bluuebunny/crossref_metadata_2025 huggingface dataset:
Weighted enumeration of Bruhat chains in the symmetric group
Authors: Gaetz Christian , Gao Yibo
Published: January 2020

We use the recently introduced padded Schubert polynomials to prove a common generalization of the fact that the weighted number of maximal chains in the strong Bruhat order on the symmetric group is

(

n
2

)

!

{n \choose 2}!

for both the code weights and the Chevalley weights, generalizing a result of Stembridge. We also define weights which give a one-parameter family of strong order analogues of Macdonald’s well-known reduced word identity for Schubert polynomials.
Spectral 𝜁-invariants lifted to coverings
Authors: Azzali Sara , Paycha Sylvie
Published: January 2020

The canonical trace and the Wodzicki residue on classical pseudodifferential operators on a closed manifold are characterised by their locality and shown to be preserved under lifting to the universal covering as a result of their local feature. As a consequence, we lift a class of spectral

ζ
\zeta

-invariants using lifted defect formulae which express discrepancies of

ζ
\zeta

-regularised traces in terms of Wodzicki residues. We derive Atiyah’s

L
2

L^2

-index theorem as an instance of the

Z

2

\mathbb {Z}_2

-graded generalisation of the canonical lift of spectral

ζ
\zeta

-invariants and we show that certain lifted spectral

ζ
\zeta

-invariants for geometric operators are integrals of Pontryagin and Chern forms.
Criterion for rays landing together
Authors: Zeng Jinsong
Published: January 2020

We give a criterion to determine when two external rays land at the same point for polynomials with locally connected Julia sets. As an application, we provide an elementary proof of the monotonicity of the core entropy along arbitrary veins of the Mandelbrot set.
The monodromy of meromorphic projective structures
Authors: Allegretti Dylan , Bridgeland Tom
Published: January 2020

We study projective structures on a surface having poles of prescribed orders. We obtain a monodromy map from a complex manifold parameterising such structures to the stack of framed

PGL
2

⁡
(

C

)

\operatorname {PGL}_2(\mathbb {C})

local systems on the associated marked bordered surface. We prove that the image of this map is contained in the union of the domains of the cluster charts. We discuss a number of open questions concerning this monodromy map.
Deformation of Einstein metrics and 𝐿² cohomology on strictly pseudoconvex domains
Authors: Matsumoto Yoshihiko
Published: January 2020

We construct new complete Einstein metrics on smoothly bounded strictly pseudoconvex domains in Stein manifolds. This is done by deforming the Kähler–Einstein metric of Cheng and Yau, the approach that generalizes the works of Roth and Biquard on the deformations of the complex hyperbolic metric on the unit ball. Recasting the problem into the question of the vanishing of an

L
2

L^2

cohomology and taking advantage of the asymptotic complex hyperbolicity of the Cheng–Yau metric, we establish the possibility of such a deformation when the dimension of the domain is larger than or equal to three.
An old and new approach to Goormaghtigh’s equation
Authors: Bennett Michael , Gherga Adela , Kreso Dijana
Published: January 2020

We show that if

n
≥
3

n \geq 3

is a fixed integer, then there exists an effectively computable constant

c
(
n
)

c (n)

such that if

x
x

,

y
y

, and

m
m

are integers satisfying

x
m

−
1

x
−
1

=

y
n

−
1

y
−
1

,

y
>
x
>
1
,

m
>
n
,

\begin{equation*} \frac {x^m-1}{x-1} = \frac {y^n-1}{y-1}, \; \; y>x>1, \; m > n, \end{equation*}

with

gcd
(
m
−
1
,
n
−
1
)
>
1

\gcd (m-1,n-1)>1

, then

max
{
x
,
y
,
m
}
>
c
(
n
)

\max \{ x, y, m \} > c (n)

. In case

n
∈
{
3
,
4
,
5
}

n \in \{ 3, 4, 5 \}

, we solve the equation completely, subject to this non-coprimality condition. In case

n
=
5

n=5

, our resulting computations require a variety of innovations for solving Ramanujan-Nagell equations of the shape

f
(
x
)
=

y
n

f(x)=y^n

, where

f
(
x
)

f(x)

is a given polynomial with integer coefficients (and degree at least two), and

y
y

is a fixed integer.
Biological applications of knowledge graph embedding models
Authors: Mohamed Sameh K , Nounu Aayah , Nováček Vít
Published: January 2020

Complex biological systems are traditionally modelled as graphs of interconnected biological entities. These graphs, i.e. biological knowledge graphs, are then processed using graph exploratory approaches to perform different types of analytical and predictive tasks. Despite the high predictive accuracy of these approaches, they have limited scalability due to their dependency on time-consuming path exploratory procedures. In recent years, owing to the rapid advances of computational technologies, new approaches for modelling graphs and mining them with high accuracy and scalability have emerged. These approaches, i.e. knowledge graph embedding (KGE) models, operate by learning low-rank vector representations of graph nodes and edges that preserve the graph’s inherent structure. These approaches were used to analyse knowledge graphs from different domains where they showed superior performance and accuracy compared to previous graph exploratory approaches. In this work, we study this class of models in the context of biological knowledge graphs and their different applications. We then show how KGE models can be a natural fit for representing complex biological knowledge modelled as graphs. We also discuss their predictive and analytical capabilities in different biology applications. In this regard, we present two example case studies that demonstrate the capabilities of KGE models: prediction of drug–target interactions and polypharmacy side effects. Finally, we analyse different practical considerations for KGEs, and we discuss possible opportunities and challenges related to adopting them for modelling biological systems.
DeepHIT: a deep learning framework for prediction of hERG-induced cardiotoxicity
Authors: Ryu Jae Yong , Lee Mi Young , Lee Jeong Hyun , Lee Byung Ho , Oh Kwang-Seok
Published: January 2020

Motivation

Blockade of the human ether-à-go-go-related gene (hERG) channel by small compounds causes a prolonged QT interval that can lead to severe cardiotoxicity and is a major cause of the many failures in drug development. Thus, evaluating the hERG-blocking activity of small compounds is important for successful drug development. To this end, various computational prediction tools have been developed, but their prediction performances in terms of sensitivity and negative predictive value (NPV) need to be improved to reduce false negative predictions.

Results

We propose a computational framework, DeepHIT, which predicts hERG blockers and non-blockers for input compounds. For the development of DeepHIT, we generated a large-scale gold-standard dataset, which includes 6632 hERG blockers and 7808 hERG non-blockers. DeepHIT is designed to contain three deep learning models to improve sensitivity and NPV, which, in turn, produce fewer false negative predictions. DeepHIT outperforms currently available tools in terms of accuracy (0.773), MCC (0.476), sensitivity (0.833) and NPV (0.643) on an external test dataset. We also developed an in silico chemical transformation module that generates virtual compounds from a seed compound, based on the known chemical transformation patterns. As a proof-of-concept study, we identified novel urotensin II receptor (UT) antagonists without hERG-blocking activity derived from a seed compound of a previously reported UT antagonist (KR-36676) with a strong hERG-blocking activity. In summary, DeepHIT will serve as a useful tool to predict hERG-induced cardiotoxicity of small compounds in the early stages of drug discovery and development.

Availability and implementation

https://bitbucket.org/krictai/deephit and https://bitbucket.org/krictai/chemtrans

Supplementary information

Supplementary data are available at Bioinformatics online.
Census of halide-binding sites in protein structures
Authors: Skitchenko Rostislav K , Usoltsev Dmitrii , Uspenskaya Mayya , Kajava Andrey V , Guskov Albert
Published: January 2020

Motivation

Halides are negatively charged ions of halogens, forming fluorides (F−), chlorides (Cl−), bromides (Br−) and iodides (I−). These anions are quite reactive and interact both specifically and non-specifically with proteins. Despite their ubiquitous presence and important roles in protein function, little is known about the preferences of halides binding to proteins. To address this problem, we performed the analysis of halide–protein interactions, based on the entries in the Protein Data Bank.

Results

We have compiled a pipeline for the quick analysis of halide-binding sites in proteins using the available software. Our analysis revealed that all of halides are strongly attracted by the guanidinium moiety of arginine side chains, however, there are also certain preferences among halides for other partners. Furthermore, there is a certain preference for coordination numbers in the binding sites, with a correlation between coordination numbers and amino acid composition. This pipeline can be used as a tool for the analysis of specific halide–protein interactions and assist phasing experiments relying on halides as anomalous scatters.

Availability and implementation

All data described in this article can be reproduced via complied pipeline published at https://github.com/rostkick/Halide_sites/blob/master/README.md.

Supplementary information

Supplementary data are available at Bioinformatics online.
Estimating the power of sequence covariation for detecting conserved RNA structure
Authors: Rivas Elena , Clements Jody , Eddy Sean R
Published: January 2020

Pairwise sequence covariations are a signal of conserved RNA secondary structure. We describe a method for distinguishing when lack of covariation signal can be taken as evidence against a conserved RNA structure, as opposed to when a sequence alignment merely has insufficient variation to detect covariations. We find that alignments for several long non-coding RNAs previously shown to lack covariation support do have adequate covariation detection power, providing additional evidence against their proposed conserved structures.

Availability and implementation

The R-scape web server is at eddylab.org/R-scape, with a link to download the source code.

Supplementary information

Supplementary data are available at Bioinformatics online.
Novel localizations and interactions of intercellular bridge proteins revealed by proteomic profiling†
Authors: Iwamori Tokuko , Iwamori Naoki , Matsumoto Masaki , Imai Hiroyuki , Ono Etsuro
Published: January 2020

Intercellular bridges (ICBs) connecting germ cells are essential for spermatogenesis, and their deletion causes male infertility. However, the functions and component factors of ICBs are still unknown. We previously identified novel ICB-associated proteins by proteomics analysis using ICB enrichment. Here, we performed immunoprecipitation–proteomics analyses using antibodies specific to known ICB proteins MKLP1, RBM44, and ectoplasmic specialization-associated protein KIAA1210 and predicted protein complexes in the ICB cores. KIAA1210, its binding protein topoisomerase2B (TOP2B), and tight junction protein ZO1 were identified as novel ICB proteins. On the other hand, as well as KIAA1210 and TOP2B, MKLP1 and RBM44, but not TEX14, were localized at the XY body of spermatocytes, suggesting that there is a relationship between ICB proteins and meiotic chromosomes. Moreover, small RNAs interacted with an ICB protein complex that included KIAA1210, RBM44, and MKLP1. These results indicate dynamic movements of ICB proteins and suggest that ICB proteins could be involved not only in the communication between germ cells but also in their epigenetic regulation. Our results provide a novel perspective on the function of ICBs and could be helpful in revealing the biological function of the ICB.
Glacier Retreat and Pacific Salmon
Authors: Pitman Kara J , Moore Jonathan W , Sloat Matthew R , Beaudreau Anne H , Bidlack Allison L , Brenner Richard E , Hood Eran W , Pess George R , Mantua Nathan J , Milner Alexander M , Radić Valentina , Reeves Gordon H , Schindler Daniel E , Whited Diane C
Published: January 2020

Glaciers have shaped past and present habitats for Pacific salmon (Oncorhynchus spp.) in North America. During the last glacial maximum, approximately 45% of the current North American range of Pacific salmon was covered in ice. Currently, most salmon habitat occurs in watersheds in which glacier ice is present and retreating. This synthesis examines the multiple ways that glacier retreat can influence aquatic ecosystems through the lens of Pacific salmon life cycles. We predict that the coming decades will result in areas in which salmon populations will be challenged by diminished water flows and elevated water temperatures, areas in which salmon productivity will be enhanced as downstream habitat suitability increases, and areas in which new river and lake habitat will be formed that can be colonized by anadromous salmon. Effective conservation and management of salmon habitat and populations should consider the impacts of glacier retreat and other sources of ecosystem change.
p130Cas induces bone invasion by oral squamous cell carcinoma by regulating tumor epithelial–mesenchymal transition and cell proliferation
Authors: Yaginuma Tatsuki , Gao Jing , Nagata Kengo , Muroya Ryusuke , Fei Huang , Nagano Haruki , Chishaki Sakura , Matsubara Takuma , Kokabu Shoichiro , Matsuo Kou , Kiyoshima Tamotsu , Yoshioka Izumi , Jimi Eijiro
Published: January 2020

Bone invasion is a critical factor in determining the prognosis of oral squamous cell carcinoma (OSCC) patients. Transforming growth factor β (TGF-β) is abundantly expressed in the bone matrix and is involved in the acquisition of aggressiveness by tumors. TGF-β is also important to cytoskeletal changes during tumor progression. In this study, we examined the relationship between TGF-β signaling and cytoskeletal changes during bone invasion by OSCC. Immunohistochemical staining of OSCC samples from five patients showed the expression of p130Cas (Crk-associated substrate) in the cytoplasm and phosphorylated Smad3 expression in the nucleus in OSCC cells. TGF-β1 induced the phosphorylation of Smad3 and p130Cas, as well as epithelial–mesenchymal transition (EMT) accompanied by the downregulation of the expression of E-cadherin, a marker of epithelial cells, and the upregulation of the expression of N-cadherin, or Snail, a marker of mesenchymal cells, in human HSC-2 cells and mouse squamous cell carcinome VII (SCCVII) cells. SB431542, a specific inhibitor of Smad2/3 signaling, abrogated the TGF-β1-induced phosphorylation of p130Cas and morphological changes. Silencing p130Cas using an short hairpin RNA (shRNA) or small interfering RNA in SCCVII cells suppressed TGF-β1-induced cell migration, invasion, EMT and matrix metalloproteinase-9 (MMP-9) production. Compared with control SCCVII cells, SCCVII cells with silenced p130Cas strongly suppressed zygomatic and mandibular destruction in vivo by reducing the number of osteoclasts, cell proliferation and MMP-9 production. Taken together, these results showed that the expression of TGF-β/p130Cas might be a new target for the treatment of OSCC bone invasion.
Spatiotemporal Differences in the Regional Cortical Plate and Subplate Volume Growth during Fetal Development
Authors: Vasung Lana , Rollins Caitlin K , Velasco-Annis Clemente , Yun Hyuk Jin , Zhang Jennings , Warfield Simon K , Feldman Henry A , Gholipour Ali , Grant P Ellen
Published: January 2020

The regional specification of the cerebral cortex can be described by protomap and protocortex hypotheses. The protomap hypothesis suggests that the regional destiny of cortical neurons and the relative size of the cortical area are genetically determined early during embryonic development. The protocortex hypothesis suggests that the regional growth rate is predominantly shaped by external influences. In order to determine regional volumes of cortical compartments (cortical plate (CP) or subplate (SP)) and estimate their growth rates, we acquired T2-weighted in utero MRIs of 40 healthy fetuses and grouped them into early (<25.5 GW), mid- (25.5–31.6 GW), and late (>31.6 GW) prenatal periods. MRIs were segmented into CP and SP and further parcellated into 22 gyral regions. No significant difference was found between periods in regional volume fractions of the CP or SP. However, during the early and mid-prenatal periods, we found significant differences in relative growth rates (% increase per GW) between regions of cortical compartments. Thus, the relative size of these regions are most likely conserved and determined early during development whereas more subtle growth differences between regions are fine-tuned later, during periods of peak thalamocortical growth. This is in agreement with both the protomap and protocortex hypothesis.
Segregated Expression of ENaC Subunits in Taste Cells
Authors: Lossow Kristina , Hermans-Borgmeyer Irm , Meyerhof Wolfgang , Behrens Maik
Published: January 2020

Salt taste is one of the 5 basic taste qualities. Depending on the concentration, table salt is perceived either as appetitive or aversive, suggesting the contribution of several mechanisms to salt taste, distinguishable by their sensitivity to the epithelial sodium channel (ENaC) blocker amiloride. A taste-specific knockout of the α-subunit of the ENaC revealed the relevance of this polypeptide for low-salt transduction, whereas the response to other taste qualities remained normal. The fully functional ENaC is composed of α-, β-, and γ-subunits. In taste tissue, however, the precise constitution of the channel and the cell population responsible for detecting table salt remain uncertain. In order to examine the cells and subunits building the ENaC, we generated mice carrying modified alleles allowing the synthesis of green and red fluorescent proteins in cells expressing the α- and β-subunit, respectively. Fluorescence signals were detected in all types of taste papillae and in taste buds of the soft palate and naso-incisor duct. However, the lingual expression patterns of the reporters differed depending on tongue topography. Additionally, immunohistochemistry for the γ-subunit of the ENaC revealed a lack of overlap between all potential subunits. The data suggest that amiloride-sensitive recognition of table salt is unlikely to depend on the classical ENaCs formed by α-, β-, and γ-subunits and ask for a careful investigation of the channel composition.
Can China Change the International System? The Role of Moral Leadership
Authors: Larson Deborah Welch
Published: January 2020

Yan Xuetong’s Leadership and the Rise of Great Powers argues that China should follow moral values in its foreign policy in order to attain international leadership. Drawing on ancient Chinese thought, Yan makes the case that China should strive for humane authority, influencing other states by leading through moral example and attracting supporters through providing benefits rather than using coercion. This essay evaluates the feasibility of China’s attainment of humane authority, which is related to status. Humane authority follows norms consistently toward rivals as well as friendly states whereas a hegemon uses a double standard. But double standards may not be so easily avoided because they derive from inherent psychological bias. The option of acquiring followers by providing them with security guarantees is not available to China in East Asia because of the prior existence of the US alliance system. Yan predicts that China’s growth will lead to a bipolar structure but points out that the conditions for a Cold War are absent. Nevertheless, technological competition between the US and China could lead to a ‘new Cold War’, which would hamper China’s efforts to widen its circle of followers. To be a humane authority, China should also avoid a war with the USA. There is a risk that naval competition could lead to local conflicts as a result of security dilemma dynamics. The two states should control status rivalry through a division of labour, by accepting the other’s pre-eminence in different areas through social cooperation.
Diagnostic Test Accuracy of Commercial Tests for Detection of Shiga Toxin–Producing Escherichia coli: A Systematic Review and Meta-Analysis
Authors: Tarr Gillian A M , Lin Chu Yang , Vandermeer Ben , Lorenzetti Diane L , Tarr Phillip I , Chui Linda , Hartling Lisa , Freedman Stephen B
Published: January 2020

Background

Rapid detection of Shiga toxin–producing Escherichia coli (STEC) enables appropriate monitoring and treatment. We synthesized available evidence to compare the performance of enzyme immunoassay (EIA) and PCR tests for the detection of STEC.

Methods

We searched published and gray literature for studies of STEC EIA and/or PCR diagnostic test accuracy relative to reference standards including at least one nucleic acid amplification test. Two reviewers independently screened studies, extracted data, and assessed quality with the second version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Bivariate random effects models were used to meta-analyze the clinical sensitivity and specificity of commercial EIA and PCR STEC diagnostic tests, and summary receiver operator characteristic curves were constructed. We evaluated the certainty of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Results

We identified 43 articles reflecting 25 260 specimens. Meta-analysis of EIA and PCR accuracy included 25 and 22 articles, respectively. STEC EIA pooled sensitivity and specificity were 0.681 (95% CI, 0.571–0.773; very low certainty of evidence) and 1.00 (95% CI, 0.998–1.00; moderate certainty of evidence), respectively. STEC PCR pooled sensitivity and specificity were 1.00 (95% CI, 0.904–1.00; low certainty of evidence) and 0.999 (95% CI, 0.997–0.999; low certainty of evidence), respectively. Certainty of evidence was downgraded because of high risk of bias.

Conclusions

PCR tests to identify the presence of STEC are more sensitive than EIA tests, with no meaningful loss of specificity. However, given the low certainty of evidence, our results may overestimate the difference in performance.
Cochlear Implant Nonuse: Insight from Deaf Adults
Authors: Salehomoum Maryam
Published: January 2020

Research examining the outcome of pediatric cochlear implantation consists of certain limitations, including the use of assessments that are often restricted to auditory-spoken skills, biased recruitment practices, and lack of consideration for identity development. To better understand the long-term outcome of implantation, it is vital to seek out individuals who decide to stop using their device and elicit feedback related to their decision. Thus, 11 adults, who were past cochlear implant (CI) users, were interviewed to gain insight into factors that had led to their decision regarding cochlear implant nonuse. Results indicated several variables to have played a role, but the most prominent factors were limitations in postimplant auditory perceptual development and development of a d/Deaf identity. Although cochlear implant practices and technology have improved over the past few decades, we need to recognize the continued variability in outcome to ensure the provision of the most accurate information and appropriate services.
Multilayer network analysis of oil linkages
Authors: Casarin Roberto , Iacopini Matteo , Molina German , ter Horst Enrique , Espinasa Ramon , Sucre Carlos , Rigobon Roberto
Published: January 2020

This manuscript proposes a new approach for unveiling existing linkages within the international oil market across multiple driving factors beyond production. A multilayer, multicountry network is extracted through a novel Bayesian graphical vector autoregressive model, which allows for a more comprehensive, dynamic representation of the network linkages than do traditional or static pairwise Granger-causal inference approaches. Building on previous work, the layers of the network include country- and region-specific oil production levels and rigs, both through simultaneous and lagged temporal dependences among key factors, while controlling for oil prices and a world economic activity index. The proposed approach extracts relationships across all variables through a dynamic, cross-regional network. This approach is highly scalable and adjusts for time-evolving linkages. The model outcome is a set of time-varying graphical networks that unveil both static representations of world oil linkages and variations in microeconomic relationships both within and between oil producers. An example is provided, illustrating the evolution of intra- and inter-regional relationships for two major interconnected oil producers: the United States, with a regional decomposition of its production and rig deployment, and the Arabian Peninsula and key Middle Eastern producers, with a country-based decomposition of production and rig deployment, while controlling for oil prices and global economic indices. Production is less affected by concurrent changes in oil prices and the overall economy than rigs. However, production is a lagged driver for prices, rather than rigs, which indicates that the linkage between rigs and production may not be fully accounted for in the markets.
Three-dimensional changes in the craniofacial complex associated with soft-diet feeding
Authors: Kono Kana , Tanikawa Chihiro , Murata Yuka , Yanagita Takeshi , Kamioka Hiroshi , Yamashiro Takashi
Published: January 2020

Background and objectives

The masticatory force affects craniofacial development. We aimed to quantify the topological deviation of the growing craniofacial structure due to soft-food diet feeding and to map the region where the phenotypes appeared on three-dimensional (3D) images.

Material and methods

Mice were fed a powdered soft diet (SD) or conventional hard diet (HD) of regular rodent pellets at 3 weeks of age until 9 weeks of age. The heads, excluding the mandibles, were scanned by micro-computed tomography. The topographic deviation of the bony surface was quantitatively assessed by a wire mesh fitting analysis. The actual displacement and significant differences were mapped and visualized in each x-, y-, and z-axis on the 3D craniofacial image. On these reconstructed images, two-dimensional linear measurements between the landmark points confirmed the 3D skeletal displacement.

Results

In the transverse direction, the zygomatic arches and the region in which the temporal muscle attaches to the parietal and temporal bones were narrow in the SD group. The temporal muscle attachment regions significantly shifted anteriorly, and consequently, the sagittal zygomatic arch shortened. Although the cranial sagittal length was not affected, the vertical height was also reduced in the SD group compared to the HD group.

Conclusions

Our 3D surface-based analysis demonstrated that SD feeding resulted in reduced 3D bony development at the region where the chewing muscles attach to the zygomatic arches and the temporal and parietal bones. Interestingly, SD feeding induced an anterior shift in the temporal and parietal bone regions, which can affect the skeletal inter-jaw relationship.
Population-Specific Genetic and Expression Differentiation in Europeans
Authors: Jiang Xueyuan , Assis Raquel
Published: January 2020

Much of the enormous phenotypic variation observed across human populations is thought to have arisen from events experienced as our ancestors peopled different regions of the world. However, little is known about the genes involved in these population-specific adaptations. Here, we explore this problem by simultaneously examining population-specific genetic and expression differentiation in four human populations. In particular, we derive a branch-based estimator of population-specific differentiation in four populations, and apply this statistic to single-nucleotide polymorphism and RNA-seq data from Italian, British, Finish, and Yoruban populations. As expected, genome-wide estimates of genetic and expression differentiation each independently recapitulate the known relationships among these four human populations, highlighting the utility of our statistic for identifying putative targets of population-specific adaptations. Moreover, genes with large copy number variations display elevated levels of population-specific genetic and expression differentiation, consistent with the hypothesis that gene duplication and deletion events are key reservoirs of adaptive variation. Further, many top-scoring genes are well-known targets of adaptation in Europeans, including those involved in lactase persistence and vitamin D absorption, and a handful of novel candidates represent promising avenues for future research. Together, these analyses reveal that our statistic can aid in uncovering genes involved in population-specific genetic and expression differentiation, and that such genes often play important roles in a diversity of adaptive and disease-related phenotypes in humans.
Genome-wide analysis of the H3K27me3 epigenome and transcriptome in Brassica rapa
Authors: Payá-Milans Miriam , Poza-Viejo Laura , Martín-Uriz Patxi San , Lara-Astiaso David , Wilkinson Mark D , Crevillén Pedro
Published: January 2020

Background

Genome-wide maps of histone modifications have been obtained for several plant species. However, most studies focus on model systems and do not enforce FAIR data management principles. Here we study the H3K27me3 epigenome and associated transcriptome of Brassica rapa, an important vegetable cultivated worldwide.

Findings

We performed H3K27me3 chromatin immunoprecipitation followed by high-throughput sequencing and transcriptomic analysis by 3′-end RNA sequencing from B. rapa leaves and inflorescences. To analyze these data we developed a Reproducible Epigenomic Analysis pipeline using Galaxy and Jupyter, packaged into Docker images to facilitate transparency and reuse. We found that H3K27me3 covers roughly one-third of all B. rapa protein-coding genes and its presence correlates with low transcript levels. The comparative analysis between leaves and inflorescences suggested that the expression of various floral regulatory genes during development depends on H3K27me3. To demonstrate the importance of H3K27me3 for B. rapa development, we characterized a mutant line deficient in the H3K27 methyltransferase activity. We found that braA.clf mutant plants presented pleiotropic alterations, e.g., curly leaves due to increased expression and reduced H3K27me3 levels at AGAMOUS-like loci.

Conclusions

We characterized the epigenetic mark H3K27me3 at genome-wide levels and provide genetic evidence for its relevance in B. rapa development. Our work reveals the epigenomic landscape of H3K27me3 in B. rapa and provides novel genomics datasets and bioinformatics analytical resources. We anticipate that this work will lead the way to further epigenomic studies in the complex genome of Brassica crops.
The impact of pill counting on resource-limited health facilities: a thematic qualitative analysis in eSwatini
Authors: Krezanoski Joseph D , Matshotyana Kidwell , Nxumalo Nkosinathi , Comfort Alison B , Khumalo Phinda , Krezanoski Paul J
Published: January 2020

Research on health systems in resource-limited settings has garnered considerable attention, but the dispensing of individual prescriptions has not been thoroughly explored as a specific bottleneck to effective delivery of care. The rise of human immunodeficiency virus/tuberculosis prevalence and non-communicable diseases in the Kingdom of eSwatini has introduced significant pressures on health facilities to meet patient demands for lifelong medications. Because automated pill counting methods are impracticable and expensive, most prescriptions are made by means of manually counting individual prescriptions using a plastic dish and spatula. The aim of this work was to examine the perceptions of health providers of causes for pill counting errors, and pill counting’s impact on clinic workflow. Our study took place in 13 randomly selected public health facilities in eSwatini, stratified by three groups based on monthly patient volumes. Thirty-one participants who count pills regularly and 13 clinic supervisors were interviewed with semi-structured materials and were audio-recorded for later transcription. Interviews were thematically analysed with inductive coding and three major themes emerged: workflow, counting error causes and effect on clinic function. Findings demonstrate large variety in how facilities manage pill counting for prescription making. Due to patient demands, most facilities utilize all available personnel, from cleaners to nurses, to partake in prescription making. Major causes for pill counting errors were distractions, exhaustion and being hurried. Participants mentioned that patients said that they had initially received the wrong quantity of pills and this affected medication adherence measurements based off pill counts. Most participants described how efforts put into pill counting detracted from their work performance, wasted valuable time and increased patient wait times. Future research is needed to quantify prescription accuracy, but our data suggest that interventions directly alleviating the burden of pill counting could lead to improved clinic quality and possibly improve patient outcomes.
Risk of Venous Thromboembolism After Hospital Discharge in Patients With Inflammatory Bowel Disease: A Population-based Study
Authors: McCurdy Jeffrey D , Kuenzig M Ellen , Smith Glenys , Spruin Sarah , Murthy Sanjay K , Carrier Marc , Nguyen Geoffrey C , Benchimol Eric I
Published: January 2020

Background

Inflammatory bowel disease (IBD) is associated with a high risk of venous thromboembolism (VTE) during hospitalization. It is unclear if this association persists after discharge. We aimed to assess the incidence of postdischarge VTE in IBD patients and to determine if IBD is associated with increased VTE risk.

Methods

We performed a population-based cohort study between 2002 and 2016 using Ontario health administrative data sets. Hospitalized (≥72 hours) adults with IBD were stratified into nonsurgical and surgical cohorts and matched on propensity score to non-IBD controls. Time to postdischarge VTE was assessed by Kaplan-Meier methods, and VTE risk was assessed by Cox proportional hazard models.

Results

A total of 81,900 IBD discharges (62,848 nonsurgical and 19,052 surgical) were matched to non-IBD controls. The cumulative incidence of VTE at 12 months after discharge was 2.3% for nonsurgical IBD patients and 1.6% for surgical IBD patients. The incidence increased in the nonsurgical IBD cohort by 4% per year (incidence rate ratio, 1.04; 95% CI, 1.02–1.05). In our propensity score-matched analysis, the risk of VTE at 1-month postdischarge was greater in nonsurgical IBD patients (hazard ratio [HR], 1.72; 95% CI, 1.51–1.96) and surgical patients with ulcerative colitis (HR, 1.68; 95% CI, 1.16–2.45) but not surgical patients with Crohn’s disease. These trends persisted through 12 months.

Conclusions

Nonsurgical IBD patients and surgical patients with ulcerative colitis are 1.7-fold more likely to develop postdischarge VTE than non-IBD patients. These findings support the need for increased vigilance and consideration of thromboprophylaxis in this population.
Clinical Validation of a 106-SNV MALDI-ToF MS Pharmacogenomic Panel
Authors: Williams Grace R , Cook Leanne , Lewis Lionel D , Tsongalis Gregory J , Nerenz Robert D
Published: January 2020

Background

Laboratorians have the opportunity to help minimize the frequency of adverse drug reactions by implementing pharmacogenomic testing and alerting care providers to possible patient/drug incompatibilities before drug treatment is initiated. Methods combining PCR with MALDI-ToF MS have allowed for sensitive, economical, and multiplexed pharmacogenomic testing results to be delivered in a timely fashion.

Method

This study evaluated the analytical performance of the Agena Biosciences iPLEX® PGx 74 panel and a custom iPLEX panel on a MassARRAY MALDI-TOF MS instrument in a clinical laboratory setting. Collectively, these panels evaluate 112 SNVs across 34 genes implicated in drug response. Using commercially available samples (Coriell Biorepository) and in-house extracted DNA, we determined ideal reaction conditions and assessed accuracy, precision, and robustness.

Results

Following protocol optimization, the Agena PGx74 and custom panels demonstrated 100% concordance with the 1000 Genomes Project Database and clinically validated hydrolysis probe genotyping assays. 100% concordance was also observed in all assessments of assay precision when appropriate QC metrics were applied.

Conclusions

Significant development time was required to optimize sample preparation and instrumental analysis and 3 assays were removed due to inconsistent performance. Following modification of the manufacturer’s protocol and instituting manual review of each assay plate, the Agena PGx74 and custom panel constitute a cost-effective, robust, and accurate method for clinical identification of 106 SNVs involved in drug response.
Cannabinol (CBN) Cross-Reacts with Two Urine Immunoassays Designed to Detect Tetrahydrocannabinol (THC) Metabolite
Authors: Kroner Grace M , Johnson-Davis Kamisha L , Doyle Kelly , McMillin Gwendolyn A
Published: January 2020

Background

The psychoactive component of cannabis, tetrahydrocannabinol (THC), is one of many cannabinoids present in the plant. Since cannabinoids have extensive structural similarity, it is important to be aware of potential cross-reactivity with immunoassays designed to detect THC metabolite. This is especially important as cannabinoid products are increasingly marketed as legal supplements. The objective of this study was to assess the cross-reactivity of 2 commercial immunoassays designed to detect THC metabolite with 4 cannabinoids: cannabidiol, cannabinol, cannabichromene, and cannabigerol.

Methods

Deidentified residual patient urine samples that tested negative for THC metabolite on initial testing were pooled and fortified with the above compounds to detect cross-reactivity. We next tested a range of CBN concentrations to determine what concentration of CBN was required to trigger a positive immunoassay result. Finally, we tested whether CBN has an additive effect with THC in the immunoassay by adding CBN to 21 samples weakly positive for THC by a mass spectrometry method but negative by the EMIT II Plus immunoassay.

Results

Both the EMIT II Plus assay and the Microgenics MultiGent assay demonstrated cross-reactivity with CBN. For the EMIT II Plus assay, about 5-fold more CBN than THC metabolite was required to produce an assay signal equivalent to the cutoff concentration, and CBN displayed an additive effect with THC metabolite. For the Microgenics assay, 20-fold more CBN than THC metabolite was required to cross the cutoff concentration.

Conclusions

These data may help guide the need for confirmatory testing when results of THC metabolite testing by immunoassay are inconsistent with expectations.
Determination of 5-MeO-DIPT in Human Urine Using Gas Chromatography Coupled with High-Resolution Orbitrap Mass Spectrometry
Authors: Yan Xiuying , Xiang Ping , Zhao Yunli , Yu Zhiguo , Yan Hui
Published: January 2020

5-Methoxy-N,N-Diisopropyltryptamine (5-MeO-DIPT) is a designer hallucinogen derived from tryptamine and its use has been banned by many countries. In this study, a qualitative and quantitative method was developed for determining 5-MeO-DIPT in urine by gas chromatography high-resolution mass spectrometry. 5-hydroxy-N,N-diisopropyltryptamine (5-OH-DIPT) and 5-methoxy-N-isopropyltryptamine (5-MeO-IPT) were identified as 5-MeO-DIPT metabolites in abusers’ urine. 5-MeO-DIPT was extracted from urine by liquid–liquid extraction with ethyl acetate under alkaline conditions. The extract was analyzed by GC-Orbitrap-MS in full scan mode with a resolution of 60,000 full width at half maxima (FWHM). The linear range of this method was 2–300 ng/mL with r > 0.99, and the limit of detection was 1 ng/mL. The accuracy and precision were 93–108.7% and 3.1–10.3%, respectively. This method is simple and sensitive. It has been successfully used to detect 5-MeO-DIPT in drug abusers’ urine, which showed that the concentrations of 5-MeO-DIPT were between 1 and 2.8 ng/mL. 5-OH-DIPT and 5-MeO-IPT, two urinary major metabolites of 5-MeO-DIPT, were identified in urine samples from 5-MeO-DIPT users. Furthermore, the stability of 5-MeO-DIPT in human urine was investigated. It was discovered that the concentration of 5-MeO-DIPT in urine decreased by 22.8, 33.2 and 38.2% after samples were stored for 24 h at 25°C, 5 days at 4°C and 7 days at 4°C, respectively. And 5-MeO-DIPT in urine were stable after they were stored for 30 days at −20°C. Therefore, it is recommended that urine should be stored under freezing conditions before performing 5-MeO-DIPT analysis.
Detection of Chemical Weapon Nerve Agents in Bone by Liquid Chromatography–Mass Spectrometry
Authors: Rubin Katie M , Goldberger Bruce A , Garrett Timothy J
Published: January 2020

A recently proposed model for the incorporation of xenobiotics of forensic interest into the human skeleton suggests nerve agent metabolites may incorporate into bone at relatively elevated concentrations based on their unique chemical properties. To test the hypothesis that nerve agent metabolites interact with bone, methods for the extraction, isolation and semi-quantitative detection of nerve agent metabolites (MPA, EMPA, IMPA, iBuMPA, CMPA and PMPA, corresponding to the nerve agents VX, Russian VX, sarin, cyclosarin and soman, respectively) from osseous tissue were developed using liquid chromatography–mass spectrometry with both quadrupole time-of-flight and triple quadrupole (QqQ) instruments. The optimized methods were validated on the QqQ instrument. Despite high ion suppression, the achieved limits of detection (5–20 pg/g for four analytes; 350 pg/g for the fifth analyte) were lower than many of those published for the same analytes in other biomatrices, including serum and urine. These methods were tested on the skeletal remains of minipigs exposed to the chemical weapon VX in vivo. The VX metabolite was detected in multiple minipig bone samples; to the authors’ knowledge, this is the first time in vivo nerve agent exposure has been detected from bone. Further, detected concentrations and diaphyseal-to-epiphyseal area count ratios reflect animal exposure history. Although the results are limited, they are promising, indicating that nerve agent metabolites may interact with bone as a pharmacokinetic compartment and can be extracted from bone postmortem. Additional studies, assessing the effects of different agents, exposure pathways and taphonomic variables, are needed; however, these results suggest the method may be used with human bone to detect use of chemical weapons from postmortem biomatrices even well after a suspected attack. More general implications for both nerve agent toxicology and skeletal toxicology are also discussed.
Designing an early failure indicator channel for an in-tank hydrogen valve via a fatigue-based approach
Authors: Cao Thanh Binh , Kedziora Slawomir , Sellen Stephan , Maas Stefan , Repplinger Christian
Published: January 2020

This study introduced a fatigue-based approach to design and implement an indicator channel into an in-tank hydrogen valve. It was aimed at providing a mean to point out multiple early valve's damages. To achieve the goal, the study was proposed to handle via three main phases. They included (i) the risk point determinations, (ii) the new valve design and the crack nucleation life estimations, as well as (iii) the simplified crack growth analyses. The obtained results firstly highlighted the construction of the test channel (TC), whose branches were located close to the predicted damage's sites. The damages could be identified either when a crack reaches the TC (then forms a leakage) or indirectly via the crack propagations’ correlation. The results also pointed out that the TC-implemented valve could perform as similarly as the non-TC one in the non-treated condition. More importantly, this new structure was proved to have a capacity of satisfying the required minimal life of 1.5E5 cycles, depending on the combined uses of the specific material and the pre-treatment, among those considered. In addition, the results emphasized the complexity of the TC that could not be formed by the traditional manufacturing process. Hence, direct metal laser sintering was proposed for the associated prototype and the final TC was issued based on the fundamental requirements of the technique. Finally, it was suggested that practical experiments should essentially be carried out to yield more evidence to support the demonstrated results.
Neuropathologic Changes in Sudden Unexplained Death in Childhood
Authors: McGuone Declan , Leitner Dominique , William Christopher , Faustin Arline , Leelatian Nalin , Reichard Ross , Shepherd Timothy M , Snuderl Matija , Crandall Laura , Wisniewski Thomas , Devinsky Orrin
Published: January 2020

Sudden unexplained death in childhood (SUDC) affects children >1-year-old whose cause of death remains unexplained following comprehensive case investigation and is often associated with hippocampal abnormalities. We prospectively performed systematic neuropathologic investigation in 20 SUDC cases, including (i) autopsy data and comprehensive ancillary testing, including molecular studies, (ii) ex vivo 3T MRI and extensive histologic brain samples, and (iii) blinded neuropathology review by 2 board-certified neuropathologists. There were 12 girls and 8 boys; median age at death was 33.3 months. Twelve had a history of febrile seizures, 85% died during apparent sleep and 80% in prone position. Molecular testing possibly explained 3 deaths and identified genetic mutations in TNNI3, RYR2, and multiple chromosomal aberrations. Hippocampal abnormalities most often affected the dentate gyrus (altered thickness, irregular configuration, and focal lack of granule cells), and had highest concordance between reviewers. Findings were identified with similar frequencies in cases with and without molecular findings. Number of seizures did not correlate with hippocampal findings. Hippocampal alterations were the most common finding on histological review but were also found in possibly explained deaths. The significance and specificity of hippocampal findings is unclear as they may result from seizures, contribute to seizure pathogenesis, or be an unrelated phenomenon.
Pectin methylesterase selectively softens the onion epidermal wall yet reduces acid-induced creep
Authors: Wang Xuan , Wilson Liza , Cosgrove Daniel J
Published: January 2020

De-esterification of homogalacturonan (HG) is thought to stiffen pectin gels and primary cell walls by increasing calcium cross-linking between HG chains. Contrary to this idea, recent studies found that HG de-esterification correlated with reduced stiffness of living tissues, measured by surface indentation. The physical basis of such apparent wall softening is unclear, but possibly involves complex biological responses to HG modification. To assess the direct physical consequences of HG de-esterification on wall mechanics without such complications, we treated isolated onion (Allium cepa) epidermal walls with pectin methylesterase (PME) and assessed wall biomechanics with indentation and tensile tests. In nanoindentation assays, PME action softened the wall (reduced the indentation modulus). In tensile force/extension assays, PME increased plasticity, but not elasticity. These softening effects are attributed, at least in part, to increased electrostatic repulsion and swelling of the wall after PME treatment. Despite softening and swelling upon HG de-esterification, PME treatment alone failed to induce cell wall creep. Instead, acid-induced creep, mediated by endogenous α-expansin, was reduced. We conclude that HG de-esterification physically softens the onion wall, yet reduces expansin-mediated wall extensibility.