Spectral-Sensing System for Distinguishing CH3OH and CD3OD.

Spectrally discriminating CH3OH and CD3OD, and even detecting CH3OH contents in the CD3OD solvent, are important yet have not been achieved so far, likely owing to their very similar chemical/physical properties. Herein, dynamic transesterification reactions, which can be achieved via two-step proton transfers, can be signaled via ultraviolet UV-visible (UV/vis) absorption and fluorescence spectroscopies under mild experimental conditions. Introduction of strong electron-withdrawing groups, such as -NO2, to the aromatic ring (benzoic acid moiety or phenol moiety) of carboxylate esters to activate the esters is important for transesterification reactions and is an intriguing method for modulating the selectivity of the spectral response. The rate constant of the transesterification reaction enhanced with increasing the total number of strong electron-withdrawing groups. Furthermore, the rate constants of esters in which substituent(s) are connected to the phenol moiety are higher than those of corresponding esters in which substituent(s) are connected to the benzoic acid moiety. In transesterification systems, added aliphatic amines mainly play two roles: (i) lowering the energy barrier of the first transesterification step via the formation of intermolecular hydrogen bonding in ternary systems and (ii) deprotonating the released 4-nitrophenol in UV/vis absorption spectral systems to generate an UV/vis absorption spectral signal reporter, i.e., nitrophenolate anions. As a result of the methanol-mediated transesterification reaction, spectral-sensing systems can be established for discriminating CH3OH and CD3OD and even detecting low CH3OH contents in the CD3OD solvent, owing to the kinetic isotope effect. This is the first example of spectral recognition between CD3OD and CH3OH.

The association between circulating fatty acids and stroke in hypertensive patients.

BACKGROUND: Stroke is prevalent in hypertensive population. It has been suggested that unsaturated fatty acids (USFA) have protective effect on stroke. The effect of saturated fatty acids (SFAs) on stroke is still unclear. Therefore, we studied the relationship between circulating fatty acids and acute ischemic stroke (AIS) in hypertensive patients. METHODS: Eighty-nine pairs including 100 men and 78 women matched by sex and age were recruited. Each pair included a hypertensive patient within 48h of AIS onset and a hypertensive patient without stroke. Six circulating fatty acids were methylated before concentration determination which was repeated twice with percent recovery estimated. RESULTS: There were differences in educational level (P = 0.002) and occupation (P < 0.001) between stroke and non-stroke participants. All the 6 fatty acid levels were higher in non-stroke participants (P = 0.017 for palmitoleic acid, 0.001 for palmitic acid, <0.001 for linoleic acid, <0.001 for behenic acid, <0.001 for nervonic acid and 0.002 for lignoceric acid). In logistic regression analysis, AIS was inversely associated with fatty acid levels except for lignoceric acid. After adjustment for education and occupation, the palmitoleic acid and palmitic acid levels were no longer inversely associated with AIS. After further adjustment for systolic blood pressure, smoking, drinking, total cholesterol and triglyceride, the inverse associations of linoleic acid (OR = 0.965, 95%CI = 0.942-0.990, P = 0.005), behenic acid (OR = 0.778, 95%CI = 0.664-0.939, P = 0.009), nervonic acid (OR = 0.323, 95%CI = 0.121-0.860, P = 0.024) with AIS remained significant. CONCLUSIONS: Circulating fatty acids except lignoceric acid were inversely associated with AIS. Both USFAs and SFAs may have beneficial effect on stroke prevention in hypertensive population.

Polyfluoroalkyl Chain-Based Assemblies for Biomimetic Catalysis.

Amphiphobic fluoroalkyl chains are exploited for creating robust and diverse self-assembled biomimetic catalysts. Long terminal perfluoroalkyl chains (Cn F2n+1 with n=6, 8, and 10) linked with a short perhydroalkyl chains (Cm H2m with m=2 and 3) were used to synthesize several 1,4,7-triazacyclononane (TACN) derivatives, Cn F2n+1 -Cm H2m -TACN. In the presence of an equimolar amount of Zn2+ ions that coordinate the TACN moiety and drive the self-assembly into micelle-like aggregates, the critical aggregation concentration of polyfluorinated Cn F2n+1 -Cm H2m -TACN⋅Zn2+ was lowered by ∼1 order of magnitude compared to the traditional perhyroalkyl counterpart with identical carbon number of alkyl chain. When 2'-hydroxypropyl-4-nitrophenyl phosphate was used as the model phosphate substrate, polyfluorinated Cn F2n+1 -Cm H2m -TACN⋅Zn2+ assemblies showed higher affinity and catalytic activity, compared to its perhyroalkyl chain-based counterpart. Coarse-grained molecular dynamic simulations have been introduced to explore the supramolecular assembly of polyfluoroalkyl chains in the presence of Zn2+ ions and to better understand their enhanced catalytic activity.

Coordination-Induced Multivalent Self-Assembling Catalysts for Spectral Sensing Zn2+ with High Selectivity and Sensitivity.

The introduction of signal amplification to molecular spectral sensing systems is an intriguing topic in supramolecular analytical chemistry. In this study, click chemistry was used to generate a triazole moiety to bridge with a long hydrophobic alkyl chain (Cn) and another short alkyl chain (Cm) bearing a 1,4,7-triazacyclonane (TACN) group for efficiently generating a self-assembling multivalent catalyst, Cn-triazole-Cm-TACN·Zn2+ (n and m represent the carbon numbers of both alkyl chains, respectively; n = 16, 18, and 20; m = 2 and 6), to catalyze the hydrolysis of 2-hydroxypropyl-4-nitrophenyl phosphate (HPNPP) when Zn2+ was added. The triazole moiety introduced adjacent to the TACN group plays an important role in improving the selectivity of Zn2+ because the triazole moiety can participate in the coordination interaction between the Zn2+ and neighboring TACN group. The supplementary triazole complexing increases the space requirement for coordinated metal ions. This catalytic sensing system also shows high sensitivity, with a favorable limit of detection down to 350 nM, even if only UV-vis absorption spectra rather than more sensitive fluorescence techniques were used for signaling, and can be used to determine the concentration of Zn2+ in tap water, which demonstrates the practical application feasibility.

Genomic characterization and therapeutic utilization of IL-13-responsive sequences in asthma.

Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques to identify IL-13-responsive regulatory elements in bronchial epithelial cells and used these data to develop a CRISPR interference (CRISPRi)-based therapeutic approach to downregulate airway obstruction-inducing genes in a cell type- and IL-13-specific manner. Using single-cell RNA sequencing (scRNA-seq) and acetylated lysine 27 on histone 3 (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) in primary human bronchial epithelial cells, we identified IL-13-responsive genes and regulatory elements. These sequences were functionally validated and optimized via massively parallel reporter assays (MPRAs) for IL-13-inducible activity. The top secretory cell-selective sequence from the MPRA, a novel, distal enhancer of the sterile alpha motif pointed domain containing E-26 transformation-specific transcription factor (SPDEF) gene, was utilized to drive CRISPRi and knock down SPDEF or mucin 5AC (MUC5AC), both involved in pathologic mucus production in asthma. Our work provides a catalog of cell type-specific genes and regulatory elements involved in IL-13 bronchial epithelial response and showcases their use for therapeutic purposes.

A Non-Hydrolysis Reaction-Based Imine for Fluorescence Response toward Al3+ Ions with Extremely High Selectivity.

Designing an imine-based fluorescent probe capable of greatly suppressing the tendency of intrinsic hydrolysis reaction is an attractive topic in the field of chemo-/biosensing. In this work, hydrophobic 1,1'-binaphthyl-2,2'-diamine containing two amine groups was introduced to synthesize probe R-1 bearing two imine bonds linked by two salicylaldehyde (SAs). The hydrophobicity of binaphthyl moiety and the unique clamp-like structure formed from double imine bonds and from ortho-OH on SA part make probe R-1 is able to function as an ideal receptor to coordinate with Al3+ ions, leading to the fluorescence originated from the complex rather than from the assumed hydrolyzed fluorescent amine is turned on. Further study revealed that, when Al3+ ions were introduced, both the hydrophobic binaphthyl moiety and the clamp-like double imine structure in the designed imine-based probe showed important contributions to suppress the intrinsic hydrolysis reaction, resulting in generating a stable coordination complex with an extremely high selectivity in fluorescence response.

Minimalistic Artificial Catalysts with Esterase-Like Activity from Multivalent Nanofibers Formed by the Self-Assembly of Dipeptides.

Imitating and incorporating the multiple key structural features observed in natural enzymes into a minimalistic molecule to develop an artificial catalyst with outstanding catalytic efficiency is an attractive topic for chemists. Herein, we designed and synthesized one class of minimalistic dipeptide molecules containing a terminal -SH group and a terminal His-Phe dipeptide head linked by a hydrophobic alkyl chain with different lengths, marked as HS-C n+1-His-Phe (n = 4, 7, 11, 15, and 17; n + 1 represents the carbon atom number of the alkyl chain). The His (-imidazole), Phe (-CO2 -) moieties, the terminal -SH group, and a long hydrophobic alkyl chain were found to have important contributions to achieve high binding ability leading to outstanding absolute catalytic efficiency (k cat/K M) toward the hydrolysis reactions of carboxylic ester substrates.

Modulating Dual Fluorescence Emissions in Imine-Based Probes to Distinguish D2O and H2O.

How to distinguish D2O and H2O and determine the trace H2O content in D2O solvent, by using molecule-based spectral probes, is an intriguing topic in analytical chemistry, yet considerably few examples remain up to now, likely due to the very similar physical/chemical properties between D2O and H2O. In this work, we found that both the hydrolysis reactions to release fluorescent amines and aggregation-induced emission (AIE) of imines, functioning as dual fluorescence signals to distinguish D2O and H2O, could be modulated by changing the imine structures. The hydrophobicity of imines showed an important contribution to the ability of modulating the hydrolysis reactions and AIE, demonstrating a significant difference on fluorescence signals in D2O and H2O solvents. Among all tested imines, probe 3, condensed from 2-naphthylamine and salicylaldehyde, was found to have the potential ability to act as an ideal candidate for probing the H2O content in D2O solvent, particularly in a low H2O content range, using the ratiomeric emission signals.

Tandem Förster resonance energy transfer induced visual ratiometric fluorescence sensing of tetracyclines based on zeolitic imidazolate framework-8 incorporated with carbon dots and safranine T.

Developing new methods for efficiently detecting tetracycline antibiotics in water has gained much importance. In this work, zeolitic imidazolate framework-8 (ZIF-8) was used as a host to encapsulate carbon dots (CDs) and safranine T (ST) during its self-assembly process to synthesize CDs/ST@ZIF-8, which was then applied as the dual-emissive probe for detecting tetracycline antibiotics. Benefiting from the confinement effects of ZIF-8 and its fluorescence enhancement effects toward tetracycline (TC), a unique tandem Förster resonance energy transfer (FRET) system from CDs to TC and then to ST could be established, with a low limit of detection of 46 nM and excellent selectivity. More importantly, as compared to the CDs/ST system without tandem FRET, the sensitivity of the CDs/ST@ZIF-8 toward TC increased ∼69-fold, and naked eye recognition could also be achieved. Furthermore, by analyzing the R, G, and B values of photos containing different concentrations of tetracycline with the help of a mobile phone and correlating them with the concentration of tetracycline, we can perform the on-site detection of tetracycline, which is convenient, fast, and accurate. This study shows that new insight can be gained for the rational design and application of ratiometric fluorescence sensors based on tandem Förster resonance energy transfer in metal-organic framework materials.

Reaction-based fluorescence probes for "turn on" sensing fluoride ions.

Introducing a weak covalent bond into an originally highly fluorescent molecule to create a non-fluorescent probe is able to provide a new way to detect some nucleophilic targets with enhanced sensitivity. Herein, this is the first time that a tetraphenylethene (TPE)-based probe (TPEONO2) bearing a p-nitrobenzenesulfonyl moiety for the sensing of F- ions in aqueous solution via a cleavage reaction of the sulfonyl ester bond to induce aggregation-induced emission (AIE) has been reported.

The Type 2 Asthma Mediator IL-13 Inhibits Severe Acute Respiratory Syndrome Coronavirus 2 Infection of Bronchial Epithelium.

Asthma is associated with chronic changes in the airway epithelium, a key target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many epithelial changes, including goblet cell metaplasia, are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown. We found that IL-13 stimulation of differentiated human bronchial epithelial cells (HBECs) cultured at air-liquid interface reduced viral RNA recovered from SARS-CoV-2-infected cells and decreased double-stranded RNA, a marker of viral replication, to below the limit of detection in our assay. An intact mucus gel reduced SARS-CoV-2 infection of unstimulated cells, but neither a mucus gel nor SPDEF, which is required for goblet cell metaplasia, were required for the antiviral effects of IL-13. Bulk RNA sequencing revealed that IL-13 regulated 41 of 332 (12%) mRNAs encoding SARS-CoV-2-associated proteins that were detected in HBECs (>1.5-fold change; false discovery rate < 0.05). Although both IL-13 and IFN-α each inhibit SARS-CoV-2 infection, their transcriptional effects differed markedly. Single-cell RNA sequencing revealed cell type-specific differences in SARS-CoV-2-associated gene expression and IL-13 responses. Many IL-13-induced gene expression changes were seen in airway epithelium from individuals with type 2 asthma and chronic obstructive pulmonary disease. IL-13 effects on airway epithelial cells may protect individuals with type 2 asthma from COVID-19 and could lead to identification of novel strategies for reducing SARS-CoV-2 infection.

Enantioselective Dynamic Exchange Reactions of Imines.

Although dynamic reactions of imines have been extensively studied, the dynamic behaviors manipulated by chirality remain nearly unexplored. In this work, enantioselective amine exchange reactions were demonstrated as a first example via the reaction of enantiomeric chiral amines such as natural amino acids with a series of innovative axially chiral 1,1'-binaphthyl-2,2'-diamine (BNDA)-based imines that were prepared from the condensation reactions between BNDA and salicylaldehyde (SA) or its derivatives. This enantioselective dynamic behavior can be directly indicated by the degree of the fluorescence response of the R-configuration of imines to the d-enantiomer of chiral amine, because the released BNDA can serve as the fluorescence signal output when the amine exchange reaction occurs, which is far higher than the response to its l-enantiomer under identical experimental conditions. For the S-configuration of chiral imines, the fluorescence response is the opposite. The enantioselective exchange reaction can be tuned by altering the electron-withdrawing or electron-donating capability of the substituent at position 4 or 5 of the SA part of chiral imines. Not only o-OH groups in SA-based imines but also protic solvents used as reaction media were found to be important to the dynamic behavior at high rates.

A Multi-Catalytic Sensing for Hydrogen Peroxide, Glucose, and Organophosphorus Pesticides Based on Carbon Dots.

In this work, a facile one-pot hydrothermal route was employed to synthesize a series of fluorescent carbon dots (CDs) by using 20 natural amino acids, respectively, as the starting materials. It was found that the CDs synthesized using phenylalanine could possess the intrinsic peroxidase-like activity that could effectively catalyze a traditional peroxidase substrate like 3, 3', 5, 5'- tetramethylbenzidine (TMB) in the presence of H2O2 to produce a blue solution; thereby, a catalytic sensing system for H2O2 has been developed. On the basis of this catalytic reaction, together with the fact that glucose oxidase (GOx) can catalyze the hydrolysis of glucose to generate H2O2, a sensitive catalytic sensing system for glucose could be further established. Furthermore, based on this catalytic reaction, taken together with the two enzymatic catalytic systems of acetylcholinesterase (AChE) and choline oxidase (CHO), a highly sensitive multi-catalytic sensing system could be successfully developed for organophosphorus (OPs) pesticides such as dimethoate, DDVP, and parathion-methyl. Limit of detections (LODs) of H2O2 and glucose were estimated to be 6.5 and 0.84 µM, respectively. The limit of detection of the sub-nM level could be obtained for tested dimethoate, DDVP, and parathion-methyl OPs pesticides. The established sensing systems can exhibit good practical application performance in serum and several fruit samples.

Self-Assembled Multivalent Ag-SR Coordination Polymers with Phosphatase-Like Activity.

We show herein the phosphatase-like catalytic activity of coordination polymers obtained after adding Ag+ -ions to thiols bearing hydrophobic alkyl chains terminated with a 1,4,7-triazacyclononane (TACN) group. The subsequent addition of Zn2+ -ions to the self-assembled polymers resulted in the formation of multivalent metal coordination polymers capable of catalysing the transphosphorylation of an RNA-model compound (2-hydroxypropyl-4-nitrophenyl phosphate, HPNPP) with high reactivity. Analysis of a series of metal ions showed that the highest catalytic activity was obtained when Ag+ -ions were used as the first metal ions to construct the backbone of the coordination polymer through interaction with the -SH group followed by Zn2+ -ions as the second metal ions complexed by the TACN-macrocycle. Furthermore, it was demonstrated that the catalytic activity could be modulated by changing the length of the hydrophobic alkyl chain.

The type 2 asthma mediator IL-13 inhibits SARS-CoV-2 infection of bronchial epithelium.

RATIONALE: Asthma is associated with chronic changes in the airway epithelium, a key target of SARS-CoV-2. Many epithelial changes are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown. OBJECTIVES: We sought to discover how IL-13 and other cytokines affect expression of genes encoding SARS-CoV-2-associated host proteins in human bronchial epithelial cells (HBECs) and determine whether IL-13 stimulation alters susceptibility to SARS-CoV-2 infection. METHODS: We used bulk and single cell RNA-seq to identify cytokine-induced changes in SARS-CoV-2-associated gene expression in HBECs. We related these to gene expression changes in airway epithelium from individuals with mild-moderate asthma and chronic obstructive pulmonary disease (COPD). We analyzed effects of IL-13 on SARS-CoV-2 infection of HBECs. MEASUREMENTS AND MAIN RESULTS: Transcripts encoding 332 of 342 (97%) SARS-CoV-2-associated proteins were detected in HBECs (≥1 RPM in 50% samples). 41 (12%) of these mRNAs were regulated by IL-13 (>1.5-fold change, FDR < 0.05). Many IL-13-regulated SARS-CoV-2-associated genes were also altered in type 2 high asthma and COPD. IL-13 pretreatment reduced viral RNA recovered from SARS-CoV-2 infected cells and decreased dsRNA, a marker of viral replication, to below the limit of detection in our assay. Mucus also inhibited viral infection. CONCLUSIONS: IL-13 markedly reduces susceptibility of HBECs to SARS-CoV-2 infection through mechanisms that likely differ from those activated by type I interferons. Our findings may help explain reports of relatively low prevalence of asthma in patients diagnosed with COVID-19 and could lead to new strategies for reducing SARS-CoV-2 infection.

Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups.

Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.

Identification of Regulatory Modules That Stratify Lupus Disease Mechanism through Integrating Multi-Omics Data.

Although recent advances in genetic studies have shed light on systemic lupus erythematosus (SLE), its detailed mechanisms remain elusive. In this study, using datasets on SLE transcriptomic profiles, we identified 750 differentially expressed genes (DEGs) in T and B lymphocytes and peripheral blood cells. Using transcription factor (TF) binding data derived from chromatin immunoprecipitation sequencing (ChIP-seq) experiments from the Encyclopedia of DNA Elements (ENCODE) project, we inferred networks of co-regulated genes (NcRGs) based on binding profiles of the upregulated DEGs by significantly enriched TFs. Modularization analysis of NcRGs identified co-regulatory modules among the DEGs and master TFs vital for each module. Remarkably, the co-regulatory modules stratified the common SLE interferon (IFN) signature and revealed SLE pathogenesis pathways, including the complement cascade, cell cycle regulation, NETosis, and epigenetic regulation. By integrative analyses of disease-associated genes (DAGs), DEGs, and enriched TFs, as well as proteins interacting with them, we identified a hierarchical regulatory cascade with TFs regulated by DAGs, which in turn regulates gene expression. Integrative analysis of multi-omics data provided valuable molecular insights into the molecular mechanisms of SLE.

Facile access to versatile aza-macrolides through iridium-catalysed cascade allyl-amination/macrolactonization.

Direct access to benzo-fused aza-macrolides was successfully achieved through iridium-catalysed intermolecular decarboxylative coupling of vinylethylene carbonates with isatoic anhydrides under relatively mild reaction conditions. Notably, this reaction proceeded through sequential allyl-amination/macrolactonization upon extrusion of CO2. Moreover, favourable fluorescence properties could be observed in the title macrocyclic products.

A solvatochromic AIE tetrahydro[5]helicene derivative as fluorescent probes for water in organic solvents and highly sensitive sensors for glyceryl monostearate.

In this paper, a tetrahydro[5]helicene-based imide dye with thienyl group (THID) was studied on its solvatochromism and aggregation-induced emission (AIE) properties by dissolved in various organic solvents. The linear relationship between Stokes shift and aprotic solvent polarity parameter was well fitted with Lippert-Mataga model. Furthermore, Stokes shift also were positively correlated with the normalized molar electronic transition energy, suggested that THID exceptionally depends on solvent polarity for twisted intramolecular charge transfer. In addition, THID demonstrated typical AIE features when adding large amounts of water into good solvent. Meanwhile, it can function as intensity and wavelength-based fluorescence sensor for detecting low-level water content in water soluble solvents, even the low of detection was 0.014 vol% in ACN. Therefore, a simple and highly selective fluorescence analysis for glyceryl monostearate has been established on basis of its AIE property.

A label-free "SEF-FRET" fluorescent sensing platform for ultrasensitive DNA detection based on AgNPs SAMs.

In this paper, deoxyribonucleic acid (DNA) with different lengths were used to control the distance between carbon dots (CDs) and silver nanoparticles (AgNPs) in self-assembled multilayers (SAMs). Surface-enhanced fluorescence and fluorescence resonance energy transfer (SEF-FRET) could be achieved based on changing DNA strands. The fluorescence intensity of CDs SAMs with 6-base DNA strands could be enhanced up to ca. 5.6 times by AgNPs. As-fabricated CDs SAMs with excellent luminescent properties, superior stability have been employed for the development of a label-free fluorescence sensing platform for DNA detection. Since DNA would hybridize with the complemented one which was attached on the surface of SAMs, resulting in a close distance between CDs and AgNPs, FRET could thus occur between AgNPs and CDs, resulting in quenching the fluorescence of CDs SAMs. This sensitive sensing platform could show excellent analytical performance for detecting DNA with a linear response ranging from 93.07 pM to 5.433 nM and a detection limit of 16.36 pM, which could be further employed to probe human blood samples. This could prove a promising method for the detection of DNA.