The evolution of small-molecule Akt inhibitors from hit to clinical candidate.

Akt, a key regulator of cell survival, proliferation, and metabolism, has become a prominent target for treatment of cancer and inflammatory diseases. The journey of small-molecule Akt inhibitors from discovery to the clinic has faced numerous challenges, with a significant emphasis on optimization throughout the development process. Early discovery efforts identified various classes of inhibitors, including ATP-competitive and allosteric modulators. However, during preclinical and clinical development, several issues arose, including poor specificity, limited bioavailability, and toxicity. Optimization efforts have been central to overcoming these hurdles. Researchers focused on enhancing the selectivity of inhibitors to target Akt isoforms more precisely, reducing off-target effects, and improving pharmacokinetic properties to ensure better bioavailability and distribution. Structural modifications and the design of prodrugs have played a crucial role in refining the efficacy and safety profile of these inhibitors. Additionally, efforts have been made to optimize the therapeutic window, balancing effective dosing with minimal adverse effects. The review highlights how these optimization strategies have been key in advancing small-molecule Akt inhibitors toward clinical success and underscores the importance of continued refinement in their development.

Identification of autophagy-related genes ATG18 subfamily genes in potato (Solanum tuberosum L.) and the role of StATG18a gene in heat stress.

Autophagy is a highly conserved process in eukaryotes that is used to recycle the cellular components from the cytoplasm. It plays a crucial function in responding to both biotic and abiotic stress, as well as in the growth and development of plants. Autophagy-related genes (ATG) and their functions have been identified in numerous crop species. However, their specific tasks in potatoes (Solanum tuberosum L.), are still not well understood. This work is the first to identify and characterize the potato StATG18 subfamily gene at the whole-genome level, resulting in a total of 6 potential StATG18 subfamily genes. We analyzed the phylogenetic relationships, chromosome distribution and gene replication, conserved motifs and gene structure, interspecific collinearity relationship, and cis-regulatory elements of the ATG18 subfamily members using bioinformatics approaches. Furthermore, the quantitative real-time polymerase chain reaction (qRT-PCR) analysis suggested that StATG18 subfamily genes exhibit differential expression in various tissues and organs of potato plants. When exposed to heat stress, their expression pattern was observed in the root, stem, and leaf. Based on a higher expression profile, the StATG18a gene was further analyzed under heat stress in potatoes. The subcellular localization analysis of StATG18a revealed its presence in both the cytoplasm and nucleus. In addition, StATG18a altered the growth indicators, physiological characteristics, and photosynthesis of potato plants under heat stresses. In conclusion, this work offers a thorough assessment of StATG18 subfamily genes and provides essential recommendations for additional functional investigation of autophagy-associated genes in potato plants. Moreover, these results also contribute to our understanding of the potential mechanism and functional validation of the StATG18a gene's persistent tolerance to heat stress in potato plants.

Epigenetics and immunotherapy in colorectal cancer: progress and promise.

Colorectal cancer (CRC) is a common malignant tumor with the third and second highest incidence and mortality rates among various malignant tumors. Despite significant advancements in the present therapy for CRC, the majority of CRC cases feature proficient mismatch repair/microsatellite stability and have no response to immunotherapy. Therefore, the search for new treatment options holds immense importance in the diagnosis and treatment of CRC. In recent years, clinical research on immunotherapy combined with epigenetic therapy has gradually increased, which may bring hope for these patients. This review explores the role of epigenetic regulation in exerting antitumor effects through its action on immune cell function and highlights the potential of certain epigenetic genes that can be used as markers of immunotherapy to predict therapeutic efficacy. We also discuss the application of epigenetic drug sensitization immunotherapy to develop new treatment options combining epigenetic therapy and immunotherapy.

Sodium alginate supramolecular nanofibers in synergy with surface crack engineering to prepare tough and highly sensitive hydrogels.

Soft and wet hydrogels often struggle to achieve both toughness and high sensitivity simultaneously, limiting their usefulness in flexible devices. To tackle this challenge, we devised a strategy that combines supramolecular sodium alginate nanofibers, utilizing Zr4+ as physical crosslinkers, with surface crack engineering via the micro-phase separation of polyaniline, to create a physically and chemically dual crosslinked polyacrylamide (PAM)/sodium alginate (SA)/polyaniline (PANI) hydrogel with exceptional toughness and high sensitivity. Owing to the supramolecular sodium alginate nanofibers, the dual crosslinked hydrogel exhibited a tensile strength of 0.391 MPa, an elongation at break of 568.9 %, and a toughness of 1.020 MJ/m3. The in-situ polymerized polyaniline layer, confined within the dense network, introduced micro-cracks onto the hydrogel surface, resulting in a high gauge factor of 11.4 for the fabricated hydrogel. Furthermore, integrating this hydrogel into a triboelectric nanogenerator transformed it into self-powered sensors capable of detecting external forces and generating various signals without power supply. These findings suggest that the developed hydrogel held great potential in diverse fields, including human motion detection, human-machine interaction, and wearable electronic devices.

Photonic probabilistic machine learning using quantum vacuum noise.

Probabilistic machine learning utilizes controllable sources of randomness to encode uncertainty and enable statistical modeling. Harnessing the pure randomness of quantum vacuum noise, which stems from fluctuating electromagnetic fields, has shown promise for high speed and energy-efficient stochastic photonic elements. Nevertheless, photonic computing hardware which can control these stochastic elements to program probabilistic machine learning algorithms has been limited. Here, we implement a photonic probabilistic computer consisting of a controllable stochastic photonic element - a photonic probabilistic neuron (PPN). Our PPN is implemented in a bistable optical parametric oscillator (OPO) with vacuum-level injected bias fields. We then program a measurement-and-feedback loop for time-multiplexed PPNs with electronic processors (FPGA or GPU) to solve certain probabilistic machine learning tasks. We showcase probabilistic inference and image generation of MNIST-handwritten digits, which are representative examples of discriminative and generative models. In both implementations, quantum vacuum noise is used as a random seed to encode classification uncertainty or probabilistic generation of samples. In addition, we propose a path towards an all-optical probabilistic computing platform, with an estimated sampling rate of  ~1 Gbps and energy consumption of  ~5 fJ/MAC. Our work paves the way for scalable, ultrafast, and energy-efficient probabilistic machine learning hardware.

High-throughput screening identifies ibuprofen as an sEV PD-L1 inhibitor for synergistic cancer immunotherapy.

Programmed death-ligand 1 (PD-L1) on tumor-derived small extracellular vesicles (sEVs) limits therapeutic effectiveness by interacting with the PD-1 receptor on host immune cells. Targeting the secretion of sEV PD-L1 has emerged as a promising strategy to enhance immunotherapy. However, the lack of small-molecule inhibitors poses a challenge for clinical translation. In this study, we developed a target and phenotype dual-driven high-throughput screening strategy that combined virtual screening with nanoflow-based experimental verification. We identified ibuprofen (IBP) as a novel inhibitor that effectively targeted sEV PD-L1 secretion. IBP disrupted the biogenesis and secretion of PD-L1+ sEVs in tumor cells by physically interacting with a critical regulator of sEV biogenesis, hepatocyte growth factor-regulated tyrosine kinase substrate. Notably, the mechanism of action of IBP is distinct from its commonly known targets, cyclooxygenases. Administration of IBP stimulated antitumor immunity and enhanced the efficacy of anti-PD-1 therapy in melanoma and oral squamous cell carcinoma mouse models. To address potential adverse effects, we further developed an IBP gel for topical application, which demonstrated remarkable therapeutic efficacy when combined with anti-PD-1 treatment. The discovery of this specific small inhibitor provides a promising avenue for establishing durable, systemic antitumor immunity.

Chinese EFL learners' processing of English binomials: the role of interlexical and intralexical factors.

Binomials have been relatively understudied compared to other types of multiword expressions (MWEs) in second language research, such as collocations and idioms. This study investigated English as a Foreign Language (EFL) learners' processing of English binomials and how it is influenced by interlexical factors (L1-L2 congruency and L1-lexicalization) and intralexical factors (word and binomial frequency, binomial reversibility, and binomial predictability). Forty Chinese EFL learners participated in a phrase acceptability judgment task of 64 target binomials (16 congruent L1-lexicalized, 16 congruent L1-nonlexicalized, and 32 incongruent) and 64 non-binomial controls. Results revealed that learners experienced difficulty judging the formulaicity of binomials. They processed binomial stimuli significantly faster than non-binomial baselines, demonstrating a binomial phrase effect. They also processed L1-L2 congruent items faster and more accurately than incongruent items, showing a robust congruency effect. The congruent items which are lexicalized in the L1 showed further processing advantage than the non-lexicalized items, indicating a graded congruency effect. Moreover, binomial reversibility and binomial predictability (measured with cloze probability) also showed significant effects. These findings highlight the need to distinguish and investigate different types of congruency, explore appropriate measures for MWE predictability, and to examine binomials focusing on their unique features.

Effects of phytosterol ester supplementation on egg weight, biochemical indices, liver immunity and gut microbiota of laying hens during peak laying period.

This experiment was aimed to investigate the effects of Phytosterol Ester (PSE) supplementation on egg weight, biochemical indices, liver immunity and gut microbiota of Hy-Line Brown laying hens during peak laying period. A total of 256 healthy Hy-Line Brown laying hens were randomly allocated into 4 groups. Laying hens in the control group were fed a basal diet (CON), while those in the experimental groups received a basal diet containing 10 mg/kg (PSE10), 20 mg/kg (PSE20), or 40 mg/kg (PSE40) mg/kg PSE, respectively. We found that PSE supplementation significantly increased the egg weight in PSE20 and PSE40 groups (P < 0.05) and the serum magnesium (Mg) content in PSE10 and PSE20 groups (P < 0.05), but significantly decreased the serum calcium (Ca) content in PSE40 group (P < 0.05). Moreover, PSE supplementation significantly increased the total protein (TP) content of ovary in all experimental groups (P < 0.01) and decreased the total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) contents of the ovary in PSE20 and PSE40 groups (P < 0.001). In serum, PSE supplementation significantly increased TP content in all experimental groups (P < 0.01) and albumin (ALB) content in PSE20 group (P < 0.05). Alkaline phosphatase (AKP) in PSE20 group, TC content in all experimental groups and LDL-C content in PSE20 and PSE40 groups were significantly decreased (P < 0.05). In egg yolk, PSE supplementation significantly increased TP content in PSE20 and PSE40 groups (P < 0.01) and decreased TC content in PSE20 group (P < 0.01). In liver immunofluorescence, PSE supplementation altered the content of CD163, especially in PSE20 group. Dietary PSE significantly decreased the relative abundance of Bacteroides and Desulfovibrio, while increased the relative abundance of Faecalibacterium, g_unclassified_f_Lachnospiraceae, g_norank_f_Ruminococcaceae, g__unclassified_f__Oscillospiraceae and other bacteria. In conclusion, PSE supplementation increased the average egg weight and total protein, lowered egg yolk, serum and ovary cholesterol of Hy-Line Brown laying hens. At the same time, it can also promote serum magnesium levels, enhanced liver immunity, and improved gut microflora.

Discovery of novel substituted pyridine carboxamide derivatives as potent allosteric SHP2 inhibitors.

Src homology-2-containing protein tyrosine phosphatase 2 (SHP2), a critical regulator of proliferation pathways and immune checkpoint signaling in various cancers, is an attractive target for cancer therapy. Here, we report the discovery of a novel series of substituted pyridine carboxamide derivatives as potent allosteric SHP2 inhibitors. Among them, compound C6 showed excellent inhibitory activity against SHP2 and antiproliferative effect on MV-4-11 cell line with IC50 values of 0.13 and 3.5 nM, respectively. Importantly, orally administered C6 displayed robust in vivo antitumor efficacy in the MV-4-11 xenograft mouse model (TGI = 69.5 %, 30 mg/kg). Subsequent H&E and Ki67 staining showed that C6 significantly suppressed the proliferation of tumor cells. Notably, flow cytometry, ELISA and immunofluorescence experiments showed that C6 remarkably decreased the population of CD206+/Ly6C+ M2-like tumor-associated macrophages (TAMs), the expression level of interleukin-10 (IL-10), and the number of F4/80+/CD206+ M2-like TAMs, suggesting that C6 could effectively alleviate the activation and infiltration of M2-like TAMs. Taken together, these results illustrate that C6 is a promising SHP2 inhibitor worthy of further development.

Evaluation of phytohormone facilitation in microalgal biomass production using mathematical modeling.

How to improve the growth efficiency of microalgae is the bottleneck of microalgae large-scale application. The addition of trace substances can promote the growth of microalgae, but there is no suitable model that can be used to predict the effects of trace substance concentrations on the growth of microalgae. In the present study, a mathematical model based on hormesis is proposed to describe the effects produced by trace substances on the biomass of microalgae and applied to assess the dose-response of four phytohormones on Scenedesmus sp. LX1 with a high coefficient of determination (R2 ≥ 0.90). Several new mathematical parameters, such as starting effective dose (SD), inflection point dose (PD), concentration for 0 % of maximal effect, end effective dose (ED), maximum stimulatory effect (MSE), and maximum inhibitory effect (MIE), were extracted and useful to help researchers in applying trace substances to assist in the production of microalgal biomass for data reference and prediction. In concrete terms, the above model parameters can be well applied to screen the trace substances, dominant algal species and determine the concentration range. This study provides valuable insights into the potential of using phytohormones to enhance the biomass production of microalgae and offers a new approach to optimizing the culture of microalgae.

Bidirectional pH Buffer Effect Facilitates High-Reversible Aqueous Zinc Ion Batteries.

Aqueous zinc ion batteries (AZIBs) stand out from the crowd of energy storage equipment for their superior energy density, enhanced safety features, and affordability. However, the notorious side reaction in the zinc anode and the dissolution of the cathode materials led to poor cycling stability has hindered their further development. Herein, ammonium salicylate (AS) is a bidirectional electrolyte additive to promote prolonged stable cycles in AZIBs. NH4 + and C6H4OHCOO- collaboratively stabilize the pH at the interface of the electrolyte/electrode and guide the homogeneous deposition of Zn2+ at the zinc anode. The higher adsorption energy of NH4 + compared to H2O on the Zn (002) crystal plane mitigates the side reactions on the anode surface. Moreover, NH4 + is similarly adsorbed on the cathode surface, maintaining the stability of the electrode. C6H4OHCOO- and Zn2+ are co-intercalation/deintercalation during the cycling process, contributing to the higher electrochemical performance of the full cell. As a result, with the presence of AS additive, the Zn//Zn symmetric cells achieved 700 h of highly reversible cycling at 5 mA cm-2. In addition, the assembled NH4V4O10(NVO)//Zn coin and pouch batteries achieved higher capacity and higher cycle lifetime, demonstrating the practicality of the AS electrolyte additive.

A Standard Measure of Structural Racism, Do We Have One? Can We Have One? A Narrative Review of Commonly Used Measures and Domains of Use.

BACKGROUND: A lack of a "gold standard" operationalized index to measure structural racism (SR) in the current literature limits the comparison of the evidence available. This study aims to synthesize the measures of SR from the current literature to identify the measures used to date, study the indicators included, and investigate its expanding domain. METHODS: A literature search of original quantitative studies in the Google Scholar and PubMed databases for articles dated January 1, 2000-July 31, 2023, was conducted with search terms: ["Institutionalized Racism" OR "Systemic Racism", OR "Structural Racism"] AND "Health" AND "United States." The studies were summarized and extracted based on the type of SR index used, the domains of SR incorporated, and the health outcomes studied. RESULTS: A total of 74 articles were included in the final review. The historical redlining score, G-statistics, index of concentration, and structural racism index were common quantifiable measures of SR. These indices capture 56 indicators across 11 significant domains to measure SR. Similarly, SR indices are being used mostly to study the impact of SR on cardiovascular diseases and other chronic health conditions, women's and maternal health-related issues, and COVID-19 outcomes. CONCLUSION: Multiple indices have been developed to capture SR, and since the COVID-19 pandemic, we have observed an increased interest in understanding health disparities through the lens of SR. With the rise in evidence on experiences of minority races related to racism, there is a high need for a standard approach to measuring SR.

Aortic isthmus flow reversal in fetal coarctation of the aorta and the associated factors.

INTRODUCTION: The aim of this study was to investigate the presence of aortic isthmus flow reversal and its associated factors in fetuses with positive and false-positive coarctation of the aorta (CoA) compared with normal controls. MATERIAL AND METHODS: Pregnant women with fetuses suspected of CoA and normal control were enrolled, and these women experienced prenatal ultrasound scan and followed up for 6 months after birth to confirm the presence of CoA. All the ultrasound parameters were analyzed. RESULTS: A total of 134 pregnant women were enrolled, with 43 CoA-positive fetuses and 91 CoA false-positive fetuses, and 334 matched pregnant women were enrolled in the control group. Aortic isthmus flow reversal occurred in 28 (65.1%) fetuses in the CoA-positive group, significantly (p < 0.05) more than in the false-positive (37 or 40.7%) or control group (64 or 19.2%). Aortic isthmus flow reversal was mostly in the full systole (n = 17 or 60.7%) or late systole and early-middle diastole (n = 10 or 35.7%) in the CoA-positive fetuses (n = 27 or 96.4%), significantly (p < 0.001) different from that in the false-positive or control group. The aortic isthmus flow reversal peak systolic velocity (PSV), flow volume, and ratio of reversed flow/forward flow were significantly (p < 0.05) increased in the CoA-positive and false-positive groups than in the control group. The aortic isthmus flow reversal incidence was significantly (p < 0.05) correlated with the middle cerebral artery (MCA) PSV in the total three groups or in the false-positive group but was significantly (p < 0001) negatively correlated with the MCA resistance index (RI) in the CoA-positive group. The incidence of the aortic isthmus flow reversal was significantly (p < 0.05) positively correlated with the umbilical artery (UA) RI in the false-positive group and with the UA RI in the total three groups. Independently associated factors for aortic isthmus flow reversal were isthmic flow volume/CCO (combined cardiac output) in the CoA-positive group. CONCLUSIONS: Reversal of flow in the aortic isthmus is much more common in true-positive cases of CoA as compared to controls, and isthmic flow reversal in the full systolic phase only suggests presence of CoA. The aortic isthmic reversed flow volume accounts for over half of the isthmic forward flow volume in the CoA-positive fetuses than in the normal controls.

Retrospective motion correction for cardiac multi-parametric mapping with dictionary matching-based image synthesis and a low-rank constraint.

PURPOSE: To develop a model-based motion correction (MoCo) method that does not need an analytical signal model to improve the quality of cardiac multi-parametric mapping. METHODS: The proposed method constructs a hybrid loss that includes a dictionary-matching loss and a signal low-rankness loss, where the former registers the multi-contrast original images to a set of motion-free synthetic images and the latter forces the deformed images to be spatiotemporally coherent. We compared the proposed method with non-MoCo, a pairwise registration method (Pairwise-MI), and a groupwise registration method (pTVreg) via a free-breathing Multimapping dataset of 15 healthy subjects, both quantitatively and qualitatively. RESULTS: The proposed method achieved the lowest contour tracking errors (epicardium: 2.00 ± 0.39 mm vs 4.93 ± 2.29 mm, 3.50 ± 1.26 mm, and 2.61 ± 1.00 mm, and endocardium: 1.84 ± 0.34 mm vs 4.93 ± 2.40 mm, 3.43 ± 1.27 mm, and 2.55 ± 1.09 mm for the proposed method, non-MoCo, Pairwise-MI, and pTVreg, respectively; all p < 0.01) and the lowest dictionary matching errors among all methods. The proposed method also achieved the highest scores on the visual quality of mapping (T1: 4.74 ± 0.33 vs 2.91 ± 0.82, 3.58 ± 0.87, and 3.97 ± 1.05, and T2: 4.48 ± 0.56 vs 2.59 ± 0.81, 3.56 ± 0.93, and 4.14 ± 0.80 for the proposed method, non-MoCo, Pairwise-MI, and pTVreg, respectively; all p < 0.01). Finally, the proposed method had similar T1 and T2 mean values and SDs relative to the breath-hold reference in nearly all myocardial segments, whereas all other methods led to significantly different T1 and T2 measures and increases of SDs in multiple segments. CONCLUSION: The proposed method significantly improves the motion correction accuracy and mapping quality compared with non-MoCo and alternative image-based methods.

Advances in biomacromolecule-functionalized magnetic particles for phytopathogen detection.

Due to the increasing crop losses caused by common and newly emerging phytopathogens, there is a pressing need for the development of rapid and reliable methods for phytopathogen detection and analysis. Leveraging advancements in biochemical engineering technologies and nanomaterial sciences, researchers have put considerable efforts on utilizing biofunctionalized magnetic micro- and nanoparticles (MPs) to develop rapid and reliable systems for phytopathogen detection. MPs facilitate the rapid, high-throughput analysis and in-field applications, while the biomacromolecules, which play key roles in the biorecognitions, interactions and signal amplification, determine the specificity, sensitivity, reliability, and portability of pathogen detection systems. The integration of MPs and biomacromolecules provides dimensionality- and composition-dependent properties, representing a novel approach to develop phytopathogen detection systems. In this review, we summarize and discuss the general properties, synthesis and characterization of MPs, and focus on biomacromolecule-functionalized MPs as well as their representative applications for phytopathogen detection and analysis reported over the past decade. Extensively studied bioreceptors, such as antibodies, phages and phage proteins, nucleic acids, and glycans that are involved in the recognitions and interactions, are covered and discussed. Additionally, the integration of MPs-based detection system with portable microfluidic devices to facilitate their in-field applications is also discussed. Overall, this review focuses on biomacromolecule-functionalized MPs and their applications for phytopathogen detection, aiming to highlight their potential in developing advanced biosensing systems for effective plant protection.

Design, synthesis, and biological evaluation of diphenyl ether substituted quinazolin-4-amine derivatives as potent EGFRL858R/T790M/C797S inhibitors.

Epidermal growth factor receptor (EGFR) is a validated target for non-small-cell lung cancer (NSCLC). However, the treatment for EGFR-C797S mutation induced by third-generation EGFR inhibitors remains a concern. Therefore, the development of the fourth-generation EGFR inhibitors to overcome the EGFR-C797S mutation has great potential for clinical treatment. In this article, we designed and synthesized a series of diphenyl ether substituted quinazolin-4-amine derivatives that simultaneously occupy the ATP binding pocket and the allosteric site of EGFR. Among the newly synthesized compounds, 9d displayed excellent kinase activity against EGFRL858R/T790M/C797S with an IC50 value of 0.005 µM, and exhibited anti-proliferation activity in BaF3-EGFRL858R/T790M/C797S cells with the IC50 value of 0.865 µM. Furthermore, 9d could suppress phosphorylation of EGFR and induce cell apoptosis and cycle arrest at G2 phase in a dose-dependent manner in BaF3-EGFRL858R/T790M/C797S cells. More importantly, 9d displayed significant antitumor effects in BaF3-EGFRL858R/T790M/C797S xenograft mouse model (30 mg/kg, TGI = 71.14 %). All the results indicated compound 9d might be a novel fourth-generation EGFR inhibitor for further development in overcoming the EGFR-C797S resistance mutation.

Regional differences, dynamic evolution, and influencing factors of high-quality medical resources in China's ethnic minority areas.

Background: In China, as people's standard of living improves and the medical service system becomes more sophisticated, the demand for higher-quality and improved healthcare services is steadily rising. Inequality in health resource allocation (HRA) is more pronounced in ethnic minority areas (EMAs) than in developed regions. However, little research exists on high-quality medical resources (HQMRs) in China's EMAs. Hence, we examined the spatiotemporal dynamic evolution of HQMRs in China's EMAs from 2007 to 2021 and identified the main factors affecting their respective HQMR levels. Methods: We selected tertiary hospitals to represent the quality of healthcare resources. We employed descriptive statistical techniques to analyze changes in the distribution of HQMRs from 2007 to 2021. We used the Dagum Gini coefficient and kernel density approach to analyze the dynamic evolution of HQMRs in China's EMAs. We utilized the least squares dummy variable coefficient (LSDVC) to identify key factors affecting HQMR. Results: The number of HQMRs in each EMA has risen annually. The average number of tertiary hospitals increased from 175 in 2007 to 488 in 2021. The results of the Dagum Gini coefficient revealed that the differences in the HQMR level in China's EMAs have slowly declined, and intra-regional disparities have now become the primary determining factor influencing overall variations. The kernel density plot indicated that the HQMR level improved significantly during the study period, but bifurcation became increasingly severe. Using the LSDVC for analysis, we found that gross domestic product (GDP) per capita, the size of the resident population, and the number of students enrolled in general higher education exhibited a significant negative correlation with HQMR levels, while GDP and urbanization rate had a significant promoting effect. Conclusion: The HQMR level in EMAs has risen rapidly but remains inadequate. The differences in HQMR between regions have continued to narrow, but serious bifurcation has occurred. Policymakers should consider economic growth, education, and population size rather than simply increasing the number of HQMRs everywhere.

The Past, Present, and Future of Plant Activators Targeting the Salicylic Acid Signaling Pathway.

Plant activators have emerged as promising alternatives to conventional crop protection chemicals for managing crop diseases due to their unique mode of action. By priming the plant's innate immune system, these compounds can induce disease resistance against a broad spectrum of pathogens without directly inhibiting their proliferation. Key advantages of plant activators include prolonged defense activity, lower effective dosages, and negligible risk of pathogen resistance development. Among the various defensive pathways targeted, the salicylic acid (SA) signaling cascade has been extensively explored, leading to the successful development of commercial activators of systemic acquired resistance, such as benzothiadiazole, for widespread application in crop protection. While the action sites of many SA-targeting activators have been preliminarily mapped to different steps along the pathway, a comprehensive understanding of their precise mechanisms remains elusive. This review provides a historical perspective on plant activator development and outlines diverse screening strategies employed, from whole-plant bioassays to molecular and transgenic approaches. We elaborate on the various components, biological significance, and regulatory circuits governing the SA pathway while critically examining the structural features, bioactivities, and proposed modes of action of classical activators such as benzothiadiazole derivatives, salicylic acid analogs, and other small molecules. Insights from field trials assessing the practical applicability of such activators are also discussed. Furthermore, we highlight the current status, challenges, and future prospects in the realm of SA-targeting activator development globally, with a focus on recent endeavors in China. Collectively, this comprehensive review aims to describe existing knowledge and provide a roadmap for future research toward developing more potent plant activators that enhance crop health.

The Influence of Barley Proteome on Hop Bitter Acid Yield during Brewing.

A persistent challenge in brewing is the efficient utilization of hop bitter acids, with about 50% of these compounds precipitating with trub during wort boiling. This study aims to uncover the correlation between the barley cultivar proteome and hop bitter acid utilization during wort boiling. Therefore, comparative experiments were conducted using two cultivars, Liga and Solist, with varying proteomes to identify specific proteins' role in hop bitter acids precipitation. High-performance liquid chromatography (HPLC) was used to measure hop bitter acid content, while liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify and identify proteins. The 107 protein groups, particularly enzymes linked to barley metabolic defense mechanisms, exhibited significant differences between the two cultivars. Results revealed significantly lower α- and iso-α-acid content in wort produced from the barley cultivar Liga. This study highlights the critical role of the barley proteome in optimizing process efficiency by enhancing hop utilization through barley cultivar selection.