Integrated PBPK-EO modeling of osimertinib to predict plasma concentrations and intracranial EGFR engagement in patients with brain metastases.

The purpose of this study was to develop and validate a physiologically based pharmacokinetic (PBPK) model combined with an EGFR occupancy (EO) model for osimertinib (OSI) to predict plasma trough concentration (Ctrough) and the intracranial time-course of EGFR (T790M and L858R mutants) engagement in patient populations. The PBPK model was also used to investigate the key factors affecting OSI pharmacokinetics (PK) and intracranial EGFR engagement, analyze resistance to the target mutation C797S, and determine optimal dosing regimens when used alone and in drug-drug interactions (DDIs). A population PBPK-EO model of OSI was developed using physicochemical, biochemical, binding kinetic, and physiological properties, and then validated using nine clinical PK studies, observed EO study, and two clinical DDI studies. The PBPK-EO model demonstrated good consistency with observed data, with most prediction-to-observation ratios falling within the range of 0.7 to 1.3 for plasma AUC, Cmax, Ctrough and intracranial free concentration. The simulated time-course of C797S occupancy by the PBPK model was much lower than T790M and L858R occupancy, providing an explanation for OSI on-target resistance to the C797S mutation. The PBPK model identified ABCB1 CLint,u, albumin level, and EGFR expression as key factors affecting plasma Ctrough and intracranial EO for OSI. Additionally, PBPK-EO simulations indicated that the optimal dosing regimen for OSI in patients with brain metastases is either 80 mg once daily (OD) or 160 mg OD, or 40 mg or 80 mg twice daily (BID). When used concomitantly with CYP enzyme perpetrators, the PBPK-EO model suggested appropriate dosing regimens of 80 mg OD with fluvoxamine (FLUV) itraconazole (ITR) or fluvoxamine (FLUC) for co-administration and an increase to 160 mg OD with rifampicin (RIF) or efavirenz (EFA). In conclusion, the PBPK-EO model has been shown to be capable of simulating the pharmacokinetic concentration-time profiles and the time-course of EGFR engagement for OSI, as well as determining the optimum dosing in various clinical situations.

Deciphering the brain-gut axis: elucidating the link between cerebral cortex structures and functional gastrointestinal disorders via integrated Mendelian randomization.

Background: Observational studies have suggested associations between functional gastrointestinal disorders (FGIDs) and variations in the cerebral cortex. However, the causality of these relationships remains unclear, confounded by anxiety and depression. To clarify these causal relationships and explore the mediating roles of anxiety and depression, we applied univariate, multivariable, and mediation Mendelian randomization (MR) analyses. Method: We utilized genome-wide association study (GWAS) summary data from the FinnGen database and the ENIGMA consortium, identifying genetic variants associated with irritable bowel syndrome (IBS), functional dyspepsia (FD), and cerebral cortex structures. Data on anxiety and depression came from FinnGen and a large meta-analysis. Utilizing a bidirectional univariate MR approach, we explored correlations between FD, IBS, and cortex variations. Then, independent effects were assessed through multivariable MR. A meta-analysis of these results, incorporating data from two cohorts, aimed to increase precision. We also explored the potential mediating roles of anxiety and depression. Results: Our findings indicate a negative causal correlation between FD and the thickness of the rostral anterior cingulate cortex (rACC) across both global and regional adjustments (ß = -0.142, 95% confidence interval (CI): -0.209 to-0.074, P.FDR = 0.004; ß = -0.112, 95%CI: -0.163 to-0.006, P.FDR = 0.003) and a positive causal correlation with the globally adjusted thickness of the superior frontal gyrus (SFG) (ß = 0.107, 95%CI: 0.062 to 0.153, P.FDR = 0.001). The causal correlation with the rACC persisted after multiple variable adjustments (ß = -0.137, 95% CI: -0.187 to-0.087, P.FDR = 1.81 × 10-5; ß = -0.109, 95%CI: -0.158 to-0.06, P.FDR = 0.002). A significant causal association was found between globally adjusted surface area of the caudal anterior cingulate cortex (cACC) and IBS (odds ratio = 1.267, 95%CI: 1.128 to 1.424, P.FDR = 0.02). The analysis showed that neither anxiety nor depression mediated the relationship between FGIDs and cerebral cortex structures. Conclusion: Our research provides significant MR evidence of a bidirectional causal relationship between FGIDs and the cerebral cortex structures. This evidence not only confirms the two-way communication along the brain-gut axis but also illuminates the underlying pathophysiology, paving the way for identifying potential therapeutic approaches.

Nomograms for Predicting Risk and Survival of Esophageal Cancer Lung Metastases: a SEER Analysis.

Background: The overall survival rate is notably low for esophageal cancer patients with lung metastases (LM), presenting significant challenges in their treatment. Methods: Through the Surveillance, Epidemiology, and End Results (SEER) program, individuals diagnosed with esophageal cancer between 2010 and 2015 were enrolled. Based on whether esophageal cancer metastasized to the lungs, we used propensity score matching (PSM) to balance correlated variables. Propensity score matching was a critical step in our study that helped to minimize the impact of possible confounders on the study results. We balanced variables related to lung metastases using the PSM method to ensure more accurate comparisons between the study and control groups. Specifically, we performed PSM in the following steps. First, we performed a univariate logistic regression analysis to screen for variables associated with lung metastasis. For each patient, we calculated their propensity scores using a logistic regression model, taking into account several factors, including gender, T-stage, N-stage, surgical history, radiotherapy history, chemotherapy history, and bone/brain/liver metastases. We used a 1:1 matching ratio based on the propensity score to ensure more balanced baseline characteristics between the study and control groups after matching. After matching, we validated the balance of baseline characteristics to ensure that the effect of confounders was minimized. We used logistic regression to identify risk variables for LM, while Cox regression was used to find independent prognostic factors. We then created nomograms and assessed their accuracy using the calibration curve, receiver operating curves (ROC), and C index. Results: In the post-PSM cohort, individuals diagnosed with LM experienced a median overall survival (OS) of 5.0 months (95% confidence interval [CI] 4.3-5.7), which was significantly lower than those without LM (P<0.001). LM has been associated to sex, T stage, N stage, surgery, radiation, chemotherapy, and bone/brain/liver metastases. LM survival was affected by radiation, chemotherapy, and bone/liver metastases. The nomograms' predictive power was proved using the ROC curve, C-index, and validation curve. Conclusion: Patients with LM have a worse chance of surviving esophageal cancer. The nomograms can effectively predict the risk and prognosis of lung metastases from esophageal cancer.

FgFAD12 Regulates Vegetative Growth, Pathogenicity and Linoleic Acid Biosynthesis in Fusarium graminearum.

Polyunsaturated fatty acids (PUFAs), as important components of lipids, play indispensable roles in the development of all organisms. ∆12 fatty acid desaturase (FAD12) is a speed-determining step in the biosynthesis of PUFAs. Here, we report the characterization of FAD12 in Fusarium graminearum, which is the prevalent agent of Fusarium head blight, a destructive plant disease worldwide. The results demonstrated that deletion of the FgFAD12 gene resulted in defects in vegetative growth, conidial germination and plant pathogenesis but not sexual reproduction. A fatty acid analysis further proved that the deletion of FgFAD12 restrained the reaction of oleic acid to linoleic acid, and a large amount of oleic acid was detected in the cells. Moreover, the ∆Fgfad12 mutant showed increased resistance to osmotic stress and reduced tolerance to oxidative stress. The expression of FgFAD12 did show a temperature-dependent manner, which was not affected at a low temperature of 10 °C when compared to 25 °C. RNA-seq analysis further demonstrated that most genes enriched in fatty acid metabolism, the biosynthesis of unsaturated fatty acids, fatty acid biosynthesis, fatty acid degradation, steroid biosynthesis and fatty acid elongation pathways were significantly up-regulated in the ∆Fgfad12 mutants. Overall, our results indicate that FgFAD12 is essential for linoleic acid biosynthesis and plays an important role in the infection process of F. graminearum.

Perceived Determinants of Health-Related Behaviors Among Patients with Coronary Heart Disease After Percutaneous Coronary Intervention: A Longitudinal Qualitative Study.

Purpose: Studies had reported some influencing factors of health behavior among patients with coronary heart disease(CHD) after percutaneous coronary intervention(PCI). However, considering that human perceptions are complex, unrestricted and dynamically changing. A longitudinal qualitative study was conducted to explore the determinants of health-related behaviors of patients after PCI and dynamic changes of these determinants at the 1st, 3rd, and 6th months. Patients and Methods: Using purposive sampling, 18 patients undergoing PCI were interviewed. The conventional content analysis method was used to identify categories and subcategories. Semi-structured, face-to-face or telephone in-depth interviews were conducted at the cardiology unit of a tertiary referral hospital in Yunnan Province, China from March 2022 to January 2023. Results: Seven categories with some subcategories were constructed from the data, categorized into three domains. Firstly, individual factors include (i) Personal coping with healthy lifestyle requirements (tried but failed; I can do it), (ii) individual perception and feeling toward disease (knowing about the disease; belief of cure; fears of relapse), and (iii) personal benefits (improved health; meaning of life). Secondly, social factors include (i) social facilitators (family resources; healthcare support), (ii) social barriers (inconvenient medical care service; conflicting information). Finally, cultural factors include (i) way of living (dietary habits; key roles of yan (cigarette) and jiu (alcohol) in Chinese society), (ii) way of thinking (fatalism and Confucian familism). Conclusion: The determinants of health-related behaviors of patients after PCI are multifaceted and dynamic. Different interventions should be formulated to promote patients' adherence to health behaviors. Moreover, priority should be given to the impact of traditional Chinese philosophy on the health behaviors of patients after PCI, and the health promotion program for these patients should be culturally sensitive. In addition, future research should further explore the determinants of health behaviors among diverse ethnic minorities after PCI, which has not been fully inquired in this study.

Exploring inter-ethnic and inter-patient variability and optimal dosing of osimertinib: a physiologically based pharmacokinetic modeling approach.

Purpose: This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for osimertinib (OSI) to predict plasma trough concentration (Ctrough) and pulmonary EGFRm+ (T790M and L858R mutants) inhibition in Caucasian, Japanese, and Chinese populations. The PBPK model was also utilized to investigate inter-ethnic and inter-patient differences in OSI pharmacokinetics (PK) and determine optimal dosing regimens. Methods: Population PBPK models of OSI for healthy and disease populations were developed using physicochemical and biochemical properties of OSI and physiological parameters of different groups. And then the PBPK models were validated using the multiple clinical PK and drug-drug interaction (DDI) study data. Results: The model demonstrated good consistency with the observed data, with most of prediction-to-observation ratios of 0.8-1.25 for AUC, Cmax, and Ctrough. The PBPK model revealed that plasma exposure of OSI was approximately 2-fold higher in patients compared to healthy individuals, and higher exposure observed in Caucasians compared to other ethnic groups. This was primarily attributed to a lower CL/F of OSI in patients and Caucasian. The PBPK model displayed that key factors influencing PK and EGFRm+ inhibition differences included genetic polymorphism of CYP3A4, CYP1A2 expression, plasma free concentration (fup), albumin level, and auto-inhibition/induction on CYP3A4. Inter-patient PK variability was most influenced by CYP3A4 variants, fup, and albumin level. The PBPK simulations indicated that the optimal dosing regimen for patients across the three populations of European, Japanese, and Chinese ancestry was OSI 80 mg once daily (OD) to achieve the desired range of plasma Ctrough (328-677 nmol/L), as well as 80 mg and 160 mg OD for desirable pulmonary EGFRm+ inhibition (>80%). Conclusion: In conclusion, this study's PBPK simulations highlighted potential ethnic and inter-patient variability in OSI PK and EGFRm+ inhibition between Caucasian, Japanese, and Chinese populations, while also providing insights into optimal dosing regimens of OSI.

An Ultra-low Detection Limit Fe3+ Optical Fiber Fluorescent Sensor Based on a Anti-B18H22 Derivative with Aggregation-induced Emission Enhancement.

A fluorescent Fe3+ probe ((C10H7NO2)2B18H20, M1) by introducing two isoquinoline-1-carboxylic acid group into the 6,9-position of anti-B18H22 was designed and synthesized. The structure of M1 was investigated by 1H NMR, MS, FT-IR and theoretical calculation, and its optical properties were characterized with UV-Vis and PL. M1 showed aggregation induced emission enhancement (AIEE) properties in THF/H2O solution, and exhibited an excellent selectivity toward Fe3+ in THF/H2O (v/v, ƒw = 95%) solution with a detection limit of 1.93 × 10-5 M. The interaction mechanism of probe for detecting Fe3+ is attributed to the involvement of intramolecular charge transfer (ICT) process. Furthermore, a optical fiber fluorescent Fe3+ sensor based on M1 sensing film was developed, the detection limit of the optical fiber Fe3+ fluorescent sensor could be improved to13.8 pM, the ultra-low detection limit is superior to most reported fluorescent probes (or sensors) towards Fe3+. This method has the advantages of high sensitivity, anti-interference and easy to operate, and has great potential in the field of the analysis of environmental and biological samples.

Boosting the Downconversion Luminescence of Tm3+-Doped Nanoparticles for S-Band Polymer Waveguide Amplifier.

Polymer waveguide devices have attracted increasing interest in several rapidly developing areas of broadband communications since they are easily adaptable to on-chip integration and promise low propagation losses. As a key member of the waveguide gain medium, lanthanide doped nanoparticles have been intensively studied to improve the downconversion luminescence. However, current research efforts are almost confined to erbium-doped nanoparticles and amplifiers operating at the C-band; boosting the downconversion luminescence of Tm3+ for S-band optical amplification still remains a challenge. Here we report a Tb3+-induced deactivation control to enhance Tm3+ downconversion luminescence in a stoichiometric Yb lattice without suffering from concentration quenching. We also demonstrate their potential application in an S-band waveguide amplifier and record a maximum optical gain of 18 dB at 1464 nm. Our findings provide valuable insights into the fundamental understanding of deactivation-controlled luminescence enhancement and open up a new avenue toward the development of an S-band polymer waveguide amplifier with high gain.

A qualitative study on patients' and health care professionals' perspectives regarding care delivered during CIED operation.

BACKGROUND: Cardiac implantable electronic devices (CIEDs) has proven to be an invaluable tool in the practice of cardiology. Patients who have undergone CIED surgery with local anesthesia may result in fear, insecurity and suffering. Some studies have put efforts on ways to improve intraoperative experience of patients with local anesthesia, but researches concerning experiences of CIED patients during surgery is in its infancy. METHODS: Based on semi-structured and in-depth interviews, a qualitative design was conducted in a tertiary general hospital in China from May 2022 to July 2023.Purposeful sampling of 17 patients received CIED surgery and 20 medical staff were interviewed. Thematic analysis with an inductive approach was used to identify dominant themes. RESULTS: Four themes emerged from the data: (1) Safety and success is priority; (2) Humanistic Caring is a must yet be lacking; (3) Paradox of surgery information given; (4) Ways to improve surgery experiences in the operation. CONCLUSIONS: Intraoperative care is significant for CIED surgery. To improve care experience during surgery, healthcare professionals should pay attention to patients' safety and the factors that affecting humanistic caring in clinical practice. In addition, information support should consider information-seeking styles and personal needs. Besides, the four approaches presented in this study are effective to improve the intraoperative care experience.

Multifunctional Novel Nanoplatform for Effective Synergistic Chemo-Photodynamic Therapy of Breast Cancer by Enhancing DNA Damage and Disruptions of Its Reparation.

Photodynamic therapy (PDT) is an effective noninvasive therapeutic strategy that has been widely used for anti-tumor therapy by the generation of excessive highly cytotoxic ROS. However, the poor water solubility of the photosensitizer, reactive oxygen species (ROS) depleting by high concentrations of glutathione (GSH) in the tumor microenvironment and the activation of DNA repair pathways to combat the oxidative damage, will significantly limit the therapeutic effect of PDT. Herein, we developed a photosensitizer prodrug (CSP) by conjugating the photosensitizer pyropheophorbide a (PPa) and the DNA-damaging agent Chlorambucil (Cb) with a GSH-responsive disulfide linkage and demonstrated a multifunctional co-delivery nanoplatform (CSP/Ola nanoparticles (NPs)) together with DSPE-PEG2000 and PARP inhibitor Olaparib (Ola). The CSP/Ola NPs features excellent physiological stability, efficient loading capacity, much better cellular uptake behavior and photodynamic performance. Specifically, the nanoplatform could induce elevated intracellular ROS levels upon the in situ generation of ROS during PDT, and decrease ROS consumption by reducing intracellular GSH level. Moreover, the CSP/Ola NPs could amplify DNA damage by released Cb and inhibit the activation of Poly(ADP-ribose) polymerase (PARP), promote the upregulation of γ-H2AX, thereby blocking the DNA repair pathway to sensitize tumor cells for PDT. In vitro investigations revealed that CSP/Ola NPs showed excellent phototoxicity and the IC50 values of CSP/Ola NPs against MDA-MB-231 breast cancer cells were as low as 0.05-01 µM after PDT. As a consequence, the co-delivery nanoplatform greatly promotes the tumor cell apoptosis and shows a high antitumor performance with combinational chemotherapy and PDT. Overall, this work provides a potential alternative to improve the therapeutic efficiency of triple negative breast cancer cell (TNBC) treatment by synergistically enhancing DNA damage and disrupting DNA damage repair.

Highly applicable dual-cathode electro-Fenton system with self-adjusting pH and ferrous species.

Due to the high dependence on the pH of influent water and the level of ferrous species, the applicability of the electro-Fenton (EF) system is poor. A highly applicable dual-cathode (DC) EF system with self-adjusting pH and ferrous species is proposed: gas diffusion electrode (GDE) for generation H2O2 and Fe/S doped multi-walled carbon nanotubes (Fe/S-MWCNT) modification active cathode (AC) for adjusting pH and iron species. The strong synergistic enhancement effect between two cathodes (synergy factor up to 90.3%) improves the catalytic activity of this composite system about 12.4 times higher than that of cathode alone. Impressively, AC has the ability of self-regulate to shift towards the optimal Fenton pH (around 3.0) without adding reagents. Even pH can be adjusted from 9.0 to 3.4 within 60 min. This characteristic gives the system a wide range of pH applications, while avoiding the disadvantage of the high cost of traditional EF in pre-acidification. Furthermore, DC has a high and stable ferrous species supply, and the iron leaching amount is about twice less than that of heterogeneous EF system. Long-term stability of the DC system and its easy activity regeneration exhibit the potential of environmental remediation in industrial application.

Carrier-free nanomedicines self-assembled from palbociclib dimers and Ce6 for enhanced combined chemo-photodynamic therapy of breast cancer.

Palbociclib is the world's first CDK4/6 kinase inhibitor to be marketed. However, it is not effective in the treatment of triple negative breast cancer (TNBC) due to the loss of retinoblastoma protein expression. Thus, combinatorial chemotherapy is indispensable for TNBC treatment. Herein, a carrier-free nanomedicine self-assembled from palbociclib dimers and Ce6 for enhanced combined chemo-photodynamic therapy of breast cancer is reported. The dimeric prodrug (Palb-TK-Palb) was synthesized by conjugating two palbociclib molecules to the connecting skeleton containing a ROS-responsive cleavable thioketal bond. The Palb-TK-Palb/Ce6 NP co-delivery nanoplatform was prepared through the self-assembly of Palb-TK-Palb, Ce6 and DSPE-PEG2000. This novel carrier-free formulation as an efficient therapeutic agent showed efficient therapeutic agent loading capacity, high cellular uptake and huge therapeutic performance against breast cancer cells. The results of in vitro antitumor activity and cell apoptosis demonstrated that Palb-TK-Palb/Ce6 NPs presented a better inhibitory effect on the growth of cancer cells due to the palbociclib and Ce6 co-delivery nanomedicine-mediated synergistic chemo-photodynamic therapy. The IC50 values of Palb-TK-Palb/Ce6 NPs in MDA-MB-231 cells were around 1-2 µM and 2 µM and the Palb-TK-Palb/Ce6 NPs showed an increase in apoptosis up to 91.9%. In general, the carrier-free nanomedicine self-assembled from palbociclib dimers and Ce6 provides options for combinatorial chemo-photodynamic therapy.

Diffuse large B-cell lymphoma involving multiple immunoprivileged sites presenting as painful ophthalmoplegia: A case report.

RATIONALE: Primary diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. It is very rare to find lymphoma in immune -privileged sitesat the same time. We report a case of rapidly progressing DLBCL involving multiple sites in the central nervous system, testis, and orbit. PATIENT CONCERNS: A 57-years-old man developed diplopia 1 month ago with severe right periorbital pain and right eyelid ptosis. He developed dysphagia 1 week ago and hoarseness 5 days ago. DIAGNOSES: The pathology of the left testicle confirmed DLBCL. Immunohistochemical analysis showed that CD20, CD79α, multiple myeloma oncogene-1, BCL2, BCL6 atypical lymphocyte aggregation was positive. Positron emission tomography reveals DLBCL involving the central nervous system, testes, eyes, and other parts of the body. INTERVENTIONS: We administered glucocorticoids for pre-chemotherapy treatment, but the patient's condition progressed quickly and was generally poor. The patient's family decided to discharge automatically. OUTCOMES: Two weeks after he was discharged, we called for a follow-up visit and were told the patient had died. LESSONS: Atypical clinical symptoms of the disease often confuse the doctor's diagnosis. Adequate examination should be performed before glucocorticoid treatment in order to avoid obscuring the true condition. In some rare diseases, early use of PET-CT may lead to early detection.

Investigating the electrochemical advanced oxidation mechanism of N-doped graphene aerogel: Molecular dynamics simulation combined with DFT method.

Nitrogen-doped graphene as a perfectly-efficient and environmentally compatible electrocatalyst won widespread attention in electrochemical advanced oxidation processes (EAOP). However, the relationship between surface structure regulation and activity of catalysts is still lacking in systematic scientific guidance. Herein, nitrogen-doped graphene aerogel (NGA) was conveniently prepared through hydrothermal treatment, and then utilized to fabricate the gas diffusion electrode (GDE) as the cathode for tetracycline (TC) removal. High free radical yield (81.2 µM) and fast reaction rate (0.1469 min-1) were found in NGA system. The molecular dynamics simulation (MD) results showed that the interaction energy of NGA was greater than the raw graphene aerogel (GA). The adsorption activation of H2O2 and the degradation of TC occurred in the first adsorption layer of catalysts, and both processes turned more orderly after nitrogen doping. Moreover, the van der Waals interaction was stronger than the electrostatic interaction. Density function theory (DFT) revealed that the adsorption energy of H2O2 at graphitic N, pyridinic N, and pyrrolic N sites was -0.03 eV, -0.39 eV, and -0.30 eV, respectively. Pyridinic N sites were inferred as the main functional regions of in-situ activation •OH, there were more likely to occur ectopic reaction in pyrrolic N, and graphitic N were responsible for improving H2O2 production. By revealing the microstructure and activation characteristics of NGA, an experiment-simulation complementary strategy is provided in the EAOP to discover or to optimize new catalysts.

New insights into enhanced electrochemical advanced oxidation mechanism of B-doped graphene aerogel: Experiments, molecular dynamics simulations and DFT.

B-doped graphene, as an efficient and environmental-friendly metal-free catalyst, has aroused much attention in the electrochemical advanced oxidation process (EAOP), but the bottleneck in this field is to determine the relationship between the surface structure regulation and activity of catalysts. Herein, the B-doped graphene aerogel (BGA) fabricated gas diffusion electrode was prepared and used as a cathode for EAOP to remove tetracycline (TC). Higher free radical yield (169.59 µM), faster reaction speed (0.35 min-1) and higher TC removal rate (99.93%) were found in the BGA system. Molecular dynamics simulation unveiled the interaction energy of BGA was greater than the raw graphene aerogel (GA). The adsorption-activation process of H2O2 and the degradation process of TC occurred in the first adsorption layer of catalysts. And both processes turned more orderly after B doping, which accelerated the reaction efficiency. Results of density functional theory displayed the contribution of three B-doped structures to improve the binding strength between H2O2 and BGA was: - BCO2 (-0.23 eV) > - BC2O (-0.16 eV) > - BC3 (-0.09 eV). -BCO2 was inferred to be the main functional region of H2O2 in-situ activation to hydroxyl radical (•OH), while -BC2O and -BC3 were responsible for improving H2O2 production.

Preparation of novel HKUST-1-glucose oxidase composites and their application in biosensing.

Copper-based metal-organic frameworks (MOF) and multi-walled carbon nanotubes (HKUST-1-MWCNTs) composite were synthesized by one-step hydrothermal method, and PDA-enzyme-HKUST-1-MWCNTs composite was prepared by one-pot method for the construction of glucose biosensors, which realized the sensitive amperometric detection of glucose at 0.7 V (vs. SCE). The sensitivity of the sensor for glucose detection was 178 µA mM-1cm-2 in the wide linear range of 0.005 ~ 7.05 mM, the detection limit was 0.12 µM and the corresponding RSD was 3.8%. Its high performance is mainly benefitted from the high porosity and large specific surface area of HKUST-1, the good conductivity of MWCNTs, and the excellent adhesion and dispersion of PDA. The strategy of combining PDA and MWCNTs to improve the dispersion and conductivity of MOF is expected to achieve a wider application of MOF-based materials in the electrochemical biosensing field.

Microbial Fuel Cell-Based Biosensor for Simultaneous Test of Sodium Acetate and Glucose in a Mixed Solution.

Most microbial fuel cell (MFC) sensors only focus on the detection of mixed solutions with respect to the chemical oxygen demand (COD) or toxicity; however, the concentrations of the individual analytes in a mixed solution have rarely been studied. Herein, we developed two types of MFC sensors, adapted with sodium acetate (MFC-A) and glucose (MFC-B) as organic substrates in the startup period. An evident difference in the sensor sensitivities (the slope value of the linear-regression curve) was observed between MFC-A and MFC-B. MFC-A exhibited a superior performance compared with MFC-B in the detection of sodium acetate (4868.9 vs. 2202 mV/(g/L), respectively) and glucose (3895.5 vs. 3192.9 mV/(g/L), respectively). To further compare these two MFC sensors, the electrochemical performances were evaluated, and MFC-A exhibited a higher output voltage and power density (593.76 mV and 129.81 ± 4.10 mW/m2, respectively) than MFC-B (484.08 mV and 116.21 ± 1.81 mW/m2, respectively). Confocal laser scanning microscopy (CLSM) and microbial-community analysis were also performed, and the results showed a richer anode biomass of MFC-A in comparison with MFC-B. By utilizing the different sensitivities of the two MFC sensors towards sodium acetate and glucose, we proposed and verified a novel method for a simultaneous test on the individual concentrations of sodium acetate and glucose in a mixed solution. Linear equations of the two variables (concentrations of sodium acetate and glucose) were formulated. The linear equations were solved according to the output voltages of the two MFC sensors, and the solutions showed a satisfactory accuracy with regard to sodium acetate and glucose (relative error less than 20%).

Periodontal ligament cells derived small extracellular vesicles are involved in orthodontic tooth movement.

OBJECTIVES: Small extracellular vesicles (EVs) from human periodontal ligament cells (hPDLCs) are closely associated with periodontal homeostasis. Far less is known about EVs association with orthodontic tooth movement (OTM). This study aimed to explore the role of small EVs originated from hPDLCs during OTM. MATERIALS AND METHODS: Adult C57BL/6 mice were used. Springs were bonded to the upper first molars of mice for 7 days to induce OTM in vivo. To block small EVs release, GW4869 was intraperitoneally injected and the efficacy of small EVs inhibition in periodontal ligament was verified by transmission electron microscope (TEM). Tooth movement distance and osteoclastic activity were studied. In vitro, hPDLCs were isolated and administered compressive force in the EV-free culture media. The cell morphologies and CD63 expression of hPDLCs were studied. Small EVs were purified and characterized using a scanning electron microscope, TEM, western blot, and nanoparticle tracking analysis. The expression of proteins in the small EVs was further processed and validated using a human immuno-regulated cytokines array and an enzyme-linked immunosorbent assay (ELISA). RESULTS: The small EV depletion significantly decreased the distance and osteoclastic activity of OTM in the mice. The hPDLCs displayed different morphologies under force compression and CD63 expression level decreased verified by western blot and immunofluorescence staining. Small EVs purified from supernatants of the hPDLCs showed features with <200 nm diameter, the positive EVs marker CD63, and the negative Golgi body marker GM130. The number of small EVs particles increased in hPDLCs suffering force stimuli. According to the proteome array, the level of soluble intercellular adhesion molecule-1 (sICAM-1) displayed the most significant fold change in small EVs under compressive force and this was further confirmed using an ELISA. LIMITATIONS: Further mechanism studies are warranted to validate the hPDLC-originated small EVs function in OTM through proteins delivery. CONCLUSIONS: The notable decrease in the OTM distance after small EV blocking and the significant alteration of the sICAM-1 level in the hPDLC-originated small EVs under compression provide a new vista into small EV-related OTM biology.