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  • 1
    Publication Date: 2018-09-15
    Description: Purpose: Cancer stem-like cells (CSC) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. As CSCs depend on their specific niche, including tumor-associated macrophages (TAM), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer. Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA sequencing, co-immunoprecipitation, chromatin immunoprecipitation, and other assays. A coculture system and cytokine antibody arrays were used to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance. Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via β-catenin, which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation, and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages toward TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via IL6/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model. Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer. Clin Cancer Res; 24(18); 4612–26. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    ISSN: 0038-1098
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 3
    Publication Date: 2018-06-28
    Description: Aimed at the problem of exhaust gas recirculation (EGR) performance evaluation and optimal EGR rate determination of turbocharged diesel engines, an optimized decision-making method, based on grey theory and entropy weight, was proposed. The internal combustion pressure, fuel consumption rate, NO X , CO and smoke were selected as the decision-making targets and the initial decision-making model was established based on the traditional grey decision-making theory. According to the characteristics and optimization requirements of EGR, the optimal compromise between combustion and emission performance is proposed to transform into decision-making target weighting problem, then an optimized subjective weighting method based on expert scoring and grey relational analysis is proposed. Finally, the entropy weight method was used to solve the objective weight and the optimized multi-objective grey decision-making model was established, which can not only weaken the human error of subjective empowerment, but also fully explore the intrinsic relationship of the evaluation indexes. At last, an optimization simulation platform for EGR performance evaluation based on MATLB/GUIDE was designed and established. The results show that the optimization simulation platform can effectively improve the efficiency of simulation calculation, which is more convenient for practical engineering applications. The optimized method can successfully realize EGR performance evaluation and optimal EGR rate determination under different working conditions. The decision-making result was consistent with the present EGR control strategies, which provide a new research idea for EGR performance optimization.
    Keywords: mechanical engineering, energy, applied mathematics
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 4
    Publication Date: 2018-09-06
    Description: The Triassic represented an important period that witnessed the diversification of marine and terrestrial ecosystems. The radiations of terrestrial plants and vertebrates during this period have been widely investigated; however, the Triassic history of insects, the most diverse group of organisms on Earth, remains enigmatic because of the rarity of Early-Middle Triassic fossils. We report new insect fossils from a Ladinian deposit (Tongchuan entomofauna) dated to approximately 238 to 237 million years ago and a Carnian deposit (Karamay entomofauna) in northwestern China, including the earliest definite caddisfly cases (Trichoptera), water boatmen (Hemiptera), diverse polyphagan beetles (Coleoptera), and scorpionflies (Mecoptera). The Tongchuan entomofauna is near the Ladinian-Carnian boundary in age, providing a calibration date for correlation to contemporaneous biotas. Our findings confirm that the clade Holometabola, comprising most of the modern-day insect species, experienced extraordinary diversification in the Middle-Late Triassic. Moreover, our results suggest that the diversification of aquatic insects (a key event of the "Mesozoic Lacustrine Revolution") had already begun by the Middle Triassic, providing new insights into the early evolution of freshwater ecosystems.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 5
    Publication Date: 2018-09-15
    Description: Complex, three-dimensional (3D) mesostructures that incorporate advanced, mechanically active materials are of broad, growing interest for their potential use in many emerging systems. The technology implications range from precision-sensing microelectromechanical systems, to tissue scaffolds that exploit the principles of mechanobiology, to mechanical energy harvesters that support broad bandwidth operation. The work presented here introduces strategies in guided assembly and heterogeneous materials integration as routes to complex, 3D microscale mechanical frameworks that incorporate multiple, independently addressable piezoelectric thin-film actuators for vibratory excitation and precise control. The approach combines transfer printing as a scheme for materials integration with structural buckling as a means for 2D-to-3D geometric transformation, for designs that range from simple, symmetric layouts to complex, hierarchical configurations, on planar or curvilinear surfaces. Systematic experimental and computational studies reveal the underlying characteristics and capabilities, including selective excitation of targeted vibrational modes for simultaneous measurements of viscosity and density of surrounding fluids. The results serve as the foundations for unusual classes of mechanically active 3D mesostructures with unique functions relevant to biosensing, mechanobiology, energy harvesting, and others.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 6
    Publication Date: 2018-11-07
    Description: Long terminal repeat-retrotransposons (LTR-RTs) are a major component of all flowering plant genomes. To analyze the time dynamics of LTR-RTs, we modeled the insertion rates of the 35 most abundant LTR-RT families in the genome of Aegilops tauschii , one of the progenitors of wheat. Our model of insertion rate (birth) takes into account random variation in LTR divergence and the deletion rate (death) of LTR-RTs. Modeling the death rate is crucial because ignoring it would underestimate insertion rates in the distant past. We rejected the hypothesis of constancy of insertion rates for all 35 families and showed by simulations that our hypothesis test controlled the false-positive rate. LTR-RT insertions peaked from 0.064 to 2.39 MYA across the 35 families. Among other effects, the average age of elements within a family was negatively associated with recombination rate along a chromosome, with proximity to the closest gene, and weakly associated with the proximity to its 5' end. Elements within a family that were near genes colinear with genes in the genome of tetraploid emmer wheat tended to be younger than those near noncolinear genes. We discuss these associations in the context of genome evolution and stability of genome sizes in the tribe Triticeae. We demonstrate the general utility of our models by analyzing the two most abundant LTR-RT families in Arabidopsis lyrata , and show that these families differed in their insertion dynamics. Our estimation methods are available in the R package TE on CRAN.
    Print ISSN: 0016-6731
    Topics: Biology
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  • 7
    Publication Date: 2018-12-04
    Description: Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology. Experimental Design: We developed a quantitative method to categorize the PDAC morphology on pretherapy CT scans from multiple datasets of patients with resectable and metastatic disease and correlated these patterns with clinical/pathologic measurements. We modeled macroscopic lesion growth computationally to test the effects of stroma on morphologic patterns, hypothesizing that the balance of proliferation and local migration rates of the cancer cells would determine tumor morphology. Results: In localized and metastatic PDAC, quantifying the change in enhancement on CT scans at the interface between tumor and parenchyma (delta) demonstrated that patients with conspicuous (high-delta) tumors had significantly less stroma, higher likelihood of multiple common pathway mutations, more mesenchymal features, higher likelihood of early distant metastasis, and shorter survival times compared with those with inconspicuous (low-delta) tumors. Pathologic measurements of stromal and mesenchymal features of the tumors supported the mathematical model's underlying theory for PDAC growth. Conclusions: At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease.
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 8
    Publication Date: 2018-12-14
    Description: Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, did demonstrate association with mutations localized to promoter regions. We found that the strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.
    Keywords: Development, Genetics, Neuroscience, Online Only
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2018-08-17
    Description: Molecular docking provides a computationally efficient way to predict the atomic structural details of protein–RNA interactions (PRI), but accurate prediction of the three-dimensional structures and binding affinities for PRI is still notoriously difficult, partly due to the unreliability of the existing scoring functions for PRI. MM/PBSA and MM/GBSA are more theoretically rigorous than most scoring functions for protein–RNA docking, but their prediction performance for protein–RNA systems remains unclear. Here, we systemically evaluated the capability of MM/PBSA and MM/GBSA to predict the binding affinities and recognize the near-native binding structures for protein–RNA systems with different solvent models and interior dielectric constants ( in ). For predicting the binding affinities, the predictions given by MM/GBSA based on the minimized structures in explicit solvent and the GB GBn1 model with in = 2 yielded the highest correlation with the experimental data. Moreover, the MM/GBSA calculations based on the minimized structures in implicit solvent and the GB GBn1 model distinguished the near-native binding structures within the top 10 decoys for 117 out of the 148 protein–RNA systems (79.1%). This performance is better than all docking scoring functions studied here. Therefore, the MM/GBSA rescoring is an efficient way to improve the prediction capability of scoring functions for protein–RNA systems.
    Print ISSN: 1355-8382
    Electronic ISSN: 1469-9001
    Topics: Biology , Medicine
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  • 10
    Publication Date: 2013-10-15
    Description: The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium- and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904662/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904662/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Hui -- Goehring, April -- Wang, Kevin H -- Penmatsa, Aravind -- Ressler, Ryan -- Gouaux, Eric -- R37 MH070039/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 7;503(7474):141-5. doi: 10.1038/nature12648. Epub 2013 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24121440" target="_blank"〉PubMed〈/a〉
    Keywords: Antidepressive Agents, Second-Generation/metabolism/*pharmacology ; Antidepressive Agents, Tricyclic/metabolism/*pharmacology ; Bacterial Proteins/antagonists & inhibitors/chemistry/genetics/metabolism ; Binding, Competitive/drug effects ; Biogenic Amines/*metabolism ; Chlorides/metabolism ; Crystallography, X-Ray ; Humans ; Mazindol/metabolism/pharmacology ; Models, Molecular ; Mutation ; Norepinephrine/metabolism ; *Plasma Membrane Neurotransmitter Transport Proteins/antagonists & ; inhibitors/chemistry/genetics/metabolism ; Protein Conformation/drug effects ; Recombinant Fusion Proteins/*chemistry/genetics/metabolism ; Reproducibility of Results ; Serotonin Plasma Membrane Transport Proteins/*chemistry/genetics/*metabolism ; Serotonin Uptake Inhibitors/metabolism/*pharmacology ; Sertraline/metabolism/pharmacology ; Sodium/metabolism ; Structure-Activity Relationship
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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