bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving interpretability of deep learning models: splicing codes as a case study
Authors: Jha Anupama , Aicher Joseph K. , Singh Deependra , Barash Yoseph
Published: July 2019

Despite the success and fast adaptation of deep learning models in a wide range of fields, lack of interpretability remains an issue, especially in biomedical domains. A recent promising method to address this limitation is Integrated Gradients (IG), which identifies features associated with a prediction by traversing a linear path from a baseline to a sample. We extend IG with nonlinear paths, embedding in latent space, alternative baselines, and a framework to identify important features which make it suitable for interpretation of deep models for genomics.
The CIViC knowledge model and standard operating procedures for curation and clinical interpretation of variants in cancer
Authors: Danos Arpad M. , Krysiak Kilannin , Barnell Erica K. , Coffman Adam C. , McMichael Joshua F. , Kiwala Susanna , Spies Nicholas C. , Sheta Lana M. , Pema Shahil P. , Kujan Lynzey , Clark Kaitlin A. , Wollam Amber Z. , Rao Shruti , Ritter Deborah I. , Sonkin Dmitriy , Raca Gordana , Kim Raymond H. , Wagner Alex H. , Madhavan Subha , Griffith Malachi , Griffith Obi L.
Published: July 2019

Manually curated variant knowledgebases and their associated knowledge models are serving an increasingly important role in distributing and interpreting variants in cancer. These knowledgebases vary in their level of public accessibility, and the complexity of the models used to capture clinical knowledge. CIViC (Clinical Interpretations of Variants in Cancer - www.civicdb.org) is a fully open, free-to-use cancer variant interpretation knowledgebase that incorporates highly detailed curation of evidence obtained from peer-reviewed publications. Currently, the CIViC knowledge model consists of four main components: Genes, Variants, Evidence Items, and Assertions. Each component has an associated knowledge model and methods for curation. Gene and Variant data contextualize the genomic region(s) involved in the clinical statement. Evidence Items provide structured associations between variants and their clinically predictive/therapeutic, prognostic, diagnostic, predisposing, and functional implications. Finally, CIViC Assertions summarize collections of CIViC Evidence Items for a specific Disease, Variant, and Clinical Significance with incorporation of clinical and technical guidelines. Here we present the CIViC knowledge model, curation standard operating procedures, and detailed examples to support community-driven curation of cancer variants.
Restoration of wild-type motility to flagellin-knockoutEscherichia coli
Authors: Thomson Nicholas M. , Pallen Mark J.
Published: July 2019

Flagellin is the major constituent of the flagellar filament and faithful restoration of wild-type motility to flagellin mutants may be beneficial for studies of flagellar biology and biotechnological exploitation of the flagellar system. Therefore, we explored the restoration of motility by flagellin expressed from a variety of combinations of promoter, plasmid copy number and induction strength. Motility was only partially restored using the tightly regulated rhamnose promoter, but wild-type motility was achieved with the T5 promoter, which, although leaky, allowed titration of induction strength. Motility was little affected by plasmid copy number when dependent on inducible promoters. However, plasmid copy number was important when expression was controlled by the nativeE. coliflagellin promoter. Motility was poorly correlated with flagellin transcription levels, but strongly correlated with the amount of flagellin associated with the flagellar filament, suggesting that excess monomers are either not exported or not assembled into filaments. This study provides a useful reference for further studies of flagellar function and a simple blueprint for similar studies with other proteins.
Heterogeneities in intrinsic excitability and frequency-dependent response properties of granule cells across the blades of the rat dentate gyrus
Authors: Mishra Poonam , Narayanan Rishikesh
Published: July 2019

The dentate gyrus (DG), the input gate to the hippocampus proper, is anatomically segregated into three different sectors, namely the suprapyramidal blade, the crest region and the infrapyramidal blade. Although there are well-established differences between these sectors in terms of neuronal morphology, connectivity patterns and activity levels, differences in electrophysiological properties of granule cells within these sectors have remained unexplored. Here, employing somatic whole-cell patch-clamp recordings from the rat DG, we demonstrate that granule cells in these sectors manifest considerable heterogeneities in their intrinsic excitability, temporal summation, action potential characteristics and frequency-dependent response properties. Across sectors, these neurons showed positive temporal summation of their responses to inputs mimicking excitatory postsynaptic currents, and showed little to no sag in their voltage responses to pulse currents. Consistently, the impedance amplitude profile manifested low-pass characteristics and the impedance phase profile lacked positive phase values at all measured frequencies, voltages and for all sectors. Granule cells in all sectors exhibited class I excitability, with broadly linear firing rate profiles, and granule cells in the crest region fired significantly less action potentials compared to those in the infrapyramidal blade. Finally, we found weak pairwise correlations across the 18 different measurements obtained individually from each of the three sectors, providing evidence that these measurements are indeed reporting distinct aspects of neuronal physiology. Together, our analyses show that granule cells act as integrators of afferent information, and emphasize the need to account for the considerable physiological heterogeneities in assessing their roles in information encoding and processing.
CoralP: Flexible visualization of the human phosphatome
Authors: Min Amit , Deoudes Erika , Bond Marielle L. , Davis Eric S. , Phanstiel Douglas H.
Published: July 2019

Protein phosphatases and kinases play critical roles in a host of biological processes and diseases via the removal and addition of phosphoryl groups. While kinases have been extensively studied for decades, recent findings regarding the specificity and activities of phosphatases have generated an increased interest in targeting phosphatases for pharmaceutical development. This increased focus has created a need for methods to visualize this important class of proteins within the context of the entire phosphatase protein family. Here, we present CoralP, an interactive web application for the generation of customizable, publication-quality representations of human phosphatome data. Phosphatase attributes can be encoded through edge colors, node colors, and node sizes. CoralP is the first and currently the only tool designed for phosphatome visualization and should be of great use to the signaling community. The source code and web application are available at https://github.com/PhanstielLab/coralp and http://phanstiel-lab.med.unc.edu/coralp respectively.
Molecular mechanism of mitochondrial phosphatidate transfer by Ups1/Mdm35
Authors: Lu Jiuwei , Chan Kevin , Yu Leiye , Fan Jun , Zhai Yujia , Sun Fei
Published: July 2019

Cardiolipin plays many important roles for mitochondrial physiological function and is synthesized from phosphatidic acid (PA) at inner mitochondrial membrane (IMM). PA synthesized from endoplasmic reticulum needs to transfer to IMM via outer mitochondrial membrane (OMM). The transfer of PA between IMM and OMM is mediated by Ups1/Mdm35 protein family. Although there are many structures of this family available, the detailed molecular mechanism of how PA is transferred between membranes is yet unknown. Here, we report another crystal structures of Ups1/Mdm35 in the authentic monomeric apo state and the DHPA bound state. By combining subsequent all-atom molecular dynamics simulations, extensive structural comparisons and biophysical assays, we discovered the conformational changes of Ups1/Mdm35, identified key structural elements and residues during membrane binding and PA entry. We found the monomeric Ups1 on membrane is an important transit for the success of PA transfer, and the equilibrium between monomeric Ups1 and Ups1/Mdm35 complex on membrane affects the PA transfer rate and can be regulated by many factors including environmental pH.
Application of a gut-immune co-culture system for the study of N-glycan-dependent host-pathogen interactions ofCampylobacter jejuni
Authors: Zamora Cristina Y. , Ward Elizabeth M. , Kester Jemila C. , Kelly Chen Wen Li , Velazquez Jason G. , Griffith Linda G. , Imperiali Barbara
Published: July 2019

An in vitro gut-immune co-culture model with apical and basal accessibility, designed to more closely resemble a human intestinal microenvironment, was employed to study the role of the Nlinked protein glycosylation (Pgl) pathway in Campylobacter jejuni pathogenicity. The gutimmune co-culture (GIC) was developed to model important aspects of the human small intestine by the inclusion of mucin producing goblet cells, human enterocytes, and dendritic cells, bringing together a mucus-containing epithelial monolayer with elements of the innate immune system. The utility of the system was demonstrated by characterizing host-pathogen interactions facilitated by N-linked glycosylation, such as host epithelial barrier functions, bacterial invasion and immunogenicity. Changes in human intestinal barrier functions in the presence of 11168 C. jejuni (wildtype) strains were quantified using GICs. The glycosylationdeficient strain 11168 ΔpglE was 100-fold less capable of adhering to and invading this intestinal model in cell infectivity assays. Quantification of inflammatory signaling revealed that 11168ΔpglE differentially modulated inflammatory responses in different intestinal microenvironments, suppressive in some but activating in others. Virulence-associated outer membrane vesicles produced by wildtype and 11168ΔpglE C. jejuni were shown to have differential composition and function, with both leading to immune system activation when provided to the gut-immune co-culture model. This analysis of aspects of C. jejuni infectivity in the presence and absence of its N-linked glycome, is enabled by application of the gut-immune model and we anticipate that this system will be applicable to further studies of C. jejuni and other enteropathogens of interest.
Auditory contrast gain control predicts perceptual performance and is not dependent on cortical activity
Authors: Lohse Michael , Bajo Victoria M. , King Andrew J. , Willmore Ben D.B.
Published: July 2019

Neural adaptation enables sensory information to be represented optimally in the brain despite large fluctuations over time in the statistics of the environment. Auditory contrast gain control represents an important example, which is thought to arise primarily from cortical processing. We find, however, that neurons in both the auditory thalamus and midbrain of mice show robust contrast gain control, and that this is implemented independently of cortical activity. Although neurons at each level exhibit contrast gain control to similar degrees, adaptation time constants become longer at later stages of the processing hierarchy, resulting in progressively more stable representations. We also show that auditory discrimination thresholds in human listeners compensate for changes in contrast, and that the strength of this perceptual adaptation can be predicted from physiological measurements. Contrast adaptation is therefore a robust property of both the subcortical and cortical auditory system and accounts for the short-term adaptability of perceptual judgments.
A Pan-Cancer assessment of alterations of the kinase domain of ULK1, an upstream regulator of autophagy
Authors: Kumar Mukesh , Papaleo Elena
Published: July 2019

Autophagy is a key clearance process to recycle damaged cellular components. One important upstream regulator of autophagy is the ULK1 kinase. Several structures of the ULK1 kinase domain have been solved, but a comprehensive study, including molecular dynamics, is missing. Also, an exhaustive description of ULK1 alterations found in cancer samples is presently lacking. We here applied a framework which links -omics data to structural protein ensembles to study ULK1 alterations from genomics data available for more that 30 cancer types. Moreover, we predicted the effects of mutations on ULK1 function and structural stability, accounting for protein dynamics and the different layers of changes that a mutation can induce in a protein at the functional and structural level.

We find that ULK1 is down-regulated in gynecological tumors. In other cancer types, ULK2 could compensate for ULK1 downregulation and, in the majority of the cases, no marked changes in expression have been found. 36 missense mutations of ULK1 are co-occurring with mutations in a large number of ULK1 interactors, suggesting a pronounced effect of the upstream steps of autophagy in many cancer types. Moreover, our results pinpoint that more than 50% of the ULK1 mutations that we studied are predicted to affect protein stability. Three mutations (S184F, D102N, and A28V) are predicted with only impact on kinase activity, either modifying the functional dynamics or the capability to exert effects from distal site to the functional and catalytic regions. The framework here applied could be extended to other protein targets to aid the classification of missense mutations from cancer genomics studies, as well as to prioritize variants for experimental validation, or to select the appropriate biological readouts for experiments.
Distinct synchronization, cortical coupling and behavioural function of two basal forebrain cholinergic neuron types
Authors: Laszlovszky Tamás , Schlingloff Dániel , Hegedüs Panna , Freund Tamás F. , Gulyás Attila , Kepecs Adam , Hangya Balázs
Published: July 2019

Basal forebrain cholinergic neurons (BFCN) densely innervate the forebrain and modulate synaptic plasticity, cortical processing, brain states and oscillations. However, little is known about the functional diversity of cholinergic neurons and whether distinct types support different functions. To examine this question we recorded BFCN in vivo, to examine their behavioral functions, and in vitro, to study their intrinsic properties. We identified two distinct types of BFCN that markedly differ in their firing modes, synchronization properties and behavioral correlates. Bursting cholinergic neurons (BFCNBURST) fired in zero-lag synchrony with each other, phase-locked to cortical theta activity and fired precisely timed bursts of action potentials after reward and punishment. Regular firing cholinergic neurons (BFCNREG) were found predominantly in the posterior basal forebrain, displayed strong theta rhythmicity (5-10 Hz), fired asynchronously with each other and responded with precise single spikes after behavioral outcomes. In an auditory detection task, synchronization of BFCNBURST neurons to auditory cortex predicted the timing of mouse responses, whereas tone-evoked cortical coupling of BFCNREG predicted correct detections. We propose that cortical activation relevant for behavior is controlled by the balance of two cholinergic cell types, where the precise proportion of the strongly activating BFCNBURST follows an anatomical gradient along the antero-posterior axis of the basal forebrain.
Finite Element and deformation analyses predict pattern of bone failure in loaded zebrafish spines
Authors: Newman Elis , Kague Erika , Aggleton Jessye A. , Fernee Christianne , Brown Kate Robson , Hammond Chrissy L
Published: July 2019

The spine is the central skeletal support structure in vertebrates consisting of repeated units of bone, the vertebrae, separated by intervertebral discs that enable the movement of the spine. Spinal pathologies such as idiopathic back pain, vertebral compression fractures and intervertebral disc failure affect millions of people world-wide. Animal models can help us to understand the disease process, and zebrafish are increasingly used as they are highly genetically tractable, their spines are axially loaded like humans, and they show similar pathologies to humans during ageing. However biomechanical models for the zebrafish are largely lacking. Here we describe the results of loading intact zebrafish spinal motion segments on a material testing stage within a micro Computed Tomography machine. We show that vertebrae and their arches show predictable patterns of deformation prior to their ultimate failure, in a pattern dependent on their position within the segment. We further show using geometric morphometrics which regions of the vertebra deform the most during loading, and that Finite Element models of the trunk subjected reflect the real patterns of deformation and strain seen during loading and can therefore be used as a predictive model for biomechanical performance.
CNAPE: A Machine Learning Method for Copy Number Alteration Prediction from Gene Expression
Authors: Mu Quanhua , Wang Jiguang
Published: July 2019

Copy number alteration (CNA), the abnormal number of copies of genomic regions, plays a key role in cancer initiation and progression. Current high-throughput CNA detection methods, including DNA arrays and genomic sequencing, are relatively expensive and require DNA samples at a microgram level, which are not achievable in certain occasions such as clinical biopsies or single-cell genomes. Here we proposed an alternative method—CNAPE to computationally infer CNA using gene expression data. A prior knowledge-aided machine learning model was proposed, trained and tested on the transcriptomic profiles with matched CNA data of 9,740 cancers from The Cancer Genome Atlas. Using brain tumors as a proof-of-concept study, CNAPE achieved over 90% accuracy in the prediction of arm-level CNAs. Prediction performance for 12 gene-level CNAs (commonly altered genes in glioma) was also evaluated, and CNAPE achieved reasonable accuracy. CNAPE is developed as an easy-to-use tool at http://wang-lab.ust.hk/software/Software.html.
UDSMProt: Universal Deep Sequence Models for Protein Classification
Authors: Strodthoff Nils , Wagner Patrick , Wenzel Markus , Samek Wojciech
Published: July 2019

Motivation

Inferring the properties of a protein from its amino acid sequence is one of the key problems in bioinformatics. Most state-of-the-art approaches for protein classification tasks are tailored to single classification tasks and rely on handcrafted features such as position-specific-scoring matrices from expensive database searches. We argue that this level of performance can be reached or even be surpassed by learning a task-agnostic representation once, using self-supervised language modeling, and transferring it to specific tasks by a simple finetuning step.

Results

We put forward a universal deep sequence model that is pretrained on unlabeled protein sequences from Swiss-Prot and finetuned on protein classification tasks. We apply it to three prototypical tasks, namely enzyme class prediction, gene ontology prediction and remote homology and fold detection. The proposed method performs on par with state-of-the-art algorithms that were tailored to these specific tasks or, for two out of three tasks, even outperforms them. These results stress the possibility of inferring protein properties from the sequence alone and, on more general grounds, the prospects of modern natural language processing methods in omics.

Availability

Source code is available under https://github.com/nstrodt/UDSMProt.

Contact

firstname.lastname@hhi.fraunhofer.de
Extracellular matrix-inducing Sox9 orchestrates basal progenitor proliferation and gliogenesis in developing neocortex
Authors: Güven Ayse , Stenzel Denise , Long Katherine R. , Florio Marta , Brandl Holger , Huttner Wieland B.
Published: July 2019

Neocortex expansion is largely based on the proliferative capacity of basal progenitors (BPs), which is increased by extracellular matrix (ECM) components via integrin signaling. Here we show that Sox9 drives expression of ECM components and that laminin 211 increases BP proliferation in embryonic mouse neocortex. Examination of Sox9 expression reveals that Sox9 is expressed in BPs of developing ferret and human, but not mouse neocortex. Functional studies by conditional Sox9 expression in the mouse BP lineage demonstrate increased BP proliferation, reduced Tbr2 and induction of Olig2 expression, indicative of premature gliogenesis. Conditional Sox9 expression also results in cell non-autonomous stimulation of BP proliferation followed by increased production of upper-layer neurons. Collectively, our findings demonstrate that Sox9 exerts concerted effects on transcription, BP proliferation, neuron production, and neurogenic as well as gliogenic BP cell fate, suggesting that Sox9 acts a master regulator in the subventricular zone to promote neocortical expansion.
Pro-inflammatory cytokines disrupt β-cell circadian clocks in diabetes
Authors: Javeed Naureen , Brown Matthew R. , Rakshit Kuntol , Her Tracy , Ye Zhenqing , Lee Jeong Heon , Ordog Tamas , Matveyenko Aleksey V.
Published: July 2019

Intrinsic β-cell circadian clocks are a prerequisite for the control of glucose homeostasis through regulation of β-cell function and turnover. However, little is known about the contributions of circadian clock disruption to the natural progression of β-cell failure in diabetes. To address this, we examined the effects of cytokine-mediated inflammation, common to the pathophysiology of Type 1 and Type 2 diabetes, on the physiological, molecular, and epigenetic regulation of circadian clocks in β-cells. Specifically, we provide evidence that the key diabetogenic cytokine IL-1β disrupts functionality of the β-cell circadian clock and circadian regulation of insulin secretion through impaired expression of the key transcription factor Bmal1, evident at the level of promoter activation, mRNA, and protein expression. Additionally, IL-1β-mediated inflammation was shown to augment genome-wide DNA-binding patterns ofBmal1(and its heterodimer,Clock) in β-cells towards binding sites in the proximity of genes annotated to pathways regulating β-cell apoptosis, inflammation, and dedifferentiation. Finally, we identified that the development of hyperglycemia in humans is associated with compromised β-cell BMAL1 expression suggestive of a causative link between circadian clock disruption and β-cell failure in diabetes.
Demography, genetic, and extinction process in a spatially structured population of lekking bird
Authors: Cayuela Hugo , Prunier Jérôme G. , Laporte Martin , Gippet Jérôme , Boualit Laurent , Preiss Françoise , Laurent Alain , Foletti Francesco , Jacob Gwenaël
Published: July 2019

Understanding the mechanisms underlying biological extinctions is a critical challenge for conservation biologists. Both deterministic (e.g. habitat loss, fragmentation) and stochastic (i.e. demographic stochasticity, Allee effect) demographic processes are involved in population decline. Simultaneously, a decrease of population size has far-reaching consequences for genetics of populations by increasing the risk of inbreeding and the effects of genetic drift, which together inevitably results in a loss of genetic diversity and a reduced effective population size (Ne). These genetic factors may retroactively affect vital rates (a phenomenon coined ‘inbreeding depression’), and therefore reduce population growth and accelerate the extinction process of small populations. To date, few studies have simultaneously examined the demographic and genetic mechanisms driving the extinction of wild populations, and have most of the time neglected the spatial structure of populations. In this study, we examined demographic and genetic factors involved in the extinction process of a spatially structured population of a lekking bird, the western capercaillie (Tetrao urogallus). To address this issue, we collected capture-recapture and genetic data over a 6-years period in Vosges mountains, France. Our study showed that the population ofT.urogallusexperienced a severe decline between 2010 and 2015. We did not detect any Allee effect on survival and recruitment. By contrast, individuals of both sexes dispersed to avoid small leks, suggesting a behavioral response to a mate finding Allee effect. In parallel to this demographic decline, the population showed a low genetic diversity and high inbreeding. In addition, the effective population sizes at both lek and population levels was low. Despite this, we did not detected evidence of inbreeding depression: neither survival nor recruitment were affected by individual inbreeding level. Our study underlines the benefit from combining demographic and genetic approaches to investigate processes that are involved in biological extinctions.
Multiple acyl-CoA thioesterases occupy distinct functional niches within the mitochondrial matrix
Authors: Bekeova Carmen , Anderson-Pullinger Lauren , Boye Kevin , Boos Felix , Sharpadskaya Yana , Herrmann Johannes M. , Seifert Erin L.
Published: July 2019

Acyl-CoA thioesterases (Acots) hydrolyze fatty acyl-CoA esters. Acots in the mitochondrial matrix are poised to mitigate β-oxidation overload that may contribute to lipotoxicity. Several Acots associate with mitochondria, but whether they all localize to the matrix, and are redundant or have different roles is unresolved. We compared mitochondrial Acots (Acot2, 7, 9, and 13) in terms of suborganellar localization, activity, expression and regulation, in mitochondria from multiple mouse tissues and from a new model of Acot2 depletion. Acot7, 9 and 13 localized to the matrix, joining Acot2 that was previously shown to localize there. Mitochondria from heart, skeletal muscle, brown adipose tissue and kidney robustly expressed Acot2, 9 and 13, though Acot9 was substantially higher in brown adipose tissue and kidney mitochondria, as was activity for C4:0-CoA, a unique substrate of Acot9. In all these tissues, Acot2 accounted for ∼half of the thioesterase activity for C14-CoA and C16:0-CoA. In contrast, liver mitochondria from fed and fasted mice expressed little Acot activity, and this activity was confined to long-chain CoAs, and due mainly to Acot7 and Acot13 activity. Matrix Acots occupied different functional niches, based on substrate specificity (Acot9vs. Acot2 and 13) and strong CoA inhibition (Acot7, 9, 13 but not Acot2). Interpreting these results in the context of β-oxidation, CoA inhibition would prevent Acot-mediated suppression of β-oxidation while providing for an Acot-mediated release valve when CoA is limiting. This release valve would operate across a wide range of acyl-CoA chain lengths. In contrast, CoA-insensitive Acot2 could provide a constitutive syphon for long-chain fatty acyl-CoAs. These results reveal how the family of matrix Acots can help to mitigate β-oxidation overload and prevent a CoA limitation.
Searching for Simple Rules in Pseudomonas aeruginosa Biofilm Formation
Authors: Deveaux William , Selvarajoo Kumar
Published: July 2019

Living cells display complex and non-linear behaviors, especially when posed to environmental threats. Here, to understand the self-organizing cooperative behavior of a microorganism Pseudomonas aeruginosa, we developed a discrete spatiotemporal cellular automata model based on simple physical rules, similar to Conway’s game of life. The time evolution model simulations were experimentally verified for P. aeroginosa biofilm for both control and antibiotic azithromycin (AZM) treated condition. Our model suggests that AZM regulates the single cell motility, thereby resulting in delayed, but not abolished, biofilm formation. In addition, the model highlights the importance of reproduction by cell to cell interaction is key for biofilm formation. Overall, this work highlights another example where biological evolutionary complexity may be interpreted using rules taken from theoretical disciplines.
DNA mismatches reveal widespread conformational penalties in protein-DNA recognition
Authors: Afek Ariel , Shi Honglue , Rangadurai Atul , Sahay Harshit , Al-Hashimi Hashim M. , Gordan Raluca
Published: July 2019

Transcription-factor (TF) proteins recognize specific genomic sequences, despite an overwhelming excess of non-specific DNA, to regulate complex gene expression programs1–3. While there have been significant advances in understanding how DNA sequence and shape contribute to recognition, some fundamental aspects of protein-DNA binding remain poorly understood2,3. Many DNA-binding proteins induce changes in the DNA structure outside the intrinsic B-DNA envelope. How the energetic cost associated with distorting DNA contributes to recognition has proven difficult to study and measure experimentally because the distorted DNA structures exist as low-abundance conformations in the naked B-DNA ensemble4–10. Here, we use a novel high-throughput assay called SaMBA (Saturation Mismatch-Binding Assay) to investigate the role of DNA conformational penalties in TF-DNA recognition. The approach introduces mismatched base-pairs (i.e. mispairs) within TF binding sites to pre-induce a variety of DNA structural distortions much larger than those induced by changes in Watson-Crick sequence. Strikingly, while most mismatches either weakened TF binding (~70%) or had negligible effects (~20%), approximately 10% of mismatches increased binding and at least one mismatch was found that increased the binding affinity for each of 21 examined TFs. Mismatches also converted sites from the non-specific affinity range into specific sites, and high-affinity sites into “super-sites” stronger than any known canonical binding site. These findings reveal a complex binding landscape that cannot be explained based on DNA sequence alone. Analysis of crystal structures together with NMR and molecular dynamics simulations revealed that many of the mismatches that increase binding induce distortions similar to those induced by TF binding, thus pre-paying some of the energetic cost to deform the DNA. Our work indicates that conformational penalties are a major determinant of protein-DNA recognition, and reveals mechanisms by which mismatches can recruit TFs and thus modulate replication and repair activities in the cell11,12.
Blastula stage specification of avian neural crest
Authors: Prasad Maneeshi S. , Uribe-Querol Eileen , Marquez Jonathan , Vadasz Stephanie , Yardley Nathan , Shelar Patrick B. , Charney Rebekah M. , Garcia-Castro Martin I.
Published: July 2019

Cell fate specification defines the earliest steps towards a distinct cell lineage. Neural crest, a multipotent stem cell population, is thought to be specified from the ectoderm, but its varied contributions defy canons of segregation potential and challenges its embryonic origin. Aiming to resolve this conflict, we have assayed the earliest specification of neural crest using blastula stage chick embryos. Specification assays on isolated chick epiblast explants identify an intermediate region specified towards the neural crest cell fate. Furthermore, low density culture suggests that the specification of intermediate cells towards the neural crest lineage is independent of contact mediated induction. Finally, we have validated the regional identity of the intermediate region towards the neural crest cell fate using fate map studies in blastula stage chick embryos. Our results suggest a model of neural crest specification at blastula stage, with restricted ectoderm and mesoderm capacities.
BIN overlap confirms transcontinental distribution of pest aphids (Hemiptera: Aphididae)
Authors: Naseem Muhammad Tayyib , Ashfaq Muhammad , Khan Arif Muhammad , Rasool Akhtar , Asif Muhammad , Hebert Paul D.N.
Published: July 2019

DNA barcoding is highly effective for identifying specimens once a reference sequence library is available for the species assemblage targeted for analysis. Despite the great need for an improved capacity to identify the insect pests of crops, the use of DNA barcoding is constrained by the lack of a well-parameterized reference library. The current study begins to address this limitation by developing a DNA barcode reference library for the pest aphids of Pakistan. It also examines the affinities of these taxa with conspecific taxa from other geographic regions based on both conventional taxonomy and Barcode Index Numbers (BINs). A total of 809 aphids were collected from 123 plant species at 87 sites across Pakistan. Morphological study and DNA barcoding allowed 774 specimens to be identified to one of 42 species while the others were placed to a genus or subfamily. The 801 sequences obtained from these specimens were assigned to 52 BINs whose monophyly were supported by neighbor-joining (NJ) clustering and Bayesian inference. The 42 species were assigned to 41 BINs with 38 showing BIN concordance; one species (Rhopalosiphum padi) was assigned to two BINs, while two others (Aphis affinis, Aphis gossypii) were assigned to the same BIN, while one species (Aphis astragalina) lacked a qualifying sequence. The 42 Linnaean species were represented on BOLD by 7,870 records from 69 countries. Combining these records with those from Pakistan produced to 60 BINs with 12 species showing a BIN split and three a BIN merger. Geo-distance correlations showed that intraspecific divergence values for 18 of 37 species were not affected by the distance between populations. Forty four of the 52 BINs from Pakistan had counterparts in 73 countries across six continents, documenting the broad distributions of pest aphids.
A hierarchical Bayesian latent class mixture model with censorship for detection of linear temporal changes in antibiotic resistance
Authors: Zhang Min , Wang Chong , O’Connor Annette
Published: July 2019

Identifying and controlling the emergence of antimicrobial resistance (AMR) is a high priority for researchers and public health officials. One critical component of this control effort is timely detection of emerging or increasing resistance using surveillance programs. Currently, detection of temporal changes in AMR relies mainly on analysis of the proportion of resistant isolates based on the dichotomization of minimum inhibitory concentration (MIC) values. In our work, we developed a hierarchical Bayesian latent class mixture model that incorporates a linear trend for the mean log2MIC of the non-resistant population. By introducing latent variables, our model addressed the challenges associated with the AMR MIC values, compensating for the censored nature of the MIC observations as well as the mixed components indicated by the censored MIC distributions. Inclusion of linear regression with time as a covariate in the hierarchical structure allowed modelling of the linear creep of the mean log2MIC in the non-resistant population. The hierarchical Bayesian model was accurate and robust as assessed in simulation studies. The proposed approach was illustrated using Salmonella enterica I,4,[5],12:i:- treated with chloramphenicol and ceftiofur in human and veterinary samples, revealing some significant linearly increasing patterns from the applications. Implementation of our approach to the analysis of an AMR MIC dataset would provide surveillance programs with a more complete picture of the changes in AMR over years by exploring the patterns of the mean resistance level in the non-resistant population. Our model could therefore serve as a timely indicator of a need for antibiotic intervention before an outbreak of resistance, highlighting the relevance of this work for public health. Currently, however, due to extreme right censoring on the MIC data, this approach has limited utility for tracking changes in the resistant population.
Chinese culture, materialism and corporate supply of trade credit
Authors: Chen Xian , Arnoldi Jakob , Chen Xin
Published: July 2019

Purpose

The purpose of this paper is to investigate how cultural value in materialism affects corporate supply of trade credits.

Design/methodology/approach

Using a sample of 14,710 firm-year observations of Chinese listed firms from 1998 to 2012, the authors examine the influence of regional materialism on accounts receivable.

Findings

The authors find that listed firms within more materialistic tend to extend less trade credit to their customers, in particular in long-term categories of trade credit. Such negative effects can be significantly mitigated by state control, suggesting the effects are more pronounced in privately controlled listed firms. The negative effects of materialism still hold after controlling for other regional factors, such as trust, GDP per capita or institutional development.

Research limitations/implications

The authors show materialism as a cultural construct varies across Chinese regions, and it could have important impact on corporate supply of trade credits, besides the previous found effects on consumer use of credit.

Originality/value

This paper expands the literature about the influence of materialism on economic decision making from the individual level to the corporate level.
Information privacy concern and deception in online retailing
Authors: Li Yang , Liu Hefu , Lee Matthew , Huang Qian
Published: July 2019

Purpose

Previous studies have attempted to address online uncertainties from the relationship marketing perspective. The purpose of this paper is to argue that the integration of media richness theory (MRT) and cognitive fit theory (CFT) can contribute a new perspective in addressing consumers’ transaction-specific uncertainties in online retailing.

Design/methodology/approach

On the basis of MRT and CFT, a research model was developed by correlating online channel media richness (OCMR), online–offline information integration (OOII), information privacy concern, perceived deception and online loyalty. The model was empirically examined based on survey data collected from 258 multi-channel consumers in China.

Findings

An analysis of structural equation model showed that OCMR is negatively associated with information privacy concern and perceived deception but is not significant to online loyalty. Information privacy concern has a negative influence on online loyalty, but the effect of perceived deception is not significant. Moreover, information privacy concern is positively related to perceived deception. The OOII strengthens the influence of OCMR but not the moderating effect of integrated promotion, product and price information on the relationship between OCMR and online loyalty.

Originality/value

This study contributes to the extant literature on online retailing by examining the effect of OCMR on online transaction uncertainties. Information integrity in the form of OOII was proposed to complement OCMR. Results have shown that OCMR is significant in reducing online uncertainties, and OOII strengthens this effect, thereby enhancing online loyalty.
Factors influencing teaching as a career choice in both public and private universities in Ghana
Authors: Amoako George Kofi , Dartey-Baah Kwasi , Sokro Evans
Published: July 2019

Purpose

The purpose of this paper is to explore how lecturers in both public and private universities in Ghana are motivated to take up teaching as a career using Herzberg’s two-factor theory.

Design/methodology/approach

In this paper, qualitative research design was adopted. Data were collected from 24 lecturers from both public and private universities in Ghana and analysed with NVivo.

Findings

Results from the analysis indicate that public sector university lecturers are generally better motivated than their counterparts at the private sector. Workload is higher at private universities, affecting research and publications negatively. The study also revealed that there are differences in motivation in relation to the hygiene factors between the public and private university teachers.

Research limitations/implications

This study has a few limitations that must be considered and could provide guidance for future study; as this study addressed faculty point of view, future study could investigate from manager’s and other stakeholders’ point of view in order to get a holistic view of the issues under investigation. The sample size could be improved and the study could be conducted in other African countries for the purposes of comparison.

Practical implications

The study shows that many lecturers are not happy in the job for both public and private universities. The findings of the study provide managers in the higher education industry with practical guidelines for strategies to motivate lecturers.

Originality/value

Despite the rapid growth in the educational industry in Ghana, limited studies have been conducted into how lecturers are motivated to stay in teaching. This makes this research unique in Ghana. This study makes an original contribution by comparing how public sector and private sector university lecturers differ in their motivation to teach at the university using Herzberg’s two-factor theory.
Geomicrobiology of the carbon, nitrogen and sulphur cycles in Powell Lake: a permanently stratified water column containing ancient seawater
Authors: Haas Sebastian , Desai Dhwani K. , LaRoche Julie , Pawlowicz Rich , Wallace Douglas W. R.
Published: July 2019

We present the first geomicrobiological characterization of the meromictic water column of Powell Lake (British Columbia, Canada), a former fjord, which has been stably stratified since the last glacial period. Its deepest layers (300–350 m) retain isolated, relict seawater from that period. Fine‐scale vertical profiling of the water chemistry and microbial communities allowed subdivision of the water column into distinct geomicrobiological zones. These zones were further characterized by phylogenetic and functional marker genes from amplicon and shotgun metagenome sequencing. Binning of metagenomic reads allowed the linkage of function to specific taxonomic groups. Statistical analyses (analysis of similarities, Bray–Curtis similarity) confirmed that the microbial community structure followed closely the geochemical zonation. Yet, our characterization of the genetic potential relevant to carbon, nitrogen and sulphur cycling of each zone revealed unexpected features, including potential for facultative anaerobic methylotrophy, nitrogen fixation despite high ammonium concentrations and potential micro‐aerobic nitrifiers within the chemocline. At the oxic–suboxic interface, facultative anaerobic potential was found in the widespread freshwater lineage acI (Actinobacteria), suggesting intriguing ecophysiological similarities to the marine SAR11. Evolutionary divergent lineages among diverse phyla were identified in the ancient seawater zone and may indicate novel adaptations to this unusual environment.
Antioxidant Characteristics and Identification of Peptides from Sorghum Kafirin Hydrolysates
Authors: Xu Shiwei , Shen Yanting , Chen Gengjun , Bean Scott , Li Yonghui
Published: July 2019

Grain sorghum is gaining interest for various uses as a highly sustainable crop. Kafirin is the main storage protein in grain sorghum. However, the antioxidant activities of kafirin hydrolysates have not been systematically investigated. The objectives of this study were to characterize the antioxidative hydrolysates and their ultrafiltrated fractions from sorghum kafirin using chemical assays and model systems and to identify the representative peptides. Kafirin Neutrase hydrolysates displayed promising yield and antioxidant capacity among those prepared with several different proteases. The effects of critical variables including protein substrate content, enzyme‐to‐substrate ratio, and reaction time on antioxidant production were studied. Selected hydrolysates were further fractionated through ultrafiltration and gel filtration chromatography (GFC). Medium‐sized fraction (3 to 10 kDa) revealed relatively higher total phenolic content and stronger antioxidative activities with regard to free radical scavenging activity, metal ion chelating activity, reducing power, and oxygen radical absorbance capacity. In an oil‐in‐water emulsion system, incorporation of selected fraction of hydrolysates inhibited the formation of primary and secondary oxidation products by 83.03% and 65.59%, respectively, by the end of a 14‐day incubation period. Similar oxidation inhibition effect was also observed in a ground meat system. Peptide compositions of the most promising fraction from GFC and reversed‐phase high‐performance liquid chromatography were identified using matrix‐assisted laser desorption ionization–time of flight/time of flight mass spectrometry.

Practical Application

This study provided a feasible approach to produce peptide antioxidants from sorghum kafirin. The novel naturally derived antioxidants could be potentially used as alternatives or synergetic components to synthetic antioxidants in improving the oxidative stability of various food products.
Schizophrenia is associated with increased risk of subsequent substance abuse diagnosis: A nation‐wide population‐based register study
Authors: Petersen Stine Mai , Toftdahl Nanna Gilliam , Nordentoft Merete , Hjorthøj Carsten
Published: July 2019

Aims

We aimed to investigate whether or not a diagnosis of schizophrenia increases the risk of a substance abuse diagnosis.

Design

Prospective cohort study using a longitudinal study design.

Setting and participants

Individuals born in Denmark from 1955 to 1999 and registered in the Danish registers between 1 January 1968 and 1 July 2013.

Measurements

We investigated the associations between schizophrenia and ICD diagnoses of substance abuse, both established through various Danish registers. The Cox regression model was used and adjusted for calendar year, gender, urbanicity, co‐abuse, other psychiatric diagnoses, parents' substance abuse and psychiatric history, parents' immigration and parents' socio‐economic position. Individuals diagnosed with substance abuse less than a year after diagnosis of schizophrenia were classified as not diagnosed with schizophrenia.

Findings

The cohort consisted of 3 133 968 individuals. During follow‐up (103 212 328 person‐years at risk), a total of 14 007 individuals developed schizophrenia, with 2885 subsequently diagnosed with substance abuse. A diagnosis of schizophrenia was positively associated with the risk of developing substance abuse [hazard ratio (HR) = 3.69, 95% confidence interval (CI) = 3.56–3.83]. Additionally, adjusting for a co‐abuse markedly affected the associations, making schizophrenia primarily associated with an increased risk of abuse of cannabis, alcohol, stimulants and other substances (adjusted HR = 2.48, 95% CI = 2.34–2.64 for cannabis; HR = 1.94, 95% CI = 1.87–2.02 for alcohol; HR = 1.77, 95% CI = 1.61–1.95 for stimulants; HR = 1.36, 95% CI = 1.20–1.54 for other substances). The association was still significant 10–15 years subsequent a diagnosis of schizophrenia (HR = 2.50, 95% CI = 2.26–2.76).

Conclusions

In Denmark a diagnosis of schizophrenia is significantly associated with increased risk of subsequent diagnosis of substance abuse.