Simulation-Guided Rational Design of DNA Walker-Based Theranostic Platform.

Biomolecule-functionalized nanoparticles represent a type of promising biomaterials in biomedical applications owing to their excellent biocompatibility and versatility. DNA-based reactions on nanoparticles have enabled emerging applications including intelligent biosensors, drug delivery, and biomimetic devices. Among the reactions, strand hybridization is the critical step to control the sensitivity and specificity of biosensing, and the efficiency of drug delivery. However, a comprehensive understanding of DNA hybridization on nanoparticles is still lacking, which may differ from the process in homogeneous solutions. To address this limitation, coarse-grained model-based molecular dynamic simulation is harnessed to disclose the critical factors involved in intermolecular hybridization. Based on simulation guidance, DNA walker-based smart theranostic platform (DWTP) based on "on-particle" hybridization is developed, showing excellent consistency with simulation. DWTP is successfully applied for highly sensitive miRNA 21 detection and tumor-specific miRNA 21 imaging, driven by tumor-endogenous APE 1 enzyme. It enables the precise release of antisense oligonucleotide triggered by tumor-endogenous dual-switch miRNA 21 and APE 1, facilitating effective gene silencing therapy with high biosafety. The simulation of "on-particle" DNA hybridization has improved the corresponding biosensing performance and the release efficiency of therapeutic agents, representing a conceptually new approach for DNA-based device design.

Phenotype and genotype spectra of a Chinese cohort with nephronophthisis-related ciliopathy.

BACKGROUND: Nephronophthisis-related ciliopathies (NPHP-RC) account for the majority of cases of monogenetically caused end-stage renal disease (ESRD) in children. Exploring the correlation between the phenotype and genotype of NPHP-RC is helpful for early diagnosis and management. We investigated the phenotype and genotype spectra of NPHP-RC in a Chinese multicentre cohort. METHODS: Crosss-ectional and longitudinal data of 60 patients from 57 families with pathogenic NPHP-RC gene mutations distributed in 22 regions of China were collected into a unified, anonymous database. The mean observation time of this cohort was 3.5±3.1 years. RESULTS: Mutations in NPHP1 and NPHP3 were the most common genetic defects. Overall, 45% of patients presented with isolated nephronophthisis (NPH), and 55% exhibited the extrarenal phenotype, which frequently involved the liver (41.7%, n=25), central nervous system (26.7%, n=16), eyes (26.7%, n=16) and skeletal system (11.7%, n=7). Accidental detection of elevated serum creatinine and non-specific symptoms caused by chronic kidney disease occurred in 65% of patients. Patients carrying NPHP1 mutations mainly presented with isolated NPH (90%, 18/20) and progressed to ESRD at a mean age of 12.9±0.5 years. The mean age of ESRD onset in the non-NPHP1 group was lower than that in the NPHP1 group (6.2±1.4 years, p<0.001), especially for patients carrying NPHP3 mutations (3.1±1.2 years), showing a heterogeneous phenotype characterised by Bardet-Biedl syndrome (12.5%, n=5), Joubert syndrome (7.5%, n=3), COACH syndrome (2.5%, n=1), Mainzer-Saldino syndrome (2.5%, n=1), short-rib thoracic dysplasia (2.5%, n=1) and unclassified symptoms (32.5%, n=13). CONCLUSIONS: The Chinese Children Genetic Kidney Disease Database registry characterised the spectrum of the phenotype and genotype of NPHP-RC in the Chinese population. NPHP1 and NPHP3 were the most common pathogenic genes. Rapid progression to ESRD and liver involvement were noted in patients with NPHP3 mutations.

Remote Generation of Magnon Schrödinger Cat State via Magnon-Photon Entanglement.

The magnon cat state represents a macroscopic quantum superposition of collective magnetic excitations of large number spins that not only provides fundamental tests of macroscopic quantum effects but also finds applications in quantum metrology and quantum computation. In particular, remote generation and manipulation of Schrödinger cat states are particularly interesting for the development of long-distance and large-scale quantum information processing. Here, we propose an approach to remotely prepare magnon even or odd cat states by performing local non-Gaussian operations on the optical mode that is entangled with the magnon mode through pulsed optomagnonic interaction. By evaluating key properties of the resulting cat states, we show that for experimentally feasible parameters, they are generated with both high fidelity and nonclassicality, as well as with a size large enough to be useful for quantum technologies. Furthermore, the effects of experimental imperfections such as the error of projective measurements and dark count when performing single-photon operations have been discussed, where the lifetime of the created magnon cat states is expected to be t∼1 µs.

Yin-xing-tong-mai decoction attenuates atherosclerosis via activating PPARγ-LXRα-ABCA1/ABCG1 pathway.

Atherosclerosis is now the major cause of mortality and morbidity worldwide. Formation of macrophage-derived foam cells is a hallmark of atherosclerosis, which is regulated by cholesterol uptake, intracellular metabolism, and efflux. PPARγ-LXRα-ABCA1/ABCG1 pathway plays an important part in regulating cholesterol efflux and this pathway could be a promising target for treating atherosclerosis. However, due to undesirable systemic effects, PPARγ agonist therapy for atherosclerosis remains challenging. Many traditional Chinese medicine has been well accepted and applied in atherosclerosis treatment. Yin-xing-tong-mai decoction (YXTMD) has been applied for treating atherosclerosis for decades. However, the mechanism remains to be explored. Here, we showed that YXTMD effectively attenuated atherosclerosis in ApoE-/- mice. YXTMD increased cholesterol efflux of foam cell by upregulation of ABCA1 and ABCG1 in vivo and in vitro. Through bioinformatic analysis and experimental validation, we found that PPARγ was an important downstream effector of YXTMD in macrophages. Reduction of PPARγ significantly decreased LXRα, ABCA1, and ABCG1 expression in macrophages, with reduced cholesterol efflux. In conclusion, these findings confirmed that YXTMD attenuated atherosclerosis by activating the PPARγ-LXRα- ABCA1/ABCG1 pathway to enhance cholesterol efflux.

MXene-Copper/Cobalt Hybrids via Lewis Acidic Molten Salts Etching for High Performance Symmetric Supercapacitors.

MXenes have attracted great interests as supercapacitors due to their metallic conductivity, high density, and hydrophilic nature. Herein we report Ti3 C2 -Cu/Co hybrids via molten salt etching in which the existence of metal atoms and their interactions with MXene via surficial O atoms were elucidated by XAFS for the first time. The electrochemical investigation of Ti3 C2 -Cu electrode demonstrated the pseudocapacitive contribution of Cu and a splendid specific capacitance of 885.0 F g-1 at 0.5 A g-1 in 1.0 M H2 SO4 . Symmetric supercapacitor Ti3 C2 -Cu//Ti3 C2 -Cu was demonstrated with operating voltage of 1.6 V, areal capacitance of 290.5 mF cm-2 at 1 mA cm-2 , and stability over 10 000 cycles. It delivered an areal energy density of 103.3 µWh cm-2 at power density of 0.8 mW cm-2 , based on which a supercapacitor pouch was fabricated. It provides deeper insights into the molten salt mechanism and strategies for designing MXene-based materials for electrochemical energy storage.

Steady Bell State Generation via Magnon-Photon Coupling.

We show that parity-time (PT) symmetry can be spontaneously broken in the recently reported energy level attraction of magnons and cavity photons. In the PT-broken phase, the magnon and photon form a high-fidelity Bell state with maximum entanglement. This entanglement is steady and robust against the perturbation of the environment, which is in contrast to the general wisdom that expects instability of the hybridized state when the symmetry is broken. This anomaly is further understood by the compete of non-Hermitian evolution and particle number conservation of the hybrid system. As a comparison, neither PT-symmetry breaking nor steady magnon-photon entanglement is observed inside the normal level repulsion case. Our results may open an exciting window to utilize magnon-photon entanglement as a resource for quantum information science.

Ultrathin nanosheet-assembled accordion-like Ni-MOF for hydrazine hydrate amperometric sensing.

The ultrathin 2D metal-organic framework structure effectively increases the metal sites of the active molecules and endows Ni-MOF with good current sensing performance. The ultrathin 2D nanosheet Ni-MOF assemblies have been successfully synthesized by using (Ni3(OH)2(C8H4O4)2(H2O)4)·2H2O as the molecular formula. The sensor performance of Ni-MOF assemble was investigated by amperometric method. The resulting products are characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The electric signal generated by the electrochemical reaction on the electrode surface indicates that the assemble of Ni-MOF with ultrathin folded-like structure and special aggregation state has high electrocatalytic performance. In the detection of hydrazine hydrate, Ni-MOF assemble shows good stability, low detection limit (0.23 nm), and high selectivity in the range of 0.5 µM to 8.0 mM at a voltage of 0.25 V. This study provides a new idea for the application of MOF assemble in hydrazine hydrate sensor. Graphical abstract Schematic of illustration of the synthesis of the Ni-MOF and the Ni-MOF applied for catalyzing N2H4.

Correction to: Ultra-thin nanosheet-assembled accordion-like Ni-MOF for hydrazine hydrate amperometric sensing.

The published article is revised due to diagram errors. The authors express their sincere apology, and corrected Figure 2a (XPS), Figure S4 (IR), and Figure S7 (XPS) are given.

The State of Research Regarding Ordered Mesoporous Materials in Batteries.

Ordered mesoporous materials, porous materials with a pore size of 2-50 nm which are prepared via the sol-gel process using surfactant molecular aggregates as a template to assemble channels through the interfacial action of organic and inorganic substances, have recently triggered a heated debate. In addition to applications in the catalytic cracking of heavy oils and residues, the manufacturing of graft materials, the purification of water, the conversion of automobile exhaust, biochips, and the treatment of environmental pollutants via photocatalysts, ordered mesoporous materials have drawn substantial attention in the field of electrochemical energy storage due to advantages such as large specific surface area, uniform and continuously adjustable pore size, and orderly arrangement. Here, a general summary and appraisal of the study of ordered mesoporous materials for batteries in recent years is given, including the synthesis methods, meso/nanostructural features, and electrochemical capabilities of such materials.

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system.

To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole-exome sequencing (WES) and trio-WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio-WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.

Divergent synthesis of 5',7'-difluorinated dihydroxanthene-hemicyanine fused near-infrared fluorophores.

We describe an expedient access to a 5',6',7'-trifluoro dihydroxanthene-hemicyanine fused scaffold in 2 steps and 54% overall yield from the corresponding salicylic aldehyde. A 6'-regioselective nucleophilic aromatic substitution (SNAr) reaction with a wide range of nitrogen, sulfur or selenium nucleophiles then gives access to 16 near-infrared (NIR) fluorophores emitting in the 710-750 nm range. We also report the experimental and theoretical photophysical investigations of these unique optical agents that include the first series of 6'-heavy atom substituted dihydroxanthenes, extending the pool of polyfluorinated markers for biomedical and material applications.

Recent Progress in Some Amorphous Materials for Supercapacitors.

A breakthrough in technologies having "green" and sustainable energy storage conversion is urgent, and supercapacitors play a crucial role in this area of research. Owing to their unique porous structure, amorphous materials are considered one of the best active materials for high-performance supercapacitors due to their high specific capacity, excellent cycling stability, and fast charging rate. This Review summarizes the synthesis of amorphous materials (transition metal oxides, carbon-based materials, transition metal sulfides, phosphates, hydroxides, and their complexes) to highlight their electrochemical performance in supercapacitors.

Molecular Mechanisms Underlying the Link between Diet and DNA Methylation.

DNA methylation is a vital modification process in the control of genetic information, which contributes to the epigenetics by regulating gene expression without changing the DNA sequence. Abnormal DNA methylation-both hypomethylation and hypermethylation-has been associated with improper gene expression, leading to several disorders. Two types of risk factors can alter the epigenetic regulation of methylation pathways: genetic factors and modifiable factors. Nutrition is one of the strongest modifiable factors, which plays a direct role in DNA methylation pathways. Large numbers of studies have investigated the effects of nutrition on DNA methylation pathways, but relatively few have focused on the biochemical mechanisms. Understanding the biological mechanisms is essential for clarifying how nutrients function in epigenetics. It is believed that nutrition affects the epigenetic regulations of DNA methylation in several possible epigenetic pathways: mainly, by altering the substrates and cofactors that are necessary for proper DNA methylation; additionally, by changing the activity of enzymes regulating the one-carbon cycle; and, lastly, through there being an epigenetic role in several possible mechanisms related to DNA demethylation activity. The aim of this article is to review the potential underlying biochemical mechanisms that are related to diet modifications in DNA methylation and demethylation.

Echinacea purpurea Extract Polarizes M1 Macrophages in Murine Bone Marrow-Derived Macrophages Through the Activation of JNK.

Echinacea purpurea is an indigenous North American purple cone flower used by North Americans for treatment of various infectious diseases and wounds. This study investigated the effect of polysaccharide enriched extract of Echinacea purpurea (EE) on the polarization of macrophages. The results showed that 100 µg/mL of EE could markedly activate the macrophage by increasing the expression of CD80, CD86, and MHCII molecules. Meanwhile, EE upregulated the markers of classically activated macrophages (M1) such as CCR7 and the production of IL-1ß, IL-6, IL-12p70, TNF-αand NO. The functional tests showed that EE enhanced the phagocytic and intracellular bactericidal activity of macrophage against ST. Furthermore, we demonstrated that JNK are required for EE-induced NO and M1-related cytokines production. Together, these results demonstrated that EE can polarize macrophages towards M1 phenotype, which is dependent on the JNK signaling pathways. J. Cell. Biochem. 118: 2664-2671, 2017. © 2017 Wiley Periodicals, Inc.

Fabrication of Metal Molybdate Micro/Nanomaterials for Electrochemical Energy Storage.

Currently, metal molybdates compounds can be prepared by several methods and are considered as prospective electrode materials in many fields because the metal ions possess the ability to exist in several oxidation states. These multiple oxidation states contribute to prolonging the discharge time, improving the energy density, and increasing the cycling stability. The high electrochemical performance of metal molybdates as electrochemical energy storage devices are discussed in this review. According to recent publications and research progress on relevant materials, the investigation of metal molybdate compounds are discussed via three main aspects: synthetic methods, material properties and measured electrochemical performance of these compounds as electrode materials. The recent progress in general metal molybdate nanomaterials for LIBs and supercapacitors are carefully presented here.

Twist1 and Twist2 Contribute to Cytokine Downregulation following Chronic NOD2 Stimulation of Human Macrophages through the Coordinated Regulation of Transcriptional Repressors and Activators.

Proper regulation of microbial-induced cytokines is critical to intestinal immune homeostasis. Acute stimulation of nucleotide-binding oligomerization domain 2 (NOD2), the Crohn's disease-associated sensor of bacterial peptidoglycan, induces cytokines. However, chronic NOD2 stimulation in macrophages decreases cytokines upon pattern recognition receptor (PRR) restimulation; cytokine attenuation to PRR stimulation is similarly observed in intestinal macrophages. The role for the transcriptional repressors Twist1 and Twist2 in regulating PRR-induced cytokine outcomes is poorly understood and has not been reported for NOD2. We found that Twist1 and Twist2 were required for optimal cytokine downregulation during acute and, particularly, chronic NOD2 stimulation of human macrophages. Consistently, Twist1 and Twist2 expression was increased after chronic NOD2 stimulation; this increased expression was IL-10 and TGF-ß dependent. Although Twist1 and Twist2 did not coregulate each other's expression, they cooperated to enhance binding to cytokine promoters after chronic NOD2 stimulation. Moreover, Twist1 and Twist2 contributed to enhance expression and promoter binding of the proinflammatory inhibitor c-Maf and the transcriptional repressor Bmi1. Restoring c-Maf and Bmi1 expression in Twist-deficient macrophages restored NOD2-induced cytokine downregulation. Furthermore, with chronic NOD2 stimulation, Twist1 and Twist2 contributed to the decreased expression and cytokine promoter binding of the transcriptional activators activating transcription factor 4, C/EBPα, Runx1, and Runx2. Knockdown of these transcriptional activators in Twist-deficient macrophages restored cytokine downregulation after chronic NOD2 stimulation. Finally, NOD2 synergized with additional PRRs to increase Twist1 and Twist2 expression and Twist-dependent pathways. Therefore, after chronic NOD2 stimulation Twist1 and Twist2 coordinate the regulation of both transcriptional activators and repressors, thereby mediating optimal cytokine downregulation.

TAM receptor-dependent regulation of SOCS3 and MAPKs contributes to proinflammatory cytokine downregulation following chronic NOD2 stimulation of human macrophages.

Microbial-induced cytokine regulation is critical to intestinal immune homeostasis. Acute stimulation of nucleotide-binding oligomerization domain 2 (NOD2), the Crohn's disease-associated sensor of bacterial peptidoglycan, induces cytokines. However, cytokines are attenuated after chronic NOD2 and pattern recognition receptor stimulation of macrophages; similar attenuation is observed in intestinal macrophages. The role of Tyro3, Axl, and Mer (TAM) receptors in regulating chronic pattern recognition receptor stimulation and NOD2-induced outcomes has not been examined. Moreover, TAM receptors have been relatively less investigated in human macrophages. Whereas TAM receptors did not downregulate acute NOD2-induced cytokines in primary human macrophages, they were essential for downregulating signaling and proinflammatory cytokine secretion after chronic NOD2 and TLR4 stimulation. Axl and Mer were similarly required in mice for cytokine downregulation after chronic NOD2 stimulation in vivo and in intestinal tissues. Consistently, TAM expression was increased in human intestinal myeloid-derived cells. Chronic NOD2 stimulation led to IL-10- and TGF-ß-dependent TAM upregulation in human macrophages, which, in turn, upregulated suppressor of cytokine signaling 3 expression. Restoring suppressor of cytokine signaling 3 expression under TAM knockdown conditions restored chronic NOD2-mediated proinflammatory cytokine downregulation. In contrast to the upregulated proinflammatory cytokines, attenuated IL-10 secretion was maintained in TAM-deficient macrophages upon chronic NOD2 stimulation. The level of MAPK activation in TAM-deficient macrophages after chronic NOD2 stimulation was insufficient to upregulate IL-10 secretion; however, full restoration of MAPK activation under these conditions restored c-Fos, c-Jun, musculoaponeurotic fibrosarcoma oncogene homolog K, and PU.1 binding to the IL-10 promoter and IL-10 secretion. Therefore, TAM receptors are critical for downregulating proinflammatory cytokines under the chronic NOD2 stimulation conditions observed in the intestinal environment.

The IL18RAP region disease polymorphism decreases IL-18RAP/IL-18R1/IL-1R1 expression and signaling through innate receptor-initiated pathways.

Fine-tuning of cytokine-inducing pathways is essential for immune homeostasis. Consistently, a dysregulated increase or decrease in pattern-recognition receptor (PRR)-induced signaling and cytokine secretion can lead to inflammatory bowel disease. Multiple gene loci are associated with inflammatory bowel disease, but their functional effects are largely unknown. One such region in chromosome 2q12 (rs917997), also associated with other immune-mediated diseases, encompasses IL18RAP. We found that human monocyte-derived macrophages (MDMs) from rs917997 AA risk carriers secrete significantly less cytokines than G carriers upon stimulation of multiple PRRs, including nucleotide-binding oligomerization domain 2 (NOD2). We identified that IL-18 signaling through IL-18RAP was critical in amplifying PRR-induced cytokine secretion in MDMs. IL-18RAP responded to NOD2-initiated early, caspase-1-dependent autocrine IL-18, which dramatically enhanced MAPK, NF-κB, PI3K, and calcium signaling. Reconstituting MAPK activation was sufficient to rescue decreased cytokines in NOD2-stimulated IL-18RAP-deficient MDMs. Relative to GG carriers, MDM from rs917997 AA carriers had decreased expression of cell-surface IL-18RAP protein, as well as of IL-18R1 and IL-1R1, genes also located in the IL18RAP region. Accordingly, these risk-carrier MDMs show diminished PRR-, IL-18-, and IL-1-induced MAPK and NF-κB signaling. Taken together, our results demonstrate clear functional consequences of the rs917997 risk polymorphism; this polymorphism leads to a loss-of-function through decreased IL-18RAP, IL-18R1, and IL-1R1 protein expression, which impairs autocrine IL-18 and IL-1 signaling, thereby leading to decreased cytokine secretion in MDMs upon stimulation of a broad range of PRRs.

Directed meta-Selective Bromination of Arenes with Ruthenium Catalysts.

A Ru-catalyzed direct CH activation/meta-bromination of arenes bearing pyridyl, pyrimidyl, and pyrazolyl directing groups has been developed. A series of bromo aryl pyridines and pyrimidines have been synthesized, and further coupling reactions have also been demonstrated for a number of representative functionalized arenes. Preliminary mechanistic studies have revealed that this reaction may proceed through radical-mediated bromination when NBS is utilized as the bromine source. This type of transformation has opened up a new direction for the radical non-ipso functionalization of metal with regard to future CH activation development that would allow the remote functionalization of aromatic systems.

[Correlation of gene polymorphism of interleukin 4 receptor alpha peptide chain and total serum IgE levels in asthmatic children in Guiyang area].

OBJECTIVE: To explore the correlation of gene polymorphism of interleukin 4 receptor alpha chain (IL-4Rα) and total serum IgE levels in children of bronchial asthma in Guiyang area. METHODS: A total of 160 asthmatic children at Affiliated Hospital, Guiyang Medical College from August 2010 to February 2011 were selected as asthma group. There were 96 males and 64 females with an average age of (6.9 ± 3.3) years. During the same period, 143 healthy children from outpatient physical examination center of this hospital were chosen as control group. There were 75 males and 68 females with an average age of (4.9 ± 3.9) years. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele-specific polymerase chain reaction (AS-PCR) were used to determine the polymorphisms of Q576R on exon 12 and I75V on exon 5 of IL-4Rα in both groups. The total serum IgE levels were determined by enzyme-linked immune sorbent assay (ELISA). Comparisons of two groups were made for genotype and allele frequency, serum total IgE and different genotypes, different groups of total serum IgE levels. RESULTS: Three genotypes of AA, AG and GG existed on Q576R and I75V loci between two groups. The genotypic frequencies of two loci had significant differences in two groups (χ(2) = 30.972, 16.776, both P < 0.001). The subjects with variant allele on Q576R and I75V loci had higher risks for asthma than those without variant allele (χ(2) = 33.236, 13.845, both P < 0.001). The total serum levels of IgE in asthma group were higher than those in control group ((312 ± 297) vs (61 ± 48) U/ml, t = 9.959, P < 0.001). However, these three genotypes of two loci showed no significant inter-group difference (all P > 0.05). In mutation allele carriers and non-carriers of Q576R locus, total IgE levels showed no significant difference (t = -0.028, 1.279; P = 0.978, 0.203). Differences in total IgE levels between I75V polymorphic variant allele carriers and non-carriers were also not statistically significant in control group (t = -0.763, P = 0.447). However, in asthma group, total IgE levels of I75V polymorphic variant allele carriers were significantly higher than those of non-carriers (t = -2.112, P = 0.036). CONCLUSIONS: The 576 and 75 loci of IL-4Rα are important candidate genes of asthmatic children in Guiyang area. And the serum total IgE levels of variant allele G at 75 locus in IL-4Rα are higher than those without it.