Radiotherapy activates picolinium prodrugs in tumours.

Radiotherapy-induced prodrug activation provides an ideal solution to reduce the systemic toxicity of chemotherapy in cancer therapy, but the scope of the radiation-activated protecting groups is limited. Here we present that the well-established photoinduced electron transfer chemistry may pave the way for developing versatile radiation-removable protecting groups. Using a functional reporter assay, N-alkyl-4-picolinium (NAP) was identified as a caging group that efficiently responds to radiation by releasing a client molecule. When evaluated in a competition experiment, the NAP moiety is more efficient than other radiation-removable protecting groups discovered so far. Leveraging this property, we developed a NAP-derived carbamate linker that releases fluorophores and toxins on radiation, which we incorporated into antibody-drug conjugates (ADCs). These designed ADCs were active in living cells and tumour-bearing mice, highlighting the potential to use such a radiation-removable protecting group for the development of next-generation ADCs with improved stability and therapeutic effects.

Association between soybean product consumption and executive function in Chinese Tibetan children and adolescents.

Objective: This sought to explore the association between soybean product consumption and executive function (EF) in Chinese Tibetan adolescents in high-altitude areas. Methods: A total of 1,184 Tibetan children and adolescents were tested on demographic variables, soybean product consumption, and executive function in Lhasa and Nagchu regions of Tibet, China, using stratified whole population sampling. One-way ANOVA, linear regression analysis, and logistic regression analysis were used to analyze the associations existing between soybean product consumption and executive function. Results: The proportions of Hardly ever, Occasionally, and Often in Soy Consumption among Tibetan children and adolescents in high altitude areas of Tibet, China were 21.7, 50.3, and 28.0%, respectively. The difference in 2 back reaction time among Tibetan children and adolescents with different soybean product consumption was statistically significant (F = 6.374, p = 0.002). The difference in conversion function reaction time was also statistically significant (F = 8.129, p < 0.001). Taking the soybean product consumption ≥6 t/w group as the reference group, after adjusting the relevant factors, those with soybean product consumption ≤1 t/w showed a statistically significant increase in Inhibit Function Dysfunction (OR = 1.844, 95% CI: 1.152, 2.951) and Conversion Function Dysfunction (OR = 2.008, 95% CI: 1.106, 3.646) had an increased risk of Conversion Function Dysfunction (OR = 2.008, 95% CI: 1.106, 3.646), which was significantly different (p < 0.05). Conclusion: There is an association between soybean product consumption and inhibitory control and translational flexibility of brain executive functions in Chinese Tibetan children and children and adolescents at high altitude.

Novel Nitrophenyl Substituted Anthranilic Diamide Derivatives: Design, Synthesis, Selectivity, and Antiresistance.

Diamide insecticides have gained popularity due to their high efficacy and low toxicity to nontarget organisms. However, diamide-associated resistance has emerged recently, causing a significant reduction in their potency, thereby hindering sustainable agricultural development. Here, we explored novel diamide insecticide analogs and, using a structure-based approach, rationally designed and synthesized 28 nitrophenyl substituted anthranilic diamides. Most of the compounds showed moderate to good activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. Among them, compounds Ia and Im showed extraordinarily high activity and their mode of action was verified on isolated neurons. Additionally, Im exhibited over 10-fold greater potency than chlorantraniliprole in a HEK293 cell line stably expressing S. frugiperda ryanodine receptors (SfRyRs) containing the resistance mutations, G4891E and I4734M. The binding modes of Im in the SfRyRs were predicted using in silico molecular docking analysis. Our novel nitrophenyl substituted anthranilic diamide derivatives provide valuable insights for the design of insecticidal RyR-targeting compounds to effectively control both wild type and diamide insecticide-resistant lepidopteran pests.

Bioorthogonal chemistry for prodrug activation in vivo.

Prodrugs have emerged as a major strategy for addressing clinical challenges by improving drug pharmacokinetics, reducing toxicity, and enhancing treatment efficacy. The emergence of new bioorthogonal chemistry has greatly facilitated the development of prodrug strategies, enabling their activation through chemical and physical stimuli. This "on-demand" activation using bioorthogonal chemistry has revolutionized the research and development of prodrugs. Consequently, prodrug activation has garnered significant attention and emerged as an exciting field of translational research. This review summarizes the latest advancements in prodrug activation by utilizing bioorthogonal chemistry and mainly focuses on the activation of small-molecule prodrugs and antibody-drug conjugates. In addition, this review also discusses the opportunities and challenges of translating these advancements into clinical practice.

Relationship between cardiorespiratory fitness and executive function of Chinese Tibetan adolescents aged 13-18.

OBJECTIVES: Explore the correlation between cardiorespiratory fitness (CRF) and execution function (EF) of Chinese Tibetan adolescents at high altitude (HA) areas. DESIGN: A cross-sectional survey was used to study 1138 participants aged 13-18 (47.72% boys) at baseline. METHODS: Lhasa (3650 m), Nagqu (4500 m), Qamdo (3500 m), and Nyingchi (3100 m) in China were chosen. CRF was measured by the 20 m shuttle run test (20mSRT) and a subsequent estimation of their maximal oxygen consumption (V̇O2max) was calculated using the Léger equations. The three core EFs (inhibition, working memory, and cognitive flexibility) were tested by a modified Eriksen flanker, N-back, and a more-odd shifting. The association between CRF and EF was explored by Pearson correlation, one-way ANOVA, and stratified regression. RESULTS: The reaction time (RT) of 1-back, cognitive flexibility with V̇O2max showed a declining trend, (F = 34.475, 27.498, P < 0.01). Interestingly, 2-back RT went up and then went down with V̇O2max. (F = 29.55, P < 0.01). After increasing V̇O2max as a variable, a stratified regression analysis with the RT for 1-back, 2-back, and cognitive flexibility showed that ΔR2 equaled 0.107 ms, 0.071 ms, and 0.091 ms, respectively (P < 0.01). With V̇O2max increased by 1 mL/kg/min, the RT of 1-back, 2-back, and cognitive flexibility shortened 14.697 ms, 15.689 ms, and 11.771 ms, respectively. CONCLUSIONS: CRF was positively associated with working memory, and cognitive flexibility development among Chinese Tibetan adolescents living at HA areas, respectively.

Associations between waist circumference and executive function among Chinese Tibetan adolescents living at high altitude.

Background: Associations between body composition and execution function (EF) were currently studied in low altitude (LA) areas. However, the research on the correlation between waist circumference (WC) and EF among adolescents living at high altitude (HA) was limited. Objective: We sought to explore the association between WC and EF in Chinese Tibetan adolescents aged 13-18 years in HA areas. Methods: After excluding invalid data and extreme values, 1,228 participants (583 boys and 645 girls) were eventually included. The areas of Lhasa (average elevation of 3650 m), Nagqu (4500 m), Qamdo (3500 m), and Nyingchi (3100 m) in China were chosen as study sites. Participants completed tasks to measure inhibitory control, working memory, and cognitive flexibility. The predictive association between WC and EF was explored by One-way ANOVA, Pearson correlation, and linear regression analysis. Results: After controlling for concomitant variables, the reaction time (RT) of responding to inhibitory control (difference incongruent and congruent), working memory (1-back, 2-back), and cognitive flexibility (heterogeneous, difference in heterogeneous and homogeneous) stimuli in subjects with WC ≥ 85th percentile was longer than that in those with WC of the 15th percentile or below [by 1.785 ms (95% CI: 0.078, 3.491), 208.734 ms (95% CI: 96.886, 320.582), 106.679 ms (95% CI: 16.485, 196.873), 82.307 ms (95% CI: 19.171, 145.442), and 58.397 ms (95% CI: 0.343,116.452), respectively], (P < 0.05). Conclusion: After adjustment for concomitant variables, WC was significantly positively associated with the RT of inhibitory control, working memory, and cognitive flexibility among Chinese Tibetan adolescents in HA areas.

Proportion of Chinese Children and Adolescents Meeting 24-Hour Movement Guidelines and Associations with Overweight and Obesity.

Background: Since there is little knowledge about the 24-hour movement behaviors of Chinese children and adolescents, the purposes of this study were to investigate the proportion of Chinese children and adolescents meeting the 24-Hour Movement Guidelines and to further evaluate its relationship with overweight and obesity. Methods: A total of 440 children and adolescents aged 7−18 years from 7 cities in China were selected to measure physical activity using accelerometers, and sleep (SLP) and screen time (ST) using questionnaires. The data were analyzed with the independent T-test, Mann−Whitney U test, Cox−Stuart test, chi-square test, and logistic regression. Results: The proportion of Chinese children and adolescents meeting the overall 24-Hour Movement Guidelines was 7.3%. Boys (11.8%) were higher than girls (3.4%) (p < 0.001) and showed a downward trend with age (Ptrend = 0.03). The rates of overweight and obesity among children and adolescents who met the ST, MVPA + ST, ST + SLP, and MVPA + SLP + ST guidelines were 39%, 15%, and 36%, and 25% did not meet any guidelines. The rates of overweight and obesity among those who met 1, 2, and 3 guidelines were lower than the rate among those who did not meet any guidelines (odds ratio (OR) = 0.51, 95% confidence interval (CI): 0.22−1.17; OR = 0.32, 95% CI: 0.13−0.77; OR = 0.23, 95% CI: 0.07−0.81) and showed a decreasing trend (Ptrend = 0.006). Conclusions: The proportion of Chinese children and adolescents meeting the overall 24-Hour Movement Guidelines was low. The rate of overweight and obesity among children and adolescents who met the overall 24-Hour Movement Guidelines was the lowest compared with the rates among those who met any one or two. There was a dose−response relationship between the number of guidelines met and the overweight and obesity rate.

The predictive equations of resting metabolic rate for Tibetan adolescents aged 13-18 in Tibet, China.

OBJECTIVES: The resting metabolic rate (RMR) predictive equations suitable for Tibetan adolescents in Tibet, China, were developed to provide a reference for their reasonable energy intake. METHODS: We measured RMR by indirect calorimetry and body composition by bioelectrical impedance analysis in 325 Tibetan adolescents aged 13-18 years in Tibet, China. Stepwise regression analysis was used to develop the predictive equations. Pearson correlation analysis, paired sample t test, bias rate, concordance correlation coefficient (CCC) and Bland-Altman were used to verify the validity of the predictive equations. RESULTS: The R2 of Model 8 (0.642) was larger than Model 2 (boys, 0.642; girls, 0.533) and Model 7 (0.540), and Model 10 (0.534) was larger than Model 4 (boys, 0.531; girls, 0.443) and Model 9 (0.477).Compared with the existing predictive equations, the correlation (0.68-0.84) between the predicted values and the measured values, CCC (0.74-0.81) and consistency (Similar proportions within the upper and lower limits but lower differences) were higher and the bias rate (-1.0% to -2.5%) and root mean square error (207.4-263.7 kcal/day) were lower in this study. By comprehensive comparison, Model 8 and Model 10 were more valid. CONCLUSIONS: The existing predictive equations cannot accurately predict the RMR of Tibetan adolescents in Tibet, China. In this study, the age segmentation predictive equations with age, sex, and fat free mass (FFM) as independent variables were more valid. The predictive equations were as follows: RMR (kcal/day) = 50.1 × FFM (kg) - 202.8 × Sex (F: 0; M: 1) - 72.1 × Age + 930.3, 13-15 years; RMR (kcal/day) = 58.4 × FFM (kg) - 441.1 × Sex (F: 0; M: 1) - 702.2, 16-18 years.

Comparison of Cardiorespiratory Fitness of Chinese Tibetan Adolescents with Their Han Counterparts: A Cross-Sectional Retrospective Study.

Cardiorespiratory fitness (CRF) is a core element of healthy physical fitness. Foreign attention to CRF in adolescents at different altitudes is high, while less research has been conducted on Chinese adolescents. In order to compare the CRF of Chinese Tibetan adolescents with their Han counterparts born and raised at high altitude and Chinese Han adolescents at sea level. A total of 2748 participants, including Chinese Tibetan adolescents, Chinese Han adolescents born and raised at high altitudes, and Chinese Han adolescents at sea level aged 12-18 years old, were obtained using convenience sampling and random cluster sampling. The method of the 20 m shuttle run test (20 m SRT) test was used to derive VO2max by equation. One-way ANOVA and LSD methods were conducted, and effect sizes were calculated to compare the CRF of the three types of adolescents. Regression analysis was used to analyze the relationship between altitude and VO2max. The VO2max scores of Chinese Tibetan adolescents and Chinese Han adolescents at sea level were higher than Chinese Han adolescents born and raised at high altitudes. For both boys and girls, the VO2max scores of Chinese Tibetan adolescents exceeded Chinese Han adolescents at sea level after the age of 16 years old. Regression analysis showed that altitude was inversely associated with VO2max. The pace of lung growth may distinguish Chinese Tibetan adolescents from Chinese Han adolescents born and raised at high altitudes. The results of the study suggest that we should focus on the changes in CRF in adolescents at different altitudes and should adopt different CRF interventions for adolescents at different altitudes.

The Multistage 20-Meter Shuttle Run Test Reference Values for Tibetan Children and Adolescents in Tibet, China.

OBJECTIVE: Cardiorespiratory fitness (CRF) reference data for Tibetan (Zang ethnicity) children and adolescents at high altitudes in Tibet of China are lacking. The present study aimed to develop sex- and age-specific 20mSRT norms for Chinese Tibetan children and adolescents at high altitudes. METHOD: A total of 4667 participants from Lhasa (3650 m), Nagqu (4500 m), and Amdo (4700 m) were selected by a stratified random cluster sampling method in two stages. The 20 m SRT test was used to estimate cardiorespiratory fitness. The 20 m SRT norms were developed by the lambda, mu, and sigma method (LMS). RESULTS: The 20 m SRT laps, completed stages/minutes, and the speed at the last complete stage of Chinese Tibetan children and adolescents aged 7-18 years increased with age. CONCLUSION: Given the importance of CRF for children and adolescents' health, the government should strengthen the monitoring of the CRF of Tibetan children and adolescents in high-altitude areas, strengthen physical education curriculum reform, and increase the level of physical activity in order to improve the level of CRF in children and adolescents.

Associations between Sedentary Time and Sedentary Patterns and Cardiorespiratory Fitness in Chinese Children and Adolescents.

The increase in sedentary behavior in children and adolescents has become a worldwide public health problem. This study aimed to explore the associations between sedentary time (ST) and sedentary patterns (SP) and the cardiorespiratory fitness (CRF) of Chinese children and adolescents. The CRF of 535 participants was determined using a 20-m shuttle run test. ST and SP were measured with accelerometers. Questionnaires were used to investigate the different types of ST. Multiple linear regression models were used to test the associations between ST and SP and CRF. In this study, only some ST and SP indicators were found to be significantly associated with CRF in girls. With each additional 10 min of screen time or passive traffic time, VO2max decreases by 0.06 mL/kg/min (B = -0.006, 95% CI: -0.010~-0.001) and 0.31 mL/kg/min (B = -0.031, 95% CI: -0.061~-0.002), respectively, with MVPA control. With each additional 10 min of breaks in ST or duration of breaks in ST, VO2max increases by 0.41 mL/kg/min (B = 0.041, 95% CI: 0.007~0.076) and 0.21 mL/kg/min (B = 0.021, 95% CI: 0.007~0.035), respectively, with control total ST. Breaks in ST (B = 0.075, 95% CI: 0.027~0.123) and the duration of breaks in ST (B = 0.021, 95% CI: 0.012~0.146) were positively correlated with CRF when controlling for LPA, but these associations were not significant when controlling for MVPA (B = 0.003, 95% CI: -0.042~0.048; B = 0.001, 95% CI: -0.024~0.025). The total ST of children and adolescents was found to not be correlated with CRF, but when ST was divided into different types, the screen time and passive traffic time of girls were negatively correlated with CRF. More breaks in ST and the duration of breaks in ST were positively associated with higher CRF in girls. MVPA performed during breaks in ST may be the key factor affecting CRF. Schools and public health departments should take all feasible means to actively intervene with CRF in children and adolescents.

The RECEPTOR-LIKE PROTEIN53 immune complex associates with LLG1 to positively regulate plant immunity.

Pattern recognition receptors (PRRs) sense ligands in pattern-triggered immunity (PTI). Plant PRRs include numerous receptor-like proteins (RLPs), but many RLPs remain functionally uncharacterized. Here, we examine an Arabidopsis thaliana RLP, RLP53, which positively regulates immune signaling. Our forward genetic screen for suppressors of enhanced disease resistance1 (edr1) identified a point mutation in RLP53 that fully suppresses disease resistance and mildew-induced cell death in edr1 mutants. The rlp53 mutants showed enhanced susceptibility to virulent pathogens, including fungi, oomycetes, and bacteria, indicating that RLP53 is important for plant immunity. The ectodomain of RLP53 contains leucine-rich repeat (LRR) motifs. RLP53 constitutively associates with the LRR receptor-like kinase SUPPRESSOR OF BRASSINOSTEROID INSENSITIVE1-ASSOCIATED KINASE (BAK1)-INTERACTING RECEPTOR KINASE1 (SOBIR1) and interacts with the co-receptor BAK1 in a pathogen-induced manner. The double mutation sobir1-12 bak1-5 suppresses edr1-mediated disease resistance, suggesting that EDR1 negatively regulates PTI modulated by the RLP53-SOBIR1-BAK1 complex. Moreover, the glycosylphosphatidylinositol (GPI)-anchored protein LORELEI-LIKE GPI-ANCHORED PROTEIN1 (LLG1) interacts with RLP53 and mediates RLP53 accumulation in the plasma membrane. We thus uncovered the role of a novel RLP and its associated immune complex in plant defense responses and revealed a potential new mechanism underlying regulation of RLP immune function by a GPI-anchored protein.

Design, synthesis and biological activity of diamide compounds based on 3-substituent of the pyrazole ring†.

BACKGROUND: Diamide insecticides have attracted significant attention due to their high efficacy and low toxicity to non-target organisms since they were introduced to the market. In order to tackle the problems of insecticide resistance and ecological safety, 16 novel nitrobenzene substituted anthranilic diamides with ester, hydroxyl or sulfonyl at the 3-position of the pyrazole ring were designed and synthesized. RESULTS: All of these compounds possessed good activity against the ryanodine receptor (RyR) from Spodoptera frugiperda and relatively lower activity against mammalian RyR1, showing a better insect-selectivity compared to chlorantraniliprole in a cell-based assay. The molecular docking analysis predicted the binding conformations of these compounds, which showed a good correlation between the insecticidal activity and the binding scores. In vitro studies using a calcium imaging method demonstrated that the novel compounds could not only activate the RyR but may also target the dihydropyridine receptor on the plasma membrane of insect neurons, implicating a similar but not same mode of action. CONCLUSION: Substituted anthranilic diamides with an ester at the 3-position of the pyrazole ring exhibited a promising insecticidal activity and better insect-selectivity, which provided insight into the rational design of a new generation of effective diamide insecticides.

Arabidopsis E3 ligase KEG associates with and ubiquitinates MKK4 and MKK5 to regulate plant immunity.

Mitogen-activated protein kinase (MAPK) cascades are highly conserved signaling modules that regulate plant immune responses. The Arabidopsis thaliana Raf-like MAPK kinase kinase ENHANCED DISEASE RESISTANCE1 (EDR1) is a key negative regulator of plant immunity that affects the protein levels of MKK4 and MKK5, two important MAPK cascade members, but the underlying mechanism is poorly understood. Here, genome-wide phosphorylation analysis demonstrated that the E3 ligase KEEP ON GOING (KEG) is phosphorylated in the edr1 mutant but not the wild type, suggesting that EDR1 negatively affects KEG phosphorylation. The identified phosphorylation sites in KEG appear to be important for its accumulation. The keg-4 mutant, a previously identified edr1 suppressor, enhances susceptibility to the powdery mildew pathogen Golovinomyces cichoracearum. In addition, MKK4 and MKK5 protein levels are reduced in the keg-4 mutant. Furthermore, we demonstrate that MKK4 and MKK5 associate with full-length KEG, but not with truncated KEG-RK or KEG-RKA, and that KEG ubiquitinates and mediates the degradation of MKK4 and MKK5. Taken together, these results indicate that MKK4 and MKK5 protein levels are regulated by KEG via ubiquitination, uncovering a mechanism by which plants fine-tune immune responses by regulating the homeostasis of key MAPK cascade members via ubiquitination and degradation.

Synthesis, Insecticidal Activities, and Structure-Activity Relationship of Phenylpyrazole Derivatives Containing a Fluoro-Substituted Benzene Moiety.

Fluorinated organic compounds represent a growing and important family of commercial chemicals. Introduction of fluorine into active ingredients has become an effective way to develop modern crop protection products. Given the particular properties of fluorine and high efficiency and selectivity of diamide insecticides, we designed and synthesized 27 anthranilic diamides analogues containing fluoro-sustituted phenylpyrazole. A preliminary bioassay indicated that most target compounds exhibited good biological activity against Mythimna separata and Plutella xylostella. Compound IIIf containing a 2,4,6-trifluoro-substituted benzene ring showed 43% insecticidal activity against M. separata at 0.1 mg L-1, while the control chlorantraniliprole was 36%. The activity of IIIe against P. xylostella at 10-5 mg L-1 was 94%, compared with that of the control being 70%. Thus, introduction of fluorine into diamide insecticides was useful for increasing activity. Insect electrophysiology studies showed that the calcium concentration in the nerve cells of third M. separata larvae was elevated by IIIf, which further confirmed that ryanodine receptor (RyR) was its potential target.

Synthesis, biological activities, and SAR studies of novel 1-(2-chloro-4,5-difluorophenyl)-1H-pyrazole derivatives.

In order to search for the new ryanodine receptor (RyR) regulator, a series of 35 novel fluoro-substituted compounds introduced 1-(2-chloro-4,5-difluorophenyl)-1H-pyrazole moiety containing modified pyrazole heterocycle were designed and synthesized. Then, they were tested for the insecticidal activities against Mythimna separata and Plutella xylostella in our greenhouse. After a systematic biological screening, it was found out that IVc showed 50% larvicidal activities against Mythimna separata at 0.1 mg L-1, equivalent to that of chlorantraniliprole (36%, 0.1 mg L-1). The activity of IVc against Plutella xylostella was 90% at 10-5 mg L-1, whereas the chlorantraniliprole was 70% at the same concentration. Then, insect electrophysiology experiments were conducted to study the pattern of action of IVc and IVe. It was confirmed by the experimental results that both compounds could lead to the release of calcium from the endoplasmic reticulum of neurons as classical anthranilic diamide insecticides.

Ligand-Promoted Iron(III)-Catalyzed Hydrofluorination of Alkenes.

An iron-catalyzed hydrofluorination of unactivated alkenes has been developed. The use of a multidentate ligand and the fluorination reagent N-fluorobenzenesulfonimide (NFSI) proved to be critical for this reaction, which afforded various fluorinated compounds in up to 94 % yield.

[Antimicrobial activities of ant Ponericin W1 against plant pathogens in vitro and the disease resistance in its transgenic Arabidopsis].

The antimicrobial peptides (AMPs) exhibit a broad antimicrobial spectrum. The application of AMPs from non-plant organisms attracts considerable attention in plant disease resistance engineering. Ponericin W1, isolated from the venom of ant (Pachycondyla goeldii), shows antimicrobial activities against Gram-positive bacteria, Gram-negative bacteria and the budding yeast (Saccharomyces cerevisiae); however, it is not clear whether Ponericin W1 is effective against plant pathogens. The results of this study indicated synthesized Ponericin W1 inhibited mycelial growth of Magnaporthe oryzae and Botrytis cinerea, as well as hyphal growth and spore production of Fusarium graminearum. Besides, Ponericin W1 exhibited antibacterial activities against Pseudomonas syringae pv. tomato and Xanthomonas oryzae pv. oryzae. After codon optimization, Ponericin W1 gene was constructed into plant expression vector, and transformed into Arabidopsis thaliana by floral dip method. The Ponericin W1 was located in intercellular space of the transgenic plants as expected. Compared with the wild-type plants, there were ungerminated spores and less hyphal, conidia on the leaves of transgenic plants after innoculation with the powdery mildew fungus Golovinomyces cichoracearum. After innoculation with the pathogenic bac-terium Pseudomonas syringae pv. tomato, the baceria in the leaves of transgenic plants was significantly less than the wild-type plants, indicating that the transgenic plants displayed enhanced disease resistance to pathogens. These results demonstrate a potential use of Ponericin W1 in genetic engineering for broad-spectrum plant disease resistance.