bluuebunny/crossref_metadata_2025 huggingface dataset:
Re-Targeting of Macroh2A Following Mitosis to Cytogenetic-Scale Heterochromatic Domains
Authors: Sato Hanae , Wu Bin , Delahaye Fabien , Singer Robert H. , Greally John M.
Published: May 2018

The heritability of chromatin states through cell division is a potential contributor to the epigenetic maintenance of cellular memory of prior states. The macroH2A histone variant has properties of a regulator of epigenetic cell memory, including roles controlling gene silencing and cell differentiation. Its mechanisms of regional genomic targeting and maintenance through cell division are unknown. Here we combinedin vivoimaging with biochemical and genomic approaches to show that human macroH2A is incorporated into chromatin in the G1 phase of the cell cycle following DNA replication. The newly-incorporated macroH2A re-targets the same, large heterochromatic domains where macroH2A was already enriched in the previous cell cycle. It remains heterotypic, targeting individual nucleosomes that do not already contain a macroH2A molecule. The pattern observed resembles that of new deposition of centromeric histone variants during the cell cycle, indicating mechanistic similarities for macrodomain-scale regulation of epigenetic properties of the cell.
High-order interactions dominate the functional landscape of microbial consortia
Authors: Sanchez-Gorostiaga Alicia , Bajić Djordje , Osborne Melisa L. , Poyatos Juan F. , Sanchez Alvaro
Published: May 2018

Understanding the link between community composition and function is a major challenge in microbial ecology, with implications for the management of natural microbiomes and the design of synthetic consortia. For this purpose, it is critical to understand the extent to which community functions and properties can be predicted from species traits and what role is played by complex interactions. Inspired by the study of complex genetic interactions and fitness landscapes, here we have examined how the amylolytic function of combinatorial assemblages of seven starch-degrading soil bacteria depends on the functional contributions from each species and their interactions. Filtering our experimental results through the theory of enzyme kinetics, we show that high-order functional interactions dominate the amylolytic rate of our consortia, even though this function is biochemically simple, redundantly distributed in the community, and additive in the absence of inter-species interactions. As the community grows in size, the contribution of high-order functional interactions grows too, making the community function increasingly unpredictable. We can explain the prevalence of high order effects and their sign from the redundancy of ecological interactions in the network, in particular from redundant facilitation towards a high-performing community member. Our results suggest that even simple functions can be dominated by complex interactions, posing challenges for the predictability and bottom-up engineering of ecosystem function in complex multi-species communities.
Hmgcr promotes a long-range signal to attract germ cells which is aided by Wunens but independent ofhh
Authors: Kenwrick Kim , Mukherjee Amrita , Renault Andrew
Published: May 2018

Summary Statement

MigratingDrosophilagerm cells are attracted by a long range Hmgcr mediated signal which is aided and acts simultaneously with Wunens suggesting that these pathways converge on a single chemoattractant.

In a developing embryo, many cell types migrate from their point of specification to their final position. This usually involves highly stereotyped routes which are determined through deployment of cell surface or secreted guidance molecules. Whilst genetic techniques have been successful in identifying these molecules, the distances over which such signals operate in their native context can be difficult to determine. Here we have quantified the range of an attractive signal for the migration ofDrosophilagerm cells. Their migration is guided by an attractive signal generated by the expression of genes in the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (Hmgcr) pathway, and by a repulsive signal generated by the expression of Wunens. We demonstrate that the attractive signal downstream of Hmgcr operates over a long range and is sufficient to reach germ cells for the entirety of their migration. Furthermore, Hmgcr-mediated attraction and Wunen-mediated repulsion can operate simultaneously ruling out a model in which these pathways operate consecutively. Indeed, we show that Hmgcr-mediated attraction is boosted by Wunens suggesting the action of these two pathways is linked. Lastly, several papers have pointed to the secreted molecule Hedgehog (Hh) as being the germ cell attractant, whose secretion is increased byhmgcr. In this paper, we provide evidence that Hh is not downstream ofhmgcrin germ cell migration.
Cryptic Native American ancestry recapitulates population-specific migration and settlement of the continental United States
Authors: Jordan I. King , Rishishwar Lavanya , Conley Andrew B.
Published: May 2018

European and African descendants settled the continental US during the 17th-19thcenturies, coming into contact with established Native American populations. The resulting admixture among these groups yielded a significant reservoir of cryptic Native American ancestry in the modern US population. We analyzed the patterns of Native American admixture seen for the three largest genetic ancestry groups in the US population: African American, European American, and Hispanic/Latino. The three groups show distinct Native American ancestry profiles, which are indicative of their historical patterns of migration and settlement across the country. Native American ancestry in the modern African American population does not coincide with local geography, instead forming a monophyletic group with origins in the southeastern US, consistent with the Great Migration of the early 20thcentury. European Americans show Native American ancestry that tracks their geographic origins across the US, indicative of ongoing contact during westward expansion, and Native American ancestry can resolve Hispanic/Latino individuals into distinct local groups formed by more recent migration from Mexico and Puerto Rico. We found an anomalous pattern of Native American ancestry from the US southwest, which most likely corresponds to theNuevomexicanodescendants of early Spanish settlers to the region. We addressed a number of controversies surrounding this population, including the extent of Sephardic Jewish ancestry.Nuevomexicanosare less admixed than nearby Mexican-American individuals, with more European and less Native American and African ancestry, and while they do show demonstrable Sephardic Jewish ancestry, the fraction is no greater than seen for other Hispanic/Latino populations.
On an algorithmic definition for the components of the minimal cell
Authors: Martínez Octavio , Reyes-Valdés M. Humberto
Published: May 2018

Living cells are highly complex systems comprising a multitude of elements that are engaged in the many convoluted processes observed during the cell cycle. However, not all elements and processes are essential for cell survival and reproduction under steady-state environmental conditions. To distinguish between essential from expendable cell components and thus define the ‘minimal cell’ and the corresponding ‘minimal genome’, we postulate that the synthesis of all cell elements can be represented as a finite set of binary operators, and within this framework we show that cell elements that depend on their previous existence to be synthesized are those that are essential for cell survival. An algorithm to distinguish essential cell elements is presented and demonstrated within an interactome. Data and functions implementing the algorithm are given as supporting information. We expect that this algorithmic approach will lead to the determination of the complete interactome of the minimal cell, which could then be experimentally validated. The assumptions behind this hypothesis as well as its consequences for experimental and theoretical biology are discussed.
Structural basis for σ1 receptor ligand recognition
Authors: Schmidt Hayden R. , Betz Robin M. , Dror Ron O. , Kruse Andrew C.
Published: May 2018

The σ1 receptor is a poorly understood integral membrane protein expressed in most cells and tissues in the human body. It has been shown to modulate the activity of other membrane proteins such as ion channels and G protein-coupled receptors1–4, and ligands targeting the σ1 receptor are currently in clinical trials for treatment of Alzheimer’s disease5, ischemic stroke6, and neuropathic pain7. Despite its importance, relatively little is known regarding σ1 receptor function at the molecular level. Here, we present crystal structures of the human σ1 receptor bound to the classical antagonists haloperidol and NE-100, as well as the agonist (+)-pentazocine, at crystallographic resolutions of 3.1 Å, 2.9 Å, and 3.1 Å respectively. These structures reveal a unique binding pose for the agonist. The structures and accompanying molecular dynamics (MD) simulations demonstrate that the agonist induces subtle structural rearrangements in the receptor. In addition, we show that ligand binding and dissociation from σ1 is a multistep process, with extraordinarily slow kinetics limited by receptor conformational change. We use MD simulations to reconstruct a ligand binding pathway that requires two major conformational changes. Taken together, these data provide a framework for understanding the molecular basis for agonist action at σ1.
Transformation of Quotient Values for their use as Continuous Cladistic Characters
Authors: Vidovic Steven Uros
Published: May 2018

Recent advances in cladistic technology have produced novel methods for introducing morphological data into cladistic analyses, such as the landmark and continuous character functions in the software TNT and RevBayes. While these new methods begin to address the problem of representing morphology, there has been little consideration of how to transform and code the operational taxonomic units’ (OTUs) dimensions into the datamatrix. Indeed, angles, serial counts, percentages and quotient values can be used as continuous characters, but little has been said about how coding these data affect the trees discovered. Logically, counts of elements and angles measured off specimens may be coded directly into continuous character matrices but percentages and quotient values are more problematic, being transformed data. Quotient values and percentages are the simplest way of representing proportional differences between two dimensions and reducing the effect of inter-taxonomic magnitude differences. However, both are demonstrated to be problematic transformations that produce continuous characters with weighted states that are non-representative of morphological variation. Thus, two OTUs may be represented as less/more similar morphologically than other OTUs that display the same degree of morphological variation. Furthermore, the researcher’s choice of which dimension is the divisor and dividend will have a similar affect. To address this problem, a trigonometric solution and a logarithmic solution have been proposed. Another solution called linear transposition scaling (LTS) was recently presented, with the intention of best representing and coding observable morphological variation. All three methods are reviewed to establish the best way to represent and code morphology in a cladistic analysis using continuous characters.
Cost-efficient high throughput capture of museum arthropod specimen DNA using PCR-generated baits
Authors: Knyshov Alexander , Gordon Eric R.L. , Weirauch Christiane
Published: May 2018

Gathering genetic data for rare species is one of the biggest remaining obstacles in modern phylogenetics, particularly for megadiverse groups such as arthropods. Next generation sequencing techniques allow for sequencing of short DNA fragments contained in preserved specimens >20 years old, but approaches such as whole genome sequencing are often too expensive for projects including many taxa. Several methods of reduced representation sequencing have been proposed that lower the cost of sequencing per specimen, but many remain costly because they involve synthesizing nucleotide probes and target hundreds of loci. These datasets are also frequently unique for each project and thus generally incompatible with other similar datasets.

Here, we explore utilization of in-house generated DNA baits to capture commonly utilized mitochondrial and ribosomal DNA loci from insect museum specimens of various age and preservation types without the a priori need to know the sequence of the target loci. Both within species and cross-species capture are explored, on preserved specimens ranging in age from one to 54 years old.

We found most samples produced sufficient amounts of data to assemble the nuclear ribosomal rRNA genes and near complete mitochondrial genomes and produce well-resolved phylogenies in line with expected results. The dataset obtained can be straightforwardly combined with the large cache of existing Sanger-sequencing-generated data built up over the past 30 years and targeted loci can be easily modified to those commonly used in different taxa. Furthermore, the protocol we describe allows for inexpensive data generation (as low as ∼$35/sample), of at least 20 kilobases per specimen, for specimens at least as old as ∼1965, and can be easily conducted in most laboratories.

If widely applied, this technique will accelerate the accurate resolution of the Tree of Life especially on non-model organisms with limited existing genomic resources.
Mapping Antarctic suspension feeder abundances and seafloor food-availability, and modelling their change after a major glacier calving
Authors: Jansen Jan , Hill Nicole A. , Dunstan Piers K. , Cougnon Eva A. , Galton-Fenzi Benjamin K. , Johnson Craig R.
Published: May 2018

Seafloor communities are a critical part of the unique and diverse Antarctic marine life. Processes at the ocean-surface can strongly influence the diversity and abundance of these communities, even when they live at hundreds of meters water depth. However, even though we understand the importance of this link, there are so far no quantitative spatial predictions on how seafloor communities will respond to changing conditions at the ocean surface.

Here, we map patterns in abundance of important habitat-forming suspension feeders on the seafloor in East Antarctica, and predict how these patterns change after a major disturbance in the icescape, caused by the calving of the Mertz Glacier Tongue. We use a purpose-built ocean model for the time-period before and after the calving of the Mertz-Glacier Tongue in 2010, data from satellites and a validated food-availability model to estimate changes in horizontal flux of food since the glacier calving. We then predict the post-calving distribution of suspension feeder abundances using the established relationships with the environmental variables, and changes in horizontal flux of food.

Our results indicate strong increases in suspension feeder abundances close to the glacier calving site, fueled by increased food supply, while the remainder of the region maintains similar suspension feeder abundances despite a slight decrease in total food supply. The oceanographic setting of the entire region changes, with a shorter ice-free season, altered seafloor currents and changes in food-availability.

Our study provides important insight into the flow-on effects of a changing icescape on seafloor habitat and fauna in polar environments. Understanding these connections is important in the context of current and future effects of climate change, and the mapped predictions of the seafloor fauna as presented for the study region can be used as a decision-tool for planning potential marine protected areas, and for focusing future sampling and monitoring initiatives.
Synergy and convergence of pathways controlling functional regeneration in the spinal cord
Authors: Carlstrom Lucas P. , Cheever Thomas R. , Schoenfuss Heiko L. , McGee Meghan R. , Ekker Stephen C. , Henley John R.
Published: May 2018

Barriers to regeneration in the mammalian central nervous system (CNS) include the presence of inhibitory factors like myelin-associated glycoprotein (MAG) that block re-growth of injured axons. Inhibition by MAG antagonizes the induction of integrin-based substrate adhesions in axonal growth cones by brain-derived neurotrophic factor (BDNF). Here, using a novel approach to overcome inhibitory actions of MAG by activating integrins, we provide cellular and molecular evidence that integrin activity modulates the actions of chemotropic cues on substrate adhesions and supports axon regeneration in vertebrates. Potentiating integrin activity in cultured spinal neurons blocked negative integrin remodeling and inhibition of axon outgrowth induced by MAG, but also restored BDNF-dependent integrin clustering and stimulated outgrowth. In a zebrafish complete spinal cord transection model, combined integrin activation and BDNF treatment synergistically triggered functional regeneration of long projection axons that lack regenerative capacity from the hindbrain. The combined treatment also promoted functional repair even in the presence of exogenous mammalian inhibitory factors, including MAG, which alone impaired recovery of swimming movements. Thus, integrin activation state plays complementary roles in modulating the output activity of opposing cues on integrin-based adhesions and supports functional nerve regenerationin vivo. Our findings reveal effective reversal of downstream actions of inhibitory cues, thereby overcoming a major barrier to regeneration in the mammalian CNS, while simultaneously supporting neurotrophin-stimulated outgrowth. Discovery of therapeutic strategies targeting integrin activation state therefore holds promise for promoting axon regeneration after traumatic injury, which is a critical step in restoring connectivity and functional recovery.
Anywhere but here: local conditions alone drive dispersal inDaphnia
Authors: Erm Philip , Hall Matthew D. , Phillips Ben L.
Published: May 2018

Dispersal is fundamental to population dynamics and it is increasingly apparent that, despite most models treating dispersal as a constant, many organisms make dispersal decisions based upon information gathered from the environment. Ideally, organisms would make fully informed decisions, with knowledge of both intra-patch conditions (conditions in their current location) and extra-patch conditions (conditions in alternative locations). Acquiring information is energetically costly however, and extra-patch information will typically be costlier to obtain than intra-patch information. As a consequence, theory suggests that organisms will often make partially informed dispersal decisions, utilising intra-patch information only. We test this proposition in an experimental two-patch system using populations of the aquatic crustacean,Daphnia carinata. We manipulated conditions (food availability) in the population’s home patch, and in its alternative patch. We found thatD. carinatamade use of intra-patch information (resource limitation in the home patch induced a ten-fold increase in dispersal probability) but made no use of extra-patch information (resource limitation in the alternative patch did not affect dispersal probability). Our work highlights the very large influence that information can have on dispersal probability, but also that dispersal decisions will often be made in only a partially informed manner. The magnitude of the response we observed also adds to the growing chorus that condition-dependence may be a significant driver of variation in dispersal.
Genotypic diversity, circulation patterns, and co-detections among rhinoviruses in Queensland, 2001
Authors: Arden Katherine E. , Greer Ristan M. , Wang Claire Y.T. , Mackay Ian M.
Published: May 2018

Rhinoviruses (RVs) occur more frequently than other viruses and more often in people displaying symptoms than in those without. RVs exacerbate chronic airway disease and confound the clinical diagnosis of influenza-like illness. We sought to estimate the spectrum of RV diversity, RV species seasonality and to breakdown RV involvement in respiratory virus co-detections by comprehensive molecular testing of a convenience collection of airway sample extracts from patients with suspected respiratory infections, collected during 2001.

RVs were the most common virus detected. We were able to genotype ∼90% of RV detections, identifying 70 distinct RVs, spanning all three species. RV-Bs were under-represented. We found RV species co-circulated at times, although one species usually dominated. Each species displayed a bimodal distribution.

Notably, RVs and influenza A viruses (IFAV) seldom co-occurred, supporting their roles as primary pathogens of the airway among acutely ill infants. Whether RV circulation has a moderating or controlling effect on the IFAV season or is controlled by it cannot be determined from these data.

Despite the frequent perception that RVs commonly co-occur with another virus, our findings indicated this was not the case. Nearly 80% of RV detections occurred alone. Understanding more about population-level interference between viruses may allow us to harness aspects of it to generate a non-specific antiviral intervention that mimics a putative protective effect.

For routine respiratory virus screening to best serve the patient, RV testing should be a principal component of any acute respiratory illness testing algorithm throughout the year.
BDNF controls cognitive processes related to neuropsychiatric manifestations via autophagic regulation of p62 and GABAA receptor trafficking
Authors: Tomoda Toshifumi , Sumitomo Akiko , Shukla Rammohan , Hirota-Tsuyada Yuki , Miyachi Hitoshi , Oh Hyunjung , French Leon , Sibille Etienne
Published: May 2018

Reduced BDNF and GABAergic inhibition co-occur in neuropsychiatric diseases, including major depression. Genetic rodent studies show a causal link, suggesting the presence of biological pathways that mediate this co-occurrence. Here we show that mice with reduced Bdnf (Bdnf+/-) have upregulated expression of sequestosome-1/p62, an autophagy-associated stress response protein, and reduced surface presentation of α5 subunit-containing GABAA receptor (α5-GABAAR) in prefrontal cortex (PFC) pyramidal neurons. Reducing p62 gene dosage restored α5-GABAAR surface expression and rescued the PFC-relevant behavioral deficits of Bdnf+/- mice, including cognitive inflexibility and sensorimotor gating deficits. Increasing p62 levels was sufficient to recreate the molecular and behavioral profiles of Bdnf+/- mice. Finally, human postmortem corticolimbic transcriptome analysis suggested reduced autophagic activity in depression. Collectively, the data reveal that autophagy regulation through control of p62 dosage may serve as a mechanism linking reduced BDNF signaling, GABAergic deficits, and psychopathology associated with PFC functional deficits across psychiatric disorders.

HIGHLIGHTS

BDNF constitutively promotes autophagy in cortical pyramidal neurons

Reduced BDNF causes elevated autophagy-regulator p62 expression, leading to lower surface α5-GABAAR presentation

Increasing p62 levels mimics cognition-related behavioral deficits in Bdnf+/- mice

Altered postmortem corticolimbic gene expression suggests reduced autophagic activity in depression
Tracing a protein’s folding pathway over evolutionary time using ancestral sequence reconstruction and hydrogen exchange
Authors: Lim Shion A. , Bolin Eric R. , Marqusee Susan
Published: May 2018

The conformations populated during protein folding have been studied for decades; yet, their evolutionary importance remains largely unexplored. Ancestral sequence reconstruction allows access to proteins across evolutionary time, and new methods such as pulsed-labeling hydrogen exchange coupled with mass spectrometry allow determination of folding intermediate structures at near amino-acid resolution. Here, we combine these techniques to monitor the folding of the ribonuclease H family along the evolutionary lineages ofT. thermophilusandE. coliRNase H. All homologs and ancestral proteins studied populate a similar folding intermediate despite being separated by billions of years of evolution. Even though this conformation is conserved, the pathway leading to it has diverged over evolutionary time, and rational mutations can alter this trajectory. Our results demonstrate that evolutionary processes can affect the energy landscape to preserve or alter specific features of a protein’s folding pathway.
Nucleotide-pair encoding of 16S rRNA sequences for host phenotype and biomarker detection
Authors: Asgari Ehsaneddin , Münch Philipp C. , Lesker Till R. , McHardy Alice C. , Mofrad Mohammad R.K.
Published: May 2018

Identifying combinations of taxa distinctive for microbiome-associated diseases is considered key to the establishment of diagnosis and therapy options in precision medicine and imposes high demands on accuracy of microbiome analysis techniques. We propose subsequence based 16S rRNA data analysis, as a new paradigm for microbiome phenotype classification and biomarker detection. This method and software called DiTaxa substitutes standard OTU-clustering or sequence-level analysis by segmenting 16S rRNA reads into the most frequent variable-length subsequences. These subsequences are then used as data representation for downstream phenotype prediction, biomarker detection and taxonomic analysis. Our proposed sequence segmentation called nucleotide-pair encoding (NPE) is an unsupervised data-driven segmentation inspired by Byte-pair encoding, a data compression algorithm. The identified subsequences represent commonly occurring sequence portions, which we found to be distinctive for taxa at varying evolutionary distances and highly informative for predicting host phenotypes. We compared the performance of DiTaxa to the state-of-the-art methods in disease phenotype prediction and biomarker detection, using human-associated 16S rRNA samples for periodontal disease, rheumatoid arthritis and inflammatory bowel diseases, as well as a synthetic benchmark dataset. DiTaxa identified 17 out of 29 taxa with confirmed links to periodontitis (recall= 0.59), relative to 3 out of 29 taxa (recall= 0.10) by the state-of-the-art method. On synthetic benchmark data, DiTaxa obtained full precision and recall in biomarker detection, compared to 0.91 and 0.90, respectively. In addition, machine-learning classifiers trained to predict host disease phenotypes based on the NPE representation performed competitively to the state-of-the art using OTUs or k-mers. For the rheumatoid arthritis dataset, DiTaxa substantially outperformed OTU features with a macro-F1 score of 0.76 compared to 0.65. Due to the alignment- and reference free nature, DiTaxa can efficiently run on large datasets. The full analysis of a large 16S rRNA dataset of 1359 samples required ≈1.5 hours on 20 cores, while the standard pipeline needed ≈6.5 hours in the same setting.

Availability

An implementation of our method called DiTaxa is available under the Apache 2 licence at http://llp.berkeley.edu/ditaxa.
Semi-supervised Encoding for Outlier Detection in Clinical Observation Data
Authors: Estiri Hossein , Murphy Shawn N
Published: May 2018

Background and Objective

To evaluate the utility of encoding for outlier detection in clinical observation data from Electronic Health Records (EHR).

Methods

This article presents a semi-supervise encoding approach (super-encoding) for constructing a non-linear exemplar data distribution from EHR data and detecting non-conforming observations as outliers. Two hypotheses are tested using experimental design and non-parametric hypothesis testing procedures to evaluate the outlier detection performance of the semi-supervised encoding approach and increasing demographic precision in encoding.

Results

The experiments involved applying 492 encoders to 30 laboratory tests extracted from the Research Patient Data Registry (RPDR) from Partners HealthCare. We report results obtained from 14,760 encoders. The semi-supervised encoders (super-encoders) outperformed conventional autoencoders in outlier detection. Adding age at observation to the baseline encoder (that only included observation value as the feature) slightly improved outlier detection. Top-nine performing encoders are introduced. The best outlier detection performance was from a semi-supervised encoder, with observation value as the single feature and a single hidden layer, built on one percent of the data and one percent reconstruction error. At least one encoder had a Youden’s J index higher than 0.9999 for all 30 observations.

Conclusion

Given the multiplicity of distributions for a single observation in EHR data (i.e., same observation represented with different names or units), as well as non-linearity of human observations, encoding offers huge promises for outlier detection in large-scale data repositories.
Disinhibition as a canonical neural mechanism for flexible behavior
Authors: Standage Dominic , Paré Martin , Blohm Gunnar
Published: May 2018

Flexibility is a hallmark of human and animal behavior, but the context-dependent neural computations that generate flexible behavior are poorly understood. Here, we use a biophysically-based cortical network model to explore the hypothesis that vasoactive intestinal polypeptide (VIP) expressing inhibitory interneurons control local circuit dynamics by targeting other classes of inhibitory interneuron, supporting context-dependent computations. Depending on the strength of this disinhibition (simulating VIP activity), network dynamics support multiple-item working memory (WM, strong disinhibition) or decision making (DM, weak disinhibition). Within these regimes, disinhibition controls WM capacity and speedaccuracy-trade-off in choice behavior. Our findings suggest that long-range trans-cortical VIP-mediated disinhibition is a canonical neural mechanism for the top-down control of flexible behavior.
Using machine learning models to predict oxygen saturation following ventilator support adjustment in critically ill children: a single center pilot study
Authors: Ghazal Sam , Sauthier Michael , Brossier David , Bouachir Wassim , Jouvet Philippe , Noumeir Rita
Published: May 2018

Clinicians’ experts in mechanical ventilation are not continuously at each patient’s bedside in an intensive care unit to adjust mechanical ventilation settings and to analyze the impact of ventilator settings adjustments on gas exchange. The development of clinical decision support systems analyzing patients’ data in real time offers an opportunity to fill this gap. The objective of this study was to determine whether a machine learning predictive model could be trained on a set of clinical data and used to predict hemoglobin oxygen saturation 5 min after a ventilator setting change. Data of mechanically ventilated children admitted between May 2015 and April 2017 were included and extracted from a high-resolution research database. More than 7.105 rows of data were obtained from 610 patients, discretized into 3 class labels. Due to data imbalance, four different data balancing process were applied and two machine learning models (artificial neural network and Bootstrap aggregation of complex decision trees) were trained and tested on these four different balanced datasets. The best model predicted SpO2 with accuracies of 76%, 62% and 96% for the SpO2 class “< 84%”, “85 to 91%” and “> 92%”, respectively. This pilot study using machine learning predictive model resulted in an algorithm with good accuracy. To obtain a robust algorithm, more data are needed, suggesting the need of multicenter pediatric intensive care high resolution databases.
Inferring Tumour Proliferative Organisation from Phylogenetic Tree Measures in a Computational Model
Authors: Scott Jacob G. , Maini Philip K. , Anderson Alexander R. A. , Fletcher Alexander G.
Published: May 2018

We use a computational modelling approach to explore whether it is possible to infer a tumour’s cell proliferative hierarchy, under the assumptions of the cancer stem cell hypothesis and neutral evolution. We focus on inferring the symmetric division probability for cancer stem cells in our model, as this is believed to be a key driving parameter of tumour progression and therapeutic response. Given the advent of multi-region sampling, and the opportunities offered by them to understand tumour evolutionary history, we focus on a suite of statistical measures of the phylogenetic trees resulting from the tumour’s evolution in different regions of parameter space and through time. We find strikingly different patterns in these measures for changing symmetric division probability which hinge on the inclusion of spatial constraints. These results give us a starting point to begin stratifying tumours by this biological parameter and also generate a number of actionable clinical and biological hypotheses including changes during therapy, and through tumour evolution.
Gamete fusion rapidly reconstitutes a bi-partite transcription factor to block re-fertilization
Authors: Vještica Aleksandar , Merlini Laura , N’kosi Pedro , Martin Sophie G
Published: May 2018

The ploidy cycle, integral to sexual reproduction, requires not only meiosis to halve the number of chromosomes, but also mechanisms that ensure zygotes are formed by exactly two partners1–5. During sexual reproduction of the fungal model organismSchizosaccharomyces pombe, haploid P- and M-cells normally fuse to form a diploid zygote that immediately enters meiosis6. Here, we reveal that fast post-fusion reconstitution of a bi-partite transcription factor actively blocks re-fertilization. We first identify mutants that undergo transient cell fusion involving cytosol exchange but not karyogamy, and show this drives distinct cell fates in the two gametes: The P-partner undergoes lethal, haploid meiosis while the M-cell persists in mating. Consistently, we find that the zygotic transcription that drives meiosis is initiated rapidly only from the P-parental genome, even in wild type cells. This asymmetric gene expression depends on a bi-partite complex formed post-fusion between the nuclear P-cell-specific homeobox protein Pi and a cytosolic M-specific peptide Mi7,8, which is captured by Pi in the P-nucleus. Zygotic transcription is thus poised to initiate in the P-nucleus as fast as Mi reaches it. The asymmetric nuclear accumulation is inherent to the transcription factor design, and is reconstituted by a pair of synthetic interactors, one localized to the nucleus of one gamete and the other in the cytosol of its partner. Strikingly, imposing a delay in zygotic transcription, by postponing Mi expression or deleting its transcriptional target in the P-genome, leads to zygotes fusing with additional gametes, thus forming polyploids and eventually aneuploid progeny. We further show that the signaling cascade to block re-fertilization shares components with, but bifurcates from, meiotic induction9–11. Thus, cytoplasmic connection upon gamete fusion leads to rapid reconstitution of a bi-partite transcription factor in one partner to block re-fertilization and induce meiosis, thus ensuring genome maintenance during sexual reproduction.
Extremely hypomorphic and severe deep intronic variants in the ABCA4 locus result in varying Stargardt disease phenotypes
Authors: Zernant Jana , Lee Winston , Nagasaki Takayuki , Collison Frederick T. , Fishman Gerald A. , Bertelsen Mette , Rosenberg Thomas , Gouras Peter , Tsang Stephen H. , Allikmets Rando
Published: May 2018

Autosomal recessive Stargardt disease (STGD1, MIM 248200) is caused by mutations in the ABCA4 gene. Complete sequencing of the ABCA4 locus in STGD1 patients identifies two expected disease-causing alleles in ∼75% of patients and only one mutation in ∼15% of patients. Recently, many possibly pathogenic variants in deep intronic sequences of ABCA4 have been identified in the latter group. We extended our analyses of deep intronic ABCA4 variants and determined that one of these, c.4253+43G>A (rs61754045), is present in 29/1155 (2.6%) of STGD1 patients. The variant is found at statistically significantly higher frequency in patients with only one pathogenic ABCA4 allele, 23/160 (14.38%), MAF = 0.072, compared to MAF = 0.013 in all STGD1 cases and MAF = 0.006 in the matching general population (P < 1 × 10−7). The variant, which is not predicted to have any effect on splicing, is the first reported intronic “extremely hypomorphic allele” in the ABCA4 locus; that is, it is pathogenic only when in trans with a loss-of-function ABCA4 allele. It results in a distinct clinical phenotype characterized by late onset of symptoms and foveal sparing. In ∼70% of cases the variant was allelic with the c.6006-609T>A (rs575968112) variant, which was deemed nonpathogenic. Another rare deep intronic variant, c.5196+1056A>G (rs886044749), found in 5/834 (0.6%) of STGD1 cases is, conversely, a severe allele. This study determines pathogenicity for three noncoding variants in STGD1 patients of European descent accounting for ∼3% of the disease. Defining disease-associated alleles in the noncoding sequences of the ABCA4 locus can be accomplished by integrated clinical and genetic analyses.
Propagation of uncertainty in experiment: structures of Ni (II) coordination complexes
Authors: Schalken Martin J. , Chantler Christopher T.
Published: May 2018

Accurate experimental XAFS (X-ray absorption fine-structure) data including uncertainties are required during analysis for valid comparison of results and conclusions of hypothesis testing on structural determinations. Here an approach is developed to investigate data without standard interpolation of experimental data and with minimal loss of information content in the raw data. Nickel coordination complexes bis(i-n-propylsalicylaldiminato)nickel(II) (i-pr) and bis(N-n-propylsalicylaldiminato)nickel(II) (n-pr) are investigated. The additional physical insight afforded by the correct propagation of experimental uncertainty is used to determine newly refined structures for the innermost co-ordination shell. Two sets of data are investigated for each complex; one optimized for high point accuracy and one optimized for high point density. Clearly both are important and in this investigation the quality of the physical insight from each is directly provided by measured and propagated uncertainties to fairly represent the relevant accuracies. The results provide evidence for an approximate tetrahedral geometry for the i-pr Ni complex that is more symmetric than previously concluded, with our high point accuracy data yielding ligand lengths of 2.017 ± 0.006 Å and 2.022 ∓ 0.006 Å for Ni—N and Ni—O bonds, respectively, and an even more skewed square-planar (i.e. rhombohedral) arrangement for the n-pr complex with corresponding bond lengths of 2.133 ± 0.004 Å and 1.960 ∓ 0.003 Å. The ability to distinguish using hypothesis testing between the subtle differences in XAFS spectra arising from the approximate local tetrahedral and square-planar geometries of the complexes is also highlighted. The effect of standard interpolation on experimental XAFS spectra prior to fitting with theoretical model structures is investigated. While often performed as a necessary step for Fourier transformation into position space, this will nonetheless skew the fit away from actual data taken, and fails to preserve the information content within the data uncertainty. The artificial effects that interpolation imposes on χ
r

2 are demonstrated. Finally, a method for interpolation is introduced which locally preserves the χ
r

2 and thus information content, when a regular grid is required, e.g for further analysis in r-space.
The challenge of constructing an international XAFS database
Authors: Asakura Kiyotaka , Abe Hitoshi , Kimura Masao
Published: May 2018

The present state of XAFS databases, particularly in Japan, and proposals for future directions are presented. International collaboration is important for enlarging the database for further development of XAFS spectroscopy.
Hydrogen bonding and fluorous weak interactions in the non-isomorphous {4,4′-bis[(2,2,3,3-tetrafluoropropoxy)methyl]-2,2′-bipyridine-κ2
N,N′}dibromidopalladium and -platinum complexes
Authors: Lu Norman , Kung Chih-Chieh , Huang Jia-Yu , Li Yu-Xuan , Yang Chung-Kuang , Wen Yuh-Sheng , Liu Ling-Kang
Published: May 2018

The polyfluorinated title compounds, [MBr2(C18H16F8N2O2)] or [4,4′-(HCF2CF2CH2OCH2)2-2,2′-bpy]MBr2, (1) (M = Pd and bpy is bipyridine) and (2) (M = Pt), have –CH(α)2OCH(β)2CF2CF2H side chains with methylene H-atom donors at the α and β sites, and methine H-atom donors at the terminal sites, in addition to aromatic H-atom donors. In contrast to the original expectation of isomorphous structures, (1) crystallizes in the space group C2/c and (2) in P21/n, with similar unit-cell volumes and Z = 4. The asymmetric unit of (1) is one half of the molecule, which resides on a crystallographic twofold axis. Both (1) and (2) display stacking of the molecules, indicating a planar (bpy)MBr2 skeleton in each case. The structure of (1) exhibits columns with C—H(β)...Br hydrogen bonds between consecutive layers which conforms to a static (β,β) linkage between layers. In the molecular plane, (1) shows double C—H(α)...Br hydrogen bonds self-repeating along the b axis, the planar molecules being connected into infinite belts. Compound (2) has no crystallographic symmetry and forms π-dimer pairs as supermolecules, which then stack parallel to the a axis. The π-dimer-pair supermolecules exhibit (Pt—)Br...Br(—Pt) contacts [3.6937 (7) Å] to neighbouring π-dimer pairs crosslinking the columns. The structure of (2) reveals many C—H...F(—C) interactions between F atoms and aromatic C—H groups, in addition to those between F atoms and methylene C—H groups.
Current approaches for the fitting and refinement of atomic models into cryo-EM maps usingCCP-EM
Authors: Nicholls Robert A. , Tykac Michal , Kovalevskiy Oleg , Murshudov Garib N.
Published: May 2018

Recent advances in instrumentation and software have resulted in cryo-EM rapidly becoming the method of choice for structural biologists, especially for those studying the three-dimensional structures of very large macromolecular complexes. In this contribution, the tools available for macromolecular structure refinement into cryo-EM reconstructions that are availablevia CCP-EMare reviewed, specifically focusing onREFMAC5 and related tools. Whilst originally designed with a view to refinement against X-ray diffraction data, some of these tools have been able to be repurposed for cryo-EM owing to the same principles being applicable to refinement against cryo-EM maps. Since both techniques are used to elucidate macromolecular structures, tools encapsulating prior knowledge about macromolecules can easily be transferred. However, there are some significant qualitative differences that must be acknowledged and accounted for; relevant differences between these techniques are highlighted. The importance of phases is considered and the potential utility of replacing inaccurate amplitudes with their expectations is justified. More pragmatically, an upper bound on the correlation between observed and calculated Fourier coefficients, expressed in terms of the Fourier shell correlation between half-maps, is demonstrated. The importance of selecting appropriate levels of map blurring/sharpening is emphasized, which may be facilitated by considering the behaviour of the average map amplitude at different resolutions, as well as the utility of simultaneously viewing multiple blurred/sharpened maps. Features that are important for the purposes of computational efficiency are discussed, notably theDivide and Conquerpipeline for the parallel refinement of large macromolecular complexes. Techniques that have recently been developed or improved inCootto facilitate and expedite the building, fitting and refinement of atomic models into cryo-EM maps are summarized. Finally, a tool for symmetry identification from a given map or coordinate set,ProSHADE, which can identify the point group of a map and thus may be used during deposition as well as during molecular visualization, is introduced.
Communicating corporate social responsibility (CSR) on social media
Authors: Wang Ruoxu , Huang Yan
Published: May 2018

Purpose

The purpose of this paper is to examine the effects of message source and types of corporate social responsibility (CSR) message on stakeholder’s perception toward CSR and behavioral intention toward the company.

Design/methodology/approach

A 2 (message source: CEO’s Facebook account vs organization’s Facebook account) × 3 (types of CSR messages: internal CSR vs external CSR vs control) between-subjects online experiment (n=242) was conducted online.

Findings

Internal CSR message elicited greater perceptions of trust, satisfaction, control mutuality, and commitment toward the organization among the stakeholders than the external CSR message and the CEO’s personal life message. A significant two-way interaction between the message source and the type of CSR message on behavior intention toward the organization was obtained.

Originality/value

Internal CSR message does matter when it comes to social media posting. The general public do pay attention to what the CEO and the organizations are posting on their social media accounts. Message source does not matter when it comes to social media message posting. However, organizations and CEOs should try to stay consistent when it comes to creating a public CSR message.
What determines the presence of works councils in Polish companies?
Authors: Skorupińska-Cieślak Katarzyna
Published: May 2018

Purpose

The purpose of this paper is to analyze the factors influencing the presence of works councils in Polish companies. The study also considers the incidence of councils in organizations and management’s attitude towards these institutions of employee participation.

Design/methodology/approach

Based on a sample of 402 Polish private companies, the probit model was calculated to identify the determinants of a works councils’ presence. The coverage of active councils was evaluated on the MRPiPS database and the GUS database.

Findings

The data show that the coverage of works councils in Polish organizations fell suddenly after the introduction of the amendment of the Act from 2009. Moreover, trade union density has a strong positive influence on the occurrence of works councils in companies. Councils are also more likely to be found in older foreign-owned companies in which forms of direct participation are used. Additionally, a higher share of shift workers in companies is associated with a higher probability of works councils’ presence.

Research limitations/implications

There are some difficulties with obtaining a precise analysis of the coverage of works councils in Poland.

Practical implications

Polish findings may be useful for other countries of Central and Eastern Europe with similar characteristics of industrial relations and similarly short traditions of works councils.

Originality/value

This paper extends the previous research on the operation of works councils in Polish industrial relations by providing an econometric analysis of the determinants of councils’ presence in companies. Such an analysis has been conducted in Poland for the first time.