bluuebunny/crossref_metadata_2025 huggingface dataset:
DETERMINATION OF THE TOTAL EFFECTIVE DOSE OF EXTERNAL AND INTERNAL EXPOSURE BY DIFFERENT IONIZING RADIATION SOURCES
Authors: Kudryashev V A , Kim D S
Published: July 2019

The purpose of the research is to develop an integrated technique for determining the effective dose (E) of external and internal exposure by different sources of ionizing radiation. The proposing technique for determining the total effective dose is based on three methods of calculation. The first one is multiplying the value of the individual dose equivalent $H_{p}(10)$ by the factor of 0.642 to account for radiation shielding by various organs and tissues and its backscattering. The second method is multiplying $H_{p}(10)$ by the conversion factor of air kerma in free air in a plate phantom, depending on the photon energy. The third method is multiplying $H_{p}(10)$ by the sum of the radiosensitivity coefficients of various organs and tissues. As a result of research, a complex method was developed for determining the total effective dose, composed of doses of cosmic radiation, external gamma-, beta- and neutron radiation, internal exposure from radionuclides, including CDP of radon and thoron, entering the body through the organs of digestion and respiration. The proposed technique for determining the total effective dose allows one to take into account the comprehensive effect of ionizing radiation sources on a person and to obtain a more accurate measure of radiation risk than the existing methods provide.
Aerobic capacity predicts skeletal but not cardiac muscle damage after a full distance Ironman triathlon - the Iron(wo)man-study
Authors: Danielsson Tom , Carlsson Jörg , Siethoff Lasse Ten , Ahnesjö Jonas , Bergman Patrick
Published: July 2019

Purpose

This study examines the association between aerobic capacity and biomarkers of skeletal- and cardiac muscle damage among amateur triathletes after a full distance Ironman.

Methods

Men and women (N=55) were recruited from local sport clubs. One month before an Iron-man triathlon, they conducted a 20m shuttle run test to determine aerobic capacity. Blood samples were taken immediately after finishing the triathlon, and analyzed for biomarkers of cardiac- and skeletal muscle damage. Regression models examining the association between aerobic capacity expressed in both relative terms (mLO2*kg-1*min-1) and absolute terms (LO2*min-1) controlled for weight and were fitted.

Result

A total of 39 subjects (26% females) had complete data and were included in the analysis. No association between aerobic capacity and cardiac muscle damage but a significant negative association between aerobic capacity and skeletal muscle damage was observed. This association was independent of how aerobic capacity was expressed, although the model with aerobic capacity expressed in absolute terms and controlled for weight resulted in slightly higher r2 values, than when aerobic capacity was expressed in relative terms.

Conclusion

A negative association between aerobic capacity and skeletal muscle damage was seen but despite the well-known cardio-protective health effect of high aerobic fitness no such association could be observed in this study.
Mechanistic diversification of XIST regulatory network in mammals
Authors: Rosspopoff Olga , Huret Christophe , Collier Amanda J. , Casanova Miguel , Rugg-Gunn Peter J. , Ouimette Jean-François , Rougeulle Claire
Published: July 2019

X chromosome inactivation (XCI) is a developmental regulatory process that initiates with remarkable diversity in various mammalian species. Here we addressed the contribution of XCI regulators, most of which are lncRNA genes characterized in the mouse, to this mechanistic diversity. By combining analysis of single-cell RNA-seq data from early human embryogenesis with various functional assays in naïve and primed pluripotent stem cells and in differentiated cells, we demonstrate that JPX is a major regulator of XIST expression in human and in mouse. However, the underlying mechanisms differ radically between species and require Jpx RNA in the mouse and the act of transcription of JPX locus in the human. Moreover, biogenesis of XIST is affected at different regulatory steps between these species. This study illustrates how diversification of LRGs modes of action during evolution provide opportunities for innovations within constrained gene regulatory networks.

Graphical abstract
Model-based decoupling of evoked and spontaneous neural activity in calcium imaging data
Authors: Triplett Marcus A. , Pujic Zac , Sun Biao , Avitan Lilach , Goodhill Geoffrey J.
Published: July 2019

The pattern of neural activity evoked by a stimulus can be substantially affected by ongoing spontaneous activity. Separating these two types of activity is particularly important for calcium imaging data given the slow temporal dynamics of calcium indicators. Here we present a statistical model that decouples stimulus-driven activity from low dimensional spontaneous activity in this case. The model identifies hidden factors giving rise to spontaneous activity while jointly estimating stimulus tuning properties that account for the confounding effects that these factors introduce. By applying our model to data from zebrafish optic tectum and mouse visual cortex, we obtain quantitative measurements of the extent that neurons in each case are driven by evoked activity, spontaneous activity, and their interaction. This broadly applicable model brings new insight into population-level neural activity in single trials without averaging away potentially important information encoded in spontaneous activity.
Distinct patterns of selective sweep and polygenic adaptation
Authors: Barghi Neda , Schlötterer Christian
Published: July 2019

The central paradigm of molecular population genetics is selective sweeps, where targets of selection have independent effects on the phenotype and quickly rise to fixation. In quantitative genetics, many loci contribute epistatically to adaptation and subtle frequency changes occur at many loci. Since both paradigms could result in a sweep-like genomic signature, additional criteria are needed to distinguish them. Using the framework of experimental evolution, we performed computer simulations to study the pattern of selected alleles under both paradigms. We identify several distinct patterns of selective sweeps and polygenic adaptation in populations of different sizes. These features could provide the foundation for development of quantitative approaches to differentiate the two paradigms.

Author’s summary

The selective sweep model assumes an independent frequency increase of favorable alleles and has been the basis of many tests for selection. While, polygenic adaptation is typically modelled by small frequency shifts in many loci. Recently, some theoretical and empirical work demonstrated that polygenic adaptation, similar to sweep, could also results in pronounced allele frequency changes. These results suggest that other distinct features need to be identified. Using computer simulations, we identified distinctive features for each paradigm that can be used to differentiate the sweep model from polygenic adaptation. Features such as allele frequency trajectories, time-series fitness, distribution of selected alleles on haplotypes, and parallelism among replicates can be used for development of suitable tests to distinguish between different adaptive architectures. These features provide the basis for theoretical modeling, design of selection experiments and data analysis.
DNA end-resection in highly accessible chromatin produces a toxic break
Authors: van den Berg Jeroen , Joosten Stacey E.P. , Kim YongSoo , Manjón Anna G. , Krenning Lenno , Koob Lisa , Feringa Femke M. , Klompmaker Rob , van den Broek Bram , Jalink Kees , Zwart Wilbert , Medema René H.
Published: July 2019

The authors have withdrawn their manuscript whilst they perform additional experiments to test some of their conclusions further.

Despite repetitive attempts to reproduce the data shown in figure 2I, we have failed to obtain convincing evidence that chemical inhibition of Mre11 can improve the fitness of cells exposed to the so-called “halt” breaks. Upon re-analysis of the raw data used to compose figure 2I, we noted inconsistencies in the inclusion of datapoints, for which a satisfactory motivation was not apparent.

In order to reproduce the experiments with the DNA-PK inhibitor, we ordered new batches of this compound, but noticed that the IC50 was significantly lower than that of the earlier batch (as determined in suppl. fig.1). While this might be due to a difference in batches, the IC50 of the newer batches was more comparable to the IC50 of this compound described for other cell lines. This sheds doubts on the quality of the batch used for the experiments shown in our manuscript, and we no longer wish to draw any conclusions based on these experiments.

The authors hope that future experiments can resolve if open chromatin does indeed produce a potentially more toxic DNA break. The authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Genome sequencing of Musa acuminata Dwarf Cavendish reveals a duplication of a large segment of chromosome 2
Authors: Busche Mareike , Pucker Boas , Viehöver Prisca , Weisshaar Bernd , Stracke Ralf
Published: July 2019

Different Musa species, subspecies, and cultivars are currently investigated to reveal their genomic diversity. Here, we compare the genome sequence of one of the commercially most important cultivars, Musa acuminata Dwarf Cavendish, against the Pahang reference genome assembly. Numerous small sequence variants were detected and the ploidy of the cultivar presented here was determined as triploid based on sequence variant frequencies. Illumina sequence data also revealed a duplication of a large segment on the long arm of chromosome 2 in the Dwarf Cavendish genome. Comparison against previously sequenced cultivars provided evidence that this duplication is unique to Dwarf Cavendish. Although no functional relevance of this duplication was identified, this example shows the potential of plants to tolerate such aneuploidies.
Thermal and Chemical Unfolding of a recombinant monoclonal IgG1 antibody: Application of the Multi-State Zimm-Bragg Theory
Authors: Garidel P. , Eiperle A. , Blech M. , Seelig J.
Published: July 2019

The thermal unfolding of a recombinant monoclonal antibody IgG1 (mAb) was measured with differential scanning calorimetry (DSC). The DSC thermograms reveal a pre-transition at 72°C with an unfolding enthalpy of ΔHcal∼ 200-300 kcal/mol and a main transition at 85 °C with an enthalpy of ∼900 - 1000 kcal/mol. In contrast to single-domain molecules, mAb unfolding is a complex reaction that is analysed with the multi-state Zimm-Bragg theory. For the investigated mAb, unfolding is characterised by a cooperativity parameter σ ∼10−4and a Gibbs free energy of unfolding of gnu∼100 cal/mol per amino acid. The enthalpy of unfolding provides the number of amino acid residuesvparticipating in the unfolding reaction. On average,v∼220±50 amino acids are involved in the pre-transition andv∼850±30 in the main transition, accounting for ∼90% of all amino acids. Thermal unfolding was further studied in the presence of guanidineHCl. The chemical denaturant reduces the unfolding enthalpy ΔHcaland lowers the midpoint temperature T0. Both parameters depend linearly on the concentration of denaturant. The guanidineHCl concentrations needed to unfold mAb at 25 °C are predicted to be 2-3 M for the pre-transition and 5-7 M for the main transition, varying with pH. GuanidineHCl binds to mAb with an exothermic binding enthalpy, which partially compensates the endothermic mAb unfolding enthalpy. The number of guanidineHCL molecules bound upon unfolding is deduced from the DSC thermograms. The bound guanidineHCl-to-unfolded amino acid ratio is 0.79 for the pre-transition and 0.55 for the main transition. The pre-transition binds more denaturant molecules and is more easily destabilised than the main transition.

Overall, the current study shows the strength of the Zimm-Bragg model for the quantitative description of unfolding events of large, therapeutic proteins, such as a monoclonal antibody.

Statement of significance

First quantitative thermodynamic study of an antibody with differential scanning calorimetry and analyzed with the multi-state Zimm-Bragg theory.
Colicin E1 opens its hinge to plug TolC
Authors: Budiardjo S. Jimmy , Stevens Jacqueline J. , Calkins Anna L. , Ikujuni Ayotunde P. , Wimalasena Virangika K. , Firlar Emre , Case David A. , Biteen Julie S. , Kaelber Jason T. , Slusky Joanna S.G.
Published: July 2019

The double membrane architecture of Gram-negative bacteria forms a barrier that is effectively impermeable to extracellular threats. Bacteriocin proteins evolved to exploit the accessible, surface-exposed proteins embedded in the outer membrane to deliver cytotoxic cargo. Colicin E1 is a bacteriocin produced by, and lethal to, Escherichia coli that hijacks the outer membrane proteins TolC and BtuB to enter the cell. Here we capture the colicin E1 translocation domain inside its membrane receptor, TolC, by high-resolution cryoEM, the first reported structure of a bacteriocin bound to TolC. Colicin E1 binds stably to TolC as an open hinge through the TolC pore—an architectural rearrangement from colicin E1’s unbound conformation. This binding is stable in live E. coli cells as indicated by single-molecule fluorescence microscopy. Finally, colicin E1 fragments binding to TolC plugs the channel, inhibiting its native efflux function as an antibiotic efflux pump and heightening susceptibility to three antibiotic classes. In addition to demonstrating that these protein fragments are useful starting points for developing novel antibiotic potentiators, this method could be expanded to other colicins to inhibit other outer membrane protein functions.
Linking transcriptome and chromatin accessibility in nanoliter droplets for single-cell sequencing
Authors: Chen Song , Lake Blue B , Zhang Kun
Published: July 2019

Linked profiling of transcriptome and chromatin accessibility from single cells can provide unprecedented insights into cellular status. Here we developed a droplet-based Single-Nucleus chromatin Accessibility and mRNA Expression sequencing (SNARE-seq) assay, that we used to profile neonatal and adult mouse cerebral cortices. To demonstrate the strength of single-cell dual-omics profiling, we reconstructed transcriptome and epigenetic landscapes of cell types, uncovered lineage-specific accessible sites, and connected dynamics of promoter accessibility with transcription during neurogenesis.
Cancer Type-Dependent Correlations betweenTP53Mutations and Antitumor Immunity
Authors: Li Lin , Li Mengyuan , Wang Xiaosheng
Published: July 2019

Many studies have shown thatTP53mutations play a negative role in antitumor immunity. However, a few studies reported thatTP53mutations could promote antitumor immunity. To explain these contradictory findings, we analyzed five cancer cohorts from The Cancer Genome Atlas (TCGA) project. We found thatTP53-mutated cancers had significantly higher levels of antitumor immune signatures thanTP53-wildtype cancers in breast invasive carcinoma (BRCA) and lung adenocarcinoma (LUAD). In contrast,TP53-mutated cancers had significantly lower antitumor immune signature levels thanTP53-wildtype cancers in stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC). Moreover,TP53-mutated cancers likely had higher tumor mutation burden (TMB) and tumor aneuploidy level (TAL) thanTP53-wildtype cancers. However, the TMB differences were more marked betweenTP53-mutated andTP53-wildtype cancers than the TAL differences in BRCA and LUAD, and the TAL differences were more significant in STAD and COAD. Furthermore, we showed that TMB and TAL had a positive and a negative correlation with antitumor immunity and that TMB affected antitumor immunity more greatly than TAL did in BRCA and LUAD while TAL affected antitumor immunity more strongly than TMB in STAD and HNSC. These findings indicate that the distinct correlations betweenTP53mutations and antitumor immunity in different cancer types are a consequence of the joint effect of the altered TMB and TAL caused byTP53mutations on tumor immunity. Our data suggest that theTP53mutation status could be a useful biomarker for cancer immunotherapy response depending on cancer types.
GSDB: a database of 3D chromosome and genome structures reconstructed from Hi-C data
Authors: Oluwadare Oluwatosin , Highsmith Max , Cheng Jianlin
Published: July 2019

Advances in the study of chromosome conformation capture (3C) technologies, such as Hi-C technique - capable of capturing chromosomal interactions in a genome-wide scale - have led to the development of three-dimensional (3D) chromosome and genome structure reconstruction methods from Hi-C data. The 3D genome structure is important because it plays a role in a variety of important biological activities such as DNA replication, gene regulation, genome interaction, and gene expression. In recent years, numerous Hi-C datasets have been generated, and likewise, a number of genome structure construction algorithms have been developed. However, until now, there has been no freely available repository for 3D chromosome structures. In this work, we outline the construction of a novel Genome Structure Database (GSDB) to create a comprehensive repository that contains 3D structures for Hi-C datasets constructed by a variety of 3D structure reconstruction tools. GSDB contains over 50,000 structures constructed by 12 state-of-the-art chromosome and genome structure prediction methods for publicly used Hi-C datasets with varying resolution. The database is useful for the community to study the function of genome from a 3D perspective. GSDB is accessible at http://sysbio.rnet.missouri.edu/3dgenome/GSDB
Vaccination against antibiotic resistant gonorrhoea for men who have sex with men in England: a modelling study
Authors: Whittles Lilith K , White Peter J. , Didelot Xavier
Published: July 2019

Background

Gonorrhoea incidence is increasing rapidly: diagnoses in men who have sex with men (MSM) in England increased eight-fold 2008-2017. Concurrently, antibiotic resistance is making treatment more difficult, leading to renewed interest in a gonococcal vaccine. The MeNZB meningococcal B vaccine is partially protective, and several other candidates are in development. We modelled realistic vaccination strategies under various scenarios of antibiotic resistance and vaccine protection level and duration, to assess the impact of vaccination and examine the feasibility of the WHO’s target of reducing gonorrhoea incidence by 90% between 2016 and 2030.

Methods

We fitted a stochastic transmission-dynamic model, incorporating asymptomatic and symptomatic infection and heterogeneous sexual behaviour, to gonorrhoea incidence in MSM in England, 2008-17, using particle Markov Chain Monte Carlo methods. Bayesian forecasting was used to examine future scenarios, including emergence of extensively antibiotic-resistant (ABR) gonorrhoea.

Findings

Even in the worst-case scenario of untreatable infection emerging, the WHO target could be met by vaccinating all MSM attending sexual health clinics with a 53%-protective vaccine lasting for >6 years, or a 70%-protective vaccine lasting >3 years. A vaccine like MeNZB, conferring 30% protection for 2-4 years, could reduce incidence in 2030 by 45% in the worst-case scenario, and by 75% if >70% of ABR gonorrhoea is treatable.

Interpretation

Our statistically-rigorous assessment shows that even a partially-protective vaccine, delivered through a practical targeting strategy, could have substantial benefit in reducing gonorrhoea incidence in the context of an epidemic with rising antibiotic resistance.
The codon frustration index as a new metric for mRNA stability, translation efficiency, and rates of protein synthesis
Authors: Forcelloni Sergio , Giansanti Andrea
Published: July 2019

Taking the human genome as a case of study, we propose a new classification of codons based only on two genomic information. We use the relative synonymous codon usage (RSCU) as a measure of non-uniform usage of synonymous codons. Similarly, we introduce here the relative gene frequencies of cognate tRNAs (RGFCt) to quantify the non-uniform availability of cognate tRNAs in each family of synonymous codons. Using these two quantities, we define two general groups of codons: non-frustrated codons, whose usage in the coding sequences is in proportion to the expected cognate tRNA levels, and frustrated codons, which do not satisfy this proportionality. With this decoding for every codon, we defined the Codon Frustration Index (CFI) as the net frustration of a gene, normalized for its length. Notably, we find that CFI correlates very well with other independent measures of CUB and a high content of non-frustrated codons increases both translation efficiency and mRNA stability. Finally, we show that genes with either a high content of frustrated or of non-frustrated codons are differentially enriched in specific functional classes that typically comprise nucleic acid binding proteins, mRNA processing factors, RNA helicase, and in several transcription factors.
Evolutionary dynamics of abundant 7 bp satellites in the genome ofDrosophila virilis
Authors: Flynn Jullien M. , Long Manyuan , Wing Rod A. , Clark Andrew G.
Published: July 2019

The factors that drive the rapid changes in satellite DNA genomic composition we see in eukaryotes are not well understood.Drosophila virilishas one of the highest relative amounts of simple satellites of any organism that has been studied, with an estimated >40% of its genome composed of a few related 7 bp satellites. Here we useD. virilisas a model to understand technical biases affecting satellite sequencing and the evolutionary processes that drive satellite composition. By analyzing sequencing data from Illumina, PacBio, and Nanopore platforms, we identify platform-specific biases and suggest best practices for accurate characterization of satellites by sequencing. We use comparative genomics and cytogenetics to demonstrate that the highly abundant satellite family arose from a related satellite in the branch leading to the virilis phylad 4.5 - 11 million years ago before exploding in abundance in some species of the clade. The most abundant satellite is conserved in sequence and location in the pericentromeric region but has diverged widely in abundance among species, whereas the satellites nearest the centromere are rapidly turning over in sequence composition. By analyzing multiple strains ofD. virilis, we saw that one centromere-proximal satellite is increasing in abundance along a geographical gradient while the other is contracting in an anti-correlated manner, suggesting ongoing conflicts at the centromere. In conclusion, we illuminate several key attributes of satellite evolutionary dynamics that we hypothesize to be driven by processes like selection, meiotic drive, and constraints on satellite sequence and abundance.
High-Resolution Cryo-EM Reveals Dynamics in the Murine Norovirus Capsid
Authors: Snowden Joseph S. , Hurdiss Daniel L. , Adeyemi Oluwapelumi O. , Ranson Neil A. , Herod Morgan R. , Stonehouse Nicola J.
Published: July 2019

Rather than acting as rigid symmetrical shells to protect and transmit their genomes, the capsids of non-enveloped, icosahedral viruses co-ordinate multiple, essential processes during the viral life-cycle, and undergo extensive conformational rearrangements to deliver these functions. Capturing conformational flexibility has been challenging, yet could be key in understanding and combating infections that viruses cause. Noroviruses are non-enveloped, icosahedral viruses of global importance to human health. They are a common cause of acute non-bacterial gastroenteritis, yet no vaccines or antiviral agents specific to norovirus are available. Here, we use cryo-electron microscopy to study the high-resolution solution structures of infectious, inactivated and mutant virions of murine norovirus (MNV) as a model for human noroviruses. Together with genetic studies, we show that the viral capsid is highly dynamic. While there is little change to the shell domain of the capsid, the protruding domains that radiate from this are flexible and adopt distinct states both independently and synchronously. In doing so the viral capsid is able to sample a defined range of conformational space, with implications for the maintenance of virion stability and infectivity. These data will aid in developing the first generation of effective control measures against this virus.
An adaptive algorithm for fast and reliable online saccade detection
Authors: Schweitzer Richard , Rolfs Martin
Published: July 2019

To investigate visual perception around the time of eye movements, vision scientists manipulate stimuli contingent upon the onset of a saccade. For these experimental paradigms, timing is especially crucial, as saccade offset imposes a deadline on the display change. Although efficient online saccade detection can greatly improve timing, most algorithms rely on spatial-boundary techniques or absolute-velocity thresholds, which both suffer from their respective weaknesses: late detections and false alarms. We propose an adaptive, velocity-based algorithm for online saccade detection that surpasses both standard techniques in speed and accuracy and allows the user to freely define detection criteria. Inspired by the Engbert-Kliegl-algorithm for microsaccade detection, our algorithm computes two-dimensional velocity thresholds from variance in preceding fixation samples, while compensating for noisy or missing data samples. An optional direction criterion limits detection to the instructed saccade direction, further increasing robustness. We validated the algorithm by simulating its performance on a large saccade dataset and found that high detection accuracy (false-alarm rates of <1%) could be achieved with detection latencies of only 3 milliseconds. High accuracy was maintained even under simulated high-noise conditions. To demonstrate that purely intra-saccadic presentations are technically feasible, we devised an experimental test, in which a Gabor patch drifted at saccadic peak velocities. While this stimulus was invisible when presented during fixation, observers reliably detected it during saccades. Photodiode measurements verified that – including all system delays – stimuli were physically displayed on average 20 ms after saccade onset. Thus, the proposed algorithm provides valuable tool for gaze-contingent paradigms.
CX3CL1 and CX3CR1 Expressing Tendon Cells – A novel Immune Cell Population in the Tendon Core
Authors: Lehner Christine , Spitzer Gabriel , Gehwolf Renate , Wagner Andrea , Weissenbacher Nadja , Deininger Christian , Emmanuel Katja , Wichlas Florian , Tempfer Herbert , Traweger Andreas
Published: July 2019

Tendon disorders frequently occur and recent evidence has clearly implicated the presence of immune cells and inflammatory events during early tendinopathy. However, the origin and properties of these cells remain poorly defined. Therefore, the aim of this study was to determine the presence of myleoid cells in healthy rodent and human tendon tissue and to characterize them. Using various transgenic reporter mouse models, we demonstrate the presence of tendon cells in the dense matrix of the tendon core expressing the fractalkine (Fkn) receptor CX3CR1 and its cognate ligand CX3CL1/Fkn. Pro-inflammatory stimulation of 3D tendon-like constructsin vitroresulted in a significant increase in the expression of IL-1β, IL-6, Mmp3, Mmp9, Cx3cl1, and epiregulin which has been reported to contribute to inflammation, wound healing, and tissue repair. Furthermore, we demonstrate that inhibition of the fractalkine receptor blocked tendon cell migrationin vitroand show the presence of CX3CR1/CX3CL1/EREG expressing cells in healthy human tendons. Taken together, we demonstrate the presence of CX3CL1+/CX3CR1+ “tenophages” within the healthy tendon proper potentially fulfilling surveillance functions in tendons.

Summary Statement

Here, we demonstrate the presence of a macrophage-like, CX3CL1/CX3CR1-expressing cell population within the healthy tendon proper potentially fulfilling a surveillance function.
Investigating the Effects of Osmolytes and Environmental pH on Bacterial Persisters
Authors: Karki Prashant , Orman Mehmet A.
Published: July 2019

Bacterial persisters are phenotypic variants that temporarily demonstrate an extraordinary tolerance towards antibiotics. Persisters have been linked to the recalcitrance of biofilm related infections; hence, a complete understanding of the physiology of persisters can lead to improvement of therapeutic strategies associated with such infections. Mechanisms pertaining to persister formation are known to be related to stress response pathways triggered from intra- or extra-cellular stress factors. Unfortunately, studies demonstrating the effects of osmolyte- and/or pH- induced stresses on bacterial persistence are largely missing. To fill this knowledge gap within the field, here we studied the effects of various osmolytes and pH conditions onEscherichia colipersistence with the use of phenotype microarrays and antibiotic tolerance assays. Although we found that a number of chemicals and pH environments, including urea, sodium nitrite and acidic pH, significantly reduced persister formation inE. colicompared to no-osmolyte/no-buffer controls, this reduction in persister levels was lessened in late-stationary-phase cultures. Our results further demonstrated a positive correlation between cell growth and persister formation, which challenges the general notion in the field that slow-growing cultures have more persister cells than fast-growing cultures.
Perifolliculitis capitis abscedens et suffodiens treatment with tumor necrosis factor inhibitors: A case report and review of published cases
Authors: Takahashi Toshiya , Yamasaki Kenshi , Terui Hitoshi , Omori Ryoko , Tsuchiyama Kenichiro , Fujimura Taku , Aiba Setsuya
Published: July 2019

Perifolliculitis capitis abscedens et suffodiens (PCAS) or dissecting cellulitis is a rare condition presenting deep follicular occlusions, follicular ruptures and follicular infections in the scalp area with unknown etiology, which consequently cause primary neutrophilic cicatricial alopecia by the repeated follicular inflammation. PCAS is categorized as one of the “follicular occlusion tetrad” along with hidradenitis suppurativa, acne conglobata and pilonidal cyst. In the pathogenesis of the follicular occlusion tetrad, the involvement of neutrophils and its activator tumor necrosis factor (TNF) have been discussed. Here, we report a case of PCAS that was successfully treated with adalimumab, a human anti‐TNF monoclonal antibody. This is the first Asian case of PCAS that was improved by a TNF inhibitor.
Circulating miR‐99b‐5p as a novel predictor of erosion progression on high‐resolution peripheral quantitative computed tomography in early rheumatoid arthritis: A prospective cohort study
Authors: Yue Jiang , Lau Terrence C. K. , Griffith James F. , Xu Jiankun , Xiao Fan , Shi Lin , Wang Defeng , Wong Priscilla C. H. , Li Edmund K. , Tam Lydia P. , Li Martin , Li Tena K. , Mak Wah Yan , Hung Vivian , Qin Ling , Tam Lai‐Shan
Published: July 2019

Objectives

To compare micro RNA (miRNA) expression: (a) between healthy individuals and early rheumatoid arthritis (ERA) patients with and without erosion on high‐resolution peripheral quantitative computed tomography (HR‐pQCT) at baseline; and (b) to explore whether these miRNAs could inform a signature predictive of erosion progression despite treatment with conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs).

Methods

The second metacarpophalangeal head (MCP2) was scanned by HR‐pQCT at baseline and 1 year in 117 ERA patients. We performed global profiling of 377 miRNAs in 10 ERA patients with and without erosion on HR‐pQCT at baseline and six healthy controls. Validation of the miRNAs of interest were conducted using TaqMan® quantitative real‐time polymerase chain reaction in the validation ERA cohort (n = 117) at baseline. Correlation between the candidate miRNAs and erosion progression over 1 year were also assessed.

Results

In the 377 screened miRNAs, 94 (60.6%) miRNAs were upregulated in patients with erosions, with 13 (8.4%) upregulated more than 2‐fold. Sixty‐one (39.4%) miRNAs were downregulated in patients with erosions, with 6 (3.9%) downregulated more than 2‐fold. Expression of miR‐143‐3p, miR‐145‐5p and miR‐99b‐5p were significantly higher in the plasma of ERA patients with erosions compared with those without erosions. Logistic regression analysis revealed that the baseline expression of miR‐99b‐5p was an independent predictor of erosion progression at month 12 (Exp [B] = 4.257, 95% CI 1.178‐15.386, P = 0.027).

Conclusions

Differential expressions of circulating miR‐143‐3p, miR‐145‐5p and miR‐99b‐5p in the plasma of ERA patients may characterize a severe form of the disease. MiR‐99b‐5p, in particular, may serve as a possible predictor for erosion progression.
Market response to dividend change announcements: unregulated versus regulated US firms
Authors: Khokhar Abdul‐Rahman , Sarkar Sudipto
Published: July 2019

This paper attempts to determine whether there is a significant difference in how the stock market responds to dividend change announcements of regulated (both utilities and financials) versus unregulated firms and, if so, which factors cause this difference. An analysis of dividend change announcements of US firms over the period 1962–2016 shows that the market response is larger for unregulated than for regulated firms, but this difference is statistically significant only for dividend increases (not for dividend decreases). Further, cross‐sectional analysis indicates that, for dividend increases, the difference between regulated and unregulated firms increases with diffused ownership and informational asymmetry. When both these factors are controlled for, the difference between regulated and unregulated firms becomes statistically insignificant. Thus, the evidence suggests that the significant difference in market response to dividend increases of regulated versus unregulated firms can be explained by differences in diffused ownership and informational asymmetry. There seems to be no intrinsic difference between regulated and unregulated firms in the market response to dividend decreases.
Carbapenem sparing in the management of post‐transrectal prostate biopsy bacteraemia
Authors: Trad Mohamad‐Ali , Materne Mishael , Reynolds Gemma , Yao Jinna , Miyakis Spiros , Skyring Tim , Newton Peter
Published: July 2019

Background

Sepsis following transrectal ultrasound (TRUS)‐guided prostate biopsy is a major complication. With the emergence of multidrug‐resistant organisms, empirical use of carbapenem antibiotics has been increasing. This study, conducted in the Illawarra Shoalhaven Local Health District (ISLHD), Australia, quantifies how much we can spare carbapenem use.

Methods

A retrospective audit of patients who underwent TRUS prostate biopsy and were admitted post‐operatively with proven bacteraemia between January 2007 and April 2016.

Results

Of 2719 TRUS procedures, 50 (1.84%) cases had bacteraemia. The most common isolate was Escherichia coli in 44 of 50 (88%) of which six of 50 (12%) were extended‐spectrum beta‐lactamase (ESBL)‐producing. Sixteen different empirical antimicrobial regimens were used, to which 42 of 50 (84%) of isolates were susceptible. Eight (16%) isolates were resistant to the chosen empiric combination, with five switched over to appropriate treatment once antimicrobial sensitivity results became available. Empirical carbapenem was utilized in 12 of 50 (24%) patients with only two of the ESBL isolates covered. A further 10 of 50 patients received carbapenems during their admission. Carbapenems could have been avoided in 18 of 22 (82%). A total of 86% of organisms (n = 43) were susceptible to the combination of amoxicillin–clavulanate and gentamicin.

Conclusion

Although the rates of bacteraemia with ESBL‐producing organisms post‐TRUS biopsy are increasing, use of carbapenem‐free combination antimicrobials as empirical therapy appears to be safe and effective in our setting. Clinicians can utilize local resistance patterns to inform targeted and appropriate therapy for septic patients.
Inferior load generated by preloaded versus manually loaded haemorrhoid banding devices: the effect of ‘creep relaxation’
Authors: Moloney Jayson , Hiscock Richard , Nguyen M. Hung
Published: July 2019

Background

The efficacy of rubber band ligation of haemorrhoids relies on the load generated on haemorrhoidal tissue by bands as they return to their preformed shape after being deployed. ‘Preloaded’ haemorrhoid banding devices are widely available, but the effect of the resultant prolonged stretch on bands while stored in this manner has never been examined by comparing these to manually loaded devices, which are stretch immediately prior to being deployed. A difference could have clinical relevance, potentially resulting in a higher rate of clinical failure. The present study aimed to investigate any difference in load generated by preloaded versus manually loaded devices.

Methods

A preloaded and a manually loaded device were selected for comparison. Each type was measured on a testing rig. The device type, load generated by each band and the time to expiry were recorded.

Results

A total of 137 haemorrhoid bands were tested: 66 preloaded and 71 manually loaded. There was a statistically significant overall reduction in load generated by preloaded versus manually loaded devices (284.0 versus 272.1 g, mean difference −11.9 g, 95% confidence interval −17.5 to −6.3 g, P = 0.0001). Adjusted for time, the load generated by preloaded bands fell 3.7 g (95% confidence interval 2.7–4.8, P < 0.001) for each month closer to the expiry date.

Conclusions

The load generated by haemorrhoid bands from preloaded devices is lower and deteriorates significantly towards their expiry date compared with bands from manually loaded devices. This is mostly likely due to their storage in a stretched state. This should be considered by clinicians when using haemorrhoid banding devices.
Medication management needs information and communications technology‐based approaches, including telehealth and artificial intelligence
Authors: Eggerth Alphons , Hayn Dieter , Schreier Günter
Published: July 2019

Life expectancy is rising in most parts of the world as is the prevalence of chronic diseases. Suboptimal adherence to long‐term medications is still rather the norm than the exception, although it is well known that suboptimal adherence compromises the therapeutic effectiveness. Information and communications technology provides new concepts for improving adherence to medications. These so‐called telehealth concepts or services help to implement closed‐loop healthcare paradigms and to establish collaborative care networks involving all stakeholders relevant to optimising the overall medication therapy. Together with data from Electronic Health Records and Electronic Medical Records, these networks pave the way to data‐driven decision support systems. Recent advances in machine learning, predictive analytics, and artificial intelligence allow further steps towards fully autonomous telehealth systems. This might bring advances in the future: disburden healthcare professionals from repetitive tasks, enable them to timely react to critical situations, and offer a comprehensive overview of the patients' medication status. Advanced analytics can help to assess whether patients have taken their medications as prescribed, to improve adherence via automatic reminders. Ultimately, all relevant data sources need to be collated into a basis for data‐driven methods, with the goal to assist healthcare professionals in guiding patients to obtain the best possible health status, with a reasonable resource utilisation and a risk‐adjusted safety and privacy approach. This paper summarises the state‐of‐the‐art of telehealth and artificial intelligence applications in medication management. It focuses on 3 major aspects: latest technologies, current applications, and patient related issues.
The mechanism of Psoralen and Isopsoralen hepatotoxicity as revealed by hepatic gene expression profiling in SD rats
Authors: Song Lei , Yu Bin , Yang Li , Wang Zhao‐xin , Zhang Yue , Yu Ying‐li , Zhou Kun
Published: July 2019

Background

The main bioactive components of Fructus psoraleae, such as psoralen and isopsoralen, are known to be hepatotoxic. However, its underlying mechanism is to be elucidated.

Methods

To address this, SD rats were randomly divided into control group, 60 mg/kg psoralen group and 60 mg/kg isopsoralen group. Blood was collected to detect serum biochemical indices. RNA was extracted from liver samples, and then, cDNA gene expression profiles were analysed.

Results

Psoralen administration significantly up‐regulated serum AST (aspartate aminotransferase) while addition of isopsoralen increased serum ALT (alanine aminotransferase), AST, TBA (total bile acid) and TG (total triglyceride) levels. A total of 172 differentially expressed genes (DEGs) were acquired between psoralen group and control group while 884 DEGs were screened between isopsoralen group and control group. Chemical Carcinogenesis and Metabolism of Xenobiotics by Cytochrome P450 were the two most significantly enriched pathways as revealed by DEGs. Liver was the most impacted organ, and endoplasmic reticulum was the most impacted organelle in subcellular level. Finally, some kinds of cancers and cytochrome p450 oxidoreductase deficiency were predicted. Taken together, psoralen and isopsoralen might cause hepatotoxicity mainly through cytochrome P450 metabolism of xenobiotics. Furthermore, Cyp1a1, Cyp1a2, Gstm1 and Akr7a3 worked as key genes in hepatotoxicity. Moreover, endoplasmic reticulum was the main target subcellular structure in hepatotoxicity induced by psoralen and isopsoralen.
Mycorrhizal types differ in ecophysiology and alter plant nutrition and soil processes
Authors: Tedersoo Leho , Bahram Mohammad
Published: July 2019

Mycorrhizal fungi benefit plants by improved mineral nutrition and protection against stress, yet information about fundamental differences among mycorrhizal types in fungi and trees and their relative importance in biogeochemical processes is only beginning to accumulate. We critically review and synthesize the ecophysiological differences in ectomycorrhizal, ericoid mycorrhizal and arbuscular mycorrhizal symbioses and the effect of these mycorrhizal types on soil processes from local to global scales. We demonstrate that guilds of mycorrhizal fungi display substantial differences in genome‐encoded capacity for mineral nutrition, particularly acquisition of nitrogen and phosphorus from organic material. Mycorrhizal associations alter the trade‐off between allocation to roots or mycelium, ecophysiological traits such as root exudation, weathering, enzyme production, plant protection, and community assembly as well as response to climate change. Mycorrhizal types exhibit differential effects on ecosystem carbon and nutrient cycling that affect global elemental fluxes and may mediate biome shifts in response to global change. We also note that most studies performed to date have not been properly replicated and collectively suffer from strong geographical sampling bias towards temperate biomes. We advocate that combining carefully replicated field experiments and controlled laboratory experiments with isotope labelling and ‐omics techniques offers great promise towards understanding differences in ecophysiology and ecosystem services among mycorrhizal types.
The puborectal continence reflex functions independently of the pudendal nerve
Authors: Jonker J. E. , van Meegdenburg M. M. , Trzpis M. , Broens P. M. A.
Published: July 2019

Aim

The ability of patients with poor pudendal nerve function to voluntarily contract their external anal sphincter is limited. However, it is not known whether the condition of the pudendal nerve influences voluntary puborectal muscle contraction. Recently, we described the puborectal continence reflex that maintains faecal continence by involuntary contractions of the puborectal muscle. We aim to investigate whether both voluntary and involuntary contractions of the puborectal muscle are influenced by the condition of the pudendal nerve.

Method

We retrospectively analysed 129 adult patients who underwent anorectal function tests at the Anorectal Physiology Laboratory. Anal electrosensitivity was used as a measurement of the pudendal nerve function. Voluntary and involuntary contractions of the puborectal muscle were defined as maximum puborectal muscle contractility and maximum pressure at the level of the puborectal muscle during the balloon retention test.

Results

Voluntary contraction of the puborectal muscle was significantly decreased in patients with pudendal nerve damage (P = 0.002). Involuntary contractions, however, were not associated with the condition of the pudendal nerve (P = 0.63). Multiple linear regression analysis showed that the condition of the pudendal nerve and patients’ sex significantly predicted voluntary contraction but not involuntary contraction.

Conclusion

Voluntary contractions of the puborectal muscle are significantly decreased in patients with pudendal nerve damage, while involuntary contractions of the puborectal muscle are comparable to those of patients without nerve damage. We conclude that the puborectal continence reflex, which controls involuntary contractions of the puborectal muscle, is not regulated by the pudendal nerve.
Evidential Strength of Intonational Cues and Rational Adaptation to (Un‐)Reliable Intonation
Authors: Roettger Timo B. , Franke Michael
Published: July 2019

Intonation plays an integral role in comprehending spoken language. Listeners can rapidly integrate intonational information to predictively map a given pitch accent onto the speaker's likely referential intentions. We use mouse tracking to investigate two questions: (a) how listeners draw predictive inferences based on information from intonation? and (b) how listeners adapt their online interpretation of intonational cues when these are reliable or unreliable? We formulate a novel Bayesian model of rational predictive cue integration and explore predictions derived under a concrete linking hypothesis relating a quantitative notion of evidential strength of a cue to the moment in time, relative to the unfolding speech signal, at which mouse trajectories turn towards the eventually selected option. In order to capture rational belief updates after concrete observations of a speaker's behavior, we formulate and explore an extension of this model that includes the listener's hierarchical beliefs about the speaker's likely production behavior. Our results are compatible with the assumption that listeners rapidly and rationally integrate all available intonational information, that they expect reliable intonational information initially, and that they adapt these initial expectations gradually during exposition to unreliable input. All materials, data, and scripts can be retrieved here:https://osf.io/dnbuk/