A Facile Raman Spectroscopy Method for Online Monitoring of Crystal Plane Orientation of Favipiravir.

The efficiency of pharmacotherapy is significantly influenced by the crystal habit and polymorphic form of the drugs. Especially due to the anisotropy of different facets in crystalline material, crystal habit impacts the physicochemical properties and behaviors of a drug, which has been rarely reported. This paper describes a facile method for online monitoring of crystal plane orientation of favipiravir (T-705) by Raman spectroscopy. Firstly, we investigated the synergy of multiple physicochemical fields (solvation, agitated flow fields, etc.), and then prepared favipiravir crystals with different orientations in a controllable manner. Secondly, to establish the connection between crystal planes and Raman spectra, the favipiravir crystals were theoretically analyzed at the molecular and structural levels using density functional theory (DFT) and three dimensional (3D) visualization tools. Finally, we based on standard samples and applied it to 12 actual samples to evaluate the crystal habit of favipiravir. The results are similar to the classical X-ray diffraction (XRD) method. Additionally, the XRD method is difficult to be monitored online, while the Raman method is non-contact, fast, and requires no sample preparation, showing a great application prospect in the pharmaceutical process.

A Novel Integrated APCI and MPT Ionization Technique as Online Sensor for Trace Pesticides Detection.

The misuse of pesticides poses a tremendous threat to human health. Excessive pesticide residues have been shown to cause many diseases. Many sensor detection methods have been developed, but most of them suffer from problems such as slow detection speed or narrow detection range. So, the development of rapid, direct and sensitive means of detecting trace amounts of pesticide residues is always necessary. A novel online sensor technique was developed for direct analysis of pesticides in complex matrices with no sample pretreatment. The portable sensor ion source consists of an MPT (microwave plasma torch) with desolventizing capability and an APCI (atmosphere pressure chemical ionization), which provides abundant precursor ions and a strong electric field. The performance which improves the ionization efficiency and suppresses the background signal was verified by using pesticide standard solution and pesticide pear juice solution measurements with an Orbitrap mass spectrometer. The limit of detection (LOD) and the limit of quantization (LOQ) of the method were measured by pear juice solutions that were obtained in the ranges of 0.034-0.79 µg/L and 0.14-1 µg/L. Quantitative curves were obtained ranging from 0.5 to 100 µg/L that showed excellent semi-quantitative ability with correlation coefficients of 0.985-0.997. The recoveries (%) of atrazine, imidacloprid, dimethoate, profenofos, chlorpyrifos, and dichlorvos were 96.6%, 112.7%, 88.1%, 85.5%, 89.2%, and 101.9% with the RSDs ranging from 5.89-14.87%, respectively. The results show that the method has excellent sensitivity and quantification capability for rapid and direct detection of trace pesticide.

60-nt DNA Direct Detection without Pretreatment by Surface-Enhanced Raman Scattering with Polycationic Modified Ag Microcrystal Derived from AgCl Cube.

Direct detection of long-strand DNA by surface-enhanced Raman scattering (SERS) is a valuable method for diagnosis of hereditary diseases, but it is currently limited to less than 25-nt DNA strand in pure water, which makes this approach unsuitable for many real-life applications. Here, we report a 60-nt DNA label-free detection strategy without pretreatment by SERS with polyquaternium-modified Ag microcrystals derived from an AgCl cube. Through the reduction-induced decomposition, the size of the about 3 × 3 × 3 µm3 AgCl cube is reduced to Ag, and the surface is distributed with the uniform size of 63 nm silver nanoparticles, providing a large area of a robust and highly electromagnetic enhancement region. The modified polycationic molecule enhances the non-specific electrostatic interaction with the phosphate group, thereby anchoring DNA strands firmly to the SERS enhanced region intactly. As a result, the single-base recognition ability of this strategy reaches 60-nt and is successfully applied to detect thalassemia-related mutation genes.

Functional conservation and divergence of duplicated the suppressor of cytokine signaling 1 in blunt snout bream (Megalobrama amblycephala).

The suppressor of cytokine signaling 1 (SOCS1) is an essential feedback regulator extensively involved in many different cytokine signaling pathways, such as regulation of the immune system and growth of organism. However, the molecular and functional information on socs1 genes in freshwater fish is unclear. In the present paper, we identified and characterized the full-length closely related but distinct socs1 genes (socs 1a and -1b) in blunt snout bream (Megalobrama amblycephala). The bioinformatic analysis results showed that duplicated socs1s shared majority conserved motifs with other vertebrates. Both socs1a and -1b mRNAs were detected throughout embryogenesis, and gradually increase and then constantly expressed after 16 hpf. Whole-mount in situ hybridization demonstrated that socs1a and socs1b mRNAs were detected in the brain at 12hpf and 24hpf, and in the notochord and brain at 36hpf. In adult fish, the socs1a mRNA were strongly expressed in the heart, eye, kidney, spleen and gonad, but were found to be relatively low in the intestine and liver. On the other hand, the expression of socs1b mRNA was significantly high in the muscle, eye and spleen, and relatively low in the intestine, liver, skin and heart. The results of hGH treatment experiment showed that socs1a and 1b mRNAs were upregulated markedly in the kidney, muscle and liver. Overexpression of socs1s significantly inhibit the GH and JAK/STAT factor stat3 and the inhibitory effect of SOCS1s on GH may be involved in JAK-STAT signaling pathway. These results indicate that SOCS1 plays an important role in regulating growth and development.

Micelle-Enabled Suzuki-Miyaura Cross-Coupling of Heteroaryl Boronate Esters.

We report a micellar protocol for Suzuki-Miyaura cross-coupling of heteroaryl boronic esters with aryl or heteroaryl halides. The micellar catalysis enables this coupling reaction to run under mild conditions, which avoids the decomposition of heteroaryl boronate esters and allows for high chemoselectivity for cross-coupling reaction with 6-chloropridine-2-boronic ester. The micellar protocol expands the scope of the cross-coupling reaction with challenging heteroaryl boronic esters and complements the existing cross-coupling methods for construction of heterobiaryl building blocks.

A novel steric effect-regulated isothermal exponential amplification technology for the one-step homogeneous sensing of proteins.

A simple and homogeneous technology, the steric effect-regulated isothermal exponential amplification reaction (SER-EXPAR), was developed to sense proteins. By using a small molecule linked DNA nanostructure, termed enzyme-binding hairpin (EBH), the protein-small molecule binding events could be readily sensed by utilizing the steric effect generated between the protein and enzyme. It set free the enzyme to be active again, thus regulating the amplification rate of EXPAR.

Circumventing silver oxidation induced performance degradation of silver surface-enhanced Raman scattering substrates.

Surface-enhanced Raman scattering (SERS) has been recognized as a promising sensing technique in biomedical/biosensing applications and analytical chemistry. Silver (Ag) nanostructures have the strongest SERS enhancement, but suffer from severe enhancement degradation induced by oxidation. Here, we introduce electrochemical reduction of silver oxide to produce Ag SERS substrates on request to partially circumvent the SERS enhancement degradation problem of Ag SERS substrates. Silver oxide nanostructures were first prepared in pure silver citrate aqueous solutions with controllable morphologies depending on the electrodeposition parameters. The transition process from silver oxide to Ag was investigated by density functional theory calculations. Based on the understanding of the transition mechanism, heating treatment, applying reducing agent, and electrochemical reduction were adopted to transform silver oxide to Ag. Notably, no organic agents were introduced neither in the electrodeposition of silver oxide nor electrochemical transformation of silver oxide to Ag. The electrochemical reduction strategy could produce Ag SERS substrates with a 'clean' surface with outstanding SERS performance in a simple as well as cost and time effective manner. Ag SERS substrates can be used in biomedical/biosensing fields. The approach through electrochemical reduction of silver oxide to generate Ag SERS substrate may push forward practical application process of Ag SERS substrates.

Development of a cyclosporin A derivative with excellent anti-hepatitis C virus potency.

Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand. Identification of advanced crystalline intermediates enabled practical supply of key intermediates. Finally, macrocyclization was carried out at 10% weight concentration by a general and unconventional "slow release" concept.

Silver Nanoparticle Generators: Silicon Dioxide Microspheres.

A green and simple approach has been developed to synthesize un-coated Ag nanoparticles (AgNPs) in situ on the surface of thiol-group-functionalized silica dioxide microspheres (TSMs) in the aqueous solution. As soon as the Ag+ ions attach onto the surface of TSMs, nucleation and growth of AgNPs can spontaneously complete within one minute without other reducing agents or capping agents. The main reason is that the self-assembled silane-layer formed by mercaptosilane molecules could reduce the Ag0 formation energy, transport electrons efficiently, improve the nucleation density, and protect AgNPs against oxidation. Thus, the supported AgNPs show excellent chemical/photochemical stability in air and solution. Meanwhile, the size of as-prepared AgNPs could be controlled by tuning the concentration of Ag+ ions. This process provides a general route to generate bare AgNPs on the surface of silica dioxide in situ, which might be extended to other materials and is promising in developing novel methodologies for making supported noble metal NPs with desired structure and properties.

Syntheses of 4-(Heteroaryl)cyclohexanones via Palladium-Catalyzed Ester α-Arylation and Decarboxylation.

An alternative synthesis of 4-(heteroaryl)cyclohexanones is described featuring a palladium-catalyzed ester α-arylation followed by decarboxylation. The substrate scope is broad with a wide range of heteroaryl halides. In particular, the reaction robustness is demonstrated by the synthesis of >10 g of 4-(pyrazin-2-yl)cyclohexanone with 85% overall yield.

Grb2 interacts with SGEF and antagonizes the ability of SGEF to enhance EGF-induced ERK1/2 activation.

Previously, we demonstrated that SGEF enhances EGFR stability; however, SGEF-mediated downstream signaling of EGFR is not well understood. Here, we show that SGEF enhances EGF-induced ERK1/2 activation independent of its guanine nucleotide exchange (GEF) activity. We further show that SGEF interacts with Grb2, a critical downstream transducer of EGFR. Surprisingly, we found that interaction of Grb2 to SGEF antagonizes the ability of SGEF to enhance EGF-induced ERK1/2 activation. Taken together, this study reports a novel function of SGEF that excludes GEF and also provides important insights into the complex role of Grb2 in EGFR signal transduction.

Characteristics of white coat hypertension in Chinese Han patients with type 2 diabetes mellitus.

OBJECTIVES: This study documented the prevalence and clinical features of white coat hypertension (WCH) among Chinese Han patients with type 2 diabetes mellitus (T2DM). METHODS: Clinic and ambulatory blood pressure (BP) measurements were compared in 856 patients with T2DM to determine the frequency of WCH (WCH was defined as clinical blood pressure ≥140/90 mmHg and daytime blood pressure <135/85 mmHg and/or 24-h ambulatory BP (ABP) mean value of <130/80 mmHg on ambulatory BP monitoring (ABPM). Weight, waist circumference (WC), body mass index (BMI), waist to height ratio (WHtR), fasting blood glucose, glycosylated hemoglobin level and circadian BP patterns were also measured to find clinical features predictive of WCH in T2DM. RESULTS: The prevalence of WCH was 7.36% (63/856) in the overall population, 6.13% (29/473) in male and 8.88% (34/383) in female (p < 0.05). WCH accounted for 14.03% (63/449) of diagnosed hypertension. Age, course of T2DM, male WC were independent protective factors, whereas female sex, smoking and alcohol consumption were independent risk factors for WCH in T2DM. Non-dippers and reverse dippers made up larger proportion of the WCH group (p < 0.01). CONCLUSION: WCH is relatively common among T2DM patients, it is a unique condition distinct from essential hypertension (EH), and WCH patients also exhibit significant differences in clinical parameters.

SGEF enhances EGFR stability through delayed EGFR trafficking from early to late endosomes.

Previously, we demonstrated an elevated SH3-containing guanine nucleotide exchange factor (SGEF) expression in clinical specimens with prostate cancer and implicated the role of SGEF in prostate tumorigenesis. However, the molecular mechanism behind the SGEF regulation of prostate cancer development is not known. In this study, we show that SGEF expression delays epidermal growth factor receptor (EGFR) degradation in prostate cancer cells and is independent from its guanine nucleotide exchange factor (GEF) function. We further show that the delayed degradation is due to a delay in EGFR trafficking from early to late endosomes and not to a decrease in EGFR ubiquitination. Finally, we show that depletion of SGEF significantly inhibits epidermal growth factor-induced EGFR signaling cascade and cell migration in the prostate cancer cells. We report for the first time an SGEF function for RhoG that excludes GEF and the ability of SGEF to enhance EGFR stability and signaling by delaying its lysosomal sorting and degradation. This could be one mechanism by which SGEF contributes to prostate cancer progression.

Efficient syntheses of 2,3-disubstituted natural quinazolinones via iridium catalysis.

Natural products sclerotigenin, pegamine, deoxyvasicinone, mackinazolinone, and rutaecarpine were synthesized. Core quinazolinone structures were constructed via Ir catalysis.

Dual ambient plasma source ionization mass spectrometry for the rapid detection of trace sterols in urban water: Rapid detection of trace sterols in urban water.

A direct analytical method based on dual ambient plasma ion source tandem mass spectrometry was used for the simultaneous determination of four sterols in the environment. This technology has very high sensitivity and the method detects the four sterols in methanol-water (1:3) solutions with limits of detection (LOD) and limits of quantification (LOQ) ranging from 1.2 ng/L to 6.9 ng/L and 7.6 ng/L to 10.0 ng/L, respectively. The method was also used to test water quality at three locations within the city and successfully detected all four sterols at very low concentrations. The dual plasma source tandem mass spectrometry technique is extremely simple, rapid, sensitive and highly efficient compared to other traditional methods, providing a useful screening tool for sterols in water.

LDADN: a local discriminant auxiliary disentangled network for key-region-guided chest X-ray image synthesis augmented in pneumoconiosis detection.

Pneumoconiosis is deemed one of China's most common and serious occupational diseases. Its high prevalence and treatment cost create enormous pressure on socio-economic development. However, due to the scarcity of labeled data and class-imbalanced training sets, the computer-aided diagnostic based on chest X-ray (CXR) images of pneumoconiosis remains a challenging task. Current CXR data augmentation solutions cannot sufficiently extract small-scaled features in lesion areas and synthesize high-quality images. Thus, it may cause error detection in the diagnosis phase. In this paper, we propose a local discriminant auxiliary disentangled network (LDADN) to synthesize CXR images and augment in pneumoconiosis detection. This model enables the high-frequency transfer of details by leveraging batches of mutually independent local discriminators. Cooperating with local adversarial learning and the Laplacian filter, the feature in the lesion area can be disentangled by a single network. The results show that LDADN is superior to other compared models in the quantitative assessment metrics. When used for data augmentation, the model synthesized image significantly boosts the performance of the detection accuracy to 99.31%. Furthermore, this study offers beneficial references for insufficient label or class imbalanced medical image data analysis.

Thermal Degradation Characteristics of Styrene-Butadiene-Styrene Copolymer Asphalt Binder Filled with an Inorganic Flame-Retarding Agent.

Asphalt binder is a complex mixture of dark brown polymers composed of hydrocarbons with generally poor fire resistance. To improve its flame retardancy when used in tunnel asphalt pavements, a new inorganic flame-retardant filler (FR) containing magnesium hydroxide, aluminum hydroxide, inorganic phosphate, and melamine salt was explored. Thereafter, limiting oxygen index (LOI) and smoke suppression tests for the flame-retarded asphalt binder (FRA) mastics mixed with FR and styrene-butadiene-styrene (SBS) copolymer asphalt binder were conducted. Thermogravimetric (TG) and differential scanning calorimetry (DSC) curves for the FRA were correspondingly generated. Based on the TG data, the reaction function g(α), apparent activation energy Ea, and pre-exponential factor A were quantitatively evaluated using kinetic analysis. In addition, a Fourier transform infrared spectrometry (FTIR) test was utilized to assess the effects of the presence of FR on the chemical composition of the asphalt binder. Dynamic shear rheometer (DSR) tests were also performed to evaluate the rheological behavior of FRA. Results show that the presence of the FR significantly reduced the LOI and improved the smoke suppression during combustion of the asphalt binder mastics. The presence of FR was found to increase the Ea and the complexity of the combustion reaction, thereby improving the flame retardancy of the asphalt binder. FTIR analysis indicated that the presence of FR did not induce any strong chemical reactions to significantly impact or alter the functional groups of the asphalt binder. Furthermore, it was also observed that the rutting parameter and critical failure temperature of FRA increased with the addition of FR due to the stiffening effect of the solid FR particles.

One-pot synthesis of quinazolinones via iridium-catalyzed hydrogen transfers.

A one-pot oxidative cyclization of primary alcohols with o-aminobenzamides to quinazolinones was successfully achieved using [Cp*IrCl(2)](2) (Cp* = pentamethylcyclopentadienyl) as a catalyst under hydrogen transfer conditions.

[Expression of high mobility group box chromosomal protein 1 in mice with lupus nephritis].

OBJECTIVE: To determine the role of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 (HMGB-1) in the pathogenesis of lupus nephritis. METHODS: Serum levels of anti-dsDNA antibodies were determined by enzyme linked immunosorbent assay (ELISA). Renal morphologic features were examined by light microscopy, electron microscopy, and immunohistologic analyses. The mRNA expression of HMGB-1 and monocyte chemoattractant protein-1 (MCP-1) was detected by RT-PCR. RESULT: MRL/lpr mice demonstrated characteristic alterations of serum immune parameters, with progressively increased anti-dsDNA antibodies with age, compared with age-matched C57BL/6J mice. MRL/lpr mice showed progressive development of renal damage, starting at 12 weeks of age and reached the peak at 20 weeks. The observed lesions included the presence of enlarged hypercellular glomeruli, with increased numbers of both resident cells and infiltrating leukocytes. Higher expression of HMGB-1 mRNA was found in MRL/lpr mice than what in C57BL/6J mice. Expression of HMGB-1 was positively correlated with that of MCP-1 mRNA. CONCLUSION: The results demonstrate that the higher expression of HMGB-1 may contribute to the pathogenesis of lupus nephritis.

An Adversarial Learning Approach for Super-Resolution Enhancement Based on AgCl@Ag Nanoparticles in Scanning Electron Microscopy Images.

Scanning electron microscopy (SEM) plays a crucial role in the characterization of nanoparticles. Unfortunately, due to the limited resolution, existing imaging techniques are insufficient to display all detailed characteristics at the nanoscale. Hardware-oriented techniques are troubled with costs and material properties. Computational approaches often prefer blurry results or produce a less meaningful high-frequency noise. Therefore, we present a staged loss-driven neural networks model architecture to transform low-resolution SEM images into super-resolved ones. Our approach consists of two stages: first, residual channel attention network (RCAN) with mean absolute error (MAE) loss was used to get a better peak signal-to-noise ratio (PSNR). Then, discriminators with adversarial losses were activated to reconstruct high-frequency texture features. The quantitative and qualitative evaluation results indicate that compared with other advanced approaches, our model achieves satisfactory results. The experiment in AgCl@Ag for photocatalytic degradation confirms that our proposed method can bring realistic high-frequency structural detailed information rather than meaningless noise. With this approach, high-resolution SEM images can be acquired immediately without sample damage. Moreover, it provides an enhanced characterization method for further directing the preparation of nanoparticles.