Pillararene-Inspired Macrocycles: From Extended Pillar[n]arenes to Geminiarenes.

chemistry since their establishment due to their innate functional features of molecular recognition and complexation. The rapid development of modern supramolecular chemistry has also significantly benefited from creating new macrocycles with distinctive geometries and properties. For instance, pillar[n]arenes (pillarenes), a relatively young generation of star macrocyclic hosts among the well-established ones (e.g., crown ethers, cyclodextrins, cucurbiturils, and calixarenes), promoted a phenomenal research hotspot all over the world in the past decade. Although the synthesis, host-guest properties, and various supramolecular functions of pillarenes have been intensively studied, many objective limitations and challenges still cannot be ignored. For example, high-level pillar[n]arenes (n > 7) usually do not possess applicable large-sized cavities due to structural folding and cannot be synthesized on a large scale because of the uncompetitive cyclization process. Furthermore, two functional groups must be covalently para-connected to each repeating phenylene unit, which severely limits their structural diversity and flexibility. In this context, we have developed a series of pillarene-inspired macrocycles (PIMs) using a versatile and modular synthetic strategy during the past few years, aiming to break through the synthetic limitations in traditional pillarenes and find new opportunities and challenges in supramolecular chemistry and beyond. Specifically, by grafting biphenyl units into the pillarene backbones, extended pillar[n]arenes with rigid and nanometer-sized cavities could be obtained with reasonable synthetic yields by selectively removing hydroxy/alkoxy substitutes on pillarene backbones, leaning pillar[6]arenes and leggero pillar[n]arenes with enhanced structural flexibility and cavity adaptability were obtained. By combining the two types of bridging modes in pillarenes and calixarenes, a smart macrocyclic receptor with two different but interconvertible conformational features, namely geminiarene, was discovered. Benefiting from the synthetic accessibility, facile functionalization, and superior host-guest properties in solution or the solid state, this new family of macrocycles has exhibited a broad range of applications, including but not limited to supramolecular assembly/gelation/polymers, pollutant detection and separation, porous organic polymers, crystalline/amorphous molecular materials, hybrid materials, and controlled drug delivery. Thus, in this Account, we summarize our research efforts on these PIMs. We first present an overview of their design and modular synthesis and a summary of their derivatization strategies. Thereafter, particular attention is paid to their structural features, supramolecular functions, and application exploration. Finally, the remaining challenges and perspectives are outlined for their future development. We hope that this Account and our works can stimulate further advances in synthetic macrocyclic chemistry and supramolecular functional systems, leading to practical applications in various research areas.

[Hepatotoxicity and mechanism of Rhododendri Mollis Flos based on zebrafish model].

This study used the zebrafish model to explore the hepatotoxicity of Rhododendri Mollis Flos(RMF). The mortality was calculated according to the number of the survival of zebrafish larvae 4 days after fertilization under different concentration of RMF, and the dose-toxicity curve was fitted to preliminarily evaluate the toxicity of RMF. The liver phenotypes under the sublethal concentration of RMF in the treatment group and the blank control group were observed by hematoxylin-eosin(HE) staining and acridine orange(AO) staining. Meanwhile, the activities of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were determined to confirm the hepatotoxicity of RMF. Real-time quantitative polymerase chain reaction(real-time PCR) and Western blot were used to determine the expressions of genes and proteins in zebrafish larvae. Gas chromatography time-of-flight mass spectrometry(GC-TOF-MS) was used to conduct untargeted metabolomics testing to explore the mechanism. The results showed that the toxicity of RMF to zebrafish larvae was dose-dependent, with 1 100 µg·mL~(-1) of the absolute lethal concentration and 448 µg·mL~(-1) of sublethal concentration. The hepatocyte apoptosis and degeneration appeared in the zebrafish larvae under the sublethal concentration of RMF. The content of ALT and AST in zebrafish larvae at the end of the experiment was significantly increased in a dose-dependent manner. Under the sublethal concentration, the expressions of genes and proteins related to apoptosis in zebrafish larvae were significantly increased as compared with the blank control group. The results of untargeted metabolomics showed that the important metabolites related to the he-patotoxicity of RMF were mainly enriched in alanine, aspartic acid, glutamic acid, and other pathways. In conclusion, it is inferred that RMF has certain hepatotoxicity to zebrafish larvae, and its mechanism may be related to apoptosis.

Macrocycle-Based Crystalline Supramolecular Assemblies Built with Intermolecular Charge-Transfer Interactions.

Synthetic macrocycles have served as principal tools for supramolecular chemistry, have greatly extended the scope of organic charge transfer (CT) complexes, and have proved to be of great practical value in the solid state during the past few years. In this Minireview, we summarize the research progress on the macrocycle-based crystalline supramolecular assemblies primarily driven by intermolecular CT interactions (a.k.a. macrocycle-based crystalline CT assemblies, MCCAs for short), which are classified by their donor-acceptor (D-A) constituent elements, including simplex macrocyclic hosts, heterogeneous macrocyclic hosts, and host-guest D-A pairs. Particular attention will be focused on their diverse functions and applications, as well as the underlying CT mechanisms from the perspective of crystal engineering. Finally, the remaining challenges and prospects are outlined.

Gene co-expression network based on part mutual information for gene-to-gene relationship and gene-cancer correlation analysis.

BACKGROUND: Finding correlation patterns is an important goal of analyzing biological data. Currently available methods for correlation analysis mainly use non-direct associations, such as the Pearson correlation coefficient, and focus on the interpretation of networks at the level of modules. For biological objects such as genes, their collective function depends on pairwise gene-to-gene interactions. However, a large amount of redundant results from module level methods often necessitate further detailed analysis of gene interactions. New approaches of measuring direct associations among variables, such as the part mutual information (PMI), may help us better interpret the correlation pattern of biological data at the level of variable pairs. RESULTS: We use PMI to calculate gene co-expression networks of cancer mRNA transcriptome data. Our results show that the PMI-based networks with fewer edges could represent the correlation pattern and are robust across biological conditions. The PMI-based networks recall significantly more important parts of omics defined gene-pair relationships than the Pearson Correlation Coefficient (PCC)-based networks. Based on the scores derived from PMI-recalled copy number variation or DNA methylation gene-pairs, the patients with cancer can be divided into groups with significant differences on disease specific survival. CONCLUSIONS: PMI, measuring direct associations between variables, extracts more important biological relationships at the level of gene pairs than conventional indirect association measures do. It can be used to refine module level results from other correlation methods. Particularly, PMI is beneficial to analysis of biological data of the complicated systems, for example, cancer transcriptome data.

Activation of TRPV4 stimulates transepithelial K+ secretion in rat epididymal epithelium.

The maturation of sperms is dependent on the coordinated interactions between sperm and the unique epididymal luminal milieu, which is characterized by high K+ content. This study investigated the involvement of transient receptor potential vanilloid 4 (TRPV4) in the K+ secretion of epididymal epithelium. The expression level and cellular localization of TRPV4 and Ca2+-activated K+ channels (KCa) were analyzed via RT-PCR, real-time quantitative PCR, western blot and immunofluorescence. The functional role of TRPV4 was investigated using short-circuit current (ISC) and intracellular Ca2+ imaging techniques. We found a predominant expression of TRPV4 in the corpus and cauda epididymal epithelium. Activation of TRPV4 with a selective agonist, GSK1016790A, stimulated a transient decrease in the ISC of the epididymal epithelium. The ISC response was abolished by either the TRPV4 antagonists, HC067047 and RN-1734, or the removal of basolateral K+. Simultaneously, the application of GSK1016790A triggered Ca2+ influx in epididymal epithelial cells. Our data also indicated that the big conductance KCa (BK), small conductance KCa (SK) and intermediate conductance KCa (IK) were all expressed in rat epididymis. Pharmacological studies revealed that BK, but not SK and IK, mediated TRPV4-elicited transepithelial K+ secretion. Finally, we demonstrated that TRPV4 and BK were localized in the epididymal epithelium, which showed an increased expression level from caput to cauda regions of rat epididymis. This study implicates that TRPV4 plays an important role in the formation of high K+ concentration in epididymal intraluminal fluid via promoting transepithelial K+ secretion mediated by BK.

A Water-Soluble Leggero Pillar[5]arene.

The study of aqueous-phase molecular recognition of artificial receptors is one of the frontiers in supramolecular chemistry since most biochemical processes and reactions take place in an aqueous medium and heavily rely on it. In this work, a water-soluble version of leggero pillar[5]arene bearing eight positively charged pyridinium moieties (CWP[5]L) was designed and synthesized, which exhibited good binding affinities with certain aliphatic sulfonate species in aqueous solutions. Significantly, control experiments demonstrate that the guest binding performance of CWP[5]L is superior to its counterpart water-soluble macrocyclic receptor in traditional pillararenes.

[Construction of a high-throughput screening model for mitochondrial function of Aconiti Lateralis Radix Praeparata by machine learning algorithm and mechanism analysis].

A high-throughput screening machine learning model for mitochondrial function was constructed, and compounds of Aco-niti Lateralis Radix Praeparata were predicted. Deoxyaconitine with the highest score and benzoylmesaconine with the lowest score among the compounds screened by the model were selected for mitochondrial mechanism analysis. Mitochondrial function data were collected from PubChem and Tox21 databases. Random forest and gradient boosted decision tree algorithms were separately used for mo-deling, and ECFP4(extended connectivity fingerprint, up to four bonds) and Mordred descriptors were employed for training, respectively. Cross-validation test was carried out, and balanced accuracy(BA) and overall accuracy were determined to evaluate the performance of different combinations of models and obtain the optimal algorithm and hyperparameters for modeling. The data of Aconiti Lateralis Radix Praeparata compounds in TCMSP database were collected, and after prediction and screening by the constructed high-throughput screening machine learning model, deoxyaconitine and benzoylmesaconine were selected to measure mitochondrial membrane potential, reactive oxygen species(ROS) level and protein expression of B-cell lymphoma 2(Bcl-2), Bcl-2-associated X protein(Bax) and peroxisome proliferator-activated receptor-γ-coactivator 1α(PGC-1α). The results showed that the model constructed using gradient boosted decision tree+Mordred algorithm performed better, with a cross-validation BA of 0.825 and a test set accuracy of 0.811. Deoxyaconitine and benzoylmesaconine changed the ROS level(P<0.001), mitochondrial membrane potential(P<0.001), and protein expression of Bcl-2(P<0.001, P<0.01) and Bax(P<0.001), and deoxyaconitine increased the expression of PGC-1α protein(P<0.01). The high-throughput screening model for mitochondrial function constructed by gradient boosted decision tree+Mordred algorithm was more accurate than that by random forest+ECFP4 algorithm, which could be used to build an algorithm model for subsequent research. Deoxyaconitine and benzoylmesaconine affected mitochondrial function. However, deoxyaconitine with higher score also affected mitochondrial biosynthesis by regulating PGC-1α protein.

Modulating Supramolecular Charge-Transfer Interactions in the Solid State using Compressible Macrocyclic Hosts.

Modulating intermolecular charge-transfer (ICT) interactions between specific donor and acceptor species in host-guest systems is a big challenge and full of research value in supramolecular chemistry and materials science. In this work, a strategy to modulate the supramolecular ICT interactions in the solid state is developed by compressing the binding cavity of a macrocyclic host named perethylated leaning pillar[6]arene (p-EtLP6). The solid-state ICT affinities of p-EtLP6 toward multi-types of electron-deficient planar guests could be significantly enhanced by transforming the macrocyclic backbone from the original para-bridged mode into a hybrid para- and meta-bridged isomeric form (m-EtLP6). X-ray single-crystal structural analyses incorporating theoretical calculation demonstrate that the improved ICT affinities are mainly attributed to the superior host-guest size fit arising from the compressed binding cavity in m-EtLP6 as compared with p-EtLP6.

FIGS: Featured Ion-Guided Stoichiometry for Data-Independent Proteomics through Dynamic Deconvolution.

Data-independent acquisition (DIA) has significant advantages for mass spectrometry (MS)-based peptide quantification, while mixed spectra remain challenging for precise stoichiometry. We here choose to analyze the library spectra in specific sets preferentially and locally. Accordingly, the featured ions are defined as the fragment ions uniquely assigned to corresponding precursors in a given spectrum set, which are generated by dynamic deconvolution of the mixed mass spectra. Then, we present featured ion-guided stoichiometry (FIGS), a universal method for accurate and robust peptide quantification for the DIA-MS data. We validate the high performance on the quantification sensitivity, accuracy, and efficiency of FIGS. Notably, our FIGS dramatically improves the quantification accuracy for the full dynamic range, especially for low-abundance peptides.

Bottom-Up Solid-State Molecular Assembly via Guest-Induced Intermolecular Interactions.

The manipulation of molecular motions to construct highly ordered supramolecular architectures from chaos in the solid state is considered to be far more complex and challenging in comparison to that in solution. In this work, a bottom-up molecular assembly approach based on a newly designed skeleton-trimmed pillar[5]arene analogue, namely the permethylated leggero pillar[5]arene MeP[5]L, is developed in the solid state. An amorphous powder of MeP[5]L can take up certain guest vapors to form various ordered linker-containing solid-state molecular assemblies, which can be further used to construct a thermodynamically favored linker-free superstructure upon heating. These approaches are driven by vapor-induced solid-state molecular motions followed by a thermally triggered phase-to-phase transformation. The intermolecular interactions play a crucial role in controlling the molecular arrangements in the resulting assemblies. This research will open new insights into exploring controllable molecular motions and assemblies in the solid state, providing new perspectives in supramolecular chemistry and materials.

Recyclable Supramolecular Assembly-Induced Emission System for Selective Detection and Efficient Removal of Mercury(II).

An efficient strategy for simultaneously detecting and removing Hg2+ from water is vital to address mercury pollution. Herein a supramolecular assembly G⊂H with photoluminescent properties is facilely constructed through the self-assembly of a functional pillar[5]arene bearing two N,N-dimethyldithiocarbamoyl binding sites (H) and an AIE-active tetraphenylethene derivative (G). Remarkably, the fluorescence of G⊂H can be exclusively quenched by Hg2+ among the 30 cations due to the formation of non-luminous ground state complex and only L-cysteine can restore fluorescence in the common 20 amino acids. Meanwhile, the probe G⊂H has a considerable thermal and pH stability, a good anti-interference property from various cations, and a satisfactory sensitivity. More importantly, G⊂H exhibits a prominent capability of Hg2+ removal with rapid capture rate (within 1 h) and excellent adsorption efficiency (98 %), as well as a highly efficient recyclability without losing any adsorption activity.

CNIT: a fast and accurate web tool for identifying protein-coding and long non-coding transcripts based on intrinsic sequence composition.

As more and more high-throughput data has been produced by next-generation sequencing, it is still a challenge to classify RNA transcripts into protein-coding or non-coding, especially for poorly annotated species. We upgraded our original coding potential calculator, CNCI (Coding-Non-Coding Index), to CNIT (Coding-Non-Coding Identifying Tool), which provides faster and more accurate evaluation of the coding ability of RNA transcripts. CNIT runs âˆ¼200 times faster than CNCI and exhibits more accuracy compared with CNCI (0.98 versus 0.94 for human, 0.95 versus 0.93 for mouse, 0.93 versus 0.92 for zebrafish, 0.93 versus 0.92 for fruit fly, 0.92 versus 0.88 for worm, and 0.98 versus 0.85 for Arabidopsis transcripts). Moreover, the AUC values of 11 animal species and 27 plant species showed that CNIT was capable of obtaining relatively accurate identification results for almost all eukaryotic transcripts. In addition, a mobile-friendly web server is now freely available at http://cnit.noncode.org/CNIT.

Synthetic Macrocycle-Based Nonporous Adaptive Crystals for Molecular Separation.

The exploitation of new materials for adsorptive separation of industrially important hydrocarbons is of great importance in both scientific research and petrochemical industry. Nonporous adaptive crystals (NACs) as a robust class of synthetic materials have drawn much attention during the past five years for their superior performance in adsorption and separation. Pillararenes are the main family of macrocyclic arenes used for NACs construction, where the structure-function relationship has been intensively studied. In the past two years, some emerging types of synthetic macrocyclic arenes have been successfully brought into this research field, showing the gradual enrichment and diversification of NACs materials. This Minireview summarizes the recent advances of synthetic macrocycle-based NACs, which are categorized by various practical applications in molecular separation. Besides, NACs-based vapochromic supramolecular systems are also discussed. Finally, future perspectives and challenges of NACs are given. We envisage that this Minireview will be a useful and timely reference for those who are interested in new molecular and supramolecular crystals for storage and separation applications.

Macrocyclic Arenes-Based Conjugated Macrocycle Polymers for Highly Selective CO2 Capture and Iodine Adsorption.

Incorporating synthetic macrocycles with unique structures and distinct conformations into conjugated macrocycle polymers (CMPs) can endow the resulting materials with great potentials in gas uptake and pollutant adsorption. Here, four CMPs (CMP-n, n=1-4) capable of reversibly capturing iodine and efficiently separating carbon dioxide are constructed from per-triflate functionalized leaning tower[6]arene (LT6-OTf) and [2]biphenyl-extended pillar[6]arene (BpP6-OTf) via Pd-catalyzed Sonogashira-Hagihara cross-coupling reaction. Intriguingly, owing to the appropriate cavity size of LT6-OTf and the numerous aromatic rings in the framework, the newly designed CMP-4 possesses an outstanding I2 affinity with a large uptake capacity of 208 wt % in vapor and a great removal efficiency of 94 % in aqueous solutions. To our surprise, with no capacity to accommodate nitrogen, CMP-2 constructed from BpP6-OTf is able to specifically capture carbon dioxide at ambient conditions.

Elongated-Geminiarene: Syntheses, Solid-State Conformational Investigations, and Application in Aromatics/Cyclic Aliphatics Separation.

Energy-saving separation and purification of industrially important compounds with similar physical and chemical properties by novel molecular crystalline materials are of great importance and highly desired. Here a newly enlarged version of geminiarene, namely elongated-geminiarene (ElGA), is first designed and synthesized. Taking advantages of both geminiarenes and biphenarenes, ElGA shows great features including scalable synthesis, nanometer-sized cavity, rich blend of conformational features, and excellent solid-state host-guest properties. Significantly, the functional crystalline materials of ElGA are highly effective in the separation of aromatics and cyclic aliphatics, showing a preference for dimethylbenzene over its corresponding hydrogenation products and paving a new avenue for separation science and industry.

Separation of Bromoalkanes Isomers by Nonporous Adaptive Crystals of Leaning Pillar[6]arene.

Haloalkanes are important chemicals in synthetic chemistry and petrochemical industry, but the separation of their isomers is a big hurdle. Herein, we report a facile energy-efficient adsorptive separation strategy using a new class of nonporous adaptive crystals based on leaning pillar[6]arene. Desolvated perethylated leaning pillar[6]arene crystals (EtLP6) with interesting nonporous character show a preference for 1-bromoalkane isomers over 2-bromoalkane isomers. EtLP6 is capable of separating 1-bromopropane, 1-bromobutane, and 1-bromopentane from the corresponding 1:1 (v/v) mixtures of 1/2-positional isomers with purities from 89.6 % to 96.3 % in only one adsorption cycle. The selectivity is endowed by the different host-guest binding modes and different stabilities of EtLP6 crystalloids loaded with 1- and 2-positional isomers. Significantly, the guest-adsorbed assemblies are highly stable at room temperature and EtLP6 can be reused many times without any decrease in performance.

Geminiarene: Molecular Scale Dual Selectivity for Chlorobenzene and Chlorocyclohexane Fractionation.

In this work, a new version of macrocyclic arenes, namely geminiarene, has been designed and synthesized for guest complexation and chlorobenzene/chlorocyclohexane mixture separation with excellent dual selectivity. Due to its unique dual/gemini conformational feature, not only chlorocyclohexane can be separated from chlorobenzene with exceeding 97% purity but also chlorobenzene can be separated from chlorocyclohexane with purity over 88%, and the dual selective fractionation process could be achieved in only one cycle of operation. Significantly, we demonstrate that the dual selectivity capability is essentially a competition of the stability between the guest-free and guest-loaded crystalline phases of geminiarene. We strongly believe that this work and the idea of multiple selective separation systems will open up new perspectives on macrocycle-based solid-state host-guest chemistry and molecular scale separation materials.

Supramolecular Assembly-Induced Emission Enhancement for Efficient Mercury(II) Detection and Removal.

New strategies that can simultaneously detect and remove highly toxic environmental pollutants such as heavy metal ions are still in urgent need. Herein, through supramolecular host-guest interactions, a fluorescent supramolecular polymer has been facilely constructed from a newly designed [2]biphenyl-extended pillar[6]arene equipped with two thymine sites as arms (H) and a tetraphenylethylene (TPE)-bridged bis(quaternary ammonium) guest (G) with aggregation-induced emission (AIE) property. Interestingly, supramolecular assembly-induced emission enhancement (SAIEE) could be switched on upon addition of Hg2+ into the above-mentioned supramolecular polymer system to generate spherical-like supramolecular nanoparticles, due to the restriction of intramolecular rotation (RIR)-related AIE feature of G. Significantly, this supramolecular polymer with integrated modalities has been successfully used for real-time detection and removal of toxic heavy metal Hg2+ ions from water with quick response, high selectivity, and rapid adsorption rates, which could be efficiently regenerated and recycled without any loss via a simple treatment with Na2S. The newly developed supramolecular polymer system combines the inherent rigid and spacious cavity of novel extended-pillarene host with the AIE characteristics of TPE-based guest, suggesting a great potential in the treatment of heavy metal pollution and environmental sustainability.

Comparative efficacy of Chinese herbal injections for treating chronic heart failure: a network meta-analysis.

BACKGROUND: On account of deterioration of chronic heart failure (CHF) and extensive exploration of Chinese herbal injections (CHIs), we performed a network meta-analysis to investigate the efficacy of CHIs (Huangqi injection, Shenfu injection, Shengmai injection, Shenmai injection, Shenqi Fuzheng injection, Yiqifumai injection) on the basis of western medicine (WM) treatment in CHF. METHODS: Literature search was conducted in Embase, the Cochrane Library, Pubmed, Chinese Biological Medicine Database, China National Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journal Database from inception to June 12nd 2017, and study selection was abided by a prior eligible criteria. RESULTS: Ultimately, a total of 113 randomized controlled trials (RCTs) were enrolled. The clinical data of the effective clinical rate, left ventricular ejection fraction, cardiac output and others outcomes was estimated by Stata software and Winbugs software. Risk of bias was assessed by Cochrane Collaboration's tools. Integrating the each outcome's results, a combination of Shengmai injection/Shenmai injection and WM obtain a first rank in most outcomes, particularly primary outcomes. CONCLUSIONS: In conclusion, on the basis of WM, Shengmai injection or Shenmai injection may be a perforable treatment in CHF. In terms of insufficient of this study, more high quality RCTs needed to implement to support our conclusions.

Comparative efficacy of Chinese herbal injections for treating acute cerebral infarction: a network meta-analysis of randomized controlled trials.

BACKGROUND: Chinese herbal injections (CHIs) are prepared by extracting and purifying effective substances from herbs (or decoction pieces) using modern scientific techniques and methods. CHIs combined with aspirin + anticoagulants + dehydrant + neuroprotectant (AADN) are believed to be effective for the treatment of acute cerebral infarction (ACI). However, no randomized controlled trial (RCT) has been performed to directly compare the efficacies of different regimens of CHIs. Therefore, we performed a systematic review and network meta-analysis (NMA) to compare the efficacies of different regimens of CHIs for ACI. METHODS: We conducted an overall and systematic retrieval from literature databases of RCTs focused on the use of CHIs to treat ACI up to June 2016. We used the Cochrane Handbook version 5.1.0 and CONSORT statement to assess the risk of bias. The data were analyzed using STATA 13.0 and WinBUGS 1.4.3 software. RESULTS: Overall, 64 studies with 6225 participants involving 15 CHIs were included in the NMA. In terms of the markedly effective rate, Danhong (DH) + AADN had the highest likelihood of being the best treatment. In terms of the improvement of neurological impairment, Shuxuening (SXN) + AADN had the highest likelihood of being the best treatment. Considering two outcomes, injections of SXN, Yinxingdamo (YXDM), DH, Shuxuetong (SXT), HongHuaHuangSeSu (HHHSS), DengZhanXiXin (DZXX) and Shenxiong glucose (SX) plus AADN were the optimum treatment regimens for ACI, especially SXN + AADN and YXDM + AADN. CONCLUSIONS: Based on the NMA, SXN, YXDM, DH, SXT, HHHSS, DZXX and SX plus AADN showed the highest probability of being the best treatment regimens. Due to the limitations of the present study, our findings should be verified by well-designed RCTs.