bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Neonatal Rotavirus Vaccine (RV3-BB) Produces Vaccine Take Irrespective of Histo-Blood Group Antigen Status
Authors: Boniface Karen , Byars Sean G , Cowley Daniel , Kirkwood Carl D , Bines Julie E
Published: July 2019

Background

VP4 [P] genotype binding specificities of rotaviruses and differential expression of histo-blood group antigens (HBGAs) between populations may contribute to reduced efficacy against severe rotavirus disease. P[6]-based rotavirus vaccines could broaden protection in such settings, particularly in Africa, where the Lewis-negative phenotype and P[6] rotavirus strains are common.

Methods

The association between HBGA status and G3P[6] rotavirus vaccine (RV3-BB) take was investigated in a phase 2A study of RV3-BB vaccine involving 46 individuals in Dunedin, New Zealand, during 2012–2014. FUT2 and FUT3 genotypes were determined from DNA extracted from stool specimens, and frequencies of positive cumulative vaccine take, defined as an RV3-BB serum immune response (either immunoglobulin A or serum neutralizing antibody) and/or stool excretion of the vaccine strain, stratified by HBGA status were determined.

Results

RV3-BB produced positive cumulative vaccine take in 29 of 32 individuals (91%) who expressed a functional FUT2 enzyme (the secretor group), 13 of 13 (100%) who were FUT2 null (the nonsecretor group), and 1 of 1 with reduced FUT2 activity (i.e., a weak secretor); in 37 of 40 individuals (93%) who expressed a functional FUT3 enzyme (the Lewis-positive group) and 3 of 3 who were FUT3 null (the Lewis-negative group); and in 25 of 28 Lewis-positive secretors (89%), 12 of 12 Lewis-positive nonsecretors (100%), 2 of 2 Lewis-negative secretors, and 1 of 1 Lewis-negative weak secretor.

Conclusions

RV3-BB produced positive cumulative vaccine take irrespective of HBGA status. RV3-BB has the potential to provide an improved level of protection in settings where P[6] rotavirus disease is endemic, irrespective of the HBGA profile of the population.
A comparison of the anatomical and gastrointestinal functional development between gilt and sow progeny around birth and weaning1
Authors: Craig Jessica R , Dunshea Frank R , Cottrell Jeremy J , Furness John B , Wijesiriwardana Udani A , Pluske John R
Published: July 2019

Gilt progeny (GP) often have restricted growth performance and health status in comparison to sow progeny (SP) from birth, with the underlying mechanisms responsible for this yet to be fully understood. The present study aimed to compare differences in growth and development between GP and SP in the first 24 h after birth and in the periweaning period. Two cohorts of pigs including 36 GP and 37 SP were euthanized at 1 of 4 time points: a birth cohort (at birth before suckling, 0 h; and 24 h after birth, 24 h; n = 33) and a weaning cohort (at approximately 29 d of age; “pre-weaning,” PrW; and 24 h after weaning; “post-weaning,” PoW; n = 40). Pigs were individually weighed at 0 h, 24 h, PrW, and PoW up until the point of euthanasia, at which time the weights of selected tissues and organs were recorded and analyzed relative to BW. The length of the small intestine (SI), femur, and body were also measured, and a serum sample was collected and analyzed for IgG concentration. Samples of jejunal and ileal mucosa were collected and analyzed for total protein and specific activity of lactase. Euthanized GP were lighter (P < 0.01) than SP at all time points. At all time points, the ratios of quadriceps weight to femur length, BW to body length, spleen to BW (all P < 0.05), and SI weight to length (P < 0.10) were lower in GP than in SP. There was no difference (P ≥ 0.05) in stomach or heart to BW ratios between GP and SP in either cohort. The brain to liver weight ratio was greater (P = 0.044) in GP than in SP in the birth cohort, and the brain to BW ratio was greater (P < 0.01) in GP in both the birth and weaning cohorts. The liver to BW ratio was similar (P = 0.35) at birth but greater (P = 0.014) in GP around weaning. Total mucosal protein content in the jejunum and ileum was lower (P = 0.007) in GP at 24 h compared with SP, and specific activity of lactase was greater (P = 0.022) in GP in the birth cohort, whereas there were no differences in the weaning cohort (P ≥ 0.10). Gilt progeny had lower (P < 0.001) serum IgG concentration compared with SP at 24 h, but there was no difference (P ≥ 0.10) in the weaning cohort. Collectively, these findings suggest that the early development of GP may be delayed compared with SP and that a number of the anatomical differences between GP and SP that exist after birth are also present at weaning.
Dynamic agglomeration economies and learning by working in specialised regions
Authors: Peters Jan Cornelius
Published: July 2019

This study provides new evidence on the magnitude of dynamic agglomeration economies. It estimates the elasticity of entry wage with regard to the size of the regional labour markets in which previous work experience was acquired and considers, furthermore, the workforce compositions in these regions. The results indicate that not only the sheer size of regional labour markets determine individual knowledge accumulation. Benefits from acquiring experience in large labour markets by workers in service sector occupations are partly caused by human capital externalities, whereas manufacturing workers experience additional dynamic gains from localisation economies, in Germany particularly outside urban centres.
Mutant p53—a potential player in shaping the tumor–stroma crosstalk
Authors: Stein Yan , Aloni-Grinstein Ronit , Rotter Varda
Published: July 2019

A plethora of studies suggest that the non-transformed cellular and non-cellular components of the tumor, collectively known as the tumor microenvironment, have a significant impact on the tumorigenic process. It was suggested that the microenvironment, which initially restricts tumor development, is recruited by the tumor and maintains a crosstalk that further promotes cancer progression. Indeed, many of the molecules that participate in the tumor–stroma crosstalk have been characterized. However, the crucial factors that are responsible for the initiation of this crosstalk or the ‘recruitment’ process remain poorly understood. We propose that oncogenes themselves may influence the ‘recruitment’ of the stromal cells, while focusing on mutant p53. Apart from losing its tumor-suppressing properties, mutant p53 gains novel oncogenic functions, a phenomenon dubbed mutant p53 gain of function (GOF). Here, we discuss possible ways in which mutant p53 may modulate the microenvironment in order to promote tumorigenesis. We thus propose that mutant p53 may serve as a key player in the modulation of the tumor–stroma crosstalk in a way that benefits the tumor. Further elucidation of these ‘recruitment’ processes, dictated by mutant p53, may be utilized for tailoring personalized therapeutic approaches for patients with tumors that harbor p53 mutation.
Collusive Algorithms as Mere Tools, Super-tools or Legal Persons
Authors: Zheng Guan , Wu Hong
Published: July 2019

The widespread use of algorithmic technologies makes rules on tacit collusion, which are already controversial in antitrust law, more complicated. These rules have obvious limitations in effectively regulating algorithmic collusion. Although some scholars and practitioners within antitrust circles in the United States, Europe and beyond have taken notice of this problem, they have failed to a large extent to make clear its specific manifestations, root causes, and effective legal solutions. In this article, the authors make a strong argument that it is no longer appropriate to regard algorithms as mere tools of firms, and that the distinct features of machine learning algorithms as super-tools and as legal persons may inevitably bring about two new cracks in antitrust law. This article clarifies the root causes why these rules are inapplicable to a large extent to algorithmic collusion particularly in the case of machine learning algorithms, classifies the new legal cracks, and provides sound legal criteria for the courts and competition authorities to assess the legality of algorithmic collusion much more accurately. More importantly, this article proposes an efficacious solution to revive the market pricing mechanism for the purposes of resolving the two new cracks identified in antitrust law.
Can Clearcutting Reset Successional Trajectories in Upland Oak–Hickory Forests? A Case Study from Mid-Missouri
Authors: Knapp Benjamin O , Anderson Samantha E , Curtin Patrick J , Ghilardi Casey , Rives Robert G
Published: July 2019

Securing oak regeneration is a common management challenge in the central and eastern United States. We quantified the abundance of tree species groups in clearcuts in mid-Missouri more than 30 years following harvest to determine differences in species dominance based on aspect (exposed, protected, or ridge sites). Each tree was classified as “dominant” or “suppressed” based on its relative contribution to cumulative stand stocking, following concepts of the tree–area relation. Although maples or understory species were the most abundant across all sites, oaks and hickories contributed to more than 60 percent of the dominant stems on the exposed sites. In contrast, oaks and hickories made up less than 25 percent of the dominant stems on protected and ridge sites. Results indicate that clearcutting reset the successional trajectory, from a transition to maple dominance to maintaining oak–hickory dominance, on exposed sites but not on ridge or protected sites.
Measurement of Monoclonal Immunoglobulin Protein Concentration in Serum Protein Electrophoresis: Comparison of Automated vs Manual/Human Readings
Authors: Clavijo Alex , Ryan Nathan , Xu Hongyan , Singh Gurmukh
Published: July 2019

Background

Protein concentration of monoclonal immunoglobulin in plasma-cell myeloma/multiple myeloma provides an estimate of the tumor mass and allows for monitoring of the response to treatment. Accurate and reproducible estimates of the monoclonal immunoglobulin concentration are important for patient care.

Objective

To address the optimum method for estimation of the concentration of monoclonal immunoglobulins.

Methods

Serum protein electrophoresis and immunofixation electrophoresis were conducted by using the Helena SPIFE Touch instrument. Estimation of the protein concentration of monoclonal immunoglobulin in the gamma region by computer-assisted reading was compared with the reading by technologists and pathology residents, in 300 gels. The data were compared using t-testing and analysis of variance.

Results

Computer-generated readings had a consistent positive bias. The correlation coefficient of the average reading by technologists and residents with the computer generated value was 0.997. The average positive bias by the computer reading was 0.29 g per dL. The intercept on the regression analysis was 0.22 g per dL. The reading by the computer was significantly higher than each of the human-interpreted readings. The readings by the 3 human groups were not significantly different amongst them. The main reason for the higher reading by the computer was inclusion of a greater area on the anodal size of the peak on the densitometric scan.

Conclusions

Human- and computer-interpreted readings of the protein concentration of monoclonal immunoglobulin have a high degree of correlation. The consistent positive bias by the computer reading occurred due to inclusion of a greater area of the densitometric scan on the anodal side of the peak. We suggest that vendors should adjust such computer programs to provide readings comparable to those generated by expert humans. We recommend manual delineation of the monoclonal peaks for measuring the concentration of monoclonal immunoglobulins.
Author identification with feature transformation method
Authors: Tamboli Mubin Shoukat , Prasad Rajesh
Published: July 2019

Over the last few decades, there has been tremendous growth in online communication through different types of media. Communication via the Internet is anonymous, which causes a critical issue regarding identity tracing. Authorship identification can apply to tasks such as identifying an anonymous author, detecting plagiarism, or finding a ghostwriter. Previous research has outlined the various methods and their improvements for the identification of anonymous authors based on stylometry. However, changes in the writing style of an author over a long period has not been addressed. In this article, we propose a methodology for author identification where the writing style of an author changes. The proposed methodology consists of two phases: the first will show the change in writing style of the author and in another phase the change is mitigated by a new feature normalization technique. A novel Transform Feature to Current Time function is proposed for normalization, where features are shifted to current time and made available for further classification. A machine-learning algorithm is used to identify an author candidate. The experiments of the proposed methodology conducted on a set of text samples by several authors were collected over a different time period and the results show an improvement in performance.
United States Air Force Academy Cadets’ Perceived Costs of Concussion Disclosure
Authors: Rawlins Michelle L Weber , Johnson Brian R , Register-Mihalik Johna K , DeAngelis Karin , Schmidt Julianne D , D’Lauro Christopher J
Published: July 2019

Introduction

Concussion is unique among sport-related injuries as effective clinical diagnosis and treatment often rely on symptom-report for clinician diagnosis and treatment. However, at-risk populations such as collegiate athletes and military academy cadets often have been shown to under-report concussions and symptoms, complicating diagnosis, treatment, and policy-based interventions. The purpose of this study was to explore factors influencing concussion reporting in United States Air Force Academy (USAFA) cadets.

Materials and Methods

Semi-structured interviews were conducted on 34 cadets (18 with concussion history; 16 without concussion history). This study was approved by the USAFA Institutional Review Board. Analysis included a five-cycle process of clarifying the topic at hand through an introduction, conducting a literature review, data collection and summarization, relating current findings to current literature, and making final interpretations. Data were summarized by creation of a codebook after reading five transcripts and identifying meaningful units. A four-person research team read and identified meaningful units individually, then met to discuss common meaningful units and codebook creation. Once the codebook was created, the lead researcher used the codebook to code all transcripts.

Results

Eight themes were generated from interview transcripts. This manuscript focuses on the perceived costs following a concussion theme and the following subthemes: perceived costs to physical fitness, military career aspirations, pilot qualifications, sport, reputation, academics, and lack of time.

Conclusions

Cadet interviews described a complex environment where concussions were often viewed as costly to future career ambitions and provided potential reasons for non-disclosure largely including disruption in daily life. Reduction in perceived and actual harms due to concussion disclosure will require not only improving clinical care, but also addressing barriers to self-disclosure. Additionally, research suggests the sooner one reports a concussion, the sooner they return to physical or military activity. Educational interventions should be designed to address the perceived costs identified from our study and educate cadets that while some costs may be reality, others may not. Secondly, it should also be stressed to cadets that the sooner one seeks medical attention following a concussion, the sooner they may return to activity. Messaging around these themes may decrease the costs associated with time removed from academics, athletics, or military activities therefore minimizing attempts at concussion self-management. Lastly, if efforts are made to improve the overall concussion disclosure stigma, cadets may increase seeking care after injury because their reputation may not be as impacted.
Normative Uncertainty and the Dependence Problem
Authors: Podgorski Abelard
Published: July 2019

In this paper, I enter the debate between those who hold that our normative uncertainty matters for what we ought to do, and those who hold that only our descriptive uncertainty matters. I argue that existing views in both camps have unacceptable implications in cases where our descriptive beliefs depend on our normative beliefs. I go on to propose a fix which is available only to those who hold that normative uncertainty matters, ultimately leaving the challenge as a threat to recent skepticism about such views.
Truncated γ-exponential models: evaporation and mass-segregation effects in the bi-component system
Authors: Gomez-Leyton Yuvineza J , Velazquez Luisberis
Published: July 2019

The γ-exponential models were previously proposed as a phenomenological attempt to characterize the properties of stellar systems with a quasi-stationary evolution under the incidence evaporation, e.g. globular clusters. They represent a parametric family of distributions that unify profiles with isothermal cores and polytropic haloes, thus providing a suitable generalization for several models available in the literature. We start our discussion revisiting some results concerning the case of single-mass systems. In particular, we emphasized that these models predict the existence of a new type of collective phenomenon: the asymptotic gravothermal collapse. This gravitational instability differs from the normal gravothermal collapse (e.g. the one associated with isothermal model) because it requires that the system releases an infinite amount of energy. Afterwards, we enter to analyse how a mass spectrum modifies the thermodynamics of these models, in particular, the associated collective phenomena. Although the theoretical description concerns to any multimass system, our computational study addresses the simplest case: the bi-component system. This analysis allows a major understanding about the thermodynamics of stellar systems under the presence of evaporation and mass segregation. For the present models, the growth of mass segregation does not affect the system evaporation disruption but favours gravothermal collapse, e.g. it tends to reduce the energy interval of stability by increasing the lower bound critical energy associated with this collective phenomenon. Extreme cases appear under certain conditions, where gravothermal collapse changes its character from asymptotic to normal.
A colour-excess extinction map of the southern Galactic disc from the VVV and GLIMPSE surveys
Authors: Soto M , Barbá R , Minniti D , Kunder A , Majaess D , Nilo-Castellón J L , Alonso-García J , Leone G , Morelli L , Haikala L , Firpo V , Lucas P , Emerson J P , Moni Bidin C , Geisler D , Saito R K , Gurovich S , Contreras Ramos R , Rejkuba M , Barbieri M , Roman-Lopes A , Hempel M , Alonso M V , Baravalle L D , Borissova J , Kurtev R , Milla F
Published: July 2019

An improved high-resolution and deep $A_{K_{s}}$ foreground dust extinction map is presented for the Galactic disc area within 295° ≲ l ≲ 350°, −1.0° ≲ b ≲ +1.0°. At some longitudes the map reaches up to |b| ∼ 2.25°, for a total of ∼148 deg2. The map was constructed via the Rayleigh–Jeans colour excess (RJCE) technique based on deep near-infrared (NIR) and mid-infrared (MIR) photometry. The new extinction map features a maximum bin size of 1 arcmin, and relies on NIR observations from the Two Micron All-Sky Survey (2MASS) and new data from ESO’s Vista Variables in the Vía Láctea (VVV) survey, in concert with MIR observations from the Galactic Legacy Infrared Mid-Plane Survey Extraordinaire. The VVV photometry penetrates ∼4 mag fainter than 2MASS, and provides enhanced sampling of the underlying stellar populations in this heavily obscured region. Consequently, the new results supersede existing RJCE maps tied solely to brighter photometry, revealing a systematic underestimation of extinction in prior work that was based on shallower data. The new high-resolution and large-scale extinction map presented here is readily available to the community through a web query interface.
Observable tests of self-interacting dark matter in galaxy clusters: BCG wobbles in a constant density core
Authors: Harvey David , Robertson Andrew , Massey Richard , McCarthy Ian G
Published: July 2019

Models of cold dark matter (CDM) predict that the distribution of dark matter in galaxy clusters should be cuspy, centrally concentrated. Constant density cores would be strong evidence for beyond CDM physics, such as self-interacting dark matter (SIDM). An observable consequence would be oscillations of the brightest cluster galaxy (BCG) in otherwise relaxed galaxy clusters. Offset BCGs have indeed been observed – but only interpreted via a simplified, analytic model of oscillations. We compare these observations to the BAryons and HAloes of MAssive Sysmtes (BAHAMAS)–SIDM suite of cosmological simulations, which include SIDM and a fully hydrodynamical treatment of star formation and feedback. We predict that the median offset of BCGs increases with the SIDM cross-section, cluster mass, and the amount of stellar mass within 10 kpc, while CDM exhibits no trend in mass. Interpolating between the simulated cross-sections, we find that the observations (of 10 clusters) are consistent with CDM at the ∼1.5σ level, and prefer cross-section σ/m < 0.12(0.39) cm2 g−1 at 68 per cent (95 per cent) confidence level. This is on the verge of ruling out velocity-independent dark matter self-interactions as the solution to discrepancies between the predicted and observed behaviour of dwarf galaxies, and will be improved by larger surveys by Euclid or Super-pressure Balloon-borne Imaging Telescope (SuperBIT).
Numerical convergence of simulations of galaxy formation: the abundance and internal structure of cold dark matter haloes
Authors: Ludlow Aaron D , Schaye Joop , Bower Richard
Published: July 2019

We study the impact of numerical parameters on the properties of cold dark matter haloes formed in collisionless cosmological simulations. We quantify convergence in the median spherically averaged circular velocity profiles for haloes of widely varying particle number, as well as in the statistics of their structural scaling relations and mass functions. In agreement with prior work focused on single haloes, our results suggest that cosmological simulations yield robust halo properties for a wide range of gravitational softening parameters, ϵ, provided: (1) ϵ is not larger than a ‘convergence radius’, rconv, which is dictated by two-body relaxation and determined by particle number, and (2) a sufficient number of time-steps are taken to accurately resolve particle orbits with short dynamical times. Provided these conditions are met, median circular velocity profiles converge to within ≈10 per cent for radii beyond which the local two-body relaxation time-scale exceeds the Hubble time by a factor $\kappa \equiv t_{\rm relax}/t_{\rm H}\rm{\,\, \buildrel\gt \over \sim \,\,}0.177$, with better convergence attained for higher κ. We provide analytic estimates of rconv that build on previous attempts in two ways: first, by highlighting its explicit (but weak) softening-dependence and, second, by providing a simpler criterion in which rconv is determined entirely by the mean inter-particle spacing, l, for example better than 10 per cent convergence in circular velocity for $r\rm{\,\, \buildrel\gt \over \sim \,\,}0.05\, l$. We show how these analytic criteria can be used to assess convergence in structural scaling relations for dark matter haloes as a function of their mass or maximum circular speed.
Time variations of H2O and SiO masers in the proto-Planetary Nebula OH 231.8+4.2
Authors: Kim Jaeheon , Cho S-H , Bujarrabal V , Imai H , Dodson R , Yoon D-H , Zhang B
Published: July 2019

H2O (22 GHz) and SiO masers (43, 86, 129 GHz) in the bipolar proto-planetary nebula OH 231.8+4.2 were simultaneously monitored using the 21-m antennas of the Korean VLBI Network in 2009–2015. Both species exhibit periodic flux variations that correlate with the central star’s optical light curve, with a phase delay of up to 0.15 for the maser flux variations with respect to the optical light curve. The flux densities of SiO v = 2, J = 1→0 and H2O masers decrease with time, implying that they may disappear in 10–20 years. However, there seems to have been a transient episode of intense H2O maser emission around 2010. We also found a systematic behaviour in the velocity profiles of these masers. The velocities of the H2O maser components appear to be remarkably constant, suggesting ballistic motion for the bipolar outflow in this nebula. On the other hand, those of the SiO maser clumps show a systematic radial acceleration of the individual clumps, converging to the outflow velocity of the H2O maser clumps. Measuring the full widths at zero power of the detected lines, we estimated the expansion velocities of the compact bipolar outflow traced by H2O maser and SiO thermal line, and discussed the possibility of the expanding SiO maser region in the equatorial direction. All of our analyses support that the central host star of OH231.8 is close to the tip of the AGB phase, and that the mass-loss rate recently started to decrease because of incipient post-AGB evolution.
On the road to percent accuracy: non-linear reaction of the matter power spectrum to dark energy and modified gravity
Authors: Cataneo M , Lombriser L , Heymans C , Mead A J , Barreira A , Bose S , Li B
Published: July 2019

We present a general method to compute the non-linear matter power spectrum for dark energy (DE) and modified gravity scenarios with per cent-level accuracy. By adopting the halo model and non-linear perturbation theory, we predict the reaction of a lambda cold dark matter (ΛCDM) matter power spectrum to the physics of an extended cosmological parameter space. By comparing our predictions to N-body simulations we demonstrate that with no-free parameters we can recover the non-linear matter power spectrum for a wide range of different w0–wa DE models to better than 1 per cent accuracy out to k ≈ 1 $h \,{\rm Mpc}^{-1}$. We obtain a similar performance for both DGP and f(R) gravity, with the non-linear matter power spectrum predicted to better than 3 per cent accuracy over the same range of scales. When including direct measurements of the halo mass function from the simulations, this accuracy improves to 1 per cent. With a single suite of standard ΛCDM N-body simulations, our methodology provides a direct route to constrain a wide range of non-standard extensions to the concordance cosmology in the high signal-to-noise non-linear regime.
Observational properties of ultra-diffuse galaxies in low-density environments: field UDGs are predominantly blue and star forming
Authors: Prole D J , van der Burg R F J , Hilker M , Davies J I
Published: July 2019

While we have learnt much about ultradiffuse galaxies (UDGs) in groups and clusters, relatively little is known about them in less dense environments. More isolated UDGs are important for our understanding of UDG formation scenarios because they form via secular mechanisms, allowing us to determine the relative importance of environmentally driven formation in groups and clusters. We have used the public Kilo-Degree Survey together with the Hyper Suprime-Cam Subaru Strategic Program to constrain the abundance and properties of UDGs in the field, targeting sources with low surface brightness (24.0 ≤ $\bar{\mu }_{\mathrm{ e},r}$ ≤ 26.5) and large apparent sizes (3.0 arcsec ≤ $\bar{r}_{\mathrm{ e},r}$ ≤ 8.0 arcsec). Accounting for several sources of interlopers in our selection based on canonical scaling relations, and using an empirical UDG model based on measurements from the literature, we show that a scenario in which cluster-like red-sequence UDGs occupy a significant number of field galaxies is unlikely, with most field UDGs being significantly bluer and showing signs of localized star formation. An immediate conclusion is that UDGs are much more efficiently quenched in high-density environments. We estimate an upper limit on the total field abundance of UDGs of 8 ± 3 × 10−3 cMpc−3 within our selection range. We also compare the total field abundance of UDGs to a measurement of the abundance of H i-rich UDGs from the literature, suggesting that they occupy at least one-fifth of the overall UDG population. The mass formation efficiency of UDGs implied by this upper limit is similar to what is measured in groups and clusters.
A complex suite of loci and elements in eukaryotic type II topoisomerases determine selective sensitivity to distinct poisoning agents
Authors: Blower Tim R , Bandak Afif , Lee Amy S Y , Austin Caroline A , Nitiss John L , Berger James M
Published: July 2019

Type II topoisomerases catalyze essential DNA transactions and are proven drug targets. Drug discrimination by prokaryotic and eukaryotic topoisomerases is vital to therapeutic utility, but is poorly understood. We developed a next-generation sequencing (NGS) approach to identify drug-resistance mutations in eukaryotic topoisomerases. We show that alterations conferring resistance to poisons of human and yeast topoisomerase II derive from a rich mutational ‘landscape’ of amino acid substitutions broadly distributed throughout the entire enzyme. Both general and discriminatory drug-resistant behaviors are found to arise from different point mutations found at the same amino acid position and to occur far outside known drug-binding sites. Studies of selected resistant enzymes confirm the NGS data and further show that the anti-cancer quinolone vosaroxin acts solely as an intercalating poison, and that the antibacterial ciprofloxacin can poison yeast topoisomerase II. The innate drug-sensitivity of the DNA binding and cleavage region of human and yeast topoisomerases (particularly hTOP2β) is additionally revealed to be significantly regulated by the enzymes’ adenosine triphosphatase regions. Collectively, these studies highlight the utility of using NGS-based methods to rapidly map drug resistance landscapes and reveal that the nucleotide turnover elements of type II topoisomerases impact drug specificity.
Specificity of protein–DNA interactions in hypersaline environment: structural studies on complexes of Halobacterium salinarum oxidative stress-dependent protein hsRosR
Authors: Kutnowski Nitzan , Shmulevich Fania , Davidov Geula , Shahar Anat , Bar-Zvi Dudy , Eichler Jerry , Zarivach Raz , Shaanan Boaz
Published: July 2019

Interactions between proteins and DNA are crucial for all biological systems. Many studies have shown the dependence of protein–DNA interactions on the surrounding salt concentration. How these interactions are maintained in the hypersaline environments that halophiles inhabit remains puzzling. Towards solving this enigma, we identified the DNA motif recognized by the Halobactrium salinarum ROS-dependent transcription factor (hsRosR), determined the structure of several hsRosR–DNA complexes and investigated the DNA-binding process under extreme high-salt conditions. The picture that emerges from this work contributes to our understanding of the principles underlying the interplay between electrostatic interactions and salt-mediated protein–DNA interactions in an ionic environment characterized by molar salt concentrations.
Parallel G-triplexes and G-hairpins as potential transitory ensembles in the folding of parallel-stranded DNA G-Quadruplexes
Authors: Stadlbauer Petr , Kührová Petra , Vicherek Lukáš , Banáš Pavel , Otyepka Michal , Trantírek Lukáš , Šponer Jiří
Published: July 2019

Guanine quadruplexes (G4s) are non-canonical nucleic acids structures common in important genomic regions. Parallel-stranded G4 folds are the most abundant, but their folding mechanism is not fully understood. Recent research highlighted that G4 DNA molecules fold via kinetic partitioning mechanism dominated by competition amongst diverse long-living G4 folds. The role of other intermediate species such as parallel G-triplexes and G-hairpins in the folding process has been a matter of debate. Here, we use standard and enhanced-sampling molecular dynamics simulations (total length of ∼0.9 ms) to study these potential folding intermediates. We suggest that parallel G-triplex per se is rather an unstable species that is in local equilibrium with a broad ensemble of triplex-like structures. The equilibrium is shifted to well-structured G-triplex by stacked aromatic ligand and to a lesser extent by flanking duplexes or nucleotides. Next, we study propeller loop formation in GGGAGGGAGGG, GGGAGGG and GGGTTAGGG sequences. We identify multiple folding pathways from different unfolded and misfolded structures leading towards an ensemble of intermediates called cross-like structures (cross-hairpins), thus providing atomistic level of description of the single-molecule folding events. In summary, the parallel G-triplex is a possible, but not mandatory short-living (transitory) intermediate in the folding of parallel-stranded G4.
Single-molecule detection of deoxyribonucleoside triphosphates in microdroplets
Authors: Breiner Boris , Johnson Kerr , Stolarek Magdalena , Silva Ana-Luisa , Negrea Aurel , Bell Neil M , Isaac Tom H , Dethlefsen Mark , Chana Jasmin , Ibbotson Lindsey A , Palmer Rebecca N , Bush James , Dunning Alexander J , Love David M , Pachoumi Olympia , Kelly Douglas J , Shibahara Aya , Wu Mei , Sosna Maciej , Dear Paul H , Tolle Fabian , Petrini Edoardo , Amasio Michele , Shelford Leigh R , Saavedra Monica S , Sheridan Eoin , Kuleshova Jekaterina , Podd Gareth J , Balmforth Barnaby W , Frayling Cameron A
Published: July 2019

A new approach to single-molecule DNA sequencing in which dNTPs, released by pyrophosphorolysis from the strand to be sequenced, are captured in microdroplets and read directly could have substantial advantages over current sequence-by-synthesis methods; however, there is no existing method sensitive enough to detect a single nucleotide in a microdroplet. We have developed a method for dNTP detection based on an enzymatic two-stage reaction which produces a robust fluorescent signal that is easy to detect and process. By taking advantage of the inherent specificity of DNA polymerases and ligases, coupled with volume restriction in microdroplets, this method allows us to simultaneously detect the presence of and distinguish between, the four natural dNTPs at the single-molecule level, with negligible cross-talk.
The medical necessity of advanced molecular testing in the diagnosis and treatment of brain tumor patients
Authors: Horbinski Craig , Ligon Keith L , Brastianos Priscilla , Huse Jason T , Venere Monica , Chang Susan , Buckner Jan , Cloughesy Timothy , Jenkins Robert B , Giannini Caterina , Stupp Roger , Nabors L Burt , Wen Patrick Y , Aldape Kenneth J , Lukas Rimas V , Galanis Evanthia , Eberhart Charles G , Brat Daniel J , Sarkaria Jann N
Published: July 2019

Accurate pathologic diagnoses and molecularly informed treatment decisions for a wide variety of cancers depend on robust clinical molecular testing that uses genomic, epigenomic, and transcriptomic-based tools. Nowhere is this more essential than in the workup of brain tumors, as emphasized by the incorporation of molecular criteria into the 2016 World Health Organization classification of central nervous system tumors and the updated official guidelines of the National Comprehensive Cancer Network. Despite the medical necessity of molecular testing in brain tumors, access to and utilization of molecular diagnostics is still highly variable across institutions, and a lack of reimbursement for such testing remains a significant obstacle. The objectives of this review are (i) to identify barriers to adoption of molecular testing in brain tumors, (ii) to describe the current molecular tools recommended for the clinical evaluation of brain tumors, and (iii) to summarize how molecular data are interpreted to guide clinical care, so as to improve understanding and justification for their coverage in the routine workup of adult and pediatric brain tumor cases.
Sovereignty
Authors: Heller Hermann
Published: July 2019

This 1927 work addresses the paradox of sovereignty, that is, how the sovereign can be both the highest authority and subject to law. Unlike Kelsen and Schmitt who seek to dissolve the paradox, this text sees the tensions that the paradox highlights as an essential part of a society ruled by law. Sovereignty, in the sense of national sovereignty, is often perceived in liberal democracies today as being under threat, or at least “in transition,” as power devolves from nation states to international bodies. This threat to national sovereignty is at the same time considered a threat to a different idea of sovereignty, popular sovereignty—the sovereignty of “the people”—as important decisions seem increasingly to be made by institutions outside of a country’s political system or by elite-dominated institutions within. This text was written in 1927 amidst the very similar tensions of the Weimar Republic. In an exploration of history, constitutional and political theory, and international law, it shows that democrats must defend a legal idea of sovereignty suitable for a pluralistic world.
Good Governance
Authors: Addink Henk
Published: July 2019

The pivotal aim of this book is to explain the creation, development, and impact of good governance from a conceptual, principal perspective and in the context of national administrative law. Three lines of reasoning have been worked out: developing the concept of good governance; specification of this concept by developing principles of good governance; and implementation of these principles of good governance on the national level. In this phase of further development of good governance, it is important to have a clear concept of good governance, presented in this book as the third cornerstone of a modern state, alongside the concepts of the rule of law and democracy. That is a rather new national administrative law perspective which is influenced by regional and international legal developments; thus, we can speak about good governance as a multilevel concept. But the question is: how is this concept of good governance further developed? Six principles of good governance (which in a narrower sense also qualify as principles of good administration) have been further specified in a systematic way, from a legal perspective. These are the principles of properness, transparency, participation, effectiveness, accountability, and human rights. Furthermore, the link has been made with integrity standards. The important developments of each of these principles are described on the national level in Europe, but also in countries outside Europe (such as Australia, Canada, and South Africa). This book gives a systematic comparison of the implementation of the principles of good governance between countries.
Comparative Company Law
Authors: Gerner-Beuerle Carsten , Schillig Michael Anderson
Published: July 2019

This book provides an exposition of company law from a comparative perspective. It analyses important policy issues in the area of company law, including the emergence and nature of the business corporation, EU company law, incorporation and corporate representation, agency problems in the firm, rights of stakeholders and shareholders, minority shareholder protection in corporate control transactions, legal capital, and piercing the corporate veil, as well as corporate insolvency and restructuring law. The book’s main focus is the law of public and private companies in the common law sense (the law of partnerships is referred to and taken into account as necessary). The book’s analysis encompasses the corporate laws of the US, the UK, Germany, and France, as well as the legislative measures adopted by the EU and the relevant case law of the Court of Justice of the EU. It includes edited and, where necessary, translated extracts from leading company case law. The cases are discussed and interpreted in the context of the national and European regulatory frameworks and in light of economic and legal theory, as well as legal history.
Between relevance and excellence? Research impact agenda and the production of policy knowledge
Authors: Bandola-Gill Justyna
Published: July 2019

The recent moves towards incentivising ‘impact’ within the research funding system pose a growing challenge to academic research practices, charged with producing both scientific, and social impact. This article explores this tension by drawing on interviews with sixty-one UK academics and policymakers involved in publicly-funded knowledge exchange initiatives. The experiences of the interviewed academics point to a functional separation of academic practices into three distinct types: producing traditional research, translating research, and producing policy-oriented research. These three types of practices differ in terms of both the epistemic qualities of the produced knowledge and its legitimacy as valid academic work. Overall, the article argues that the relationship between relevance and excellence of research within the impact agenda is characterised by simultaneous contradiction and co-dependence, leading to hybridisation of academic knowledge production and expansion of the boundaries of policy expertise into the traditionally-academic spaces.
Household Debt and Children’s Risk of Food Insecurity
Authors: Brewer Mackenzie
Published: July 2019

In the United States, almost one in six households with children cannot access adequate food for a healthy and active lifestyle. Although food insecurity disproportionately affects lower-income households, it remains unclear why some lower-income families are more vulnerable to food insecurity than others. Household unsecured debt, such as debt incurred from credit cards and medical bills, may be an unexplored financial constraint associated with food insecurity. Using data from the 2014 Child Development Supplement (CDS) of the Panel Study of Income Dynamics (PSID), I assess whether unsecured debt, by amount and type of debt, is associated with food insecurity among lower-income households with children (N=1,319). Results indicate that medical debt increases odds of household food insecurity even after accounting for key sociodemographic and economic risk factors, while no relationship exists between other forms of unsecured debt and food insecurity. Moreover, although liquid assets decrease the risk of household food insecurity and attenuate the harmful effects associated with unpaid medical bills, few households have enough liquid assets to mitigate the risks associated with medical debt. Efforts to prevent medical debt may be essential for eliminating food insecurity among lower-income households with children.
Biochemical and Functional Analysis of Cyanobacterium Geitlerinema sp. LPS on Human Monocytes
Authors: Swanson-Mungerson Michelle , Williams Philip G , Gurr Joshua R , Incrocci Ryan , Subramaniam Vijay , Radowska Kinga , Hall Mary L , Mayer Alejandro M S
Published: July 2019

Cyanobacterial blooms are an increasing source of environmental toxins that affect both human and animals. After ingestion of cyanobacteria, such as Geitlerinema sp., toxins and lipopolysaccharide (LPS) from this organism induce fever, gastrointestinal illness, and even death. However, little is known regarding the effects of cyanobacterial LPS on human monocytes after exposure to LPS upon ingestion. Based on our previous data using Geitlerinema sp. LPS (which was previously named Oscillatoria sp., a genus belonging to the same order as Geitlerinema), we hypothesized that Geitlerinema sp. LPS would activate human monocytes to proliferate, phagocytose particles, and produce cytokines that are critical for promoting proinflammatory responses in the gut. Our data demonstrate that Geitlerinema sp. LPS induced monocyte proliferation and TNF-α, IL-1, and IL-6 production at high concentrations. In contrast, Geitlerinema sp. LPS is equally capable of inducing monocyte-mediated phagocytosis of FITC-latex beads when compared with Escherichia coli LPS, which was used as a positive control for our experiments. In order to understand the mechanism responsible for the difference in efficacy between Geitlerinema sp. LPS and E. coli LPS, we performed biochemical analysis and identified that Geitlerinema sp. LPS was composed of significantly different sugars and fatty acid side chains in comparison to E. coli LPS. The lipid A portion of Geitlerinema sp. LPS contained longer fatty acid side chains, such as C15:0, C16:0, and C18:0, instead of C12:0 found in E. coli LPS which may explain the decreased efficacy and toxicity of Geitlerinema sp. LPS in comparison to E. coli LPS.
New Drugs 2019, part 3
Authors: Hussar Daniel A.
Published: July 2019

This article reviews seven drugs recently approved by the FDA, including indications, precautions, adverse reactions, and nursing considerations.
Insomnia Increases Symptom Severity and Health Care Utilization in Patients With Fibromyalgia
Authors: Huang Chun-Jen , Huang Chin-Liang , Fan Yen-Chun , Chen Ting-Yu , Tsai Pei-Shan
Published: July 2019

Objective:

This study aimed to determine whether comorbid insomnia is associated with increased use of fibromyalgia-related medications and health resources in fibromyalgia (FM) patients.

Materials and Methods:

We analyzed data retrieved from the Longitudinal Health Insurance Database 2010, which contains claims data of 1 million beneficiaries randomly selected from Taiwan’s National Health Insurance program. Patients treated for FM (n=17,920) on 2 separate visits between 2000 and 2001 were selected and subsequently divided into 2 groups: patients with and without comorbid insomnia (n=5466 and 12,454, respectively). Insomnia was identified through diagnosis on 2 separate visits after the index FM date. FM-related pharmacotherapies and ambulatory care visits were tracked from the index date to the end of 2013.

Results:

Insomnia was associated with increased likelihood of future use of antidepressants (adjusted odds ratio [OR]=3.84, P<0.001), gabapentin (adjusted OR=1.67, P<0.001), pregabalin (adjusted OR=1.79, P=0.046), muscle relaxants (adjusted OR=3.05, P<0.001), and opioids and tramadol (adjusted OR=1.59, P<0.001) among FM patients compared with FM patients without insomnia. In addition, a diagnosis of insomnia was associated with an increased frequency of visits to ambulatory care services for both FM (β=1.79; 95% confidence interval, 1.57-2.02; P<0.001) and other conditions (β=108.51; 95% confidence interval, 103.14-113.89; P<0.001).

Discussion:

This study demonstrates the substantial burden of comorbid insomnia in patients with FM.