Construction of a novel model based on PVT1-MYC duet-related genes for predicting survival and characterization of the tumor microenvironment in pancreatic cancer.

Pancreatic cancer is an extremely malignant tumor. PVT1 and MYC signaling has been considered as a therapeutic target recently. Nonetheless, the prognostic values and critical regulatory networks of PVT1-MYC duet in pancreatic cancer remain unclear. Firstly, we identified PVT1-MYC duet-related genes using public databases. Then we analyzed our Hi-C and ChIP-seq data to confirm PVT1-MYC duet. We performed LASSO regression and multivariate Cox regression analysis to build a prognostic model whose effectiveness and robustness were validated by Cox regression, ROC analysis, calibration curve, and nomogram. Besides, we conducted functional enrichment analyses, mutation profiles analyses and the immune features analyses to compare low- and high-risk group. Functional enrichment analyses revealed that several terms associated with cancer progression were enriched in the high-risk group. Mutation profile analysis showed that high-risk group had higher tumor mutation burden, and immune analysis demonstrated high-risk group had more immunosuppressive tumor microenvironment. Finally, we detected PVT1 expression in pancreatic cancer and paracancer tissues from the PUMCH cohort, which showed that PVT1 was significantly upregulated in pancreatic cancer and associated with invasion, metastasis, and poor prognosis. We further performed transwell and proliferation assays and found that PVT1, CDC6, and COL17A1 could promote migration or proliferation of PDAC cells. This study constructed a prognostic model based on three PVT1-MYC duet-related genes, which had a significant potential in predicting the prognosis and tumor microenvironment of pancreatic cancer. These results suggested that targeting PVT1-MYC duet or its regulatory processes could be a therapeutic option with great interests.

Integrated analysis of microbiome and metabolome reveals signatures in PDAC tumorigenesis and prognosis.

Pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), is one of the most malignant tumors of the digestive system. Emerging evidence suggests the involvement of the microbiome and metabolic substances in the development of PDAC, yet the results remain contradictory. This study aims to identify the alterations and relationships in intratumoral microbiome and metabolites in PDAC. We collected matched tumor and normal adjacent tissue (NAT) samples from 105 PDAC patients and performed a 6-year follow-up. 2bRAD-M sequencing, untargeted liquid chromatography-tandem mass spectrometry, and untargeted gas chromatography-mass spectrometry were performed. Compared with NATs, microbial α-diversity decreased in PDAC tumors. The relative abundance of Staphylococcus aureus, Cutibacterium acnes, and Cutibacterium granulosum was higher in PDAC tumor after adjusting for confounding factors body mass index and M stage, and the presence of Ralstonia pickettii_B was found associated with a worse overall survival. Metabolomic analysis revealed distinctive differences in composition between PDAC and NAT, with 553 discriminative metabolites identified. Differential metabolites were revealed to originate from the microbiota and showed significant interactions with shifted bacterial species through KO (KEGG Orthology) genes. These findings suggest that the PDAC microenvironment harbors unique microbial-derived enzymatic reactions, potentially influencing the occurrence and development of PDAC by modulating the levels of glycerol-3-phosphate, succinate, carbonate, and beta-alanine. IMPORTANCE: We conducted a large sample-size pancreatic adenocarcinoma microbiome study using a novel microbiome sequencing method and two metabolomic assays. Two significant outcomes of our analysis are: (i) commensal opportunistic pathogens Staphylococcus aureus, Cutibacterium acnes, and Cutibacterium granulosum were enriched in pancreatic ductal adenocarcinoma (PDAC) tumors compared with normal adjacent tissues, and (ii) worse overall survival was found related to the presence of Ralstonia pickettii_B. Microbial species affect the tumorigenesis, metastasis, and prognosis of PDAC via unique microbe-enzyme-metabolite interaction. Thus, our study highlights the need for further investigation of the potential associations between pancreatic microbiota-derived omics signatures, which may drive the clinical transformation of microbiome-derived strategies toward therapy-targeted bacteria.

A dual-stator threaded linear ultrasonic motor with preload mechanism.

The cylindrical ultrasonic motor, noted for its straightforward design, ease of miniaturization, and high precision, has significant potential in fields such as optics, healthcare, and precision engineering. However, miniaturization presents challenges, including diminished output force and complications in applying preloading stress. To address the reduced output force, this study presents a dual-stator, high-thrust cylindrical linear ultrasonic motor. This innovative motor features two stators, a mover, and a mechanism for applying preloading stress. A key design element is the parallel arrangement of the two stators along a threaded output shaft, separated by elastic components. This setup enables axial preloading via the threads' engagement. Simulations were conducted to refine the stators' parameters, assess their operational modes, and evaluate their in-plane paths. A prototype was subsequently built to test its impedance characteristics and mechanical performance. Test results showed that under a 200 Vpp drive, the single-stator motor generated a maximum force of 4.3 N, while the dual-stator configuration produced 6.8 N. After applying preloading stress, the output force of the dual-stator motor increased to 9.4 N.

CALB2 drives pancreatic cancer metastasis through inflammatory reprogramming of the tumor microenvironment.

BACKGROUND: Early dissemination to distant organs accounts for the dismal prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). Chronic, dysregulated, persistent and unresolved inflammation provides a preferred tumor microenvironment (TME) for tumorigenesis, development, and metastasis. A better understanding of the key regulators that maintain inflammatory TME and the development of predictive biomarkers to identify patients who are most likely to benefit from specific inflammatory-targeted therapies is crucial for advancing personalized cancer treatment. METHODS: This study identified cell-specific expression of CALB2 in human PDAC through single-cell RNA sequencing analysis and assessed its clinicopathological correlations in tissue microarray using multi-color immunofluorescence. Co-culture systems containing cancer-associated fibroblasts (CAFs) and patient-derived organoids (PDOs) in vitro and in vivo were employed to elucidate the effects of CALB2-activated CAFs on PDAC malignancy. Furthermore, CUT&RUN assays, luciferase reporter assays, RNA sequencing, and gain- or loss-of-function assays were used to unravel the molecular mechanisms of CALB2-mediated inflammatory reprogramming and metastasis. Additionally, immunocompetent KPC organoid allograft models were constructed to evaluate CALB2-induced immunosuppression and PDAC metastasis, as well as the efficacy of inflammation-targeted therapy. RESULTS: CALB2 was highly expressed both in CAFs and cancer cells and correlated with an unfavorable prognosis and immunosuppressive TME in PDAC patients. CALB2 collaborated with hypoxia to activate an inflammatory fibroblast phenotype, which promoted PDAC cell migration and PDO growth in vitro and in vivo. In turn, CALB2-activated CAFs upregulated CALB2 expression in cancer cells through IL6-STAT3 signaling-mediated direct transcription. In cancer cells, CALB2 further activated Ca2+-CXCL14 inflammatory axis to facilitate PDAC metastatic outgrowth and immunosuppression. Genetic or pharmaceutical inhibition of CXCL14 significantly suppressed CALB2-mediated metastatic colonization of PDAC cells in vivo and extended mouse survival. CONCLUSIONS: These findings identify CALB2 as a key regulator of inflammatory reprogramming to promote PDAC metastatic progression. Combination therapy with αCXCL14 monoclonal antibody and gemcitabine emerges as a promising strategy to suppress distant metastasis and improve survival outcomes in PDAC with CALB2 overexpression.

Comprehensive multi-omics profiling identifies novel molecular subtypes of pancreatic ductal adenocarcinoma.

Pancreatic cancer, a highly fatal malignancy, is predicted to rank as the second leading cause of cancer-related death in the next decade. This highlights the urgent need for new insights into personalized diagnosis and treatment. Although molecular subtypes of pancreatic cancer were well established in genomics and transcriptomics, few known molecular classifications are translated to guide clinical strategies and require a paradigm shift. Notably, chronically developing and continuously improving high-throughput technologies and systems serve as an important driving force to further portray the molecular landscape of pancreatic cancer in terms of epigenomics, proteomics, metabonomics, and metagenomics. Therefore, a more comprehensive understanding of molecular classifications at multiple levels using an integrated multi-omics approach holds great promise to exploit more potential therapeutic options. In this review, we recapitulated the molecular spectrum from different omics levels, discussed various subtypes on multi-omics means to move one step forward towards bench-to-beside translation of pancreatic cancer with clinical impact, and proposed some methodological and scientific challenges in store.

The significant role of amino acid metabolic reprogramming in cancer.

Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can influence the behavior of stromal cells, such as cancer-associated fibroblasts, regulate ECM remodeling and promote angiogenesis, thereby facilitating tumor growth and metastasis. Understanding the intricate interplay between amino acid metabolism and the tumor microenvironment is of crucial significance. Expanding our knowledge of the multifaceted roles of amino acid metabolism in tumor microenvironment holds significant promise for the development of more effective cancer therapies aimed at disrupting the metabolic dependencies of cancer cells and modulating the tumor microenvironment to enhance anti-tumor immune responses and inhibit tumor progression.

Histone lactylation dynamics: Unlocking the triad of metabolism, epigenetics, and immune regulation in metastatic cascade of pancreatic cancer.

Cancer cells rewire metabolism to sculpt the immune tumor microenvironment (TME) and propel tumor advancement, which intricately tied to post-translational modifications. Histone lactylation has emerged as a novel player in modulating protein functions, whereas little is known about its pathological role in pancreatic ductal adenocarcinoma (PDAC) progression. Employing a multi-omics approach encompassing bulk and single-cell RNA sequencing, metabolomics, ATAC-seq, and CUT&Tag methodologies, we unveiled the potential of histone lactylation in prognostic prediction, patient stratification and TME characterization. Notably, "LDHA-H4K12la-immuno-genes" axis has introduced a novel node into the regulatory framework of "metabolism-epigenetics-immunity," shedding new light on the landscape of PDAC progression. Furthermore, the heightened interplay between cancer cells and immune counterparts via Nectin-2 in liver metastasis with elevated HLS unraveled a positive feedback loop in driving immune evasion. Simultaneously, immune cells exhibited altered HLS and autonomous functionality across the metastatic cascade. Consequently, the exploration of innovative combination strategies targeting the metabolism-epigenetics-immunity axis holds promise in curbing distant metastasis and improving survival prospects for individuals grappling with challenges of PDAC.

Methylisothiazolinone pollution inhibited root stem cells and regeneration through auxin transport modification in Arabidopsis thaliana.

Methylisothiazolinone (MIT) is a widely used preservative and biocide to prevent product degradation, yet its potential impact on plant growth remains poorly understood. In this study, we investigated MIT's toxic effects on Arabidopsis thaliana root growth. Exposure to MIT significantly inhibited Arabidopsis root growth, associated with reduced root meristem size and root meristem cell numbers. We explored the polar auxin transport pathway and stem cell regulation as key factors in root meristem function. Our findings demonstrated that MIT suppressed the expression of the auxin efflux carrier PIN1 and major root stem cell regulators (PLT1, PLT2, SHR, and SCR). Additionally, MIT hindered root regeneration by downregulating the quiescent center (QC) marker WOX5. Transcriptome analysis revealed MIT-induced alterations in gene expression related to oxidative stress, with physiological experiments confirming elevated reactive oxygen species (ROS) levels and increased cell death in root tips at concentrations exceeding 50 µM. In summary, this study provides critical insights into MIT's toxicity on plant root development and regeneration, primarily linked to modifications in polar auxin transport and downregulation of genes associated with root stem cell regulation.

The Protective Efficacy of a SARS-CoV-2 Vaccine Candidate B.1.351V against Several Variant Challenges in K18-hACE2 Mice.

The emergence of SARS-CoV-2 variants of concern (VOCs) with increased transmissibility and partial resistance to neutralization by antibodies has been observed globally. There is an urgent need for an effective vaccine to combat these variants. Our study demonstrated that the B.1.351 variant inactivated vaccine candidate (B.1.351V) generated strong binding and neutralizing antibody responses in BALB/c mice against the B.1.351 virus and other SARS-CoV-2 variants after two doses within 28 days. Immunized K18-hACE2 mice also exhibited elevated levels of live virus-neutralizing antibodies against various SARS-CoV-2 viruses. Following infection with these viruses, K18-hACE2 mice displayed a stable body weight, a high survival rate, minimal virus copies in lung tissue, and no lung damage compared to the control group. These findings indicate that B.1.351V offered protection against infection with multiple SARS-CoV-2 variants in mice, providing insights for the development of a vaccine targeting SARS-CoV-2 VOCs for human use.

Human Equilibrative Nucleoside Transporter 1: Novel Biomarker and Prognostic Indicator for Patients with Gemcitabine-Treated Pancreatic Cancer.

Aim: This article aimed to find appropriate pancreatic cancer (PC) patients to treat with Gemcitabine with better survival outcomes by detecting hENT1 levels. Methods: We collected surgical pathological tissues from PC patients who received radical surgery in our hospital from September 2004 to December 2014. A total of 375 PC tissues and paired adjacent nontumor tissues were employed for the construction of 4 tissue microarrays (TMAs). The quality of the 4 TMAs was examined by HE staining. We performed immunohistochemistry analysis to evaluate hENT1 expression in the TMAs. Moreover, we detected hENT1 expression level and proved the role of hENT1 in cell proliferation, drug resistance, migration and invasion in vivo and vitro. Results: The results indicated that low hENT1 expression indicated a significantly poor outcome in PC patients, including shortened DFS (21.6±2.8 months versus 36.9±4.0 months, p<0.001) and OS (33.6±3.9 versus 39.6±3.9, p=0.004). Meanwhile, patients in stage I/II of TNM stage had a longer OS (40.2±3.4 versus 15.4±1.7, p=0.002) and DFS (31.0±3.1 versus 12.4±1.9, p=0.016) than patients in stage III/IV. Patients in M0 stage had a longer OS (39.7±3.4 versus 16.2±1.9, p=0.026) and DFS(30.7±3.0 versus 11.8±2.2, p=0.031) than patients in M1 stage, and patients with tumors not invading the capsule had a better DFS than those with tumor invasion into the capsule (30.8±3.0 versus 12.6±2.3, p=0.053). Patients with preoperative CA19-9 values ≤467 U/mL have longer DFS than that of patients who had preoperative CA19-9 values >467 U/mL (37.9±4.1 versus 22.9±4.0, p=0.04). In the subgroup analysis, a high hENT1 expression level was related to a longer OS(39.4±4.0 versus 31.5±3.9, p=0.001) and DFS(35.7±4.0 versus 20.6±2.7; p<0.0001) in the Gemcitabine subgroup. Conclusion: PC patients with high hENT1 expression have a better survival outcomes when receiving Gemcitabine. hENT1 expression can be a great prognostic indicator for PC patients to receive Gemcitabine treatment.

Systematic identification and functional analysis of root meristem growth factors (RGFs) reveals role of PgRGF1 in modulation of root development and ginsenoside production in Panax ginseng.

Panax ginseng C.A. Mey., known for its medicinal and dietary supplement properties, primarily contains pharmacologically active ginsenosides. However, the regulatory mechanisms linking ginseng root development with ginsenoside biosynthesis are still unclear. Root meristem growth factors (RGFs) are crucial for regulating plant root growth. In our study, we identified five ginseng RGF peptide sequences from the ginseng genome and transcriptome libraries. We treated Arabidopsis and ginseng adventitious roots with exogenous Panax ginseng RGFs (PgRGFs) to assess their activities. Our results demonstrate that PgRGF1 influences gravitropic responses and reduces lateral root formation in Arabidopsis. PgRGF1 has been found to restrict the number and length of ginseng adventitious root branches in ginseng. Given the medicinal properties of ginseng, We determined the ginsenoside content and performed transcriptomic analysis of PgRGF1-treated ginseng adventitious roots. Specifically, the total ginsenoside content in ginseng adventitious roots decreased by 19.98 % and 63.71 % following treatments with 1 µM and 10 µM PgRGF1, respectively, compared to the control. The results revealed that PgRGF1 affects the accumulation of ginsenosides by regulating the expression of genes associated with auxin transportation and ginsenoside biosynthesis. These findings suggest that PgRGF1, as a peptide hormone regulator in ginseng, can modulate adventitious root growth and ginsenoside accumulation.

How to choose a design thinking method for teaching the design of localization: A two-dimension linguistic fuzzy model with two-tuples.

There are many different types of scientific design thinking methods, but it is necessary to evaluate the applicability of the methods to the components of the design teaching curriculum in universities. Therefore, this study assesses the applicability of design thinking in terms of "design practice" and "locality" based on the local design education philosophy and the characteristics of the students and courses. A two-dimensional linguistic fuzzy model with two-tuples was proposed, and the assessment values of 36 experts were statistically analysed using the Delphi, triangular fuzzy number, Euclidean distance, two-dimension linguistic label (2DLL), and two-dimensional linguistic weighted arithmetic aggregation (2DLWAA) methods. The results highlighted the 12 categories of design thinking methods that are most applicable to teaching and learning, indicating the basic views of university design faculty on the application of design thinking methods. Finally, the new design teaching methods have been validated and constructed through years of teaching practice, and have some reference value for teaching design courses in universities.

Photoswitchable Cascades for Allosteric and Bidirectional Control over Covalent Bonds and Assemblies.

Studies of complex systems and emerging properties to mimic biosystems are at the forefront of chemical research. Dynamic multistep cascades, especially those exhibiting allosteric regulation, are challenging. Herein, we demonstrate a versatile platform of photoswitchable covalent cascades toward remote and bidirectional control of reversible covalent bonds and ensuing assemblies. The relay of a photochromic switch, keto-enol equilibrium, and ring-chain equilibrium allows light-mediated reversible allosteric structural changes. The accompanying distinct reactivity further enables photoswitchable dynamic covalent bonding and release of substrates bidirectionally through alternating two wavelengths of light, essentially realizing light-mediated signaling cycles. The downfall of energy by covalent bond formation/scission upon photochemical reactions offers the driving force for the controlled direction of the cascade. To show the molecular diversity, photoswitchable on-demand assembly/disassembly of covalent polymers, including structurally reconfigurable polymers, was realized. This work achieves photoswitchable allosteric regulation of covalent architectures within dynamic multistep cascades, which has rarely been reported before. The results resemble allosteric control within biological signaling networks and should set the stage for many endeavors, such as dynamic assemblies, molecular motors, responsive polymers, and intelligent materials.

Aromatic-Carbonyl Interactions as an Emerging Type of Non-Covalent Interactions.

Aromatic-carbonyl (Ar···C═O) interactions, attractive interactions between the arene plane and the carbon atom of carbonyl, are in the infancy as one type of new supramolecular bonding forces. Here the study and functionalization of aromatic-carbonyl interactions in solution is reported. A combination of aromatic-carbonyl interactions and dynamic covalent chemistry provided a versatile avenue. The stabilizing role and mechanism of arene-aldehyde/imine interactions are elucidated through crystal structures, NMR studies, and computational evidence. The movement of imine exchange equilibria further allowed the quantification of the interplay between arene-aldehyde/imine interactions and dynamic imine chemistry, with solvent effects offering another handle and matching the electrostatic feature of the interactions. Moreover, arene-aldehyde/imine interactions enabled the reversal of kinetic and thermodynamic selectivity and sorting of dynamic covalent libraries. To show the functional utility diverse modulation of fluorescence signals is realized with arene-aldehyde/imine interactions. The results should find applications in many aspects, including molecular recognition, assemblies, catalysis, and intelligent materials.

Comprehensive analysis of bulk and single-cell transcriptomic data reveals a novel signature associated with endoplasmic reticulum stress, lipid metabolism, and liver metastasis in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high probability of recurrence and distant metastasis. Liver metastasis is the predominant metastatic mode developed in most pancreatic cancer cases, which seriously affects the overall survival rate of patients. Abnormally activated endoplasmic reticulum stress and lipid metabolism reprogramming are closely related to tumor growth and metastasis. This study aims to construct a prognostic model based on endoplasmic reticulum stress and lipid metabolism for pancreatic cancer, and further explore its correlation with tumor immunity and the possibility of immunotherapy. METHODS: Transcriptomic and clinical data are acquired from TCGA, ICGC, and GEO databases. Potential prognostic genes were screened by consistent clustering and WGCNA methods, and the whole cohort was randomly divided into training and testing groups. The prognostic model was constructed by machine learning method in the training cohort and verified in the test, TCGA and ICGC cohorts. The clinical application of this model and its relationship with tumor immunity were analyzed, and the relationship between endoplasmic reticulum stress and intercellular communication was further explored. RESULTS: A total of 92 characteristic genes related to endoplasmic reticulum stress, lipid metabolism and liver metastasis were identified in pancreatic cancer. We established and validated a prognostic model for pancreatic cancer with 7 signatures, including ADH1C, APOE, RAP1GAP, NPC1L1, P4HB, SOD2, and TNFSF10. This model is considered to be an independent prognosticator and is a more accurate predictor of overall survival than age, gender, and stage. TIDE score was increased in high-risk group, while the infiltration levels of CD8+ T cells and M1 macrophages were decreased. The number and intensity of intercellular communication were increased in the high ER stress group. CONCLUSIONS: We constructed and validated a novel prognostic model for pancreatic cancer, which can also be used as an instrumental variable to predict the prognosis and immune microenvironment. In addition, this study revealed the effect of ER stress on cell-cell communication in the tumor microenvironment.

Neighboring Effects of Sulfur Oxidation State on Dynamic Covalent Bonds and Assemblies.

The impact of a varied sulfur oxidation state (sulfide, sulfoxide, and sulfone) on imine dynamic covalent chemistry is presented. The role of noncovalent interactions, including chalcogen bonds and CH hydrogen bonds, on aldehyde/imine structures and imine exchange reactions was elucidated through experimental and computational evidence. The change in the sulfur oxidation state and diamine linkage further allowed the regulation of imine macrocycles, providing a platform for controlling molecular assemblies.

The study on mechanical model considering optimal self-adaption in the bottleneck area.

It aims to solve the problem that the evacuation state of pedestrians depicted by the traditional social force model in a crowded multiexit scenario has a relatively large difference with the actual state, especially the 'optimal path' considered by the self-driving force is the problem of shortest path, and the multiexit evacuation mode depicted by the 'herd behavior' is the local optimum problem. Through in-depth analysis of actual evacuation data of pedestrians and causes of problem, a new crowd evacuation optimization model is established in order to effectively improve the simulation accuracy of crowd evacuation in a multi-exit environment. The model obtains the direction of motion of pedestrians using a field model, fully considers the factors such as exit distance, distribution of pedestrians and regional crowding degree, makes a global optimization for the self-driving force in the social force model using a centralized and distributed network model, and makes a local optimization for it using an elephant herding algorithm, so as to establish a new evacuation optimization method for optimal self-adaption in the bottleneck area. The performance status is compared between the improved social force model and the new model by experiments, and the key factors that affect the new model are analyzed in an in-depth manner. The results show that the new model can optimize the optimal path choice at the early stage of evacuation and improve the evacuation efficiency of pedestrians at the late stage, so as to ensure relatively even distribution of pedestrians at each exit, and also make the simulated evacuation process be more real; and the improvement in overall evacuation efficiency is greater when the number of pedestrians to be evacuated is larger. Therefore, the new model provides a method to solve the phenomenon of disorder in overall pedestrian evacuation due to excessive crowd density during the process of multi-exit evacuation.

An exposome atlas of serum reveals the risk of chronic diseases in the Chinese population.

Although adverse environmental exposures are considered a major cause of chronic diseases, current studies provide limited information on real-world chemical exposures and related risks. For this study, we collected serum samples from 5696 healthy people and patients, including those with 12 chronic diseases, in China and completed serum biomonitoring including 267 chemicals via gas and liquid chromatography-tandem mass spectrometry. Seventy-four highly frequently detected exposures were used for exposure characterization and risk analysis. The results show that region is the most critical factor influencing human exposure levels, followed by age. Organochlorine pesticides and perfluoroalkyl substances are associated with multiple chronic diseases, and some of them exceed safe ranges. Multi-exposure models reveal significant risk effects of exposure on hyperlipidemia, metabolic syndrome and hyperuricemia. Overall, this study provides a comprehensive human serum exposome atlas and disease risk information, which can guide subsequent in-depth cause-and-effect studies between environmental exposures and human health.

Multiple control of azoquinoline based molecular photoswitches.

Multi-addressable molecular switches with high sophistication are creating intensive interest, but are challenging to control. Herein, we incorporated ring-chain dynamic covalent sites into azoquinoline scaffolds for the construction of multi-responsive and multi-state switching systems. The manipulation of ring-chain equilibrium by acid/base and dynamic covalent reactions with primary/secondary amines allowed the regulation of E/Z photoisomerization. Moreover, the carboxyl and quinoline motifs provided recognition handles for the chelation of metal ions and turning off photoswitching, with otherwise inaccessible Z-isomer complexes obtained via the change of stimulation sequence. Particularly, the distinct metal binding behaviors of primary amine and secondary amine products offered a facile way for modulating E/Z switching and dynamic covalent reactivity. As a result, multiple control of azoarene photoswitches was accomplished, including light, pH, metal ions, and amine nucleophiles, with interplay between diverse stimuli further enabling addressable multi-state switching within reaction networks. The underlying structural and mechanistic insights were elucidated, paving the way for the creation of complex switching systems, molecular assemblies, and intelligent materials.