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Background To determine the necessity of tourniquet use in arthroscopic meniscal repair by comparing outcomes including arthroscopic visibility, operative time, postoperative pain and subjective function of the knee joint. Methods This was a retrospective, single-centre, single-surgeon study. A total of 148 patients who underwent arthroscopic meniscal repair were allocated to the tourniquet group (n=82) or the nontourniquet group (n=66). The primary outcome measures were arthroscopic visibility and operative time. The secondary outcomes were postoperative pain measured by a visual analogue scale and subjective function of the knee joint measured by The International Knee Documentation Committee (IKDC) and Lysholm scores. Results The 2 groups did not differ in terms of age, male‒female ratio, body mass index, or operative side. There was no significant difference between the 2 groups regarding arthroscopic visibility and operative time. At 1 week postoperatively, the VAS score and Lysholm score of the nontourniquet group were better than those of the tourniquet group (P 0.05). Conclusions Tourniquet use for arthroscopic meniscal repair does not affect primary outcome or secondary outcomes. Based on the results of the analysis, the use of a tourniquet is no longer advisable for routine arthroscopic meniscal repair. Level of Evidence：LEVEL III

Brown and beige fat protect against cold environments and obesity by catabolizing stored energy to generate heat. This process is achieved by controlling thermogenesis-related gene expression and the development of brown/beige fat through the induction of transcription factors, most notably PPARγ. However, the cofactors that induce the expression of thermogenic genes with PPARγ are still not well understood. In this study, we explored the role of SOX4 in adaptive thermogenesis and its relationship with PPARγ.

BACKGROUND The misuse and overuse of antibiotics contribute to the acceleration of antimicrobial resistance (AMR), but public knowledge on appropriate antibiotic use and AMR remained low despite ongoing health promotion efforts. App gamification has gained traction in recent years for health promotion and to affect change in health behaviors. Hence, we developed an evidence-based serious game app “SteWARdS Antibiotic Defence” to educate the public on appropriate antibiotic use and AMR and address knowledge gaps. OBJECTIVE We aim to evaluate the effectiveness of the “SteWARdS Antibiotic Defence” app in improving the knowledge of, attitude toward, and perception (KAP) of appropriate antibiotic use and AMR among the public. The primary objective is to assess the changes in KAP of antibiotic use and AMR in our participants, while the secondary objectives are to assess the extent of user engagement with the app and the level of user satisfaction in using the app. METHODS Our study is a parallel 2-armed randomized controlled trial with a 1:1 allocation. We plan to recruit 400 participants (patients or their caregivers) aged 18-65 years from government-funded primary care clinics in Singapore. Participants are randomized in blocks of 4 and into the intervention or control group. Participants in the intervention group are required to download the “SteWARdS Antibiotic Defence” app on their smartphones and complete a game quest within 2 weeks. Users will learn about appropriate antibiotic use and effective methods to recover from uncomplicated upper respiratory tract infections by interacting with the nonplayer characters and playing 3 minigames in the app. The control group will not receive any intervention. RESULTS The primary study outcome is the change in participants’ KAP toward antibiotic use and AMR 6-10 weeks post intervention or 6-10 weeks from baseline for the control group (web-based survey). We will also assess the knowledge level of participants immediately after the participant completes the game quest (in the app). The secondary study outcomes are the user engagement level (tracked by the app) and satisfaction level of playing the game (via the immediate postgame survey). The satisfaction survey will also collect participants’ feedback on the game app. CONCLUSIONS Our proposed study provides a unique opportunity to assess the effectiveness of a serious game app in public health education. We anticipate possible ceiling effects and selection bias in our study and have planned to perform subgroup analyses to adjust for confounding factors. The app intervention will benefit a larger population if it is proven to be effective and acceptable to users. CLINICALTRIAL ClinicalTrials.gov NCT05445414; https://clinicaltrials.gov/ct2/show/NCT05445414 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/45833

Multiple genetic variants and their interplay with environmental factors have hindered the progress of mental disease research and the development of effective markers of neuropsychiatric disorders. Intermediate phenotypes like neuroimaging brain patterns offer unique opportunities to understand multifaceted etiologies of neuropsychiatric diseases such as depression. Neuroimaging intermediate phenotypes bridging etiologic differences and disease behavioral features may facilitate translational applications of animal models to humans with depression. We identified cross-species neuroimaging patterns of the amplitude of low-frequency fluctuations (ALFF) that correlated with anhedonia in rodent genetic and stress models of depression and depressed individuals. Compared to controls, converse ALFF patterns in subcortical and sensorimotor regions were found between P11 knockout mice and chronic unpredictable mild stress rats. Similarly, two ALFF subtypes with converse patterns in frontal, subcortical, and sensorimotor regions were identified and validated in two independent human cohorts for depression. Importantly, anhedonia was significantly increased across all rodent models and human subtypes when compared to controls, despite differences in ALFF patterns. Further, anhedonia correlated with subcortical-sensorimotor ALFF in rodent models and human cohorts. Thus, subcortical-sensorimotor ALFF may serve as an intermediate phenotype that bridges etiologic differences and anhedonia in depression. These results deepened our knowledge of disease mechanisms underlying depression which can be explored in translational research and clinical applications treating depression and other psychiatric disorders.

BackgroundUpper respiratory tract infections (URTIs) account for substantial non-urgent ED attendances. Hence, we explored the reasons for such attendances using a mixed-methods approach.MethodsWe interviewed adult patients with URTI who visited the second busiest adult ED in Singapore from June 2016 to November 2018 on their expectations and reasons for attendance. A structured questionnaire, with one open-ended question was used. Using the Andersen’s Behavioural Model for Healthcare Utilisation, the topmost reasons for ED attendances were categorised into (1) contextual predisposing factors (referral by primary care physician, family, friends or coworkers), (2) contextual enabling factors (convenience, accessibility, employment requirements), (3) individual enablers (personal preference and trust in hospital-perceived care quality and efficiency) and (4) individual needs (perceived illness severity and non-improvement). Multivariable multinomial logistic regression was used to assess associations between sociodemographic and clinical factors, patient expectations for ED visits and the drivers for ED attendance.ResultsThere were 717 patients in the cohort. The mean age of participants was 40.5 (SD 14.7) years, 61.2% were males, 66.5% without comorbidities and 40.7% were tertiary educated. Half had sought prior medical consultation (52.4%) and expected laboratory tests (55.7%) and radiological investigations (46.9%). Individual needs (32.8%) and enablers (25.1%) were the main drivers for ED attendance. Compared with ED attendances due to contextual enabling factors, attendances due to other drivers were more likely to be aged ≥45 years, had prior medical consultation and expected radiological investigations. Having a pre-existing medical condition (adjusted OR (aOR) 1.78, 95% CI 1.05 to 3.04) and an expectation for laboratory tests (aOR 1.64, 95% CI 1.01 to 2.64) were associated with individual needs while being non-tertiary educated (aOR 2.04, 95% CI 1.22 to 3.45) and having pre-existing comorbidities (aOR 1.79, 95% CI 1.04 to 3.10) were associated with individual enablers.ConclusionsMeeting individual needs of perceived illness severity or non-improvement was the topmost driver of ED visits for URTI, while contextual enabling factors such as convenience was the lowest. Patients’ sociodemographic and clinical factors and visit expectations influence their motivations for ED attendances. Addressing these factors and expectations can alleviate the overutilisation of ED services.

Organic-inorganic piezoelectric nanogenerators (PNGs) have attracted extensive attention for transforming mechanical energy into electricity in the field of self-powered wearables. Generally, the output electrical performance of PNGs can be enhanced by choosing various materials. Herein, the flexible PNG is fabricated by embedding the Sm-doped Pb(Mg1/3Nb2/3)O3–PbTiO3 (Sm-PMN-PT) polycrystalline piezoelectric ceramics into polyvinylidene fluoride-trifluoroethylene (P(VDF-TrFE)) composite film. The ceramics with high piezoelectric voltage coefficient g33 of Sm-PMN-PT are selected as piezoelectric fillers, and the silver nanowires (Ag NWs) with high aspect ratio are embedded as conductive fillers. The optimized electrical properties are achieved for the Ag NWs/15 wt%Sm-PMN-PT/P(VDF-TrFE) PNG, with the open-circuit voltage of up to 83.5 V and instantaneous power density of 7.48 μW/cm2. In particular, the good mechanical stability up to 6000 bending–releasing cycles are obtained after aging for two months. The finite element analysis is utilized to calculate the electric potential of piezoelectric composite materials. Moreover, the Ag NWs/15 wt%Sm-PMN-PT/P(VDF-TrFE) PNG could harvest mechanical energy from different types of human motion, such as taping, bending and pressing. All these results indicated that the Ag NWs/15 wt%Sm-PMN-PT/P(VDF-TrFE) PNG can serve as a promising candidate for the harvest mechanical energy in the surrounding environment.

A simplified bubble model and its solver optimization method are proposed to solve the problem of poor realistic simulation and complex solutions for bubble-motion behavior in water. Firstly, the internal velocity of the bubble was avoided, and the bubble model was established by only considering the net flux of the inlet and outlet bubbles, which reduced the computational complexity. The bubble constraint was then introduced into the motion equation of water, and the mixed Euler–Lagrangian method was used to solve it. FLIP particles tracked the bubble position, velocity, and deformation, and the mesh updated the vector field. At the same time, the viscosity term was simplified. Finally, it was combined with implicit incompressible SPH particles to achieve the purpose of volume correction. The experimental results show that the method in this paper can present a simulation effect of bubbles in water with rich detail and a realistic sense, whether compared with actual pictures or with existing methods.

Excessive amounts of molybdenum (Mo) and cadmium (Cd) are toxicant, but their combined immunotoxicity are not clearly understood. To estimate united impacts of Mo and Cd on pyroptosis and autophagy by PI3K/AKT axis in duck spleens, Mo or/and Cd subchronic toxicity models of ducks were established by feeding diets with different dosages of Mo or/and Cd. Data show that Mo or/and Cd cause oxidative stress by increasing MDA concentration, and decreasing T-AOC, CAT, GSH-Px and T-SOD activities, restrain PI3K/AKT axis by decreasing PI3K, AKT, p-AKT expression levels, which evokes pyroptosis and autophagy by elevating IL-1β, IL-18 concentrations and NLRP3, Caspase-1, ASC, GSDME, GSDMA, NEK7, IL-1β, IL-18 expression levels, promoting autophagosomes, LC3 puncta, Atg5, LC3A, LC3B, LC3II/LC3I and Beclin-1 expression levels, and reducing expression levels of P62 and Dynein. Furthermore, the variations of abovementioned indexes are most pronounced in co-treated group. Overall, results reveal that Mo or/and Cd may evoke pyroptosis and autophagy by PI3K/AKT axis in duck spleens. The association of Mo and Cd exacerbates the changes.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to a high rate of tumour metastasis and disease recurrence. In physiological conditions, tetraspanins interact with specific partner proteins in tetraspanin‐enriched microdomains and regulate their subcellular localization and function. However, the function of Tspan5 in pathological processes, particularly in cancer biology and its clinical significance, are still unclear. Here, we describe that a high expression of Tspan5 is significantly associated with some clinicopathological features including invasive length, vascular invasion, clinical stage and poor overall survival of HCC patients. Alterations of Tspan5 expression by lentivirus transductions in HCC cells demonstrated that Tspan5 promotes wound healing and cell migration in vitro and tumour metastasis of HCC cells in vivo. Mechanistic studies revealed that Tspan5 promoted cell migration and tumour metastasis by increasing the enzymatic maturation of ADAM10 and activating Notch signalling via the increase of the cleavage of the Notch1 receptor catalysed by the γ‐secretase complex. Activation of Notch signalling by Tspan5 was shown further to enhance the epithelial–mesenchymal transition (EMT) and actin skeleton rearrangement of tumour cells. In clinical HCC samples, Tspan5 expression is strongly correlated with many key molecules acting in Notch signalling and EMT, highlighting the role of Tspan5 in the regulation of Notch signalling, EMT and tumour metastasis of HCC. Our findings provide new insights into the mechanism of tumour metastasis and disease progression of HCC and may facilitate the development of novel clinical intervention strategies against HCC., We demonstrated that Tspan5 promotes the enzymatic maturation of ADAM10 and activates Notch signalling. The γ‐secretase complex catalyses the cleavage of Notch1 for the release of NICD, which is then translocated to the nucleus where it activates Notch target gene transcription. By activating Notch signalling, Tspan5 promoted epithelial–mesenchymal transition, actin skeleton rearrangement, tumour migration and metastasis of HCC, resulting in poor patient survival.

Flexible piezoelectric energy harvesters (PEHs) have attracted extensive interest because of their ability to transform mechanical energy into electric power. Here, PEHs were fabricated using P(VDF-TrFE)-based piezoelectric composite films containing lead zirconate titanate (PZT) powder and –OH-functionalized graphene (HOG) nanosheets (HOG-P/P). Among all composites, a high open-circuit voltage (Voc) of approximately 50 Vp-p and a maximum power density of 1.4 μW/cm2 were obtained from a HOG-P/P PEH with 0.10 wt% HOG nanosheets and 15 wt% PZT under bending–releasing mode. Moreover, the PEH exhibited a stable voltage output after 3000 bending–releasing cycles. In addition, the PEH harvested mechanical energy from human body movements and generated an output voltage and current of 60 V and 8 μA during the finger bending–releasing process, lighting up 30 commercial white LEDs. The enhanced piezoelectric performance can be attributed to the introduction of HOG nanosheets and PZT powder. This work provides an effective strategy for improving the output performance of P(VDF-TrFE)-based PEHs.

Aim Bone marrow mesenchymal stem cells (BMSCs) are ideal seed cells for tissue engineering cartilage construction. However, the underlying mechanism of it has not been illuminate well. In this study, the effects of circATRNL1 (hsa_circ_0020093) on the differentiation of BMSCs into chondrocytes were investigated. Methods The degrees of chondrogenic differentiation of BMSCs on day 0, 14 and 21 mediums were detected by Alcian blue staining. Expressions of cartilage differentiation related factors SOX9, COL2 and Aggrecan, and circATRNL1 in BMSCs under differentiation were determined by western blot and quantitative real-time polymerase chain reaction (qRT-PCR) as needed. circATRNL1 knockdown or overexpression was performed in BMSCs. Then the viability of BMSCs and cartilage differentiation related factors were separately investigated through MTT assay, qRT-PCR, and western blot. Target gene of circATRNL1 and binding site were predicted using starbase and validated it by dual luciferase reporter. The effect of circATRNL1 and its target gene on chondrogenic differentiation of BMSCs was assessed using Alcian blue staining further. Results The degrees of chondrogenic differentiation of BMSCs were increased with time. Expressions of SOX9, COL2 and Aggrecan as well as circATRNL1 were enhanced during chondrogenic differentiation. Furthermore, overexpression of circATRNL1 enhanced BMSCs proliferation, SOX9, COL2 and Aggrecan expressions and the degree of chondrogenic differentiation of BMSCs. Further research showed that circATRNL1 targeted miR-338-3p. MiR-338-3p inhibited differentiation of BMSCs into cartilage but overexpression of circATRNL1 reversed it. Conclusion CircATRNL1 is beneficial to BMSCs differentiation into cartilage by regulating miR-338-3p, which may be a new mechanism of action in the treatment of cartilage repair.

Redox-responsive colloidal mesoporous silica nanoparticles (CMS) drug delivery systems based on fluorescence resonance energy transfer (FRET) was successfully designed for targeting and real-time monitoring in potential cancer therapy. FRET-CMS indicated the typical type IV isotherm with uniform distribution and wormhole arrangement of mesopores. In vitro release studies indicate the redox-sensitive drug release behaviors. Furthermore, the release of entrapped drugs in real time is monitored by the changed FRET signals of FRET-CMS, which is effectively controlled due to the eliminating FRET with the dissociation of FRET donor–acceptor pair. Fluorescent images of cellular uptake and cell viability test revealed that FRET-CMS enhanced significantly 6-MP accumulation in Hela cells with CD44 receptor over-expressed compared to MCF-7 cells due to the existence of hyaluronic acid and subsequently induced selective cytotoxicity to Hela cells. The obtained results illustrate that FRET-CMS may be a promising nanocarrier for drug delivery systems in cancer therapy.

High molybdenum (Mo) and cadmium (Cd) are harmful to the body, but pulmonary toxicity induced by Mo and Cd co-exposure is unknown. To assess the combined impacts of Mo and Cd on fibrosis through M1 polarization in the lung of ducks, 80 healthy 8-day-old Shaoxing ducks (Anas platyrhyncha) were randomly assigned to 4 groups and fed with containing unequal doses of Mo or/and Cd diet. Lung tissues were collected on the 16th week. Results indicated that Mo or/and Cd significantly increased their contents in the lungs, and led to trace elements disorder and histological abnormality, and oxidative stress accompanied by promoting contents of H

In this work, a series of 7-azaindole analogs were designed by the bioisosteric principle based on the pharmacodynamic parent nucleus. Moreover, 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyrimidin-2-amine (compound P1) with the strongest interaction with colony-stimulating factor 1 receptor (CSF-1R) was screened by molecular docking. Compound P1 was successfully prepared by the six-step reaction with HPLC purity of 99.26 % and characterized by

The conversion of ecofriendly waste energy into useable electrical energy is of significant interest for energy harvesting technologies. Piezoelectric nanogenerators based on organic/inorganic hybrid materials are a key promising technology for harvesting mechanical energy due to their high piezoelectric coefficient and good mechanical flexibility. However, the negative piezoelectric effect of the polymer component in composite devices severely undermines its overall piezoelectricity, compromising the output performance of PVDF-based piezoelectric hybrid nanogenerators. Here, to conquer this, we report a two-step poling schedule to orient the dipoles of organic and inorganic components in the same direction. The optimized nanogenerator delivers a combination of high piezoelectric coefficient, great output performance, and remarkable stability. The isotropic piezoelectricity in the composite device collaborates to output a maximum voltage of 110 V and a power density of 7.8 μW cm

Cadmium (Cd) is detrimental to animals, but nephrotoxic effects of Cd on duck have not been fully elucidated. To evaluate the impacts of Cd on Ca homeostasis and autophagy via PLC-IP

Resolvin D1 (RvD1) suppresses inflammatory, postoperative, and neuropathic pain. The present study assessed the roles and mechanisms of RvD1 in mechanical allodynia after burn injury. A rat model of burn injury was established for analyses, and RvD1 was injected intraperitoneally. Pain behavior and the expression levels of spinal dorsal horn Iba-1 (microglia marker), GFAP (astrocyte marker), p-p38 mitogen-activated protein kinase (MAPK), brain-derived neurotrophic factor (BDNF), and tropomyosin-related kinase B (TrkB) were detected by behavioral and immunocytochemical assays. The results showed that RvD1 attenuated mechanical allodynia after burn injury, prevented microglial and astroglial activation, and downregulated p-p38 MAPK in microglia and BDNF/TrkB following burn injury. Similarly, inhibition of p38 MAPK and BDNF/TrkB signaling attenuated mechanical allodynia after burn injury. In addition, inhibition of p38 MAPK prevented spinal microglial activation and downregulated BDNF/TrkB following burn injury. Furthermore, inhibition of BDNF/TrkB signaling prevented spinal microglial activation and downregulated p-p38 MAPK within spinal microglia. Taken together, this study demonstrated that RvD1 might attenuate mechanical allodynia after burn injury by inhibiting spinal cord glial activation, microglial p38 MAPK, and BDNF/TrkB signaling in the spinal dorsal horn.

Excessive molybdenum (Mo) and cadmium (Cd) are deleterious to animals, but immunotoxicity co-induced by Mo and Cd remains unclear. To ascertain the confederate impacts of Mo and Cd on endoplasmic reticulum (ER) stress-mediated apoptosis by Helper T (Th) cells 1 polarization in the spleen of ducks, we randomly allocated forty 8-day-old Shaoxing ducks (Anas platyrhyncha) into 4 groups and reared them with having different doses of Mo and/or Cd basic diet. At the 16th week of the experiment, serum and spleen tissues were extracted. Data confirmed that Mo and/or Cd strikingly promoted their levels in spleen, caused histological abnormality and trace elements imbalance, and disrupted Th1/Th2 balance to divert toward Th1, then triggered ER stress by increasing three branches PERK/eIF2α/CHOP, IRE1/Caspase-12 and TRAF2/JNK signaling pathways-related genes mRNA and proteins levels, which stimulated apoptosis by elevating Bak-1, Bax, Caspase-9, Caspase-3 mRNA expression, and cleaved-Caspase-9/Caspase-9, cleaved-Caspase-3/Caspase-3 proteins expression as well as apoptosis rate, and decreasing Bcl-xL, Bcl-2 mRNA expression and Bcl-2/Bax ratio. Besides, the variation in combined group was most evident. Briefly, the study indicates that Mo and/or Cd exposure trigger ER stress-induced apoptosis via Th1 polarization in duck spleens, and its mechanism is somehow closely linked with the deposition of Cd and Mo, which may aggravate toxic damage to spleen.

Montmorillonite (MMT) clay modified with lanthanum (La) ions and Fe3O4 nanoparticles was proposed for the effective removal of phosphate ions from aqueous solution. Characterisation of the adsorbent using FTIR, SEM, XRD, XPS, XRF, BET and VSM techniques were carried out. The effects of initial phosphate concentration, contact time, dosage and pH on the phosphorus adsorption were investigated. La-MMT/Fe3O4 exhibited an excellent adsorption capacity of up to 14.35 mg/g, with 97.8% removal within 60 min. Langmuir isotherm model fits well with the equilibrium isotherm data, with a maximum adsorption capacity of 15.53 mg/g at room temperature. The kinetic study was well fitted with pseudo-second-order kinetics, and the adsorption rate was mainly controlled by liquid-film diffusion. The manufactured adsorbent was effectively regenerated using 0.1 M NaOH solutions, with 90.18% adsorption efficiency remaining after six adsorption/desorption cycles. These results demonstrate that La-MMT/Fe3O4 provides an example of regenerable high-performance adsorbents for removal of PO4 3− from wastewater.

Lead-free Na0.5K0.5NbO3 (KNN) piezoelectric ceramics is regarded as a potential candidate for PZT material, while high performance is difficult to be obtained due to its poor sinterability and non-stoichiometric component. In this work, oscillatory pressure-assisted hot pressing (OPAHP) is utilized to fabricate KNN ceramics with high density. The KNN ceramics sintered at 860 °C exhibits superior performance with piezoelectric parameter (d33) of 142 pC/N, electromechanical coupling factors (kp) of 0.41, and relative permittivity (eT33/e0) of 472–620. Additionally, hardness and flexural strength are measured as 3.55 GPa and 99.13 MPa, respectively. This work indicates that OPAHP technique is effective for fabricating KNN piezoelectric ceramics with high performance.

Our previous study indicated that Clock gene could affect the thrombotic potential. In this present study, we examined the differential expression of proteins in Clock knockdown mice’s plasma, incl...

A therapeutic nanoplatform with effective photothermal cancer treatment attracts enormous attention but still faces great challenges, such as a tedious preparation process, poor biocompatibility and low efficiency. In this study, we prepared Au/Bi2S3 nanoflowers (NFs) as high-performance cancer photothermal agents for the first time. This was achieved in a facile and mild way by using bovine serum albumin (BSA) as reducer and stabilizer. In this process, Bi3+ and Au3+ underwent in situ reduction and growth, and then formed flower-like Au/Bi2S3 nanocomposites. The results revealed that the as-prepared Au/Bi2S3 NFs with special morphology showed high stability, excellent biocompatibility and good photostability. Apart from these, it was also observed that the Au/Bi2S3 NFs can efficiently convert the near-infrared (NIR) light into heat leading to high performance in photothermal conversion efficiency (up to 58.34%), and then suppressed the growth of tumor cells under NIR laser irradiation. This work highlights the potential of Au/Bi2S3 NFs as photothermal agents for cancer ablation treatment in the future.

Background: Novel anti-tumor bioactivity compounds were designed by the strategy of modular hybridization with the bioactivity advantages of 5-fluorouracil and dithiocarbamate derivatives. Methods: A series of novel 5-fluorouracil-dithiocarbamate conjugates were synthesized, characterized and evaluated for their cytotoxic activities in vitro against B16, Hela and U87MG by MTT assay. Colony-formation, transwell migration, cell apoptosis and cell cycle distribution assays were performed to explore the anti-tumor activities and mechanism of conjugates for compounds P3 and P4. Conjugates, dithiocarbamate derivatives combined with copper ions and 5-fluorouracil were investigated by molecular docking. Results: The results of cytotoxicity assays illuminated that these conjugates had anti-tumor activity against B16, Hela and U87MG. Interestingly, the cytotoxicity of these conjugates was significantly increased when combined with copper ions, and compound P3 displayed better bioactivity compared to the other compounds. Conjugates might be metabolized in the cells to produce dithiocarbamates, and then metabolites formed complexes with copper ions, generating better anti-tumor effects. Molecular docking studies exhibited that compound P3 appeared the strongest interaction with the receptors 6CCY and 5T92. Conclusion: Compound P3 exhibited better anti-tumor bioactivity and might be emerged as the lead compound for the treatment of glioma. Further research in vivo will be performed in our following work. result: The results of cytotoxicity assays illuminated that these conjugates had anti-tumor activity against B16, Hela and U87MG. Interestingly, the cytotoxicity of these conjugates was significantly increased when combined with copper ions and compound P3 displayed better bioactivity compared to the other compounds. Conjugates might be metabolized in the cells to produce dithiocarbamates, then metabolites formed complexes with copper ions, generating better anti-tumor effects. Molecular docking studies exhibited that compound P3 appeared the strongest interaction with the receptors 6CCY and 5T92. other: None

The motivations that govern the adoption of digital contact tracing (DCT) tools are complex and not well understood. Hence, we assessed the factors influencing the acceptance and adoption of Singapore's national DCT tool - TraceTogether - during the COVID-19 pandemic. We surveyed 3943 visitors of Tan Tock Seng Hospital from July 2020 to February 2021 and stratified the analyses into three cohorts. Each cohort was stratified based on the time when significant policy interventions were introduced to increase the adoption of TraceTogether. Binary logistic regression was preceded by principal components analysis to reduce the Likert items. Respondents who 'perceived TraceTogether as useful and necessary' had higher likelihood of accepting it but those with 'Concerns about personal data collected by TraceTogether' had lower likelihood of accepting and adopting the tool. The injunctive and descriptive social norms were also positively associated with both the acceptance and adoption of the tool. Liberal individualism was mixed in the population and negatively associated with the acceptance and adoption of TraceTogether. Policy measures to increase the uptake of a national DCT bridged the digital divide and accelerated its adoption. However, good public communications are crucial to address the barriers of acceptance to improve voluntary uptake widespread adoption. Nanyang Technological University Published version This project is supported by the NISTH Seed Grant from the NTU Institute of Science and Technology for Humanity, Nanyang Technological University.

Cadmium (Cd) and excess molybdenum (Mo) have multiple organ toxicity, and testis is one of their important target organs, but the reproductive toxicity of Mo and Cd combined treatment is still unclear. To explore the effects of Mo and Cd co-exposure on DNA damage and autophagy from the insight of ATM/AMPK/mTOR axis in duck testes, we randomly assigned 40 healthy 8-day-old ducks to control, Mo (100 mg/kg Mo), Cd (4 mg/kg Cd), and Mo + Cd groups for 16 weeks. Results found that Mo and/or Cd exposure caused trace elements imbalance, oxidative stress with a decrease in the activities of GSH-Px, CAT, T-SOD and GSH content, an increase in the concentrations of H

To effective capture and universal enrichment of His-tagged protein, polyacrylic acid (PAA) brushes were used to encapsulate Fe3O4 nanoparticles, connect NTA, and Ni2+ to prepare magnetic beads. These materials provide many advantages, such as excellent stability, tuneable particle size, and a surface for further functionalisation with biomolecules. His-tagged green fluorescence protein (GFP) was separated efficiently, and the binding capacity of Fe3O4/MPS@PAA/NTA-Ni2+ was 93.4 mg/g. Compared with High-Affinity Ni-NTA Resin and Ni-NTA Magnetic Agarose Beads, Fe3O4/MPS@PAA/NTA-Ni2+ nanocomposites exhibited higher separation efficiency and binding capacity towards His-tagged GFP. Moreover, the selectivity and recyclability of them for the target proteins were maintained well after six cycles. This study would widen the application of PAA in constructing multifunctional nanocomposites for biomedical fields.

Aberrant activation of EGFR due to overexpression or mutation is associated with poor prognosis in many types of tumors. Here we show that blocking the sorting system that directs EGFR to plasma membrane is a potent strategy to treat EGFR-dependent tumors. We find that EGFR palmitoylation by DHHC13 is critical for its plasma membrane localization and identify ARF6 as a key factor in this process. N-myristoylated ARF6 recognizes palmitoylated EGFR via lipid-lipid interaction, recruits the exocyst complex to promote EGFR budding from Golgi, and facilitates EGFR transporting to plasma membrane in a GTP-bound form. To evaluate the therapeutic potential of this sorting system, we design a cell-permeable peptide, N-myristoylated GKVL-TAT, and find it effectively disrupts plasma membrane localization of EGFR and significantly inhibits progression of EGFR-dependent tumors. Our findings shed lights on the underlying mechanism of how palmitoylation directs protein sorting and provide an potential strategy to manage EGFR-dependent tumors.

Antimicrobial stewardship programmes (ASPs) in hospitals are predominantly led by specific ASP physicians and pharmacists. Limited studies have been conducted to appreciate non-ASP-trained hospital pharmacists' perspectives on their roles in antimicrobial stewardship. Focus group discussions (FGDs) were conducted with 74 pharmacists, purposively sampled from the 3 largest acute-care public hospitals in Singapore, to explore facilitators and barriers faced by them in antimicrobial stewardship. Applied thematic analysis was conducted and codes were categorised using the social-ecological model (SEM). At the intrapersonal level, pharmacists identified themselves as reviewers for drug safety before dispensing, confining to a restricted advisory role due to lack of clinical knowledge, experience, and empowerment to contribute actively to physicians' prescribing decisions. At the interpersonal level, pharmacists expressed difficulties conveying their opinions and recommendations on antibiotic therapy to physicians despite frequent communications, but they assumed critical roles as educators for patients and their caregivers on proper antibiotic use. At the organisational level, in-house antibiotic guidelines supported pharmacists' antibiotic interventions and recommendations. At the community level, pharmacists were motivated to improve low public awareness and knowledge on antibiotic use and antimicrobial resistance. These findings provide important insights into the gaps to be addressed in order to harness the untapped potential of hospital pharmacists and fully engage them in antimicrobial stewardship. National Medical Research Council (NMRC) Published version This work was supported by the National Medical Research Council Singapore, Health Services Research Grant, Grant number: NMRC/HSRG/0083/2017).

Excessive molybdenum (Mo) and cadmium (Cd) are toxic environmental pollutants. Our previous research confirmed excessive Mo and Cd co-induced calcium homeostasis disorder and autophagy in duck kidneys, but how calcium ion (Ca

A sensitive unlabeled ratiometric biosensor was developed to the detection of cardiac troponin I (cTnI). This biosensor was established by using the glassy carbon electrode coated with graphene oxide to form a platform bonded with N, Zn co-doped graphene quantum dots (N, Zn-GQDs). The N, Zn-GQDs was successfully prepared as the raw materials of graphite powder and characterized. Antibodies of cTnI were bonded to the surface of N, Zn-GQDs as the nanoprobe by amide bonds. The signals of electrochemiluminescence (ECL) and differential pulse voltammetry (DPV) were exposed to decrease in the presence of cTnI, which caused the signal substance to move farther away from the electrode. It was found that the immune complex layer attenuated the intensity of ECL and DPV which could be used as the good overall signal for determining concentration of cTnI. The ratiometric biosensor had a good response to cTnI with the detection limit is 4.59 pg L

Background Singapore’s healthcare system presents an ideal context to learn from diverse public and private operational models and funding systems. Aim To explore processes underpinning decision-making for antibiotic prescribing, by considering doctors’ experiences in different primary care settings. Methods Thirty semi-structured interviews were conducted with 17 doctors working in publicly funded primary care clinics (polyclinics) and 13 general practitioners (GP) working in private practices (solo, small and large). Data were analysed using applied thematic analysis following realist principles, synthesised into a theoretical model, informing solutions to appropriate antibiotic prescribing. Results Given Singapore’s lack of national guidelines for antibiotic prescribing in primary care, practices are currently non-standardised. Themes contributing to optimal prescribing related first and foremost to personal valuing of reduction in antimicrobial resistance (AMR) which was enabled further by organisational culture creating and sustaining such values, and if patients were convinced of these too. Building trusting patient-doctor relationships, supported by reasonable patient loads among other factors were consistently observed to allow shared decision-making enabling optimal prescribing. Transparency and applying data to inform practice was a minority theme, nevertheless underpinning all levels of optimal care delivery. These themes are synthesised into the VALUE model proposed for guiding interventions to improve antibiotic prescribing practices. These should aim to reinforce intrapersonal Values consistent with prioritising AMR reduction, and Aligning organisational culture to these by leveraging standardised guidelines and interpersonal intervention tools. Such interventions should account for the wider systemic constraints experienced in publicly funded high patient turnover institutions, or private clinics with transactional models of care. Thus, ultimately a focus on Liaison between patient and doctor is crucial. For instance, building in adequate consultation time and props as discussion aids, or quick turnover communication tools in time-constrained settings. Message consistency will ultimately improve trust, helping to enable shared decision-making. Lastly, Use of monitoring data to track and Evaluate antibiotic prescribing using meaningful indicators, that account for the role of shared decision-making can also be leveraged for change. Conclusions These VALUE dimensions are recommended as potentially transferable to diverse contexts, and the model as implementation tool to be tested empirically and updated accordingly.

BACKGROUND Singapore’s national digital contact-tracing (DCT) tool—TraceTogether—attained an above 70% uptake by December 2020 after a slew of measures. Sentiment analysis can help policymakers to assess public sentiments on the implementation of new policy measures in a short time, but there is a paucity of sentiment analysis studies on the usage of DCT tools. OBJECTIVE We sought to understand the public’s knowledge of, concerns with, and sentiments on the use of TraceTogether over time and their preferences for the type of TraceTogether tool. METHODS We conducted a cross-sectional survey at a large public hospital in Singapore after the COVID-19 lockdown, from July 2020 through February 2021. In total, 4097 respondents aged 21-80 years were sampled proportionately by sex and 4 age groups. The open-ended responses were processed and analyzed using natural language processing tools. We manually corrected the language and logic errors and replaced phrases with words available in the syuzhet sentiment library without altering the original meaning of the phrases. The sentiment scores were computed by summing the scores of all the tokens (phrases split into smaller units) in the phrase. Stopwords (prepositions and connectors) were removed, followed by implementing the bag-of-words model to calculate the bigram and trigram occurrence in the data set. Demographic and time filters were applied to segment the responses. RESULTS Respondents’ knowledge of and concerns with TraceTogether changed from a focus on contact tracing and Bluetooth activation in July-August 2020 to QR code scanning and location check-ins in January-February 2021. Younger males had the highest TraceTogether uptake (24/40, 60%), while older females had the lowest uptake (8/34, 24%) in the first half of July 2020. This trend was reversed in mid-October after the announcement on mandatory TraceTogether check-ins at public venues. Although their TraceTogether uptake increased over time, older females continued to have lower sentiment scores. The mean sentiment scores were the lowest in January 2021 when the media reported that data collected by TraceTogether were used for criminal investigations. Smartphone apps were initially preferred over tokens, but the preference for the type of TraceTogether tool equalized over time as tokens became accessible to the whole population. The sentiments on token-related comments became more positive as the preference for tokens increased. CONCLUSIONS The public’s knowledge of and concerns with the use of a mandatory DCT tool varied with the national regulations and public communications over time with the evolution of the COVID-19 pandemic. Effective communications tailored to subpopulations and greater transparency in data handling will help allay public concerns with data misuse and improve trust in the authorities. Having alternative forms of the DCT tool can increase the uptake of and positive sentiments on DCT.

Schizophrenia (SZ) is a neurodevelopmental disorder. There remain significant gaps in understanding the neural trajectory across development in SZ. A major research focus is to clarify the developmental functional changes of SZ and to identify the specific timing, the specific brain regions, and the underlying mechanisms of brain alterations during SZ development. Regional homogeneity (ReHo) characterizing brain function was collected and analyzed on humans with SZ (hSZ) and healthy controls (HC) cross-sectionally, and methylazoxymethanol acetate (MAM) rats, a neurodevelopmental model of SZ, and vehicle rats longitudinally from adolescence to adulthood. Metabolomic and proteomic profiling in adult MAM rats and vehicle rats was examined and bioanalyzed. Compared to HC or adult vehicle rats, similar ReHo alterations were observed in hSZ and adult MAM rats, characterized by increased frontal (medial prefrontal and orbitofrontal cortices) and decreased posterior (visual and associated cortices) ReHo. Longitudinal analysis of MAM rats showed aberrant ReHo patterns as decreased posterior ReHo in adolescence and increased frontal and decreased posterior ReHo in adulthood. Accordingly, it was suggested that the visual cortex was a critical locus and adolescence was a sensitive window in SZ development. In addition, metabolic and proteomic alterations in adult MAM rats suggested that central carbon metabolism disturbance and mitochondrial dysfunction were the potential mechanisms underlying the ReHo alterations. This study proposed frontal-posterior functional imbalance and aberrant function developmental patterns in SZ, suggesting that the adolescent visual cortex was a critical locus and a sensitive window in SZ development. These findings from linking data between hSZ and MAM rats may have a significant translational contribution to the development of effective therapies in SZ.

BackgroundWe assessed the preferences and trade-offs for social interactions, incentives, and being traced by a digital contact tracing (DCT) tool post lockdown in Singapore.MethodsWe conducted a discrete choice experiment (DCE) among visitors of a large public hospital in Singapore between July 2020 – February 2021. Respondents were sampled proportionately by gender and four age categories (21 – 80 years). The DCE questionnaire had three attributes (1. Social interactions, 2. Being traced by a DCT tool, 3. Incentives to use a DCT tool) and two levels each. The final dataset comprised 3839 respondents after dropping 53 with “irrational” responses. Panel fixed conditional logit model was used to analyze the data.ResultsRespondents were more willing to trade being traced by a DCT tool for social interactions than incentives and unwilling to trade social interactions for incentives. The proportion of respondents preferring no incentives and could only be influenced by their family members increases with age. Among proponents of monetary incentives, the preferred median value for a month’s usage of DCT tools amounted to S$10 (USD7.25) and S$50 (USD36.20) for subsidies and lucky draw.ConclusionsDCE can be used to elicit profile-specific preferences to optimize the uptake of DCT tools during a pandemic. Social interactions are highly valued by the population, who are willing to trade them for being traced by a DCT tool during the COVID-19 pandemic. Although a small amount of incentive is sufficient to increase the satisfaction of using a DCT tool, incentives alone may not increase DCT tool uptake.

The concentration of Cys C in the patient's serum can reflect the level of glomerular filtration rate and indicate the occurrence of renal failure. The establishment of a simple and rapid analytical method to quantitatively monitor the concentration of Cys C in serum could help timely detection of renal failure. In this study, we have developed an Eu (III) chelate nanoparticles based lateral flow immunoassay to fulfill real-time monitoring of Cys C concentration in serum within 15 min. This method was performed as a sandwich immunoassay with a wide detection range (0.05-10 μg/mL) and a low limit of detection (24.54 ng/mL). The intra and inter-assay coefficients of variation were 8.31-8.61% and 8.92-9.95%, respectively. Furthermore, the application of this method was evaluated by comparing the determined results with those obtained by chemiluminescence immunoassay, exhibiting a satisfactory correlation (R

Melittin (Mel), a natural detergent, is a major component of bee venom. Mel exhibits favorable clinical effects on the treatment of rheumatoid osteoarthritis, myositis, lumbar muscle strain, and peripheral neurological disorders. Interleukin-1β (IL-1β) contributes to the progression of osteoarthritis and is one of the key proinflammatory cytokines. However, the effect of Mel on IL-1β-induced osteoarthritis has not been reported. We examined the effects of Mel on the expressions of inducible NO synthase (iNOS), nuclear transcription factor κB (NF-κB), and I kappa B (I-κB) in the knee joint cells of C518 rats induced by IL-1β. Western blot and qPCR results showed that Mel at 0.1µg/mL or higher significantly inhibited iNOS expression. Similarly, 1µg/mL of Mel prevented IL-β-induced I-κB degradation in the cytoplasm and NF-κB migration from cytoplasm to nucleus. Mel exerts an inhibitory effect on IL-β-induced NF-κB activation by inhibiting both I-κB degradation and NF-κB migration and can potentially be developed as a new anti-osteoarthritis drug. Further research is needed to clarify the detailed mechanism.