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Background the ageing population has increased in many countries, including China. However, reference intervals (RIs) for older people are rarely established because of difficulties in selecting reference individuals. Here, we aimed to analyse the factors affecting biochemical analytes and establish RI and age-related RI models for biochemical analytes through mining real-world big data. Methods data for 97,220 individuals downloaded from electronic health records were included. Three derived databases were established. The first database included 97,220 individuals and was used to build age-related RI models after identifying outliers by the Tukey method. The second database consisted of older people and was used to establish variation source models and RIs for biochemical analytes. Differences between older and younger people were compared using the third database. Results sex was the main source of variation of biochemical analytes for older people in the variation source models. The distributions of creatinine and uric acid were significantly different in the RIs of biochemical analytes for older people established according to sex. Age-related RI models for biochemical analytes that were most affected by age were built and visualized, revealing various patterns of changes from the younger to older people. Conclusion the study analysed the factors affecting biochemical analytes in older people. Moreover, RI and age-related RI models of biochemical analytes for older people were established to provide important insight into biological processes and to assist clinical use of various biochemical analytes to monitor the status of various diseases for older people.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression posttranscriptionally by silencing or degrading their targets and play important roles in the host response to pathogenic infection. Although infectious bursal disease virus (IBDV)-induced apoptosis in host cells has been established, the underlying molecular mechanism is not completely unraveled. Here, we show that infection of DF-1 cells by IBDV induced gga-miR-16-5p (chicken miR-16-5p) expression via demethylation of the pre-miR-16-2 (gga-miR-16-5p precursor) promoter. We found that ectopic expression of gga-miR-16-5p in DF-1 cells enhanced IBDV-induced apoptosis by directly targeting the cellular antiapoptotic protein B-cell lymphoma 2 (Bcl-2), facilitating IBDV replication in DF-1 cells. In contrast, inhibition of endogenous miR-16-5p markedly suppressed apoptosis associated with enhanced Bcl-2 expression, arresting viral replication in DF-1 cells. Furthermore, infection of DF-1 cells with IBDV reduced Bcl-2 expression, and this reduction could be abolished by inhibition of gga-miR-16-5p expression. Moreover, transfection of DF-1 cells with gga-miR-16-5p mimics enhanced IBDV-induced apoptosis associated with increased cytochrome c release and caspase-9 and -3 activation, and inhibition of caspase-3 decreased IBDV growth in DF-1 cells. Thus, epigenetic upregulation of gga-miR-16-5p expression by IBDV infection enhances IBDV-induced apoptosis by targeting the cellular antiapoptotic protein Bcl-2, facilitating IBDV replication in host cells. IMPORTANCE Infectious bursal disease (IBD) is an acute, highly contagious, and immunosuppressive disease in young chickens, causing severe economic losses to stakeholders across the globe. Although IBD virus (IBDV)-induced apoptosis in the host has been established, the underlying mechanism is not very clear. Here, we show that infection of DF-1 cells by IBDV upregulated gga-miR-16-5p expression via demethylation of the pre-miR-16-2 promoter. Overexpression of gga-miR-16-5p enhanced IBDV-induced apoptosis associated with increased cytochrome c release and caspase-9 and -3 activation. Importantly, we found that IBDV infection induced expression of gga-miR-16-5p that triggered apoptosis by targeting Bcl-2, favoring IBDV replication, while inhibition of gga-miR-16-5p in IBDV-infected cells restored Bcl-2 expression, slowing down viral growth, indicating that IBDV induces apoptosis by epigenetic upregulation of gga-miR-16-5p expression. These findings uncover a novel mechanism employed by IBDV for its own benefit, which may be used as a potential target for intervening IBDV infection.

Summary Background Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X. Methods COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more [range 0–10] in at least three of the four domains [patient global, spinal pain, function, and inflammation] without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov , number NCT02757352 . Findings Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (ixekizumab Q4W: 34 [35%] of 96, p=0·0094 vs placebo; ixekizumab Q2W: 41 [40%] of 102, p=0·0016; placebo: 20 [19%] of 105) and ASAS40 at week 52 (ixekizumab Q4W: 29 [30%] of 96, p=0·0045; ixekizumab Q2W: 32 [31%] of 102, p=0·0037; placebo: 14 [13%] of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the ixekizumab Q4W group. The frequency of serious adverse events was low (four [1%] of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified. Interpretation Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy. Funding Eli Lilly and Company.

As the most popular blockchain that supports smart contracts, there are already more than 296 thousand kinds of cryptocurrencies built on Ethereum. However, not all cryptocurrencies can be controlled by users. For example, some money is permanently locked in wallets' accounts due to attacks. In this paper, we conduct the first systematic investigation on locked cryptocurrencies in Ethereum. In particular, we define three categories of accounts with locked cryptocurrencies and develop a novel tool named CLUE to discover them. Results show that there are more than 216 million dollars value of cryptocurrencies locked in Ethereum. We also analyze the reasons (i.e., attacks/behaviors) why cryptocurrencies are locked. Because the locked cryptocurrencies can never be controlled by users, avoid interacting with the accounts discovered by CLUE and repeating the same mistakes again can help users to save money., Comment: In Proceedings of the 36th ACM/SIGAPP Symposium on Applied Computing

Being the most popular permissionless blockchain that supports smart contracts, Ethereum allows any user to create accounts on it. However, not all accounts matter. For example, the accounts due to attacks can be removed. In this paper, we conduct the first investigation on erasable accounts that can be removed to save system resources and even users’ money (i.e., ETH or gas). In particular, we propose and develop a novel tool named Glaser, which analyzes the State DataBase of Ethereum to discover five kinds of erasable accounts. The experimental results show that Glaser can accurately reveal 508,482 erasable accounts and these accounts lead to users wasting more than 106 million dollars. Glaser can help stop further economic loss caused by these detected accounts. Moreover, Glaser characterizes the attacks/behaviors related to detected erasable accounts through graph analysis.

Natural gas hydrates (NGHs) are a form of natural gas widespread in the seafloor, and the realization of commercial exploitation is of great significance to solve the energy problem. There must be large amount of seawater and gas migration during the hydrate exploitation process. Studies have shown that seawater flow at a constant flow rate will enhance hydrate exploitation, especially at high flow rates. However, the seawater flow rate varies as a result of different seawater saturation in different areas of hydrate reservoir. There is little research on the effects of variational flow rate on hydrate decomposition characteristics. In this study, the effects of step-up flow rate and step-down flow rate modes on hydrate decomposition were investigated using the magnetic resonance imaging (MRI) system. The experimental results showed that the flowing seawater filled the pores that were occupied by free gas or generated by hydrate decomposition, which is beneficial to maintain the hydrate reservoir stability during the exploitation process. Through comprehensive comparison, the energy consumption of the variational flow rate mode was more than 60% less than that of the constant flow rate mode. For low hydrate saturation (22.5%), large seawater flow rate maintained a large driving force (fugacity difference) for hydrate decomposition, the efficiency of step-down flow rate mode was 131.1% greater than the efficiency of step-up mode; for high hydrate saturation (36.5%), low seawater flow rate made the mass transfer between seawater and hydrate more sufficient, the efficiency of step-up mode was 40.6% greater than that of step-down mode.

Avian reovirus (ARV) is an important pathogen causing multiple types of clinical diseases in chickens, including viral arthritis, chronic respiratory diseases, retarded growth, and malabsorption syndrome, leading to considerable economic losses to the poultry industry across the globe. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression post transcriptionally by silencing or degrading their targets, thus playing important roles in the host response to pathogenic infection. However, the role of miRNAs in host response to ARV infection is still not clear. Here, we show that infection of DF-1 cells (a chicken fibroblast cell line) with ARV markedly altered the expressions of 583 chicken miRNAs(gga-miR), and that transfection of DF-1 cells with gga-miR-29a-3p, an upregulated miRNA in ARV-infected cells, significantly suppressed ARV-induced apoptosis via directly targeting Caspase-3, retarding ARV growth in cells. In contrast, knockdown of endogenous gga-miR-29a-3p in DF-1 cells by specific miRNA inhibitor enhanced ARV-induced apoptosis and increased the content and activity of caspase-3, facilitating viral growth in cells. Consistently, inhibition of Caspase-3 activity by inhibitors decreased viral titers in cell cultures. Thus, gga-miR-29a-3p plays an important antiviral role in host response to ARV infection by suppression of apoptosis via targeting Caspase-3. This information will further our understandings of how host cells combat against ARV infection by self-encoded small RNA and increase our knowledge of the role of microRNAs in host response to pathogenic infection.

BACKGROUND: Minimally invasive radical trachelectomy has emerged as an alternative to open radical hysterectomy for patients with early-stage cervical cancer desiring future fertility. Recent data suggest worse oncologic outcomes after minimally invasive radical hysterectomy than after open radical hysterectomy in stage I cervical cancer. OBJECTIVE: We aimed to compare 4.5-year disease-free survival after open vs minimally invasive radical trachelectomy. STUDY DESIGN: This was a collaborative, international retrospective study (International Radical Trachelectomy Assessment Study) of patients treated during 2005–2017 at 18 centers in 12 countries. Eligible patients had squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma; had a preoperative tumor size of ≤2 cm; and underwent open or minimally invasive (robotic or laparoscopic) radical trachelectomy with nodal assessment (pelvic lymphadenectomy and/or sentinel lymph node biopsy). The exclusion criteria included neoadjuvant chemotherapy or preoperative pelvic radiotherapy, previous lymphadenectomy or pelvic retroperitoneal surgery, pregnancy, stage IA1 disease with lymphovascular space invasion, aborted trachelectomy (conversion to radical hysterectomy), or vaginal approach. Surgical approach, indication, and adjuvant therapy regimen were at the discretion of the treating institution. A total of 715 patients were entered into the study database. However, 69 patients were excluded, leaving 646 in the analysis. Endpoints were the 4.5-year disease-free survival rate (primary), 4.5-year overall survival rate (secondary), and recurrence rate (secondary). Kaplan-Meier methods were used to estimate disease-free survival and overall survival. A post hoc weighted analysis was performed, comparing the recurrence rates between surgical approaches, with open surgery being considered as standard and minimally invasive surgery as experimental. RESULTS: Of 646 patients, 358 underwent open surgery, and 288 underwent minimally invasive surgery. The median (range) patient age was 32 (20–42) years for open surgery vs 31 (18–45) years for minimally invasive surgery (P=.11). Median (range) pathologic tumor size was 15 (0–31) mm for open surgery and 12 (0.8–40) mm for minimally invasive surgery (P=.33). The rates of pelvic nodal involvement were 5.3% (19 of 358 patients) for open surgery and 4.9% (14 of 288 patients) for minimally invasive surgery (P=.81). Median (range) follow-up time was 5.5 (0.20–16.70) years for open surgery and 3.1 years (0.02–11.10) years for minimally invasive surgery (P

Smart city construction has penetrated all aspects of human life. People can continue to feel the convenience of life brought by new technologies and new services. In order to further optimize the smart city system, aiming at the sparsity of scoring data and the difficulty of two-way decisions to deal with uncertain decisions in the recommendation algorithm, a three-way Naive Bayesian Collaborative Filtering Recommendation model (3NBCFR) for smart city is constructed by integrating Naive Bayesian, three-way decisions and collaborative filtering algorithm. Firstly, we consider the influence of item attributes on user scoring. Naive Bayesian classifier is used to score unrated items, which can effectively fill in the missing values in the score matrix and solve the problem of data sparsity. Secondly, to ensure sustainable recommendations for uncertain goals, the three-way decisions is introduced into the collaborative filtering recommendation system, three-way recommendation rules are formulated, and 3NBCFR is constructed. Finally, the model is applied to the movie recommendation system. The experiment on Movielens shows that compared with the traditional collaborative filtering recommendation algorithm, 3NBCFR algorithm reduces the recommendation cost and improves the recommendation quality. At the same time, it lays a foundation for promoting the construction of smart city.

Extraintestinal pathogenic Escherichia coli (ExPEC) are important human pathogens responsible for urinary tract infection and meningitis. Therefore, infection of chickens by highly pathogenic E. coli with multi-drug resistance has become a major concern to food safety. In this study, we isolated a strain of E. coli (HB2016) from the oviduct of a diseased chicken with colibacillosis. Inoculation of chickens with 2 × 106 CFU of the isolate E. coli HB2016 by intraperitoneal injection successfully reproduced colibacillosis in chickens. We also found that E. coli HB2016 harbored four more virulence genes (tsh, trat, cvaC and cvaA/B) than E. coli reference strain CVCC1428. Importantly, E. coli HB2016 was resistant to cefuroxime, tobramycin, medemycin, cefazolin, cefoperazone, streptomycin and ampicillin, and carried multiple antibiotic resistance genes such as strA, strB, blaCMY-2, blaCTX-M-19, blaTEM-1B, fosA, mph(A), floR, sul2, tet(A) and tet(B). These findings suggest that the causative E. coli act as a potential zoonotic agent affecting human health.

Objective To report the reproductive and obstetric outcomes of patients undergoing abdominal radical trachelectomy (ART) for the treatment of early-stage cervical cancers in Fudan, China. Methods We retrospectively reviewed a prospectively collected database of 360 patients with stage IA1-IB1 cervical cancers who underwent ART between 2004 and 2018. Results Overall, 211 women (58.6%) did not plan to get pregnant immediately after ART, and 89.6% of them were due to childbearing before surgery or unmarried. Among 149 women who attempted to conceive, 26 (17.4%) of them achieved 30 pregnancies. Eighty-six patients (57.7%) had infertility problems, 44 attempted to conceive with assisted reproductive technologies, and 12 (27.3%) succeeded. Post-operative cervical stenosis (26, 27.4%) and fallopian tube obstruction (22, 23.2%) were the most common reasons for infertility after surgery. Among the patients who conceived, there were 3 first-trimester miscarriages, 6 second-trimester miscarriages, and 2 elective terminations. A total of 19 pregnancies reached the third trimester, and 84.2% of them ended after 36 weeks. Twelve of 20 cases in patients with cerclage placed had full-term birth, while 3 of 5 patients without cerclage placed suffered from second-trimester miscarriage or preterm birth. Conclusions Immediately after ART, many patients were reluctant to conceive, while others suffered from cervical stenosis or fallopian tube obstruction, which had led to low pregnancy rate. Pregnant patients might experience miscarriage or preterm labor which could be prevented by cervical cerclage. Assisted reproductive technology should be encouraged to improve obstetric outcomes.

A new bilayer chiral stationary phase for use in open tubular capillary electrochromatography (OT-CEC) system is described. Gold nanoparticles were modified with L-cysteine, with a tetramethylammonium lactobionate ionic liquid that acts as the chiral selector. The gold nanoparticle-coated column provides good enantioseparation and favorable reproducibility. Compared with an uncoated separation system, the column developed displays improved separation of the racemic β-blockers propranolol, esmolol, bisoprolol and sotalol (resolutions of enotiomers are 6.29, 6.11, 6.12 and 6.02, respectively). The materials and coatings were characterized by scanning electron microscopy and transmission electron microscopy. The main driving forces (CEC and electro-osmotic flow) were studied to evaluate the variation of the immobilized columns. The effects of buffer pH value, concentration of chiral selector, type of organic modifier and applied voltage were optimized. Satisfactory relative standard deviations were achieved in run-to-run, day-to-day and column-to-column experiments. Graphical abstractSchematic preparation of a capillary column with bilayer chiral selectors coated gold nanoparticles. This novel OT-CEC system was applied for separation of four basic racemic β-blockers.

In this paper, highly uniform and band gap tunable CH3NH3PbI3-xBrx perovskite film was successfully prepared by a polymer blends (Polyvinyl Pyrrolidone/polyethylene glycol) modified sequential deposition method in ambient atmosphere. Moreover, the influences of the Br content on the surface morphology, structure, optical absorption and luminescence properties of CH3NH3PbI3-xBrx films and the photovoltaic performance of the corresponding perovskite solar cells based on ZnO-TiO2 nanorod arrays were investigated. The results revealed that introducing bromine ion can decrease the convert rate from PbI2 to CH3NH3PbI3. Furthermore, bromine doping can expand the bang gap of the CH3NH3PbI3, which is benefit to the improvement of open-circuit voltage. The CH3NH3PbI3-xBrx perovskite solar cell shows the best device performance with an open-circuit voltage (Voc) of 0.87 V, a short-circuit current density (Jsc) of 17.41 mA/cm2, fill factor (FF) of 0.6 and power conversion efficiency of 9.12% when the molar ratio of PbBr2/PbI2 = 15/85.

MicroRNAs (miRNAs), as post-transcriptional regulators, play important roles in the process of viral infection through inhibiting virus replication or modulating host immune response. However, the role of miRNAs in host response against infectious bursal disease virus (IBDV) infection is still unclear. In this study, we found that gga-miR-454 of the host was decreased in response to IBDV infection and that transfection of DF-1 cells with miR-454 inhibited IBDV replication via directly targeting the specific sequence of IBDV genomic segment B, while blockage of endogenous miR-454 by inhibitors enhanced virus replication. Furthermore, gga-miR-454 increased the expression of IFN-β by targeting Suppressors of Cytokine Signaling 6 (SOCS6), enhancing the antiviral response of host cells. These findings highlight a crucial role of gga-miR-454 in host defense against IBDV infection.

Six new cyclopentenone derivatives (+)-nigrosporione A (+)-1, (-)-nigrosporione A (-)-1, nigrosporione B (2), nigrosporione C (3), (+)-nigrosporione D (+)-4, and (-)-nigrosporione D (-)-4 were isolated from an endophytic fungus Nigrospora sphaerica ZMT05, collected from the rice grasshopper ( Oxya chinensis Thunberg), which is an insect pest in rice and which is also used as a food for people in some countries. Their planar and spatial structures were determined by spectroscopic analyses and eletronic circular dichroism (ECD) calculations. Compounds (+)-1, (-)-1, and 2 inhibited the plant pathogens Fusarium oxysporum, Colletotrichum musae, Penicillium italicum, and Fusarium graminearum, compounds 3 and (-)-4 inhibited F. oxysporum, C. musae, and P. italicum, and compound (+)-4 inhibited F. oxysporum, C. musae, and F. graminearum, showing antifungal activities stronger than triadimefon. Additionally, compounds (+)-1, (-)-1, 2, and 3 displayed moderate antibacterial activities against Staphyloccocus aureus and Escherichia coli.

Viruses have developed a variety of methods to evade host immune response. Our previous study showed that infectious bursal disease virus (IBDV) inhibited type I interferon production via interaction of VP4 with cellular glucocorticoid-induced leucine zipper (GILZ) protein. However, the exact underlying molecular mechanism is still unclear. In this study, we found that IBDV VP4 suppressed GILZ degradation by inhibiting K48-linked ubiquitylation of GILZ. Furthermore, mutation of VP4 (R41G) abolished the inhibitory effect of VP4 on IFN-β expression and GILZ ubiquitylation, indicating that the amino acid 41R of VP4 was required for the suppression of IFN-β expression and GILZ ubiquitylation. Moreover, IBDV infection or VP4 expression markedly inhibited endogenous GILZ ubiquitylation. Thus, IBDV VP4 suppresses type I interferon expression by inhibiting K48-linked ubiquitylation of GILZ, revealing a new mechanism employed by IBDV to suppress host response.

Infectious bursal disease (IBD) is an acute, highly contagious, and immunosuppressive avian disease caused by IBD virus (IBDV). IBDV VP3 is a multifunctional protein playing a key role in virus assembly and pathogenesis. To investigate the role of VP3 in pathogenesis, we transfected DF-1 cells with pRK5-FLAG-vp3 and found that VP3 enhanced type I interferon expression and suppressed IBDV replication. Furthermore we found that VP3 interacted with chicken Ribosomal Protein L18 (chRPL18) in host cells and knockdown of chRPL18 by RNAi significantly promoted Type I interferon expression and inhibited IBDV replication. Moreover, our data show that chicken double-stranded RNA-activated protein kinase (chPKR) interacted with both VP3 and chRPL18. Thus chRPL18 in association with VP3 and chPKR affects viral replication.

A thorough understanding of supercritical CO2 (scCO2) transport through nanochannels is of prime significance for the effective exploitation of shale resources and the mitigation of greenhouse gas emission. In this work, we employed the non-equilibrium molecular dynamics simulations method to investigate the pressure-driven scCO2 transport behavior through silica nanochannels with different external forces and pore sizes. The simulations reveal that the capability of scCO2 diffusion enhances both in the bulk region and the surface adsorbed layer with the increasing of pressure gradient or nanochannel size, in addition, the slip length increases nonlinearly with the external acceleration or nanochannel width increases and finally reaches a maximum value. The negative slippage occurs at lower pressure gradient or within the narrower nanochannel. Overall, it is the combined effect of strong adsorption, surface diffusion and slippage that causes the nonlinear relation between flow rate and pressure gradient or nanochannel size. The present work would provide theoretical guidance for the scCO2 enhanced shale oil/gas recovery, CO2 storage, and mass transport in nanoporous materials.

X-ray photoelectron (XPS) and near-edge X-ray absorption fine structure (NEXAFS) spectra as well as the ground-state electronic/geometrical structures of #540C54 captured in experiment and the most controversial isomer #369C54 (C2v- and Cs-symmetry, respectively) have been calculated at the density functional theory (DFT) level. After chlorination, significant changes were observed in the electronic structure and X-ray spectra. Both XPS and NEXAFS spectra showed strong isomer dependence. The results indicated that the “fingerprints” in the X-ray spectra afforded an effective way to identify the fullerene isomers mentioned above. Ultraviolet-visible (UV-Vis) absorption spectroscopy of C54Cl8 was also simulated at the time-dependent (TD) DFT level, and the simulated UV-Vis spectrum was in accordance with the experimental result. The results of this study can provide valuable information for further experimental and theoretical studies of new fullerenes and their derivatives through X-ray and ultraviolet spectroscopy. The study of newly synthesized fullerene isomers and their derivatives using X-ray and UV-Vis spectra offers valuable information for further experimental and theoretical exploration.

Glutathione (GSH) is the most abundant intracellular thiol with the concentration in the millimolar range. It has also been reported that GSH plays a crucial role in human pathologies, so it is meaningful to develop an effective probe for GSH. In this work, we report a coumarin-chlorine malononitrile “off-on” sensor for highly selective fluorescence detection of GSH over Cys/Hcy. The chlorine of the probe can be rapidly replaced by thiolates of biothiols through thiol-halogen nucleophilic substitution. The amino groups of Cys/Hcy but not GSH further replace the thiolate to form amino-substituted compound. Subsequently, an intramolecular Michael addition between the α, β -unsaturated malonitrile and thiol group may occur. However, GSH only forms thiol-substituted compound. The significantly different mechanisms enable the discrimination of GSH over Cys/Hcy through fluorescence response. Finally, fluorescence imaging of A549 cells indicated that probe 1 could be used for monitoring GSH in living cells. It would be a useful tool to understand the mechanisms of many related diseases.

The configurational temperature and translational and rotational granular temperatures of particles are simulated using CFD-DEM in a flat bottomed spout bed. The distributions of velocity and volume fraction of particles are obtained in the bed. The translational and rotational granular temperatures are calculated from simulated instantaneous translational and angular velocities of particles. The statistical framework is proposed to define the configurational temperature or compactivity of particles in a flat bottomed spout bed. The configurational temperatures of particles are calculated from simulated instantaneous overlaps of particles. The configurational temperatures are larger at high solids volume fraction than that at low solids volume fractions. The simulated translational and rotational granular temperatures decrease with the increase of solids volume fractions. The predicted configurational temperatures are larger than that translational and rotational granular temperature, indicating that the rate of energy dissipation does contribute by deformation of elastic particles in a flat bottomed spout bed. The lower rotational granular temperature means the translational mechanism dominates the flow behaviors of particles. The influence of air jet velocity on granular temperatures and configurational temperature is analyzed. Increasing air jet velocity, the translational and rotational granular temperatures and configurational temperature are increased.

Background:Radiographic-axial spondyloarthritis (r-axSpA) is a progressive chronic inflammatory disease primarily affecting the spine and sacroiliac joints. However, about 30-40% of patients (pts) with axSpA can have peripheral joint involvement, including joint tenderness and swelling, which can contribute significantly to burden of disease. Ixekizumab (IXE), a monoclonal antibody that neutralizes the pro-inflammatory cytokine interleukin-17A, has demonstrated a high level of efficacy in the treatment of r-axSpA.Objectives:The aim of this study is to evaluate the efficacy of IXE through 52 weeks (wks) in improving peripheral joint pain and swelling for pts with r-axSpA.Methods:Data was derived from two phase III randomised, double-blind, placebo (PBO)-controlled trials: one in pts with r-axSpA, who were biological disease-modifying anti-rheumatic drug (bDMARD)-naïve (COAST-V: NCT02696785), and the other in pts who were tumor necrosis factor inhibitor-experienced (COAST-W: NCT02696798). All pts had a confirmed diagnosis of r-axSpA and had to meet ASAS (Assessment of SpondyloArthritis international Society) criteria. IXE (80 mg) or PBO were administered subcutaneously every 2 (Q2W) or 4 (Q4W) wks during a 52-wk treatment period, after receiving a starting dose of 80 mg or 160 mg at wk 0. COAST-V/W pts originally randomised to PBO were re-randomised 1:1 to IXE Q4W or Q2W at wk 16. We present a post-hoc analysis of data from an integrated dataset from COAST-V and W (COAST-V/W); with intent to treat (ITT) pts categorized by baseline (BL) peripheral joint status. The presence of peripheral joint involvement was defined using a 46-joint tender joint count (TJC) >0 or 44-joint swollen joint count (SJC) >0. Treatment response through wk 52 was evaluated based on % improvement (20%, 50% or 70%) and resolution of tender or swollen joints of pts with BL TJC>0 or SJC>0, respectively. Missing data were imputed by non-responder imputation (NRI). Treatment comparison vs PBO at wk 16 was performed using Cochran-Mantel-Haenszel test.Results:This analysis includes 359 pts (63.4% of ITT) with baseline TJC>0 and 203 pts (35.9% ITT) with baseline SJC>0. The mean (SD) baseline TJC and SJC were 7.7 (8.3) and 4.3 (4.5), respectively. Mean BL TJC and SJC values by treatment group are presented in Table 1. A significant improvement of SJC by 20% and 50% was seen in pts treated with IXE Q4W compared to PBO at wk 16. Pts treated with IXE resulted in a numerically higher improvement in TJC and SJC symptoms up to wk 16 compared to PBO, and efficacy was sustained up to wk 52 (Table 1). A higher proportion of IXE-treated pts achieved high-hurdle efficacy endpoints (50% and 70% improvements) in comparison to PBO at wk 16 (Table 1). Over this time period, IXE treatment led to a high proportion of pts experiencing complete resolution of TJC or SJC vs PBO at wk 16, which was sustained up to wk 52 (Fig 1).Conclusion:In this post hoc analysis, pts with r-axSpA treated with IXE showed substantial improvement in peripheral joint pain and swelling.Table 1.Improvement of Tender or Swollen Joint Counts for pts with radiographic-axSpA with TJC>0 or SJC>0 at baseline (COAST-V/W)a - NRI Results% ImprovementRadiographic-AxSpAWk1652bPBOIXE Q4WIXE Q2WIXE Q4WIXE Q2WN (TJC>0)116129114129114BL TJC mean (SD)7.4 (8.8)8.4 (8.4)7.3 (7.5)%TJC improvement20%66.475.271.168.272.850%52.661.264.9*65.167.570%37.947.35055.854.4N (SJC>0)6772647264BL SJC mean (SD)3.8 (4.6)5.2 (5.2)3.8 (3.3)%SJC improvement20%64.283.3*76.677.878.150%56.777.8†70.37576.670%46.362.560.969.471.9Abbreviations: COAST-V/W= integrated COAST-V and COAST-W; PBO = placebo; IXE= ixekizumab; Q4W = 80 mg IXE every 4 wks; Q2W = 80 mg IXE every 2 wksaImprovement in the number of tender or swollen joints were summarized on ITT patients who had tender (TJC>0) or swollen (SJC>0) joints at baseline, respectivelybCOAST-V/W PBO data are not available at wk 52 as pts originally randomised to PBO were re-randomised 1:1 to IXE Q4W or IXE Q2W at wk 16p-value vs. PBO at wk 16: *PAcknowledgements:Writing support was provided by Sinéad O’ Loughlin, an employee of Eli Lilly and CompanyDisclosure of Interests:Marina Magrey Consultant of: Novartis, UCB, Pfizer, Eli Lilly, Abbvie, Janssen, Kurt de Vlam Speakers bureau: UCB, Novartis, Pfizer, Eli Lilly, Amgen, Celgene, Paid instructor for: UCB, Amgen, Celgene, Consultant of: UCB, Novartis, Pfizer, Eli Lilly, Amgen, Celgene, Grant/research support from: Pfizer, Amgen, Celgene, Andris Kronbergs Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Rebecca Bolce Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, David Sandoval Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Xiaoqi Li Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Soyi Liu Leage Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Denis Poddubnyy Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Biocad, Gilead, GlaxoSmithKline, Eli Lilly, MSD, Novartis, Pfizer, Samsung Bioepis, and UCB, Grant/research support from: AbbVie, Eli Lilly, MSD, Novartis, and Pfizer

Purpose Previous work by our group has demonstrated the value of N-methyl-N-nitrosourea (MNU)-induced corneal endothelial decompensation in animal models. The aim of this study was to investigate the effect of molecular hydrogen (H2) on MNU-induced corneal endothelial cell (CEC) injury and the underlying mechanism. Methods MNU-induced animal models of CEC injury were washed with hydrogen-rich saline (HRS) for 14 days. Immunofluorescence staining, immunohistochemical staining, and corneal endothelial assessment were applied to determine architectural and cellular changes on the corneal endothelium following HRS treatment. MNU-induced cell models of CEC injury were co-cultured with H2. The effect of H2 was examined using morphological and functional assays. Results It was shown that MNU could inhibit the proliferation and specific physiological functions of CECs by increasing apoptosis and decreasing the expression of ZO-1 and Na+/K+-ATPase, whereas H2 improved the proliferation and physiological function of CECs by anti-apoptosis. Cell experiments further confirmed that H2 could reverse MNU damage to CECs by decreasing oxidative stress injury, interfering with the NF-κB/NLRP3 pathway and the FOXO3a/p53/p21 pathway. Conclusions This study suggests that topical application of H2 could protect CECs against corneal damage factors through anti-apoptotic effect, reduce the incidence and severity of corneal endothelial decompensation, and maintain corneal transparency.

As a novel separation mode of capillary electrophoresis (CE), liposome electrokinetic capillary chromatography (LEKC) has aroused considerable attention in recent years; however, the enantioseparation based on this new system has not been previously investigated. In this study, we proposed a brand-new LEKC chiral separation approach using liposomes comprised of phosphatidylcholine (PC) and cholesterol as pseudo-stationary phase and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) as chiral selector. Compared with the single CD system and CD-SDS-MEKC system, this LEKC method presented an obviously preferable enantioseparation of four model drugs (naproxen, warfarin, ketoprofen and amlodipine). In this new established system, all the enantiomers represented baseline separations with the resolution and selectivity respectively achieving 1.584/1.067 (for naproxen), 2.226/1.045 (for warfarin), 1.537/1.038 (for ketoprofen) and 2.592/1.097 (for amlodipine), while other two comparative systems demonstrated no separation or a poor separation. Several important parameters affecting the enantioseparation, such as buffer pH, concentration of liposomes, phosphate buffer solution (PBS) and chiral selector (SBE-β-CD), and applied voltage were systematically investigated. Satisfactory repeatability was achieved through intra-day, inter-day and batch-to-batch investigations with relative standard deviations less than 3.40%. Furthermore, the established method was successfully applied to test the chiral impurity of naproxen sample.

Alzheimer’s disease is still incurable and neurodegenerative, and there is a lack of detection methods with high sensitivity and specificity. In this study, by taking different month old Alzheimer’s mice as models, we have explored the possibility of the target bioimaging of diseased sites through the initial injection of zinc gluconate solution into Alzheimer’s model mice post-tail vein and then the combination of another injection of ferrous chloride (FeCl2) solution into the same Alzheimer’s model mice post-stomach. Our observations indicate that both zinc gluconate solution and FeCl2 solution could cross the blood–brain barrier (BBB) to biosynthesize the fluorescent zinc oxide nanoclusters and magnetic iron oxide nanoclusters, respectively, in the lesion areas of the AD model mice, thus enabling high spatiotemporal dual-modality bioimaging (i.e., including fluorescence bioimaging (FL) and magnetic resonance imaging (MRI)) of Alzheimer’s disease for the first time. The result presents a novel promising...

Introduction The SAMe-TT 2 R 2 score has been proposed to predict whether patients with atrial fibrillation (AF) would be well anti-coagulated with warfarin or not. However, it might over-estimate the number of patients under suboptimal warfarin treatment in non-Caucasians. This study was designed to modify the SAMe-TT 2 R 2 score with genotypes and validate it in Chinese AF patients treated with warfarin. Material and methods Consented Chinese-Han patients (n=510) with AF under the treatment of warfarin for at least 3months were randomly divided into a derivation (n=310) and a validation cohort (n=200). For each patient, CYP2C9*3 and VKORC1 −1639 A/G genotyping was performed, and the time in therapeutic range (TTR) was calculated over this period. Results The modified SAMe-TT 2 R 2 score was established by adding "warfarin genotype bins" to replace "the non-white race" variable. In the validation cohort, the discrimination performance of the modified score for good anticoagulation control (TTR≥70%) was significantly improved (c- index increased from 0.60 to 0.67). Significantly increased risks of major bleedings (HR: 4.91; 95% CI: 1.03–23.37; adjusted p=0.04) and all bleedings (HR: 1.93; 95% CI: 1.14–3.25; adjusted p=0.01) were found in patients with modified scores ≥2, as compared with patients with modified scores of 0–1. Conclusions The modified SAMe-TT 2 R 2 score could improve the ability for the identification of good anticoagulation control, and the prediction of major bleeding events in Chinese patients with AF treated by warfarin.

In daily life, sulfite and bisulfite have been extensively used as antimicrobial agent and antioxidant for food products, beverages and pharmaceutical products, but, SO32−/HSO3− are fantastically harmful to human health, so it is meaningful to develop an effective probe for these two anions. In this work, a new fluorescent material probe 1 was designed and constructed, which was able to sense sulfite and bisulfite through fluorescence “turn-on” manner. Compared with correlative fourteen other anions used, probe 1 showed great selectivity toward sulfite or bisulfite. Furthermore, the probe can detect SO32−/HSO3− with fast response (within 4 min) as well as low detection limit (8.8 nM) compared with the previous work. We characterized the adduct through NMR and X-ray diffraction analysis and further confirmed the detection mechanism of probe 1. Finally, fluorescence imaging of MCF-7 cells indicated that 1 could be used for monitoring SO2 derivatives in living cells with low cytotoxicity.

Composite-metal joints with a metal insert are one kind of connecting structure. In this paper, tensile experimental tests were carried out to investigate tensile properties of a composite-metal joint with a novel metal insert design. Finite element models of the joint were established, and strain distribution and tensile strength were analyzed. The numerical results are in good agreement with the experimental results. Results show that the joint failure is dominated by shear properties of the resin layer. Increasing the resin layer thickness in a certain range will improve the tensile strength of the joint, while increasing the radius of the fillet on the ending side of the metal insert will decrease the joint strength. Increasing the resin layer plasticity will improve the joint strength. The effect of the embedded depth of the metal insert can be ignored.

To avoid unresponsiveness, Android developers utilize asynchronous programming to schedule long-running tasks in the background. In this work, we conduct a systematic study on IntentService, one of the async constructs provided by Android using static program analysis, and find that in Android 6, 974 intents can be sent by third-party applications without protection. Based on this observation, we develop a tool, ATUIN, to demonstrate the feasibility of attacking a CPU automatically by exploiting the intents that can be handled by an Android system. Furthermore, by investigating the unprotected intents, we discover tens of critical vulnerabilities that have not been reported before, including Wi-Fi DoS, telephone signal blocking, SIM card removal, homescreen hiding, and NFC state cheating. Our study sheds light on research into protecting asynchronous programming from being exploited by hackers.

Early diagnosis remains highly important for efficient cancer treatment, and hence, there is significant interest in the development of effective imaging strategies. This work reports a new multimodal bioimaging method for accurate and rapid diagnosis of cancer cells by introducing aqueous Fe2+ and Zn2+ ions into cancer cells (i.e., HeLa, U87, and HepG2 cancer cells). We found that the biocompatible metal ions Fe2+ and Zn2+ forced the cancer cells to spontaneously synthesize fluorescent ZnO nanoclusters and magnetic Fe3O4 nanoclusters. These clusters could then be used for multimodal cancer imaging by combining fluorescence imaging with magnetic resonance imaging and computed tomography imaging. Meanwhile, for normal cells (i.e., L02) and tissues, neither fluorescence nor any other obvious difference could be detected between preand post-injection. This multimodal bioimaging strategy based on the in situ biosynthesized Zn&Fe oxide nanoclusters might therefore be useful for early cancer diagnosis and therapy.

Background:Patients with ankylosing spondylitis (AS) are burdened with decreased work productivity.1Ixekizumab (IXE), a high-affinity monoclonal antibody selectively targeting interleukin-17A, has been shown to improve disease signs and symptoms in 2 phase 3 trials assessing patients with active AS.2, 3Objectives:This study investigated the effect of IXE treatment for 52 weeks on work productivity and activity impairment as measured by absenteeism, presenteeism, overall work impairment, and activity impairment in patients with active AS.Methods:COAST-V (NCT02696785) and COAST-W (NCT02696798) were phase 3, multicenter, randomized, double-blind, placebo (PBO)-controlled (COAST-V active-controlled with adalimumab) trials investigating the efficacy of IXE every 4 weeks (Q4W) and every 2 weeks (Q2W) in 341 patients with active AS naïve to biologic disease-modifying antirheumatic drugs (bDMARDs; COAST-V) and in 316 patients who were inadequate responders or intolerant to 1 or 2 tumor necrosis factor inhibitors (TNFi; COAST-W). Patients receiving PBO were switched to IXE Q4W or Q2W at Week 16; patients receiving adalimumab (ADA) were switched to IXE Q4W or Q2W at Week 20. Data for IXE Q4W and Q2W were combined for PBO/IXE and ADA/IXE groups. Changes from baseline in work productivity were measured for those reporting full- or part-time work at Weeks 16 and 52 with the Work Productivity and Activity Impairment (WPAI) Questionnaire for Spondyloarthritis.Results:Compared to bDMARD-naïve patients (COAST-V), TNFi-experienced patients (COAST-W) were slightly older, had longer disease duration, reported less paid employment, and had greater scores for impaired work productivity, signifying more severe baseline disease. At Week 16, bDMARD-naïve patients treated with IXE Q4W or Q2W had significant improvements in activity impairment compared to placebo (pConclusion:Both bDMARD-naïve and TNFi-experienced patients with AS receiving IXE had greater improvements in aspects of work productivity compared to placebo. Improvements were sustained through Week 52.References:[1]Boonen, van der Linden. (2006).J Rheumatol Suppl.78:4-11.[2]Van der Heijde, et al. (2018)Lancet. 392(10163):2441-51.[3]Deodhar, et al. (2019)Arthritis Rheumatol.71(4):599-611.Disclosure of Interests:Helena Marzo-Ortega Grant/research support from: Janssen, Novartis, Consultant of: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Speakers bureau: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Takeda, UCB, Philip J Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Janssen, Eli Lilly, Novartis, Pfizer, Sun Pharma, UCB Pharma, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer, Sun Pharma, UCB Pharma, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Novartis, Pfizer, UCB Pharma, Proton Rahman Grant/research support from: Janssen and Novartis, Consultant of: Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, and Pfizer., Speakers bureau: Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, Pfizer, Victoria Navarro-Compán Consultant of: Abbvie, Lilly, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, MSD, Lilly, Novartis, Pfizer, UCB, Vibeke Strand Consultant of: AbbVie, Amgen, Biogen, Celltrion, Consortium of Rheumatology Researchers of North America, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, UCB, Maxime Dougados Grant/research support from: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Speakers bureau: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, James Cheng-Chung Wei Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eisai, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, UCB Pharma, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Theresa Hunter Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, David Sandoval Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Xiaoqi Li Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Baojin Zhu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Louis Bessette Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sanofi, Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCBFigure.Changes from baseline in Overall Work Impairment in A) bDMARD-naïve (COAST-V) and B) TNFi-experienced (COAST-W) patients and Activity Impairment in C) bDMARD-naïve and D) TNFi-experienced patients.

The very close structural similarities between cysteine and homocysteine present a great challenge to achieve their selective detection using regular fluorescent probes, limiting the biological and pathological studies of these two amino thiols. A coumarin-based fluorescent probe was designed featuring pH-promoted distinct turn-on followed by ratiometric fluorescence responses for Cys and turn-on fluorescence response for Hcy through two different reaction paths. These specific responses demonstrate the activity differences between Cys and Hcy qualitatively for the first time. The probe could also be used for Cys and Hcy imaging in living cells.

Objectives To compare disease-free survival (DFS) between patients who underwent open (ORT) versus minimally invasive (MIS) radical trachelectomy (RT) [laparoscopic (LRT) or robotic (RRT)]. Methods Eligibility criteria included 1) RT and pelvic lymphadenectomy with/without sentinel lymph node mapping, 2) 1/2005 to 12/2017 3) squamous, adenocarcinoma, or adenosquamous histology, 4) stage IA2-IB1, 5) tumors ≤2 cm, 6) 15 or more cases per center. Results A total of 698 patients [open (n=388) vs. MIS (310)] were included. The median follow-up time was 40.9 months (range, 1–179.1) [MIS 38.6 (range, Conclusions Surgical approach in radical trachelectomy for low-risk cervical cancer was not associated with differences in recurrence rates or survival. MIS had worse perioperative outcomes.