CXCR4 antagonists have been claimed to reduce mortality after myocardial infarction in myocardial infarction (MI) animals, presumably due to suppressing inflammatory responses caused by myocardial ...ischemia-reperfusion injury, thus, subsequently facilitating tissue repair and cardiac function recovery. This study aims to determine whether a newly designed CXCR4 antagonist DBPR807 could exert better vascular-protective effects than other clinical counterparts (e.g., AMD3100) to alleviate cardiac damage further exacerbated by reperfusion. Consequently, we find that instead of traditional continuous treatment or multiple-dose treatment at different intervals of time, a single-dose treatment of DBPR807 before reperfusion in MI animals could attenuate inflammation via protecting oxidative stress damage and preserve vascular/capillary density and integrity via mobilizing endothelial progenitor cells, leading to a desirable fibrosis reduction and recovery of cardiac function, as evaluated with the LVEF (left ventricular ejection fraction) in infarcted hearts in rats and mini-pigs, respectively. Thus, it is highly suggested that CXCR4 antagonists should be given at a single high dose prior to reperfusion to provide the maximal cardiac functional improvement. Based on its favorable efficacy and safety profiles indicated in tested animals, DBPR807 has a great potential to serve as an adjunctive medicine for percutaneous coronary intervention (PCI) therapies in acute MI patients.
This study explores the synergistic impact of Programmed Death Ligand 1 (PD-L1) and Protein Kinase B (Akt) overexpression in adipose-derived mesenchymal stem cells (AdMSCs) for ameliorating cardiac ...dysfunction after myocardial infarction (MI). Post-MI adult Wistar rats were allocated into four groups: sham, MI, ADMSC treatment, and ADMSCs overexpressed with PD-L1 and Akt (AdMSC-PDL1-Akt) treatment. MI was induced via left anterior descending coronary artery ligation, followed by intramyocardial AdMSC injections. Over four weeks, cardiac functionality and structural integrity were assessed using pressure-volume analysis, infarct size measurement, and immunohistochemistry. AdMSC-PDL1-Akt exhibited enhanced resistance to reactive oxygen species (ROS) in vitro and ameliorated MI-induced contractile dysfunction in vivo by improving the end-systolic pressure-volume relationship and preload-recruitable stroke work, together with attenuating infarct size. Molecular analyses revealed substantial mitigation in caspase3 and nuclear factor-κB upregulation in MI hearts within the AdMSC-PDL1-Akt group. Mechanistically, AdMSC-PDL1-Akt fostered the differentiation of normal T cells into CD25
regulatory T cells in vitro, aligning with in vivo upregulation of CD25 in AdMSC-PDL1-Akt-treated rats. Collectively, PD-L1 and Akt overexpression in AdMSCs bolsters resistance to ROS-mediated apoptosis in vitro and enhances myocardial protective efficacy against MI-induced dysfunction, potentially via T-cell modulation, underscoring a promising therapeutic strategy for myocardial ischemic injuries.
Epithelial cell adhesion molecule (EpCAM) is known to highly expression and promotes cancer progression in many cancer types, including colorectal cancer. While metastasis is one of the main causes ...of cancer treatment failure, the involvement of EpCAM signaling in metastatic processes is unclear. We propose the potential crosstalk of EpCAM signaling with the HGFR signaling in order to govern metastatic activity in colorectal cancer.
Immunoprecipitation (IP), enzyme-linked immunosorbent assay (ELISA), and fluorescence resonance energy transfer (FRET) was conducted to explore the extracellular domain of EpCAM (EpEX) and HGFR interaction. Western blotting was taken to determine the expression of proteins in colorectal cancer (CRC) cell lines. The functions of EpEX in CRC were investigated by proliferation, migration, and invasion analysis. The combined therapy was validated via a tail vein injection method for the metastasis and orthotopic colon cancer models.
This study demonstrates that the EpEX binds to HGFR and induces downstream signaling in colon cancer cells. Moreover, EpEX and HGF cooperatively mediate HGFR signaling. Furthermore, EpEX enhances the epithelial-to-mesenchymal transition and metastatic potential of colon cancer cells by activating ERK and FAK-AKT signaling pathways, and it further stabilizes active β-catenin and Snail proteins by decreasing GSK3β activity. Finally, we show that the combined treatment of an anti-EpCAM neutralizing antibody (EpAb2-6) and an HGFR inhibitor (crizotinib) significantly inhibits tumor progression and prolongs survival in metastatic and orthotopic animal models of colon cancer.
Our findings illuminate the molecular mechanisms underlying EpCAM signaling promotion of colon cancer metastasis, further suggesting that the combination of EpAb2-6 and crizotinib may be an effective strategy for treating cancer patients with high EpCAM expression.
To investigate the effect of Er:YAG laser treatment on lipopolysaccharide (LPS) clearance and fibroblast adhesion on titanium disks. Grade IV titanium discs (n = 216) were used and allocated to 6 ...groups. Group 1 was the negative control without Porphyromonas gingivalis inoculation. Discs in Groups 2-6 were incubated with P. gingivalis to form a biofilm. Group 3 received 0.12% chlorhexidine irrigation and Group 4 received titanium curettage to remove the biofilm. Group 5 was treated with Er:YAG laser irradiation and Group 6 was treated with titanium curettage plus Er:YAG laser irradiation. The contact angle and surface roughness were measured after the various treatments. The surface microstructure and residual bacteria were examined using scanning electron microscopy and confocal laser scanning microscopy, respectively. Residual LPS was examined using a limulus amoebocyte lysate assay and human gingival fibroblast adhesion was quantified using fluorescent microscopy. Curettage plus Er:YAG laser irradiation was the most effective method for removing bacteria and LPS. No significant difference in the amount of fibroblast adhesion was found between the control and Group 6. Combined use of Er:YAG laser irradiation and curettage optimizes LPS clearance and fibroblast adhesion on titanium discs.
Transcranial focused ultrasound (tFUS) is a novel neuromodulating technique. It has been demonstrated that the neuromodulatory effects can be induced by weak ultrasound exposure levels (spatial-peak ...temporal average intensity, I
< 10 mW/cm
) in vitro. However, fewer studies have examined the use of weak tFUS to potentially induce long-lasting neuromodulatory responses in vivo. The purpose of this study was to determine the lower-bound threshold of tFUS stimulation for inducing neuromodulation in the motor cortex of rats. A total of 94 Sprague-Dawley rats were used. The sonication region aimed at the motor cortex under weak tFUS exposure (I
of 0.338-12.15 mW/cm
). The neuromodulatory effects of tFUS on the motor cortex were evaluated by the changes in motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). In addition to histology analysis, the in vitro cell culture was used to confirm the neuromodulatory mechanisms following tFUS stimulation. In the results, the dose-dependent inhibitory effects of tFUS were found, showing increased intensities of tFUS suppressed MEPs and lasted for 30 min. Weak tFUS significantly decreased the expression of excitatory neurons and increased the expression of inhibitory GABAergic neurons. The PIEZO-1 proteins of GABAergic neurons were found to involve in the inhibitory neuromodulation. In conclusion, we show the use of weak ultrasound to induce long-lasting neuromodulatory effects and explore the potential use of weak ultrasound for future clinical neuromodulatory applications.
Abstract
Background
The progression of nasopharyngeal carcinoma (NPC) is profoundly affected by Epstein-Barr virus (EBV) infection. However, the role of EBV in the intercommunication between NPC and ...surrounding stromal cells has yet to be explored.
Methods
NPC biopsies were obtained for immunohistochemical (IHC) analyses. Clinical correlations between the expression of active YAP1/FAPα and the fibrotic response and between YAP1/FAPα and the density of cytotoxic CD8a
+
T lymphocytes were determined. Survival times based on IHC scores were compared between groups using Kaplan-Meier survival and log-rank tests. Independent prognostic factors for metastasis/recurrence-free survival and overall survival were identified using univariate and multivariate Cox regression models. Fibroblasts were isolated from human nasopharyngeal biopsies. Exosomes were purified from culture supernatants of EBV
+
-positive NPC cells. The effects of EBV product-containing exosomes on fibroblast activation, fibrotic response, tumor growth, immune response, and correlations between the expression of featured genes were investigated using gel contraction assays, ELISAs, EdU incorporation assays, real-time impedance assays, RNA sequencing, immunostaining, 3D cancer spheroid coculture systems, and an NPC xenograft model.
Results
NPC patients who developed metastasis had significantly higher levels of active YAP1 and FAPα in their tumor stroma, which was further correlated with tumor fibrosis and poorer metastasis-free survival. Exosomes released from EBV
+
-NPC cells contained abundant FAPα protein and EBV-encoded latent membrane protein 1. Viral product-containing exosomes markedly enhanced the fibrotic response and tumor growth in a mouse xenograft model. IHC analyses of human NPC and NPC xenografts revealed positive correlations between levels of active YAP1 and FAPα, YAP1 and the fibrotic response, and FAPα and the fibrotic response. Mechanistic studies showed that treatment of fibroblasts with viral product-containing exosomes promoted the characteristics of cancer-associated fibroblasts by stimulating YAP1 signaling and the production of the immunosuppressive cytokines IL8, CCL2, and IL6. Inhibition of YAP1 activation markedly reversed these exosome-mediated protumoral effects, resulting in reduced contractility, inactivation of YAP1 signaling, and decreased production of immunosuppressive cytokines in fibroblasts. Furthermore, fibroblasts stimulated with these viral product-containing exosomes promoted NPC resistance to T cell-mediated cytotoxicity within tumor spheroids. In NPC tissues, a significant negative correlation was found between YAP1/FAPα and the density of CD8a
+
T lymphocytes with a granzyme B signature.
Conclusion
EBV orchestrates interactions with the host and surrounding stroma by stimulating the functions of YAP1 and FAPα in fibroblasts through exosome cargos to create a more immunosuppressive, proinvasive microenvironment.
Pulmonary hypertension (PH) is highly prevalent in patients with heart failure with preserved ejection fraction (HFpEF), and it is a strong predictor of adverse outcomes. We aimed to determine ...possible echocardiographic parameters to predict the presence of PH in patients with HFpEF.
A total of 113 patients with HFpEF were prospectively enrolled from November 2017 to July 2022. The patients underwent invasive cardiac catheterization and simultaneous echocardiography at rest and during exercise. The parameters indicating right ventricle-pulmonary artery uncoupling, including tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) and tricuspid annular systolic velocity (TAS')/PASP were calculated. Receiver operating characteristic curve analysis was used to determine the optimal cut-off points of TAPSE/PASP and TAS'/PASP to differentiate patients with HFpEF with PH from those without PH. Sixty-eight patients with HFpEF with PH and 45 without PH were included. Those with PH had lower TAPSE/PASP and TAS'/PASP at rest and during exercise compared with those without PH. Both resting/stress TAPSE/PASP and TAS'/PASP were correlated with rest/exercise pulmonary capillary wedge pressure and mean pulmonary artery pressure. In multivariable regression analysis, TAPSE/PASP remained a significant predictor of exercise pulmonary capillary wedge pressure and mean pulmonary artery pressure. In receiver operating characteristic curve analysis, the optimal cut-off points of TAPSE/PASP and TAS'/PASP to differentiate patients with HFpEF with PH from those without PH were ≤0.62 and ≤0.47, respectively.
Right ventricle-pulmonary artery uncoupling is closely correlated with abnormal rest/exercise hemodynamics (pulmonary capillary wedge pressure and mean pulmonary artery pressure) in patients with HFpEF. TAPSE/PASP and TAS'/PASP can be useful parameters to detect PH in patients with HFpEF.
This letter investigates the double-ended resistive switching characteristics of indium tin oxide (ITO) resistance random access memory (RRAM). Resistive switching can be achieved around both the ...active TiN electrode and the inert Pt electrode. In addition, complementary resistance switching (CRS) characteristics can be observed without current compliance during dc voltage sweep operations. Electrical measurement data fitting results indicate that the oxygen-rich ITO near top and bottom electrodes works as a double-ended resistive switching layer. Based on the analysis of the current conduction mechanism, we propose a physical model to interpret the CRS behaviors in ITO RRAM devices.
Conspectus Lithium (Li) metal is the ultimate negative electrode due to its high theoretical specific capacity and low negative electrochemical potential. However, the handling of lithium metal ...imposes safety concerns in transportation and production due to its reactive nature. Recently, anode-free lithium metal batteries (AFLMBs) have drawn much attention because of several of their advantages, including higher energy density, lower cost, and fewer safety concerns during cell production compared to LMBs. Pushing the reversible Coulombic efficiency (CE) of AFLMBs up to 99.98% is key to achieving their 80% capacity retention over more than 1000 cycles. However, interfacial irreversible phenomena such as electrolyte decomposition reactions on both electrodes, dead Li formation, and Li dendrite formation result in poor capacity retention and short circuits in LMBs and AFLMBs. Therefore, it is of great importance and scientific interest to explore those interfacial irreversible phenomena to improve the cell’s cycle life. Although significant contributions toward mitigating electrolyte decomposition, dead lithium, and dendritic lithium formation have been reported at the lithium anode, real irreversible phenomena are usually hidden or difficult to discover due to excess lithium employed in LMBs and simultaneous events taking place in both electrodes or at the interfaces. An integrated protocol is suggested to include Li||Cu, cathode||Li, and cathode||Cu configurations to provide overall quantification and determination of various sources of irreversible Coulombic efficiency (irr-CE) in AFLMBs and LMBs. Combining Li||Cu, cathode||Li, and cathode||Cu configurations is essential for separating the root sources of the capacity loss and irr-CE in LMBs and AFLMBs. Remarkably, integrating an anode-free cell with various analytical techniques can serve as a powerful protocol to decouple and quantify those interfacial irreversible phenomena according to our recent reports. In this Account, we focus on the protocol based on an anode-free cell combined with various analytical methods to investigate interfacial irreversible phenomena. Complementary advanced tools such as transmission X-ray microscopy (visualizing Li plating/stripping mechanism), nuclear magnetic resonance spectroscopy (quantifying dead lithium), and gas chromatography–mass spectroscopy (decoupling interfacial reactions) were employed to extract the intrinsic reasons and sources of individual irreversible reactions in LMBs and AFLMBs. Quantitative evaluation of nucleation and growth of Li metal deposition are addressed, along with solid electrolyte interphase (SEI) fracture, visualization of lithium dendrite growth, decoupling of oxidative and reductive electrolyte decomposition mechanisms, and irreversible efficiency (i.e., dead Li and SEI formation) to reveal the intrinsic causes of individual irr-CE in AFLMBs. Meanwhile, an anode-free protocol can also be utilized as a powerful and multifunctional tool to develop electrolyte formulations or artificial layers for LMBs and AFLMBs. Therefore, we also suggest that the anode-free configurations with significant irreversible phenomena can effectively screen and develop new electrolytes. Finally, the concepts of the protocol with an anode-free cell combined with various advanced analytical tools can be extended to provide an in-depth understanding of other metal batteries and solid-state anode-free metal batteries.
Marathons have recently become popular sporting activities. Due to the competitive nature of marathons, organizers often use automatic timing systems to ensure fairness and impartiality. However, for ...small- and medium-sized marathon organizers, the existing timing systems are too costly to deploy, so human supervision and timing are still often used. This study proposes an automatic timing system for marathons based on Bluetooth Low Energy (BLE) with multiple antennas. Compared to similar studies, this design has higher timing stability. By comparing the characteristics of the received signal strength (RSS) received from multiple antennas, our system can determine when the runner passes the checkpoint. This study uses deep learning algorithms to deal with noisy RSS from multiple antennas. During the evaluation, 20 runners participated in experiments at four locations, demonstrating the scalability of the proposed system. The results showed that the accurate detection of the timing for marathon runners was 96.8%, which could be further increased to 100% if a 1-s timing error is acceptable.
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