Evaluation of Prebiotic Glycan Composition in Human Milk and Infant Formula: Profile of Galacto-Oligosaccharides and Absolute Quantification of Major Milk Oligosaccharides by UPLC-Cyclic IM-MS and UPLC-MS/MS.

Prebiotic oligosaccharides have attracted immense interest in the infant formula (IF) industry due to their unique health benefits for infants. There is a need for the reasonable supplementation of prebiotics in premium IF products. Herein, we characterized the profile of galacto-oligosaccharides (GOS) in human milk (HM) and IF using ultrahigh-performance liquid chromatography-cyclic ion mobility-mass spectrometry (UPLC-cIM-MS) technique. Additionally, we further performed a targeted quantitative analysis of five essential HM oligosaccharides (HMOs) in HM (n = 196), IF (n = 50), and raw milk of IF (n = 10) by the high-sensitivity UPLC-MS/MS method. HM exhibited a more abundant and variable HMO composition (1183.19 to 2892.91 mg/L) than IF (32.91 to 56.31 mg/L), whereas IF contained extra GOS species and non-negligible endogenous 3'-sialyllactose. This also facilitated the discovery of secretor features within the Chinese population. Our study illustrated the real disparity in the prebiotic glycome between HM and IF and provided crucial reference for formula improvement.

A 110-170 GHz Wideband LNA Design Using the InP Technology for Terahertz Communication Applications.

This paper proposes a low-noise amplifier (LNA) for terahertz communication systems. The amplifier is designed based on 90 nm InP high-electron-mobility transistor (HEMT) technology. In order to achieve high gain of LNA, the proposed amplifier adopts a five-stage amplification structure. At the same time, the use of staggered tuning technology has achieved a large bandwidth of terahertz low-noise amplification. In addition, capacitors are used for interstage isolation, sector lines are used for RF bypass, and Microstrip is used to design matching circuits. The entire LNA circuit was validated using accurate electromagnetic simulation. The simulation results show that at 140 GHz, the small signal gain is 25 dB, the noise figure is 4.4 dB, the input 1 dB compression point is -19 dBm, and the 3 dB bandwidth reaches 60 GHz (110-170 GHz), which validates the effectiveness of the design.

Krill Oil Turns Off TGF-ß1 Profibrotic Signaling in the Prevention of Diabetic Nephropathy.

Diabetic nephropathy (DN), a severe microvascular complication of diabetes mellitus (DM), results in high mortality due to the lack of effective interventions. The current study investigated the preventive effect of krill oil (KO) on DN using a type 2 DM mouse model induced by streptozotocin and high-fat diet for 24 weeks. The diabetic mice developed albuminuria, mesangial matrix accumulation, glomerular hypertrophy, and fibrosis formation, with an increase in renal proinflammatory, oxidative and profibrotic gene expression. KO significantly prevented these effects but did not improve hyperglycemia and glucose intolerance. In high-glucose-treated mesangial cells (MCs), KO preferably modulated TGF-ß1 signaling as revealed by RNA-sequencing. In TGF-ß1-treated MCs, KO abolished SMAD2/3 phosphorylation and nuclear translocation and activated Smad7 gene expression. The action of KO on the SMADs was confirmed in the diabetic kidneys. Therefore, KO may prevent DN predominantly by suppressing the TGF-ß1 signaling pathway.

An Intelligent Nanovehicle Armed with Multifunctional Navigation for Precise Delivery of Toll-Like Receptor 7/8 Agonist and Immunogenic Cell Death Amplifiers to Eliminate Solid Tumors and Trigger Durable Antitumor Immunity.

Cancer immunotherapy is revolutionary in oncology and hematology. However, a low response rate restricts the clinical benefits of this therapy owing to inadequate T lymphocyte infiltration and low delivery efficiency of immunotherapeutic drugs. Herein, an intelligent nanovehicle (folic acid (FA)/1-(4-(aminomethyl) benzyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (IMDQ)-oxaliplatin (F/IMO)@CuS) armed with multifunctional navigation is designed for the accurate delivery of cargoes to tumor cells and dendritic cells (DCs), respectively. The nanovehicle is based on a near infrared-responsive inorganic CuS nanoparticles, acting as a photosensitizer and carrier of the chemotherapeutic agent oxaliplatin, and enters tumor cells owing to the presence of folic acid on the surface of CuS upon intratumoral injection. Furthermore, a toll-like receptor (TLR) 7/8 agonist-conjugated polymer, anchored on the surface of CuS, is modified with mannose to bind with DCs in the tumor microenvironment. Upon exposure to laser irradiation, nanovehicles disassemble, releasing oxaliplatin, to ablate tumor cells and amplify immunogenic cell death in combination with photothermal therapy. Mannose-modified polymer-TLR7/8 agonist conjugates are subsequently exposed, leading to the activation of DCs and proliferation of T cells. Collectively, these intelligent nanovehicles reduce tumor burden, exert a robust antitumor immune response, and generate long-term immune protection to prevent tumor recurrence.

Krill Oil Inhibits NLRP3 Inflammasome Activation in the Prevention of the Pathological Injuries of Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus (DM), resulting in high mortality. Myocardial fibrosis, cardiomyocyte apoptosis and inflammatory cell infiltration are hallmarks of DCM, leading to cardiac dysfunction. To date, few effective approaches have been developed for the intervention of DCM. In the present study, we investigate the effect of krill oil (KO) on the prevention of DCM using a mouse model of DM induced by streptozotocin and a high-fat diet. The diabetic mice developed pathological features, including cardiac fibrosis, apoptosis and inflammatory cell infiltration, the effects of which were remarkably prevented by KO. Mechanistically, KO reversed the DM-induced cardiac expression of profibrotic and proinflammatory genes and attenuated DM-enhanced cardiac oxidative stress. Notably, KO exhibited a potent inhibitory effect on NLR family pyrin domain containing 3 (NLRP3) inflammasome that plays an important role in DCM. Further investigation showed that KO significantly upregulated the expression of Sirtuin 3 (SIRT3) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which are negative regulators of NLRP3. The present study reports for the first time the preventive effect of KO on the pathological injuries of DCM, providing SIRT3, PGC-1α and NLRP3 as molecular targets of KO. This work suggests that KO supplementation may be a viable approach in clinical prevention of DCM.

Development of a high-throughput method for the comprehensive lipid analysis in milk using ultra-high performance supercritical fluid chromatography combined with quadrupole time-of-flight mass spectrometry.

Milk lipids are one of the most complex materials in nature and are associated with many physiological functions, hence it is important to comprehensively characterize lipids profiles to evaluate the nutritional value of milk. A quick method was developed by ultra-high performance supercritical fluid chromatography coupled to electrospray ionization quadrupole time-of-flight mass spectrometry (UHPSFC-ESI-QTOF-MS) to analyze the non-polar and polar lipids profiles of cow, goat, buffalo, human milk, and infant formulas in 7 min. All chromatographic conditions were carefully optimized and their effect on the chromatographic behavior of lipid classes and species was discussed. Under optimized conditions, 12 lipid classes (triacylglycerols, diacylglycerols, monoglyceride, fatty acids, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, sphingomyelin, lyso-phosphatidylcholine, and lyso-phosphatidylethanolamine) were separated and each class was further separated in single analysis to facilitate the identification. 250 lipid species in real samples were characterized and quantified. This result demonstrates the applicability of the UHPSFC-ESI-QTOF-MS method in the high-throughput and comprehensive lipid analysis of milk, and will hopefully help to provide nutritionists with the lipid distribution in different types of milk, as well as help in the design of more suitable infant formula for babies.

A risk classification strategy for migrants of food contact material combined with three (Q)SAR tools in silico.

The chemical constituents in food contact materials (FCMs) may transfer into food during the contact, which may pose potential risk to humans. So, it is important to evaluate the safety of FCMs. Due to the advantages of cost-effectiveness and high throughput, (Q)SAR tools have been gradually used for risk assessment. In this work, a risk classification strategy for migrants of food contact materials combined with three (Q)SAR tools was developed based on a single endpoint (Mutagenicity) assessment and risk matrix approach, respectively. 419 migrants existing in a self-built toxicology database beneficial from Python crawler technology were evaluated. 5 toxic hazard ranks and 4 risk ranks were obtained for single endpoint assessment and risk matrix respectively, with 21 substances assigned as Toxic hazard Class I and 43 substances assigned as RISK Ⅰ which need the highest safety concern. Besides, for the Toxic hazard Class I substances assessed by the single endpoint, 19 of them were confirmed experimentally, and all of them were overlapped in the RISK Ⅰ substances, which suggests the effectiveness and reliability of this strategy.

Investigation of alterations in phospholipids during the production chain of infant formulas via HILIC-QTOF-MS and multivariate data analysis.

Phospholipids play a key role in infant nutrition and cognitive function. In this study, hydrophilic interaction liquid chromatography coupled to quadrupole time-of-flight mass spectrometry method was firstly developed to analyze the composition of phospholipids. Then we characterized and quantified phospholipids extracted from raw, pasteurized, homogenized, and spray-dried milk to investigate the effect of the technological process on the composition of the phospholipids. Results indicate that the composition of the phospholipids underwent minor changes after pasteurization, while the concentration of phospholipids was significantly affected by the spray-drying process, especially phosphatidylethanolamine and phosphatidylinositol. Multivariate data analysis further verified the results and indicated that phospholipids containing polyunsaturated fatty acids had undergone significant changes during the production chain, especially in spray-drying. This work reveals the changes of phospholipids composition during the production chain of infant formulas and serve as a reference for the subsequent optimization of infant formulas to meet nutritional need of infants.

Graphene Buffer Layer on SiC as a Release Layer for High-Quality Freestanding Semiconductor Membranes.

Free-standing crystalline membranes are highly desirable owing to recent developments in heterogeneous integration of dissimilar materials. Van der Waals (vdW) epitaxy enables the release of crystalline membranes from their substrates. However, suppressed nucleation density due to low surface energy has been a challenge for crystallization; reactive materials synthesis environments can induce detrimental damage to vdW surfaces, often leading to failures in membrane release. This work demonstrates a novel platform based on graphitized SiC for fabricating high-quality free-standing membranes. After mechanically removing epitaxial graphene on a graphitized SiC wafer, the quasi-two-dimensional graphene buffer layer (GBL) surface remains intact for epitaxial growth. The reduced vdW gap between the epilayer and substrate enhances epitaxial interaction, promoting remote epitaxy. Significantly improved nucleation and convergent quality of GaN are achieved on the GBL, resulting in the best quality GaN ever grown on two-dimensional materials. The GBL surface exhibits excellent resistance to harsh growth environments, enabling substrate reuse by repeated growth and exfoliation.

Non-targeted analysis and risk assessment of non-volatile compounds in polyamide food contact materials.

Small molecules in food contact materials may migrate into food during their contact. To extensively analyze the migrants, non-targeted screening is needed to detect the migrants. The migrants' detection is difficult because of the complexity and the trace amount of the migrants. In this work, the dissolution precipitation method was used to extract small molecules in Polyamide (PA) kitchenware. The extract solutions were screened by ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF-MS) for non-targeted analysis and 64 different small molecules in materials were identified through the screening of a self-built database. Then, migration tests were performed to analyze migrants in food simulants. It suggests that the abundance of PA oligomers was the highest in migrants. The risk assessment of migrants revealed that the exposure of most migrants was at a safer level unlike the exposure of PA oligomers that exceeded their threshold of toxicological concern (TTC).

Few-cycle optical pulse characterization under phase-mismatching.

The phase-matching bandwidth of nonlinear crystal is of great significance in ultrashort laser pulse characterization. In order to satisfy the phase-matching bandwidth, ultra-thin nonlinear crystals are generally required. However, the significantly reduced conversion efficiency, as well as the machining difficulties, limits its applications. Here, we show that sufficient spectrum bandwidth response can be achieved for a thick crystal when the phase-matching wavelength is tuned outside of the spectral window of the measured pulse. By applying this phenomenon to a single-shot second-harmonic generation frequency resolved optical gating (SHG-FROG) device, we successfully characterized a few-cycle pulse using a 150µmß-barium borate (BBO) crystal. The accuracy of the method was verified by comparing the conventional pulse retrieving approach with a 5µm BBO crystal, which has a sufficient phase-matching bandwidth.

Source profiles and emission factors of VOCs from solvent-based architectural coatings and their contributions to ozone and secondary organic aerosol formation in China.

Volatile organic compounds (VOCs) from solvent-based architectural coatings (SBACs) play an important role in photochemical air pollution with increasing consumption of architectural coatings in China. In this study, we collected 148 typical SBACs of 3 types in China. The TVOC emission factors and source profiles were established, the contributions of SBACs to ozone and secondary organic aerosol (SOA) formation were investigated. The VOC emissions and O3 and SOA amounts formed in chemical reactions from SBACs in 2017 were estimated. Key organic groups and VOC species with high reactivity were identified. According to the results, the TVOC emission factors were 507.17 g L-1 for solvent-based anticorrosive coatings, 381.34 g L-1 for solvent-based floor coatings and 459.68 g L-1 for solvent-based fire-retardant coatings. The VOC emissions were 186,902.11 t, 88,225.41 t and 71,352.32 t; the O3 amounts formed were 742,001.39 t, 397,896.60 t and 244,738.46 t; the SOA amounts formed were 3934.29 t, 2488.04 t and 1104.61 t, respectively, from 3 types of SBACs in 2017. The O3 production factors were 1781.82 g O3 (kg paint)-1, 1457.50 g O3 (kg paint)-1 and 1176.63 g O3 (kg paint)-1, the SOA production factors were 9.45 g SOA (kg paint)-1, 9.11 g SOA (kg paint)-1 and 5.31 g SOA (kg paint)-1, for 3 types of SBACs. Priority should be given to organic group of aromatics and top 17 VOC species with high reactivity for O3 and SOA eliminating strategies, especially three xylenes (o-xylene, m-xylene and p-xylene), ethylbenzene, trimethyl benzenes (1,3,5-trimethyl benzene, 1,2,3-Trimethyl benzene) and toluene.

Boronoisophthalic acid as a novel affinity ligand for the selective capture and release of glycoproteins near physiological pH.

Boronic acid-based affinity materials have gained tremendous attention for the selective separation and recognition of cis-diol containing biomolecules. But often, these boronate affinity materials are stuck to some serious issues like high binding pH and weak affinity, especially in the case of glycoproteins. Here in this study, we used 5-boronoisophthlic acid as a novel affinity ligand for the selective capture and release of glycoproteins. The pKa value of 5-boronoisophthalic acid is investigated to be 7.8 which is just closed to physiological pH and is ideally suitable for the fast binding and elution kinetics of glycoproteins to avoid their degradation and deactivation. The affinity ligand is attached to the surface of polymer support using branched polyethyleneimine (PEI) which enhances the binding strength as it has multiple amine groups available for the attachment of 5-boronoisophthalic for synergistic interactions. The resulting affinity material is characterized and packed in a micropipette-tip using hydrophilic melamine foam as a frit to make the separation process smooth, simple, reliable, and robust. This boronic acid-based affinity tip exhibits binding constants for model glycoproteins in the range of 10-6-10-7 M, binding capacities in the range of 0.662 µM/g, and selectivity up to 1:1000 (HRP to BSA) under optimized extraction conditions. Finally, the boronic-based affinity tip is successfully applied to selectively capture the glycoproteins from the human milk sample, especially lactoferrin which is highly important in dairy manufacture.

Supercritical Fluid Extraction Combined with Ultrahigh Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry for Determination of Extractables to Evaluate Compatibility of Drugs with Rubber Closures.

Biological activity and pharmacological efficacy of protein drugs may be affected by the compatibility between drug and packaging materials. The compatibility of rubber closures seal cap has become the focus of many studies due to its complicated formulation. Despite of the significance of the issue, currently, there is little available data about organic leachables in drugs which is also not comprehensive. Since the concentration of migrants in drug is usually low and the matrix is complicated, the establishment of overall profile of extractables is crucial for the characterization of leachables. Herein, the supercritical fluid extraction (SFE) method was used because of its great extraction capacity and efficiency for low to medium polar extractables in rubber stoppers. The SFE conditions were optimized by response surface methodology (RSM). Experimental results of the extract yield were close to the predicted values (R2 = 0.95). Then the extractables were qualitatively and quantitatively analyzed with ultrahigh performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). Finally, risk assessment was made by comparing predicted exposure with injection permitted daily exposure (pPDE) limit or threshold recommended by threshold of toxicological concern (TTC). The results showed that there are many extractables such as glyceride, fatty acids and derivatives, antioxidants, and degradation products. Among them degradation products were in the majority and content of 17 substances exceeded corresponding limits. Considering their unknown toxicology, more experiments are therefore needed to provide information on their toxicology and risk assessment. The study provides a reference for the compatibility of drugs, and quality supervision of pharmaceuticals packaging.

Assessment of heavy metal contamination in the atmospheric deposition during 1950-2016 A.D. from a snow pit at Dome A, East Antarctica.

Antarctic trace element records could provide important insights into the impact of human activities on the environment over the past few centuries. In this study, we investigated the atmospheric concentrations of 14 representative heavy metals (Al, As, Cd, Co, Cu, Fe, K, Mg, Mn, Pb, Sb, Sr, Tl and V) from 174 samples collected in a 4-m snow pit at Dome Argus (Dome A) on the East Antarctic Plateau, covering the period from 1950 to 2016 A.D. We found great variability in the annual concentration of all metals. The crustal enrichment factors suggest that the concentrations of some heavy metals (Cd, Sb, Cu, As and Pb) were likely influenced by anthropogenic activities in recent decades. An analysis of source regions suggests that heavy metal pollution at Dome A was largely caused by human activities in Australia and South America (e.g. mining production, leaded gasoline). Based on the relationship between the trace elements fluxes and sea ice concentration (SIC), sea surface temperature (SST) and annual mean air temperature at 2 m above the ground (T2m), our analysis shows that deposition and transport of atmospheric aerosol at Dome A were influenced by circum-Antarctic atmospheric circulations.

Protective role of NRF2 in macrovascular complications of diabetes.

Macrovascular complications develop in over a half of the diabetic individuals, resulting in high morbidity and mortality. This poses a severe threat to public health and a heavy burden to social economy. It is therefore important to develop effective approaches to prevent or slow down the pathogenesis and progression of macrovascular complications of diabetes (MCD). Oxidative stress is a major contributor to MCD. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) governs cellular antioxidant defence system by activating the transcription of various antioxidant genes, combating diabetes-induced oxidative stress. Accumulating experimental evidence has demonstrated that NRF2 activation protects against MCD. Structural inhibition of Kelch-like ECH-associated protein 1 (KEAP1) is a canonical way to activate NRF2. More recently, novel approaches, such as activation of the Nfe2l2 gene transcription, decreasing KEAP1 protein level by microRNA-induced degradation of Keap1 mRNA, prevention of proteasomal degradation of NRF2 protein and modulation of other upstream regulators of NRF2, have emerged in prevention of MCD. This review provides a brief introduction of the pathophysiology of MCD and the role of oxidative stress in the pathogenesis of MCD. By reviewing previous work on the activation of NRF2 in MCD, we summarize strategies to activate NRF2, providing clues for future intervention of MCD. Controversies over NRF2 activation and future perspectives are also provided in this review.

Application of dispersive liquid-liquid microextraction based on solidification of floating organic drop for the determination of extractables from pharmaceutical packaging materials.

A new method was established for the determination of the extractables from pharmaceutical packaging materials using dispersive liquid-liquid microextraction based on solidification of floating organic drop (DLLME-SFO) coupled with ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). Packaging samples were filled with three kinds of buffer solutions: acid buffer (pH = 3), alkaline buffer (pH = 9) and 0.9% NaCl solution to extract as many extractables as possible, and then the extractables in buffer solutions were enriched by DLLME-SFO technique. Parameters affecting the efficiency of the extraction procedure were evaluated and optimized, including the type and volume of dispersant, extractant volume, pH and vortex-mixing time. After optimization, the values obtained for limits of detection and quantification for three kinds of common antioxidants were 0.3 and 1.0 µg/L respectively, and good linearity (R2 > 0.99) was observed in their respective concentration ranges. The recoveries ranged from 80.61% to 117.87% at three spiked levels with the relative standard deviations (RSDs) between 0.92% and 9.29% (n = 6) in all three buffer solutions. The developed method was successfully applied to the analysis of extractables from pharmaceutical packaging materials. The results indicated that the proposed procedure is a novel, sensitive, fast and repeatable method and has a great significance for evaluation of safety of pharmaceutical packaging materials.

Laser-Ablation-Produced Cobalt Nickel Phosphate with High-Valence Nickel Ions as an Active Catalyst for the Oxygen Evolution Reaction.

Cost-effective, highly efficient and stable non-noble metal-based catalysts for the oxygen evolution reaction (OER) are very crucial for energy storage and conversion. Here, an amorphous cobalt nickel phosphate (CoNiPO4 ), containing a considerable amount of high-valence Ni3+ species as an efficient electrocatalyst for OER in alkaline solution, is reported. The catalyst was converted from Co-doped Ni2 P through pulsed laser ablation in liquid (PLAL) and exhibits a large specific surface area of 162.5 m2 g-1 and a low overpotential of 238 mV at 10 mA cm-2 with a Tafel slope of 46 mV dec-1 , which is much lower than those of commercial RuO2 and IrO2 . This work demonstrates that PLAL is a powerful technology for generating amorphous CoNiPO4 with high-valence Ni3+ , thus paving a new way towards highly effective OER catalysts.

Laser synthesis of oxygen vacancy-modified CoOOH for highly efficient oxygen evolution.

Introducing oxygen vacancies into transition-metal oxide materials would improve their catalytic activity but usually needs high-temperature or high-pressure conditions, and multi-step procedures, and thus are time consuming and not energy efficient. Herein, laser ablation in liquids (LAL), a green, mild and effective approach, has been, for the first time, employed to prepare CoOOH nanosheets with abundant oxygen vacancies and relatively thin thickness. Our theoretical and experimental results demonstrate that oxygen vacancies can optimize the absorption of oxygen evolution reaction (OER) intermediates and improve electrical conductivity; meanwhile, the relatively thin thickness can provide more active sites, thus leading to excellent OER activity of oxygen vacancy-modified CoOOH nanosheets. This work may provide guidance for exploring other efficient non-noble metal catalysts for water oxidation.