bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanical reinforcement of protein L fromFinegoldia magnapoints to a new bind-and-search mechanism
Authors: Dahal Narayan R. , Nowitzke Joel , Eis Annie , Popa Ionel
Published: August 2019

Several significant bacterial pathogens in humans secrete surface proteins that bind antibodies in order to protect themselves from the adaptive immune response and have evolved to operate under the mechanical sheer generated by mucus flow, coughing or urination. Protein L is secreted byFinegoldia magnaand has several antibody-binding domains. These domains have two antibody-binding sites with vastly different avidity and the function of the second weaker binding interface is currently unknown. Here we use magnetic tweezers and covalent attachment via HaloTag and SpyTag to expose Protein L to unfolding forces in the absence and presence of antibody-ligands. We find that antibody binding increases the mechanical stability of protein L. Using the change in mechanical stability as a binding reporter, we determined that the low-avidity binding site is acting as a mechano-sensor. We propose a novel mechanism where the high-avidity binding site engages the tether, while the low-avidity binding site acts as a mechano-sensor, allowing bacteria to sample the antibody surface concentration and localize its search during successful binding under strain.

Significance

It is well known that bacteria have an arsenal of tools to invade and to avoid dislocation. Based on the molecular response of a protein used by anaerobic bacteria to attach to antibodies and disrupt the immune system, here we report on a force-sensor-like behavior, triggered by antibody clusters and force. This pseudo-catch bond between bacteria and antibodies is activated through a second binding site which has lower avidity to antibodies, and which acts as a mechanical sensor, potentially regulating the search radii of the bacterium. Understanding of the bacteria attachment mechanism is of great importance toward developing new antibiotics and mechano-active drugs.
Heritable gene expression variability governs clonal heterogeneity in circadian period
Authors: Nikhil K.L. , Korge Sandra , Achim Kramer
Published: August 2019

A ubiquitous feature of circadian clocks across life forms is its organization as a network of coupled cellular oscillators. Individual cellular oscillators of the network often exhibit a considerable degree of heterogeneity in their intrinsic periods. While the interaction of coupling and heterogeneity in circadian clock networks is hypothesized to influence clock’s entrainability, our knowledge of mechanisms governing network heterogeneity remains elusive. In this study, we aimed to explore the principles that underlie inter-cellular period variation in circadian clock networks (clonal period-heterogeneity). To this end, we employed a laboratory selection approach and derived a panel of 25 clonal cell populations exhibiting circadian periods ranging from 22 h to 28 h. We report that while a single parent clone can produce progeny clones with a wide distribution of circadian periods, heterogeneity is not entirely stochastically driven but has a strong heritable component. By quantifying the expression of 20 circadian clock and clock-associated genes across our panel, we found that inheritance of different expression patterns in at least three clock genes might govern clonal period-heterogeneity in circadian clock networks. Furthermore, we provide preliminary evidence suggesting that epigenetic variation might underlie such gene expression variation.
Surfaceome dynamics during neuronal development and synaptic plasticity reveal system-wide surfaceome reorganization independent of global proteostasis
Authors: van Oostrum Marc , Campbell Benjamin , Müller Maik , Pedrioli Patrick G. A. , Tyagarajan Shiva K. , Wollscheid Bernd
Published: August 2019

Neurons are highly compartmentalized cells with tightly controlled subcellular protein organization. While broad brain transcriptome, connectome and global proteome maps are being generated, system-wide analysis of temporal protein dynamics at the subcellular level are currently lacking for neuronal development and synapse formation. We performed a temporally-resolved surfaceome analysis of developing primary neuron cultures to a depth of 1000bona fidesurface proteins and reveal dynamic surface protein clusters that reflect the functional requirements during distinct stages of neuronal development. Moreover, our data shows that synaptic proteins are globally trafficked to the surface prior to synapse formation. Direct comparison of surface and total protein pools demonstrates that, depending on the time scale, surface abundance changes can correlate or differ from total protein abundance. The uncoupling of surface and total abundance changes has direct functional implications as shown in the context of synaptic vesicle transport. To demonstrate the utility of our approach we analyzed the surfaceome modulation in response to homeostatic synaptic scaling and found dynamic remodeling of the neuronal surface, which was largely independent of global proteostasis, indicative of wide-spread regulation on the level of surface trafficking. Finally, we present a quantitative analysis of the neuronal surface during early-phase long-term potentiation (LTP) and reveal fast externalization of diverse classes of surface proteins beyond the AMPA receptor, providing new insights into the requirement of exocytosis for LTP. Our resource and finding of organizational principles highlight the importance of subcellular resolution for systems-level understanding of cellular processes, which are typically masked by broad omics-style approaches.
Anomalous phylogenetic behavior of ribosomal proteins in metagenome assembled genomes
Authors: Garg Sriram G. , Kapust Nils , Lin Weili , Tria Fernando D. K. , Nelson-Sathi Shijulal , Gould Sven B. , Fan Lu , Zhu Ruixin , Zhang Chuanlun , Martin William F.
Published: August 2019

Metagenomic studies have claimed the existence of novel lineages with unprecedented properties never before observed in prokaryotes. Such lineages include Asgard archaea1–3, which are purported to represent archaea with eukaryotic cell complexity, and the Candidate Phyla Radiation (CPR), a novel domain level taxon erected solely on the basis of metagenomic data4. However, it has escaped the attention of most biologists that these metagenomic sequences are not assembled into genomes by sequence overlap, as for cultured archaea and bacteria. Instead, short contigs are sorted into computer files by a process called binning in which they receive taxonomic assignment on the basis of sequence properties like GC content, dinucleotide frequencies, and stoichiometric co-occurrence across samples. Consequently, they are not genome sequences as we know them, reflecting the gene content of real organisms. Rather they are metagenome assembled genomes (MAGs). Debates that Asgard data are contaminated with individual eukaryotic sequences5–7are overshadowed by the more pressing issue that no evidence exists to indicate that any sequences in binned Asgard MAGs actually stem from the same chromosome, as opposed to simply stemming from the same environment. Here we show that Asgard and CPR MAGs fail spectacularly to meet the most basic phylogenetic criterion8fulfilled by genome sequences of all cultured prokaryotes investigated to date: the ribosomal proteins of Asgard and CPR MAGs do not share common evolutionary histories. Their phylogenetic behavior is anomalous to a degree never observed with genomes of real organisms. CPR and Asgard MAGs are binning artefacts, assembled from environments where up to 90% of the DNA is from dead cells9–12. Asgard and CPR MAGs are unnatural constructs, genome-like patchworks of genes that have been stitched together into computer files by binning.
Does Vision Extract Absolute Distance from Vergence?
Authors: Linton Paul
Published: August 2019

Since Kepler (1604) and Descartes (1638), ‘vergence’ (the angular rotation of the eyes) has been thought of as one of our most important absolute distance cues. But vergence has never been tested as an absolute distance cue divorced from obvious confounding cues such as binocular disparity. In this article we control for these confounding cues for the first time by gradually manipulating vergence, and find that observers fail to accurately judge distance from vergence. We consider a number of different interpretations of these results, and argue that the most principled response to these results is to question the general effectiveness of vergence as an absolute distance cue. Given other absolute distance cues (such as motion parallax and vertical disparities) are limited in application, this poses a real challenge to our contemporary understanding of visual scale.
Hierarchical Ensembles of Intrinsically Disordered Proteins at Atomic Resolution in Molecular Dynamics Simulations
Authors: Pietrek Lisa M. , Stelzl Lukas S. , Hummer Gerhard
Published: August 2019

Intrinsically disordered proteins (IDPs) constitute a large fraction of the human proteome and are critical in the regulation of cellular processes. A detailed understanding of the conformational dynamics of IDPs could help to elucidate their roles in health and disease. However the inherent flexibility of IDPs makes structural studies and their interpretation challenging. Molecular dynamics (MD) simulations could address this challenge in principle, but inaccuracies in the simulation models and the need for long simulations have stymied progress. To overcome these limitations, we adopt an hierarchical approach that builds on the “flexible meccano” model of Bernadó et al. (J. Am. Chem. Soc. 2005, 127, 17968-17969). First, we exhaustively sample small IDP fragments in all-atom simulations to capture local structure. Then, we assemble the fragments into full-length IDPs to explore the stereochemically possible global structures of IDPs. The resulting ensembles of three-dimensional structures of full-length IDPs are highly diverse, much more so than in standard MD simulation. For the paradigmatic IDPα-synuclein, our ensemble captures both local structure, as probed by nuclear magnetic resonance (NMR) spectroscopy, and its overall dimension, as obtained from small-angle X-ray scattering (SAXS) in solution. By generating representative and meaningful starting ensembles, we can begin to exploit the massive parallelism afforded by current and future high-performance computing resources for atomic-resolution characterization of IDPs.
CRISPR-Cas systems in the plant pathogenXanthomonasspp. and their impact on genome plasticity
Authors: Martins Paula Maria Moreira , da Silva Xavier Andre , Takita Marco Aurelio , Alfemas-Zerbini Poliane , de Souza Alessandra Alves
Published: August 2019

Xanthomonasis one of the most important bacterial genera of plant pathogens causing economic losses in crop production worldwide. Despite its importance, many aspects of basicXanthomonasbiology remain unknown or understudied. Here, we present the first genus-wide analysis of CRISPR-Cas inXanthomonasand describe specific aspects of its occurrence. Our results show thatXanthomonasgenomes harbour subtype I-C and I-F CRISPR-Cas systems and that species belonging to distantlyXanthomonas-related genera inXanthomonadaceaeexhibit the same configuration of coexistence of the I-C and I-F CRISPR subtypes. Additionally, phylogenetic analysis using Cas proteins indicated that the CRISPR systems present inXanthomonasspp. are the result of an ancient acquisition. Despite the close phylogeny of these systems, they present significant variation in both the number and targets of spacers. An interesting characteristic observed in this study was that the identified plasmid-targeting spacers were always driven toward plasmids found in otherXanthomonasstrains, indicating that CRISPR-Cas systems could be very effective in coping with plasmidial infections. Since many effectors are plasmid encoded, CRISPR-Cas might be driving specific characteristics of plant-pathogen interactions.
Impact of Candida auris infection in a neutropenic murine model
Authors: Torres Steven R. , Pichowicz Amber , Torres-Velez Fernando , Song Renjie , Singh Navjot , Nesselquist Erica Lasek , De Jesus Magdia
Published: August 2019

Candida auris has become a global public health threat due to its multidrug resistance and persistence in hospital and nursing home settings. Although a skin colonizer, C. auris can cause fatal bloodstream infections and most patients succumb to multi-organ failure. Currently, there are limited animal models to study the progression of C. auris infection. Here we compare two murine models of neutrophil depletion using monoclonal antibodies 1A8, anti-Ly6G+ and RB6-8C5 anti-Ly6G+-Ly6C+. We also compare inoculums of 107 and 108 as well as the intravenous and gavage routes of infection. The results reveal that neutrophil depletion in BALB/c mice is sustained long-term with the 1A8 antibody and short-term with RB6-8C5. Target organs were kidney, heart and brain as these had the highest organ fungal burden in neutrophil depleted and to some extent in infected control mice. We found that C. auris is shed in urine and feces for neutrophil depleted mice. The gavage model is not an ideal route as dissemination was not detected. Eight days post C. auris infection all surviving mice display a unique behavioral phenotype characterized by torticollis and tail spin that progresses to head bobbing and body curling like phenotype by day 22, that continues to persist even 104 days post infection. Lastly, we found C. auris remains in tissues of infected control mice, 34 plus days post infection suggesting that C. auris stays present in the host without causing disease but becomes opportunistic upon a change in the hosts immune status such as neutrophil depletion.
Separable codes for read-out of mouse primary visual cortex across attentional states
Authors: Wilson Ashley M. , Beck Jeffrey M. , Glickfeld Lindsey L.
Published: August 2019

Attentional modulation of neuronal activity in sensory cortex could alter perception by enhancing the local representation of attended stimuli or its behavioral read-out downstream. We tested these hypotheses using a task in which mice are cued on interleaved trials to attend visual or auditory targets. Neurons in primary visual cortex (V1) that encode task stimuli have larger visually-evoked responses when attention is directed toward vision. To determine whether the attention-dependent changes in V1 reflect changes in representation or read-out, we decoded task stimuli and choices from population activity. Surprisingly, both visual and auditory choices can be decoded from V1, but decoding takes advantage of unique activity patterns across modalities. Furthermore, decoding of choices, but not stimuli, is impaired when attention is directed toward the opposite modality. The specific effect on choice suggests behavioral improvements with attention are largely due to targeted read-out of the most informative V1 neurons.
A Game of Thrones at Human Centromeres I. Multifarious structure necessitates a new molecular/evolutionary model
Authors: Rice William R.
Published: August 2019

Human centromeres form over arrays of tandemly repeated DNA that are exceptionally complex (repeats of repeats) and long (spanning up to 8 Mbp). They also have an exceptionally rapid rate of evolution. The generally accepted model for the expansion/contraction, homogenization and evolution of human centromeric repeat arrays is a generic model for the evolution of satellite DNA that is based on unequal crossing over between sister chromatids. This selectively neutral model predicts that the sequences of centromeric repeat units will be effectively random and lack functional constraint. Here I used shotgun PacBio SMRT reads from a homozygous human fetal genome (female) to determine and compare the consensus sequences (and levels of intra-array variation) for the active centromeric repeats of all the chromosomes. To include the Y chromosome using the same technology, I used the same type of reads from a diploid male. I found many different forms and levels of conserved structure that are not predicted by –and sometimes contradictory to– the unequal crossing over model. Much of this structure is based on spatial organization of three types of ~170 bp monomeric repeat units that are predicted to influence centromere strength (i.e., the level of outer kinetochore proteins): one with a protein-binding sequence at its 5’ end (a 17 bp b-box that binds CENP-B), a second that is identical to the first except that the b-box is mutated so that it no longer binds CENP-B, and a third lacking a b-box but containing a 19 bp conserved “n-box” sequence near its 5’ end. The frequency and organization of these monomer types change markedly as the number of monomers per repeat unit increases, and also differs between inactive and active arrays. Active arrays are also much longer than flanking, inactive arrays, and far longer than required for cellular functioning. The diverse forms of structure motivate a new hypothesis for the lifecycle of human centromeric sequences. These multifarious levels of structures, and other lines of evidence, collectively indicate that a new model is needed to explain the form, function, expansion/contraction, homogenization and rapid evolution of centromeric sequences.
Among family variation in survival and gene expression uncovers adaptive genetic variation in a threatened fish
Authors: Harder Avril M. , Willoughby Janna R. , Ardren William R. , Christie Mark R.
Published: August 2019

Variation in among-family transcriptional responses to different environmental conditions can help to identify adaptive genetic variation, even prior to a selective event. Coupling differential gene expression with formal survival analyses allows for the disentanglement of treatment effects, required for understanding how individuals plastically respond to environmental stressors, from the adaptive genetic variation responsible for among-family variation in survival and gene expression. We applied this experimental design to investigate responses to an emerging conservation issue, thiamine (vitamin B1) deficiency, in a threatened population of Atlantic salmon (Salmo salar). Thiamine is an essential vitamin that is increasingly limited in many ecosystems. In Lake Champlain, Atlantic salmon cannot acquire thiamine in sufficient quantities to support natural reproduction; fertilized eggs must be reared in hatcheries and treated with supplemental thiamine. We evaluated transcriptional responses (RNA-seq) to thiamine treatment across families and found 3,616 genes differentially expressed between control (no supplemental thiamine) and treatment individuals. Fewer genes changed expression additively (i.e., equally among families) than non-additively (i.e., family-by-treatment effects) in response to thiamine. Differentially expressed genes were related to known physiological effects of thiamine deficiency, including oxidative stress, cardiovascular irregularities, and neurological abnormalities. We also identified 1,446 putatively adaptive genes that were strongly associated with among-family survival in the absence of thiamine treatment, many of which related to neurogenesis and visual perception. Our results highlight the utility of coupling RNA-seq with formal survival analyses to identify candidate genes that underlie the among-family variation in survival required for an adaptive response to natural selection.
Decoding and modulating multiregional communication in the mood processing network
Authors: Qiao Shaoyu , Sedillo J. Isaac , Brown Kevin A. , Ferrentino Breonna , Pesaran Bijan
Published: August 2019

Neural decoding and neuromodulation technologies hold great promise for treating mood and other brain disorders in next-generation therapies that manipulate functional brain networks. Here, we perform a novel causal network analysis to decode multiregional communication in the primate mood processing network and determine how neuromodulation, short-burst tetanic microstimulation (SB-TetMS), alters multiregional network communication. The causal network analysis revealed a mechanism of network excitability that regulates when a sender stimulation site communicates with receiver sites. Decoding network excitability from neural activity at modulator sites predicted sender-receiver communication while SB-TetMS neuromodulation specifically disrupted sender-receiver communication. These results reveal specific network mechanisms of multiregional communication and suggest a new generation of brain therapies that combine neural decoding to predict multiregional communication with neuromodulation to disrupt multiregional communication.

One Sentence Summary

Decoding and modulating multiregional network communication.
Efficient multiplex genome editing using CRISPR-Mb3Cas12a in mice
Authors: Wang Zhuqing , Wang Yue , Wang Shawn , Gorzalski Andrew J , McSwiggin Hayden , Yu Tian , Castaneda-Garcia Kimberly , Zheng Huili , Yan Wei
Published: August 2019

Despite many advantages over Cas9, Cas12a has not been widely used in genome editing in mammalian cells largely due to its strict requirement of the TTTV protospacer adjacent motif (PAM) sequence. Here, we report that Mb3Cas12a (Moraxella bovoculi AAX11_00205) could edit the genome in murine zygotes independent of TTTV PAM sequences and with minimal on-target mutations and close to 100% editing efficiency when crRNAs of 23nt spacers were used.

Summary statement

CRISPR-Mb3Cas12a can target a broader range of sequences in murine zygotes compared to AsCas12a and LbCas12a, and has lower on-target effects than Cas9 and high overall knock-in efficiency.
Whole-brain MEG decoding of symbolic and non-symbolic number stimuli reveals primarily format-dependent representations
Authors: Bankson Brett B. , Janini Daniel , Baker Chris I.
Published: August 2019

The human brain can rapidly form representations of numerical magnitude, whether presented with symbolic stimuli like digits and words or non-symbolic stimuli like dot displays. Little is known about the relative time course of these symbolic and non-symbolic number representations. We investigated the emergence of number representations for three stimulus formats - digits, words, and dot arrays - by applying multivariate pattern analysis to MEG recordings from 22 participants. We first conducted within-format classification to identify the time course by which individual numbers can be decoded from the MEG signal. Peak classification accuracy for individual numbers in all three formats occurred around 110 ms after stimulus onset. Next, we used between-format classification to determine the time course of shared number representations between stimulus formats. Classification accuracy between formats was much weaker than within format classification, but it was also significant at early time points, around 100 ms for both digit / dot and digit / word comparisons. We then used representational similarity analysis to determine if we could explain variance in the MEG representational geometry using two models: a GIST feature model capturing low-level visual properties and an approximate number model capturing the numerical magnitude of the stimuli. Model RSA results differed between stimulus formats: while the GIST model explained unique variance from 100-300 ms for all number formats, the performance of the approximate number model differed between formats. Together, these results are consistent with the view that distinct, format-specific number representations, moreso than a single “abstract” number representation, form the basis of numerical comparison.
Microbial diversity of the Arabian Sea in the Oxygen minimum zones by metagenomics approach
Authors: Paingankar Mandar S. , Ahire Kedar , Mishra Pawan , Rajpathak Shriram , Deobagkar Deepti D.
Published: August 2019

Large oxygen depleted areas known as oxygen minimum zones (OMZ) have been observed in the Arabian Sea and recent reports indicate that these areas are expanding at an alarming rate. In marine waters, oxygen depletion may also be related to global warming and the temperature rise, acidification and deoxygenation can lead to major consequences wherein the plants, fish and other biota will struggle to survive in the ecosystem.

The current study has identified the microbial community structure using NGS based metagenomics analysis in the water samples collected at different depth from the oxygen depleted and non-OMZ areas of Arabian Sea. Environmental variables such as depth, site of collection and oxygen concentration appeared to influence the species richness and evenness among microbial communities in these locations. Our observations clearly indicate that population dynamics of microbes consisting of nitrate reducers accompanied by sulphate reducers and sulphur oxidizers participate in the interconnected geochemical cycles of the OMZ areas. In addition to providing baseline data related to the diversity and microbial community dynamics in oxygen-depleted water in the OMZ; such analysis can provide insight into processes regulating productivity and ecological community structure of the ocean.
Effect of Vitamin D Supplementation on Vascular Function and Inflammation in Patients with Chronic Kidney Disease: A Controversial Issue
Authors: Hu Chun , Wu Xiaoyan
Published: August 2019

Vitamin D deficiency is common in patients with CKD and is associated with vascular dysfunction and inflammation. In recent years, some randomized controlled trials have revealed the effect of vitamin D supplementation on vascular function and inflammation in CKD patients, but the results are inconsistent. Thus, in light of the controversy, we performed a systematic review and meta‐analysis of the effect of vitamin D in patients with CKD. We searched the literature in multiple databases for clinical trials from the date of inception to December 2018. The standardized mean difference (SMD) effect size was pooled using fixed and random effects models. A total of 10 randomized controlled trials involving 579 patients were included in the meta‐analysis; among these, 313 patients were treated with vitamin D, and the control group included 266 who received a placebo. This meta‐analysis revealed no statistical significance in the levels of flow‐mediated dilatation (SMD, 0.94; 95% CI, −0.33 to 2.21; P = 0.15); pulse wave velocity (SMD, −0.13; 95% CI, −0.38 to 0.13; P = 0.33); systolic BP (SMD, −0.04; 95% CI, −0.29 to 0.22; P = 0.77); diastolic BP (SMD, 0.01; 95% CI, −0.26 to 0.27; P = 0.97); and CRP (SMD, −0.09; 95% CI, −0.44 to 0.26; P = 0.61) between the vitamin D group and controls for patients with CKD. Short‐term intervention with vitamin D was not associated with improvements in vascular function and inflammation, as measured by flow‐mediated dilatation, pulse wave velocity, systolic BP, diastolic BP and CRP. This suggested that there is insufficient evidence to conclude the benefit of vitamin D supplementation on vascular function and inflammation in CKD patients.
Using machine vision to estimate fish length from images using regional convolutional neural networks
Authors: Monkman Graham G. , Hyder Kieran , Kaiser Michel J. , Vidal Franck P.
Published: August 2019

An image can encode date, time, location and camera information as metadata and implicitly encodes species information and data on human activity, for example the size distribution of fish removals. Accurate length estimates can be made from images using a fiducial marker; however, their manual extraction is time‐consuming and estimates are inaccurate without control over the imaging system. This article presents a methodology which uses machine vision to estimate the total length (TL) of a fusiform fish (European sea bass).

Three regional convolutional neural networks (R‐CNN) were trained from public images. Images of European sea bass were captured with a fiducial marker with three non‐specialist cameras. Images were undistorted using the intrinsic lens properties calculated for the camera in OpenCV; then TL was estimated using machine vision (MV) to detect both marker and subject. MV performance was evaluated for the three R‐CNNs under downsampling and rotation of the captured images.

Each R‐CNN accurately predicted the location of fish in test images (mean intersection over union, 93%) and estimates of TL were accurate, with percent mean bias error (%MBE [95% CIs]) = 2.2% [2.0, 2.4]). Detections were robust to horizontal flipping and downsampling. TL estimates at absolute image rotations >20° became increasingly inaccurate but %MBE [95% CIs] was reduced to −0.1% [−0.2, 0.1] using machine learning to remove outliers and model bias.

Machine vision can classify and derive measurements of species from images without specialist equipment. It is anticipated that ecological researchers and managers will make increasing use of MV where image data are collected (e.g. in remote electronic monitoring, virtual observations, wildlife surveys and morphometrics) and MV will be of particular utility where large volumes of image data are gathered.
MiR‐21‐5p/dual‐specificity phosphatase 8 signalling mediates the anti‐inflammatory effect of haem oxygenase‐1 in aged intracerebral haemorrhage rats
Authors: Ouyang Yetong , Li Dongling , Wang Han , Wan Zhigang , Luo Qinghua , Zhong Yuqin , Yin Min , Qing Zhengfang , Li Zhengyu , Bao Bing , Chen Zhiying , Yin Xiaoping , Zhu Ling‐Qiang
Published: August 2019

Intracerebral haemorrhage (ICH) is a severe neurological disorder caused by bleeding within the brain tissue. Inflammation has been implicated in ICH pathogenesis and is a potential therapeutic target for ICH. Haemin, an activator of haem oxygenase‐1 (HO‐1), rapidly increases HO‐1 protein expression and activity and has been shown to distinctly affect anti‐inflammatory functions after central nervous system (CNS) injury. However, less is known about the mechanisms that underlie the anti‐inflammatory effects of haemin in aged rats post‐ICH. Here, we performed microarray analysis to identify miRNAs that respond strongly to HO‐1 regulation in ICH rats and found that miR‐21‐5p induced the most significant change. Using Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and Gene Ontology (GO) analysis, we focused on dual‐specificity phosphatase 8 (DUSP8) from the predicted miR‐21‐5p targets. Luciferase reporter assays confirmed that miR‐21‐5p bound directly to DUSP8. MiR‐21‐5p upregulation in vitro downregulated DUSP8 expression. Importantly, intracerebroventricularly injecting antagomir for miR‐21‐5p (A‐miR‐21‐5p), which was used to inhibit miR‐21‐5p in aged ICH rats, significantly reduced the neurological defects, repaired cognitive impairment, alleviated blood–brain barrier (BBB) permeability, inhibited neuronal apoptosis posthaemorrhage and accelerated haematoma absorption. In addition, serum miR‐21‐5p levels were notably elevated in patients relative to healthy individuals and were correlated with National Institutes of Health Stroke Scale (NIHSS) scores and clinical outcomes. In summary, A‐miR‐21‐5p increased HO‐1 expression in cerebral haematomas, thus eliciting the DUSP8‐modulated perifocal neuroprotective effect of haemin. MiR‐21‐5p with haemin therapy may be a potential therapy post‐ICH.
Why is trait scepticism not consistently reflected in state scepticism? An exploratory study into the role of aesthetic engagement
Authors: Khan Mohammad Jahanzeb , Harding Noel
Published: August 2019

Where an auditor's sceptical disposition (trait scepticism) is directed toward non‐diagnostic information, there is a risk that a sceptical consideration of diagnostic information could be diluted. This may be one reason why trait scepticism is not consistently reflected in sceptical judgments and actions (state scepticism). We develop a scale to measure an individual's predisposition toward engaging with visual elements of the environment (aesthetic engagement) and test, in two experiments employing students and practicing auditors, whether aesthetic engagement moderates the trait – state scepticism relationship. We find that aesthetic engagement attenuates the positive relationship between trait and state scepticism.
Confirmation bias in accounting judgments: the case for International Financial Reporting Standards for small and medium‐sized enterprises
Authors: Perera Dinuja , Chand Parmod , Mala Rajni
Published: August 2019

We conduct an experiment that investigates confirmation bias in the reporting judgments of accountants when applying International Financial Reporting Standards (IFRS) for small and medium‐sized enterprises (SMEs). The results indicate that accountants’ judgments are biased towards the recognition and measurement principles of full IFRS when applying IFRS for SMEs. The results also suggest that confirmation bias in judgments can be mitigated by increasing accountants’ awareness of justification requirements and by using appropriate decision aids. These results are likely to be of interest to the 70‐plus countries that have adopted the SME standard and countries that continue to contemplate its adoption.
Identification and characterization of latent classes based on drug use among men who have sex with men at risk of sexually transmitted infections in Amsterdam, the Netherlands
Authors: Achterbergh Roel C. A. , de Vries Henry J. C. , Boyd Anders , Davidovich Udi , Drückler Susanne , Hoornenborg Elske , Prins Maria , Matser Amy
Published: August 2019

Background and Aims

Men who have sex with men (MSM) are at high risk for both drug use and sexually transmitted infections (STI). We aimed to (1) identify subgroups of drug use during sex among MSM in Amsterdam and after classifying participants and (2) compare sexual behaviour and STI across groups.

Design

Cross‐sectional study. Latent class analysis was used to identify subgroups with similar drug use patterns, between which sexual behaviour and STI prevalence were compared.

Setting

Four different studies conducted at the STI out‐patient clinic in Amsterdam, the Netherlands, between January 2014 and June 2016.

Participants

A total of 1130 self‐declared MSM, aged ≥ 18 years.

Measurements

Self‐reported drug use, laboratory‐confirmed STI, socio‐demographics, sexual behaviour (including number of partners), condom use.

Findings

Median age was 40 years [interquartile range (IQR) = 32–47]. We identified five latent classes of users, which we labelled: ‘no substance’ (n = 162), ‘alcohol’ (n = 159), ‘nitrites and erectile dysfunction drugs (EDD)’ (n = 286), ‘polydrug’ (n = 257) and ‘chems’ (n = 266). Median number of sex partners significantly differed across classes (P < 0.001), ranging from two (IQR = 1–6) in the ‘no substance’ class to 20 (IQR = 10–45) in the ‘chems’ class. The proportion of MSM reporting condomless anal sex also differed across classes (P < 0.001), ranging from 45.6% in the ‘no substance’ class to 86.5% in the ‘chems’ class. Compared with the ‘no substance’ class, the odds of STI were 3.9‐fold [95% confidence interval (CI) = 1.1–14.4] higher in the ‘alcohol’ class, 8.9‐fold (95% CI = 2.7–29.2) higher in the ‘nitrites and EDD’ class, 12.8‐fold (95% CI = 3.9–41.9) higher in the ‘polydrug’ class and 15.0‐fold (95% CI = 4.6–48.8) higher in the ‘chems’ class.

Conclusion

There are five distinct classes of drug use in a sexual context among men who have sex with men in Amsterdam, the Netherlands. Classes with higher levels of drug use appear to coincide with higher levels of sexual risk behaviour and sexually transmitted infections.
Pannexin‐1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration
Authors: Tozzi Marco , Hansen Jacob B. , Novak Ivana
Published: August 2019

Aim

Extracellular ATP signalling is involved in many physiological and pathophysiological processes in several tissues, including adipose tissue. Adipocytes have crucial functions in lipid and glucose metabolism and they express purinergic receptors. However, the sources of extracellular ATP in adipose tissue are not well characterized. In the present study, we investigated the mechanism and regulation of ATP release in white adipocytes, and evaluated the role of extracellular ATP as potential autocrine and paracrine signal.

Methods

Online ATP release was monitored in C3H10T1/2 cells and freshly isolated murine adipocytes. The ATP release mechanism and its regulation were tested in cells exposed to adrenergic agonists, insulin, glucose load and pharmacological inhibitors. Cell metabolism was monitored using Seahorse respirometry and expression analysis of pannexin‐1 was performed on pre‐ and mature adipocytes. The ATP signalling was evaluated in live cell imaging (Ca2+, pore formation), glycerol release and its effect on macrophages was tested in co‐culture and migration assays.

Results

Here, we show that upon adrenergic stimulation white murine adipocytes release ATP through the pannexin‐1 pore that is regulated by a cAMP‐PKA–dependent pathway. The ATP release correlates with increased cell metabolism and is sensitive to glucose. Extracellular ATP induces Ca2+ signalling and lipolysis in adipocytes and promotes macrophage migration. Importantly, ATP release is markedly inhibited by insulin, which operates via the activation of phosphodiesterase 3.

Conclusions

Our findings reveal an insulin‐pannexin‐1‐purinergic signalling crosstalk in adipose tissue and we propose that deregulation of this signalling may contribute to adipose tissue inflammation and type 2 diabetes.
Making them visible and usable — vegetation‐plot observations from Fennoscandia based on historical species‐quantity scales
Authors: Pätsch Ricarda , Jašková Anni , Chytrý Milan , Kucherov Ilya B. , Schaminée Joop H. J. , Bergmeier Erwin , Janssen John A. M.
Published: August 2019

Aims

Present‐day large‐scale and plot‐based vegetation analyses contribute to the transnational characterization and interpretation of biodiversity patterns and to habitat typologies which are important for planning, monitoring and decision making in nature conservation. Many historical vegetation surveys applied cover abundance, relative occurrence or density scales (species‐quantity scales) that are nowadays poorly known and consequently disregarded or misinterpreted. Therefore, it is worthwhile to put effort into making them compatible with the datasets sampled using mainstream methods. Within Europe, this especially applies to historical data from Fennoscandia. Here, we aim to propose how to transform the species‐quantity scales frequently used in Fennoscandia into percentage cover scales, based on the conversion of their individual grades.

Study area

Fennoscandia, including Norway, Sweden, Finland and the Fennoscandian part of Russia (Republic of Karelia, Karelian Isthmus, Murmansk Region).

Methods and results

We inventoried Fennoscandian vegetation‐plot studies and identified that the most frequently applied species‐quantity scales were those of Norrlin, Hult–Sernander and Drude. We reviewed the definitions and applications of these scales in the literature and, if not available, calculated hypothetical species covers to approximate realistic conversions to the percentage scale. As a result, we propose alternative ways of conversion of the individual scale grades to mid‐percentage cover values.

Conclusion

Historical vegetation plot data from Fennoscandia can be used as quantitative information for vegetation research if their grades are consistently transformed into percentage cover values using the proposals presented in this paper.
The role of different patterns of psychomotor symptoms in major depressive episode: Pooled analysis of the BRIDGE and BRIDGE‐II‐MIX cohorts
Authors: Barbuti Margherita , Mainardi Cecilia , Pacchiarotti Isabella , Verdolini Norma , Maccariello Giuseppe , Angst Jules , Azorin Jean‐Michel , Bowden Charles L. , Mosolov Sergey , Young Allan H. , Vieta Eduard , Perugi Giulio
Published: August 2019

Background

Psychomotor agitation (PA) or retardation (PR) during major depressive episodes (MDEs) have been associated with depression severity in terms of treatment‐resistance and course of illness.

Objectives

We investigated the possible association of psychomotor symptoms (PMSs) during a MDE with clinical features belonging to the bipolar spectrum.

Methods

The initial sample of 7689 MDE patients was divided into three subgroups based on the presence of PR, PA and non‐psychomotor symptom (NPS). Univariate comparisons and multivariate logistic regression models were performed between subgroups.

Results

A total of 3720 patients presented PR (48%), 1971 showed PA (26%) and 1998 had NPS (26%). In the PR and PA subgroups, the clinical characteristics related to bipolarity, along with the diagnosis of bipolar disorder (BD), were significantly more frequent than in the NPS subgroup. When comparing PA and PR patients, the former presented higher rates of bipolar spectrum features, such as family history of BD (OR = 1.39, CI = 1.20‐1.61), manic/hypomanic switches with antidepressants (OR = 1.28, CI = 1.11‐1.48), early onset of first MDE (OR = 1.40, CI = 1.26‐1.57), atypical (OR = 1.23, CI = 1.07‐1.42) and psychotic features (OR = 2.08, CI = 1.78‐2.44), treatment with mood‐stabilizers (OR = 1.39, CI = 1.24‐1.55), as well as a BD diagnosis according to both the DSM‐IV criteria and the bipolar specifier criteria. When logistic regression model was performed, the clinical features that significantly differentiated PA from PR were early onset of first MDE, atypical and psychotic features, treatment with mood‐stabilizers and a BD diagnosis according to the bipolar specifier criteria.

Conclusions

Psychomotor symptoms could be considered as markers of bipolarity, illness severity, and treatment complexity, particularly if PA is present.
Permutation inference methods for multivariate meta‐analysis
Authors: Noma Hisashi , Nagashima Kengo , Furukawa Toshi A.
Published: August 2019

Multivariate meta‐analysis is gaining prominence in evidence synthesis research because it enables simultaneous synthesis of multiple correlated outcome data, and random‐effects models have generally been used for addressing between‐studies heterogeneities. However, coverage probabilities of confidence regions or intervals for standard inference methods for random‐effects models (eg, restricted maximum likelihood estimation) cannot retain their nominal confidence levels in general, especially when the number of synthesized studies is small because their validities depend on large sample approximations. In this article, we provide permutation‐based inference methods that enable exact joint inferences for average outcome measures without large sample approximations. We also provide accurate marginal inference methods under general settings of multivariate meta‐analyses. We propose effective approaches for permutation inferences using optimal weighting based on the efficient score statistic. The effectiveness of the proposed methods is illustrated via applications to bivariate meta‐analyses of diagnostic accuracy studies for airway eosinophilia in asthma and a network meta‐analysis for antihypertensive drugs on incident diabetes, as well as through simulation experiments. In numerical evaluations performed via simulations, our methods generally provided accurate confidence regions or intervals under a broad range of settings, whereas the current standard inference methods exhibited serious undercoverage properties.
Development of ligand‐coated beads to measure macrophage antimicrobial activities
Authors: Tram Trinh T. B. , Ha Vu T. N. , Thu Do D. A. , Dinh Tran D. , Vijay Srinivasan , Hai Hoang T. , Hanh Nguyen T. , Phu Nguyen H. , Thwaites Guy E. , Thuong Nguyen T. T.
Published: August 2019

Background information

After macrophage recognises and phagocytoses the microorganism, their phagosome undergoes a maturation process, which creates a hostile environment for the bacterium. The lumen is acidified, and proteolysis occurs to kill and degrade pathogen for further antigen presentation. It is important to understand the association between the macrophage intracellular activities and the outcome of infection. Different methods have been developed to measure the phagosome dynamics of macrophages, but there are still limitations.

Results

We used Mycobacterium tuberculosis (Mtb) antigens, the causative agent of tuberculosis (TB), as a model of infectious disease. Adopting a fluorescent bead‐based assay, we developed beads coated with trehalose 6,6′dimycolate (TDM) from Mtb cell wall and β‐glucan from yeast cell wall to measure the macrophage phagosomal activities using a microplate reader. We examined the consistency of the assay using J774 cells and validated it using human monocyte‐derived macrophages (hMDM) from healthy volunteers and TB patients. There was a decreased pH and increased proteolysis in the lumen of J774 cells after phagocytosing the ligand‐coated beads. J774 macrophage showed no difference in the acidification and proteolysis in response to control IgG beads, TDM and β‐glucan beads. hMDM from healthy volunteers or TB patients showed heterogeneity in the intracellular activities when treated with ligand‐coated beads.

Conclusions and significance

The beads coated with specific ligands from Mtb worked well in both macrophage cell line and human primary macrophages, which can be exploited to further study the phagosomal function of macrophage in TB. Our bead model can be applied to different ligands from other pathogens, which could extend the understanding of the associations between macrophage antimicrobial functions and outcomes of infectious diseases and the possible cellular mechanisms involved.
The role of chemokines and chemokine receptors in pulmonary arterial hypertension
Authors: Mamazhakypov Argen , Viswanathan Gayathri , Lawrie Allan , Schermuly Ralph Theo , Rajagopal Sudarshan
Published: August 2019

Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary artery remodelling leading to increased right ventricular pressure overload, which results in right heart failure and premature death. Inflammation plays a central role in the development of PAH, and the recruitment and function of immune cells are tightly regulated by chemotactic cytokines called chemokines. A number of studies have shown that the development and progression of PAH are associated with the dysregulated expression of several chemokines and chemokine receptors in the pulmonary vasculature. Moreover, some chemokines are differentially regulated in the pressure‐overloaded right ventricle. Recent studies have tested the efficacy of pharmacological agents targeting several chemokines and chemokine receptors for their effects on the development of PAH, suggesting that these receptors could serve as useful therapeutic targets. In this review, we provide recent insights into the role of chemokines and chemokine receptors in PAH and RV remodelling and the opportunities and roadblocks in targeting them.

LINKED ARTICLES

This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visithttp://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc
Young Children Are Wishful Thinkers: The Development of Wishful Thinking in 3‐ to 10‐Year‐Old Children
Authors: Wente Adrienne O. , Goddu Mariel K. , Garcia Teresa , Posner Elyanah , Fernández Flecha María , Gopnik Alison
Published: August 2019

Previously, research on wishful thinking has found that desires bias older children’s and adults’ predictions during probabilistic reasoning tasks. In this article, we explore wishful thinking in children aged 3‐ to 10‐years‐old. Do young children learn to be wishful thinkers? Or do they begin with a wishful thinking bias that is gradually overturned during development? Across five experiments, we compare low‐ and middle‐income United States and Peruvian 3‐ to 10‐year‐old children (N = 682). Children were asked to make predictions during games of chance. Across experiments, preschool‐aged children from all backgrounds consistently displayed a strong wishful thinking bias. However, the bias declined with age.