bluuebunny/crossref_metadata_2025 huggingface dataset:
Sphingosine-1-Phosphate (S1P) analogue Phyto-sphingosine-1-Phosphate (P1P) improves thein vitromaturation efficiency of porcine oocytes via regulation of oxidative stress and apoptosis
Authors: Park Kyu-Mi , Wang Jae Woong , Yoo Yeong-Min , Jang Ji Eun , Choi Myeong Jun , Hyun Sang Hwan , Hwang Kyu Chan , Jeung Eui-Bae , Jeong Yeon Woo , Hwang Woo Suk
Published: December 2018

Phytosphingosine-1-Phosphate (P1P) is a signaling sphingolipid regulating various physiological activities. Yet, little is known of the effect of P1P in the context of reproduction. As such, we aimed to investigate the influence of P1P on oocyte maturation during porcinein vitromaturation (IVM). Here we report the expression of S1PR1-3 among P1P receptors (S1PR1-4) in cumulus cells and oocytes. When P1P was treated by concentrations 10 nM, 50 nM, 100 nM, and 1000 nM during IVM, Metaphase II rate was significantly increased in 1000 nM (=1 μM) P1P treatment group. Maturation rate improvement by P1P supplementation was only observed in the presence of EGF. Oocytes under the influence of P1P decreased intracellular ROS levels yet did not show significant differences in GSH levels. In our molecular studies, P1P treatment up-regulated gene expressions involved in cumulus expansion (Has2andEGF), antioxidant enzyme (SOD3andCat), and developmental competence (Oct4) while activating ERK1/2 and Akt signaling. P1P treatment also influenced oocyte survival by shifting the ratio ofBcl-2toBax, while inactivating JNK signaling. We further demonstrated that oocytes matured with P1P significantly displayed not only higher developmental competence (cleavage and blastocyst formation rate), but also greater blastocyst quality (total cell number and the ratio of apoptotic cells) when activated via parthenogenetic activation (PA) andin vitrofertilization (IVF). Despite low levels of endogenous P1P found in animals, exogenous P1P was able to influence animal reproduction as shown by increased porcine oocyte maturation as well as preimplantation embryo development.
Proteome thermal stability reflects organ physiology and identifies drug-target engagement in vivo
Authors: Perrin Jessica , Werner Thilo , Kurzawa Nils , Childs Dorothee D , Kalxdorf Mathias , Rutkowska Anna , Poeckel Daniel , Sevin Daniel C , Stonehouse Eugenia , Strohmer Katrin , Heller Bianca , Thomson Douglas , Vappiani Johanna , Krause Jana , Eberl H Christian , Rau Christina E , Franken Holger , Huber Wolfgang , Faelth-Savitski Maria , Savitski Mikhail M , Bantscheff Marcus , Bergamini Giovanna
Published: December 2018

Studying biological processes at a molecular level and monitoring drug-target interactions is established for simple cell systems but challenging in vivo. We introduce and apply a methodology for proteome-wide thermal stability measurements to characterize organ physiology and activity of many fundamental biological processes across tissues, such as energy metabolism and protein homeostasis. This method, termed tissue thermal proteome profiling (tissue-TPP), also enabled target and off-target identification and occupancy measurements in tissues derived from animals dosed with the non-covalent histone deacetylase inhibitor, panobinostat. Finally, we devised blood-CETSA, a thermal stability-based method to monitor target engagement in whole blood. Our study generates the first proteome-wide map of protein thermal stability in tissue and provides tools that will be of great impact for translational research.
Schizophrenia polygenic risk scores, urbanicity and treatment-resistant schizophrenia
Authors: Gasse Christiane , Wimberley Theresa , Wang Yungpeng , Horsdal Henriette Thisted
Published: December 2018

Introduction

To investigate the impact of a polygenic risk score for schizophrenia (PRS-SZ) and urbanicity on the risk of treatment-resistant schizophrenia in people with a diagnosis of schizophrenia and to evaluate the association between PRS-SZ and TRS across areas of urbanicity.

Methods

Cohort study of people born after 1981 with a first time diagnosis of schizophrenia between 1996 and 2012 using Danish population registry data. Through linkage to genome-wide data, we calculated PRS-SZ based on a Psychiatric Genomics Consortium meta-analysis. We assessed urbanicity at birth (capital, provincial and rural areas). TRS was defined using prescription and hospital data. Performing Cox regression analysis, we calculated hazard rate ratios (HRs) and 95% confidence intervals (CI).

Results

Among 4,475 people with schizophrenia, we identified 593 (13.3%) with TRS during 17 558 person years of follow-up. The adjusted HR for TRS associated with 1 standard deviation (SD) increase in the PRS-SZ was 1.11 (95% CI: 1.00–1.24). The adjusted HRs for urbanicity and TRS were 1.20 (95% CI: 0.98–1.47) for provincial areas and 1.19 (95% CI 0.96–1.47) for rural areas compared with the capital area. Across strata of urbanicity, the adjusted HR for TRS was 1.39 (95% CI: 1.14–1.70) in the capital area with 1 SD increase in the PRS-SZ, 0.99 (95% CI 0.84–1.17) in provincial areas, and 1.03 (95% CI: 0.86–1.25) in rural areas.

Conclusion

The risk of TRS associated with genetic liability varied across urbanicity areas and was highest in people with schizophrenia who resided in the capital areas at birth.
The validity and consistency of continuous joystick response in perceptual decision-making
Authors: Szul Maciej J. , Bompas Aline , Sumner Petroc , Zhang Jiaxiang
Published: December 2018

A computer joystick is an efficient and cost-effective response device for recording continuous movements in psychological experiments. Movement trajectories and other measures from continuous responses have expanded the insights gained from discrete responses (e.g. button presses) by providing unique information on how cognitive processes unfold over time. However, few studies have evaluated the validity of joystick responses with reference to conventional key presses, and response modality can affect cognitive processes. Here, we systematically compared human participants’ behavioural performance of perceptual decision-making when they responded with either joystick movements or key presses in a four-alternative motion discrimination task. We found evidence that the response modality did not affect raw behavioural measures including decision accuracy and mean reaction time (RT) at the group level. Furthermore, to compare the underlying decision processes between the two response modalities, we fitted a drift-diffusion model of decision-making to individual participant’s behavioural data. Bayesian analyses of the model parameters showed no evidence that switching from key presses to continuous joystick movements modulated the decision-making process. These results supported continuous joystick actions as a valid apparatus for continuous movements, although we highlighted the need for caution when conducting experiments with continuous movement responses.
Sensory Cue Combination in Children Under 10 Years of Age
Authors: Negen James , Chere Brittney , Bird Laura , Taylor Ellen , Roome Hannah E. , Keenaghan Samantha , Thaler Lore , Nardini Marko
Published: December 2018

Cue combination occurs when two independent noisy perceptual estimates are merged together as a weighted average, creating a unified estimate that is more precise than either single estimate alone. Surprisingly, this effect has not been demonstrated compellingly in children under the age of 10 years, in contrast with the array of other multisensory skills that children show even in infancy. Instead, across a wide variety of studies, precision with both cues is no better than the best single cue – and sometimes worse. Here we provide the first consistent evidence of cue combination in children from 7–10 years old. Across three experiments, participants showed evidence of a bimodal precision advantage (Experiments 1a and 1b) and the majority were best-fit by a combining model (Experiment 2). The task was to localize a target horizontally with a binaural audio cue and a noisy visual cue in immersive virtual reality. Feedback was given as well, which could both (a) help participants judge how reliable each cue is and (b) help correct between-cue biases that might prevent cue combination. A feedback effect was found in Experiment 2, with children who were given single-cue feedback showing the highest rate of cue combination. Given this, we suggest that children at 7–10 years old are capable of cue combination in principle, but must have sufficient representations of reliabilities and biases in their own perceptual estimates as relevant to the task, which can be facilitated through task-specific feedback.
Exploration of Anti-Yo and Anti-Hu paraneoplastic neurological disorders by PhIP-Seq reveals a highly restricted pattern of antibody epitopes
Authors: O'Donovan Brian D , Mandel-Brehm Caleigh , Vazquez Sara E , Liu Jamin , Parent Audrey V , Anderson Mark S , Kassimatis Travis , Zekeridou Anastasia , Hauser Stephen L , Pittock Sean J , Chow Eric , Wilson Michael R , DeRisi Joseph L
Published: December 2018

Paraneoplastic neurological disorders (PNDs) are immune-mediated diseases of the nervous system understood to manifest as part of a misdirected anti-tumor immune response. Identifying PND-associated autoantibodies and their cognate antigens can assist with proper diagnosis and treatment while also enhancing our understanding of tumor-associated immune processes, triggers for autoimmune disease, and the functional significance of onconeuronal proteins. Here, we employed an enhanced version of phage display immunoprecipitation and sequencing (PhIP-Seq) leveraging a library of over 731,000 unique phage clones tiling across the entire human proteome to detect autoantibodies and create high-resolution epitope profiles in serum and CSF samples from patients suffering from two common PNDs, the anti-Yo (n = 36 patients) and anti-Hu syndromes (n = 44 patients). All patient samples positive for anti-Yo antibody by a validated clinical assay yielded polyspecific enrichment of phage presenting peptides from the canonical anti-Yo (CDR2 and CDR2L) antigens, while 38% of anti-Hu patients (17/44) had a serum and/or CSF sample that significantly enriched peptides deriving from the ELAVL family of proteins, the anti-Hu autoantigenic target. The anti-Hu antibodies showed a remarkably convergent antigenic signature across 15/17 patients corresponding to residues surrounding and including the degenerate motif, RLDxLL, shared by ELAVL2, 3 and 4. Lastly, PhIP-Seq identified several known and novel autoantigens in these same patient samples, representing potential biomarkers that could aid in the diagnosis and prognosis of PND and cancer.
Precision phenotyping reveals novel loci for quantitative resistance to septoria tritici blotch in European winter wheat
Authors: Yates Steven , Mikaberidze Alexey , Krattinger Simon , Abrouk Michael , Hund Andreas , Yu Kang , Studer Bruno , Fouche Simone , Meile Lukas , Pereira Danilo , Karisto Petteri , McDonald Bruce
Published: December 2018

Accurate, high-throughput phenotyping for quantitative traits is the limiting factor for progress in plant breeding. We developed automated image analysis to measure quantitative resistance to septoria tritici blotch (STB), a globally important wheat disease, enabling identification of small chromosome intervals containing plausible candidate genes for STB resistance. 335 winter wheat cultivars were included in a replicated field experiment that experienced natural epidemic development by a highly diverse but fungicide-resistant pathogen population. More than 5.4 million automatically generated phenotypes were associated with 13,648 SNP markers to perform a GWAS. We identified 26 chromosome intervals explaining 1.9-10.6% of the variance associated with four resistance traits. Seventeen of the intervals were less than 5 Mbp in size and encoded only 173 genes, including many genes associated with disease resistance. Five intervals contained four or fewer genes, providing high priority targets for functional validation. Ten chromosome intervals were not previously associated with STB resistance. Our experiment illustrates how high-throughput automated phenotyping can accelerate breeding for quantitative disease resistance. The SNP markers associated with these chromosome intervals can be used to recombine different forms of quantitative STB resistance that are likely to be more durable than pyramids of major resistance genes.
Scaling tree-based automated machine learning to biomedical big data with a dataset selector
Authors: Le Trang T , Fu Weixuan , Moore Jason H
Published: December 2018

Automated machine learning (AutoML) systems are helpful data science assistants designed to scan data for novel features, select appropriate supervised learning models and optimize their parameters. For this purpose, Tree-based Pipeline Optimization Tool (TPOT) was developed using strongly typed genetic programming to recommend an optimized analysis pipeline for the data scientist's prediction problem. However, TPOT may reach computational resource limits when working on big data such as whole-genome expression data. We introduce two new features implemented in TPOT that helps increase the system's scalability: Dataset selector and Template. Dataset selector (DS) provides the option to specify subsets of the features as separate datasets, assuming the signals come from one or more of these specific data subsets. Built in at the beginning of each pipeline structure, DS reduces the computational expense of TPOT to only evaluate on a smaller subset of data rather than the entire dataset. Consequently, DS increases TPOT's efficiency in application on big data by slicing the dataset into smaller sets of features and allowing genetic programming to select the best subset in the final pipeline. Template enforces type constraints with strongly typed genetic programming and enables the incorporation of DS at the beginning of each pipeline. We show that DS and Template help reduce TPOT computation time and may provide more interpretable results. Our simulations show TPOT-DS significantly outperforms a tuned XGBoost model and standard TPOT implementation. We apply TPOT-DS to real RNA-Seq data from a study of major depressive disorder. Independent of the previous study that identified significant association with depression severity of the enrichment scores of two modules, in an automated fashion, TPOT-DS corroborates that one of the modules is largely predictive of the clinical diagnosis of each individual.
Trichoderma asperelloides enhances local and systemic acquired resistance response under low nitrate nutrition in Arabidopsis
Authors: Wany Aakanksha , Pathak Pradeep K. , Fernie Alisdair R , Gupta Kapuganti Jagadis
Published: December 2018

Nitrogen (N) is essential for growth, development and defense but, how low N affects defense and the role of Trichoderma in enhancing defense under low nitrate is not known. Low nitrate fed Arabidopsis plants displayed reduced growth and compromised local and systemic acquired resistance responses when infected with both avirulent and virulent Pseudomonas syringae DC3000. These responses were enhanced in the presence of Trichoderma. The mechanism of increased local and systemic acquired resistance mediated by Trichoderma involved increased N uptake and enhanced protein levels via modulation of nitrate transporter genes. The nrt2.1 mutant is compromised in local and systemic acquired resistance responses suggesting a link between enhanced N transport and defense. Enhanced N uptake was mediated by Trichoderma elicited nitric oxide (NO). Low NO producing nia1,2 mutant and nsHb+ over expressing lines were unable to induce nitrate transporters and thereby compromised defense in the presence of Trichoderma under low N suggesting a signaling role of Trichoderma elicited NO. Trichoderma also induced SA and defense gene expression under low N. The SA deficient NahG transgenic line and the npr1 mutant were also compromised in Trichoderma-mediated local and systemic acquired resistance responses. Collectively our results indicated that the mechanism of enhanced plant defense under low N mediated by Trichoderma involves NO, ROS, SA production as well as the induction of NRT and marker genes for systemic acquired resistance.

One-sentence summary

Trichoderma enhances local and systemic acquired resistance under low nitrate nutrition
Microglia-dependent presynaptic disruption in an organotypic hippocampal slice culture model of neuroinflammation
Authors: Sheppard Olivia , Coleman Michael P , Durrant Claire S
Published: December 2018

Background: Systemic inflammation, such as occurs during sepsis, bone fracture, infections or post-operative trauma, has been linked to synapse loss and cognitive decline in human patients and animal models. Organotypic hippocampal slice cultures (OHSCs) represent an underused tool in neuroinflammation; retaining much of the neuronal architecture, synaptic connections and diversity of cell types present in the hippocampus in vivo whilst providing convenient access to manipulate and sample the culture medium and observe cellular reactions as in other in vitro methods. Here we report the development of an OHSC model of synaptic disruption after aseptic inflammation and investigate the underlying mechanism. Methods: OHSCs were generated from P6-P9 C57BL/6, the APP transgenic TgCRND8 model, or wild-type littermate mice according to the interface method. Aseptic inflammation was induced via addition of lipopolysaccharide (LPS) and cultures were analysed for changes in synaptic proteins via western blot. qPCR and ELISA analysis of the slice tissue and culture medium respectively determined changes in gene expression and protein secretion. Microglia were selectively depleted using the toxin clodronate and the effect of IL1β was assessed using a specific neutralising monoclonal antibody. Results: Addition of LPS caused a loss of the presynaptic protein synaptophysin via a mechanism dependent on microglia and involving IL1β. Washout of LPS via medium exchange allows for partial recovery of synaptic protein levels after 2 weeks. TgCRND8 OHSCs do not show alterations in IL1β expression at a timepoint where they exhibit spontaneous synaptophysin loss, and LPS does not alter levels of APP or Aβ in wild-type OHSCs. This indicates that although synaptophysin loss is seen in both systems, there is likely to be distinct underlying pathogenic mechanisms between the neuroinflammatory and amyloid models. Conclusions: We report the development of an OHSC model of LPS-induced synaptophysin loss and demonstrate a key role for microglia and involvement of IL1β. We propose that distinct molecular mechanisms lead to synaptophysin protein loss in LPS- exposed versus TgCRND8 OHSCs and provide a new experimental paradigm for assessing chronic changes in synaptic proteins, and synaptic plasticity, following acute inflammatory insults.
Prophages and satellite prophages are widespread amongStreptococcusspecies and may play a role in pneumococcal pathogenesis
Authors: Javan Reza Rezaei , Ramos-Sevillano Elisa , Akter Asma , Brown Jeremy , Brueggemann Angela B
Published: December 2018

Prophages (viral genomes integrated within a host bacterial genome) are abundant within the bacterial world and are of interest because they often confer various phenotypic traits to their hosts, such as by encoding genes that increase pathogenicity. Satellite prophages are ‘parasites of parasites’ that rely on the bacterial host and another helper prophage for survival. We analysed >1,300 genomes of 70 differentStreptococcusspecies for evidence of prophages and identified nearly 800 prophages and satellite prophages, the majority of which are reported here for the first time. We show that prophages and satellite prophages were widely distributed among streptococci, were two clearly different entities and each possessed a structured population. There was convincing evidence that cross-species transmission of prophages is not uncommon. Furthermore,Streptococcus pneumoniae(pneumococcus) is a leading human pathogen worldwide, but the genetic basis for its pathogenicity and virulence is not yet fully understood. Here we report that over one-third of pneumococcal genomes possessed satellite prophages and demonstrate for the first time that a satellite prophage was associated with virulence in a murine model of infection. Overall, our findings demonstrate that prophages are widespread components ofStreptococcusspecies and suggest that they play a role in pneumococcal pathogenesis.
Cell type purification by single-cell transcriptome-trained sorting
Authors: Baron Chloé S , Barve Aditya , Muraro Mauro J , Dharmadhikari Gitanjali , van der Linden Reinier , Lyubimova Anna , de Koning Eelco J. P. , van Oudenaarden Alexander
Published: December 2018

Traditional cell type enrichment using fluorescence activated cell sorting (FACS) relies on methods that specifically label the cell type of interest. Here we propose GateID, a computational method that combines single-cell transcriptomics for unbiased cell type identification with FACS index sorting to purify cell types of choice. We validate GateID by purifying various cell types from the zebrafish kidney marrow and the human pancreas without resorting to specific antibodies or transgenes.
Genome-wide Association Study of Multisite Chronic Pain in UK Biobank
Authors: Johnston Keira J.A. , Adams Mark J. , Nicholl Barbara I. , Ward Joey , Strawbridge Rona J , Ferguson Amy , McIntosh Andrew , Bailey Mark E.S. , Smith Daniel J.
Published: December 2018

Chronic pain is highly prevalent worldwide, contributing a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype, chronic pain grade, have been shown to be complex, heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual’s overall sensitivity to experiencing and reporting chronic pain have also been suggested. We have here made use of a measure of the number of sites of chronic pain in individuals within the general UK population. This measure, termed Multisite Chronic Pain (MCP), is also a complex trait, but its genetic architecture has not previously been investigated. To address this, a large-scale genome-wide association study (GWAS) of MCP was carried out in ~380,000 UK Biobank participants to identify associated genetic variants. Findings were consistent with MCP having a significant polygenic component with a SNP heritability of 10.2%, and 76 independent lead single nucleotide polymorphisms (SNPs) at 39 risk loci were identified. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as being enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits including major depressive disorder (MDD), asthma and BMI. Furthermore, in Mendelian randomisation (MR) analyses a bi-directional causal relationship was observed between MCP and MDD. A polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. These findings support the proposition that chronic pain involves a strong nervous system component and have implications for our understanding of the physiology of chronic pain and for the development of novel treatment strategies.
Pre-Clinical Blocking of PD-L1 molecule, which expression is down regulated by NF-κB, JAK1/JAK2 and BTK inhibitors, induces regression of activated B-cell lymphoma
Authors: Vincent-Fabert Christelle , Roland Lilian , Zimber-Strobl Ursula , Feuillard Jean , Faumont Nathalie
Published: December 2018

Escape from immune control must be important in the natural course of B-cell lymphomas, especially for those with activation of NF-κB. The pre-clinical L.CD40 transgenic mouse model is characterized by B-cell specific CD40 signaling responsible for NF-κB continuous activation with a spleen monoclonal B-cell tumor after one year in 60% of cases. L.CD40 tumors B-cells expressed high levels of PD-L1. This expression was dependent on activation of either NF-κB, JAK1/JAK2 or BTK pathways since ex vivo treatment with the inhibitory molecules PHA-408, ruxolitinib and ibrutinib led to decrease of its expression. Treatment of L.CD40 lymphomatous mice with an anti-PD-L1 monoclonal antibody induced tumor regression with decreased spleen content, activation and proliferation rate of B-cells as well as a marked increase in T cell activation, as assessed by CD62L and CD44 expression. These results highlight the interest of therapies targeting the PD-1/PD-L1 axis in activated lymphomas with PD-L1 expression, with possible synergies with tyrosine kinase inhibitors.
Phototrophic lactate utilization by Rhodopseudomonas palustris is stimulated by co-utilization with additional substrates
Authors: Govindaraju Alekhya , McKinlay James B , LaSarre Breah
Published: December 2018

The phototrophic purple nonsulfur bacterium Rhodopseudomonas palustris is known for its metabolic versatility and is of interest for various industrial and environmental applications. Despite decades of research on R. palustris growth under diverse conditions, patterns of R. palustris growth and carbon utilization with mixtures of carbon substrates remain largely unknown. R. palustris readily utilizes most short chain organic acids but cannot readily use lactate as a sole carbon source. Here we investigated the influence of mixed-substrate utilization on phototrophic lactate consumption by R. palustris. We found that lactate was simultaneously utilized with a variety of other organic acids and glycerol in time frames that were insufficient for R. palustris growth on lactate alone. Thus, lactate utilization by R. palustris was expedited by its co-utilization with additional substrates. Separately, experiments using carbon pairs that did not contain lactate revealed acetate-mediated inhibition of glycerol utilization in R. palustris. This inhibition was specific to the acetate-glycerol pair, as R. palustris simultaneously utilized acetate or glycerol when either was paired with succinate or lactate. Overall, our results demonstrate that (i) R. palustris commonly employs simultaneous mixed-substrate utilization, (ii) mixed-substrate utilization expands the spectrum of readily utilized organic acids in this species, and (iii) R. palustris has the capacity to exert carbon catabolite control in a substrate-specific manner.
Remote focusing system for simultaneous dual-plane mesoscopic multiphoton imaging
Authors: Tsyboulski Dmitri , Orlova Natalia , Griffin Fiona , Seid Sam , Lecoq Jerome , Saggau Peter
Published: December 2018

We present a dual-plane mesoscopic imaging system capable of simultaneous image acquisition from two independent focal planes. The system was designed as an add-on to a recently introduced large field-of-view two-photon microscopy system, developed by Sofroniew, et al., eLife, 5, e14472, 2016. In this work, we merge two advanced multiphoton imaging technologies, i.e., temporal-division multiplexing and remote focusing, to maintain diffraction-limited resolution at both imaging planes, and achieve a more than 2-fold increase in the system's overall imaging throughput. We introduce a novel solution to decode temporally interleaved analog signals at nanosecond timescales to achieve high-speed time-multiplexed imaging. Detailed characterization and comparison of the modified and the original two-photon microscopy system was performed.
Immunological responses to the relapsing fever spirochete Borrelia turicatae in infected Rhesus macaques: implications for pathogenesis and diagnosis.
Authors: Embers Monica E , Krishnavjhala Aparna , Armstrong Brittany , Curtis Michael W. , Pahar Bapi , Wilder Hannah K , Allen Michael S , Beare Paul A , Hasenkampf Nicole R , Lopez Job E.
Published: December 2018

The global public health impact of relapsing fever (RF) spirochetosis is significant, as the pathogens exist on five of seven continents. The hallmark sign of infection is episodic fever and the greatest threat is to the unborn. With the goal of better understanding the specificity of B cell responses and the role of immune responses in pathogenicity, we infected Rhesus macaques with Borrelia turicatae (a new world RF spirochete species) by tick bite and monitored the immune responses generated in response to the pathogen. Specifically, we evaluated inflammatory mediator induction by the pathogen, host antibody responses to specific antigens, and peripheral lymphocyte population dynamics. Our results indicate that B. turicatae elicits from peripheral blood cells key inflammatory response mediators (IL-1β and TNF-α) which are associated with pre-term abortion. Moreover, a global decline in peripheral B cell populations was observed in all animals at 14 days post-infection. Serological responses were also evaluated to assess the antigenicity of three surface proteins, BipA, BrpA and Bta112. Interestingly, a distinction was observed between antibodies generated in non-human primates (NHPs) and mice. Our results provide support for the nonhuman primate model not only in studies of prenatal pathogenesis, but for diagnostic and vaccine antigen identification and testing.
Geometric constraints in protein folding
Authors: Molkenthin Nora , Muehle Steffen , Mey Antonia , Timme Marc
Published: December 2018

The intricate three-dimensional geometries of protein tertiary structures underlie protein function and emerge through a folding process from one-dimensional chains of amino acids. The exact spatial sequence and configuration of amino acids, the biochemical environment and the temporal sequence of distinct interactions yield a complex folding process that cannot yet be easily tracked for all proteins. To gain qualitative insights into the fundamental mechanisms behind the folding dynamics and generic features of the folded structure, we propose a simple model of structure formation that takes into account only fundamental geometric constraints and otherwise assumes randomly paired connections. We find that despite its simplicity, the model results in a network ensemble consistent with key overall features of the ensemble of Protein Residue Networks we obtained from more than 1000 biological protein geometries as available through the Protein Data Base. Specifically, the distribution of the number of interaction neighbors a unit (amino acid) has, the scaling of the structure's spatial extent with chain length, the eigenvalue spectrum and the scaling of the smallest relaxation time with chain length are all consistent between model and real proteins. These results indicate that geometric constraints alone may already account for a number of generic features of protein tertiary structures.
On cross-correlations, averages and noise in electron microscopy
Authors: Radermacher Michael , Ruiz Teresa
Published: December 2018

Biological samples are radiation-sensitive and require imaging under low-dose conditions to minimize damage. As a result, images contain a high level of noise and exhibit signal-to-noise ratios that are typically significantly smaller than 1. Averaging techniques, either implicit or explicit, are used to overcome the limitations imposed by the high level of noise. Averaging of 2D images showing the same molecule in the same orientation results in highly significant projections. A high-resolution structure can be obtained by combining the information from many single-particle images to determine a 3D structure. Similarly, averaging of multiple copies of macromolecular assembly subvolumes extracted from tomographic reconstructions can lead to a virtually noise-free high-resolution structure. Cross-correlation methods are often used in the alignment and classification steps of averaging processes for both 2D images and 3D volumes. However, the high noise level can bias alignment and certain classification results. While other approaches may be implicitly affected, sensitivity to noise is most apparent in multireference alignments, 3D reference-based projection alignments and projection-based volume alignments. Here, the influence of the image signal-to-noise ratio on the value of the cross-correlation coefficient is analyzed and a method for compensating for this effect is provided.
Professional skills development for mathematics undergraduates
Authors: Russell Ewan , Rowlett Peter
Published: December 2018

Purpose

The purpose of this paper is to describe the design and development of a final year undergraduate mathematics module designed to address professional skills development at a UK university, including via input to curriculum and assessment from employers, and to investigate student acquisition of skills from this module.

Design/methodology/approach

Literature on skills development in mathematics informs module design and development. Students optionally completed Likert-style competency questionnaires before and after the taught module content, and reflected on skills development via an end of module questionnaire. Data collection took place over three academic years.

Findings

Several key competencies exhibit median increases over the course of the module in each academic year, indicating a perceived skills development. Problem solving and presentation skills are particularly highlighted.

Research limitations/implications

Numbers of students were small, though the study is repeated with three different cohorts. Some students study mathematics jointly with another discipline and hence may have experience in skills development from the other subject.

Practical implications

This study indicates that innovations in teaching style and assessment in mathematics modules can enhance student confidence and competence with key professional skills.

Originality/value

Undergraduate modules in mathematics which have a focus on professional skills development are still fairly rare in UK universities. Often such modules do not embed the professional skills development activities with subject-specific technical tasks and projects as this module does. There are few formal studies of the effectiveness of this style of module, especially longitudinal studies covering several academic years.
Volatility in frontier markets: a Multivariate GARCH analysis
Authors: Seth Neha , Singhania Monica
Published: December 2018

Purpose

The purpose of this paper is to analyze the existence of volatility spillover effect in frontier markets. This study also examines whether any linkages exist among these markets or not.

Design/methodology/approach

Monthly data of regional frontier markets, from 2009 to 2016, are analyzed using Multivariate GARCH (BEKK and Dynamic Conditional Correlation (DCC)) models.

Findings

The result of cointegration test shows that the sample frontier markets are not linked in long run, and Granger causality test reveals that the markets under consideration do not cause each other even in the short run. BEKK test says that the effect of the arrival of shock from the own market does not last for longer, whereas shock from other markets lasts with the stronger persistence, and according to DCC test, the volatility spillover exists for all the markets.

Practical implications

The results of present study suggest that the frontier markets are not cointegrated in the long run as well as in the short run, which opens the doors for long-term investments in these markets in future, which may lead to decent returns. Long-term investors may draw the benefits from including the financial assets in their portfolios from these non-integrated frontier markets; nevertheless, they have to consider and implement diversification and hedging strategies during the period of financial turmoil, so as to protect themselves against economic and financial distress.

Originality/value

Significant work has been done on developed, developing and emerging markets but frontier markets are not explored much so far. This paper is an attempt to see the status of frontier stock markets as potential financial markets for diversification benefits.
Analysis of patients with drug‐induced pemphigoid using the Japanese Adverse Drug Event Report database
Authors: Tanaka Hiroyuki , Ishii Toshihiro
Published: December 2018

To clarify the incidence of drug‐induced pemphigoid in Japan, we conducted a database search and analysis using the Japanese Adverse Drug Event Report database (JADER). Among the cases recorded in JADER between April 2004 and November 2017, we targeted “pemphigoid” and analyzed the patients’ backgrounds, drug involvement, time of pemphigoid onset, outcomes and year reported. For cases where three or more drugs were reportedly involved, the signal index was calculated using the reporting odds ratio (ROR) method. The total number of reported pemphigoid cases was 769. Males accounted for 58% (446 cases) and patients over the age of 60 years accounted for 82% (630 cases). The most frequently reported causative drug was vildagliptin (288 cases), followed in order by sitagliptin phosphate hydrate (102 cases), teneligliptin hydrobromide hydrate (86 cases), linagliptin (64 cases) and furosemide (46 cases). For the 27 causative drugs, the safety signal was detected by the ROR method. The median time to onset tended to be long for these drugs. For vildagliptin with the largest reported number, the value was 508 days (range, 2–1871). Analysis of outcomes demonstrated recovery or improvement in 66.3% of cases. Analysis of the years in which reports had been published revealed that the number of pemphigoid cases has increased rapidly in recent years. Our survey was able to reveal useful data on the incidence of drug‐induced pemphigoid. We expect that these results will aid the early detection and treatment of this condition.
Cascading effects of forested area and isolation on seed dispersal effectiveness of rodents on subtropical islands
Authors: Zeng Di , Swihart Robert K. , Zhao Yuhao , Si Xingfeng , Ding Ping
Published: December 2018

Habitat loss and fragmentation often leads to defaunation of large‐bodied mammals, and their loss could trigger release from top‐down control or food resource competition for small mammal seed dispersers, which in turn may affect the effectiveness of seed dispersal by altering the number of dispersed seeds or the manner in which they are dispersed. Although rodents are primary seed dispersers in habitat subjected to defaunation, changes in seed dispersal effectiveness of rodents along mammalian defaunation gradients, and empirical support for mechanisms underlying alteration of this ecological process, are unclear.

We assessed the direct and indirect effects of forested area and isolation on seed dispersal effectiveness of rodents on 21 study islands with varying levels of defaunation in the Thousand Island Lake, China. We used camera sampling, live traps and semi‐quantitative acorn counts to assess occurrence of large‐bodied mammal species, relative abundance of small rodent species and seed crop size respectively. Seed dispersal, post‐dispersal seed survival, seedling emergence, and seedling survival were estimated by tracking fates of tagged acorns and by planting acorns in exclosures.

Forested area had positive indirect effects on seed dispersal effectiveness through defaunation and rodent competition for acorns, whereas isolation had negative direct and weaker positive indirect effects on seed dispersal effectiveness mediated by loss of large‐bodied mammals and rodent competition for acorns. Loss of large‐bodied mammals negatively affected seed dispersal effectiveness indirectly by virtue of its impact on rodent competition for acorns. Seed dispersal effectiveness exhibited a unimodal relationship with intensity of rodent competition for acorns, peaking at intermediate levels.

Synthesis. Indirect effects of island attributes mediated by defaunation of large‐bodied mammals on small or isolated islands appear to drive altered competition for food among rodents and decreased seed dispersal effectiveness. Altered interactions between acorns and their rodent consumers/dispersers can substantially affect oak population demography in the Thousand Island Lake system. More broadly, our findings highlight the importance to the seed dispersal process of multiple interwoven effects between habitat fragmentation and defaunation of large‐bodied mammals.
MicroRNA let‐7c‐5p promotes osteogenic differentiation of dental pulp stem cells by inhibiting lipopolysaccharide‐induced inflammation via HMGA2/PI3K/Akt signal blockade
Authors: Yuan Hao , Zhao Hongyan , Wang Jiafeng , Zhang Hong , Hong Lihua , Li He , Che Hongze , Zhang Zhimin
Published: December 2018

Pulpitis suppressed the level of let‐7c‐5p that promotes osteogenesis and bone formation by repressing HMGA2. In the current study, the function of let‐7c‐5p in the inflammation and osteogenesis in dental pulp stem cells (DPSCs) was explored. The level of let‐7c‐5p in DPSCs was up‐regulated, and the cells were subjected to lipopolysaccharide (LPS) to induce inflammation. The effect of let‐7c‐5p on cell proliferation potential, osteogenic differentiation potential, and activity of HMGA2/PI3K/Akt pathway was detected. The administration of LPS suppressed the cell proliferation of DPSCs and suppressed calcium deposition, activity of alkaline phosphatase (ALP), and levels of OCN, OPN, OSX, MSX2, and RUNX2 in inflamed DPSCs. The impaired osteogenic differentiation of inflamed DPSCs was associated with the increased levels of HMGA2, p‐PI3K, and p‐Akt. In let‐7c‐5p‐overexpressed inflamed DPSCs, the proliferation and osteogenic differentiation potential of DPSCs were restored, and the activation of HMGA2/PI3K/Akt signalling was inhibited. In rat pulpitis models, the injection of let‐7c‐5p agomir restored the osteogenic differentiation potential of dental pulp cells and inhibited HMGA2/PI3K/Akt signalling. The findings demonstrated the anti‐inflammation and pro‐osteogenesis effect of let‐7c‐5p during the attack of pulpitis, which depended on the inhibition of HMGA2/PI3K/Akt signalling.
Dietary Exposures to Common Emulsifiers and Their Impact on the Gut Microbiota: Is There a Cause for Concern?
Authors: Vo Trung D. , Lynch Barry S. , Roberts Ashley
Published: December 2018

Emulsifiers are commonly used in food processing for the technological purpose of altering the flavor or to improve the texture of foods. Due to their ubiquity, these substances are consumed daily at low levels in the human diet. Recently published in vitro and in vivo studies suggest dietary exposure to emulsifiers modulate the gut microbiota and contribute to the increasing prevalence of metabolic disease. A literature search was conducted which identified eight studies investigating the interaction of sodium carboxymethyl cellulose, polysorbate 80, gum arabic, carrageenan, and arabinogalactan with the gut microbiota in murine and in vitro models. Numerous inconsistent changes in various phyla and genera were identified. These studies were conducted at high doses that have no relevance to the current dietary levels consumed in the United States. Subtle changes in gut microbiota composition as a toxicological endpoint is not supported by established internationally recognized toxicology testing guidelines. Therefore, the results of these studies are difficult to interpret and extrapolate to humans and are not supported by previous safety conclusions of international food safety authorities. The current understanding of the gut microbiota is that the structure is highly dynamic and is heavily influenced by the diet. Thus, the results of these studies may not necessarily suggest a safety concern, but rather reflect an adaptive response of the gut microbiota to an external stressor. Future research will need to further elucidate the mechanisms of metabolic disease in rodents and humans and establish clinically relevant and reliable endpoints to assess changes in gut microflora.
Probiotic research in neonates with congenital gastrointestinal surgical conditions – Now is the time
Authors: Rao Shripada C. , Patole Sanjay K.
Published: December 2018

Neonates with congenital gastrointestinal surgical conditions (CGISC) receive parenteral nutrition, get exposed to multiple courses of antibiotics, undergo invasive procedures, and are nursed in intensive care units. They do not receive early enteral feeding and have limited opportunities for skin to skin contact with their mothers. Many of these infants receive gastric acid suppression therapies. All these factors increase the risk of gut dysbiosis in these infants. Gut dysbiosis is known to be associated with increased risk of infections and other morbidities in ICU patients. Experimental studies have shown that probiotics inhibit gut colonization with pathogenic bacteria, enhance gut barrier function, facilitate colonization with healthy commensals, protect from enteropathogenic infection through production of acetate, reduce antimicrobial resistance, enhance innate immunity, and increase the maturation of the enteric nervous system and promote gut peristalsis. Through these mechanisms, probiotics have the potential to decrease the risk of sepsis and inflammation, improve feed tolerance and minimise cholestasis in neonates with CGISC. Among preterm non‐surgical infants, evidence from more than 35 RCTs and multiple observational studies have shown probiotics to be safe and beneficial. A RCT in neonates (N=24) with gastroschisis found that probiotic supplementation partially attenuated gut dysbiosis. Two ongoing RCTs (total N=168) in neonates with gastrointestinal surgical conditions are expected to provide feasibility data to enable the conduct of large RCTs. Rigorous quality assurance of the probiotic product, ongoing microbial surveillance and clinical vigilance are warranted while conducting such RCTs.
Discovering millions of plankton genomic markers from the Atlantic Ocean and the Mediterranean Sea
Authors: Arif Majda , Gauthier Jérémy , Sugier Kevin , Iudicone Daniele , Jaillon Olivier , Wincker Patrick , Peterlongo Pierre , Madoui Mohammed‐Amin
Published: December 2018

Comparison of the molecular diversity in all plankton populations present in geographically distant water columns may allow for a holistic view of the connectivity, isolation and adaptation of organisms in the marine environment. In this context, a large‐scale detection and analysis of genomic variants directly in metagenomic data appeared as a powerful strategy for the identification of genetic structures and genes under natural selection in plankton. Here, we used discosnp++, a reference‐free variant caller, to produce genetic variants from large‐scale metagenomic data and assessed its accuracy on the copepod Oithona nana in terms of variant calling, allele frequency estimation and population genomic statistics by comparing it to the state‐of‐the‐art method. discosnp ++ produces variants leading to similar conclusions regarding the genetic structure and identification of loci under natural selection. discosnp++ was then applied to 120 metagenomic samples from four size fractions, including prokaryotes, protists and zooplankton sampled from 39 tara Oceans sampling stations located in the Atlantic Ocean and the Mediterranean Sea to produce a new set of marine genomic markers containing more than 19 million of variants. This new genomic resource can be used by the community to relocate these markers on their plankton genomes or transcriptomes of interest. This resource will be updated with new marine expeditions and the increase of metagenomic data (availability: http://bioinformatique.rennes.inria.fr/taravariants/).