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Graphite materials are promising aerospace structural materials owing to their low density, high thermal conductivity, and high temperature stability. However, the poor mechanical properties and inferior ablation resistance of graphite materials limit their application in advanced space vehicles. To address this problem, three-dimensional zirconium carbide (3D ZrC) skeleton-reinforced graphite composites (mesocarbon microbeads, MCMBs) were designed and fabricated by combination of molten salt coating and spark plasma sintering (SPS). The effects of ZrC content on the mechanical and ablation properties were investigated in detail. With the ZrC content of 45 vol%, the bending strength and fracture toughness of the MCMB@ZrC composite were 112 MPa and 1.72 MPa·m1/2, respectively. After ablation at 2.4 MW·m−2 for 60 s, the MCMB@ZrC composites with 30 vol% ZrC exhibited the best ablation performance and remained intact after ablation, with linear and mass ablation rates of 2.13 μm·s−1 and 4.24 mg·s−1, respectively. The 3D ZrC skeleton with moderate content provides effective support for the graphite matrix and thermal protection during the ablation process to a certain extent.

To study the nutritional composition and flavor characteristic substances of fresh Amomum tsao-ko, gas chromatography-mass spectrometry (GC-MS), amino acid autoanalyzer, and gas chromatography-sniffing were used to analyze and identify the nutritional composition and volatile flavor substances of fresh Amomum tsao-ko. The results showed that fresh Amomum tsao-ko contained the highest moisture content of 70.61%, crude fat of 2.35%, crude protein of 2.76%, and total ash of 5.94%. A total of 30 fatty acids were detected in fresh Amomum tsao-ko, with contents ranging from 0.10 to 3.45 mg/mL, among which, 12 saturated fatty acids accounted for 57.99% of the total amount, and 18 unsaturated fatty acids accounted for 47.23% of the total amount. Among the nine amino acids detected, lysine was the highest and valine was the lowest. By comparing the aroma characteristics, mass spectra, and retention indices with those of the standards, 46 volatile flavor substances were identified from them, and citral, (Z)-3,7-dimethyl-2,6-octadienal, (E)-3,7-dimethyl-2,6-octadienal, trans-2-dodecenal, and trans-2-octadienal were found to be in high contents. The key aroma components of fresh Amomum tsao-ko were identified as nine substances, namely, trans-2-dodecenal, (E,Z)-2,4-decadienal, trans-2-octenal, n-octanal, 4-isopropyltoluene, (Z)-3,7-dimethyl-2,6-octadienal, (E)-3,7-dimethyl-2,6-octadienal, citral, and eucalyptol, based on the intensity value of the aroma and its odor activity value. The results would provide a theoretical basis for the drying and processing of fresh Amomum tsao-ko and product development.

Adding edible fungal polysaccharides to animal diets improves growth performance, meat quality, intestinal health, and immunity without adverse effects. This study aimed to evaluate the impact of Pleurotus citrinopileatus polysaccharide (PCP, including PCP250, PCP500, PCP750, and PCP1000 mg/kg) on the growth performance, meat quality, and microbial composition of Arbor Acre (AA) broilers (total 180) by metabolomics and high-throughput sequencing. The results showed that adding PCP enhanced chicken meat tenderness, redness (a*), and water retention and raised essential amino acids and flavor amino acids (such as umami and sweet amino acids) content. The metabolomics revealed that IMP, creatine, betaine, sarcosine, and taurine were related to improving meat quality in broilers by PCP addition. In addition, amino acid, purine, and lipid metabolism were the main metabolic pathways. Moreover, PCP could regulate muscle metabolism by increasing the relative abundance of Lachnospiraceae and Lactobacillus and the content of short-chain fatty acids (SCFAs). Therefore, PCP may become a promising new dietary supplement in the future, which may improve the yield and quality of broiler chickens.

The purpose of this experiment was to explore the influence of different cooking temperatures on the deterioration characteristics of pork batter gel by using proteomics, gel electrophoresis, size and chemical bond of aggregates. The results showed that the protein molecules of the pork batter gel was degraded during heating cooking and the protein aggregates were composed of many degraded protein fragments; compared with the control group 75 °C (0 min), the significant degradation of cytoskeleton showed at 110 °C (30 min) and 121 °C (30 min) and the significant degradation of myosin complexonly appeared at 121 °C (30 min). As the heating temperature points increased, compared with the control group 75 °C (0 min), the different temperatures could promote the separation of metal ions with proteins especially at 110 °C (30 min) and 121 °C (30 min), which could ultimately influence quality of pork batter gel by the size of particle. As the increase of heating temperature points, the recombination of aggregates composed of different proteins was not conducive to the retention of capillary water, which reduced the texture of pork batter gel. This research provided theoretical support for improving the process property of the meat products.

Ceramic-coated graphite powders are considered as effective raw materials to fabricate three-dimensional continuous ceramic skeleton-reinforced graphite matrix composites which can overcome their inherent poor densification and improve their mechanical and antioxidation properties. However, the morphology and thickness regulation of ceramic coatings on graphite particles are still a great challenge. Herein, SiC-coated graphite (graphite@SiC) powders were prepared by nitriding combustion synthesis using Si and graphited mesocarbon microbead (MCMB) as raw powders with polytetrafluoroethylene (PTFE) as a promoter. The effects of the PTFE content and the Si/MCMB molar ratio on the phase composition and coating morphology were investigated. The phase transition and microstructure evolution of a combustion synthesis (CS) process were revealed by a gas-released quenching experiment. When the Si/MCMB molar ratio was 1 : 3 and the PTFE content was 10 wt%, the thickness of the SiC coating synthesized under 2 MPa N2 reached 1.14 μm. The corresponding sintered graphite@SiC composite had relative density of 99.2% and flexural strength of 231 MPa, accompanied by a significant improvement in high-temperature antioxidation properties. The as-synthesized graphite@SiC powders with good sinterability and antioxidation properties show great promise for applications in the nuclear industry and other extreme fields.

Abstract Forkhead box D1 (FOXD1) belongs to the FOX protein family, which has been found to function as a oncogene in multiple cancer types, but its role in head and neck squamous cell carcinoma (HNSCC) requires further investigation. Our research aimed to investigate the function of FOXD1 in HNSCC. Bioinformatics analysis indicated that mRNA level of FOXD1 was highly expressed in HNSCC tissues, and over-expressed FOXD1 was related to poor prognosis. Moreover, FOXD1 knockdown increased the ratio of senescent cells but decreased the proliferation ability, while FOXD1 overexpression obtained the opposite results. In vitro experiments revealed that FOXD1 bound to the p21 promoter and inhibited its transcription, which blocked the cyclin dependent kinase 2 (CDK2)/retinoblastoma (Rb) signaling pathway, thus preventing senescence and accelerating proliferation of tumor cells. CDK2 inhibitor could reverse the process to some extent. Further research has shown that miR-3oe-5p serves as a tumor suppressant by repressing the translation of FOXD1 through combining with the 3’-untranslated region (UTR). Thus, FOXD1 resists cellular senescence and facilitates HNSCC cell proliferation by affecting the expression of p21/CDK2/Rb signaling, suggesting that FOXD1 may be a potential curative target for HNSCC.

Background The effect of combined nicorandil and beta-adrenergic receptor blockers (BBs) compared with that of BBs alone on long-term clinical outcomes in patients with coronary artery disease (CAD) remains undetermined. Methods A multicenter retrospective cohort study was performed. Adult patients who had been hospitalized for CAD and treated for angina with a combination of nicorandil and BBs or BBs alone were included. The effect of different treatments on the cumulative incidence of major adverse cardiovascular event (MACE) and their components within a follow-up duration of 2.5 years were analyzed using Kaplan–Meier survival curves. An inverse probability of treatment weighting (IPTW) method was used to adjust for the possible effect of confounding factors. Results A total of 137,714 patients were screened, of whom 16,912 individuals (mean age: 61.5 years, men: 67.1%) were successfully enrolled. Among the enrolled participants, 4669 received the combined treatment of nicorandil and BBs, while 12,243 received BBs alone. After IPTW, the results demonstrated that the combined treatment was associated with a significantly reduced incidence of MACE (hazard ratio [HR] 0.79, 95% conidence interval [CI] 0.72-0.87) and stroke (HR 0.48, 95% CI 0.42-0.54) but not of MI (HR 1.03, 95% CI 0.92-1.15) or all-cause mortality (HR 0.93, 95% CI 0.64-1.37). Sensitivity analyses revealed similar results. Conclusions A combined antiangina treatment of nicorandil and BBs may be more effective than treatment of BBs alone in reducing the long-term incidence of MACE in patients with CAD.

Objective: To investigate the flavor difference of chicken bone homogenate before and after enzymatic hydrolysis. Methods: On the basis of single factor experiments, response surface experimental design was used to optimize the enzymatic hydrolysis process of chicken bone homogenate. Then, the amino acid automatic analyzer and headspace solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) combined with taste activity value (TAV) and odor activity value (OAV) were used to carry out the key free amino acids and volatile aroma compounds for the flavor. Results: The optimal process was as follows: Time 5.1 h, enzyme addition 0.61%, solid-liquid ratio 1:3 g/mL, hydrolysis degree 33.68%±1.53%. The degree of hydrolysis was verified (33.24%±0.61%). A total of 13 free amino acids had TAV greater than 1, among which 8 free amino acids had TAV greater than 10, which made great contribution to the taste of chicken bone homogenate. A total of 92 volatile compounds were identified, 63 before and 66 after enzymatic hydrolysis. The 13 and 16 compounds of OAV≥1 was found before and after enzymatic hydrolysis, including 4 alcohols, 2 esters, 2 furans and 9 aldehydes. Before the enzymatic hydrolysis, the chicken bone homogenate had a strong fat flavor, but after the enzymatic hydrolysis, the fat flavor was weakened, and the roasted, bean and melon and meat flavor were increased at the same time, which increased the overall flavor. Conclusion: This paper would provide experimental basis for the study of flavor components of chicken bone homogenate before and after enzymatic hydrolysis.

Objective: This study was aimed at investigating whether the addition of nicorandil to a dihydropyridine calcium channel blocker (DHP-CCB) regimen might decrease the occurrence of major adverse cardiovascular events (MACE) in patients with coronary heart disease (CHD). Methods: A multicenter, retrospective, real-world study was conducted. Between August 2002 and March 2020, 7413 eligible patients with CHD were divided into DHP-CCB plus nicorandil combination (n = 1843) and DHP-CCB (n = 5570) treatment groups. The primary outcome was MACE, defined as a composite of myocardial infarction, stroke, and all-cause mortality. Propensity score matching was used to adjust for confounding factors. Results: After propensity score matching, combination therapy, compared with DHP-CCBs alone, was associated with a lower risk of MACE (HR: 0.80, 95% CI: 0.67–0.97). The combination group also had a lower risk of stroke (HR: 0.55, 95% CI: 0.44–0.69), but not myocardial infarction (HR: 1.21, 95% CI: 0.91–1.61) or all-cause mortality (HR: 1.24, 95% CI: 0.63–2.44). Subgroup analysis revealed more prominent benefits of the combined treatment on MACE in patients with than without diabetes. Conclusions: The combination of nicorandil and DHP-CCBs may be more beneficial than DHP-CCBs alone in decreasing long-term risks of MACE and stroke in patients with CHD.

Danon disease (DD) is a rare glycogen storage lysosomal disorder caused by mutations in the LAMP2 gene. Patients with DD are usually characterized clinically by severe multisystem syndromes. We describe a specific family with a novel pathogenic splice-altering mutation in the LAMP2 gene (c.741+2T>C) with cardiac-only symptoms (frequent ventricular tachycardia, intraventricular block, and hypertrophic cardiomyopathy). Minigene assays were used to evaluate the consequence of the splice-site mutation in the LAMP2 gene. The results showed that the c.741+2T>C mutation led to extra 6-bp preservation of intron 5 at the junction between exons 5 and 6 during transcriptional processing of the mRNA, which creates a stop codon and truncated the LAMP2 protein to 248-amino-acid residues. The mutant LAMP2 protein was predicted to have a conformational change, lacks the important transmembrane domain, and subsequent protein destabilization.

Midu pork roll (MPR), produced in Midu County, Dali Bai Autonomous Prefecture, Yunnan, China, is a traditional fermented meat product with a long history. This study aims to enhance the physical and flavor profile of MPR by improving its process, fermentation conditions and formulations. There were three different formulations, including traditional craft (control group: C), optimization process of Sichuan spicy flavor formula (Test group 1: T1) and optimization process of halogen flavor formula (Test group 2: T2). Higher moisture content, L*, a* and b* values and lower hardness, chewiness and shear force were observed in T1 and T2 compared to C (p < 0.05). A total of 15 free amino acids were detected throughout the fermentation process, during which the content of umami amino acids, sweet amino acids and bitter amino acids underwent significant changes. A total of 88, 85 and 75 volatile compounds were detected in C, T1 and T2, respectively, in which the relative content of alkanes and ketones in T1 and T2 were higher than those in C (p < 0.05). The process and formulas have improved the color, texture characteristics and tenderness of MPR to a certain extent, meanwhile, they have enhanced the flavor of MPR.

The N-terminal domain of the cardiac ryanodine receptor (RyR2) harbors a large number of naturally occurring mutations that are associated with stress-induced ventricular tachyarrhythmia and sudden death. Nearly all these disease-associated N-terminal mutations are located at domain interfaces or buried within domains. Mutations at these locations would alter domain-domain interactions or the stability/folding of domains. Recently, a novel RyR2 mutation H29D associated with ventricular arrhythmia at rest was found to enhance the activation of single RyR2 channels by diastolic levels of cytosolic Ca2+. Unlike other N-terminal disease-associated mutations, the H29D mutation is located on the surface of the N-terminal domain. It is unclear how this surface-exposed H29D mutation that does not appear to interact with other parts of the RyR2 structure could alter the intrinsic properties of the channel. Here we carried out detailed functional characterization of the RyR2-H29D mutant at the molecular and cellular levels. We found that the H29D mutation has no effect on the basal level or the Ca2+ dependent activation of [3H]ryanodine binding to RyR2, the cytosolic Ca2+ activation of single RyR2 channels, or the cytosolic Ca2+- or caffeine-induced Ca2+ release in HEK293 cells. In addition, the H29D mutation does not alter the propensity for spontaneous Ca2+ release or the thresholds for Ca2+ release activation or termination. Furthermore, the H29D mutation does not have significant impact on the thermal stability of the N-terminal region (residues 1-547) of RyR2. Collectively, our data show that the H29D mutation exerts little or no effect on the function of RyR2 or on the folding stability of the N-terminal region. Thus, our results provide no evidence that the H29D mutation enhances the cytosolic Ca2+ activation of RyR2.

The present study aims to evaluate the effects of enzyme, ultrasound, and ultrasound-assisted enzyme treatments at different ultrasound times on the quality of the spent-hen breast meat (SHBM). The enzyme, ultrasound, and ultrasound-assisted enzyme treatments had a slight adverse effect on the color and pH, significantly reduced shear force, and increased water holding capacity (WHC) (P < 0.05), but the shear force and WHC gradually worsened with the extension of ultrasound radiation time over 20 min. Low-field NMR results showed that ultrasound-assisted treatment increases the percentage of immobilized water (T21) in the meat by promoting the migration and uniform distribution of water; thus, improving the WHC of meat. Myofibrillar fragmentation index (MFI), myofibril microstructure and rupture status revealed that enzymes and ultrasound softened meat texture by destroying muscle fiber structure. These results indicated that ultrasound technology is a promising auxiliary method to improve meat quality, and ultrasound with enzymes has a synergistic effect on the improvement of meat quality. [ABSTRACT FROM AUTHOR]

Reduced protein expression of the cardiac ryanodine receptor type 2 (RyR2) is thought to affect the susceptibility to stress-induced ventricular tachyarrhythmia (VT) and cardiac alternans, but direct evidence for the role of RyR2 protein expression in VT and cardiac alternans is lacking. Here, we used a mouse model (crrm1) that expresses a reduced level of the RyR2 protein to determine the impact of reduced RyR2 protein expression on the susceptibility to VT, cardiac alternans, cardiac hypertrophy, and sudden death. Electrocardiographic analysis revealed that after the injection of relatively high doses of caffeine and epinephrine (agents commonly used for stress test), wild-type (WT) mice displayed long-lasting VTs, whereas the crrm1 mutant mice exhibited no VTs at all, indicating that the crrm1 mutant mice are resistant to stress-induced VTs. Intact heart Ca2+ imaging and action potential (AP) recordings showed that the crrm1 mutant mice are more susceptible to fast-pacing induced Ca2+ alternans and AP duration alternans compared with WT mice. The crrm1 mutant mice also showed an increased heart-to-body-weight ratio and incidence of sudden death at young ages. Furthermore, the crrm1 mutant hearts displayed altered Ca2+ transients with increased time-to-peak and decay time (T50), increased ventricular wall thickness and ventricular cell area compared with WT hearts. These results indicate that reduced RyR2 protein expression suppresses stress-induced VTs, but enhances the susceptibility to cardiac alternans, hypertrophy, and sudden death. [ABSTRACT FROM AUTHOR]

Recent three-dimensional structural studies reveal that the central domain of ryanodine receptor (RyR) serves as a transducer that converts long-range conformational changes into the gating of the channel pore. Interestingly, the central domain encompasses one of the mutation hotspots (corresponding to amino acid residues 3778-4201) that contains a number of cardiac RyR (RyR2) mutations associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) and atrial fibrillation (AF). However, the functional consequences of these central domain RyR2 mutations are not well understood. To gain insights into the impact of the mutation and the role of the central domain in channel function, we generated and characterized eight disease-associated RyR2 mutations in the central domain.Wefound that all eight central domain RyR2 mutations enhanced the Ca2+-dependent activation of [3H]ryanodine binding, increased cytosolic Ca2+-induced fractional Ca2+ release, and reduced the activation and termination thresholds for spontaneous Ca2+ release in HEK293 cells. We also showed that racemic carvedilol and the non-beta-blocking carvedilol enantiomer, (R)-carvedilol, suppressed spontaneous Ca2+ oscillations in HEK293 cells expressing the central domain RyR2 mutations associated with CPVT and AF. These data indicate that the central domain is an important determinant of cytosolic Ca2+ activation of RyR2. These results also suggest that altered cytosolic Ca2+ activation of RyR2 represents a common defect of RyR2 mutations associated with CPVT and AF, which could potentially be suppressed by carvedilol or (R)-carvedilol. [ABSTRACT FROM AUTHOR]

β-Blockers are a standard treatment for heart failure and cardiac arrhythmias. There are ~30 commonly used β-blockers, representing a diverse class of drugs with different receptor affinities and pleiotropic properties. We reported that among 14 β-blockers tested previously, only carvedilol effectively suppressed cardiac ryanodine receptor (RyR2)-mediated spontaneous Ca2+ waves during store Ca2+ overload, also known as store overload-induced Ca2+ release (SOICR). Given the critical role of SOICR in arrhythmogenesis, it is of importance to determine whether there are other β-blockers that suppress SOICR. Here, we assessed the effect of other commonly used β-blockers on RyR2-mediated SOICR in HEK293 cells, using single-cell Ca2+ imaging. Of the 13 β-blockers tested, only nebivolol, a β-1-selective β-blocker with nitric oxide synthase (NOS)-stimulating action, effectively suppressed SOICR. The NOS inhibitor (N-nitro-Larginine methyl ester) had no effect on nebivolol's SOICR inhibition, and the NOS activator (histamine or prostaglandin E2) alone did not inhibit SOICR. Hence, nebivolol's SOICR inhibition was independent of NOS stimulation. Like carvedilol, nebivolol reduced the opening of single RyR2 channels and suppressed spontaneous Ca2+ waves in intact hearts and catecholaminergic polymorphic ventricular tachycardia (CPVT) in the mice harboring a RyR2 mutation (R4496C). Interestingly, a non-β-blocking nebivolol enantiomer, (l)-nebivolol, also suppressed SOICR and CPVT without lowering heart rate. These data indicate that nebivolol, like carvedilol, possesses a RyR2-targeted action that suppresses SOICR and SOICR-evoked VTs. Thus, nebivolol represents a promising agent for Ca2+-triggered arrhythmias. [ABSTRACT FROM AUTHOR]

The cardiac Ca2+ release channel [ryanodine receptor type 2 (RyR2)] is modulated by thiol reactive agents, but the molecular basis of RyR2 modulation by thiol reagents is poorly understood. Cys3635 in the skeletal muscle RyR1 is one of the most hyperreactive thiols and is important for the redox and calmodulin (CaM) regulation of the RyR1 channel. However, little is known about the role of the corresponding cysteine residue in RyR2 (Cys3602) in the function and regulation of the RyR2 channel. In the present study, we assessed the impact of mutating Cys3602 (C3602A) on store overload-induced Ca2+ release (SOICR) and the regulation of RyR2 by thiol reagents and CaM. We found that the C3602A mutation suppressed SOICR by raising the activation threshold and delayed the termination of Ca2+ release by reducing the termination threshold. As a result, C3602A markedly increased the fractional Ca2+ release. Furthermore, the C3602A mutation diminished the inhibitory effect of N-ethylmaleimide on Ca2+ release, but it had no effect on the stimulatory action of 4,4'-dithiodipyridine (DTDP) on Ca2+ release. In addition, Cys3602 mutations (C3602A or C3602R) did not abolish the effect of CaM on Ca2+ -release termination. Therefore, RyR2-Cys3602 is a major site mediating the action of thiol alkylating agent N-ethylmaleimide, but not the action of the oxidant DTDP. Our data also indicate that residue Cys3602 plays an important role in the activation and termination of Ca2+ release, but it is not essential for CaM regulation of RyR2. [ABSTRACT FROM AUTHOR]

Activation of the cardiac ryanodine receptor (RyR2) by elevating cytosolic Ca2+ is a central step in the process of Ca2+-induced Ca2+ release, but the molecular basis of RyR2 activation by cytosolic Ca2+ is poorly defined. It has been proposed recently that the putative Ca2+ binding domain encompassing a pair of EF-hand motifs (EF1 and EF2) in the skeletal muscle ryanodine receptor (RyR1) functions as a Ca2+ sensor that regulates the gating of RyR1. Although the role of the EF-hand domain in RyR1 function has been studied extensively, little is known about the functional significance of the corresponding EF-hand domain in RyR2. Here we investigate the effect of mutations in the EF-hand motifs on the Ca2+ activation of RyR2. We found that mutations in the EF-hand motifs or deletion of the entire EF-hand domain did not affect the Ca2+-dependent activation of [3H]ryanodine binding or the cytosolic Ca2+ activation of RyR2. On the other hand, deletion of the EF-hand domain markedly suppressed the luminal Ca2+ activation of RyR2 and spontaneous Ca2+ release in HEK293 cells during store Ca2+ overload or store overload-induced Ca2+ release (SOICR). Furthermore, mutations in the EF2 motif, but not EF1 motif, of RyR2 raised the threshold for SOICR termination, whereas deletion of the EF-hand domain of RyR2 increased both the activation and termination thresholds for SOICR. These results indicate that, although the EF-hand domain is not required for RyR2 activation by cytosolic Ca2+, it plays an important role in luminal Ca2+ activation and SOICR. [ABSTRACT FROM AUTHOR]

The NH2-terminal region (residues 1-543) of the cardiac ryanodine receptor (RyR2) harbors a large number of mutations associated with cardiac arrhythmias and cardiomyopathies. Functional studies have revealed that the NH2-terminal region is involved in the activation and termination of Ca2+ release. The three-dimensional structure of the NH2-terminal region has recently been solved. It is composed of three domains (A, B, and C). However, the roles of these individual domains in Ca2+ release activation and termination are largely unknown. To understand the functional significance of each of these NH2-terminal domains, we systematically deleted these domains and assessed their impact on caffeine- or Ca2+-induced Ca2+ release and store overload-induced Ca2+ release (SOICR) in HEK293 cells. We found that all deletion mutants were capable of forming caffeine- and ryanodine-sensitive functional channels, indicating that the NH2-terminal region is not essential for channel gating. Ca2+ release measurements revealed that deleting domain A markedly reduced the threshold for SOICR termination but had no effect on caffeine or Ca2+ activation or the threshold for SOICR activation, whereas deleting domain B substantially enhanced caffeine and Ca2+ activation and lowered the threshold for SOICR activation and termination. Conversely, deleting domain C suppressed caffeine activation, abolished Ca2+activation and SOICR, and diminished protein expression. These results suggest that domain A is involved in channel termination, domain B is involved in channel suppression, and domain C is critical for channel activation and expression. Our data shed new insights into the structure-function relationship of the NH2-terminal domains of RyR2 and the action of NH2-terminal disease mutations. [ABSTRACT FROM AUTHOR]