bluuebunny/crossref_metadata_2025 huggingface dataset:
Chinese Open Relation Extraction and Knowledge Base Establishment
Authors: Jia Shengbin , E Shijia , Li Maozhen , Xiang Yang
Published: February 2018

Named entity relation extraction is an important subject in the field of information extraction. Although many English extractors have achieved reasonable performance, an effective system for Chinese relation extraction remains undeveloped due to the lack of Chinese annotation corpora and the specificity of Chinese linguistics. Here, we summarize three kinds of unique but common phenomena in Chinese linguistics. In this article, we investigate unsupervised linguistics-based Chinese open relation extraction (ORE), which can automatically discover arbitrary relations without any manually labeled datasets, and research the establishment of a large-scale corpus. By mapping the entity relations into dependency-trees and considering the unique Chinese linguistic characteristics, we propose a novel unsupervised Chinese ORE model based on Dependency Semantic Normal Forms (DSNFs). This model imposes no restrictions on the relative positions among entities and relationships and achieves a high yield by extracting relations mediated by verbs or nouns and processing the parallel clauses. Empirical results from our model demonstrate the effectiveness of this method, which obtains stable performance on four heterogeneous datasets and achieves better precision and recall in comparison with several Chinese ORE systems. Furthermore, a large-scale knowledge base of entity and relation, called COER, is established and published by applying our method to web text, which conquers the trouble of lack of Chinese corpora.
Integrating Shallow Syntactic Labels in the Phrase-Boundary Translation Model
Authors: Salami Shahram , Shamsfard Mehrnoush
Published: February 2018

Using a novel rule labeling method, this article proposes a hierarchical model for statistical machine translation. The proposed model labels translation rules by matching the boundaries of target side phrases with the shallow syntactic labels including POS tags and chunk labels on the target side of the training corpus. The boundary labels are concatenated if there is no label for the whole target span. Labeling with the classes of boundary words on the target side phrases has been previously proposed as a phrase-boundary model which can be considered as the base form of our model. In the extended model, the labeler uses a POS tag if there is no chunk label in one boundary. Using chunks as phrase labels, the proposed model generalizes the rules to decrease the model sparseness. The sparseness is a more important issue in the language pairs with a lot of differences in the word order because they have less number of aligned phrase pairs for extraction of rules. The extended phrase-boundary model is also applicable for low-resource languages having no syntactic parser. Some experiments are performed with the proposed model, the base phrase-boundary model, and variants of Syntax Augmented Machine Translation (SAMT) in translation from Persian and German to English as source and target languages with different word orders. According to the results, the proposed model improves the translation performance in the quality and decoding time aspects. Using BLEU as our metric, the proposed model has achieved a statistically significant improvement of about 0.5 point over the base phrase-boundary model.
Akt1 deficiency diminishes skeletal muscle hypertrophy by reducing satellite cell proliferation
Authors: Moriya Nobuki , Miyazaki Mitsunori
Published: February 2018

Skeletal muscle mass is determined by the net dynamic balance between protein synthesis and degradation. Although the Akt/mechanistic target of rapamycin (mTOR)-dependent pathway plays an important role in promoting protein synthesis and subsequent skeletal muscle hypertrophy, the precise molecular regulation of mTOR activity by the upstream protein kinase Akt is largely unknown. In addition, the activation of satellite cells has been indicated as a key regulator of muscle mass. However, the requirement of satellite cells for load-induced skeletal muscle hypertrophy is still under intense debate. In this study, female germline Akt1 knockout (KO) mice were used to examine whether Akt1 deficiency attenuates load-induced skeletal muscle hypertrophy through suppressing mTOR-dependent signaling and satellite cell proliferation. Akt1 KO mice showed a blunted hypertrophic response of skeletal muscle, with a diminished rate of satellite cell proliferation following mechanical overload. In contrast, Akt1 deficiency did not affect the load-induced activation of mTOR signaling and the subsequent enhanced rate of protein synthesis in skeletal muscle. These observations suggest that the load-induced activation of mTOR signaling occurs independently of Akt1 regulation and that Akt1 plays a critical role in regulating satellite cell proliferation during load-induced muscle hypertrophy.
Role of respiration in the cardiovascular response to orthostatic and mental stress
Authors: Javorka Michal , El-Hamad Fatima , Czippelova Barbora , Turianikova Zuzana , Krohova Jana , Lazarova Zuzana , Baumert Mathias
Published: February 2018

The objective of this study was to determine the response of heart rate and blood pressure variability (respiratory sinus arrhythmia, baroreflex sensitivity) to orthostatic and mental stress, focusing on causality and the mediating effect of respiration. Seventy-seven healthy young volunteers (46 women, 31 men) aged 18.4 ± 2.7 yr underwent an experimental protocol comprising supine rest, 45° head-up tilt, recovery, and a mental arithmetic task. Heart rate variability and blood pressure variability were analyzed in the time and frequency domain and modeled as a multivariate autoregressive process where the respiratory volume signal acted as an external driver. During head-up tilt, tidal volume increased while respiratory rate decreased. During mental stress, breathing rate increased and tidal volume was elevated slightly. Respiratory sinus arrhythmia decreased during both interventions. Baroreflex function was preserved during orthostasis but was decreased during mental stress. While sex differences were not observed during baseline conditions, cardiovascular response to orthostatic stress and respiratory response to mental stress was more prominent in men compared with women. The respiratory response to the mental arithmetic tasks was more prominent in men despite a significantly higher subjectively perceived stress level in women. In conclusion, respiration shows a distinct response to orthostatic versus mental stress, mediating cardiovascular variability; it needs to be considered for correct interpretation of heart rate and blood pressure phenomena.
Novel compound heterozygousCLCNKBgene mutations (c.1755A>G/c.848_850delTCT) cause classic Bartter syndrome
Authors: Wang Chunli , Chen Ying , Zheng Bixia , Zhu Mengshu , Fan Jia , Wang Juejin , Jia Zhanjun , Huang Songming , Zhang Aihua
Published: February 2018

Inactivated variants in CLCNKB gene encoding the basolateral chloride channel ClC-Kb cause classic Bartter syndrome characterized by hypokalemic metabolic alkalosis and hyperreninemic hyperaldosteronism. Here, we identified two cBS siblings presenting hypokalemia in a Chinese family due to novel compound heterozygous CLCNKB mutations (c.848_850delTCT/c.1755A>G). Compound heterozygosity was confirmed by amplifying and sequencing the patientʼs genomic DNA. The synonymous mutation c.1755A>G (Thr585Thr) was located at +2 bp from the 5′ splice donor site in exon 15. Further transcript analysis demonstrated that this single nucleotide mutation causes exclusion of exon 15 in the cDNA from the proband and his mother. Furthermore, we investigated the expression and protein trafficking change of c.848_850delTCT (ΔTCT) and exon 15 deletion (ΔE15) mutation in vitro. The ΔE15 mutation markedly decreased the expression of ClC-Kb and resulted in a low-molecular-weight band (~55 kDa) trapping in the endoplasmic reticulum, while the ΔTCT mutant only decreased the total and plasma membrane ClC-Kb protein expression but did not affect the subcellular localization. Finally, we studied the physiological functions of mutations by using whole cell patch-clamp and found that the ΔE15 or ΔTCT mutation decreased the current of the ClC-Kb/barttin channel. These results suggested that the compound defective mutations of the CLCNKB gene are the molecular mechanism of the two cBS siblings.
Mechanisms of altered renal sodium handling in age-related hypertension
Authors: Frame Alissa A. , Wainford Richard D.
Published: February 2018

The prevalence of hypertension rises with age to approximately two out of three adults over the age of 60 in the United States. Although the mechanisms underlying age-related hypertension are incompletely understood, sodium homeostasis is critical to the long-term regulation of blood pressure and there is strong evidence that aging is associated with alterations in renal sodium handling. This minireview focuses on recent advancements in our understanding of the vascular, neurohumoral, and renal mechanisms that influence sodium homeostasis and promote age-related hypertension.
Role of the serotonergic system in urethral continence reflexes during sneezing in rats
Authors: Suzuki Takahisa , Shimizu Takahiro , Kwon Joonbeom , Takaoka Eiichiro , Yoshikawa Satoru , Sumino Yasuhiro , Kitta Takeya , Miyazato Minoru , Miyake Hideaki , Yoshimura Naoki
Published: February 2018

To clarify the role of serotonin (5-HT) in the prevention of stress urinary incontinence (SUI) during sneezing, we investigated the effect of intraperitoneal application of p-chlorophenylalanine (PCPA; a serotonin synthesis inhibitor) and intravenous application of CP-809101 (a 5-HT2C agonist) or LP44 (a 5-HT7 agonist) using female rats, in which the neurally evoked continence reflex during sneezing was examined. Amplitudes of urethral pressure response during sneezing (A-URS), urethral baseline pressure (UBP) at the middle urethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats with or without drug administration. PCPA decreased A-URS by 35.1 cmH2O and UBP by 13.3 cmH2O compared with normal rats. In PCPA-administrated rats, CP-809101 increased A-URS by 24.1 cmH2O and UBP by 15.1 cmH2O, and LP44 also increased A-URS by 20.6 cmH2O and UBP by 11.4 cmH2O compared with rats treated with PCPA alone. SUI was observed with S-LPP of 40.1 cmH2O in PCPA-administrated rats, in which CP-809101 and LP44 increased S-LPP by 28.0 and 15.2 cmH2O, respectively, compared with rats treated with PCPA alone. The effects of CP-809101 and LP44 were antagonized by SB-242084 (a selective 5-HT2C antagonist) and SB-269970 (a selective 5-HT7 antagonist), respectively. These results indicate that activation of 5-HT receptors enhances the active urethral closure reflex during sneezing, at least in part via 5-HT2C and 5-HT7 receptors.
Neural mechanisms of navigation involving interactions of cortical and subcortical structures
Authors: Hinman James R. , Dannenberg Holger , Alexander Andrew S. , Hasselmo Michael E.
Published: February 2018

Animals must perform spatial navigation for a range of different behaviors, including selection of trajectories toward goal locations and foraging for food sources. To serve this function, a number of different brain regions play a role in coding different dimensions of sensory input important for spatial behavior, including the entorhinal cortex, the retrosplenial cortex, the hippocampus, and the medial septum. This article will review data concerning the coding of the spatial aspects of animal behavior, including location of the animal within an environment, the speed of movement, the trajectory of movement, the direction of the head in the environment, and the position of barriers and objects both relative to the animal’s head direction (egocentric) and relative to the layout of the environment (allocentric). The mechanisms for coding these important spatial representations are not yet fully understood but could involve mechanisms including integration of self-motion information or coding of location based on the angle of sensory features in the environment. We will review available data and theories about the mechanisms for coding of spatial representations. The computation of different aspects of spatial representation from available sensory input requires complex cortical processing mechanisms for transformation from egocentric to allocentric coordinates that will only be understood through a combination of neurophysiological studies and computational modeling.
Optical study of interactions among propagation waves of neural excitation in the rat somatosensory cortex evoked by forelimb and hindlimb stimuli
Authors: Hama Noriyuki , Kawai Minako , Ito Shin-Ichi , Hirota Akihiko
Published: February 2018

Multisite optical recording has revealed that the neural excitation wave induced by a sensory stimulation begins at a focus and propagates in the cortex. This wave is considered to be important for computation in the sensory cortex, particularly the integration of sensory information; however, the nature of this wave remains largely unknown. In the present study, we examined the interaction between two waves in the rat sensory cortex induced by hindlimb and forelimb stimuli with different interstimulus intervals. We classified the resultant patterns as follows: 1) the collision of two waves, 2) the hindlimb response being evoked while the forelimb-induced wave is passing the hindlimb focus, and 3) the hindlimb response being evoked after the forelimb-induced wave has passed the hindlimb focus. In pattern 1, the two waves fused into a single wave, but the propagation pattern differed from that predicted by the superimposition of two singly induced propagation courses. In pattern 2, the state of the interaction between the two waves varied depending on the phase of optical signals constituting the forelimb-induced wave around the hindlimb focus. Although no hindlimb-induced wave was observed in the rising phase, the propagating velocity of the forelimb-induced wave increased. At the peak, neither the hindlimb-induced response nor a modulatory effect on the forelimb-induced wave was detected. In pattern 3, the hindlimb-induced wave showed a reduced amplitude and spatial extent. These results indicate that the state of the interaction between waves was strongly influenced by the relative timing of sensory inputs.

NEW & NOTEWORTHY Sensory stimulation-induced cortical excitation propagates as a wave and spreads over a wide area of the sensory cortex. To elucidate the characteristics of this relatively unknown phenomenon, we examined the interaction between two individually induced waves in the somatosensory cortex. Either the waves collided or the preceding wave affected the emergence of the following one. Our results indicate that the state of the interaction was strongly influenced by the relative timing of sensory inputs.
Pharmacoperones as Novel Therapeutics for Diverse Protein Conformational Diseases
Authors: Tao Ya-Xiong , Conn P. Michael
Published: February 2018

After synthesis, proteins are folded into their native conformations aided by molecular chaperones. Dysfunction in folding caused by genetic mutations in numerous genes causes protein conformational diseases. Membrane proteins are more prone to misfolding due to their more intricate folding than soluble proteins. Misfolded proteins are detected by the cellular quality control systems, especially in the endoplasmic reticulum, and proteins may be retained there for eventual degradation by the ubiquitin-proteasome system or through autophagy. Some misfolded proteins aggregate, leading to pathologies in numerous neurological diseases. In vitro, modulating mutant protein folding by altering molecular chaperone expression can ameliorate some misfolding. Some small molecules known as chemical chaperones also correct mutant protein misfolding in vitro and in vivo. However, due to their lack of specificity, their potential as therapeutics is limited. Another class of compounds, known as pharmacological chaperones (pharmacoperones), binds with high specificity to misfolded proteins, either as enzyme substrates or receptor ligands, leading to decreased folding energy barriers and correction of the misfolding. Because many of the misfolded proteins are misrouted but do not have defects in function per se, pharmacoperones have promising potential in advancing to the clinic as therapeutics, since correcting routing may ameliorate the underlying mechanism of disease. This review will comprehensively summarize this exciting area of research, surveying the literature from in vitro studies in cell lines to transgenic animal models and clinical trials in several protein misfolding diseases.
Using Real-Time Syndromic Surveillance to Analyze the Impact of a Cold Weather Event in New Mexico
Authors: Dirmyer Victoria F.
Published: February 2018

Objective. This report describes the development of a novel syndromic cold weather syndrome for use in monitoring the impact of cold weather events on emergency department attendance. Methods. Syndromic messages from seven hospitals were analyzed for ED visits that occurred over a 12-day period. A cold weather syndrome was defined using terms in the self-reported chief complaint field as well as specific ICD-10-CM codes related to cold weather. A κ statistic was calculated to assess the overall agreement between the chief complaint field and diagnosis fields to further refine the cold weather syndrome definition. Results. Of the 3,873 ED visits that were reported, 487 were related to the cold weather event. Sixty-three percent were identified by a combination of diagnosis codes and chief complaints. Overall agreement between chief complaint and diagnosis codes was moderate (κ=0.50; 95% confidence interval = 0.48–0.52). Conclusion. Due to the near real-time reporting of syndromic surveillance data, analysis results can be acted upon. Results from this analysis will be used in the state’s emergency operations plan (EOP) for cold weather and winter storms. The EOP will provide guidance for mobilization of supplies/personnel, preparation of roadways and pedestrian walkways, and the coordination efforts of multiple state agencies.
Speciation, Fate and Transport, and Ecological Risks of Cu, Pb, and Zn in Tailings from Huogeqi Copper Mine, Inner Mongolia, China
Authors: Chen Liwei , Wu Jun , Lu Jian , Xia Chulin , Urynowicz Michael A. , Huang Zaixing , Gao Li , Ma Mingying
Published: February 2018

Tailings collected from the tailing reservoir at Huogeqi Copper Mine, located in Inner Mongolia, China, were used in a leachate study to evaluate the acid potential, neutralization potential, and possibility for producing acid mine drainage (AMD) from the site. The speciation of Cu, Pb, and Zn contained in the tailings was also determined during the leachate study to further access the potential migration abilities of these metals. The results showed that the tailings did not produce significant AMD as the pH of the leachate ranged from 7 to 9 and decreased with time. The Cu, Pb, and Zn concentrations were high, ranging from 439.1 to 4527 mg/kg in the tailings and from 0.162 to 7.964 mg/L in the leachate, respectively. Concentrations of metals in the leachate and tailings were positively correlated. Over 60% of the Cu in the tailing samples existed in an oxidizable form. Most of the Pb also existed in its oxidized form, as did the silicate and Zn. Metals usually have higher mobility in their exchangeable and oxidizable forms and as such represent a higher potential risk to the environment. Results of risk assessment code also revealed that metals in tailings exerted medium to high risks to the environment.
Exploiting Proximity-Based Mobile Apps for Large-Scale Location Privacy Probing
Authors: Zhao Shuang , Luo Xiapu , Ma Xiaobo , Bai Bo , Zhao Yankang , Zou Wei , Yang Zeming , Au Man Ho , Qiu Xinliang
Published: February 2018

Proximity-based apps have been changing the way people interact with each other in the physical world. To help people extend their social networks, proximity-based nearby-stranger (NS) apps that encourage people to make friends with nearby strangers have gained popularity recently. As another typical type of proximity-based apps, some ridesharing (RS) apps allowing drivers to search nearby passengers and get their ridesharing requests also become popular due to their contribution to economy and emission reduction. In this paper, we concentrate on the location privacy of proximity-based mobile apps. By analyzing the communication mechanism, we find that many apps of this type are vulnerable to large-scale location spoofing attack (LLSA). We accordingly propose three approaches to performing LLSA. To evaluate the threat of LLSA posed to proximity-based mobile apps, we perform real-world case studies against an NS app named Weibo and an RS app called Didi. The results show that our approaches can effectively and automatically collect a huge volume of users’ locations or travel records, thereby demonstrating the severity of LLSA. We apply the LLSA approaches against nine popular proximity-based apps with millions of installations to evaluate the defense strength. We finally suggest possible countermeasures for the proposed attacks.
Low-Cost Printed Flexible Antenna by Using an Office Printer for Conformal Applications
Authors: Paracha Kashif Nisar , Rahim Sharul Kamal Abdul , Chattha Hassan Tariq , Aljaafreh Saqer Saleh , Rehman Sabih ur , Lo Yew Chiong
Published: February 2018

A low-cost inkjet printing method for antenna fabrication on a polyethylene terephthalate (PET) substrate is presented in this paper. An office inkjet printer is used to have desired patterns of silver nanoparticle ink on the PET substrate without any postprocessing. Silver nanoparticle ink cures instantly as soon as it is ejected from the printer on a chemically treated PET substrate. The thickness of the silver nanoparticle layer was measured to be 300 nm with a sheet resistance of as low as 0.3 Ω/sq and a conductivity around 1.11 × 107 S/m with single layer deposition. A coplanar waveguide- (CPW-) fed Z-shape planar antenna on the PET substrate achieved the measured radiation efficiency of 62% and the IEEE gain of 1.44 dBi at 2.45 GHz. The printed antenna is also tested in bending conditions to ascertain its performance for the Internet of things (IoT) conformal applications for the future 5G network.
Design of Frequency- and Pattern-Reconfigurable Wideband Slot Antenna
Authors: Han Liping , Wang Caixia , Zhang Wenmei , Ma Runbo , Zeng Qingsheng
Published: February 2018

A wideband slot antenna with frequency- and pattern-reconfigurable characteristics for TD-LTE (3.4–3.8 GHz) and C-band (3.7–4.2 GHz) applications is proposed. The antenna consists of two symmetric slots that are fed by a fork-shaped microstrip line. Two PIN diodes are loaded in the slots to produce two different frequency bands. Meanwhile, two additional PIN diodes are inserted in the feed line to achieve the pattern reconfigurability. The wideband operation is realized by using the symmetric slots and fork-shaped feed line. Simulated and measured results show that the antenna provides 25° and 20° beam-steering in 3.4–3.8 and 3.7–4.2 GHz bands, respectively. Also, an impedance bandwidth of at least 12.8% is obtained in the operating bands.
Multicomponent Exercise Improves Hemodynamic Parameters and Mobility, but Not Maximal Walking Speed, Transfer Capacity, and Executive Function of Older Type II Diabetic Patients
Authors: Coelho Junior Hélio José , Callado Sanches Iris , Doro Marcio , Asano Ricardo Yukio , Feriani Daniele Jardim , Brietzke Cayque , Gonçalves Ivan de Oliveira , Uchida Marco Carlos , Capeturo Erico Chagas , Rodrigues Bruno
Published: February 2018

The present study aimed to investigate the effects of a 6-month multicomponent exercise program (MCEP) on functional, cognitive, and hemodynamic parameters of older Type 2 diabetes mellitus (T2DM) patients. Moreover, additional analyses were performed to evaluate if T2DM patients present impaired adaptability in response to physical exercise when compared to nondiabetic volunteers. A total of 72 T2DM patients and 72 age-matched healthy volunteers (CG) were recruited and submitted to functional, cognitive, and hemodynamic evaluations before and after six months of a MCEP. The program of exercise was performed twice a week at moderate intensity. Results indicate T2DM and nondiabetic patients present an increase in mobility (i.e., usual walking speed) after the MCEP. However, improvements in maximal walking speed, transfer capacity, and executive function were only observed in the CG. On the other hand, only T2DM group reveals a marked decline in blood pressure. In conclusion, data of the current study indicate that a 6-month MCEP improves mobility and reduce blood pressure in T2DM patients. However, maximal walking speed, transfer capacity, and executive function were only improved in CG, indicating that T2DM may present impaired adaptability in response to physical stimulus.
The Complexity of Social Capital: The Influence of Board and Ownership Interlocks on Implied Cost of Capital in an Emerging Market
Authors: Rossoni Luciano , Aranha Cezar Eduardo , Mendes-Da-Silva Wesley
Published: February 2018

Starting from sociological perspectives on complexity, we show how the social capital of boards and owners networks affects the implied cost of capital of companies listed on Brazilian stock exchange. We specifically show arguments and evidence that the effect of the relational resources found in the direct, indirect, and heterogeneous board’s ties reduces the cost of capital while relational resources embedded in shareholder networks increase the cost of capital. Our results show that while the increase in the relational resources of the board reduces the implied cost of capital, an increase in these shared resources in the ownership relationships of the firm increases the cost of financial capital.
Respiratory Epithelial Orbital Cyst: A Case Report and Literature Review
Authors: Al Abdulmohsen Sally , Ayoubi Ayman , Al-Dandan Sadeq
Published: February 2018

A 44-year-old male with schizophrenia presented with progressive right proptosis for one year and conjunctivitis for two months. An orbital cyst was seen in the superotemporal region on computerized tomography and was surgically removed. There was no history or radiological signs of paranasal sinus disease or previous trauma. Histopathologic evaluation revealed a cyst lined with respiratory epithelium. Respiratory choristomatous cysts of the orbit are considered rare in both pediatric and adult patients. We review the literature of respiratory orbital cysts and conclude that they tend to present in adults and should be considered in the differential diagnoses of orbital cysts.
Transplantation of Hypoxic-Preconditioned Bone Mesenchymal Stem Cells Retards Intervertebral Disc Degeneration via Enhancing Implanted Cell Survival and Migration in Rats
Authors: Wang Weiheng , Wang Yang , Deng Guoying , Ma Jun , Huang Xiaodong , Yu Jiangming , Xi Yanhai , Ye Xiaojian
Published: February 2018

Objective. Special hypoxic and hypertonic microenvironment in intervertebral discs (IVDs) decreases the treatment effect of cell transplantation. We investigated the hypothesis that hypoxic preconditioning (HP) could improve the therapeutic effect of bone mesenchymal stem cells (BMSCs) to IVD degeneration. Methods. BMSCs from green fluorescent protein-transgenic rats were pretreated with cobalt chloride (CoCl2, 100 μM, 24 h) for hypoxic conditions in vitro. Apoptosis (related pathways of caspase-3 and bcl-2) and migration (related pathways of HIF-1α and CXCR4) were detected in BMSCs. In vivo, BMSCs and HP BMSCs (H-BMSCs) were injected into the rat model of IVD degeneration. The IVD height, survival, migration, and differentiation of transplanted BMSCs and matrix protein expression (collagen II, aggrecan, and MMP-13) were tested. Results. H-BMSCs could extensively decrease IVD degeneration by increasing IVD height and collagen II and aggrecan expressions when compared with BMSCs. Significantly, more GFP-positive BMSCs were observed in the nucleus pulposus and annulus fibrosus regions of IVD. HP could significantly decrease BMSC apoptosis (activating bcl-2 and inhibiting caspase-3) and improve BMSC migration (increasing HIF-1α and CXCR4) in vitro. Conclusion. HP could significantly enhance the capacity of BMSCs to repair DDD by increasing the survival and migration of implanted cells and increasing matrix protein expression.
Chromium(VI) Toxicity in Legume Plants: Modulation Effects of Rhizobial Symbiosis
Authors: Stambulska Uliana Ya. , Bayliak Maria M. , Lushchak Volodymyr I.
Published: February 2018

Most legume species have the ability to establish a symbiotic relationship with soil nitrogen-fixing rhizobacteria that promote plant growth and productivity. There is an increasing evidence of reactive oxygen species (ROS) important role in formation of legume-rhizobium symbiosis and nodule functioning. Environmental pollutants such as chromium compounds can cause damage to rhizobia, legumes, and their symbiosis. In plants, toxic effects of chromium(VI) compounds are associated with the increased production of ROS and oxidative stress development as well as with inhibition of pigment synthesis and modification of virtually all cellular components. These metabolic changes result in inhibition of seed germination and seedling development as well as reduction of plant biomass and crop yield. However, if plants establish symbiosis with rhizobia, heavy metals are accumulated preferentially in nodules decreasing the toxicity of metals to the host plant. This review summarizes data on toxic effects of chromium on legume plants and legume-rhizobium symbiosis. In addition, we discussed the role of oxidative stress in both chromium toxicity and formation of rhizobial symbiosis and use of nodule bacteria for minimizing toxic effects of chromium on plants.
Carotid Intima Media Thickness Reference Intervals for a Healthy Argentinean Population Aged 11–81 Years
Authors: Diaz Alejandro , Bia Daniel , Zócalo Yanina , Manterola Hugo , Larrabide Ignacio , Lo Vercio Lucas , Del Fresno Mariana , Cabrera Fischer Edmundo
Published: February 2018

Reference intervals (RIs) of carotid intima media thickness (CIMT) from large healthy population are still lacking in Latin America. The aim of this study was to determine CIMT RIs in a cohort of 1012 healthy subjects from Argentina. We evaluated if RIs for males and females and for left and right carotids were necessary. Second, mean and standard deviation (SD) age-related equations were obtained for left, right, and average (left + right)/2) CIMT using parametric regression methods based on fractional polynomials, in order to obtain age-specific percentiles curves. Age-specific percentile curves were obtained. Males showed higher A-CIMT (0.577±0.003 mm versus 0.566±0.004 mm, P=0.039) in comparison with females. For males, the equations were as follows: A-CIMT mean = 0.42 + 8.14×10-5⁎Age2; A-CIMT SD = 5.9 × 10−2 + 1.09×10-5⁎Age2. For females, they were as follows: A-CIMT mean = 0.40 + 8.20×10-5⁎Age2; A-CIMT SD = 4.67 × 10−2 + 1.63×10-5⁎Age2. Our study provides the largest database concerning RIs of CIMT in healthy people in Argentina. Specific RIs and percentiles of CIMT for children, adolescents, and adults are now available according to age and gender, for right and left common carotid arteries.
Analysis of the Clinicopathological Characteristics and Risk Factors in Patients with Lung Cancer and Chronic Obstructive Pulmonary Disease
Authors: Miao Jian-Long , Cai Jing-Jing , Qin Xiao-Feng , Liu Rui-Juan
Published: February 2018

Objective. To investigate the clinicopathological characteristics and risk factors in patients with lung cancer and COPD. Materials and Methods. We retrospectively reviewed the clinical data of 282 patients with lung cancer, including 174 and 108 patients with and without COPD, respectively. Information on age, sex, smoking status, and histologic type was obtained from medical records. Results. Lung cancer patients with COPD and those with the chronic bronchitis (CB) phenotype had higher smoking indices compared to those without COPD (723.95±631.48 and 920.95±712.93 versus 418.40±506.84; P=0.010; P=0.001, resp.), and current smokers accounted for significantly higher proportions of lung cancer patients with COPD and the CB phenotype versus without COPD (51.15% and 63.74% versus 35.19%; P=0.009; P=0.001, resp.). Adenocarcinoma was significantly more common in lung cancer patients without versus with COPD (48.15% versus 35.63%; P=0.037), whereas small cell lung cancer was more common in patients with COPD (23.56% versus 13.89%). Among patients with COPD, male sex (odds ratio [OR], 19.946; P<0.001), current smokers (OR: 6.588; P=0.001), and age ≥ 75 years (OR: 2.670; P=0.008) were identified as high-risk factors. Conclusion. The risk factors for COPD among lung cancer patients were age ≥ 75 years, current smokers with the CB phenotype, and male sex.
Design and Simulation of a Railway Vehicle for the Transport of People with Reduced Mobility
Authors: Bosso Nicola , Gugliotta Antonio , Zampieri Nicolò
Published: February 2018

One of the most important aspects of the design activity of passenger railway vehicles is the optimization of the comfort level that is often in contrast with other requirements, such as low weight, to reduce energy consumption, and high and flexible seating capacity. Due to the coach weight reduction, the car body structure becomes more susceptible to structural vibrations that affect the passenger comfort. In modern vehicles, seats are important elements to achieve the desired comfort, but in order to design and estimate the actual comfort level, the whole system must be considered, including the track excitations, a vehicle detailed dynamic model, and the coach and the seat flexibility. This paper describes a numerical model of a double‐deck vehicle developed using a MB code that considers measured track irregularities, a detailed vehicle model, and a transfer function of the seat obtained by experimental tests on an optimized seat. In order to make the numerical model more realistic, the coach has been modeled as a flexible body to consider the effect of its natural frequencies. The work has been performed within the “CARITAS” project, whose aim is the design of a high comfort vehicle for people with reduced mobility.
Nephroprotective Effect of Sonchus oleraceus Extract against Kidney Injury Induced by Ischemia‐Reperfusion in Wistar Rats
Authors: Torres-González Liliana , Cienfuegos-Pecina Eduardo , Perales-Quintana Marlene M. , Alarcon-Galvan Gabriela , Muñoz-Espinosa Linda E. , Pérez-Rodríguez Edelmiro , Cordero-Pérez Paula
Published: February 2018

Introduction. Kidney ischemia‐reperfusion (I/R) injury is the main cause of delayed graft function in solid organ transplantation. Sonchus oleraceus is a plant with well‐known antioxidant and anti‐inflammatory activities; however, its effects on renal I/R are unknown. Objective. To evaluate whether S. oleraceus extract (S.O.e.) has nephroprotective activity in an I/R model in Wistar rats. Materials and Methods. Animal groups (n = 6): sham, I/R (45 min/15 h), S.O.e (300 mg/kg p.o.), and S.O.e + I/R (300 mg/kg, p.o.; 45 min/15 h). Renal function, proinflammatory cytokines, alanine aminotransferase, markers of oxidative stress, and histology were evaluated. Results. None of the mediators evaluated differed significantly between the S.O.e and sham groups. Levels of blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and proinflammatory cytokines were higher, and superoxide dismutase (SOD) was lower in the I/R group than in the sham group. Histology showed tubular epithelial necrosis in the medulla and cortex in the I/R group. In the S.O.e + I/R group, S.O.e pretreatment attenuated the I/R‐induced increases in BUN, creatinine, MDA, and proinflammatory cytokines induced, SOD was maintained, and histology showed discontinuous necrosis in the medulla but no necrosis in the cortex. Conclusions. S.O.e was neither hepatotoxic nor nephrotoxic. S.O.e. pretreatment showed a nephroprotective effect against I/R.
Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-infiltrating Lymphocytes
Authors: Mohme Malte , Schliffke Simon , Maire Cecile L. , Rünger Alessandra , Glau Laura , Mende Klaus C. , Matschke Jakob , Gehbauer Christina , Akyüz Nuray , Zapf Svenja , Holz Mareike , Schaper Miriam , Martens Tobias , Schmidt Nils O. , Peine Sven , Westphal Manfred , Binder Mascha , Tolosa Eva , Lamszus Katrin
Published: February 2018

Purpose: Immunotherapeutic treatment strategies for glioblastoma (GBM) are under investigation in clinical trials. However, our understanding of the immune phenotype of GBM-infiltrating T cells (tumor-infiltrating lymphocytes; TILs) and changes during disease progression is limited. Deeper insight is urgently needed to therapeutically overcome tumor-induced immune exhaustion.

Experimental Design: We used flow cytometry and cytokine assays to profile TILs and peripheral blood lymphocytes (PBLs) from patients with GBM, comparing newly diagnosed or recurrent GBM to long-term survivors (LTS) and healthy donors. TCR sequencing was performed on paired samples of newly diagnosed and recurrent GBM.

Results: We identified a clear immune signature of exhaustion and clonal restriction in the TILs of patients with GBM. Exhaustion of CD8+ TILs was defined by an increased prevalence of PD-1+, CD39+, Tim-3+, CD45RO+, HLA-DR+ marker expression, and exhibition of an effector-/transitional memory differentiation phenotype, whereas KLRG1 and CD57 were underrepresented. Immune signatures were similar in primary and recurrent tumors; however, restricted TCR repertoire clonality and a more activated memory phenotype were observed in TILs from recurrent tumors. Moreover, a reduced cytokine response to PHA stimulation in the blood compartment indicates a dysfunctional peripheral T-cell response in patients with GBM. LTS displayed a distinct profile, with abundant naïve and less exhausted CD8+ T cells.

Conclusions: TILs and PBLs exhibit contrasting immune profiles, with a distinct exhaustion signature present in TILs. While the exhaustion profiles of primary and recurrent GBM are comparable, TCR sequencing demonstrated a contracted repertoire in recurrent GBM, concomitant with an increased frequency of activated memory T cells in recurrent tumors. Clin Cancer Res; 24(17); 4187–200. ©2018 AACR.

See related commentary by Jackson and Lim, p. 4059
A Correlative Analysis of PD-L1, PD-1, PD-L2, EGFR, HER2, and HER3 Expression in Oropharyngeal Squamous Cell Carcinoma
Authors: Steuer Conor E. , Griffith Christopher C. , Nannapaneni Sreenivas , Patel Mihir R. , Liu Yuan , Magliocca Kelly R. , El-Deiry Mark W. , Cohen Cynthia , Owonikoko Taofeek K. , Shin Dong M. , Chen Zhuo G. , Saba Nabil F.
Published: February 2018

We explored potential associations of the PD-1/PD-L1/PD-L2 pathway with clinical characteristics, outcome, and expression of EGFR, HER2, HER3 in oropharyngeal squamous cell carcinoma (OPSCC) using an institutional database. Protein expression was assessed by IHC on tissue microarray sections (EGFR, HER2, HER3) or whole tissue sections (PD-1/PD-L1/PD-L2). Expression of EGFR, HER2, HER3, PD-L1, and PD-L2 was quantified on tumor cells. Maximum density of PD-1 positive lymphocytes was measured on a scale of 0 to 4 within the tumor mass and peritumoral stroma. Associations between biomarkers and patient outcomes were tested using descriptive and inferential statistics, logistic regression, and Cox proportional hazards models. We analyzed tissue samples from 97 OPSCC cases: median age 59 years, p16+ (71%), male (83.5%), never smokers (18%), stage 3 to 4 disease (77%). Twenty-five percent of cases were PD-L1 positive. The proportion of PD-L1+ tumors was higher in p16+ (29%) than p16− OPSCC (11%, P = 0.047). There was no correlation between PD-L1, PD-L2, PD-1, EGFR, HER2, or HER3 expression. Positive PD-L1 status correlated with advanced nodal disease on multivariate analysis (OR 5.53; 95% CI, 1.06–28.77; P = 0.042). Negative PD-L2 expression was associated with worse survival (HR 3.99; 95% CI, 1.37–11.58; P = 0.011) in p16− OPSCC. Lower density of PD-1 positive lymphocytes in peritumoral stroma was associated with significantly increased risk of death on multivariate analysis (HR 3.17; 95% CI, 1.03–9.78; P = 0.045) after controlling for prognostic factors such as stage and p16 status. PD-L1 expression on tumor cells correlates with p16 status and advanced nodal status in OPSCC. PD-1 positive lymphocytes in peritumoral stroma serve as an independent prognostic factor for overall survival. Mol Cancer Ther; 17(3); 710–6. ©2018 AACR.
A Spatio-Temporal Model of Macrophage-Mediated Drug Resistance in Glioma Immunotherapy
Authors: Zheng Yongjiang , Bao Jiguang , Zhao Qiyi , Zhou Tianshou , Sun Xiaoqiang
Published: February 2018

The emergence of drug resistance is often an inevitable obstacle that limits the long-term effectiveness of clinical cancer chemotherapeutics. Although various forms of cancer cell-intrinsic mechanisms of drug resistance have been experimentally revealed, the role and the underlying mechanism of tumor microenvironment in driving the development of acquired drug resistance remain elusive, which significantly impedes effective clinical cancer treatment. Recent experimental studies have revealed a macrophage-mediated drug resistance mechanism in which the tumor microenvironment undergoes adaptation in response to macrophage-targeted colony-stimulating factor-1 receptor (CSF1R) inhibition therapy in gliomas. In this study, we developed a spatio-temporal model to quantitatively describe the interplay between glioma cells and CSF1R inhibitor–targeted macrophages through CSF1 and IGF1 pathways. Our model was used to investigate the evolutionary kinetics of the tumor regrowth and the associated dynamic adaptation of the tumor microenvironment in response to the CSF1R inhibitor treatment. The simulation result obtained using this model was in agreement with the experimental data. The sensitivity analysis revealed the key parameters involved in the model, and their potential impacts on the model behavior were examined. Moreover, we demonstrated that the drug resistance is dose-dependent. In addition, we quantitatively evaluated the effects of combined CSFR inhibition and IGF1 receptor (IGF1R) inhibition with the goal of designing more effective therapies for gliomas. Our study provides quantitative and mechanistic insights into the microenvironmental adaptation mechanisms that operate during macrophage-targeted immunotherapy and has implications for drug dose optimization and the design of more effective combination therapies. Mol Cancer Ther; 17(4); 814–24. ©2018 AACR.
Small Molecule–Mediated Activation of RAS Elicits Biphasic Modulation of Phospho-ERK Levels that Are Regulated through Negative Feedback on SOS1
Authors: Howes Jennifer E. , Akan Denis T. , Burns Michael C. , Rossanese Olivia W. , Waterson Alex G. , Fesik Stephen W.
Published: February 2018

Oncogenic mutation of RAS results in aberrant cellular signaling and is responsible for more than 30% of all human tumors. Therefore, pharmacologic modulation of RAS has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)–catalyzed nucleotide exchange on RAS and inhibit downstream signaling. Here, we describe how pharmacologically targeting SOS1 induced biphasic modulation of RAS-GTP and ERK phosphorylation levels, which we observed in a variety of cell lines expressing different RAS-mutant isoforms. We show that compound treatment caused an increase in phosphorylation at ERK consensus motifs on SOS1 that was not observed with the expression of a non-phosphorylatable S1178A SOS1 mutant or after pretreatment with an ERK inhibitor. Phosphorylation at S1178 on SOS1 is known to inhibit the association between SOS1 and GRB2 and disrupt SOS1 membrane localization. Consistent with this, we show that wild-type SOS1 and GRB2 dissociated in a time-dependent fashion in response to compound treatment, and conversely, this interaction was enhanced with the expression of an S1178A SOS1 mutant. Furthermore, in cells expressing either S1178A SOS1 or a constitutively membrane-bound CAAX box tagged SOS1 mutant, we observed elevated RAS-GTP levels over time in response to compound, as compared with the biphasic changes in RAS-GTP exhibited in cells expressing wild-type SOS1. These results suggest that small molecule targeting of SOS1 can elicit a biphasic modulation of RAS-GTP and phospho-ERK levels through negative feedback on SOS1 that regulates the interaction between SOS1 and GRB2. Mol Cancer Ther; 17(5); 1051–60. ©2018 AACR.
Evaluation of the Accuracy of a New Cuffless Magnetoplethysmography Blood Pressure Monitor in Hypertensive Patients
Authors: Kim Sua , Lee Jung Dong , Park Jeong Bae , Jang Seungjin , Kim Jungchae , Lee Sang-Suk
Published: February 2018

Objective: There is a growing demand for cuffless blood pressure (BP) measurement as an easy alternative to cuff-occlusion-based BP measurement. We assessed the accuracy of a new cuffless, watch-style BP monitor with a magnetoplethysmography (MPG) sensor compared to two standard auscultatory and oscillatory BP monitors. Subjects and Methods: A total of 34 patients with uncontrolled hypertension (systolic BP ≥150 mm Hg or diastolic BP ≥95 mm Hg) were enrolled in the study. BP was measured by two conventional monitors and the new device during the pre-exercise phase, during isometric handgrip exercise, and during the recovery phase (5 min after exercise). The correlation between monitors was assessed using intraclass correlation coefficient (ICC) and Bland-Altman plots. Results: Although two reference monitors produced highly correlated BP measurements, each was differentially correlated with BP measurements obtained by the new MPG monitor. During exercise, the mean difference between systolic BP obtained by the MPG and oscillatory monitors was >7 mm Hg with an ICC of 0.549 (95% CI 0.264-0.746) in systole and 0.737 (95% CI 0.534-0.859) in diastole. The ICC between the auscultatory monitor and the MPG monitor was 0.753 (95% CI 0.559-0.868) in systole and 0.841 (95% CI 0.706-0.918) in diastole after exercise. Bland-Altman plots also indicated that the performance of the new MPG device was very similar to that of the auscultatory monitor. Conclusion: Although the performance of the new MPG monitor was comparable to that of the reference monitors used in this study, improved stability and accuracy are necessary for accurate BP evaluation during dynamic activity.
Primary Extraskeletal Osteosarcoma Arising from the Optic Nerve: A Rare Case Report
Authors: Lyngdoh Bifica , Mishra Jaya , Dey Biswajit , Harris Caleb , Kakati Arindom , Chowdhury Zachariah , Marak Rintu , Marbaniang Evarisalin
Published: February 2018

Orbital location of extraskeletal osteosarcoma is extremely rare with only 4 cases reported so far in the English literature. We present the case of a 32-year-old female who presented with proptosis and complete loss of vision of the left eye. Contrast-enhanced computed tomography scan showed a densely calcified lobulated lesion in the left optic nerve showing strong enhancement. A left fronto-occipito-zygomatic osteotomy was conducted and a greyish brown tumor was identified. Histopathological and immunohistochemical examination of the curetted material revealed it to be extraskeletal osteosarcoma. A left partial maxillectomy with ethmoidectomy and left orbital exenteration was done and the patient was advised chemotherapy with radiotherapy.