bluuebunny/crossref_metadata_2025 huggingface dataset:
DIMEdb: an integrated database and web service for metabolite identification in direct infusion mass spectrometery
Authors: O’Shea Keiron , Kattupalli Divya , Mur Luis AJ , Hardy Nigel W , Misra Biswapriya B , Lu Chuan
Published: March 2018

Motivation

Metabolomics involves the characterisation, identification, and quantification of small molecules (metabolites) that act as the reaction intermediates of biological processes. Over the past few years, we have seen wide scale improvements in data processing, database, and statistical analysis tools. Direct infusion mass spectrometery (DIMS) is a widely used platform that is able to produce a global fingerprint of the metabolome, without the requirement of a prior chromatographic step - making it ideal for wide scale high-throughput metabolomics analysis. In spite of these developments, metabolite identification still remains a key bottleneck in untargeted mass spectrometry-based metabolomics studies. The first step of the metabolite identification task is to query masses against a metaboite database to get putative metabolite annotations. Each existing metabolite database differs in a number of aspects including coverage, format, and accessibility - often limiting the user to a rudimentary web interface. Manually combining multiple search results for a single experiment where there may be potentially hundreds of masses to investigate becomes an incredibly arduous task.

Results

To facilitate unified access to metabolite information we have created the Direct Infusion MEtabolite database (DIMEdb), a comprehensive web-based metabolite database that contains over 80,000 metabolites sourced from a number of renowned metabolite databases of which can be utilised in the analysis and annotation of DIMS data. To demostrate the efficacy of DIMEdb, a simple use case for metabolic identification is presented. DIMEdb aims to provide a single point of access to metabolite information, and hopefully facilitate the development of much needed bioinformatic tools.

Availability

DIMEdb is freely available at https://dimedb.ibers.aber.ac.uk.

Contact

keo7@aber.ac.uk

Supplementary information

Supplementary data are available at Bioinformatics online.
Locomotor response to acute stressors requires hypothalamic-pituitary-interrenal axis activation and glucocorticoid receptor
Authors: Lee Han B. , Schwab Tanya L. , Sigafoos Ashley N. , Gauerke Jennifer L. , Krug Randall G. , Serres MaKayla R. , Jacobs Dakota C. , Cotter Ryan P. , Das Biswadeep , Petersen Morgan O. , Daby Camden L. , Urban Rhianna M. , Berry Bethany C. , Clark Karl J.
Published: March 2018

When vertebrates face acute stressors, their bodies rapidly undergo a repertoire of physiological and behavioral adaptations, which is termed the stress response (SR). Rapid physiological changes in heart rate and blood sugar levels occur via the interaction of glucocorticoids and their cognate receptors following hypothalamic-pituitary-adrenal (HPA) axis activation. These physiological changes are observed within minutes of encountering a stressor and the rapid time domain rules out genomic responses that require gene expression changes. Although behavioral changes corresponding to physiological changes are commonly observed, it is not clearly understood to what extent HPA axis activation dictates adaptive behavior. We hypothesized that rapid locomotor response to acute stressors in zebrafish requires HPI axis activation. In teleost fish, interrenal cells (I) are functionally homologous to the adrenal gland cortical layer. We derived 8 frameshift mutants in genes involved in HPI axis function: two mutants in exon 2 ofmc2r(adrenocorticotropic hormone receptor), two in each of exon 2 and exon 5 ofnr3c1(glucocorticoid receptor), and two in exon 2 ofnr3c2(mineralocorticoid receptor). Exposing larval zebrafish to mild environmental stressors, acute changes in salinity or light illumination, results in a rapid locomotor response. We show here that this locomotor response requires a functioning HPI axis via the action ofmc2r(adrenocorticotropic hormone receptor) and the canonical glucocorticoid receptor encoded bynr3c1gene, but not mineralocorticoid receptor (nr3c2). Our rapid behavioral assay paradigm based on HPI axis biology may prove useful to screen for genetic, pharmacological, or environmental modifiers of the HPA axis.

Significance

Altered HPA axis activity is acknowledged as a causative and critical prognostic factor in many psychiatric disorders including depression. Nonetheless, genome wide association studies (GWAS) on depression have revealed conflicting findings about susceptibility loci, while identifying several genetic loci that warrant further investigations in the process. Such findings indicate that psychiatric disorders with complex genetic foundations require functional studies as well as genetic analyses. We developed a sensitive behavioral assay paradigm that leverages the genetic amenability and rapid development of zebrafish and demonstrated that our assay system reliably detects changes in HPA axis responsiveness. Our functional genetics and behavioral assay approach provides a useful platform to discover novel genetic, pharmacological, or environmental modifiers of the HPA axis.
A large-scale whole-genome sequencing analysis reveals highly specific genome editing by both Cas9 and Cpf1 nucleases in rice
Authors: Tang Xu , Liu Guanqing , Zhou Jianping , Ren Qiurong , You Qi , Tian Li , Xin Xuhui , Zhong Zhaohui , Liu Binglin , Zheng Xuelian , Zhang Dengwei , Malzahn Aimee , Gong Zhiyun , Qi Yiping , Zhang Tao , Zhang Yong
Published: March 2018

Targeting specificity has been an essential issue for applying genome editing systems in functional genomics, precise medicine and plant breeding. Understanding the scope of off-target mutations in Cas9 or Cpf1-edited crops is critical for research and regulation. In plants, only limited studies had used whole-genome sequencing (WGS) to test off-target effects of Cas9. However, the cause of numerous discovered mutations is still controversial. Furthermore, WGS based off-target analysis of Cpf1 has not been reported in any higher organism to date. Here, we conducted a WGS analysis of 34 plants edited by Cas9 and 15 plants edited by Cpf1 in T0 and T1 generations along with 20 diverse control plants in rice, a major food crop with a genome size of ~380 Mb. The sequencing depth ranged from 45X to 105X with reads mapping rate above 96%. Our results clearly show that most mutations in edited plants were created by tissue culture process, which caused ~102 to 148 single nucleotide variations (SNVs) and ~32 to 83 insertions/deletions (indels) per plant. Among 12 Cas9 single guide RNAs (sgRNAs) and 3 Cpf1 CRISPR RNAs (crRNAs) assessed by WGS, only one Cas9 sgRNA resulted in off-target mutations in T0 lines at sites predicted by computer programs. Moreover, we cannot find evidence for bona fide off-target mutations due to continued expression of Cas9 or Cpf1 with guide RNAs in T1 generation. Taken together, our comprehensive and rigorous analysis of WGS big data across multiple sample types suggests both Cas9 and Cpf1 nucleases are very specific in generating targeted DNA modifications and off-targeting can be avoided by designing guide RNAs with high specificity.
Trends in outpatient antibiotic prescribing practice among US older adults, 2011-2015: an observational study
Authors: Olesen Scott W. , Barnett Michael L. , MacFadden Derek R. , Lipsitch Marc , Grad Yonatan H.
Published: March 2018

Structured abstract

Objective

To identify temporal trends in outpatient antibiotic use and antibiotic prescribing practice among older adults.

Design

Observational study using United States Medicare administrative claims during 2011-2015. Trends in antibiotic use were estimated using multivariable regression adjusting for beneficiaries’ demographic and clinical covariates.

Setting

Medicare.

Participants

4.6 million Medicare beneficiaries from a nationwide, 20% sample of fee-forservice Medicare beneficiaries ≥65 years old.

Main outcome measurements

Overall rates of antibiotic prescription claims, rates of appropriate and inappropriate prescribing, rates for each of the most frequently prescribed antibiotics, and rates of antibiotic claims associated with specific diagnoses.

Results

Antibiotic claims fell from 1362.2 to 1361.6 claims per 1,000 beneficiaries per year during 2011-2015, an overall 0.2% decrease (95% CI 0.07-0.32). Inappropriate antibiotic claims fell from 552 to 533 claims per 1,000 beneficiaries, a 4.1% decrease (CI 3.9-4.3). Individual antibiotics had heterogeneous changes in use. For example, azithromycin claims per beneficiary decreased by 18.4% (CI 18.2-18.7) while levofloxacin claims increased by 28.1% (CI 27.5-28.6). Azithromycin use associated with each of the potentially appropriate and inappropriate respiratory diagnoses we considered decreased, while levofloxacin use associated with each of those diagnoses increased.

Conclusion

Among US Medicare beneficiaries, overall antibiotic use and inappropriate use declined modestly, but individual drugs experienced divergent changes in use. Trends in drug use across indications were stronger than trends in use for individual indications, suggesting that guidelines and concerns about antibiotic resistance were not major drivers of change in antibiotic use.
ADS-J1 Disaggregates Semen-derived Amyloid Fibrils
Authors: Li J. , Yang Z. , Liu H. , Lan Y. , Zhang T. , Li W. , Qi T. , Qiu Y. , Li L. , Zhou X , Liu S. , Tan S.
Published: March 2018

Semen-derived amyloid fibrils, composing SEVI (semen-derived enhancer of viral infection) fibrils and SEM1 fibrils, could remarkably enhance HIV-1 sexual transmission and thus, are potential targets for the development of an effective microbicide. Previously, we found that ADS-J1, apart from being an HIV-1 entry inhibitor, could also potently inhibit seminal amyloid fibrillization and block fibril-mediated enhancement of viral infection. However, the remodeling effects of ADS-J1 on mature seminal fibrils were unexplored. Herein, we investigated the capacity of ADS-J1 to disassemble seminal fibrils and the potential mode of action by applying several biophysical and biochemical measurements, combined with molecular dynamic (MD) simulations. We found that ADS-J1 effectively remodeled SEVI, SEM186-107 fibrils and endogenous seminal fibrils. Unlike epi-gallocatechin gallate (EGCG), a universal amyloid fibril breaker, ADS-J1 disaggregated SEVI fibrils into monomeric peptides, which was independent of oxidation reaction. MD simulations revealed that ADS-J1 displayed strong binding potency to the full-length PAP248-286 via electrostatic interactions, hydrophobic interactions and hydrogen bonds. ADS-J1 might initially bind to the fibrillar surface and then occupy the amyloid core, which eventually lead to fibril disassembly. Furthermore, the binding of ADS-J1 with PAP248-286 might induce conformational changes of PAP248-286. Disassembled PAP248-286 might not be favor to re-aggregate into fibrils. ADS-J1 also exerts abilities to remodel a panel of amyloid fibrils, including Aβ1-42, hIAPP1-37 and EP2 fibrils. ADS-J1 displays promising potential to be a combination microbicide and an effective lead-product to treat amyloidogenic diseases.
Optical recording of action potential initiation and propagation in mouse skeletal muscle fibers
Authors: Banks Q. , Pratt S.J.P. , Iyer S.R. , Lovering R.M. , Hernández-Ochoa E.O. , Schneider M.F.
Published: March 2018

Individual skeletal muscle fibers have been used to examine a wide variety of cellular functions and pathologies. Among other parameters, skeletal muscle action potential propagation has been measured to assess the integrity and function of skeletal muscle. In this paper, we utilize Di-8-ANEPPS, a potentiometric dye and mag-fluo-4, a low-affinity intracellular calcium indicator to non-invasively and reliably measure action potential conduction velocity in skeletal muscle. We used an extracellular bipolar electrode to generate an electric field that will initiate an action potential at one end of the fiber or the other. Using enzymatically dissociated flexor digitorum brevis (FDB) fibers, we demonstrate the strength and applicability of this technique. Using high-speed line scans, we estimate the conduction velocity to be approximately 0.4 m/s. In addition to measuring the conduction velocity, we can also measure the passive electrotonic potentials elicited by pulses by either applying tetrodotoxin (TTX) or reducing the bath sodium levels. We applied these methodologies to FDB fibers under elevated extracellular potassium conditions, and found that the conduction velocity is significantly reduced compared to our control concentration. Lastly, we have constructed a circuit model of a skeletal muscle in order to predict passive polarization of the fiber by the field stimuli. Our predictions from the model fiber closely resemble the recordings acquired from in vitro assays. With these techniques, we can examine how many different pathologies and mutations affect skeletal muscle action potential propagation. Our work demonstrates the utility of using Di-8-ANEPPS or mag-fluo-4 to non-invasively measure action potential conduction velocity.
Mapping the Dark Side: Visual Selectivity of Default Network Deactivations
Authors: Knapen Tomas , van Es Daan , Barendregt Martijn
Published: March 2018

The default network (DN) activates for internally referenced mental states, whereas it deactivates in response to sensory stimulation. We show that BOLD signal decreases in the DN are tuned to the spatial location of visual stimuli, allowing us to decode the location of a visual stimulus from DN regions. Our results indicate that the DN represents sensory information, and suggest it may utilize this reference frame for higher-level cognition.
Influence of elevated CO2 on development and food utilization of target armyworm Mythimna separata fed on transgenic Bt maize infected by nitrogen-fixing bacteria
Authors: Li Zhuo , Song Yingying , Li Likun , Wang Long , Liu Bin , Parajulee Megha N. , Chen Fajun
Published: March 2018

Bt crops will face a new ecological risk of reduced effectiveness against target-insect pests owing to the general decrease in exogenous-toxin content in Bt crops grown under elevated CO2. How to deal with this issue may affect the sustainability of transgenic crops as an effective pest management tool especially under future CO2 raising. In this study, azotobacters, as being one potential biological regulator to enhance crops’ nitrogen utilization efficiency, were selected and the effects of Bt maize and non-Bt maize infected by Azospirillum brasilense and Azotobacter chroococcum on development and food utilization of target Mythimna separate were studied under ambient and elevated CO2. The results indicated that azotobacter infection significantly increased larval life-span, pupal duration, RCR and AD of M. separata, and significantly decreased RGR, ECD and ECI of M. separata fed on Bt maize; There were opposite trends in development and food utilization of M. separata fed on non-Bt maize infected with azotobacters compared with the buffer control regardless of CO2 level. Presumably, the application of azotobacter infection could make Bt maize facing lower field hazards from the target pest of M. separate, and finally improve the resistance of Bt maize against target lepidoptera pests especially under elevated CO2.

Summary statement

Elevated CO2 effect on development and food utilization of target armyworm Mythimna separata fed on Bt maize infected by azotobacter, Azospirillum brasilense and Azotobacter chroococcum
Short cracks in knee meniscus tissue cause strain concentrations, but do not reduce ultimate stress, in single-cycle uniaxial tension
Authors: Peloquin John M. , Santare Michael H. , Elliott Dawn M.
Published: March 2018

Tears are central to knee meniscus pathology and, from a mechanical perspective, are crack-like defects (cracks). In many materials, cracks create stress concentrations that cause progressive local rupture and reduce effective strength. It is currently un-known if cracks in meniscus have these consequences; if they do, this would have repercussions for management of meniscus pathology. The objective of this study was to determine if a short crack in meniscus tissue, which mimics a preclinical meniscus tear, (a) causes crack growth and reduces effective strength, (b) creates a near-tip strain concentration, and (c) creates unloaded regions on either side of the crack. Specimens with and without cracks were tested in uniaxial tension and compared in terms of macroscopic stress–strain curves and digital image correlation strain fields. The strain fields were used as an indicator of stress concentrations and unloaded regions. Effective strength was found to be insensitive to the presence of a crack (potential effect < 0.86 s.d.; β = 0.2), but significant strain concentrations, which have the potential to lead to long-term accumulation of tissue or cell damage, were observed near the crack tip.
Integrating Predicted Transcriptome From Multiple Tissues Improves Association Detection
Authors: Barbeira Alvaro N. , Pividori Milton D. , Zheng Jiamao , Wheeler Heather E. , Nicolae Dan L. , Im Hae Kyung
Published: March 2018

Integration of genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) studies is needed to improve our understanding of the biological mechanisms underlying GWAS hits, and our ability to identify therapeutic targets. Gene-level association test methods such as PrediXcan can prioritize candidate targets. However, limited eQTL sample sizes and absence of relevant developmental and disease context restricts our ability to detect associations. Here we propose an efficient statistical method that leverages the substantial sharing of eQTLs across tissues and contexts to improve our ability to identify potential target genes: MulTiXcan. MulTiXcan integrates evidence across multiple panels while taking into account their correlation. We apply our method to a broad set of complex traits available from the UK Biobank and show that we can detect a larger set of significantly associated genes than using each panel separately. To improve applicability, we developed an extension to work on summary statistics: S-MulTiXcan, which we show yields highly concordant results with the individual level version. Results from our analysis as well as software and necessary resources to apply our method are publicly available.
Receptor binding and proteolysis do not induce large conformational changes in the SARS-CoV spike
Authors: Kirchdoerfer Robert N. , Wang Nianshuang , Pallesen Jesper , Wrapp Daniel , Turner Hannah L. , Cottrell Christopher A. , Corbett Kizzmekia S. , Graham Barney S. , McLellan Jason S. , Ward Andrew B.
Published: March 2018

Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 as a highly transmissible pathogenic human betacoronavirus. The viral spike glycoprotein (S) utilizes angiotensin-converting enzyme 2 (ACE2) as a host protein receptor and mediates fusion of the viral and host membranes, making S essential to viral entry into host cells and host species tropism. As SARS-CoV enters host cells, the viral S undergoes two proteolytic cleavages at S1/S2 and S2’ sites necessary for efficient membrane fusion. Here, we present a cryo-EM analysis of the trimeric SARS-CoV S interactions with ACE2 and of the trypsin-cleaved S. Surprisingly, neither binding to ACE2 nor cleavage by trypsin at the S1/S2 cleavage site impart large conformational changes within S or expose the secondary cleavage site, S2’. These observations suggest that S2’ cleavage does not occur in the S prefusion conformation and that additional triggers may be required.
Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity
Authors: Olova Nelly , Simpson Daniel J , Marioni Riccardo , Chandra Tamir
Published: March 2018

Induced pluripotent stem cells (IPSCs), with their unlimited regenerative capacity, carry the promise for tissue replacement to counter age-related decline. However, attempts to realise in vivo iPSC have invariably resulted in the formation of teratomas. Partial reprogramming in prematurely aged mice has shown promising results in alleviating age-related symptoms without teratoma formation. Does partial reprogramming lead to rejuvenation (i.e. “younger” cells), rather than dedifferentiation, which bears the risk of cancer? Here we analyse the dynamics of cellular age during human iPSC reprogramming and find that partial reprogramming leads to a reduction in the epigenetic age of cells. We also find that the loss of somatic gene expression and epigenetic age follow different kinetics, suggesting that they can be uncoupled and there could be a safe window where rejuvenation can be achieved with a minimised risk of cancer.
Small RNA-mediated genomic silencing promotes telomere stability in the absence of telomerase
Authors: Longtine Charlie , Frenk Stephen , Ahmed Shawn
Published: March 2018

Telomerase deficiency in human somatic cells results in telomere erosion and senescence. Small RNAs that target telomeres have been observed in diverse organisms but their functions are not well characterized. We define an endogenous small RNA pathway in Caenorhabditis elegans that promotes heterochromatin formation at telomeres via Dicer, the perinuclear Argonaute protein WAGO-1 and the nuclear Argonaute protein HRDE-1. Loss of telomerase induces biogenesis of siRNAs that target the telomeric lncRNA TERRA, whereas loss of both telomerase and small RNA-mediated telomeric silencing induces TERRA expression, DNA damage, and an accelerated sterility phenotype. These phenotypes can be rescued by exogenous telomeric siRNAs or by loss of the DNA damage response protein EXO-1. Thus, endogenous siRNAs interact with TERRA to promote heterochromatin formation in a manner that is critical for the stability of naturally eroding telomeres. We propose that small RNA-mediated genome silencing could be broadly relevant to regulation of proliferative aging.
Predictive control of electrophysiological network architecture using direct, single-node neurostimulation in humans
Authors: Khambhati Ankit N. , Kahn Ari E. , Costantini Julia , Ezzyat Youssef , Solomon Ethan A. , Gross Robert E. , Jobst Barbara C. , Sheth Sameer A. , Zaghloul Kareem A. , Worrell Gregory , Seger Sarah , Lega Bradley C. , Weiss Shennan , Sperling Michael R. , Gorniak Richard , Das Sandhitsu R. , Stein Joel M. , Rizzuto Daniel S. , Kahana Michael J. , Lucas Timothy H. , Davis Kathryn A. , Tracy Joseph I. , Bassett Danielle S.
Published: March 2018

Chronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multi-modal intracranial recordings and diffusion tensor imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.
Structural Analysis of Inhibitor Binding to CAMKK1 Identifies Features Necessary for Design of Specific Inhibitors
Authors: Santiago André da Silva , Couñago Rafael M. , Zonzini Ramos Priscila , Godoi Paulo H. C. , Massirer Katlin B. , Gileadi Opher , Elkins Jonathan M.
Published: March 2018

The calcium/calmodulin-dependent protein kinases (CAMKKs) are upstream activators of CAMK1 and CAMK4 signalling and have important functions in neural development, maintenance and signalling, as well as in other aspects of biology such as Ca2+ signalling in the cardiovascular system. To support the development of specific inhibitors of CAMKKs we have determined the crystal structure of CAMKK1 with two ATP-competitive inhibitors. The structures reveal small but exploitable differences between CAMKK1 and CAMKK2, despite the high sequence identity, which could be used in the generation of specific inhibitors. Screening of a kinase inhibitor library revealed molecules that bind potently to CAMKK1. Isothermal titration calorimetry revealed that the most potent inhibitors had binding energies largely dependent on favourable enthalpy. Together, the data provide a foundation for future inhibitor development activities.
Protein structure and function analyses to understand the implication of mutually exclusive splicing
Authors: Lam Su Datt , Orengo Christine , Lees Jonathan
Published: March 2018

Alternative splicing (AS) has been suggested as one of the major processes expanding the diversity of proteomes in multicellular organisms. Mutually exclusive exons (MXE) provide one form of AS that is less likely to disrupt protein structure and is over-represented in the proteome compared to other forms of AS. We used domain structure information from the CATH classification to perform a systematic structural analysis of the effects of MXE splicing in high quality animal genomes (e.g. human, fly, mouse and 2 fishes) and we were able to annotate approximately 50% of MXE events with structural information. For those MXE events which can be mapped to a structure, we found that although embedded in domains, they were strongly enriched in surface exposed residues. We also demonstrated that the variable residues between splicing events lie close to known and/or predicted functional sites. We present some examples of MXE events in proteins that have important roles in cells. This work presents the first large scale systematic study of the structural/functional effects of MXE splicing using predominantly domain based modelling and functional annotation tools. Our study supports and expands on previous work in this field and helps to build a picture of how MXE events facilitate evolution of new functions.
Directional selection limits ecological diversification and promotes ecological tinkering during the competition for substitutable resources
Authors: Good Benjamin H. , Martis Stephen , Hallatschek Oskar
Published: March 2018

Microbial communities can evade competitive exclusion by diversifying into distinct ecological niches. This spontaneous diversification often occurs amid a backdrop of directional selection on other microbial traits, where competitive exclusion would normally apply. Yet despite their empirical relevance, little is known about how diversification and directional selection combine to determine the ecological and evolutionary dynamics within a community. To address this gap, we introduce a simple, empirically motivated model of eco-evolutionary feedback based on the competition for substitutable resources. Individuals acquire heritable mutations that alter resource uptake rates, either by shifting metabolic effort between resources or by increasing overall fitness. While these constitutively beneficial mutations are trivially favored to invade, we show that the accumulated fitness differences can dramatically influence the ecological structure and evolutionary dynamics that emerge within the community. Competition between ecological diversification and ongoing fitness evolution leads to a state of diversification-selection balance, in which the number of extant ecotypes can be pinned below the maximum capacity of the ecosystem, while the ecotype frequencies and genealogies are constantly in flux. Interestingly, we find that fitness differences generate emergent selection pressures to shift metabolic effort toward resources with lower effective competition, even in saturated ecosystems. We argue that similar dynamical features should emerge in a wide range of models with a mixture of directional and diversifying selection.
Polygonal motion and adaptable phototaxis via flagellar beat switching in Euglena gracilis
Authors: Tsang Alan C. H. , Lam Amy T. , Riedel-Kruse Ingmar H.
Published: March 2018

Biological microswimmers exhibit versatile strategies for sensing and navigating their environment 1–7, e.g., run-and-tumble 2 and curvature modulation 3. Here we report a striking behavior of Euglena gracilis, where Euglena cells swim in polygonal trajectories due to exposure to increasing light intensities. While smoothly curved trajectories are common for microswimmers 3, 8, such quantized ones have not been reported previously. This polygonal behavior emerges from periodic switching between the flagellar beating patterns of helical swimming 6, 9 and spinning 10 behaviors. We develop and experimentally validate a biophysical model that describes the phase relationship between the eyespot, cell orientation, light detection, and cellular reorientation, that accounts for all three behavioral states. Coordinated switching between these behaviors allows ballistic, superdiffusive, diffusive, or subdiffusive motion 11,12 (i.e., the tuning of the diffusion constant over 3 orders of magnitude) and enables navigation in structured light fields, e.g., edge avoidance and gradient descent. This feedback-control links multiple system scales (flagellar beats, cellular behaviors, phototaxis strategies) with implications for other natural and synthetic microswimmers 13.
Optimal feedback mechanisms for regulating cell numbers
Authors: Modi Saurabh , Singh Abhyudai
Published: March 2018

How living cells employ counting mechanisms to regulate their numbers or density is a long-standing problem in developmental biology that ties directly with organism or tissue size. Diverse cells types have been shown to regulate their numbers via secretion of factors in the extracellular space. These factors act as a proxy for the number of cells and function to reduce cellular proliferation rates creating a negative feedback. It is desirable that the production rate of such factors be kept as low as possible to minimize energy costs and detection by predators. Here we formulate a stochastic model of cell proliferation with feedback control via a secreted extracellular factor. Our results show that while low levels of feedback minimizes random fluctuations in cell numbers around a given set point, high levels of feedback amplify Poisson fluctuations in secreted-factor copy numbers. This trade-off results in an optimal feedback strength, and sets a fundamental limit to noise suppression in cell numbers. Intriguingly, this fundamental limit depends additively on two variables: relative half-life of the secreted factor with respect to the cell proliferation rate, and the average number of factors secreted in a cell’s lifespan. We further expand the model to consider external disturbances in key physiological parameters, such as, proliferation and factor synthesis rates. Intriguingly, while negative feedback effectively mitigates disturbances in the proliferation rate, it amplifies disturbances in the synthesis rate. In summary, these results provide unique insights into the functioning of feedback-based counting mechanisms, and apply to organisms ranging from unicellular prokaryotes and eukaryotes to human cells.
Antibody-based vaccine for tuberculosis: validation in horse foals challenged with the TB-related pathogen Rhodococcus equi
Authors: Cywes-Bentley C. , Rocha J. N. , Bordin A. I. , Vinacur M. , Rehman S. , Zaidi T.S. , Meyer M. , Anthony S. , Lambert M. , Vlock D. R. , Giguère S. , Cohen N. D. , Pier G. B.
Published: March 2018

Immune correlates for protection against Mycobacterium tuberculosis (Mtb) infection and other intracellular pathogens are largely undetermined. Whether there is a role for antibody-mediated immunity is controversial. Rhodococcus equi is an intracellular pathogen causing severe pneumonia in young horse foals, eliciting a disease with many similarities to TB including intracellular residence, formation of granulomas and induction of severe respiratory distress. No purified vaccine antigens exist for R. equi or Mtb infections. Both express the microbial surface polysaccharide antigen poly-N-acetyl glucosamine (PNAG). In a randomized, controlled, blinded challenge trial, vaccination of pregnant mares with a synthetic PNAG oligosaccharide conjugated to tetanus toxoid elicited antibody that transferred to foals via colostrum and provided nearly complete protection against R. equi pneumonia. Infusion of PNAG-hyperimmune plasma protected 100% of foals against R. equi pneumonia. Vaccination induced opsonic antibodies that killed extracellular and intracellular R. equi and other intracellular pathogens. Killing of intracellular organisms was dependent on antibody recognition of surface expression of PNAG on infected macrophages, complement deposition and PMN-assisted lysis of infected macrophages. Protection also correlated with PBMC release of interferon-γ in response to PNAG. Antibody-mediated opsonic killing and interferon-γ release in response to PNAG may protect against disease caused by intracellular bacterial pathogens.
Tricin inhibits the CCL5 induction required for efficient growth of human cytomegalovirus
Authors: Itoh Akimasa , Sadanari Hidetaka , Takemoto Masaya , Matsubara Keiko , Daikoku Tohru , Murayama Tsugiya
Published: March 2018

Treatment of human embryonic lung fibroblast (HEL) cells with tricin (4′, 5, 7‐trihydroxy‐3′, 5′‐dimethoxyflavone) following infection with human cytomegalovirus (HCMV) reportedly significantly suppresses HCMV replication. In the present work, the mechanisms for the anti‐HCMV effects of tricin in HEL cells were examined. It was found that exposure of HEL cells to tricin inhibited HCMV replication, with concomitant decreases in amounts of transcripts of the CC chemokine RANTES (CCL5)‐encoding gene and in expression of the CCL5 protein. It was also found that transcripts of HCMV immediate early 1 (IE1), and HCMV UL54 (encoding DNA polymerase) and replication of HCMV was significantly lower in CCL5 gene‐knockdown cells. These results suggest that the anti‐HCMV activity of tricin differs from that of ganciclovir and that CCL5 is one of the chemokines involved in HCMV replication. In addition, it is possible that chemokine CCL5 is one of the targets of tricin.
Soil microbes promote complementarity effects among co‐existing trees through soil nitrogen partitioning
Authors: Luo Shan , Schmid Bernhard , De Deyn Gerlinde B. , Yu Shixiao
Published: March 2018

Plant resource partitioning is a mechanism promoting species coexistence and ecosystem functioning. Yet, we still have limited understanding of how soil microbes, especially plant symbiotic microbes, influence resource partitioning. We hypothesized that soil‐borne microbes, in particular mycorrhizal fungi, facilitate differential performance of tree species depending on different nitrogen sources and that this leads to a positive plant diversity–community productivity relationship.

We conducted two complementing glasshouse experiments. In a “monoculture experiment,” we supplied nitrogen as ammonium, nitrate or glycine and tested the growth response of three tree species associated with different root symbionts: one associated with ectomycorrhizal fungi, one associated with arbuscular mycorrhizal fungi, and the third associated with both arbuscular mycorrhizal fungi and N‐fixing bacteria. In an “intermixed experiment,” we grew the tree species at three richness levels (one, two or three species) in soil supplied with a mix of the three nitrogen forms or no added nitrogen, and with or without soil microbes.

The monoculture experiment showed that in the presence of soil microbes, the ectomycorrhizal plant species grew best when supplied with glycine and the two arbuscular mycorrhizal plant species grew best with either nitrate or ammonium addition. When the different forms of nitrogen were mixed in the intermixed experiment, plant mixtures produced more biomass than plant monocultures in the presence of soil microbes, with positive complementarity effects indicating microbe‐mediated plant resource partitioning.

Our results suggest that co‐existing tree species can partition soil nitrogen when grown with their particular mycorrhizal symbionts or other soil microbes, resulting in positive biodiversity effects in complex resource environments.

A plain language summary is available for this article.
Soil fungi underlie a phylogenetic pattern in plant growth responses to nitrogen enrichment
Authors: Wooliver Rachel C. , Senior John K. , Potts Brad M. , Van Nuland Michael E. , Bailey Joseph K. , Schweitzer Jennifer A.
Published: March 2018

Under increasing anthropogenic nitrogen (N) deposition, some plant species will thrive while others will not. Previous work has shown that plant phylogeny can predict these responses, and that interactions with mycorrhizal fungi are a mechanism that drives variation in plant responses to N enrichment. Yet, much of this work has ignored the roles of other root‐associated fungi and whole soil fungal communities in driving these responses.

We tested whether soil fungi mediate responses of plant growth and plant–soil feedbacks (between close and distant plant relatives) to N enrichment by implementing a greenhouse experiment in which we applied factorial treatments of N fertilization, host‐specific soil inocula and fungicide to 15 eucalypt tree species that co‐occur on the island state of Tasmania, Australia, and form two phylogenetic lineages within the subgenus Symphyomyrtus.

Conspecific‐conditioned soil fungi enhanced growth responses to N enrichment for plants within one lineage (lineage 1) but depressed growth responses to N enrichment for plants within another lineage (lineage 2). Lineage‐specific shifts in ectomycorrhizal (ECM) colonization were consistent with previous evidence that more vs. less successful strategies under N enrichment are those where carbon allocation to mycorrhizal fungi is reduced vs. maintained, respectively. The latter was also accompanied by a stronger reduction in root colonization of non‐filamentous fungi (of unknown function) under N enrichment. Plant–soil feedbacks were neutral for lineage 1 but negative for lineage 2 (i.e. greater growth in soils conditioned by opposite vs. same lineage individuals), but were not altered by N enrichment or fungicide. Lineage‐level differences in root colonization suggest that these feedbacks could be driven by differential plant responsiveness to dark septate endophytes and non‐filamentous fungi, the colonization of which seemed to benefit plant growth.

Synthesis: Our results confirm that interactions with soil fungi (ECM fungi, in particular) underlie phylogenetic patterns in tree species' growth responses to N enrichment and may, thus, influence which plants win or lose under future N deposition scenarios. Yet, we provide some of the first evidence (albeit from controlled rather than natural conditions) that N deposition may not play a strong role in shifting plant–soil feedbacks.
Ability of the endangered species Papaver fauriei to produce hybrids with a cultivated poppy (Papaver sp.)
Authors: Yamagishi Masumi , Onuma Hiroki , Kondo Tetsuya , Kosugi Kazuki
Published: March 2018

Papaver fauriei is an endemic and endangered species that grows only on the gravelly alpine slopes of Mt. Rishiri, Japan. Cultivated poppy (Papaver sp.), the species name of which is unknown, has been introduced to the natural habitats of P. fauriei through human activities. Because the appearance and internal transcribed spacer (ITS) sequences of these two poppies are highly similar, it is of concern that they could produce hybrids in their natural habitats. Thus, first, the ability of these two poppies to produce hybrids was analyzed by artificial fertilization in this study. A large number of seeds were produced by reciprocal crosses between P. fauriei and the cultivated poppy, comparable with the number of seeds obtained by self‐ or cross‐fertilization of P. fauriei or the cultivated poppy. In addition, high germination was observed for seeds obtained from crosses between the two poppies, and deleterious phenotypes, such as albinism and dwarfism, were not detected in the F1 generation. These results indicate that after pollination, there is no reproductive isolation between the two poppies. Second, we sequenced the internal transcribed spacer (ITS) region of 240 poppy individuals collected from the gravelly alpine slopes of Mt. Rishiri, and 66 showed the sequence of P. fauriei, whereas 174 showed the sequence of the cultivated poppy. However, the ITS sequence that confirms hybridism between the two poppies was not detected in these individuals, indicating that hybridization of P. fauriei and the cultivated poppy rarely occurs under natural conditions. Unknown mechanism(s) appear to prevent cross‐pollination between the two poppies.
Breaking Bad News: Penal Populism, Tabloid Adversarialism and Brexit
Authors: Greer Chris , Mclaughlin Eugene
Published: March 2018

This article analyses the role that British conservative tabloid newspapers play in promoting penal populism and delegitimising liberal prison reform initiatives. Principally, we consider how different sections of the British press reacted to the then Prime Minister David Cameron's prison reform speech of 8 February 2016. The analysis illustrates how different newspapers cohered around two diametrically opposing interpretations of the scandalous state of the prison system, reflecting distinctive penal philosophies and moral positions. In the context of penal populism and the populist furies unleashed by the Brexit campaign, the central research finding is that the comparatively passive and equivocal support offered by the broadsheets was no match for the vitriolic attack mounted by the conservative tabloids on the ‘soft justice’ parts of Cameron's prison reform agenda. We conclude by arguing that the stark lesson to be learned is that the scandal‐ridden prison is a particularly toxic issue marked by serial policy failure. Consequently, in a febrile, intermediatised penal populist context, why would any political leader take on the manifest risks associated with embarking on liberal prison reform?
Conceptualising women's motivations for social egg freezing and experience of reproductive delay
Authors: Baldwin Kylie
Published: March 2018

As the average age of motherhood in many Western countries continues to rise, the spectacle of the older mother and the trend towards delayed childbearing has been the subject of much public debate and interest. Concurrent to this trend has been the development and use of a new form of fertility preservation – social egg freezing – a technology which by its very nature is meant to enable reproductive delay. Whilst previous studies have been able to provide insights into the complex and often interrelating structural, economic, and relational factors shaping the timing of motherhood, and in some cases women's use of social egg freezing, fewer studies have clearly demonstrated the way these factors themselves, as well as the accounts of individual women, can be seen as being shaped by ideological and discursive forces. Drawing on interviews with 31 users of social egg freezing this article will demonstrate how women's accounts of reproductive delay and use of egg freezing technology can be seen as being shaped by neoliberal rationality, heteronormativity, discourses of ‘appropriate parenting’ and gendered ideologies of parenthood.
Probing the Syntax of a Problematic Particle: Old French ‘si’ Revisited
Authors: Wolfe Sam
Published: March 2018

This article presents the findings of a corpus analysis of seven Old French texts to better understand the syntax of the particlesi. It is argued that the texts display clear evidence of synchronic and diachronic variation, much of which has not been noted in the literature. A diachronic grammaticalisation pathway is proposed forsifrom a temporal deictic adverb to a Topic continuity marker and then to a FinP expletive which undergoes upwards reanalysis as a ForceP expletive.
Identifying Key Flavors in Strawberries Driving Liking via Internal and External Preference Mapping
Authors: Oliver Penelope , Cicerale Sara , Pang Edwin , Keast Russell
Published: March 2018

Australian consumers desire the development of a more flavorsome Australian strawberry cultivar. To aid in the development of well‐liked strawberries, the attributes driving liking need to be identified. The objective of this research is to apply Preference Mapping (PM) techniques to the descriptive profile of commercial and newly bred strawberry cultivars, together with consumer preference data to determine the flavors contributing to liking. A trained sensory panel (n = 12) used Quantitative Descriptive Analysis (QDA®) methodology to evaluate two appearance, seven aroma, five texture, 10 flavor and 10 aftertaste attributes of three commercial strawberry cultivars and six elite breeding lines grown in Victoria, Australia. Strawberry consumers (n = 150) assessed their liking of the same strawberry cultivars. QDA® significantly discriminated strawberries on 28 of the 34 sensory attributes. There were significant differences in hedonic ratings of strawberries (F(8,714) = 11.5, P = 0.0001), with Hierarchical Cluster Analysis (HCA) identifying three consumer clusters each displaying differing patterns of preference. Internal and external PM techniques were applied to the data to identify the attributes driving consumer acceptability. Sweet, berry, caramel, fruity and floral attributes were identified as most contributing to liking. Sour, citrus, green, astringent, firm and gritty attributes were conversely associated with a reduction in consumer liking. Elite Lines 2 and 6 have been identified as having the broadest appeal, satisfying between 60% and 70% of consumers in the population assessed, thus the introduction of these cultivars should satisfy the largest group of consumers in the Australian market.

Practical Application

The results of this research could be applied to breeding programs, to ensure newly bred cultivars express characteristics that were identified as well‐liked amongst consumers. In addition, this research provides evidence for marketing strawberries by cultivar, to assist consumers in identifying those strawberries for which they have a preference.
Ohmic Heating Assisted Lye Peeling of Pears
Authors: Gupta Sarvesh , Sastry Sudhir K.
Published: March 2018

Currently, high concentrations (15% to 18%) of lye (sodium hydroxide) are used in peeling pears, constituting a wastewater handling and disposal problem for fruit processors. In this study, the effect of ohmic heating on lye peeling of pears was investigated. Pears were peeled using 0.5%, 1%, 2%, and 3% NaOH under different electric field strengths at two run times and their peeled yields were compared to that obtained at 2% and 18% NaOH with conventional heating. Results revealed that ohmic heating results in greater than 95% peeled yields and the best peel quality at much lower concentrations of lye (2% NaOH at 532 V/m and 3% NaOH at 426 and 479 V/m) than those obtained under conventional heating conditions. Treatment times of 30 and 60 s showed no significant differences. Within the studied range, the effects of increasing field strength yielded no significant additional benefits. These results confirm that the concentration of lye can be significantly lowered in the presence of ohmic heating to achieve high peeled yields and quality.

Practical Application

Our work shows that lye concentrations can be greatly reduced while peeling pears, resulting in significant savings in use of caustic chemicals, reduced costs for effluent treatment and waste disposal.