bluuebunny/crossref_metadata_2025 huggingface dataset:
Fungal Diversity Revisited: 2.2 to 3.8 Million Species
Authors: Hawksworth David L. , Lücking Robert
Published: July 2017

The question of how many species of
Fungi
there are has occasioned much speculation, with figures mostly posited from around half a million to 10 million, and in one extreme case even a sizable portion of the spectacular number of 1 trillion. Here we examine new evidence from various sources to derive an updated estimate of global fungal diversity. The rates and patterns in the description of new species from the 1750s show no sign of approaching an asymptote and even accelerated in the 2010s after the advent of molecular approaches to species delimitation. Species recognition studies of (semi-)cryptic species hidden in morpho-species complexes suggest a weighted average ratio of about an order of magnitude for the number of species recognized after and before such studies. New evidence also comes from extrapolations of plant:fungus ratios, with information now being generated from environmental sequence studies, including comparisons of molecular and fieldwork data from the same sites. We further draw attention to undescribed species awaiting discovery in biodiversity hot spots in the tropics, little-explored habitats (such as lichen-inhabiting fungi), and material in collections awaiting study. We conclude that the commonly cited estimate of 1.5 million species is conservative and that the actual range is properly estimated at 2.2 to 3.8 million. With 120,000 currently accepted species, it appears that at best just 8%, and in the worst case scenario just 3%, are named so far. Improved estimates hinge particularly on reliable statistical and phylogenetic approaches to analyze the rapidly increasing amount of environmental sequence data.
Selection and Transmission of Antibiotic-Resistant Bacteria
Authors: Andersson Dan I. , Hughes Diarmaid
Published: July 2017

Ever since antibiotics were introduced into human and veterinary medicine to treat and prevent bacterial infections there has been a steady selection and increase in the frequency of antibiotic resistant bacteria. To be able to reduce the rate of resistance evolution, we need to understand how various biotic and abiotic factors interact to drive the complex processes of resistance emergence and transmission. We describe several of the fundamental factors that underlay resistance evolution, including rates and niches of emergence and persistence of resistant bacteria, time- and space-gradients of various selective agents, and rates and routes of transmission of resistant bacteria between humans, animals and other environments. Furthermore, we discuss the options available to reduce the rate of resistance evolution and/ or transmission and their advantages and disadvantages.
How to use tests for disorders of copper metabolism
Authors: Armer Jane , De Goede Christian
Published: July 2017

In paediatrics, one of our main aims in the diagnostic process is to identify any treatable conditions. The copper metabolism disorder Wilson’s disease (WD) is one such condition that is caused by mutations in the ATP7B gene. Delay in treatment could result in irreversible disability or even death. Although liver disease is the most common presenting feature in children, some children may initially present with a subtle neurological presentation only. In patients presenting with dystonia, tremor, dysarthria or with a deterioration in school performance, there should be a high index of suspicion for WD. However, the differential of these clinical presentations is wide and exclusion of WD is difficult. No single diagnostic test can exclude WD and each of the biochemical tests has limitations. In this article, we discuss copper metabolism disorders including WD and Menke’s disease. We then discuss the available diagnostic tests and how to investigate children for these rare disorders.
Bacteraemia and liver abscess due toFusobacterium necrophorum
Authors: García Carretero Rafael , Lopez-Lomba Marta , Vazquez-Gomez Oscar , Rodriguez-Maya Belen
Published: July 2017

Fusobacterium necrophorumis the oropharyngeal pathogen usually associated with Lemierre's syndrome, a pharyngeal infection which evolves to sepsis, septic emboli and thrombophlebitis of the adjacent neck vessels. It is an uncommon causative bacteria of a liver abscess, and an extensive workup should, therefore, be performed in order to rule out potential sources of the infection. This case report describes the workup that led to the diagnosis of a colorectal carcinoma, which was deemed to be the source of theFusobacteriumbacteraemia.
Adjunctive extracorporeal carbon dioxide removal in refractory status asthmaticus
Authors: Jiang Chuan , Galaydick Jodi , Fernandez Harold , Caronia Jonathan
Published: July 2017

Status asthmaticus (SA) is a life-threatening disorder. Severe respiratory failure may require extracorporeal membrane oxygenation (ECMO). Previous reports have demonstrated utility of ECMO in SA in various patients with varying success. A 25-year-old man was admitted with status asthmatics and severe hypercapnic respiratory failure. Despite tailored ventilator therapies, such as pressure control ventilation and maximal pharmacological therapy, including general anaesthesia, the patientâ€™s condition deteriorated rapidly. Veno-venous ECMO (VV-ECMO) was provided for respiratory support. The patientâ€™s clinical condition improved over the following 72â€‰hours and was discharged from the intensive care unit on day 3. This case report demonstrates the successful use of VV-ECMO in a patient with severe respiratory failure due to SA, who failed to respond to maximal therapy. This case adds support to a growing body of literature that shows that ECMO can be used with success for refractory status asthmaticus.
Beyond menstrual hygiene: addressing vaginal bleeding throughout the life course in low and middle-income countries
Authors: Sommer Marni , Phillips-Howard Penelope A , Mahon Therese , Zients Sasha , Jones Meredith , Caruso Bethany A
Published: July 2017

Girls and women experience numerous types of vaginal bleeding. These include healthy reproductive processes, such as menstruation and bleeding after childbirth, but also bleeding related to health conditions, such as fibroids or cancer. In most societies, the management of menstruation is handled covertly, something girls are often instructed about at menarche. The management of other vaginal bleeding is often similarly discreet, although behaviours are not well documented. In many societies, cultural taboos frequently hinder open discussion around vaginal bleeding, restricting information and early access to healthcare. Additionally, the limited availability of clean, accessible water and sanitation facilities in many low and middle-income countries augments the challenges girls and women face in conducting daily activities while managing vaginal bleeding, including participating in school or work, going to the market or fetching water. This paper aims to highlight the key vaginal bleeding experiences throughout a woman’s life course and the intersection of these bleeding experiences with their access to adequate water and sanitation facilities, information and education sources, and supplies. The aim is to address the silence around girls and women’s vaginal bleeding and their related social, physical and clinical management needs across the life course; and highlight critical gaps that require attention in research, practice and policy around this neglected topic of health and gender equality.
Respiratory syncytial virus: a systematic scientometric analysis of the global publication output and the gender distribution of publishing authors
Authors: Brüggmann Dörthe , Köster Corinna , Klingelhöfer Doris , Bauer Jan , Ohlendorf Daniela , Bundschuh Matthias , Groneberg David A
Published: July 2017

Objective

Worldwide, the respiratory syncytial virus (RSV) represents the predominant viral agent causing bronchiolitis and pneumonia in children. To conduct research and tackle existing healthcare disparities, RSV-related research activities around the globe need to be described. Hence, we assessed the associated scientific output (represented by research articles) by geographical, chronological and socioeconomic criteria and analysed the authors publishing in the field by gender. Also, the 15 most cited articles and the most prolific journals were identified for RSV research.

Design

Retrospective, descriptive study.

Setting

The NewQIS (New Quality and Quantity Indices in Science) platform was employed to identify RSV-related articles published in the Web of Science until 2013. We performed a numerical analysis of all articles, and examined citation-based aspects (eg, citation rates); results were visualised by density equalising mapping tools.

Results

We identified 4600 RSV-related articles. The USA led the field; US-American authors published 2139 articles (46.5%% of all identified articles), which have been cited 83 000 times. When output was related to socioeconomic benchmarks such as gross domestic product or Research and Development expenditures, Guinea-Bissau, The Gambia and Chile were ranked in leading positions. A total of 614 articles on RSV (13.34% of all articles) were attributed to scientific collaborations. These were primarily established between high-income countries. The gender analysis indicated that male scientists dominated in all countries except Brazil.

Conclusions

The majority of RSV-related research articles originated from high-income countries whereas developing nations showed only minimal publication productivity and were barely part of any collaborative networks. Hence, research capacity in these nations should be increased in order to assist in addressing inequities in resource allocation and the clinical burden of RSV in these countries.
Guideline recommendations and antimicrobial resistance: the need for a change
Authors: Elias Christelle , Moja Lorenzo , Mertz Dominik , Loeb Mark , Forte Gilles , Magrini Nicola
Published: July 2017

Objectives

Antimicrobial resistance has become a global burden for which inappropriate antimicrobial use is an important contributing factor. Any decisions on the selection of antibiotics use should consider their effects on antimicrobial resistance. The objective of this study was to assess the extent to which antibiotic prescribing guidelines have considered resistance patterns when making recommendations for five highly prevalent infectious syndromes.

Design

We used Medline searches complemented with extensive use of Web engine to identify guidelines on empirical treatment of community-acquired pneumonia, urinary tract infections, acute otitis media, rhinosinusitis and pharyngitis. We collected data on microbiology and resistance patterns and identified discrete pattern categories. We assessed the extent to which recommendations considered resistance, in addition to efficacy and safety, when recommending antibiotics.

Results

We identified 135 guidelines, which reported a total of 251 recommendations. Most (103/135, 79%) were from developed countries. Community-acquired pneumonia was the syndrome mostly represented (51, 39%). In only 16 (6.4%) recommendations, selection of empirical antibiotic was discussed in relation to resistance and specific microbiological data. In a further 69 (27.5%) recommendations, references were made in relation to resistance, but the attempt was inconsistent. Across syndromes, 12 patterns of resistance with implications on recommendations were observed. 50% to 75% of recommendations did not attempt to set recommendation in the context of these patterns.

Conclusion

There is consistent evidence that guidelines on empirical antibiotic use did not routinely consider resistance in their recommendations. Decision-makers should analyse and report the extent of local resistance patterns to allow better decision-making.
Attempted suicide among adolescents in Mexico: prevalence and associated factors at the national level
Authors: Valdez-Santiago Rosario , Solórzano Elisa Hidalgo , Iñiguez Mariana Mojarro , Burgos Leticia Ávila , Gómez Hernández Hugo , Martínez González Ángela
Published: July 2017

Objective

To determine the prevalence and associated factors of attempted suicide (AS) in a sample of Mexican adolescents between 10 and 19 years of age.

Methods

A cross-sectional study was conducted with data from the 2012 National Health and Nutrition Survey (ENSANUT 2012 by its initials in Spanish). Based on multi-stage stratified probability sampling, ENSANUT 2012 canvassed 50 528 households including 21 519 adolescents. A logistic regression model was used to identify the factors associated with AS. The model was selected based on the maximum likelihood test.

Results

Lifetime prevalence of AS amounted to 2.7% and was heterogeneously distributed across Mexico. Women showed significantly higher risk for AS than men (ORA(adjusted OR)) 6.3, 95% confidence interval CI 4.94 to 8.06), and individuals who experienced damage to health caused by violence over the last 12 months were 4.35 times (ORA4.35, 95% CI 3.27 to 5.80) more likely to engage in AS than those who did not. The likelihood of engaging in AS was 1.5 times higher (ORA1.5 (95% CI 1.12 to 2.01)) among subjects with mild and 4.22 times higher (95% CI 3.21 to 5.54) among subjects with moderate eating disorders compared to those with no eating disorders. Other AS-associated factors included age, smoking, consuming alcohol and living with relatives other than parents.

Conclusions

Awareness of the risk factors associated with AS can help identify the populations who are exposed to injury or death by suicide. This can orient the actions of the health sector towards those who are most vulnerable. Actions must be matched by more qualitative and quantitative research on the subject.
Ethics consultation in paediatric and adult emergency departments: an assessment of clinical, ethical, learning and resource needs
Authors: Colaco Keith A , Courtright Alanna , Andreychuk Sandra , Frolic Andrea , Cheng Ji , Kam April Jacqueline
Published: July 2017

Objective

We sought to understand ethics and education needs of emergency nurses and physicians in paediatric and adult emergency departments (EDs) in order to build ethics capacity and provide a foundation for the development of an ethics education programme.

Methods

This was a prospective cross-sectional survey of all staff nurses and physicians in three tertiary care EDs. The survey tool, called Clinical Ethics Needs Assessment Survey, was pilot tested on a similar target audience for question content and clarity.

Results

Of the 123 participants surveyed, 72% and 84% of nurses and physicians fully/somewhat agreed with an overall positive ethical climate, respectively. 69% of participants reported encountering daily or weekly ethical challenges. Participants expressed the greatest need for additional support to address moral distress (16%), conflict management with patients or families (16%) and resource issues (15%). Of the 23 reported occurrences of moral distress, 61% were associated with paediatric mental health cases. When asked how the ethics consultation service could be used in the ED, providing education to teams (42%) was the most desired method.

Conclusions

Nurses report a greater need for ethics education and resources compared with their physician colleagues. Ethical challenges in paediatric EDs are more prevalent than adult EDs and nurses voice specific moral distress that are different than adult EDs. These results highlight the need for a suitable educational strategy, which can be developed in collaboration with the leadership of each ED and team of hospital ethicists.
Pig empire under infectious threat: risk of African swine fever introduction into the People's Republic of China
Authors: Vergne Timothée , Chen‐Fu Cao , Li Shuo , Cappelle Julien , Edwards John , Martin Vincent , Pfeiffer Dirk Udo , Fusheng Guo , Roger Francois Louis
Published: July 2017

Pig production and pork consumption are very important to the People's Republic of China for both economic and cultural reasons. The incursion and spread of a disease such as African swine fever (ASF), which emerged in Eastern Europe in 2007, could have devastating socioeconomic consequences for both the Chinese and the global pig industry. The Chinese government consequently attributes a very high priority to ASF and is actively seeking to improve its preparedness. This paper discusses different drivers and pathways of potential emergence of ASF in China in light of the country's specificities, including international movements of people, pigs and pig products, swill feeding practices and wild boar populations. It suggests that effective ASF risk management in China will require a comprehensive and integrated approach linking science and policy and will need to involve all relevant stakeholders to develop realistic policies.
Bernstein type results for complete spacelike hypersurfaces immersed in a weighted conformally stationary spacetime
Authors: de Lima Henrique F. , Oliveira Arlandson M. , Santos Márcio S. , Velásquez Marco A. L.
Published: July 2017

In this paper, we deal with complete noncompact spacelike hypersurfaces immersed in a weighted conformally stationary spacetime endowed with a closed conformal timelike vector field [Formula: see text]. Under suitable constraints on the weighted mean curvature of such a spacelike hypersurface, we establish sufficient conditions to ensure that it must be an integral leaf of the foliation orthogonal to [Formula: see text].
Module cancellation properties
Authors: Anderson D. D. , Juett J. R. , Mooney C. P.
Published: July 2017

We perform an in-depth study of several different cancellation properties for modules. Among those we consider are (half) (weak) cancellation modules, restricted cancellation modules, and (half) join principal modules. We also investigate which commutative rings have every nonzero (finitely generated) ideal (respectively, module) satisfying some cancellation property.
Külshammer ideals of algebras of quaternion type
Authors: Zimmermann Alexander
Published: July 2017

For a symmetric algebra [Formula: see text] over a field [Formula: see text] of characteristic [Formula: see text] Külshammer constructed a descending sequence of ideals of the center of [Formula: see text]. If [Formula: see text] is perfect, this sequence was shown to be an invariant under derived equivalence and for algebraically closed [Formula: see text] the dimensions of their image in the stable center were shown to be invariant under stable equivalence of Morita type. Erdmann classified algebras of tame representation type which may be blocks of group algebras, and Holm classified Erdmann’s list up to derived equivalence. In both classifications, certain parameters occur in the classification, and it was unclear if different parameters lead to different algebras. Erdmann’s algebras fall into three classes, namely of dihedral, semidihedral and of quaternion type. In previous joint work with Holm, we used Külshammer ideals to distinguish classes with respect to these parameters in case of algebras of dihedral and semidihedral type. In the present paper, we determine the Külshammer ideals for algebras of quaternion type and distinguish again algebras with respect to certain parameters.
Realizability and the Avrunin–Scott theorem for higher-order support varieties
Authors: Bergh Petter Andreas , Jorgensen David A.
Published: July 2017

We introduce higher-order support varieties for pairs of modules over a commutative local complete intersection ring and give a complete description of which varieties occur as such support varieties. In the context of a group algebra of a finite elementary abelian group, we also prove a higher-order Avrunin–Scott-type theorem, linking higher-order support varieties and higher-order rank varieties for pairs of modules.
Effect of elastic constants of liquid crystals in their electro-optical properties
Authors: Parang Z. , Ghaffary T. , Gharahbeigi M. M.
Published: July 2017

Recently following the success of the density functional theory (DFT) in obtaining the structure and thermodynamics of homogeneous and inhomogeneous classical systems such as simple fluids, dipolar fluid and binary hard spheres, this theory was also applied to obtain the density profile of a molecular fluid in between hard planar walls by Kalpaxis and Rickayzen. In the theory of molecular fluids, the direct correlation function (DCF) can be used to calculate the equation of state, free energy, phase transition, elastic constants, etc. It is well known that the hard core molecular models play an important role in understanding complex liquids such as liquid crystals. In this paper, a classical fluid of nonspherical molecules is studied. The required homogeneous (DCF) is obtained by solving Orenstein–Zernike (OZ) integral equation numerically. Some of the molecules in the liquid crystals have a sphere shape and this kind of molecular fluid is considered here. The DCF sphere of the molecular fluid is calculated and it will be shown that the results are in good agreement with the pervious works and the results of computer simulation. Finally the electro-optical properties of ellipsoid liquid crystal using DCF of these molecules are calculated.
PDBlocal: A web-based tool for local inspection of biological macromolecular 3D structures
Authors: Wang Pan , Yang Guangxiao , He Guangyuan
Published: July 2017

Functional research on biological macromolecules must focus on specific local regions. PDBlocal is a web-based tool developed to overcome the limitations of traditional molecular visualization tools for three-dimensional (3D) inspection of local regions. PDBlocal provides an intuitive and easy-to-manipulate web page interface and some new useful functions. It can keep local regions flashing, display sequence text that is dynamically consistent with the 3D structure in local appearance under multiple local manipulations, use two scenes to help users inspect the same local region with different statuses, list all historical manipulation statuses with a tree structure, allow users to annotate regions of interest, and save all historical statuses and other data to a web server for future research. PDBlocal has met expectations and shown satisfactory performance for both expert and novice users. This tool is available at http://labsystem.scuec.edu.cn/pdblocal/ .
Spin–Orbit Torques in Metallic Magnetic Multilayers: Challenges and New Opportunities
Authors: Wang Tao , Xiao John Q. , Fan Xin
Published: July 2017

Two decades after the discovery of the giant magnetoresistance that revolutionizes the hard disk drive, the rapid development of spin torque-based magnetic random access memory has once again demonstrated the great potential of spintronics in practical applications. While the industrial application is mainly focusing on the implementation of current-induced spin transfer torque (STT) in magnetic tunnel junctions, a new type of spin torque emerges due to the spin–orbit interaction in magnetic multilayers. A great effort has been devoted by the scientific community to study the so-called spin–orbit torque (SOT), which is not only of interest to fundamental science, but also exhibits potential for the application of current-induced magnetization switching. In this paper, we will review recent development in the SOTs including the fundamental understanding, materials development and measurement techniques. We will also discuss the challenges of using the SOT in potential applications, particularly on the switching of perpendicularly magnetized films.
Study of the Photocatalytic Property of Polysulfone Membrane Incorporating TiO2 Nanoparticles
Authors: Chen Xingxing , Zhou Weiqi , Chen Zhe , Yao Lei
Published: July 2017

In order to investigate the effect of the incorporated nanoparticles on the photocatalytic property of the hybrid membranes, the uncovered and covered polysulfone/TiO2 hybrid membranes were prepared. Positron annihilation [Formula: see text]-ray spectroscopy coupled with a positron beam was utilized to examine the depth profiles of the two membranes. The photocatalytic activities of the membranes were evaluated by the degradation of Rhodamine B (RhB) aqueous solution under the irradiation of Xe lamp. UV-Vis spectroscopy was applied to study the UV transmission through the polysulfone layer. Electrochemical impedance spectroscopy was used to detect the photo-generated charges by the covered membrane during the irradiation. It can be found that UV light can penetrate through the covered layer (about 230[Formula: see text]nm), and the incorporated nanoparticles can still generate charges under irradiation, which endows the photocatalytic ability of the covered membrane.
Current and future role of instrumentation and monitoring in the performance of transport infrastructure slopes
Authors: Smethurst J. A. , Smith A. , Uhlemann S. , Wooff C. , Chambers J. , Hughes P. , Lenart S. , Saroglou H. , Springman S. M. , Löfroth H. , Hughes D.
Published: July 2017

Instrumentation is often used to monitor the performance of engineered infrastructure slopes. This paper looks at the current role of instrumentation and monitoring, including the reasons for monitoring infrastructure slopes, the instrumentation typically installed and parameters measured. The paper then investigates recent developments in technology and considers how these may change the way that monitoring is used in the future, and tries to summarize the barriers and challenges to greater use of instrumentation in slope engineering. The challenges relate to economics of instrumentation within a wider risk management system, a better understanding of the way in which slopes perform and/or lose performance, and the complexities of managing and making decisions from greater quantities of data.
In search of video event semantics
Authors: Mazloom Masoud
Published: July 2017

In this thesis we aim to represent an event in a video using semantic features. We start from a bank of concept detectors for representing events in video.
Multiple paper types for SIGCSE 2018
Authors: Perez-Quinones Manuel A. , Hawthorne Elizabeth K.
Published: July 2017

Exciting program changes are ahead for the 2018 SIGCSE Technical Symposium!
A simple, cost-effective method for generating murine colonic 3D enteroids and 2D monolayers for studies of primary epithelial cell function
Authors: Fernando Elizabeth H. , Dicay Michael , Stahl Martin , Gordon Marilyn H. , Vegso Andrew , Baggio Cristiane , Alston Laurie , Lopes Fernando , Baker Kristi , Hirota Simon , McKay Derek M. , Vallance Bruce , MacNaughton Wallace K.
Published: July 2017

Cancer cell lines have been the mainstay of intestinal epithelial experimentation for decades, due primarily to their immortality and ease of culture. However, because of the inherent biological abnormalities of cancer cell lines, many cellular biologists are currently transitioning away from these models and toward more representative primary cells. This has been particularly challenging, but recent advances in the generation of intestinal organoids have brought the routine use of primary cells within reach of most epithelial biologists. Nevertheless, even with the proliferation of publications that use primary intestinal epithelial cells, there is still a considerable amount of trial and error required for laboratories to establish a consistent and reliable method to culture three-dimensional (3D) intestinal organoids and primary epithelial monolayers. We aim to minimize the time other laboratories spend troubleshooting the technique and present a standard method for culturing primary epithelial cells. Therefore, we have described our optimized, high-yield, cost-effective protocol to grow 3D murine colonoids for more than 20 passages and our detailed methods to culture these cells as confluent monolayers for at least 14 days, enabling a wide variety of potential future experiments. By supporting and expanding on the current literature of primary epithelial culture optimization and detailed use in experiments, we hope to help enable the widespread adoption of these innovative methods and allow consistency of results obtained across laboratories and institutions.

NEW & NOTEWORTHY Primary intestinal epithelial monolayers are notoriously difficult to maintain culture, even with the recent advances in the field. We describe, in detail, the protocols required to maintain three-dimensional cultures of murine colonoids and passage these primary epithelial cells to confluent monolayers in a standardized, high-yield and cost-effective manner.
Recent advances in oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction
Authors: Strielkov Ievgen , Pak Oleg , Sommer Natasha , Weissmann Norbert
Published: July 2017

Hypoxic pulmonary vasoconstriction (HPV) is a physiological reaction, which adapts lung perfusion to regional ventilation and optimizes gas exchange. Impaired HPV may cause systemic hypoxemia, while generalized HPV contributes to the development of pulmonary hypertension. The triggering mechanisms underlying HPV are still not fully elucidated. Several hypotheses are currently under debate, including a possible decrease as well as an increase in reactive oxygen species as a triggering event. Recent findings suggest an increase in the production of reactive oxygen species in pulmonary artery smooth muscle cells by complex III of the mitochondrial electron transport chain and occurrence of oxygen sensing at complex IV. Other essential components are voltage-dependent potassium and possibly L-type, transient receptor potential channel 6, and transient receptor potential vanilloid 4 channels. The release of arachidonic acid metabolites appears also to be involved in HPV regulation. Further investigation of the HPV mechanisms will facilitate the development of novel therapeutic strategies for the treatment of HPV-related disorders.
Imaging approaches to understand disease complexity: chronic obstructive pulmonary disease as a clinical model
Authors: Sanders Karin J. C. , Ash Samuel Y. , Washko George R. , Mottaghy Felix M. , Schols Annemie M. W. J.
Published: July 2017

The clinical manifestations of chronic obstructive pulmonary disease (COPD) reflect an aggregate of multiple pulmonary and extrapulmonary processes. It is increasingly clear that full assessment of these processes is essential to characterize disease burden and to tailor therapy. Medical imaging has advanced such that it is now possible to obtain in vivo insight in the presence and severity of lung disease-associated features. In this review, we have assembled data from multiple disciplines of medical imaging research to review the role of imaging in characterization of COPD. Topics include imaging of the lungs, body composition, and extrapulmonary tissue metabolism. The primary focus is on imaging modalities that are widely available in clinical care settings and that potentially contribute to describing COPD heterogeneity and enhance our insight in underlying pathophysiological processes and their structural and functional effects.
Automated full-range pressure-volume curves in mice and rats
Authors: Robichaud Annette , Fereydoonzad Liah , Limjunyawong Nathachit , Rabold Richard , Allard Benoit , Benedetti Andrea , Martin James G. , Mitzner Wayne
Published: July 2017

Pressure-volume (PV) curves constructed over the entire lung volume range can reliably detect functional changes in mouse models of lung diseases. In the present study, we constructed full-range PV curves in healthy and elastase-treated mice using either a classic manually operated technique or an automated approach using a computer-controlled piston ventilator [flexiVent FX; Scientific Respiratory Equipment (SCIREQ), Montreal, Quebec, Canada]. On the day of the experiment, subjects were anesthetized, tracheotomized, and mechanically ventilated. Following an initial respiratory mechanics scan and degassing of the lungs with 100% O2, full-range PV curves were constructed using either the classic or the automated technique. In control mice, superimposable curves were obtained, and statistical equivalence was attained between the two methodologies. In the elastase-treated ones, where significant changes in respiratory mechanics and lung volumes were expected, very small differences were observed between the two techniques, and the criteria for statistical equivalence were met in two out of four parameters assessed. The automated technique was adapted to rats and used to estimate the functional residual capacity (FRC) by volume subtraction. This novel approach generated FRC estimates consistent with the literature, with added accuracy relative to the existing method in diseased subjects. In conclusion, the automated technique generated full-range PV curves that were equivalent or very close to those obtained with the classic method under physiological or severe pathological conditions. The automation facilitated some technical aspects of the procedure, eased its use across species, and helped derive a more accurate estimate of FRC in preclinical models of respiratory disease.

NEW & NOTEWORTHY Partial and full-range pressure-volume (PV) curves are frequently used to characterize lung disease models. Whereas automated techniques exist to construct partial PV curves, a manually operated approach is classically employed to build the full-range ones. In this study, the full-range PV curve technique was automated using a computer-controlled piston ventilator. The automation simplified the technique, facilitated its extension to other species, and inspired a novel way of estimating the functional residual capacity in laboratory rodents.
Epigenetic research in multiple sclerosis: progress, challenges, and opportunities
Authors: Zheleznyakova Galina Y. , Piket Eliane , Marabita Francesco , Pahlevan Kakhki Majid , Ewing Ewoud , Ruhrmann Sabrina , Needhamsen Maria , Jagodic Maja , Kular Lara
Published: July 2017

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system. MS likely results from a complex interplay between predisposing causal gene variants (the strongest influence coming from HLA class II locus) and environmental risk factors such as smoking, infectious mononucleosis, and lack of sun exposure/vitamin D. However, little is known about the mechanisms underlying MS development and progression. Moreover, the clinical heterogeneity and variable response to treatment represent additional challenges to a comprehensive understanding and efficient treatment of disease. Epigenetic processes, such as DNA methylation and histone posttranslational modifications, integrate influences from the genes and the environment to regulate gene expression accordingly. Studying epigenetic modifications, which are stable and reversible, may provide an alternative approach to better understand and manage disease. We here aim to review findings from epigenetic studies in MS and further discuss the challenges and clinical opportunities arising from epigenetic research, many of which apply to other diseases with similar complex etiology. A growing body of evidence supports a role of epigenetic processes in the mechanisms underlying immune pathogenesis and nervous system dysfunction in MS. However, disparities between studies shed light on the need to consider possible confounders and methodological limitations for a better interpretation of the data. Nevertheless, translational use of epigenetics might offer new opportunities in epigenetic-based diagnostics and therapeutic tools for a personalized care of MS patients.
Elevation of fumarase attenuates hypertension and can result from a nonsynonymous sequence variation or increased expression depending on rat strain
Authors: Usa Kristie , Liu Yong , Geurts Aron M. , Cheng Yuan , Lazar Jozef , Baker Maria Angeles , Grzybowski Michael , He Yongcheng , Tian Zhongmin , Liang Mingyu
Published: July 2017

The activity of fumarase, an enzyme in the tricarboxylic acid cycle, is lower in Dahl salt-sensitive SS rats compared with SS.13BN rats. SS.13BN rats have a Brown Norway (BN) allele of fumarase and exhibit attenuated hypertension. The SS allele of fumarase differs from the BN allele by a K481E sequence variation. It remains unknown whether higher fumarase activities can attenuate hypertension and whether the mechanism is relevant without the K481E variation. We developed SS-TgFh1 transgenic rats overexpressing fumarase on the background of the SS rat. Hypertension was attenuated in SS-TgFh1 rats. Mean arterial pressure in SS-TgFh1 rats was 20 mmHg lower than transgene-negative SS littermates after 12 days on a 4% NaCl diet. Fumarase overexpression decreased H2O2, while fumarase knockdown increased H2O2. Ectopically expressed BN form of fumarase had higher specific activity than the SS form. However, sequencing of more than a dozen rat strains indicated most rat strains including salt-insensitive Sprague-Dawley (SD) rats had the SS allele of fumarase. Despite that, total fumarase enzyme activity in the renal medulla was still higher in SD rats than in SS rats, which was associated with higher expression of fumarase in SD. H2O2 can suppress the expression of fumarase. Renal medullary interstitial administration of fumarase siRNA in SD rats resulted in higher blood pressure on the high-salt diet. These findings indicate elevation of total fumarase activity attenuates the development of hypertension and can result from a nonsynonymous sequence variation in some rat strains and higher expression in other rat strains.
Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival
Authors: Zhai Lijie , Ladomersky Erik , Lauing Kristen L. , Wu Meijing , Genet Matthew , Gritsina Galina , Győrffy Balázs , Brastianos Priscilla K. , Binder David C. , Sosman Jeffrey A. , Giles Francis J. , James Charles D. , Horbinski Craig , Stupp Roger , Wainwright Derek A.
Published: July 2017

Purpose: Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome.

Experimental Design: Patient-resected GBM, The Cancer Genome Atlas, human T-cell:GBM cocultures, as well as nu/nu, NOD-scid, and humanized (NSG-SGM3-BLT) mice-engrafted human GBM form the basis of our investigation.

Results: In situ hybridization for IDO1 revealed transcript expression throughout patient-resected GBM, whereas immunohistochemical IDO1 positivity was highly variable. Multivariate statistical analysis revealed that higher levels of IDO1 transcript predict a poor patient prognosis (P = 0.0076). GBM IDO1 mRNA levels positively correlated with increased gene expression for markers of cytolytic and regulatory T cells, in addition to decreased patient survival. Humanized mice intracranially engrafted human GBM revealed an IFNγ-associated T-cell–mediated increase of intratumoral IDO1.

Conclusions: Our data demonstrate that high intratumoral IDO1 mRNA levels correlate with a poor GBM patient prognosis. It also confirms the positive correlation between increased GBM IDO1 levels and human-infiltrating T cells. Collectively, this study suggests that future efforts aimed at increasing T-cell–mediated effects against GBM should consider combinatorial approaches that coinhibit potential T-cell–mediated IDO1 enhancement during therapy. Clin Cancer Res; 23(21); 6650–60. ©2017 AACR.
Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged Cancers
Authors: Fuse Miho J. , Okada Koutaroh , Oh-hara Tomoko , Ogura Hayato , Fujita Naoya , Katayama Ryohei
Published: July 2017

Neurotrophic receptor tyrosine kinase 1 (NTRK1) gene rearrangement leads to constitutive activation of NTRK1, which induces high-transforming ability. NTRK-rearranged cancers have been identified in several cancer types, such as glioblastoma, non–small cell lung cancer, and colorectal cancer. Although there are currently no clinically approved inhibitors that target NTRK1, several tyrosine kinase inhibitors (TKI), such as entrectinib and LOXO-101, are in clinical trials. The purpose of this study was to identify potential mechanisms of resistance to NTRK inhibitors and find potential therapeutic strategies to overcome the resistance. We examined the sensitivity of TPM3-NTRK1-transformed Ba/F3 cells and TPM3-NTRK1-harboring KM12 cells to multiple NTRK inhibitors. Acquired NTRK inhibitor-resistant mutations were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3-TPM3-NTRK1 cells or by the establishment of NTRK-TKI-resistant cells from KM12 cells continuously treated with NTRK-TKIs. We identified multiple novel NTRK-TKI resistance mutations in the NTRK1 kinase domain, including G595R, and insulin growth factor receptor type 1 (IGF1R) bypass pathway-mediated resistance. After identifying the resistance mechanisms, we performed drug screening with small-molecule inhibitors to overcome the resistance. As a result, we found that ponatinib and nintedanib effectively inhibited the survival of TPM3-NTRK1-G667C but not G595R mutants, both of which showed resistance to entrectinib or larotrectinib (LOXO-101). Furthermore, cabozantinib with an IGF1R inhibitor such as OSI-906 could overcome bypass pathway-mediated resistance. We developed a comprehensive model of acquired resistance to NTRK inhibitors in cancer with NTRK1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance. Mol Cancer Ther; 16(10); 2130–43. ©2017 AACR.
TTK Inhibitors as a Targeted Therapy forCTNNB1(β-catenin) Mutant Cancers
Authors: Zaman Guido J.R. , de Roos Jeroen A.D.M. , Libouban Marion A.A. , Prinsen Martine B.W. , de Man Jos , Buijsman Rogier C. , Uitdehaag Joost C.M.
Published: July 2017

The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small-molecule inhibitors. Although the first TTK inhibitors have entered phase I dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy is still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, we profiled a set of preclinical and clinical TTK inhibitors from different chemical series on a panel of 66 genetically characterized cell lines derived from different tumors (Oncolines). Cell lines harboring activating mutations in the CTNNB1 gene, encoding the Wnt pathway signaling regulator β-catenin, were on average up to five times more sensitive to TTK inhibitors than cell lines wild-type for CTNNB1. The association of CTNNB1-mutant status and increased cancer cell line sensitivity to TTK inhibition was confirmed with isogenic cell line pairs harboring either mutant or wild-type CTNNB1. Treatment of a xenograft model of a CTNNB1-mutant cell line with the TTK inhibitor NTRC 0066-0 resulted in complete inhibition of tumor growth. Mutations in CTNNB1 occur at relatively high frequency in endometrial cancer and hepatocellular carcinoma, which are known to express high TTK levels. We propose mutant CTNNB1 as a prognostic drug response biomarker, enabling the selection of patients most likely to respond to TTK inhibitor therapy in proof-of-concept clinical trials. Mol Cancer Ther; 16(11); 2609–17. ©2017 AACR.
mTOR (Mechanistic Target of Rapamycin) Inhibition Decreases Mechanosignaling, Collagen Accumulation, and Stiffening of the Thoracic Aorta in Elastin-Deficient Mice
Authors: Jiao Yang , Li Guangxin , Li Qingle , Ali Rahmat , Qin Lingfeng , Li Wei , Qyang Yibing , Greif Daniel M. , Geirsson Arnar , Humphrey Jay D. , Tellides George
Published: July 2017

Objective—

Elastin deficiency because of heterozygous loss of an
ELN
allele in Williams syndrome causes obstructive aortopathy characterized by medial thickening and fibrosis and consequent aortic stiffening. Previous work in
Eln
-null mice with a severe arterial phenotype showed that inhibition of mTOR (mechanistic target of rapamycin), a key regulator of cell growth, lessened the aortic obstruction but did not prevent early postnatal death. We investigated the effects of mTOR inhibition in
Eln
-null mice partially rescued by human
ELN
that manifest a less severe arterial phenotype and survive long term.

Approach and Results—

Thoracic aortas of neonatal and juvenile mice with graded elastin deficiency exhibited increased signaling through both mTOR complex 1 and 2. Despite lower predicted wall stress, there was increased phosphorylation of focal adhesion kinase, suggestive of greater integrin activation, and increased transforming growth factor-β–signaling mediators, associated with increased collagen expression. Pharmacological blockade of mTOR by rapalogs did not improve luminal stenosis but reduced mechanosignaling (in delayed fashion after mTOR complex 1 inhibition), medial collagen accumulation, and stiffening of the aorta. Rapalog administration also retarded somatic growth, however, and precipitated neonatal deaths. Complementary, less-toxic strategies to inhibit mTOR via altered growth factor and nutrient responses were not effective.

Conclusions—

In addition to previously demonstrated therapeutic benefits of rapalogs decreasing smooth muscle cell proliferation in the absence of elastin, we find that rapalogs also prevent aortic fibrosis and stiffening attributable to partial elastin deficiency. Our findings suggest that mTOR-sensitive perturbation of smooth muscle cell mechanosensing contributes to elastin aortopathy.
Association of Coronary Perivascular Adipose Tissue Inflammation and Drug-Eluting Stent–Induced Coronary Hyperconstricting Responses in Pigs
Authors: Ohyama Kazuma , Matsumoto Yasuharu , Amamizu Hirokazu , Uzuka Hironori , Nishimiya Kensuke , Morosawa Susumu , Hirano Michinori , Watabe Hiroshi , Funaki Yoshihito , Miyata Satoshi , Takahashi Jun , Ito Kenta , Shimokawa Hiroaki
Published: July 2017

Objective—

Although coronary perivascular adipose tissue (PVAT) may play important roles as a source of inflammation, the association of coronary PVAT inflammation and coronary hyperconstricting responses remains to be examined. We addressed this important issue in a porcine model of coronary hyperconstricting responses after drug-eluting stent implantation with
18
F-fluorodeoxyglucose (
18
F-FDG) positron emission tomographic imaging.

Approach and Results—

An everolimus-eluting stent (EES) was randomly implanted in pigs into the left anterior descending or the left circumflex coronary artery while nonstented coronary artery was used as a control. After 1 month, coronary vasoconstricting responses to intracoronary serotonin (10 and 100 μg/kg) were examined by coronary angiography in vivo, followed by in vivo and ex vivo
18
F-FDG positron emission tomographic/computed tomographic imaging. Coronary vasoconstricting responses to serotonin were significantly enhanced at the EES edges compared with the control site (
P
<0.01; n=40). Notably, in vivo and ex vivo
18
F-FDG positron emission tomographic/computed tomographic imaging and autoradiography showed enhanced
18
F-FDG uptake and its accumulation in PVAT at the EES edges compared with the control site, respectively (both
P
<0.05). Furthermore, histological and reverse transcription polymerase chain reaction analysis showed that inflammatory changes of coronary PVAT were significantly enhanced at the EES edges compared with the control site (all
P
<0.01). Importantly, Rho-kinase expressions (ROCK1/ROCK2) and Rho-kinase activity (phosphorylated myosin phosphatase target subunit-1) at the EES edges were significantly enhanced compared with the control site.

Conclusions—

These results indicate for the first time that inflammatory changes of coronary PVAT are associated with drug-eluting stent–induced coronary hyperconstricting responses in pigs in vivo and that
18
F-FDG positron emission tomographic imaging is useful for assessment of coronary PVAT inflammation.