bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein Corona Modulates Distribution and Toxicological Effects of Silver Nanoparticles In Vivo
Authors: Barbir Rinea , Goessler Walter , Ćurlin Marija , Micek Vedran , Milić Mirta , Vuković Barbara , Milić Marija , Ljubojević Marija , Domazet Jurašin Darija , Vinković Vrček Ivana
Published: June 2019

Exploitation of silver nanoparticles (AgNPs) in biomedicine represents more than one third of their overall applications. Despite their wide use, detailed toxicokinetic data and information on their action mechanisms in vivo are still scarce. One important obstacle is their fate and transformation patterns in biological environments where AgNPs get a “new face” after interaction with biomolecules, particularly proteins. The impact of protein corona on AgNP effects in vivo is eludicated. The in vivo effects of AgNPs prepared with two different protein coronas, albumin, and metallothionein, with polymer‐coated AgNPs are compared in male and female Wistar rats after intravenous administration. The results demonstrate that the character of the protein coronas on the AgNP surface affects not only distribution, but also oxidative stress response and genotoxicity in tissues of rat exposed to AgNPs. Additionally, sex‐related effects are observed. By emphasizing the importance of protein corona formation and sex‐related response, the obtained data support a reliable evidence base needed for assessing the health risks of the steadily increasing human exposure to AgNPs.
The 1,3‐diyne linker as a rigid “i,i+7” staple for α‐helix stabilization: Stereochemistry at work
Authors: Verlinden Steven , Geudens Niels , Van holsbeeck Kevin , Mannes Morgane , Martins José C. , Verniest Guido , Ballet Steven
Published: June 2019

Short alphahelical peptide sequences were stabilized through Glaser‐Hay couplings of propargylated l‐ and/or d‐serine residues at positions i and i+7. NMR analysis confirmed a full stabilization of the helical structure when a d‐Ser (i), l‐Ser (i+7) combination was applied. In case two l‐Ser residues were involved in the cyclization, the helical conformation is disrupted outside the peptide's macrocycle.
Design considerations for photovoltaic panel arrays made from aluminium: a case study
Authors: Bardopoulos Foivos , Papagiannopoulos George , Pnevmatikos Nikos
Published: June 2019

This paper presents the design considerations for typical photovoltaic panel arrays having aluminium members. Section and member design checks are performed according to Eurocode 9 on the basis of the wind, snow and seismic loads of Eurocodes 1 and 8. Improvements to the design are then sought, starting by reducing the distance between the vertical posts and then by changing the thickness of specific sections. Following that, the effects of member imperfections and connection flexibility are studied using a reduced flexural rigidity and different rotational stiffness values respectively. The degree of dynamic coupling when the array is placed on the top floor of an existing building as well as the influence of founding the vertical posts on compliant ground are also evaluated.
Research needs in systems engineering: Report from a University of Alabama in Huntsville workshop
Authors: White Christopher J. , Mesmer Bryan L.
Published: June 2019

The success of systems engineering (SE) efforts to solve development issues benefit from the mutually advantageous relationship between academia and practice. This relationship can be threatened by lag in adoption and differences in focus between the two worlds. In an effort to help maintain alignment between SE research and practice, a 2‐day workshop was held at the University of Alabama in Huntsville on research needs in SE. The workshop was attended by individuals from academia, the Department of Defense, NASA, and the aerospace industry. This paper presents summaries of the discussions that took place, as well as possible research questions informed by the results of the workshop. The workshop consisted of an introductory roundtable and three breakouts sessions focusing on requirements, verification, and validation; configuration and data management; and systems acquisition and design. Several topics emerged as important concepts for future research, and research questions were developed relating to model‐based systems engineering (MBSE), requirements, modeling, sociotechnical issues, and education.
Review of numerical solution of Richardson–Richards equation for variably saturated flow in soils
Authors: Zha Yuanyuan , Yang Jinzhong , Zeng Jicai , Tso Chak‐Hau M. , Zeng Wenzhi , Shi Liangsheng
Published: June 2019

Modeling variably saturated flow in the vadose zone is of vital importance to many scientific fields and engineering applications. Richardson–Richards equation (RRE, which is conventionally known as Richards' equation) is often chosen to physically represent the fluxes in the vadose zone when the accurate characterization of the soil water dynamics is required. Being a highly nonlinear partial differential equation, RRE is often solved numerically. Although there are mature software and codes available for simulating variably saturated flow by solving RRE, the numerical solution of RRE is nevertheless computationally expensive. Moreover, sometimes the robustness and the efficiency of RRE‐based models can deteriorate rapidly when certain unfavorable conditions are met. These demerits of RRE hinder its application on large‐scale vadose zone hydrology problems and uncertainty quantification, both of which requires many runs of the prediction model. To address these challenges, the accuracy, convergence, and efficiency of the numerical schemes of RRE should be further improved by testing a wide variety of cases covering different initial conditions, boundary conditions, and soil types. We reviewed and highlighted several critical issues related to the numerical modeling of RRE, including spatial and temporal discretization, the different forms of RREs, iterative and noniterative schemes, benchmark solutions, and available software and codes. Based on the review, we summarize the challenges and future work for solving RRE numerically.

This article is categorized under:

Science of Water > Hydrological Processes

Science of Water > Methods
Bond zone model for a conductive crack at the interface of piezoelectric materials under anti‐plane mechanical and in‐plane electric loadings
Authors: Onopriienko Oleg , Loboda Volodymyr , Sheveleva Alla , Lapusta Yuri
Published: June 2019

An electrically conductive crack between two semi‐infinite piezoelectric spaces under the action of anti‐plane mechanical loading and in‐plane electrical field parallel to the crack faces is considered. An exact analytical solution of this problem is found and the oscillating singularity is revealed at the crack tips. A new model, which is free from oscillation, is also developed for a conductive interface crack. This model is based on the introduction of a mechanically bonded zone at the conducting crack tip characterizing by zero crack faces displacement jump. The most reasonable length of this zone is found from the condition of a smooth crack closing. The validity confirmation of the bond zone model is given by means of description of conductive crack formation process. Some recommendations concerning the use of suggested model for the study of finite and infinite sized bodies with electrically conducting interface cracks are formulated.
Social interaction analysis in captive orcas (Orcinus orca)
Authors: Sánchez–Hernández Paula , Krasheninnikova Anastasia , Almunia Javier , Molina–Borja Miguel
Published: June 2019

The management of socially complex species in captivity is challenging. Research on their social behavior improves our understanding of interactions in captive animals and captive‐group management. We conducted a detailed analysis of social relationships shown by the orcas kept at Loro Parque zoo and their tendency to reconcile after aggressive episodes. Affiliative interactions were the most frequent social activities compared to agonistic or sexual interactions. Within affiliative behaviors, we documented the pattern “gentle tongue bite”, where an animal touches the other's tongue with his teeth but does not bite it. Affiliative interactions between a specific pair of orcas occurred significantly more often than expected by chance, and together with low levels of agonistic interactions, indicated particular affinity between some individuals. The most frequently observed low‐level agonistic relationship was that of the two older males (Tekoa–Keto); however, they also showed frequent sexual and affiliative interactions. Sexual‐like behaviors (pursuit, mount, and penis between males) were found in both sexes. Finally, the observed corrected conciliatory tendency (31.57%) was within the range described for other primate and cetacean species. This study provides a systematic way to assess social interactions as well as conflict management strategies in cetaceans housed in zoos and zoo‐like facilities and may help to improve animal welfare and management of animals in controlled environments.
Integral of two-loop modular graph functions
Authors: D’Hoker Eric
Published: June 2019

Abstract

The integral of an arbitrary two-loop modular graph function over the fundamental domain for SL(2, ℤ) in the upper half plane is evaluated using recent results on the Poincaré series for these functions.
Time-dependent compactification to de Sitter space: a no-go theorem
Authors: Russo J. G. , Townsend P. K.
Published: June 2019

Abstract

It is known that the Einstein gravitational field equations in D > 4 spacetime dimensions have no time-independent non-singular compactification solutions to de Sitter space if the D-dimensional stress tensor satisfies the Strong Energy Condition (SEC). Here we show, by example, that the SEC alone does not exclude time-dependent non-singular compactifications to de Sitter space, in Einstein conformal frame. However, this possibility is excluded by the combined SEC and Dominant Energy Condition (DEC) because the DEC forces a time-evolution towards a singular D-metric.
Testing Device for Radon Migration Experiments, the Construction and Preliminary Results
Authors: Bonczyk M. , Chałupnik S. , Howaniec N. , Smoliński A. , Wysocka M.
Published: June 2019

The main goal of the research presented was to design and construct a device, enables estimation of the diffusion time and diffusion length for radon in core samples collected from the geological layers of Upper Silesian Coal Basin (USCB). Another goal will be investigations of the advection of 222Rn with other gases like carbon dioxide or methane, occurring in the Carboniferous strata in USCB. This knowledge will support the precision of the assessment of radon hazard in working environment. Moreover, it should give an answer to some questions, related to the radon migration issues—if the results of measurements of the transport of radon with other gases in the strata could be applied for the prediction of geodynamic phenomena in the mining areas, like tremors and outbursts. The study was focused on the flow measurements of the following gases: radon, carbon dioxide, nitrogen and their mixtures, as the use of methane was excluded due to potential hazard of explosion. In this article results of measurements of diffusive migration are presented: radon itself and simultaneous migration of radon, nitrogen and carbon dioxide. For this purpose a special device was designed and constructed. This device consists of the container for the sample of coal, mineral or rock and two reservoirs—the inlet and outlet one. The gas (e.g. air or carbon dioxide) with radon is introduced into inlet reservoir, while the content of marker gases and radon is monitored in the outlet reservoir. The preliminary experiments were also performed and are presented in this paper. In the literature, there are only rare results of such investigations, while our previous research in USCB region showed some correlation between sudden changes of radon level and geodynamic events. Therefore, the results of the investigations presented in this study are expected to contribute to the improvement of the models of these phenomena. The future work planned will be aimed at investigations of advective flow of radon with various carrier gases.
Paradoxical lucidity: A potential paradigm shift for the neurobiology and treatment of severe dementias
Authors: Mashour George A. , Frank Lori , Batthyany Alexander , Kolanowski Ann Marie , Nahm Michael , Schulman‐Green Dena , Greyson Bruce , Pakhomov Serguei , Karlawish Jason , Shah Raj C.
Published: June 2019

Unexpected cognitive lucidity and communication in patients with severe dementias, especially around the time of death, have been observed and reported anecdotally. Here, we review what is known about this phenomenon, related phenomena that provide insight into potential mechanisms, ethical implications, and methodologic considerations for systematic investigation. We conclude that paradoxical lucidity, if systematically confirmed, challenges current assumptions and highlights the possibility of network‐level return of cognitive function in cases of severe dementias, which can provide insight into both underlying neurobiology and future therapeutic possibilities.
Separated After a Disaster: Trust and Privacy Issues in Sharing Children’s Personal Information
Authors: Charney Rachel L. , Rebmann Terri , Esposito Flavio , Schmid Kristin , Chung Sarita
Published: June 2019

Background:

After disasters, unaccompanied children may present to an emergency department requiring reunification. An effective reunification system depends on the willingness of guardians to utilize it.

Objective:

Assess guardian willingness to share children’s personal information for reunification purposes after a disaster, perceived concerns and beliefs, and trust in reunification agencies.

Methods:

Guardians of children presenting to 2 pediatric emergency departments were approached to participate in a survey-based study. Willingness to share their children’s personal information was scored on a scale of 1 to 19 (1 point per item). Perceived concerns about and importance of sharing information, level of trust in reunification agencies, and guardian demographics were collected. Chi-square was used to compare trust and attitudes/beliefs. Multivariate linear regression was used to determine factors associated with willingness to share information.

Results:

A total of 363 surveys were completed (response rate, 80%). Most guardians (95.6%) were willing to share at least some information (mean, 16 items; range, 1-19). Half were concerned about protection (55.4%) or abuse (52.3%) of their child’s information. Hospitals were trusted more than other reunification agencies (P < .001). Perception of reunification importance was associated with willingness to share (P < .001).

Conclusions:

Guardians are willing to share their children’s information to facilitate reunification after disasters, but have privacy concerns.
Powerful postures do not lead to risky behaviors
Authors: Chen Outong , Yang Zhaoning , Tan Xuyun , Gu Zibei , Chen Jun
Published: June 2019

Recent research has found that a specific manipulation of body postures can influence psychological states associated with power, including an individual’s feeling of power and risk-taking tendency, but the results vary. The purpose of this study is to replicate previous studies. A pilot experiment examined the validity of 10 postures extracted from multiple former studies. Only 4 postures were consistent with former studies. Experiment 1 replicates the study conducted by Carney, Cuddy, and Yap ( 2010 ). The results revealed that posture manipulations did not affect the participants’ risk-taking tendency. Experiment 2 is a preregistered experiment to replicate the study of Carney et al. ( 2010 ). Different from Experiment 1, data were analyzed with a Bayesian approach. The results of the former study again failed to be replicated, which indicates that the posture manipulations could not yield any effect on both power feelings and individuals’ risk-taking tendency. Thus, we concluded that (a) holding a specific series of body posture perceived as high or low power does not affect individuals’ feeling of power, and (b) holding a specific series of body posture perceived as high or low power does not affect individuals’ risk-taking tendency.
Three-dimensional visualization of top-down superimposed thrust sheets in the SW Grenville Province, Ontario
Authors: Strong Jacob W.D. , Dickin Alan P.
Published: June 2019

To properly understand the tectonic history of the Grenville Province it is necessary to have a reliable, scientifically based understanding of the present-day three-dimensional (3D) structure of the orogen. Based on detailed Nd isotope mapping of surface boundaries and Lithoprobe seismic sections, this study provides the first detailed visualization of the 3D structure of the Grenville gneiss belt in Ontario using the SketchUp software package. The 3D visualization supports a model in which thrust geometry was imposed from the top downwards, controlled by the NW boundary of the Central Metasedimentary Belt that originated as a failed back-arc rift zone. The Central Metasedimentary Belt boundary controlled the trajectory of the Allochthon Boundary Thrust, its underlying tectonic duplex and, ultimately, the Grenville Front. This process of superimposed thrusting explains the large-scale change in the trajectory of the Grenville Front north of Georgian Bay that has been called the ‘Big Bend’. To assist in visualizing the 3D model, a fly-through animation is provided in the supplementary material.
Holding agencies accountable: Exploring the effect of oversight on citizens’ approval of members of Congress
Authors: Miller Susan M. , Ruder Alexander I.
Published: June 2019

We seek to understand the incentives facing Congress members to hold executive agencies accountable. Specifically, we explore whether Congress members are rewarded for taking politically costly oversight actions. We evaluate the effect of oversight activities on citizens’ evaluations of Congress members, taking into account the member’s partisanship, the citizen’s partisanship and agency ideology. Using a survey experiment, we find evidence that citizens’ evaluations of members are affected by the members’ oversight activity, with both copartisan and cross-party members rewarded for oversight efforts. Politically costly actions against ally agencies, however, do not appear to be rewarded to a greater extent by copartisans. These results provide insight into the way in which citizens interpret oversight activities by Congress members, suggesting that while good governance actions hold value for citizens, costly oversight actions aimed at ally agencies are not rewarded by copartisan citizens more than politically expedient oversight actions.
Theoretical Study of Global Scale Analysis Method for Agile Bionic Leg Mechanism
Authors: Zang Hongbin , Zhao Dengfeng , Shen Lianguan
Published: June 2019

Agile bionic leg mechanism (ABLM) has attracted more and more attention in the development of jumping robots and high-speed running robots. However, theoretical study of the global structure for motility characteristics and its evolution is few. By using the modern mathematical tools such as singular theory, geometric topology, and group theory, a global scale analysis method for kinematic performance of mechanisms is proposed. Taking 6-bar with two rings mechanism as an example, a detailed analysis process is studied. The 6-bar ABLM designed by this theory is verified by virtual prototype simulation experiment. The global scale analysis of 4-bar linkage is also carried out by using this method, and the result is compared with the “Grashof criterion” to verify the correctness of this method. It provides a general theory and method for innovative design and global scale analysis of ABLM.
A self-tracking study of international students in France: Exploring opportunities for language and cultural learning
Authors: Guichon Nicolas
Published: June 2019

This exploratory study focuses on international students’ usage of digital tools in order to understand what role such tools play in the transition to their new academic environments and what learning opportunities they provide. Not only do digital tools accompany international students’ social, cultural, and linguistic transitions as they move to France to further their language competence, but their usage also reveals part of the social and semiotic adjustments they have to make in the process. Sixteen international students who volunteered for the study were given a smartphone application with which they could track learning opportunities by taking pictures and writing textual commentaries. The data, collected over a period of five weeks, thus include the resulting entries these participants shared in their mobile multimodal diaries with the researchers, as well as an end-of-project debriefing that was conducted to shed further light on the international students’ digital habits and their attitudes towards self-tracking. This study indicates that digital tools can play an important and pervasive role in facilitating international students’ linguistic development and their dealings with everyday life abroad. It also confirms that self-tracking apps can be instrumental in enhancing students’ awareness of learning opportunities outside the classroom.
Prevalence of underweight in children and adolescents (aged 3–18 years) from Kraków (Poland) in 1983 and 2010
Authors: Kowal Małgorzata , Woz´niacka Renata , Bac Aneta , Z˙aro´w Ryszard
Published: June 2019

Objective:

To estimate the changes in the prevalence of underweight among girls and boys living in Kraków that occurred between 1983 and 2010.

Design:

The study was based on two cross-sectional surveys conducted in 1983 and 2010. The prevalence of underweight was estimated based on the International Obesity Task Force (IOTF) and Centers for Disease Control and Prevention (CDC) cut-off points.

Setting:

The study was conducted in Kraków, Poland.

Participants:

Children aged 3–18 years (n5245).

Results:

Between 1983 and 2010 the prevalence of underweight decreased in both sexes. Using the IOTF criteria, the prevalence of underweight decreased from 10·5 to 10·3 % in girls and from 8·9 to 7·5 % in boys, but it was still higher in girls than in boys. According to the CDC criteria, this prevalence decreased from 5·1 to 4·4 % and from 5·9 to 4·6 %, respectively, and was slightly lower in girls. According to the IOTF criteria, underweight prevalence increased slightly during childhood in both sexes while according to the CDC criteria it decreased in boys and did not change in girls. Among juveniles and adolescents, it decreased regardless of the method used.

Conclusions:

The frequency of underweight in the population of children and adolescents from Kraków changed slightly in 1983 and 2010 despite economic and social changes. Depending on the cut-off points used, not only the magnitude but also the direction of changes between series could be different. In order to aid global monitoring, the prevalence of underweight as well as overweight should always be evaluated by several methods.
A Logic Framework for P2P Deductive Databases
Authors: CAROPRESE LUCIANO , ZUMPANO ESTER
Published: June 2019

This paper presents a logic framework for modeling the interaction among deductive databases in a peer-to-peer (P2P) environment. Each peer joining a P2P systemprovides or imports datafrom its neighbors by using a set ofmapping rules, that is, a set of semantic correspondences to a set of peers belonging to the same environment. By using mapping rules, as soon as it enters the system, a peer can participate and access all data available in its neighborhood, and through its neighborhood it becomes accessible to all the other peers in the system. A query can be posed to any peer in the system and the answer is computed by using locally stored data and all the information that can be consistently imported from the neighborhood. Two different types of mapping rules are defined: mapping rules allowing to import a maximal set of atoms not leading to inconsistency (calledmaximal mapping rules) and mapping rules allowing to import a minimal set of atoms needed to restore consistency (calledminimal mapping rules). Implicitly, the use of maximal mapping rules statesit is preferable to import as long as no inconsistencies arise; whereas the use of minimal mapping rules states thatit is preferable not to import unless a inconsistency exists. The paper presents three different declarative semantics of a P2P system: (i) theMax Weak Model Semantics, in which mapping rules are used to importas much knowledge as possiblefrom a peer’s neighborhood without violating local integrity constraints; (ii) theMin Weak Model Semantics, in which the P2P system can be locally inconsistent and the information provided by the neighbors is used to restore consistency, that is, to only integrate the missing portion of a correct, but incomplete database; (iii) theMax-Min Weak Model Semanticsthat unifies the previous two different perspectives captured by the Max Weak Model Semantics and Min Weak Model Semantics. This last semantics allows to characterize each peer in the neighborhood as a resource used either to enrich (integrate) or to fix (repair) the knowledge, so as to define a kind ofintegrate–repairstrategy for each peer. For each semantics, the paper also introduces an equivalent and alternative characterization, obtained by rewriting each mapping rule into prioritized rules so as to model a P2P system as a prioritized logic program. Finally, results about the computational complexity of P2P logic queries are investigated by consideringbraveandcautiousreasoning.
L’éruption patriote: The Revolt against Dalhousie and the Petitioning Explosion in Nineteenth-Century French Canada
Authors: Carpenter Daniel , Brossard Doris
Published: June 2019

As much as any other site in the nineteenth century, Francophone Lower Canada saw immense waves of popular petitioning, with petitions against British colonial administration attracting tens of thousands of signatures in the 1820s. The petition against Governor Dalhousie of 1827–28 attracted more than 87,000 names, making it one of the largest mass petitions of the Atlantic world on a per-capita scale for its time. We draw upon new archival evidence that shows the force of local organization in the petition mobilization, and combine this with statistical analyses of a new sample of 1,864 names from the anti-Dalhousie signatory list. We conclude that the Lower Canadian petitioning surge stemmed from emergent linguistic nationalism, expectations of parliamentary democracy, and the mobilization and alliance-building efforts of Patriote leaders in the French-Canadian republican movement. As elsewhere in the nineteenth-century Atlantic, the anti-Dalhousie effort shows social movements harnessing petitions to recruit, mobilize, and build cross-cultural alliances.
Role of Latent Heating Vertical Distribution in the Formation of the Tropical Cold Trap
Authors: Chang Kai‐Wei , L'Ecuyer Tristan S.
Published: June 2019

This study examines the role of latent heating (LH) vertical distribution in tropical tropopause layer (TTL) cooling and upper‐tropospheric warming associated with equatorial wave responses using LH from the Tropical Rainfall Measurement Mission and temperature from radio occultation observations. We distinguish the effects of convective and stratiform LH in tropical convection on temperature in the upper troposphere and lower stratosphere. Cross‐spectral analysis of time series of temperature and LH shows that stratiform LH exhibits higher coherence with temperature throughout most of the upper troposphere and lower stratosphere, especially in the equatorial Rossby wave response. Coherence between total LH and temperature tends to increase with the altitude of heating. Highest coherences occur almost exclusively at time scales of the Madden‐Julian Oscillation, suggesting the importance of mesoscale convective activity in TTL cooling and subsequent dehydration processes. These results demonstrate that TTL and upper‐tropospheric temperature perturbations depend on the vertical distribution of LH and that stratiform LH release has strong relationship with the formation of the horseshoe‐shaped cold trap over the Maritime Continent and West Pacific.
Demystifying Sea Level Changes Along the New England Coast
Authors: Cook Terri
Published: June 2019

No direct causal connection exists between coastal sea level changes and the strength of the North Atlantic’s overturning circulation, according to new, longer-term observational records.
Instabilities of Finite‐Amplitude Internal Wave Beams
Authors: Onuki Y. , Tanaka Y.
Published: June 2019

Beam‐like internal waves are commonly generated by tides in the ocean, but their dissipation processes that cause vertical mixing remain poorly understood. Previous studies examined small‐amplitude beams to find that parametric subharmonic instability (PSI) induces latitude‐dependent wave dissipation. Using a novel approach based on Floquet theory, this study analyzes the stability of finite‐amplitude beams over a wide range of parameters. If beam amplitude is small, PSI is indeed the principal mode under the condition f/σ ≤ 0.5, where f is the Coriolis parameter and σ is the beam frequency, and the growth rate is maximum when equality holds. However, as beam amplitude is increased, instability arises even when f/σ>0.5, but the location of maximum instability shifts toward lower f/σ; thus, the latitudinal dependence of instability is significantly altered. Furthermore, the resulting energy spectrum is strongly Doppler shifted to higher frequencies, which therefore distinguishes this configuration from the common cases of PSI.
GnRH impairs diabetic wound healing through enhanced NETosis
Authors: Lee Yun Sang , Kang Sung Un , Lee Myung-Hoon , Kim Haeng-Jun , Han Chang-Hak , Won Ho-Ryun , Park Young Uk , Kim Chul-Ho
Published: June 2019

It has been reported that neutrophil extracellular traps (NETs) impair wound healing in diabetes and that inhibiting NET generation (NETosis) improves wound healing in diabetic mice. Gonadotropin-releasing hormone (GnRH) agonists are associated with a greater risk of diabetes. However, the role of GnRH in diabetic wound healing is unclear. We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing. A mouse model of diabetes was established using five injections with streptozotocin. Mice with blood glucose levels >250 mg/dL were then used in the experiments. GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice. In contrast, GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing. The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients. In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate (PMA)-induced NETosis in mouse and human neutrophils. Furthermore, GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis, which were increased by GnRH treatment. These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds. Thus, inhibition of GnRH might be a novel treatment of diabetic foot ulcers.
Mass cytometry reveals systemic and local immune signatures that distinguish inflammatory bowel diseases
Authors: Rubin Samuel J. S. , Bai Lawrence , Haileselassie Yeneneh , Garay Gotzone , Yun Chohee , Becker Laren , Streett Sarah E. , Sinha Sidhartha R. , Habtezion Aida
Published: June 2019

Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis. Each disease is characterized by a diverse set of potential manifestations, which determine patients’ disease phenotype. Current understanding of phenotype determinants is limited, despite increasing prevalence and healthcare costs. Diagnosis and monitoring of disease requires invasive procedures, such as endoscopy and tissue biopsy. Here we report signatures of heterogeneity between disease diagnoses and phenotypes. Using mass cytometry, we analyze leukocyte subsets, characterize their function(s), and examine gut-homing molecule expression in blood and intestinal tissue from healthy and/or IBD subjects. Some signatures persist in IBD despite remission, and many signatures are highly represented by leukocytes that express gut trafficking molecules. Moreover, distinct systemic and local immune signatures suggest patterns of cell localization in disease. Our findings highlight the importance of gut tropic leukocytes in circulation and reveal that blood-based immune signatures differentiate clinically relevant subsets of IBD.
Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia
Authors: Minuesa Gerard , Albanese Steven K. , Xie Wei , Kazansky Yaniv , Worroll Daniel , Chow Arthur , Schurer Alexandra , Park Sun-Mi , Rotsides Christina Z. , Taggart James , Rizzi Andrea , Naden Levi N. , Chou Timothy , Gourkanti Saroj , Cappel Daniel , Passarelli Maria C. , Fairchild Lauren , Adura Carolina , Glickman J. Fraser , Schulman Jessica , Famulare Christopher , Patel Minal , Eibl Joseph K. , Ross Gregory M. , Bhattacharya Shibani , Tan Derek S. , Leslie Christina S. , Beuming Thijs , Patel Dinshaw J. , Goldgur Yehuda , Chodera John D. , Kharas Michael G.
Published: June 2019

The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08–2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI’s oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.
Sub-stoichiometric 2D covalent organic frameworks from tri- and tetratopic linkers
Authors: Banerjee Tanmay , Haase Frederik , Trenker Stefan , Biswal Bishnu P. , Savasci Gökcen , Duppel Viola , Moudrakovski Igor , Ochsenfeld Christian , Lotsch Bettina V.
Published: June 2019

Covalent organic frameworks (COFs) are typically designed by breaking down the desired network into feasible building blocks - either simple and highly symmetric, or more convoluted and thus less symmetric. The linkers are chosen complementary to each other such that an extended, fully condensed network structure can form. We show not only an exception, but a design principle that allows breaking free of such design rules. We show that tri- and tetratopic linkers can be combined to form imine-linked [4 + 3] sub-stoichiometric 2D COFs featuring an unexpected bex net topology, and with periodic uncondensed amine functionalities which enhance CO2 adsorption, can be derivatized in a subsequent reaction, and can also act as organocatalysts. We further extend this class of nets by including a ditopic linker to form [4 + 3 + 2] COFs. The results open up possibilities towards a new class of sub-valent COFs with unique structural, topological and compositional complexities for diverse applications.
Adenoviral vaccine targeting multiple neoantigens as strategy to eradicate large tumors combined with checkpoint blockade
Authors: D’Alise Anna Morena , Leoni Guido , Cotugno Gabriella , Troise Fulvia , Langone Francesca , Fichera Imma , De Lucia Maria , Avalle Lidia , Vitale Rosa , Leuzzi Adriano , Bignone Veronica , Di Matteo Elena , Tucci Fabio Giovanni , Poli Valeria , Lahm Armin , Catanese Maria Teresa , Folgori Antonella , Colloca Stefano , Nicosia Alfredo , Scarselli Elisa
Published: June 2019

Neoantigens (nAgs) are promising tumor antigens for cancer vaccination with the potential of inducing robust and selective T cell responses. Genetic vaccines based on Adenoviruses derived from non-human Great Apes (GAd) elicit strong and effective T cell-mediated immunity in humans. Here, we investigate for the first time the potency and efficacy of a novel GAd encoding multiple neoantigens. Prophylactic or early therapeutic vaccination with GAd efficiently control tumor growth in mice. In contrast, combination of the vaccine with checkpoint inhibitors is required to eradicate large tumors. Gene expression profile of tumors in regression shows abundance of activated tumor infiltrating T cells with a more diversified TCR repertoire in animals treated with GAd and anti-PD1 compared to anti-PD1. Data suggest that effectiveness of vaccination in the presence of high tumor burden correlates with the breadth of nAgs-specific T cells and requires concomitant reversal of tumor suppression by checkpoint blockade.
PTPN21 and Hook3 relieve KIF1C autoinhibition and activate intracellular transport
Authors: Siddiqui Nida , Zwetsloot Alexander James , Bachmann Alice , Roth Daniel , Hussain Hamdi , Brandt Jonathan , Kaverina Irina , Straube Anne
Published: June 2019

The kinesin-3 KIF1C is a fast organelle transporter implicated in the transport of dense core vesicles in neurons and the delivery of integrins to cell adhesions. Here we report the mechanisms of autoinhibition and release that control the activity of KIF1C. We show that the microtubule binding surface of KIF1C motor domain interacts with its stalk and that these autoinhibitory interactions are released upon binding of protein tyrosine phosphatase PTPN21. The FERM domain of PTPN21 stimulates dense core vesicle transport in primary hippocampal neurons and rescues integrin trafficking in KIF1C-depleted cells. In vitro, human full-length KIF1C is a processive, plus-end directed motor. Its landing rate onto microtubules increases in the presence of either PTPN21 FERM domain or the cargo adapter Hook3 that binds the same region of KIF1C tail. This autoinhibition release mechanism allows cargo-activated transport and might enable motors to participate in bidirectional cargo transport without undertaking a tug-of-war.
Intertwined topological phases induced by emergent symmetry protection
Authors: González-Cuadra Daniel , Bermudez Alejandro , Grzybowski Przemysław R. , Lewenstein Maciej , Dauphin Alexandre
Published: June 2019

The dual role played by symmetry in many-body physics manifests itself through two fundamental mechanisms: spontaneous symmetry breaking and topological symmetry protection. These two concepts, ubiquitous in both condensed matter and high energy physics, have been applied successfully in the last decades to unravel a plethora of complex phenomena. Their interplay, however, remains largely unexplored. Here we report how, in the presence of strong correlations, symmetry protection emerges from a set of configurations enforced by another broken symmetry. This mechanism spawns different intertwined topological phases, where topological properties coexist with long-range order. Such a singular interplay gives rise to interesting static and dynamical effects, including interaction-induced topological phase transitions constrained by symmetry breaking, as well as a self-adjusted fractional pumping. This work paves the way for further exploration of exotic topological features in strongly-correlated quantum systems.
Progressive expression of PPARGC1α is associated with hair miniaturization in androgenetic alopecia
Authors: Ho Bryan Siu-Yin , Vaz Candida , Ramasamy Srinivas , Chew Elaine Guo Yan , Mohamed Jameelah Sheik , Jaffar Huma , Hillmer Axel , Tanavde Vivek , Bigliardi-Qi Mei , Bigliardi Paul Lorenz
Published: June 2019

Current opinion views androgens as the pathogenic driver in the miniaturization of hair follicles of androgenetic alopecia by interfering with the dermal papilla. This cannot be the sole cause and therefore it is important for therapeutic and diagnostic purposes to identify additional pathways. Comparative full transcriptome profile analysis of the hair bulb region of normal and miniaturized hair follicles from vertex and occipital region in males with and without androgenetic alopecia revealed that next to the androgen receptor as well the retinoid receptor and particularly the PPAR pathway is involved in progressive hair miniaturization. We demonstrate the concurrent up-regulation of PPARGC1a in the epithelial compartment and androgen receptor in the dermal papilla of miniaturized hair. Dynamic Ppargc1a expression in the mouse hair cycle suggests a possible role in regulating hair growth and differentiation. This is supported by reduced proliferation of human dermal papilla and predominantly epithelial keratinocytes after incubation with AICAR, the agonist for AMPK signaling which activates PPARGC1a and serves as co-activator of PPARγ. In addition, miRNA profiling shows enrichment of miRNA-targeted genes in retinoid receptors and PPARGC1α/PPARγ signaling, and antigen presentation pathways.
Structure-Activity Relationships of Baicalein and its Analogs as Novel TSLP Inhibitors
Authors: Park Bernie Byunghoon , Choi Jae Wan , Park Dawon , Choi Doyoung , Paek Jiwon , Kim Hyun Jung , Son Se-Young , Mushtaq Ameeq Ul , Shin Hyeji , Kim Sang Hoon , Zhou Yuanyuan , Lim Taehyeong , Park Ji Young , Baek Ji-Young , Kim Kyul , Kwon Hongmok , Son Sang-Hyun , Chung Ka Young , Jeong Hyun-Ja , Kim Hyung-Min , Jung Yong Woo , Lee Kiho , Lee Ki Yong , Byun Youngjoo , Jeon Young Ho
Published: June 2019

Thymic stromal lymphopoietin (TSLP) plays an important role in the differentiation and proliferation of Th2 cells, resulting in eosinophilic inflammation and numerous allergic diseases. Baicalein (1), a major component of Scutellaria baicalensis, was found to be the first small molecule to block TSLP signaling pathways. It inhibited effectively eosinophil infiltration in house dust mite-induced and ovalbumin-challenged mouse models. Structure-activity relationship studies identified compound 11a, a biphenyl flavanone analog, as a novel human TSLP inhibitor for the discovery and development of new anti-allergic drugs.
Crustal CO2 contribution to subduction zone degassing recorded through calc-silicate xenoliths in arc lavas
Authors: Whitley Sean , Gertisser Ralf , Halama Ralf , Preece Katie , Troll Valentin R. , Deegan Frances M.
Published: June 2019

Interaction between magma and crustal carbonate at active arc volcanoes has recently been proposed as a source of atmospheric CO2, in addition to CO2 released from the mantle and subducted oceanic crust. However, quantitative constraints on efficiency and timing of these processes are poorly established. Here, we present the first in situ carbon and oxygen isotope data of texturally distinct calcite in calc-silicate xenoliths from arc volcanics in a case study from Merapi volcano (Indonesia). Textures and C-O isotopic data provide unique evidence for decarbonation, magma-fluid interaction, and the generation of carbonate melts. We report extremely light δ13CPDB values down to −29.3‰ which are among the lowest reported in magmatic systems so far. Combined with the general paucity of relict calcite, these extremely low values demonstrate highly efficient remobilisation of crustal CO2 over geologically short timescales of thousands of years or less. This rapid release of large volumes of crustal CO2 may impact global carbon cycling.
Differences in Colistin Administration and Bacterial and Treatment Outcomes in Critically Ill Patients
Authors: Jung Sunmi , Chung Eun Kyoung , Jun Min Sun , Son Eun Sun , Rhie Sandy Jeong
Published: June 2019

The desired target steady-state average colistin concentration (Css,avg) to balance between therapeutic effectiveness and nephrotoxicity is largely unclear. The objective of this study was to evaluate the effect of the desired target colistin Css,avgon the effectiveness and safety of IV colistin therapy in critically ill patients. Overall, 153 critically ill patients (71% males) receiving IV colistin were retrospectively analyzed. The desired target colistin Css,avgwas estimated based on the daily colistin dose and creatinine clearance of each patient. No significant predictor for clinical cure was identified. However, microbiological outcome was significantly associated with pneumonia compared to bacteremia (odds ratio [OR] 0.092, 95% confidence interval [CI] [0.033–0.251],P < 0.001) and the use of IV colistin loading dose (OR 2.783, 95% CI [1.126–6.880],P = 0.027). Colistin-associated nephrotoxicity was significantly less likely to occur in patients who received inhaled colistin close to the time of IV colistin therapy (OR 0.331, CI [0.119–0.925],P = 0.035). The desired target Css,avgof colistin was not associated with treatment outcomes or the risk of nephrotoxicity. Loading dose and inhaled colistin use near the time of IV colistin therapy may be considered to maximize therapeutic effectiveness and minimize the risk of colistin-associated nephrotoxicity, respectively.
Framework to Estimate Total Particulate Mass and Nicotine Delivered to E-cig Users from Natural Environment Monitoring Data
Authors: Hensel Edward C. , Eddingsaas Nathan C. , DiFrancesco A. Gary , Jayasekera Shehan , O’Dea Sean , Robinson Risa J.
Published: June 2019

A framework describing the joint effect of user topography behavior and product characteristics of one exemplar device on the total particulate mass (TPM) and aerosol constituent yield delivered to a user is presented and validated against seven user-specific ‘playback’ emissions observations. A pen-style e-cig was used to collect emissions across puff flow rates and durations spanning the range observed in the natural environment. Emissions were analyzed with GC-MS and used to construct empirical correlations for TPM concentration and nicotine mass ratio. TPM concentration was demonstrated to depend upon both puff flow rate and duration, while nicotine mass ratio was not observed to be flow-dependent under the conditions presented. The empirical model for TPM and nicotine yield demonstrated agreement with experimental observations, with Pearson correlation coefficients of r = 0.79 and r = 0.86 respectively. The mass of TPM and nicotine delivered to the mouth of an e-cig user are dependent upon the puffing behavior of the user. Product-specific empirical models of emissions may be used in conjunction with participant-specific topography observations to accurately quantify the mass of TPM and nicotine delivered to a user.
Genome of the tropical plant Marchantia inflexa: implications for sex chromosome evolution and dehydration tolerance
Authors: Marks Rose A. , Smith Jeramiah J. , Cronk Quentin , Grassa Christopher J. , McLetchie D. Nicholas
Published: June 2019

We present a draft genome assembly for the tropical liverwort, Marchantia inflexa, which adds to a growing body of genomic resources for bryophytes and provides an important perspective on the evolution and diversification of land plants. We specifically address questions related to sex chromosome evolution, sexual dimorphisms, and the genomic underpinnings of dehydration tolerance. This assembly leveraged the recently published genome of related liverwort, M. polymorpha, to improve scaffolding and annotation, aid in the identification of sex-linked sequences, and quantify patterns of sequence differentiation within Marchantia. We find that genes on sex chromosomes are under greater diversifying selection than autosomal and organellar genes. Interestingly, this is driven primarily by divergence of male-specific genes, while divergence of other sex-linked genes is similar to autosomal genes. Through analysis of sex-specific read coverage, we identify and validate genetic sex markers for M. inflexa, which will enable diagnosis of sex for non-reproductive individuals. To investigate dehydration tolerance, we capitalized on a difference between genetic lines, which allowed us to identify multiple dehydration associated genes two of which were sex-linked, suggesting that dehydration tolerance may be impacted by sex-specific genes.