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Studies have shown that some peptides and small molecules can induce non IgE-mediated anaphylactoid reactions through mast cell activation. Upon activation, mast cells degranulate and release vasoactive and proinflammatory mediators, from cytoplasmic granules into the extracellular environment which can induce a cascade of severe adverse reactions. This study describes a lead optimization strategy to select NaV1.7 inhibitor peptides that minimize acute mast cell degranulation (MCD) toxicities. Various in vitro, in vivo, and PKPD models were used to screen candidates and guide peptide chemical modifications to mitigate this risk. Anesthetized rats dosed with peptides demonstrated treatment-related decreases in blood pressure and increases in plasma histamine concentrations which were reversible with a mast cell stabilizer, supporting the MCD mechanism. In vitro testing in rat mast cells with NaV1.7 peptides demonstrated a concentration-dependent increase in histamine. Pharmacodynamic modeling facilitated establishing an in vitro to in vivo correlation for histamine as a biomarker for blood pressure decline via the MCD mechanism. These models enabled assessment of structure-activity relationship (SAR) to identify substructures that contribute to peptide-mediated MCD. Peptides with hydrophobic and cationic characteristics were determined to have an elevated risk for MCD, which could be reduced or avoided by incorporating anionic residues into the protoxin II scaffold. Our analyses support that in vitro MCD assessment in combination with PKPD modeling can guide SAR to improve peptide lead optimization and ensure an acceptable early in vivo tolerability profile with reduced resources, cycle time, and animal use. [ABSTRACT FROM AUTHOR]

Methods for detecting mycotoxins are very important because of the great health hazards of mycotoxins. However, there is a high background and low signal-to-noise ratio in real-time sensing, and therefore it is difficult to meet the fast, accurate, and convenient requirements for control of food quality. Here we constructed a quantitative fluorescence image analysis based on multicolor upconversion nanocrystal (UCN)-encoded microspheres for detection of ochratoxin A and zearalenone. The background-free encoding image signal of UCN-doped microspheres was captured by fluorescence microscopy under near-infrared excitation, whereas the detection image signal of phycoerythrin-labeled secondary antibodies conjugated to the microspheres was captured under blue light excitation. We custom-wrote an algorithm to analyze the two images for the same sample in 10 s, and only the gray value in the red channel of the secondary probe confirmed the quantity. The results showed that this novel detection platform performed feasible and reliable fluorescence image measurements by this method. Additionally, the limit of detection of was 0.34721 ng/mL for ochratoxin A and 0.41162 ng/mL for zearalenone. We envision that this UCN encoding strategy will be usefully applied for fast, accurate, and convenient testing of multiple food contaminants to ensure the safety of the food. [ABSTRACT FROM AUTHOR]

Objective: Antihyperglycemic agents, such as empagliflozin, stimulate proximal tubular natriuresis and improve cardiovascular and renal outcomes in patients with type 2 diabetes. Because dipeptidyl peptidase 4 (DPP-4) inhibitors are used in combination with sodium-glucose cotransporter 2 (SGLT2) inhibitors, we examined whether and how sitagliptin modulates fractional sodium excretion and renal and systemic hemodynamic function.Research Design and Methods: We studied 32 patients with type 2 diabetes in a prospective, double-blind, randomized, placebo-controlled trial. Measurements of renal tubular function and renal and systemic hemodynamics were obtained at baseline, then hourly after one dose of sitagliptin or placebo, and repeated at 1 month. Fractional excretion of sodium and lithium and renal hemodynamic function were measured during clamped euglycemia. Systemic hemodynamics were measured using noninvasive cardiac output monitoring, and plasma levels of intact versus cleaved stromal cell-derived factor (SDF)-1α were quantified using immunoaffinity and tandem mass spectrometry.Results: Sitagliptin did not change fractional lithium excretion but significantly increased total fractional sodium excretion (1.32 ± 0.5 to 1.80 ± 0.01% vs. 2.15 ± 0.6 vs. 2.02 ± 1.0%, P = 0.012) compared with placebo after 1 month of treatment. Moreover, sitagliptin robustly increased intact plasma SDF-1α1-67 and decreased truncated plasma SDF-1α3-67. Renal hemodynamic function, systemic blood pressure, cardiac output, stroke volume, and total peripheral resistance were not adversely affected by sitagliptin.Conclusions: DPP-4 inhibition promotes a distal tubular natriuresis in conjunction with increased levels of intact SDF-1α1-67. Because of the distal location of the natriuretic effect, DPP-4 inhibition does not affect tubuloglomerular feedback or impair renal hemodynamic function, findings relevant to using DPP-4 inhibitors for treating type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic gastritis (EoG) has rarely been reported in conjunction with gluten-sensitive enteropathy (GSE). When this does occur, patients typically present with gastrointestinal symptoms. To our knowledge, hypoproteinemia has not been reported as the primary manifestation. Anti-IgE therapy, such as omalizumab, lowers eosinophil counts in the blood, lungs, and gut. Its efficiency in treating active EoG remain unknown. Case presentation: We report a 33-month-old boy with a history of food allergy and atopic dermatitis who developed recurrent edema, hypoproteinemia, and eosinophilia at the age of 14 months. The diagnoses of EoG and GSE were confirmed based on the clinical presentation and results of gastrointestinal biopsies and serological testing. Although prednisone and dietary intervention were initially effective, the boy developed prednisone-related facial swelling. After stopping prednisone, his symptoms relapsed. Subsequent treatment with omalizumab, combined with dietary intervention, showed good efficacy and safety. Conclusions: To our knowledge, this is the first case of concurrent EoG and GSE that presented primarily with hypoproteinemia. We highlight the rare manifestations of these two diseases to raise clinical suspicion and prevent missed and delayed diagnoses. The pathogenesis of EoG is heterogeneous and complex. Omalizumab showed good efficacy, indicating that IgE-mediated processes may be involved in the pathogenesis of this patient's diseases. [ABSTRACT FROM AUTHOR]

At present, it is known that when there is clay in concrete, polycarboxylates (PCE) will preferably adsorb in the clay, so that PCE cannot be fully combined with cement particles, which reduces the workability of the cement slurry. In this paper, a new type of maltitol–ammonium salt cationic (KN-lm) sacrificial agent (SA) has been successfully developed via a simple method, which makes PCE easier to bond with cement particles in the cement slurry containing clay. The effect of KN-lm on the fluidity of clay-containing cement paste is studied, and the experimental results show that KN-lm, as an efficient SA of cement slurry, makes PCE more compatible with clay-containing cement slurry, and increases the initial fluidity of cement slurry by about 19%. Further investigations of TOC, XRD, and zeta potential measurements reveal that a KN-lm ion is only preferably adsorbed into clay compared to PCE through electrostatic adsorption but without having any crystal structure change, thus resulting in good dispersion of cement particles. The addition of KN-lm plays an important role in hindering the hydration expansion of the clay by preferential electrostatic adsorption, which means PCE cannot easily insert into the interlayer of the clay. [ABSTRACT FROM AUTHOR]

Lipids are structurally diverse molecules that play a pivotal role in a plethora of biological processes. However, deciphering the biological roles of the specific lipids is challenging due to the existence of numerous isomers. This high chemical complexity of the lipidome is one of the major challenges in lipidomics research, as the traditional liquid chromatography–mass spectrometry (LC-MS) based approaches are often not powerful enough to resolve these isomeric and isobaric nuances within complex samples. Thus, lipids are uniquely suited to the benefits provided by multidimensional liquid chromatography–ion mobility–mass spectrometry (LC-IM-MS) analysis. However, many forms of lipid isomerism, including double-bond positional isomers and regioisomers, are structurally similar such that their collision cross section (CCS) differences are unresolvable via conventional IM approaches. Here we evaluate the performance of a high resolution ion mobility (HRIM) system based on structures for lossless ion manipulation (SLIM) technology interfaced to a high resolution quadrupole time-of-flight (QTOF) analyzer to address the noted lipidomic isomerism challenge. SLIM implements the traveling wave ion mobility technique along an ∼13 m ion path, providing longer path lengths to enable improved separation of isomeric features. We demonstrate the power of HRIM-MS to dissect isomeric PC standards differing only in double bond (DB) and stereospecific number (SN) positions. The partial separation of protonated DB isomers is significantly enhanced when they are analyzed as metal adducts. For sodium adducts, we achieve close to baseline separation of three different PC 18:1/18:1 isomers with different cis-double bond locations. Similarly, PC 18:1/18:1 (cis-9) can be resolved from the corresponding PC 18:1/18:1 (trans-9) form. The separation capacity is further enhanced when using silver ion doping, enabling the baseline separation of regioisomers that cannot be resolved when measured as sodium adducts. The sensitivity and reproducibility of the approach were assessed, and the performance for more complex mixtures was benchmarked by identifying PC isomers in total brain and liver lipid extracts. [ABSTRACT FROM AUTHOR]

The creep life prediction of austenitic heat-resistant steel is necessary to guarantee the safe operation of the high-temperature components in thermal power plants. This work presents a machine learning model that can be applied to predict the creep life of austenitic steels, offering a novel method and approach for such predictions. In this paper, creep life data from six typical austenitic heat-resistant steels are used to predict their creep life using various machine learning models. Moreover, the dissimilarities between the machine learning model and the conventional lifetime prediction method are compared. Finally, the influence of different input characteristics on creep life is discussed. The results demonstrate that the prediction accuracy of machine learning depends on both the model and the dataset used. The Gaussian model based on the second dataset achieves the highest level of prediction accuracy. Additionally, the accuracy and the generalization ability of the machine learning model prediction are significantly better than those of the traditional model. Lastly, the effect of the input characteristics on creep life is generally consistent with experimental observations and theoretical analyses. [ABSTRACT FROM AUTHOR]

Objective: To establish a pre-operative acute ischemic stroke risk (AIS) prediction model using the deep neural network in patients with acute type A aortic dissection (ATAAD). Methods: Between January 2015 and February 2019, 300 ATAAD patients diagnosed by aorta CTA were analyzed retrospectively. Patients were divided into two groups according to the presence or absence of pre-operative AIS. Pre-operative AIS risk prediction models based on different machine learning algorithm was established with clinical, transthoracic echocardiography (TTE) and CTA imaging characteristics as input. The performance of the difference models was evaluated using the receiver operating characteristic (ROC), precision-recall curve (PRC) and decision curve analysis (DCA). Results: Pre-operative AIS was detected in 86 of 300 patients with ATAAD (28.7%). The cohort was split into a training (211, 70% patients) and validation cohort (89, 30% patients) according to stratified sampling strategy. The constructed deep neural network model had the best performance on the discrimination of AIS group compare with other machine learning model, with an accuracy of 0.934 (95% CI: 0.891–0.963), 0.921 (95% CI: 0.845–0.968), sensitivity of 0.934, 0.960, specificity of 0.933, 0.906, and AUC of 0.982 (95% CI: 0.967–0.997), 0.964 (95% CI: 0.932–0.997) in the training and validation cohort, respectively. Conclusion: The established risk prediction model based on the deep neural network method may have the big potential to evaluate the risk of pre-operative AIS in patients with ATAAD. [ABSTRACT FROM AUTHOR]

Background: Thoracic aortic aneurysm and dissection (TAAD) is a life‐threatening pathology that remains a challenge worldwide. Up to 40% of TAAD cases are hereditary with complex heterogeneous genetic backgrounds. The purposes of this study were to determine the diagnostic rate of patients with TAAD, investigate the molecular pathologic spectrum of TAAD by next‐generation sequencing (NGS), and explore the future preclinical prospects of genetic diagnosis in patients at high ‐risk of study. Methods: NGS was used to screen 15 genes associated with genetic TAAD in 212 patients from northwestern China. Clinical data of patients were gathered by electrocardiography, transthoracic echocardiography, and computed tomography. Results: Of the 212 patients, 67 (31.60%) tested positive for a (likely) pathogenic variant, 42 (19.81%) had a variant of uncertain significance (VUS), and 103 (48.58%) had no variant (likely benign/benign/negative). A total of 135 reportable variants were detected in our test, among which 77 (57.04%) are first reported in this paper. A genotype–phenotype correlation of FBN1 was assessed, and the data showed that the patients with truncating and splicing mutations are more prone to developing severe aortic dissection than those with missense mutations, especially frameshift mutations (82.76% vs. 42.86%). In this study, 43 (20.28%) patients had a family history of sudden death or TAAD, whereas 132 (62.26%) did not (the remaining 37 were not available), and the positive rate of genetic testing was higher in TAAD patients with family history than in those without (76.74% vs. 18.94%). Conclusion: Our study concludes that genetic variation is an important consideration in the risk stratification of individualized prediction and disease diagnosis. [ABSTRACT FROM AUTHOR]

The correct location and identification of critical points, including terminations, three-branch points, and four-branch points, for curvilinear structures in images is a crucial task in many curvilinear structure reconstruction processes. Few methods have been proposed to detect all three types of critical points simultaneously. In this article, we upgraded the existing ray-shooting model to a multifunctional ring-like ray-shooting model that can efficiently detect all types of critical points for curvilinear structures at the same time. First, we measured the minimum and maximum radii of the region of interest based on a sphere-growing method and the modified ray-burst model, respectively. Second, the estimated minimum and maximum radii are used to determine the inner and outer radii of the ring-like ray-shooting model, allowing the proposed model to adaptively extract the pixel intensity distribution feature along the potential branches. Finally, the density-based spatial clustering of applications with noise (DBSCAN) algorithm is used to detect critical points of curvilinear structures by analyzing the number of clusters of pixel intensity distribution extracted from the ring-like ray-shooting model. The experimental results on multiple data sets confirmed that the proposed method can achieve very accurate detection results efficiently and provide the reconstruction of curvilinear structures with beneficial information. [ABSTRACT FROM AUTHOR]

Background: Although microsatellite instability (MSI) is most commonly detected in colorectal cancer (CRC), improvement in MSI analysis method can always help us better assessing MSI phenotypes and gaining useful information in challenging cases. The purpose of current study is to explore whether the ProDx® MSI analysis System (ProDx® MSI) can improve MSI classification in CRC. Methods: We compared the MSI profiles of 97 FFPE samples from CRC patients by ProDx® MSI with Promega MSI analysis System 1.2 and NCI panel. The result is then confirmed by IHC test, which evaluate MMR protein expression. Furthermore, next generation sequencing was performed to double confirm the specimens with discordant results. Results: Among the total 97 CRC cases, 35 were scored as MSI-High by ProDx® MSI, Promega MSI analysis System 1.2, and NCI panel simultaneously. Three extra MSI-High cases were identified by ProDx® MSI. These three cases were classified as MSI-Low by NCI panel, while two of these as MSI-Low, and 1 as MSS by Promega MSI analysis System 1.2. ProDx® MSI had higher concordance with IHC detection compared with Promega MSI Analysis System 1.2 and NCI panel at 99.0%, 96.9%, and 95.9%, respectively. The ProDx® MSI distinguished MSI status with 100% sensitivity and 98.4% specificity. Our data showed that MSI-High phenotype occurred most frequently in tumor development stage I and stage II. Conclusions: The colorectal cancer can be classified according to MSI status accurately by ProDx® MSI. More cases with MSI-High feature may be revealed by ProDx® MSI than by previous test systems in colorectal cancer. [ABSTRACT FROM AUTHOR]

Abstract Ginger (Zingiber officinale Roscoe), one of the most economically valuable plants in the Zingiberaceae family, is widely used as a spice and flavoring agent for beverages, bakery, confectionary, and pharmaceutics. Bacterial wilt disease, caused by Ralstonia solanacearum , is one of the most detrimental production constraints in ginger cultivation. Field cultivation experiments indicated that soil moisture affects the incidence of bacterial wilt disease. However, the relationship between soil moisture and bacterial wilt incidence as well as the mechanism that underlie this infection remain unclear. This study confirms that high soil moisture elevates the susceptibility to R. solanacearum infection; transcriptome sequencing was performed to elucidate the underlying mechanisms. Differential expression indicates that a small number of genes is involved in both the response to high soil moisture as well as post successful R. solanacearum infection; furthermore, a large number of genes is involved in the defense of the infection. In response to high soil moisture, higher ABA contents, and higher expression levels of ABF4 may be related to higher tiller density in ginger. More importantly, WAK16 and WAK3-2 may be determinative genes that weaken the resistance to R. solanacearum in ginger under high soil moisture. The down-regulated expression levels of PRX , CPY , and XET genes indicate that in response to successful R. solanacearum infection, the normal cell wall metabolism may be disturbed and the hypersensitive response may be inhibited. In summary, our study deepens our understanding of the molecular mechanisms of the soil moisture dependent wilt susceptibility of ginger. Graphical abstract Image 1 Highlights • High soil moisture elevates ginger susceptibility to R. solanacearum. • Comparative transcriptome analysis was performed under low and high soil moistures • High ABA and ABF4 related to high tiller density of ginger under high soil moisture. • WAK16 and WAK3-2 may weaken the resistance of ginger to R. solanacearum. • Low PRX, CPY, and XET showed cell wall metabolism was disturbed after infection. [ABSTRACT FROM AUTHOR]

With the rapid growing of wearable computing devices, indoor navigation guidance will become popular in the near future like the GPS-based navigation tools for drivers today. However, how the guided indoor navigation affects human’s memory of a novel environment has not been well studied. In this paper, we investigate route memory with three types of navigation assistance, that is, 2D map, wearable navigation assistant, and human usher. Twenty participants were asked to remember the route while being guided through a novel indoor environment. Our results show that the participants have similar patterns in remembering visual scenes, even using different types of assistance. These findings support previous work on scene memorability and provide the new insight that scene memorability is not affected by the type of navigation guidance. This may indicate that spatial working memory and visual memory are dissociated. We also show that scenes with navigation information are more memorable than scenes without such information. Finally, we provide some evidence that the location of a scene is linked to its memorability. In general, our findings provide valuable information about indoor scene memorability. [ABSTRACT FROM PUBLISHER]

Melatonin confers profound protective effect against myocardial ischemia-reperfusion injury ( MI/ RI). Activation of Notch1/ Hairy and enhancer of split 1 ( Hes1) signaling also ameliorates MI/ RI. We hypothesize that melatonin attenuates MI/ RI-induced oxidative damage by activating Notch1/ Hes1 signaling pathway with phosphatase and tensin homolog deleted on chromosome 10 ( Pten)/ Akt acting as the downstream signaling pathway in a melatonin membrane receptor-dependent manner. Male Sprague Dawley rats were treated with melatonin (10 mg/kg/day) for 4 wk and then subjected to MI/ R surgery. Melatonin significantly improved cardiac function and decreased myocardial apoptosis and oxidative damage. Furthermore, in cultured H9 C2 cardiomyocytes, melatonin (100 μmol/L) attenuated simulated ischemia-reperfusion ( SIR)-induced myocardial apoptosis and oxidative damage. Both in vivo and in vitro study demonstrated that melatonin treatment increased Notch1, Notch1 intracellular domain ( NICD), Hes1, Bcl-2 expressions, and p- Akt/ Akt ratio and decreased Pten, Bax, and caspase-3 expressions. However, these protective effects conferred by melatonin were blocked by DAPT (the specific inhibitor of Notch1 signaling), luzindole (the antagonist of melatonin membrane receptors), Notch1 si RNA, or Hes1 si RNA administration. In summary, our study demonstrates that melatonin treatment protects against MI/ RI by modulating Notch1/ Hes1 signaling in a receptor-dependent manner and Pten/ Akt signaling pathways are key downstream mediators. [ABSTRACT FROM AUTHOR]