π-π+ Interaction Promoting the Absorption of Electroactive Chiral Selectors into the Cavity of Conductive Covalent Organic Framework for Enantioselective Sensing of Electrochemically Silent Molecules.

To date, achieving enantioselective electroanalysis for electrochemically silent chiral molecules is still highly desired. Here, an ionic covalent organic framework (COF) consisting of the pyridinium cation was derived from the tripyridinium Zincke salt and 1,4-phenylenediamine in a one-pot reaction. The electrochemical measurements revealed that the ionic backbone contributed to the electron transfer with a low charge transfer resistance. Besides, the π-π+ interaction between the pyridinium cation and ferrocenyl unit can promote the absorption of electroactive chiral ferrocenyl reagents into the hole of COF, so as to afford the electrochemical signals by themselves, replacing the testing enantiomers. As a result, the electroactive complex used as an electrochemical platform was highly effective at enantiomerically recognizing amino alcohols (prolinol, valinol, leucinol, and alaninol) and amino acids (methionine, serine, and penicillamine), giving the ratios of current intensity between l- and d-enantiomers in the range of 1.46-1.72. Moreover, the density functional theory calculations determined the possible intermolecular interactions between the testing enantiomers and chiral selector: namely, hydrogen bonds and electrostatic attractions. Overall, the present work offers an effective strategy to enlarge the electrochemical scope for chiral recognition based on electroactive chiral COFs.

Postsynthetic Modification Strategy for Constructing Electrochemiluminescence-Active Chiral Covalent Organic Frameworks Performing Efficient Enantioselective Sensing.

Electrochemiluminescence (ECL), integrating the characteristics of electrochemistry and fluorescence, has the advantages of high sensitivity and low background. However, only a few studies have been reported for enantioselective sensing based on the ECL-active platform because of the huge challenges in constructing tunable chiral ECL luminophores. Here, we developed a facile strategy to design and prepare ECL-active chiral covalent organic frameworks (COFs) Ph-triPy+-(R)-Ru(II) for enantioselective sensing. In such an artificial structure, the ionic skeleton of COFs was beneficial to the electron transfer on the working electrode surface and the chiral Ru-ligand was used as the chiral ECL-active luminophore. It was found that Ph-triPy+-(R)-Ru(II) coupled with sodium persulfate (Na2S2O8) as the coreactant exhibited obvious ECL signals. More importantly, a clear difference toward l- and d-enantiomers was observed in the response of the ECL intensity, resulting in a uniform recognition law. That is, for amino alcohols, d-enantiomers (1 mM) measured by Ph-triPy+-(R)-Ru(II) showed a higher ECL intensity compared with l-enantiomers. Differently, amino acids (1 mM) gave an inverse recognition phenomenon. The ECL intensity ratios between l- and d-enantiomers (1 mM) are in the range of 1.25-1.94 for serine, aspartic acid, glutamic acid, valine, leucine, leucinol, and valinol. What is more interesting is that the ECL intensity was closely related to the concentration of l-amino alcohols and d-amino acids, whereas their inverse configurations remained unchanged. In a word, the present concept demonstrates a feasible direction toward chiral ECL-active COFs and their potential for efficient enantioselective sensing.

A Liquid-Liquid Interfacial Strategy for Construction of Electroactive Chiral Covalent-Organic Frameworks with the Aim to Enlarge the Testing Scope of Chiral Electroanalysis.

Although electroactive chiral covalent-organic frameworks (CCOFs) are considered an ideal platform for chiral electroanalysis, they are rarely reported due to the difficult selection of suitable precursors. Here, a facile strategy of liquid-liquid interfacial polymerization was carried out to synthesize the target electroactive CCOFs Ph-Py+-(S,S)-DPEA·PF6- and Ph-Py+-(R,R)-DPEA·PF6-. That is, a trivalent Zincke salt (4,4',4″-(benzene-1,3,5-triyl)tris(1-(2,4-dinitrophenyl)pyridin-1-ium)) trichloride (Ph-Py+-NO2) and enantiopure 1,2-diphenylethylenediamine (DPEA) were dissolved in water and chloroform, respectively. The Zincke reaction occurs at the interface, resulting in uniform porosity. As expected, the cyclic voltammetry and differential pulse voltammetry measurements showed that the tripyridinium units of the CCOFs afforded obvious electrochemical responses. When Ph-Py+-(S,S)-DPEA·PF6- was modified onto the surface of a glassy carbon electrode as a chiral sensor, the molecules, which included tryptophan, aspartic acid, serine, tyrosine, glutamic acid, mandelic acid, and malic acid, were enantioselectively recognized in the response of the peak current. Very importantly, the discriminative electrochemical signals were derived from Ph-Py+-(S,S)-DPEA·PF6-. The best peak current ratios between l- and d-enantiomers were in the range of 1.31-2.68. Besides, a good linear relationship between peak currents and enantiomeric excess (ee) values was established, which was successfully harnessed to determine the ee values for unknown samples. In a word, the current work provides new insight and potential of electroactive CCOFs for enantioselective sensing in a broad range.

Recent advances of optically active helical polymers as adsorbents and chiral stationary phases for chiral resolution.

Chiral resolution is very important and still a big challenge due to different biological activity and same physicochemical property of one pair (R)- and (S)-isomer. There is no doubt that chiral selectors are essentially needed for chiral resolution, which can stereoselectively interact with a pair of isomers. To date, a large amount of optically active helical polymers as chiral selectors have been synthesized via two strategies. First, the target helical polymers are derived from natural polysaccharide such as cellulose and amylose. Second, they can be synthesized by polymerization of chiral monomers. Alternatively, an achiral polymer is prepared first followed by static or dynamic chiral induction. Furthermore, a part of them is harnessed as chiral stationary phases for chromatographic chiral separation and as chiral adsorbents for enantioselective adsorption/crystallization, resulting in good enantioseparation efficiency. In summary, the present review will focus on recent progress of the polymers with optical activity for chiral resolution, especially the literature published in the past 10 years. In addition, development prospects and future challenges of optically active helical polymers will be discussed in detail.

Competitive Self-Assembly Interaction between Ferrocenyl Units and Amino Acids for Entry into the Cavity of ß-Cyclodextrin for Chiral Electroanalysis.

At present, chiral electroanalysis of nonelectroactive chiral compounds still remains a challenge because they cannot provide an electrochemical signal by themselves. Here, a strategy based on a competitive self-assembly interaction of a ferrocene (Fc) unit and the testing isomers entering into the cavity of ß-cyclodextrin (ß-CD) was carried out for chiral electroanalysis. First of all, the Fc derivative was directly bridged to silica microspheres, followed by inclusion into the cavity of ß-CD. As expected, once it was modified onto the surface of a carbon working electrode as an electrochemical sensor, SiO2@Fc-CD-WE, its differential pulse voltammetry signal would markedly decrease compared with the uncovered Fc. Next, when l- and d-isomers of amino acids that included histidine, threonine, phenylalanine, and glutamic acid were examined using SiO2@Fc-CD-WE, it showed an enantioselective entry of amino acids into the cavity of ß-cyclodextrin instead of Fc, resulting in the release of Fc with signal enhancement. For histidine, glutamic acid, and threonine, l-isomers showed a higher peak current response compared with d-isomers. The peak current ratios between l- and d-isomers were 2.88, 1.21, and 1.40, respectively. At the same time, the opposite phenomenon occurred for phenylalanine with a peak current ratio of 3.19 between d- and l-isomers. In summary, we are assured that the recognition strategy based on the supramolecular interaction can enlarge the detection range of chiral compounds by electrochemical analysis.

Low shear stress-induced endothelial mesenchymal transformation via the down-regulation of TET2.

Atherosclerotic cardiovascular disease is the major cause of death worldwide. Low shear stress plays key roles on the initiation and progression of atherosclerosis (As). However, its underlying mechanism remains unclear. In this study, the effect of low shear stress on endothelial mesenchymal transformation (EndMT) and its underlying mechanism were explored. Results showed that in cultured human umbilical vein endothelial cells, low shear stress down-regulated the expression of TET2 and promoted EndMT. Loss of TET2 promoted EndMT with the Wnt/ß-catenin signaling pathway. The enhancement in EndMT induced by low shear stress was attenuated by TET2 overexpression. In apoE-/- mice subjected to carotid artery local ligation, the EndMT and atherosclerotic lesions induced by low shear stress was attenuated by TET2 overexpression. Taken together, low shear stress promoted EndMT through the down-regulation of TET2, indicating that intervention with EndMT or the up-regulation of TET2 might be an alternative strategy for preventing As.

Chiral Ru-Based Covalent Organic Frameworks as An Electrochemiluminescence-Active Platform for the Enantioselective Sensing of Amino Acids.

Although several studies related with the electrochemiluminescence (ECL) technique have been reported for chiral discrimination, it still has to face some limitations, namely, complex synthetic pathways and a relatively low recognition efficiency. Herein, this study introduces a facile strategy for the synthesis of ECL-active chiral covalent organic frameworks (COFs) employed as a chiral recognition platform. In this artificial structure, ruthenium(II) coordinated with the dipyridyl unit of the COF and enantiopure cyclohexane-1,2-diamine was harnessed as the ECL-active unit, which gave strong ECL emission in the presence of the coreactant reagent (K2S2O8). When the as-prepared COF was used as a chiral ECL-active platform, clear discrimination was observed in the response of the ECL intensity toward l- and d-enantiomers of amino acids, including tryptophan, leucine, methionine, threonine, and histidine. The biggest ratio of the ECL intensity between different configurations was up to 1.75. More importantly, a good linear relationship between the enantiomeric composition and the ECL intensity was established, which was successfully employed to determine the unknown enantiomeric compositions of the real samples. In brief, we believe that the proposed ECL-based chiral platform provides an important reference for the determination of the configuration and enantiomeric compositions.

A Real-Time Strategy for Chiroptical Sensing and Enantiomeric Excess Determination of Primary Amines via an Acid-Base Reaction.

Two achiral aromatic carboxylic acids that included the 1,8-naphthalimide group and an imidazolium cation were synthesized and exploited as chiroptical sensors. These compounds showed the real-time discrimination and enantiomeric excess determination of chiral amines and amino alcohols via an acid-base interaction, especially for UV-silent chiral compounds.

Breast Cancer Molecular Subtype Prediction on Pathological Images with Discriminative Patch Selection and Multi-Instance Learning.

Molecular subtypes of breast cancer are important references to personalized clinical treatment. For cost and labor savings, only one of the patient's paraffin blocks is usually selected for subsequent immunohistochemistry (IHC) to obtain molecular subtypes. Inevitable block sampling error is risky due to the tumor heterogeneity and could result in a delay in treatment. Molecular subtype prediction from conventional H&E pathological whole slide images (WSI) using the AI method is useful and critical to assist pathologists to pre-screen proper paraffin block for IHC. It is a challenging task since only WSI-level labels of molecular subtypes from IHC can be obtained without detailed local region information. Gigapixel WSIs are divided into a huge amount of patches to be computationally feasible for deep learning, while with coarse slide-level labels, patch-based methods may suffer from abundant noise patches, such as folds, overstained regions, or non-tumor tissues. A weakly supervised learning framework based on discriminative patch selection and multi-instance learning was proposed for breast cancer molecular subtype prediction from H&E WSIs. Firstly, co-teaching strategy using two networks was adopted to learn molecular subtype representations and filter out some noise patches. Then, a balanced sampling strategy was used to handle the imbalance in subtypes in the dataset. In addition, a noise patch filtering algorithm that used local outlier factor based on cluster centers was proposed to further select discriminative patches. Finally, a loss function integrating local patch with global slide constraint information was used to fine-tune MIL framework on obtained discriminative patches and further improve the prediction performance of molecular subtyping. The experimental results confirmed the effectiveness of the proposed AI method and our models outperformed even senior pathologists, which has the potential to assist pathologists to pre-screen paraffin blocks for IHC in clinic.

MicroRNAs: Important Regulators of Induced Pluripotent Stem Cell Generation and Differentiation.

Induced pluripotent stem (iPS) cells can differentiate into nearly all types of cells. In contrast to embryonic stem cells, iPS cells are not subject to immune rejection because they are derived from a patient's own cells without ethical concerns. These cells can be used in regenerative medical techniques, stem cell therapy, disease modelling and drug discovery investigations. However, this application faces many challenges, such as low efficiency, slow generation time, partially reprogrammed colonies and tumourigenicity. Numerous techniques have been formulated in the past decade to improve reprogramming efficiency and safety, including the use of different transcription factors, small molecule compounds and non-coding RNAs. Recently, microRNAs (miRNAs) were found to promote the generation and differentiation of iPS cells. The miRNAs can more effectively and safely generate iPS cells than transcription factors. This process ultimately leads to the development of iPSC-based therapeutics for future clinical applications. In this comprehensive review, we summarise advances in research and the application of iPS cells, as well as recent progress in the use of miRNAs for iPS cell generation and differentiation. We examine possible clinical applications, especially in cardiology.