Enzymatic synthesis of N-succinyl-L-phenylalanine and exploration of its potential as a novel taste enhancer.

N-succinyl-L-phenylalanine (SP) has been identified as a taste-active contributor in an array of foods. Despite its recognized importance, the understanding of its synthesis and taste enhancement properties remains rudimentary. The study examined the enzymatic synthesis of SP with 45.58 ± 1.95% yield. This was achieved under optimized conditions: 0.3 mol/L L-phenylalanine, 0.9 mol/L succinic acid, 30,000 U/L of the AY 50C, pH 4 and 55 °C for 24 h. Sensory evaluation and electronic tongue revealed that the incorporation of a mere 1 mg/L SP substantially increased the kokumi, umami, and saltiness intensities, indicating the potential of SP as a potent taste enhancer. Moreover, time-intensity (TI) results demonstrated a significant increase of umami duration in samples containing 1 mg/L of SP (210.0 ± 0 s), a significant extension compared to the control group (150.0 ± 0 s). Notably, the intensity of umami and saltiness in the SP sample were consistently higher than that of control group. The sigmoid curve analysis further confirmed that SP exhibited a synergistic effect on umami and saltiness perceptions. Moreover, the study also illuminated interaction of SP with T1R1, T1R3, TMC4, TRPV1, and CaSR receptors, resulting in significant enhancement in umami, saltiness, and kokumi.

A Novel Compound with Kokumi Properties: Enzymatic Preparation and Taste Presentation Evaluation of N-Lauroyl Phenylalanine.

To satisfy the demands of the food industry, innovative flavor enhancers need to be developed urgently to increase the food flavor. In our work, N-lauroyl phenylalanine (LP) was prepared from phenylalanine (l-Phe) and lauric acid (Lau) in water through the use of commercial enzymes (Promatex, Sumizyme FP-G, and Trypsin), and its flavor-presenting properties and mechanism were investigated. The highest LP yields obtained under one-factor optimized conditions were 61.28, 63.43, and 77.58%, respectively. Sensory assessment and an e-tongue test revealed that 1 mg/L LP enhanced the kokumi, saltiness, and umami of the simulated chicken broth solution and attenuated the bitterness of the l-isoleucine solution. The molecular simulation results suggested that the mechanisms of LP enhancement of kokumi and umami were related to hCaSR and hT1R1-hT1R3, and that hydrophobic forces and hydrogen bonds were involved in the binding of LP to taste receptors. The results implied that LP is a potential flavor enhancer for food applications.

Resilience mediates the prediction of alienation towards parents on subjective well-being in rural left-behind children: a 12-month longitudinal study.

Objective: Parent-child relationship is critical for children's well-being. In China, the large number of left-behind children (LBC, one or both parents leaving for work for at least 6 months) raises public concern. Although LBC often report poor mental health status and higher alienation towards parents, the dynamic trend of subjective well-being in this population, as well as the prediction of alienation towards parents on LBC's subjective well-being, remain unrevealed. This study aimed to examine the dynamic trend of subjective well-being in Chinese LBC and further explore the predictional influence of alienation towards parents, with resilience as a potential mediator. Methods: We recruited 916 rural LBC in China and investigated them at five waves (baseline, and 1, 3, 6, and 12 months later) using Inventory of Alienation towards Parents (IAP), Resilience Scale for Chinese Adolescents (RSCA) and Subjective Happiness Scale (SHS). We used hierarchical linear modeling (HLM) for analysis. Results: At baseline, no significant differences were found in the scores of alienation towards parents, resilience, and subjective well-being on gender, grade, or type of LBC. A significant correlation existed between the scores of alienation towards parents, resilience, and subjective well-being. HLM showed a linear increase in the subjective well-being of rural LBC. Alienation toward both mother and father negatively predicted the developmental trajectory of children's subjective well-being over 12 months. Moreover, resilience partially mediated this prediction. Conclusion: This study is among the first to reveal that alienation towards parents predicts the developmental trajectory of later LBC's subjective well-being, with resilience as a mediator. These findings warrant the necessity of paying attention to alienation toward parents to ensure the mental health of LBC, giving valuable guidance to parents, schools and governments.

Neuregulin 1 mitigated prolactin deficiency through enhancing TRPM8 signaling under the influence of melatonin in senescent pituitary lactotrophs.

The age-related alterations in pituitary function, including changes in prolactin (PRL) production contributes to the systemic susceptibility to age-related diseases. Our previous research has shown the involvement of Nrg1 in regulating the expression and secretion of PRL. However, the precise role of Nrg1 in mitigating the senescence of pituitary lactotrophs and the underlying mechanisms are yet to be comprehended. Here, data from the GEPIA database was used to evaluate the association between transient receptor potential cation channel subfamily M member 8 (TRPM8) and PRL in normal human pituitary tissues, followed by immunofluorescence verification using a human pituitary tissue microarray. TRPM8 levels showed a significant positive association with PRL expression in normal human pituitary tissues, and both TRPM8 and PRL levels declined during aging, suggesting that TRPM8 may regulate pituitary aging by affecting PRL production. It was also found that treatment with exogenous neuregulin 1 (Nrg1) markedly delayed the senescence of GH3 cells (rat lactotroph cell line) generated by D-galactose (D-gal). In addition, melatonin reduced the levels of senescence-related markers in senescent pituitary cells by promoting Nrg1 / ErbB4 signaling, stimulating PRL expression and secretion. Further investigation showed that Nrg1 attenuated senescence in pituitary cells by increasing TRPM8 expression. Downregulation of TRPM8 activation eliminated Nrg1-mediated amelioration of pituitary cell senescence. These findings demonstrate the critical function of Nrg1 / ErbB signaling in delaying pituitary lactotroph cell senescence and enhancing PRL production via promoting TRPM8 expression under the modulation of melatonin.

Quercetin intervention reduced hepatic fat deposition in patients with nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled crossover clinical trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become a growing public health problem worldwide. However, there is still lack of effective treatment strategies except lifestyle intervention. OBJECTIVES: To evaluate whether quercetin improves intrahepatic lipid content in patients with NAFLD. METHODS: In this randomized, double-blind, placebo-controlled crossover trial, 41 patients with NAFLD were randomly assigned to receive the quercetin (500 mg) or placebo capsules for 12 wk, then switched interventions for another 12 wk after a 4-wk washout period. The primary outcome was intrahepatic lipid content evaluated by magnetic resonance imaging estimated proton density fat fraction. The secondary outcomes were liver function measurements, etc. Safety outcomes included blood routine. RESULTS: A total of 36 patients completed the trial. In intention-to-treat analyses, the quercetin intervention moderately decreased the intrahepatic lipid contents from 11.5% ± 6.4% to 9.6% ± 5.8%, compared with the placebo intervention (decreased by 0.1% ± 2.6%, P = 0.013 and adjusted P value is 0.028). Body weight and body mass index were mildly reduced by 1.5 ± 2.6 kg and 0.5 ± 0.9 kg/m2 after the quercetin intervention (P < 0.05 and both adjusted P values are 0.038), whereas the reductions were only 0.2 ± 1.8 kg and 0.1 ± 0.7 kg/m2 after the placebo intervention. The intrahepatic lipid content reductions were noticeably positively associated with the body weight losses after the quercetin and placebo interventions (r = 0.557 and 0.412, P < 0.001 and P = 0.007, respectively). Subgroup analyses found that the reduction of intrahepatic lipid contents in females (3.0% ± 3.7%) was about twice as large as that in males (1.4% ± 2.5%) with a trend of statistical significance (P = 0.113 and adjusted P value is 0.061). There were no significant differences in other secondary and safety outcomes. No adverse events associated with study intervention were found. CONCLUSIONS: Twelve weeks treatment of quercetin could reduce intrahepatic lipid contents in patients with NAFLD, possibly explained by a slightly larger body weight loss in the quercetin group. TRIAL REGISTRATION: The trial is registered at www.chictr.org.cn as ChiCTR2100047904.

Multiple algorithms highlight key brain genes driven by multiple anesthetics.

Anesthesia serves as a pivotal tool in modern medicine, creating a transient state of sensory deprivation to ensure a pain-free surgical or medical intervention. While proficient in alleviating pain, anesthesia significantly modulates brain dynamics, metabolic processes, and neural signaling, thereby impairing typical cognitive functions. Furthermore, anesthesia can induce notable impacts such as memory impairment, decreased cognitive function, and diminished intelligence, emphasizing the imperative need to explore the concealed repercussions of anesthesia on individuals. In this investigation, we aggregated gene expression profiles (GSE64617, GSE141242, GSE161322, GSE175894, and GSE178995) from public repositories following second-generation sequencing analysis of various anesthetics. Through scrutinizing post-anesthesia brain tissue gene expression utilizing Gene Set Enrichment Analysis (GSEA), Robust Rank Aggregation (RRA), and Weighted Gene Co-expression Network Analysis (WGCNA), this research aims to pinpoint pivotal genes, pathways, and regulatory networks linked to anesthesia. This undertaking not only enhances comprehension of the physiological changes brought about by anesthesia but also lays the groundwork for future investigations, cultivating new insights and innovative perspectives in medical practice.

Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer.

The phosphoinositide 3-kinase (PI3K)-Akt axis is one of the most frequently activated pathways and is demonstrated as a therapeutic target in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated colorectal cancer (CRC). Targeting the PI3K-Akt pathway has been a challenging undertaking through the decades. Here we unveiled an essential role of E3 ligase SMAD ubiquitylation regulatory factor 1 (Smurf1)-mediated phosphoinositide-dependent protein kinase 1 (PDK1) neddylation in PI3K-Akt signaling and tumorigenesis. Upon growth factor stimulation, Smurf1 immediately triggers PDK1 neddylation and the poly-neural precursor cell expressed developmentally downregulated protein 8 (poly-Nedd8) chains recruit methyltransferase SET domain bifurcated histone lysine methyltransferase 1 (SETDB1). The cytoplasmic complex of PDK1 assembled with Smurf1 and SETDB1 (cCOMPASS) consisting of PDK1, Smurf1 and SETDB1 directs Akt membrane attachment and T308 phosphorylation. Smurf1 deficiency dramatically reduces CRC tumorigenesis in a genetic mouse model. Furthermore, we developed a highly selective Smurf1 degrader, Smurf1-antagonizing repressor of tumor 1, which exhibits efficient PDK1-Akt blockade and potent tumor suppression alone or combined with PDK1 inhibitor in KRAS-mutated CRC. The findings presented here unveil previously unrecognized roles of PDK1 neddylation and offer a potential strategy for targeting the PI3K-Akt pathway and KRAS mutant cancer therapy.

Predicting distant metastasis in nasopharyngeal carcinoma using gradient boosting tree model based on detailed magnetic resonance imaging reports.

BACKGROUND: Development of distant metastasis (DM) is a major concern during treatment of nasopharyngeal carcinoma (NPC). However, studies have demonstrated improved distant control and survival in patients with advanced NPC with the addition of chemotherapy to concomitant chemoradiotherapy. Therefore, precise prediction of metastasis in patients with NPC is crucial. AIM: To develop a predictive model for metastasis in NPC using detailed magnetic resonance imaging (MRI) reports. METHODS: This retrospective study included 792 patients with non-distant metastatic NPC. A total of 469 imaging variables were obtained from detailed MRI reports. Data were stratified and randomly split into training (50%) and testing sets. Gradient boosting tree (GBT) models were built and used to select variables for predicting DM. A full model comprising all variables and a reduced model with the top-five variables were built. Model performance was assessed by area under the curve (AUC). RESULTS: Among the 792 patients, 94 developed DM during follow-up. The number of metastatic cervical nodes (30.9%), tumor invasion in the posterior half of the nasal cavity (9.7%), two sides of the pharyngeal recess (6.2%), tubal torus (3.3%), and single side of the parapharyngeal space (2.7%) were the top-five contributors for predicting DM, based on their relative importance in GBT models. The testing AUC of the full model was 0.75 (95% confidence interval [CI]: 0.69-0.82). The testing AUC of the reduced model was 0.75 (95%CI: 0.68-0.82). For the whole dataset, the full (AUC = 0.76, 95%CI: 0.72-0.82) and reduced models (AUC = 0.76, 95%CI: 0.71-0.81) outperformed the tumor node-staging system (AUC = 0.67, 95%CI: 0.61-0.73). CONCLUSION: The GBT model outperformed the tumor node-staging system in predicting metastasis in NPC. The number of metastatic cervical nodes was identified as the principal contributing variable.

Enzymatic synthesis and sensory evaluation of the novel kokumi compound N-butyryl phenylalanine.

In this study, food-grade glutamine transaminase (TGase) was utilized for the green-catalyzed preparation of N-butyryl amino acids. For improving the reusability of the enzyme preparation, immobilized TG enzyme (94.23% immobilization rate) was prepared. Furthermore, the yield of N-butyryl phenylalanine (BP) synthesized by TGase was obtained as 20.73% by one-factor experiment. The BP synthesis yield of immobilized TGase was 95.03% of that of TGase and remained above 60% of the initial enzyme activity after five runs. The sensory evaluation and E-tongue results showed that the addition of BP significantly increased the umami, saltiness, and richness intensities of the samples, and decreased the intensities of sourness, bitterness, and aftertaste-B. The molecular docking results indicated that hydrogen bonding dominated the binding of BP to taste receptors in the taste presentation mechanism of BP. These results confirmed the potential of BP as a flavor enhancer with promising applications in the food industry.

Auraptene-ameliorating depressive-like behaviors induced by lipopolysaccharide combined with chronic unpredictable mild stress in mice mitigate hippocampal neuroinflammation mediated by microglia.

An inflammatory response is one of the pathogeneses of depression. The anti-inflammatory and neuroprotective effects of auraptene have previously been confirmed. We established an inflammatory depression model by lipopolysaccharide (LPS) injection combined with unpredictable chronic mild stress (uCMS), aiming to explore the effects of auraptene on depressive-like behaviors in adult mice. Mice were divided into a control group, vehicle group, fluoxetine group, celecoxib group, and auraptene group. Then, behavioral tests were conducted to evaluate the effectiveness of auraptene in ameliorating depressive-like behavior. Cyclooxygenase-2 (COX-2), C-reactive protein (CRP), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) were examined by ELISA. Interleukin-10 (IL-10), interleukin-4 (IL-4), and transforming growth factor-ß (TGF-ß) were examined by protein chip technology. The morphology of microglia was observed by the immunohistochemical method. The data showed that, compared with the control group, the vehicle group mice exhibited a depressive-like behavioral phenotype, accompanied by an imbalance in inflammatory cytokines and the activation of microglia in the hippocampus. The depressive behaviors of the auraptene group's mice were significantly alleviated, along with the decrease in pro-inflammatory factors and increase in anti-inflammatory factors, while the activation of microglia was inhibited in the hippocampus. Subsequently, we investigated the role of auraptene in vitro-cultured BV-2 cells treated with LPS. The analysis showed that auraptene downregulated the expression of IL-6, TNF-α, and NO, and diminished the ratio of CD86/CD206. The results showed that auraptene reduced the excessive phagocytosis and ROS production of LPS-induced BV2 cells. In conclusion, auraptene relieved depressive-like behaviors in mice probably via modulating hippocampal neuroinflammation mediated by microglia.

Integrated virtual screening coupled with sensory evaluation identifies N-succinyl-L-tryptophan as a novel compound with multiple taste enhancement properties.

N-Succinyl amino acids (N-Suc-AAs) are garnering attention for their potential as taste-active compounds. The intricate variety of N-Suc-AAs presented considerable challenges in identifying those with taste-active properties. Consequently, we employed structure-based virtual screening to pinpoint taste-active N-Suc-AAs, revealing N-succinyl-L-tryptophan (ST) as a compound with high affinity for different taste receptors. Following this discovery, ST was synthesized through an enzymatic process, achieving a yield of 40.2%, with its structure verified via NMR spectroscopy. Sensory evaluation alongside electronic tongue assessments indicated that ST at a concentration of 1 mg/L significantly enhances umami, kokumi, and saltiness intensities, while concurrently mitigating bitterness from various bitter compounds, whilst itself remaining tasteless. Additionally, time-intensity (TI) results elucidated a marked augmentation in umami duration and a notable diminution in bitterness duration for solutions imbued with 1 mg/L ST. Molecular docking study suggested ST interacted with diverse taste receptors as an agonist or antagonist, primarily through hydrogen bonds and hydrophobic interactions. This study marked the inaugural report on the enzymatic synthesis of ST and its efficacy in improving taste characteristics, underscoring the importance of ST in improving sensory qualities of food products and fostering innovation within the seasoning industry.

Investigation of the multiple taste enhancement properties of N-succinyl-amino acids and their relationship to chemical structure using dynamic sensory techniques.

The present study aimed to explore the similarity and difference in taste enhancement properties of N-succinyl-L-phenylalanine (N-Suc-Phe), N-succinyl-L-tryptophan (N-Suc-Trp), and N-succinyl-L-tyrosine (N-Suc-Tyr) using temporal dominance of sensations (TDS), temporal check-all-that-apply (TCATA), and time-intensity (TI) techniques. Meanwhile, leading taste enhancers in the market, such as N'-[(2,4-dimethoxyphenyl)methyl]-N-(2-pyridin-2-ylethyl) oxamide (DE) was chosen to conduct a comparative analysis with the aforementioned three compounds. Findings from TDS and TCATA revealed that all compounds under investigation notably enhanced umami and saltiness while reducing bitterness in a concentration-dependent fashion (0.25-1 mg/L). Additionally, the TI results indicated that the duration of umami was extended by 50-75%, and the duration of bitterness was decreased by 20-40% upon addition of DE, N-Suc-Phe, N-Suc-Trp, and N-Suc-Tyr (1 mg/L). Among these, N-Suc-Trp was identified as the most effective in augmenting umami and mitigating bitterness, whereas N-Suc-Tyr excelled in enhancing saltiness intensity. Partial least squares regression (PLSR) pinpointed the carbon­carbon double bond as the important structure influencing the enhancement of umami and reduction of bitterness, whereas the phenolic hydroxyl group was identified as critical for enhancing saltiness. This investigation provided insights into the different characteristics of taste enhancement of N-Suc-AAs and the impact of chemical structure on such specificity.

A protein sequence-based deep transfer learning framework for identifying human proteome-wide deubiquitinase-substrate interactions.

Protein ubiquitination regulates a wide range of cellular processes. The degree of protein ubiquitination is determined by the delicate balance between ubiquitin ligase (E3)-mediated ubiquitination and deubiquitinase (DUB)-mediated deubiquitination. In comparison to the E3-substrate interactions, the DUB-substrate interactions (DSIs) remain insufficiently investigated. To address this challenge, we introduce a protein sequence-based ab initio method, TransDSI, which transfers proteome-scale evolutionary information to predict unknown DSIs despite inadequate training datasets. An explainable module is integrated to suggest the critical protein regions for DSIs while predicting DSIs. TransDSI outperforms multiple machine learning strategies against both cross-validation and independent test. Two predicted DUBs (USP11 and USP20) for FOXP3 are validated by "wet lab" experiments, along with two predicted substrates (AR and p53) for USP22. TransDSI provides new functional perspective on proteins by identifying regulatory DSIs, and offers clues for potential tumor drug target discovery and precision drug application.

Molecular simulation screening and sensory evaluation unearth a novel kokumi compound with bitter-masking effect: N-lauroyl-L-tryptophan.

N-lauroyl-L-tryptophan (LT), which has the strongest potential flavor-presenting activity, was skillfully screened from numerous N-Lau-AAs docked to different taste receptors by molecular simulation techniques. Subsequently, LT was synthesized employing food-grade commercial enzymes and structurally characterized, the optimized yields of LT could reach 69.08%, 76.16%, and 50.40%, respectively. Sensory and E-tongue evaluations showed that LT at 1 mg/L significantly benefited the performance of different taste sensations and exhibited different bitter taste masking effects: L-Ile (68.42%), L-Trp (68.18%), D-salicylic acid (48.48%) and quinine (35.00%). The molecular docking results illustrated that LT had a high affinity for various taste receptors, dominated by hydrogen bonding and hydrophobic interactions. This work provided a rare systematic elucidation of the potential and mechanism of enzymatically synthesized LT in enhancing taste properties. It provides novel insights into the directions and strategies for the excavation and innovation of flavor enhancers and food flavors.

Synthesis, taste characteristics and taste mechanism of N-lactoyl leucine from soy sauce using sensory analysis and UPLC-MS/MS.

Recently, amino acid derivatives gradually gained attention, but studies on N-lactoyl-leucine (Lac-Leu) and N-lactoyl-isoleucine (Lac-Ile) are limited. This study aims to explore the contributions of Lac-Leu and Lac-Ile to soy sauce. Lac-Leu and Lac-Ile were synthesized via enzymatic synthesis method catalyzed by Tgase. The mixed solutions containing Lac-Leu were found to have greater taste improvement than those containing Lac-Ile. Sensory evaluation indicated the sour, bitter, and astringent taste of Lac-Leu in water as well as its kokumi, astringent, and umami-enhancing taste in MSG solution. The taste threshold and umami-enhancing threshold of Lac-Leu measured by TDA and cTDA, respectively, were 0.08 mg/mL and 0.16 mg/mL. Molecular docking of Lac-Leu and Lac-Ile with the kokumi receptor CaSR and the umami receptors T1R1 and T1R3 indicated that Lac-Leu had higher affinities with receptors than Lac-Ile. These findings demonstrated the underlying contribution Lac-Leu made to soy sauce, indicating its potential to improve the flavor quality of soy sauce.

Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis.

Linear ubiquitination catalyzed by HOIL-1-interacting protein (HOIP), the key component of the linear ubiquitination assembly complex, plays fundamental roles in tissue homeostasis by executing domain-specific regulatory functions. However, a proteome-wide analysis of the domain-specific interactome of HOIP across tissues is lacking. Here, we present a comprehensive mass spectrometry-based interactome profiling of four HOIP domains in nine mouse tissues. The interaction dataset provides a high-quality HOIP interactome resource with an average of approximately 90 interactors for each bait per tissue. HOIP tissue interactome presents a systematic understanding of linear ubiquitination functions in each tissue and also shows associations of tissue functions to genetic diseases. HOIP domain interactome characterizes a set of previously undefined linear ubiquitinated substrates and elucidates the cross-talk among HOIP domains in physiological and pathological processes. Moreover, we show that linear ubiquitination of Integrin-linked protein kinase (ILK) decreases focal adhesion formation and promotes the detachment of Shigella flexneri-infected cells. Meanwhile, Hoip deficiency decreases the linear ubiquitination of Smad ubiquitination regulatory factor 1 (SMURF1) and enhances its E3 activity, finally causing a reduced bone mass phenotype in mice. Overall, our work expands the knowledge of HOIP-interacting proteins and provides a platform for further discovery of linear ubiquitination functions in tissue homeostasis.

A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson's Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway.

Parkinson's disease (PD) is characterized not only by motor symptoms but also by non-motor dysfunctions, such as olfactory impairment; the cause is not fully understood. Our study suggests that neuronal loss and inflammation in brain regions along the olfactory pathway, such as the olfactory bulb (OB) and the piriform cortex (PC), may contribute to olfactory dysfunction in PD mice, which might be related to the downregulation of the trace amine-associated receptor 1 (TAAR1) in these areas. In the striatum, although only a decrease in mRNA level, but not in protein level, of TAAR1 was detected, bioinformatic analyses substantiated its correlation with PD. Moreover, we discovered that neuronal death and inflammation in the OB and the PC in PD mice might be regulated by TAAR through the Bcl-2/caspase3 pathway. This manifested as a decrease of anti-apoptotic protein Bcl-2 and an increase of the pro-apoptotic protein cleaved caspase3, or through regulating astrocytes activity, manifested as the increase of TAAR1 in astrocytes, which might lead to the decreased clearance of glutamate and consequent neurotoxicity. In summary, we have identified a possible mechanism to elucidate the olfactory dysfunction in PD, positing neuronal damage and inflammation due to apoptosis and astrocyte activity along the olfactory pathway in conjunction with the downregulation of TAAR1.

Energy focusing of broadband Lamb wave by designing excitation waveforms and elastic metamaterials.

In the field of structure health monitoring (SHM), the use of Lamb wave to locate damage is a common method. Energy focusing is beneficial for damage localization because of higher SNR and higher resolution. Optimization design of elastic metamaterials is promising for energy focusing based on speed modulation. However, current design scheme is effective only for narrowband Lamb waves. Compared to narrowband waves, broadband Lamb waves with a larger frequency range carry richer structural information. In this study, an energy focusing method based on broadband Lamb waves by simultaneous designing excitation waveforms and elastic metamaterials is proposed. Firstly, COMSOL finite element simulation software is used to calculate the relationship between the metamaterial structure and the excitation wave. Subsequently, the metamaterial structure and the excitation signal form are designed according to the relationship. Finally, the metamaterial structure is bonded with the aluminum plate using 3D printing PA2200 nylon to verify the effectiveness of the method.

Design, Synthesis, Biological Evaluation and Molecular Docking of Novel F-18-Labeled Focal Adhesion Kinase Inhibitors as Potential Tumor Radiotracers.

Tumor diagnosis, especially at the early stages, holds immense significance. Focal adhesion kinase (FAK) is often highly expressed across various types of tumors, making it a promising target for both therapy and diagnosis. In this study, seven novel inhibitors were designed and synthesized. The inhibitory activity of these compounds against FAK was notably potent, with an IC50 range of 1.27-1968 nM. In particular, compounds 7a and 7c, with IC50 values of 5.59 nM and 1.27 nM, respectively, were radiolabeled with F-18 and then evaluated with S-180 tumor-bearing mice. Subsequently, they exhibited moderate-to-high tumor uptake values, with [18F]7a showing 1.39 ± 0.30%ID/g at 60 min post injection and [18F]7c demonstrating 6.58 ± 0.46%ID/g at 30 min post injection. In addition, the results from docking studies revealed the binding specifics of the studied compounds. Overall, these findings hold the potential to offer valuable guidance for enhancing the development of radiotracers and enzyme inhibitors.