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Background: Definitive chemoradiation therapy (dCRT) is the standard treatment for patients with nonsurgical esophageal squamous cell carcinoma (ESCC), yet patients have demonstrated great variations in their responses to dCRT and inevitably progressed following treatment. Methods: To identify prognostic biomarkers, we performed targeted next‐generation sequencing of 416 cancer‐related genes on primary tumors from 47 nonsurgical ESCC patients prior to dCRT treatment. The association between genetic alterations and patients' local recurrence‐free survival (LRFS), progression‐free survival (PFS), and overall survival (OS) was analyzed. Results: TP53 (78% of patients), NOTCH1 (32%), ARID1A (13%), FAT1 (13%), and CDKN2A (13%) were commonly mutated in ESCC patients, while gene amplifications frequently occurred in MCL1 (36%), FGF19 (34%), MYC (32%), CCND1 (27%), ZNF217 (15%), CDKN2A (13%), and YAP1 (11%). Univariate and multivariate analyses of clinical factors and genetic alterations indicated that sex is an independent prognostic factor, with males tending to have better LRFS (hazard ratio [HR], 0.25; 95%CI, 0.08‐0.77, P =.015) and progression‐free survival (PFS) (HR, 0.35; 95%CI, 0.13‐0.93, P =.030) following dCRT. Meanwhile, YAP1 amplification (n = 7) was an adverse prognostic factor, and patients with this alteration demonstrated a tendency toward worse outcomes with shorter LRFS (HR, 4.06; 95%CI, 1.26‐13.14, P =.019) and OS (HR, 2.78; 95%CI, 0.95‐8.17, P =.062). In a subgroup analysis, while sex and M‐stage were controlled, a much stronger negative effect of YAP1 amplification vs wild‐type in LRFS was observed (log‐rank P =.0067). Conclusion: The results suggested that YAP1 amplification is a potentially useful biomarker for predicting treatment outcomes and identifying patients with a high risk of relapse who should be closely monitored. [ABSTRACT FROM AUTHOR]

In this paper, bimetallic sulfide Co9S8/N−C@MoS2 dodecahedral heterogeneous nanocages (DHNCs) are designed and synthesized via pyrolysis and sulfidation. The Co9S8/N−C@MoS2 DHNCs with unique structure and composition display superior lithium storage performance (a reversible capacity of approximate 557 mA h g−1 at 5 A g−1 after 400 cycles) and potassium storage performance (a reversible capacity of about 100 mA h g−1 at 1 A g−1 after 100 cycles). The remarkable electrochemical properties are attributed to the synergistic effect of bimetallic sulfides and the special polyhedral hollow structure with the conductive N‐doped mesoporous carbon. This method could be used to develop new types of electrode materials with a heterogeneous hollow nanocages structure, which could enhance structural stability and mass transport kinetics for lithium‐ion batteries and potassium‐ion batteries. [ABSTRACT FROM AUTHOR]

Previous studies have shown that single‐nucleotide polymorphisms (SNPs) of a disintegrin and metalloproteinase with thrombospondin type 1 motif 4 (ADAMTS4) may involve in the pathogenesis of some diseases. However, it is not clear whether they are associated with hepatocellular carcinoma (HCC). A hospital‐based case‐control study, including 862 cases with HCC and 1120 controls, was conducted to assess the effects of 258 SNPs in the coding regions of ADAMTS4 on HCC risk and prognosis. We found that six SNPs in ADAMTS4 were differential distribution between cases and controls via the primary screening analyses; however, only rs538321148 and rs1014509103 polymorphisms were further identified to modify the risk of HCC (odds ratio: 2.73 and 2.95; 95% confidence interval, 2.28‐3.29 and 2.43‐3.58; P‐value, 5.73 × 10−27 and 1.36 × 10−27, respectively). Significant interaction between these two SNPs and two known causes of hepatitis B virus and aflatoxin B1 were also observed. Furthermore, rs538321148 and rs1014509103 polymorphisms were associated not only with clinicopathological features of tumor such as tumor stage and grade, microvessel density, and vessel metastasis, but with poor overall survival. Additionally, these SNPs significantly downregulated ADATMS4 expression in tumor tissues. These data suggest that SNPs in the coding region of ADAMTS4, such as rs538321148 and rs1014509103, may be potential biomarkers for predicting HCC risk and prognosis. [ABSTRACT FROM AUTHOR]

Background: Patients with brain metastases (BMs) have a poor prognosis and limited therapeutic options. Lung cancer is the most common primary malignancy giving rise to BMs; thus, understanding the molecular mechanisms behind increased BM risk is essential for identifying therapeutic targets and developing effective interventions.Methods: Sixty-one patients who underwent surgical resection of primary non-small cell lung cancer (NSCLC) and BMs were retrospectively studied. Comprehensive genomic profiling of primary NSCLC and matched BMs was performed with next-generation sequencing targeting 416 cancer-relevant genes.Results: Mutations of major drivers, including EGFR, KRAS, TP53, and ALK, were highly concordant between primary NSCLC and matched BMs (>80%), whereas discordance suggested the unique genomic evolution and oncogenic mechanisms of NSCLC BMs. BMs also demonstrated higher levels of copy number variations in comparison with primary NSCLC. Furthermore, the alterations of genes encoding CDK4/CCND1, CDKN2A/2B, and PI3K signaling pathways were enriched in BMs, and this suggested their correlation with increased metastatic risk. Indeed, patients with activated PI3K signaling in their primary NSCLC had significantly shorter BM-free survival (hazard ratio, 8.49; P = .0005). In addition, mutated TP53 or an activated WNT pathway via CTNNB1, APC, and AXIN2 mutations trended toward shorter BM-free intervals but not significantly so.Conclusions: These findings yield detailed insights into the genomic complexity and heterogeneity of primary NSCLC and matched BMs. This study highlights the significant correlation of PI3K signaling with increased metastatic risk in patients with NSCLC and identifies genomic alterations enriched in NSCLC BMs that could serve as prognostic markers and potential therapeutic targets for treating patients with NSCLC BMs. [ABSTRACT FROM AUTHOR]

Purpose: To automatically and precisely detect a large quantity of landmark pairs between two lung computed tomography (CT) images to support evaluation of deformable image registration (DIR). We expect that the generated landmark pairs will significantly augment the current lung CT benchmark datasets in both quantity and positional accuracy. Methods: A large number of landmark pairs were detected within the lung between the end‐exhalation (EE) and end‐inhalation (EI) phases of the lung four‐dimensional computed tomography (4DCT) datasets. Thousands of landmarks were detected by applying the Harris‐Stephens corner detection algorithm on the probability maps of the lung vasculature tree. A parametric image registration method (pTVreg) was used to establish initial landmark correspondence by registering the images at EE and EI phases. A multi‐stream pseudo‐siamese (MSPS) network was then developed to further improve the landmark pair positional accuracy by directly predicting three‐dimensional (3D) shifts to optimally align the landmarks in EE to their counterparts in EI. Positional accuracies of the detected landmark pairs were evaluated using both digital phantoms and publicly available landmark pairs. Results: Dense sets of landmark pairs were detected for 10 4DCT lung datasets, with an average of 1886 landmark pairs per case. The mean and standard deviation of target registration error (TRE) were 0.47 ± 0.45 mm with 98% of landmark pairs having a TRE smaller than 2 mm for 10 digital phantom cases. Tests using 300 manually labeled landmark pairs in 10 lung 4DCT benchmark datasets (DIRLAB) produced TRE results of 0.73 ± 0.53 mm with 97% of landmark pairs having a TRE smaller than 2 mm. Conclusion: A new method was developed to automatically and precisely detect a large quantity of landmark pairs between lung CT image pairs. The detected landmark pairs could be used as benchmark datasets for more accurate and informative quantitative evaluation of DIR algorithms. [ABSTRACT FROM AUTHOR]

Nanopore biosensors, as an extremely sensitive tool, are widely applied to single‐molecule analysis. Compared with the commonly used α‐hemolysin, aerolysin nanopore possess a narrower channel, which distributes the abundant charged residues in the lumen. We replaced the commonly used potassium cations (K+) with tetramethylammonium cations (TMA+) to explore the cation effects. Experimental results demonstrate that the blockage of oligonucleotides in the TMA+ system is distinctly more considerable than that in K+ system. In particular, the blockade currents of Poly(dA)5 are very closed to 0 pA. In addition, the capture rate of oligonucleotides is distinctly increased, and it is speculated that amphipathic TMA+ can enhance the affinity of aerolysin nanopore for oligonucleotides. Furthermore, the estimated effective charges (Zinside) of oligonucleotides inside aerolysin nanopore in two solutions suggest that the screening of K+ on Poly(dA)3, Poly(dA)4, and Poly(dA)5 is more effective than that for TMA+. This report deepens our understanding of the effects of cations in electrolyte. [ABSTRACT FROM AUTHOR]

The weight function method is a powerful method for the determination of key parameters of stress intensity factors and crack opening displacements that are fundamental for crack analyses in fracture mechanics. The method has a remarkable computational efficiency without compromising solution accuracy and is especially suited for cracks in real‐world components with complex stress gradients. A critical issue for successful development and reliable application of the weight function method is how to achieve verifiable and high solution accuracy. This paper provides several reflections on the current state of the art in weight function methods, including a brief historical perspective and description of several analytical and numerical weight methods, with main focus on the two‐dimensional (2D) analytical approaches. A variety of typical application examples are presented. A platform for point‐by‐point accuracy assessment by using the Green's functions is established on a completely independent numerical approach with validated accuracy. Rigorous and systematic verification of the accuracy levels of different 2D analytical weight function approaches are conducted using several benchmark crack geometries. The sources of inaccuracy of different analytical weight function methods are analysed. A brief account on weight function methods for analysing three‐dimensional (3D) crack problems with arbitrary univariant and bivariant stress distributions is provided. [ABSTRACT FROM AUTHOR]

On the basis of theoretical models and calculations, CN‐substituted difuropyrene systems have been investigated as potential singlet fission (SF) candidates for solar cell applications. Calculations indicate that the fusion of difuran and pyrene in different arrangements could introduce variable diradical properties, and the fused compound ab‐trans‐DFP has moderate diradical character (y0=0.45) while satisfying the main condition (ΔE1) of SF. Furthermore, CN‐substituted ab‐trans‐DFP (substituted at distinct positions) is used to adjust the frontier molecular orbital energy level to satisfy the SF secondary condition (ΔE2). Interestingly, the position of the cyano substituents has almost no effect on the diradical character, which can be explained by the insensitivity of the ring aromaticity to the cyano position. Both time dependent density functional theory (TD‐DFT) and multi‐configurational self‐consistent field (MCSCF) results confirm that the 4‐ and 5‐position cyano‐substituted ab‐trans‐DFP derivatives can satisfy the two energy conditions and may become potential SF candidates. This work provides an effective strategy for the rational design of new suitable diradical SF candidates, and it is expected that more polycyclic aromatic hydrocarbons such as pyrene can achieve SF conditions by chemical modification, such as fusion or substitution, to adjust the diradical character and the vertical excitation energy. [ABSTRACT FROM AUTHOR]

A fluorophilic fluorescent probe based on a perfluoroalkyl‐substituted bis(binaphthyl) compound was designed and synthesized. It displayed a highly enantioselective fluorescence response toward structurally diverse amino acids in a biphasic fluorous/aqueous system with enantiomeric fluorescent enhancement ratio (ef; ΔID/ΔIL) values up to 45.2 (histidine). It can be used to determine the enantiomeric compositions of amino acids and also allows the amino acid enantiomers to be visually discriminated. NMR and mass‐spectroscopic investigations provided insights into the observed high enantioselectivity. This biphasic fluorescent recognition was used to determine the enantiomeric composition of the crude phenylalanine products generated by an enzyme‐catalyzed asymmetric hydrolysis under various reaction conditions. The fluorous‐phase‐based fluorescence measurement under the biphasic conditions was able to minimize the interference of other reaction components and thus has potential in asymmetric reaction screening. [ABSTRACT FROM AUTHOR]

Kinase domain duplications of the epidermal growth factor receptor (EGFR‐KDD) have been identified and implicated to be oncogenic in nonsmall cell lung cancers (NSCLCs). However, its prevalence and clinical contributions in lung cancer are largely unknown. Here, we conducted a multicenter record review of 10,759 NSCLC patients who underwent genetic testing using next‐generation sequencing (NGS) targeting EGFR exons and the introns involved in EGFR‐KDD rearrangements. EGFR‐KDDs were identified in a total of 13 patients, which is approximately 0.12% of the total population reviewed, and also consisted of 0.24% (13/5394) of EGFR mutation‐positive patients. A total of 85% of patients (11/13) were identified with the canonical EGFR‐KDD duplication of exons 18–25, while the remaining two cases harbored duplications of EGFR exons 14–26 and exons 17–25, which have not been previously described. Importantly, none of the 13 patients had other coexisting driver mutations, highlighting the potential oncogenic role of this type of alteration. Three out of five patients who had exon 18–25 duplications showed partial antitumor responses to targeted therapies, while the other two patients demonstrated no clinical improvement. Furthermore, our data suggested that the EGFR T790 M mutation and EGFR amplification may represent the major resistance mechanisms against targeted therapies in tumors bearing EGFR‐KDD. In summary, our findings provide valuable insight into the prevalence of EGFR‐KDDs in NSCLCs and their clinical outcomes to targeted therapies. What's new? A rare class of mutation could provide a therapeutic target for lung cancer. Many NSCLCs arise with mutations in the EGFR tyrosine kinase domain, and treatment with EGFR tyrosine kinase inhibitors often boosts survival in these patients. Usually, these are deletions or point mutations, but sometimes the mutation is a kinase domain duplication (KDD). These authors investigated how frequently EGFR‐KDDs occur, and whether tyrosine kinase inhibitors work against them. By reviewing records from thousands of NSCLC patients, they discovered 13 EGFR‐KDDs. Tyrosine kinase inhibitors did suppress some of the tumors, although resistance arose in the event of additional EGFR mutations. [ABSTRACT FROM AUTHOR]

Open‐pit mining results in large amounts of degraded lands that require ecological recovery. Adequate‐species selection for ecological recovery is of great importance. In this study, field investigations along the disturbance gradients (marginal area, restoration area, and control area) in a manganese ore deposit of Guangxi in Southern China were carried out. We screened the adequate species from two aspects. In the marginal area, the result of corrected Akaike information criterion revealed that Mn was the most important soil parameter affecting vegetation diversity. Cyclosorus parasiticus (L.) Farwell., Setaria viridis (L.) Beauv., Mimosa sepiaria Benth., and Bidens pilosa L. were selected for their abilities to adapt to high‐Mn‐content soils. In the restoration area and control area, we combined important values and field performance (Dickson quality index, DQI) of species to select adequate species. Miscanthus sinensis Anderss. and Arundinella hirta (Thunb.) Tanaka were selected using the similar DQI (p > 0.05) in both areas. In summary, C. parasiticus (L.) Farwell., S. viridis (L.) Beauv., M. sinensis Anderss., and A. hirta (Thunb.) Tanaka were selected as adequate species because of their high potential to adapt to these disturbed sites. Our results and methodology could have a demonstrating effect for restoration programmes in manganese ore mining areas of China. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to expedite the contouring process for MRI‐guided adaptive radiotherapy (MR‐IGART), a convolutional neural network (CNN) deep‐learning (DL) model is proposed to accurately segment the liver, kidneys, stomach, bowel and duodenum in 3D MR images. Methods: Images and structure contours for 120 patients were collected retrospectively. Treatment sites included pancreas, liver, stomach, adrenal gland, and prostate. The proposed DL model contains a voxel‐wise label prediction CNN and a correction network which consists of two sub‐networks. The prediction CNN and sub‐networks in the correction network each includes a dense block which consists of twelve densely connected convolutional layers. The correction network was designed to improve the voxel‐wise labeling accuracy of a CNN by learning and enforcing implicit anatomical constraints in the segmentation process. Its sub‐networks learn to fix the erroneous classification of its previous network by taking as input both the original images and the softmax probability maps generated from its previous sub‐network. The parameters of each sub‐network were trained independently using piecewise training. The model was trained on 100 datasets, validated on 10 datasets and tested on the remaining 10 datasets. Dice coefficient, Hausdorff distance (HD) were calculated to evaluate the segmentation accuracy. Results: The proposed DL model was able to segment the organs with good accuracy. The correction network outperformed the conditional random field (CRF), a most comparable method that is usually applied as a post‐processing step. For the 10 testing patients, the average Dice coefficients were 95.3 ± 0.73, 93.1 ± 2.22, 85.0 ± 3.75, 86.6 ± 2.69, and 65.5 ± 8.90 for liver, kidneys, stomach, bowel, and duodenum, respectively. The mean Hausdorff Distance (HD) were 5.41 ± 2.34, 6.23 ± 4.59, 6.88 ± 4.89, 5.90 ± 4.05, and 7.99 ± 6.84 mm, respectively. Manual contouring, as to correct the automatic segmentation results, was four times as fast as manual contouring from scratch. Conclusion: The proposed method can automatically segment the liver, kidneys, stomach, bowel, and duodenum in 3D MR images with good accuracy. It is useful to expedite the manual contouring for MR‐IGART. [ABSTRACT FROM AUTHOR]

Doped clusters by Si16 cage encapsulating group‐IV metal atoms (M@Si16, M = Ti, Zr and Hf) are computationally investigated by both density functional theory (DFT) and high‐level CCSD(T) method. Their low‐energy structures are globally searched using a genetic algorithm based on DFT. The ground state structures of neutral and anionic M@Si16 are determined by calculating the vertical and adiabatic detachment energies and comparing them with the experimental data. For neutral Ti@Si16, the Frank‐Kasper (FK) deltahedron with Td symmetry and distorted FK isomer with C3v symmetry are nearly degenerate as the ground state and may coexist in laboratory, while the distorted FK isomer is the most probable structure for Ti@Si16− anion. For neutral and anionic Zr@Si16 and Hf@Si16 clusters, the ground states at finite temperatures up to 300 K are the fullerene‐like D4d bitruncated square trapezohedron. These theoretical results establish a more complete picture for the most stable structures of M@Si16 clusters, which possess large gaps and may serve as building blocks for electronic and optoelectronic applications. By comparing the simulated photoelectron spectra with the experimental data, the ground states of the M@Si16 (M = Ti, Zr, and Hf) clusters were identified. The FK1 isomer is the most probable ground state for the Ti@Si16− anion, and the f isomer is always the lowest‐energy state at temperatures up to 300 K for Zr@Si16 and Hf@Si16 clusters. [ABSTRACT FROM AUTHOR]

Background: ALK‐tyrosine kinase inhibitors (TKIs) have been proven effective for treating ALK‐positive non‐small cell lung cancer (NSCLC), although patients present with variable responses and disease progression courses. The detailed underlying molecular mechanisms require further investigation to yield a better prognosis. Methods: Targeted next‐generation sequencing (NGS) mutation profiling was performed on samples from 42 NSCLC patients confirmed positive for ALK rearrangements by fluorescence in situ hybridization or immunohistochemistry who experienced disease progression after crizotinib treatment. Results: ALK rearrangements were not confirmed in six patients (14%) with other potential oncogenic drivers identified by NGS, who therefore did not respond to crizotinib and had significantly shorter overall survival (OS) compared to NGS ALK ‐positive patients. Fifteen ALK activating mutations were detected in 8 out of 26 post‐treatment samples (31%), among which ALK L1196M and G1269A were the most common acquired mutations detected in half of the patients with ALK activating mutations. Dynamic monitoring of the genetic evolution in one patient revealed both spatial and temporal heterogeneity of resistant mechanisms during different ALK‐TKI treatment courses. Activation of ALK downstream or bypass pathways was detected in patients without ALK activating mutations, such as genetic alterations in PIK3CA, MET, and KRAS. Interestingly, we identified two patients with acquired mutations in the DNA mismatch repair gene POLE, which resulted in a dramatically increased tumor mutation burden, and might contribute to the poor response to crizotinib. Conclusions: Heterogeneous resistant mechanisms have been identified and correlate to diverse responses to crizotinib. Comprehensive and dynamic mutation profiling is required to better predict clinical outcomes. [ABSTRACT FROM AUTHOR]

Osteosarcoma is a primary malignant bone tumor that has a high potential to metastasize to lungs. Little is known about the mechanisms underlying the dissemination of OS cancer cells to lungs. We performed whole exome sequencing of 13 OS primary tumors, with matched lung metastases and normal tissues. Phylogenetic analyses revealed that lung metastatic tumors often harbor clones that are nonexistent or rare in the matched primary OS tumors. Spatially and temporally separated lung metastases were from parallel seeding events with a polyphyletic pattern. Loss of TP53 or RB1 is among the early events during OS tumorigenesis, while loss of PTEN is involved at the later stages associated with lung metastases. Finally, KEAP1 was identified as a novel biomarker for increased metastatic risk. Patients whose primary tumors harbored KEAP1 amplification have significantly poorer lung‐metastasis free survival. This finding was validated in two independent datasets. Further, in vitro experiments exhibited that KEAP1 depletion suppressed the invasion of OS cells. Our findings uncover the patterns of clonal evolution during OS progression and highlight KEAP1 as a novel candidate associated with the risk of lung metastasis in OS patients. [ABSTRACT FROM AUTHOR]

Abstract: Hypertension is an increasingly serious public‐health challenge worldwide. The traditional blood pressure measurement method could easily and reliably detect blood pressure. However, the delayed symptom onset may influence the screening of essential hypertension (EH). In addition, EH is significantly associated to cardiovascular disease, stroke and kidney disease. Hence, it is urgent to define associated biomarkers with early diagnosis potential for EH. A dried blood spot method integrated with direct infusion mass spectrometry (MS) metabolomic analysis was applied for the detection of metabolites toward 87 EH patients and 91 healthy controls (HC). Multiple algorithms were run on training set (62 EH and 64 HC) for selecting differential metabolites as potential biomarkers. A test set (25 EH and 27 HC) was used to verify and evaluate selected potential biomarkers. A novel blood biomarker model based on Gly, Orn, C10, Orn/Cit, Phe/Tyr, and C5‐OH/C8 exhibited potential to differentiate EH patients from HC individuals, with a sensitivity of 0.8400 and a specificity of 0.8889 in test set. The metabolomic analysis of EH is beneficial to the definition of disease‐associated biomarkers and the development of new diagnostic approaches. © 2018 IUBMB Life, 70(8):777–785, 2018 [ABSTRACT FROM AUTHOR]

Premise of the Study: Microsatellite markers were developed for Smilax rotundifolia (Smilacaceae), an understory vine widely distributed in eastern North America, to investigate genetic diversity and structure. Cross‐amplification was tested in three congeneric species: S. china, S. riparia, and S. walteri. Methods and Results: A total of 6153 simple sequence repeat primer pairs were detected from the de novo–assembled transcriptome data (88,3962 contigs) of S. rotundifolia. Thirty‐three polymorphic microsatellite loci were selected for further analysis among 96 individuals representing four natural populations of the species. The number of alleles ranged from two to 15, and 87.9% of the developed primer pairs could be cross‐amplified in at least one of three congeneric Smilax species. Conclusions: The simple sequence repeat markers developed in this study will facilitate further studies on genetic diversity and phylogeographic patterns of S. rotundifolia and provide additional potential microsatellite resources for other Smilax species. [ABSTRACT FROM AUTHOR]

Our recent studies demonstrate that X‐linked inhibitor of apoptosis protein (XIAP) is essential for regulating colorectal cancer invasion. Here, we discovered that RhoGDIβ was a key XIAP downstream effector mediating bladder cancer (BC) invasion in vitro and in vivo. We found that both XIAP and RhoGDIβ expressions were consistently elevated in BCs of N‐butyl‐N‐(4‐hydroxybutyl)‐nitrosamine (BBN)‐treated mice in comparison to bladder tissues from vehicle‐treated mice and human BCs in comparison to the paired adjacent normal bladder tissues. Knockdown of XIAP attenuated RhoGDIβ expression and reduced cancer cell invasion, whereas RhoGDIβ expression was attenuated in BBN‐treated urothelium of RING‐deletion knockin mice. Mechanistically, XIAP stabilized RhoGDIβ mRNA by its positively regulating nucleolin mRNA stability via Erks‐dependent manner. Moreover, ectopic expression of GFP‐RhoGDIβ in T24T(shXIAP) cells restored its lung metastasis in nude mice. Our results demonstrate that XIAP‐regulated Erks/nucleolin/RhoGDIβ axis promoted BC invasion and lung metastasis. [ABSTRACT FROM AUTHOR]

Abstract: Human GWAS and Mendelian genetic studies have linked polymorphic variants and mutations in the human uromodulin gene (UMOD) with chronic kidney disease. The primary function of this kidney‐specific and secreted protein remains elusive. This study investigated whether UMOD deficiency modified responses to unilateral ureteral obstruction (UUO)‐induced kidney injury. Kidneys harvested from groups of wild‐type (UMOD+/+) and knockout (UMOD−/−) male mice (n = 7–10 each) were studied on days 7, 14, and 21. Compared to sham kidneys, UMOD protein levels increased 9–13x after UUO and were associated with increased urinary UMOD levels. Kidney KIM‐1 protein levels were higher in the UMOD−/− groups at all time‐points (4–14x). The UMOD−/− groups also had higher KIM‐1 kidney‐to‐urine relative ratios (5–35x). In vitro studies using KIM‐1 expressing 769‐P cells showed lower KIM‐1 levels in the presence of UMOD protein. Levels of proapoptotic genes and the epithelial cell apoptotic protein marker M30 were significantly lower in the UMOD−/− groups. Both M30 and KIM‐1 colocalized with intraluminal UMOD protein deposits. Interstitial inflammation was less intense in the UMOD−/− groups. Renal fibrosis severity (kidney collagen mRNA and protein) was similar in both genotypic groups on days 7, 14, and 21. Our findings suggest a role for UMOD‐dependent inhibition of KIM‐1 expression and its apoptotic cell scavenging responses during chronic obstruction‐associated tubular injury. [ABSTRACT FROM AUTHOR]

Abstract: Forecasting the intensity of tropical cyclones is a challenging problem. Rapid intensification is often preceded by the formation of “hot towers” near the eyewall. Driven by strong release of latent heat, hot towers are high‐reaching tropical cumulonimbus clouds that penetrate the tropopause. Hot towers are a potentially important source of stratospheric gravity waves. Using 13.5 years (2002–2016) of Atmospheric Infrared Sounder observations of stratospheric gravity waves and tropical cyclone data from the International Best Track Archive for Climate Stewardship, we found empirical evidence that stratospheric gravity wave activity is associated with the intensification of tropical cyclones. The Atmospheric Infrared Sounder and International Best Track Archive for Climate Stewardship data showed that strong gravity wave events occurred about twice as often for tropical cyclone intensification compared to storm weakening. Observations of stratospheric gravity waves, which are not affected by obscuring tropospheric clouds, may become an important future indicator of storm intensification. [ABSTRACT FROM AUTHOR]

Acute ischaemia causes a significant loss of blood vessels leading to deterioration of organ function. Multiple ischaemic conditions are associated with up-regulation of activin A, but its effect on endothelial cells ( EC) in the context of hypoxia is understudied. This study evaluated the role of activin A in vasculogenesis in hypoxia. An in vitro vasculogenesis model, in which EC were cocultured with adipose stromal cells ( ASC), was used. Incubation of cocultures at 0.5% oxygen led to decrease in EC survival and vessel density. Hypoxia up-regulated inhibin BA (monomer of activin A) mRNA by 4.5-fold and activin A accumulation in EC-conditioned media by 10-fold, but down-regulated activin A inhibitor follistatin by twofold. Inhibin BA expression was also increased in human EC injected into ischaemic mouse muscles. Activin A secretion was positively modulated by hypoxia mimetics dimethyloxalylglycine and desferrioxamine. Silencing HIF1α or HIF2α expression decreased activin A secretion in EC exposed to hypoxia. Introduction of activin A to cocultures decreased EC number and vascular density by 40%; conversely, blockade of activin A expression in EC or its activity improved vasculogenesis in hypoxia. Activin A affected EC survival directly and by modulating ASC paracrine activity leading to diminished ability of the ASC secretome to support EC survival and vasculogenesis. In conclusion, hypoxia up-regulates EC secretion of activin A, which, by affecting both EC and adjacent mesenchymal cells, creates a micro-environment unfavourable for vasculogenesis. This finding suggests that blockade of activin A signalling in ischaemic tissue may improve preservation of the affected tissue. [ABSTRACT FROM AUTHOR]

BACKGROUND Carboxylesterases (CCEs) are one of three large detoxification enzyme families. Some CCEs are active on synthetic insecticides with ester structures. Anopheles sinensis is an important malaria vector in eastern Asia. This study identified and characterized the CCE genes in the A. sinensis genome and determined CCE genes associated with pyrethroid resistance using RNA sequencing (RNA-seq) and quantitative reverse transcription − polymerase chain reaction (qRT-PCR), in A. sinensis from Anhui, Chongqing, and Yunnan in China. RESULTS Fifty-seven putative CCEs were identified and placed into three classes, 12 subfamilies and 14 clades through phylogenetic and homology analyses. Exon sizes ranged from 31 to 4317 bp, with 49 CCEs having two to five exons and eight having six to 11 exons. A total of 183 introns were recognized with sizes ranging from 31 to 4317 bp. The 57 CCEs were located on 14 scaffolds, with 70% located on four scaffolds. The alpha-esterase subfamily was significantly expanded compared with that of Anopheles gambiae. In a pyrethroid-resistant strain, RNA-seq detected five upregulated CCE genes and qRT-PCR detected 12 upregulated CCE genes. The α-esterase 10 ( AsAe10) and acetylcholinesterase 1 ( AsAce1) genes were the main CCE genes associated with pyrethroid resistance. CONCLUSION This information will be useful for further study of the CCE gene family and pyrethroid resistance mechanisms mediated by CCEs. © 2017 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Cardiac patch is considered a promising strategy for enhancing stem cell therapy of myocardial infarction (MI). However, the underlying mechanisms for cardiac patch repairing infarcted myocardium remain unclear. In this study, we investigated the mechanisms of PCL/gelatin patch loaded with MSCs on activating endogenous cardiac repair. PCL/gelatin patch was fabricated by electrospun. The patch enhanced the survival of the seeded MSCs and their HIF-1α, Tβ 4, VEGF and SDF-1 expression and decreased CXCL14 expression in hypoxic and serum-deprived conditions. In murine MI models, the survival and distribution of the engrafted MSCs and the activation of the epicardium were examined, respectively. At 4 weeks after transplantation of the cell patch, the cardiac functions were significantly improved. The engrafted MSCs migrated across the epicardium and into the myocardium. Tendency of HIF-1α, Tβ 4, VEGF, SDF-1 and CXCL14 expression in the infarcted myocardium was similar with expression in vitro. The epicardium was activated and epicardial-derived cells (EPDCs) migrated into deep tissue. The EPDCs differentiated into endothelial cells and smooth muscle cells, and some of EPDCs showed to have differentiated into cardiomyocytes. Density of blood and lymphatic capillaries increased significantly. More c-kit+ cells were recruited into the infarcted myocardium after transplantation of the cell patch. The results suggest that epicardial transplantation of the cell patch promotes repair of the infarcted myocardium and improves cardiac functions by enhancing the survival of the transplanted cells, accelerating locality paracrine, and then activating the epicardium and recruiting endogenous c-kit+ cells. Epicardial transplantation of the cell patch may be applied as a novel effective MI therapy. [ABSTRACT FROM AUTHOR]

Background To investigate the value of Ubiquitin specific peptidase 8 (USP8), Chitinase 3-like 1 (YKL40), Heat shock protein 90a (HSP90α), glutathione S-transferase P1 (GSTP1), carcinoembryonic antigen (CEA), neuron specific enolase (NSE) and cytokeratin fragment antiogen 21-1 (CYFRA21-1) in bronchoalveolar lavage fluid (BALF) and serum for diagnosis in patients with peripheral lung cancer. Methods The concentration of these markers were measured in 50 patients with peripheral lung cancer and 50 patients with benign lung diseases by using enzyme-linked immuno sorbent assay methods. Results There were significant differences between the peripheral lung cancer group and the benign lung disease group ( P < 0.05) in the BALF of USP8, YKL40, HSP90α, CEA, NSE and CYFRA21-1. There were significant differences between the peripheral lung cancer group and the benign lung disease group ( P < 0.05) in the serum of HSP90α and CEA. There were no differences in others. There were no correlation between the concentration of all markers and age, histological type, TNM stage (I-IV). There was a weak correlation between the primary foci diameters and the concentration of YKL40 in BALF. (Pearson's correlation: 0.203, P = 0.048) The diagnostic efficiencies of USP8, YKL40, HSP90α were superior to CYFRA21-1 and NSE, being lower CEA. Conclusion: Detection of tumor markers in BALF was superior to serum specimens. The measurement of USP8, HSP90α and YKL40 in BALF had more clinical value for the diagnosis of peripheral pulmonary carcinoma. [ABSTRACT FROM AUTHOR]

Although two-dimensional (2D) metal oxide/sulfide hybrid nanostructures have been synthesized, the facile preparation of ultrathin 2D nanosheets in high yield still remains a challenge. Herein, we report the first high-yield preparation of solution-processed ultrathin 2D metal oxide/sulfide hybrid nanosheets, that is, Ti xTa1− xS yO z ( x=0.71, 0.49, and 0.30), from Ti xTa1− xS2 precursors. The nanosheet exhibits strong absorbance in the near-infrared region, giving a large extinction coefficient of 54.1 L g−1 cm−1 at 808 nm, and a high photothermal conversion efficiency of 39.2 %. After modification with lipoic acid-conjugated polyethylene glycol, the nanosheet is a suitable photothermal agent for treatment of cancer cells under 808 nm laser irradiation. This work provides a facile and general method for the preparation of 2D metal oxide/sulfide hybrid nanosheets. [ABSTRACT FROM AUTHOR]

ABSTRACT The Sarcolipin (SLN) is a single trans-membrane protein that can self-assembly to dimer and oligomer for playing importantphysiological function. In this work, we addressed the dimerization of wild type SLN (wSLN) and its mutants (mSLNs) - I17A and I20A, using both coarse-grained (CG) and atomistic (AT) molecular dynamics (MD) simulations. Our results demonstrated that wSLN homodimer assembled as a left-handed helical complex, while mSLNs heterodimers assembled as right-handed complexes. Analysis of residue-residue contacts map indicated that isoleucine (Ile)-leucione (Leu) zipper domain played an important role in dimerization. The potential of mean force (PMF) demonstrated that wSLN homodimer was more stable than mSLNs heterodimers. Meanwhile, the mSLNs heterodimers preferred right-handed rather than left-handed helix. AT-MD simulations for wSLN and mSLNs were also in line with CG-MD simulations. These results provided the insights for understanding the mechanisms of SLNs self-assembling. Proteins 2017; 85:1065-1077. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The ability to monitor and quantify glutathione (GSH) in live cells is essential in order to gain a detailed understanding of GSH-related pathological events. However, owing to their irreversible response mechanisms, most existing fluorescent GSH probes are not suitable for this purpose. We have developed a ratiometric fluorescent probe (QG- 1) for quantitatively monitoring cellular GSH. The probe responds specifically and reversibility to GSH with an ideal dissociation constant ( Kd) of 2.59 m m and a fast response time ( t1/2=5.82 s). We also demonstrate that QG- 1 detection of GSH is feasible in a model protein system. QG- 1 was found to have extremely low cytotoxicity and was applied to determine the GSH concentration in live HeLa cells (5.40±0.87 m m). [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third leading causes of cancer mortality, and the early-stage detection could significantly enhance survival rates. Cancer influences the important metabolic pathways and the changes in metabolite levels had been used in many studies as the potential biomarkers. This study is aimed at screening metabolite biomarkers with CRC diagnosis potentials. The direct infusion mass spectrometry (MS) metabolomic analysis based on dried blood spot was used to distinguish CRC from polyp. The target metabolites were composed of 23 amino acids and 26 acylcarnitines. The 21 metabolites in blood were selected via multivariate analysis. A regression model was established based on parameters C16, Arg, C4/C8, C5/C3, Val, Phe/Tyr, Ala, C4/C3. Tenfold cross validation (CV) method was used to test this model and showed sensitivity of 81.18% and specificity of 83.95%. The metabolomic analysis is a practicable method for CRC detection. The use of direct MS analysis in metabolite screening could be finished in several minutes and served as a higher-throughput method to distinguish CRC and polyps. © 2017 IUBMB Life, 69(5):347-354, 2017 [ABSTRACT FROM AUTHOR]

The incorporation of metal-organic frameworks (MOFs) into membrane-shaped architectures is of great importance for practical applications. The currently synthesized MOF-based membranes show many disadvantages, such as poor compatibility, low dispersity, and instability, which severely limit their utility. Herein, we present a general, facile, and robust approach for the synthesis of MOF-based composite membranes through the in situ growth of MOF plates in the channels of anodized aluminum oxide (AAO) membranes. After being used as catalysis reactors, they exhibit high catalytic performance and stability in the Knoevenagel condensation reaction. The high catalytic performance might be attributed to the intrinsic structure of MOF-based composite membranes, which can remove the products from the reaction zone quickly, and prevent the aggregation and loss of catalysts during reaction and recycling process. [ABSTRACT FROM AUTHOR]

Praeruptorin A (PA) and B (PB) are two important compounds isolated from Bai-hua Qian-hu and have been reported to exert multiple biochemical and pharmacological activities. The present study aims to determine the inhibition of PA and PB on the activity of important phase II drug-metabolizing enzymes uridine 5'-diphospho-glucuronosyltransferase (UGTs) isoforms. In vitro UGT incubation system was used to determine the inhibition potential of PA and PB on the activity of various UGT isoforms. In silico docking was performed to explain the inhibition difference between PA and PB towards the activity of UGT1A6. Inhibition behaviour was determined, and in vitro-in vivo extrapolation was performed by using the combination of in vitro inhibition kinetic parameter (Ki ) and in vivo exposure level of PA. Praeruptorin A (100 μM) exhibited the strongest inhibition on the activity of UGT1A6 and UGT2B7, with 97.8% and 90.1% activity inhibited by 100 μM of PA, respectively. In silico docking study indicates the significant contribution of hydrogen bond interaction towards the stronger inhibition of PA than PB towards UGT1A6. Praeruptorin A noncompetitively inhibited the activity of UGT1A6 and competitively inhibited the activity of UGT2B7. The inhibition kinetic parameter (Ki ) of PA towards UGT1A6 and UGT2B7 was calculated to be 1.2 and 3.3 μM, respectively. The [I]/Ki value was calculated to be 15.8 and 5.8 for the inhibition of PA on UGT1A6 and UGT2B7, indicating high inhibition potential of PA towards these two UGT isoforms in vivo. Therefore, closely monitoring the interaction between PA and drugs mainly undergoing UGT1A6 or UGT2B7-catalyzed metabolism is very necessary. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Samarium and nitrogen co-doped Bi2WO6 nanosheets were successfully synthesized by using a hydrothermal method. The crystal structures, morphology, elemental compositions, and optical properties of the prepared samples were investigated. The incorporation of samarium and nitrogen ions into Bi2WO6 was proved by X-ray diffraction, energy dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy. UV/Vis diffuse reflectance spectroscopy indicated that the samarium and nitrogen co-doped Bi2WO6 possessed strong visible-light absorption. Remarkably, the samarium and nitrogen co-doped Bi2WO6 exhibited higher photocatalytic activity than single-doped and pure Bi2WO6 under visible-light irradiation. Radical trapping experiments indicated that holes (h+) and superoxide radicals ( .O2−) were the main active species. The results of photoluminescence spectroscopy and photocurrent measurements demonstrated that the recombination rate of the photogenerated electrons and holes pairs was greatly depressed. The enhanced activity was attributed to the synergistic effect of the in-built Sm3+/Sm2+ redox pair centers and the N-doped level. The mechanism of the excellent photocatalytic activity of Sm-N-Bi2WO6 is also discussed. [ABSTRACT FROM AUTHOR]

(C) The invasion abilities of BECN1 knockdown in UMUC3 cells were evaluated in comparison to their vector transfectants using a BD BioCoatTM MatrigelTM Invasion Chamber applied with the matrigel. ATG7 Promotes Bladder Cancer Invasion via Autophagy-Mediated Increased ARHGDIB mRNA Stability A) The invasion abilities of the indicated cells were evaluated. gl GLO:I6Z7/17nov21:advs202104365-fig-0003.jpg PHOTO (COLOR): S1 (A) The potential microRNAs binding sites in ATG7 mRNA 3'-UTR were analyzed using the TargetScan, PicTar, and miRanda databases. [Extracted from the article]

Sertoli cells ( SCs) possess inherent immunosuppressive properties and are major contributors to the immunoprivileged status of mammalian testis. SCs have been reported to inhibit the activation of B cells, T cells and natural killer cells but not dendritic cells ( DCs). Herein, we present evidence that co-culture with SCs results in a persistent state of DC immaturity characterized by down-regulation of the surface molecules I-A/E, CD80, CD83, CD86, CCR7 and CD11c, as well as reduced production of pro-inflammatory cytokines. SC-conditioned DCs ( SC- DCs) displayed low immunogenicity and enhanced immunoregulatory functions, including the inhibition of T-cell proliferation and the promotion of Foxp3+ regulatory T-cell development. Mechanistically, the activation of p38, extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription 3 was suppressed in SC- DCs. More importantly, we demonstrate that galectin-1 secreted by SCs plays a pivotal role in the differentiation of functionally tolerogenic SC- DCs. These findings further support the role of SCs in maintaining the immunoprivileged environment of the testis and provide a novel approach to derive tolerogenic DCs, which may lead to alternative therapeutic strategies for the treatment of immunopathogenic diseases. [ABSTRACT FROM AUTHOR]

Background Targeted therapies including monoclonal antibodies and small molecule inhibitors have dramatically changed the treatment of cancer over past 10 years. Their therapeutic advantages are more tumor specific and with less side effects. For precisely tailoring available targeted therapies to each individual or a subset of cancer patients, next-generation sequencing ( NGS) has been utilized as a promising diagnosis tool with its advantages of accuracy, sensitivity, and high throughput. Methods We developed and validated a NGS-based cancer genomic diagnosis targeting 115 prognosis and therapeutics relevant genes on multiple specimen including blood, tumor tissue, and body fluid from 10 patients with different cancer types. The sequencing data was then analyzed by the clinical-applicable analytical pipelines developed in house. Results We have assessed analytical sensitivity, specificity, and accuracy of the NGS-based molecular diagnosis. Also, our developed analytical pipelines were capable of detecting base substitutions, indels, and gene copy number variations ( CNVs). For instance, several actionable mutations of EGFR, PIK3 CA, TP53, and KRAS have been detected for indicating drug susceptibility and resistance in the cases of lung cancer. Conclusion Our study has shown that NGS-based molecular diagnosis is more sensitive and comprehensive to detect genomic alterations in cancer, and supports a direct clinical use for guiding targeted therapy. [ABSTRACT FROM AUTHOR]

The ability to analyze highly toxic chemical warfare agents (CWAs) and related chemicals in a rapid and precise manner is essential in order to alleviate serious threats to humankind and public security caused by unexpected terrorist attacks and industrial accidents. In this investigation, we designed a o-phenylenediamine-pyronin linked dye that is capable of both fluorogenic and colorimetric discrimination between phosgene and the prototypical nerve-agent mimic, diethyl chlorophosphate (DCP) in the solution or gas phase. Moreover, this dye has been used to construct a portable kit that can be employed for real-time monitoring of DCP and phosgene in the field, both in a discriminatory manner, and in a simple and safe way. [ABSTRACT FROM AUTHOR]

Thioredoxin-interacting protein ( TXNIP) is a multifunctional protein involved in diverse cellular processes such as cell proliferation and apoptosis. TXNIP stability is controlled by the ubiquitin-proteasome pathway, and the E3 ubiquitin ligase Itch directly interacts with TXNIP via PPxY motifs of TXNIP. In a previously published study, we have shown that phosphorylation of the PPxY tyrosyl residue switches TXNIP selectivity between different binding partners. Here, we describe that tyrosine-phosphorylated PPxY motifs also bind to SH2 domains of Vav2 and Src with dissociation constants around 10 μ m and that phosphorylation is indispensable for these interactions as well. The crystal structure of the complex between a phosphorylated PPxY motif, and the SH2 domain of Vav2 reveals a conserved recognition mechanism. [ABSTRACT FROM AUTHOR]

Gastric cancer is one of the most common malignancies worldwide. Interleukin-1-beta ( IL-1β) is a pro-inflammatory cytokine and potent inhibitor of gastric acid secretion. Some studies provided evidence of the association between IL-1B 31 polymorphism and gastric cancer risk while other studies did not. Therefore, we conducted a comprehensive meta-analysis to reassess the association. A systematic literature search of the PubMed and EMBASE databases identified 37 studies with 6108 cases and 8980 controls for this meta-analysis. The crude odd ratios ( ORs) and the 95% confidence intervals ( CIs) were calculated to evaluate the strength of the association. Meta-regression was used to determine the major source of heterogeneity across the studies. The pooled analysis did not suggest the significant association of IL-1B 31 C>T polymorphism with gastric cancer risk. Stratified analysis was performed by ethnicity, source of control, genotype method, and indicated a significantly increased gastric cancer risk associated with IL-1B 31T variant in the population-based subgroup (heterozygous model: OR = 1.22, 95% CI = 1.03-1.45). Moreover, stratified analysis by Helicobacter pylori infection status indicated that IL-1B 31 polymorphism increased gastric cancer risk in infection-positive subgroup (homozygous model: OR = 1.35, 95% CI = 1.02-1.78; heterozygous model: OR = 1.31, 95% CI = 1.04-1.66; recessive model: OR = 1.29, 95% CI = 1.04-1.61). The study suggested that IL-1B 31 polymorphism might confer susceptibility to gastric cancer in the presence of H. pylori infection, indicating a gene-environment interaction in gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Drug-metabolizing enzymes inhibition-based drug-drug interaction remains to be the key limiting factor for the research and development of efficient herbal components to become clinical drugs. The present study aims to determine the inhibition of uridine 5'-diphospho-glucuronosyltransferases (UGTs) isoforms by two important efficient herbal ingredients isolated from Atractylodes macrocephala Koidz, atractylenolide I and III. In vitro recombinant UGTs-catalysed glucuronidation of 4-methylumbelliferone was used to determine the inhibition capability and kinetics of atractylenolide I and III towards UGT2B7, and in silico docking method was employed to explain the possible mechanism. Atractylenolide I and III exhibited specific inhibition towards UGT2B7, with negligible influence towards other UGT isoforms. Atractylenolide I exerted stronger inhibition potential than atractylenolide III towards UGT2B7, which is attributed to the different hydrogen bonds and hydrophobic interactions. Inhibition kinetic analysis was performed for the inhibition of atractylenolide I towards UGT2B7. Inhibition kinetic determination showed that atractylenolide I competitively inhibited UGT2B7, and inhibition kinetic parameter (Ki) was calculated to be 6.4 μM. In combination of the maximum plasma concentration of atractylenolide I after oral administration of 50 mg/kg atractylenolide I, the area under the plasma concentration-time curve ration AUCi /AUC was calculated to be 1.17, indicating the highly possible drug-drug interaction between atractylenolide I and drugs mainly undergoing UGT2B7-catalysed metabolism. [ABSTRACT FROM AUTHOR]

The Sarcolipin (SLN) is a transmembrane protein that can form a self-assembled pentamer. In this work, the homology modeling and all-atom molecular dynamic (MD) simulation was performed to study the model of SLN pentamer in POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) membrane. The potential of mean force (PMF) was calculated for transmembrane transportation of Na+, Cl- and water molecule along the pore channel of penta-SLN complex. The root mean square deviation (RMSD) of the SLN pentamer in POPC membrane showed that the stabilized SLN protein complex could exist in the membrane and that the Na+ and Cl- could not permeate through the channel when the pore was under the vacuum state, but the water could permeate through from cytoplasm to lumen. Under the aqueous state, our simulation demonstrated that hydrated state of Na1 and Cl- could pass through the channel. The PMF and radii of the pore showed that the channel had a gate at Leu21 that is a key hydrophobicity residue in the channel. Our simulations help to clarify and to understand better the SLN pentamer channel that had a hydrophobic gate and could switch Na+ and Cl- ion permeability by hydrated and vacuum states. [ABSTRACT FROM AUTHOR]