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Normal contractile function of the heart depends on a constant and reliable production of ATP by cardiomyocytes. Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. Further, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and estrogen-related receptor (ERR)-induced regulator, muscle 1) that is enriched in skeletal and cardiac-muscle mitochondria and transcriptionally regulated by PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1) and ERR. The role of Perm1 in the heart is poorly understood and is studied here. We utilized cell culture, mouse models, and human tissue, to study its expression and transcriptional control, as well as its role in transcription of other factors. Critically, we tested Perm1's role in cardiomyocyte mitochondrial function and its ability to protect myocytes from stress-induced damage. Our studies show that Perm1 expression increases throughout mouse cardiogenesis, demonstrate that Perm1 interacts with PGC-1α and enhances activation of PGC-1 and ERR, increases mitochondrial DNA copy number, and augments oxidative capacity in cultured neonatal mouse cardiomyocytes. Moreover, we found that Perm1 reduced cellular damage produced as a result of hypoxia and reoxygenation-induced stress and mitigated cell death of cardiomyocytes. Taken together, our results show that Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction induced by ischemic injury.

RationaleZO-1 (Zonula occludens-1), a plasma membrane-associated scaffolding protein regulates signal transduction, transcription, and cellular communication. Global deletion of ZO-1 in the mouse is lethal by embryonic day 11.5. The function of ZO-1 in cardiac myocytes (CM) is largely unknown.ObjectiveTo determine the function of CM ZO-1 in the intact heart, given its binding to other CM proteins that have been shown instrumental in normal cardiac conduction and function.Methods and resultsWe generated ZO-1 CM-specific knockout (KO) mice using α-Myosin Heavy Chain-nuclear Cre (ZO-1cKO) and investigated physiological and electrophysiological function by echocardiography, surface ECG and conscious telemetry, intracardiac electrograms and pacing, and optical mapping studies. ZO-1cKO mice were viable, had normal Mendelian ratios, and had a normal lifespan. Ventricular morphometry and function were not significantly different between the ZO-1cKO versus control (CTL) mice, basally in young or aged mice, or even when hearts were subjected to hemodynamic loading. Atrial mass was increased in ZO-1cKO. Electrophysiological and optical mapping studies indicated high-grade atrioventricular (A-V) block in ZO-1cKO comparing to CTL hearts. While ZO-1-associated proteins such as vinculin, connexin 43, N-cadherin, and α-catenin showed no significant change with the loss of ZO-1, Connexin-45 and Coxsackie-adenovirus (CAR) proteins were reduced in atria of ZO-1cKO. Further, with loss of ZO-1, ZO-2 protein was increased significantly in ventricular CM in a presumed compensatory manner but was still not detected in the AV nodal myocytes. Importantly, the expression of the sodium channel protein NaV1.5 was altered in AV nodal cells of the ZO-1cKO versus CTL.ConclusionsZO-1 protein has a unique physiological role in cardiac nodal tissue. This is in alignment with its known interaction with CAR and Cx45, and a new function in regulating the expression of NaV1.5 in AV node. Uniquely, ZO-1 is dispensable for function of the working myocardium.

Mitochondria and oxidative metabolism are critical for maintaining cardiac muscle function. Research has shown that mitochondrial dysfunction is an important contributing factor to impaired cardiac function found in heart failure. By contrast, restoring defective mitochondrial function may have beneficial effects to improve cardiac function in the failing heart. Therefore, studying the regulatory mechanisms and identifying novel regulators for mitochondrial function could provide insight which could be used to develop new therapeutic targets for treating heart disease. Here, cardiac myocyte mitochondrial respiration is analyzed using a unique cell culture system. First, a protocol has been optimized to rapidly isolate and culture high viability neonatal mouse cardiomyocytes. Then, a 96-well format extracellular flux analyzer is used to assess the oxygen consumption rate of these cardiomyocytes. For this protocol, we optimized seeding conditions and demonstrated that neonatal mouse cardiomyocytes oxygen consumption rate can be easily assessed in an extracellular flux analyzer. Finally, we note that our protocol can be applied to a larger culture size and other studies, such as intracellular signaling and contractile function analysis.

Facilitating inspirational experiences for customers is an emerging topic in the field of tourism and hospitality. Based on the Stimulus-Organism-Response paradigm, we proposed novel effects that substantive servicescape has a positive effect on inspiration, which has a positive downstream effect on satisfaction. The present research, including a field survey with customers from 10 three- to four-star hotels (N 1 = 644) and three experimental studies (N 2 = 133, N 3 = 115, N 4 = 227), examined the effects of substantive and communicative servicescape on inspiration, the downstream effect of inspiration on satisfaction, and the moderating roles of openness to experience and prior experience. The results supported our proposed effects. Furthermore, openness to experience and prior experience moderated the effects of substantive servicescape on inspiration and inspiration on satisfaction, respectively. This research contributes to the extant literature by offering a more nuanced understanding of the drivers of customer inspiration and the boundary conditions. [ABSTRACT FROM AUTHOR]

Both epoxy resin (ER) and SBS are considered effective pavement materials for avoiding ruts. However, epoxy resin asphalt suffers from poor low-temperate performance and a high material cost in practical applications. Aiming to tackle these issues, a new type of composite asphalt modifier (ER-SBS) has been fabricated by combining epoxy resin with SBS. This work prepared modified asphalt with different doping amounts using the above composite asphalt modifier (ER-SBS), intending to explore the properties of composite-modified asphalt and the modification mechanism of the modifier. Furthermore, the effects of the composite modifier at different doping amounts on the viscoelastic property of asphalt were explored through rheological tests, and then the prepared composite-modified asphalt was compared with matrix asphalt and SBS-modified asphalt. In addition, the modification mechanism of the composite modifier was investigated by fluorescence microscopy and infrared spectroscopy. The difference in pavement performance between the composite-modified asphalt and SBS-modified asphalt was compared by a rut test and dynamic modulus test. The research results showed that the composite modifier improved the high- and low-temperature performances and viscoelastic property of matrix asphalt. When the doping amount was raised to 9%, the composite-modified asphalt exhibited better a modification effect than SBS-modified asphalt. The rut test results indicated that composite-modified asphalt demonstrated a stronger deformation resistance than SBS-modified asphalt. The dynamic modulus test showed that the composite-modified asphalt has better viscoelastic properties and temperature sensitivity. Fluorescence microscopy suggested that the crosslinking between the composite modifier and asphalt forms a mesh structure which greatly improves its resistance to deformation. From infrared spectroscopy, the composite modifier clearly functions as a physical modifier. [ABSTRACT FROM AUTHOR]

Currently, fast-melting SBS (Styrene-Butadiene-Styrene)-modified asphalt is widely used in pavements. However, in practical applications, complex environmental factors accelerate the deterioration of asphalt material properties, significantly affecting the service life of roads during their operational period. This study aims to examine the effects of complex environmental factors, including thermal oxidation, ultraviolet radiation, and various concentrations of salt solutions, on the high and low-temperature rheological properties of fast-melting SBS-modified asphalt (abbreviated as SBS-T-modified asphalt). Pressure aging–ultraviolet aging coupling and pressure aging–ultraviolet aging different concentration salt solution coupling were selected as the aging groups to simulate complex environmental conditions. Additionally, base asphalt and pressure-aged asphalt were used as control groups. The rheological properties of SBS-T-modified asphalt were evaluated using a dynamic shear rheometer (DSR) and bending beam rheometer (BBR). The results indicate that multiple-factor coupling aging reduces both the high-temperature and low-temperature performance of SBS-T-modified asphalt compared to single-factor aging, although the impact on rheological properties is not consistent across all conditions. After the combined effects of UV aging and pressure aging, the rutting resistance and high-temperature performance of SBS-T-modified asphalt are most severely impacted. However, when coupled with salt-solution aging, the rutting resistance of SBS-T-modified asphalt improves, with the complex modulus increasing by approximately 30%. This indicates that the presence of the salt solution enhances the high-temperature performance of the asphalt. An analysis of the low-temperature rheological properties of SBS-T-modified asphalt based on Burgers model shows that the low-temperature rheological performance of SBS-T-modified asphalt worsens under three-factor coupling aging compared to two-factor or single-factor aging, leading to poorer crack resistance. Notably, after adding salt solutions, the thermal sensitivity of SBS-T-modified asphalt increases significantly, with the ΔTc value decreasing approximately sixfold for every 2% increase in salt concentration. [ABSTRACT FROM AUTHOR]

Moisture accelerates the degradation of asphalt properties, significantly impacting the service life of roads. Therefore, this study uses simplified viscoelastic continuous damage theory and employs frequency scanning, linear amplitude scanning, and fatigue–healing–fatigue tests with a dynamic shear rheometer. The objective is to investigate the effects of aging time, moisture conditions, and aging temperature on the fatigue and self-healing performance of SBS (Styrene–Butadiene–Styrene block copolymer)-modified asphalt, nano-SiO2-modified asphalt, and nano-SiO2/SBS composite modified asphalt in a moisture-rich environment. The results indicate that nano-SiO2 powder enhances the low-temperature performance of modified asphalt, whereas the SBS modifier reduces temperature sensitivity and increases the recovery percentage after deformation. Compared to SBS-modified asphalt, the deformation resistance of nano-SiO2/SBS composite modified asphalt has increased by about 30%, while nano-SiO2-modified asphalt shows relatively poor deformation resistance. The fatigue performance of SBS-modified asphalt deteriorates under moisture, whereas the addition of nano-SiO2 powder improves its fatigue life. Nano-SiO2/SBS composite modified asphalt exhibits strong self-healing capabilities. Although self-healing can enhance the fatigue life of modified asphalt, moisture inhibits this improvement after self-healing. [ABSTRACT FROM AUTHOR]

In order to reduce the content of carcinogenic polycyclic aromatic hydrocarbons in coal asphalt and realize its green application, polyurethane monomer, trioxymethylene, polyethylene glycol, divinyl benzene and epoxy resin were respectively used to react with coal-tar pitch alone or mixed. The removal rate of benzo [a] pyrene ( BaP), a representative carcinogen in coal-tar pitch, was used as an evaluation index to analyze the effects of each single modifier and composite modifier on BaP in coal-tar pitch. The results showed that all the selected modifiers could effectively reduce the mass fraction of BaP in coal-tar pitch, the order of detoxification effect of a single modifier in descending was polyurethane monomer, trioxymethylene, polyethylene glycol, divinyl benzene, epoxy resin; the optimal combination (mass fraction) of composite modifiers was 6% polyurethane monomer +10% trioxymethylene + 8% polyethylene glycol, which reduction rate of BaP could reach 82.16% with the optimal reaction conditions. [ABSTRACT FROM AUTHOR]

Purpose: Lenvatinib and programmed cell death protein-1 (PD-1) inhibitor on infiltrative hepatocellular carcinoma (HCC) have obtained demonstrated efficacy and still need improvement. Hepatic arterial infusion chemotherapy (HAIC) has shown promising results for advanced HCC. This study aimed to compare the efficacy of HAIC combined Lenvatinib and PD-1 inhibitor versus Lenvatinib combined PD-1 inhibitor for infiltrative HCC. Patients and Methods: A total of 232 patients were enrolled. There were 114 patients received Lenvatinib combined PD-1 inhibitor (Len+PD-1 group) and 118 patients received HAIC combined Lenvatinib and PD-1 inhibitor (HAIC+Len+PD-1 group). Overall survival (OS), progression-free survival (PFS) and safety of patients were compared between the two groups by propensity score–matching (PSM). Results: The 6-, 12-, and 24-month OS rates were 93.8%, 65.1% and 13.4% in Len+PD-1 group, and 100%, 77.3% and 32.1% in HAIC+Len+PD-1 group, respectively. The 3-, 6-, and 12-month PFS rates were 86.4%, 45.7% and 14.1% in Len+PD-1 group, and 95.1%, 59.3% and 25.9% in HAIC+Len+PD-1 group, respectively. The HAIC+Len+PD-1 group had obviously better survival than the Len+PD-1 group both in OS (P=0.002) and PFS (P=0.004). Subgroup analysis revealed that OS in patients with metastasis was improved with HAIC+Len+PD-1 treatment. Patients with alpha-fetoprotein (AFP) response after treatment showed better survival than the non-response. In addition, HAIC+Len+PD-1 group showed manageable adverse events (AEs). Conclusion: Patient with infiltrative HCC, HAIC+Len+PD-1 treatment had longer OS and PFS than Len+PD-1 treatment. Early AFP response was an effective indicator of better survival and tumor response to therapy. Plain Language Summary: Infiltrative hepatocellular carcinoma (HCC) is an odd group that is not well adjudicated in the current staging systems, and treatment options for patients with infiltrative HCC are challenging with scant and insufficient clinical evidence. In this multi-center study, we innovatively analyzed the outcome of hepatic arterial infusion chemotherapy (HAIC) combined lenvatinib and PD-1 inhibitor (HAIC+Len+PD-1) was associated longer progression-free survival and overall survival than Lenvatinib plus PD-1 inhibitor combination (Len+PD-1) for patient with infiltrative HCC. In addition, further intragroup analysis revealed that OS of patients with and without metastasis in Len+PD-1 group was significant difference. However, no difference was observed in OS for patients with and without metastasis in HAIC+Len+PD-1 group. Patients with alpha-fetoprotein (AFP) response after treatment showed better survival than the non-response. Our research provides evidence that HAIC combined Lenvatinib and PD-1 inhibitor results in clinically significant improvements in infiltrative HCC. It could be recommended as a first choice for infiltrative HCC therapy. [ABSTRACT FROM AUTHOR]

Continuous contraction-relaxation cycles of the heart require strong and stable connections of cardiac myocytes (CMs) with the extracellular matrix (ECM) to preserve sarcolemmal integrity. CM attachment to the ECM is mediated by integrin complexes localized at the muscle adhesion sites termed costameres. The ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that links integrins ultimately to the sarcomere. There are two talin genes, Tln1 and Tln2. Here, we tested the function of these two Tln forms in myocardium where Tln2 is the dominant isoform in postnatal CMs. Surprisingly, global deletion of Tln2 in mice caused no structural or functional changes in heart, presumably because CM Tln1 became up-regulated. Tln2 loss increased integrin activation, although levels of the muscle-specific β1D-integrin isoform were reduced by 50%. With this result, we produced mice that had simultaneous loss of both CM Tln1 and Tln2 and found that cardiac dysfunction occurred by 4 wk with 100% mortality by 6 mo. β1D integrin and other costameric proteins were lost from the CMs, and membrane integrity was compromised. Given that integrin protein reduction occurred with Tln loss, rescue of the phenotype was attempted through transgenic integrin overexpression, but this could not restore WT CM integrin levels nor improve heart function. Our results show that CM Tln2 is essential for proper β1D-integrin expression and that Tln1 can substitute for Tln2 in preserving heart function, but that loss of all Tln forms from the heart-muscle cell leads to myocyte instability and a dilated cardiomyopathy.

Saline–alkaline solutions have a detrimental impact on the durability of bituminous pavements. Thus, it is important to understand the interaction between saline–alkaline environments and bitumen and investigate the corresponding interfacial characteristics. In this study, molecular dynamics simulations were carried out to evaluate the interfacial interaction behavior between different saline–alkaline solutions and bitumen. The interaction energy, mean square displacement, interfacial molecular arrangement, and Na+ distribution were analyzed for different bitumen-solution systems. The results revealed that the interaction between bitumen and alkaline salt solutions is more powerful than between bitumen and neutral salt solutions. The damaging impact of different solutions on bitumen can be written as: alkaline salt solution > neutral salt solution > deionized water. Oxidative aging can further strengthen the interaction between saline solutions and bitumen. Bitumen molecules diffusion is the fastest in an alkaline salt solution, as indicated by the high diffusion coefficient. Furthermore, adsorption occurs at the interface between a neutral salt solution and bitumen, leading to interspersing of the salt and bitumen molecules. The water molecules and Na+ ions in an alkaline salt solution can penetrate the bitumen surface, leading to a more chaotic molecular arrangement at the interface. The interfacial film formed in the bitumen-alkaline solution system has the highest thickness owing to the extremely strong interaction. Furthermore, Na+ ions aggregate at the bitumen surface, and aging accelerates the diffusion of Na+ ions toward the bitumen surface. [ABSTRACT FROM AUTHOR]