bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis of internally alkylated azuliporphyrins
Authors: Moriones Julian S. D. , Latham Alissa N. , Lash Timothy D.
Published: December 2019

Examples of internally alkylated azuliporphyrins were prepared by MacDonald-type “3 + 1” condensations. 2-Methyl- and 2-ethylazulene reacted with an acetoxymethylpyrrole in the presence of an acid catalyst to give azulitripyrranes. Following cleavage of the terminal protective groups, condensation with a diformylpyrrole in the presence of hydrochloric acid and oxidation with ferric chloride afforded 21-alkylazuliporphyrins. An azulene dialdehyde similarly reacted with an [Formula: see text]-methyltripyrrane to generate a 23-methylazuliporphyrin. The products could only be isolated in protonated form and the free-base internally alkylated azuliporphyrins proved to be unstable. Nevertheless, the dications are highly diatropic and the internal alkyl group resonances were shifted upfield to beyond -3 ppm. Reaction of a 23-methylazuliporphyrin with palladium(II) acetate primarily afforded a palladium(II) complex with loss of the internal methyl substituent. However, two palladium(II) benzocarbaporphyrins were also identified that were formed by sequential oxidative ring contraction and methyl group migration. Internally alkylated azuliporphyrins provide new insights into the reactivity of the system and the results show that the introduction of alkyl substituents within porphyrinoid cavities greatly modifies the properties of these structures.
The “China Miracle”: Thinking on Economic Theory Innovation
Authors: Xia Bin
Published: December 2019

Starting with explaining the differences between theory and experience, based on various schools of economic theories, this paper sorts out and evaluates different views of Chinese Economists’ theoretical summaries of the “economic miracle” for 40 years since reform and opening-up, and then analyses four fundamental reasons behind the divergence among the economists. The paper expresses the understanding of Chinese Economics, the School of Chinese Economics and the Socialist Political Economy with Chinese Characteristics and puts forward several issues for further improvement on innovations of economic theory.
Engineering on the precipice: the performance of mountain road rehabilitation in the Central Cordillera of the Philippines
Authors: Hearn G. J. , Hart J. R.
Published: December 2019

Parts of the Central Cordillera of Luzon are among the most challenging locations on Earth in which to build and maintain transport infrastructure, a situation perhaps most epitomized by the Halsema Highway. Since its original construction in the 1920s, the highway has undergone phased improvement and has become a socio-economic lifeline to the rural communities it serves. Unfortunately, in 1990, continuing road improvement works had to be abandoned owing to the outcome of a 7.8 M
s
earthquake and the effects of subsequent typhoon damage. Earthquake reinstatement works were designed in 1998 and constructed between 2001 and 2006. The engineering geological challenge this posed was compounded by the effects of severe typhoon rains during the reconstruction period, requiring continual assessment of changing slope and drainage conditions. Since construction, the road has been affected by several new typhoons including, most notably, Typhoons Pepeng and Ompong in 2009 and 2018 respectively. Field inspections in 2010 and 2018, combined with the interpretation of satellite imagery available in Google Earth, have allowed the performance of the works implemented between 2001 and 2006 to be assessed and the outcome has been largely favourable. Very little of the recorded damage has occurred in the locations of earthquake reinstatement. Instead, several new areas of slope failure and subsequent blockage and damage to the road have developed. Many of these areas can be explained with respect to their underlying engineering geology and geomorphology. However, there are just as many that owe their origin to the pattern of rainfall and runoff arising during the passage of individual and successive typhoons, modified significantly by drainage management practices in the road corridor, where engineering serviceability and land use practices sometimes have conflicting objectives.
The UNESCO–IUGS International Geoscience Programme (IGCP) in the service of society since 1972
Authors: Heirman K. , Adiyaman Lopes O.
Published: December 2019

Developing an advanced understanding of the Earth's fundamental processes and resources is essential to fulfil the United Nations 2030 Agenda for Sustainable Development. The International Geoscience Programme (IGCP) is the oldest and most successful example of scientific co-operation between a non-governmental organization, the International Union of Geological Sciences (IUGS), and an intergovernmental organization, UNESCO. During almost 50 years, this programme has been the gateway to successful scientific careers in pioneering research for thousands of IGCP project scientists.

After almost 50 years of evaluating IGCP projects, the programme itself was evaluated through statistical analysis of the annual progress report during four periods: 1981–82, 1991–92, 2001–02 and 2011–12. Subsequently, these trends were compared to the trends of the last four years (2015–18). This study provided insight into trends and changes in the location of studies, participating countries, involvement of developing countries, gender equality, etc. To fully understand the added value of the IGCP brand identity and its seed funding, project leaders over a period of five years (2008–12) were asked to complete a survey about its work.

Overall, both studies confirmed the value of the main aim of the IGCP: enabling and facilitating international collaboration between Earth scientists. Even though IGCP funding has been reduced, the IGCP brand still opens doors to new collaborators, new research and national funding agencies, often impacting the career of the involved researchers very positively.
Stepping Stone Graph
Authors: Kannangara Sameera , Tanin Egemen , Harwood Aaron , Karunasekera Shanika
Published: December 2019

There are many real world applications that require identifying public movements such as identifying movement corridors in cities and most popular paths. If one is not given user trajectories but rather sporadic location data, such as location-based social network data, finding movement related information becomes difficult. Rather than processing all points in a dataset given a query, a clever approach is to construct a graph, based on user locations, and query this graph to answer questions such as shortest paths, most popular paths, and movement corridors. Shortest path graph is one of the popular graphs. However, the shortest path graph can be inefficient and ineffective for analysing movement data, as it calculates the graph edges considering the shortest paths over all the points in a dataset. Therefore, edge sets resulting from shortest path graphs are usually very restrictive and not suitable for movement analysis because of its global view of the dataset. We propose the stepping stone graph, which calculates the graph considering point pairs rather than all points; the stepping stone graph focuses on possible local movements, making it both efficient and effective for location-based social network related data. We demonstrate its capabilities by applying it in the Location-Based Social Network domain and comparing with the shortest path graph. We also compare its properties to a range of other graphs and demonstrate how stepping stone graph relates to Gabriel graph, relative neighbourhood graph, and Delaunay triangulation.
Harnessing the Granularity of Micro-Electrode-Dot-Array Architectures for Optimizing Droplet Routing in Biochips
Authors: Roy Pushpita , Banerjee Ansuman , Wille Robert , Bhattacharya Bhargab B.
Published: December 2019

In this article, we consider the problem of droplet routing for Microelectrode-Dot-Array (MEDA) biochips. MEDA biochips today provide a host of useful features for droplet movement by making it possible to manoeuvre droplets at a much finer granularity and with significantly increased flexibility. More precisely, MEDA biochips support more degrees of freedom in navigation and volumetric manipulation such as diagonal movement, droplet reshaping, and fractional-level split-and-merge. This helps improve routing of droplets on microfluidic grids—in particular, when the space available on the grid is limited or blocked by obstacles. In this work, we discuss how these improved capabilities can be utilized in the realization of the desired routes on those biochips. To this end, we introduce a routing method that utilizes satisfiability solvers and guarantees the generation of optimal solutions, considering the set of MEDA operations we model. This significantly improves the state of the art, since previously proposed solutions either (1) relied on heuristics and, hence, were not able to guarantee the optimum or (2) only considered a subset of the MEDA features. The solution proposed in this work includes a formulation of
all
MEDA features, which, as illustrated by examples, allows for the determination of routing solutions with smaller completion times. Experimental evaluations confirm these findings.
The Book Review Column
Authors: Green Frederic
Published: December 2019

In this column we review the following books: 1. Factor Man, by Matt Ginsberg. A fictional account of what might happen if it turns out that P=NP. Review by William Gasarch. 2. Kolmogorov Complexity and Algorithmic Randomness, by A. Shen, V. A. Uspensky, and N. Vereshchagin. A textbook on this important topic. Review by Hadi Shafei. As always, please contact me to write a review; choose from among the books listed on the next pages, or, if you are interested in anything not on the list, just send me a note.
Redundancy with Processor Sharing servers
Authors: Anton Elene , Ayesta Urtzi , Jonckheere Matthieu , Verloop Ina Maria
Published: December 2019

The main motivation to investigate redundancy models comes from empirical evidence suggesting that redundancy can help improve the performance of real-world applications. Under redundancy, a job that arrives to this system is dispatched to d servers uniformly chosen at random in order to benefit from the variability of the length of these queues. As soon as one of the copies finishes service, the job (and its copies) is removed from the system, and as a consequence, a job's delay is given by the minimum delay among the servers its copies are sent to.

Most of the literature on performance evaluation of redundancy systems has been carried out when First Come First Served (FCFS) is implemented in the servers. In particular, for exponential service time distributions, Gardner et al. [4, 5] and Bonald and Comte [2] show that the stability region is not reduced due to adding redundant copies. In this extended abstract, we focus instead on Processor Sharing (PS) service policy and study how redundancy impacts the stability condition. In particular, we aim to study the impact that the correlation structure of the copies has on the performance of the redundancy-d model. In a recent paper, Gardner et al. [3] showed that the assumption of independent and identically distributed (i.i.d.) copies, can be unrealistic, and that it might lead to theoretical results that do not reflect the results of replication schemes in real-life computer systems. We consider the two extreme cases of correlation; (i) the copies are i.i.d. (ii) the copies of a job are exact replicas (identical copies). We observe that the stability condition strongly depends on the correlation structure, as well as on the number of redundant copies.
Simple Near-Optimal Scheduling for the M/G/1
Authors: Scully Ziv , Harchol-Balter Mor , Scheller-Wolf Alan
Published: December 2019

We consider the problem of preemptively scheduling jobs to minimize mean response time of an M/G/1 queue. When the scheduler knows each job's size, the shortest remaining processing time (SRPT) policy is optimal. Unfortunately, in many settings we do not have access to each job's size. Instead, we know only the job size distribution. In this setting, the Gittins policy is known to minimize mean response time, but its complex priority structure can be computationally intractable. A much simpler alternative to Gittins is the shortest expected remaining processing time (SERPT) policy. While SERPT is a natural extension of SRPT to unknown job sizes, it is unknown how close SERPT is to optimal.
Tighter Lyapunov Truncation for Multi-Dimensional Continuous Time Markov Chains with Known Moments
Authors: Somashekar Gagan , Delasay Mohammad , Gandhi Anshul
Published: December 2019

Continuous Time Markov chains (CTMCs) are widely used to model and analyze networked systems. A common analysis approach is to solve the system of balance equations governing the state transitions of a CTMC to obtain its steadystate probability distribution, and use the state probabilities to derive or compute various performance measures.

In many systems, the state space of the underlying CTMC is infinite and multi-dimensional with state-dependent transitions; exact analysis of such models is challenging. For example, the exact probability distribution of the number of jobs in the Discriminatory Processor Sharing (DPS) system, first proposed by Kleinrock in 1967 [4], is still an open challenge. Likewise, obtaining the exact state probabilities of quasi-birth-and-death (QBD) processes with leveldependent transitions is known to be challenging [1]; QBDs are infinite state space multi-dimensional Markov chains in which states are organized into levels and transitions are skip-free between the levels.
Effect of high altitude on human placental amino acid transport
Authors: Vaughan Owen. R. , Thompson Fredrick , Lorca Ramón. A. , Julian Colleen G. , Powell Theresa L. , Moore Lorna G. , Jansson Thomas
Published: December 2019

Women residing at high altitudes deliver infants of lower birth weight than at sea level. Birth weight correlates with placental system A-mediated amino acid transport capacity, and severe environmental hypoxia reduces system A activity in isolated trophoblast and the mouse placenta. However, the effect of high altitude on human placental amino acid transport remains unknown. We hypothesized that microvillous membrane (MVM) system A and system L amino acid transporter activity is lower in placentas of women living at high altitude compared with low-altitude controls. Placentas were collected at term from healthy pregnant women residing at high altitude (HA; >2,500 m; n = 14) or low altitude (LA; <1,700 m; n = 14) following planned, unlabored cesarean section. Birth weight, but not placenta weight, was 13% lower in HA pregnancies (2.88 ± 0.11 kg) compared with LA (3.30 ± 0.07 kg, P < 0.01). MVM erythropoietin receptor abundance, determined by immunoblot, was greater in HA than in LA placentas, consistent with lower placental oxygen levels at HA. However, there was no effect of altitude on MVM system A or L activity, determined by Na+-dependent [14C]methylaminoisobutyric acid uptake and [3H]leucine uptake, respectively. MVM abundance of glucose transporters (GLUTs) 1 and 4 and basal membrane GLUT4 were also similar in LA and HA placentas. Low birth weights in the neonates of women residing at high altitude are not a consequence of reduced placental amino acid transport capacity. These observations are in general agreement with studies of IUGR babies at low altitude, in which MVM system A activity is downregulated only in growth-restricted babies with significant compromise.

NEW & NOTEWORTHY Babies born at high altitude are smaller than at sea level. Birth weight is dependent on growth in utero and, in turn, placental nutrient transport. We determined amino acid transport capacity in placentas collected from women resident at low and high altitude. Altitude did not affect system A amino acid transport across the syncytiotrophoblast microvillous membrane, suggesting that impaired placental amino acid transport does not contribute to reduced birth weight in this high-altitude population.
Sleep Spindles: Mechanisms and Functions
Authors: Fernandez Laura M. J. , Lüthi Anita
Published: December 2019

Sleep spindles are burstlike signals in the electroencephalogram (EEG) of the sleeping mammalian brain and electrical surface correlates of neuronal oscillations in thalamus. As one of the most inheritable sleep EEG signatures, sleep spindles probably reflect the strength and malleability of thalamocortical circuits that underlie individual cognitive profiles. We review the characteristics, organization, regulation, and origins of sleep spindles and their implication in non-rapid-eye-movement sleep (NREMS) and its functions, focusing on human and rodent. Spatially, sleep spindle-related neuronal activity appears on scales ranging from small thalamic circuits to functional cortical areas, and generates a cortical state favoring intracortical plasticity while limiting cortical output. Temporally, sleep spindles are discrete events, part of a continuous power band, and elements grouped on an infraslow time scale over which NREMS alternates between continuity and fragility. We synthesize diverse and seemingly unlinked functions of sleep spindles for sleep architecture, sensory processing, synaptic plasticity, memory formation, and cognitive abilities into a unifying sleep spindle concept, according to which sleep spindles 1) generate neural conditions of large-scale functional connectivity and plasticity that outlast their appearance as discrete EEG events, 2) appear preferentially in thalamic circuits engaged in learning and attention-based experience during wakefulness, and 3) enable a selective reactivation and routing of wake-instated neuronal traces between brain areas such as hippocampus and cortex. Their fine spatiotemporal organization reflects NREMS as a physiological state coordinated over brain and body and may indicate, if not anticipate and ultimately differentiate, pathologies in sleep and neurodevelopmental, -degenerative, and -psychiatric conditions.
Intubation of a Patient with a Large Goiter: The Advantageous Role of Videolaryngoscopy
Authors: Heinz Eric , Quan Theodore , Nguyen Hieu , Pla Raymond
Published: December 2019

Fiberoptic bronchoscopy has long been considered the gold standard for patients who present with a difficult airway. In the case presented, a patient has a large palpable goiter and requires intubation. After the unsuccessful attempt to intubate with the use of fiberoptic bronchoscopy, the decision to switch to videolaryngoscopy afforded a positive result. We present this case to suggest that the utilization of videolaryngoscopy may be an alternative option for intubation when other methods have failed. It is imperative for anesthesiologists to understand the benefits that this modality may provide.
Hopf Bifurcation and Control of Magnetic Bearing System with Uncertain Parameter
Authors: Wang Jing , Ma Shaojuan , Hao Peng , Yuan Hehui
Published: December 2019

In this paper, the Hopf bifurcation and control of the magnetic bearing system under an uncertain parameter are investigated. Firstly, the two‐degree‐of‐freedom magnetic bearing system model with uncertain parameter is established. The method of orthogonal polynomial approximation is used to obtain the equivalent magnetic bearing model which is deterministic. Secondly, combining mathematical analysis tools and numerical simulations, the Hopf bifurcation of the equivalent model is analyzed. Finally, a hybrid feedback control method (linear feedback control method combined with nonlinear stochastic feedback control method) is introduced to control the Hopf bifurcation behavior of the magnetic bearing system.
An Exceptional Responder to Nivolumab in Metastatic Non-Small-Cell Lung Cancer: A Case Report and Literature Review of Long-Term Survivors
Authors: Baseri Babak , Samra Bachar , Tam Eric , Chiu Edwin , Leaf Andrea
Published: December 2019

Background. Exceptional responders to immune checkpoint inhibitors in metastatic non-small-cell lung cancer (NSCLC) are rare. Furthermore, the optimal duration of immunotherapy in patients who achieve complete remission and the benefit of rechallenge after recurrence remain unknown. Studying the clinical course of exceptional responders can help identify potential predictors of response to immunotherapy and further fine-tune our management algorithms in the absence of standard of care in challenging scenarios. Case Presentation. We highlight the case of a 73-year-old Vietnam War Veteran with active tobacco dependence who achieved complete response with nivolumab for metastatic NSCLC after four prior lines of chemotherapy. Nivolumab was discontinued after 10 cycles due to immune-mediated hepatitis that resolved with steroids. He remained in complete remission for 14 months while off therapy. Then, his tumor recurred twice locally in the mediastinum and he again achieved complete and durable responses after each recurrence with radiotherapy. Due to recurrence in both lungs one year later, he was rechallenged with nivolumab and achieved partial response after two months of therapy. He continues to do well five and a half years since his initial diagnosis of de novo metastatic NSCLC. Conclusion. Optimal management of exceptional responders to immune checkpoint inhibitors in metastatic NSCLC is largely unknown. Our case report adds to the limited data supporting the use of localized therapy for oligometastatic recurrences and rechallenge with immunotherapy for widespread disease in achieving disease control and long-term survival.
Evaluating the Potential of Laser Beam Quality Improvement by Adaptive Optics System
Authors: Han Kai , Cui Wenda , Yang Yi , Xi Fengjie , Li Xiao , Du Shaojun
Published: December 2019

AO (adaptive optics) systems have been extensively used to improve the beam quality in high-energy lasers; however, few studies have focused on how much the beam quality could be improved. A novel evaluation criteria and factor is presented in this paper. The factor, defined as power in ring (PIR), is expressed by distinguishing the low- and high-spatial frequency components in the far-field laser intensity distribution. Beams with different PIR values are generated in our model, and then they are compensated by AO systems. Calculation result shows that the PIR factor could evaluate a laser beam’s improvement potential by an AO system quantitatively.
Dynamic Game and Coordination Strategy of Multichannel Supply Chain Based on Brand Competition
Authors: Ma Junhai , Zhang Fang , Bao Binshuo
Published: December 2019

In this paper, two noncooperative dynamic pricing strategies are used in a supply chain. Two dynamic Stackelberg game models have been built involving both a manufacturer and a retailer assumed to be the leader in order. In the two models, the manufacturer sells national‐brand (NB) product to an independent retailer or directly to consumers through a direct channel. The retailers sell a store‐brand (SB) product when they sell the NB product coming from the manufacturer. Thus, there is competition both in different channels and in products with different brands. To analyze the complexity of the model, parameter bifurcation diagrams and strange attractor diagrams have been therefore plotted. The results show that the game leader has advantages when the market is stable, but it turns disadvantageous if the state falls into unstable as the game follower can quickly adjust the strategy to seize the market. The wholesale price and the direct selling price are high that they incur larger profits if the manufacturer is dominant, but it gets worse when the adjustment speed increases. While in the model where the retailer plays a dominant role, the increase in the adjustment speed is unfavorable to retailer. By controlling the total cost of the direct channel and increasing channel competition strength and brand competition strength, the manufacturers can increase their profits in the game dominated by the retailer. In addition, the stable region within the system will be narrow since the market is sensitive to the channel competition, brand competition, and advertising indifference.
Exosomal circHIPK3 Released from Hypoxia-Pretreated Cardiomyocytes Regulates Oxidative Damage in Cardiac Microvascular Endothelial Cells via the miR-29a/IGF-1 Pathway
Authors: Wang Yan , Zhao Ranzun , Liu Weiwei , Wang Zhenglong , Rong Jidong , Long Xianping , Liu Zhijiang , Ge Junbo , Shi Bei
Published: December 2019

Background/Aims. Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs that regulate gene expression in eukaryotes. Recently, exosomes from cardiomyocytes (CMs) have been found to facilitate cell proliferation and survival by transporting various bioactive molecules, including circRNA. However, the functions of exosomal circRNAs are not clear. The present research is aimed at determining whether circHIPK3 released from hypoxia-pretreated CMs is transferred into cardiac microvascular endothelial cells (CMVECs) by exosomes and becomes functionally active in the CMVECs under oxidative stress conditions. Methods. Quantitative polymerase chain reactions were conducted to detect the expression pattern of circHIPK3 in CMVECs under oxidative stress. Annexin V-FITC/propidium iodide (PI) staining assays, TUNEL assays, ROS assays, and Western blot analysis were conducted to detect the role of exosomal circHIPK3 in CMVEC function in vitro. Luciferase activity assays and RNA immunoprecipitation studies were conducted in vitro to reveal the mechanism of circHIPK3-mediated CMVEC function. Results. circHIPK3 expression was significantly upregulated in hypoxic exosomes (HPC-exos) compared with normoxic exosomes (Nor-exos). Moreover, HPC-exos induced stronger antioxidant effects than Nor-exos. The silencing or overexpression of circHIPK3 changed CMVEC survival under oxidative conditions in vitro. Furthermore, circHIPK3 silencing in HPC-exos abrogated the protective effects of HPC-exos in CMVECs, as shown by increased levels of apoptosis, ROS, MDA, and proapoptotic proteins. circHIPK3 acted as an endogenous miR-29a sponge to sequester and inhibit miR-29a activity, which led to increased IGF-1 expression. The ectopic expression of miR-29a mimicked the effect of circHIPK3 silencing in CMVECs in vitro. Conclusions. circHIPK3 in HPC-exos plays a role in CMVECs under oxidative conditions through miR-29a-mediated IGF-1 expression, leading to a decrease in oxidative stress-induced CMVECs dysfunction. These data suggest that the exosomal circRNA in CMs is a potential target to control CMVECs dysfunction under oxidative conditions.
A Novel Selection Approach for Genetic Algorithms for Global Optimization of Multimodal Continuous Functions
Authors: Haq Ehtasham-ul , Ahmad Ishfaq , Hussain Abid , Almanjahie Ibrahim M.
Published: December 2019

Genetic algorithms (GAs) are stochastic-based heuristic search techniques that incorporate three primary operators: selection, crossover, and mutation. These operators are supportive in obtaining the optimal solution for constrained optimization problems. Each operator has its own benefits, but selection of chromosomes is one of the most essential operators for optimal performance of the algorithms. In this paper, an improved genetic algorithm-based novel selection scheme, i.e., stairwise selection (SWS) is presented to handle the problems of exploration (population diversity) and exploitation (selection pressure). For its global performance, we compared with several other selection schemes by using ten well-known benchmark functions under various dimensions. For a close comparison, we also examined the significance of SWS based on the statistical results. Chi-square goodness of fit test is also used to evaluate the overall performance of the selection process, i.e., mean difference between observed and expected number of offspring. Hence, the overall empirical results along with graphical representation endorse that the SWS outperformed in terms of robustness, stability, and effectiveness other competitors through authentication of performance index (PI).
Increased Soluble Epoxide Hydrolase in Human Gestational Tissues from Pregnancies Complicated by Acute Chorioamnionitis
Authors: Hung Tai-Ho , Chen Szu-Fu , Wu Chun-Hu , Kao Chuan-Chi , Wu Chung-Pu
Published: December 2019

Chorioamnionitis (CAM) is primarily a polymicrobial bacterial infection involving chorionic and amniotic membranes that is associated with increased risk of preterm delivery. Epoxyeicosatrienoic acids (EETs) are eicosanoids generated from arachidonic acid by cytochrome P450 enzymes and further metabolized mainly by soluble epoxide hydrolase (sEH) to produce dihydroxyeicosatrienoic acids (DHETs). As a consequence of this metabolism of EETs, sEH reportedly exacerbates several disease states; however, its role in CAM remains unclear. The objectives of this study were to (1) determine the localization of sEH and compare the changes it undergoes in the gestational tissues (placentas and fetal membranes) of women with normal-term pregnancies and those with pregnancies complicated by acute CAM; (2) study the effects of lipopolysaccharide (LPS) on the expression of sEH in the human gestational tissues; and (3) investigate the effect of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a specific sEH inhibitor, on LPS-induced changes in 14,15-DHET and cytokines such as interleukin- (IL-) 1β and IL-6 in human gestational tissues in vitro and in pregnant mice. We found that women with pregnancies complicated by acute CAM had higher levels of sEH mRNA and protein in fetal membranes and villous tissues compared to those in women with normal-term pregnancies without CAM. Furthermore, fetal membrane and villous explants treated with LPS had higher tissue levels of sEH mRNA and protein and 14,15-DHET than those present in the vehicle controls, while the administration of AUDA in the media attenuated the LPS-induced production of 14,15-DHET in tissue homogenates and IL-1β and IL-6 in the media of explant cultures. Administration of AUDA also reduced the LPS-induced changes of 14,15-DHET, IL-1β, and IL-6 in the placentas of pregnant mice. Together, these results suggest that sEH participates in the inflammatory changes in human gestational tissues in pregnancies complicated by acute CAM.
Research on the Optimization Model of the Abrasive Blocks Using Weighted Case‐Based Reasoning
Authors: Gao Wei , Yang Shengqiang , Tian Jianyan , Yang Yan , Fan Xiaojian , Wei Wanzhen
Published: December 2019

Barrel finishing process is a universal method to improve the surface quality of parts. It is widely used in high‐performance parts of high‐end equipment. As a necessary tool consumable for barrel finishing process, the characteristic parameters of the abrasive blocks affect the processing quality and production efficiency. However, the current method for selecting the abrasive blocks requires large number of experiments based on the operator’s extensive experience, which does not meet the rapid development needs of the barrel finishing process. Therefore, this paper proposes a case‐based reasoning model with variable weights to achieve the intelligent optimization of the abrasive blocks. Based on the in‐depth analysis of the characteristics of the barrel finishing process, a reasonable case base is established firstly, which is to determine the comprehensive case features and the solution of the case. AHP (analytic hierarchy process) is proposed to determine the weight of case features and to dynamically adjust the weight of case features according to the characteristics of the parts to be processed and users’ processing requirements. The results show that the proposed case‐based reasoning model with variable weights can quickly, accurately, and reasonably select the abrasive blocks during the process of making processing technique of the barrel finishing, which will lay a necessary foundation for the effective implementation of the barrel finishing process and contribute significantly to the improvement of its efficiency.
Simultaneous Quantification of Brigatinib and Brigatinib-Analog in Rat Plasma and Brain Homogenate by LC-MS/MS: Application to Comparative Pharmacokinetic and Brain Distribution Studies
Authors: Li Bo , Lu Min , Jin Lei , Zheng Maoen , Sun Peilu , Lei Shanshan , Xiong Shan , Chen Suhong
Published: December 2019

Brigatinib and brigatinib-analog are potent and selective ALK inhibitors with the similar structure. A simple and sensitive high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of brigatinib and brigatinib-analog in rat plasma and brain homogenate was developed and validated. Chromatographic separation was carried out on an ODS column with acetonitrile and 0.1% formic acid in water as the mobile phase with gradient elution at a flow rate of 0.5 mL/min. Detections were performed using a TSQ Quantum Ultra mass spectrometric detector with electrospray ionization (ESI) interface, which was operated in the positive ion mode. A simple protein precipitation preparation process was used. The lower limits of quantification (LLOQs) were 1.0 ng/mL and 0.5 ng/mL for analytes in rat plasma and brain homogenate, respectively. The intrabatch and interbatch precision and accuracy of brigatinib and brigatinib-analog were well within the acceptable limits of variation. The simple and sensitive LC-MS/MS method was successfully applied to the pharmacokinetic and brain distribution studies following a single oral administration of brigatinib and brigatinib-analog to rats. The above studies would lay a good foundation for the further applications of brigatinib and brigatinib-analog.
Comparative Effect of Aqueous and Methanolic Bupleuri Radix Extracts on Hepatic Uptake of High-Density Lipoprotein and Identification of the Potential Target in HFD-Fed Mice
Authors: Tan Zhibin , Huang Yijia , Chen Fenglian , Cao Cheng , Wang Shuling
Published: December 2019

Our previous study found saikosaponin b2 (SSb2) increased high-density lipoprotein (HDL) uptake in HepG2 cells. SSb2 is only found in aqueous Bupleuri Radix extract, and it is one of the secondary saponins derived from saikosaponin d (SSd), which exists in the methanolic extract. This study aimed to compare the effect of aqueous extract of Bupleuri Radix on hepatic uptake of HDL with methanolic extract and to reveal the underlying mechanism of enhancing HDL uptake in mice fed with high-fat diet (HFD). Cellular HDL uptake in each group was quantified by flow cytometry. Bioactive components bound to the HepG2 cytomembrane were detected with HPLC-DAD. RNA sequencing was performed to screen the underlying target on hepatic HDL-uptake, and western blotting was conducted to verify differential protein expression. Significant increases of HDL uptake by HepG2 cells were observed in all groups of aqueous extract of Bupleuri Radix, while no effect or negative effect was observed in the methanolic extract. Saikosaponin b1 (SSb1) and SSb2 were detected in the desorption elute of the aqueous extract from the HepG2 cytomembrane, while saikosaponin a (SSa) and SSd were not found. Remarkable upregulation of FGF21 in HFD-fed mice liver was affirmed after treatment with aqueous extract. This study suggested that aqueous Bupleuri Radix extract could promote hepatic HDL uptake in vitro but methanolic extract could not, and FGF21 might be the potential target.
Cooperative Blockade of PKCα and JAK2 Drives Apoptosis in Glioblastoma
Authors: Wong Robyn A. , Luo Xujun , Lu Mimi , An Zhenyi , Haas-Kogan Daphne A. , Phillips Joanna J. , Shokat Kevan M. , Weiss William A. , Fan Qi Wen
Published: December 2019

The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting mTOR as a robust target for therapy. Inhibitors of mTOR have had limited success clinically, however, in part because their mechanism of action is cytostatic rather than cytotoxic. Here, we tested three distinct mTOR kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation of glioblastoma cells, whereas PP242 uniquely induced apoptosis. Apoptosis induced by PP242 resulted from off-target cooperative inhibition of JAK2 and protein kinase C alpha (PKCα). Induction of apoptosis was also decreased by additional on-target inhibition of mTOR, due to induction of autophagy. As EGFR inhibitors can block PKCα, EGFR inhibitors erlotinib and osimertinib were tested separately in combination with the JAK2 inhibitor AZD1480. Combination therapy induced apoptosis of glioblastoma tumors in both flank and in patient-derived orthotopic xenograft models, providing a preclinical rationale to test analogous combinations in patients.

Significance:

These findings identify PKCα and JAK2 as targets that drive apoptosis in glioblastoma, potentially representing a clinically translatable approach for glioblastoma.
Identification of Therapeutic Vulnerabilities in Small-cell Neuroendocrine Prostate Cancer
Authors: Corella Alexandra N. , Cabiliza Ordonio Ma Victoria Andrea , Coleman Ilsa , Lucas Jared M. , Kaipainen Arja , Nguyen Holly M. , Sondheim Daniel , Brown Lisha G. , True Lawrence D. , Lee John K. , MacPherson David , Nghiem Paul , Gulati Roman , Morrissey Colm , Corey Eva , Nelson Peter S.
Published: December 2019

Purpose:

Small-cell neuroendocrine prostate cancer (SCNPC) exhibits an aggressive clinical course and incidence rates seem to be increasing following resistance to potent androgen receptor (AR) antagonists. Currently, treatment options are limited and few model systems are available to identify new approaches for treatment. We sought to evaluate commonalities between SCNPC and other aggressive neuroendocrine carcinomas to identify therapeutic targets.

Experimental Design:

We generated whole transcriptome RNA-sequencing data from AR-active prostate cancers (ARPCs) and SCNPCs from tumors collected at rapid autopsy and two other neuroendocrine carcinomas, Merkel cell carcinoma (MCC), and small-cell lung cancer. We performed cross-tumor comparisons to identify conserved patterns of expression of druggable targets. We tested inhibitors to highly upregulated drug targets in a panel of prostate cancer cell lines and in vivo patient-derived xenograft (PDX) models.

Results:

We identified BCL2 as highly upregulated in SCNPC compared with ARPC. Inhibitors targeting BCL2 induced apoptotic cell death in SCNPC cell lines at nanomolar concentrations while ARPC cell lines were resistant. Treatment with the BCL2 inhibitor navitoclax leads to a reduction of growth of SCNPC PDX tumors in vivo, whereas ARPC PDX models were more resistant. We identified Wee1 as a second druggable target upregulated in SCNPC. Treatment with the combination of navitoclax and the Wee1 inhibitor AZD-1775 repressed the growth of SCNPC PDX resistant to single-agent BCL2 inhibitors.

Conclusions:

The combination of BCL2 and Wee1 inhibition presents a novel therapeutic strategy for the treatment of SCNPC.
A Prospective, Open-Label Comparison of Tamsulosin plus Serenoa repens and Bovine Colostrum versus Tamsulosin Alone in the Treatment of Benign Prostatic Hyperplasia
Authors: Di Maida Fabrizio , Mari Andrea , Rubino Roberta , Minervini Andrea , Carini Marco , Siena Giampaolo
Published: December 2019

Objective: To compare the efficacy and safety of oral supplementation with Serenoa repens (SR) and bovine colostrum (BC) plus tamsulosin (TAM) versus TAM alone over 12 months in men suffering from lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). Methods: Between February 2018 and February 2019, men with symptomatic BPH (IPSS ≥10) were prospectively recruited. This prospective, open-label, 12-month study included two different protocols: (1) group A, SR 320 mg/day + BC 30 mg/day + TAM 0.4 mg/day, and (2) group B, TAM 0.4 mg/day only. Results: Overall, 148 patients entered the study, 76 in group A and 72 in group B. At 12 months, the total IPSS had decreased by 5.5 with TAM + SR + BC and by 5.1 with TAM only (p = 0.21). However, when the total IPSS was divided into storage and voiding subscores, at 6 months the storage symptoms had improved significantly more with TAM + SR + BC (–1.6 vs. –0.9 with TAM only, p = 0.02), with the benefit persisting also at the 1-year evaluation (–1.8 vs. –0.8, p = 0.02). Moreover, the improvement in LUTS-related quality of life (QoL) was significantly different between the groups, with a mean decrease in IPSS QoL subscore of –2.5 ± 0.2 for TAM + SR + BC versus –1.8 ± 0.3 for TAM at 6 months (p = 0.04), and of –2.9 ± 0.4 for TAM + SR + BC versus –2.1 ± 0.4 for TAM at 12 months (p = 0.04). Conversely, no significant differences were found in maximal urinary flow rate (p = 0.38), postvoid residual volume (p = 0.12), prostate-specific antigen (p = 0.41), and prostate volume (p = 0.16). Conclusion: Combination treatment with SR and BC plus TAM was shown to be more effective than treatment with TAM only in improving IPSS storage and QoL subscores in BPH patients after 6 months and up to 12 months of treatment.
Incidental Findings Identified on Head MRI for Investigation of Cognitive Impairment: A Retrospective Review
Authors: Glasmacher Stella Andrea , Thomas Hannah Sam , Stirland Lucy , Wilkinson Tim , Lumsden Jane , Langlands Gavin , Waddell Briony , Holloway Guy , Thompson Gerard , Pal Suvankar
Published: December 2019

Introduction: Incidental findings are common in presumed healthy volunteers but are infrequently studied in patients in a clinical context. Objective: To determine the prevalence, nature, and management implications of incidental findings on head MRI in patients presenting with cognitive symptoms, and to quantify and describe unexpected MRI abnormalities that are of uncertain relevance to the patient’s cognitive symptoms. Methods: A single-centre retrospective review of patients attending a regional early-onset cognitive disorders clinic between March 2012 and October 2018. Medical records of consecutive patients who underwent head MRI were reviewed. Unexpected MRI findings were classified according to their severity and likelihood of being incidental. Markers of small vessel disease and cerebral atrophy were excluded. Results: Records of 694 patients were reviewed (median age 60 years, 49.9% female), of whom 514 (74.1%) underwent head MRI. 54% of the patients received a diagnosis of a neurodegenerative disorder. Overall 111 incidental findings were identified in 100 patients of whom 18 patients (3.5%, 95% CI 2.2–5.6%) had 18 incidental findings classified as requiring additional medical evaluation. 82 patients (16%, 95% CI 13.0–19.5%) had 93 incidental findings without clearly defined diagnostic consequences. 17 patients (3.3%) underwent further investigations, 14 patients (2.7%) were referred to another specialist clinic and 3 patients (0.6%) were treated surgically. Two patients had MRI findings of uncertain relevance to their cognitive symptoms, necessitating prolonged clinic follow-up. Conclusion: Incidental findings are common in patients with cognitive impairment from this large clinic-based series; however, few required additional medical evaluation. These data could help inform discussions between clinicians and people with cognitive symptoms regarding the likelihood and potential implications of incidental imaging findings.
Dilatation of Retinal Arterioles Induced by Topical Dorzolamide for One Week Is Impaired in Patients with Type 1 Diabetes and Mild Retinopathy
Authors: Tilma Kathrine Kleis , Bek Toke
Published: December 2019

Background: Diabetic retinopathy is characterised by morphological lesions in the retina secondary to disturbances in retinal blood flow. Previous studies have shown that the carbonic anhydrase inhibitor (CAI) dorzolamide can induce immediate dilatation of retinal arterioles and a sustained increase in retinal blood flow in primary open-angle glaucoma. However, the effect of sustained treatment with CAI on retinal arterioles in normal persons and in patients with diabetic retinopathy is unknown. Methods: The Dynamic Vessel Analyzer was used to assess the baseline diameter and the diameter response of retinal arterioles during an increase in arterial blood pressure induced by isometric exercise and during flicker stimulation before and 2 h, 24 h and 1 week after onset of topical treatment with dorzolamide. At each examination the diameter responses were studied before and during breathing in of a hypercapnic gas mixture. Results: Treatment with dorzolamide for 1 week significantly increased the diameter of retinal arterioles in normal persons, and breathing in of a hypercapnic gas mixture reduced this response. The pathological vasodilatation and reduced retinal autoregulation in patients with diabetic retinopathy were unaffected by dorzolamide and hypercapnia. Conclusions: The study suggests a lack of relevance of CAI for the treatment of pathological vasodilatation in early diabetic retinopathy.
IL-35 Inhibited Th17 Response in Children with Allergic Rhinitis
Authors: Xie Fengmei , Hu Quanfu , Cai Qinfang , Yao Rongwei , Ouyang Shaoji
Published: December 2019

Objective: Previous studies have proved that Th17 (T helper 17) cell subsets, a unique proinflammatory CD4+ T cell lineage, are deeply involved in the pathophysiology of allergic rhinitis (AR). IL-35, secreted mainly by natural Treg (nTreg) and depending on the expression of Foxp3, can effectively alleviate allergen-induced specific airway inflammation. However, the regulation of IL-35 in AR is not clear. Methods: Twenty AR children and 20 healthy controls were enrolled. The expression of serum IL-35 protein was detected and the correlation with Th17 cytokines (IL-17, IL-23, IL-27) expression was analyzed by enzyme-linked immunosorbent assay (ELISA). Peripheral blood mononuclear cells were prepared and stimulated by IL-35 to explore its effect on Th17 inflammation. Results: Serum IL-35 levels in AR were negatively correlated with serum IL-17 and IL-23 levels in AR. Recombinant IL-35 inhibits the Th17 response of PBMCs, which were mediated by the mitogen-activated protein kinase (MEK) and c-Jun N-terminal kinase (JNK) pathways. Conclusions: Our data demonstrate that IL-35 can inhibit Th17 response in AR through MEK and JNK pathways.
Allergic Rhinitis to Weed Pollen in Germany: Dominance by Plantain, Rising Prevalence, and Polysensitization Rates over 20 Years
Authors: Forkel Susann , Beutner Caroline , Heetfeld Anne , Fuchs Thomas , Schön Michael P. , Geier Johannes , Buhl Timo
Published: December 2019

Background: In contrast to the 3 major aeroallergens tree pollen, grass pollen, and house dust mites, allergic rhinitis caused by herbal pollen has received comparatively little attention in recent clinical studies. Since various weeds flower during summer until fall, allergic rhinitis to weeds may be underdiagnosed and/or mistakenly diagnosed as grass pollen allergy. Objective: To investigate (i) the currently most frequent weed allergy between mugwort, ragweed, plantain, chamomile, nettle, and oilseed rape and (ii) time trends in prevalence of sensitization to weed pollen in the middle of Germany over the last 20 years. Methods: This study, the largest of its kind to date, monocentrically evaluated the prick test results of a total of 6,220 patients with suspected RCA over a period of 20 years (1998–2017). Results: In the study cohort, sensitization rates to plantain almost doubled from 26.6% in the decade 1998–2007 to 50.5% in 2008–2017. Identical increases were observed for ragweed, while sensitization rates for mugwort stayed largely unchanged. The most prominent increase in positive skin prick tests to plantain and ragweed pollen was mainly observed in younger patients. Further, we identified a trend toward polysensitization, currently dominated by plantain and ragweed. Sensitization to weed pollen was found to be highly associated with additional sensitizations to grass and/or birch pollen. Conclusion: Plantain is currently the best choice to screen rhinitis patients for weed allergy which identifies 86% of all weed-sensitized individuals, at least in Germany. Over the last 20 years, we demonstrate a significant rise in the total number of weed pollen sensitization as well as increases in polysensitization, predominantly in younger patients.