bluuebunny/crossref_metadata_2025 huggingface dataset:
Morbidity and Mortality Following Total Hip Replacement in Dogs
Authors: Israel Sarah , Liska William
Published: April 2018

Objective The objective of this study was to determine morbidity and mortality rates in dogs that had undergone a total hip replacement surgery with implantation of either a cemented or a cementless prosthesis (BioMedtrix LLC, Whippany, NJ).

Methods The survival time after surgery, the date of death and the cause of death were collated from an ongoing registry maintained on consecutive total hip replacement procedures by a single surgeon.

Results A review of the 1,864 dogs entered in the total hip replacement registry revealed 642 in which the date of death and cause of death were known. The mean life span of the dogs in this study was 11.3 years, with the longest being 17.1 years. The mean survival after total hip replacement was 4.66 years, with the longest being 16.1 years. Multiorgan system failure was more common than any single organ system failure. The most common pathophysiological process leading to death was neoplasia.

Clinical Significance Morbidity and mortality rates are helpful for surgeons to compare outcomes and to inform animal owners about anaesthesia and procedural risks when contemplating this surgery. This information can be used for a better understanding of expectations for a dog's health after total hip replacement surgery.
Surgical Site Infection Rate after Hemilaminectomy and Laminectomy in Dogs without Perioperative Antibiotic Therapy
Authors: Schmökel Hugo , Dyall Barbara
Published: April 2018

Objective The aim of this study was to retrospectively review the surgical site infection (SSI) rate in dogs undergoing laminectomies without perioperative antibiotics, and compare those data with the expected infection rate for clean surgical wounds in dogs undergoing similar procedures.

Methods This was a retrospective single-centre study composed of dogs that underwent hemilaminectomies or laminectomies for thoracolumbar disc herniation or lumbosacral disease during a 2-year period (during 2015 and 2016). All incisional complications within 30 days were recorded and divided into superficial, deep or organ/space infections. Those dogs that received perioperative or postoperative antibiotics due to non-related comorbidities and those with incomplete medical records during the study period were excluded.

Results Of 221 consecutive hemilaminectomy and laminectomy procedures, 154 were included in this research study. One superficial wound infection was recorded and treated with antimicrobials. Overall, the SSI rate was 0.6%, while the expected SSI rate in clean operative wounds in dogs and cats is 2.0 to 4.8%. The SSI rate in human spinal surgery is 0.7 to 4.3%.

Clinical Significance Considering the low incidence of SSI in our study group, the routine use of perioperative antibiotic prophylaxis in dogs undergoing laminectomy procedures should be reconsidered to help address the global problem of bacterial resistance.
Tissue Factor Coagulant Activity is Regulated by the Plasma Membrane Microenvironment
Authors: Yu Yuanjie , Böing Anita , Hau Chi , Hajji Najat , Ruf Wolfram , Sturk Auguste , Nieuwland Rienk
Published: April 2018

Background Tissue factor (TF) can be present in a non-coagulant and coagulant form. Whether the coagulant activity is affected by the plasma membrane microenvironment is unexplored.

Objective This article studies the presence and coagulant activity of human TF in plasma membrane micro-domains.

Methods Plasma membranes were isolated from human MIA PaCa2 cells, MDA-MB-231 cells and human vascular smooth muscle cells by Percoll gradient ultracentrifugation after cell disruption. Plasma membranes were fractionated by OptiPrep gradient ultracentrifugation, and the presence of TF, flotillin, caveolin, clathrin, protein disulphide isomerase (PDI), TF pathway inhibitor (TFPI) and phosphatidylserine (PS) were determined.

Results Plasma membranes contain two detergent-resistant membrane (DRM) compartments differing in density and biochemical composition. High-density DRMs (DRM-H) have a density (ρ) of 1.15 to 1.20 g/mL and contain clathrin, whereas low-density DRMs (DRM-L) have a density between 1.09 and 1.13 g/mL and do not contain clathrin. Both DRMs contain TF, flotillin and caveolin. PDI is detectable in DRM-H, TFPI is not detectable in either DMR-H or DRM-L and PS is detectable in DRM-L. The DRM-H-associated TF (> 95% of the TF antigen) lacks detectable coagulant activity, whereas the DRM-L-associated TF triggers coagulation. This coagulant activity is inhibited by lactadherin and thus PS-dependent, but seemed insensitive to 16F16, an inhibitor of PDI.

Conclusion Non-coagulant and coagulant TF are present within different types of DRMs in the plasma membrane, and the composition of these DRMs may affect the TF coagulant activity.
Duration of Spontaneous Active Labor and Perinatal Outcomes Using Contemporary Labor Curves
Authors: Hoppe Kara , Schiff Melissa , Benedetti Thomas , Delaney Shani
Published: April 2018

Objective Evaluate the association between spontaneous active labor duration utilizing contemporary labor curves and risk of adverse outcomes.

Materials and Methods This is a retrospective cohort study from January 2012 to January 2015. Subjects were nulliparous, 18 to 44 years, with a cephalic, singleton ≥37 weeks in spontaneous labor. Subjects were placed into three subgroups, defined by active labor duration from 6 to 10 cm as less than the median, the median-95th, and >95th percentile based on contemporary labor curves published by Zhang et al. We evaluated the association between subgroups and cesarean delivery, chorioamnionitis, estimated blood loss, Apgar score < 7 at 5 minutes, and neonatal intensive care unit admission using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI).

Results Six-hundred forty two women met the inclusion criteria. Compared with women whose active labor was less than the median, the risk of cesarean was higher in the median-95th percentile ([adjusted OR, aOR] 3.1, 95% CI 1.8–5.5) and the >95th percentile ([aOR] 6.8, 95% CI 3.9–11.7) subgroups. There was an increased odds of chorioamnionitis in the median-95th percentile subgroup ([aOR] 2.5, 95% CI 1.1–5.9).

Conclusion Chorioamnionitis and cesarean delivery increased significantly as labor duration exceeded the median. This study provides a better understanding regarding the potential risk of cesarean and chorioamnionitis using contemporary labor curves.
Neuer Therapieansatz bei fragilen Patienten
Authors: Arnheim Katharina
Published: April 2018

Bei älteren Patienten mit Philadelphia-Chromosom-positiver akuter lymphatischer Leukämie (Ph+ALL) kann durch die Kombinationstherapie mit Ponatinib plus Steroid eine hohe Rate kompletter hämatologischer Remissionen (CHR) von über 90 % erreicht werden. Zudem führt diese Therapie zu einer raschen Eradikation von BCR-ABL-Transkripten und einer langfristig hohen Rate kompletter molekularer Remissionen (CMR).
Daratumumab bewährt sich in der Rezidivtherapie
Authors: Arnheim Katharina
Published: April 2018

Die aktualisierte Auswertung der Phase-III-Studie POLLUX untermauert den anhalten-den Benefit von Daratumumab zusätzlich zu Lenalidomid/Dexamethason (Rd) bei Patientien mit rezidiviertem oder refraktärem MM (rrMM): Durch die Daratumumab-Addition werden anhaltend tiefe Remissionen und eine rasche Eradikation der minimalen Resterkrankung (MRD) erreicht, erläuterte Prof. Meletios A. Dimopoulos, Athen/Griechenland, auf der ASH-Jahrestagung.
Ion acoustic wave assisted laser beat wave terahertz generation in a plasma channel
Authors: Tyagi Yachna , Tripathi Deepak , Walia Keshav , Garg Deepak
Published: April 2018

Resonant excitation of terahertz (THz) radiation by non-linear mixing of two lasers in the presence of an electrostatic wave is investigated. The electrostatic wave assists in k matching and contributes to non-linear coupling. In this plasma channel, the electron plasma frequency becomes minimum on the axis. The beat frequency ponderomotive force imparts an oscillating velocity to the electrons. In the presence of an ion-acoustic wave, density perturbation due to the ion-acoustic wave couples with the oscillating velocity of the electrons and give rise to non-linear current that gives rise to an ion-acoustic wave frequency assisted THz radiation field. The normalized field amplitude of ion acoustic wave assisted THz varies inversely for ω/ωp. The field amplitude of ion acoustic wave assisted THz decreases as ω/ωp increases.
Magnetic resonance of the interphase boundary in ferromagnetic films with modulated anisotropy under orientational phase transition conditions
Authors: Dzhezherya Yu. I. , Azarkh D. P. , Klimuk E. S. , Khrebtov A. O.
Published: April 2018

The Landau-Lifshitz equations for the dynamics of magnetization are used to describe the formation of an interphase boundary with spatial modulation of the anisotropy constant over the thickness of the film. The Lagrange equations for the collective variables of the magnetization field are derived and used to study the dynamics of the oscillations of the interphase boundary in a variable magnetic field. It is shown that under certain conditions the development of the resonance in the interphase boundary is extremely sensitive to the direction and magnitude of the external magnetic field. Therefore, it is natural to use this system as a highly directional magnetic field detector.
Local magnetic anisotropy of rare-earth elements in the iron-containing oxypnictides RFeAsO (R = Ce, Nd, Sm)
Authors: Gornostaeva O. V. , Lamonova K. V. , Orel S. M. , Pashkevich Yu. G.
Published: April 2018

This is a detailed study of the local magnetic anisotropy of rare-earth ions in RFeAsO (R = Ce, Nd, Sm) compounds. A modified crystal field theory method is used to calculate the energy levels of the rare-earth ions and the g-factors. The temperature dependences of the components of the magnetic susceptibility are constructed, along with the fourth order anisotropy constants. A method is proposed for determining the “easy” direction of the magnetic moment. The calculations show that the “easy” directions of the magnetic moments of Ce3+ and Nd3+ ions in the orthophase are the [100] and [010] axes, respectively, and in the tetraphase the [110] axis is the “easy” axis for both ions. In the case of Sm3+ the “easy” direction is the [001] axis regardless of the symmetry of the phase.
Integer channels in nonuniform non-equilibrium 2D systems
Authors: Shikin V.
Published: April 2018

We discuss the non-equilibrium properties of integer channels in nonuniform 2D electron (hole) systems in the presence of a strong magnetic field. The results are applied to a qualitative explanation of the Corbino disk current-voltage characteristics (IVC) in the quantum Hall effect (QHE) regime. Special consideration is paid to the so-called “QHE breakdown” effect, which is readily observed in both the Hall bar and Corbino geometries of the tested cells. The QHE breakdown is especially evident in the Corbino samples, allowing for a more in-depth study of these effects.
Features of light absorption by a low-dimensional disordered molecular aggregate
Authors: Ropakova I. Yu. , Zvyagin A. A.
Published: April 2018

Absorption of light by the exciton system of quantum molecular low-dimensional complexes (aggregates) is studied theoretically. It is shown that in the ground state, a rather low degree of disorder of H-aggregate impurities in the chain of J-aggregates causes a significant lowering of the J-band absorption intensity (along with the appearance of the H-band). A further increase in the degree of disorder of the impurities does not lead to a substantial rearrangement of the absorption spectrum of the system. There is no absorption in the case of the complete disorder.
Hormone-induced spawning of the critically endangered northern corroboree frog Pseudophryne pengilleyi
Authors: Silla Aimee J. , McFadden Michael , Byrne Phillip G.
Published: April 2018

Fundamental knowledge of the optimal hormone concentrations required to stimulate amplexus and spawning in breeding pairs of amphibians is currently lacking, hindering our understanding of the proximate mechanisms underpinning mating behaviour. The present study investigated the effects of: (1) the dose of a gonadotropin-releasing hormone analogue (GnRH-a) administered; (2) male–female hormone administration interval; and (3) topical application of GnRH-a, on spawning success in the northern corroboree frog. Administration of GnRH-a at doses of 0.5, 1.0 and 2.0 μg g−1 were highly successful, with a significantly greater proportion of hormone-treated pairs ovipositing (89–100%) compared with the 0 μg g−1 treatment (22%). Of the hormone-treated pairs, those receiving 0.5 μg g−1 GnRH-a exhibited the highest fertilisation success (61%). Administration of GnRH-a to males and females simultaneously (0 h) was more effective than injecting males either 48 or 24 h before the injection of females. Overall, administration of GnRH-a was highly successful at inducing spawning in northern corroboree frogs. For the first time, we also effectively induced spawning following the topical application of GnRH-a to the ventral pelvic region. Topical application of GnRH-a eliminates the need for specialised training in amphibian injection, and will allow assisted reproductive technologies to be adopted by a greater number of captive facilities globally.
A curcumin-diglutaric acid conjugated prodrug with improved water solubility and antinociceptive properties compared to curcumin
Authors: Muangnoi Chawanphat , Jithavech Ponsiree , Ratnatilaka Na Bhuket Pahweenvaj , Supasena Wiwat , Wichitnithad Wisut , Towiwat Pasarapa , Niwattisaiwong Nuansri , Haworth Ian S , Rojsitthisak Pornchai
Published: April 2018

In this work, a curcumin-diglutaric acid (CurDG) prodrug was synthesized by conjugation of curcumin with glutaric acid via an ester linkage. The water solubility, partition coefficient, release characteristics, and antinociceptive activity of CurDG were compared to those of curcumin. The aqueous solubility of CurDG (7.48 μg/mL) is significantly greater than that of curcumin (0.068 μg/mL). A study in human plasma showed that the CurDG completely releases curcumin within 2 h, suggesting the ability of CurDG to serve as a prodrug of curcumin. A hot plate test in mice showed the highest antinociceptive effect dose of curcumin at 200 mg/kg p.o., whereas CurDG showed the same effect at an effective dose of 100 mg/kg p.o., indicating that CurDG significantly enhanced the antinociceptive effect compared to curcumin. The enhanced antinociceptive effect of CurDG may be due to improved water solubility and increased oral bioavailability compared to curcumin.
Johan Auwerx: Sowing the seeds of translational research
Authors: Infarinato Nicole
Published: April 2018

Auwerx studies the signaling networks that underlie mitochondrial function and metabolism.
Improving draft genome contiguity with reference-derived in silico mate-pair libraries
Authors: Grau José Horacio , Hackl Thomas , Koepfli Klaus-Peter , Hofreiter Michael
Published: April 2018

Background

Contiguous genome assemblies are a highly valued biological resource because of the higher number of completely annotated genes and genomic elements that are usable compared to fragmented draft genomes. Nonetheless, contiguity is difficult to obtain if only low coverage data and/or only distantly related reference genome assemblies are available.

Findings

In order to improve genome contiguity, we have developed Cross-Species Scaffolding—a new pipeline that imports long-range distance information directly into the de novo assembly process by constructing mate-pair libraries in silico.

Conclusions

We show how genome assembly metrics and gene prediction dramatically improve with our pipeline by assembling two primate genomes solely based on ~30x coverage of shotgun sequencing data.
The host galaxy of the γ-ray-emitting narrow-line Seyfert 1 galaxy PKS 1502+036
Authors: D’Ammando F , Acosta-Pulido J A , Capetti A , Baldi R D , Orienti M , Raiteri C M , Ramos Almeida C
Published: April 2018

The detection of γ-ray emission from narrow-line Seyfert 1 galaxies (NLSy1) has challenged the idea that large black hole (BH) masses (≥108 M⊙) are needed to launch relativistic jets. We present near-infrared imaging data of the γ-ray-emitting NLSy1 PKS 1502+036 obtained with the Very Large Telescope. Its surface brightness profile, extending to ∼20 kpc, is well described by the combination of a nuclear component and a bulge with a Sérsic index n = 3.5, which is indicative of an elliptical galaxy. A circumnuclear structure observed near PKS 1502+036 may be the result of galaxy interactions. A BH mass of ∼7 × 108 M⊙ has been estimated by the bulge luminosity. The presence of an additional faint disc component cannot be ruled out with the present data, but this would reduce the BH mass estimate by only ∼30 per cent. These results, together with analogous findings obtained for FBQS J1644+2619, indicate that the relativistic jets in γ-ray-emitting NLSy1 are likely produced by massive black holes at the centre of elliptical galaxies.
Generalizability of Competency Assessment Scores Across and Within Clerkships: How Students, Assessors, and Clerkships Matter
Authors: Zaidi Nikki L. Bibler , Kreiter Clarence D. , Castaneda Peris R. , Schiller Jocelyn H. , Yang Jun , Grum Cyril M. , Hammoud Maya M. , Gruppen Larry D. , Santen Sally A.
Published: April 2018

Purpose

Many factors influence the reliable assessment of medical students’ competencies in the clerkships. The purpose of this study was to determine how many clerkship competency assessment scores were necessary to achieve an acceptable threshold of reliability.

Method

Clerkship student assessment data were collected during the 2015–2016 academic year as part of the medical school assessment program at the University of Michigan Medical School. Faculty and residents assigned competency assessment scores for third-year core clerkship students. Generalizability (G) and decision (D) studies were conducted using balanced, stratified, and random samples to examine the extent to which overall assessment scores could reliably differentiate between students’ competency levels both within and across clerkships.

Results

In the across-clerkship model, the residual error accounted for the largest proportion of variance (75%), whereas the variance attributed to the student and student–clerkship effects was much smaller (7% and 10.1%, respectively). D studies indicated that generalizability estimates for eight assessors within a clerkship varied across clerkships (G coefficients range = 0.000–0.795). Within clerkships, the number of assessors needed for optimal reliability varied from 4 to 17.

Conclusions

Minimal reliability was found in competency assessment scores for half of clerkships. The variability in reliability estimates across clerkships may be attributable to differences in scoring processes and assessor training. Other medical schools face similar variation in assessments of clerkship students; therefore, the authors hope this study will serve as a model for other institutions that wish to examine the reliability of their clerkship assessment scores.
Systematic conservation planning for intraspecific genetic diversity
Authors: Paz-Vinas Ivan , Loot Géraldine , Hermoso Virgilio , Veyssière Charlotte , Poulet Nicolas , Grenouillet Gaël , Blanchet Simon
Published: April 2018

Intraspecific diversity informs the demographic and evolutionary histories of populations, and should be a main conservation target. Although approaches exist for identifying relevant biological conservation units, attempts to identify priority conservation areas for intraspecific diversity are scarce, especially within a multi-specific framework. We used neutral molecular data on six European freshwater fish species (Squalius cephalus,Phoxinus phoxinus, Barbatula barbatula,Gobio occitaniae,Leuciscus burdigalensisandParachondrostoma toxostoma) sampled at the riverscape scale (i.e. the Garonne-Dordogne river basin, France) to determine hot- and coldspots of genetic diversity, and to identify priority conservation areas using a systematic conservation planning approach. We demonstrate that systematic conservation planning is efficient for identifying priority areas representing a predefined part of the total genetic diversity of a whole landscape. With the exception of private allelic richness (PA), classical genetic diversity indices (allelic richness, genetic uniqueness) were poor predictors for identifying priority areas. Moreover, we identified weak surrogacies among conservation solutions found for each species, implying that conservation solutions are highly species-specific. Nonetheless, we showed that priority areas identified using intraspecific genetic data from multiple species provide more effective conservation solutions than areas identified for single species or on the basis of traditional taxonomic criteria.
CNV Neurons Are Rare in Aged Human Neocortex
Authors: Chronister William D. , Wierman Margaret B. , Burbulis Ian E. , Wolpert Matthew J. , Haakenson Mark F. , Kleinman Joel E. , Hyde Thomas , Weinberger Daniel R. , Bekiranov Stefan , McConnell Michael J.
Published: April 2018

Megabase-scale somatic copy number variants (CNVs) alter allelic diversity in a subset of human neocortical neurons. Reported frequencies of CNV neurons range from ∼5% of neurons in some individuals to greater than 30% in other individuals. Genome-wide and familial studies implicitly assume a constant brain genome when assessing the genetic risk architecture of neurological disease, thus it is critical to determine whether divergent reports of CNV neuron frequency reflect normal individual variation or technical differences between approaches. We generated a new dataset of over 800 human neurons from 5 neurotypical individuals and developed a computational approach that measures single cell library quality based on Bayesian Information Criterion and identifies integer-like variant segments from population-level statistics. A brain CNV atlas was assembled using our new dataset and published data from 10 additional neurotypical individuals. This atlas reveals that the frequency of neocortical CNV neurons varies widely among individuals, but that this variability is not readily accounted for by tissue quality or CNV detection approach. Rather, the age of the individual is anti-correlated with CNV neuron frequency. Fewer CNV neurons are observed in aged individuals than young individuals.
Motor cortical inactivation reduces the gain of kinematic primitives in mice performing a hold-still center-out reach task
Authors: Bollu Tejapratap , Whitehead Samuel C. , Prasad Nikil , Walker Jackson , Shyamkumar Nitin , Subramaniam Raghav , Kardon Brian , Cohen Itai , Goldberg Jesse Heymann
Published: April 2018

Motor sequences are constructed from primitives, hypothesized building blocks of movement, but mechanisms of primitive generation remain unclear. Using automated homecage training and a novel forelimb sensor, we trained freely-moving mice to initiate forelimb sequences with clearly resolved submillimeter-scale micromovements followed by millimeter-scale reaches to learned spatial targets. Hundreds of thousands of trajectories were decomposed into millions of kinematic primitives, while closed-loop photoinhibition was used to test roles of motor cortical areas. Inactivation of contralateral motor cortex reduced primitive peak speed but, surprisingly, did not substantially affect primitive direction, initiation, termination, or complexity, resulting in isomorphic, spatially contracted trajectories that undershot targets. Our findings demonstrate separable loss of a single kinematic parameter, speed, and identify conditions where loss of cortical drive reduces the gain of motor primitives but does not affect their generation, timing or direction. The combination of high precision forelimb sensing with automated training and neural manipulation provides a system for studying how motor sequences are constructed from elemental building blocks.
Genomic SEM Provides Insights into the Multivariate Genetic Architecture of Complex Traits
Authors: Grotzinger Andrew D. , Rhemtulla Mijke , de Vlaming Ronald , Ritchie Stuart J. , Mallard Travis T. , Hill W. David , Ip Hill F. , McIntosh Andrew M. , Deary Ian J. , Koellinger Philipp D. , Harden K. Paige , Nivard Michel G. , Tucker-Drob Elliot M.
Published: April 2018

Methods for using GWAS to estimate genetic correlations between pairwise combinations of traits have produced “atlases” of genetic architecture. Genetic atlases reveal pervasive pleiotropy, and genome-wide significant loci are often shared across different phenotypes. We introduce genomic structural equation modeling (Genomic SEM), a multivariate method for analyzing the joint genetic architectures of complex traits. Using formal methods for modeling covariance structure, Genomic SEM synthesizes genetic correlations and SNP-heritabilities inferred from GWAS summary statistics of individual traits from samples with varying and unknown degrees of overlap. Genomic SEM can be used to identify variants with effects on general dimensions of cross-trait liability, boost power for discovery, and calculate more predictive polygenic scores. Finally, Genomic SEM can be used to identify loci that cause divergence between traits, aiding the search for what uniquely differentiates highly correlated phenotypes. We demonstrate several applications of Genomic SEM, including a joint analysis of GWAS summary statistics from five genetically correlated psychiatric traits. We identify 27 independent SNPs not previously identified in the univariate GWASs, 5 of which have been reported in other published GWASs of the included traits. Polygenic scores derived from Genomic SEM consistently outperform polygenic scores derived from GWASs of the individual traits. Genomic SEM is flexible, open ended, and allows for continuous innovations in how multivariate genetic architecture is modeled.
Intratumoral MAPK and PI3K signaling pathway heterogeneity in glioblastoma tissue correlates with selective CREB signaling and specific functional gene signatures
Authors: Daniel Paul M. , Filiz Gulay , Tymms Martin J. , Ramsay Robert G. , Kaye Andrew H. , Stylli Stanley S. , Mantamadiotis Theo
Published: April 2018

Limitations in discovering useful tumor biomarkers and drug targets is not only due to patient-to-patient differences but also due to intratumoral heterogeneity. Heterogeneity arises due to the genetic and epigenetic variation of tumor cells in response to microenvironmental interactions and cytotoxic therapy. We explored specific signaling pathway activation in glioblastoma (GBM) by investigating the intratumoral activation of the MAPK and PI3K pathways. We present data demonstrating a striking preponderance for mutual exclusivity of MAPK and PI3K activation in GBM tissue, where MAPK activation correlates with proliferation and transcription factor CREB activation and PI3K activation correlates with CD44 expression. Bioinformatic analysis of signaling and CREB-regulated target genes supports the immunohistochemical data, showing that the MAPK-CREB activation correlates with proliferative regions. In-silico analysis suggests that MAPK-CREB signaling activates a pro-inflammatory molecular signature and correlates with a mesenchymal GBM subtype profile, while PI3K-CREB activation correlates with the proneural GBM subtype and a tumor cell invasive gene signature. Overall, the data suggests the existence of intratumoral subtype heterogeneity in GBM and that using combinations of both MAPK and PI3K drug inhibitors is necessary for effective targeted therapy.
Determining the Quantitative Principles of T Cell Response to Antigenic Disparity: The Case of Stem Cell Transplant Donor-Recipient Exome Wide Mismatching and HLA Bound Alloreactive Peptides
Authors: Salman Ali , Koparde Vishal , Hall Charles , Jameson-Lee Max , Roberts Catherine , Serrano Myrna , AbdulRazzaq Badar , Manjili Masoud , Wijesinghe Dayanjan , Hashmi Shahrukh , Buck Greg , Qayyum Rehan , Neale Michael , Reed Jason , Toor Amir
Published: April 2018

Alloreactivity compromising clinical outcomes in stem cell transplantation is observed despite HLA matching of donors and recipients. This has its origin in the variation between the exomes of the two, which provides the basis for minor histocompatibility antigens (mHA). The mHA presented on the HLA class I and II molecules and the ensuing T cell response to these antigens results in graft versus host disease. In this paper, results of a whole exome sequencing study are presented, with resulting alloreactive polymorphic peptides and their HLA class I and HLA class II (DRB1) binding affinity quantified. Large libraries of potentially alloreactive recipient peptides binding both sets of molecules were identified, with HLA-DRB1 presenting an order of magnitude greater number of peptides. These results are used to develop a quantitative framework to understand the immunobiology of transplantation. A tensor-based approach is used to derive the equations needed to determine the alloreactive donor T cell response from the mHA-HLA binding affinity and protein expression data. This approach may be used in future studies to simulate the magnitude of expected donor T cell response and risk for alloreactive complications in HLA matched or mismatched hematopoietic cell and solid organ transplantation.
Interference hypothesis for recombination suppression in chromosomal inversion heterozygotes: A formal genetics analysis inDrosophila melanogaster
Authors: Koury Spencer A.
Published: April 2018

Suppressed recombination in chromosomal inversion heterozygotes is a well-known but poorly understood phenomenon. Recombination suppression is the result of at least four different regional effects of inversion heterozygosity; surprisingly, this includes areas outside inversions where there are no barriers to normal pairing, synapsis, double strand break formation, or recovery of crossover products. The interference hypothesis of recombination suppression proposes heterozygous inversion breakpoints possess chiasma-like properties such that recombination suppression extends from breakpoints in a process analogous to crossover interference. This hypothesis is qualitatively consistent with chromosome-wide patterns of recombination suppression, unifying the various regional effects under a single mechanism. The present study generates quantitative predictions for this hypothesis using a probabilistic model of crossover interference as a stationary renewal point process with gamma-distributed interarrival distances. These predictions were tested with formal genetic data (>40,000 meioses) on crossing-over in intervals external and adjacent to four cosmopolitan inversions ofDrosophila melanogaster. The decay of recombination suppression differs for each of the four cosmopolitan inversions, with a strong dependence on proximity to the centromere. Counterintuitively, greater than expected recombination was observed in centromeric regions for the most proximally placed inversions. Structural features of chromosomes are discussed as potentially confounding variables in modelling recombination suppression. The true form of the decay function is not currently known and will require high-resolution mapping of rare crossover events in regions immediately adjacent to inversion breakpoints. A simple extension of the present experimental system can be conducted as a genetic screen for those rare crossover events.
Precision in a rush: trade-offs between reproducibility and steepness of the hunchback expression pattern
Authors: Tran Huy , Desponds Jonathan , Perez Romero Carmina Angelica , Coppey Mathieu , Fradin Cecile , Dostatni Nathalie , Walczak Aleksandra M.
Published: April 2018

Fly development amazes us by the precision and reproducibility of gene expression, especially since the initial expression patterns are established during very short nuclear cycles. Recent live imaging ofhunchbackpromoter dynamics shows a stable steep binary expression pattern established within the three minute interphase of nuclear cycle 11. Considering expression models of different complexity, we explore the trade-o between the ability of a regulatory system to produce a steep boundary and minimize expression variability between different nuclei. We show how a limited readout time imposed by short developmental cycles affects the gene’s ability to read positional information along the embryo’s anterior posterior axis and express reliably. Comparing our theoretical results to real-time monitoring of thehunchbacktranscription dynamics in live flies, we discuss possible regulatory strategies, suggesting an important role for additional binding sites, gradients or non-equilibrium binding and modified transcription factor search strategies.
Introduced populations of ragweed show as much evolutionary potential as native populations
Authors: McGoey Brechann V. , Stinchcombe John R.
Published: April 2018

Invasive species are a global economic and ecological problem. They also offer an opportunity to understand evolutionary processes in a colonizing context. The impacts of evolutionary factors, such as genetic variation, on the invasion process are increasingly appreciated but there remain gaps in the empirical literature. The adaptive potential of populations can be quantified using genetic variance-covariance matrices(G), which encapsulate the heritable genetic variance in a population. Here, we use a multivariate, Bayesian approach to assess the adaptive potential of introduced populations of ragweed,Ambrosia artemisiifolia, a serious allergen and agricultural weed. We compared several aspects of genetic architecture and the structure of G matrices between three native and three introduced populations, based on data collected in the field in a common garden experiment. We find moderate differences in the quantitative genetic architecture among populations, but we do not find that introduced populations suffer from a limited adaptive potential compared to native populations. Ragweed has an annual life history, is an obligate outcrosser, and produces billions of seeds and pollen grains per. These characteristics, combined with the significant additive genetic variance documented here, suggest ragweed will be able to respond quickly to selection pressures in both its native and introduced ranges.
LCA robustly reveals subtle diversity in large-scale single-cell RNA-seq data
Authors: Cheng Changde , Easton John , Rosencrance Celeste , Li Yan , Ju Bensheng , Williams Justin , Mulder Heather L , Chen Wenan , Chen Xiang
Published: April 2018

Single-cell RNA sequencing has emerged as a powerful tool for characterizing the cell-to-cell variation and dynamics. We present Latent Cellular Analysis (LCA), a machine learning– based analytical pipeline that features a dual-space model search with inference of latent cellular states, control of technical variations, cosine similarity measurement, and spectral clustering. LCA has proved to be robust, accurate, scalable, and powerful in revealing subtle diversity in cell populations.
Sub-2 Å Ewald Curvature Corrected Single-Particle Cryo-EM
Authors: Tan Yong Zi , Aiyer Sriram , Mietzsch Mario , Hull Joshua A. , McKenna Robert , Grieger Joshua , Samulski R. Jude , Baker Timothy S. , Agbandje-McKenna Mavis , Lyumkis Dmitry
Published: April 2018

Single-particle cryogenic electron microscopy (cryo-EM) provides a powerful methodology for structural biologists, but the resolutions typically attained with experimentally determined structures have lagged behind microscope capabilities. Here, we have exploited several technical solutions to improve resolution, including sub-Angstrom pixelation, per-particle CTF refinement, and most notably a correction for Ewald sphere curvature. The application of these methods on micrographs recorded on a base model Titan Krios enabled structure determination at ∼1.86-Å resolution of an adeno-associated virus serotype 2 variant (AAV2), an important gene-delivery vehicle.
A double-edged sword: supramolecular complexes of triazavirine display multicenter binding effects which influence aggregate formation
Authors: Zabrodskaya Yana A , Shvetsov Alexey V , Tsvetkov Vladimir B , Egorov Vladimir V
Published: April 2018

Triazavirine (TZV), a small molecule with a broad spectrum of antiviral activity, shows a tendency to induce the aggregation of melittin (MLT), a cationic membrane-disrupting peptide from the poison of the European bee. In MLT:TZV mixtures, high molecular weight precipitates form once a critical MLT:TZV ratio has been exceeded. Molecular dynamics simulation of MLT-TZV interactions, followed by molecular docking, led us to the hypothesis of multicenter binding of TZV supramolecular complexes to MLT.
Spatial distribution of private gene mutations in clear cell renal cell carcinoma
Authors: Moore Ariane L. , Batavia Aashil A. , Kuipers Jack , Singer Jochen , Burcklen Elodie , Schraml Peter , Beisel Christian , Moch Holger , Beerenwinkel Niko
Published: April 2018

Intra-tumour heterogeneity is the molecular hallmark of renal cancer, and the molecular tumour composition determines the treatment outcome of renal cancer patients. In renal cancer tumourigenesis, in general, different tumour clones evolve over time. We analysed intra-tumour heterogeneity and subclonal mutation patterns in 178 tumour samples obtained from 89 clear cell renal cell carcinoma patients. In an initial discovery phase, whole-exome and transcriptome sequencing data from paired tumour biopsies from 16 ccRCC patients were used to design a gene panel for follow-up analysis. In this second phase, 826 selected genes were targeted at deep coverage in an extended cohort of 89 patients for a detailed analysis of tumour heterogeneity. On average, we found 22 mutations per patient. Pairwise comparison of the two biopsies from the same tumour revealed that on average 62% of the mutations in a patient were detected in one of the two samples. In addition to commonly mutated genes (VHL,PBRM1,SETD2andBAP1),frequent subclonal mutations with low variant allele frequency (<10%) were observed inTP53and in mucin coding genesMUC6,MUC16, andMUC3A. Of the 89 ccRCC tumours, 87 (~98%) harboured private mutations, occurring in only one of the paired tumour samples. Clonally exclusive pathway pairs were identified using the WES data set from 16 ccRCC patients. Our findings imply that shared and private mutations significantly contribute to the complexity of differential gene expression and pathway interaction, and might explain clonal evolution of different molecular renal cancer subgroups. Multi-regional sequencing is central for the identification of subclones within ccRCC.
Rethomics: an R framework to analyse high-throughput behavioural data
Authors: Geissmann Quentin , Rodriguez Luis Garcia , Beckwith Esteban J. , Gilestro Giorgio F.
Published: April 2018

The recent development of automatised methods to score various behaviours on a large number of animals provides biologists with an unprecedented set of tools to decipher these complex phenotypes. Analysing such data comes with several challenges that are largely shared across acquisition platform and paradigms. Here, we presentrethomics, a set ofRpackages that unifies the analysis of behavioural datasets in an efficient and flexible manner.rethomicsoffers a computational solution to storing, manipulating and visualising large amounts of behavioural data. We propose it as a tool to bridge the gap between behavioural biology and data sciences, thus connecting computational and behavioural scientists.rethomicscomes with a extensive documentation as well as a set of both practical and theoretical tutorials (available athttps://rethomics.github.io).
Dynamics of ion fluxes between neurons, astrocytes and the extracellular space during neurotransmission
Authors: Rouach Nathalie , Dao Duc Khanh , Sibille Jeremie , Holcman David
Published: April 2018

Ionic homeostasis in the brain involves redistribution of ionic fluxes in several cell types and compartments, including neurons, astrocytes and the extracellular space. How the major ionic activity-dependent fluxes of potassium and sodium are individually regulated remains difficult to dissociate and to track experimentally. We here review recent progress in modeling the ionic fluxes evoked by neuronal activity based on mass conservation. Excitability of neurons indeed relies on inward sodium and outward potassium fluxes during action potential firing. Recently, we have developed a tri-compartment model based on mass-action kinetics equations that account for potassium dynamics between neurons, astrocytes and the extracellular space. This review describes how such type of model can be used to spatially and temporally predict potassium fluxes during various regimes of neuronal activity. In particular, the model initially showed that it takes several seconds for astrocytes to buffer the majority of the potassium rapidly released by neurons in both basal and high regime of activity. Such model can also probe the selective contribution of ionic channels, and revealed for instance that disruption of the main astroglial potassium Kir4.1 channels not only favors the emergence of epileptiform activity, but also dysregulates neuronal excitability specifically during slow rhythmic activities. We here also extend the predictions of the model by assessing the selective contribution of the astroglial and neuronal Na/K ATPase, or volume of the extracellular space on potassium dynamics. We discuss these findings and their implications for neuronal information processing in the healthy and diseased brain.
Elevated O-GlcNAcylation Enhances Pro-Inflammatory Th17 Function by Altering the Lipid Microenvironment
Authors: Machacek Miranda , Zhang Zhen , Tan Ee Phie , Li Jibiao , Li Tiangang , Villar Maria T. , Artigues Antonio , Lydic Todd , Slawson Chad , Fields Patrick
Published: April 2018

Chronic, low-grade inflammation increases the risk of atherosclerosis, cancer, and autoimmunity in diseases like obesity and diabetes. Here, we show that increased levels of the nutrient-responsive, post-translational protein modification, O-GlcNAc (O-linked β-N-acetylglucosamine) are present in naïve CD4+ T cells from a diet-induced obesity murine model, and elevation in O-GlcNAc leads to increased pro-inflammatory IL-17A production. Importantly, CD4+ T helper 17 (Th17) cells, which secrete IL-17A, are increased in obesity and contribute to the inflammatory milieu. We found increased binding of the Th17 master transcription factor, RORγt, at the IL-17 locus and significant alterations in the lipid microenvironment, leading to increased ligands capable of increasing RORγt transcriptional activity. Importantly, the rate-limiting enzyme of fatty acid biosynthesis, acetyl CoA carboxylase 1 (ACC1), is necessary for production of these RORγt activating ligands and is O-GlcNAcylated. Thus, we have identified O-GlcNAc as a critical link between excess nutrients and pathological inflammation.
In Silico Analysis Reveals a Shared Immune Signature in CASP8-Mutated Carcinomas with Varying Correlations to Prognosis
Authors: Ghanekar Yashoda , Sadasivam Subhashini
Published: April 2018

Background

Sequencing studies across multiple cancers continue to reveal the spectrum of mutations and genes involved in the pathobiology of these cancers. Exome sequencing of oral cancers, a subset of Head and Neck Squamous cell Carcinomas (HNSCs) common among tobacco-chewing populations, revealed that ~34% of the affected patients harbor mutations in the CASP8 gene. Uterine Corpus Endometrial Carcinoma (UCEC) is another cancer type where about 10% cases harbor CASP8 mutations. Caspase-8, the protease encoded by CASP8 gene, plays a dual role in programmed cell death, which in turn has an important role in tumor cell death and drug resistance. CASP8 is a protease required for the extrinsic pathway of apoptosis and is also a negative regulator of necroptosis. Using bioinformatics approaches to mine data in The Cancer Genome Atlas, we compared the molecular features and survival of these carcinomas with and without CASP8 mutations.

Results

Our in silico analyses showed that HNSCs with CASP8 mutations displayed a prominent signature of genes involved in immune response and inflammation, and were rich in immune cell infiltrates. However, in contrast to Human Papilloma Virus-positive HNSCs, a subtype that exhibits high immune cell infiltration and better overall survival, HNSC patients with mutant-CASP8 tumors did not display any survival advantage. A similar bioinformatic analyses in UCECs revealed that while UCECs with CASP8 mutations also displayed an immune signature, they had better overall survival, in contrast to the HNSC scenario. On further examination, we found that there was significant up-regulation of neutrophils as well as the cytokine, IL33 in mutant-CASP8 HNSCs, both of which were not observed in mutant-CASP8 UCECs.

Conclusions

These results suggested that carcinomas with mutant CASP8 have broadly similar immune signatures albeit with different effects on survival. We hypothesize that subtle tissue-dependent differences could influence survival by modifying the micro-environment of mutant-CASP8 carcinomas. High neutrophil numbers, which is a well-known negative prognosticator in HNSCs, and/or high IL33 levels may be some of the factors affecting survival of mutant-CASP8 cases.
Loop-mediated isothermal amplification assay forEnterococcus sp., E. coliandS. aureusin chicken
Authors: Song HyeSoon , Bae YouChan , Kwon HyukMan , Kwon YongKuk , Joh SeongJoon
Published: April 2018

Bacterial chondronecrosis with osteomyelitis (BCO) is a major cause of lameness in broiler chicken, and results in serious economic losses worldwide. Although the pathogenesis mechanism leading to lameness is not entirely understood, some strains ofEnterococcus sp., avian pathogenicEscherichia coli, orStaphylococcus aureushave been long recognized as important causative pathogens. To prevent the progression ofEnterococcus sp., avian pathogenicE. coli, orS. aureusinfections, we developed rapid, sensitive, and convenient diagnostic assays using loop-mediated isothermal amplification (LAMP). Entero-Common-LAMP assays were developed for a simultaneous detection of eightEnterococcusspecies. To target specific microorganisms, seven Entero-Specific-LAMP assays forE. faecalis, E. faecium, E. hirae, E. gallinarum, E. avium, E. duransandE. cecorum, andE. coli-LAMP andS. aureus-LAMP assays, were developed. Considering the prevalence and economic impact ofEnterococcus sp., E. coli, andS. aureus, the developed ten different LAMP assays have a considerable potential as routine diagnostic methods in the field or in resource-limited environments.
Trend and pattern of antimicrobial resistance in molluscanVibriospecies sourced to Canadian estuaries
Authors: Banerjee Swapan K. , Farber Jeffrey M.
Published: April 2018

Emergence of antimicrobial resistance (AMR) in foodborne bacteria is a growing concern worldwide. AMR surveillance is a key element in understanding the implications resulting from the use of antibiotics for therapeutic as well as prophylactic needs. The emergence and spread of AMR in foodborne human pathogens is an indirect health hazard. This surveillance study reports the trend and pattern of AMR detected inVibriospecies isolated from molluscs harvested in Canada, between 2006 and 2012, against 19 commonly used antibiotics. Five common antibiotics, ampicillin, cephalothin, erythromycin, kanamycin and streptomycin, predominantly contributed to AMR including multi-drug resistance (MDR) in the molluscanVibriospp. isolated in 2006. A prospective follow-up analysis of these drugs showed a declining trend in the frequency of MDR/AMR-Vibriospp. in subsequent years until 2012. The observed decline appears to have been influenced by the specific downturn in resistance to the aminoglycosides, kanamycin and streptomycin. Frequently observed MDR/AMR-Vibriospp. in seafood is a potential health concern associated with seafood consumption. Our surveillance study provided an indication of the antibiotics that challenged the marine bacteria, sourced to Canadian estuaries, during and/or prior to the study period.