 95%CI: 1.16-2.22) and dual sensory loss (OR=1.78, 95%CI: 1.32-2.41) were associated with incident depression. Limitations Not all potential confounding factors are measured and adjusted in the analysis. Apart from that, all measurements of interest are self-reported scales. Conclusion Vision loss and dual sensory loss are significantly associated with both onset and increased depressive symptoms over time, while hearing loss is not associated with depression. Interactions between all types of sensory loss and social activities are not significant. Our results suggest that target mental health intervention programs should be delivered to vision loss or dual sensory loss populations.

Introduction: DNA-dependent protein kinase (DNA-PK) plays a crucial role in the repair of DSBs via non-homologous end joining (NHEJ). Several DNA-PK inhibitors are being investigated for potential anticancer treatment in clinical trials.Area covered: This review aims to give an overview of patents published since 2010 by analyzing the patent space and structure features of scaffolds used in those patents. It also discusses the recent clinical developments and provides perspectives on future challenges and directions in this field.Expert opinion: As a key component of the DNA damage response (DDR) pathway, DNA-PK appears to be a viable drug target for anticancer therapy. The clinical investigation of a DNA-PK inhibitor employs both a monotherapy and a combination strategy. In the combination strategy, a DNA-PK inhibitor is typically combined with a DSB inducer, radiation, a chemotherapy agent, or a PARP inhibitor, etc. Patent analyses suggest that diverse structures comprising different scaffolds from mono-heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl are capable to achieve good DNA-PK inhibitory activity and good DNA-PK selectivity over other closely related enzymes. Several DNA-PK inhibitors are currently being evaluated in clinics, with the hope to get approval in the near future.

In this paper, we propose a multi-channel medium access control (MMAC) protocol for the exploitation of retro-directive array antennas in Flying Ad Hoc Networks (named FA-MMAC). This FA-MMAC employs multiple channels and retro-directive array antennas to adjacent unmanned aerial vehicles (UAVs) to transmit simultaneously over the same channel without causing interference. The channel utilization characteristic of FA-MMAC increases the spatial reuse of channel and thus improve the system performance. The key idea is that UAVs first exchange control packets in control window to select data channels and to align beams before exchanging data packets in the data window. In this way, the hidden-terminal and deafness problems are reduced. UAVs can reserve channels and align beams through a circular directional transmission of control frames so that the protocol can take advantage of the benefits of retro-directive array antennas of spatial reuse and increased coverage without prior knowledge of the locations. We develop both antenna model and channel model for FA-MMAC protocol. Analysis and simulation results show that our proposed FA-MMAC can offer a significant performance gain for both static and mobile scenarios than the existing MMAC and 802.11-based protocols. Our findings reported in this paper provide some insights into the performance of multi-channel Flying Ad Hoc Networks which might help network researchers to contribute in the development of next generation UAVs.

Foxp3+ regulatory T cells (Treg) play an important part in the glioma immunosuppressive microenvironment. This study analyzed the effect of Foxsp3 on the immune microenvironment and constructed a Foxp3-related immune prognostic signature (IPS)for predicting prognosis in glioblastoma multiforme (GBM). Immunohistochemistry (IHC) staining for Foxp3 was performed in 72 high-grade glioma specimens. RNA-seq data from 152 GBM samples were obtained from The Cancer Genome Atlas database (TCGA) and divided into two groups, Foxp3 High (Foxp3_H) and Foxp3 Low (Foxp3_L), based on Foxp3 expression. We systematically analyzed the influence of Foxp3 on the immune microenvironment. Least Absolute Shrinkage and Selection Operator (LASSO) Cox analysis was conducted for immune-related genes that were differentially expressed between Foxp3_H and Foxp3_L GBM patients. We found a differential expression of Foxp3 in high-grade glioma tissues. The presence of Foxp3 was significantly associated with poor OS. From the four-gene IPS developed, GBM patients were stratified into low-risk and high-risk groups in both the training set and validation sets. Furthermore, we developed a novel nomogram to evaluate the overall survival in GBM patients. This study offers innovative insights into the GBM immune microenvironment and these findings contribute to individualized treatment and improvement in the prognosis for GBM patients.

Purpose This paper aims to present a new framework that describes the relationship among market entry order and timing, the advantages accruing to first-movers and late-movers, entry timing premium (ETP), marketing strategy and enduring market performance of the firms. The framework, empirically tested using data from 241 business executives, expands extant research into new territory beyond first- and late-mover advantages in an attempt to reconcile a few streams of research in the area and provides an entry related, strategic assessment tool (ETP) for the managers. Contribution to marketing strategy theory and managerial implications are also presented. Design/methodology/approach Participants included informants in a firm’s strategic business unit who were the most familiar with a new product’s commercial launch, market condition at launch, competitor offerings, marketing activities and capabilities and eventual integration into or withdrawal from the product’s portfolio. Therefore, for the survey, the study targeted chief executive officers, vice presidents of marketing or sales, product or sales managers, general managers and regional managers. Both preference bias (Narus, 1984) and survivor biases among the respondents were addressed. Findings The research result of this study reveals two very significant aspects of marketing and marketing strategies. First, the importance of financial, pricing and cost strategies further attests to the fiercely competitive nature of the global market today and the tendency for firms to commoditize most products and services. An effective financial and pricing strategy, coupled with a higher level of ETP, is capable of leading a firm to initial market success in the product-market in which it competes. Both ETP (a positional advantage and resource of the firm) and financial and pricing strategies (a deliberate strategic decision of the management) are important to achieve this goal. Research limitations/implications This study is limited in several ways. The effects of entry order and timing on market performance could be dependent on the types of industries and types of product categories involved. However, as the hypotheses were well supported, the “industry specific” factors would provide “fine-tuning” in the future study. Second, the nature of the product (goods or services) may also present varying effects on the relationship studied (for differences between manufacturing and service firms in pioneering advantages, see Song et al., 1999). Services’ intangible nature, difficulty in protecting property rights, high involvement of boundary-spanning employees and customers, high reliance on delivery and quality, and ease of imitation may alter the proposed relationships in the model and the moderating effects. Third, although this study used a “retrospective” protocol approach in the data collection by encouraging respondents to recall market, product and business information, this study is not longitudinal. Lack of longitudinal data in any study involving strategic planning, strategy execution and the long-term effects is no doubt a weakness. In addition, due to peculiarity and complexity with regard to regulation and other aspects in pharmaceutical and other industries, the theory might be limited to a certain extent. Practical implications In all, the integrated framework contributes to the understanding of the intricate issues surrounding first-mover advantage, late-mover advantage, entry order and timing and the role of marketing strategy. The framework provides practitioners guidance as to when to enter a product-market to gain advantageous positions and how to maintain that advantage. Firms that use a deliberate late-mover strategy could also benefit from the research finding in mapping out their strategic courses of action. Originality/value This study believes that the halo effect surrounding first-mover advantage may have obscured the visions of some researchers and managers, and the pursuit of a silver bullet has led to frenzied interests in becoming a “first-mover” or a deliberate “late-mover”. The theoretical framework, which is substantiated by empirical testing, invalidates the long-held claim that entry of a particular kind (first-movers or late-movers) yields any unique competitive advantage. It is a firms’ careful selection of marketing strategies and careful execution of the strategies through effective operational tactics that would lead to enduring competitive advantage, under an adequate level of ETP.

Accumulating evidence suggests that chronic inflammation may play a critical role in various malignancies, including bladder cancer. This hypothesis stems in part from inflammatory cells observed in the urethral microenvironment. Chronic inflammation may drive neoplastic transformation and the progression of bladder cancer by activating a series of inflammatory molecules and signals. Recently, it has been shown that the microbiome also plays an important role in the development and progression of bladder cancer, which can be mediated through the stimulation of chronic inflammation. In effect, the urinary microbiome can play a role in establishing the inflammatory urethral microenvironment that may facilitate the development and progression of bladder cancer. In other words, chronic inflammation caused by the urinary microbiome may promote the initiation and progression of bladder cancer. Here, we provide a detailed and comprehensive account of the link between chronic inflammation, the microbiome and bladder cancer. Finally, we highlight that targeting the urinary microbiome might enable the development of strategies for bladder cancer prevention and personalized treatment.

The practical application of lithium–sulfur batteries (LSBs) has been impeded by several chronic problems related to the insulating nature of sulfur and lithium sulfide, in addition to the dissolution and diffusion of lithium polysulfides. In view of these problems, a large variety of carbonaceous materials have been employed to enhance the electronic conductivity of the cathode and/or sequester lithium polysulfides within conductive matrixes. Although they may exhibit impressive electrochemical performance, the fabrication of most carbon materials involves costly precursors and complicated procedures. Waste paper—the main constituent of municipal waste—is composed of carbohydrates, and can be an ideal precursor for carbon materials. Herein, carbon microfiber meshes (CMFMs) obtained by the pyrolysis of common filter paper in argon (A-CMFM) or ammonia (N-CMFM) were used to form sulfur cathodes. Compared with LSBs based on A-CMFM, those based on N-CMFM demonstrated higher specific capacity and better rate capability, with a capacity of 650 mA h g−1 at 0.2 C and 550 mA h g−1 at 0.5 C. This was owing to the strong immobilization of lithium polysulfides resulting from the heteroatom doping and hydrophilicity of N-CMFM. The results indicate that cellulose paper-derived carbon is a promising candidate for application in high-performance LSBs.

Supplemental Digital Content is available in the text., Background: For most disease-related traits the magnitude of the contribution of genetic factors in adolescents remains unclear. Methods: Twenty continuous traits related to anthropometry, cardiovascular and renal function, metabolism, and inflammation were selected from the ongoing prospective Tracking Adolescents’ Individual Lives Survey cohort in the Netherlands with measurements of up to 5 waves from age 11 to 22 years (n=1354, 47.6% males) and all traits available at the third wave (mean age [SD]=16.22 [0.66]). For each trait, unweighted and weighted genetic risk scores (GRSs) were generated based on significantly associated single nucleotide polymorphisms identified from literature. The variance explained by the GRSs in adolescents were estimated by linear regression after adjustment for covariates. Results: Except for ALT (alanine transaminase), all GRSs were significantly associated with their traits. The trait variance explained by the GRSs was highest for lipoprotein[a] (39.59%) and varied between 0.09% (ALT) and 18.49% (LDL [low-density lipoprotein]) for the other traits. For most traits, the variances explained in adolescents were comparable with or slightly smaller than those in adults. Significant increases of trait levels (except ALT) and increased risks for overweight/obesity (odds ratio, 6.41 [95% CI, 2.95–15.56]) and hypertension (odds ratio, 2.86 [95% CI, 1.39–6.17]) were found in individuals in the top GRS decile compared with those at the bottom decile. Conclusions: Variances explained by adult-based GRSs for disease-related traits in adolescents, although still relatively modest, were comparable with or slightly smaller than in adults offering promise for improved risk prediction at early ages.

Optical networks that distribute entanglement among various quantum systems will form a powerful framework for quantum science but are yet to interface with leading quantum hardware such as superconducting qubits. Consequently, these systems remain isolated because microwave links at room temperature are noisy and lossy. Building long distance connectivity requires interfaces that map quantum information between microwave and optical fields. While preliminary microwave-to-optical transducers have been realized, developing efficient, low-noise devices that match superconducting qubit frequencies (gigahertz) and bandwidths (10 kilohertz – 1 megahertz) remains a challenge. Here we demonstrate a proof-of-concept on-chip transducer using trivalent ytterbium-171 ions in yttrium orthovanadate coupled to a nanophotonic waveguide and a microwave transmission line. The device′s miniaturization, material, and zero-magnetic-field operation are important advances for rare-earth ion magneto-optical devices. Further integration with high quality factor microwave and optical resonators will enable efficient transduction and create opportunities toward multi-platform quantum networks., Long distance interfaces between superconducting quantum information processing nodes would require coherent, efficient and low-noise microwave-to-optical conversion. Here, the authors use Yb ion ensembles in yttrium orthovanadate to demonstrate a transducer with the potential to fulfill these requirements.

Background: Many human diseases are associated with dysregulation of HDACs. HDAC6 exhibits deacetylase activity not only to histone protein but also to non-histone proteins such as α- tubulin, HSP90, cortactin, and peroxiredoxin. These unique functions of HDAC6 have gained significant attention in the medicinal chemistry community in recent years. Thus a great deal of effort has devoted to developing selective HDAC6 inhibitors for therapy with the hope to minimize the side effects caused by pan-HDAC inhibition. Objective: The review intends to analyze the structural feature of the scaffolds, to provide useful information for those who are interested in this field, as well as to spark the future design of the new inhibitors. Methods: The primary tool used for patent searching is SciFinder. All patents are retrieved from the following websites: the World Intellectual Property Organization (WIPO®), the United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents. The years of patents covered in this review are between 2016 and 2019. Results: Thirty-six patents from seventeen companies/academic institutes were classified into three categories based on the structure of ZBG: hydroxamic acid, 1,3,4-oxadiazole, and 1,2,4-oxadiazole. ZBG connects to the cap group through a linker. The cap group can tolerate different functional groups, including amide, urea, sulfonamide, sulfamide, etc. The cap group appears to modulate the selectivity of HDAC6 over other HDAC subtypes. Conclusion: Selectively targeting HDAC6 over other subtypes represents two fold advantages: it maximizes the pharmacological effects and minimizes the side effects seen in pan-HDAC inhibitors. Many small molecule selective HDAC6 inhibitors have advanced to clinical studies in recent years. We anticipate the approval of selective HDAC6 inhibitors as therapeutic agents in the near future.

Cancer is a common and complex disease with various genetic and environmental risks. Chemotherapy and targeted therapy are one of the main therapeutic approaches for the treatment of advanced cancer patients. However, prolonged patient treatment often provokes drug resistance phenomena that render the therapeutic treatment highly ineffective. Therefore, the development of novel and effective treatment strategies to overcome drug resistance is urgent for cancer therapy. A variety of factors contribute to drug resistance, including tumor cell heterogeneity, drug efflux, drug inactivation, changes in tumor microenvironment, DNA damage repair disorders, epigenetic alterations in cancer cells and so on. However, how to circumvent drug resistance to improve anticancer efficacy remains to be determined. Currently, the most important approach for overcoming drug resistance is drug combination therapeutic regimen, however, it is easy to induce new drug resistance or even multi-drug resistance (MDR) which is defined as the resistance of cancer cells to multiple anticancer drugs with different structures and mechanisms of action. Whereas, the “multi-components and multi-targets” manifestations of Traditional Chinese Medicine (TCM) make them an attractive direction for developing new adjuvant therapeutics to reverse drug resistance. In recent years, several compounds derived from TCM have been reported to augment sensitivity or overcome resistance of anticancer therapeutic drugs, including elemene, bufalin, curcumin, magnolol, honokiol, resveratrol, quercetin, and so on. Thus, the combination of TCM and conventional anticancer drugs will hopefully provide a novel strategy for enhancing the effects of anticancer strategies and overcoming their resistance in the treatment of cancer patients. In the current paper, we review the molecular mechanisms of drug resistance and the therapeutic strategies. We also discuss the current basic research and clinical studies in overcoming drug resistance from Traditional Chinese Medicine. Finally, we focus the integrated traditional Chinese and Western medicine as a promising new therapeutic approach to enhance the effects of anticancer strategies or overcome their resistance in the treatment of cancer patients.

Gliomas are the most common tumor of the central nervous system. However, the presence of the brain barrier blocks the effective delivery of drugs and leads to the treatment failure of various drugs. The development of a nanoparticle drug delivery system (NDDS) can solve this problem. In this review, we summarized the brain barrier (including blood-brain barrier (BBB), blood-brain tumor barriers (BBTB), brain-cerebrospinal fluid barrier (BCB), and nose-to-brain barrier), NDDS of glioma (such as passive targeting systems, active targeting systems, and environmental responsive targeting systems), and NDDS efficacy improvement strategies and deficiencies. The research prospect of drug-targeted delivery systems for glioma is also discussed.

Background Deubiquitinase OTU domain containing 4 (OTUD4) is initially identified as a K48-specific deubiquitinase and plays an important role in DNA damage repair signaling transduction. However, the expression level, prognostic role, biological function and mechanism of OTUD4 in multiple human cancers are unclear. Methods GEPIA online (http://gepia.cancer-pku.cn/; The Cancer Genome Atlas (TCGA) database) was used to analyze the mRNA expression of OTUD4 in multiple human cancers. Kaplan-Meier plotter (KM plotter) database and TCGA database were used to evaluate the prognostic value of OTUD4 expression in multiple human cancers. MTT, Transwell and 3D culture assays were used to detect the role of OTUD4 in breast, liver and lung cancer cells. The correlation between OTUD4 and apoptosis signaling pathway and AKT signaling pathway was analyzed by Gene set enrichment analysis (GSEA). Results OTUD4 mRNA expression is significantly downregulated in multiple human cancer tissues. Survival analysis establishes that the downregulation of OTUD4 predicts poor prognosis in many solid tumors, including breast invasive carcinoma (BRCA), esophageal carcinoma (ESCA), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), and ovarian serous cystadenocarcinoma (OV). Furthermore, overexpression of OTUD4 could inhibit tumor cell proliferation, migration and invasion of breast, liver and lung cancer cells through inhibiting the AKT signaling pathway. Conclusion This study found that OTUD4 may be a potential predictive factor for several human cancers and a tumor suppressor for breast, liver and lung cancer. The overexpression of OTUD4 restrained proliferation, migration and invasion of human breast, liver and lung cancer cells through promoting cancer cells apoptosis and inhibiting AKT signaling pathway. Notably, our results indicated that OTUD4 could be a useful biomarker for the prognosis of human cancers and a potential molecular target for diagnosis and treatment of breast, liver and lung cancer.

High-intensity interval training (HIIT) is a time-efficient alternative to moderate-intensity continuous training (MICT) to improve metabolic health in older individuals. However, differences in adipose tissue metabolism between these two approaches are unclear. Here, we evaluated the effects of HIIT and MICT on metabolic phenotypes in aged rats. HIIT significantly decreased fat mass, increased percent lean mass, decreased fat-to-lean ratio, reduced serum high-sensitivity C-reactive protein, increased serum interleukin-10 levels, and decreased perirenal adipose tissue leptin compared with rats in the sedentary (SED) group. HIIT also increased pregnenolone, cortisol, and corticosterone in both adipose tissue and serum. Both exercise modalities enhanced hormone-sensitive lipase and adipose triglyceride lipase expression compared with the SED group and decreased palmitic acid, stearic acid, octadecadienoic acid, urea, 1-heptadecanol, and α-tocopherol. MICT was related to glycerolipid metabolism, whereas HIIT was related to steroid hormone biosynthesis. Overall, HIIT showed more favorable regulation of anti-inflammatory activity than MICT.

Rationale: Tumor vascular normalization (TVN) is emerging to enhance the efficacy of anticancer treatment in many cancers including glioblastoma (GBM). However, a common and severe challenge being currently faced is the transient TVN effect, hampering the sustained administration of anticancer therapy during TVN window. Additionally, the lack of non-contrast agent-based imaging biomarkers to monitor TVN process postpones the clinical translation of TVN strategy. In this study, we investigated whether dual inhibition of VEGF and the glycolytic activator PFKFB3 could reinforce the TVN effect in GBM. Dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI) and intravoxel incoherent motion (IVIM)-MRI were performed to monitor TVN process and to identify whether IVIM-MRI is a candidate or complementary imaging biomarker for monitoring TVN window without exogenous contrast agent administration. Methods: Patient-derived orthotopic GBM xenografts in mice were established and treated with bevacizumab (BEV), 3PO (PFKFB3 inhibitor), BEV+3PO dual therapy, or saline. The vascular morphology, tumor hypoxia, and lactate level were evaluated before and at different time points after treatments. Doxorubicin was used to evaluate chemotherapeutic efficacy and drug delivery. Microarray of angiogenesis cytokines and western blotting were conducted to characterize post-treatment molecular profiling. TVN process was monitored by DCE- and IVIM-MRI. Correlation analysis of pathological indicators and MRI parameters was further analyzed. Results: Dual therapy extended survival and delayed tumor growth over each therapy alone, concomitant with a decrease of cell proliferation and an increase of cell apoptosis. The dual therapy reinforces TVN effect, thereby alleviating tumor hypoxia, reducing lactate production, and improving the efficacy and delivery of doxorubicin. Mechanistically, several angiogenic cytokines and pathways were downregulated after dual therapy. Notably, dual therapy inhibited Tie1 expression, the key regulator of TVN, in both endothelial cells and tumor cells. DCE- and IVIM-MRI data showed that dual therapy induced a more homogenous and prominent TVN effect characterized by improved vascular function in tumor core and tumor rim. Correlation analysis revealed that IVIM-MRI parameter D * had better correlations with TVN pathological indicators compared with the DCE-MRI parameter K trans. Conclusions: Our results propose a rationale to overcome the current limitation of BEV monotherapy by integrating the synergistic effects of VEGF and PFKFB3 blockade to enhance chemotherapy efficacy through a sustained TVN effect. Moreover, we unveil IVIM-MRI parameter D * has much potential as a complementary imaging biomarker to monitor TVN window more precisely without exogenous contrast agent injection.

Purpose: To investigate the correlation between the expression of PD-L1, SOCS3 and immune-related biomarkers CD276, CD4, CD8 in hepatocellular carcinoma (HCC) and further determine the relationship with clinicopathologic characteristics and the prognostic value of their co-expression in HCC patients. Methods: We assessed the expression of PD-L1, CD276, SOCS3, CD4 and CD8 by immunohistochemistry in tumor tissue from 74 HCC patients who underwent curative hepatectomy. Results: High expression of PD-L1 was significantly associated with high Edmondson grade (p0.05). High expression of CD8 was respectively significantly associated with worse overall survival (OS) (p=0.002). There was no significantly difference between CD4 and CD8 high-expression and overall survival (OS) (p=0.100). Both high expression of PD-L1 (p=0.003) and low expression of SOCS3 (p=0.015) was significantly associated with worse overall survival (OS). But CD276 only had a trendency (p=0.166). Additionally, multivariate Cox regression models implied that PD-L1, SOCS3, as well as both CD4 and CD8 was an independent prognostic factor for OS (p

Malignant tumors represent some of the most intractable diseases that endanger human health. A glioma is a tumor of the central nervous system that is characterized by severe invasiveness, blurred boundaries between the tumor and surrounding normal tissue, difficult surgical removal, and high recurrence. Moreover, the blood-brain barrier (BBB) and multidrug resistance (MDR) are important factors that contribute to the lack of efficacy of chemotherapy in treating gliomas. A liposome is a biofilm-like drug delivery system with a unique phospholipid bilayer that exhibits high affinities with human tissues/organs (e.g., BBB). After more than five decades of development, classical and engineered liposomes consist of four distinct generations, each with different characteristics: (i) traditional liposomes, (ii) stealth liposomes, (iii) targeting liposomes, and (iv) biomimetic liposomes, which offer a promising approach to promote drugs across the BBB and to reverse MDR. Here, we review the history, preparatory methods, and physicochemical properties of liposomes. Furthermore, we discuss the mechanisms by which liposomes have assisted in the diagnosis and treatment of gliomas, including drug transport across the BBB, inhibition of efflux transporters, reversal of MDR, and induction of immune responses. Finally, we highlight ongoing and future clinical trials and applications toward further developing and testing the efficacies of liposomes in treating gliomas.

Two-dimensional (2D) heterostructures composed of the single layer V2O5 and graphene achieve good chemical diffusion of Li+, high conductivity and cycling stability. Hence, a simple and novel bottom-up approach has been proposed to build the true single layer V2O5 nanoribbon/graphene heterostructures. The single layer V2O5 nanoribbon, which has a thickness of 800 p.m. and are approximate 80 nm in wide, is combined with graphene as sandwich-like heterostructures through the layer-by-layer assembly method. The distinct heterostructures can effectively shorten the practical diffusion pathway for Li+ and improve the electrical conductivity of the overall electrode. Therefore, the as-prepared ultrathin V2O5 nanoribbon/graphene heterostructures exhibit excellent reversible capacity and stable cycling performance as a cathode material for lithium storage. Under the current density of 10 C, the electrode made from the ultrathin V2O5 nanoribbon/graphene heterostructures has an ultrahigh initial discharge capacity of 225 mAh g−1 (with corresponding coulombic efficiency of 99.6%) and a superior capacity retention of 92.8% after 600 charge and discharge cycles. In all, rapid ion and electron diffusions, which are the kinetic demands of alternative electrode material for lithium storage, will be satisfied by our single layer heterostructures.

Empiric broad-spectrum antimicrobials therapy is suggested to be started immediately for sepsis patients. Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established. However, the detailed mechanisms of de-escalation strategy are still unclear. Here we hypothesized neutrophil extracellular traps (NETs) played an essential role and de-escalation strategy might alleviate organs injury through regulation of NETs formation in sepsis. We evaluated the effect of imipenem and ceftriaxone on NETs formation in vitro and examined the role of reactive oxygen species (ROS). Next, we designed de-escalation and escalation strategy in cecum ligation and puncture (CLP) models. Organ injury, inflammatory cytokines, NETs levels were compared and evaluated. In CLP models, de-escalation therapy resulted in an increased serum MPO-DNA level during the early stage and decreased MPO-DNA level during late stage, which exerted the reverse effects in escalation therapy. Inflammatory response and organ injury exacerbated when eliminated NETs with DNAse I during the early stage of sepsis (p p p p = 0.051). The in vitro study showed that the imipenem could promote, while the ceftriaxone could inhibit the formation of NETs in PMA-activated PMNs through a ROS-dependent manner. We firstly demonstrate that de-escalation, not escalation, therapy reduces organ injury, decreases inflammatory response by promoting NETs formation in the early stage, and inhibiting NETs formation in the late stage of sepsis.

The coronavirus disease‐19 (COVID‐19) pandemic has become a global threat since its first outbreak at the end of 2019. Several review articles have been published recently, focusing on the aspects of target biology, drug repurposing, and mechanisms of action (MOAs) for potential treatment. This review gathers all small molecules currently in active clinical trials, categorizes them into six sub‐classes, and summarizes their clinical progress. The aim is to provide the researchers from both pharmaceutical industries and academic institutes with the handful information and dataset to accelerate their research programs in searching effective small molecule therapy for treatment of COVID‐19.

More than 150 cellular networks worldwide have rolled out massive IoT services such as smart metering and environmental monitoring. Such cellular IoT services share the existing cellular network architecture with non-IoT (e.g., smartphone) ones. When they are newly integrated into the cellular network, new security vulnerabilities may happen from imprudent integration. In this work, we explore the security vulnerabilities of the cellular IoT from both system-integrated and service-integrated aspects. We discover five vulnerabilities spanning cellular standard design defects, network operation slips, and IoT device implementation flaws. Threateningly, they allow an adversary to remotely identify IP addresses and phone numbers assigned to cellular IoT devices and launch data/text spamming attacks against them. We experimentally validate these vulnerabilities and attacks with three major U.S. IoT carriers. The attack evaluation result shows that the adversary can raise an IoT data bill by up to $226 with less than 120 MB spam traffic and increase an IoT text bill at a rate of $5 per second; moreover, cellular IoT devices may suffer from denial of IoT services. We finally propose, prototype, and evaluate recommended solutions.

Three-dimensional (3D) bioprinting has rapidly developed in the last decade, playing an increasingly important role in applications including pharmacokinetics research, tissue engineering, and organ regeneration. As a cutting-edge technology in 3D printing, gel bath-supported 3D bioprinting enables the freeform construction of complex structures with soft and water-containing materials, facilitating the in vitro fabrication of live tissue or organ models. To realize in vivo-like organs or tissues in terms of biological functions and complex structures by 3D printing, high resolution and fidelity are prerequisites. Although a wide range of gel matrices have recently been developed as supporting materials, the effect of bath properties and printing parameters on the print resolution is still not clearly understood. This review systematically introduces the decisive factors for resolution in both bulk gel bath systems and granular microgel bath systems, providing guidelines for high-resolution 3D bioprinting based on bath properties and printing parameters.

Malignant tumors are life-threatening, and chemotherapy is one of the common treatment methods. However, there are often many factors that contribute to the failure of chemotherapy. The multidrug resistance of cancer cells during chemotherapy has been reported, since tumor cells’ sensitivity decreases over time. To overcome these problems, extensive studies have been conducted to reverse drug resistance in tumor cells. Elemene, an extract of the natural drug Curcuma wenyujin, has been found to reverse drug resistance and sensitize cancer cells to chemotherapy. Mechanisms by which elemene reverses tumor resistance include inhibiting the efflux of ATP binding cassette subfamily B member 1(ABCB1) transporter, reducing the transmission of exosomes, inducing apoptosis and autophagy, regulating the expression of key genes and proteins in various signaling pathways, blocking the cell cycle, inhibiting stemness, epithelial–mesenchymal transition, and so on. In this paper, the mechanisms of elemene’s reversal of drug resistance are comprehensively reviewed.

The primary aims of this study were to determine the effects of lifelong exercise and detraining on age-related alterations in mitochondrial function, inflammation associated with senescence-associated secretory phenotype (SASP), and lipolysis in the perirenal fat and liver of rats. Female Sprague-Dawley rats were randomly assigned to four groups: young control (n = 12), old control (n = 12), detraining (n = 12), and lifelong exercise (n = 12). We then investigated mitochondrial function, SASP-associated inflammation, and lipolysis in the perirenal fat and liver using qRT-PCR and western blotting to assess the expression of AKT, hypoxia-inducible factor 1α (HIF-1α), nuclear factor-kappa B (NF-κB), c-jun kinase (JNK), and p38 mitogen-activated protein kinase (p38MAPK). In the tissues of both the perirenal fat and liver, lifelong exercise significantly improved mitochondrial function, SASP-associated inflammation, and lipolysis. Meanwhile, pathways associated with inflammatory regulation were inhibited, predominantly via the activation of phosphorylated-AKT (p-AKT) and suppression of HIF-1α in both tissues, and via JNK in the perirenal fat and p38MAPK in the liver. Furthermore, detraining activated NF-κB expression in both tissues and induced the upregulation of serum high-sensitivity C-reactive protein (hsCRP) levels. Collectively, lifelong exercise was found to exert beneficial effects by ameliorating age-related alterations in mitochondrial function, SASP-associated inflammation, and lipolysis in perirenal fat and liver tissues, potentially inhibiting inflammation via the JNK and p38 MAPK pathways, respectively, as well as the HIF-1α and AKT pathways in both tissues. In contrast, detraining induced high levels of circulating hsCRP by activating the NF-κB signaling pathway in both tissues.

This paper proposes a deep learning model, which classifies web pages based on deep feature fusion. The model has the function of using Text CNN to extract the text of important tags in the web page. It also has the function of using XL Net to extract the text of other tags in the web page. The two parts of the function in the webpage are combined together, which effectively solves the problem of feature collinearity and vector sparseness in the process of network deep feature fusion. This article discusses a deep merging mechanism that can improve the merging of the semantic features of important tags with the semantic features of other web pages. Experimental results show that this method is based on a deep fusion deep learning model and can be used for efficient and high-precision classification of website text. At the same time, the development index of an effective English language model for business research and index system is established in the study. The research is based on theoretical analysis, concept deduction, teaching reform projects, textbook drafts, teaching materials, teacher training basic knowledge, and teaching competitions. Theoretical model of English teaching development index. In addition, this article also introduces the actual soil of a certain area of China as the research object, and 16 kinds of phthalate esters were tested in the soil of this area. By determining the physical and chemical properties of soil enzymes, the effects of phthalate microbial communities, and soil microbial communities on different planting methods were analyzed. This paper uses deep functional fusion technology to detect soil pollution and display the concentration of phthalate pollutants in the soil, as well as the response of business English to the construction of teaching index.

MUC4, a transmembrane mucin, plays important roles in epithelial renewal and differentiation. Recent studies suggest that MUC4 has been implicated in pancreatic cancer pathogenesis and is expressed in various normal and cancer tissues. The underlying features of MUC4 across various cancer types may allow us to ensure appropriate treatment and patient monitoring. However, the contributions of MUC4 to pan-cancer have not been well characterized. In this study, we investigated the expression pattern and prognostic value of MUC4 across multiple databases. We further explored genomic and epigenetic alterations of MUC4, its association with proliferation and metastasis, and the correlation with immune infiltration in different cancers. Our results characterized the distinct expression profile and prognostic values of MUC4 in pan-cancer. Through examining its association with genomic alteration, tumor proliferation, and metastasis, as well as tumor infiltration, we revealed multiple function effects of MUC4. MUC4 may influence prognosis, proliferation, metastasis, and immune response in opposite directions. In conclusion, our findings suggested the necessity to more carefully evaluate MUC4 as a biomarker and therapeutic target and develop the new antibodies for cancer detection and intervention.

In this paper, the development of a novel dual-arm robot is introduced. With the use of modular actuator technology, a dual-arm robot consists of two 7-degree-of-freedom (7-DOF) robotic arms. The robot's high degree of freedom enables it to effectively avoid the joint limitations and singularities of the arm. A solo controller for both arms is proposed and this dual-arm robot has the human sized body and arms. Firstly, a modular actuator is presented and a dual-arm robot is introduced. Then, the kinematic and dynamic analysis for this dual-arm robot is presented. Finally, the prototype of this dual-arm robot is presented and discussed.

Currently, little is known regarding the association between dietary choline intake and osteoporosis in elderly individuals, as well as if such intakes affect bone health and result in fractures. This study was aimed to examine associations between daily dietary choline intake and osteoporosis in elderly individuals. A total of 31 034 participants from the National Health and Nutritional Examination Survey (NHANES) during 2005–2010 were enrolled, and 3179 participants with complete data and aged 65 years and older were identified. Baseline characteristics and dietary intake data were obtained through method of in-home administered questionnaires. Of 3179 individuals with a mean age of 73.7 ± 5.6 years, female (P < 0.001) and non-hispanic white (P < 0.001) occupied a higher proportion in the osteoporosis group. The logistic regression analysis indicated that the prevalence of osteoporosis in three tertile categories with gradually enhanced dietary choline intake was decreased progressively (P for trend

Resistance to anticancer drugs is a major problem in oncology, which causes the failure of antitumor treatment. A variety of factors contribute to drug resistance, including drug efflux and metabolism, tumor cell heterogeneity, tumor microenvironment stress-induced genetic or epigenetic alterations in the cancer cells and so on. However, how to circumvent this resistance to improve anticancer efficacy remains to be determined. To circumvent chemotherapeutic resistance, many reversal agents have been developed, but most of them fail in clinical trials due to severe adverse effects. Recently, several natural products have been reported to augment sensitivity or overcome resistance of anticancer chemotherapeutic drugs, including elemene, curcumin, Shenqi Fuzheng Injection (), PHY906, etc. Thus, understanding the novel function of Chinese medicine may allow us to develop a promising therapeutic approach to enhance the effects of anticancer strategies and prevent or overcome their resistance in the treatment of cancer patients.

5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 (PCDH17) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between PCDH17 and 5-FU resistance in CRC remains unclear. Here, we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of PCDH17 was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death. Furthermore, autophagy played a dominant role in PCDH17-induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity. Mechanistically, we showed that c-Jun NH2-terminal kinase (JNK) activation was a key determinant in PCDH17-induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells. Taken together, our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.

Realizing high mobile data rates in high mobility scenarios has been an important yet challenging target for wireless communications. One typical scenario of such "double high" communications is the HST, which has been one of the most representative infrastructures in more and more countries, especially in China. However, the current SE in HST communications according to the measurements is far from satisfactory to meet the data rate demand generated by the intensive users on HSTs. To address this issue, potential technologies to improve the SE performance of HST communications under various CSI assumptions are presented in this article. Specifically, two open loop beamforming methods with the help of location information (i.e., the location based MIMO precoding and the location assisted MIMO precoder cycling) are first proposed, which are shown to be robust to HST channel variations. Then, we study closed loop beamforming strategies, where channel prediction is proposed to be the key to obtain the essential CSI (e.g., channel matrix or channel covariance) with a low overhead. As HSTs usually go through complicated environments, a big data aided adaptation mechanism between the investigated methods is further proposed. Numerical results demonstrate that the proposed approaches are capable of achieving over 10x SE performance than the current HST transmission strategies and worthy to be studied and discussed in the future 5G New Radio (NR) standardization. It is anticipated that communications with high data rates in high mobility scenarios will be well supported for HSTs in the 5G era.

Lung cancer has the highest morbidity and mortality among all cancers. Discovery of early diagnostic and prognostic biomarkers of lung cancer can greatly facilitate the survival rate and reduce its mortality. In our study, by analyzing Gene Expression Omnibus and Oncomine databases, we found a novel potential oncogene uridine‐cytidine kinase 2 (UCK2), which was overexpressed in lung tumor tissues compared to adjacent nontumor tissues or normal lung. Then we confirmed this finding in clinical samples. Specifically, UCK2 was identified as highly expressed in stage IA lung cancer with a high diagnostic accuracy (area under the receiver operating characteristic curve > 0.9). We also found that high UCK2 expression was related to poorer clinicopathological features, such as higher T stage and N stage and higher probability of early recurrence. Furthermore, we found that patients with high UCK2 expression had poorer first progression survival and overall survival than patients with low UCK2 expression. Univariate and multivariate Cox regression analyses showed that UCK2 was an independent risk factor related with worse DFS and OS. By gene set enrichment analysis, tumor‐associated biological processes and signaling pathways were enriched in the UCK2 overexpression group, which indicated that UCK2 might play a vital role in lung cancer. Furthermore, in cytology experiments, we found that knockdown of UCK2 could suppress the proliferation and migration of lung cancer cells. In conclusion, our study indicated that UCK2 might be a potential early diagnostic and prognostic biomarker for lung cancer.

Functional annotation of protein sequence with high accuracy has become one of the most important issues in modern biomedical studies, and computational approaches of significantly accelerated analysis process and enhanced accuracy are greatly desired. Although a variety of methods have been developed to elevate protein annotation accuracy, their ability in controlling false annotation rates remains either limited or not systematically evaluated. In this study, a protein encoding strategy, together with a deep learning algorithm, was proposed to control the false discovery rate in protein function annotation, and its performances were systematically compared with that of the traditional similarity-based and de novo approaches. Based on a comprehensive assessment from multiple perspectives, the proposed strategy and algorithm were found to perform better in both prediction stability and annotation accuracy compared with other de novo methods. Moreover, an in-depth assessment revealed that it possessed an improved capacity of controlling the false discovery rate compared with traditional methods. All in all, this study not only provided a comprehensive analysis on the performances of the newly proposed strategy but also provided a tool for the researcher in the fields of protein function annotation.

Given the non-repeatability, complexity, and unpredictability of unconventional public health emergencies, building accurate models and making effective response decisions based only on traditional prediction–response decision-making methods are difficult. To solve this problem, under the scenario–response paradigm and theories on parallel emergency management and discrete event system (DES), the parallel simulation decision-making framework (PSDF), which includes the methods of abstract modeling, simulation operation, decision-making optimization, and parallel control, is proposed for unconventional public health emergency response processes. Furthermore, with the example of the severe acute respiratory syndrome (SARS) response process, the evolutionary scenarios that include infected patients and diagnostic processes are transformed into simulation processes. Then, the validity and operability of the DES–PSDF method proposed in this paper are verified by the results of a simulation experiment. The results demonstrated that, in the case of insufficient prior knowledge, effective parallel simulation models can be constructed and improved dynamically by multi-stage parallel controlling. Public health system bottlenecks and relevant effective response solutions can also be obtained by iterative simulation and optimizing decisions. To meet the urgent requirements of emergency response, the DES–PSDF method introduces a new response decision-making concept for unconventional public health emergencies.

Hybrid heterostructures are a promising type of materials framework for optoelectronic conversion. We designed a ternary energy-dependent thin layer of Cu2S-Pt-WO3 (p-type-metal-n-type) heterojunction to explore an alternative way of realizing efficient charge separation. First-principles calculations showed that the Fermi level of the whole system is lined up via the mediation of Pt metal, which fosters the combination of holes in Cu2S and electrons in WO3 and keeps electrons in Cu2S and holes in WO3 well separated. Importantly, creation of band bending and charge polarization steer low-energy charges selectively to the intermediate metal and keep high-energy charges on individual semiconductors apart. Our simulation analysis of two-dimensional layers with the metal bridge shows increased charge flows across the junction compared to that of their bulk counterparts. Overall, this heterojunction is viable for suppressing recombination of photogenerated electron-hole pairs and augmented electrons per surface that would allow enhanced optoelectronic conversion.

Tm3+/Yb3+: Y2Ti2O7 phosphors with color-tunable upconversion (UC) luminescence and optical thermometric property were synthesized and characterized. The phosphors exhibit intense blue and red UC emission bands under 980 nm excitation. The blue to red emission intensity ratio shows an enhancement with increasing excitation power. Hence, the UC color can be tuned from almost white to blue by control of the excitation power density. The temperature sensing behaviors are studied based on fluorescence intensity ratio (FIR) technique at different excitation powers. FIR-1 from the thermally coupled levels (1G4(a) and 1G4(b)) is insensitive to the excitation power, which can obtain consistent measurement results at different excitation powers. Meanwhile, the utilization of FIR-2 from non-thermally coupled levels (3F2,3 and 1G4(b)) can achieve higher sensing sensitivities with the maximal value of ∼0.81%K−1 at 398 K. Hence, Tm3+/Yb3+:Y2Ti2O7 phosphor has promising application prospects in the fields of upconverter, optical thermometer and color tunable device.