bluuebunny/crossref_metadata_2025 huggingface dataset:
Activity of Group 2 Innate Lymphoid Cells is Associated with Chronic Inflammation and Dysregulated Metabolic Homoeostasis in Type 2 Diabetic Nephropathy
Authors: Lu P. , Ji X. , Wan J. , Xu H.
Published: December 2017

The metabolic syndrome (MS) is an independent risk factor for type 2 diabetic nephropathy and accompanied by subclinical inflammation which involves immune‐deriving factors. Emerging studies indicate that group 2 innate lymphoid cells (ILC2s) can regulate adipose metabolism, but much less is known about the activity of ILC2s in metabolic imbalance in obesity and diabetes. This study explored the effect of ILC2s‐related molecules on the occurrence of MS in type 2 diabetic nephropathy. Thirty patients with type 2 diabetic nephropathy were included in the study; the mRNA expression of ILC2s‐associated molecules from peripheral blood mononuclear cell and the correlation of the ILC2s activity and the MS‐related indicators were analysed. The results indicated that the waist circumference, fasting blood glucose, systolic blood pressure, diastolic blood pressure and triglyceride in patients with simple diabetes and diabetic nephropathy were increased, and the incidence of MS was 46.67% and 86.67%, respectively. The ILC2s‐associated factors RORα, T1/ST2 and IL‐5/IL‐13 mRNA were increased in diabetic nephropathy. There was a positive correlation between the expression level of IL‐13 or T1/ST2 mRNA and some MS indexes. In addition, the levels of plasma sTNFR, eotaxin‐2 and I‐309 were also increased in patients with type 2 diabetic nephropathy. It suggested that the patients with type 2 diabetic nephropathy were more likely to have multiple components of MS than those with simple type 2 diabetes mellitus, and enhanced ILC2s activity might be involved in the formation of MS in diabetic nephropathy via influencing blood pressure and lipid metabolism.
Outcomes of red blood cell transfusions prescribed in organ donors by the Digital Intern, an electronic decision support algorithm
Authors: Connor Joseph P. , Raife Thomas , Medow Joshua E.
Published: December 2017

BACKGROUND

The Digital Intern (DI) is an electronic decision support tool for the management of organ donors. One algorithm determines the dose, in units of red blood cells to be transfused, based on hematocrit (Hct) thresholds and targets. The effectiveness of the transfusion dose calculated by the DI in terms of achieving the selected Hct target and the duration of the targeted dose is not known.

STUDY DESIGN AND METHODS

This was a retrospective study to describe the outcomes of transfusions prescribed by the DI. Pre‐ and posttransfusion Hct levels were compared to define response and all posttransfusion Hct values were plotted to evaluate the duration of the prescribed dose.

RESULTS

A total of 120 organ donors were studied and 22 donors had 28 transfusions (six were transfused twice). The transfused donors were a mix of trauma and medical admissions and brain death and cardiac death donors. The transfusion target of 24% Hct was attained in 96% of transfusions. The mean number of units transfused was 1.4 and the mean time from transfusion to procurement was 19.8 hours. There was a decline in Hct over time after transfusion in all but one case with a mean decline of 1.9% Hct over 13 hours. Six donors were transfused twice, likely due to a longer donor time period (41.7 hr vs. 27 hr).

CONCLUSIONS

The DI provided transfusion dosing that achieved the desired threshold in the majority of organ donors transfused. Ongoing work focuses on application of this technology to transfusions in general patient populations.
HORACE M. KALLEN'S USE OF EVOLUTIONARY THEORY IN SUPPORT OF AMERICAN JEWS AND DEMOCRACY
Authors: Kaufman Matthew
Published: December 2017

This article examines the rhetorical deployment of Darwinian natural selection by the Jewish social philosopher Horace M. Kallen (1882–1974), in what is now widely regarded as the first articulation of cultural pluralism, “Democracy versus the Melting‐Pot” (1915). My analysis proceeds in two steps. First, I identify specific strategies by means of which Kallen endeavored to insert his ideas more deeply into national discourse. I also trace reactions to his essay in the Jewish press, and argue that these indicate ongoing conversations concerning Kallen's ideas, and they also reveal how he was reinterpreted for different reading audiences. Second, I argue that Kallen's strategy was to stress the survival value of cooperation rather than competition in natural selection, and he believed that this view supported both the natural biological inclinations of social groups and reflected American democratic values. Kallen's intervention serves as a striking example of how Darwinian natural selection was deployed to support Jewish participation in American life.
PANENTHEISM AND THE UNDOING OF DISENCHANTMENT
Authors: Main Roderick
Published: December 2017

In this article, I draw on historical and conceptual arguments to show, first, that disenchantment and the influential view of the relationship between science and religion to which disenchantment gives rise are rooted in the metaphysics of theism. I then introduce the alternative metaphysical position of panentheism and identify Jungian psychology as an important, if implicit, mid‐twentieth‐century instance of panentheistic thought. Using the example of Jungian psychology, I demonstrate how the viewpoint of panentheism undoes the implications of disenchantment for the relationship between science and religion, promoting greater opportunities for dialogue and reconciliation between science and religion. I note, however, that these closer relations may depend on understanding science and religion differently from how they are understood under disenchantment. While the original tension between science and religion is eased, another tension—between panentheistic and disenchanted understandings of science and religion—is exposed. I conclude by reflecting on some implications of this discussion for sociology.
BIOLOGY TEACHERS’ CONCEPTIONS ABOUT THE ORIGIN OF LIFE IN BRAZIL, ARGENTINA, AND URUGUAY: A COMPARATIVE STUDY
Authors: Silva Heslley Machado , Clément Pierre , Leão Isabela Maria Silva , Garros Tiago Valentim , Carvalho Graça Simões
Published: December 2017

Teachers’ conceptions about the origin of life in three Latin American countries with contrasting levels of secularism were analyzed: Argentina (Catholic constitution), Brazil (formally secular but not in practice), and Uruguay (consolidated secularism). A European survey questionnaire was used and the interpretation of the results drew on Barbour's four categories concerning the relationships of science and religion. A large majority of Argentinian and Uruguayan teachers were clearly evolutionist, even when believing in God (Independence or Dialogue category), with no difference between Argentina and Uruguay. The majority of Brazilian teachers assumed a religious position about the origin of life, being creationist (Conflict or Independence categories) or evolutionary creationist (Dialogue or Integration categories). Differences of Brazilian teachers’ conceptions may result from the higher percentage of evangelicals and lower proportion of agnostics/atheists. Brazilian Catholic teachers were more creationist than their Catholic colleagues in Argentina and Uruguay. Distinct patterns were found, but further research is needed to understand possible classroom impacts.
PANENTHEISM AND NATURAL SCIENCE: A GOOD MATCH?
Authors: Drees Willem B.
Published: December 2017

Is panentheism a metaphysical and religious understanding of the divine and of the world that aligns better with science than classical theism? In order to address this question, I'll present brief descriptions of theism, pantheism, and panentheism, and of religious visions as integrating models of the world and models for the world. In this respect, science has its limitations. The conclusion that I will argue for is that naturalistic varieties of theism, pantheism, and panentheism do equally well with respect to the natural sciences, and hence that there is no argument from science that favors a panentheistic metaphysics. There may be philosophical or religious arguments that make one prefer one position over another. Science can be involved in the choice for one interpretation of a religious‐metaphysical view such as panentheism. Thus, science might play a role in the development of positions, once chosen, and hence in intra‐religious competition, even though it cannot be decisive on fundamental choices in metaphysics.
#WhyITold: A Pilot Test of Twitter Messages Aimed at Promoting Bystander Intervention against Domestic Violence
Authors: Wong Norman C. H. , Bostwick Eryn
Published: December 2017

This study examined the effectiveness of various messaging via Twitter in persuading bystanders of domestic violence (DV) to intervene on behalf of DV victims. Using Fishbein’s (2000) integrative model of behavioral prediction as a guiding framework, an experiment was conducted with 196 undergraduates from a large Southwestern university. Participants were randomly assigned to read either a: (1) tweet describing warning signs associated with DV motivating bystander intervention, (2) gain or loss framed tweet emphasizing why a bystander chose to intervene, or (3) control tweet that simply provided statistics on the prevalence of DV in the U.S. Results indicate injunctive norms were the best predictor of participants’ intent to intervene in a DV situation, and that the most effective approach to promoting bystander intervention is to highlight warning signs of DV. Implications for practice are also discussed.
Endothelial Piezo1 channels as sensors of exercise
Authors: Beech David J.
Published: December 2017

Piezo1 channels are newly discovered ion channels which have come to the fore as players in endothelial biology. They have a key role as sensors of shear stress, a frictional force which arises in vascular biology because of blood flow. Endothelial Piezo1 channels are critical in murine embryonic development, just after the heart starts to beat and drive blood into the nascent endothelial network. In contrast they are not critical at the adult stage but they are important for performance in whole body physical activity where they have a vascular bed‐specific effect to cause mesenteric resistance artery vasoconstriction, achieved through opposition to the vasodilatory mechanism of endothelium‐derived hyperpolarization. These are our first insights into the relevance of endothelial Piezo1 channels and there is clearly much more to be done to understand the significance and underlying molecular mechanisms. The suggestion that they constitute an exercise sensor by virtue of their shear stress‐sensing capability is intriguing and could open the way to better understanding of the molecular basis of the response to exercise and determination of how the health benefits of exercise arise. Enhanced Piezo1 channel activity has been demonstrated in response to the Yoda1 molecule and this suggests the possibility for developing tools which probe and manipulate this aspect of the exercise system. Whether such agents might progress to ‘exercise pills’ and whether the existence of such pills would be desirable are matters for further work and debate.

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Evaluation of Genetic and Biochemical Factors in Patients with Acute Coronary Syndrome
Authors: Bastidas Viritch Katerina , Botero Bermúdez Mónica , Salamanca Ternera María Lucia , Ayala Ramírez Paola Andrea , García Robles Reggie , Bermúdez Martha
Published: December 2017

Introduction: The cardiovascular diseases are the principal cause of death worldwide and a public health problem in Colombia. From the cardiac related illnesses, the most frequent is the Acute Coronary Syndrome (ACS). One of its risk factor is high plasma levels of homocysteine. The enzyme Paraoxonase 1 (PON1) hydrolyzes Homocysteine-thiolactone, producing homocysteine, avoiding damage to endothelium related to Homocysteine-thiolactone. Two genetic variants in PON1 gene have been associated with levels of homocysteine and acute coronary syndrome. Objective: to determine the relationship between the polymorphisms Q192R and L55M from gene PON1 and the levels of homocysteine, HDL, apo A-1 and the enzymatic activity of Paraoxonase I in patients who suffered acute coronary syndrome. Methods: sixteen unrelated patients with Acute Coronary Syndrome (ACS) and sixteen healthy controls were enrolled. The paraoxonase activity, levels of homocysteine, HDL and apo A-1 were assessed. The DNA polymorphism analysis was performed using Polymerase Chain Reaction (PCR) and digestion with restriction enzymes. Results: levels of homocysteine are higher in cases (p<0.0001) and the genotypes 192RR and QR are associated with higher levels of homocysteine (p=0.0234). Conclusion: polymorphisms in PON1 gene could be related to homocysteine levels in Acute Coronary Syndrome patients.
Guía de práctica clínica (GPC) para la prevención, diagnóstico y tratamiento del sobrepeso y la obesidad en adultos
Authors: Escobar Duque Iván Dario
Published: December 2017

Objetivo: Generar recomendaciones para la prevención del sobrepeso y la obesidad en niños, adolescentes y adultos, así como el manejo del sobrepeso y la obesidad en la población adulta, Materiales y métodos: Se conformó el Grupo Desarrollador de la Guía (GDG) con un grupo interdisciplinario de profesionales y representantes de pacientes. Se definieron alcance, objetivos, preguntas y desenlaces de la guía. Se realizó una búsqueda de literatura de revisiones sistemáticas-metanálisis, ensayos clínicos, estudios de cohorte, estudios de casos y controles, en las bases de datos Medline, Embase y Central. Se evaluó la calidad metodológica de los artículos seleccionados. Resultados: Se presentan las recomendaciones de prevención del sobrepeso y la obesidad para población infantil, así como recomendaciones para el manejo (con intervenciones multicomponente o quirúrgicas) para población adulta. Conclusiones: La presente guía ofrece importantes lineamientos para la prevención y el manejo integral de los pacientes con sobrepeso y obesidad de nuestro país, los cuales se espera que repercutan de manera positiva en nuestra población.
Riesgo diferencial de hemorragia intracraneana en pacientes con fibrilación auricular no valvular con el uso de nuevos anticoagulantes orales vs. warfarina. Revisión sistemática de la literatura y análisis de subpoblaciones
Authors: Aurachán Torres Samir Alejandro , Ayala Copete Ana María , Patiño Hermández Daniela , Rios Zuluaga Julián David , García Peña Ángel Alberto , Cano Gutiérrez Carlos Alberto
Published: December 2017

Introducción: La anticoagulación en pacientes con fibrilación auricular no valvular previene eventos tromboembólicos con incremento implícito en el riesgo de complicaciones hemorrágicas, principalmente la hemorragia intracraneana. Métodos: Se realizó una revisión sistemática de la literatura del periodo 2011-2016 en bases de datos (Pubmed-Embase). Se incluyeron metanálisis, revisiones sistemáticas y ensayos clínicos aleatorizados de las moléculas de interés (apixabán, dabigatrán, edoxabán, rivaroxabán). Se identificaron 512 artículos, tras lo cual se seleccionaron catorce estudios para el análisis final. Resultados: Durante la evaluación comparativa de las cuatro moléculas en diferentes dosis versus warfarina se evidenció una menor prevalencia de hemorragia intracraneana en pacientes manejados con nuevos anticoagulantes orales; en todos los artículos evaluados, los resultados apoyan su uso. Sin embargo, al evaluar desenlaces hemorrágicos en el caso de subpoblaciones, los resultados parecen tener menor impacto y, en algunos casos, no logran la significancia estadística y se encontró reducción o desaparición del beneficio. Conclusiones: Los resultados pueden aportar herramientas de utilidad que apoyarían al clínico en la toma de decisiones acerca de la elección del tipo de anticoagulante en escenarios clínicos específicos.
Aproximaciones a un estimativo de la capacidad para formar el talento humano en el campo de la salud en un centro médico académico
Authors: Brando Moreno Claudio Romano , Castellanos Ramírez Julio Cesar
Published: December 2017

Uno de los mayores retos en la formación del talento humano en salud son los cálculos relacionados con la capacidad instalada de los centros de práctica para lograr la adecuada exposición al ambiente clínico y facilitar el logro de competencias. El artículo presenta un análisis desde la visión de un centro médico académico como es el Hospital Universitario San Ignacio en relación con la Pontificia Universidad Javeriana de Colombia.
Impact of Bearing Clearance on Measured Stiffness and Damping Coefficients and Thermal Performance of a High-Stiffness Generation 3 Foil Journal Bearing
Authors: Wilkes Jason C. , Wade Jonathan , Rimpel Aaron , Moore Jeff , Swanson Erik , Grieco Joseph , Brady Jerry
Published: December 2017

High-speed foil bearings are currently used in increasingly demanding, high performance applications. The application under consideration is a 120 krpm natural gas turboexpander-compressor, which requires 38 mm (1.5 in.) foil journal bearings with high stiffness and load capacity to help enhance rotordynamic stability. This paper describes the development of the foil bearing for this application and includes measured stiffness and damping coefficients recorded on a high-speed dynamic bearing test rig. The dynamic test data were taken for several different foil bearing configurations with varying spring-element foil thicknesses, number of spring-element foils, and bearing shim thickness. All three parameters have a direct impact on bearing clearance. The influence of these different parameters on measured stiffness and damping coefficients and thermal performance of the bearings are presented and discussed.
Analysis of Operational Strategies of a SOFC/Micro Gas Turbine Hybrid Power Plant
Authors: Hohloch Martina , Huber Andreas , Aigner Manfred
Published: December 2017

The present work deals with the analysis of operational concepts for a solid oxide fuel cell/micro gas turbine (SOFC/MGT) hybrid power plant based on a test rig at the DLR, Institute of Combustion Technology. Here, a Turbec T100 MGT and a fuel cell emulator are used. The emulator is composed of two pressure vessels. The first represents the cathode volume of the fuel cell to simulate the residence time and pressure loss. The second is equipped with a natural gas combustor to emulate the varying heat input of the fuel cell. The MGT and the SOFC are connected via different piping paths. The procedures start-up, load change, and shutdown are analyzed in matters of temperature gradients, pressure gradients, and fluctuations, as well as the air mass flow provided at the interconnections to the coupling elements. To achieve the required inlet conditions of the SOFC, transient operations, using the different piping paths, are investigated. Concepts for heating up and cooling the SOFC using hot air from the recuperator and relatively cold air from the compressor outlet are experimentally tested and characterized. Selected critical situations and their effect on the SOFC are investigated. An emergency operation and its impact on both subsystems and limitations are shown. Further operational limits of the MGT control system and power electronic were observed and analyzed. Based on the experimental results, the applicability of the used MGT procedures in a hybrid power plant was reconsidered. Finally, adaptions and strategies for the operational concept are derived and discussed.
Micromechanical Progressive Failure Analysis of Fiber-Reinforced Composite Using Refined Beam Models
Authors: Kaleel I. , Petrolo M. , Waas A. M. , Carrera E.
Published: December 2017

An efficient and novel micromechanical computational platform for progressive failure analysis of fiber-reinforced composites is presented. The numerical framework is based on a recently developed micromechanical platform built using a class of refined beam models called Carrera unified formulation (CUF), a generalized hierarchical formulation which yields a refined structural theory via variable kinematic description. The crack band theory is implemented in the framework to capture the damage propagation within the constituents of composite materials. The initiation and orientation of the crack band in the matrix are determined using the maximum principal stress state and the traction-separation law governing the crack band growth is related to the fracture toughness of the matrix. A representative volume element (RVE) containing randomly distributed fibers is modeled using the component-wise (CW) approach, an extension of CUF beam model based on Lagrange type polynomials. The efficiency of the proposed numerical framework is achieved through the ability of the CUF models to provide accurate three-dimensional (3D) displacement and stress fields at a reduced computational cost. The numerical results are compared against experimental data available in the literature and an analogous 3D finite element model with the same constitutive crack band model. The applicability of CUF beam models as a novel micromechanical platform for progressive failure analysis as well as the multifold efficiency of CUF models in terms of CPU time are highlighted.
Native phonological processing abilities predict post-consolidation nonnative contrast learning in adults
Authors: Earle F. Sayako , Arthur Dana T.
Published: December 2017

This study examined the relationship between native phonological processing ability and the learning outcome of a trained nonnative (Hindi /ɖ/ - /d̪/) contrast. Participants were perceptually trained and assessed in the evening, and reassessed early the next morning. Native phonological processing ability did not predict the learning of the nonnative contrasts on Day 1. However, after a period of post-training sleep, Blending ability predicted nonnative Discrimination performance, and Nonword Repetition predicted nonnative Identification. These findings may point to similarities between processes involved in maintaining native phonological representations and that in the retention of nonnative acoustic-phonetic features in adulthood.
Characteristics of seismic survey pulses and the ambient soundscape in Baffin Bay and Melville Bay, West Greenland
Authors: Martin S. Bruce , Matthews Marie-Noël R. , MacDonnell Jeff T. , Bröker Koen
Published: December 2017

In 2012 a seismic survey campaign involving four vessels was conducted in Baffin Bay, West Greenland. Long-distance (150 km) pre-survey acoustic modeling was performed in accordance with regulatory requirements. Four acoustic recorders, three with hydrophones at 100, 200, and 400 m depths, measured ambient and anthropogenic sound during the survey. Additional recordings without the surveys were made from September 2013 to September 2014. The results show that (1) the soundscape of Baffin Bay is typical for open ocean environments and Melville Bay's soundscape is dominated by glacial ice noise; (2) there are distinct multipath arrivals of seismic pulses 40 km from the array; (3) seismic sound levels vary little as a function of depth; (4) high fidelity pre-survey acoustic propagation modeling produced reliable results; (5) the daily SEL did not exceed regulatory thresholds and were different using Southall, Bowles, Ellison, Finneran, Gentry, Greene, Kastak, Ketten, Miller, Nachtigall, Richardson, Thomas, and Tyack [(2007) Aquat. Mamm. 33, 411–521] or NOAA weightings [National Marine Fisheries Service (2016). NOAA Technical Memorandum NMFS-OPR-55, p. 178]; (6) fluctuations of SPL with range were better described by additive models than linear regression; and (7) the survey increased the 1-min SPL by 28 dB, with most of the energy below 100 Hz; energy in the 16 000 Hz octave band was 20 dB above the ambient background 6 km from the source.
Envisioning Slovenia, Telecast From Brazil: Relationships Between National Identity and Slovenian Viewership of the 2016 Rio Summer Olympic Games
Authors: Brown Kenon A. , Ličen Simon , Billings Andrew C. , Devlin Michael B.
Published: December 2017

Given Slovenia’s independence in 1991, examining the potential impact of Olympic media consumption on this young nation offers a unique opportunity for scholarly investigation. Prior examinations of Olympic telecasts in Slovenia have uncovered core elements of nationalized pride and focus (Ličen & Billings, 2013a), yet have not fully explored the potential effect of the mass viewership found within the Olympics. This study explores how social cognitive and social identification theories interact to influence consumption behaviors relating to international competition—in this case, the Olympics. For this study, 175 respondents were surveyed to examine the relationship among personal determinants defined by one’s national identity, Olympic fan involvement, and behaviors related to Olympic media consumption. Findings revealed that basic identification with Slovenia as a nation, and a need to defend Slovenia when faced with discouraging opinions, influenced one’s fan involvement with the Olympics, which in turn influenced digital and televisual media consumption.
Shotgun Metagenomics and Volatilome Profile of the Microbiota of Fermented Sausages
Authors: Ferrocino Ilario , Bellio Alberto , Giordano Manuela , Macori Guerrino , Romano Angelo , Rantsiou Kalliopi , Decastelli Lucia , Cocolin Luca
Published: December 2017

Changes in the microbial gene content and abundance can be analyzed to detect shifts in the microbiota composition due to the use of a starter culture in the food fermentation process, with the consequent shift of key metabolic pathways directly connected with product acceptance. Meat fermentation is a complex process involving microbes that metabolize the main components in meat. The breakdown of carbohydrates, proteins, and lipids can lead to the formation of volatile organic compounds (VOCs) that can drastically affect the organoleptic characteristics of the final products. The present meta-analysis, performed with the shotgun DNA metagenomic approach, focuses on studying the microbiota and its gene content in an Italian fermented sausage produced by using a commercial starter culture (a mix of
Lactobacillus sakei
and
Staphylococcus xylosus
), with the aim to discover the connections between the microbiota, microbiome, and the release of volatile metabolites during ripening. The inoculated fermentation with the starter culture limited the development of
Enterobacteriaceae
and reduced the microbial diversity compared to that from spontaneous fermentation. KEGG database genes associated with the reduction of acetaldehyde to ethanol (EC 1.1.1.1), acetyl phosphate to acetate (EC 2.7.2.1), and 2,3-butanediol to acetoin (EC 1.1.1.4) were most abundant in inoculated samples (I) compared to those in spontaneous fermentation samples (S). The volatilome profiles were highly consistent with the abundance of the genes; elevated acetic acid (1,173.85 μg/kg), ethyl acetate (251.58 μg/kg), and acetoin (1,100.19 μg/kg) were observed in the presence of the starters at the end of fermentation. Significant differences were found in the liking of samples based on flavor and odor, suggesting a higher preference by consumers for the spontaneous fermentation samples. Inoculated samples exhibited the lowest scores for the liking data, which were clearly associated with the highest concentration of acetic acid.

IMPORTANCE
We present an advance in the understanding of meat fermentation by coupling DNA sequencing metagenomics and metabolomics approaches to describe the microbial function during this process. Very few studies using this global approach have been dedicated to food, and none have examined sausage fermentation, underlying the originality of the study. The starter culture drastically affected the organoleptic properties of the products. This finding underlines the importance of starter culture selection that takes into consideration the functional characteristics of the microorganism to optimize production efficiency and product quality.
Draft Genome Sequence of a Clinical Enterococcus faecium Sequence Type 18 Strain from South Africa
Authors: Mbelle Nontombi Marylucy , Maningi Nontuthuko Excellent , Tshisevhe Vhudzani , Modipane Lesedi , Amoako Daniel Gyamfi , Osei Sekyere John
Published: December 2017

We report the first draft genome sequence of an
Enterococcus faecium
sequence type 18 (ST18) strain isolated from a tuberculosis patient in Africa. The genome is comprised of 3,202,539 bp, 501 contigs, 37.70% GC content, 3,202 protein-encoding genes, and 61 RNA genes. The resistome and virulome of this important pathogen are presented herein.
Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
Authors: Nywening Timothy M , Belt Brian A , Cullinan Darren R , Panni Roheena Z , Han Booyeon J , Sanford Dominic E , Jacobs Ryan C , Ye Jian , Patel Ankit A , Gillanders William E , Fields Ryan C , DeNardo David G , Hawkins William G , Goedegebuure Peter , Linehan David C
Published: December 2017

Objective

Chemokine pathways are co-opted by pancreatic adenocarcinoma (PDAC) to facilitate myeloid cell recruitment from the bone marrow to establish an immunosuppressive tumour microenvironment (TME). Targeting tumour-associated CXCR2+neutrophils (TAN) or tumour-associated CCR2+ macrophages (TAM) alone improves antitumour immunity in preclinical models. However, a compensatory influx of an alternative myeloid subset may result in a persistent immunosuppressive TME and promote therapeutic resistance. Here, we show CCR2 and CXCR2 combined blockade reduces total tumour-infiltrating myeloids, promoting a more robust antitumour immune response in PDAC compared with either strategy alone.

Methods

Blood, bone marrow and tumours were analysed from PDAC patients and controls. Treatment response and correlative studies were performed in mice with established orthotopic PDAC tumours treated with a small molecule CCR2 inhibitor (CCR2i) and CXCR2 inhibitor (CXCR2i), alone and in combination with chemotherapy.

Results

A systemic increase in CXCR2+ TAN correlates with poor prognosis in PDAC, and patients receiving CCR2i showed increased tumour-infiltrating CXCR2+ TAN following treatment. In an orthotopic PDAC model, CXCR2 blockade prevented neutrophil mobilisation from the circulation and augmented chemotherapeutic efficacy. However, depletion of either CXCR2+ TAN or CCR2+ TAM resulted in a compensatory response of the alternative myeloid subset, recapitulating human disease. This was overcome by combined CCR2i and CXCR2i, which augmented antitumour immunity and improved response to FOLFIRINOX chemotherapy.

Conclusion

Dual targeting of CCR2+ TAM and CXCR2+ TAN improves antitumour immunity and chemotherapeutic response in PDAC compared with either strategy alone.
Contextualising Safety in Numbers: a longitudinal investigation into change in cycling safety in Britain, 1991–2001 and 2001–2011
Authors: Aldred Rachel , Goel Rahul , Woodcock James , Goodman Anna
Published: December 2017

Introduction

The ’Safety in Numbers’ (SiN) phenomenon refers to a decline of injury risk per time or distance exposed as use of a mode increases. It has been demonstrated for cycling using cross-sectional data, but little evidence exists as to whether the effect applies longitudinally —that is, whether changes in cycling levels correlate with changes in per-cyclist injury risks.

Methods

This paper examines cross-sectional and longitudinal SiN effects in 202 local authorities in Britain, using commuting data from 1991, 2001 and 2011 censuses plus police -recorded data on ’killed and seriously injured’ (KSI) road traffic injuries. We modelled a log-linear relationship between number of injuries and number of cycle commuters. Second, we conducted longitudinal analysis to examine whether local authorities where commuter cycling increased became safer (and vice versa).

Results

The paper finds a cross-sectional SiN effect exists in the 1991, 2001 and 2011 censuses. The longitudinal analysis also found a SiN effect, that is, places where cycling increased were more likely to become safer than places where it had declined. Finally, these longitudinal results are placed in the context of changes in pedestrian, cyclist and motorist safety. While between 1991 and 2001 all modes saw declines in KSI risk (37% for pedestrians, 36% for cyclists and 27% for motor vehicle users), between 2001 and 2011 pedestrians and motorists saw even more substantial declines (41% and 49%), while risk for cyclists increased by 4%.

Conclusion

The SiN mechanism does seem to operate longitudinally as well as cross-sectionally. However, at a national level between 2001–11 it co-existed with an increase in cyclist injury risk both in absolute terms and in relation to other modes.
Carbon dots based dual-emission silica nanoparticles as ratiometric fluorescent probe for chromium speciation analysis in water samples
Authors: Xiang Guoqiang , Ren Yue , Zhang Heng , Fan Huanhuan , Jiang Xiuming , He Lijun , Zhao Wenjie
Published: December 2017

A simple and effective strategy for designing a ratiometric fluorescent nanosensor was described. A carbon dots (CDs) based dual-emission nanosensor for chromium speciation analysis was developed by coating CDs on the surface of dye-doped silica nanoparticles. The fluorescence of the resulting dual-emission silica nanoparticles was quenched in acetic acid through potassium bromate (KBrO3) oxidation. Cr(VI) was able to catalyze KBrO3 oxidation, resulting in ratiometric fluorescence accelerated quenching response of the dual-emission silica nanoparticles. Several important parameters affecting the nanosensor performance, including acid type, concentrations of KBrO3, and reaction temperature and time were examined. Under the optimized conditions, the detection limit of the nanosensor towards Cr(VI) reached 1.3 ng mL−1, and pretty good linearity was obtained between 20 to 500 ng mL−1. More importantly, the sensor was found suitable for speciation analysis of both Cr(III) and Cr(VI) in different water samples with satisfactory results.
Dynamic atomicity: optimizing swift memory management
Authors: Ungar David , Grove David , Franke Hubertus
Published: December 2017

Swift is a modern multi-paradigm programming language with an extensive developer community and open source ecosystem. Swift 3's memory management strategy is based on Automatic Reference Counting (ARC) augmented with unsafe APIs for manually-managed memory. We have seen ARC consume as much as 80% of program execution time. A significant portion of ARC's direct performance cost can be attributed to its use of atomic machine instructions to protect reference count updates from data races. Consequently, we have designed and implemented dynamic atomicity, an optimization which safely replaces atomic reference-counting operations with nonatomic ones where feasible. The optimization introduces a store barrier to detect possibly intra-thread references, compiler-generated recursive reference-tracers to find all affected objects, and a bit of state in each reference count to encode its atomicity requirements.

Using a suite of 171 microbenchmarks, 9 programs from the Computer Language Benchmarks Game, and the Richards benchmark, we performed a limit study by unsafely making all reference counting operations nonatomic. We measured potential speedups of up to 220% on the microbenchmarks, 120% on the Benchmarks Game and 70% on Richards.

By automatically reducing ARC overhead, our optimization both improves Swift 3's performance and reduces the temptation for performance-oriented programmers to resort to unsafe manual memory management. Furthermore, the machinery implemented for dynamic atomicity could also be employed to obtain cheaper thread-safe Swift data structures, or to augment ARC with optional cycle detection or a backup tracing garbage collector.
Automatic generation of virtual learning spaces driven by CaVa
DSL
: an experience report
Authors: Martini Ricardo Giuliani , Henriques Pedro Rangel
Published: December 2017

Several applications are based on Domain-Specific Languages (DSL). They provide the right terminology to a peculiar problem/subject, because they use a particular domain vocabulary that defines abstract concepts, different from general-purpose languages. Aiming an easy generation of virtual Learning Spaces (LS) for the use of the responsible of institutional archives or museums, we have idealized and developed an external domain-specific language, called CaVa DSL, to describe, in an abstract level, virtual exhibition rooms in the museum curator's viewpoint, giving the curator the possibility to specify the virtual LS upon a domain ontology vocabulary. We also contribute with a set of processors that deal with CaVa DSL and generates virtual Learning Spaces, turning available the navigation over important and real information contained in archival documents to the public through virtual museums. To demonstrate the obtained results, we present a running example along the paper showing the virtual LS generation process.
Refining semantics for multi-stage programming
Authors: Ge Rui , Garcia Ronald
Published: December 2017

The multi-stage programming paradigm supports runtime code generation and execution. Though powerful, its potential is impeded by the lack of static analysis support. Van Horn and Might proposed a general-purpose approach to systematically develop static analyses by transforming an environmental abstract machine, which evolves a control string, an environment and a continuation as a program evaluates. To the best of our knowledge, no such semantics exists for a multi-stage language like MetaML.

We develop and prove correct an environmental abstract machine semantics for MetaML by gradually refining the reference substitutional structural operational semantics. Highlights of our approach include leveraging explicit substitutions to bridge the gap between substitutional and environmental semantics, and devising meta-environments to model the complexities of variable bindings in multi-stage environmental semantics.
Staging for generic programming in space and time
Authors: Ofenbeck Georg , Rompf Tiark , Püschel Markus
Published: December 2017

Metaprogramming is among the most promising candidates to solve the abstraction vs performance trade-off that plagues software engineering through specialization. Metaprogramming has been used to enable low-overhead generic programming for a long time, with C++ templates being one of the most prominent examples. But often a single, fixed pattern of specialization is not enough, and more flexibility is needed. Hence, this paper seeks to apply generic programming techniques to challenges in metaprogramming, in particular to abstract over the execution stage of individual program expressions. We thus extend the scope of generic programming into the dimension of time. The resulting notion of stage polymorphism enables novel abstractions in the design of program generators, which we develop and explore in this paper. We present one possible implementation, in Scala using the lightweight modular staging (LMS) framework, and apply it to two important case studies: convolution on images and the fast Fourier transform (FFT).
Accurate reification of complete supertype information for dynamic analysis on the JVM
Authors: Rosà Andrea , Rosales Eduardo , Binder Walter
Published: December 2017

Reflective supertype information (RSI) is useful for many instrumentation-based dynamic analyses on the Java Virtual Machine (JVM). On the one hand, while such information can be obtained when performing the instrumentation within the same JVM process executing the instrumented program, in-process instrumentation severely limits the code coverage of the analysis. On the other hand, performing the instrumentation in a separate process can achieve full code coverage, but complete RSI is generally not available, often requiring expensive runtime checks in the instrumented program. Providing accurate and complete RSI in the instrumentation process is challenging because of dynamic class loading and classloader namespaces. In this paper, we present a novel technique to accurately reify complete RSI in a separate instrumentation process. We implement our technique in the dynamic analysis framework DiSL and evaluate it on a task profiler, achieving speedups of up to 45% for an analysis with full code coverage.
Programming Cells to Work for Us
Authors: Qian Yili , McBride Cameron , Del Vecchio Domitilla
Published: December 2017

The past decade has witnessed the rise of an exciting new field of engineering: synthetic biology. Synthetic biology is the application of engineering principles to the fundamental components of biology with the aim of programming cells with novel functionalities for utilization in the health, environment, and energy industries. Since its beginnings in the early 2000s, control design principles have been used in synthetic biology to design dynamics, mitigate the effects of uncertainty, and aid modular and layered design. In this review, we provide a basic introduction to synthetic biology, its applications, and its foundations and then describe in more detail how control design approaches have permeated the field since its inception. We conclude with a discussion of pressing challenges in this field that will require new control theory, with the hope of attracting researchers in the control theory community to this exciting engineering area.
Novel Radiotherapy Techniques for Breast Cancer
Authors: Bradley Julie A. , Mendenhall Nancy P.
Published: December 2017

During the early decades of radiation therapy for breast cancer, local control of disease was documented consistently but, enigmatically, an anticipated impact on breast cancer survival was not observed, leading to confusion in our understanding of the natural history of breast cancer and radiation effects. Now, almost 90 years after its first use in breast cancer, technology developments in diagnostic imaging and radiation therapy have elucidated parts of this enigma. The data now available demonstrate a significant impact of radiation therapy on survival as well as disease control and treatment-related mortality, opening a doorway to understanding the powerful impact of radiation therapy on both breast cancer and critical organs. Efforts are focused on leveraging novel techniques to maximize the benefits of radiation for breast cancer patients.
The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future
Authors: Plog Benjamin A. , Nedergaard Maiken
Published: December 2017

The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudolymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters the brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute. Here, we review the role of the glymphatic pathway in CNS physiology, the factors known to regulate glymphatic flow, and the pathologic processes in which a breakdown of glymphatic CSF-ISF exchange has been implicated in disease initiation and progression. Important areas of future research, including manipulation of glymphatic activity aiming to improve waste clearance and therapeutic agent delivery, are also discussed.
Bacterial Mechanosensors
Authors: Cox Charles D. , Bavi Navid , Martinac Boris
Published: December 2017

Bacteria represent one of the most evolutionarily successful groups of organisms to inhabit Earth. Their world is awash with mechanical cues, probably the most ancient form of which are osmotic forces. As a result, they have developed highly robust mechanosensors in the form of bacterial mechanosensitive (MS) channels. These channels are essential in osmoregulation, and in this setting, provide one of the simplest paradigms for the study of mechanosensory transduction. We explore the past, present, and future of bacterial MS channels, including the alternate mechanosensory roles that they may play in complex microbial communities. Central to all of these functions is their ability to change conformation in response to mechanical stimuli. We discuss their gating according to the force-from-lipids principle and its applicability to eukaryotic MS channels. This includes the new paradigms emerging for bilayer-mediated channel mechanosensitivity and how this molecular detail may provide advances in both industry and medicine.
Acetylsalicylic Acid Governs the Effect of Sorafenib in RAS-Mutant Cancers
Authors: Hammerlindl Heinz , Ravindran Menon Dinoop , Hammerlindl Sabrina , Emran Abdullah Al , Torrano Joachim , Sproesser Katrin , Thakkar Divya , Xiao Min , Atkinson Victoria G. , Gabrielli Brian , Haass Nikolas K. , Herlyn Meenhard , Krepler Clemens , Schaider Helmut
Published: December 2017

Purpose: Identify and characterize novel combinations of sorafenib with anti-inflammatory painkillers to target difficult-to-treat RAS-mutant cancer.

Experimental Design: The cytotoxicity of acetylsalicylic acid (aspirin) in combination with the multikinase inhibitor sorafenib (Nexavar) was assessed in RAS-mutant cell lines in vitro. The underlying mechanism for the increased cytotoxicity was investigated using selective inhibitors and shRNA-mediated gene knockdown. In vitro results were confirmed in RAS-mutant xenograft mouse models in vivo.

Results: The addition of aspirin but not isobutylphenylpropanoic acid (ibruprofen) or celecoxib (Celebrex) significantly increased the in vitro cytotoxicity of sorafenib. Mechanistically, combined exposure resulted in increased BRAF/CRAF dimerization and the simultaneous hyperactivation of the AMPK and ERK pathways. Combining sorafenib with other AMPK activators, such as metformin or A769662, was not sufficient to decrease cell viability due to sole activation of the AMPK pathway. The cytotoxicity of sorafenib and aspirin was blocked by inhibition of the AMPK or ERK pathways through shRNA or via pharmacologic inhibitors of RAF (LY3009120), MEK (trametinib), or AMPK (compound C). The combination was found to be specific for RAS/RAF–mutant cells and had no significant effect in RAS/RAF–wild-type keratinocytes or melanoma cells. In vivo treatment of human xenografts in NSG mice with sorafenib and aspirin significantly reduced tumor volume compared with each single-agent treatment.

Conclusions: Combination sorafenib and aspirin exerts cytotoxicity against RAS/RAF–mutant cells by simultaneously affecting two independent pathways and represents a promising novel strategy for the treatment of RAS-mutant cancers. Clin Cancer Res; 24(5); 1090–102. ©2017 AACR.