bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of extracellular vesicles in stem cell biology
Authors: Bruno Stefania , Chiabotto Giulia , Favaro Enrica , Deregibus Maria Chiara , Camussi Giovanni
Published: May 2019

The extracellular vesicles (EVs) are membrane vesicles carrying proteins, nucleic acids, and bioactive lipids of the cell of origin. These vesicles released within the extracellular space and entering into the circulation may transfer their cargo to neighboring or distant cells and induce phenotypical and functional changes that may be relevant in several physiopathological conditions. In an attempt to define the biological properties of EVs, several investigations have focused on their cargo and on the effects elicited in recipient cells. EVs have been involved in modulation of tumor microenvironment and behavior, as well as in the immune and inflammatory response. In the present review, we address the paracrine action of EVs released by stem cells and their potential involvement in the activation of regenerative programs in injured cells.
Gut and immune effects of bioactive milk factors in preterm pigs exposed to prenatal inflammation
Authors: Ren Shuqiang , Hui Yan , Goericke-Pesch Sandra , Pankratova Stanislava , Kot Witold , Pan Xiaoyu , Thymann Thomas , Sangild Per T. , Nguyen Duc Ninh
Published: May 2019

Prenatal inflammation may predispose to preterm birth and postnatal inflammatory disorders such as necrotizing enterocolitis (NEC). Bioactive milk ingredients may help to support gut maturation in such neonates, but mother’s milk is often insufficient after preterm birth. We hypothesized that supplementation with bioactive ingredients from bovine milk [osteopontin (OPN), caseinoglycomacropeptide (CGMP), colostrum (COL)] supports gut, immunity, and NEC resistance in neonates born preterm after gram-negative infection before birth. Using preterm pigs as a model for preterm infants, fetal pigs were given intraamniotic injections of lipopolysaccharide (LPS; 1 mg/fetus) and delivered 3 days later (90% gestation). For 5 days, groups of LPS-exposed pigs were fed formula (FOR), bovine colostrum (COL), or formula enriched with OPN or CGMP. LPS induced intraamniotic inflammation and postnatal systemic inflammation but limited effects on postnatal gut parameters and NEC. Relative to FOR, COL feeding to LPS-exposed pigs showed less diarrhea, NEC severity, reduced gut IL-1β and IL-8 levels, greater gut goblet cell density and digestive enzyme activities, and blood helper T-cell fraction. CGMP improved neonatal arousal and gut lactase activities and reduced LPS-induced IL-8 secretion in intestinal epithelial cells (IECs) in vitro. Finally, OPN tended to reduce diarrhea and stimulated IEC proliferation in vitro. No effects on villus morphology, circulating cytokines, or colonic microbiota were observed among groups. In conclusion, bioactive milk ingredients exerted only modest effects on gut and systemic immune parameters in preterm pigs exposed to prenatal inflammation. Short-term, prenatal exposure to inflammation may render the gut less sensitive to immune-modulatory milk effects.

NEW & NOTEWORTHY Prenatal inflammation is a risk factor for preterm birth and postnatal complications including infections. However, from clinical studies, it is difficult to separate the effects of only prenatal inflammation from preterm birth. Using cesarean-delivered preterm pigs with prenatal inflammation, we documented some beneficial gut effects of bioactive milk diets relative to formula, but prenatal inflammation appeared to decrease the sensitivity of enteral feeding. Special treatments and diets may be required for this neonatal population.
Clathrin and GRK2/3 inhibitors block δ-opioid receptor internalization in myenteric neurons and inhibit neuromuscular transmission in the mouse colon
Authors: DiCello Jesse J. , Rajasekhar Pradeep , Eriksson Emily M. , Saito Ayame , Gondin Arisbel B. , Veldhuis Nicholas A. , Canals Meritxell , Carbone Simona E. , Poole Daniel P.
Published: May 2019

Endocytosis is a major mechanism through which cellular signaling by G protein-coupled receptors (GPCRs) is terminated. However, recent studies demonstrate that GPCRs are internalized in an active state and continue to signal from within endosomes, resulting in effects on cellular function that are distinct to those arising at the cell surface. Endocytosis inhibitors are commonly used to define the importance of GPCR internalization for physiological and pathophysiological processes. Here, we provide the first detailed examination of the effects of these inhibitors on neurogenic contractions of gastrointestinal smooth muscle, a key preliminary step to evaluate the importance of GPCR endocytosis for gut function. Inhibitors of clathrin-mediated endocytosis (Pitstop2, PS2) or G protein-coupled receptor kinase-2/3-dependent phosphorylation (Takeda compound 101, Cmpd101), significantly reduced GPCR internalization. However, they also attenuated cholinergic contractions through different mechanisms. PS2 abolished contractile responses by colonic muscle to SNC80 and morphine, which strongly and weakly internalize δ-opioid and μ-opioid receptors, respectively. PS2 did not affect the increased myogenic contractile activity following removal of an inhibitory neural influence (tetrodotoxin) but suppressed electrically evoked neurogenic contractions. Ca2+ signaling by myenteric neurons in response to exogenous ATP was unaffected by PS2, suggesting inhibitory actions on neurotransmitter release rather than neurotransmission. In contrast, Cmpd101 attenuated contractions to the cholinergic agonist carbachol, indicating direct effects on smooth muscle. We conclude that, although PS2 and Cmpd101 are effective blockers of GPCR endocytosis in enteric neurons, these inhibitors are unsuitable for the study of neurally mediated gut function due to their inhibitory effects on neuromuscular transmission and smooth muscle contractility.

NEW & NOTEWORTHY Internalization of activated G protein-coupled receptors is a major determinant of the type and duration of subsequent downstream signaling events. Inhibitors of endocytosis effectively block opioid receptor internalization in enteric neurons. The clathrin-dependent endocytosis inhibitor Pitstop2 blocks effects of opioids on neurogenic contractions of the colon in an internalization-independent manner. These inhibitors also significantly impact cholinergic neuromuscular transmission. We conclude that these tools are unsuitable for examination of the contribution of neuronal G protein-coupled receptor endocytosis to gastrointestinal motility.
Role of phospholipase D in bleomycin-induced mitochondrial reactive oxygen species generation, mitochondrial DNA damage, and pulmonary fibrosis
Authors: Suryadevara Vidyani , Huang Longshuang , Kim Seok-Jo , Cheresh Paul , Shaaya Mark , Bandela Mounica , Fu Panfeng , Feghali-Bostwick Carol , Di Paolo Gilbert , Kamp David W. , Natarajan Viswanathan
Published: May 2019

Idiopathic pulmonary fibrosis (IPF) is a pernicious lung disease characterized by alveolar epithelial apoptosis, dysregulated repair of epithelial injury, scar formation, and respiratory failure. In this study, we identified phospholipase D (PLD)-generated phosphatidic acid (PA) signaling in the development of pulmonary fibrosis (PF). Of the PLD isoenzymes, the protein expression of PLD2, but not PLD1, was upregulated in lung tissues from IPF patients and bleomycin challenged mice. Both PLD1 ( Pld1−/−)- and PLD2 ( Pld2−/−)-deficient mice were protected against bleomycin-induced lung inflammation and fibrosis, thereby establishing the role of PLD in fibrogenesis. The role of PLD1 and PLD2 in bleomycin-induced lung epithelial injury was investigated by infecting bronchial airway epithelial cells (Beas2B) with catalytically inactive mutants of PLD ( hPLD1-K898R or mPld2-K758R) or downregulation of expression of PLD1 or PLD2 with siRNA. Bleomycin stimulated mitochondrial (mt) superoxide production, mtDNA damage, and apoptosis in Beas2B cells, which was attenuated by the catalytically inactive mutants of PLD or PLD2 siRNA. These results show a role for PLD1 and PLD2 in bleomycin-induced generation of mt reactive oxygen species, mt DNA damage, and apoptosis of lung epithelial cells in mice. Thus, PLD may be a novel therapeutic target in ameliorating experimental PF in mice.
Habitual cigarette smoking raises pressor responses to spontaneous bursts of muscle sympathetic nerve activity
Authors: Cui Jian , Drew Rachel C. , Muller Matthew D. , Blaha Cheryl , Gonzalez Virginia , Sinoway Lawrence I.
Published: May 2019

Smoking is a risk factor for cardiovascular diseases. Prior reports showed a transient increase in blood pressure (BP) following a spontaneous burst of muscle sympathetic nerve activity (MSNA). We hypothesized that this pressor response would be accentuated in smokers. Using signal-averaging techniques, we examined the BP (Finometer) response to MSNA in 18 otherwise healthy smokers and 42 healthy nonsmokers during resting conditions. The sensitivities of baroreflex control of MSNA and heart rate were also assessed. The mean resting MSNA, heart rate, and mean arterial pressure (MAP) were higher in smokers than nonsmokers. The MAP increase following a burst of MSNA was significantly greater in smokers than nonsmokers (Δ3.4 ± 0.3 vs. Δ1.6 ± 0.1 mmHg, P < 0.001). The baroreflex sensitivity (BRS) of burst incidence, burst area, or total activity was not different between the two groups. However, cardiac BRS was lower in smokers than nonsmokers (14.6 ± 1.7 vs. 24.6 ± 1.5 ms/mmHg, P < 0.001). Moreover, the MAP increase following a burst was negatively correlated with the cardiac BRS. These observations suggest that habitual smoking in otherwise healthy individuals raises the MAP increase following spontaneous MSNA and that the attenuated cardiac BRS in the smokers was a contributing factor. We speculate that the accentuated pressor increase in response to spontaneous MSNA may contribute to the elevated resting BP in the smokers.
Cystitis-induced bladder pain is Toll-like receptor 4 dependent in a transgenic autoimmune cystitis murine model: a MAPP Research Network animal study
Authors: Cui Xiangrong , Jing Xuan , Lutgendorf Susan K. , Bradley Catherine S. , Schrepf Andrew , Erickson Bradley A. , Magnotta Vincent A. , Ness Timothy J. , Kreder Karl J. , O’Donnell Michael A. , Luo Yi
Published: May 2019

Altered Toll-like receptor (TLR)4 activation has been identified in several chronic pain conditions but has not been well studied in interstitial cystitis/bladder pain syndrome (IC/BPS). Our previously published human studies indicated that patients with IC/BPS present altered systemic TLR4-mediated inflammatory responses, which were significantly correlated with reported pain severity. In the present study, we sought to determine whether altered TLR4 activation plays a role in pelvic/bladder pain seen in patients with IC/BPS using our validated IC/BPS-like transgenic autoimmune cystitis model (URO-OVA). URO-OVA mice developed responses consistent with pelvic and bladder pain after cystitis induction, which was associated with increased splenocyte production of TLR4-mediated proinflammatory cytokines IL-1β, IL-6, and TNF-α. Increased spinal expression of mRNAs for proinflammatory cytokines IL-6 and TNF-α, glial activation markers CD11b and glial fibrillary acidic protein, and endogenous TLR4 ligand high mobility group box 1 was also observed after cystitis induction. Compared with URO-OVA mice, TLR4-deficient URO-OVA mice developed significantly reduced nociceptive responses, although similar bladder inflammation and voiding dysfunction, after cystitis induction. Intravenous administration of TAK-242 (a TLR4-selective antagonist) significantly attenuated nociceptive responses in cystitis-induced URO-OVA mice, which was associated with reduced splenocyte production of TLR4-mediated IL-1β, IL-6, and TNF-α as well as reduced spinal expression of mRNAs for IL-6, TNF-α, CD11b, glial fibrillary acidic protein, and high mobility group box 1. Our results indicate that altered TLR4 activation plays a critical role in bladder nociception independent of inflammation and voiding dysfunction in the URO-OVA model, providing a potential mechanistic insight and therapeutic target for IC/BPS pain.
MCP-1 promotes detrimental cardiac physiology, pulmonary edema, and death in thecpkmodel of polycystic kidney disease
Authors: Salah Sally M. , Meisenheimer James D. , Rao Reena , Peda Jacqueline D. , Wallace Darren P. , Foster Dawson , Li Xiaogang , Li Xiaoyan , Zhou Xia , Vallejo Julian A. , Wacker Michael J. , Fields Timothy A. , Swenson-Fields Katherine I.
Published: May 2019

Polycystic kidney disease (PKD) is characterized by slowly expanding renal cysts that damage the kidney, typically resulting in renal failure by the fifth decade. The most common cause of death in these patients, however, is cardiovascular disease. Expanding cysts in PKD induce chronic kidney injury that is accompanied by immune cell infiltration, including macrophages, which we and others have shown can promote disease progression in PKD mouse models. Here, we show that monocyte chemoattractant protein-1 [MCP-1/chemokine (C-C motif) ligand 2 (CCL2)] is responsible for the majority of monocyte chemoattractant activity produced by renal PKD cells from both mice and humans. To test whether the absence of MCP-1 lowers renal macrophage concentration and slows disease progression, we generated genetic knockout (KO) of MCP-1 in a mouse model of PKD [congenital polycystic kidney ( cpk) mice]. Cpk mice are born with rapidly expanding renal cysts, accompanied by a decline in kidney function and death by postnatal day 21. Here, we report that KO of MCP-1 in these mice increased survival, with some mice living past 3 mo. Surprisingly, however, there was no significant difference in renal macrophage concentration, nor was there improvement in cystic disease or kidney function. Examination of mice revealed cardiac hypertrophy in cpk mice, and measurement of cardiac electrical activity via ECG revealed repolarization abnormalities. MCP-1 KO did not affect the number of cardiac macrophages, nor did it alleviate the cardiac aberrancies. However, MCP-1 KO did prevent the development of pulmonary edema, which occurred in cpk mice, and promoted decreased resting heart rate and increased heart rate variability in both cpk and noncystic mice. These data suggest that in this mouse model of PKD, MCP-1 altered cardiac/pulmonary function and promoted death outside of its role as a macrophage chemoattractant.
Can Met-PET/CT Predict Sporadic Multiglandular Hyperparathyroidism? Report of a Case and Review of the Literature
Authors: Hillenbrand Andreas , Lemke Johannes , Henne-Bruns Doris , Beer Ambros J. , Prasad Vikas
Published: May 2019

Background. Primary hyperparathyroidism (pHPT) is a common endocrine disorder of the parathyroid glands. In most cases pHPT is caused by single gland disease, but about 10% of patients suffer from sporadic multiglandular disease (MGD). Patients with MGD, especially with ectopic parathyroid adenomas, have an increased risk for persistence/recurrence after surgery. Normally, sporadic MGD cannot be diagnosed preoperatively by parathyroid scintigraphy. We analyzed the potential of positron emission tomography/computed tomography (Met-PET/CT) to predict MGD. Methods and Case Presentation. We reviewed the literature, if preoperative Met-PET/CT could predict MGD in patients with pHPT. Further, we present a 71-year-old female with ectopic MGD. Preoperative localization via Met-PET/CT showed MGD with two areas suspected to be enlarged parathyroid glands (left lateral to the thyroid lobe and posterior mediastinum). Both diagnostic findings were extirpated and parathormone dropped into normal levels. Results. We identified four additional manuscripts, referring to MGD and Met-PET/CT with divergent results. Preoperative localization diagnostics using Met-PET/CT may not necessarily identify MGD. In most cases, Met-PET/CT localized only one adenoma and localizes larger adenomas more reliably than smaller adenomas. Conclusion. Identifying patients at risk of MGD preoperatively remains challenging. We found MET-PET/CT seems to predict MGD in patients with large size and high weight PTH adenomas. For ectopic parathyroid adenomas, accurate preoperative localization is the key to successful surgical removal. Met-PET/CT appears to have great potential in soft-tissue analysis of complex anatomical regions and can predict ectopic parathyroid adenomas.
The Neuroscience of Nonpharmacological Traditional Chinese Therapy (NTCT) for Major Depressive Disorder: A Systematic Review and Meta-Analysis
Authors: Ye Jiajia , Cheung Wai Ming , Tsang Hector Wing Hong
Published: May 2019

Background.Depression is a common disease affecting a large number of people across the world. Many researchers have focused on treatment for depression based on Western scientific approaches, but research based on traditional Chinese medicine (TCM) interventions, studying its clinical effectiveness and the underlying mechanisms involved, has been limited. The aim of this review is to conduct a pioneering systematic review with meta-analysis of existing studies that investigate the neuroscience basis of nonpharmacological traditional Chinese therapy (NTCT).Methods.Both English (Pubmed,Embase,Scopus,SPORTDiscus,PsycINFO) and Chinese (China National Knowledge Infrastructure(CNKI)) databases were searched from inception to October 2018. The effects of NTCT on major depressive disorder, brain activity, and neurophysiological biomarker related outcomes were extracted. Study quality was assessed using the Physiotherapy Evidence Database (PEDro) scale. The effect size of each study was reported by the mean difference of change scores.Results.Six of twelve eligible studies showed that there was a significant improvement in favor of acupuncture in depressive symptoms (SMD -0.69, 95%CI-1.09 to -0.28,p=0.002,I2= 73%,p< 0.0008). Based on the available evidence, NTCT including acupuncture, Qigong, and Tai Chi was found to possibly improve brain metabolites, brain activity, and immune and endocrine systems in patients with major depressive disorder.Conclusions.Acupuncture could effectively relieve depressive syndromes. The clinical effects of acupuncture might be attributable to their influence on three proposed pathways, namely, the hypothalamic–pituitary–adrenal (HPA) axis, the locus coeruleus (LC)-immunity pathway, and the negative feedback loop of the hippocampus. Nevertheless, conclusions are limited due to the small number of studies included and the low-quality of the study designs. In the future, a cross-sectional study is needed to test the proposed plausible pathways. PROSPERO registration number isCRD42017080937.
Semantic‐Aware Top‐k Multirequest Optimal Route
Authors: Wang Shuang , Xu Yingchun , Wang Yinzhe , Liu Hezhi , Zhang Qiaoqiao , Ma Tiemin , Liu Shengnan , Zhang Siyuan , Li Anliang
Published: May 2019

In recent years, research on location‐based services has received a lot of interest, in both industry and academic aspects, due to a wide range of potential applications. Among them, one of the active topic areas is the route planning on a point‐of‐interest (POI) network. We study the top‐k optimal routes querying on large, general graphs where the edge weights may not satisfy the triangle inequality. The query strives to find the top‐k optimal routes from a given source, which must visit a number of vertices with all the services that the user needs. Existing POI query methods mainly focus on the textual similarities and ignore the semantic understanding of keywords in spatial objects and queries. To address this problem, this paper studies the semantic similarity of POI keyword searching in the route. Another problem is that most of the previous studies consider that a POI belongs to a category, and they do not consider that a POI may provide various kinds of services even in the same category. So, we propose a novel top‐k optimal route planning algorithm based on semantic perception (KOR‐SP). In KOR‐SP, we define a dominance relationship between two partially explored routes which leads to a smaller searching space and consider the semantic similarity of keywords and the number of single POI’s services. We use an efficient label indexing technique for the shortest path queries to further improve efficiency. Finally, we perform an extensive experimental evaluation on multiple real‐world graphs to demonstrate that the proposed methods deliver excellent performance.
The Influence of Initial Normal Stress Assumption of Slip Surface on Safety Factor of Symmetrical Three-Dimensional Slopes
Authors: Liu Huali
Published: May 2019

By using the explicit solution of three-dimensional slope stability based on modification of normal stress distribution over the slip surface, the influence of assumption of the three-dimensional initial normal stress on the safety factor is investigated. The initial normal stress distribution over the 3D slip surface was assumed, and then it was modified by a function with 2 parameters to satisfy two force equilibrium conditions about two axes and one moment equilibrium condition around one axis. An iterative equation was derived that would yield a value to 3D safety factor. The values of three-dimensional safety factor of symmetrical slopes are computed with different assumptions of initial normal stresses. The computation results show that the influence of assumption of initial normal stress on the safety factor of symmetrical three-dimensional slopes is negligible because the maximum different value of the three-dimensional safety factor is below 5%.
Compounded Calibration Based on FNN and Attitude Estimation Method Using Intelligent Filtering for Low Cost MEMS Sensor Application
Authors: Wang Lei , Guan Ying , Hu Xuedong
Published: May 2019

Micro electro mechanical system (MEMS) inertial sensors have advantages, including small size and low power consumption. The performances of Micro Inertial measurement unit (IMU), which is composed of MEMS inertial sensors, degrade, and error, will become larger in high dynamic environment. In order to solve the problem, a novel combined calibration method for compensating the deterministic error of MEMS sensors is proposed. Considering the rotation of different sensitive axes in high dynamic and low dynamic environment, the compounded calibration based on fuzzy neural network (FNN) is adopted to identify the coupling coefficients to eliminate the adverse coupling effects between different rotation axes. Furthermore, the self‐developed Micro IMU and magnetometer are applied in attitude estimation system. Considering the large attitude error occurred in most cases, the approach utilizing the estimation of error quaternion vector could avoid the calculation error due to inaccurate modeling in the skew symmetric matrix that comprises attitude error vector components. The intelligent Kalman filter (IKF) based on complexity state equation of error quaternion is designed to improve the performance by adjusting the parameters of filter on line. The experimental results show that the proposed approach could have a higher level of stability and accuracy in comparison to other attitude estimation algorithms.
Efficient Unconstrained Iris Recognition System Based on CCT‐Like Mask Filter Bank
Authors: Fathee Hala N. , Ucan Osman N. , Abdul-Jabbar Jassim M. , Bayat Oguz
Published: May 2019

In this paper, a new personal identification method based on unconstrained iris recognition is presented. We apply a nontraditional step for feature extraction where a new circular contourlet filter bank is used to capture the iris characteristics. This idea is based on a new geometrical image transform called the circular contourlet transform (CCT). An efficient multilevel and multidirectional contourlet decomposition method is needed to form a reduced‐length quantized feature vector with improved performance. The CCT transform provides both multiscale and multioriented analysis of iris features. Circular contourlet‐like mask filters can be used with shapes just like the 2D circular‐support regions in different scales and directions. A reduced recognition system is realized using a single branch of the whole decomposition bank, highlighting a system realization with lower complexity and fewer computations. In the proposed recognition system, only five out of seven elements of the gray level cooccurrence matrix are required in the creation of the feature vector, which leads to a further reduction in computations. In addition, the highly discriminative frequency regions due to the use of circular‐support decompositions can result in highly accurate feature vectors, reflecting good recognition rates for the proposed system. It is shown that the proposed system has encouraging performance in terms of high recognition rates and a reduced number of elements of the feature vector. This reflects reliable and rapid recognition properties. In addition, some promising characteristics of the system are apparent since it can efficiently be realized with lower computation complexity.
Quantitative Reinforcement Analysis of Loess Slope with Anisotropy
Authors: Shi Yuling , Wang Rui , Yuan Hang , Bao Han , Yan Changgen
Published: May 2019

The loess slope in east Gansu presents a large degree of anisotropy which should be considered both in the slope stability analysis and in the reinforcement design. To investigate the mechanical anisotropy presented in the loess soil, the undisturbed loess specimens are taken from the field with different sampling directions (α, defined as the angle between the normal direction of specimen and sedimentation direction). The direct shear tests are conducted on specimens of different α, and it is found that the anisotropy has slight influence on the friction angle (φ), while the specimen with α = 0° presents the smallest cohesion and the specimen with α = 90° has the largest cohesion. The anisotropy behaviors have also been observed from the one‐dimensional consolidation test and tension test. After that, the principle of point safety factor and the degree of reinforcement demand are introduced, and the method of quantitative reinforcement of anisotropic loess slope is proposed. The proposed approach is then implemented in the Fast Lagrangian Analysis of Continua in 3D (FLAC3D), and the point safety factor and the degree of reinforcement demand are investigated on slope with different slope ratios. It is found that the proposed approach could effectively be used to analyze the slope involving anisotropy through the comparison with the conventional limit equilibrium method. Meanwhile, the reinforcement zone and the reinforcement demanding of anisotropy slope are obtained, and relevant reinforcement design in practice is proposed.
Preparation and Sound Insulation Performance of Superfine Metal Powder/Nitrile-Butadiene Rubber-Polyvinyl Chloride Microcellular Foaming Material
Authors: Hu Sheng , Cai Jun , Liao Guofeng , Fu Qiang
Published: May 2019

Lightweight sound insulation materials have received much attention. In this study, a series of superfine metal powder (SFM)/nitrile-butadiene rubber (NBR)-polyvinyl chloride (PVC) microcellular foaming materials were prepared with NBR-PVC as matrix and SFM as modifiers by employing the method of molding foaming. Analysis on the morphology of cross section, pore size, and pore distribution possessed by SFM/NBR-PVC was conducted by scanning electron microscopy (SEM), as well as the image processing software of Image-Pro. Then detailed discussion on the effect of SFM with different mass fractions in the matrix on the foaming quality was provided. In the meanwhile, the performance of sound insulation was tested by four-channel impedance tube system. The results show significant improvement for foaming quality and sound insulation performance of NBR-PVC microcellular foaming material through the addition of SFM. In comparison with the pure NBR-PVC materials, the microcellular foaming material exhibits the best performance of foaming quality and sound insulation when the SFM content in matrix is 30 wt%. It is shown that the average pore diameter and the foaming capacity decrease by 60% and 31%, respectively, while the surface density increases by 131%. In the meantime, the sound insulation index of SFM/NBR-PVC microcellular material increases by 7.2 dB to 30.5 dB, which conforms to the requirements of new lightweight sound insulation materials in modern time. Finally, the mechanism of the optimization conducted for sound insulation performance after the addition of SMF is explained.
A Case of Carbon Monoxide-Induced Delayed Neurological Sequelae Successfully Treated with Hyperbaric Oxygen Therapy, N-Acetylcysteine, and Glucocorticoids: Clinical and Neuroimaging Follow-Up
Authors: Spina Vincenzo , Tomaiuolo Francesco , Celli Lorenzo , Bonfiglio Luca , Cecchetti Luca , Carboncini Maria Chiara
Published: May 2019

Carbon monoxide (CO) poisoning is a leading cause of intentional and unintentional poisoning worldwide, associated with mortality and severe morbidity. Some survivors of CO poisoning develop, after a lucid interval, a potentially permanent encephalopathy in the form of cognitive impairment and movement disorders, such as Parkinsonism. One of the most frequent neuroimaging findings is a cerebral white matter damage, but so far its precise cause and specific therapy are still debated. We here report the case of a 33-year-old woman with severe carbon monoxide poisoning who, after a period of lucid interval, presented symptoms of declining motor and cognitive functions. She was treated with 40 sessions of Hyperbaric Oxygen Therapy (HBOT). The therapeutic use of oxygen at supraphysiological pressures might either increase systemic oxidative stress or cause an overproduction of oxygen free radicals as drawbacks. Concurrent use of antioxidants and anti-inflammatory drugs may prevent the side effects of oxygen therapy at supraphysiological pressure due to oxidative stress. For this reason, the patient was also treated with high-dose N-Acetylcysteine and glucocorticoids. Here, we describe the longitudinal monitoring of patient’s cognitive abilities and leukoencephalopathy associated with her positive clinical outcome.
Cancer-Associated Fibroblasts Produce Netrin-1 to Control Cancer Cell Plasticity
Authors: Sung Pei-Ju , Rama Nicolas , Imbach Jeromine , Fiore Stephany , Ducarouge Benjamin , Neves David , Chen Huei-Wen , Bernard David , Yang Pan-Chyr , Bernet Agnès , Depil Stephane , Mehlen Patrick
Published: May 2019

Netrin-1 is upregulated in a large fraction of human neoplasms. In multiple animal models, interference with netrin-1 is associated with inhibition of tumor growth and metastasis. Although netrin-1 upregulation was initially described in cancer cells, we report here that in the human colorectal cancer database, the expression of netrin-1 and its receptor UNC5B correlates with a cancer-associated fibroblasts (CAF) signature. Both colon and lung CAF secreted netrin-1 when cocultured with respective cancer cells, and netrin-1 upregulation in CAF was associated with increased cancer cell stemness. Pharmacologic inhibition of netrin-1 with a netrin-1–mAb (Net1–mAb) abrogated the CAF-mediated increase of cancer stemness both in coculture experiments and in mice. Net-1–mAb inhibited intercellular signaling between CAF and cancer cells by modulating CAF-mediated expression of cytokines such as IL6. Together these data demonstrate that netrin-1 is upregulated not only in cancer cells but also in cancer-associated stromal cells. In addition to its direct activity on cancer cells, inhibition of netrin-1 may reduce proneoplastic CAF–cancer cell cross-talk, thus inhibiting cancer plasticity.

Significance:

Netrin-1, a navigation cue during embryonic development, is upregulated in cancer-associated fibroblasts and regulates cancer cell stemness.
Metabolic Reprogramming by MYCN Confers Dependence on the Serine-Glycine-One-Carbon Biosynthetic Pathway
Authors: Xia Yingfeng , Ye Bingwei , Ding Jane , Yu Yajie , Alptekin Ahmet , Thangaraju Muthusamy , Prasad Puttur D. , Ding Zhi-Chun , Park Eun Jeong , Choi Jeong-Hyeon , Gao Bei , Fiehn Oliver , Yan Chunhong , Dong Zheng , Zha Yunhong , Ding Han-Fei
Published: May 2019

MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to MYCN-amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in MYCN-amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activation of ATF4 mRNA expression and ATF4 stabilization of MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy.

Significance:

This study identifies a MYCN-dependent metabolic vulnerability and suggests a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited for cancer therapy.

See related commentary by Rodriguez Garcia and Arsenian-Henriksson, p. 3818
DFMO and 5-Azacytidine Increase M1 Macrophages in the Tumor Microenvironment of Murine Ovarian Cancer
Authors: Travers Meghan , Brown Stephen M. , Dunworth Matthew , Holbert Cassandra E. , Wiehagen Karla R. , Bachman Kurtis E. , Foley Jackson R. , Stone Meredith L. , Baylin Stephen B. , Casero Robert A. , Zahnow Cynthia A.
Published: May 2019

Although ovarian cancer has a low incidence rate, it remains the most deadly gynecologic malignancy. Previous work has demonstrated that the DNMTi 5-Azacytidine (5AZA-C) activates type I interferon signaling to increase IFNγ+ T cells and natural killer (NK) cells and reduce the percentage of macrophages in the tumor microenvironment. To improve the efficacy of epigenetic therapy, we hypothesized that the addition of α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, may further decrease immunosuppressive cell populations improving outcome. We tested this hypothesis in an immunocompetent mouse model for ovarian cancer and found that in vivo, 5AZA-C and DFMO, either alone or in combination, significantly increased survival, decreased tumor burden, and caused recruitment of activated (IFNγ+) CD4+ T cells, CD8+ T cells, and NK cells. The combination therapy had a striking increase in survival when compared with single-agent treatment, despite a smaller difference in recruited lymphocytes. Instead, combination therapy led to a significant decrease in immunosuppressive cells such as M2 polarized macrophages and an increase in tumor-killing M1 macrophages. In this model, depletion of macrophages with a CSF1R-blocking antibody reduced the efficacy of 5AZA-C + DFMO treatment and resulted in fewer M1 macrophages in the tumor microenvironment. These observations suggest our novel combination therapy modifies macrophage polarization in the tumor microenvironment, recruiting M1 macrophages and prolonging survival.

Significance:

Combined epigenetic and polyamine-reducing therapy stimulates M1 macrophage polarization in the tumor microenvironment of an ovarian cancer mouse model, resulting in decreased tumor burden and prolonged survival.
Oncolytic Herpes Virus Armed with Vasculostatin in Combination with Bevacizumab Abrogates Glioma Invasion via the CCN1 and AKT Signaling Pathways
Authors: Tomita Yusuke , Kurozumi Kazuhiko , Yoo Ji Young , Fujii Kentaro , Ichikawa Tomotsugu , Matsumoto Yuji , Uneda Atsuhito , Hattori Yasuhiko , Shimizu Toshihiko , Otani Yoshihiro , Oka Tetsuo , Kaur Balveen , Date Isao
Published: May 2019

Anti-VEGF treatments such as bevacizumab have demonstrated convincing therapeutic advantage in patients with glioblastoma. However, bevacizumab has also been reported to induce invasiveness of glioma. In this study, we examined the effects of rapid antiangiogenesis mediated by oncolytic virus (RAMBO), an oncolytic herpes simplex virus-1 expressing vasculostatin, on bevacizumab-induced glioma invasion. The effect of the combination of RAMBO and bevacizumab in vitro was assessed by cytotoxicity, migration, and invasion assays. For in vivo experiments, glioma cells were stereotactically inoculated into the brain of mice. RAMBO was intratumorally injected 7 days after tumor inoculation, and bevacizumab was administered intraperitoneally twice a week. RAMBO significantly decreased both the migration and invasion of glioma cells treated with bevacizumab. In mice treated with bevacizumab and RAMBO combination, the survival time was significantly longer and the depth of tumor invasion was significantly smaller than those treated with bevacizumab monotherapy. Interestingly, RAMBO decreased the expression of cysteine-rich protein 61 and phosphorylation of AKT, which were increased by bevacizumab. These results suggest that RAMBO suppresses bevacizumab-induced glioma invasion, which could be a promising approach to glioma therapy.
First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study
Authors: Khot Amit , Brajanovski Natalie , Cameron Donald P. , Hein Nadine , Maclachlan Kylee H. , Sanij Elaine , Lim John , Soong John , Link Emma , Blombery Piers , Thompson Ella R. , Fellowes Andrew , Sheppard Karen E. , McArthur Grant A. , Pearson Richard B. , Hannan Ross D. , Poortinga Gretchen , Harrison Simon J.
Published: May 2019

RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar–plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable.

Significance:

CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies.

This article is highlighted in the In This Issue feature, p. 983
ДИНАМІКА ЗАХВОРЮВАНОСТІ Й ПОШИРЕНОСТІ ПАТОЛОГІЇ ЩИТОПОДІБНОЇ ЗАЛОЗИ СЕРЕД ДОРОСЛОГО НАСЕЛЕННЯ УКРАЇНИ
Authors: Chukur O. O.
Published: May 2019

Мета: оцінити стан захворюваності та динаміку поширеності захворювань щитоподібної залози серед дорослого населення України протягом 2013–2017 рр.  

Матеріали і методи. Проведено порівняльний аналіз офіційних обліково-звітних статистичних даних МОЗ України та Інституту ендокринології та обміну речовин ім. В. П. Комісаренка АМН України «Основні показники діяльності ендокринологічної служби України».

Результати. В Україні зріс обсяг тиреоїдної патології і становить 46 % від загальної ендокринологічної захворюваності. Найпоширенішою патологією є дифузний та вузловий зоб. Їх рівень в західному регіоні вищий за середньодержавні показники та показники північно-східних областей. За 5 років зросла на 28,4 %  захворюваність на гіпотиреоз. Приріст тиреотоксикозу становив 8 %, а поширеність тиреоїдитів зросла на 12,7 %.  

Висока частота тиреоїдної патології залежить від недостатності йоду в харчуванні населення, незбалансованості мікроелементного і вітамінного складу в раціоні харчування на тлі погіршення екологічної ситуації та недостатньо ефективних профілактичних заходів.

Висновки. Проведений аналіз свідчить про необхідність диференційованого підходу до проведення діагностики, лікування та профілактики хворих із різною патологією щитоподібної залози в окремих регіонах України.
Children, Rights, and Powers
Authors: Giesinger Johannes
Published: May 2019

A long-standing debate on the concept of rights sets the so-called choice theory in contrast to the interest theory. As has been noted in the literature, the debate is relevant for the question of whether children can be conceived as rights-holders at all. This essay reflects on the concept of rights as applied to children, motivated by the view that instead of settling the conceptual issue, we should directly discuss the moral status of children as possible rights-holders. In this way, two main insights are gained. First, it is pointed out that the moral position of children – if they have rights – is very different from the status of adult rights-holders. Second, it is made clear that regardless of whether children have rights, the focus on duties towards children, rather than a focus on their rights, provides us with a clearer picture of children’s moral status.
Age is Just a Number? Supporting Migrant Young People with Precarious Legal Status in the UK
Authors: Prabhat Devyani , Singleton Ann , Eyles Robbie
Published: May 2019

This paper challenges the focus on age 18 as an exclusionary point in law for migrant young people, particularly unaccompanied migrants, with insecure legal status. Initially meant to provide a protective category of “childhood” in law, focus on age 18 creates a sharp transition point in law for young people. This chronological concept of age does not match up with the reality of lives of many young people who step into adulthood without being able to live in a self-supporting manner. Law recognises the constraints and provides some respite for British national children who are in care; however, non-UK migrant and/or asylum-seeking young people in this situation are immediately at risk of losing their liberty. We suggest that non-British migrant young people aged 18–21 should be treated as a youth category in a manner similar to that used for British young people in care.
Islam and Cultural Heritage on Tajik Television
Authors: Gatling Benjamin
Published: May 2019

For many members of the Tajik governing elite, Muslim piety remains problematic—a stubborn, socially regressive holdover of anti-modern Tajiks—and Muslim leaders are often thought of merely as anachronistic cultural survivals. This paper interrogates the depiction of Muslim exemplars as they appear on Tajik state television by comparing a 2009 documentary about the life of Imomi Abūḣanifa, the eponymous founder of the Ḣanafī school of jurisprudence, with an exposé about Ėshoni Temur, a local Naqshbandī Sufi pir tried and convicted in 2015 for polygyny and various indeterminate offenses against official notions of Muslim religiosity. This article considers different regimes of Muslim alterity as depicted on state media and argues that the Tajik governing elite alternately renders problematic Islam as innocuous heritage or in need of swift extermination.
The Transformation of Tajikistan’s Religious Field: From Religious Pluralism to Authoritarian Inertia
Authors: Nozimova Shahnoza , Epkenhans Tim
Published: May 2019

The recent transformation of Tajikistan’s political system has significantly altered the social and political context in which the country’s lay Muslims and religious elites negotiate Islam and Islamic normativity. The quasi-governmental Islamic Center (Markazi Islomi) has taken on a more dominant role, becoming the sole official (state-approved) Islamic institution in Tajikistan defining Islamic normativity. In this work, we explore the rationale behind the Tajik state’s pursuit of this political trajectory, conduct a detailed examination of the religious edicts ( fatwas) issued by the Islamic Center, and identify its conservative trends. Our research suggests that the Islamic Center offers the Tajik government a way to achieve its much-desired monopoly over the religious field. Furthermore, we argue that the Islamic Center’s conservative interpretation of Islam, with its emphasis on political conformity, social patriarchy, and limited mystical experience, is far more “legible” and administratively manageable for the authoritarian regime than the previous religious pluralism.
Creating the Thai National Corpus
Authors: Aroonmanakun Wirote
Published: May 2019

This paper reports on the progress of Thai National Corpus development. The TNC is designed as a general corpus of standard Thai. Only written texts are collected in the first phase. It aims to include at least eighty million words. Various text types produced by various authors are included in the TNC so that it would closely represent written language in general. Texts are word segmented and tagged following the Text Encoding Initiative (TEl) guidelines on text encoding. The TNC was designed as a resource for general applications, such as lexicography, language teaching, and linguistic research. In addition, the TNC is designed to be comparable to the British National Corpus so that a comparative study between the two languages is also possible.
Areal Typology of Mainland Southeast Asia: What We Learn from the Wals Maps
Authors: Comrie Bernard
Published: May 2019

Mainland Southeast Asia has long been recognized as a classic example of a linguistic area, but earlier characterizations of this language area have typically been intuitive, for instance providing seemingly impressive lists of features known to be shared by Mainland Southeast Asian languages but without considering a list of features on which these languages differ, without explicitly considering the extent to which the features in question are common or rare across the world as a whole. By using the maps in the World Atlas of Language Structures, it is possible to build up a more structured assessment of the extent to which Mainland Southeast Asia constitutes a linguistic area. Many maps show a clear delimitation between Mainland Southeast Asia and the rest of Eurasia, although the precise boundary varies from map to map, as does the presence and location of intermediate zones. The dividing line between Mainland Southeast Asia and Insular Southeast Asia is much less clear-cut, thus providing some evidence for a more general Southeast Asian linguistic area.
Another Look at Aspect in Thai
Authors: Kullavanijaya Pranee , Bisang Walter
Published: May 2019

The aim of the paper is twofold. The first aim is to analyse aspect in Thai in the framework of the selection-theory approach developed by Breu and Sasse (1991). The second aim is to study all possible co-occurrenc;es of each of the three aspect markers: lεεw, kamlaƞ, yùu with the four classes of verbs and with the verbs occurring with other strategies within the five classes of states of affairs. It was found that the selectional approach chosen helped explaining the inceptive-stative state of affairs in Thai clearly. It also pointed out that the Thai aspectuality focused on the initial boundary and terminative boundary of the state of affairs. It is here that combinations of the three aspect markers occur. The study shows that they have certain rules of co-occurances.