Impacts of audiovisual simultaneity perception on single-task and dual-task gaits in middle-aged and older adults.

BACKGROUND: While dual-task walking requires the ability to integrate sensory information from multiple ongoing sources, it remains unknown whether dual-task walking is more affected than single-task walking by the multisensory integration ability. RESEARCH QUESTION: How does the audiovisual temporal integration ability affect single-task and dual-task gaits in the aging population? METHODS: One hundred and thirty healthy middle-aged and older adults (age = 64.7 ± 6.4 years) completed an audiovisual simultaneity judgment (AVSJ) task and underwent single-task, motor dual-task, and cognitive dual-task gait assessments. In the AVSJ task, participants judged whether a flash and an auditory stimulus presented at different stimulus onset asynchronies were simultaneous. The accuracy and precision of the AVSJ performance were assessed using the point of subjective simultaneity (PSS) and the temporal binding window (δ), respectively. A lower absolute PSS and δ indicated better performance. Participants held a cup of water and performed serial-7 subtraction for motor and cognitive dual-task gait assessments, respectively. The spatiotemporal gait parameters and their variability were calculated. The influences of PSS and δ on the gait parameters of the three gaits were examined with multiple hierarchical regressions. RESULTS: Only the cognitive dual-task gait was significantly affected by PSS and δ. Greater PSS predicted a longer single support time (ß = 0.195, p = 0.024) and its variability (ß = 0.224, p = 0.011). Greater δ predicted greater step time variability (ß = 0.198, p = 0.022). SIGNIFICANCE: Declined perception of audiovisual simultaneity particularly degrades temporal control of cognitive dual-task walking, highlighting the importance of assessing and training this ability after midlife.

Structural basis and synergism of ATP and Na+ activation in bacterial K+ uptake system KtrAB.

The K+ uptake system KtrAB is essential for bacterial survival in low K+ environments. The activity of KtrAB is regulated by nucleotides and Na+. Previous studies proposed a putative gating mechanism of KtrB regulated by KtrA upon binding to ATP or ADP. However, how Na+ activates KtrAB and the Na+ binding site remain unknown. Here we present the cryo-EM structures of ATP- and ADP-bound KtrAB from Bacillus subtilis (BsKtrAB) both solved at 2.8 Å. A cryo-EM density at the intra-dimer interface of ATP-KtrA was identified as Na+, as supported by X-ray crystallography and ICP-MS. Thermostability assays and functional studies demonstrated that Na+ binding stabilizes the ATP-bound BsKtrAB complex and enhances its K+ flux activity. Comparing ATP- and ADP-BsKtrAB structures suggests that BsKtrB Arg417 and Phe91 serve as a channel gate. The synergism of ATP and Na+ in activating BsKtrAB is likely applicable to Na+-activated K+ channels in central nervous system.

Preparation of (S)-epichlorohydrin using a novel halohydrin dehalogenase by selective conformation adjustment.

Chiral epichlorohydrin (ECH) is an attractive intermediate for chiral pharmaceuticals and chemicals preparation. The asymmetric synthesis of chiral ECH using 1,3-dicholoro-2-propanol (1,3-DCP) catalyzed by a haloalcohol dehalogenase (HHDH) was considered as a feasible approach. However, the reverse ring opening reaction caused low optical purity of chiral ECH, thus severely restricts the industrial application of HHDHs. In the present study, a novel selective conformation adjustment strategy was developed with an engineered HheCPS to regulate the kinetic parameters of the forward and reverse reactions, based on site saturation mutation and molecular simulation analysis. The HheCPS mutant E85P was constructed with a markable change in the conformation of (S)-ECH in the substrate pocket and a slight impact on the interaction between 1,3-DCP and the enzyme, which resulted in the kinetic deceleration of the reverse reactions. Compared with HheCPS, the catalytic efficiency (kcat(S)-ECH/Km(S)-ECH) of the reversed reaction dropped to 0.23-fold (from 0.13 to 0.03 mM-1 s-1), while the catalytic efficiency (kcat(1,3-DCP)/Km(1,3-DCP)) of the forward reaction only reduced from 0.83 to 0.71 mM-1 s-1. With 40 mM 1,3-DCP as substrate, HheCPS E85P catalyzed the synthesis of (S)-ECH with the yield up to 55.35% and the e.e. increased from 92.54 to >99%. Our work provided an effective approach for understanding the stereoselective catalytic mechanism as well as the green manufacturing of chiral epoxides.

[Pollution Characteristics and Ecological Risk Assessment of Microplastics in the Yangtze River Basin].

The Yangtze River, the largest river in China, has not been comprehensively studied for its basin's microplastic pollution status. Therefore, a comprehensive investigation and assessment system of microplastics was developed at the river basin scale to characterize the spatial distribution and composition of microplastics in the Yangtze River Basin in order to analyze their influencing factors and assess their ecological risks. The results showed that the microplastic abundance in the study area ranged from 21 to 44 080 n·m-3, with an average abundance of 4 483 n·m-3. The spatial distribution of microplastic abundance was higher in the tributaries than in the main streams (except the Ganjiang Basin), with the Chengdu of the Minjiang Basin being the tributary area with the highest abundance of microplastics detected. The size of microplastics in the river basin was concentrated in the 0-1 mm range; the shapes were mainly fiber and fragment; and the colors were mainly colored and transparent. Further, introducing the diversity index of microplastics, it was found that both the Simpson index and the Shannon-Wiener index could quantify the diversity of microplastic characteristic composition in the river basin, but there were certain differences in the changing trends between the two. Regression analysis showed that anthropogenic activities were significantly and positively correlated with microplastic abundance (P<0.05), and among the eight anthropogenic activity factors, civilian vehicle ownership and tourism income were the most strongly correlated with microplastic abundance, indicating that transportation and tourism were the main factors influencing microplastic distribution. From the perspective of the potential ecological risk index of microplastics, microplastics in the Yangtze River Basin posed a certain ecological risk, with 68.97% of the area falling within risk zones III and IV, with the ecological risk of microplastics in Taihu Lake warranting more widespread attention.

Macrophage-Capturing Self-Assembly Photosensitizer Nanoparticles Induces Immune Microenvironment Re-Programming and Golgi-Responsive Immunogenic Cell Death in Head and Neck Carcinoma.

Head and neck carcinoma treatment is shifted toward the combination of therapy causing immune checkpoint blockade (ICB) and immunogenic cell death. In this study, a CSFRi-chimeric TAMCSFR+-targeting extracellular vesicle (EV@CSFRi) platform is developed and designed an intracellular protoporphyrin conjugated with RVRR peptide sequence for furin-cleavage to perform Golgi-targeting and generating ROS (GT-RG). The graphical abstract illustrates the self-assembly of GT-RG nanoparticles into nanofiber through the hydrophily of RVRR and hydrophobicity of RG, and the red line indicates the site of furin cleavage. As is shown in the Graphical abstract, the Golgi-targeting Protoporphyrin-RVRR platform is composed with CSFRi-chimeric extracellular vesicles and forms the tumor-responsive TAM-reprogramming bilayers (GT-RGEV@CSFRi). The GT-RGEV@CSFRi acted as a multifunctional theranostic platform, which can induce immunogenic cell death and further help modulate TAM, thus suppressing the HNC xenograft model by combination therapy with anti-PD-1.

Leaching kinetics and bioaccumulation potential of additive-derived organophosphate esters in microplastics.

Considerable research has been conducted to evaluate microplastics (MPs) as vehicles for the transfer of hazardous pollutants in organisms. However, little effort has been devoted to the chemical release of hazardous additive-derived pollutants from MPs in gut simulations. This study looked at the leaching kinetics of organophosphate esters (OPFRs) from polypropylene (PP) and polystyrene (PS) MPs in the presence of gut surfactants, specifically sodium taurocholate, at two biologically relevant temperatures for marine organisms. Diffusion coefficients of OPFRs ranged from 1.71 × 10-20 to 4.04 × 10-18 m2 s-1 in PP and 2.91 × 10-18 to 1.51 × 10-15 m2 s-1 in PS. The accumulation factors for OPFRs in biota-plastic and biota-sediment interactions ranged from 1.52 × 10-3-69.1 and 0.02-0.7, respectively. Based on B3LYP/6-31G (d,p) calculations, the biodynamic model analysis revealed a slight increase in the bioaccumulation of OPFRs at a minor dose of 0.05% MPs. However, at higher concentrations (0.5% and 5% MPs), there was a decrease in bioaccumulation compared to the lower concentration for most OPFR compounds. In general, the ingestion of PE MPs notably contributed to the bioaccumulation of OPFRs in lugworms, whereas the contribution of PP and PS MPs was minimal. This could vary among sites exhibiting varying levels of MP concentrations or MPs displaying stronger affinities towards chemicals.

Within-Session Reliability of fNIRS in Robot-Assisted Upper-Limb Training.

Functional near-infrared spectroscopy (fNIRS) seems opportune for neurofeedback in robot-assisted rehabilitation training due to its noninvasive, less physical restriction, and no electromagnetic disturbance. Previous research has proved the cross-session reliability of fNIRS responses to non-motor tasks (e.g., visual stimuli) and fine-motor tasks (e.g., finger tapping). However, it is still unknown whether fNIRS responses remain reliable 1) in gross-motor tasks, 2) within a training session, and 3) for different training parameters. Hence, this study aimed to investigate the within-session reliability of fNIRS responses to gross-motor tasks for different training parameters. Ten healthy participants were recruited to conduct right elbow extension-flexion in three robot-assisted modes. The Passive mode was fully motor-actuated, while Active1 and Active2 modes involved active engagement with different resistance levels. FNIRS data of three identical runs were used to assess the within-session reliability in terms of the map- ( R2 ) and cluster-wise ( Roverlap ) spatial reproducibility and the intraclass correlation (ICC) of temporal features. The results revealed good spatial reliability ( R2 up to 0.69, Roverlap up to 0.68) at the subject level. Besides, the within-session temporal reliabilities of Slope, Max/Min, and Mean were between good and excellent ( ICC < 0.86). We also found that the within-session reliability was positively correlated with the intensity of the training mode, except for the temporal reliability of HbO in Active2 mode. Overall, our results demonstrated good within-session reliability of fNIRS responses, suggesting fNIRS as reliable neurofeedback for constructing closed-loop robot-assisted rehabilitation systems.

Reliable quantitative detection of uric acid in urine by surface-enhanced Raman spectroscopy with endogenous internal standard.

Abnormal levels of uric acid (UA) in urine serve as warning signs for gout and metabolic cardiovascular diseases, necessitating the monitoring of UA levels for early prevention. However, the current analytical methods employed suffer from limitations in terms of inadequate suitability for home-based applications and the requirement of non-invasive procedures. In this approach, creatinine, a metabolite with a constant excretion rate, was incorporated as an endogenous internal standard (e-IS) for calibration, presenting a rapid, pretreatment-free, and accurate strategy for quantitative determination of UA concentrations. By utilizing urine creatinine as an internal reference value to calibrate the signal fluctuation of surface-enhanced Raman spectroscopy (SERS) of UA, the quantitative accuracy can be significantly improved without the need for an external internal standard. Due to the influence of the medium, UA, which carries a negative charge, is selectively adsorbed by Au@Ag nanoparticles functionalized with hexadecyltrimethylammonium chloride (CTAC) in this system. Furthermore, a highly convenient detection method was developed, which eliminates the need for pre-processing and minimizes matrix interference by simple dilution. The method was applied to the urine detection of different volunteers, and the results were highly consistent with those obtained using the UA colorimetric kit (UACK). The detection time of SERS was only 30 s, which is 50 times faster than UACK. This quantitative strategy of using urinary creatinine as an internal standard to correct the SERS intensity of uric acid is also expected to be extended to the quantitative detection needs of other biomarkers in urine.

Increased Risk of Coronary Artery Disease in People with Diagnosis of Neuromuscular Disorders: A Nationwide Retrospective Population-Based Case-Control Study.

The existing literature has explored carpal tunnel syndrome (CTS) and determined that it could be a risk for coronary artery disease (CAD), but there has been little research comparing the relevance of CAD with other neuromuscular disorders (NMDs) to CTS. This case-control study explored the association between CTS, stenosing tenosynovitis (ST), and ulnar side NMDs and CAD. The study utilized data from Taiwan's National Health Insurance Research Database, focusing on health insurance claims. Between January 2000 and December 2011, we employed the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes to identify 64,025 CAD patients as the case group. The control group consisted of an equal number of individuals without CAD, matched for age, sex, and index year of CAD. Logistic regression analysis was employed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for each variable. Multivariate analysis, after adjusting for sociodemographic factors and comorbidities, revealed a significantly higher likelihood of a previous diagnosis of CTS in the CAD group compared to the comparison control group. However, neither ST nor the ulnar side NMDs had any statistical significance. These results indicated that median nerve injury, rather than other NMDs, may uniquely serve as a predisposing factor of CAD.

Exploring quantitative measures in metacognition of emotion.

Metacognition of emotion (meta-emotion) refers to the ability to evaluate and identify one's emotional feelings. No previous study has defined and measured this construct through objective and quantitative procedures. We established a reliable method to measure meta-emotion. With a two-interval forced-choice procedure, participants selected which of two pictures elicited stronger positive emotion; via the Law of Comparative Judgment, their responses were used to compute individual psychological distances for the emotional responses triggered by the pictures. Then, participants were asked to judge whether a pre-exposed picture induced a stronger positive emotion than the median of that elicited by the whole picture set, followed by a confidence rating. By utilizing each individual's psychological distance, the correctness of a participant's emotional experience was quantified by d', and meta-emotion was quantified using meta-d', M-ratio, and M-diff as indices of metacognitive sensitivity and efficiency based on Signal-Detection Theory. Test-retest reliabilities, validated by Spearman correlation, were observed in meta-d', M-ratio, and marginally with M-diff, suggesting the stability of meta-emotion in the current design. This study unveils a validated procedure to quantify meta-emotion, extendable for assessing metacognition of other subjective feelings. Nevertheless, caution is warranted in interpretation, as the measured processes may be influenced by non-metacognitive factors.

Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy.

Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.

Chronic neurotoxicity of Tetrabromobisphenol A: Induction of oxidative stress and damage to neurons in Caenorhabditis elegans.

Tetrachlorobisphenol A (TCBPA) has been used as an alternative flame retardant in various fields. However, the long-term effects of TCBPA on the nervous system remain unclear. Thus, Caenorhabditis elegans (L4 larvae) were selected as a model animal to investigate the neurotoxic effects and underlying mechanisms after 10 d of TCBPA exposure. Exposure to TCBPA (0.01-100 µg/L) decreased locomotive behavior in a concentration-dependent manner. In addition, reactive oxygen species (ROS) formation and lipofuscin accumulation were significantly increased, and the expression of sod-3 was upregulated in the exposed nematodes, indicating that TCBPA exposure induced oxidative damage. Furthermore, 100 µg/L TCBPA exposure caused a reduction in dopamine and serotonin levels, and damage in dopaminergic and serotoninergic neurons, which was further confirmed by the downregulated expression of related genes (e.g., dop-1, dop-3, cat-1, and mod-1). Molecular docking analysis demonstrated the potential of TCBPA to bind to the neurotransmitter receptor proteins DOP-1, DOP-3, and MOD-1. These results indicate that chronic exposure to TCBPA induces neurotoxic effects on locomotive behavior, which is associated with oxidative stress and damage to dopaminergic and serotoninergic neurons.

Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.

Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid ß-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.

The silk gland proteome of Stenopsyche angustata provides insights into the underwater silk secretion.

Caddisworms (Trichoptera) spin adhesive silks to construct a variety of underwater composite structures. Many studies have focused on the fibroin heavy chain of caddisworm silk and found that it contains heavy phosphorylation to maintain a stable secondary structure. Besides fibroins, recent studies have also identified some new silk proteins within caddisworm silk. To better understand the silk composition and its secretion process, this study reports the silk gland proteome of a retreat-building caddisworm, Stenopsyche angustata Martynov (Trichoptera, Stenopsychidae). Using liquid chromatography tandem mass spectrometry (LC-MS/MS), 2389 proteins were identified in the silk gland of S. angustata, among which 192 were predicted as secreted silk proteins. Twenty-nine proteins were found to be enriched in the front silk gland, whereas 109 proteins were enriched in the caudal silk gland. The fibroin heavy chain and nine uncharacterized silk proteins were identified as phosphorylated proteins. By analysing the sequence of the fibroin heavy chain, we found that it contains 13 Gly/Thr/Pro-rich regions, 12 Val/Ser/Arg-rich regions and a Gly/Arg/Thr-rich region. Three uncharacterized proteins were identified as sericin-like proteins due to their larger molecular weights, signal peptides and repetitive motifs rich in serine. This study provides valuable information for further clarifying the secretion and adhesion of underwater caddisworm silk.

The Clinical Value of Apparent Diffusion Coefficient of Readout Segmentation of Long Variable Echo Trains and Correlation With Ki-67 Expression in Distal Rectal Cancer.

OBJECTIVE: The aim of the study is to explore the clinical value of the apparent diffusion coefficient (ADC) derived from the readout segmentation of long variable echo trains (RESOLVE) technique for identifying clinicopathologic features of distal rectal cancer and correlations between ADC and Ki-67 expression. METHODS: The data of 112 patients with a proven pathology of distal rectal cancer who underwent preoperative magnetic resonance imaging were retrospectively analyzed. The mean ADC value was measured using the "full-layer and center" method. Differences in ADC values and Ki-67 expression in different clinical stages, pathological types, and tumor differentiation were compared using analysis of variance. Correlations between ADC value and clinicopathologic features were assessed using Spearman correlation analysis. RESULTS: Interobserver agreement of confidence levels from 2 radiologists was excellent for ADC measurement ( k =  0.85). Patients with a lower clinical stage, well-differentiated adenocarcinomas, and a higher possibility of mucinous adenocarcinoma exhibited a positive correlation with higher ADC values, but these factors were negatively correlated with Ki-67 expression (all P < 0.05). We found that ADC value was negatively correlated with Ki-67 expression ( r = -0.62, P < 0.001). CONCLUSIONS: The ADC value generated by RESOLVE sequences was significantly associated with clinicopathologic features and Ki-67 expression in patients with distal rectal cancer in this study. Thus, the ADC value could be considered a new noninvasive imaging biomarker that could be helpful in predicting the biological properties of distal rectal cancer.

Construction of n-type homogeneous to improve interfacial carrier transfer for enhanced photoelectrocatalytic hydrolysis.

Photoelectrocatalyzed hydrogen production plays an important role in the path to carbon neutrality. The construction of heterojunctions provides an ideal example of an oxygen precipitation reaction. In this work, the performance of the n-n type heterojunction CeBTC@FeBTC/NIF in the photoelectronically coupled catalytic oxygen evolution reaction (OER) reaction is presented. The efficient transfer of carriers between components enhances the catalytic activity. Besides, the construction of heterojunctions optimizes the energy level structure and increases the absorption of light, and the microstructure forms holes with a blackbody effect that also enhances light absorption. Consequently, CeBTC@FeBTC/NIF has excellent photoelectric coupling catalytic properties and requires an overpotential of only 300 mV to drive a current density of 100 mA cm-2 under illumination. More importantly, the n-n heterojunction was found to be effective in enhancing charge and photogenerated electron migration by examining the carrier density of each component and carrier diffusion at the interface.

[Research progress in signaling pathways related to treatment of functional dyspepsia with traditional Chinese medicine].

Functional dyspepsia(FD) is a prevalent functional gastrointestinal disease characterized by recurrent and long-lasting symptoms that significantly impact the quality of life of patients. Currently, western medicine treatment has not made breakthrough progress and mainly relies on symptomatic therapies such as gastrointestinal motility agents, acid suppressants, antidepressants/anxiolytics, and psychotherapy. However, these treatments have limitations in terms of insufficient effectiveness and safety. Traditional Chinese medicine(TCM) possesses unique advantages in the treatment of FD. Through literature search in China and abroad, it has been found that the mechanisms of TCM in treating FD is associated with various signaling pathways, and research on these signaling pathways and molecular mechanisms has gradually become a focus. The main signaling pathways include the SCF/c-Kit signaling pathway, 5-HT signaling pathway, CRF signaling pathway, AMPK signaling pathway, TRPV1 signaling pathway, NF-κB signaling pathway, and RhoA/ROCK2/MYPT1 signaling pathway. This series of signaling pathways can promote gastrointestinal motility, alleviate anxiety, accelerate gastric emptying, reduce visceral hypersensitivity, and improve duodenal micro-inflammation in the treatment of FD. This article reviewed the research on TCM's regulation of relevant signaling pathways in the treatment of FD, offering references and support for further targeted TCM research in the treatment of FD.

Correlation Between Lipoprotein-Related Phospholipase A2 and Metabolic Syndrome.

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been recognized as a valuable biomarker for identifying the risk of cardiovascular diseases and inflammation. Furthermore, there is strong evidence to suggest that metabolic syndrome is closely associated with chronic inflammation. Accordingly, the present study endeavors to examine the potential correlation between metabolic syndrome and the levels of Lp-PLA2. Methods: To explore the relationship between Lp-PLA2 levels and metabolic syndrome, and to establish the predictive cut-off value of Lp-PLA2, a retrospective analysis was conducted using medical data from a sample of 3549 Chinese adults (comprising 2182 men and 1367 women) aged between 18 and 50 years, who had undergone health check-ups. In addition, the study also sought to investigate any potential differences in Lp-PLA2 levels based on sex and age. Results: The analysis of the data indicated that participants had a mean age of 44.2 years, a mean Lp-PLA2 level of 589 IU/L, and a metabolic syndrome prevalence of 22%. Lp-PLA2 levels were significantly different between males and females, and a significant correlation was observed between Lp-PLA2 levels and clinical and metabolic characteristics, including BMI, cholesterol, and triglycerides. Interestingly, Lp-PLA2 demonstrated potential as an indicator of metabolic syndrome, particularly in females, despite other biomarkers, such as TG/HDL-C and WHR, exhibiting better area under the curve. Conclusion: Our findings suggest that Lp-PLA2 may serve as a useful biomarker for identifying individuals at risk of developing metabolic syndrome, particularly in females. Further research is needed to explore the potential of Lp-PLA2 as a diagnostic and therapeutic target for metabolic syndrome.

Development of triazole-based PKC-inhibitors to overcome resistance to EGFR inhibitors in EGFR-mutant lung cancers.

Protein kinase C delta (PKCδ) is prominently expressed in the nuclei of EGFR-mutant lung cancer cells, and its presence correlates with poor survival of the patients undergoing EGFR inhibitor treatment. The inhibition of PKCδ has emerged as a viable approach to overcoming resistance to EGFR inhibitors. However, clinical-grade PKCδ inhibitors are not available, highlighting the urgent needs for the development of effective drugs that target PKCδ. In this study, we designed and synthesized a series of inhibitors based on the chemical structure of a pan PKC inhibitor sotrastaurin. This was achieved by incorporating a triazole ring group into the original sotrastaurin configuration. Our findings revealed that the sotrastaurin derivative CMU-0101 exhibited an elevated affinity for binding to the ATP-binding site of PKCδ and effectively suppressed nuclear PKCδ in resistant cells in comparison to sotrastaurin. Furthermore, we demonstrated that CMU-0101 synergistically enhanced EGFR TKI gefitinib sensitivity in resistant cells. Altogether, our study provides a promising strategy for designing and synthesizing PKCδ inhibitors with improved efficacy, and suggests CMU-0101 as a potential lead compound to inhibit PKCδ and overcome TKI resistance in lung cancers.

Coffee as a dietary strategy to prevent SARS-CoV-2 infection.

BACKGROUND: To date, most countries lifted the restriction requirement and coexisted with SARS-CoV-2. Thus, dietary behavior for preventing SARS-CoV-2 infection becomes an interesting issue on a daily basis. Coffee consumption is connected with reduced COVID-19 risk and correlated to COVID-19 severity. However, the mechanisms of coffee for the reduction of COVID-19 risk are still unclear. RESULTS: Here, we identified that coffee can inhibit multiple variants of the SARS-CoV-2 infection by restraining the binding of the SARS-CoV-2 spike protein to human angiotensin-converting enzyme 2 (ACE2), and reducing transmembrane serine protease 2 (TMPRSS2) and cathepsin L (CTSL) activity. Then, we used the method of "Here" (HRMS-exploring-recombination-examining) and found that isochlorogenic acid A, B, and C of coffee ingredients showed their potential to inhibit SARS-CoV-2 infection (inhibitory efficiency 43-54%). In addition, decaffeinated coffee still preserves inhibitory activity against SARS-CoV-2. Finally, in a human trial of 64 subjects, we identified that coffee consumption (approximately 1-2 cups/day) is sufficient to inhibit infection of multiple variants of SARS-CoV-2 entry, suggesting coffee could be a dietary strategy to prevent SARS-CoV2 infection. CONCLUSIONS: This study verified moderate coffee consumption, including decaffeination, can provide a new guideline for the prevention of SARS-CoV-2. Based on the results, we also suggest a coffee-drinking plan for people to prevent infection in the post-COVID-19 era.